Untersuchungen an 1,3-Thiazinen, 14. Mitt. Neue und bekannte Möglichkeiten zur Darstellung von N-monosubstituierten 3-Carbamoylmercaptopropionsäuren und deren Cyclisierung zu Tetrahydro-1,3-thiazin-2,4-dionen – ein Vergleich

1,3-Thiazines, XIV: Comparison of New and Known Methods for the Preparation of N-Monosubstituted 3-(Carbamoylmercapto)propionic Acids and their Cyclisation to Tetrahydro-1,3-thiazine-2,4-diones Three newly developed synthetic methods for N-monosubstituted 3-carbamoylmercapto propionic acids 2 have been compared with known methods concerning scope and yield. Method C - addition of 3-mercapto propionic acid methyl ester to isocyanates followed by acid hydrolysis to 2 proved best. With phosphorus pentoxide/p-toluene sulfonic acid/toluene higher yields of the tetrahydro-1,3-thiazine-2,4-diones 12 could be achieved from the acids 2 than by known methods.     

Untersuchungen an 1,3-Thiazinen, 32. Mitt.1) Oxidationen an Thiourethanen, 6. Mitt.2). 3-Amino-5,6-dihydro-2H-1,3-thiazin-2,4(3H)-dione,neuartige cyclische Thiolcarbazate

1,3-Thiazines, XXXII¹⁾; Oxidations of Thiourethanes, VI²⁾: 3-Amino-5,6-dihydro-2H-1,3-thiazine-2,4(3H)-diones, Novel Cyclic Thiolcarbazates 3-Amino-5,6-dihydro-2H-1,3-thiazine-2,4(3H)-diones 2 were synthesized by oxidative desulfurisation of the 2-thioxo analogues 1 or by cyclisation of the 3-(carbazoylthio)-propionic acids 4 . Some of the compounds are biologically active.     

3-Alkoxyoxazolidin-2,4-dione aus N-Alkoxy-2-hydroxycarbonsäureamiden und 1,1′-Carbonyldiimidazol

3-Alkoxyoxazolidine-2,4-diones from N-Alkoxy-2-hydroxycarboxamides and 1,1′-Carbonyldiimidazole Reaction of N-alkoxy-2-hydroxycarboxamides 3 with 1,1′-carbonyldiimidazole produces N-alkoxy-oxazolidine-2,4-diones 4 . Hydrolysis of N-(tetrahydro-2H-2-pyranyloxy)oxazolidine-2,4-diones affords 3-hydroxyoxazolidine-2,4-diones 5 which are converted by the reaction with phenyl isocyanate into 7 and with benzoyl chloride into 8 . Benzylaminolysis of 4 gave 3-benzyloxazolidine-2,4-diones 10 .     

Synthesis of 3-substituted phenacyl-5-[2-phenyl-4H-4-oxo-1-benzopyran-6- yl)methylenyl]-thiazolidine-2,4-diones and evaluation of their antimicrobial activity

Synthesis and physico-chemical properties of two 3-substituted phenacyl-thiazolidine-2,4-diones (2c-d) and four 3-substituted phenacyl-5-[2-phenyl-4H-4-oxo-1-benzopyran-6-yl)methyl-enyl]-thiazolidin e- 2,4-diones (4a-d) are described. These products were synthesized by Knoevenagel reaction from flavone-6-carboxaldehyde (3) and 3-(substituted phenacyl)- thiazolidine-2,4-diones (2a-d). Antibacterial and antifungal activities were investigated for these compounds.     

Synthese und Eigenschaften 4-unsubstituierter und 4-monosubstituierter Perhydro-1,5,2-dioxazin-3,6-dione

Synthesis and Properties of 4-Unsubstituted and 4-Monosubstituted Perhydro-1,5,2-dioxazine-3,6-diones The reaction of N-alkyl(aralkyl)glycolohydroxamic acids 2 with 1,1′-carbonyldiimidazole produces either perhydro-1,5,2-dioxazine-3,6-diones 3 , linear acylation products of type 1 or phenylglyoxylamides 4 . The formation of 3, 1 and 4 depends on the nature of the substituents at C-2 and the reaction conditions. In the presence of hydrazines 6 the heterocycles 3 are transformed into 3-aminooxazolidine-2,4-diones 8 .     

8-Methoxy-chinolin-5,6-dione, 2. Mitt

8-Methoxy-quinoline-5,6-diones, II Nine 8-methoxy-quinoline-5,6-diones with varying substituents in the 2-, 3-, and/or 4-position 3a-i were synthesized by oxidation of the corresponding 6-amino-5,8-dimethoxyquinolines 1a-i . By this oxidation quinones of type 3 are obtained only if the 8-position of the quinoline nucleus is substituted. Oxidation of 6-amino-2,4-dimethyl-5-methoxyquinoline ( 4 ) yields 2,4-dimethyl-8-((2,4-dimethyl-5-methoxy-6-quinolyl)amino)-quinoline-5,6-dione ( 5 ).     

Mehrcyclische Azine mit Heteroatomen in 1- und 3-Stellung. 41. Mitt. Synthese heterocyclischer Immunmodulatoren. 3. Mitt.: Darstellung von N-1-substituierten 3-(2-Mercaptoethyl)chinazolin-2,4(1H,3H)-dionen über Bis[2-(2-amino-benzoylamino)ethyl]disulfane und Prüfung auf immunstimulatorische Wirksamkeit

Synthesis of N-1-Substituted 3-(2-Mercaptoethyl)quinazoline-2,4(1H,3H)-diones via Bis[2-(2-amino-benzoylamino)ethyl]sulfanes and Test for Immuno-Stimulating Activity A 3-step synthesis, starting from substituted isatoic anhydride was used to prepare substituted 3-(2-mercaptoethyl)quinazoline-2,4(1H,3H)-diones 4 . Reaction of 1 with cystamine afforded bis[2-(2-amino-benzoylamino)ethyl]disulfanes 2 . Reaction of 2 with ethyl chloroformate and subsequent reduction of the heterocyclic disulfanes 3 gave mercaptoethylquinazoline-2,4-diones 4a – f . N-1 methyl and benzyl substituted derivatives 4b and 4c , respectively, show immuno-show immuno-stimulating activity in various tests.     

4-Benzyloxy-2,3,5-morpholintrione und 3-Benzyloxy-2,4-oxazolidindione aus N-Benzyloxyglykolamiden und Oxalylchlorid

4-(Benzyloxy)morpholine-2,3,5-triones and 3-(Benzyloxy)oxazolidine-2,4-diones from N-(Benzyloxy)glycolamides and Oxalyl Chloride The reaction of N-(benzyloxy)-2-hydroxycarboxamides 1 with oxalyl chloride produces, depending on the substituents at C-2, either 4-(benzyloxy)morpholine-2,3,5-triones 5 and 3-(benzyloxy)oxazolidine-2,4-diones 3 or exclusively heterocycles of type 5 . Hydrogenolysis of 5 gives N-hydroxyimides 8 .     

5-[(Halo)fluoralkyl]-5-hydroxyimidazolidin-2,4-dione aus 2,4,5-Imidazolidintrionen

5-[(Halo)fluoroalkyl]-5-hydroxyimidazolidine-2,4-diones from 2,4,5-Imidazolidinetriones (Halo)fluoroalkyltrimethylsilanes 2 smoothly react with imidazolidinetriones 1 in the presence of tetrabutylammonium fluoride (TBAF) to give 5-[(halo)fluoroalkyl]-5-hydroxyimidazolidine-2,4-diones 4 .     

2-Alkoxyimino-1,4-oxathian-6-one und 4-Alkoxy(hydroxy)perhydro-1,4-thiazin-3,5-dione aus Thiodiglycolsäuren mit Alkoxyaminen und Hydroxylamin

2-(Alkoxyimino)-1,4-oxathian-6-ones and 4-Alkoxy(hydroxy)perhydro-1,4-thiazine-3,5-diones from Thiodiglycolic Acids with Alkoxyamines and Hydroxylamine Thiodiglycolic acids 4 react with alkoxyamines 5 in the presence of dicyclohexylcarbodiimide to yield 2-(alkoxyimino)-1,4-oxathian-6-ones 6 and 4-alkoxyperhydro-1,4-thiazine-3,5-diones 7 . A catalytic amount of imidazole converts the isoimides 6 into the imides 7 . The cyclization of 4 with hydroxylamine and dicyclohexylcarbodiimide gives only the 4-hydroxyperhydro-1,4-thiazine-3,5-diones 7g–i .     

Synthesis and antimicrobial activity of substituted imidazolidinediones and thioxoimidazolidinones.

Synthesis and physico-chemical properties of new 3-benzyl-4-thioxo-5-arylideneimidazolidine-2-ones and 3-benzyl-5-arylideneimidazolidine-2,4-dione are described. These compounds were synthesized by condensation reaction from aromatic aldehydes and 3-substituted imidazolidine-2,4-diones or 4-thioxoimidazolidine-2-ones. The N-alkylation of 5-benzylideneimidazolidine-2,4-dione led simultaneously to mono- and dialkylated derivatives. The nucleophilic addition of 1-methyl-3-benzylimidazolidine-2,4-dione with 2-cyano-3-(3,4-dichlorophenyl) acrylate also yielded the 3-substituted 5-arylideneimidazolidine-2,4-dione derivative. Antimicrobial in vitro activity was determined on some compounds.     

1,5-Benzodiazepine, 1. Mitt.: Racemate und Enantiomere von 3,3-Dialkyl-1,5-benzodiazepin-2,4-dionen: Synthese,Konfiguration und enantiomere Reinheit

1,5-Benzodiazepines, I: Racemates und Enantiomers of 3,3-Dialkyl-1,5-benzodiazepine-2,4-diones: Synthesis, Configuration, and Enantiomeric Purity The syntheses of the rac. and the enantiomeric 3,3-dialkyl-1,5-benzodiazepine-2,4-diones 1 - 3 were performed as shown in Scheme 5, starting from 4- resp. 5-chloro-2-nitro-N-methylaniline ( 10/11 ) and the rac. or enantiomeric dialkylcyanoacetic acid chlorides 6a/6b . The enantiomers of ethylmethylcyanoacetic acid ( 5a ) are known. From butylmethylcyanoacetic acid ( 5b ) the (S)-(-)-enantiomer was obtained using codeine as resolving agent. By ring closure of 14/15 the benzodiazepines 16/17 were obtained, but the main products were the benzimidazoles 18/19 . The yield of 16/17 could be increased to 62–80 % when the conditions of the reaction were modified. The N-phenylation of 16/17 according to a modified Ullmann reaction gave the rac. and the enantiomeric 1,5-benzodiazepines 1 - 3 in high yields. - The absol. configurations of the new enantiomeric compounds are compiled in Tab. 1. The enantiomeric purities (e/e) of the 1,5-benzodiazepines 1 und 3 and of all intermediates are > 95 %. The enantiomeric purities of (R)-(-)-2 and the corresponding intermediates were not determined.     

1,2,3,4-Tetrahydrophthalazine, 3. Mitt. 2,4-Dialkyl-2,3,4,5,7,12-hexahydro-1H-(1,2,5)triazepin[1,2-b]phthalazin-1,5-dione

1,2,3,4-Tetrahydrophthalazines, III: 2,4-Dialkyl-2,3,4,5,7,12-hexahydro-1H-[1,2,5]triazepino[1,2-b]phthalazine-1,5-diones A series of 3-substituted 2,4-dialkyl-2,3,4,5,7,12-hexahydro-1H-[1,2,5]triazepino[1,2-b]phthalazine-1,5-diones was obtained by condensation of 2,3-bis-(2-bromoacyl)-1,2,3,4-tetrahydrophthalazines with primary amines.     

Reactions with pyrrolidine-2,4-diones, Part 4: Synthesis of some 3-substituted 1,5-diphenylpyrrolidine-2,4-diones as potential antimicrobial, anti-HIV-1 and antineoplastic agents.

The condensation of 1,5-diphenylpyrrolidine-2,4-dione (1) with ethyl orthoformate yielded 3-ethoxymethylene-1,5-diphenylpyrrolidine-2,4-dione (2). Reaction of the latter with hydrazine hydrate, secondary amines 7a-c or urea afforded the corresponding 3-substituted aminomethylene-1,5-diphenylpyrrolidene-2,4-diones 3, 8a-c or 9. On the other hand, condensation of 3 with veratraldehyde (5a) yielded 3-[(3,4-dimethoxybenzylidene)hydrazinomethylene]-1,5-diphenylpyrrolidine- 2,4-dione (6). Whereas, cyclization of 9 with the reactive malonate ester 11 produced 3-[(5-butyl-4-hydroxy-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-1-yl) methylene]-1,5-diphenylpyrrolidine-2,4-dione (12). The condensation of some selected aromatic aldehydes 5a-c and addition of morpholine (7c) or piperidine (7d) to some of the resulting 3-arylidene-1,5-diphenylpyrrolidine-2,4-diones 13b, c gave the respective 3-substituted methyl-4-hydroxy-1,5-diphenyl-delta 3-pyrrolin-2-ones 14a-c. Selected members of the new series were screened for their in vitro antimicrobial, anti-HIV-1 and antineoplastic activities. Two compounds 14a, b showed pronounced inhibitory activities against Gram-positive bacteria; whereas, in the in vitro anti-HIV-1 screening, only one compound 13c displayed a moderate activity. However, in the antineoplastic screening protocol, the tested compounds were devoid of activity.     

Synthesis and evaluation of anticonvulsant activities of some new arylhexahydropyrimidine-2,4-diones

In this study, some new 3-alkyl-6-arylhexahydropyrimidine-2,4-dione derivatives were synthesized as anticonvulsant agents. 6-Arylhexahydropyrimidine-2,4-diones which were used as starting materials in the synthesis of the compounds were prepared in acidic media by the cyclization of potassium cyanate and the appropriate ureido acids that were gained by the reaction of beta-aminoacids, malonic acid and ammonium acetate. The structures of the synthesized compounds were confirmed by UV, IR, 1H-NMR and elementary analysis. Their anticonvulsant activities were determined by maximal electroshock (MES), subcutaneous metrazol (scMet) and rotorod toxicity tests for neurological deficits. According to the activity studies, 3-arylalkyl-6-(p-chlorophenyl) derivatives were found to be protective against scMet, whereas 6-phenyl derivatives were not. 6-Phenyl-3-(2-morpholinoethyl)hexahydropyrimidine-2,4-dione was the only compound determined to be active against MES at 300 mg/kg dose at half an hour.     

Substituted thiazolidinediones and thioxothiazolidinones: synthesis and structure]

Synthesis and physico-chemical properties of 3-(4-bromobenzyl)-, 3-(4-chlorobenzyl)-5-arylidene-thiazolidine-2,4-diones and 3-(4-chlorobenzyl)-4-thioxo-5-arylidene-thiazolidin-2- ones are described. Twelve new products were synthesized by the aldolisation-crotonisation reaction from aromatic aldehydes and N-alkylated thiazolidinediones or thioxothiazolidinones. Seven compounds were preliminary tested for their bacteriostatic activity.     

Thiophene systems. 9. Thienopyrimidinedione derivatives as potential antihypertensive agents

A series of thieno[3,4-d]-, thieno[3,2-d]-, and thieno[2,3-d]pyrimidine-2,4-diones with (phenylpiperazinyl)alkyl substitution at N-3 have been synthesized and evaluated for antihypertensive effects in spontaneously hypertensive rats (SHR). These 49 compounds were compared to the vasodilator standards prazosin and the isosteric quinazoline-2,4-dione SGB 1534. Substitution at the 2-, 3-, or 4-position of the phenyl ring was examined, with that at the 2-position more potent than 4-substitution while the isomeric 3-substituted compounds were least potent. Neither alkylation nor acylation at the N-1 position improved the antihypertensive effects as compared to hydrogen. The three thienopyrimidine-2,4-diones (3-5) that contain a [(2-methoxyphenyl)piperazinyl]ethyl moiety at N-3 and hydrogen at N-1 were found to be potent oral antihypertensive agents in the SHR with doses (mg/kg, po) for reducing systolic blood pressure (SBP) by 50 mmHg (ED-50SBP) of 0.21, 0.19, and 1.0, respectively. The compounds 1-5 were further evaluated for alpha blocking potency by measuring the iv doses necessary to antagonize the phenylephrine pressor response by 50% (ED50) in the SHR. The ED50 values (micrograms/kg) are 10.4, 3.3, 1.7, 2.1, and 15.4, respectively. These results clearly show that all three thiophene systems have potent activity as antihypertensive agents and that 3 and 4 are more potent than 1 or 2 as alpha 1-antagonists in vivo.     

Pyrido[2,1-f]purine-2,4-dione derivatives as a novel class of highly potent human A(3) adenosine receptor antagonists

1H,3H-Pyrido[2,1-f]purine-2,4-diones, which can be described as fused xanthine structures, have been synthesized by a novel synthetic procedure, and their affinities for the human adenosine A(1), A(2A), and A(3) receptors have been evaluated in radioligand binding studies. The synthetic procedure employed was developed in our laboratory and involved a two-step one-pot reaction that consists of the treatment of 6-aminouracil derivatives with N-bromosuccinimide to generate a 5,5-dibromo-6-imino intermediate that reacts "in situ" with pyridine, 4-methoxypyridine, 4-tert-butylpyridine, or 4-phenylpyridine to afford the corresponding 1H,3H-pyrido[2,1-f]purine-2,4-diones (2-5). Functionalization at the N(3) position in compounds 2-5 was performed by reaction with DBU and different alkyl, alkenyl, alkynyl, or benzyl halides. Binding studies at human adenosine A(1), A(2A), and A(3) receptors revealed significant antagonist effects in the low nanomolar range, in particular against the A(3) receptor. Thus, the 1-benzyl-3-propyl-1H,3H-pyrido[2,1-f]purine-2,4-dione derivative 6, which can be considered a lead compound in this series, exhibited a K(i) value of 4.0 +/- 0.3 nM against the hA(3) receptor. Because xanthine derivatives have traditionally been considered poor A(3) antagonists, the described pyrido[2,1-f]purine-2,4-dione derivatives represent a new family of adenosine receptor antagonists which deserves further exploration.     

The oriented development of antituberculotics (Part II): halogenated 3-(4-alkylphenyl)-1,3-benzoxazine-2,4-(3H)-diones

Based on our previous studies, 21 new halogenated 3-(4-alkylphenyl)-1,3-benzoxazine-2,4-(3H)-diones were synthesized by the reaction of salicylanilides and methyl-chloroformate. All compounds were screened in vitro against three different strains of mycobacterium, and Free-Wilson method was used to establish structure-activity relationships. 6-Bromo-3-(4-butylphenyl)-1,3-benzoxazine-2,4-(3H)-dione 3b proved to be the most active compound of the series.