Synthesis, analgesic activity and computational study of new isothiazolopyridines of Mannich base type.

A series of new 4-arylpiperazine derivatives of isothiazolopyridine of Mannich base type and their non-4-arylpiperazine analogues (3 and 4) were synthesized and assayed as potential analgesic agents. Pharmacological assay demonstrated that all the compounds prepared, without exception, displayed significant activity in the mouse writhing assay. The analgesic action, expressed as ED50, was found to be 2-10 times more potent than that of acetylsalicylic acid and 1.5-10 times weaker than that of morphine, these being used as standards. The toxicities (LD50) of the investigated derivatives varied and ranged from 250 to 2000 mg/kg. Additionally, the computational investigations were performed in order to find correlation between molecular structure and biological effects (toxicity, analgesic action) of discussed compounds. Useful model was found for toxicity assessment.

Synthesis and analgesic action of N-(substituted-ethyl)pyrrole-3,4-dicarboximides.

We prepared a series of new N-[2-(4-substitutedpiperazin-1-yl)ethyl]-1-(n-butyl or phenyl)-2,5-dimethyl-3,4-pyrroledicarboximides 3 and the related products 4 and 5, nine representatives of which were evaluated as potential analgesic agents in an animal model (mice). The new pyrroledicarboximides were not toxic (LD50 > or = 1466 mg/kg) and eight of them displayed analgesic activity approximately 1.5-5 times superior to that of ASA in the writhing test. However, the compounds were found to be unstable in methanol solution and in dilute bases (methanol/NaOMe). The S-A relationship is discussed.

Preparation of novel derivatives of pyridothiazine-1,1-dioxide and their CNS and antioxidant properties.

Starting from isothiazolopyridine-1,1-dioxide (1), corresponding derivatives of 3-aryl-4-hydroxypyrido[3,2-e]-1,2-thiazine-1,1-dioxide (6) possessing the 3-[4-(substituted-phenyl)piperazinyl]propyl or 3-(4-substituted-piperidinyl)propyl side chain by the nitrogen atom of the thiazine ring were prepared. Under pharmacological central nervous system (CNS) screening in animal models (mice), all of the six pyridothiazines 6 tested exhibited analgesic action as the predominant profile of their activity ('writhing' test 12.5-50 mg/kg). Moreover, the radical scavenging activity against peroxyl radicals of the representative pyridothiazines 6 was evaluated in vitro in water environment and some of them proved to be moderate antioxidants.

Synthesis of some pyrrolo[3,4-d]pyridazinones and their preliminary anticancer, antimycobacterial and CNS screening.

Starting from 1-substituted-2,5-dimethyl-3,4-pyrroledicarboxylic acid anhydrides 1 and N-methylhydrazine, 1,2,3,4-tetrahydro-6-substituted-2,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin- 1,4-ones 2 were prepared. Reaction of compounds 2 with alkylating agents give 3-N- or 4-O-alkylated products 3, 4 or mixtures of these isomers in ratios depending on the alkylating agents. Under preliminary pharmacological screening two of four new pyrrolo[3,4-d]pyridazinones were active as cystostatic agents, all the eight compounds displayed moderate activity against Mycobacterium tuberculosis and two compounds were active as CNS-depressive agents.

Synthesis and in vivo pharmacology of new derivatives of isothiazolo[5,4-b]pyridine of Mannich base type.

Recently we reported on 2H-4,6-dimethyl-2-[(4-phenylpiperazin-1-yl)methyl]-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridine (V), which exhibited high anorectic action in animal models as a result of stimulation of serotoninergic system. This paper describes the synthesis of the series 3-5 of analogues of V prepared from 2-hydroxymethyl-4,6-dimethylisothiazolopyridine (2) and corresponding 4-substituted-piperazines(piperidines) or tetrahydroisoquinoline. The 12 compounds obtained were screened in standard CNS tests in in vivo (mice and rats). In contrast to V, none of its analogues showed serotoninergic activity, whereas several of these compounds were found to be active as weak to moderate analgesic agents. According to X-ray and molecular modeling studies the different pharmacological profile of V and its o-OCH3 analog 3a, taken as an example, should be referred back to the conformational restriction incorporated by the o-substitution rather than effects of different lipophlicity or basicity of these compounds.

Synthesis and preliminary screening of derivatives of 2-(4-arylpiperazin-1-ylalkyl)-3-oxoisothiazolo[5,4-b] pyridines as CNS and antimycobacterial agents.

We have synthesized several new isothiazolopyridines possessing a side chain at the isothiazole ring typical, among others, for trazodone or NAN-195. Representatives of the novel isothiazolopyridines were examined for acute toxicity and in several commonly used CNS tests in mice and for arterial blood pressure in rats. Three of the five compounds tested showed significant analgesic activity. The most active compound (3b) exhibited analgesic action in the "writhing" test in a dose 1/1280 of LD50 (LD50 = 1135.5 mg/kg) after administration i.p. to mice. Additionally, the compounds described here and related isothiazolopyridines obtained previously were evaluated against Mycobacterium tuberculosis H37Rv at 12.5 micrograms/ml in in vitro assays. Seven of the nineteen compounds tested showed 100% inhibition of that mycobacterium.

Synthesis of some N-substituted 3,4-pyrroledicarboximides as potential CNS depressive agents.

As a continuation of our work on N-[4-aryl(heteroaryl)piperazin-1-ylalkyl]-3,4-pyrro ledicarboximides, which were characterized by strong analgesic activity and CNS depressive action, several novel N-substituted 3,4-pyrroledicarboximides were prepared and eleven representatives were examined in a series of in vivo CNS tests. A few of these compounds displayed a similar profile of biological selectivity to that of 3,4-pyrroledicarboximides described previously; their structure-activity relationships are discussed.

Synthesis and pharmacological screening of some N-(4-substituted-piperazin-1-ylalkyl)-3,4-pyrroledicarboximides.

As an extension of our previous work we describe the synthesis and pharmacological investigation of a new series of derivatives of pyrrole-3,4-dicarboximide possessing the 4-substituted-piperazin-1-ylalkyl group linked to the imide nitrogen. The products were evaluated for acute toxicity, and effectiveness in a series of CNS and arterial blood pressure tests. The preliminary pharmacological screening was determined in animal models. Several compounds demonstrated moderate to high analgesic activity in the 'writhing syndrome' test (5f-1/640 LD50). Some of the structure-activity relationships are also discussed.

2-Substituted-3-oxoisothiazolo[5,4-b]pyridines as potential central nervous system and antimycobacterial agents.

The 2-[3-(substituted-amino)-2-hydroxypropyl]-4,6-dimethyl-3-oxo-2,3- dihydroisothiazolo[5,4-b]pyridines 3 were synthesized and pharmacologically evaluated in animal models. The preliminary pharmacological screening study showed that the investigated compounds were toxic and had no significant activity in central nervous system (CNS) tests. Additionally, compounds 3, and several other 2-substituted-4,6- dimethyl-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridines described here (2), together with those (4) reported in a previous paper, were evaluated in vitro against Mycobacterium tuberculosis H37Rv. For comparison, products of the rearrangement of some isothiazolopyridine 1,1-dioxides (4a,b) with the corresponding pyrido[3,2-e]-1,2-thiazines (5a,b) and different N2-substituted derivatives of the latter (5c-i) were also prepared and investigated in antimycobacterial tests. The most potent antituberculars of the 23 compounds assayed are 2-[3-(4-benzylpiperidin-1-yl)-2-hydroxypropyl]-4,6-dimethyl-3-oxo- 2,3- dihydroisothiazolo[5,4-b]pyridine 3d and ethyl (4,6-dimethyl-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridin-2-yl)acet ate 4c (MIC < 12.5 micrograms/ml, 100 and 98% inhibition, respectively).

Synthesis and cytostatic properties of 5-substituted derivatives of 3-methylisoxazolo[5,4-d]1,2,3-triazine-4-ones and 3-methyl-5-triazene 4-isoxazolecarboxylic acid ethyl esters.

Six new 5-substituted derivatives of 3-methyl-isoxazolo[5,4-d]1,2,3-triazine-4-one and 3-methyl-5-triazene-4-isoxazolecarboxylic acid ethyl ester have been synthesized from 5-amino-3-methylisoxazole-4-carboxylic acid amides, and ethyl ester. They were examined for cytostatic activity in comparison with Dacarbazine. The 3-methyl-5-(4-chlorophenyl)isoxazolo[5,4-d]1,2,3-triazine-4-one showed better activity than Dacarbazine.

Synthesis and anorectic activity of 2H-4,6-dimethyl-2-[(4- phenylpiperazin-1-yl)methyl]-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridin e.

The synthesis of 2H-4,6-dimethyl-2-[(4- phenylpiperazin-1-yl)methyl]-3-oxo-2,3-dihydroisothiazolo[5, 4-b]pyridine. (3) and its biological properties are described. Compound 3 pharmacologically evaluated in vivo by use of behavioral tests showed to have a profile of activity characteristic of stimulation of the central serotoninergic system, mostly 5-HT52A receptors (anorectic action: 2 mg/kg i.p., 8.5 mg/kg po) However, receptor activity of isothiazolopyridine 3 was not confirmed in vitro using 5-HT2A and 5-HT1A receptor binding technique. Molecular modeling studies demonstrated that it is difficult to predict bioactive conformation of title molecule 3.

Synthesis and biological evaluation of 7-azaanalogues of ipsapirone.

The synthesis and preliminary pharmacological evaluation of 4,6-dimethyl-7-azaipsapirone (5c) and related compounds bearing the r-(phenyl, pyridyl, pyrimidinyl)-1-piperazinyl moiety linked through a butyl or ethoxyethyl chain with the isothiazolo[5,4-b]pyridine system, are described.

Synthesis and pharmacological study of some derivatives of pyrazolo[4,3-c]pyrido[3,2-c]-1,2-thiazine-5,5-dioxide, a novel heterocyclic ring system.

Starting from pyridothiazines 1 and N-methyl(phenyl)hydrazines isomeric derivatives 2 and 3 of the pyrazolo[4,3-c]pyrido[3,2-e]-1,2-thiazine, a new heterocyclic ring system, have been obtained. The structure of the synthesized compounds was confirmed by spectroscopic and elemental analyses. The results of the preliminary pharmacological study of CNS effects caused by compounds 2 are reported.

Studies on synthesis and biological properties of pyrazolo[4,3-c]-pyrido[3,2-e]-1,2-thiazine-5,5-dioxide bearing 4-substituted-1-piperazinylpropyl moiety.

Derivatives of the pyrazolopyridothiazine-5,5-dioxide 6 and the pyridothiazine-1,1-dioxide 2 bearing 4-phenyl-(heteroaryl)-1-piperazinylpropyl substituent at the nitrogen of the thiazine ring were synthesized. The acute toxicity and preliminary results of the CNS activity of some derivatives 2 and 6 are described. A structure-activity relationship is discussed.

Synthesis and biological evaluation of derivatives of N-[4-substituted-1-piperazinylalkyl]-1-(butyl,aryl)-2,5- dimethylpyrrole-3,4-dicarboxymide (Part II).

A series of new N-[4-substituted-1-piperazinyl-alkyl]-3,4-pyrroledicarboxyimides 7 have been prepared by reaction of N-haloalkylimide derivatives 6 with corresponding N-monosubstituted piperazines. Compounds 7 tested in preliminary pharmacological investigation produced a general depressive action on the central nervous system.

Synthesis and pharmacological properties of N-(4-substituted-1-piperazinylalkyl)-1-butyl-2,5-dimethylpyrrole-3,4- dicarboxyimide derivatives.

The preparation of a number of N-(4-substituted-1-piperazinylalkyl)-1-butyl-2,5-dimethylpyrrol e-3,4- dicarboxyimides (3) is described. The structures of the novel compounds were confirmed by elemental and spectral analyses. The results of a preliminary pharmacological study of CNS effects caused by compounds 3 are reported.

Synthesis and properties of 4-substituted-1-piperazinyl-propyl derivatives of 1-phenyl-7-methylpyrimido-[4,5-d]pyrimidin-4-one.

In reactions of 1-phenyl-7-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimido[ 4,5-d]pyrimidin e (1) with 1-(3-chloropropyl)-4-methyl(phenyl, 3-chlorophenyl, 2-pyrimidynyl, 2-thiazolyl)piperazines (5), mixtures of isomeric N- and S-substituted derivatives of compound 1 (3 and 4) were obtained. Isomers were separated by fractional crystallization. The structure of novel compounds 3 and 4 was confirmed by elemental and spectral analyses. In pharmacological screening compounds 3b and 4b displayed rather strong analgesic action, inhibited amphetamine hyperactivity and abolished apomorphine stereotypy. Compounds 3e,3d and 4e attenuated m-chlorophenylpiperazine-induced hypothermia.

Synthesis and properties of 2H-2-(4-substituted -1-piperazinylalkyl)-4,6-dimethyl-3-oxo-2,3-dihydroisothiazolo [5,4-b] pyridines.

The preparation of a number of derivatives of 2H-4,6-dimethyl-3-oxo-2,3-dihydroisothiazolo [5,4-b] pyridine (1) containing 4-methyl(phenyl, heteroaryl)-1-piperazinylalkyl moiety by two routes has been described. Preliminary results of pharmacological screening of compounds synthesized showed antipsychotic activity of 2H-2-13-(4-phenyl-1-piperazinyl)propyl-3-oxo-2,3-dihydroisothiazolo [5.4-b] pyridine (4f).

Syntheses and properties of selected derivatives of pyrimido[5,4-e]-1,3-thiazine and pyrimido[4,5-d]pyrimidine.

In the reactions of ethyl 4-chloro/tosyloxy/-2-methylpyrimidine-5-carboxylate with differently substituted thioureas, new derivatives of 2,3-dihydro-7-methylpyrimido-[5,4-e]-1,3-thiazine (5-9) and of 7-methyl-1,2,3,4-tetrahydropyrimido[4,5-d]pyrimidine (12, 13) were obtained. Besides, some derivatives of 4-phenylamino-2-methylpyrimidine-5-carboxylic acid (15-20) were also synthesized. Structure of the compounds was confirmed by spectral analysis (IR, H-NMR) and chemical transformations. In the screening pharmacological examinations some of the compounds revealed analgesic, antiinflammatory and immunosuppressive activity.