吡唑并[1，5-α]嘧啶类化合物的合成及其抗肿瘤活性

目的设计合成新的吡唑并[1,5-a]嘧啶类化合物,并评价其抗肿瘤活性。方法根据吡唑并[1,5-a]嘧啶类抗肿瘤药物的基本结构设计了一系列5-胺甲基-7-苯胺基吡唑并[1,5-a]嘧啶类化合物,并以丙二腈和原甲酸三乙酯为起始原料,经5步反应得到目标产物。采用MTT法,以顺铂为阳性对照药,以Bel-7402和HT-1080为测试细胞株对目标化合物的抗肿瘤活性进行评价。结果与结论合成了11个未见文献报道的化合物,结构经质谱和核磁共振氢谱确证。化合物6显示出很好的抗肿瘤活性。     

Synthesis and anti-tumor activities of novel pyrazolo[1,5-a]pyrimidines

A series of novel pyrazolo[1,5-a]pyrimidines were designed and synthesized in order to find novel potent anti-tumor compounds. The structures of all the compounds were confirmed by IR, (1)H-NMR, elemental analysis, and MS. Their anti-tumor activities against cancer cell lines were tested by the MTT method in vitro. Compound 19 displayed potent anti-tumor activity.     

[1,2,4]三氮唑并[1,5-a]嘧啶类化合物的合成及其抗肿瘤活性

目的寻找具有抗肿瘤活性的新化合物,设计合成[1,2,4]三氮唑并[1,5-a]嘧啶衍生物,并评价其体外抗肿瘤活性。方法以γ-丁内酯为起始原料,经环合、氯代、取代、硫醚化和氨甲基化等反应合成7-苯基氨基-2-[3-(5-取代氨基甲基-呋喃-2-基-甲硫基)丙基]-5-甲基-[1,2,4]三氮唑并[1,5-a]嘧啶类化合物。采用MTT法,以顺铂为阳性对照药,以Bel-7402和HT-1080为测试细胞株对目标化合物的抗肿瘤活性进行了评价。结果与结论合成了12个未见文献报道的新化合物,结构经质谱、红外光谱和核磁共振氢谱确证。体外活性实验表明:化合物16显示出很好的抗肿瘤活性。     

5,7-二取代吡唑并[1,5-a]嘧啶类化合物的合成及其抗肿瘤活性

目的设计并合成吡唑并[1,5-a]嘧啶类化合物,并评价其抗肿瘤活性。方法根据吡唑并[1,5-a]嘧啶类抗肿瘤药物的基本结构,设计了14个5-胺甲基-7-苯胺基吡唑并[1,5-a]嘧啶类化合物,并以丙二腈和原甲酸三乙酯为起始原料,经5步反应得到目标产物。采用MTT法,顺铂为阳性对照药,以Bel-7402和HT-1080为测试细胞株对目标化合物进行抗肿瘤活性评价。结果与结论合成了14个未见文献报道的新化合物,结构经MS、IR和1H-NMR确证。体外活性实验表明:化合物12显示出较好的抗癌活性。     

Pharmacological activity of some pyrazolo[1,5-a]pyrimidines.

The paper reports the pharmacological activity in vitro and in vivo of a series of pyrazolo[1,5-a]pyrimidine derivatives. Some of these compounds have proved to be active in decreasing the body temperature. They are also very active inhibitors of the guinea-pig lung prostaglandin-sintetase.     

7-Aminopyrazolo[1,5-a]pyrimidines as potent multitargeted receptor tyrosine kinase inhibitors

7-Aminopyrazolo[1,5- a]pyrimidine urea receptor tyrosine kinase inhibitors have been discovered. Investigation of structure-activity relationships of the pyrazolo[1,5- a]pyrimidine nucleus led to a series of 6-(4- N, N'-diphenyl)ureas that potently inhibited a panel of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases. Several of these compounds, such as 34a, are potent inhibitors of kinase insert domain-containing receptor tyrosine kinase (KDR) both enzymatically (<10 nM) and cellularly (<10 nM). In addition, compound 34a possesses a favorable pharmacokinetic profile and demonstrates efficacy in the estradiol-induced murine uterine edema (UE) model (ED 50 = 1.4 mg/kg).     

Synthesis of 2,8-disubstituted imidazo[1,5-a]pyrimidines with potent antitumor activity

Seventeen 1,2,3,4-tetrahydroimidazo[1,5-a]pyrimidine derivatives bearing electron-withdrawing substituents were designed and synthesized by novel ring closure as potential antitumor agents. They were screened for their activities against mouse leukemia L1210 and human oral epidermoid carcinoma KB cell lines, and relationships of structure and antitumor activity in vitro are discussed. It was found that 8-thiocarbamoyl-1,2,3,4-tetrahydroimidazo[1, 5-a]pyrimidin-2(1H)-thione (8c) exhibited activity comparable to that of 5-fluorouracil against both L1210 and KB cells. The existence of both 2-thioxo and 8-substituent with a thioxo group in the molecule is crucial for the cytotoxicity against L1210 and KB cells. A novel procedure for introduction of a double bond between C-3 and C-4 in 8c was developed. Introduction of the 3,4-double bond increased the activity against L1210, but against KB cells the activity decreased by 4-fold. Cytotoxicity of compounds 8c and 8-thiocarbamoyl-1,2-dihydroimidazo[1,5-a]pyrimidin-2(1H)-thione (11c) against human solid tumor and leukemia cell lines was further evaluated. The saturation of the 3,4-double bond led to a significant increase in cytotoxicity against tumor cell lines tested.     

Activated Nitriles in Heterocyclic Chemistry. A Novel Synthesis of Pyridones,Pyrazolo[1,5-a]pyrimidines and Pyrazolo[1,5-b]oxazines

Several new pyridones, pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-b]oxazines were prepared from the cyanoacetohydrazide derivatives 1, 11 and the cinnamonitrile derivatives 2a – c .     

Hexahydroimidazo[1,5-a]pyrazine. I. Synthesis of 7-methyl-1,5,6,7,8a-hexahydroimidazo[1,5-a]pyrazin-3(2H)-one and derivatives]

The synthesis and pharmacological activity of a series of 2-aryl or alkyl substituted 7-methyl-1,5,6,7,8,8a-hexahydroimidaso[1,5-a]pyrazin-3(2H)-ones, are reported. The 2-aryl derivatives (VI) have been prepared by reaction of 3-(arylaminomethyl)-1-methylpiperazines (IV) have been prepared by reaction of 3-(arylaminomethyl)-1-methylpiperazines (IV) with N,N'-carbonyldiimidazole. Reaction of various anilines with 3-carbomethoxy-1-methylpiperazine (II) and subsequent reduction of the amides (III) afforded the bases (IV). The synthesis of the unsubstituted compound (XII) has been accomplished either by cyclization with sodium methoxide of methyl (1-me-thylpiperazin-3-yl)methylcarbamate (XI) or by reaction of 3-aminomethyl-1-methylpiperazine (XV) with N,N'-carbonyldiimidazole. Reduction of 1-benzyl-2-cyano-4-methylpiperazine (VII) followed by reaction with methyl chloroformate and debenzylation afforded the urethane (XI). The 2-alkyl and 2-alkenyl derivatives (XIII) have been prepared by alkylation of the sodium salt of (XII) in DMF. The compounds of these series have been tested for antiinflammatory, coronary dilator and C.N.S. depressant activities.     

Synthesis and antifungal activity of 2-aryl-1,2,4-triazolo[1,5-a]pyridine derivatives

A series of novel antifungal triazole derivatives 2-aryl-1,2,4-triazolo[1,5-a]pyridine 9a-m were synthesized and tested in vitro for their growth inhibitory activities against C. albicans and T. rubrum. The MIC values indicate that the activities of three compounds were superior or comparable to fluconazole against both tested fungi, worthy of further investigation of its antifungal activities.     

Synthesis and antimicrobial activity of certain new 1,2,4-triazolo[1,5-a]pyrimidine derivatives

Certain new derivatives of 1,2,4-triazolo[1,5-a]pyrimidines were synthesized through the reaction of 1,2,4-triazolo[1,5-a]pyrimidine-7-ol with ethyl bromoacetate to afford the ethyl acetate ester, which upon hydrazinolysis gives the corresponding hydrazide. The hydrazide is the key intermediate which was used for the synthesis of the target compounds. The structures of the new compounds were assigned by spectral and elemental methods of analyses. The synthesized compounds were tested for their in vitro antibacterial and antifungal activities. Most of the tested compounds showed comparable results with those of ampicillin and fluconazole reference drugs.     

Pyrimidine Derivatives and Related Compounds,XI: Synthesis of some new Mercaptopyrazolo[1,5-a]pyrimidines and Mercaptopyrazolo[1,5-c]-as-triazines

Several new substituted pyrazolo[1,5-c]-as-triazines and pyrazolo[1,5-a]pyrimidines were synthesised using 5-amino-4-mercapto-3-phenylpyrazole and 5-amino-4-bromo-3-phenylpyrazole as starting materials.     

Synthesis of new 3-(pyridin-6-yl)pyrazolo[1,5-a]pyrimidines

New 3-(pyridin-6-yl)pyrazolo[1,5-a]pyrimidines were synthesized from (pyridin-6-yl)malonodinitrile 5a , ethyl (pyridin-6-yl)cyanoacetate 5b and (pyridin-6-yl)benzoylacetonitrile 5c. Compounds 5a-c were obtained from the 4,4,4-trichlorobut-2-enenitriles 2 and 1-phenylethylidene)malonodinitrile (1) .     

Nitrogen bridgehead compounds. Part 7: Synthesis of anti-atherosclerotic pyrido[1,2-a]pyrimidines

The synthesis of 9-substituted-pyrido[1,2-a]pyrimidines are described. The new compounds exhibit antiatherosclerotic effects. The 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-acetic acid (Chinoin-123) has the most favourable effects.     

Pyrazolo[1,5-a]pyrimidines: receptor binding and anxiolytic behavioral studies

Pyrazolo[1,5-a]pyrimidines (PZP) have been reported to be specific anxiolytic agents which do not potentiate ethanol or barbiturates. To further investigate these compounds, three of the most promising analogs were synthesized and a tritium-labeled analog of one of them prepared by a new synthetic procedure. These analogs did not compete with [3H]flunitrazepam or [3H]beta-carboline ethyl ester binding nor did they potentiate the [3H]flunitrazepam binding. Receptor binding studies with the [3H]PZP revealed a low affinity receptor site, distinct from that of the benzodiazepines, but with only a small fraction (20%) of specific binding. Behavioral tests using three different animal models for anxiety: muricide, approach/avoidance conflict and two-chamber exploration tests gave conflicting results, positive in the first and negative in the latter two. Furthermore, these compounds were found not to be antagonists of diazepam's anticonvulsant activity. Taken together, these results, while provocative, do not support evidence that these analogs are promising specific anxiolytic agents.     

Synthesis and SAR of a new series of COX-2-selective inhibitors: pyrazolo[1,5-a]pyrimidines.

The synthesis and pharmacological activity of a series of bicyclic pyrazolo[1,5-a]pyrimidines as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema and air-pouch model). Modification of the pyrimidine substituents showed that 6,7-disubstitution provided the best activity and led to the identification of 3-(4-fluorophenyl)-6,7-dimethyl-2-(4-methylsulfonylphenyl)pyrazolo[1,5-a]pyrimidine (10f) as one of the most potent and selective COX-2 inhibitor in this series.     

Nitriles in Heterocyclic Synthesis: Synthesis of New Pyrazolo [1,5-a]pyrimidines,Pyrano[2,3-c]pyrazoles and Pyrano[3,4-c] pyrazoles

New pyrazolo[1,5-a]pyrimidines, pyrano[2,3-c]pyrazoles and pyrano[3,4-c]pyrazoles were synthesised by reaction of the α,β-unsaturated nitriles 1, 13 and 16 with 3-amino-2-pyrazolin-5-one (2) , 1-phenylpyrazolidine-3,5-dione (5) , and 5-amino-3-phenylpyrazole (10) .