JPS62146B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the following general formula ' [Here, the dotted line optionally indicates the presence of a second bond, R represents a hydrogen atom or an alkenyl or alkynyl group having 2 to 4 carbon atoms, and R ₆ represents the group OR′ _A (where R′ _A is a hydrogen atom, a tetrahydropyranyl group, or a group COR″ _A (R″ _A is an alkyl group having 1 to 3 carbon atoms, which may be substituted with a carboxyl group, or a carboxyl group) represents a phenyl group), or R and R ₆ together form a ketone group and R ₇ represents a group -(CH ₂ ) m _A -CH ₃ (where m _A
represents an integer equal to 3, 4, 5 or 6), or R ₆ and R ₇ together represent a group

(where n _A represents an integer equal to 2, 3, 4 or 5), the wavy line indicates that the bond can be in one or the other of the possible configurations, and the pentane ring and the bond between the oxygen atom and the oxygen atom is an α bond]. In particular, the invention relates to the following general formula: [Here, the dotted line optionally indicates the presence of a second bond, R represents a hydrogen atom or an alkenyl or alkynyl group having 2 to 4 carbon atoms, and R ₁ represents the group OR' (here R' represents a hydrogen atom, a tetrahydropyranyl group or a group COR''(R'' is a phenyl group optionally substituted by an alkyl group or carboxyl group having 1 to 3 carbon atoms); , or R and R ₁ together form a ketone group and R ₂ represents the group -(CH ₂ ) _n -CH ₃ (where m represents an integer equal to 3, 4 or 5), or R ₁ and R ₂ together form the group

(where n represents an integer equal to 2, 3 or 4), the wavy line means that the bond can be in one or the other of the possible configurations, and the pentane ring and the oxygen It is to be understood that the bond between the atoms is an α bond.] A novel lactone derivative of cyclopentanol. The radical R can in particular represent a hydrogen atom, a vinyl, propenyl, butenyl, ethynyl, propargyl group. The groups R″ and R″ _A are methyl, ethyl, propyl,
It can represent an isopropyl group. In particular, the present invention provides that the dotted line indicates the presence of a second bond, R represents a hydrogen atom or an alkenyl or alkynyl group having 2 or 3 carbon atoms, and R ₁ is a group OR' (where R' is represents a hydrogen atom, a tetrahydropyranyl group, a group COR''(R'' is a phenyl group substituted with a carboxyl group), and R ₂ is a group -(CH ₂ ) _n -CH ₃ (where m is 3,
represents an integer equal to 4 or 5), or
R ₁ and R ₂ together form the group

Compounds of the general formula forming the formula (where n represents an integer equal to 2, 3 or 4) are intended. More particularly, the invention provides that the dotted line indicates the presence of a double bond, R represents a hydrogen atom or an alkenyl or alkynyl group having 2 or 3 carbon atoms, and R ₁ is a group OR' (where R' is a hydrogen atom) and _R2 is a group -( _CH2 ) _n - _CH3 , where m represents an integer equal to 4. Among the compounds of the general formula or -octenyl) cyclopentanecarboxylic acid lactone and (1RS・2SR・5RS・3′SR)(1′E)2-hydroxy-5-(3′-hydroxy-1′-decenyl)cyclopentanecarboxylic acid lactone. I can give it to you. Similarly, (1RS・2SR・5RS・3′SR)(1′E)2
Mention may be made of the lactone of -hydroxy-5-[3'-(2''-hydroxybenzoyloxy)-1'-octenyl]cyclopentanecarboxylic acid. A process for preparing a compound, in particular a compound of the formula, in which the compound of the formula 'a is obtained by the following formula a (wherein A, R, R ₆ and R ₇ have the meanings given above) can be reacted with an acid-functional derivatization agent or to obtain a compound of formula (wherein A, R, R ₁ and R ₂ have the above-mentioned meanings) A lactone ring is formed by reacting the obtained functional derivative with a hydroxyl group by reacting the compound with an acid-functional derivatization agent, The object is thus to obtain a process for the preparation of compounds of formula ' or. In a preferred method of carrying out the above process, the acid-functional derivatizing agent on which the compound of formula a or is acted upon is tosyl chloride, which forms a functional derivative that is a mixed anhydride. It is preferably carried out in the presence of triethylamine, but other bases can be used as well, such as, for example, alkali metal carbonates or organic bases such as methylmorpholine, pyridine or other trialkylamines. It can also be carried out in the presence of diazabicyclooctane. Furthermore, the compound of formula a or can be acted upon with other mixed anhydride forming agents. For example, mention may be made of isobutyl chloroformate or other alkyl chloroformates. In this case too, the reaction is carried out in the presence of a basic agent selected from the same group as mentioned above. Similarly, other forming agents such as dialkylcarbodiimides or dicycloalkylcarbodiimides, such as dicyclohexylcarbodiimide, can also be used. Finally, acid chloride forming agents such as thionyl chloride in the presence of a basic agent selected from the group of bases as mentioned above can also be used. Thus, in the process for preparing compounds of formula ' and as described above, the acid-functional derivatizing agent is selected from the group consisting of tosyl chloride, alkyl chloroformate, dicycloalkylcarbodiimide, dialkylcarbodiimide and thionyl chloride; and the bases used in some cases are alkali metal carbonates,
selected from the group consisting of triethylamine, methylmorpholine, pyridine and diazabicyclooctane. The present invention also provides the following general formula B (Herein, the wavy line, dotted line, _A , B and _m have the meanings given above) CH ₂ ) _n −CH ₃
Corresponding to a compound of the formula A], which corresponds to a compound of the formula A (wherein A, R and m have the above-mentioned meanings) [in which R ₁ represents a group OR' (here R' represents a tetrahydropyranyl group) and R ₂ represents a group -(CH ₂ ) corresponds to a compound of the formula representing _n -CH ₃ ] is subjected to the action of an acid hydrolyzing agent. Compounds of general formula A used at the start of this process are acid-functional derivatizing agents of the following formula: (Here, A, R and m have the above-mentioned meanings.) It can be produced by acting on the compound. In a preferred method of carrying out the process for the preparation of compounds of formula B, the hydrolysis is carried out in the presence of acetic acid. However, other inorganic or organic acids such as hydrochloric acid, sulfuric acid or trifluoroacetic acid can also be used. Moreover, the following general formula C of the present invention (wherein A, R, R _' ' and m have the meanings already given)
COR''), and R ₂ is a group -(CH ₂ ) _n -
corresponds to a compound of the formula representing CH ₃ ] refers to the compound of the formula B as an acid of the formula R″CO ₂ H or
It is prepared by treatment with an acid chloride of R″COC1, or an acid anhydride or mixed anhydride of the formula (R″CO) ₂ O. A preferred method of carrying out the above process uses an anhydride of the formula (R″CO) ₂ O. However, acid chlorides of the formula R″COCl can also be used. In that case, it is carried out in the presence of a hydrochloric acid acceptor, such as an alkali carbonate or bicarbonate or a tertiary organic base, such as triethylamine, pyridine or picoline. In addition, the following formula 'C of the present invention (wherein A, R and mA have the meanings given above and R represents an alkylene group containing 1 to ₃ carbon atoms _{) nA} −CH ₃ and R ₆ is a group

corresponds to a compound of the formula [formula], in which _R''A represents an alkyl group having 1 to 3 carbon atoms and substituted by a carboxyl group] corresponds to a compound of the formula 'B (where _the wavy line, dotted line, A _, R _{and mA} have _the meanings _given above) corresponding to a compound of formula '] with an anhydride of formula (RCO) ₂ O. A preferred method of carrying out the above preparation is in the presence of a third party organic base such as triethylamine, pyridine, dimethylaminopyridine, picoline or a mixture of these bases. Compounds of formula 'B can be prepared, for example, by the processes described above starting from the corresponding compound a or, depending on the meaning of m _A . Furthermore, the following general formula D of the present invention (where A, R and n have the meanings given above) [This is a compound in which R ₁ and R ₂ together represent a group

[corresponding to the compound of the formula forming the formula]] is produced by treating the compound of the formula A or B as described above with a dehydrating agent. In a preferred method of carrying out the above process, p-toluenesulfonic acid is used as the dehydrating agent, although other strong aqueous acids such as concentrated sulfuric acid, phosphoric acid or polyphosphoric acid can also be used. Similarly, the following general formula E of the present invention (wherein A and m have the meanings given above) [which is a compound in which R and R ₁ together form a ketone group and R ₂ represents the group -(CH ₂ ) _n -CH ₃ corresponds to a compound of the following formula "B" (wherein A and m have _the meanings given _above ) [corresponding to a compound of the formula representing the group -( _CH2 ) _n - _CH3 ]] with an oxidizing agent. In a preferred method of carrying out the above process, dichlorodicyanoquinone is used as the oxidizing agent, but silver silicate can also be used. Compounds of formula "B" used at the start of this process can be prepared using the process of the invention starting from compounds of formula F. (where R ₃ represents a hydrogen atom or a saturated alkyl group, and A and R' have the meanings shown above) [This is a compound where R represents a hydrogen atom or a saturated alkyl group, and R ₁ represents a group OR' and R ₂ is a group -
(CH ₂ ) _n -CH ₃ ] corresponds to the compound of the formula 'F (Here, A, R, R ₁ and m have the meanings given above, provided that R and R ₁ together cannot represent a ketone group) [This is a compound in which R ₂ is a group] -( _CH2 ) _n - _CH3 , where the dotted line indicates the presence of a double bond] with hydrogen in the presence of a catalyst. In a preferred method of carrying out the above process, palladium on charcoal is used as catalyst, but platinum or platinum salts can be used as well. Other carriers such as barium sulfate can also be used. The compounds of formula 'F used at the start of this process can be prepared starting from compounds of formula using the process of the invention. Furthermore, the following formula H of the present invention (Here, A and m _A have the meanings shown above, and R
represents an alkenyl group having 2 to 4 carbon atoms) [this is a compound of the formula ′ in which R=R〓, R ₆ represents a hydroxyl group, and R ₇ represents a group −(CH ₂ ) _nA −CH ₃ ] corresponds to the compound of the following formula 'H (where R ₁ represents an alkynyl group having 2 to 4 carbon atoms) [This is a compound in which R = ₁ , R ₆ represents a hydroxyl group, and R ₇ represents a group -(CH ₂ ) _nA - corresponding to a compound of formula ', representing CH ₃ ] with hydrogen in the presence of a catalyst. Barium sulfate on palladium in the presence of traces of quinoline is preferably utilized as hydrogenation catalyst. However, palladium on calcium carbonate in the presence of lead acetate, or palladium on carbon black in the presence of pyridine, or Raney nickel can also be used. The compounds of the formula 'H used at the start of the abovementioned preparation process can be prepared, for example, by the abovementioned process starting from the corresponding compound a or, depending on the meaning of m _A . The wavy lines in most of the formulas shown above represent the various possible configurations of the substituent around the carbon atom to which it is attached. The components of mixtures that may be formed by these various compounds can be separated by conventional physical methods, especially chromatography. Compounds of formula ' and can exist in racemic or optically active forms, and optically active isomers can be separated by conventional methods. These compounds exhibit pharmacological hypotensive activity. The pharmacological results obtained with the compounds of the invention are presented in the experimental section below. The pharmacological properties of the compounds of the invention allow them to be used as medicaments, in particular in the treatment of hypertension and circulatory disorders. Thus, pharmaceutically acceptable compounds of formula ' as described above, particularly those listed below in the Examples, can be used as medicaments. Accordingly, the present invention extends to antihypertensive compositions containing as an active ingredient at least one of the pharmaceutically acceptable compounds of formula ' and above. These pharmaceutical compositions can be administered orally, directly, parenterally or by topical routes. These compositions may be solid or liquid;
It can be provided in pharmaceutical forms currently used in human medicine, such as tablets or dragees, gelatin capsules, granules, suppositories, injectable preparations. These are manufactured by conventional methods. The active ingredient can be incorporated with the adjuvants customary in these pharmaceutical compositions, such as talc, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles. The dosage will vary depending on the disease to be treated, the subject, the route of administration and the test compound. For example,
injections in men, e.g. by slow injection method as in Example 2 and
For the compound described in 15, it can be between 0.5 mg and 200 mg. used at the start of the process of the invention, in which R ₁ and R ₂ together represent the group

A compound of the formula which cannot be formed and m represents the number 4 can be produced by the method described in JP-A-52-31053. This method uses the following formula B (wherein R ₄ represents an alkyl group having 1 to 12 carbon atoms and R ₅ represents a hydrogen atom or a 2-tetrahydropyranyl group). Examples of the preparation of compounds of formula are given in the experimental section below. R ₁ and R ₂ together form a group

A compound of the formula forming the formula can be produced by reacting a compound of the formula B in which R ₅ represents a 2-tetrahydropyranyl group with 2,4-dinitrobenzenesulfinyl chloride. The compound of the formula in which m represents the number 3 or 5 or n represents the number 2 or 4 has the following formula B' (Here, m' represents the number 3 or 5.) It can be produced starting from the following compound. This preparation mode is the same as that used starting from the compound of formula B. The following formula a′ (Here, R and m _A have the meanings indicated above, and R″ ₁
represents an alkyl group having 1 to 3 carbon atoms and substituted with a carboxyl group). (where alk represents an alkyl group having 1 to 4 carbon atoms). Compound A' itself can be produced by the method described in Japanese Patent Publication No. 60-32617. This method is
The following formula Starting from the compound of formula B ₁ (wherein R ₃ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms). Also, the following formula B ₂ The compounds of (where m _A has the meaning given above) are obtained by applying methods analogous to those derived for the compounds of formulas B ₁ and E. Thus, the compound of formula a' can be converted into a compound of formula B ₂ by the following formula of the anhydride and then optionally hydrolyzed. Finally, compounds of formula _A that do not contain double bonds are obtained by hydrogenation of the corresponding compounds that contain double bonds. Compounds of formula H are in the same manner as described above for the corresponding compounds of formula, except that as starting materials the following formula B It can be produced using the following compounds. These manufacturing methods are summarized below. (i) a compound of formula B ₁ can be treated with hydrogen in the presence of a catalyst to obtain a compound free of double bonds, and (ii) the same compound as above can be treated with hydrogen to selectively oxidize allyl alcohol. Treated with an oxidizing agent to produce R and
Compounds in which R ₁ represents a keto group can be obtained and the compounds thus obtained can then be treated with organometallic derivatives to obtain compounds in which R represents an alkyl group, (iii) the allylic hydroxyl function is a tetrahydro A compound of formula B ₁ protected by a pyranyl group is treated with 2,4-dinitrobenzenesulfinyl chloride to form a compound of formula R ₁ .

Compounds of the formula can be obtained. The acid corresponding to the obtained ester is produced by saponification in a conventional manner. The following examples are illustrative of the invention and are not intended to limit it in any way. Example 1 (1RS・2SR・5RS・3′SR)(1′E)2-Hydroxy-5-(3′-α-tetrahydropyranyloxy-1′-octenyl)cyclopentanecarboxylic acid lactone 600 mg of (1RS・2SR・5RS・3′SR)(1′E)2
-Hydroxy-5-(3'-α-tetrahydropyranyloxy-1'-octenyl)cyclopentanecarboxylic acid, 12 c.c. of anhydrous chloroform, 1 c.c. of triethylamine and 402 mg of tosyl chloride are introduced. Stir for 4 hours at 20°C, pour into sodium hydrogen phosphate solution, decant, extract with methylene chloride and evaporate to dryness under vacuum. 700 mg of product was obtained, which was diluted with cyclohexane.
Ethyl acetate-triethylamine (75/25/0.1)
The mixture is chromatographed on silica gel. 336 mg of the expected β-lactone are obtained. Used at the time of departure in Example 1 (1RS, 2SR, 5RS,
3'SR)(1'E)2-hydroxy-5-(3'-α-tetrahydropyranyloxy-1'-octenyl)cyclopentanecarboxylic acid was produced as follows. Step A: (1RS・2SR・5RS・3′SR) (1′E) Ethyl hydroxy-5-(3′-α-tetrahydropyranyloxy-1′-octenyl)cyclopentanecarboxylate 14 g of 3-(3 of ethyl ′-α-tetrahydropyranyloxy-trans-1′-octenyl)cyclopentanone-2-carboxylate, 200 c.c. of isopropyl alcohol, 20 c.c. of water and 5.6 g of sodium borohydride. The mixture is stirred for 2 hours, acetone is slowly added to the mixture, and then poured into a saturated monosodium phosphate solution. Filter, dry and dissolve in ethyl acetate. Wash with water, dry and then evaporate the solvent. The residue is chromatographed on silica eluting with a cyclohexane-ethyl acetate (8/2) mixture containing 0.1% triethylamine to give 3.4 g of the desired α-OH (2SR) isomer. Process B: (1RS・2SR・5RS・3′SR) (1′E) 2−
Hydroxy-5-(3'-α-tetrahydropyranyloxy-1'-octenyl)cyclopentanecarboxylic acid A mixture of 3.1 g of the ester obtained in step A, 50 c.c. of methanol and 8.15 c. of 2N soda was 200℃
Stir for 3 hours at 35-40° C., then evaporate the solvent at 35-40° C., dissolve in water, wash with ether, saturate the solution with sodium chloride and then acidify with hydrochloric acid. Extract with ether, wash with water, dry and evaporate the solvent. 2.6 g of the expected compound are obtained. Example 2 (1RS・2SR・5RS・3′SR)(1′E) Lactone of 2-hydroxy-5-(3′-hydroxy-1′-octenyl)cyclopentanecarboxylic acid 336 mg of β obtained in Example 1 - The lactone is dissolved in 10 volumes of acetic acid containing 20% water in the presence of 5 mg of sodium iodide. After standing at 20 °C for 16 h, pouring into water, extracting with methylene chloride, washing with sodium bisulfite and drying, 280 mg of product was obtained, which was purified using a cyclohexane-ethyl acetate (75/25) mixture. Chromatograph on silica gel. 160 mg of the expected compound is obtained. Example 3 (1RS・2SR・5RS・3′SR)(1′E)2-hydroxy-5-(3′-α-hemiphthaloyloxy-
Lactone of 1'-octenyl)cyclopenlenecarboxylic acid 160 mg of the β-lactone obtained in Example 2, 1.6 cc of pyridine and 200 mg of phthalic anhydride are introduced.
Leave at ambient temperature for 9 days. Pour into cooled 1N hydrochloric acid, extract with ether, wash and reduce the organic phase to 10
% bicarbonate, dry the ether phase and dry under vacuum. The alkaline aqueous phase is acidified with 1N hydrochloric acid, extracted with ether and evaporated to dryness under vacuum. Cyclohexane-ethyl acetate (1/
Chromatograph the acidic fraction on silica gel using 1). 172 mg of the expected compound are obtained in the form of a colorless resin which crystallizes.

[Table] Example 4 (1RS・2SR・5RS・3′SR) (1′E)2-hydroxy-5-(3′-hydroxy-3′-ethynyl-
1′-octenyl)cyclopentanecarboxylic acid lactone 530 mg (1RS・2SR・5RS・3′SR)(1′E)
2,3'-dihydroxy-5-(3'-ethynyl-1'-
octenyl) cyclopentanecarboxylic acid, 5.3cc
of chloroform, 0.78cc of triethylamine and
Mix 430 mg of tosyl chloride. Stir for 30 minutes at +5°C, then return to 20°C. Leave for 1 hour, pour into water, add sodium hydrogen phosphate, wash with water,
Extract with methylene chloride. Dehydration and chromatography on silica gel using benzene-ethyl acetate (80/20) gives 106 mg of the expected compound. Rf
=0.4. Example 5 (1RS・2SR・5RS・3′SR)(1′E)2-hydroxy-5-(3′-hydroxy-3′-ethynyl-
720 mg of lactone of 1-octenyl)cyclopentanecarboxylic acid (1RS・2SR・5RS・3′SR)(1′E)2
-Hydroxy-5-(3'-hydroxy-3'-ethynyl-1'-octenyl)cyclopentanecarboxylic acid, 7.2 cc of chloroform, 1.44 cc of triethylamine, and 586 mg of tosyl chloride are mixed. 20℃
Stir to nitrogenize. Pour into the mixture with water and sodium hydrogen phosphate. Washing with water, extraction with methylene chloride, drying and evaporation to dryness give 1 g of product, which is chromatographed on silica gel using a benzene-ethyl acetate (80/20) mixture. 128 mg of the expected compound is obtained. Rf=0.4. Used at departure in Example 4 (1RS, 2SR, 5RS,
3′SR)(1′E)2-hydroxy-5-(3′-hydroxy-3′-ethynyl-1′-octenyl)cyclopentanecarboxylic acid and (1RS・2SR・5RS -3'SR)(1'E)2-hydroxy-5-(3'-hydroxy-3'-ethynyl-1'-octenyl)cyclopentanecarboxylic acid was produced as follows. Process A: (1RS・2SR・5RS・3′SR) (1′E) 2−
Ethyl hydroxy-5-(3'-hydroxy-1'-octenyl)cyclopentanecarboxylate 572 mg of 3-(3'-α-hydroxy-trans-
ethyl 1'octenyl)cyclopentanone-2-carboxylate, 23 c.c. ethanol, 2.3 cc water and 85
Mix 2 mg of sodium borohydride at 5°C.
Stir for an hour, add a few drops of acetone, then pour into saturated monosodium phosphate solution. Filter, evaporate the solvent, dissolve in ethyl acetate, wash with water, dry and evaporate to dryness. 520 mg of a mixture of 2α-OH and 2β-OH isomers are obtained, which is separated on silica gel using a methylene chloride eluent containing 2% methanol.
203 mg of the desired α-isomer are obtained. Step B: (1RS・2SR・5RS)(1′E) Ethyl 2-hydroxy-5-(3′-oxo-1′-octenyl)cyclopentanecarboxylate 1 g of the compound obtained in Step A was added to 20 c.c. of dioxane and add 1.6 g of dichlorodicyanoquinone. Stir at ambient temperature for 20 hours. Dry and then wash. Wash with cooled N/10 soda until pH 9. Filter, wash with water and dry to obtain 987 mg of crude product. Chromatograph on silica using eluent (cyclohexane-ethyl acetate (1/1). 930 mg of desired compound is recovered. Step C: (1RS, 2SR, 5RS, 3'SR and RS).
(1'E) Ethyl 2-hydroxy-5-(3'-hydroxy-3'-ethynyl-1'octenyl)cyclopentanecarboxylate 2.1 g of the compound obtained in step B are introduced into 2.1 cc of tetrahydrofuran. Warm to 38℃, and
A solution of 45 c.c. of ethynylmagnesium bromide in 1N tetrahydrofuran (warmed to 40°C) is quickly introduced. Stir for 30 minutes at 38°C. Pour into ice-cold aqueous ammonium chloride solution, pour out with methylene chloride, wash with water, dry, filter and evaporate to dryness. Chromatography on silica using an eluent consisting of methylene chloride-ethyl acetate (85/15) gives 1.67 g of the expected compound. Process D: (1RS・2SR・5RS・3′RS) (1′E) 2−
Hydroxy-5-(3′-hydroxy-3′-ethynyl-1′-octenyl)cyclopentanecarboxylic acid and (1RS・2SR・5RS・3′RS)(1′E)2
-Hydroxy-5-(3'-hydroxy-3'-ethynyl-1'-octenyl)cyclopentanecarboxylic acid 1.67 g of the ester obtained in step C was dissolved in 17 c.c. of ethanol and 8.5 cc of 1N soda with nitrogen Introduced below. Stir for 2 hours at 20°C, pour into water, extract with ether, wash with N/2 soda, then wash with water, dry and filter to obtain a fraction consisting of 0.37 g of impurities. The aqueous phases are collected, acidified with monosodium phosphate, extracted with ether, washed with water, dried and evaporated to give 1.33 g of compound. The two isomers are separated by pressure chromatography in isopropyl ether containing 4% acetic acid. 530 mg αOH (3′SR) isomer Rf = 0.15 and 720
mg of βOH (3'RS) isomer Rf = 0.10 is obtained. Example 6 Lactone of (1RS・2SR・5RS)(1′E・3′E)2-hydroxy-5-(1′・3′-octadienyl)cyclopentanecarboxylic acid 150 mg of the β-lactone produced in Example 2 3c.c.
of benzene, add 15 mg of p-toluenesulfonic acid, and heat at 40° C. for 3 hours under nitrogen.
Neutralize with 150 mg of sodium carbonate, filter and evaporate the solvent. 139 mg of an oil are obtained which is chromatographed on silica, eluting with cyclohexane-ethyl acetate (95/5). 36 mg of pure compound is recovered. Rf=0.25, cyclohexane-ethyl acetate (90/10).

[Table] Example 7 (1RS・2SR・5RS) (1′E)2-hydroxy-5
Lactone of -(3'-oxo-1'-octenyl)cyclopentanecarboxylic acid 15 c.c. of dry methylene chloride and 1.5 c.c. of anhydrous pyridine were placed under a dry nitrogen atmosphere and heated to 900 m
Add mg of chromium oxide slowly at 20°C. 15
Stir, then add 358 mg of (1RS・2SR・5RS・3′SR)(1′E)2 dissolved in 15 c.c. of methylene chloride.
-Hydroxy-5-(3'-α-hydroxy-1'-
The lactone of (octenyl)cyclopentanecarboxylic acid (obtained in Example 2) is quickly added. Stir at 20° C. for 2 hours, then add 4 g of Celite and 15 c.c. of methylene chloride. Filter and concentrate the liquid in vacuo and purge with nitrogen to drive off the pyridine to give 375 mg of a brown oil. Chromatograph on silica, eluting with a cyclohexane-ethyl acetate (6/4) mixture. 329 mg of the expected compound are obtained. Rf=0.45.

【table】 /
Conjugate system

[Table] Example 8 (1RS・2SR・5RS・3′SR)2-Hydroxy-
Lactone of 5-(3'-hydroxyoctanyl)cyclopentanecarboxylic acid 105 mg (1RS.
2SR・5RS・3′SR)(1′E)2-hydroxy-5-
The lactone of (3'-α-hydroxy-1'-octenyl)cyclopentanecarboxylic acid (obtained in Example 2) is placed in a hydrogenator. Add 20 mg of 5% palladium on charcoal. Hydrogenate for 7 hours (10.4cc of hydrogen absorbed). The catalyst is separated, the liquid is concentrated in vacuo and the residual oil is chromatographed on silica, eluting with cyclohexane-ethyl acetate (50/50). 97 mg of the expected compound is obtained. Rf=0.35. IR spectrum C=O 1800cm ^-1 OH 3600cm ^-1 Example of absence of transC=C 9 (1RS・2SR・5RS・3′RS)(1′E)2-hydroxy-5-(3′-hydroxy-3′ -Ethenyl-
Lactone of 1'-octenyl)cyclopentanecarboxylic acid 45 mg of barium sulfate on 0.475% palladium in 5 c.c. of ethyl acetate is saturated with hydrogen at atmospheric pressure. 150mg (1RS・2SR・5RS・3′SR)
(1′E)2-hydroxy-5-(3′-hydroxy-
The lactone of 3'-ethynyl-1'-octenyl)cyclopentanecarboxylic acid (obtained in Example 4), 10 mg of quinoline and 1 c.c. of ethyl acetate are added. Hydrogenate at 21°C. After 30 minutes, 14.3cc of hydrogen was absorbed.
The catalyst is filtered and washed with 0.1N hydrochloric acid solution and then with brine. The organic phase is dried and evaporated to give 153 mg of crude product. This product was mixed with benzene-ethyl acetate (80/20).
The mixture is chromatographed on silica,
It is then purified by dispersion chromatography using the same eluent. Obtain 110 mg of pure product. Rf=0.41. The IR spectrum shows the absence of C≡CH, the presence of β-lactone, ethenyl and hydroxyl groups.

[Table] Example 10 (1RS・2SR・5RS・3′SR) (1′E)2-hydroxy-5-(3′-hydroxy-3′-ethenyl-
150 mg of lactone of (1′-octenyl)cyclopentanecarboxylic acid (1RS・2SR・5RS・3′RS)(1′E)2
Starting from the lactone of -hydroxy-5-(3'-hydroxy-3'-ethynyl-1'-octenyl)cyclopentanecarboxylic acid (obtained in Example 5), it is carried out as in Example 9. Obtain 127 mg of pure compound. The infrared spectrum shows the absence of C≡C, the presence of β-lactone, ethenyl and hydroxyl groups.

【table】

[Table] Example 11 (1RS・2SR・5RS・3′SR)(1′E)2-Hydroxy-5-(3′-acetoxy-1′-octenyl)cyclopentanecarboxylic acid lactone 0.2g of (1RS・2SR・5RS・3′SR)(1′E)2−
Lactone of hydroxy-5-(3'-α-hydroxy-1'-octenyl)cyclopentanecarboxylic acid (obtained in Example 2), 2 c.c. of methylene chloride, 0.47 cc of triethylamine, 0.091 cc of acetic anhydride and a mixture of trace amounts of dimethylaminopyridine at ambient temperature.
Stir the time. Add 3 c.c. of water and dilute with monosodium phosphate.
Acidify to PH5 and extract with methylene chloride. Dehydration and evaporation to dryness under reduced pressure gave 266 mg of crude oil, which was dissolved in cyclohexane-ethyl acetate (60/
40) Purify the mixture by chromatography on silica as eluent. 211 mg of pure compound are thus obtained. Rf=0.5.

[Table] Example 12 (1RS・2SR・5RS・3′SR) (1′E) Hemisuccinic acid ester of lactone of 2-hydroxy-5-(3-hydroxy-1′-octenyl)cyclopentanecarboxylic acid 119mg (1RS・2SR・5RS・3′SR) (1′E)2
-Hydroxy-5-(3'-α-hydroxy-1'-
octenyl) lactone of cyclopentanecarboxylic acid (prepared in Example 2), 2 c.c. of anhydrous methylene chloride, 100
Mix mg of succinic anhydride, 0.15 cc of pure triethylamine, and 15 mg of 4-dimethylaminopyridine. Reflux for 8 hours and then evaporate the solvent. 2
Add cc of absolute ethanol and let stand at ambient temperature for 1 hour. Excess succinic anhydride is removed in the form of succinic acid hemiethyl ester. Evaporate under vacuum, 226
mg of crude product is obtained. Chromatograph on silica using pure ethyl acetate. 132 mg of pure compound is isolated. Rf=
0.3.

[Table] Example 13 (1RS・2SR・5RS・3′SR) (1′E)2-hydroxy-5-(3′-hydroxy-1′-decenyl)
Lactone of cyclopentanecarboxylic acid 0.15g of (1RS・2SR・5RS・3′SR)(1′E)2
-Hydroxy-5-(3'-hydroxy-1'-decenyl)cyclopentanecarboxylic acid in 4 c.c. of chloroform, 0.315 g of triethylenediamine and
Add to 0.16 g of tosyl chloride. The reaction is instantaneous. Pour into water and extract with ethyl acetate. After treatment, 183 mg of an oil are obtained, which is chromatographed on silica using a cyclohexane-ethyl acetate (60/40) mixture as eluent. Obtain 41 mg of pure compound. Rf=0.25.

[Table] Used at the departure of Example 13 (1RS, 2SR,
5RS・3′SR)(1′E)2-hydroxy-5-(3′-
Hydroxy-1'-decenyl)cyclopentanecarboxylic acid was prepared as follows. (a) 1,2-epoxy-3-α-tetrahydropyranyloxypropane 3.9 g of glycidol (2,3-epoxy-
1-propanol), 18.5 cc of dihydropyran, and 150 mg of p-toluenesulfonic acid.
Warm to 40℃. After 30 minutes, 150 mg of p-toluenesulfonic acid are added, followed by neutralization with potassium carbonate after 15 minutes at ambient temperature. Filter, wash with ethyl acetate and remove the solvent under reduced pressure. 8.48 g of the expected compound are obtained. Rf=0.6 (cyclohexane-ethyl acetate 8/2). (b) Methyl 3-keto-6-hydroxy-7-α-tetrahydropyranyloxyheptanoate by dissolving 3.554 g of a 50% suspension of sodium hydride in oil in 16 c.c. of anhydrous tetrahydrofuran.
A solution containing 8 c.c. of methyl acetyl acetate and 16 c.c. of anhydrous tetrahydrofuran is added to the suspension maintained at 0.degree. C. over a period of 30 minutes. Add 39 c.c. of butyllithium to this mixture at 0°C.
Introduce at 30°C. Stir for half an hour, then -70
Keep at ℃. Add 5.8 g of this solution to 1.
A solution containing 2-epoxy-3-α-tetrahydropyranyloxypropane and 16 c.c. of tetrahydrofuran at 0° C. is introduced for 45 minutes. 3 hours 30
Mix it up. Pour into excess cold concentrated monosodium phosphate solution, stir for 10 minutes, then extract with ethyl acetate and wash until neutral.
After evaporation of the solvent, 16.9 g of an oil was obtained, which was then dissolved in silica (cyclohexane-ethyl acetate 6/
Purify in step 4). 8.02g of pure compound is recovered. Rf=0.15. (c) Methyl 3,6-dioxo-7-α-tetrahydropyranyloxyheptanoate A solution of 6.9 g of chromic acid dissolved in 9.7 cc of pyridine is slowly introduced into 148 c.c. of methylene chloride. . A solution of 1.1 g of the compound obtained in step (b) in 10 c.c. of methylene chloride is then introduced. After 15 minutes, add 150 c.c. of ether, filter the precipitate, wash with ether and evaporate the solvent. 1.3 g of crude product are obtained, which is purified by chromatography on silica (methylene chloride-ethyl acetate 8/2). Obtain 473 mg of pure compound. Rf=0.45. (d) Methyl 2-(α-tetrahydropyranyloxymethyl)-5-oxo-1-cyclopentenecarboxylate A solution of 291 mg of potassium bicarbonate dissolved in 72 c.c. of distilled water and 220 mg of process ( A solution of the crude product obtained in step c) dissolved in 2.4 cc of methylene chloride is vigorously stirred. After half an hour, acidify to PH3 with cylic acid, then saturate with sodium chloride and extract with methylene chloride.
After evaporation 205 mg of the expected compound are obtained. (e) (1RS・5SR) Methyl 2-oxo-5-(α-tetrahydropyranyloxymethyl)cyclopentanecarboxylate 215 mg of the compound obtained in step (d), 10 c.c. of methanol and 21 mg of 10 % palladium on charcoal is stirred under an atmosphere of hydrogen. The theoretical quantity
Absorbed in 40 minutes, filtered, washed with ethyl acetate and evaporated the solvent to give 172 mg of an oil which was chromatographed on silica (cyclohexane-ethyl acetate 50/50). 122 mg of the expected compound are obtained. (f) (1RS・5SR) Methyl 2-oxo-5-hydroxymethylcyclopentanecarboxylate 43 g of the compound obtained in step (e), 860 c.c. of methanol, 86 c.c. of water and 12.7 g of Continue stirring the oxalic acid mixture at 60°C for 3 hours. Concentrate under reduced pressure at 40°C, dissolve in chloroform, wash with water, and dehydrate. Evaporation of the solvent gives 29.2 g of crude product, which is chromatographed on silica (cyclohexane-ethyl acetate 2/8).
14 g of pure oil are obtained. (g) (5RS) Methyl 2-methoxy-5-hydroxymethyl-1-cyclopentenecarboxylate 4g
A methylene chloride solution of the β-ketoester obtained in step (f), 10 c.c. of methylene chloride, and 50 c.c. of diazomethane is stirred at ambient temperature for 4 hours. Evaporate excess diazomethane and solvent;
4.3 g of yellow oil is obtained, which is used directly in the next step. (h) (5RS)2-methoxy-5-formyl-1-
Methyl Cyclopentene Carboxylate 25.5 g of chromium oxide is introduced little by little into a solution of 41 c.c. of pyridine dissolved in 400 c.c. of anhydrous methylene chloride and maintained at 15-20°C. Stir for 4 hours, then cool the resulting solution to -15 DEG C. and then add 4.3 g of the compound obtained in the previous step dissolved in 10 c.c. of methylene chloride. After 1 hour and 30 minutes, 50 g of Celite and 100 c.c. of ether are introduced, filtered, washed with ether and the solvent is evaporated at 30°C. (i) (5RS) (1'E) Methyl 2-methoxy-5-(3'-oxo-1'-decenyl)-1-cyclopentenecarboxylate 9.674 g of dimethyl (2-oxononyl)phosphonate was added to 20 c.c. of glyme is introduced into a suspension of 1.85 g of 50% sodium hydride in oil. After solidification, a solution of 5 g of the aldehyde prepared in step (h) dissolved in 30 c.c. of grime is added over a period of 20 minutes. The reaction is complete after 20 minutes. Pour into a solution saturated with monosodium phosphate and extract with ethyl acetate. 13.2
g of an oil is obtained which is chromatographed on silica eluting with a cyclohexane-ethyl acetate (60/40) mixture. Thus 4.652g
A pure oil is obtained. Rf = 0.25. infrared spectrum (j) (5RS・3′SR)(1′E)2-methoxy-5-
Methyl (3′-hydroxy-1′-decenyl)-1-cyclopentenecarboxylate and (5RS・3′RS)
(1'E)2-methoxy-5-(3'-hydroxy-
Methyl 1'-decenyl)-1-cyclopentenecarboxylate A solution of 4.6 g of the ketone obtained in step (i) dissolved in 100 c.c. of glyme (distilled with sodium) was cooled to 0°C and then 200 c.c. of 0.13 M/glyme solution of zinc borohydride is introduced in 45 minutes. Return to ambient temperature and then stir for 4 hours. Pour into saturated monosodium phosphate solution,
Extract with ethyl acetate. After processing, 7.3 g of oil are obtained. Chromatography is carried out twice on silica using benzene-ethyl acetate (60/40) and (containing 1% triethylamine) as eluent. 901 mg of α(3′SR) isomer and 810 mg of β
(3'RS) isomer as well as 503 mg of a mixture are obtained. (k) (1RS・2SR・5RS・3′SR) (1′E) 2-hydroxy-5-(3′-hydroxy-1′-decenyl)cyclopentanecarboxylic acid (α) Hydrolysis of enol ether 8.49mg The 3'SR isomer produced in step (j) of
A solution of cc methanol and 2 c.c. of 0.1N hydrochloric acid is stirred at ambient temperature for 15 hours.
Neutralize with 2 c.c. of 0.1N soda and extract the aqueous phase with ether. By chromatography
Obtain 763 mg of pure oil. Rf=0.32 (benzene-ethyl acetate 60/40). (β) Reduction of ketone 763 mg of the above oil in solution was mixed with 4 c.c. of tetrahydrofuran and 5.14 cc of L kept at -60°C.
Add to a 1M solution of selectride in tetrahydrofuran. Stir at this temperature for 2 hours and 30 minutes, then pour into saturated monosodium phosphate solution for hydrolysis and extract with ethyl acetate. 1.7 g of crude oil are obtained. Rf=0.25 (cyclohexane-
ethyl acetate 40/60). (γ) Saponification The oil obtained above is stirred for 2 hours in the presence of 3 c.c. of ethanol and 24 c.c. of 1N soda. Drive off the ethanol and extract with ethyl acetate. PH the aqueous phase with monosodium phosphate.
Acidify to 5 and extract with ethyl acetate. The organic phase is washed with water and then dried. After removing the solvent under reduced pressure, chromatography was performed.
365 mg of pure colorless oil is obtained. Rf=0.1~0.36
(Ethyl acetate).

[Table] Example 14 (1RS・2SR・5RS・3′SR)(1′E)Lactone of 2-hydroxy-5-(3′-α-hydroxy-1′-octenyl)cyclopentanecarboxylic acid Described in Example 1 Using the same method as above, but replacing triethylamine with diazabicyclooctamine, (1RS・2SR・5RS・3′SR)(1′E)2-hydroxy-5-(3′-α-tetrahydro The lactone of pyranyloxy-1'-octenyl)cyclopentanecarboxylic acid is obtained and treated as in Example 2 to give the expected compound. Pharmacological study The following compounds will be used in this study. Compound A: (1RS・2SR・5RS・3′SR)(1′E)2
-Hydroxy-5-(3'-hydroxy-1'-octenyl)cyclopentanecarboxylic acid lactone) Compound B: (1RS・2SR・5RS・3′SR)(1′E)2
-Hydroxy-5-(3'-hydroxy-3'-ethynyl-1'-octenyl)cyclopentanecarboxylic acid lactone compound C: (1RS・2SR・5RS・3′RS) (1′E)2
-Hydroxy-5-(3'-hydroxy-3'-ethenyl-1'-octenyl)cyclopentanecarboxylic acid lactone compound D: (1RS・2SR・5RS・3′SR) (1′E)2
-Hydroxy-5-(3'-acetoxy-1'-octenyl)cyclopentanecarboxylic acid lactone compound E: (1RS・2SR・5RS・3′SR) (1′E)2
-Hydroxy-5-(3'-hydroxy-1'-decenyl)cyclopentanecarboxylic acid lactone (1) Antihypertensive activity in anesthetized dogs (a) Method This study was conducted in male and female hybrids weighing 14-20 kg. It was performed on a dog with its chest closed.
Animals were anesthetized with chloralose (125 mg/Kg). A tube was passed through the trachea and the animal was artificially ventilated with a pump. Arterial pressure, expressed in mmHg, was read in the carotid artery by a pressure head. Effect of the cardiovascular system on mean arterial pressure (diastolic pressure + 1/3 pressure difference: systolic pressure - diastolic pressure)
were studied for compound A in amounts of 10-1000 γ/Kg and for compound B in amounts of 30-1000 γ/Kg. The table below shows the maximum rate of change in mean arterial pressure as well as the time required to return the pressure to its initial state. (b) Results

[Table] These compounds are 0.1 for compound A.
From the amount of mg/Kg, for compound B, 1 mg/Kg
It shows interesting antihypertensive activity based on the amount of Kg. A second study was conducted on male and female mongrel dogs weighing 14 to 20 kg with their chests closed. Animals were anesthetized with a barbiturate mixture. A tube was passed through the trachea and the animal was artificially ventilated with a pump. Arterial pressure was read in the carotid artery by pressure head. The drug dose that reduces mean arterial pressure by at least 20% for at least 20 minutes was determined. The results were as follows. Compound C: 0.5 mg/Kg Compound D: 1 mg/Kg Compound E: 1 mg/Kg (2) Antihypertensive activity in rabbits The compounds were used in the form of a solution of physiological serum containing 10% ethanol. This solution was administered intravenously to rabbits anesthetized with urethane, and carotid artery pressure was measured. We determined the amount of drug that would reduce this pressure by 30%. 20 μg/Kg for Compound E 50 μg/Kg for Compound C (3) Toxicity test of compounds of the present invention The compound of Example 2 prepared as gelatin capsules was administered to four 11-month-old beagle dogs (2 males, 2 females). 2 and 2 in a group of lots
30 mg/kg once per day
Administer orally for days. On the other hand, as a control example, 4 beagle dogs (2 male
A lot of animals (1 female, 2 females) were given only the capsule excipient under the same conditions. The general condition of the beagles was satisfactory during the study, and their appearance and behavior were normal.
Also, body weight changes, nutrient consumption, and laboratory test results were normal. Histopathological examination of the liver and kidneys did not demonstrate any lesions attributable to the above treatment.

Claims (1)

[Claims] First-order general formula' [Here, the dotted line indicates that a second bond may be present, R represents a hydrogen atom or an alkenyl or alkynyl group having 2 to 4 carbon atoms,
R ₆ is a group OR′ _A (where R′ _A is a hydrogen atom, a tetrahydropyranyl group, or a group COR″ _A (R″ _A is an alkyl group having 1 to 3 carbon atoms that may be substituted with a carboxyl group) or a phenyl group which may be substituted with a carboxyl group), or R and R ₆ together form a ketone group, and R ₇ is a group -(CH ₂ ) m _A -CH ₃ (where m _A represents an integer equal to 3, 4, 5 or 6), or R ₆ and R ₇ together represent the group [Formula] (where n _A represents 2, 3, 4 or (representing an integer equal to 5), and the wavy line indicates that the bond may be in one or the other of the possible configurations. In addition, the bond between the pentane ring and the oxygen atom is an α bond. 2nd order general formula [Here, the dotted line indicates that a second bond may be present, R represents a hydrogen atom or an alkenyl or alkynyl group having 2 to 4 carbon atoms,
R ₁ is a group OR' (where R' is a hydrogen atom, a tetrahydropyranyl group, or a group COR''(R'' is a phenyl group optionally substituted by an alkyl group or carboxyl group having 1 to 3 carbon atoms) or R and R ₁ together form a ketone group and R ₂ is a group -(CH ₂ ) _n -CH ₃ (where m is 3, 4 or 5); or R ₁ and R ₂ together form a group (where n represents an integer equal to 2, 3 or 4), and the wavy line indicates the steric structure in which the bond is possible. Indicates that one or the other of the configurations is possible. Furthermore, the bond between the pentane ring and the oxygen atom is an α bond.] A compound of formula ' according to claim 1, which corresponds to the compound of 3 A dotted line indicates the presence of a second bond, R represents a hydrogen atom or an alkenyl or alkynyl group having 2 or 3 carbon atoms, and R ₁ is a group
OR′ (where R′ represents a hydrogen atom, a tetrahydropyranyl group, a group COR″ (R″ is a phenyl group substituted with a carboxyl group)), and R ₂
is the group -(CH ₂ ) _n -CH ₃ (where m is 3, 4 or 5
) or R ₁ and R ₂
3. A compound of the general formula according to claim 2, in which together form the group , where n represents an integer equal to 2, 3 or 4. 4 The dotted line indicates the presence of a double bond, R represents a hydrogen atom or an alkenyl or alkynyl group having 2 or 3 carbon atoms, and R ₁ is a group
OR′ (where R′ is a hydrogen atom) and R ₂
A compound of the general formula according to claim 2, wherein represents the group -( _CH2 ) _n - _CH3 , where m represents an integer equal to 4. 5 Claim 2, which is a lactone of (1RS・2SR・5RS・3′SR)(1′E)2-hydroxy-5-(3′α-hydroxy-1′-octenyl)cyclopentanecarboxylic acid Compounds described. 6 (1RS・2SR・5RS・3′SR)(1′E)2-hydroxy-5-(3′-hydroxy-1′-decenyl)
The compound according to claim 2, which is a lactone of cyclopentanecarboxylic acid. 7 The following general formula' [Here, the dotted line indicates that a second bond may be present, R represents a hydrogen atom or an alkenyl or alkynyl group having 2 to 4 carbon atoms,
R ₆ is a group OR′ _A (where R′ _A is a hydrogen atom, a tetrahydropyranyl group, or a group COR″ _A (R″ _A is an alkyl group having 1 to 3 carbon atoms that may be substituted with a carboxyl group) or a phenyl group which may be substituted with a carboxyl group), R and R ₆ together form a ketone group, and R ₇ is a group -(CH ₂ ) m _A -CH ₃ (where m _A represents an integer equal to 3, 4, 5 or 6), or R ₆ and R ₇ together represent the group [Formula] (where n _A represents 2, 3, 4 or (representing an integer equal to 5), and the wavy line indicates that the bond may be in one or the other of the possible configurations. In addition, the bond between the pentane ring and the oxygen atom shall be an α bond.] In producing the compound of the following formula a (wherein A, R, R ₆ and R ₇ have the meanings given above) and an acid-functional derivative selected from the group consisting of tosyl chloride, alkyl chloroformate, dialkylcarbodiimide, dicyclohexylcarbodiimide and thionyl chloride. 1. A method for producing a compound of general formula ', which comprises reacting with a forming agent and then reacting with a hydroxyl group to form a lactone ring. 8 The compound of formula a has the following formula [Here, the dotted line indicates that a second bond may be present, R represents a hydrogen atom or an alkenyl or alkynyl group having 2 to 4 carbon atoms,
R ₁ is a group OR' (where R' is a hydrogen atom, a tetrahydropyranyl group, or a group COR''(R'' is a phenyl group optionally substituted by an alkyl group or carboxyl group having 1 to 3 carbon atoms) or R and R ₁ together form a ketone group and R ₂ is a group -(CH ₂ ) _n -CH ₃ (where m is 3, 4 or 5); or R ₁ and R ₂ together form a group (where n represents an integer equal to 2, 3 or 4), and the wavy line indicates the steric structure in which the bond is possible. Indicates that one or the other of the configurations is possible. Furthermore, the bond between the pentane ring and the oxygen atom is an α bond. 9. Claim 7, characterized in that the reaction is carried out in the presence of a base selected from the group consisting of alkali metal carbonate, triethylamine, methylmorpholine, pyridine and diazabicyclooctane.
Or the method described in Section 9. 10 General formula B [Here, the dotted line indicates the presence of a second bond, R represents a hydrogen atom or an alkenyl or alkynyl group having 2 or 3 carbon atoms, m represents an integer equal to 3, 4 or 5, and the wavy line indicates that the bond may be in one or the other of the possible configurations. In addition, the bond between the pentane ring and the oxygen atom shall be an α bond.] In producing the compound of the following formula A (Here, A, R and m have the above-mentioned meanings.) A method for producing a compound of general formula B, which comprises reacting the compound with an acid hydrolyzing agent. 11 The following general formula' [Here, the dotted line indicates that a second bond may be present, R represents a hydrogen atom or an alkenyl or alkynyl group having 2 to 4 carbon atoms,
R ₆ is a group OR′ _A (where R′ _A is a hydrogen atom, a tetrahydropyranyl group, or a group COR″ _A (R″ _A is an alkyl group having 1 to 3 carbon atoms that may be substituted with a carboxyl group) or a phenyl group which may be substituted with a carboxyl group), or R and R ₆ together form a ketone group, and R ₇ is a group -(CH ₂ ) m _A -CH ₃ (where m _A represents an integer equal to 3, 4, 5 or 6), or R ₆ and R ₇ together represent the group [Formula] (where n _A represents 2, 3, 4 or (representing an integer equal to 5), and the wavy line indicates that the bond may be in one or the other of the possible configurations. Furthermore, the bond between the pentane ring and the oxygen atom is an α bond.] An antihypertensive composition containing at least one compound as an active ingredient.