Metal Free Formation of Various 3-Iodo-1H-pyrrolo[3',2':4,5]imidazo-[1,2-a]pyridines and [1,2-b]Pyridazines and Their Further Functionalization.

3-iodo-1H-pyrrolo[3',2':4,5]imidazo-[1,2-a]pyridines and [1,2-b]pyridazines were prepared following Groebke-Blackburn-Bienaymé MCR combined with I2-promoted electrophilic cyclization. The flexibility of the method enables the introduction of diversity in the 2, 5, 6, and 7 positions on the resulting scaffold using commercially available starting materials. Furthermore, subsequent palladium-catalyzed reactions were successfully achieved using our iodinated derivatives.

Access to 1H-indazoles, 1H-benzoindazoles and 1H-azaindazoles from (het)aryl azides: a one-pot Staudinger-aza-Wittig reaction leading to N-N bond formation?

The synthesis of various substituted 1H-indazoles is reported through N-N bond formation from an iminophosphorane derivative. Supported by control experiments, an original Staudinger-aza-Wittig tandem mechanism is proposed for this transformation.

Three successive and regiocontroled palladium cross-coupling reactions to easily synthesize novel series of 2,4,6-tris(het)aryl pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidines.

The first access to tris(het)arylated pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidine derivatives is reported. The series were generated from 4-chloroaminopyridinium, which afforded the key intermediate bearing three leaving groups, i.e. a C-2 methylsulfanyl, a lactame carbonyl group in C-4 and a chlorine atom in C-6. The regioselective reactions led to the tris(het)aryl derivatives with satisfying to high yields. The three successive cross-coupling reactions occurred first in C-6 by the displacement of chlorine, next in C-4 position by a sequential Pd-catalyzed phosphonium coupling and finally in C-2 under a Pd/Cu-catalyzed desulfitative cross-coupling reaction. The optimization and scope of each reaction are discussed and the original compounds characterized.

Recent advances in the chemistry and biology of pyridopyrimidines.

The interest in pyridopyrimidine cores for pharmaceutical products makes this scaffold a highly useful building block for organic chemistry. These derivatives have found applications in various areas of medicine such as anticancer, CNS, fungicidal, antiviral, anti-inflammatory, antimicrobial, and antibacterial therapies. This review mainly focuses on the progress achieved since 2004 in the chemistry and biological activity of pyridopyrimidines.

Novel nonopioid non-antiinflammatory analgesics: 3-(aminoalkyl)- and 3-[(4-aryl-1-piperazinyl)alkyl]oxazolo[4,5-b]pyridin-2(3H)-ones.

A series of 3-(aminoalkyl)- and 3-[(4-aryl-1-piperazinyl)alkyl]oxazolo[4,5-b]pyridin-2(3H)-ones were prepared from their respective oxazolo[4,5-b]pyridin-2(3H)-ones. Several members of this group were found to possess potent analgesic activity in the mouse during a p-phenylquinone writhing induced test. Among them, phenylpiperazine compounds with two-carbon length alkyl chains, 2a and 2b, appeared by high analgesic with little toxicity having neither an antiinflammatory effect nor opioid receptor affinity. The synthesis and structure-affinity relationships for this series are detailed.

A novel series of 2,6,7-substituted 2,3-dihydro-1,4-benzodioxin and 2,6,7-substituted 1,4-benzodioxin derivatives as lipid peroxidation inhibitors. Structure-activity relationships for high inhibition of human low-density lipoprotein peroxidation.

A series of 6- or 7-substituted 2-carboxamido- or 2-(aminomethyl)-1,4-benzodioxin and -2,3-dihydro-1,4-benzodioxin derivatives were synthesized and evaluated to determine the necessary structural requirements for a high inhibition of human low-density lipoprotein copper-induced peroxidation. The most active compounds (21, 25, 28, 36, and 37) were found between 5 and >45 times more active than probucol itself. Due to both their potency and their structural features, compounds 25 and 36 were selected with others for complementary in vitro and in vivo investigations. Both of them exhibit calcium antagonist properties in the same range of potency as flunarizine itself. Compound 36 was also found to have significant hypolipaemic activity in mice at 100 and 300 mg/kg po, while compound 25 proved to be clearly active in a normobar hypoxia test.

3,4-Dihydro-3-amino-2H-1-benzopyran derivatives as 5-HT1A receptor ligands and potential anxiolytic agents. 1. Synthesis and structure--activity relationship studies.

A series of 3,4-dihydro-3-amino-2H-1-benzopyran derivatives were prepared in order to determine the necessary structural requirements for good affinity for 5-HT1A receptors and high selectivity versus other receptors. Modifications of the extracyclic amino substituents, the length of the alkyl side chains, and their substituents were explored. The best compounds (9g, 9k, 15b, 15d) possess imido or sulfonamido functional groups with a preferential length of four methylenes for the side chain. After resolution, the dextrorotatory enantiomers showed better affinity and selectivity for 5-HT1A receptors. These compounds have been proven to be full agonists. 9g and its enantiomers showed anxiolytic activity in vivo in various comportemental models. The compound (+)-9g is currently under clinical investigation.

2-Benzodioxinylaminoethanols: a new class of beta-adrenergic blocking and antihypertensive agents.

Various 2-benzodioxinylaminoethanol derivatives were synthetized and investigated for beta-adrenergic blocking activity. Most compounds demonstrated a beta-blocking activity of a competitive type when evaluated in guinea pig atrial and tracheal preparations. Three compounds were more potent than practolol and propranolol. All compounds demonstrated antihypertensive properties in spontaneously hypertensive rats. The most active compound was 1-(1,4-benzodioxin-2-yl)-2-[N4-(2-methoxyphenyl)piperazino]ethanol (11), which at 2.5 mg/kg iv lowered blood pressure by 41%.

New substituted 1,4-benzoxazine derivatives with potential intracellular calcium activity.

Substituted 1,4-benzoxazines bearing an amino side chain at the 2-position were prepared and were found to have a moderate activity on intracellular calcium. Of the compounds studied it was found that those which possess a homoveratrylamino moiety exhibited superior potency. The chain length and the nature of the amine (4-fluorophenylpiperazine, 4-fluorobenzhydryloxyethylamine, N-substituted homoveratrylamine) is discussed. The 4-benzyl-3, 4-dihydro-2-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-2H-1, 4-benzoxazine (3c) is the most potent derivative of the series with a ratio of IC50 values against PE (phenylephrine) and K+ of 2.1. Under these test conditions a ratio near 1 indicates potential intracellular calcium activity while a ratio greater than 100 an action on extracellular calcium influx.

Pharmacophoric search and 3D-QSAR comparative molecular field analysis studies on agonists of melatonin sheep receptors.

Conformational analysis was used to characterize the agonist pharmacophore for melatonin sheep brain receptor recognition and activation. The molecular geometry shared by all conformations of the selected active ligands was determined. Assuming that all the compounds interact at the same binding site at the receptor level, 2-iodomelatonin pharmacophoric conformation served as a template for the superimposition of 64 structurally heterogeneous agonists constituting the training set used to perform a three-dimensional quantitative structure-activity relationship study via the comparative molecular field analysis method. A statistically significant model was obtained for the totality of the compounds (n = 64, q2 = 0.62, N = 6, r2 = 0.96, s = 0.28, F = 249) with steric, electrostatic, and lipophilic relative contributions of 28%, 35%, and 37%, respectively. The predictive power of the proposed model was discerned by successfully testing the 78 agonist ligands constituting the test set. The model so obtained and validated brings important structural insights to aid the design of novel melatoninergic agonist ligands prior to their synthesis.

N-substituted oxazolo[5,4-b]pyridin-2(1H)-ones: a new class of non-opiate antinociceptive agents.

A series of 1-(aminoalkyl)- and 1-[(4-aryl-1-piperazinyl)alkyl]oxazolo[5,4-b]pyridin-2(1H)-one derivatives of oxazolo[5,4-b]pyridin-2(1H)-one, incorporating modifications to the length of the alkyl side chain and to the amino or 4-aryl-1-piperazinyl substituents, were tested for safety and analgesic efficacy in mice and rats. Some compounds with 4-(substituted or nonsubstituted phenyl)-1-piperazinyl substituents and a 3-4-carbon alkyl side chain had significantly greater analgesic activity than that of the oxazolo[4,5-b]pyridin-2(3H)-one analogs. To reduce the metabolic N-dealkylation of the piperazine observed in our previous work on oxazolo[4,5-b]-pyridin-2(3H)-ones, analogs of the most active compounds with steric hindrance on the alkyl side chain were prepared and tested. The compound with the maximal combination of safety and analgesic efficacy was 1-[[4-(4-fluorophenyl)-1-piperazinyl]propyl]oxazolo[5,4-b]pyridin- 2(1H)-one (compound 3b), with ED50 values of 5.6 mg/kg po (mouse, phenylquinone writhing test) and 0.5 mg/kg po (rat, acetic acid writhing test). Compound 3b is a potent, rapid-acting, non-opioid, nonantiinflammatory analgesic with low acute toxicity and sustained effect.

3D-QSAR CoMFA study on imidazolinergic I(2) ligands: a significant model through a combined exploration of structural diversity and methodology.

Displaying an unprecedented structural diversity, 119 I(2) ligands, and their pK(i) values, were collected and submitted to a comparative molecular fields analysis (CoMFA) study. They were discerned into three structural subsets (A, B, C), to explore the I(2) 3D-QSARs from finite structural systems (A, B, C) to more complex ones (AB, AC, BC, ABC). In addition, various key steps of the CoMFA methology were explored. The applied method used two pharmacophore templates and seven molecular field combinations (electrostatic, lipophilic, steric), as well as eight alignment methods (two point-by-point and six similarity-based variations). That way, 644 CoMFA models were obtained and further selected according to their predictive ability through two filters. The first filter was mainly based on the q(2), which internally evaluates the predictive ability from the training set. For the second filter, the predictive ability was externally evaluated through the prediction of test sets. Finally, one model was extracted from the whole data as the best. Indeed, it combines three features of upmost importance for the further design of ligands endowed with high I(2) affinity: structural diversity (n = 73), robustness (N = 9, r(2) = 0.96, s = 0. 28, F = 148), and a great fully assessed predictive ability (q(2) = 0.50, r(2)(test set) = 0.81, n(test set) = 46). On the basis of structural data and CoMFA isocontours, some elements of the I(2) tridimensional pharmacophore are also suggested.

3-amino-3,4-dihydro-2H-1-benzopyran derivatives as 5-HT1A receptor ligands and potential anxiolytic agents. 2. Synthesis and quantitative structure-activity relationship studies of spiro[pyrrolidine- and piperidine-2,3'(2'H)-benzopyrans].

In continuation of our work on 3-amino-3,4-dihydro-2H-1-benzopyran derivatives with high affinity for 5-HT1A receptors, we have prepared rigid spirobenzopyran analogues designed from the pharmacophore models of Mellin and selected via a quantitative structure-activity relationship approach mainly based on similarity indices. A series of spiro[pyrrolidine- and piperidine-2,3'(2'H)-benzopyrans] with various substitutions on the aromatic ring as well as on the extracyclic spiranic nitrogen atom were then synthesized and evaluated for their serotonergic and dopaminergic activities. Good correlation between the predicted and the experimental binding values was observed with an average difference of 0.2 unit on log(IC50). Affinities for the 5-HT1A receptors were in the nanomolar range for the best compounds ((+)-11a,23) with a high selectivity versus other 5-HT (5-HT1B, 5-HT2, 5-HT3) or dopamine (D1, D2) receptor subtypes. As for the 3-amino-3,4-dihydro-2H-1-benzopyran series, the dextrorotatory enantiomer (+)-11a showed better affinity and selectivity for 5-HT1A receptors than its levorotatory analogue (-)-11a. Compound (+)-11a proved in vitro to be a full agonist and in vivo to be active in various comportmental tests predictive of psychotropic activity, such as the forced swim test and the tail suspension test, and is currently under complementary investigations.

Synthesis of 2-substituted-2,3- dihydro-1,4-dioxino[2,3-b]pyridine derivatives.

[reaction--see text] A variety of 2-substituted-2,3-dihydro-1,4-dioxino[2,3-b]pyridines B have been synthesized from the readily available 2-nitro-3-oxiranylmethoxypyridine 1 via a Smiles rearrangement. We demonstrate how variations of reaction conditions affect the product distribution of A and B.

Anxiolytic-like effects of a selective 5-HT1A agonist, S20244, and its enantiomers in mice.

The action of a selective 5-HT1A agonist S20244 and its two enantiomers (+)-S20499 and (-)-S20500 were assessed in mice. The animals were confronted with a free exploratory test especially adapted to reveal behavioural sedation, and with a two-box light/dark choice situation validated for the detection of anti-anxiety agents. These drugs were found to have anxiolytic properties at low doses, like benzodiazepines. Furthermore, the drugs exhibited sedative effects at higher doses. These results closely resemble those we found after administration of two other 5-HT1A agonists, 8-OH-DPAT and MDL 73005EF (NeuroReport, 1, 267-270, 1990).

Aggressive behavior induced by the steroid sulfatase inhibitor COUMATE and by DHEAS in CBA/H mice.

The steroid sulfatase enzyme (STS) regulates the formation of dehydroepiandrosterone (DHEA) from dehydroepiandrosterone-sulfate (DHEAS). DHEAS is a well-known negative allosteric modulator of the GABA(A) receptor-gated chloride channels. It is classified as an excitatory neurosteroid. The implication of GABA(A) receptor activity in aggressive behavior in rodents is well-documented. In addition a genetic correlation between STS level in the liver and aggressive behavior across 12 strains of mice suggest that STS activity could be involved in aggression in mice. We assessed herein whether COUMATE (an STS inhibitor) and DHEAS modulate aggression in CBA/H mice. We hypothesized that inhibiting STS activity in vivo followed by DHEAS injections which increase the level of sulfated steroid that cross the blood-brain barrier and then modulate neurotransmitter receptors could modify the attack behavior in mice. COUMATE (10 mg/kg) was administrated p.o. alone or in combination with the neurosteroid DHEAS (0-50 mg/kg) i.p. Animals were thereafter tested for aggression. A single dose of COUMATE significantly inhibited STS activity both in the brain (70.57%) and in the liver (87%) 24 h following administration. Behavioral tests showed that the inhibitor and DHEAS enhanced aggressive behavior when animals were simultaneously subjected to both molecules. These results confirm the correlation between aggressive behavior and STS concentration in mice. In addition, we confirm that the steroid metabolism can modulate the behavior in rodents.

The selective labelling of central 5-HT1A receptor binding sites by [3H]5-methoxy-3-(di-n-propylamino)chroman.

Investigations on the pharmacological properties of a series of chroman derivatives indicated that 5-methoxy-3-(di-n-propylamino)chroman (5-MeO-DPAC) acts in the nM range on 5-HT1A sites but recognizes very poorly other 5-HT sites and D2 sites in rat brain membranes. As expected from these observations, the tritiated derivative [3H]5-MeO-DPAC bound to a single class of specific sites which exhibited the same pharmacological properties as 5-HT1A sites labelled by [3H]8-OH-DPAT in hippocampal and cortical membranes. In contrast to [3H]8-OH-DPAT, [3H]5-MeO-DPAC did not bind to presynaptic striatal sites (possibly associated with 5-HT reuptake in serotoninergic terminals), which indicated that this new chroman derivative was even more selective than the [3H]tetralin ligand for the in vitro labelling of 5-HT1A sites. Comparison of the chemical structures of 5-MeO-DPAC and other 5-HT1A ligands suggests that electronic enrichment due to isosteric O-substitution in the chroman derivative may play an important role in the highly selective recognition of the 5-HT1A receptor by this drug.

Direct high-performance liquid chromatographic separation of the enantiomers of methoxy and hydroxy derivatives of 3,4-dihydro-3-(dipropylamino)-2H-1-benzopyrans with dopaminergic activity.

The direct HPLC resolution of the enantiomers of methoxy and hydroxy derivatives of 3,4-dihydro-3-(dipropylamino)-2H-1-benzopyrans and of unsubstituted amino compounds was achieved using Chiralcel OD and/or Chiralpak AD stationary phases. The position of the substituent (methoxyl or hydroxyl) in the aromatic ring has a strong effect on the enantioselectivity. Circular dichroism spectra of the single enantiomers of one compound were measured.

Production and characterization of polyclonal anti-S 20499 antibodies: influence of the hapten structure on stereospecificity.

Immunoassays were studied as an alternative to HPLC methods for the stereoselective determination of a chiral drug, S 20499, a new anxiolytic compound that is chemically related to buspirone. The production of highly stereospecific polyclonal antibodies was sought following the construction of appropriately optimized hapten-protein conjugates. This process involved the selection of the structure and the length of the spacer arm used to couple S 20499 to the carrier protein as well as deciding on the location of the coupling site with respect to the chiral center. Two haptens were prepared: one a derivative resembling the original structure of S 20499, with the effective addition of a carboxylic acid group, and a second with the effective addition of a butanoic acid moiety that is supposed to favor stereorecognition. Six stereospecific polyclonal antisera were obtained in rabbits with two groups of antibody families defined in terms of specificity. Both approaches gave high levels of stereospecificity (cross-reactivity towards the optical antipode of S 20499 ranged from 4.1% to < 0.1%). Although it did not decrease the mean apparent affinity constant, the longer spacer improved antibody specificity by decreasing cross-reactions towards dealkylated S 20499 derivatives. Hence, the addition of a four carbon atom bridge should be a valuable tool for increasing antibody stereospecificity with no drawbacks in terms of specificity and affinity. It was also shown that long immunization periods appear to have no effect on the stereospecificity of the antibodies obtained.

Design and synthesis of substituted compounds containing the 1, 4-benzodioxin subunit. New potential calcium antagonists.

New compounds possessing 1,4-benzodioxin or its saturated analogous heterocyclic system were synthesized and tested for calcium antagonist activity. Biological differences were seen between the different modifications applied. These compounds have been shown to be representative of a novel series of calcium channel antagonists.