Synthesis and analgesic activity of 4-(3-oxo-1,2-benzoisothiazoline-2-yl)phenylalkanoic derivatives

The synthesis of a new series of 4-(3-oxo-1,2-benzisothiazolin-2-yl)phenylalkanoic compounds and some of their functional derivatives is described. The compounds, on the basis of data obtained from 1,2-benzisothiazolin-3-one derivatives, were biologically examined mainly for their antiphlogistic and analgesic actions. Results obtained, in analyzing the relationship between structure and pharmacological actions, suggest that both 4-(3-oxo-1,2-benzisothiazolin-2-yl)-phenyalkanoic acids and o-sulphobenzimido alkanoic esters are endowed with pain-killing effects comparable in potency and efficacy with phenylbutazone.     

4-(3-Oxo-1,2-benzisothiazolin-2-yl)alkanoic, phenyl and phenoxyalkanoic acids: synthesis and anti-inflammatory, analgesic, and antipyretic properties

Based on previous observations, the preparation, some physicochemical (partition coefficient, pKa) and pharmacological properties of 4-(3-oxo-1,2-benzisothiazolin-2-yl)alkanoic, benzoic, phenyl, phenoxyalkanoic acids and of some of their functional derivatives are reported. All new compounds were biologically examined for their antiphlogistic, analgesic and antipiretic actions, in comparison with those of 1,2-benzisothiazolin-2-one and with those of ibuprofen as the antiphlogistic, analgesic, antipyretic arylalkanoic prototype. Structure-activity relationships showed that the 1,2-benzisothiazolin-2-one and its new alkanoic and arylalkanoic derivatives have strong actions which are however specific for some of the tested pharmacological properties. From this point of view, the synthesized substances have a narrow spectrum of activity, if compared with ibuprofen which is at the same time an antiphlogistic, analgesic and antipiretic substance. The antiphlogistic and antipyretic activities of 4-(3-oxo-1,2-benzisothiazolin-2-yl)benzoic, phenylacetic and phenylmethylacetic acids and the antipyretic and analgesic actions of 3-oxo-1,2-benzisothiazolin-2-ylacetic acid, which are comparable or higher in "potency" than those of ibuprofen, are noteworthy.     

4-(1,2-Benzisothiazol-3-yl)alkanoic and phenylalkanoic acids: synthesis and anti-inflammatory, analgesic and antipyretic activities.

Continuing their studies on benzisothiazolyl derivatives, Authors refer to the preparation and pharmacological properties of 4-(1,2-benzisothiazol-3-yl) alkanoic and phenylalkanoic acids. All substances were tested for anti-inflammatory, analgesic and antipyretic properties. As reference compounds, 1,2-benzisothiazolin-3-one and 4-(3-oxo-1,2-benzisothiazolin-3-yl) phenylacetic acid, as prototypes of benzisothiazolinonic derivation. Ibuprofen, as a prototype of substituted arylalkanoic acids, and Phenylbutazone were used. Analysis of the data leaded to the following conclusions. Introduction of the aryl moiety, passing from benzisothiazolylalkanoic to benzisothiazolyl-phenylalkanoic structures, produced a remarkable increase of activity. 2-[4-(1,2-benzisothiazol-3-yl)phenyl] propionic and 2-[4-(1,2-benzisothiazol-3-yl)phenyl]butyiric acids showed anti-inflammatory, analgesic and antipyretic properties comparable to those of Ibuprofen. Substantial differences in variations in activities were observed comparing the properties of benzisothiazolylphenylalcanoic acids with those of the benzisothiazolinonic series, object of preceding studies.     

pH-partition profiles of 4-(3-oxo-1,2-benzisothiazolin-2-yl)phenyl and phenoxyalkanoic acids

The 1,2-benzisothiazolin-3-one nucleus is well known in the medicinal chemistry literature for the variety of biological effects exerted by its derivatives. In the present paper, the dependence of the n-octanol/buffer distribution coefficient (D) on pH of four 4-(3-oxo-1,2-benzisothiazolin-2-yl)phenyl and phenoxyalkanoic acids was investigated, employing the reference shake-flask method. From the analysis of the pH-partition profiles in the chosen partition system, the logP(AH), the logP(A(-)) and the pK(a) values for each compound were determined. The physico-chemical data obtained were compared to the pK(a) and logP values of the corresponding phenyl and phenoxyalkanoic acids, and an estimation of the lipophilic and electronic contribution of the 1,2-benzisothiazolin-3-one substituent in the para-position is proposed. The 1,2-benzisothiazolin-3-one nucleus behaves as a lipophilic, moderately electron-withdrawing group.     

Synthesis and antifungal activity of new N-(1-phenyl-4-carbetoxypyrazol-5-yl)-, N-(indazol-3-yl)- and N-(indazol-5-yl)-2-iodobenzamides

N-(1-Phenyl-4-carbetoxypyrazol-5-yl)-, N-(indazol-3-yl)- and N-(indazol-5-yl)-2-iodobenzamides 6, with a Benodanil-like structure, were synthesized by refluxing in acetic acid the corresponding benzotriazinones 5 with potassium iodide for 1 h in order to study the role on the antifungal activity of the N-substitution with an aromatic heterocyclic system on benzamide moiety. Among the tested iododerivatives, compounds 6d,f,g,h possess interesting activities toward some phytopathogenic fungal strains.     

Antipyretic activity of new compounds 4-(3-oxo-1,2-benzisothiazolin-2-yl)phenylalkanoic acids, their esters, amides and 1,1-dioxide derivatives

Antipyretic activity of new compounds, 4-(3-oxo-1,2-benzisothiazolin-2-yl)phenylalkanoic acids, their esters, amides and 1,1-dioxide derivatives has been studied. The acid compound of the benzoic series (I:a), tested at graded doses, exerted a noticeable antipyretic action; it had two times the "potency" of benzisothiazolone but an almost equal "efficacy". Its "potency" however was not proportional to the development of gastric lesions and to the acute toxicity. A decreased pharmacological activity has been observed in phenylalkanoic acids in the following order: R = COOH greater than CH2COOCH greater than CH(CH3)COOH greater than CH(C2H5)COOH, probably due to their increasing lipophilic character. By contrast among 1,1-dioxide derivatives the most effective in preventing pyrogen-induced fever was the ethyl ester (V:c) of benzoic series which appeared to be as active as paracetamol. The interest arising from these observations is here after discussed.     

Synthesis, physicochemical and anticonvulsant properties of new N-4-arylpiperazin-1-yl amides of (2-aza-1,3-dioxospiro[4.4]non-2-yl)- and [4.5]dec-2-yl)-propionic acid

In continuation of the search of new anticonvulsants, a series of N-4-arylpiperazin-1-yl 2-aza-1,3-dioxospiro[4.4]non-2-yl- (5-8) and [4.5]dec-2-yl- (9-15) propionamides, structurally related to the previously described N-4-arylpiperazin-1-yl amides of 2-aza-1,3-dioxospiro[4.5]dec-2-yl-acetic acid, were synthesized. The designed compounds 5-15 were prepared by condensation of the formerly obtained (2-aza-1,3-dioxospiro[4.5]dec-2-yl)- (3) and (2-aza-1,3-dioxo[4.4]non-2-yl)-(4) propionic acids with the appropriately substituted 4-arylpiperazines, in the presence of the N,N-carbonyldiimidazole (CDIM) reagent. All the compounds were tested for their anticonvulsant activity in the maximum electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Several compounds 7-10, 13 and 14 revealed protection in the MES screening.     

Synthesis and antimicrobial activity of acyclo C-nucleosides: 3-(alditol-1-yl)-7-oxo-5-phenyl-1,2,4-triazolo[4,3-a]pyrimidines

Condensation of 2-hydrazino-4-oxo-6-phenylpyrimidine (1) with aldopentoses 2a-d or aldohexoses 2e-g gave the corresponding aldehydo-sugar (4-oxo-6-phenylpyrimidin-2-yl)hydrazones 3a-g which were acetylated to the corresponding poly-O-acetyl-aldehydo-sugar (3-acetyl-4-oxo-6-phenylpyrimidin-2-yl)hydrazones 4a-g. The latter compounds underwent oxidative cyclization with bromine in acetic acid and in the presence of sodium acetate to the corresponding 8-acetyl-3- (poly-O-acetyl-alditol-1-yl)-7-oxo-5-phenyl-1,2,4-triazolo[4,3-a]pyrimid ines 6a-g. Compounds 6a-g were also obtained by consecutive one-pot oxidative cyclization/acetylation in which the parent hydrazones 3a-g were treated with bromine/acetic acid/sodium acetate followed by acetic anhydride. Deacetylation of 6a-g with ammonium hydroxide in methanol gave the title compounds 7a-g. The antibacterial and antifungal activities of compounds 3c, 3f, 7c and 7f are reported.     

Synthesis of biologically active 1'-(2-oxo-2H-benzopyran-6-yl)- 5'-hydroxy-2'-methylindole-3'-amido-2"-phenyl-thiazolidene-4"-ones

6-Aminocoumarins on refluxing with ethyl acetoacetate in 1,2-dichloroethane gave two products: 3'-(2-oxo-2H-benzopyran-6-yl-amino)-but-2'-enoic acid ethyl ester 2a-c and N-(-2-oxo-2H-benzopyran-6-yl)-3'-oxo-butyramide 3a-c. Compounds 2a-c on treatment with 1,4-benzoquinone in N2-atmosphere yielded 1'-( 2-oxo-2H-benzopyran-6-yl)-5'-hydroxy-2'-methyl-3'-carbethoxyindoles 4a-c, which on further treatment with hydrazine hydrate gave 1'-(2-oxo-2H-benzopyran-6-yl)-5'-hydroxy-2'-methylindole-3'-acid hydrazides 5a-c. These acid hydrazides were treated with benzaldehyde to give 1'-(2-oxo-2H-benzopyran-6-yl)-5'-hydroxy-2'-methylindole-3'-benzylidene hydrazides 6a-c, which on further treatment with mercaptoacetic acid in 1,4-dioxane yielded 1'-(2-oxo-2H-benzopyran-6-yl)-5'-hydroxy-2'-methylindole-3'-amido-2"-phenylthiazolidene-4"-ones 7a-c. The structures of the compounds have been established on the basis of spectral and analytical data. All compounds have been screened for their antimicrobial activity and have been found to exhibit significant antibacterial and antifungal activities.     

2-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)- and 2-(2,2-dioxo-1,4-dihydro-2H-2lambda6-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxy-acetamides as potent and selective peptide deformylase inhibitors

Potent, selective, and structurally new inhibitors of the Fe(II) enzyme Escherichia coli peptide deformylase (PDF) were obtained by rational optimization of the weakly binding screening hit (5-chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid hydrazide (1). Three-dimensional structural information, gathered from Ni-PDF complexed with 1, suggested the preparation of two series of related hydroxamic acid analogues, 2-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-N-hydroxy-acetamides (A) and 2-(2,2-dioxo-1,4-dihydro-2H-2lambda(6)-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxy-acetamides (B), among which potent PDF inhibitors (37, 42, and 48) were identified. Moreover, two selected compounds, one from each series, 36 and 41, showed good selectivity for PDF over several endoproteases including matrix metalloproteases. However, these compounds showed only weak antibacterial activity.     

Synthesis and antimicrobial activity of 2,4-dioxothiazolidine-5-acetic acid amides

The antimicrobial activity of 2,4-dioxothiazolidine-5-acetic acid amides and their 3-substituted analogs has been studied. The initial acid was obtained by an effective one-pot method using the reaction of thiourea with maleic anhydride in hydrochloric acid. The maximum anti-staphylococcal activity was exhibited by N-[5-(R-benzyl)thiazol-2-yl]-2-(2,4-dioxothiazolidin-5-yl)acetamides. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 6, pp. 13–16, June, 2006.     

Reactions of 4-oxo-4H-pyrido(3',2':4,5)thieno(3,2-d)-1,3-oxazines with amines]

The reaction of the title compounds with amines gave in dependence of the reaction conditions and the structure of the title compounds and the amine 3-acylamino-thieno[2,3-b]pyridine-2-carbonamides (B), 4-oxo-4 H-pyrido[3',2':4,5]thieno[3,2-d]pyrimidines (D),N-(2-carboxy-thieno[2,3-b]pyridine-3-yl)amidines (C) and N-(thieno[2,3-b]pyridin-3-yl)amidines (E). Substances of structure C and E seem to be of biological interest, especially for their antianaphylactic reactions.     

Synthesis and evaluation of N-(3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-1H-indole-carboxamides as cholecystokinin antagonists

The structure-activity relationship optimization of the pyrazoline template 3a resulted in novel 3-oxo-1,2-diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-indole carboxamides 4a-4e. These non-peptidal CCK ligands have been shown to act as potent CCK1 ligands in a [125]I-CCK-8 receptor binding assay. The best amides (4c and 4d) of this series displayed an IC50 of 20/25 nM for the CCK1 receptor. In a subsequent in-vivo evaluation using various behaviour pharmacological assays, an anxiolytic effect of these novel 3-oxo-1,2-diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-indole carboxamides was found at high doses in the elevated plus-maze. In the despair swimming test, a model for testing antidepressants, an ED50 of 0.33/0.41 mg kg(-1) was determined for amide 4c/4d and the antidepressant effect had a magnitude comparable to desimipramine.     

Novel,highly potent aldose reductase inhibitors: cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives

Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives were synthesized and tested as a novel class of aldose reductase (ALR2) inhibitors. Each compound was evaluated as a diastereomeric mixture, due to tautomeric equilibria in solution. The parent compound 39 exhibited a good inhibitory activity with an IC(50) value of 0.85 microM, similar to that of the well-known ARI sorbinil (IC(50) 0.50 microM). The concurrent introduction of a halogen and a lipophilic group in the 5- and in the 1-positions, respectively, of the indole nucleus of 39, gave compound 55, cyano[5-fluoro-1-(4-methylbenzyl)-2-oxo-2,3-dihydroindol-3-yl]acetic acid, which displayed the highest activity (IC(50) 0.075 microM, very close to that of tolrestat IC(50) 0.046 microM), with a good selectivity toward ALR2 compared with aldehyde reductase (ALR1) (16.4-fold), and no appreciable inhibitory properties against sorbitol dehydrogenase (SD), or glutathione reductase (GR). The isopropyl ester 59, a prodrug of 55, was found to be almost as effective as tolrestat in preventing cataract development in severely galactosemic rats when administered as an eye drop solution. Docking simulation of 55 into a three-dimensional model of human ALR2 made it possible to formulate the hypothesis that the 2-hydroxy tautomer was the active species binding into the catalytic site of the enzyme. This was fully consistent with the structure-activity relationships within this series of cyanooxoindolylacetic acid derivatives.     

Hypolipidemic activity of phthalimide derivatives. 3. A comparison of phthalimide and 1,2-benzisothiazolin-3-one 1,1-dioxide derivatives to phthalimidine and 1,2-benzisothiazoline 1,1-dioxide congeners

Previously it has been observed that N-substituted phthalimide derivatives with chain lengths of four carbon or oxygen atoms showed potent hypolipidemic activity in rodents at 20 (mg/kg)/day ip. The 1,2-benzisothiazolin-3-one 1,1-dioxide (saccharin) nucleus, itself, had also been observed to be active at the same dose. An investigation was undertaken to examine a series of 1,2-benzisothiazolin-3-one 1,1-dioxide analogues for their hypolipidemic activity in mice and to compare them to their respective phthalimide congeners. In addition, a series of 1,2-benzisothiazoline 1,1-dioxide and phthalimidine analogues was prepared, and their hypolipidemic activity was compared to the phthalimide analogues. These studies show that the respective congeners of 1,2-benzisothiazolin-3-one 1,1-dioxide compared favorably to phthalimide congeners in reducing serum triglyceride and cholesterol levels in male CF1 mice at 20 (mg/kg)/day ip. Of the saccharin derivatives, 3-oxo-1,2-benzisothiazoline-2-propionic acid 1,1-dioxide was the most effective in lowering serum cholesterol levels by 53% after 16 days dosing and 3-oxo-1,2-benzisothiazoline-2-valeric acid 1,1-dioxide lowered serum triglycerides 56% after 14 days dosing. The 1,2-benzisothiazoline 1,1-dioxide and phthalimidine compounds were less active as hypolipidemic agents than their 1,2-benzisothiazolin-3-one 1,1-dioxide and phthalimide analogues, respectively.     

Synthesis and evaluation of antioxidant properties of novel 2-[2-(4-chlorophenyl) benzimidazole-1-yl]-N-(2-arylmethylene amino) acetamides and 2-[2-(4-chlorophenyl) benzimidazole-1-yl]-N-(4-oxo-2-aryl-thiazolidine-3-yl) acetamides-I

Our approach was to synthesize and examine the antioxidant properties of some new 2-[2-(4-chlorophenyl)benzimidazole-1-yl]-N-(2-arylmethyleneamino) acetamide (1-18) and 2-[2-(4-chlorophenyl)benzimidazole-1-yl]-N-(4-oxo-2-aryl-thiazolidine-3-yl)acetamide (1t-18t) derivatives. Their in vitro effects on rat liver microsomal NADPH-dependent lipid peroxidation levels (LP assay) and microsomal ethoxyresorufin O-deethylase activities (EROD assay) were determined. The free radical scavenging properties of the compounds were also examined in vitro determining the interaction of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical. The compounds showed significant effects in the above tests.     

Synthesis and neuroleptic activity of benzamides. Cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-(methylamino)benzamide and related compounds

Three series of benzamides of N,N-disubstituted ethylenediamines (linear alkane-1,2-diamines), 1-substituted 2-(aminomethyl)pyrrolidines, and 1-substituted 3-aminopyrrolidines (cyclic alkane-1,2-diamines) were designed and synthesized as potential neuroleptics. All target compounds were evaluated for their inhibitory effects on apomorphine-induced stereotyped behavior in rats, and a good correlation between structure and activity was found throughout the series. In the linear series (analogues of metoclopramide), introduction of a benzyl group on the terminal nitrogen, rather than an ethyl group, and a methyl group on the p-amino group of metoclopramide both enhanced the activity. The resulting N-[2-(N-benzyl-N-methylamino)ethyl]-5-chloro-2-methoxy-4-(methylamino) benzamide(23) was about 15 times more active than metoclopramide. In the cyclic series, particularly among the benzamides of 1-benzyl-3-aminopyrrolidine, most of the compounds tested were more active than the corresponding linear benzamides. cis-N-(1-Benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-(methylamino) benzamide (YM-09151-2, 55) was the most active among all of the compounds tested, being 13 and 408 times more potent than haloperidol and metoclopramide, respectively. Moreover, compound 55 exhibited a fairly high ratio of antistereotypic activity to cataleptogenicity compared with haloperidol and metoclopramide. It is expected that compound 55 may be used as a potent drug with few side effects in the treatment of psychosis.     

N-(3-甲基-1-吡咯烷基)-1-丁酮基-乙酰胺的合成研究

以BOC-L-缬氨酸羟基琥珀酰亚胺酯为原料,两步反应合成IL-1R/MyD88-TIR拟似物N-(3-甲基-1-吡咯烷基)-1-丁酮基-乙酰胺,该反应条件温和,操作方便,收率较高,产物结构经NMR和MS得到了确证.     

Synthesis of 2-(3,3-dimethyl-3,4-dihydroisoquinol-1-yl)propanoic acid amides and their influence on blood coagulation

A series of new 2-(3,3-dimethyl-3,4-dihydroisoquinol-1-yl)propanoic acid amides have been synthesized using the reaction of methyliodide with 2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-idene)ethanamides that proceeds on the β-atom of the enamine fragment to form iodides of 2-(isoquinol-1-yl)propanoic acid derivatives. Investigation of the influence of the synthesized compounds on blood coagulation showed that all of them are hemostatics. The most active compounds possess radicals such as morpholine and 2-(3,4-dimethoxyphenyl)ethylamine, are not substituted at the amide fragment, and decrease the blood coagulation time by 14–16%. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 43, No. 2, pp. 20–22, February, 2009.     

Synthesis of 3-(1,3,4-thiadiazol-2-yl)pyrazolo[1,5-a] pyrimidine derivatives as potential antimicrobial agents

The synthesis of some 3-(1,3,4-thiadiazol-2-yl)pyrazolo[1,5-a]-pyrimidine derivatives is performed by reacting 2-(3-amino-1,2-dihydro-5-oxo-5H-pyrazol-4-il)-1,3,4- thiadiazoles with 2,4-pentanedione, ethyl 3-oxobutyrate and diethyl ethoxymethylenemalonate. The antimicrobial activity of the synthesized compounds is reported.