5-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-7-phenyl-2,3,6,7-tetrahydro-1,4-thiazepines as compounds with high affinity at the benzodiazepine binding site on GABA(A) receptors.

A series of thiazepines has been studied as new ligands for the benzodiazepine binding site of the GABAA receptor. Compounds with high affinity and weak selectivity regarding alpha beta3gamma2, alpha2beta3gamma2, alpha3beta3gamma2, and alpha5beta3gamma2 subtypes were found. The pharmacophore is discussed based on experimental and theoretical results. The thiazepine sulfur atom was found to be able to act as hydrogen bond acceptor.

Synthesis of disubstituted 1,4-diazepines with affinity to GABAA-receptor subtypes.

A series of tetrahydro-1 H-1,4-diazepines 4a-c, dihydro-1 H-1,4-diazepine 5 and pyrido diazepines 8 and 10 was prepared. Originated form dehydroacetic acid (DHA) and aromatic aldehydes cinnamoyl compounds 3a-c were obtained and converted with ethylenediamine to give tetrahydro-1H-1,4-diazepines 4a-c. For the synthesis of pyrido[1,2-d][1,4]diazepines 8 and 10 a new snythetic approach is described. Compounds 4b and 5 were investigated concerning their affinity to different benzodiazepine receptor subtypes. The determined IC50 values for 5 are 1.5 microM and 1.1 microM at 10 microM respectively.

Substituted 2-aminothiopen-derivatives: a potential new class of GluR6-antagonists.

In the course of search for new therapeutic agents against epilepsy new inhibitors for the kainate receptor subtypes GluR5 and GluR6 were synthesized. We were able to synthesize new substituted thieno[2,3-d]pyrimidines 3a,b, 4a,b, 5a,b as well as thiophene-3-carboxamides 2a-d and a multitude of substituted 4-methyl-5-phenylthiophene-3-carboxylic acids. All compounds described herein were tested for their antagonistic effect towards the kainate receptor subtypes GluR5 and GluR6. The highest activity was observed for ethyl 2-amino-4-methyl-5-phenylthiophene-3-carboxylate 1c with an IC50=0.75 microM at the GluR6 receptor.

Synthesis of thieno[2,3-d]oxazines and thieno[2,3-d]thiazines as subtype specific kainate receptor antagonists.

For the development of new antiepileptics the kainate receptors GluR6 and GluR5 are important targets. Based on the anticonvulsant effects of chinazolines and thieno[2,3-d]pyrimidines that are known from the literature, thieno[2,3-d][1.3]oxazines were synthesized and studied for their inhibitory properties at GluR6 and GluR5 receptors. The strongest inhibitor activity was observed with 5-methyl-6-phenyl-thieno[2,3-d][1.3]oxazines with C1 or C3-substituents in position 2 (3b-f). The 2-trihalide-methyl-substituted compounds 3c and 3d were the most active inhibitors at the GluR5-receptor (IC50=23.4 micromol, 16 microl). The 2-isopropyl-substituted compound 3f displayed the strongest activity at the GluR6-receptor (IC(50)=8.7 micromol). A number of thieno[2,3-d][1.3]thiazines and thieno[2,3-d] pyrimidines that were synthesized from the thieno[2,3][1.3]oxazines did not show any activity.

[A convenient synthesis of furans using bromacetyl-pyran-2-one]. / Eine neue Furansynthese aus Bromacetylpyran-2-on.

Conversions of 3-bromacetyl-4-hydroxy-6-methyl-2H-pyran-2-ones (3beta-brom-dehydroacetic acids) with amines are highly influenced by the type of amine. In contrast to aniline, where a dehydroacetic acid derivative was obtained, utilization of phenylethylamine in acetone gave a rearrangement-reaction to a basically substituted furan-2-one. In natural products furan-2-ones as butenolides are of particular importance.

[Thieno[2,3-d]pyrimidines as antagonists of the glutamate receptors]. / Thieno[2,3-d]pyrimidine als glutamatantagonisten.

Although the function of the kainate receptors in the brain is still not clear, they are increasingly defined as targets in the development of new classes of anti-epileptics. The thienopyrimidines described in this report were tested for their antagonistic effect at the kainate receptor subtypes GluR5 and GluR6. The highest effectiveness was obtained by a 4-ethoxy-thieno[2,3-d]pyrimidin with an IC50 = 68 microM at the GluR6 receptor.

[Synthesis of substituted 6-phenylpyrazolo[3,4-d]pyrimidines with potential adenosin-A2A antagonistic activity]. / Synthese substituierter 6-Phenylpyrazolo[3,4-d]pyrimidine mit potenziell Adenosin-A2A-antagonistischer Wirkung.

Substituted pyrazolo[3,4-d]pyrimidines were prepared by reaction of methyl- or phenylhydrazine with pyrimidine derivatives containing a methylthio or chlorine substituent as nucleofuge. Using a methylthio-6-imino-1,3-thiazine as starting material instead of a methylthiopyrimidine the conversion with phenylhydrazine could already be achieved under mild conditions thus leading first to the formation of a hydrazinopyrimidine. The affinity of the products against the human adenosine A2A receptor was determined.

3-Amino- and 5-aminopyrazoles with anticonvulsant activity.

New 3-amino- and 5-aminopyrazoles were synthesised. 3-Aminopyrazoles exert a strong anticonvulsant effect, 4-Chlorophenyl-3-(morpholin-4-yl)-1 H-pyrazole 2 distinctively blocks sodium channels and is strongly effective in the Maximal Electroshock Seizure (MES) test.

Synthesis, anticonvulsant activity, and structure-activity relationships of sodium channel blocking 3-aminopyrroles.

Starting from the corresponding acetophenone and glycine derivatives, a series of new 3-aminopyrroles was synthesized in few steps. Using this procedure with hydrazine and hydroxylamine instead of the glycinates provides access to 3-aminopyrazoles and 5-amino 1,2-oxazoles. The various derivatives were tested for anticonvulsant activity in a variety of test models. Several compounds exhibit considerable activity with a remarkable lack of neurotoxicity. 4-(4-Bromophenyl)-3-morpholinopyrrole-2-carboxylic acid methyl ester, 3, proved to be the most active compound. It was protective in the maximal electroshock seizure (MES) test in rats with an oral ED50 of 2.5 mg/kg with no neurotoxicity noted at doses up to 500 mg/kg. Compound 3 blocks sodium channels in a frequency-dependent manner. The essential structural features which could be responsible for an interaction with an active site of the voltage-dependent sodium channel are established within a suggested pharmacophore model.

AWD 140-190: a new anticonvulsant with a very good margin of safety.

The anticonvulsant activity of the novel drug AWD 140-190 (4-(p-bromophenyl)-3-morpholino-1H-pyrrole-2-carboxylic acid methyl ester) was evaluated in animal models of epileptic seizures. AWD 140-190 was active at nontoxic doses after oral and intraperitoneal administration in rats and mice in a range of anticonvulsant tests. The compound was active against electrically-induced seizures (MES, ED50 rat p.o. = 2.47 mg/kg), in a genetic animal model the DBA/2 mouse, and in corneally kindled rats. It was not active against seizures induced chemically by pentylenetetrazole, bicuculline and strychnine. Effective doses in mice following both oral and intraperitoneal administration are similar indicating good oral absorption. During 14 days chronic oral treatment of mice with 10 mg/kg, no development of tolerance was observed. The protective indices (TD50/MES ED50) in rats and mice following oral administration are favorable when compared to phenytoin, carbamazepine and valproate. No motor impairment, evaluated with the rotarod test and by observation in the open field test, was observable following oral administration of doses up to 500 mg/kg. There was no influence on spontaneous motility and learning performance in rats and no interaction with ethanol in mice after administration of doses which are above anticonvulsant effective doses indicating the absence of central side effects. AWD 140-190 thus presents an orally active and safe anticonvulsant agent, which is structurally unrelated to anticonvulsants currently used.

[Synthesis and anticonvulsant activity of 3-carbamoyl-4-aryl-isoquinolin-1(2H)-ones]. / Synthese und antikonvulsive Aktivität von 3-Carbamoyl-4-aryl-isochinolin-1(2H)-onen.

The syntheses of nineteen 3-carbamoyl-4-aryl-isoquinoline-1(2H)-ones are described. The compounds show anticonvulsant activity in maximal electroshock test (i.p. administration). A representative substance is 3-carbamoyl-2-isopropyl-4-(4-chlorophenyl)-isoquinoline-1(2H)-one, ED50 = 2.1 x 10(-4) mol/kg. This agent shows 20% of the activity of phenytoin (ED50 = 0.44 x 10(-4) mol/kg).

[Synthesis and pharmacologic testing of 1-oxo-pyridazine and 1-oxo-phthalazine-2-acetic acid derivatives]. / Synthese und pharmakologische Testung von 1-oxo-pyridazin-bzw. 1-Oxo-phthalazin-2-essigs5aaurederivaten.

The title compounds, starting from variously substituted beta-benzoylpropionic or beta-benzoylbenzoic acids, were prepared by cyclocondensation with alpha-ethylhydrazinoacetate monohydrochloride and subsequent alcaline hydrolysis or aminolysis of the 2-carbethoxymethyl-1,2,5,6-tetrahydro-1-oxo-pyridazines or 1,2-dihydro-1-oxo-phthalazines respectively. The 1-oxo-phthalazines 42 and 34 have a weak anticonvulsive effect. Like a large number of the other synthezized compounds, they show a central sedative component and are relatively nontoxic.