Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~L0~03~ r
case 10
MONO-DEUTERATED,15-HYDROXYPROSTAGLANDINS
The present invention relates to deuterated
prostaglandins and intermediates for their production.
It is to be appreciated that the present prostaglandings
an2 intermediates are non-radioactive in the sense that
they do not contain, e.g. hydrogen, atoms containing more
than the nat~ral amount o~ radioactive isotopes, e.g. triti~.
In particul2r, the present invention provides mono-
deuterated, 15-hvdroxy group-containing prostaglandins,
the deuterium atom beins attached to the carbon atom in
the 15-position. Such prcs~2slancins m2~ be in race~ic form
or op,icall~ active form.
The present invention also provides a process for
the production of such mono-deuterated, 15-hydroxy group-
containins prostaalandins, which comprises splitting off
the prGteCting croup or groups in a corresponding prosta-
slandin having a deuterium ato-~ attached to the carbon
atom in the 15-position and in which at least one hydro~
and/or carboxylic acid aroup is protected.
In a more particular aspect the present invention provides
compouncs of fon~ula I,
A ~ i
C
D OH
I
~og5032
].00-~361
wherein A is a group of formula
O O
Al A2
A3
or
A4 A5 A~
B is a group of formula
COX ' ~ N - N
Bl B2 N- N
COX or ~ COX
B3 B4
wherein X is hydroxy, al~oxy of 1 to 10 carbon atoms,
lysergyloxy, lysergylamino or dihydrolyser-
gylamino, and
C is a prostaglandin end group.
10~032
100-43Gl
A is pre~erably A2, ~3 or A4.
B is preferably Bl or B4. X is preferably hydroxy
or alko~y. When ~ is alkoxy it is preferably of 1 to 4
carbon atoms, especially methoxy or ethoxy.In B4 it is to
~e appreciated that the substituents of the cyclopropyl ring
are trans to each other.
C is a prostaglandin end group which corresponds to
that of a natural or syr.thetic-prostaglandin. In particu]ar
C may be a hydrocaxbyl group conveniently containing up
to 16 carbon atoms which may con~ain a cyclic moiety
and~or may contain unsaturation and/or may contain a
~-- heteroatom, such as oxygen. Prostaglandin end groups
which are contemplated .include
a) alkyl of 1 to 16 atoms,
par~icularly a group
Rl R2
/~ ~
- wherein Rl and ~2 are independently ~ydrogen or
alkyl of 1 to 4 carbon atoms,
b) a group
1 ~ 2
C 2
~O~S03Z
100-4361
w'nerein ~1 and R2 are as defined above,
Z is -CH2- or -0-,
R3 is hydrogen, fluorine, chlorine or
trifluoromethyi,
c) alkenyl of 3 to 10 carbon atoms, or
d) cycloalkyl of 3 to 10 carbon atoms ~hlch is unsubstituted
or substituted by alkyl cf up to 6 carbon atom~s.
C is preferably C a) as defined above. Rl and/or
R2 when alkyl are preferably of 1 or 2 carbon atoms,
especially methyl. When one f ~1 and R2 is alkyl and the
other of Rl and R2 is hydrogen, the 15 carbon atom may have
the R or S configuration.
It will be appreciaied that D stands for deuterium.
As indicated by the wa~7y lines in formula I tre
hydroxy group attached to the 15-carbon ato~ may have
the ~- or ~-configuration.
As indicated by the bro~en lines in formula I,
the 5 and 6 carbon atoms may be linked by a single bond
or a cis double bond, and the 13 and 14 carbon atoms
2Q may be linked by a single bond or a trans double bond.
The present invention further provides a process
for the production of a compound of formula I as defined
above, by splitti~g off with acid an acid sensitive
protecting group or grou~s ~resen' in a co~ound of
formula II,
~503Z , 00-4361
I II
A ~ ~
D OR4
wherein A is A as defined above, or
HO .
or
O'R OR5
A7 A8
wherein R4 and R5 are, independently, hydrogen or an
acid sensitive protecting ~roup,
B is B as defined above, or
COOR6 or
- ~D~ '
B7
wherein R6 is an acid sensitive protecting group, and
C is as d~fined above,
with the proviso that there is present at least one
acid sensitive protecting group.
lO~S~3Z 100-4~61
The deprote~ting process as deiined above may be
effected in conventional manner for such reactions.
Prefexably the protecting group is a group stable
to basic conditions. Suitable groups include tetrahydro-
pyranyl and tert.-butyldimethylsilyl. Suitable conditions
are well known in the art, e.g. acetic acid/tetrahydro-
furan/water; methanol/hydrochloric acid; sulphuric acid;
acetone/hydrochloric acid. Suitable temperatures are
from -10 to 50C, preferably room temperature.
It will be appreciated that the prostaglandins
of formulae I and II may be interconverted into other
prostaglandins of formulae I and II respectivelyr e.g.
in conventional ~anner for such reactions.
For example, lysergyl esters, lysergyl amides and
dihydro-lysergylamides may be made in conventional manner
for producing such esters and amides, e.g~ as in Example 32.
Additionally, the moiety A2 may be changed into a moiety
A6 by reaction with imidazole in conventional manner for
the addition of an amine to the double bond of an ~,~
unsaturated ketone. Suitable conditions include reacting
with imidazole at room temperature over several days. The
imidazole may be in free form or the form of carbonyldi- -
imidazole. ~urther reaction conditions are apparent from
Example 33 which it is appreciated involves both ester
formation and conversion from moiety A2 into A6.
'10~03~
100-~361
The compounds of formula II may also be prepared
in conventiollal manner. ~or example a compound of formula
III,
E ~ III
D OR4
wherein E is
Ho H HO ~ H H~o ~ Y
~'' O , ~.,
El OR5
E2
E3
and R4, R5 and C are as defined above,
may be reacted under Wittig conditions with a compound
of formula IV,
p~ ~
( 6 5)3 - CH - B IV
wherein B is as defined above,
with, if desired, further reaction of the resulting
product according to methods known in the prostaglandin
art, e~g. selective oxidation at the 9 position.
A compound of formula III, 2s defined above, may
be produced by selectively reducing the lactone moiety
~ in a compound of formula V,
7 ~
10~3~ 100-~361
F ~ C
V
D OR~
wherein C is as defined above,
o , ~ is O
O~
~ 0~
Fl F2 OR5
F3
. R~ and R5 are as defined above,
in conventional manner, e.g. using diisobutylaluminium
hydride.
The invention further provides a process for the
production of a compound of formula V, which comprises
deuterating a compound of formula VI,
\ ~ ~ VI
wherein C is as defined above, and
F is F1, F2, F3 or
-- 8 --
~0~503Z loo-~ 361
,'
F4
wherein P~7 is hydrogen or a bulky group capable of
inrluencing the proportion of ~:~ alcohol
formed,
and if necessary converting any group R7 present into a
group R5 as defined above, and if desired protecting the
3-hydroxy group with an acid sensitive protecting group.
The reaction may be carried out in conventional
manner ~for such deuterations bearing in mind the other
groups present. For example a deuterating agent such a5
sodium or zinc borodeuteride may be used. An anhydrous
inert organic solvent such as dimethyl formamide or
dimethoxyethane may be present. Suitable tempera~ures
are bet~een ~40 and 50C. Preferably the reaction is
effected under an inert gas atmosphere.
The ~- and ~-alcohols which may both be formed
may be s~parated in conventional manner.
The group R7 may be chosen such that it influences
by virtue of its size the proportion of a:B alcohol formed
generally increasing the amount of ~-alcohol.
10~503Z loo-~ 3~]
Such ~roups are well known ill the art.
An e~ample of a suitable protecting group R7 i~
para-phenylbenzoyl or benzoyl. Such groups are split
off under alkaline conditions, and may be exhanged
for a group RS in conventional manner.
The 3-hydroxy group may be protected in conventional
manner.
Free forms of prostaglandins being suitably basic,
e.g. a compound of formula I, wherein A is A6, or X is
lysergyloxy, lysergylamino or dihydrolysergylamino, may
be converted into acid addition salt forms in conventional
manner and vice versa. A suitable acid is methanesulphonic
acid. Free forms of prostaglandins being suitably acidic,
e.g. a compound of formula I, wherein X is hydroxy, may
be converted into cationic salt forms in ccnventional
manner and vice versa. A suitable cation is the sodilm~ cation.
Insofar as the production of any starting material
is not particularly described these compounds are known,
or may be produced and purified in accordance with known
~0 processes, or in a manner analogous tc processes described
herein, e.g. in the Ex~amples, or to known processes.
It will be appreciated that optically active
products may be obtcined from optically active starting
materials.
-- 10 --
10~5032 loo-~ 3~;1
The deutexa~ed pLostaalandins of the inven~ion,
D especially the compounds of formula I~e~nibit interesting
pharmacological activity. In particular the deuterated
prostaglandins exhibit the same type of activity as the
non-deuterated analogues, but have a longer duration
of action. Thus the compounds of formula I in general,
and especially the PGE and PGF~ compounds exhibit uterotonic
activity, as indicated by a uterotonic effect on the
rat uterus ln situ according to the principles of
Bisset G.W. et al, Memoirs of the Society for Endocrinology
No. 14 - Endogenous substances affecting the myometrium.
Edited by W.R. Pickles and R.J. Fitzpatrick, Cambridg~
University frey 1966, p. 185-198.
The deuterated prostaglandins may be administered
in the same way and at the same dosage as the nor.-deuterated
analogue~. An indicated daily dose for the uterotonic
effect is from about 0.1 to about 20 mg, conveniently
administered in divided doses 2 to 4 times a day in unit
dosage form containing from about 0.02 to about 10 mg
of the compound or in sustained release form. If the
prostaglandin is suitably basic a pharmacologically
acceptable acid addition salt form may be used. If the
prostaglandin is suitably acidic a pharmacologically
acceptable cationic salt form may be u5ed. Such salt
forms are readily made in conventional manner from the
-- 11 --
10~503Z loo--~ 361
free form and exhibit the same order of activ,it~ as the
free form. Accordingly the present invention also provides
a pharmaceutical composition comprising a mono-deuterated
15-hydroxy group-containing prostaglandin, the deuterium
atom being attached to the carbon atom in the 15 position,
or a compound of formula I, in association with a pharma-
ceutical carrier or diluent. Such compositions may be
formulated in conventional manner so as to be, for example,
a solution or tablet,
A group of compounds of formulae I and V comprises
those whexein C is Cl wherein Rl and R2 are independently
hydrogen or methyl, or C2 wherein Z is O and R3 is p- or
m-fluoro- or p- or m-chloro or m-trifluoromethyl.
In the following Examples all temperatures are
in degrees Centigrade and are uncorrected.
I.R. refers to characteristic bands exhibited
in the infra-red spectrum of a methylene chloride
solution.
- 12 -
10~5032 100-4361
EXAMPIE 1: 15 ~eutero-ll~ 15R-dih~drox~-16,16-dimeth~
9-~eto-2,3-(~)-trans-methylene-~rosta-5cis,
___________.__.__________ _____,._ _________
13tlans-dlenoic acld
~00 mg of 15-deu';ero-lla,15~-bis-tetrahydro-
pyranyloxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-
prosta-5cis,13trans-dienoic acid tert.-butyldimethyl
silyl ester is dissolved in 18 ml of a mixture of equal
parts by volume of acetic acid, tetrahydrofuran, and
water. The reaction mixture is maintained for 38 hours
at room temperature, and then evaporated under a vacuum.
The residue is chromatographed on silica gel using
- chloroform ~ 2% methanol as eluant to yield the pure
title compound.
IR 3550, 3~00, 1720, 16~5 cn 1
lS In analogous manner to that described in Example 1
the following compounds of formula I are obtained from
the corresponding 15-tetrahydropyranyl ether. When there
is an ll-hydroxy group present in the final product the
starting material is the appropriate 11,15-bis-tetra-
hydropyranyl ether. When there is a 9-keto group and a
carbonyl group present in the final product the carboxyl
group is protected as the tert.-butyldimethyl silyl ester
in the starting materiali otherwise the free acid is used
as the starting materialqror the production of a final
compound having a carboxyl group.
- 13 -
~0 ~t-30 3 ~
100-4361
E~ 5PI.E 2: 15-Deutero~16,16-dimethyl-2,3-(+)-trans-
methylene-9~ ,15R-trihydroxy-prosta-5cis,
13trans-dienoic acid.
I~ 3600, 3400, 1695 cm
.
EXA~IPLE 3: 15-Deutero-11~,15R-dihydroxy-16,16-dimethyl-
_
9-keto-2,3-(+)-trans-methylene-prosta-5cis,
13trans-dienoic acid.
IR 3600, 3450, 1740l 1695 cm
EXAl'~PLE 4: 15-Deutero-16,16-dimethyl-15R-hydroxy-2,3-
0 (t) -trans-methylene-9-keto-prosta-5cis,10,
13trans-trienoic acid.
IR 3600, 1700, 1140 cm
EXAMPLE 5: 15-Deutero-16,16-dimethyl-2,3-(~)-trans-
methylene-9a,11a,15R-trihydroxy-prosta-5cis,
13trans-dienoic acid methyl ester.
IR 3600, 3400, 1720, 1710 cm
XA~LE 6: 15-Deutero-16,16-dimRthyl-2,3-(-)-trans-
methylene~9a,11a,15R-trihydroxy-prosta-5cis,
13trans-dienoic acid.
IR 3600, 3500, 1715, 1700 cm
- 14 -
~0~?5i032
100-~361
EXA_5~Lr 7: 15-Deutero-16,16-dimethyl--2,3~ trans-
methylelle-9~x,11(~,15 ~ trlhydroxy-prosta-13-
trans-enoic acid.
IR 3550 - 3400, 1700 cm
EXAMPLE 8: 15-Deutero-lla,15R-dihydroxy-16,16-dimethyl-
9-keto-2,3-(-)-trans-methylene-prosta-13 trans-
enoic acid.
IR 3600 - 3400, 1740r 1695 cm
EXA~5PLE 9: 15-Deutero-16,16-dimethyl-15R-hydroxy-9-keto-
2,3 (-)-trans-methylene-prosta-10,13trans-
dienoic acid.
IR 3600, 1700 cm
YAMPLE 10. 15-Deutero-2-ethylene-16,16-dimethyl-9~,lla,
15R-trihydroxy-prosta-5cis,13trans-dienoic
acid.
IR 3400, 1690 cm 1.
EXA~PLE 11: 15-Deutero-2-ethylene-16,16-dimethyl-11~,15R-
dihydroxy-9-keto-prosta-5cis,13trans-dienoic
acid.
20 IR 3400, 1740-- 1730, 1700 - 1680 cm
EY~IPLE 12: 15-Deutero-2-ethylene-16,16-dimethyl-15R-
hydroxy-9-keto-prota-5cis,10,13trans-trienoic
acid~
IR 3600, 1710 - 1685 cm
- -- 15 -- -
~0~503~ 100-43~1
~XArlPT~ 13: 16-n butyl-15-deutero-2,3-(-)-trans-methylene-
9~ 15S-trihydroxy- -
prosta-5cis,13trans dienoic acid
IR 3550 - 3350, 1715 - 1680 cm
EY~lPLE 14: 16-n-butyl-15-deutero-11~,15S-dihydroxy-9-
keto-2,3-(-)-trar,s-methylene-prosta-5cis,
13trans-dienoic acid.
IR 3550 - 3350, 1745 - 1690 cm
EXAMPLE 15: 16-n-butyl-15-deutero-15S-hydroxy-9-keto-
(2,3)-(-)-trans-methylene-prosta-5cis,10,13
trans-trienoic acid.
IR 3600, 1745 - 1690 cm
EXAMPLE 16: 15-Deutero-lla,15R-dihydroxy-9-keto-16R-
methyl-2,3-(-)-trans-methylene-prostanoic
acid.
IR 3600 - 3300, 1740 - 1690 em
EYAMPLE 17: 15-Deutero-lla,15R-dihydroxy-9-keto-16R-
methyl-2,3-(-)-trans-methylene-prosta-5cis-
enoic acid.
IR 3600 - 3350j 1735 - 1685 em
EXAMPLE 18: 15-Deutero-11~,15R-dihydroxy-16,16-dimethyl-
9-keto-2,3-(-)-trans-methylene-prosta-5cis,
13trans dienoic acid methyl ester.
IR 3600 - 3400, 1750 - 1700 cm
- 16 -
~0~5032
100-~361
EXAMPLE 19: 15-Deutero-16jl6-dimethyl-9~ a,lSR-trihydro~y--
__ _
17 t 18/19,20-tetranor-16-(3' trifluoromethyl-
phenoxy)-2,3-(-)-trans-methylene-prosta--5cis,
13trans-dienoic acid.
IR 3500 - 3300, 1730 - 1670 cm
EXA~LE 20: 1-Descarboxy-15-deutero 16,16--dimethyl-2-
(5'-tetrazolyl)-9a,11a,15R-trihydroxy-17,18,
19,20-tetranor-16-(3'-trifluoromethylphenoxy)-
prosta-5cis,13trans-dienoic acid.
IR 3500 - 3300 cm
EXAMPLE 21: 15-Deutero-lla,15 R -dihydroxy-16,16-dimethyl-
2,3-(-)-trans-methylene-9-keto-17,18,19,20-
tetranor-16-(3'-trifluoromethylpheno~y)-
prosta-5cis,13trans-dienoic acid.
IR 3500 - 3300, 1760 - 1720, 1720 - 1670 cm
EXAMPLE 22: 15-Deutero-9a~11a,15S-trihydroxy-prosta-5cis,
13trans-dienoic acid lysergyl ester.
IR 3550 - 3400, 1740 (broad).
EXAMPLE 23: 15-Deutero-15S-hydroxy-ll~imidazol-l'-yl-9-
keto-prosta-5cis,13trans-dienoic acid
(l'-dècanyl) ester.
IR 3550 - 3350, 1740, 1720 cm
- 17 -
03Z
100-~36l
F.XA~IPLE 24: 15-Deutero-15S-hydroxy~ imida~ol -l'-yl-
9-keto-prosta-13-trans-enoic acid lysergyl
ester.
--1
IR 3500 - 3400, 1745, 1725, 1505 cm
EXA~IPLE 2_: 15-Deutero~ ,15S-dihydroxy-9-keto-prosta-
13trans-enoic acid lysergyl ~mide.
IR (CH2C12 + 1% CH30H) 3400 ~broad), 1745, 1665, 1525 cm
EXAMPLE_ 26: 15-Deutero-16,16-dimethyl-9a,11a,15R-trihydroxy-
prosta~5cis,13trans~dienoic acid
IR 3650 - 3300, 1750 - 1700 cm
EX~PLE 27: 15-Deutero-lla,15R-dihydroxy-16,16-dimethyl
9~keto-prosta-5cis,13trans-dienoic acid
IR 3600 - 3300, 1760 - 1710, 1710 - 1630 cm
EXAMPLE 28: (~)-15-Deutero-15~^hydroxy--9-ketoprostanoic acid.
IR 3550, 1760 - 1700 cm
EXAMPLE 29: ~+)-15-Deutero-17,18,19,20-tetranor-16-[3'-tri-
fluoromethylphenoxy]-9a,11a,15~-hydroxy-pros'a--
5cis,13trans-dienoic acid.
IR 36Q0, 3350, 1710 cm
EXAMPLE 30: 15-Deutero-11~,15R-dihydroxy-9-keto-16R-
methyl-prosta-5cis enoic acid methyl ester.
IR 3700 - 3300, 1740 cm 1.
-- 1~ --
~0~ 50~2 loo - ~ 3Gl
ExAr~lPLE 31: 15-Deutero-11~,15S~dihydroxy-9-keto-prost2-
5cis,13trans-dienoic acid lysergyl ester.
IR 1740 ~broad) cm
Preparation of starting materials, e.g. for Example 1.
a) (-)-2R-~3'~deutero-3'a-hvdroxv~4r,4'-dimethyl-trans-1'-
OCteIlyl ~ -50;-hydroxy-30;-para-phenylbenzoyloxy-lc~-cyclo-
pantyl acetic acid ~-lactone and
~-)-2~-(3'-deutero-3'B-hydroxy-4',4'-dimethyl-trans-1l-
octeni~-5~-hydroxy~3u-para-phenylbenzoyloxy-la-cyclo-
pentyl acetic acid ~"lactone(inter,ediate co~pounds
of formula V having a bulky aroup R7)
A solution of 1.45 g of (-)-5~-hydroxy-2B-(3'-oxo-
4',~' dimethyl-trans-1l-octenyl)-3~-para-phenylbenzoyl-
oxy-la-cyclopentyl acetic acid ~-lactone in 8 ml of
absolute dimethoxyethane is added dropwise to a suspension
of 2.25 g of zinc borodeuteride in 20 ml of absolute
dimethoxyethane at -15C in a nitrogen atmosphere.
Stirring is subse~uently effected at 3 to 5C for 3.5
- hours and at 5 to 10~ for one hour. The mixture is then
again cooled to -15C and 3 ml of an aqueous 10% (w/v)
sodium hydrogen tartrate solution are slo~ly added. The
mixture is extracted ~ith 2x 100 ml of ether. The organic
phase is washed with 100 ml of a saturated aqueous sodium
chloride solution, dried with sodium sulphate and
concentrated by evaporation at reduced pressure, ~?hereby
19 - .
~~ ~ ~ 100-4361
a mixture oi the corresponding a and ~ isomers is
obtained. The residue is chromatoyraphed on 50 g of
neutral silicagel, whereupon the ~- and then the ~-isomer
is eluted ~ith chloroform (5% ethyl acetate).
a-isomer:
Thin layer chromatography (Silica gel):
Methylene chloride (5% acetic ester) Rf = 0.4, M.Pt.
107 108C
` IR (methylene chloride) inter alia bands at:
3500, 1770, 1710, 1660 cm 1
~-isomer:
Thin layer chromatography (Silica gel):
Methylene chlorlde (5% acetic ester) Rf = 0.3.
Spectral data approximately as for a-isomer.
The abo~e mentioned (-)a isomer is reacted further
in step b) ~hrough to step f) yielding optically pure products
as follows:-
b) 2B-(3'-deutero-3'a-hydrox~y-4',4~-dimethyl-trans-~-
octenyl)-3~,5a-dihydroxy-la-cyclopentyl acetic acid
~-lactone (compound of formula:V, wherein R5 = H).
A solution of 104 mg of sodium in 5.2 ml of
absolute methanol is added at room temperature to a
solution of 2.5 g of 2B-(3'-deutero-3'a-hydroxy-4',4'-
dimethyl-trans-l'-octenyl)-5a-hydroxy-3a-para-phenyl-
2i benzoyloxy-l~-cyclopentyl acetic acid ~-lactone in 104 ml
of absolute methanol at room temperature. After 5 hours,
the mix~ure is cooled to 10C and 6.3 ml of tartaric
. - 20 -
10'3~03Z 100-43Gl
acid solution in methanol are added. The mixture is
subsequently concentrated by evaporation at reduced
pressure and the residue is taken up in 250 Irl of methyl~ne
chloride. The organic phase is washed ~ith 100 ml of
saturated aqueous sodium chloride solution, is dried with
sodium sulphate and concentrated by evaporation at reduced
pressure. The residue is chromatographed on 150 g of
silicagel. The compound is elu~ed with ben7ene
(20~ acetone). M.Pt. 82 - 84C.
c) 2~-(3'-deutero-3`c;-hvdroxy-4'l4'-dimethyl-trans~
octenyl)-3c;,5c[-dihydroxy-l~x-cyclopentyl acetic acid
2r-lactone-3,3'-bistetrahydropvranyl ether.
(Compound of formula V with acid sen~itive protecting
groups).
A solution of 1~6 g of 2~-(3'-deutero-3'a-hydroxy-
4',4'-dimethyl-trans-1'-octenyl)-3a,5c~-dihydroxy-lc~-
cyclopentyl acetic acid ~-lactone, 31 mg of p-toluene
sulphonic acid monohydrate and 1.33 g of 3,4-dihydro-
2H-pyrane in 103 ml of absolute toluene is produced at
-10C and is then allowPd to warm to room temperature.
After one hour, the solution is washed with 50 ml of 109
(W/V) aqueous potassium bicarbonate solution and twice
with 100 ml of saturated aqueous sodium chloride solution.
The organic phase is dried with sodium sulphate and
concentrated by evaporation at reduced pressure. The
-- 21 --
~0'~?5~3Z loo-~ 3Gl
s~ight:Lv yello~ oily resid~le is cllroma~ographed from
120 g of silicagel with toluene (+5~ acetone), whereupon
the pure title compound is isolated.
Thin layer chromatography (toluene; acetone; 2:1)
Rf = 0.7 (Silica gel)
IR (methylene chloride) inter alia bands at 1770 cm 1.
d) 2~-(3'-deutero-3'~-hydroxy-4',4'-dimethvl-trans-~-
octenyl)-3a,5a-dihydroxy-1~-cyclopentyl-acetaldehyde-
~-lactol-3l3~-bis tetrahydropyranyl ether (Compound
of formula III)
8.73 ml of diisobutylaluminium hydride are slowly
; added dropwise to a stirred solution of 2.43 g of
2B-~3'-deutero-3'~-hydroxy-4',4'-dimethyl-trans-1'-octenyl)-
3a,5a-dihyclroxy-1-cyclopentyl acetic acid ~-lactone-
3,3'-bis-tetrahydropyranyl ether in 102 ml of absolute
toluene cooled to -70C in a nitrogen atmosphere. The
mixture is further stirred at -70C for one hour, and
subsequently 65.3 ml of tetrahydrofuran:water (2:1) are
carefully added over 30 minutes. The organic phase is
washed w~th 150 ml of saturated a~ueous sodium solution
at room te~perature, is dried with sodium sulphate and
is concentrated by evaporation at reduced pressure. The
resulting title compound is obtained as viscous oil.
IR (methylene chloride) inter alia bands at: 3600, 1200 cm
- 22 -
10~503~ 100-4361
~) 15-deutero-16,16-dimethyl-9~-h~droxy-lla,15~-bis-tetra--
hydrop~ran~lo~y~2,3-(-) trans-methylene-prosta-5cis,
l~trans-dien~ic acid (compound of formula II, A = ~.7).
380 m~ of sodium hydride are suspended in 3.8 ml
of absolute di~Rthyl sulphoxide and are kept under
nitrogen for 55 minutes at 75C. Upon cooling, 2.1 ml
of this solution are slowly added dropwise to a prepared
solution of 1.89 g of triphenylphosphonium salt of
2-~2'-bromoethyl)-(-)-trans-cyclopropyl-1-carboxylic acid
in 5 ml of absolute dim.ethyl sulphoxide and are stirred
under nitrogen for 45 ~,inutes to produce an ylide solution.
4 ml of the ylide solution are added at 20C to a prepared
solution of 980 mg of 2~-~3'-deutero-3'~-hydroxy-4r,4'-
dimethyl-trans-l'-octenyl)-3~,5~-dihydroxy-1~-cyclopentyl-
acetaldehyde-~-lactol-3,3'-bis-tetrahydropyran~l ether
in 3 ml of absolute dimethyl sulphoxide and 3 ml of
absolute tetrahydrofuran. The reaction mixture is kept
for 30 minutes at 55C. Upon the addition oi another
4 ml of ylide solution, stirring is effected for another
l.S hours at 55C. The cooled reaction mixture is poured
into lOn g of ice, the aqueous phase is adjusted to pH
3-4, and is eYtracted thrice with chloroform. The organic
- phase is washed, dried and concentrated by evaporation
at reduced pressure. The resulting crude product is
chromato~raphed on 100 g of silicagel with chloroform
~05~503.~
100-~3~1
with I-5R methanol, whereupon the desired compound is
obtained.
IR ~methylene chloride) inter alia bands at: 3600, 3500,
16~5 cm
f) 15-deutero-16,16-dimethy]-9-keto-11~,15~-bis-tetra-
hydropyranyloxy-2,3~ -trans-methylene-prosta-5cis,
13trans-dienoic acid tert.~butyldimethyl silyl ester.
To 460 mg of 15-deutero-16,16-dimethyl-9~-hydroxy-
lla,15~-bis-tetrahydropyran~loxy-2,3-(-)-trans-methylene-
prosta-5cis,13trans-dienoic acid in 4.5 ml of absolute
toluene, 137 mg of tert.-butyldimethyl chlorosilane are
added under nitrogen to form the corresponding silyl ester.
The reaction solution is cooled to 0 and g3 mg of tri-
ethylamine in 9 ml of absolute toluene are added. After
stirring at 4 hours at room temperature, the reaction
mixture is cooled to -25C and is siowly added dropwise
to a solution of 500 mg of N-chloro-succinimide in 19 ml
of absolute toluene and 0.33 ml of dimethylsulphide
~ during the course of the next 30 minutes. After a further
3 hours 1 ml of triethylamine in 5 ml of pentane are
added dropwise. The mixture is stirred for 25 minutes at
room temperature and ~Jorked up with ether/water to give
the desired starting rnaterial.
In analogous manner to that described above,
prostaglandins are obtained from the following compounds
- 2~ -
~0~50~ 0-~361
of formula ~, wherein R4 and R5 are ~oth hydrogen deriveo
from the c~orresponding 3-para-phenylbenzoyl and 3-benzoyl
derivatives which are then converted into their correspon~lna
3,3'-bis-tetrahydropyranyl ethers.
ba)*2~-(3'-deutero-3'B-hydroxy-4',4'-dimethyl-trans-1;-
octenyl)-30,5a-dihydroxy-la-cyclopentyl acetic acid
~-lactone.
- bb)~2B-(3'-deutero-3'a-hydrOxy-trans-l'-
octenyl)-3a,5a~dihydrox~r-la-cyclopentyl acetic acid Y
lâctone.
bc)*2~-(3l-deutero-3lB-hydroxy-trâns~
octenyl)-3a.,5a-dihydroxy-la-cyclopentyl acetic acid Y
lactone.
bd) 2~-(3'-deutero~3'a-hydroxy-4'-methyl-trans-1-octenyl)-
3a,5a-dihydroxy-la-cyclopentyl acetic acid ~lactone.
be)~2~-(3~-deutero-3l~-hydroxy-4'-methyl-trâns-l-octenyl3
3a,5a-dihydroxy-la-cyclopentyl acetic acid ~-lactone.
bf)~2~-(3'-deutero-4,~-dimeth~1-3'a-hydroxy-trans-1~-
octenyl)-5a-hydroxy-la-cyclopent-3^enyl acetic acid
~lactone.
bg) 2B-(4-n-butyl-3'-deutero-3'S-hydroxy-trans-l'-octenyl)-
3a,5a-dihydroxy-la-cyclopenty' acetic acid ~-lactone.
bh) 2~ -n-butyl-3'-deutero 3'S-hydroxy-trans-l-octenyl~-
5a-hydroxy-la-cyclopent-3-enyl acetic acid a-lactone.
- 25 -
lO~ 03~ loo-~ 361
bi) 2~~(3'~deutero~3'R--hydroxy-4R-Incthyl~trans-l'-OCtenyl)-
3a~a-diny~roxy-la-cyclopentyl acetic acid ~-lactone.
bj) 2p-(3'-deutero-3'R-hydroxy-4'-mcthyl~4'-[3"-trifluoro-
methylphenoxy]~trans-l-pentenyl)-3a,5a-dihydroxy-la-
cyclopentyl acetic acid ~ lactone.
bk) 2B~(3'~deutero-3'S-hydrQxy-trans~l'-octenyl)-3a,5a-
dihydroxy-l-cyclopen4yl acetic acid ~-lactone.
bl) 2~-(3'-deutero-3'S-'nydroxy-trans-l'-octenyl)-5a-hydroxy-
l~-cyclopent-3-enyl acetic acid ~-lactone.
bm)*2~-(3'~deutero-3'~-hydroxy-octyl~-5a-h~rdroxy-la-cyclo-
pentyl acetic acid ~~lactone.
- bn) 2B~(3'-deutero-3'~-hydroxy~~'~(3"-trifluoromethyl-
phenoxy3-trans-1-butenyl)-3a,5~~dihydroxy-la-cyclo-
pentyl acetic acid ~-lactone.
* obtained in (+) racemic form and in 3'R or 3'S optically
active form. ~ompounds bd) and be) may be obtained as ~he
4'a-methyl isomer or the 4'~-methyl isomer.
- 26 -
10~503Z ~ ~J~
E~A~IPI,E 32: 15-Deutero-~n-h~d-o~ ,15~-bis-tetrah~dro-
_______________~____ ________________________
~ran~lox~-~rosta-5cis,13trans-d~enoic_acid
l~ser~ l_ester
lstarting material for Example 22)
a) ca. 275 mg of 15-deutero-9~-hydrox~r-11~,155-bis-tetra-
h~rdrop~Tranyl~xyprosta-5cis,13trans-dienoic ~cid is reacted
with 167 mg of 2,2-dithiop~rridine and 199 mg of triphenyl-
phosphine in 5 ml of xylene at 20 for 24 hours. After
evaporation of the solvent, the residual oil is chromato-
graphed on "Sephadex LH20"* using methylene chloride + 2~
methanol to afford the corresponding 2-thiopyridyl ester.
b) 190 mg of 15-deutero-9~-hydroxy-11~,15S-bis-tetrahydro-
pyranyloxyprosta-5cis,13trans-aienoic acid 2-thiopyridyl
ester are reacted with 90 mg of lysergol in 5 ml of
tetrahydrofuran at 20C for 24 hours. The reaction mixture
is worked up on "Sephadex LH20"* with methylene chloride +
0.5% methanol to obtain the title compound.
The starting materials for Examples 25 an~ 31 may
be obtained in analogous manner using the appropriate
starting materials.
*Trademark for macroscopic beads of highly cross-linked
polysaccharide (derived from dextran); used in chromatography.
- 27 -
B
~O~S~3~ 10~-4361
EXA~I~LF, 33~ Deutero~i5S-te~rahydro~ran~loxv-l la-
imida7O-i'_yl-9 keto-,~rosta-13.rans-enoic
acid lyser~l ester
___ __ _~_ _______
[starting material for Example 24]
A solution of 180 mg of 15-deutero-15S-tetrahydro-
pyranyloxy-9-ke~o-prosta-10,13trans-dienoic acid in 4 ml
of absolute dimethyl formamide may be reacted with 76 mg
of carbonyldiimidazole and stirred under nitrogen for
3.5 hours. ca. 145 mg of finely powdered lysergol as well
as a catalytic amount of freshly prepared sodium imidazole-
tetrahydrofuran solution are added. After 7 days stirring
at room temperature the solvent is evaporated to room
temperature and the oily residue is chromatographed on
Sephadex LH20 with methylene chloride with the addition
of 1% methanol to yield the title compound.
The starting material for Example 23 may be made
in an analogous manner.
- 2B
