Studies on calcium antagonist activities of 2-ethyl-3-carbmethoxy-4-aryl- 5-oxo-6,6-dimethyl-1,4,5,6,7,8-hexahydroquinoline derivatives.

In this study, 23 new compounds having 2-ethyl-3-carbmethoxy-4-aryl-5-oxo-6,6-dimethyl-1,4,5,6,7, 8-hexahydroquinoline structure have been synthesised and screened for their calcium antagonistic activities. The structure of the compounds were characterised by IR, 1H-NMR, 13C-NMR, mass spectroscopy and elemental analyses. The calcium antagonistic activities of the compounds were determined by the tests performed on isolated rat ileum and lamb carotid artery. Although none of the synthesized compounds were as active as nicardipine in isolated rat ileum, the compounds 9, 10 and 19 have shown high activity. In screening studies on lamb carotid artery, compounds 10, 14 and 19 have been found active at a concentration of 10(-4) mol/l.     

Synthesis and in vitro calcium antagonist activity of 4-aryl-7,7-dimethyl/1,7,7-trimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-dione derivatives

In this study, a series of 4-aryl-7,7-dimethyl and 1,7,7-trimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-diones (1-25) were synthesized by condensing urea or N-methylurea with 5,5-dimethyl-1,3-cyclohexanedione and appropriate aromatic aldehydes according to the Biginelli reaction. The structures of the compounds were confirmed by spectral data and elementary analysis. The calcium antagonist activity of the compounds was tested in vitro on isolated rat ileum and lamb carotid artery. Compounds 16 and 19 were the most active derivatives on isolated rat ileum compared with the standard nicardipine. On isolated aortic strips of lamb the calcium antagonist activity of compound 16 (maximum relaxant effect: 38.83+/-5.84%) was found as high as that of nicardipine (maximum relaxant effect: 35.50+/-4.16%) used as a reference drug.     

Synthesis,evaluation of the calcium antagonistic activity and biotransformation of hexahydroquinoline and furoquinoline derivatives

The objective of this study was to synthesise new condensed 1,4-dihydropyridine derivatives and investigate their calcium channel blocking activity. In addition, the in vitro hepatic microsomal bio-transformation of one hexahydroquinoline derivative was studied, 2,6,6-Trimethyl-3-carbmethoxy (carbethoxy)-4-aryl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives were synthesised bymodified Hantzsch synthesis. 1,3,4,5,6,7,8,9-octahydro-7,7-dimethyl-9-arylfuro [3,4-b]quinoline-1,8-dione derivatives were synthesised the reaction of hexahydroquinoline derivatives with pyridinium bromide perbromide. The calcium antagonistic activities of the compounds were determined by tests performed on isolated rat ileum and lamb carotid artery. In vitro hepatic biotransformation of one compound was studied in rat microsomes. Although compounds 3, 18 and 28 showed promising relaxant activity, they were less active than nicardipine (CAS 55985-32-5) in isolated rat ileum. In all studied concentrations, compounds 5 and 20 were more active than nicardipine in lamb carotid artery. These compounds showed high tissue selectivity compared with nicardipine. In addition, in vitro hepatic microsomal biotransformation of compound 2 produced its lactone derivative (compound 34). This metabolite was verified by HPLC. In the hexahydroquinoline series, the compounds having ortho substituted phenyl substituent were more active than the meta isomers. Lactone derivatives were found less active than hexahydroquinoline derivatives in respect to calcium antagonistic activity.     

Studies on the synthesis and biological activitiy of 6-ethyl-4-aryl-5-methoxycarbonyl-3,4-dihydropyrimidin-2(1H)-ones

6-Ethyl-4-aryl-5-methoxycarbonyl-3,4-dihydropyrimidin-2(1H)-one derivatives (1-10) were synthesized by condensing urea with methyl 3-oxopentanoate and aromatic aldehydes in absol. ethanol using HCl as a catalyst according to the Biginelli reaction. The structures of the compounds were confirmed by spectroscopic and elemental analysis. The calcium channel blocker activities of the compounds were determined by the tests performed on isolated rat ileum and lamb carotid artery. On the isolated rat ileum, compound 2 was found to be more effective at 10(-5) mol/L concentration than nicardipine (CAS 55985-32-5). On the lamb carotid artery compounds 5, 6 and 4, 5, 6 were significantly active at 10(-6) mol/L and 10(-5) mol/L concentrations, respectively.     

Studies on 3-diethylaminocarbonyl-1,4,5,6,7,8-hexahydroquinoline derivatives and their calcium channel antagonistic activities in vitro

In this study, thirteen 2,6,6-trimethyl-3-carbamoyl-4-aryl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives were synthesized and screened for their calcium channel antagonistic actitivities. The hexahydroquinoline derivatives were synthesized according to Hantzsch reaction. The structures of the compounds were elucidated by IR, 1H-NMR, 13C-NMR, Distortionless Enhancement Polarization Transfer (DEPT), Correlation Spectroscopy (COSY), mass spectroscopy and elemental analyses. The calcium antagonistic activities of the compounds were determined by tests performed on isolated rat ileum and lamb carotid artery. In isolated rat ileum, compounds 8, 12 and 13 were found to be more active than nicardipine (CAS 55985-32-5) at a concentration of 10(-5) mol/L. At the concentration 10(-4) mol/L, compounds 7 and 12 were more active than nicardipine and compounds 5, 8 and 13 were equipotent. In lamb carotid artery studies, at the concentration 10(-5) mol/L all compounds were found to be less active than nicardipine; at the concentration 10(-4) mol/L compounds 5 and 13 showed greater inhibition than nicardipine. At this concentration, compound 9 was found to be as active as nicardipine.     

Studies on calcium modulatory activities of 2,6,6-trimethyl-3-acetyl-4-aryl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives.

Twenty-two new 2,6,6-trimethyl-3-acetyl-4-aryl-5-oxo-1,4,5,6,7,8-hexahydroquinoline+ ++ derivatives (compounds 1-22) have been prepared. The structures of the compounds were characterised by IR, 1H-NMR, mass spectroscopy and elemental analyses. The calcium antagonistic activities of the compounds were determined by the tests performed on isolated rabbit ileum and lamb carotid artery. According to the isolated rabbit ileum activity tests the most active compounds are 10 and 12 and according to the lamb carotid activity tests the most active compounds are 6 and 10.     

A pharmacological analysis of the contractile action of histamine upon the ileal region of the isolated, blood-perfused small intestine of the rat.

1. The mode of action of histamine was investigated on the rat isolated small intestine perfused at a fixed flow rate through the superior mesenteric artery with blood from the carotid artery of a heparinized donor rat. Compounds were closely injected into the superior mesenteric artery. 2. Increasing doses (1 to 100 micrograms) of histamine caused a monophasic fast contraction of the ileum. 3. The fast contraction was abolished by tetrodotoxin, hexamethonium, morphine or mepyramine, but was not prevented by atropine. 4. The present study indicates that histamine produces the fast contraction of the ileum by primarily acting on the myenteric nerve plexus involving cholinergic interneurones.     

Studies on condensed 1,4-dihydropyridine derivatives and their calcium modulatory activities

Hexahydroquinoline and furoquinoline derivatives were synthesized and their calcium modulatory activity was investigated on isolated rat ileum and lamb carotid artery. In addition, the in vitro hepatic microsomal biotransformation of one hexahydroquinoline derivative was studied in rat microsomes.     

4-aryl-6,6-dimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-diones: synthesis, chromatographic resolution and pharmacological activity

In this study, a series of 4-aryl-6,6-dimethyl-1,2,3,4,5,6,7,8- octahydroquinazoline-2,5-diones were synthesized by condensing urea with 4,4-dimethyl-1,3-cyclohexanedione and appropriate aromatic aldehydes according to the Biginelli reaction. The structures of the compounds were characterized by spectroscopic methods. The racemic compounds were resolved into the enantiomers by HPLC on amylose tris(3,5-dimethylphenylcarbamate) (Chiralpak AD). The compounds were tested in vitro for their calcium antagonistic activities. BaCl2-induced contractions of rat ileum were inhibited dose-dependently. Compounds 3 and 5 exerted weak calcium antagonistic activity on smooth muscles compared with the standard, nicardipine.     

Comparative Analysis of the Vascular Actions of Diterpenes Isolated from Euphorbia canariensis

We have analysed the effects of 2,3-diepiingol 7,12-diacetate-8-isobutyrate (compound 1 ), ingenol-3-angelate-17-benzoate (compound 2 ), ingenol-3-angelate-17-benzoate-20-acetate (compound 3 ) and 3,5,7,8,9,15-hexahydroxyjatropha-6(17),11-dien-14-one-5,8-bis(2-methylbutyrate)-7-(2-methylpropionate) (compound 4 ), four diterpenes isolated from E. canariensis, on the isometric tension developed by isolated rabbit basilar and carotid arteries. Concentration-response curves to these compounds were obtained cumulatively in both arteries at resting tension and active tone (KCl, 50 mM). At resting tension a concentration-dependent contraction was induced by the four compounds. In the basilar artery the order of potency was 3 = 1 > 2 = 4 , without significant differences between E_max values. In the carotid artery the order of potency was 3 > 2 = 1 = 4 and there were no significant differences between the E_max (maximum effect) values of compounds 1–3 , all of which were higher than that of compound 4 . In pre-contracted basilar artery compounds 1–3 induced concentration-dependent relaxation and compound 4 was almost ineffective; the order of potency was 3 > 2 = 1 without significant differences between E_max values. In the carotid artery with active tone the four compounds tested induced further contractions; the order of potency was 3 > 2 = 4 > 1 without significant differences between E_max values. These results show that the four diterpenes are potent active substances in rabbit basilar and carotid arteries and that there are regional differences between their action. The four compounds tested contract basilar and carotid arteries at resting tension. Compounds 1–3 relax pre-contracted basilar artery but not carotid artery.     

Nitric oxide/cGMP mediates the spasmolytic action of 3,4'-dihydroxy-5,5'-dimethoxybibenzyl from Scaphyglottis livida

Five aromatic compounds, 3,4'-dihydroxy-5,5'-dimethoxybibenzyl (1), batatasin III (2), coelonin (3), 3,7-dihydroxy-2,4-dimethoxyphenanthrene (4), and 3,7-dihydroxy-2,4,8-trimethoxyphenanthrene (5) were isolated from the orchid Scaphyglottis livida (Lindley) Schltr. Compounds 1-5 induced a concentration-dependent inhibition of the spontaneous contractions of the rat ileum with potencies comparable or higher to that of papaverine. The relaxation evoked by compounds 1-4 was blocked by L-NAME, an inhibitor of nitric oxide synthase. It was also demonstrated that 1 increased cyclic GMP content in rat ileum rings. Compound 1-induced elevation of cGMP was inhibited by L-NAME and ODQ, inhibitors of nitric oxide synthase and soluble guanylyl cyclase, respectively. These results indicate that nitric oxide/cGMP formation constitute the signaling pathway in the spasmolytic action of compound 1.     

温郁金挥发油的化学成分

目的对温郁金(Curcuma wenyujin)挥发油的化学成分进行研究。方法采用硅胶柱色谱、正反相MPLC及HPLC等进行分离纯化,通过波谱分析鉴定其结构。结果从温郁金挥发油中分离得到10个化合物,鉴定为莪术醇(1)、莪术二酮(2)、(4S,5S)-germacrone-4,5-epoxide(3)、germa-crone-1,10-epoxide(4)、新莪术二酮(5)、(5R,6R,7αR)-5-isopropenyl-3,6-dimethyl-6-vinyl-5,6,7α-tetrahydro-4H-enzofuran-2-one(6)、hydroxyisogermafurenolide(7)、(5R,6R,7aS)-5-isopropenyl-3,6-dimethyl-6-vinyl-5,6,7,7-αtetrahydro-4-Hbenzo-furan-2-one(8)、脱-氢1,8-桉叶素(9)、p-menth-2-ene-1,8-diol(10)。并通过核磁共振手段对其碳氢信号进行了全归属。结论化合物6、7为新的天然产物;化合物4、8、10为首次从该属植物中分离得到;化合物4、6、7、8、10为首次从该种植物中分离得到。     

Synthesis and anticonvulsant activity of a new series of 1,4-dihydropyridine derivatives

A series of 1,4-dihydropyridine derivatives (1a-g) were prepared from three compounds condensation of Hantzsch synthesis. A new series of 2,2'-{[4-(aryl)-2,6-dimethyl-1,4-dihydropyridine-3,5-diyl]dicarbonyl}dihydrazinecarbothioamide (2a-g) were prepared from compounds diethyl 4-(aryl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1a-g) reacted with thiosemicarbazide to give the corresponding compounds (2a-g) by hydrazinolysis method. The synthesized compounds were confirmed by IR, (1)HNMR, (13)CNMR, mass spectral and elemental analyses. The newly synthesized compounds (2a-g) were screened for anticonvulsant activity against in swiss albino rat. The test was evaluated by maximal electrode induced convulsion method. Synthesized compounds were used two (50 and 100 mg/kg) concentrations. Compounds (1a-g) were inactive while compounds (2a-g) have moderate anti-convulsant activity compared with standard phenytoin drug. The compound 2,2'-{[4-(furan-2-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-diyl]dicarbonyl} dihydrazinecarbothioamide (2a) has highly active compared with other compound (2b-2g).     

Synthesis and spasmolytic action of 2-substituted thienopyrimidin-4-one derivatives

In the search for novel compounds to treat disorders of smooth muscle function, efforts have focused on some 2-substituted thieno[2,3-d]pyrimidin-4-one derivatives that show interesting spasmolytic action. Our laboratories have developed a new series of quaternary salts of 2-substituted thieno[2,3-d]pyrimidin-4-one and thieno[3,2-d]pyrimidin-4-one isomers with therapeutic potential. Thesesubstances were prepared starting from simple derivatives of thiophene. Their spasmolytic activity was evaluated on transmurally stimulated guinea-pig ileum. The most active compounds (IC50 1.12-2.71 microM) 7f-7h, 12d and 12f had the terminal piperidino nucleus in the thioalkyl chain and lacked two methyl groups in the thiophene ring. Their relaxant activity on the isolated ileum was potentiated (approx. 20-25%) by phosphodiesterase inhibitors. Compounds 7f-h, 12d and 12f were less effective in inhibiting contractions of the guinea-pig ileum induced by acetylcholine (IC50 26.7-41.4 microM) or histamine (IC50 41.5-63.4 microM) and had a moderate binding activity to muscarinic receptors in membrane homogenates from the rat heart (M2 sites; pKi values between 5.55+/-0.08 and 5.14+/-0.12; n = 3) and submaxillary gland (M3 sites; pKi values between 6.15+/-0.07 and 5.76+/-0.08; n = 3). Action involving soluble guanylyl cyclase or any potential binding to guinea-pig ventricular L-type calcium channels was not considered likely. It is concluded that at least two different mechanisms of action contribute to their spasmolytic activity.     

3-Alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxides structurally related to diazoxide and pinacidil as potassium channel openers acting on vascular smooth muscle cells: design, synthesis, and pharmacological evaluation

A series of 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides structurally related to diazoxide and pinacidil were synthesized and tested as possible K(ATP) channel openers on isolated pancreatic endocrine tissue as well as on isolated vascular, intestinal, and uterine smooth muscle. In contrast to previously described 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1, 1-dioxides, most of the new compounds were found to be poorly active on B-cells but exhibited clear vasorelaxant properties. 3-(3, 3-Dimethyl-2-butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (4d) and 7-chloro-3-(3, 3-dimethyl-2-butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (5d), two compounds bearing the alkyl side chain of pinacidil, were found to be the most active representatives of their respective series on rat aorta rings. 3-Cycloalkylalkylamino- and 3-aralkylamino-7-chloro-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides also expressed myorelaxant activity on electrically stimulated guinea pig ileum and on oxytocin-induced contractions of the rat uterus. Further biological investigations ((86)Rb efflux measurements, vasodilator potency on 30 and 80 mM KCl-induced contractions in the absence and presence of glibenclamide) revealed that compounds 4d and 5d, but not compound 5f, expressed the pharmacological profile of classical K(ATP) channel openers. In conclusion, by changing the position of the nitrogen atom in the pyridine ring, we now have obtained a family of drugs expressing an opposite tissue selectivity. Taken as a whole, the present findings also suggest that 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides such as 4c, 4d, 5c, and 5d may be considered as new examples of K(ATP) channel openers expressing a pharmacological profile similar to that of pinacidil and diazoxide.     

The effect of the volatile oil from ginger rhizomes (Zingiber officinale), its fractions and isolated compounds on the 5-HT3 receptor complex and the serotoninergic system of the rat ileum

A contribution of the volatile oil from ginger rhizomes (Zingiber officinale Roscoe) on inhabiting the 5-HT3 receptor complex had been shown. In the present study a possible interaction of some compounds of the volatile oil with the 5-HT3 receptor system expressed in N1E-115 cells and with the serotoninergic system of the rat ileum was investigated. The volatile oil was obtained by steam distillation and fractionated using a silica gel column resulting in five fractions. Compounds of the fractions were identified by GC-MS. The influence of the volatile oil, its fractions and pure components on serotonin-induced [14C]guanidinium influx into N1E-115 cells was measured indicating the inhibitory interaction with the 5-HT3 receptor channel system. Most potent inhibitors of cation influx were the volatile oil, fraction 4, beta-pinene, terpinolene, alpha-copaene and alpha-phellandrene. The volatile oil and fractions 1 and 4 were not able to significantly influence either serotonin (10 microM)-induced maximum contraction of the rat ileum or the second phase of the biphasic contraction 2.5 min after serotonin addition. However, beta-pinene, terpinolene and alpha-phellandrene reduced both contractions. In conclusion, the volatile oil and distinct compounds such as terpinolene, beta-pinene and alpha-phellandrene interact with 5-HT3 receptor channel system and possess an antispasmodic effect at the rat ileum.     

Synthesis and 5-HT2A antagonist activity of derivatives of the novel heterocycles indolo[3,2-d]pyrrolo[3,2-g]azecine and benzo[d]pyrrolo[3,2-g]azecine compared to the benz[d]indolo[2,3-g]azecine derivative LE 300

An indolo[3,2-d]pyrrolo[3,2-g]azecine and a benzo[d]pyrrolo[3,2-g]azecine analogue of the potent dopamine receptor antagonist LE 300 (7-methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2,3-g]azecine) have been prepared in multi-step reactions via C-N bond cleavage of corresponding quaternary N-methylquinolizinium iodides. LE 300, the target compounds and two precursor quinolizines have been tested in vitro for antagonist activity at 5-HT2A receptors (rat tail artery) and H1 receptors (guinea-pig ileum), respectively. LE 300 and compound 19 (3,6-dimethyl-4,5,6,7,8,13-hexahydro-3H-benzo[d]pyrrolo[3,2-g]azecine) competitively inhibited 5-HT-induced contractions with similar nanomolar potency (pA2 = 8.32 and 8.01, respectively) but were less active than the reference antagonist ketanserin (pA2 = 9.55). Compound 19 displayed moderate H1-antihistaminic activity in the guinea-pig ileum assay (pA2 = 7.37).     

Cellular effects of some metabolic oxidation products pertinent to 4-ethoxyaniline.

The toxicity of some metabolic products pertinent to 4-ethoxyaniline in isolated hepatocytes were investigated. The compounds investigated were 4-ethoxynitrosobenzene (1), 4-ethoxy-4'-nitrosodiphenylamine (2), 3,6-bis(4-ethoxy-phenylimino)-4-ethoxy-1,4-cyclohexadienylamine (3), 4-(4-ethoxyphenylimino)-2,3-dimethyl-2,5-cyclohexadiene-1-one (4) and 4-(4-ethoxyphenylimino)-2,6-dimethyl-2,5-cyclohexadiene-1-one (5). Of these, 1, 2 and 3 are oxidation products of 4-ethoxyaniline. Compounds 4 and 5 are dimethyl analogues of previously investigated oxidation product 4-(4-ethoxyphenylimino(-2,5-cyclohexadiene-1-one (NEPBQI). Among the investigated compounds, 1 and 2 were the most toxic towards isolated hepatocytes. In hepatocytes treated with compounds 1, 2 and 4, loss of cell viability was also accompanied by surface bleb formation. All compounds except 3 reacted with GSH resulting in depletion of cellular GSH. No formation of GSSG was observed, however. Thus, the GSH depletion was apparently due to conjugate formation rather than oxidation. No superoxide dismutase inhibitable reduction of acetylated cytochrome c was observed, thus none of the compounds undergoes measurable redox cycling.     

Cellular Effects of Some Metabolic Oxidation Products Pertinent to 4-Ethoxyaniline

Abstract: The toxicity of some metabolic products pertinent to 4-ethoxyaniline in isolated hepatocytes were investigated. The compounds investigated were 4-ethoxynitrosobenzene (1), 4-ethoxy-4′-nitrosodiphenylamine (2), 3,6-bis(4-ethoxy-phenylimino)-4-ethoxy-1,4-cyclohexadienylamine (3), 4-(4-ethoxyphenylimino)-2,3-dimethyl-2,5-cyclohexadiene-1-one (4) and 4-(4-ethoxyphenylimino)-2,6-dimethyl-2,5-cyclohexadiene-1-one (5). Of these, 1, 2 and 3 are oxidation products of 4-ethoxyaniline. Compounds 4 and 5 are dimethyl analogues of previously investigated oxidation product 4-(4-ethoxyphenyl-imino(-2,5-cyclohexadiene-1-one (NEPBQI). Among the investigated compounds, 1 and 2 were the most toxic towards isolated hepatocytes. In hepatocytes treated with compounds 1, 2 and 4, loss of cell viability was also accompanied by surface bleb formation. All compounds except 3 reacted with GSH resulting in depletion of cellular GSH. No formation of GSSG was observed, however. Thus, the GSH depletion was apparently due to conjugate formation rather than oxidation. No superoxide dismutase inhibitable reduction of acetylated cytochrome c was observed, thus none of the compounds undergoes measurable redox cycling.     

Beta-lactam analogues of oxotremorine. 3- and 4-methyl-substituted 2-azetidinones

Four beta-lactam analogues (8-11) of oxotremorine were synthesized and assayed for muscarinic and antimuscarinic activity on the isolated guinea pig ileum. The pharmacological results were compared with those obtained previously with the beta-lactam analogue 7 and the 3-, 4-, and 5-methyl-substituted 2-pyrrolidones 2-6. The new compounds were less potent than the corresponding 2-pyrrolidones, regardless of whether they showed agonist (10 and 11), partial agonist (8), or antagonist properties (9) in the ileum assay. The agonists 10 and 11 were about 200-fold less potent than 7. Compounds 8-11 also were less potent than the similarly substituted 2-pyrrolidones in inhibiting the binding of the muscarinic antagonist (-)-[3H]-N-methylscopolamine in homogenates of the rat cerebral cortex.