Folic acid analogs. Modifications in the benzene-ring region. 5. 2′,6′-diazafolic acid

The synthesis of 2′,6′-diazafolic acid was accomplished by the condensation of 2-acetylamino-4(3H)pteridinone-6-earboxaldehyde (XIV) with diethyl N-[(5-amino-2-pyrimidinyl)carbonyl]-L-glutamate (XIII) followed by reduction of the anil double bond and alkaline hydrolylic cleavage of the N²-acetyl and ethyl ester protecting groups. Intermediate XIII was prepared by starling with 5-nitro-2-styrylpyrimidine (VI) and proceeding via 5-arnino-2-styrylpyrimidine (IX). The henzyloxycarbonyl derivative of IX was prepared and oxidized to the corresponding 5-benzyloxycarbonylaminopyrimidine-2-carboxylic acid (XI). The coupling of XI with diethyl L-glutamate followed by hydrogenolysis of the henzyloxycarbonyl function afforded the desired intermediate XIII. 2′,6′-Diazafolic acid was a potent inhibitor of Streptococcus faecium and displayed marginal activity against leukemia 1,1210 in mice.     

Synthesis and anticonvulsant activity of 3-[3-[(dimethylamino)-methyl]-5-methyl-4H-1,2,4-triazol-4-yl]-4-(o-chlorobenzoyl)pyridine

Wolff-Kishner reduction of 3-amino-4-(o-chlorobenzoyl)pyridine ( 3 ) afforded 3-amino-4-(o-chlorobenzyl)pyridine ( 5 ), which on subsequent reaction with triethyl orthoformate and then acetyl hydrazide yielded 1-acetyl-2-[N-[4-(o-chlorobenzyl)pyridin-3-yl]formimidoyl]hydrazone ( 7 ). Cyclization of hydrazone 7 gave 3-(3-methyl-4H-1,2,4-triazol-4-yl)-4-(o-chlorobenzyl)pyridine ( 8 ), which on Jones oxidation yielded 3-(3-methyl-4H-1,2,4-triazol-4-yl)-4-(o-chlorobenzyl)pyridine ( 9 ). The Mannick reaction of 3-(3-methyl-4H-l,2,4-triazol-4-yl)-4-(o-chlorobenzyl)pyridine ( 9 ) with aqueous formalin and dimethylamine hydrochloride afforded 3-[3-[(dimethylamino)methyl]-5-methyl-4H-1,2,4-triazol-4-yl]-4-(o-chlorobenzoyl)-pyridine ( 10 ). 3-[3-[(Dimethylamino)methyl]-5-methyl-4H-1,2,4-triazol-4-yl]-4-(o-chlorobenzoyl)pyridine ( 10 ) exhibited good anticonvulsant activity in the subcutaneous pentylenetetrazole anticonvulsant screen indi cating that an appropriately substituted-pyridine ring moiety can serve as a bioisostere of a chlorobenzene ring with respect to anticonvulsant activity.     

Electrophilic cyclization of <Emphasis Type="Italic">N</Emphasis>-allyl(propargyl)-5-amino-1<Emphasis Type="Italic">H</Emphasis>-pyrazole-4-carboxamides. Synthesis of 4-[(dihydro)oxazol-2-yl]-1<Emphasis Type="Italic">H</Emphasis>-pyrazol-5-amines

N-Allyl-5-amino-1H-pyrazole-4-carboxamides in reactions with polyphosphoric acid, with N-halosuccinimides in chloroform, and with (chlorosulfanyl)benzenes in nitromethane in the presence of lithium perchlorate underwent cyclization involving the N-allylamide fragment to give 4-[5-methyl(halomethyl)-4,5-dihydrooxazol-2-yl]-1H-pyrazol-5-amines and 2-(5-amino-1H-pyrazol-4-yl)-5-[(arylsulfanyl)methyl]-4,5-dihydro-1,3-oxazolium perchlorates, respectively. Analogous reactions of N-propargyl-5-amino-1H-pyrazole-4-carboxamides with polyphosphoric acid afforded 4-(5-methyloxazol-2-yl)-1H-pyrazol-5-amines, and with (chlorosulfanyl) benzenes, 2-(5-amino-1H-pyrazol-4-yl)-5-[(arylsulfanyl)methylidene]-4,5-dihydro-1,3-oxazolium perchlorates.     

Monocyclic pteridine analogues. A pyrazine analogue of methotrexate

Reaction of aminocyanoacetamide with bromomethylpyruvaldoxime provided 3-amino-6-bromomethyl-2-carbamoylpyrazine 4-oxide (7) , which was converted to a pyrazine analogue (3) of methotrexate by subsequent condensation with diethyl N-[4-(methylamino)benzoyl]-L-glutamate, deoxygenation, and hydrolysis. The methotrexate analogue 3 was a poor inhibitor (I₅₀ > 150 μM) of bacterial or mammalian dihydrofolate reductase.     

Synthesis of novel dihydrothiazolo[3,2-a]pyrimidinone derivatives

Condensation of 2-amino-4-hydroxy-2-mercaptopyrimidine (2) hydrate and ethyl 4-bromocrotonate gave a mixture of ethyl 7-amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-acetate (4) and 2a,3-dihydro-1-thia-5,8,8b-triazaacenaphthylene-4,7(2H)-dione (5) whereas reaction of 2 with 4-bromocrotononitrile afforded only 7-amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a] pyrimidine-3-acetonitrile. Reaction of the tricycle 5 (which was isolated as a hemihydrate) with excess methyl iodide/potassium carbonate in dimethylformamide resulted in both ring hydrolysis and methylation to give 3,4-dihydro-1,7-dimethyl-4- [(methylthio)methyl]-2H-pyrimido[1,6-a]pyrimidine-2,6,8(1H,7H)-trione (10). Methylating 5 with excess methyl iodide/sodium methoxide in methanol also resulted in ring fragmentation and methylation but instead afforded methyl 7-methyl-amino-2,3-dihydro-5-oxo-7H-thiazolo[3,2-a]pyrimidine-3-acetate. The mechanistic aspects of these reactions are discussed.     

Reactions of 2-isocyanatobenzoyl chloride and 2-carbomethoxyphenyl isocyanate with 5-aminotetrazole

Treatment of 2-isocyanatobenzoyl chloride ( 4 ) with 5-aminotetrazole (5-AT) gave 3-(5-tetrazolyl)quinazoline-2,4(1H,3H)-dione ( 1 ) directly. Treatment of 2-carbomethoxyphenyl isocyanate ( 5 ) with 5-AT gave 2-[((5-amino-1H-tetrazol-1-yl)carbonyl)amino]benzoic acid methyl ester ( 6 ) as a kinetic product, which was thermally isomerized to 2-[((1H-tetrazol-5-ylamino)carbonyl)amino]benzoic acid methyl ester ( 7 ), the thermodynamically more stable urea. Cyclization of 7 with polyphosphoric acid gave 2-(1H-tetrazol-5-ylamino)-4H-3,1-benzoxazin-4-one ( 2 ). Urea 6 was quite labile in solution, as shown by nmr, and readily reacted with methanol to give 2-[(methoxycarbonyl)amino]benzoic acid methyl ester ( 10 ).     

Synthesis of NSC-341,964: An unexpected study on the stability of 2-aryl-4H-3,1-benzoxazin-4-ones

Resynthesis of NSC 341,964, which had been assigned structure 1 (1-[[3-(7-chloro-4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]methyl]pyridinium chloride) was approached via 7-chloro-2-(3-methylphenyl)-4H-3,1-benzoxazin-4-one ( 5 ) obtained from 3-methylbenzoyl chloride ( 2 ) and 2-amino-4-chlorobenzoic acid ( 3 ) followed by dehydration in acetic anhydride. Radical bromination provided 6 which with pyridine afforded the bromide analog 7 of 1 . Ion exchange, however, gave ring-opened benzoic acid 8 rather than 1 . The original sample of NSC 341,964 also proved to be ring-opened material. However, 7 upon standing exhibited slow hydrolysis to 8 so that the structure of the original NSC 341,964 remains uncertain. A more direct route to compound 8 is also described.     

Synthesis of 2-alkoxy-6-aryl-5-cyano-4(3H)-pyrimidinones

The reaction of methyl 3-aryl-2-cyano-3-methoxypropenoates 1 with cyanamide and sodium methoxide in methanol afforded after acid hydrolysis the methyl 3-[(aminocarbonyl)amino]-3-aryl-2-cyanopropenoates 4 . By performing the reaction in higher boiling alcohols the 2-alkoxy-6-aryl-5-cyano-4(3H)-pyrimidinones 2 were obtained in good yields.     

Synthesis of aromatic carbamates derivatives with a chromen-2-one fragment

Condensation of methyl N-(3-hydroxyphenyl)carbamate with ethyl trifluoromethylacetoacetate, 2-methoxyethyl acetoacetate in the presence of conc. sulfuric acid, and also with acetonedicarboxylic acid formed in situ from citric acid under the action of conc. sulfuric acid afforded chromene derivatives. The esterification of 2-{7-[(methoxycarbonyl)amino]-2-oxo-2H-chromen-4-yl}acetic acid with methanol in the presence of TsOH provided the corresponding ester. The oxidation of its α-methylene group with selenium dioxide led to the formation of methyl 2-{7-[(methoxycarbonyl)amino]-2-oxo-2H-chromen-4-yl}-2-oxo-acetate entering into a condensation with o-phenylenediamine resulting in a derivative with a dihydroquinoxaline fragment. The reaction of phenyl N-(4-formylphenyl)carbamate with 3-acetyl-2H-chromen-2-one in butanol in the presence of catalytic quantity of piperidine and acetic acid furnished 4-[(E)-3-oxo-2H-chromen-3-yl)-1-propenyl]phenyl N-phenylcarbamate.     

Synthesis of pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5-ones. Cyclization reaction of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride

Treatment of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid (X) with acetic anhydride under refluxing conditions afforded 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]-pyrimido[4,5-d]pyrimidin-5-one acetate (IX). The intermediate X was prepared from 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (V). The reaction of V with the sodium salt of 2-amino-3-hydroxypyridine at room temperature gave 4-(2-amino-3-pyridyloxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (VI). Treatment of VI with a hot aqueous sodium hydroxide solution and subsequent acidification gave X. Involvement of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecaroboxylic acid ethyl ester (VIII) (Smiles rearrangement product) as an intermediate in the above alkaline hydrolysis reaction of VI to X was demonstrated by the isolation of VIII and its subsequent conversion into X under alkaline hydrolysis conditions. Acetylation of VIII with acetic anhydride in pyridine solution gave 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester acetate (XI), which afforded IX on fusion at 220°. This alternative synthesis of IX from XI supported the structural assignment of IX. Fusion of VI gave 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]pyrimido]4,5-d]pyrimidin-5-one (VII). The latter was also obtained when VIII was fused at 210°. Acetylation of VII with acetic anhydride afforded IX.     

A new method for the synthesis of [1,4]diazepino[6,5-b]indole derivatives

Reactions of 3-[(N-aryl-N-chloroacetyl)amino]-2-formylindoles with substituted anilines gave 1,4-diaryl-2-oxo-1,2,3,6-tetrahydro[1,4]diazepino[6,5-b]indol-4-ium chlorides and those with 4-aminopyridine yielded 4-amino-1-(1-aryl-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indol-3-yl)pyridinium chlorides. Reduction of 1,2,3,6-tetrahydrodiazepinoindol-4-ium chlorides afforded the corresponding hexahydro derivatives. An alternative synthesis of 1-(4-nitrophenyl)-3-oxo-4-phenyl-1,2,3,4,5,6-hexahydro[1,4]diazepino[6,5-b]indole from 3-[N-(4-nitrophenyl)amino]-2-[(phenylimino)methyl]indole was developed. The method involves the following sequence of transformations: reduction, chloroacetylation, and intramolecular alkylation. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2193–2199, December, 2006.     

Chemistry of iminofurans: X. Synthesis and hydrolysis of 5-aryl(hetaryl)-2-[(4,5,6,7-tetrahydro-1-benzothiophen-2-yl)imino]furan-3(2<Emphasis Type="Italic">H</Emphasis>)-ones

5-Aryl(hetaryl)furan-2,3-diones reacted with N-(triphenyl-λ⁵-phosphanylidene)-4,5,6,7-tetrahydro-1-benzothiophen-2-amines to give 5-aryl(hetaryl)-2-[(4,5,6,7-tetrahydro-1-benzothiophen-2-yl)imino]furan-3(2H)-ones whose acid hydrolysis afforded 4-aryl(hetaryl)-2-hydroxy-4-oxo-N-(4,5,6,7-tetrahydro-1-benzothiophen- 2-yl)but-2-enamides.     

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 1,2,4-triazole, 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine derivatives of benzotriazole

A novel series of 1-(1-carbonylmethyl-1H-benzotriazole) thiosemicarbazides 3a-e was synthesized and then cyclized with sodium hydroxide to afford 1-(4-substituted-4H-1,2,4-triazole-3-thion-5-yl)methyl-1H-benzotriazoles 4a-e , which were alkylated with ethyl iodide to l-(3-ethylthio-4-substituted-4H-1,2,4-triazol-5-yl)-methyl-1H-benzotriazoles 5b-e . The reaction of 1H-benzotriazol-1-acetic acid hydrazide ( 2 ) with carbon disulphide and potassium hydroxide followed by hydrazine hydrate gave 1-(4-amino-4H-1,2,4-triazole-3-thion-5-yl)methyl-1H-benzotriazole ( 6 ). Its subsequent condensation with carboxylic acids in the presence of phosphorus oxychloride or with phenacyl bromides afforded two series of fused heterocycles namely; 6-substituted-3-[1-(1H-benzotriazole)methyl]-1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles 7a-e and 6-substituted phenyl-3-[1-(1H-benzotriazole)methyl]-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 8a-e respectively. The structure of the newly synthesized compounds was elucidated by elemental analyses, ir and nmr spectra.     

Synthesis and urease inhibition studies of some new quinazolinones

In this study, novel quinazolinones were designed, synthesized, characterized by FT-IR, ¹H-NMR, ¹³C-NMR spectral data, and LC–MS. New compounds inhibitory activities on urease were assessed. All of the compounds exhibited potent urease inhibitory activities. Especially in the synthesized compounds, 2-benzyl-3-({5-[(4-nitrophenyl)amino]-1,3,4-thiadiazol2-yl}methyl)quinazolin-4(3H)-one has the best inhibitory effect against Jack bean urease with IC₅₀ = 3.30 ± 0.09 μg/mL. And also, N-(4-nitrophenyl)-2-[(4-oxoquinazolin-3(4H)-yl)acetyl] hydrazinecarbothioamide, N-(4-fluorophenyl)-2-[(4-oxoquinazolin-3(4H)-yl)acetyl] hydrazinecarbothioamide, and 2-benzyl-3-({5-[(4-fluorophenyl)amino]-1,3,4-thiadiazol-2yl} methyl)quinazolin-4(3H)-one have best activities among the synthesized compounds.     

Structure of reaction products of 3-cyanochromones with ethylenediamine

A reaction of 3-cyanochromones with ethylenediamine in ethanol afforded N,N′-ethyl-ene-bis(2-amino-3-iminomethylchromones), which depending on the time of reflux in acetic acid give 2-amino-3-formylchromones or products of their dimerization, 2-(chromon-3-yl)-5H-chromeno[2,3-d]pyrimidin-5-ones.     

5-Deaza-7-desmethylene analogues of 5,10-methylene-5,6,7,8-tetrahydrofolic acid and related compounds: Synthesis and in vitro biological activity

1-[4-(tert-Butyloxycarbonyl)phenyl]-3-pyrrolidinone and 1-[3-(tert-butyloxycarbonyl)phenyl]-4-piperidinone were condensed with ethyl cyanoacetate or malononitrile to form ylidene derivatives, which were then subjected sequentially to (i) catalytic or chemical reduction, (ii) condensation with guanidine, and (iii) gentle tri-fluoroacetic acid treatment to obtain 3-(2,4-diamino-6(5H)-oxopyrimidin-5-yl)-1-(4-carboxyphenyl)pyrrolidine ( 27 ), 4-(2,4-diamino-6(5H)-oxopyrimidin-5-yl)-1-(carboxyphenyl)piperidine ( 35 ), and 3-(2,4,6-triaminopyrimidin-5-yl)-1-(carboxyphenyl)pyrrolidine ( 40 ). Condensation of 27, 35 , and 40 with diethyl or di-tert-butyl L-glutamate followed by removal of the ester groups yielded N-[4-[3-(2,4-diamino-6(5H)-oxopyrimidin-5-yl)pyr-rolidino]benzoyl]-L-glutamic acid ( 13 ), N-[4-[4-(2,4-diamino-6-(5H)-oxopyrimidin-5-yl)piperidino]benzoyl]-L-glutamic acid ( 14 ), and N-[4-[3-(2,4,6-triaminopyrimidin-5-yl)pyrrolidino]benzoyl]-L-glutamic acid ( 15 ). Compounds 13 and 14 may be viewed as 5-deaza-7-desmethylene analogues of 5,10-methylene-5,6,7,8-tetrahydrofolic and 5,10-ethylene-5,6,7,8-tetrahydrofolic acid, respectively. Compounds 13 and 15 were good substrates for mouse liver folylpolyglutamate synthetase, with K_m values of 20 and 18 μM and a relative first-order rate constant V_max/K_m of 2.2 (aminopterin = 1.0). In contrast, 14 was a very poor substrate, with a K_m of 490 μM and a relative V_max/K_m of 0.052. As expected from its structure, 15 was a dihydrofolate reductase inhibitor. However its potency was unexceptional (IC₅₀ = 1.2 μM). Compounds 13 and 14 were inactive at concentrations of up to 100 μM, and likewise showed no activity against thymidylate synthase or glycinamide ribotide formyltransferase, two other key enzymes of folate-mediated one-carbon metabolism. Compound 15 was moderately active as an inhibitor of the growth of cultured tumor cells (SCC25 human squamous cell carcinoma), with an IC₅₀ of 0.37 μM (72 hour exposure). By comparison the IC₅₀ of aminopterin was 0.0069 μM. Thus, even though 15 is a good folylpolyglutamate synthetase substrate, the deep-seated skeletal changes embodied in this structure are unfavorable for DHFR binding and may also be unfavorable for transport into cells.     

The synthesis of azole derivatives from 3-[(4-methylphenyl)amino]propanehydrazide and its N′-phenylcarbamoyl derivatives, and their antibacterial activity

Abstract  

5-[2-[(4-Methylphenyl)amino]ethyl]-1,3,4-oxadiazol-2(3H)-thione, 5-[2-[(4-methylphenyl)amino]ethyl]-1,3,4-oxadiazol-2(3H)-one, N-(2,5-dimethyl-1H-pyrrol-1-yl)-3-[(4-methylphenyl)amino]propanamide, and a series of N-[(phenylcarbamoyl)amino]-3-[(4-methylphenyl)amino]propanamides and 3-[(4-methylphenyl)(phenylcarbamoyl)amino]-N-[(phenylcarbamoyl)amino]propanamides, and their thio analogues were synthesized from 3-[(4-methylphenyl)amino]propanehydrazide. 1,3,4-Oxadiazole-2(3H)-thione was converted to 4-amino-2,4-dihydro-5-[2-[(4-methylphenyl)amino]ethyl]-3H-1,2,4-triazole-3-thione, whereas cyclization of N′-phenylcarbamoyl derivatives provided thiazole, oxadiazoles, and thiadiazole, as well as triazole derivatives. Two of the synthesized compounds exhibited good antibacterial activity against Rhizobium radiobacter.     

Synthesis of New 2-[(Substituted-pyrazol-1-yl)carbonyl]-thieno[2,3b]pyridine Derivatives Using 1,3-Diketones,Alkylethoxymethylenes and Ketene Dithioacetals

The reaction of 3-amino-4,6-dimethyl-2-thieno[2,3-b]pyridine carbohydrazide ( 1 ) with appropriate 1,3-diketones 2a-2d in glacial acetic acid afforded 3-amino-2-[(3,5-disubstituted-pyrazo)-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 3a-3d. 3-Amino-2-[(5-amino-3,4-disubstituted-pyrazol-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 5a-5h were also prepared by treatment of carbohydrazide 1 with appropriate alkylethoxymethylenes and ketene dithioacetals 4a-4h , respectively.     

β-Carbolines as agonistic or antagonistic benzodiazepine receptor ligands. 1. Synthesis of some 5-, 6- and 7-amino derivatives of 3-methoxycarbonyl-β-carboline (β-CCM) and of 3-ethoxycarbonyl-β-carboline (β-CCE)

Condensation of diethyl formylamino- or diethyl acetylaminomalonate with 4-, 5- or 6-nitrogramine 1 afforded the diethyl formylamino- or the diethyl acetylamino[(nitroindol)-3-ylmethyl]malonates 2 ; reduction of the nitro group followed by N-formylation or acetylation of the resulting amino compounds 3 , led to the 4-, 5-and 6-acylamino derivatives 4 . Cyclization of 4 in the presence of polyphosphoric esters gave the 3,3-bis(ethoxycarbonyl)-3,4-dihydro-β-carbolines 5 , which underwent lithium chloride/water catalyzed monodeethoxycarbonylation to the corresponding 5-, 6- and 7-acylamino-3-ethoxycarbonyl-β-carbolines 6 , whose acidic hydrolysis led finally to the 5-, 6- and 7-amino-3-ethoxycarbonyl-β-carbolines 9 . The 6-amino compounds 9b-e were obtained also by direct nitration of 3-methoxycarbonyl-β-carboline 7a and of 3-ethoxycarbonyl-β-carboline 7c , followed by the nitro group reduction of the resulting nitro carbolines 8 . Preliminary studies of the binding to rabbit brain benzodiazepine receptor sites indicate compounds 9b and 9c to inhibit the ³H-diazepam binding at 10^?8 M concentrations.