Pharmacological studies on quaternized 4(3H)-quinazolinones.

Locomotor activity-inhibiting, anticonvulsant, muscle relaxant, analgesic, and antimicrobial properties of 2-methyl-3-pyridinium-acetylamino-4(3H)-quinazolinone chloride (1), 2-methyl-3-(4-methylpyridinium)acetylamino-4(3H)-quinazolinone chloride (2), 2-methyl-3-(4-ethylpyridinium)acetylamino-4(3H)-quinazolinone chloride (3), 2-methyl-3-(3-carboxamidopyridinium)acetylamino-4(3H)-quinazolinon e chloride (4), and 2-methyl-3-(4-carboxamidopyridinium)-acetylamino-4(3H)- quinazolinone chloride (5) were investigated. The locomotor activity-inhibiting properties and anticonvulsant activity of 2 were almost equal to those of methaqualone. The analgesic activities of 2 and 3 in the hot-plate test were equal to that of aspirin, whereas in the Koster test, the analgesic activity of 2 was higher. The compounds did not exhibit antimicrobial or muscle relaxant properties. Most active compounds had higher lipophilicity values than those of inactive compounds.

Enhancement of skin permeation of miconazole by phospholipid and dodecyl 2-(N,N-dimethyl amino)propionate (DDAIP).

Miconazole (MCZ) has very low solubility in both water and oil. Permeation rates through shed snakeskin from an aqueous suspension and a mineral oil suspension were 0.5 microg/cm(2)/h and almost none, respectively. When hydrogenated phosphatidylcholine (HPC) was added to mineral oil and heated to 95 degrees C, the solubility of MCZ increased in proportion to the HPC concentration. DSC measurements also indicated an interaction between them. Thus, a gel formed by hydrogenated phospholipid and mineral oil, as vehicle was prepared. The solubility of MCZ in the gel was around 1% and the permeation rate was 1.3 microg/cm(2)/h, which was about 2.5 times that from an aqueous suspension. As an alternative approach, a skin permeation enhancer, dodecyl 2-(N,N-dimethyl amino)propionate (DDAIP) was applied 2 h before a skin permeation study. The permeation from an aqueous suspension became 11 times that of the suspension without DDAIP pretreatment. The concentration of MCZ in the skin increased 8-fold, indicating that the enhancement effect involved high partition of MCZ into the skin. On the other hand, when a gel formulation was used, pretreatment with DDAIP was not as effective as incorporation of DDAIP in the gel formulation. Following pretreatment, permeation was only two times that of the gel without DDAIP pretreatment, and half that of the water suspension with DDAIP pretreatment. This suggested that release from the gel was the rate-limiting step with the gel formulation. When DDAIP was added to the gel, the permeation rate of MCZ was 3.3 microg/cm(2)/h. It was also a release limited type permeation. The gel with DDAIP is potentially a useful formulation, because of relatively high permeation while possibly avoiding overdosing.

Synthesis and structure elucidation of some 4-substituted benzylidene amino-5-[3(5)-methyl-5(3)-phenyl-1H-1-pyrazolyl]-2,4-dihydro-3H-1,2,4- triazole-3-thione derivatives with their antimicrobial activities.

A new series of 4-substituted benzylideneamino-5[3(5)-methyl-5(3)-phenyl-1H-1-pyrazolyl]-2 ,4-dihydro-3H- 1,2,4-triazole-3-thione was synthesized by reaction of I with suitable aldehyde and tested for their antimicrobial activities against six microorganisms. Most of the compounds showed antibacterial activity against Gram positive bacteria.

Some 3-hydrazono-2-indolinones and N-Mannich bases as potential anticonvulsants.

In this study a new series of 3-aryloxy/arylthioxyacetylhydrazono-2-indolinones obtained by condensation of isatin with aryloxy/arythioxyacetylhydrazines were treated with morpholine and formaldehyde to yield 1-morpholinomethyl-3-aryloxy/arylthioxyacetylhydrazono-2- indolinones. Structures of all the compounds were assigned on the basis of spectral data (UV, IR, 1H-NMR, EIMS) and elemental analyses. Anticonvulsant evaluation of the compounds revealed varying degrees of activity against pentylenentetrazole induced seizures.

[Quinazolinones. 16. Synthesis and in vitro pharmacology of 2-aryl-1- ([3-(imidazol-4-yl)propyl]-guanidinylalkyl)-2,3-dihydro-4(1H)- quinazolinones]. / Chinazolinone, 16. Mitt. Synthese und in vitro pharmakologie von 2-Aryl-1- ([3-(imidazol-4-yl)propyl]-guanidinoalkyl)-2,3-dihydro-4(1H)- chinazolinonen.

A series of 2-aryl-1- ([3-(imidazol-4-yl)propyl]guanidinylalkyl)-2,3-dihydro-4(1H)- quinazolinones were prepared starting with appropriate aminoalkyl-quinazolinones. The substances proved to be moderate H1-antagonists at the isolated guinea-pig ileum as well as H2-agonists, maximally achieving 1.6 times the activity of histamine at the isolated guinea-pig right atrium. Compounds with a three-membered carbon chain connecting the bicyclus and the guanidine system are up to 100 times more active at the atrium (chronotropic effect) than the corresponding lower homologues.

[Quinazolinones. 18. Synthesis and H1/H2-antihistaminic action of omega-[2-aryl-2,3-dihydro-4(1H)-quinazolinone-1-yl]alkyl substituted ureas and cyanoguanidines]. / Chinazolinone, 18. Mitt.: Synthese und H1/H2-antihistaminische Wirkung omega-[2-aryl-2,3-dihydro-4(1H)-chinazolinon-1-yl]alkyl-substituierter Harnstoffe und Cyanoguanidine.

A series of (2-aryl-2,3-dihydro-4(1H)-quinazolinon-1-yl)alkyl-substituted cyanoguanidines and ureas with histamine, cimetidine or roxatidine partial structure was prepared and tested for H1- and H2-antagonism at the isolated ileum and the isolated right atrium of the guinea-pig. All compounds investigated were only very weak H1-antagonists, whereas the 3-[3-(1-piperidinyl-methyl)phenoxy]propyl-cyanoguanidines and -ureas were more potent H2-antagonists than cimetidine, maximally achieving about ranitidine's potency.

Synthesis of 3-[2-(2,3-dihydro-5-phenyl-4-substituted-3H-1,2,4- triazole-3-thione-2-yl)-acetylamino]-2-methyl-4(3H)-quinazolinones and their pharmacological activities.

Some 2-methyl-3-triazole-substituted-4(3H)-quinazolinones 3a-f were prepared and tested for their H1- and H2-antihistaminic activities. In addition these compounds are central nervous system depressants and anticonvulsants. 3e shows highly significant decrease of locomotor activity.

Synthesis and antimicrobial evaluation of some arylhydrazones of 4-[(2-methylimidazo[1,2-a]pyridine-3-yl)azo]benzoic acid hydrazide.

A short series of arylhydrazones of 4-[(2-methylimidazo[1,2-a]pyridine-3-yl)azo]benzoic acid hydrazide was synthesized and tested for antimicrobial activity. All of the compounds show antimicrobial activity against Escherichia coli. A few members were also active against Klebsiella pneumoniae, Staphylococcus aureus and Pseudomonas aeruginosa. The interplanar angle (theta) between the aryl ring and the adjacent azomethine group of some representative compounds was measured by electronic absorption spectroscopy. No structure-activity-relationship between interplanar angle or lipophily and activity was found.

Synthesis and enhancing effect of dodecyl 2-(N,N-dimethylamino)propionate on the transepidermal delivery of indomethacin, clonidine, and hydrocortisone.

The biodegradable transdermal penetration enhancer, dodecyl 2-(N,N-dimethylamino)propionate (II; DDAIP), was prepared by reacting dodecyl 2-bromopropionate (I), obtained by reaction of n-dodecanol with 2-bromopropionyl halogenide, with dimethylamine. The penetration enhancing effects of DDAIP on the transport of indomethacin, clonidine, and hydrocortisone across shed snake skin (Elaphe obsoleta) were evaluated. Azone and lauryl alcohol, a possible decomposition product of DDAIP, were used as standard enhancers for comparison. In terms of flux, DDAIP showed 4.7 and 7.5 times the promoting effect for indomethacin compared to azone and lauryl alcohol, respectively. With clonidine this effect was 1.7 and 3.1 times, whereas with hydrocortisone it was 2.4 and 2.8 times higher, respectively. In vitro biodegradability of DDAIP was demonstrated in the presence of porcine esterase. The results indicate that DDAIP increases markedly the transepidermal delivery of several types of drug substances.