Synthesis of fused [1,2,6]thiadiazine 1,1-dioxides as potential transition-state analogue inhibitors of xanthine oxidase and guanase.

Ring closure of ethyl 3-aminopyrazole-4-carboxylate with sulfamoyl chloride gave 1,7-dihydropyrazolo[3,4-c][1,2,6]thiadiazine-4(3H)-one 2,2-dioxide. The corresponding 4-amino analogue of this new heterocyclic ring system was similarly prepared from 3-aminopyrazole-4-carbonitrile. Treatment of 4,5,6-triamino-2H-1,2,6-thiadiazine 1,1-dioxide with N-thionylaniline gave a derivative of another new ring system, 7-amino-4H-[1,2,5]thiadiazolo[3,4-c][1,2,6]thiadiazine 5,5-dioxide. These compounds and the corresponding 4-amino- and 4-hydroxyimidazol[4,5-c][1,2,6]thiadiazine 2,2-dioxides were examined as potential transition-state analogue inhibitors of xanthine oxidase and guanine aminohydrolase. Two of the compounds possessed Ki values of about 2x 10(-4) M with guanine aminohydrolase, but no inhibition of xanthine oxidase was observed by any at 5 x 10(-4) M.     

Novel bronchodilators: synthesis, transamination reactions, and pharmacology of a series of pyrazino[2,3-c][1,2,6]thiadiazine 2, 2-dioxides

The synthesis, pharmacological evaluation, and structure-activity relationships of a new class of bronchodilator agents, derivatives of pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides are described. The compounds were prepared by reaction of 3,4,5-triamino-1,2, 6-thiadiazine 1,1-dioxide with suitable 1,2-dicarbonyl compounds or alpha-hydroxyiminoketones and subsequent N-alkylation. A transamination procedure for synthesizing derivatives with different substituents at the 4-amino group is reported for the first time. The pyrazino[2,3-c][1,2,6]thiadiazine derivatives were screened for tracheal relaxing activity in vitro, and the active compounds were evaluated in vivo in guinea pigs as bronchodilator agents in comparison to theophylline. Among the compounds studied, the most interesting properties were displayed by the 4-amino-1-ethyl-6-methyl derivative (21). The toxicological evaluation of this derivative is also reported.     

Novel arylpyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides as platelet aggregation inhibitors. 2. Optimization by quantitative structure-activity relationships.

In the previous paper (Part 1), we described the synthesis and antiplatelet activity of a series of phenyl- and heteroarylpyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides. In this paper, we report the optimization of the platelet aggregation inhibitory activity by an iterative sequence of quantitative structure-activity relationship studies which encompassed synthesis and evaluation of the effects of structure variations at the 1-, 6-, and 7-positions of the heterocyclic system. A model has been established that correctly correlates antiplatelet activity in this series with the partial atomic charges calculated by a local density functional ab initio method. As a result of this study, the experimental platelet aggregation inhibitory activity of the lead compound was improved 300-fold.     

Novel arylpyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides as inhibitors of platelet aggregation. 1. Synthesis and pharmacological evaluation.

A series of N-1-substituted derivatives of pyrazino[2,3-c][1,2, 6]thiadiazine 2,2-dioxides bearing aryl groups at the pyrazino moiety have been prepared. The synthesis involves ring formation between the diaminothiadiazine and suitable dicarbonyl compounds and subsequent introduction of the substituent at N-1. The compounds have been tested in vitro, as inhibitors of rabbit and human platelet aggregation, and ex vivo against rat platelet aggregation induced by arachidonic acid, ADP, collagen, U46619, and I-BOP. The results obtained indicate that some pyrazino[2,3-c][1,2, 6]thiadiazine derivatives show significant platelet aggregation inhibition similar to other antithrombotic agents and that the antiplatelet properties may be mediated by interference with the arachidonic acid pathway.     

Fused 1,2,6-Thiadiazines Tetrahydrobenzo[b]thieno[2,3-c] [1,2,6]thiadiazine 2,2-Dioxides

Suitably substituted derivatives of tetrahydrobenzo[b]thiophene were treated with sulfamoyl chlorides to give sulfamoyl esters and nitriles. Ring closure of these compounds, under various conditions, afforded tetrahydrobenzo[b]thieno[2,3-c][1,2,6]thiadiazine 2,2-dioxides. Their herbicidal activities were tested.     

Synthesis and cytostatic screening of an SO2 analogue of doridosine

Imidazo[4,5-c][1,2,6]thiadiazine ribosides have been prepared from furazano[3,4-c][1,2,6]thiadiazine 5,5-dioxides in a reaction sequence which involves introduction of the glycosidic rest, reductive cleavage of the furazan ring and cyclization. The ribosides were screened against HeLa cell cultures but showed no significant activity.     

Synthesis, isomerization, and antimicrobial evaluation of some pyrazolopyranotriazolopyrimidine derivatives

6-Amino-5-imino-pyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidine derivative 4 and pyrazolo-[4',3':5,6]pyrano[2,3-d]pyrimidin-5-ylhydrazine derivative 5 were prepared starting from 6-amino-3-methyl-4-(p-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile 1. The synthesis and structure characterization of 9,11-dihydropyrazolo[4',3':5,6]pyrano[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 7 and 9 and their isomerization to 9,11-dihydropyrazolo[4',3':5,6]pyrano[3,2-e] [1,2,4]triazolo[1,5-c]pyrimidine derivatives 6 and 8, respectively, under different suitable reaction conditions are reported. Moreover, the synthesis of 9,11-dihydropyrazolo[4',3':5,6]pyrano[3,2-e] tetrazolo[1,5-c]pyrimidine derivative 14 and N(9)-acyclic nucleoside 15 are described. Some of the prepared products showed potent antimicrobial activity.     

Paullones, a series of cyclin-dependent kinase inhibitors: synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity.

The paullones represent a novel class of small molecule cyclin-dependent kinase (CDK) inhibitors. To investigate structure-activity relationships and to develop paullones with antitumor activity, derivatives of the lead structure kenpaullone (9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one, 4a) were synthesized. Paullones with different substituents in the 2-, 3-, 4-, 9-, and 11-positions were prepared by a Fischer indole reaction starting from 1H-[1]benzazepine-2,5(3H,4H)-diones 5. Selective substitutions at either the lactam or the indole nitrogen atom were accomplished by treating kenpaullone with alkyl halides in the presence of sodium hydride/THF or potassium hydroxide/acetone, respectively. S-Methylation of the kenpaullone-derived thiolactam 18 yielded the methylthioimidate 19, which gave the hydroxyamidine 20 upon reaction with hydroxylamine. The new paullones were tested both in a CDK1/cyclin B inhibition assay and in the in vitro antitumor cell line-screening program of the National Cancer Institute (NCI). With respect to the CDK1/cyclin B inhibition, electron-withdrawing substituents in the 9-position as well as a 2,3-dimethoxy substitution on the paullone basic scaffold turned out to be favorable. A 9-trifluoromethyl substituent was found to be equivalent to the 9-bromo substituent of kenpaullone. Replacement of the 9-bromo substituent of kenpaullone by a 9-cyano or 9-nitro group produced a substantial increase in enzyme-inhibiting potency. Substitutions in other positions or the replacement of the lactam moiety led to decreased CDK1 inhibition. Noteworthy in vitro antitumor activities (GI(50) values between 1 and 10 microM) were found with the 9-bromo-2,3-dimethoxy-7,12-dihydroindolo[3, 2-d][1]benzazepin-6(5H)-one (4t), its 9-trifluoromethyl analogue 4u, the 12-Boc-substituted paullone15, and the methylthioimidate 19, respectively. The 9-nitro-7,12-dihydroindolo[3, 2-d][1]benzazepin-6(5H)-one (4j, named alsterpaullone) showed a high CDK1/cyclin B inhibitory activity (IC(50) = 0.035 microM) and exceeded the in vitro antitumor potency of the other paullones by 1 order of magnitude (log GI(50) mean graph midpoint = -6.4 M).     

Synthesis, reactions and biological activity of some new thieno[2,3-f]-1,3-benzodioxoles.

The reaction of 7-chlorothieno[2,3-f]-1,3-benzodioxole-6-carbonyl chloride (2) with some aromatic or heterocyclic amines gave the corresponding 6-(aryl or heterocyclyl) carbamoyl-7-chlorothieno [2,3-f]-1,3-benzodioxoles (3a-c, 4a, b and 5). Compound 2 was also reacted with potassium thiocyanate, ethanol or sodium azide to afford the isothiocyanto compound 6, the ester 7 and the acid azide 9, respectively. Hydrazinolysis of 7 gave the carbohydrazide 8. The compounds 6, 8 and 9 were used as precursors in the synthesis of the target heterocycles, 7-chlorothieno[2,3-f]-1,3-benzodioxoles substituted with a variety of moieties at position-6 (10-15, 17, 19-26, 28-31). Also, 2-methyl-1,3-dixolo[5,6][1]benzothieno[2,3-c]quinolin- 6(5 H)-one (33) was prepared. The antibacterial and antifungal activities of some selected compounds were also reported.     

4-Hydroxycoumarin in heterocyclic synthesis. Part III. Synthesis of some new pyrano[2,3-d]pyrimidine, 2-substitute

The synthesis of new [1]benzopyrano[3',4':5,6]pyrano[2,3-d]pyrimidines and related heterocycles has been reported. The key intermediate 2-amino-3-cyano-4-methyl-4H,5H-pyrano[3,2-c][1]benzopyran-5-one (3) was obtained in one pot synthesis from the reaction of 4-hydroxycoumarin and acetaldehyde-malononitrile (2). The antimicrobial screening was performed for some of the synthesized compounds.     

Synthesis and biological evaluation of new thiazolopyrimidines

In this study, a series of 4-amino-5-cyano-3-substituted-2,3-dihydrothiazol-2-thiones (1a-c), as well as their triazolo and triazinopyrimidine derivatives such as 8-substituted-3-benzyl-5-methylthiazolo[5,4-e][1,2,4] triazolo[1,5-c]pyrimidin-2-thiones (4-6, 10) and 3-benzyl-5-methyl thiazolo[5,4-e]pyrimidino[3,4-b][1,2,4]triazin-2-thiones (7a-b) were prepared as potential antimicrobial and antitumor agents. Some of the tested compounds showed promising antimicrobial activity and non of them showed any appreciable antitumor activity.     

Synthesis and biological activity of new heterocyclic structures: [1,3]thiazino[2,3-i]purine, thiazolo[3,2-c] [1,2,3]triazolo[4,5-e]pyrimidine and [1,2,3]triazolo [4', 5': 4,5] pyrimido[6,1-b][1,3]thiazine.

Some derivatives of thiazolo[3,2-c]pyrimidine, pyrimido[6,1-b][1,3]thiazine, thiazolo[2,3-i]purine, [1,3]thiazino[2,3-i]purine, thiazolo[3,2-c][1,2,3]triazolo[4,5-e]pyrimidine and [1,2,3]triazolo[4',5':4,5]pyrimido[6,1-b][1,3]thiazine were prepared. The compounds were tested for antimicrobial and antimycotic activity on a number of strains, namely, Escherichia coli, Proteus vulgaris, P. mirabilis, Pseudomonas aeruginosa, Salmonella sp., Staphylococcus aureus, Streptococcus faecalis, Bacillus subtilis, Sarcina lutea, Candida albicans, Aspergillus sp., and for antiviral activity on Herpes simplex virus, Type 1 (HSV-1), Vesicular stomatitis virus (VSV) and Coxsackievirus B5 (CoxB5). The compounds proved to be devoid of activity against viruses, mycetes and gram-negative bacteria, while some of them exhibited a modest activity against gram-positive bacterial strains.     

Effect of A-ring modifications on the DNA-binding behavior and cytotoxicity of pyrrolo[2,1-c][1,4]benzodiazepines.

Several A-ring-modified analogues of the DNA-binding antitumor agent DC-81 (5) have been synthesized in order to study structure-reactivity/cytotoxicity relationships. For two molecules (23 and 30) the modifications required the addition of a fourth ring to give the novel dioxolo[4,5-h]- and dioxano[5,6-h]pyrrolo[2,1-c][1, 4]benzodiazepin-11-one (PBD) ring systems, respectively. Another three analogues (34, 38, and 48) have the native benzenoid A-ring replaced with pyridine, diazine, or pyrimidine rings to give the novel pyrrolo[2,1-c][1,4]pyridodiazepine, pyrrolo[2,1-c][1, 4]diazinodiazepine, and pyrrolo[2,1-c][1,4]pyrimidinodiazepine systems, respectively. The other new analogues (16a,b) have extended chains at the C8-position of the DC-81 structure. During the synthesis of these compounds, a novel tin-mediated regiospecific cleavage reaction of the dioxole intermediate 18 was discovered, leading to the previously unknown iso-DC-81 (20). In addition, an unusual simultaneous nitration-oxidation reaction of 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (8) was found to produce 3-(4-carboxy-2-methoxy-5-nitrophenoxy)propanoic acid (9), a key intermediate, in high yield. In general, the results of cytotoxicity and DNA-binding studies indicated that none of the changes made to the A-ring of the PBD system significantly improved either binding affinity or cytotoxicity in comparison to DC-81. This result suggests that the superior potency of natural products such as anthramycin (1), tomaymycin (2), and sibiromycin (3) is due entirely to differences in C-ring structure, and in particular exo or endo unsaturation at the C2-position and C2-substituents containing unsaturation. This study also provided information regarding the influence of A-ring substitution pattern on the relative stability of the interconvertible N10-C11 carbinolamine, carbinolamine methyl ether, and imine forms of PBDs.     

Formations and reactions of aromatic furazan compounds]

A reaction from various kinds of nitroquinoline with hydroxylamine in potassium hydroxide alkalinity produced a novel product, furazanoquinoline, besides the known amino derivatives. The products obtained were furazano [3,4-f] quinoline (5) from 5-nitroquinoline (1) and 6-nitroquinoline (6), and furazano [3,4-h] quinoline (10) from 7-nitroquinoline (8) and 8-nitroquinoline (11). The reaction mechanism was believed to be as shown in Figs. 2 and 3. The photoreaction of benzofuroxan (19) in acetonitrile containing a little water, under a high pressure mercury lamp, produced 1H-azepine-2,7-dione (20), while under irradiation using a low pressure lamp, 6H-furazano [4,5-c] carbazole-3-oxide (21) and compound 20 were obtained. Then the photoproduct 20 produced photodimer 22 by irradiation in acetonitrile: water (9:1, v/v) using a high or low pressure mercury lamp, while photolysis with alkali proceeded as in the photoreaction of N-alkylimide to give 7-hydroxy-1H-azepine-2-one (23). When pyrido [2,3-c] furoxan (24) was irradiated in acetonitrile containing a little water with a low pressure mercury lamp, 3-nitro-2-pyridone (25) was obtained. When compound 24 was irradiated in the presence of morpholine with a low pressure mercury lamp in an argon atmosphere, 6-morpholinopyridine 2,3-dioxime (26) was produced. Quinoxaline 1,4-dioxide derivatives (31, 33), phenazine 5,10-dioxide derivatives (36, 37) and pyrido [2,3-b] pyrazine derivatives (38, 39) were synthesized from the corresponding furoxan catalyzed by silica gel or molecular sieves, and their antibacterial properties were evaluated. The results of antibacterial screening tests in vitro, revealed strong activity against Bacteroides fragilis.     

New antiinflammatory agents. 2. 5-Phenyl-3H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-ones: a new class of nonsteroidal antiinflammatory agents with potent activity like glucocorticoids.

We previously described new antiinflammatory agents, 4-hydroxy-2-oxo-1-phenyl-1H-1,8-naphthyridine-3-carboxamides 1. Further modification of the compounds bearing 1-phenyl-1,8-naphthyridin-2-one as a mother skeleton led to 5-phenylimidazo[4,5-c][1,8]naphthyridin-4(5H)-one derivatives 2 and 3. Regioselective synthesis of these compounds bearing a substituent at the 1- or 3-position was conducted according to the method shown in Schemes I and II. In this series of compounds, antiinflammatory activities were greatly influenced by the position and nature of substituents on imidazole. 3-Alkyl or 3-benzyl substitution result in the potent activity, but 1-substitution did not. Minor modification of the benzyl group reduced or eliminated the activity. Detailed examination of structure-activity relationships led to 3-benzyl-5-phenyl-3H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (22), which exhibited potent oral antiinflammatory activities in carrageenan-, zymosan-, and reversed passive Arthus reaction-induced rat paw edemas (ED40 = 5.3, 0.37 mg/kg, ED50 = 0.47 mg/kg, respectively). This broad activity of 22 was like that of glucocorticoids. Compound 22 did not affect activities of CO and 5-LO enzymes and receptor binding of various ligands. As one of the mechanisms of action, induction of release of glucocorticoids was postulated. These results suggest that 22 represents a novel class of antiinflammatory agents.     

New bronchodilators. 3. Imidazo[4,5-c][1,8]naphthyridin-4(5H)-ones.

In order to develop new oral bronchodilators, a series of novel imidazol[4,5-c][1,8]naphthyridin-4(5H)-ones 5 were designed and synthesized. Some of these new heterocycles exhibited more potent bronchodilator activity in vitro and in vivo than theophylline. With respect to modification at the 5-position, both phenyl and n-butyl substitution produced potent activity. Though bulk tolerance at N-3 is observed with short and small lipophilic groups, any substitution at the other positions and transformations of the parent skeleton eliminated activity. Thus 5-phenyl-1H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (23) (KF17625), which satisfied these conditions, was selected for further studies (antigen inhalation-induced bronchospasm model; minimum effective dose (MED) = 1 mg/kg, po; antigen-induced contraction of trachea (the Schultz-Dale reaction), IC50 = 2.2 microM). Compound 23 inhibited carbachol-, histamine-, or leukotriene D4-induced contraction and relaxed spontaneous tone in guinea pig isolated tracheal preparations with, 4- to 16-fold greater potency than aminophylline. Thus it appeared to relax directly the airway smooth muscle. 23 did not have any influence on adenosine binding at 10 microM, but inhibited canine tracheal phosphodiesterase (PDE) IV (IC50 = 12 microM) and concanavalin-A-induced histamine release from rat mast cells (44% inhibition at 10 microM). Although the detailed mechanisms of these compounds remain to be elucidated, this series of novel tricyclic heterocycles represents a new class of bronchodilator.     

Synthesis and evaluation of pharmacological and pharmacokinetic properties of 11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones

A series of 2,3-benzodiazepine derivatives has been previously described as noncompetitive AMPA-type glutamate receptor antagonists potentially useful for treatment of epilepsy. To further explore the structure-activity relationships of AMPA antagonists, a series of 11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones (6) was synthesized starting from the corresponding bicyclic 1-aryl-3, 5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-ones (2, CFM). The new compounds were found to possess anticonvulsant effects against seizures induced both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. In addition, they antagonize the AMPA-induced seizures, and their anticonvulsant activity is reversed by pretreatment with aniracetam, thus suggesting the involvement of AMPA receptors. The pharmacological studies revealed that the 11H-[1,2,4]triazolo[4, 5-c][2,3]benzodiazepin-3(2H)-ones (6) herein reported show anticonvulsant activity comparable to that of their bicyclic precursors. Furthermore, an HPLC study put in evidence that these tricyclic derivatives 6 were converted in vivo into the corresponding 2, the agents likely to be mainly responsible for the anticonvulsant properties observed.