Studies on uricosuric diuretics. II. Substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids.

A series of substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids 9 and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids 12 were synthesized and evaluated for uricosuric and diuretic activities in rats. Many of the benzisoxazole derivatives 9 showed uricosuric and only weak diuretic activities, whereas the benzoxazoles 12 exhibited potent diuretic activities with little affecting urate excretion. Among these compounds, 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carbo xylic acid (9b, AA-193) was found to be a potent uricosuric agent without diuretic activity and was selected for further development.     

Benzothiazolo[3,2-c]-1,3-dioxolo[4,5-g]quinazolines

Zusammenfassung Es wurde eine Reihe von 5,12a-Dihydro-6-alkyl/aryl-6H-benzothiazolo [3,2-c]-1,3-dioxolo[4,5-g]chinazoline, sowohl mitcis-als auchtrans-ständigen Wasserstoffatomen an Kohlenstoff 6 und 12a, synthetisiert. Ebenso wurden auch Verbindungen dieses Systems mit Thiazol an Position 6 hergestellt. Die Strukturen wurden mittels IR- und NMR-spektroskopischen Daten abgesichert.

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Benzothiazolo[3,2-c]-1,3-dioxolo[4,5-g]quinazolines

Some 5,12a-dihydro-6-alkyl/aryl-6H-benzothiazolo[3,2-c]-1,3-dioxolo [4,5-g]quinazolines withcis as well astrans stereochemistry of the hydrogens at carbon 6 and 12a have been synthesised. The synthesis of another series of compounds of the above system with thiazole ring at position 6 has also been accomplished. The structures have been established on the basis of IR and PMR data.

     

Studies on uricosuric diuretics. I. Syntheses and activities of xanthonyloxyacetic acids and dihydrofuroxanthone-2-carboxylic acids

A series of substituted xanthonyloxyacetic acids (5 and 6), 1,2-dihydrofuro[2,3-c]xanthone-2-carboxylic acids (7) and 2,3-dihydrofuro[3,2-b]xanthone-2-carboxylic acids (8) were synthesized and tested for diuretic and uricosuric activities in rats. Most of the xanthon-3-yloxyacetic acids (5) and 7 showed potent diuretic activities, while 8 had lower activities. Uricosuric activities were found in 5c, 5f, 5k, 5m, 5o, 5p, 5r, 7m, 7p and 8q.     

Synthesis of 1,4-dihydro-4-oxopyridazino[1,6-a]indole-3-carboxylic acids and 1,4-dihydro-4-oxopyrido[3′,2′:4,5]pyrrolo[1,2-b]-pyridazine-3-carboxylic acids as potential antibacterial agents

A few aza analogues of the quinolones have been prepared in the two families of the 1,4-dihydro-4-oxopyridazino[1,6-a]indole-3-carboxylic acids and the 1,4-dihydro-4-oxopyrido[3′,2′:4,5]pyrrolo[1,2-b]-pyridazine-3-carboxylic acids to check their antibacterial potential. One compound 6c shows antibacterial activities of the level of nalidixic acid and represents a new lead structure differing from the classical quinolones.     

Studies on antibacterial agents. II. Synthesis and antibacterial activities of substituted 1,2-dihydro-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acids

A series of substituted 1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acids for the treatment of systemic infections was synthesized via 7-bromo-3-ethylthio-4,5-difluoro-2-methylindole (3), which was prepared by Gassman's indole synthesis in excellent yield. The synthesized pyrroloquinolines were tested for their antibacterial activities. 8-Fluoro-1,2-dihydro-2-methyl-9-(4-methyl-1-piperazinyl)-6-oxo-6H- pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid showed a potent antibacterial activity against gram-positive and gram-negative bacteria.     

Synthesis of 5H-pyridazo[4,5-b]indoles by condensation of 2-acylindole-3-carboxylic acids with hydrazine

5H-Pyridazo[4,5-b]indol-1-ones were obtained by heating 2-acetylindole-3- or 2-aroylindole-3-carboxylic acids with hydrazine hydrate in ethylene glycol or alcohol. 1-Chloro-5H-pyridazo[4,5-b]indoles are formed by treatment of 5H-pyridazo[4,5-b]indol-1-ones with phosphorus oxychloride.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1064–1066, August, 1982.     

Novel heterocyclic systems based on 8-R-4,5-dihydro-4,4-dimethyl-[1,2]dithiolo[3,4-c]quinoline-1-thiones

Based on the reaction of 8-R-4,5-dihydro-4,4-dimethyl[1,2]dithiolo[3,4-c]quinoline-1-thiones with oxalyl chloride followed by the reactions of 1,3-dipolar cycloaddition and diene synthesis with participation of acetylenedicarboxylic acid dimethyl ester, we have developed approaches to synthesis of novel polycondensed heterocyclic systems: [1,2]dithiolo[3,4-c]pyrrolo[3,2,1-ij]quinoline-4,5-dione, 6-(1,3-dithiol-2-ylidene)-1,2-dioxo-5-thioxo-7H-pyrrolo[3,2,1-ij]quinoline and 4,5-dioxospiro(pyrrolo)-[3,2,1-ij]thiopyrano[2,3-c]quinoline-11,2′-[1,3]dithiole. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 610–615, April, 2006.     

Quino[1,2-c]quinazolines. I. Synthesis of quino[1,2-c]quinazolinium derivatives and the related indazolo[2,3-a]quinoline derivatives as analogs of the antitumor benzo[c]phenanthridine alkaloids

9,10-Dimethoxy-1,2,3,4,12,13-hexahydro-1-oxoquino[1,2-c]quinazolinium perchlorate, 1,2,3,4,13,24-hexahydro-1-oxo[1,3]dioxolo[4,5-g]quino[1,2-c]quinazolinium perchlorate, 6-methyl-2,3,9,10-tetramethoxyquino-[1,2-c]quinazolinium perchlorate and 2,3-dimethoxy-13-methyl[1,3]dioxolo[4′,5′:6,7]quino[1,2-c]quinazolinium perchlorate were synthesized as analogs of the potent antitumor benzo[c]phenanthridine alkaloids nitidine and fagaronine. The related 2,3,8,9-tetramethoxyindazolo[2,3-a]quinoline and 2,3-dimethoxy[1,3]dioxolo-[4,5-g]indazolo[2,3-a]quinoline were also synthesized. Further, the novel formation of 6,7-dimethoxy-2-(2-ethylamino-4,5-dimethoxyphenyl)quinoline via reductive alkylation with Raney nickel in refluxing ethanol is also reported.     

New heterocyclic structures. [1,3]Thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine

Derivatives of two new molecular structures, namely, [1,3]thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d]-[1,3]thiazino[3,2-a]pyrimidine, were synthesized together with other heterocyclic compounds. Retrosynthetic analysis of their molecular skeletons suggested a simple way of obtaining 3,4-dihydro-7,8-diamino-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one, which is a useful intermediate for their synthesis. This intermediate and the thiazole homologue were obtained directly by reaction of 5,6-diamino-2,3-dihydro-2-thioxo-4(lH)-pyrimidi-none with 1,3- or 1,2-dibromoalkane, respectively.     

Synthesis of 1-(1,3-dialkyl-2-oxo-2,3-dihydro-1<Emphasis Type="Italic">H</Emphasis>-imidazo-[4,5-<Emphasis Type="Italic">b</Emphasis>]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acids

Nitration of 2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one gave its 5-nitro derivative which was subjected to alkylation with dimethyl sulfate, diethyl sulfate, and benzyl(dimethyl)phenylammonium chloride. The resulting 1,3-dimethyl-, 1,3-diethyl-, and 1,3-dibenzyl-5-nitro-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones were reduced to the corresponding 1,3-dialkyl-5-amino-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones, and the latter reacted with itaconic acid to produce 1-(1,3-dialkyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acids. 1-(2-Oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acid was obtained by analogous reaction with 5-amino-2,3-dihydro-1H-imidazo[4,5-b]-pyridin-2-one.     

The preparation of the benzo[4,5]cyclohepta[1,2-b]pyrazine and benzo[4,5]cyclohepta[1,2-b]quinoxaline systems

Benzo[4,5]cyclohepta[1,2-b]quinoxaIine 2 , benzo[4,5]cyclohepta[1,2-b]pyrazine 3a and benzo[4,5]cyclohepta[1,2-b]quinoxaline 4 were prepared from 4,5-benzotropolone and 1,2-phenylenediamine, ethylenediamine and 1,2-diaminocyclohexane, respectively. Compound 3a was methylated to 3b .     

Synthesis and photoreactivity of aryl substituted 4,5-dithienyl[1,3]dithiol-2-ones

UV irradiation of hitherto unknown 4,5-bis-benzo[b]thiophen-3-yl-[1,3]dithiol-2-one gave 3-(3-benzo[b]thienyl)-thieno[3,4-c]benzo[e][1,2]dithiine by loss of carbon monoxide and rearrangement, whereas 4,5-bis-(2-bromo-phenyl)-[1,3]dithiol-2-one gave a polymeric material containing S-S bridges. The structures of both photoproducts were demonstrated on the basis of chemical behaviour and/or X-ray diffraction.     

Facile synthesis of some novel pyrido[3',2':4,5]thieno[2,3-b][1,4]thiazine-8-carboxylic acids

Model tetrahydropyrido[3',2':4,5]thieno[2,3-b][1,4]thiazines 9a-c were synthesized via reductive lactamization, using sodium dithionite, of the respective 2-[(carboxyalkyl)thio]-3-nitro-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acids 7a-c. The latter derivatives were made via interaction of 2-chloro-7-cyclopropyl-3-nitro-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (6) with each of alpha-mercaptoacetic, alpha-mercaptopropionic, and alpha-mercaptosuccinic acids and triethylamine in aqueous acetone at room temperature. The structures of 7a-7c and 9a-9c are supported by microanalytical and spectral (IR, MS, NMR) data. Compounds 9a and 9c showed potent inhibitory activity against the IGROV1 (Ovarian Cancer) cell line.     

Selective C-acylation of 2-aminoimidazo[1,2-a]pyridine: application to the synthesis of imidazopyridine-fused [1,3]diazepinones

A series of 20 optically pure 3,4-dihydro-5H-pyrido[1',2':1,2]imidazo[4,5-d][1,3]diazepin-5-ones which form a new family of azaheterocycle-fused [1,3]diazepines were synthesized in four steps with 17-66% overall yields. The key step consists of a selective C-acylation reaction of easily accessible 2-aminoimidazo[1,2-a]pyridine at C-3.     

v-Triazolines. Part XIX. Thiocino[4,5-d]-1,2,3-triazole and thiocino[4,5-d]isoxazole derivatives

5-Amino-2,3,6,7-tetrahydrothiocines were reacted with arylazides yielding 1-aryl-9a-amino-1,3a,4,5,7,8,9,9a-octahydrothiocino[4,5-d]-1,2,3-triazoles which could be deaminated to 1-aryl-1,4,5,7,8,9-hexahydrothiocino-[4,5-d]-1,2,3-triazoles. Similarly, the above enamines yielded, with nitrile oxides, 3-aryl-9a-amino-3a,4,5,8,9,9a-hexahydrothiocino[4,5-d]isoxazoles which were transformed with acids into 3-aril-4,5,8,9-tetrahydrothiocino-[4,5-d]isoxazoles.     

Synthesis of [4,5-Bis(hydroxymethyl)-1,3-dithiolan-2-yl]nucleosides as Potential Inhibitors of HIV(1)

The synthesis of [4,5-bis(hydroxymethyl)-1,3-dithiolan-2-yl]nucleosides is described. (2S,3S)-1,2:3,4-Diepoxybutane (13) was reacted with potassium thiocyanate to give (2R,3R)-1,2:3,4-diepithiobutane (14). Thiiranering opening with acetate followed by deacetylation gave (2R,3R)-2,3-dithiothreitol (19) which was silylated and treated with trimethyl orthoformate to give the 2-methoxy-1,3-dithiolane 20. Condensation of 20 with silylated thymine, uracil, N(4)-benzoylcytosine and 6-chloropurine using a modified Vorbrüggen procedure, followed by deprotection, gave the nucleoside analogues. Compounds 26, 28, and 30 were found to be inactive when tested for anti-HIV activity in vitro.     

Synthesis and some properties of N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]pyrazinones

Reactions of methyl 2-(2-formyl-1H-pyrrol-1-yl)alkanoates with unsubstituted aliphatic 1,2-, 1,3-, and 1,4-diamines gave N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]-pyrazinones. Some of them show ring-chain tautomerism. Transformations of these compounds led to a number of novel heterocyclic systems: 2,10-dihydro-3H,5H-imidazo[1,2-a]-pyrrolo[1,2-d]pyrazines, 2,3,4,11-tetrahydro-6H-pyrrolo[1??,2??:4,5]pyrazino[1,2-a]pyrimidines, 1,2,3,5,6,10b-hexahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazines, 1,3,4,6,7,11b-hexahydro-2H-pyrrolo[2??,1??:3,4]pyrazino[1,2-a]pyrimidines, and 2,3,4,5,6,7-hexahydro-1H-pyrrolo[2,1-c]-[1,4,7]triazacycloundecin-8(9H)-one.     

Derivatives of benzo[4,5]cyclohepta[1,2-b]thiophene. 4. Synthesis of 1-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)-3-alkylaminoazetidines

Thirteen 1-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)-3-alkylaminoazetidines 11 have been synthesized in three steps from 4-amino-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene ( 6 ), which was obtained from the reduction of either 4-azido 4 or 4-hydroxyimino 5 derivatives. All the compounds have been evaluated as potential antidepressive agents.     

Aryloxyacetic acid diuretics with uricosuric activity. II. Substituted [(4-oxo-4H-1-benzopyran-7-yl)oxy]acetic acids and the related compounds.

Di- and tri-substituted [(4-oxo-4H-1-benzopyran-7-yl)oxy]acetic acids, and 4-oxo-3-phenyl-4H-furo[2,3-h]-[1]benzopyran-8-carboxylic acid were synthesized and tested for natriuretic and uricosuric activities. Among the compounds tested, 3,5-disubstituted [(4-oxo-4H-1-benzopyran-7-yl)oxy]acetic acids (6c-f, h, n and x) showed potent natriuretic and uricosuric activities, whereas 4-oxo-3-phenyl-4H-furo[2,3-h][1]benzopyran-8-carboxylic acid (6dd) possessed only potent natriuretic activity. The structure-activity relationships are also discussed.     

Synthesis of 3,5-Disubstituted-4,5-dihydroindeno[1,2-c] [1,2]diazepin-6(1H)-ones

3,5-Disubstituted 4,5-dihydroindeno[1,2-c][1,2]diazepin-6 (1H)-ones ( 3a–g ) were obtained in 29–72% yields by condensing 2-(substituted-2-acylethyl)-1,3-indandiones ( 1a–n ) with hydrazine. The NH group of the indenodiazepinones 3a–g is quite unreactive. Two methods based on the Michael reaction were used for preparing the acylethylindandiones 1a–n : one from 1,3-indandione and chalcone-type compounds and the other from 2-benzylidene-1,3-indandione and acetophenones. The latter method was found more practical and of more general application.