Syntheses based on 2-ethoxycarbonylmethyl-7-methyl-1,3,4-thiadiazolo[3,2-a]pyrimidin-5(5H)-one

2-Ethoxycarbonylmethyl-7-methyl-1,3,4-thiadiazolo[3,2-a]pyrimidin-5(5H)-one containing the active methylene group reacts easily with carbon disulfide and phenyl isothiocyanate in the presence of sodium hydride. Further alkylation of the reaction product by alkyl halides results in the formation of the corresponding 1,3,4-thiadiazolo[3,2-a]pyrimidine derivatives containing a ketene dithioacetal fragment. Deceased. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2371–2373, November, 1998.     

Synthesis and transformations of 2-(5-amino-(mercapto)-1,3,4-thiadiazolylthio)-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidines

The reactions of 2-amino-5-mercapto-(or 2,5-dimercapto)-1,3,4-thiadiazoles with 2-bromo-7-methyl-5-oxo-5H-1, 3,4-thiadiazolo[3, 2-a]pyrimidine to give the corresponding sulfides have been studied. The possibility of S-alkylation and addition of quinone at the free mercapto group in the 1,3,4-thiadiazole ring has been shown. The reactions at the amino group with benzoyl chloride and chloroformates have been investigated. The conditions of cyciodehydration at the amino group with ethyl acetoacetate and bromination of the pyrimidine fragment of 7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine have been found.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1954–1957, November, 1993     

Synthesis of derivatives of a new heterocyclic system, 9-oxo-1,3,4-thiadiazolo[3,2-a]pyrido[3,2-e]pyrimidine

Reaction of 2-substituted 5-imino-7-oxo-1,3,4-thiadiazolo[3,2-a]pyrimidines with pentane-2,4-dione in polyphosphoric acid yields 9-oxo-1,3,4-thiadiazolo[3,2-a]pyrido[3,2-e]pyrimidines.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2037–2038, October, 1995.The authors are grateful to V. A. Dorokhov for the skilled preparation of the paper for publication.     

Purines, pyrimidines, and related fused systems. 21. Oxidative amination of 3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione

Oxidative amination of 3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione with primary alkylamines and potassium amide in liquid ammonia gives rise to the corresponding 4-amino derivatives as the major products. The reactions with acyclic secondary amines are accompanied by annelation of the pyrrole moiety to the starting heterosystem to form 1-R-3-R"-6,8-dimethylpyrrolo[2",3";3,4]pyrimido[4,5-c]pyridazine-7,9(6H,8H)-diones. The reaction with piperidine as the aminating agent occurs exclusively as aminodehalogenation. The Sonogashira cross-coupling of 4-amino-3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones with terminal alkynes affords 1-R-2-R"-6,8-dimethylpyrrolo[3",2";3,4]pyrimido[4,5-c]pyridazine-7,9(6H,8H)-diones.     

Zur Synthese von Imidazo(2,1-b)-1,3,4-thiadiazolo(3,2-a)-pyrimidonen-(6)

2-Amino-6-aryl-imidazo(2,1-b)-1,3,4-thiadiazoles (1 a-f) were condensed with 1,3-ketocarboxylates e. g. ethyl-butyroacetate, ethyl-benzoylacetate, 4-nitrobenzoylacetate or ethyl-cyclopentanone(2)-carboxylate and ethyl-cyclohexanone(2)-carboxylate directly to imidazo(2,1-b)-1,3,4-thiadiazolo(3,2-a) pyrimidones-(6) (4 a-f, 5 a-f, 6 d, e, 7 a-f, 8 a, d).

11. Mitt. über Heterocyclen; 10. Mitt.Paul, H., Sitte, A., Wessel, R., Arch. Pharm. (Weinheim), im Druck.     

Efficient Synthesis of New Tetracyclic Benzofuro[3,2-d]-imidazo[1,2-a] pyrimidine-2,5-(1 H,3 H)-diones

The aza‐Wittig reaction of iminophosphorane ( 1 ) with aromaic isocyanates gave carbodiimides ( 2 ), which were allowed to react further with (‐amino ester in the presence of a catalytic amount of sodium ethoxide to give selectively new tetracyclic benzofuro[3,2‐d]imidazo[1,2‐a]pyrimidine‐2,5‐(1H,3H)‐diones ( 5 ) in good yields. X‐ray structure analysis of 5i verified the proposed structure and the reaction selectivity.     

[f]-Fused purine-2,6-diones: Synthesis of new [1,3,5]- and [1,3,6]-thiadiazepino-[3,2-f]-purine ring systems

Summary 6-Phenyl-1,3-dimethyl-2,4-dioxo-1,2,3,4,8,9-hexahydro-[1,3,5]-thiadiazepino-[3,2-f]-purine (5) was obtained by a three-step synthesis from 8-mercapto-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1) and 2-(benzoylamino)-ethyl chloride (2)via 8-(benzoylaminoethylthio)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (3) and its chloromido derivative4. The analogous 9-phenyl-1,3-dimethyl-2,4-dioxo-1,2,3,4,6,7-hexahydro-[1,3,6]-thiadiazepino-[3,2-f]-purine (7) was synthesized either from compound1 and N-(2-chloroethyl)-benzimido chloridevia N-(chloroethyl)-S-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-7H-purin-8-yl)-benzothioimide (6), or alternatively from 7-(2-benzoylaminoethyl)-8-bromo-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (9), its 8-mercapto derivative10 and the corresponding chloroimido compound11 being the intermediates.Part of this paper was presented as a preliminary report at the Congress of Czech and Slovak Chemical Societies, Olomouc, Czech Republic, September 13–16, 1993     

Reaction of 6-methoxybenzo[b]furan-3(2H)-one and benzo[b]thiophen-3(2H)-one with 2-aryl-1,1-dicyanoethylenes as a convenient synthetic route to substituted 2-amino-4-aryl-1,3-dicyano-7-methoxydibenzo[b,d]furans and 2-amino-4-aryl-3-cyano-4H-benzothieno[3,2-b]pyrans

The reactions of 6-methoxybenzo[b]furan-3(2H)-one with 2-aryl-1,1-dicyanoethylenes and malononitrile or with aromatic aldehyde and two moles of malononitrile afford 2-amino-4-aryl-1,3-dicyano-7-methoxydibenzo[b,d]furans. The reactions of benzo[b]thiophen-3(2H)-one with 2-aryl-1,1-dicyanoethylenes or with aromatic aldehyde and one mole of malononitrile produce 2-amino-4-aryl-3-cyano-4H-benzothieno[3,2-b]pyrans.     

Benzimidazole condensed ring systems,III . Synthesis of some substituted 2,3-dihydrocyclopenta-1H-[4′,5′: 2,3]pyrido[1,2-a]benzimidazole-11-carbonitriles

Summary The synthesis of compound3 by condensing 1H-benzimidazole-2-acetonitrile (1) with ethyl cyclopentanone-2-carboxylate (2) in the presence of ammonium acetate is described. Methylation of3 with trimethyl phosphate yielded the N-methyl derivative4. Methods for converting3 to some of its related derivatives in which the carbonyl function was replaced by Cl, N₃ and amines are also reported.

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Kondensierte Ringsysteme des Benzimidazols, 3. Mitt.. Synthese von substituierten 2,3-Dihydrocyclopenta[4,5:2,3]pyrido[1,2-a]benzimidazol-11-carbonitrilen

Zusammenfassung Die Synthese der tetracyclischen Verbindung3 durch Kondensation von 1H-Benzimidazol-2-acetonitril (1) mit Cyclopentanon-2-carbonsäureester (2) in Gegenwart von Ammonacetat wird beschrieben. Die Methylierung von3 mit Trimethylphosphat liefert das N-Methylderivat4. Die Sauerstoffunktion in3 kann durch Chlor, Azid und Aminogruppen ersetzt werden.

     

Studies with Polyfunctionally Substituted Heterocycles: New Synthesis of Pyrido[5′, 4′:2,3][1,3,4]oxadiazolo[3,2-a]pyridine; Pyridazine; 1,3,4-Oxadiazote; and Pyrazolo[1,5-a]Pyrimidine Derivatives

Cyanoacetohydrazide 1a reacts with 2-arylhydrazoketons 2a,b and 3a,b in refluxing ethanol to yield pyrido[5′,4′:2,3][1,3,4]oxadiazolo[3,2-a]pyridine and pyridazine derivatives; in the absence of solvent pyrazolo[1,5-a]pyrimidine derivatives were obtained. The reaction of 2a,b and 3a,b will) benzoylhydrazine afforded 1,3,4-oxadiazole and pyrazole derivatives.     

Synthesis and Neurotropic Activity of New Heterocyclic Systems: Pyridofuro[3,2-d]pyrrolo[1,2-a]pyrimidines,Pyridofuro[3,2-d]pyrido[1,2-a]pyrimidines and Pyridofuro[3′,2′:4,5]pyrimido[1,2-a]azepines

Background: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. Objective: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. Methods: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. Results: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of “open field” and “elevated plus maze” (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of “forced swimming” (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABA_A receptor with a value of the scoring function that estimates free energy of binding (ΔG) at −7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT_1A receptor. Conclusions: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.     

A novel synthesis of N(1)-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones

A new synthesis of N₁-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones, which are analogues of the natural product toxoflavin, is reported. Condensation of preformed alkyl or aryl hydrazones with 6-chloro-3-methyl-5-nitrouracil efficiently provides pyrimidotriazinediones in a three-step process that broadens the scope of R₁ substituents.     

A novel synthesis of 3-(substituted)pyrimido[4,5-c]pyridazine-5,7(1H,6H)-diones

An improved synthesis of 3-(substituted)pyrimido[4,5-c]pyridazine-5,7(1H,6H)-diones, a known subclass of 4-deazatoxoflavins, is reported. The approach involves treatment of 3-methyl-6-(1-methylhydrazinyl)uracil with representative phenyl and alkyl glyoxal monohydrates, which in turn are obtained by selenium dioxide oxidation of the corresponding phenyl and alkyl methyl ketones. The first entry into 4-monosubstituted isomers is also reported.     

The reaction of 2-amino-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]-pyrimidine with carbon disulfide and alkylation of its products

In the reaction with carbon disulfide, 2-amino-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine (1) forms the alkaline salts of substituted dithiocarbamic or iminodithiocarbonic acids depending on the molar ratio between1, CS₂, and the alkali. The alkylation of these salts leads to the esters ofN-(7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-2-yl)dithiocarbamic (2) and diesters of (7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-2-yl)iminodithiocarbonic acids (3). The synthesis of asymmetric diesters3 may be fulfilled based on monoesters2.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 14–14, August, 1994.     

A novel and convenient synthesis of thiazolo[3,2-a]pyrimidin-7-ones and pyrido[1,2-a]pyrimidin-2-ones using Vilsmeier reagent

A novel route for the synthesis of thiazolo[3,2-a]pyrimidin-7-ones and pyrido[1,2-a]pyrimidin-2-ones from acetylated 2aminothiazoles and 2-aminopyridines under Vilsmeier conditions has been developed.The plausible mechanism has also been proposed.     

Preparation of benzo[4,5]thiazolo[3,2-a]chromeno[4,3-d]pyrimidin-6-one derivatives using MgO-MgAl2O4 composite nano-powder

MgO-MgAl₂O₄ nanocomposite was prepared from the co-precipitation of Mg(NO₃)₂ and Al(NO₃)₃ salts, characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDS) and fourier transform infrared spectroscopy (FTIR) techniques and evaluated in the synthesis of thirty five derivatives of benzo[4,5]thiazolo[3,2-a]chromeno[4,3-d]pyrimidin-6-ones (d₁-d₃₄) via the multi-component reaction of 4-hydroxycoumarins, aldehydes, and 2-aminobenzothiazole derivatives under solvent free condition. The catalytic activity of MgO-MgAl₂O₄ nanocomposite and the synthesis of the above mentioned compounds were investigated under thermal solvent free (times: 1.4–3 h; yields: 75–95%), ultrasonic irradiation (US) conditions (times: 1–2.5 h; yields: 69–97%) and using high-speed ball milling (HSBM) technique (times: 0.7–2.5 h; yields: 67–97%). In all cases, the products were obtained in excellent yields. Nuclear Magnetic Resonance (NMR) and MASS spectroscopy were used to characterize the structure of the desired product. The mechanism for the preparation of compounds d₁-d₃₄ was proposed and confirmed by ¹H NMR investigations.     

Synthesis of novel 3-(1,3-thiazol-2-yl)-7,8-dihydroquinoline-2,5(1H,6H)-diones

An efficient method for the synthesis of novel 3-(1,3-thiazol-2-yl)-7,8-dihydroquinoline-2,5(1H,6H)-diones from various 2-dimethylaminomethylidenecyclohexane-1,3-diones, (1,3-thiazol-2-yl)acetonitriles, and dimethylformamide dimethyl acetal was developed. These transformations proceeded through intermediate 2-[2-(4-aryl-1,3-thiazol-2-yl)-2-cyanoethenyl]-3-oxocyclohex-1-en-1-olates. They were isolated as piperidinium salts and used in further heterocyclization reactions with aromatic amines, giving novel 1-aryl-3-(1,3-thiazol-2-yl)-7,8-dihydroquinoline-2,5(1H,6H)-diones. These compounds were also obtained by preparative three-step “one pot” synthesis under controlled microwave irradiation. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 412–417, February, 2008.     

Synthesis of thiazolo[3,2-a]pyridines via an unusual Mannich-type cyclization

The Mannich-type reaction of N-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates with 3-(1,3-benzodioxol-5-yl)-2-methylpropanal (ocean propanal) and p-toluidine afforded 7-aryl-2-(1,3-benzodioxol-5-ylmethyl)-2-methyl-3-[(4-methylphenyl)amino]-5-oxo-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyridine-8-carbonitriles in modest (25–46%) yields. The structure of the key compound was confirmed by X-ray crystal structure analysis.     

Some chemical properties of 2,3-dihydro-4H-[1,3]thiazino[3,2-a]benzimidazol-4-one and 2-aryl-2,3-dihydro-4H-[1,3]thiazino[3,2-a]benzimidazol-4-ones

We have studied the reaction of 2,3-dihydro-4H-[1,3]thiazino[3,2-a]benzimidazol-4-one and 2-aryl-2,3-dihydro-4H-[1,3]thiazino[3,2-a]benzimidazol-4-ones with amines, alkylating reagents, and hydrogen peroxide. We have shown that the presence of an aryl substituent at the 2 position of [1,3-thiazino[3,2-a]benzimidazol-4-ones has a substantial effect on the direction of the reactions. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 445–452, March, 2006.