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Enantiomers of four potent nonprostanoid thromboxane A2 (TXA2) receptor antagonists, (+/-)-7-(4-fluorophenyl)-7-(2-hydroxyphenyl)heptanoic acids (1-4), were synthesized stereoselectively by direct ortho-alkylation of phenols under modified Mitsunobu conditions. The reaction of 5 eq of phenols (6a-c) with 1 eq of (S)- or (R)-methyl 7-(4-fluorophenyl)-7-hydroxyheptanoate ((S)- or (R)-7) afforded ortho-alkylated phenol derivatives (6a-c) enantioselectively in 33 to 42% chemical yield and 90 to 93% ee. In these compounds, the (R)-enantiomers (1-4) exhibited potent TXA2 receptor antagonistic activity and the (S)-isomer (3) was much less active. In particular, compound (R)-3 strongly inhibited U-46619-induced human platelet aggregation (IC50 = 48 nM), and also showed a very potent inhibitory effect with a minimum effective dose (MED) of 0.3 mg/kg (p.o.) on U-46619-induced bronchoconstriction in guinea pigs.

A novel series of (3-pyridylmethyl)benzoquinone derivatives was molecular designed and synthesized for the dual purpose of inhibiting thromboxane A2 and leukotriene biosynthesis enzymes and scavenging active oxygen species (AOS). They were evaluated for inhibition of TXA2 synthase, inhibition of 5-lipoxygenase, and for their scavenging activity of AOS using the thiobarbituric acid method. 2,3,5-Trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (24, CV-6504) was the most promising derivative since it showed efficient AOS scavenging activity (inhibition of lipid peroxidation in rat brain homogenates: IC50 = 1.8 x 10(-6) M) as well as potent, specific, and well-balanced inhibitory effects on both enzymes (inhibitory effect on TXA2 synthase in human blood, IC50 = 3.3 x 10(-7) M; inhibitory effect on 5-lipoxygenase in human blood, IC50 = 3.6 x 10(-7) M). In adriamycin-induced proteinuria in a rat model, compound 24 at 10 mg/kg per day (po) suppressed proteinuria by more than 50%. The proteinuria, however, could not be reduced by single administration of an inhibitor specific for thromboxane A2 synthase [(E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (2, CV-4151)] or for 5-lipoxygenase [2-(12-hydroxy-5,10-dodecadiynyl)-3,5,6-trimethyl-1,4-benzoquinone (1, AA-861)]. The proteinuria was also not reduced by administration of an AOS scavenger, 2-O-octadecylascorbic acid (4, CV-3611). Triple function compounds such as compound 24 that specifically inhibit both enzymes as well as scavenge AOS possess a variety of pharmacologically beneficial effects.

ortho-Substituted phenol derivatives with high optical purity have been obtained directly by Mitsunobu reaction between an appropriate phenol and an optically active benzyl alcohol. In this reaction, the chemical yield was well balanced with the optical purity of the ortho-substituted compound when 5 equiv. of phenol was allowed to react with 1 equiv. of alcohol in a solvent such as dichloroethane or toluene. In addition, it was confirmed by an X-ray analysis of the product that stereochemical inversion of the asymmetric centre took place in this reaction, as well as the usual Mitsunobu reaction. This reaction is useful in the preparation of optically active phenol derivatives possessing a diarylmethane moiety.

Enantiomers of four potent nonprostanoid thromboxane A2 (TXA2) receptor antagonists, (+/-)-7-(4-fluorophenyl)-7-(2-hydroxyphenyl)heptanoic acids (1-4), were synthesized stereoselectively by direct ortho-alkylation of phenols under modified Mitsunobu conditions. The reaction of 5 eq of phenols (6a-c) with 1 eq of (S)- or (R)-methyl 7-(4-fluorophenyl)-7-hydroxyheptanoate ((S)- or (R)-7) afforded ortho-alkylated phenol derivatives (6a-c) enantioselectively in 33 to 42% chemical yield and 90 to 93% ee. In these compounds, the (R)-enantiomers (1-4) exhibited potent TXA2 receptor antagonistic activity and the (S)-isomer (3) was much less active. In particular, compound (R)-3 strongly inhibited U-46619-induced human platelet aggregation (IC50 = 48 nM), and also showed a very potent inhibitory effect with a minimum effective dose (MED) of 0.3 mg/kg (p.o.) on U-46619-induced bronchoconstriction in guinea pigs.

We were interested in RCS (rabbit aorta contracting substance) and SRS-A (slow reacting substance of anaphylaxis) and their involvement in human bronchial asthma. When we started our anti-asthmatic drug research in the 1970's. We synthesized a lot of chemical compounds and eventually discovered that AA-861 inhibited the generation of SRS-A from the lung tissue of actively sensitized guinea pigs. AA-861 was found to be a potent 5-lipoxygenase inhibitor. This compound reduced experimental allergic asthma in guinea pigs, but it is easily metabolized in the body. More recently, we found a novel compound, AA-2414 (seratrodast), which is not metabolized in the body. AA-2414 proved to be not a 5-lipoxygenase inhibitor, but a thromboxane A2 (TXA2) receptor antagonist. Seratrodast is the first receptor antagonist that is being developed as an anti-asthmatic drug. Seratrodast inhibits both immediate-, late asthmatic responses in guinea pigs, and also reduces airway hyperresponsiveness in dogs. The anti-asthmatic action of seratrodast in animal models indicates that the drug should be of use in the treatment of human asthmatics. In clinical studies, seratrodast showed a marked effect to improve clinical parameters in bronchial asthma. It is also reported that seratrodast is free from harmful aftereffects. Clinical trials are under way in the US.

6-(10-Hydroxydecyl)-2, 3-dimethoxy-5-methyl-1, 4-benzoquinone (idebenone) has been found to have a membrane-stabilizing activity in studies using lysosomes. Using dimyristoyl L-α-phosphatidylcholine (DMPC) as a substrate, the effects of idebenone and related benzoquinones on phospholipid digestion by phospholipase A2 (PLA2) was investigated. Free myristic acid, released from DMPC upon PLA2 treatment, was anthrylmethylated with 9-anthryldiazomethane (ADAM) and determined by reversed-phase HPLC. Idebenone and a related benzoquinone, 2, 3-dimethoxy-5-methyl-6-(10-morpholinodecyl)-1, 4-benzoquinone hydrochloride (QS-10·Mor), inhibited the hydrolysis of the substrate with PLA2 in a dose-dependent manner. It is suggested that the effect of idebenone on PLA2, in addition to its antioxidant activity against lipid peroxidation, can be attributed to membrane-stabilizing activity.

Leukotrienes C4 (LTC4) and D4 (LTD4), major components of slow-reacting substances of anaphylaxis (SRS-A), caused dose-dependent contractions of rabbit coronary arteries in concentrations of 10−9 to 10−7 M and 10−10 to 10−7 M, respectively. The potency of LTC4 and LTD4, when compared with the concentration that elicits half of the contraction induced by 25 mM KCl, was 17 and 76 times, respectively, greater than that of histamine. In contrast, other blood vessels from rabbits were either unresponsive (renal artery and vein, mesenteric artery and thoracic aorta) or only weakly responsive (pulmonary artery and vein and portal vein) to both leukotrienes even at 10−7 M. The LTD4-induced coronary contraction was inhibited by FPL 55712 (10−7 and 10−6 M), a selective SRS-A inhibitor, in a dose-dependent manner, but not by diphenhydramine (10−7 M), a histamine H1-receptor blocker or by indomethacin (10−5 M), a prostaglandin synthetase inhibitor, suggesting that LTD4 has a direct effect on the coronary arteries. These results indicate that the leukotrienes may act as potent, selective coronary vasoconstrictors and that SRS-A responsive receptors exist in the rabbit coronary artery.

高圧水銀ランプ照射のもとにテストステロンアセテートと12種のオレフィンとの反応を行ない,シクロブタノ[1',2':4,5]アンドロスタン-3-オン誘導体を合成した。本反応では常に4α-cis付加体が得られる。しかし,オレフィンとしてビあるいはアクリロニトリルを用いた場合には通常の付加体(4α-cis体)のほかに4α-trans付加体が生成した。これらの4α-体は定量的に熱または塩基性触媒のもとで容易に4β-cis体に異性化した。表1にtrans体およびcis体の特性を示す分光学的データを記載し,表3にそれらの興味ある知見をまとめた。4α-trans体に1molの臭素を作用させると4α-モノブロモシクロブタノケトステロイドが得られる。一方,4α-cisおよび4β-cis体に同様の反応を行なうと2β-および2α-プロム体がそれぞれ得られる。このように臭素化による方向性が異なることは興味がある。幼若去勢ラットにテストステロンプロピオネートを投与し,その精のう,腹部および背部前立腺の重量の変化を指標として,抗男性ホルモン作用を調べた結果,N-アリルアセトアミドおよびN,N'-ジメチルアリルアミンの付加体は抗男性ホルモン作用を示した。

As successive discoveries were made of thromboxane A2, prostacyclin, and the leukotrienes from 1975 to 1979, the physiological and pathological roles of the arachidonate cascade metabolites were clarified. With these discoveries as a turning point, novel concepts for designing new drugs which specifically control and manipulate the metabolites have rapidly grown and developed.Any new approach to treating and preventing cardio- and cerebro- vascular diseases requires urgent and careful evaluation. Recent research into thromboxane synthetase inhibitors (TXSI) and thromboxane receptor antagonists (TXRA) has focussed attention mainly on platelets and blood vessel walls, and the interaction between the two. Some TXSI and TXRA have been studied in a variety of in vitro systems and animal models, and are now in various stages of clinical evaluation.In the present review, TXSI, TXRA, and the structure-activity relationships are described together with the results of our experiments on this subjects.

Ausgehend von dem aus der Vorstufe (I) dargestellten Alkohol (IIa) werden durch verschiedene Folgereaktionen bzw. deren Wiederholung die Analogen (IIb) und (IIc) dargestellt; die aus (IIa)-(IIc) erhaltlichen Bromderivate (IId)-(IIf) werden in die Ester (IV) und (V) und weiter in die Sauren (VIa)-(VIc) bzw. (VIIa)-(VIIc) ubergefuhrt.