Synthesis of new thieno[2,3‐d]pyrimidines,thieno[3,2‐e]pyridines,and thieno[2,3‐d][1,3]oxazines

o‐Aminothiophene dicarbonitrile 1 on neat reaction with cyclic ketones in anhydrous ZnCl₂ yielded mixture of fused aminopyridine 3 and iminospirooxazine 4 derivatives. Similarly, pyrimidine derivatives 5 and 8 were obtained by the reaction of this intermediate 1 with formic acid and DMF‐DMA followed by hydrazine hydrate, respectively. The reaction of o‐amino‐thiophene dicarboxamide 2 at ambient temperature with cyclic ketones yielded spiropyrimidine 10 as a sole product in quantitative yield. The regioselective anellated pyrimidine 9 , 11 , and dihydropyrimidine 12 derivatives were also obtained by the reaction with aromatic aldehydes in presence of piperidine and iodine respectively. J. Heterocyclic Chem., (2012).     

Synthesis of three carbon atom bridged 2,4‐diaminopyrrolo[2,3‐d]‐pyrimidines as nonclassical dihydrofolate reductase inhibitors

A series of seven nonclassical three carbon atom bridged 2,4‐diamino‐5‐substituted‐pyrrolo[2,3‐d]‐pyrirnidines 1a‐g were synthesized as potential inhibitors of dihydrofolate reductase. Selective oxidation of diols 7a‐g affords α‐hydroxy ketones 8a‐g. Subsequent condensation with malononitrile gave the requisite 2‐amino‐3‐cyano‐4‐substituted furan precursors 9a‐g. Cyclocondensation with guanidine in refluxing ethanol in one step affords the three carbon atom bridged 2,4‐diamino‐5‐substituted‐pyrrolo[2,3‐d]‐pyrimidines 1a‐g. Preliminary biological results indicated that these compounds showed moderate inhibitory activities against dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium and rat liver with IC₅₀ values in the 0.66 μM ‐ 70.1 μM range and some compounds had marginal selectivity for T. gondii dihydrofolate reductase.     

Synthesis of a pyrrolo annulated pyrido[2,3-D]pyrimidine as a potential nonclassical antifolate

Cyclocondensation of 2,4,6-triaminopyrimidine ( 4 ) with ethyl N-benzyl-4-oxo-3-pyrrolidine carboxylate ( 5 ) in diphenyl ether regiospecifically afforded a new tricyclic, angular 1,3,8-trisubstituted pyrrolo[3′,4′:4,5]-pyrido[2,3-d]pyrimidine-6-one 1 in excellent yield. The ketoester 5 was prepared by a literature method. Compound 1 in addition to being a new heterocyclic system is an important key precursor to a variety of classical and nonclassical tricyclic, 5-deaza analogues of the folate cofactor 5,10-methylenetetrahydrofolate 3 .     

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 and Cytotoxicity of Some Thieno[2,3‐d]pyrimidine Derivatives

A series of compounds 5‐amino‐2‐ethylmercapto‐4‐phenyl‐6‐subistitutedthieno[2,3‐d]pyrimidines ( 8a–d ), 4‐chloro‐7‐ethylmercapto‐9‐phenylpyrimido[5′,4′:4,5]thieno[3,2‐d]triazine ( 9 ), and 2‐ethylmercapto‐8‐oxo‐4‐phenyl‐7‐(4‐chlorophenyl)pyrimido [4′,5′:4,5]thieno[2,3‐d]pyrimidine ( 10 ) were synthesized and their structures were confirmed by ¹H NMR , ¹³C NMR, and MS . All compounds were evaluated for their IC₅₀ values against three cancer cell lines (MCF ‐7, HUH ‐7 and BHK ) and WISH cells. The IC₅₀ of compound ( 8d ) was calculated for each cell line. Interestingly, the IC₅₀ for the normal human amnion WISH cell line was much higher (723 µg/mL) than those found for the tumor cell lines BHK (17 µg/mL), HUH ‐7 (5.8 µg/mL), and MCF ‐7 (8.3 µg/mL). The proliferation inhibition of normal (WISH ) and tumor (BHK , HUH ‐7, and MCF ‐7) cells by compound ( 8d ) was investigated using MTT assay, and the IC₅₀ was calculated after 48 h of treatment for each cell line.     

The synthesis of new 2,4‐diaminofuro[2,3‐d]pyrimidines with 5‐biphenyl,phenoxyphenyl and tricyclic substitutions as dihydrofolate reductase inhibitors

Nonclassical 2,4‐diamino‐5‐substituted furo[2,3‐d]pyrimidines 4a‐i, 5a‐b and 7a‐f were synthesized as extended aromatic ring appended analogs of previously reported antifolates 1a‐b. The extended aromatic system was designed to better interact with a phenylalanine residue (Phe69) of dihydrofolate reductase from the opportunistic pathogen Pneumocystis carinii to afford potent and selective inhibitors of Pneumocystis carinii dihydrofolate reductase. The target compounds were synthesized by nucleophilic displacement of 2,4‐diamino‐5‐(chloromethyl)furo[2,3‐d]pyrimidine 3 with the appropriate aromatic amine or thiol. The compounds were evaluated as inhibitors of dihydrofolate reductase from Pneumocystis carinii and Toxoplasma gondii, and their selectivity was determined using rat liver dihydrofolate reductase as the mammalian reference. In the C8‐N9 bridged series, compound 4e , with a 3‐(2‐methoxydibenzofuran)‐ side chain, exhibited greatest potency and was more than 3 times as selective for Pneumocystis carinii dihydrofolate reductase compared to rat liver dihydrofolate reductase. Compounds 4b and 4c also exhibited selectivity. Compounds in the C8‐S9 bridged series showed comparable potencies, and each showed higher selectivity for Pneumocystis carinii dihydrofolate reductase compared to rat liver dihydrofolate reductase.     

Syntheses of substituted pyrrolo[2,3‐d]imidazole‐5‐carboxylates and substitued pyrrolo[3,2‐d]imidazole‐5‐carboxylates

Starting from readily available p‐substituted‐benzylamines a series of ethyl 2‐alkylthio‐1‐substituted‐ben‐zylpyrrolo[2,3‐d]imidazole‐5‐carboxylates was prepared. In addition, starting from 2‐alkyl‐4(or 5)‐formylimidazoles and methyl 4′‐bromomethylbiphenyl‐2‐carboxylate a series of methyl substituted‐pyrrolo[2,3‐d]imidazole‐5‐carboxylates and methyl substituted‐pyrrolo[3,2‐d]imidazole‐5‐carboxylates was prepared.     

微波辐射下吡啶[2,3-d]嘧啶衍生物的高效合成

本文以等摩尔的芳醛,巴比妥酸（或1,3-二甲基巴比妥酸）,5-氨基-2-甲基苯[d]噻唑为原料,以醋酸和乙二醇为溶剂,微波辐射下多组分一锅法合成了一系列新的吡啶[2,3-d]嘧啶衍生物。这种方法具有产率高,操作简便,反应时间短等优点。     

Synthesis of [1,4]benzodioxino[2,3‐c and 2,3‐d]pyridazinones

Reaction of chloropyridazin‐3‐one 1, 5 and 10 with catechol in the presence of potassium carbonate gave the corresponding [1,4]benzodioxino[2,3‐e and/or 2,3‐d]pyridazinones 2, 7, 8 and 11 .     

Paal knorr reaction for novel pyrrolo[2,3‐d]pyrimidines

An expeditious and convenient solid supported synthesis of 1,3,7‐triaryl‐6‐phenyl‐2‐thioxo‐1,2,3,7‐tetrahydropyrrolo [2,3‐d]pyrimidin‐4‐one derivatives from readily accessible N,N‐disubstituted thiobarbituric acids under microwaves utilising Paal Knorr reaction is described.     

Synthesis of substituted thieno[2,3‐bpyrroles

Thieno[2,3‐b]pyrroles can be synthesized through three steps: Gewald synthesis, alkylation, and Thorpe–Ziegler cyclization. Diethyl 3,6‐bis((ethoxycarbonyl)methyl)‐4‐amino‐6H‐thieno[2,3‐b]pyrrole‐2,5‐dicarboxylate ( 13 ) has been obtained by one‐pot method in DMF in good yield and high quality. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:236–238, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20290     

Synthesis of new condensed thieno[2,3-b]pyridines containing pyrimidine and imidazole rings

Two different convenient methods have been developed for the synthesis of condensed thieno[2,3-b]pyridines. The intramolecular cyclization of 3-amino-2-hydrazinocarbonyl-7,7-dimethyl-7,8-dihydo-5H-pyrano[3,4-e]-thieno[2,3-b]pyridine was carried out to give 7,7-dimethyl-2-oxo-1,2,6,7-tetrahydro-9H-pyrano[3′,4′-e]-imidazo[4″,5″∶2,3]thieno[5,4-b]pyridine, which is the first representative of a new heterocyclic system.     

Synthesis of 2,4‐diaminothieno‐ and pyrrolo[2,3‐d]pyrimidine‐6‐carboxylic acid derivatives

A series of new 2,4‐diaminothieno[2,3‐d]‐ and 2,4‐diaminopyrrolo[2,3‐d]pyrimidine derivatives were synthesised. Reaction of 2‐amino‐4,6‐dichloropyrimidine‐5‐carbaldehyde ( 1 ) with ethyl mercaptoacetate, methyl N‐methylglycinate or ethyl glycinate afforded ethyl (2‐amino‐4‐chloro‐5‐formylpyrimidin‐6‐yl)thioacetate ( 2a ), methyl N‐(2‐amino‐4‐chloro‐5‐formylpyrimidin‐6‐yl)‐N‐methylglycinate ( 2b ) and ethyl N‐(2‐amino‐4‐chloro‐5‐formylpyrimidin‐6‐yl)glycinate ( 2c ), respectively. Compounds 2a,b by treatment with bases cyclised to the corresponding 2‐amino‐4‐chlorothieno‐ and pyrrolo[2,3‐d]pyrimidine‐6‐carboxylates ( 3a,b ). Heating 2,4‐diamino‐6‐chloropyrimidine‐5‐carbaldehyde ( 5 ) with ethyl mercaptoacetate or methyl N‐methylglycinate gave 2,4‐diaminothieno[2,3‐d]‐ and 2,4‐diaminopyrrolo[2,3‐d]‐pyrimidine‐6‐carboxylates ( 6a,b ), whereas compound 5 with ethyl glycinate under the same reaction conditions afforded ethyl N‐(2,4‐diamino‐5‐formylpyrimidin‐6‐yl)glycinate ( 7 ). Treatment of 2,4‐diaminothieno[2,3‐d]pyrimidine‐6‐carboxylic acid ( 8a ) with 4‐methoxy‐, 3,4,5‐trimethoxyanilines or ethyl N‐(4‐aminobenzoyl)‐L‐glutamate in the presence of dicyclohexylcarbodiimide and 1‐hydroxybenzotriazole furnished the corresponding N‐arylamides 9‐11.     

Design,synthesis and biological evaluation of 2,4‐diamino‐6‐methyl‐5‐substitutedpyrrolo[2,3‐d]pyrimidines as dihydrofolate reductase inhibitors

Nine novel nonclassical 2,4‐diamino‐6‐methyl‐5‐mioarylsubstituted‐ 7H ‐pyrrolo[2,3‐d]pyrimidines 2‐10 were synthesized as potential inhibitors of dihydrofolate reductase and as antitumor agents. The analogues contain various electron donating and electron withdrawing substituents on the phenylsulfanyl ring of the side chains and were synthesized from the key intermediate 2,6‐diamino‐6‐methyl‐7H‐pyrrolo[2,3‐d]‐pyrimidine, 14 . Compound 14 , was in turn obtained by chlorination of 4‐position of 2‐amino‐6‐methylpyrrolo[2,3‐d]pyrimidin‐4(3H)‐one, 16 followed by displacement with ammonia. Appropriately substituted phenyl thiols were appended to the 5‐position of 14 via an oxidative addition reaction using iodine, ethanol and water. The compounds were evaluated against rat liver, rat‐derived Pneumocystis, Mycobacterium avium and Toxoplasma gondii dihydrofolate reductase. The most potent and selective inhibitor, (2) has a 1‐naphthyl side chain. In this series of compounds electron‐withdrawing and bulky substituents in the side chain afford marginally active dihydrofolate reductase inhibitors. The single atom sulfur bridge in the side chain of these compounds is not conducive to potent dihydrofolate reductase inhibition.     

Synthesis of some new bipyridines,thieno[2,3‐b]pyridines,and pyrazolo[3,4‐b]pyridines

Cyclocondensation of cyanoacetamide and cyanothioacetamide with sodium salt of 3‐hydroxy‐1‐(pyridin‐3‐yl)prop‐2‐en‐1‐one gave 6‐oxo‐[2,3′]bipyridine 5a and 6‐thioxo‐[2,3′]bipyridine 5b derivatives, respectively. Compound 5b upon treatment with different methylenes 8 gave thieno[2,3‐b]pyridines 10 . Treatment of 5b with iodomethane gave bipyridine derivative 7 , which cyclocondensed with hydrazines 11 to give pyrazolo[3,4‐b]pyridines 13 . J. Heterocyclic Chem., (2012).     

New fused pyrazines. Synthesis of pyrido[3′,2′:4,5]‐thieno[2,3‐e]pyrrolo[1,2‐a]pyrazine derivatives

The synthesis of the title compounds was achieved using the key intermediate ethyl 4,6‐dimethyl‐3‐(pyrrol‐1‐yl)thieno[2,3‐b]pyridine‐2‐ carboxylate 2. This latter compound was obtained via the interaction of the thienopyridine amino ester 1 with 2,5 dimethoxytetrahydrofuran in acidic medium.     

Synthesis of thieno[2,3‐b][1,5]benzoxazepine derivatives

A new series of 4‐(4‐methylpiperazin‐1‐yl)thieno[2,3‐b][1,5]benzoxazepines 1a‐k has been synthesized from 4‐bromo‐2‐methylthiophene 6 or ethyl 2‐amino‐4,5‐dimethyl‐3‐thiophencarboxylate 10 . Preparation of the key intermediate thieno[2,3‐b][1,5]benzoxazepine‐4(5H)‐ones 4a‐i, 4k were carried out by treatment of 2‐bromo‐N‐(2‐hydroxyphenyl)‐3‐thiophencarboxamides 5a‐i, 5k with potassium carbonate in DMSO. Compounds 1 are thienoanalogues of loxapine, a potent antipsychotic drug. Of these compounds, the neu‐roleptic activity of 2‐methyl‐4‐(4‐methylpiperazin‐l‐yl)thieno[2,3‐b][1,5]benzoxazepine 1a (R¹, R³=H, R²=CH₃) demonstrated potent antipsychotic activity.