CA1076569A - Prostaglandin analogues - Google Patents

Abstract

Abstract of the Disclosure Novel prostaglandin analogues of the general formula:

(I) wherein the ring P represents one of the groups:

Description

~L~'765~9 This invention relates to novel prostaglandin-like compounds and a process for their preparation. The novel pros~aglandin analogues ; have the general formula CH2 ~ / CH2 H / \ COOR
\ p \ R4 IORl ~~~~~~ ~ B C ---- C 2 ~ Rs R3 ~I) .
wherein the ring P represents one of the groups O

~ \ / CH ~ CH

; OH OH

Ca) ~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; Rl 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; R~ is hydrogen or methyl; and R5 is hydroxy; or R4 and R5 taken together represent an oxo group. In formula I above the broken lines represents bonds which extend behind the plane of the paper (~--configuration) while the thickened lines represent bonds which extend out of the plane of the paper ~-configuration).
; Unless otherwise specified, the expression "alkyl of 1 to 6 carbon atoms" denotes a straight or branched alkyl radical such as for example , .

~765~51 methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl.
The term "cation" denotes a pharmaceutically acceptable nontoxic cation such as for instance Na , Ca , NH4 and organic ammonium cations.
The new compounds have potent prostaglandin-like activity, i.e. they have luteoly*ic, antihyper~ensive, bronchodilating and anti-secretory activity.
In some ins~ances they also display an inhibitory effect of the catabolism of natural prostaglandins.
The compounds o~ the inven~ion may be prepared by following general methods which are widely employed in prostaglandin chemistry. The starting compounds for preparing the new products of this invention are cyclopentane aldehydes of the formula OR6 ~ .

2 COOR

, CHO

wherein A and R hav~ the meanings given above; R6 and R7 each ind~pendently reptesent hydrogen or a protecting group of the hydroxy function, such as for instance lower alkyl o~ 1 to 6 c~rbon atoms, lower alkoxy-lower alkyl wherein ~he lower alkoxy and the lower alkyl portions each have 1 to 6 carbon atoms, trityl, tetrahydropyran-2~yl, ~4-lower alkoxy)-tetrahydrop-yran-4-yl, phenylcarbamyl, biphenylyl-carbamyl, terphenylylcarbamyl or ~n acyl radical selected from 1) alkanoyl of 2 to 8 carbon atoms ~e.g. acetyl, propionyl, butyryl, isobutyryl, pentanoylJ pivaloyl, hexan~yl, heptanoyl, or ;~ octanoyl) 2) benzoyl or mono-substituted ben~oyl wherein the substituent is selec~ed from chloro, bromo, fluoro, nitro, carbo(lower alkoxy~, lower alkyl, ; lower alkoxy, phenyl-lower alkyl (wherein "lower alkoxy" and "lower alkyl"

~ 30 each have I to 4 carbon ato=s), pheryl and cyclohexyl 3) lower alkoxy-,,. ' '.
. .
.

~7656~
carbonyl wherein "lower alkoxy" covers alkoxy having 1 to 4 carbons and halogenated lower alko~y radicals, e.g. 2,2,2-trichloroethoYy and 2,2,2-tribromoethoxy; 4) phenoxycarbonyl;
5) benzylocycarbonyl; and 6) biphenylyloxycarbonyl. The above Starting compounds may be prepared according to methods described in the literature. For instance, D.O.S. 2,217,930 publishcd October 19, 1972 assigned to ICI Ltd. and Belgian Patent 807,161 issued May 9, 1974 assigned to ICI l.td. disclose useful procedures for preparing these intermediates.
The present invention provides a process for preparing a compound of the formula /' - A / 2 / 2 ~ :~
~'~" ' ,.
4 tI) B / R \ C 2 S

herein the ring P represents one of the groups:

0~ , .
O O , -:

/ CH / \ CH' / C \ , CH2 ¦ CH2 ¦ CH

C~l , Oil OH
(a) (b) ~c) ; the symbol A represents -Cll2-CH2- or cis-CI-I=CII-;
- the symbol B represents -CH2-Cll2- or trans CH=CH-;
R is hydrogen, alkyl of 1 to 6 carbon atoms~ or a cation;
Rl is alkyl of 1 to 6 carbon atoms, ~ _ 3 -r.l~
~g ~0~65~9 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; ~-R5 is hydroxy;
or R4 and R5 taken together represent an oxo group; which comprises condensing a cyclopentane aldehyde of the formula ~:

, 2 A ~ \ CH '~' \ COOR

\ j (II) CHO
: ':

wherein R6 and R7 each independently represent hydrogen or a protecting : group of the hydroxyl function, with a reagent of the formula:

OR

R
' "' ~: "
wherein Z represents a group: R
I
(R'0)2P-CH2-CO- or (C6H5~3P=CH-C-wherein R, R2, R3, R4 and R5 have the meanings given above and .
.. ' . ~ - 3a -, .'~.~' . . .

1~76569 is a lower alkyl gxoup of 1 to 5 carbon atoms. in an anhydrous inert solvent at a temperature between 0C and 80C, and in the case when a prostaglandln analogue of formula I is obtained having an oxo group in the 15- position, optionally reducing said group to hydroxy by means of a reagent selected ~rom NaBH4, Zn(BH4~2, diphenyl tin dihydride or a lithium trialkyl borohydride, and in the case when a mixture of stereoisomers is obta~ned, optionally separating out individual isomers from the stereoisomeric mixture.
The aldehyde II may be prepared just prior to contacting with the phosphorus reagent by cleavage of a corresponding acetal or similar derivative in which carbonyl function i5 protected. The condensation between the aldehyde of formula II and the phosphonate or phosphoranylidene derivative leads to a prostaglandin-like compound of formula I wherein B
is a group -C~I~CH-. The use of the above phosphonates or of stabilized phosphoranylidene derivatives (R4+R5-oxo) lead with high specificity to a vinylene group having trans (E) conforma-tion while the use of unstabilized phosphoranylidene derivatives may lead to a mixture of ci~CZ~ and trans (E~ products. In this latter case, separation of the mixture of cis and trans isomers by : ' : .
. .

-3b-~7~5~g~

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 a~ positions 9 and ll protected and said protect-ing group~s~ are still present in ~he f;nal condensation products, they may be eliminated by hydrolytic cleavage. Acid or base catalyzed hydrolysis may be employed depending on the chemical nature of the protecting groups.
Ether and acetal groups are advantageously broken off by acidic cleavage whilst ester groups are cleaYed preferably by hydrolysis with diluted bases or by transesterification.
A product of formula I, wherein B represents a group -CH=CH- may be easily converted to the corresponding derivative wherein B is a group -CH~-CH~- by hydrogenation of the vinylene group in the presence of a hydro-genation catalyst such as a noble metal. This step allows simultaneous hydrogenation of the vinylene group in the upper chain if A represents cis-Ct~=CH_.
A product I resulting from condensation bet~een the aldehyde II
and a phosphorus reagent and having an oxo group in 15-position of the pros-taglandin skeleton ~R4+R5=oxo) may be reduced to the corresponding hydroxy derivative by means of borohydride type reagents, e.g. NaBH4, Zn(BH4)2, diphenyl tin dihydride or lithium trialkyl borohydrides. Alternatively, the oxo group in the 15-posi~ion may be converted into hydroxy with simultaneous introduction of a methyl group on the same carbon center 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 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, dimethoxyethane, benzeneJ
dioxane at a temperature between 0C and 80C.

~07~s~g When a phosphonate deri~ative is employed as the reaction partner, it is first transformed into the corresponding anion by addition of about one equimolecular propor~ioD of an alkali me~al hydrideO The phosphoranylid-ene reagen~s in turn are ob~ained in 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 or two hydroxy groups ~for instance Rl-H and/or R5 =OH), two or three equimolecular propor~ions respectively, of the dehydrohalogenating base are required.
The products of formula I may have one or two asyn~tric carbon atoms in the lower side chain. More par~icularly, when R5 represents a hydroxy group, the carbon atoms bearing this substituent and the neighbouring carbon bearing the group-ORl are asymmetric centers. Therefore, four diff-erent isomeric compounds of formula I may be obtained each having at the correspondingly substituted car~ons of the prostaglandin skeleton ( C15 and C16) one of the following combinations of absolute configurations: tR,R);
(P,S); tS,R); and (S,S).
When R4 and R5 taken together represent an oxo group at the 15-position the possible isomers are two in number, due to the chirality centerat C16 The several isomers may be directly prepared by using reagents with the appropriate configurations at the asymmetric centers, or by stere-ospecific reactions or, alternatively, when the course of reaction does not allow any control of the stereochemistry, the isomers may be separated by common techinques which are well known in the art, such as for instance, chromatographic methods.
According to the process outlined above, prostaglandin-like deri-vatives belonging to F series (i.e. having ring P with structure a) are obtained directly from the condensation reaction between the aldehyde II and 6~i69 ~he phosphorus reagent. Prostaglandin-like derivative of formula I belonging to A and E series (i.e. having ring P with structur0s corresponding respectiv-ely to b and c) are easily prepared by converstion of F series derivatives according to chemical procedures well known in the prostaglandin field.
The starting phosphorane reagen~s may be prepared by condensing methylphosphonic acid lower alkyl esters with ~-substituted carboxlic acid lower alkyl esters ~or the corresponding acid chlorides) according to the following reaction scheme:

, O IORl O p 1 10 (R 0)2PCH3 I XOC-I-R2 - ~ (R'0~2-P-CH2-CO-I-R2 ~ XH

X = OR"; Cl wherein Rl , P~2 , R3 and R' have the meanings given above and R" represents an aliphatic radical of 1 to 5 carbon ato~s. This procedure involves firstly transformation of the methyl phosphonates into the corresponding anion by addition of butyl lithil~ at -78C in tetrahydrofuran and then contacting with the carboxylic acid ester ~or the corresponding acid chloride) for about one hour at the same temperature.
The phosphorane s~ar~ing reagents may be prepared rom the corres-ponding phosphonium halides which in turn may be obtained by reaction oftriphenylphosphine with a suitable halogenide of the formula 40Rl I f wherein halo stands for iodo, chloro or bromo and Rl, R2, R3, R4 and R5 have the meanings given above.
When R4 and R5 taken together represent an oxo group, the correspon-ding phosphorane reagents are more conveniently prepared by acylation of .

~76~

methylenetriphenyl phosphorane with a lower alkyl ester or chloride of an acid of the formula fRl HOOC-C-R

wherein Rl, R2 and R3 have the meanings given above. These aliphatic acids and the corresponding esters and chlorides may be prepared according to literature methods such as, for example, those described respectively by 10 E.J, Salmi in Ann. Acad. Sci~ ~ennicae, A 48, 17, 1937 (see C.A. 33, 81743 and V.F. Kucherov in Zhur. Obshchei Khim.20, 1885, 1950 (see C.A. 45, 2928).
This invention is illustrated by the following non-limitati~e specific Examples.

9 ~-Acetoxy-ll -hydroxy-16-methoxy-15-oxo-prosta- ~ diene-l-oic acid methyl ester (16R and 16S isomers) A) 1.3 Grams ~30 m moles) of a 55% suspension of sodium hydride in mineral oil are washed under nitrogen atmosphere with hexane and then 20 ml. of -~ anhydrous dimethoxyethane are added thereto. To this suspension at a tem-; 20 perature of about o~C, 8 g. ~32 m ~oles)of the dimethyl ester of ~3-methoxy-2-oxo-heptyl) phosphonic acid dissolved in 50 ml. of anhydrous dimethoxy-ethane are added. After standing for 15 minutes at the room temperakure ;~ the mixture is cooled to 0C and 6.24 g. of the methyl ester of 7-~5 -;, ' , .acetoxy- 2 ~ - formyl-3 a -hydroxycyclopent-l -yl)-5tZ)-hepten-l-oic acid ~20 m moles), dissolved in lnO ml. of anhydrous dimethoxyethane, are added.
The temperature is then allowed to rise to about 20C and ~he mixture is ; maintained under stirring for four hours. The reaction mixture is then ;~ poured into an aqueous solution saturated with NaH2P04 which is subsequently extracted with ethyl acetate.

The organic extrac~ is evaporated to give 14.1 g. of a crude pro-~37~56g3 duct containing two components. The two products which are the R and S
isomers at the 16 position are separated by preparative thin layer chromato-graphy by eluting first with ethyl ether/hexane 7:3 and then with ethyl ether/hexane 85:15. In this way, 1.38 g. of the less polar isomer and 1.410 g. of the more polar isomer are obtained.
The less polar isomer is an oily product having the ollowing phy-sical characteristis:
[~] D =~ 85.4 (c = 0.985% in CHC13) ; U.V.absorption spectrum in methanol:
~ max(m~ 238, Elcm = 267 I.R. absorption spectrum (neat): the most significant absorption bands occur ~ at the following frequencies (cm. l);
; 3400, 2910, 2860, 1740, 1700(sharp), 1625, 1440, 1370, 1240, 1100.N.M.R. spectrum: the mos~ significant absorption peaks in CDC13 occur at the following frequencies expressed in C uni~s:
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.
The micronaly~ical data are in agreement with the row formula C24H3807.
The more polar isomer is an oily product having the following physical characteristics:
[~]2D0 = +lg.8 (c=1.05 in CHC13) U,V. absorp~ion spectrum in methanol:
max ~m ~) 238, El%cm =282 I.R. absorption spectrum (neat): the most significant absorption bands occur at the following frequencies(cm. 1):
3450, 2920, 2860, 1730, 1700(sharp), 1620, 1435, 1370, 13209 1240, 1100, 1040, 985.
N.M.R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
0.8~; 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 row formula C24H3807.

~7~

33 The crude methyl ester of 7-(5- ~ -acetoxy-2 ~-formyl-3 ~ -hydroxy-cyclopent-l ~ -yl)-5(Z)-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 7-~5~ -(4-phenyl-benzoyloxy)-2 ~-formyl-3 a -hydroxy-cyclopent-l ~-yl)-5(Z)-hepten-l-oic acid methyl ester, the only difference residing in the acylation of the 5 a -hydroxy group on the cyclo-pentane ring with acetyl chloride ins~ead of 4-phenylbenzoyl chloride.
The corresponding precursor from which the above starting material is obtained by hydrolysis wi*h 60% acetic acid is the methyl ester of 7-~5 ~ -acetoxy-2 ~-dime~hoxymethyl-3 ~ -(tetrahydropyran-2-yloxy)-cyclopent-1 ~ -yl)-5(Z~-hepten-l_oic acid which is an oil having the following physical characteristics:

~n = + 26.5 (c=1.02% in CHC13) I.R. absorption spectrum (neat~: the most significan¢ absorption bands occur at the following frequencies (cm. ):
2900, 2850, 1730, 1435, 1365, 1240, 1120, 1083-1040, 1020, 870. N.M~R.
spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units: 1.24-2,48; 2.02 and 2.03;

3.22-4.44; 3.40 and 3.42; 4.54-4.75; 4.gO-5.20; 5.22-5.51.
The microanalytical data are in aggreement wi~h the row formula EXAMplE 2 9 ~ , 11 ~ , 15-trihydroxy-16-methoxy-prosta-5(Z2~ 13(E)-diene-l-oic acids risomers:(l5S,16S),(15S,16R),(lSR,16S)and(15R~16R) A) To a solution of 1.3 g. of the more polar C16- isomer obtained in Example 1 (i.e. the product having [~]DO= +19.8) in 150 ml. of methanol are added dropwise at -10C, 300 mg. of NaBH4 in 15 ml. of ice water. m e reaction mixture is stirred at -10 C until the reaction is completed ~the reaction course is followed by thin layer chromatography) and then it is poured into a saturated solution of NaH2P04. Extraction with ethyl aceta~e ~7~
and evaporation of the organic extract gives 1.15 g. of a mixture of isomeric 9~-acetoxy~ , 15-dihydroxy-16-methoxy-prosta-5(Z), 13(E)-diene-l-oic acid methyl esters having the same absolu~e configuration at the 16-position and ~he opposite absolute configurations at the 15-position. m e N.M.R. spectrum and the microanalytical data are in ag~ecment 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 50% methanol is added and the mixture is stirred for one hour at room temperature after which period of time the ; reaction is generally completed.
A saturated solution of NaH2P04 is added to the reaction mixture, which is then extracted with ethyl acetateO
m e organic phase is evaporated in vacuo yielding 1 g. of a product consisting of an isomeric mixture of the corresponding prostanoic acids which is chromatographed through an acid washed silicagel column. By eluting with ethyl 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:
[~]D - + 7.6 (c=0.92% in CHC13~ IoR~ absorption spectrum(in CDC13):
most significant absorption bands occur at the following frequencies . ~ .
(cm. ): 3580, 3500, 2960, 2935, 2870, 2830, 2240 (complex CDC13-product), 1710(Broad), 1600, 1452~ 1405, 1240(Broad), 1090, 1040, 970.

,~ , .

~L~76S~;9 N.M.R. spec~rum: the mos~ significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
0.88; 1.12-2.57; 2.84-3.29; 3.~0; 3.80-4.32; 4.41; 5.21-5.70.
The second product which is eluted ~200mg) is an oil ha~ing the following characteristics:
[]D =~31.2 (c=1.05% in CHC13) N.M.R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
0.88; 1.13-2.62; 3.~4-3.37; 3.40, 3,72-4.3S; 4.84; 5.21-5.70.

B) By operating in the same manner as before9 1.35 g. of the less polar C16-isomer obtained in example 1 (i.e the product ha~ing ~a]D =~85.4) are reduced with NaBH4 and then hydrolyzed with KOH ;n 50% methanol to give 920 mg. of a mixture of the two corresponding isomeric prostanoic acids having the opposite configurations at C15.
The first eluted product ~300 mg.) is an oil having the following physical characteristics:
[]D =~16.2 (c=1.85% in CHC13).
N.M.R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:

0.88; 1.11-2.63;'3.04-3.37; 3.40; 3.72-4.35; 4.86; ~.21-5.70.
The second product which is eluted (200 mg.) is an oil having the following physical characteristics:
[a]D=t 31.7 ~c=1.26% in CHC13~
N.M.R. spectrum: the most signiicant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
0.88, 1.11-2.63; 3.04-3.37; 3.40, 3.72-4.35; 4.86; 5.21-5.7~.
All four isomers show microanalytical data in agreement with the theoretical row formula:

~U

~76S6~

9a -Acetoxy-ll -hydroxy-16-methoxy-15-oxo-prosta-13~E)-ene-l-oic acid methyl ester (16R and 16S isomers) A) Two grams of the methyl ester of 7-[5-acetoxy-2B -formyl-3a- thydroxy) : -cyclopent-l a-yl]-hepten-l-oic acid are reacted with the anion of the dimethyl ester of (3-methoxy-2-oxo-heptyl)phosphonic acid by following the same procedure described in Example 1, paragraph A.
The two isomers at the 16-position are separated.by preparative thin layer chromatography on silicagel plates by using the same eluting system as in Example 1. The less polar C16-isomer of ~he title product is an oily produc~ having the following characteristics:
[~]2=~69 (c=1.04% in CHC13) I.R. absorption spectrum ~neat): the most significant absorption bands occur at the following frequencies (cm. 1):
3440(broad), 2920, 2850, 2820, 1740, 1695, 1625, 1460, 1440, 1375, 1240 (broad) J 1170, 1120, 1100, 1030, 980.
N.M.R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ unilts:
0,9; 2.10; 3.48; 3,70; 3.7~; 3.90-4.36; 5.12-5.45; 6.6, 7.04.
: The more polar G15-isomer is an oily product with the following characteristics:
[a]D =~ 8.3 (c=1.07% in CHC13) The I.R. and N,M.R. absorption spectra do not show any significant difference if compared with those of the less polar C16-isomer.
B) The methyl ester of 7-[5~ -acetoxy-2~ -dimethoxymethyl-3a - (tetrahydro-pyran-2-yloxy)-cyclopent-la-yl~-5tZ)-hepten-l-oic acid is prepared according to the procedure described in Belgian Patent 8~7,161 for the corresponding 5a-(4-phenylbenzyloxy)homolog by employing acetyl chloride instead of 4-phenylbenzoyl chloride. See paragraph B of example 1, 32 Grams of the above product are hydrogenated in 4 liters of ethyl acetate at atmospheric pressure ~d at room temperature in the presence of 10 g.

, ~7656~3 of 5% Pd on charcoal as the catalyst. After evaporation of the solvent, 32 g, of ~he methyl ester of 7-[5~ -acetoxy-2 ~ -dimethoxymethyl-3a -(tetra-hydropyran-2-yloxy)-cyclopent-1 ~ -yl]-heptan-l-oic acid are obtained: this product having [ ]D0 =~ 34.3 (c=1~95% in CHCl ) is converted by heating on a steam bath for 30 minutes with 60% acetic acid to 7-[5- ~ acetoxy-2~ -form-yl-3a -(hydroxy)-cyclopent-l~ -yl]-heptan-l-oic acid which is employed in the condensation step without any further purification.

9~ , 15-trihydroxy-16-methoxy-prosta-13(E)-eD0-l-oic acid methyl esters ~isomers : (15S, 16S); (15S, 16R); (15R, 16S) and (15R, 16R)]

A) The more polar C16 -isomer obtained in Example 3, paragraph A (i.e, the product having [~]D0 = ~8.3)~ is reduced with NaBH4 according to ~he proced-ure described in Example 2, paragraph A. The 9a-acetate derivative obtained is par~ially hydrolized with K2C03 methanol to afford a mixture of isomeric esters of the title compound having the same absolute configuration at C16 and opposite absolute config~rations at C15.
The two C15-isomers are separated by preparative thin layer chro-matography by operating in the same manner as described in Example 2, parag-raph A and show respectively the following characteristics:20 a) less polar product (oil):
~a 3D0 =~6.1 (c-1.47% in CHC13) I,R. absorptio~ spectrum (neat): the most significant absorption bands occur at the following frequencies (cm. 1):
3400 ~broad), 2920, 2845, 1745, 1670, 1460, 1440, 1260 (broad), 1200, 1175, 1095 (broad), 1030, 970.
N.M.R. spectrum: ~he most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
0,91-1.12; 2.84; 2.90; 3.34-3.46; 3.68-3.80; ~.40; 5.52-5.78.

b) more polar product ~oil):
[ ~]D + 19.3~c=1.81% in CHC13).

~65~

I.R. absorption spectrum (neat): the most significant absorption bands occur at the following frequencies (cm. 1):
3380(broad), 2920~ 2~50, 1740, 1670, 1460, 1440, 1260, 1190, 1170, 1090, 1025, 97~, 800.
N.M,R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
0.91-1.12; 2.90; 2.95; 3.35-3.~7; 3.68-3.84; 4.38; 5.43-5.74.
B) The less polar C16 -isomer obtained in Example 3, paragraph A, ([]20 = ~ 69~ is reduced with NaBI-14 and then partially hydrolized with K2C03 in methanol to give a mixture of isomeric prostanoic esters having the same absolute configuration at C16 and opposite absolute configurations at C15.
The two isomers are separated by preparative thin layer chroma-tography and have the following characteristics:
c) less polar product (oil) has:
[a]D = + 13.5 (C=0.96% in CHC13).
d) more polar product (oil) has:
[a]D = ~ 19.7 (C=0.66~ in CHC13).
Thése two isomers have ~he same IR and NMR spectra as the two isomers described under paragraph A.
~xample 5 9 -Acetoxy-ll -hydroxy-16-phenoxy-15-oxo-prosta-5 (Z), 13 (E)-diene-l-oic ; - acid methyl ester (16R and 16S isomers) . _ . . . .. . .
By the following the procedure described in Example 1, but using the dimethyl ester of (3-phenoxy-2-oxo-heptyl) phosphonic acid instead of the dimethyl ester of (3-methoxy-2-oxo-heptyl) phosphonic acid, the 9a-acetoxy-ll-hydroxy-16-phenoxy-15-oxo-prosta-5 (Z), 13 (E)-diene-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 follow-ing characteristics:

56~

N.M.R. spectrum: the most significant absorption peaks in CDC13 ~ccur a~
the following frequencies expressed in ~ 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 theoretical row formula: C29~1407 Example 6 9~ , 15-trihydroxy-16-phenoxy-prosta-5 (Z), 13_(E? diene-l-oic acid methyl esters [isomers (15S, 16S and 16R) and ~15R, 16S and_l6R~]
In the same way as describcd in Example 2, 9a-acetoxy-11~-hydroxy-16-phenoxy-15-oxo-prosta-5 (Z), 13(E)-diene-l-oic acid methyl ester (mixture of C16 isomers) ob~ained in Example 5 (10 g.) is reduced with NaBH4 at -78 C.
The product consisting of a mixture of four isomeric 9~-acetoxy-11~, 15-dihydroxy-16-phenoxy-prosta-5(Z), 13(E)-diene-l-oic acid methyl esters is chromatographed through a silica gel column. By eluting with ethyl ether/
hexane two mixtures of isomeric products are obtained. Each of these mixtures consists of a pair of products having the same absolute configur-ations at C15- and opposite configurations at C16. The first eluted mixture ~4.3 g.) is an oil having the following characteristics:
N.M.R. spectrum: the most significant absorption p~aks in CDC13 occur at the following frequencies expressed in ~ uni~s:
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 significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
2.04; 3.67; 3.7-4.4; 5.0-5.8; 6.8-7.5 The ~wo mixtures were indlvidually hydrolized to the two title com-pounds by dissolving respectively in 160 and 80 ml. of methanol, adding respec~ively 3.2 and 1.6gof K2C~3 and allowing the mixtures to s~and for ~bout 20 hours at room temperature. After neutralization of the reaction ~76~6~

mixture with sa~urated aqueous solutions of NaH2P04 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 characteristics:
N.M.R. spec~rum: the most significant absorption peaks in CDCl3 occur at the following frequencies expressed in C 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 significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
3.65; 3.7-4.4; 5.2-5.8; 6.8-7.5 Example 7 9-Acetoxy-ll~-hydroxy~16-methoxy-16-methyl-15-oxo-prosta~5(Z), 13 (E)-diene-l-oic acid methyl ester tl6R c~nd 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 t55% suspension in mineral oil~
in 60 ml. of dimethoxy ethane, 8.65 g. of the dimethyl ester of (3-methyl-3-methoxy -2-oxo-heptyl) phosphonic acid in 60 ml. of dimethoxye~hane, and 5 g. of 7-~5a-acetoxy-2~-formyl-3~-hydroxy-cyclopent-1~-yl~-5 tZ~-hepten-l-oic acid methyl ester in 45 ml, of dimethoxyethane.
The two products are the R and S isomers at C16 and are separated in the same way as described in Example I.
The less polar isomer ~2.5 g.) is an oil having the following chara-cteristicsO
[~]2Do _ +58.7 ~C=0.98% in CHC13) N.M.R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
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 characteri-~L~7656~

stics:
[a]20= +26.8 (C=0.86% in CIIC13) N.M.R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
1.28; 2.06; 3.18; 3.66; 3.8-4.3; 5.0-5.5; 6.6-6.70 Example 8 9a,11~,15-Trihydroxy-16-methoxy-16-me~hyl-prosta-5 (Z), 13 ~E)-diene-l-oic acid methyl esters [isomers: ~15S, 16S), (15R, 16S), ~lSR, 16R)?~15S, 16R)]
A) 2.31 grams of the more polar product obtained according to Example 7 ~[a]D= ~26.8) are reduced with NaBH4 and after chromatographic separation, ; 10 the two 9a-acetate precursors of the title compounds are partially hydrolized according to the procedure described in Example 6.
The two products obtained are diastIereoisomeric 9,11 ~, 15-trihydr-oxy-16-methoxy-16-methyl-prosta-5~Z), 13~E)-diene-l-oic acid methyl es~ers having the same absolute configuration at C16 and opposite absolute configuration at C15. The two products are purified by chromatography through an acid washed silicagPl column, by eluting with ethyl ether/hexane.
The less polar produc~ (310 mg.) is an oil having the following characteris-tics:

N.M.R. spectrum: the most significan~ absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:

1.07; 3.23; 3.67; 3.8-4.3; 5.2-5.7.

[~lD =~6.4(C=2.67% CHC13) The more polar product ~220 mg.) is an oil having the following characteristics:

[a]D = ~ 50~0.8% CHC13) N.M.R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
1.07; 3.23; 3.68; 3.8-4.3; 5.2-5.65 B) By opera~ing as described under paragraph A but u~iliæing as the starting ~76~

material 1.5 g. of the less polar product obtained according to Example 7 ; ~[u]20 =~58.7), the following pair of diastereoisomeric compounds having the same absolute configuratio~ at C16 and the opposite absolute configuration at C15 is obtained.
The less polar product (500 mg.) is an oil having the following characteristics:
N.M.R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
1.12; 3.25; 3.67; 3.8-4.3; 5.3-5.8 [a]D =~9.9 (C=2.2% CHC13) The more polar product ~300 mg.) is an oil having the following characteristics:
N.M R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
1.1; 3.25; 3.68; 3.8-4.3; 5.3-5.8.
i [a]20 =~23.3 ~C=1.33% CHC13) Exam~_e 9 lla?15-Dihydroxy-16-methoxy-9-oxo-prosta-5(Z), 13(E)-diene-l-oic acids and methyl esters risomers:(l5S,16S), (15R,16S) , (15S,16R), (15R,16R)]
A) 11.10 grams of the mixture of isomeric 9a-acetoxy-lla, 15-dihydroxy-16-methoxy-prosta-5 (Z), 13 (E)-diene-l-oic acid methyl esters (obtained as in paragraph A o Example 2) dissolved in 600 ml. of benzene and dried by azeotropic distillation, are treated with 72 ml. of 3,4-dihydro-2H-pyran and 102 mg. of anhydrous p-toluen-sulfonic acid. After 35 minutes ~he reaction mixture is neutralized with a solution of NaHC03 and extracted with ethyl ether. The organic extract is evaporated to give 14 grams of the corresponding lla,15-bis-tetrahydropyranylether. 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.

~6569 A saturated solution of NaH2PO~ is added to the reaction mixture, which is then extracted witll ethyl acetate. The organic phase is evaporated in vacuo yi~lding 6 5 g. of lla, 15-bis[(tetrahydro-2H-pyran-2-yl)oxy] -9-hydroxy-16-methoxy-prosta-5 (Z), 13 (E)-dîene-l-oic acid. The compound is an oil having the following characteristics:
N.M.R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
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 (Py2CrO3) dissolved in 400 ml. of anhy-drous methylene chloride, 20 grams of celite and a solution of the previouslydescribed compound (6.5 g. dissolved in 100 ml. of anhydrous methylene chloride) are added.
The reaction mixture is stirred at room temperature for 30 minutes after which period of time the reaction is generally complete. The reaction mixture is poured into one liter of ethyl ether, and khen filtered and washed with water.
The organic phase is concentrated to dryness in vacuo. The oily residue is chromatographed on a silicagel column by eluting with ethyl ether:hexane with increasing proportions of ethyl ether to give 3.4 grams of lla,15-bis[(tetrahydro-2H-pyran-2-yl)oxy ]-9-oxa-16-methoxy-prosta-5 (Z), 13 tE)-diene-l-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). The reaction mixture is heated at 40C for 24 hours after which period of time the reaction is generally completed. The reaction mixture is saturated by adding NaCl and cxtracted with ethyl acetate. The organic phase is washed with water, dried and then concentrated in 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 silicagel 1~

~765~g column by eluting with ethyl ether:hexane with increasing proportions of ethyl ether to givs two of the four isomeric acids of the title compound in practically pure form. These acids have the same absolute cQnfiguration a* C16 and opposite absolute configurations at C15.
The first eluted product (630 mg.) is an oil having the following physical characteristics:
[a]D =~77-g (C=0.77% in CHC13) N.M.R. spectrum: the most signiicant absorption peaks in CHC13 occur at the following frequencies eXpressed in ~ 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 CDC13): the most significant absorption bands occur at the following frequencies ~cm. 1):
3400,3005,2955,2930,2~70,2660,2~40,1740,1710,1600,1455,1405,1240,1150,109~, 970.
The second eluted product (300 mg.) is an oil having the following characteristics:
[ ]D 46 ~C=0.93% in CHC13) N.M.R. spectrum: the most significant absorp~ion peaks in CDC13 occur at the following frequencies expressed in ~ 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 CDC13): the most significant absorption bands occur at the following requencies (cm. 1):
3380,3010,2955,2930,2870,2660,~240,1747,1715,1610,151~,1455,1410,1265,1240, 1155,10909970.
B) 1.35 grams of a mixture of isomeric 9~ acetoxy~ , 15-dihydroxy-16-methoxy-prosta-5 tZ), 13(E)-diene-l-oic acid methyl esters obtained by reduction with ~aBH4 of the less polar C16-isomer o Example 1 ~see also paragraph B of Example 2), are transformed into the corresponding 11,15-bis-tetrahydropyranyl ether by following the procedure described under para-graph A~ of this Example.

:~7~56~

1.30 grams of 11~, 15-bis-tetrahydropyranyl ether are dissolved in 50 ml. of anhydrous methanol, then 800 mg. of anhydrous K2C03 are added. -~
The reaction mixture is stirred at room tem~erature for 24 hours af~er which - period of time the reaction is generally complete. The reaction mixture is neutralized by adding a strongly acidic resin ~Yhich is very easily eliminated by filtration. The filtrate is concentrated to dryness under vacuum to give l.lB g. of a mixture of two diastereoisomeric 9a-hydroxy-11~,15-bis [~tetrahydro-2~-l-pyran-2-yl)oxy~-9-oxa-16-methoxy-prosta-5~Z),13(E)-diene-l-oic acid methyl esters.
~ By following the proc~dure described in paragraph Aofthis Example, the above mixture is transformed into a mixture of two diastereoisomeric 11 15-dihydroxy-16-methoxy-9-oxa^prosta-5(~), 13 (E?-diene-l-oic acid methyl esters. These ~sters have the same absolute configuration at C16 (which is opposite to that of the two acids obtained according to paragraph A) and opposite absolute configurations at C15.
The mixture of diastereoisomeric esters is chromatographed ~as described in paragraph A for the t~Yo C16 isomeric acids) giving the two products in practically pure form. The first eluted ester is an oil having ~he following charac~eristics:
[~]D =-85 (C=0.82% ~C13) N.M.R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
; 3,47; 3.72; 3.8-4.5; 5.3-5.6; 5.7-5.9.
I.R. absorption spectrum ~solution of CDC13): the most significant absorption bands oceur at the follo~ing frequencies (cm. );
3470,3005,2950,2925,2870,2240,1740,1600,1455,1438,1~0571245,1220,1155,1090, 970.
The second eluted ester is an oil having the following characte-ristics:
[~]D = ~77 7 (C=0.67% CHC13) : ~.

.
,: ' , ~L~76569 N.M.R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
3.43; 3.68; 3.9-4.4; 5.2-5.5; 5.6-5.8.
I.R. absorption spectrum (neat): the most significant absorption bands occur a~ the following frequencies tcm. 1):
3400,3005,2950~2930,2870,2240,1740,1455,1440,1405,1250,1220,1155,10gO,970.
xample 10 11,15-Dihydroxy-16-me~hyl-16-methoxy-9-oxo-prosta-5 (Z), 13 (E)-diene-l-. -- . .
oic acid me~hyl esters [isomers ~15S,16S), (15R,16S), (15S,16R), ~15R,16R)]

A) 310 milligrams of the 9~-acetate precursor of the more polar product of paragraph A, Example 8([~]2 =+50), are dissolved in 30 ml. of benzene and dried by aseotropic distillation. To the dried product are added 1 ml. of 3,4-dihydro-2~1-pyran and 30 mg. of p-toluenesulfonic acid. After 15 minutes the reaction is generally complete. The reaction mixture is neutralized by shaking with a solution of NaHC03 and washed with water. The organic phase is concentrated to dryness under vacuo to give a residue of 400 mg.
of the 11~, 15-bis-tetrahydropyranyl ether derivative. To this product dissolved in 100 ml. of anhydrous methanol are added 400 mg. of anhydrous K2CO3. After 24 hours the reaction mixture is neutralized by the addition of ac;dic resin, and filtered. The filtrate is concentrated to dryness u_der vacuo to give 360 mg. of 9~-hydroxy-11~, 15-bis-[(tetrahydropyran-2-yl) oxy]-16-methyl-16-me*hoxy-prosta-5 ~Z), 13 ~E)-diene oic acid me~hyl ester.
To 50 ml. of anhydrous methylene chloride are added with mechanical stirring, 2.5 g. of Collins reagent ~Py2CrO3), 2 g. of celite and 360 mg. of the com-pound pre~iously obtained.
After 2 hours the reaction mixture is poured into 200 ml. of ethyl ether, filtered, and washed with a solution of NaHC03 and with wa~er.

The e~hereal phase is concentrated undér vacuo to give a residue o 350mg. of 11~15-bis[(tetrahydropyran-2-yl)oxy]-16-methyl-16-methoxy-9-oxo-prosta-5 ~Z), 13 (E)-diene-l-oic acid methyl esters.

1Q17~;~i6~

150 milligrams of the compound previoùsly obtained are dissol~ed in 2 ]nl. of a mixture of CH3COOH, H20, THF (19:11:3) and heated at 40C for 2 hoursO After this period of time the reaction mixture is neutralized wi~h solid NaHC03 and extracted with ethyl ether.
The organic phrse is concentrated in vacuo todryness to give a residue that is chroma~ograph~d on an acid washed silicagel column.
The compound obtained is one of the four isomeric esters of the title compound and has the following characteristics:
[]2=_45 (C=0.46% in CHC13) B) By following the procedure described in paragraph A, from 630 mg. of the less polar 9-acetate precursor of the product of paragraph A, Example 8, ([a~20 =l6.0), 400 mg. of one of the four isomeric title products are obtained. This product has:
[~]D =-60.6 (C=1.15% in CHC13) C) By following the procedure described in paragraph A, from 600 mg. of the less polar 9a-acetate precursor of the product of paragraph B, Example 3 ~[a]D =~9.9)400 mg. of one of the four i~ meric title products are obtained.
This product has:
[]20 = -62(C=2.52% in CHC13) D) By following the procedure described in paragraph A~ from 700 mg. of the more pslar 9a-acetate precursor of the product of paragraph B, Example 8 - [a]20 =-23.3), 420 mg. of one of the four isomeric title products are obtainet.
This product has: -[a]20 =-48 (C=1.02% in CHC13) Example 11 lla? 15-Dihydroxy 16-methoxy-9-oxa-prosta-13 ~E)-ene-l-oic acids ~isomers C15S,16S), (15R,16S), (15S, 16R), (15R,16R)]
A) 1.7 grams of the 9-acetate precursor of the less polar product of para-graph B, Example 4, ([]D0 = ~13~5) are transformed according to the procedure described in paragraph A of Example 10 into the corresponding 11-15-dihydro-~3 ~L~7~5~9 ; xy-16-methoxy-9-oxa-prosta-13 (E)-ene-l-oic acid methyl ester. Yield 1.02 grams. Ihe compound has the following characteristics:
[~]D = -67.6 (C=1.08% in CHC13) ; N.M.R. spectrum: the most signific~t absorption peaks in CDC13 occur at the following frequen~ies expressed in ~ units:
;~ 0.93; 3.47; 3.6~; 3.8~4.5; 5.6-5.9.
B) By operating as described above in paragraph A, starting from the 9a-acetate precursor of the more polar product of paragr~ph B, Example 4, ([]D = ~lY.7), the corresponding 11~, 15-dihydroxy-16-methoxy-9-oxa-pros~a-13 (E)-ene-l-oic acid methyl ester isomer is obtained having the following characteristics:
[~]20 = -63.6 (C=1.07% in CHC13) N.M.R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
0.93; 3.48; 3.70; 3.8-4.3; 5.6-5.9.
By following the above procedure and utilizing as the starting ma-terials the two diastereoisomers obtained according to Example 4, paragraph ~! A, the corresponding diastereoisomeric lla,15-dihydroxy-16-methoxy-9-oxa-prosta~l3 (E)-ene-l-oic acid methyl esters are obtained.
~xample 12 ~A ~ E)-triene-l-oic acids methyl esters [isomers: (lSS,16S), (15R,16S); (15S,16R); (15RJ16R?]
A) 300 milligrams of ~he 11~,15-bis[(tetrahydro-2H-pyran 2-yl)oxy] -16-methyl-16-methoxy-9-oxo-prosta-5 (Z),13 (E)-diene-l-oic acid methyl ester obtained in Example 109 paragraph A, are dissolved in a mixture of 2 ml.
of 2N oxalic acid and 2 ml. of THF and then heated ~o 50C for 48 hours.
i The reaction mixture is neutralized with solid NaHC03 and extracted with ethyl ether. The organic phase is concentrated in vacuo; the residue is chromatographed on an acid washed silicagel column by elution with ethyl ether/hexane to give a practically pure product (150 mg) having:

~i'65~i~
[~]D =~48.2 ~C=1.68% in CHC13) B) By following the same procedure but utilizing as the starting material the 11~,15-bis [~tetrahydro-2H-pyran-2-yl)oxy]-16-methyl-16-methoxy-9-oxo-prosta-5 (Z),13 ~E)-diene-l-oic acid methyl ester obtained according to Exam-ple 10, paragraph B, the corresponding 15-hydroxy-16-methyl-16-methoxy-9-oxa-prosta-5 (Z)~1OJ13 ~E~-triene-l-oic acids methyl esters isomer is obtained. This compound has:

[~]~ 74-1 ~C=1.3% in CHC13) The two other diastereoisomeric are prepared according to the same procedure by employing as the starting materials the other two isomeric 11~, 15-bis~tetrahydro-2H-pyran-2-yl)oxy]-16 methyl-16-methoxy-9-oxo-prosta-5 ~Z)-13 ~E)-diene-l-oic acid methyl esters obtained according to Example 10, paragraphs C and D.
Example 13 , 15-Hydroxy-16-methoxy-9-oxa-prosta-5 ~Z),10,13 ~E)-triene-l-oic acids and methyl esters [isomer_(lSS,l~ 15R,16S), (15S,16R), (15R,16R)].
A) By following the procedure of Example 12 and utilizing as the starting materials the mixture of isomeric 11~,15-bis[(tetrahydro-2H-pyran-2-yl) oxy]
-16-methoxy-9-oxa-prosta-5 (Z),13 (E)-diene-l-oic acids obtained in Example 9, paragraph A, the corresponding mixture of diastereoisomeric 15-hydroxy-16-methoxy-9-oxa-prosta 5 ~Z),10,13 ~E)-triene-l-oic acid is obtained.
The mixture has the following characteristics:
N.M.R. spectrum: the most significant absorption peaks in CDC13 occur at the following frequencies expressed in ~ units:
3.47; 3.68; 3.8-4.3; 5-5.5; 6.16; 7.45.
B) By follo~ing the procedure of Example 12 and utilizing as the starting material the mixture of 11~,15-bis-[~tetrahydro-2H-pyran-2-yl)oxy]-16-methoxy -9-oxa-prosta-5 ~Z),13~E)-diene-l-oic acid methyl esters obtained as in Example 9, paragraph B, the corresponding mixture of diastereoisomeric 15-hydroxy-16-methoxy-9-oxa-prosta-5 ~Z),10,13 ~E)-triene-l-oic acid methyl ~76S~

ester is obtained. Th0 two diastereoisomers are separated by preparative thin layer chromatography ~eluant hexane: ethyl ester) and have the following characteristics:
a) less polar product:[a]D = l 41.2 ~C=1.02% in CHC13) b3 more polar product:~a]20 = + 170.8 (C=0,35% in CHC13) By following procedures analagous to those described in the fore-going Examples the following compounds of the formula I were prepared and, optionally, separated into their stereoisomeric components:

5~ ~ ' : ,' C~ !r4 :r, .C ~ -- X T ~r X ~ .

' ' ~ ~ I O ~ ~ ~ S , 2~ ~ h ~ ~ h D

t-~
, ~ ','' ',' ~+z c ~ a~
+~
. ~
~ 3 a a ~ ~ a ~ a a a 3 ~ ~i a ~ ~ -q q ~i q ~ q q ~ 3, q q a a q q : -a~ 3 ~ 3 ~ ' 3N ~ `
¢ ~ 3 ~, ~, 3 q ~ a, q q q a, 3~ q 3, .

i5~

o o r I r-~
~ ~ .
e~ x r-l ~4 r~r-l r I r-l _I r-l r-l ) 5 5 3 h ~ ~ a 3 ,s ~3~ ~ ,1:) ~~D ~ .0 D 0 .

h O
r-l r-lr-l O S ~ r~ I ~ r-li .r~ r-l O r-l v~ r ,s ~ h el 0 ~ ~
C 0 h I . ~ .c I ,s e e ~ P~ 4 e ,~

. ' .
N
rO
~_, r r _~ r r X ~ ~ 0 :S ~ lt a ~' a ~ a ~ ~ a ~

~ a a a a ' ' 3 a ' ~ a a,,,, v ~, " ~
a 3 ~ 3 ~
.

.

~L~7 b;S69 In representative biological assays the last isomer described in Example 2, paragraph B ~[~]D0 = ~31.7) has shown 100~ abortifacient effect on preganant female hamsters when administered subcutaneously ~rom the 4th to ~he 6th day of pregnancy in a dose of 0.5 mg/kg.
The last isomer described in paragraph A (~]20 = -46~ and the last isomer described in paragraph B (~]D0 = _77.7~ of Example 9 have shown a long lasting effect in lowering the blood pressure when administered to anaesthetized dogs and cats intravenously at dose levels of 3 to lOug/kg.
The two isomeric mixtures of prostanoic acids obtained in Example 2, paragraphs A and B, before chromatographic separation have been tested in anaesthetized clogs for the inhibitory effects on gastric secretion according to the technique described by Rertaccini et al. in Jour. Pharmacol.
28, 360,1974 and British J~ Pharmacol. 52, 219,1974. Both mixtures have been found effective at doses of 4 to 10 ~g/kg.
The mix~ure obtained according to paragraph A of Example 2 before the chromatographic separation of the isomers, in vitro,has shown good tracheal relaxant activity without ideal stimulant effect, at a concentration of S~g/ml.

. . .

:

:

Claims (10)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the 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;
R5 is hydroxy;
or R4 and R5 taken together represent an oxo group; which comprises con-densing a cyclopentane aldehyde of the formula (II) wherein R6 and R7 each independently represent hydrogen or a protecting group of the hydroxyl function, with a reagent of the formula:
wherein Z represents a group:

or wherein R, R2, R3, R4 and R5 have the meanings given above and R' is a lower alkyl group of 1 to 5 carbon atoms in an anhydrous inert solvent at a temperature between 0°C and 80°C, and in the case when a prostaglandin ana-logue of formula I is obtained having an oxo group in the 15- position, optionally reducing said group to hydroxy by means of a reagent selected from NaBH4, Zn(BH4)2, diphenyl tin dihydride or a lithium trialkyl borohydride, and in the case when a mixture of stereoisomers is obtained, optionally sepa-rating out individual isomers from the stereoisomeric mixture.

2. A process according to claim 1, wherein:
R is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl, or a pharmaceutically acceptable non-toxic cation; and R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl.

3. A process according to claim 1, wherein the symbol .beta. represents trans-CH=CH-;
R is hydrogen or methyl;
R1 is methyl;
R2 is butyl; and R4 is hydrogen.

4. A compound 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;
R5 is hydroxy; or R4 and R5 taken together represent an oxo group, and stereoisomers thereof, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.

5. A compound according to claim 4, wherein R is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl, or a pharmaceutically acceptable non-toxic cation; and R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl, whenever prepared by the process claimed in claim 2, or by an obvious chemical equivalent thereof.

6. A compound according to claim 4, wherein the symbol B represents a group trans-CH=CH-;
R is hydrogen or methyl;
R1 is methyl;
R2 is butyl; and R4 is hydrogen, whenever prepared by the process claimed in claim 3, or by an obvious chemical equivalent thereof.

7. A process according to claim 1 which comprises condensing 7-(5.alpha.-acetoxy-2.beta.-formyl-3.alpha.-hydroxycyclopent-1.alpha.-yl)-5(2)-hepten-1-oic acid with (3-methoxy-2-oxo-heptyl) phosphonic acid dimethyl ester to give 9.alpha.-acetoxy-11.alpha.-hydroxy-16-methoxy-15 oxo-prosta-5(Z), 13(E)-dione-1-oic acid methyl ester, reducing the 15 oxo atom to 15 hydroxyl group, and then converting the 9.alpha.-acetoxy group to a 9 oxo atom to give 11.alpha., 15-dihydroxy-16-methoxy-9-oxo-prosta-5(Z, 13(E)-diene-1-oic acid methyl ester.

8. 11.alpha., 15-Dihydroxy-16-methoxy-9-oxo-prosta-5(Z), 13(E)-diene-1-oic acid methyl ester, whenever prepared by the process claimed in claim 7, or by an obvious chemical equivalent thereof.

9. A process according to claim 1 which comprises condensing 7-(5.alpha.-acetoxy-2.beta.-formyl-3.alpha.-hydroxy-cyclopent-1.alpha.-yl)-5(Z)-hepten-1-oic acid methyl ester with (3-methyl-3-methoxy-2-oxo-heptyl) phosphoric acid dimethyl ester to give 9.alpha.-acetoxy-11.alpha.-hydroxy-16-methoxy-16-methyl-15-oxo-prosta-5(Z), 13(E) -diene-1-oic acid methyl ester, reducing the 15 oxo atom to 15 hydroxy group, and then converting the 9.alpha.-acetoxy group to a 9 oxo atom to give 11.alpha.,15-dihydroxy-16-methoxy-16-methyl-9-oxo-prosta-5(Z), 13(E)-diene-1-oic acid methyl ester.

10. 11.alpha., 15-Dihydroxy-16-methoxy-16-methyl-9-oxo-prosta-5(Z), 13(E)-diene-1-oic acid methyl ester, whenever prepared by the process claimed in claim 9, or by an obvious chemical equivalent thereof.