AU9282398A - 4, 5-diaryloxazole compounds - Google Patents

Description

WO 99/21843 PCT/JP98/04455 DESCRIPTION 4,5-DIARYLOXAZOLE COMPOUNDS 5 TECHNICAL FIELD This invention relates to new 4,5-diaryloxazole compounds and pharmaceutically acceptable salts thereof which are useful as a medicament. 10 BACKGROUND ART Prostaglandins are known as autacoids that show a various kind of biological effects. Specifically, prostaglandin 12 (hereinafter, referred as PGI 2 ) is known to have inhibitory activity on platelet aggregation, vasodilating activity, antihypertensive activity and the 15 like. Therefore, PGI 2 agonists are expected to show the above activities which are useful as a medicament for therapeutic and/or prophylactic treatment of arterial obstruction, cerebrovascular disease, hepatic cirrhosis, arteriosclerosis, ischemic heart disease, restenosis after percutaneous transluminal coronary angioplasty, 20 hypertension, dermatosis or the like. So far, some 4,5-diaryloxazole compounds having pharmacological activities as PGI 2 agonists have been known, for example, in WO 95/17393, WO 95/24393, WO 97/03973, EP 0 542 203 and USP 5,362,879. 1 WO 99/21843 PCT/JP98/04455 DISCLOSURE OF INVENTION This invention relates to 4,5-diaryloxazole compounds having novel structures. More particularly, it relates to new 4,5 5 diaryloxazole compounds and pharmaceutically acceptable salts thereof, their production process, a pharmaceutical composition containing the same and a use thereof for the manufacture of medicaments. Accordingly, an object of this invention is to provide new 10 and useful 4,5-diaryloxazole compounds and pharmaceutically acceptable salts thereof. Another object of this invention is to provide processes for the production of the 4,5-diaryloxazole compounds and salts thereof. 15 A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, said 4,5-diaryloxazole compounds or pharmaceutically acceptable salts thereof. Another object of this invention is to provide a use of the 20 4,5-diaryloxazole compounds and pharmaceutically acceptable salts thereof as a prostaglandin I2 agonist. Still further object of this invention is to provide a use of the 4,5-diaryloxazole compounds and pharmaceutically acceptable salts thereof for the manufacture of medicament for therapeutic 2 WO 99/21843 PCT/JP98/04455 and/or prophylactic treatment of arterial obstruction, cerebrovascular disease, hepatic cirrhosis, arteriosclerosis, ischemic heart disease, restenosis after percutaneous transluminal coronary angioplasty, hypertension, dermatosis or 5 the like. The 4,5-diaryloxazole compounds of this invention can be represented by the following formula (I) R

R

9

R

7 O ',N R 2 R3 4 X R X R5 OCH2COOR' R 6 10 wherein R 1 is a hydrogen atom or a carboxy protective group,

R

2 , R 5 , R 6 and R 7 are each a hydrogen atom or a hydroxy group, R and R 4 are each a hydrogen atom, or are combined together to form an epoxy group or a single bond, 15 R 8 and R 9 are each an optionally substituted aryl group, and X is a single bond or a methylene group, in addition to the above definitions,

R

2 and R 3 may be combined together to form a single bond; 3 WO 99/21843 PCT/JP98/04455 provided that when R 2 , R 5 , R 6 and R 7 are each a hydrogen atom, then R 3 and R 1 are combined together to form an epoxy group; when R 3 and R 4 are combined together to form a 5 single bond, then at least one of R 2 , R 5 , R 6 and R 7 is a hydroxy group and the other(s) is(are) hydrogen atom(s); and when R 3 and R 4 are each a hydrogen atom, then at least one of R 2 , R 5 , R 6 and R 7 is a hydroxy 10 group and the other(s) is(are) hydrogen atom(s), and X is a methylene group. The new 4,5-diaryloxazole compounds (I) can be prepared by the following processes. 15 Process 1

R

8

R

9

R

8

R

9

R

7 O ,N R 7 O , N R2 Oxidation X, b5 X X X a Ra

OCH

2 COOR R 6OCH 2

COOR

1 R (II- 1) (I- 1) or its salt or its salt 4 WO 99/21843 PCT/JP98/04455 Process 2

R

8

R

9

R

8

R

9

R

7 O N

R

7 0 ,N R2 R2 0 Epoxidation R R

OCH

2 COOR R OCH 2 COOR R6 (I-2) (I-3) or its salt or its salt Process 3

R

8

R

9

R

8

R

9

R

7 0 ,N 1) Cyclization R 7 0, N

R

2 OH

R

2 0 OH 2) Removal of 1 I SX Rs 5 X Rs5 oR 10

R

6 3) Y1-CH 2 COORR ORor its salt OCH2COOR1 R' or its salt (11-2) (I-3) 5 or its salt or its salt Process 4

R

8

R

9

R

8

R

9 R 7b O, N 1) Removal of Rio R 7 O ,N R 2 3,2 3 Rb R b R2 R34

R

4 b 2) Y 1

-CH

2 COOR' R or its salt ____X___ __ Xs Rb R

OR

1 0 6 3) Elimination of 1 6 hydroxy protective OCH 2 COOR (11-3) group(s) if necessary (I-4) or its salt or its salt 5 WO 99/21843 PCT/JP98/04455 Process 5

R

8

R

9

R

8

R

9

R

7 O, N R 7 O ,N

SNR

4 R 2 R R 3 4R2R34 Hydrolysis R R

OCH

2

COOR

1 Ra6 OCH 2 COOH R 6 (I-5) (I-6) or its salt or its salt 5 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and X are as defined above, Y1 is a leaving group, RIO is a hydroxy protective group,

R

1 a is a carboxy protective group, 10 any one of R 2 a and R 5 sa is a hydroxy group and the other is a hydrogen atom or a hydroxy group,

R

2 b, R 5 b, R 6 b and R 7 b are each a hydrogen atom, a hydroxy group or a protected hydroxy group, and

R

3 b and R 4 b are each a hydrogen atom or are combined 15 together to form a single bond, in addition to the above definitions,

R

2 b and R 3 b may be combined together to form a single bond. 6 WO 99/21843 PCT/JP98/04455 Some of the starting compounds are novel and can be prepared by the following processes. Process A OMe OMe 1) OMe I "OMe O AD-mix-ac or 0 p-TSA 0 HO 0 2) Hydrolysis OH X X (III) (IV) OH 1) O-c-CI S1) Swern HO O SOxidation 0 Bu 3 SnH, AIBN X 2) (.Br - X 2) p-TSA

OR

1 0 OR 1 o (V) n-BuLi (VI) OH Swern Oxidation 11 HO & R O Protection X I X

OR

I0

OR

10 (VII) (VIII)

R

8

R

9 R 8M 9 R 8

R

9 1) ON O , N n-BuLi

R

11 0 2) Burgess reagent X~

OR

10 5 (11-4) Process B 7 WO 99/21843 PCT/JP98/04455 R8 R9

R

8

R

9 O.N ON

R

11 0 Hydrogenation R1O X X

OR

10

OR

10 (II-4) (II-5) Process C

R

8

R

9

R

8

R

9

R

7 0, N R 7 0 ,N R2 R2 OH N Hydroxylation OH X Xs R R X R

OR

1 0 R OR 10

R

6 (IX) (II-2) 5 wherein R 2 , R s , R 6 , R 7 , R 8 , R 9 , Rlo and X are as defined above, and R" is a hydroxy protective group; AIBN means 2,2'-azobis(isobutyronitrile) and p-TSA means p toluenesulphonic acid. 10 Suitable pharmaceutically acceptable salts of the object compounds (I) are conventional non-toxic salts, specifically metal salts such as alkali metal salts (e.g., sodium or potassium salt) and alkaline earth metal salts (e.g., calcium or magnesium salt), 15 ammonium salts, organic base salts (e.g., trimethylamine, 8 WO 99/21843 PCT/JP98/04455 triethylamine, pyridine, picoline, dicyclohexylamine or dibenzylethylenediamine salt), organic acid salts (e.g., acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate or trifluoroacetate), inorganic acid salts (e.g., 5 hydrochloride, hydrobromide, sulfate or phosphate), salts with an amino acid (e.g., arginine salt, aspartate or glutamate) and the like. In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various 10 definitions which the present invention includes within the scope thereof are explained in detail as follows. The term "lower" is intended to mean 1 to 6 carbon atoms, unless otherwise indicated. 15 Suitable lower alkyl groups may include straight or branched ones having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl or the like, preferably the one having 1 to 4 carbon atoms. 20 Suitable aryl groups may contain 6 to 12 carbon atoms and may be optionally substituted with suitable substituent(s) such as a halogen, amino, hydroxy, a lower alkyl, a lower alkoxy or the like. Specific examples thereof are phenyl, tolyl, xylyl, mesityl, cumenyl and naphthyl. 9 WO 99/21843 PCT/JP98/04455 Suitable carboxy protective groups may include lower alkyl groups (e.g., methyl, ethyl or tert-butyl), mono-(or di- or tri-)halo(lower)alkyl groups (e.g., 2-iodomethyl or 2,2,2 trichloroethyl), ar(lower)alkyl groups (e.g., benzyl) and the like, 5 among which the lower alkyl group is preferred. Suitable hydroxy protective groups may include lower alkyl, benzyl, acyl, tri(lower)alkylsilyl, diaryl(lower)alkylsilyl and the like. Suitable examples of the lower alkyl groups are those as exemplified above. 10 Suitable examples of the acyl groups may include aliphatic acyl groups such as a lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl or pivaloyl), a lower alkoxycarbonyl (e.g., methoxycarbonyl or ethoxycarbonyl), a lower alkanesulfonyl (e.g., mesyl or ethanesulfonyl), and an 15 arenesulfonyl (e.g. benzenesulfonyl or tosyl); and acyl groups containing an aromatic or heterocyclic ring such as an aroyl (e.g., benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl or indancarbonyl), an ar(lower)alkanoyl (e.g., phenylacetyl or phenylpropionyl), an ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl or 20 phenethyloxycarbonyl), and the like. Suitable examples of the tri(lower)alkylsilyl groups may include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, tert-butyldimethylsilyl and the like. 10 WO 99/21843 PCT/JP98/04455 Suitable examples of the diaryl(lower)alkylsilyl groups may include tert-butyldiphenylsilyl and the like. Suitable leaving groups may include a halogen (e.g., chlorine, bromine, iodine or fluorine), a lower alkoxy (e.g., methoxy, 5 ethoxy, propoxy, isopropoxy or butoxy) and the like. Preferred embodiments of the object compounds (I) are as follows : Compounds of the formula (I), 10 wherein RI is a hydrogen atom or a carboxy protective group, any one of R 2 , R 5 , R 6 and R 7 is a hydroxy group and the others are hydrogen atoms,

R

3 and R 4 are each a hydrogen atom,

R

8 and R 9 are each a phenyl group, and 15 X is a methylene group; compounds of the formula (I), wherein R 1 is a hydrogen atom or a carboxy protective group, any one of R 2 , R 5 , R 6 and R 7 is a hydroxy group and the others are hydrogen atoms, 20 R 3 and R 4 are combined together to form an epoxy group or a single bond,

R

8 and R 9 are each a phenyl group, and X is a single bond or a methylene group; and 11 WO 99/21843 PCT/JP98/04455 X is a single bond or a methylene group; and compounds of the formula (I), wherein RI is a hydrogen atom or a carboxy protective group,

R

2 , R 5 , R 6 and R 7 are each a hydrogen atom, 5 R 3 and R 4 are combined together to form an epoxy group,

R

8 and R 9 are each a phenyl group, and X is a single bond or a methylene group. More specifically, the preferred embodiments are as follows: 10 (1) sodium {3-{[2-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2 cyclohexen- 1 -yl]methyl}phenoxy}acetate, (2) sodium {3-{[( 1S)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxy-2 cyclohexen- 1-yl] methyl}phenoxy}acetate, (3) sodium {3-{[( 1S)-2-(4,5-diphenyloxazol-2-yl) -2,3-epoxy-1 15 cyclohexyl]methyl}phenoxy}acetate, (4) sodium (R)-{3-{[2-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2 cyclohexen- 1-yl] methyl}-phenoxy}acetate, (5) sodium {3-{[( 1R,2S)-2-(4,5-diphenyloxazol-2-yl)-1-hydroxy 1-cyclohexyl]methyl}phenoxy}acetate, 20 (6) sodium (S)-{3-{[2-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2 cyclohexen- 1-yl]methyl}phenoxy}acetate, (7) sodium (S)-{3-{[2-(4,5-diphenyloxazol-2-yl)- 1-hydroxy-2 cyclopenten- 1-yl]methyl}phenoxy}acetate, 12 WO 99/21843 PCT/JP98/04455 (8) sodium (R)-{3-{[2-(4,5-diphenyloxazol-2-yl)- 1-hydroxy-2 cyclopenten- 1-yl]methyl}phenoxy}acetate, (9) sodium {3-{[( 1S,2R,3S)-2-(4,5-diphenyloxazol-2-yl)-2,3 epoxy- 1-cyclohexyl]methyl}phenoxy}acetate, 5 (10) sodium {3-{[( 1S,2S,3R)-2-(4,5-diphenyloxazol-2-yl)-2,3 epoxy-1-cyclohexyl]methyl}phenoxy}acetate, and (11) sodium {3-{[( 1S)- 2 -(4,5-diphenyloxazol-2-yl)-2,3-epoxy- 1 cyclopentyl]methyl}phenoxy}acetate. It is to be noted that the object compounds (I) may include 10 one or more stereoisomers due to asymmetric carbon atom(s) and double bond, and that all of such isomers and a mixture thereof are included within the scope of the present invention. It is further to be noted that isomerization or rearrangement of the object compounds (I) may occur due to the effect of the light, 15 acid, base or the like, and the compounds obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention. It is also to be noted that the solvating form of the compounds (I) (e.g., hydrate) and any crystalline form of the 20 compounds (I) are included within the scope of the present invention. Also included in the scope of the invention are radiolabelled derivatives of the compounds (I) which are suitable for biological studies. 13 RECTIFIED SHEET (RULE 91) WO 99/21843 PCT/JP98/04455 The processes for preparing the object and starting compounds of the present invention are explained in detail in the following. 5 Process 1 A compound (I-1) or its salt can be prepared by treating a compound (II-1) or its salt with an oxidant which is capable of oxidizing at the allylic position in the compound (II-1). 10 Suitable oxidants are selenium dioxide, or the like. The reaction is usually carried out in a conventional solvent such as water, an alcohol (e.g., methanol, ethanol or isopropyl alcohol), tetrahydrofuran, dioxane, dichloromethane, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N 15 dimethylacetamide or any other organic solvent which does not adversely affect the reaction. The reaction may be usually carried out under cooling to heating since the reaction temperature is not critical. The compound (I-1) can be also prepared by (1) reacting the 20 corresponding allylic hydroperoxide, which is prepared by reacting a compound (II-1) with singlet oxygen, an alkali (e.g., sodium hydroxide) or a reducing agent (e.g., sulfide) or (2) hydrolysis of the corresponding allylic ester, which is prepared by reacting a compound (II-1) with a lower alkyl peroxycarboxylate (e.g., tert 14 WO 99/21843 PCT/JP98/04455 butyl peroxyacetate, hydroperoxide or tert-butyl perbenzoate). Process 2 A compound (I-3) or its salt can be prepared by subjecting a 5 compound (I-2) or its salt to an epoxidation. Epoxidation of a double bond in the cyclopentene or cyclohexene ring can be accomplished by using an oxidant, for example, hydrogen peroxide or its derivatives. Suitable derivatives of the hydrogen peroxides are a lower alkyl 10 hydroperoxide (e.g., tert-butyl hydroperoxide), a peroxy acid (e.g., peroxyacetic acid, peroxytrifluoroacetic acid or m chloroperoxybenzoic acid) or the like. Other oxidants such as dimethyldioxirane, ozone, sodium hypochlorite or the like may be used for the epoxidation. 15 This reaction is preferably carried out in the presence of an inorganic base or an organic base such as an alkali metal [e.g., sodium or potassium], hydroxide, carbonate or bicarbonate thereof, a trialkylamine [e.g., trimethylamine or triethylamine] or the like. The reaction is usually carried out in a conventional solvent 20 such as water, an alcohol (e.g., methanol, ethanol or isopropyl alcohol), tetrahydrofuran, dioxane, dichloromethane, ethylene dichloride, chloroform, N,N-dimethylformamide,

N,N

dimethylacetamide or any other organic solvent which does not adversely affect the reaction. 15 WO 99/21843 PCT/JP98/04455 The reaction may be usually carried out under cooling to heating since the reaction temperature is not critical. Process 3 5 A compound (I-3) or its salt can be also prepared by subjecting a compound (II-2) or its salt to 1) a cyclization reaction, 2) a removal of a hydroxy protective group in the phenol residue and then 3) a reaction with Yl-CH 2 COOR1 or its salt. The cyclization can be accomplished by reacting a 10 dihydroxy compound (II-2) or its salt with orthoactic acid trimethyl ester and p-toluenesulfonic acid. The reaction is usually carried out in a conventional solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methylene chloride, chloroform, dimethylformamide or any other 15 organic solvent which does not adversely affect the reaction. The reaction may be usually carried out under cooling to heating since the reaction temperature is not critical. The removal of the hydroxy protective group in the phenol residue can be carried out by a conventional method known in the 20 art to give a phenol residue, e.g., by treating with tetrabutylammonium fluoride. The reaction of the resultant phenol compound with a compound of the formula Y1-CH 2 COOR is preferably carried out in the presence of a base in the case where Y' is a halogen atom. 16 WO 99/21843 PCT/JP98/04455 Suitable Y1-CH 2

COOR

1 may include halo-acetates such as methyl or ethyl bromoacetate, methyl or ethyl chloroacetate and methyl or ethyl iodoacetate. Suitable bases may include inorganic bases and organic 5 bases such as an alkali metal [e.g., sodium or potassium], hydroxide, carbonate or bicarbonate thereof, a trialkylamine [e.g., trimethylamine or triethylamine] or the like. The reaction is usually carried out in a solvent such as water, an alcohol [e.g., methanol or ethanol], methylene chloride, 10 tetrahydrofuran, 1,2-dimethoxyethane, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base can be also used as a solvent. The reaction may be usually carried out under cooling to warming since the reaction temperature is not critical. 15 Process 4 A compound (I-4) or its salt can be prepared by subjecting a compound (II-3) or its salt to 1) a removal of a hydroxy protective group in the phenol residue, 2) a reaction with a compound of the 20 formula Y1-CH 2 COOR1 and then 3) a removal of protective group(s) from the remaining protected hydroxy group(s) for R 2 b, R 5 b, R 6 b and

R

7 b, if necessary. The reaction of the above steps 1) and 2) can be carried out in the same manner as the steps 2) and 3) in the above Process 3, 17 WO 99/21843 PCT/JP98/04455 respectively. And the removal of the hydroxy protective group(s) in the step 3) can be carried out by a conventional method, e.g., using tetrabutylammonium fluoride. 5 Process 5 A compound (I-6) or its salt can be prepared by subjecting a compound (I-5) or its salt to an elimination of the carboxy protective group for R'a. 10 This reaction can be conducted by a conventional method such as hydrolysis or the like. The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid. Suitable bases may include inorganic bases and organic 15 bases such as an alkali metal [e.g., sodium or potassium], hydroxide, carbonate or bicarbonate thereof, a trialkylamine [e.g., trimethylamine or triethylamine] or the like. Suitable acids may include organic acids [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid or trifluoroacetic 20 acid] and inorganic acids [e.g., hydrogen chloride, hydrochloric acid, hydrogen bromide, hydrobromic acid or sulfuric acid]. The elimination using Lewis acid such as trihaloacetic acid [e.g., trichloroacetic acid or trifluoroacetic acid] or the like is preferably carried out in the presence of a cation trapping agent [e.g., anisole 18 WO 99/21843 PCT/JP98/04455 or phenol]. The reaction is usually carried out in a solvent such as water, an alcohol [e.g., methanol or ethanol], methylene chloride, tetrahydrofuran, 1,2-dimethoxyethane, a mixture thereof or any 5 other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as a solvent. The reaction may be usually carried out under cooling to warming since the reaction temperature is not critical. 10 Process A A compound (II-4) can be prepared from a compound (III) according to a method described in Preparations 1 to 6, 8 to 13, 14 to 19, 20 to 25 or similar method thereto. 15 Process B A compound (II-5) can be prepared by subjecting a compound (II-4) to hydrogenation. The hydrogenation can be carried out according to a method described in Preparation 7 or similar manner thereto. 20 Process C A compound (II-2) can be prepared by subjecting a compound (IX) to hydroxylation. The hydroxylation can be carried out in accordance with a method described in Preparations 26, 27 19 WO 99/21843 PCT/JP98/04455 A compound (II-2) can be prepared by subjecting a compound (IX) to hydroxylation. The hydroxylation can be carried out in accordance with a method described in Preparations 26, 27 or similar manner thereto. 5 The pharmaceutically acceptable salts of the compounds (I) as mentioned above may be prepared by treating the compound (I) with an appropriate base or acid in accordance with the conventional method. 10 The object compounds (I) of this invention and pharmaceutically acceptable salt thereof may exert pharmacological activities such as an inhibitory activity on platelet aggregation, vasodilating activity, antihypertensive activity or the like, which are believed to be PGI 2 agonist. Accordingly, they can 15 be used for treating and/or preventing thrombosis, arterial obstruction (e.g., chronic arterial obstruction), cerebrovascular disease, gastric ulcer, hepatitis, hepatic insufficiency, hepatic cirrhosis, arteriosclerosis, ischemic heart disease, restenosis or ischemic complications after coronary angioplasty (e.g., PTCA or 20 coronary stenting), hypertension, inflammation, autoimmune disease, heart failure, renal disease (e.g., renal failure or nephritis), diabetic complication (e.g., diabetic neuropathy, diabetic nephropathy or diabetic retinopathy), peripheral circulatory disturbance, and the like. Moreover, they can be used for 20 WO 99/21843 PCT/JP98/04455 protecting organs after transplantation or surgery. Further, the object compounds (I) and pharmaceutically acceptable salts thereof can be also used as a component for organ preserving fluids and as an agent for inhibiting metastasis of 5 cancer. Still further, the object compounds (I) may be also useful for treating and/or preventing dermatosis (e.g., chilblain, bedsore or baldness). The compounds (I) of the present invention have much 10 advantages, such as stronger activity, more suitable half-life period, decreased adverse effect, or the like, compared to the known 4,5 diaryloxazole compounds shown in the prior arts. In order to show the utility of the object compounds (I), 15 pharmacological data of the representative compounds thereof are shown in the following. Inhibition of human platelet aggregation induced 20 by ADP [I] Test Compound : 21 WO 99/21843 PCT/JP98/04455 (1) Sodium {3-{[2-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2 cyclohexen- 1-yl]methyl}phenoxy}acetate, (2) Sodium {3-{[( 1S)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxy-2 cyclohexen- 1-yl]methyl}phenoxy}acetate, 5 (3) Sodium {3-{[( 1S)-2-(4,5-diphenyloxazol-2-yl)-2,3-epoxy- 1 cyclohexyl]methyl}phenoxy}acetate. [II] Test Method : 10 Human blood was collected from healthy volunteers and mixed with 1/10 volume of 3.8% sodium citrate solution, pH 7.4. The citrate blood was centrifuged at 150 X g for 10 minutes and the platelet rich plasma (PRP) was removed. The remaining blood was centrifuged for a further 10 minutes at 1500 X g to prepare the 15 platelet poor plasma (PPP), which was used as a reference for platelet aggregation. Aggregation studies were carried out using HEMATRACER 801 (NBS, Japan), a 8 channel aggregometer. 25 1 of a solution of Test compound in Tris-acetate buffer pH 7.4 and 225 1 of PRP were mixed and stirred at 1000 rpm for 2 minutes at 20 37 0 C. Aggregation was induced by ADP (adenosin 5'-diphosphate) solution at the final concentration of 2.5 a M. [III] Test result : 22 WO 99/21843 PCT/JP98/04455 Test Compound Inhibition (%) (1.Ox10- 7 M) (1) >90 (2) >90 (3) >90 The pharmaceutical composition of the present invention which contains the object compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be used in the 5 form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form (e.g., tablet, pellet, troche, capsule, suppository, cream, ointment, aerosol, powder, solution, emulsion or suspension), which are suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or 10 parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation. The pharmaceutical composition of this invention may contain various organic or inorganic carrier materials which are conventionally used for pharmaceutical purpose, such as 15 excipients (e.g., sucrose, starch, mannite, sorbit, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), binding agents (e.g., cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), disintegrators (e.g., starch, 23 WO 99/21843 PCT/JP98/04455 carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydroxypropylstarch, sodium glycol-starch, sodium bicarbonate, calcium phosphate or calcium citrate), lubricants (e.g., magnesium stearate, talc or sodium laurylsulfate), flavoring agents (e.g., citric 5 acid, mentol, glycine or orange powders), preservatives (e.g-, sodium benzoate, sodium bisulfite, methylparaben or propylparaben), stabilizers (e.g., citric acid, sodium citrate or acetic acid), suspending agents (e.g., methyl cellulose, polyvinylpyrrolidone or aluminum stearate), dispersing agents, 10 aqueous diluting agents (e.g., water) and base waxes (e.g., cacao butter, polyethyleneglycol or white petrolatum). The compound (I) may usually be administered with a unit dose of 0.01 mg/kg to 50 mg/kg, 1 to 4 times a day. However, the above dosage may be increased or decreased according to age, 15 weight, conditions of the patient or the administering method. Abbreviations used in this application are as follows: THF : Tetrahydrofuran EtOAc : Ethyl acetate 20 DMF : N,N-Dimethylformamide DMSO : Dimethylsulfoxide MeOH : Methyl alcohol tBuOH: tertButyl alcohol 24 WO 99/21843 PCT/JP98/04455 nBuLi : n-Butyllithium AD-mix- a: reagent for Sharpless Asymmetric Dihydroxylation containing a chiral ligand hydroquinine 1,4-phthalazinediyl diether, KaFe(CN) 6 , 5 K 2

CO

3 and K 2 OsO 4 *2H 2 0 AD-mix- f: reagent for Sharpless Asymmetric Dihydroxylation containing a chiral ligand hydroquinine 1,4-phthalazinediyl diether, K 3 Fe(CN) 6 ,

K

2 CO and K 2 OsO 4 *2H 2 0 10 The patents, patent applications and publications cited herein are incorporated by reference. BEST MODE FOR CARRING THE INVENTION 15 The following Examples are given only for the purpose of illustrating the present invention in more detail. Preparation 1 A solution of AD-mix-0 (300 g) in a mixture of t-BuOH 20 (1000ml) and water (1000 ml) was stirred for 1 hour, and then methanesulfonamide (22 g) and 1-cyclohexen-1-ylmethyl 4 (methoxy)benzoate (53g) were added to the solution at 0OC. After being stirred for 20 hours at the same temperature, the reaction 25 WO 99/21843 PCT/JP98/04455 mixture was added with sodium sulfite (120 g) and stirred for 30 minutes. The mixture was partitioned between EtOAc and water. The organic layer was washed with 1N-HC1 solution, sat. NaHCO 3 solution and then brine(a saturated sodium chloride aqueous 5 solution). Then it was dried over MgSO 4 and evaporated in.vacuo. The residue was purified by crystallization from a mixture of diethyl ether and hexane to afford [(1R,2R)-1,2-(dihydroxy)-1 cyclohexyl]methyl 4-(methoxy)benzoate (35 g). IR (Neat) : 3300 cm-1 10 NMR (CDC1 3 , 6) : 1.0-1.8(8H, m), 2.6(1H, s), 2.96(1H, d, J = 4Hz), 3.87(3H, s), 4.00(1H, d, J = 11.6Hz), 4.57(1H, d, J = 11.6Hz), 6.93(2H, d, J = 8Hz), 8.00(2H, d, J = 8Hz). MS m/z : 281 (M'+1) HPLC: chiralcel OD, 10% isopropanol/hexane, 29.6 15 ml/min Preparation 2 To a solution of [(1R,2R)- 1,2-(dihydroxy)- 1 cyclohexyl]methyl 4-(methoxy)benzoate (30 g) in dichloromethane 20 (300 ml) were added dimethoxypropnane (50 ml) and p toluenesulphonic acid (0.3g) at room temperature. After being stirred for 4 hours, the reaction mixture was evaporated in vacuo. The residue was diluted with EtOAc, and the mixture was washed 26 WO 99/21843 PCT/JP98/04455 with water and brine. After evaporating the solvent, the residue was dissolved in a mixture of MeOH (200ml) and THF (100ml), followed by addition of 1N-NaOH(160 ml) at room temperature. After stirring for 12 hours at room temperature, the mixture was 5 evaporated to remove the solvent. The resultant was partitioned between EtOAc and water. The organic layer was washed with water and brine, and evaporated in vacuo. The residue was purified by chromatography on silica gel to give (3aR,7aR)-2,2 dimethyl-hexahydro-1,3-benzodioxol-3a-yl) methanol (14g). 10 NMR (CDCl3, 6) : 1.29(3H, s), 1.52(3H, s), 1.0-1.8(7H, m), 2.0-2.2(2H, m), 3.58(2H, d, J = 8.0Hz), 4.16(1H, m) Preparation 3 To a solution of (COC1) 2 (9.8ml) in CH 2 C1 2 (200ml) was 15 dropwise added DMSO (10.7ml) at -78oC. After 10minutes, a solution of (3aR,7aR)-2,2-dimethyl-hexahydro-1,3-benzodioxol 3a-yl)methanol (14g) in CH 2 Cl 2 (50ml) was added to the above solution at the same temperature. After 10 minutes, the mixture was added with triethylamine (42ml) and allowed to stand at room 20 temperature. After evaporating the solvent, the resultant was partitioned between EtOAc and water. The organic layer was washed with water and brine, and evaporated in vacuo to give an aldehyde compound. 27 WO 99/21843 PCT/JP98/04455 To a solution of 3-tertbutyldiphenylsilyloxyphenylbromide (33g) in THF(300ml) was added nBuLi (54ml, 1.5N-solution in THF) at -78oC. After stirring for 1 hour, the above aldehyde compound (10g) was added to the mixture at the same temperature. After 5 stirring for 1 hour, the mixture was partitioned between EtOAc and water. The organic layer was washed with 1N-HC1 solution, water and brine, and evaporated in vacuo. The residue was purified by chromatography on silica gel to give 3-[((3aR,7aR)-2,2-dimethyl hexahydro- 1,3-benzodioxol-3a-yl)hydroxymethyl]- 1 10 (tertbutyldiphenylsilyloxy)benzene (16g). IR (Neat) : 3070, 1600 cm- 1 NMR (CDC1 3 , 6): 1.22(9H, s), 1.0-1.6(8H, m), 1.30(3H, s), 1.46(3H, s), 2.54(1H, d, J = 8Hz), 4.22(1H, m), 4.44(1H, d, J = 8Hz), 6.6-7.2(4H, m), 7.2-7.8(10H, m) 15 MSm/z : 517(M++1) Preparation 4 To a solution of 3-[((3aR,7aR)-2,2-dimethyl-hexahydro 1,3-benzodioxol-3a-yl)hydroxymethyl]- 1-(tertbutyldiphenyl 20 silyloxy)benzene (45g) in CH 2 C1 2 (450ml) were added phenyl chlorothionoformate (14.5ml) and pyridine (18ml) at 0OC. After being stirred for 12 hours at room temperature, the mixture was evaporated and the resultant was partitioned between EtOAc and 28 WO 99/21843 PCT/JP98/04455 water. The organic layer was washed with water, 1N-HCI solution, sat.NaHCO 3 solution and then brine. The solvent was evaporated in vacuo to give an oily residue. The residue was dissolved in toluene (400ml) to which tributyltinhydride (50 ml) and 2,2' 5 azobis-(isobutyronitrile)(100mg) were added. The mixture was refluxed for 4 hours under stirring and then purified by chromatography on silica gel to give an oily compound. The oily compound was dissolved in a mixture of MeOH (200 ml) and THF (lOO1ml), to which p-toluenesulphonic acid (200mg) was added at 10 room temperature. The mixture was stirred for 12 hours and evaporated. The residue was partitioned between EtOAc and water. The organic layer was washed with water, sat. NaHCO 3 solution and then brine. The solvent was evaporated in vacuo to give (1R,2R)-1-[3-(tertbutyldiphenylsilyloxy)benzyl]-1,2 15 dihydroxycyclohexane (30g). IR (Neat) : 3420, 1600 cm - 1 NMR (CDCl 3 , 6) : 1.10(9H, s), 0.8-1.8(8H, m), 2.57(1H, d, J = 12Hz), 2.67(1H, d, J = 12Hz), 3.15(1H, m), 6.51(1H, m), 6.73(2H, m), 7.07(1H, t, J = 8.0Hz), 7.2-7.7(10H, m) 20 MS m/z: 461 (MI+1) Preparation 5 29 WO 99/21843 PCT/JP98/04455 To a solution of (COC1) 2 (3.4ml) in CH 2 Cl 2 (100ml) was dropwise added DMSO (3.7ml) at -78 0 C. After 10minutes, a solution of (1R,2R)-1-[3-(tertbutyldiphenylsilyloxy)benzyl]-1,2 dihydroxycyclohexane (12g) in CH 2 Cl 2 (50ml) was added to the 5 above mixture at the same temperature. After 10 minutes, the mixture was added with triethylamine (15ml) and allowed to stand at room temperature. After evaporating the solvent, the residue was partitioned between EtOAc and water. The organic layer was washed with water and brine. The organic solvent was evaporated 10 in vacuo to give an oily compound. The oily compound was dissolved in DMF (50 ml) and then added with trimethylsilychloride (6.6ml) and imidazole(7.0g) at room temperature. After stirring for 5 hours, the mixture was partitioned between EtOAc and water. The organic solvent was evaporated in vacuo. The residue was 15 purified by chromatography on silica gel to give (R)- 1-[3 (tertbutyldiphenylsilyloxy)benzyl]-1-trimethylsilyoxy-2 cyclohexanone (11.5g). IR (Neat): 1720 cm- 1 NMR(CDC13, 6): 0.016(9H, s), 1.05(9H, s), 1.2-1.8(6H, 20 m), 2.2-2.4(2H, m), 2.70(1H, d, J = 13.6Hz), 2.84(1H, d, J = 13.6Hz), 6.4-6.8(3H, m), 6.90(1H, t, J = 8Hz), 7.2-7.8(10H, m) MSm/z: 531 (M*+1) 30 WO 99/21843 PCT/JP98/04455 Preparation 6 To a solution of (4,5-diphenyl)oxazole (17g) in THF (100ml) was added n-BuLi (57ml, 1.6N-solution in hexane) at -78oC. After 5 stirring for 30 minutes, a solution of (R)-1-[3-(tertbutyldiphenyl silyloxy)benzyl]-1-trimethylsilyoxy-2-cyclohexanone (27g) in THF (50 ml) was added to the above mixture at the same temperature. After stirring for 1 hour, the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with 10 1N-HC1 solution and brine. The organic solvent was evaporated in vacuo to give a residue. The residue was dissolved in toluene (100 ml) and then added with (methoxycarbonylsulfamoyl)triethyl ammonium hydroxide, inner salt(20.4g) at room temperature. After refluxing under stirring for 5 hours, the reaction mixture was 15 evaporated in vacuo. The residue was purified by chromatography on silica gel to give (R)-2-(4,5-diphenyloxazol-2 yl)-1-trimethylsilyloxy- 1-[3-(tertbutyldiphenylsiloxy)benzyl]-2 cyclohexene (36g). IR (Neat) : 1600, 1585 cm - 1 20 NMR (CDC1 3 , 6) : 0.036(9H, s), 1.12(9H, s), 1.4-1.8(4H, m), 2.1-2.4(2H, m), 3.10(1H, d, J = 13.4 Hz), 3.48(1H, d, J = 13.4Hz), 6.6-7.0(5H, m), 7.2-7.8(10H, m) MSm/z: 735(M++1) 31 WO 99/21843 PCT/JP98/04455 Preparation 7 A mixture of (R)-2-(4,5-diphenyloxazol-2-yl)-1 trimethylsilyloxy- 1-[3-(tertbutyldiphenylsiloxy)benzyl]-2 5 cyclohexene (24g) and 10% Pd/C (10g) in a mixture of MeOH (200 ml) and EtOAc (500ml) was stirred under H2 for 8 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel to give (1R, 2S)-2-(4,5-diphenyloxazol-2-yl)-1-trimethylsilyoxy- 1-[3 10 (tertbutyldiphenylsiloxy)benzyl]cyclohexane (21g). IR (Neat): 1600, 1583 cm- 1 NMR (CDCl 3 , 56) : 1.08(9H, s), 1.0-2.0(8H, m), 2.63(1H, d, J = 13.8Hz), 2.71(1H, dJ = 13.8Hz), 3.1(1H, m), 6.6-7.0(4H, m), 7.2-7.7(10H, m) 15 Preparation 8 [(1 S,2S)-1,2-(Dihydroxy)- 1-cyclohexyl]methyl 4 (methoxy)benzoate was obtained in the same manner as in Preparation 1 except using AD-mix- a instead of AD-mix-/3. 20 IR (Neat) : 3300 cm- 1 NMR (CDCl 3 , 6) : 1.0-1.8(8H, m), 2.6(1H, s), 2.96(1H, d, J = 4Hz), 3.87(3H, s), 4.00(1H, d, J = 11.6Hz), 4.57(1H, d, J = 11.6Hz), 6.93(2H, d, J = 8Hz), 8.00(2H, d, J = 8Hz) 32 WO 99/21843 PCT/JP98/04455 MS m/z: 281 (M++1) HPLC : chiralcel OD, 10% isopropanol/hexane, 19.9 ml/min 5 Preparation 9 ((3aS,7aS)-2,2-Dimethyl-hexahydro- 1,3-benzodioxol-3a yl)methanol (14g) was obtained in the same manner as in Preparation 2. NMR (CDC13, 6) : 1.29(3H, s), 1.52(3H, s), 1.0-1.8(7H, 10 m), 2.0-2.2(2H, m), 3.58(2H, d, J = 8.0Hz), 4.16(1H, m) Preparation 10 3- [((3aS,7aS)-2,2-Dimethyl-hexahydro- 1,3-benzodioxol-3a yl)hydroxymethyl]-1-(tertbutyldiphenylsilyloxy) benzene was 15 obtained in the same manner as in Preparation 3. IR (Neat) : 3070, 1600 cm-1 NMR (CDC1 3 , 6): 1.22(9H, s), 1.0-1.6(8H, m), 1.30(3H, s), 1.46(3H, s), 2.54(1H, d, J = 8Hz), 4.22(1H, m), 4.44(1H, d, J = 8Hz), 6.6-7.2(4H, m), 7.2-7.8(10H, m) 20 MS m/z : 517 (M++1) Preparation 11 (1S,2S)-1-[3-(Tertbutyldiphenylsilyloxy)benzyl]-1,2 33 WO 99/21843 PCT/JP98/04455 dihydroxycyclohexane was obtained in the same manner as in Preparation 4. IR (Neat) : 3420, 1600 cm- 1 NMR (CDC1 3 , 6) : 1.10(9H, s), 0.8-1.8(8H, m), 2.57(1H, d, 5 J = 12Hz), 2.67(1H, d, J = 12Hz), 3.15(1H, m), 6.51(1H, m), 6.73(2H, m), 7.07(1H, t, J = 8.0Hz), 7.2-7.7(10H, m) MS m/z : 461 (Ml+1) Preparation 12 10 (S)-1-[3-(Tertbutyldiphenylsilyloxy)benzyl]-1 trimethylsilyoxy-2-cyclohexanone was obtained in the same manner as in Preparation 5. IR (Neat) : 1720 cm - 1 NMR (CDC1 3 , 6) : 0.016(9H, s), 1.05(9H, s), 1.2-1.8(6H, 15 m), 2.2-2.4(2H, m), 2.70(1H, d, J = 13.6Hz), 2.84(1H, d, J = 13.6Hz), 6.4-6.8(3H, m), 6.90(1H, t, J = 8Hz), 7.2-7.8(10H, m) MS m/z : 531 (M'+1) 20 Preparation 13 (S)-2-(4,5-Diphenyloxazol-2-yl)-1-trimethylsilyloxy- 1-[3 (tertbutyldiphenylsiloxy)benzyl]-2-cyclohexene was obtained in the same manner as in Preparation 6. 34 WO 99/21843 PCT/JP98/04455 IR (Neat): 1600, 1585 cm- 1 NMR (CDC13, 6) : 0.036(9H, s), 1.12(9H, s), 1.4-1.8(4H, m), 2.1-2.4(2H, m), 3.10(1H, d, J = 13.4 Hz), 3.48(1H, d, J= 13.4Hz), 6.6-7.0(5H, m), 7.2-7.8(10H, m) 5 MS m/z: 735 (MI+1) Preparation 14 [(1S,2S)-1,2-(Dihydroxy)-1-cyclopentyl]methyl 4 (methoxy)benzoate was obtained in the same manner as in 10 Preparation 8. IR (Neat) : 3300 cm- 1 NMR (CDC1 3 , 6) : 1.0-1.8(6H, m), 2.69(1H, d, J = 5.2Hz), 3.07(1H, s), 3.86(3H, s), 4.22(1H, d, J = 11.6Hz), 4.35(1H, d, J = 11.6Hz), 6.91(2H, d, J = 8Hz), 8.00(2H, d, J = 8Hz) 15 MS m/z: 267 (M++1) Preparation 15 ((3aS,6aS)-2,2-Dimethyl-tetrahydro-4H-cyclopenta- 1,3 dioxol-3a-yl)methanol was obtained in the same manner as in 20 Preparation 2. IR (Neat) : 3400 cm- 1 NMR (CDC13, 6) : 1.39(3H, s), 1.48(3H, s), 1.0-2.0(7H, m), 3.5-3.8(2H, m), 4.44(1H, d, J = 4.0Hz) 35 WO 99/21843 PCT/JP98/04455 MS m/z: 173 (Ml+1) Preparation 16 3-[((3aS, 6aS)-2,2-Dimethyl-tetrahydro-4H-cyclopenta-1,3 5 dioxol-3a-yl)hydroxymethyl]-1-(tertbutyldiphenylsilyloxy)benzene was obtained in the same manner as in Preparation 3. IR (Neat) : 3400, 1600 cm - 1 NMR(CDC1 3 , 6): 1.22(9H, s), 1.0-1.8(6H, m), 1.32(3H, s), 1.41(3H, s), 4.2-4.6(2H, m), 6.6-7.2(4H, m), 7.2-7.8(10H, 10 m) MS m/z: 503 (M'+1) Preparation 17 (1 S,2S)-1-[3-(Tertbutyldiphenylsilyloxy)benzyl]-1,2 15 dihydroxycyclopentane was obtained in the same manner as in Preparation 4. IR (Neat) : 3300, 1600 cm - 1 NMR (CDC1 3 , 6) : 1.09(9H, s), 0.8-1.8(6H, m), 2.57(2H, s), 3.59(1H, m), 6.52(1H, m), 6.7-6.9(2H, m), 7.06(1H, t, J = 20 8Hz), 7.2-7.7(10H, m) MSm/z: 445(M++1) 36 WO 99/21843 PCT/JP98/04455 Preparation 18 (S)- 1-[3-(Tertbutyldiphenylsilyloxy)benzyl]- 1 trimethylsilyoxy-2-cyclopentanone was obtained in the same manner as in Preparation 5. 5 IR (Neat) : 1749 cm - 1 NMR (CDC1 3 , 6) : 0.016(9H, s), 1.04(9H, s), 1.2-2.0(6H, m), 2.56(2H, s), 6.4-6.8(3H, m), 6.93(1H, t, J = 8Hz), 7.2 7.8(10H, m) MS m/z: 517 (M++1) 10 Preparation 19 (S)-2-(4,5-Diphenyloxazol-2-yl)-1-trimethylsilyloxy- 1-[3 (tertbutyldiphenylsiloxy)benzyl]-2-cyclopentene was obtained in the same manner as in Preparation 6. 15 IR (Neat) : 1600, 1585 cm - 1 NMR (CDC1 3 , 6) : 0.036(9H, s), 1.09(9H, s), 1.4-2.2(4H, m), 2.9-3.3(2H, m), 6.4-7.0(4H, m), 7.10(1H, t, J = 8Hz), 7.2-7.8(10H, m) MS m/z: 721 (M++1) 20 Preparation 20 37 WO 99/21843 PCT/JP98/04455 [(1R,2R)-1,2-(Dihydroxy)- 1-cyclopentyl]methyl 4 (methoxy)benzoate was obtained in the same manner as in Preparation 1. IR (Neat) : 3300 cm-1 5 NMR (CDC1 3 , 6) : 1.0-1.8(6H, m), 2.69(1H, d, J = 5.2Hz), 3.07(1H,s), 3.86(3H, s), 4.22(1H, d, J = 11.6Hz), 4.35(1H, d, J = 11.6Hz), 6.91(2H, d, J = 8Hz), 8.00(2H, d, J = 8Hz) MS m/z: 267 (M'+1) HPLC : chiralcel OD, 10% isopropanol/hexane, 8.3 ml/min 10 Preparation 21 (3aR,6aR)-(2,2-Dimethyl-tetrahydro-4H-cyclopenta- 1,3 dioxol-3a-yl)methanol was obtained in the same manner as in Preparation 2. 15 IR (Neat) : 3400 cm- 1 NMR (CDC1 3 , (56): 1.39(3H, s), 1.48(3H, s), 1.0-2.0(7H, m), 3.5-3.8(2H, m), 4.44(1H, d, J = 4.0Hz) MSm/z: 173 (M++1) 20 Preparation 22 3-[((3aR, 6aR)-2,2-Dimethyl-tetrahydro-4H-cyclopenta 1,3-dioxol-3a-yl)hydroxymethyl]-1-tertbutyldiphenylsilyloxy benzene was obtained in the same manner as in Preparation 3. 38 WO 99/21843 PCT/JP98/04455 IR (Neat) : 3400, 1600 cm- 1

NMR(CDC

3 , 6) : 1.22(9H, s), 1.0-1.8(6H, m), 1.32(3H, s), 1.41(3H, s), 4.2-4.6(2H, m), 6.6-7.2(4H, m), 7.2-7.8(10H, m) 5 MSm/z: 503(M++1) Preparation 23 (1R,2R)- 1-[3-(Tertbutyldiphenylsilyloxy)benzyl]-1,2 dihydroxycyclopentane was obtained in the same manner as in 10 Preparation 4. IR (Neat) : 3300, 1600 cm- 1 NMR (CDC1 3 , 6): 1.09(9H, s), 0.8-1.8(6H, m), 2.57(2H, s), 3.59(1H, m), 6.52(1H, m), 6.7-6.9(2H, m), 7.06(1H, t, J = 8Hz), 7.2-7.7(10H, m) 15 MS m/z : 445 (Ml+1) Preparation 24 (R)-1-[3-(Tertbutyldiphenylsilyloxy)benzyl]-1 trimethylsilyoxy-2-cyclopentanone was obtained in the same 20 manner as in Preparation 5. IR (Neat): 1749 cm- 1 39 WO 99/21843 PCT/JP98/04455 NMR (CDC1 3 , 6) : 0.016(9H, s), 1.04(9H, s), 1.2-2.0(6H, m), 2.56(2H, s), 6.4-6.8(3H, m), 6.93(1H, t, J = 8Hz), 7.2 7.8(10H, m) MSm/z: 517(M++1) 5 Preparation 25 (R)-2-(4,5-Diphenyloxazol-2-yl)-1-trimethylsilyloxy- 1-[3 (tertbutyldiphenylsiloxy)benzyl]-2-cyclopentene was obtained in the same manner as in Preparation 6. 10 IR (Neat) : 1600, 1585 cm -1 NMR (CDC1 3 , 6) : 0.036(9H, s), 1.09(9H, s), 1.4-2.2(4H, m), 2.9-3.3(2H, m), 6.4-7.0(4H, m), 7.10(1H, t, J = 8Hz) , 7.2-7.8(10H, m) MS m/z : 721 (M++1) 15 Preparation 26 (1S,2R,3S)-2-(4,5-Diphenyloxazol-2-yl)-2,3-dihydroxy- 1 [3-(tertbutyldiphenylsiloxy)benzyl] cyclohexane was obtained in the same manner as in Preparation 8. 20 IR (Neat) : 3600 cm-1 NMR (CDC1 3 , 6) : 1.06(9H, s), 1.2-2.4(9H, m), 3.98(1H, m), 6.4-6.7(3H, m), 6.88(1H, t, J = 8Hz), 7.2-7.7(10H, m) 40 WO 99/21843 PCT/JP98/04455 Ms m/z: 680 (M+-17) Preparation 27 (1S,2S,3R)-2-(4,5-Diphenyloxazol-2-yl)-2,3-dihydroxy- 1 5 [3-(tertbutyldiphenylsiloxy)benzyl] cyclohexane was obtained in the same manner as in Preparation 1. IR (Neat) : 3600 cm- 1 NMR (CDCl 3 , 6) : 1.08(9H, s), 1.2-2.4(9H, min), 4.32(1H, m), 6.4-6.7(3H, m), 6.938(1H, t, J = 8Hz), 7.2-7.7(10H, m) 10 Ms m/z : 680 (M+-17) Example 1 A solution of ethyl (S)-{3-{[2-(4,5-diphenyloxazol-2 yl)-2-cyclohexen-1-yl]methyl}phenoxy}acetate (380 mg) (prepared 15 by a method described in WO 95/17393) and selenium dioxide (SeO 2 ) (170 mg) in dichloromethane (230 ml) was refluxed for 2 hours under stirring. The mixture was filtered and the filtrate was evaporated. The residue was purified by chromatography on silica gel to give ethyl {3-{[2-(4,5-diphenyloxazole-2-yl)-1-hydroxy 20 2-cyclohexen-1-yl]-methyl}phenoxy}acetate (60 mg) as a first fraction and ethyl {3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxy 2-cyclohexen-1-yl]methyl}phenoxy}acetate (80 mg) as a second fraction. 41 WO 99/21843 PCT/JP98/04455 First fraction: IR (Neat) : 3400, 1758 cm-' NMR (CDC1 3 , 6) : 1.28 (3H, t, J=7.OHz), 1.4-2.0 (5H, m), 2.2-2.4 (2H, m), 3.05 (1H, d, J=13.6Hz), 3.40 (1H, d, 5 J=13.6Hz), 4.26 (2H, q, J=7.0Hz), 4.51 (2H, s), 6.70 (1H, d, J=8Hz), 6.8-7.0 (3H, m), 7.15 (1H, t, J=8Hz), 7.2-7.8 (10H, m) MS m/z : 510 (M++1) 10 Second fraction: IR (Neat) : 3400, 1758 cm 1 NMR (CDC1 3 , 6) : 1.25 (3H, t, J=7.0Hz), 1.4-2.0 (5H, m), 2.47 (1H, dd, J=10.0, 12.6Hz), 3.1 (1H, m), 3.29 (1H, dd, J=3.2, 12.6Hz), 4.24 (2H, q, J=7.OHz), 4.39 (1H, m), 4.59 15 (2H, s), 6.73 (1H, d, J=8Hz), 6.8-7.0 (3H, m), 7.21 (1H, t, J=8Hz), 7.2-7.8 (10H, m) MSm/z: 510(M'+1) Example 2 20 A solution of ethyl (S)-{3-{[2-(4,5-diphenyloxazol-2 yl)-2-cyclohexen-1-yl]methyl}phenoxy}acetate (800 mg) and m-chloroperbenzoic acid (600 mg) in dichloromethane (20 ml) was stirred for 2 hours at room temperature. The mixture was diluted 42 WO 99/21843 PCT/JP98/04455 with EtOAc and washed with water and brine. Then, it was dried over MgSO 4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to give ethyl {3-{[(1S)-2-(4,5 diphenyloxazol-2-yl)-2,3-epoxy- 1-cyclohexyl] methyl}phenoxy} 5 acetate (400 mg). IR (Neat) : 1760 cm- 1 NMR (CDC1 3 , 6) : 1.28 (3H, t, J=7.OHz), 1.4-2.0 (6H,m), 2.59 (1H, dd, J=9.0, 12.8Hz), 2.9-3.1 (1H, m), 3.22 (1H, dd, J=5.0, 12.8Hz), 4.26 (2H, q, J=7.0Hz), 4.51 (2H, s), 6.66 (1H, 10 d, J=8Hz), 6.7-7.0 (2H, m), 7.16 (1H, t, J=8Hz), 7.2-7.8 (10H, m) MSm/z: 510(M+1) Example 3 15 A solution of ethyl (S)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2 cyclopenten-1-yl]methyl}phenoxy}acetate (1.0g) (prepared by a method described in WO 95/17393) and m-chloroperbenzoic acid (0.45g) in dichloromethane (20 ml) was stirred for 2 hours at room temperature. The mixture was diluted with EtOAc and washed 20 with water and brine. Then it was dried over MgSO 4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to give ethyl {3-{[(1S)-2-(4,5 diphenyloxazol-2-yl)-2,3-epoxy- 1-cyclopentyl]methyl}phenoxy} acetate (400mg). 43 WO 99/21843 PCT/JP98/04455 IR (Neat): 1760 cm- 1 NMR (CDCl3, 6) : 1.28(3H, t, J = 7.0Hz), 1.4-2.0(4H, m), 2.4-3.2(3H, m), 4.26(2H, q, J = 7.0Hz), 4.51(2H, s), 6.6 7.1(4H, m), 7.2-7.8(10H, m) 5 MS m/z: 496 (M++1) Example 4 To a solution of (1S,2R,3S)-2-(4,5-diphenyloxazol-2-yl) 2,3-dihydroxy- 1- [3-(tertbutyldiphenylsiloxy)benzyl] cyclohexane 10 (8.7 g) in CH2C12 (100 ml) were added orthoacetic acid trimethyl ester (2.8 ml) and p-toluenesulfonic acid (150 mg) at room temperature under N 2 gas. After being stirred for 30 minutes, the mixture was evaporated in vacuo. The residue was diluted with CH2Cl2 (100 ml), followed by addition of acetylbromide (3.0 ml) at 15 O'C under N 2 gas. After being stirred for 2 hours at room temperature, the mixture was evaporated in vacuo. The residue was diluted with MeOH (100 ml) and added with K2CO3 (5 g) at room temperature. The mixture was stirred for 2 hours at the same temperature and then partitioned between EtOAc and water. 20 The organic layer was washed with 1N-HCI solution, water, sat. NaHCO3 solution and brine. The organic solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give an oily compound. The oily compound was dissolved in 44 WO 99/21843 PCT/JP98/04455 THF (50 ml), followed by addition of tetrabutylammonium fluoride (15 ml, 1M solution in THF) at room temperature. After being stirred for 4 hours, the mixture was diluted with EtOAc. The mixture was washed with 1N-HCI solution and brine and 5 evaporated. The residue was dissolved in DMF (50 ml), followed by addition of K2CO3 (5 g) and ethyl bromoacetate (2.Oml) at room temperature. The mixture was stirred for 2 hours at the same temperature and partitioned between EtOAc and water. The organic layer was washed with water and brine and evaporated in 10 vacuo. The residue was purified by chromatography on silica gel to give ethyl {3-{[(1S,2R,3S)-2-(4,5-diphenyloxazol-2-yl)-2,3 epoxy-1-cyclohexyl]methyl}phenoxy}acetate (4.3g). IR (Neat) : 1760 cm- 1 NMR (CDCl3, 65) : 1.28(3H, t, J = 7.0Hz), 1.4-2.0(6H, m), 15 2.59(1H, dd, J = 9.0, 12.8Hz), 2.9-3.1 (1H, m), 3.22 (1H, dd, J = 5.0, 12.8Hz), 3.76(1H, m), 4.22(2H, q, J = 7.0Hz), 4.51(2H, s), 6.66(1H, d, J = 8Hz), 6.7-7.0(2H, m), 7.16(1H, t, J = 8Hz), 7.2-7.8(10H, m) MSm/z: 510(M++1) 20 Example 5 45 WO 99/21843 PCT/JP98/04455 Ethyl 3-{[(1S,2S,3R)-2-(4,5-diphenyloxazol-2-yl)-2,3-epoxy 1-cyclohexyl]methyl}phenoxy}acetate was obtained in the same manner as in Example 4. IR (Neat) : 1760 cm- 1 5 NMR (CDCl3, 6) : 1.28(3H, t, J = 7.0Hz), 1.4-2.2(6H, m), 2.65(1H, dd, J = 12Hz, 14Hz), 2.9-3.1 (2H, m), 3.98(1H, m), 4.22(2H, q, J = 7.0Hz), 4.50(2H, s), 6.66(1H, d, J = 8Hz), 6.7-6.9(2H, m), 7.16(1H, t, J = 8Hz), 7.2-7.8(10H, m) MSm/z: 510(M++1) 10 Example 6 To a solution of (R)-2-(4,5-diphenyloxazol-2-yl)-1 trimethylsilyloxy- 1-[3-(tertbutyldiphenylsiloxy) benzyl]-2 cyclohexene (10 g) in THF (50 ml) was added tetrabutylammonium 15 fluoride (41 ml, 1M solution in THF) at room temperature. After being stirred for 4 hours, the mixture was diluted with EtOAc. The mixture was washed with 1N-HCI solution and brine and evaporated. The residue was dissolved in DMF (50 ml), followed by addition of K2CO3 (5 g) and ethyl bromoacetate (2.0ml) at room 20 temperature. The mixture was stirred for 2 hours at the same temperature and partitioned between EtOAc and water. The organic layer was washed with water and brine and evaporated in vacuo. The residue was purified by chromatography on silica gel 46 WO 99/21843 PCT/JP98/04455 to give ethyl (R)-{3-{[2-(4,5-diphenyloxazole-2-yl)-1-hydroxy-2 cyclohexen-l-yl]methyl}phenoxy}-acetate (5.3 g). IR (Neat) : 3400, 1750 cm- 1 NMR (CDC13, 56) : 1.25(3H, t, J = 8Hz), 1.6-2.0(4H, m), 5 2.2-2.4(2H, m), 3.05(1H, d, J = 14Hz), 3.40(1H, d, J = 14Hz), 4.25(2H, q, J = 8Hz), 4.51 (2H, s), 5.63(1H, s), 6.6-7.0(4H, m), 7.19(1H, t, J = 8Hz), 7.2-7.8(10H, m) MSm/z: 510(M*+1) HPLC : chiralcel AD, 10% isopropanol/hexane, 11.3 10 ml/min Example 7 Ethyl {3-{[( 1R,2S)-2-(4,5-diphenyloxazole-2-yl)-l1-hydroxy 1-cyclohexyl]methyl}phenoxy}acetate was obtained in the same 15 manner as in Example 6. IR (Neat): 3300, 1735 cm- 1 NMR (CDCl3, 56) : 1.25(3H, t, J = 8Hz), 1.3-2.2(7H, m), 2.2-2.4(1H, m), 2.80(1H, d, J = 14Hz), 2.90(1H, d, J = 14Hz), 3.13 (1H, dd, J = 4.0, 11Hz), 3.79(1H, br.s), 4.25(2H, q, J = 20 8Hz), 4.48 (2H, s), 6.6-6.9(3H, m), 7.16(1H, t, J = 8Hz), 7.2-7.8(10H, m) MS m/z : 512(M'+1) 47 WO 99/21843 PCT/JP98/04455 Example 8 Ethyl (S)-{3-{[2-(4,5-diphenyloxazole-2-yl)-1-hydroxy-2 cyclohexen- 1 -yl]methyl}phenoxy}acetate was obtained in the same 5 manner as in Example 6. IR (Neat) : 3400, 1750 cm- 1 NMR (CDC13, 6) : 1.25(3H, t, J = 8Hz), 1.6-2.0(4H, m), 2.2-2.4(2H, m), 3.05(1H, d, J = 14Hz), 3.40(1H, d, J = 14Hz), 4.25(2H, q, J = 8Hz), 4.51 (2H, s), 5.63(1H, s), 6.6-7.0(4H, 10 m), 7.19(1H, t, J = 8Hz), 7.2-7.8(10H, m) MSm/z: 510(M+1) Example 9 Ethyl (S)-{3-{[2-(4,5-diphenyloxazole-2-yl)- 1-hydroxy-2 15 cyclopenten-1-yl]methyl}phenoxy}acetate was obtained in the same manner as in Example 6. IR (Neat) : 3400, 1750 cm - 1 NMR (CDCl3, 6) : 1.25(3H, t, J = 8Hz), 1.6-2.5(4H, m), 3.1-3.3(2H, m), 4.25(2H, q, J = 8Hz), 4.54 (2H, s), 5.63(1H, 20 s), 6.5-7.0(4H, m), 7.19(1H, t, J = 8Hz), 7.2-7.8(10H, m) MSm/z: 496(M++1) 48 WO 99/21843 PCT/JP98/04455 Example 10 Ethyl (R)-{3-{[2-(4,5-diphenyloxazole-2-yl)- 1-hydroxy-2 cyclopenten-1-yl]methyl}phenoxy}acetate was obtained in the same manner as in Example 6. 5 IR (Neat) : 3400, 1750 cm-1 NMR (CDC13, 6) : 1.25(3H, t, J = 8Hz), 1.6-2.5(4H, m), 3.1-3.3(2H, m), 4.25(2H, q, J = 8Hz), 4.54 (2H, s), 5.63(1H, s), 6.5-7.0(4H, m), 7.19(1H, t, J = 8Hz), 7.2-7.8(10H, m) MS m/z: 496 (M'+1) 10 Example 11 Ethyl {3-{[( 1R,5S)-2-(4,5-diphenyloxazole-2-yl)-5-hydroxy 2-cyclohexen-1-yl]methyl}phenoxy}acetate was obtained in the same manner as in Example 6. 15 IR (Neat) : 3400, 1750 cm - 1 NMR (CDCl3, 6) : 1.25(3H, t, J = 8Hz), 1.5-3.0(7H, m), 4.25(2H, q, J = 8Hz), 4.51 (2H, s), 6.7-7.0(4H, m), 7.2 7.8(11H, m) MSm/z: 510(M++1) 20 Example 12 Ethyl {3-{[( 1R,5R)-2-(4,5-diphenyloxazole-2-yl)-5-hydroxy 2-cyclohexen-1-yl]methyl}phenoxy}acetate was obtained in the 49 WO 99/21843 PCT/JP98/04455 same manner as in Example 6. IR (Neat) : 3400, 1750 cm- 1 NMR (CDC13, (56) : 1.25(3H, t, J = 8Hz), 1.5-2.2(4H, m), 2.4-2.8(2H, m), 3.32(1H, m), 4.25(2H, q, J = 8Hz), 4.60 (2H, 5 s), 6.7-7.0(4H, m), 7.2-7.8(11H, m) MSm/z: 510(M*+1) Example 13 Ethyl {3-{[2-(4,5-diphenyloxazole-2-yl)-2-cyclohexen-1-yl] 10 hydroxymethyl}phenoxy}acetate was obtained in the same manner as in Example 6. IR (Neat) : 3400, 1750 cm- 1 NMR (CDCl3, 6) : 1.25(3H, t, J = 8Hz), 1.2-1.9(4H, m), 2.2-2.6(2H, m), 3.2(1H, m), 4.25(2H, q, J = 8Hz), 4.60 (2H, 15 s), 6.9-7.2(4H, m), 7.2-7.8(11H, m) MS m/z: 510(M++1) Example 14 Ethyl {3-{[2-(4,5-diphenyloxazole-2-yl)- 1-cyclohexen- 1-yl] 20 hydroxymethyl}phenoxy}acetate was obtained in the same manner as in Example 6. IR (Neat) : 3400, 1750 cm - 1 50 WO 99/21843 PCT/JP98/04455 NMR (CDCl3, 6) : 1.25(3H, t, J = 8Hz), 1.4-2.0(4H, m), 2.0-2.8(4H, m), 4.25(2H, q, J = 8Hz), 4.58 (2H, s), 6.7 7.1(3H, m), 7.0-7.8(11H, m) MS m/z: 510 (M++1) 5 Example 15 To a solution of ethyl {3-{[2-(4,5-diphenyloxazole-2-yl)-1 hydroxy-2-cyclohexen- 1-yl]methyl}phenoxy}acetate (60 mg) in ethanol (5 ml) was added 1N-NaOH solution (0.12 ml) at room 10 temperature. After being stirred for 6 hours, the mixture was evaporated. The residue was added with diethyl ether. The resulting solid was collected by filtration to give sodium {3-{[2 (4,5-diphenyloxazol-2-yl)-1-hydroxy-2-cyclohexen- 1 yl]methyl}phenoxy}acetate (34 mg). 15 IR (KBr) : 3500, 1635 cm -1 NMR (DMSO-d 6 , 6) : 1.4-1.9 (4H, m), 2.1-2.3 (2H, m), 3.99 (2H, s), 6.5-6.7 (3H, m), 6.8 (1H, m), 7.0 (1H, m), 7.3 7.8 (10H, m) MS m/z: 504 (M++1) 20 Example 16(1) The following compounds in (1) and (2) were obtained according to a similar manner to that of Example 15. 51 WO 99/21843 PCT/JP98/04455 (1) Sodium {3-{[( 1S)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxy-2 cyclohexen- 1-yl]methyl}phenoxy}acetate IR (KBr) : 3500, 1635 cm- 1 5 NMR (DMSO-d 6 , 6) : 1.3-2.0 (4H, m), 2.9-3.2 (2H, m), 4.09 (2H, s), 4.21 (1H, m), 6.6-6.8 (4H, m), 7.1 (1H, m), 7.3-7.8 (10H, m) MS m/z : 504 (M'+1) 10 (2) Sodium {3-{[( 1S)-2-(4,5-diphenyloxazol-2-yl)-2,3-epoxy- 1 cyclohexyl]methyl}phenoxy}acetate IR (KBr) : 1635 cm -1 NMR (DMSO-d 6 , 6) : 1.2-1.8 (5H, m), 1.9-2.1 (2H, m), 3.0-3.2 (2H, m), 3.81 (1H, s), 4.04 (2H, s), 6.59 (1H, d, 15 J=8Hz), 6.6-6.8 (2H, m), 7.09 (1H, t, J=8Hz), 7.3-7.8 (10H, m) MS m/z : 504 (M++1) Example 16(3) 20 To a solution of ethyl (R)-{3-{[2-(4,5-diphenyloxazole-2-yl) 1-hydroxy-2-cyclohexen-1-yl]methyl}phenoxy}acetate (7.8 g) in a mixture of ethanol (50 ml) and THF (50 ml) was added 1N-NaOH solution (15.3 ml) at room temperature. After being stirred for 4 52 WO 99/21843 PCT/JP98/04455 hours at the same temperature, the mixture was evaporated. The residue was washed with diethyl ether to afford sodium (R)-{3-{[2 (4,5-diphenyloxazol-2-yl)- 1-hydroxy-2-cyclohexen- 1-yl]methyl} phenoxy}acetate(6.7 g). 5 IR (Neat) ; 3500-3300, 1650 cm-1 NMR (DMSO-d6, 6) ;1.5-1.9(4H, m), 2.2(2H, m), 3.0 3.4(2H, m), 4.025(2H, s), 5.08(1H, br.s), 6.4-6.7(3H, m), 6.86(1H, m), 7.05(1H, t, J = 8Hz), 7.2-7.8(10H, m) MS m/z; 504 (MI+1) 10 Example 16 The following compounds in (4) to (14) were obtained according to a similar manner to that of Example 16(3). 15 (4) Sodium {3-{[( 1R,2S)-2-(4,5-diphenyloxazol-2-yl)- 1 hydroxy- 1-cyclohexyl]methyl}phenoxy}acetate IR (Neat) : 3500-3300, 1650 cm-1 NMR (DMSO-d6, 6) : 1.0-2.0(8H, m), 2.72(1H, d, J = 13.6Hz), 2.82(1H, d, J = 13.6Hz), 3.03(1H, m), 4.05(2H, s), 20 4.69(1H, s), 6.5-6.8(3H, m), 7.03(1H, t, J = 8Hz), 7.2 7.6(10H, m) MS m/z: 506 (M++1) 53 WO 99/21843 PCT/JP98/04455 (5) Sodium (S)-{3-{[2-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2 cyclohexen- 1-yl]methyl}phenoxy}acetate IR (Neat) : 3500-3300, 1650 cm - 1 5 NMR (DMSO-d6, 65) : 1.5-1.9(4H, m), 2.2(2H, m), 3.0 3.4(2H, m), 4.025(2H, s), 5.08(1H, br.s), 6.4-6.7(3H, m), 6.86(1H, m), 7.05(1H, t, J = 8Hz), 7.2-7.8(10H, m) MS m/z: 504(Ml+1) 10 (6) Sodium (S)-{3-{[2-(4,5-diphenyloxazol-2-yl)- 1-hydroxy-2 cyclopenten- 1-yl]methyl}phenoxy}acetate IR (Neat): 3500-3300, 1650 cm- 1 NMR (DMSO-d6, 6) : 1.5-1.9(4H, m), 4.14(2H, s), 6.4 6.8(4H, m), 7.04(1H, t, J = 8Hz), 7.2-7.8(10H, m) 15 MS m/z: 490 (M+1) (7) Sodium (R)-{3-{[2-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2 cyclopenten- 1-yl]methyl}phenoxy}acetate IR (Neat) : 3500-3300, 1650 cm- 1 20 NMR (DMSO-d6, 6):1.5-1.9(4H, m), 4.14(2H, s), 6.4 6.8(4H, m), 7.04(1H, t, J = 8Hz), 7.2-7.8(10H, m) MSm/z: 490(M++1) 54 WO 99/21843 PCT/JP98/04455 (8) Sodium {3-{[( 1S,2R,3S)-2-(4,5-diphenyloxazol-2-yl)-2,3 epoxy- 1-cyclohexyl]methyl}phenoxy}acetate IR (KBr) : 1635 cm - 1 5 NMR (DMSO-d6, 65) : 1.2-2.1(6H, m), 3.0-3.2(2H, m), 3.81(1H, s), 4.07(2H, s), 6.59(1H, d, J = 8Hz), 6.6-6.8(2H, m), 7.09 (1H, t, J = 8Hz), 7.3-7.8(10H, m) MS m/z: 504 (M++1) 10 (9) Sodium {3-{[( 1S,2S,3R)-2-(4,5-diphenyloxazol-2-yl)-2,3 epoxy- 1-cyclohexyl]methyl}phenoxy}acetate IR (KBr) : 1635 cm- 1 NMR (DMSO-d6, 6) : 1.2-2.1(6H, m), 2.6-3.0(3H, m), 3.95(1H, m), 4.02(2H, s), 6.5-6.8(3H, m), 7.08 (1H, t, J = 15 8Hz), 7.3-7.8(10H, m) MS m/z : 504 (M++1) (10) Sodium {3-{[( 1S)-2-(4,5-diphenyloxazol-2-yl)-2,3-epoxy- 1 cyclopentyl]methyl}phenoxy}acetate 20 IR (KBr) : 1635 cm- 1 NMR (DMSO-d6, 6) : 1.2-2.0(4H, m), 2.7-3.1(2H, m), 3.81(1H, s), 4.05 and 4.08(2H, each s), 6.4-7.0(3H, m), 7.0-7.2(1H, m), 7.3-7.8(10H, m) 55 WO 99/21843 PCT/JP98/04455 MSm/z: 490(M++1) (11) Sodium {3-{[( 1R,5S)-2-(4,5-diphenyloxazol-2-yl)-5 hydroxy-2-cyclohexen- 1 -yl] methyl}phenoxy}acetate 5 IR (Neat) : 3500-3300, 1650 cm-1 NMR (DMSO-d6, 6) : 1.5-1.9(4H, m), 4.05(2H, s), 6.5 6.8(4H, m), 7.0-7.8(11H, m) MSm/z : 504(M++1) 10 (12) Sodium {3-{[( 1R,5R)-2-(4,5-diphenyloxazol-2-yl)-5 hydroxy-2-cyclohexen- 1 -yl]methyl}phenoxy}acetate IR (Neat) : 3500-3300, 1650 cm-1 NMR (DMSO-d6, 6) : 1.5-1.9(4H, m), 3.0-3.4(3H, m), 4.13(2H, s), 6.5-6.8(4H, m), 7.0-7.8(11H, m) 15 MS m/z : 504 (M++1) (13) Sodium {3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1 yl]hydroxymethyl}phenoxy}acetate IR (Neat): 3500-3300, 1650 cm- 1 20 NMR (DMSO-d6, 65) : 1.2-2.0(5H, m), 2.0-2.2(2H, m), 4.06(2H, s), 4.97(1H, m), 6.5-7.0(4H, m), 7.11(1H, t, J = 8Hz), 7.0-7.8(10H, m) 56 WO 99/21843 PCT/JP98/04455 MS m/z: 504 (Ml+1) (14) Sodium {3-{[2-(4,5-diphenyloxazol-2-yl)-1-cyclohexen- 1 yl]hydroxymethyl}phenoxy}acetate 5 IR (Neat) : 3500-3300, 1650 cm-1 NMR (DMSO-d6, 6) : 1.2-2.0(4H, m), 4.03(2H, s), 6.5 6.7(2H, m), 6.8-7.0(2H, m), 7.10(1H, t, J = 8Hz), 7.0 7.8(10H, m) MS m/z: 504 (M++1) 10 57

Claims (13)

1. A compound of the formula: R 8 R 9 R 7 O N R 2 R 3 \__ R 4(1 X R"R5 5 OCH 2 COOR R 6 wherein R 1 is a hydrogen atom or a carboxy protective group, R 2 , R 5 , R 6 and R 7 are each a hydrogen atom or a hydroxy 10 group, R 3 and R 4 are each a hydrogen atom, or are combined together to form an epoxy group or a single bond, R 8 and R 9 are each an optionally substituted aryl group, and 15 X is a single bond or a methylene group, in addition to the above definitions, R 2 and R 3 may be combined together to form a single bond; provided that when R 2 , R 5 , R 6 and R 7 are each a hydrogen atom, then R 3 and R 4 are combined together to form an 20 epoxy group; 58 WO 99/21843 PCT/JP98/04455 when R 3 and R 4 are combined together to form a single bond, then at least one of R 2 , R 5 , R 6 and R 7 is a hydroxy group and the other(s) is(are) hydrogen atom(s); and 5 when R 3 and R 4 are each a hydrogen atom, then at least one of R 2 , R 5 , R 6 and R 7 is a hydroxy group and the other(s) is(are) hydrogen atom(s), and X is a methylene group, or its salt. 10

2. A compound of Claim 1, wherein R 3 and R 4 are combined together to form a single bond or an epoxy group and R 8 and R 9 are each a phenyl group. 15

3. A compound of Claim 2, wherein at least one of R 2 , R 5 , R 6 and R 7 is a hydroxy group and the other(s) is(are) hydrogen atom(s).

4. A compound of Claim 3, wherein one of R 2 , R 5 , R 6 and R 7 is a hydroxy group and the others are hydrogen atoms. 20

5. A compound of Claiml , wherein R 1 is a hydrogen atom or a carboxy protective group, any one of R 2 , R 5 S , R 6 and R 7 is a hydroxy group and the others are hydrogen atoms, 59 WO 99/21843 PCT/JP98/04455 R 3 and R 4 are each a hydrogen atom, R" and R 9 are each a phenyl group, and X is a methylene group, or its salt. 5

6. A compound of Claim 1, wherein R 1 is a hydrogen atom or a carboxy protective group, any one of R 2 , R 5 , R 6 and R 7 is a hydroxy group and the others are hydrogen atoms, 10 R 3 and R 4 are combined together to form an epoxy group or a single bond, R 8 and R 9 are each a phenyl group, and X is a single bond or a methylene group, or its salt. 15

7. A compound of Claim 1, wherein R' is a hydrogen atom or a carboxy protective group, R 2 , R 5 , R 6 and R 7 are each a hydrogen atom, R 3 and R 4 are combined together to form an epoxy group, 20 R 8 and R 9 are each a phenyl group, and X is a single bond or a methylene group, or its salt. 60 WO 99/21843 PCT/JP98/04455

8. A compound of Claim 1, which is selected from the group consisting of sodium {3-{[2-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2 cyclohexen- 1-yl]methyl}phenoxy}acetate, 5 sodium {3-{[( 1S)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxy-2 cyclohexen- 1-yl]methyl}phenoxy}acetate, sodium {3-{[( 1S)-2-(4,5-diphenyloxazol-2-yl)-2,3-epoxy- 1 cyclohexyl] methyl}phenoxy}acetate, sodium (R)-{3-{[2-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2 10 cyclohexen- 1 -yl] methyl}-phenoxy}acetate, sodium {3-{[( 1R,2S)-2-(4,5-diphenyloxazol-2-yl)-1-hydroxy 1-cyclohexyl]methyl}phenoxy}acetate, sodium (S)-{3-{[2-(4,5-diphenyloxazol-2-yl)- 1-hydroxy-2 cyclohexen- 1-yl]methyl}phenoxy}acetate, 15 sodium (S)-{3 -{[2-(4,5-diphenyloxazol-2-yl)- 1-hydroxy-2 cyclopenten- 1 -yl]methyl}phenoxy}acetate, sodium (R)-{3-{[2-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2 cyclopenten- 1-yl]methyl}phenoxy}acetate, sodium {3-{[( 1S,2R,3S)-2-(4,5-diphenyloxazol-2-yl)-2,3 20 epoxy- 1-cyclohexyl]methyl}phenoxy}acetate, sodium {3-{[( 1S,2S,3R)-2-(4,5-diphenyloxazol-2-yl)-2,3 epoxy- 1-cyclohexyl]methyl}phenoxy}acetate, and sodium {3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-2,3-epoxy- 1 cyclopentyl]methyl}phenoxy}acetate. 61 WO 99/21843 PCT/JP98/04455

9. A process for preparing a compound of the formula: R 8 R 9 R 7 O, N R 3 R 3 R4 OCH2COOR1 R 6 5 wherein RI is a hydrogen atom or a carboxy protective group, R 2 , R 5 , R 6 and R 7 are each a hydrogen atom or a hydroxy group, 10 R 3 and R 4 are each a hydrogen atom, or are combined together to form an epoxy group or a single bond, R 8 and R 9 are each optionally a substituted aryl group, and X is a single bond or a methylene group, in addition to the above definitions, 15 R 2 and R 3 may be combined together to form a single bond; provided that when R 2 , R 5 , R 6 and R 7 are each a hydrogen atom, then R 3 and R 4 are combined together to form an epoxy group; when R and R 4 are combined together to form a 20 single bond, 62 WO 99/21843 PCT/JP98/04455 then at least one of R 2 , R 5 , R 6 and R 7 is a hydroxy group and the other(s) is(are) hydrogen atom(s); or when R 3 and R 4 are each a hydrogen atom, then at least one of R 2 , R 5 , R 6 and R 7 is a hydroxy 5 group and the other(s) is(are) hydrogen atom(s), and X is a methylene group, or its salt, which comprises 10 (1) subjecting a compound of the formula: R 8 R 9 R 7 O XN (II-1) / X OCH 2 COOR R 6 or its salt, to an oxidation reaction to give a compound of the formula: R8 R 9 R 7 O7 N R2 a(I-1) / Xs 5a OCH 2 COOR' R6 63 WO 99/21843 PCT/JP98/04455 or its salt, wherein RI, R 6 , R 7 , R 8 , R 9 and X are as defined above, and any one of R 2 a and R 5 a is a hydroxy group and the other is a hydrogen atom or a hydroxy group, 5 (2) subjecting a compound of the formula: R 8 R 9 R 7 O, N R2 (1-2) R 5 OCH 2 COOR R6 or its salt, to an epoxidation reaction to give a compound of the formula: R R 9 R 7 O ,N R 2 O (1-3) Xx R5 10 OCH 2 COOR R6 or its salt, wherein R 1 , R 2 , R s , R 6 , R 7 , R 8 , R 9 and X are as defined above, (3) subjecting a compound of the formula: 64 WO 99/21843 PCT/JP98/04455 R 8 R 9 R 7 O , N(11-2) R 2OH OH IR5 OR 10 R 6 or its salt, to a cyclization, a removal of RIO and then a reaction with Y 1 -CH 2 COOR 1 to give a compound of the formula: R 8 R 9 R 7 O , N R2 (1-3) / X, R5 OCH 2 COOR R 6 5 or its salt, wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 and X are as defined above, RIO is a hydroxy protective group, and Y' is a leaving group, 10 (4) subjecting a compound of the formula: 65 WO 99/21843 PCT/JP98/04455 R 8 R 9 or its salt, to a removal of R 1° and a reaction with yl-CH 2 COOR1 , followed by removal of hydroxy protective groups in the protected hydroxy groups for Rb to R 7 b if necessary, to give a compound of the 5 formula : H(I-4) R 7b O0 N R b R b \ R 4b (I-3) OCH 2 OOR R or its salt, to a removal of RIO and a reaction with Y-CH2COOR , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and X are as defined above, 10 Y' is a leaving group, R 2 b, R~b, R 6 b and R~b are each a hydrogen atom, a hydroxy followed by removal of hydroxy protective groups in the protected hydroxy groups forand R2bto are each a hydrogen ary, to give aor compoubined togef the to form a single bond, 15 in addition to the above definitions, 66 R2" R9 R 2 R 3 4 X R (-4) x R5 OCH2COOR 1R 6 or its salt, wherein RI, R2, R3, R4, R5, R6, R7,R89 and X are as defined above, 10 Y' is a leaving group, R2 b, R5b, R6b and R7 bare each a hydrogen atom, a hydroxy group or a protected hydroxy group, and R3 band R b are each a hydrogen atom or combined together to form a single bond, 15 in addition to the above definitions, 66 WO 99/21843 PCT/JP98/04455 R 2 b and R 3 b may be combined together to form a single bond, or (5) subjecting a compound of the formula: R 8 R 9 (H-6 R 7 O N R 2 R 34 X R 4 (I-5) R5 5 or its salt, to a hydrolysis to give a compound of the formula: R 8 R 9 R 7 O , N | 2 " '3 (1-6) R 2R 34 / X R R OCH2COOH R 6 or its salt, wherein R 2, R3 , R 4, R 5, R 6, R 7, R , R 9 and X are as defined above, 10 and RIa is a carboxy protective group.

10. A pharmaceutical composition which comprises, as an active ingredient, a compound of Claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically 15 acceptable carrier. 67 WO 99/21843 PCT/JP98/04455

11. A use of a compound of Claim 1 or a pharmaceutically acceptable salt thereof as a prostaglandin 12 agonist. 5

12. A method for treating or preventing arterial obstruction, restenosis after percutaneous transluminal coronary angioplasty, arteriosclerosis, cerebrovascular disease or ischemic heart disease which comprises administering a compound of Claim 1 or a pharmaceutically acceptable salt thereof to human being or 10 animals.

13. A process for preparing a pharmaceutical composition which comprises admixing a compound of Claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically 15 acceptable carrier. 68