Gérard Leclerc

New thiazolo[3,2-a]pyrimidine derivatives, synthesis and structure-activity relationships

Abstract Twenty-six derivatives of 5- and 7-oxo or 5- and 7-aminothiazolo[3,2-a]pyrimidines were prepared and evaluated as positive inotropic, anti-inflammatory and antihypertensive agents both in vitro and in vivo. The structures of the 5- and 7-isomers have been confirmed unambiguously by IR, UV, 1H and 13C NMR and MS. The structure of 1a was confirmed by the synthesis of compound 1 whose structure had been previously established by X-ray analysis. The 5-aminothiazolo-pyrimidine-6-carbonitrile derivatives 5a and 5e exhibited potent inotropic activities. 5e was more potent than the classical reference amrinone. Three compounds 5e, 5i and 5j displayed moderate antihypertensive activities. The 4-chlorophenyl derivative 5d exhibited an anti-inflammatory activity 2-fold that of aspirin. This study has demonstrated that thiazolo[3,2-a]pyrimidine compounds have interesting biological potentialities, particularly as inotropic agents, a field which had never been explored so far for this series.

New series of aryloxypropanolamines with both human β3-adrenoceptor agonistic activity and free radical scavenging properties

A series of 13 novel hybrid molecules designed to possess both free radical scavenging activity and to stimulate the beta(3)-adrenoceptors in order to improve antidiabetic effect and to restore insulin sensitivity was synthesized and evaluated. Compounds were of quinolyl-, isoquinolyl-, pyridoindolyl- or carbazolyloxypropanolamine structure with a terminal amino group of benzopyranolyl-, di-tert-butylphenolyl- or methoxyindolyl-type. Some of the products possessed both the expected activities.

New α, β and y semicarbazone and thiosemicarbazone 1,3-dithiolanes as radioprotectors. Anticonvulsant activity

Summary Ten semicarbazone and nine thiosemicarbazone 1,3-dithiolanes (α, β and γ) were prepared and tested as radioprotector agents. Dithiolane is well known for its radioprotective properties; this compound protects 78% of mice if 500 mg/kg is administered 15 min before a 850 cGy irradiation dose [1]. For the first time, the combination of a semicarbazone or thiosemicarbazone group with a dithiolane moiety has been achieved within a single molecule. We also studied the potential anticonvulsant activities of these compounds, since benzodiazepines have been observed to greatly decrease radioinduced convulsions. Among the tested compounds, the correlation between the anticonvulsant activity and the radioprotective effect was not systematic.

Preparation and pharmacological evaluation of the R- and S-enantiomers of 3-(2'-butylamino)-4H- and 3-(3'-methyl-2'-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide, two tissue selective ATP-sensitive potassium channel openers

The preparation and the pharmacological evaluation of the R- and S-isomers of 3-(2-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (BPDZ 42) and 3-(3-methyl-2-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (BPDZ 44), two potassium channel openers, is described. Their optical purity was estimated by means of capillary electrophoresis (R- and S-BPDZ 42) and chiral HPLC (R- and S-BPDZ 44). The absolute configuration of each isomer of BPDZ 44 was deduced from crystallographic data. Pharmacological assays performed with the R- and S-isomers of BPDZ 44 revealed only slight differences in their activity on pancreatic B-cells but significant differences in their activity on vascular smooth muscle cells: the R-isomer being sixfold more potent than its corresponding S-isomer. The R-isomer of BPDZ 42 was shown to be more potent than its corresponding S-isomer on the endocrine pancreas. S-BPDZ 44 as well as R- and S-BPDZ 42 were found to exhibit tissue selectivity for the pancreatic versus the vascular smooth muscle tissue.

Synthesis and vasodilator effects of 3- and 7-sulfonylurea-1,2,4-benzothiadiazin-1,1-dioxides on rat aorta

A series of substituted-1,2,4-benzothiadiazin-1,1-dioxide derivatives was designed and synthesized as potassium channel modulators. Various sulfonylurea moieties were introduced on positions 3 and 7 of the heterocycle without, or by means of, methylene and phenyl spacers. On rat aortic rings, several compounds displayed vasodilating activities, especially compound 24, which was more active than cromakalim and diazoxide at low doses (0.1 microM) and more active than diazoxide between 1 and 10 microM.

New β- or γ-oximinoether-1,3-dithiolanes as radioprotectors

Abstract Seventeen β- or γ-oximinoether-1,3-dithiolanes were prepared and tested as radioprotector agents. Dithiolanes are well known for their radioprotective properties, and, for the first time, the combination of an oximinoether group and dithiolane moiety has been achieved within a single molecule. Five molecules 2a, 2d, 3a, 3b and 3j have immediate and sustained radioprotective activity.

New N-ethanethiol pyrroles as radioprotectors

Abstract Seventeen N -ethanethiol pyrroles have been prepared and tested as radioprotective agents. This is the first time that pyrrole compounds with radioprotective activity have been reported. The dimethyl pyrrole derivative 3a and its corresponding disulfur 4a exhibited strong long-lasting effects.

Synthesis of 4-N,N-dialkylaminoethyl-2-indolones as potential dopamine agonists†

Summary A set of fourteen 4-{2-[N-propyl-N-alkyl-(or alkylaryl-) amino]ethyl}-2-indolone analogues of dopamine were synthesized in 15 steps and evaluated for their affinities towards the D2 receptor using [3H]sulpiride or [3H]spiperone as radioligands. Six analogues displayed D2 agonist activities comparable (Ki = 450–650 nM) to Ropinirole or SK&F 101468. The functionalized amino side chain introduced in the 4-position can be used to modulate the lipophilicity of the analogues without significantly affecting D2 activity.

Synthesis and biological evaluation of new arylthiophene analogs of DuP 753

Abstract We described synthesis and biological results of analogs of DuP 753 where the central phenyl ring has been replaced by a 2,5-disubstituted thiophene.

One-Pot Synthesis of Thiazolidino [3,2-a] Pyrimidine Derivatives

Abstract Reaction of 2-aminothiazoline with an aromatic aldehyde and an activated methylene group (malonitrile, diethylmalonate or ethylcyanoacetate) gave the title compounds. The structures are unambiguously assigned using spectroscopic data and chemical proofs.