Synthesis of Thieno[2,3-d]oxazines and Thieno[2,3-d]thiazines as Subtype Specific Kainate Receptor Antagonists

Abstract

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.

Thieno[2,3‐d]pyrimidines and ‐[1,3]oxazines as glutamate antagonists and investigations on the inhibitory potency toward human leukocyte elastase

“…The synthetic routes to bicyclic thiophenes with the common 5‐methyl‐6‐phenyl substitution pattern are outlined in Scheme . Using known methods, the fused pyrimidine ring was formed in the reaction of the thiophene‐3‐carboxamide 1b [16] with ethyl orthoformate. Subsequent treatment with phosphorous oxychloride afforded the 4‐chlorothienopyrimidine 3 .…”

“…The corresponding replacement by an ethyl amidine substructure in 6b was accomplished when 3 was treated with ethylamine. The reactions of the thiophene‐3‐carboxylic acid 1c [17] with carboxylic anhydrides or carboxylic acid ortho esters provided an access to thieno[2,3‐ d ][1, 3]oxazin‐4‐ones 2 . Oxazinones 2 bear two electrophilic sites, C‐2 and C‐4.…”

“…Treatment of 4 with thionyl chloride furnished compounds 7a , 7b with N‐ethyl lactam structure. The thieno[2,3‐ d ][1, 3]thiazine‐4‐thione 5 , accessible by thionation of the corresponding oxazinone 2b with diphosphorous pentasulfide [17], was reacted with ethylamine to give the thienopyrimidine 8 with N‐ethyl thiolactam structure. It should be noted that 8 was directly produced and a corresponding ring‐open thiophene derivative could not be isolated.…”

“…IR spectra were recorded on a Perkin–Elmer FT‐IR PC 16 instrument. 5‐Methyl‐6‐phenylthieno[2,3‐ d ][1, 3]oxazin‐4‐one ( 2a ) [17], 2,5‐dimethyl‐6‐phenylthieno[2,3‐ d ][1, 3]oxazin‐4‐one ( 2b ) [17], and 4‐chloro‐5‐methyl‐6‐phenylthieno[2,3‐ d ]pyrimidine ( 3 ) [16] were prepared as reported.…”

“…Ethylamine (10 mL of a 70% aqueous solution, 0.126 mol) was added dropwise to compound 2a [17] (1.4 g, 5.7 mmol). The mixture was kept at 0°C until the crystallization was finished.…”