Microwave-assisted solvent-free synthesis of 3-[(4-substituted piperazin-1-yl)alkyl] imidazo[2,1-b][1,3]benzothiazol-2(3H)-ones as serotonin3 (5-HT3) receptor antagonists

A series of novel 3-[(4-substituted piperazin-1-yl)alkyl]imidazo[2,1-b][1,3]benzothiazol-2(3H)-ones were prepared by microwave irradiation using alumina as solid support and also by a conventional method. The compounds were characterized by spectral data and the purity was ascertained by microanalysis. The synthesized compounds were evaluated for 5-hydroxytryptamine3 antagonisms in a longitudinal muscle-myenteric plexus preparation from guinea pig ileum against the 5-hydroxytryptamine3 agonist, 2-methyl-5-hydroxytryptamine. Among the test compounds, 3-[2-(4-methylpiperazin-1-yl)ethyl]imidazo[2,1-b][1,3]benzothiazol-2(3H)-one (3b) showed most favorable 5-hydroxytryptamine3 antagonism (pA2 6.7) in the isolated guinea pig ileum.     

The role of the 5-HT1D receptor as a presynaptic autoreceptor in the guinea pig

The present study investigated the role of the 5-hydroxytryptamine (5-HT, serotonin)1D receptor as a presynaptic autoreceptor in the guinea pig. In keeping with the literature, the 5-HT1B selective antagonist, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine]oxalate (SB224289) potentiated [3H]5-HT outflow from pre-labelled slices of guinea pig cerebral cortex confirming its role as a presynaptic autoreceptor in this species. In addition, the 5-HT1D receptor-preferring antagonists, 1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl]-3-pyridin-4-yl-methyl-tetrahydro-pyrimidin-2-one (LY367642), (R)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6-carboxamide (LY456219), (S)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6-carboxamide (LY456220) and 1-[2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl]-3,3-dimethyl-1,2-dihydro-indol-2-one (LY310762), potentiated [3H]5-HT outflow from this preparation with potencies (EC50 values=31-140 nM) in the same range as their affinities for the guinea pig 5-HT1D receptor (Ki values=100-333 nM). The selective 5-HT1D receptor agonist, R-2-(4-fluoro-phenyl)-2-[1-[3-(5-[1,2,4]triazol-4-yl-1H-indol-3-yl)-propyl]-piperidin-4-ylamino]-ethanol dioxylate (L-772,405), inhibited [3H]5-HT outflow. In microdialysis studies, administration of either SB224289 or LY310762 at 10 mg/kg by the intraperitoneal (i.p.) route, potentiated the increase in extracellular 5-HT concentration produced by a maximally effective dose of the selective serotonin re-uptake inhibitor, fluoxetine (at 20 mg/kg i.p.). In addition, the 5-HT1D receptor-preferring antagonist and 5-HT transporter inhibitor, LY367642 (at 10 mg/kg i.p.), elevated extracellular 5-HT concentrations to a greater extent than a maximally effective dose of fluoxetine. It is concluded that the 5-HT1D receptor, like the 5-HT1B receptor, may be a presynaptic autoreceptor in the guinea pig.     

Synthesis and antimicrobial activity of novel pyrazolo[3,4-b]quinoline derivatives

New pyrazolo[3,4-b]quinoline derivatives have been prepared by cyclization of the intermediate 2-chloroquinoline-3-carbonitrile 7, namely 3-amino-1H-pyrazolo[3,4-b]quinoline 8a, 3-amino-1-phenyl/(p-substituted)phenyl/-1H-pyrazolo[3,4-b]-quinoline 8b-f. Furthermore, 3-[(3-aryl-4-oxothiazolidin-2-ylidene)amino]-1H-pyrazolo[3,4-b]quinolines 11a,b; 3-[(3-aryl-4-oxothiazin-2-ylidene)amino]-1H-pyrazolo[3,4-b]quinolines 12a,b and 3-(2-aryl-4-oxothiazolidin-3-yl)-1H-pyrazolo[3,4-b]quinolines 13a,b were synthesized. The antimicrobial activity was evaluated for most of the prepared compounds.     

Pharmacologic characterization of receptor types mediating coronary vasodilator actions of sensory neuropeptides in the guinea pig

The receptor types mediating sensory neuropeptide-induced coronary vasodilatation were elucidated on isolated guinea pig hearts perfused with isotonic buffer containing 20 mM KCl. Substance P and the selective neurokinin-1 (NK1) receptor agonist [Sar9, Met(O2)11]-substance P produced dose-dependent reductions in perfusion pressure, but the selective NK2 receptor agonist [Nle10]-neurokinin A4-10 and the selective NK3 receptor agonist [MePhe7]-neurokinin B produced no change. The vasorelaxant effects of substance P and the NK1 receptor agonist were abolished by the selective NK1 receptor antagonist FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-methy l-N-phenylmethyl-3-(2-naphthyl)-L-alaninamide), whereas the selective NK2 receptor antagonist SR48968 ((S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl )-butyl] benzamide) and the selective NK3 receptor antagonist SR142801 ((S)-(N)-( 1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)4-p henylpiperidin-4-yl)-N-methylacetamide) produced partial inhibition on their responses. Calcitonin gene-related peptide (CGRP) produced dose-dependent vasodilatation on the guinea pig coronary blood vessels, which was significantly (p = 0.0067) inhibited by the selective CGRP1 receptor antagonist hCGRP8-37. The selective CGRP2 receptor agonist [Cys(acetomethoxy)2,7]CGRP had no effect on perfusion pressure. These results demonstrate that the sensory neuropeptides substance P and CGRP are effective vasodilators of the guinea pig coronary vascular bed. The receptor types mediating their vasorelaxant effects were identified to be the NK1 receptors and CGRP1 receptors, respectively.     

New antihistaminic theophylline or theobromine derivatives

A series of 3,4-dihydro-1,3-dimethyl-7-[3-(4-substituted-piperazin-1-yl)- substituted-alkyl]-1H-purine-2,6-diones and 3,7-dihydro-3,7-dimethyl-1-[3-(4-substituted-piperazin-1-yl)- substituted-alkyl]-1H-purine-2,6-diones was synthesized and evaluated for antihistaminic activity. Some of them displayed good inhibition of both histamine-induced bronchospasm in the anesthetized guinea pig at 10 micrograms/kg by the intravenous route and of passive cutaneous anaphylaxis in the rat at 10 mg/kg by the oral route. Comparison of the two most active compounds revealed a higher antihistaminic activity with the compounds containing a (phenylthio)propyl group (1 and 2) as compared with that containing a phenoxy group. Compound 2 [RS-49014, 3,4-dihydro-1,3-dimethyl-7-[3-[4-[3-(phenylthio)propyl]piperazin-1 -yl]- 2-hydroxypropyl]-1H-purine-2,6-dione] was selected for clinical trials on the basis of a comparative pharmacological study with chlorpheniramine, ketotifen, promethazine, and theophylline.     

Synthesis of some thiazole-, 1,3,4-thiadiazole-, and 4H-1,2,4-triazole derivatives of pyrazolo[3,4-b]quinoline

Three novel series of pyrazolo[3,4-b]quinolines were prepared, namely: 1-(3-substituted-4-phenylthiazolin-2-ylidene)hydrazinocarbonylm ethyl-1H-pyrazolo[3,4-b]quinolines 3a-d; 1-(5-substituted amino-1,3,4-thiadiazol-2-yl)methyl-1H-pyrazolo[3,4-b]quinolines 4b-d, and 1-(4-substituted-4H-5- thioxo-1,2,4-triazole-3-yl)methyl-1H-pyrazolo[3,4-b]quinolines 5a-d. These compounds were prepared by cyclization of the new key intermediates 1-(substituted thiocarbamoylhydrazinocarbonyl)methyl-1H- pyrazolo[3,4-b]quinolines 2a-d. The alkylthio, aralkylthio 6a-f as well as the Mannich bases 8a-f derived from compounds 5a-d were also prepared. The structures of the new compounds were elucidated by elemental analyses, IR, 1H-NMR-, and mass spectra. The antimicrobial as well as inotropic and chronotropic activities were studied.     

Interferon inducing activities of derivatives of 1,3-dimethyl-4-(3-dimethylaminopropylamino)-1H-pyrazolo(3,4-b)quinoline and related compounds.

Syntheses and interferon inducing acitivites are reported for 137 relatives of 1,3-dimethyl-4-(3-dimethylamino-propylamino)-1H-pyrazolo[3,4-b]quinoline (1). Three different generalized synthetic schemes for the preparation of pyrazolo[3,4-b]quinolines are presented and limitations contrasted. Other heterocyclic nuclei containing the 3-dimethylaminopropylamino side chain include pyridine, quinoline, acridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-B][1,8]naphthyridine, pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine, dipyrazolo[3,4-b:4',3'-e]pyridine, pyrrolo-[2,3-b]quinoline, isothiazolo[5,4-b]quinoline, and pyrido[2,3-h]pyrazolo[3,4-b]quinoline. Structural requirements for interferon induction in this series are discussed and two of the more active compounds (172 and 196) are compared directly with tilorone.     

Synthesis and structure-activity relationship studies in translocator protein ligands based on a pyrazolo[3,4-b]quinoline scaffold

As a further development of our large program focused on the medicinal chemistry of translocator protein [TSPO (18 kDa)] ligands, a new class of compounds related to alpidem has been designed using SSR180575, emapunil, and previously published pyrrolo[3,4-b]quinoline derivatives 9 as templates. The designed compounds were synthesized by alkylation of the easily accessible 4-methyl-2-phenyl-1H-pyrazolo[3,4-b]quinolin-3(2H)-one derivatives 13-15 with the required bromoacetamides. Along with the expected 2-(4-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazolo[3,4-b]quinolin-1-yl)acetamide derivatives 10, 2-(4-methyl-3-oxo-2-phenyl-2H-pyrazolo[3,4-b]quinolin-9(3H)-yl)acetamide isomers 11 were isolated and characterized. The high TSPO affinity shown by new pyrazolo[3,4-b]quinoline derivatives 10 and especially 11 leads the way to further expand the chemical diversity in TSPO ligands and provides new templates and structure-affinity relationship data potentially useful in the design of new anxiolytic and neuroprotective agents.     

Synthesis and receptor binding studies relevant to the neuroleptic activities of some 1-methyl-4-piperidylidene-9-substituted-pyrrolo[2,1-b][3]benzazepine derivatives

The synthesis of a series of 1-methyl-4-(9-substituted-11H-pyrrolo[2,1-b]benzazepin-11-ylidene)piperidines (4a-f) and 1-methyl-4-(9-substituted-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-ylidene)piperidines (4g-l) is described. As with th e 3-substituted cyproheptadine compounds 1b-e, atropisomerism exists in 4b-f, but unlike the enantiomers of 1b-e, the pyrrolobenzazepine enantiomers racemize at room temperature. Thus, the bromo compound (+)-4b has a half-life of 128 +/- 1 min at 25 degrees C, while the chloro compound (-)-4c has a half-life of 114 +/- 9 min at 25 degrees C. Compounds 4a-l have been examined for receptor binding affinities in assays that have been recognized as predictive for antipsychotic activity. The displacement of specifically bound tritiated ligands, comprising the dopamine antagonist [3H]spiperone, the dopamine agonist [3H]apomorphine, the muscarinic cholinergic antagonist [3H]quinuclidinyl benzilate (QNB), the alpha-adrenergic antagonist [3H]prazosin, the alpha-adrenergic agonist [3H]clonidine, the serotonin-1 binding agent [3H]serotonin, and the mixed serotonin agonist-antagonist [3H]lysergic acid diethylamide (LSD), by 4a-l has been measured utilizing membrane preparations of mammalian brain. Certain of the features of the receptor binding of these compounds have been shown to be common to several of the receptor sites. Data from these binding studies have been compared to corresponding data previously obtained for a series of chiral 3-substituted cyproheptadine analogues, and the receptor binding data of the two classes of compounds are discussed with respect to their molecular geometries.     

Effects of novel pyridothiazepines and pyridothiazines on contractility of isolated guinea-pig heart muscle and vascular smooth muscle preparations.

The effects of newly synthesized pyridothiazepines MM 4 (1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminoacetyl]-1,2,3,4 -tetrahydro-pyrido[2,3-b][1,4]thiazepine fumarate), MM 6 (1-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylaminopropionyl]-1,2, 3,4-tetrahydro-pyrido[2,3-b][1,4]thiazepine fumarate) and the novel pyridothiazines MM 10 (2,3-dihydro-1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylaminoacetyl+ ++]-1H-pyrido[2,3-b][1,4]thiazine fumarate) and MM 11 (2,3-dihydro-1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminopropio nyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) on the contractility of isolated papillary muscles and aortic preparations of guinea pigs were studied using isometric contraction force measurements. The EC50 values for the negative inotropic effect were 27 micromol/l (MM 4), 19 micromol/l (MM 6), 32 micromol/l (MM 10) and 24 micromol/l (MM 11). In K+-precontracted aortic rings ([K+]o 60 mmol/l), the compounds induced relaxation with EC50 values of 27 micromol/l (MM 4), 24 micromol/l (MM 6), 84 micromol/l (MM 10) and 68 micromol/l (MM 11). Pyridothiazepines as well as pyridothiazines (100 micromol/l) were able to depress norepinephrine bitartrate (NE 10 micromol/l)-induced contraction of aortic rings in a calcium-free solution. It was concluded that the investigated compounds exert calcium antagonistic properties in both cardiac and smooth muscle. This antagonistic effect might be due to the inhibition of transmembrane calcium influx and/or intracellular calcium release.     

Synthesis and in vitro pharmacology of arpromidine and related phenyl(pyridylalkyl)guanidines, a potential new class of positive inotropic drugs

Replacement of the cimetidine moiety in impromidine (1,N1-[3-(1H-imidazol-4-yl)propyl]-N2-[2-[[(5-methyl-1H-imidazol-4- yl)methyl]thio]ethyl]guanidine) by more lipophilic H2-nonspecific pheniramine-like structures resulted in potent H2 agonists with up to 160 times the activity of histamine in the isolated, spontaneously beating guinea pig right atrium. Additionally, the compounds proved to be moderate H1 antagonists. Highest H2-agonistic potency was found in compounds characterized by a three-membered carbon chain connecting the aromatic rings and the guanidine group. The activity in the atrium was increased 2-4-fold by halogen substituents in the meta or para position of the phenyl ring. Highest H1-antagonistic potency resides in the group of para-halogenated compounds, p-F representing the optimal substituent in both receptor models. The corresponding guanidine 52 (arpromidine, N1-[3-(4-fluorophenyl)-3-pyridin-2-ylpropyl]-N2-[3-(1H-imidazol-4- yl)propyl]guanidine) combines about 100 times the activity of histamine at the H2 receptor with H1-antagonistic potency in the range of pheniramine. Further increase in the activity on the atrium was achieved by disubstitution with halogen on the phenyl ring, such as 3,4-F2, 3,5-F2, and 3,4-Cl2 (63-65). The 2-pyridyl group in arpromidine was replaced by 3-pyridyl without significant change in H2 agonistic activity, whereas the 4-pyridyl and phenyl analogues were less active. The rank order of potency in the atrium was in good agreement with the positive inotropic effects found in isolated, perfused guinea pig hearts, where 63-65 were the most potent compounds as well.     

Effect of 1-acyl-5,6-dialkoxy-2-alkylthiobenzo[d] imidazoles on the action potential duration and isometric contraction in guinea pig atrium activated by carbachol and in guinea pig heart papillary muscles

BACKGROUND: Studies have shown that some benzo[d]imidazole derivatives (1-(5,6-dimethoxy-2-methylthio-1H-benzo[d]imidazol-1-yl)-1-ethanone (1), 1-(6-ethylthio-5H[1,31dioxolo[4',5':4,5] benzo[d]imidazol-5-yl)-1-propanone (2), 1-(2-ethylthio-6,7-dihydro-1H[1,4]dioxino [2:3':4,5]benzo[d]imidazol-1-yl)-1-pro-panone (3) and 2,3,9,10-tetrahydro-8H [1,4]dioxino[2' 3":4',5']benzo[4,5]imid-azo[2,1-b][1,3]thiazin-10-one (4)) possess strong cardiotonic activity. The goal of this study was to investigate the effect of compounds 1-4 on the action potential (AP) duration and contractile force in guinea pig atrium activated by carbachol and in guinea pig heart papillary muscles. METHODS: The experiments were carried out on the guinea pig papillary muscles and atrium. Isometric contraction and transmembrane potential were recorded using a force transducer and standard microelectrode technique. RESULTS: Compounds 1-4 exerted a positive inotropic effect in a dose-dependent manner on the electrically driven left atrium and papillary muscles, more pronounced in atrium. In response to 1 micromol/L carbachol the AP duration at a 90 % repolarization in atrium shortened more than 70 %, the isometric contraction decreased to the similar level as well. Compounds 1 and 4 significantly antagonized the shortening of the AP duration induced by carbachol and increased it. Compound 1 abolished the reduction of isometric contraction as well. Derivative 3 significantly lengthened (31 ms) the AP duration at a 90 % repolarization in papillary muscles, while 1 and 4 failed to affect this index. The selective blockade of the rapid component of the delayed rectifier potassium current (Ikr) by dl-sotalol (1 micromol/L) did not show the substantial influence on benzimidazole effects. CONCLUSION: These findings support the hypothesis that the tested benzo[d] imidazole derivatives abolish the influence of carbachol on AP and the isometric contraction by inhibition of acetylcholine-activated potassium current (KACh) in guinea pig atrial myocytes and therefore may be beneficial for the prognosis of patients with advanced heart failure and atrial fibrillation.     

Biphenylcarboxamide derivatives as antagonists of platelet-activating factor

A series of N-[4-(3-pyridinyl)butyl]-1,1'-biphenyl-4-carboxamides was prepared, and the compounds were evaluated for platelet-activating factor (PAF) antagonist activity in a binding assay employing washed, whole dog platelets and in vivo for their ability to inhibit PAF-induced bronchoconstriction in the guinea pig. The inclusion of a methyl group in the R configuration on the side-chain carbon adjacent to the carboxamide nitrogen atom of these derivatives resulted in a marked enhancement of potency in the binding assay for compounds unsubstituted in the biphenyl 2-position and, more importantly, in improved oral bioavailability. Previous work with related pyrido[2,1-b]-quinazoline-8-carboxamides suggests that the presence of such an alkyl group improves bioavailability by rendering the resulting compounds resistant to degradation by liver amidases. The most interesting compounds to emerge from this work are (R)-2-bromo-3',4'-dimethoxy-N-[1-methyl-4-(3-pyridinyl)butyl]-1,1'-bi phe nyl- 4-carboxamide (33) and (R)-2-butyl-3',4'-dimethoxy-N-[1-methyl-4-(3-pyridinyl)butyl]- 1,1'-biphenyl-4-carboxamide (40) each of which inhibits PAF-induced bronchoconstriction in the guinea pig by greater than 55%. 6 h after an oral dose of 50 mg/kg.     

N-(heterocyclic alkyl)pyrido[2,1-b]quinazoline-8-carboxamides as orally active antiallergy agents

A series of N-(heterocyclic alkyl)pyrido[2,1-b]quinazoline-8-carboxamides were evaluated for their ability to antagonize slow-reacting substance of anaphylaxis (SRS-A) induced contractions of guinea pig ilea and to inhibit thromboxane synthase in vitro. The results indicated that those pyrido[2,1-b]quinazoline-8-carboxamides bearing a branched-chain alkyl moiety in the 2-position and a four to six atom linear chain between a 3- or 4-substituted pyridine or a 1-substituted imidazole ring and the carboxamide nitrogen atom showed the best combination of potencies in the two assays. Several of these compounds were found to be orally active inhibitors of LTE4-induced bronchoconstriction in the guinea pig and LTE4-induced skin wheal formation in the rat. One of the most potent analogues, 2-(1-methyl-ethyl)-N-(1H-imidazol-1-ylbutyl)-11-oxo-11H-pyrido [2,1-b]quinazoline-8-carboxamide (36), was selected for extensive pharmacological investigation. It was found that this compound was not a specific inhibitor of LTE4-induced symptomatology, but exhibited more general activity by inhibiting bronchospasm in guinea pigs induced by LTC4, LTD4, PAF, and histamine and skin wheal formation in rats and guinea pigs induced by LTC4, LTD4, and PAF. In addition, 36 was orally active in the passive cutaneous anaphylaxis assay, suggesting that it also exhibits mediator release inhibitory activity. On the basis of the overall pharmacological profile of 36 and its closely related analogues, it was concluded that these compounds may be useful for the treatment of asthma.     

Cigarette smoke increases mucosal permeability in guinea pig trachea via tachykinin NK2 receptor activation

We investigated whether exposure to cigarette smoke increases the mucosal permeability in guinea pig trachea and if this effect could be mediated by tachykinin NK2 receptor activation. Guinea pigs were exposed to either three different doses of cigarette smoke or room air. Mucosal permeability was measured by monitoring the rate of appearance in the circulation of horseradish peroxidase (HRP) that had been instilled into the isolated tracheal segment. Exposure to 20 and 30 puffs but not 10 puffs of cigarette smoke increased the tracheal mucosal permeability. Pretreatment with the tachykinin NK2 receptor antagonist SR48,968 [(S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide] completely inhibited the increase in the permeability of the tracheal mucosa induced by exposure to cigarette smoke, whereas the tachykinin NK1 receptor antagonist SSR240,600 [(R)-2-(1-{2-[4-{2-[3,5-bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl}-4-piperidinyl)-2-methylpropanamide] and the tachykinin NK3 receptor antagonist SR142,801 [(S)-(N)-(1-[3-(1-benzoyl-3(3,4-dichlorophenyl)piperidine-3-yl)propyl]-4-phenylpiperidin-4-yl)-N-methyl-acetamide] had no effect. It is concluded that endogenous tachykinins via NK2 receptor activation mediate the increase in the permeability of the tracheal mucosa induced by exposure to cigarette smoke in guinea pigs.     

Synthesis and reactivity of debenzorutaecarpine derivatives]

A series of 7,12-dihydropyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-ones was prepared by Fischer indolization of 9-arylhydrazono-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one s. Quantumchemical calculations (ab initio and AM1) indicate that position 3 of 7,12-dihydro-pyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-one can be involved in electrophilic substitutions, while position 2 is sensitive towards nucleophilic attack. Bromination of 6-methyl-7,12-dihydropyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-o ne (16) with bromine afforded 3-bromo derivative (25), which was reacted with cyclic amines to give 2-amino-7,12-dihydro-pyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-ones (26-30) in an addition-elimination reaction. Vielsmeier-Haack formylation of compound (16) give 12-formyl (31) and 3,12-diformyl (32) derivatives (an N-formyl-1-aza derivative of nauclefidine alkaloid (34) at 60 degrees C and 100 degrees C, respectively. 3,12-dformyl compound (32) was oxidized to 3-carboxyl derivative (33). The quaternary salt (35), obtained from compound (16) with dimethyl sulphate, suffered a ring opening on the action of aqueous sodium hydroxide. The new compounds have been characterized by elemental analyses uv, 1H nmr and in some cases by 13C ruler, CD spectra and X-ray investigations.     

Hemodynamic and electrophysiological effects of a novel positive inotropic drug, OPC-8212, in normal and "failing" guinea pig heart preparations

OPC-8212, 3,4-dihydro-6-[4-(3,4-dimethoxy-benzoyl)-1-piperazinyl]-2 (1H)-quinolinone, significantly decreased heart rate and increased contractility (+ dP/dt) and coronary flow in isolated, perfused guinea pig Langendorff and work-performing heart preparations. The effect on contractility, but not on coronary flow, was significantly greater when the negative chronotropic effect was prevented by pacing. In guinea pig hearts made incompetent by aortic stenosis, OPC-8212 produced a significant increase in contractility and coronary flow and greater negative chronotropic effects than in control hearts. OPC-8212 improved the work performance of normal and "failing" isolated work-performing guinea pig hearts during pressure load and during volume load. In electrophysiological studies, OPC-8212 enhance Vmax, amplitude, and duration of fast action potentials (APs) in guinea pig papillary muscles. Tetraethylammonium (TEA)-induced slow APs were also potentiated with respect to Vmax, amplitude, and duration. OPC-8212 in the absence of TEA also lowered the voltage threshold for inducing the slow APs. Positive inotropic effects, but not the slow APs, of guinea pig papillary muscles were greatly enhanced by OPC-8212 at higher frequencies of stimulation (2-3 Hz), indicating an important mechanism of action that may be at least in part independent of Isi.     

Effects of novel synthesized pyridothiazines on various guinea pig heart muscle preparations

Calcium channel blockers have become important tools in the treatment of cardiovascular disorders and other diseases. Hybridization of well established calcium antagonist subclasses was an attempt to optimize their pharmacological profile. The intension of this study was to investigate the electrophysiological properties of MM 10 and MM 11 two newly synthesized compounds structurally closely related to KT-362 (5-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-1-oxopropyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate) in various isolated guinea pig heart muscle preparations by means of the conventional intracellular microelectrode tech-nique. MM 10 (2,3-dihydro-1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylaminoacetyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) and MM 11 (2,3-dihydro-1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylaminopropionyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) exerted very similar effects though the action of MM 11 was more pronounced. Whereas action potential amplitude and maximum upstroke velocity (V(max)) in papillary muscle, left atria and spontaneously beating Purkinje fibers was not affected by the compounds in a concentration range from 3 to 30 micromol/l, action potential duration at 90% time to repolarization was significantly prolonged in a concentration-dependent manner. Action potential duration at 20% time to repolarization was decreased in spontaneously beating Purkinje fibers and remained unchanged in papillary muscles and left atria. In sinoatrial nodes both compounds reduced rate of activity, action potential amplitude, maximum upstroke velocity and slope of slow diastolic depolarization while time to repolarization was prolonged. In 3 out of 6 experiments with spontaneously beating Purkinje fibers, MM 11 (30 micromol/l) led to the occurrence of early afterdepolarizations with a take off potential between -50 and -60 mV. All observed effects were completely reversible during washout with drug-free physiological salt solution. From these results it was concluded that both compounds in addition to their calcium antagonistic properties might depress repolarizing potassium currents. In contrast to the mother compound KT-362 they do not seem to affect the fast sodium inward current. Replacement of the benzothiazepine nucleus by a pyridothiazine structure may weaken or even eliminate sodium channel blocking ability. Shortening of the side chain might result in a general loss in activity.     

Synthesis and biological evaluation of certain C-4 substituted pyrazolo[3,4-b]pyridine nucleosides

A series of C-4 substituted pyrazolo[3,4-b]pyridine nucleosides have been synthesized and evaluated for their biological activity. Successful synthesis of various C-4 substituted pyrazolo[3,4-b]pyridine nucleosides involves nucleophilic displacement by a suitable nucleophile at the C-4 position of 4-chloro-1H-pyrazolo[3,4-b]pyridine (5), followed by glycosylation of the sodium salt of the C-4 substituted pyrazolo[3,4-b]pyridines with a protected alpha-halopentofuranose. Use of this methodology furnished a simple and direct route to the beta-D-ribofuranosyl, beta-D-arabinofuranosyl, and 2-deoxy-beta-D-erythro-pentofuranosyl nucleosides of C-4 substituted pyrazolo[3,4-b]pyridines, wherein the C-4 substituent was azido, amino, methoxy, chloro, or oxo. The regiospecificity of these glycosylations was determined on the basis of UV data and the anomeric configuration was established by 1H NMR analysis. Conclusive structural assignment was made by a single-crystal X-ray diffraction study of three compounds, 15, 31, and 42, as representatives of ribo-2'-deoxy-, and aranucleosides, respectively. The stereospecific attachment of all three alpha-halogenoses appears to occur by a Walden inversion (SN2 mechanism) at the C-1 carbon of the halogenose by the anionic N-1 of pyrazolo[3,4-b]pyridine. All deprotected nucleosides were tested against various viruses and tumor cells in culture. The effects of these compounds on de novo purine and pyrimidine nucleotide biosynthesis was also evaluated. Among the compounds tested, 4-chloro-1-beta-D-ribofuranosylpyrazolo[3,4-b]pyridine (16) and 1-beta-D-ribofuranosyl-4,7-dihydro-4-oxopyrazolo[3,4-b]pyridine (19) were found to be moderately cytotoxic to L1210 and WI-L2 in culture.     

Pyrido[2,1-b]quinazolinecarboxamide derivatives as platelet activating factor antagonists

A series of N-[(heteroaryl)alkyl]pyrido[2,1-b]quinazolines were evaluated for their ability to inhibit the binding of radiolabeled platelet activating factor (PAF) to its receptor on dog platelets. The most potent compounds in this series were found to be pyrido[2,1-b]quinazoline-8-carboxamides possessing a four- or six-carbon chain between the carboxamide nitrogen atom and a 3-pyridinyl or 5-pyrimidinyl moiety. Since earlier metabolism studies with pyridoquinazolinecarboxamides suggest that the carboxamide moiety is labile to hydrolysis in vivo, attempts were made to find isosteric replacements for this group. The substitutions examined led to a loss of activity; however, insertion of a methyl group on the carbon atom alpha to the carboxamide nitrogen led to an enantioselective enhancement of potency. (R)-2-(1-Methylethyl)-N-[1-methyl-4-(3-pyridinyl)butyl]-11-oxo-11H- pyrido[2,1-b]quinazoline-8-carboxamide (34) was more potent than the corresponding S enantiomer in the PAF binding assay and was also shown to be more resistant to degradation by amidases present in whole liver homogenates obtained from guinea pig, dog, and squirrel monkey. The corresponding rac-2-(1-methylethyl)-N-[1-methyl-4-(3-pyridinyl)butyl]-11-oxo-11H- pyrido[2,1-b]quinazoline-8-carboxamide (33) was found to inhibit transient PAF-induced thrombocytopenia and decreases in blood pressure in guinea pigs after intravenous or oral administration and to have a duration of action of greater than 5 h after an oral dose of 200 mg/kg. Compound 33 thus represents the prototype of a new class of orally active PAF antagonists.