THIAZOLIDINE COMPOUNDS, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: Thiazolidine and pyrrolidine compounds which have the general formula and salts thereof for preventing or relieving diabetic complications and for reducing blood pressure, the processes for their preparation, and the compositions comprising them and pharmaceutically acceptable excipient(s).

Description: TITLE OF INVENTION THIAZOLIDINE AND PYRROLIDINE COMPOUNDS, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM BACKGROUND OF INVENTION This invention relates to thiazolidine and pyrrolidine compounds of the general formula EMI1.1 wherein QÚ and Qê each is methylene or sulfur, but QÚ and Qê are not sulfur at the same time, RA is Ra or Rb; RB and RC each is Rc; ; EMI1.2 wherein X, Y and Z each is single bond, EMI1.3 EMI2.1 Ra is selected from the group consisting of (i) hydrogen, lower alkyl and lower alkenyl, and (ii) lower alkyl and lower alkenyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, hydroxy, lower alkoxy, halogenolower alkoxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkylox- carbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfcnyl and lower alkylsulfinyl; ; Rb is selected from the group consisting of (a) (i) aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl, and (ii) aralkyl, heteroalkyl, aralkenyl and heteroaralkenvi substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, halogenolower alkyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, mercapto acylmercapto, lower alkylthio, carboxy, lower elkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl, and (iii) carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl and heteroaryloxycarbonyl; ; (b) (i) phenyl and nphthyl, and (ii) phenyl and naphthyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, halogeno-lower alkyl, hydroxy, lower alkoxy, halogenolower alkoxy, aralkyloxy, aryloxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, irercapto, acylmercapt, lower alkylthio, carboy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; ; (c) (i) furyl, thienyl and pyridyl, and (ii) furyl, thienyl and pyridyl substituted by at least oil substituent selected from the group consisting of lower alkyl, lower alkenyl, halogeno-lower alkyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, aralkyloxy, aryloxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylamincsulfonyl and lower alkylsulfinyl; ; RCis selected from the group consisting of (a) (i) hydroxy, lower alkoxy and amino, and (ii) lower alkoxy, and amino substituted by at least one substituent selected from the group consisting of lower alkyl, aralkyl, heteroaralkyl, aralkenyl, heteroaralkenyl, hydroxy, lower alkoxy, aralkyloxy, heteroaralkyloxy, aryloxy, heteroaryloxy, acyloxy, aryl, heteroaryl, substitated aralkyl and substituted aiyl wherein the substituent is lower alkyl, lower alkoxy, halogen or amino; ; (b) (i) aryloxy and heteroaryloxy, and (ii) aryloxy and heteroaryloxy substituted by at least one substituent selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, n-losen and amino, and EMI3.1 Rod is selected from the group consisting of (a) (i) hydrogen, lower alkyl, lower alkenyl, aralkyl, heteroaralkyl, alkanoyl, arylalkanoyl, heteroarylalkanoyl, hydroxy, carboxy, amino, mercapto and sulfo, and (ii) lower alkyl, lower alkenyl, aralkyl, heteroaralkyl, alkanoyl, arylalkanoyl, heteroarylalkanoyl, hydroxy, carboxy, amino, mercapto and sulfo substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, lower alkanoyl, aryl, heteroaryl, acyloxy, aroyl, hydroxy, carboxy, amino, guanidino, 'nercapto, acylamino, acy3mercapto, lower alkoxycarbonyl, sulfo, halogen, nitro, cyano, sulfamoyl, lower alkylaminosulfonyl, lower alkylthio and lower alkylsulfinyl; (b) (i) phenyl and naphthyl, and (ii) phenyl and naphthyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkanoyl, acyloxy, hydroxy, carboxy, amino, halogen, nitro, cyano, cylgmino, mercapto, acylmercapto, halogenolower alkyl, halogeno-lower alkoxy, lower alkylenedioxy, lower alkoxycarbonyl, sulfo, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; ; (c) (i) furyl, thienyl and pyridyl, and (ii) furyl, thienyl and pyridyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkanoyl, ac;loxy, hydroxy, carboxy, amino, halogen, nitro, cyano, acylamino, mercapto, acylmercapto, halogeno-lower alkyl, halogeno-lower alkoxy, lower alkylenedioxy, lower alkoxycarbonyl, sulfo, sulfamoyl, lower alkyl aminosulfonyl and lower alkylsulfinyl; and salts thereof which are useful as agents for therapy or prophylaxis of the diabetic complication because they inhibit strongly aldose reductase, and as antihypertensive agents because they inhibit angiotensin I-converting enzyme. The compounds [I] of this invention can be prepared by following process. (i) A compound of the formula [I] is yielded by the-reaction of a compound of the formula [IIJ EMI5.1 wherein RA and RB may be protected by any suitable groups (e.g., lower alkyl, acyl, aralkyl, aralkyloxy, etc.) when RA and RB include reactive groups (e.g., amino, hydroxy, mercapto, hydroxyamino, etc.), with the reactive derivative of carboxylic acid of the formula [1II] (e.g., acyl halide, acid anhydide, mixed anhydride, active ester, lactone, etc.) by general methods used in peptide syntheses or amide formation reactions HOOC-W-CO-RC [III], wherein W and RC may be protected by any suitable groups (e.g., lower alkyl, acyl, aralkyl, aralkyloxy, etc.) when W and RC include reactive groups (e.g., amino, hydroxy, mercapto, hydroxyamino, etc.), followed by removal of protective groups by well-known methods (e.g., hydrolysis, hydrogenolysis, ammonclysis, alcoholysis, etc.). This procedures c deprotecticn can be applied in the following methods. (ii) A compound of the formula [I] is yielded by the reaction of a compound of the formula [II] with the reactive derivative of carboxylic acid of [IV] (e.g., above-mentioned) HOOC-W1-L [IV], wherein W1 is EMI6.1 and may be protected such as (i) above, L is a leaving group (e.g., halogen, alkylsulfonyl, arylsulfonyl, etc.), by the same methods as described in (i) above to produce a compound of the formula [V] EMI6.2 and then reation of a compound of the formula [V] with a compound of the formula [VI] (H) X-Wê-Y-W -Z-W4-CO-RC [VI], wherein W2is EMI6.3 W4 is EMI6.4 and Wê, W , W4, X, Y, Z and RC may be protected such as (i) above, in the presence of p:oper alkaline and/or organic bases, if necessary, by known methods. (iii) A. compound of the formula [I] is yielded by the reaction of a compound of the formula [II] with the reactive derivative of carboxylic acid of the formula [VII] (e.g:, metioned in (i) above) HOOC-WÚ-X-Wê-L [VII] and then with a compound of the formula (VIII] Y-W -Z-W4-CO-RC [VIII] by the same method as (ii) above. (iv) A compound of the formula [I] is yielded by the reaction of a compound of the formula [II] with the reactive derivative of carboxylic acid of the formula [IX] (e.g., mentioned in (i) above) HOOc-WÚ-X-Wê-Y-W -L [IX], and then with a compound of the formula LX] (H)Z-W4-CO-RC [X] by the same method as (ii) above. (v) A compound of the formula [I] is yielded by the reaction of a compound of the formula [II] with the reactive derivative of carboxylic acid [XI] (e.g., acyl halide, acid anhydride, mixed anhydride, active ester, lactone, thiolactone, etc.) HOOC-W1-X(H) [wI], and then with a compound of the formula [XII] L-Wê-Y-W -Z-W4-CO-RC [XII] by the same method as (ii) above. (vi) A compound of the formula [I] is yielded by the reaction of a compound of the formula [II] with the reactive derivative of carboxylic acid of the formula [XIII] (e.g., mentioned in (v) above) HOOC-WÚ-X-Wê-Y(H) [XIII] and then with a ccflpound of the formula [XIV] L-W -Z-W4-CO-RC [XIV] by the same method as (ii) above. (vii) A compound of the formula [I] is yielded by the reaction of a compound of the formula [II] with the reactive derivative of carboxylic acid of the formula '[XV]. (e.g., mentioned in (v) above) HOOC-W1-X-W2-Y-W3-Z(H) lXV], and then with a compound of the formula [XVj L-W4-CO-RC [XVI] by the same method as (ii) above (viii) A compound of the formula [I] is also yielded by converting a compound of the formula [I] prepared by any method above-metioned by well-known methods (e.g., oxidation, formation of oxime, hydrazone and semicarbazone, addition to double bond, etc.) The compounds [I] of this invention are effective on preventing or relieving diabetic complications. In diabetic patients, high levels of hexoses (e.g., glucose, galactose. etc.) in blood lead to the accumulation of sugar alcohols (e.g., sorbitcl, galactitol, etc.) in tissues. It is known that this accumulation causes the swelling of cells to induce ccmplications of diabetic cataract, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, etc. [R. Quan-Ma et al., Biochom. Diophys. Res. Comm., 22, 492 (1961)]. or example, R. Gitzelman et al. have presented that cataract is caused by the accmulaion of sugar alcohols [Exptl. Eye. Res., 6, 1 (1967)]. A report of Kinoshita et al. has demonstrated that aldose reductase which reduced aldose to the corresponding sugar alcohols was involved in the initiation of these diabetic complications and that effective inhibitors of alose reductase were useful [Jpn. J. Ophthalmol., 20, 339 (1976)]. On the basis of the above information, aldose reductase inhibitIon of the compounds [I] of this invention was tested. The results of the examinations demonstrated that these compounds have potent inhibitory activities on aldose reductase, and therefore they are useful as drugs for therapy or prophylaxis of the diabetic complications. On the other hand, it has been known that a kind of the derivatives of thiazolidine- or pyriolidinecarborylic acid have potent inhibitory activity to angiotensin I-converting enzyme, DUt thiazolidine and pyrrolidine compounds o this Invention are novel compounds, and have more potent inhibitory activities to angiotensin I-converting enzyme. Furthermore, the compounds of this invention are prepared by convenient methods, and are superior to the stability. Thus, the compounds of this invention are useful as therapeutic or prophylactic agents and antihypertensive agents. The compound of formula [I] can form the conventional salts to be generally ustd as medicine such as sodium salt, potassium salt, calcium salt, magnesium salt, alminum salt, ammonium salt, diethylamine salt, triethanolamine, etc. The compounds of formula [I] have the stereoisomers which are within the lin.lt of this invention, because they have one or more asymmetric carbon atoms. Typical examples are shown below, although this invention is not limited to these examples. EXAMPLE 1 (4R)-3-(7-Carboxyheptanoyl)-2-(2-hydroxyphenyl)-4thiazolidinecarboxylic acid (compound 20) (4R)-2-(2-Hydroxyphenyl)-4-thiazolidinecarboxylic acid (6.8g,) in N sodium hydroxide (30ml) and octanedioly dichloride (6.3g,) were added dropwise to lM potzssium carbonate (60ml) with stirring under ice-cooling. After the addition, the reaction mixture was stirred for 1 hour at the sane temperature and for additional 1 hour at room temperature. The solution was acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrcus magnesium sulfate, and evaporated in vacuo. The residual oil was purified by silica gel column chrcmatography to give 7.0g (61%) of the titled compound: mp 1'5-157 C (dec.) (ethyl acetate); [&alpha;]27D 27 +134.1 (c=0.5, methanol). IR (nujol, cm1): 3220 (OH), 1710 (COOH) , 1620 (CON) , 1600 (aromatic). 1415, 1235, 1172, 950, 760, NMR (DMSO-d6,@): 0,53-1,73 (8H, m, EMI12.1 1,7702,57 (4H, m EMI12.2 3,03 (1H, AB q (A part), d, J=11.5, 8,5Hz, C+1-HA), 3,37 (1H, ABq (B part), d, J=11.5 6.5Hz, C5-HB), 4.60 (1H, dd, J=8.5, 6.5Hz, C4-H), 6.28 (1H, s, C2-H), 6.45-8.07 (4H, m, arom. H), 9.77 (1H, s, -COOH). TLC: Rf value 0.52. *1 The numbers represent the positions on thiazolidine or pyrrolidinc ring. The same shall be applied hereinafter. *2 Two spots were observed on the TLC (ethyl acetate chloroform-acetic acid (10:5:3)), and two products could be separated by silica gel column chromatography. From NMR spectra, the upper and lower spots were identified as the titled compound and (4R,4R')-3,3'- (oetanedioyl)bis[2-(2-hydroxyphenyl)--t-thiazolidine- carboxylic acid] (compound 40), respectively. *3 Silica gel, ethyl acetate-chloroform-acetic acid (10:5:3) The compounds shown in Table I and III were prepared by the same procedure as described above. The following compounds are also prepared by the same procedure as EXAMPLE 1. (4R)-3-carboxyacetyl-4-thiazolidinecarboxylic acid (4R) -3- (3-carboxypropanoyl) -2-phenyl-4-thiazolidine- carboxylic acid (4R)-3-[3-(2-carboxyethylsulfinyl)propanoyl]-2-(2 hydroxyphenyl) -4-thiazolidinecarboxylic acid (4R)-3-[[[2-(carboxymethyloxy)ethyl]oxylacetyl]-2-(2 hydroxyphenyl)-4-thiazolidinecarboxylic acid (4R) -3- (4-carboxybutanoyl) -2- (3-hydroxyphenyl) -4- thiazolidinecarboxylic acid (4R)-3-(5-carboxypentaoyl)-2-(4-methyulphenyl)-4 thiazolidinecarbowylic acid (4R)-3-(6-carboxyhexanoyl)-2-(4-chlorophenyl)-4thiazolidinecarboxylic acid (4R)-3-(7-carboxyheptanoyl)-2-(4-methoxyphenyl)-4thiazolidinecarboxylic acid (4R)-3-(13-carboxytridecanoyl)-2-(2-nitrophenyl)-4thiazolidinecarboxylic acid (4R)-3-(7-carboxyheptanoyl)-2-(3-nitrohphenyl)-4thiazolidinecarboxylic acid (4R)-3-[3-(2-carbosythylthio)propanoyl]-2-(@-nitro- phenyl)-4-thirzolidinecarboxylic acid (4R)-3-[[[2-(carboxymethyloxy)ethyl]oxylacetyl]-2 (3-nitrophenyl)-4-thiazolidinecarboxylic acid (4R)-3-(6-carboxyhexanoyl)-2-(4-nitrophenyl)-4- thiazolidinecarboxylic acid (4R)-3-(9-carboxynonanoyl)-2-(4-nitrophenyl)-4 thiazolidinecarboxylic acid (4R)-3-(11-carboxyundecanoyl)-2-(4-nitrophenyl)-4- thizolidinecarboxylic acid (4R)-3-[4-(3-carboxypropyloxy)butanoyl]-2-(4-nitrophenyl)4-thiazolidinecarboxylic acid (4R)-3-[3-(2-carboxyethylsulfonyl)propanoyl]-2-(4-nitro phenyl) -4-thiazolidinecarboxylic dcid (4R)-3-(9-carboxynonanoyl)-2-(5-chloro-2-hydrOxyphenyl)- 4-ttliazolidinecarboxylic cid (4R)-3-(11-carboxyundecancyl)-2-(3,4,5-trimethOxyphengl)- 4-thiazolidinecarboxylic acid (4R)-3-(l-carboxy.ridecanoyl)-2-(2-acetoxipheryl)-4- thiazolidinecarboxylic acid (4R) -3- (6-carboxyhexanoyl) -2- (2-furyl) -4-thiazolidine carboxylic acid (4R)-3-(7-carboxyheptanoyl)-2-(2-thienyl)-4-thiazolidine carboxylic acid (4R)-3-(8-carboxyoctanoyl)-2-(3-pyridyl)-4-thiazolidine carboxylic acid (4R)-3-(9-carDoxynonanoyl)-2-(1-naphthyl)-4-thiazolidine- carboxylic acid (4R)-3-(5-carboxypentanoyl)-2-(2-hydroxy-4-sulfamoyl- phenyl)-4-thiazolidinecarboxylic acid (4R)-3-(6-carboxyhexanoyl)-2-(3-cyanophenyl)-4- thiazolidinecarboxylic acid (4R)-3-(7-carboxyheptanoyl)-2-(3-difluormethoxyphenyl) 4-thiazolidinecarbosylic acid (4R) -3- (8-carboxyoctanoyl) -2- (4-carboxyphenyl) -4- thiazolidinecarboxylic acid (4R)-3-(9-carboxynonanoyi)-2-(3-methylsulfinylphenyl)-4 thiazolidinecarboxylic acid EXAMPLE 2 (4R,4'R)-3,3'-(Octanedioyl)bis[2-(2-hydroxyphenyl)-4thiazolidinecarboxylic acid (compound 40) To a stirred solution of (4R)-2-(2-hydroxyphenyl)- 4-thiazolidinecarboxylic acid (6.8g) in 1 potassium carbonate (45ml), octanedioyl dichioride (3.2g) was added dropwise under ice-cooling. After the addition, the reaction mixture was stirred for 1 hour at the same tempera Lure and for additional 1 hour at room temperature. The solution was acidified with dilute hydrochloric acid, extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residual oil was purified by silica gel column chromatography to give 7.6g (86%) of the titled compound: mp 93-97 C (dec.) [&alpha;]27D + 123.6 (c=0,5, methanol). IR (nujol, cm-1): 1720 (COOH), 1620 (CON), 1600 (aromatic) , 1230, 1090, 855, 765. MNR (CD30D) 6: 0.7-1.7 (8H, m, EMI17.1 1.8-2.4 (4H, m, EMI17.2 3.25 (4H, d, J=7.5Hz , C5-H), 4.81 (2H, t, J-7, 5H2, C4-H), 6.35 (2H, s, C2-H) , 6,7-8.0 (8H, m, * arom. H). TLC: Rf value 0.34. * Silica gel, ethyl acetate-chloroform-acetic acid (10:5:3). The compounds shown in Table II and III were prepared by the same procedure as described above. EXAMPLE 3 (4R,4'R)-3,3'-(heptanedioyl)bis[2-(3-cyansphenyl)-4- thiazolidinecarbosylic acid] (compound 36) To a stirred solution of [4R]-2-(3-cyanophenyl)-4- thiazolidinecarboxylic acid (4.7g) in lM sodium carbonate (30ml), heptanedioly dichloride (2.lg) was added dropwise under ice-cooling. The reaction mixture was stirred for 30 minutes at the sam tomperature, and filtered to give the precipitates. The precipitates were dissolved in hot water (100ml), and acidified with concentrated hydrochloric acid. The separated crystals were collected by filtration to give 3.5g (59%) of the titled compound: mp 105-112 C; [&alpha;]25D +115.0 (c=1.0, methanol). IR (nujol, cm-1): 2270 (CN), 1735 (COOH) 1640 (CON), 1610 (arcDatic), 1195, 790 (aromatic) . NMR (DMSO-d6) 6: 0.69-1.66 (6H, r EMI18.1 1.70-2.50 (4H, m, EMI18.2 2.85-3.66 (4H, m, 4.69 (1H, dd, J=8.2, 6.0Hz, C4-H), 5.13(1H, m C4-H), 6.16 (1H, s, C2-H), 6.43 (1H, s, C2-H), 7.3-8.3 (8H, m, arom. H). TLC: Rf value 0.33. * Silica gel, ethyl acetate-chloroform-acetic acid (10:5:3). The compounds shown in Table II were prepared by the same procedure as described above. The following compounds are also prepred by the same procedure as EXAMPLE 2 or 3. (4R,4'R)-3,3'-(propanedioyl)bis(4-thiazolidinecarboxylie acid) (4R,4'R)-3,3'-(butanedioyl)bisf2-phenyl)-4-thiazolidine- carboxylic acid) (4R,4'R)-3,3'-(3,3'-sulfinyldipropanoyl)bis(2-(2-hydroxy phenyl)-4-thiazolidinecarboxylic acid] (4R, 4'R)-3,3'-[(3thylenedioxy)diacetyl]bis[2-(2-hydroxy phenyl)-4-thiazolidinecarboxylic acid] (4R,4'R)-3,3'-[(3thylenedithio)diacetyl]bis[2-(2-hydroxy phenyl)-4-thiazolidinecarboxylic acid] (4R,4'R)-3,3'-(pentanedioyl)bis[2-(3-hydroxyphenyl)4-thiazolidinecarboxylic acid] (4R,4lR)-3t3l-hexanedioyl)bis[2-(4-methylphenyl)-4 thiazolidinecarboxylic acid] (4R,4'R)-3,3'-(heptanedioyl)bis[2-(4-chlorophenyl)-4thiazolidinecarboxylic acid] (4R,4'R)-3,3'-(octanedioyl)bis[2-(4-methoxyphenyl)-4- thiazolidinecarboxylic acid] <RTI ID=19.3> (4R,a'R)-3,3'-(etradecanedioyl)bis[2-(?-nitrophenyl)-4- thiazolidinecarboxylic acid] (4R,4'R)-3,3'-(3,3'-thiodipropanoyl)bis[ 4-thiazolidinecarboyxlic acid] (4R,4'R)-3,3'-[(ethylenedioxy)diacetyl]bis[2-(3-nitrophenyl)- 4-thiazolidinecarboxylic acid] (4R,4'R)-3,3'-(heptanedioyl)bis[2-(4-nitrophenyl)-4- thiazolidinecarboxylic acid] (4R,4'R)-3,3'-(decanedioyl)bis[2-(4-nitrophenyl)-4thiazolidinecarboxylic acid] (4R,4'R)-3,3'-(dozecanedioyl)bis[2-(4-nitrophenyl)-4- thiazolidinecarboxylic acid] (4R,4'R)-3,3'-(4,4'-oxydibutanoyl)bis[2-(4-nitrophenyl)4-thiazolidinecarboxylic acid] (4R,4'R)-3,3'-(3,3'-sulfonyldipropanoyl)bis[2-(4-nitrophenyl)-4-thiazolidinecarboxylic acid] (4R,4'R)-3,3'-(decanedioyl)bis[2-95-chloro-2-hydroxyphenyl) 4-thíazolidinecarboxylic acid] (4R,4'R)-3,3'-(dodecanedioyl)bis[2-(3,4,5-trimethoxy phenyl) -4-thiazolidinecarboxylic acids (4R,4'R)-3,3'-(tetradecanedioly)bis[2-(2-acetoxyphenyl) 4-thiazolidinecarboxylic acid] (4R,4'R)-3,3'-(heptanedioyl)bis[2-(2-furyl)-4-thiazolidine carboxylic acid] (4R,4'R)-3,3'-(octanedioyl)bis[2-(2-thienyl)-4-thiazolidine carboxylic acid] (4R,4'R)-3,3'-(nonanedioyl)bis[2-(3-pyridyl)-4-thiazolidine carboxylic acid] (4R,4'R)-3,3'-(decanedioyl)bis[2-(1-naphtyl)-4-thiazolidine carboxylic acid] (4R,4'R)-3,3'-(hexanedioyl)bis[2-(2-hydroxy-6-sulfamoyl- phenyl) -4-thiazolidinecarboxylic acid] (4R,4'R)-3,3'-(octanedioyl)bis í 2-(3-difluoromethoxyphenyl)- 4-thiazolidinecarboxylic acid] (4R,4'R)-3,3'-(nonanedioyl)bis[2-(4-carboxyphenyl)-4 thiazolidinecarboxylic acid] <RTI ID=20.4> (4R,4'R)-3,3'-(decanedioyl)bis[2-(3-methylsulfinyl- phenyl)-4-thiazolidinecarboxylic acid] EXAMPLE 4 (4R,4'R)-3,3'-(Heptanedioyl)bis[2-(3-nitrophenyl)-4thiazolidinecarboxylic acid] (compound 35) To a stirred solution of (4R)-2-(3-nitrophenyl)4-thiazolidinecarboxylic acid (5.lg)inlM sodium carbonate (40ml), heptanedioyl dichloride (2.lg) was added dropwise unbar ice-coolin. The reaction mixture was stirred for 1 hour at the same temperature, and the separated crystals were filtered to give 417g (69%) of the titled compound as disodium salt: 25 mp lll-1130C (dec.) (water); [a] D +88.20 (c=0.5, methanol). IR (nujol, cm ): 1635 (CON), 1585 (COO ), 1520 and 1355 * (NO2) , 1095, 730. TLC: Rf value 0.28. * Silica gel, ethyl acetate-chloroform-acetic acid (10:5:3) EXAMPLE 5 (4R)-3-(3-Carboxypropanoyl)-2-(2-hydroxyphenyl)-4thiazolidinecarboxylic acid (compound 6) To a stirred solution of (4R)-2-(2-hydroxyphenyl)4-thiazolidinecarbcxylic acid (4.5g) and triethylemine (4.0g) in acetone (100ml). succinic anhydride (2.0g) was added at room temperature, and stirred for 3 hours at the same temperature. The reaction mixture was concentrated in vacuo, and acidified with dilute hydrochloric acid. The separated oil was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated in vacuc to give 4.9g (758) of the titled compound: mp 190-i9i C (dec.) (ethyl acetate methanol): [&alpha;]27D +181.6 (c=1.0, methanol). IR (aujol. cm-1): 3210 (OH), 1720 (COOH), 1618 (CON), 1602 (aromatic), 1245, 1173, 940, 763. NMR (DMSO-d6,6): 2.0-2.7 (4H, m, -CH2CH2-), 3.03 (1H, ABq (A part), d, J=11.0, 10.0Hz, C5-HA), 3.36 (1H, ABq (B part), d, J=11.0, 7.0Hz, C5-HB), 4.61 and 5.07 (1H, dd, J=10.0, 7.0Hz and m, C4 -H), 6.36 (1H, s, C2-H), * 6.5-8.0 (4H, arom. H). TLC: Rf value 0.35. * Silica gel, ethyl acetate-chloroform-acetic acid (10:5:3). The compounds shown in Table I and III were prepared by the same procedure as described above. The following compounds are also prepared by the same procedure as EXAMPLE 5. (4R)-3-\4-carboxy-4-oxobutanoyl)-2-(2-hydroxyphenyl)-4- thiazolidinecarboxylic acid (4R)-3-(6-carboxy-3,5-dioxohexanoyl)-2-(2-hydroxyphenyl)4-thiazolidinecarboxylic acid (4R)-3-[4-carboxy-3-(methoxyimino)butanoyl]-2-(2-hydroxy Whenyl)-4-thiazolidinecarboxylic acid. EXAMPLE 6 (4R)-3-[3-(Methoxycarbonyl)-2-methylpropanoyl]-2-(2 hydroxyphenyl) -4-thiazolidinecarboxylic acid (compound 4) To a stirred solution of (4R)-2-(2-hydroxyphenyl)4-thiazolidinecarboxylic acid (11.3g) in 1M sodium carbonate (80ml), dl-3-methoxycarbonyl-2-methylpropanoyl chloride (8.2g) was added dropwise under ice-cooling. After the addition, the reaction mixture was stirred for 1.5 hours at the same temperature. After the filtration of solution, the filtrate was acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium, sulfate, and evaporated in vacuo. The residual oil was purified by si].ica gel column chromatography to give 7.8g (44%) of the titled compound: [&alpha;]25D + 161.6 (c=1.0, methanol). IR (KBr, cm-1): 3380 (OH), 1723 (COOH, COOCH3), 1624 (CON), 1235, 12C0, 1174, 764. The compounds shown in Table I and II were prepared by the same procedure as described above. EXAMPLE 7 (4R) -3- (3-Carboxy-2-methylpropanoyl) -2-(2-hydroxytenyl) - 4-thiazolidinecarboxylic acid (compound 5) (4R)-3-[2-(Methoxycarbonyl)-2-methyllpropanoyl]-2 (2-hydroxyphenyl) -4-thiazolidinecarboxylic acid (compound 4) (7.lg) was dissolved in 2N sodium hydroxide (40ml) and stirred for 1 hour at room temperature. The resulting solution was acidified with dilute hydrochloric acid and the separated crystals were filtered to give 5.19 (75 ) of thr titled compound: Ip.p 163-161cC (dec.) (ethyl acetate); [&alpha;]25D +174.1 (c=1.0, methanol). IR (nujol, cm-1): 3330 (CH), 1730 and 1710 (COOH), 1629 (CON), 1280, 1234, 856, 771. The compounds shown in Table I and 1I were prepared by the same procedure as described above. Th following compounds are aloo prepared by the same procedure as EXAMPLE 6 and 7. (4R)-3-[4-(carboxymethyl)benzoyl]-2-(2-hydroxyphenyl) 4-thiazolidinen-2rboxylic acid (4R)-3-[(4-carboxyphenyl)acetyl]-2-phenyl-4-thiazolidinecarboxylic acid (4R) -3- (4-carboxy-3-butenoyl) -2- (-2-hydroxyphenyl) -4- thiazolidinecarboxylic acid (4R)-3-(4-carboxy-2-butenoyl)-2-(2-hydroxyphenyl)-4- thiazolidinecarboxylic acid (4R)-3-(4-carboxy-3-butynoyl)-2-(2-hydroxyphenyl)-4thiazolidinecarboxylic ac EXAMPLE 8 (4R)-3-[3-(N-dydroxycarbamoyl)propanoyl]-2-(2-hydroxy- phenyl)-4-thiazolidinecarboxylic acid ethyl ester (compound 10a) To a stirred solution of (4R)-3-(3-carboxypropanoyl)2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid ethyl ester (compound 8a) (1.06g) and N-methylmorpholine (0.33ml) in 20ml of anhydrous tetrahydrofuran, isobutyl chloroformate (0.39ml) was added dropwise at -150C, and stirred for additional 2 hours at this temperature. To this solution, the methanol solution of hydroxylamine (0.3g) was added dropwise at -500C. The reaction mixture was stirred for 1 hour at room temperature, acidified with N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual oil was purified by silica gel column chlromatography to give 0.7g (63%) of the titled compound. IR -1 (KBr, cm ) 3220, 1727, 1625, 1595, 1200, 1092, 753. NMR (acetone-d6, 8): 1.24 (3H, t, J=7.5Hz, SO2CH2CH3), 2.17-3.07 (4H, m, EMI25.1 3.30 (lH, ABq (A part), d, J=10.0, 2.0Hz. C5-HA), 3.47 (1H, AB@ (B part), d, J=10.0, 7.0Hz, C5HB)l 4.i4 (2H, q, J=7.5Hz, CO2CH2), 5.18 (1H, dd, J=2.0, 7.0Hz, C4-H) , 6.40 (1H, S, C2-H), 6.88-7.27 (4H, m, arom. H), 8.60 (2K, br. s, NHOH), 9.77 (1H, br. s, OH) The compounds shown in Table I were prepared by the same procedure as described above. EXAMPLE 9 (4R,4'R)-3,3'-(Nonanedioyl)bis(2-(3-nitrophenyl)-4 thiazolidinecarboxylic acid methyl ester] (compound 46) To a stirred solution of (4R,4'R)-3,3'-(nonanedioyl)bis- [2-(3-nitrophenyl)-4-thiazolidinecarboxylic acid] (compound 47) (3.3g) in ethyl acetate (50ml), 2% etcher solution of diazomethane was added dropwise until the yellow color of diazomethane was not disappeared, and stirred continuously for 30 minutes. The reaction mixture was concentrated in vacuo to give 3.3g (96%) of the titled compound: mp 61-63 C (benzene); [&alpha;]23D+79.4 (c=1.0, methanol) . IR (KBr, cm : 1740, 166d, 1530, 1350, 1198, 725. EXAMPLE 10 (4R)-3-[(2-Carboxymethylthio-3-phenyl)propanoyl]-4thiazolidinecarboxylic acid (compound 75a and 75b) (4R)-3-[(2-Merc¯pto-3-phenyl)propanoyl]-4-thizolidine- carboxylic acid (l.Og), potassium carbonate (0.7g;, chloroacetic acid (0.2g) and potassium iodide (0.05g) were dissolved in water (5ml), and stirred for 6 hours at room temperature. The reaction mixture was acidified with SN hydrochloric acid an3 extracted with methyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The titled compounds (75a and 75b) were separated from the oily residue by silica gel column chromatography. 75a 75b yield 0.4g (37%) 0.5g (47%) [&alpha;]25D -52.2 (c=1.2, MeOH) -60.4 (c=1.0, MeOH) IR 1720, 1620, 1422, 1722, 1620, 1420, (neat, 1217, 756 1215, 755 cm01) NMR .2.67-3.63 (6H, m, 2.70-3.50 (6H, m, (CODl3, #) -S-CH2-CO2H, C5-H, -S-CH2-CO2H, C5-H, -CH2-Ph), 3,83-4,83 (3H, m, -CH2-Ph), -CO-CH-S-, C2-H) , 4.00-4.j7 (3H, m, - -CO-CH 4.98 rlH, dd, J=4.5, - 2 6.5Hz, C4-H), 5.02 (1H, dd, J=4.5, 7.22 (5H, s, -C6H5) 9.5Hz, C4-H), 9.55 (-CO2H) 7.23 (5H, s, -C6H5), 10.00 (-C02H) The compounds shown in Table IV were prepared by the same procedure as described above. EXAMPLE 11 (4R)-3-[(Carboxymethylamino)acetyl]-2-(2-hydroxyphneyl)4-thiazolidinecarboxylic acid (compound 81) (4R)-3-Chloroacetyl-2-(2-hydroxyphenyl)-4-thiazolidine carboxylic acid (6g) was added to a stirred solution of glycine (1.5g) in N sodium hydroxide (80ml), and stirred overnight at room temperature. The solution was adjusted to pH 1.5 by 205 hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjsted to pH 3.2, and the separated crystals were collected by filtration to 3.28g (48.2%) of the titled compound: mp 181-182 C (dec.) (water); [&alpha;]24D +271.2 (c=0.5, MeOH). IR (KBR, cm-1); 3400, 3200, '740, 1672, 1560, 1440, 1380, 1335, 1212, 752, 648, NMR (K2CO3 in D2O, 6): 3.0-4.3 (6H, m, C5-H, COCH2NHCH2CO2H), 5.33 and 6.43 (1H, each s, C2-H), 6.67.3 (3H, m, arom. H), 7.82 (lH, br. d, J=8Hz, arom. H), 9.0-10.3 (2H, br; s, -OH, -CO2H) The compounds shown in Table V were prepared by the same procedure as described above. EXAMPLE 12 (28)-1-[(28)-2-Bis(ethoxycarbonylmethyl)amino]propanoyl]2-pyrrolidinecarboxylic acid benzyl ester (compound 88) Ethyl bromoacetate (0.92g) was added dropwise unden ice-cooling to a stirred solution of L-alanyl-L-proline benzyl ester p-toluenesulfonate (2.24g) end triethylamine (1.53ml) in dry methylenechloride. After the addition, the reaction mixture was stirred for 2 hours at room temperature, refluxed for another 5 hours, and washed with water and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual oil was purified by silica gel column chromatography to give 1.02g (44.8%) of the titled compound: [&alpha;]24D -67.9 (c=1.2, MeOH). IR (neat, cm-1): 3460, 1742, 1642, 1428, 1180. NMR (CDC13, 6) : 1.23 (6H, t, J=7Hz, -CO2CH2CH3), 1.25 (3H, d, J=7.2Hz, EMI29.1 1.672.40 (4H, m, C3-H and C4-H), 3.57 (4H, s, -N-CH2CO2Et?, 3.50-4.00 (2H, m, C5-H), 4.13 (4H, q, J=7Hz, -COCH2CH3), 4.10-4.67 (2H, m, C2-H and EMI29.2 5.03, 5.20 (2H, ABq, J=12Hz, -CH2-Ph), 7.30 (5H, s, -C6H5). The compounds shown in Table V were prepared by the same procedure as described above. EXAMPLE 13 (2S)-1-[(2S)-Bis(ethoxycarbonylementhyl)amino]propanoyl]2-pyrrolidinecarboxylic acid (compound 86) (2S)-1-[[(2S)-2-bis(ethoxycarbenylmethyl)amino]propanob 2-pyrrolidinecarboxylic acid benzyl ester (compound 88) (0.50g) was dissolved in ethanol (10ml), and hydrogenated with 10% palladium on charcoal catalyst (50mg). The titled compound was obtained as a colorless oil. Yield 0.40g (quant. yild); [&alpha;]24D -52.2 (c=1.1, MeOH). IR (neat, cm ); 1742, 16.40, 1442, 1190, 1130, 752. NMR (CDCl3, @): 1.23 (6H, @, @=7Hz, -CO2CH2CH3, 1.25 (@H, d, EMI29.3 i.G7-2.50 (4H, m, C3-K and C4-H), 3,53 (4H, s, N-CH2-CO2Et), 3.50-4.00 (2H, m, C5-H), 4.10 (4H, q, J=7Hz, -CO2CH2CH3), 4.10-4.33 (1H, m, EMI30.1 4.47 (1H, dd, J=6.5, 5.0Hz, C2-H), 9.20 (1K, br. s, -CO2H). The compounds shown in Table V were prepared by the same procedure as described above. The following compouds are also prepared by the same procedure as EXAMPLE 12 and 13. t2S)-1-[[4- carboxy-3-pheny]propyl)amino]benzoyl]-2- pyrrolidinecarboxylic acid. (4R)-3-[[4-(1-carboxy-3-phenylpropyl)amino]benzOyl]-2- (2-hydroxyphenyl) -4-thiazolidinecarboxylic acid EXAMPLE 14 (25)-1-[[(2S)-2-(N-Ethoxycarbonylmethyl-N-phenyLacety.l-)- amino]propanoyl]-2-pyrrolidinecarboxylic acid benzyl ester (compound 90) Phenylacetyl chloride (0.44ml) was added dropwise at room temperature to a stirred solution of (2S)-1-[[(2S)- 2-(ethoxycarbonylmentyl)aminolpropanoyl]-2-pyrrolidinecarboxylic acid benzyl ester (l.lg) and triethylamine (0.47ml) in dry acetone (15ml). After the addition, the reaction mixture was stirred for 1 hour at the same temperature, and the precipitate was removed by filtration. The filtrate was evaporated in vacuo, and the residual oil was dissolved in ethyl acetate, and washed with water and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residual oil was purified by silica gel column chromatography to give 1.3g (89%) of the titled compound: mp 110-110.5 C (benzene-hezane); [&alpha;]24D -114.0 (c=1.0, MeOH). IR (KB@, cm-1); 3460, 1739, 1635, 1436, 1200, 1166. NMR (CDC13, @): 1.23 (3H, d, J=7Hz, EMI31.1 1.28 (3H, t, J=7Hz,-CO2CH2CH3), 1.67-2.50 (4H,m, C3-H and C4-H), 3.60 (2K. s, -COCH2Ph ), 3.33-3.90 (2H, m, C5-K) 4.16 (2H, q, J=7Hz, -COCH2CH3), 4.23 (2H, s, -N-CH2CO2Et) 4.30-4.60 (1H, m, C2-H), 5.03, 5.23 (2H, ABq, J=12.5Hz, -CO2CH2Ph), 5.58 (1H, q, J=7Hz, EMI31.2 ), 7.23 (5H, s, -COCH2C6H5), 7.30 (5, s, -CO2CH2C6H5) The compounds shown in Table V were prepared by the same procedure as described above. EXAMPLE 15 (2S)-1-[(2S)-2-[(1-Carboxy-3-phenylpropyl)thio]propanoyl). 2-pyrrolidinecarboxylic acid (compound 79) (2S)-1-[(2S)-2-Mecaptopropanyl]-2-pytrolidinecarboxylic acid (2.0g), potassium carbonate (2.8g) and 2bromo-4-phenylbutaneic acid (2.9g) were dissolved in water (40ml), and stirred overni@ht at room temperature. The reaction mixture was acidified with 6N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual oil was purified by silica gel column chromatography to give 2.3g (62%) of the titled compound: 23 -82.2 (c=1.2, MeOH). IR (KBr, cm 1): 1/40, 1/20, 161Q, 1455, 1438, 1185, 748, 700. The compounds shown in Table IV were prepared by the same procedure as described above. EXAMPLE 16 l-[[(l-Carboo-y-3-phenylpropyl)amino]acetyl-2-(2-hvdroxy- phenyl)-5-pyrrolidinecarboxylic acid (compound 99) l-(Chloroacetyl)-5-(2-hydroxyphenyl)-2-pyrrolidinecarboxylic acid [mp 204-206 C(dec.), 24 +24.5 @ [&alpha;]D MeOH)] (2.8g) was added to a stirred solution of 2-amino4-phenylbutanoic acid (1.8g)in N sodium hydroxide (40m1). The reaction mixure was stirred overnight at room temperature. The solution was adjusted to pH 1.5 by 20% hydrochloric acid, and washed with ethyl acetate. The aqueous layer was adjusted to pH 3.0, and the separated solid was collected by filtration to give 1.0g (24%) of the titled compound. IR (nujol, cm : 3425, 1735, 1625, 1588. The compounds shown in Table V were prepared by the same procedure as described above. In EXAMPLEs and TABLEs I, II, III, It and V, "a" and "b" of compound No. represent diastereolsomers roach other. TABLEs I, II, III, IV and V show various compounds and their physical constants including the compounds specified in EXAMPLEs. Table I EMI34.1 Compound No. 1 Compound No. 2a and 2b Compound 3-32 Method mp ( C) [&alpha;]p deg. IR spectrum Rf #2 of Yield (Recrystn. (c, solv., C) value Compd.+ TÚ Tê T m n prepn. (%) solvent) SamplingÚ cm-1 (SiO2) No. (Examp. method No.) 1 OH OH 0 6 1 55 oil -84.3 C 1720, 1605, 1420, 1190, 0.39 (0.8, MeOH, 26) 1015, 880 2a OH OH 0 3 5 26 oil -19.8 C 1733, 1710, 1650, 1600, 0.60#3 (1.1, MeOH, 24) 1410, 1240, 1040 2b OH OH 0 3 5 51 oil -113.8 C 1730, 1650, 1610, 1410, 0.55#3 (1.1, MeOH, 24) 1240, 1042 3 2-OH OH OH 0 1 1 65 154.0-154.5 (dec.) +201.4 B 3340, 1725, 1625, 1600, 0.25 (H2O) (0.7, MeOH, 25) 1460, 1430, 1235, 1100, 915, 770 4 2-OH OH OMe 1 1 6 44 oil +161.6 A 3380, 1723, 1624, 1235, 0.51 (1.0, MeOH, 25) 1200, 1174, 764 5 2-OH OH OH 1 1 7 75 163-164 (dec.) +174.1 B 3330, 1730, 1710, 1629, 0.41 (EtOAc) (1.0, MeOH, 25) 1280, 1234, 856, 771 Table-continued Method mp ( C) [&alpha;]D deg. IR spectrum Rf #2 of Yield (Recrystn. (c, solv., C) Compd.+ TÚ Tê T m n prepn. (%) solvent) Sampling#1 cm-1 value No. (Examp. method (Sio2) No.) 6 2-OH OH OH 0 2 1 75 190-191 (dec.) +181.6 B 3210, 1720, 1618, 1602, 1245, 1173, 0.35 5 (EtOAc-MeOH) (1.0, MeOH, 27) 940, 763 7 2-OH OH OMe 0 2 6 83 165-166 (dec.) +164.5 A 3370, 1750, 1693, 1635, 1215, 1165, 0.47 (EtOAc) (1.0, MeOH, 25) 755 8a 2-OH OEt OH 0 2 5 45 181-182 -2.8 A 3310, 1727, 1703, 1637, 1595, 1235, 0.55 (EtOAc) (0.5, MeOH, 21) 1190, 745 8b 2-OH OEt OH 0 2 5 23 116-118 -311.6 A 3370, 1735, 1708, 1635, 1597, 1220, 0.55 (EtOAc) (0.5, MeOH, 21) 1180, 760 9a 2-OH OH NHOH 0 2 7 172-173 (dec.) A 3375, 3290, 1720, 1657, 1625, 1590, 0.22 (EtOH-H2O) 1240, 1088, 748 9b 2-OH OH NHOH 0 2 7 amorph. A 3220, 1717, 1655, 1625, 1595, 1225, 0.33 1092, 752 10a 2-OH OEt NHOH 0 2 8 amorph. A 3220, 1727, 1625, 1595, 1200, 1092, 0.25#4 753 10b 2-OH OEt NHOH 0 2 8 amorph. 0.32#4 11#5 2-OH OH OMe 1 2 6 amorph. +55.5 B 1738, 1630, 1585, 1310, 1258, 750 (0.8, MeOH, 24) 11a#5 2-OH OH OMe 1 2 6 205-207 (dec.) +94.6 B 3110, 1730, 1625, 1610, 1192, 1121, (benzene) (0.5, MeOH, 23) 758 12a 2-OH OH OH 1 2 7 79 168-170 (dec.) +168.0 A 3370, 1718, 1625, 1598, 758 0.25#4 (acetone- (0.4, MeOH, 23) cyclohexane) 12b 2-OH OH OH 1 2 7 163-164 (dec.) +149.2 A 3300, 1720, 1708, 1615, 1598, 1242, 0.25#4 (acetone- (0.4, MeOH, 23) 753 cyclohexane) 13 2-OH OH OH 0 3 5 65 161-162 (dec.) +153.8 B 3190, 1713, 1632, 1598, 1253, 1098, 0.38 (H2O) (0.5, MeOH, 24) 943, 760 14 2-OH OH OEt 0 3 6 88 157-158 (dec.) +145.6 A 3340, 1725, 1638, 1597, 1218, 1120, 0.48 (EtOAc-benzene) (1.0, MeOH, 25) 768 15 H OH OH 0 3 5 73 139-140 +106.3 B 3170, 1753, 1709, 1631, 1423, 1177, 0.39 (EtOAc-MeOH) (1.0, MeOH, 24) 729 Table-continued Method mp ( C) [&alpha;]D deg. IR spectrum Rf of Yield (Recrystn. (c, solv., C) #2 Compd.+ TÚ Tê T m n prepn. (%) solvent) SamplingÚ cm-1 value No. (Examp. method (Sio2) No.) 16 4-CN OH OH 0 3 5 59 190-191 +137.7 B 2225, 1710, 1665, 1412, 0.31 (EtOAc-MeOH) (1.0, MeOH, 24) 1258 17 2-OH OH OH 0 4 1 62 amorph. +115.6 B 3300, 1700, 1622, 1595, 0.43 (1.0, MeOH, 24) 760, 723 18 2-OH OH OH 0 5 1 60 158-159 (dec.) +128.6 B 3300, 1710, 1620, 1595, 0.47 (EtOAc) (0.5, MeOH, 25) 1280, 1095, 895, 850, 760 19 H OH OH 0 6 1 33 oil +80.5 0.50 (1.0, MeOH, 24) 20 2-OH OH OH 0 6 1 61 155-157 (dec.) +134.1 B 3220, 1710, 1620, 1600, 0.52 (EtOAc) (0.5, MeOH, 27) 1415, 1235, 1172, 950, 760 21 2-OH OH OH 0 7 1 63 153-154 (dec.) +70.9 B 3220, 1705, 1620, 1600, 0.55 (EtOAc) (0.5, MeOH, 26) 1415, 1235, 1173, 1090, 830, 760 22 3-NO2 OH OH 0 7 1 45 oil +72.1 C 1710, 1615, 1525, 1405, 0.56 (0.4, MeOH, 27) 1350, 1095, 735 23 3-NO2 OH OEt 0 7 6 79 oil +72.8 C 1735, 1663, 1620, 1533, 0.57 (1.0, MeOH, 23) 1352, 1240, 1190, 728 24 2-F OH OH 0 7 1 53 oil +69.9 C 1730, 1660, 1625, 1587, 0.57 (0.5, MeOH, 23) 1228, 1043, 756 25 3-F OH OH 0 7 1 50 oil +63.4 C 1730, 1655, 1610, 1590, 0.57 (0.5, MeOH, 23) 1243, 1042, 775 26 4-F OH OH 0 7 1 oil +57.9 0.51#4 (0.8, MeOH, 23) 27 2-Cl OH OH 0 7 1 45 amorph. +108.3 A 1720, 1660, 1580, 1526, 0.57 5-NO2 (0.5, MeOH, 23) 1240, 1050, 745 Table-continued Method mp ( C) [&alpha;]D deg. IR spectrum Rf of Yield (Recrystn. (c, solv., C) #2 Compd.+ TÚ Tê T m n prepn. (%) solvent) SamplingÚ cm-1 value No. (Examp. method (Sio2) No.) 28 2-OH OH OH 0 8 1 58 oil +100.3 C 1710, 1620, 1600, 1410, 0.58 (1.0, MeOH, 24) 1230, 1090, 850, 760 29 2-OH OH OH 0 10 1 55 123-124 (EtOAc-cyclo- +120.4 B 3320, 1705, 1620, 1595, 0.61 hexane) (0.5, MeOH, 25) 1410, 1233, 1090, 943, 30 3-CN OH OH 0 10 1 56 oil +56.4 850, 760 (0.3, MeOH, 23) 0.56#4 31 2-OH OH OH 0 12 1 59 amorph. +101.4 B 3280, 1700, 1620, 1575, 0.52 (1.0. MeOH, 24) 760, 722 32 3-CN OH OH 0 12 1 43 oil +61.7 0.53#4 (0.6, MeOH, 23) + a and b represent diastereoisomers of the compound. #1 A: KBr disk, B; nujol mull, C; neat. #2 EtOAc-CHCl3-AcOH (10:5:3). #3 CHCl3-EtOH-AcOH (10:2:1). #4 EtOAc-CHCl3-AcOH (7:5:1). #5 Dicyclohexylamine salt. Table II EMI38.1 Compound No. 33-37, 39-62 Compound No. 38 Method of mp ( C) IR spectrum Rf Compd. TÚ n prepn. Yield (Recrystn. [&alpha;]D deg. value#2 No. (Examp. (%) solvent) (c, solv, C) Sampling#1 cm-1 (SiO2) No.) method 33 2-OH 4 2 73 124-128 +182.2 B 3280, 1726, 1620, 1596, 775, 0.23 (MeOH) (1.0, DMF, 24) 34 2-OH 5 2 67 oil +106.1 C 1725, 1625, 1600, 1410, 1235, 0.27 (0.5, MeOH, 26) 1095, 1045, 850, 765 35 3-NO2#5 5 4 69 111-113 (dec.) +88.2 B 1635, 1585, 1520, 1355, 1095, 0.28 (H2O) (0.5, MeOH, 25) 730 36 3-CN 5 3 59 105-112 +115.0 B 2270, 1735, 1640, 1610, 1195, 0.33 (H2O) (1.0, MeOH, 25) - 790 37 4-CN 5 3 52 amorph. +148.2 B 2255, 1731, 1655, 1620, 785 0.32 (0.9, MeOH, 25) 38 6 2 77 oil -124.5 C 1720, 1580, 1410, 1180, 1015, 0.09 (0.5, MeOH, 26) 880 39 H 6 2 79 amorph. +97.4 B 1720, 1625, 1585, 732 0.42 (1.0, MeOH, 24) Table-continued Method of mp ( C) IR spectrum Rf Compd. TÚ n prepn. Yield (Recrystn. [&alpha;]D deg. value#2 No. (Examp. (%) solvent) (c, solv, C) Sampling#1 cm-1 (SiO2) No.) method 40 2-OH 6 2 86 amorph. +123.6 B 1720, 1620, 1600, 1230, 1090, 0.34 (0.5, MeOH, 27) 855, 765 41 3-NO2 6 2 56 amorph. +97.5 B 1730, 1650, 1605, 1520, 1345, 0.34 (0.5, MeOH, 21) 1095, 730 42 3-CN 6 2 58 amorph. +98.3 B 2250, 1730, 1640, 1615, 1200, 0.38 (0.9, MeOH, 25) 790 43 4-CN 6 2 41 amorph. +130.2 B 2248, 1729, 1650, 1618, 790 0.36 (0.9, MeOH, 25) 44 2-OH 7 2 75 amorph. +142.7 B 1720, 1620, 1600, 1410, 1230, 0.40 (0.5, MeOH, 26) 1173, 1090, 855, 763 45 2-NO2 7 2 47 amorph. +191.2 B 1735, 1655, 1515, 1345, 1190, 0.38 (0.6, MeOH, 25) 730 46#6 3-NO2 7 9 96 61-63 +79.4 A 1740, 1660, 1530, 1350, 1198, 0.57 (benzene) (1.0, MeOH, 23) 725 47 3-NO2 7 2 82 amorph. +96.2 B 1725, 1615, 1520, 1445, 1350, 0.41 (0.5, MeOH, 27) 1095, 730 48 4-NO2 7 2 53 amorph. +118.5 B 1730, 1650, 1600, 1510, 1345, 0.48 (0.5, MeOH, 25) 1185, 1110, 735 49 3-CN 7 3 65 amorph. +112.1 B 2250, 1729, 1640, 1610, 790 0.41 (1.1, MeOH, 25) 50#5 2-F 7 4 85 140-220 (dec.) +117.5 A 1580, 1225, 1173, 758 0.50 (H2O) (1.0, MeOH, 24) 51#5 3-F 7 4 88 195-210 (dec.) +103.9 A 1590, 1238, 1142, 767 0.50 (H2O) (0.5, MeOH, 25) 52 4-F 7 2 76 oil +75.8 0.39#3 (1.0, MeOH, 23) Table-continued Method of mp ( C) IR spectrum Rf Compd. TÚ n prepn. Yield (Recrystn. [&alpha;]D deg. value#2 No. (Examp. (%) solvent) (c, solv, C) Sampling#1 cm-1 (SiO2) No.) method 53 2-Cl 7 2 79 amorph. +167.9 A 1725, 1640, 1575, 1520, 1342, 0.51 5-NO2 (0.5, MeOH, 23) 1047, 740 54 2-OH 7 2 75 amorph. +140.9 B 1725, 1620, 1595, 1310, 1150, 0.42#4 5-SO2NH2 (0.6, MeOH, 23) 930 55 2-OH 8 2 68 amorph. +122.1 B 3300, 1730, 1628, 1575, 767, 0.45 (1.0, MeOH, 24) 725 56 3-CN 8 2 47 amorph. +104.6 B 2245, 1726, 1630, 1610, 790 0.37 (1.0, MeOH, 25) 57 3-NO2 8 2 84 amorph. +102.2 A 1735, 1620, 1523, 1190, 728 0.47 (0.5, MeOH, 25) 58#5 3-NO2 8 4 74 amorph. +93.9 A 1597, 1520, 1269, 1096, 723 (0.5, MeOH, 23) 59 2-OH 10 2 61 99-100.5 (dec.) +124.7 B 3300, 1740, 1620, 1600, 1565, 0.49 (EtOAc-benzene) (0.5, MeOH, 27) 1230, 1160, 1090, 895, 770 60#5 3-CN 10 4 63 190-195 +109.3 B 3400, 2240, 1640, 1600, 1208, (H2O) (0.5, H2O, 23) 778, 720 61 2-OH 12 2 66 amorph. +69.5 B 3300, 1728, 1630, 1590, 762, 0.45 (1.0, MeOH, 24) 725 62#5 3-CN 12 4 52 amorph. 104.2 B 3400, 2225, 1605, 1320, 1207, 0.46#3 (0.5, MeOH, 23) 775, 720 #1 A; KBr disk, B; nujol mull, C; neat. #2 EtOAc-CHCl3-AcOH (10:5:3). #3 EtOAc-CHCl3-AcOH (7:5:1). #4 CHCl3-MeOH-AcOH (3:1:1). #5 Disodium salt. #6 Dimethyl ester. Table III EMI41.1 Compound No. 63-68 Compound No. 69-71 EMI41.2 <SEP> Method <tb> <SEP> of <SEP> mp <SEP> ( C) <SEP> IR <SEP> spectrum <SEP> Rf <tb> Compd. <SEP> TÚ <SEP> W <SEP> prepn. <SEP> Yield <SEP> (Recrystn. <SEP> [&alpha;]D <SEP> deg. <SEP> value#2 <tb> <SEP> No. <SEP> (Examp. <SEP> (%) <SEP> solvent) <SEP> (c, <SEP> solv, <SEP> C) <SEP> Sampling#1 <SEP> cm-1 <SEP> (SiO2) <tb> <SEP> No.) <SEP> method <tb> <SEP> 63 <SEP> 2-OH <SEP> -CH2COCH(COCH3)- <SEP> 5 <SEP> 31 <SEP> amorph. <SEP> +149.2 <SEP> B <SEP> 1743, <SEP> 1720, <SEP> 1630, <SEP> 1600, <SEP> 0.38#3 <tb> <SEP> (1.2, <SEP> MeOH, <SEP> 25) <SEP> 1238 <tb> <SEP> 64 <SEP> 2-OH <SEP> -CH2-O-CH2- <SEP> 1 <SEP> 35 <SEP> amorph. <SEP> +138.6 <SEP> A <SEP> 3300, <SEP> 1726, <SEP> 1640, <SEP> 1453, <SEP> 0.24#4 <tb> <SEP> (1.1, <SEP> MeOH, <SEP> 25) <SEP> 1234, <SEP> 1142 <tb> <SEP> 65 <SEP> 3-NO2 <SEP> # <SEP> 1 <SEP> 36 <SEP> amorph. <SEP> +81.7 <SEP> A <SEP> 3400, <SEP> 1702, <SEP> 1618, <SEP> 1525, <SEP> 0.55#3 <tb> <SEP> (0.9, <SEP> MeOH, <SEP> 24) <SEP> 1400, <SEP> 1347 <tb> <SEP> 66 <SEP> 2-OH <SEP> -(CH2)2-O-(CH2)2- <SEP> 1 <SEP> 33 <SEP> 136-137 <SEP> +147.6 <SEP> B <SEP> 3320, <SEP> 1750, <SEP> 1710, <SEP> 1625, <SEP> 0.28 <tb> <SEP> (EtOAc) <SEP> (0.5, <SEP> MeOH, <SEP> 25) <SEP> 1595, <SEP> 1235, <SEP> 1110, <SEP> 855, <tb> <SEP> 770 <tb> <SEP> 67 <SEP> 2-OH <SEP> -(CH2)2-S-(CH2)2- <SEP> 1 <SEP> 40 <SEP> 159-160 <SEP> (dec.) <SEP> +136.4 <SEP> B <SEP> 3360, <SEP> 1710, <SEP> 1627, <SEP> 1599, <SEP> 0.42 <tb> <SEP> (EtOAc) <SEP> (0.5, <SEP> MeOH, <SEP> 27) <SEP> 1435, <SEP> 1235, <SEP> 1099, <SEP> 852, <tb> <SEP> 763 <tb> <SEP> 68 <SEP> 2-OH <SEP> -(CH2)2-S-(CH2)2-S-(CH2)2- <SEP> 1 <SEP> 35 <SEP> amorph. <SEP> +78.1 <SEP> B <SEP> 3300, <SEP> 1715, <SEP> 1627, <SEP> 1590, <SEP> 0.31 <tb> <SEP> (1.0, <SEP> MeOH, <SEP> 24) <SEP> 760 <tb> <SEP> 69 <SEP> 3-NO2 <SEP> # <SEP> 2 <SEP> 44 <SEP> amorph. <SEP> +106.9 <SEP> A <SEP> 3425, <SEP> 1730, <SEP> 1640, <SEP> 1525, <SEP> 0.38#3 <tb> <SEP> (1.1, <SEP> MeOH, <SEP> 24) <SEP> 1400, <SEP> 1350 <tb> Table-continued EMI42.1 <SEP> Method <tb> <SEP> of <SEP> mp <SEP> ( C) <SEP> IR <SEP> spectrum <SEP> Rf <tb> Compd. <SEP> TÚ <SEP> W <SEP> prepn. <SEP> Yield <SEP> (Recrystn. <SEP> [&alpha;]D <SEP> deg. <SEP> value#2 <tb> <SEP> No. <SEP> (Examp. <SEP> (%) <SEP> solvent) <SEP> (c, <SEP> solv, <SEP> C) <SEP> Sampling#1 <SEP> cm-1 <SEP> (SiO2) <tb> <SEP> No.) <SEP> method <tb> <SEP> 70 <SEP> 2-OH <SEP> -(CH2)2-O-(CH2)2- <SEP> 2 <SEP> 47 <SEP> amorph. <SEP> +83.0 <SEP> B <SEP> 1720, <SEP> 1625, <SEP> 1600, <SEP> 1230, <SEP> 1090, <SEP> 0.15 <tb> <SEP> (0.5, <SEP> MeOH, <SEP> 26) <SEP> 850, <SEP> 760 <tb> <SEP> 71 <SEP> 2-OH <SEP> -(CH2)2-S-(CH2)2- <SEP> 2 <SEP> 53 <SEP> amorph. <SEP> +129.3 <SEP> B <SEP> 1720, <SEP> 1620, <SEP> 1600, <SEP> 1420, <SEP> 1230, <SEP> 0.30 <tb> <SEP> (0.5, <SEP> MeOH, <SEP> 27) <SEP> 1093, <SEP> 852, <SEP> 763 <tb> #1 <SEP> A; <SEP> KBr <SEP> disk, <SEP> B; <SEP> nujol <SEP> mull. <tb> #2 <SEP> EtOAc-CHCl3-AcOH <SEP> (10:5:3). <tb> #3 <SEP> EtOAc-EtOH-AcOH <SEP> (40:1:1). <tb> #4 <SEP> CHCl3-EtOH-AcOH <SEP> (10:2:1). <tb> Table IV EMI43.1 Compound No. 72-76 Compound No. 77-80 EMI43.2 <SEP> Method <SEP> mp <SEP> ( C) <SEP> [&alpha;]D <SEP> deg. <SEP> IR <SEP> spectrum <SEP> Rf <tb> <SEP> of <SEP> Yield <SEP> (Recrystn. <SEP> value#2 <tb> Compd.+ <SEP> T4 <SEP> T5 <SEP> T6 <SEP> T7 <SEP> prepn. <SEP> (%) <SEP> solvent) <SEP> (c, <SEP> solv., <SEP> C) <SEP> Sampling#1 <SEP> cm-1 <SEP> (SiO2) <tb> <SEP> No. <SEP> (Examp. <SEP> method <tb> <SEP> No.) <tb> <SEP> 72a <SEP> H <SEP> CH3 <SEP> Ph <SEP> H <SEP> 10 <SEP> 38 <SEP> 151-153 <SEP> +8.6 <SEP> A <SEP> 3030, <SEP> 1737, <SEP> 1720, <SEP> 1615, <SEP> 1413, <SEP> 0.26#3 <tb> <SEP> (EtOAc) <SEP> (1.0, <SEP> MeOH, <SEP> 23) <SEP> 1215, <SEP> 1150, <SEP> 717 <tb> <SEP> 72b <SEP> H <SEP> CH3 <SEP> Ph <SEP> H <SEP> 10 <SEP> 49 <SEP> oil <SEP> -161.5 <SEP> C <SEP> 1735, <SEP> 1623, <SEP> 1413, <SEP> 1243, <SEP> 1170, <SEP> 0.22#3 <tb> <SEP> (1.0, <SEP> MeOH, <SEP> 23) <SEP> 1043, <SEP> 699 <tb> <SEP> 73 <SEP> # <SEP> H <SEP> CH2CH2Ph <SEP> H <SEP> 10 <SEP> 81 <SEP> amorph. <SEP> +122.1 <SEP> A <SEP> 1720-1710, <SEP> 1625, <SEP> 1600, <SEP> 1400, <SEP> 0.74 <tb> <SEP> (1.2, <SEP> MeOH, <SEP> 25) <SEP> 1235, <SEP> 752, <SEP> 698 <tb> <SEP> 74 <SEP> H <SEP> CH3 <SEP> CH2CH2Ph <SEP> H <SEP> 10 <SEP> 52 <SEP> amorph. <SEP> -97.9 <SEP> A <SEP> 1720, <SEP> 1620, <SEP> 1415, <SEP> 750, <SEP> 700 <SEP> 0.65 <tb> <SEP> (1.1, <SEP> MeOH, <SEP> 25) <tb> <SEP> 75a <SEP> H <SEP> CH2Ph <SEP> H <SEP> H <SEP> 10 <SEP> 37 <SEP> oil <SEP> -52.2 <SEP> C <SEP> 1720, <SEP> 1620, <SEP> 1422, <SEP> 1217, <SEP> 756 <SEP> 0.13#4 <tb> <SEP> (1.2, <SEP> MeOH, <SEP> 25) <tb> <SEP> 75b <SEP> H <SEP> CH2Ph <SEP> H <SEP> H <SEP> 10 <SEP> 46 <SEP> oil <SEP> -60.4 <SEP> C <SEP> 1722, <SEP> 1620, <SEP> 1420, <SEP> 1215, <SEP> 755 <SEP> 0.13#4 <tb> <SEP> (1.0, <SEP> MeOH, <SEP> 25) <tb> <SEP> 76 <SEP> H <SEP> CH2CH2Ph <SEP> H <SEP> H <SEP> 10 <SEP> 84 <SEP> oil <SEP> -61.2 <SEP> C <SEP> 1735, <SEP> 1630, <SEP> 1615, <SEP> 1420, <SEP> 1242, <SEP> 0.66 <tb> <SEP> (1.3, <SEP> MeOH, <SEP> 24) <SEP> 1172, <SEP> 1043, <SEP> 702 <tb> Table-continued Method mp ( C) [&alpha;]D deg. IR spectrum Rf of Yield (Recrystn. value#2 Compd.+ T4 T5 T6 T7 prepn. (%) solvent) (c, solv., C) Sampling#1 cm-1 (SiO2) No. (Examp. method No.) 77 H COPh Et 15 36 oil -46.2 C 1733, 1678, 1632, 1610, 1447, 0.32#3 (0.8, MeOH, 30) 1258, 1187, 1025, 1001, 751 78 H CH2CH2Ph H 15 46 oil -48.4 C 1730, 1610, 1450, 1240, 1190, 0.72#5 (1.1, MeOH, 26) 750, 703 79 CH3 CH2CH2Ph H 15 62 amorph. -82.2 A 1740, 1720, 1610, 1455, 1438, 0.38 (1.2, MeOH, 23) 1185, 748, 700 80 H COCH3 Et 15 45 oil -49.6 C 1736, 1597, 1398, 1378, 1333, 0.29#3 (0.9, MeOH, 30), 1250, 1191, 1047, 860, 752 + a and b represent diastereoisomers of the compound. #1 A; KBr disk, C; neat. #2 EtOAc-CHCl3-AcOH (10:5:3). #3 Benzene-EtOAc-EtOH-AcOH (14:14:2:1). #4 Benzene-EtOAc-AcOH (25:25:1). #5 CHCl3-EtOH-AcOH (10:2:1) Table V EMI45.1 Compound No. 81-85 Compound No. 86-98, 100-102 Compound No. 99 EMI45.2 <SEP> Method <SEP> mp <SEP> ( C) <SEP> [&alpha;]D <SEP> deg. <SEP> IR <SEP> spectrum <SEP> Rf <tb> <SEP> of <SEP> Yield <SEP> (Recrystn. <SEP> value#2 <tb> Compd.+ <SEP> T4 <SEP> T7 <SEP> T8 <SEP> T9 <SEP> T10 <SEP> prepn. <SEP> (%) <SEP> solvent) <SEP> (c, <SEP> solv., <SEP> C) <SEP> Sampling#1 <SEP> cm-1 <SEP> (SiO2) <tb> <SEP> No. <SEP> (Examp. <SEP> method <tb> <SEP> No. <tb> <SEP> 81 <SEP> # <SEP> H <SEP> H <SEP> -CH2- <SEP> H <SEP> 11 <SEP> 48.2 <SEP> 181-182 <SEP> (dec.) <SEP> +271.2 <SEP> A <SEP> 3400, <SEP> 3200, <SEP> 0.25#2 <tb> <SEP> (H2O) <SEP> (0.5, <SEP> N <SEP> NaOH, <SEP> 24) <SEP> 1740, <SEP> 1672, <tb> <SEP> 1560, <SEP> 1440, <tb> <SEP> 1380, <SEP> 1335, <tb> <SEP> 1210, <SEP> 752 <tb> <SEP> 82 <SEP> # <SEP> H <SEP> H <SEP> -CH2- <SEP> H <SEP> 11 <SEP> 32.8 <SEP> 150-155 <SEP> +94.7 <SEP> B <SEP> 3420, <SEP> 3210, <SEP> 0.45#3 <tb> <SEP> (H2O) <SEP> (0.5, <SEP> N <SEP> NaOH, <SEP> 23) <SEP> 1650, <SEP> 1240, <tb> <SEP> 839, <SEP> 790 <tb> <SEP> 83 <SEP> # <SEP> H <SEP> H <SEP> # <SEP> H <SEP> 11 <SEP> 44.8 <SEP> 150-153 <SEP> (dec.) <SEP> +86.5 <SEP> A <SEP> 3370-2900, <SEP> 0.74#4 <tb> <SEP> (EtOH-ether) <SEP> (0.4, <SEP> MeOH, <SEP> 26) <SEP> 1655, <SEP> 1602, <tb> <SEP> 1175 <tb> <SEP> 84 <SEP> # <SEP> H <SEP> H <SEP> # <SEP> H <SEP> 11 <SEP> 50.3 <SEP> 172-173 <SEP> (dec.) <SEP> +78.9 <SEP> A <SEP> 3350, <SEP> 1720, <SEP> 0.69#4 <tb> <SEP> (EtOAc) <SEP> (0.8, <SEP> MeOH, <SEP> 25) <SEP> 1670, <SEP> 1644, <tb> <SEP> 1236, <SEP> 744 <tb> <SEP> 85 <SEP> # <SEP> H <SEP> H <SEP> CH2CH2Ph <SEP> H <SEP> 11 <SEP> 27.2 <SEP> 174-175 <SEP> (dec.) <SEP> A <SEP> 3400, <SEP> 1720, <SEP> 1660, <tb> <SEP> -CH- <SEP> (H2O) <SEP> 1610, <SEP> 1492, <SEP> 1452, <tb> <SEP> 1240, <SEP> 752, <SEP> 700 <tb> <SEP> 86 <SEP> H <SEP> Et <SEP> CH2CO2Et <SEP> -CH2- <SEP> H <SEP> 13 <SEP> quant. <SEP> oil <SEP> -52.2 <SEP> C <SEP> 1742, <SEP> 1640, <SEP> 0.21#5 <tb> <SEP> (1.1, <SEP> MeOH, <SEP> 24) <SEP> 1442, <SEP> 1190, <tb> <SEP> 1130, <SEP> 752 <tb> Table-continued EMI46.1 <SEP> Method <SEP> mp <SEP> ( C) <SEP> [&alpha;]D <SEP> deg. <SEP> IR <SEP> spectrum <SEP> Rf <tb> <SEP> of <SEP> Yield <SEP> (Recrystn. <SEP> value#2 <tb> Compd.+ <SEP> T4 <SEP> T7 <SEP> T8 <SEP> T9 <SEP> T10 <SEP> prepn. <SEP> (%) <SEP> solvent) <SEP> (c, <SEP> solv., <SEP> C) <SEP> Sampling#1 <SEP> cm-1 <SEP> (SiO2) <tb> <SEP> No. <SEP> (Examp. <SEP> method <tb> <SEP> No.) <tb> <SEP> 87 <SEP> H <SEP> H <SEP> CH2CO2H <SEP> -CH2- <SEP> H <SEP> 7 <SEP> 26 <SEP> amorph. <SEP> -32.8 <SEP> B <SEP> 3400, <SEP> 1720, <SEP> 1640, <SEP> 0.10#2 <tb> <SEP> (1.0, <SEP> MeOH, <SEP> 24) <SEP> 1460, <SEP> 1380 <tb> <SEP> 88 <SEP> H <SEP> Et <SEP> CH2CO2Et <SEP> -CH2- <SEP> CH2Ph <SEP> 12 <SEP> 45.2 <SEP> oil <SEP> -67.9 <SEP> C <SEP> 3460, <SEP> 1742, <SEP> 1642, <SEP> 0.70#5 <tb> <SEP> (1.2, <SEP> MeOH, <SEP> 24) <SEP> 1428, <SEP> 1180 <tb> <SEP> 89a <SEP> H <SEP> H <SEP> H <SEP> # <SEP> H <SEP> 16 <SEP> 33 <SEP> 216-218 <SEP> (dec.) <SEP> -141.1 <SEP> B <SEP> 2600, <SEP> 1743, <SEP> 1550, <SEP> 0.20#6 <tb> <SEP> (H2O) <SEP> (0.3, <SEP> MeOH, <SEP> 23) <SEP> 1250, <SEP> 1230, <SEP> 800 <tb> <SEP> 89b <SEP> H <SEP> H <SEP> H <SEP> # <SEP> H <SEP> 16 <SEP> 45 <SEP> 218-226 <SEP> (dec.) <SEP> +1.5 <SEP> B <SEP> 3310, <SEP> 1610, <SEP> 1575, <SEP> 0.20#6 <tb> <SEP> (H2O) <SEP> (0.5, <SEP> MeOH, <SEP> 23) <SEP> 1160, <SEP> 742 <tb> <SEP> 90 <SEP> H <SEP> Et <SEP> COCH2Ph <SEP> -CH2- <SEP> CH2Ph <SEP> 14 <SEP> 89 <SEP> 110-110.5 <SEP> -114.0 <SEP> A <SEP> 3460, <SEP> 1739, <SEP> 1635, <SEP> 0.45#7 <tb> <SEP> (benzene-n-hexane) <SEP> (1.0, <SEP> MeOH, <SEP> 24) <SEP> 1436, <SEP> 1200, <SEP> 1166 <tb> <SEP> 91 <SEP> H <SEP> Et <SEP> COCH2Ph <SEP> -CH2- <SEP> H <SEP> 13 <SEP> quant. <SEP> oil <SEP> -99.7 <SEP> D <SEP> 1743, <SEP> 1640, <SEP> 1445, <SEP> 0.35#5 <tb> <SEP> (1.1, <SEP> MeOH, <SEP> 23) <SEP> 1187 <tb> <SEP> 92 <SEP> H <SEP> H <SEP> COCH2Ph <SEP> -CH2- <SEP> H <SEP> 7 <SEP> 83 <SEP> 205-206 <SEP> -123.5 <SEP> A <SEP> 3430, <SEP> 1727, <SEP> 1635, <SEP> 0.38#8 <tb> <SEP> (EtOAc-MeOH) <SEP> (1.0, <SEP> MeOH, <SEP> 24) <SEP> 1598, <SEP> 1426, <SEP> 1184 <tb> <SEP> 93 <SEP> H <SEP> Et <SEP> CO(CH2)2Ph <SEP> -CH2- <SEP> CH2Ph <SEP> 14 <SEP> 93 <SEP> oil <SEP> -93.2 <SEP> C <SEP> 1746, <SEP> 1655, <SEP> 1647, <SEP> 0.51#7 <tb> <SEP> (1.0, <SEP> MeOH, <SEP> 24) <SEP> 1447, <SEP> 1188 <tb> <SEP> 94 <SEP> H <SEP> Et <SEP> CO(CH2)2Ph <SEP> -CH2- <SEP> H <SEP> 13 <SEP> quant. <SEP> oil <SEP> -94.7 <SEP> D <SEP> 1746, <SEP> 1642, <SEP> 1449, <SEP> 0.38#5 <tb> <SEP> (1.2, <SEP> MeOH, <SEP> 23) <SEP> 1190, <tb> <SEP> 95 <SEP> H <SEP> H <SEP> CO(CH2)2Ph <SEP> -CH2- <SEP> H <SEP> 7 <SEP> 96 <SEP> amorph. <SEP> -104.3 <SEP> A <SEP> 3440, <SEP> 1735, <SEP> 1610, <SEP> 0.45#8 <tb> <SEP> (1.0, <SEP> MeOH, <SEP> 24) <SEP> 1450, <SEP> 1185 <tb> <SEP> 96 <SEP> H <SEP> Et <SEP> CH2Ph <SEP> -CH2- <SEP> CH2Ph <SEP> 12 <SEP> 46 <SEP> oil <SEP> -66.0 <SEP> D <SEP> 1740, <SEP> 1639, <SEP> 1450, <SEP> 0.57#7 <tb> <SEP> (1.2, <SEP> MeOH, <SEP> 25) <SEP> 1425, <SEP> 1185 <tb> <SEP> 97 <SEP> H <SEP> H <SEP> CH2Ph <SEP> -CH2- <SEP> H <SEP> 7 <SEP> 87 <SEP> amorph. <SEP> -59.0 <SEP> A <SEP> 3420, <SEP> 1720, <SEP> 1638, <SEP> 0.17#2 <tb> <SEP> (1.1, <SEP> MeOH, <SEP> 25) <SEP> 1448, <SEP> 1385 <tb> <SEP> 98 <SEP> H <SEP> H <SEP> COCH3 <SEP> CH2CH2Ph <SEP> H <SEP> 14 <SEP> 62 <SEP> 195-196 <SEP> (dec.) <SEP> B <SEP> 1758, <SEP> 1720, <SEP> 1615, <tb> <SEP> -CHCO2H <SEP> (EtOAc) <SEP> 1600, <SEP> 1380, <SEP> 750, <tb> <SEP> 700 <tb> Table-continued EMI47.1 <SEP> Method <SEP> mp <SEP> ( C) <SEP> [&alpha;]D <SEP> deg. <SEP> IR <SEP> spectrum <SEP> Rf <tb> <SEP> of <SEP> Yield <SEP> (Recrystn. <SEP> value#2 <tb> Compd.+ <SEP> T4 <SEP> T7 <SEP> T8 <SEP> T9 <SEP> T10 <SEP> prepn. <SEP> (%) <SEP> solvent) <SEP> (c, <SEP> solv., <SEP> C) <SEP> Sampling#1 <SEP> cm-1 <SEP> (SiO2) <tb> <SEP> No.) <tb> <SEP> 99#11 <SEP> # <SEP> H <SEP> CH2CH2Ph <SEP> H <SEP> H <SEP> 16 <SEP> 24 <SEP> amorph. <SEP> B <SEP> 3425, <SEP> 1735, <SEP> 0.66#2 <tb> <SEP> -CHCO2H <SEP> 1625, <SEP> 1588 <tb> <SEP> 100 <SEP> H <SEP> Et <SEP> # <SEP> # <SEP> CH2Ph <SEP> 14 <SEP> 37 <SEP> oil <SEP> -46.9 <SEP> C <SEP> 1740, <SEP> 1642, <SEP> 0.20#9 <tb> <SEP> (0.5, <SEP> MeOH, <SEP> 23) <SEP> 1453, <SEP> 1425, <tb> <SEP> 1170, <SEP> 740 <tb> <SEP> 101 <SEP> H <SEP> Et <SEP> # <SEP> # <SEP> H <SEP> 13 <SEP> 90 <SEP> oil <SEP> -35.9 <SEP> 0.25#2 <tb> <SEP> (0.5, <SEP> MeOH, <SEP> 23) <tb> <SEP> 102 <SEP> H <SEP> H <SEP> # <SEP> # <SEP> H <SEP> 7 <SEP> 90 <SEP> 228-230 <SEP> (dec.) <SEP> -33.9 <SEP> B <SEP> 3450, <SEP> 1720, <SEP> 0.34#10 <tb> <SEP> (MeOH) <SEP> (0.4, <SEP> MeOH, <SEP> 23) <SEP> 1610, <SEP> 1305, <tb> <SEP> 1228, <SEP> 1200, <tb> <SEP> 680 <tb> + a and b represent diastereoisomers of the compound. #1 A; KBr disk, B; nujol mull, C; Neat, D; liquid cell (CHCl3). #2 n-BuOH-AcOH-H2O (4:2:1). #3 n-BuOH-AcOH-H2O (4:1:2). #4 EtOAc-CHCl3-AcOH (10:5:3). #5 EtOAc-EtOH-AcOH (40:1:1). #6 EtOAc-CHCl3-AcOH (7:5:1). #7 Benzene-EtOAc-AcOH (25:25:1). #8 CHCl3-EtOH-AcOH (10:2:1). #9 EtOAc #10 n-Propanol-28% aq. NH3 (7:3). #11 Starting material: 1-(chloroacetyl)-5-(2-hydroxyphenyl)-2-pyrrolidinecarboxylic acid: mp 204-206 C (dec.), [&alpha;]D24 +24.5 (c=1.2, MeOH), IR (nujol, cm-1) 3370, 1698, 1645, 1610, 1595, 1238, 758. PHARMACOLOGICAL TEST 1 It has been known that aldose reductase participates in diabetic cataract which is one of the diabetic complications and that appearance is retarded or depressed by inhibition of the aldose reductse [Acta Societatis Ochth.lmologicae Japonicae, 8D, 1362 (1976)]. The following method is used for the present test. (Method) Aldose reductase is purified from rat lenses according to the method of Hoyman et al. [J. Biol. Chem., 240, 877 (1965)]. Action of the compounds (I) of this invention is evaluated b measurement of optical density according to the J.H. Kinoshita's method [Invest. Ophthal., 1, 713 (1974)]. The reaction mixture for the measurement of the aldose reductase activity is 3.0ml [0.007M phosphate buffer solution (pH 6.2), 0.46M lithium sulfate, 5 x 10-5 NADPH, 4 x 10-4M DL glyceraldehyde, 10U aldose reductase, 10 4 to 10-10M the compounds (I)] as total volume, and the absorbance thereof is measured at 340nm. (Result) Table VI shows that the compounds (I) of this invention have a strong aldose reductase inhibition effect. Table VI. Inhibitory Activity of the Thiazolidine Compounds against Aldose Reductase Compd. 10 (M)*1 No. 50 22 8.2 x 10 10 23 1.1 x 47 1,6 x 10 10 56 1.7 x 57 5.4 x 10-9 Control*2 1.0 x 10-7 Molar concentration of a compound producing 50% inhibition of aldose reductase. *2 Ouercitrin: referred to Acta Societatis Ophthalmologicae Japonicae, 80, 1369-1.w70 (1976). PHARMACOLOGICAL TEST 2 As the method of measurement of angiotensin Iconverting enzyme activity, bioassay fo the contractile response of isolated smooth muscle or the press response of normal animals and biochernical assay for the enyme isolated from lung or other organs of animals are known. The former is found more advantageous than the latter for the examination of the convertion of angiotensin I to angiotensin II in vivo. In the present study, therefore, we adopted the bioassay for contractile response of isolated guinea pig ileum to angiotensin I. (Method) Isolated guinea pig ileum was suspended ip the organ bath containing 20ml of Tyrode's solution of 30 C gassed with 95% O2 + 5% CO2. The contraction induced by the addition of angiotensin I (0.1g/rnl) at intervals of 10 minutes was recorded on a recticorder (Nihon Koden) for 90 seconds using FD pick up (ST-1T-H, Nihon Koden) The test compounds were added to the bath 5 minutes before the addition of angiotensin I. The inhibitory activity of angiotensin I-converting enzyme was calculated by the following formula. A - B A x 100 A: contractile intensity of angiotensin I before addition of the compound B: contractile intensity of angiotensin I after addition of the compound From the fact that kininase II, which destroys bradykinin having contractive action on isolated guinea pig ileum, is thought to be identical with angiotensin I-converting enzyme augmentation of the contractile response to bradykinin by test compounds was examined by using bradykinin (0.005pg/ml) in place of angiotensin I according to the above mentioned method. (Result) Concentration of a number of the compounds of this invention, which produced 50% inhibition of angiotensin I activity or augmentation of bradykinin nativity inducing the contraction of guinea pig ileum, fell in the range of 10 @ 10-9M. PHARMACOLOGICAL TEST 3 The activity of angiotensin I-converting enzyme was measured by spectrophotometry according to the method of D.W. Cushman and H.S. Cheung [Biochem. Pharmacol., 20, 1637 (1971)] . That is, the absorbance of hippuric acid was measured, which is livberated by incubating hippuryl-L-histidyl-L-leucine (HHL) as substrate in the presence of angiotensin I-converting enzyme extracted from rabbit lung. (Method) The reaction mixture is as follows: 100mM phosphate buffer (pH 8.3) 300mM sodium chloride 5mM H)IL 10-3 - 10-9M enzyme inhibitor 5mO enzyme 0.25ml of the above mixture was incubated at 370C for 30 minutes and the reaction was stopped by adding 0.25ml of 1 N hydrochloric acid. To this solution, 1.5ml of ethyl acetate was added in order to extract hippuric acid. 1.0ml of ethyl acetate laier was collected and evaporated to dryness, and the residue obtained was dissolved in 1.0ml of water. The absorbance of this solution was measured at 228nm. The inhibitory activity of angiotensin I-converting enzyme was calculated by the following formula: Percent inhibition = A-B 100 A A: absorbance of reaction solution before addition of the compound B: absorbance of reaction solution after addition of the compound Concentration of compound producing 50% inhibition of angiotensin I-converting enzyme (IC50) The solution containing compounds at the concentration of 1 x 10 -3M to 1 x 10 9 was incubated and percent inhibition at each concentration was calculated according to the above formula, and then IC50, concentration of the compound producing i0% inhibition of the enzyme activity was determined. (Result) IC50 of a number of the compounds of this invention, fell in the range of 10 10 10M. TOXICITY TEST The acute toxicity of compounds 47 and 56 is 1000 1500mg/kg. (Experimental animals) The male ddy-std. strain mice (4 weeks of age, weighing 19-21g) were placed in a breeding room of con- stant temperature and humidity (23+10C, 55+5%) and fed freely pellet diet (CE-2, Clea Japan, Inc.) and water ad. libitum for a week. The mice showing the normal growth were selected for the experiment. (Method of administration) Test compounds ae dissolved in distilled water and admin.stered (i.v.) in a dose of 0.5ml/20g body weight. It is found in the above pharmacological and toxicity test that the compounds (I) of this invention are useful as drugs for therapy or prophylaxis of the diabetic complications and as antihypertensive agents. In case the compounds are used for preventing or relieving diabetic complications, the dosage forms are tablet, capsule, granule, powder, suppository, injection, ophthalmic solution, ophthalmie ointment, etc. These preparations can alse contain general excipients. On the other hand, in case the compounds are used for reducing blood pressure, they can be given with the combination of diuretics such as probenecid, carinamide, hydroflumethiazide, furosemide, and bumetanide same as other antihypertensive agents. The compounds an be administered either orally or parenteralry. The dosage forms are tablet, capsule, granule, powder, suppository, injection, etc. In the treatment of hypertension, these preparations can contain not only general excipi & ts but also other antihypertensive agents such as reserpine, a-methyldopa, guanethidine, clonidine, hydralazine, etc., or S-adrenergic blocking agents such as propranolol, alprenolol, pindolol, bufetolol, bupranolol, bunitrolol, practolol, oxprenolol, indenolol, timolol, bunolol, etc. The dose is adjusted depending on symptom dosage form, etc. But, usual daily dosage is 1 to 5000mg, preferably 10 to 1000mg, in one or a few divided doses.. EXAMPLES OF FORMULATION (1) Oral drug (a) tablet compound 13 SOmg lactose 1 20irg crystalline cellulose 60mg calcium carboymethylcellulose 7mg magnesium separate 3mg Total 240mg compound 22 100mg' lactose 95mg crystalline cellulose 45mg calcium carboxymethylcellulose 7mg magnesium stearate 3mg Total 240mg compound 23 150mg lactose 60mg crystalline cellulose 30mg calcium carboxymethylcellulose 7mg magnesium stearate 3mg Total 250mg compound 56 150mg lactose 60mg crystalline cellulose 30mg calcium carboxymethylcellulose 7mg magnesium stearate 3mg Total 250mg compound 74 150mg lactose 60mg crystalline cellulose 30mg calcium ¯arboxymetìlylcelluJose 7mg magnesium stearate 3mg, Total 250mg compound 88 150mg lactose 60mg crystalline cellulose 30mg calcium carboxymethylcellulose 7mg magnesium stearate 3mg Total 250mg The tablets may be treated with common film-coating and further with sugar-coating. (b) granule compound 13 30mg polyvinylpyrrolidone 25mg lactose 385mg hydroxypropylcellulose 50mg talc 1 Omg Total 500mg compound 22 30mg polyvinylpyrrolidone 25mg lactose 385mg hydroxypropyicellulose 50mg talc 10mg Total 500mg compound 94 30mg polyvinylpyrrolidone 25mg lactose 385mg hydroxypropylcellulose 5 Omg talc 10mg Total 500mg (c) powder compound 13 250mg lactose 240mg starch 480mg colloidal silica 30ng Total 1000mg compound 65 300mg lactose 230mg starch 440mg colloidal silica 30mg Total 1000mg compound 79 300mg lactose 230mg starch 440mg colloidal silica 30mg Total 1000mg compound 100 300mg lactose 230mg starch 440mg colloidal silica 30mg Total 1000mg (d) capsule compound 13 50mg lactose 102mg crystalline cellulose 36mg colloidal silica 2mg Total 190mg compound 23 100mg lactose 52mg crystalline cellulose 36mg coiloidal silica 2mg Total 190mg compound 74 200mg glycerin 179.98mg butyl p-hydroxybenzoate 0.02mg Total 380mg compound 81 30mg glycerin 349.98mg butyl phydro'cybenzoate 0.02mg Total 380mg compound 98 200mg glycerin 179.98mg butyl p-hydroxybenzoate 0.02mg Total 380mg (2) Injection (a) 1 to 30mg of compound 9B is contained in 1ml cf the aqueous solution (pH 6.5-7.0). (b) 1 to 30mg of compound 73 is contained in 1m1 of the aqueous solution (pH 6.5-7.0). (3) Ophtha'mic solution The following composition is contained in 5ml of the aqueous solution (pH 6.0). Compound 23 50mg propyl p-hydroxybenzoate 0.7mg methyl p-hydroxybenzoate 1.3mg sodium hydroxide proper quantity (4) Ophthalmic ointment The following composition is contained in lg. compound 22 2Cmg white petrolatum 889.8mg mineral oil 100mg butyl p-hydroxybenzoate 0.2mg (5) Suppository The followirg composition is contained in lg. compound 47 50mg polyethylene glycol 1000 800mg polyethylene glycol 4000 150mg

Claims: @ '- 'a v s V CLAIMS 1. A compound of the formula [I] EMI61.1 wherein QÚ and Q2 each is methylene or sulfur, but Q1 and Q2 are not sulfur at the same time; RA is Ra or Rb RB and RC each is RC; EMI61.2 wherein EMI61.3 Ra is selected from the group consisting of (i) hydrogen, lower alkyl and luwer alkenyl, and (ii) lower alkyl and lower alkenyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, mercapto. acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; ; Rbis selected from the group consisting of (a) (i) aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl,...and (ii) aralkyl, heteroaitalkyl, aralkenyl and heteroaralkenyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, halogeno-lower alkyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, acyloxy, halogen, nitro, cyao, amino, lower alkylamino, dialkylamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl, and (iii) carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl and heteroaryloxycarbonyl; ; (b) (i) phenyl and naphthyl, and (ii) phenyl and naphthyl substituted by at least one substituent elected from the group consisting of lower alkyl, lower alkenyl, halogeno-lower alkyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, arolkyloxy, aryloxy, acyloy, halogen, nitro, cyano, amino, lower alkylamino, dialkilamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; ; (c) (i) furyl, thienyl and pyridyl, and (ii) furyl, thienyl and pyridyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, halogeno-lower alkyl, hydroxy, lower-alko, halogeno-lower alkoxy, aralkyloxy, aryloxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, aclaninc, mercapto, acylmercapto, lower alkylthio, car.F,oxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyi, sulfamoyl, lower alkylaminosulfonyl d lower alkylsulfinyl; ; RC is selected from the group consisting of (a) (i) hydroxy, lower alkoxy and amino, and (ii) lower alkoxy and amino substituted by at least one substituent selected from the group consisting of lower alkyl, aralkyl, heteroaralkyl, aralkenyl, heteroaralkenyl, hydroxy, lower alkoxy, aralkyloxy, heteroaralkylony, aryloxy, heteroaryloxy, acyloxy, aryl, heteroaryl, substituted aralkyl and substituted aryl wherein the substituent is lower alkyl, lower alkoxy, halogen or amino; ; (b) (i) aryloxy and heteroaryloxy, and (ii) aryloxy and hettroaryloxy substituted by at least one substituent selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, halogen and amino, and EMI63.1 Rdis selected from the group consisting of (a) (i) hydrogen, lower alkyl, lower alkenyl, aralkyl, heteroaralkyl, a'kanoyl, arylalkanoyl, heteroarylalkanoyl, hydroxy, carboxy, amino, mercapto and sulfo, and (ii) lower alkyl, lower alkenyl, aralkyl, heteroaralkyl, alkanoyl, arylalkanoyl, heteroarylalkanoyl, hydroxy, carboxy, amino, mercapto and sulfo substituted by at least one substituent selected from the group consisting of lover alkyl, lower alkonyl, lower alkoxy, lower alkanoyl, aryl, heteroaryl, acyloxy, aroyl, hydroxy, carboxy, amino, guanidino, mercapto, acylamino, acylmerca -to, lower alkoxycarbonyl, sulfo, halogen, nitro, cyano, sulfamoyl, lower alkylaminosulfonyl, lower alkylthio and lower alkylsulfinyl; (b) (i) phenyl and naphdiyl, and (ii) phenyl and naphthyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkanoyl, acyloxy, hvdroxy, carboxy, amino, halogeh, nitro, cyano, acylamino, mercapto, acylmercapto, halogeno-lower alkyl, halogeno-lower alkoxy, lower alkylenedioxy, lower alkoxycarbonyl, sulfo, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; ; (c) (i) furyl, thienyl and pyridyl, and (ii) furyl, thienyl and pyridyl substituted by at least bne substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkanoyl, acyloxy, hydroxy, carboxy, amino, halogen, nitro, cyano, acylamino, mercapto, acylmercapto, halogeno-lower alkyl, halogeno-lower alkoxy, lower alkylenedioxy, loer alkoxycarbonyl, sulfo, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; and salts thereof. 2. A compound of claim 1 wherein -Q1-Q2- is -CH2CH2-, -SCH2- or -CH2S-. 3. A compound of claim 1 wherein Ra is hydrogen, methyl, thyl, 1-methylethyl, propyl, 2-methylpropyl, butyl, 2,6dimethyl-5-heptenyl, cyclohexyl, S-acetyl-2-mercaptoethyl or 2-mercaptcthy1. 4. A compound of claim 1 wherein Rb is benzyl, 2-phenylethyl, 4-methylbenzyl, 4-methoxybenzyl, 2-hydroxybenzyl, 4hydroxybenzyl, 3-fluorobenzyl, 3-nitrobenzyl, 3-cyanobenzyl, 2-(4-methoxyphenyl)ethyl, 2-(2-hydroxyphenyl)ethyl, 2-(4hydroxyphenyl)ethyl, 2-(3-fluorophenyl)ethyl, 2-[3-(trifluoro- methyl)phenyl]ehtyl, 2-(3-nitrophenyl)ethyl, 2-(3-cyanophenyl)ethyl, 2-pyridylmethyl, 4-pyridlmethyl, 2-furylmethyl, 2- (2- pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(2-furyl)ethyl, phenyl, 4-methylphenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-chloro-5-nitrophenyl, 4-dimethy aminophenyl, 4-acetaminophenyl, 4-[(benzyloxycarbonyl)amino]phenyl, 2-carboxyphenyl, 4-carboxyphenyl, 2-hydroxyphenyl, 3-hydroxy phenyl, 4-hydroxyphenyl, 3-benzoxyphenyl, 4-(benzylosycarbonyloxy)- phenyl, 3,4-dihydroxyphenyl, 5-chloro-2-hydroxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-hydroxy-3-methoxyphenyl, 2-hydroxy-4-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 3,4-methylenedioxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-nitrosophenyl, 3nitrosophenyl, 4-nitrosophanyl, 2-hydroxy-5-sulfamoylphenyl, 2-hydroxy-5-[(dipropylamino)sulfonyl)phenyl, 3-(methylsulfinyl)phenyl, 3-(difloromethoxy)phenyl, l-naphthyl, 2-furyl, 2-(5-methyl) furyl, 2-thienyl, 3-pyridyl or 4-pyridy. 5. A compound of claim 1 wherein Rc is hydroxy, methoxy, ethoxy, butoxy, amino, hydroxyamino, succinimidomethoxy, 1succinimidoethoxy, phthalimidomethoxy, 2-phthalimidoethoxy, pivaloyloxymethoxy, l-pivaloyloxyethoxy, benzyloxy, phenoxy, benzyloxyarnino or EMI65.1 6. A compound of claim 1 wherein R@ is hydrogen, methyl, ethyl, propyl, 1-methylethyl, 2-methylpropl, 4-methylpentyl, vinyl, allyl, 2-butenyl, 1,3-butanedienyl, 1-methylvinyl, hydroxymethyl, carboxymethyl, 2-carboxyethyl, cyclohexyl, cyclohexylmethyl, benzyl, 2-phenylethyl. 3-phenylbutyl, 2-(1-naphthyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(3,4-dichlorophenyl)ethyl, 4-methoxybenzyl, 2-(4-methoxyphenyl) ethyl, 4-hydroxybenzyl, 2-(4-hydroxyphenyl)ethyl, (2-pyridyl)methyl, (4-pyridyl)methyl, 2-(2-pyridyl)ethyl, 2-(4-pyridyl)ethyl, (4-imidazolyl)methyl, 3-indolylrtethyl, 2-(methylthiojethyl, 4-aminobutyl, 5-aminopentyl, 4-guanidinobutyl, 4- (aminomethyl)benzyl, phenoxy- methyl, (phenylthio)methyl, 1-amino-2-phenylethyl, l-amino 3-methylb.'yl phenyl, naphthyl, 4-methylphenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-chloro-5-nitrophenyl, 4-dimethylaminophenyl, 4-acetaminophenyl, 2-carboxyphenyl, 4-carboxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-benzoxyphenyl, 3,4 dihydroxyphenyl, 5-chloro-2-hydroxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-ydroxy-3-methoxyphenyl, 2-hydroxy-5-sulfamoylphenyl, 3 (methylsulfinyl) phenyl, 3-(difluoromethoxy)phenyl, 2-furyl, 2-(5 methyl)furyl, 2-thienyl, 3-pyridyl or 4-pyridyl. EMI66.1 9. A compound of claim 4 which is (4R)-3-[8-(ethoxycarbonyl)octanoyl]-2-(3-nitrophenyl)-4-thiazolidinecarboxylic acid. 10. A compound of claim 4 which is (4R,4'R)-3,3'-(nonane diOyl)bis[2-(3-nitrophenyl)-4-thiazolidineearboxylie acid methyl ester]. 11. A compound according to claim 4 which is (4R)-3-(11- carboxyundecanoyl)-2-(3-cyanophenyl)-4-thiazolidinecarboxylic acid: (4R.4'R)-3,3'-(decaredioyl)bis(2-(3-cyanophenyl)-4-thiazelidine carboxylic aídJZ (4R,4'R)-3,3'-(dececanedioyl)bis(2-(3-cyanophenyl)-4thiazolidinecarboxylic acid; (4R)-3-(3-carboxyoctanoyl)-2-(3-nitrophenyl)-4-thiazolidine carboxylic acid; (4R,4'R)-3,3'-(nonanedioyl)bis[2-(3-nitrophenyl)-4-thiazolidine- carboxylic acid]; (4R)-3-(7-carboxyheptanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid. 12. A compound according to claim 4 which is (4R)-3 [[(1-carboxy-3-phneylpyropyl)amino]acetyl)-2-(20hydroxyphenyl)4-thiazolidinecarboxylic acid; (4R)-3-[ [[l-(ethoxycarbonyl)-3-phenylpropyl]amino]acetyi]-2- (2-hydroxyphenyl)-4-thiazolidinecarboxylic acid. 13. A compound according to claim 4 which is 1-[[(1- carboxy-3-phenylpropyl)amino]acetyl]-2-(2-hydroxyphenyl)-5pyrrolidinecarboxylic acid; 1-[[[1-(ethoxycarbonyl)-3-phneylpropyl]-amino]acetyl]-2-(2hydroxyphenyl)-5-pyrrolidinecarboxylic acid. 14. A compound of claim 4 which is (4R)-3-[[(l-carboxy- 30phenylpropyl)thio]acetyl]-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid. 15. A compound of claim 4 which is (4p)-3-(4-carboxy- butanoyl)-2-(2-hydroxyphneyl)-4-thiazolidinecarboxylic acid. 16. A process for preparing a compound of the formula [I] EMI68.1 wherein QÚ and Qê each is methylene or sulfur, but QÚ and Qê are not sulfur at the same time; RA is Ra or Rb; RB and RC each is Rc; EMI68.2 where X, Y and Z each is sinyle bond, EMI68.3 EMI68.4 Ra is selected from the group consisting of (i) hydrogen, lower alkyl snd lower alkenyl, and (ii) lower alkyl and lower alkenyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, merapto, acylmercapto, lower alkylthto, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; Rbis selected from the group consisting of (a) (i) aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl, and (ii) aralkyl, heterQaralkyl, aralkenyl and heteroaralkenyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, halogeno-lower alkyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, 'nercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl, and fiii) carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl and heteroaryloxycarbonyl; ; (b) (i) phenyl and naphthyl, an2 (ii) phenyl and naphthyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower a:kenyl, halogeno-lower alkyl1 hydroxy, lower alkoxy, halogeno-lower alkoxy, aralkyloxy, aryloxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamiiio, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxyca-bonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; ; (c) (i) furyl, thienyl and pyridyl, and (ii) furyl, thienyl and pyridyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, halogeno-lower alkyl, hydroxy, lower alkoxy, halogeno-lower alkoxy aralkyloxy, aryloxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbo.nyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; ; RC is selected from the group consisting of (a) (i) hydroxy, lower alkoxy and amino, and (ii) lower alkoxy anJ aminc substituted by at least one substituent selected from the group consisting of lower alkyl, aralkyl, heteroaralkyl, aralkenyl, heteroaralkenyl, hydroxy, lower alkoxy, aralkyloxy, heteroaralkyloxy, aryloxy, heteroaryloxy, acyboxy; aryl, heteroaryl, srtstituted aralkyl and substituted aryj wherein the substituent is lower alkyl, lower alkoxy, halogen or amino; ; (b) (i) aryloxy and heteroaryloxy, and (ii) aryloxy and heteroaryloxy substituted by at least one substituent selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, halogen and amino, and EMI70.1 RC is selected from the group consisting of (a) (i) hydrogen, lower alkyl, lower alkenyl, aralkyl, heteroaralkyl, alkanoyl, arylalkanoyl, heteroarylalkanoyl, hydroxy, carboxy, amino, mercapto and sulfo, and (ii) lower alkyl, lower alkenyl, aralkyl, heteroaralkyl, alkanoyl arylalkanoyl, heteroarylalkanoyl, hydroxy, carboxy, amino, mercapto and sulfo substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, lower alkanoyl, aryl, heteroaryl, acyloxy, aroyl, hydroxy, carboxy, amino, quanidino, mercapto, acylamiflo, acylmercapto, lower alkoxycarbonyl, sulfo, halogen, nitro, cyano, sulfamoyl, lower alkylaminosulfonyl, lower alkylthio and lower alkylsulfinyl; (b) (i) phenyl and naphthyl, and (ii) phenyl and naphthyl substituted by at least one substituent selected from the group consisting of lo:;er alkyl, lower alkoxy, lower alkanoyl, acyloxy, hydroxy, carboxy, amino, halogen, nitro, cyano, acylamino, mercaptc, acylmercapto, halogeno-lower alkyl, halogeno-lower alko, lower alkylenedioxy, lower alkoxycarbonyl, sulfo, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; ; (c) (i) furyl, thienyl and pyridy3, and (ii) furyl, thienyl and pyridyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkanoyl, acyloxy, hydroxy, carboxy, amino, halogen, nitro, cyano, acylamino, mercapto, acylmercapto, halogeno-lower alkyl, halogeno-lower alkoxy, lower alkylenedioxy, lower alkoxycarbonyl, sulfo, sulfamoyl, lower alkyl aminosulfonyl and lower alkylsulfinyl; and salts thereof which comprises (i) reacting a compound of the formula [II] EMI71.1 wherein RA and RB may include suitable protection of any reactive groups with the reactive derivative of a carboxylic acid of the formula [,IIj (e.g., acyl halide, acid nahydride, mixed anhydride, active ester, etc.) HOOC-W-CO-RC t wherein RC and W may include suitable protection of any reactive groups, followed by removal of protective groups, if necessary, to yield a compound of the formula [I]; ; (ii) reacting a compound of the formula [IT] with the reactive derivative of carboxylic acid of the formula [IV] HOOC-W1-L [IV] wherein W- is EMI72.1 and may include suitable protection of any reactive groups, and L is a leaving group to yield a compoun of the formula [V] EMI72.2 and then reacting z compound of the formula [V] with a compounds of the formula [V1] (H)X-Wê-Y-W -Z-W4-CO-RC [VI] wherein W¯ EMI72.3 and W2, W3, W4, X, Y, Z and RC may include suitable protection of any reactive groups, followed by removal of protective groups, if necessary, to yield a compound of the formula II]; ; (iii) reacting a compound of the formula [II] with the reactive derivative of carboxylic acid of the formula [VII] HOOC-WÚ-X-Wê-L [VII], and then with a compound of the formula [VIII] (H)Y-W -Z-W4-CO-RC [VIII] by the same method as (ii) above to yield a compound of the formula [I]; (iv) reacting a compound of the formula [II] with the reactive derivative of carboxylic acid of the formula IIX] HOOC-WÚ-X-Wê-Y-W -L [IX] and then with a compound of the formula [X] (H)Z-W4-CO-RC [X] by the same method as (ii) above to yield a compound of the formula [I'; ; (v) reacting a compound of the formula [II] with the reactive derivative of carboxylic acid of the formula [XIj HOOC-WÚ-X(H) [XI], and then with a compound of the formula IXII] L-Wê-Y-W -Z-W4-CO-RC [XII] by the same method as (ii) above to yield a compcund of the formula [I]; ; (vi) reacting a compound of the formula [II] with the reactive derivative of carboxylic acid of the formula [XIII] HOOC-W1-X-W2-Y(H) [XIII], and then with a compound of the formula [XIV3 L-W -Z-W4-CO-RC [XIV] by the same method as (ii) above to yield a compound of the formula [I], or (vii) reacting a con pound of the formula [II] with the reactive derivative of carboxylic acid of the formula [XV] HOOC-WÚ-X-Wê-Y-W -Z(H) [XV], and then with a compound of the formula [XVI] L-W4-CO-R C [XVI] by the same method as (ii) above to yield a compound of the formula [I]; furthermore converting RB, RC, X, Y and Z to other functional groups by the general methods, if desired, to obtain a desired compound of the formula [I]. 17. A composition comprising a compound of the formula EMI75.1 wherein 2 Q1 and @ each is methylene or @@@@@@@ but @ and Q2 are not sulfur at the same time; RA is Ra or Rb; RB and RC each is RC; EMI75.2 wherein X, Y and Z each is single bond, EMI75.3 EMI75.4 EMI76.1 1, m, n, p, q, r, s and t each is 0, 1, 2 or 3; ; R1 R2, R3 .., R20 and R21 each is Rd R is selected from the group consisting of (i) hydrogen, lower alkyl and lower alkenyl, and (ii) lower alkyl and lower alkenyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; ; Rub is selected from the group consisting of (a) (i) aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl, and (ii) aralkyl, heteroaralkyl, aralkenyl and her.eroaralkenyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, halogenolower alkyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino. dialkylamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloe yzarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl, and (iii) carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl and heteroaryloxycarbonyl; (b) (i) phenyl and naphthyl, and (ii) phenyl and naphthyl subst: :.tuted by at least one subsituent selected from the group consisting of lower alkyl, lower alkenyl, halogeno-lower alkyl, hydroxy, lower alkoxy, halogeno-lowr alkoxy, aralkyloxy, aryloxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsdlfinyl; ; (c) (i) furyl, thienyl and pyridyl, and (ii) furyl, thienyl and pyridyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, halogeno-lower alkyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, aralkyloxy, aryloxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonvl, sulfamoyl, lower alkylc-.minosulfonyl.and lower alkylsulfinyl; ; Rc is selected from the group consisting of (a) (i) hydroxy, lower alkoxy and amino, and (ii) lower alkoxy and amino substituted by at least one substituent selected from the group consisting ol¯ lower alkyl, aralkyl, heteroaralkyl, aralkenyl, heteroaralkenyl, hydroxy, lower alkoxy, aralkyloxy, heteroaraikyloxy, aryloxy, heteroaryloxy, acyloxy, aryl, heteroaryl, substituted aralkyl and substituted aryl wherein the substituent is lower alkyl, lower alkoxy, halogen, or amino; ; (b) (i) aryloxy and heteroaryloxy, and (ii) aryloxy ard heteroaryloxy substituted by at least one subsituent selected from the group consisting of lcwer alkyl, hydroxy, lower alkoxy, halogen and amino, and EMI77.1 Rd is selected from the group consisting of (a) (i) hydrogen, lower alkyl, lower alkenyl, aralkyl, heteroaralkyl, alkanoyl, arylalkanoyl, heteroaryllkanoyl, hydroxy, carboxy, amino, mercapto and sulfo, and (a) (ii) lower alkyl, lower alkenyl, aralkyl, heteroaralkyl, alkanoyl, arylalkanoyl, heteroarylalkanoyl, hydroxy, darboxy, amino, mercapto and sulfo substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, lower alkanoyl, aryl, heteroaryl, acyloxy, aroyl, hydroxy, carboxy, amino, guanidino, mercapto, acylamino, acylmercapto, lower alkoxycarbonyl, sulfo, halogen, nitro, cyano, sulfamoyl, lower alkylaminosulfonyl, lower alkylthio and lower alkylsulfinyl; (b) (i) phenyl and naphthyl, and (ii) phenyl and naphthyl substituted by at least on substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkanoyl, acyloy, hydroxy, carboxy, amino, halogen, nitro, cyano, acylamino, mercapto, acylmercapto, halogeno-lower alkyl, halogeno-lower alkoxy, lower alkylenedioxy, lower alkoxycarbonyl, sulfo, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; ; (c) (i) furyl, thienyl and pyridyl, and (ii) furyl, thienyl and pyridyl substituted by at least one substituent selected from the group consistIng of lower alkyl, lower alkoxy, lower alkanoyl, acyloy, hydroxy, carboxy, amino, halogen, nitro, cyano, acylamino, mercap'o, acylmercapto, halogeno-lower alkyl, halogeno-lower alkoxy, lower lkylenedioxy, lowe.t alkoxycarbonyl, sulfo, sulfaTDoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; or. salts thereof in an amount sufficient to prevent or relieve diabetes mellitus associated complications consisting of cataracts, neuropathy, nephropathy and retinopathy, and pharmaceutically acceptable excipient(s) 18. A composition comprising a compound of the formula [I] EMI79.1 wherein QÚ and Qê each is methylene or sulfur, but QÚ and Qê are not sulfur at the same time; RA is Ra or Rb; RB and RC each is Rc; EMI79.2 wherein X, Y and Z each is single bond, -CH2-, #, -C#C-, EMI79.3 1, m, n, p, q, r, s and t each is 0, 1, 2 or 3; ; R1 R2 R3 ..., R20 and R21 each is Rd RA is Rb when W is or , wherein R EMI79.4 R23 R24 R25 and R26 each is Rd Ra is selected from the group consisting of (i) hydrogen, lower alkyl and lower alkenyl, and (ii) lower alkyl and lower alkenyl substituted by at least one substitnt selected from the group consisting of lower alkyl, lower alkenvl, hydroxy, lower alkoxy, halogeno-lower alkoxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; ; Rub is selected from the group consisting of (a) (i) aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl, and (ii) aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl substitutd d b at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, halogenolower alkyl, hydroxy lower alkoxy, halogeno-lower alkoxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamino, dialkylamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxy carbonyl, aryloxycarbonyl, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl, and (iii) carboxy, lower alkoxycarbonyl, aralkyloxycarbony', aryloxycarbonyl and heteroaryloxycarbonyl; ; (b) (i) phenyl and naphthyl, and (ii) phenyl and naphthyl substituted by at least one substituent selected from. the group consisting of lower alkyl, lower alkenyl, halogeno-lower alkyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, aralkyloxy, aryloxy, acyloxy, halogen, nitro, canto, amino, lower alkylamino, dialkylamino, acylamino, mercapto, acvlmel-apto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, sulfamoyl, lower alkylsulfonyl and lower alkylsulfinyl; ; (c) (i) furyl, thienyl and pyridyl, and (ii) furyl, thienyl and pyridyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, halogeno-lower alkyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, aralkyloxy, aryloxy, acyloxy, halogen, nitro, cyano, amino, lower alkylamio, dialkylamino, acylamino, mercapto, acylmercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, aryloxttcarbonyl, sulfamoyl, lower alkylsulfonyl, and lower alkylsulfinyl; ; RC is selected from the group consisting of (a) (i) hydroxy, lower alkoxy and amino, and (ii) lower alkoxy and amino substituted by at least one substituent selected from the group consisting of lower alkyl, aralkyl, heteroaralkyl, aralkenyl, heteroaralkenyl, hydroxy, lower alkoxy, aralkyloxy, heteroaralkyloxy, aryloxy, heteroaryloxy, acyloxy, aryl, heteroaryl, substituted aralkyl and substituted aryl wherein the substitutent is lower alkyl, lower alkoxy, halogen or amino; ; (b) (i) aryloxy and heteroaryloxy, a.d (ii) aryloxy and heteroaryloxy substituted by at least one substituent selected from the group consisting of lower alkyl, hydroxy, lower -alkoxy,halogen and and amino, and EMI81.1 Rod is selected from the group consisting of (a) (i) hydrogen, lower alkyl, lower alkenyl, aralkyl, heteroaralkyl, alkanoyl, arylalkanoyl, heteroarylalkanoyl, hydroxy, carboxy, amino, mercapto and sulfo, and (ii) lower alkyl, lower alkenyl, aralkyl, heteroaralkyl, alkacyl, arylalkanoyl, heteroarylalkanoyl, hydroxy, carboxy, amino, mercapto and sulfo substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, lower alkanoyl, aryl, heteroaryl, acyloxy, aroyl, hydroxy, carboxy, amino, quanidino, mercapto, acylamino, acylmercapto, lower alkoxycarbonyl, sulfo, halogen, nitro, cyano, sulfamoyl, lower alkylaminosulfonyl, lower alkylthio and lower alkylsulfinyl; (b) (i) phenyl and naphthyl, and (ii) phenyl and naE:'lthyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkanoyl, acyloxy, hydroxy, cabroxy, amino, halogen: nitro, cyano, acylamino, mercarto, acylmercapto, halogeno-lower alkyl, halogeno-lower alkoxy, lower alkylenedioxy, lower alkoxycarbonyl, sulfc, sulfamoyl, lower alkylaminosulfonyl and lower alkylsulfinyl; (c) (i) furyl, thienyl and pyridyl, and (ii) furyl, thienyl and pyridyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkanoyl, acyloxy, hydroxy, carboxy, amino, halogen, nitro, cyano, acylamino, mercapto, acylmercapto, halogeno-lower alkyl, halogenolower alkoxy, lower alkylenedioxy, lower alkoxycarbonyl, sulfo, sulfamoyl, lower alkylaminosulfonyl and lower alkylslfinyl; ; or salts thereof in an amount sufficient to reduce blood pressure and pharmaceutically acceptable excipient(s) 19. A compound according to claim I to 16 for use In a method for therapy or prophyl3xis. 20. Use of a compound according to claim 1 to 16 in a process for producing pharmaceutical compositions.

Inventors: ISO, TADASHI, OYA, MASAYUKI
Applicants: SANTEN PHARMACEUTICAL CO., LTD.
Application year: 1980
Main classification: C07D277
IPC codes: A61P27, C07D207, A61K31, C07K5, C07D277, A61K38, A61P3