CH667265A5 - CYCLOPENTYL ETHER AND THEIR PRODUCTION AND PHARMACEUTICAL FORMULATION. - Google Patents

Description

DESCRIPTION 55 Prostaglandin E2 is a naturally occurring substance that has many physiological effects. For example, it inhibits gastric acid secretion and creates gastrointestinal cyto-protection or cell protection, lowers blood pressure, stimulates and relaxes smooth muscles, inhibits platelet aggregation and inhibits lipolysis.

Synthetic PGE2 analogs offer the possibility of different effectiveness, longer activity duration and increased effectivity of selectivity and are therefore of considerable interest.

Many different PGE2 analogs have been proposed for use in medicine in the past, but only in one case have 13-oxa compounds been used in the

3rd

667 265

proposed. For example, British Patent Specification 2,082,176A describes a group of compounds which include 2- (heptyloxy) -3-hydroxy-5-oxo-cyclopentaneheptanoic acid and a 15-hydroxy derivative thereof. These compounds are said to inhibit platelet aggregation and have bronchodilator activity and are proposed for use as antithrombotic and anti-asthmatic agents.

A new group of cyclopentyl ethers has now been found which have PGE2-type activity. Compound fertilizers in this class have a particularly useful profile of biological activity. In particular, they have been shown to have a high activity and prolonged activity in terms of inhibiting gastric acid secretion and gastrointestinal cyto protection, and are therefore of interest in the treatment of ulcers, particularly gastric ulcers.

The invention therefore provides compounds of the general formula (1)

20th

/ \

s (CH2) nX (CH2) mC02Rl

(1)

25th

HO OY

where n = 1 or 2; 30th

m = 2 to 5 and

X is ice or trans-CH = CH- or -CH2-CH2- or m = 1 to 4 and X is -CH = C = CH-;

R1 means

(a) Phenyl [optionally substituted by Q 4-alkyl, 35 Ci 4-alkoxy, Q 4-alkanoyl, methylthio, methylsulfinyl, methylsulfonyl, halogen (e.g. chlorine or bromine), -C02R2 [wherein R2 is a hydrogen atom or Q 4-alkyl or is phenyl], -NHCOR2 [wherein R2 is as defined above or represents a phenyl group, optionally substituted 40

by hydroxyl, CH3-CONH- or ^ jV ~ CONH-,

-CONR3R4 [? 'Orin R3 and R4 are the same or different and are each a hydrogen atom or a Q 4-alkyl group], -NHCONH2, -CH2CH (CONH2) NHCOCH3 or

Includes compounds as well as mixtures of the enantiomers including the racemates.

In general, the compounds of formula (1) are those in which the carbon atom bearing the group - (CH2) nX (CH2) mCO2R 'and / or the carbon atom in group Y which carries the -OH group (especially the first-right group) ) in R configuration and mixtures containing such isomers are preferred.

The alkyl groups mentioned above in the definition of the compounds of the formula (1) can be straight-chain or branched.

When R1 in the compounds of formula (1) is phenyl substituted by a group -C02H, the compounds are capable of forming salts with bases. Examples of suitable salts are alkali metal (e.g. sodium and potassium) -

In compounds where X is -CH = CH- or -CH2CH2-, m is preferably 3 when n is 1 and m is preferably 2 or 4 when n is 2. When X is CH = C = CH-, m is preferably 2 and n = 1, and 1 or 3 when n = 2.

When X is -CH = CH-, it is preferably cis-CH = CH-.

If R1 is a substituted phenyl group, it can be, for example, phenyl, substituted in the meta, ortho or in particular para position by a chlorine or bromine atom, or a group methyl, ethyl, propyl, n-butyl, t-butyl, methoxy, Ethoxy, propoxy, butoxy, acetyl, propionyl, methylthio, methylsulfinyl, methylsulfonyl, -C02H,

-C02CH3, -C02CH2CH3, -CO;

NHCHO,

50

55

-CH2CH (CONH2) NHCOH ^ J ^] or (b) 2-naphthyl;

R6 R7 \ /

Y means -CH2-C-C-OAr

/ \

Rs OH

wherein R5, R6 and R7 are each a hydrogen atom or a methyl group and at least one is a hydrogen atom; and

Ar is a phenyl group (optionally substituted by one or two Q 4 alkyl, Q 4 alkoxy, Q 4 alkyl thio, C 4 alkylsulfinyl, Q 4 alkylsulfonyl, halogen or trifluoromethyl groups); and the physiologically acceptable salts thereof.

The structural formula given here should be understood to mean that the enantiomers of each of the concerned

-NHCOCH3, benzoylamino, (acetylamino) -benzoylamino, (hydroxy) -benzoylamino, -CONH ,, -CONHCH3, -CON (CH3) 2, CONHCH, CH3, -CONH (CH2CH3K -NHCONH ,, -CH2CH (CÓNH2) NHCOCH3 or

-CH2CH (CONH2) NHCO- <Q>.

Particularly useful substituents which may be present on a substituted phenyl group R1 include the groups C1_4-alkoxy, C1_4-alkanoyI, methylthio, methylsulfonyl, -C02R2, -NHCOR2, -CONR3R4 [wherein R2, R3 and R4 are as for formula (1) are defined], -NHCONH2 or -CH2CH (CONH2) NHCOCH3. Particularly useful substituents of this type include methoxy, acetyl, methylthio, methylsulfonyl, -C02CH3,

-NHCOCH3, benzoylamino, (p-acetylamino) -benzoylami-no, (p-hydroxy) -benzoylamino, -CONH1, -CON (CH3) ->, -NHCONH2 or -CH2CH (CONH2) NHCOCH3.

The group R 'is preferably a substituted phenyl group, where the substituent can be in the meta, ortho or especially para position, or a 2-naphthyl group.

Compounds in which R1 is a phenyl group substituted (especially in the para position) by a group methoxy, acetyl, -C02CH3, -NHCOCH3, benzoylamino, -CONH2, -CON (CH3) 2 or -CH2CH (CONH2) NHCOCH3, or R1 represents a 2-naphthyl group are particularly useful.

In group Y, R6 and R7 are preferably hydrogen atoms. Compounds in which R5 = H or -CH3 and R6 and R7 are hydrogen atoms are also preferred.

If the Ar-phenyl group is substituted, the substituent can be in the meta, ortho or para position and can be, for example, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, methylthio, methylsulfinyl, methylsulfonyl, fluorine, chlorine , Bromine or trifluoromethyl. There is preferably only a single substituent, especially in the para position. Generally, Ar

667 265 4

preferably phenyl or phenyl, substituted by halo-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopen gene, especially fluorine or chlorine. tanheptanoate; and

The preferred embodiments given above, [IR- [la (E), 2ß (R *), 3a]] - (-) - 4- (aminocarbonyl) phenyl, apply not only separately, but also in combination 7 - [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclo-ion with one or more of the aforementioned other preferred 5-pentyl] -5-heptenoate.

opportunities. A particularly useful group of compounds that

A preferred group of Verses type according to the invention comprises:

Accordingly, bonds has the formula (1), in which [lR- [la (Z), 2ß (R *), 3a]] - (-) - 4-acetylphenyI-7- [3-hydro-

X is -CH = CH- or -CH2CH2- and n = 1 and xy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-

m = 3 or n = 2 and m = 2 or 4, or X is 10 heptenoate;

-CH = C = CH- and n = 1 and m = 2 or n = 2 and [lR- [la (Z), 2ß (R *), 3a]] - (-) - 4- (acetylamino) phenyl -7-

m = 1 or 3; [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclo-

R 'is a phenyl group substituted (preferably in pentyl] -5-heptenoate;

para position) by a group methoxy, acetyl, [lR- [la (Z), 2ß (R *), 3a]] - (-) - 4- (benzoylamino) phenyl-7-

-C02CH3, -NHCOCH3, benzoylamino, -CONH2, 15 [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5- oxocyclo-

-CON (CH3) 2 or -CH2CH (CONH2) NHCOCH3, or R 'pentyl] -5-heptenoate;

is a 2-naphthyl group; [lR- [la (Z), 2ß (R *), 3a]] - (-) - 4- (aminocarbonyl) -phe-

R5 is a hydrogen atom or a methyl group; nyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxo-

R6 and R7 are hydrogen atoms; and cyclopentyl] -5-heptenoate;

Ar is phenyl or 20 [IR- [la (Z), 2ß (R *), 3a]] - (-) - 3- (benzoylamino) phenyl-7-phenyl substituted by fluorine or chlorine. [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclo-

pentyl] -5-heptenoate;

Compounds of this type, in which the group [lR- [la (Z), 2ß (R *), 3a]] - (-) - 4- (N, N-dimethylaminocar-

Carbon atoms bearing (CH2) nX (CH2) mC02R1 in the R-bonyl) phenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxyprop configuration are particularly preferred ) -5-oxocyclopentyl] -5-heptenoate;

preferred compounds of this type are those in which R1 is - [lR- [lcc (Z), 2β (R *), 3a]] - (-) - methyl-4 - [[7- [3-hydroxy-2-ne Phenyl group, substituted (preferably in para-Stel- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -l-oxo-5-lung) by benzoylamino or -CONH2, especially the ereptenyl] -oxy] benzoate ;

stere is. [IR- [la (Z), 2β (R *), 3a]] - 2-naphthalenyl-7- [3-hydroxy-2-

A particularly useful group of compounds according to the invention is 30 (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-hepte: noat;

[lR- [la (Z), 2ß (R *), 3a]] - (-) -4-acetylphenyl-7- [3-hy- [lR- [la (Z), 2ß, 3a]] - 4 -Methoxyphenyl-7- [2- [3- (4-fluoro-

hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] phenoxy) -2-hydroxypropoxy] -3-hydroxy-5-oxocyclopentyl] -5-heptenoate; 5-heptenoate;

[lR- [la (Z), 2ß (R *), 3a] '] - (-) - 4- (acetylamino) phenyl-7- 35 [lR- [la (Z), 2ß (R *), 3a]] - (-) - 4- (Benzoylamino) phenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclo- [3-hydroxy-2- (2-hydroxy -3-phenoxypropoxy) -5-oxocyclopentyl] -5-heptenoate; pentyl] -4-heptenoate; and

[lR- [la (Z) -2ß (R *), 3a]] - (-) - 4- (benzoylamino) phenyl-7- [lR- [la, 2ß (R *), 3a]] - ( -) - 4- (Benzoylamino) phenyl-3- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclohydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5- oxocyclopenentyl] -5-heptenoate; 40 tanheptanoate.

[lR- [la (Z, S *), 2ß (R *), 3a]] - (+) - [2- (acetylamino) -3- Another important group of compounds according to amino-3-oxopropyl] phenyl -7- [3-hydroxy-2- (2-hydroxy-3- of the invention with particularly useful physico-chemical phenoxypropoxy) -5-oxocyclopentyl] -5-heptenoate; Properties they have for pharmaceutical preparations

[lR- [la (Z), 2ß (R *), 3a]] - (-) - 4- (aminocarbonyl) phenyl- makes very suitable, includes:

7- [3-Hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclo- 45 [IR- [la (Z), 2ß (R *), 3a]] - (-) - 4-acetylphenyl ) -7- [3-hy-pentyl] -5-heptenoate; droxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -

[1 R- [la (Z), 2ß (R *), 3a]] - (-) - 3- (benzoylamino) phenyl 5-heptenoate;

7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclo- [IR- [la (Z), 2ß (R *), 3a]] - (-) - 4- (acetylamino ) phenyl-7-pentyl] -5-heptenoate; [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclo-

[IR- [la (Z) -2ß (R *), 3a]] - (-) - 4- (N, N-dimethylaminocar-so pentyl] -5-heptenoate;

bonyl) phenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxyprop- [IR- [la (Z), 2ß (R *), 3a]] - (-) - 4- (benzoylamino -phenyl-7-

oxy) -5-oxocyclopentyl] -5-heptenoate; [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclo-

flR- [la (Z), 2ß (R *), 3a]] - (-) methyl 4- [[7- [3-hydroxy-2-pentyl] -5-heptenoate;

(2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -l-oxo-5- [lR- [la (Z), 2ß (R *), 3a]] - (-) - 4- [4- ( Acetylamino) benzo-heptenyl] oxy] benzoate; 55 ylamino] phenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxy-

[IR- [la (Z), 2ß (R *), 3a]] - 2-naphthalenyl 7- [3-hydroxy-2-propoxy) -5-oxocyclopentyl] -5-heptenoate;

(2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-hepte- [IR- [la (Z), 2ß (R *), 3a]] - (-) - 4- (aminocarbonyl) -phe-

noat; nyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxo-

[IR- [la (Z), 2ß, 3a]] - (-) - 4- (benzoylamino) phenyl-7-cyclopentyl] -5-heptenoate;

[3-hydroxy-2- (2-hydroxy-2-methyl-3-phenoxypropoxy) -5- 60 [IR- [la (Z, S *), 2ß (R *), 3a]] - (+) - [2- (acetylamino) -3- ami-oxocyclopentyl] -5-heptenoate; no-3-oxopropyl] phenyI-7- [3-hydroxy-2- (2-hydroxy-3-phen-

[IR- [la (Z), 2ß, 3a]] - 4-methoxyphenyl-7- [2- [3- (4-fluoro-oxypropoxy) -5-oxocyclopentyl] -5-heptenoate;

phenoxy) -2-hydroxypropoxy] -3-hydroxy-5- oxocyclopen- flR- [la (Z), 2ß (R *), 3a]] - (-) - 3- (benzoylamino) phenyl-7-

tyl] -5-heptenoate; [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclo-

[IR- [la (Z), 2ß (R *), 3a]] - (-) - 4- (benzoylamino) phenyl-7- 65 pentyl] -5-heptenoate; [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclo- [lR- [la (Z), 2ß (R *), 3a]] - (-) - methyl-4 - [[ 7- [3-hydroxy-2-

pentyl] -4-heptenoate; (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -l-oxo-5-

[IR- [la, 2ß (R *), 3a]] - (-) - 4- (benzoylamino) phenyl-3-heptenyl] oxy] benzoate;

667 265

[IR- [la (Z), 2ß (R *), 3a]] - 2- (benzoylamino) phenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclo- pentyl] -5-heptenoate;

[IR- [la (Z) -2ß (R *), 3a]] - 2-naphthalenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-hepte -noat;

[lR- [la (Z), 2ß, 3a]] - (4- (methylsulfonyl) phenyl-7r [3-hydroxy-2- [2-hydroxy-3- [4- (methylthio) phenoxy] -propoxy] -5 ~ oxocyclopentyl] -5-heptenoate;

[lR- [la (Z), 2ß (R *), 3a]] - (-) - 4- (benzoylamino) phenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) - 5-oxocyclopentyl] -4-heptenoate;

[1 R- [la (Z) -2ß (R *), 3a]] - (-) - 4- (benzoylamino) phenyl-9- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclo-pentyl] -7-nonenoate; and

[IR- [la, 2ß (R *), 3a]] - (-) - 4- (benzoylamino) phenyl-3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopen tanheptanoate.

A particularly preferred compound according to the invention is [IR- [la (Z) -2ß (R *), 3a]] - (-) - 4- (benzoylamino) -phenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxo-cyclopentyl] -5-heptenoate.

Compounds of formula (1) inhibit gastric acid secretion, as exemplified by their ability to inhibit histamine-induced secretory responses to the perfused rat stomach using the method of Gosh M.N. and Schild in Br. J. Pharmacol., 1958, 13, 54, modified from Parsons M.E., Ph.D. Thesis, University of London, 1969.

The compounds also provide gastrointestinal cell protection, as exemplified by their ability to inhibit ethanol-induced injury in the conscious rat according to the method of Robert et al. in Ga-streoenterology, 1979, 77, 433, modified using 5 mg / kg / s.c. Indomethacin was determined before administration of the test compound.

The compounds are therefore of interest in the prevention and / or treatment of ulcers or gastric ulcers. They can also be used in the treatment of other conditions that occur due to gastric acid hypersecretion. They can be formulated in the usual way with one or more pharmaceutical carriers, e.g. for oral, buccal, parenteral or rectal administration.

The compounds can be formulated for oral administration, for example, as tablets, capsules, powders, solutions or syrups made by conventional means with acceptable excipients.

The compounds can be formulated for parenteral administration by bolus injections or continuous infusion. Formulations for injection can be presented in unit dose form in ampoules or in multi-dose containers with added preservative.

For buccal administration, the compounds can be formulated in the usual way as tablets or lozenges; and for rectal administration, compositions such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter or another glyceride, can be used.

The compounds are preferably administered orally, e.g. in amounts of 0.5 to 300 (ig / kg body weight, 1 to 4 times a day. For parenteral administration, the compounds can be administered in amounts of 0.01 to 10 (xg / kg body weight 1 to 4 times a day. The exact dose will of course depend on the age and condition of the patient.

Suitable methods for the preparation of the

Compounds are described below, with the various groups and symbols being as defined above unless otherwise stated.

(a) Compounds of the formula (1) can be prepared by deprotection of a corresponding compound in which the ring hydroxyl group and the hydroxyl group in Y are protected.

The protected compounds therefore have the formula (2)

10th

O

..., (CH2) nX (CH2) mC02Rl

/ \ .X *

I 1

15

Rb0

OY1

where R8 is a suitable hydroxyl protecting group [e.g. Tetrahydropyran-2-yl, tetrahydrofuran-2-yl, ethoxyethyl, tri-20 (hydrocarbyl) silyl or arylmethyl] and Y 'is as one group

R6 R7

\ /

-CH2-C-C-OAr

/ \

25th

R5 OH

30 defined.

The two R8 groups in the compounds of the formula (2) are expediently the same, but they can also be different if desired.

When R8 is tri (hydrocarbyl) silyl, the hydro-35 carbyl substituents may be the same or different, e.g. Ci_6 alkyl, C2-6 alkenyl, C3 7 cycloalkyl, C7 20 aralkyl and C6-2o aryl groups. Such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, allyl, phenyl and benzyl. Preferred hydrocarbyl groups are 40 Ci_4 alkyl, e.g. Methyl and t-butyl. Trimethylsilyl and t-butyldimethylsilyl groups are particularly preferred.

If R8 represents an arylmethyl group, it can contain up to 20 carbon atoms, e.g. Benzyl, diphenylmethyl or triphenylmethyl.

45 The method used to deprotect the protected hydroxyl group will depend on the nature of the R8 group, but acid hydrolysis or reduction can generally be used.

50 For example, when R8 is a tetrahydropyran-2-yl, tetrahydrofuran-2-yl or ethoxyethyl group, the protecting group can be removed 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), dipolar, aprotic solvents (e.g. acetone, acetonitrile, dimethyl sulfoxide and dimenothethylformamide) and alcohols (e.g. methanol, Ethanol and ethylene glycol). If desired, the solvents can be used in combination with water. The reaction can be carried out at any suitable temperature, such as from 0 to 50 ° C, e.g. 40 to 50 ° C, are carried out.

65 A tri (hydrocarbyl) silyl group can be removed, for example, by acidic hydrolysis, e.g. with dilute mineral acid or trifluoroacetic acid, or by treatment with fluoride ions (e.g. from a quaternary ammonium

667 265

6

nium fluoride, such as tetra-n-butylammonium fluoride) or by treatment with aqueous hydrogen fluoride. Aryl methyl groups can be reduced by e.g. by hydro-genolysis, e.g. with a noble metal catalyst, such as platinum or palladium, or by treatment with a Lewis acid (e.g. boron trifluoroetherate) in the presence of a thiol, e.g. Ethanethiol, in a suitable solvent such as dichloromethane, for example at room temperature.

Compounds of formula (2) can be obtained by oxidation of a compound of formula (3)

OH

À / CH ^ nXCCHîUOîR1

R8Ó OY1

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. -10 ° C to room temperature). Alternatively, oxidation with dimethyl sulfoxide activated by N, N'-dicyclohexylcarbodiimide in the presence of pyridinium trifluoroacetate in a solvent such as dichloromethane in e.g. —10 ° C to room temperature. Other common oxidation methods can also be used, e.g. Jones reagent.

Intermediate compounds of formula (3) can be prepared by methods generally described in European Patent Specification 160,495.

It should be noted that the method (a) of deprotection is usually used in connection with the formation of the cyclopentyl ring oxo group by oxidation. Thus, the compounds of formula (1) can generally be prepared by oxidizing a corresponding compound of formula (3).

However, the formation of the ring oxo group can be effected by esterification (e.g. by the following method b)) before the introduction of the desired R1 group and the protective groups can then be removed.

(b) The compounds of formula (1) can also be esterified by the corresponding carboxylic acids, i.e. of the compounds in which R1 is a hydrogen atom can be prepared by conventional methods. For example, a compound of the formula (1) can be prepared by converting the corresponding carboxylic acid into an activated derivative (for example a corresponding mixed anhydride) which is formed for example by reaction of an alkyl chloroformate (for example isobutyl chloroformate) or an acid chloride (for example pivaloyl chloride) in the presence of a suitable base, e.g. Triethylamine or pyridine. The activated derivative can then be reacted with a suitable compound R'OH, which are either known compounds or can be prepared by methods analogous to those used for the preparation of known compounds. Suitable solvents include dipolar, aprotic solvents (e.g. acetone, acetonitrile and dimethylformamide) and halogenated hydrocarbons (e.g. dichloromethane). The reaction can be carried out at any suitable temperature, e.g. from 0 ° C to room temperature.

The same group of compounds of formula (1) can also be prepared by first reacting the corresponding carboxylic acid with dicyclohexylcarbodiimide in the presence of 4-dimethylaminopyridine and then treating the product with a phenol R'OH. This reaction is conveniently carried out at a suitable temperature, e.g. 0 ° C to room temperature, carried out in a solvent such as ether or dichloromethane. 5 The carboxylic acids which are required as starting materials for this reaction can be prepared by methods which are generally described in European patent specification 160 495.

(c) Compounds of formula (1) in which X is a -CH2-io CH2 group can be prepared by reduction of a corresponding compound in which X represents an ice or trans-CH = CH group or an acetylene group. Suitable methods of reduction include hydrogen in the presence of a catalyst, e.g. Palladium, on

15 a carrier (e.g. carbon). Suitable solvents include ethyl acetate, ethanol and methanol.

(d) Compounds of formula (1) in which X represents the group -CH = CH- can be prepared by selective reduction of a corresponding compound in which

20 X represents an acetylene group. Suitable methods for the reduction include hydrogen in the presence of a catalyst, e.g. Palladium on a carrier (e.g. CaC03 or BaS04) and poisoned with lead or cholinolin, for example. Suitable solvents include ethyl acetate and methanol. This reaction is particularly suitable for the preparation of compounds in which X is cis-CH = CH-.

The acetylenes required as starting materials can be prepared from the corresponding acetylenic acids by esterification using the methods described above. The intermediate acetylenic acids can be prepared by methods generally described in European Patent Specification 160,495.

(e) compounds of the formula (1) in which X is a trans

35 CH = CH group can be prepared by isomerization of a corresponding compound, wherein X is a cis-CH = CH group.

The isomerization can be accomplished, for example, by treating the corresponding eis compound with toluene-p-sulfinic acid in dioxane (e.g. at reflux) or azo-bis-isobutyronitrile and thiophenol using, for example, a hydrocarbon solvent (e.g. benzene) with any suitable one Temperature to the reflux temperature.

45 The methods in methods (b-e) can also be applied to compounds of the formulas (2) and (3) and the products can subsequently be converted into compounds of the formula (1) by the methods described above.

50 If a special enantiomer of formula (1) is required, the starting materials with the desired stereochemical configuration should be used in the above processes. Such starting materials can be prepared, for example, from an enantiomeric intermediate, as described in European patent specification 74 856, using the methods as described 55 in European patent specification 160 495.

The following examples illustrate the invention. The 60 temperatures are given in ° C; "Dried" means drying with anhydrous magnesium sulfate; TLC means thin layer chromatography on silica; the chromatography was carried out on silica gel or silica gel.

65 The following abbreviations are used: ER ether; EA - ethyl acetate; PE - petroleum ether (bp 60-80 °, unless otherwise stated); DIBAL - diisobutylaluminum hydride; THF - tetrahydrofuran; CH2C12 - dichlorme

than; CHC13 - chloroform; CHBr3 - bromoform; DMF -dimethylformamide; DMSO - dimethyl sulfoxide; EtOH ethanol; MeOH - methanol; CH3CN - acetonitrile; Et3N triethylamine; N.T.P. - normal temperature and pressure.

Between connection 1

[IS- [la (Z), 2ß (2S *), 3a, 5a]] - 7- [5-hydroxy-2- [3-phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) - oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoic acid

Between connection 2

[IS- [la (Z), 2ß, 3a, 5a]] - (+) - methyl-7- [5-hydroxy-2- [2-methyl-3-phenoxy-2- [(tetrahydro-2H -pyran-2-yl) -oxy] -prop-oxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate

Interconnection 3

(a) [lS- [lß (Z), 2ß, 3a, 5a]] - (+) - methyl-7- [2- [3- (4-f! uorphen-oxy) -2- [(tetrahydro- 2H-pyran-2-yl) -oxy] -propoxy] -5-hydroxy-3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate

(b) [IS- [la (Z), 2ß, 3a, 5a]] - (+) - methyl-7- [2- [3- (3-chlorophenoxy) -2- [(tetrahydro-2H- pyran-2-yl) -oxy] -propoxy] -5-hydroxy-3- [(tetrahydro-2H-pyran-2-yl) -oxyj-cyclopentyl] -5-heptenoate

(c) [IS- [la (Z), 2β, 3a, 5a]] - (+) - methyl-7- [5-hydroxy-2- [3- [4- (methylthio) phenoxy] -2- [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoate

Between connection 4

[3aR- [3aa, 4a (2R *), 5β, 6aa]] - hexahydro-4- [3-phenoxy-2- [(tetrahydro-2H-pyran-2-yl) -oxy] -propoxy] -5- [(tetrahydro-2H-pyran-2-yl) -oxy] -2H-cyclopenta [b] furan-2-ol

Interconnection J

[IR- [la, 5a, 6a, 8R * (R *)]] - 8- (2-hydroxy-3-phenoxypropoxy) -6- (phenylmethoxy) -2-oxa-bicyclo [3.2.1] octane -3-one

Interconnection 6

[IS- [la (Z), 2ß (2S *), 3a, 5a]] - (+) - methyl-9- [5-hydroxy-2- [3-phenoxy-2- [(tetrahydro-2H-pyran -2-yl) -oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -7-nonenoate

Interconnects 1 to 6 are made as described in European Patent Specification 160,495.

Interconnection 7

Methyl 4- [(tetrahydro-2H-pyran-2-yl) oxy] benzoate

A solution of 10 g of methyl 4-hydroxybenzoate in 60 ml of EA containing 3.5 ml of saturated ethereal.HCl was treated with 12 ml of dihydropyran and the solution was left to stand at room temperature for 24 hours. A further amount of dihydropyran (12 ml) and 3.5 ml of ethereal HCl were added and the solution was left to stand for 17 hours. The solvent was evaporated and the residue was dissolved in 100 ml ER and washed with 2 × 50 ml 2N NaOH solution and 50 ml brine and then dried. Evaporation gave a residue which, when purified by chromatography using ER toluene (3/97) as the eluant, gave the title compound as a white solid (10.2 g), mp 58-62 °.

Interconnection 8

4- [(tetrahydro-2H-pyran-2-yl) oxy] benzoic acid

A suspension of 10.0 g of intermediate 7 in

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200 ml of MeOH and 30 ml of 5N NaOH solution were stirred at room temperature for 24 h. The solution was evaporated to about 50 ml and diluted with 100 ml of water. The mixture was filtered through Hyflo and the filtrate washed with 2 x 30 ml ER and acidified by dropwise addition of 5N hydrochloric acid. The resulting precipitate was filtered off and gave the title compound as a white solid (8.25 g), mp. 138 to 399 C.

Interconnection 9

N- (4-Hydroxyphenyl) -4- [(tetrahydro-2H-pyran-2-yl) oxy] benzamide

A solution of 8.1 g of intermediate 8 in 200 ml of dry THF at 0 was treated with 6.0 ml of Et3N and then with 5.4 ml of pivaloyl chloride and the mixture was then stirred at 0 ° for 30 min. A solution of 3.0 g of 4-aminophenol in 30 ml of DMF 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 evaporated and the residue dissolved in 200 ml ER. Pouring into 200 ml of water gave a precipitate which was filtered off and crystallized from EA-MeOH. The title compound was obtained as a white solid (5.6 g), mp. 173 to 174 °.

Interconnection 10

(a) [IS- [la (Z), 2ß (2S *), 3a, 5a]] - (+) - 4-acetylphenyl-7- [5-hydroxy-2- [3-phenoxy-2- [( tetrahydro-2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate

A solution of 0.45 g of Intermediate 1 in 15 ml of dry CH3CN at -10 ° was treated with 0.2 ml of Et3N and then with 0.14 ml of isobutyl chloroformate. After stirring for 45 minutes, 0.23 g of p-hydroxyacetophenone was added. Stirring was continued for 2 hours -10 to 0 ° and the mixture was then diluted with water and extracted with 3 x 50 ml ER. The combined extracts were washed with 75 ml of 10% copper sulfate solution and 10 ml of water and then dried. Evaporation gave a residue which, after purification by chromatography using ER-PE (40-60 °) (2/1) as the eluent, gave the title compound as a gum (0.43 g). IR (CHBr3): 3550, 1753, 1678 cm- '; [a2 = + 19.6 ° (MeOH).

The following compounds were prepared in a similar manner from intermediate 1 and the appropriate phenol:

(b) [IS- [la (Z), 2ß (2S *), 3a, 5a]] - (+) - 4-6acetylamino) phenyl-7- [5-hydroxy-2- [3-phenoxy-2 - [(tetrahydro-2H-py-ran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate; IR (CHBr3): 3580, 3425, 1750, 1690 cm- '; [a2 = + 7.9 ° (MeOH).

(c) [IS- [la (Z), 2ß (2S *), 3a, 5a]] - (+) - 4- [(aminocarbonyl) amino] phenyl-7- [5-hydroxy-2- [ 3-phenoxy-2- [(tetrahydro-2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate; IR (CHBr3): 3510, 3410, 1748, 1682 cm- '; [a2 = + 15.4 ° (MeOH).

(d) [IS- [la (Z), 2ß (2S *), 3a, 5a]] - (+) - 4- (benzoylamino) phenyl-7- [5-hydroxy-2- [3-phenoxy- 2- [(tetrahydro-2H-py-ran-2-yl) -oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] cyclopentyl] -5-heptenoate. 0.18 g of pivaloyl chloride was added to a solution of 0.7 g of intermediate 1 and 0.38 g of Et3N in 5 ml of dry DMF at 0 °. After 10 minutes, a solution of 0.53 g of 4- (benzoylamino) phenol in 2 ml of DMF was added and stirring was continued for 6 hours at 0 ° and 18 hours at room temperature. The reaction mixture was diluted with 150 ml EA and successively with 2 x 50 ml water, 2 x 50 ml 10% copper sulfate solution,

Washed 50 ml of water and 50 ml of saline. The getrock7

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The organic extract was evaporated to give a residue which was purified by chromatography on Et3N deactivated silica using cyclohexane EA (1/1) as eluent. The title compound was obtained as a gum (0.55 g). IR (CHBr3): 3520, 3425, 1750, 1673 cm- '; [a0 = + 20 ° (CHC13).

The following compounds were obtained in a manner similar to intermediate 10d from intermediate 1 and the appropriate phenol:

(e) [IS- [la (Z), 2ß (2S *), 3a, 5a]] - (+) - 4- [4- (acetylamino) benzoylamino] phenyl-7- [5-hydroxy -2- [3-phenoxy-2- [(te-trahydro-2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl ] -5-heptenoate; IR (CHBr3): 3580, 3520, 3425, 1745, 1690, 1670 cm "1; [a0 = + 20.6 ° (CHClj).

(f) [ÌS- [la (Z), 2ß (2S *), 3a, 5a]] - (+) - 4- (aminocarbonyl) phenyl-7- [5-hydroxy-2- [3-phenoxy- 2- [(tetrahydro-2H-py-ran-2-yl) oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoate; IR (CHBr3): 3520, 3400, 1755, 1672 cm- '; [a0 = + 20 ° (CHC13).

(g) [IS- [la (Z, R *), 2ß (2S *), 3a, 5a]] - (+) - 4- [2- (acetylamino-no) -3-amino-3-oxoprópyl] -phenyl-7- [5-hydroxy-2- [3-phen-oxy-2- [(tetrahydro-2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetra-hydro-2H- pyran-2-yl) oxy] cyclopentyl] -5-heptenoate; IR (CHBr,): 3500, 3400, 1745, 1690, 1660 cm "1; [aß0 = + 24; (CHClj).

(h) [IS- [la (Z), 2ß (2S *), 3a, 5a]] - (+) - 3- (benzoylamino) phenyl-7- [5-hydroxy-2- [3-phenoxy- 2- [(tetrahydro-2H-py-ran-2-yl) -oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] cyclopentyl] -5-heptenoate; IR (CHBr3): 3700-3100, 1755. 1677 cm "1; [aß0 = + 27; (CHClj).

(i) [IS- [la (Z), 2ß (2S *), 3a, 5a]] - 4- (N, N-dimethylamino-carbonyl) phenyl-7- [5-hydroxy-2- [3- phenoxy-2- [(tetrahy-dro-2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-py-ran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoate; IR (CHBr3): 3530, 1750, 1740, 1626 cm "1.

(j) [IS- [la (Z), 2ß (2S *), 3a, 5a]] - methyl-4 - [[7- [5-hydroxy-2- [3-phenoxy-2- [(tetrahydro- 2H-pyran-2-yl) -oxy] -prop-oxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -1-oxo-5-heptenyl] -oxy] - benzoate; IR (CHBr3): 3590, 3520, 1750, 1715 cm- '.

(k) [IS- [la (Z), 2ß (2S *), 3a, 5a]] - (+) -4 - [[[4- [(tetrahydro-2H-pyran-2-yl) -oxy] -phenyl] -carbonyl] -amino] -phenyl-7- [5-hydroxy-2- [3-phenoxy-2- [(tetrahydro-2H-pyran-2-yl) -oxy] -propoxy] -3- [ (tetrahydro-2H-pyran-2-yl) -oxy] -cyclopenyl] -5-heptenoate; from interconnections 1 and 9; IR (CHBr,): 3580, 3420, 1748, 1668 cm- '; [a0 = +21 (CHCl,).

(1) [IS- [la (Z), 2ß (2S *), 3a, 5a]] - 2- (benzoylamino) phenyl-7- [5-hydroxy-2- [3-phenoxy-2- [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoate; IR (CHBr3): 3520, 3440, 1728, 1688, 1516 cm- '.

(m) [1 S- [la (Z), 2ß (2S *), 3a, 5a]] - 2-naphthalenyl-7- [5-hydroxy-2- [3-phenoxy-2- [(tetrahydro-2H -pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate; IR (CHBr3): 3530, 1750 cm- '.

(n) [IS- [la (Z), 2ß, 3a, 5a]] - 4- (benzoylamino) phenyl-7- [5-hydroxy-2- [2-methyl-3-phenoxy-2- [( tetrahydro-2H-py-ran-2-yl) -oxy] - propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate, from intermediate 12a; IR (CHBr,): 3520, 3430, 1750, 1675 cm "'.

(o) [IS- [la (Z), 2ß, 3a, 5a]] - 4-methoxyphenyl-7- [2- [3- (4-fluorophenoxy) -2- [(tetrahydro-2H-pyran-2- yl) -oxy] -prop-oxy] -5-hydroxy-3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate, from intermediate 12b; IR (CHBr,): 3590, 3530, 1748 cm- '.

(p) [IS- [la (Z), 2ß, 3a, 5a]] - 4- (methylthio) phenyl-7- [2- [3- (3-chlorophenoxy) -2- [(tetrahydro-2H- pyran-2-yl) -oxy] -prop-oxy] -5-hydroxy-3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate, from intermediate 12c; IR (CHBr3): 3580, 3520.1750 cm- '.

(q) [IS- [la (Z), 2ß, 3a, 5a]] - 4- (methylsulfonyl) phenyl-7- [5-hydroxy-2- [3- [4- (methylthio) phenoxy] - 2- [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoate, from intermediate 12d; IR (CHBr3): 3520, 1758 cm- '.

(r) [IS- [la, 2ß (2S *), 3a, 5a]] - 4- (aminocarbonyl) phenyl-7- [5-hydroxy-2- [3-phenoxy-2- [(tetrahydro -2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cy-clopentyl] -4,5-heptadienoate, from intermediate 12e; IR (CHBr3): 3520, 3405, 3600-3200, 1960, 1758, 1675 cm- '.

(s) [IS- [la (Z), 2ß (S *), 3a, 5a]] - 4- (benzoylamino) phenyl-7- [5-hydroxy-2- [3-phenoxy-2- [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -4-heptenoate, from intermediate 12f; IR (CHBr3): 3520, 3420, 1750, 1678 cm- '.

(t) [IS- [la (Z), 2ß (2S *), 3a, 5a]] - 4- (benzoylamino) phenyl-9- [5-hydroxy-2- [3-phenoxy-2- [(tetrahydro-2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cy-clopentyl] -7-nonenoate, from intermediate 12g; IR (CHBr3): 3520, 3420, 1748, 1672 cm- '.

Interconnection 11

(a) [lR- [la (Z), 2ß (2R *), 3a]] - (-) - 4-acetylphenyl-7- [5-0X0-2- [3-phenoxy-2- [(tetrahydro- 2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate

A stirred solution of 0.39 g of intermediate 10a in 4 ml of dry CH2C12 and 0.4 ml of dry DMSO was treated with 0.5 g of dicyclohexylcarbodiimide and then with 0.17 g of pyridinium trifluoroacetate. After 5 h at room temperature the mixture was poured into 50 ml water and extracted with 3 x 75 ml ER. Evaporation of the dried extracts gave a residue which was purified by chromatography on acid washed (pH 3.8) silica. The title compound was obtained in the form of a colorless gum (0.27 e); IR (CHBr,): 1760, 1743, 1680 cm- '; [a2-2 = -13.7 (MeOH).

The following connection was made in a similar manner.

(b) [lR- [la (Z), 2ß (2R *), 3a]] - (+) - 4- (acetylamino) -phenyl-7- [5-oxo-2- [3-phenoxy- 2- [(tetrahydro-2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate, from intermediate Compound 10b; IR (CHBr3): 3420, 1740, 1685 cm- '; [a8-6 = +16.7 (MeOH).

(c) [lR- [la (Z), 2ß (2R *), 3a]] - 5- [(aminocarbonyl) amino] phenyl-7- [5-oxo-2- [3-phenoxy- 2- [(tetrahydro-2H-py-ran-2-yl) -oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] cyclopentyl] -5-heptenoate

A cold (0), stirred suspension of 0.15 g of intermediate 10c and 0.05 g of anhydrous sodium acetate in 2 ml of CH2C12 was treated with 0.13 g of pyridinium chlorochromate. The mixture was stirred for 30 min at 0 and 1 h at room temperature and then purified by chromatography on acid-washed (pH 3.8) silica using EA as the eluent. The title compound was obtained as a gum (0.09 g); TLC EA Rf 0.3.

The following connections were made in a similar manner:

(d) [lR- [la (Z), 2ß (2R *), 3a]] - (-) - 4- (benzoylamino) -phenyl-7- [5-oxo-2- [3-phenoxy- 2- [(tetrahydro-2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate, from intermediate lOd; IR

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(CHBr3): 3430, 1740.1675 cm "1; [a0 = -11 ° (CHC13).

(e) [lR- [la (Z) -2ß (2R *), 3a]] - (-) - [4- (acetylamino) -benzo-ylamino] phenyl-7- [5-oxo-2- [ 3-phenoxy-2- [(tetrahydro-2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate, from interconnect 10e; IR (CHBr3) 3420, 1740, 1690, 1670 cm- '; [a0 = -5 ° (CHC13).

(f) [lR- [la (Z), 2ß (2R *), 3a]] - (-) - 4- (aminocarbonyl) phenyl-7- [5-oxo-2- [3-phenoxy-2- [(tetrahydro-2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cy-clopentyl] -5-heptenoate, from intermediate lOf; IR (CHBr3): 3525, 3405, 1742, 1675, 1599 cm-1; [a0 = -16.3 ° (CHC13).

(g) [IR- [la (Z, S *), 2ß (2R *), 3a]] - (-) - 4- [2- (acetylamino) -3-amino-3-oxopropyl] phenyl-7 - [5-oxo-2- [3-phenoxy-2-

[(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoate, from intermediate 10 g; IR (CHBr3): 3505, 3400, 1740, 1690, 1665 cm-1; [a0 = -3.4 ° (CHC13).

(h) [lR- [la (Z), 2ß (2R *), 3a]] - (-) - 3- (benzoylamino) -phenyl-7- [5-oxo-2- [3-phenoxy- 2- [(tetrahydro-2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate, from intermediate 10h; IR (CHBr3): 3430, 1742, 1680.1526 cm "1; [a0 = -7 °

(CHC13).

(i) [IR- [la (Z), 2ß (2R *), 3a]] - 4- (N, N-dimethylaminocarbonyl) phenyl-7- [5-oxo-2- [3- (phenoxy -2- [(tetrahydro-2H-pyran-2-yl) -oxy] -propxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cycl ° pentyl] -5-heptenoate Intermediate lOi; IR (CHBr3): 1740, 1622 cm- '.

(j) [lR- [la (Z), 2ß (2R *), 3a]] - methyl-4- [[7- [5-oxo-2- [3-phenoxy-2- [(tetrahydro-2H- pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -l-oxo-5-hep-tenyl] -oxy] -benzoate; from interconnect 10j; IR (CHBr3): 1745, 1720 cm- '.

(k) [IR- [la (Z), 2ß (2R *), 3a]] - (-) - 4- [[[4- [(tetrahydro-2H-pyran-2-yl) oxy] phenyl ] -carbonyl] -amino] -phenyl-7- [5-oxo-2- [3-phenoxy-2- [(tetrahydro-2H-pyran-2-yl) -oxy] -prop-oxy-3- [( tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-hep-tenoate, from intermediate 10k; IR (CHBr3): 3435, 1745, 1720, 1672 cm "1; [a] è0 = -8.9 ° (CHC13).

(111) [lR- [la (Z), 2ß (2R *), 3a]] - 2- (benzoylamino) -phenyl-7- [5-oxo-2- [3-phenoxy-2- [( tetrahydro-2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate, from between compound 10 1; IR (CHBr3): 3440, 1760, 1740, 1678 cm-1.

(Ilm) [lR- [la (Z), 2ß (2R *), 3a]] - 2-naphthalenyl-7- [5-oxo-2- [3-phenoxy-2- [(tetrahydro-2H-pyran 2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate, from intermediate 10m; IR (CHBr3): 1745 cm-1.

(lin) [lR- [la (Z), 2ß, 3a]] - 4- (benzoylamino) phenyl-7- [2- [2-methyl-3-phenoxy-2- [(tetrahydro-2H-pyran 2-yl) -oxy] -propoxy] -5-oxo-3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate, from intermediate lOn; IR (CHBr3): 3430, 1740, 1672 cm-1.

(1 lo) [IR- [la (Z), 2ß, 3a]] - 4-methoxyphenyl-7- [2- [3- (4-fluorophenoxy) -2- [(tetrahydro-2H-pyran-2-yl ) -oxy] -prop-oxy] -5-oxo-3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopen-tyl] -5-heptenoate, from intermediate lOo; IR (CHBr3): 1744 cm-1.

The following compounds were prepared in a manner similar to Intermediate 1 la.

(11p) [IR- [la (Z) -2ß, 3a]] - 4- (methylthio) phenyl-7- [2- [3- (3-chlorophenoxy) -2- [(tetrahydro-2H-pyran 2-yl) -oxy] -prop-oxy] -5-oxo-3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopen-tyl] -5-heptenoate, from intermediate 10p; IR (CHBr3): 1742 cm- '.

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(q) [IR- [la (Z), 2β, 3a]] - 4- (methylsulfonyl) phenyl-7- [2- [3- [4- (methylthio) phenoxy] -2- [(tetrahydro- 2H-pyran-2-yl) -oxy] -propoxy] -5-oxo-3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptenoate, from intermediate lOq; IR (CHBr3); 1740 cm-1.

The following compounds were prepared in a manner similar to Intermediate 1 lc.

(r) [IR- [la, 2ß (2R *), 3a]] - 4- (aminocarbonyl) phenyl-7- [5-oxo-2- [3-phenoxy-2- [(tetrahydro-2H-pyran -2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -4,5-heptadienoate, from intermediate lOR; IR (CHBr3): 3520, 3410, 1962, 1742, 1676 cm-1.

(s) [IR- [loc (Z), 2ß (2R *), 3a]] - 4- (benzoylamino) phenyl-7- [5-oxo-2- [3-phenoxy-2- [(tetrahydro- 2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -4-heptenoate, from intermediate 10s; IR (CHBr3): 3430, 1742, 1675 cm-1.

(t) [lR- [la (Z), 2ß (2R *), 3a]] - 4- (benzoylamino) phenyl-9- [5-0X0-2- [3-phenoxy-2- [(tetrahydro- 2H-pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -7-nonenoate, from intermediate 10t; IR (CHBr3): 3430, 1742, 1678 cm- '.

Interconnection 12

(a) [IS- [la (Z), 2ß, 3a, 5a]] - 7- [5-hydroxy-2- [2-methyl-3-phenoxy-2- [(tetrahydro-2H-pyran-2- yl) -oxy] -propoxy] -3-

[(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] heptenic acid

A solution of 0.98 g between compound 2 in 15 ml MeOH was treated with 6 ml 5N NaOH solution. After 30 min the mixture was poured into 100 ml water and extracted with 150 ml ER. The aqueous solution was acidified with 150 ml saturated NH4C1 solution and then extracted with 4 x 50 ml EA. The combined extracts were dried and evaporated to give the title compound as a gum (0.88 g); IR (CHBr3): 3510, 3400-2500, 1730, 1708 cm- '.

The following compounds were made in a similar manner.

(b) [IS- [la (Z), 2ß, 3a, 5a]] - 7- [2- [3- (4-fluorophenoxy) -2- [(tetrahydro-2H-pyran-2-yl) -oxy ] -propoxy] -5-hydroxy-3-

[(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoic acid, from intermediate 3a; IR (CHBr3): 3510, 3400-2400, 1730, 1708 cm- '.

(c) [IS- [la (Z), 2β, 3a, 5a]] - 7- [2- [3- (3-chlorophenoxy) -2- [(tetrahydro-2H-pyran-2-yl) -oxy ] -propoxy] -5-hydroxy-3-

[(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoic acid, from intermediate 3b; IR (CHBr3): 3590, 3510, 3700-2400, 1730, 1705 cm- '.

(d) [IS- [la (Z), 2ß, 3a, 5a]] - 7- [5-hydroxy-2- [3- [4- (methylthio) phenoxy] -2- [(tetrahydro- 2H-pyran-2-yl) -oxy] -prop-oxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -5-heptensic acid, from intermediate 3c; IR (CHBr3): 3520, 3600-2500, 1730, 1708 cm- '.

(e) [IS- [la, 2ß (2S *), 3a, 5a]] - 7- [5-hydroxy-2- [3-phen-oxy-2- [(tetrahydro-2H-pyran-2-yl ) -oxy] -propoxy] -3- [(te-trahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -4,5-heptenedienoic acid, from intermediate 15; IR (CHBr3): 3500, 1920, 1730 cm- '.

(0 [IS- [la (Z), 2ß (2S *), 3a, 5a]] - 7- [5-hydroxy-2- [3-phen-oxy-2- [(tetrahydro-2H-pyran-2 - yl) -oxy] -propoxy] -3- [(te-trahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -4-heptensic acid

1.11 g (3-carboxypropyl) triphenylphosphonium bromide and 0.58 g of potassium tert-butoxide in 10 ml of dry THF were stirred at ambient temperature for 45 min. A solution of 0.58 g of intermediate 19 in 10 ml of dry THF was added and stirring continued for 1 h at ambient temperature. Another identical amount of preformed ylide was added to the reaction mixture and

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stirred another 1.5 h. 20 ml water was added and the mixture washed with 3 x 50 ml ER. The organic wash water was back-extracted with 2 x 20 ml of 8% NaHC03 solution. The combined aqueous extracts were treated with 30 ml saturated NH4C1 and the product extracted with 3 x 50 ml ER. The extracts were washed with 15 ml of brine, dried and concentrated in vacuo. The title compound was obtained as an oil (0.55 g); IR (CHBr3): 3500, 3600-2300, 1728, 1710 cm- '.

The following connection was made in a manner similar to Between Connection 12a.

(g) [IS- [la (Z), 2ß (2S *), 3a, 5a]] - 7- [5-hydroxy-2- [3-phen-oxy-2- f (tetrahydro-2H-pyran 2-yl) -oxy] -propoxy] -3- [(te-trahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -7-nonenoic acid, from intermediate 6; IR (CHBr3): 3510, 3000-2500, 1730, 1710 cm "1.

Interconnection 13

[IS- [la, 2ß (2S *), 3a, 5a]] - methyl-6-methyl-6-hydroxy-7- [5-hydroxy-2- [3-phenoxy-2- [(tetrahydro-2H- pyran-2-yl) -oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -4-heptinoate

61.5 ml of n-butyllithium (1.6M in hexane) were added at 0 ° under nitrogen to a solution of 13.8 ml of diisopropylamine and 17.5 ml of hexamethylphosphoramide in 140 ml of ER. The solution was cooled to -70 ° and a solution of 4.87 g of 4-pentynoic acid in 50 ml of THF was added. The mixture was then allowed to warm to room temperature and after 1 h a solution of 3.5 g of intermediate 4 in 60 ml of ER was added. After 18 h, a solution of 14 g of oxalic acid dihydrate in 200 ml of water was added and the organic phase was separated off. The aqueous phase was extracted with 200 ml EA. The combined organic phases were dried and evaporated. The residue was dissolved in 30 ml DMF and treated with 12 ml methyl iodide and 8 g potassium fluoride. After 3 h the solution was back extracted with 200 ml EA and the combined organic phases were dried and evaporated. The residue was purified by chromatography using ER-EA (4/1, increasing to 2/1) as the eluent. 2.9 g of the title compound were obtained as an oil; IR (CHBr3): 3580, 3500, 1728 cm * 1.

Interconnection 14

[IR- [la, 2ß (2R *), 3a, 5a]] - methyl-6-acetyloxy-7- [5-acetyl-oxy-2- [3-phenoxy-2- [(tetrahydro-2H-pyran 2-yl) -oxy] -prop-oxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -4-heptinoate

8.2 ml of triethylamine, 6.7 ml of acetic anhydride and 70 ml of 4-dimethylaminopyridine were added to a stirred solution of 2.8 g of intermediate 13 in 60 ml of CH2C12. After 2 h the solvent was removed and chromatography of the residue using ER-PE (40-60) (4/1) as the eluent gave the title compound as an oil (3.1 g); IR (CHBr3) 1728 cm- '.

Interconnection 15

[lR- [la, 2ß (2R *), 3a, 5a]] - methyl-7- [5-acetyloxy-2- [3-phen-oxy-2- [(tetrahydro-2H-pyran-2-yl) -oxy] -propoxy] -3- [(te-trahydro-2H-pyran-2-yl) -oxy] -cyclopentyl] -4,5-heptadienoate

44.5 ml of methyl lithium (1.6M in ER) was added to a stirred suspension of 6.8 g of copper (I) iodide in 120 ml of ER at -10 under nitrogen. After the addition was complete, a clear solution was obtained which was then cooled to -78 °. A solution of 0.85 g of intermediate 14 in 50 ml of ER was added at -78 °. After 1.5 h, 200 ml of saturated NH4C1 solution were added and the mixture was stirred at room temperature for 1 h. The organic

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Phases were washed with 200 ml saturated saline and the aqueous phase extracted with 200 ml ER. The dried organic extracts were evaporated and the residue was purified by chromatography using 5 ER-PE (40-60 °) (3/1) as the eluent. The title compound was obtained as an oil (1.2 g); IR (CHBr3): 1960, 1728 cm-1.

Intermediate 16 io [IR- [la, 5a, 6a, 8R * (R *)]] - 8- (2-hydroxy-3-phenoxyprop-oxy) -6- (phenylmethoxy) -2-oxy-bicyclo [3.2. 1] octan-3-ol 10 ml of DIB AL (IM in hexane) was added to a cold (-78 °), stirred solution of 2.7 g of intermediate 5 in 50 ml of CH2C12. After 2 hours a further amount of 6.7 ml of DIBAL was added and stirring continued for 2.5 hours. 20 ml of MeOH were added dropwise and 60 ml of ether were added after 15 minutes at room temperature. The resulting mixture was filtered through Hyflo and the filtrate was evaporated. 2.6 g of the title compound were obtained as a gum; 20 IR (CHBr3): 3580, 2720, 1718 cm- '.

Interconnection 17

[IS- [la, 2ß (S *), 3a, 5a]] - 3-hydroxy-2- (2-hydroxy-3-phen-oxypropoxy) -5- (phenoxymethoxy) -cyclopentane propanal 25 To a 0 ° cold solution of 2.9 g of potassium tert-butoxide in 40 ml of THF, 8.84 g of (methoxy-methyl) triphenylphosphonium chloride were added under N2. After 5 minutes, a solution of 2.6 g of intermediate 16 in 25 ml of THF was added and the mixture was stirred at 0 ° for 30 minutes. 50 ml of a saturated solution of NH4C1 were added and the mixture was extracted with 3 × 60 ml of ER. The combined extracts were dried and evaporated; 9.1 g of an oil were obtained. The crude product was stirred for 48 h at ambient temperature in 1: 1 0.25N sulfuric acid acetone 35 (80 ml). The organic solvent was then removed in vacuo and the aqueous residue was extracted with 3 × 50 ml of EA. The combined organic phases were washed with 30 ml saturated brine, dried and evaporated. The residue was purified by chroma-40 tography using ER as the eluent. 1.5 g of the title compound were obtained as an oil; IR (CHBr3): 3580, 3460, 2720, ni ^ cm-1.

Intermediate 18 45 [IS- [la, 2ß (2S *), 3a, 5a]] - 2- [3-phenoxy-2- [(tetrahydro-2H-pyran-2-yl) -oxy] propoxy] -5- (phenylmethoxy) -3- [(tetrahy-dro-2H-pyran-2-yl) oxy] cyclopentane propanal

0.95 ml of dihydropyran and 0.1 g of pyridinium toluene p-sulfonate were added to a stirred solution of 1.44 g of intermediate 50 in 40 ml of CH2C12 at 0 °. After stirring at room temperature for 20 hours, the mixture was washed with 2 × 10 ml of water, 2 × 10 ml of 8% NaHCO 3 solution and 2 × 10 ml of brine. The solvent was evaporated and the residue was purified by Chroma-55 tography using ER-PE (40-60 °) (1/1) as the eluent. 1.9 g of the title compound were obtained as a gum; IR (CHBr3): 2720, 1720 cm-1.

Intermediate 19 60 [4aR- [4aa, 5a (2R *), 6ß, 7aa]] - octahydro-5- [3-phenoxy-2- [(tetrahydro-2H-pyran-2-yl) -oxy] propoxy] -6- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopenta [b] pyran-2-ol

A solution of 0.94 g of intermediate 18 in 50 ml of EA was stirred at N.T.P. Hydrogenated over pre-reduced 10% 65 palladium-on-carbon (0.97 g). The catalyst and solvent were removed and the remaining oil (0.75 g) was purified by chromatography using ER-PE (40-60 °) (3/1) as the eluent

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and gave 0.49 g of the title compound as an oil; IR (CHBr3): 3570 cm "1.

Where no experimental details are given in the following examples, the compounds were prepared in a manner similar to the compound of Example 1. 5

example 1

[1R ~ [la. (Z), 2ß (R *), 3a]] - (-) -4- acetylphenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5 - oxocyclopentyl] -5-heptenoate

A solution of 0.24 g of intermediate 1 la in acetic acid-water-THF (2.5 ml) (20/10/3) was heated at 40 ° for 4 h. The solvent was removed in vacuo and the residue was purified by chromatography on acid washed (pH 3.8) silica using ER-MeOH (75/1) as the eluent. 0.14 g of the title compound was obtained as a white solid, mp. 55 to 56.5 °. Crystallization from methyl acetate-PE gave a white solid, mp 64 to 65, [aß2-4 = -18.1 ° (MeOH).

Analysis: calculated for Ci9H3408: C 68.22%, H 6.71%

found: 68.02, 6.63.

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Example 2 25

[IR- [la (Z), 2ß (R * J, 3aJ] - (-) -4- (acetylamino) phenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) - 5-oxocyclopentyl] -5-heptenoate

A solution of 0.3 g of intermediate 1 lb in acetic acid * water-THF (3 ml) (20/10/3) was heated at 40 to 43 ° 30 for 4 h. The solvent was removed in vacuo and the residue was purified by chromatography on acid washed (pH 3.8) silica using EA as the eluent. 0.12 g of the title compound was obtained as a white solid, mp. 60 to 63 °. Crystallization from 35 t-butyl methyl ether gave a white solid, mp 74.5 to 75, [aß0-9 = -19.4 ° (MeOH).

Analysis: for C-> 9H35NÖ8 calculated: C 66.27% H 6.71% N 2.57%

found: 65.86 6.71 2.66 40

Example 3

[IR- [la (Z), 2ß (R *), 3a]] - 4- [(aminocarbonyl) amino] phenyl-7- [3-hydroxy-2- [2-hydroxy-3-phenoxypropoxy) - 5-oxocyclopentyl] -5-heptenoate 45

(0.04 g) from 0.09 g of intermediate 11c, purified using EA-MeOH (20/1) as eluent. TLC EA-MeOH (20/1) Rf 0.25; IR (CHBr3): 3570, 3500, 3400, 1740, 1680 cm- '.

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Example 4

[lR- [la (Z), 2ß (R *), 3a]] - (-) -4- (benzoylamino) phenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) - 5-oxo-cyclopentyl] -5-heptenoate

A solution of 0.24 g of intermediate 1 ld in acetic acid-water-THF (3 ml) (20/10/3) was heated at 40 to 42 ° for 3 h. The solvent was removed in vacuo and the residue was purified by chromatography on acid washed (pH 3.8) silica using EA cyclohexane (7/3) as the eluent. After 60 triturations with ER, 0.07 g of the title compound was obtained as a white powder, mp. 125 to 127 °; [a0 = -29.3 ° (CHCI3).

Analysis: Calculated for c34h37no8: c 69.5% h 6.4% n 2.4%

found: 69.4 6.4 2.3 65

Example 5

flR- [la (Z), 2ß (R *), 3a]] - (-) -4- [4-acetylamino) benzoylamino] phenyl-7- [3-hydroxy-2- (2-hydroxy- 3-phenoxyprop-oxy) -5-oxocyclopentyl] -5-heptenoate

A solution of 0.24 g of intermediate 1 l in acetic acid-water-THF (3 ml) (20/10/3) was heated at 40 to 42 ° for 4 h. The solvent was removed in vacuo. A solid residue was obtained which was purified by chromatography on acid washed (pH 3.8) silica using EA as the eluent. After trituration with ER, 0.06 g of the title compound was obtained as a white powder, mp. 150 to 154 °; [a0 = -10 ° (MeOH).

Analysis: calculated for C36H40NiO9: C 67.1% H 6.3% N 4.4%

found: 66.7 6.3 4.5

Example 6

[IR- [Ia (Z), 2ß (R *), 3a]] - (-) -4- (aminocarbonyl) phenyl-7 - [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) - 5-oxocyclopentyl] -5-heptenoate

A solution of 0.44 g of intermediate 11 fin acetic acid-water-THF (5 ml) (20/10/3) was heated at 40 ° for 4 h. The solvent was removed in vacuo and the residue was purified by chromatography on acid washed silica (pH 3.8) using EA-EtOH as eluent (95/5). Trituration with ER and subsequent crystallization from EA-PE gave 0.14 g of the title compound as a white solid, mp. 104 to 105 °; [a0 = -13.2 ° (EtOH).

Analysis: calculated for C28H33N08: C 65.7% H 6.5% N 2.7%

found: 65.65 6.7 2.7

Example 7

[IR- [la (Z, S *), 2ß (R *), 3a]] - (+) - 4- [2- (acetylamino) -3-amino-3-oxopropyl] phenyl-7- [3 -hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-heptenoate

A solution of 0.37 g of intermediate 11 g in acetic acid-water-THF (6 ml) (20/10/3) was heated at 40 ° for 3 h. The solvent was removed in vacuo and a portion of the residue (0.19 g) was purified by chromatography on acid-washed (pH 3.8) silica gel using CH2Cl2-Et0H (9/1) as the eluent. Trituration with ER and subsequent crystallization from EA-PE gave 0.04 g of the title compound as a white solid, mp. 105 °; [a0 = + 3.5 ° (EtOH); IR (Nujol): 1740, 1720, 1660, 1645 cm-1.

Example 8

[IR- [la (Z), 2ß (R *), 3a]] - (-) -3- (benzoylamino) phenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy ) -5-oxo-cyclopentyl] -5-heptenoate

A solution of 0.35 g of intermediate 11 h in acetic acid-water THF (5 ml) (20/10/3) was heated at 40-42 ° for 2.5 h. The solvent was removed in vacuo and the residue was purified by chromatography on acid washed (pH 3.8) silica using EA cyclohexane as eluent (3/1). After trituration with ER, 0.16 g of the title compound was obtained as a white powder, mp. 89 to 91 °; [a0 = -25.7 ° (CHC13).

Analysis; calculated for C34H37N08: C 69.5% H 6.4% N 2.4%

found: 69.3 6.4 2.2

Example 9

[IR- [la (Z), 2ß (R *), 3a]] - (-) -4- (N, N-dimethylaminocarbonyl) phenyl-7- [3-hydroxy-2- (2-hydroxy -3-phenoxyprop-oxy) -5-oxocyclopentyl] -5-heptenoate

(0.08 g) from 0.24 g of intermediate 1 Ii, purified and

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ter using EA as eluent; IR (CHBr3): 3580, 3420, 1745, 1624 cm-1; [a0 = -29 ° (CHC13).

Analysis: calculated for C30H37NO8: C 66.77% H 6.91% N 2.60%

found: 66.53 7.04 2.53

Example 10

[lR- [lafZj, 2ß (R *), 3a]] - (-) - methyl-4- [[7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] - ! - oxo-5-heptenyl] oxy] benzoate

A solution of 0.19 g of intermediate 1 Ii in acetic acid-water-THF (10 ml) (20/10/3) was heated at 40 'for 3 h. The solvent was removed in vacuo and the residue was purified by chromatography on acid washed (pH 3.8) silica using ER as the eluent. 0.1 g of the title compound was obtained as a white solid, mp. 45 to 47 °; [a0 = -33 "(CHC13).

Analvse: calculated for C19H34O9: C 66.15% H 6.51%

found: 66.25 6.63

Example 11

[IR- [la (Z), 2ß (R *), 3aJ] - (-) -4- [4- (hydroxy) - benzoylamino] phenyl-7- [3-hydroxy-2- (2-hydroxy- 3-phenoxypropoxy j-5-oxocyclopentyl] -5-heptenoate

A solution of 0.57 g of intermediate 1 l in acetic acid-water-THF (10 ml) (20/10/3) was heated at 40 for 3.5 h. The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH 3.8) silica using EA-PE (4 1) as the eluent. After trituration with ER, 0.22 g of a white powder was obtained. Crystallization from EA-PE gave 0.18 g of the title compound as a white solid, mp. 108 to 110 °; [cc ° = -13.9C (EtOH).

Analvse: calculated for C34H37NO9: C 67.65% H 6.2% N 2.3%

found: 67.35 6.1 2.3

Example 12

[lR- [laf Z), 2ßf R *), 3a.]] - 2- (Benzoylamino) -phenvl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl J- 5-heptenoate

(0.029 g) from 0.050 g of Intermediate 111 purified using EA cyclohexane (2/1) as eluent; TLC EA cyclohexane (2/1) Rf 0.2; IR (CHBr3): 3580, 3440, 1742, 1675 cm "1.

Example 13

[IR-f la (Z), 2ß (R *), 3a]] - naphthalenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-hepte-noate

A solution of 0.44 g of intermediate 1 Im in acetic acid-water THF (12 ml) (20/10/3) was heated at 40-42 for 3 h. The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH 3.8) silica using ER-EA (3 l) as the eluent. After trituration with ER, 0.15 g of the title compound was obtained as a white powder. M.p. 71 to IV- [a0 = -35 (CHC13).

Analysis: calculated for C31H34O7: C 71.79% H 6.61%

found '71.79 6.60

Example 14

IIR- [la (Zi, 2ß, 3a]] - (-) -4- (benzoylamino) phenyl-7- [3-hydroxy-2- (2-hydroxy-2-methyl-3-phenoxypropoxy) -5- oxocyclopentyl] -5-heptenoate

(0.06 g) from 0.11 g of intermediate lln, purified using ER as eluent; IR (CHBr3): 3580, 3420, 1742, 1672 cm- '; [a0 = -7 ° (MeOH).

Analysis: calculated for C35H39NO8: C 69.87% H 6.53% N 2.3%

found: 69.42 6.85 2.21

Example 15

[IR- [la (Z), 2ß, 3a]] - (4-methoxyphenyl-7- [2- [3- (4-fluorophenoxy) -2-hydroxypropoxy] -3-hydroxy-5-oxocyclopentyl] - 5-heptenoate

(0.06) from 0.09 g of intermediate 1 lo, purified using ER-MeOH (97/3) as eluent; IR (CHBr3): 3580, 3450.1745 cm-1.

Analysis: Calculated for C28H33F08: C 65.10% H 6.44%

found: 64.75 6.59

Example 16

[IR- [la (Z), 2ß, 3a]] - 4- (methylthio) phenyl-7-] 2-] 3- (4-chlorophenoxy) -2-hydroxypropoxy] -3-hydroxy-5-oxocyclo- pentyl] -5-heptenoate

(0.1 g) from 0.16 g of intermediate 1 lp, purified using ER-MeOH (98/2) as eluent; IR (CHBr3): 3580, 3440, 1742 cm-1; TLC: ER-MeOH (98/2) Rf 0.25.

Example 17

] IR- [la (Z), 2ß, 3a]] - 4- (methylsulfonyl) phenyl-7- [3-hydroxy-2- [2-hydroxy-3- [4- (methylthio) phenoxy] -propoxy] -5- oxocyclopentyl] -5-heptenoate

A solution of 0.14 g of intermediate 1 1q in acetic acid-water-THF (3 ml) (20/10/3) was heated at 40-42 for 3 h. The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH 3.8) silica using EA-ER (initially 75/25, increasing to 90/10) as the eluent. 0.09 g of the title compound was obtained as a white solid, mp. 73 to 76; IR (CHBr3): 3580, 3440, 1742 cm-1.

Example 18

[IR- [la, 2ß (R *), 3a]] - (-) -4- (aminocarbonyl) phenyl-7-13-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -4,5-heptadienoate

(0.19 g) from 0.35 g of intermediate 1 lr, purified using EA-CH3CN (3/2) as eluent; TLC EA-CH3CN (3/2) Rf 0.3; IR (CHBr,): 3580, 3520, 3400, 1960, 1740, 1672 cm- '; [a0 = -21.0 (CHC13).

Example 19

[1R-] la (Z), 2ß (R *), 3a]] - (-) -4- (benzoylamino) phenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) - 5-oxocyclopentyl] -4-heptenoate

A solution of 0.17 g of intermediate 1 l in acetic acid-water THF (10 ml) (20/10/3) was heated at 40 for 2 h. The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH 3.8) silica using EA cyclohexane (2/1) as the eluent. 0.11 g of the title compound was obtained as a solid, mp 85 to 88; IR (CHBr3): 3580, 3430, 1745, 1675 cm "'; [a0 = -27 (CHCI3).

Example 20

11R-] la (Z), 2ß (R *), 3a]] - (-) -4- (benzoylamino) -phenyl-9- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxo-cyclopentyl] -7-nonenoate

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A solution of 0.55 g of intermediate 11t in acetic acid-water-THF (15 ml) (20/10/3) was heated at 40 ° for 4 h. The solvent was removed in vacuo and the residue was purified by chromatography on acid washed (pH 3.8) silica using EA cyclohexane (7/3) as the eluent. After trituration with ER, 0.24 g of the title compound was obtained as a white solid, mp. 121 to 122 °; [a] ff = -34 ° (CHC13).

Analysis: calculated for C36H41N08: C 70.22% H 6.71% N 2.27%

found: 70.23 6.66 2.17

Example 21

[IR- [la, 2ß (R *), 3aJJ - (-) - 4- (benzoylamino J-phenyl-3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopen tanheptanoate

A solution of 0.1 g of compound from Example 4 in 35 ml of EA was stirred at N.T.P. Hydrogenated over pre-reduced 10% palladium-on-carbon and then the solvent and the catalyst removed. 0.07 g of the title compound was obtained as a white solid, mp. 127 to 130 °; [a] g> = -29.3 ° (CHC13).

Analysis: calculated for C34H39N08: C 69.25% H 6.67% N 2.38%

found: 69.38 6.69 2.15

Example 22

[IR- [Ia (E), 2ß (R *), 3a]] - (-) - 4- (aminocarbonyl) phenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) - 5-oxocyclopentyl] -5-heptenoate

A solution of 0.15 g of the compound of Example 6, 0.46 ml of thiophenol and 0.1 g of azo-bis-isobutyronitrile in 3 ml of CH3CN and 3 ml of benzene was stirred under reflux for 6.5 h. Purification twice by chromatography on acid washed (pH 3.8) silica using EA-CH3CN (9/1) as eluent gave 0.13 g of the title compound as a gum; IR (CHBr3): 3580, 3515, 3400, 1742, 1672 cm- '; [a] §> = -30 ° (CHCI3).

Analysis: calculated for C28H33N08: C 65.74% H 6.5% N 2.74%

found: 66.12 6.8 2.52

Example 23

[lR- [la (Z), 2ß (R * J, 3a]] - (-) - 4- (benzoylamino) phenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) - 5-oxo-cyclopentyl] -5-heptenoate

0.01 ml of pivaloyl chloride was added at 0 'to a solution of 0.03 g of intermediate 1 and 0.01 ml of Et3N in 1 ml of dry DMF. After 10 min, a solution of 0.17 g of 4- (benzoylamino) phenol and 0.01 ml of Et3N in 1 ml of DMF was added and the stirring was carried out for 2 h at 0C and 3.5 h

Room temperature continued. The reaction mixture was diluted with 30 ml EA and washed successively with 10 ml water, 15 ml 10% copper sulfate solution, 10 ml water and 15 ml brine. The dried organic extract was evaporated to give a residue which was purified by chromatography on acid washed (pH 3.8) silica using cyclohexane EA as eluent (1/1). 0.05 g of the title compound was obtained as a white solid; IR (CHBr3): 3580, 3430, 1745, 1675 cm "1; TLC: cyclohexane EA (1/1) Rf 0.15.

The following are examples of pharmaceutical formulations using the compounds according to the invention. In the examples, the term "active ingredient" is used to refer to a compound of the invention, such as a compound as described in the previous examples, e.g. the connection of example 4.

1. tablets

These can be produced by direct pressing.

mg / tablet active ingredient 0.015 to 0.2

Magnesium stearate BP 1.5

microcrystalline cellulose, USP 150.0

on grouting weight

The active ingredient is mixed with about 10% of the microcrystalline cellulose, then mixed with the remaining microcrystalline cellulose and magnesium stearate. The mixture is then compressed into tablets in a suitable machine using a 6 mm punch diameter.

The tablets can be coated with suitable film-forming materials, e.g. Methyl cellulose or hydroxypropylmethyl cellulose can be film-coated using standard techniques.

2. Capsules mg / tablet active ingredient 0.015 to 0.2 magnesium stearate, BP 1.0 starch 1500 (a form of a directly compressible starch) 100.0 Top up to weight

The active ingredient is premixed with part of starch 1500 and then this premix is mixed with the remaining starch 1500 and magnesium stearate. The mixture is then filled into size 2 hard gelatin capsules using a suitable machine.

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c

Claims (14)

667 265 2nd PATENT CLAIMS 1. Compounds of the general formula (I) o where n is 1 or 2; m is 2 to 5 and X represents ice or trans-CH = CH- or -CHi-CH -, -; or m is 1 to 4 and X represents -CH = C = CH-; R1 is (a) Phenyl, optionally substituted by Q 4-alkyl, Cj 4-alkoxy, C ^ alkanoyl, methylthio, methylsulfinyl, methylsulfonyl, halogen, -C02R2, where R2 is a hydrogen atom or C | ^ alkyl or phenyl, -NHCOR2 , in which R2 is as defined above or a phenyl group, optionally substituted by hydroxyl, CH3CONH- or benzoylamino, -CONR3R4, in which R3 and R4 may be identical or different and each represent a hydrogen atom or a Q 4-alkyl group, -NHCONH2, -CH2CH (CONH2) NHCOCH3 or -CH2CH (CONH2) NHCO- or (b) 2-naphthyl; Y is wherein R5, R6 and R7 each represent a hydrogen atom or a methyl group and at least one of them is a hydrogen atom; and Ar is a phenyl group, optionally substituted by one or two groups C, _4-alkyl, CM-alkoxy, Q ^ -alkylthio, C, 4-alkylsulfonyl, Q 4-alkylsulfonyl, halogen or trifluoromethyl, and the salts of the compounds in which R2 is a hydrogen atom. 2. Compounds according to claim 1, wherein X is -CH = CH- or -CH2-CH2- and m = 3 if n = 1, and m = 2 or 4 if n = 2; or X is -CH = C = CH- and m = 2 if n = 1, and m = 1 or 3 if n = 2. 3. Compounds according to claim 1 or 2, wherein R1 is phenyl, substituted by a group Ci_4-alkoxy, C |. 4-alkanoyl, methylthio, methylsulfonyl, -C02R2, -NHCOR2, -CONR3R4, -NHCONH2 or -CH2CH (CONH2) NH-COCH3, or R1 is a 2-naphthyl group. 4. Compounds according to claim 1 or 2, wherein R1 is phenyl, substituted by a group methoxy, acetyl, -CO, CH3, -NHCOCH3, benzoylamino, -CONH2, -CON (CH3) 2 or -CH2CH (CONH2) NHCOCH3, or R1 is a 2-naphthyl group. 5. Compounds according to any one of the preceding claims, wherein R5, R6 and R7 are hydrogen atoms and Ar is phenyl or phenyl, substituted by fluorine or chlorine. 6. Compounds according to claim 1, wherein: X is -CH = CH- or -CH2CH2- and n is 1 and m is 3 or n is 2 and m is 2 or 4, or X is -CH = C = CH- and n is 1 and m is 2, or n is 2 and m is 1 or 3; and R1 is a phenyl group substituted by a group 5 methoxy, acetyl, -COoCH3, -NHCOCH3, benzoylamino, -CONH2, -CON (CH3) 2 or -CH2CH (CONH2) NH-COCH3, or R1 is a 2-naphthyl group; R5 is a hydrogen atom or a methyl group; R6 and R7 are hydrogen atoms; and 10 Ar is a phenyl group or a fluorine or substituted phenyl group. 7. Compounds according to any one of the preceding claims, wherein the carbon atom carrying the group - (CH2) nX (CH2) mC02R 'is in the R configuration. 15 8. Compound according to claim 1, namely [IR- [la (Z), 2ß (R *), 3a]] - (-) - 4- (benzoylamino) phenyl-7- [3-hydroxy-2- ( 2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-hepte-noate. 9. Connection according to claim 1, namely [IR- [la (Z), 20 2ß (R *), 3a]] - (-) - 4- (benzoylamino) phenyl-7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -4-hepte-noate. 10. A pharmaceutical composition comprising a compound according to any one of the preceding claims 25 together with one or more pharmaceutical carriers. 11. A process for the preparation of a compound according to claim 1, characterized in that in a corresponding compound in which the ring hydroxyl group 30 and the hydroxyl group in Y are protected, the protective groups split off. 12. A process for the preparation of a compound according to claim 1, characterized in that a corresponding compound in which R1 represents a hydrogen atom, 35 esterified. 13. A process for the preparation of a compound of formula I, in which X represents -CH2-CH2- and the other symbols have the meanings given in claim 1, characterized in that 40 bond, wherein X represents -CH = CH- or an acetylene group, reduced. 14. A process for the preparation of a compound of the formula I in which X represents -CH = CH- and the other symbols have the meanings given in claim 1, 45 characterized in that a corresponding compound in which X is an acetylene group is selectively reduced. 15. A process for the preparation of a compound of formula I, wherein X represents trans-CH = CH- and the other symbols have the meanings given in claim 1. 50 ben, characterized in that a corresponding compound, wherein X is cis-CH = CH-, isomerized.