Satoru Kuroda

Discovery of FR166124, a novel water-soluble pyrazolo-[1,5-a]pyridine adenosine A1 receptor antagonist

Novel 3-(2-cycloalkyl and cycloalkenyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazo lo [1,5-a]-pyridines were synthesized and evaluated for their adenosine A1 receptor binding activities. In this series, FR166124 (3) was found to be the most potent and selective adenosine A1 receptor antagonist, and the double bond of the cyclohexenyl acetic acid group was essential for selectivity of A1 receptor binding. Furthermore, the solubility in water of the sodium salt of FR 166124 was high.

Stereoselective synthesis of (2E,4Z)-dien-1-ols; key intermidiates for synthesis of sex pheromones of silk worm and of grape vine moth

Abstract Two (2 E ,4 Z )-dien-1-ols, synthetic key intermediates for the insect pheromones with a ( E , Z )-diene system, were synthesized stereoselectively by using a combination of zirconium-mediated [2,3]Wittig rearrangement reaction and Peterson reaction as key steps.

A formal synthesis of aplysiatoxin: enantioselective synthesis of kishi's aldehyde

Abstract This paper describes the enantioselective synthesis of key fragments (12, 18, 24, and 35) for the synthesis of aplysiatoxin (1a), a potent cancer promoter, and their convergent assembly to Kishis aldehyde (2). Since 2 has already been transformed into 1a in a short step, its synthesis constitutes a formal total synthesis of 1a Synthesis of fragments of aplysiatoxin (1a) and their convergent assembly to the key intermediate, Kishis aldehyde (2), for the synthesis of 1a are described.

Novel adenosine A1 receptor antagonists. Synthesis and structure-activity relationships of a novel series of 3-(2-cyclohexenyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5 -a]pyridines.

A novel series of 3-(2-cyclohexenyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazol o[1,5-a]pyridines was synthesized and evaluated for in vitro adenosine A1 and A2A receptor binding activities. Most of the cyclohexenyl derivatives (7a-e, 8a-s) were found to be potent adenosine A1 receptor antagonists. In a series of analogues of FR166124 (3a), alcohol 7c, nitrile 7e and amide derivatives (7d, 8c, 8r) were found to be more potent A1 antagonists with higher A2A/A1 selectivity than FR166124. Amongst them, 8r showed considerable water solubility (33.3 mg/mL), but lower than that of the sodium salt of FR166124 (> 200 mg/mL). Additionally, FR166124 had strong diuretic activity by both p.o. and iv administration in rats (minimum effective dose=0.1 and 0.032 mg/kg, respectively).

Synthesis of aplysiatoxin: stereoselective synthesis of key fragments

Abstract Stereoselective synthesis of key fragments for the synthesis of aplysiatoxin has been achieved. All the stereogenic carbons contained in fragments B≈E were elaborated on the basis of [2,3] Wittig rearrangement and titanium-mediated asymmetric epoxidation.

Stereoselectivity in [2,3]wittig rearrangement of isopropyl [(2E)-1 -(ω-benzyloxyalkyl)-2-butenyl]oxyacetate. Preparation of potent building blocks for the synthesis of polyoxo compounds

Abstract The stereochemistry of [2,3]Wittig rearrangement of isopropyl [(2 E )-1-(ω-benzyloxyalkyl)-2-butenyl]oxyacetates was found to depend on the position of benzyloxy group and the metal ion used, and in some suitable combinations, ( syn , E )- or ( syn , Z )-product was obtained with high selectivity.

A formal total synthesis of aplysiatoxin

Abstract A total synthesis of aplysiatoxin was achieved formally by construction of Kishis intermediate 13 which carried all the stereochemistry required for the synthesis of aplysiatoxin, from four fragments described in the preceding communication.

Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems--I. 2-Alkoxymethyl derivatives.

The synthesis and in vitro antibacterial activity of a novel series of 2-alkoxymethyl-4-pyrrolidinylthio-1 beta-methyl carbapenems are described. As a result of these studies, we discovered that FR27743 (19j) containing a novel 2-fluoroethoxymethyl substituent possesses a broad spectrum of antibacterial activity against both Gram-positive and Gram-negative organisms, including Pseudomonas aeruginosa. Furthermore, FR27743 exhibited excellent stability against renal dehydropeptidase-I (DHP-I), good urinary recovery, and superior in vivo activity compared to that for Meropenem against several systemic infections.

Synthesis and antibacterial evaluation of novel 2-[N-Imidoylpyrrolidinyl] carbapenems

The synthesis, antibacterial activity and DHP-susceptibility of a series of novel carbapenems, directly linked with heterocyclic moiety are described. Especially, the compounds linked pyrrolidine-carbapenem exhibited to have a good antibacterial activity against Staphylococcus aureus (MRSA) as well as Pseudomonas aeruginosa to maintain a good stability towards DHP-I.

SYNTHESIS OF THE WATER-SOLUBLE ADENOSINE A1 RECEPTOR ANTAGONIST FR166124 THROUGH A NOVEL SEQUENTIAL HORNER-EMMONS/ISOMERIZATION REACTION

Abstract An efficient synthesis of FR166124 ( 1 ) was achieved through a novel sequential Horner-Emmons -isomerization reaction of cyclohexanone ( 2 ) with tert -butyl diethylphosphonoacetate ( 3 ) as the key process. Extensive studies of the key reaction indicated that temperature, base and conformation of the Horner-Emmons products were important factors in the isomerization reaction, leading to a proposed mechanism for this unusual Horner-Emmons reaction.