Intracerebroventricular administration of histamine H3 receptor antagonists decreases seizures in rat models of epilepsia.

The effects of histamine H3 antagonists on amygdaloid kindled and maximal electroshock seizures in rats were studied to determine their potential as new antiepileptic drugs. Under pentobarbital anesthesia, rats were fixed to a stereotaxic apparatus and a stainless steel guide cannula for drug administration was implanted into the lateral ventricle. In amygdaloid kindled seizures, electrodes were implanted into the right amygdala and electroencephalogram was recorded bipolarly; stimulation was applied bipolarly every day by a constant current stimulator and continued until a generalized convulsion was obtained. In the maximal electroshock (MES) seizure test, electroconvulsion was induced by stimulating animals through ear-clip electrodes, and the durations of tonic and clonic seizures were measured. Thioperamide, clobenpropit, iodophenpropit, VUF5514, VUF5515 and VUF4929 caused a dose-dependent inhibition of both seizure stage and afterdischarge (AD) duration of amygdaloid kindled seizures. The duration of tonic seizure induced by MES was also inhibited by H3 antagonists, but the duration of clonic seizures were unchanged. Among the H3 antagonists tested, clobenpropit and iodophenpropit were somewhat more potent than the other drugs on amygdaloid kindled seizures and MES seizures, respectively. These results indicate that some H3 antagonists may be useful as antiepileptic drugs, especially for secondary generalized seizures and/or tonic-clonic seizures in humans.

Efficient and beta-stereoselective synthesis of 4(5)-methyl-5(4)-(5-amino-5-deoxy-beta-D-ribofuranosyl)imidazole and related compounds exhibiting antiulcer activity.

The reaction of 2,3,5-tri-O-benzyl-D-ribose with the lithium salt of an imidazole derivative gave an adduct 17RS. Treatment of 17RS with 1.5N HCl in refluxing tetrahydrofuran gave the beta-4(5)-ribofuranosylimidazole 19 (35%) and the ribosylimidazole 18 (51%). The latter was converted into beta-19 in 86% yield by the Mitsunobu cyclization. This synthetic method produced only the desired beta-anomer. Protection of the imidazole nitrogen of 19 with an ethoxycarbonyl group followed by debenzylation gave 21, which was successively derived to the 5'-amino derivative 1 via the 5'-substituted phthalimide 23, followed by hydrazine degradation in excellent yield. Compound 1 was then converted into the 5'-cyanoguanidine 2 in 79% yield. The 5'-amino derivatives 3-9 lacking a methyl group were efficiently synthesized. Among them, the cyanoguanidine 5 and phenylthiourea 8 exhibited antiulcer activities with half the efficacy of cimetidine. The molecular conformation of 5 was determined by X-ray structure analysis.

Meisenheimer rearrangement of azetopyridoindoles. VIII. Synthesis and antiviral activities of 12-carbaeudistomin analogs.

Eudistomins, isolated from the colonial tunicate Eudistoma olivaceum, have been a synthetic target due to their strong antiviral activity against Herpes simplex virus (HSV-1) and activities against certain types of tumors in vivo. In order to examine the structure-activity relationship of eudistomins, 12-carbaeudistomin analogs were synthesized and their activities against influenza A and B virus, HSV-1, HSV-2 and human cytomegalovirus were investigated. Among them, racemic 6-methoxy-12-carbaeudistomin showed similar activity to (-)-debromoeudistomin K, synthesized as a control compound.

Meisenheimer rearrangement of azetopyridoindoles, VI. Synthesis of 12-carbaeudistomin and related compounds.

For structure-activity relationship investigation of eudistomins 1, 12-carbaeudistomin 3, its 1,10-trans isomer 4, and 11,12-didehydro-12-carbaeudistomin 5 have been synthesized. The [2,3]-Meisenheimer rearrangement of the corresponding N-oxide of the 2-vinylazetopyridoindole 12a bearing a benzenesulfonyl group as a protective group of the indole nitrogen atom afforded the oxazepino ester 14, which was easily isomerized to 20a. Compounds 3 and 4 were synthesized from 14 and 20a, respectively, according to the following reaction sequences [hydrogenation of the double bond (Pd-C/H2), desulfonylation (Mg in MeOH), hydrolysis (AlBr3-EtSH), and Curtius rearrangement (a mixed anhydride method using NaN3), followed by debenzylation (Pd-C/H2)]. The Curtius reaction of the carboxylic acid 27 using DPPA gave the carbamate 29, which was subjected to debenzylation (AlBr3-EtSH) followed by desulfonylation (LiAlH4) to afford 5. Evaluation of anti-influenza virus activities of the amino compounds 3, 4, and 5 revealed that 12-carbaeudistomin 3 possesses a specific activity against influenza virus B.