3-substituted-1,2-benzisoxazoles: novel antipsychotic agents.

A series of 3-substituted-6-fluoro-1,2-benzisoxazoles (II) was synthesized and evaluated for potential antipsychotic activity. Many of the compounds displayed potent antipsychotic-like activity in the apomorphine induced climbing in mice (CMA) or spiroperidol binding assays, and compound 42 (HRP 392, 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-(2-methoxyphenyl) piperazine) was selected for more detailed antipsychotic evaluation in a battery of preclinical assays. The results of these studies suggests that 42 is a potential antipsychotic drug with less propensity for EPS than some standard neuroleptics in monkeys. The compound was advanced for toxicological evaluation.     

Synthesis and neuroleptic activity of a series of 1-[1-(benzo-1,4-dioxan-2-ylmethyl)-4-piperidinyl]benzim idazolone derivatives

A series of 1-[1-(benzo-1,4-dioxan-2-ylmethyl)-4-piperidinyl]benzimid azolones with various substituents in both aromatic rings have been synthesized and tested for neuroleptic activity (antiapomorphine effects and [3H]spiroperidol binding) as well as extrapyramidal effects (cataleptogenic effect). A strong dependence of activity on the 5-substituent in the benzimidazolone moiety could be demonstrated. Some compounds show a large split between the desired antiapomorphine and the undesired extrapyramidal effect. From these, 1-[1-(benzo-1,4-dioxan-2-ylmethyl)-4-piperidinyl]-5-chlor obenzimidazol-2-one hydrochloride (HR 723), 12, has been selected for further preclinical and toxicological profiling.     

Synthesis and antibacterial activity of 3-substituted-6-(3-ethyl-4-methylanilino)uracils

Numerous 3-substituted-6-(3-ethyl-4-methylanilino)uracils (EMAU) have been synthesized and screened for their capacity to inhibit the replication-specific bacterial DNA polymerase IIIC (pol IIIC) and the growth of Gram+ bacteria in culture. Direct alkylation of 2-methoxy-6-amino-4-pyrimidone produced the N3-substituted derivatives, which were separated from the byproduct 4-alkoxy analogues. The N3-substituted derivatives were heated with a mixture of 3-ethyl-4-methylaniline and its hydrochloride to effect displacement of the 6-amino group and simultaneous demethylation of the 2-methoxy group to yield target compounds in good yields. Certain intermediates, e.g. the 3-(iodoalkyl) compounds, were converted to a variety of (3-substituted-alkyl)-EMAUs by displacement. Most compounds were potent competitive inhibitors of pol IIIC (K(i)s 0.02-0.5 microM), and those with neutral, moderately polar 3-substituents had potent antibacterial activity against Gram+ organisms in culture (MICs 0.125-10 microg/mL). Several compounds protected mice from lethal intraperitoneal (ip) infections with S. aureus (Smith) when given by the ip route. A water soluble derivative, 3-(4-morpholinylbutyl)-EMAU hydrochloride, given subcutaneously, prolonged the life of infected mice in a dose dependent manner.     

(1-(3-(Phenothiazin-10-yl)propyl)-4-piperidinyl)phenylmethanones, a novel class of long-acting neuroleptic agents.

In previous studies the phenyl-4-piperidinylmethanone moiety was shown to be a neuroleptic pharmacophore. A short series of [1-[3-(phenothiazin-10-yl)propyl]-4-piperidinyl]phenylmethanones was prepared and tested for neuroleptic activity using the blockade of d-amphetamine lethality in aggregated mice and suppression of conditioned avoidance behavior as the end points. Most compounds were shown to be potent neuroleptic agents and two were found to possess a long duration of action.     

Synthesis and antihyperlipidemic activity of some novel 4-(substitutedamino)-5-substituted-3-mercapto- (4H)-1,2,4-triazoles

Hyperlipidemia is considered one of the key factors for cardiovascular diseases. Based on earlier work on a series of 5-alkyl-4-aryl-3-mercapto-(4H)-1,2,4-triazoles, for further lead modification, a series of 4-(substituted)amino-5-substituted-3-mercapto-(4H)-1,2,4-triazoles was designed. Target compounds were synthesized by the well known Hoggarth synthesis of substituted 1,2,4-triazoles. Synthesized compounds were screened for lipid lowering activity using the "Poloxamer 407 induced hyperlipidemia in rats" model at a dose of 100 mg/kg p.o. Compounds were found to alter serum lipid levels significantly. Most of the compounds significantly reduced serum cholesterol and triglyceride levels. Some of the compounds were found to reduce triglycerides and elevate high density lipoprotein (HDL) levels more than the standard drug atorvastatin (CAS 134523-03-8). Compounds with chloro substitution on aryl rings were found more active in reducing serum lipid levels than other substitutions.     

Synthesis and anti-inflammatory and analgesic activity of some 3-(1-adamantyl)-4-substituted-5-mercapto-1,2,4-triazoles.

The synthesis of a series of 4,5-disubstituted-3-(1-adamantyl)- 1,2,4-triazoles is described. The compounds 3-(1-adamantyl)4-methyl, ethyl and benzyl-5-mercapto-1,2,4-triazoles (3a, 3b and 3f) produced a high dose-dependent anti-inflammatory activity against carrageenin-induced paw oedema in rats. The analgesic activity of these active compounds correlated with their anti-inflammatory activities.     

Synthesis and antiinflammatory activity of metabolites of 4-(3-dimethylaminopropionyl)-1,2-dimethoxybenzene

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 28, No. 10, pp. 56–58, October, 1994.     

New antihistaminic N-heterocyclic 4-piperidinamines. 1. Synthesis and antihistaminic activity of N-(4-piperidinyl)-1H-benzimidazol-2-amines

The synthesis of a series N-(4-piperidinyl)-1H-benzimidazol-2-amines and the preliminary evaluation of their in vitro and in vivo antihistaminic activity are described. Cyclodesulfurization of (2-aminophenyl)thioureas with mercury(II) oxide resulted in 2-aminobenzimidazole intermediates, which were monoalkylated on the endo-nitrogen atom. After deprotection of the piperidine nitrogen atom with 48% aqueous hydrobromic acid solution, the title compounds were obtained by three different methods, viz. alkylation, reductive amination, or oxirane ring-opening reactions. The in vivo antihistaminic activity was evaluated by the compound 48/80 induced lethality test in rats and histamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. The duration of action, for a selected number of compounds, was studied in the guinea pig. The phenylethyl derivatives showed the most potent antihistamine properties after oral administration in both animal species.     

Psychotropic agents. 3. 4-(4-Substituted piperidinyl)-1-(4-fluorophenyl)-1-butanones with potent neuroleptic activity.

A series of 1-(4-fluorophenyl)-4-(1-piperidinyl)-1-butanones substituted with benzimidazole, benzotriazole, or quinoxaline at the 4 position of the piperidine ring was synthesized and subjected to neuroleptic tests. Neuroleptic activities of several compounds were comparable to those of haloperidol. In particular, 4-[4-(2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone (10) was characterized by having a potent neuroleptic activity with less liability to the extrapyramidal side effect.     

Synthesis and anticonvulsant evaluation of 3-substituted-4-(4-hexyloxyphenyl)-4H-1,2,4-triazoles

A series of 3-substituted-4-(4-hexyloxyphenyl)-4H-1,2,4-triazole derivatives (3a-s) were synthesized as open-chain analogues of 7-hexyloxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines (1c) using 4-hexyloxyaniline, acyl hydrazines, and dimethoxy-N,N-dimethylmethanamine as the starting material. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES test) and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). MES test showed that all open-chain compounds exhibited strong anticonvulsant activity and lower neurotoxicity, and that some possessed obviously stronger activity than compound 1c. Compound 3d, 3-propyl-4-(4-hexyloxyphenyl)-4H-1,2,4-triazole was found to be the most potent with an ED₅₀ value of 5.7 mg/kg and protective index (PI = TD₅₀/ED₅₀) value of 11.5, which was much greater than that of the prototype drug phenytoin (PI = 6.9).     

Synthesis and H1-antihistaminic activity of some novel 1-substituted-4-(3-methylphenyl)-1,2,4-triazolo[4,3-a]quinazolin-5(4H)-ones

A series of novel 1-substituted-4-(3-methylphenyl)-1,2,4-triazolo[4,3-a]quinazolin-5(4H)-ones were synthesized by the cyclization of 2-hydrazino-3-(3-methylphenyl) quinazolin-4(3H)-one with various one carbon donors. The starting material 2-hydrazino-3-(3-methylphenyl)quinazolin-4(3H)-one, was synthesized from 3-methylaniline by a novel innovative route. When tested for their in vivo H(1)-antihistaminic activity on conscious guinea pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly, whereas the compound 1-methyl-4-(3-methylphenyl)-1,2,4-triazolo[4,3-a]quinazolin-5(4H)-one II was found to be equipotent (percent protection 70.0%) with the reference standard chlorpheniramine maleate (percent protection 71%). Compound II show negligible sedation (7%) when compared to chlorpheniramine maleate (25%). Hence it could serve as prototype molecule for further development as a new class of H(1)-antihistamines.     

Synthesis and anticonvulsant activity of novel 1-substituted-1,2-dihydro-pyridazine-3,6-diones

The synthesis and pharmacological evaluation of novel 1-substituted-1,2-dihydro-pyridazine-3,6-diones (4a--l, 5a--j) as potential anticonvulsant agents are described. The compounds were tested in vivo for the anticonvulsant activity. The compound which have maximum protection against MES induced seizures is 1-[3-(2-aminophenylamino)-2-hydroxypropyl)-1,2-dihydro-pyridazine-3,6-dione 4h (ED(50)=44.7 mg x kg(-1) i.p.) 1-[2-hydroxy-3-piperazin1-yl-propyl)-1,2-dihydro-pyridazine-3,6-dione 4c (ED(50)=72 mg x kg(-1) i.p.) and 1-[2-hydroxy-3-imidazol-1-yl-propyl)-1,2-dihydro-pyridazine-3,6-dione 4d (ED(50)=79 mg x kg(-1) i.p.) were also found to have maximum protection against MES induced seizures. Whereas all these compounds failed to protect the animals from subcutaneous pentylenetetrazole (Metrozol) seizure threshold test (sc-Met).     

Synthesis and schistosomicidal activity of 4-methyl-5-(aryl vinyl)-1,2-dithiole-3-thiones

The synthesis of vinylogous of 1,2-dithiole-3-thione is described. The activity in experimental schistosomiasis (schistosomicidal activity) was tested with mice infected with Schistosoma mansoni. The reference compound was 4-methyl-5-(pyrazinyl)-1,2-dithiole-3-thione (oltipraz).     

Antipsychotic properties of new N-(4-substituted-1-piperazinylethyl)- and N-(4-substituted-1-piperidinylethyl)-phthalimides

A series of N-(4-phenyl- and 4-pyridyl-1-piperazinylethyl)- and N-(4-phenyl-1-piperidinylethyl)-phthalmides were synthesized and tested for antipsychotic activity. All compounds suppressed the spontaneous motor activity and the apomorphine-induced climbing in mice and pergolide-induced locomotor activity in rats, demonstrating psychotropic properties equal to the corresponding properties of sulpiride. Although the compounds, like sulpiride, were less potent than haloperidol in blocking the locomotor activities, they caused no catalepsy, a major side effect following treatment with conventional antipsychotic agents. It is likely that the new compounds produce their neuroleptic activities through inhibition of limbic dopamine receptors.     

1—（1H—1，2，4—三唑—1—基）—2—（2，4—二氟苯基）—3—取代—2—丙醇的合成及抗真菌活性研究（Ⅱ）

基于计算机辅助药物设计系统及靶酶模建的需要。根据氮唑类抗真菌药物的构效关系和作用机理。设计合成了15个1-（1H-1,2,4-三唑-1-基）-2-（2,4-二氟苯基）-3-取代-2-丙醇类化合物,均为首次报道。运用微量注偌倍比稀释法对8种常见致病真菌进行外抑菌试验。化合物Ⅳg具有较强的体外抗真菌活性。