(E)-4-芳酰氧基苯基丁烯-3-酮-2衍生物的合成及生物活性

设计合成了 11个 (E) 3 甲氧基 4 芳酰氧基苯基丁烯 3 酮 2衍生物 .其中 10个目标物未见文献报道 .体内药理筛选结果表明 ,部分目标化合物具有不同程度的抗炎活性和抗血小板聚集活性 .     

n-(4-芳酰胺基苯基)甲磺酰胺类化合物的合成及抗炎活性

目的研究n-(4-芳酰胺基苯基)甲磺酰胺类化合物的抗炎作用。方法以对硝基苯胺为起始原料经三步反应合成目标化合物，并以二甲苯致小鼠耳肿胀模型测试目标化合物的抗炎活性。结果共合成11个化合物，经IR，¹HNMR和MS光谱确证结构；初步药理试验结果显示大部分化合物对二甲苯致小鼠耳肿胀具有较强的抑制作用。结论n-(4-芳酰胺基苯基)甲磺酰胺类化合物具有较强的抗炎活性。     

4-甲氧基-1,3-苯二磺酰胺系列化合物的合成及体外抗血小板聚集活性的研究

目的为发现新的抗血小板聚集化合物,参照吡考他胺及其衍生物的构效关系,按照电子等排理论,设计新的4-甲氧基-1,3-苯二磺酰胺类化合物。方法以吡考他胺为先导化合物,通过对其1,3-位两个侧链进行结构改造,进行目标化合物结构设计。以苯甲醚为起始原料,与氯磺酸反应制得中间体4-甲氧基-1,3-苯二磺酰氯,与相应不同取代苯胺进行胺解反应得到目标化合物。目标化合物的结构经~1H-NMR、ESI-MS、IR和~(13)C-NMR谱确证。以吡考他胺和阿司匹林为阳性对照药,以ADP(二磷酸腺苷)为诱导剂,采用Born比浊法进行目标化合物的体外抗血小板聚集活性筛选。结果合成了9个未见报道的4-甲氧基-1,3-苯二磺酰胺类化合物(3a-3i)。在1.30μmol·L~(-1)浓度下,各化合物具有不同的抗血小板聚集活性,其中化合物3d的活性最高。结论侧链引入杂环取代基的化合物活性较高;苯基上连有强吸电子基的化合物的活性较高。     

N~1,N~3-二苯甲基-4-甲氧基-1,3-苯二磺酰胺类化合物的合成及体外抗血小板聚集活性

目的合成作用更强、选择性更好的血小板聚集抑制剂。方法按照前期吡考他胺衍生物的构效关系,设计了新的4-甲氧基-1,3-苯二磺酰胺类化合物,以苯甲醚为原料,通过磺酰化反应和胺解反应制得目标化合物。以吡考他胺(picotamide)、阿司匹林(aspirin)和氯吡格雷(clopidogrel)为阳性对照药物,采用Born比浊法进行体外抗血小板聚集活性初筛,并与具有相同母体结构的7个二取代苯基类化合物进行抗血小板聚集活性评价和比较。结果与结论合成了10个未见文献报道的新化合物,其结构均经13C-NMR、1H-NMR、IR和MS谱确证。在1.3μmol·L~(-1)时,5个化合物(1a、1b、1c、1e、1f)具有抗ADP诱导的家兔体外血小板聚集作用,且优于阳性对照药阿司匹林;化合物1b和1e的抑制活性优于阳性对照药吡考他胺;其中,活性最好的化合物1b的抑制率(62.3%)超过氯吡格雷(55.6%)。两个系列化合物的活性对比表明,新合成的目标化合物中具有抗血小板聚集活性的化合物的数目更多,此类化合物有进一步研究的价值。     

4-甲氧基-N,N′-二(2-取代苯基)-1,3-苯二磺酰胺类化合物的合成及体外抗血小板聚集活性研究

目的 寻找新的抗血小板聚集药物并研究4-甲氧基-N,N′-二(2-取代苯基)- 1,3-苯二磺酰胺类化合物的不同2-位取代苯基对抗血小板聚集活性的影响。方法 以吡考他胺为先导化合物,用取代苯磺酰氨基代替3-吡啶甲氨基对先导化合物进行结构改造：以苯甲醚为原料,采用文献方法与氯磺酸反应直接制得重要中间体4-甲氧基-1,3-苯二磺酰氯;该中间体与2-取代苯胺类化合物经胺解反应制得目标化合物。以吡考他胺和阿司匹林为阳性对照药物,采用Born比浊法对目标化合物进行体外抗血小板聚集活性初筛。结果与结论 共制得12个化合物(4a~4l),其化学结构由IR、1H-NMR和MS光谱确证,其中9个化合物(4a~4c, 4e~4i和4l)未见文献报道。药理试验结果表明,5个化合物表现出较好的体外抗血小板聚集活性：化合物4g、4f和4b的活性优于吡考他胺和阿司匹林;化合物4i的活性略低于阿司匹林;化合物4h的活性与吡考他胺相当。     

2-(E)-亚苄基-5-氨甲基环戊醇类化合物的合成及抗炎活性研究

目的设计合成2-(E)-亚苄基-5-氨甲基环戊醇类化合物,并对其抗炎活性进行初步的评价。方法以环戊酮为起始原料,通过Stork烯胺反应、Mannich反应、选择性还原制备目标化合物;以二甲苯致小鼠耳肿胀模型测试目标化合物的抗炎活性。结果共合成了12个新化合物,经1H-NMR、MS和IR确证结构。初步药理实验结果显示10个目标化合物具有较强的抗炎活性。结论目标化合物稳定性有所提高并且保留了抗炎活性。     

2-（E）-亚苄基-5-芳氨基甲基环戊醇类化合物的合成及其抗炎活性研究

目的设计合成2-（E）-亚苄基-5-芳氨基甲基环戊醇类化合物，并对其抗炎活性进行初步的评价。方法以环戊酮为起始原料，通过Stork烯胺反应、Mannich缩合反应、胺交换反应和选择性还原制备目标化合物；以二甲苯致小鼠耳肿胀模型测试目标化合物的抗炎活性。结果共合成16个新化合物，其结构经^1H-NMR和MS谱确证。结论初步药理实验结果显示，4个目标化合物具有较强的抗炎活性。     

（Ｅ）—4—芳酰氧基丁烯—3—酮—2衍生物的合成及生物活性

设计合成了11个（E）-3-甲氧基-4-芳酰氧基苯基丁烯-3-酮-2衍生物,其中10个目标物未见文献报道,体药理筛选结果表明,部分目标化合物具有不同程度的抗炎活性和抗血小板聚集活性。     

N,N’-二卤代苯基-4-甲氧基-1,3-苯二磺酰胺类化合物的设计、合成及体外抗血小板聚集活性评价

依据药物化学结构设计中拼合和等排原则,拼合抗血小板聚集药物吡考他胺(picotamide)和利曲他班(linotroban)的结构,用磺酰基代替甲酰基,设计合成了N,N’-二卤代苯基-4-甲氧基-1,3-苯二磺酰胺系列化合物(4a~4m、5a~5n),各化合物的结构由IR、1H NMR和HR-MS光谱确证。以吡考他胺为阳性对照药,采用Born比浊法检测目标化合物抗二磷酸腺苷(ADP)诱导的体外抗血小板聚集活性,结果显示其中12个化合物(4b、4f、4l、5b、5d~5g、5j、5k、5m和5n)对ADP诱导的血小板聚集的抑制活性优于阳性对照药吡考他胺。此外,初步探讨了目标化合物的构效关系。     

2-氰基-3,12-二氧代齐墩果烷-1,9(11)-二烯-28-酰胺类化合物的合成与抗乳腺癌活性研究

目的设计合成一系列2-氰基-3,12-二氧代齐墩果烷-1,9(11)-二烯-28-酰胺类化合物,以期寻找活性更好的抗肿瘤化合物。方法以2-氰基-3,12-二氧代齐墩果烷-1,9(11)-二烯-28-羧酸(CDDO)为先导化合物,将CDDO的17位羧基通过连接基团与各种氨基化合物进行偶联制得目标化合物;采用MTT法测试偶联物对乳腺癌MDA-MB-468细胞的增殖抑制活性。结果与结论目标化合物的结构经IR、MS及1H-NMR谱确证,合成的10个化合物对乳腺癌MDA-MB-468细胞显示出不同程度的增殖抑制活性,明显优于先导化合物CDDO,其中,化合物2i、2j的活性最强(IC50值分别为1.12、1.37μmol·L-1)。构效关系研究发现,二胺偶联物的活性最好,氨基酸和正丙醇胺偶联物的活性次之,而芳胺偶联物的活性较弱,化合物2i和2j值得进一步研究。     

Synthesis of beta-hydroxypropanoic acid derivatives as potential anti-inflammatory, analgesic and antimicrobial agents

A series of new 3-(substituted) 3-hydroxy-propanoic acid ethyl esters 1a-c, hydrazides 2a-c, thiosemicarbazides 3a-f, and semicarbazides 3g, 3h has been synthesized. Cyclization of compounds 3a-d in basic medium yielded 1,2,4-triazole-5-thiones 4a-d. On the other hand, reaction of hydrazides 2a-c with CS(2 )in basic medium afforded 1,3,4-oxadiazole-5-thiones 5a-c. All the synthesized compounds were characterized by their physical and spectral analyses data. The newly synthesized compounds were evaluated for their anti-inflammatory, analgesic, and antimicrobial activities. Compounds 1c, 3g, 4a, 4b, 4c, and 5c exhibited comparable anti-inflammatory activity to that of indomethacin and compounds 1c, 4c, and 5c were more analgesics than acetyl salicylic acid. Compounds 4b, 4c, and 5c showed superior GI safety profile (33.3%, 33.3% and 50.0% ulceration) than that of indomethacin (100% ulceration) at 100 mg/kg oral dose. Compounds 4b, 4c, and 5c were also non-toxic with a median lethal dose (LD(50)) up to 200 mg/kg. The antibacterial and antifungal screenings identified compounds 3c, 4b, 4d, 5a, and 5b as the most effective against a variety of tested microorganisms.     

Synthesis and Pharmacological Investigation of 5-Substituted-3-methylsulfanyl-1H-pyrazole-4-carboxylic Acid Ethyl Esters as New Analgesic and Anti-inflammatory Agents

To synthesize a new series of 5-substituted-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl esters for their analgesic and anti-inflammatory activity.The title compound synthesized by reacting the amino group of 5-amino-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester with acid anhydrides, acid chlorides and phenyl dithiocarbamates. The synthesized compounds were characterized by IR, 1H-NMR and mass spectral data; the purity of the compounds was determined by elemental analysis. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic behaviour.The compound 5-benzoylamino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (4c) emerged as the most active compound and exhibiting imperative analgesic and anti-inflammatory activities. Interestingly the test compounds showed only mild ulcerogenic potential when compared to indomethacin.The compound (4c) could serve as a lead molecule for further modification to obtain a clinically useful novel class of analgesic and anti-inflammatory agents.     

Synthesis and anti-inflammatory activities of some thiazolo[3,2-a]pyrimidine derivatives.

Sixteen new 2-benzylidene-7-methyl-3-oxo-5-(substituted phenyl)-2, 3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid methyl esters (1a-4d) have been synthesized by reacting 1,2,3,4-tetrahydropyrimidine-2-thiones (1-4) with chloroacetic acid and appropriate benzaldehydes in a single step. Their structures have been proved by IR, 1H NMR, mass spectra and elemental analysis. The compounds were tested for their anti-inflammatory activities. Test results revealed that compounds 1b, 1c, 4a and 4c exerted moderate anti-inflammatory activity at the 100 mg/kg dose level compared with indomethacin.     

Synthesis and evaluation of analgesic,anti-inflammatory and antimicrobial activities of 6-acyl-3-piperazinomethyl-2-benzoxazolinones

In this study, 16 new 6-difluorobenzoyl-3-piperazinomethyl-2-benzoxazolinones were synthesized by Mannich reaction. Their chemical structures were proven by IR, 1H-NMR and elemental analysis. The compounds were screened for their analgesic and anti-inflammatory activities. A modified Koster test, using acetylsalicylic acid (ASA, CAS 50-78-2) as the reference drug, was used to assess analgesic activity. The anti-inflammatory activity was evaluated by the carrageenan induced hind-paw oedema test. The analgesic activities of all compounds were higher than their anti-inflammatory activities and therefore the prominent analgesic actions of the compounds are thought to be due to a central effect. The microbiological effects of the compounds were evaluated in vitro against various pathogenic fungi and bacteria using the microdilution method. Most of the compounds were found to be inactive against bacteria and fungi. One of the compounds (31) possessed considerable analgesic activity as well as moderate antibacterial activity against S. aureus. Another compound (3m) showed analgesic and antifungal activities comparable to those of ASA and fluconazole (CAS 86386-73-4), respectively.     

天然产物4-O-β-D-葡萄糖-苯并噁唑酮及 4-取代苯并噁唑酮衍生物的合成与活性研究

目的 设计合成天然产物4-O-β-D-葡萄糖-苯并噁唑酮及4-取代苯并噁唑酮类衍生物,并对其抗炎活性、抗乙肝病毒活性进行初步的评价。方法 以2-氨基-间苯二酚为原料,与固体三光气缩合制得4-羟基-苯并噁唑酮,再与溴代糖经过糖苷化反应制得4-取代苯并噁唑酮糖苷类化合物;4-羟基-苯并噁唑酮与酰氯及磺酰氯反应制得4-取代苯并噁唑酮酯类化合物。采用二甲苯致小鼠耳肿胀法测定目标化合物的抗炎活性;采用MTT法测定抗乙肝病毒活性。结果与结论 共合成了10个目标化合物,其中9个化合物未见文献报道,其结构经IR、ESI-MS、¹H-NMR谱确证;活性测试表明,化合物2d、4a、4b具有较好的抗炎活性,化合物2c具有一定的抗乙肝病毒活性。     

Synthesis of some triazolophthalazine derivatives for their anti-inflammatory and antimicrobial activities

Several novel series of triazolophthalazine derivatives namely; pyrazolylethenyltriazolophthalazinones (4a-d), styryltriazolophthalazinones (5a,b), aryloxopropenyltriazolophthalazinones (7a,b), pyrazolinyl- (8a,b), (9a,b) and (10a-f), pyrazolyl- (11a-d), (1,2-oxazol-5-yl)-1,2,4-triazolo[3,4-a]phthalazin-6(5H)-ones (14a,b), triazolo[3,4-a]phthalazin-3-yl-pyridine-3-carbonitriles (12a,b), triazolo[3,4-a]phthalazin-3-yl)ethylthioacetic acids (13a,b) and 2-aryl-5-arylamino-1H,5H-pyrazolo[2″,3″-1',5']imidazo[3',4'-1,5]-1,2,4-triazolo[3,4-a]phthalazin-12(13H)-ones (15a-c) have been synthesized. The anti-inflammatory activity of representative compounds has been studied. Compounds 8b, 10c, 10f, 11b, 12a, 13b, and 15a showed anti-inflammatory activities comparable to that of the reference standard, indomethacin. They exhibit also minimal ulcerogenic effect relevant to the reference standard and were found to be non-toxic up to 120 mg/kg orally or up to 75 mg/kg through parenteral route. Concerning the antimicrobial activity; compounds 12b and 13b were found to be equipotent to ampicillin against Staphylococcus aureus, while compounds 10a and 10f were found to be as potent as ampicillin against E. coli, whereas compound 14b exhibited equipotency to clotrimazole against Candida albicans. Compounds 8b, 10f, 11b, 12a, and 13b exhibited, besides their antimicrobial activity, moderate to potent anti-inflammatory profiles. This represents a fruitful matrix for the development of a new class of dual non-acidic anti-inflammatory/antimicrobial agents.     

2-(E)-(4-甲磺酰基)亚苄基环戊酮Mannich碱类化合物的合成及其抗炎活性

目的设计合成2-(E)-(4-甲磺酰基)亚苄基环戊酮Mannich碱类化合物,并对其抗炎活性进行初步评价.方法以环戊酮、4-甲磺酰基苯甲醛及胺类化合物为原料,经多步反应合成目标化合物,并以二甲苯致小鼠耳肿胀模型测试目标化合物的抗炎活性.结果与结论共合成10个新化合物,经1H-NMR和MS确证其结构.初步药理实验结果显示9个目标化合物均具有一定的抗炎活性.     

Synthesis and analgesic and antiinflammatory activity of methyl 6-substituted-3(2h)-pyridazinone-2-ylacetate derivatives

A series of methyl 6-substituted-3(2H)-pyridazinone-2-ylacetates 9 were synthesized and their analgesic and anti-inflammatory effects were evaluated in the phenylbenzoquinone-induced writhing test (PBQ test) and carrageenan-induced paw edema method, respectively. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with reference nonsteroidal anti-inflammatory drugs. Methyl 6-(4-(4-fluorophenyl)piperazine)-3(2H)-pyridazinone-2-ylacetate 9e was found to be more active than acetylsalicylic acid (ASA). Methyl 6-(4-(2-ethoxyphenyl)piperazine)-3(2H)-pyridazinone-2-ylacetate 9c has shown an anti-inflammatory activity as compared to the standard compound indometacin at the carrageenan-induced paw edema method.A significant dependence of the anti-inflammatory effect on the substituents has been observed. The pharmacological study of these compounds confirms that modification of the chemical group at the position 6 of the 3(2H)-pyridazinone system influences analgesic and anti-inflammatory activities. The structures of these new pyridazinone derivatives were confirmed by their IR and (1)H-NMR spectra and elemental analysis.     

Synthesis of some new 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones and their anti-inflammatory activities.

Sixteen 1-(1-naphthyloxy)acetyl-4-substituted-3-thiosemicarbazides, 2-substituted amino-5-(1-naphthyloxy)methyl-1,3,4-oxadiazoles, 2-substitutedamino-5-(1-naphthyloxy) methyl-1,3,4-thiadiazoles and 3-(1-naphthyloxy)methyl-4-substituted-1,2,4-triazole-5-thiones were synthesized. The structures of the compounds have been elucidated by UV, IR, 1H-NMR, 13C-NMR spectra and elemental analysis. The anti-inflammatory activities of the compounds were evaluated by carregeenan induced hind paw edema and air-pouch inflammation tests in mice. In carrageenan induced hind paw edema test, compounds 1a, 1d, 3d, 4a showed equivalent or higher activity compared to naproxen and phenylbutazone. In the air-pouch inflammatory model, compounds 1a, 1b, 1d, 2c, 3c, 3d, 4a and 4d showed marked anti-inflammatory activity. The ED50 values of these compounds ranged between 24-36 mg/kg. Side effects of the compounds on gastrointestinal system and kidneys were examined and none of the compound showed significant side effects.     

Synthesis and evaluation of the analgesic and anti-inflammatory activity of new 3(2H)-pyridazinone derivatives

A series of 6-substituted-3(2H)-pyridazinone derivatives were synthesized and evaluated for analgesic and anti-inflammatory activities. The structures of these new pyridazinone derivatives were confirmed by their IR, 1H-NMR spectra and elementary analysis. Analgesic and anti-inflammatory activities of the title compounds have been evaluated. Four of the ten tested compounds possessed significant analgesic effects in the phenylbenzoquinone-induced writhing test (PBQ test). The most active derivatives 8a, 8b, 8d, 8e were void of gastric ulcerogenic effect or acute toxicity at the maximal dose (200 mg/kg p.o.). In the carrageenan-induced paw edema model, compound 8d (6- [4- (2-fluorophenyl) piperazin-1-yl]-3(2H)-pyridazinone) showed anti-inflammatory activity similar to that of the standard drug indometacin (CAS 53-86-1). A significant dependence of the anti-inflammatory effect on the substituents was observed; The pharmacological study of these compounds confirms that modification of the chemical group at position 6 of the 3(2H)-pyridazinone ring influences analgesic and anti-inflammatory activities.