Synthesis and in vitro phototoxicity of 5-(arylmethylene)-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-6-ones, a class of potential sunscreens.

A series of 5-(arylmethylene)-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-6- ones was prepared by reaction of (+)-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-6-one with aromatic aldehydes in an alkaline medium. These compounds can be considered as potential UVB or UVA sunscreens. In vitro phototoxicity tests (photohemolysis and Candida albicans) showed that they exhibit in general a low phototoxicity level.

5-substituted 4-isoxazoleacetic acids with analgesic activity.

The synthesis of some 5-substituted 4-isoxazoleacetic acids starting from 5-substituted 4-isoxazolemethanols via their conversion to 4-(bromomethyl)isoxazoles, 4-isoxazoleacetonitriles and acid hydrolysis of the latter is described. 5-Ethyl- and 5-propyl-4-isoxazoleacetic acids showed in the writhing test an analgesic activity comparable to that of aspirin.

1-Phenyl-1H-indazole derivatives with analgesic and anti-inflammatory activities.

The synthesis of 4-hydroxy-1-phenyl-1H-indazole-5-acetic acid 5 4-methoxy-1-phenyl-1H-indazole-5-yl-acetic acid 7 and 5-benzyl-1-phenyl-1H-indazol-4-ol 8, starting from 1,5,6,7-tetrahydro-1-phenyl-4H-indazol-4-one, is described. These compounds showed in mice an analgesic activity superior to that of acetylsalicylic acid and comparable to that of dipyrone; moreover, compound 5 exhibited an appreciable anti-inflammatory activity in rats. Grossbehavioral effects and acute toxicity in mice are also reported.

4H-thieno[3,4-c]pyrazole derivatives with antiinflammatory, analgesic, antipyretic and platelet antiaggregating activities.

The synthesis of a series of 1-aryl-1,6-dihydro-4H-thieno[3,4-c]pyrazol-4-ones by cyclization of 3-[(2-arylhydrazino)methylene]thiophene-2,4(3H,5H)-diones, prepared by reacting 3-dimethylaminomethylenethiophene-2,4(3H,5H)-dione with arylhydrazines, is described. The 4-fluorophenyl derivative showed remarkable analgesic, antiinflammatory and antipyretic activities in mice or rats, as well as a platelet antiaggregating activity in vitro comparable to that of acetylsalicylic acid.

omega-Dialkylaminoalkyl ethers of 5-(arylmethylene)-1,3,3-trimethyl-2- oxabicyclo[2.2.2]octan-6-hydroxyimines with platelet antiaggregating and other activities.

The synthesis of omega-dialkylaminoalkyl ethers 3 by the reaction of some 5-(arylmethylene)-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-6- hydroxyimines as sodium salts with the appropriate omega-chloroalkyldialkylamine in DMF solution is described. Some aminoethers 3 showed strong platelet antiaggregating activity in vitro superior to that of acetylsalicylic acid, as well as weak antiarrhythmic activity in rats and moderate infiltration anesthesia in mice.

1-Aryl-1H-pyrazole-5-acetic acids with antiinflammatory, analgesic and other activities.

Reaction of methyl 4-methoxy-2-dimethylaminomethylene-3-oxobutanoate with arylhydrazines gave methyl 1-aryl-5-(methoxymethyl)-1H-pyrazole-4-carboxylates 1 in high yields. Esters 1 were hydrolyzed to the relative carboxylic acids, which were converted by heating to 1-aryl-5-(methoxymethyl)-1H-pyrazoles 3 in good yields. Reaction of 3 with hydrobromic acid afforded the intermediate 1-aryl-5-(bromomethyl)-1H-pyrazoles, which were converted with potassium cyanide to 1-aryl-1H-pyrazole-5- acetonitriles, whose hydrolysis gave the required 1-aryl-1H-pyrazole-5-acetic acids. Some acids 5 showed a strong antiinflammatory and analgesic activity in rats and mice, respectively, as well as moderate antipyretic and in vito platelet antiaggregating effects.

N-substituted 4-carboxy-1-phenyl-1H-pyrazole-5-propanamides with antiinflammatory, analgesic, antipyretic and platelet antiaggregating activities.

The synthesis of a series of N-substituted 4-carboxy-1-phenyl-1H-pyrazole-5-propanamides by reaction of 1-phenyl-1H-oxepino[4,3-c]pyrazole-4(8H),6(7H)-dione with aromatic primary amines is described. Some amides showed a platelet antiaggregating activity in vitro superior or comparable to that of acetylsalicylic acid, as well as moderate antiinflammatory, analgesic and antipyretic activities in rats or mice.

Ethyl or methyl 6-substituted 3-(benzoylamino)-2-oxo-2H-pyran-5-carboxylates and 3-(benzoylamino)-7,8-dihydro-2H-1-benzopyran-2,5(6H)-diones with local anesthetic, platelet antiaggregating and other activities.

The synthesis of ethyl or methyl 6-substituted 3-(benzoylamino)-2-oxo-2H-pyran-5-carboxylates 2 and 3-(benzoylamino)-7,8-dihydro-2H-1-benzopyran-2,5(6H)-diones 4 by reaction of hippuric acid in acetic anhydride with ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates and 2-dimethylaminomethylene-1,3-cyclohexanediones, respectively, is described. Some compounds 2 and 4 showed a strong local anesthetic activity in mice and a platelet antiaggregating activity in vitro comparable to that of acetylsalicylic acid, as well as moderate analgesic, antiinflammatory and antiarrhythmic activities in rats and mice.

2H,5H-[1]benzothiopyrano [4,3-b]pyran derivatives with platelet antiaggregating activity.

The synthesis of some N,N-disubstituted 4-amino-3-phenyl-2H,5H-[1]benzothiopyrano [4,3-b]pyran-2-ones by reaction of phenylchloroketene with a series of N,N-disubstituted 3-aminomethylene-2,3-dihydro-4H-1-benzothiopyran-4-ones, followed by dehydrochlorination of the primary adducts with DBN, is described. Some of these compounds showed a strong platelet antiaggregating activity in vitro, superior to that of acetylsalicylic acid.

4-Substituted 1-phenyl-1H-indazoles with analgesic, antiinflammatory, antipyretic and local anesthetic activities.

The synthesis of amides 3 and 4 starting from (1-phenyl-1H-indazol-4-yl)acetic and [(1-phenyl-1H-indazol-4-yl)oxy]acetic acids, respectively, as well as of 2-(1-phenyl-1H-indazol-4-yl)ethanamines 5 starting from 3, is described. Moreover, a number of 2-[(1-phenyl-1H-indazol-4-yl)oxy]ethanamines 7 and 3-[(1-phenyl-1H-indazol-4-yl)oxy]propanamines 8 were prepared starting from 1-phenyl-1H-indazol-4-ol. Some compounds 3, 4 and 7 showed an appreciable analgesic activity in mice, whereas compounds 4 were moderately active as antiinflammatory agents in rats. Some compounds 3, 4, 5, 7 and 8 showed also local anesthetic and a weak antipyretic activity in mice and rats, respectively.

5-substituted 4-isoxazolecarboxamides with platelet antiaggregating and other activities.

The synthesis of a series of 5-substituted 4-isoxazolecarboxamides by reaction of eight 5-substituted 4-isoxazolecarbonyl chlorides with pyrrolidine, piperidine, morpholine and 4-trifluoromethylaniline is described. Some of these amides showed platelet antiaggregating activity in vitro slightly inferior to that of acetylsalicylic acid, as well weak antiinflammatory, analgesic and antipyretic activities in rats and mice.

Synthesis and cardiotonic activity of 2-substituted 5-cyano-1,6-dihydro-6-oxo-3-pyridinecarboxylic acids and their methyl or ethyl esters.

The synthesis of ethyl or methyl esters of 5-cyano-1,6-dihydro-6-oxo-3- pyridinecarboxylic acids carrying as 2-substituent a polar group such as CO2C2H5, (CH2)2CO2CH3, (CH2)3CO2C2H5, CH2OCH3, or CF3 group is described. Also 2-[5-cyano-1,6-dihydro-2-(1,1-dimethylethyl)-6-oxo-3-pyridyl]-2- oxoacetic acid and 2,5,6,8-tetrahydro-2,5-dioxo-1H-thiopyrano[3,4-b]pyridine-3-carbon itrile were prepared. Nearly all the above esters gave routinely the corresponding carboxylic acids by alkaline hydrolysis followed by acidification. As milrinone analogues, the above compounds were tested on contractile activity and frequency rate of spontaneously beating atria from reserpine-treated guinea-pigs. 5-Cyano-2-trifluoromethyl-1,6- dihydro-6-oxo-3-pyridinecarboxylic acid and, in a lesser degree, the relative ethyl ester showed an appreciable positive inotropic activity, although inferior to that of milrinone.

3,5-Diphenyl-1H-pyrazole derivatives. IV--N,N-disubstituted 3-(3,5-diphenyl-1H-pyrazol-1-yl)propanamides and 3-(3,5-diphenyl-1H-pyrazol-1-yl)propanamines with sedative, platelet antiaggregating and local anesthetic activities.

The synthesis of N,N-disubstituted 3-(3,5-diphenyl-1H-pyrazol-1-yl)propanamides 2 a-d and 3-(3,5-diphenyl-1H-pyrazol-1-yl)propanamines 3 a-d starting from 3-(3,5-diphenyl-1H-pyrazol-1-yl)propanoic acid is described. Some of the above compounds showed considerable sedative and local anesthetic activities in mice, as well as a remarkable platelet antiaggregating activity in vitro. Moreover, the above compounds usually exhibited moderate analgesic and antiinflammatory activities in mice and rats, respectively.

3,5-Diphenyl-1H-pyrazole derivatives. V--1-Acetyl-4-hydroxy-3,5-diphenyl-2-pyrazoline esters, 4-hydroxy-3,5-diphenyl-1H-pyrazole esters and N-substituted 4-(3-amino-2-hydroxy-1-propoxy)-1-methyl-3,5-diphenyl-1H-pyrazoles with antiarrhythmic, sedative and platelet antiaggregating activities.

The synthesis of 1-acetyl-4-hydroxy-3,5-diphenyl-2-pyrazoline esters 3, 4-hydroxy-3,5-diphenyl-1H-pyrazole esters 5 and N-substituted 4-(3-amino-2-hydroxy-1-propoxy)-1-methyl-3,5-diphenyl-1H-pyrazoles 7, starting from 4-hydroxy-3,5-diphenyl-2-pyrazoline is described. Some of compounds 3, 5 and 7 showed a considerable antiarrhythmic and sedative activity in rats and mice, respectively, as well as a remarkable in vitro platelet antiaggregating activity. Moreover, the above compounds usually exhibited moderate antihypertensive, local anesthetic, analgesic and antiinflammatory activities in rats and mice.

1-phenyl-1H-pyrazole derivatives with antiinflammatory, analgesic and antipiretic activities.

Reaction of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates 2 with phenylhydrazine gave the corresponding esters of 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids 3 in high yields. Esters 3 were hydrolyzed to the relative carboxylic acids 4, which were converted by heating to 5-substituted 1-phenyl-1H-pyrazoles 5 in excellent yields. Reaction of methyl 5,5-dimethyl-3-dimethylaminomethylene-2,4-dioxohexanoate with phenylhydrazine afforded methyl 1-phenyl-4-pivaloyl-1H-pyrazole-5-carboxylate 8 b, which was converted as above to the corresponding carboxylic acid 10 b and this to 1-phenyl-4-pivaloyl-1H-pyrazole 11 b. Starting from 5-methoxymethyl-1-phenyl-1H-pyrazole, 1-phenyl-1H-pyrazole-5-acetic acid 18 and its alpha-methyl derivative 19 were also synthesized. Compounds 18, 19, 10 b and 11 b showed a strong antiinflammatory activity in rats; the same compounds in general as well as 8 b, showed appreciable analgesic and antipyretic activities in mice and rats, respectively.

Amides of 1,3,3-trimethyl-n-[(2-pyridyl)methyl]-2-oxabicyclo [2.2.2]octan-6-amine with depressant and antiarrhythmic activities.

The synthesis of 1,3,3-trimethyl-N-[(2-pyridyl)methyl]-2- oxabicyclo [2.2.2]octan-6-amine (II) (exo, endo mixture) starting from 1,3,3-trimethyl-N-nitro-2-oxabicyclo [2.2.2]octan-6-imine (I), as well as of a series of amides (III) derived from the above amine, is described. Some compounds (III) showed remarkable depressant and antiarrhythmic activities in rats and mice, respectively, whereas the clofibric acid amide (III e) showed an appreciable hypolipidemic activity in rats. Moreover, the above compounds usually exhibited a moderate infiltration anesthesia in mice, as well as a weak hypotensive and bradycardic activity in rats.

Cyclohepta[b]pyran derivatives with platelet antiaggregating and other activities.

The synthesis of some N,N-disubstituted 4-amino-6,7,8,9-tetrahydro-3-phenylcyclohepta[b]pyran-2(5H)-ones by reaction of phenylchloroketene with a series of N,N-disubstituted 2-aminomethylenecycloheptanones, followed by dehydrochlorination of the primary adducts with DBN, is described. Some compounds showed a platelet antiaggregating activity in vitro superior or comparable to that of acetylsalicylic acid, as well as weak local anesthetic, antiinflammatory and analgesic activities in mice and rats.

2H-1-benzopyran derivatives with platelet antiaggregating and other activities.

The synthesis of some N,N-disubstituted 4-amino-5,6,7,8-tetrahydro-3,6- diphenyl-2H-1-benzopyran-2-ones by reaction of phenylchloroketene with a series of N,N-disubstituted 2-aminomethylene-4-phenylcyclohexanones, followed by dehydrochlorination in situ of the primary adducts with DBN, is described. Some compounds showed a platelet antiaggregating activity in vitro superior or comparable to that of acetylsalicylic acid and an appreciable antiarrhythmic activity, as well as weak anti-inflammatory and local anesthetic activities in rats and mice.

3,5-diphenyl-1H-pyrazole derivatives. XI. N-aryl-5(3)-phenyl-4-(3,5- diphenyl-1-pyrazolyl)-3(5)-pyrazole amines, 5-substituted 4,5-dihydro-3-phenyl-4-(3,5-diphenyl-1-pyrazolyl)-1H-pyrazoles and 2,6-disubstituted 1,6-dihydro-4- phenyl-5-(3,5-diphenyl-1-pyrazolyl)pyrimidines with antipyretic, antiinflammatory and other activities.

The synthesis of N-aryl-5(3)-phenyl-4-(3,5-diphenyl-1-pyrazolyl)-3(5)- pyrazoleamines 3 by reaction of some N-aryl-3-oxo-3-phenyl-2-(3,5-diphenyl-1- pyrazolyl)propanecarbothioamides with hydrazine is described. Also prepared were 4,5-dihydro-3-phenyl-4-(3,5-diphenyl-1-pyrazolyl)-1H-pyrazoles 6 and 1,6-dihydro-4-phenyl-5-(3,5-diphenyl-1-pyrazolyl)pyrimidines 7 by reaction of 1-phenyl-2-(3,5-diphenyl-1-pyrazolyl)-2-buten-1-one with hydrazine or guanidine and benzamidine, respectively. Some compounds 3, 6 and 7 showed remarkable antipyretic, antiinflammatory and in vitro platelet antiaggregating activities, as well as weak analgesic, antiarrhythmic, hypotensive and local anesthetic activities in rats and mice.

N-substituted 4,5(3)-diphenyl-3(5)-pyrazoleamines with antipyretic, antiarrhythmic, hypotensive and other activities.

The synthesis of N-substituted 4,5(3)-diphenyl-3(5)-pyrazoleamines by reaction of N-substituted 3-oxo-2,3-diphenylpropane-carbothioamides with hydrazine is described. Some compounds showed remarkable antipyretic, antiarrhythmic and hypotensive activity in rats, as well as weak antiinflammatory, analgesic and in vitro platelet antiaggregating activity.