1,3-二甲基-6-[2-(对甲苯磺酰氧基)乙基氨基]尿嘧啶的合成

目的:合成盐酸尼非卡兰中间体1,3-二甲基-6-[2-(对甲苯磺酰氧基)乙基氨基]尿嘧啶.方法:以二甲基脲和氰乙酸为原料经3步反应合成目标产物.结果:以氰乙酸计,总收率44.4%.目标产物的光谱数据与文献报道一致.结论:新的合成方法所用原料价廉易得,适合生产.     

Cardiovascular effect of a novel substance, 3-[2-[4-(o-methoxyphenyl)-1-piperazinyl] ethyl]-2,4 (1H, 3H)-quinazolinedione monohydrochloride (SGB 1534)

During the search for a new antihypertensive substance, the author and his co-workers found that SGB 1534 has a potent vasodepressor action. However, its pharmacological properties are not well-known. Therefore, we examined the cardiovascular effect and the site of action of this substance. In anesthetized beagle dogs, SGB 1534 (0.01 micrograms/kg, i.v.) caused a 8% fall in mean systemic blood pressure. It caused a transient increase in aortic blood flow. Heart rate was increased transiently and was decreased thereafter. Systemic vascular resistance was reduced, but Vpm and time constant "T" were little influenced by this substance. The phenylephrine-induced vasopressor effect was eliminated by SGB 1534. In dogs pretreated with propranolol and prazosin, the norepinephrine-induced vasopressor effect was suppressed by yohimbine, but not by SGB 1534. In dogs pretreated with prazosin and yohimbine, isoproterenol-induced increase in heart rate was not influenced by this substance. The results indicate that SGB 1534 is a potent alpha 1-adrenoreceptor blocking substance.     

Synthesis, saludiuretic, and antihypertensive activity of 6,7-disubstituted 1(2H)- and 3,4-dihydro-1(2H)-phthalazinones

The synthesis of the isomeric series 6-chloro-7-sulfamoyl- and 7-chloro-6-sulfamoyl-1(2H)-phthalazinones (1 and 2) and 6-chloro-7-sulfamoyl- and 7-chloro-6-sulfamoyl-3,4-dihydo-1(2H)-phthalazinones (3 and 4), combining structural features characteristic to furosemide and hydralazine, is described, the mechanism of the formation of 1 and 2 is discussed, and their structure-activities relationships are studied. Preliminary screening in the rat shows that series 1 and 3 exhibit diuretic and saluretic activity similar to that of chlorothiazide with, however, Na+/K+ ratios more favorable than chlorothiazide and furosemide. The compounds of series 2 and 4 are practically inactive. All four series show initial antihypertensive activity lower than that of hydralazine. However, compounds 1a, 1c, and 4a show a higher activity at 8 and/or 24 h after administration and thus may offer a unique combination of a "loop" diuresis with direct long-acting peripheral vasodilating effects.     

Isolation, synthesis, and pharmacology of metabolites of 1-(3,4-dichlorobenzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidone

The metabolism of 1-(3,4-dichlorobenzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidone, an antianxiety/antidepressant agent, in dogs is reported. Two metabolites, 3-[1-(3,4-dichlorobenzyl)-1-ureido]propanoic acid and 1-(3,4-dichlorobenzyl)uracil, were isolated, characterized, and synthesized. Neither metabolite was acutely toxic, and they did not exhibit antidepressant or antianxiety/anticonvulsant activity.     

Effect of 5-(Arylmethylidene)-2,4,6-Pyrimidine-2,4,6(1H,3H,5H)-Triones on the Course of Experimental Leprosy Infection

Pharmaceutical Chemistry Journal - The anti-leprosy activity of 5-(phenylmethylidene)- and 5-[(4-chlorophenyl)methylidene]-2,4,6-pyrimidine-2,4,6(1H,3H,5H)-triones was confirmed in in vivo...     

One-pot synthesis of 5-[[Bis(azolylmethylthio)]methylene]pyrimidine-2,4,6-(1H,3H,5H)-triones

A new class of hitherto unknown trisheterocycles, bisoxadiazolyl/bisthiadiazolyl pyrimidinetriones/thioxopyrimidinediones was prepared in a one-pot reaction and their antimicrobial activity was studied.     

Synthesis, antimalarial activity, and structure-activity relationship of 7-(2-phenoxyethoxy)-4(1H)-quinolones

ICI 56,780 (5) displayed causal prophylactic and blood schizonticidal activity (ED50=0.05 mg/kg) in rodent malaria models but produced rapid acquisition of parasitological resistance in P. berghei infected mice. Herein we describe the synthesis of analogues of 5 with EC50 as low as 0.15 nM against multidrug resistant P. falciparum. Optimal activity with low cross-resistance indexes (RI) to atovaquone was achieved by introducing ortho-substituted aryl moieties at the 3-position of the 7-(2-phenoxyethoxy)-4(1H)-quinolone core.     

3-(S)-(-)-(1-氨甲酰基-1,1-二苯甲基)吡咯烷酒石酸盐的制备

以L-苹果酸(2)为原料,经与苄胺缩合、还原、氢解脱苄、磺酰化、烷基化、脱保护基、水解后成盐制得氢溴酸达非那新关键中间体3-(S)-(-)-(1-氨甲酰基-1,1-二苯甲基)吡咯烷酒石酸盐,总收率约22%(以2计).     

Synthesis and antibacterial activity of 4-(1-naphthyl)-6-arylpyrimidin-2-(1H)-ones

A series of new 4-(1-naphthyl)-6-arylpyrimidin-2-(1H)-ones has been synthesized directly from 2-amino-4-(1-naphthyl)-6-arylpyrimidines by nitrosation reaction and also from 1-(1-naphthyl)-3-arylprop-2-en-1-ones in an alcohol solution of urea containing sodium ethoxide. The synthesized compounds were characterized by various spectroscopic methods. All substances showed significant antimicrobial activity in vitro against several standard strains. Published in Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 5, pp. 22–24, May, 2007.     

Alpha(1L)-, but not alpha(1H)-, adrenoceptor antagonist prevents allergic bronchoconstriction in guinea pigs in vivo

alpha-Adrenoceptors have been classified into alpha(1)- and alpha(2)-adrenoceptors. Recently, the alpha(1)-adrenoceptors were divided into two subtypes: alpha(1L) with low affinity and alpha(1H) with high affinity for prazosin. Little is known concerning the role of each subtype of alpha(1)-adrenoceptor in asthma. We investigated the effects of specific antagonists of alpha(1)- and alpha(2)-, alpha(1H)-, alpha(1L)-, and alpha(2)-adrenoceptors, namely moxisylyte, prazosin, 3-[N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy) ethyl]-N-methylaminomethyl]-4-methoxy-2, 5, 6-trimethylphenol hemifumarate (JTH-601), and yohimbine, respectively, on antigen-induced airway reactions in guinea pigs. Fifteen minutes after intravenous administration of moxisylyte (0.01, 0.1 or 1 mg/kg), prazosin (0.01, 0.1, 1 or 10 mg/kg), JTH-601 (1, 3, 6 or 10 mg/kg) or yohimbine (0.1 or 1 mg/kg), passively sensitized and artificially ventilated animals received an aerosolized antigen challenge. Bronchial responsiveness to inhaled methacholine was assessed as the dose of methacholine required to produce a 200% increase in the pressure at the airway opening (PC(200)) in non-sensitized animals. JTH-601 and moxisylyte, but not prazosin or yohimbine, dose dependently inhibited antigen-induced bronchoconstriction. None of the tested drugs altered PC(200). JTH-601 significantly reduced leukotriene C(4) levels in bronchoalveolar lavage fluid obtained 5 min after antigen challenge, but prazosin did not. These results indicate that prevention of antigen-induced bronchoconstriction by blockade of alpha-adrenoceptors is due to the inhibition of mediator release via alpha(1L)-adrenoceptor antagonism.     

Design, synthesis and antihistaminic (H1)activity of some condensed 2-(substituted)arylaminoethylpyrimidin-4(3H)-ones

The synthesis and potential H1 receptor antagonistic activity of two novel series of condensed 2-arylaminoethylpyrimidin-4(3H)-ones (4, 5) and 4-amino-2-arylaminoethyl pyrimidines (6) have been reported. All the novel compounds were found to antagonize histamine in a competitive and reversible manner. When tested on guinea-pig ileum, compounds exhibited H1-antagonistic activity, (pA2 values) in the range of 8.6 to 9.7. Some of the lead compounds were evaluated by an in vivo method and were found to protect the guinea pigs against the histamine induced asphyxic shock at the doses comparable to or lower than those of the standard drugs, cetirizine (CAS 83881-51-0) and terfenadine (CAS 50679-08-8). The pA2 acetylcholine values of some of the lead compounds reflect about 1000-fold selectivity for histamine (H1) receptors. The 4-aminopyrimidines (6) were found to be more selective than their 4-one analogs (4, 5). In the radioligand binding study, one of the lead compounds, 6e, was found to bind reversibly at the histamine H1 receptor with the K1 value of 1.3 mumol/l and IC50 of 3.8 mumol/l. The lead compounds were found to have negligible sedative potential when tested in vivo. An indirect type of molecular modeling approach, using temelastine (CAS 86181-42-2) as the standard ligand, indicates that the potent activity of 4, 5 and 6 may be due to the increased spacer chain length between the pyrimidine nucleus and the side-chain aromatic ring.     

1-(3-氟苯基) -5-甲基-2-(1H)吡啶酮对肝星状细胞的影响

目的探讨吡啶酮类化合物1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮(FMP)抗肝纤维化的机制.方法MTT法观察FMP对肝星状细胞(HSC)增殖的影响,免疫细胞化学观察FMP对HSC Ⅰ、Ⅲ型胶原表达的影响.结果FMP 200、300、400、500、600 μg/mL 在24、48 h 可抑制HSC增殖, 显著强于阳性对照组(P＜0.05).免疫细胞化学显示FMP在 200 μg/mL 可抑制HSCⅠ、Ⅲ型胶原蛋白表达.结论FMP治疗肝纤维化的原理可能与抑制HSC增殖和HSC Ⅰ、Ⅲ型胶原蛋白表达有关.     

含氧叔丁基三唑醇类化合物的合成及其体外抗真菌活性

目的设计合成含氧取代的叔丁基三唑醇类化合物并研究其体外抗真菌活性。方法以一氯频那酮为起始原料经多步反应合成目标化合物,化合物结构经1H-NMR谱、IR谱确证;选择8种真菌为实验菌株,按国际标准抗真菌敏感性实验方法测定体外抑菌活性。结果与结论合成了12个新化合物。所有目标化合物对8种真菌均具有一定的抑制作用。可以将现有的三唑醇类抗真菌药物结构中的2,4-二氟苯基替换成其他疏水性基团来设计抗真菌化合物。     

Pharmacology of 1-(3,4-dichlorobenzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidone, a novel antidepressant compound with antianxiety activity

1-(3,4-dichlorobenzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidone (I) was evaluated in selected pharmacological tests, and its activity was compared to that of some clinically useful psychotropic drugs. Based on the results, it is evident that I has a unique profile of antidepressant and antianxiety activities that are evident in the same dose range. The mechanism of its antidepressant activity is proposed to be similar to the tricyclic antidepressants, that is, inhibition of norepinephrine uptake. Neither I nor the tricyclic antidepressants possess monoamine oxidase-inhibiting activity. However, unlike the tricyclic antidepressants, I is devoid of any significant anticholinergic activity and presumably is free of anticholinergic side effects.     

H1- and H2-receptor sensitivity to 3-(beta-aminoethyl)-1,2,4-triazole derivatives]

Histamine-like derivatives of 3-(beta-aminoethyl)-1,2,4-trizole were synthetized and subjected to a pharmacological study. The sensitivity of H1- and H2-receptors to these substances was defined by the following tests, viz. in the isolated uterus of a rat, on the isolated atrium of a guinea pig and measurements of the blood pressure nn a cat. The derivative 3-(beta-aminoethyl)-5-amino-1,2,4-triazole (IEM-813) affects predominantly H1-receptors, while 3-(aminoethyl)-5-amino-1,2,4,triazole (IEM-759) has the closest affinity for H2-receptors, The authors presume that corresponding zones of histamine recpetors differ in their lyophilic and hydrophilic properties.