Synthesis of (6R)- and (6S)-5,10-dideazatetrahydrofolate oligo-gamma-glutamates: kinetics of multiple glutamate ligations catalyzed by folylpoly-gamma-glutamate synthetase

Folylpoly-gamma-glutamate synthetase (FPGS, EC 6.3.2.17) catalyzes the ATP-dependent ligation of glutamic acid to reduced folates including (6S)-5,6,7,8-tetrahydrofolate (H4PteGlu), as well as to anticancer drugs such as 5,10-dideaza-5,6,7,8-tetrahydrofolate ((6R)-DDAH4PteGlu1, (6R)-DDATHF, Lometrexol). Synthesis of unlabeled mono- and polyglutamates, DDAH4PteGlu(n) (6R, n = 1-6; 6S, n = 1-2), as well as (6R)-DDAH4Pte[14C]Glu1, was effected from (6R)- or (6S)-5,10-dideazatetrahydropteroyl azide and glutamic acid, H-Glu-gamma-Glu(n)-gamma-Glu-OH (n = 0-4), or [14C]glutamic acid, respectively. These compounds were evaluated as FPGS substrates to determine steady-state kinetic constants. Michaelis-Menten kinetics were observed for (6R)-DDAH4PteGlu1, the isomer corresponding to H(4)PteGlu, whereas marked substrate inhibition was observed for (6S)-DDAH4PteGlu(n) (n = 1-2) and (6R)-DDAH4PteGlu(n) (n = 2-5), but not (6R)-DDAH4PteGlu6. Multiple ligation of glutamate renders a quantitative analysis of these data difficult. However, approximate values of K(M) = 0.65-1.6 microM and K(I) = 144-417 microM for DDAH4PteGlu(n) were obtained using a simple kinetic model.     

Über Pterinchemie. 69 Mitteilung [1]. Konformationsanalyse von 5,6,7,8-Tetrahydropteroinsäure und 5,6,7,8-Tetrahydro-L-folsäure

Conformational analysis of 5,6,7,8-tetrahydropteroic acid and 5,6,7,8-tetrahydro-L -folic acid In the 360-MHz-¹H-NMR.-spectrum of (6R, S)-9,9-dideuterio-5, 6, 7, 8-tetrahydropteroic acid (racemic) (XIII) (AMX-System, Fig. 4) and (6R, S)-9,9-dideuterio-5, 6, 7, 8-tetrahydro-L -folic acid (diastereomeric) (XVI) the H_a–C(6) and H_a–C(7) show a vicinal coupling constant of 6,7 Hz and the H_a–C(6) and H_e–C(7) one of 3,2 Hz. The first coupling constant provides evidence for an approximate trans-diaxal arrangement of H_a–C(6) and H_a–C(7), and the second for a gauche conformation of H_a–C(6) and H_e–C(7). The tetrahydropyrazine ring in the racemic 5, 6, 7, 8-tetrahydropteroic acid (III) and in the diastereomeric 5, 6, 7, 8-tetrahydro-L -folic acid (XVII) exists therefore in a half-chair conformation with a pseudoequatorial position of the side chain at C(6) (Fig.5).     

Notizen zur Synthese sulfonierter Derivate von 5,6,7,8-Tetrahydro-1-naphthylamin und 5,6,7,8-Tetrahydro-2-naphthylamin

Notes on the Synthesis of Sulfonated Derivatives of 5,6,7,8-Tetrahydro-1-naphthylamine and 5,6,7,8-Tetrahydro-2-naphthylamine Sulfonation of 5,6,7,8-tetrahydro-1-naphthylamine ( 1 ) with sulfuric acid gave a mixture of 1-amino-5,6,7,8-tetrahydronaphthalene-2-sulfonic acid ( 2 ), 4-amino-5,6,7,8-tetrahydronaphthalene-2-sulfonic acid ( 13 ) and 4-amino-5,6,7,8-tetrahydronaphthalene-1-sulfonic acid ( 3 ). The same reaction with 5,6,7,8-tetrahydro-2-naphthylamine ( 20 ) yielded 3-amino-5,6,7,8-tetrahydronaphthalene-2-sulfonic acid ( 21 ); formation of 2-amino-5,6,7,8-tetrahydronaphthalene-1-sulfonic acid ( 16 ) or of 3-amino-5,6,7,8-tetrahydronaphthalene-1-sulfonic acid ( 24 ) was not observed. Treatment of 4-bromo-5,6,7,8-tetrahydro-1-naphthylamine ( 4 ) or of its 4-chloro analogue 5 with amidosulfuric acid gave 1-amino-4-bromo-5,6,7,8-tetrahydronaphthalene-2-sulfonic acid ( 9 ) and its 4-chloro analogue 10 , respectively, which were dehalogenated to 2 . Preparations of 13 and 24 were achieved by sulfonation of 5-nitro-1,2,3,4-tetrahydronaphthalene ( 14 ) and 6-nitro-1,2,3,4-tetrahydronaphthalene ( 22 ) to 4-nitro-5,6,7,8-tetrahydronaphthalene-2-sulfonic acid ( 15 ) and 3-nitro-5,6,7,8-tetrahydronaphthalene-1-sulfonic acid ( 23 ), respectively, followed by Béchamp reductions. The sulfonic acid 13 was also obtained by hydrogenolysis of 4-amino-1-bromo-5,6,7,8-tetrahydronaphthalene-2-sulfonic acid ( 11 ) or of its 1-chloro analogue 12 ; compounds 11 and 12 were synthesized from N-(4-bromo-5,6,7,8-tetrahydro-1-naphthyl)acetamide ( 7 ) and from its 4-chloro analogue 8 , respectively, by sulfonation with oleum and subsequent hydrolysis. By ‘baking’ the hydrogensulfate salt of 1 or 20 compounds 3 and 21 were obtained, respectively. Synthesis of 16 was achieved by sulfur dioxide treatment of the diazonium chloride derived from 2-nitro-5,6,7,8-tetrahydro-1-naphthylamine ( 17 ) giving 2-nitro-5,6,7,8-tetrahydronaphthalene-1-sulfonyl chloride ( 18 ), followed by hydrolysis of 18 to the corresponding sulfonic acid 19 and final reduction.     

Reaction of 5,6,7,8-Tetrahydropterin with Iron(III) Acetylacetonate. Detection of Radical Cations by Electrospray Ionization Mass Spectrometry

The experimental conditions developed for the detection of rather stable radical cations in solution by electrospray-ionization mass spectrometry (ESI-MS) of a Fe^II complex of 2-amino-5,6,7,8-tetrahydro-5-methylpteridin-4 (3H)-one ( 1c ) are used to observe the formation of the more unstable radical cations formed from 2-amino-5,6,7,8-tetrahydropteridin-4(3H)-one ( 1a ) and tris(pentane-2,4-dionato)iron(III) ([Fe^III(acac)₃]; 4 ) and to monitor their oxidation to the corresponding p-quinonoid dihydropterin complexes. These results contribute to the understanding of the important role played by 6β-5,6,7,8-tetrahydro-L -biopterin ( 1b ; a homologue of 1a ) together with iron as constituent of some cofactors. The complexes obtained from 1a and iron may be considered, e.g. as a model of the cofactor of the phenylalanine hydroxylase. Moreover, we describe an improved synthesis of 1c .     

Synthesis of the 7-deaza and 5-aza-7-deaza purine analogs of the antiherpes agent 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG)

Synthesis of 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyrimidin-4-one (3) a 7-deaza purine analogue and 2-amino-8-[(1,3-dihydroxy-2-propoxy)methyl]imidazo[1,2-a]-s-triazin-4-one (4) a 5-aza-7-deaza purine analogue of DHPG (2) are reported.     

Acetals of lactams and acid amides. 40. Synthesis and hydrolytic cleavage of one-ring and two-ring derivatives of 4-pyrimidinone

The reaction of 1-benzyl-5-cyano-6-dimethylaminomethylene-1, 6-dihydro-4-pyrimidinone with acid leads to 5-benzyl-1,2,7,8-tetrahydropyrido[4,3-d]pyrimidine-1,8-dione, whereas the reaction with ammonia leads to a mixture of 3-cyano-4-benzylamino-2-pyridone and 1-amino-5-benzyl-7,8-dihydropyrido[4,3-d]-pyrimidin-8-one. Heating of the latter in aqueous ethylene glycol is accompanied by recyclization to give 4-benzylamino-5,6-dihydropyrido[2,3-d]pyrimidin-5-one. The reaction of 1-benzyl-4-ditnethylaminomethylene-5-cyano-1,6-dihydro-6-pyrimidinone with ammonia leads to 1-amino-7-benzyl-7,8-dihydropyrido[4,3-d]-pyrimidin-8-one. The rate constants for cleavage of the pyrimidine ring in a number of 4-pyrimidinone derivatives were measured.See [1] for communication 39.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 532–537, April, 1984.     

Synthesis of 7-arylmethyl-substituted derivatives of 2-amino-2-pyrrolydin-1-yl-5,6,7,8-tetrahydropyrido-[3,4-<Emphasis Type="Italic">d</Emphasis>]pyrimidine

7-Benzyl-2-pyrrolidin-1-yl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one was prepared by condensation of 1-benzyl-4-ethoxycarbonyl-3-oxopiperidine with pyrrolidine-1-carboxamidine. Subsequent treatment of the product with trifluoromethansulfonyl anhydride, aqueous ammonia, and hydrogen in the presence of palladium on carbon gave 4-amino-2-pyrrolidin-1-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine in 80% yield. The given compound was used in the reductive amination of aldehydes in the synthesis of various 7-arylmethyl-substituted derivatives of 4-amino-2-pyrrolidin-1-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1374–1381, September, 2007.     

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.     

Polycyclic nitrogen compounds. Part II. Tricyclic quinoxalinones and their 4- or 6-aza analogues

1,2,3,3a-Tetrahydro-9-nitropyrrolo[1,2-α]quinoxalin-4-one and 7,8,9,10-tetrahydro-3-nitropyrido[1,2-α]quin-oxalin-6-one (V-VI) were reduced and deaminated to give new parent tricyclic quinoxalinone skeletons I-II. The latter compounds were identical with the tricycles obtained by an unambiguous independent synthesis. New 6-aza-1,2,3,3a-tetrahydropyrrolo[1,2-α]quinoxalin-4-one (III) and 4-aza-7,8,9,10-tetrahydropyrido[1,2-α]-quinoxalin-6-one (IV) were prepared by selective hydrogen transfer reductive cyclisation of esters of N-(2-nitro-3-pyridyl)pyrrolidine-2-carboxylic acid and N-(2-nitro-3-pyridyl)piperidine-2-carboxylic acid (Xb and XIb) respectively.     

A novel synthesis of the isoxazolo[5,4,3-kl]acridine ring system

The Schmidt reaction of 6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one ( 1 ) is described. In addition to the expected isomeric lactams, 3-phenyl-5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepin-4-one ( 3 ) and 7,8-dihydro-3-phenyl-4H-isoxazolo[4,5-b]azepin-5(6H)-one ( 4 ), 4-amino-3-phenyl 1,2-benzisoxazole (5) was isolated, along with 4,5-dihydro-3H-isoxazolo[5,4,3-kl]acridine ( 6 ). Possible mechanisms for the formation of these products are discussed and some chemistry of the little-known ring system represented by 6 is also described.     

Acid-Catalyzed Rearrangement of 3-Aza-8-oxatricyclo[3.2.1. 02,4]octan-6-one Acetals. Highly Stereoselective Total Synthesis of 3-Amino-3-deoxy-D-altrose and Derivatives

Ethyl and tert-butyl azidoformate added to 7-oxabicyclo[2.2.1]hept-5-en-2-one dimethyl ( 5 ) and dibenzyl ( 6 ) acetals to give mixtures of regioisomeric triazolines. The latter gave the corresponding aziridines (6,6-dialkoxy-3-aza-8-oxatricyclo[3.2.1.0^2,4]octane-3-carboxylates 15 , 19 , 23 , and 27 and 31 ) on UV irradiation. In the presence of protic acids, the aziridines were rearranged into protected amines ([3-endo-alkoxy-5-oxo-7-oxabicyclo[2.2.1]hept-2-exo-yl]carbamates 16 , 20 , 24 , and 28 and 33 ). Using (+)-(1R, 4R)-5,5-bis(benzyloxy)7-oxabicyclo[2.2.1]hept-2-ene((+)- 6 ) derived from furan and l-cyanovinyl (1S)-camphanate, the method was applied to prepare 2-O-benzyl-3-[(tert-butoxy)carbonyiamino]-5-O-(3-chlorobenzoyl)-3-deoxy-β-D -altrofuranurono-6,1-lactone ((?)- 37 ). This compound was converted to methyl 3-amino-3-deoxy-α-D-altropyranoside hydrochloride ( 44 ) and several derivatives.     

Synthesis of optically active 2-benzyldihydrobenzopyrans for the hypoglycemic agent englitazone

Two syntheses of some optically active 2-benzyl-2,3-dihydro-4H-benzopyrans and benzopyran-4-ones are presented. An asymmetric synthesis starting from D- and L-phenylalanine was used to provide both enantiomers of 2-benzyl-6-(methoxycarbonyl)-2,3-dihydro-4H-benzopyran-4-one 19. Phenylalanine was diazotized in aqueous sulfuric acid to 2-hydroxy-3-phenylpropionic acid 6 which was converted in four steps to 1-bromo-2-(4-methoxycarbonylphenoxy)-3-phenylpropane 11. (4R,S)-Benzamido-2-benzyl-2,3-dihydro-6-(methoxycarbonyl)-4H-1-benzopyran-4-carboxylic acid 16 was prepared from 11 by amidoalkylation with α-hydroxyhippuric acid in methanesulfonic acid solution followed by spiroalkylation to (4R,S)-2-benzyl-2,3-dihydro-6-(methoxycarbonyl)spiro[4H-benzopyran-4,4′-2′-phenyloxazolidin]-5′-one 15. After the phenyloxazolidin-5-one 15 was hydrolyzed to the spirobenzamido carboxylic acid 16 , oxidative decarboxylation with sodium hypochlorite yielded optically active 2-benzyl-6-(methoxycarbonyl)-2,3-dihydro-4H-benzopyran-4-one 19. The ketone in 19 was reduced by hydrogenation over palladium on carbon to a methylene group and the ester was converted to the aldehyde to give both isomers of the desired intermediate 2-benzyl-6-(formyl)-2,3-dihydro-4H-benzopyran 25. The second synthesis relied on an enzymatic hydrolysis of ethyl 2,3-dihydrobenzopyran-2-carboxylate 27 with the lipase from P. fluorescens to provide the desired 2R-ester. The ester group in (R)- 27 was converted to the triflate (R)- 29. Displacement of the triflate group with phenylmagnesium bromide and cuprous bromide as catalyst gave 2R-benzyl-2,3-dihydro-4H-benzopyran (R)- 30. Formylation of (R)- 30 provided 2R-benzyl-6-(formyl)-2,3-dihydro-4H-benzopyran (R)- 25 identical with that from the first synthesis. These optically active intermediates are used in the preparation of the hypoglycemic agent englitazone.     

8-Aza-7-deaza-2′,3′-dideoxyguanosine: Deoxygenation of its 2′deoxy-β-D-ribofuranoside

The synthesis of 6-amino-1-(2′,3′-dideoxy-β-D -glycero-pentofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( =8-aza-7-deaza-2′,3′-dideoxyguanosine; 1 ) from its 2′-deoxyribofuranoside 5a by a five-step deoxygenation route is described. The precursor of 5a, 3a , was prepared by solid-liquid phase-transfer glyscosylation which gave higher yields (57%) than the liquid-liquid method. Ammonoloysis of 3b furnished the diamino nucleoside 3c . Compound 1 was less acid sensitive at the N-glycosydic bond than 2′,3′-dideoxyguanosine ( 2 ).     

Synthesis of 11-aza-5H-benzophenoxazin-5-one and 11-Aza-5H-pyridophenoxazin-5-one derivatives

The 1,6-disubstituted- and 4,6-disubstituted-11-aza-5H-benzo[a]phenoxazin-5-one as well as 6-substituted-11-aza-5H-pyrido[a]phenoxazin-5-one derivatives were prepared by the condensation of 2-amino-3-hydroxypyridine with 5-substituted-2,3-dihalogeno-1,4-naphthoquinones and 6,7-dibromo-5,8-quinolinequinone respectively. The resulting compounds were subjected to reduction, acetylation, dehalogenation and reaction with aniline.     

The synthesis of 1-substituted 6-amino-1H-pyrrolo-[3,2-c]pyridin-4(5H)-ones

The synthesis of 1-methyl- ( 1a ) and 1-benzyl-6-amino-1H-pyrrolo[3,2-c]pyridin-4(5H)-one ( 1b ) from the appropriate N-alkylaminoacetaldehyde is described. These provide examples of a synthetic procedure that can be used to prepare 1-substituted 6-amino-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones wherein the N-1 substituent is regiospecifically placed.     

Synthesis of analogues of the 2,3,6,-triazaphenothiazine ring system

Treatment of 2,3-dichloroquinoxalines with 2-amino-6-picoline-3-thiol gave a mixture of 2,3-bis(2-amino-6-picolinyl-3-thio)quinoxalines ( 16 , R = H, CI) and 2,3-bis (N,N-dimethylamino)quinoxalines ( 15 , R = H, CI) separated by fractional crystallization. A similar reaction of 3-amino-6-methoxypyridine-2(1H)-thione ( 9 ) with 4,5-dichloropyridazin-3(2H)-one ( 21 ) gave 4-chloro-5-(3-amino-6-methoxypyridyl-2-thio)pyridazin-3(2H)-one ( 22 ). Concentrated hydrochloric acid-catalysed cyclization of 22 gave the non-rearranged 7-methoxy-2,3,6-triazaphenothiazin-1(2H)-one. The action of compound 22 in refluxing glacial acetic acid gave, on the other hand, 7-methoxy-2,3,6-triazaphenothiazin-4(3H)-one via a Smiles rearrangement. These cyclized compounds are the first known derivatives of the new 2,3,6-triazaphenothiazine ring system.     

Electrospray-Ionization Mass Spectrometry: Detection of a radical cation present in solution: New results on the chemistry of (tetrahydropteridinone)-metal complexes

This paper marks the first reported detection of radical cations by Electrospray-Ionization Mass Spectrometry (ESI-MS). Electron Spin Resonance (ESR) measurements have proven that the detected radical cation existed already in solution and has not been generated by the electrospray ionization technique. However, we observed that the radical cation can be generated by changes in the ionization conditions. A molar mixture of 2-amino-5,6,7,8-tetrahydro-5-methylpterin-4(4H)-one dihydrochloride ( = 5,6,7,8-tetrahydro-N(5)-methylpterin-2 HCl, N(5)-MTHP-2 HCl), and tris(pentane-2,4-dionato)iron(III) in MeCN at pH 2–3 leads to the formation of a [bis(pentane-2,4-dionato)(2-amino-5,6,7,8-tetrahydro-5-methylpteridin-4 (4H)-one)]iron complex ( = [bis(pentane-2,4-dionato) (5,6,7,8-tetrahydro-N(5)-methylpteridin)]iron complex) which can be detected by ESI-MS. The results suggest that this complex might be an Fe^II radical cation, which could possibly be a suitable model complex for the active center of the phenylalanine hydroxylase. In the same solution, the stable radical cation of N(5)-MTHP is identified by ESI-MS and ESR.     

Synthesis of piperidinones incorporating an amino acid moiety as potential SP antagonists

Substituted (±)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3-carboxamides (type I) and the acylated derivatives of (±)-trans-5-amino-1-benzyl-6-phenylpiperidin-2-one (type II) were prepared by the reaction of (±)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3-carboxylic acid and some common reagents to provide the products in satisfactory yields. Newly synthesized compounds share the same moiety with common SP antagonists and thus similar activities might be expected.     

Photoinduzierte Cycloadditionen von 3-Benzyl-2H-azirin

Irradiation of 2-azido-3-phenyl-propene ( 5 ) in pentane or benzene solution with a high pressure lamp (pyrex filter) yields 3-benzyl-2H-azirin ( 6 ), which on further irradiation behind quartz or vycor in the presence of trifluoroacetic acid methylester or carbon dioxide yields 4-benzyl-5-methoxy-5-trifluoromethyl-3-oxazolin ( 8 ) and 4-benzyl-3-oxazolin-5-one ( 9 ), respectively (scheme 2). A small amount of 3-phenylacetonitrile is also formed.     

Synthesis of pyrido[3,4-<Emphasis Type="Italic">d</Emphasis>]pyrimidines by condensation of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate with morpholine-4-carboxamidine

A method has been developed for the synthesis of 4-amino-substituted 7-benzyl-2-morpholin-4-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidines by condensation of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate with morpholine-4-carboxamidine and subsequent reaction of the 7-benzyl-2-morpholin-4-yl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one with trifluoromethanesulfonic anhydride and secondary amines. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 762–768, May, 2007.