JPS61249951A - Cyclopentyl ethers, manufacture and medicinal composition - Google Patents

Abstract

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

Description

[Detailed description of the invention]

Prostaglandin Et (hereinafter abbreviated as PGE) is a naturally occurring substance that has many physiological effects.For example, it inhibits gastric acid secretion and protects gastrointestinal cells;
Lowers blood pressure, stimulates and relaxes smooth muscle, inhibits platelet aggregation, and suppresses lipolysis. Synthetic PGE, analogs, may offer different potencies, longer durations of activity, and increased selectivity of action and are therefore the focus of attention. Although in the past many different PGE analogues have been suggested for use as medicines, only one example in this regard has been published.
A 3-oxa compound was proposed. Thus, the second British patent
No. 082176A discloses a group of compounds comprising 2-(heptyloxy)-3-hydroxy-5-oxo-cyclopentanehebutanoic acid and its 15-hydroxy derivatives. These compounds are said to inhibit platelet aggregation and have bronchodilatory effects, and have been proposed for use as antithrombotic or antiasthmatic agents. The inventors have now discovered a new group of cyclopentyl ethers with PGE-type activity. This group of compounds has particularly good properties of biological action. In particular, they exhibit high potency and long duration of action with respect to gastric acid secretion inhibition and gastrointestinal cell protection, and are therefore of interest in the treatment of ulcers. Thus, the present invention provides compounds of general formula (1) and physiologically acceptable salts thereof, wherein n is 1 or 2; m is 2-5 and X is cis or trans-CH=
CH- or -CH, -CH,-, or m is 1-4 and X is -C)I=C=CH-; R'' is (a) a phenyl group (Ct-4 alkyl Group *C1-4 alkoxy group, C1-4 alkanoyl group, methylthio group, methylsulfinyl group, methylsulfonyl group, halogen atom (e.g. chlorine or bromine), -Co, R'' (where R2 is a hydrogen atom, C1□alkyl or a phenyl group), -NHCOR'' (where R2 is as defined above, or a hydroxyl group, CI, C0NH-
or 1) a phenyl group optionally substituted with -CONH-). -CONR3R' (where R1 and R4 are the same or different and are each a hydrogen atom or a C1-4 alkyl group), -N)IcONH,, -CH,C)l (CO
NH,)NHCOCH, or -CH,CH(CON
H,) optionally substituted with NHCO-Q], or (b) 2-naphthyl group: (where ns, nG and R7 are each a hydrogen atom or a methyl group, but at least one of these one is a hydrogen atom, and Ar is a phenyl group (one or two 01
-, alkyl group, C1-, alkoxy group% Ct-*alkylthio group, C1-, alkylsulfinyl group. (Optionally substituted with a C1-4 alkylsulfonyl group, halogen atom or trifluoromethyl group)]
It is. Structural formulas as used herein are to be understood to encompass the respective enantiomers of the compound as well as enantiomeric mixtures, including racemates. In general, the groups -(C1l, ), X (CI+, ),
Co, a carbon atom with R' and - in l or group Y
Preference is given to compounds of formula (1) in which the carbon atom bearing the OH group (in particular the former) is in the R configuration and mixtures containing isomers of this type. The alkyl groups mentioned above in the definition of the compounds of formula (1) may be straight-chain or branched. When R1 in the compound of formula (1) is a phenyl group substituted with a group -CO□H, the compound is capable of forming a salt with a base. Examples of suitable salts are alkali metal salts such as sodium and potassium salts. In the compound where X is -CH=CH- or -CH,CH,-, m is preferably 3 when n is 1. When n is 2, m is preferably 2 or 4. X
When 100=C=Cl-, m is preferably 2 and n is 1, and when n is 2, m is 1 or 3. When X is 100=CH-, it is preferably cis-CH=Cl-. When R1 is a substituted phenyl group, it is for example a chlorine atom, a bromine atom,
Methyl, ethyl, propyl, n-butyl, t-butyl,
Methoxy, ethoxy, propoxy, butoxy, acetyl, propionyl, methylthio, methylsulfinyl, methylsulfonyl, -CO□H1-CO□CH,, -Go
, CH, C1,, -co, -Q -NHCHO1-NHCOCH,, benzoylamino,
(acetylamino)benzoylamino, (hydroxy)
Benzoylamino, -CONHs, -CONHCH
a, -CON(CHa)z --CONHCH,C1
,,-CON(CH,CI,),,-NICONH,
. It can be a phenyl group substituted with -CII, CH(CONH,)NHCOCH3 or 10H, CH(CONH,)NHCO-0. Particularly useful substituents that may be present on the substituted phenyl group R'' include C1-, alkoxy, C1-, alkanoyl, methylthio, methylsulfonyl, -CO, R2, -N
IICOR"-CONR"R' [where R2, R3 and R4 are as defined in formula (1)],
-NHCONH, or -C1l, CI(CONH,
) NHCOCH3 is included. The most useful substituents of this type include methoxy, acetyl, methylthio, methylsulfonyl, -CO,C1,, -NHCOCH,, benzoylamino, (p-acetylamino)benzoylamino, (
p-hydroxy)benzoylamino, -CONH,, -
CON(C1,)! , -NHCONH, or -CH
, CI (CONH,) NHCOCR, are included. The radical R1 is preferably a substituted phenyl group, the substituent of which is in the meta, ortho or especially para position, or a 2-naphthyl group. R1 is methoxy, acetyl, -Co, CH3, -NHC
OCH,. Benzoylamino, -CONH,, -CON (CHa
) *Mataha-CH, CI (CONH,) NHC
Particularly useful are compounds in which the phenyl group is substituted (especially in the para position) with OCH, or in which R1 is a 2-naphthyl group. R" and R7 in group Y are preferably hydrogen atoms. Compounds in which Rs is H or -CH, and Rs and R7 are hydrogen atoms are preferred. When the Ar phenyl group is substituted, the The substituents are meta,
It can be present in the ortho or para position and can be, for example, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo or trifluoromethyl. Preferably, only one substituent is present, especially in the para position. Generally, it is preferred that Ar is an unsubstituted phenyl group or a phenyl group substituted with a halogen atom (particularly fluoro or chloro). The above-mentioned preferences may be used both separately or in combination with one or more of the other above-mentioned preferences. Therefore, a preferred group of the compounds of the present invention is, in formula (1), when and m
is 2 or 4, or X is -CH=C=CH-
, then n is 1 and m is 2, or n is 2
and m is 1 or 3: R1 is methoxy, acetyl, -CO, C1,, -NHC
OCH3,, Henshii) Lt 7 Mi/, -CONH
z, -CON(CHi)z or -CH,C)I-(C
ONH, ) NHCOCH, is a phenyl group substituted (preferably at the para position), or R1 is a 2-naphthyl group; RS is a hydrogen atom or a methyl group; R6 and R?
is a hydrogen atom; and Ar is a phenyl group,
Alternatively, it is a phenyl group substituted with fluoro or chloro. Particularly preferred are compounds of this type in which the carbon atom bearing the -(CI,)nX(CH,), Co, R' group is in the R-configuration. The most preferred compounds of this type are those in which R1 is a phenyl group substituted (preferably para-substituted) with benzoylamino or 100NH, especially the former. Particularly useful compounds of the invention are: (IR-(
1a (Z), 2β (R umbrella), 35E)) - (-)
-4-7ceti)L/phenyl 7-[3-hydroxy-
2-(2-hydroxy-3-phenoxypropoxy)-
5-oxocyclopentyl]-5-heptenoate; (IR-(1a (Z), 2β(Rs, 3(ri)-
(-)-4-C7cetylamino)phenyl 7-[3-
Hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-hebutenoate; (IR-(la(Z), 2β(R-), 3α))-
(-)-4-(benzoylamino)phenyl 7-

[3
-Hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; (IR-(1a (Z, S, 2β(R
e), 3α]]-(+)-4-(2-(acetylamino)-3-amino-3-oxopropyl)phenyl 7
-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5
-Hebutenoate: (IR-(1a (Z), 2β(R), 3G))
-(-)-4-(aminocarbonyl)phenyl 7-[
3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; (IR-(la(Z), 2β(
R, 3rx)]-(-)-3-(benzoylamino)phenyl 7-[3-hydroxy-2-(2-
Hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; (IR-(l
a (Z), 2β(R”), 3α))-(-)-
4-(N,N-dimethylaminocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-
phenoxypropoxy)-5-oxocyclopentyl]
-5-heptenoate: (IR-(1a (Z), 2
β(Re), 3α]]-(-)-methyl 4-([7-
[3-Hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-1-
Oxo-5-heptenyl]oxy)-benzoate; (
IR-(la(Z), 2β(Re), 3α))
-2-su7ta17 2/l/7-[3-hydroxy-2
-(2-hydroxy-3-phenoxypropoxy)-5
-oxocyclopentyl]-5-heptenoate; (IR-(la(Z), 2β≠pass, 3α))-(-)
-4-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-2-methyl-3-phenoxypropoxy)-5-oxocyclopentyl]-
5-hebutenoate;
-(4-fluorophenoxy)-2-hydroxypropoxy)-3-hydroxy-5-oxocyclopentyl]
-5-hebutenoate; [IR-[1a (Z), 21 (R”), 3a
)]-(-)-4-(benzoylamino)phenyl 7-[3-hydroxy-2-(2-bidroxy-3
-phenoxypropoxy)-5-oxocyclopentyl]-4-hebutenoate; (IR-(la, 2β(R umbrella), 3α))-(-)-4-(benzoylamino)phenyl 3-hydroxy-2-( 2-Hydroxy-3-phenoxypropoxy)-5-oxocyclopentaneheptanoate; and (IR-(la(E), 2β(R umbrella), 3α))-(
-) -4-(aminocarbonyl)phenyl 7-[3
-Hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-hebutenoate. Particularly useful compounds of this type are: (IR-
(1a (Z), 2β(Rs, 3(E))-(-)
-4-7 cetyl phenyl 7-[3-hydroxy-2-
(2-hydroxy-3-phenoxypropoxy)-5-
Oxocyclopentyl]=5-heptenoate; (IR-(1a (Z), 2β(Re), 3α)]
-(-)-4-(7cetylamino)phenyl 7-[3
-Hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-hebutenoate; (IR-(1α(Z), 2β(R”L 3α)) -
(-)-4-(benzoylamino)phenyl 7-(3
-Hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; (IR-(I a (Z) , 2β(R
e), 3a)]-(-)-4-(7minocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-hebutenoate ;(IR-(l
a (Z), 2β (Rs, 3 tx )) - (-)
-3-(Benzoylamino)phenyl 7-(3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-hebutenoate; (IR-(1a (Z), 2β( R,
3a])-(-)-4-(N,N-dimethylaminocarbonyl)phenyl 7-[3-hydroxy-2-(2
-Hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-hebutenoate; (IR-(
1a (Z), 2β (R fist), 3α]] - (-)
-Methyl 4-([7-(3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl-1-oxo-5-heptenyl]oxy]-benzoate; (IR-(1a ( Z), 2β(
Re), 3 a)) -2-Natsuta L/:, Jl/7
-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5
-heptenoate; (IR-(lα(Z), 2β, 3α)]-4-methoxy7 x n/L/7-[2-(3-(4-fluorophenoxy)-2-hydroxypropoxy]-3 −
Hydroxy-5-oxocyclopentyl]-5-heptenoate 1 (IR-Oa (Z), 2β, 3a)) -(
-) -4-(Benzoylamino)phenyl 7-(3
-hydroxy-2-(2-hydroxy-2-methyl-3
-phenoxypropoxy)-5-oxocyclopentyl]-5-hebutenoate; and (IR-(1α(Z)
, 2β(R umbrella), 3α))-(-)-4-(benzoylamino)phenyl 3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentala) 7072-1 −. Further important compounds of the invention which have useful physicochemical properties and are suitable as pharmaceutical compositions are: (IR-[1α(Z), 2β(R umbrella), 3α))-(
-)-4-acetylphenyl 7-[3-hydroxy-
2-(2-hydroxy-3-phenoxypropoxy)-
5-oxocyclopentyl]-5-hebutenoate; (IR-(lα(Z), 2β(R umbrella), 3α))-(
-) -4-<7cetylamino)phenyl 7-[3-
Hydroxy-2(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-hebutenoate; (IR-(1α(Z), 2β(R fist), 3α))-(
-) -4-(Benzoylamino)phenyl 7-[3
-Hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate: (IR-(1a (Z), 2β(R”)
, 3α))-(-)-4-(4-(7cetylamino)
Benzoylaminocophenyl 7-[3-hydroxy-2
-(2-hydroxy-3-phenoxypropoxy)-5
-oxocyclopentyl]-5-hebutenoate: (IR-(1a (Z), 2 fj (Re), 3
a))-(-)-4-(7minocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-
3-phenoxypropoxy)-5-oxocyclopentyl]-5-hebutenoate; (IR-(1(!(Z,
S umbrella), 2 β (R fist), 3 (ri) - (+
)-4-(2-(acetylamino)-3-amino-3-
Oxopropyl]phenyl 7-[3-hydroxy-2
-(2-hydroxy-3-phenoxypropoxy)-5
-oxocyclopentyl]-5-hebutenoate; (IR-(la (Z)-2β(R umbrella), 3 a
))-(-)-3-(benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-
phenoxypropoxy)-5-oxocyclopentyl]
-5-heptenoate; (IR-(1a (Z), 2
β(Rs, 3cx))-(-) Methyl 4-((7-
(3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl-1-
Oxo-5-heptenyl]oxy]-benzoate; (
IR-(1a (Z), 2β, 3a)]-(
-) -4-(Benzoylamino)phenyl 7-[3
-hydroxy-2-(2-hydroxy-2-methyl-3
-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; CIR-C1a (Z)-2
j! l (R-), 3 a ))-2-su7talenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-
5-hebutenoate; (IR-(1a (Z), 2β, 3cz))-4-
(methy/l/s/l/honyl)phenyl 7-[3-
Hydroxy-2-[2-hydroxy-3-(4-(methylthio)phenoxy]propoxy]-5-oxocyclopentyl]-5-heptenoate; (IR(I C1(
Z), 2β(Rst3(X))-(-)-4-
to C:ysoylamino)phenyl 7-1:3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl-4-heptenoate; (IR-(1(!(Z), 2β( R-), 3(
X))-(-)-4-(he/silylamino)phenyl 9-(3-hydroxy-2-(2-hydroxy-3-
phenoxypropoxy)-5-oxynecyclopentyl]
-7-nonenoate; and (IR-(1α, 2β (R books), 6α))-(-)-4
-(Benzoylamino)phenyl 6-hydroxy-2
-(2-hydroxy-6-phenoxypropoxy)-5
- Butanote to oxocyclopentane. Lopentane heptanoate. A particularly preferred compound of the present invention is (IR-(1α(Z), 2
β(R・), 3α))-(-)-4-(benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl go 5-betenoate be. The compound of formula (1) is manufactured by Parsons M,
Ghosh (M, N,) and Schild (1969), modified by the doctoral thesis of Ghosh (M, N,) and Schild, University of London (1969). Br, J. Pharmacol, 13.54 (1
958), gastric acid secretion as measured by their efficacy in suppressing histamine-induced secretory responses in the perfused stomach of rats. In addition, the compound of the present invention was administered at 5 g before administering the test compound.
Robert et al.'s Gastroe improved by subcutaneous administration of indomethacin/kg
Gastrointestinal cells are protected as measured by their efficacy in suppressing ethanol-induced injury in sentient rats according to the method described in Terology 77, 433 (1979). The compounds of the invention are thus of interest in the prevention and/or treatment of ulcers. They can also be used to treat other conditions caused by hypersecretion of stomach acid. They are prepared in conventional manner, eg, for oral, buccal, parenteral or rectal administration, in combination with one or more pharmaceutical carriers. The compounds of the invention are prepared in conventional manner for oral administration, eg as tablets, capsules, powders, solutions or syrups, with acceptable excipients. The compounds of this invention are formulated for parenteral administration by single injection or continuous infusion. Injectable compositions can be prepared in ampoules or in multi-dose containers containing a preservative.
It may be provided in unit dosage form in the form of a container. For buccal administration, the compounds of the invention may be prepared in conventional manner as tablets or lozenges, and for rectal administration as suppositories or enemas containing conventional suppository bases such as cocoa butter or other glycerides. Compositions such as are used. The compound of the present invention is preferably administered orally at a dose of 0.5 to 300 μg/kg (body weight) 1 to 4 times a day, and parenterally at a dose of 0.01 to IO μg/kg (body weight). Administer 1 to 4 times a day. The exact dose will of course depend on the age and condition of the patient. Suitable methods for preparing the compounds of the present invention are described below, with the various groups and symbols being as defined above unless otherwise specified. (a) The compound of formula (1) can be produced by removing the protecting group of a corresponding compound in which the ring hydroxyl group and the hydroxyl group in group Y are protected. The protected compound is represented by the formula (2) 20+1 (2) where R" is a suitable hydroxy protecting group [e.g. tetrahydrobilane-2
Y'' is the following group: two R6 groups in the compound of formula (2) are preferably the same, but in some cases they may be different. When R@ is a tri(hydrocarbyl)silyl group, the hydrocarbyl substituents are the same or different. For example C0,6 alkyl, C2-6 Flukenyl, C1-
7cycloalkyl, C71, aralkyl and C6-2
゜Can be an aryl group. This type of group includes methyl and ethyl. Includes n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, allyl, phenyl and benzyl. Preferred hydrocarbyl groups are C□-4 alkyl, such as methyl and t-butyl. Particularly preferred are trimethylsilyl and t-butyldimethylsilyl. When R1 is an arylmethyl group, it contains up to 20 carbon atoms and can be, for example, benzyl, diphenylmethyl or triphenylmethyl. Preservation of protected hydroxyl groups! ! i! The method to remove S is R
1, generally acid hydrolysis or reduction is used. Thus, for example, when R1 is a tetrahydrobilan-2-yl group, a tetrahydrofuran-2-yl group or an ethoxyethyl group, removal of the protecting group is carried out with an acid. Suitable acids include inorganic acids such as hydrochloric acid and 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),
Included are dipolar neutral solvents (eg acetone, acetonitrile, dimethyl sulfoxide and dimethyl formamide) and alcohols (eg methanol, ethanol and ethylene glycol). If desired, solvents in combination with water can also be used. This reaction takes place between 0°C and 5°C.
It is carried out at a suitable temperature, such as 0°C (eg 40°C to 50°C). The tri(hydrocarbyl)silyl group can be removed by acid hydrolysis, e.g. with dilute mineral acids or trifluoroacetic acid, or by treatment with fluoride ions (e.g. from quaternary ammonium fluoride, such as tetra-n-butylammonium fluoride), or by aqueous oxidation. Can be removed by treatment with hydrogen fluoride. The arylmethyl group can be removed by reduction (e.g. hydrogenolysis with a noble metal catalyst such as platinum or palladium) or by reaction with a Lewis acid (e.g. trifluorofluoride) in the presence of a thiol (e.g. ethanethiol) in a suitable solvent such as dichloromethane at room temperature. It can be removed by td treatment with boron etherate). The compound of formula (2) can be prepared by preparing a compound of formula (3) R'OOYl with, for example, pyridinium chlorochromate in the presence of a buffer (e.g. sodium acetate) in a suitable solvent (e.g. dichloromethane) at a suitable temperature (e.g. -1O℃ to room temperature)
It can be produced by oxidation in Alternatively,
The oxidation can be carried out using dimethyl sulfoxide activated with N,N'-dicyclohexylcarbodiimide in the presence of pyridinium trifluoroacetate in a solvent such as dichloromethane, for example at -10°C to room temperature. Other conventional oxidation methods (e.g. Jones reagent)
can also be used. The intermediate compound of formula (3) is produced by the method described in EP 160,495. It will be appreciated that the protecting group removal method (a) is usually carried out in conjunction with the formation by oxidation of the oxo group of the cyclopentyl ring, so that compounds of formula (1) are generally replaced by the corresponding formula (3). It is produced by oxidizing a compound of However, the formation of the ring oxo group is carried out prior to the introduction of the R1 group by esterification [eg, method (b) below], after which the protecting group is removed. (b) Compounds of formula (1) can also be prepared by esterifying the corresponding carboxylic acid (ie, a compound in which R1 is a hydrogen atom) in a conventional manner. Thus, for example, a compound of formula (1) is formed by reaction with an alkyl chloroformate (e.g. isbutyl chloroformate) or an acid chloride (e.g. pivaloyl chloride) in the presence of a suitable base (e.g. triethylamine or pyridine). They can be prepared by converting the corresponding carboxylic acid into an activated derivative (eg, the corresponding mixed acid anhydride). The activated derivative is then reacted with a suitable compound R'OH, which is a known compound or can be prepared by methods analogous to those used for the preparation of known compounds. Suitable solvents include dipolar neutral solvents (e.g. acetone,
acetonitrile and dimethylformamide) and a halogenated hydrocarbon (eg dichloromethane), this reaction is carried out at a suitable temperature, for example from 0°C to room temperature. The compound of formula (1) can also be produced by first reacting the corresponding carboxylic acid with dicyclohexylcarbodiimide in the presence of 4-dimethylaminopyridine, and then reacting the product with phenol R'OH. Soothe it. This reaction is advantageously carried out in a solvent such as ether or dichloromethane at a suitable temperature (eg 0°C to room temperature). The starting material for this reaction, the carboxylic acid, is disclosed in European Patent No. 16
No. 0495. (c) A compound of formula (1) in which X is a =CH, -CH2- group can be produced by reducing a corresponding compound in which X is a cis or trans -CH=CH- group or an acetylene group. Suitable reduction methods include a support (e.g. carbon).
hydrogen in the presence of a supported catalyst (e.g. palladium). A suitable solvent is ethyl acetate. ethanol and methanol. (d) Formula (1) (7) where X is -CII=CH- group
The compounds can be prepared by selectively reducing the corresponding compounds in which X is an ace, tyrene group. Suitable reduction methods include hydrogen in the presence of a catalyst (eg, palladium) supported on a support (eg, CaCO3 or Ba5O4) and poisoned, for example, by lead or quinoline. Suitable solvents include ethyl acetate and methanol. This reaction is particularly suitable for preparing compounds in which X is cis-CH=CH-. The acetylenic compounds required as starting materials are prepared from the corresponding acetylenic acids by esterification using the methods described above. Acetylenic acid intermediate has the first European patent
No. 60495. (e) Formula (1) in which X is a trans-C)I=CH- group
) can be prepared by isomerization of the corresponding compounds in which sulfinic acid,
or by treatment with azobisisobutyronitrile and thiophenol in a hydrocarbon solvent (eg benzene) at a suitable temperature up to reflux. The above methods (b) to (a) are also applicable to compounds of formula (2) and (3), and the products are then converted to compounds of formula (1) by the above methods. If a specific enantiomer of formula (1) is required, starting materials with a specific configuration should be used in the above process. Starting materials of this type are e.g.
It can be prepared from the enantiomeric intermediates described in EP 74,856 using the method described in EP 74,856. The following examples illustrate the invention. Temperatures are in °C, 'dry' means dried over anhydrous MgO, t, 1.c, thin layer chromatography on silica, chromatography was performed on silica gel, and Abbreviations used: 2ER-ether; EA-ethyl acetate; PE-petroleum ether (boiling point 60-80°C unless otherwise specified) iDIBAL-diisobutylaluminum hydride: THF-tetrahydrofuran; CH,C1,-dichloromethane: CHCb
-Chloroform: CHBr3-bromoform; DM
F-dimethylformamide: DMSO-dimethylsulfoxide: HtOH-ethanol; MaOH-methanol; C13CN-acetonitrile; Et, N-triethylamine; N, T, P, - standard condition. soil! Intermediate 2 1-2-3-3-glolphenoxy-2-tetrahydro-2H-bilan-2-yloxypropoxy-5
- Vin-2-ol l5-1aZ 2 (2S113a 5a -
(+Methyl 9-5-hydroxy-2-3-phenoxy-
2--Rahi intermediates 1-6 were prepared using the method described in EP 160,495. EA (60 m
A solution of methyl 4=hydroxybenzoate (10 g) in m) was treated with dihydrobilane (12sji) and the solution was left at room temperature for 24 hours. In addition, dihydrobirane (1
2 mjl) and ether HCI (3,5 mff1) were added and left to stand for 17 hours. The solvent was evaporated and the residue was dissolved in ER (100 mjl),
2N NaOH solution (2X50) and brine (50mM
) and dried. The residue after evaporation was purified by chromatography (eluent ER/toluene 3:97) to give the title compound (10.2 g) as a white solid. Melting point 58
~62℃. Imperial dish Ikumi 4- Tetrahydro-2H-bilan-2-yloxy 5
N NaOH solution (30 mm) and MeOH (200 mm
intermediate in mm)? (10,0 g) suspension at room temperature
Stirred for 4 hours. This solution was evaporated to about 50 ■Ω,
Diluted with water (100 mm). Add this mixture to Hyflo (
hyflo) and the filtrate was filtered through ER (2X30m
fi) and acidified by dropwise addition of 5N hydrochloric acid. The obtained precipitate was collected by filtration to obtain the title compound as a white solid (
8.25g) was obtained. Melting point: 138-139°C. A solution of intermediate 8 (8,1 g) in dry THF (200 mm) was treated at 0 °C with Et3N (6-Omfl)-then pivaloyl chloride (5,4-Q) and the mixture was heated at 0 °C for 30 min. Stir for a minute. 4-aminophenol (3,0
A solution of g) was added and the mixture was stirred at room temperature for 17 hours and at 80° C. for 1.5 hours. The mixture was filtered, the filtrate was evaporated and the residue was dissolved in ER (200 mL) and poured into water (200 mL) to form a precipitate, which was filtered and crystallized from EA/MeOH. The title compound (5,6 g) was obtained as a white solid, melting point 173-174°C. Intermediate 1 (0,4
A solution of 5g) of Et, N(0,2
) and then treated with isobutyl chloroformate (0,14weQ). After stirring for 45 minutes, p-hydroxyacetophenone (0.23 g) was added. Continue stirring for 2 hours at −IO°C to θ°C and dilute the mixture with water to ER (3X 50+1).
1. The combined extracts were diluted with a 10% copper sulfate solution (75
+m12) and water (10mffi) and dried. The residue obtained by evaporation was subjected to chromatography [eluent ER
/PE (40-60") 2:1) to give the gummy title compound (0.43 g). 1,r,<CHBr,) 3550.1753.1
678cae-'. (a) 5" + 19.6" (MeOH) The following compounds were prepared from Intermediate 1 and the appropriate phenol using a similar method. 1, r, (CHBr3) 358G, 3425.17
50.1690cm-”.Ca)fi”+7.9@(MaOH)1, r, (C
HBr3) 351G, 3410.1748.168
2cm-'. [α] too” + 15.4° (Mealy) (d)
l5-1aZ 2 2S* 3a 5α
−+−4 Intermediate 1 (0,7
pivaloyl chloride (0.18 g) was added to a solution of g) and Et,N (0.38 g) at 0.degree. After 10 minutes DMF (
4-(Benzoylamino)phenol (0
, 53 g) at 0°C for 6 hours and at room temperature for 1 hour.
Stirred for 8 hours. The reaction mixture was diluted with HA (150mff) and subsequently washed with water (2X 5αmffi), 10% copper sulfate solution (2X 50a+1), water (50mff) and brine (Some). Evaporation and chromatography of the resulting residue on silica quenched with Et, N (eluent cyclohexane/H
A 1:1) to give the gummy title compound (0,
55g) was obtained. 1, r, (CHBr,) 3520. 3425.
1750. 1673cm''''! . [α]6@+20° (CHCl3) The following compounds were prepared from Intermediate 1 and the appropriate phenol using a method analogous to that of Intermediate 10d. 1, r, (CHBr,') 3580.352G, 3
425.1?45.1690゜1670cken-1 [α]fi'+20.6" (CIC1,)1, r, (
CHBr, ) 3520.3400.1755.167
2cm-”. [α]bl′+20.6°(CHCl,)(g) l
5-4αZ Re 2 2S* 3a Sa-
+-4-2-acetyl mino-3-amino-3-oxolo1. r, (CHBrs) 3500. 3400
．． 1745. 1690. 1660cm-'. [α]'D1+24° (CIC1,) 1, r, (C)lBr,) 3700-3100.17
55.1677cm-'. (α]?)@+27@(CICIm) Hydro-2H-bilan-2-yloxy cyclobenthyl-5-hebutenoate 1, r, (CHBra) 353Q, 1750.17
40.1626cm-'1, r, (CHBr,) 35
90.3520.1750.1715c**-1 Roux 5
-hebutenoate, prepared from intermediates 1 and 9. 1, r, (CHBra) 3580.3420.174
8.1668cm-'. [α] is also '+21'' (CHCI,) (1) l5-1αZ 2 2S* 3a 5a
-2-Hensylamino phenyl 7-5-hydroxy-2-31, r, (CHBr,) 3520.344
0.1728.1688.1516cm-'1, r, (
C% (Br, ) 3530.17 SOem''''1 Bootsate, prepared from Intermediate 12a. 1, r, (CHBrs) 352G, 3430.
1750. 1675c+a-'(o) l5-
1aZ 2 3a 5a -4-Methoxyphenyl 7-2-3-4-fluorophenoxy-2-noate, prepared from Intermediate 12b. 1, r, (CHBr,) 359G-3530-17
48 cm-'il ball 25, produced from intermediate 12c. 1, r, (CHBr,) 3580.3520.175
0 cm-'-5-hebutenoate, prepared from intermediate 12d. 1,r, (CHBr,) 3520.1758 cm-'
(r) l5-1(E, 2 2S* 3a
5a - Produced from 4-ami252dama25, intermediate 12a. 1, r, (CHBr,) 3520.3405.360
0-3200.1960°1.758. 1675c+
a-' Phate, prepared from intermediate 12f. 1, r, (CHBr,) 3520. 3430.
175G, 1678cm''1ran-2-ruoxycyclopene-7-no-52Σ, intermediate 12.
Manufactured from. 1, r, (CHBr,) 3520. 3420.
1748. 1672cm-'Dry CI, C1, (4m
Jl) and a stirred solution of intermediate 10a (0,39g) in dry DMSO (0,4+5jl) was treated with dicyclohexylcarbodiimide (0,5g) and then with pyridinium trifluoroacetate (0,71g). . After 5 hours at room temperature, the mixture was poured into water (50w*ff1) and extracted with ER (3X75-n). Dry the extract;
Evaporation gave a residue which was purified by chromatography on acid-washed (pH 3,8) silica to give the title compound (0.27 section) as a colorless gum. 1, r, (CHBr,) 1760. 1743.
1680cm-'. (α)i,*.”-13,7” (MaOH) The following compound was prepared by a similar method. (b) IR-1aZ 22R umbrella 3a -+-4-7, produced from intermediate 10b. 1, r, (CHBr,) 3420.1740.168
5cm-'. [α]ra'・'+16.7° (MeOH) ate CI, C1! (2 fat Q) intermediate 10c (0.15g
) and anhydrous sodium acetate (0,05 g) in cold (
0°C) stirred suspension was added to pyridinium chlorochromate (0°C).
13g). This mixture was heated at 0°C for 30 minutes in room 1.
Stir for an hour. It was then purified by chromatography on acid-washed (pH 3,8) silica using EA as eluent. The gummy title product (0.09 g) was obtained. tie EA
Rf O,3° The following compounds were prepared in a similar manner. ate, prepared from intermediate 10d. 1, r, (CHBr,) 3430. 1740.
1675 cm-' [α] also @-11° (CHCl, ) Chil-5-hepunoate, prepared from Intermediate 10a. 1, r, (CHBr,) 3420. 1740.
1690. 1670cm-'. (α]b@-5°(CHCII) (f) IR-1aZ 2 2R* 3a -
--4-7minocarponylphenyl 7-5-oxo-
2-3-phenoxy-2-rahi'low 2H-bilan-2-ruate, prepared from Intermediate 10f. 1, r, (CHBr3) 3525.3405.174
2.1675.1599 cm-'. [α] is also manufactured from 10 g of @-16.3” (CICI,) body. 1, r, (CHBrs) 3505.3400.174
0.1690.1665 cm-'. [α]′D. -3,4@(C)IC1,)C-2-yloxycyclopentyl-5-heptenoate, prepared from Intermediate 10h. 1, r, (CHBr,) 3430.1?42.168
0.1526 cm-'. [α]'D''-7@(CHCl3) Thenoate, prepared from intermediate 10i. 1, r, (CHBr,) 1740.1622c+a-
'nzoate, prepared from intermediate 10j. 1, r, (CHBr,) 1745.1720 cm-'
Nylcarbonylamino phenyl 7-5-oxo-2-
3-phenoxy-2--trahydro-2tobiran-21
, r, (CHBr,) 3435.1745.1720
．． 1672 cm-1 [α) Ho-8,9@(CHCl,
) 1, r, (CHBr3) 344G, 1760.17
40.1678cm-'' lobentyl-5-hebutenoate, prepared from intermediate 10 irises. 1,r,(C)IBr,) 1745cm-'(n)
(Produced from IR-La (Z 2 3a -4-pensiyla body 10n. 1, r, (CHBr,) 3430.1740.167
Manufactured from 2cm-1 interbody 10o. 1,r,(CHBr,) 1744 cm'' The next compound was prepared in a similar manner to Intermediate 11a. cyclopentyl-5-heptenoate, prepared from intermediate LOP. 1. r, (CHBrs) 1742 cm-'' Thenoate, prepared from Intermediate 10q. 1, r, (CHBr,) 1740 cm'' 1 The following compound was prepared in an analogous manner to Intermediate 11c. Manufactured from earthwork intermediate 10r. 1, r, (CHBrs) 3520. 341G,
1962. 1742. 1676c “1(8)
IR-1 (!Z 2 2R umbrella 3a -4-benzoylamino phenyl 7-5-oxo-2-3-phenoxy-2-tetrahydro-2H-bilan-2-yl Oxy intermediate 10s. 1, r, (CHBra) 3430.1?42.167
Produced from 5cs+-' intermediate 101. 1, r, (CHBr,) 3430.1742.167
Intermediate 2 (0,
A solution of 98 g) was treated with 5N NaOH solution (6 Q). After 30 minutes the mixture was poured into water (100 mA) and extracted with IER (150 mA). This aqueous solution was acidified with saturated Nu4C1 solution (150-Q) and then EA
(Dry the combined extracts extracted with 4 x 50 m,
Evaporation gave the gummy title compound (0.88g). 1, r, (CHBr,) 3510.3400-250
0.1730.1708 cm-' The following compound was prepared in a similar manner. Lopentyl-5-heptene, prepared from Intermediate 3a. 1, r, (CHBr,) 3510.3400-240
0.1730.1708 cm-' lointhyl-5-hepoon, produced from intermediate 3b. 1, r, (CHBr,) 3590.3510.370
0-2400.1730°1705cm-' (d) l5-1αZ 2 3a 5(!
-7-5- Manufactured from humans. 1, r, (C'HBr,) 3520.3600-25
00.1730.1708c+w-'ru45-hebutadiene, prepared from Intermediate 15. 1, r, (CHBr3) 3500.1920.173
0c+a'''1 Bromide (3-
carboxypropyl)triphenylphosphonium (1,
11 g) and potassium t-butoxide (0,58 g)
was stirred at room temperature for 45 minutes. Intermediate 19 (0,58 g) in dry THF (10 mm)
A solution of was added thereto, and the mixture was stirred at room temperature for 1 hour. The same amount of the ylide compound prepared in advance was added to this reaction mixture, and stirring was continued for 1.5 hours. Water (20sffi) was added and the mixture was washed with ER (3X50mQ). Add organic washing solution to 8% NaH
The combined aqueous extracts were back-extracted with CO, solution (2 x 20 mjl) and the combined aqueous extracts were treated with saturated NH, C1 (30 mM) and the product was extracted with OR (3 x 50 mjl). The extract was washed with brine (15mjl), dried and concentrated in vacuo to give the title compound as an oil (0.55g). 1, r, (CHBra) 3500. 3600-2
300. 1728. 1710cm-' intermediate 12a
The following compounds were prepared in a similar manner to that of . Manufactured from 1 piece, 2 screws, 4 pieces - 1 intermediate, 6 pieces. 1, r, (CHBra) 3510. 300G-2
Diisopropylamine (13
, 8mjl) and hexamethylphosphoramide (17
, 5 mH of n-butyllithium (1.5 mH in hexane).
6M, 61.5m(1) was added at 0°C under nitrogen. The solution was cooled to -70°C and 4-
A solution of pentic acid (4.87 g) was added. after that,
Warm this mixture to room temperature. Intermediate 4 (3,5 g) in 1 hour ER (60 sffi)
A solution of was added. After 18 hours, oxalic acid dihydrate (14
A solution of g) was added and the organic phase was separated. The aqueous phase was mixed with EA (2
The combined organic phases were dried and evaporated. The residue was dissolved in DMF (30 sffi) and treated with methyl iodide (12 mm) and potassium fluoride (8 g). 3
After time the solution was diluted with EA (200 mfi) and water (3X
200++1) and braai: / (200mJ1)
't' washed. The aqueous washings were back-extracted with EA (200 vQ) and the combined organic phases were dried and evaporated. This residue was chromatographed (ER/C as eluent).
To a stirred solution of intermediate 13 (2,8 g) in H,C1, (60 mm) was added triethylamine (8,2 mff1), acetic anhydride (6,7 ml) and 4-dimethylaminopyridine (70 g). After 2 hours, the solvent was removed and the residue was chromatographed [ER/PH (40
~60@) 4:1] to give the title compound as an oil (3.1 g). 1, r, (CHBr,) 1728cm-"e acetyloxy-2-3-phenoxy-2-trahi'ro2
H-bilane-2-ruoxypropoxy-3-cupric iodide (6,
8 g) of methyllithium (1.6 M in ER)
, 44.5 mfi) was added. After the addition was complete a clear solution was obtained which was cooled to -78<0>C and a solution of intermediate 14 (0.85 g) in ER (Some) was added. After 1.5 hours, saturated NH4Cl solution (200 kg) was added and the mixture was stirred at room temperature for 1 hour. The organic phase was washed with saturated brine (2
The aqueous phase was extracted with ER (200 mjl). The dried organic extracts were evaporated and the residue was chromatographed with ER/PIE (40-6
0m') 3:1] to give the title compound (1.2 g) as an oil. 1, r, (CHBrs) 1960.1728cm-'
Intermediate 5 (2,7g in eCI, CI, (50mM)
)+7) AL (LM in hexane, 10 ml) was added from the cooled (-78° C.) stirred solution D. After 2 hours more DIBAL (6,7 mji) was added and stirring continued for a further 2.5 hours. MaOH (20mffi)
was added dropwise, and Kiko-tel (60i+jl) was added at room temperature for 15 minutes. The resulting mixture was filtered through Hyflo and the filtrate was evaporated to give the gummy title compound (2.6 g). 1, r, (CHBr,) 358G, 2720@
17g8cm-'*THF (40w+1) under nitrogen
Cooling of potassium t-butoxide (2.9 g) in
) To the solution was added (methoxymethyl)triphenylphosphonium chloride (8.84 g). 5 Kiko THF (25sI
A solution of intermediate 16 (2.6 g) in Q) was added and the mixture was stirred at 0° C. for 30 minutes. A saturated solution of NH4Cl (50tQ) was added and the mixture was evaporated to ER (3*a0mj
The combined extracts extracted in l) were dried and evaporated to give an oil (9.1 g). 0.25N of this crude product
The organic solvent was removed in vacuo and the aqueous residue was dissolved in H
The combined organic phases extracted with A (3×50*jl) were washed with saturated brine (30×l), dried and evaporated. The residue was purified by chromatography (ER as eluent) to give the title compound (1.5 g) as an oil. 1, r-(CHBra) 3580.3460.272
To a stirred solution of intermediate 17 (1,44 g) in 0.1718 cm-'CHsC1, (40sIQ) was added dihydropyran (0,95IQ) and pyridinium toluene-P-sulfonate (0,1g) at 0 °C. . After stirring at room temperature for 20 hours, the mixture was diluted with water (2 x 10 Q), 8
% NaHCO, (2X 10-) and brine (2X
10sIQ). The solvent was evaporated and the residue was chromatographed [ER/PE (40-6
0") 1:1] to give the gummy title compound (1,9 g). 1,r, (CHBr, ) 272G, 1720c
m-” Intermediate 18 (0,94
g) solution with pre-reduced 10% palladium/carbon (0
, 97g) to N, τ. Hydrogenation was carried out for 22 hours with P. The catalyst and solvent were removed and the residual oil (0.75 g) was purified by chromatography using ER/PR (40-6G) 3:1 as eluent to give the title compound as an oil (0.49 g). Ta. 1, r, (CHBr,) 3570 cm-1° In the examples below, unless details of the experiment are explained, they were manufactured in a similar manner to Example 1. Phenyl 7-3-hydroxy-2-2-hydroxy-
A mixed solvent of 3-phenoxypropoxy-5-oxocyclopentyl acetic acid/water/HF 20:10:3 (2.5 m
A solution of intermediate 11a (0.24 g) in jl) was heated to 40°C.
It was heated for 4 hours. The solvent was removed in vacuo and the residue was chromatographed on acid-washed (pH 3,8) silica (ER/Me as eluent).
Purification using OH 75:1) gave the title compound (0.14 g) as a white solid. Crystallization from methyl acetate/PH gave a white solid, melting point 64-65°C. (a)il"・'-18-1' (Neon) *
Elemental analysis (as C*sHa*Os) Actual value C, 68,02; H, 6,63° Calculated value C
, 68,22; H, 6,71%. Mixed solvent of acetic acid/THF 2G:10:3 (:3*
A solution of intermediate 11b (0.3 g) in a) was added to 40-43
Heated at ℃ for 4 hours. The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH 3,8) silica to give the title compound (0,12g) as a white solid. Melting point 60-63°C. Crystallized from t-butyl methyl ether, melting point 74.
A white solid was obtained at 5-75°C. [α] is also “-19,4@(MaO)l). Elemental analysis (as CsJatNOs) Actual value C, 65,86; H, 6,71; N, 2
．． 66° Calculated value C, 66, 27; H, 6, 71;
N, 2.57%. Prepared from intermediate 11c (0.09 g) and purified using EA/eOH 20:1 as eluent (0.04
g). tie HA/MeOH20:I Rf o,zs;1
, r, (C)lBr, ) 3570. 350G,
3400. 174 (1,1680cm-'Large IR-La Z 2 Re 3a ---4
-H'J A solution of intermediate 11d (0.24 g) in a mixed solvent of acetic acid/water/THF 20:10:3 (3a+fi) was heated at 40-42<0>C for 3 hours. The solvent was evaporated in vacuo and the residue was washed with acid (pH 3,8)
Purification by chromatography on silica (using EA/cyclohexane:1 as eluent) gave the title compound (0.07 g) as a white powder after trituration in ER. Melting point 125-127°C; [α] also '-29,3° (CHCl, ). Elemental analysis (as CsJatNOs) Actual value C, 69,4; H, 6,4; N, 2.3
° Calculated value C, 69,5: H, 6,4; N, 2.
4%. Hoxie 5-oxocyclopentyl-5-hebutenoe:
2E acetic acid/water IF 20:10:3 mixed solvent (3am)
A solution of intermediate 11e (0.24 g) in 40-42°C
It was heated for 4 hours. The solvent was removed in vacuo and the resulting solid residue was acid washed (p
H3,8) Purification by chromatography on silica (using EA as eluent) gave the title compound (0.06 g) as a white powder after fine trituration in the ER. Melting point: 150-154°C; [α] is also 10@(MeOH). Elemental analysis (as CxsH4aN*o*) Actual value C,
66,7; H, 6,3; N, 4.5° calculated value C
,67,1: H,6,3; N, 4.4%, ・
Acetic acid l water/THF 20:10:3(F) mixed solvent (5
A solution of 1 ff (0.44 g) of the intermediate in 40
Heated at ℃ for 3 hours. The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (PH3,8) silica using EA/EtOH 95:5 as eluent. Finely trituration in ER followed by crystallization from HA/PE gave the title compound (0.14 g) as a white solid. Melting point 104-105℃; [α] et al”-13,2@(E
tOH). Elemental analysis (as CzsHiiNO-) Actual value C, 6
6,65: H, 6,7: N, 2.7°calculated value C
,65,7; H,6,5; N, 2.7%. A solution of 11 g (0.37 g) of this body was heated at 40°C for 3 hours, and the solvent was removed in vacuo, and part of the residue (0.19 g) was heated at 40°C for 3 hours.
was purified by chromatography on acid-washed (PH 3,8) silica gel using CH,CI,/EtOH 9:1 as eluent. After finely grinding with ER
The title compound crystallized from A/PH as a white solid (0,0
4g) was obtained. Melting point 105°C; [α]i) @+3.5° (HtOH): 1, r, (Nujol) 1740.1720.1660.1645c
A solution of intermediate 11h (0.35 g) in a mixed solvent of m''''1° acetic acid/water/THF 20:10:3 (5 mffi) was heated at 40-42° C. for 2.5 hours. The solvent was removed in vacuo and the residue was chromatographed on acid-washed (pH 3,8) silica (EA/cyclohexane 3 as eluent).
:1) to give the title compound (0.16 g) as a white powder after finely trituration in the ER. Melting point 89-91°C; (a)i+” 25.7@(CHC
la) - Elemental analysis (as CsJstNOs) Actual value C, 69,3: H, 6,4; N, 2.2
° Calculated value C, 69,5; H, 6,4; N, 2.
4%. 11'' - Prepared from Intermediate 11i (0.24 g) and purified using EA as eluent (0.08 g). 1, r, (CHBr,) 3580.3420.1?4
5.1624cwa-1゜〔α〕 is also 6-29゜(CHC
l,). Elemental analysis (Ca. H3, No, closed) Actual value C, 6
6,53; H, 7,04; N, 2.53° Calculated value C, 66,77; H, 6,91; N, 2.60
%. A mixed solvent of acetic acid, water, HF, 20:10:3 (10 Oboro Q
) of intermediate 11j (0.19 g) at 40°C.
heated for an hour. The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (PH3,8) silica (using ER as eluent) to give the title compound (0,1 g) as a white solid. Melting point: 45-47°C; [α]'D@-33@(CHCl). Elemental analysis (as C!1IH1401) Actual value C,6
6,25; H,6,63°calculated value C,66,15:
Intermediate 11k (0
, 57g) was heated at 40°C for 3.5 hours. The solvent was removed in vacuo and the residue was chromatographed on acid-washed (PH3,8) silica (HR/PH as eluent).
A white powder (0.22 g) was obtained after fine grinding in the ER. Crystallization from HA/PR gave the title compound (0.18 g) as a white solid with a melting point of 108-110°C. [α] is also @-13,9@(EtOH) Elemental analysis (as CsJa7NOs) Actual value C, 67,35; H, 6,1; N, 2.
2゜Calculated value C, 67, 65; H, 6, 2; N,
2.3%. Prepared from intermediate 114 (0,056 g) and purified by elution with EA/cyclohexane 2:1 (0.029 g)
, tlc HA/cyclohexane 2:I Rf O,
2; 1, r, (CHBr,) 3580.3440.174
2.1675 cm-” ethyl acetic acid, water, HF 20:10:3 mixed solvent (12tQ
) solution of intermediate 11m (0.44g) in 40-42
The solvent was removed in vacuo and the residue was chromatographed on acid-washed (pH 3,8) silica (
Purification using ER/HA 3:l as eluent) gave the title compound (0.15 g) as a white powder after finely trituration in ER. Melting point 71-73°C; [α] also @-35° (CHCI, ). Elemental analysis (as CslHa*Ot) Actual value C,? 1.79; H, 6, 60° calculated value C
，? 1.79: H, 6,61%. Prepared from intermediate 11n (0.11 g) and purified by elution with ER (0.06 g). 1, r, (CHBr,) 35110.3420.17
42.1672cm-'. (α) M 7° (in eOH) Elemental analysis (as CasHssNOs) Actual value C, 6
9,42: H, 6,85; N, 2.21° Calculated value C, 69,87; H, 6,53; N, 2.3%
. Prepared from intermediate 11o (1,09 g) and ER/MeO
Purified by elution with H97:3 (Oa06g
)-1, r, (CHBr,) 3580.3450.1
745cm-'. Elemental analysis (as CaJaaFOs) Actual value C, 64, F5; H, 6,59° Calculated value C
, 65,10; H, 6,44%. Produced from intermediate 11p (0.16 g) and ER/MaO
Purified by elution with H98°:2 (0.1 g
). 1, r, (CHBr,) 3580. 3440.
1742cm-';tie ER/MaOH98:2
Rf O, 25°acetic acid l water/THF 20:10
: Intermediate 11q (0,14
The solution in g) was heated at 40-42°C for 3 hours. The solvent was removed in vacuo and the residue was chromatographed on acid-washed (pH 3,8) silica ([EA/E
R75:25 to 90:10 gradient) to give the title compound (0.09 g) as a white solid. Melting point 7
3-76℃. 1, r, (CHBr,) 3580.3440.174
2cm+-', 'prepared from intermediate 11r (0.35g) and purified by elution with HA/CHsCN 3:2 (0.19g). tie HA/CH,CN 3:2 Rf O,3;I
-r- (CHBrs) 358G, 3520s 340
0- 1960- 1740-1672c■-1゜〔α〕also@-21,0" (CICI,)acetic acid l water phar
A solution of 11 g (0.17 g) of the intermediate in a mixed solvent (loal) of F 20:10:3 was heated at 40° C. for 2 hours. The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH 3,8) silica (using HA/cyclohexane z;1 as eluent) to give the title compound as a solid (0,11 g). Ta. Melting point 85-88°C. 1, r, (CHBrs) 3580.3430.174
5.1675゜[α)5@-27'' (CICI halamino phenyl 9-3-hydroxy-2-2-hydroxy-3-phenoxypropoxy-5-oxosifacetic acid/water/HF 20:10:3 mixed solvent (1
A solution of 11t (0.55 g) of intermediate in 5 mjl)
Heated at 0°C for 4 hours. The solvent was removed in vacuo and the residue was purified by acid washing (PH 3,8) chromatography on silica (using HA/cyclohexane 3) to give the title compound as a white solid (after finely trituration in ER). 0.24 g) was obtained. Melting point 121-122°C; [α]Moo-34° (CHCI, ). Elemental analysis (as Cs@tktNOs) Actual value C, 7
0,23; H, 6,66; N, 2.17° Calculated value C, 7G, 22; H, 6,71; N, 2.27
%. A solution of the compound of Example 4 (0.1 g) in EA (35 ■Q) was prereduced with 10% palladium on carbon (0.03
g) with N, T, P for 40 minutes, then the solvent and catalyst were removed. The title compound (0,
07g) was obtained. Melting point 127-130°C; [α] is also '-29,3'' (CHCIs). Elemental analysis (as CaJasNOs) Actual value C, 69,38; H, 6,69: N, 2
．． 15° Calculated value C, 69, 25: )l, 6.67
: N, 2.38%. CI, CH (3 mjl) and benzene (compound of Example 6 (0,15 g) in 3 ml, thiophenol (0
, 4610) and azobisisobutyronitrile (0,
A solution of 1 g) was stirred under reflux for 6.5 hours. Acid cleaning (
PH3,8) Chromatography on silica (HA/C
Purification using H,CN 9:1) gave the gummy title compound (0.13 g). 1, r, (CHBr) 358G, 3515.340
0.1742.1672cm-”. [α] is also @-30@(CHCIs) Elemental analysis (as Ca, HsaNOs) Actual value C, 6
6, 12; H, 6, 8: N, 2.52° calculated value
C, 65,74: H, 6,5: N, 2.74%. Intermediate 1 (0,03 g) in dry DMF (1 m+jl)
Pivaloyl chloride (0.01Q) was added to a solution of Et, N (0.0l-Q) at 0°C. 4-(benzoylamino)phenol (o, i7g) and EtsN (0,01 ■a) in 10 min Kiko MF (1 mjl)
A solution of was added and stirred at 0° C. for 2 hours and at room temperature for 3.5 hours. The reaction mixture was diluted with HA (30 Q),
Water (10 ■Q), 10% copper sulfate solution (15 ■Q), water (
Washed sequentially with 10 mffi) and brine (15 mffi). The dried organic extracts were evaporated and the resulting residue was chromatographed on acid-washed (pH 3,8) silica (
(using cyclohexane/EA 1:1 as eluent)
It was purified by Title compound as a white solid (0.05g)
I got it. 1, r, (CHBr) 3580. 3430. 17
45. 1675cm-';tie cyclohexane/E
A 1:I Rf O, 15 The following are nine examples of pharmaceutical compositions containing the compounds of the present invention.
The term "active ingredient" refers to a compound of the invention as described in the examples above (eg, the compound of Example 4).These are prepared by direct compression. 015-0.2
Magnesium Stearate, BP 1.5 Microcrystalline Cellulose, USP 150.0 (on compressed weight) The active ingredient is mixed with approximately 10% microcrystalline cellulose and then the remaining microcrystalline cellulose and stearic acid are mixed together. Mix with magnesium. This mixture is then compressed into tablets using a 6-diameter punch on a suitable tablet machine. The tablets are prepared by standard techniques using a suitable film-forming material (e.g. methylcellulose or hydroxypropylmethylcellulose).
It can be coated with a coating. Active ingredient 0.015-0.2
Magnesium Stearate, BP 1.0 Umbrella Starch 1
500 100.0 (based on fill weight) - Starch form capable of direct compression. The active ingredient is premixed with a portion of Starch 1500 and then mixed with the remaining Starch 1500 and magnesium stearate. This mixture is then filled into hard gelatin capsules of size Nc2 using a suitable capsule filling machine. The ability of the compounds of the invention to inhibit histamine-induced gastric acid secretion was refined by Persons, M. [E., Dissertation, University of London 1969] G.
hosh, M, N, and 5child's method (Br, J
, Pharmacol. (1958, 13.54) on perfused rat stomachs. The HD value of inhibition of gastric acid secretion was determined by administering one dose of the test compound to one rat. This was determined by repeating this for at least 4 rats at each of the 3 or more dose levels. The results obtained were used to determine the EDs values by standard least squares method. Thus, for example, Example 2.
4.5.6.7.8.9.10.14 Compounds 15, 17 and 22 may have EDsll values in the range of 0.08 to 0.4 μg/kg/■i (30 minutes). Shown. In particular, the compounds of Examples 4 and 6 had an E! of 0.26 and 0.35 ug/kg/5in (30 minutes), respectively. D. It was shown that it has value. The compounds of the invention are generally non-toxic at therapeutically effective doses. Thus, for example, the compound of Example 4 has 2H/k
No adverse effects occurred when administered orally to rats at doses up to 100 g.

Claims (1)

[Claims] 1. A salt of a compound of general formula (I) and a compound in which R^2 is hydrogen. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) In the formula, n is 1 or 2; m is 2 to 5 and X is cis or trans-CH
=CH- or -CH_2-CH_2-, or m is 1 to 4 and X is -CH=C=CH-; R^1 is (a) phenyl group [C_1_-_4 alkyl group, C_1
____4 alkoxy group, C_1_-_4 alkanoyl group, methylthio group, methylsulfinyl group, methylsulfonyl group, halogen atom, -CO_2R^2 (here R^
2 is a hydrogen atom or a C_1_-_4 alkyl group or a phenyl group), -NHCOR^2 (where R^2 is as defined above, or a hydroxy group, CH_3
CONH- or a phenyl group optionally substituted with a benzoylamino group), -CONR^3R^4 (where R^3 and R^4 are the same or different and each is a hydrogen atom or a C_1_-_4 alkyl group) ), -NHC
ONH_2, -CH_2CH(CONH_2)NHCO
or (b) is a 2-naphthyl group; Y is ▲ has a mathematical formula, chemical formula, table, etc. , R^6 and R^7 are each a hydrogen atom or a methyl group, at least one of which is a hydrogen atom, and Ar is a phenyl group (one or two C_1_-_4 alkyl groups, C_1_ -_4 alkoxy group, C_1_-_4 alkylthio group, C_1_-
_4 alkylsulfinyl group, C_1_-_4 alkylsulfonyl group, one optionally substituted with a halogen atom or a trifluoromethyl group]. 2, X is -CH=CH- or -CH_2-CH_2-
and when n is 1, m is 3, or when n is 2
when m is 2 or 4; or when X is -CH=C=CH- and n is 1 then m is 2; or when n is 2 then m is 1 or 3 A compound according to claim 1. 3, R^1 is C_1_-_4 alkoxy group, C_1_-
_4 Alkanoyl group, methylthio group, methylsulfonyl group, -CO_2R^2, -NHCOR^2, -CONR
^3R^4, -NHCONH_2 or -CH_2CH
The compound according to claim 1 or 2, wherein (CONH_2) is a phenyl group substituted with a NH-COCH_3 group, or R^1 is a 2-naphthyl group. 4, R^1 is methoxy group, acetyl group, -CO_2CH
_3-, -NHCOCH_3, benzoylamino group, -
CONH_2-, -CON(CH_3)_2 or -C
3. The compound according to claim 1 or 2, wherein R^1 is a phenyl group substituted with H_2CH(CONH_2)NHCOCH_3, or R^1 is a 2-naphthyl group. 5, R^5, R^6 and R^7 are hydrogen atoms, and A
5. The compound according to any one of claims 1 to 4, wherein r is a phenyl group or a phenyl group substituted with fluoro or chloro. 6, X is -CH=CH- or -CH_2CH_2-, n is 1 and m is 3, or n is 2 and m is 2 or 4; or X is -CH=C=C
H-, and n is 1 and m is 2, or n is 2 and m is 1 or 3; R^1 is a methoxy group, an acetyl group, -CO_2CH_3
, -NHCOCH_3, benzoylamino group, -CON
H_2, -CON(CH_3)_2 or -CH_2C
H(CONH_2) is a phenyl group substituted with NHCOCH_3, or R^1 is a 2-naphthyl group; R^5 is a hydrogen atom or a methyl group; R^6 and R^7 are hydrogen atoms and Ar is a phenyl group or a phenyl group substituted with fluoro or chloro; The compound according to claim 1. 7. Group -(CH_2)_nX(CH_2)_mCO_2
7. A compound according to any one of claims 1 to 6, wherein the carbon atom with R^1 is in the R-configuration. 8. The compound is [1R[1α(Z), 2β(R*)]
, 3α]]-(-)-4-(benzoylaminophenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-
A compound according to claim 1 which is 5-heptenoate. 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 together with one or more pharmaceutical carriers. 10. A method for producing a compound according to claim 1, comprising: (a) removing the protecting group of a corresponding compound in which the ring hydroxy group and the hydroxy group in the group Y are protected; (b) R^1
is a hydrogen atom; (c) When producing a compound in which X is -CH_2-CH_2-, reducing a corresponding compound in which X is -CH=CH- or an acetylene group; d) to prepare a compound in which X is -CH=CH-, by selectively reducing the corresponding compound in which X is an acetylene group; or (e) to prepare a compound in which X is trans -CH=CH-. When produced, the corresponding compound in which X is cis-CH═CH- is isomerized;