IE46103B1

IE46103B1 - Prostaglandin derivatives

Info

Publication number: IE46103B1
Application number: IE2455/77A
Authority: IE
Original assignee: Hoffmann La Roche
Priority date: 1976-12-08
Filing date: 1977-12-02
Publication date: 1983-02-23
Also published as: IL53505A0; FR2373527B1; IE46103L; NL7713542A; NZ185836A; DE2754063A1; DK545177A; BE861562A; SE7713899L; ZA777142B; IT1089402B; FR2373527A1; JPS5371040A; GB1594368A; LU78644A1; AU3118577A

Abstract

The present invention relates to novel chemical compounds. [FR2373527A1]

Description

The present invention relates to prostaglandin derivatives More particularly, the invention is concerned with prostaglandin derivatives, a process for the manufacture thereof and pharmaceutical and veterinary preparations containing same.

The prostaglandin derivatives provided by the present invention are compounds of the general formula wherein R represents a hydrogen atom or a lower alkyl group, R^ represents a hydrogen atom or a lower alkyl group, R2 represents a hydroxy group and R^ represents a hydrogen atom or R2 and R^ together represent an oxo group, R^ represents a hydrogen or fluorine atom or a lower alkyl group, R^ represents a trifluoromethyl group or, when R^ represents a fluorine atom, may also represent a fluorine atom and X represents the -CH=CH- or -CH2-CH2-group, and enantiomers and racemates thereof, the double bond of the substituted octenyl side chain having trans configuration, and the optional double bond in X having cis or trans configuration.

A particular aspect of the present invention is concerned with those prostaglandin derivatives defined earlier in which R^ represents a lower alkyl group. In a preferred aspect of this invention, R represents a hydrogen atom.

According to the process provided by the present invention, the prostaglandin derivatives aforesaid (i.e, the compounds of formula I and enantiomers and racemates thereof) are manufactured by hydrolysing the group denoted by Rg in a compound of the general formula , wherein R, R^, R2, Ry R^, R', X and the double bond or bonds have the significance given earlier and Rg represents a hydroxy group protected by a hydrolysable ether or ester group, into a hydroxy group, and, if desired, esterifying a carboxy group to form a lower alkoxycarbonyl group or converting a lower alkoxycarbonyl group into a carboxy group by basic hydrolysis.

As used in this Specification, the term lower alkyl includes both straight-chain and branched-chain alkyl groups containing from 1 to 7 carbon atoms such as methyl, ethyl and propyl, preferably methyl. The term lower alkoxy comprehends groups containing from 1 to 7 carbon atoms such as methoxy and ethoxy. The term lower alkanoic acid comprehends an alkanoic acid containing from 1 to 7 carbon atoms such as formic acid and 6 16 3 - 4 acetic acid. The term halogen or halo comprehends fluorine, chlorine, bromine and iodine or fluoro, chloro, bromo and iodo, respectively, unless otherwise stated.

In the process provided by this invention, all compounds 5 containing one or more asymmetric carbon atoms can be produced as racemic mixtures. These racemic mixtures which are obtained can be resolved according to well-known methods, whereupon subsequent products may be obtained as the corresponding optically pure enantiomers.

In the formulae given in this Specification, a thickened tapered line () indicates a substituent which has the 0-orientation (above the plane of the molecule), a brushed line (llllllll) indicates a substituent which has the a-orientation (below the plane of the molecule) and a wavy line (uvwv) indicates a substituent which has either the «- or (3-orientation or a mixture thereof. It will be appreciated that the formulae given in this Specification are set forth for convenience and are to be construed as including other forms (i.e. enantiomers and racemates) and are not to be construed as being limited to the particular form shown.

The term aryl used in this Specification signifies a mononuclear aromatic hydrocarbon group (e.g. phenyl and tolyl) , which can be unsubstituted or which can carry one or more substituents selected from lower alkylenedioxy, halogen, nitro, lower alkyl or lower alkoxy, or a polynuclear aryl group (e.g. naphthyl, anthryl, phenanthryl and azulyl), which can carry one or more of the aforementioned substituents. The preferred aryl groups are the substituted and unsubstituted mononuclear aryl groups, particularly phenyl. The term aryl-(lower alkyl) comprehends groups in which the aryl and lower alkyl moieties are as defined earlier, particularly benzyl.

The term hydrolysable ester or ether group used in this Specification designates any ester or ether group which can be hydrolysed to give the hydroxy group. Examples of such ester groups are those in which the acyl moiety is derived from a lower alkanoic acid, an aryl-(lower alkanoic) acid, phosphoric acid, carbonic acid or a lower alkanedicarboxylic acid. Among the acids which can be used to form such ester groups are the acid anhydrides and the acid halides, preferably acid chlorides or acid bromides, with the lower alkanoic acid anhydrides (e.g. acetic anhydride and caproic anhydride), the aryl-(lower alkanoic) acid anhydrides, lower alkanedicarboxylic acid anhydrides (e.g. succinic anhydride) and chloroformates (e.g. trichloroethylchloroformate) being preferred. A suitable ether providing a protecting group is, for example, the tetrahydro20 pyranyl ether or 4-methoxy-5,6-dihydro-2H-pyranyl ether. Other suitable ethers are the arylmethyl ethers such as the benzyl, benzhydryl and trityl ethers, the a-(lower alkoxy)-(lower alkyl) ethers such as the methoxymethyl ether, the allylic ether and the trialkylsilyl ethers such as the trimethylsilyl ether and the dimethyltert.butylsilyl ether.

The removal of the aforementioned protecting groups can be carried out in a conventional manner and liberates the free hydroxy group. If the hydroxy group is protected by a hydrolysable ether group, any conventional ether hydrolysis technique can be used, preferably treatment with an aqueous inorganic acid. Hydrolysable ester groups can be removed by treatment with a base in an aqueous medium in a conventional manner. Among the preferred bases there may be mentioned aqueous sodium hydroxide. Such treatment will also convert a lower alkoxycarbonyl group denoted by R^ and/or the —COOR group into a carboxy group.

A carboxy group present (R = H) can be converted into a lower alkoxycarbonyl group by conventional esterification techniques. As the esterification agent there is used, for example, diazomethane or a lower alkanol or a reactive derivative thereof (e.g. a lower alkyl halide). Any conventional conditions can be adopted for this esterification.

The starting materials of formula II can be prepared according to the following Formula Scheme In which R^, R^, R* 4 and Rg and the double bond or bonds have the significance given earlier.

Formula Scheme Having regard to the foregoing Formula Scheme, a compound of formula III is converted into a compound of formula IV by reaction with a phosphonium salt of the general formula r50— p—CHg—CO—C—(CH2)3—ch3 (ix) I Y® I R51 R,4 , wherein R^ and R'4 have the significance given earlier, Rg, Q and R^ each represent an aryl or di(lower alkylamino) group and Υθ represents a halogen anion, or with a phosphonate of the general formula CHg—CO—C—(CHg)3—CH3 R-4 (X) wherein earlier aryloxy R4 and R'4 have the significance given and Ry and R^^ each represent an aryl, or lower alkoxy group.

The reaction of a compound of formula III with a phosphonium 15 salt of formula IX to give a compound of formula IV is carried out by means of a Wittig reaction. Any of the conditions which are conventional in Wittig reactions can be used in carrying out this reaction.

The reaction of a compound of formula III with a phosphonate 20 of formula X to give a compound of formula IV is carried out by means of a Horner reaction. Any of the conditions which are <ίϋ iUO conventional in Horner-type reactions can be used in carrying out this reaction.

A compound of formula V can be obtained by treating a compound of formula XV with a reducing agent. In carrying out this reduction, any conventional reducing agent which will selectively reduces carbonyl group to a hydroxy group can be used. Preferred reducing agents are the hydrides, particularly the aluminium hydrides such as the alkali metal aluminium hydrides, and the borohydrides such as the alkali metal borohydrides, with zinc borohydride being quite particularly preferred. In carrying out this reduction, temperature and pressure are not critical, and the reduction can be carried out at room temperature and atmospheric pressure or at elevated or reduced temperatures and pressures. Generally, it is preferred to carry out this reduction at a temperature of from -30°C to the reflux temperature of the reduction mixture. This reduction can be carried out in the presence of an inert organic solvent. Any conventional inert organic solvent such as the conventional inert organic solvents mentioned hereinbefore or water can be used. Among the preferred solvents are methanol, dimethoxyethyleneglycol and ethers such as tetrahydrofuran, diethyl ether and dioxane.

A compound of formula V may be separated into its two isomers by conventional methods to produce one isomer of the general formula 0' Λ Ft.

(VA) CH=CH—CH—C—(CH2)3—C H3 S p1 OH 4 and the other isomer of the general formula Rd 14 (VB) H=CH—CH—C—(CH2)3—CH3 OH R,4 wherein R^, R^ and R'^ have the significance given earlier.

Any conventional separation method such as column chromatography, vapour phase chromatography etc can be used to carry out this separation. Either of the aforementioned isomers can be used in the subsequent step. The configuration of the hydroxy group on the octenyl side-chain will be carried through the subsequent steps so that the hydroxy group on the octenyl side-chain in the prostaglandin derivatives provided by this invention will have the same configuration as in the compound of formula VA and VB, respectively.

A compound of formula V, VA or VB can be converted into a compound of formula VI by esterifying or etherifying the free hydroxy group with a hydrolysable ether or ester protecting group. This esterification or etherification can be carried out according to conventional esterification or etherification procedures. Among the preferred hydrolysable ester groups are the lower alkanoyl groups, especially acetyl. Among the preferred hydrolysable ether groups are 2—tetrahydropyranyl groups A compound of formula VI in which represents a lcwer 10 alkoxycarbonyl group and Rg represents a hydroxy group protected by a hydrolysable ether group can be subjected to alkaline hydrolysis (e.g. with aqueous sodium hydroxide solution) to yield a compound of formula VI in which R^ represents a carboxy group without removing the protecting group present on the hydroxy group.

A compound of formula VI is converted into a compound of formula VII by treatment with a reducing agent. In carrying out this reduction, any conventional reducing agent which will selectively reduce a carbonyi group to a hydroxy group can be used.

Preferred reducing agents are the hydrides, particularly the aluminium hydrides such as the alkali metal aluminium hydride, and the borohydrides such as alkali metal borohydrides, with diisobutylaluminium hydride being particularly preferred.

Also, this reduction can be carried out using a di(branched-chain lower alkyDborane such as bis(3-methyl-2-butyl)borane. In carrying out this reduction, temperature and pressure are not critical and the reduction can be carried out at room temperature and atmospheric pressure or at elevated or reduced temperatures and pressures. Generally, it is preferred to carry out this reduction at a temperature of from -70°C to room temperature (3O°C). This reduction can be carried out in the presence of an inert organic solvent. Any conventional inert organic solvents Can be Used in carrying out this reduction. Among the preferred solvents are dimethoxyethyleneglycol and ethers such as tetrahydrofuran, diethyl ether and dioxane.

A compound of formula IIA is obtained from a compound of 10 formula VII by reaction with a phosphonium salt of the general formula R50~?^“(CH2'4—COOH (xi) I Y® R51 wherein Rg, RgQ, Rgj_ and Y® have the significance given earlier.

It has been found that a compound of formula VII will react with a phosphonium salt of formula XI to produce a compound of formula IIA having a predominantly cis double-bond in the 5-position of the acid chain in a solvent medium containing hexamethylphosphoramide using sodium bistrimethyl20 silylamide as a base. If solvents other than hexamethylphosphoramide or bases other than sodium bistrimethylsilylamide are used, the compound of formula IIA may result in poorer yields. However, conventional inert organic solvents may be mixed with the hexamethylphosphoramide to form the solvent medium. If other solvents are used, these solvents can be conventional inert organic solvents. On the other hand, the solvent system can contain only the hexamethylphosphoramide. Therefore, this reaction is carried out using hexamethylphosphoramide as the solvent and sodium bistrimethylsilylamide as the base. Xn carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and pressure. However, if desired, higher or lower temperatures can be used. Generally, it is preferred to carry out this reaction at a temperature of from 0°C to 50°C.

A compound of formula IIA can be converted into a compound of the general formula , wherein R^, R^, R'4 and Rg have the significance given earlier, by treatment with an oxidising agent. Any conventional oxidising agent which will convert a hydroxy group into an oxo group can be used in carrying out this oxidation. Among the preferred oxidising agents are chromate oxidising agents such as chromium trioxide. Any of the conditions which are conventional in using these oxidising agents can be used to carry out the present oxidation.

A compound of formula IXA or IIB can be converted into a compound of formula II in which X represents the —CHj—CH^— group by hydrogenation. Any conventional hydrogenation method such as catalytic hydrogenation can be used to carry out this hydrogenation. Among the preferred hydrogenation methods is the use of hydrogen in the presence of a noble metal catalyst such as platinum or palladium under conventional conditions.

The carboxy group in a compound of formula II, IIA or IIB can be converted into a lower alkoxycarbonvl group by esterification with diazomethane or a reactive derivative Of a lower alkanol such as a lower alkyl halide. Any conventional esterification conditions can be used in carrying out this esterification.

The phosphonium salts of formula IX and the phosphonates of formula X can be obtained from a compound of the general formula I4 —(CH2)3—CH3 (VIII) r , wherein R^ and R’ have the significance given earlier and Rg represents a lower alkyl group, via the following intermediates: HO—CO—C—(CH2)3— CH3 Rq o~~co—g (XII) (XIII) -(XIV), and (XV) nee given earlier (CH2)3~Ch3 ΐ4 N2CH —CO—C—!CH2)3—CH3 R,4 XCHg CO C—^0H2^3—C H3 k wherein and R'4 have the signifies 5 and X represents a halogen atom.

A compound of formula VIII is converted into a compound of formula XII by acid hydrolysis. Any conventional method of acid hydrolysis can be used. Generally, this acid hydrolysis is carried out at a temperature from 20°C to 120°C in the presence of an aqueous mineral acid such as sulphuric acid.

A compound of formula XII is converted into a compound of formula XIII by treatment with a halogenating agent. Any conventional halogenating agent can be used. Among the preferred halogenating agents there may be mentioned oxalyl chloride, thionyl chloride and phosphorus pentachloride. Any of the conditions which are conventional in using these halogenating agents can be used in carrying out this halogenation. 6 * Ο 3 Λ compound of formula XIII can be converted into a compound of formula XIV by reaction with diazomethane under conditions which are conventional in reacting an acid halide with diazomethane.

A compound of formula XIV is converted into a compound of formula XV by treatment with a gaseous hydrohalide acid such as gaseous hydrogen bromide under conditions which are conventional for converting a diazo compound into a halide.

A compound of formula XV is converted into a phosphonate 10 of formula X by reaction with a tri(lower alkyl)phosphite under conventional conditions.

A compound of formula XV can be converted into a phosphonium salt of formula IX by reaction with a tri [aryl or di(lower alkyl)amino]phosphine under conventional conditions.

A compound of formula VIII hereinbefore in which R'4 represents a trifluoromethyl group can be prepared from a compound of the general formula COOH RgO—CO—C—(CH2)3—-CH3 (XVI) R4 , wherein R^ and Rg have the significance given earlier, by reaction with sulphur tetrafluoride. The sulphur tetrafluoride is reacted with a compound of formula XVI in a closed container at a temperature of from 20°C to 85°C. Generally, from about 1 to 4 mol of sulphur tetrafluoride are present per mol of the compound of formula XVI. Amounts of sulphur tetrafluoride greater than 4 mol per mol of the compound of formula XVI may, however, be used. If desired, acid catalysts and/or a solvent may be present in the reaction medium. Any conventional inert organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, may, if desired, be present in the reaction medium. If desired, any conventional acid catalyst such as hydrofluoric acid, boron trifluoride etc can be added to the reaction medium. On the other hand, no solvent and/or acid catalyst need be added to the reaction medium.

The prostaglandin derivatives provided by the present invention have the ability to modify the activity of the alimentary and reproductive smooth muscles, to block mucous and enzyme secretions by the stomach, to stimulate the synthesis of adrenal corticoids and to modify blood pressure and lipolysis. Furthermore, they are active in inducing labour during pregnancy in females and for therapeutically terminating pregnancy. The present prostaglandin derivatives in which R2 and together represent an oxo group are useful in that they lower blood pressure and inhibit blood platelet aggregation. The present prostaglandin derivatives in which R2 and Rg together represent an oxo group are especially valuable as anti-ulcerogenic agents.

The present prostaglandin derivatives in which R2 represents a hydroxy group and R^ represents a hydrogen atom are active as blood pressure raising agents in the same manner as prostaglandin The aforementioned anti-ulcerogenic effect is evidenced by the fact that the Εϋ^θ of a derivative such as 7-[3a-methyl-5-0X0-20-(3a-hydroxy-4-trifluoromethyl-4-methyl-l-trans-octenyl)-la-cyclopentyl]-cis-5-heptenoic acid is 0.47 i.£. and 0.0001 £.o. when administered to rats in the following test: Rats were fasted for 16 hours prior to the subcutaneous administration of indomethacin at a dosage of 100 mg/kg. Simultaneously with the indomethacin administration, the prostaglandin derivatives to be tested were administered intraperitoneally at three dosage levels and orally at six dosage levels. These dosages of the prostaglandin derivatives were repeated every 30 minutes for 6 hours (12 dosages).. After 6 hours, the rats were killed and the stomachs were examined for ulceration or haemorrhage. Protection from incidence of ulceration was used to determine activity. 5 rats were used per dosage level and EDgQ values were calculated.

The prostaglandin derivatives provided by the present invention can be used in the pharmaceutical and veterinary fields in a variety of pharmaceutical or veterinary preparations which can take the form of tablets, pills, powders, capsules, injectables, solutions, suppositories, emulsions, dispersions, feed pre-mixes and other suitable forms. The pharmaceutical or veterinary preparations conveniently, contain a prostaglandin derivative provided by this invention in admixture with a non-toxic pharmaceutical organic carrier or a non-toxic pharmaceutical inorganic carrier. Typical pharmaceutically acceptable carriers are, for example, water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkyleneglycols, petroleum jelly and other conventionally used pharmaceutically acceptable carriers. The pharmaceutical preparations may also contain non-toxic auxiliary substances such as emulsifying agents, preserving agents and wetting agents for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sobitan and dioctyl sodium sulphosuccinate. - 20 The following Examples illustrate the process provided by the present invention: Example 1 To a mixture of 6 g of chromium trioxide and 9.5 g of 5 pyridine in 150 ml of methylene chloride were added at 0°C 4.5 g of 7-/ 3a-methyl-5a~hydroxy-20-[3a-(2-tetrahydropyranyloxy)-4-trifluoromethvl-l-trans-octenyl]-la-cyclopentyl_/-cis-5-heptenoic acid dissolved in 50 ml of methylene chloride. The mixture was stirred for 1 hour at room temperature and filtered 10 through a bed of Celite (registered Trade Mark). The Celite was washed with methylene chloride and the combined methylene chloride solutions were washed with dilute hydrochloric acid to remove any remaining pyridine. The methylene chloride was then removed under reduced pressure and the residue was treated with 50 ml of acetic acid/ water (3:1 parts by volume) at 35°C for 15 hours. The solvents were then removed under a high vacuum and the residue was purified by column chromatography to give the product, 7-[3a-methyl-5-oxo-2p-(3a-hydroxy-4-trifluoromethyl-l-trans-octenyl)20 -la-cyclopentyl]-cis-5-heptenoic acid.

The starting material was prepared as follows: To a 4 litre stainless steel bomb were added 237 g (1.26 mol) of 2-carboethoXyhexanoic acid, 260 ml of methylene chloride and 19 ml of 48% hydrofluoric acid. The bomb was sealed with an assembly consisting of a rupture disc (1400-1600 psi) and a needle valve. It was then cooled in a dry ice/ acetone bath for 30 minutes and evacuated to less than 10 mm Hg pressure. While maintaining the bomb in the cooling bath, 600 g (5.56 mol) of sulphur tetrafluoride were condensed into the bomb from an attached lecture bottle. The needle valve closed and the bomb was removed from the cooling bath and allowed to remain at room temperature with only occasional agitation for 13 days. After this period, the bomb was vented and the residual materials were taken up in 2.2 litres of pentane and dried over sodium fluoride/magnesium sulphate. Distillation of the filtered pentane solution gave 117 g (44%) of ethyl 2-trifluoromethylhexanoate of boiling point 69°-76°C/ mm Hg. .05 g of ethyl 2-trifluoromethylhexanoate were mixed with 50 ml of concentrated sulphuric acid and warmed to 75 °C for 20 hours. After cooling, the acid was poured into excess ice. The resulting mixture was saturated with sodium chloride and extracted with three 100 ml portions of diethyl ether. Tlie combined ether extracts were dried over magnesium sulphate and evaporated to give a residual oil which yielded 7.50 g of 2-trifluoromethylhexanoic acid upon distillation; boiling point 80°-85°C/ 2.8 mm Hg. 2.3 g of 2-trifluoromethylhexanoic acid were added dropwise to 10 g of oxalyl chloride and the mixture was heated to reflux for 2 hours. Distillation of the mixture after this time yielded 2.27 g (90%) of 2-trifluoromethylhexanoyl chloride of boiling point 67°-70°C/43 mm Hg. tyi <3 β 1 Ο 3 2.27 g of 2-trifluoromethylhexanoyl chloride were added dropwise to an excess of ethereal diazomethane solution at 0°C. After 1 hour, the excess diazomethane was removed with a stream of nitrogen. The ether solution at 0°C was then treated with an excess of hydrdgen bromide gas. After 15 minutes, the solution was washed with three 10 ml portions of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to constant weight in a vacuum to give 2.56 g (88%) of 3-trifluoromethyl-l-bromoheptan-2-one which was not further purified.

A mixture of 2.50 g of 3-trifluoromethyl-l-bromoheptan-2-one and 5.1 g of triethylphosphite was heated to 1OO°C and continuously flushed with a slow stream of nitrogen. After 6 hours, the mixture was distilled to give 2.60 g of a mixture of diethyl (3-trifluoromethyl-2-oxoheptyl)phosphonate and diethyl (3-trifluoromethylhept-l-err/l)-phosphate. Tne diethyl (3-trifluoromethyl-2-oxoheptyl)phosphonate was isolated from this mixture.

To a suspension of 0.7 g of sodium hydride in 150 ml of diglyme were added 6 g of diethyl (3-trifluoromethyl-2-oxoheptyl)phosphonate. After stirring for 1.5 hour, 5 g of 3,3ai>, 4,5,6,6a/3-hexahydro- 4/3-f ormyl-5 a-methyl-2-oxo-2H-cyclopenta[b]furan dissolved in 30 ml of glyme were added dropwise at 0°C. After stirring for 3 hours at room temperature, 500 ml of diethyl ether were added and the mixture was washed with water. The organic layer was then dried over magnesium sulphate and the solvent was removed under reduced pressure. The 610 3 residue was then washed through 75 g of silica gel to give 3,3ad,4,5,6,6a/3-hexahydro-4B- (3-oxo-4-trifiuoromethyl-l-trans-octenyl)-5a-methyl-2-oxo-2H-cyclopenta[b]furan.

To a solution of 4.5 g of 3,3a6,4,5,6,6a0-hexahydro-40-(3-oxo-4-trifluoromethyl-l-trans-octenyl)-5a-methyl-2-oxo-2H-cyclopenta[b]furan in 100 ml of diglyme was added an excess of zinc borohydride in 50 ml of glyme and the resulting solution was stirred for 3 hours. The solution was cooled to 0°C and treated with 200 ml of water,400 ml of diethyl ether and 10ml of O.5-N aqueous sulphuric acid. The ether was separated and dried over magnesium sulphate, and the solvent was removed under reduced pressure to give 3,3ae,4,5,6,6a0-hexahydrO-4fi-(3-hydroxy-4-trifluoromethyl-l-t£sas-octenyl)-5a-methyl-2-oxo-2H-cyclopenta[b]furan. Column chromatography on silica gel using diethyl ether/hexane (70:30 parts by volume) then afforded first 3,3ab,4,5,6,6afl-hexahydro-45-(3u-hydroxy-4-tri£luoromethyl-l-trajlS-octenyl)-5a-methyl-2-oxo-2H-cyclopenta[b]furan and then 3,3ai3,4,5,6,6a5-hexahydro-45-(3fl-hydroxy-4-trifluoromethyl-l-trans-octenyl)-5a-methyl-2-oxo-2H-cyclopenta[b]furan.

A solution of 5 g of 3,3afi,4,5,6,6a5-hexahydro-4S-(3a-hydroxv-4-trifluoromethvl-l-trans-octenvl)-5a-methyl-2-oxo-2H-cyclopentatb]furan, 12 g of dihydropyran and 25 mg of p-toluenesulphonic acid in 200 ml of methylene chloride was stirred at 25°C for 3 hours. The solution was washed with saturated sodium bicarbonate solution, the methylene chloride solution was dried over magnesium sulphate and the volatile components were evaporated under reduced pressure to give 6.4 g - 24 46103 of 3,3a0,4,5,6,6a0-hexahydro-40-[3a-(2-tetrahydropyranyloxy)-4-trifluoromethyl-l-trans-octenyl]-5a-methyl-2-oxo-2H-cyclopenta[b] furan.

To a solution of 3,3a0,4,5,6,6a0-hexahydro-40-[3a-(2-tetrahydropyranyloxy)-4-trifluoromethvl-l-trans-octenvl)-5a-methyl-2~oxo-2H-cyclopenta[b]furan in 150 ml of toluene was added dropwise at -78°C 1 equivalent of diisobutylaluminium hydride in the same solvent. The mixture was stirred at this temperature for 2 hours, after which time 20 ml of methanol were slowly added and the mixture was stirred for 2 hours at room temperature. The mixture was then filtered through a bed of Celite, the Celite was washed with ethyl acetate and the solvents were then removed under reduced pressure. The residue was then washed through a column of silica gel to give 3,3aj3,4,5,6,6a6-hexahydro-40-[3 a-(2-tetrahydropyranyloxy)-4-trlfluoromethvl-l-trans-octenvll-5a-methyl-2H-cyclopenta[b]furan-2-ol. 3.6 g of 3,3a/3,4,5,6,6a0-hexahydro-4fi-[3a-(2-tetrahydropyranyloxy) -4-trifluoromethvl-l-trans-octenvl]-5a-methyl-2H-cyclopenta[b]furan-2-ol in 150 ml of hexamethylphosphoric acid triamide were reacted With 2.2 equivalents of Wittig reagent generated by the reaction of 7.0 g (0.0384 mol) of sodium bistrimethylsilylamide with 8.4 g (0.19 mol) of 4-carboxybutyltriphenylphosphonium bromide. After stirring for 30 minutes, the mixture was acidified to pH 6.5 with dilute sulphuric acid and the hexamethylphosphoramide was removed under a high vacuum. The mixture was then extracted several times with ether and the ether solution was dried over sodium sulphate. The solvent was then removed under reduced pressure and the residue was chromatographed on silica gel to give 3.5 g of 7-/ 3a-methyl-5a-hydroxy-26-[3a-(2-tetrahydropyranyloxy)-4-trifluoromethy1-1-trans-octenyl]-Ια-cyclopentyl /-cis-5-heptenoic acid.

Example 2 According to the procedure described in Example 1, 7-/-3a-methyl-5a-hydroxy-30-[3a-<2-tetrahydropyranyloxy)-4-trifluoromethy1-4-methyl-l-trans-octenyl]-Ια-cyclopentyl 7~cis-5-heptenoic acid was converted into 7-[3a-methyl-5-oxo-23-(3a-hydroxy-4-trifluoromethy1-4-methyl-1-trans-octenyl)-la-cyclopentyl) -cis-5-heptenoic acid.

The starting material was prepared according to the procedure described in Example 1 via the following intermediates Ethyl 2-trifluoromethyl-2-methylhexanoate, diethy1 (3-trifluoromethy1-2-oxohepty1)phosphonate, 3,3ad, 4,5,6,6 a/3-hexahydro-4/3- (3-oxo-4-methyl-4-trif luorome thy1-1-trans-octenyl)-5a-methyl-2-oxo-2H-cyclopenta[b]furan, 3,3afl,4,5,6,6a/3-hexahydro-4/3- (3 a-hydroxy-4-trif luoromethy 1-4-methyl-1-trans-octenyl)-5α-methyl-2-oxo-2H-cyclopenta[b]furan, 3,3afi,4,5,6,6a/3-hexahydro-40-[3a-(2-tetrahydropyranyloxy)-4-trifluoromethy1-4-methyl-l-trans-octenyl]-5α-methyl-2-oxo-2H-cyclopenta[b]furan, and 3,3afl,4,5,6,6a0-hexahydro-4i3-[3a-(2-tetrahydropyranyloxy)26 -4-trifluoromethyl-4-methyl-l-trans-octenyl]-5a-methyl-2H-cyclopenta[b]furan-2-ol.

Example 3 A solution of 200 mg of 7-/ 3a-methyl-5a-hydroxy-20-[3a5 -(2-tetrahydropyranyloxy)-4-trifluoromethyl-l-trans-octenyl]-la-cyclopentyl_/-cis-5-heptenoic acid in 5 ml of acetic acid/water (3:1 parts by volume) was kept at 35°C for 15 hours. The solvent was then removed under a high vacuum and the residue was purified by column chromatography to give the product, 7-[3a-methyl-5a-hydroxy-2/3-(3a-hydroxy-4-trifluoromethyl-l-trans-octenyl)-la-cyclopentyl]-cis-5-heptenoic acid.

Example 4 According to the procedure described in Example 3, 7-/~3a-methyl-5a-hydroxy-20-[3a-(2-tetrahydropyranyloxy)-4-trifluoro15 methyl-4-methyl-l-trans-octenyl]-la-cyclopentyl /-cis-5-heptenoic acid was converted into 7-[3a-methyl-5a-hydroxy-20-(3a-hydroxy-4-trifluoromethyl-4-methyl-l-trans-octenyl)-la-cyclopentyl]-cis-5-heptenoic acid.

Example 5 According to the procedure described in Example 1, 7-/—5a-hydroxy-20-[3a-(2-tetrahydropyranyloxy)-4-trifluoromethyl-l-trans-octenyl]-la-cyclopentyl 7-cis-5-heptenoic acid was converted into 7-[5-οχο-2β-(3a-hydroxy-4-trifluoromethyl-l—trans-octenvl-1a-cvclopentvl1-cis-5-heptenoic acid. 6 I 03 - 27 Example 6 According to the procedure described in Example 1, 7-/ 5a~ -hydroxy-2(3- [3a-(2-tetrahydropyranyloxy)-4-trifluoromethyl-4-methyl-l-trans-octenyl]-la-cyclopentyl /-cis-5-heptenoic acid was converted into 7- [5-oxo-2/3-(3a-hydroxy-4-trifluoromethyl-4-methyl-l-trans-octenyl)-la-cyclopentyl]-cis-5-heptenoic acid.

Example 7 According to the procedure described in Example 3, 7-/ 5a-hyaroxy-20-[3a-(2-tetrahydropyranyloxy)-4-trifluoromethyl-l10 -trans-octenyl·]-la-cyclopentyl /-cis-5-heptenoic acid was converted into 7-[5a-hydroxy-25-(3a-hydroxy-4-tri£luoromethyl-l-trans-octenyl)-la-cyclopentyl]-cis-5-heptenoic acid.

Example 8 According to the procedure described in Example 3, 7-/ 5a15 -hydroxy-20-[3a-(2-tetrahydropyranyloxy)-4-trifluoromethyl-4-methyl-l-trans-octenyl]-la-cyclopentyl /-cis-5-heptenoic acid was converted into 7-[5a-hydroxy-2i3-(3a-hydroxy-4-trifluoromethyl-4-methyl-l-trans-octenyl)-la-cyclopentyl]-cis-5-heptenolc acid.

Example 9 Nat - (5Z ,13E) -ll(B)-methyl-16,16-difluoro-15 (R) - (tetrahydro-2H-2-pyranyloxy)-9fe)-hydroxyprosta-5,13-dienoic acid was warmed at 40°C with a mixture of acetic acid/water/tetrahydrofuran (55:30:15) to yield nat. (5Z,13E)-ll(R)-mathyl-16,16-difluoro-9(S), 15@-dihydroxyprosta-5,13-dienoic acid, a light yellow viscous oil. The mass spectrum is in agreement with the structure indicated.

The starting material was prepared via the following intermediates: Ethyl 2,2-difluorohexanoate, dimethyl (2-oxo-3,4-difluoroheptyl)phosphate, 3,3s®, 4,5,6, 6a®-hexahydro-4®- (4,4-difluoro-3-oxo-l-trans -octenyl) -5®-methy1-2H-eyelopenta[b]furan-2-one, 3,3a®, 4,5,6,6a(3)-hexahydro-4(g)- (4,4-difluoro-3R-hydroxy-l-trans-octenyl)-5®-methyl-2H-cyclopenta[b]furan-2-one, 3,3afe), 4,5,6,6a^)-hexahydro-4®- [4,4-difluoro-3®- (tetrahydro-2H-2-py rany loxy) -1-trans-octenyl]-5®-methyl-2H-cyclopenta[b]furan-2-one, and 3,3aCg), 4,5,6,6 a®-hexahydro-4(8)- [4,4-difluoro-3(8)- (tetrahydro-2H-2-pyranyloxy)-l-trans-octenyll-5®-methyl-2I}-cyclopenta[b]furan-2-ol.

Example 10 In an analogous manner to that described in Example 1, nat. (5/,13E)-11 (R) - methyl-16,16-difluoro-15!Sl·· (tetrahydro-2H-2-pyranyloxy)-9©-hydroxyprosta-5,13-dienoic acid was converted into nat. {5Z^,13E)-11 (R) — methyl-16,16-difluoro-15®-hydroxy-9-oxo25° prosta-5,13-dienoic acid, a light yellow viscous oil; [a]D = -67.76 (in chloroform).

The following Example illustrates a typical preparation containing one of the prostaglandin derivatives provided by the present invention: Example A A tablet containing the following ingredients was prepared: Ingredient Per tablet 7- [3a-Methyl-5-oxo-23-(3a-hydroxy-4-trifluoromethvl-l-trans-octenvl)-la-cyclopentyl]-cis-5-heptenoic acid 25 mg Dicalcium phosphate dihydrate, unmilled 175 mg Corn starch 24 mg Magnesium stearate 1 mg Total weight 225 mg

Claims

1. Compounds of the general formula , wherein R represents a hydrogen atom or a lower alkyl group, represents a hydrogen atom or a lower alkyl group, R^ represents a hydroxy group and R^ together represents an oxo group, R^ represents a hydrogen or fluorine atom or a lower Blkyl group, R 1 ^ represents a triflucromethyl group or, when R^ represents a fluorine atom, R 11 ^ may also represent a fluorine atom and X represents the -CH=CH- or —CH^—CH^— group, and enantiomers and racemates thereof, the double bond of the substituted octenyl side chain having trans configuration and the optional double bond in X having cis or trans configuration.

2. Prostaglandin derivatives as set forth in claim 1, wherein R^ represents a lower elkyl group.

3. Prostaglandin derivatives as set forth in claim 1 or claim 2, wherein R represents a hydrogen atom.

4. 7-[3o-Methyl-5-oxo-2B-(3a-hydroxy-4-trifluoromethyl-1-trans-rflcLenyD.-la-cyciopentyll-cis-S-heptenoic acid. 31 46103

5. ) 7-[3a-Methyl-5a-hydroxy-23-(3a-hydroxy-4-trifluoromethyl-1-trans-octenyl)-la-cyclopentyl]-cis-5-heptenoic acid.

6. )

7. -[3a-Methyl-5-oxo-23-(3a-hydroxy-4-trifluoromethyl-4-methy1-1-trans-octenyl)-la-cyclopentyl]-cis-5-heptenoic acid. 5 7) 7-[3a-Methyl-5a-hydroxy-20-(3a-hydroxy-4-trifluoromethyl-4-methy1-1-trans-octenyl)-la-cyclopentyl]-cis-5-heptsnoic acid

8. ) 7- [5 o-Hydroxy-2 3- (3a-hydroxy-4-trifluoromethyl-l-trans-octenyl)-la-cyclopentyl]-cis-5-heptenoic acid.

9. ) 7-[5a-Hydroxy-213-(3a-hydroxy-4-trifluoromethyl-4-methyl10 -1-trans-octenyl)-la-cyclopentyl]-cis-5-heptenoic acid.

10. ) A process for the manufacture of the prostaglandin derivatives set forth in claim 1, which process comprises hydrolysing the group denoted by Rg in a compound of the general formula R 2 £H 2 —X—(CH 2 ) 3 —COOR (ID , wherein R, & 2 , R^, » 4 , , x and the double bond or bonds have the significance given in claim 1 and Rg represents a hydroxy group protected by a hydrolysable ether or ester group, into a hydroxy group, and, if desired, esterifying a carboxy group to form a lower alkoxycarbonyl group or converting a lower alkoxycarbonyl group into a carboxy group by basic hydrolysis.

11. ) A process according to claim 10, wherein R^ represents a 5 lower alkyl group.

12. ) A process according to claim 10 or claim 11, wherein R represents a hydrogen atom.

13. ) A process for the manufacture of the prostaglandin derivatives set forth in claim 1, substantially as hereinbefore 10 described with reference to any one of Examples 1 to

14. ) A prostaglandin derivative as set forth in claim 1, when manufactured by the process claimed in any one of claims 10 to 13 inclusive or by an obvious chemical equivalent thereof.

15. ) A pharmaceutical preparation or veterinary preparation 15 containing a prostaglandin derivative as set forth in any one of claims 1 to 9 inclusive or 14 in association with a compatible carrier.