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.     

Recent developments in the synthesis of acetylcholinesterase inhibitors

The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of a series of pyrano[2,3-b]quinolines (2, 3), [1,8]naphthyridines (5, 6), 4-amino-2,3-diaryl-5,6,7,8-tetrahydrofuro[2,3-b]quinolines (11-13)/ 4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]furo[2,3-b]pyridine (14), 4-amino-5,6,7,8-tetrahydro-2,3-diphenylthieno[2,3-b]quinoline (15)/ 4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]thieno[2,3-b]pyridine (16) are described. These compounds are tacrine analogues that have been prepared from readily available polyfunctionalized ethyl [6-amino-5-cyano-4H-pyran]-3-carboxylates (9, 10), ethyl [6-amino-5-cyanopyridine]-3-carboxylates (7, 8), 2-amino-3-cyano-4,5-diarylfurans (17-19) and 2-amino-3-cyano-4,5-diphenylthiophene (20) via Friedl?nder condensation with selected ketones. These compounds are competitive and, in a few cases, non-competitive inhibitors for AChE, the most potent being compound (14), though three-fold less active than tacrine. The BuChE inhibitory activity is only significant in compounds 11 and 14, ten-fold less active than tacrine. Furthermore, the products 12 and 13 are selective and moderate AChE inhibitors.     

Synthesis and antifungal activity of novel pyrano[2',3':4,5]thiazolo[2,3-b]quinazolines, pyrido[2',3':4,5]thiazolo[2,3-b]quinazolines and pyrazolo[2',3':4,5]thiazolo[2,3-b]quinazolines

The starting materials thiazolo[2,3-b]quinazolines (5a,b) were obtained in one pot synthesis by treating octahydroquinazoline (2) with chloroacetic acid and aromatic aldehydes. Thiazoloquinazoline (5) was reacted with CH2(CN)2/piperidine and CH2(CN)2/NaOH (CH3OH), to furnish pyrano[2',3':4,5]thiazolo[2,3-b]quinazolines (6a,b) and pyrido[2',3':4,5]thiazolo[2,3-b]quinazoline (7), respectively. Refluxing of 5a with NH2CSNH2/KOH and hydrazines in ethanol furnished the corresponding, [1,3]thiazino[4'5':4,5]thiazolo[2,3-b]quinazoline (10) and pyrazolo[3',4':4,5]thiazolo[2,3-b]quinazolines (11a,b), respectively. Antifungal activity was shown for some of the synthesized compounds.     

3-Acyl-pyrano [2,3-b]indol-4-one

3-Acylpyrano[2,3-b]indol-4-ones The mixture which is obtained by treating 1-methyloxindole ( 1 ) with phosgene reacts with the alkali salts of the 1,3-dicarbonyl compounds 10a - 10d to yield the 3-acylpyrano[2,3-b]indol-4-ones 11a - 11d . Reactions with the salts of 1, 3-dimethylbarbituric acid and of 1 lead to the pyrone derivatives 12 and 13 , respectively.     

Reactions of 4-oxo-4H-pyrido(3',2':4,5)thieno(3,2-d)-1,3-oxazines with amines]

The reaction of the title compounds with amines gave in dependence of the reaction conditions and the structure of the title compounds and the amine 3-acylamino-thieno[2,3-b]pyridine-2-carbonamides (B), 4-oxo-4 H-pyrido[3',2':4,5]thieno[3,2-d]pyrimidines (D),N-(2-carboxy-thieno[2,3-b]pyridine-3-yl)amidines (C) and N-(thieno[2,3-b]pyridin-3-yl)amidines (E). Substances of structure C and E seem to be of biological interest, especially for their antianaphylactic reactions.     

奥氮平原料药中相关杂质的合成及结构鉴定

目的合成奥氮平原料药中的相关杂质并进行结构鉴定。方法分别以奥氮平的合成中间体4-氨基-2-甲基-10H-噻吩并[2,3-b][1,5]苯二氮杂艹卓盐酸盐和奥氮平为起始原料合成奥氮平的3个相关杂质:2-甲基-10H-噻吩并[2,3-b][1,5]苯二氮杂艹卓-4-(5H)-酮(1)、1-氯甲基-1-甲基-4-(2-甲基-10H-苯并[b]噻吩并[2,3-e][1,4]二氮杂艹卓-4-哌嗪基)-1-氯化物(2)和2-甲基-4-(4-甲基-1-哌嗪基)-10H-苯并[b]噻吩并[2,3-e][1,4]二氮杂艹卓4’-N-氧化物(3)。结果与结论合成并鉴定了奥氮平质量标准中提及的3种杂质,其结构经1H-NMR、13C-NMR谱及高分辨质谱确证;并且探讨了3种杂质可能的产生途径,以期为奥氮平的质量研究和相关杂质的控制提供帮助。     

Synthesis of imidazo[2,1-b]thiazoles as herbicides

A series of imidazo[2,1-b]thiazoles bearing halogens or a sulfonylurea group or an imidazolidone group, were synthesized and subjected to pre- and post-emergence herbicidal tests. 5-Bromo-6-(3-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole (4e) and 6-(2,3,4-trichlorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole-5-carboxylic acid (8b) showed moderate activity in the post-emergence herbicidal tests only.     

3,6-双羧甲基-4-氨基-6H-噻吩并[2,3-B]吡咯-2-羧酸的合成研究

目的设计并合成3,6-双羧甲基-4-氨基-6H-噻吩并[2,3-B]吡咯-2-羧酸。方法以柠檬酸为起始原料,经氧化酯化、Gewald反应、氮取代、环合、水解、脱羧反应制备得到目标化合物。结果合成了目标化合物,并利用质谱和核磁数据确证了结构;HPLC归一化法测得质量分数为96.98%。目标化合物的总收率为2.7%。结论 3,6-双羧甲基-4-氨基-6H-噻吩并[2,3-B]吡咯-2-羧酸的合成为雷奈酸锶中杂质的研究提供了方便。     

5-HT and benzodiazepine receptor ligands. III. Synthesis and receptor affinities of 1,2,4-triazolo[4',3':1,6]pyridazino[4,5-b]quinoline and 2,3-dihydro-9-phenyl-1H-pyrrolo[3,4-b]quinoline-1-one derivatives

The syntheses as well as 5-HT and Benzodiazepine receptor binding studies of some 1,2,4-Triazolo[4',3':1,6]piridazino[4,5-b]quinoline and 2,3-Dihydro-9-phenyl-1H-pyrrolo[3,4-b]quinoline-1-one derivatives are reported. While the triazole-containing heterocycles are devoid of any biological activity, 2-benzyl-2,3-dihydro-9-phenyl-1H-pyrrolo[3,4-b]quinoline-1-one shows some affinity for the central type of benzodiazepine receptors.     

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 pharmacological profile of non-peptide vasopressin antagonists

Recently we presented a series of 6-ethyl and 6-benzylthieno[2,3-b][1,4]thiazine derivatives with relaxing effects on vascular smooth muscle and terminal ileum. In this report the synthesis of further thieno[2,3-b][1,4]thiazine derivatives and related compounds with a thieno[2,3-b][1,4]thiazepine or thieno[3,2-b][1,4]thiazine ring system is described. The pharmacological effect of the agents was tested in isolated smooth (terminal ileum, pulmonary artery, aortic rings, myometrial strips) and heart (papillary muscle, spontaneously beating right atrium) muscle preparations of the guinea pig. Contractions were measured isometrically, and smooth muscle preparations were either precontracted with high K⁺ (60 or 90 mM KCl containing nutrient solution) or with agonists, while papillary muscles were electrically stimulated (1 Hz). The vasopressin antagonistic activity of the test compounds was tested in isolated papillary muscles in which the V_1A-receptor subtype is located. The biphasic response to vasopressin was antagonized, dependent on the chemical structure of the test compound. Thieno[3,2-b][1,4]thiazines were more potent than thieno[2,3-b][1,4]thiazine and thieno[2,3-b][1,4]thiazepine compounds. In addition, substitution of a methyl substituted terminal benzyl ring instead of a phenyl- or dichlorobenzoyl moiety attenuated the vasopressin antagonistic effect.     

Spiro hydantoin aldose reductase inhibitors derived from 8-aza-4-chromanones

A series of spiro hydantoins derived from 8-azachromanones (2,3-dihydro-4H-pyrano[2,3-b]pyridin-4-ones) has been prepared and tested for aldose reductase inhibitory activity. The standard Bucherer-Bergs conditions had to be drastically modified to increase yields from less than 1% to an acceptable 50% range. One of the most potent compounds was cis-6'-chloro-2',3'-dihydro-2'-methylspiro[imidazolidine-4,4'-4'H- pyrano[2,3-b]pyridine]-2,5-dione; resolution of this compound showed that the 2'R,4'S enantiomer 16 was the most active spiro hydantoin in this series with an IC50 of 7.5 x 10(-9) against human placenta aldose reductase.     

Hydrierte Pyrrolo[2,3-b] pyridine

Hydrogenated Pyrrolo[2,3-b]pyridines The mercuric-EDTA dehydrogenation of 1-methyl-3-(2-aminoalkyl)-piperidines gives in addition to a little 6-piperidone, mixtures of 7-methyl-2,3,3a,4,5,6-hexahydro-7H-pyrrolo[2,3-b]pyridines and 7-methyl-perhydro-pyrrolo[2,3-b]pyridines.     

Naphthannelated azepinones: synthesis and antitumor activity.

5H-Benzo[b]naphth[2,3-e]azepine-6,13-diones 4a, 4b and 4H-naphtho[2,3-e]thieno[3,2-b]azepine-5,12-dione (6) were prepared by aldol condensation of phthalic dialdehyde (3) with the fused azepinediones 2a, 2b and 5, respectively. The Schmidt reaction of naphthacene-5,12-quinone (7) yielded 6H-benzo[e]naphth[2,3-b]azepine-7,12-dione (10). Several derivatives of the heterocyclic basic scaffolds 4, 6 and 10 were prepared by standard procedures, e.g. Grignard reaction, deoxygenation with triethylsilane, and sodium borohydride reduction. Evaluation of the synthesized compounds in the NCI in vitro cell line screening revealed a modest antitumor activity without marked cell line selectivity for the majority of the derivatives. The 2-bromo-5H-benzo[b]naphth[2,3-e]azepin-6(13H)-one (19) was the only representative in this series exhibiting a noteworthy growth inhibitory effect for human tumor cells.     

6-Chloro-1,2,4-triazolo[4,3-b]pyrido[2,3-d]-and [3,2-d]pyridazines - Synthesis and Structure Determination

5,8-Dichloropyrido[2,3-d]pyridazine ( 2 ) gave with hydrazine hydrate in dioxane 5-chloro-8-hydrazino- and 8-chloro-5-hydrazinopyrido[2,3-d]pyridazines 3 and 4 . When 3 and 4 were allowed to react with formic acid they gave a mixture of the 6-chloro-1,2,4-triazolo[4,3-b]pyrido[2,3-d] - and [3,2-d]pyridazines ( 5 and 6 ).     

Synthesis and properties of 2H-2-(4-substituted -1-piperazinylalkyl)-4,6-dimethyl-3-oxo-2,3-dihydroisothiazolo [5,4-b] pyridines

The preparation of a number of derivatives of 2H-4,6-dimethyl-3-oxo-2,3-dihydroisothiazolo [5,4-b] pyridine (1) containing 4-methyl(phenyl, heteroaryl)-1-piperazinylalkyl moiety by two routes has been described. Preliminary results of pharmacological screening of compounds synthesized showed antipsychotic activity of 2H-2-13-(4-phenyl-1-piperazinyl)propyl-3-oxo-2,3-dihydroisothiazolo [5.4-b] pyridine (4f).     

New isoxazol /5,4-b/ pyridine-3-acetic acids]

We prepared two isoxazol [5,4-b] piridin-3-acetic acids by two different synthetic methods. 4,6-Dimethylisoxazole [5,4-b] pyridin-3-acetic acid was obtained by reaction with hydroxylamine of 4-hydroxy-5,7-dimethyl-2H-pyrano [2,3-b]pyridin-2-one, which was in turn prepared starting from 2-hydroxy-3-acetyl-4,6-dimethylpyridine. Isoxazolo [5,4-b] pyridine-3-acetic acid was obtained starting from 3-methyl-5-aminoisoxazole and has shown interesting auxin activity.     

Synthesis and biological activity of pyrido(2,3-e)-1,4-diazepine and of pyrido(2,3-b)(1,4)diazepine]

The Schmidt reaction on tetrahydro-1,8-naphthyridin-4-ones gave pyrido [2,3-e]-1,4-diazepines and pyrido[2,3-b][1,4]diazepines. The preliminary pharmacological screening of some of these compounds showed no appreciable activity.     

Sterically controlled regiospecific heterocyclization of 3-hydrazino-5-methyl-1,2,4-triazino[5,6-b]indole to 10-methyl-1,2,4-triazolo[4',3':2,3[1,2,4-triazino[5,6-b]indoles

3-Hydrazino-5-methyl-1,2,4-triazino[5,6-b]indole underwent sterically controlled regiospecific heterocyclizations with a variety of one-carbon cyclizing agents to give the sterically more favored linearly annulated 10-methyl-1,2,4-triazolo[4',3':2,3[1,2,4-triazino[5,6-b]indoles rather than the sterically less favored angularly annulated 10-methyl-1,2,4-triazolo[3',4':3,4]1,2,4-triazino[5,6-b]indoles. The assigned structures were corroborated by comparison with unequivocally synthesized authentics, chemical and spectral data. The antimicrobial activity of some of the prepared compounds was investigated.