Synthesis of novel pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidines,pyrido[3″,2″:4′,5′]thieno[3′,2′:4,5]pyrimido[l,6‐a]benzimidazoles and related fused systems

3‐Amino‐4‐aryl‐5‐ethoxycarbonyl‐6‐methylthieno[2,3‐b]pyridine‐2‐carboxamides 3a‐c were prepared from ethyl 4‐aryl‐3‐cyano‐6‐methyl‐2‐thioxo‐1,2‐dihydropyridine‐5‐carbonylates 1a‐c and reacted with some carbonyl compounds to give tetrahydropyridothienopyrimidine derivatives 6a‐c, 7a‐c and 8a‐c , respectively. Treatment of compound 3c with chloroacetyl chloride led to the formation of a next key compound, ethyl 2‐chloromethyl‐4‐oxo‐3,4‐dihydropyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine‐8‐carboxylate 9 . Also, 3‐amino‐2‐benzimidazolylthieno[2,3‐b]pyridine‐5‐carboxylate 5 and 2‐(3′‐aminothieno [2,3‐b]pyridin‐2′‐yl)‐4‐oxo‐3,4‐dihydropyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine‐8‐carboxylate 17 were prepared from 1c. The compounds 5, 9 and 17 were used as good synthons for other pyridothienopyrimidines and pyridothienopyrimidobenzimidazoles as well as for related fused polyheterocyclic systems.     

Polycyclic N‐Heterocyclic Compounds. Part 84: Reaction of N‐(pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidin‐4‐yl)amidines or N‐(pyrido[2′,3′:4,5]furo[3,2‐d]pyrimidin‐4‐yl)amidines with Hydroxylamine Hydrochloride

The reactions of nine N‐(pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidin‐4‐yl)amidines ( 3 ) with hydroxylamine hydrochloride produced new cyclization products. These were formed via ring cleavage of the pyrimidine component followed by a 1,2,4‐oxadiazole‐forming ring closure to give N‐[2‐([1,2,4]oxadiazol‐5‐yl)thieno[2,3‐b]pyridin‐3‐yl]formamide oximes ( 11 ). Reaction of six N‐(pyrido[2′,3′:4,5]furo[3,2‐d]pyrimidin‐4‐yl)amidines ( 12 ) with hydroxylamine hydrochloride gave similar results. Effects of the newly synthesized compounds on pentosidine formation were also evaluated.     

Syntheses of some new azolopyrido‐[4′,3′:4,5]thieno[2,3‐d]pyrimidines

Diethyl 2‐[(ethoxythioxomethyl)amino]‐4,5,6,7‐tetrahydrothieno[2,3‐c]‐pyridine‐3,6‐dicarboxylate 2 , prepared from diethyl 2‐isothiocyanato‐4,5,6,7‐tetrahydrothieno[2,3‐c]pyridine‐3,6‐dicarboxylate 1 by boiling in anhydrous ethanol, was converted into pyrido[4′,3′:4,5]thieno[2,3‐d]pyrimidine derivatives 3, 4 by treatment with hydrazine hydrate. The tetracyclic systems imidazo[1,2‐a]pyrido‐[4′,3′:4,5]thieno[2,3‐d]pyrimidine 9 and pyrido[4′,3′:4,5]thieno[2,3‐d][1,3]thiazolo‐[3,2‐a]pyrimidine 10 were synthesized by the reaction of 2 with 1,2‐diaminoethane and aminoethanethiol, respectively. The hydrazino derivative 4 underwent cyclization reactions with orthoesters and nitrous acid to give the corresponding pyrido[4′,3′:4,5]thieno[2,3‐d][1,2,4]triazolo[1,5‐a]pyrimidines 5, 6 and pyrido[4′,3′:4,5]thieno[3,2‐e][1,2,3,4]tetrazolo[1,5‐a]pyrimidine 8 , respectively. Moreover, reactions of 3 with cyanogen bromide, N‐carbethoxyhydrazine, carbon disulfide, and ethylchloroformate resulted in the formation of the new pyrido[4′,3′:4,5]thieno[2,3‐d][1,3,4]thiadiazolo[3,2‐a]pyrimidine derivatives 12–15 . © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:280–286, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10030     

Polycyclic N‐Heterocyclic Compounds. Part 80: Synthesis and Evaluation of Effects on In Vitro Pentosidine Formation of 5,6‐Dihydro[1]benzothieno[3′,2′:2,3]thiepino[4,5‐d]pyrimidine and Related Compounds

Reaction of 3‐(3‐cyanopropylthio)[1]benzothiophene‐2‐carbonitrile with tert‐BuONa gave 5‐amino‐1,2‐dihydro[1]benzothieno[3,2‐d]thieno[2,3‐b]pyridine and 5‐amino‐2,3‐dihydro[1]benzothieno[3,2‐b]thiepin‐4‐carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles, [1]benzothieno[3′,2′:2,3]thiepino[4,5‐d]pyrimidines. All of our new tetracyclic products were evaluated for in vitro inhibitory activity on the formation of pentosidine, which is one of representative advanced glycation end products.     

Synthesis of 3‐substituted pyrido[4′,3′:4,5]thieno[2,3‐d]pyrimidines and related fused thiazolo derivatives

Convenient syntheses of 3‐substituted ethyl 4‐oxo‐2‐thioxo‐1,2,3,4,5,6,7,8‐octahydropyrid[4′,3′:4,5]thieno[2,3‐d]pyrimidine‐7‐carboxylates 3a, b, 6, 11–13 , ethyl 3‐methyl‐5‐oxo‐2,3,6,9‐tetrahydro‐5 H‐pyrido[4′,3′:4,5]thieno[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidine‐8‐7H‐carboxylate ( 4 ), and ethyl 2‐methyl‐5‐oxo‐2,3,6,9‐tetrahydro‐5H‐pyrido[4′,3′:4,5]thieno[2, 3‐d][1,3]thiazolo[3,2‐a]pyrimidine‐8[7H]carboxylate ( 8 ) from diethyl 2‐isothiocyanato‐4,5,6,7‐tetrahythieno[2,3‐c]pyridine‐3,6‐dicarboxylate ( 1 ) are reported. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:201–207, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10131     

Thieno[2,3‐d]pyrimidines in the Synthesis of New Fused Heterocyclic Compounds of Prospective Antitumor and Antioxidant Agents (Part II)

Diethyl azodicarboxylate and 3,4,5,6‐tetrachloro‐1,2‐benzoquinone react with cyclopentano‐ and cycloheptano‐fused thienopyrimidines to form the oxidative dimer of the starting material via S—S bond formation. Reaction of two equivalents of 2,2′‐(cyclohexa‐2′,5′‐diene‐1,4‐diylidene)dimalononitrile with thienopyrimidines afforded 3‐(4′,4′‐dicyanomethylene‐cycloalka[a]‐2,5‐dienyl)‐4‐oxo‐6,7,8,9‐tetrahydro‐5H‐cyclo‐hepta[4,5]‐[1,3]thiazolo[3,2‐a]‐thieno[2,3‐d]pyrimidin‐2‐ylidene‐2‐dicarbonitriles. The thioenopyrimidines react with 2‐[1,3‐dioxo‐1H‐inden‐2(3H)‐ylidene]malononitrile to produce 1,3,5′‐trioxo‐1,3,3′,5′‐tetrahydrospiro‐(indene‐2,2′‐thiazolo[2,3‐b]‐cycloalkyl[b]‐thieno[2,3‐d]pyrimidine)‐3′‐carbonitriles. However, the reaction of thienopyrimidines with 2,3‐dicyano‐1,4‐naphthoquinone proceeded to afford the fused cycloalkyl‐thieno form of naphtho[1,3]thiazolo[3,2‐a]thieno[2,3‐d]pyrimidine‐6.7,12‐triones. Reaction of 2‐hydrazino‐5,6,7,8‐tetrahydrobenzo[b]thieno[2,3‐d]pyrimidine‐4(1H)‐one with dimethyl acetylenedicarboxylate and ethyl propiolate, respectively, afforded cyclohexano‐fused (Z)‐dimethyl 2[(E)‐4‐oxo‐3,4‐dihydrothieno[2,3‐d]pyrimidine‐2(1H)‐ylidene)hydrazono]succinate and thieno‐pyrimidinotriazine. Both oxidative dimers of thienopyrimidines showed high inhibition of Hep‐G2 cell growth compared with the growth of untreated control cells. Moreover, the cycloheptano‐fused thiazinothienopyrimidine indicates a promising specific antitumor agent against Hep‐G2 cells because its IC₅₀ is < 20 μM.     

Reactions with 3,6‐diaminothieno[2,3‐b]‐pyridines: Synthesis and characterization of several new fused pyridine heterocycles

6‐Aminopyridine‐2(1H)thiones 1 reacting with α‐halo‐compounds 2a–c afforded the alkylthiopyridine derivatives 3a–c which in turn cyclized to the corresponding thieno[2,3‐b]pyridine derivatives 4a–c . Several thieno[2,3‐b]pyridine derivatives 7, 16, 19 , pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine derivatives 6a,b, 11a–c, 21 and pyrido[3′,2′:4,5]thieno[3,2‐c]pyridazine derivatives 13, 17 were prepared starting from compounds 4a–c . © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:405–413, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20313     

Synthesis of New Fused Pirano[4,3-b]pyridine Derivatives

A method was developed for the synthesis of pyrano[4,3-b]thieno[3,2-e]pyridine derivatives based on the reaction of 3-amino-7-ethyl-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]thieno[3,2-e]pyridine-2-carboxylic acid ethyl ester with chloroacetic acid chloride, triethyl orthoformate, hydrazine hydrate, and also phenyl chloroformate. The synthesis of various new representatives of pyrano[2″,3″:5′,6′]pyrido[3′,2′:4,5]thieno[3,2-dl-pyrimidine series was carried out.

     

Synthesis of new heteroaromatic nitrogen ligands: Pyrimido‐[4″,5″:4′,5′]‐thieno[3′,2′:4,5]thieno[3,2‐d]pyrimidines and 1,2,3‐triazine[4″,5″:4′,5′]thieno[3′,2′:4,5]thieno[3,2‐d]‐1,2,3‐triazines

An efficient one‐pot access for the synthesis of the previously unreported tetracyclic fused pyrimido‐[4″,5″:4′,5′]thieno[3′,2′:4,5]thieno[3,2‐d]pyrimidine ( 3 ) and 1,2,3‐triazine[4″,5″:4′,5′]thieno‐[3′,2′:4,5]thieno‐[3,2‐d]‐1,2,3‐triazine ( 5 ) heteroaromatic nitrogen ligands is described. The title compounds 3 and 5 were obtained from 3,4‐diaminothieno[2,3‐b]thiophene‐2,5‐dicarbonitrile and phosgeniminium chloride and sodium nitrite/HCl, respectively. Substituted condensed thieno[2,3‐b]thiophene derivatives 4 and 6 were synthesized by nucleophilic displacement of the chloroderivatives 3 and 5 .     

Synthesis of Novel Pyrido[3′,2′:4,5]furo[3,2‐d]pyrimidine Derivatives and Their Cytotoxic Activity

The 3‐amino‐6‐(trifluoromethyl)furo[2,3‐b]pyridine‐2‐carbohydrazide ( 5 ) was prepared from 3‐cyano‐6‐trifluoromethyl‐2(1H)pyridone ( 2 ) in series of steps via selective O‐alkylation, Thorpe–Ziegler cyclization followed by reaction with hydrazine hydrate. The 2‐carbohydrazide ( 5 ) was further reacted with aliphatic acids under different reaction temperatures to form a series of novel N‐acylfuro[2,3‐b]pyridine‐2‐carbohydrazide ( 6 ) and pyrido[3′,2′:4,5]furo[3,2‐d]pyrimidine derivatives ( 7 ). All the compounds 6 and 7 were screened for cytotoxic activity against breast carcinoma MD Anderson‐Metastatic Breast (MDA‐MB) 231 (aggressive) cell lines at 10 µM concentration. Compounds 6a , 6b , and 6c showed promising activity.     

Synthesis of novel pyrido[3′,2′:5,6]thiopyrano[3,2‐b]indol‐5(6H)‐ones and 6H‐pyrido[3′,2′:5,6]thiopyrano[4,3‐b]quinolines,two new heterocyclic ring systems

The synthesis of new pyrido[3′,2′:5,6]thiopyrano[3,2‐b]indol‐5(6H)‐ones was accomplished by the Fischer‐indole cyclization of some 2,3‐dihydro‐3‐phenylhydrazonothiopyrano[2,3‐b]pyridin‐4(4H)‐ones, obtained from the 2,3‐dihydro‐3‐hydroxymethylenethiopyrano[2,3‐b]pyridin‐4(4H)‐one, by the Japp‐Klingemann reaction. 6H‐Pyrido[3′,2′:5,6]thiopyrano[4,3‐b]quinolines were obtained by reaction of 2,3‐dihydrothiopyrano‐[2,3‐b]pyridin‐4(4H)‐ones with o‐aminobenzaldehyde or 5‐substituted isatins. The preparation of some derivatives, functionalized with an alkylamino‐substituted side chain, is also described.     

Synthesis and S-methylation of 2-thioxopyrido[3′,2′:4,5]thieno[3,2-d]-pyrimidin-4(3H)-ones with and without a phase transfer catalyst

A number of 2-thioxopyrido[3′,2′:4,5]thieno[3,2-H]pyrimdin-4(3H-ones (5) have been synthesized by cyclocondensation of 2-carbethoxy-3-amino-4-phenyl-6-substituted-thieno[2,3-b]pyridines (3) with various isothiocyanates. Compounds 5 were S-methylated routinely and the reactions compared under solid-liquid phase transfer conditions to obtain 2-methylthiopyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-^ones (6). The new triheterocyclic pyridothienopyrimidines were prepared with the objective to study their pharmacological properties.     

Reactions of hydrazonoyl halides 43 : Synthesis of some new 2,3‐dihydro‐1,3,4‐thiadiazoles,pyrazoles, pyrazolo[3,4‐d]‐pyridazines,thieno[2,3‐b]pyridines,pyrimidino[4′,5′:4,5]thieno[2,3‐b]‐pyridines and pyrrolo[3,4‐d]pyrazoles

2,3‐Dihydro‐1,3,4‐thiadiazoles, pyrazoles, pyrazolo[3,4‐d]pyridazines, thieno[2,3‐b]pyridines, pyrim‐idino[4′,5′:4,5]thieno[2,3‐b]pyridines and pyrrolo[3,4‐d]pyrazoles were obtained in a good yields by treatment of hydrazonoyl halides with each of alkyl carbodithioates, 3‐(dimethylamino)‐1‐naphtho[1,2‐d]furan‐2‐ylprop‐2‐en‐1‐one and N‐arylmalemides.     

Synthesis of Novel Pyridothienopyrimidines,Pyridothienopyrimidothiazines, Pyridothienopyrimidobenzthiazoles and Triazolopyridothienopyrimidines

The reaction of 3‐amino‐4,6‐dimethylthieno[2,3‐b]pyridine‐2‐carboxamide (1a) or its N‐aryl derivatives 1b‐d with carbon disulphide gave the pyridothienopyrimidines 2a‐d , whilst when the same reaction was carried out using N¹‐arylidene‐3‐amino‐4,6‐dimethylthieno[2,3‐b]pyridine‐2‐carbohydrazides (1e‐h) , pyridothienothiazine 3 was obtained. Also, refluxing of 1b‐d with acetic anhydride afforded oxazinone derivative 4 . Compounds 2a and 2b‐d were also obtained by the treatment of thiazine 3 with ammonium acetate or aromatic amines, respectively. When compound 2a was allowed to react with arylidene malononitriles or ethyl α‐cyanocinnamate, novel pyrido[3″,2″:4′,5′]thieno[3′,2′:4,5]pyrimido[2,1‐b][1,3] thiazines 5a‐c were obtained. Treatment of 2b‐d with bromine in acetic acid furnished the disulphide derivatives 6a‐c . U.V. irradiation of 2b‐d resulted in the formation of pyrido[3″,2″:4′,5′]thieno[3′,2′:4,5]pyrimido[2,1‐b]benzthiazoles 7a‐c . The reaction of 2a‐d with some halocarbonyl compounds afforded the corresponding S‐substituted thiopyrido thienopyrimidines 8a‐j . Compound 8b was readily cyclized into the corresponding thiazolo[3″,2″‐a]‐pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine 9 upon treatment with conc. sulphuric acid. Heating of 2a,b with hydrazine hydrate in pyridine afforded the hydrazino derivatives 11a,b . Reaction of ester 8c with hydrazine hydrate in ethanol gave acethydrazide 10 . Compounds 10 and 11a,b were used as versatile synthons for other new pyridothienopyrimidines 12–15 as well as [1,2,4] triazolopyridothienopyrimidines 16–19.     

Convenient Synthesis and Antimicrobial Evaluation of Multicyclic Thienopyridines

Thieno[2,3-b]pyridines 7, 8, and 10 could be obtained via the S-alkylation of 3-cyano-4,6-di-2-furyl-2(1H)pyridinethione (3) with a variety of alkylating agents. These compounds were conveniently converted into novel pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines 12–15 and 17–20 and thieno[2,3-b;4,5-b′]dipyridine 11 derivatives. Structures of the products have been determined by elemental analyses and spectral data studies. All the tested compounds were found to exhibit moderate antimicrobial activity.     

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.     

Heterocyclization reaction of 2‐(2‐methylaziridin‐1‐yl)‐3‐ureidopyridines under appel's conditions

The reaction of 2‐(2‐methylaziridin‐1‐yl)‐3‐ureidopyridines 12 with triphenylphosphine, carbon tetra‐chloride, and triethylamine (Appel's conditions) led to the corresponding carbodiimides 13 , which underwent intramolecular cycloaddition reaction with aziridine under the reaction conditions to give the pyridine‐fused heterocycles, 2,3‐dihydro‐1H‐imidazo[2′,3′:2,3]imidazo[4,5‐b]pyridines 16 and 12,13‐dihydro‐5H‐1,3 ‐benzodiazepino [2′,3′:2,3] imidazo[4,5‐b]pyridines 17 .     

Construction of new heteroacenes based on benzo[b]thieno[2,3-d]thiophene / quinoline or 1,8-naphthyridine systems using the Friedländer reaction

Two new classes of heteroacenes, namely benzo[4′,5′]thieno[2′,3′:4,5]thieno[3,2-b]quinolines and benzo[4′,5′]thieno[2′,3′:4,5]thieno[3,2-b][1,8]naphthyridines, have been formed using the Friedländer reaction to annulate the benzo[b]thieno[2,3-d]thiophene scaffold to quinoline or 1,8-naphthyridine fragments. In accordance with this synthetic strategy, benzo[b]thieno[2,3-d]thiophen-3(2H)-ones were treated with 2-aminobenzaldehydes or 2-aminonicotinaldehyde in the presence of pyrrolidine in glacial acetic acid at reflux to give the desired quinoline- or 1,8-naphthyridine-fused compounds, respectively. The optical and electrochemical properties of selected heteroacenes were determined.     

An Efficient One‐pot Synthesis of Novel Spiro Cyclic 2‐Oxindole Derivatives of Pyrimido[4,5‐b]Quinoline,Pyrido[2,3‐d:6,5‐d′]Dipyrimidine and Indeno[2′,1′:5,6]Pyrido [2,3‐d]Pyrimidine in Water

A novel and facile one‐pot synthesis of spiro cyclic 2‐oxindole derivatives of pyrimido[4,5‐b]quinoline‐4,6‐dione, pyrido[2,3‐d:6,5‐d′]dipyrimidine‐2,4,6‐trione, and indeno[2′,1′:5,6]pyrido [2,3‐d]pyrimidine employing 6‐aminothiouracil (or 6‐aminouracil), isatin, and cyclic 1,3‐diketone (e.g. 1,3‐indanedione, dimedone, or barbituric acid) has been developed.     

Chemistry of thienopyridines. XXXVIII. Diels-Alder reactions of thienopyridine sulfones. Part 2

Thieno[3,2-b]pyridine 1,1-dioxide ( 2 ) undergoes Diels-Alder condensation with the dienophiles cyclopentadiene, anthracene, and naphthacene in a manner analogous to its isomer thieno[2,3-b]pyridine 1,1-dioxide ( 1 ). Compound 2 dimerizes in refluxing xylene with the loss of sulfur dioxide plus either the loss or transfer of hydrogen to give a small yield (ca. 2%) of pyrido[2′,3′:4,5]thieno[3,2-f]quinoline 7,7-dioxide ( 7 ) and its 5,6-dihydro derivative 12 . Formation of 7 and 12 are compared and contrasted with products reported from dimerization of 1 and of benzo[b]thiophene 1,1-dioxide and its derivatives.