CN101870684A - Scutellarin aglycone derivative for treating vascular dementia and preparation method and application thereof - Google Patents
Scutellarin aglycone derivative for treating vascular dementia and preparation method and application thereof Download PDFInfo
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- CN101870684A CN101870684A CN201010213663A CN201010213663A CN101870684A CN 101870684 A CN101870684 A CN 101870684A CN 201010213663 A CN201010213663 A CN 201010213663A CN 201010213663 A CN201010213663 A CN 201010213663A CN 101870684 A CN101870684 A CN 101870684A
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- CN
- China
- Prior art keywords
- benzopyran
- hydroxyphenyl
- oxo
- trihydroxyl
- ester
- Prior art date
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- DJSISFGPUUYILV-ZFORQUDYSA-N scutellarin Chemical compound O1[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC(O)=CC=1)O2 DJSISFGPUUYILV-ZFORQUDYSA-N 0.000 title claims abstract description 109
- DJSISFGPUUYILV-UHFFFAOYSA-N UNPD161792 Natural products O1C(C(O)=O)C(O)C(O)C(O)C1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC(O)=CC=1)O2 DJSISFGPUUYILV-UHFFFAOYSA-N 0.000 title claims abstract description 106
- NPLTVGMLNDMOQE-UHFFFAOYSA-N carthamidin Natural products C1=CC(O)=CC=C1C1OC2=CC(O)=C(O)C(O)=C2C(=O)C1 NPLTVGMLNDMOQE-UHFFFAOYSA-N 0.000 title claims abstract description 106
- 229930190376 scutellarin Natural products 0.000 title claims abstract description 106
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 title claims abstract description 96
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 title claims abstract description 96
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 title claims abstract description 96
- 238000002360 preparation method Methods 0.000 title claims abstract description 62
- 201000004810 Vascular dementia Diseases 0.000 title claims abstract description 32
- -1 organic acid salt Chemical class 0.000 claims abstract description 61
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
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- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 59
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Natural products CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
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- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 24
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 14
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to a scutellarin aglycone derivative which can treat vascular dementia and has structures shown in the following structural formulas I and II, and pharmacologically acceptable inorganic or organic acid salt, a preparation method and application thereof. A pharmacological test proves that the scutellarin aglycone derivative has obvious activity of resisting nerve cell damage caused by induction of hydrogen peroxide and can be used for the application in the preparation of a medicament for resisting vascular dementia.
Description
Technical Field
The present invention relates to the field of pharmaceutical synthesis and pharmacology. In particular to a preparation method of scutellarin aglycone L-amino acid ester or ether derivatives, scutellarin aglycone N, N-disubstituted aminomethyl benzoate or ether and a composition thereof, and application of the compounds in preparing anti-Vascular Dementia (VD) medicaments.
Background
Vascular Dementia (VD) is a group of clinical syndromes based on higher neurocognitive dysfunction that develop on the basis of brain tissue damage caused by cerebrovascular disease (Castro, J Curr Alzheimer Res, 2008, 5 (1): 61). The morbidity and mortality of VD are rising year by year in recent years, and the VD becomes the third fatal disease after heart disease and cancer in the world (the Chinese medicine clinical rehabilitation of Lemna delavayi, 2004, 8 (25): 5338). Clinically common types of vascular dementia include: multi-infarct dementia, large-area cerebral infarct dementia, subcortical arteriosclerotic encephalopathy (Binswager's disease), dementia due to specific infarctions, hemorrhagic dementia, etc. (Proc. of Beijing university of traditional Chinese medicine, Tianjin Zhou, 2000, 23 (5): 24). According to epidemiological investigation, VD accounts for about 60% of senile dementia in China. VD seriously threatens the health and the life quality of the old, and causes huge burden to families and society.
The treatment of vascular dementia is divided into two types, namely preventive treatment and symptomatic treatment. Prophylactic treatment is focused on the control of vascular risk factors, i.e., primary and secondary prevention of stroke. Symptomatic treatment involves a variety of pharmacological mechanisms including cholinesterase inhibitors (cheis), neurotrophic and neuroprotective drugs, N-methyl-D-aspartate (NMDA) receptor antagonists, antioxidants, agents to improve microcirculation, nootropic agents, hormone replacement therapy, and anti-inflammatory therapy (Desmond, d.w. clinical Neuroscience Research, 2004, 3, 437; wichuri, journal of chinese rehabilitation medicine, 2009, 24 (1): 92).
Although research on the treatment of VD is actively ongoing, to date, no drug has been approved for the treatment of VD. Therefore, the intensive research on the pathogenesis of VD in order to search for effective therapeutic drugs has become an important research topic in the international medical community.
In recent years, it has been found that oxidative damage is a key factor in the development of central neurodegenerative diseases such as Vascular Dementia (VD) and Alzheimer's Disease (AD) because of the low content of endogenous free radical damage defensive substances in brain tissue and is very sensitive to oxidative damage caused by free radicals (Shima, Y.S. journal of the Neurological Sciences 2009, 283, 240; Lethenm, R.the Lancet 1997, 349, 1189; Ihara, Y.journal of Neurological Sciences 1997, 153, 76). The research finds that the level of free radical resisting substances such as superoxide dismutase (SOD), Glutathione (GSH) and the like in the frontal cortex and the hippocampus of VD and AD patients is obviously reduced to normal people. Due to the low endogenous antioxidant levels in the brain tissue of VD patients, excessive Reactive Oxygen Species (ROS) build up in brain cells, leading to lipid peroxidation, which alters the fluidity and permeability of neural cell membranes, thereby impairing cell function or membrane-associated enzyme or receptor function (Danuta R. journal of the Neurological Sciences 2002, 203, 195). It was also found that brain cells lack histone protection from mitochondrial dna (mtdna) and are therefore highly sensitive to oxidative damage caused by ROS, which accelerates the progression of neurodegenerative diseases. Therefore, the method has important significance for treating VD by inhibiting the generation of oxygen free radicals, promoting the elimination of the oxygen free radicals and inhibiting nerve cell damage caused by the oxygen free radicals.
Erigeron breviscapus (Erigerm brevicapus) is a whole plant of erigeron breviscapus (Erigerm brevicapus) of the genus erigeron of the family Compositae, is mainly distributed in Yunnan and Guizhou provinces in southwest of China, and has the effects of promoting blood circulation to remove blood stasis, clearing and activating the channels and collaterals and the like. Scutellarin is the most important active ingredient in erigeron breviscapus. Pharmacodynamic tests show that scutellarin can remarkably reduce the content of Malondialdehyde (MDA) which is a brain tissue peroxidation product, increase the level of superoxide dismutase (SOD), inhibit the generation of ROS, remarkably improve the form of hippocampal neurons and relieve peroxidation damage of brain tissues (Xiong Z.biol.pharm.Bull.2006, 29 (9): 1880; Hong H.Life Sciences 2004, 74, 2959). Therefore, the development of scutellarin series derivatives can promote the elimination of the scutellarin series derivatives through the generation of oxygen free radicals and inhibit the nerve cell damage caused by the scutellarin series derivatives, thereby having higher value for VD treatment.
At present, various preparations of scutellarin are widely used for treating cardiovascular and cerebrovascular diseases clinically, and have high medicinal value and economic value. However, the oral bioavailability of scutellarin is extremely low, so that the advantages of scutellarin are not fully utilized and exerted. The reason is that the water solubility and the fat solubility of the scutellarin are poor, and the common tablets and granules have the defects of extremely low oral bioavailability, wide metabolism, elimination of rapid pharmacokinetics and the like; the common injection and powder injection have the defects of short half-life, quick elimination in vivo, poor patient compliance, inconvenient use and the like. Modern research results show that the in vivo real absorption and drug effect form of scutellarin after oral administration is the aglycone thereof, but the absolute bioavailability of the scutellarin aglycone is still very low and is only 7.0% (Shaoyun, Chinese natural medicine, 2007, 5 (3): 229; Cheqingming, Chinese pharmaceutical journal, 2007, 42 (18): 1418). Therefore, the design of a prodrug type with improved absorption by using scutellarin aglycone as a lead compound is very urgent, which may become a key breakthrough for solving the problems of extremely low bioavailability and weak drug effect of scutellarin oral administration, but the design of an optimized prodrug aiming at the scutellarin aglycone has not been reported at home and abroad so far.
Aiming at the defects of low bioavailability and weak drug effect of scutellarin oral administration, the preparation method uses erigeron breviscapus which is a real estate herb in Guizhou province as a main raw material, adopts a modern extraction and separation technology to obtain high-purity scutellarin aglycone as a lead compound, and adopts the successful experience of improving the bioavailability of the oral antiviral drugs according to the active transport principle of a small intestinal mucosal peptide transporter 1(hPept1) on L-amino acid prodrugs and the design strategy of the L-amino acid prodrugs (Isabel, Rubio-A.trends in Pharmacological Sciences, 2003, 23, (9): 434; Xiaozhong Fu.bioorganic & Medicinal Chemistry Letters, 2007, 17 (2): 465); meanwhile, the influence of the structural modification of N, N-disubstituted aminomethyl benzoate on the stability of oral drugs and the stability of in vivo metabolism is used as a reference (Bundgaard, H.pharmacological Research, 1991, 8 (9): 1087). An L-amino acid and N, N-disubstituted aminomethyl benzoate structure is introduced on the 4 '-hydroxyl of the scutellarin aglycone structure, and a novel scutellarin aglycone 4' -L-amino acid ester and N, N-disubstituted aminomethyl benzoate prodrug with improved oral bioavailability and anti-free radical oxidative damage activity and independent intellectual property rights is designed and synthesized. The PC12 cell oxidative damage model is adopted to evaluate the effect of the compound on the nerve cell oxidative damage resistance.
The patent aims to improve the oral bioavailability, the activity and the action selectivity of vascular dementia resistance by utilizing L-amino acid ester and N, N-disubstituted aminomethyl benzoate fragments in a scutellarin aglycone prodrug structure, and adopts a design strategy of L-amino acid and N, N-disubstituted aminomethyl benzoate prodrugs as a breakthrough for solving the two defects of low oral bioavailability and unsatisfactory drug effect in clinical application of scutellarin, thereby laying an important theoretical and practical foundation for creating a novel vascular dementia resistant scutellarin aglycone prodrug with independent intellectual property rights.
Disclosure of Invention
The invention aims to provide a scutellarin aglycone prodrug with vascular dementia resisting activity and pharmacologically acceptable inorganic or organic salt crystal hydrate and solvate thereof.
Another object of the present invention is to provide a process for the preparation of the above compounds
It is a further object of the present invention to provide pharmaceutical compositions comprising the above compounds
It is still another object of the present invention to provide medicinal uses of the above compounds
It is still another object of the present invention to provide a pharmaceutical use of the above composition
The invention provides a scutellarin aglycone prodrug with the structure shown in the following structural formula I and II and pharmacologically acceptable inorganic or organic salt crystal hydrate and solvate thereof.
Wherein,
r1 is C1-4 hydrocarbyl;
r2 is a nitrogen containing heterocycle;
n is 0, 2, 3
Preferably, representative compounds of the present invention may be the following compounds:
1)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-valine ester
2)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-alanine ester
3)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-leucine ester
4)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-isoleucine ester
5)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-phenylalanine ester
6)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-proline ester
7)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-methionine ester
8)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-valine Ethyl Ether
9)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-leucine Ethyl Ether
10)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-isoleucine Ethyl Ether
11)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-PhenylalanineEthyl Ether
12)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-leucine propyl Ether
13)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-isoleucine propyl Ether
14)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-phenylalanine propyl Ether
15)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((diethylamino) methyl) benzoate
16)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((benzylamino) methyl) benzoate
17)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- (Morpholinylmethyl) benzoate
18)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- (pyrrol-1-ylmethyl) benzoate
19)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((4-methylpiperazin-1-yl) methyl) benzoate
20)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((4-piperidin-1-yl) methyl) benzoate
21)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((diethylamino) methyl) benzoic acid propyl ether
22)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((benzylamino) methyl) benzoic acid propyl Ether
23)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- (Morpholinylmethyl) benzoic acid propyl Ether
24)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((diethylamino) methyl) benzoic acid Ethyl Ether
25)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- (Morpholinylmethyl) benzoic acid Ethyl Ether
26)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- (pyrrol-1-ylmethyl) benzoic acid ethyl ether
The structural formula of the representative compound of the present invention is shown in Table 1
TABLE 1 Compounds 1-14 of the present invention are of the formula
TABLE 1 structural formulas of representative compounds 15-26 of the present invention
The invention also provides a method for preparing the compound
The method for preparing the compound comprises the following steps:
(1) preparation of scutellarin aglycone
According to a patent report method (Cheqingming, CN1657042A), using a scutellarin semi-finished product as a raw material, performing reflux hydrolysis on a system for 20 hours under the condition of 8% sulfuric acid solution, cooling, performing suction filtration, extracting a filter cake with acetone, combining acetone layers, drying with anhydrous magnesium sulfate, filtering, evaporating to remove a solvent to obtain a crude product of scutellarin aglycone, and recrystallizing the obtained product with the solvent to obtain the scutellarin aglycone with the purity higher than 90%:
(2) preparation of scutellarin aglycone ketal protected intermediate
Dissolving scutellarin aglycone and a catalytic amount of 4-Dimethylaminopyridine (DMAP) in a proper amount of N, N-Dimethylformamide (DME) according to a literature method (Chen Shiwei et al, pharmaceutical science 2005, 40(11)1001, adding dichlorodiphenylmethane with the same mole as the aglycone, heating the system to 160-180 ℃, reacting for 2h, cooling, evaporating the solvent, and separating and purifying the residue by silica gel column chromatography to obtain a scutellarin aglycone ketal protected intermediate:
(3) synthesis of scutellarin aglycone 4' -L-amino acid ester derivatives
N-Boc-L-amino acid and ketal protected scutellarin aglycone in the presence of N, N-Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) under the reaction condition of tetrahydrofuran solventCondensing to form scutellarin aglycone 4' N-Boc-L-amino acid ester derivative, and passing the obtained product through CH3And (3) carrying out low-temperature reaction on a COCl/MeOH system and simultaneously removing a diphenyl ketal protecting group and an N-Boc (N-tert-butyloxycarbonyl) protecting group to obtain a final target compound:
(4) synthesis of scutellarin aglycone 4' -L-amino acid ether derivative
N-Boc L-amino acid is used as a substrate, the N-Boc L-amino acid is condensed with 2-bromoethanol or 3-bromo-1-propanol under the condition of DMAP/DCC to obtain N-Boc L-amino acid-2-bromoethyl ester or 3-bromopropyl ester, and the obtained compound and ketal-protected scutellarin aglycone are added into cesium carbonate or 4
Condensing in the presence of MS to obtain ketal protected scutellarin aglycone 4' -N-Boc-L-amino acid ethyl ether and propyl ether, and passing the obtained product through CH3And (3) carrying out low-temperature reaction on a COCl/MeOH system and simultaneously removing a diphenyl ketal protecting group and an N-Boc (N-tert-butyloxycarbonyl) protecting group to obtain a final target compound:
(5) synthesis of scutellarin aglycone 4' -aminomethyl benzoate derivatives
Condensing p-chloromethylbenzoic acid and substituted amine under the condition of absolute ethyl alcohol, using concentrated hydrochloric acid to regulate system pH to 3.4, precipitating, extracting precipitate with isopropanol, evaporating isopropanol layer to remove solvent, separating residue by silica gel column chromatography to obtain substituted amine methylbenzoic acid, reacting obtained product with ketal protected scutellarin aglycone at room temperature under the condition of using tetrahydrofuran as solvent and using DMAP/DCC as condensation reagent to obtain ketal protected methyl benzoic acidScutellarin aglycone 4' -substituted aminomethyl benzoate, and subjecting the obtained product to CH treatment3Removing the ketal protecting group by COCl/MeOH system low-temperature reaction to obtain the target compound:
(6) synthesis of scutellarin aglycone 4' -aminomethyl benzoic acid ether derivative
Condensing the obtained substituted aminomethyl benzoic acid with 2-bromoethanol or 3-bromo-1-propanol under DMAP/DCC condition to obtain substituted aminomethyl benzoic acid 2-bromoethyl ester or 3 bromopropyl ester, and reacting the substituted aminomethyl benzoic acid with ketal protected scutellarin aglycone in cesium carbonate or 4
Condensation reaction in the presence of molecular sieve, and then passing through CH3Removing the ketal protecting group by COCl/MeOH system low-temperature reaction to obtain the target compound:
the specific preparation of the target compounds 1-14 is shown in scheme (I):
wherein, a: n, N-Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) at the temperature of 20-65 ℃; b: n, N-Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) at the temperature of 20-65 ℃; c: cs2CO3N-methylpyrrolidone (NMP), 4
Molecular sieve, 40-100 ℃; d: acetyl chloride/methanol, ethyl acetate-5-25 ℃.
Specifically, the preparation of the target compounds 15-26 is shown in scheme (II)
Wherein, a: absolute ethyl alcohol, 25-80 ℃; b: n, N-Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) at the temperature of 20-65 ℃; c: n, N-Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) at the temperature of 20-65 ℃; d: cs2CO3N-methylpyrrolidone (NMP), 4
Molecular sieve, 40-100 ℃; e: acetyl chloride/methanol, ethyl acetate-5-25 ℃.
The embodiment of the scheme (I) is explained in detail as follows:
1. synthesizing a ketal-protected scutellarin aglycone 4' -N-tert-butyloxycarbonyl L-amino acid ester intermediate by using ketal-protected scutellarin aglycone and N-tert-butyloxycarbonyl-L-amino acid as reaction raw materials according to a literature report method (Tetrahedron Lett.1979, 20, (40), 3811-;
2. condensation of N-tert-butoxycarbonyl-L-amino acid with 3-bromo-1-propanol or 2-bromoethanol under DCC/DMAP conditions to form N-tert-butoxycarbonyl-L-amino acid-2-bromoethyl ester and 3-bromopropyl ester (Tetrahedron Lett.1979, 20, (40), 3811-
Reacting for 2-24 hours at 40-100 ℃ in the presence of a molecular sieve, wherein the optimal reaction condition is that N-tert-butoxycarbonyl-L-amino acid 3-bromopropyl ester or 2-bromoethyl ester and ketal protected scutellarin aglycone are reacted for 4-10 hours at 60-80 ℃ under the conditions that cesium carbonate is used as an acid binding agent and N-methylpyrrolidone is used as a solvent according to the ratio of 1.5-2.0: 1mol to obtain the ketal protected scutellarin aglycone 4' -N-tert-butoxycarbonyl L-amino acid ethyl and propyl ether intermediate;
3. reacting the obtained ketal-protected scutellarin aglycone 4 '-N-tert-butoxycarbonyl L-amino acid ester intermediate with ketal-protected scutellarin aglycone 4' -N-tert-butoxycarbonyl L-amino acid ethyl and propyl ether in a polar or non-polar solvent at-10-25 ℃ for 0.2-16 hours, wherein the optimal reaction condition is that the reaction is carried out in an acetyl chloride/methanol system at 0-25 ℃ for 4-8 hours to obtain a target compound 1-14;
the embodiment of scheme (II) is described in detail as follows:
1. condensing 4-chloromethylbenzoic acid and substituted amine or heterocycle as reaction raw materials under the condition of taking absolute ethyl alcohol as a reaction solvent according to a literature report method (J.G. Lombardino, US 4623486) to obtain a 4-substituted aminomethyl benzoic acid intermediate;
2. synthesizing a 4-substituted aminomethyl benzoic acid intermediate and ketal-protected scutellarin aglycone 4' -aminomethyl benzoate intermediate by a literature report method (J.chem.Res.1991, 10, 292-302) under the condition that N, N-Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) are used as condensation reagents;
3. condensing 4-substituted aminomethyl benzoic acid with 3-bromo-1 propanol or 2-bromoethanol under DCC/DMAP condition to form 4-substituted aminomethyl benzoic acid-2-bromoethyl ester and 3-bromopropyl ester (Tetrahedron Lett.1979, 20, (40), 3811-Reacting for 2-24 hours at 40-100 ℃ in the presence of a molecular sieve, wherein the optimal reaction condition is that 4-substituted aminomethyl benzoic acid 3-bromopropyl ester or 2-bromoethyl ester and ketal protected scutellarin aglycone are reacted for 4-10 hours at 60-80 ℃ under the condition that cesium carbonate is used as an acid binding agent and N-methyl pyrrolidone is used as a solvent according to the ratio of 1.5-2.0: 1mol, and obtaining ketal protected scutellarin aglycone 4' -aminomethyl benzoic acid ethyl ether and propyl ether intermediates;
3. reacting the obtained ketal-protected scutellarin aglycone 4 '-aminomethyl benzoate intermediate with ketal-protected scutellarin aglycone 4' -aminomethyl ethyl benzoate and propyl ether intermediate in a polar or non-polar solvent at-10-25 ℃ for 0.2-16 hours by using an acetyl chloride/methanol system, wherein the optimal reaction condition is that the reaction is carried out in the acetyl chloride/methanol system at 0-25 ℃ for 4-8 hours, so as to obtain the target compound 15-26.
The present invention also provides pharmaceutical compositions comprising the above flavonoid glycoside derivatives, which comprise a therapeutically effective amount of the compounds of the present invention as an active ingredient, together with adjuvants.
The invention also provides application of the flavonoid glycoside derivative in preparation of drugs for treating vascular dementia.
The invention also provides application of the medicine composition in medicines for treating vascular dementia.
Unless otherwise indicated, the terms used herein have the following definitions:
the "alkyl group" represents a saturated or unsaturated, substituted or unsubstituted, straight-chain or branched alkane chain, and specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 2-methylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, and 3, 3-dimethylbutyl. Among these groups, an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and the like is preferable, and a methyl group, an ethyl group and a propyl group are more preferable.
Specific examples of the "pharmaceutically acceptable salt" include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphonic acid, acid addition salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, and citric acid, acid amino acids such as aspartic acid and glutamic acid, and salts with basic amino acids such as lysine, arginine, and ornithine.
Detailed Description
Preparation example 1: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-valine ester
The ketal-protected scutellarin aglycone (30mg, 67. mu. mol) was dissolved in 5ml Tetrahydrofuran (THF), followed by addition of N-Boc-L-valine (18.6mg, 81. mu. mol) and 4-Dimethylaminopyridine (DMAP) (4mg, 33. mu. mol). Then, 3mL of a tetrahydrofuran solution of N, N-Dicyclohexylcarbodiimide (DCC) (17mg, 81. mu. mol) was added, and the reaction was carried out for 14 hours while stirring at room temperature. TLC monitoring till the material conversion is complete, decompressing, concentrating the residue, eluting with petroleum ether, ethyl acetate and dichloromethane (7: 1: 5), and separating by silica gel column chromatography to obtain 30.6mg of a yellow oily target product, namely, ketal-protected 4' -L-valine ester derivative of scutellarin aglycone, with the yield of 83%.
1H-NMR(400MHz，CDCl3)δ：7.93(d，J＝8.8Hz，2H，Ar’-H3，5)，7.82-7.80(m，4H，Ph-4H)，7.64-7.61(m，4H，Ph-6H)，6.98(d，J＝8.8Hz，2H，Ar’-H2，6)，6.62(s，1H，Ar-H8)，6.57(s，1H，Ar-H3)，5.08(d，J＝6.4Hz，1H，NHBoc)，4.21-4.18(m，1H，CHNH)，3.11-3.09(m，1H，CH(CH3)2)，1.41(d，J＝6.4Hz，6H，2×CH3).
Under the condition of an ice salt bath, methanol (27 mu L, 667 mu mol) and acetyl chloride (39 mu L, 556 mu mol) are sequentially added into 2ml of ethyl acetate, the ice salt bath is kept to be stirred for reaction for 3 hours, the obtained ketal-protected scutellarin 4' -L-valine ester derivative (30.6mg, 55.6 mu mol) is dissolved in 1.5ml of ethyl acetate, then the obtained solution is added into the reaction system, the ice salt bath is kept for reaction for 2 hours, the reaction temperature is gradually increased to the room temperature for reaction for 12 hours, orange yellow precipitates are attached to the wall, the obtained precipitates are washed by ethyl acetate for three times after the reaction system is subjected to ultrasonic treatment and centrifugation, 12mg of an orange oily target product is obtained, and the yield is 56.1%.
1H-NMR(400MHz，DMSO-d6)δ：12.59(brs，1H，5-OH)，10.61(brs，1H，7-OH)，8.65(brs，1H，6-OH)，8.18(d，J＝8.4Hz，2H，Ar’-H3，5)，7.42(d，J＝8.4Hz，2H，Ar’-H3，6)，6.95(s，1H，Ar-H8)，6.65(s，1H，Ar-H3)，4.20(d，J＝4.4Hz，1H，COCHNH2)，2.38-2.33(m，1H，CH(CH3)2)，1.12(d，J＝7.2Hz，3H，CH3)，1.10(d，J＝7.2Hz，3H，CH3)
Preparation example 2: 5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-alanine ester
Prepared by the method similar to the example 1 by using the ketal-protected scutellarin aglycone and N-Boc L-alanine as reaction raw materials. The desired product was obtained as an orange oil in 63.3% yield.
1H-NMR(400MHz，DMSO-d6)δ：12.62(brs，1H，5-OH)，10.74(brs，1H，7-OH)，8.73(brs，1H，6-OH)，8.29(d，J＝8.8Hz，2H，Ar’-H3，5)，7.42(d，J＝8.8Hz，2H，Ar’-H3，6)，6.98(s，1H，Ar-H8)，6.67(s，1H，Ar-H3)，4.43(m，1H，COCHNH2)，1.33(d，J＝6.8Hz，3H，CH3).
Preparation example 3: 5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-leucine ester
Prepared by the method similar to the example 1 by using the ketal-protected scutellarin aglycone and N-Boc L-leucine as reaction raw materials. The desired product is obtained in the form of an orange oil with a yield of 76.5%.
1H-NMR(400MHz，DMSO-d6)δ：12.57(brs，1H，5-OH)，10.76(brs，1H，7-OH)，8.74(brs，1H，6-OH)，8.17(d，J＝8.8Hz，2H，Ar’-H3，5)，7.42(d，J＝8.8Hz，2H，Ar’-H3，6)，6.93(s，1H，Ar-H8)，6.71(s，1H，Ar-H3)，4.27(m，1H，COCHNH2)，1.96-1.79(m，3H，CH2CH(CH3)2)，1.05-1.01(m，6H，2×CH3).
Preparation example 4: 5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-isoleucine ester
Scutellarin aglycone and N-Boc L-isoleucine protected by ketal are used as reaction raw materials and are prepared by a method similar to the example 1. The expected product is obtained in the form of an orange oil with a yield of 69.8%.
1H-NMR(400MHz，DMSO-d6)δ：12.57(brs，1H，5-OH)，10.78(brs，1H，7-OH)，8.76(brs，1H，6-OH)，8.17(d，J＝8.8Hz，2H，Ar’-H3，5)，7.41(d，J＝8.8Hz，2H，Ar’-H3，6)，6.94(s，1H，Ar-H8)，6.65(s，1H，Ar-H3)，4.25(m，1H，COCHNH2)，2.07(m，1H，CH(CH3)C2H5)，1.62-1.59(m，1H，CH2CH3-1H)，1.41-1.37(m，1H，CH2CH3-1H)，1.06(d，J＝6.8Hz，3H，CH(CH3))，0.97(t，J＝7.6Hz，3H，CH2CH3).
Preparation example 5: 5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-phenylalanine ester
Prepared by the method similar to the example 1 by using the ketal-protected scutellarin aglycone and N-Boc L-phenylalanine as reaction raw materials. The expected product is obtained in the form of an orange oil with a yield of 75.4%.
1H-NMR(400MHz，DMSO-d6)δ：12.58(brs，1H，5-OH)，10.69(brs，1H，7-OH)，8.83(brs，1H，6-OH)，8.17(d，J＝8.8Hz，2H，Ar’-H3，5)，7.41-7.32(m，5H，Ph-5H)，7.18(d，J＝8.8Hz，2H，Ar’-H3，6)，6.90(s，1H，Ar-H8)，6.63(s，1H，Ar-H3)，4.59(t，J＝6.8Hz，1H，COCH)，3.25-3.20(m，2H，CH2Ph).
Preparation example 6: 5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-proline ester
Prepared by the method similar to the example 1 by using the ketal-protected scutellarin aglycone and N-Boc L-proline as reaction raw materials. The desired product is obtained in the form of an orange oil with a yield of 50.7%.1H-NMR(400MHz，DMSO-d6)δ：12.58(brs，1H，5-OH)，10.48(brs，1H，7-OH)，8.68(brs，1H，6-OH)，8.16(d，J＝8.0Hz，2H，Ar’-H3，5)，6.93(d，J＝8.8Hz，2H，Ar’-H3，6)，6.83(s，1H，Ar-H8)，6.56(s，1H，Ar-H3)，4.23-4.18(m，1H，COCH)，2.29-2.23(m，2H，NHCH2)，2.01-1.88(m，4H，NHCHCH2CH2)
Preparation example 7: 5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-methionine ester
Prepared by the method similar to the example 1 by using the ketal-protected scutellarin aglycone and N-Boc L-methionine as reaction raw materials. The expected product is obtained in the form of an orange oil with a yield of 64.5%.
1H-NMR(400MHz，DMSO-d6)δ：12.80(brs，1H，5-OH)，10.41(brs，1H，7-OH)，8.85(brs，1H，6-OH)，8.24(d，J＝9.2Hz，2H，Ar’-H3，5)，7.57(d，J＝8.8Hz，2H，Ar’-H3，6)，6.98(s，1H，Ar-H8)，6.67(s，1H，Ar-H3)，4.46(t，J＝6.0Hz，1H，COCH)，2.73-2.67(m，2H，CH2SCH3)，2.34-2.29(m，2H，CH2CH2S)，2.11(s，3H，CH3).
Preparation example 8: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-valine ethyl ether
Ketal-protected scutellarin aglycone (50mg, 111. mu. mol), dissolved in 3ml of N-methylpyrrolidone (NMP), was added with N-t-butyloxycarbonyl-L-valine 3-bromoethyl ester (43.5mg, 167. mu. mol), cesium carbonate (36.2mg, 111. mu. mol), 4
Counting the molecular sieve particles, stirring and reacting for 4 hours at 80 ℃, removing 4 in the reaction system
Adding a proper amount of trichloromethane after molecular sieving, washing with 0.5% hydrochloric acid solution for 5 times to remove N-methylpyrrolidone, drying the trichloromethane layer with anhydrous magnesium sulfate, concentrating the solution under reduced pressure, and separating the residue by silica gel column chromatography with petroleum ether, ethyl acetate and dichloromethane of 7: 1: 5 as eluent to obtain 23mg of ketal-protected scutellarin 4' -L-valine ethyl ether derivative with the yield of 30%.
1H-NMR(400MHz，CDCl3)δ：7.82(d，J＝8.4Hz，2H，Ar’-H3，5)，7.63-7.60(m，4H，Ph-4H)，7.44-7.37(m，4H，Ph-6H)，7.02(d，J＝8.4Hz，2H，Ar’-H2，6)，6.63(s，1H，Ar-H8)，6.57(s，1H，Ar-H3)，5.04(d，J＝8.8Hz，1H，NHBoc)，4.57-4.48(m，2H，CH2OCO)，4.28-4.25(m，3H，Ar’OCH2，CHNH)，1.87-1.83(m，1H，CH(CH3)2)，0.98(d，J＝6.8Hz，3H，CH3)，0.91(d，J＝6.8Hz，3H，CH3).
Under the condition of an ice salt bath, methanol (16 mu L, 400 mu mol) and acetyl chloride (20 mu L, 333 mu mol) are sequentially added into 2ml of ethyl acetate, the ice salt bath is kept to be stirred and react for 3 hours, the obtained ketal-protected scutellarin 4' -L-valine ethyl ether derivative (23mg, 33.1 mu mol) is dissolved in 1.5ml of ethyl acetate and then added into the reaction system, the ice salt bath is kept to react for 2 hours, the reaction temperature is gradually increased to the room temperature to react for 12 hours, an orange-yellow precipitate is attached to the wall, the precipitate obtained after the reaction system is subjected to ultrasonic treatment and centrifugation is washed with ethyl acetate for three times, and 8mg of an orange oily target product is obtained, and the yield is 56.3%.
1H-NMR(400MHz，DMSO-d6)δ：12.71(brs，1H，5-OH)，10.62(brs，1H，7-OH)，8.48(brs，1H，6-OH)，8.13(d，J＝8.8Hz，2H，Ar’-H3，5)，7.13(d，J＝8.8Hz，2H，Ar’-H3，6)，6.83(s，1H，Ar-H8)，6.62(s，1H，Ar-H3)，4.66-4.63(m，1H，CH2OCO-1H)，4.49-4.46(m，1H，CH2OCO-1H)，4.34(m，2H，Ar’OCH2)，3.95(m，1H，COCH)，2.18-2.14(m，1H，CH(CH3)2)，0.98(d，J＝6.0Hz，3H，CH3)，0.94(d，J＝6.8Hz，3H，CH3).
Preparation example 9: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-leucine Ethyl Ether
Prepared by the method similar to the example 8 by using ketal-protected scutellarin aglycone and N-Boc L-leucine-2-bromoethyl ester as reaction raw materials. The expected product is obtained in the form of an orange oil with a yield of 47.3%.
1H-NMR(400MHz，DMSO-d6)δ：12.70(brs，1H，5-OH)，10.65(brs，1H，7-OH)，8.52(brs，1H，6-OH)，8.03(d，J＝8.8Hz，2H，Ar’-H3，5)，7.11(d，J＝8.8Hz，2H，Ar’-H3，6)，6.84(s，1H，Ar-H8)，6.63(s，1H，Ar-H3)，4.59-4.57(m，1H，CH2OCO-1H)，4.49-4.45(m，1H，CH2OCO-1H)，4.35-4.33(m，2H，Ar’OCH2)，3.99(m，1H，COCH)，1.72-1.70(m，1H，CH(CH3)2)，1.64-1.59(m，2H，CH2CH(CH3)2)，0.83(d，J＝8.0Hz，6H，2×CH3).
Preparation example 10: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-isoleucine ethyl ether
Scutellarin aglycone protected by ketal and N-Boc L-isoleucine-2-bromoethyl ester are used as reaction raw materials, and the preparation method is similar to the example 8. The expected product is obtained in the form of an orange oil with a yield of 58.8%.
1H-NMR(400MHz，DMSO-d6)δ：12.75(brs，1H，5-OH)，10.75(brs，1H，7-OH)，8.53(brs，1H，6-OH)，8.03(d，J＝8.0Hz，2H，Ar’-H3，5)，7.11(d，J＝8.0Hz，2H，Ar’-H3，6)，6.83(s，1H，Ar-H8)，6.64(s，1H，Ar-H3)，4.66-4.63(m，1H，CH2OCO-1H)，4.47-4.44(m，1H，CH2OCO-1H)，4.33(m，2H，Ar’OCH2)，3.98(m，1H，COCH)，1.89(m，1H，CH(CH3)C2H5)，1.47-1.44(m，1H，CH2CH3-1H)，1.30-1.23(m，1H，CH2CH3-1H)，1.05(t，J＝6.8Hz，3H，CH(CH3))，0.90(d，J＝6.8Hz，3H，CH2CH3).
Preparation example 11: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-phenylalanine ethyl ether
Prepared by the method similar to the example 8 by using ketal-protected scutellarin aglycone and N-Boc L-phenylalanine-2-ethyl bromide as reaction raw materials. The expected product is obtained in the form of an orange oil with a yield of 67.5%.
1H-NMR(400MHz，DMSO-d6)δ：12.71(brs，1H，5-OH)，10.65(brs，1H，7-OH)，8.56(brs，1H，6-OH)，8.04(d，J＝8.8Hz，2H，Ar’-H3，5)，7.23(m，5H，Ph-5H)，7.10(d，J＝8.8Hz，2H，Ar’-H2，6)，6.84(s，1H，Ar-H8)，6.62(s，1H，Ar-H3)，4.51-4.10(m，2H，CH2OCO)，4.35-4.32(m，1H，COCH)，4.24-4.17(m，2H，OCH2CH2)，3.24-3.16(m，1H，CH2Ph-1H)，3.09-3.04(m，1H，CH2Ph-1H).
Preparation of 1-benzopyran-4-L-leucine propyl ether
Prepared in analogy to example 8 using ketal-protected scutellarin aglycone and N-Boc L-leucine 3-bromopropyl ester as starting materials. The desired product is obtained in the form of an orange oil with a yield of 45.3%.
1H-NMR(400MHz，DMSO-d6)δ：12.72(brs，1H，5-OH)，10.58(brs，1H，7-OH)，8.44(brs，1H，6-OH)，8.03(d，J＝8.8Hz，2H，Ar’-H3，5)，7.13(d，J＝8.8Hz，2H，Ar’-H2，6)，6.84(s，1H，Ar-H8)，6.61(s，1H，Ar-H3)，4.33(m，2H，CH2OCO)，4.18(m，2H，PhOCH2)，3.98(m，1H，COCH)，2.13-2.10(m，2H，OCH2CH2CH2O)，1.71-1.58(m，3H，CH2CH(CH3)2)，0.87(d，J＝6.4Hz，6H，2×CH3).
Preparation example 13: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-isoleucine propyl ether
Prepared by the method similar to example 8 using ketal-protected scutellarin aglycone and N-Boc L-isoleucine 3-bromopropyl ester as reaction raw materials. The expected product is obtained in the form of an orange oil with a yield of 51.7%.
1H-NMR(400MHz，DMSO-d6)δ：12.72(brs，1H，5-OH)，10.58(brs，1H，7-OH)，8.44(brs，1H，6-OH)，8.13(d，J＝8.8Hz，2H，Ar’-H3，5)，7.13(d，J＝8.8Hz，2H，Ar’-H2，6)，6.83(s，1H，Ar-H8)，6.61(s，1H，Ar-H3)，4.37(m，2H，CH2OCO)，4.17(m，2H，PhOCH2)，3.97(m，1H，COCH)，2.13-2.10(m，2H，OCH2CH2CH2O)，1.45-1.40(m，1H，CH(CH3))，1.27-1.21(m，2H，CH2CH3)，0.89-0.83(m，6H，2×CH3).
Preparation example 14: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-phenylalanine propyl ether
Preparation of a ketal-protected scutellarin aglycone and N-Boc L-phenylalanine 3-bromopropyl ester as reaction starting materials was carried out in a similar manner to example 8. The desired product is obtained in the form of an orange oil with a yield of 58.1%.
1H-NMR(400MHz，DMSO-d6)δ：12.70(brs，1H，5-OH)，10.57(brs，1H，7-OH)，8.61(brs，1H，6-OH)，8.12(d，J＝8.8Hz，2H，Ar’-H3，5)，7.31-7.27(m，5H，Ph-5H)，7.13(d，J＝8.8Hz，2H，Ar’-H2，6)，6.85(s，1H，Ar-H8)，6.64(s，1H，Ar-H3)，4.30-4.23(m，3H，CH2OCO，COCH)，3.99-3.97(m，2H，PhOCH2)，3.22-3.16(m，1H，CH2Ph-1H)，3.09-3.03(m，1H，CH2Ph-1H)，2.08-1.98(m，2H，OCH2CH2CH2O).
Preparation example 15: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((diethylamino) methyl) benzoate
Dissolving diethylamine methylbenzoic acid (20mg, 95 mu mol) in a small amount of dimethyl sulfoxide, diluting to 5mL with tetrahydrofuran, dissolving ketal-protected scutellarin aglycone (30mg, 67 mu mol) in 5mL of Tetrahydrofuran (THF), sequentially adding 5mL of a THF solution of diethylamine methylbenzoic acid and 4-Dimethylaminopyridine (DMAP) (4mg, 33 mu mol), dropwise adding 3mL of a tetrahydrofuran solution containing N, N-Dicyclohexylcarbodiimide (DCC) (17mg, 81 mu mol) to the reaction system, and reacting for 14 hours at room temperature under stirring. And (3) after TLC monitoring till the raw material is completely converted, concentrating the system under reduced pressure to remove tetrahydrofuran, extracting for 3 times by using a chloroform-water system, washing out a DMSO solvent in the system, collecting a chloroform layer, adding anhydrous magnesium sulfate, drying for 1h, filtering, concentrating the filtrate, and performing silica gel column chromatography separation by using chloroform and methanol as an eluent at the ratio of 30: 1 to obtain 37.8mg of diphenyl ketal protected scutellarin-4' -p-diethylamine methyl benzoate with the yield of 80%.
1H-NMR(400MHz，DMSO-d6)δ：12.72(brs，1H，5-OH)，8.12(d，J＝8.0Hz，2H，Ar’-H3，5)，7.95(d，J＝8.4Hz，2H，Ar’-H2，6)，7.63-7.61(m，2H，Ar”-H3，5)，7.58-7.56(m，2H，Ar”-H2，6)，7.41-7.37(m，10H，2×Ph-5H)，6.67(s，2H，Ar-H3，8)，3.84(s，2H，Ar”-CH2N)，2.73(q，J＝7.2Hz，4H，2×NCH2CH3)，1.15(t，J＝6.8Hz，6H，2×CH3).
Adding 3ml of ethyl acetate into a 25ml dry eggplant-shaped bottle, adding methanol (0.03ml, 0.7mmol) and acetyl chloride (0.028ml, 0.4mmol) into the dry eggplant-shaped bottle in sequence under stirring in a cold salt bath (-5 ℃), keeping the temperature for reaction for 3h, dropwise adding 2ml of ethyl acetate solution containing diphenylketal protected scutellarin-4' -p-diethylamine methyl benzoate (26mg, 0.04mmol) into the reaction system, keeping the temperature for reaction for 2h, raising the temperature to room temperature for reaction for 12h, attaching a yellow precipitate to the wall, adding a proper amount of ethyl acetate, performing ultrasonic treatment, and washing to obtain a yellow solid target compound 10mg, wherein the yield is 52.6%.
1H-NMR(400MHz，DMSO-d6)δ：12.67(brs，1H，5-OH)，10.67(brs，1H，7-OH)，8.68(brs，1H，6-OH)，8.29-8.17(m，4H，Ar’-H3，5，Ar”-H3，5)，7.89(d，J＝8.0Hz，Ar’-H2，6)，7.53(d，J＝8.4Hz，Ar”-H2，6)，6.97(s，1H，Ar-H8)，6.65(s，1H，Ar-H3)，3.76(s，2H，Ar”-CH2N)，3.06(m，4H，2×NCH2CH3)，1.25-1.23(m，6H，2×CH3).
Preparation example 16: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((benzylamino) methyl) benzoate
The yellow solid target product is prepared by the method similar to example 15 by using benzylamino methylbenzoic acid and ketal protected scutellarin aglycone as reaction raw materials, and the yield is 46.7 percent
1H-NMR(400MHz，DMSO-d6)δ：12.63(brs，1H，5-OH)，10.70(brs，1H，7-OH)，8.83(brs，1H，6-OH)，8.28-8.23(m，4H，Ar’-H3，5，Ar”-H3，5)，7.79(d，J＝8.8Hz，Ar’-H2，6)，7.57-7.55(m，5H，Ph-5H)，7.51(d，J＝8.8Hz，Ar”-H2，6)，6.97(s，1H，Ar-H8)，6.66(s，1H，Ar-H3)，4.29(s，2H，Ar”-CH2N)，4.18(s，2H，CH2Ph).
Preparation example 17: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((morpholinyl) methyl) benzoate
Takes morpholine methylbenzoic acid and ketal protected scutellarin aglycone as reaction raw materials to prepare a dark yellow solid target product according to the method similar to the example 15, and the yield is 56.4 percent
1H-NMR(400MHz，DMSO-d6)δ：12.63(brs，1H，5-OH)，10.65(brs，1H，7-OH)，8.31(brs，1H，6-OH)，8.31-8.17(m，4H，Ar’-H3，5，Ar”-H3，5)，7.83(d，J＝7.2Hz，Ar’-H2，6)，7.52(d，J＝8.8Hz，Ar”-H2，6)，6.98(s，1H，Ar-H8)，6.65(s，1H，Ar-H3)，3.92(s，2H，Ar”-CH2N)，3.75(m，4H，2×CH2O)，2.52(m，4H，2×CH2N).
Preparation example 18: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((tetrahydropyrrolyl) methyl) benzoate
The target product is prepared by the method similar to example 15 by taking tetrahydropyrrole methylbenzoic acid and ketal protected scutellarin aglycone as reaction raw materials, and the yield is 32.1 percent
1H-NMR(400MHz，DMSO-d6)δ：12.65(brs，1H，5-OH)，10.70(brs，1H，7-OH)，8.24-8.19(m，4H，Ar’-H3，5，Ar”-H3，5)，7.88(d，J＝8.8Hz，Ar’-H2，6)，7.52(d，J＝8.8Hz，Ar”-H2，6)，6.99(s，1H，Ar-H8)，6.68(s，1H，Ar-H3)，4.50(s，2H，Ar”-CH2N)，2.54-2.50(m，4H，2×CH2N)，1.69-1.51(m，4H，2×NCH2CH2).
Preparation example 19: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((4-methylpiperazin-1-yl) methyl) benzoate
The target product was prepared in a similar manner to example 15 using (p-methylpiperazin-1-yl) methylbenzoic acid, ketal-protected scutellarin aglycone as the starting material in a brown-yellow solid yield of 17.6%
1H-NMR(400MHz，DMSO-d6)δ：12.68(brs，1H，5-OH)，10.65(brs，1H，7-OH)，8.17(d，J＝8.0Hz，2H，Ar’-H3，5)，7.94(d，J＝8.4Hz，2H，Ar”-H3，5)，7.63-7.61(m，4H，Ar’-H2，6，Ar”-H2，6)，6.97(s，1H，Ar-H8)，6.59(s，1H，Ar-H3)，3.61(s，2H，Ar”-CH2N)，2.52-2.32(m，8H，4×CH2N)，2.30(s，3H，CH3).
Preparation example 20: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((piperidinyl) methyl) benzoate
The target product is prepared by the method similar to example 15 by using piperidine methylbenzoic acid and ketal protected scutellarin aglycone as reaction raw materials, and the yield is 37.6 percent
1H-NMR(400MHz，DMSO-d6)δ：12.68(brs，1H，5-OH)，10.65(brs，1H，7-OH)，8.19(d，J＝8.4Hz，Ar’-H3，5)，7.98(d，J＝8.4Hz，2H，Ar”-H3，5)，7.56-7.46(m，4H，Ar’-H2，6，Ar”-H2，6)，6.97(s，1H，Ar-H8)，6.64(s，1H，Ar-H3)，3.71(s，2H，Ar”-CH2N)，2.59-2.39(m，4H，2×CH2N)，1.84-1.57(m，6H，3×CH2).
Preparation example 21: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((diethylamino) methyl) benzoic acid propyl ether
Taking dry diethylamine methyl benzoic acid (0.1g, 0.48mmol), placing in a 50ml eggplant-shaped bottle, adding a small amount of dimethyl sulfoxide (DMSO) to promote dissolution, adding dichloromethane to dissolve to 15ml, making the system to be a clear solution, then adding 3-bromo-1-propanol (0.07g, 0.48mmol), p-Dimethylaminopyridine (DMAP) (0.025g, 0.24mmol) in sequence, dropwise adding 10ml dichloromethane solution containing N, N' -Dicyclohexylcarbodiimide (DCC) (0.069g, 0.33mmol) under stirring at room temperature, reacting for 12h at room temperature, monitoring by TLC for complete reaction, concentrating, using chloroform-methanol-30: 1 as eluent, purifying by silica gel column chromatography to obtain white waxy p-diethylamine methyl benzoic acid propyl bromide, 85mg, yield 71%.
1H-NMR(400MHz，CDCl3)δ：7.98(d，J＝8.0Hz，2H，Ar-H2，6)，7.43(d，J＝8.0Hz，2H，Ar-H3，5)，4.4(t，J＝6.4Hz，2H，CH2OCO)，3.71-3.57(m，4H，BrCH2，Ar-CH2N)，2.55-2.51(q，J＝6.4Hz，4H，2×NCH2)，2.32-2.29(m，2H，OCH2CH2CH2Br)，1.07(t，6H，J＝6.4Hz，2×CH3).
Taking dry ketal-protected scutellarin aglycone (50mg, 0.11mmol) and p-diethylamine methyl propyl benzoate (50mg, 0.15mmol), placing in a 25ml eggplant-shaped bottle, adding 4ml N-methylpyrrolidone (NMP), fully dissolving, adding cesium carbonate (24mg, 0.07mmol), then adding a plurality of molecular sieves (4A), and stirring and reacting for 6h at 100 ℃. After the reaction is finished, the reaction system is placed in chloroform, then is washed for 4-6 times by 0.5M dilute hydrochloric acid, the reaction solvent N-methyl pyrrolidone (NMP) is washed away, an organic layer is separated, dried and concentrated, and is separated by silica gel column chromatography, and an eluent: chloroform-methanol (30: 1) gave 33mg of the desired product as a yellow oil in 42.9% yield.
1H-NMR(400MHz，CDCl3)δ：12.54(brs，1H，5-OH)，7.98-7.88(m，4H，Ar’-H3，5，Ar”-H3，5)，7.80(d，J＝8.8Hz，2H，Ar’-H2，6)，7.41-7.37(m，10H，2×Ph-5H)，7.23(d，J＝8.8Hz，2H，Ar”-H2，6)，6.92(s，1H，Ar-H8)，6.82(s，1H，Ar-H3)，4.77(t，J＝6.0Hz，2H，Ar’-OCH2)，4.37(s，2H，Ar”-CH2N)，4.30(t，J＝6.8Hz，2H，CH2OCO)，3.15-3.09(m，4H，2×NCH2)，2.43-2.36(m，2H，OCH2CH2CH2O)，1.66(t，J＝7.6Hz，2×CH3).
Adding 3ml of ethyl acetate into a 25ml dry eggplant-shaped bottle, adding methanol (0.03ml, 0.7mmol) and acetyl chloride (0.028ml, 0.4mmol) into the dry eggplant-shaped bottle in sequence under stirring in a cold salt bath (-5 ℃), keeping the temperature for reaction for 3h, dropwise adding 2ml of ethyl acetate solution containing diphenyl ketal protected scutellarin-4' -p-diethylamine methyl propyl benzoate (28mg, 0.04mmol) into the reaction system, keeping the temperature for reaction for 2h, raising the temperature to room temperature for reaction for 12h, attaching yellow precipitates to the wall, adding a proper amount of ethyl acetate, performing ultrasonic treatment, and washing to obtain a brown oily target compound 10mg, wherein the yield is 47.6%.
1H-NMR(400MHz，DMSO-d6)δ：12.64(brs，1H，5-OH)，10.68(brs，1H，7-OH)，8.36(brs，1H，6-OH)，8.04-7.98(m，4H，Ar’-H3，5，Ar”-H3，5)，7.76(d，J＝8.8Hz，2H，Ar’-H2，6)，7.13(d，J＝8.8Hz，2H，Ar”-H2，6)，6.82(s，1H，Ar-H8)，6.61(s，1H，Ar-H3)，4.47(t，J＝6.0Hz，2H，Ar’-OCH2)，4.44(s，2H，Ar”-CH2N)，4.26(t，J＝6.8Hz，2H，CH2OCO)，3.05-2.99(m，4H，2×NCH2)，2.23-2.16(m，2H，OCH2CH2CH2O)，1.23(t，J＝7.6Hz，2×CH3).
Preparation example 22: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((benzylamino) methyl) benzoic acid propyl ether
The yellow oily target product is prepared by the method similar to example 21 by using benzylamino methylbenzoic acid, 3-bromo-1-propanol and ketal protected scutellarin aglycone as reaction raw materials, and the yield is 44.9 percent
1H-NMR(400MHz，DMSO-d6)δ：12.68(brs，1H，5-OH)，10.64(brs，1H，7-OH)，8.32(brs，1H，6-OH)，8.22(d，J＝8.8Hz，2H，Ar’-H3，5)，8.13(d，J＝8.8Hz，2H，Ar”-H3，5)，7.62-7.47(m，5H，Ph-5H)，7.38-7.31(m，4H，Ar’-H2，6，Ar”-H2，6)，6.97(s，1H，Ar-H8)，6.61(s，1H，Ar-H3)，4.54(d，J＝6.4Hz，2H，Ar’-OCH2)，4.32(d，J＝6.4Hz，2H，CH2OCO)，3.83(s，2H，PhCH2N)，3.72(s，2H，NCH2Ph)，2.19(m，2H，OCH2CH2CH2O).
Preparation example 23: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((morpholinyl) methyl) benzoic acid propyl ether
The yellow oily target product is prepared by the method similar to example 21 by using morpholine methylbenzoic acid, 3-bromo-1-propanol and ketal protected scutellarin aglycone as reaction raw materials, and the yield is 44.3 percent
1H-NMR(400MHz，DMSO-d6)δ：12.85(s，1H，5-OH)，10.65(s，1H，7-OH)，8.05-7.98(m，4H，Ar’-H3，5，Ar”-H3，5)，7.37(d，J＝8.8Hz，2H，Ar’-H2，6)，7.13(d，J＝8.8Hz，2H，Ar”-H2，6)，6.82(s，1H，Ar-H8)，6.61(s，1H，Ar-H3)，4.47(t，J＝6.4Hz，2H，Ar’-OCH2)，4.40(s，2H，PhCH2N)，4.25(t，J＝6.0Hz，2H，CH2OCO)，3.78-3.66(m，4H，2×OCH2CH2)，3.17-3.14(m，4H，2×NCH2CH2)，2.21-2.18(m，2H，OCH2CH2CH2O).
Preparation example 24: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((diethylamino) methyl) benzoic acid ethyl ether
The target product was prepared in a brown-yellow oil by the method similar to example 21 using diethylamine methylbenzoic acid, bromoethanol, ketal protected scutellarin aglycone as the reaction raw material, with a yield of 41.9%.
1H-NMR(400MHz，DMSO-d6)δ：12.74(brs，1H，5-OH)，10.68(brs，1H，7-OH)，8.36(brs，1H，6-OH)，8.09-8.03(m，4H，Ar’-H3，5，Ar”-H3，5)，7.74(d，J＝8.8Hz，2H，Ar’-H2，6)，7.18(d，J＝8.8Hz，2H，Ar”-H2，6)，6.85(s，1H，Ar-H8)，6.62(s，1H，Ar-H3)，4.67(t，J＝6.0Hz，2H，Ar’-OCH2)，4.48(s，2H，Ar”-CH2N)，4.38(t，J＝6.8Hz，2H，CH2OCO)，3.18-3.05(m，4H，2×NCH2CH3)，1.21(t，J＝7.6Hz，6H，2×CH3).
Preparation example 25: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((morpholinyl) methyl) benzoic acid ethyl ether
Takes morpholine methylbenzoic acid, bromoethanol and ketal protected scutellarin aglycone as reaction raw materials to prepare brown oily target products according to the method similar to the example 21, and the yield is 13.6 percent
1H-NMR(400MHz，DMSO-d6)δ：12.65(s，1H，5-OH)，10.65(s，1H，7-OH)，8.76(brs，1H，6-OH)，8.02-7.98(m，4H，Ar’-H3，5，Ar”-H3，5)，7.70(d，J＝8.0Hz，2H，Ar’-H2，6)，7.14(d，J＝8.8Hz，2H，Ar”-H2，6)，6.81(s，1H，Ar-H8)，6.58(s，1H，Ar-H3)，4.63(m，2H，Ar’-OCH2)，4.44(s，2H，PhCH2N)，4.37(m，2H，CH2OCO)，3.51-3.28(m，4H，2×OCH2CH2)，3.26-3.13(m，4H，2×NCH2CH2).
Preparation example 26: preparation of 5, 6, 7-trihydroxy-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((pyrrolyl) methyl) benzoic acid ethyl ether
The brown oily target product is prepared by the method similar to the example 21 by using tetrahydropyrrole methylbenzoic acid, bromoethanol and ketal protected scutellarin aglycone as reaction raw materials, and the yield is 45.5 percent
1H-NMR(400MHz，DMSO-d6)δ：12.72(brs，1H，5-OH)，10.81(brs，1H，7-OH)，9.16(brs，1H，6-OH)，8.03-7.99(m，4H，Ar’-H3，5，Ar”-H3，5)，7.94(d，J＝8.4Hz，Ar’-H2，6)，7.16(d，J＝8.8Hz，Ar”-H2，6)，6.83(s，1H，Ar-H8)，6.62(s，1H，Ar-H3)，4.65(s，2H，Ar”-CH2N)，4.20(m，2H，Ar’-OCH2)，4.05-4.01(m，2H，CH2OCO)，3.15-3.04(m，4H，2×CH2N)，2.54-2.50(m，4H，2×CH2N)，1.89-1.83(m，4H，2×NCH2CH2).
Experimental examples
1. Experimental materials and instruments
The PC12 cell strain is provided by the institute of medical and biotechnology of Chinese academy of medical sciences; test compounds were provided by the medical institute of Guiyang medical school; vitamin E was purchased from Sigma; DMEM high-glucose medium was purchased from Gibco; fetal calf serum was purchased from Hangzhou ilex bioengineering materials, Inc.; MTT was purchased from Sigma; the LDH determination kit is purchased from Nanjing technology Co Ltd; the microplate reader is Berle 680 Model.
2. Test method
(1) Cytotoxicity assays
The inhibition effect of the medicament on the growth of PC12 cells is detected by a tetrazole reduction method and 3- (4, 5-dimethylthiazolidi-2-yl) -2, 5-diphenyltetrazolium bromide, MTT). PC12 cells were digested into a single cell suspension and cell density was adjusted to 5X 104One/ml of the cells were inoculated into a 96-well plate (100. mu.l/well) at 37 ℃ with 5% CO2The incubator was incubated overnight. After the cells are attached to the wall, the supernatant is aspirated, a culture solution containing concentration gradient dilution drugs (1 mu M, 10 mu M, 50 mu M and 100 mu M) is added, and the cells are placed in an incubator for continuous culture. At 24h after the addition of the drug, the supernatant was aspirated, a serum-free medium containing MTT (0.25mg/ml) was added, the culture was incubated for 4 hours, the culture solution was aspirated, 100. mu.l of DMSO was added and the Formazan crystals were dissolved by shaking, and the absorbance at 490nm was measured for each well to calculate the cell survival rate. The test results are shown in Table-1.
(2) PC12 cytoprotective assay for hydrogen peroxide damage
Selecting PC12 cells in logarithmic growth phase, and selecting 100 mu l of PC12 cells in each well, wherein the cell size is 5-10 multiplied by 104Planting in 96-well culture plate at 37 deg.C under 5% CO2Incubate in incubator for 24 h. The experiment is divided into a normal control group, a positive control group and a drug-adding group. After filtration of the medium, the cell plates were removed, the culture medium carefully aspirated, and the medium changed and dosed. Adding 100 mul of DMEM culture solution into each well of the normal control group; model groups containing 1000 μ MH per well2O2The culture solution of (4) was added to each well of the positive control group in an amount of 100. mu.l, and the positive control group contained 1000. mu. M H per well2O2And 20. mu.M vitamin E in 100. mu.l; the medicine is added into each hole and contains 1000 mu M H2O2And 1, 10, 20. mu.M test compound in 100. mu.l culture medium, applied to PC12 cells for 6 hoursAnd (5) detecting the LDH release rate. Measuring the activity of LDH in the supernatant of the cell culture solution by taking 10 mul of the cell culture solution, then adding 100 mul of 1% Triton X-100 into the discarded culture solution, standing for 10min at 4 ℃, cracking the cells, and measuring the activity of LDH in the cells by taking 10 mul of cell lysate. The determination method of LDH activity is carried out according to the specification method of building an LDH kit by Nanjing, an enzyme-linked immunosorbent assay (OD) value of absorbance of each hole at the wavelength of 490nm is detected by an enzyme-linked immunosorbent assay (ELISA) instrument, each concentration is parallel to 4 holes, and the experiment is repeated for 3 times. The test results are shown in Table-2.
3. Test results
(1) Results of the cytotoxicity test of the compound against PC12
Experimental results show that scutellarin aglycone and serial compounds thereof act on PC12 cells for 24 hours at 1-100 mu M and have small influence on the growth of the PC12 cells. Wherein SC-AG and WX-13, 15, 16, WZ-3, 4, 5, 8-13 have no significant influence on cell growth. (watch-1)
(2) Protective effect of compound on hydrogen peroxide-damaged PC12 cells
The protection effect of scutellarin aglycone and serial compounds thereof on PC12 cells damaged by hydrogen peroxide is evaluated by inspecting the release amount of LDH. The experimental result shows that scutellarin aglycone with the concentration of 1-20 mu M, serial compounds thereof and H2O2Together acting on PC12 cells for 6h, the tested compounds protected peroxide in a non-cytotoxic manner against oxidative damage to PC12 cells. Wherein the effects of SC-AG, WX-3, 4, 7, 9, WZ-1, 3, 11, 12 and 13 are better than that of the positive drug vitamin E. (watch-2)
Claims (9)
1. Scutellarin aglycone derivatives shown in the following structural formulas (I) and (II) and pharmacologically acceptable organic and inorganic salt crystal hydrates and solvates thereof.
Wherein,
r1 is C1-4 hydrocarbyl;
r2 is a nitrogen containing heterocycle;
n is 0, 2, 3.
2. The purine compound according to claim 1, wherein the compound is:
1)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-valine ester
2)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-alanine ester
3)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-leucine ester
4)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-isoleucine ester
5)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-phenylalanine ester
6)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-proline ester
7)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-methionine ester
8)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-valine Ethyl Ether
9)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-leucine Ethyl Ether
10)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-isoleucine Ethyl Ether
11)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-PhenylalanineEthyl Ether
12)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-leucine propyl Ether
13)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-isoleucine propyl Ether
14)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-L-phenylalanine propyl Ether
15)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((diethylamino) methyl) benzoate
16)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((benzylamino) methyl) benzoate
17)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- (Morpholinylmethyl) benzoate
18)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- (pyrrol-1-ylmethyl) benzoate
19)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((4-methylpiperazin-1-yl) methyl) benzoate
20)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((4-piperidin-1-yl) methyl) benzoate
21)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((diethylamino) methyl) benzoic acid propyl ether
22)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((benzylamino) methyl) benzoic acid propyl Ether
23)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- (Morpholinylmethyl) benzoic acid propyl Ether
24)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- ((diethylamino) methyl) benzoic acid Ethyl Ether
25)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- (Morpholinylmethyl) benzoic acid Ethyl Ether
26)5, 6, 7-Trihydroxyl-4-oxo-2- (4-hydroxyphenyl) -4H-1-benzopyran-4- (pyrrol-1-ylmethyl) benzoic acid ethyl ether.
3. A process for the preparation of scutellarin aglycone derivatives according to claim 1, characterized in that said process comprises the steps of:
(1) synthesis of scutellarin aglycone 4' -L-amino acid ester derivatives
Condensing N-Boc-L-amino acid and ketal protected scutellarin aglycone in the presence of N, N-Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) under the reaction condition of tetrahydrofuran solvent to form scutellarin aglycone 4' N-Boc-L-amino acid ester derivative, and passing the obtained product through CH3And (3) carrying out low-temperature reaction on a COCl/MeOH system and simultaneously removing a diphenyl ketal protecting group and an N-Boc (N-tert-butyloxycarbonyl) protecting group to obtain a final target compound:
(2) synthesis of scutellarin aglycone 4' -L-amino acid ether derivative
N-Boc L-amino acid is used as a substrate, the N-Boc L-amino acid is condensed with 2-bromoethanol or 3-bromo-1-propanol under the condition of DMAP/DCC to obtain N-Boc L-amino acid-2-bromoethyl ester or 3-bromopropyl ester, and the obtained compound and ketal-protected scutellarin aglycone are added into cesium carbonate or 4Condensing in the presence of MS to obtain ketal protected scutellarin aglycone 4' -N-Boc-L-amino acid ethyl ether and propyl ether, and passing the obtained product through CH3And (3) carrying out low-temperature reaction on a COCl/MeOH system and simultaneously removing a diphenyl ketal protecting group and an N-Boc (N-tert-butyloxycarbonyl) protecting group to obtain a final target compound:
(3) synthesis of scutellarin aglycone 4' -aminomethyl benzoate derivatives
Condensing p-chloromethylbenzoic acid and substituted amine under the condition of absolute ethyl alcohol, regulating system pH to 3.4 by using concentrated hydrochloric acid to precipitate, extracting the precipitate by using isopropanol, evaporating solvent from isopropanol layer, separating residue by using silica gel column chromatography to obtain substituted amine methylbenzoic acid, reacting obtained product and ketal protected scutellarin aglycone at room temperature under the condition of using tetrahydrofuran as solvent and DMAP/DCC as condensation reagent to obtain ketal protected scutellarin aglycone 4' -substituted aminomethyl benzoate, and then carrying out CH reaction on obtained product3Removing the ketal protecting group by COCl/MeOH system low-temperature reaction to obtain the target compound:
(4) synthesis of scutellarin aglycone 4' -aminomethyl benzoic acid ether derivative
Condensing the obtained substituted aminomethyl benzoic acid with 2-bromoethanol or 3-bromo-1-propanol under DMAP/DCC condition to obtain substituted aminomethyl benzoic acid 2-bromoethyl ester or 3 bromopropyl ester, and reacting the substituted aminomethyl benzoic acid with ketal protected scutellarin aglycone in cesium carbonate or 4
Condensation reaction in the presence of molecular sieve, and then passing through CH3Removing the ketal protecting group by COCl/MeOH system low-temperature reaction to obtain the target compound:
4. the method of claim 3, wherein in step (2) N-t-butyloxycarbonyl-L-amino acid-2-bromoethyl ester and 3-bromopropyl ester and ketal-protected scutellarin aglycone are in cesium carbonate/4
Reacting for 2-24 hours at 40-100 ℃ in the presence of a molecular sieve, wherein the optimal reaction condition is that N-tert-butoxycarbonyl-L-amino acid 3-bromopropyl ester or 2-bromoethyl ester and ketal protected scutellarin aglycone are reacted for 4-10 hours at 60-80 ℃ under the condition that cesium carbonate is used as an acid binding agent and N-methylpyrrolidone is used as a solvent according to the ratio of 1.5-2.0: 1 mol.
5. The method of claim 3, wherein in step (4) 4-substituted aminomethyl benzoic acid-2-bromoethyl ester and 3-bromopropyl ester and ketal protected scutellarin aglycone are in cesium carbonate/4
Reacting for 2-24 hours at 40-100 ℃ in the presence of a molecular sieve, wherein the optimal reaction condition is that 4-substituted aminomethyl benzoic acid 3-bromopropyl ester or 2-bromoethyl ester and ketal protected scutellarin aglycone are reacted for 4-10 hours at 60-80 ℃ under the condition that cesium carbonate is used as an acid binding agent and N-methylpyrrolidone is used as a solvent according to the ratio of 1.5-2.0: 1 mol.
6. The method of claim 3, wherein the solvent used in the deprotection process in steps (1) - (4) is chloroform, dichloromethane, tetrahydrofuran or ethyl acetate, or the reaction is carried out in an acetyl chloride/methanol system at-10-25 ℃ for 0.2-16 hours, preferably in an acetyl chloride/methanol system at 0-25 ℃ for 5-12 hours.
7. A pharmaceutical combination characterized by comprising a therapeutically effective amount of the scutellarin aglycone derivative according to claim 1 and an adjuvant.
8. Use of scutellarin aglycone derivative according to claim 1 in the preparation of a medicament for treating vascular dementia.
9. Use of scutellarin aglycone derivative according to claim 1 in a medicament for treating vascular dementia.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103087024A (en) * | 2013-01-15 | 2013-05-08 | 四川大学 | Flavone alkylamine compounds as well as preparation method and application thereof |
| CN103739642A (en) * | 2013-10-10 | 2014-04-23 | 贵阳医学院 | Carbamate derivates of scutellarin and seutellarein, and application thereof |
| CN118459447A (en) * | 2024-05-10 | 2024-08-09 | 贵州医科大学 | A scutellarin aglycone-7-amino acid carbamate-4'-substituted aminopropyl ether derivative and its preparation and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101337956A (en) * | 2008-08-22 | 2009-01-07 | 四川大学 | Scutellarin aglycone carbamate derivatives, preparation method and use thereof |
| WO2009026166A2 (en) * | 2007-08-17 | 2009-02-26 | Herbalscience Group Llc | Antiinfective flavonol compounds and methods of use thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009026166A2 (en) * | 2007-08-17 | 2009-02-26 | Herbalscience Group Llc | Antiinfective flavonol compounds and methods of use thereof |
| CN101337956A (en) * | 2008-08-22 | 2009-01-07 | 四川大学 | Scutellarin aglycone carbamate derivatives, preparation method and use thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103087024A (en) * | 2013-01-15 | 2013-05-08 | 四川大学 | Flavone alkylamine compounds as well as preparation method and application thereof |
| CN103739642A (en) * | 2013-10-10 | 2014-04-23 | 贵阳医学院 | Carbamate derivates of scutellarin and seutellarein, and application thereof |
| CN118459447A (en) * | 2024-05-10 | 2024-08-09 | 贵州医科大学 | A scutellarin aglycone-7-amino acid carbamate-4'-substituted aminopropyl ether derivative and its preparation and application |
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