No abstract

A series of 5-(naphthalenylsulfonyl)-2,4-thiazolidinediones were synthesized and evaluated for antihyperglycemic activity in an insulin-resistant, genetically diabetic db/db mouse model of non-insulin-dependent diabetes mellitus (NIDDM). The sulfones could be synthesized by a novel, selective C-5 sulfonylation of dilithio-2,4-thiazolidinedione with appropriate sulfonyl chlorides. Within this series, naphthalene was found to be superior to other groups for eliciting antihyperglycemic activity, including the p-alkoxyphenyl group found in ciglitazone, a prototypical agent for this activity. Attachment of the 5-sulfonyl-2,4-thiazolidinedione moiety to the 2-naphthalene position led to optimum activity. Other linkers between the naphthalene and 2,4-thiazolidinedione rings, such as thio, methylene, oxy, and sulfinyl led to decreased antihyperglycemic activity. The best analogue, 5-(2-naphthalenylsulfonyl)-2,4-thiazolidinedione (AY-31,637) was equipotent to ciglitazone in two animal models of NIDDM.

A series of N-substituted 3-amino-2-cyclohexen-I-ones and 3-amino-5,5-dimethyl-2-cyclohexen-I-ones(1-9) has been prepared. Halogenation of these co~npounds with bromine, NBS, cyanogen bromide, and iodine is described. The tendency of enaminoketones to form salts of the corresponding enol-ketimine form was observed and structures of the salts are supported by their p.m.r. and i.r. properties. The reaction of 3-benzylamino-2-bromo-5,5-dimethyl-2-cyclohexen-l-one with concentrated s u l f~~r i c acid effected debenzylation. Treatment of 3-benzylamino-2-iodo-5,5-dimethyl-2-cyclohexen-I-one with dibenzoyl peroxide gave 8,8a-dihydro-5-iodo-8,8-dimethyl-2,3-diphenyl-4H-I ,4-benzoxazine-6,7-diol.The above secondary enaminoketones 1-9 were shown to react with phenyl isocyanates, phenyl isothiocyanate. and methyl isothiocyanate under fi~sion conditions to yield substituted 2-amino-6-0x0-I-cyclohexene-I-carboxamides and corresponding thiocarboxamides. 2-Benzylaniino-6-oxo-N-phenyl-1-cyclohexene-I-carboxamide and its 5.5-dimethyl analog were found to undergo facile transamination in position 2, when heated with a primary amine. This reaction is of synthetic utility for the preparation of biologically active derivatives with a basically substituted side chain. Addition of 4-niethylaniino-3-pentene-2-one to phenyl isocyanate afforded 2-acetyl-3-methylaminoisocrotonanilide; the spectroscopic properties of this product are discussed.Une skrie d'amino-3 cyclohexen-2 ones-1 et d'an~ino-3 dimethyl-5,5 cyclohexene-2 ones-I, N-substituees a ete preparie. L'halogenation d e ces composts par le bron~e, la NBS, le bromure decyanogtne et l'iode est decrite. La tendance des enaminocttones a former les sels de la forme enol-cetimine correspondante a kte observCe et les structures de ces sels ont etC etablies a partir de leurs propriktts en r.m.n. et i.r. La reaction du benzylamino-3 tromo-2 dimethyl-5,5 cyclohexene-2 one-l avec I'acide sulfurique conc. produit une debenzylation. Le triatement du benzylamino-3 iodo-2 dimethyl-5,5 cyclohexene-2 one-l par le peroxyde dibenzoique conduit au dihydro-8,89 iodo-5 dimethyl-8,8 diphenyl-2,3 4H-benzoxazine-1,4 diol-6,7. On a montre que les enaminocetones 1-9 secondaires ci-dessus reagissent avec les isocyanates de phenyle, I'isothiocyanate de phenyle et I'isothiocyanate de mkthyle, sous des conditions de fusion, pour donner les amino-2 0x0-6 cyclohexene-l carboxamides-l substitukes et les thiocarboxamides correspondantes. On a trouve que la benzylamino-2 0x0-6 N-phenyl-cyclohexene-1 carboxamide-1 et ses analogues dimethyles en 5,5 subissent facilement une transamination en position 2, lorsqu'ils sont chauffes en presence d'une amine primaire. Cette reaction prksente un interit synthetique pour la preparation de derives biologiquement actifs avec unesubstitution basique. L'addition de methylamino-4 pentene-3 one-2 a I'isocyanate de phenyle conduit a I'acetyl-2 methylamino-3 isocrotonanilide; les propriktks spectroscopiques de ce compose sont discutkes.[Traduit par le journal]Can. J. Chem., 52, 55 (1...

A series of alpha-amino-3-(phosphonoalkyl)-2-quinoxalinepropanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H] CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Some analogues also were evaluated in the [3H]-glycine binding assay. Several compounds of the AP-6 type show potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular alpha-amino-7-chloro-3-(phosphonomethyl)-2-quinoxalinepropanoic acid (1) displayed an ED50 of 1.1 mg/kg ip in the NMDA lethality model. Noteworthy is alpha-amino-6,7-dichloro-3-(phosphonomethyl)-2-quinoxalinepropanoic++ + acid (3) with a unique dual activity, displaying in the NMDA receptor binding assay an IC50 of 3.4 nM and in the glycine binding assay an IC50 of 0.61 microM.

In order to investigate new antiulcer agents, spizofurone 1 (AG-629) was fragmented and reassembled to generate 5-phenyl-2,2-dimethyl-3(2H)-furanone (bullatenone, 2). Because of the antiulcer activity of 2,5-phenyl-substituted 2,2-dimethyl-3(2H)-furanones (3-6) were made and shown to have poor activity. Insertion of an ethenyl link between the furanone and phenyl rings gave 5-(2-phenylethenyl)-2,2-dimethyl-3(2H)- furanone (7). This compound had better activity than 2. Compounds 8-41 were synthesized to evaluate the SAR in 5-(2-ethenyl substituted)-3(2H)-furanones. Electron-withdrawing substituents on the aromatic ring (8, 10, 19, and 20) gave 2-3-fold higher activity. Further increases in the activity were found when the phenyl ring was replaced by heterocyclic nuclei. Compounds that contained a thiophene (29), pyridine (24-26), or quinoline ring (32) had the best activity. Replacement of the methyl group on the furanone ring with a phenyl (34) or p-fluorophenyl (40) substituent in the 2-pyridine series gave compounds with activity that ranked with the best obtained in this study. The best compounds from the above SAR studies were evaluated in the ethanol-necrosis model for duration of cytoprotection action. Compounds 19, 24, and 29, which had the best duration of action, were tested with AG-629 in the acidified aspirin and indomethacin-induced lesion models. Only compound 24 had equivalent activity with AG-629 in both models.