Synthesis and biological evaluation of 6-amino-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (3,7-dideazaguanine)

The synthesis of 6-amino-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (3,7-dideazaguanine, 2) has been accomplished from 3-(ethoxycarbonyl)pyrrole-2-acetonitrile. In contrast to 3-deazaguanine, compound 2 did not show any antitumor, antiviral, or antibacterial properties. Furthermore, it was not a substrate for hypoxanthine-guanine phosphoribosyltransferase or purine nucleoside phosphorylase.     

Dihydroisochinolinumlagerung, 31. Mitt.1) 4-Allyl-5-methyl-4,5-dihydrothieno[3,2-c]pyridin+)

Dihydroisoquinoline Rearrangement, XXXI: 4-Allyl-5-methyl-4,5-dihydrothieno[3,2-c]pyridine The synthesis of 4-allyl-5-methyl-4,5-dihydrothieno[3,2-c]pyridine (4) is described. With 1N-HCl 4 rearranges with 23% yield to the 6-allyl compound 5. To a small extent 4 disproportionates to yield the compounds 3 and 7 .     

Synthesis and biological activity of certain 6-substituted and 2,6-disubstituted 2'-deoxytubercidins prepared via the stereospecific sodium salt glycosylation procedure

A number of 6-substituted and 2,6-disubstituted pyrrolo[2,3-d]pyrimidine 2'-deoxyribonucleosides were prepared by the direct stereospecific sodium salt glycosylation procedure. Reaction of the sodium salt of 4-chloro-6-methyl-2-(methylthio)pyrrolo[2,3-d]pyrimidine (6a) or 4,6-dichloro-2-(methylthio)pyrrolo[2,3-d]pyrimidine (6b) with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-alpha-D-erythro-pentofuranose (9) provided the corresponding N7 2'-deoxy-beta-D-ribofuranosyl blocked derivatives (8a and 8c) which, on ammonolysis, gave 4-amino-6-methyl-2-(methylthio)-7-(2-deoxy-beta-D-erythro-pentofuranosyl )pyrrolo[2,3-d]pyrimidine (11a) and 4-amino-6-chloro-2-(methylthio)-7-(2-deoxy-beta-D-erythro-pentofuranosyl )pyrrolo[2,3-d]pyrimidine (11b), respectively. Dethiation of 11a and 11b afforded 6-methyl-2'-deoxytubercidin (10a) and 6-chloro-2'-deoxytubercidin (10b), respectively. Dehalogenation of 10b provided an alternate route to the reported 2'-deoxytubercidin (3a). Application of this glycosylation procedure to 4,6-dichloro and 4,6-dichloro-2-methyl derivatives of pyrrolo[2,3-d]pyrimidine (15a and 15b) gave the corresponding blocked 2'-deoxyribonucleosides (18a and 18b), which on ammonolysis furnished 10b and 4-amino-6-chloro-2-methyl-7-(2-deoxy-beta-D-erythro- pentofuranosyl)pyrrolo[2,3-d]pyrimidine (17), respectively. This stereospecific attachment of the 2-deoxy-beta-D-ribofuranosyl moiety appears to be due to a Walden inversion at the C1 carbon by the anionic heterocyclic nitrogen. Controlled deacylation of 4-chloro-7-(2-deoxy-3,5-di-O-p-toluoyl-beta-D-erythro-pentofuranosyl) pyrrolo[2,3-d]pyrimidine (20a) gave 4-chloro-7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d] pyrimidine (20b). Dehalogenation of 20b gave the 2'-deoxynebularin analogue 7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine (19), and reaction of 20b with thiourea gave 7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine-4(3H)- thione (21). All of these compounds were tested in vitro against certain viruses and tumor cells. Only compounds 12a, 20b, and 21 showed significant activity against measles in vitro, and the activity is comparable to that of ribavirin. Although compounds 3a and 12b are slightly more active than ribavirin against HSV-2 in vitro, they are relatively more toxic to Vero cells. Compounds 3a and 20b exhibited moderate cytostatic activity against L1210 and P388 leukemia in vitro but are considerably less active than 2-chloro-2'-deoxyadenosine (1).     

Synthesis of Substituted Benzamides,Benzimidazoles and Benzoxazines as Potential Anthelmintic and Antimicrobial Agents

A number of substituted benzamides 5–21 , 2,5(6)-disubstituted benzimidazoles 12–24 , 6-chloro-3-(2-nitro-5R-phenyl)-2,3-benzoxazines 15–28 and 3,8-dichloro-6-oxobenzimidazo[3,2-α] [1,3]benzoxazine ( 19 ) have been synthesized. Their anthelmintic and antimicrobial activities are reported.     

Synthesis and antiviral activity of certain 4-substituted and 2,4-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines

Treatment of the sodium salt of 4-chloro-2-(methylthio)pyrrolo[2,3-d]pyrimidine (2) with (2-acetoxyethoxy)methyl bromide (3) has provided 4-chloro-2-(methylthio)-7[(2-acetoxyethoxy)methyl]pyrrolo[2,3- d]pyrimidine (4). Ammonolysis of 4 at room temperature gave 4-chloro-2-(methylthio)-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3- d]pyrimidine (5). However, ammonolysis of 5 at 130 degrees C furnished 4-amino-2-(methylthio)-7-[(2-hydroxyethoxy)methyl]-pyrrolo[2,3- d]pyrimidine (6), which on desulfurization with Raney Ni yielded 4-amino-7-[(2-hydroxyethoxy)-methyl]pyrrolo[2,3-d]pyrimidine (7) (acyclic analogue of tubercidin). The oxidation of 6 with m-chloroperbenzoic acid provided the sulfone derivative 8. A nucleophilic displacement of the 2-methylsulfonyl group from 8 with methoxide anion provided 4-amino-2-methoxy-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (9). Demethylation of 9 with iodotrimethylsilane gave 4-amino-2-hydroxy-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (10). Treatment of 2,4-dichloropyrrolo[2,3-d]pyrimidine (11) with 3 gave the protected acyclic compound 12, which on deacetylation and ammonolysis under controlled reaction conditions gave 2,4-dichloro-7-[(2-hydroxyethoxy)-methyl]pyrrolo[2,3-d]pyrimidine (13) and 4-amino-2-chloro-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3- d]pyrimidine (14), respectively. The condensation of 2-acetamido-4-chloropyrrolo[2,3-d]pyrimidine (15) with 3 gave the protected acyclic compound 16, which on concomitant deacetylation and ammonolysis with methanolic ammonia at an elevated temperature yielded 2,4-diamino-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (17) in moderate yield. In tests involving human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1), only slight activity and cytotoxicity were observed. The most active compounds (12 and 13) were slightly more active against HCMV than acyclovir, but both compounds were inactive against HSV-1. The activity against HCMV, however, was not well separated from cytotoxicity leading to the conclusion that these compounds did not merit further study.     

Dihydroisochinolinumlagerung, 29. Mitt. 4-Benzyl-5-methyl-4,5-dihydrofuro[3,2-c]pyridine

Dihydroisoquinoline Rearrangement, XXIX: 4-Benzyl-5-methyl-4,5-dihydrofuro[3,2-c]pyridines The synthesis of 4-benzyl-5-methyl-4,5-dihydrofuro[3,2-c]pyridine (7) is described. With diluted acids 7 does not undergo the dihydroisoquinoline rearrangement, and no reaction product can be isolated. Introduction of a methyl group at C-2 (compound 14 ) does not change this situation. The tetrahydro compound 10 is stable under the conditions of the dihydroisoquinoline rearrangement.     

Nucleic acid related compounds. 74. Synthesis and biological activity of 2'(and 3')-deoxy-2'(and 3')-methylenenucleoside analogues that function as mechanism-based inhibitors of S-adenosyl-L-homocysteine hydrolase and/or ribonucleotide reductase.

Treatment of 2-amino-6-chloro-9-(beta-D-ribofuranosyl)purine (21) with TBDMS chloride/imidazole/DMF gave a separable mixture of 5'-O, 2',5'-bis-O (22), 3',5'-bis-O (23), and 2',3',5'-tris-O-TBDMS derivatives. Oxidation of 22 and 23 with CrO3/pyridine/Ac2O, treatment of the respective ketonucleosides with methylenetriphenylphosphorane, and deprotection gave 2-amino-6-chloro-9-[3(and 2)-deoxy-3(and 2)-methylene- beta-D-erythro-pentofuranosyl]purines (28 and 37) that were converted into other 2-amino-6-substituted-purine analogues. Tubercidin was converted into 2'-deoxy-2'-methylenetubercidin (49) by an analogous route. Inactivation of S-adenosyl-L-homocysteine hydrolase by 2'- and 3'-methyleneadenosine analogues was investigated. Mechanism-based inhibition of S-adenosyl-L-homocysteine hydrolase and anticancer and antiviral activities of 2'(and 3')-deoxy-2'(and 3')-methylenenucleoside analogues are discussed.     

Structure-activity studies of 4,6-disubstituted 2-(morpholinocarbonyl)furo[3,2-b]indole derivatives with analgesic and antiinflammatory activities

4,6-Disubstituted 2-(morpholinocarbonyl)furo[3,2-b]indole derivatives showed analgesic and antiinflammatory activities when assayed by the acetic acid writhing test in mice and the carrageenin edema test in rats. To understand how the substituents affect the biological activities, the quantitative structure-activity relationships (QSAR) of 38 compounds were analyzed using the adaptive least-squares method (ALS method). The resulting QSAR suggested that some chemical modifications of 4,6-disubstituted furo[3,2-b]indole derivatives would improve their biological activities. Thus, 15 additional compounds were synthesized to reinforce and confirm the correlation. Among these compounds, particularly 4-(2-ethylhexanoyl)-2-(morpholinocarbonyl)-6-(trifluoromethy l) furo[3,2-b]indole showed pronounced biological activities. This compound gave a pharmacological activity spectrum similar to that of tiaramide but exhibited much higher potency.     

Synthesis and antitumor evaluation in mice of certain 7-deazapurine (pyrrolo[2,3-d]pyrimidine) and 3-deazapurine (imidazo[4,5-c]pyridine) nucleosides structurally related to sulfenosine, sulfinosine, and sulfonosine

7-Deaza (pyrrolo[2,3-d]pyrimidine) and 3-deaza (imidazo[4,5-c]pyridine) congeners of sulfenosine (5a and 9), sulfinosine (6a and 10), and sulfonosine (7a) have been prepared and evaluated for their antileukemic activity in mice. Amination of 2-amino-7-beta-D-ribofuranosylpyrrolo[2,3-d]pyrimidine-4(3H)-th ion e (4a) and its 2'-deoxy analogue (4c) with a chloramine solution gave the corresponding 4-sulfenamides (5a and 5c, respectively), which on selective oxidation with m-chloroperoxybenzoic acid (MCPBA) gave the respective diastereomeric 2-amino-7-beta-D-ribofuranosyl-pyrrolo[2,3-d]pyrimidine-4-sulfinamide (7-deazasulfinosine, 6a) and its 2'-deoxy derivative (6c). A similar amination of 7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine-4(3H)- thione (4b) gave the corresponding 4-sulfenamide derivative (5b). Oxidation of 5b with 1 molar equiv of MCPBA furnished (R,S)-7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine- 4- sulfinamide (6b), whereas use of excess of MCPBA afforded the corresponding sulfonamide derivative (7b). Treatment of 3-deaza-6-thioguanosine (8) with a chloramine solution gave 3-deazasulfenosine (6-amino-1-beta-D- ribofuranosylimidazo[4,5-c]pyridine-4-sulfenamide, 9). Controlled oxidation of 9 with MCPBA afforded 3-deazasulfinosine (10). As gauged by increases in the mean postinoculation life spans of L1210 inoculated mice, none of these nucleosides exhibited biologically significant activity (T/C greater than or equal to 125). Even so, antileukemic activity appeared to be influenced, albeit not uniformly, by structural modifications in the base and carbohydrate moieties of sulfenosine and sulfinosine. Thus, while several of the compounds were lacking in cytotoxic activity, eight others (4c, 5a, 5c, 6a, 6b, 7b, 9, and 10) were estimated to have reduced body burdens of viable L1210 cells by 16-77%.     

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 biological properties of purine and pyrimidine 5'-deoxy-5'-(dihydroxyphosphinyl)-beta-D-ribofuranosyl analogues of AMP, GMP, IMP, and CMP

Methyl 2,3-O-isopropylidene-D-ribofuranoside (1) was converted to 1-O-acetyl-5-bromo-5-deoxy-2,3-di-O-benzoyl-D-ribofuranose (6) in five steps with good yield. The Arbuzov condensation of compound 6 with triethyl phosphite resulted in the synthesis of 1-O-acetyl-2,3-di-O-benzoyl-5-deoxy-5-(diethoxyphosphinyl)-D-ribofuranos e (7). Compound 7 was used for direct glycosylation of both purine and pyrimidine bases. The glycosylation was accomplished with the dry silylated heterocyclic base in the presence of trimethylsilyl triflate. Deblocking of the glycosylation products gave exclusively the beta anomer of the 5'-phosphonate analogues of 9-[5'-deoxy-5'-(dihydroxyphosphinyl)-beta-D-ribofuranosyl]adenine (13), 9-[5'-deoxy-5'-(dihydroxyphosphinyl)-beta-D-ribofuranosyl]guanosin e (16), 9-[5'-deoxy-5'-(dihydroxyphosphinyl)-beta-D-ribofuranosyl]hypoxant hine (17), and 9-[5'-deoxy-5'-(dihydroxyphosphinyl)-beta-D-ribofuranosyl]cytosine (15), described here for the first time. The target compounds as well as their intermediates showed no in vitro antiviral or antitumor activity, although phosphorylation of 15 and 16 to di- and triphosphate analogues was demonstrated with use of isolated cellular enzymes.     

The thieno[3,2-c]pyridine and furo[3,2-c]pyridine rings: new pharmacophores with potential antipsychotic activity

Two new arylpiperazine derivatives, the 4-(1-piperazinyl)thieno- and -furo[3,2-c]pyridine ring systems, have been synthesized and appended via tetramethylene chains to various imide rings. Target compounds from each series were found to have significant activity in the blockade of apomorphine stereotypy and apomorphine-induced climbing, the Sidman avoidance response, and the conditioned avoidance response. In addition, while potent affinity for serotonin 5-HT1 and 5-HT2 receptors was observed for both the thieno- and furo[3,2-c]pyridine derivatives, the interaction of these molecules with the dopamine D2 receptor was weak. Electrophysiological studies of the lead prototypes from each series, involving compounds 22 and 33, indicate these two molecules have distinctively different effects on dopamine neurons in areas A9 and A10. Despite the similarity these molecules share in their behavioral indices of antipsychotic activity, it is likely that the thieno- and furo[3,2-c]pyridine rings employ different mechanisms to achieve this convergence of biological effects.     

Synthesis of perhydropyrazino [1,2-c] pyrimidine derivatives

The reaction of 1-benzoyl-2-oxo-4,6-dihydroxyazetino-[3,2-d] pyrimidine (III) with diethanolamine affords the amide (IV). Heating of the last with SOCl2 yields 2-beta-chloroethyl-8-hydroxy-9-benzoylamino-perhydropyrazino [1,2-c] pyrimidine-1,6-dione (VI). Reaction of compound (VI) with different amines gives the respective 2-beta-aminosubstituted derivatives (VII-XIII). Some of the obtained compounds showed central activity.     

Synthesen von 3,7-Dioxo-3H,7H-benzo[1,2-c:4,5-c']diisoxazol-4,8-diol-salzen

Syntheses of 3,7-Dioxo-3H,7H-benzo[l,2-c:4,5-c′]diisoxazole-4,8-diolates Compounds la , lb react with diisopropylammonium thiophenolate 2/3 to yield the salt 4 and 2 moles of phenyl ethyl thioether. Compound l a reacts with triethylamine to yield the salt 6 , whereas lb reacts with triethylamine to yield 7 . Compound 8a was isolated by the reaction of pyridine with lb whereas compound 8b was obtained by the reaction of la with pyridine. On the other hand, lb reacts with pyridine and p-toluenesulfonic acid to yield 8c and 11 ; Grignard reagents such as methyl magnesium iodide yield the Mg salt 10 .     

Thieno[3,2-c]quinoline-4-yl-amines--synthesis and investigation of activity against malaria

Thieno[3,2-c]quinoline-4-yl-amines - synthesis and investigation of activity against malaria pH-Dependant reduction of the methyl 2-(2-nitrophenyl)thiophene-3-carboxylate 3, formed by Suzuki coupling of methyl 2-iodothiophene-3-carboxylate (2) with 2-nitrophenylboronic acid, yielded the cyclic hydroxamic acid 4 and the lactam 5, respectively. The 4-chlorothieno[3,2-c]quinoline 6 was formed from the lactam 5 by heating with POCI3/PCI5s. Melting of 6 with the novaldiamine base in phenol gave the chloroquine analogue 7, whereas the amodiaquine and the pyronaridine analogues 8 and 9 were obtained using phenol Mannich bases. The reaction of 6 with putrescine and N,N'-bis(3-aminopropyl)piperazine as spacer formed the bisquinoline derivatives 10 and 11 as well as the monosubstituted quinoline 12. In the same manner the isomeric 4-chlorothieno[2,3-c]quinoline 13 reacted to yield the quinoline-4-yl-amines 14-16. The compounds 7-12 and 14-16 were tested for in vitro growth inhibition of the malaria parasite Plasmodium falciparum. As most active compound the pyronaridine derivative 9 displayed an IC50 value of 210 nM with the chloroquine sensitive P. falciparum strain 3D7 and 750 nM with the chloroquine resistant P. falciparum strain Dd2. The N,N'-bis(3-aminopropyl)piperazine derivative 11 displayed in vivo activity in Plasmodium vinckei infected mice with an ED50 value of 30 mg/kg after i.p. administration.     

Synthesis and biological evaluation of some pyrimidine, pyrimido[2,1-b][1,3]thiazine and thiazolo[3,2-a]pyrimidine derivatives

4,6-Diamino-1H-pyrimidine-2-thione (1) was used for the preparation of pyrimidine derivatives 2-5. Compound 5 was cyclized to produce pyrimido[2,1-b][1,3]thiazine derivative 6 which was condensed with p-chlorobenzaldehyde to give compound 7. The latter compound was reacted with hydroxylamine to give isoxazolo[4,5-d]thiazino[2,3-a]pyrimidine 8. Compound 8b was treated with 2-chloroethyl methyl ether to afford compound 9. Similarly, compound 3 reacted with chloroacetic acid to give thiazolo[3,2-a]pyrimidine 10, which was condensed with p-chlorobenzaldehyde to give compound 11. Compound 11 was condensed with hydroxylamine to give isoxazolo[4,5-d]thiazolo[2,3-a]pyrimidine 12. Compound 12b was treated with 2-chloroethyl methyl ether to afford compound 13. Biological evaluation of some prepared products showed that many of them revealed promising antimicrobial activity.     

Fluorine-containing heterocycles: synthesis and some reactions of new 3-amino-2-functionalized-6-(2'-thienyl)-4-trifluoromethylthieno [2,3-b]pyridines

3-Cyano-6-(2'-thienyl)-4-trifluoromethylpyridine-2(1H)-thione (2) was prepared and reacted with chloroacetone or phenacyl bromide to yield the 2-acetyl or benzoyl-3-amino-6-(2'-thienyl)-4-trifluoromethylthieno[2,3-b]pyridines (3a, b). In contrast, the reaction of 2 with chloroacetamide or its N-aryl derivatives gave the corresponding 2-carbamoylmethyl thiopyridines 4a-c. Upon treatment of these educts with K2CO3 or C2H5ONa in ethanol, they underwent intramolecular Thorpe-Ziegler cyclization to afford 3-amino-2-carbamoyl-6-(2'-thienyl)-4-trifluoromethyl-thieno[2,3-b]pyridine (5a) and its N-aryl analogs 5b, c. Compounds 5a-c underwent some reactions to yield new pyrido[3',2':4,5]thieno[3,2-d]pyrimidines and pyrido[3',2':4,5]thieno[3,2-d][1,2,3] triazines.     

Synthesis, isomerization, and antimicrobial evaluation of some pyrazolopyranotriazolopyrimidine derivatives

6-Amino-5-imino-pyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidine derivative 4 and pyrazolo-[4',3':5,6]pyrano[2,3-d]pyrimidin-5-ylhydrazine derivative 5 were prepared starting from 6-amino-3-methyl-4-(p-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile 1. The synthesis and structure characterization of 9,11-dihydropyrazolo[4',3':5,6]pyrano[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 7 and 9 and their isomerization to 9,11-dihydropyrazolo[4',3':5,6]pyrano[3,2-e] [1,2,4]triazolo[1,5-c]pyrimidine derivatives 6 and 8, respectively, under different suitable reaction conditions are reported. Moreover, the synthesis of 9,11-dihydropyrazolo[4',3':5,6]pyrano[3,2-e] tetrazolo[1,5-c]pyrimidine derivative 14 and N(9)-acyclic nucleoside 15 are described. Some of the prepared products showed potent antimicrobial activity.     

Synthesis and biological activity of functionalized indole-2-carboxylates, triazino- and pyridazino-indoles

Condensation of aryl hydrazines with ethyl pyruvate gave the respective hydrazones 4-6; Fischer indolization led to substituted-1H-indole-2-carboxylic acid ethyl esters 7-9. The Mannich reaction of these compounds with formaldehyde and morpholine yielded ethyl 3-(morpholinomethyl)-substituted-1H-indole-2-carboxylates 10-12. The 5,7-dichloro-1H-indole-2-carbohydrazide 13 was cyclized with methyl orthoformate in DMF to give 6,8-dichloro[1,2,4]triazino[4,5-a]indol-1(2H)-one 14. Vilsmeier-Haack formylation of 7-9 gave ethyl 3-formyl-substituted-1H-indole-2-carboxylates 15-17 whose 2,2'-((5-chloro-2-(ethoxycarbonyl)-1H-indol-3-yl)methylene)bis-(sulfanediyl) diacetic acid 18 was prepared. The reaction of 15 and 16 with substituted anilines by conventional and microwave methods gave ethyl 3-(N-aryliminomethyl)-5-halo-1H-indole-2-carboxylates 19-29. In a cyclocondensation reaction of 19-25 with thiolactic acid or thioglycolic acid substituted indolylthiazolidinones 30-33 were prepared. Reaction of hydrazine hydrate with 15-17 did not give the respective hydrazones but directly led to the cyclized products substituted-3H-pyridazino[4,5-b]indol-4(5H)-ones 34-36, while a reaction with 2,4-dichlorophenylhydrazine yielded the uncyclized hydrazones. The chlorination of 35 and 36 with POCl3 gave pyridazino[4,5-b]indoles 39 and 40, respectively; reaction of the latter compounds with morpholine gave 4-(substituted-5H-pyridazino[4,5-b]indol-4-yl)morpholine 41 and 42. Mannich reaction of 34 with formaldehyde and N-ethylpiperazine gave 8-chloro-3-((4-ethylpiperazin-1-yl)methyl)-3H-pyridazino[4,5-b]indol-4(5H)-one 43. The microwave assistance of selected reactions has a profound effect on the reaction speed. The structures of the new compounds were confirmed by both analytical and spectral data. Some compounds were subjected to investigations concerning their antimicrobial, tranquilizing, and anticonvulsant activities.     

Synthesis and antiviral properties of some 2'-deoxy-5-(fluoroalkenyl)uridines

The following 5-substituted 2,4-dimethoxypyrimidines were synthesized: 5-(2,2,2-trichloro-1-hydroxyethyl), 5-(2,2,2-trichloro-1-fluoroethyl),5-(2,2-dichloro-1-fluorovinyl) (5), and 5-(perfluoropropen-1-yl) (a mixture of E and Z isomers, 6 and 7). Demethylation of 5 gave 5-(2,2-dichloro-1-fluorovinyl)uracil, and demethylation of the mixture of 6 and 7 gave some pure (E)-5-(perfluoropropen-1-yl)uracil. Compound 5 was converted into its 2'-deoxyribonucleoside (12) and its alpha-anomer by standard procedures. 2'-Deoxy-3,5-dilithio-3',5'-O-bis(trimethylsilyl)uridine was reacted with the appropriate fluoroalkene to give the following 5-substituted 2'-deoxyuridines in low yield (6-24%): 5-(2-chloro-1,2-difluorovinyl) (a mixture of E and Z isomers, 15 and 16, which were separated on a small scale), 5-(perfluoropropen-1-yl), 5-(perfluorocyclohexen-1-yl), and 5-(perfluorocyclopenten-1-yl). In these reactions, 2'-deoxy-5-(trimethylsilyl)uridine and 2'-deoxyuridine were also formed. The 5-substituted 2'-deoxyuridines were tested for activity against herpes simplex virus type 1. Compound 12 and the mixture of 15 and 16 had an ID50 of 20-26 micrograms/mL in Vero cells. The activity of the mixture resided in one isomer, which by analogY with the corresponding (Z)- and (E)-5-(2-bromovinyl)-2'-deoxyuridines was concluded to be the Z isomer (16).