JPS63122665A - Cyclopentyl ether, manufacture and medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Prostaglandin E, (hereinafter referred to as rPGE, J)
For example, is a natural product that has various physiological effects.

PGE inhibits gastric acid secretion, provides gastrointestinal cell protection, lowers blood pressure, tenses and relaxes smooth muscles, inhibits platelet aggregation, and further inhibits fat breakdown.

Synthetic PGE analogs may have different potencies - longer duration of activity, increased selectivity of action, etc. Therefore, it is of great interest.

The present inventors have discovered some new cyclopentyl ethers having PSE type 2 activity. The compounds of the present invention have extremely useful biological effects. In particular, the compounds of the invention exhibit high potency and excellent selectivity with respect to inhibition of gastric acid secretion and gastrointestinal cell protection. Therefore, the compounds of the invention are promising for the treatment of ulcers. Furthermore, since the compounds of the present invention have a lipid-lowering effect, they are also useful for treating pathological conditions where the underlying cause is lipid imbalance or hyperlipidemia.

, Therefore, one object of the present invention is to provide compounds represented by the following formula (1) and physiologically acceptable salts, solvates and complexes thereof (e.g. cyclodextrin complexes). .

[In the formula, m is 1 to 4; n is Oll or 2; p is 1 to 4; Z is GO, RL group [where nL is (a) hydrogen atom, C1-6 Alkyl, 07~□. Phenylalkyl or 2-naphthyl group 7 or.

(b) Phenyl (this phenyl is optionally C1-
4 alkyl, C1_4 flukoxy, C1_4 alkanoyl, methylthio, methylsulfinyl, methylsulfonyl, halogen, -CO,R" (wherein R2 is a hydrogen atom, C1_4 alkyl or phenyl).

-NH(1:0R2, where -R2 is a group as defined above, or hydroxyl, CH, CONH- or -CONR3R', where R3 and R4 are the same or different, each , hydrogen or C1~
3 alkyl group), -NHCONH2, -C)It
CH(CONH,)NHCOCH, Mamoyoi); or (c)-C)I2COR' group (where R5 is phenyl (this phenyl is optionally C1-4 alkyl,
C1-4 alkoxy, 01-4 alkanoyl, methylthio, methylsulfinyl, methylsulfonyl, halogen, -〇O□R' (where R' is a hydrogen atom, 01-4
alkyl or phenyl), -CONR'R"
(where R7 and R8 are the same or
different, each a hydrogen atom or C□~. alkyl group), -NHCOR'' (where R1 is a group as defined above or optionally hydroxyl, CH,C0
NH- or -NHCONH, -CH,CH(CON
H2) NHCOCH, or R5
is 2-naphthyl> or Z is -CH,0H1-CHO or -CONHR' (
:,,: t', R9 is a hydrogen atom, C1-3 alkyl,
aryl, -COR" (wherein R2O is a hydrogen atom, carbon, alkyl or aryl group) or -5
O□R11 (here, RLl is C engineering~.

is an alkyl or aryl group); (wherein,
R11, R13 and RL4 are each a hydrogen atom or methyl, and at least one is a hydrogen atom; Ar is a phenyl group (this phenyl group may be 01 to
4 alkyl, 01-4 alkoxy, C engineering.

Alkylthio, Cel4alkylsulfinyl, C-
.

(optionally substituted with one or two of alkylsulfonyl, halogen or trifluoromethyl groups). ] Structural formulas shown herein refer to enantiomers of each related compound and mixtures of such enantiomers (including racemates).
This includes:

Generally, -(CHz)-S (0) -(CHz
) OH in the carbon atom with pZ group and/or Y group
The carbon atom bearing the group is in the R configuration. In particular, the former carbon atom is in the R configuration. Mixtures containing such positional isomers are preferred.

When the term "alkyl" is used as a group or as part of a group in the definition of a compound of formula (1), this term is used to include straight chain or branched chain moieties. . Specific examples include methyl, ethyl,
Examples include n-propyl, i-propyl, n-butyl, S-butyl, and t-butyl groups.

The term "halogen" means fluorine, chlorine, bromine or iodine.

An aryl group mentioned in the definition of Z is, for example, phenyl.

A compound of formula (1) in which Z contains C02H or -CO□H group produces an acid with a base. Such salts are, for example,
alkali metals (e.g. sodium and potassium),
alkaline earth metal (eg, calcium) and amine (eg, piperazine) salts, and the like.

When Z is 100
1 is hydrogen and R1 is preferably methyl or 2-
It is naphthyl.

When 2 is a -CO2R'' group, suitable R1 groups of type (b) above are, for example, optionally in the ortho, meta or especially bara position, a chlorine atom, a bromine atom, methyl, ethyl, propyl, n -butyl, t-butyl, methoxy, nidoxy, propoxy, butoxy, acetyl, propionyl, methylthio, methylsulfinyl, methylsulfonyl, -CO□H5-CO, CH,, nzoylamino, (
acetylamino)benzoylamino, (hydroxy)benzoylamino, -CONH2, -CONHCH,, -
CON(C)I, ), -CONHCH2CH,, -
CON (CH2Cl, )2. -NHCONH2,-
CH2Cl (,”,0NH2)NHCOCH.

or a phenyl group substituted with a -CH,CH(CONH,)NHCO-<I> group.

Particularly useful substituents that can be present on the R1 phenyl group are °C1-4 flukoxy, C1-, alkanoyl, methylthio, methylsulfonyl, -CO, R'', -
NHCOR", -CONR3R' (where RZR3
and R4 is a group as defined in formula (1)), -
NHCONH, or -CH,C)I (CONH,)
NHCOCH, etc. Very useful substituents of this type are methoxy, acetyl, methylthio, methylsulfonyl, -CO, CH,, -N)IcOcH, benzoylamino, (p-acetylamino)benzoylamino, (p-hydroxy)benzoylamino, -CONH2
, -CON (CH3)2, -NHCONH, or -
CH, CH(CONH,)NHCOCH.

Generally, when R1 is a group of type (b), R1 is preferably methoxy, acetyl, -CO□CH, -
NHCOCR, Benzoylamino, -CONH,
-c o N(cu z ) z or -CHzCH
(CONH2) A phenyl group substituted with an NHCOCH3 group (particularly substituted at the para position).

When Z is a -CO2R'' group, suitable R' groups of type (c) are e.g.
Rs, methoxyacetyl, -〇O□CR,, -NHC
OCR,, benzoylamino, -CONH,, -CON
(CH3)! or -CH,CH(CONH,)NH
is a phenyl group substituted (especially substituted in the para position) with a COCH, group, or

R5 is a 2-naphthyl group). Particularly useful substituents of this type are -Nl(COCI(3), benzoylamino, acetyl or -CONH, which are preferably attached in the para position of the phenyl group.

When Z is a group other than -CO2R'', suitable Z groups are, for example, -CH20H1-C)10 or -CONHR'
(where R9 is a hydrogen atom, methyl, ethyl, phenyl, -COR" (where R10 is methyl or phenyl) or -5o, R" (where R1" is methyl or phenyl) ), preferably Z is -CH20H1-CHOl-CONH,, -C
ONHCH,, -CONI(COCH,.

-CONH3O, CH, or -CONH5O, <I>
It is.

Preferably, RL3 and R14 in the Y group are hydrogen.

If the Ar phenyl group is substituted, the substituents are, for example, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, or trifluoromethyl. be. Preferably, only one substituent is present, especially in the para position. In general, Ar is preferably phenyl or phenyl substituted with halogen (especially fluorine or chlorine).

Generally, compounds of formula (1) where n is 0 are preferred.

The preferred embodiments mentioned above may be applied alone or in combination of one or more of the several preferred embodiments mentioned.

A preferred group of compounds of the invention are compounds of formula (1) in which the groups are as follows, and their physiologically acceptable salts, solvates and complexes (eg cyclodextrin complexes).

n is 0, m is 3 or 4, and p is 1; or m is 2 or 3, and p is 2; or m is 1 and p is 4.
or.

m is 2 and p is 3.

Z is 100, R” group (here, R1 is a hydrogen atom, 01
~． Alkyl, 2-naphthyl or substituted phenyl (substituents include methoxy, acetyl, -CO□CH,, -NHC
OCH,, benzoylamino, -CONH,, -CON
(CH2)2 or -CH2CH(CONH2)NH
R12 is a hydrogen atom or methyl; Ro and R14 are hydrogen atoms; Ar is phenyl or phenyl substituted with fluorine or chlorine.

Among the aforementioned compounds, -(CH2)-5(0),
Particularly preferred compounds of this type are compounds in which the carbon atom having the (CH2)Pz group is in the R-configuration.
or -layer preferably methyl or -CO,
phenyl substituted at the para position with CH3 or benzoylamino).

Particularly important compounds of the present invention are the following three compounds and their complexes (e.g., cyclodextrin complexes).
It is.

[lR-[1α, 2β(R*), 3α)-4-Cbenzoylamino)phenyl 4-([2-(3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)
-5-oxocyclopentyl]ethyl]thio]butanoate; (IR-(1α, 2β(R*), 3α)]-methyl 4- (((2-[3-hydroxy-2-(2-
Hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]ethyl]thio]1-oxobutyl]oxy]benzoate;
3α)]-(-)-methyl 4-((2-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]ethyl]thio]butanoate.

The compounds of formula (1) also have gastrointestinal cytoprotective effects.

Indomethacin 5 mg/kg before administering test compound
R ob e modified to use (subcutaneous)
rt et al. “G,astroanterology”,
1979.77, 433, the ability to suppress ethanol-induced lesions in conscious rats is demonstrated.

Compounds of formula (1) can also reduce lipid levels, as demonstrated in standard animal models.

For example, exemplified by the ability to reduce non-esterified fatty acid levels in starved rats (P, P.

Lovisolo et al.+”Pharmacologica
lResearchCommunications''
, 1981.13.163-174; E, Sch
Illinger and O. Loge, “Bioch
amical Pharmacology”, 1974
．． 23.2283-2289).

Therefore, a compound of the present invention is promising for the prevention and/or treatment of ulcers. The compounds of the invention can also be used to treat other conditions caused by hypersecretion of gastric acid. Furthermore, the compounds of the invention can also be used for the prevention and/or treatment of pathological conditions whose underlying etiology is associated with lipid imbalance or hyperlipidemia.

Another object of the invention is the use of compounds of formula (1) or physiologically acceptable salts or complexes thereof, such as , cyclodextrin complex)°.

Another object of the invention is a compound of formula (1) or a physiologically acceptable salt thereof for use in the prevention and/or treatment of pathological conditions whose underlying etiology is associated with lipid imbalance or hyperlipidemia. or complexes (e.g.

cyclodextrin complex).

Yet another object of the present invention is to provide a method for the treatment of humans or animals with ulcers and other conditions resulting from hypersecretion of gastric acid or whose underlying etiology is associated with lipid imbalance or hyperlipidemia. It is to provide. This method of treatment comprises a compound of formula (1) or a physiologically acceptable salt or complex thereof (e.g. cyclodextrin complex).
effective amount.

It consists of administering to said human or animal.

The compounds of the invention may be advantageously used in combination with one or more other therapeutic agents, such as non-steroidal anti-inflammatory agents or other anti-ulcer agents. Therefore.

The scope of the invention also extends to the use of a compound of formula (1) or a physiologically acceptable salt or complex thereof (eg, a cyclodextrin complex) in combination with one or more other therapeutic agents.

Yet another object of the invention is to provide a compound of formula (1) or a physiologically acceptable salt or complex thereof (for example a cyclodextrin complex) as an active ingredient, together with one or more pharmaceutical carriers or excipients. An object of the present invention is to provide a pharmaceutical composition containing the following.

The compounds can be formulated in conventional manner, for example, for oral, light chain, parenteral, or rectal administration, with one or more pharmaceutical carriers.

The compounds of the invention may be formulated for oral administration, eg, as powders, solutions or syrups prepared in conventional manner with acceptable excipients.

The compounds of the invention can be formulated for parenteral administration by injection or infusion. The dosage form for injection may be in unit dosage form in ampoules or vials with a preservative.

For light chain administration, the compounds of the present invention can be formulated into tablets, troches, etc. by conventional methods. For rectal administration, compositions such as hydrating or slow-release enemas containing conventional hydrating bases such as cocoa butter or other glycerides can be used.

The compounds of the invention are preferably administered orally at a dosage of 0.5 to 300 μg/kg (body weight) 1 to 4 times a day.

In the case of parenteral administration, the compounds of the present invention are 0.01 to 10
It can be administered at a dosage of μg/kg (body weight) from 1 to 4 times a day. The exact dosage will, of course, vary depending on the age and condition of the patient.

Suitable methods for making compounds of the invention are disclosed below. Unless otherwise specified, various groups and symbols are as defined above.

(a) The compound of formula (1) can be produced by deprotecting the compound of formula (2) below.

+ 1 (2) R"OOY" zl is 2 groups as defined for formula (1) or -CH,OR" group, where RLS is a suitable hydroxyl protecting group (e.g. tetrahydro- pyran-2-yl, tetrahydrofuran-2-yl, ethoxyethyl,
tri(hydrocarbyl)silyl or arylmethyl)
The two R1s groups in the compound of formula (2) can be the same, but can also be different if desired.

When 81% is tri(hydrocarbyl)silyl, the hydrocarbyl substituents are the same or different, e.g.
ct-2, alkyl, C2-6 fluorenyl, C1-7 cycloalkyl*ct-2o aralkyl, and C2-aryl. Such groups include, for example, methyl, ethyl, n-propyl, isopropyl. -butyl, isobutyl, t-butyl, allyl, phenyl and benzyl. Preferred hydrocarbyl groups are C1-3
is alkyl (e.g. methyl and t-butyl),
Particularly preferred are trimethylsilyl and t-butyldimethylsilyl.

When Rls is an arylmethyl group, R can contain up to 20 carbon atoms. Specific examples are benzyl, diphenylmethyl or triphenylmethyl.

The method used to deprotect the protected hydroxyl group will depend on the nature of R, but generally acidic hydrolysis or reduction can be used.

Thus, for example, when R is tetrahydropyran-2-yl, deprotection of the tetrahydrofuran-2-yl or ethoxyethyl group can be carried out with an acid. Suitable acids are inorganic acids such as hydrochloric acid or organic acids such as acetic acid or trifluoroacetic acid. Suitable solvents include ethers (e.g. diethyl ether, dioxane, and tetrahydrofuran), halogenated hydrocarbons (e.g.
dichloromethane), hydrocarbons (e.g. toluene),
Dipolar neutral solvents (e.g. acetone, acetonitrile, dimethyl sulfoxide and dimethylformamide)
and alcohols (e.g. methanol).

ethanol and ethylene glycol). If desired, the solvents mentioned above can also be used in combination with water.

The reaction can be carried out at any suitable temperature, such as from 0<0>C to 50<0>C, for example from 40<0>C to 50<0>C.

Tri(hydrocarbyl)silyl groups can be removed, for example, by acid hydrolysis with dilute mineral acids or trifluoroacetic acid, or by fluoride ions (e.g. those derived from quaternary ammonium fluorides such as tetra-n-butylammonium fluoride). or a hydrogen fluoride aqueous solution. The arylmethyl group can be prepared, for example, by reduction (e.g. hydrogenolysis with a noble metal catalyst such as platinum or palladium) or by Lewis reaction in the presence of a thiol (e.g. ethanethiol) in a suitable solvent such as dichloromethane at room temperature. It can be removed by treatment with an acid (eg boron trifluoride-etherate).

The compound of formula (2) is the compound H of the following formula (3)? −(cHt), s(○)−(CH,)pZ”,・
・Formula yL, zL and Ro are as defined above, for example, in the presence of pyridinium trifluoroacetate in a solvent such as dichloromethane at −10° C. to room temperature. , N,N'-dicyclohexylcarbodiimide activated by oxidation with dimethyl sulfoxide. Other conventional oxidation methods such as pyridinium chlorochromate, pyridinium dichromate or Jones reagent can also be used.

In this reaction, group 21 is a group other than -CHO. Zl
When is 10)1.0)1, this -OH group needs to be protected during the conversion reaction. Therefore, the 21 group can be, for example, the above-mentioned -CH,OR'' group.

Deprotection method (a) is usually applied in conjunction with the oxidative generation of the cyclopentyl ring oxo group. Therefore, 1 equation (1
) are generally produced by oxidizing the corresponding compound of formula (3) and subsequent removal of the protecting group.

However, the ring oxo group can be produced using method (b) described later.

It is also possible to carry out prior to the introduction of the desired Z group according to (c), (f) or (g) and then remove the protecting group.

The compound of formula (2) in which zl is -CHO is, for example, -2
using an activated sulfur reagent (e.g. N-chlorosuccinimide dimethyl sulfoxide complex) in a suitable solvent (e.g. toluene or dichloromethane) at a temperature of 5°C to +25°C, or preferably at 0°C to room temperature. Using pyridine-SO, complex in dimethyl sulfoxide, Z
L is -C)1. It can be produced by oxidizing the corresponding compound which is OH.

Is the intermediate of formula (3) where n is O the sulfonate of formula (4)? H2-(CH2), O20, R''R''OOY' (wherein Ro and Yl are as defined above, and R1'' is C1-3 alkyl or aryl.

For example, a monocyclic aryl such as 4-methylphenyl) can be produced by reacting a thiol of the formula H5(CH,)pZl or a salt thereof (eg, the sodium salt). This alkylation is carried out at a suitable temperature (e.g. 0°C
to room temperature) in a solvent such as dimethylformamide in the presence of a base such as sodium hydride or potassium 1-butoxide.

The thiol of formula H5(CH,)pZl is a known compound and can also be produced by agricultural methods analogous to those used to produce this known compound.

Is the intermediate of formula (4) the corresponding diol of formula (5)? H R... (wherein Yl and Rls are groups as defined above) of the formula R"So□C1 (wherein R111 is a group as defined above) It can be produced by reaction with a sulfonyl halide, for example sulfonyl chloride. The sulfonylation is preferably carried out in the presence of a suitable acid scavenger, for example an organic base such as pyridine which can also be used as a solvent. Preferably, the reaction is carried out at 0°C.

The compound of formula (4) can be prepared and purified, but
It can also be generated on the spot and used immediately.

The compound of formula (3) in which zl is -C02H can be heated from room temperature to 5
It can also be produced by hydrolysis of the corresponding ester (eg 01-6 alkyl ester) using a base such as sodium hydroxide or potassium hydroxide in a suitable solvent (eg methanol) at a temperature of 0°C.

The intermediate diol of formula (5) can be produced as shown in the reaction formula below.

(6) (5), m is 2°＼ Δ 20Y1 R...δ (5), m is 1° (9) (5) 1m is 3° (admiration)
○HCO, R17R...6 (1 (11) (5), m
For example, in reaction formula (i), diols of formula (5) where m is 2 can be prepared by mixing the lactone of formula (6) with a suitable solvent (e.g. ,
Tetrahydrofuran) by reduction with lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride or diisobutylaluminum hydride.

Diols of formula (5) in which 1 m is 1 in reaction formula (it) are treated with a suitable solvent (
For example, in ethanol-dichloromethane mixture), the formula (8
The enol ether of ) is ozonolyzed and subsequently reduced in situ with 1 e.g. borohydride. Enol ethers of formula (8) can be obtained by preparing lactol of formula (7) in the presence of a base (e.g. triethylamine or pyridine) in a suitable solvent (e.g. dichloromethane) at an appropriate temperature (e.g. -78°C to room temperature). can be produced by reacting R''5O2CI with sulfonyl chloride.

It can be produced by reacting the resulting intermediate with alkaline hydrogen peroxide. This reaction can be carried out in a suitable solvent (eg, tetrahydrofuran) at a suitable temperature (eg, 0°C to room temperature).

The olefin of formula (9) is a lactol of formula (7).
"CHz" (where "Q, R" is aryl, eg, monocyclic aryl such as phenyl).

Preferred solvents are tetrahydrofuran and dimethyl sulfoxide. This reaction can be carried out at any temperature within the range of -70°C to 50°C, preferably at room temperature.

In reaction formula (tv), the diol of formula (5) where m is 4 can be obtained by the same method as the above method for converting the lactone of formula (6) to the diol of formula (5) where m is 2. , can be produced by reducing the ester of formula (11). Esters of formula (11) can be converted to the corresponding α of formula (10) by hydrogenation in a suitable solvent such as an alcohol (e.g. ethanol) in the presence of a noble metal catalyst such as platinum or palladium.

9 that can be produced by reducing β-unsaturated esters
The unsaturated ester of formula (10) is organic! (e.g. acetic acid) in a suitable solvent such as ethanol.
,-,7) Li Ki/L/or 07~□. (phenylalkyl, Rls is a group as defined above) and a lactone of formula (7).

Lactones of formula (6) and lactols of formula (7) can be produced by the method disclosed in European Patent Specification No. 160495.

(b) Compounds of formula (1) in which z is -CO2R'' (where R'' is a group of the (a) type or (b) type) may be esterified with the corresponding compounds in which Z is -CO□H. It can be generated by

Such compounds can be prepared, for example, by reaction with an alkyl chloroformate (e.g. isobutyl chloroformate) or an acid chloride (e.g. pivaloyl chloride) in the presence of a suitable base (e.g. triethylamine or pyridine). The acid is converted into an active derivative (e.g.
mixed acid anhydrides). This active derivative is then heated at any suitable temperature (e.g. -
10°C to room temperature) in a dipolar neutral solvent (e.g. acetone,
R10H can be reacted with the appropriate alcohol using a solvent such as acetonitrile or dimethylformamide) or a halogenated hydrocarbon (eg dichloromethane).

Furthermore, compounds of formula (1) in which R1 is a C1-3 alkyl group can be obtained by esterifying the corresponding carboxylic acid with a diazoalkane (e.g. diazomethane) in a suitable solvent (e.g. dichloromethane or ether) at room temperature. It can be generated by

(c) Compounds of formula (1) in which Z is -CONHR' are group carboxylic acids or alkyl esters of formula (1), i.e., Z is -CO2R'' (wherein R1 is a hydrogen atom or c, -8 alkyl can be produced by amidation of the corresponding compound which is a group).

Conventional methods of converting acids and esters to amides can be used. For example, a reactive derivative of a carboxylic acid of the formula R' is prepared in a suitable solvent such as acetone or acetonitrile.
Treat with a compound of Nl2. This reactive derivative is, for example, a mixed anhydride of the acid produced by treating the acid with a chloroformate in the presence of a suitable base such as triethylamine or pyridine. Chloroformic acid esters are, for example, C1-5 alkyl (eg, isobutyl), aryl (eg, phenyl) or aralkyl (eg, benzyl) esters of chloroformic acid. Alternatively, the monoreactive derivative can be an imidazole produced by treating an acid with 1,1'-carbonyldiimidazole.

The ring hydroxy group must be protected during these reactions. Conventional protection and deprotection methods such as those described in method (a) above can be used.

(d) A compound of formula (1) where n is 1 can also be produced by oxidizing a compound of formula (1) where n is ○ with a suitable oxidizing agent in a suitable solvent (e.g. methanol). .

(e) Compounds of formula (1) where n is 2 can be prepared by combining a compound of formula (1) where n is 0 with a suitable oxidizing agent (e.g. metachloroperbenzoic acid) in a suitable solvent (e.g. dichloromethane). It can also be produced by oxidation with peracids (such as peracids).

(f) The compound of formula (1) in which Z is -CO,H can also be produced by hydrolyzing the corresponding ester. This ester is preferably an unstable ester, such as a compound of formula (1) in which Z is 1002R'' (where R1 is tetrahydropyran-2-yl or tri(hydrocarbyl)silyl), Decomposition is carried out with an acid (eg acetic acid or trifluoroacetic acid) in a suitable solvent (eg aqueous tetrahydrofuran or dichloromethane) at a suitable temperature.

(g) Compounds of formula (1) in which Z is -CO, R'' (wherein R1 is a group of type (c)), wherein 2 is -C
The corresponding compound which is O2H is the ketone XCH2COR' of formula (12) (12)
(where X is a leaving group such as halogen (e.g., bromine)) The reaction can also be produced by alkylation with acetonitrile or dimethylformamide at a suitable temperature (e.g., room temperature). Preferably it is carried out in a solvent in the presence of a base such as diisopropylethylamine or potassium fluoride.

The ketone of formula (12) is a known compound, and can also be produced by methods similar to those used for producing known compounds.

(h) If a salt of a compound of formula (1) is desired, the salt may be prepared in a conventional manner, for example by preparing an acid of formula (1) with a base (e.g. an amine such as piperazine) in a solvent such as an ether. It can be generated by processing.

The complex (for example, cyclodextrin complex) can be prepared by a conventional method, for example, by adding the compound of formula (1) to α in a suitable solvent.
-1 can be produced by treatment with β-1 or γ-cyclodextrin.

The approaches of methods (b) to (g) are also applicable to compounds of formula (2) and in particular to compounds of formula (3). The product obtained can then be converted into a compound of formula (1) by the method described above.

If a specific enantiomer of formula (1) is required, starting materials with the desired stereoisomerism must be used in the process described above. Such starting materials include, for example:
It can be produced using the method disclosed in European Patent Specification No. 160495 from the mirror image intermediate disclosed in European Patent Specification No. 74856.

Hereinafter, the present invention will be explained in more detail with reference to Examples.

In the examples below, the following abbreviations are used for convenience of explanation:
Abbreviations etc. were used.

All temperatures are in degrees Celsius.

The term "dried" means drying with anhydrous MgSO4.

"TLC" stands for silica thin layer chromatography.

Chromatography was performed on silica gel.

ER=ether; EA=ethyl acetate; PE=petroleum ether (unless otherwise stated, from 9.40 to 60'C);THF=tetrahydrofuran; C) I, Cl2
=dichloromethane; CHBr, =bromoform;
MeO)l = methanol; DMF = dimethylformamide; CHCl, = chloroform.

Stop jB(L [3aR-(3aα, 4α(娨*), 5β, 6aα])
-(÷)-hexahydro-4-[3-phenoxy-2-
[(tetrahydro-2H-pyran-2-yl)oxyfupropoxy)-5-((tetrahydro-2, pyran-2
-yl)oxy) -2! i-cyclopenta(b)furan-2-one earthenware raw matata [3aand-(3aα, 4α(岨*), 5β, 6aα]]
-hexahydro-4-[3-phenoxy-2-[(tetrahydro-pyran-2-yl)oxyfupropoxy]-5-((tetrahydro-28-pyran-2-yl)
Oxy]-21-cyclopenta(b)furan-2-one intermediates 1 and 2 were produced as disclosed in European Patent Specification No. 160495.

Fresh plate standing [1G [1α, 2β (2 needles), 3α, 5α]] -5-
Hydroxy-2-[3-phenoxy-2-[(tetrahydro-pyran-2-yl)oxyfupropoxy]-
A solution consisting of 3-((tetrahydro-2ji-pyran-2-yl)oxy]-cyclopentaneethanol intermediate 1 (Ig) and THF (20 ml) was mixed with LiAQH4 (0.08 g) and THF (5 d
) under stirring under a nitrogen atmosphere. After 3 hours, LiAQH+ (0.08g)
was further added. After 2 hours, water (2+nQ) was added and the mixture was stirred for 10 minutes. Then, ER(5
It was separated into two phases using 0n+Q) and 2NHCn (50mm). The organic phase was separated and diluted with 8% NaC0° solution (SOmQ
) and brine, and the aqueous wash solution was washed with ER
(50 mffi). The organic phase was dried and evaporated. EA −+ EA-Me as eluent
Purified by chromatography using OH (97:3). 0.79 g of the oily title compound was obtained. IR(CHBr,): 3600.3420c
m-"Main dish clay -2!i-pyran-2-yl)oxyfupropoxy]-3-[(tetrahydro-2
total pyran-2-yl)oxy]-cyclopentyl]ethyl]thio]butanoate 4-methylbenzenesulfonyl chloride (0,36 g) and intermediate 3 (0,69 g
) was dissolved in dry pyridine (6 ml) at 0° C. under nitrogen atmosphere. After 6 hours, γ-thiobutyrolactone (0.6n
+Q), sodium methoxide (0,27g) and M
A solution consisting of ast ((7m12) was added.O”C
After standing for 18 hours at room temperature, the reaction mixture was allowed to warm to room temperature. After leaving it for another 7 hours, ER (40+n1
2) and the solution was dissolved in 2N HCQ (2X 50m
R), 8% NaHCO, aqueous solution (50+aQ) and saturated brine (50ml). The washings were post-extracted with ER and the organic phases were combined and dried. Evaporation of the solvent and purification by chromatography using ER-PE (9:1) as eluent gave 0.39 g of the title compound as an oil. IR (CHBr3): 35g0
．． 3510.1725 cm-” Intermediate 5 [3aR-(3a a , 4 a (2R*), 5β,
6a a )]-]4.5,6,6a-tetrahydro4
-[3-phenoxy-2-[(tetrahydro-28-pyran-2-yl)oxypropoxy]-5-[(tetrahydro-27pyran-2-yl)oxy]-3a total cyclopenta[b]furan intermediate Methanesulfonyl chloride (1,0 Uaf
1) was added with stirring. After 18 hours, the solution was cooled to -30°C and water (0.4 mQ) was added. The solution was warmed to room temperature and after 20 minutes ether (200d) and 2N NaOH solution (200m
u), separated into two phases with saturated brine (200ml), dried and evaporated. The residue was purified by chromatography using ER as eluent to give 0.66 g of the title compound as an oil. TLC(P
E-ER, 3: 2) Rf=0.24 Main body [1-[1α, 2β (2 needles), 3α, 5α]]-5-
Hydroxy-2-[3-phenoxy-2-[(tetrahydro-pyran-2-yl)oxypropoxy)-
3-((tetrahydro-27pyran-2-yl)oxycyclopentane methanol intermediate 5 (0.71 g), CH2Cl2z (30 m
12) -EtO)+ (12mQ) and Sudan
ozone was bubbled into a -78°C solution consisting of 0.5 mg of sodium borohydride (0.34 g of sodium borohydride).
) was added. -78℃ for 10 minutes, 0℃ for 30 minutes,
After standing for 1 hour at room temperature, saturated ammonium chloride solution (50d) was added. This mixture was mixed with CH2CR2(2
Extract with X 50 mQ) and dry the organic phase.

Evaporated. EA-MeOH (98,5:
The residue was purified by chromatography using 0.1-+96:4) to give the title compound as an oil.
I got g. to IR): 3400cm-1 Main I [1-[1α, 2β, 3β (2 needles), 4α)] -(
+)-3-(3-phenoxy-2-[(tetrahydro-
2-pyran-2-yl)oxypropoxy)-2-(
2-propenyl)-4-[:(tetrahydro-2pyran-2-yl)oxycocyclopentanol potassium t-butoxide (1,40 g) and (methyl)triphenylphosphonium bromide (4,50 g) were dissolved in THF. (50 mR) under nitrogen atmosphere for 20 minutes. Intermediate 2 (2.09g) in THF (25+Q)
After the solution was added and stirred at room temperature for 18 hours, saturated ammonium chloride solution (100 mu) was added. ER(2X
100d), drying, evaporation of the solvent and purification by chromatography using ER-PE (3:1) as eluent to give the oily title compound as 1.
98g was obtained. IR (CHBr3) '3590, 353
0cm-';[α)♂'=+23.8°(CHCI
2. ) Lord 1st birthday [1 and - [1α, 2β (2 needles), 3α, 5α)] - (+
)-5-hydroxy-2-[3-phenoxy-2-[(
Tetrahydro-2H-pyran-2-yl)oxypropoxy)-3-((tetrahydro-pyran-2-yl)oxycocyclobentaneprobanol Intermediate 7 (1,93 g) T) IF (30 mR) A THFIM solution of borane (4, OmQ) was added to the solution at 0° C. under nitrogen atmosphere.

After 4 hours, more borane solution (5, OmQ) was added. After a further 2 hours water (5 mff) was added followed by 2N NaOH (4.5 mQ) and 30% perdispersed hydrogen (3.4 mU). After 30 minutes, 20% aqueous sodium sulfite solution (50 mQ) was added and an additional 3
After stirring for 0 min, the mixture was immersed in ER (2X 60mu
) and the organic phase was dried and then evaporated. The residue was purified by chromatography using EA→EA-MeOH (93:3) as eluent;
1.84 g of the oily title compound was obtained. IR(CHBr,
): 3600.3520cm-1; [α] also' =
+9.5' (MeOH) Intermediate 9 [1 Do-[1α, 2β (2 needles), 3α, 5α]]-ethyl 4-[5-hydroxy-2-[3-phenoxy-2
-[(tetrahydro-2[-pyran-2-yl)oxypropoxy]-3-[(tetrahydro-岨-pyran-
2-yl)oxy]cyclopentyl]2-butanoate E:Z, containing 1 drop of 60:40 acetic acid, intermediate 2 (
(carbethoxymethylene)triphenylphosphorane (1.05 g) in EtOH (40 mM) solution of
was added. After 5 days, more (carbethoxymethylene)triphenylphosphorane (0.5 g) was added. 2 more
After a day, evaporate the solvent.

The residue was partitioned into two phases with EA (40 mI2) and 8% NaHCO, aqueous solution (40 mM). The organic phase was washed with saturated brine (40mM) and the aqueous phase was washed with EA (40mM) and the aqueous phase was washed with EA (40mM).
0 mm).

Combine the organic phases, dry, evaporate the solvent, and
The residue was purified by chromatography using ER-PE (9:1) as eluent to give 1.14 g of the title compound as an oil. IR(CHBr,): 3
520゜1705c+a-1 Fresh bile [1 G [1α, 2β (2 needles), 3α, 5α)] −(
+)-Ethyl 4-[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-pyran-2-yl)
Oxy]propoxy]-3-[(tetrahydro-pyran-2-yl)oxy]cyclopentyl]2-butanonite 10% palladium oxide on carbon (0,28 g), Intermediate 9 (1,08 g) and EA (50 mm ) was stirred for 2 hours under a hydrogen atmosphere. Filter the catalyst 5 times,
Evaporation of the solvent gave 1.06 g of the title compound as an oil.

IR(C)IBr, ): 3590.3520.17
50cm-1; [α] also' = +23.2° (CHl, )
Sat 1st birthday [1dan - [1α, 2β (岨*), 3α, 5α)] - (+
)-5-hydroxy-2-[3-phenoxy-2-[(
A solution of tetrahydro-2(pyran-2-yl)oxypropoxy)-3-((tetrahydro-28-pyran-2-yl)oxycocyclopentanebutanol intermediate 10 (1,02 g) in THF (20 mm)) A 3.4 M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (1.0 ml
2) was added. After 1 hour, saturated ammonium chloride (2
5d) was added.

This mixture was extracted with EA (2×40ml). The residue was purified by drying, evaporation of the solvent and chromatography using EA as eluent to give 0.78 g of the title compound as an oil. IR(CHBr,):
3600°3520cm-'; Ca) also'=+
26' (CHCI2.) Main and raw U (12a) Cl5-(1a, 2β (2S pieces),
3 a , 5 a )) -5-hydroxy-2-[3
-phenoxy-2-[(tetrahydro-2H,-pyran-2-yl)oxypropoxy)-3-[(tetrahydro-2H-pyran-2-yl)oxycocyclopentaneethanol 4-methylbenzenesulfonate 4 -Methylbenzenesulfonyl chloride (0.47g)
and Intermediate 3 (0.9g) at 0°C with pyridine (10n
+u) and the resulting solution was stirred for 8 hours to obtain the title compound. TLC(ER-PE, 5:1)R
f=0.35(12b) [l5-(1α, 2β(2
needle), 3α, 5α]]-5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-2!U-pyran-2
-yl)oxypropoxy)-3-((tetrahydro-28-pyran-2-yl)oxycocyclopentaneethanol 4-methylbenzenesulfonate intermediate 6 (0,29g), 4-methylbenzenesulfonyl chloride ( A solution consisting of 0.15 g) and pyridine (3 mn) was allowed to stand at 4°C for 24 hours.ER(40-)
and this solution was diluted with 2N HCQ (40mM), 8%
NaHCO, aqueous solution (40 mm) and saturated brine (
40 mΩ). The washings were post-extracted with ER (30 mm), the organic phases were combined, dried and the solvent was evaporated. The residue was purified by chromatography using ER-PE (9:1) as eluent to give 0.28 g of the title compound as an oil.

IR(CHBr,) 3580.3520.1360c
m-1 The following compound was produced by a similar method.

(12c) (Niichi [1α, 2β (2 needles), 3α, 5
α]]-5-hydroxy-2-[3-phenoxy-2-
[(tetrahydro-2[-pyran-2-yl)oxypropoxy] -3-((tetrahydro-pyran-2-yl)
2-yl)oxycocyclobentabanol produced from 4-methylbenzenesulfonate intermediate 8. Engineering R (CHBr, ); 35
20.1352am-" (12d) (15-(1μ, 2β (2dansha), 3α, 5α):l-(+)-5-hydroxy-2-[3-phenoxy-2-[( Tetrahydro-27pyran-2-yl)oxyfupropoxy)-3
-((tetrahydro-pyran-2-yl)oxycocyclopentanebutanol Produced from 4-methylbenzenesulfonate intermediate 11.IR(CHBri); 3
600° 3530, 1352cn+-L; [α] also'=+21° (CHCI2.) Lord's birth sphere (13a) (Is-(lα, 2β (2 needles), 3
(!, 5 cg))-methyl 3-((2-[5-
Hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxyfupropoxy]
-3-((tetrahydro-2pyran-2-yl)oxy]cyclopentyl]ethyl]thio]propionate was stirred for 1 hour in advance. Methyl 3-mercaptopropionate (1,1 mff1), potassium t-butoxide ( 1,0 g) and dimethylformamide (15
Intermediate 12 produced immediately before using a solution consisting of a+Q)
It was added to the pyridine (Iong) solution of a at 0°C. 0℃
After standing for 17 hours, ER (100mM) was added, and this solution was diluted with 2NHCQ (100mM), 8% NaHC
Washed with O, aqueous solution (100d), water (100 ports 12) and saturated brine (100mQ). Wash the cleaning solution with ER (
After extraction with i00 mΩ), the organic phases were combined and dried. The residue was purified by evaporation in the presence of Et3N (1 ml) and chromatographed using ER-PE (9:1) as eluent to give 0.45e of the title compound as an oil. TLC (ER-PE, 9:1
) Rf=0.25(13b) (1-[1α, 2β
(around, 3α, 5α]]-methyl 5-[[[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-
28-pyran-2-yl)oxyfupropoxy]-3-
((tetrahydro-214-pyran-2-yl)oxy]cyclopentyl]methyl]thio]pentanoate 5-
Methyl (acetylthio)pentanoate in dry MeOH (6
++Q) Sodium methoxide (0.22 g) was added to the solution while stirring under nitrogen atmosphere. After 3 hours, the solvent was evaporated and the solid residue was dissolved in dimethylformamide (5
mQ) and a solution of intermediate 12b (0.25 g) in dimethylformamide (511 U) was added.
After stirring for days, ER (70d) was added and the solution was diluted with 2N HCn (70aQ), water (3X 70++jl).
and saturated brine (70IIIn). The aqueous washes were post-extracted with ER (70aQ) 1' and the organic phases were combined and dried. Evaporate the solvent and use ER- as eluent.
Purification by chromatography using PE (9:1) gave 0.2 g of the title metal as an oil. IR
(CHBr,): 3490.3430.1731c
m"" The following compounds were produced in a similar manner.

(13c) (IS-(L a , 2β (2 di),
3 tx , 5 a ))-Methyl [[3-[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxyfupropoxy]-3
-(Tetrahydro-2!i-pyran-2-yl)oxy]cyclopentyl]propyl]thio]pentanoate intermediate 12c and methyl mercaptoacetate. IR (CHBr, ): 3490.3430.
1731cm-” (13d) (1dan-[1α, 2β
(2 needles), 3α, 5α]]-methyl 3-((3-(5
-Hydroxy-2-[3-phenoxy-2-[(tetrahydro-pyran-2-yl)oxyfupropoxy]
-3-((Tetrahydro-pyran-2-yl)oxy]cyclopentyl]propyl]thio]propionate produced from intermediate 12c and methyl 3-mercapdrobionate. TLC (ER) Rf = 0.34 ( 1
3e) [1G [1α, 2β (2 needles), 3α, 5α
]]-(lymethyl((4-(5-hydroxy-2-[
3-phenoxy-2-[(tetrahydro-2[-pyran-2-yl)oxyfupropoxy)-3-((tetrahydro-27pyran-2-yl)oxy]cyclopentyl]butyl]thio]acetate intermediate 12d and methyl mercaptoacetate. IR (CHBr, ): 3520.1728
cm-';[α]♂' = + 25.6 CCHCQ
, ) Main Akio U [1dan - [1α, 2β (2 needles), 3α, 5α)) -4
-([2-(5-hydroxy-2-[3-phenoxy-
2-[(tetrahydro-2[-pyran-2-yl)oxyfupropoxy)-3-((tetrahydro-2-pyran-2-yl)oxy]cyclopentyl]ethyl]thio]
5 in MeOH (14tQ) solution of butanoic acid intermediate 4 (0.6g)
NNaOH (3tjl) was added. After 2 hours, the mixture was poured into water (100 d) and ER (1
00o+Q). The aqueous extract was acidified with ammonium chloride (80mffi).

Extracted with EA (3X 75ml). The organic extracts were combined, dried and evaporated to give 0.6g of the title compound as an oil. IR (CHBr3): 3500.
3400-2500.1728cm-” Saturday student (15a) (Is-(1a, 2β(25*), 3
α, 5ct)]-4-(benzoylamino)phenyl 4
-((2-(5-hydroxy-2-[3-phenoxy-
2-[(tetrahydro-2pyran-2-yl)oxy]propoxy]-3-((tetrahydro-2[-pyran-2-yl)oxy]cyclopentyl]ethyl]thio]
butanoate intermediate 14 (0,6 g), Et, N (0,5 mQ) and dry dimethylformamide (5 mfl) at 0 °C.
Pivaloyl chloride (0.15ml) was added to the solution.
After 15 minutes, 4-(benzoylaminophenol) (0,
A solution of 53 g) in dimethylformamide (2 mQ) was added and stirring was continued for 6 hours at 0°C and 18 hours at room temperature. The reaction mixture was diluted with EA (100 mQ) and water (2X
60mM) and brine (50mM).

The aqueous washings were post-extracted with EA (100mu) and the organic phases were combined, dried and evaporated. Et using chlorohexane-EA (2:1) as eluent,
Purification by chromatography on N-deactivated silica gel gave 0.35 g of the title compound in the form of a gum. IR(CHBr,): 3520.3420.1
748°1728.1672 cm-1 The following compound was produced in a similar manner.

(15b) [1-[1α, 2β (2 needles), 3α,
5α]]-Methyl 4-(4-((2-(5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-A-pyran-2-yl)oxy]propoxy)-3-((
Tetrahydro-2(pyran-2-yl)oxy[cyclopentyl]ethyl]thio]-1-oxobutoxy]benzoate (-IR(C)lBrz) produced from intermediate 14 and 4-hydroxybenzoic acid methyl ester): 352
0-1754°1715cm-1 Main 1 hedge (16a) (IR-(1a, 2β(2R*),
3 a))-4-(Benzoylamino)phenyl 4
-[[2-[5-oxo-2-[3-phenoxy-2-
[(tetrahydro-2H-pyran-2-yl)oxy]
propoxy)-3-[(tetrahydro-pyran-2
-yl)oxy]cyclopentyl]ethyl]thio]butanoate intermediate 15a (0,33 g), dry CH2CJ1z (
A stirred solution consisting of dicyclohexylcarbodiimide (0.53 g) and pyridinium trifluoroacetate (0.33 g) was treated with stirring. After 22 hours, water (5 companies) was added and after 5 minutes the mixture was
filtered and evaporated.

The residue was dissolved in ER (20mM) and water (10+aQ
), 10% aqueous copper sulfate solution (20 sajl) and brine (20+*1). E the aqueous cleaning solution
Post-extracted with R(20-), the extracts were combined and dried,
and evaporated.

Purification by chromatography on acid-washed (pH 3,8) silica using cyclohexane-EA (2:1) as eluent gave 0.25 g of the title compound as an oil. IR(CHBr,): 3420.1738.
2 (16b) [1fi-Elα, 2β (2),
3α]]-methyl[4-((2-[5-oxo-2-[
3-phenoxy-2-[(tetrahydro-2!U-pyran-2-yl)oxy]propoxy]-3=[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]ethyl]thio]butoxy]benzoate Produced from intermediate 15b. IR (CHBri):
1740-1717cm-1 (16c) (IR-(1a, 2β (2R car),
3 a )]-methyl(4-((2-[5-oxo-2
-[3-phenoxy-2-[(tetrahydro-2!U-
pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-pyran-2-yl)oxy]cyclopentyl]ethyl]thio]butanoate Intermediate 4. TLC (ER-PE, 2:1) Rf=0
．． 28 (16d) (IR-[lα, 2β(娨*), 3α]
]-Methyl(4-((2-[5-oxo-2-[3-phenoxy-2-[(tetrahydro-2!i-pyran-2
-yl)oxy]propoxy]-3-[(tetrahydro-2Ii-pyran-2-yl)oxy]cyclopentyl]ethyl]sulfinyl]penzoate intermediate 17a. IR(CHBr,):
173 g cm-” ER-PE (2:1) as eluent
→The following compound was purified in the same manner as above except that it was purified by chromatography using ER.

(16e) (1 shaku - [1α, 2β (娨*), 3α]
]-Methyl 3-((2-[5-oxo-2-[3-phenoxy-2-[(tetrahydro-214-pyran-2
-yl)oxyfupropoxy]-3-[(tetrahydro-2+!i-pyran-2-yl)oxy]cyclopentyl]ethyl]thio]propionate intermediate 13a. Oa g of the target compound was obtained in the form of an oil. DingLC(ER-PE, 2:1)Rf=0.24(1
6f) [1dan-[1α, 2β(娨*), 3α]]-
Methyl 5-[[(5-oxo-2-[3-phenoxy-
2-[(tetrahydro-2H-pyran-2-yl)oxyfupropoxy)-3-((tetrahydro-2-pyran-2-yl)oxy]cyclopentyl]methyl]thio]
Produced from pentanoate intermediate 13b. IR(CH
Br, ): 1740 cm-1 (16 g) (1 piece-[1α, 2β (2 shakukyo), 3α]]-methyl ((3-
(5-oxo-2-[3-phenoxy-2-[(tetrahydro-2-pyran-2-yl)oxyfupropoxy)-3-((tetrahydro-2H,-pyran-2-yl)oxy]cyclopentyl [propyl]thio]acetate intermediate 13c. IR (CHBr, ):
1735cm-1 (16h) (1 total [1α, 2β(
*), 3α]]-methyl ([:3-[:5-oxo-
2-[3-phenoxy-2-[(tetrahydro-pyran-2-yl)oxyfupropoxy)-3-((tetrahydro-28-pyran-2-yl)oxy]cyclopentyl]propyl]thio]propionate intermediate body 13d
Generated from. IR (CHBr3): 1735cm
-1 (16i) (Yang - [1α, 2β (岨*), 3α
)) -(-)-Methyl [(4-(5-oxo-2-[
3-phenoxy-2-[(tetrahydro-2-pyran-
2-yl)oxyfupropoxy]-3-[(tetrahydro-24j-pyran-2-yl)oxy]cyclopentyl]butyl]thio]acetate intermediate 13e. IR (CHBr3): 1736 cm-'; [α
]ra'=-15,30@(CHCQ,)(16j)
[1 shaku-[1α, 2β (2R*), 3α]]-methyl (
(4-[5-oxo-2-[3-phenoxy-2-[(
Tetrahydro-2[-pyran-2-yl)oxyfupropoxy)-3-((tetrahydro-27pyran-2-yl)oxy]cyclopentyl]butyl]sulfinyl]
Produced from acetate intermediate 17b. IR(CHBr
): 1732cn+-' (16k) [1 shaku-
[1α, 2β (娨*), 3α]]-methyl (1:4-[
5-Oxo-2-[3-phenoxy-2-[(tetrahydro-pyran-2-yl)oxyfupropoxy)-
Produced from 3-((tetrahydro-2-pyran-2-yl)oxy[cyclopentyl]butyl]sulfonyl]acetate intermediate 17c. IR(CHBr, ):
1740cm-Intermediate 17 (17a) l:1s-[:1α, 2β (2 needles), 3
α, 5α]]-methyl 4-((2-(5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-28
-pyran-2-yl)oxyfupropoxy]-3-((
Tetrahydro-pyran-2-yl)oxy[cyclopentyl]ethyl]orfinyl]butanoate Sodium periodate (0.25g) in water (5ml)
The solution of intermediate 4 (0.22 g) in MaOH (10 mM)
Added to solution with stirring. After 18 hours, EA (50
mM) and this solution was diluted with half-saturated brine (40d).
and saturated brine (40mM). The washings were post-extracted with EA (40o+Q) and the organic phases were combined and dried. Evaporate and use EA MeOH (9
2:8-+85:15) to give the title compound as an oil at 0.1
I got 8e. IR(CHBr,): 3520.173
EA-MeOH (16:1
), and the following compound was purified in the same manner as above, except that it was purified by chromatography.

(17b) (1 stitch [1α, 2β (娨*), 3α, 5
α)] -(+)-methyl((4-[5-hydroxy-
2-[3-phenoxy-2-[(tetrahydro-27biran-2-yl)oxyfupropoxy)-3-((tetrahydro-pyran-2-yl)oxy]cyclopentyl]butyl]sulfinyl]acetate intermediate Produced from compound 13e (0.39 g). 0.39 g of oily target compound was obtained. IR (CHBr, ):
3520.1736 cm-1; [α]20-D+24a (CHCQ, ) (17c)
(Is-(1α, 2β(2nd), 3α, 5α)]-methyl[[4-[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-pyran-2-yl)oxy] [propoxy]-a-((tetrahydro-2pyran-2-yl)oxy]cyclopentyl]butyl]sulfonyl]acetate intermediate 17b (0,2 g) CHz CQz (5+a
Q) NaHCO, (0.2 g) and meta-chloroperbenzoic acid (purity 80-91%, 0.07 g) at 0 °C in solution
was added with stirring. After 1 hour, the solution was slowly warmed to room temperature and after a further 4 hours, further meta-chloroperbenzoic acid (5 mg) was added. After a further 2 hours, ER (40d) was added and the solution was washed with 8% NaHCO, aqueous (40mM) and saturated brine (40mM).
) and the organic phases were combined and dried. Evaporation of the solvent gave 0.19 g of the title compound as an oil. IR(
CHBr, ): 3590.3520.1740cm
-1 Futachigoyo (IR-(1α, 2β(2R*), 3α))-4-(benzoylamino)phenyl 4([2-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy )
~5-oxocyclopentyl]ethyl]thio]butanoate intermediate 16a (0,24 g) and acetic acid/water/TH
A solution consisting of a mixture of F (20:10:3) (7 mQ) was heated at 40°C for 4.5 hours. The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH 3,8) silica using EA-cyclohexane (3:1) as eluent to give the title compound as a white solid. 0.09 g was obtained.

m, p, 103-205℃ Elemental analysis values: C, 3H3, No, S.

Actual value (%): C, 65,28; H, 5,98;
N, 2. H1 theoretical value (%): C, 65, 22;
H, 6, 14; N, 2.30 The following compounds were produced in a similar manner.

115 main 0R-(1α, 2β(Rs, 3α)]-methyl 4- (
[4-[:2-C3-Hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]ethyl]thio]-1-oxobutoxy]benzoate from dark body x6b (o, 3g) generated. However, toluene-acetonitrile (2:1) was used as the eluent.
It was used. 0.12g of oily target compound was obtained.

IR (CHBr3): 3580.3440.174
5.1718cm-1; Elemental analysis value: C2°H340,
As S, actual measured value (%): C, 61, 64; H,
6,28 Theoretical value (%): C, 61,6; H, 6,
23 loss 1 and standing [1 total [1α, 2β (strong), 3α)]-(-)-methyl 4-([2-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5 -Oxocyclopentyl]ethyl]thio]butanoate intermediate 16c (0.4 g). However, ER-Meal ((97:3) was used as the eluent. 0.2 g of the target compound as an oil was obtained. .

IR(CHBr,): 3580.3540.173
8cm-';[α]♂' = -36,0° (CHCQ
,) Elemental analysis value: as Cz z H3o 07 S.

Actual value (%): C, 58,87; H, 7,19 Theoretical value (%): C, 59,13; 3α]]-methyl 4-
([2-[3-hydroxy-2-(2-hydroxy-3
-phenoxypropoxy)-5-oxocyclopentyl]ethyl]thio]sulfinyl]butanoate intermediate 16d (0.12 g). However, ER-MeOH (9:1) was used as the eluent. 0.066 g of oily target compound was obtained.

TLC (ER-MeO) 1.8: 1) Rf=0.2
8; IR(C)IBr, ): 3580°1736
cm-/ erect mtan [1 几-[1α, 2β(Rsu, 3α)]-methyl 3-
[2-[3-hydroxy-2-(2-hydroxy-3
-phenoxypropoxy)-5-oxocyclopentyl]ethyl]thio]propionate intermediate 16e (0.08 g). However, ER-MeOH (97:3) was used as the eluent. 0.03g of oily target compound was obtained.

TLC (ER-MeOH, 97:3) Rf = 0.
23 NIR (CHBrj): 3580-3440
, 1735cm-1
((1”3-hydroxy-2-(2-hydroxy-3-
phenoxypropoxy)-5-oxocyclopentyl]
Produced from methyl]thio]pentanoate intermediate 16f (0.12 g). However, ER-AeOH (97:3) was used as the eluent. 0.036g of oily target compound was obtained.

IR(CHBr,): 3580.3540.174
0cm-/Elemental analysis value: C2t H) a Actual value (%) as O7S: C, 59,06; H, 7,
16 Theoretical value (%): C, 59,13;
Produced from 16 g (0.18 g) of 3-(3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]propyl]thio]acetate intermediate. However, ER-MeOH was used as the eluent. (97:3) was used. 0.077 g of the oily target compound was obtained.

IR(CHBr,): 3580.3440.173
7cm-1 elemental analysis value: Cm o Hz m Ot
As S.

Actual value (%): C, 5g, 58; H, 7,15 Theoretical value (%): C, 58,23; H, 6,84 SJ
l-broiled [1-[lα, 2β (Rs, 3α])]-methyl 3-
((3-[3-hydroxy-2-(2-hydroxy-3
-phenoxypropoxy)-5-oxocyclopentyl]propyl]thio]propionate intermediate 16h (0,093 g). however,
ER-MeOH (97:3) was used as the eluent. 0.04g of oily target compound was obtained.

TLC (ER-MeOH, 97: 3) Rf=0.27
; IR (CHBr, ): 3580°3440, 1
738 cm' Daigo and [1 total [1α, 2β (Rs, 3α))-(-)-methyl ((4-(3-hydroxy-2-(2-hydroxy-3
-phenoxypropoxy)-5-oxocyclopentyl]butyl]thio]acetate intermediate 16i (0.12 g). However, εR-MeOH (97:3) was used as the eluent. 0.1 g of an oily target compound was obtained.

IR(CHBr,): 3580.3450.174
0c+++-/; [α] is also '=-40.6@(CHCR
3) Elemental analysis value: as CzzHzaOtS.

Actual value (%): C, 58,98: H, 7,33 Theoretical value (%): C, 59, 13; ]]-Methyl C(4-
Produced from (3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]butyl]sulfinyl]acetate intermediate 16j (0.12 g). However, ER-MeOH (97 g) was used as the eluent. : 3) was used. 0.068 g of the oily target compound was obtained.

IR (CHBr3): 3590.1740cm-/
; Elemental analysis value: As Cz 1H3o Os S, actual value (%): C, 57,12; H, 7,09 theoretical value (%): C, 57,00; H, 6,83 x-
2-(2-hydroxy-3-phenoxypropoxy)-
Produced from 5-oxocyclopentyl[butyl]sulfinyl]acetate intermediate 16k (0.14 g). However, ER-MeO)I (97:3) was used as the eluent.

0.084 of the desired oily compound was obtained.

TLC (ER-MeOH, 97:3) Rf = 0
, 27; IR (CHBr, ): 3580.

3450, 1742 cm-1 Below are examples of pharmaceutical formulations using compounds of the invention. In the Examples below, the term "active ingredient" refers to a compound of the invention such as the compounds disclosed in the Examples above.

L=L-ri Tablets were manufactured by direct compression method.

Belly - Once again, Isayama Super Nail Active Ingredients
o, ois ~ 0.2 Magnetium Stearate (British Pharmacopoeia) 1.5 The active ingredient is mixed with about 10% of the microcrystalline cellulose, followed by the remaining microcrystalline cellulose and magnesium stearate. The mixture is compressed into tablets using a suitable tablet press using rods having a diameter of 6 InI11.

The resulting tablets can also be film-coated with film-forming materials such as methylcellulose or hydropropylmethylcellulose due to their sub-dimensional dimensions.

Active ingredient 0.015~0
．． 2 Add 1,500 yen of starch powder, 10
0.0 (Note) * Starch is starch for direct compression.

The active ingredient is pre-mixed with a small amount of starch 1500.
This mixture is then mixed with the remaining starch 1500 and magnesium stearate. This mixture is filled into size &2 hard gelatin capsules using a suitable filling machine.

The ability of the compounds of the present invention to suppress histamine-induced gastric acid secretion was demonstrated in a paper submitted to the University of London in 1959 by M.E.
, as improved by Parsons' doctoral thesis.”
Br, J, Phar+1acol,', 1958.
This was demonstrated in perfused rat stomachs according to the method of Ghosch and 5child, as disclosed in 13.54. HD, regarding inhibition of histamine-induced gastric acid secretion. Values were determined by administering the test compound intravenously to a single rat at a given dose and repeating this administration in at least four rats at each of three or more dose levels. The results obtained were determined by the standard least squares method, as used for dose-response curves. used to calculate the value. Thus, the compounds of Examples 1.2.3.7.8 and 9 have 0.006 to 0.22 p g/kg/llin
ED within the range of (30 min). It was confirmed that it has a value.

These compounds are generally non-toxic in therapeutically effective amounts.

Claims (1)

[Claims] 1. A compound represented by the following general formula (1) or a physiologically acceptable salt, solvate or complex thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (1) [In the formula, m is 1 to 4; n is 0, 1 or 2; p is 1 to 4; Z is CO_2R^1 group Yes; R^1 is (a) hydrogen atom, C_1_~_6 alkyl, C_7_~
_1_0 phenylalkyl or 2-naphthyl group; or (b) phenyl {this phenyl is C_1_~_4
Alkyl, C_1_~_4 Alkoxy, C_1_~_4
Alkanoyl, methylthio, methylsulfinyl, methylsulfonyl, halogen, -CO_2R^2 (where,
R^2 is a hydrogen atom, C_1_-_4 alkyl or phenyl), -NHCOR^2 (where R^2 is a group as defined above, or optionally hydroxyl, CH_3CONH- or ▲formula , chemical formula, table, etc. is a phenyl group substituted with ▼), -CON
R^3R^4 (where R^3 and R^4 are the same or different and each represents hydrogen or C_1_~_
4 alkyl group), -NHCONH_2, -CH_
2CH(CONH_2)NHCOCH_3 or ▲There are mathematical formulas, chemical formulas, tables, etc.}; Or, (c) -CH_2COR＾5 group (here, R＾5 is phenyl {this phenyl is necessary) Accordingly, C_1_-_4 alkyl, C_1_-_4 alkoxy, C_1_-_4 alkanoyl, methylthio, methylsulfinyl, methylsulfonyl, halogen, -CO_2R^6 (where R
^6 is a hydrogen atom, C_1_~_4 alkyl or phenyl), -CONR^7R^8 (where R^7 and R^8 are the same or different and each is a hydrogen atom or C_1_~ _4 alkyl group), -N
HCOR^6 (where R^6 is a group or hydroxyl as defined above, CH_3CONH_- or phenyl substituted with ▲formula, chemical formula, table, etc.), -NHCONH_2, -CH_2CH_( C
ONH_2) NHCOCH_3 or ▲mathematical formula, chemical formula,
(Optionally substituted with ▼} or R^5 is 2-naphthyl);
Alternatively, Z is -CH_2OH, -CHO or -CONH_R^
9 {Here, R^9 is a hydrogen atom, C_1_~_4 alkyl, aryl, -COR^1^0 (here, R^1^0
is a hydrogen atom, C_1_-_4 alkyl or aryl group) or -SO_2R^1^1 (where R^1
^1 is C_1_~_4 alkyl or aryl group); Y is ▲a mathematical formula, chemical formula, table, etc.▼ (where R^1^2, R^1^3 and R^1^4 are each is a hydrogen atom or methyl, and at least one is a hydrogen atom; Ar is a phenyl group (this phenyl group may optionally be C_1_-_4 alkyl, C_1_-_
4 alkoxy, C_1_~_4 alkylthio, C_1_
~_4 alkylsulfinyl, C_1_-_4 alkylsulfonyl, halogen or trifluoromethyl group)
It is. ] 2. Z is -COOR^1 group [Here, R^1 is (a)
Hydrogen atom, C_1_-_3 alkyl or 2-naphthyl group; or (b) methoxy, acetyl, -CO_2CH_3, -N
HCOCH_3, benzoylamino, -CONH_2,
-CON(CH_3)_2 or -CH_2CH(CO
NH_2) phenyl substituted with NHCOCH_3 group;
Alternatively, (c) -CH_2COR^5 (where R^5 is methoxy, acetyl, -CO_2CH_3, -NHCOCH_
3, benzoylamino, -CONH_2, -CON(C
H_3)_2, or -CH_2CH(CONM_2)
Is it a phenyl group substituted with NHCOCH_3 group,
or R^5 is a 2-naphthyl group); or Z is -CH_2OH, -CHO, -C
ONH_2, -CONHCH_3, -CONHCOCH
_3, -CONHSO_2CH_3 or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The compound according to claim 1. 3. The compound according to claim 1 or 2, wherein n is 0. 4, R^1^3 and R^1^4 are hydrogen atoms, and Ar is phenyl or phenyl substituted with chlorine or fluorine, according to any one of claims 1 to 3. Compounds described. 5, n is 0, m is 3 or 4 and p is 1, or m is 2 or 3 and p is 2, or m is 1 and p is 4
or m is 2 and p is 3; Z is -CO_2R^1 group {where R^1 is a hydrogen atom,
C_1_-_3 alkyl, 2-naphthyl or substituted phenyl (substituents include methoxy, acetyl, -CO_2CH
_3, -NHCOCH_3, benzoylamino, -CO
NH_2, -CON(CH_3)_2 or -CH_2
CH(CONH_2)NHCOCH_3); R^1^2 is a hydrogen atom or methyl;
The compound according to claim 1, or a physiologically acceptable salt thereof, wherein R^1^3 and R^1^4 are hydrogen atoms; Ar is phenyl or phenyl substituted with fluorine or chlorine; Solvate or complex. 6, Z is -CO_2R^1 group (here, R^1 is a hydrogen atom, methyl, or phenyl substituted at the para position by -CO_2CH_3 or benzoylamino)
The compound according to claim 5, which is 7, -(CH_2)_mS(O)_n(CH_2)_p
7. A compound according to any one of claims 1 to 6, wherein the carbon atom having the Z group is in the R-configuration. 8, [1R-[1α, 2β(R*), 3α]-4-[benzoylamino)phenyl 4-[[2-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-] Oxocyclopentyl]ethyl]thio]butanoate; or [1R-[1α, 2β(R*), 3α
]]-Methyl 4-[[[[2-[3-hydroxy-2
-(2-hydroxy-3-phenoxypropoxy)-5
-oxocyclopentyl]ethyl]thio]1-oxobutyl]oxy]benzoate; or [1R-[1α,
2β(R*), 3α]]-(-)-methyl 4-[[2-
The compound or complex according to claim 1, which is [3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]ethyl]thio]butanoate. 9. A pharmaceutical composition containing the compound according to any one of claims 1 to 8 together with one or more pharmaceutical carriers. 10. A method for producing the compound of formula (1), which comprises any one or more of the following steps (a) to (h). (a) Deprotect the compound of the following formula (2) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (2) [In the formula, Y^1 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ group; Z^1 is a Z group as defined for formula (1) or -CH_2OR^1^5 group (where R^1
(b) Z is -CO_2R^1 group (where R^1 is (a
) or (b) is a group of type ), the corresponding compound in which Z is -CO_2H is esterified; (c) in the case of producing a compound in which Z is -CONHR^9, Formula (1
); (d) When preparing a compound where n is 1, oxidize the corresponding compound where n is 0; (e) When preparing a compound where n is 2, when n is Oxidize the corresponding compound where Z is 0 or 1; (f) When producing a compound where Z is -CO_2H,
Hydrolyze the corresponding ester; (g) Z is -CO_2R^1 (where R^1 is (c)
type group), the corresponding compound where Z is -CO_2H is converted into a ketone of formula (12) XCH_2COR^5 (12) where R^5 is a leaving group. alkylating; or (h) treating the acid of formula (1) with a base to produce a salt, or treating the compound of formula (1) with a cyclodextrin to produce a complex;