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.     

A novel synthesis and potent antiinflammatory activity of 4-hydroxy-2(1H)-oxo-1-phenyl-1,8-naphthyridine-3-carboxamides.

New antiinflammatory agents 4-hydroxy-2(1H)-oxo-1-phenyl-1,8-naphthyridine-3- carboxamides 7 were designed and synthesized via a valuable intermediate, 1-phenyl-2H-pyrido[2,3-d][1,3]oxazine-2,4(1H)-dione (9). The nature of substituents on the amide nitrogen had a pronounced effect on antiinflamatory activity. Studies of structure-activity relationships led to compounds 33 and 34 bearing a pyridine ring on the amide nitrogen. Compounds 33 and 34 were active against carrageenin-, zymosan-, and arachidonic acid-induced rat paw edemas and also potently inhibited the reversed passive Arthus reaction in rats. Thus, they possess a broader spectrum of antiinflammatory activity than the classical nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin and piroxicam.     

Nitro and amino substitution in the D-ring of 5-(2-dimethylaminoethyl)- 2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-ones: effect on topoisomerase-I targeting activity and cytotoxicity

5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one exhibits potent TOP1-targeting activity and pronounced antitumor activity. It was hypothesized that replacement of the two methoxyl groups with a nitro substituent would allow for retention of similar activity. In this study 8-, 9-, and 10-nitro-5H-2,3-methylenedioxy-5-(2-N,N-dimethylaminoethyl)dibenzo[c,h][1,6]naphthyridin-6-one and their amino derivatives were synthesized and assessed for their relative TOP1-targeting activity and cytotoxicity. In the case of both the 8- and 9-nitro analogues, their TOP1-targeting activity and cytotoxicity are greater than that of camptothecin and comparable to that of 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one.     

Antiallergy agents. 1. Substituted 1,8-naphthyridin-2(1H)-ones as inhibitors of SRS-A release

A novel class of antiallergy agents, the substituted 1,8-naphthyridin-2(1H)-ones, is described. The present compounds are orally active, potent inhibitors of allergic and nonallergic bronchospasm in animal models. Structure-activity studies of the lead compound in this series, 1-phenyl-3-n-butyl-4-hydroxynaphthyridin-2(1H)-one (11), identified three compounds of interest, 1-phenyl-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H)-one (12), 1-(3'-chlorophenyl)-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H )-one (87), and 1-(3'-methoxyphenyl)-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1 H)-one (89). The mechanism of antiallergy activity may involve inhibition of the release of the sulfidopeptide leukotrienes. 1-Phenyl-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H)-one, Sch 33303 (12), was selected for preclinical development as an antiallergy agent.     

Imidazo[4,5-c]pyridines (3-deazapurines) and their nucleosides as immunosuppressive and antiinflammatory agents

A variety of imidazo[4,5-c]pyridines (3-deazapurines) were synthesized. With use of these aglycons as pentosyl acceptors, the corresponding ribonucleosides and 2'-deoxyribonucleosides were prepared by an enzymatic method involving transfer of the pentosyl moiety from appropriate pyrimidine nucleosides. With most of the imidazo[4,5-c]pyridines, the products obtained from the enzyme-catalyzed reactions were pentosylated exclusively in the 1-position. However, some 3-pentosylation occurred with aglycons that had H or N3 in the 4-position. In addition to the 2'-deoxy congener of the ribonucleoside of 4-amino-1H-imidazo[4,5-c]pyridine, the 5'-deoxy and 2',5'-dideoxy congeners were synthesized. All of the aglycons and their nucleosides were tested for toxicity to mammalian cells in culture. None were markedly cytotoxic. These compounds were also evaluated for their ability to inhibit lymphocyte-mediated cytolysis in vitro. 3-Deazaadenosine (23) and its 2'-deoxy congener (38) were the most potent inhibitors (ED50 = 20 microM). In addition to these two in vitro tests, in vivo inhibition of the inflammatory response in the rat carregeenan pleurisy model was determined. 3-Deazaadenosine (23) was the most potent compound (ED50 = 3 mg/kg) in this in vivo test.     

Synthesis and benzodiazepine binding activity of a series of novel [1,2,4]triazolo[1,5-c]quinazolin-5(6H)-ones.

Investigation of tricyclic heterocycles related to the 2-arylpyrazolo[4,3-c]quinolin-3(5H)-ones, structures with high affinity for the benzodiazepine (BZ) receptor, led to the synthesis of 2-phenyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one, a compound with 4 nM binding affinity to the BZ receptor. Analogues were prepared to assess the importance of the 2-substituent and ring substitution in modifying activity. Several novel synthetic routes were designed to prepare the target compounds, including a two-step synthesis beginning with an anthranilonitrile and a hydrazide. Of the 34 compounds screened in this series, three compounds were found to be potent BZ antagonists in rat models. The leading compound, 9-chloro-2-(2-fluorophenyl) [1,2,4]triazolo[1,5- c]quinazolin-5(6H)-one (CGS 16228), showed activity comparable to that of CGS 8216 from the pyrazolo[4,3-c]quinoline series.     

Non-steroidal antiinflammatory agents. Synthesis of novel 2-pyrazolyl-4(3H)-quinazolinones

Four novel series of pyrazolyl-4(3H)-quinazolinones have been prepared through the reaction of 3-aryl-2-hydrazino-4(3H)-quinazolinones with antipyrylazo-derivatives of ethyl acetoacetate, acetylacetone or diethyl malonate. These series of compounds are 3-aryl-2-[1-ethoxycarbonyl-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H - pyrazol-4-yl)hydrazono-2-propylidene]hydrazino-4(3H)-quinazo linones; 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) hydrazono-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]-4(3H)-quinaz olinones; 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)azo -3,5- dimethyl-1H-pyrazol-1-yl]-4(3H)-quinazolinones and 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) hydrazono-3,5-dioxo-pyrazolidin-2-yl]-4(3H)-quinazolinones. The antiinflammatory activity of some representatives of the prepared compounds was studied.     

Carboxyarylindoles as nonsteroidal antiinflammatory agents.

An extensive series of carboxyarylindoles has been evaluated for antiinflammatory activity in the carrageenin paw edema assay. The requirements for optimal antiinflammatory activity in this series are relatively specific: a central pyrrole nucleus with (a) a 3-carboxy-4-hydroxyphenyl moiety substituted directly on the nitrogen, (b) a 2-phenyl group (R2) with a substituent of low electronegativity, (c) absence of a substituent in the 3 position (R3), and (d) a system fused across the 4,5 positions (X), which is lipophilic, quasiplanar, and does not interact sterically with the N-phenyl group. One derivative, 3-(3-carboxy-4-hydroxyphenyl)-2-phenyl-4,5-dihydro-3H-benz[e]indole (42), has been selected for further study.     

Structure-activity relationships of acronycin

Contribution to the Structure-Activity Relationships of Acronycine. The synthesis of 1b , an azaanalogue of acronycine (1a) , is reported. The solubility of 1b in water is 15-times that of 1a . Screening tests with the transplantation tumor leukemia P388 showed 1b to be inactive, like 1a and noracronycine. 6-Hydroxy-3,3,12-trimethyl-3-12-dihydrochromeno[5,6-b][1,8]naphthyridin-7-one, 5-hydroxy-2,2,11-trimethyl-2,11-dihydrochromeno[7,6-b][1,8]naphthyridin-6-one and 6-hydroxy-3,3-dimethyl-3H-pyrano[2′,3′:7,8]chromeno[2,3-b]pyridin-7-one, which are structurally related to 1a , are also inactive.     

Syntheses and antiinflammatory actions of 4,5,6,7-tetrahydroindazole-5-carboxylic acids.

A novel series of 1-aryl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acids and 2-aryl-4,5,6,7-tetrahydro-2H-indazole-5-carboxylic acids were synthesized via condensation between a phenylhydrazine and a 2-(hydroxymethylene)cyclohexanone-4-carboxylate, and the antiinflammatory activity was determined. In the carrageenan edema test, 1-aryl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acids exhibited fairly high antiinflammatory activity. However, the 2-aryl isomers were far less active than the former. The most active compound of the series was 1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid, which had an ED50 value of 3.5 mg/kg.     

Central nervous system activity of a novel class of annelated 1,4-benzodiazepines, aminomethylene-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepin-1-ones.

The synthesis and CNS activity of a noval class of annelated 1,4-benzodiazepines, the aminomethylene-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepines, are described. An investigation of the structure--activity relationships in the series derived from 8-chloro-2,4-dihydro-2-dimethylaminomethylene-6-phenyl-1H-imidazo[1,2-a][1,4]-benzodiazepin-1-one (10) led to the synthesis of a group of compounds with potent minor tranquillizer activity.     

New thiazolo[4,5-d]pyrimidine derivatives as potential antimicrobial agents

In this study, by starting from ethyl 4-amino-2,3-dihydro-3-phenyl-2-thioxothiazole-5-carboxylate (1), three compounds having 2,3-dihydro-3-phenyl-5-mercapto-6-alkyl/phenyl-2-thioxothiazolo[4,5- d]pyrimidin-7(6H)-one (2a-c) structure and their 5-(4'-nonsubstituted/-substituted benzoylmethyl)thio derivatives (3a-l) were synthesized. The antimicrobial activities of the synthesized compounds were investigated against some bacteria and fungi using the microdilution method. 2,3-Dihydro-3,6-diphenyl-5-(4'-bromobenzoylmethyl)thio-2-thioxothiazolo [4,5-d]pyrimidin-7(6H) one (3k) possessing remarkable activity against Gram-positive bacteria and yeast like fungi was found to be the most active compound in this series.     

Synthesis and antiinflammatory/analgesic activities of N-heterocyclic carboxamides of thiopyrano-1,2-benzothiazine

We report the synthesis of N-heterocyclic carboxamides of 5-methyl-4-oxo-2,3,4,5-tetrahydrothiopyrano [3,2-c][1,2]benzothiazine 6,6-dioxide, their antiinflammatory and analgesic activities and the attempts to obtain a corresponding sulfoxidate series. Compounds (II c) and (II l) showed a good antiinflammatory activity which is comparable to that of piroxicam. No compound showed any significant analgesic activity.     

Synthesis and analgesic-antiinflammatory activities of novel acylarylhydrazones with a 5-phenyl-4-R-3-pyrrolyl-acyl moiety

A new series of arylidene 5-phenyl-4-R-pyrrole-3-carbohydrazides 1a-j were prepared and evaluated for their analgesic-antiinflammatory activities. All synthesized compounds showed a significant analgesic action in mice after intraperitoneal administration at a dose of 100 microM/kg. Two of these, 1b, (4'-methylbenzylidene)-5-phenyl-1H-pyrrole-3-carbohydrazide, and 1d, (4'-chlorobenzylidene)-5-phenyl-1H-pyrrole-3-carbohydrazide, were found to be more potent as antinociceptive agents respect to dipyrone and indometacin, used as reference drugs. Among compounds 1, only 1b showed a moderate antiinflammatory effect in rats while 1d proved to be a potent non antiinflammatory analgesic.     

Anxiolytic properties of certain annelated [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones.

Modification of the benzodiazepine (BZ) receptor binding template 2-aryl[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one by replacement of the annelated benzene ring with various alicyclic and heterocyclic moieties led to novel structures with potent BZ receptor binding affinity. High affinity was found in some cycloalkyl-annelated [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones and in some 7,8,9,10-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 5(6H)-ones, in which the degree of activity was strongly dependent on the N-substituent in the 9-position. Nine compounds with BZ receptor IC50 binding affinity values equal or superior to diazepam were evaluated in secondary screening. One of these, 9-benzyl-2-phenyl-7,8,9,10-tetrahydropyrido[3,4-e] [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one, showed good activity in rats as a potential anxiolytic agent without sedative liability. However, it increased the rotorod deficit produced by ethanol at anxiolytic doses, an indication of alcohol interaction. Thus, none of the compounds showed an advantage over CGS 9896 (Yokoyama et al. J. Med. Chem. 1982, 25, 337-339), which is free of sedative and alcohol interaction potential as measured by the test procedures described.     

Facile synthesis of fused pyrazolo[1,5-a]pyrimidinepyrazolo [1,5-a]triazines and N-sulphonamidopyrazoles as antiinflammatory

Interaction of hydrazine hydrate with methyl (2-E)-2-cyano-3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]-3-(methylsulphanyl)-2-propenoate 2 which was obtained by the reaction of methyl-2-cyano-3,3-bis(methylsulphanyl) acrylate 1 with 4-amino-1-phenyl-2,3-dimethyl pyrazoline-5-one afforded methyl-5-amino-3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]-1H-pyrazole-4-carboxylate 3a. The pyrazolin derivative 3a is a good precursor for the synthesis of pyrazolo[1,5-a]pyrimidines which is based on the interaction of 3a with alpha,beta-unsaturated nitrile derivatives. The biological effects of some of the newly synthesized compounds were also investigated as antiinflammatory, analgesic and antipyretic drugs. Compounds 2b, 4a, 3a, 3b, 2a and 4b were found to have significant antiinflammatory activity in descending order in comparison to control groups phenylbutazone. Compounds 3a, 2a, 4b, 4a, 2b and 3b have analgesic activity in decreasing order. Compound 3a was the most potent and had 82.6% potency of Novalgin. Compounds 2b, 2a, 3b, 4b, 3a and 4a were found to have significant antipyretic activity in descending order. Compounds 2a, 4b induced no ulcerogenic activity, while compounds 3b, 2b, 4a and 3a showed only slight ulcerogenic activity.     

Synthesis and evaluation of antiinflammatory activity of substituted chalcone derivatives

In an effort to develop potent antiinflammatory agents, a series of substituted chalcone derivatives was synthesized and evaluated for antiinflammatory activity through monitoring of their ability to inhibit xylene-induced ear edema in mice. Some of the tested compounds exhibited significant activity, and compounds 3f [(E)-1-(2,4-dihydroxyphenyl)-3-(4-dimethylamino)phenyl)prop-2-en-1-one] and 3h [(E)-3-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one] showed the highest antiinflammatory activity (62 and 68% inhibition, respectively, 2 h before administration), comparable with or even slightly more potent than the reference drug ibuprofen (53%). Furthermore, the structure–activity relationship of these substituted chalcone derivatives was demonstrated.     

6-aminopyrazolo[4,3-c]pyridin-4(5H)-one, a novel analogue of guanine.

Treatment of dimethyl alpha-ethoxymethylidineacetonedicarboxylate with hydrazine gave methyl 3-(methoxy-carbonylmethyl)pyrazole-4-carboxylate which, upon ammonolysis and dehydration, afforded methyl 3-(cyanomethyl)pyrazole-4-carboxylate. This compound, when heated with liquid ammonia, gave 6-aminopyrazolo[4,3-c]pyridin-4(5H)-one, a new guanine analogue, which did not possess any of the potent antiviral activity shown by 6-aminoimidazo[4,5-c]pyridin-4(5H)-one (3-deazaguanine).     

Synthesis of carboxyarylindoles and benzofurans as nonsteroidal antiinflammatory agents

2-Carboxyaryl-substituted dihydrobenz[e]indoles, tetrahydroindoles, and tetrahydrobenzofurans have been synthesized as structural analogues of fendosal, a new antiinflammatory agent, and tested in the carrageenan-induced rat paw edema assay. Two of these, 2-(3-carboxy-4-hydroxyphenyl)-3-phenyl-4,5-dihydrobenz[e]indole and 1-(n-butyl)-2-(3-carboxy-4-hydroxyphenyl)-4,5,6,7-tetrahydroindole, were found to have significant activity, albeit of a lower order than fendosal.     

吡酮酸类抗菌药物的研究Ⅷ.1-对氟苯基-6-氟-1,4-二氢-4-氧-7-(1-哌嗪)噌啉-3-羧酸及其类似物的合成和构效关系

为探讨构效关系,合成了1-对氟苯基-6-氟-1,4-二氢-4-氧-7-(1-哌嗪)噌啉-3-羧酸及其喹啉、萘啶、吡啶[2,3-C]哒嗪环系类似物16个。测定了对大肠杆菌的MIC。用Hückel分子轨道理论(HMO)方法计算了四个母体环上电子密度。结果表明:环中氮的位置对药效团——3位羧基和4位羰基氧原子上电子密度的影响较大而影响其抗菌活性。喹啉、萘啶两环系的3位羧基和4位羰基氧原子上的电子密度较高,其体外抗菌活性较高;而噌啉及吡啶[2,3-C]哒嗪两环系的电子密度较低,其体外抗菌活性较低甚至消失。