JPS6360757B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel epithiocyclohexane-type prostaglandin-like compounds. Prostaglandin formula Various types of prostaglandins are known, and generally have the effect of stimulating smooth muscle contraction, lowering blood pressure, and
diuretic effect, bronchodilator effect, lipolysis inhibitory effect,
A fat-soluble substance that is useful for treating hypertension, thrombosis, asthma, gastrointestinal ulcers, inducing labor and abortion in pregnant mammals, preventing arteriosclerosis, and as a diuretic because of its effects on inhibiting platelet aggregation and gastric acid secretion, etc. It is. Extensive research has been carried out to discover new compounds that possess the pharmacological effects of "natural" prostaglandins, or that have greater activity in one or more of their properties. New epithiocyclohexane-type prostaglandin-like compounds, in which the cyclopentane ring of the acid is replaced with an epithiocyclohexane ring, have very weak activities of many of the pharmacological properties that natural prostaglandins have, or Prostaglandin H ₂ shows almost no activity, but has the following formula:
Or, in the biosynthesis in which G ₂ () changes to thromboxane B _{2 () via thromboxane A 2 (} ), it strongly inhibits the biosynthesis of thromboxane A ₂ , which natural prostaglandins do not have. The present invention has been completed based on the discovery that it has the activity of The present invention is based on the general formula [Wherein, X represents an ethylene group (-CH ₂ CH ₂ -) or a cis-vinylene group [formula], Y represents an ethylene group or a trans-vinylene group [formula], R ¹ is a hydrogen atom, or represents an alkyl group having 1 to 12 carbon atoms, R ² is a hydrogen atom,
or represents a hydroxyl group, R ³ represents a single bond or an alkylene group having 1 to 5 carbon atoms, R ⁴ represents a hydrogen atom,
or an alkyl group having 1 to 8 carbon atoms, or a cycloalkyl group having 4 to 7 carbon atoms which is unsubstituted or substituted with at least one alkyl group having 1 to 8 carbon atoms, and m is 1 to 6 represents an integer. However, when X represents a cis-vinylene group and Y represents an ethylene group, R ² is not a hydrogen atom. ] The present invention relates to epithiocyclohexane-type prostaglandin-like compounds shown in the following, their cyclodextrin clathrate compounds, and non-toxic salts of their acids when R ¹ represents a hydrogen atom. The present invention relates to a compound represented by the general formula (), that is, an optically active "natural type" or its enantiomer, or a mixture thereof (particularly a racemate consisting of a mixture of equal amounts of the "natural type" and its enantiomer). Regarding. In this specification including the claims, alkyl groups, alkylene groups, and alkyl and alkylene moieties of functional groups represent straight chains and branched chains. In the structural formulas herein, including the claims, dotted lines indicate, in accordance with generally accepted nomenclature rules, that the group attached to it is behind the plane, i.e., in the α-configuration; 〓 indicates that the group attached to it is in front of the plane, that is, β-configuration, and the wavy line indicates that the group attached to it is α- or β-configuration.
- indicates a configuration or a mixture thereof. As is clear to those skilled in the art, general formula (V)
The compound represented by has at least four asymmetric centers, and these four asymmetric centers are at the 8th and 9th positions.
These are carbon atoms at positions 1, 11, and 12. Furthermore, when the alkyl group and alkylene group represent a branched chain,
Alternatively, when R ² represents a hydroxyl group, other asymmetric centers may occur. As is well known, the presence of asymmetric centers gives rise to isomers. However, all of the compounds represented by the general formula () have a configuration in which the substituents on the 8th and 12th carbon atoms of the epithiocyclohexane ring are trans. Therefore, isomers in which the substituents on the 8th and 12th carbon atoms of the compound represented by the general formula () have a trans configuration, and mixtures thereof are included within the scope of the compound represented by the general formula (). . When R ² represents a hydroxyl group, the configuration of the carbon atom at position 15 is α- or β-configuration, or a mixture thereof (αβ). -(CH ₂ ) in the compound represented by general formula (V)
The m-group is methylene, ethylene, trimethylene,
It represents tetramethylene, pentamethylene, and hexamethylene groups, and the preferred group is trimethylene. The alkyl group having 1 to 12 carbon atoms represented by R ¹ in the compound represented by the general formula () is methyl,
Examples include ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl groups, and isomers thereof. Preferably R ¹ is a hydrogen atom or has 1 carbon number
~4 alkyl groups, i.e. methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Sec-butyl and tert-butyl groups, and more preferred R ¹ is a hydrogen atom or a methyl group. Preferred -R ³ -R ⁴ groups include, for example, methyl,
Ethyl, 1-methylethyl, propyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, butyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylbutyl,
2-ethylbutyl, pentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,
4-Methylpentyl, 1,1-dimethylpentyl, 1,2-dimethylpentyl, 1,4-dimethylpentyl, 1-ethylpentyl, 2-ethylpentyl, 1-propylpentyl, 2-propylpentyl, hexyl, 1- Methylhexyl, 2-methylhexyl, 1,1-dimethylhexyl, 1-
Ethylhexyl, 2-ethylhexyl, heptyl, 2-ethylheptyl, nonyl, undecyl,
Cyclobutyl, 1-propylcyclobutyl, 1-
Butylcyclobutyl, 1-pentylcyclobutyl, 1-hexylcyclobutyl, 2-methylcyclobutyl, 2-propylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl,
2,3,4-triethylcyclobutyl, cyclopentyl, cyclopentylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 2-cyclopentylpropyl, 3-cyclopentylpropyl, 2-pentylcyclopentyl, 2,2-dimethylcyclopentyl, 3-ethyl Cyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl, 3-tert-butylcyclopentyl, (1-methyl-3-propyl)cyclopentyl, (2-methyl-3-propyl)cyclopentyl, (2-methyl-4-propyl) Cyclopentyl, cyclohexyl, cyclohexylmethyl, 1
-Cyclohexylethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, (1-methyl-2-cyclohexyl)ethyl, 2-cyclohexylpropyl, (1-methyl-1-cyclohexyl)ethyl, 4-cyclohexylbutyl, 3-
Ethylcyclohexyl, 3-isopropylcyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-propylcyclohexyl, 4-tert-butylcyclohexyl, 2,6-
Dimethylcyclohexyl, 2,2-dimethylcyclohexyl, (2,6-dimethyl-4-propyl)
These include cyclohexyl, 1-methylcyclohexyl, cycloheptyl, cycloheptylmethyl, 1-cycloheptylethyl, and 2-cycloheptylethyl groups, and a more preferred -R3 _- ^R4 group is a pentyl group. According to the present invention, the epithiocyclohexane-type prostaglandin analog compound represented by the general formula () has the general formula (In the formula, R ^2a represents a hydrogen atom, a hydroxyl group, or an acyloxy group, R ₅ represents a hydrogen atom, or a [formula] group (wherein, Q represents an oxygen or sulfur atom, and R ⁷ has 1 to 1 carbon atoms. 4 represents an alkyl group or a phenyl group), R ⁶ represents an alkylsulfonyl group or an arylsulfonyl group, and the other symbols have the same meanings as above.] A compound represented by the above is subjected to a cyclization reaction. The cyclization reaction is carried out in the presence of a base, such as an alkali metal hydroxide such as sodium, potassium, or lithium, a carbonate, or an alkoxide having 1 to 4 carbon atoms in an inert organic solvent such as methanol or ethanol. Alkanols having 1 to 4 carbon atoms such as diethyl ether, tetrahydrofuran, dioxane, 1,2-
Ethers such as dimethoxyethane, dialkyl sulfoxides such as dimethyl sulfoxide, N,N
- in a dialkylformamide such as dimethylformamide, or a mixed solvent of two or more thereof, -20
C. to the reflux temperature of the reaction solvent, preferably from room temperature to the reflux temperature of the reaction solvent. The compounds represented by the general formula (), that is, the compounds represented by the general formulas (A) and (B), can be obtained by a series of reaction steps shown in the following scheme A. In the formula, R ^1a represents an alkyl group having 1 to 12 carbon atoms, R ^2b represents a hydrogen atom or an acyl group,
R ⁸ represents a hydroxyl protecting group that can be removed under acidic conditions, R ⁹ and R ¹⁰ both represent a hydrogen atom, or together represent an oxo group, and other symbols have the same meanings as above. . To explain scheme A, steps [a] and [i]
is carried out by subjecting it to an oxidation reaction that converts a hydroxyl group into an oxo group. The oxidation reaction that converts a hydroxyl group into an oxo group is well known, for example (a) "Organic Synthesis Chemistry Volume 1" edited by Tetsuji Kametani, published by Nankodo, pp. 176-206 (August 1, 1976);
or (b) “Compendium of Organic Synthetic” published by John Wiley & Sons, Inc. (USA).
Methods” Volume 1 (1971), Volume 2 (1974)
), Volume 3 (1977), Section 48 or 168
is described in detail. Particularly preferred oxidation under mild neutral conditions is, for example, dimethylsulfide-N-chlorosuccinimide complex, thioanisole-N-chlorosuccinimide complex, dimethylsulfide-chlorine complex, thioanisole-
Chlorine complexes, J.Amer.Chem.Soc., 94 ,
7586 (1971), dicyclohexylcarbodiimide-dimethylsulfoxide complex [J.Amer.
Chem.Soc., 87 , 5661 (1965)], pyridinium chlorochromate (C ₅ H ₅ NHCrO ₃ Cl)
[See Tetrahedron Letters, 2647 (1975)],
Sulfuric anhydride. Pyridine complex [J.Amer.Chem.Soc.,
89, 5505 (1967)], chromyl chloride [J.
Amer.Chem.Soc., 97 , 5929 (1975)], a chromium trioxide-pyridine complex (for example, Collins reagent), or Johns reagent. Step [b] is carried out by subjecting the oxo group to a reduction reaction that converts it into a hydroxyl group. Reduction reactions for converting oxo groups into hydroxyl groups are well known, and include, for example, inert organic solvents, lower alkanols such as methanol, ethanol, isopropanol, or ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, or the like. in a mixed solvent of two or more known reducing agents, such as sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, lithium tri-tert-butoxyaluminum hydride, lithium trimethoxyaluminum hydride, It is carried out at temperatures from room temperature to -78°C using sodium cyanoborohydride, potassium tri-sec-butylborohydride, lithium aluminum hydride-quinine complex, (-)-isobornyloxymagnesium iodide, etc. , or a method using the diisobornyloxyaluminum isopropoxide compound described in the specification of Japanese Patent Application No. 142283/1983 (Japanese Patent Application No. 76552/1983), Japanese Patent Application No. 62310/1983
The method using a diisobutyl (substituted phenoxy)aluminum compound described in the specification of No. 54-154739, and the hydrogenated 1,1-binaphthyl-2,2'-di A method using oxyaluminum lithium compound or J.
Amer.Chem.Soc., 94 , 8616 (1972). Since the obtained product is a mixture of the compound of general formula () and the compound of general formula (), it can be separated into each compound by conventional separation means, such as a thin layer of silica gel, a column, or high performance liquid chromatography. or may be reacted without separation. Step [c] is carried out by subjecting the 9α-hydroxy group to a reaction that inverts it to a 9β-hydroxy group. The reversal reaction can be carried out using an inert organic solvent, such as a hydrocarbon such as benzene or toluene, an ether such as diethyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, a halogenated hydrocarbon such as methylene chloride or dichloroethane, or the like. In a mixed solvent of two or more, the general formula (R ¹¹ ) ₃ P (wherein R ¹¹ is an alkyl group having 1 to 4 carbon atoms, or is unsubstituted or at least one alkyl group having 1 to 4 carbon atoms) phosphine compound represented by (representing a substituted phenyl group),
For example, triphenylphosphine or tolbutylphosphine, and the general formula R ¹² OOCN=NCOOR ¹² (wherein R ¹² represents an alkyl group having 1 to 4 carbon atoms).
Azodicarboxylic acid dialkyl ester represented by, for example, azodicarboxylic acid diethyl ester,
The presence of the general formula R ¹³ OH (where R ¹³ has 2 carbon atoms)
-5 represents an alkanoyl group, benzoyl group, p-phenylbenzoyl group or formyl group. ), such as formic acid, acetic acid, propionic acid, benzoic acid or p-phenylbenzoic acid, at temperatures from room temperature to 0°C. The obtained product is prepared using a water-miscible solvent such as dioxane, ether such as tetrahydrofuran, carbon number 1 to 4 such as methanol, ethanol, etc.
The reaction is carried out in an aqueous solution of a hydroxide or carbonate of an alkali metal such as sodium, potassium, or lithium in the presence of an alkanol, usually at room temperature, or using potassium carbonate in an anhydrous alkanol having 1 to 4 carbon atoms such as anhydrous methanol or ethanol. The compound is converted into a compound represented by the general formula (2) by saponification at a temperature from 0°C to the reflux temperature of the reaction solvent, preferably from room temperature to 60°C. Step [d] is an inert organic solvent such as methanol, in the presence of a hydrogenation catalyst such as palladium on carbon, palladium black, or platinum dioxide in a hydrogen atmosphere.
Alkanols having 1 to 4 carbon atoms such as ethanol,
Alternatively, the reaction may be carried out in ethyl acetate at room temperature to the reflux temperature of the reaction solvent under normal pressure or under a hydrogen pressure of 15 kg/cm ² from atmospheric pressure. Step [e] is carried out by subjecting it to a sulfonylation reaction. The sulfonylation reaction is carried out using an alkylsulfonyl halide, such as methanesulfonyl chloride, ethanesulfonyl chloride, or an arylsulfonyl halide, such as benzenesulfonyl, in the presence of an inert organic solvent, such as methylene chloride, pyridine, triethylamine, or a tertiary amine such as pyridine. chloride, p-toluenesulfonyl chloride,
The test is carried out at temperatures between -30°C and 50°C. Step [f] is carried out in an inert organic solvent, such as dimethyl sulfoxide or a mixed solvent of dimethyl sulfoxide and 1,2-dimethoxyethane, using the general formula [Formula] (wherein R ⁷ and Q represent the same meanings as above). ) from 0℃ using the compound shown in
It is carried out at a temperature of 50°C. Step [g] is carried out by subjecting the OR ⁸ group (R ⁸ in the group has the same meaning as above) to a reaction to convert it into a hydroxyl group. The reaction of converting the ^OR8 group into a hydroxyl group is well known and is usually carried out under mild acidic conditions. For example, the reaction may be carried out (1) in an aqueous solution of an organic acid such as acetic acid, propionic acid, oxalic acid, p-toluenesulfonic acid, or in an aqueous solution of an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, preferably miscible with water; organic solvents such as methanol, alkanols having 1 to 4 carbon atoms such as ethanol, preferably methanol, or 1,2-
(2) in the presence of an organic acid such as p-toluenesulfonic acid, trifluoroacetic acid, anhydrous methanol, ethanol, etc. in anhydrous alkanol having 1 to 4 carbon atoms at a temperature of 0°C to 45°C, or (3) in the presence of p-toluenesulfonic acid-pyridine complex or trifluoroacetic acid-pyridine complex, in anhydrous alkanol having 1 carbon number, such as anhydrous methanol or ethanol. ~4
in anhydrous alkanol at temperatures from 10°C to 60°C. Preferred examples include a mixture of dilute hydrochloric acid and tetrahydrofuran, a mixture of dilute hydrochloric acid and methanol, a mixture of acetic acid, water and tetrahydrofuran, a mixture of phosphoric acid, water and tetrahydrofuran, a mixture of p-toluenesulfonic acid and methanol, and p-toluene. This is carried out using a mixture of a sulfonic acid-pyridine complex and methanol, and a mixture of a trifluoroacetic acid-pyridine complex and methanol. Step [h] is carried out by silylating the primary hydroxyl group, converting the secondary hydroxyl group into an OR ⁸ group, and then subjecting it to a reaction to remove the silyl group. The silylation reaction is carried out from room temperature using a suitable silylating agent such as trimethylsilyl chloride, trimethylsilyldiethylamine, triphenylsilyl chloride in the presence or absence of pyridine or triethylamine in an inert organic solvent such as methylene chloride, acetone. It is carried out at a temperature of 30°C. The conversion reaction from hydroxyl group to ^OR8 group is carried out in an inert organic solvent such as methylene chloride, chloroform, diethyl ether, using a condensing agent such as p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, trifluoroacetic acid, trifluoroborane-etherate, In the presence of phosphorus oxychloride, camphorsulfonic acid, 2,3-dihydropyran, 2,3-dihydrofuran, 2,3-
dihydrothiopyran, ethyl vinyl ether,
It is carried out at temperatures ranging from room temperature to -30°C using 2-methoxypropene, 1-methoxycyclohexene, α-methoxystyrene, or the like. The desilylation reaction is carried out using water, potassium fluoride, or an acid, such as oxalic acid, in the presence or absence of an inert solvent such as ethyl acetate, hexamethylphosphamide, at temperatures from room temperature to 60°C. It will be done. Process [j] is the general formula [In the formula, R ¹⁴ represents an alkyl group having 1 to 4 carbon atoms, preferably a methyl or ethyl group, and other symbols have the same meanings as above. ] Sodium derivative of dialkylphosphonate (general formula (
) manufactured from dialkylphosphonate and sodium hydride], or the general formula [In the formula, R ¹⁵ is unsubstituted or has 1 to 1 carbon atoms
4 represents a phenyl group, preferably a phenyl group, or an alkyl group having 1 to 6 carbon atoms, preferably a butyl or hexyl group, or a cyclohexyl group, and other symbols have the same meanings as above. represent ] A phosphorane compound represented by the general formula (R ¹⁵ ) ₃ P=CH-CH ₂ -R ³ -R ⁴ (XI) [wherein, all symbols have the same meanings as above. ] This is carried out by subjecting a phosphorane compound represented by the following to Wittig reaction. The Wittig reaction is well known, e.g.
It is described in "Organic Reactions", Volume 14, Chapter 3 (1965), published by John Wiley & Song, Inc. (USA). Preferred Wittig reactions are carried out using inert organic solvents such as diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, xylene, hexane, dialkyl sulfoxides such as dimethyl sulfoxide, N,N
- Dialkylformamide such as dimethylformamide, methylene chloride, halogenated hydrocarbon such as chloroform, alkanol having 1 to 4 carbon atoms such as methanol, ethanol, or a mixed solvent of two or more thereof in a solvent ranging from -78°C to the reflux temperature of the reaction solvent. It will be held in When the Wittig reaction is carried out using the Wittig reagents represented by the general formulas () and (), a trans-enone form is stereospecifically formed, but when the Wittig reagent shown by the general formula () is used forms a mixture of trans- and cis-isomers, and the desired trans-isomer can be obtained by separation using conventional separation means, such as a thin layer of silica gel, a column, or high performance liquid chromatography. Wittig reagents of the general formulas (), () and () are well known or can be obtained by known methods. In step [k], when R ⁹ and R ¹⁰ are combined to represent an oxo group, the double bond of the enone is optionally reduced, and then the oxo group is converted to the oxo group in the above-mentioned step [b].
It is carried out by reducing the hydroxyl group under the following conditions and then subjecting the obtained hydroxyl group to an acylation reaction, and R ⁹ and R ¹⁰
When both represent hydrogen atoms, the double bond may be catalytically reduced under the conditions of step [d] described above, if desired. The double bond of enone can be reduced by a known method, for example _, lithium 1-pentylhydrocuprate [LiCuH-C≡C- _C3H7 ] [J.Amer..Chem.Soc.,
96, 3686 (1974)]. Acylation is carried out by reacting the corresponding acyl chloride or acid anhydride in an inert organic solvent, for example methylene chloride, pyridine, in the presence of a tertiary amine such as triethylamine, pyridine, at a temperature below room temperature, preferably at a temperature below 0°C. It is done using Step [l] is carried out using the saponification conditions of step [c] described above. The protecting group for the hydroxyl group that can be removed under acidic conditions as shown in ^R8 may be any protecting group that does not affect other parts of the compound upon removal and that can be easily removed under mild conditions. . Such protecting groups include, for example, (1) a heterocyclic group such as a tetrahydropyran-2-yl group, a tetrahydrofuran-2-yl group, a tetrahydrothiopyran-2-yl group, or (2) a 1-ethoxyethyl group, 1-methoxy-1-
Examples include ether groups such as methylethyl group, 1-methoxycyclohexyl group, and 1-methoxy-1-phenylethyl group, and a preferred protecting group is tetrahydropyran-2-yl group. When R ^2a and R ^2b represent an acyloxy group, examples of the acyl group include an acetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a trifluoroacetyl group, a propionyl group,
Butyryl group, isobutyryl group, benzoyl group, p
Examples include -phenylbenzoyl group and naphthyloyl group, and a preferred acyl group is acetyl group. The starting material represented by the general formula () can be obtained by a series of reaction steps shown in the following scheme B. In the formula, all symbols have the same meanings as above. To illustrate Scheme B, step [m] is carried out using sodium cyanide or potassium cyanide in dimethylsulfoxide or hexamethylphosphamide at a temperature between room temperature and 60°C, and step [n] is carried out in the presence of an aqueous potassium bicarbonate solution. It is carried out at room temperature using potassium triiodide. Step [o] is a known dehydriodination reagent, such as 1,5-diazabicyclo[5.4.0]undecene-5 (DBU), 1,5-
Diazabicyclo [4.3.0] Nonene-5 (DBN), 1,
Bicyclic amines such as 4-diazabicyclo[2.2.2]octane (DABCO), or alkali metals with 1 carbon number such as sodium and potassium
-4 alkoxides, such as sodium methoxide, potassium tert-butoxide, in the presence or absence of inert organic solvents such as toluene, benzene, dimethyl sulfoxide, dioxane when using bicyclic amines; When using , the reaction is carried out in an alkanol having 1 to 4 carbon atoms such as methanol, tert-butanol, or N,N-dimethylformamide at a temperature of from room temperature to 110°C, preferably at a temperature of from room temperature to 80°C. Step [p] is carried out using sodium methoxide in methanol under ice cooling, and step [q] is carried out using sodium methoxide in methanol.
This is carried out using the conditions for converting a hydroxyl group into an OR ⁸ group in step [h] described above. Step [r] is carried out under the conditions of step [g] and then carried out using an aqueous solution of sodium or potassium hydroxide in ethanol at the reflux temperature of the reaction solvent, and step [s] is carried out using tributyltin hydride in benzene. This is carried out in the presence of azobisisobutyronitrile at room temperature by irradiation with light from a high-pressure mercury lamp, and step [t] is carried out using diisobutylaluminum hydride in toluene at a temperature below -60°C. Process [u]
is the general formula (R ¹⁵ ) ₃ P−CH ₂ −(CH ₂ )m−COOH・X
() [In the formula, X represents a halogen atom, and the other symbols have the same meanings as above. This is carried out by subjecting the ylide of the phosphonium compound represented by ] to the Wittig reaction, and then esterifying the obtained carboxylic acid by a known method (see esterification below). The Wittig reaction is carried out using the conditions of the above-mentioned step [j], but in particular, the cis-
in dimethyl sulfoxide to obtain a double bond.
It is carried out at temperatures between 10°C and 60°C. Ylide is a phosphonium compound represented by the general formula () with a suitable base such as butyl lithium, lithium diisopropylamide, dimsyl sodium, sodium methoxide, potassium tert-butoxide,
Obtained by reaction in the presence of triethylamine. The phosphonium compound represented by the general formula () is known per se or can be obtained by a known method. The starting material represented by formula () is (E)-3-
It is obtained using methyl formyl acrylate and 1,3-butane diene according to the method described in Can. J. Chem., 54 , 3304 (1976). A carboxylic acid represented by the general formula () in which R ¹ represents a hydrogen atom and the other symbols have the same meanings as above, that is, the general formula [In the formula, R ² , R ³ and R ⁴ have the same meanings as above. ] The carboxylic acid represented by is the corresponding ester represented by the general formula () in which R ¹ represents something other than a hydrogen atom, and the other symbols have the same meanings as above, i.e., the general formula [In the formula, R ^1a , R ² , R ³ and R ⁴ have the same meanings as above. ] It can be obtained by saponifying the ester represented by the following using a known method. For example, John explains how to saponify
"Compenpium of Organic Synthetic" published by Wiley & Sons, Inc. (USA)
Methods” Volume 1 (1971), Volume 2 (1974),
Volume 3 (1977), section 23, preferred saponifications include sodium, potassium,
Alkali metals such as lithium, or calcium,
Using an aqueous solution of an alkaline earth metal hydroxide or carbonate, such as barium, the presence of a water-miscible solvent, such as an ether, such as dioxane, tetrahydrofuran, or an alkanol containing 1 to 4 carbon atoms, such as methanol or ethanol. The reaction is carried out at a temperature of -10°C to 100°C, preferably at room temperature, or using a hydroxide or carbonate of an alkali metal such as sodium, potassium, or lithium in the presence or absence of carbon atoms such as anhydrous methanol or ethanol. The reaction is carried out in anhydrous alkanol of 1 to 4 at a temperature of -10 DEG C. to 100 DEG C., preferably at room temperature. Esters represented by the general formula () in which R ¹ represents an atom other than a hydrogen atom and other symbols have the same meanings as above, that is, the general formula [In the formula, each symbol represents the same meaning as above. ] In the ester represented by R ¹ represents a hydrogen atom,
Other symbols have the same meanings as above. General formula ()
The corresponding carboxylic acid with the general formula [In the formula, each symbol represents the same meaning as above. ] It is obtained by esterifying the carboxylic acid represented by the following using a known method. Methods for esterifying carboxylic acids are well known, such as (1) a method using a diazoalkane, (2) a method using an N,N-dimethylformamide dialkyl acetal [Helu.Chim.Acta,
48, 1746 (1965)], (3) method using alkyl halide, (4) method using dicyclohexylcarbodiimide [see Japanese Patent No. 762305 specification], (5) method using pivaloyl halide [Japan (6) Method using alkylsulfonyl halide or arylsulfonyl halide [Japanese Patent No. 756972]
759351], (7) a method using isobutyl chloroformate [see British Patent No. 1492439], (8) a method using dipyridyl sulfide and triphenylphosphine [Tetrahedron Letters,
3409 (1976)]. Esterification using a diazoalkane is carried out using the corresponding acid and a suitable diazoalkane in an inert organic solvent such as diethyl ether, ethyl acetate, methylene chloride, acetone, methanol, or a mixture of two or more thereof, starting at room temperature. -10℃ temperature,
Preferably it is carried out at 0°C. Esterification with N,N-dimethylformamide-dialkyl acetals is carried out using the corresponding acid in anhydrous benzene and a suitable N,N-dimethylformamide-dialkyl acetal, e.g. It is carried out at a temperature of °C. ∴ Esterification with alkyl halides is performed using the corresponding acid and a suitable alkyl halide, such as methyl iodide, butyl bromide, decyl bromide (i) carbonate of an alkali metal such as sodium or potassium in acetone. In the presence [J.Org.Chem., 34 ,
3717 (1969)], (ii) N,N-dimethylacetamide or N,N-
(iii) In the presence of an alkali metal bicarbonate such as sodium or potassium in dimethylformamide [see Advan.Org, Chem., 5 , 37 (1965)], (iii) In the presence of calcium oxide in dimethyl sulfoxide [Synthesis, 262 (1972)] ], (iv) N,N.dimethylacetamide or N,N-
In the presence of tetramethylammonium hydroxide in dimethylformamide [Synthetic
Comm., 2 , 215 (1972)] It is carried out at a temperature between room temperature and 0°C. Esterification with dicyclohexylcarbodiimide is carried out using the corresponding acid and a suitable alcohol in the presence of a base such as pyridine, picoline, preferably pyridine, in an inert organic solvent, such as chloroform, a halogenated hydrocarbon such as methylene chloride, at room temperature. It is carried out at temperatures ranging from 0°C to 0°C. Esterification using pivaloyl halide, alkylsulfonyl halide, arylsulfonyl halide or isobutyl chloroformate can be carried out using inert organic solvents such as chloroform, halogenated hydrocarbons such as methylene chloride, diethyl ether,
Acids corresponding to tertiary amines such as triethylamine, pyridine, in the presence or absence of ethers such as tetrahydrofuran, and pivaloyl halides such as pivaloyl chloride, alkylsulfonyl halides such as methanesulfonyl chloride, ethanesulfonyl chloride, An arylsulfonyl halide, such as benzenesulfonyl chloride, p-toluenesulfonyl chloride, or isobutyl chloroformate, is reacted to form a mixed acid anhydride, then a suitable alcohol is added and the temperature is reduced from room temperature to 0.
It is carried out at a temperature of °C. The esterification with dipyridyl disulfide and triphenylphosphine is carried out using the corresponding acid and a suitable alcohol in an inert organic solvent such as toluene, benzene, xylene at temperatures from room temperature to 80°C. The cyclodextrin inclusion compound of the epithiocyclohexane type prostaglandin analog compound represented by the general formula () is α-, β- or γ-
It can be obtained by the method described in Japanese Patent Publication Nos. 50-3362 and 52-31404 using cyclodextrin or a mixture thereof. The stability of the prostaglandin-like compound represented by the general formula () is increased by converting it into a cyclodextrin clathrate. The acid represented by the general formula () in which R ¹ represents a hydrogen atom is converted into a salt by a known method. Preferably, the salt is a non-toxic salt. A non-toxic salt is one that is relatively non-toxic to animal tissue and that, when used in the amount necessary for treatment, the effective pharmacological properties of the compound represented by the general formula () are not affected by the side effects caused by the cation. Refers to cationic salts that are not damaged by oxidation. Preferably the salt is water soluble. Suitable salts include, for example, alkali metal salts such as sodium, potassium, alkaline earth metal salts such as calcium, magnesium, ammonium salts, and pharmaceutically acceptable (non-toxic) amine salts. Suitable amines that form such salts with carboxylic acids are well known and include, for example, amines that could theoretically be obtained by replacing one or more hydrogen atoms of ammonia with other groups. The groups may be the same or different when one or more hydrogen atoms are substituted, and are selected from, for example, alkyl groups having 1 to 6 carbon atoms and hydroxyalkyl groups having 2 or 3 carbon atoms. Suitable non-toxic amine salts include salts of tetraalkylammonium such as tetramethylammonium, and methylamine,
Examples include salts of organic amines such as dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, lysine, and arginine. The salt is obtained by preparing the acid represented by the general formula () by a known method.
For example, by reacting an acid represented by the general formula () with a suitable base, such as an alkali metal or alkaline earth metal hydroxide or carbonate, ammonium hydroxide, ammonia, or an organic amine in a stoichiometric amount in a suitable solvent. can get. The salt can be lyophilized from the solution or, if sufficiently insoluble in the reaction solvent,
It can be isolated by filtration or, if necessary, by filtration after removing a portion of the solvent. The compound of the present invention represented by the general formula () has the activity of inhibiting the biosynthesis of thromboxane _A2 , and therefore, when it is desired to control the biosynthesis of thromboxane _A2 in mammals including humans. is useful for its control. For example, in a laboratory experiment, (5Z, 13E) - (9α, 11α, 15S) - 9, 11 -
Epithio-15-hydroxy-11a-homoprost-5,13-dienoic acid and (5Z,13E)-(9α,
11α,15R)-9,11-epithio-15-hydroxy-11a-homoprosta-5,13-dienoic acid inhibited rabbit platelet thromboxane-synthetase at 1.4×10 ^-7 and 3.0×10 ^-7 molar concentrations, respectively. 50% inhibition. Controlling thromboxane _A2 biosynthesis can prevent inflammation, hypertension, thrombosis, cerebral palsy, asthma, myocardial infarction, angina pectoris, cerebral infarction, and acute cardiac death in mammals, including humans, especially humans. It is useful for treatment. Preferred epithiocyclohexane-type prostaglandin analogue compounds included in the present invention include (5Z, 13E)-(9α, 11α, 15α)-9,11-epithio-15-hydroxy-11a-homoprosta-5,
13-dienoic acid, (5Z,13E)-(9α,11α)-9,11-epithio-
11a-Homoprosta-5,13-dienoic acid, (13E)-(9α,11α,15α)-9,11-epithio-
15-hydroxy-11a-homoprost-13-enoic acid, (13E)-(9α,11α)-9,11-epithio-11a-
Homoprost-13-enoic acid, (9α,11α,15α)-9,11-epithio-15-hydroxy-11a-homoprostanic acid, (9α,11α)-9,11-epithio-11a-homoprostanic acid, (5Z) -(9α, 11α, 15α)-9,11-epithio-15
-Hydroxyprost-5-enoic acid, (5Z,13E)-(9α,11α,15β)-9,11-epithio-15-hydroxy-11a-homoprost-5,
13-dienoic acid, (13E)-(9α, 11α, 15β)-9,11-epithio-
15-hydroxy-11a-homoprost-13-enoic acid, (9α, 11α, 15β)-9,11-epithio-15-hydroxy-11a-homoprostanic acid, their esters, and their cyclodextrin clathrates and non-toxic salts. Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples, but the present invention is not limited to these Examples. In addition, "TLC" in reference examples and examples,
The symbols “IR,” “NMR,” and “MS” stand for “thin layer chromatography,” “infrared absorption spectrum,” respectively.
"Nuclear Magnetic Resonance Spectrum" and "Mass Spectrometry" and the proportion of solvent described in the section of separation by chromatography indicates the volume ratio,
The solvent inside the “TLC” box indicates the developing solvent.
"IR" is measured by the liquid film method unless otherwise specified, and "NMR" is measured using a deuterated chloroform (CDCl ₃ ) solution unless otherwise specified. Example 1 (5Z, 13E)-(9α, 11α, 15α)-9,11-epithio-15-hydroxy-11a-homoprosta-
5,13-dienoic acid methyl ester 0.065 ml of a 28% methanol solution of sodium methoxide was added dropwise to 70 mg of the product of Reference Example 27 (described below) dissolved in 1.5 ml of methanol, and the mixture was stirred at 55°C for 30 minutes. The reaction solution was treated with acetic acid and saturated aqueous sodium hydrogen carbonate solution under ice cooling, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (6:1) as an eluent to obtain 46 mg of the title compound having the following physical properties. TLC (cyclohexane: ethyl acetate = 4:1):
Rf=0.23. IR: ν=3450, 1745, 975 cm ^-1 . NMR: δ=5.69−5.53 (2H, m), 5.46−5.29
(2H, m), 4.19−4.00 (1H, m), 3.68 (3H, s),
3.58-3.19 (3H, m), 3.02-2.70 (1H, m), 2.30
(2H, t), 0.89 (3H, m). Ms: m/e=380, 362, 349, 329, 321, 309. The following compound was obtained in the same manner. (a) From the product of Reference Example 27(a) (5Z, 13E) − (9α,
11α,15β)-9,11-epithio-15-hydroxy-11a-homoprosta-5,13-dienoic acid methyl ester was obtained. TLC (cyclohexane: ethyl acetate = 4:1):
Rf = 0.28. IR: ν=3450, 1745, 975 cm ^-1 . NMR: δ=5.69−5.54 (2H, m), 5.47−5.32
(2H, m), 4.20−3.96 (1H, m), 3.68 (3H, s),
3.55-3.19 (3H, m), 3.02-2.70 (1H, m), 2.31
(2H, t), 0.90 (3H, m). MS: m/e=380, 362, 349, 329, 309. Example 2 (5Z, 13E)-(9α, 11α, 15α)-9,11-epithio-15-hydroxy-11a-homoprosta-
5,13-dienoic acid Product of Example 1 dissolved in 0.6 ml of ethanol
Drop 0.6ml of 5% potassium hydroxide aqueous solution to 42mg,
Stir for 30 minutes at 40°C. PH the reaction solution with 1N hydrochloric acid
2, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (4:1) as an eluent to obtain 38 mg of the title compound having the following physical properties. TLC (benzene: ethyl acetate = 2:1): Rf =
0.29. IR: ν=3400, 2970, 2930, 2860, 1707, 1240,
980 cm ^-1 . NMR: δ=5.72−5.55 (2H, m), 5.50−5.28
(2H, m), 5.27-5.00 (1H, m), 4.28-4.06
(1H, m), 3.61-3.22 (3H, m), 3.02-2.70
(1H, m), 2.34 (2H, t), 0.90 (3H, m). MS: m/e=366,348. The following compound was obtained in the same manner. (a) From the product of Example 1(a) (5Z, 13E)-(9α,
11α,15β)-9,11-epithio-15-hydroxy-11a-homoprosta-5,13-dienoic acid was obtained. TLC (benzene: ethyl acetate = 2:1): Rf =
0.32. IR: ν=3370, 2960, 2930, 2850, 1705, 1240,
980 cm ^-1 . NMR: δ=5.67−5.51 (2H, m), 5.50−4.91
(4H, m), 4.28-4.04 (1H, m), 3.50-3.25
(2H, m), 2・97−2.70 (1H, m), 2.33 (2H,
t), 0.89 (3H, m). MS: m/e=366,348. Reference Example 1 Methyl trans-2-formyl-4-cyclohexenecarboxylate (E) 1,3-butadiene gas was added to a mixture of 209 mg of methyl 3-formyl acrylate, 6 ml of methylene chloride, and 0.21 ml of tin chloride under ice cooling. was bubbled in for 1 hour, the reaction solution was poured into ice water, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate,
Concentrate under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (10:1) as an eluent to obtain 217 mg of the title compound having the following physical properties. IR: ν=2730, 1735, 1660 cm ^-1 . NMR: δ=9・725 (1H, d), 5.72 (2H, m),
3.72 (3H, s), 3.05−2.74 (2H, m), 2.35 (4H,
m). Ms: m/e=168. Reference Example 2 Methyl trans-2-hydroxymethyl-4-cyclohexenecarboxylate A mixture of 201 mg of the compound obtained in Reference Example 1, 181 mg of sodium borohydride, and 5 ml of methanol was stirred at -40°C for 10 minutes, and acetic acid was added at the same temperature. Acidify to PH5 using a solution and concentrate under reduced pressure. The residue is dissolved in ethyl acetate, washed with water, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was used as an eluent in a mixture of cyclohexane and ethyl acetate (1:1).
Purification by silica gel column chromatography using 154 mg of the title compound having the following physical properties was obtained. IR: ν=3450, 1740, 1660 cm ^-1 . Ms: m/e=170, 152, 139, 138. Reference example 3 trans-2-methanesulfonyloxy-4-
Methyl cyclohexenecarboxylate Product of Reference Example 2 dissolved in 3 ml of methylene chloride
-25 0.10ml of methanesulfonyl chloride to 150mg
Add dropwise at ℃, then add 0.184 ml of triethylamine at the same temperature, and stir at -25℃ for 15 minutes. The reaction solution was diluted with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 228 mg of the title compound having the following physical properties. IR: ν=1735, 1360, 1180, 950, 840 ^{cm -1} . NMR: δ=5.69 (2H, m), 4.21 (2H, d), 3.73
(3H, s), 3.01 (3H, s). Ms: m/e=248, 217, 152. Reference Example 4 Methyl trans-2-cyanomethyl-4-cyclohexenecarboxylate A mixture of 55 g of the product of Reference Example 3, 500 ml of hexamethylphosphamide, and 16.3 g of sodium cyanide was stirred at 60°C for 1 hour. The reaction solution is poured into ice water and extracted with ethyl acetate. The extract is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (8:1) as an eluent to obtain 33 g of the title compound having the following physical properties. IR: ν=2270, 1740, 1660 cm ^-1 . NMR: δ = 5.19 (2H, m), 3.74 (3H, s). MS: m/e=179, 164, 148. Reference Example 5 Trans-2-cyanomethyl-4-cyclohexenecarboxylic acid 114 mg of the product of Reference Example 4, 2.5 ml of ethanol, 5
Stir the mixture of 2.5 ml of % potassium hydroxide aqueous solution at room temperature for 30 minutes and concentrate under reduced pressure. The residue is dissolved in water, acidified to PH1 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 108 mg of the title compound having the following physical properties. IR: ν=3200, 2260, 1705 cm ^-1 . MS: m/e=165. Reference example 6 2-iodo-4-syn-cyanomethyl-7-oxycys-bicyclo[3.2.1]octane-
6-one 2 g of the product of Reference Example 5, potassium bicarbonate 7.2
Potassium triiodide solution (prepared from 6.15 g of iodine, 12.0 g of potassium iodide, and 33 ml of water) was added dropwise to a mixed solution of 26 ml of water and 6.15 g of iodine under ice cooling, and the mixture was stirred at room temperature for 6 hours. Add sodium sulfite and sodium chloride to the reaction solution, extract with ethyl acetate, dry the extract over anhydrous sodium sulfate, and concentrate under reduced pressure. Using the residue as an eluent, a mixture of benzene and ethyl acetate (8:
When purified by silica gel column chromatography using 1), 26 g of the title compound having the following physical properties were obtained.
was gotten. IR: ν=2250, 1790cm ^-1 . NMR: δ = 4.93 (1H, dd), 4.49−4.30 (1H,
m). MS: m/e=291,164. Reference example 7 4-syn-cyanomethyl-7-oxa-cis-
Bicyclo [3.2.1] Oct-2-en-6-one Product of Reference Example 6 31 dissolved in 300 ml of benzene
20.6 ml of 1,5-diazabicylo[5.4.0] undecene-5 (DBU) was added dropwise to the solution and stirred at room temperature for 1.5 hours. Pour the reaction solution into ice water containing 1N hydrochloric acid, extract with ethyl acetate, wash the extract with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. Using the residue as eluent, a mixture of benzene and ethyl acetate (4:1)
Purification by silica gel column chromatography using silica gel column chromatography gave 14.4 g of the title compound having the following physical properties. IR: ν=2250, 1780, 1635 cm ^-1 . NMR: δ=6.43 (1H, dd), 5.81 (1H, d), 4.83
(1H.t), 2.96 (1H, m), 2.91 (1H, m). MS: m/e=163. Reference Example 8 Methyl 2α-cyanomethyl-5β-hydroxy-3-cyclohexene-1β-carboxylate Product of Reference Example 7 dissolved in 200 ml of methanol
Add 5.72 g of sodium methoxide dissolved in 50 ml of methanol to 14.4 g over 20 minutes while cooling on ice, and stir at the same temperature for 30 minutes. Add 65 ml of acetic acid to the reaction solution dropwise and concentrate under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (1:1) as an eluent to obtain 17.3 g of the title compound having the following physical properties. IR: ν=3430, 2250, 1735, 1655 ^{cm -1} . NMR: δ=5.93 (1H, d), 5.65 (1H, dt), 4.36
(1H, bs), 3.75 (3H, s). MS: m/e=195, 177, 136, 118. Reference example 9 2α-cyanomethyl-5β-(tetrahydropyran-2-yloxy)-3-cyclohexene-1β
-Methyl carboxylate 1 g of the product of Reference Example 8, 10 ml of methylene chloride, p
- Stir a mixture of 17.6 mg of toluenesulfonic acid and 0.60 ml of 2,3-dihydropyran for 20 minutes under ice cooling. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (4:1) as an eluent to obtain 1.30 g of the title compound having the following physical properties. IR: ν=2270, 1745, 1660 cm ^-1 . NMR: δ=6.08−5.83 (1H, m), 5.64 (1H,
dt), 4.76 (1H, m), 4.40 (1H, ds), 3.74 (3H,
s). MS: m/e=279, 248, 195, 178. Reference example 10 2α-cyanomethyl-5β-(tetrahydropyran-2-yloxy)-3-cyclohexene 1β-
Carboxylic acid In the same manner as Reference Example 5, the product of Reference Example 9 1.30
The title compound 1.2 from the ester has the following physical properties:
g was obtained. TLC (benzene: ethyl acetate = 2:1): Rf =
0.17. Reference example 11 1β-hydroxymethyl-2α-cyanomethyl-
5β-(tetrahydropyran-2-yloxy)
-3-Cyclohexene To 200 mg of the product of Reference Example 10 dissolved in 5 ml of diethyl ether, 0.126 ml of traethylamine was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. Add 0.079 ml of ethyl chloroformate dropwise to this solution under ice cooling, and incubate for 30 minutes at the same temperature.
Stir for a minute. The reaction solution was filtered through a layer of magnesium sulfate, and the solution was concentrated under reduced pressure. Add 5 ml of ethanol and 114 mg of sodium borohydride to the residue.
Add under ice-cooling and stir at the same temperature for 20 minutes. The reaction solution was acidified to pH 5 with acetic acid and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (1:1) as an eluent to obtain 148 mg of the title compound having the following physical properties. IR: ν=3450, 2255, 1660 cm ^-1 . NMR: δ=6.10−5.84 (1H, m), 5.80−5.59
(1H, m), 4.78 (1H, m), 4.30 (1H, bs). MS: m/e=251, 233, 167, 150, 132. Reference example 12 1β-tetrahydropyran-2-yloxy)
Methyl-2α-cyanomethyl-5β-(tetrahydropyran-2-yloxy)-3-cyclohexene The product 132 of Reference Example 11 was prepared in the same manner as in Reference Example 9.
156 mg of the title compound having the following physical properties was obtained. IR: ν=2255, 1660 cm ^-1 . NMR: δ=6.07−5.84 (1H, m), 5.74−5.65
(1H, m), 4.77 (1H, m), 4.56 (1H, m), 4.50
−4.27 (1H, m). Ms: m/e=335, 251, 234, 132. Reference example 13 1β-(tetrahydropyran-2-yloxy)
Methyl-2α-carboxymethyl-5β-(tetrahydropyran-2-yloxy)-3-cyclohexene 148 mg of the product of Reference Example 12, 2 ml of ethanol, 10
% sodium hydroxide aqueous solution at 100℃.
Stir overnight and concentrate under reduced pressure. The residue was dissolved in water, acidified to pH 5 with acetic acid, extracted with ethyl acetate, the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 156 mg of the title compound having the following physical properties. It was done. IR: ν=3220, 1718, 1615 cm ^-1 . MS: m/e=270, 253. Reference example 14 2-oxane-6-syn-(tetrahydropyran-2-yloxy)methyl-8-syn-(tetrahydropyran-2-yloxy)-9-iodo-cis-bicyclo[4.3.0]nonane-3-
13g of the product of Reference Example 13 in the same manner as Reference Example 6
15.4 g of the title compound having the following physical properties were obtained. IR: ν=1795cm ^-1 . NMR: δ=4.93 (1H, m), 4.84−4.65 (1H,
m), 4.56 (1H, m), 2.67 (1H, m). MS: m/e=480,395. Reference example 15 2-oxa-6-syn-(tetrahydropyran-2-yloxy)methyl-8-syn-(tetrahydropyran-2-yloxy)-cis-bicyclo[4.3.0]nonan-3-one Reference example 14 A mixture of 15.4 g of the product, 70 ml of benzene, 11.03 ml of tributyltin hydride, and 872 mg of azobisisobutyronitrile was stirred at room temperature for 30 minutes while irradiated with light from a high-pressure mercury lamp. Add 140 ml of saturated aqueous sodium carbonate solution to the reaction solution and stir at room temperature for 3 hours. Dilute the reaction solution with benzene,
Wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (4:1) as an eluent to obtain 10.5 g of the title compound having the following physical properties. IR: ν=1785cm ^-1 . NMR: δ=4.79−4.61 (2H, m), 4.60−4.48
(1H, m). MS: m/e=354, 269, 253, 169. Reference example 16 2-oxa-6-syn-(tetrahydropyran-2-yloxy)methyl-8-syn-(tetrahydropyran-2-yloxy)-cis-bicyclo[4.3.0]nonan-3-ol in 150 ml of toluene Melted product of Reference Example 15
21 ml of a toluene solution of 25% (W/V) diisobutylaluminum hydride was added dropwise to 10.5 g at -78°C, and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was treated with aqueous methanol, filtered, and concentrated under reduced pressure to obtain 10.3 g of the title compound having the following physical properties. TLC (cyclohexane: ethyl acetate = 1:1):
R=0.33. Reference example 17 (Z)-2α-(6-methoxycarbonyl-2-
hexenyl)-3β-(tetrahydropyran-2
-yloxy)methyl-5β-(tetrahydropyran-2-yloxy)cyclohexane-1α
-ol A solution of dimyl sodium (prepared from 5.3 g of sodium hydride (content 64.1%) and 100 ml of dimethyl sulfoxide) was added dropwise to 31.5 g of 4-carboxybutyltriphenylphosphonium bromide dissolved in 100 ml of dimethyl sulfoxide at 25°C, and then Add 10.3 g of the product of Reference Example 16 dissolved in 10 ml of dimethyl sulfoxide, and stir at 25° to 45°C for 2 hours.
Pour the reaction solution into ice water, wash with a mixture of diethyl ether and ethyl acetate (2:1), acidify to pH 5 with a saturated aqueous oxalic acid solution, and extract with a mixture of diethyl ether and hexane (2:1). The solution is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diazomethane etherate was added to the residue under ice-cooling until the reaction mixture turned slightly yellow, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (1:1) as an eluent to obtain 12.4 g of the title compound having the following physical properties. IR: ν=3475, 1745 cm ^-1 . NMR: δ=5.52−5.34 (2H, m), 4.72 (1H,
m), 4.57 (1H, m), 3.67 (3H, s), 2.33 (2H,
t). MS: m/e=454, 370, 353, 352, 286, 268,
251. Reference example 18 (Z)-2α-(6-methoxycarbonyl-2-
hexenyl)-3β-(tetrahydropyran-2
-yloxy)methyl-5β-(tetrahydropyran-2-yloxy)cyclohexane-1-
On 3.6 g of the product of Reference Example 17, 30 ml of methylene chloride,
A mixture of 2.84 g of pyridinium chlorochromate is stirred at room temperature for 1.5 hours. The reaction solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (4:1) as the eluent to obtain the title compound having the following physical properties:
3.18g was obtained. IR: ν=1735, 1710cm ^-1 . NMR: δ=5.41−5.27 (2H, m), 4.82−4.51
(2H, m), 3.67 (3H, s), 2.33 (2H, t). MS: m/e=452, 368, 350, 284, 256. Reference example 19 (Z)-1αβ-methanesulfonyloxy-2α-
(6-methoxycarbonyl-2-hexenyl)-
3β-(tetrahydropyran-2-yloxy)
Methyl-5β-(tetrahydropyran-2-yloxy)cyclohexane In the same manner as Reference Example 2 and Reference Example 3, Reference Example 18
2.89 g of the title compound having the following physical properties were obtained from 3.18 g of the product. IR: ν=1745, 1360, 1180, 920 ^{cm -1} . NMR: δ=5.54−5.34 (2H, m), 4.81−4.44
(3H, m), 3.67 (3H, s), 3.03 (3H, s), 2.33
(2H, t). MS: m/e=268, 250. Reference example 20 (Z)-1αβ-acetylthio-2α-(6-methoxycarbonyl-2-hexenyl)-3β-(tetrahydropyran-2-yloxy)methyl-
5β-(tetrahydropyran-2-yloxy)
0.72 ml of S-thioacetic acid was added dropwise to 291 mg of sodium hydride (64.1% content) suspended in 6 ml of cyclohexane dimethyl sulfoxide, and the mixture was stirred at room temperature for 30 minutes. Here is a reference example dissolved in 3ml of dimethyl sulfoxide.
Add 690 mg of the product No. 19 dropwise and stir at 45°C for 24 hours. The reaction solution is poured into ice water and extracted with dimethyl ether. The extract is washed with water, a saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (8:1) as an eluent to obtain 400 mg of the title compound having the following physical properties. TLC (benzene:ethyl acetate=4:1):Rf=
0.59. Reference example 21 (Z)-1α-acetylthio-2α-(6-methoxycarbonyl-2-hexenyl)-3β-hydroxymethylcyclohexane-5β-ol 400 mg of the product of Reference example 20, 4 ml of methanol, pyridine-p-toluenesulfone Stir a mixture of 39 mg of acid complex at 60°C for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (1:4) as an eluent to obtain 156 mg of the title compound having the following physical properties. Melting point: 98℃. IR (KBγ tablet method): ν = 3360, 1730, 1688 cm ^-1 . NMR: δ=5.46−5.29 (2H, m), 4.12 (1H,
m), 4.03-3.78 (1H, m), 3.71-3.60 (5H, m),
3.67 (3H, s), 2.33 (3H, s). MS: m/e = 344, 326, 313, 301, 283. Reference example 22 (Z)-1α-acetylthio-2α-(6-methoxycarbonyl-2-hexenyl)-3β-hydroxymethyl-5β-(tetrahydropyran-2-
methylene chloride to a mixture of 41 mg of the product of Reference Example 21, 1 ml of methylene chloride, and 0.0182 ml of triethylamine.
Triphenylsilyl chloride dissolved in 0.3ml
Add 38.6 mg dropwise at -25°C and stir at the same temperature for 20 minutes. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add methylene chloride 0.5ml to the residue, 2,3
- Add 0.01 ml of dihydropyran and a catalytic amount of camphorsulfonic acid, and stir under ice cooling for 10 minutes. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue contains 0.5ml of hexamethylphosphamide and 5.9ml of potassium fluoride.
mg and stir at 60°C for 20 minutes. The reaction solution was diluted with diethyl ether, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (2:1) as an eluent to obtain 22 mg of the title compound having the following physical properties. IR: ν=3450, 1740, 1690 cm ^-1 . NMR: δ=5.45−5.27 (2H, m), 4.83−4.59
(1H, m), 4.13 (1H, m), 3.67 (3H, s), 2.33
(3H, s), 2.32 (2H, t). MS: m/e=428, 410, 397, 385, 344, 326,
301, 283. Reference example 23 (5Z, 13E)-(9α-11β)-9-acetylthio-
11-(tetrahydropyran-2-yloxy)-
15-oxo-11a-homoprosta-5,13-dienoic acid methyl ester 500 mg of diatomaceous earth was added to a chromium trioxide-pyridine complex solution (prepared from 787 mg of chromium trioxide, 1.27 ml of pyridine, and 12 ml of methylene chloride) under ice-cooling. Stir at temperature for 5 minutes, add 337 mg of the product of Reference Example 22 dissolved in 5 ml of methylene chloride under ice cooling,
Stir for 10 minutes at the same temperature. Add 5.4 g of sodium hydrogen sulfate to the reaction solution and stir for 5 minutes under ice cooling.
It was filtered through a layer of magnesium sulfate, and the liquid was concentrated under reduced pressure to obtain 310 mg of a 3β-formin compound having the following physical properties. TLC (benzene:ethyl acetate=2:1):Rf=
0.65. IR: ν=2720, 1740, 1730, 1695 ^{cm -1} . 297 mg of diethyl 2-oxoheptylphosphonate dissolved in 2 ml of tetrahydrofuran was added dropwise to 44 mg of sodium hydride (content 64.1%) suspended in 8 ml of tetrahydrofuran, stirred at room temperature for 30 minutes, and then dissolved in 2 ml of tetrahydrofuran.
Add 310 mg of 3β-formyl compound dropwise and stir at room temperature for 2 hours. Acidify the reaction solution to pH 5 with acetic acid.
Filter through a layer of silica gel and concentrate under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (8:1) as an eluent to obtain 295 mg of the title compound having the following physical properties. IR: ν=1740, 1695, 1675, 1630 ^{cm -1} . NMR: δ=6.61 (1H, dd), 6.08 (1H, d), 5.40
-5.18 (2H, m), 4.76 - 4.57 (1H, m), 4.11
(1H, m), 3.66 (3H, s), 2.52 (2H, t), 2.34
(3H, s), 2.28 (2H, t), 0.89 (3H, m). MS: m/e=522, 491, 479, 466, 438, 420. Reference example 24 (5Z, 13E)-(9α, 11β, 15α)-9-acetylthio-11-(tetrahydropyran-2-yloxy)-15-hydroxy-11a-homoprost-5,13-dienoic acid methyl ester and ( 5Z,
13E)-(9α, 11β, 15β)-9-acetylthio-
11-(tetrahydropyran-2-yloxy)-
15-hydroxy-11α-homoprosta-5,13
-dienoic acid methyl ester The product 295 of Reference Example 23 was prepared in the same manner as in Reference Example 2.
137 mg of a 15α-hydroxy compound and 146 mg of a 15β-hydroxy compound having the following physical properties were obtained from mg. (a) 15α-hydroxy compound: TLC (benzene: ethyl acetate = 4:1): Rf =
0.29. IR: ν=3450, 1740, 1695, 970 ^{cm -1} . NMR: δ=5.53−5.12 (4H, m), 4.78−4.52
(1H, m), 4.10 (1H, m), 3.67 (3H, s),
2.33 (3H, s), 2.29 (2H, t), 0.89 (3H, m). MS: m/e=524, 506, 481, 463, 440,
422, 404, 380. (b) 15β-hydroxy compound: TLC (benzene: ethyl acetate = 4:1): Rf =
0.39. IR: ν=3450, 1740, 1695, ^{980cm -1} . Reference example 25 (5Z, 13E)-(9α, 11β, 15α)-9-acetylthio-11-(tetrahydropyran-2-yloxy)-15-acetoxy-11a-homoprosta-5,13-dienoic acid methyl ester Methylene chloride Add 0.095 ml of pyridine and 0.025 ml of acetyl chloride to 124 mg of the product of Reference Example 24(a) dissolved in 2 ml of
Add ml dropwise under ice-cooling and stir at the same temperature for 20 minutes.
The reaction solution is diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (9:1) as an eluent to obtain 104 mg of the title compound having the following physical properties. TLC (benzene: ethyl acetate = 9:1): Rf =
0.27. IR: ν=1745, 1695, 1245, 975 ^{cm -1} . The following compound was obtained in the same manner. (a) From the product of Reference Example 24(b) (5Z, 13E) − (9α,
11β,15β)-9-acetylthio-11-(tetrahydropyran-2-yloxy)-15-acetoxy-11a-homoprosta-5,13-dienoic acid methyl ester was obtained. TLC (benzene: ethyl acetate = 9:1): Rf =
0.29. IR: ν=740, 1695, 1240, 970 ^{cm -1} . Reference example 26 (5Z, 13E)-(9α, 11β, 15α)-9-acetylthio-11-hydroxy-15-acetoxy-11a
-Homoprosta-5,13-dienoic acid methyl ester 97 mg of the product of Reference Example 25 in the same manner as Reference Example 21
69 mg of the title compound having the following physical properties was obtained. TLC (benzene:ethyl acetate=4:1):Rf=
0.17. IR: ν=3450, 1745, 1700, 1250, ^{980cm -1} . NMR: δ=5.52−5.07 (5H, m), 4.06 (1H,
m), 3.98−3.74 (1H, m), 3.67 (3H, s), 2.33
(3H, s), 2.29 (2H, t), 2.04 (3H, s), 0.88
(3H, m). MS: m/e = 482, 451, 439, 422, 379, 346. The following compound was obtained in the same manner. (a) From the product of Reference Example 25(a) (5Z, 13E) − (9α,
11β, 15β)-9-acetylthio-11-hydroxy-15-acetoxy-11a-homoprosta-
5,13-dienoic acid methyl ester was obtained. TLC (benzene:ethyl acetate=4:1):Rf=
0.23. IR: ν=3400, 1740, 1695, 1245, ^{970cm -1} . NMR: δ=5.52−5.03 (5H, m), 4.07 (1H,
m), 3.94-3.73 (1H, m), 3.67 (3H, s), 2.33
(3H, s), 2.30 (2H, t), 2.03 (3H, s), 0.88
(3H, m). Ms: m/e=482, 439, 422, 404, 379, 361,
346, 328. Reference Example 27 (5Z, 13E)-(9α, 11β, 15α)-9-acetylthio-11-methanesulfonyloxy-15-acetoxy-11a-homoprosta-5,13-dienoic acid methyl ester Same as Reference Example 3 , 65 mg of the product of Reference Example 26
76 mg of the title compound having the following physical properties was obtained. The reaction product was purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (4:1) as an eluent. TLC (benzene:ethyl acetate=4:1):Rf=
0.53. IR: ν=1740, 1700, 1365, 1250, 1180, 980,
950cm ^-1 . NMR: δ=5.63−5.08 (5H, m), 5.00−4.70
(1H, m), 4.10 (1H, m), 3.67 (3H, s), 2.99
(3H, s), 2.35 (3H, s), 2.29 (2H, t), 2.04
(3H, s), 0.88 (3H, m). Ms: m/e=560, 529, 517, 500, 464, 457,
424, 421, 404, 361, 328. The following compound was obtained in the same manner. (a) From the product of Reference Example 26(a) (5Z, 13E) − (9α,
11α,15β)-9-acetylthio-11-methanesulfonyloxy-15-acetoxy-11a-homoprosta-5,13-dienoic acid methyl ester was obtained. TLC (benzene:ethyl acetate=4:1):Rf=
0.54. IR: ν=1740, 1698, 1360, 1245, 1180, 970,
950cm ^-1 . NMR: δ=5.52−5.08 (5H, m), 5.02−4.69
(1H, m), 4.10 (1H, m), 3.66 (3H, s), 2.99
(3H, s), 2.53 (3H, s), 0.88 (3H, m). MS: m/e=560, 517, 500, 457, 424, 404,
361, 328. The present invention has within its scope novel and therapeutically useful compounds of the general formula (), cyclodextrin clathrates thereof, and at least one non-toxic salt thereof when R ¹ represents a hydrogen atom. In addition, it also contains a pharmaceutical composition containing a pharmaceutical carrier or coating. In clinical practice, the novel compounds of the invention are usually administered orally;
Administered rectally or parenterally. Solid formulations for oral administration include tablets, pills, powders, and granules. In such solid formulations, one or more active substances are mixed with at least one inert diluent, such as calcium carbonate, potato starch, dextrin, alginic acid, lactose, mannitol or cocoa butter. The formulations may contain additives other than diluents in conventional manner, such as lubricants such as magnesium stearate. If desired, the tablets or pills may be coated with one or more layers of sugar, gelatin, enteric materials, films, and the like. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, containing commonly used inert diluents such as water or liquid paraffin. including. In addition to inert diluents, the formulations may also contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, and preservatives. Orally administered formulations according to the invention also include capsules of absorbable materials such as gelatin with or without one or more active substances and diluents or excipients. Solid preparations for rectal administration include suppositories containing one or more active substances and formulated in a manner known per se. Products for parenteral administration according to the invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solutions include propylene glycol, polyethylene glycol, ethanol, vegetable oils such as olive oil, and injectable organic acid esters such as ethyl oleate and sorbitan esters. Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These are sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of a sterilizing agent, or by irradiation. Alternatively, a sterile solid preparation may be prepared and dissolved in sterile water or a sterile injection solvent before use. The percentage of active substance in the pharmaceutical compositions of the invention may vary, and the proportions should be adjusted to provide a dose that is consistent with the desired therapeutic effect. Of course, several units of the preparation may be administered at once. Generally, products will usually contain at least 0.025% by weight of active substance for administration by injection and at least 0.1% by weight of active substance for oral administration. The dosage to be used is determined depending on the desired therapeutic effect, administration method, treatment period, age, body weight, etc. For adults, one dose per person is generally for the prevention and treatment of inflammation, hypertension, blood clots, stroke, asthma, myocardial infarction, angina pectoris, cerebral infarction, and acute cardiac death. For rectal, intravenous, intramuscular, or subcutaneous administration, doses range from 0.1 mg to 1 g.

Claims (1)

[Claims] 1. General formula [wherein, X represents an ethylene group (-CH ₂ CH ₂ -) or a cis-vinylene group [formula], Y represents an ethylene group or a trans-vinylene group [formula], R ¹ is a hydrogen atom, or represents an alkyl group having 1 to 12 carbon atoms, R ² is a hydrogen atom,
or represents a hydroxyl group, R ³ represents a single bond or an alkylene group having 1 to 5 carbon atoms, R ⁴ represents a hydrogen atom,
or an alkyl group having 1 to 8 carbon atoms, or a cycloalkyl group having 4 to 7 carbon atoms which is unsubstituted or substituted with at least one alkyl group having 1 to 8 carbon atoms, and m is 1 to 6 represents an integer. However, when X represents a cis-vinylene group and Y represents an ethylene group, R ² is not a hydrogen atom. ] An epithiocyclohexane-type prostaglandin-like compound represented by the following, or a cyclodextrin clathrate compound thereof, or a non-toxic salt of an acid thereof when R ¹ represents a hydrogen atom. 2 (5Z, 13E)-(9α, 11α, 15α)-9,11-epithio-15-hydroxy-11a-homoprosta-
The compound according to claim 1, which is 5,13-dienoic acid methyl ester. 3 (5Z, 13E)-(9α, 11α, 15β)-9,11-epithio-15-hydroxy-11a-homoprosta-
The compound according to claim 1, which is 5,13-dienoic acid methyl ester. 4 (5Z, 13E)-(9α, 11α, 15α)-9,11-epithio-15-hydroxy-11a-homoprosta-
The compound according to claim 1, which is a 5,13-dienoic acid. 5 (5Z, 13E)-(9α, 11α, 15β)-9,11-epithio-15-hydroxy-11a-homoprosta-
The compound according to claim 1, which is a 5,13-dienoic acid.