Renal vasodilators. The role of the 4-substituent in isoquinolin-3-ol cardiovascular agents: 4-ureido derivatives of isoquinolin-3-ol with selective renal vasodilator properties

The synthesis and cardiovascular evaluation of a series of isoquinolin-3-ol derivatives bearing a variety of nitrogen substituents (amino, acylamino, carbamate, and ureido) at C-4 are described. Certain of these compounds have a selective renal vasodilating profile and have minimal effects on arterial blood pressure or heart rate when administered intravenously in the instrumented anesthetized dog. The most potent renal vasodilator in the series is 4-(allylureido)-6,7-dimethoxyisoquinolin-3-ol (38), which at a dose of 1.2 mg/kg iv produces a 97% maximal increase in renal blood flow without significant hypotensive or chronotropic effects. Structure-activity observations on the nature of the 4-substituent and the alkoxy substitution pattern in the aromatic ring of the isoquinolinol nucleus are discussed.     

Synthesis and anti-measles virus activity of new isoquinolin-4-one derivatives

Despite intense efforts to increase vaccine coverage, measles virus (MV) still causes significant morbidity and mortality in the world sometimes as a results of severe, chronic and lethal diseases. In an effort to develop therapies to supplement immunization strategies a number of 1-oxo-2-[[(1E)-phenylmethylene]amino]-1,2-dihydroisoquinoline-4-carboxylic acid derivatives were synthesized and evaluated for anti-measles activity. The substituents on the aromatic ring were chosen in order to evaluate the influence of electron-withdrawing or electron-donating effects on the electronic density of the aromatic moiety. We also evaluated the introduction of a vinyl chain between the exocyclic nitrogen and phenyl moiety. The biological results allow to outline some preliminary considerations on structure-activity relationship.     

Compounds with positive inotropic activity, III: Synthesis of 4-aminoquinoline derivatives as potential positive inotropic agents

Anilinoacrylic acid derivatives 2-4 are the key intermediates from which 1-alkyl substituted 4-aminoquinoline 10-15 as well as 4-alkylaminoquinoline derivatives 16-23 are synthesized and examined for positive inotropic activity on isolated left atria and papillary muscles from guinea-pig. Structure activity relationships indicate that the effect depends on the alkyl side chain of the target compounds.     

Cardiotonic agents. 2. (Imidazolyl)aroylimidazolones, highly potent and selective positive inotropic agents

A series of 4-alkyl-1,3-dihydro-5-[(1H-imidazolyl)benzoyl]-2H-imidazol-2-ones 9 was synthesized and evaluated in vitro for positive inotropic and cyclic AMP phosphodiesterase inhibitory activity. A wide range of inotropic and enzyme-inhibitory potencies was observed, substitution on the imidazolyl moiety being the major determinant of activity. The 4-ethyl-5-[4-(1H-imidazol-1-yl)benzoyl] congener 9g exhibited the highest potency in vitro. Incorporation of a methyl group at the imidazolyl 2-position gave 9h, which was less potent but remarkably selective in vivo for positive inotropic effects over heart rate and hypotensive effects.     

Cardiotonic agents. 8. Selective inhibitors of adenosine 3',5'-cyclic phosphate phosphodiesterase III. Elaboration of a five-point model for positive inotropic activity

Inhibitors of adenosine 3',5'-cyclic phosphate phosphodiesterase III (cAMP PDE III) were studied by using solid-state, solution, and theoretical methods in order to refine a five-point model for positive inotropic activity. Cyclic AMP PDE III inhibitors bear a striking resemblance to cAMP itself. This investigation supports the importance of an overall planar topography for selective and potent cAMP PDE III inhibition. (Possible reasons for the potency of certain nonplanar compounds are discussed.) Cardiotonics like imazodan (1; CI-914) and 2 (CI-930) can readily achieve essentially planar geometries, as shown with X-ray crystallographic, IR, UV, NMR, and theoretical data. Small alkyl substituents that occupy space corresponding to certain portions of the cAMP sugar region increase potency (see, e.g., 2, 4). Selective inhibition of cAMP PDE III can be achieved by mimicking the attractive electrostatic potential associated with the phosphate group (e.g., with an amide) and by providing an additional attractive potential spatially opposite to the previous one, in the vicinity of the adenine N1 and extending to N3 (e.g., with an imidazole), together with a partial dipole moment comparable to the adenine dipole moment. This extends and better defines our five-point model in terms of cAMP, a natural substrate for PDE.     

苯并吡喃类化合物的合成及生物活性研究

合成了13个苯并吡喃类化合物，用3T3-L1前脂肪细胞对这些化合物进行了促脂肪细胞分化活性筛选，并用db糖尿病小鼠模型对化合物8进行了降糖活性研究。结果表明，化合物3、8和11在3T3-L1脂肪细胞模型上表现出较强的促脂肪细胞分化活性，化合物8能显著降低db糖尿病小鼠的血糖水平。     

Synthesis and antitumor activity of a series of lactone-opened camptothecin derivatives

A series of E-ring lactone-opened camptothecin (CPT) derivatives bearing with terminal aza-heterocyclic groups were synthesized, and their antitumor activity was evaluated both in vitro and in vivo. Hydroxyl-amide analogues with morpholin-4-yl displayed excellent antitumor activity in vitro and efficient inhibition on tumor xenograph model in nude mice. Ester-amide compounds acted less active in vitro cytotoxicity and lower inhibition activity in vivo. Substitutions at 7- and 10- positions favored the antitumor activity.     

Cardiotonic agents. Synthesis and cardiovascular properties of novel 2-arylbenzimidazoles and azabenzimidazoles.

Novel 2-arylbenzimidazoles and azabenzimidazoles were synthesized, and their inotropic action was evaluated. Changes in left ventricular pressure, dP/dt max, were measured as an index of cardiac contractility. The structural features that impart optimal inotropic activity are presented. The most potent compounds were evaluated orally in conscious dogs with implanted Konigsberg pressure transducers. To investigate the mechanism of action, the most potent compounds were tested for their calcium-sensitizing properties and their potential for the inhibition of phosphodiesterase. Two compounds, 1 and 41, showed interesting in vitro and oral activity without side effects. They have a more potent calcium-sensitizing effect than MCI-154 and are under further investigation.     

Cardiotonic agents. 5. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitriles and related compounds. Synthesis and inotropic activity

Several 1,2-dihydro-5-(substituted phenyl)-2(1H)-pyridinones were synthesized and evaluated for inotropic activity. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitrile (5a) and the corresponding unsubstituted analogue 14a were the most potent positive inotropic agents in this series. Although the 4,6-dimethyl analogue 6a retained most of the activity of 5a, the 4-methyl analogue 8a was substantially less potent. The synthesis and structure-activity relationships are discussed.     

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).     

Cardiotonic agents. 6. Synthesis and inotropic activity of 2,4-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones: ring-contracted analogues of imazodan (CI-914)

A series of 2,4-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones was synthesized and evaluated for positive inotropic activity. Only compounds with two small alkyl groups at C-4 showed significant activity. The structure-activity relationships for optimal inotropic activity are presented and compared with those of the 4,5-dihydro-3(2H)-pyridazinone series. The phosphodiesterase inhibitory activity is also reported and correlated with the substitution pattern at C-4 in the pyrazolone ring.     

Synthesis and antitumor activity of tropolone derivatives. 3

As part of a study on the antitumor activities of tropolone derivatives prepared from hinokitiol, which naturally occurs in the plants of Chamaecyparis species, effects of aromatic substituents of alpha,alpha-bis(7-hydroxy-5-isopropyltropon-2-yl)toluenes on the activity were examined. Several of the compounds showed high potency in the P388 leukemia assay. 4-Hydroxy analogue 4d showed the most potent activity (T/C = 195%) at a 5 mg/kg dose. The introduction of large-size substituents, of which the steric influence prevents coplanarity of the substituted aromatic function, resulted in a remarkable decrease in the potency. X-ray structural analysis of highly potent 4-methoxy analogue 4b was undertaken.     

Atypical antipsychotic agents: patterns of activity in a series of 3-substituted 2-pyridinyl-1-piperazine derivatives

A series of 3-substituted 2-pyridinyl-1-piperazine derivatives have been appended to cyclic imide groups and evaluated for their potential antipsychotic activity. The dopamine receptor affinities of these target molecules, as well as their ability to block apomorphine-induced stereotypy or reverse neuroleptic-induced catalepsy, was dependent on the lipophilic and electronic characteristics of the substituent situated on the pyridine ring. Groups with + omega and - phi values were most consistent with the desired biological profile of the target molecules, the cyano moiety being the optimum choice. Evaluation of compound 12 in a monkey model of amphetamine psychosis, and the regional selectivity it expresses for the A10 dopaminergic cell bodies in electrophysiological experiments, suggest this compound would be an atypical antipsychotic agent with few side effects.     

Synthesis and antibacterial activity of a novel series of potent DNA gyrase inhibitors. Pyrazole derivatives

We have previously found that a pyrazole derivative 1 possesses antibacterial activity and inhibitory activity against DNA gyrase and topoisomerase IV. Here, we synthesized new pyrazole derivatives and found that 5-[(E)-2-(5-chloroindol-3-yl)vinyl]pyrazole 16 possesses potent antibacterial activity and selective inhibitory activity against bacterial topoisomerases. Many of the synthesized pyrazole derivatives were potent against clinically isolated quinolone- or coumarin-resistant Gram-positive strains and had minimal inhibitory concentration values against these strains equivalent to those against susceptible strains.