Note: Descriptions are shown in the official language in which they were submitted.
~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
OH 0
~ \ / 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
, .
-- 1 --
~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
OR7
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 ~:
OR6
, 2 A ~ \ CH '~' \ COOR
\ j (II)
CHO
: ':
OR7
wherein R6 and R7 each independently represent hydrogen or a protecting
: group of the hydroxyl function, with a reagent of the formula:
OR
1 2
R
' "' ~: "
wherein Z represents a group: R
I
(R'0)2P-CH2-CO- or (C6H5~3P=CH-C-
R5
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
R3 R3
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
5 3
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
R3
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.
EXAMPLE 1
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
C23 38 8
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:
21 36 6-
~U
~76S6~
EXAMPLE 3
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.
-12
,
~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.
EXAMPLE 4
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).
13
~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:
14
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
17
~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.
18
~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)
21
: ~.
.
,: ' ,
~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:
24
~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
- 25 -
~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:
26
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,
.
27
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 ~
.
.
28
~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.
. . .
:
29
:
