Benzenesulfonamide compounds

Abstract: Benzenesulfonamide compounds of formula (I) (R 1 is hydroxy, C1-4 alkoxy, NR 6 R 7 (each R 6 and R 7 is, independently, H or C1-4 alkyl); R 2 is H, C1-4 alkyl; R 3 , R 4 are C1-4 alkyl, halogen, trifluoromethyl; R 5 is H, C1-4 alkyl, halogen, trifluoromethyl; Y is cis-vinylene, trans-vinylene; and the symbol is single bond, double bond) can bind strongly to the EP1 receptor which is a prostaglandin E 2 receptor subtype and scarcely bind to the other receptor subtypes. Therefore, they are considered to be useful as antipyretic agents, as analgesics or as agents for the prevention and/or treatment of pollakiuria having little side effect.

Description: The present invention relates to benzenesulfonamide compounds, processes for their preparation and prostaglandin E 2 receptor antagonists which comprise them as an active ingredient. Background Prostaglandin E 2 (abbreviated as PGE 2 ) has been known as a metabolite in the arachidonate cascade. It has been known that PGE 2 possesses a cyto-protective activity, a uterine contractile activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awakening effect, a suppressive effect on gastric acid secretion, a blood pressure reducing effect and a diuretic activity. In a recent study, it was found that the PGE 2 receptor was divided into some subtypes which possess different physical roles from each other. At present, four receptor subtypes are known and they are called EP1, EP2, EP3 and EP4 (Negishi M. et al, J. Lipid Mediators Cell Signalling 12 , 379-391 (1995)). PGE 2 possesses a variety of physiological activities, so the undesired action other than the aimed one is shown as side effect. The research for the role of each receptor subtype and the investigation of the compound which only shows the effect on the specific subtype have been carried out to overcome such a problem. In these subtypes, it has been known that the EP1 subtype relates to induction of pain, fever and diuresis (Br. J. Pharmacol. 1994, 112 , 735-40; European J. Pharmacol. 152 (1988) 273-279; Gen Pharmacol. Sep1992, 23(5) p805-809). Therefore, compounds which antagonize against this receptor are considered to be useful as analgesics, as antipyretic agents and as agents for treating pollakiuria. The present inventors have studied to find compounds which can bind to the EP1 receptor selectively, have found that the benzenesulfonamide compounds of formula (I), as hereinafter defined, can bind to the EP1 receptor selectively and strongly and scarcely bind to other receptor subtypes, and then have achieved the present invention. Related Arts As for the compound having a similar structure of the present invention compound of the formula (I), the following related arts have been known. In the specification of Japanese Patent Application Kokai Hei 6-279395 (European Patent Publication No. 608,847), it was disclosed that the sulfonamide compound possessing carbocyclic ring of the formula (A) (wherein, the symbol is (i) the group of the formula or (ii) the group of the formula R 100 is C4-7 alkylene or C4-7 alkenylene, R 200 is hydroxy, C1∼20 alkoxy or NR 230 R 240 (wherein, each R 230 and R 240 is, independently, hydrogen, C1∼4 alkyl or NR 230 R 240 is amino acid residue.), R 300 is single bond or C1∼4 alkylene, R 400 is hydrogen or C1∼4 alkyl, each R 500 and R 900 is, independently, (i) (wherein, R 600 is hydrogen, C1∼4 alkyl, C1∼4 alkoxy, hydroxy, halogen, trifluoromethyl or nitro, and nn is 1, 2 or 3.), (ii) (wherein, R 610 is hydrogen, C1∼4 alkyl, C1∼4 alkoxy, hydroxy, halogen, trifluoromethyl or nitro, and mm is 1, 2 or 3.), (iii) (wherein, R 620 is hydrogen, C1∼4 alkyl, C1∼4 alkoxy, hydroxy, halogen, trifluoromethyl or nitro, and kk is 1, 2 or 3.), (iv) C1~7 alkyl or (v) hydrogen.), cyclodextrin clathrate thereof and non-toxic salt thereof, and the compound of the formula (B) (wherein, R 1 is i) COOR 11 , or ii) CONR 13 R 14 (wherein, R 11 is hydrogen, C1∼20 alkyl, and each R 13 and R 14 is hydrogen, C1∼4 alkyl, or NR 13 R 14 is amino acid residue.), and the symbol is or (wherein, the symbol is the group of the formula Ba is i)-CH 2 -CH 2 -(CH 2 ) m - or ii) cis-CH=CH-(CH 2 ) m - (wherein, m is 1∼6.), R 2a is single bond or C1∼4 alkylene, R 3a is benzene, naphthalene or C4-7 cycloalkyl unsubstituted or substituted by 1 to 3 of C1∼4 alkyl, C1∼4 alkoxy, hydroxy, cyano, halogen, trifluoromethyl or nitro, or R 2a and R 3a together forms C1∼12 alkyl, the symbol is the group of the formula Xb is i) single bond, ii) C1∼4 alkylene or iii) C2∼4 alkenylene (with the proviso that, group of -αCH=CH-CH 2 β- and -αCH 2 -CH=CH-CH 2 β- is excluded.), R 2b is hydrogen, C1∼4 alkyl, C1∼4 alkoxy, hydroxy, cyano, halogen, trifluoromethyl or nitro, configuration of C5-C6 double bond in the formula (Ab) is cis, the symbol is the group of the formula Lc is C1∼4 alkylene, R 2C is hydrogen, C1∼4 alkyl, C1∼4 alkoxy, hydroxy, cyano, halogen, trifluoromethyl or nitro. The configuration of C5-C6 bond in the formula (Ac) is cis or trans.).), cyclodextrin clathrate thereof and non-toxic salt thereof are useful for the prevention and/or treatment of abortion, pain, diarrhea or sleeping disorder as PGE 2 receptor antagonist or for the prevention and/or treatment of constipation, ulcer, gastritis and hypertension, or induction of labor as PGE 2 agonist. On the other hand, the following two patent applications relate to similar structure compounds showing a different activity. That is to say, in Japanese patent application Kokai Hei 2-180862 (European Patent Publication No. 312,906) and Japanese patent application Kokai Sho 63-139161 (European Patent Publication No. 226,346), it was disclosed that compounds having a similar structure to the compounds of the present invention showed thromboxane A2 antagonistic activity. Disclosure of the Invention The present invention provides (1) benzenesulfonamide compounds of formula (I) (wherein the group is a group of formula R 1 is hydroxy, C1-4 alkoxy or a group of formula NR 6 R 7 (wherein R 6 and R 7 are each independently hydrogen or C1-4 alkyl, R 2 is hydrogen or C1-4 alkyl, R 3 and R 4 are each independently C1-4 alkyl, halogen or trifluoromethyl, R 5 is hydrogen, C1-4 alkyl, halogen or trifluoromethyl, Y is cis-vinylene or trans-vinylene, and the symbol represents a single bond or double bond, or a non-toxic salt thereof or cyclodextrin clathrate thereof, (2) processes for their preparation and (3) antagonists of the EP1 receptor which is a PGE 2 receptor subtype comprising them as an active ingredient. In the formula (I), C1∼4 alkyl represented by R 2 to R 7 means methyl, ethyl, propyl, butyl and isomer thereof. In the formula (I), C1∼4 alkoxy represented by R 1 means methoxy, ethoxy, propoxy, butoxy and isomer thereof. In the formula (I), halogen represented by R 3 to R 5 means fluorine, chlorine, bromine and iodine. Unless otherwise specified, in the present invention, the symbol indicates that the substituent attached thereto is in front of the sheet and the symbol indicates that the substituent attached thereto is behind the sheet as clear for the skilled person in the art. Unless otherwise specified, all isomers are included in the present invention. For example, alkyl includes straight-chain or branched-chain ones. Isomers generated by asymmetric carbon(s) e.g. branched alkyl are also included in the present invention. In the compounds of the present invention of formula (I), the compounds described in the Examples, the following 5-cis type compounds numbered (1) to (75), the corresponding ester and/or 5-trans type compounds and the corresponding amide and/or 5-trans type compounds are preferred. These ester and amide compounds are preferred as prodrugs of the corresponding carboxylic acid compounds. In the compounds of the present invention of formula (I), the compounds of formula (I-1) wherein R 1a is hydroxy or C1-4 alkoxy, and the other symbols are as defined hereinbefore, are also preferred. 6-[3-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(2,4-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(2,4-dibromophenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(4-bromo-2-chlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(4-bromo-2-fluorophenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(4-chloro-2-fluorophenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-2E,5Z-hexadienoic acid, 6-[3-(2,4,6-trichlorophenylsulfonylaminomethyl)bicycle[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(2-chloro-4-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(4-chloro-2-trifluoromethylphenylsulfonylaminomethyl)bicyclo[2.2.2]-octane-2-yl]-5Z-hexenoic acid, 6-[3-(2,4,6-trimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-5E-hexenoic acid and 6-[3-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-5E-hexenoic acid 6-[3-[2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid, 6-[3-(4-bromo-2-fluorophenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid, 6-[3-(4-bromo-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid, 6-[3-(4-chloro-2-fluorophenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid, 6-[3-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid, 6-[3-(2,4,6-trichlorophenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid, 6-[3-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid and 6-[3-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid 6-[6-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-y|]-5Z-hexenoic acid, 6-[6-(2,4,6-trichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-chloro-2-fluorophenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid 6-[6-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-bromo-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid and 6-[6-(2,4-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid 6-[6-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-chloro-2-fluorophenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(2,4,6-trichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-bromo-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid and 6-[6-(2,4-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid 6-[2-(2,4-dichlorophenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid, 6-[2-(4-bromo-2-fluorophenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid, 6-[2-(4-bromo-2-methylphenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid, 6-[2-(4-chloro-2-fluorophenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid, 6-[2-(2,4,6-trichlorophenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid, 6-[2-(4-chloro-2-methylphenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid, 6-[2-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid and 6-[2-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid 6-[5-(2,4-dichlorophenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid, 6-[5-(4-chloro-2-methylphenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid, 6-[5-(4-chloro-2-fluorophenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid, 6-[5-(4-bromo-2-fluorophenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid, 6-[5-(2,4,6-trichlorophenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid, 6-[5-(4-bromo-2-methylphenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid, 6-[5-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid and 6-[5-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid 6-[2-(2,4-dichlorophenylsulfonylaminomethyl)cycloheptyl]-5Z-hexenoic acid and methyl esters thereof. Salts The compounds of the present invention of the general formula (I) may be converted into the corresponding salts by known methods. Non-toxic and water-soluble salts are preferable. Suitable salts, for example, are as follows: salts of alkali metals (potassium, sodium), salts of alkaline earth metals (calcium, magnesium), ammonium salts, salts of pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine). Cyclodextrin clathrates The present invention compounds of formula (I) may be converted into their cyclodextrin clathrates using α-, β- or γ-cyclodextrin or mixture thereof by the method described in the specification of Japanese Patent Kokoku Sho 50-3362, 52-31404 or 61-52146. Converting into their cyclodextrin clathrates serves to increase the stability and solubility in water and therefore it is useful in the use for pharmaceuticals. Process for the preparation of the present invention compound The present invention compounds of formula (I) may be prepared by the following processes, the methods described in the Examples or known methods. (1) In the present invention compounds of formula (I), a compound wherein R 1 is hydroxy or C1-4 alkoxy, i.e., a compound of formula (la) (wherein, R 1a is hydroxy or C1-4 alkoxy, and the other symbols are as defined hereinbefore.) may be prepared by (a) reacting a compound of formula (II) (wherein, R 10 is C1-4 alkoxy, and the other symbols are as defined hereinbefore.) or salt thereof with a compound of formula (III) (wherein, X is halogen, and the other symbols are as defined hereinbefore.) to form an amide bond, optionally followed by hydrolysis under alkaline conditions or using an enzyme or (b) reacting a compound of formula (XI) (wherein, all symbols are as defined hereinbefore.) with a compound of formula (III-A) (wherein Z a is C1-4 alkyl or an amino-protecting group which may be removed under acidic conditions and the other symbols are as defined hereinbefore) optionally followed by removing the amino-protecting group under acidic conditions and/or by hydrolysis under alkaline conditions or using an enzyme. Reaction to form amide bond is well known. For example, it may be carried out in an organic solvent (methylene chloride, tetrahydrofuran (THF), benzene, acetone or acetonitrile) in the presence or absence of tertiary amine (triethylamine, dimethylaminopyridine or pyridine) by using or without a condensing agent ((1 -ethyl-3-[3-(dimethylamino)propyl]carbodiimido (EDC), 1 ,3-dicyclohexylcarbodiimido (DCC)) at -10∼50°C.The hydrolysis under alkaline conditions is known. For example, it may be carried out in a water-miscible organic solvent (THF, methanol, ethanol, dimethoxyethane or mixture thereof), using an alkaline (e.g., sodium hydroxide, potassium hydroxide) solution, at 0∼50°C.The hydrolysis using an enzyme is known. For example, it may be carried out in a mixture of a water-miscible organic solvent (ethanol, dimethylsulfoxide or mixture thereof) and water, in the presence or absence of buffer, by using esterase (esterase, lipase), at 0-50°C.The reaction of an alcohol compound of formula (XI) with an amine compound of formula (Ill-A) may be carried out by a known method. For example, it may be carried out in an organic solvent (e.g. acetone, THF, methylene chloride), in the presence of triphenylphosphine and diethylazo dicarboxylate at 0-50°C.Removing an amino-protective group under acidic conditions is known. For example, it may be carried out in a solvent (methylene chloride, dioxane, ethyl acetate, acetic acid, water or mixture thereof etc.), using an organic acid (e.g., trifluoroacetic acid) or an inorganic acid (e.g. HCI, HBr) at 0-120°C.As for an amino-protecting group which may be removed under acidic conditions, for example, t-butoxycarbonyl is included. (2) In the present invention compounds of formula (I), a compound wherein R 1 is NR 6 R 7 (wherein, each R 6 and R 7 is, independently, hydrogen or C1-4 alkyl.), i.e., a compound of formula (Ib) (wherein, R 1b is NR 6 R 7 (wherein, each R 6 and R 7 is, independently, hydrogen or C1∼4 alkyl.), and the other symbols are as defined hereinbefore.) may be prepared by reacting a compound of formula (I) wherein R 1 is hydroxy, i.e., a compound of formula (Ic) (wherein, all symbols are as defined hereinbefore.) with a compound of formula (IV) NHR 6 R 7 (wherein, all symbols are as defined hereinbefore.) to form an amide bond. The reaction to form amide bond may be carried out by the procedure as described hereinbefore. The compounds of formula (II) and (Xl) may be prepared by the procedure as described in the specification of Japanese Patent Application Kokai Hei 6-279395 (European Patent Publication No. 608,847), Japanese Patent Application Kokai Hei 2-180862 (European Patent Publication No. 312,906), Japanese Patent Application Kokai Sho 63-139161 (European Patent Publication No. 226,346) or the following Reaction Scheme (A) to (E). The symbols in the Reaction Scheme (A) to (E) are as defined hereinbefore or as follows: Z 1 : hydroxy-protecting group containing silyl group, Ph : phenyl, LiHMDS : lithium hexamethyldisilazido, (PhSe) 2 : diphenyl diselenide. TBAF : tetrabutylammonium fluoride, LiAlH 4 : Lithium aluminum hydride, TsCl : tosylchloride, aq. KOH : aqueous solution of potassium hydroxide, Ph 3 P: triphenylphosphine, DEAD : diethyl azodicarboxylate, X 1 : halogen, R 20 : C1-4 alkyl, Z 2 : amino-protecting group which may be removed under acidic conditions. Starting materials and reagents The starting materials and reagents in the present invention are known per se or may be prepared by known methods. The compounds of the formula (V), (VIII), (IV) are known per se or may be prepared by known methods. In the compounds of the formula (III), for example, 2,4-dichlorobenzenesulfonylchloride is available in the market. The compounds of the formula (III-A) may be prepared by reacting the compounds of the formula (III) with ammonia and then introducing an alkyl group or an amino-protecting group which may be removed under acidic conditions (Z a ). In each reaction in the present specification, obtained products may be purified by conventional techniques. For example, purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography, by thin layer chromatography or by column chromatography using silica gel or magnesium silicate, by washing or by recrystallization. Purification may be carried out after each reaction, or after a series of reactions. Pharmacological activity of the present invention compounds The compounds of formula (I) of the present invention can bind strongly to the EP1 receptor which is a subtype receptor of prostaglandin E 2 and show antagonistic activity. As mentioned hereinbefore, it is known that the EP1 receptor relates to inducing pain, fever or diuresis. The compounds of formula (I) of the present invention, non-toxic salts thereof and cyclodextrin clathrates thereof, which antagonize this receptor, are therefore useful as analgesics, as antipyretic agents or as agents for the prevention and/or treatment of pollakiuria. In addition, the present invention compounds scarcely bind to the other subtypes of the PGE 2 receptor. Therefore, they are considered not to relate to the other various activities of PGE 2 and are expected to provide agents having little side effect. For example, in standard laboratory test, it was confirmed that they showed such activities according to assay using expression cell of prostanoid receptor subtype. (i) Binding assay using expression cell of prostanoid receptor subtype The preparation of membrane fraction was carried out according to the method of Sugimoto et al (J. Biol. Chem. 267 , 6463-6466 (1992)), using expression CHO cell of prostanoid receptor subtype (mouse EP1 and EP3). The standard assay mixture containing membrane fraction (0.5 mg/ml), 3 H-PGE 2 in a final volume of 200 microliter was incubated for 1 hour at room temperature. The reaction was terminated by addition of 3 ml of ice-cold buffer. The mixture was rapidly filtered through a glass filter (GF/B). The radioactivity associated with the filter was measured by liquid scintillation counting. Kd and Bmax values were determined from Scatchard plots (Ann. N.Y. Acad. Sci., 51 , 660 (1949)). Non-specific binding was calculated as the binding in the presence of an excess (2.5 microM) of unlabeled PGE 2 . In the experiment for competition of specific 3 H-PGE 2 binding by the compounds of the present invention, 3 H-PGE 2 (2.5 nM) and the present invention compounds were added. The following buffer was used in all reaction. Buffer: potassium phosphate (pH6.0, 10 mM), EDTA (1 mM), MgCl 2 (10 mM), NaCI (0.1M). The dissociation constant Ki (microM) of each compound was calculated by the following equation. Ki = IC50/(1+([C]/Kd)) The results are shown in Table 1. dissociation constant to receptor subtype of the present invention compounds (Ki, microM) Example No. EP1 EP3 2 0.0005 0.12 2(c) 0.0018 0.20 2(d) 0.0014 0.085 2(g) 0.0034 0.95 2(k) 0.0024 1.4 2(n) 0.0051 1.9 3(a) 0.0031 0.018 3(e) 0.0084 0.11 3(f) 0.0011 0.041 4(b) 0.017 0.052 4(c) 0.039 0.18 4(f) 0.0057 0.012 5(a) 0.012 0.28 5(d) 0.023 1.2 5(e) 0.0072 0.20 6(a) 0.0039 0.37 6(e) 0.0042 1.1 7(d) 0.0039 1.4 7(f) 0.0072 1.5 In addition, the same experiment was carried out using the compounds (each structure is shown as hereinafter) described concretely as PGE 2 receptor antagonists or agonists in European Patent Publication No. 608,847 corresponding to Japanese Patent Application Kokai Hei 6-279395 (referred to as Related Art (1) hereinafter). The results are shown in the following Table 2. For reference, corresponding experimental data for the compounds described concretely as TXA 2 antagonists in European Patent Publication No. 312,906 corresponding to Japanese Patent Application Kokai Hei 2-180862 (referred to as Related Art (2) hereinafter) are also shown in Table 2. dissociation constant to receptor subtype of the compounds of Related Arts (1) and (2) (Ki, microM) Example No. or order in Table 1 of Related Art (1) EP1 EP3 Example 5(d) 1.3 0.17 Example 6-17 >10 0.0027 Example 6-19 2.3 0.013 31st Compound in Table 1 0.069 0.095 Example No. of Related Art (2) EP1 EP3 Example 1(p) 0.46 0.29 Example 1(aa) 3.6 0.48 Example 1(bb) 0.19 0.14 The structure of the compounds described concretely in the corresponding examples or Table 1 of Related Art (1) (European Patent Publication No. 608,847) in the above Table 2 is as follows: Example 5(d): . Example 6-17: Example 6-19: The 31st compound in Table 1: The structure of the compounds described concretely in the corresponding examples of Related Art (2) (European Patent Publication No. 312,906) in the above Table 2 is as follows: Example 1(p): Example 1(aa): Example 1(bb): The data of Tables 1 and 2 show that the present invention compounds of the formula (I) possess superior activity with respect to the strength and selectivity in binding onto EP1 receptor compared with the compounds of European Patent Publication No. 608,847 corresponding to Japanese Patent Application Kokai Hei 6-279395 (Related Art (1)). Toxicity The toxicity of the compounds of the present invention is very low and therefore, it is confirmed that these compounds are safe for use as medicine. Application for Pharmaceuticals For the purpose above described, the present invention compounds of the formula (I), non-toxic salts thereof or cyclodextrin clathrates thereof may be normally administered systemically or partially, usually by oral or parenteral administration. The doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment. In the human adult, the doses per person per dose are generally from 1 mg to 100 mg, by oral administration, up to several times per day, and from 0.1 mg to 10 mg, by parenteral administration (preferred into vein) up to several times per day, or continuous administration for from 1 to 24 hrs. per day into vein. As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used. The compounds of the present invention may be administered in the form of, for example, solid compositions, liquid compositions or other compositions for oral administration, or as injections, liniments or suppositories for parenteral administration. Solid compositions for oral administration include tablets, pills, capsules, dispersible powders, and granules. Capsules include hard capsules and soft capsules. In such solid compositions, one or more of the active compound(s) is or are, admixed with at least one inert diluent e.g. lactose, mannitol, mannit, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone, magnesium metasilicate aluminate. Such compositions may contain additional substances other than inert diluent, for example, lubricating agents e.g. magnesium stearate, disintegrating agents e.g. cellulose calcium glycolate, assisting agents for dissolving e.g. glutamic acid, asparaginic acid. Tablets or pills may, if desired, be coated with gastric or enteric films such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl cellulose phthalate etc., or be coated with two or more films. And further, the compositions also include capsules of absorbable materials such as gelatin. Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, syrups and elixir. In such liquid compositions, one or more of the active compound(s) is or are comprised in the inert diluent(s) commonly used in the art (e.g. purified water, ethanol). Besides inert diluents, such compositions may also comprise adjuvants such as wetting agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, preserving agents. Other compositions for oral administration include spray compositions which may be prepared by known methods and which comprise one or more of the active compound(s). Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents such as sodium hydrogen sulfate, stabilizing agents to give isotonicity, isotonic buffer such as sodium chloride, sodium citrate, citric acid. For preparation of such spray compositions, for example, the method described in the United States Patent No. 2868691 or 3095355 may be used. Injections for parenteral administration of the present invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Aqueous solutions or suspensions include distilled water for injection and physiological salt solution. Non-aqueous solutions or suspensions include propylene glycol, polyethylene glycol, plant oil such as olive oil, alcohol such as ethanol, POLYSORBATE80®. Such compositions may comprise additional diluents: e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agent, assisting agents such as assisting agents for dissolving (for example, glutamic acid, asparaginic acid). They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They also be manufactured in the form of sterile solid compositions and which can be dissolved in sterile water or some other sterile diluents for injection immediately before used. Other compositions for parenteral administration include liquids for external use, and endemic liniments, ointment, suppositories for rectal administration and pessaries for vaginal administration which comprise one or more of the active compound(s) and may be prepared by known methods. Reference examples and Examples The following Reference examples and Examples are intended to illustrate, but not limit, the present invention. The solvents in parentheses show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations. Example 1 6-[(2S, 3S)-3-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid methyl ester To a solution of 6-[(2S, 3S)-3-aminomethylbicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid methyl ester (1.70 g) in methylene chloride (30 ml), triethylamine (2.6 ml) was added. A solution of 2,4-dichlorobenzenesulfonylchloride (2.04 g) in methylene chloride (10 ml) was dropwise thereto. The solution was stirred for 1 hour at 0°C. After the termination of reaction, the solution was quenched by adding 1 N HCI and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution succeedingly, dried over anhydrous sodium sulfate and concentrated under the reduced pressure to give the crude compound. This crude compound was purified with column chromatography (ethyl acetate-hexane) to give the title compound (1.842 g) having the following physical data as colorless viscous oil. TLC: Rf 0:55 (AcOEt : hexane=1 : 2); NMR (CDCl 3 ): δ 8.03 (1 H, d, J = 8 Hz), 7.55 (1 H, d, = 2 Hz), 7.40 (1 H, dd, J = 8, 2 Hz), 5.50-5.22 (2 H, m), 5.00 (1 H, t, J = 5 Hz), 3.67 (3 H, s), 2.97-2.72 (2 H, m), 2.30 (2 H, t, J = 7 Hz), 2.12-1.87 (3 H, m), 1.80-1.20 (13 H, m). Example 2 6-[(2S, 3S)-3-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid A compound prepared in Example 1 was dissolved in methanol (10 ml) and dimethoxyethane (20 ml). To this solution, 2N sodium hydroxide aqueous solution (5 ml) was added at room temperature. The solution was stirred at room temperature overnight. After the termination of reaction, to the reaction solution, 2N HCI was added at room temperature. The solution was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution succeedingly, dried over anhydrous sodium sulfate, filtrated and concentrated under the reduced pressure to give the crude compound. This crude compound was purified with column chromatography (methanol/methylene chloride) to give the title compound (1.44g) having the following physical data. TLC : Rf 0. 26 (hexane : AcOEt=2 : 3); NMR (CDCl 3 ): δ 8.02 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz), 7.40 (1H, dd, J=8.5 and 2Hz), 5.50-5.24 (2H, m), 5.07 (1 H, t, J=6Hz), 2.84 (2H, m), 2.35 (2H, t, J=7Hz), 2.18-1.92 (3H, m), 1.79-1.21 (13H, m). Example 2 (a)∼2 (n) By the same procedure as Examples 1 and 2, the title compounds having the following physical data were obtained. Example 2 (a) 6-[(2S, 3S)-3-(2,4-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid TLC : Rf 0. 09 (hexane AcOEt=1 : 1); NMR (CDCl 3 ); δ 7.83 (1 H, d, J=8.4Hz), 7.1 (2H, m), 5.5-5.3 (2H, m), 4.66 (1 H, t, J=6Hz), 3.0-2.7 (2H, m), 2.58 (3H, s), 2.38 (3H, s), 2.36 (2H, t), 2.2-1.9 (m), 1.8-1.2 (m). Example 2 (b) 6-[(2S, 3S)-3-(2,4-dibromophenylsulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid TLC : Rf 0.41 (AcOEt); NMR (CDCl 3 ): δ 7.99 (1H, d, J=8.5H), 7.90 (1 H, d, J=2Hz), 7.61 (1H, dd, J=8.5 and 2H), 5.51-5.23 (2H, m), 5.16 (1H, t, J=6Hz), 2.95-2.67 (2H, m), 2.35 (2H, t, J=7Hz), 2.15-1.90 (3H, m), 1.78-1.20 (13H, m). Example 2 (c) 6-[(2S, 3S)-3-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]-octan-2-yl)-5Z-hexenoic acid TLC:Rf 0.51 (CHCl 3 : MeOH : AcOH=100 : 5 : 1); NMR(CDCl 3 ): δ 7.88 (1H, d, J=9.0Hz), 7.26-7.31 (2H, m), 5.25-5.51 (2H, m), 4.80 (1H, t, J=5.8Hz), 2.86 (2H, m), 2.59 (3H, s), 2.36 (2H, t, J=7.4Hz), 1.92-2.18 (3H, m), 1.20-1.82 (13H, m). Example 2 (d) 6-[(2S, 3S)-3-(4-bromo-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]-octan-2-yl]-5Z-hexenoic acid TLC : Rf 0.53 (AcOEt : hexane : AcOH=5 : 14 : 1); NMR (CDCl 3 ): δ 7.81 (1H, d, J=9.0Hz), 7.48 (1H, s), 7.46 (1H, d, J=9.0Hz), 5.55-5.25 (2H, m), 4.80 (1H, t, J=6.0Hz), 3.00-2.70 (2H, m), 2.59 (3H, s), 2.36 (2H, t, J=7.0Hz), 2.20-1.90 (3H, m), 1.72 (2H, q, J=7.0Hz), 1.80-1.10 (11H, m). Example 2 (e) 6-[(2S, 3S)-3-(4-bromo-2-fluorophenylsulfonylaminomethyl)bicyclo[2.2.2]-octan-2-yl]-5Z-hexenoic acid TLC : Rf 0.42 (AcOEt); NMR (CDCl 3 ): δ 7.76 (1H, m), 7.48-7.35 (2H, m), 5.52-5.25 (2H, m), 4.91 (1H, d, J=6Hz), 2.92 (2H, m), 2.36 (2H, t, J=7Hz), 2.16-1.93 (3H, m), 1.82-1.20 (13H, m). Example 2 (f) 6-[(2S, 3S)-3-(4-chloro-2-fluorophenylsulfonylaminomethyl)bicyclo[2.2.2]-octan-2-yl]-5Z-hexenoic acid TLC : Rf 0. 41 (AcOEt); NMR (CDCl 3 ): δ 7.84 (1 H, m), 7.34-7.20 (2H, m), 5.53-5.24 (2H, m), 4.91 (1H, d, J=6Hz), 2.92 (2H, m), 2.36 (2H, t, J=7.5Hz), 2.17-1.93 (3H, m), 1.81-1.20 (13H, m). Example 2 (g) 6-[(2S, 3S)-3-(2,4,6-trichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid TLC : Rf 0. 53 (AcOEt : hexane : AcOH=5 : 14 : 1); NMR (CDCl 3 ): δ 7.49 (2H, s), 5.55-5.25 (3H, m), 3.10-2.80 (2H, m), 2.36 (2H, t, J=7.0Hz), 2.20-1.95 (3H, m), 1.80-1.20 (13H, m). Example 2 (h) 6-[(2S, 3S)-3-(2-chloro-4-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]-octan-2-yl]-5Z-hexenoic acid TLC : Rf 0. 45 (AcOEt : hexane : AcOH=5 : 14 : 1); NMR (CDCl 3 ): δ 7.96 (1H, d, J=8.0Hz), 7.34 (1H, d, J=1.0Hz), 7.21 (1H, dd, J=8.0, 1.0Hz), 5.50-5.22 (2H, m), 5.01 (1H, t, J=6.0Hz), 2.95-2.67 (2H, m), 2.41 (3H, s), 2.34 (2H, t, J=7.0Hz), 2.15-1.90 (3H, m), 1.80-1.60 (2H, q, J=7.5Hz), 1.80-1.20 (11H, m). Example 2 (i) 6-[(2S, 3S)-3-(4-chloro-2-trifluoromethylphenylsulfonylaminomethyl)bicyclo-[2.2.2]octan-2-yl]-5Z-hexenoic acid TLC : Rf 0.24 (hexane : AcOEt= 1 : 1); NMR (CDCl 3 ): δ 8.08 (1H, d, J=8.6Hz), 7.77 (1H, d, J=2Hz), 7.60 (1H, dd, J=8.6, 2Hz), 5.4-5.2 (2H, m), 4.75 (1H, t, J=5.4Hz), 2.9-2.7 (2H, m), 2.28 (2H, t, J=7.2Hz), 2.1-1.9 (3H, m), 1.7-1.2 (13H, m). Example 2 (j) 6-[(2S, 3S)-3-(2,4,6-trimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid TLC : Rf 0.51 (AcOEt : hexane : AcOH=5 : 14 : 1); NMR (CDCl 3 ): δ 6.95 (2H, s), 5.52-5.17 (2H, m), 4.64 (1H, t, J=6.0Hz), 2.98-2.65 (2H, m), 2.62 (6H, s), 2.35 (2H, t, J=6.0Hz), 2.30 (3H, s), 2.17-1.90 (3H, m), 1.70 (2H, q, J=7.0Hz), 1.80-1.20 (11H, m). Example 2 (k) 6-[(2S, 3S)-3-(2,4-dichloro-6-methylphenylsutfonylaminomethyl)bicyclo[2.2.2]-octan-2-yl]-5Z-hexenoic acid TLC : Rf 0.45 (AcOEt); NMR (CDCl 3 ): δ 7.40 (1 H, d, J=2Hz), 7.24 (1H, d, J=2Hz), 5.50-5.24 (3H, m), 2.99-2.73 (2H, m), 2.69 (3H, s), 2.34 (2H, t, J=7Hz), 2.16-1.90 (3H, m), 1.77-1.23 (13H, m). Example 2 (l) 6-[(2S, 3S)-3-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]-octan-2-yl]-5Z-hexenoic acid TLC : Rf 0.47 (AcOEt); NMR (CDCl 3 ): δ 7.15 (2H, s), 5.51-5.23 (2H, m), 4.74 (1 H, t, J=6Hz), 2.98-2.70 (2H, m), 2.63 (6H, s), 2.35 (2H, t, J=7Hz), 2.16-1.90 (3H, m), 1.80-1.22 (13H, m). Example 2(m) 6-[(2S, 3S)-3-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-5E-hexenoic acid TLC : Rf 0. 24 (AcOE : Hexane = 3 : 2); NMR (CDCl 3 ): δ 8.03 (1H, d, J=8Hz), 7.54 (1H, d, J=8Hz), 7.40(1 H, dd, J=8, 2Hz), 5.53-5.27 (3H, m), 3.00-2.83 (1H, m), 2.83-2.67 (1H, m), 2.50-2.20 (2H, m),2.17-2.00 (2H, m), 1.83-1.20 (14H, m). Example 2(n) 6-[(2S, 3S)-3-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]-octan-2-yl]-5E-hexenoic acid TLC : Rf 0.37 (AcOE : Hexane = 3 : 2); NMR (CDCl 3 ): δ 7.89 (1H, d, J=8Hz), 7.33 (1H, s), 7.30(1H, d, J=8Hz), 5.58-5.30 (3H, m), 3.06-2.86(1H, m), 2.80-2.58 (1H, m), 2.62 (3H, s), 2.51-2.00 (4H, m), 1.90-1.20 (14H, m). Example 3 (a)∼3 (h) By the same procedure as Examples 1 and 2, the title compounds having the following physical data were obtained. Example 3 (a) 6-[(1R, 2S)-2-(2,4-dichlorophenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid TLC : Rf 0. 44 (AcOEt : hexane : AcOH=5 : 14 : 1); NMR (CDCl 3 ): δ 8.00 (1H, d, J=8.5Hz), 7.53 (1H, d, J=2.0Hz), 7.39 (1H, dd, J=8.5, 2.0Hz), 5.34 (1 H, dt, J=11.0, 7.0Hz), 5.15 (1H, t, J=11.0Hz), 5.10 (1H, t, J=6.0Hz), 2.90 (1H, ddd, J=13.0, 6.0, 4.5Hz), 2.64 (1H, dt, J=13.0, 7.0Hz), 2.33 (2H, t, J=7.0Hz), 2.15-1.85 (3H, m), 1.85-1.40 (6H, m), 1.40-0.80 (5H, m). Example 3 (b) 6-[(1R, 2S)-2-(4-bromo-2-fluorophenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid TLC : Rf 0.55 (MeOH : CHCl 3 = 1 : 5); NMR (CDCl 3 ): δ 7.75 (1H, t, J=8Hz), 7.47-7.33 (2H, m), 5.43-5.10 (2H, m), 4.93 (1H, t, J=6Hz), 3.05-2.90 (1H, m), 2.82-2.60 (1H, m), 2.36 (2H, t, J=7Hz), 2.16-1.86 (3H, m), 1.86-0.80 (11H, m). Example 3 (c) 6-[(1R, 2S)-2-(4-bromo-2-methylphenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid TLC : Rf 0.58 (MeOH : CHCl 3 = 1:5); NMR (CDCl 3 ): δ 7.78 (1H, d, J=8Hz), 7.47 (1H, s), 7.45 (1H, d, J=8Hz), 5.43-5.05 (2H, m), 4.75 (1 H, m), 3.00-2.80 (1 H, m), 2.80-2.46 (1 H, m), 2.60 (3H, s), 2.34 (2H, t, J=7Hz), 2.17-1.80 (3H, m), 1.80-0.80 (10H, m). Example 3 (d) 6-[(1R, 2S)-2-(4-chloro-2-fluorophenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid TLC : Rf 0.54 (MeOH : CHCl 3 =1 : 5); NMR (CDCl 3 ): δ 7.81 (1H, t, J=8Hz), 7.33-7.18 (2H, m), 5.44-5.05 (2H, m), 4.93 (1H, t, J=7Hz), 3.08-2.90 (1H, m), 2.84-2.63 (1H, m), 2.33 (2H, t, J=7Hz), 2.20-1.87 (4H, m), 1.87-0.80 (10H, m). Example 3 (e) 6-[(1R, 2S)-2-(2,4,6-trichlorophenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid TLC : Rf 0.59 (MeOH : CHCl 3 =1 : 5); NMR(CDCl 3 ): δ 7.48 (1H, s), 5.47-5.10 (3H, m), 3.10-2.93 (1H, m), 2.87-2.60 (1H, m), 2.34 (2H, t, J=7Hz), 2.17-1.88 (3H, m), 1.88-0.80 (11H, m). Example 3 (f) 6-[(1R, 2S)-2-(4-chloro-2-methylphenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid TLC : Rf 0.56 (MeOH : CHCl 3 =1 : 5); NMR (CDCl 3 ): δ 7.88 (1H, d, J=8Hz), 7.32 (1H, s), 7.35-7.24 (1H, m), 5.47-5.10 (2H, m), 4.74 (1H, m), 3.06-2.83 (1H, m), 2.80-2.50 (1H, m), 2.63 (3H, s), 2.35 (2H, t, J=7Hz), 2.15-0.80 (14H, m). Example 3 (g) 6-[(1R,2S)-2-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid TLC : Rf 0.25 (MeOH : CHCl 3 =1 : 10); NMR (CDCl 3 ): δ 7.15 (2H, s), 5.43-5.22 (1 H, m), 5.22-5.05 (1 H, m), 4.74 (1H, m), 3.00-2.80 (1H, m), 2.77-2.45 (1H, m), 2.63 (6H, s), 2.33 (2H, t, J=7Hz), 2.20-1.83 (3H, m), 1.83-1.33 (7H, m), 1.33-0.80 (4H, m). Example 3 (h) 6-[(1R, 2S)-2-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid TLC : Rf 0.28 (MeOH : CHCl 3 =1 : 10); NMR (CDCl 3 ): δ 7.40 (1H, d, J=2Hz), 7.23 (1H, d, J=2Hz), 5.47-5.25 (2H, m), 5.15 (1H, t, J=10Hz), 3.00-2.83 (1H, m), 2.80-2.50 (1H, m), 2.68 (3H, s), 2.33 (2H, t, J=7Hz), 2.20-1.87 (3H, m), 1.87-1.35 (7H, m), 1.35-0.80 (4H, m). Example 4 (a)∼4 (h) By the same procedure as Examples 1 and 2, the title compounds having the following physical data were obtained. Example 4 (a) 6-[(4R, 5S)-5-(2,4-dichlorophenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid TLC : Rf 0.63 (CHCl 3 : MeOH : AcOH=100 : 5 : 1); NMR (CDCl 3 ): δ 8.01 (1H, d, J=8.4Hz), 7.54 (1H, d, J=2.0Hz), 7.39 (1H, dd, J=2.0, 8.4Hz), 5.63 (2H, m), 5.22-5.48 (2H, m), 5.18 (1 H, t, J=6.6Hz), 2.97 (1H, m), 2.73 (1H, m), 2.29-2.50 (3H, m), 1.92-2.29 (4H, m), 1.56-1.92 (5H, m). Example 4 (b) 6-[(4R, 5S)-5-(4-chloro-2-methylphenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid TLC : Rf 0.61 (CHCl 3 : MeOH : AcOH=100 : 5 : 1); NMR (CDCl 3 ): δ 7.87 (1H, m), 7.29 (2H, m), 5.61 (2H, m), 5.23-5.47 (2H, m), 4.90 (1H, t, J=6.4Hz), 2.99 (1H, m), 2.74 (1H, m), 2.61 (3H, s), 2.26-2.52 (3H, m), 1.92-2.26 (4H, m), 1.56-1.92 (5H, m). Example 4 (c) 6-[(4R, 5S)-5-(4-chloro-2-fluorophenylsulfonylaminomethyl]cyclohexen-4-yl]-5Z-hexenoic acid TLC : Rf 0.55 (CHCl 3 : MeOH : AcOH=100 : 5 : 1); NMR (CDCl 3 ): δ 7.82 (1H, dd, J=8.2, 9.2Hz), 7.26 (2H, m), 5.63 (2H, m), 5.22-5.47 (2H, m), 5.03 (1H, t, J=6.6Hz), 3.05 (1H, m), 2.81 (1H, m), 2.29-2.50 (3H, m), 1.94-2.29 (4H, m), 1.56-1.94 (5H, m). Example 4 (d) 6-[(4R, 5S)-5-(4-bromo-2-fluorophenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid TLC : Rf 0.63 (CHCl 3 : MeOH : AcOH=100 : 5 : 7 ); NMR (CDCl 3 ): δ 7.75 (1 H, dd, J=8.2, 8.8Hz), 7.42 (2H, m), 5.63 (2H, m), 5.22-5.47 (2H, m), 5.04 (1H, t, J=6.2Hz), 3.05 (1 H, m), 2.81 (1H, m), 2.29-2.50 (3H, m), 1.92-2.29 (4H, m), 1.58-1.92 (5H, m). Example 4 (e) 6-[(4R, 5S)-5-(2,4,6-trichlorophenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid TLC : Rf 0.49 (CHCl 3 : MeOH : AcOH=100 : 5 : 1); NMR (CDCl 3 ): δ 7.49 (2H, s), 5.64 (2H, m), 5.25-5.50 (3H, m), 3.09 (1H, m), 2.84 (1H, m), 2.28-2.48 (3H, m), 1.93-2.28 (4H, m), 1.60-1.93 (5H, m). Example 4 (f) 6-[(4R, 5S)-5-(4-bromo-2-methylphenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid TLC : Rf 0.52 (CHCl 3 : MeOH : AcOH=100 : 5 : 1); NMR (CDCl 3 ): δ 7.79 (2H, d, J=8.0Hz), 7.45 (2H, m), 5.61 (2H, m), 5.24-5.47 (2H, m), 4.90 (1H, t, J=6.4Hz), 2.94 (1H, m), 2.74 (1H, m), 2.60 (3H, s), 2.26-2.48 (3H, m), 1.90-2.26 (4H, m), 1.54-1.90 (5H, m). Example 4 (g) 6-[(4R, 5S)-5-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)cyclohexen-4-yl]-52-hexenoic acid TLC : Rf 0.51 (CHCl 3 : MeOH : AcOH=100 : 5 : 1); NMR (CDCl 3 ): δ 7.41 (1H, d, J=2.2Hz), 7.23 (1H, d, J=2.2Hz), 5.64 (2H, m), 5.22-5.47 (3H, m), 2.98 (1H, m), 2.73 (1H, m), 2.68 (3H, s), 2.28-2.50 (3H, m), 1.92-2.28 (4H, m), 1.56-1.92 (5H, m). Example 4 (h) 6-[(4R, 5S)-5-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid TLC : Rf 0.47 (CHCl 3 : MeOH : AcOH=100 : 5 : 1); NMR (CDCl 3 ): δ 7.15 (2H, s), 5.61 (2H, m), 5.22-5.47 (2H, m), 4.86 (1H, t, J=7.0Hz), 2.97 (1H, m), 2.71 (1H, m), 2.64 (6H, s), 2.27-2.46 (3H, m), 1.90-2.24 (4H, m), 1.57-1.90 (5H, m). Example 5 (a)∼5 (h) By the same procedure as Examples 1 and 2, the title compounds having the following physical data were obtained. Example 5 (a) 6-[(1R, 2S, 3S, 4S)-3-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.1]-heptan-2-yl]-5Z-hexenoic acid TLC : Rf 0.21 (hexane : AcOEt=2 : 1); NMR (CDCl 3 ): δ 8.03 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2.0Hz), 7.41 (1H, dd, J=2.0 and 8.5Hz), 5.26-5.17 (2H, m), 4.95 (1H, t, J=6Hz), 3.07-2.72 (2H, m), 2.38-2.31 (2H, m), 2.19-2.02 (3H, m), 1.90-1.88 (1H, m), 1.77-1.23 (10H, m). Example 5 (b) 6-[(1R, 2S, 3S, 4S)-3-(4-bromo-2-fluorophenylsulfonylam(nomethyl)bicyclo-[2.2.1]heptan-2-yl]-5Z-hexenoic acid TLC : Rf 0.49 (CHCl 3 : MeOH : H 2 O=9 : 1 : 0.1); NMR (CDCl 3 ): δ 7.81-7.73 (1H, m), 7.47-7.38 (2H, m), 5.33-5.14 (2H, m), 4.86 (1H, t-like), 3.12-2.83 (2H, m), 2.34 (2H, t, J=7.4Hz), 2.19-1.10 (14H, m). Example 5 (c) 6-[(1R, 2S, 3S, 4S)-3-(4-bromo-2-methylphenylsulfonylaminomethyl)bicyclo-[2.2.1]heptan-2-yl]-5Z-hexenoic acid TLC : Rf 0.47 (CHCl 3 : MeOH : H 2 O=9 : 1 : 0.1); NMR (CDCl 3 ):δ 7.83 (1H, d, J=9.0Hz), 7.48-7.43 (2H, m),5.34-5.14 (2H, m), 4.72 (1H, t-like), 3.07-2.75 (2H, m), 2.60 (3H, s), 2.34 (2H, t, J=7.4Hz), 2.15-1.09 (14H, m). Example 5 (d) 6-[(1R, 2S, 3S, 4S)-3-(4-chloro-2-fluorophenylsulfonylaminomethyl)bicyclo-[2.2.1]heptan-2-yl]-5Z-hexenoic acid TLC : Rf 0.45 (CHCl 3 : MeOH : H 2 O=9 : : 1 : 0.1); NMR (CDCl 3 ): δ 7.89-7.81 (1H, m), 7.31-7.22 (2H, m), 5.33-5.14 (2H, m), 4.84 (1H, t-like), 3.12-2.83 (2H, m), 2.34 (2H, t, J=7.4Hz), 2.19-1.09 (14H, m). Example 5 (e) 6-[(1R, 2S, 3S, 4S)-3-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo-[2.2.1]heptan-2-yl]-5Z-hexenoic acid TLC : Rf 0.42 (CHCl 3 : MeOH : H 2 O=9 : 1 : 0.1); NMR (CDCl 3 ) : δ 7.90 (1H, d, J=9.0Hz), 7.32-7.26 (2H, m), 5.35-5.14 (2H, m), 4.70 (1H, t-like), 3.07-2.75 (2H, m), 2.60 (3H, s), 2.34 (2H, t, J=7.4Hz), 2.13-1.09 (14H, m). Example 5 (f) 6-[(1R, 2S, 3S, 4S)-3-(2,4,6-trichlorophenylsulfonylaminomethyl)bicyclo[2.2.1]-heptan-2-yl]-5Z-hexenoic acid TLC : Rf 0.52 (CHCl 3 : MeOH : H 2 O=9 : 1 : 0.1); NMR (CDCl 3 ): δ 7.49 (2H, s), 5.34-5.16 (3H, m), 3.18-2.85 (2H, m), 2.36 (2H, t, J=7.4Hz), 2.18-1.09 (14H, m). Example 5 (g) 6-[(1R, 2S, 3S, 4S)-3-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)-bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid TLC : Rf 0.48 (AcOEt : hexane : AcOH=5 : 14 : 1); NMR(CDCl 3 ): δ 7.16 (2H, s), 5.50-5.10(2H, m), 4.57 (1H, brt, J=6.0Hz), 3.10-2.90 (1H, m), 2.90-2.70 (2H, m), 2.65 (6H, s), 2.36 (2H, t, J=7.0Hz), 2.20-2.00 (3H, m), 1.94-1.85 (13H, m), 1.85-1.40 (6H, m), 1.40-1.00 (4H, m). Example 5 (h) 6-[(1R, 2S, 3S, 4S)-3-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)-bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid TLC : Rf 0.46(AcOEt : hexane : AcOH=5 : 14 : 1); NMR(CDCl 3 ): δ 7.41 (1H, d, J=1.5Hz), 7.25 (1H, d, J=1.5Hz), 5.40-5.10 (3H, m), 3.12-2.94 (1H, m), 2.90-2.74 (1H, m), 2.70 (3H, s), 2.35 (2H, t, J=7.5Hz), 2.20 (1H, m), 2.15-2.00 (2H, m), 1.94-1.86 (1H, m), 1.82-1.40 (6H, m), 1.40-1.00 (4H, m). Example 6 (a)∼6 (h) By the same procedure as Examples 1 and 2, the title compounds having the following physical data were obtained. Example 6 (a) 6-[(1S, 4R, 5S, 6S)-6-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]-oct-2-en-5-yl]-5Z-hexenoic acid TLC : Rf 0. 24 (hexane : AcOEt= 1 : 1); NMR (CDCl 3 ): δ 8.04 (1H, d, J=8.6Hz), 7.55 (1H, d, J=1.6Hz), 7.43 (1H, dd, J=8.6, 1.6Hz), 6.32 (1H, t, J=7.5Hz), 6.16 (1H, t, J=7Hz), 5.4-5.0 (3H, m), 3.0-2.8 (2H, m), 2.5-2.2 (3H, m), 2.2-2.0 (3H, m), 1.8-1.6 (2H, m), 1.5-1.0 (6H, m). Example 6 (b) 6-[(1S, 4R, 5S, 6S)-6-(2,4,6-trichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]-oct-2-en-5-yl]-5Z-hexenoic acid TLC : Rf 0.15 (hexane : AcOEt= 1 : 1); NMR (CDCl 3 ):δ 7.49 (2H, s), 6.3 (1H, m), 6.2 (1H, m), 5.4-5.0 (3H, m), 3.2-2.9 (1H, m), 2.4 (1H, m), 2.37 (2H, t, J=7.4Hz), 2.3 (1H, m), 2.2-2.0 (4H, m), 1.8-1.0 (6H, m). Example 6 (c) 6-[(1S, 4R, 5S, 6S)-6-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo-[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid TLC : Rf 0.17 (hexane : AcOEt=1 : 1); NMR(CDCl 3 ):δ 7.89 (1H, d, J=8Hz), 7.3-7.2 (2H, m), 6.3 (1H, m), 6.15 (1H, t, J=7Hz), 5.3-5.0 (2H, m), 4.7 (1H, m), 3.1-2.8 (2H, m), 2.61 (3H, s), 2.4 (1H, m), 2.37 (2H, t, J=7Hz), 2.3 (1H, m), 2.2-2.0 (4H, m), 1.8-1.0 (6H, m). Example 6 (d) 6-[(1S, 4R, 5S, 6S)-6-(4-chloro-2-fluorophenylsulfonylaminomethyl)bicyclo-[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid TLC : Rf 0.14 (hexane : AcOEt=1 : 1); NMR (CDCl 3 ): δ 7.84 (1H, t, J=8Hz), 7.3-7.2 (2H, m), 6.3 (1 H, m), 6.16 (1H, t, J=7Hz), 5.3-5.0 (2H, m), 4.9 (1H, m), 3.2-2.9 (1H, m), 2.4 (1H, m), 2.37 (2H, t, J=7.4Hz), 2.3 (1H, m), 2.2-2.0 (4H, m), 1.8-1.0 (6H, m). Example 6 (e) 6-[(1S, 4R, 5S, 6S)-6-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)-bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid TLC : Rf 0.56 (CHCl 3 : MeOH=9 : 1); NMR (CDCl 3 ): δ 7.16 (2H, s), 6.30 (1 H, dt, J=1.0, 7.2Hz), 6.14 (1H, dt, J=1.0, 7.2Hz), 5.3-5.0 (2H, m), 4.7-4.6 (1H, m), 3.1-2.9 (1H, m), 2.9-2.7 (1H, m), 2.64 (6H, s), 2.4-1.0 (14H, m). Example 6 (f) 6-[(1S, 4R, 5S, 6S)-6-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)-bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid TLC : Rf 0.60 (CHCl 3 : MeOH=9 : 1); NMR (CDCl 3 ): δ 7.41 (1H, d, J=2.2Hz), 7.25 (1H, d, J=2.2Hz), 6.32 (1H, t, J=6.8Hz), 6.16 (1H, t, J=6.8Hz), 5.4-5.0 (3H, m), 3.1-2.9 (1H, m), 2.9-2.7 (1H, m), 2.70 (3H, s), 2.5-1.0 (14H, m). Example 6 (g) 6-[(1S, 4R, 5S, 6S)-6-(4-bromo-2-methylphenylsulfonylaminomethyl)bicyclo-[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid TLC : Rf 0.57 (CHCl 3 : MeOH=9 : 1); NMR (CDCl 3 ): δ 7.82 (1H, d, J=8.8Hz), 7.5-7.4 (2H, m), 6.21 (1H, dt, J=1.0, 6.6Hz), 6.15 (1H, t, J=6.6Hz), 5.3-5.0 (2H, m), 4.70 (1H, t, J=6.0Hz), 3.1-2.8 (2H, m), 2.60 (3H, s), 2.4-2.2 (4H, m), 2.2-1.9 (3H, m), 1.8-1.6 (2H, m), 1.6-1.0 (5H, m). Example 6 (h) 6-[(1S, 4R, 5S, 6S)-6-(2,4-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]-oct-2-en-5-yl]-52-hexenoic acid TLC : Rf 0.50 (CHCl 3 : MeOH=9 : 1); NMR (CDCl 3 ): δ 7.84 (1H, d, J=8.4Hz), 7.2-7.1 (2H, m), 6.31 (1H, dt, J=1.0, 6.6Hz), 6.14 (1H, t, J=6.6Hz), 5.3-5.0 (2H, m), 4.57 (1H, t, J=6.0Hz), 3.1-2.7 (2H, m), 2.58 (3H, s), 2.37 (3H, s), 2.4-1.9 (7H, m), 1.8-1.6 (2H, m), 1.5-0.9 (5H, m). Example 7 (a)∼7 (h) By the same procedure as Examples 1 and 2, the title compounds having the following physical data were obtained. Example 7 (a) 6-[(1R, 4S, 5S, 6S)-6-(2,4-dichlorophenylsulfonylaminomethyl]bicyclo[2.2.2]-oct-2-en-5-yl]-5Z-hexenoic acid TLC : Rf 0. 24 (hexane : AcOEt=1 : 1); NMR (CDCl 3 ): δ 7.99 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2.0Hz), 7.40 (1H, dd, J=8.6, 2Hz), 6.37 (1H, t, J=7Hz), 6.04 (1H, t, J=7Hz), 5.4-5.3 (2H, m), 5.10 (1H, t, J=6Hz), 2.61 (2H, t, J=6Hz), 2.4 (1H, m), 2.36 (2H, t, J=7Hz), 2.2 (1 H, m), 2.1-2.0 (2H, m), 1.9 (1H, m), 1,8-1.7 (3H, m), 1.5-1.2 (3H, m), 1.2-1.0 (1H, m). Example 7 (b) 6-[(1R, 4S, 5S, 6S)-6-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)-bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid TLC : Rf 0.40 (AcOEt); NMR (CDCl 3 );δ 7.15 (2H, s), 6.36 (1H, m), 5.99 (1H, m), 5.48-5.28 (2H, m), 4.79 (1H, t, J=6Hz), 2.68-2.57 (2H, m), 2.63 (6H, s), 2.41-2.00 (6H, m), 1.91-1.58 (4H, m), 1.50-0.92 (4H, m). Example 7 (c) 6-[(1R, 4S, 5S, 6S)-6-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)-bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid TLC : Rf 0.42(AcOEt); NMR (CDCl 3 ): δ 7.41 (1H, d, J=2Hz), 7.23 (1H, d, J=2Hz), 6.38 (1H, m), 6.06 (1H, m), 5.47-5.25 (3H, m), 2.72-2.20 (9H, m), 2.18-2.00 (2H, m), 1.94-1.60 (4H, m), 1.52-0.96 (4H, m). Example 7 (d) 6-[(1R, 4S, 5S, 6S)-6-(4-chloro-2-fluorophenylsulfonylaminomethyl)bicyclo-[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid TLC : Rf 0.58 (AcOEt : hexane : AcOH=5 : 14 :1); NMR (CDCl 3 ): δ 7.81 (1H, t, J=7.5Hz), 7.35-7.20 (2H, m), 6.37 (1H, t, J=7.0Hz), 6.05 (1H, t, J=7.0Hz), 5.60-5.25 (2H, m), 4.94 (1H, t, J=6.0Hz), 2.82-2.50 (2H, m), 2.50-2.30 (1H, m), 2.37 (2H, t, J=7.5Hz), 2.30-2.20 (1H, m), 2.20-1.95 (2H, m), 1.95-1.82 (1H, m), 1.82-1.60 (3H, m), 1.60-0.95 (4H, m). Example 7 (e) 6-[(1R, 4S, 5S, 6S)-6-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo-[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid TLC : Rf 0.56 (AcOEt : hexane : AcOH = 5 : 14 : 1); NMR(CDCl 3 ):δ 7.86 (1H, d, J=8.0Hz), 7.31 (1H, s), 7.28 (1H, d, J=8.0Hz), 6.36 (1H, t, J=7.0Hz), 5.99 (1H, t, J=7.0Hz), 5.60-5.20 (2H, m), 4.84 (1H, t, J=6.0Hz), 2.70-2.68 (2H, m), 2.60 (3H, s), 2.45-2.30 (1H, m), 2.37 (2H, t, J=7.0Hz), 2.30-2.20 (1H, m), 2.20-2.00 (2H, m), 1.95-1.80 (1H, m), 1.80-1.60 (3H, m), 1.55-0.95 (4H, m). Example 7 (f) 6-[(1R, 4S, 5S, 6S)-6-(2,4,6-trichlorophenylsulfonylaminomethyl)bicyclo-[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid TLC:Rf 0.59 (AcOEt : hexane : AcOH=5 : 14 : 1); NMR (CDCl 3 ): δ 7.48 (2H, s), 6.39 (1H, t, J=7.5Hz), 6.08 (1H, t, J=7.5Hz), 5.60-5.25 (3H, m), 2.72 (2H, t, J=6.5Hz), 2.50-2.40 (1H, m), 2.37 (2H, t, J=7.5Hz), 2.35-2.20 (1H, m), 2.20-2.10 (2H, m), 2.00-1.85 (1H, m), 1.80-1.60 (3H, m), 1.60-0.95 (4H, m). Example 7 (g) 6-[(1R, 4S, 5S, 6S)-6-(4-bromo-2-methylphenylsulfonylaminomethyl)bicyclo-[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid TLC : Rf 0.5 (MeOH : CHCl 3 =1 : 9); NMR (CDCl 3 ): δ 7.78 (1H, d, J=8.4Hz), 7.5-7.4 (2H, m), 6.36 (1H, t, J=7.4Hz), 6.00 (1H, t, J=7.4Hz), 5.5-5.3 (2H, m), 4.85 (1H, t, J=6.0Hz), 2.59 (3H, s), 2.7-2.5 (1H, m), 2.4-2.0 (6H, m), 1.9-1.6 (4H, m), 1.5-1.0 (5H, m). Example 7 (h) 6-[(1R, 4S, 5S, 6S)-6-(2,4-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]-oct-2-en-5-yl]-5Z-hexenoic acid TLC : Rf 0.48 (MeOH : CHCl 3 =1 : 9); NMR (CDCl 3 ): δ 7.80 (1H, d, J=8.6Hz), 7.2-7.0 (2H, m), 6.34 (1H, t, J=7.4Hz), 5.98 (1H, t, J=7.4Hz), 5.5-5.3 (2H, m), 4.72 (1H, t, J=6.2Hz), 2.58 (3H, s), 2.7-2.5 (2H, m), 2.37 (3H, s), 2.4-2.0 (6H, m), 1.9-1.6 (4H, m), 1.5-1.2 (3H, m), 1.1-1.0 (1H, m). Example 8 (a) By the same procedure as Examples 1 and 2, the title compound having the following physical data was obtained. Example 8 (a) 6-[(1R, 2S)-2-(2,4-dichlorophenylsulfonylaminomethyl)cycloheptyl]-5Z-hexenoic acid TLC : Rf 0.31 (MeOH : CHCl 3 = 1 : 10); NMR(COCl 3 ): δ 7.98 (1H, d, J=8Hz), 7.53 (1H, d, J=2Hz), 7.39 (1H, dd, J=8, 2Hz), 5.37-5.17 (2H, m), 5.10 (1H, t, J=5Hz), 2.82 (1H, m), 2.68 (1H, m), 2.33 (2H, t, J=7Hz), 2.22-1.87 (3H, m), 1.87-1.10 (13H, m). Reference Example 1 6-[(2S, 3S)-3-(t-butoxycarbonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid methyl ester To a solution of 6-[(2S, 3S)-3-aminomethylbicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid methyl ester (2.80 g) in methylene chloride (20 ml), triethylamine (1.8 ml) was added at 0°C. To this solution, a solution of di-t-butyl dicarbonate (2.92 ml) in methylene chloride (10 ml) was added dropwise. The solution was stirred for 16 hours at room temperature. After the termination of reaction, the solution was quenched by adding water at 0°C. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution succeedingly, dried over anhydrous sodium sulfate, filtrated and concentrated under the reduced pressure to give the crude compound. This crude compound was purified with column chromatography (hexane-ethyl acetate) to give the title compound (3.10 g) having the following physical data as colorless oil. TLC : Rf 0.44 (AcOEt : hexane=1 : 3); NMR(CDCl 3 ): δ 5.50 (1H, dd, J=10, 10 Hz), 5.32 (1H, dt, J=10, 7 Hz), 4.57 (1H, brs), 3.67 (3H, s), 3.06 (2H, m), 2.32 (2H, t, J=7 Hz), 2.20-1.90 93H, m), 1.80-1.20 (22H, m). Reference Example 2 6-[(2S, 3S)-3-(t-butoxycarbonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-2E,5Z-hexadienoic acid methyl ester To a solution of lithium hexamethyldisilazido (1.0 M, 7 ml) in tetrahydrofuran (10 ml), a solution of the compound prepared in Reference Example 1 (1.02 g) in tetrahydrofuran (5 ml) was added dropwise at -78°C. The solution was stirred for 1 hour at -78°C. Succeedingly, a solution of diphenyl diselenide (1.92 g) in tetrahydrofuran (5 ml) was added dropwise thereto at -78°C. The solution was stirred for 20 minutes at -78°C, warmed to 0°C and then stirred for 2 hours additionally. After the termination of reaction, water was added thereto at 0°C. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution succeedingly, dried over anhydrous sodium sulfate, filtrated and concentrated under the reduced pressure to give the crude compound. This crude compound was purified with column chromatography (hexane-ethyl acetate) to give the phenylselenyl compound (0.592 g) as bright yellow oil. To a solution of this phenylselenyl compound (0.580 g) in mixture of tetrahydrofuran (6 ml) and ethyl acetate (12 ml), sodium hydrogen carbonate (0.196 g) was added. At 0°C, 30% H 2 O 2 (0.250 ml) was added dropwise thereto. The solution was stirred for 1 hour at room temperature. The reaction mixture was poured into iced water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution succeedingly, dried over anhydrous sodium sulfate, filtrated and concentrated under the reduced pressure to give the crude compound. This crude compound was purified with column chromatography (ethyl acetate-toluene) to give the title compound (0.259 g) having the following physical data as colorless viscous oil. TLC : Rf 0.37 (AcOEt : toluene=1 : 10); NMR (CDCl 3 ): δ 6.94 (1H, dt, J=15, 7 Hz), 5.84 (1H, dt, J=15, 1 Hz), 5.64 (1H, t, J=10 Hz), 5.37 (1H, dt, J=10, 7 Hz), 4.47 (1H, m), 3.72 (3H, s), 3.15-2.85 (4H, m), 2.10-1.90, (1H, m), 1.78-1.20 (20H, m). Reference Example 3 6-[(2S, 3S)-3-aminomethylbicyclo[2.2.2]octan-2-yl]-2E,5Z-hexadienoic acid methyl ester·HCl salt To a solution of the compound prepared in Reference Example 2 (0.245 g) in methanol (5 ml), 4N HCI-dioxane (2 ml) was added at 0°C. The solution was stirred for 12 hours. After the termination of reaction, the solution was concentrated under the reduced pressure to give the title compound (0.194 g) having the following physical data as white powder. TLC : Rf 0.17 (MeOH : CHCl 3 =1 : 5). Example 9 6-[(2S, 3S)-3-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-2E,5Z-hexadienoic acid methyl ester To a solution of a compound prepared in Reference Example 3 (0.194 g) in methylene chloride (10 ml), 2,4-dichlorobenzenesulfonylchloride (0.198 g) was added. The solution was cooled to 0°C. Triethylamine (0.226 ml) was added dropwise thereto. The solution was stirred for 1 hour at 0°C. After the termination of reaction, the solution was quenched by adding iced water, acidified by HCI and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution succeedingly, dried over anhydrous sodium sulfate, filtrated and concentrated under the reduced pressure to give the crude compound. This crude compound was purified with column chromatography (hexane-ethyl acetate) to give the title compound (0.285 g) having the following physical data as colorless viscous oil. TLC : Rf 0.54 (AcOEt : hexane =1 : 2); NMR (CDCl 3 ) : δ 8.02 (1H, d, J=8Hz), 7.55 (1H, s), 7.41 (1H, d, J=8Hz), 6.92 (1H, dt, J=15, 7 Hz), 5.81 (1H, dd, J=15, 2 Hz), 5.54 (1H, dd, J=10, 10 Hz), 5.38 (1H, dt, J=10, 7 Hz), 4.89 (1H, t, J=5 Hz), 3.75 (3H, s), 3.00-2.70 (4H, m), 1.94 (1H, m), 1.80-1.20 (13 H, m). Example 10 6-[(2S, 3S)-3-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-2E,5Z-hexadienoic acid A compound prepared in Example 9 (0.267 g) was suspended with dimethylsulfoxide (25 ml) and buffer (pH 7.4, 50 ml). To this suspension, pig liver esterase (0.16 ml, 720 units) was added at 0°C. The suspension was stirred for 16 hours at room temperature. After then, to this suspension, pig liver esterase (0.16 ml, 720 units) was added at room temperature. The suspension was stirred for 16 hours at room temperature additionally. After the termination of reaction, the suspension was acidified by 1N HCI and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution succeedingly, dried over anhydrous sodium sulfate, filtrated and concentrated under the reduced pressure to give the crude compound. This crude compound was purified with column chromatography (methanol-chloroform) to give the title compound (0.114 g) having the following physical data as colorless viscous oil. TLC : Rf 0. 24 (MeOH : CHCl 3 =1 : 10); NMR (CDCl 3 ): δ 8.02 (1H, d, J=8Hz), 7.54 (1H, d, J=2Hz), 7.40 (1H, dd, J=8, 2Hz), 7.00 (1H, dt, J=15. 7Hz), 5.82 (1H, d, J=15Hz), 5.57 (1H, t, J=10Hz), 5.38 (1H, dt, J=10, 7Hz), 4.93 (1H, t, J=5Hz), 2.96 (2H, t, J=5Hz), 2.82 (2H, m), 1.95 (1H, m), 1.74-1.20 (11H, m). Formulation example 1: The following compounds were admixed in conventional method and punched out to obtain 100 tablets each containing 10 mg of active ingredient. 6-[(2S, 3S)-3-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid ··· 1.0 g cellulose calcium glycolate ··· 200 mg Magnesium stearate ··· 100 mg Micro crystalline cellulose ··· 9.7 g

Claims: A benzenesulfonamide compound of formula (I) wherein the group is a group of formula R 1 is hydroxy, C1-4 alkoxy or a group of formula NR 6 R 7 wherein R 6 and R 7 are each independently hydrogen or C1-4 alkyl, R 2 is hydrogen or C1-4 alkyl, R 3 and R 4 are each independently C1-4 alkyl, halogen or trifluoromethyl, R 5 is hydrogen, C1-4 alkyl, halogen or trifluoromethyl, Y is cis-vinylene or trans-vinylene, and the symbol represents a single bond or double bond, or a non-toxic salt thereof or cyclodextrin clathrate thereof. A compound according to claim 1, wherein the group is a group of formula (a) A compound according to claim 1 which is of formula (I-1) wherein R 1a is hydroxy or C1-4 alkoxy, and the other symbols are as defined in claim 1, or a non-toxic salt thereof or cyclodextrin clathrate thereof. A compound according to claim 2, which is selected from the group consisting of 6-[3-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(2,4-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(2,4-dibromophenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(4-bromo-2-chlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-[4-bromo-2-fluorophenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(4-chloro-2-fluorophenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-2E,5Z-hexadienoic acid, 6-[3-(2,4,6-trichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(2-chloro-4-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(4-chloro-2-trifluoromethylphenylsulfonylaminomethyl)bicyclo[2.2.2]-octane-2-yl]-5Z-hexenoic acid, 6-[3-(2,4,6-trimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]octane-2-yl]-5Z-hexenoic acid, 6-[3-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-5E-hexenoic acid and 6-[3-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-5E-hexenoic acid and methyl esters thereof. A compound according to claim 1, wherein the group is a group of formula (b) A compound according to claim 5, which is selected from the group consisting of 6-[3-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid, 6-[3-(4-bromo-2-fluorophenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid, 6-[3-(4-bromo-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid, 6-[3-(4-chloro-2-fluorophenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid, 6-[3-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid, 6-[3-(2,4,6-trichlorophenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid, 6-[3-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid and 6-[3-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)blcyclo[2.2.1]heptan-2-yl]-5Z-hexenoic acid and methyl esters thereof. A compound according to claim 1, wherein the group is a group of formula (c) A compound according to claim 1, wherein the group is a group of formula (d) A compound according to claim 1, wherein the group is a group of formula (e) A compound according to claim 9, which is selected from the group consisting of 6-[6-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(2,4,6-trichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-chloro-2-fluorophenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid 6-[6-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-bromo-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid and 6-[6-(2,4-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid and methyl esters thereof. A compound according to claim 1, wherein the group is a group of formula (f) A compound according to claim 11, which is selected from the group consisting of 6-[6-(2,4-dichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-chloro-2-fluorophenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-chloro-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-52-hexenoic acid, 6-[6-(2,4,6-trichlorophenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid, 6-[6-(4-bromo-2-methylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid and 6-[6-(2,4-dimethylphenylsulfonylaminomethyl)bicyclo[2.2.2]oct-2-en-5-yl]-5Z-hexenoic acid and methyl esters thereof. A compound according to claim 1, wherein the group is a group of formula (g) A compound according to claim 13, which is selected from the group consisting of 6-[2-(2,4-dichlorophenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid, 6-[2-(4-bromo-2-fluorophenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid, 6-[2-(4-bromo-2-methylphenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid, 6-[2-(4-chloro-2-fluorophenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid, 6-[2-(2,4,6-trichlorophenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid, 6-[2-(4-chloro-2-methylphenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid, 6-[2-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid and 6-[2-(2,4-dichloro-6-methylphenylsulfonylaminomethyl)cyclohexyl]-5Z-hexenoic acid and methyl esters thereof. A compound according to claim 1, wherein the group is a group of formula (h) A compound according to claim 15, which is selected from the group consisting of 6-[5-(2,4-dichlorophenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid, 6-[5-(4-chloro-2-methylphenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid, 6-[5-(4-chloro-2-fluorophenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid, 6-[5-(4-bromo-2-fluorophenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid, 6-[5-(2,4,6-trichlorophenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid, 6-[5-(4-bromo-2-methylphenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid, 6-[5-(2,4-dichloro-6-methylphenylsulfonylaminomethyt)cyclohexen-4-yl]-5Z-hexenoic acid and 6-[5-(4-chloro-2,6-dimethylphenylsulfonylaminomethyl)cyclohexen-4-yl]-5Z-hexenoic acid and methyl esters thereof. A compound according to claim 1, wherein the group is a group of formula (i) A compound according to claim 17, which is selected from the group consisting of 6-[2-(2,4-dichlorophenylsulfonylaminomethyl)cycloheptyl]-5Z-hexenoic acid and methyl ester thereof. A process for the preparation of a compound of formula (I) as defined in claim 1, which is of formula (Ia) wherein R 1a is hydroxy or C1-4 alkoxy, and the other symbols are as defined in claim 1, or a non-toxic salt thereof or cyclodextrin clathrate thereof, which process comprises (a) reacting a compound of formula (II) wherein R 10 is C1-4 alkoxy, and the other symbols are as defined in claim 1, or a salt thereof, with a compound of formula (III) wherein X is halogen, and the other symbols are as defined in claim 1, to form an amide bond, optionally followed by hydrolysis under alkaline conditions or using an enzyme or (b) reacting a compound of formula (XI) wherein R 10 is C1-4 alkoxy, and the other symbols are as defined in claim 1, with a compound of formula (III-A) wherein Z a is C1-4 alkyl or an amino-protecting group which may be removed under acidic conditions, and the other symbols are as defined in claim 1, optionally followed by removing the amino-protecting group under acidic conditions and/or by hydrolysis under alkaline conditions or using an enzyme, and (c) optionally converting a compound of formula (I) thus obtained into a non-toxic salt or cyclodextrin clathrate thereof. A process for the preparation of a compound of formula (I) as defined in claim 1, which is a compound of formula (Ib) wherein R 1b is a group of formula NR 6 R 7 and the other symbols are as defined in claim 1, or a cyclodextrin clathrate thereof, which process comprises reacting a compound of formula (Ic) wherein all symbols are as defined in claim 1, with a compound of formula (IV) NHR 6 R 7 wherein all symbols are as defined in claim 1, to form an amide bond, and optionally converting a compound of formula (I) thus obtained into a cyclodextrin clathrate thereof. A pharmaceutical composition which comprises a compound of formula (I) as defined in claim 1, or a non-toxic salt thereof or cyclodextrin clathrate thereof, with a carrier or coating. Use of a compound of formula (I) as defined in claim 1, or a non toxic salt thereof or cyclodextrin clathrate thereof, in the manufacture of a medicament for use as an antagonist of the EP1 receptor.

Inventors: MARUYAMA TAKAYUKI, NAGAO YUUKI, OHUCHIDA SHUICHI, MARUYAMA,TAKAYUKI, NAGAO, YUUKI, OHUCHIDA, SHUICHI, Maruyama,Takayuki, c/o Ono Pharmaceutical Co. Ltd., Nagao, Yuuki, c/o Ono Pharmaceutical Co. Ltd., Ohuchida, Shuichi, c/o Ono Pharmaceutical Co. Ltd.
Applicants: ONO PHARMACEUTICAL CO, ONO PHARMACEUTICAL CO., LTD.
Application year: 1998
Main classification: C07C311
IPC codes: C07C311