Ionized prodrugs of dehydroepiandrosterone for transdermal iontophoretic delivery.

PURPOSE: The aim of this work was to synthesize ionized dehydroepiandrosterone (DHEA) prodrugs with higher water solubility, useful for iontophoretic transdermal application. METHODS: The synthesized derivatives were characterized and tested for sensitivity to chemical and enzymatic hydrolysis. Solid state and solution stability was also determined. Transdermal iontophoretic anodal transport in vitro was studied using excised rabbit skin. RESULTS: Two DHEA ionized prodrugs were synthesized: PRO1, a primary amine derivative, and PRO2, a quaternary ammonium salt. The two derivatives possess higher water solubility and lower octanol/saline partition coefficients than DHEA. Prodrugs were sensitive to enzymatic hydrolysis; in particular the primary amine was hydrolyzed faster than the quaternary salt by esterase from porcine liver in vitro. Transdermal flux of the two prodrugs was slightly higher than the parent drug. In the case of passive diffusion, only DHEA was found in the receptor compartment, indicating the complete breakdown of the prodrug in the skin. Current application gave higher drug flux and a significant amount of prodrug was found in the receptor. CONCLUSIONS: The use of ionized prodrugs of DHEA can increase the flux attainable during transdermal anodal iontophoresis by up to 7 times, but they are useful for passive transport as well.

Research on heterocyclic compounds. XXXVIII. Synthesis and pharmacological activity of imidazo[1,2-b]pyridazine-2-carboxylic derivatives.

A series of imidazo[1,2-b]pyridazine-2-carboxylic acids, esters and amides was synthesized and tested for antiinflammatory, analgesic and ulcerogenic activities. The ethyl esters were prepared by cyclocondensation of some 3-aminopyridazines with ethyl bromopyruvate, followed by hydrolysis or ammonolysis in order to obtain the corresponding acids and amides. The inhibitory activity on the carrageenan-induced edema in the rat paw and on writhes induced by acetic acid in mice was evaluated, as well as the ulcerogenic action on the rat gastric mucosa. The pharmacological activity was discussed in terms of structure-activity relationships. In particular, the analgestic activity shown by these carboxylic derivatives was compared with that found in other series of imidazo[1,2-b]pyridazine analogues previously examined.

Research on heterocyclic compounds. XXXIII--Synthesis and analgesic activity of imidazo[1,2-b]pyridazine-2-acetic acid derivatives.

A series of imidazo[1,2-b]pyridazine-2-acetic esters, acids and amides was synthesized and tested for antiinflammatory, analgesic and ulcerogenic activities. The ethyl esters were prepared by cyclocondensation of some 3-aminopyridazines with ethyl 4-chloroacetoacetate, followed by hydrolysis or ammonolysis in order to obtain the corresponding acids and amides. The capacity of inhibiting the carrageenan-induced edema in the rat paw and the writhes induced by acetic acid in mice were evaluated, as well as the ulcerogenic action in rats. The acidic derivatives showed significant analgesic activity which is comparable to that found in other series of imidazo[1,2-b]pyridazine analogs previously examined.

Research on heterocyclic compounds. XXX. Synthesis and pharmacological activity of 2-methylimidazo[1,2-b]pyridazine-3-carboxylic acids.

A group of ethyl 2-methylimidazo[1,2-b]pyridazine-3-carboxylates were prepared by reaction in anhydrous ethanol of some substituted 3-amino-pyridazines with ethyl 2-chloroacetoacetate. The corresponding carboxylic acids were obtained via alkaline or acid hydrolysis and then tested both in vivo to evaluate their antiinflammatory, analgesic and ulcerogenic actions and in vitro for their ability to inhibit the prostaglandin biosynthesis. The pharmacological results are discussed in terms of both structure-activity relationships and mechanism of action.

Research on heterocyclic compounds. XXVIII. Imidazo[1,2-c]pyrimidines.

A group of 24 imidazo[1,2-c]pyrimidines was taken into consideration in order to study their relationships between chemical structure and antiinflammatory activity. Some of these compounds were synthesized by us in the past, the others have been synthesized and characterized to complete the series. Antiinflammatory, analgesic, antipyretic and gastric ulcerogenic activities of such compounds were compared with those of indomethacin and discussed in terms of the effects exerted by the presence on the heterocyclic system of various substituents and an acidic or nonacidic moiety.

Research on heterocyclic compounds. XXVII. Synthesis and antiinflammatory activity of 2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acids.

A group of ethyl esters of 2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acids 3 were obtained by reaction in anhydrous ethanol of some substituted 3-aminopyridazines 1 with ethyl 2-benzoyl-2-bromoacetate 2. The acids 4 obtained via alkaline hydrolysis were tested in vivo for their antiinflammatory, analgesic and ulcerogenic actions and in vitro for their ability to inhibit the prostaglandin biosynthesis. Almost all of the new compounds showed high analgesic activity, whereas the activities exhibited in the other tests were sharply lower. These results are discussed in terms of mechanism of action.

Research on heterocyclic compounds. XXVI. Antiinflammatory and related activities of some 2-phenylimidazo[1,2-b]pyridazines.

Five acidic phenyl derivatives of the imidazo[1,2-b]pyridazine system were subjected to some tests in vivo in order to evaluate their biological activity. Antiinflammatory activity was studied by means of the carrageenin rat paw edema, whereas writhing induced in mice by acetic acid was used to assess analgesic activity. The irritative and ulcerogenic action on the rat gastric mucosa was examined after oral administration of larger doses. The inhibitory activity on platelet malondialdehyde production was studied in vitro. The experimental results are discussed from the point of view of structure-activity relationships and mode of action.

Research on heterocyclic compounds. XXV. Phenyl derivatives of fused imidazole systems: antiinflammatory activity.

A group of seven acidic phenyl derivatives of some fused imidazole systems were subjected to a series of tests in vivo in order to evaluate their pharmacological activity. Antiinflammatory activity was studied by means of the carrageenin-induced rat paw edema. Hot plate test and writhing induced by acetic acid in mice were used to evaluate analgesic activity. Yeast-induced hyperthermia in rats was employed to study antipyretic action. Irritative and ulcerogenic action on the rat gastric mucosa was examined at higher doses. The antiaggregating activity and the inhibition of platelet malondialdehyde production were studied in vitro. All experimental results are discussed from the point of view of structure-activity relationships and mode of action.

Research on heterocyclic compounds. XXIV. Antiinflammatory activity of some imidazo[1,2-c]pyrimidine derivatives.

A group of four acidic imidazo[1,2-c]pyrimidine derivatives were subjected to a series of tests in vivo in order to assess their pharmacological activity. Antiinflammatory activity was studied by means of the carrageenin-induced paw edema and pleurisy in rats. Hot plate test and writhing induced by acetic acid in mice were employed to evaluate analgesic activity, whereas the yeast-induced hyperthermia in rats was used to study antipyretic activity. The irritative and ulcerogenic action on the rat gastric mucosa was examined at higher doses. The inhibitory activity on the platelet malondialdehyde production was studied in order to obtain information about the mechanism of action of test compounds.

Research on heterocyclic compounds. XXII. Imidazo[1,2-a]pyrimidines.

We have taken into consideration a group of 21 imidazo [1,2-a]pyrimidine derivatives, some of which were already known, whereas the others were synthesized and characterized by us to complete the series. Antiinflammatory, analgesic, antipyretic and ulcerogenic activities of such compounds were evaluated in comparison with indomethacin, in order to get useful information about structure-activity relationships.

Research on heterocyclic compounds. XIX--2-Methylimidazo[1,2-a]pyridine-3-acetic acids.

A group of methyl substituted imidazo[1,2-a]pyridine-3-acetic acids was synthesized by reaction of some methyl derivatives of 2-aminopyridine with ethyl 3-bromolevulinate and subsequent hydrolysis. These new acidic compounds were tested for their antiinflammatory, analgesic, antipyretic and ulcerogenic activities in order to compare the results with those previously obtained with similar compounds.

Research on heterocyclic compounds. XVIII. Imidazo[2,1-b]-1,3,4-thiadiazole derivatives.

The synthesis of a series of 6-carbethoxy-, 6-carbethoxy-methyl-, and 5-carbethoxy-6-methylimidazo[2,1-b]-1,3,4-thiadiazoles was accomplished by reacting some 2-amino-1,3,4-thiadiazoles with ethyl bromopyruvate, 4-chloroacetoacetate, and 2-chloroacetoacetate, respectively; such carbethoxy derivatives afforded the corresponding carboxylic acids by hydrolysis. The antiinflammatory, analgesic, antipyretic and ulcerogenic activities were studied on three of the new acidic compounds.

Research on heterocyclic compounds. XVII. 2-Methylimidazo[1,2-a]pyrimidine-3-carboxylic acids.

A group of ethyl 2-methylimidazo[1,2-a]pyrimidine-3-carboxylates were prepared by reaction of ethyl 2-chloroacetoacetate with some 2-aminopyrimidines. These ethyl esters were then converted into the corresponding carboxylic acids via alkaline hydrolysis. The acids so obtained were evaluated for antiinflammatory, analgesic, antipyretic and ulcerogenic activities.

Research on heterocyclic compounds. XV. Substitution influence on the pharmacological activity in a series of imidazo[1,2-a]pyridines.

We have taken into consideration a group of 28 imidazo [1,2-a]pyridine derivatives, some of which were already known, whereas the others have been synthesized and characterized to complete the series. Antiinflammatory, analgesic, antipyretic and ulcerogenic activities of such compounds were evaluated in comparison with indomethacin. The pharmacological data demonstrated the effects exerted on activity by the presence on the heterocyclic system of methyl substituents and/or an acidic moiety.

Research on heterocyclic compounds. XII - Preparation and antiinflammatory activity of 2-methylimidazo [1,2-a]pyridine-3-carboxylic acids.

The synthesis of a series of 2-methylimidazo[1,2-a]pyridine-3-carboxylic acids was accomplished by reacting some 2-aminopyridines with ethyl 2-chloroacetoacetate and then hydrolyzing the resulting ethyl carboxylates. Such new carboxylic acids were evaluated for antiinflammatory, analgesic, antipyretic, and ulcerogenic activities.

[Synthesis of p-aminobenzenesulfonyldiazine]. / Sintesi di p-amminobenzensolfonildiazine.

New sulfones were synthesized; these are analogues of bis-(4-aminophenyl)sulfone (DDS) but contain, instead of one benzene nucleus, a heterocycle that is a pyrimidine, pyrazine or pyridazine nucleus. This was substituted with amine, methoxy, methyl groups or halogens in order to obtain long-acting drugs, similarly to those obtained in the field of sulfonamides. The synthesis was accomplished by reaction of sodium p-amino- or p-acetamidobenzensulfinate with the corresponding halodiazine; only the p-aminophenyl 3-aminopyridazin-6-yl sulfone was obtained by acid hydrolysis. The compounds showed good antitubercular activity in vitro.

[Structure-activity relationship in reactivators of acetylcholinesterase inhibited by phosphoric esters. XII. Hydroxyiminomethylalkylpyridine iodomethylate]. / Relazione struttura-attività nei riattivatori dell'acetilcolinesterasi inibita da esteri fosforici. XII. Idrossiminometilalchilpiridine iodometilate.

2-Hydroxyiminomethyl-4-alkylpyridine methiodides were prepared and tested for their in vitro reactivating potency on phosphorylated electric eel cholinesterase. They were also tested as in vivo protecting agents: only one of the compounds, 4-methyl-2-hydroxyiminopyridine, offered a greater protection from DFP than 2-PAM, the others had little to no effect.