The synthesis of ω-dialkylaminoalkylaminopyrazino[2,3-d]-, pyrido[2,3-d]-, imidazo[4,5-c]- and imidazo[4,5-d]pyridazines

The synthesis of 5-chloro-8-(ω-dialkylaminoalkylamino)pyrazino[2,3-d]pyridazine (II) proceeded smoothly when 5,8-dichloropyrazino[2,3-d]pyridazine (I) was allowed to react with ω-dialkylaminoalkylamines. Similarly, the reaction of 5,8-dichloropyrido[2,3-d]pyridazine (IV) with ω-dialkylaminoalkylamines gave the two expected products 8-chloro-5-(ω-dialkylaminoalkylamino)pyrido[2,3-d]pyridazine (V) and 5-chloro-8-(ω-dialkylaminoalkylamino)pyrido[2,3-d]pyridazine (VI) in a 2:3 ratio. 4,7-Dichloroimidazo[4,5-d]pyridazine (XII) was found to be much less reactive towards nucleophilic substitutions and more vigorous conditions resulted in disubstituted products (XIII). 7-Chloroimidazo[4,5-c]pyridazine (XVIII) was also found to be much less reactive towards nucleophilic substitution. In both of these cases one of the imidazole nitrogen atoms was blocked by a tetrahydropyranyl group which increased the reactivities and led to the desired monosubstituted products XVII from XII and in the latter case the expected products (XIX).     

The synthesis of pyridazino[4,5-d] pyridazines,pyrazino [2,3-d] pyridazines and a pyrimido [4,5-d] pyridazine

The synthetic chemistry of the relatively unknown pyridazino [4,5-d]pyridazine ring system has been extended. 1,4-Diaminopyridazino [4,5-d]pyridazine (VIII) has been prepared by two routes, the most interesting of these being the one-step conversion of 4,5-dicyanopyridazine into VIII with hydrazine. Upon nitration VIII gave only the mononitramine (X). Attempts to prepare 1,4-dichloropyridazino [4,5-d]pyridazine gave only 4-chloro-2H-pyridazino [4,5-d]pyridazin-1-one (XII). Pyrimido [4,5-d]pyridazine-1,3-dione (XIV) was prepared from pyridazine-4,5-dicarboxamide (IV). The hydrolysis of 5,8-dichloropyrazino [2,3-d]pyridazine (XV) gave 5-chloropyrazino [2,3-d]pyridazin-8-one (XVII) and likewise the ammonolysis of XV gave 5-amino-8-chloropyrazino [2,3-d]pyridazine (XX). As expected the hydrolysis of 5,8-dibromo-pyrazino [2,3-d]pyridazine (XXI) gave 5-bromopyrazino [2,3-d]pyridazin-8-one (XXII). Attempted catalytic dechlorination of 5-chloropyrazino [2,3-d]pyridazin-8-one (XVII) gave 1,2,3,4-tetrahydropyrazino [2,3-d]pyridazin-5-one (XIX).     

The synthesis of lmidazo[4,5-d] pyridazines. VI. v-Triazolo[4,5-d] pyridazines,pyrazino[ 2,3-d ] pyridazines and 7H-Imidazo [4,5-d] tetrazolo[ 1,5-b] pyridazine

Several pyridazines have been prepared as intermediates in the synthesis of monosubstituted imidazo[4,5-d]pyridazines, monosubstituted v-triazoIo[4,5-d]pyridazines and monosubstituted pyrazino [2,3d] pyridazines. The new ring system, 7H-imidazo[4,5-d]tetrazolo[l,5-b] pyridazine (XIV) has been prepared unsubstituted. Furthermore, unsubstituted imidazo[4,5-d]pyridazine (XI) has been prepared. Calculations for XI and XIV were made by approximate SCF LCAO-MO with CNSO II theory.     

Synthesis of 1,2,3-thiadiazolo[4,5-d] pyridazines,A new heterocyclic ring system

A method was developed for the synthesis of 5-carbethoxy-4-formyl-1,2,3-thiadiazole (I), its isomer (II); 5-benzoyl-4-formyl-1,2,3-thiadiazole (III), and its isomer (IV). It was demonstrated that although compounds I, III and IV with hydrazine gave 7H-1,2,3-thiadiazolo[4,5-d]-pyridazin-7-one (XXII), 7-phenyl-1,2,3-thiadiazolo[4,5-d]pyridazine (XXIII) and 4-phenyl-1,2,3-thiadiazolo[4,5-d]pyridazine (XXV), respectively; however, compound I gave its corresponding hydrazone (XXIV).     

The synthesis of pyrimido[4,5-d] pyridazines

The synthesis of pyrimido[4,5-d]pyridazin-2-one-4-thione (II), pyrimido[4,5-d]pyridazine-2,4-dithione (VI), 4-aminopyrimido[4,5-d]pyridazine-2-thione (III), 2-aminopyrimido[4,5-d]-pyridazin-4-one (X), 2-methylpyrimido[4,5-d]pyridazin-4-one (XII), and pyrimido[4,5-d]-pyridazin-4-one (XIII) are reported together with several new pyridazine intermediates.     

The synthesis of imidazo[4,5-c] - and v-triazolo[4,5-c] pyridazines

The parent imidazo[4,5-c]pyridazine (IV) has been prepared for the first time by three different routes. 1-Methylimidazo[4,5-c]pyridazine (XX) and 3-methylimidazo[4,5-c]pyridazine (XXVII) have been prepared by unequivocal syntheses. The constitution of the methylation product of imidazo[4,5-c]pyridazine-2-thiol (VIII) has been shown to be 2-methylthioimidazo[4,5-c]-pyridazine (IX) by the unequivocal syntheses of 1-methylimidazo[4,5-c]pyridazine-2-thiol (XXIII) and 3-methylimidazo[4,5-c]pyridazine-2-thiol (XXXIII). Likewise, the structure of the methylation product (XIII) was shown to be S-methylation by the unequivocal syntheses of 1-methyl-2-methylthio-6-chloroimidazo[4,5-c]pyridazine (XXIV) and 3-methyl-2-methylthio-6-chloroimidazo[4,5-c]pyridazine (XXXI), respectively. Several 7-substituted amino-v-triazolo-[4,5-c]pyridazines (XXXVIII) have been prepared from 7-chloro-v-triazolo[4,5-c]pyridazine (XXXVII).     

Synthesis and biological evaluation of certain 4-alkylamino and 4-arylalkylamino derivatives of the imidazo[4,5-d]pyridazine and v-triazolo[4,5-d]pyridazine ring systems

Certain 4-alkylamino and 4-arylalkylamino derivatives of the imidazo- and v-triazolo[4,5-d]pyridazine ring systems were prepared and evaluated against two human colon carcinomas (DLD-1 and HCT-15) and one human lung carcinoma (LX-1), in vitro. 4-Methylthioimidazo[4,5-d]pyridazine ( 1 ) and 4-methylthio-v-triazolo-[4,5-d]pyridazine ( 9 ) served as precursors to the title compounds. Treatment of these heterocycles with the appropriate amine (ammonia, methylamine, dimethylamine, benzylamine and hydrazine) provided the desired derivatives of that ring system. 4-AIP ( 2 ) and 2-aza-4-AIP ( 10 ) served as precursors to the 4-dimethylaminomethyleneamino derivatives 6 and 14 , respectively. Likewise, the 4-hydrazino analogs ( 7 and 15 ) served as intermediates in the syntheses of benzaldehyde-p-[bis(2-chloroethyl)amino]amino[4,5-d]-pyridazin-4-yl-hydrazone ( 8 ) and benzaldehyde-p-[bis(2-chloroethyl)amino]amino-v-triazolo[4,5-d]pyridazin-4-yl-hydrazone ( 16 ), respectively.     

A series of novel acyclic nucleosides. II. Synthesis of acyclic nucleosides bearing an imidazo[4,5-d] [1,3]oxazine ring

Novel acyclic nucleosides 3a,b,c where N-1 of acyclovir is replaced by oxygen atom were prepared. Thus, 1-[(2-acetoxyethoxy)methyl]-5-amino-4-ethoxycarbonylimidazole ( 9 ) was treated with ethoxycarbonyl isothiocyanate or benzoyl isothiocyanate to give 11e,f . Methylation of the latter with methyl iodide afforded S-methylisothiourea derivative 12f which was treated with alkali and subsequently the mixture was neutralized to give 5-amino-3-[(2-hydroxyethoxy)methyl]-3H-imidazo[4,5-d][1,3]oxazin-7-one ( 3a ). Compounds 3b,c were obtained by treatment of acetic anhydride or propionic anhydride with sodium 5-amino-1-[(2-hydroxyethoxy)methyl]imidazole-4-carboxylate ( 7 ) which was prepared via 5-amino-[(2-acetoxyethoxy)methyl]-imidazole-4-carboxamide ( 5 ). Evaluation of acyclic oxanosine analogs for cytotoxicity and activity against herpes simplex virus type 1 (HSV-1) revealed that all the derivatives tested were inactive, but cytotoxicity were similar or less as compared to that of acyclovir.     

Synthesis of imidazo[4,5-d]pyridazine nucleosides related to inosine

Several imidazo[4,5-d]pyridazine nucleosides which are structurally similar to inosine were synthesized. Anhydrous stannic chloride-catalyzed condensation of persilylated imidazo[4,5-d]-pyridazin-4(5H)one (1) and imidazo[4,5-d]pyridazine-4,7(5H,6H)dione ( 16 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose ( 3 ) provided (after sodium methoxide deblocking) 6-β-D-ribo furanosylimidazo[4,5-d]pyridazin-4(5H)one (5) and 3,6-di-(β-D-ribofuranosyI)imidazo[4,5-d]pyridazin-4-one ( 7 ); and 1-(β-D-ribofuranosyl)imidazo[4,5-d]pyridazine-4,7(5H,6H)dione ( 19 ) and 1,5 or 6-di-(β-D-ribofuranosyl)imidazo[4,5-d ]pyridazine-4,7(5H or 6H)dione ( 21 ), respeeitvely. 4,7-Diehloro-1-β-D-ribofuranosylimidazo[4,5-d]pyridazine ( 12 ) and dimethyl 1-β-D-ribofuranosylimidazole-4,5-dicarboxylate ( 26 ), both prepared from stannic chloride-catalyzed ribosylations of the corresponding heterocycles, were converted in several steps to 3-β-D-ribo-furanosy limidazo[4,5-d]pyridazin-4(5H)one ( 14 ) and nucleosidc 19 , respectively. Acid-catalyzed isopropylidenation of mesomeric betaine 7 or nuclcoside 14 provided 3-(2,3-isopropylidene-β-D-ribofuranosyl)imidazo[4,5-d]pyrizin-4(5H)one ( 31 ). 1-β-D-Ribofuranosylimidazo[4,5-d]-pyridazine ( 29 ) was obtained in several steps from nueleoside 12 . The structure of the nucleosides was established by the use of carbon-13 and proton nmr.     

Synthesis of 3-substituted bicyclic imidazo[1,2-d][1,2,4]thiadiazoles and tricyclic benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazoles

A versatile synthetic route to potentially useful fused-ring [1,2,4]thiadiazole scaffolds (e.g., 7a and 10b) via exchange reactions of the precursor [1,2,4]thiadiazol-3-(2H)one derivatives (e.g., 6 and 9) with appropriately substituted nitriles (e.g., cyanogen bromide or p-toluenesulfonyl cyanide) under mild conditions is described. For example, the tricyclic 3-bromo [1,2,4]THD derivative (7a) underwent S(N)Ar substitution with a variety of nucleophiles, which included amines, malonate esters and alcohols. Likewise, the bicyclic 3-p-tosyl [1,2,4]THD (10b) was employed as a template in reaction with diamines, and the resulting substituted diamines (e.g., 12a or 12e) were further selectively derivatized at the N1 and/or N2 positions in a linear fashion. The X-ray crystal structure of the 3-methyl bicyclic [1,2,4]THD (21) was obtained, and selective methylation at the N1 position via a protection-alkylation-deprotection protocol, as illustrated in Scheme 6, was confirmed. Alternatively, a short convergent synthesis of N1-functionalized derivatives from the reaction of 10b with appropriately substituted secondary amines was also developed. Hence, these synthetic strategies were advantageously exploited to provide access to a variety of diversely derivatized 3-substituted fused-ring [1,2,4]thiadiazole derivatives.     

Synthesis of derivatives of a new heterocyclic system pyrazolo[3,4-b]pyrido[1′,2′: 1,2]imidazo[4,5-d]pyridine

1-[4-Aminoarylpyrazolo[3,4-b]pyridin-5-yl]pyridinium chlorides undergo cyclization under reflux in tert-butanol in the presence of an excess of potassium tert-butoxide to form tetracyclic derivatives of pyrazolo[3,4-b]pyrido[1′,2′:1,2]imidazo[4,5-d]pyridine. The reaction scheme of the processes is proposed. The structures of the reaction products were confirmed by physicochemical methods. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 710–714, April, 2006.     

The synthesis of a new polycyclic heterocyclic ring system: Pyrimido[5,6,1-d,e]acridine

The synthesis of a new heterocylic ring system is reported. The condensation of 9,10-dihydro-9-oxo-4-acridine carboxamide (7) with diethoxymethyl acetate gave pyrimido[5,6,1-d,e]acridine-3,7-dione (8). The amide 7 reacts with ethyl chloroformate to afford 2H-pyrimido[5,6,1-d,e]acridine-1,3,7-trione (9).     

A new route to the synthesis of imidazo [4,5-c]pyrazoles

A new synthesis of imidazo [4,5-c] pyrazoles, obtained through cyclisation of 4-nitroso-5-alkylamino-pyrazoles, is described.     

N-oxides of imidazo[4,5-b]quinoxalines and imidazo[4,5-b]pyrazines

The N-oxides and N,N-dioxides of methyl derivatives of imidazo[4,5-b]quinoxaline and imidazo[4,5-b]pyrazine were synthesized. The higher reactivity of the 2-methyl group in the N-oxides of 2-methylimidazo[4,5-b]quinoxaline as compared with the corresponding unoxidized derivatives was demonstrated.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1266–1270, September, 1972.     

新型[1,2,3]三唑-[4,5-d]嘧啶酮类衍生物的微波法合成

以卤代烃、邻甲基苯胺、氰基乙酸和乙酰氯为原料,经取代、成环、偶联和关环4步反应,用微波法合成了9个[1,2,3]三唑-[4,5-d]嘧啶酮类衍生物（5a~5i）,其中5a~5e, 5g和5i为新化合物,其结构经¹H NMR, ¹³C NMR和HR-MS(ESI)表征。