CA1056376A - PGF .beta.-PROSTAGLANDINS AND PROCESS FOR THEIR PREPARATION - Google Patents

Abstract

A B S T R A C T

New therapeutically useful PGF.beta. prostaglandins having the formula (I) (I) wherein R is a tetrazolyl or a -CH2-OH group or a -COOR"' group, wherein R " ' is an amino group or an-ORIV radical, wherein RIV is hydrogen, C1-C12 alkyl, trihaloalkyl or a pharmaceutically acceptable cation; R1 may be hydrogen or a CORb acyl, wherein Rb may be hydrogen or C1-C10 alkyl, a ? -(CH2)n1 -radical,wherein n1 may be zero or an integer number of 1 to 5 and ? is a phenyl radical which may be unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkoxy, trifluoromethyl, phenyl and cycoalkyl-alkyl, or Rb may be the following radical:

wherein m is an integer number of 1 to 4, X is -CH2- or an oxygen or a sulphur atom and n1 is s above defined; one of R2 and R3 is hydroxy and the other is hydrogen or C1-C6 alkyl R4 and R5 are independently hydrogen or C1-C6 alkyl;
n is zero or n integer of 1 to S; R6 is hydrogen or a

Description

1~5~;37f~
It is well-known that PGF~-prostaglandins, especially PGF2B, (5c,13t-9~,lla,15S-trihydroxy-prostadienoic acid) possess useful pharmacologi-cal properties; in particular, they have a relaxing effect on the bronchial muscle, proving therefore to be suitable for the treatment of asthma.
PGF~-prostaglandins have been always prepared up to now by reduction ~`` ~
of the corresponding PGE prostaglandins ~ ¦ ~

- In all cases, however, this reaction, either the reduction be per-formed with mixed hydrides, for example, alkaline borohydrides, or, when pos-sible, catalytically, leads to a mixture of the two epimer alcohols (9~ and 9), which mixture has to be separated by means of complex and expensive chromatographic techniques resulting in a yield of PGF~ derivatives not higher than 50%.
We have now found a new general method for the synthesis of PGF~ prostaglandins ~ wherein R' is hydrogen or acyl, OH
starting from the corresponding PGF -prostaglandins enabling to obtain practically quantitative yields.
Object of the present invention is therefore a process for the pre-paration of PGF~ prostaglandins,and their 9-acyloxy derivatives comprising the selective esterification with a carboxylic acid of the 9a-hydroxy group of a PGFa prostaglandin, in presence of a compound of formula MV y3, wherein M is a metalloid of the V group and Y is an alkyl, a dialkylamino or an aryl group, and of a hydrogen-acceptor agent; so as to obtain directly a PGF~-9acyloxy derivative which may be converted into the desired PGF~ prostaglandin by con-ventional methods.

In the PGF prostaglandin, used as starting material, since the esterification must be selective, only the 9a-hydroxy group is free, while the other hydroxy groups, in particular the 11- and 15- hydroxy groups, are pro-tected by conventional protecting groups, especially by the formation of ethers wherein the ethereal bond may be splitted under mild reaction conditions.

- 2 -, " , ~ ~ . ., ' : ' 5~37t; 3-Y'h~ afore-cit~d estsrif`ication re~cliol1, inv~lvln~ th~ coMpletc inver~
sion of conli~llratjon of t~le hydroYy group in the 9-positiorl, is trlsr~IGre particll]arly impoItant, not on]y for the reason that, as before said,~allows ~o obtain practically quantitative yields, but also in view of the fact that a PGI~ prostaclandin with the frce hydroxy group in the 9-position and the hydroxy groups in the 11- and 15-pv~itions protected~ in particular by the formation of ethereal bonds as ahove reportedt is the usual intermediate in the most common m~thods of total synthesis of natural prostaglandins and prosta=
giandin-like compounds [Fried et al., J. Am. Chem. Soc., 94, 4342 (1972); Corey et al., J. Am. Chem. Soc., 91, 5675 (1969) and 92, 397 (1970)~

The above-mentioned reaction is preferably carried out at room temperature in an in~rt anhydrous solvent, preferably selected from the group consisting of aromatic hydrocarbons, such as, benzene and toluenet linear or cyclic ethers, for example, ethylether, dimethoxyethane, tetrahydrofuran and dioxane, and halogenated hydrocarbons, such as, dichloromethane and di=
chloroethane.
All the used reagents, that are, the compound of formula M~ Y3, the esterifying acid and the hydrogen-acceptor agent, are employed in the proportion of at lea6t 1.5 mole per each mole of alcohol;
2 to 4 moles of the reagents per each mole of alcohol are preferably used.

In the compo1md of formula M~ Y3~ MY is preferably P, As, Sb, especially P. Again in the same compound, when Y is alkyl, it is preferably a C1-C6 alkyl group, preferably methyl, while, when Y i8 aryl, it iæ preferably phenyl; when Y is dialkylamino, it is preferably dimethylamino.

The compound of formula MY Y3 is preferably selected from the group consisting of triphenylphosphine, triphenylarsine, triphenylstilbi~e and hexamethyltriaminophosphine of formula ~CH3)2N l P-. .. "' ` ' ` : : ' -lOS~37f~

The hydrogen acceptor used is preferably an ester or an amide of the azodicarboxylic acid, but also other hydrogen-acceptors may be used, for instance, quinones, such as chloranil (2,3,5,6-tetrachloro-benzoquinone) and 2,3-dicyano-5,6-dichloro-benzoquinone, or azobisformamide.
Preferred example of a hydrogen-acceptor is the compound of formula N - COOR"
N - COOR"
wherein R" is a generic alkyl group.
The esterification reaction with inversion of configuration of the hydroxy group in the 9- position takes place therefore according to the following scheme:

HO " ~M y3 Y3MV-~ O ' ~ "`
N-COOR" HN-COOR" +
~+ N-COOR" HN-COOR"
Ra-COOH

wherein Z is an acyloxy group or a known protecting group bound to the ring by means of an ethereal oxygen atom and Ra is the residue of a generic carboxylic acid, and with the following reaction sequence, involving the formation of an oxonium intermediate salt, from which the oxide of the com-pound of formula Mv y3 and the ester of the inverted alcohol are formed:

"O a ~ v N-COOR"
R -C-OH + b - C-OH + M Y +
c N-COOR" '~
[Ra-C'O(-) a ~ ~ (+! v HNI-COOR"

~ c ~ ~ HN-COOR" -g R -C-O-C - b + MVY -~ O
a ~ c 3 rAl ~ --4--, . . . . .
' ' -, '' ' "., ''' - ,. ' ' -'~ ', ,. ' ' 105f~37~
whereill ti)e syni~ols n, b, c on the carbon atom of the ~lcohol m~l three ~u~s-titu~n~s different th one from the others (i.e., the carbon atom of` tho alcohol i6 asy~etrical).

~]lere is no restriction as concerns ~h~ kind of carboxylic acid to be used as esterifying agent, which may be either aliphatic, such as, acetic, formic or propionic acid, or aromatic, such as, benzoic and ~-phenylbenzo~c,~or cycloaliphatic, æuch as, cyclopentyl-pro=
pionic ac~d,-or cycloaro~.atic, such as, phenylacetic, heterocyclic or cycloheterocyclic acid, for example, (2'-tetrahydrofuryl)-propio=

nic acid.
As stated above, the hydroxy groups present in the 1t- and 15-positions in the PGF~ pros-taglandin used as starting material as well as othsr hydroxy groups eventually present,are protected in conven=
tional manner by means of suitable protecting groups, such as, the ester and the ethereal groups.
Examples of conventional protecting ~thereal groups are the acetalic ethers, the enolethers and the silylethers.
The preferred ethereal groups are:
CH
I 3 ~\ PAlk (CH3)3S i O-~ ((`H3)3-C-C-S i O- , JXo ~-- ' O(OAIk ' ~
wherein W is -O- or -CH2- and Alk is a C1-C6 alkyl group.
The protection of the hydroxy groups, as hereabove said, m~y take place also by acylation with suitable acids, such as, for example, acetic acid or p-phenylbenzoic acid. Again, the carboxylic group at the end of the ~ -chain, when present, as well as other carboxylic groups cventually present, are analogously protected by means of esterification with a generic alcohol.

- : : -' - ~: . ,.', - :

-105~376 As hereabove stated, the reaction is practically quantitative, in that the quantity of ~8(9) unsaturated derivatives is always lower than 10%
and usually not higher than 2-3%, in particular, by using the p-phenyl-benzoic acid or the benzoic acid as esterifying agent.
The PGF~-9-acyloxy prostaglandin obtained by the reaction may be, in any sequence order, purified, deetherified, and optionally saponified, re-acylated or salified.
The purification may be easily performed with column chromatography, preferably of silica gel, using as eluents for example methylPnechloride, ethylether, cyclohexane, ethylacetate.
When the compound of formula MV y3 is hexamethyltriaminophosphine, the resulting oxide [(CH3)2N]3P~O may be directly removed by washing with acids, and thus, the purification process is simpler, avoiding the purifica-tion step on column at this stage.
The purification step may take place either before or after the deetherification and saponification steps.
The deetherification is preferably carried out in water-miscible solvents, such as aliphatic alcohols with a low molecular weight, linear or cyclic ethers, tetrahydrofuran, dioxan, dimethoxyethane or ketones, for ex-ample acetone, by reaction with aqueous mineral acids, e.g. hydrochloric acid or sulphuric 0.5-2N acid or a polycarboxylic acid; e.g. 0.25 N oxalic acid at a temperature ranging between the room temperature and the boiling tempera-ture and by subsequent evaporation of the organic solvent under vacuum.
Dependently from the reaction conditions used, the saponification of the compound resulting from the esterification of the 9-hydroxy-PGF
prostaglandin may lead to different results.
In fact, when the saponification is perfo-rmed in an alcohol, preferably an aliphatic alcohol, in presence of a base, such as anhydrous potassium carbonate, PGF~ prostaglandins are obtained, ~-105~i37~
whercin tne cet~boY.ylic gl~ol~p at the en~ of thc ~ -chain~ whon p1~esent, as well as othcr eventual carboxylic ~,roups~ re~ain estcrified, hhile when -the saponi~icc;tion takes placs in aqueo1ls alcohols~ frce carboxylic groups ~re obtained.
In both cases~ from the saporification~ compourlds are obtained~
wherein either tha 9 ~-hydroxy group or the other hydroxy groups~
if previously protected by acylation, are free }~dro~y groups.
Both the optional re-acylation of the 9~ -hydroxy group and the optional salification with pharmaceutically ac=
ceptable bases are performed in a conventional manner according to the usual methods of organic chemistry.

The above-reported method may be used in the synthesis of any PGF~ prostaglandin, either natural or synthetic~
whichever are the modifications on the ~-and ~-side chains.

Examples of PGF~ prostaglandins obtainable according to this method are those havi*~-the following general formula (N):

R10 ~ `~ D
~ i (C~-chain) HO ~ ~
~ chain) wherein D is a free or salified carboxy group, a carboxy~mide , a carboxyester~ a tetrazol~l or a -CH2-OH group;
R1 is hydrogen or a -CO-R acyl group~ wherein R is the residue of a generic carboxylic acid;-one of R2 and R3 is hydroxy and the other is hydrogen or alkyl;

A is -CH2-CH2- or cis-CH=CH- ;
B may be -CH2-CH2-~ tracs-CH=CH- or -C _ C- ;
-~- (CH2) -R6 g oup~ or the ci~-CH2-CH=CH-CH -CH grou wherein n may be zero or an integer number of 1 to 5;

`" 105637~ ~3 R4 and R5 may be hydrogen or alkyl; ~ C~i2) R6 may be hy~-ogen or a radical -CH ¦ , wherein X may X
be -CH2- or an oxygen or a sulphu.r atom and m is an integer mlmber of 1 to 4; a which prostaglandins may be obtained star.ting from/PGF~ pro=

staglandin of the following formula.(Q) :
HO H
' ~ A'^~ D' (Q) - ~G

R'2 R'3 wherein D' may be a carboxyester, a carboxyamide, a tetra~o~lor a -CH2-OH radical having the hydroxy group free or protected in a conventional manner;
A, B and G are as above defined;
Z and one of R'2 and R'3 are an acyloxy group or a protecting group bound to the ring or respectivaly to the chain through an ethereal oxygen atom, and the other f R'2 and R'3 is hydrogen or alkyl;
by reaction with a carboxylic acid R -COOH, wherei.n R is as above defined~ in presence of a compound of formula M~ Y3, wherein M~ and Y are as defined above and of a hydrogen-acz I

1; ceptorlto give a compound of the following general formula (T):
1;~ , ' .
R CO~ D"

B ~ (T) Z
'2 ~R~
: wherein D" is a carboxy ester, a carboxy amide~ a tetrazo~¦or a : -CH20COR ~roup or a -CH20H radical having the hydroxy group protected in a conventional manner, as above reported, and R , R'2~ R'3~ A, B, G and Z are as hereabove defined, which,in any sequence order, is purified, deetherified, : and optionally saponified~ re-acylated or salified.
__ .. .................. ........ . . . . . . . .

~': ' .'' ' `' " - .

---` 105~376i The PGF prostaglandins of formula (Q), used as starting materials, may be prepared according to methods described in literature; for instance, the PGF prostaglandins, wherein B is trans-CH=CH-, may be obtained according to the hereabove-described Corey's general method, the prostaglandins wherein B is -CH2-CH2- may be obtained from those wherein B is -CH-CH- by catalytic hydrogenation e.g. with palladium on charcoal, while the PFG prostaglandins wherein B is -C_C- may be prepared for example as described by C. Gandolfi et al., II Farmaco, Ed.Sc., 27, 1125 (1972). The various substituents may be easily obtained on the ~-chain, using a suitable phosphonate obtainable ac-cording to E. J. Corey et al., J. Am. Chem. Soc., 90, 3247 (1968) and E. J.
Corey and G.K. Kwiatkowsky, J. Am. Chem. Soc., 88, 5654 (1966).
Object of the present invention are also new PGF~ prostaglandinshaving the following general formula (I) A~'~ ~'--~ R

~ I R2 R4 H OH C-C-C- ~~ (CH2) -R6 (I) wherein R is a tetrazolyl of a -CH2-OH group or a -COR"' group, wherein R"' is an amino group or an -ORIV radical, wherein RIV is hydrogen, Cl-C12 alkyl, trihaloalkyl or a pharmaceutically acceptable cation; Rl may be hy-drogen or a -CORb acyl, wherein Rb may be hydrogen or Cl-C10 alkyl, a P
-~CH2)n - radical, wherein n1 may be zero or an integer number of 1 to 5 and 0 is a phenyl radical which may be unsubstituted or substituted by one or -more substituents selected from ~he group consisting of halogen, alkoxy, tri-fluoromethyl, phenyl and cycloalkyl-alkyl, or Rb may be the following radical: -tC~ - .-.-- .

¦ / CH-(CH2)n -. . .

105~ 7~

wherein m is an integer number of 1 to 4, X is -CH2- or an oxygen or a sul-phur atom and nl is as above defined; one of R2 and R3 is hydroxy and the other is hydrogen or Cl-C6 alkyl; R4 and R5 are independently hydrogen or Cl-C6 alkyl; n is zero or an integer of 1 to 5;

(CH2)m R6 is hydrogen or a -CH \ ¦ group, wherein X and m are as above defined; A may be -CH2-CH2 or cis-CH=CH-; and -wherein - when R is a -COR" ' group, wherein R"' is an -ORIV radical, n is

3 or 4, A is cis-CH=CH-, Rl and R6 are hydrogen and one of R4 and R5 is hydrogen - the other is a 16S- or 16R- Cl-C6 alkyl;
which prostaglandins may be obtained according to the above-described method ; from a PGF~ derivative of formula ~II) RV
(II) =R'2 R4 C_C-~ CH2)n R6 , Rr3 5 wherein RV is a tetrazolyl or a -CH2-OH group having the hydroxy group free or protected in a conventional manner, or a -COR"' group, wherein R"' is an amino or an -ORIV radical, wherein RIV is C~-C12 alkyl or trihaloalkyl;
A, R4, R5, R6 n, Z, R'2 and R'3 are as hereabove defined.
The PGF derivatives of formula ~II), used as starting materials, are obtained according to the method hereabove described with respect to the preparation of the PGF~ derivatives of formula (Q) wherein B is -C_C-.
In the formulae of the present specification, the broken lines ~//////) indicate that the substituents are in the ~-configuration, i.e. be-low the plane of the ring or, respectively, of the chain, while the heavy solid lines ~ _ ) indicate that the substituents are in the ~-configuration, i.e. above the plane of the ring or, respectively, of the chain.

As is evident from the above-reported formulae, ~he hydroxy group bound to the carbon atom in the 15- position may be either in the ~-configu-15 ` 15 ration ( -~C - ~: 15S-ols), or in the ~-configuration ~ -~C j : 15R-ols).

.. " , . . . .
-, . . ' :: ,- . , - :

:` 10563'76 And again, in the above-reported formulae, - when R is a -COR" ' group, wherein R"' is an -ORIV radical, n is 3 or 4, A is cis-CH=CH-, Rl and R6 are hydrogen and only an alkyl group is present on the carbon atom in the 16- position - this substituent may only be in ~-position.
t -146) or in the ~-position ( -l) That is to say, in other words, that when at the same time R is a COR"' group, wherein R"' is an -OR V radical, n is 3 or 4, A is cis-CH=CH-, Rl and R6 are hydrogen and only an alkyl group is present on the carbon atom in ~he 16-position, said alkyl group can never be a 16~S,R)-alkyl group, but it can only be 16S- or 16R- alkyl group, while, when R is different from -COR" ', wherein R"' is an -ORIV radical, and/or n is different from 3 or 4, and/or A is -CH2-CH2 , and/or Rl and/or R6 are different from hydrogen, the above formulae include also 16(S,R~-alkyl compounds, i.e., the mixture of the two 16R- and 16S- diastereoisomers.
- / ~fH2)m In formula ~I), when R6 is the -CH X group, it is prefer-ably selected from the group consisting of cyclohexyl, cyclopentyl, 2'-tetra-hydrofuryl; n is preferably 2 or 4, while nl is preferably zero, 1 or 2.
When 0 is substituted by a cycloalkyl-alkyl group, said group is preferably cyclopentyl-methyl or cyclopentyl-ethyl or cyclohexyl-methyl or cyclohexyl-ethyl.
When Rb is Cl-C10 alkyl, it is preferably methyl, or ethyl or propyl; when it is a 0-~CH2)n -radical, it is preferably phenyl, benzyl or ~CH2) p-phenyl-phenyl; when, the Rb is (C 2)nl C~ \ X

It is preferably cyclopentyl-ethyl or cyclohexyl-ethyl or (2'-tetrahydro~uryl)-ethyl. When R is trihaloalkyl, it is preferably -CH2-CC13. The alkyl groups may be branched or straight chain.
Examples of cations of pharmaceutically acceptable bases are either metallic cations, such as, sodium, potassium, calcium and aluminium, or organ-ic amino cations, such as trialkylamines.

.. ~

`` 105~;37~;

The ~-homo compounds are the compounds wherein n is 4.
The nor-compounds are the compounds wherein n is zero or 1 or 2.
Particularly preferred compounds of the invention are the following:

16S-methyl-13,14-dehydro-PGF2~;
16S-methy~-20~-homo-13,14-dehydro-PGF2~;
16R-methyl-13,14-dehydro-PGF2~;
16R-methyl-20~-homo-13,14-dehydro-PGF2~.

- lla -lOSf~37~

The new compounds of formula (I) may be used for the same Sherapeutical indications as natural prostaglandins, with respect to which~ however, they are characterized by a more reduced inactivation rate, in that, they are ~o substrates for the enzyme 15-hydroxy-prostaglandin dehydrogenase, which, as is known~ quickly inactivates natural prostaglandins, and by a more selective action.
In particular, as PCF2~ , they may be used as gastric anti-secretory and anti-ulcer agents~ but if compared with PGF
they show a higher activity, as can be seen from the follow=
ing Table, where the value 1 is conventionally given to the antiulcer and anti-secretory activities of the PGF2n:
~~~~ ~ T A ~ L E ~ ~~~

r Anti-Ulcer Anti-Secretory Activity () In Rats Activity () In Rats . . .
Potency Ratio E 5o( ) Potency Ratio ED50(Q) _ .. , PGF2~ 1-579 _ 1-45 i 16S-methyl-13t14-r~-~C72~ ~-5 0.472 _ .

() The ulcers are induced according to the method of Takagi-Okabe (K. Takagi et al., Jap. J. Pharm., 18, 9 (1968);
() According to Shay (H. Shay et al.~ Gastroenter., 26, 906 (1954);
(Q) Expressed in mg/kg.
Even the compound 16R-methyl-13~14-dehydro-pGF2~ m the same tests haa proven to be about four times more active as anti-ulcer and ~nti-secretory agent if compared with PGF2~ .

r i . . .

105637~

In the above tests, the compounds were administered subcutaneously.
Furthermore, the compounds of formula (I) are even endowed with broncho-dilatator activity and are therefore useful as anti-asthma agents.
For example, the 16S-methyl-13,14 dehydro-PGF2~ shows about 5-6 times the activity of the natural PGF2~ on bronchospasm in guinea pig. Said antibronchopastic ~anti-asthmatic) activity was determined in guinea pigs divided into groups, and treated with a histamine spray (0.2% aqueous solu-tion of histamine hydrochloride); the time when the animal showed broncho-spasm was then recorded. Four hours later, the same animals were treated with a spray of the test compounds at different dilutions in saline, and with a spray of standard PGF2~ solution. They were then given another histamine spray (0.2%) and again, the times taken for bronchospasm to appear were noted.
The compounds of general formula (I) can be administered orally, parenterally or!intravenously, by rectal suppositories or by inhalation. For example, they can be administered by intravenous infusion of a sterile iso-tonic saline solution at the rate of 0.01 to 10, preferably 0.05 to 1, ~g/kg of mamma~ body weight per minute.
The invention therefore also provides a pharmaceutical composition comprising a compound of general formula (I) and a pharmaceutically accept-able carrier or diluent.
The compositions may be prepared by conventional methods and can be, for example, in the form of tablets, capsules, pills suppositories or bougies, or in liquid form e.g. solutions, suspensions or emulsions.
Examples of substances which can serve as carriers or diluents are water, gelatin, lactose, starches, magnesium stearate, talc, vegtable oil, 6enzyl alcohol and cholesterol.
The invention is illustrated by the following examples, wherein the ab6reviation "THP", "DIOX", "THFt' refer to tetrahydropyranyl, dioxanyl and tetrahydrofuran respectively.

, - . ' ' ': ' ' - . '' ' - .

~ X~ 05637~;

A solution of a odicarboxylic acid diethylestc-r (0. 26 9, 1~44 10 3 mole) in dry Tl-IF (2 ml) is added dropwise over 5 minutes, to a stirred solution of triphcnylpho-sphine (0~33 9, 1..~.10 3 mole3 and Sc,13t-9a,11a-15S-trihydroxy-plostadienoic acid methylester-11,15-bis-THP~ether (0. 2 9, 3.73.10 4 mole), cooli~ at 20-22C.
After an additional stirring for 15 minutes, the reaction mixture is evaporated in vacuo to dryness affording a crude product which is dissolved in ethylether.
The organic layer is washed with saturated NaHC03 and water until neutral, dried (Na2S04) and the solvent is evaporated in vacuo to dryness.
The obtained mixture of triphenylphosphine oxide and 5c,13t-9~ ,15S-trihydroxy-prostadienoic acid methyl-ester-11,15-bis-THP-ether-9-p-phenylbenzoate istreated with acetone (8 ml) and aqueous 0.2N oxalic acid (~ ml) at reflux temperature for 30 minutes.
After removal of the acetone in vacuo, the aqueous phase is extracted with ethylacetate, the combined organic extracts are washed with saturated (NH4)2S04, dried ~Na2S04) and evaporated to dryness.
The crude resulting material is absorbed on a short silica gel column (10 9) to afford after elution with cyclohexane-eihylether 60:40 (to remove the impurities) -and then with~ether/pure Sc,13t-9~,11a,15S-trihydroxY-prostadienoic acid-methylester-9-p-phenylbenzoate, 180 mg, oil, ~a]D = -44.1, ra]365O - -198 (CHC13).
A solution of this compound in dry methanol is heated at reflux temperature for 1 hour and 30 minutes in presence of K2C03 (55 mg). The solvent is evaporated in vacuum, the oily residue is iaken up in methylene chloride and water. The organic layer is washed until neutral, dried (Na~S04), concentrated to a small volume and then the residue is absorbed on a small silica gel column (3 9). Following elution with ethyl ether to remove methyl-p-phenylbenzoate and then with eth)~lether-1~
.
-,, 105f~;~7f~ 15.
etllylacctat~ afford~ 5c,l~t-9n,l1,15S-tlihydroxy-prosttl-dienoic acicl methylester, lt7 m9, 93~, yicld, m.p. ~3-~
(fl-olll ethylether-i~opropylether), []D = ~ 4-9; ~aJ3fSO- -2 (EtOH).
By thin layer chromatographic analysis on silica gel plates using ethyl acetate as eluent, two 17 cm runs at 20C, this compound, Rf 0.076, appears to be entirely free frorn PGF2a-methylester (Rf o. 116) .
A solution of PGF2~-methylester (lOO mg) in 6% K2C03 in 80 aqueous methanol (6 ml) is refluxed for 1 hour.
After evaporation of excess solvent and 2C i dification to pH 4.5, by extraction with ethyl acetate~pure 5c,13t-9~, 11a,15S-trihydroxy-prostadienoic acid (PGF2~), 89 mg, ]D = ~ 1-8~ [~]36So= ~ 2-60 (EtOH) is obtained.

Example_2 A solution of azodicarboxylic acid diethylester (0.2fi 9) in dry THF (2 ml) is added dropwise over 5 minutes to a stirred solution of triphenylphosphine (0.38 9, 1. 44.10 3 mole), propionic acid (0.107 g, 1.44.10 3 mole) and 5c,13t-9a,11a,15S-trihydroxy-prostadienoic acid methylester-11,15-bis-THP-ether (0.2 9, 3.73.10 4 mole).
After an additional stirring for 15 minutes, the reaction mixture is evaporated in vacuo to dryness and the crude material, a mixture of triphenylphosphine oxide and PGF2~-methylester-11,15-bis-THP-ether-9-propionate is treated with ~% K2C03 in ~0% aqueous methanol at reflux temperature for 2.5 hours.
After removal of most of the alcohol in vacuum, the aqueous phase is diluted with 0.25N KOH (8 ml) and extracted with benzene-ethylether ~30:70) to remove the triphenylphosphine ox~de.
The aqueous phase is AC i dified to pH 4.5-4.8, extracted with pen*ane-ethylether (1:1) and then organic extracts, after washing Witll saturated (NH~)2S04 until the washing are neutral, are evaporated to dryness, affording PGF2~-105~37~; 1~,.

1l,15-bis-THP-etller (1(i8 mc~ fi~ yiclcl~.
A solut i on of th i S compound in acetone (10 ml), 0.2N
a~ueous oxalic acid (~ ml) is hcated at 40C for h hours; after removal of acetone in vacuo, by extraction with ethylether, PGF2B, m.p. 94-9~, (90 mg; 82% yield) is obtained.

Example 3 To a stirred solution of triphenylphosphine (0.79 9), acetic acid (0.18 9) and 5c-9a,11a,15S-trihydroxy-prost-5-en-13-ynoic acid ethylester-11,15S-bis-THP-ether (535 mg) in dry benzene (30 ml), azodicarboxylic acid diethyl ester (523 mg) in dry benzene (10 ml), is added dropwise over 5-7 minutes.
After 10 minutes the reaction mixture is washed-with 5% NaHC03 and water, dried (Na~S04) and evaporated to dryness. The residue dissolved in acetone (20 ml) and ~.2N aqueous oxalic acid (15 ml), is refluxed for 1 hour; the acetone is evaporated and the aqueous phase is extracted with ethylether. The combined extracts are evaporated to give crude 5c-9~,11a,15S-trihydroxy-prost-5-en-13-ynoic acid-ethylester-9-acetate.
Pure compound r]D = -19. 2 ( EtOH), 530 mg, 90% yield was obtained by purification on a short silica gel column (20 9) using cyclohexane-ether (75:25) as eluent.
A solution of the pure inverted ester in 6~ K2C03 in MeOH-H20 (80:20), 25 ml, is refluxed for 2 hours. After concentration in vacuo to remove the methanol, the solution is acidified and extracted with ethylether.
The combined extracts are washed with saturated (NH4)2S04, dried and evaporated to dryness to afford 5cis-9~,lla, 15S-trihydroxy-prost-S-en-13-ynoic acid (13,14-dehydro-PGF2p) ~ 4~ (Et~#~.

Example ~

A solution of 1.05 9 of diethyl azodicarboxylate in dry ...
,.

lOS~37f~ ,., THF (10 ml) is a~ed dropwise o~er 5 min~tes 1O a stirr~?c~
solution of 1.095 9 of 5c-9~ a~l~s-tlikydroxy-l~s-meth prost-5-en-13-ynoic acid-methylester-11a,15-bis-THP-efhcr, 1.5 9 of triphenylphosphine ~nd 0.735 9 of benzoic acid in dry THF (25 ml), cooled at 20-22C.
After 15 minutes, the reaction mixture is evaporated to dryness and the residue is taken up with ethyl ether and pentane (2:1) to remove most of the tripO.enylphosphine oxide.
The organic phase is concentrated to a small volume and absorbed on a silica gel column (40 9). ~y elution with cyclohexane-ethyl ether (80:20) 1.15 9 of Sc-9~,11a,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid methyl ester-9-benzoate-11,15-bis-THP-ether [a]D= -2~ (CHCI3) is obtained.
Using basically the same procedure, but replacing benzoic acid with the molar equivalentSof ~ormic, propionic, acetic, butyrric, p-phenylbenzoic, caproic, cyclopentyl_ propionic, cyclohexyl_propionic, 2-tetrahydrofuryl_pro-pionic, phenylacetic and phenyl_propionic acids, the following 9-esters are prepared of 5c-9~,11 a, 1 5S-trihy-droxy-16S-methyl-prost-5-en-13-ynoic acid methylester-11,15-bis-THP-ether:
- form~ate, [a]D = ~4~ (CHC13);
- acetate, ra]D = - 38 (CHCI3);
- propionate, [a]D = - 37 (CHCI3);
- butyrrate, [a]D = - 360 (CHCI3);
- p-phenylbenzoate, [u]D ~ - 30 (CHCI3); ~a]365O= -103 (CHCI3);
- capronate, ra]D - -40 (CHCI3); -- cyclopentyl_propionate, ~a]~ = -37 (CHCI3);
cyclohexyl~propionate, ra]D = -37 (CHCI3);
- 2'-tetrahydrofuryl propionate ra]D = -1~ (CHCI3);
- phenylacetate, phenyl~propionate and the corresponding trichloroethyl esters, in the same way.
.
Example $

A solution of 0.83 9 of 5c-9~,11 a ,1 5S-trihydroxy-16S-methyl-.
- , .. . .

105~;~7f~
prost-5-en-t3--ylloic ac;d--nletllyl estcr-~3-bell~onte 11,15-~i 8-Tl--'P-ether in ~5 ml of acetone is trc~ted with 0.4N citric AC i d (1 5 1111 ) for 2 hours at the reFlux tcmperature. The acetone is ev~porated in ~acuo and the aqueous phase is extracted with dichloromethane~ The com~incd organic phases are washed un~il neutral, dried (Na2S04) and evaporated tc afford Sc-9~,11a,15S-trihydro~y-l6S-methyl-prost-5-en-13-ynoic acid methyl ester-9-benzoate (16S-methyl-13,14-dehydro-PGF2~-methyl ester-9-benzoate) 0.59 9, [a]D = -29 (CI~C13).
Working basically accordiny to the same procedure and startin~ out from the esters in Example ~, the following are obtained: -16S-methyl-13,14-dehydro-PGF2B-methyl ester-9-form~ate Ea]D = -32 (~HC13);
16S-methyl-13,14-dehydro-PGF2~-methyl ester-9-acetate [a]D = ~ 34 (CHC13);
1fiS-methyl-13,14-dehydro-PGF2~-methyl ester-9-propionate [a~D = -1~ (CHC13);
16S-methyl-13,14-dehydro-PGF2~-methyl ester-9-butyrrate [a]D = -32 (CHC13);
16S-methyl-13,14-dehydro-PGF2~-methyl ester-9-p-phenyl benzoate [a]D = -25.7 (CHC13); Ea]365O - -123 (CHC13);
16S-methyl-13,14-dehydro-PGF2~-methyl ester-9-capronate ~a]D = ~ 34 (CHC13);
16S-methyl-13,14-dehydro-PGF2~-~ethyl ester-9-cyclopentyl-propionate Ea]D = ~ 31 (CHC13);
16S-methyl-13,14-dehydro-PGF2~-methyl ester-9-cyclohexyl-propionate [a]D = -29 (CHC13);
16S-methyl-13,14-dehydro-PGF2~-methyl ester-9-(2'-tetrahy-drofuryl)-propionate [a]D = -27 (CHC13);
16S-methyl-13,14-dehydro~PGF2~-methyl ester-phenylacetate ~a]D = -31 (CHC13);
1hS-methyl-13,14-dehydro-PGF2~-methyl ester-phenyl_propionate and their trichloroethyl esters.

.. . , , . ! . . . .
: . , .
' ~' ' `, "' ,' ' . . ,' " '` ' . , : ' , ~ ' .

lOS~i37f~ '9 Ex~mE. I c ~
__ _ A solution of a (l-ester obtaincd in Example 5, for example 0.~7 9 of 5c-~ l5S-trih~clroxy-1f)S-methyl-prost-5-en-13-ynoic acid-methyl-ester-9-ben~oate in io ml of 6~ K2C03 in MeOH-H20 (80:20) i~ refluxed for 1 hour, concentrated to a small ~olume, acidified to pH 5.2, and extracted with ethyl ether Tlle combined organic phases are evaporated to dryness, The residue is absorbed on 2 9 of acid silica gel and eluted with ethyl ether and ethyl acetate (8:2), yielding 345 mg of 16S-methyl-13,14-dehydro-PGF2~(or 5c-g~,11a,15$-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid), [a]D = ~ 2.80; r~]36So = + 20.5 (EtOH).

Exam~
.
A solution of a 9-ester given in Example ~ (for example 430 mg of 5c-~,11,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid-methyl-ester-9-acetate, 1 x 10 3 mole) in dry methanol (10 ml) is stirred with 154 mg of anhydrous potassium carbonate for 2 hours at room temperature and after neutralization with 15% aqueous acetic acid, evapo-rated almost to dryness, diluted with wa+er and extracted with ethyl acetate.
The combined organic phases are washed until neutral, dried and evaporated to dryness, yielding 0.36 9 of Sc-g~,11a,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid-methyl ester (13,14-dehydro-16S-methyl-PGF2~-methyl ester) ra]~ = +4.7; ~a]3650 = ~261 (EtOH)-Example ~

Working in dry conditionsfto a stirred sol~tion of 0.67g of 5c-9a,11a,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid-trichloroethyl ester-11,15-bis-THP-ether, 1.05 g of triphenylphosphine and 600 mg of phenyl-propionic acid in dry THF (25 ml)~ a solution of diethyl a~odicarbo-xylate (700 mg) in 10 ml of THF, is added dropwise, at a temperature of about 20-22C.
. ~9 - - , ~ ., - , - - .
. ~ . ~-- - . ' : : -,- .

105~7~ 20.
Thc stirrin~ continued for another ~ milutes .~nd thcn the react:io~l mixture is evapolated to dryness and the residue is absorbed on 2~ 9 of silica gcl to yield, after elution with cyclohexane-ethyl ether (95: 5), 0. 7 9 of Sc-913,11a,15S-trihyc!roxy-16S-methyl-prost-5-en-13-ynoic acid trichloroethyl ester-11,15-bis-THP-ether-9-phenyl pr~pionate (yield 87~). [a]D = -15 (CHCI~).
In similar experimental conditions, starting out from the isomeric 16R-methyl derivative, the Sc-9~,11 a,15S-trihy-droxy-16R-methyl-prost-5-en-13-ynoic acid-trichloro~,ethyl-ester-11,15-bis-THP-ether-9-phenylpropio.rdte is prepared [ ]D -12 (CHC13).

Example 9 A solution of 5c-9~,11 a,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid-trichloro~ethyl-ester-11,15-bis-THP-ether-9-p-phenyl propionate (0.7 9) in methanol (6 ml) and aqueous 2N citric acid (1 ml) is heated at 40C for three hours.
Evaporate the excess of methanol and extract with ethyl ether. The solvent is evaporated from the organic phases, which are perculated on 5 9 silica gel using cyclohexane-ethyl ether (1:1). 0.52 9 are obtained of 5c-9~,11a,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid trichloro-ethylester-9 phenyl propionate ~a]D = -80 (CHCI3).
Using a similar method, starting out from the 16R-isomer, the 5c-9~,11 a,15S-trihydroxy-16R-methyl-prost-5-en-13-ynoic acid-trichloroethyl ester-9-phenyl propionate is obtained ~a]D = -11 (CHCI3).

Example 10 A solution of 315 mg of 5c-9~,11 a,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid-trichloroethyl ester-9-phenyl pro-2~

1056~7~; 21.
pionate in 1 ~ ml of ~0 ~ a~lueous acetic acid is ~;tirred,holdil~g the l:emperature aroulld 30-35 and I. 5 9 of powdered zinc are added~ Aftcr 12 hours the mixture is fiItercd, washed with ethyl acet~l~e, and the eluate evaporated in vacuo to small volulne. The residue is taken up with ethyl acetate, the organic phase is washed with dilute su!plluric acid, water and saturated ammoniun- sulphate, dried and evaporated to dryness. The residue is purified on acid silica gel, using as eluent cyclohexane and ethyl acetate (70:30), to give 202 mg of pure 5c-9,3,11a,15S-trihydroxy-1tSS-methyl-prost-5-en-13-ynoic acid-9-phenyl propionate [a]D = -9 (CHCI3).

Examp!e 11 .
To a solution of 260 mg of 5c-9~,11a,15S-trihydroxy-16R-methyl-prost-5-en-13-ynoic acid-trichloroethylester-9-phenyl propionate in anhydrous methanol, 1.29 of powdered zinc are added, refluxing for 4 hours. FiIter, wash with methanol, evaporate to dryness, take up with ethyl acetate, and wash the organic phases as before with 2N H~SO4, water and saturated ammonium sùlphate. By evaporation of the solvent, 195 mg are obtained of pure 5c-~',"lla,15S-trihy-droxy-16~-methyl-prost-5-en-13-ynoic acid-9-phenyl-pro-pionate [a]D = -12 ¦~H~ 13).

Example 12 Working as described under Examples S to 11, and using one of the following acids instead of phenyl_propionic acid in Example 8 (formic, acetic, propionic, butyrric, caproic, benzoic, cyclohexyl propionic, cyclopentyl propionic, phenylacetic, 2-tetrahydrofuryl propionic) the following 9-esters are prepared:
13,t4-dehydro-1 6S-Illethyl-PGF2l3-9-form~ate;
13,14-dehydro-16S-methyl-PGF2~3-9-acetate;

: - . . ~ . . - : - -105637~;

13,1~-dehydl-o-1f)'~-m~thyl-PGF2~-9-propionate;
13,t4-dellydro-l6S-met:hyl-PGF2~-9-blltyrrate;
13,14-dehydro-16S-methyl-PGF2~-9-capronate;
13~l4-dehydro-l6s-methyl-pGF2!3-9-benzoate 13,14-dehydro-16S-methyl-PGF2~-9-cyclohexyl- propionate;
13,14-dehydro-16S-methyl-PGF2~-9-cyclopentyl_propionate;
13,14-dehydro-16S-methyl-PGF2~-9-phenylac~+ate;
13,1 ~-dehydro-l6S-methyl-P(:~F2~-9-[2'~-tetrahydrofuryl propionate;
13,14-dehydro~16R-methyl-PGF2~-9-form~!ate;
13,14-dehydro-16R-methyl-PGF2~-9-acetate;
13,14-dehydro-16R-methyl-PGF2~-9-propionate;
13,14-dehydro-16R-methyl-PGF2~-9-butyrrate;
13,14-dehydro-16R-methyl-PGF2~-9-capronate;
13,14-dehydro-16R-methyl-PGF2~-ben~oate;
13,14-dehydro-1 6R-methyl-PGF2~-9-cyclohexyl_propionate;
13,14-dehydro-16R-methyl-PGF2~-9-cyclopentyl--propionate;
13,14-dehydro-16!~-methyl-PGF2~-9-phenyl -acetate;
13,14-dehydro-16R~methyl-PGF2~-9-r2']-tetrahydrofuryl propionate.
All the compounds in this example show marked IR absorption at -1718 cm and around -1150 cm 1, typical of the carboxyl ester at ~ 9.

Example 13 At 20-22C,a solution of 2,3-dicyano-5,6-dichlorobenzoquinone (640 mg) in dry THF is added dropw.ise to a stirred solution .of Sc,13t-9a,11a,15S-trihydroxy-16,16-dimethyl-prosta-5,13-dienoic acid-methyl ester-11,15-bis-DlOX-ether (0.57 9), triphenylphosphine (740 mg) and benzoic acid (345 mg)in dry THF (30 ml).
After 15 minutes, the solvent is evaporated in vacuo and the residue is taken up with benzene and absorbed on a short silica gel col--mn.

~ -' . - . . . - . --- lOS637f~
23.
Elution w;tlI cyclolIex.ine-etllyl cthcn ~35:1 S) afl~ords O.f~.3 -g o~ 5c~l3t-9f3~11a~1 5S-trihydro~y-1~,1 (-dirnethyl-prosta-5,13-dienoic acid-1netllvlester-9-ben-oate- 11,15-bis-DlOX-etl1err [~ 1D = +- 2 (~ IICI3).
Alkaline cleavage of ester groups is accomplished by treatment of this compound (0.3 9) with 6~o 1~2CO~ in 80%
aqueous methanol (15 ml) at reflux temperature l~or 2 hours. The resulting alkaline solution of the 16,16-dime-thyl-PGF2~-11,15-bis-DlOX-ether is cooled, acidified to pH 1.5 by adding 0.3M citric acid and then heated at 35 for 3 hours to achieve the deacetalisation reaction.
After concentration in vacuo to remove most of the alcohol, the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated (NH4)2S~4 until neutral, dried (Na2S04) and evaporated to dryness.
The crude product is absorbed on acid silica gel column and the following elution with CH2CI2-ethyl acetate (6:4) affords 151 mg of 5c,13t-9~,11a,15S-trihydroxy-16,16-dimethyl-prosta-5,13-dienoic acid (16,16-dimethyl-PGF2~) [a]D -- +7-9; Ea]3650 = +38.30 ~EtOH); methylester ra]D = +7.80 (EtOH); methylester-9-benzoate [a]D = -8~70 (CHCI3).

Example 14 A solution of diethylazodicarboxylate (~5 mg) in dry benzene (4 ml) is added dropwise (over 5 minutes) to a stirred suspension of p-phenylbenzoic acid (120 mg) in a solution of triphenylphosphine (158 mg) and PGF1 -methyIester-11,15-bis-trimethylsilyl ether (154 mg). At the end of the addition, all the acid is dissolved and after 15 minutes the solvent is evaporated in vacuo to dryness. A solution of the residue in acetone (6 ml) and 0.2N aqueous oxalic acid (2 ml) is heated for 3 hours at 40C, concentrated in vacuo to remove the acetone, diluted with water (2 ml) and extracted with ethyl acetate.
The collected organic phases are washed until neutral, dried, concentrated to a small volume and then absorbed on silica gel column.

. .
- :- :-- .- . - . : . : . .-"\ 1056~7~i 24.
Following elution witl) cyclohexal-e-ether (~O:f~O) and then wi~ll ether affords P~F1~-methylester-9-/~-phenylben,oate (15~ m~).
Starting from this compound and working as described under Example 1, the following are obtained:
PGF1~-methyl ester, m.p. 106-1 07C;
PGF1~, m.p. 126-12~C [a]D = -19. 7 (EtOH).
Similarly, starting with the 13,14-dehydro-PGF1 -methyl-ester-11,15-bis-THP-ether the following are obtained:
13,14-dehydro-PGF1~-methylester-9-p-phenylbenzoate; (oil) 13,14-dehydro-PGF1~-methylester; (oil) 13,14-dehydro-PGF1~; r~ V ~!I ~ ).

Example_15 A solution of 4.10 ~ mole of 5c-9a,11a,15S-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid-11,15-bis-THP-ether (224 mg), [a]D = -7.80 (EtOH) in dry benzene (10 ml) is treated with an ethereal solu-tion of distillateJdiazoethane (1.2 mol equiv.) at room temperature for 30 minutes.
The mixture is evaporated in vacuo to dryness and the stirred solution of the resulting ethyl -ster in dry THF (6 ml) is consecutively added with three mol. equiv.
of triphenylphosphine, three mol. equiv. of p-phenyl-benz~ic acid and then with a solution of azobiscarboxylic amide (218 mg) in dry THF (3 ml).
After 15 minutes, THF is removed in vacuo and the resulting crude bis acetalic-9-inverted ester is -hydrolyzed by treatment with acetone (10 ml) and 0.3N
aqueous oxalic acid (5 ml) for 3 hours, at reflux temperature.
Following removal of the acetone in-vacuum, extraction with ethyl acetate and chromatographic purification on a silica gel column, afford Sc-9s,l1a,15S-trihydroxy-1~,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid ethyl ester-9-p-phenylbenzoate.

2g ., .
.
.

~-~ 1056i37~
25.
~orkin~ as c~escribed undcl- Examplc t, this compound is converted to the sc-sir~ 5S-trihydroxy-18,1,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid (13,19,20-trinor-17-cyclohexyl-t3,1~-dehydro-PGF2B) [a]D = -2 (EtOH) and its etllylester [a~ - -3 (~`HCI3~.

Example 16 -A stirred solution of 570 mg of 5c-ga,11a,15R-trihydroxy-16S-methyl-20 ~-homo-prost-5-en-13-ynoic acid-methylester-11,15-bis-THP-ether in 25 ml dry dimethcxyethane is con-secutively treated with 790 mg of triphenylphosphine and 370 mg o~ benzoic acid~and then, with external cooling at 20-22C with a solution of 350 mg of azodicarboxylic amide in dry dimethoxyethane. After 20 minutes the reaction mixture is evaporated to dryness and separated into water and ethyl ether. The organic extracts are combined, dried and evaporated to dryness. After acid hydrolysis with acetone and 0.2N oxalic acid, the crude 5c-g~,11,15R-trihydroxy-16S-methyl-20~J-homo-prost-5-en-13-ynoic acid methylester-9-benzoate is purified on silica gel, using cyclohexane and ethylether (80:20) as eluent, to give 470 mg od pure 15-epi-16S-methyi-13,14-dehydro-20 ~-homo-PGF2~-methylester-9-benzoate.
Working as described under Example 1, the Sc-9~,lla,15R-trihydroxy-16S-methyl-20~1homo-prost-5-en-13-ynoic acid and its methyl ester are obtained.

Example 17 Working according to the method described under Examples 1 and 16, using as a hydrogen acceptor an azoderivativc selected from the azodicarboxylic amide and diethyl azo-dicarboxylate, and starting out from an 11,15-bis-tetrahydropyranylether methylester of the following prostanoic acids:
5c-9,11a,15S-trihydroxy-16S-methyl-20 ~-homo-prost-5-en-13-ynoic;
2~

` - ` 105~7~ 26.
5c-(~a,1.tQ,tSS-t~ ydroxy-t-~-(netllyl-20 ~-llolno-plost-S-cn-13-ynoic;
Sc-9a,1ta,l5R-tril~yclroxy-1(~R-methyl-20~J-horno-prost-5-en-13-ynoic;
5c-9a,11a,1SR-trihydroxy-prost-S-en-13-ynoic;
Sc-9a,1ta,15R-trihydroxy-16S-methyl--prost-5-en-13-ynoic acid;
Sc-9a,11a,l5R-trihydroxy-lfiR-methyl-prost-5-en-13-ynoic acid;
5c-4,11a,15S-trihydroxy-t~,19,20-trinor-i7-cyclopentyl-prost-5-en-13-ynoic;
Sc-9a,11a,15S-trihydroxy-1~,19,20-trinor-17-(2'-tetrahy-drofuryl)-prost-5-en-13-ynoic acid;
5c-9, 11 a ,1 SS-trihydroxy-l9~2o-di -nor-18-cyclohexyl-prost-S-en-13-ynoic acid;
Sc-9a,11a,15S-trihydroxy-17,13,19,20-tetra-nor-16-cyclo-hexyl-prost-S-en-13-ynoic acid;
5c-9a,11a,15S-trihydroxy-20~-homo-prost-5-en-13-ynoic;
5c-9a~l1a~tSR-trihydroxy-~ow -homo-prost-S-en-13-ynoic;
Scj13t-9a, 11 a,15S-trihydroxy-15-methyl-prosta-dienoic;
- 9a,11a,15S-trihydroxy-prost-13-ynoic acid;
9a, 11 a,15S-trihydroxy-20 ~-homo-prost-13-ynoic acid, and using as acylating agent formic, acetic, propionic, butyrric, caproic, benzoic, p-phenylbenzoic, phenylacetic or cyclohexylpropionic acid, after deacetylation, a 9-ester o~ the form~ate, acetate, propionate, butyrrate, capronate, benzoate, p-phenylbenzoate, phenylacetate or cyclohexylpropionate group was obtained of the prostanoic methylesters of the following 9~-hydroxy acids:
Sc-9~,lla,15S-trihydroxY-16S-methyl-20w -homo-prost-5-en-13-ynoic;
5c-9~,lla,15S-trihydroxy-t6R-methyl-20~)-homo-prost-S-en-f3-ynoic;-5c-9~ ,11 a,lSR-trihydroxy-16R-methyl-20 ~-homo-prost-5-en-13-ynoic;

105637~; 27.
sc-~B ~ s~-t~ r~oxy-pl-o~ 5~ 3-yno i c;
Sc-9~ ,tS~-tl~ihydroxy~ S-metllyl-prost- 5-cn-t 3-yno i c;
5c-9~,lt~,15R-trillydroxy-16~-methyl-prost-5-en-13-ynoic;
5c-9~,tt~,15S-trihydroxy-20 ~-homo-prost-5-en-13-ynoic;
~c-9~ ,15R-trihydroxy-20~ -homo-prost-5-en-13-ynoic;
5c-9~ ,15S-trihydroxy-1~,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic;
Sc-9~,lla,15~-trihydroxy-1~,19,20-trinor-17-(2'-tetrahy-dro~uryl)-prost-5-en-13-ynoic;
5c-9p,11a,15S-trihydroxy-19,20-di -nor-1~-cyclohexyl-prost-5-en-13-ynoic;
5c-9~11a~15S-trihydroxy-17~ 19~20-tetra-nor-1~`-cyclohexyl-prost-5-en-13-ynoic;
Sc~13t-9~,11a,15S-trihydroxy-15-methyl-prosta-dienoic acid;
9~11a~15S-trihydroxy-prost-13-ynoic acid;
9~11a~15S-trihydroxy-20~J-homo-prost-13-ynoic acid.
These are saponified to give the corresponding free acids.

.
Example 18 A solution of 353 mg of ethyl azodicarboxylate in THF
(4 ml) is added dropwise to a stirred solution of 270 mg of PGF3 -methylester-11,15-bis-THP-ether (5c,13tt17c-9a,11a,15S-trihydroxy-prosta-5,13,17-trienoic acid~
methylester-11,15-bis-THP-ether), 520 mg of triphenyl-phosphine and 395 mg of p-phenylbenzoic acid in 9 ml of dry THF.
After 10 minutes the reaction mixture is concentrate to dryness, d;luted with 15 ml of acetone and 6 ml of 0.2N
oxalic acid and then refluxed for 2 hours. The acetone is evaporated in vacuo, and repeated extractions are carried out with ethyl acetate. The organic phases are combined, washed until neutral, dried and evaporated to dryness. The residue is absorbed on a short column of silica gel (7 9) eluting with cyclohexane and ethyl ether (~)0:~0) then with ethyl ether. 32~ mg are obtained -.. ~ . . . ~ .
. . .. . . . . - ` . .. -1056376 28.
of PGF3p-methylester-9-p-phenylbenzoate (5c,13t,17c-9~, 11a,15S-trihydroxy-prosta-5,13,17-trienoic acid-methyl-ester-9-p-phenylbenzoate).
Working as described under Example 1, starting with this compound, the PGF3~ and its methyiester are obtained by saponification.

Example 19 .
Sc-9~,11,lSS-trihydroxy-16S-methyl-prosta-5-en-13-ynoic acid (100 mg), dicyclohexylcarbodiimide (100 mg) are consecutively added to a stirred mixture of 5 ml of anhydrous dichloromethane, 0.3 9 of n-octanol and 0.3 ml of anhydrous pyridine.
The mixture is stirred for three hours, then absorbed on 50 9 of silica gel, eluting with cyclohexane, petroleum ether nnd ethyl ether. 103 mg are obtained of 5c-9~,lla,lSS-trihydroxy-16S-methyl-prosta-5-en-13-ynoic acid-n-octylester [a~D = +3 (OHCI3)~

Example 20 - j A solution of 5c-9a,11a,15S-trihydroxy-16S-methyi-prost-5-en-13-ynoic acid methyl ester-11,15-bis-THP-ether [a]D = ~9 7 (THF) (1.65 9) in anhydrous ether (5 ml) is dropwise added to a suspension of LiAlH4 (0.4 9) in anhydrous ether.
After stirring for two hours at room temperature, decomposition of the excess reagent, fiItration from the inorganic precip itate and evaporation to dryness, 5c~1,9a,11a,15S-tetrahydroxy-16S-methyl-prost-13-yn-5-ene-11,15-bis-THP-ether (1.54 9) [aJD=-2 (CHC13) is obtained.
A stirred so!ution of this compound in dry benzene ~30 ml) is consecutively treated with triphenylphosphine (3.15 9), p-phenylbenzoic acid (1.19 9), then with a solution of ethyl azodicarboxylate (1.05 9), cooling .: .

, lOS~7~ 29.
externally at about 5C to 10C.
After 15 minutes, the organic phase is washed with water, 2N H2S04, then with water a~ain to neutrality, dried Na2S04 and evaporated to dryness. By fiItration of the residue on silica gel (using CH2C12 as eluent), Sc-1,9~,lla,15~;-tetrahydroxy-1t~S-methyl-prost-13-yn-5-ene-1,9~-di-p-phenyl-benzoate-ll~l5-bis-THp-ether (2.42 9) is obtained.
A solution of this compound in acetone (30 ml) is hydrolyzed by treatment for 8 hours at 36C with O.~N oxalic acid (20 ml).
After evaporation of the excess acetone and extraction with ethyl acetate, the obtained crude 11a,15S-diol is treated in methanol (25 ml) with K2C03 (0.5 9) for ~
hours at room temperature, then acidified to pH 4.5 with H2S04 2N, fiItered, and evaporated to dryness.
The residue is absorbed on silica gél (20 9) and eluted with cyclohexane-ethylacetate (1:1) to remove the methyl p-phenyl-benzoate, then with ethylacetate and ethylacetate/
methanol to give 5c-1,9~,lla,15S-tetrahydroxy-16S-methyl- !
prost-13-yn-5-ene [a]D = +60 (EtOH) (0.86 9).
~n the same way, starting from the;1-tetrazolyl and the 1-carboxy amide derivatives, the following compounds were prepared:
5c-9~,lla,15S-trihydroxy-lbS-methyl-prost-5-en-13-yn-1-carboxy amide;
5c-9~,11a,15S-trihydroxy-16S-methyl-prost-5-en-1-yn-1-tetrazolyl.
.'. ' Examp ! e 21 To a solution consisting of PGF2 -11,15-bis-THP-ether methylester (0.44 9), hexamethyltriaminophosphine (0.48 9) and p-phenylbenzoic acid (570 mg) in benzene ~30 ml), a solution of ethyl azobiscarboxylate (0.5 9) in benzene (10 ml) is added. ~ontinuous stirring for an hour dilution with benzene, washing with H2S04 2N, water, sodium bicarbonate and water, and evaporation to dryness , ; .... . . . . .

lOSti37~
30.
allow to obtain PGF~3-1l,15-bis-THP-etller mctllylcster-9-p-phenylben oate (5c,t3t-9~3,11c~,15S-trihydtoxy-prost-5-en-13-ynoic acid methyl estcr-9-p-phenylbenzoate-ll,tS-bis-THP-ether) (0.95 g) which was converted into PGF2~-1l,t5-hydroxy-methylester-9-p-phenylbenzoate (5c,13t-9~ ,lSS-trihydroxy-prost-5-en-13-ynoic acid methylester-9-p-phenylben-oate), according to the method followed in Example 5.
.

Claims (34)

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

1. Process for the preparation of PGF.beta. prostaglandins and their 9-acyloxy derivatives comprising the selective esterification with a carboxylic acid of the 9.alpha.-hydroxy group of a PGF.beta. prostaglandin, in presence of a com-pound of formula Mv Y3, wherein Mv is a metalloid of the V group and Y is an alkyl, a dialkylamino or an aryl group, and of a hydrogen-acceptor agent, so as to obtain directly a PGF.beta.-9-acyloxy derivative which may be converted into the desired PGF.beta. prostaglandin by conventional methods.

2. Process as claimed in claim 1, wherein the hydroxy groups present in the PGF.alpha. prostaglandin other than the 9.alpha. -hydroxy group are protected in a conventional manner.

3. Process as claimed in claim 1, wherein the carboxy groups present in the PGF.alpha. prostaglandin are protected in a conventional manner.

4. Process as claimed in claim 1, wherein the compound of formula Mv y3 is selected from the group consisting of triphenylphosphine, triphenyl-arsine, triphenylstilbine and hexamethyltriaminophosphine.

5. Process as claimed in claim 1, wherein the hydrogen-acceptor agent is selected from the group consisting of an ester or an amide of the azodi-carboxylic acid, a quinone and azobisformamide.

6. Process as claimed in claim 5, wherein the quinone is 2,3,5,6-tetrachloro-benzoquinone or 2,3-dicyano-5,6-dichloro-benzoquinone.

7. Process as claimed in claim 1 for the preparation of a PGF.beta. pros-taglandin of formula (N) (N) wherein D is a free or salified carboxy group, a carboxyamide, a carboxyester, a tetrazolyl or a -CH2-OH group; R1 is hydrogen or a -CO-Ra acyl group, wherein Ra is the residue of a generic carboxylic acid; one of R2 and R3 is hydroxy and the other is hydrogen or alkyl; A is -CH2-CH2- or cis-CH=CH- ;
B may be -CH2-CH2-, trans-CH=CH- or -C? C- ; G may be the group, or the cis-CH2-CH=CH-CH2-CH3 group, wherein n may be zero or an integer number of 1 to 5; R4 and R5 may be hydrogen or alkyl; R6 may be hydrogen or a radical wherein X may be -CH2- or an oxygen or a sulphur atom and m is an integer number of 1 to 4; the process comprising esterifying the 9-.alpha.-hydroxy group of a PGF.alpha. prostaglandin of formula (Q) (Q) wherein D' may he a carhoxyester, a carboxyamide, a tetrazolyl or a -CH2-OH
radical having the hydroxy group free or protected in a conventional manner;
A, B and G are as defined ahove; Z and one of R'2 and R'3 are an acyloxy group or a protecting group bound to the ring or respectively to the chain through an ethereal oxygen atom, and the other of R'2 and R'3 is hydrogen or alkyl;
by reaction with a carboxylic acid of formula Ra-COOH, wherein Ra is as defined above, in presence of a hydrogen-acceptor agent and of a compound of formula MVY3, wherein MV is a metalloid of the V group and Y is an alkyl, a dialkylamino or an aryl group, to give a compound of formula (T) (T) wherein D" is a carboxy ester, a carboxy amide, a tetrazolyl or a -CH2OCORa group or a -CH2OH radical having the hydroxy group protected in a conventional manner, as above reported, and Ra, R'2, R'3, A, B, G and Z are as hereabove defined, which, in any sequence order, is purified, deetherified, and optionally saponified, re-acylated or salified.

8. Process according to claim 7 for the preparation of a PGF.beta.
prostaglandin having the formula (I) (I) wherein R is a tetrazolyl or a -CH2-OH group or a -COR"' group, wherein R"' is an amino group or an -ORIV radical, wherein RIV is hydrogen, C1-C12 alkyl, trihaloalkyl or a pharmaceutically acceptable cation; R1 may be hydrogen or a -CORb acyl, wherein Rb may be hydrogen or C1-C10 alkyl, a ?-(CH2)n -radical, wherein n1 may be zero or an integer number of 1 to 5 and ? is a phenyl radical which may be unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkoxy, trifluoromethyl, phenyl and cycloalkyl-alkyl, or Rb may be the following radical:

wherein m is an integer number of 1 to 4, X is -CH2- or an oxygen or a sulphur atom and n1 is as defined above; one of R2 and R3 is hydroxy and the other is hydrogen or C1-C6 alkyl; R4 and R5 are independently hydrogen or C1-C6 alkyl; n is zero or an integer of 1 to 5; R6 is hydrogen or a group, wherein X and m are as defined above; A may be -CH2-CH2- or cis--CH=CH-, and wherein - when at the same time R is -COR"', wherein R"' is an -ORIV radical, n is 3 or 4, A is cis-CH=CH-, R1 and R6 are hydrogen and one of R4 and R5 is hydrogen - the other is a 16S- or 16R- C1-C6 alkyl, which comprises esterifying the 9-.alpha.-hydroxy group of a PGF.alpha. prostaglandin of formula (II) (II) wherein RV is a tetrazolyl or a -CH2-OH group having the hydroxy group free or protected in a conventional manner, or a -COR"' group, wherein R"' is an amino or an -ORIV radical, wherein RIV is C1-C12 alkyl or trihaloalkyl;
A, R4, R5, R6, n, Z. R'2 and R'3 are as defined in claim 7, by reaction with a carboxylic acid of formula Rb-COOH, wherein Rb is as defined above, in presence of a hydrogen acceptor agent and of a compound of formula MVY3, wherein MV is a metalloid of the Y group and Y is an alkyl, a dialkylamino or an aryl group, to give a compound of formula (III) (III) wherein RVI is a tetrazolyl, a CH2OCORb group or a -CH2-OH radical having the hydroxy group protected in a conventional manner or a -COR"' group wherein R'" is an amino or an -ORIV radical, wherein RIV is C1-C12 alkyl or trihaloalkyl; A, Rb, R4, R5, R6, n, Z, R'2, R'3 are as hereabove defined, which, in any sequence order, is purified, deetherified, and optionally saponified, re-acylated or salified.

9. PGF.beta. prostaglandins having the formula (I) (I) wherein R is a tetrazolyl or a -CH2-OH group or a -COR"' group wherein R"' is an amino group or an -ORIV radical, wherein RIV is hydrogen, C1-C12 alkyl, trihaloalkyl or a pharmaceutically acceptable cation; R1 may be hydrogen or a -CORb acyl, wherein Rb may be hydrogen or C1-C10 alkyl, a ?
-(CH2)n1 - radical, wherein n1 may be zero or an integer number of 1 to 5 and ? is a phenyl radical which may be unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkoxy, trifluoromethyl, phenyl and cycloalkyl-alkyl, or Rb may be the following radical:

wherein m is an integer number of 1 to 4, X is -CH2- or an oxygen or a sulphur atom and n1 is as defined above; one of R2 and R3 is hydroxy and the other is hydrogen or C1-C6 alkyl; R4 and R5 are independently hydrogen or C1-C6 alkyl;
n is zero or an integer of 1 to 5; R6 is hydrogen or a group, wherein X and m are as defined above; A may be -CH2-CH2- or cis-CH=CH-, and wherein - when at the same time R is -COR"', wherein R"' is an -ORIV
radical, n is 3 or 4, A is cis-CH=CH-, R1 and R6 are hydrogen and one of R4 and R5 is hydrogen - the other is a 16S- or 16R- C1-C6 alkyl, whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.

10. A process according to claim 8 in which 16S-methyl-13,14-dehydro-PGF2.beta.;
16R-methyl-13,14-dehydro-PGF2.beta.;
16S-methyl-13,14-dehydro-20.omega.-homo-PGF2.beta.;
16R-methyl-13,14-dehydro-20.omega.-homo-PGF2.beta.;
17-cyclohexyl-18,19,20-trinor-13,14-dehydro-PGF2.beta.;
5c-1,9.beta.,11.alpha.,15S-tetrahydroxy-16S-methyl-prost-13-yn-5-ene;
or a 1-ester, a 9-ester or a salt thereof is prepared by deetherify-ing the corresponding 11,15-bis-(tetrahydropyronyl)ether.

11. A process according to claim 8 in which 16S-methyl-13,14-dehydro-PGF2.beta.;
16R-methyl-13,14-dehydro-PGF2.beta.;
5c-1,9.beta.,11.alpha.,15S-tetrahydroxy-16S-methyl-prost-13-yn-5-ene;
or a 1-ester or 9-ester thereof is prepared by deetherifying the corresponding 11,15-bis THP-ether.

12. A process according to claim 10 in which the starting material is prepared by esterifying the corresponding 9.alpha.-hydroxy compound.

13. A process according to claim 11 in which the starting material is prepared by esterifying the corresponding 9.alpha.-hydroxy compound.

14. A process according to claim 8 in which 16S-methyl-13,14-dehydro-PGF2.beta. or a 1-ester, 9-ester or a salt thereof is prepared by deetherifying the corresponding 11,15-bis-THP-ether.

15. A process according to claim 8 in which 5-cis-9.beta.,11.alpha.,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid (16S-methyl-13,14-dehydro-PGF2.beta.)methyl ester -9-benzoate, -9-formate, -9-acetate, -9-propionate, -9-butyrate, -9-p-phenybenzoate, -9-capronate, -9-cyclopentylpropionate, -9-cyclohexyl-propionate, -9-(2'-tetrahydrofuryl)propionate, and -9-phenylacetate are prepared by deetherifying the appropriate corresponding 11,15-bis-(tetra-hydropyranyl)ether.

16. A process according to claim 15 in which the 1,9-diester obtained is hydrolysed to produce 5-cis-9.beta.,11.alpha.,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid (16S-methyl-13,14-dehydro-PGF2.beta.).

17. A process according to claim 15 in which the 1,9-diester obtained is partially hydrolysed to produce the methyl ester of 5-cis-9.beta.,11.alpha.,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid (16-S-methyl-13,14-dehydro-PGF2.beta.-methyl ester).

18. A process according to claim 8 in which 5-cis-9.beta.,11.alpha.,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid trichloroethyl ester -9-phenyl-propionate is prepared by deetherifying the corresponding 11,15-bis-(tetrahydropranyl) ether.

19. A process according to claim 18 in which the 1,9-diester is partially hydrolysed to give 5-cis-9.beta.,11.alpha.,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid -9-phenyl-propinate.

20. A process according to claim 8 in which 16R-methyl-13,14-dehydro-PGF2.beta. or a 1-ester, 9-ester or a salt thereof is prepared by deetherifying the corresponding 11,15-bis-THP-ether.

21. A process according to claim 1 in which 5-cis-9.beta.,11.alpha.,15S-trihydroxy-16R-methyl-prost-5-en-13-ynoic acid-trichloroethyl-ester-9-phenyl-propionate is prepared by deetherifying the corresponding 11,15-bis-(tetrahydropyranyl) ether.

22. A process according to claim 21 in which the 1,9-diester obtained is partially hydrolysed to give 5-cis-9.beta.,11.alpha.,15S-trihydroxy-16R-methyl-prost-5-en-13-ynoic acid-9-phenyl-propionate.

23. A process according to claim 8 in which 5-cis-1,9.beta.,11.alpha.,15S-tetrahydroxy-16S-methyl-prost-13-yn-5-ene or a 1,9-diester thereof is prepared by deetherifying the corresponding 11,15-bis-THP-ether.

24. A process according to claim 8 in which 5-cis-1,9.beta.,11.alpha.,15S-tetra-hydroxy-16S-methyl-prost-13-yn-5-ene is prepared by deetherifying and hydrolysing 5-cis-1,9.beta.,11.alpha.,15S-tetrahydroxy-16S-methyl-prost-13-yn-5-ene-1,9.beta.-di-p-phenylbenzoate-11,15-bis-(tetrahydropyranyl)ether.

25. A compound selected from the group consisting of:
16S-methyl-13,14-dehydro-PGF2.beta.;
16R-methyl-13,14-dehydro-PGF2.beta.;
16S-methyl-13,14-dehydro-20.omega.-homo-PGF2.beta.;
16R-methyl-13,14-dehydro-20.omega.-homo-PGF2.beta.;
17-cyclohexyl-18,19,20-trinor-13,14-dehydro-PGF2.beta.;
5c-1,9.beta.,11.alpha.,15S-tetrahydroxy-16S-methyl-prost-13-yn-5-ene;
an 1-ester, a 9-ester, or a salt thereof, whenever prepared by the process of claim 10 or 12 or by an obvious chemical equivalent thereof.

26. A compound selected from the group consisting of:

16S-methyl-13,14-dehydro-PGF2.beta.;
16R-methyl-13,14-dehydro-PGF2.beta.;
5c-1,9.beta.,11.alpha.,15S-tetrahydroxy-16S-methyl-prost-13-yn-5-ene;
or a 1-ester or 9-ester thereof, whenever prepared by the process of claim 11 or 13 or by an obvious chemical equivalent thereof.

27. The 9-benzoate, 9-formate, 9-acetate, 9-propionate, 9-butyrate, 9-p-phenylbenzoate, 9-capronate, 9-cyclopentyl-propionate, 9-cyclohexyl-propionate, 9-(2'-tetrahydrofuryl)propionate or 9-phenylacetate of 5-cis-9.beta.,11.alpha.,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid methyl ester, whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.

28. 5-Cis-9.beta.,11.alpha.,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid (16S-methyl-13,14-dehydro-PGF2.beta.), whenever prepared by the process of claim 16 or by an obvious chemical equivalent thereof.

29. The methyl ester of 5-cis-9.beta.,11.alpha.,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid (16-S-methyl-13,14-dehydro-PGF2.beta.-methyl ester), whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.

30. 5-Cis-9.beta.,11.alpha.,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid trichloroethyl ester -9-phenyl-propionate, whenever prepared by the process of claim 18 or by an obvious chemical equivalent thereof.

31. 5-Cis-9.beta.,11.alpha.,15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid -9-phenyl-propionate, whenever prepared by the process of claim 19 or by an obvious chemical equivalent thereof.

32. 5-Cis-9.beta.,11.alpha.,15S-trihydroxy-16R-methyl-prost-5-en-13-ynoic acid-trichloroethyl ester -9-phenyl-propionate, whenever prepared by the process of claim 21 or by an obvious chemical equivalent thereof.

33. 5-Cis-9.beta.,11.alpha.,15S-trihydroxy-16R-methyl-prost-5-en-13-ynoic acid-9-phenyl-propionate, whenever prepared by the process of claim 22 or by an obvious chemical equivalent thereof.

34. 5-Cis-1,9.beta.,11.alpha.,15S-tetrahydroxy-16S-methyl-prost-13-yn-5-ene, whenever prepared by the process of claim 24 or by an obvious chemical equivalent thereof.