JPS5845420B2 - Prostaglandin-like compounds and their production methods - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel prostaglandin-like compounds and methods for their production.

Prostaglandins are derivatives of brostanic acid with the formula:

Different types of prostaglandins are known, and the type depends, among other things, on the alicyclic structure and substituents.

For example, prostaglandin F (PGF), E (PGE)
The alicyclic rings of and A(PGA) each have the following structures.

Such compounds are subdivided by the position of the side chain double bonds at the 8- and 12-positions of the alicyclic ring.

Therefore, PG-1 compounds have a trans-double bond (trans-213) between C13C14, and PG-2 compounds have a cis-double bond between C6-C6 and a trans-double bond (cis-213) between C13C14. 15, trans-A13), the PG-3 compound has a cis-double bond between C3-C, and C17C1g, and a trans-double bond (
cis-A5, trans-, 113, cis-417).

For example, prostaglandin F, a (PGF, a) and grosstaglandin E1 (PGE1) are characterized by the following formula v and formula 2, respectively.

The structures of PGF2a and PGE2, which are compounds of the PG-2 group, correspond to the structures of formulas (1) and (2), respectively, which have a cis-double bond between the 5- and 6-position carbon atoms.

Compounds of the PG-1 group in which the double bond between the 13- and 14-position carbon atoms is replaced with an ethylene group (-CH2CH2-) are dihydroglostaglandins, such as dihydroprostaglandin-F1a (dihydro-
PGFla) and dihydroprostaglandin-E,
(dihydroPGE1).

Furthermore, if one or more methylene groups are added to or removed from the aliphatic group attached to the 12-position of the alicyclic ring of the prostaglandin, those compounds are classified according to the general rules of organic compound nomenclature. Accordingly, they are known as ω-homo-prostaglandins (methylene group added) or ω-true prostaglandins (methylene group removed), and when one or more methylene groups are added or removed, the Numbers are represented by the prefix 6 homo'' or gee, trie, etc. before the ``nor''.

It is generally known that prostaglandins have pharmacological properties.

For example, it has smooth muscle stimulating, blood pressure lowering, diuretic, bronchodilating and lipolysis inhibiting effects, and also inhibits platelet aggregation and gastric acid secretion, thus treating hypertension, thrombosis, asthma and gastric ulcers, and during pregnancy. It is useful in inducing and aborting labor in female mammals, preventing arteriosclerosis, and as a diuretic.

Prostaglandins are fat-soluble substances that can be obtained in extremely small amounts from various tissues of animals that secrete prostaglandins in vivo.

For example, PGE and PGA have the effect of suppressing gastric acid secretion and can therefore be used to treat gastric ulcers.

They also inhibit the release of free fatty acids caused by epinephrine, the effect of which is to lower the concentration of free fatty acids in the blood, thus being effective in preventing arteriosclerosis and hyperlipidemia.

PGE1 suppresses platelet aggregation and removes blood clots,
Prevent thrombosis.

PGE and PGF have a stimulatory effect on smooth muscle and increase intestinal motility.

In other words, these effects indicate its therapeutic usefulness in post-surgical intestinal obstruction and its usefulness as a laxative.

In addition, PGE and PGF can be used as labor stimulants, abortifacients in the first and second trimesters, placental expulsion after delivery, and can be used as oral contraceptives due to their ability to regulate the estrous cycle in female mammals. I can do it.

PGE and PGA have blood pressure lowering and diuretic effects.

Since PGE increases cerebral blood flow, it is effective in treating diseases of the cerebrovascular system, and since it has a bronchodilating effect, it is effective in treating asthma in patients.

During the past decade, extensive research has been carried out, among other things, to improve the pharmacological properties of natural prostaglandins or to improve one or more of these properties, or to develop new compounds with hitherto unknown pharmacological properties. This has been done for discoveries.

Prostaglandin F, the hydrogen atoms bonded to the 16th and subsequent carbon atoms of the aliphatic group bonded to the 12-position of the alicyclic group of similar compounds are replaced with phenoxy groups, and the trans-double bond is replaced with the 8-position of the alicyclic group. It has been discovered that some of the pharmacological properties of natural prostaglandins can be improved or exhibit particularly good selectivity by introducing into the 2-position an aliphatic group attached to the -position.

Therefore, the present invention provides a novel prosthetic compound represented by the general formula (wherein R4 represents a trifluoromethyl group and R6 represents a hydrogen atom or a straight-chain or branched alkyl group containing 1 to 12 carbon atoms). Grandin analogs and cyclodextrin clathrates of such acids and esters, and when R6 represents a hydrogen atom, non-toxic salts thereof (eg, sodium salts) are provided.

The symbol "-" in the general formula ■ and other formulas in this specification
” indicates that the hydroxyl group or other group in question is in the α- or β-acid position or a mixture of both.

The present invention relates to the natural forms of all the compounds of general formula (1), their enantiomers, or mixtures thereof, and more particularly to racemic forms consisting of equimolar mixtures of the natural forms and their enantiomers.

As is clear to those skilled in the art, the compound represented by the general formula (II) has at least five asymmetric centers, and these five asymmetric centers are located at the 8-position, 9-position, 11-position, and 12-position. It is located at the identified alicyclic carbon atom and at the 15-position carbon atom to which the hydroxyl group is bonded.

The presence of asymmetric centers leads to the existence of isomers, as is well known.

However, the compound of general formula (1) has such a configuration that the side chains attached to the ring carbon atoms identified as the 8- and 12-positions are trans to each other.

Therefore, all isomers and mixtures thereof of the general formula (III) in which the side chains bonded to the ring carbon atoms at the 8- and 12-positions are trans-coordinated and have a hydroxyl group at the 15-position are represented by the general formula ■It is considered to be within the range.

According to a feature of the present invention, the prostaglandin-like compound of the general formula (3), in which each symbol is defined above, is a prostaglandin-like compound of the general formula (2) in which R7 is unsubstituted or at least one
represents a 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group, or a 1-ethoxyethyl group substituted with an alkyl group, R4 is as defined above). During,
R9 represents an alkyl group containing 1 to 4 carbon atoms,
R10 represents a straight-chain or branched alkyl group containing 1 to 12 carbon atoms. ) to obtain a cyclopentane derivative represented by
The resulting ester of the general formula (wherein R4, R7 and R'' are as defined above) is converted into the corresponding ester of the general formula (wherein R4 and R7 are as defined above) The compound ■
A 2-tetrahydropyranyloxy group, a 2-tetrahydrofuranyloxy group, or a 1-ethoxyethoxy group is hydrolyzed to form a hydroxyl group, which is represented by the general formula (wherein R4 and R6 are as defined above) obtained by the method consisting of obtaining PGF1 compound.

The intermediate compounds of general formulas ① and
It can be converted to Glotaglandin.

Each symbol in the formula is as defined above.

The hydrolysis of the alkyl ester of the general formula (1) to the corresponding acid of the general formula This can be done by treating the ester with an aqueous solution.

The OR7 group in the intermediate compounds of formulas (1) and (X) can be converted into a hydroxyl group by mild hydrolysis with an organic acid such as an aqueous solution of acetic acid or a dilute inorganic acid such as dilute hydrochloric acid.

Since the compounds of general formulas (1) and (2) are insoluble in water, it is advantageous to use water-miscible organic solvents such as tetrahydrofuran or alcohols.

Treatment of compounds of general formulas ■ and It can be done with a mixture.

The PGF alicyclic ring in the compounds of general formulas (1) and (2) can be converted into an oxo group by a method known per se for the conversion of the hydroxyl group at the 9-position of prostaglandin into an oxo group.
For example, it is obtained from chromium trioxide, manganese sulphate, sulfuric acid and water.

) or can be converted into a PGE ring using Jones reagent.

The reaction between the cyclopentane derivative of general formula (■) and the dialkyl phosphonate of general formula Under normal conditions used for
It is carried out in an inert organic solvent at a temperature not exceeding .

The reaction is preferably accompanied by the evolution of hydrogen gas by suspending a strong base such as sodium hydride in an inert organic solvent (e.g. tetrahydrofuran or 1,2-dimethoxyethane) and adding the dialkyl phosphonate. ) by forming an IJium derivative and adding a cyclopentane derivative of the general formula (1) to a solution of the formed sodium alkylphosphonate.

The trans-A2 double bond is stereospecifically generated by the Wittig reaction, and a compound of general formula M is obtained.

The cyclopentane derivative of the general formula (1), which is a new compound and constitutes a feature of the present invention, can be obtained by a series of reactions shown in the following scheme B.

In the formula, φ represents a phenyl group, and the other symbols are as defined above.

Bicyclo-octane and 2-hydroxycarbonylethylidene triphenylphosphorane of general formula bromide] is carried out under the usual conditions used for carrying out Wittig reactions, for example in an inert solvent at or near room temperature.

Since the phosphorane compound is substantially insoluble in other solvents such as tetrahydrofuran, it is preferred to carry out the reaction in dimethyl sulfoxide.

For better performance of the Wittig reaction, two or more molecular equivalents of phosphorane compound are required for each mole of bicyclo-octane reactant.

The reaction is generally carried out at a temperature of 0 to 40°C, preferably 20 to 30°C, and is usually complete after about 1 to 5 hours at room temperature.

Acidic components of general formula X (cis-43- and trans-
13- and trans-A2-forms) can be extracted from the reaction mixture by conventional operations and further purified by silica gel column chromatography.

Catalytic reduction of the compound of general formula X■ can be carried out as follows.

A hydrogenation catalyst, commonly used for the hydrogenation of double bonds such as various forms of platinum, palladium or nickel, is suspended in a suitable amount of solvent acting as a reaction medium and this suspension is subjected to a catalytic reduction process. Place it in a suitable device.

The air in the apparatus is replaced by hydrogen and a solution of the cyclopentane compound in a suitable inert solvent (e.g. methanol, ethanol, water, dioxane or a mixture of two or more of these) is added to the suspension of the catalyst. .

The reaction is carried out at approximately 0°C to 50°C, and β-
As well as a cis or trans double bond in the position of the formula
Depending on whether it is desired or not to reduce the trans double bond adjacent to the carbon atom bearing the OR7 group in the starting material of , sphere *For example, 0.5
It will be held for 8 hours.

After the reaction is completed, the catalyst is removed by filtration, and the P solution is concentrated.

If necessary, the residue is purified by column chromatography using silica gel or silica gel impregnated with silver nitrate.

The trans double bond adjacent to the carbon atom carrying the OR7 group cannot be hydrogenated due to steric hindrance by the OR7 group of the 2-tetrahydropyranyloxy, 2-tetrahydrofuranyloxy, or 1-ethoxyethoxy group. Have difficulty.

The double bond between the 3- and 4-positions can be selectively reduced by appropriate selection of catalyst (palladium is suitable), reaction temperature and time.

The esterification of the acid of the general formula X to the methyl ester of the general formula This can be done by reaction with diazomethane in an active organic solvent.

The methyl ester of the general formula can be reduced to the corresponding aldehyde of general formula (2).

The dialkyl phosphonate starting material of general formula
, Amer, Chem.

5OC0, 68, 1103 (1946).

(wherein R9 and R10 are as defined above.

) A bicyclo-octane compound of the general formula
It can be prepared from 2-oxa-3-oxo-6-syn-formyl-7-anti-acetoxy-cis-bicyclo[3.3.0]octane (E, J, Corev
et, al;, J.

Amer, Chem, Soc,, Iroyu, 5657 (19
69) and the same magazine 92.397 (1970) and the specification of French Patent No. 7215314 (Publication No. 2134673)].

In the formula, R11 represents an alkyl group containing 1 to 4 carbon atoms, Ac represents an acetyl group, and the other symbols are as defined above.

The reaction between the dialkyl phosphonate of the general formula (3) and the compound of the general formula XX can be carried out by suspending sodium hydride in an inert organic solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, and reacting the dialkyl phosphonate of the general formula (XM) with the compound of the general formula XX. Preferably, this is done by adding.

The resulting sodium derivative of dialkyl phosphonate can then be reacted at a temperature of 20 DEG C. to 45 DEG C. for 1 hour to 5 hours to stereoselectively produce the trans-enone compound of general formula X.

The compound of general formula X■ can be produced by reducing the oxo group adjacent to the double bond of the compound of general formula X■, where R4 and Ac are as described above, to a hydroxyl group.

Reduction is carried out in an alcohol containing 1 to 4 carbon atoms, such as methanol, at low temperature, preferably from -30°C to -60°C, with an excess of borohydride (IJ), or in a suitable inert organic solvent, such as 1. Suitably carried out with zinc borohydride in 2-dimethoxyethane at a temperature of -10 DEG to 10 DEG C.

The product thus obtained is a mixture of isomers, of which 15
The hydroxyl group at the -position is α- or β-coordinated, respectively.

If desired, it can be separated into an isomer having an α-coordinated hydroxyl group and an isomer having a β-coordinated hydroxyl group by silica gel column chromatography.

A prostaglandin-like compound of the general formula (1) can be obtained by processing the separated isomers as described herein, and the hydroxyl group at the 15-position of this compound is in the α- or β-coordination.

Compounds of general formula xxrv can be prepared by hydrolysis under alkaline conditions of compounds of general formula XxIIH, for example with anhydrous potassium carbonate in methanol.

Compounds of general formula XX■ are prepared from compounds of general formula xxtv by reacting dihydropyran, dihydrofuran or ethyl vinyl ether in an inert solvent such as methylene chloride in the presence of a condensing agent such as p-)luenesulfonic acid. be able to.

A compound of general formula xvtH can be prepared by evaporating a compound of general formula XXV with diisobutylaluminum hydride in toluene at -60° C. for about 15 minutes.

The dialkyl phosphonate of general formula

), such as dimethyl methylphosphonate or diethyl methylphosphonate, at a temperature below 50°C, and the reaction mixture is then mixed with a solution of the general formula (wherein R4 is as defined above and , R12
represents a lower alkyl group, preferably an alkyl group containing 1 to 4 carbon atoms, such as a methyl group or an ethyl group).
C. and stirring the reaction mixture for 1.5 hours at below -50.degree. C. and then at 0.degree. C. for 18 hours to obtain the desired dialkyl phosphonate of general formula XXI. can.

Compounds of the general formula XX■, for example ethyl 3-trifluoromethylphenoxyacetate, can be prepared by methods known per se.

The bicyclo-octane compound of general formula 1972).

In the formula, R4 and R7 are as defined above, and R
13 is formyl group or acetyl group (-COCH3)
and Ts represents a tosyl group.

Each reaction can be carried out by methods known per se.

The compound of the general formula XXXVI can be produced by reacting the compound of the general formula XXX(II) with 5 tetraethylammopolmates or tetraethylammonium acetate.

Optionally, racemic intermediates of general formula XXXII can be prepared by column chromatography (Tetrahedron Letters, 326
See 9-3272.1972.

) can be divided into isomers in which the hydroxyl group is α-coordinated and isomers in which the hydroxyl group is β-coordinated.

These isomers of general formula XXXII can be prepared using the procedures described above, where R4 is as defined above and the hydroxyl group attached to the carbon atom adjacent to the double bond is in the desired α- or β-configuration. A cyclopentane derivative of the general formula (2) can be obtained.

The term "methods known per se" as used herein refers to methods previously used or described in the chemical literature.

The trans-A2-prostaglandin of the general formula (3) in which R6 represents a hydrogen atom obtained by the method of the present invention may be converted into a salt or ester, preferably an alkyl ester containing 1 to 12 carbon atoms. I can do it.

The salt is prepared from a compound of the general formula (1) in which R6 represents a hydrogen atom by a method known per se, for example, a stoichiometric amount of the acid of the general formula (2) and a suitable base, such as an alkali metal hydroxide or It can be produced by reacting carbonate, ammonium hydroxide, ammonia or amine in an appropriate solvent.

The salt can be isolated by lyophilization of the solution or, if sufficiently insoluble in the reaction medium, by filtration after removing a portion of the solvent if necessary.

The useful pharmacological properties of trans-A2-prostaglandins of the general formula (2) are due to the fact that the salts are non-toxic salts, i.e., their cations are relatively harmless when administered to animal tissues in therapeutically necessary amounts. Salts that are not compromised by side effects attributed to cations are preferred.

Preferably the salt is water soluble.

Suitable salts include alkali metal salts such as sodium and potassium salts, and ammonium salts and pharmaceutically acceptable (ie, non-toxic) amine salts.

Amines suitable for forming such salts with carboxylic acids are well known and include, for example, amines obtained by theoretically replacing 13 or more of the hydrogen atoms of ammonia with groups; The groups may be the same or different when one or more of the hydrogen atoms are replaced, such as from alkyl groups containing 1 to 6 carbon atoms and hydroxyalkyl groups containing 1 to 3 carbon atoms. selected.

trans-A of the general formula (■) in which R6 represents a hydrogen atom
Esters of 2-7'' rostaglandin can be prepared by combining the acid with (1) a diazoalkane compound, such as diazomethane, and (1j) an alcohol in the presence of dicyclohexylcarbodiimide as a condensing agent, or (iii) a tertiary amine and then a pivaloyl group.・obtained by forming a mixed acid anhydride by adding a dihydride or an arylsulfonyl halide or an alkylsulfonyl halide and then reacting with an alcohol (as described in my British Patent No. 1362956 and British Patent No. 1364125) ).

The prostaglandin compound of general formula (2) is converted into a cyclodextrin clathrate compound, if desired.

Inclusion compounds combine cyclodextrin with water and/or
It can be prepared by dissolving in a water-miscible organic solvent and adding to this solution a prostaglandin compound dissolved in a water-miscible organic solvent.

The desired cyclodextrin clathrate is then isolated by heating the mixture and concentrating the mixture under reduced pressure or cooling and separating the product by filtration or decantation.

The ratio of organic solvent to water can be varied depending on the solubility of the starting materials and product.

During the production of cyclodextrin clathrate compounds, the temperature is 70°C.
It is preferable not to exceed.

α-1β- or γ-cyclodextrin or mixtures thereof can be used to prepare cyclodextrin inclusion compounds.

Conversion of these to cyclodextrin clathrates serves to increase the stability of prostaglandin compounds.

The prostaglandin compounds and their esters and their cyclodextrin clathrates and non-toxic salts obtained by the method of the invention are in selected forms particularly effective for abortifacient and stimulatory effects on uterine contractions, luteolytic effects and It has typical pharmacological properties of prostaglandins, including the effect of inhibiting egg implantation, and the termination of pregnancy, and induction of labor in pregnant female mammals, control of oestrus in female mammals, and It is useful in preventing pregnancy in many mammals.

For example, 16-(3-)lifluoromethylphenoxy)
-ω-tetratruetrans-J2PGF1a ethyl ester (1) 100μ to rats on the 17th day of pregnancy? /k
g Animal weight Dose When administered intraperitoneally, it induced miscarriage in all five cases tested, so it is useful for abortion, and (11) 21 nf/day in pregnant rats. /
kg animal body weight in the 3rd, 4th and 58th of pregnancy.
When administered subcutaneously to the eyes, it inhibited egg implantation in all five cases tested, so it is useful for preventing pregnancy in female mammals, and (iii) it was administered intravenously to female rats on day 20 of pregnancy. When administered at a dose of 20 μt/9 animal body weight, it is useful for inducing labor as it stimulated myometrial contractions in all five pregnant rats tested.

The following examples and references illustrate the process of the invention and its products.

In Examples and Reference Examples, "IRj, l'-NMRJ and "
"TLC" stands for "infrared absorption spectrum,""nuclear magnetic resonance spectrum," and "thin layer chromatography," respectively.

Reference example 1 2-oxa-3-okino 6-syn-[3(ξ)-(2
-tetrahydropyranyloxy)-4-(3-)lifluoromethylphenoxy)-phtha-trans-1-enyl]-7-anti-(2-tetrahydropyranyloxy)
-cis-bicyclo[3.3.0]octane 22.31 of 2-oxa-3-oxo-6-syn-[3
(ξ)-Hydroxy-4-(3-trifluoromethylphenoxy)-phtha-trans-1-eny#)-7-anti-hydroxy-cis-bicyclo[3.3.0]octane in 100 rILl of methylene chloride Dissolve the solution in 16 ml of 2,3-dihydrohyrane and 230 ml of p
-) Ruethysulfonic acid was reacted at 25°C for 15 minutes.

The reaction mixture was neutralized with an aqueous solution of bicarbonate, diluted with ethyl acetate, and chlorinated with water), washed with an aqueous solution of IJ and concentrated in vacuo to give the title compound 321 with the following physical properties: Ta.

TLC (Developing solvent: methylene chloride-methanol-19:
1): Rf = 0.85° IR (liquid film method) Niji = 2950.1775.1600.
1490,980CWL'.

2-Oxa- used as starting material in the above preparation
3-oxo-6-syn-[3(ξ)-hydroxy-4-
(3-)Lifluoromethylphenoxy-but-trans-1-enyl]-7-anti-hydroxy-cis-bicyclo[3.3.0)octane can be prepared as follows.

(a) Dimethyl 2-oxo-3-(3-)lifluoromethylphenoxy)propyl-phosphonate 241 3-trifluoromethylphenol, 19.2S' ethyl chloroacetate, 22.5F sodium iodide and 20. 8f? of potassium carbonate was added to 75 ml of anhydrous acetone and the reaction mixture was refluxed for 16 hours.

The reaction mixture was then poured into a cooled aqueous hydrochloric acid solution and extracted with ethyl acetate.

The organic extract was washed with water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by vacuum distillation to obtain ethyl (3-) IJ fluoromethylphenoxy)acetate 29.59A having the following physical properties.

Boiling point: 122°C to 125°C/19mmHg.

IR (liquid film method) Niji = 1750.1590.1330.
1130 cm-1° NMR (CCI4 solution): δ = 7.65-6.90 (4
H, m), 4.64 (2H, S), 4.25 (2H, q
), 1.25 (3H, t).

33.0f! 260ml of dimethyl methylphosphonate
of anhydrous tetrahydrofuran, and add 2Nn to the solution.
- 131ml of hexane solution of butyllithium at -60℃
The mixture was added dropwise while maintaining the temperature at -55°C.

After stirring for 30 minutes, a solution of 29.51 ethyl (3-)lifluoromethylphenoxy)acetate (obtained as described above) in 100 rILl of anhydrous tetrahydrofuran was added to the previous solution.

The mixture was stirred at the same temperature for 1.5 h and then at 0 °C for 18 h.
Stir for hours.

The reaction mixture was neutralized with acetic acid and then concentrated under reduced pressure.

The residue was dissolved in a small amount of water and extracted with diethyl ether.

The ether extract was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure.

The residue was vacuum distilled at 160° C. and 10.7 Hg to remove unreacted impurities.

The resulting residue was purified by silica gel column chromatography using a mixture of ethyl acetate and cyclohexane (5:1) as the eluent to obtain the title compound 262 having the following physical properties.

IR (liquid film method) rainbow=173011590°1450.
1050-1030.750cm-0NMR (CCI4
solution): δ = 7.50-6.70 (4H, m), 4
．． 70 (2H, S), 3.65 (6H, d), 3.10
(2H1d).

(b) 2-oxa-3-oxo-6-syn-[3-oxo-4-(3-)lifluoromethylphenoxy)-but-trans-1-enyl]-7-anti-acetoxy-
Hydrogenation of cis-bicyclo[3.3.O]octane 2.22) IJium (63% content) to 38
Dissolved in 0ml of tetrahydrofuran and 20f? in 50ml of tetrahydrofuran. Dissolved dimethyl 2-oxo-3-(3-)lifluoromethylphenoxy)propylphosphonate [prepared as described in (a) above]
added.

Hydrogen gas evolved violently and the solution turned clear yellow.

The resulting solution contained 172 2-oxa-3-oxo-6-syn-formyl-two-anti-acetoxy-cis-bicyclo[3] dissolved in 40 ml of tetrahydrofuran.
・3・O) Octane [J, Amer, Chem, 5oc
0.92.397 (1970)) was added and the reaction mixture was stirred at 0°C to -5°C for 2.5 hours.

The mixture was then neutralized with acetic acid, and the resulting precipitate was removed by filtration.

Solution F was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a (1:4) mixture of ethyl acetate and benzene as the eluent to obtain 14.2 g of the title compound having the following physical properties. Obtained.

TLC (developing solvent, ethyl acetate-benzene = 1:4):
Rf=0.52°NMR (mixed solution of CDC13 and CCl4): δ=7.
65-6°15 (6H, m), 5.35-4.50 (4
H,m), 1.97 (3H,s).

(c) 2-oxa-3-oxo-6-syn-[3(ξ)
-Hydroxy-4-(3-)'Jfluoromethylphenoxy)-phth-trans-1-enyl]-7-anti-
Acetoxy-cis-bicyclo[3.3.O]octane 13.9s'2-oxa-3-oxo-6-syn-[
3-oxo-4-(3-)lifluoromethylphenoxy)-phtha-trans-1-enyl]-7-anti-acetoxy-cis-bicyclo[3.3.0]octane [as described in (b) above It was prepared as follows.

] in 1150m methanol, then 3,2?
of sodium borohydride was added while maintaining the internal temperature at -40°C.

After stirring for 15 minutes at -40°C to -30°C, the mixture was neutralized with acetic acid and the solution was concentrated under reduced pressure.

The resulting residue was dissolved in ethyl acetate, and the solution was then successively bicarbonated, washed with an aqueous solution of IJ and an aqueous solution of sodium chloride, and dried over magnesium sulfate.

The solvent was distilled off, and the residue was purified by silica gel column chromatography using a mixture of benzene and ethyl acetate (10-7:1) as the eluent to obtain the title compound 12.8S' having the following physical properties. Obtained.

IR (liquid film method) Niji = 3450, 2930.2855.
1775.1740.1600.1500.1450.
1340.1250.1170.1075.1030.
980cIfLONMR (CDCI3 solution): δ=7.
65-6.90 (4H, m), 5.90-5.55
(2H.

S), 5.25-4.72 (2H, m), 4.72
−4.30 (I Hlm ), 3.98 (2H,s
), 3.20-2.70 (I H, wide S), 2
．． 02 (3H,s).

TLC (developing solvent, methylene chloride-methanol = 20
: 1): Rf=0.43°(d) 2-oxa-3-oxo-6-syn-[3(ξ)
-Hydroxy-4-(3-)lifluoromethylphenoxy)-buta-trans-1-enyl]-7-anti-hydroxy-cis-bicyclo[3.3.0]octane 8.3f 2-oxa-3 -oxo-6-syn-(3(
(7-hydroxy-4-(3-)lifluoromethylphenoxy)-buta-trans-1-enyl)-7-7-thiacetoxy-bicyclo[3.3.0]octane [in (e) above] specially prepared], 2.764
F. potassium carbonate and 70ml methanol were mixed and stirred for 30 minutes at room temperature.

The reaction mixture was neutralized with IN hydrochloric acid and then extracted with ethyl acetate.

The extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure.

Using the residue as an eluent, a mixture of benzene and ethyl acetate (1
:3) Purify the title compound 5 by silica gel column chromatography using the mixture and have the following physical properties.
．． I got 92.

IR (liquid film method) rainbow=3400.3060°2940.
2860.1770.1600.1500.1455.
1380.1340°1250.1170.1130.
1075.1045.980crrL-1°NMR (CDCI3 solution): δ=7.60-6.80(
4H, m), 5.85-5.48 (2H.

m), 5.10 to 4.65 (IH, m), 4.65
-4.20 (I H,m), 4.20-3.10 (
5H, m).

TLC (developing solvent, ethyl acetate-benzene 3: 1.2 times development): Rf = 0.42° Reference example 2 2-oxa-3-hydroxy-6-syn-[3(ξ)-
(2-Tetrahydropyranyloxy)-4-(3-)lifluoromethylphenoxy)-phtha-trans-1-enyl]-7-anti-(2-tetrahydropyranyloxy)-cis-bicycloC3.3. 0] Octane 32f 2-oxa-3-oxo-6-syn-(3(ξ
)-(2-tetrahydropyranyloxy)-4-(3
-)Lifluoromethylphenoxy)-buta-trans-
1-enyl]-7-anti-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.O]octane[
prepared as described in Reference Example 1] was dissolved in 300 ml of toluene, and 70 ml of a 25% toluene solution of diisobutylaluminum hydride was added dropwise at -78°C.

The reaction mixture was stirred at the same temperature for 30 minutes, and then methanol was slowly added dropwise until no gas was generated.

The temperature of the reaction mixture was raised to 0°C, 30or/11 water was added, and the mixture was stirred for 30 minutes.

The mixture is filtered to remove precipitated aluminum hydroxide, and the lachrymal fluid is chlorinated).
Dry using magnesium sulfate, then concentrate under reduced pressure,
The title compound 322 was obtained with the following physical properties.

TLC (developing solvent, methylene chloride-methanol = 19:
1): Rf=0.48°IR (liquid film method) Niji=3400.2920.2850.
1590.1490.980crrL-10 Reference Example 3 9α-hydroxy-11α・15(ξ)-bis-(2-
125f dissolved in 240 ml of dimethyl sulfoxide
? A dimethylsulfoxide solution containing 0.57 mol of sodium methylsulfinyl methylide (287rIL1) was added to the 2-hydroxycarbonylethyltriphenylphosphonium bromide, and the mixture was stirred while maintaining the temperature at 25°C.

34.5F 2-oxo-3-
Hydroxy-6-syn-[3(ξ)-(2-tetrahydropyranyloxy)-4-(3-4lifluoromethylphenoxy)-phtha-trans-1-enyl]-7-anti-(2 -Tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octane (prepared as described in Reference Example 2) was added to a solution of 150 ml of dimethyl sulfoxide.

The reaction mixture was stirred at 25° C. for 2 hours, poured into 2.5 mL of ice water containing a small amount of potassium carbonate, and then extracted with a 1:1 mixture of diethyl ether and ethyl acetate.

The water was acidified with oxalic acid and then extracted with a 5:3 mixture of ethyl acetate and diethyl ether.

washing the extract with water and aqueous sodium chloride solution;
Dry with magnesium sulfate and concentrate under reduced pressure.

The residue was used as an eluent with benzene and ethanol (20
:1) was purified by silica gel column chromatography to obtain 9α-
Hydroxy-11α・15(ξ)-bis-(2-tetrahydropyranyloxy)-16-(3-)lifluoromethylphenoxy)-α-dinol-ω-tetranol-prostasis (or trans)-5) Lance-13-
Dienoic acid and 9α-hydroxy=11α・15(ξ)-bis-(2-tetrahydropyranyloxy)-16-(3
-trifluoromethylphenoxy)-α-dinol-ω-
Tetra True Prostar Trans-4, Trans-13
--) mixture of enoic acids 24.7f! I got it.

TLC (developing solvent, methylene chloride-methanol = -19
: 1) :Rf = 0.50 and 0.46°IR
(Liquid film method) Niji = 3450, 2940.1735.16
50.1595.1490.980cIrL0 The mixture thus obtained was dissolved in 300 ml of ethanol and mixed with 5 v of 5% palladium on carbon.

The reaction mixture was hydrogenated at room temperature and atmospheric pressure for 3 hours.

The catalyst was separated by filtration and the r liquid was concentrated under reduced pressure to obtain the title compound 24, Or, having the following physical properties.

TLC (after acid hydrolysis, developing solvent: use the supernatant of the mixture shown on the right, ethyl acetate-isooctane-acetic acid-water = 10
:30:20:100):Rf=0.30°IR (liquid film method) Niji=3450,2950.1735.
1600, 1500, 980cm'.

NMR (CCI4 solution): δ = 7.60-6.90 (4
H.

m), 5.70-5.00 (4H, m), 5.00
-4.25 (3H, m), 3.10-4.25 (8H
.

m).

2-hydroxycarbonylethyltriphenylphosphonium bromide used as a starting material in the above preparation can be prepared as follows.

Synthesis of 2-hydroxycarbonylethyltriphenylphosphonium bromide 90F (0,343 mol) of triphenylphosphine and 50F? (0,326 mol) of 3-bromopropionic acid was dissolved in 550 ml of acetonitrile and refluxed for 2 days.

The reaction mixture was evaporated of acetonitrile under reduced pressure, then the residue was thoroughly stirred with diethyl ether, and then the upper ether layer was removed by decantation.

This operation was repeated twice to yield a crystalline product, which was recrystallized from acetonitrile to give the title compound 115y as crystals with the following physical properties.

Melting point: 195-198°C.

IR (KBr tablet method) Niji = 2880.1740.14
34.1382.1322.1230.1105.74
5.6901520. and 505crrL-1° Reference Example 4 Methyl 9α-hydroxy-11α・15(ξ)-bis-
(2-tetrahydropyranyloxy)-16-(3-)
(lifluoromethylphenoxy)-α-dinol-ω-tetratrustotrans-13-enoate 24, Of? 9α-hydroxy-11α・15(ξ)
-bis=(2-tetrahydropyranyloxy)-16-
(3-)Lifluoromethylphenoxy)-α-dinol-
ω-Tetratrueprost-trans-13-enoic acid (prepared as described in Reference Example 3).

) was dissolved in 300 Tnl of diethyl ether.

A freshly prepared ethereal solution of diazomethane was added until the reaction mixture turned pale yellow.

The reaction mixture was concentrated under reduced pressure at low temperature.

The residue was purified by silica gel column chromatography using a (3:1) mixture of cyclohexane and ethyl acetate as eluent to give the title compound 14.8r with the following physical properties.

TLC (developing solvent, methylene chloride-methanol = 19
: 1) :Rf=0.300IR (liquid film method) Niji=3450.2950.1740.1600,1490
．． 980crn'.

NMR (CCI4 solution): δ = 7.50-6.70 (4
H1m), 5.80-5.35 (2H,m).

Reference example 5 9α-hydroxy-11α・15(ξ)-bis-(2-
Tetrahydropyranyloxy)-16-(3-)lifluoromethyl-phenoxy)-α-dinol-ω-tetratrueprost-trans-13-dinaldehyde 2.626f? Methyl 9α-hydroxy-11α・1
5(ξ)-bis-(2-tetrahydropyranyloxy)
-16-(3-trifluoromethylphenoxy)-α-
dinor-ω-tetratruprosttrans-13-
Enoate (prepared as described in Reference Example 4) at 1
Dissolved in 0TLl of toluene.

Then, 9.9 ml of a 25% toluene solution of diisobutylaluminum hydride was added dropwise at -78°C.

The reaction mixture was stirred at the same temperature for 30 minutes, then methanol was slowly added dropwise until no gas was evolved.

The temperature of the reaction mixture was raised to 0° C., 2 ml of water was added, and the mixture was stirred for 15 minutes.

The mixture was filtered to remove the precipitated aluminum hydroxide, and the P solution was then washed with aqueous sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to yield the title compound 2 with the following physical properties: .57f! I got it.

TLC (developing solvent, methylene chloride-methanol-19:
1): Rf=0.24°IR (liquid film method) Niji=3450.2940°2700.
1720.1595.1490.980crrL-1°NMR (CCI4 solution): δ = 9.60 (IH1 wide S), 7.50-6.70 (4H, m), 5.80
-5.30 (2H, m).

Reference example 6 Ethyl-9α-hydroxy-11α・15(ξ)-bis-(2-tetrahydropyranyloxy)-16-(3-
) Lifluoromethylphenoxy)-ω-tetratruprosta-trans-2, trans-13-genoate 3.94 f? of triethylphosphonoacetate was added dropwise in a nitrogen atmosphere at 25°C.

The reaction mixture was stirred at the same temperature for 30 minutes until hydrogen evolution ceased.

Then 2,571? 9α-hydroxy-11α・15
(ξ)-bis-(2-tetrahydropyranyloxy)-
16-(3-)Lifluoromethylphenoxy)-α-dinol-ω-tetratrupros)-);
Dinaldehyde (specifically prepared as described in Reference Example 5)
A solution of C. in 80 ml of tetrahydrofuran was added to the reaction mixture.

The resulting mixture was stirred at 25°C for 30 minutes and adjusted to pH 4-5.
The mixture was acidified with acetic acid, diluted with water, and extracted with diethyl ether.

The extract is washed with an aqueous solution of IJum (chlorinated with water),
Dry with magnesium sulfate and concentrate under reduced pressure.

Using the residue as an eluent, benzene and ethyl acetate (3:
The title compound 2.3 was purified by silica gel column chromatography using the mixture of 1) and has the following physical properties.
I got 29.

TLC (developing solvent, methylene chloride-methanol = 19
: 1) :Rf =0.28°IR (liquid film method):
C=3450,2940°1720.1660.160
0,1500.980cIrL'.

NMR (CCI4 solution): δ = 7.60-6.35 (
5H1m), 5.70-5.20 (3HSm), 5
．． 00-3.00 (13HSm).

Example 1 Ethyl 9α・11α・15α-trihydroxy-16-
(3-)trifluoromethylphenoxy)-ω-tetratruprosta-trans-2, trans-13-genoate (16-(3-trifluoromethylphenoxy)
-ω-tetratrue-trans-J2-PGF1a ethyl ester] 2.325' ethyl 9α-hydroxy-11α・15
(ξ)-His-(2-tetrahydropyranyloxy)-
16-(3-trifluoromethylphenoxy)-ω-tetratruprosta-trans-2, trans-13-
Genoate (specifically prepared as described in Reference Example 6).

) was dissolved in a mixture of 50 ml of tetrahydrofuran and 29 ml of IN hydrochloric acid, and the solution was stirred at 45° C. for 1 hour.

This solution was then concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography using a mixture of cyclohexane and ethyl acetate (3:2) as an eluent to obtain the title compound 540, its 15β-hydroxy isomer 6.
69 mfI and 258 ml of a mixture of the title compound and the 15β-hydroxy isomer were obtained.

The title compound exhibited the following physical properties. TLC (developing solvent, chloroform-tetrahydrofuran-acetic acid = 10:
2:1): Rf = 10.20 (15β-hydroxy isomer, Rf = 0.27).

IR (liquid film method) Niji-335012930°1720.
166011600,1500°980cIrL-1O NMR (CDCI3 solution): δ=7.60-7.05(
4H, m), 6.94 (IH, d −t ), 5.9
5-5.35 (3H1m), 4.65-4.35
(IH, m), 4.38-3.80 (6H.

m) At least one new therapeutically useful compound of general formula (2) or cyclodextrin clathrate compound or non-toxic salt thereof according to the present invention is used as a pharmaceutical composition in combination with a pharmaceutical carrier or coating. can do.

In clinical practice, the novel compounds of the present invention are usually administered orally, vaginally, rectally or parenterally.

Solid compositions for oral administration include compressed tablets, preforms, powders and granules.

In such solid compositions, one or more active compounds are mixed with at least one inert diluent such as calcium carbonate, potato starch, alginic acid or lactose.

The composition may also contain additives other than inert diluents, such as lubricants such as magnesium stearate, as is conventional practice.

Liquid compositions for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups containing water and inert diluents commonly used in the art, such as liquid paraffin. and elixirs.

Besides such inert diluents, the composition can also include adjuvants such as wetting and suspending agents, and sweetening, flavoring, perfuming and preservative agents.

Compositions for oral administration also include capsules made of absorbable material, such as gelatin, containing one or more active agent materials with or without diluents or excipients.

Solid compositions for vaginal administration include pessaries formed in a manner known per se and containing one or more of the active compounds.

Solid compositions for rectal use include herbal medicines which are formed in a manner known per se and which contain one or more active compounds.

Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.

Examples of non-aqueous solvents or suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.

These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.

These can be sterilized, for example, by filtration through a bacteria-retaining swab, by adding a sterilizing agent to the composition, or by irradiation.

They can also be prepared in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

The percentage of active ingredient in the composition can vary;
It is necessary to set the ratio so that the amount suitable for the required therapeutic effect is obtained.

Of course, several dosage units can be administered at approximately the same time.

In general, preparations are usually administered at
．． It must contain 0.025% by weight of active substance.

For oral administration it will contain at least 0.1% by weight of active substance.

The dosage employed depends on the desired therapeutic effect, the method of administration and the time of treatment.

In adults (or adult animals), the general dosage per person (or animal) is for abortion and induction of labor in pregnant female mammals, including humans, and for estrus in female mammals, including humans. 0.0 for oral, intravaginal, intrauterine, intravenous, intramuscular and extra-amniotic administration for control of pregnancy and pregnancy prevention.
5 to 500 μ2.

In domestic animals such as cows, hens, sows, ewes and ewes, dosages per animal are generally intramuscular, subcutaneous, and intrauterine for synchronization of the estrous cycle, induction of labor, and termination of pregnancy. , 0.01 to 50 Y for intravaginal and intravenous administration.

The prostaglandin compounds according to the invention can be administered orally by methods known per se, which are used for administering by inhalation of drugs which are not themselves gaseous under normal administration conditions.

A solution of the active ingredient in a suitable pharmaceutically acceptable solvent, for example water, can therefore be nebulized with a mechanical nebulizer, eg a light nebulizer, to give an aerosol of fine liquid particles suitable for inhalation.

The solution to be sprayed is preferably diluted.

1 to 10011f of active ingredient per ml of solution! , more preferably 10 to 50μ? Aqueous solutions containing are particularly suitable.

The solution may contain stabilizers such as sodium sulfite, and buffers to impart isotonicity, such as sodium chloride, sodium citrate, and citric acid.

The active ingredient can also be administered orally by inhalation in the form of an aerosol generated from a self-propelled pharmaceutical composition.

Methods for making self-propelled aerosol-generating compositions for administration as pharmaceuticals are described, for example, in U.S. Pat. No. 2,868,691.
No. 3,095,355.

The following example shows a reference example for using the compound of the present invention as a drug.

Reference example 7 Ethyl 9α・11α・15α-trihydroxy-16-
(3-)Lifluoromethylphenoxy)-ω-TetraTrue 70 Star Trans-2, Tiger No 13-Genoate 2■ was dissolved in 10rr11 ethanol 18.
Mix 55' mannitol, sieve through a 30-mesh sieve, dry at 30°C for 90 minutes, and sieve through a 30-mesh sieve.

When 200 μV of aerosol (fine silica) is added and the resulting powder is filled into 100 A62 hard gelatin capsules, 20 μV of ethyl 9α, 11α, 1 per capsule is produced.
It contains 5α-trihydroxy-16-(3-trifluoromethylphenoxy)-ω-tetratruprosta-trans-2, trans-13-genoate and is administered into the stomach by swallowing the capsule.

Claims (1)

[Claims] 1 Represented by the general formula [wherein R4 represents a trifluoromethyl group and R6 represents a hydrogen atom or a straight or branched chain alkyl group containing 1 to 12 carbon atoms] A prostaglandin analog compound or a cyclodextrin clathrate compound thereof or a non-toxic salt when R6 represents a hydrogen atom. 2. The compound according to claim 1, wherein R6 is a hydrogen atom or a straight or branched alkyl group containing 1 to 4 carbon atoms. 3 Ethyl 9α・11α・15α-trihydroxy-1
The compound according to claim 1, which is 6-(3-)lifluoromethylphenoxy)-ω-tetratruprosta-trans-2trans-13-genoate. 4 general formula [wherein R7 is a substituted 2-tetrahydropyranyl group substituted with nine or at least one alkyl group,
2-tetrahydrofuranyl group or 1-ethoxyethyl group, and other symbols are as defined in claim 1]. The symbols are as defined in claim 1.] A method for producing a novel prostaglandin-like compound. 5. The manufacturing method according to claim 4, which uses an aqueous solution of an organic acid or an inorganic acid. 6. The manufacturing method according to claim 4 or 5, wherein acetic acid is used as the organic acid. 7. The manufacturing method according to claim 4 or 5, using hydrochloric acid as the inorganic acid. 8. The manufacturing method according to claim 4.5.6 or 7, which is carried out in an organic solvent that is miscible with water. 9 Claim 4.5.6. uses tetrahydrofuran or alcohol as an organic solvent that is miscible with water.
The manufacturing method according to item 7 or 8.