IE43821B1

IE43821B1 - Prostaglandins

Info

Publication number: IE43821B1
Application number: IE120/76A
Authority: IE
Original assignee: Lepetit Spa
Priority date: 1975-01-24
Filing date: 1976-01-22
Publication date: 1981-06-03
Also published as: FI64578C; NO147714B; DD122517A5; PH14040A; YU11176A; IL48870A0; CA1076569A; DK27376A; YU40805B; PT64737B; CH609682A5; FI760002A; JPS5198249A; SE7600729L; ATA36776A; FR2298322A1; GR58537B; IE43821L; HU174185B; FR2298322B1

Abstract

Novel prostaglandin analogues of the general formula: (I) wherein the ring P represents one of the groups: (a) (b) (c) the symbol A represents -CH2-CH2 - or cis-CH=CH-; the symbol B represents-CH2 -CH2 - or trans-CH=CH-; R is hydrogen, alkyl of 1 to 6 carbon atoms, or a cation; R1 is alkyl of 1 to 6 carbon atoms, R2 represents a straight chain alkyl radical selected from methyl, ethyl, propyl, butyl, pentyl and hexyl; R3 is hydrogen or methyl; R4 is hydrogen or methyl; and R5 is hydroxy or R4 and R5 taken together represent an oxo group are disclosed, together with processes for their preparation. The new compounds have luteolytic, antihypertensive, bronchodilating and anti secretory activity. [CA1076569A]

Description

' 4332i This invention relates to novel prostaglandin-like compounds.

According to the invention there are provided novel prostaglandin analogues having the following general formula: a CH2 ^hoor (i) 1 p I f* % 1 ^ c«^l B I ^*c ^ 2 R5 1 R3 wherein the ring P represents one of the following groups: OH 8 | f/Y ζγ /Y ' y\ y\ x/\ OH ί)Η a b c 2 4 3 S St A represents -CH2-CH2- or £i_s-CH=CH- and B represents trans-CH^CH- or A and B both represent -CH2-CH2-.

R is hydrogen, an alkyl group having 1 to 6 carbon atoms, or a cation; 5 R-j is an alkyl group having 1 to 6 carbon atoms, phenyl or a phenyl group which is substituted with one or two groups or atoms each independently selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, chlorine, fluorine, bromine and trif1uoromethyl; 10 R2 represents a straight chain alkyl radical selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl; R3 is hydrogen or methyl; R^ is hydrogen or methyl; Rg is hydroxy; or 15 R^ and Rg taken together represent an oxo group, with the proviso chat where is hydrogen and Rg is hydroxy, R2 contains at least four carbon atoms.

Particularly preferred classes of compounds are those in which B represents trans-vinylene, R is hydrogen or methyl and 20 Rj is methyl or phenyl, especially those in which R2 is butyl, R, R1 and Rg are methyl and is hydrogen and Rg is hydroxy.

In the formula I above the broken lines represent bonds which extend behind the plane of the paper (α-configuration) which the thickened lines represent bonds which extend out of the 25 plane of the paper (e-configuration).

The expression "alkyl of 1 to 6 carbon atoms" when not otherwise specified identifies a straight or branched alkyl radical such as for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl. 3 438.·-- The term "cation" identifies a pharmaceutically acceptable non toxic cation such as for instance Na+, Ca++, NH^ and organic ammonium cations. The new compounds have potent prostaglandin-like activity, i.e. they have luteolytic, antihypertensive, bronchodilating and anti-secretory effect; in some instances they also display an inhibitory effect of the catabolism of natural prostaglandins.

The compounds of the invention are prepared by following general methods which are widely employed in the prostaglandins chemistry. The starting compounds for preparing the new products of this invention are cyclopentane aldehydes of the formula or6 L( 0R? CH0 wherein A and R have the same meanings as before; Rg and R^ each independently represent hydrogen or a hydroxy-protecting group such as for instance an alkyl group having 1 to 6 carbon atoms, lower alkoxy-lower alkyl wherein the lower alkoxy and lower alkyl groups have 1 to 6 carbon atoms, trityl, tetrahydropyran-2-yl, (4-lower alkoxy)-tetrahydropyran-4-yl, phenyl-carbamoyl, biphenylyl-carbamoyl, terphenylcarbamoyl or an acyl radical selected from 4 438S1 1) alkanoyl of 2 to 8 carbon atoms (e.g. acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, octanoyl; 2) benzoyl or mono-substituted benzoyl wherein the 5 substituent is selected from chlorine, bromine, fluorine, nitro, (lower alkoxy) carbonyl, lower alkyl, lower alkoxy, phenyl-lower alkyl, (wherein "lower alkoxy" and "lower alkyl" have 1 to 4 carbon atoms), phenyl and cyclohexyl; 3) lower alkoxy-carbonyl wherein "lower alkoxy" besides 10 the terms having 1 to 4 carbons includes also halogenated lower alkoxy radicals, e.g. 2,2,2-trichloroethoxy e.g. 2,2,2-tri bromoethoxy; 4) phenoxycarbonyl; 5) benzyloxycarbonyl and 15 6) diphenylyloxycarbonyl.

The above starting compounds may be prepared according to the methods described in the literature. For instance, German Offenlegungsschrift No. 2,217,930 and Belgian Patent 807,161 discloses useful procedures for preparing those intermediates.

The latter corresponds to British Patent Specification No. 1,432,950 which describes and claims a broad class of cyclopentana1dehyde derivatives. The above intermediates of formula II represent a specific class of such cyclopentan-aldehydes which are useful for preparing the novel compounds of 25 the invention.

The process for preparing the new prostaglandin analogues involves condensation of the aldehyde of the formula II with a phosphonate or a phosphoranylidene reagent having respectively 5 4 3 8 " i the following formula OR I 1 z —c —r2 '3 wherein Z represents one of the following groups; o II (R'0)2P—CH —CO — > and r4 (C6H5)3P == CH — C - R5 wherein R-|, R2, R3, R4 and Rg have the same meaning as before and R1 is an alkyl group having 1 to 5 carbon atoms.

The aldehyde II may be prepared just before it is to be contacted with the- phosphorus reagent by cleavage of a corresponding acetal or similar derivative where the carbonyl function is protected. The condensation between the aldehyde of the formula II and the phosphonate or phosphoranylidene derivative leads to a prostaglandin-like compound of the formula I wherein B is a group -CH = CH-. The use of the above phosphonates or of stabilized phosphoranylidene derivatives 6 4 3 8 21 (K^t-Ri} = oxo) lead with high specificity to a vinylene group having trans(E)conformation while the use of phosphoranylidene derivatives which are not stabilized may lead to a mixture of cis(Z) and trans(E) products. In this latter case separation 5 of the mixture of cis and trans isomers through chromatography may be necessary. For this latter reason the method employing phosphonates is particularly preferred. When the starting aldehyde has one or both hydroxy substituents at positions 9 and 11 protected and said protecting group(s) are still present in 10 the final condensation products, they may be eliminated by hydrolytic cleavage. Acid or base catalyzed hydrolysis nay be employed depending on the chemical nature of the protecting groups. Ether and acetal groups are advantageously broken by acidic cleavage whilst ester groups are cleaved preferably 15 by hydrolysis with diluted bases or by transesterification.

A product of formula I, wherein B represents trans-CH=CH- may be easily converted to the corresponding derivative wherein B is a group -CH^-CHg- by hydrogenation of the vinylene group in the presence of a hydrogenation catalyst 20 such as a nobel- metal. This step allows simultaneous hydrogenation of the vinylene group in the upper chain if A represents ci s -CH = CH-.

A product I resulting from condensation between the aldehyde II and a phosphorus reagent and having an oxo group in 25 the position 15 of the prostaglandin skeleton (R4+R5 = oxo) may be reduced to the corresponding hydroxy derivative by means of 7 43 8 21- borohydride type reagents, e.g. NaBH^, or diphenyl tin dihydride lithium trialkyl borohydrides. Alternatively the oxo group in the position 15 may be converted into hydroxy with simultaneous introduction of a methyl group on the same carbon centre by means of a Grignard reagent Such as for instance magnesium methyl bromide.

The condensation between the aldehyde and the phosphorus reagent is carried out substantially under the same conditions which are widely described in the chemical literature concerning 0 synthesis of prostaglandins from cyclopentane aldehyde precursors and phosphorus reagents.

The condensation reaction is carried out in the presence of an anhydrous inert solvent such as tetrahydrofuran, 1,2-dimethoxyethane, benzene, dioxane at a temperature between 5 0°C and 80°C.

When a phosphonate derivative is employed as the reaction partner it is first transformed into the corresponding anion by addition of about one equimolecular proportion of an alkali metal hydride. The phosphoranylidene reagents in turn are ) obtained j_n situ by dehydrohalogenation of the corresponding phosphonium halides by addition of about one equimolecular proportion of a lithium lower alkane or alkene such as butyl lithium or vinyl lithium. When the aliphatic chain portion of the phosphonium halide contains one hydroxy group (Rg = OH), two equimolecular proportions of the dehydrohalogenating base are required. 8 4382; The products of the formula I may have in the lower side chain one or two assymetric carbon atoms. More particularly, when the symbol Rg represents a hydroxy group the carbon atoms bearing this substituent and the neighbouring carbon bearing 5 the group OR^ are asymmetric centres. Therefore, four different isomeric compounds of formula I may be obtained each having at the correspondingly substituted carbons of the prostaglandin skeleton (C^g and C^g) one of the following combinations of absolute configurations: (R,R); (R,S): (S,R) and (S,S).

When in the compounds of formula I the symbol R and Rr 4 3 taken together represent an oxo group at the position 15 the possible isomers are two, due to the chirality centre at Cig.

The several isomers may be directly prepared by using reagents with the appropriate configurations at the asymmetric 15 centres, or by stereospecific reactions or, alternatively, when the course of reaction does not allow any control of the stereochemistry, the isomers may be separated by common techniques which are well known to men skilled in the art, such as for instance, chromatographic methods.

According to the process outlined before, prostaglandin like derivatives belonging to F series (i.e. having ring P with structure a) are obtained directly from the condensation reaction between the aldehyde II and the phosphorus reagents. Prostaglandin-like derivative of formula I belinging to A and 25 E series (i.e. having ring P with structures corresponding respectively to b and c) are easily prepared by convertion of F series derivatives according to chemical procedures well known in the prostaglandin field. 9 4383*· The starting phosphoranes reagents are prepared by condensing methylphosphonic acid lower alkyl esters with α-substituted carboxylic acids lower alkyl esters (or the 5 corresponding acid chlorides) according to the following reaction scheme: 0 OR, 0 OR,. i| I 1 ll I 1 (R‘02PCH3 + XOC-C —R2-*.(RO)2"P-CH2~C0-C ' r2 + xh R3 R3 X =rOR"; Cl wherein Rp R2, R3 and R’ have the same meaning as before and 0 R" represents an aliphatic radical of 1 to 5 carbon atoms. This procedure involves first transformation of the methyl phosphonates into the corresponding anion by addition of butyl lithium at -78°C in tetrahydrofuran and then contacting with the carboxylic acid ester (or the corresponding acid chloride) 5 for about one hour at the same temperature.

The phosphorane starting reagents are prepared from the corresponding phosphonium halides which in turn are obtained by reaction of triphenyl phosphine with a suitable halogenide of the formula R4 °R1 ) halo-CH2— C — C —R? 1 I * R5 R3 10 4 3 8 2 1 wherein halo stands for iodine, chlorine or bromine and the symbol , R2, R3, R4 and Rg have the same meanings as before.

When R^ and Rg taken together represent an oxo group 5 the corresponding phosphorane reagents are more conveniently prepared by acylation of methylenetriphenylphosphorane with a lower alkyl ester or chloride of an acid of the formula OR, HOOC — C — R2 ! R3 Π wherein , Rg and R3 have the same meanings as before. Λ η ο Ί 438·'·" These aliphatic acid and the corresponding esters and chlorides are prepared according to literature methods such as, for example, those described respectively by E.J. Salmi in Ann. Acad. Sci. Fennicae, /1 48, 17, 1937 (see C.A. 8174) and V. F. Kucherov in Zhur, Obshchei Khim. 20, 1885, 1950 (see C.A. 45, 2928).

This invention is illustrated by the following non limitative specific Examples. (Examples 1, 3, 5 and 7 illustrate the preparation of intermediates).

EXAMPLE 1 (5Z, 13E) -9a-Acetoxy-l1a-hydroxy-16-methyl-15-oxoprosta-5,13-di en -1-oic acid methyl ester (16R and 16S isomers).

A) 1.3 Grams (30 m moles) of a 55¾ suspension of sodium hydride in mineral oil are washed under nitrogen atmosphere with hexane and then 20 ml. of anhydrous 1,2-dimethoxyethane are added thereto. To this suspension at a temperature of about 0°C, 8g. (32 m moles) of the dimethyl ester of (3-methoxy-2-oxoheptyl)phosphonic acid dissolved in 50 ml. of anhydrous 1,2-dimethoxyethane are added. After standing for 15 minutes at the room temperature the mixture is cooled to 0°C and 6.24g. of the methyl ester of (5Z)-7-(5a-acetoxy-2β-formyl-3a-hydroxycyclopent-la-yl)-5-hepten-l-oic acid (20 m moles), dissolved in 100 ml. of anhydrous 1,2-dimethoxyethane. The temperature is then allowed to raise at about 20°C and the mixture is maintained 12 « 3 8 3 1 under stirring for hour hours. The reaction mixture is then poured into an aqueous solution saturated with NaHgPO^ j which is subsequently extracted with ethyl acetate. The ! organic extract is evaporated to give 14.1 g. of a crude 5 product containing two components. The two products which are the R and isomers at the position 16 are separated by preparative thin layer chromatography by eluting first with ethyl ether/hexane 7:3 and then with diethyl ether/hexane 85:51 v/v.

By this way, 1.38 g. of the less polar isomer and 1.410 g. of 10 the more polar isomer are obtained.

The less polar isomer is an oily product having the following physical characteristics: [t]Z0 = + 85.4 (c = 0.985 in CHC13) 15 U.V. absorption spectrum in methanol: χ max (my) 238, e]^ = 267 I.R. absorption spectrum (neat): the most significative absorption bands occur at the following frequencies (cm.-^): 3400, 2910, 2860, 1740, 1700 (sharp), 1 625,. 1440, 1370, 2Q 1240, 1100.

N.M.R. spectrum: the most significative absorption peaks in CDC13 occur at the following frequencies expressed in 6 units: 0.88; 1.08-2.88; 2.03; 3.30; 3.64; 3.67; 3.83-4.32; 4.98-5.45; 6.50; 6.90. 13 43831 The microanalytical data are in agreement with the formula Cg^HggOy.

The more polar isomer is an oily product having the following physical characteristics: !a]p° = + 19.8 (c = 1.05 in CHC13) UV absorption spectrum in methanol: λ max (mu) 238, e]^ = 282 I.R. absorption spectrum (neat): the most significative absorption bands occur at the following frequencies (cm. ); 3450,2920, 2860,1730, 1700 (sharp), 1620, 1435, 1370, 1320, 1240, 1100, 1040, 985.

N. M.R. spectrum: the most significative absorption peaks in CDClg occur at the following frequencies expressed in 6 units: O. 88; 1.07-2.84; 2.05; 3.30; 3.63; 3.67; 3.84-4.28; 4.98-5.45; 6.50; 6.90.

The microanalytical data are in agreement with the formula ^24^38^7' B) The crude methyl ester of (5Z)-7-(5a-acetoxy-2g-formyl-3o-hydroxy-cyclopent-la-yl)-5-hepten-l-oic acid which is employed as the starting compound is prepared by following the procedure described in Belgian Patent 807,161 for the close analog (5Z)-7- [5a-(4-phenylbenzoyloxy)-2 β-formyl-3a-hydroxy-cyclopent-loc-yl]-5-hepten-l-oic acid methyl ester, the only difference consisting in the acylation of the 5a-hydroxy group on the cyclopentane ring with acetyl chloride instead of 4-phenylbenzoyl chloride. 14 4 3 8 31 The corresponding precursor from which the above starting material is obtained by hydrolysis with 60% acetic acid is the methyl ester of (5Z) -7-[5a-acetoxy-2 β-dimethoxyinethyl -3a- (tetrahydropyran-2-yl oxy) -cyclopent-la-yl -5-hepten-l-oic acid which is an oil having the g following physical characteristics: &jp° = + 26.5 (c = 1.02 in CHC13) i.R. absorption spectrum (neat): the most significative absorption bands occur at the following frequencies (cm.’1): 2900, 2850, 1730, 1435, 1365, 1240, 1120, 1080-1040, 1020, 870. ]q N.M.R. spectrum : the most significative absorption peaks in CDC13 occur at the following frequencies expressed in <5 units: 1.24-2.48; 2.02 and 2.03; 3.22-4.44; 3.40 and 3.42; 4.54-4.75; 4.90-5.20; 5.22-5.51.

The microanalytical data are in agreement with the formula ]5 C23H38°8- EXAMPLE 2 (5Z,13E)-9a, 11a, 15-trihydroxy-16-methoxy-prosta 5,13-diene-l-oil acids (isomers: (155,165), (15S,16R), (15R,16S) and (15R,16R)._ (A) To a solution of 1.3 g. of the more polar C1(- isomer obtained 90 β- 2o 10 Example 1 (i.e. the product having pi] έ =+ 19.8) in 150 ml of methanol are adcM ο ~ ϋ dropwise at -10 C 300 mg. of NaBH^ in loml. of ice water. The reaction mixture is stirred at -10°C until the reaction is completed (the course of the reaction is followed by thin layer chromatography) and then it is poured into a saturated solution of Nal^PO^. Extraction with ethyl 25 acetate and evaporation of the organic extract gives 1.15g. of a mixture 15 ά 3 8 3 i of isomeric (52,13EJ-9a-acetoxy-l1α,15-dihydroxy-16-methoxy-prosta- 5,13-dlen 1- oic acids methyl esters having the same absolute configuration at the position 16 and the opposite absolute configurations at the position 15. The N.M.R. spectrum and the microanalytical 5 data are in agreement with the assigned structure.

The product obtained is dissolved in 46 ml. of methanol together with 30 ml. of water. Then a solution of 2.1 g of KOH in 30 ml. of 50¾ (by volume) aqueous methanol is added and the mixture is stirred for one hour at room temperature after which IQ period of time the reaction is generally completed.

A saturated solution of Naf^PO^ is added to the reaction mixture, which is then extracted with ethyl acetate. The organic phase is evaporated in vacuo yielding Ig. of a product consisting of an isomeric mixture of the corresponding prostadienoic acids which is chromato-5 graphed through an acid washed silica gel column. By eluting with diethyl ether/hexane the two isomeric products are obtained in practically pure forms.

The first eluted product (530 mg.) is an oil having the following physical characteristics: 3 [«]q° = + 7.6 (c = 0.92 in CHC13) I.R. absorption spectrum (in CDClj); most significative absorption bands occur at the following frequencies (cm.~^): 3580, 3500, 2960» 2.935,2870, 2830,2240 (complex CDClg-product), 1710 (Broad), 1600, 1452, 1405, 1240 (Broad), 1090, 1040, 970. 16 Λ Q Q Λ i ft Ο ί) '« i N.M.R. spectrum: the most significative absorption peaks in CDC13 occur at the following frequencies expressed in 6 units: 0.88; 1.12-2.57; 2.84-3.29; 3.40; 3.80-4.32; 4.41; 5.21-5.70.

The second product which is eluted (200 mg) is an oil having 5 the following characteristics: Γ a|20 = + 31.2 (c = .1.05 in CHC1,) ‘ D N.M.R. spectrum: the most significative absorption peaks in CDC13 occur at the following frequencies expressed in 6 units: 0.88; 1.13-2.62; 3.04-3.37; 3.40, 3.72-4.35; 4.84; 5.21-5.70.

B) By operating in the same manner as before, 1.35 g. of the less polar C^g- isomer obtained in example 1 (i.e. the product having fa ] = + 85.4) are reduced with NaBH, and then L D hydrolyzed with Κ0Η in 50% (by volume) aqueous methanol to give 920 mg. of a mixture of the two corresponding isomeric prostanoic 15 acid having the opposite configurations at the C·^.

The first eluted product (300 mg.) is an oil having the following physical characteristics: ΓαΊ 20 = + 16.2 (c = 1.85 in CHC1,).

L JD N.M.R. spectrum: the most significative absorption peaks in CDC13 20 occur at the following frequencies expressed in 6 units: 0.88; 1.11-2.63; 3.04-3.37; 3.40; 3.72-4.35; 4.86; 5.21-5.70. 17 43831 The second product which is eluted (200 mg.) is an oil having the following physical characteristics: [ct]20 = + 31.7 (c = 1.26 in CHC1,) ' D J N.M.R. spectrum: the most significative absorption peaks in CDClj occur at the following frequencies expressed in 6 units: 0.88; 1.11-2.63; 3.04-3.37; 3.40, 3.72-4.35; 4.86; 5.21-5.70.

All four isomers show microanalytical data in agreement with the formula: C21H36°6‘ EXAMPLE 3 ) (13E)-9a-Acetoxy-lla-hydroxy-16-methoxy-15-oxoprost-13-en-l-oic acid methyl ester (16R and 16S isomers) A) Two grams of the methyl ester of 7- Q5a-acetoxy-2 ¢-formyl - 3a-hydroxycyclopent-la-yl] -heptan-l-oic acid are reacted with the anion of the dimethyl ester of (3-methoxy-2-oxoheptyl)phosphonic acid by following the same procedure described under Example 1, paragraph A.

The two isomers at the position 16 are separated by preparative thin layer chromatography on silica gel plates by using the same eluting system as in Example 1. The less polar C-|g-isomer of the title product is an oily product having the following characteristics: [ct] §° = + 69 (c = 1.04 in CHC13) 18 <13 8 21 I.R. absorption spectrum (neat): the most significative absorption bands occur at the following frequencies (cm.'^)r 3440 (broad), 2920, 2850, 2820, 1740, 1695, 1625, 1460, 1440, 1375, 1240 (broad), 1170, 1120, 1100, 1030, 980.

N.M.R. spectrum: the most significative absorption peaks in CDC13 occur at the following frequencies expressed in & units: 0.9; 2.10; 3.48; 3.70; 3.74; 3.90-4.36; 5.12-5.45; 6.6, 7.04.

The most polar C^g-isomer is an oily product with the following 10 characteristics: Qxj 30 = + 8,3 (° " 1-07 1(1 CHC13J 1 he I.R. and N.M.R. absorption spectra do not show any significant difference if compared with those of the less polar C^g-isomer.

B) The methyl ester of (52)-7-Q5a-acetoxy-2g-dimethoxymethyl-15 3a-(tetrahydropyran-2-yloxy)-cyclopent-la-ylj -5-hepten-l-oic acid is prepared according to the procedure described in Belgian Patent 807,161 for the corresponding 5a-(4-phenylbenzyloxy)homolog by employing acetyl chloride instead of 4-phenyl benzoyl chloride.

See paragraph B of Example 1. 32 Grams of the above product are hydrogenated in 4 liters of ethyl acetate at the atmospheric pressure and at room temperature in the presence of 10 g. of 5% Pd on charcoal as the catalyst.

After evaporation of the solvent 32 g. of the methyl ester of 7-[ 5«-acetoxy-2 B-dimethoxymethyl-3a-(tetrahydropyran-2-yloxy)cyclo-25 pent-la-ylj -heptan-l-oic acid are obtained; This product having 19 43 8 31· 20 [α] ρ = + 34.3 (c = 1.95 in CHC13) is converted by heating on a steam bath for 30 minutes with 60¾ acetic acid to 7-Q5a-acetoxy-2g-formyl-3a-hydroxycyclopent-la-ylJ -heptan-1-oic acid which is employed in the condensation step without any further purification.

EXAMPLE 4 (13E)-9a,11a,15-trihydroxy-16-methoxy-prost-l3-en-l-oic acids methyl esters isomers: (15S,16S); (15Sal6R); (15R,16S) and (15R, 16R) A) The most polar C-jg-isomer obtained in Example 3, paragraph A on 10 (i.e. the product having [a]* = + 8.3), is reduced with NaBH^ according to the same procedure described in Example 2, paragraph A. The 9a-acetate derivative obtained is partially hydrolyzed with K2C03 methanol to afford a mixture of isomeric esters of the title having the same absolute configuration at the C-jg and opposite 1 absolute configurations at the C·^ The two C-|g-isomers are separated by preparative thin layer chromatography by operating in the same manner as described in Example 2, paragraph A and show respectively the following characteristics: i a) less polar product (oil): r η1 [aJD = + 6.1 (c = 1.47 in CHC13).

I.R. absorption spectrum (neat): the most significative absorption bands occur at the following frequencies (cm.-^): «3831 3400 (broad), 2920, 2845, 1745, 1670, 1460, 1440, 1260 (broad), 1200, 1175, 1095 (broad), 1030, 970.

N.M.R. spectrum: the most significative absorption peaks in CDClj occur at the following frequencies expressed in & units: 5 0.91-1.12; 2.844 2.90; 3.34-3.46; 3.68-3.80; 4.40; 5.52-5.78. b) more polar products (oil): [a] p° + 19.3 (c = 1.81 in CHClg).

I.R. absorption spectrum (neat): the most significative absorption bands occur at the following frequencies (cm.-1): 10 3380 (broad), 2920, 2850, 1740, 1670, 1460, 1440, 1260, 1190, 1170, 1090, 1025, 970, 800.

N. M.R. spectrum: the most significative absorption peaks in CDC13 occur at the following frequencies expressed in 5 units: O. 91-1.12; 2.90; 2.95; 3.35-3.47; 3.68-3.84; 4.38; 5.43-5.74.

B) The less polar C^-isomer obtained in Example 3, paragraph A, ([a]p° = + 69) is reduced with NaBH^ and then partially hydrolized with KgCOj in methanol to give a mixture of isomeric prostanoic esters having the same absolute configuration at the C^g and opposite absolute configurations at the C^g.

The two isomers are separated by preparative thin layer chromato graphy and have the following characteristics: Qx]p°= + 13.5 (C = 0.96 in CHC13). d) more polar product (oil) has: [u]p°= + 19.7 (C + 0.66 in CIICI3). 21 43821 These two isomers have the same IR and NMR spectra as the two isomers described under paragraph A.

EXAMPLE 5 (5Z,13E)-9a- Acetoxy-1 1a-hydroxy-16-phenoxy-l 5-oxoprosta-5 5,13-dien-l-oic acid methyl ester (16R and 16S isomers) By following the same procedure described in Example 1 but using the dimethyl ester of (3-phenoxy-2-oxoheptylJphosphonic acid instead of the dimethyl ester of (3-methoxy-2-oxoheptyl) phosphonic acid, the (5Z13£)-9a-acetoxy-lkt-hydroxy-16-10 phenoxy-15-oxoprosta-5,13-dien-l-oic acid methyl ester (16R and 16S isomers) is obtained in a 65% yield. The two isomers in this case are not separated. The isomeric mixture has the following characteristics: N.M.R. spectrum: the most significative absorption peaks in 5 C0C13 occur at the following frequencies expressed in 5 units: 0.9; 2.05; 3.70; 3.8-4.3; 4.64; 5.1-5.5 ; 6.66; 6.8-7.6 The microanalytical data are in agreement with the formula: C29H40°7· EXAMPLE 6 (5Z,13Ε)-9α, 11a,15-trihydroxy-16-phenoxyprosta-5,13-dien-1-oi c acids methyl esters [_isomers (15S,16S and 16R) and (T5R, 16S and 16R)3 In the same way as described in Example 2, (5Z,l3E)-9a-acetoxy-lla-hydroxy-15-phenoxy-15-oxoprosta-5,13-dien-l-oic acid methyl ester (mixture of C-jg-isomers) obtained in Example 5 (10g.) is reduced with NaBH^ at 22 ^ ·3 8 £ i -78°C. The product consisting of a mixture of four isomeric (5Z,13E)-9a-acetoxy-na,15-dihydroxy-16-phenoxyprosta-5,13-dien-l-oic acids methyl esters chromatographed through a silica gel column. By eluting with diethyl ether/hexanes two mixtures of isomeric products 5 are obtained. Each of these two mixtures consists of two products having the same absolute configurations at C-jg- and the opposite configuration at C-|g. The first eluted mixture (4.3 g.) is an oil having the following characteristics: N.M.R. spectrum: the most significative absorption peaks in CDClg 10 occur at the following frequencies expressed in fi units: 2.04; 3.67; 3.7 - 4.4; 5.0-5.8, 6.8-7.5.

The second eluted mixture (2.5 g.) is an oil having the following characteristics: N.M.R. spectrum: the most significative absorption peaks in CDC13 occur 15 at the following frequencies expressed in 6 units: 2.04; 3.67; 3.7-4.4; 5.0-5.8; 6.8-7.5.

The two mixtures were individually hydrolyzed to the two title compounds by dissolving respectively in 160 and 80 ml. of methanol adding respectively 3.2 and 1.6 g. of KgCOg and allowing the mixtures 20 to stand for about 20 hours at room temperature. After neutralization of the reaction mixture with saturated aqueous solutions of NaHgPO^ and extraction with ethyl acetate the title compounds were recovered by evaporation.

The less polar mixture (3.7 g.) is an oil having the following 25 characteristics: 23 4 3 8 S i N.M.R. spectrum: the most significative absorption peaks in CDClg occur at the following frequencies expressed in & units: 3.68; 3.8-4.4; 5.3-5.8; 6.8-7.5 The more polar mixture (1.9 g.) is an oil having the following characteristics: N.M.R. spectrum: the most significative absorption peaks in CDCl3 occur at the following frequencies expressed in δ units: 3.65; 3.7-4.4; 5.2-5.8; 6.8-7.5.

EXAMPLE 7 (51,13E)-9a-Acetoxy-l1a-hydroxy-16-methoxy-l6-methyl-15-oxoprosta- 5,13-dien-l-oic acid methyl ester (16R and 16S isomers) The two title products are obtained in the same way as described in the Example 1 by employing 1,2 g. of NaH (55¾ suspension in mineral oil) in 60 ml. of 1,2-dimethoxyethane, 8.65 g. of dimethyl ester of (3-methyl-3-methoxy-2-oxo-heptyl)phosphonic acid in 60 ml. of dimethoxyethane and 5 g. of (5Z)-7-(5a-acetoxy-2&-formyl-3a-hydroxycyclopent-la-yl)-5-hepten-l-oic acid methyl ester in 45 ml. of 1s2-dimethoxyethane.

The two products are the R and S isomers at the C·^ and are separated in the same way as described in the Example 1.

The less polar isomer (2.5 g.) is an oil having the following characteristics: jjsfj 20 = + 58.7 (C = 0.98 in CHClg). 24 N.M.R. spectrum: the most significative absorption peaks in CDC1^ occur at the following frequencies expressed in S units: 4 3 8 31 1.28; 2.06; 3.20; 3.67; 3.8-4.3; 5.0-5.5; 6.7-7.0.

The more polar product is an oil having the following 5 characteristics: [a] p°= + 26.8 (C = 0.86 in CHCI3).

N.M.R. spectrum; the most significative absorption peaks in CDC13 occur at the following frequencies expressed in 6 units: 1.28; 2.06; 3.18; 3.66; 3.8-4.3; 5.0-5.5; 6.6-6.70. 1° EXAMPLE 8 (5Z,13E)-9a,ll«,15-Trihydroxy-16-methoxy-16-methy1prosta- 5,13-dien-l-oic acids methyl esters-isomers: (15S,16S), (15R.16S), (15R, 16R), (15S, 16R) A) 2.31 Grams of the more polar product obtained according to PD Example 7 ([«] Q =+26.8) are reduced with NaBH^ and after chromatographic separation the two 9a-acetate precursors of the title compounds are partially hydrolyzed according to the same procedure described in Example 6.

The two products obtained are diastereoisomeric (5Z,13£) -9a,11a,15-20 trihydroxy-16-methoxy-16-methylprosta-5,13-dien-l-oic acid methyl ester having the same absolute configurations at the and the opposite absolute configuration at C^g. The two products are purified by chromatography through an acid washed silica gel column. By eluting with ethyl ether/hexane. The less polar product (310 mg.) is an oil 25 having the following characteristics: 25 N.M.R. spectrum: the most significative absorption peaks in CDClj occur at the following frequencies expressed in 6 units: 4 3 8 31 1.07; 3.23; 3.67; 3.8-4.3; 5.2-5.7. r ., 20 LaJ D = + 6,4 (C = 2·67 CHC13)· 5 The more polar product (220 mg.) is an oil having the following characteristics: [ct] 1° = + 50 (0.8 CHC13).

N.M.R. spectrum: the most significative absorption peaks in CDC13 occur at the following frequencies expressed in S units: 10 1.07; 3.23; 3.68; 3.8 - 4.3; 5.2-5.65.

B) By operating as described under paragraph A but utilizing as the starting material 1.5 g. of the less polar product obtained according ΠΛ to Example 7 (JV] D = + 58.7) the following couple of diastereoisomeric compounds having the same absolute configuration at C^g and the 5 opposite absolute configuration at C^g is obtained.

The less polar product (500 mg.) is an oil having the following characteristics: N.M.R. spectrum: the most significative absorption peaks in CDC13 occur at the following frequencies expressed in S units: 0 1.12; 3.25; 3.67; 3.8-4.3; 5.3-5.8. [a]20 = + 0.9 (C = 2,2 m\3).

The more polar product (300 mg.) is an oil having the following characteristics: N.M.R. spectrum: the most significative absorption peaks in CDC13 occur 1 at the following frequencies expressed in & units; 26 1.1; 3.25; 3.68; 3.8-4.3; 5.3-5.8. [a|j0 = + 23.3 (C = 1.33 CHC13). «3821 EXAMPLE 9 (5Z, 13E )-Πα, 15-Di hydroxy-16-methoxy-9-oxoprosta-5,l3-di en-1 -oi 1 acids 5 and methyl esters [isomers: (15S, 16S), (15R, 16S), (15S, 16R), (15R, 16R)J A) 11.10 Grams of the mixture of isomeric (5Z. 13E)-9a-acetoxy-llu,15-dihydroxy-16-methoxyprosta~5,13-dien~l-oic acid methyl esters obtained as in paragraph A of Example 2) dissolved in 600 ml. of 10 benzene and dried by azeotropic distillation, are treated with 72 ml. of 3,4-dihydro-2H-pyran and 102 ml. of anhydrous jp-toluen -sulfonic acid. After 35 minutes the reaction mixture is neutralized with a solution of NaHCOj and extracted with ethyl ether. The organic extract is evaporated to give 14 grams of the corresponding lla,15-bis-tetrahydro-15 pyranyl ether. To 8.46 g. of this latter compound dissolved in 150 ml. of methanol together with 100 ml. of water, a solution of 21 g. of KOH in 100 ml. of 80% methanol is added and the mixture is stirred for two hours at room temperature. A saturated solution of NaHgPO^ is added to the reaction mixture, which is then extracted with ethyl 20 acetate. The organic phase is evaporated in vacuo yielding 6.5 g. of (5Z.13E)-lla,15-bis [[tetrahydro-2H-pyran-2-yl} oxyj -9-hydroxy-16-methoxy-prosta-5,13-dien-l-oic acid. The compound is an oil having the following characteristics: N.M.R. spectrum: The most significative absorption peaks in C0C13 25 occur at the following frequencies expressed in δ units: 27 4 3 8 SI 1.4-1.9; 3.1-4.5; 4.7-5.0; 5.3-5.8; 3.40-3.41; 3.44-3.48.

To 22 g. of Collins reagent (Py2Cr03) dissolved in 400 ml. of anhydrous methylene chloride, 20 grams of Celite (trade mark) and a solution of the previously described compound (6.5 g. dissolved in 100 ml. of anhydrous methylehe chloride) are added.

The reaction mixture is stirred at room temperature for 30 minutes after which period of time the reaction is generally completed. The reaction mixture is poured into one liter of diethyl ether, and then filtered and washed with water.

The organic phase is concentrated to dryness in vacuo. The oily residue is chromatographed on a silica gel column by eluting with ethyl ether:hexane with increasing proportions of diethyl ether to give 3.4 grams of (5Z,13E)-llct,15-bis[(tetrahydro-2H-pyran-2-yl)oxy] -9-oxo-l6-methoxyprosta-5,T3-dien-1-oic acid. 1.650 Grams of this latter compound are dissolved in 250 ml. of a solution of acetic acid:water:tetrahydrofuran (19:11:3 v/v/v).

The reaction mixture is heated at 40°C for 24 hours after which period of time the reaction is generally completed. The reaction mixture is saturated by adding NaCl and extracted with ethyl acetate. The organic phase is washed with water, dried and then concentrated ih vacuo to give 1.4 g. of a mixture of diastereoisomeric compounds at the 15-position.

The mixture of the corresponding diastereoisomeric prostanoic acids accordingly obtained is chromatographed through an acid washed silica gel column by eluting with diethyl ether:hexane with increasing proportions of diethyl ether to give two of the four isomeric acids of the title in practically pure forms. These acids have the same 28 «3831 absolute configuration at C-jg and opposite absolute configuration at C-jg.

The first eluted product (630 rag.) is an oil having the following physical characteristics: [,¾0 = - 77.9 (C = 0.77 in CHClg) 6 N.M.R. spectrum: the most significative absorption peaks in CHClg occur at the following frequencies expressed in 6 units: 3.43; 3.9-4.4; 5.3-5.5; 5.6-5.8; 5.2-5.6.

I.R. absorption spectrum (solution in CDClg): the most significative absorption bands occur at the following frequencies (cm.~^): 10 3400, 3005, 2955, 2930, 2870, 2660, 2240, 1740, 1710, 1600, 1455, 1405, 1240, 1150, 1090, 970.

The second eluted product (300 rag.) is an oil having the following characteristics: [a]"= - 46 (C = 0.93 in CHClg).

N.M.R. spectrum: the most significative absorption peaks in CDClg occur at the following frequencies expressed in 6 units: 3.47; 3.8-4.4-, 5.3-5.5; 5.6-5.8; 5.2-5.6.

I.R. absorption spectrum (solution in CDClg): the most significative absorption bands occur at the following frequencies (cm. ^): 20 3380, 3010, 2955, 2930, 2870, 2660, 2240, 1747, 1715, 1610, 1510, 1455, 1410, 1265, 1240, 1155, 1090, 970.

B) 1.35 Grams of a mixture of isomeric (5Z,13_E)-9a-acetoxy-lla,15- dihydroxy-16-methoxy-prosta-5,13-dien -1-oic acid methyl esters obtained by reduction with NaBH^ of the less polar C16' isomer of 25 Example 1 (see also paragraph B of Example 2), are transformed into 29 4 3 8-1 the corresponding lla,15-bis-tetrahydropyranyl ether by following the same procedure described under paragraph A. 1.30 Grams of 11a,15-bis-tetrahydropyranyl ether are dissolved in 50 ml. of anhydrous methanol, then 800 mg. of anhydrous KgCOg 5 are added. The reaction mixture is stirred at room temperature for 24 hours after which period of time the reaction is generally completed. The reaction mixture is neutralized by adding a strongly acidic resin which is very easily eliminated by filtration.

The filtrate is concentrated to dryness under vacuum to give 1.8 g. of a mixture of two diastereoisomeric (5Z,13E) - 9a - hydroxy -11a,15-bis [tetrahydro-2li-pyran-2-yl)-oxyJ -16-methoxy-prosta- 5,13-dien-l-oic acid methyl esters. By following the same procedure described in paragraph A the above mixture is transformed into a mixture of two diastereoisomeric (5Z,13E)-lla,15-'dihydroxy-T6-15 methoxy-9-oxo-prosta-5,13-dien-l-oic acid methyl esters. These esters have the same absolute configuration at C^g which is opposite to that of the two acids obtained according to paragraph A) and opposite absolute configurations at C-jg. The mixture of diastereoisomeric esters is chromatographed (as described in paragraph A for the two 20 C-|g isomeric acids) giving the two products in practically pure form. The first eluted ester is an.oil having the following characteristics: [a]p° -- 85 (C = 0.82 CHClg).

N.M.R. spectrum: the most significative absorption peaks in CDClg 25 occur at the following frequencies expressed in δ units; 30 3.47; 3.72; 3.8-4.5; 5.3-5.6; 5.7-5.9. *383* I.R. absorption spectrum (solution of CDC13): the most significative absorption bands occur at the following frequencies (cm. ^): 3470, 3005, 2950, 2925, 2870, 2240, 1740, 1600, 5 1455, 1438, 1405, 1245, 1220, 1155, 1090, 970.

The second eluted ester is an oil having the following characteristics: [a]p° = - 77.7 (C = 0.67 CHC13).

N.M.R. spectrum: the most significative absorption peaks in C0C13 10 occur at the following frequencies expressed in 6 units: 3.43; 3.68; 3.9-4.4: 5.2-5.5; 5.6-5.8.

I.R. absorption spectrum (neat);, the most significative absorption bands occur at the following frequencies (cm.-^): 3400, 3005, 2950, 2930, 2870, 2240, 1740, 1455, 1440, 15 1405, 1250, 1220, 1155, 1090, 970.

EXAMPLE 10. (5Z,13E)-11α,15-Di hydroxy-16-methyl-16-methoxy-9-oxoprosta- 5,13-dien-l-oic acids methyl esters isomers (155,165), (15R,16S) _1155.168)(158,168) 20 A) 310 Milligrams of the 9a-acetateprecursor of the more ΛΛ polar product of paragraph A, Example 8 (£uj ^ = + 50), are dissolved in 30 ml. of benzene and dried by azeotropic distillation. To the dried product are added 1 ml. of 3,4-dihydro-2H- 31 i 4 3 8 3 i pyran and 30 rag. of £-toluenesulfonic acid. After 15 minutes the reaction is generally completed. The reaction mixture is neutralized by shaking with a solution of NaHCOg and washed with water. The organic phase is concentrated to dryness under vacuo to give a residue of 400 mg. of the lla,15-bis-tetrahydropyranyl ester derivative. To this product dissolved in 100 ml. of anhydrous methanol are added 400 mg. of anhydrous K2C0g. After 24 hours the reaction mixture is neutralized by addition of acidic resin, and filtered. The filtrate is concentrated to dryness under vacuo to give mg. 360 of (5Z,13j!)-9a-hydroxy-na,15-bis-Qtetrahydropyran-2-yl)- oxyj-16-methyl-l6-methoxy-prosta-5,13-dien oic acid methyl ester. To 50 ml. of anhydrous methylene chloride are added, under mechanical stirring 2.5 g. of Collins reagent (PygCrOg), 2 g. of Celite and 360 mg. of the compound previously obtained.

After 2 hours the reaction mixture is poured into 200 ml. of diethyl ether, filtered, and washed with a solution of NaHCOj and with water. The ethereal phase is concentrated under vacuo to give a residue of 350 mg. of (5Z,13E)-lla,15-bis [tetrahydropyran-2-yl)oxyJ -16-methyl-16-methoxy-9-oxoprosta-5,13-dien-l-oic acid methyl esters. 150 Milligrams of the compound previously obtained are dissolved in 2 ml. of a mixture of CH^COOH, HgO, THF (19:11:3 v/v/v) and heated at 40°C for 2 hours. After this period of time the reaction mixture is neutralized with solid NaHCOj and extracted with diethyl ether. The organic phase is concentrated in vacuo to dryness to give a residue that is chromatographed on an acid washed silica gel column. 32 4 3 8 3 1 The compound obtained is one of the four isomeric esters of the title and has the following characteristics: [o|q° = -45 (C = 0.46 in CHClj).

B) By following the same procedure described under paragraph A, 5 from 630 mg. of the less polar 9a-acetate precursor of the product of paragraph A, Example 8, C"1d^ = + 6·0)> 400 mg. one °f the four isomeric title products are obtained.

This product has: [a] = - 60.6 (C = 1.15 in CHClj).

C) By following the same procedure described under paragraph A, from 600 mg, of the less polar 9a-acetate precursor of the product of paragraph B, Example 8 [a]^ = +9.9), 400 mg. of one of the four isomeric title products are obtained. This product has: [a] p° = - 62 (C = 2.52 in CHCI3).

D) By following the same procedure described under paragraph A, from 700 mg. of the more polar 9a-acetate precursor of the product of paragraph B. Example 8 = - 23.3), 420 mg. of one of the four isomeric title products are obtained. This product has: 20 D = - 48 (C = 1.02 in CHCI3). 33 43821 EXAMPLE 11 (13E)-na,15-Dihydroxy-16-methoxy-9-oxo-prost-13-en-l-oic acids [isomers (15S.16S), (15R.16S), (15S,16R), (15R,16R)J A) 1.7 Grams of the 9a-acetate precursor of the less polar 5 product of paragraph Bs Example 4, [a J = + 13.5) are transformed according to the same procedure described in paragraph A of Example 10 into the corresponding (13EJ-lla,15-dihydroxy-16-methoxy-9-oxo-prost-13-en-l-oic acid methyl ester. Yield 1.02 grams. The compound has the following characteristics: 10 [a^° = - 67.6 (C = 1.08 in CHC13).

N. M.R. spectrum: the most significative absorption peaks in CDC13 occur at the following frequencies expressed in δ units: O. 93; 3.47; 3.69; 3.8-4.5; 5.6-5.9.

B) By operating as described above under paragraph A, 15 starting from the 9a-acetate precursor of the more polar product of paragraph B, Example 4, (C°Q = + 19.7), the corresponding (13E)-11a,15-dihydroxy-16-methoxy-9-oxo-prost-l3-en-l-oic acid methyl ester isomer is obtained having the following characteristics: 20 H20 = - 63-6 (c " T·07 in CHCI3).

N. M.R. spectrum: the most significative absorption peaks in CDCI3 occur at the following frequencies expressed in 6 units: O. 93; 3.48; 3.70; 3.8-4.3; 5.6^5.9. 34 "CO νΛ Ί t-t «3 Ο By following the above procedure and utilizing as the starting materials the two diastereoisomers obtained according to Example 4, paragraph A, the corresponding diastereoisomeric (13£)-lla,15-dihydroxy-16-methoxy-9-oxo-prost-13-en-l-oic acid methyl esters 5 are obtained.

EXAMPLE 12 (5Z, 13E)-15-Hydroxy-l6-methyl-16-methoxy-9-oxoprosta-5-10,13-trien-l-oic acids methyl esters isomers: (15S,16S); (15S.16R), (15R.16R) . '10 A) 300 Milligrams of the (5Z,13£)-lla,15-bis f"(tetrahydro-2H- pyran-Z-yl )oxyJ-16-methyl-16-methoxy-9-oxoprosta~5,13-dien-l-oic acid methyl ester obtained in Example 10, paragraph A, are dissolved in a mixture of 2 ml. of 2N oxalic acid and 2 ml. of THF and then heated to 50°C for 48 hours. The reaction mixture is neutralized lb with solid NaHCO.j and extracted with ethyl ether. The organic phase is concentrated in vacuo; the residue is chromatographed on an acid washed silica gel column by elution with diethyl ether/hexane to give a practically pure product (150 mg) having: [a]p° = + 48.2 (C = 1.68% CHClg).

B) By following the same procedure but utilizing as the starting material the (5Z,13E) - 11a,15 - bis [tetrahydro - 2H - pyran - 2- yl)oxy~] -16-methyl»16-methoxy-9-oxo-prosta-5,13-dien-l-oic acid methyl ester obtained according to Example 10, paragraph B, the corresponding (52,13EJ-15-hydroxy-l6-methyl-16-methoxy-9-oxo-prosta-5,10,13-trien-l-oi c 25 acids methyl esters isomer is obtained this compound has [a]p° = + 74.1 (C = 1.3% in CHC13). 438-1 The two other diastereoisomers are prepared according to the same procedure by employing as the starting materials the other two isomeric {5Z,13JE)-1 let, 15-bis- [(tetrahydro - 2 H - pyran - 2 - yl)oxyJ -16-methyl-16-methoxy-9-oxoprosta-5,13-dien-l-oic acid methyl esters obtained according to Example 10, paragraphs C and D.

EXAMPLE 13 (15Z,13E)-15-Hydroxy-l6-methoxy-9-oxoprosta-5,10,13-tri en -1-oic acids and methyl esters isomer (15S,16S), (15R,15S), (15S.16R), (15R.16R).

) A) By following the same procedure of Example 12 and utilizing as the starting materials the mixture of isomeric (5Ζ,13£)-11α,15-bis £(tetrahydro-2H-pyran-2-yl) oxyj-16-methoxy-9-oxoprosta-5,13-dien- 1-oic acids obtained in Example 9, paragraph A, the corresponding mixture of diastereoisomeric (5Z,13Ei)-l5-hydroxy-l6-methoxy-9-oxoprosta-5,10,13-trien-l-oic acid is obtained.

The mixture has the following characteristics: N.M.R. spectrum: the most significative absorption peaks in CDClg occur at the following frequencies expressed in 6 units: 3.47; 3.68; 3.8-4.3; 5-5.5; 6.16; 7.45.

B) By following the same procedure of Example 12 and utilizing as the starting material the mixture of (5Ζ,13Ε)-Πα,15-bis-[tetrahydro -2H-pyran-2-yl) oxy]-16- methoxy-9-oxoprosta-5,13-dien-l-oic acids methyl esters obtained as in Example 9, paragraph B, the corresponding mixture of diastereoisomeric (5Z,13E)-15-hydroxy-16-methoxy-9- 36 4 3 8 21 oxoprosta-5,13-dien-l-oic acids methyl esters obtained as in Example 9, paragraph B, the corresponding mixture of diastereoisomeric (5Z,13EJ-15-hydroxy~16-methoxy-9-oxoprost-5,10,13-trien-l-oic acid methyl ester is obtained. The two diastereoisomers are 5 separated by preparative thin layer chromatography (eluent hexane: ethyl ester) and have the following characteristics: a) less polar product: [ctj = + 41.2 (C = 1.02 in CHCTg). b) more polar product: jjx] = + 170.8 (C = 0.35 in CHClg).

By following the procedure described in the foregoing Examples 10 the following compounds of the formula I may be prepared and optionally separated into their stereoisomeric components. 37 433 Si nxxxxxxxxxx3=xxxxx x x DOOOOOOOOOOOOOOOO oo >> cxxx£xxxxxxxxxxoxoxx ω ii n -E % % Έ JP JP _c x sz __ x x ΓΧΡΧΧΡΧΧΧΧΧΧΡΧΖ^ΟΟΧΧ EE E >> *>, ?+?+? x p +? 1 -p p p p id-p p p p p p p p p 3=330)33333 3 57333333333 3J3X-CJ=3P-QPX1P ^Xl-aX)jQXIX)-aX2JD r- >» >> >> is C r- ,Ε E CO) r— >> P Φ ι— a) x: >> e o x= >> r- r— t— X CL E Φ B CL E t— >) >) >v «— CL O , P -E .C «— >) r— O S-r— f-ι— JC D- r- »— i~ J£ LQ-rjPP >, X >,S- O >,>,>, Q. >,>>>, O O- ► oxi a> a> α. Φ c or— jr c jc ·— o x p a. 3 0 £. EO-CO)3X:PO)P>^S-OCO«— s- u Q. I t- .C r— (J CUJC Φ _E O SZ Φ 1- f- O i Ο ΟI CL CLp't- E Q*EP 3P Q. CL P 3 ι CO Φ σ -Γ-Ό 0) r— 0) fc. r— p u)\ ΙΛ £.1 HM-E P P X, *> ά| fl| E| DJ · E ,— r- 4* *3* 0) >> >> r- xxxxxxxxxxx-ax-c cl >> x «s x z W p o P z + 0) E 3 Z E CL P ' CM X t I I I I I I I I I I I I I I I I I XXXXXXXXXX XX I X X XXX X OOOOOOOOOOOO CM Ο Ο Ο Ο Ο O II II II II II II II II II II ΙΓ II X II II II II η II XXXX XXXXXXXXOXXXXXX OOOOOOOOOOOO t ο ο ο ο ο o I I I i I r I Ilf I CM f I 111 I cov)co(/>t/)(/jcoco(/) cof Φ in χ to (/) co co to to CCCEECECCEECOCCCCCC fX3rOfOrt3 1 I f I 1 I 1 I I I I I CM CM CM XXXXXXXXXXXXXXX OOOOOOOOOOOOOOO CM CM CM [ II II II II II II II II II II |l II I I I X X I X XXXXXXXXXXXX CM CM CM Ο Ο X O OOOOOOOOOOOOXXX I I O I 1,1 I 1 I I I 1,1. I 1.000 CM CM If CM (0 i/iI col col l l ι X X X X •p" I ·Γ" I ·ι— I «ι-* I pi *r—I v- ♦!- ·Γ- P v- ·«- Ο Ο Ο O ο υ υ ο o| ο ο υ| of ο! οι ι>| ι ι ι . ι , υ| υ| ίΟ (Ο tO rtJ -Ο -Ο -Ο -Ο -Ο jQ Ο Ο Ο ιτ) <κ} rtj nl U U 38 * s 8:: ί In representative biological assays the last isomer described in Example 2, paragraph B ([a] + 31.7)has shown 100¾ abortifacient effect on pregnant female hamsters when administered subcutaneously from the 4th to the 6th day of pregnancy at a dose 5 of 0.5 mg/kg. r- Of) The last isomer described in paragraph A {j_aj ^=- 46) and the last isomer described in paragraph B { j_a j p =-77.7) of Example 9 have shown a long lasting effect in lowering the blood pressure when administered to anaesthetized dogs and cats intraven-10 ously at dose levels of 3 to 10 ug/kg.

The two isomeric mixtures of prostanoic acids obtained in Example 2, paragraphs A and B, before chromatographic separation have been tested in anaesthetized dogs for the inhibitory effects on gastric secretion according to the technique described by 15 Bertaccini et al. in dour. Pharmacol. 28, 360, 1974 and British J. Pharmacol, 52, 219, 1974. Both mixtures have been found effective at doses of 4 to 10 pg/kg.

The mixture obtained according to paragraph A of Example 2 before the chromatographic separation of the isomers, in vitro, 20 has shown a good tracheal relaxant activity without ileal stimulant effect, at a concentration of 5 pg/ml. 39

Claims

1. A compound of the general formula: ^U-r>. 1 | R5 r3 wherein the ring P represents one of the following groups: Γ s f yCHV /C %Lr'' / >h- ' ψ CH r V% V\ ^ v ! OH 5 Oil a be A represents -CHg-CHg- or cis-CH=CH- and B represents trans -CH=CH-, or A and B both represent -C^-CHg; R is a hydrogen, an alkyl group having 1 to 6 carbon atoms, or a cation; 40 8:2 ]_ is an alkyl group having 1 to 6 carbon atoms, phenyl or a phenyl group which is substituted with one or two groups or atoms each independently selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, chlorine, fluorine, bromine 5 and trifluoromethyl; Rg represents a straight chain alkyl radical selected from methyl, ethyl, propyl, butyl, pentyl and hexyl; R3 is hydrogen or methyl; and either is hydrogen or methyl and 10 R5 is hydroxy; or and Rg taken together represent an oxo group, with the proviso that where R^ is hydrogen and Rg is hydroxy, R2 contains at least four carbon atoms.

2. A compound according to claim 1 wherein R is hydrogen, methyl, 15 ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, or a pharmaceutically acceptable non-toxic cation; and R-j is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, phenyl, chlorophenyl, dichlorophenyl, fluorophenyl, methoxyphenyl, dimethyl phenyl or trifluoromethylphenyl. 20

3. A compound according to Claim 1 or Claim 2 wherein Rg is butyl. 4. S ο * 22. A compound as claimed in Claim 1 in which: P represents group c A is -CH2-CH2- B is -CH2-CH2- 5. is H R-] is methyl Rg is butyl R3 is H R^ is H 10 Rg is OH 23. A compound as claimed in Claim 1 in which: P represents group a A is -CH2-CH2- B is -CH=CH- 15. is _ methyl R-| is £-fluorophenyl R2 is butyl R3 is H R^j is H 20 R5 is OH 24. A compound as claimed in Claim 1 in which: P represents group a A is -CH2-CH2- B is -CH=CH- 25. is propyl R-| is £-methoxyphenyl R2 is butyl R3 H R4) ) represent = 0 R5) 48 A I* Ο Ο ί 4k a ο ^ ι 25. A compound as claimed in Claim 1 in which: P represents group a A is -CH2-CH2- B is -CH=CH- 5. is butyl R-| is pentyl R2 is butyl R3 is CH^ R4 is H 10 R5 is OH 26. A compound as claimed in Claim 1 in which: P represents group a A is -CH2-CH2- B is -CH=CH- 15. is H R-j is propyl R2 i s butyl R3 i s CHj R4 ) ,n n ) represent = 0 ^ K5 ) 27. A compound as claimed in Claim 1 in which: P represents group c A is -CH=CH- B is -CH=CH- 25. is Na R-j is m-trifluoromethylphenyl R2 is butyl R3 is H R4 is H R5 is H 1 ,.*' : ν 438S1 28. A compound as claimed in Claim 1 in which: 8 represents group c A is -CH2-CH2- B is -CH=CH- 5. is H R-| is p-f1uorophenyl R2 is butyl R3 is H is H 10 R5 is OH 29. A (5Z,13E) - 9a,11a,15 - trihydroxy - 16 - methoxyprosta -5s13 - dien - 1 - oic acid. 30. A (13E) - 9α,Πα,15 - trihydroxy - 16 - methoxyprost - 13. en - 1 - oic acid methyl ester. 15 31. A (5Z,13E) - 9α,11α,15 - trihydroxy - 16 - phenoxyprosta - 5,13 - dien - 1 - oic acid methyl ester. 32. A (5Z,13E) - 9a, 11a,15 - trihydroxy - 16 - methoxy - 16 -methylprosta - 5,13 - dien - 1 - oic acid methyl ester. 33. A (Z,13E) - Πα,15 - dihydroxy - 16 - methoxy - 9 -20 oxoprosta - 5,13-dien-l-oic acid. 34. A (5Z,13£) - Πα,15 - dihydroxy - 16 - methyl - 16 - methoxy-9 - oxoprosta - 5,13-dien-l-oic acid methyl ester. 1 (. *·% . \ 43831 35. A (13E) - llu,15 - dihydroxy - 16 - methoxy - 9 - oxo - prost 13. en-1-oic acid. 36. A (5Z.13E) - 15 - hydroxy - 16 - methyl - 16 - methoxy - 9 - oxo - prosta-5,10,13-trien-1-oic acid methyl ester. 5 37. A (5Z.13E) - 15 - hydroxy - 16 - methoxy - 9 - oxoprosta - 5,10,13 - trien-l-oic acid. 38. A methyl ester of a compound according to Claim 33. 39. A methyl ester of a compound according to Claim 37. 40. A compound according to Claim 1 and substantially as here-10 inbefore described. Dated this 22nd day of January 1976, TOMKINS & CO., Jtyarili cants1 Agents, (signed) γν 4. S " i R is H R-j is methyl R2 is pentyl R3 is H 5 R^ is H Rg is OH 20. A compound as claimed in Claim 1 in which: P represents group c A is -CH=CH- 10. is -CH=CH- R is H R-| is phenyl R2 is butyl Rg is H 15 R4 is H Rg is OH 21. A compound as claimed in claim 1 in which: P represents group c A is -CH = CH- 20. is -CH = CH- R is H2N+(benzyl)2 R-| is methyl R2 is butyl R3 is methyl 25 R4 is H Rg is OH 1 4. S η ? P represents group b A is -CH=CH- B is -CH=CH~ R is H 5 Rj is isopropyl R2 is butyl R3 i s methyl is H R5 is OH 10 15. A compound as claimed in claim 1 in which: P represents group b A is ~CH=CH- B is -CH=CH- R is H 15 R-| is hexyl R2 is butyl Rj is H R^ is H R5 is OH 20 16. A compound as claimed in Claim 1 in which: P represents group b A is -CH=CH- B is -CH=CH- R is H 25 R1 is phenyl R2 is butyl Rg is H R4 is H R5 is OH 1 4 3 8 3! 17. A compound as claimed in Claim 1 in which: P represents group b A is -CH=CH- B is -CH=CH- 5. is H R-j is m-trifluorophenyl R2 is butyl R3 is H R4 is H 10 R5 is OH 18. A compound as claimed in claim 1 in which: P represents group b A is -CH=CH- B is -CH=CH- 15. is H R-| is 3,4-dichlorophenyl R2 is butyl R3 is H R4 is H 20 Rg is OH 19. A compound as claimed in Claim 1 in which: P represents group b A is -CH=CH- B is -CH=CH- 1 4. A compound according to any preceding claim in which R3 is methyl. 41 „ o 5. A compound according to any preceding claim in which B represents trans-vinylene. 6. A compound according to any preceding claim in which is hydrogen and Rg is hydroxy. 5 7. A compound according to Claim 1 wherein A represents -CH2-CH2- or cis-CH=CH-; B represents trans - CH=CH-; R is hydrogen or methyl; R-j is methyl or phenyl; 10 R2 is butyl; R3 is hydrogen or methyl; and either R4 is hydrogen and Rg is hydroxy; or R4 and Rg taken together represent an oxo group. 8. A compound according to Claim 1 in which 15. represents group b. A represents -CH2-CH2~ or cis -CH=CH-B represents trans - CH=CH-R, R-| and are methyl R2 is butyl !0 R^ is hydrogen and Rg is hydroxy 9. A compound as claimed in Claim 1 in which: 42 4 3 8 S » P represents group a A is -CH2-CH2 B is -CH=CH- R i s Na+ 5 R^ is isopropyl R2 is butyl R.( is H R4 is H R5 is OH 10. A compound as claimed in claim 1 in which: P represents group a A is -CH=CH- B is -CH-CH- R is H 15 R1 is isopropyl R2 is butyl Rg is H R4 is H Rg is OH 20 11. A compound as claimed in claim 1 in which: P represents group a A is -CH=CH- B is -CH=CH- R is Na+ 25 R-j is sec-butyl R2 i s butyl Rg is methyl R4 is H is OH 43 4 3 8 21 12. A compound as claimed in Claim 1 in which P represents a A is -CH*CH- B is -CH=CH- R is H R-j is ethyl Rg is hexyl R3 is H R4 is H Rg is OH 13. A compound as claimed in Claim 1 in which: P represents group a A is -CH=CH- B is -CH=CH- R is H R-| is methyT R2 is butyl Rg is H R4 is methyl is OH 14. A compound as claimed in Claim 1 in which: 1

4. S .** - C LA I US

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