NZ195016A

NZ195016A - Prostacyclin derivatives,pharmaceutical compositions and intermediate compounds

Info

Publication number: NZ195016A
Application number: NZ19501680A
Authority: NZ
Inventors: G W Holland; P Rosen
Original assignee: Hoffmann La Roche
Priority date: 1980-09-22
Filing date: 1980-09-22
Publication date: 1984-09-28

Description

New Zealand Paient Spedficaiion for Paient Number 1 95016 1950 Priority Ds^s): ......

Gomp'cto C'ioc'r,CDtion Filsdr 'A°| COTCSOT, coTc,m > Afci^> p5"7!^ 1 OiibQS'. mtraaosa.nseoati. o o so...... 2 8 SEP 19.8r \0. Ji oul M B L; No.: Date: ifft s* ; '■>? r^\ si NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION PROSTACYCLINS X/We, F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss company hereby declare the invention for which we pray that a patent may be granted to pcoe^us, and the method by which it is to be performed, to be particularly described in and by the following statement:- _ 1 _ u o-"f-x> <iy t q "N ^ ff.1 - 1<\- KAN 4303/0 The present invention relates to prostacyclins. More particularly the invention relates to prostacyclins of the formula k ^ch2—(c h2)3—coo r R2' ch c h—c—(ch2)3—c h3 oh i2 wherein R is hydrogen or lower alkyl; R is hydrogen. lower alkyl, hydroxymethyl, ^ ; -C-OR R 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 R is hydro-2 ' gen, R is trifluoromethyl, and with the further 2 21 proviso that when R is fluoro, R 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 30 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 35 alkyl groups having from 1 to 7 carbon atoms, such as methyl Grn/5.8.1980 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 5 stated, comprehends fluorine, chlorine, bromine and iodine. Alkali metal includes all alkali metals such as lithium, sodium and potassium. The term "aryl" signifies mononuclear aromatic hydrocarbon groups, such as phenyl and tolyl, and polynuclear aryl groups, such as naphthyl, 10 anthryl, phenanthryl and azulyl. 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. 2 ' The compounds of formula I wherein R is fluoro or trifluoromethyl are particularly useJrul as antihypertensive and blood pressure lowering agents. 2 The compounds of formula I where R is hydrogen or 2 1 lower alkyl and R 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 rCH—CH C H-—C—(CH2)3—C H3 r2' 1-1 OH 195016 12 2 ' wherein R, R , R and R 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 reacting a compound of the formula X H ^CH <CH2)3—COOR6 O R2' IV ^CH=CH CH—C—(CHo)3—CH3 I L OH R2 1 • wherein X is halogen, R is hydrogen, lower alkyl, 6 6 2 hydroxymethyl or COOR , R is lower alkyl and R , 2 1 R 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 25 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 1 950 1 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. 5 Any conventional inert organic 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 10 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 80°C being generally preferred. The most preferred embodiment of this reaction is carrying this reaction out at reflux. If desi-15 red, 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 2,21-azobis (2-methylpropioni-trile). The presence of a free radical initiator can speed 20 up the rate of the reaction.

The conversion of an esterified carboxy group present in the so obtained compound of formula I can be effected by basic hydrolysis. Any conventional method of basic 25 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 30 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 195 0 1 HO ?CH2—CH==CH—(CH2)3—C'OOH r2* CH=CH CH—C—(CH2)3—CH3 II in ia via the intermediate III 1" wherein R is hydrogen, lower alkyl, hydroxymethyl 1' 2 21 or carboxy; and X, R , R and R aire as above.

Depending upon the particular form of the compound of formula I desired, the compound of formula II whiGh is 30 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 III by hydrohalogenation. Any conventional gg method of hydrohalogenation can be utilized in carrying out this reaction. Among the preferred methods of hydrohalo-genation is by treating the compound of formula II with a hydrohalogenating agent, such as N-halosuccinimides. 1 950 1 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 5 out this reaction, temperatures of from 0 to 35°C can be utilized. Generally it is preferred to carry out this reaction at room temperature. ..

The compound of formula III is converted to the com-10 pound 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 conven-15 tional method of esterification utilizing lower alkanols or reactive derivatives thereof can be utilized in converting the compound of formula III to the compound of formula IV. If desired, the compound of formula IV can be separated to the enantiomers formed depending on the particular 20 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 30 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 pharmaceuti-cally acceptable salts thereof. Among the preferred pharma- 1950 1 ceutically acceptable salts are the alkali metal salts, such as potassium, sodium and lithium. Another pharmaceuti-cally acceptable salt for use in accordance with this invention is the ammonium salt. In accordance with this in-5 vention, any conventional pharmaceutical^ acceptable salt can be utilized.

That the compounds of this invention are active as blood pressure lowering agents can be seen from the admini-10 stration of [6S,8R,9S,11R,12S,16R]-6,9-epoxy-ll-methyl-16-fluoro-15-hydroxyprost-(13E)-enoic acid [Compound A] by the following test: Charles River male rats weighing 170-210 grams are 15 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 20 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 150 mmHg. Systolic blood pressure is measured indirectly from the tail of unanesthetized rats (restrained in holders heated for 25 5-10 minutes at 37-38°C) 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. 30 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 [ED^q] of compound A which produced a 40 mmHg decrease in systolic blood pressure 24 35 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 1950 1 administering [6S,8R,9S,11R,12S,15R]methyl-6,9-epoxy-l1, 16 , -16-trimethyl-15-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 10 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 15 and their continuous monitoring by means of a pH microele-trode). 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 admini-20 stration. 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 25 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 (uEq/ml) and total acid output for 10 minutes (uEq/10 minutes). Results 30 showed that the acid concentrations (uEq/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 (uEq/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 1 950 1 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 5 contain the compound of formula I are conveniently admixed with a non-toxic pharmaceutical organic carrier or a nontoxic pharmaceutical inorganic carrier. Typical of pharmaceutical^ acceptable carriers are, for example, water, gelatin, lactose, starches, magnesium stearate, talc, vege-10 table oils, polylakylene glycols, petroleum jelly and other conventionally employed pharmaceutical^ 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 mono-15 laurate, 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 20 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 25 typical method for 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 intraveneously at the rate of - 0.1 microgram to 0.30 micrograms per day per 30 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 35 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. 1 S50 1 6 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. 1 950 1 Example 1 To a solution of 1.0 g of [8R,9S,11R,12S,15R,16R]-11-methyl-16-fluoro-9,15-dihydroxy-prosta(5Z),(13E)-dienoic 5 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 (MgSO^) and the solvent removed by 10 rotary evaporation at reduced pressure to give 1.2 g of a mixture of [5R,6R,8R,9S,11R,12S,15R,16R]-5-iodo-6,9-epoxy-ll-methyl-16-fluoro-15-hydroxyprost-(13E)-enoic acid and [5S,6S,8R,9S,11R,12S,15R,16R]-5-iodo-6,9-epoxy-l1-methyl-16-fluoro-15-hydroxyprost-(13E)-enoic acid. This mixture 15 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, 20 9S,11R,12S,15R,16R]-methyl-5-iodo-6,9-epoxy-ll-methyl-16-fluoro-15-hydroxyprost-(13E)-enoate, [a]^+40.55 (CHCl^, c = 1.0%) and 0.38 g of [5S,6S,8R,9S,11R,12S,15R,16R]-methyl-5-iodo-6,9-epoxy-l1-methyl-16-fluoro-l5-hydroxyprost-(13E) -enoate, [a]^+ 40. 95 (CHCl^, c = 1.0%).

Example 2 To a solution of 1.0 g of [5R,6R,8R,9S,11R,12S,15R, 16R]-methyl-5-iodo-6,9-epoxy-l1-methyl-16-fluoro-l5-30 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 50°C for three hours after which the solvent was removed and the residual materials separated by silica gel chromato-35 graphy to give 0.72 g of [6S,8R,9S,11R,12S,15R,16R]-methyl-'6,9-epoxy-l1-methyl-l6-fluoro-l5-hydroxyprost-(13E)-enoate. 1 95 G Example 3 To a solution of 0.7 g of C6S,8R,9S,11R,12S,15R,16R]- methyl-6,9-epoxy-11-methyl-16-fluoro-l5-hydroxyprost-(13E)- enoate in 30 ml of dimethoxyethane was added 25 ml of methanol and 8 ml of IN 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 (MgSO^) and the solvent removed at reduced pressure.

The residue was purified by chromatography on Sephadex LH-2 using chloroform-hexane (65/35) as the eluent, to yield. 0.6 g of [6S,8R,9S,11R,12S,15R,16R]-6,9-epoxy-11-methyl-l6- fluoro-15-hydroxyprost-(13E)-enoic acid, [alD +46.1 (CHCl^, c = 1.0%).

Example 4 By the procedure of Example 2, [5S,6S,8R,9S,11R,12S, 15R,16R]-methyl-5-iodo-6,9-epoxy-ll-methyl-16-fluoro-l5-hydroxyprost-(13E)-enoate was converted to [6R,8R,9S,11R, 12S,15R,16R]-methyl-6,9-epoxy-l1-methyl-l6-fluoro-15-hydroxyprost-(13E)-enoate.

Example 5 By the procedure of Example 3, [6R,8R,9S,11R,12S,15R, 16R]-methyl-6,9-epoxy-l1-methyl-l6-fluoro-l5-hydroxyprost-30 (13E)-enoate was converted to [6R,8R,9S,11R,12S,15R,16R]-6,9-epoxy-l1-methyl-16-fluoro-l5-hydroxprost-(13E)-enoic acid, [a]^ + 28.6 (CHCl^, c = 1.0%).

Example 6 To an ice cooled, rapidly stirred mixture of 0.45 g of [8R,9S,11R,12S,15R]-methyl-11,16,16-trimethyl-9,15-di-hydroxyprosta-(5Z),(13E)-dienoate, 5 ml of methylene chlo- 1 9 ^ 3 & V- -' ride, 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 5 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, 11R, 10 12S,15R]-methyl-5-iodo-6,9-epoxy-ll,16, 16-trimethyl-15-hydroxyprost-(13E)-enoate, ir 3610, 1733 and 974 cm \ and 0.04 g of [5S,6S,8R,9S,11R,12S,15R]-methyl-5-iodo-6,9-epoxy-11,16,16-trimethyl-15-hydroxyprost-(13E)-enoate, ir 3610, 1733 and 974 cm"\ Example 7 By the procedure of Example 2, [5R,6R,8R,9S,11R,12S, 15R]-methyl-5-iodo-6,9-epoxy-l1,16,16-trimethyl-l5-hydroxy-20 prost-(13E)-enoate was converted to [6S,8R,9S,1IR,12S,15R]-methyl-6,9-epoxy-ll,16,16-trimethyl-15-hydroxyprost-(13E) -enoate, [a]^ + 43,56 (CHCl^, c = 1.0%).

Example 8 By the procedure of Example 3, [6S,8R,9S,11R,12S, 15R ]-methyl-6,9-epoxy-l1,16,16-trimethyl-15-hydroxyprost-(13E)-enoate was converted to [6S,8R,9S,1lR,12S,15R]-6 , 9-epoxy-11,16,16-trimethyl-15-hydroxyprost-(13E)-enoic acid, 30 [a]^5+47.97 (CHC13, c = 1.0%).

Example 9 By the procedure of Example 6, [8R,9S,11R,12S,15R]-35 methyl-11-methyl-l6,16-difluoro-9,15-dihydroxyprosta-(5 Z), (13E)-dienoate was converted to a mixture of [5R,6R,8R, 9S,11R,12S,15R]-methyl-5-iodo-6,9-epoxy-l1-methyl-l6,16-difluoro-15-hydroxyprost-(13E)-enoate and [5S,6S,8R,9S, 11R,12S,15R]-methyl-5-iodo-6,9-epoxy-l1-methyl-l6,16-difluoro-15-hydroxyprost-(13E)-enoate.

Example 10 By the procedure of Example 2, [5R,6R,8R,9S,1IR,12S, 15R]-methyl-5-iodo-6,9-epoxy-l1-methyl-16,16-difluoro-15-hydroxyprost-(13E)-enoate was converted to [6S,8R,9S,1IR, 12S,15R]-methyl-6,9-epoxy-l1-methyl-l6,16-difluoro-15-10 hydroxyprost-(13E)-enoate.

Example 11 By the procedure of Example 3, [6S,8R,9S,11R,12S,15R]-15 methyl-6,9-epoxy-ll-methyl-16,16-difluoro-15-hydroxyprost-(13E)-enoate was converted to [6S,8R,9S,1IR,12S,15R]-6,9-epoxy-1l-methyl-16,16-difluoro-15-hydroxyprost-(13E)-enoic acid.

Example 12 By the procedure of Example 1 [8R,9S,1IR,12R,15R,16R]-ll-carboxy-16-fluoro-9,15-dihydroxyprosta-(5Z),(13E)-dienoic acid was converted to a mixture of [5R,6R,8R,9S,1IR,12R, 25 15R,16R]-5-iodo-6,9-epoxy-l1-carboxy-16-fluoro-15-hydroxy-pros't-( 13E)-enoic acid which was esterified and separated by chromatography as described in Example 1 to produce [5R,6R,8R,9S,11R,12R,15R,16R]-methyl-5-iodo-6,9-epoxy-l1-carbomethoxy-16-fluoro-15-hydroxyprost-(13E)-enoate and 30 [5S,6S,8R,9S,11R,12R,15R,16R]-methyl-5-iodo-6,9-epoxy-l1-carbomethoxy-16-fluoro-15-hydroxyprost-13-enoate.

Example 13 By the procedure of Example 2 [5R,6R,8R,9S,1IR,12R,- 15R,16R]-methyl-5-iodo-6,9-epoxy-ll-carbomethoxy-16-fluoro-15-hydroxyprost-(13E)-enoate was converted to [6S,8R,9S, 11R,12R,15R,16R]-methyl-6,9-epoxy-l1-carbomethoxy-16-fluoro- -hydroxyprost-(13E)-enoate.

Example 14 By the procedure of Example 3, [6S,8R,9S,1IR,12S,15R]- methyl-6,9-epoxy-l1-carbornethoxy-16-fluoro-15-hydroxyprost-(13E)-enoate was converted to [6S,8R,1IR,12S,15R]-6,9-epoxy-ll-carboxy-16-fluoro-15-hydroxyprost-(13E)-enoic acid.

Example 15 By the procedure of Example 2, [5S,6S,8R,9S,1IR,12S, 15R,16R]-methyl-5-iodo-6,9-epoxy-l1-carbornethoxy-16-fluoro-15-hydroxyprost-(13E)-enoate was converted to [6R,8R,9S, 12S,15R,16R]-methyl-6,9-epoxy-ll-carboxy-16-fluoro-15-hydroxyprost-(13E)-enoate.

Example 16 By the procedure of Example 3, [6S,8R,9S,11R,12S,15R, 16R]-methyl-6,9-epoxy-l1-carbomethoxy-16-fluoro-l5-hydroxy-prost-(13E)-enoate was converted to [6S,8R,9S,1IR,12S,15R, 16R]-6,9-epoxy-l1-carboxy-16-fluoro-l5-hydroxyprost-(13E)-enoic acid.

Example 17 To a solution "of 704 mg (1.62 mmol) of [ 8R, 9S, 12R, 15R, 16R]-methyl-16-trifluoro-methyl-16-methyl-9,15-dihydroxy- prosta-(5Z,13E)-dienoate in 10 ml of methylene chloride was added 410 mg of N-iodosuccinimide. After 2 hr., the reaction mixture was diluted with 50 ml of diethyl ether, washed with 10 ml of 2% sodium thiosulfate, and dried (MgS04). 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- fs; C-\ <zj) ^ a 6,9-epoxy-16-trifluoromethyl-16-methyl-15-hydroxyprost-(13E)-enoate.

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

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

Example 20 By the procedure of Example 23, [8R,9S,1IR,12S,15R, 16R]-methyl-ll-hydroxy-methyl-16-trifluoromethyl-9,15-dihydroxyprost-(5Z,13E)-dienoate was converted to a mixture 25 of [5R,6R,8R,9S,1IR,12S,15R,16R]-methyl-5-iodo-6,9-epoxy-ll -hydroxymethyl-16-trifluoromethyl-15-hydroxyprost-(13E)-enoate and [5S,6S,8R,9S,1IR,12S,15R,16R]-methyl-5-iodo-6,9-epoxy-ll-hydroxymethyl-16-trifluoromethyl-15-hydroxy-prost-(13E)-enoate.

Example 21 By the procedure of Example 2, [5R,6R,8R,9S,1IR,12S , 15R,16R]-methyl-5-iodo-6,9-epoxy-ll-hydroxymethyl-16-tri-35 fluoromethyl-15-hydroxyprost-C13E)-enoate was converted to [6S,8R,9S,11R,12S,15R,16R]-methyl-6,9-epoxy-l1-hydroxy-methyl-16-trifluoromethyl-15-hydroxyprost-(13E)-enoate. 1953 Example 22 To a solution of 275 mg of [6S,8R,9S,1IR,12S,15R,16R] 6,9-epoxy-l1-methyl-16-fluoro-15-hydroxyprost-(13E)-enoic 5 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 10 by chromatography over 50 g of Sephadex LH-20 using chloro form-hexane (65/35) to yield C6S,8R,9S,1IR,12S,15R,16R]-6,9-epoxy-ll-methyl-16-fluoro-15-hydroxyprostanoic acid.

Example 23 By the procedure of Example 3, [6S,8R,9S,1IR,12S,15R, 16R]-methyl-6,9-epoxy-ll-hydroxymethyl-16-trifluoromethyl-15-hydroxyprost-(13E)-enoate was converted to [6S,8R,9S, 11R,12S,15R,16R]-6,9-epoxy-l1-hydroxymethyl-16-trifluoro-20 methyl-15-hydroxyprost-(13E)-enoic acid.

Example 24 By the procedure of Example 23, [8R,9S,12R,15R,16R]-25 methyl-16-trifluoromethyl-9,15-dihydroxyprost-(5Z,13E)- dienoate was converted to [5R,6R,8R,9S,12R,15R,16R]-methyl 5-iodo-6,9-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, 16R]-methyl-5-iodo-6,9-epoxy-l6-trifluoromethyl-15-hydroxy 35 prost-(13E)-enoate was converted to [6S,8R,9S,12R,15R,16R] methyl-6,9-epoxy-l6-trifluoromethyl-15-hydroxyprost-(13E)-enoate. 1 95© 1 Example 26 By the procedure of Example 3, [6S,8R,9S,12R,15R,16R]-methyl-6,9-epox'y-16-trifluoromethyl-15-hydroxyprost-(13E) -5 enoate was converted to [6S,8R,9S,12R,15R,16R]-6,9-epoxy-16-trifluoromethyl-15-hydroxyprost-(13E)-enoic acid.

Example 2 7 A capsule was prepared containing the following ingredients: Per Tablet [6S,8R,9S,1 IR,12S,15R,16R]-6,9-epoxy-l1-15 methyl-16-fluoro-l5-hydroxyprost-(13E)- enoic acid 200 mg Dicalcium phosphate dihydrate, unmilled 235 mg Corn Starch 70 mg FD&C 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 30 to an approximate fill weight of 350 mg using a capsulating machine.

Claims

- 19 - 1 0. r ^ Example 28 A tablet was prepared containing: 5 Per Tablet [6S,8R,9S, 11R,. 12S, 15R, 16R]-6,9-epoxy-l1-methyl-16-fluoro-15-hydroxyprost-(13E)-enoic acid Dicalcium phosphate dihydrate, unmilled 25 mg 175 mg 24 mg 1 m9 2 25 mg The active ingredient and corn starch were mixed 15 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 1A screen in Model "J" Fitzmill with knives forward, and slugged. The slugs were passed 20 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. 25 30 35 - 20 - -g-laiitm"" what'jfwe claim is:

1. Compounds of the formula 1 15 wherein R is hydrogen or lower alkyl, R is lower alkyl, hydrogen, hydroxymethyl or jj ; R^ is -C-OR 2 1 hydrogen, lower alkyl or fluoro; and R is fluoro, trifluoromethyl or lower alkyl; and the dotted bond 20 is optionally hydrogenated, with the proviso that 1 21 when R is hydrogen, R is trifluoromethyl and with 2 21 the further proviso that when R is fluoro, R is lower alkyl or fluoro, and salts thereof. 25

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-l5-hydroxyprost-(13E)-enoic acid.;30;

4. [6S,8R,9S,1IR,12S,15R ]-6 , 9-Epoxy-11-methyl-16,16-difluoro-l5-hydroxyprost-(13E)-enoic acid.;

6. [6S,8R,9S,11R,12R,15R,16R]-Methyl-6, 9-epoxy-l1-carbomethoxy-16-fluoro-15-hydroxyprost-(13E)-enoate, [6S,8R,9S,llRf12R,15R,16R]-6,9-epoxy-11-carboxy-16-fluoro-15-hydroxyprost-(13E)-enoic acid, [6S,8R,9S,12R,15R,16R]-5 6,9-epoxy-l6-trifluoromethyl-16-methyl-15-hydroxyprost-(13E)-enoic acid, and [6S,8R,9S,1IR,12S,15R,16R]-methyl-6,9-epoxy-l1-hydroxymethyl-16-trifluoromethyl-15-hydroxypr ost-(13E)-enoate.;10;15;20;25;30;35;I <?<7=»{o5;i 5'50;" - 22 -;

7. Compounds of formula I in a form suitable for use as pharmaceuticals.;

8. Compounds of formula I in a form suitable for use as anti-secretory and anti-ulcerogenic agents.;

9. Compounds of formula I in a form suitable for use as anti-hypertensive agents.;/;- 23 -;1 Q K H: 1;■ ^ '--V 3;

10. A process for the preparation of compounds of the formula h2—(c h 2) 3—coo r;R2';10 x/ ch^^ch ch—c—(ch2)3—ch3;I J.2;oh r2;wherein R is hydrogen or lower alkyl, R^" is lower;15 alkyl, hydrogen, hydroxymethyl or ; R^ is hydro-;-C-OR;2 1;gen, lower alkyl or fluoro; R is fluoro, tri-;fluoromethyl or lower alkyl; and the dotted bond is optionally hydrogenated, with the proviso that;1 2 1;20 when R is hydrogen, R is trifluoromethyl and with;2 2 ';the further proviso that when R is fluoro, R is lower alkyl or fluoro,;and salts thereof, which comprises reacting a compound of the formula;25;x h ^-ch- (ch2)3— coor6;Q';30;R2';iv rch=ch—c h—c—(ch2)3—c h3;oh 1';35 wherein X is halogen, R is hydrogen, lower alkyl,;hydroxymethyl or lower alkoxycarbonyl, R^ is lower 2 2 1;alkyl and R , R and the provisos are as above,;195016;- 24 -;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 as defined in claim 1 or a salt thereof and a carrier.;

12. A process for the preparation of a compound of formula I as defined in claim 1 or a salt thereof,;substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 26.;

13. Compounds of formula I and salts thereof,;whenever prepared by the process of claim 10 or claim 12.;i;

14. Compounds of the formula;1;X;6 1 1;wherein R is lower alkyl; R is hydrogen, lower alkyl,;hydroxymethyl or ^ g; R^ is lower alkyl,• hydrogen;-C-OR;2 ';or fluoro; R is fluoro, trifluoromethyl or lower alkyl; and X is halogen; with the proviso that when;1> 2 ';R is hydrogen, R is trifluoromethyl; and with the;2 2';further proviso that when R is fluoro, R is fluoro or lower alkyl.;1950;- 25 -;

15. A pharmaceutical preparation containing a compound of formula I as defined in claim 1 or a salt thereof and a carrier, substantially as hereinbefore described with particular reference to either of the foregoing Examples 27 and 28.;£ated this : ^ day of u ^ i* A. J. PARK & SON feu ' agents for the applicants ■ ^ Jlift