Functional group metabolism of dopamine-2 agonists: conversion of 4-(2-di-n-propylaminoethyl)-2-(3H)-indolone to 4-(2-di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone

In the previous report, we reported the results of absorption, protein binding, and pharmacokinetics of the dopamine-2 agonists (D2-agonists) 4-(2-di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone, N-(2'-hydroxy-5'-[N,N-di-n-propylaminoethylphenyl])methanesulfonamide, and 4-(di-n-propylaminoethyl)-2-(3H)-indolone. Both phenolic compounds, 1 and 2, were subject to more rapid metabolism than the nonphenol 3. In the present study, we investigated the metabolic basis of the differences in the pharmacokinetics of these compounds. In both rats and dogs, the principal urinary metabolite of 1 and 2 was the corresponding glucuronide. In contrast, 3 was first converted to 1 which then was converted to a glucuronide. On the basis of the urinary excretion of 1 and its glucuronide after intravenous administration of 1 and 3, approximately 78% of the dose of 3 in rats and 58% in dogs was converted to 1. The depropyl analogue of 3 was identified as a minor urinary metabolite. 4-(2-Di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone was found in the plasma of rats, dogs, and cynomolgus monkeys treated with 3. The concentration of 1 declined in parallel with that of 3 in dogs and monkeys, indicating that the true half-life of 1 is shorter than or equal to that of 3. On the basis of plasma concentrations of 1 in dogs, the apparent conversion of 3 to 1 was 9%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis and antimicrobial activity of some 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-(4-substituted phenyl)-4-bromo-2-pyrazolines and 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-(4-substituted phenyl)-2-pyrazolin-4-ones

A series of 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-(4-substituted phenyl)-2-pyrazolin-4-ones (4a-e) have been synthesized by the oxidation of 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-(4-substituted phenyl)-4-bromo-2-pyrazolines (3a-e) with dimethylsulfoxide. The structure has been established on the basis of spectral data (IR,1H NMR). The synthesized compounds have been screened in vitro for their possible antimicrobial activity.     

2-(4-氯-3-甲基苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮的合成

对硝基邻甲苯胺经重氮化、氯代、还原、闭环、水解、脱羧6步反应得到2-（4-氯-3-甲基苯基）-1,2,4-三嗪-3,5（2H,4H）-二酮,总收率约40%。     

4-(3-coumarinyl)-4-thiazolin-2-one benzylidenehydrazones with antituberculosis activity

In this study a new series of 4-(3-coumarinyl)-4-thiazoline-2-one benzylidenehydrazones (3a-v) were synthesized by condensation of 3-(omega-bromoacetyl)coumarins (1a and 1b) with 1-substituted benzylidene-4-substituted thiosemicarbazides (2a-1). Structures of the title compounds were elucidated by elemental analyses and spectrometric data (UV, IR, 1H-NMR and EIMS). These new compounds and some previously reported compounds (1a-d) were evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv. The compounds exhibited varying degrees of inhibition in the in vitro primary screening that was conducted at 12 micrograms/ml against M. tuberculosis H37Rv in BACTEC 12B medium using the BACTEC 460 radiometric system. 1b, 3b, 3e, 3h, 3o and 3p demonstrating activity in the primary screen were re-tested at lower concentrations against M. tuberculosis H37Rv to determine the actual minimum inhibitory concentration (MIC) in CABTEC 460 and Alamar Blue assay (MABA). The most active compound was found to be 1b. The structure-activity relationships of the derivatives were investigated.     

Design and synthesis of novel 3-(4-chlorophenyl)-2-(3-substituted propyl thio) quinazolin-4-(3H)-ones as a new class of H1-antihistaminic agents

A series of novel 3-(4-chlorophenyl)-2-(3-substituted propyl) quinazolin-4-(3H)-ones have been synthesized and tested for their in vivo H1-antihistaminic activity on conscious guinea pigs. All the test compounds have protected the animals from histamine induced bronchospasm significantly. Compound 3-(4-chlorophenyl)-2-(3-(4-methylpiperazin-1-yl) propylthio) quinazolin-4(3H)-one (PC5) emerged as the most active compound (77.53% protection) of the series when compared to the reference standard chlorpheniramine maleate (70.09% protection). Compound PC5 shows negligible sedation (6.16%) compared to chlorpheniramine maleate (29.58%). Therefore, compound PC5 can serve as the lead molecule for further development into a new class of H1-antihistaminic agents.     

Synthesis and pharmacological evaluation of some 3-(2-methylphenyl)-2-substituted amino-quinazolin-4(3H)-ones as analgesic and antiinflammatory agents

A variety of novel 3-(2-methylphenyl)-2-substituted amino-quinazolin-4(3H)-ones were synthesized by reacting the amino group of 2-hydrazino-3-(2-methylphenyl)-quinazolin-4(3H)-one with a variety of aldehydes and ketones. The starting material 2-hydrazino-3-(2-methylphenyl)-quinazolin-4(3H)-one was synthesized from 2-methyl aniline. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. Among these, the compound 2-(1-ethylpropylidene)-hydrazino-3-(2-methylphenyl)-quinazolin-4(3H)-one emerged as the most active compound for analgesic activity, while the compound 2-(1-methylbutylidene)-hydrazino-3-(2-methylphenyl)-quinazolin-4(3H)-one showed most potent anti-inflamma-tory activity of the series and was moderately more potent in its anti-inflammatory activity when compared to the reference standard diclofenac sodium (CAS 15307-86-5). Interestingly, the test compounds showed only mild ulcerogenic potential when compared to acetylsalicylic acid (CAS No: 50-78-2).     

A selective human H(4)-receptor agonist: (-)-2-cyano-1-methyl-3-[(2R,5R)-5- [1H-imidazol-4(5)-yl]tetrahydrofuran-2-y] methylguanidine

A series of 16 compounds related to chiral 4(5)-(5-aminomethyltetrahydrofuran-2-yl)imidazoles (1) have been designed, synthesized, and examined in vitro by radioligand displacement studies and functional assays for both the human H(3)- and H(4)-receptors expressed in SK-N-MC cells. Among them, the (2S,5S)-isomer 1d of amino compounds showed approximately 300-fold higher selectivity at the H(3)-receptor than the H(4)-receptor. On the other hand, (2R,5S)- and (2R,5R)-cyanoguanidines 3b and 3c, in which the amino group of the compounds 1b and 1c was substituted by the cyanoguanidino moiety, bound to the H(4)-receptor with a pEC(50) value of 6.65 and 7.11, respectively, and had >40-fold selectivities over the H(3)-receptor. As such, 3b and 3c are the first selective H(4) receptor agonists.     

Synthesis and antileukemic activity of new 3-(5-methylisoxazol-3-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones

3-(3-Methylisoxazol-5-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones 8a-l and 9a,c-e,h-l were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 6 and 8 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 8a-l and 9a,c-e,h-l were tested in vitro for their antileukemic activity against L-1210 (murine leukemia), K-562 (human chronic myelogenous leukemia) and HL-60 (human leukemia) cell lines showing in some cases good activity.     

Synthesis of 2, 3-disubstituted-Quinazolin-4-(3H)-ones

The present review covers a concise account of the synthesis of bioactive 2, 3-disubstituted-quinazoline-4(3H)-ones and the recent developments in the area of versatile quinazolinones with a special emphasis on new synthetic routes and strategies.     

Synthesis of 2-deoxy-2-[(2,2-difluoro-3-hydroxytetradecanoyl)amino]-3-O- [(R)-3-(tetradecanoyloxy)tetradecanoyl]-D-glucopyranose 4-phosphate

2-Deoxy-2-[(2,2-difluoro-3-hydroxytetradecanoyl)amino]-3-O-[(R)-3- (tetradecanoyloxy)tetradecanoyl]-D-glucopyranose 4-phosphates (9H,L) were synthesized from allyl 2-amino-2-deoxy-4,6-O- isopropylidene-beta-D-glucopyranoside (1), (+/-)-3-[(benzyloxycarbonyl)oxy]-2,2-difluorotetradecanoic acid, and (R)-3- (tetradecanoyloxy)tetradecanoic acid. Both compounds 9H and 9L were more active than GLA-60 for the prostaglandin D2 releasing test on macrophages.     

Synthesis and antimicrobial activity of some new 3–[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2- styrylquinazoline-4(3H)-ones

Several 3-[5-(4-substituted)phenyl-1,3,4-oxadiazole-2-yl]-2-styryl quinazoline-4(3H)-one were synthesized and screened for antibacterial activity against Staphylococcus aureus , Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli and antifungal activity against Aspergillus niger and Fusariumoxysporum by the serial dilution technique. Compounds were prepared by reacting corresponding 2-methtyl quinazolinone and 4-subustituted benzaldehydes in glacial acetic acid. Physicochemical and spectral data were consistent with newly synthesized compounds. The prepared compounds were compared with previously synthesized 2-methyl-3-[5-(4-substituted)phenyl-1,3,4-oxadiazole-2-yl]-quinazoline-4(3H)-ones for antimicrobial activity. The present study revealed that styryl moiety at the second position of 4(3H) quinazolinone marginally increased the biological activity and exhibited better antibacterial than antifungal activities.     

Synthesis and antitubercular activity of 4-(3-coumarinyl)-3-cyclohexyl-4-thiazolin-2-one benzylidenehydrazones

In this study, a new series of 4-(3-coumarinyl)-3-cyclohexyl-4-thiazoline-2-one benzylidene hydrazones (3a-p) were synthesized. Structures of the title compounds were determined by analytical and spectral methods. 3a-p were evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv.     

(S)-5-(氮杂环亚甲基)-3-(3-氟-4-吗啉-4-基-苯基)噁唑烷-2-酮衍生物的合成及抗菌活性

目的研究具有抗菌作用的噁唑烷酮衍生物的构效关系。方法由(S)-[3-(3-氟-4-吗啉-4-基-苯基)噁唑烷-2-酮-5-基]-甲醇甲磺酸酯和仲胺的取代反应合成了7个(S)-5-氮杂环亚甲基-3-(3-氟-4-吗啉-4-基-苯基)噁唑烷-2-酮衍生物,其结构通过1HNMR和元素分析或质谱确证。结果所合成的7个化合物对所测的20株细菌均没有明显的体外抗菌活性。结论用氮杂环亚甲基取代吗啉噁酮的5位乙酰胺甲基降低化合物的抗菌活性。     

Synthesis, Antiviral and Cytotoxic Activities of 2-(2-Phenyl carboxylic acid)-3-Phenylquinazolin -4(3H)-one Derivatives

A series of novel 2,3-disubstitutedquinazolin-4(3H)-ones have been synthesized by condensation of 2-substituted benzo[1,3]oxazine-4-ones and anthranilic acid. Synthesized compounds were evaluated for in vitro antiviral activity against HIV, HSV and vaccinia viruses. 5-Bromo-2-(6-bromo-4-oxo-2-phenyl-4H-quinazolin-3-yl)-benzoic acid (MBR2) exhibited distinct antiviral activity against Herpes simplex and vaccinia viruses.     

Inverse agonist properties of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A) and 1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxyl ic acid phenylamide (CP-272871) for the CB(1) cannabinoid receptor

Two subtypes of cannabinoid receptors are currently recognized, CB(1), found in brain and neuronal cells, and CB(2), found in spleen and immune cells. We have characterized 1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxyl ic acid phenylamide (CP-272871) as a novel aryl pyrazole antagonist for the CB(1) receptor. CP-272871 competed for binding of the cannabinoid agonist (3)H-labeled (-)-3-[2-hydroxy-4-(1, 1-dimethylheptyl)-phenyl]-4-[3-hydroxypropyl]cyclohexan-1-ol ([(3)H]CP-55940) at the CB(1) receptor in rat brain membranes with a K(d) value 20-fold greater than that of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A). CP-272871 also competed for binding with the aminoalkylindole agonist (3)H-labeled (R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]1, 4-benzoxazin-6-yl](1-naphthyl)methanone ([(3)H]WIN-55212-2), as well as the aryl pyrazole antagonist [(3)H]SR141716A. Inverse agonist as well as antagonist properties were observed for both SR141716A and CP-272871 in signal transduction assays in biological preparations in which the CB(1) receptor is endogenously expressed. SR141716A augmented secretin-stimulated cyclic AMP (cAMP) accumulation in intact N18TG2 neuroblastoma cells, and this response was reversed by the agonist desacetyllevonantradol. CP-272871 antagonized desacetyllevonantradol-mediated inhibition of adenylyl cyclase in N18TG2 membranes, and increased adenylyl cyclase activity in the absence of agonist. SR141716A and CP-272871 antagonized desacetyllevonantradol-stimulated (35)S-labeled guanosine-5'-O-(gamma-thio)-triphosphate ([(35)S]GTPgammaS) binding to brain membrane G-proteins, and decreased basal [(35)S]GTPgammaS binding to G-proteins. K(+) enhanced CP-272871 and SR141716A inverse agonist activity compared with Na(+) or NMDG(+) in the assay. These results demonstrated that the aryl pyrazoles SR141716A and CP-272871 behave as antagonists and as inverse agonists in G-protein-mediated signal transduction in preparations of endogenously expressed CB(1) receptors.     

Synthesis and Cytostatic Activity of (E)-Ethyl-2-Amino-5-(3,3-Dimethyl-4-Oxobutyliden)-4-Oxo-1- (2-Phenylaminobenzamido)-4,5-Dihydro-1Hpyrrol-3-Carboxylate

Pharmaceutical Chemistry Journal - Interaction of (Z)-N-(5-tert-butyl)-2-oxofuran-3(2H)-yliden-2-phenylaminobenzohydrazide (I) with cyanoacetic ester in the presence of triethylamine was used to...     

Design and synthesis of 3-(4-chlorophenyl)-2-(2-(4-substituted)-2-oxoethylthio)quinazolin-4(3H)-one as antihistamine agents

A series of novel 3-(4-chlorophenyl)-2-(2-(4-substituted)-2-oxoethylthio)quinazolin-4(3H)-one was synthesized by the reaction of 2-(3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetyl chloride with various amines. The starting material, (3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetyl chloride was synthesized from 4-chloroaniline by a multistep synthesis. All the title compounds were tested for their in vivo H₁-antihistaminic activity on conscious guinea pigs at the dose level of 10 mg/kg using chlorpheniramine maleate as the reference standard. The results of the biological activity indicate that the test compounds protected the animals from histamine-induced bronchospasm significantly. Compound 3-(4-chlorophenyl)-2-(2-(4-methylpiperazin-1-yl)-2-oxoethylthio)quinazolin-4(3H)-one (1) emerged as the most potent compound of the series (71.13 % protection) when compared to the reference standard chlorpheniramine maleate (70.09 % protection). Interestingly, compound A1 shows negligible sedation (12 %) compared to chlorpheniramine maleate (32 %). Therefore, compound A1 can serve as the lead molecule for further development.     

Cardiotonic agents. 3. Synthesis and biological activity of novel 6-(substituted 1H-imidazol-4(5)-yl)-3(2H)-pyridazinones

Several 6-(substituted 1H-imidazol-4(5)-yl)-3(2H)-pyridazinones were synthesized and evaluated for positive inotropic activity. The 1H-imidazol-4-yl regioisomers 4,5-dihydro-6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone (25a) and 6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone (28a) were potent positive inotropic agents. By contrast, the corresponding 1H-imidazol-5-yl regioisomers 25b and 28b were only weak positive inotropic agents. Compounds 25a and 28a were also potent inhibitors of cardiac phosphodiesterase fraction III.     

Synthesis, partition coefficients and antibacterial activity of 3'-phenyl (substituted)-6'-aryl-2' (1H)-cis-3',3'a-dihydrospiro [3-H-indole-3,5'-pyrazolo (3',4'-d)-thiazolo-2-(1H)-ones

Condensation of isatin with primary aryl amines gave a series of Schiff bases (1) which on reaction with thioglycolic acid in 1,4-dioxane afforded the formation of the corresponding 4- thiazolidinones (2). Compound 2 on condensation with substituted benzaldehydes in anhydrous sodium acetate furnished 3-aryl -5'-phenyl (substituted) spiro [3H-indole-3,2'-thiazolidines]-2-(1H), 4'(5'H)-diones (3). The latter (3) on reaction with hydrazine hydrochloride in anhydrous sodium acetate gave 3'-phenyl (substituted) -6'-aryl-2'(1H)-cis-3',3'a-dihydrospiro [3H-indole-3,5'-pyrazolo (3',4'-d)-thiazolo-2-(1H)-ones] (4). The structure has been established on the basis of spectral data. The partition coefficient for n-octanol/water solvent system and in vitro antibacterial activity of the 2'(1H)-cis-3',3'a-dihydrospiro [3H-indole-3,5'-pyrazolo (3',4'-d)-thiazolo-2-(1H)-one] derivatives have been evaluated.     

3-取代-4-（2-甲基环己氧基）-6-苯乙基吡啶酮的路线改进

反式-3-异丙基-4-（2-甲基环己氧基）-6-苯乙基吡啶酮,作为逆转录酶抑制剂,对野生型HIV—1病毒株和突变株均具有非常高效的活性。为了进一步研究该化合物,其原始合成路线应被缩短以提高总收率。我们设计了一条有效的合成策略,以更高的收率得到目标化合物。