Search

We synthesized diaminobutane derivatives as potent Ca 2+ -permeable AMPA receptor antagonists with non-hypotensive activity. Compound 10c showed selective Ca 2+ -permeable AMPA receptor antagonist activity and neuroprotective effects in transient global ischemia models in gerbils.

Aliphatic and aromatic azido derivatives of semotiadil ( 1 ), a novel calcium antagonist with a 1,4-benzothiazine skeleton, were synthesized for developing photoaffinity probes of L type calcium channels. The azidophenoxy derivative 12 proved to be a potent calcium antagonist and its [ 3 H]-labeled compound 16 would be a useful tool to clarify the binding sites of 1 to the calcium channels.

A series of 2-(biphenylmethyl)glutaric acid amide derivatives were synthesized and evaluated for NEP inhibitory activity. The mode of inhibitor-enzyme interactions of the most potent compound 3a, with a thiazolylacetic acid group at the P2' position, was evaluated by a computer analysis.

A series of glutaric acid amide derivatives were synthesized and tested for NEP inhibitory activity. Compounds 14a, 14b, 16a and 22, with a biphenylmethyl group at P′1 position, showed potent inhibitory activity.

Addition-elimination reactions of lithium enolates 2 of N-acyloxazolidinones with 2-methylene-3-phenoxyalkanoates 3 and 10 proceeded diastereoselectively and regiospecifically to give chiral N-[(E)-4-alkoxycarbonyl-4-pentenoyl]oxazolidinones 4 and 12a, which are useful intermediates for the synthesis of enzyme inhibitors.

The palladium(0)-catalyzed reactions of lithium enolates 1 of N-acyloxazolidinones with 3-acetoxy-2-methylenealkanoates 2, easily prepared via DABCO-catalyzed coupling of corresponding aldehydes with acrylates, proceeded diastereoselectively and regioselectively to give chiral N-[(E)-4-alkoxycarbonyl-4-pentenoyl]oxazolidinones3, useful intermediates of metallopeptidase inhibitors.

Addition-elimination reactions of lithium enolates 2 of N-acyloxazolidinones with 2-methylene-3-phenoxyalkanoates 3 and 10 proceeded diastereoselectively and regiospecifically to give chiral N-[(E)-4-alkoxycarbonyl-4-pentenoyl]oxazolidinones 4 and 12a, which are useful intermediates for the synthesis of enzyme inhibitors.

We synthesized diaminobutane derivatives as potent Ca 2+ -permeable AMPA receptor antagonists with non-hypotensive activity. Compound 10c showed selective Ca 2+ -permeable AMPA receptor antagonist activity and neuroprotective effects in transient global ischemia models in gerbils.

A series of cis-1,2-diaminocyclohexane derivatives were synthesized with the aim of optimizing previously disclosed factor Xa (fXa) inhibitors. The exploration of 5-6 fused rings as alternative S1 moieties resulted in two compounds which demonstrated improved solubility and reduced food effect compared to the clinical candidate, compound A. Herein, we describe the synthesis and structure-activity relationship (SAR), together with the physicochemical properties and pharmacokinetic (PK) profiles of some prospective compounds.

In the early 1990's, we reported on the low-molecular selective fXa inhibitor DX-9065a having two amidino groups. However, it had poor oral bioavailability due to its strong basic amidino groups. To obtain fXa inhibitors with improved oral bioavailability, we investigated various non-amidino fXa inhibitors and finally discovered cis-1,2-diaminocyclohexane derivative 4c to have potent fXa inhibition, promising anticoagulant activity, and good oral bioavailability, compared with amidino compound DX-9065a. In addition, we will discuss the influence of the third substituent on the cyclohexane ring on anti-fXa activity, anticoagulant activity, PK profile, and lipophilicity.

The synthesis of the 3- and 21-glucuronides of allotetrahydrocortisol (allo-THF) and allotetrahydrocortisone (allo-THE) is described. 5 alpha-Dihydrocortisol (5) was prepared by selective hydrogenation of 21-acetoxy-3, 11 beta, 17 alpha-trihydroxy-3,5-pregnadien-20-one 3-ethyl ether (3), followed by acid hydrolysis and saponification. When 5 alpha-dihydrocortisol 21-tetrahydropyranyl ether (6) was treated with potassium tri-sec-butylborohydride in tetrahydrofuran under mild conditions, regioselective and stereoselective reduction at C-3 took place to give allo-THF 21-tetrahydropyranyl either (7). This compound was converted into the 3- and 21-monoacetates of allo-THF and allo-THE, key intermediates. Introduction of the glucuronyl residue at C-3 or C-21 was carried out by means of the Koenigs-Knorr reaction. Prior to saponification yielding the 3-glucuronides (20,23), the alkali-sensitive ketol side chain at C-17 was protected as 20-semicarbazones.

Serine protease factor xa (fXa) inhibitor 1 showed good ex vivo anti-fXa activity upon oral administration in rats. However, it has been revealed that 1 had low metabolic stability against human liver microsomes. To improve the metabolic stability, we attempted to modify the S1 and S4 ligands of 1. These modifications resulted in compound 34b, which exhibited selective anti-fXa activity and excellent anti-coagulation activity.

The synthesis of the 3-glucuronides of 5 alpha-cortol-20 alpha, 5 alpha-cortolone-20 alpha and their 20 beta-epimers is described. The 5 alpha-cortol 20,21-diacetates (12, 17) and 5 alpha-cortolone 20,21-diacetates (14, 19) were the key intermediates. Sodium borohydride reduction of the carbonyl group at C-20 in 5 alpha-tetrahydrocortisol 3-tert-butyldimethylsilyl ether 17,21-acetonide (8) gave the 20 alpha-hydroxy-acetonide (9). Selective removal of the acetonide ring was successful when the 20 alpha-acetoxy-17 alpha,21-acetonide (10) was treated with 50% acetic acid. Subsequent acetylation with acetic anhydride in pyridine, followed by removal of the protecting group at C-3 in the silyl ether-acetate (11) gave the desired 20 alpha-intermediate (12). The 11-ketone (14) was prepared from 11 by oxidation with pyridinium chlorochromate, followed by desilylation. The 20 beta-acetates (17, 19) were synthesized from 21-acetoxy-3 alpha,11 beta,17 alpha-trihydroxy-5 alpha-pregnan-20-one 3-tert-butyldimethylsilyl ether (15). Introduction of the glucuronyl residue at C-3 was carried out by means of the Koenigs-Knorr reaction.

The improved routes to prepare tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylic acid lithium salts (2 and 3) were developed. Route A is consisted of the improved preparation of thiazolopyridine intermediates, and Route B is applicable for a large scale synthesis of tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid derivatives. The methods we developed may serve as facile means for preparing thiazolopyridine and tetrahydrothiazolopyridine derivatives.

An enantioselective synthesis of (+)-brefeldin C has been achieved using Lewis acid mediated cyclization of a chiral epoxy-allylsilane as a key step.

The hydrindanol (2), a C/D-ring synthon of vitamin D3 metabolites, has been synthesized enantioselectively by the use of stereoselective epoxy alcohol-initiated polyalkene cyclisation as a key step.