GB2084991A

GB2084991A - Prostacyclins

Info

Publication number: GB2084991A
Application number: GB8030480A
Authority: GB
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1980-09-22
Filing date: 1980-09-22
Publication date: 1982-04-21
Also published as: GB2084991B

Abstract

Novel prostacyclins of the formula <IMAGE> wherein R is hydrogen or lower alkyl; R<1> is hydrogen, lower alkyl, hydroxymethyl, <IMAGE> R<2> is hydrogen, lower alkyl or fluoro; R<2'> is fluoro, trifluoromethyl or lower alkyl and the dotted bond is optionally hydrogenated, with the proviso that when R<1> is hydrogen, R<2'> is trifluoromethyl and with the further proviso that when R<2> is fluoro, R<2'> is lower alkyl or fluoro, and their salts are useful as anti- secretory, anti-hypertensive, anti- ulcerogenic and blood platelet aggregation inhibiting agents. The novel compounds can be prepared starting from known prostaglandin derivatives.

Description

SPECIFICATION Prostacyclins The present invention relates to prostacyclins. More particularly the invention relates to prostacyclins of the formula

wherein R is hydrogen or lower alkyl; R' is hydrogen, lower alkyl, hydroxymethyl,

R2 is hydrogen, lower alkyl or fluoro; R2 is fluoro, trifluoromethyl or lower alkyl and the dotted bond is optionally hydrogenated, with the proviso that when R1 is hydrogen, R2 is trifluoromethyl, and with the further proviso that when R2 is fluoro, R2 is lower alkyl or fluoro, and their salts.

The invention relates further to a process for the preparation of the prostacyclins of formula I and to intermediates used therein, as well as to pharmaceutical compositions containing a prostacyclin of formula I.

As used throughout this application, the term "lower alkyl" includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms, such as methyl and ethyl. As also used herein, the term "lower alkanoic acids" comprehends an alkanoic acid of 1 to 7 carbon atoms, such as formic acid and acetic acid. As further used herein, the term "halogen" or "halo", unless otherwise stated, comprehends fluorine, chlorine, bromine and iodine. Alkali metal includes all alkali metals such as lithium, sodium and potassium. The term "aryl" signifies mono-nuclear aromatic hydrocarbon groups, such as phenyl and tolyl, and polynuclear aryl groups, such as naphthyl, anthryl, phenanthryl and azplyl. The preferred aryl group is phenyl or tolyl.

The above formula I is to be understood as comprising optically active enantiomers and racemates.

The compounds of formula I are active as anti-secretory agents, bronchodilators, blood platelet inhibitors, anti-ulcerogenic agents and anti-hypertensive agents.

The compounds of formula I wherein R2 is fluoro or trifluoromethyl are particularly useful as antihypertensive and blood pressure lowering agents.

The compounds of formula I where R2 is hydrogen or lower alkyl and R2 is lower alkyl are especially useful as anti-secretory and anti-ulcerogenic agents.

Among the compounds of formula I those having 6R configuration, as indicated by formula 1-1

wherein R, Rq, F2 and R2' and the dotted bond are as above, are preferred.

According to the invention, the compounds of formula I are prepared by a process which comprises redacting a compound of the formula

wherein Xis halogen, R1 is hydrogen, lower alkyl, hydroxymethyl or COOR6, R6 is lower alkyl and R2, R2' and the provisos are as above, with a trialkyl or triaryl tin hydride and, if desired, in either sequence, hydrolysing any alkoxy carbonyl group and/or hydrogenating the olefinic double bond present in the reaction product of formula I.

The compound of formula IV can be converted to the compound of the formula I by treatment with a trialkyl tin hydride or triaryl tin hydride. Any conventional trialkyl or triaryl tin hydride can be utilized in this reaction. Among the preferred tin hydrides are the trilower alkyl tin hydrides such as tributyl tin hydride. Among the preferred triaryl tin hydrides is triphenyl tin hydride. On the other hand, this reaction can be carried out by generating the triaryl or trialkyl tin hydride in situ. This is carried out by utilizing a triaryl or trialkyl tin chloride in the presence of an alkali metal borohydride. The alkali metal borohydride converts the triaryl or trialkyl tin chloride to the corresponding tin hydride. The trialkyl or triaryl hydride is present in the conversion of the compound of formula IV to the compound of formula I either in molar amount or in catalytic quantities.This reaction is carried out in an inert organic solvent. Any conventional inert orqanic solvent can be utilized. Among the preferred inert organic solvents are the hydrocarbon solvents, such as the aliphatic and aromatic hydrocarbon solvents. Solvents, such as hexane, octane, toluene or benzene, are especially preferred. This reaction can be carried out at room temperature and atmospheric pressure. On the other hand, elevated and reduced pressures can be utilized with temperatures of from 20 to 800C being generally preferred. The most preferred embodiment of this reaction is carrying this reaction out at reflux. If desired, a free radical initiator can be utilized in carrying out this reaction. Any conventional free radical initiator can be utilized. Among the preferred free radical initiators are benzoyl oxide and 2,2'-azobis (2-methylpropionitrile).The presence of a free radical initiator can speed up the rate of the reaction.

The conversion of an esterified carboxy group present in the so obtained compound of formua I can be effected by basic hydrolysis. Any conventional method of basic hydrolysis such as treating the compound of formula I with an aqueous alkali metal hydroxide solution can be utilized to effect this conversion.

In a compound of formula I wherein the optional olefinic bond is present, said double bond can be hydrogenated to yield the corresponding saturated compound utilizing a conventional hydrogenation catalyst, such as platinum oxide. Any of the conditions conventional in catalytic hydrogenation can be utilized in this reaction.

The compounds of formula IV used as starting material in the process of this invention can be prepared from compounds of formula

via the intermediate

wherein R' is hydrogen, lower alkyl hydroxymethyl or carboxy; and X, R1, R2 and R2 are as above.

Depending upon the particular form of the compound of formula I desired, the compound of formula II which is utilized as a starting material can be either a racemate or can be in the form of its optical antipodes.

The compound of formula II is converted to the compound of formula Ill by hydrohalogenation.

Any conventional method of hydrohalogenation can be utilized in carrying out this reaction. Among the preferred methods of hydrohalogenation is by treating the compound of formula II with a hydrohalogenating agent, such as N-halosuccinimides. Generally, this reaction is carried out in the presence of a halogenated hydrocarbon solvent, such as methylene chloride or ethylene chloride. In fact, any conventional halogenated hydrocarbon solvent can be utilized. In carrying out this reaction, temperatures of from 0 to 350C can be utilized. Generally it is preferred to carry out this reaction at room temperature.

The compound of formula Ill is converted to the compound of formula IV by esterification with a lower alkanol or a reactive derivative of a lower alkanol. Any of the conventional reactive derivatives of lower alkanol, such as a lower alkyl halide, diazoalkanes including diazomethane, can be utilized in carrying out this reaction. Any conventional method of esterification utilizing lower alkanols or reactive derivatives thereof can be utilized in converting the compound of formula Ill to the compound of formula IV. If desired, the compound of formula IV can be separated to the enantiomers formed depending on the particular configuration of the carboxylic side chain. The separation of the compound of formula IV into its enantiomers can be carried out by conventional methods of separation, such as chromatography.

In the process of this invention, all compounds having one or more asymmetric carbon atoms can be produced as racemic mixtures. These racemic mixtures which are obtained can be resolved at the appropriate steps in the process of this invention by methods well known in the art whereupon subsequent products may be obtained as the corresponding optically pure enantiomers. On the other hand, the claimed optically active enantiomers or racemates of formula I can be produced depending upon the optical form of the compound of formula II utilized as a starting material.

Where R in the compound of formula I is hydrogen, the novel compounds of this invention include the pharmaceutically acceptable salts thereof. Among the preferred pharmaceutically acceptable salts are the alkali metal salts, such as potassium, sodium and lithium. Another pharmaceutically acceptable salt for use in accordance with this invention is the ammonium salt. In accordance with this invention, any conventional pharmaceutically acceptable salt can be utilized.

That the compounds of this invention are active as blood pressure lowering agents can be seen from the administration of [6S, 8R, 9S, 1 1R, 12S, 16R]-6,9-epoxy-11 -methyl-l 6-fluoro-l 5- hydroxyprost-(13E)-enoic acid [Compound A] by the following test: Charles River male rats weighing 170210 grams are used in the present study. DOCA-Na hypertension is induced in these rats by unilateral nephrectomy followed by subcutaneous implantation of a 25 mg deoxycorticosterone acetate pellet. Animals are placed in individual cages and receive 0.9% by weight sodium chloride aqueous solution and rat chow diet ad libitum. Two weeks are allowed to elapse from the time of surgery for development of hypertension, i.e. systolic blood pressure above 1 50 mmHg.Systolic blood pressure is measured indirectly from the tail of unanesthetized rats (restrained in holders heated for 5-10 minutes at 37-380C) using a pneumatic pulse transducer (piezoelektric crystal and occluding cuff.). The transducer and occluding cuff are coupled to a two-channel recorder.

Control readings are taken prior to drug and at 1,3, 6, 24, 48 and 72 hours post administration of drug.

All drugs are prepared fresh in polyethylene glycol (mw=400) and orally administered to rats. The placebo that was used was polyethylene glykol (mw=400). It was found that the effective dose [ED40] of compound A which produced a 40 mmHg decrease in systolic blood pressure 24 hours after administration was 8.6 mg/kg p.o.

That the compounds of this invention are active as anti-secretory and anti-ulcerogenic agents can be seen by administering [6S, 8R, 9S, 1 1R, 12S, 1 SR]methyl-6,9-epoxy- 1 1,16,16-trimethyl-l 5- hydroxyprost(13E)-enoate (Compound B) by the following test: Compound B was tested as gastric secretory depressant in the unanesthetized rat with acute fistula.On the day prior to the experiment, fasted female rats (average weight 250 g) were surgically catheterized in the inferior vena cava (for the constant infusion of saline and administration of compounds), the common bile duct (to divert bile and pancreatic secretions which may reflux causing contamination of gastric contents), the forestomach (for infusion of a small volume of water during the experiment) and the glandular stomach (for the collection of gastric contents and their continuous monitoring by means of a pH microelectrode. On the day of the experiment, water infusion through the stomach (for the collection of gastric contents and their continuous monitoring by means of a pH microelectrode) was begun for a period of 60 minutes prior to drug administration. During this baseline period, the pH of the secretory flow was about 1.5 for each animal.Individual samples were collected at 10-minute intervals during this baseline period to monitor the pH. The compound dissolved in polyethylene glycol (average molecular weight of about 400) was administered intravenously (i.v.), after this baseline period and samples were continuously collected for 60 minutes. The samples of gastric contents were subsequently assayed for pH, volume, total acid content (yEq/ml) and total acid output for 10 minutes (yEq/10 minutes). Results showed that the acid concentrations (yEq/ml) was inhibited by a maximum of 52% at 55 minutes after administration of Compound B in a dose of 40 ,ug/kg i.v.Also at this dose, the acid output (yEq/10 ml) was inhibited by a maximum of 72%, 55 minutes after drug administration.

The compounds of formula I can be used by the pharmaceutical and veterinary arts in a variety of pharmaceutical or veterinary preparations. In these preparations, the new compounds are administerable in the form of tablets, pills, powders, capsules, injectables, solutions, suppositories, emulsions, dispersions, feed premixes and in other suitable forms. The pharmaceutical or veterinary preparations which contain the compound of formula I are conveniently admixed with a non-toxic pharmaceutical organic carrier or a non-toxic pharmaceutical inorganic carrier. Typical of pharmaceutically acceptable carriers are, for example, water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly and other conventionally employed pharmaceutically acceptable carriers.The pharmaceutical preparations may also contain non-toxic auxiliary substances such as emulsifying, preserving and wetting agents and the like, as for example, sorbitan monolaurate, triethanol amine oleate, polyoxyethylene sorbitan, dioctyl sodium sulfosuccinate and the like.

The daily dose administered for the compounds will, of course, vary with the particular novel compounds employed because of the very potency of the compounds, the chosen route of administration and the size of the recipient. The dosage administered is not subject to definite bounds but it will usually be in effective amounts of the pharmacologically function of the prostacyclin.

Representative of a typical method of administering the prostacyclin compounds of formula I is by the injectable type administration route. By this route, a sterile solution containing the prostacyclin of formula I can be administered intravenously at the rate of 0.1 microgram to 0.30 micrograms per day per kilogram of body weight For administering the compounds of formula I to domestic animals or laboratory animals, the compounds are prepared in the form of a food pre-mix such as mixing with dried fish meal, oatmeal and the like and the prepared pre-mix is added to a regular feed thereby administering the compound to the domestic or laboratory animal in the form of a feed.

The invention is further illustrated by the following examples. These examples are illustrative but not limitative of the claimed invention. As utilized in the examples, the term "Sephadex LH-20" is a bead-form dextran gel having hydroxy propyl groups attached to the ether linkages in the glucose units of the dextran chains.

Example 1 To a solution of 1.0 g of [8R, 9S, 1 1 R, 1 2S, 15R. 1 6R]-1 1-methyl-1 6-fluoro-9,1 5-dihydroxyprosta(5Z), (13E)-dienoic acid in 10 ml of methylene chloride was added 0.67 g of N-iodosuccinimide.

After stirring for one hour at room temperature, 50 ml of diethyl ether was added and the solution was washed with dilute aqueous sodium thiosulfate. The organic layer was dried (MgSO4] and the solvent removed by rotary evaporation at reduced pressure to give 1.2 g of a mixture of [5R, 6R, 8R, 9S, 11 R, 12S, 15R, 15R]-5-iodo-6,9-epoxy-11-methyl-16-fluoro-15-hydroxyprost-(13E)-enoic acid and[5S, 6S, 8R, 9S, 11R, 12S, 15R, 1 6R]-5-iodo-6.9-epoxy-1 1-methyl-1 6-fluoro-l 5-hydroxyprost-( 1 3E)enoic acid. This mixture was dissolved in 25 ml of diethyl ether and treated at 0 C with an excess of an ethereal solution of diazomethane.After stirring for one hour, the volatiles were removed by rotary evaporation and the residual materials were purified by silica gel chromatography to give 0.62 g of [5R, 6R,8R,9S 11R, 12S, 15R, 16R]-methyl-5-iodo-6,9-epoxy-11-methyl-16-fluoro-15-hydroxyprost (1 3E)-enoate, [α]D25+40.55 (CHCI3, c=1.0%) and 0.38 g of [5S, 6S, 8R, 9S, 11R, 12S, 15R, 1 6R]- methyl-5-iodo-6,9-epoxy-11-methyl-16-fluoro-15-hydroxyprost-(13E)-enoate,[α]D26+40,95 (CHCl3 c=1.0%).

Example 2 To a solution of 1.0 g of [5R,6R,8R,9S,11R,12S,15R,16R]-methyl-5-lodo-6,9-epoxy-11methyl-16-fluoro-15-hydroxyprost-(13E)-enoate in 50 ml of hexane was added 0.75 g of tri-n-butyltin hydride and a catalytic amount of 2,2'-azobis (2-methylpropionitrile). The solution was warmed to 500C for three hours after which the solvent was removed and the residual materials separated by silica gel chromatography to give 0.72 g of [6S, 8R, 9S, 11 F, 12S, 1 5R, 1 6Rl-medthyl-6,9-epoxy-11- methyl-16-fluoro-15-hydroxyprost-13E)-enoate.

Example 3 To a solution of 0.7 gof [6S,8R,9S,11R, 12S,15R,16R]-methyl-6,9-epoxy-11-methyl-16fluoro-l 5-hydroxyprost-( 1 3E)-enoate in 30 ml of dimethoxyethane was added 25 ml of methanol and 8 ml of 1 N aqueous sodium hydroxide. After stirring for 2.5 hr. at room temperature, the solvent was removed under reduced pressure and the residue acidified with dilute sulfuric acid. The resultant mixture was extracted with diethyl ether. The combined extracts were dried (MgSO4) and the solvent removed at reduced pressure. The residue was purified by chromatography on Sephadex LH-20 using chloroform-hexane (65/35) as the eluent, to yield 0.6 g of [6S. 8R, 9S, 11 F, 12S, 15R, 1 6R]-6,9- epoxy-11-methyl-16-fluoro-15-hydroxyprost-(13E)-enolc aclc. [α]D25+46.1 (CHCl3, c=1.0%).

Example 4 By the procedure of Example 2, [5S,6S,8R,9S,11 R, 12S, 15R, 16R]-methyl-5-lodo-6,9-epoxy- 11-methyl-16-fluoro-15-hydroxyprost-(13E)-enoate was converted to [6R,8R,9S,11R,12S, 15R, 16R]-methyl-6,9-epoxy-11-methyl-16-fluoro-15-hydroxyprost-(13E)-enoate.

Example 5 By the procedure of Example 3. [6R,8R,9S,11 R, 1 2S, 1 5 R, 1 6R]-m ethyl-6,9-epoxy-l i-methyl- 16-fluoro-15-hydroxyprost-(13E)-enoate was converted to [6R,8R,9S,11R,12S,15R,16R]-6.9epoxy-11-methyl-16-fluoro-15-hydroxyprost-(13E)-anoic acid [α]D25+28.6 (CHCl3 c=1.0%).

Example 6 To an ice cooled, rapidly stirred mixture of 0.45 g of [8R,9S, 11 R, 12S,15R]-methyl-11,16,16- trimethyl-9,15-dihydroxyprosta-(5Z),(13E)-dienoate,5 ml of methylene chloride, and 10 ml of saturated aqueous sodium bicarbonate solution was added dropwise a solution of 0.34 g of iodine in 10 ml of methylene chloride. After one hour, 30 ml of ethyl ether was added and the layers separated.

The organic layer was washed with 10% aqueous sodium thiosulfate and then dried over sodium sulfate. The solvent was removed by rotary evaporation to yield 0.62 g of residual material which upon silica gel chromatography (20% ethyl acetate/hexane as the eluent) yielded 0.42 g of [5R,6R,8R, 9S, ii R, 125, 1 5F]-methyl-5-iodo-6,9-epoxy- 11,16,1 6-trimethyl- 1 5-hydroxyprost-( 1 3E)-enoate, ir 3610, 1733 and 974 cm- and 0.04 g of [5S, 6S, 8R, 9S, 11 1R, 12S, 1 SR]-methyl-5-iodo-6,9-epoxy- 1 1,16,16-trimethyl-l 5-hydroxyprost-(l SE)-enoate, ir 3610, 1733 and 974 cm- Example 7 By the procedure of Example 2, [5R,6R,8R,9S,11 1R, 12S, 1 SR]-methyl-5-iodo-6,9-epoxy- 11,16,16-trimethyl-15-hydroxyprost-(13E)-enoate was converted to [6S, 8R, 9S, 11R, 12S, 15R]methyl-6,9-epoxy-11,16,16-trimethyl-15-hydroxyprost-(13E)-enoate, [α]D25+43,56 (CHCl3, c=1.0%) Example 8 By the procedure of Example 3, [6S,8R,9S,11 R, 12S, 15R]-methyl-6,9-epoxy-11,16,16- trimethyl-15-hydroxyprost-(13E)-enoate was converted to [6S, 8R, 9S, 11R, 12S, 15R]-6,9-epoxy11,16,16-trimethyl-15-hydroxyprost-(13E)-enoic acid [α]D25+47,97 (CHCl3 c=1.0%).

Example 9 By the procedure of Example 6, [8R,9S,11 R, 12S, 1 SR]-methyl-l l-methyl-l 6,1 6-difluaro-9,1 5- dihydroxyprosta-(5Z),(? 3E)-dienoate was converted to a mixture of [5R,6R,8R,9S,11 R, 12S, 15R]- methyl-5-ioco-6,9-epoxy-11-methyl-16,16-difluoro-15-hydroxyprost-(13E)-enoate and [5S,6S,8R, 9S, 11R, 12S, 15R]-methyl-5-ioco-6,9-epoxy-11-methyl-16,16-difluoro-15-hydroxyprost-(13E)enoate.

Example 10 By the procedure of Example 2, [5R,6R,8R,9S, 11 1R, 12S, 1 SR]-methyl-5-iodo-6,9-epoxy- 1 1- methyl-16,16-difluoro-15-hydroxyprost-(13E)-enoate was vonverted to [6S,8R,9S,11R, 12S, 15R]methyl-6,9-epoxy-11-methyl-16,16-difluoro-15-hydroxyprost-(13E)-enoate.

Example 11 By the procedure of Example 3, [6S,8R,9S,11R,12S,15R]-methyl-6,9-epoxy-11-methyl16,16-difluror-15-hydroxyprost-(13E)-enoate was converted to [6S,8R,9S,11R,12S,15R]-6,9epoxy-11-methyl-16,16-difluoro-15-hydroxyprost-(13E)-enoic acid.

Example 12 By the procedure of Example 1 [8R,9S,11 1R, 12R, 15R, 16R]-1 l-carboxy-l 6fluoro-9,1 5- dihydroxyprosta-(5Z),(13E)-dienoic acid was converted to a mixture of [5R,6R,8R,9S,11R,12R,15R, 16R]-5-iodo-6,9-epoxy-11-carboxy-16-fluoro-15-hydroxyprost-(13E)-enoci acid which was esterified and separated by chromatography as described in Example 1 to produce [5R,6R,8R,9S,11 R,12R,15R, 16R]-methyl-5-iodo-6,9-epoxy-11-carbomethoxy-16-fluoro-15-hydroxyprost-(13E)-enoate and[5S, 6S,8R,9S,11R,12R,15R,16R]-methyl-5-iodo-6,9-epoxy-11-carbomethoxy-16-fluoro-15hydroxyprost-l 3-enoate.

Example 13 By the procedure of Example 2 [5R,6R,8R,9S,11 R,12R,1 5R, 1 GR1-methyl-6-iodo-6 ,9-epoxy- 1 -carbomethoxy-16-fluoro- 15-hydroxyprost-(13E)-enoate was converted to [6S,8R,9S,11 1R,12R, 15R,16R]-methyl-6,9-epoxy-11-carbomethoxy-16-fluoro-15-hydroxyprost-(13E)-enoate.

Example 14 By the procedure of Example 3, 6S,8R,9S,11 R,12S,15R]-methyl-6,9-epoxy-11 carbomethoxy-16-fluoro-15-hydroxyprost-(13E)-enoate was converted to [6S,8R,11R,12S,15R]6,9-epoxy-11-carboxy-16-fluoro-15-hydroxyprost-(13E)-enoic acid.

Example 15 By the procedure of Example 2, [5S,6S,8R,9S,11 1 1 R, 12S, 15R, 1 GR]-methyl-5-iodo-6,9-epoxy- 11 -carbomethoxy-l 6-fluoro-i S-hydroxyprost-( 1 3E)-enoate was converted to [6R, 8R, 9S, 12S, 15R, 16R]-methyl-6,9-epoxy-11-carboxy-16-fluoro-15-hydroxyprost-(13E)-enoate, Example 16 By the procedure of Example 3, [6S,8R,9S,11 1R, 12S, 15R, 1 GR]-methyl-6,9-epoxy- 1 carbomethoxy-l Gfluoro-l 5-hydroxyprost-(l 3E)-enoate was converted to [6S,8R,9S,11 R,12S,15R, 16R]-6,9-epoxy-11-carboxy-16-fluoro-15-hydroxyprost-(13E)-enoic acid.

Example 17 To a solution of 704 mg (1.62 mmol) of [8R, 9S, 12R, 15R, 1 GR]-methyl-l 6-trifluoro-methyl-l 6- methyl-9,15-dihydroxyprosta-(5Z,13E)-dienoate in 10 ml of methylene chloride was added 410 mg of N-iodosuccinimide. After 2 hr., the reaction mixture was diiuted with 50 ml of diethyl ether, washed with 10 mi of 2% sodium thiosulfate, and dried (MgSO4). Rotary evaporation of the volatiles yielded 922 mg of oily residuals which upon purification by silica gel chromatography yielded [5R,6R,8R, 9S, 12R,15R,16R]-methyl-5-iodo-6,9-epoxy-16-trifluoromethyl-16-methyl-15-hydroxyprost-(13E)enoate and [5S,6S,8R,9S,12R,15R,16R]-methyl-5-iodo-6,9-epoxy-16-trifluoromethyl-16-methyl 15-hydroxyprost-(13E)-enoate.

Example 18 By the procedure of Example 2, [5R, 6R, 8R, 9S, 12R, 1 5R, 1 6 R]-methyl-5-iodo-6,9-eeoxy-l 6- trifluoromethyl-16-methyl-15-hydroxyprost-(13E)-enoate was converted to [6S,8R,9S,12R,15R, 16R]-methyl-6,9-epoxy-16-trifluoromethyl-16-methyl-15-hydroxyprost-(13E)-enoate.

Example 19 By the procedure of Example 3 [6S, 8R, 9S, 12R, 15R, 1 GR]-methyl-6,9-epoxy- 16- trifluoromethyl-i 6-methyl-i 5-hydroxyprost-(i 3E)-enoate was converted to [6S, 8R, 9S, 12R, 15R, 16R]-6,9-epoxy-16-trifluoromethyl-16-methyl-15-hydroxyprost-(13E)-enoic acid.

Example 2b By the procedure of Example 23, [8R,9S,11 R, 12S, 1 5R, 1 GR]-methyl-l l-hydroxy-methyl-l 6- trifluoromethyl-9,1 5-dihydroxyprost-(5Z, 13E)-dienoate was converted to a mixture of [5R,6R,8R,9S, 11R,12S,15R,16R]-methyl-5-iodo-6,9-epoxy-11-hydroxymethyl-16-trifluoromethyl-15hydroxyprost-(13E)-enoate and[5S,6S,8R,9S,11R,12S,15R,16R]-methyl-5-iodo-6,9-epoxy-11hydroxymethyl-16-trifluoromethyl-15-hydroxyprost-(13E)-enoate.

Example 21 By the procedure of Example 2, [5R,6R,8R,9S,11R,12S,15R,16R]-methyl-5-iodo-6,9-epoxy- 11 -hydroxymethyl-1 6-trifluoromethyl-1 5-hydroxyprost-( 1 3E)-enoate was converted to [6S,8R,9S, 11R, 12S, 15R, 1 GR]-methyl-6,9-epoxy-1 l-hydroxymethyl-l 6-trifluoromethyl-l 5-hydroxyprost-(l 3E)- enoate.

Example 22 To a solution of 275 mg of [6S,8R,9S,11 R, 12S, 15R, 16R]-6,9-epoxy-11 i-methyl-i 6-fluoro- 15-hydroxyprost-(13E)-enoic acid in 20 ml of ethyl acetate was added 30 mg of platinum oxide. The mixture was sealed under a positive hydrogen atmosphere and vigorously stirred. After eight hours, the reaction mixture was filtered and the volatiles removed by rotary evaporation. The residual oily product was purified by chromatography over 50 g of Sephadex LH-20 using chloroform-hexane (65/35) to yield [6S,8R,9S,11R,12S,15R,16R]-6,9-epoxy-11-methyl-16-fluoro-15-hydroxyprostanoic acid.

Example 23 By the procedure of Example 3, [6S,8R,9S,11 R,12S,15R,16R]-methyl-6,9-epoxy-11 hydroxymethyl-16-trifluoromethyl-15-hydroxyprost-(13E)-enoate was converted to [6S,8R,9S,11 F, 12S, 15R, 16R]-6,9-epoxy-11-hydroxymethyl-16-trifluoromethyl-15-hydroxyprost-(13E)-enoic acid.

Example 24 By the procedure of Example 23, [8R, 9S, 12R, 1 5R, 1 GR]-methyl-l 6-trifluoromethyl-9-1 5- dihydroxyprost-(5Z,13E)-dienoate was converted to [5R,6R,8R,9S,12R,15R,16R]-methyl-5-iodo6,9-epoxy-16-trifluoromethyl-15-hydroxyprost-(13E)-enoate and [5S,6S,8R,9S,12R,15R,16R]methyl-5-iodo-6,9-epoxy-16-trifluoromethyl-15-hydroxyprost-(13E)-enoate, Example 25 By the procedure of Example 2, [5R, 6R, 8R, 9S, 12R, 15R, 1 GR]-methyl-5-iodo-6,9-epoxy- 16- trifluoromethyl-15-hydroxyprost-(13E)-enoate was converted to [6S, 8R, 9S, 12R, 15R, 1 GR]-methyl- 6,9-epoxy-16-trifluoromethyl-15-hydroxyprost-(13E)-enoate, Example 26 By the procedure of Example 3, [6S,8R,9S,12R,15R,16R]-methyl-6,9-epoxy-16- trifluoromethyl-1 5-hydroxyprost-(1 3E)-enoate was converted to [6S, 8R, 9S, 12R, 15R, 16R]-6,9- epoxy-i 6-trifluoromethyl- 1 5-hydroxyprost-( 1 3E)-enoic acid.

5.[6S,8R,9S,11R,12S,15R]-6,9-Epoxy-11,16,16-trimethyl-15-hydroxyporost-(13E)-enoic acid.

6.[6S,8R,9S,11R,12R,15R,16R]-Methyl-6,9-epoxy-11-carbomethoxy-16-fluoro-15hydroxyprost-(13E)-enoate,[6S,8R,9S,11R,12R,15R,16R]-6,9-epoxy-11,-carboxy-16-fluoro-15 hydroxyprost-( 1 3E)-enoic acid, [6S, 8R. 9S, 12R, 15R, 16R]-6,9-epoxy-1 6-trifluoromethyl-l 6-methyl- 15-hydroxyprost-(13E)-enoic acid, and [6S, 8R, 9S, 11R, 12S, 15R, 1 GR]-methyl-6,9-epoxy-1 1- hydroxymethyl-16-trifluoromethyl-15-hydroxyprost-(13E)-enoate, 7. Compounds of formula for use as pharmaceuticals.

8. Compounds of formula I for use as anti-secretory and anti-ulcerogenic agents 9. Compounds of formula I for use as anti-hypertensive agents.

10. A process for the preparation of compounds of the formula

wherein R is hydrogen or lower alkyl, R1 is lower alkyl, hydrogen, hydroxymethyl or

R2 is hydrogen, lower alkyl or fluoro; R' is fluoro, trifluoromethyl or lower alkyl; and the dotted bond is optionally hydrogenated, with the proviso that when F1 is hydrogen, R' is trifluoromethyl and with the further proviso that when R2 is fluoro, R2 is lower alkyl or fluoro, and salts thereof, which comprises reacting a compound of the formula

wherein Xis halogen, R' is hydrogen, lower alkyl, hydroxymethyl or lower alkoxycarbonyl, R6 is lower alkyl and R2, R2 and the provisos are as above, with a trialkyl or a triaryl tin hydride and, if desired, in either sequence hydrolysing any alkoxy carbonyl group and/or hydrogenating the olefinic double bond present in the reaction product of formula I.

11, Pharmaceutical preparations containing a compound of formula I or a salt thereof and a carrier.

12. The use of a compound of formula I as an anti-secretory, anti-ulcerogenic or antihypertensive agent.

13. Compounds of the formula

wherien F6 is lower alkyl; R' is hydrogen, lower alkyl, hydroxymethyl or

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

5.[6S,8R,9S,11R,12S,15R]-6,9-Epoxy-11,16,16-trimethyl-15-hydroxyporost-(13E)-enoic acid.

6.[6S,8R,9S,11R,12R,15R,16R]-Methyl-6,9-epoxy-11-carbomethoxy-16-fluoro-15hydroxyprost-(13E)-enoate,[6S,8R,9S,11R,12R,15R,16R]-6,9-epoxy-11,-carboxy-16-fluoro-15 hydroxyprost-( 1 3E)-enoic acid, [6S, 8R. 9S, 12R, 15R, 16R]-6,9-epoxy-1 6-trifluoromethyl-l 6-methyl- 15-hydroxyprost-(13E)-enoic acid, and [6S, 8R, 9S, 11R, 12S, 15R, 1 GR]-methyl-6,9-epoxy-1 1- hydroxymethyl-16-trifluoromethyl-15-hydroxyprost-(13E)-enoate,

7. Compounds of formula for use as pharmaceuticals.

8. Compounds of formula I for use as anti-secretory and anti-ulcerogenic agents

9. Compounds of formula I for use as anti-hypertensive agents.

10. A process for the preparation of compounds of the formula

wherein R is hydrogen or lower alkyl, R1 is lower alkyl, hydrogen, hydroxymethyl or

R2 is hydrogen, lower alkyl or fluoro; R' is fluoro, trifluoromethyl or lower alkyl; and the dotted bond is optionally hydrogenated, with the proviso that when F1 is hydrogen, R' is trifluoromethyl and with the further proviso that when R2 is fluoro, R2 is lower alkyl or fluoro, and salts thereof, which comprises reacting a compound of the formula

wherein Xis halogen, R' is hydrogen, lower alkyl, hydroxymethyl or lower alkoxycarbonyl, R6 is lower alkyl and R2, R2 and the provisos are as above, with a trialkyl or a triaryl tin hydride and, if desired, in either sequence hydrolysing any alkoxy carbonyl group and/or hydrogenating the olefinic double bond present in the reaction product of formula I.

11, Pharmaceutical preparations containing a compound of formula I or a salt thereof and a carrier.

12. The use of a compound of formula I as an anti-secretory, anti-ulcerogenic or antihypertensive agent.

13. Compounds of the formula

wherien F6 is lower alkyl; R' is hydrogen, lower alkyl, hydroxymethyl or

Example 27 A capsule was prepared containing the following ingredients: Per Tablet [6S,8R,9S,11R,12S,15R,16R]-6,9-epoxy-11-methyl-16-fluoro-15 hydroxyprost-(13E)-enoic acid 200 mg Dicalcium phosphate dihydrate, unmilled 235 mg Corn Starch 70 mg FDSC Yellow 5-Aluminum Lake 25% 2 mg Durkee Duratex* 25 mg Calcium Stearate 3 mg Total Weight 535 mg *Hydrogenated cotton seed oil (fully saturated) All of the above ingredients were mixed until thoroughly blended in a suitable size container. The powder was filled in to 2, two-piece, hard-shell gelatin capsules to an approximate fill weight of 350 mg using a capsulating machine.

Example 28 A tablet was prepared containing: Per Tablet E6S, 8R, 9S, 1R, 12S, 15R, 16R]-6,9-epoxy-11 i-methyl-i 64luoro-l 5- hydroxyprost-( 1 3E)-enoic acid 25 mg Dicalcium phosphate dihydrate, unmilled 175 mg Corn Starch 24 mg Magnesium stearate 1 mg Total weight 225 mg The active ingredient and corn starch were mixed together and passed through a 00 screen in Model "J" Fitzmill with hammers forward. This premix was then mixed with dicalcium phosphate and one-half of the magnesium stearate, passed through a 1 A screen in Model "J" Fitzmill with knives forward, and slugged. The slugs were passed through a 2A plate in a Model "D" Fitzmill at slow speed with knives forward and the remaining magnesium stearate was added. The mixture was mixed and compressed.

Claims

1. Compounds of the formula

wherein R is hydrogen or lower alkyl, R1 is lower alkyl, hydrogen, hydroxymethyl or

R2 is hydrogen, lower alkyl or fluoro; and R2' is fluoro, trifluoromethyl or lower alkyl; and the dotted bond is optionally hydrogenated, with the proviso that when R is hydrogen, R' is trifluoromethyl and with the further proviso that when R is lower alkyl or fluoro, and salts thereof.

2. The compounds of claim 1 where R' is lower alkyl.

3. [6S,8R,9S,11R,12S,15R,16R]-6,9-Epoxy-11-methyl-16-fluoro-15-hydroxyprost-(13E)enoci acid.

4. [6S, 8R, 9S, 11R, 12S, 15R]-6,9-Epoxy-11 -methyl-l 6,1 6-difluoro-l 5-hydroxyprost-(l 3E)- enoic acid.

R2 is lower alkyl, hydrogen or fluoro; R2 is fluoro, trifluoromethyl or lower alkyl; and X is halogen; with the proviso that when R' is hydrogen, R' is trifluoromethyl; and with the further proviso that when R2 is fluoro, R' is fluoro or lower alkyl.

14. The novel compounds, intermediates, compositions and processes herein described.