IE50969B1 - Benzo-fused carbacyclin analogues - Google Patents

Description

Price 90p - 2 BENZO-FUSED CARBACYCLIN ANALOGUES Thi; invention relates to benzo-fused carbacyclin analogues. Prostacyclin (PGI2) is an endogenouslyproduced compound in mammalian species, being struetur illy and biosynthetically related to the prostaglandins (PG's), and carbacyclin is 6a-carba-PGI2, and oft;r referred to simply as CBA^.

A stable, partially saturated, derivative of PGI2 is PGXj or 5,6-dihydro-PGI2. 5,6-Dihydro-CBA2 is CBA^.

Prostacyclin and carbacyclin may be trivially named as derivatives of PGF-type compounds, e.g. PGF2· Accordingly, prostacyclin is trivially named 9->-deoxy6,9a-epoxy-(5Z)-5,6-didehydro-PGF^ and carbacyclin is named 9-deoxy-6,9'i-methano- (5E) -5,6-didehydro-PGF^ . For description of prostacyclin and its structural identification, see Johnson et al, Prostaglandins 12:915 (1976) .

Novel compounds according to the invention are those of formulae A, B and C: wherein either and R^ are independently selected from hydroqen, methyl and fluorine, provided that CR^R^ is not CFMe, and R? is C2_g alkyl, cis-CH=Ch-Cu.,-CH3, -(Cll2) .-CHOH-CH?, - (cup 3-CH=C (CH3) 2 or optionally ring-substituted phenoxy, phenyl, benzyl, phenylethyl or phenvlpropyl ir. which there are no more than 3 ring substituents (no more than 2 of which are alkyl) independently selected from chlorine, fluorine, tri fluoromethyl, C3_3 alkyl and C3_3 alkoxy, provided that neither r<3 nor is fluorine when R? is optionally substituted phenoxy; or CR31<4-R^ is 2-(2-furyl)ethyl, 2-(3-thienyl) ethoxy, 3-thienyloxymethyl, or cycloalkyl optionally carrying up to three alkyl substituents; is α-OH: B-R5 or B-Rg:a-OH and Rg is hydrogen or methyl; 50868 R20 is H, α-OH, β-OH or =0; R8 is H, OH or CH2OH;Y1 i s trans- -CH=CH-, cis-CH=CH-, -CH2CH2 or -CSC-;Z4 and is -CH2- or -(CH2)g-CF2- and f is zero, one, 2X1 is COORj , CH,OH, CH7NL7L7 or COL. ; 4 in whi ch Rx is hydrogen, a pharmaceutically acceptable cation, J2 alkyl, cycloalkyl ' C7-12 aralkyl, phenyl optionally substituted up to 3 times by chlorine atoms or Cj_4 alkyl radicals, or phenyl substituted in the para-position by -NHCOR^g, -COR2g, benzoyloxy, acetamidobenzoyloxy or -CH=N~NH-CONH2 in which R2g is methyl, phenyl, aeetainidophenyl, benzamidophenyl or -NH2 and R2g is rethyl, methoxy, phenyl or -NH2; L2 and Lg are independently selected from hydrogen and Cj_4 alkyl; and i-4 is -nr27r28, -nr29copi,9, -nr29so2r^7 or cycloamino selected from pyrrolidine·, piperidino, morpholino, piperazino, hexamethylene imino, pyrrolino and 3,4-didehydropiperidinyl optionally substituted by one or 2 i2 alkyl radicals, in which R^.. is hydrogen, C^j,, alkyl, cycloalkyl, C.^., aralkyl, phenyl optionally substituted by up to 3 substituents selected from chlorine, alkyl, hydroxy, carboxy, (Cj_4 alkoxy)carbonyl and nitro, carboxy (C1_4 alkyl), carbamoyl(0^_4 alkyl), cyano(Cx_4 alkyl), acetyl (C1_j} alkyl), benzo (C1_j} alkyl) optionally substituted by up to 3 substituents selected from chlorine, alkyl, hydroxy, C^_2 alkoxy, carboxy, lcj_4 alkoxy)carbonyl and nitro, pyridyl optionally substituted by up to 1 substituents selected from chlorine, C^_3 alkyl and alkoxy, pyridyl (Cj_4 alkyl) optionally substituted by uj. to 3 substituents selected from chlorine, alkyl and hydroxy, or mono-, di- or tri-hydroxy(Cj_4 alkyl), R2_ is R27 other than hydrogen, R2g is hydrogen or Cg_32 alkyl, and R2g is hydrogen or Cj_,j alkyl; and pharmacologically acceptable acid addition salts thereof when X^ is CH2NL2Lg.

The nomenclature used for the prostacyclin and carbacyclin analogues described herein is the same as in GB-A-207059fi. Reference should also be made to that specification for a description of examples of the various groups in the compounds of the invention, and also for a description of blocking group introduction and removal.

Tin- novel compounds may be of utility in the study, prevention, control and treatment of disease and other undesirable physiological conditions, in mammals, 1t particularly humans, valuable domestic animals, pets, zoological specimens and laboratory animals such as mice, rats, rabbits and monkeys. In particular, the novel compounds can have utility as anti-thrombotic, anti-ulcer and anti-asthma agents, with effects more particularly described in GB-A-2070596.

The preparation of compounds ol the invention will be described with reference to the accompanying Charts, in which Ri ls the same as R^ but ar.y OH group is blocked is ORpj, R.g being a blocking group, R^g is H, -OH, -C112OH, -ORXq or -CH2ORi0, R^ is a silyl protective group, RH.}} is a hydroxy-hydrogen piotective group, Mg is j-OR10:b-R5 or a-R5:B-OR1Q, and (1) R2Q, Rgl' R22' R23 and R^ are each hydrogen (Rgo being in a or 8-configuration) , (2) R-,θ is hydrogen, R2j anc R22 together form a second valence bond, and R23 and R2j) tire either both hydrogen m together form a second Vilence bond, and (3) U22' R23 a,lfl P‘24 ar’ hydrogen ll'22 boinq in « or βconfiguration) and either R2g and R2] together are oxo or R20 is hydrogen and R23 is α-hydroxy or β-hydroxy.

With respect to Chart A, the formula CLXXVI compound (see GB-B-2122203) is transformed to the formula CLXXVII compound by ω-carboxyalkylation. Methods known in the art are employed, e.g. methods for preparing 3,7-interphenylene-PGFo compounds and corresponding phenolic intermediates. For example, the preparation of the formula CI.XXVII compound proceeds by reaction of the formula CLXXVI compound with sodium hydride and the alkyl bromoalkanoate corresponding to the -Z^-COOR^ group to be introduced into the molecule. Thereafter, the formula CI,XXVIII compound is prepared by deprotection, i.e. hydrolysis under mild acidic conditions of the protective groups, followed by transformation to various other C-l derivatives by methods described in GB-A-2070596, Chart li provide·· a method whereby novel compounds wherein at least one of R20' R21' R23 an<3 R24 nOt hydrogen tire prepared. In accordance with Chart B, the formula CLXXI1I compound (see GB-B-2122203) is oxidised to the corresponding formula CLXXII aldehyde by methods known ir the art, for example using Collins reagent.

When conversion of one C-9 stereoisomer of formula CLXXXII: to the other is required, refer tw tne procedure in Chart C.

There.ifter the formula CLXXXII aldehyde is hydrolysed to the corresponding formula CLXXIII phenol derivative by methods described above for the preparation of the formula CLXXV compound from the formula CLXXIV compound of GH-B-2122203.

Thereafter, cyclisation of the formula CLXXXIII to the corresponding formula CI.XXXIV compound is accomplished by heating, at reflux, in an organic solvent, the phenoxide anion of the formula CLXXXIII compound; see, for reference, Casiraghi et al, J.C.S. Perkin I (1979) 2027. The C-9 isomers of the formula CLXXXIV compound are conveniently separated by conventional techniques, e.g. column chromatography. Thereafter, the formula CLXXXIV compound is transformed to the formula CLXXXV compounds by methods described in Chart A for the preparation of the formula CLXXVII compound from the formula CLXXVI compound. This alcohol is then oxidised to the corresponding formula CLXXXVI ketone (e.g. by methods described above for the preparation of the formula CLXXXII compound from the formula CLXXXI compound) or dehydrated to yield the formula CLXXXVIII compound. Such dehydrations proceed by methods known in the art and include preparing the mesylate corresponding to the formula CLXXXV compound and subsequent treatment with base.

Thereafter, the formula CLXXXVI or CLXXXVIII compound is transformed, respectively, to the formula CLXXXVII or CLXXIX compound by methods hereinafter described.

Finally, the formula CLXXXIX compound thus prepared is dehydrogenated to yield the formula CXG compound by conventional means, e.g. catalytic dehydrogenation (palladium-on-carbor catalyst) or treatment with DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone).

Chart C provides a method wherebv the C-9 epimeric forms of compounds prepared according to Chart A are prepared. With respect to Chart C, the formula CXCI aldehyde, prepared as the formula CLXXXII compound of Chart B,is isomerised by treatment under basic conditions, i.e. the use of an organic base such as 1,8-diazobicyclo[5.4.0]undec-7-ene in an organic solvent, e.g. methylene chloride. Thereafter this 92-aldehyde is reduced to the corresponding formula CXCIII alcohol by treatment with a suitable reducing agent such as a borohydride reducing agent, e.g. sodium, lithium or potassium borohydride. Thereafter, the formula CXCIII 50960 alcohol thus prepared is transformed to the corresponding 9B-CBA analogue by methods described for the transformation of the formula CLXXIII to the formula CLXXVIII compound in GB-B-2122203 and Chart A, above.

Optionally, the various CBA analogues prepared according to Charts A, B and C are prepared by the procedure of Chart D. The procedure of Chart. D employs the formula CC1 starting material which is converted to the formula CCII compound prepared in accordance with methods described for the preparation of the formula CLXXVITT compound from the formula CLXXI compound of GB-B-2122203 and Chart A, the formulae CLXXXVI1, CLXXXXX and CXC compounds from the formula CLXXXI compound of Chart B and the formula CXCIV compound from the formula CXC1 compound of Chart C. The formula CCTI compound thus prepared is then transformed to the formula CCIII compounds by methods described, e.g. for the transformation of the formula LXXI compound to the formula LXXTXJ compound oi GB-A-2070596.

Chart E provides a preferred method whereby the 9-denyo-2',9-methano-3-oxa-4,5,6-trinor-3,7-(1,3-interphenylene) -PGE, compounds of formula CCXII1 are prepared. In accordance with Chart E, he formula CCXX compound, prepared as the formula CLXXXIII compound of Chart B, is treated with a methyl Grignard reagent such as methyl magnesium bromide, and heated at reilux in an organic solvent, e.g. glyme.

The formula CCXII compound thus prepared is then transformed to the formula CCXXII product by the method JO described in Chart A for the preparation of the formula CLXXVIII product from the formula CLXXV1 phenol intermediate .

Chart F provides a convenient method whereby compounds of the invention wherein Yj is _trans-CH=CH-, the formula CCXXI compound of Chart U, are transformed to corresponding formula CCXXII aldehyde intermediates.

This transformation is accomplished by ozonolysis, by methods otherwise known in the art.

The formula CCXXII intermediate is then conveniently 5 transformed to the formula CCXXIII compound of Chart F by methods described above, i.e. reaction of the formula CCXXII compound with the appropriate Wittig reagent, followed by reduction and hydrolysis. Accordingly, by the procedure described in Chart F, the C-12 side chains of the various formula CCXXI compounds are conveniently modified by the formula CCXXII aldehyde intermediates.

As discussed in GB-A-2070596, the processes herein described lead variously to carboxylic acids (X^ is -COOH) or to esters or primary alcohols (X^ is -CI^OH), and these can be transformed as desired.

The following Examples illustrate how compounds of the invention may be prepared.

Example 1 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7(1',3’-inter-phenylene)-PGFla and its methyl ester Refer to Chart A.

A. A degassed solution of 0.47 g of 9-deoxy-2‘,9amethano-3-oxa-1,2,4,5,6-pentanor-3,7-(1',3'-interphenylene) -PGFj, 11,15-bis(tetrahydropyranyl ether), the product of Example 1 of GB-B-2122203, in dry glyme (15 ml) is cooled to 0°C and treated under nitrogen with methyl bromoacetate (0.26 ml) followed by 57% sodium hydride suspension (0.136 g). 0 9 68 Following vigorous effervescence, a white precipitate is formed. The resulting suspension is stirred for 2.5 hr at 0-5°C, diluted with icecold brine (200 ml) and extracted with ethyl acetate (450 ml). The ethyl acetate extracts are washed with brine (300 ml), dried over magnesium sulfate, filtered and concentrated to a pale yellow oil (0.62 g), formula CLXXVII compound, 9-deoxy-2',9α-π^ethano-3-oxa-4,5,6trinor-3,7-(l'.S'-interphenyleneJ’-PGFj, methyl ester, ll,15-bis(tetrahydropyranyl ether). Infrared absorptions are observed at 1765 and 1740 cm”1.

B. A solution of 9-deoxy-2‘,9a-methano-3-oxa-4,5,6-trinor-3,7(Γ ,3'-inter-phenylene)-PGFη methyl ester, ll,15-bis(tetrahydropyranyl ether) (0.62 g), reaction product of Part A, in acetic acid (15 ml), water (7.5 ml) and tetrahydrofuran (5 ml) is reacted at 45°C under nitrogen for 2.75 hr, cooled and diluted with ice cold brine (200 ml). The resulting suspension is extracted with ethyl acetate (400 ml), and the organic extracts washed with brine (400 ml), saturated aqueous sodium bicarbonate (600 ml) and brine (200 ml). The ethyl acetate extracts are then dried over magnesium sulfate, filtered and concentrated to give 0.44 g of pale yellow oil.

This crude product is chromatographed on silica gel (60 g) in 50% ethyl acetate in Skellysolve B to yield 0.37 g of product which was crystallized to yield 0.216 g of title product, 9-deoxy-2‘,9a-methano3-oxa-4,5,6-tri nor-3,7-(1',3'-i nter-phenylene)-PGF 3, methyl ester. Melting range is 82-84°C. NMR absorptions are observed at 3.77, 4.62, 5.42-5.63, and 6.53-7.256. Infrared absorptions are observed at 3520, 3400, and 1735 cm1· Silica gel TLC Rf is 0.30 in 35% acetone in methylene chloride.

C· A solution of 9-deoxy-2'-9a-methano-3-oxa-4,5,6-trinor-3,7(1',3'-inter-phenylene)-PGFj, methyl ester (0.15 g), reaction product of Part G, in 51 potassium hydroxide in 9:1 methanol-water (5.5 ml) is stirred at 0°C under nitrogen. The solution is turbid initially and a precipitate forms within 5 min. The reaction is then stirred for one hr at 0°C, diluted with ice cold brine (90 ml), acidified with 1 N hydrochloric acid, and extracted with ethyl acetate (180 ml). The ethyl acetate extract is then washed with brine (270 ml), dried over magnesium sulfate, and concentrated under reduced pressure to yield a waxy, semi-solid (0.131 g), which is crystallized to yield 0.105 g of title product, 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(l’,3'30969 - 10 inter-phenylene)-PGF|. Melting range is 131-133°C. NMR absorptions are observed at 4.68, 5.48-5.72 and 6.68-7.226. Infrared absorptions are observed at 3460, 3280, 1735, 1720 and 1700 cm1.

Example 2 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7 (1 *,3'-inter-phenylene)-16,16-difluoro-PGF^ and its methyl ester Refer to Chart A.

A. Following the procedure of Example 1, Part A, 0.80 g of 9-deoxy-2',9a-methano-3-oxa-l,2,4,5,6-pentanor 3,7-(11,3'-inter-phenylene)-16,16-difluoro-PGF^, 11,15-bis(tetrahydropyranyl ether), the reaction product of Example 2 of GB-B-2122203, is converted to 1.06 g of formula CLXXVII product as a colourless oil, 9-deoxy15 21,9a-methano-3-oxa-4,5,6-trinor-3,7-(11,3'-interphenylene) -16 , 16-difluoro-PGF^ , methyl ester, 11,15bis (tetrahydropyranyl ether). Silica gel TLC R^ is 0,44 in 5% acetone and methylene chloride. - 11 B. Following the procedure of Example 1, Part A, 1.0 g of the reaction product of Part A of this example is converted to 0.62 g of crystalline methyl ester title product, a Formula CLXXVIII white solid. Recrystallization from hexane in diethyl ether yields a 5 material with melting range 93-95°C. NMR absorptions are observed at 0.95, 1.10-2.90, 2.90-4.8, 5.4-5.8 and 6.4-7.3. Infrared absorptions are observed at 3560, 3400, 1765,, 1750, 1735, 1720, 1675, 1605, 1585, 1270, 1215, 1205, 1120, 1105, 1080, 1010, 970, and 770 cm'i. The mass spectrum for the bis-trimethylsilyl derivative exhibits a high resolulotion peak at 582.2997. Silica gel TLC R^ is 0.35 in hexane and ethyl acetate (1:4).

Following the procedure of Example 1, Part B, the reaction product of Part B of this example (0.25 g) is converted to the carboxylic acid title product (158 mg) as a crystalline solid. ISMelting range is 128-130°C. NMR absorptions (C0CD3) are observed at 0.9, 1.3-3.0, 3.0-4.6, 4.68, 4.8-5.5, 6.5-6.9, 5.5-5.9, and 6.6-7.35. Infrared absorptions are observed at 3570, 3480, 3370, 3220, 2800, 1740j 1720, 1605, 1585, 1235, 1210, 1125, 1105, 1080, 1000, and 970 cm1. The mass spectrum for the tris-trimethylsilyl derivative exhi20bits a high resolution peak at 640.3232. Silica gel TLC Rf is 0.18 in the A-IX solvent system.

Following the procedure of Examples 1 and 2, there are prepared each of the various formula CLXXVIII products in free acid or ester form from corresponding formula CLXXI reactants.

Formula CLXXVIII compounds wherein Yj is unsaturated (trans- or cis-CH=CH-) are transformed to corresponding formula CLXXVIII compounds wherein Y is saturated (-CH2CH2-) by hydrogenation, as exemplified below: Example 3 9-Deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(l1,3'30 inter-phenylene)-13,14-dihydro-PGFi and its methyl ester A. A solution of the methyl ester title product of Example 1 (0.341 g) in ethyl acetate (35 ml) is treated at ambient temperature with 5% palladium-on-charcoal and hydrogenated at atmospheric pressure. The resulting suspension is then stirred for 70 minutes with a - 12 hydrogen uptake of 20 ml (atmospheric pressure). The resulting suspension is then filtered through diatomaceous earth and the filter cake washed with ethyl acetate. The combined filtrate is then concentrated under reduced pressure to yield a colorless oil which is chromatographed on silica gel eluting with ethyl acetate in Skellysolve B to yield 0.306 g of title product (methyl ester), a colorless oil. NMR absorptions (CDC13) are observed at 0.9, 0. 1.07-1.23, 3.3-4.03, 3.77, 4.62, 6.52 and 7.275. Infrared absorptions are observed at 3350, 2930, 2855, 1760, 1740, 1605, 1585, 1467, 1435, 101275, 1205, 1120, 1080, 1Q25 ' and 775 cm'1. Silica gel TLC Rf is 0.54 in ethyl acetate.

B. Following the procedure of Example 1, Part c, the title product of Part A of this example (0.177 g) is converted to 0.23 g of title product (free acid) as a solid. Recrystallization from ethyl 15acetate in hexane yields 0.096 g with melting range 121-123°C. The mass spectrum for the tris-trimethylsilyl derivatives exhibits a high resolution peak at 606.3553 and other peaks at 591-535, 516, 427, 426, 275, 274, 173, and 157. Silica gel TLC Rf is 0.27 in A-IX.

Example 4 9-Deoxy-21,9g-methano-3-oxa-4,5,6-trinor-3,7-(l' ,3‘2d inter-phenylene)-PGFj Refer to Charts A and B.

A. A solution of 0.82 g of the reaction product of Part B of Exanple 1 of GB-B-2122203 in 16 ml of methylene chloride is stirred at ambient temperatures under nitrogen atmosphere and treated with diatomaceous earth followed by 26 ml of Collins reagent prepared from 2.5 ml of pyridine and 1.55 g of chromium trioxide in 50 ml of methylene chloride. The resulting suspension is then stirred for 35 min at ambient tenperature under a nitrogen atmosphere and filtered through 30 g of silica gel, eluting with 150 ml of ethyl acetate. Concentration under reduced pressure yields 0.90 g of a pale yellow oil. Chromatographing on 85 g of silica gel eluting with 20% ethyl acetate in Skellysolve B yields 0.644 g of pure formula CLXXXII aldehyde as a colourless oil, 9-deoxo-9ct-formyl-3oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGE^, 3-(t50969 - 13 butyl dimethylsilyl ether), Il,l5-b1s(tetrahydropyranyl ether). NMR absorptions are observed at 0.18, 0.88, 0.98, 1.13-3.08, 3.23-4.35, 4.73, 5.25-5.75, 6.57-7.37, and 9.886. Infrared absorptions are observed at 2730, 1720, 1600, 1585, 1485, 1275, 1260, 1075, 1035, 1030, 1020, 975, and 840 cm*1. Silica gel TLC Rf is 0.47 in ethyl acetate and hexane (1:3).

B. A degassed solution of 1,5 g of the reaction product of Part A and 0.36 ml of l,8-diazobicyclo[5.4.0]undec-7-ene in 150 ml of methylene chloride is stirred for 40 hr at ambient temperature under a nitrogen atmosphere, washed with 100 ml of ice cold 0.15 M aqueous potassium bisulfate, 100 ml of saturated aqueous sodium carbonate, and 100 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 1.5 g of formula CXCII product as a yellow oil, 9-deoxy-9e-formyl-3-oxa-l,2,4,5,6-pentanor-3,7-interphenylene-PGFj, 3-(t-buty1dimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether). NMR absorptions (CDC13) are observed at 0.18, 0.89, 0.98, 1.1-3.2, 3.2-4.4, 4.68, 5.2-5.8, 6.58-7.4, and 9.226. Infrared absorptions are observed at 1725, 1600, 1585, 1485, 1440, 1275, 1260, 1200, 1160, 1130, 1075, 1035, 1020, 975, 870, and 840 cm*1. Silica gel TLC Rf is 0.24 in ethyl acetate and hexane (1:3).

C. A solution of 1.5 g of the reaction product of Part B in 40 ml of methanol is treated with stirring at 20°C under a nitrogen atmosphere over several minutes with 400 mg of sodium borohydride, stirred for 20 min at 20°C. The resulting mixture is then added to a cold solution of 200 ml of brine and 32 ml of 0.1 M aqueous potassium sulfate, extracted with 600 ml of ethyl acetate, washed with 200 ml of saturated aqueous sodium bicarbonate in 200 ml of brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and chromatographed on 200 g of silica gel eluting with 35% ethyl acetate in hexane to yield 1.37 g of formula CLCIII product as a colorless oil, 9-deoxy-9B-hydroxymethyl-3-oxa-l,2,4,5,6-pentanor-3,7inter-m-phenylene-PGFj, 3-(t-butyldimethy1silyl ether), ll,15-(tetrahydropyranyl ether). NMR absorptions (CDCl3) are observed at 0.17, 0.88, 0.99, 1.1-3.0, 3.0-4.35, 4.7, 5.25-5.85, and 6.5-7.46. Infrared absorptions are observed at 3460, 1665, 1605, 1685, 1490, 1275, 1260, 1200, 1160, 1135, 1115, 1075, 1120, 1005, 975, 840, and 780 cm*1. Silica gel TLC Rf is 0.20 in 35% ethyl acetate 1n hexane.

D. A degassed solution of 1.32 g of the reaction product of Part .. .5 0 9 69 - 14 B in 0.47 ml of triethyl amine and 30 ml of methylene chloride at 20°C under a nitrogen atmosphere is treated with 0.5 ml of methanesulfonyl chloride, stirred for 5 min at 0°C, warmed to 20°C over 90 min, added to 50 g of ice, diluted with 150 ml of brine, extracted with 450 ml of diethyl ether, washed with 150 ml of brine and 300 ml of saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to yield an oil, and filtered through 70 g of silica gel eluting with 30% ethyl acetate in hexane to yield 1.47 g of mesylate corresponding to the starting material, i.e., the 96 analog of formula CLXXIV. Silica gel TLC Rf is 0.23 in 30% ethyl acetate in hexane.

E. A degassed solution of 1.47 g of the reaction product of Part D and 50 ml of dry tetrahydrofuran at 0°C under a nitrogen atmosphere is treated with 3.9 ml of 0.45 M tetra-n-butyl ammonium fluoride. The resulting solution is then stirred at 0°C for 4 hr, treated with another 0.5 ml of tetra-n-butylammonium fluoride, stirred for 30 min at 0°C, diluted with 150 ml of brine, extracted with 450 ml of ethyl acetate, washed successively with 150 ml of 0.5 M aqueous ammonium chloride, 300 ml of saturated aqueous sodium bicarbonate, and 150 ml of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 1.3 g of a yellow oil, the phenol corresponding to the starting material, i.e., the 9β isomer of the formula CLXXV compound. Silica gel TLC Rf is 0.11 in 35% ethyl acetate in hexane.

F. A degassed solution of 1.3 g of the reaction product of Part E in 75 ml of dry glyme at -40°C under a nitrogen atmosphere is treated with 90 mg of 57% sodium hydride dispersion in mineral oil, stirred at -40 to -30°C for 40 min, stirred at 0°C for 15 min, stirred at ambient temperature for 15 min, heated and refluxed for 5 hr, cooled to ambient temperature, added to 200 ml of ice cold glyme, extracted with 450 ml of ethyl acetate, washed with 300 ml of brine, dried over anhydrous on 175 g of silica gel eluting with 25% ethyl acetate in hexane to yield 0.61 g of the 9β isomer corresponding to the formula CLXXVI compound as a viscous oil. NMR absorptions are observed at 0.90, 1.07-3.1, 3.1-4.4, 4.75, 5.33-6.16, and 6.5-7.26.

Infrared absorptions are observed at 3340, 1665, 1610, 1585, 1500, 1465, 1135, 1110, 1075, 1020, and 980 cm‘i. Silica gel TLC Rf is 0.26 in 25% ethyl acetate in hexane and 0.23 in 5% acetone in methylene - 15 chloride.

G. A solution of 0.50 g of the reaction product of Part F in 28 ml of methyl bromoacetate in 16 ml of dry glyme at O’C under an argon atmosphere is treated with 0.14 g of a 57% mineral oil dispersion of sodium hydride. The resulting suspension is then stirred for 2.5 hr at 0eC, quenched with 200 ml of cold brine, extracted with 460 ml of ethyl acetate, washed with 300 ml of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 0.68 g of an oil, the 9b isomer corresponding to the formula CLXXVII compound.

H. A solution of the reaction product of Part G (0.68 g) in 5 ml of tetrahydrofuran, 7.5 ml of water, and 15 ml of acetic acid is heated for 2.5 hr at 45°C, cooled, diluted with 200 ml of brine, extracted with 400 ml of ethyl acetate, washed with 400 ml of brine, washed with 200 ml of saturated aqueous sodium bicarbonate, and 200 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to yield an oil, chromatographed on 75 g of silica gel eluting with 30% hexane in ethyl acetate to 100% ethyl acetate to yield 0.32 g of title methyl ester as a white foam. Crystallization from hot diethyl ether in hexane yields 0.23 g of pure ester product as a white solid. Melting range is 85-87’C. NMR absorptions (CDCl3) are observed at 0.90, 1.07-2.9, 2.9-4.5, 4.61, 5.4-5.8. and 6.387.346. Infrared absorptions are observed at 3520, 3420, 1735, 1720, 1605, 1580, 1300, 1240, 1210, 1110, 1085, 1050, 1010, 970, 760, 720, and 710 cm’1. The mass spectrum of the bis-trimethylsilyl derivative exhibits a high resolution peak at 546.3182. Silica gel TLC Rf is 0.14 in 30% ethyl acetate in hexane.

I. Following the procedure of Example 1, Part A, the title product of Part H (158 mg) is transformed to the title free acid (129 mg) as a white solid. Melting range is 150-154’C. NMR absorptions are observed at 0.90, 1.07-3.5, 3.85-4.35, 4,70, 5.09-5.9, and 6.5-7.36. Infrared absorptions are observed at 3380, 2640, 2560, 1730, 1605, 1580, 1260, 1230, 1115, 1050, 1025, 970, and 770 cm1.

Following the procedure of Example 4, each of the various novel compounds are prepared wherein R22 is a-hydrogen. Further following the procedure of Example 3, the various 9e-methano isomers of Example 4 and corresponding novel compounds wherein Y3 is cis- or trans-CH’CH- are hydrogenated to corresponding 13,14-dihydro50969 - 16 PGFj compounds.

Example 5 9-Deoxo-2,,9-metheno-3-oxa-4,5,6-trinor-3,7-(l',3'inter-phenylene)-PGEj and its methyl ester Refer to Chart E.

A. A degassed solution of the reaction product of Example 4, Part A, (1.68 g) in dry tetrahydrofuran (50 ml) is cooled to 0°C and treated under a nitrogen atmosphere with 0.75 M tetrabutyl ammonium fluoride (4.37 ml). The resulting solution is then stirred at 0°C for 2 hr, diluted with brine (300 ml), extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 2.3 g of an oil. The oil is chromatographed on silica gel (160 g) in 25% ethyl acetate in Skellysolve B yielding 1.21 g of formula CCXI compound, 9-deoxo-9aformyl-1,2,4.5,6-pentanor-3,7-ihter-m-phenylene-PGE1, ll,15-bis(tetra15 hydropyranyl ether). NMR absorptions (COC13) are observed at 0.88, 1.13-3.15, 3.27-4.47, 4.71, 6.10, 6.53-7.41, 9.275. Infrared absorptions are observed at 3345, 2930, 2860, 2720, 1735, 1715, 1605, 1595, 1585, 1486, 1450, 1370, 1350, 1255, 1235, and 970 cm'1. Silica gel TLC Rf is 0.12 in 25% ethyl acetate and hexane and 0.39 in 50% ethyl acetate in hexane.

B. A degassed solution of 0.28 g of the reaction product of Part A in 33 ml of glyme is cooled to -40°C under argon and treated with 2.95 N methylmagnesium chloride in tetrahydrofuran (0.2 ml). The reaction mixture is stirred at -40°C for 15 min, stirred at 0°C for 15 min, permitted to warm to ambient temperature, stirred at reflux for 25115 hr under an argon atmosphere, cooled, diluted with ice cold brine (150 ml), extracted with ethyl acetate (300 ml), washed with brine (300 ml), dried over magnesium sulfate, filtered, concentrated under reduced pressure to yield 0.31 g of an oil, and chromatographed on silica gel eluting with 25% ethyl acetate in Skellysolve B to yield 0.16 g of the formula CCXII compound, 9-deoxo-2’,9-metheno-3-oxa^l^.A.S.e-pentanor-S.T-fl' .S'-inter-phenyleneJ-PGEj, ll,15-bis(tetrahydropyranyl ether). The mass spectrum of the trimethylsilyl derivative exhibits a molecular peak at 568 and other peaks at 466, 382, 50869 - 17 364, 314, 297, 267, 255, 243, 230, 270, 153, and 85. Silica gel TLC Rf is 0.25 1n 25% ethyl acetate in hexane and 0.58 in 50% ethyl acetate in hexane.

C. A degassed solution of the reaction product of Part C (0.16 g) in dry glyme (5 ml) is cooled at -5°C and treated with methylbromo acetate (0.04 ml) under a nitrogen atmosphere. The resulting solution is then treated with 50% sodium hydride dispersion in mineral oil (0. 16 g). Precipitate forms in 5 min in the resulting suspension is stirred for 1.5 hr at O’C, diluted with brine (100 ml), extracted with ethyl acetate (240 ml), washed with brine (100 ml), dried over magnesium sulfate, filtered, concentrated to yield a brown residue which solidifies on refrigeration, and chromatographed on 25 g of silica gel eluting with 20% ethyl acetate in Skellysolve B to yield 0.136 g of the bis(tetrahydropyranyl ether) of a formula CCXIII compound: 9deoxy-2 ‘,9-metheno-3-oxa-4,5,6-trinor-3,7-(1,3-inter-phenyleneJ-PGEj, methyl ester, ll,15-bis(tetrahydropyranyl ether). Melting range is 81-83’C. The mass spectrum exhibits peaks at 366, 384, 364, 279, 247,230, 215, 149, and 85. Silica gel TLC Rf is 0.45 in 5% acetone in methylene chloride.

D. A solution of the reaction product of Part C (0.12 g) in tetrahydrofuran (1 ml), water (2 ml) and acetic acid (4 ml) is heated at 45°C under a nitrogen atmosphere for 2.25 hr, cooled, and partitioned between brine (100 ml) in ethyl acetate (90 ml). The layers are separated and the aqueous layer extracted with ethyl acetate (160 ml). The organic layers are then washed successively with brine (100 ml), water (100 ml), saturated aqueous sodium bicarbonate (300 ml) and brine (200 ml), dried over magnesium sultate, filtered, concentrated to yield 0.97 g of a solid, and chromatographed on 30 g of silica gel, eluting with 85% ethyl acetate in hexane to yield 0.083 g of white crystalline formula CCXIII title product in methyl ester form. Recrystallization from diethyl ether in hexane yields 0.056 g of pure methyl ester title product. Melting range is 96-98’C. NMR absorptions (COC13) are observed at 0.94, 3.86, 3.92-4.28, 4.72, 5.58-5.86, and 6.62-7.185. Infrared absorptions are observed at 3420, 1765, 1665, 1600, 1575. 1465. 1440, 1275, 1215, 1190, 1105, 1085, 970, and 770 cm”1. The mass spectrum for the trimethylsilyl derivative exhibits a molecular ion at 554 and other peaks at 454, 383, 365, 364, 230, 229, 225. Silica gel TLC R^ is 0.41 in ethyl acetate. - 18 E. Following the procedure of Example 1, Part c, the reaction product of Part D (0.19 g) is converted to 76 mg of crystalline title product in free acid form. Melting range is 150-152°C. NMR absorptions (C0C13) are observed at 0.91, 1.2-3.48, 3.88-4.15, 4.70, .62-4.66, and 6.63-7.11. The mass spectrum for the trimethylsilyl derivative exhibits a high resolution peak at 602.3251 and other peaks at 512, 422, 287, 225, 174, and 173. Silica gel TLC Rf-is 0.23 in the A-IX solvent system.

Example 6 9-0eoxy-2 ’ ,9a-methano-3-oxa-4,5,6,13,14,15,16,17,18,10 19,20-undecanor-3,7-(l1,3'-inter-phenylene)-12-formylPGFj, methyl ester (formula CCXXII: X3 is -COOCH3, L, is -CH2-, R20, R21, and R23 are hydrogen, R22 is B-hydrogen, and Ri8 is tetrahydropyran-2-yl-oxy).

Refer to Chart F.

Ozone is bubbled through a solution of 0.72 g of the reaction product of Example 1, Part A, in 50 ml of absolute methanol at -78°C for 5 min. Thereafter oxygen is bubbled through the resulting solution for 5 min and the solution is treated with 16 ml of dimethyl sulfide. After standing at 16 hr for 0°C under a r/trogen atmosphere and 2\ ήΓ at ambient temperature, the solution is diluted with 200 ml of ethyl acetate, washed successively with 100 ml of brine, IOC· ml of saturated aqueous sodium bicarbonate and 100 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on 175 g of silica gel eluting with 35% ethyl acetate in hexane to yield 367 mg of title product as a colorless· oil. NMR absorptions (COC13) are observed at 1.0-3.0, 3.1-4.5, 3.63, 6.45-7.34, and 9.77s. The mass spectrum exhibits peaks at 388 and 304. Silica gel TLC Rf is 0.19 and 0.22 in 25% and 30% ethyl acetate in hexane.

Example 7 9-Deoxy-2',9a-methano-20-methyl-3-oxa-4,5,6trinor-3,7-(l',3'-inter-phenylene)-PGFi , Its methyl ester, its 15-eFimcr and 15-epimer methyl ester Refer to Chart f.

A. A suspension of 56 mg of a 57% sodium hydride dispersion in - 19 mineral oil and 4 ml of tetrahydrofuran at 0°C under a nitrogen atmosphere is treated with a solution of 286 mg of dimethyl-2-octylphosphonate in 4 ml of tetrahydrofuran, stirred for 5 min at 0’C, stirred for 1 hr at ambient temperature, cooled to 0°C, treated with a solution of 0.39 g of title product of Example 6 and 4 ml of tetrahydrofuran, stirred for 2¾ hr at ambient temperature, cooled to 0°C, added to a solution of 40 ml of ethyl acetate containing several drops of acetic acid , extracted with 120 ml of ethyl acetate, washed with 30 ml of saturated aqueous sodium bicarbonate, washed with 30 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to yield an oil, and chromatographed on 60 g of silica gel eluting with 25% ethyl acetate in hexane to yield 0.42 g of a colorless oil, 9,15-dideoxy-15-keto-2',9a-methano-20-methyl-4,5,6-trinor3,7-(1'.S'-inter-phenyleneJ-PGFj, methyl ester, 11-tetrahydropyranyl ether. NMR absorptions are observed at 0.89^, 1.05-3.0, 3.5-4.37, 4.62, and 5.97-7.30S. The mass spectrum exhibits peaks at 414, 396, 323, 311, and 301. Silica gel TLC Rf is 0.26 in 25% ethyl acetate in hexane.

B. A degassed solution of 42 mg of sodium borohydride and 4 ml of absolute methanol at -30°C under a nitrogen atmosphere is treated dropwise with a solution of 391 mg of the title reaction product of Part A in 0.3 ml of methylene chloride and 3 ml of methanol, stirred for . 1¼ hr at -30°C, quenched by careful addition of 0.2 ml of glacial acetic acid, diluted with 70 ml of brine, extracted with 210 ml of ethyl acetate, washed with 70 ml of saturated aqueous sodium bicarbonate, washed with 70 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to yield 0.42 g of a colorless oil, and chromatographed on 60 g of silica gel eluting with 40% ethyl acetate in hexane to yield 0.36 g of an epimeric mixture of C-15 alcohols. Silica gel TLC R^ is 0.20 in 40% ethyl acetate in hexane.

C. A solution of the reaction products of Part B above in 3 ml of tetrahydrofuran, 4.5 ml of water, and 9 ml of acetic acid is heated to 45°C under a nitrogen atmosphere for 2.5 hrs, cooled, diluted washed with 100 ml of brine, extracted with 200 ml of ethyl acetate, washed with 100 ml of brine, washed with 300 ml of satureated aqueous sodium bicarbonate and 100 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to a yellow oil, and - 20 chromatographed on 60 g of silica gel eluting with 20% ethyl acetate in methylene chloride to yield 96 mg of 9-deoxy-2',9a-methano20-methyl-3-oxa-4,5,6-tri nor-3,7-(1,3-inter-phenylene)-15-epi-PGFj, methyl ester as a colorless oil and 159 mg of 9-deoxy-2',9a-methano5 20-methyl-3-oxa-4,5,6-trinor-3,7-(l,3-inter-phenylene)-PGFi, methyl ester as a white solid. Recrystallization of the 15o-hydroxy compound from hot hexane in diethyl ether yields 140 mg as a white solid. Melting range is 79-82°C. For the title product methyl ester, NMR absorptions are observed at 0.92, 1.08-3.0, 3.38-4.5, 4.64, 5.33-5.70, and 6.5-7.4. The mass spectrum of the trimethylsilyl derivative exhibits a high resolution peak at 560.3375. Silica gel TLC R^ is 0.19 in 20% ethyl acetate in methylene chloride and 0.31 in 20% hexane in ethyl acetate. For the 15-epi compound, NMR absorptions (CDCl3) are observed at 0.89, 1.07-3.0, 3.7-4.33, 4.63, .5.5-5.8, and 6.55-7.376. Infrared absorptions are observed at 3360, 1765, 1750, 1735, 1605, 1585, 1470, 1440, 1205, 1120, 1080, 970, and 770 cm1. The mass spectrum for the trimethylsilyl derivative exhibits a high resolution peak at 560.3385. Silica gel TLC R^ is 0.35 in 20% acetone and methylene chloride and 0.45 in 20% hexane and ethyl acetate.

D. Following the procedure of Example 1, Part A, the 15ahydroxy title product of Part C (94 mg) is transformed to 9-deoxy21,9a-methano-20-methyl-3-oxa-4,5,6-trinor-3,7-(1,3-inter-phenyl ene)PGF£, title free acid, as a white solid, 81 mg. Melting range is 144-146°C. NMR absorptions (CD3C0CD3) are observed at 0.8, 1.05-2.9, 3.2-4.5, 4.65, 5.38-5.56, and 6.6-7.26. The mass spectrum of the trimethylsilyl derivative exhibits a high resolution peak at 618.3576. Silica gel TLC R^ is 0.14 in the A-IX solvent system.

E. Further following the procedure of Example 1, Part A, the 15-epi title product of Part C (93 mg) is converted to 9-deoxy-2',9a30 methano-20-methy l-3-oxa-4,5,6-trinor-3,7-(1,3-inter-phenylene)-15-epiPGF1( a white solid, 72 mg. Melting range is 105-108°C. MMR absorptions (C03C0C03) are observed at 0.90, 1.05-2.9, 3.2-4.3, 4.71, 5.0-5.84, and 6.5-7.346. Silica gel TLC Rf is 0.19 in the A-IX solvent system.

S0S69 - 21 A pharmaceutical composition according to the present invention comprises a compound of the invention in association with a physiologically acceptable excipient.

The dosage at which the novel compounds should be administered to achieve their effect, chiefly antiplatelet aggregation or blood pressure lowering, will vary according to the potency of the particular compound under study. Intravenous dosages for the desired effect are from 1 to 500, preferably 10 to 100, ng/kg/min, in man. When given orally, the compounds can show a desired effect, in man, at a dose from 0.05 to 50, preferably 0.1 to 5, mg/kg.

The compound of Example 1, 9-deoxy-2',9a-methano-3oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF^, methyl ester, was given to a rat orally at a dose of 1 mg/kg; blood pressure was lowered by 44 mg Hg. After 52 min, the blood pressure was still lower by 14 mm. 50989 CLXXVII CRgR^-R) CLXXVI11 - 24 CHART Β V CLXXXIII RtOK-Z^-O Ψ X To CLXXXVI τ„ CLXXXVIH - 25 CHART Β To CLXXXVI To CLXXXVIII 50S69 CHART B (continued) From CLXXXV CLXXXVII Yi-c— cr3R4-R7 Mi Ψ CXC 50868 CHART C CXCI CXCII CXCIII CXCIV Re Y-C—CR R4-R7 II 3 s ' Mi CCIII 50869 - 29 CHART Ε CCXI II Me CCXII CCXI11 50968 - 30 CHART F CCXXI '7 CCXXII Ψ CCXXIII S0969

Claims (13)

1. A compound of the formula wherein either Rg and R 4 are independently selected from hydrogen, methyl and fluorine, provided that CRgR 4 is 5 not CFMe, and R? is C 2 -6 alkyl, cls-CH^CH-CH^-CH,, -(CH 2 ) 2 -CHOH-CH 3 , -(CH 2 ) 3 -CH=C(CH 3 ) 2 or optionally ring-substituted phenoxy, phenyl, benzyl, phenylethyl or phenylpropyl in which there are no more than 3 ring substituents (no more than

2. Of which are alkyl) 10 independently selected from chlorine, fluorine, trifluoromethyl, 0 χ _ 3 alkyl and C 1 _ 3 alkoxy, provided that neither R 3 nor R 4 is fluorine when R ? is optionally substituted phenoxy; or CR 3 R 4 ~R 7 is 2-(2-furyl)ethyl, 2-(3-thienyl)eth15 oxy, 3-thienyloxymethyl, or C 4 _j cycloalkyl optionally carrying up to 3 C 1 _ g alkyl substituents; Mj is a-OHzS-Rg or B-Rg-.a-OH and R g is hydrogen or methyl; R 20 is H, a-OH, β-OH or =0; 20 R g is H, OH or CH 2 OH; Y 1 is trans-CH=CH-, cis-CH=CH-, -CH 2 CH 2 or -CSC-; Z 4 is -CH 2 ~ or -(CH 2 )f-CF 2 - and f is zero, one, 2 or 3; and Χ χ is COORg, CHjOH, CH 2 NL 2 L 3 or COL 4 ; 50869 - 32 in which R^ is hydrogen, a pharmacologically acceptable cation, C 1 _ 12 alkyl, C 3-io c ydoalkyl, C7_12 ara lkyl, phenyl optionally substituted up to 3 times by chlorine atoms or C3_ 4 alkyl radicals, or phenyl substituted in 5 the para-position by -NHCOR^, -COR 2 g, l5enz °yToxyr acetamidobenzoyloxy or -CH=N-NH-CONH 2 in which R 2 g is methyl,phenyl, acetamidophenyl, benzamidophenyl or -NH 2 and R 26 is methyl, methoxy, phenyl or -NH 2 ? L 2 and L 3 are independently selected from hydrogen 10 and C^_ 4 alkyl; and L4 is -ΝΙ^γϊ^θ, -NR^COR^, -ili^gSOjR^y or cycloamino selected from pyrrolidino, piperidino, morpholino, piperazino, hexamethyleneind.no, pyrrolino and 3,4-didehydropiperidinyl optionally substituted by one or 2 C|_ 32 alkyl 15 radicals,in which R 27 is hydrogen, c 1_ 1 2 alkyl, C 3-io cycloalkyl, c 7_^2 aralkyl, phenyl optionally substituted by up to 3 substituents selected from chlorine, C^_ 3 alkyl, hydroxy, carboxy, (C 1-4 alkoxy)carbonyl and nitro, carboxy(C 1 _ 4 alkyl), carbamoyl(Cj_ 4 alkyl), cyano(C 3 _ 4 20 alkyl), acetyl(Cj_ 4 alkyl), benzo(C 1-4 alkyl) optionally substituted by up to 3 substituents selected from chlorine, C 3 _ 3 alkyl, hydroxy, C 1-3 alkoxy, carboxy, (C 4 _ 4 alkoxy)carbonyl and nitro, pyridyl optionally substituted by up to 3 substituents selected from 25 chlorine, Cj_ 3 alkyl and C 3 _ 3 alkoxy, pyridyl(C 3 _ 4 alkyl) optionally substituted by up to 3 substituents selected from chlorine, C 1-3 alkyl and hydroxy, or mono-, di- or tri-hydroxy(C 4 _ 4 alkyl), R 27 is R 27 other than hydrogen, R 28 is hydrogen or alkyl, and R 2 g i s kY ro 9 en or 30 c 4 _ 4 alkyl; or a pharmacologically acceptable acid addition salt thereof when is Ct^NLjLj. 50968 33 2. A compound of the formula R 8 C —CR.R.—R. ii 3 4 7 wherein R 3 , R 4 , R ? , R g , Μ χ , Χ χ , Υ χ and Z^ are as defined in claim 1, or a pharmacologically acceptable acid 5 addition salt thereof when Xg is CHjNL Lg.

3. A compound of the formula Yj — c — CR 3 R 4 — r ? wherein Rg, R 4 , R ? , Rg, Χ χ , Υ χ and Z 4 are as defined in claim 1, or a pharmacologically acceptable acid 10 addition salt thereof when X^ is Ci^NI^Lg.

4. 9-Deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(l',3'inter-phenylenel-PGFp or its amide or methyl ester.

5. 15(R)-9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor3,7-(1',3'-inter-phenylene)-PGF| or its methyl ester.

6. 9-Deoxy-16,16-difluoro-2',9a-methano-3-oxa-4,5,6trinor-3,7-(I 1 ,S'-inter-phenyleneJ-PGFj^ or its methyl ester.

7. 9-Deoxy-l3,14-dihydro-2',9a-methano-3-oxa-4,5,65 trinor-3,7-(1',3'-inter-phenylene)-PGF^ or its methyl ester.

8.

9. -Deoxy-7,8-didehydro-2',9-methano-3-oxa-4,5,6trinor-3,7-(1 1 ,3'-inter-phenylene)-PGFj^ or its methyl ester. 10. 9. 9-Deoxy-2',9-hydroxymethano-3-oxa-4,5,6-trinor3,7-(1',3'-inter-phenylene)-PGFj^ or its methyl ester.

10. 9-Deoxy-2',9a-carbonyl-oxa-4,5,6-trinor-3.,7(1',3'-inter-phenylene)-PGFj^ or its methyl ester.

11. 9-Deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,715 (1 1 fS'-inter-phenyleneJ-PGDj^.

12. A pharmaceutical composition comprising a compound as claimed in any preceding claim in association with a physiologically acceptable excipient.

13. A compound as claimed in any of claims 1 to 11, 20 for therapeutic use.