Synthesis and anticonvulsant properties of new N-[(4-arylpiperazin-1-yl)-methyl] derivatives of 3-aryl pyrrolidine-2,5-dione and 2-aza-spiro[4.4]nonane-1,3-dione

A series of N-[(4-arylpiperazin-1-yl)-methyl] derivatives of 3-arylpyrrolidine-2,5-dione and 2-aza-spiro[4.4]nonane-1,3-dione were synthesized and tested for anticonvulsant activity in the maximum electroshock seizure (MES) and metrazole seizure threshold (sc.MET) tests. The most potent in the series were N-[[4-(3-chlorophenyl)-piperazin-1-yl]-methyl]-3-(2-chlorophenyl)-pyrrolidine-2,5-dione (ED50=14.18 mg/kg) and N-[[4-(2-methoxyphenyl)-piperazin-1-yl]-methyl]-3-(3-bromophenyl)-pyrrolidine-2,5-dione (ED50=33.64 mg/kg). Structures of the novel compounds were confirmed by elemental and spectral analyses.     

Synthesis, physicochemical and anticonvulsant properties of new N-(pyridine-2-yl) derivatives of 2-azaspiro[4.4]nonane and [4.5]decane-1,3-dione. Part II

A series of N-(pyridine-2-yl) derivatives of 2-azaspiro[4.4]nonane- (1a-e), 2-azaspiro[4.5]decane- (2a-e) and 6-methyl-2-azaspiro[4.5]decane-1,3-dione (3a-e) were synthesized and tested for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. To explain the possible mechanism of action, the most active compounds N-(3-methylpyridine-2-yl)-2-azaspiro[4.4]nonane-1,3-dione (1b), N-(3-methylpyridine-2-yl)-2-azaspiro[4.5]decane-1,3-dione (2b), N-(4-methylpyridine-2-yl)-2-azaspiro[4.5]decane-1,3-dione (2c), and N-(3-methylpyridine-2-yl)-6-methyl-2-azaspiro[4.5]decane-1,3-dione (3b) were tested in vitro for their influence on voltage-sensitive calcium channel receptors, however, they revealed low affinities. For all synthesized compounds the lipophilicity was determined by use of RP-TLC method. The correlation between the lipophilicity and anticonvulsant activity was obtained--the higher the lipophilicity the stronger the anticonvulsant efficacy.     

Synthesis and pharmacological evaluation of new 1-[3-(4-arylpiperazin-1-yl)-2-hydroxypropyl]-pyrrolidin-2-one derivatives with anti-arrhythmic, hypotensive, and alpha-adrenolytic activity

A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment was synthesized and evaluated for the binding affinity of the alpha(1)- and alpha(2)-adrenoceptors (AR) and for the antiarrhythmic and hypotensive activities of the compounds. The most potent and selective compound 1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one 8 binds with pK(i) = 6.71 for alpha(1)-AR. Derivative 8 was also the most active in the prophylactic antiarrhythmic test in adrenaline-induced arrhythmia in anaesthetized rats. Its ED(50 )value equals 1.9 mg/kg (i.v.). Compounds with substituents such as a fluorine atom 4, a methyl 5, or a hydroxyl 8 group, or two substituents such as fluorine/chlorine atoms and methoxy groups in the phenyl ring, significantly decreased the systolic and diastolic pressure in normotensive anesthetized rats at a dosages of 5-10 mg/kg (i.v.). It was found that the presence of the piperazine ring and a hydroxy group in the second position of the propyl chain are critical structural features in determining the affinity of the compounds tested.     

Synthesis, anticonvulsant properties and 5-HT1A/5-HT2A receptor affinity of new N-[(4-arylpiperazin-1-yl)-propyl]-2-aza-spiro[4.4]nonane and [4.5]decane-1,3-dione derivatives

A series of twenty new N-[(4-arylpiperazin-1-yl)-propyl]-2-aza-spiro[4.4]nonane- and [4.5]decane-1,3-dione derivatives were synthesized and their anticonvulsant activity was evaluated in maximal electroshock (MES) and sc pentertazole (sc PTZ) tests. Their neurotoxicity was examined as well. Although no antiseizure properties of the investigated compounds were found in the MES model, eight of them were active in the sc PTZ test and three, namely 2-{3-[4-(2-fluorophenyl)-piperazin-1yl]-propyl}-2-aza-spiro[4.4]nonane-1,3-dione (7), 2-{3-[4-(2-fluorophenyl)-piperazin-1-yl]-propyl}-7-methyl-2-aza-spiro[4.5]-decane-1,3- dione (22) and 2-{3-[4-(3-chlorophenyl)-piperazin-1-yl]-propyl}-7-methyl-2-aza-spiro[4.5]-decane-1,3-dione (23) were classified to the Anticonvulsant Screening Program (ASP) 1 class. In addition, since the investigated compounds belong to a class of long-chain arylpiperazines, their serotonin 5-HT1A and 5-HT2A receptor affinity was determined. All the 2-OCH3 and 3-Cl derivatives were the most potent 5-HT1A receptor ligands (Ki = 24-143 and 70-107 nM, respectively), whereas the highest 5-HT2A affinity was observed for the unsubstituted and 3-Cl derivatives (Ki = 8-66 nM). No correlation between anticonvulsant and serotonergic activity was observed.     

Antibacterial, antifungal and anticonvulsant evaluation of novel newly synthesized 1-[2-(1H-tetrazol-5-yl)ethyl]-1H-benzo[d][1,2,3]triazoles

Several novel 1-[2-(1H-tetrazol-5-yl) ethyl]-1H-benzo[d][1,2,3]triazoles (3a-h) have been synthesized by the condensation of 1-[2-(1H-tetrazol-5-yl)-ethyl]-1H-benzotriazole (2) and appropriate acid chlorides. 1-[2-(1H-tetrazol-5-yl)-ethyl]-1H-benzotriazole (2) was synthesized by reacting 3-(1H-benzo[d][1,2,3]triazol-1-yl)propanenitrile with sodium azide and ammonium chloride in the presence of dimethylformamide. The synthesized compounds were characterized by IR and PMR analysis. The titled compounds were evaluated for their in-vitro antibacterial and antifungal activity by the cup plate method and anticonvulsant activity evaluated by the maximal electroshock induced convulsion method in mice. All synthesized compounds exhibited moderate antibacterial activity against Bacillus subtilis and moderate antifungal activity against Candida albicans. Compounds 5-(2-(1H-benzo[d][1,2,3]triazo-1-yl)ethyl)-1H-tetrazol-1-yl)(4-aminophenyl)methanone 3d and 5-(2-(1 H-benzo[d][1,2,3]triazo-1-yl)ethyl)-1H-tetrazol-1-yl)(2-aminophenyl)methanone 3e elicited excellent anticonvulsant activity.     

Syntheses of stable‐isotope labeled [M+7] and [M+6] 2‐(methylamino)imidazole

Stable isotope‐labeled 2‐methylaminoimidazole (M+7 and M+6) was required as an intermediate in the synthesis of mass labeled drug candidates. These two isotopomers were synthesized with total yields of 24 and 36%, respectively. Labeled 2‐aminoimidazole (M+4) was prepared from labeled isothiourea (M+3) and 2‐aminoacetaldehyde dimethyl acetal (M+1 and M+2). The (M+1) version of 2‐aminoacetaldehyde dimethyl acetal was obtained in two steps starting with potassium [¹⁵N]phthalimide, while the (M+2) version was prepared from the reduction of diethoxyacetamide with LiAlD₄. Two different approaches for the preparation of 2‐methylaminoimidazole from aminoimidazole were explored. Attempts to prepare protected 2‐aminoimidazole to couple with CH₃I (M+4) to form the desired labeled 2‐methyl‐aminoimidazole failed. However, methylation was achieved by applying N‐formamidation followed by deutero‐reduction. These successful syntheses allowed us to selectively label with nitrogen, carbon or hydrogen isotopes at most of the positions of 2‐methylaminoimidazole. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of 2-(4-substitutedbenzyl-[1,4]diazepan-1-yl)-n-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides as inotropic agents

In an attempt to search for more potent positive inotropic agents, a series of N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(substitutedbenzyl-[1,4]diazepan-1-yl)acetamides were synthesized and evaluated for positive inotropic activity by measuring left atrium stroke volume in isolated rabbit heart preparations. Some of these derivatives exhibited favorable activity compared with the standard drug, milrinone, among which 2-(4-(4-methylbenzyl)-[1,4]-diazepan-1-yl)-N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide (6m) was the most potent, increasing stroke volume by 8.38±0.16% (milrinone 2.45± 0.06%) at 3 x 10(-5) m. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work.     

Investigations on the synthesis and pharmacological properties of 4-alkoxy-2-[2-hydroxy-3-(4-aryl-1-piperazinyl)propyl]-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones

Synthesis of 2-[2-hydroxy-3-(4-aryl-1-piperazinyl)propyl] derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones (8-12) is described. The chlorides used in the above synthesis can exist in two isomeric forms: chain (18-20) and cyclic (19a, 20a). The compounds 8-12 exhibited potent analgesic activity which was superior than that of acetylsalicylic acid in two different tests. Most of the investigated imides suppressed significantly spontaneous locomotor activity in mice.     

改进顺-[2-(2,4-二氯苯基)-2-(1H-咪唑基-1-甲基)-1,3-二氧戊环-4-]对甲苯磺酸酯的合成工艺

目的 改进酮康唑的重要中间体顺-[2-(2,4-二氯苯基)-2-(1H-咪唑基-1-甲基)-1,3-二氧戊环-4-]对甲苯磺酸酯的合成工艺.方法 以间二氯苯为原料,经过傅-克酰基化、甘油环合、溴代、苯甲酰化、异构体分离、咪唑烷基化、水解、对甲苯磺酰化等八步反应合成目标产物.结果 合成的目标化合物的熔点和核磁共振氢谱与相关文献一致,总收率为19.1%.结论 改进后的合成工艺条件温和,操作简便,适用于放大制备.     

Synthesis of new 3-(substituted phenacyl)-5-[3'-(4H-4-oxo-1-benzopyran-2-yl)-benzylidene]-2,4-thiazolidinediones and their antimicrobial activity

Synthesis of 3-(3-nitrophenacyl)thiazolidine-2,4-dione 2g and 3-(substituted phenacyl)-5-[3'-(4H-4-oxo-1-benzopyran-2-yl)-benzylidene]-2,4-thiazolidinediones 4a-g are reported in this paper. These compounds 4a-g were prepared from 3'-flavone carboxaldehyde and 3-substituted phenacyl-2,4-thiazolidinediones using Knoevenagel reaction. The structures of all compounds were confirmed by IR, 1H-NMR, mass spectral data, and elemental analyses. The molecules 4a-g were evaluated for in-vitro antimicrobial activity against Staphylococcus aureus, Candida albicans, Candida krusei, Candida glabrata, and Candida parapsilosis. Compounds 4c and 4f showed better inhibitory activity when compared to fluconazole against Candida krusei and Candida glabrata.     

Synthesis and in vitro antibacterial evaluation of novel imidazo[2',1':5,1]-1,2,4-triazolo[4,3-c]-quinazoline derivatives of 5-thioxo-1, 2, 4-triazole, 4-oxothiazolidine, and their open-chain counterparts

Two novel series of imidazo[2', 1':5, 1]-1, 2, 4-triazolo[4, 3-c]quinazolines bearing 5-thioxo-1, 2, 4-triazoles, 6a-f, and 4-oxothiazolidines, 7a-f, were synthesized from corresponding thiosemicarbazide derivatives, 5a-f. The stepwise methodology applied to the preparation of compounds 5a-f was initiated with reaction of the parent 3-amino-1, 2, 4-triazolo[4, 3-c]quinazolines, 2, with ethyl 2-chloroacetoacetate resulting in annelation of the imidazole ring to give esters, 3a-c. However, hydrazinolysis of these ester derivatives gave the corresponding acid hydrazides, 4a-c, which on reaction with the appropriate alkyl isothiocyanate yielded compounds 5a-f. In turn, compounds 5, were cyclized with potassium hydroxide or with ethyl bromoacetate to give the corresponding thioxotriazoles 6 and oxothiazolidines 7, respectively. All synthesized compounds were screened for their in vitro antibacterial activity against various Gram-positive and Gram-negative bacteria. Some test compounds were found to possess potent antibacterial activities. Compound, 7f, exhibited much higher potency than the reference standard ciprofloxacin, against both types of bacteria, particularly, Gram-positive organisms.     

Antileishmanial and antibacterial activity of a new pyrazole derivative designated 4-[2-(1-(ethylamino)-2-methyl- propyl)phenyl]-3-(4-methyphenyl)-1-phenylpyrazole

Here, we report for the first time the synthesis and the antileishmanial activity of a new pyrazole derivative, namely 4-[2-(1-(ethylamino)-2-methylpropyl)phenyl]-3-(4-methyphenyl)-1-phenylpyrazole). Micromolar concentrations of this compound were found to inhibit the in vitro multiplication of Leishmania tropica, Leishmania major, and Leishmania infantum, three species causing different forms of leishmaniasis. Furthermore, the 50% inhibitory concentration (IC50) values for the compound are only slightly higher than those of amphotericin B, one of the most active antileishmanial agents used as a satisfactory substitute in cases not responding to pentostam. The IC50 values after 48 h for L. tropica, L. major, and L. infantum promastigote growth were 0.48 microg/mL, 0.63 microg/mL and 0.40 microg/mL, respectively for the compound, while they were 0.23 microg/mL, 0.29 microg/mL and 0.24 microg/mL, respectively for amphotericin B. We also tested this compound for its antibacterial activity against several bacteria. The strongest antibacterial activity was observed against Entrococcus feacalis and Staphylococcus aureus with a minimal inhibitory concentration (MIC) of 60 microg/mL.     

Synthesis and antimicrobial activity of [2-[2-(N,N-disubstituted thiocarbamoyl-sulfanyl)-acylamino] thiazol-4-yl]acetic acid ethyl esters

[2-[2-(N, N-Disubstituted thiocarbamoyl-sulfanyl)acylamino ]thiazol-4-yl]acetic acid ethyl esters (3a-x) were synthesized by the reaction of potassium salts of N, N-disubstituted dithiocarbamoic acids with [2-(2-chloroalkanoyl)amino-thiazol-4-yl]acetic acid ethyl esters. The structures of the synthesized compounds were confirmed by elemental analyses, UV, IR, (1)H-NMR, and EI mass spectral data. The antimicrobial activities of all the compounds were investigated by microbroth dilution technique using Mueller-Hinton broth and Mueller-Hinton agar. In this study, Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, Escherichia coli ATCC 8739, Klebsiella pneumoniae ATCC 4352, Pseudomonas aeruginosa AT CC 1539, Salmonella typhi, Shigella flexneri, Proteus mirabilis ATCC 14153 and Candida albicans ATCC10231 were used as test microorganisms. Among the tested compounds 3a, d, e, f, h, k, w activity against S. epidermidis ATCC 12228 (MIC: 156 mg/L, 78 mg/L, 62.5 mg/L, 78 mg/L, 62.5 mg/L, 312 mg/L, 250 mg/L, respectively), compound 3d had some activity against S. aureus ATCC 6538 (MIC: 156 mg/L) and C. albicans ATCC 10231(MIC: 156 mg/L). Compounds 3l, 3x also evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric system and BACTEC 12B medium. The preliminary results indicated that all of the tested compounds were inactive against the test organism.     

Synthesis of non-nucleosides: 7- and 1,3-substituents of new pyrrolo[2,3-d]pyrimidin-4-ones on antiviral activity

A series of non-nucleosides 9-47 were synthesized. Compounds 1-4 were reacted with formic acid (85%) to afford compounds 5-8. Then, the latter compounds were reacted with alkyl halides a-f (2-bromopropane, 2-bromobutane, benzyl bromide, benzyl chloromethyl ether, chloromethyl ethyl ether, phenacyl bromide) in the presence of NaH in dry DMF to give the desired compounds 9-47, which were evaluated for activity against herpes simplex virus type-II (HSV-II).     

Synthesis and development of new 2-substituted 1-[3-(4-arylpiperazin-1-yl)propyl]-pyrrolidin-2-one derivatives with antiarrhythmic, hypotensive, and alpha-adrenolytic activity

A series of new 1-[3-(4-arylpiperazinyl-1-yl)-2-(N-alkylcarbamoyloxy)propyl]-pyrrolidin-2-one derivatives (4a-12a) were synthesised and tested for their electrocardiographic, antiarrhythmic and antihypertensive activity, as well as for the alpha1- and alpha2-adrenoceptor binding affinities. Of the newly synthesised derivatives, 1-{2-(N-2-methylethylcarbamoiloxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl)]propyl}pyrrolidin-2-one dihydrochloride (10a) was the most active in prophylactic antiarrhythmic tests, its ED50 value equalling 2.7 mg kg(-1), and the therapeutic index being 75.2; moreover, compound 10a was also found to possess hypotensive activity. A preliminary molecular modelling study suggested that the selected alpha1-AR antagonist distances and angles between pharmacophoric features, estimated for the tested compounds, were in good agreement with the parameters evaluated for ligands.     

Synthesis and effects on the COX-1 and COX-2 activity in human whole blood ex vivo of derivatives containing the [1]benzothienol-[3, 2-d]pyrimidin-4-one heterocyclic system

Methyl and phenyl derivatives containing the [1]Benzothieno [3, 2-d]pyrimidin-4-one system have been synthesized and tested as inhibitors of COX-1 and COX-2 activities in human whole blood (HWB) ex vivo; all compounds turned out to be weak inhibitors of COX-1 activity, as deduced from the TXB(2) (thromboxane B) generation; the acid phenyl derivative 11 b was an interesting inhibitor of COX-2 activity, as deduced from the PGE(2) (prostaglandine E) generation.     

Synthesis of Novel 3‐aryl‐1‐oxa‐2,8‐diazaspiro[4.5]dec‐2‐ene Derivatives and Their Biological Evaluation Against Protein Tyrosine Phosphatase 1B

A series of novel 3‐aryl‐1‐oxa‐2,8‐diazaspiro[4.5]dec‐2‐ene derivatives were designed, synthesized, and evaluated as a new class of inhibitors against protein tyrosine phosphatase 1B. Among them, compound 6f displayed moderate inhibitory activity with IC₅₀ of 2.87 ± 0.24  μ m and can be used as a novel lead compound for the design of inhibitors of protein tyrosine phosphatase 1B.     

Synthesis of deuterium-labeled CCR2 antagonist JNJ-26131300, [4-(1H-indol- 3-yl)-piperidin-1-yl]-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid

Synthesis of multiple deuterium-labeled CCR2 antagonist JNJ-26131300, that is, [4-(1H-indol-3-yl)-piperidin-1-yl]-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid, is described. First, condensation of indole-D₇ with 4-piperidone produced 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-D₅, which subsequently underwent catalytic hydrogenation to give 3-piperidin-4-yl-1H-indole-D₅. Next, bromo-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid was prepared through multiple steps from 3-(3,4,5-trifluoro-phenyl)-acrylic acid and bromo-piperidin-4-yl-acetic acid ethyl ester. Nucleophilic coupling of 3-piperidin-4-yl-1H-indole-D₅ with bromo-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid afforded the desired compound [4-(1H-indol-3-yl)-piperidin-1-yl]-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid-D₅.     

Synthesis and morphine enhancement activity of N-[5-(2-phenoxyphenyl)-1, 3, 4-oxadiazole-2-yl]-N'-phenylurea derivatives

The synthesis of N-[5-(2-phenoxyphenyl)-1, 3, 4-oxadiazole-2-yl]-N'-phenylurea derivatives is reported. The structures of these compounds are supported by their IR, (1)H-NMR and mass spectra. Conformational analysis and superimposition of energy minima conformers of these compounds on L-365, 260, a known 3-ureido-1, 4-benzodiazepine CCK-B antagonist, showed that the aromatic rings fell in the same contour. Morphine analgesia enhancement evaluation of the synthesized compounds in comparison with a control group showed that compounds 8a, 8c, 8h-8j, 8l, 8o have significant effects.