Synthesis and Biological Evaluation of New Fused Thiazolo[4,5-d] Pyridazine Derivatives

The synthesis of thiazolo[4,5-d]pyridazines and the unknown ring systems, thiazolo[4,5-d]-1,2,4-triazolo- and tetrazolo[4,3-b]pyridazines as well as thiazolo(4,5-d]pyridazino[2,3-c]2H triazines, has been achieved according to different pathways. Biological testing of the new tricyclic heterocycles revealed that some of these compounds possess remarkable antibacterial activity.     

Synthesis of new thiazolo[2,3-b]pyrimidine derivatives of pharmaceutical interest

2H-5-Amino-6-cyano-3,7-dioxothiazolo[2,3-b]pyrimidine was subjected to ring formation affording thiazolo[2,3-b]pyrimidine derivatives. 2H-5-Amino-6-cyano-3,7-dioxo-2-phenylmethylenethiazolo[2,3-b]pyrimidine was also subjected to ring formation affording pyrimido[4,5-d]-, pyrano[2,3-d]-, and pyrido[2,3-d]thiazolo[2,3-b]pyrimidine derivatives. 2-Anilinothiocarbonyl-3,9-dioxo-8-imino-7-phenyl-6-thioxothiazolo[2,3-b]pyrimido[4,5-d]pyrimidine and 8-amino-3,9-dioxo-6-thioxothiazolo[2,3-b]pyrimido[4,5-d]pyrimidine reacted with α-haloactive-methylene compounds to afford heterocyclic compounds containing two, fused and isolated, thiazole moieties, respectively.     

Reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride leading to purine,thiazolo[4,5-d]pyrimidine,pyrimido[4,5-e][1,3,4]thiadiazine,pyrazolo[3,4-d]pyrimidine,and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivativese

The reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride in benzene afforded purine, thiazolo[4,5-d]pyrimidine, pyrimido[4,5-e][1,3,4]thiadiazine, pyrazolo[3,4-d]pyrimidine, and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivatives, while the treatment of 6-(benzylidene-1′-methylhydrazino)-1,3-dimethyluracil with thionyl chloride in benzene gave 4-methylpyrimido[4,5-e][1,3,4]thiadiazine and 1-methylpyrazolo-[3,4-d]pyrimidine derivatives. Plausible mechanisms for the formation of these fused pyrimidines are also described.     

Microwave-assisted synthesis of novel N-(4-phenylthiazol-2-yl)-benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-carboximidamides inspired by marine topsentines and nortopsentines

We report the synthesis of novel N-(4-phenylthiazol-2-yl)-substituted benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-carboximidamides, which were inspired by marine topsentines and nortopsentines. Condensation of 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt) with various ortho-halogenated anilines, aminopyridines and aminophenols gave the corresponding aryliminodithiazoles in good to excellent yields. Copper(I)-mediated or nucleophilic-assisted cyclization of aryliminodithiazoles furnished cyano-functionalized benzo[d]thiazoles, thiazolo[4,5-b]- and thiazolo[5,4-b]-pyridines and benzo[d]oxazoles. The latter were condensed with substituted 4-phenylthiazol-2-amines to furnish twenty seven new polyaromatic carboximidamides in moderate to good yields.     

Synthesis of condensed quinoxalines

A novel efficient synthesis of fluorescent, fused quinoxalines was achieved. 6-Triazolylthiazolo[4,5-b]quinoxalines were synthesized by the diazotisation of 6-amino-2-methylthiazolo[4,5-b]quinoxaline and coupling with selected aromatic amines followed by air oxidation. Diazotised aryl amines were coupled with 6-amino-2-methylthiazolo[4,5-d]quinoxaline followed by subsequent air oxidation afforded 1,2,3-triazolo[5,4-f]quinoxalino[2,3-d]thiazoles. 6-Amino-2-methylthiazolo[4,5-b]quinoxaline was condensed with conjugated enol ethers followed by cyclization in dowtherm resulted in thiazolo[4,5-b]quinoxalino[6,5-b]pyridine.     

Thermolyzed products of naphth[1,2-d]imidazo[2,1-b]-thiazole-2,3-dione

Themolysis of naphth[1,2-d]imidazo[2,1-b]thiazole-2,3-dione ( 1 ) in dimethylformamide gave an intermediate 2-isocyanatonaphtho[1,2-d]thiazole ( 2 ), which underwent [4 + 4] cyclodimerization to yield dinaphtho-[1″,2″:4,5;1′″,2′″:4′,5′]dithiazolo[3,2-a:3′,2′-e]-1,3,5,7-tetrazocine-9,19-dione ( 3 ). The possible [4 + 2] cycloadduct, 3-(2-naphtho-[1,2-d]-thiazolyl)naphtho[1′,2′:4,5]thiazolo[3,2-a]-1,3,5-triazine-2,4-dione ( 4 ), an usual dimer type of heterocyclic isocyanates was not produced. Discrimination between the two isomers was established on the basis of spectral analyses.     

Thiazolo[4,5-d]pyrimidines. Part I. synthesis and anti-human cytomegalovirus (HCMV) activity in vitro of certain alkyl derivatives

Alkyl derivatives of the thiazolo[4,5-d]pyrimidine congeners of guanine and uracil were prepared and assessed for in vitro activity against human cytomegalovirus (HCMV). The finding that the 3-pentyl 1b and 3-hexyl 1c derivatives of 5-aminothiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (1e) had potent in vitro anti-HCMV activity prompted a broader study of alkyl derivatives in this ring system. A series of 3-alkyl derivatives of 1e , viz. 1f-w , were prepared by direct alkylation of the sodium salt of 1e and by subsequent modifications, 2a-d. For comparison with 1c , 5-amino-2-hexylaminothiazolo[4,5-d]pyrimidin-7(6H)-one (4) was prepared and studied. The 3-(2-alkenyl) derivatives of 1e were found to be the more active antiviral agents with the Z isomer of 5-amino-3-(2-penten-1-yl)thiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (1f) having the better therapeutic index. Analogous 4-(2-alkenyl) derivatives of 2-aminothiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione 6a and 6b were also prepared but were found to have poor therapeutic indices. Single crystal X-ray diffraction analysis was used to unequivocally establish the structure of 1f.     

Cyclocondensation of 3-amino-2-iminonaphtho[1,2-d]thiazole with oxalic acid derivatives

Refluxing 3-amino-2-iminonaphtho[1,2-d]thiazole ( 1 ) with diethyl oxalate ( 2a ) in a 2:1 molar ratio in dry pyridine provided 2,2′-binaphtho[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazole ( 3 ). On the other hand, when 1 was treated with excess amount of 2a in dimethylformamide, it afforded ethyl naphtho[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazole-2-carboxylate ( 4a ) on heating and ethyl N-(2-iminonaphtho[1,2-d]thiazol-3-yl)oxamate ( 5 ) by stirring at room temperature. Cyclization of 5 upon fusion led to the formation of 3-hydroxy-2H-naphtho-[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazin-2-one ( 6 ). Compound 6 could also be prepared directly from 1 by refluxing either with 2a neatly, in glacial acetic acid or with oxalic acid ( 2b ) in the same medium. The acid form of 4a might be obtained from 1 and 2b on heating in dimethylformamide, but it was decarboxylated to naphtho-[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazole ( 4b ) during the reaction.     

Synthesis,Reactions, and Antimicrobial Evaluation of Some Polycondensed Thienopyrimidine Derivatives

Some novel indeno[2,1-b]thiophenes, indeno[1′,2′:4,5]thieno[2,3-d][1,2,3]triazines, indeno[1′,2′:4,5]thieno[2,3-d]pyrimidines, indeno[1′,2′:4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidines, and indeno[1′,2′:4,5]thieno[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines 2–16 were prepared starting with 2-aminoindeno[2,1-b]thiophene-3-carboxylic acid amide ( 1 ). Furthermore, the antimicrobial evaluation of the prepared products showed that many of them revealed promising antimicrobial activity.     

Synthesis of substituted thiazolo[4,5-b]pyridines and other annulated heterocycles via SN2→Thorpe-Ziegler→Thorpe-Guareschi domino reactions

A new combinatorial method for the preparation of substituted thiazolo[4,5-b]pyridines, which utilizes cyanoacetamide, heterocumulenes (isothiocyanates, carbon bisulfide), and ethyl-4-chloroacetoacetate in a new S_N2→Thorpe-Ziegler→Thorpe-Guareschi domino reactions has been developed. The obtained thiazolo[4,5-b]pyridines were then used together with aldehydes and malononitrile in another Knoevenagel reaction→Michael reaction→hetero-Thorpe-Ziegler domino reaction for the synthesis of substituted 4,6-dihydro-5H-pyrano[2,3-d]thiazolo[4,5-b]pyridines.     

On the formation and reactivity of N(2),N(2′)-tetrasubstituted 2,4-diamino-5-(2-amino-4-thiazolyl)thiazoles

By the reaction of weak bases with N(2)-disubstituted 2-amino-4-thiazoliniminium chlorides 3, easily available by the reaction of thioureas 1 with α-chloroacetonitrile 2, N(2),N(2′)-persubstituted 2,4-diamino-5-(2-amino-4-thiazolyl)thiazoles 8 are formed. These new bis-thiazoles react, as exemplified with the dimorpholino derivative 8a, with different electrophilic reagent, such as phenyl isothiocyanate 9, 4-nitro-phenyldiazonium salt 11, or 4-dialkylaminobenzaldehydes 13 at their 5H-substituted thiazole moieties to give the corresponding thioanilides 10, azo compounds 12, and methine dyes 14, respectively. With sodium nitrite and the Vilsmeier reagent the thiazole 8a is transformed, via unstable intermediates, into the tricyclic 2,7-dimorpholinothiazolo[4,5-c]thiazolo[4,5-e]pyridazine 16 and 2,7-dimorpholinothiazolo[4,5-b]thiazolo[4,5-d]pyridine 19, respectively.     

New aromatic systems having a fused thiazolium ring

The method developed for the synthesis of thiazolo[3,2-a]pyridinium salts has been extended to the first synthesis of simple thiazolo[3,2-a]pyrimidinium, thiazolo[3,2-a]-pyrazinium and thiazolo[2, 3-b]benzo[d]thiazolium salts. No method could be found for the cyclization of 4′-bromo-2-(2-benzoxazolylthio)acetophenone to the thiazolo[2,3-b]-benzoxazolium system.     

Synthesis of substituted [1,3]thiazolo[4,5-b]pyridines and [1,3]thiazolo[4,5-d][1,2,3]triazines

In this work, we described an easy preparation of substituted 4-amino-5-cyano-1,3-thiazoles. These compounds have been used as starting materials to obtain two classes of compounds. New substituted [1,3]thiazolo[4,5-e]pyridines were synthesized in one step via Friedländer reaction. Diazotation of 4-amino-5-cyano-1,3-thiazoles afforded 4-chloro[1,3]thiazolo[4,5-d][1,2,3]triazines in one step. The later was substituted by a secondary amine to obtain substituted 4-amino[1,3]thiazolo[4,5-d][1,2,3]triazines.     

Synthesis and antimicrobial activity of new derivatives of pyrano[4',3':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine and new heterocyclic systems

Taking into account previously obtained biological results on some polyheterocyclic compounds (containing different heteroatoms) and in particular on several 8-amino-5-isopropyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines Ia-v we have carried out the synthesis of twentyone 8-amino-5-isobutyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines 6. Therefore we have slightly modified the structure of the previously studied I introducing at C-5 an isobutyl group instead of the previously examined isopropyl ones in order to see if this variation (changing a little the lipophilicity) will affect the biological activity. Furthermore thieno[3,2-d]pyrimidine-8-thione 7 and their S-alkylated 8 were synthesized. Finally by alkylation of 5-isobutyl-2,2-dimethyl-10-thioxo-1,4,10,11-tetrahydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-8(9H)-one 3 with alkyl dichlorides (bifunctional reagents) we realized the cyclization of a thiazole or thiazine ring on the [b] side of the pyrimidine ring with formation of the new condensed pentaheterocyclic systems: pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-8-one 11 and pyrano[4''',3''':4'',5'']pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-b][1,3]thiazin-8-one 12. It was found that some of the synthesized compounds showed interesting antimicrobial activity (by agar diffusion method) against some gram-positive and gram-negative bacilli strains.     

Synthesis and properties of thiazolo[5,4-d]pyrimidine 1-oxides

Synthesis and properties of hitherto unknown thiazolo[5,4-d]pyrimidine 1-oxides are described. For example, the reaction of 6-chloro-1,3-dimethyl-5-nitrouracil (I) with methyl thioglycolate in the presence of excess triethylamine afforded 2-methoxycarbonyl-4,6-dimethylthiazolo[5,4-d]pyrimidine-5,7-(4H,6H)dione 1-oxide (IIIa), which is a versatile intermediate for the preparation of various thiazolo[5,4-d]pyrimidine derivatives.     

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).     

Microwave assisted synthesis of 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones and 6,7-dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones using Mn(OAc)3

2-Hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one 2a and 7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one 2b, were obtained in high yields under mild conditions from the cyclization reactions of bis-(2,4,6-trichlorophenyl) malonate and 2-aminobenzothiazole or 2-aminothiazole, respectively. A new class of compounds, 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones and 6,7-dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones, were synthesized via the microwave assisted radical addition of compounds 2a and 2b to various alkenes using manganese(III) acetate. A preliminary acetylcholine esterase (AchE) inhibition test of compound 4e showed excellent (92%) inhibitory potential, comparable with the standard drug Donapezil®.     

Microwave synthesis of new azolyl-substituted thiazolo[5,4-<Emphasis Type="Italic">d</Emphasis>]thiazoles

One-pot condensation of dithiooxamide with 4,5-dichloro-1,2-thiazole-3-carbaldehyde and 5-phenyl-1,2-oxazole-3-carbaldehyde, followed by oxidation of intermediate 2,5-dihydro[1,3]thiazolo[5,4-d]-[1,3]thiazoles with selenium dioxide, afforded previously unknown 2,5-bis(4,5-dichloro-1,2-thiazol-3-yl)- and 2,5-bis(5-phenyl-1,2-oxazol-3-yl)[1,3]thiazolo[5,4-d][1,3]thiazoles as first representative of bis-isothiazolyl- and bis-isoxazolyl thiazolothiazoles.     

Fused polycyclic nitrogen-containing heterocycles 20. Thiazolo[3,4-<Emphasis Type="Italic">a</Emphasis>]quinoxalines from 4-hydroxy-2-phenyliminothiazolidines and C-substituted 1,2-phenylenediamines

The condensation of 4-hydroxy-3,5-diphenyl-2-phenyliminothiazolidine with 4,5-dimethyl-1,2-phenylenediamine affords 7,8-dimethyl-3-phenyl-1-phenyliminothiazolo[3,4-a]quinox-alin-4(5 H)- one; the condensation with 1,2-phenylenediamines containing different substituents at positions 4 and 5 gives both theoretically possible isomeric thiazolo[3,4-a]quinoxalines, which differ in the distribution of these substituents between positions 7 and 8 in the benzene ring of the quinoxaline system. 3a-Hydroxy-7,8-dimethyl-3-phenyl-l-phenylimino-3,3a-di-hydrothiazolo[3,4-a]quinoxalin4(5 H)- one was isolated and characterized as the intermediate of the reaction giving rise to thiazolo[3,4-a]quinoxaline from 4,5-dimethyl-1,2-phenylene-diamine. This intermediate is a covalent hydrate of the final product.     

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.