Synthesis and biological activity of some 3-(4-(substituted)-piperazin-1-yl)cinnolines

A new series of 6-substituted-4-methyl-3-(4-arylpiperazin-1-yl)cinnolines 8-10 were synthesized as potential antifungal agents via intramolecular cyclization of the respective 1-(2-arylhydrazono)-1-(4-arylpiperazin-1-yl)propan-2-ones 5-7, mediated by polyphosphoric acid (PPA). The amidrazones themselves were synthesized via direct interaction of the appropriate hydrazonoyl chlorides 4a-d with the corresponding N-substituted piperazine in the presence of triethylamine. The structures of the new prepared compounds were confirmed by elemental analyses, (1)H-NMR, (13)C-NMR, and ESI-HRMS spectral data. The antitumor, antibacterial, and antifungal activity of the newly synthesized compounds was evaluated.     

Optically active antifungal azoles. XIII. Synthesis of stereoisomers and metabolites of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456)

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone [(1R,2R)-1: TAK-456] is a new antifungal agent selected as a candidate for clinical trials. The three stereoisomers [(1S,2R)-, (1S,2S)- and (1R,2S)-1] of this compound were prepared as authentic samples to determine the enantiomeric and diastereomeric purity of TAK-456 as well as to compare their in vitro antifungal activity. Pharmacokinetic studies of TAK-456 using rats identified the existence of metabolites in the liver homogenate. The structures of the major metabolites were assigned as 4-hydroxy-2-imidazolidinone (3) and/or 5-hydroxy-2-imidazolidinone (4), based on HPLC and LC/MS/MS analyses. These hydroxylated compounds, 3 and 4, were prepared by reduction of the corresponding imidazolidinediones, 11 and 12, and confirmed to be identical to the metabolites by HPLC. In vitro antifungal activities of the three stereoisomers and the synthesized metabolites were considerably weaker than TAK-456.     

Synthesis and antibacterial activity of the metabolites of 9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1H,5H- benzo[i,j]quinolizine-2-carboxylic acid (OPC-7251)

The metabolites of 9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1H,5H- benzo[i,j]quinolizine-2-carboxylic acid (OPC-7251) (1), which has a potent antibacterial activity against gram-positive bacteria, characteristically Propionibacterium acnes, were synthesized to confirm their structures and to examine their antibacterial activity. The structures of three major metabolites (2, 3a and 4) were identified by means of comparison with the synthetic compounds. The antibacterial activity of the metabolites (2, 3a and 4) was found to be lower than that of 1.     

Syntheses of the metabolites of 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1H benzimidazole difumarate (KG-2413) and related compounds

The metabolites of 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1H-b enzimidazole difumarate (KG-2413), which has a potent H1-antihistaminic activity, were predicted on the basis of metabolic studies of related compounds and were synthesized to aid in identification of the actual metabolites and for examination of their antihistaminic activity. Among the twelve compounds prepared, nine compounds were actually found as the metabolites of KG-2413 in rat urine. The antihistaminic activities of these metabolites were found to be lower than that of KG-2413.     

(+)-(1S,7aS)-1-羟基-7a-甲基-茚满-4-烯-5-酮的合成及其烷基化反应研究

以2-甲基-2-(3-丁酮)环戊烷-1,3-二酮为原料,经环合和还原反应合成了手性(+)-(1S,7aS)-1-羟基-7a-甲基-茚满-4-烯-5-酮(3);3在其羟基未进行保护情况下与不同芳香侧链进行α,β-不饱和酮的α-位烷基化反应,制备了5个3的衍生物,其结构经1H NMR确证。     

Synthesis, and antitumor activity of some N1-(coumarin-7-yl) amidrazones and related congeners

A series of new N1-(coumarin-7-yl)amidrazones incorporating N-piperazines and related congeners were synthesized by reacting the hydrazonoyl chloride derived from 7-amino-4-methylcoumarin with the appropriate piperazines. The chemical structures of the newly prepared compounds were supported by elemental analyses, 1H-NMR, 13C-NMR, and ESI-HRMS spectral data. The antitumor activity of the newly synthesized compounds was evaluated. Among all the compounds tested, 7-{2-[1-(4-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)piperazin-1-yl)-2-oxopropylidene]hydrazinyl}-4-methyl-2H-chromen-2-one (3n) was the most potent against MCF-7 and K562 cells, with IC?? values of 20.2 and 9.3 μM, respectively.     

含3-甲基苯基-2,3-二氮杂萘-1-酮结构聚醚酰胺的合成、表征与性能

合成了一种新型芳香二胺双-(4-氨基苯基)-4-(3-甲基-4-苯氧基)-2,3-二氮杂萘-1-酮(1)[2-(4-aminophenyl)-4-(3-methyl-4-phenoxy)-2,3-phthalazinone-1,DAMPP].采用Yamazaki体系,二胺(1)能与多种芳香二酸进行溶液亲核缩聚反应,制得一类新型聚芳醚酰胺,其特性粘度为0.40～0.60dL/g;以MS,FTIR和¹HNMR等分析手段研究了新型二胺单体及其聚合物的结构;利用DSC和TGA研究了聚合物的耐热性能,结果表明,新型聚芳酰胺具有高的玻璃化转变温度为598～620K,N2气气氛中10%热质量损失温度在673K以上.聚合物2a～2c的表面电阻系数为3.75×10¹⁴～9.87×10¹⁵Ω,体积电阻系数为1.39×10¹⁶～4.09×10¹⁶Ω·cm.聚合物在二甲基甲酰胺、1-甲基吡咯烷酮和间甲酚等极性有机溶剂中可溶解,并经浇注得到透明、韧性薄膜.     

微波辐射下合成2-(未)取代苯甲酰胺基-5-(1-苯基-3-甲基-5-氯吡唑- 4-基)-1,3,4-噻二唑衍生物

分别在微波辐射和常规加热条件下, 通过2-氨基-5-(1-苯基-3-甲基-5-氯吡唑-4-基)-1,3,4-噻二唑(1)与(未)取代苯甲酰氯(2a～2j)反应, 合成了一系列未见文献报道的2-(未)取代苯甲酰胺基-5-(1-苯基-3-甲基-5-氯吡唑-4-基)-1,3,4-噻二唑衍生物(3a～3j). 标题化合物的结构经元素分析, IR, 1H NMR确证.     

Total synthesis of (±)-fangchinoline

(±)-Fangchinoline was synthesized by condensation of (±)-1-(3-bromo-4-methoxy-benzyl)-2-methyl-6-methoxy-7-hydroxy-8-bromo-1,2,3,4-tetrahydroisoquinoline ( 2 ) and (±)-1-(4-hydroxy-benzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline ( 3 ) in the presence of copper, pyridine and potassium carbonate.     

Benzylpiperazine derivatives. XI. Synthesis of compounds related to the metabolites of 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride (KB-2796)

The metabolites of 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride (KB-2796, 1), a cerebral vasodilator, and related compounds were synthesized to confirm the proposed structures. The structures of the metabolites (3-5) in rats were identified by means of synthesis of the authentic compounds.     

Synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives. II. Optimization of the phenylpiperazine moiety of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-phenylpiperazinyl-1-trans-propenes

A series of novel 3-substituted-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propenes in order to improve the in vitro and in vivo activity of our prototype 3-[4-(3-chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propene (2) were synthesized and evaluated by assays of growth inhibition against several tumor cell lines in vitro and antitumor activity against some tumor models when dosed both intraperitoneally and orally in vivo. Compounds 7a and 7e, the 3,5-difluorophenyl and 3,5-dichlorophenyl analogues of 2, respectively, showed significantly more potent cytotoxicity than 2 in vitro and potent antitumor activities without causing decrease of body temperature related to side effects.     

查尔酮衍生物E-2-(甲氨基)-7-(3-(吡啶基)丙烯酰基)卓酮的合成(英文)

以2-乙酰基-7-(甲氨基)卓酮(1)为原料,经由与各种吡啶醛的Claisen-Schmidt缩合反应得到查尔酮衍生物E-2-(甲氨基)-7-(3-(吡啶基)丙烯酰基)卓酮(2～5).全部合成产物均为新化合物,未见文献报道;其结构均由红外光谱分析、1H核磁共振、质谱及元素分析得以证实.     

Synthesis and antiulcer activity of the metabolites of 2-(4-ethyl-1-piperazinyl)-4-phenylquinoline dimaleate (AS-2646), a novel gastric antisecretory and antiulcer agent

The metabolites 3 and 4 of 2-(4-ethyl-1-piperazinyl)-4-phenylquinoline dimaleate (AS-2646, 1), a candidate as a gastric antisecretory and antiulcer drug, were synthesized to confirm the proposed structures. The effects of the metabolites 2-4 on ulcer induced by stress were determined.     

Syntheses and Crystal Structures of （S）-Methyl 2-（4-R-phenylsulfonamido）-3-（1H-indol-3-yl）propanoate （R = H （1） and Cl （2））

The title compounds （S）-methyl-2-（4-R-phenylsulfonamido）-3-（1H-indol-3- yl）propanoate （R = H （1）, Cl （2）） have been synthesized and their crystal structures also have been determined by X-ray single-crystal diffraction. Compound 1 （C18H18N2O4S） belongs to orthorhombic, space group P212121 with a = 9.6348（14）, b = 11.1517（17）, c = 16.412（3） A, V = 1763.4（5） A^3, Mr = 358.40, Z = 4, De = 1.350 g/cm^3,/t = 0.209 mm^-1, F（000） = 752, R = 0.0348 and wR = 0.0714. Compound 2 （CI8H17ClN2O4S） crystallizes in orthorhombic, space group P212121 with a = 9.3128（14）, b = 10.9655（16）, c = 17.783（3） A, V = 1815.9（5） A^3, Mr = 392.85, Z = 4, De = 1.437 g/cm^3, p = 0.352 mm^-1, F（000） = 816, R = 0.0389 and wR = 0.0845. The absolute structure Flack parameters X of compounds 1 and 2 are -0.03（8） and -0.06（7）, respectively. X-ray analysis reveals that the crystal structures of these two compounds both involve two intermolecular N-H…O hydrogen bond＇s.     

Synthesis of 2-[3′-(trifluoromethyl)anilino] -5-hydroxynicotinic acid

2-[3′-(Trifluoromethyl)anilino]-5-hydroxynicotinic acid (2) was synthesized by two routes: a) by direct hydroxylation of 2-[3′-(trifluoromethyl)anilino]nicotinie acid (1) ; and b) by the following sequence starting from 2-chloro-3-methyl-5-nitropyridine (3) via 5-amino-2-chloro-3-methylpyridine (4) , 2-ehloro-5-hydroxy-3-methylpyridine (6) , 5-acetoxy-2-chloro-3-methylpyridine (7) , 5-acetoxy-2-chloronicotinie acid (8) , and 2-chloro-5-hydroxynicotinic acid (9). The correlation of 2 with one of the metabolites of 1 has been accomplished, and the identities of both compounds have been proven.     

Synthesis of N-Substituted Derivatives of 2-(4-Amino-2-methyl-1H-indol-3-yl)- and 2-(6-Amino-2-methyl-1H-indol-3-yl)acetic Acids

A method was developed for the production of indole compounds containing an amino group at positions 4 and 6 of the benzene ring on the basis of the indolization of the 3-acetylaminophenylhydrazone of ethyl levulinate. A series of derivatives of 2-(4-amino-2-methyl-1H-indol-3-yl)- and 2-(6-amino-2-methyl-1H-indol-3-yl)acetic acids at the 4- and 6-amino group were synthesized.     

Syntheses of substituted 1-methyl-2-(1,3,4-thiadiazol-2-yl)-4-nitropyrroles and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-4-nitropyrroles

Starting from readily available ethyl-4-nitropyrrole-2-carboxylate ( 1 ), substituted 1-methyl-2-(1,3,4-thiadiazol-2-yl)-4-nitropyrroles and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-4-nitropyrroles were prepared. The reaction of 1 with diazomethane gave ethyl 1-methyl-4-nitropyrrole-2-carboxylate ( 2 ). Reaction of compound 2 with hydrazine hydrate afforded the corresponding hydrazide 3 . The reaction of 3 with formic acid yielded 1-(1-methyl-4-nitropyrrole-2-carboxyl)-2-(formyl)hydrazine ( 7 ). Refluxing of the latter with phosphorus pentasulfide in xylene yielded compound 6 in 40% yield. Reaction of compound 7 with phosphorus pentoxide afforded compound 9 . Reaction of compound 3 with 1,1′-carboxyldiimidazole in the presence of triethylamine yielded 2-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-oxadiazoline-4(H)-5-one ( 11 ). Refluxing compound 3 with cyanogen bromide in methanol gave compound 12 . Compound 13 could be obtained through the reaction of compound 3 with carbon disulfide in basic medium. Alkylation of compound 13 afforded the correspanding alkylthio derivative 14 . Reaction of 1-methyl-4-nitropyrrole-2-carboxylic acid ( 15 ) with thiosemicarbazide and phosphorus oxychloride gave 2-amino-5-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazole ( 16 ). Sandmeyer reaction of compound 16 yielded 2-chloro-5-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazole ( 17 ). Refluxing of the latter with thiourea afforded 2-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazoline-4(H)-5-thione ( 18 ). Alkylation of compound 18 gave the corresponding alkylthio derivative 19 . Oxidation of the latter with hydrogen peroxide in acetic acid yielded 2-(1-methyl-4-nitro-2-pyrrolyl)-5-methylsulfonyl-1,3,4-thiadiazole ( 20 ).     

(E)-1-alkyl-4-

(E)-1-Alkyl-4-[2-(alkylsulfonyl)-1-ethenyl]pyridinium salts were synthesized in two steps. These sulfones were stable at pH 7.3 and underwent a nucleophilic vinylic substitution (S(N)V) with mercaptans, including thiouracile, to give the corresponding 4-(thiovinyl)-pyridinium salts. The X-ray diffraction structure of (E)-1-methyl-4-[2-(ethylsulfanyl)-1-ethenyl]pyridinium iodide indicated conjugation of the sulfur with the pyridinium ring. (Z)-1-Methyl-4-[2-(methylsulfanyl)-1-ethenyl]pyridinium iodide, prepared from the corresponding thioether by reaction with methyl iodide in diethyl ether, underwent isomerization to the E isomer in a first-order reaction in deuterated [D6]DMSO with an activation energy of 14 kcalmol(-1). At pH 7, the (E)-1-methyl-4-[2-(methylsulfonyl)-1-ethenyl]pyridinium iodide (19) reacted specifically with thiols. The reaction of this sulfone with glutathione in a TES buffer at pH 7 was a second-order reaction (k = 4,100 M(-1)s(-1) at 30 degrees C) and gave the corresponding substitution product with an intense long wavelength absorption band (lambdamax=360 nm, epsilon = 27,500 M(-1)cm(-1)). The modification of different enzymes of known structure with 19 showed the high selectivity of this reagent towards thiol groups and its usefulness in the quantitative determination of free thiol groups in proteins.     

Syntheses of 3-[5-Methyl-1-(4-Methylphenyl)-1,2,3-Triazol-4-yl]-6-Substituted-s-Triazolo[3,4-b]-1,3,4-Thiadiazoles

1,2,3-Triazole derivatives have been reported as inhibiting tumor proliferation, invasion, and metastasis^[1]. The fused l,3,4-triazolo[3,4-b]-1,3,4-thiadiazoles derivatives show various biological effects such as antifungal^[2], antibacterial, hypotensive and CNS depressant activities^[3]. We have reported several 6-aryl-3-[5-methyl-1-(4-methylphenyl)-1,2,3-triazol-4-yl]-s-triazolo[3,4-b]-1,3,4-thiadiazoles in the previous paper^[4]. The novel 6-aryl-3-[5-methyl-1-(4-methylphenyl)-1,2,3-triazol-4-yl]-s-triazolo[2,4-b]-1,3,4-thiadiazoles 6a-j have been synthesized by the condensation of 4-amino-5-mercapto-3-[5-methyl-1-(4-methylphenyl)-1,2,3-triazol-4-yl]-s-triazole 5 with various aromatic carboxylic acids in the presence of phosphorus oxychloride. The mercaptotriazole 5 was prepared from 4,the latter being prepared from 1 throng 2 and 3. The title compounds 6 were depicted in scheme 1. The structures of these compounds were established by elemental analysis, NMR, MS and IR techniques.     

2-(1-苯基/取代苯基-3-甲基-5-氯-1H-4-吡唑基)-3-芳酰胺-4-噻唑啉酮的合成及生物活性

利用1-芳基-3-甲基-5-氯-1H-4-吡唑醛(2)分别与取代苯甲酰肼反应, 进一步与巯基乙酸关环, 合成了11个新的2-(1-芳基-3-甲基-5-氯-1H-4-吡唑基)-3-芳酰胺-4-噻唑啉酮类化合物 3a～3k, 并利用元素分析, IR, ¹H NMR和X-ray晶体衍射确定了其结构. 初步生物活性表明: 3e具有杀菌活性, 3e和3k具有除草活性.