Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors: synthesis and pharmacological properties of 4-(1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)benzanili de derivatives and 4'-(5,6-dihydro-4H-thiazolo[5,4-d][1]benzoaze

Abstract:

:Arginine vasopressin (AVP) has a dual action mainly in the periphery, i.e., vasoconstriction and water reabsorption via V1A and V2 receptors; it may play a role in a number of diseases, including congestive heart failure (CHF), hypertension, renal disease, edema, and hyponatremia. We have attempted to develop a new series of orally active AVP antagonists for both V1A and V2 receptors based on the hypothesis that the blockade of both V1A and V2 receptors might be beneficial to CHF patients. In this report, a series of compounds structurally related to 4'-(1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6- carbonyl)benzanilide and 4'-(5,6-dihydro-4H- thiazolo[5,4-d][1]benzoazepine-6-carbonyl)benzanilide were synthesized and examined for AVP antagonist activity for both V1A and V2 receptors. As a result, it was found that the 4'-(1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbon yl)-2- phenylbenzanilide derivatives showed potent binding affinity for both V1A and V2 receptors. Especially, 4'-(2-methyl-1,4,5,6- tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phe nylbenzanilide monohydrochloride (18, YM087 = conivaptan hydrochloride) exhibited potent binding affinity and AVP antagonist activity, after intravenous administration, for both V1A and V2 receptors. Furthermore, YM087 exhibited the most potent oral activity for the V2 receptor. Details of the synthesis and pharmacological properties of this series are presented.

authors

Matsuhisa A,Taniguchi N,Koshio H,Yatsu T,Tanaka A

doi

10.1248/cpb.48.21

subject

Has Abstract

pub_date

2000-01-01 00:00:00

pages

21-31

issue

1

eissn

0009-2363

issn

1347-5223

journal_volume

48

pub_type

杂志文章
  • Bioactive saponins and glycosides. VII. On the hypoglycemic principles from the root cortex of Aralia elata Seem.: structure related hypoglycemic activity of oleanolic acid oligoglycoside.

    abstract::The hypoglycemic component, elatoside E, was isolated from the root cortex of Aralia elata SEEM. (Araliaceae) together with elatoside F and eight known oleanolic acid glycosides, elatosides A and C, oleanolic acid 3-O-[alpha-L-arabinofuranosyl (1-->4)]-beta-D-glucopyranosiduronic acid, oleanolic acid 3-O-beta-D-glucop...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.44.1923

    authors: Yoshikawa M,Murakami T,Harada E,Murakami N,Yamahara J,Matsuda H

    更新日期:1996-10-01 00:00:00

  • Evaluation of the degree of mixing of combinations of dry syrup, powder, and fine granule products in consideration of particle size distribution using near infrared spectrometry.

    abstract::We used near infrared (NIR) spectroscopy to evaluate the degree of mixing of blended dry syrup (DS) products whose particle sizes are not specified in the Revised 16th Edition of the Japanese Pharmacopoeia, and also evaluated the degree of mixing when powder products or fine granule products were added to DS products....

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.60.624

    authors: Yamamoto Y,Suzuki T,Matsumoto M,Ohtani M,Hayano S,Fukami T,Tomono K

    更新日期:2012-01-01 00:00:00

  • Brominations of steroidal hormone having alpha,beta-unsaturated ketone, 17-O-acetyltestosterone, in the presence of silver triflate.

    abstract::Bromination of 17-O-acetyltestosterone (17beta-acetoxyandrost-4-en-3-one) (1) was performed with 1, 5, and 10 eq of Br2 in AcOH-Et2O at room temperature. In all cases 2alpha,6beta- (2) and 2alpha,6beta-dibromo-17beta-acetoxyandrost-4-en-3-one (3) were obtained, although the yields were dependent upon the conditions us...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.49.23

    authors: Shimizu T,Tobari A,Koyanagi J,Kawase M,Saito S

    更新日期:2001-01-01 00:00:00

  • Pyridonecarboxylic acids as antibacterial agents. VII. Synthesis and structure-activity relationship of amino- and hydroxyl-substituted 7-cycloalkyl and 7-vinyl derivatives of 1-cyclopropyl-6-fluoro-4-quinolone-3- carboxylic acid.

    abstract::Novel C(7)-derivatives of 1-cyclopropyl-6-fluoro-4-quinolone carboxylic acid (3a-o) have been synthesized and evaluated for in vitro antibacterial activity. Compounds 3e (3-aminocyclobutyl), 3g (1-aminocyclopropyl), 3m ((2-aminomethyl)vinyl), and 3o ((1-aminomethyl)vinyl) showed significant inhibitory activity, compar...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.42.2055

    authors: Todo Y,Nitta J,Miyajima M,Fukuoka Y,Ikeda Y,Yamashiro Y,Saikawa I,Narita H

    更新日期:1994-10-01 00:00:00

  • Studies on cardiotonic agents. II. Synthesis of novel phthalazine and 1,2,3-benzotriazine derivatives.

    abstract::A series of phthalazine and 1,2,3-benzotriazine derivatives which have heterocyclylpiperidino groups was synthesized and tested for cardiotonic activity in anesthetized dogs. Several 6,7-dimethoxyphthalazine derivatives showed relatively potent cardiotonic activity comparable to that of amrinone. ...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.38.2179

    authors: Nomoto Y,Obase H,Takai H,Teranishi M,Nakamura J,Kubo K

    更新日期:1990-08-01 00:00:00

  • Application of Ulex europaeus agglutinin I-modified liposomes for oral vaccine: Ex Vivo bioadhesion and in Vivo immunity.

    abstract::The conjugation of Ulex europaeus agglutinin I (UEAI) onto surface of liposomes has been demonstrated to effectively improve the intestinal absorption of antigen, subsequently induced strong mucosal and systemic immune responses. In this context, we prepared bovine serum albumin (BSA)-encapsulating UEAI-modified lipos...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.59.618

    authors: Li K,Zhao X,Xu S,Pang D,Yang C,Chen D

    更新日期:2011-01-01 00:00:00

  • Bilayer Tablet Dissolution Kinetics Based on a Degassing Cyclic Flow UV-Vis Spectroscopy with Chemometrics.

    abstract::Dissolution kinetics of a bilayer direct compress tablet was evaluated by using degassing cyclic flow UV-visible (Vis) spectroscopy with chemometrics. The model bilayer nicotinamide (NA)-pyridoxine hydrochloride (PH) 100.0 mg tablets were prepared via the dual compress method. The fast diffusion layer of the bilayer t...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.c18-00867

    authors: Otsuka Y,Ito A,Takahashi T,Matsumura S,Takeuchi M,Tanaka H

    更新日期:2019-01-01 00:00:00

  • 2″,4″-O-diacetylquercitrin, a novel advanced glycation end-product formation and aldose reductase inhibitor from Melastoma sanguineum.

    abstract::A new flavonoid, 2,″4″-O-diacetylquercitrin (1), along with six known flavonoids (2-7) were isolated from the aerial parts of Melastoma sanguineum. The structure of the new flavonoid was established by extensive spectroscopic studies and chemical evidence. The inhibitory effects of isolated compounds (1-7) on advanced...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.c12-00877

    authors: Lee IS,Kim IS,Lee YM,Lee Y,Kim JH,Kim JS

    更新日期:2013-01-01 00:00:00

  • Utility of 2-hydroxypropyl-beta-cyclodextrin in an intramuscular injectable preparation of nimodipine.

    abstract::Possible utility of hydroxyalkylated beta-cyclodextrin (beta-CyD) derivatives as parenteral drug carriers was investigated, using nimodipine, a dihydropyridine derivative with calcium antagonistic action, as a model drug. The aqueous solubility of nimodipine increased linearly with increase in the concentration of hyd...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.38.176

    authors: Yoshida A,Yamamoto M,Itoh T,Irie T,Hirayama F,Uekama K

    更新日期:1990-01-01 00:00:00

  • The average unwinding angle of DNA duplex produced by the binding of chromomycin A3.

    abstract::The effect of chromomycin A3 binding on the geometry of DNA duplex (plasmid pBR322) has been examined using topoisomerase I relaxation followed by gel electrophoresis. To determine the equilibrium constant of this drug-DNA binding-dissociation reaction in the same concentration range (ca. 10(-5) M) in the same buffer ...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.46.1667

    authors: Utsuno K,Kojima K,Maeda Y,Tsuboi M

    更新日期:1998-11-01 00:00:00

  • Conversion of Ginsenoside Rb1 into Six Types of Highly Bioactive Ginsenoside Rg3 and Its Derivatives by FeCl3 Catalysis.

    abstract::Ginsenoside Rb1 is an important saponin of ginseng(s); however, Rb1, with 3-O- and 20-O-sugar moieties, has low bioavailability. Here, we report the derivatization of ginsenoside Rb1 to completely generate six types of highly bioactive minor ginsenoside Rg3 and its derivatives by FeCl3 catalysis, the reaction conditio...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.c18-00426

    authors: Yu H,Wang Y,Liu C,Yang J,Xu L,Li G,Song J,Jin F

    更新日期:2018-01-01 00:00:00

  • In vitro transport of sodium diclofenac across rat abdominal skin: effect of selection of oleaginous component and the addition of alcohols to the vehicle.

    abstract::The in vitro percutaneous transport of sodium diclofenac from various oil vehicles was examined using rat abdominal skin as a model skin membrane. The overall transport of diclofenac through the skin from the oleaginous vehicles was very poor because of a poor solubility of sodium diclofenac in nonpolar oils. To incre...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.39.154

    authors: Takahashi K,Tamagawa S,Katagi T,Yoshitomi H,Kamada A,Rytting JH,Nishihata T,Mizuno N

    更新日期:1991-01-01 00:00:00

  • N-Methylniphatyne A, a New 3-Alkylpyridine Alkaloid as an Inhibitor of the Cancer Cells Adapted to Nutrient Starvation, from an Indonesian Marine Sponge of Xestospongia sp.

    abstract::In the course of searching for selective growth inhibitors of the cancer cells adapted to nutrient starvation, a new 3-alkylpyridine alkaloid named N-methylniphatyne A (1) was isolated from an Indonesian marine sponge of Xestospongia sp. The chemical structure of 1 was determined on the basis of the spectroscopic anal...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.c16-00118

    authors: Arai M,Kamiya K,Shin D,Matsumoto H,Hisa T,Setiawan A,Kotoku N,Kobayashi M

    更新日期:2016-01-01 00:00:00

  • Detection and identification of loline and its analogues in horse urine.

    abstract::Several kinds of loline-type alkaloids, norloline, loline, N-acetylnorloline, N-acetylloline, N-formylnorloline, N-formylloline and N-methylloline were detected in the urine of race-horses. Furthermore, a new compound of the alkaloids, N-senecioylnorloline, was also found and identified. These compounds were mainly id...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.39.964

    authors: Takeda A,Suzuki E,Kamei K,Nakata H

    更新日期:1991-04-01 00:00:00

  • Saponin and sapogenol. L. On the constituents of the roots of Glycyrrhiza uralensis Fischer from Xinjiang, China. Chemical structures of licorice-saponin L3 and isoliquiritin apioside.

    abstract::From the air-dried roots of Glycyrrhiza uralensis Fischer collected in Xinjiang province, China ("Shinkyo-Kanzo" in Japanese), a new oleanene-type triterpene oligoglycoside named licorice-saponin L3 and a new chalcone oligoglycoside named isoliquiritin apioside were isolated together with glycyrrhizin, 18 alpha-glycyr...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.41.1567

    authors: Kitagawa I,Hori K,Uchida E,Chen WZ,Yoshikawa M,Ren J

    更新日期:1993-09-01 00:00:00

  • Synthetic studies of vitamin D analogs. XXIV. Synthesis of active vitamin D3 analogs substituted at the 2 beta-position and their preventive effects on bone mineral loss in ovariectomized rats.

    abstract::Analogs related to 1 alpha,25-dihydroxy-2 beta-(3-hydroxypropoxy)vitamin D3 (ED-71) (4), oxa-type and carba-type analogs of vitamin D3 bearing substituents at the 2 beta-position of 1 alpha,25-dihydroxyvitamin D3 (1), were synthesized from the alpha-epoxides (6 and 13). Three analogs, ED-71 (4) and two carba-type anal...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.45.1626

    authors: Ono Y,Watanabe H,Shiraishi A,Takeda S,Higuchi Y,Sato K,Tsugawa N,Okano T,Kobayashi T,Kubodera N

    更新日期:1997-10-01 00:00:00

  • Development of a novel granular detergent with an interspersion particle comprising an anionic surfactant and a polymeric polycarboxalate.

    abstract::This paper discusses a process for making a novel granular detergent with an interspersion particle comprising an anionic surfactant and a polymeric polycarboxalate. This process contains three steps to develop the interspersion particles with anionic surfactant and polymeric ploycarboxalate. The first step was to for...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.51.743

    authors: Ebihara F,Watano S

    更新日期:2003-06-01 00:00:00

  • Synthesis and pharmacological activity of 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4- pyrrolidinyl]benzamide (TKS159) and its optical isomers.

    abstract::Of 4-amino-5-chloro-2-methoxy-N-(1-ethyl-2-hydroxymethyl-4- pyrrolidinyl)benzamide, four optical isomers, (2S,4S)-1 (TKS159), (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27, were prepared from optically active 4-amino-1-ethyl-2-hydroxymethylpyrrolidine di-p-toluenesulfonate [(2S,4S)-14, (2S,4R)-17, (2R,4S)-20 and (2R,4R)-23, r...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.47.1650

    authors: Yanagi T,Kitajima A,Anzai K,Kodama K,Mizoguchi J,Fujiwara H,Sakiyama H,Kamoda O,Kamei C

    更新日期:1999-11-01 00:00:00

  • Synthesis and biological activity of 5'-aminobenzoxazinorifamycin derivatives.

    abstract::Benzoxazinorifamycin reacted with various secondary amines to yield various 5'-substituted aminobenzoxazinorifamycin derivatives. The derivatives exhibited potent activities against gram-positive bacteria and mycobacteria. The antimicrobial activities of these compounds against Mycobacterium tuberculosis and Mycobacte...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.40.2707

    authors: Yamane T,Hashizume T,Yamashita K,Hosoe K,Hidaka T,Watanabe K,Kawaharada H,Kudoh S

    更新日期:1992-10-01 00:00:00

  • Finding of primitive polyamine toxins in the venom of a joro spider, Nephila clavata.

    abstract::A series of joro spider toxins, novel polyamines sharing a common moiety of 2,4-dihydroxyphenylacetyl cadaverine, have been identified using various bioassays, such as inhibition of a glutamatergic transmission and insecticidal activity. In this paper, we tried to chemically find still unknown polyamine toxins in the ...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.42.1864

    authors: Chiba T,Akizawa T,Matsukawa M,Pan-Hou H,Yoshioka M

    更新日期:1994-09-01 00:00:00

  • Iodine-catalyzed etherification of morroniside.

    abstract::In this study, we describe a highly selective etherification procedure of unprotected morroniside catalyzed by molecular iodine in acetone. The etherification reaction furnished 7-O-alkyl ether derivatives in reasonable yields within few hours under neutral conditions. Studies of the obtained products on cytotoxicity ...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.57.112

    authors: Sunghwa F,Sakurai H,Saiki I,Koketsu M

    更新日期:2009-01-01 00:00:00

  • Synthetic studies on (+)-biotin, part 15: A chiral squaramide-mediated enantioselective alcoholysis approach toward the total synthesis of (+)-biotin.

    abstract::An efficient stereocontrolled total synthesis of (+)-biotin (1) has been achieved via the intermediacy of Roche's lactone 5 starting from cis-1,3-dibenzyl-2-imidazole-4,5-dicarboxylic acid (2). The bifunctional cinchona alkaloid-derived squaramide-promoted enantioselective alcoholysis was utilizing as a tool for the c...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.59.488

    authors: Chen XX,Xiong F,Fu H,Liu ZQ,Chen FE

    更新日期:2011-01-01 00:00:00

  • Statistical Analysis of the Impact of Molecular Descriptors on Cytotoxicity of Thiourea Derivatives Incorporating 2-Aminothiazole Scaffold.

    abstract::Chemical reactivity descriptors and lipophilicyty (log P) were evaluated via semi-empirical method for the quantum calculation of molecular electronic structure (PM3) in order to clarify the structure-cytotoxic activity relationships of disubstutited thioureas. Analysed compounds were obtained by the linkage of 2-amin...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.c16-00317

    authors: Filipowska A,Filipowski W,Tkacz E,Nowicka G,Struga M

    更新日期:2016-01-01 00:00:00

  • Synthesis, antitumor, antitrypanosomal and antileishmanial activities of benzo[4,5]canthin-6-ones bearing the N'-(Substituted benzylidene)-carbohydrazide and N-Alkylcarboxamide groups at C-2.

    abstract::A series of novel benzo[4,5]canthin-6-ones, bearing the N'-(substituted benzylidene)-carbohydrazide (11a-e) and N-alkylcarboxamide (13a-g) moieties at position-2, were synthesized and screened for their in vitro antitumor activity, against seven human cancer cell lines, and for antitrypanosomal and antileishmanial act...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.c12-00356

    authors: Leite Silva CM,Garcia FP,Rodrigues JH,Nakamura CV,Ueda-Nakamura T,Meyer E,Ruiz AL,Foglio MA,de Carvalho JE,da Costa WF,Sarragiotto MH

    更新日期:2012-01-01 00:00:00

  • Three unusual 22-beta-O-23-hydroxy-(5 alpha)-spirostanol glycosides from the fruits of Solanum torvum.

    abstract::Three novel 22-beta-O-spirostanol oligoglycosides, torvosides J (1), K (2) and L (3) have been isolated from the fruits of Solanum torvum SWARTZ and their chemical structures have been characterized based on the spectroscopic means. They are worth of note as rare 22-beta-O-spirostanol glycosides. ...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.53.1122

    authors: Iida Y,Yanai Y,Ono M,Ikeda T,Nohara T

    更新日期:2005-09-01 00:00:00

  • Glycation and insolubility of human lens protein.

    abstract::To learn whether glycation plays a role in insolubilization or in senile cataractogenesis, the reactivity of lens protein from normal and senile cataractous lenses and individual crystallin prepared from human lens with various sugars [glucose, glucose-1-phosphate (G-1-P), glucose-6-phosphate (G-6-P) and fructose], an...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.40.2787

    authors: Kamei A

    更新日期:1992-10-01 00:00:00

  • Percutaneous absorption of clonazepam in rabbit.

    abstract::The percutaneous (p.c.) absorption of clonazepam (CZP), an antiepileptic drug, was investigated in rabbits. CZP was efficiently absorbed from a gel ointment (0.5% CZP, 1g, 9 cm2) with Azone and therapeutic plasma concentrations were maintained for 27 h. The bioavailability of CZP from the gel ointment was 47.2 +/- 3.1...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.37.442

    authors: Ogiso T,Ito Y,Iwaki M,Yamamoto Y

    更新日期:1989-02-01 00:00:00

  • Benzylidene 2-aminoimidazolones derivatives: synthesis and in vitro evaluation of anti-tumor carcinoma activity.

    abstract::A series of benzylidene 2-aminoimidazolones derivatives were synthesized. Most compounds displayed strong inhibitory activity on the proliferation of human HepG2 cells in vitro. The active compounds were further evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against five human ca...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.c13-00340

    authors: Ling Y,Wang ZQ,Xiao YA,Zhu C,Shen L,Wang XM,Hui Y,Wang XY

    更新日期:2013-01-01 00:00:00

  • Inner-hydrogen tautomerism in some 5,15-unsymmetrically disubstituted and beta-unsubstituted porphyrins.

    abstract::5,15-Unsymmetrically disubstituted and beta-unsubstituted porphyrins such as 5-R, 15-(3,5-dimethoxyphenyl) porphyrins [where R=2-benzyloxy-1-naphthyl (1), 2-(2-naphthylmethoxy)-1-naphthyl (2), anthryl (3), or 2,4,6-triphenylphenyl (4)] and 5-(2-benzyloxy-1-naphthyl), 10,15,20-tri(3,5-dimethoxyphenyl) porphyrin (1') we...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.56.1041

    authors: Tohara A,Sato M

    更新日期:2008-07-01 00:00:00

  • Studies on antiulcer drugs. V. Synthesis and antiulcer activity of aralkylbenzazoles.

    abstract::A series of 2-alkylamino-5- or 6-aralkyl-substituted benzazoles were synthesized and tested for histamine H2-receptor antagonist and anti-stress ulcer activities. These new compounds showed little or no histamine H2-receptor antagonist activity in contrast to imidazo[1,2-a]pyridine analogues (I). On antiulcer assay, h...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章

    doi:10.1248/cpb.40.2062

    authors: Katsura Y,Inoue Y,Tomoi M,Takasugi H

    更新日期:1992-08-01 00:00:00