Synthesis of N-substituted 4,6-dioxo-imidazo[3,4-c] thiazoles and their analgesic activity in mice.

A new series of N-substituted dioxo-imidazo[3,4-c]thiazoles have been prepared and evaluated for their analgesic activity. The structures of these new derivatives were confirmed by lR, 1H NMR and 13C NMR spectra, and by elemental analysis. When administered intraperitoneally to mice all derivatives were devoid of any toxic effect, even at the high dose of 800 mg kg(-1). In the phenylbenzoquinone-induced abdominal constriction test in mice, eight of the nine synthesized compounds exhibited significant antinociceptive properties with ED50 values (50% effective dose) ranging from 46.7 to 104.7 mg kg(-1) intraperitoneally. Further investigation demonstrated that analgesic activity of the most effective derivatives 5e and 5f partly involved opioidergic and/or noradrenergic pathways.

[Synthesis and antidepressive activity study of aryl and heteroaryl carboxamides of benzylpiperazine]. / Synthèse et étude de l'activité antidépressive d'aryl et hétéroaryl carboxamides de la benzylpipérazine.

The synthesis of 44 original amide derivatives of benzylpiperazine and some analogues of befuraline and piberaline is reported. All compounds have been tested as antidepressive agents. According to the tests, amides 1, 24 and mainly 31 (dihydrobefuraline) seem to provide elevated antidepressive activity.

Antioxidant properties of novel lipophilic ascorbic acid analogues.

Structural modifications of ascorbic acid by the introduction of lipophilic moieties has led to derivatives with increased stability against thermal and oxidative degradation. Two series of new lipophilic ascorbic analogues were synthesized to obtain antioxidants devoid of autooxidant properties: 4-benzoyl-3-hydroxyfuran-2(5H)-ones (3a-j) and 4-acetyl-5-aryl-3,4-dihydrofuran-2(5H)ones (5a-f). These compounds were submitted to three different tests: reduction of the stable free radical, 1,1-diphenyl-2-picrylhydrazyl (DPPH); superoxide-anion scavenging assay; and lipid-peroxidation assay. Most compounds interacted with DPPH: at a concentration of 5 x 10(-3) M, the reducing activity of 4-benzoyl derivatives, 3c and 3h, was more than 50%; under the same conditions, the rate of inhibition for 4-acetylbutanolides, 5a and 5f, reached 60.6% and 87.3%, respectively; 93.3% inhibition was observed with ascorbic acid. In the superoxide-anion scavenging assay, at a concentration of 1 mg mL(-1), 4-benzoyl derivatives, 3g and 3i, exhibited a good activity, with IC50 (dose resulting in 50% inhibition) values of 1.45 and 1.35 x 10(-3) M, respectively. 4-Acetylbutanolide, 5f, significantly inhibited the Fe2+/ADP/ascorbate-induced lipid peroxidation of rat liver microsomes with an IC50 of 4.9 x 10(-4) M. This study demonstrates that enol functions in the structure of ascorbic acid analogues are not absolutely essential to bring about antioxidant effects.

Synthesis and analgesic effects of 5-[4-(arylpiperazin-1-yl)alkylamino]-4-benzyl-3-methyl-1,2-oxa zin-6-one s.

A series of 5-[4-(arylpiperazin-1-yl)alkylamino]-4-benzyl-3-methyl-1,2-oxaz in-6-ones was synthesized and evaluated for analgesic activity. The structures of these new oxazine derivatives were confirmed by IR, 1H-NMR spectra and by elemental analysis. The three most active compounds, 3c, 3e and 3g possessed significant antinociceptive effects in the phenylbenzoquinone-induced wrigthing test (PBQ-test) in mice, with ED50 values ranging from 19.7 to 68.0 mg/kg i.p. In addition these compounds presented a low toxicity (LD50 > 800 mg/kg i.p.) and did not significantly reduce the spontaneous locomotor activity of mice. They interacted in a synergistic manner with morphine but nevertheless each compound presented its own profile. Thus the analgesic activity of 3c and 3e was naloxone sensitive, suggesting in mu opioidergic mechanism. Otherwise 3c and 3d analgesia was attenuated by oral administration of yohimbine and therefore seemed to be mediated via noradrenergic pathway. Finally, 5-hydroxytryptophan associated to carbidopa only potentiated 3e analgesia, demonstrating an involvement of a serotoninergic mechanism.

Synthesis and anticonvulsant properties of triazolo- and imidazopyridazinyl carboxamides and carboxylic acids.

Analogues of 3-amino-7-(2,6-dichlorobenzyl)-6-methyltriazolo[4,3-b]pyridazine PC25 containing amide or carboxylic acid function were synthesized and tested for anticonvulsant activity. The compounds having the imidazole ring substituted with an amide group have been found to be generally more active against maximal electroshock-induced seizures in mice (15.2 < or = ED50 < or = 37.5 mg kg(-1) orally). Furthermore, maximum activity was generally associated with a 2,6-dichlorobenzyl substitution pattern. 3-Amido-7-(2,6-dichlorobenzyl)-6-methyltriazolo[4,3-b]pyridazine 4b was also protective in the pentylenetetrazole-induced seizures test (ED50 = 91.1 mg kg(-1) orally) and blocked strychnine-induced tonic extensor seizures (ED50 = 62.9 mg kg(-1) orally). Moreover, calculated electrostatic isopotential maps of the whole active compounds were quite similar and, consequently, could be associated to optimum anticonvulsant activity.

Synthesis of thiazolotriazine derivatives and their antinociceptive effects in mice.

Ans raci A series of 2-(4-arylpiperazin-1-yl-methyl)-4-methyl-1-oxo-5,6,8,8a-tetrahydro -thiazolo[3,4-d] [1,2,4]triazines was prepared and tested for antinociceptive activity. The compounds were prepared by the Mannich reaction from the corresponding 2-unsubstituted thiazolotriazines. When administered intraperitoneally most were found to have potent analgesic activity in the mouse during tests of phenylbenzoquinone-induced abdominal constriction; ED50 values (doses resulting in half the maximum effect) ranged from 10 to 87 mg kg(-1). Derivatives with a 3-chloro- or 4-fluorophenylpiperazinylmethyl side-chain in the 2-position of the bicyclic system were, when administered intraperitoneally at doses greater than 25 mg kg(-1), also effective in the hot-plate test without associated sedative effects. The compounds have a large therapeutic index; intraperitoneal LD50 values (doses which result in the death of half the animals) were > 700 mg kg(-1). Naloxone attenuated the analgesic activity of the 3-chloro derivative, suggesting the participation of micro-receptors in the antinociceptive effects of this drug. In addition, a nonopioid mechanism, probably related to enhancement of the release of 5-hydroxytryptamine and noradrenaline, or inhibition of the neuronal re-uptake of these compounds, has been evinced to explain the analgesic properties of the 3-chloro or 4-fluoro derivatives. These results provide evidence for the involvement of noradrenergic and 5-hydroxytryptaminergic pathways in the analgesic activity of 3 and 4. Because of their potential effectiveness, the 3-chloro- or 4-fluorophenylpiperazinylmethyl derivatives might be suitable for treatment of a wide variety of painful conditions and could be attractive reserve agents for patients dissatisfied with opioids.

Antioxidant activity of some ascorbic and cinnamic acids derivatives.

Some 4-benzoyl 3-hydroxy furan-2 (5H) ones (3a-d) and 2-amino 3-hydroxymethyl 4-aryl 4-oxo 2-butenoic acids (4a-h) have been synthesized. Compound 3c with an isobutyl substituent in the 5-position of the furan ring was the most effective (IC50 = 8.69 x 10(-4) M) in scavenging the superoxide anion. In vivo, 3c was also protective against reperfusion injury.

Spirobutenolides substituted by arylpiperazinyl-carbonyl moieties. Synthesis and antinociceptive properties.

The synthesis and spectral data of some new cyclohexane-2-spiro-[2,5-dihydro-3-(N-arylpiperazin-1-yl-carbonyl) -4-methyl- 5-oxo]furanes are reported. These compounds were subjected to pharmacological tests for evaluation of antinociceptive effects and interactions with opioidergic and monoaminergic systems. With respective ED50 values of 116.4 and 87.0 mg/kg i.p., derivatives 2b and 2e were the most active spirobutenolides in the phenylbenzoquinone-induced writhing test (PBQ-test) without neurotoxic effects. They potentiated morphine analgesia and were also active at the dose of 150 mg/kg i.p. in the hot plate test while they exhibited sedative effects from the dose of 100 mg/kg i.p. In addition, 2b and 2e analgesia was antagonized by naloxone, then again potentiated by 5-hydroxytryptophan associated to carbidopa in the PBQ-test, demonstrating involvement of opioidergic and serotonergic pathways in the analgesic properties of both compounds. Furthermore, antinociceptive effects of 2e were attenuated by oral administration of yohimbine suggesting that its analgesic activity was also partly related to a noradrenergic mechanism.

Effects of two N-arylpiperazinylmethylpyrazolo [1,5-d][1,2,4]triazine derivatives in pain and antidepressant tests in mice.

The antinociceptive and antidepressant effects of two pyrazolotriazine derivatives, 2-phenyl-3,3a-dihydro-4-oxo-5-(4-phenylpiperazin-1-yl) methyl-pyrazolo[1,5-d][1,2,4]-triazine (SM1) and 2-phenyl-3,3a-dihydro-4-oxo-5-[4-(4-fluorophenyl)piperazin-1-yl] methylpyrazolo[1,5-d][1,2,4] triazine (SM3) have been investigated in mice using classical pharmacological tests. The intraperitoneal LD50 values of SM1 and SM3 were 253.4 and 218.8 mg kg-1 respectively. SM1 and SM3 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (ED50 approximately 10-15 mg kg-1, i.p.) and in the hot-plate test. The antinociceptive effects of the triazines were significantly reduced by administration of naloxone (1 and 3.2 mg kg-1, s.c.) and yohimbine (1 mg kg-1, p.o.). Acute intraperitoneal administration of both compounds (1 mg kg-1 SM1 or 1.5 mg kg-1 SM3) potentiated morphine (0.15 mg kg-1, s.c.) analgesia in the phenylbenzoquinone test. Although this synergistic activity was not reversed by methysergide (0.5 mg kg-1, i.p.), the analgesic activity of both compounds was enhanced by administration of 5-hydroxytryptophan (50 mg kg-1, i.p.) in conjunction with carbidopa (25 mg kg-1, i.p.). Furthermore, neither compound (at 100 mg kg-1, i.p.) significantly reduced the duration of immobility of mice in the forced swimming test, and both (at 75 mg kg-1, i.p.) were ineffective at enhancing the toxic effects of yohimbine (30 mg kg-1, s.c.). Only SM3 (ED50 = 74.5 mg kg-1, i.p.) significantly antagonized reserpine (2.5 mg kg-1, i.p.)-induced ptosis. Thus, the results suggest that SM1 and SM3 have antinociceptive properties related to co-involvement of opioidergic and alpha 2-adrenoceptor mechanism without associated antidepressant properties.

Synthesis and analgesic effects of 3-substituted 4,6-diarylpyridazine derivatives of the arylpiperazine class.

A new series of 4,6-diaryl pyridazines substituted in the 3-position by arylpiperazinyl moieties was synthesized and evaluated for analgesic activity. Five out of the nine tested compounds possessed significant antinociceptive effects in the phenylbenzoquinone-induced writhing test (PBQ test) with ED50 values ranging from 26.0 to 37.7 mg/kg ip. The most active derivatives 2a, 2d and 2h had a low toxicity (LD50 > 800 mg/kg ip) but showed some sedative and neurotoxic effects from the dose of 50 mg/kg ip. The three selected pyridazines were devoid of activity in the hot-plate test. However, analgesic activity of 2d and 2h was significantly reversed by naloxone in the PBQ test. Administered at the low dose of 5 mg/kg ip, 2h greatly potentiated the antinociceptive response induced by morphine (0.15 mg/kg sc). In addition, analgesic effects of 2h (2.5 mg/kg ip) were also potentiated by 5-hydroxytryptophan combined with carbidopa. These results suggest that pyridazine 2h induces analgesia, which is mediated via both opioid and serotonergic mechanisms.

Synthesis and pharmacological evaluation in mice of new non-classical antinociceptive agents, 5-(4-arylpiperazin-1-yl)-4-benzyl-1,2-oxazin-6-ones.

Several 5-(4-arylpiperazin-1-yl)-4-benzyl-1,2-oxazin-6-ones have been synthesized and tested for analgesic activity in a visceral pain model (phenylbenzoquinone-induced writhing test = PBQ test). A good correlation has been found between the antinociceptive effects of drugs and both their lipophilic and steric properties. The most active derivatives 5c and 5f, with intraperitoneal ED50 values of 10.5 and 10.3 mg kg-1 respectively, were more extensively investigated by evaluating their analgesic activity in a somatosensory pain model (hot plate test), as well as their sedative properties. Furthermore, naloxone suppressed the effect of 5c and 5f in the PBQ test, though these derivatives were ineffective to potentiate morphine analgesia. Pretreatment with yohimbine did not significantly attenuate the analgesic effects of 5c and 5f. In addition, pretreatment with 5-hydroxytryptophan associated with carbidopa also failed to potentiate the antinociceptive effects of 5c and 5f. So, a part of the analgesic activity of 5c and 5f seems to be related to an opioidergic mechanisms, especially at the mu receptor level. Molecular modeling studies performed on the opiate drug morphine and on the most stable conformer of 5f showed structural similarities between these two molecules.

Synthesis of peripherally acting analgesic 3-arylpiperazinyl-5-benzyl-pyridazines.

A series of 3-arylpiperazinyl-5-benzyl-pyridazines was synthesized and evaluated for analgesic activity. The structures of these new pyridazine derivatives were confirmed by IR, 1H-NMR spectra and by elementary analysis. With ED50 values ranging from 6.0 to 71.5 mg/kg i.p. most of the compounds were several times more potent than acetaminophen (ED50 = 228.6 mg/kg i.p.) and noramidopyrine ((ED50 = 68.8 mg/kg i.p.) in the phenylbenzoquinone-induced writhing test (PBQ-test). Quantitative structure-activity relationships were accomplished by a Hansch analysis. The most active pyridazines 2h-j exhibited sedative properties from the dose of 25 mg/kg i.p. Their lack of activity in the hot plate test was in favour of peripherally acting agents. In the PBQ test, analgesic activity of 2h-j was antagonized by naloxone. However, their antinociceptive effect added up to those of 5-hydroxytryptophan when given in association with carbidopa. These results demonstrated that analgesic properties of pyridazine derivatives might involve a serotonergic pathway without interaction with opiodergic systems.

Synthesis and trazodone-like analgesic activity of 4-phenyl-6-aryl-2-[3-(4-arylpiperazin-1-yl)propyl]pyridazin -3-ones.

A series of 4,6-diaryl pyridazinones, chemically related to trazodone, ws synthesized and evaluated for analgesic activity. With ED50 values ranging from 8.4 to 46.7 mg kg(-1) i.p. in the phenylbenzoquinone-induced writhing test (PBQ test), most compounds were several times more potent than acetaminophen (ED50 = 231.3 mg kg(-1) i.p.) and noramidopyrine (ED50 = 68.5 mg kg(-1) i.p.). A multiple linear regression analysis demonstrated a correlation between antinociceptive activity and lipophilicity, as well as electronic and steric factors. The most active pyridazinones 2c and 2j exhibited minimal sedative and neurotoxic effects at the dose of 25 mg kg(-1) i.p. They were devoid of activity in the hot plate test and their analgesic activity was not significantly reversed by naloxone in the PBQ test. The antinociceptive response induced by morphine (0.15 mg kg(-1) s.c.) in the PBQ test was greatly potentiated by 2c and 2j administered at the low doses of 1 and 2.5 mg kg(-1) i.p., respectively. On the other hand, their analgesic effects were enhanced synergistically by 5-hydroxytryptophan combined with carbidopa. All these data imply that a significant part of the antinociceptive effect induced by 2c and 2j may involve both opioid and serotonergic pathways. In addition, these two pyridazinones did not exhibit any antidepressant properties in the forced swimming test, nor did they potentiate yohimbine-induced toxicity.

Effect on free radical processes of some ascorbic acid analogues.

Ascorbic acid, present in plasma from humans at concentrations of 50 to 200 mumol/l, has multiple antioxidant properties. Structural modification of this vitamin by the introduction of lipophilic moieties has allowed to the development of ascorbate esters and ethers active as free radical quenchers. Thus, a new series of ascorbic acid analogues possessing one or two aromatic rings was prepared in an attempt to synthesize potent antioxidants with lipophilic properties. Substituted 3-hydroxy furan-2 (5H)-ones and in some cases, dihydrofuro[3,4-b]pyrones were prepared. The synthesized compounds were evaluated for their antioxidant activity in vitro. So, 4-(4-methoxybenzoyl)-3-hydroxy-5-phenylfuran-2(5H)-one 3e (IC50 = 3.06 x 10(-4) M) was found to be the most effective in scavenging the superoxide anion, whereas 4-benzoyl-3-hydroxy-5-(3,4-dimethoxyphenyl)furan- 2(5H)-one 3d (IC50 = 1.38 x 10(-4) M) was the most active in inhibiting, lipid peroxidation.

Synthesis of new serotonergic 2-substituted 4,6-diaryl pyridazin-3-ones.

A series of 4,6-diaryl pyridazin-3-ones substituted in the 2-position by [4-(4-aryl piperazin-1-yl]-but-2-ynyl moieties was synthesized and evaluated for antidepressant activity. The structures of these new pyridazine derivatives were confirmed by IR, 1H-NMR spectra and by elementary analysis. At 150 mg/kg i.p., they induced little or no reduction of the duration of immobility of mice in the forced swimming test. Head twitches produced by L-5-hydroxytryptophan in mice pretreated with pargyline were significantly potentiated by most of the tested compounds. In addition, pyridazine derivatives did not antagonize reserpine-induced palpebral ptosis or enhance the toxic effects of yohimbine and were almost devoid of anticholinergic properties in mice.

[4-Arylpiperazine derivatives: a seedbed of drugs for various therapeutic indications]. / Dérivés 4-arylpipéraziniques: une pépinière de médicaments aux indications thérapeutiques vari s?

The main focus of this review is the pharmacology and the therapeutic use of chemical related agents, the arylpiperazine derivatives. These compounds produce a variety of behavioural responses and pharmacological effects which directly and principally result from activation of serotonin systems. However, minor modifications in the chemical structure of these products involve important changes in affinity and selectivity for 5-HT receptors since it can also display significant affinity for dopaminergic, adrenergic or histaminergic receptors. The different arylpiperazine drugs therapeutically used are described as well as some compounds presently under investigation.

Behavioural profile of two potential antidepressant pyridazine derivatives including arylpiperazinyl moieties in their structure, in mice.

The potential antidepressant effects of two pyridazine derivatives, 5-benzyl 6-methyl 2-[4-(3-trifluoro-methyl phenyl) piperazin-1-yl] methylpyridazin-3-one (PC4) and 5-benzyl 6-methyl 2-[4-(3-chlorophenyl) piperazin-1-yl] methylpyridazin-3-one (PC13), were evaluated using classical psychopharmacological tests in mice. The intraperitoneal LD50 values of PC4 and PC13 were respectively 1125.8 and 429.6 mg kg-1. Only at intraperitoneal doses of 100 mg kg-1 did PC4 or PC13 significantly decrease locomotor activity. Both compounds (5-20 mg kg-1, i.p.) reduced the duration of immobility of mice in the forces swimming test, antagonized reserpine (2.5 mg kg-1, i.p.)-induced ptosis, and potentiated reserpine (2.5 mg kg-1, i.p.)-induced hypothermia. PC4 and PC13 (20 mg kg-1, i.p.) partly reversed hypothermia induced by low dose apomorphine (5 mg kg-1, s.c.) but were less effective for higher doses of apomorphine (16 mg kg-1, s.c.). At 200 mg kg-1, intraperitoneal PC13 enhanced the toxic effects of yohimbine (30 mg kg-1, s.c.), while PC4 was inactive. Head twitches produced either by L-5-hydroxytryptophan (4 mg kg-1, i.p.) in mice pretreated with pargyline (100 mg kg-1, i.p.) or by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3 mg kg-1, i.p.) were antagonized by both pyridazine derivatives (20 mg kg-1, i.p.). PC4 and PC13 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (5.0 < ED50 < 5.5 mg kg-1, i.p.) and in the hot-plate test (10 to 37% of analgesia at 10 mg kg-1, i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and anticonvulsant properties of new benzylpyridazine derivatives.

Several 3-substituted pyridazines and a series of imidazo- and triazolopyridazines were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures in mice. The most active derivatives, 3-ureidopyridazine 7 and triazolopyridazines 16, 18, 21, and 25 with oral ED50's that ranged from 6.2 to 22.0 mg/kg, were more extensively investigated by evaluating their ability to prevent chemically induced seizures and were compared with phenytoin, phenobarbital, sodium valproate, carbamazepine, and diazepam. 3-amino-7-(2,6-dichlorobenzyl)-6-methyltriazolo-[4,3-b]pyridazine (25) was also protective in the pentylenetetrazole-induced seizures test (ED50 = 76 mg/kg per os) and blocked strychnine-induced tonic extensor seizures (ED50 = 34.5 mg/kg per os). Furthermore, derivative 25 showed anticonvulsant effects on bicuculline- and yohimbine-induced seizures tests in mice. All these results suggest that the pharmacological activity of 25 is partly due to modifications of glycinergic and GABAergic transmission. Moreover, molecular modeling studies based on the antiepileptic drug lamotrigine and the most stable conformer of 25 show structural similarities between these two molecules. This conformer also agrees with the electronic tolerances and volume of benzodiazepine pharmacophore models.

Study of structure/activity relationships by multivariate statistical analysis in a series of triazaspirodecanediones with CNS activities.

The CNS activities of thirteen triazaspirodecanediones have been compared by multivariate statistical analysis. The response parameters used in this study were spontaneous motor activity, potentiation of pentobarbital effect, anticonvulsant and anxiolytic activities. Pharmacological data were analyzed using two methods: (1) a factorial correspondence analysis; (2) an automatic analysis based first on a hierarchical clustering represented by a dendrogram and second on the minimum spanning tree method. The obtained results allow to imagine the synthesis of more specific compounds.

Synthesis of new 5-substituted pyrazolo[1,5-d][1,2,4]-triazine derivatives and their analgesic, anti-inflammatory and antipyretic properties.

A series of 2-aryl-4-oxo-pyrazolo[1,5-d][1,2,4]triazines substituted in the 5-position by aminoalkyl or benzoyl moieties was synthesized and evaluated for analgesic activity. The structures of new triazine derivatives were confirmed by IR, 1H-NMR spectra and by elementary analysis. In the phenylbenzoquinone induced writhing test, only 3,3a-dihydropyrazolo triazines substituted by an arylpiperazinylmethyl group exhibited potent analgesic effect. In addition, these compounds possessed significant anti-inflammatory and antipyretic properties. A desaturation in 3,3a positions or other groups than arylpiperazinylmethyl moieties notably decreased analgesic effects.