- Leonurine derivative and application thereof in preparing medicine for preventing or treating ischemic cerebrovascular diseases
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The invention provides a leonurine derivative and application of the leonurine derivative in preparation of a medicine for preventing or treating ischemic cerebrovascular diseases. The leonurine derivative has a structure as shown in a general formula (I), wherein X is selected from O or NH; Y is selected from any one of natural amino acid, substituted amino acid or amino alcohol; Z is selected from H, proline and any substituted proline. Pharmacological experiments prove that the leonurine derivative provided by the invention has the effects of neuroprotection, cerebral infarction area reduction and animal neurobehavioral scoring, and is good in safety, so that the leonurine derivative has important significance for developing novel medicines for preventing or treating ischemic cerebrovascular diseases.
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Paragraph 0035-0037
(2021/03/30)
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- Novel Stachydrine-Leonurine Conjugate SL06 as a Potent Neuroprotective Agent for Cerebral Ischemic Stroke
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As major active ingredients of the traditional Chinese medicine motherwort, stachydrine and leonurine were found to have protective effects against cerebral ischemia. However, their bioavailability in vivo was low, and their efficacy was unsatisfactory, which limited their further application. To solve these problems, the conjugates based on the structures of stachydrine and leonurine were designed and synthesized. SL06 was found to have neuronal cell survival improvement, neuronal apoptosis restraining, activation of superoxide dismutase (SOD) activity, and inhibition of lactic dehydrogenase (LDH), reactive oxygen species (ROS), malondialdehyde (MDA) in vitro. In vivo, the infarction size was significantly reduced by SL06 in the middle cerebral artery occlusion rat model. SL06 could also activate protein kinase B (AKT)/glycogen synthase kinase 3β (GSK-3β) activity and promoted the expression of antiapoptoticprotein Bcl-2. On the other hand, the expression of the apoptosis-associated protein cleaved caspase-3 would be inhibited as well. Thus, SL06 as the neuroprotective agent has potential for the treatment of cerebral ischemic stroke.
- Hou, Chenhui,Jiang, Qihui,Li, Feng,Li, Wenbao,Pang, Tao,Zhang, Liang,Zhu, Sifeng
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p. 2478 - 2490
(2021/07/21)
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- Design and synthesis of novel SCM-198 analogs as cardioprotective agents: Structure-activity relationship studies and biological evaluations
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SCM-198 (Leonurine) has attracted great attention due to its cardioprotective effects in myocardial infarction (MI). However, no systematic modifications and structure-activity relationship (SAR) studies could be traced so far. In this study, 35 analogs of SCM-198 were designed, synthesized and their cardioprotective effects were evaluated. The cell viability assay on cardiomyocyte cell line H9c2 challenged with H2O2 showed that several analogs exhibited more potent cytoprotective effects than SCM-198 at 1 μM and 10 μM concentrations. LDH release level in cells treated with 1 μM 14o was comparable with cells treated with 10 μM SCM-198. Results of Bcl-2 expression and caspase-3 activation accordingly indicated higher protective activity of 14o than SCM-198. Moreover, in a mouse model of MI, the mice pretreated with 14o had much lower infarct size compared with that of SCM-198. The mechanism study suggested that 14o improved cardiac morphology and reduced apoptosis of cardiomyocytes in the border zone of infarction, as proved by H&E and TUNEL staining.
- Liu, Junkai,Luo, Shanshan,Ma, Fenfen,Xu, Shengtao,Zhu, Yi Zhun
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- Menthyl syringate and preparation method and application thereof
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The invention discloses menthyl syringate and a preparation method and application thereof. The preparation method of menthyl syringate comprises the steps that acetyl syringic acid and L-menthol areused as raw materials to conduct esterification so as to
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Paragraph 0036-0041; 0044-0050; 0053; 0056; 0060-0064
(2019/06/11)
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- Synthetic method for leonurine
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The invention relates to the technical field of organic chemistry, in particular to a synthetic method for leonurine. Gamma-butyrolactone is used as a starting material to be subjected to ammonolysis to obtain gamma-hydroxybutyric acid amide; the gamma-hydroxybutyric acid amide and acetyl syringic acid are subjected to a condensation reaction; a dehydration reaction and a reduction reaction are carried out to obtain leonurus amine; and the leonurus amine and S-methyl isothiourea sulfate are subjected to a reaction to obtain the leonurine. The target product leonurine is synthetized from the cheap industrial raw materials of the gamma-butyrolactone and the syringic acid used as the starting materials through reactions of ammonolysis, esterification, dehydration, reduction and the like. The reaction conditions are mild and easy to control; the yield is up to 65%; the product purity is 98% or above; and the synthetic method for leonutine provides the production with an excellent synthetic route and is suitable for large-scale production.
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Paragraph 0058; 0059
(2017/07/21)
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- Preparation method of leonurine and aspirin conjugate
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The invention belongs to the field of medicinal chemistry, and relates to a synthesizing method of leonurine and aspirin conjugate. The method comprises the steps that syringic acid, S-methylisothiourea and aspirin serve as starting materials, reactions o
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Paragraph 0034-0036
(2017/04/19)
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- Leonurine metabolite and preparation method thereof
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The invention belongs to the field of medicine synthesis, and particularly relates to a leonurine main metabolite and a preparation method thereof. The main metabolite which has a structure shown in the formula (I) (please see the formula in the descripti
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Paragraph 0046; 0047; 0048
(2017/05/02)
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- 1-[1-(BENZOYL)-PYRROLIDINE-2-CARBONYL]-PYRROLIDINE-2-CARBONITRILE DERIVATIVES
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The present invention relates to 1-[1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives having pharmacological activity formula (I) to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy and/or prophylaxis of a cognitive disorder.
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Page/Page column 36; 37
(2014/05/24)
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- 1-[1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
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The present invention relates to 1-[1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives having pharmacological activity to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy and/or prophylaxis of a cognitive disorder.
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Paragraph 0145; 0146
(2014/05/24)
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- Factors influencing the antifolate activity of synthetic tea-derived catechins
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Novel tea catechin derivatives have been synthesized, and a structure-activity study, related to the capacity of these and other polyphenols to bind dihydrofolate reductase (DHFR), has been performed. The data showed an effective binding between all molecules and the free enzyme, and the dissociation constants of the synthetic compounds and of the natural analogues were on the same order. Polyphenols with a catechin configuration were better DHFR inhibitors than those with an epicatechin configuration. Antiproliferative activity was also studied in cultured tumour cells, and the data showed that the activity of the novel derivatives was higher in catechin isomers. Derivatives with a hydroxyl group para on the ester-bonded gallate moiety presented a high in vitro binding to DHFR, but exhibited transport problems in cell culture due to ionization at physiologic pHs. The impact of the binding of catechins to serum albumin on their biological activity was also evaluated. The information provided in this study could be important for the design of novel medicinal active compounds derived from tea catechins. The data suggest that changes in their structure to avoid serum albumin interactions and to facilitate plasmatic membrane transport are essential for the intracellular functions of catechins.
- Saez-Ayala, Magali,Fernandez-Perez, Maria Piedad,Chazarra, Soledad,McHedlishvili, Nani,Tarraga-Tomas, Alberto,Rodriguez-Lopez, Jose Neptuno
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p. 8319 - 8341
(2013/08/23)
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- Leonurine-cysteine analog conjugates as a new class of multifunctional anti-myocardial ischemia agent
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The design, synthesis and biological evaluation of novel Leonurine-cysteine analog conjugates 3,5-dimethoxy-4-(2-amino-3-prop-2-ynylsulfanyl-propionyl)- benzoic acid 4-guanidino-butyl ester (1a), 3,5-dimethoxy-4-(2-animo-3- allysulfanyl-propionyl)-benzoic acid 4-guanidino-butyl ester (1b) and 3,5-dimethoxy-4-(3-(2-chlorocarbonyl-ethyldisulfanyl)-propionyl)-benzoic acid 4-guanidino-butyl ester (2) were reported in this paper. We tested their effects on hypoxia-induced neonatal rat ventricular myocytes. Our data showed that all of them had cardioprotective effects. Both of 1a and 1b were able to modulate hydrogen sulfide production, and 1a possessed higher biological activity than 1b and 2, which indicated that there was positive correlation between conjugates and their precursors. Furthermore we illuminated that the cardioprotective mechanism of 1a were related to increase SOD and CAT activity, decrease MDA and ROS level, protect some cell organs and regulate apoptosis-associated genes and proteins expression (bcl-2 and bax) via the caspase-3 pathway in molecular level. These results indicated that 1a had the potential to be a new class of multifunctional anti-myocardial ischemia agent. Most importantly, these results provided us important clues for the further design and modification of this type of Leonurine-cysteine analog conjugates in future.
- Liu, Chunhua,Guo, Wei,Shi, Xueru,Kaium,Gu, Xianfeng,Zhu, Yi Zhun
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experimental part
p. 3996 - 4009
(2011/10/31)
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- Synthesis and biological evaluation of novel leonurine-SPRC conjugate as cardioprotective agents
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The synthesis and biological evaluation of novel leonurine-SPRC conjugate, 3,5-dimethoxy-4-(2-amino-3-prop-2-ynylsulfanyl-propionyl)-benzoic acid 4-guanidino-butyl ester (1) is reported in this Letter. It is designed to improve the pharmacology efficiency by combining leonurine with S-propargyl-l-cysteine (SPRC), a cysteine analog, via a phenolic hydroxyl ester bond, which could be readily hydrolyzed to release bioactive leonurine and SPRC. Pharmacological evaluation has shown that 1 possesses potent cardioprotective effect against hypoxia-induced neonatal rat ventricular myocytes damage at lower molar concentration (10-fold less than leonurine required and 100-fold less than SPRC required). The mechanism is in partial related to improve hydrogen sulfide production, anti-oxidative stress and anti-apoptosis.
- Liu, Chunhua,Gu, Xianfeng,Zhu, Yi Zhun
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scheme or table
p. 6942 - 6946
(2011/02/16)
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- NITROGEN HETEROCYCLE BIARYLS FOR OSTEOPOROSIS AND OTHER DISEASES
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Nitrogen heterocycle biaryls having a carboxylate terminus are useful for treating endometriosis, osteoporosis, restenosis following angioplasty, rheumatoid arthritis, cancer, macular degeneration and obesity. Compounds of formula: (I) are disclosed. A re
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Page/Page column 35-36
(2010/11/25)
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- Nitrogen heterocycle biaryls for osteoporosis and other diseases
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Nitrogen heterocycle biaryls having a carboxylate terminus are useful for treating endometriosis, osteoporosis, restenosis following angioplasty, rheumatoid arthritis, cancer, macular degeneration and obesity. Compounds of formula: are disclosed. A representative example is
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Page/Page column 12-13
(2010/02/14)
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- Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them
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The invention relates to new derivatives of 2-(iminomethyl)amino-phenyl which are NO synthase inhibitors and can trap reactive oxygen species. These compounds can notably be used for the treatment of stroke, of neurodegenerative diseases and of ischemic or hemorragic cardiac or cerebral infarctions. These compounds include: N-{4-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide; N-{3-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide; N-(4-{[{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}(methyl)amino]methyl}phenyl)thiophene-2-carboximidamide; N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide; N-(3-{[(3,5-di-tert-butyl-4-hydroxybenzyl)amino]methyl}phenyl)thiophene-2-carboximidamide; N-[3-({[2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide; N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide; N-(3-{[(4-hydroxy-3,5-diisopropylbenzyl)amino]methyl}phenyl) thiophene-2-carboximidamide; N-[3-({[2-(4-hydroxy-3,5-diisopropylphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide; N-2-(3,5-di-tert-butyl-4-hydroxybenzoyl)-N-1-(4-{[imino(thien-2-yl)methyl]amino}phenyl)-L-leucinamide; and pharmaceutically acceptable salts thereof.
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- Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them
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A compound selected from the group consisting of a compound of the formula wherein A is selected from the group consisting of and the other substituents are defined in the specification having an inhibitory activity of NO-synthase enzymes producing nitrogen mono-oxide and/or an activity which traps the reactive oxygen species.
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Page column 61-62
(2008/06/13)
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- 2-(iminomethyl) amino-phenyl derivatives, preparation, application as medicines and pharmaceutical compositions containing same
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A compound of the formula wherein the substituents are defined as in the specification and their pharmaceutically acceptable salts having NOS and ROS activity.
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Page column 22-23
(2008/06/13)
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- Pyrrolobenzodiazepines
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Compounds of the formulae Ia and Ib: wherein:A is CH2, or a single bond;R2 is selected from: R, OH, OR, CO2H, CO2R, COH, COR, SO2R, CN;R6, R7 and R9 are independently selected from H, R, OH, OR, halo, amino, NHR, nitro, Me3Sn;and R8 is selected from H, R, OH, OR, halo, amino, NHR, nitro, Me3Sn, where R is as defined above, or the compound is a dimer with each monomer being the same or different and being of formula Ia or Ib, where the R8 groups of the monomers form together a bridge having the formula -X-R'-X- linking the monomers, where R' is an alkylene chain containing from 3 to 12 carbon atoms, which chain may be interrupted by one or more hetero-atoms and/or aromatic rings and may contain one or more carbon-carbon double or triple bonds, and each X is independently selected from O, S, or N; except that in a compound of formula Ia when A is a single bond, then R2 is not CH=CH(CONH2) or CH=CH(CONMe2). Other related compounds are also disclosed.
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Page 62, 117
(2010/11/29)
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- Synthesis and structure-activity relationship of diarylamide derivatives as selective inhibitors of the proliferation of human coronary artery smooth muscle cells
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A series of diarylamide derivatives were synthesized and evaluated for their inhibitory activities against human coronary artery smooth muscle cells (SMCs) and human coronary artery endothelial cells (ECs). Compound 2w was superior to the lead compound, Tranilast, in terms of the potency of the activity and cell selectivity.
- Gita, Haruhisa,Sobe, Yoshiaki,Akaku, Haruo,Ekine, Rena,Oto, Yuso,Isawa, Satoru,Hayashi, Hideya
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p. 549 - 551
(2007/10/03)
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- N-ACRYLOYLPIPERAZINE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS PAF ANTAGONISTS
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Compounds of formula (I): STR1 wherein R 1 and R 2 is each--R 5,--CH=CH--R 5 or--C C--R 5, wherein R. sup.5 is optionally substituted aryl or aromatic heterocyclic; R 3 is hydrogen, alkyl, cyano or--R 5 ; X is oxygen or sulfur; A is 1,4-piperazin-1, 4-diyl or a 1,4-homopiperazin-1,4-diyl; B' is alkylene, carbonyl, thiocarbonyl, sulfinyl or sulfonyl; and R 4 is optionally substituted phenyl and pharmaceutically acceptable salts thereof have valuable PAF antagonist activity, and may be prepared by reacting a compound containing the piperazine or homopiperazine part of the molecular with a compound containing the other part of the molecule.
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- Synthesis of aryl glycosides as vir gene inducers of Agrobacterium tumefaciens
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Aryl β-glycopyranosides have been synthesized by coupling syringaldehyde (3-methoxyvanillin) with L-fucose, D-galactose, and maltose; acetosyringone (4-hydroxy-3,5-dimethoxyacetophenone) with L-fucose and maltose; acetovanillone (4-hydroxy-3-methoxyacetophenone) with L-fucose; and syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid) with D-galactose. The procedure using peracetylated glycosyl halides and sodium phenolates in aqueous acetone afforded the acetylated β-glycosides, which were deacetylated. Aryl β-glycopyranosides have been synthesized by coupling syringaldehyde (3-methoxyvanillin) with L-fucose, D-galactose, and maltose; acetosyringone (4-hydroxy-3,5-dimethoxyacetophenone) with L-fucose and maltose; acetovanillone (4-hydroxy-3-methoxyacetophenone) with L-fucose; and syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid) with D-galactose. The procedure using peracetylated glycosyl halides and sodium phenolates in aqueous acetone afforded the acetylated β-glycosides, which were deacetylated.
- Delay,Cizeau,Delmotte
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p. 179 - 188
(2007/10/02)
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- NEW SYNTHESES OF PLANT ARYL GLYCOSIDES AS POTENTIAL GENE INDUCERS
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Aryl β-D-glycopyranosides have been synthesized by coupling acetovanillone (4-hydroxy-3-methoxyacetophenone) with D-glucose, D-galactose, and maltose; acetosyringone (4-hydroxy-3,5-dimethoxyacetophenone) with D-glucose and D-galactose; syringaldehyde (3-methoxyvanillin) with D-glucose; and syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid) with D-glucose.The Mauthner's procedure using peracetylated glycosyl bromides and phenolates in aqueous acetone afforded the acetylated β-D-glycosides, which were deacetylated.
- Delay, Didier,Delmotte, Francis
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p. 223 - 234
(2007/10/02)
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- Synthesis and pharmacological properties of a phthalide derivative containing methoxy groups.
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4,6-Dimethoxy-5-hydroxyphthalide 2 was obtained on three routes: by selective demethylation of 4,5,6-trimethoxyphthalide and by the action of formaldehyde on either syringic acid or acetylsyringic acid. Pharmacological tests carried out on rats showed that the product significantly increased bile excretion, its activity being five times higher than those of dehydrocholic acid.
- Borkowski,Kolodynska,Naciazek-Wieniawska,Wieniawski
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p. 243 - 251,245, 246
(2007/10/14)
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