Note: Descriptions are shown in the official language in which they were submitted.
~3~;i3~
Ths pres~nt in~ention r~lat~q to 20-~th,yl-13,14-did~hydro-PGl2 deri-
vativ~s, to ~ p~OC~88 for th~ir pr~paration and to phar~ .ic~l COE-
positions c~ntaining th~m.
The compc~nds of the invention hav~ th~ following formula (I)
(c~2?3-Coo~ .
`C~l2 ~; ~~~~ ~~ ~
R ~ ~~~ (I)
r ~ , .
'`''-~ OH ~`CH-CH-~5Hll -~~-~
- OH _ _ , . .
where
R is hydrogen or methyl and M is hydrogen or a pharmaceutically
acceptable cationO Objec~ive of the inven~ion are also pharma
ceutical compositions containing compounds of formula ~I). M is
Preferably the cation of an alkaline metal, sodium or potassium,
for instance. In the formulae of the invention, the broken line
~ tl) indicates that a substituent bound to a ring is in ~ ~or
endo) configuration and a substituent bound to a chain/in config
uration S; the wavy line ( ~) indicates that a substituent bound
to a ring can have either the ~ (or endo) configura*ion or the
- ~ tor exo) configuration, and that a substituent bound to a chain
can have either the S or R con,~iguration. Both the individual con
figurational isomers, for instance, the individua' I6S-methyl and
I6R-methyl-epimers, and thei.r mixtures,are included in the object
. , ... .. , .. , .. . .. ~ , .. , ....... , . . ... ~, . ,, . . . , . . , . , .~
3S~1 2-
of the invention. ~h~ compourlds of the invention are obta m ~d by
d~hydrohalogenation of dihalo compounds of formula (II)
. - ,,~ CH-(c~l )3-~1`~
' ~f~_ ,
R ( II)
~`CH" C~l ` C5H
- - OH S~H
whare R and M have the meanings given abov~ and each of -th~ groups
X1 and X 2 ~ which may ba the ~ame or different, i8 a halogen atom
chosen from the bromin~ chlorine and iodin~ group~ follow~d by op-
tional salification of th~ obtain~d compoundO
X2 is pr~ferably a bro~ine atom. Tha dohydrohalogenation raaction i~
preferably carried out by making a compound of formula (II) r0act
with an exceæs o~ d~hydrohaloganating agent chosen, for example, from
the group of a dimethyl6ulphinylcarbanion, ~n alkaline, for instance
æodiu~ or potassium, alkoxide pre~erabl~ sodium or potassium methoxide,
othoxido, propo~ide or butoxia3, operating in an inart anhydrouq solvent,
preferably chosen fro~ the group of a linear or branched alcohol con-
taining from I to 6 carbon atoms~ e.g., methyl, ethyl, propyl,butyl, isopropyl alcohol, dimethylsulphoxide and hexamethylenephos
phoramide.
The reaction temperature can vary rom room temperature to the
boiling point ~f the solvent, and the reaction time varies from
- 20 a few minutes to several hours.
The reaction is preferably carried out at temperatures ranging
from 20 to 45~C., with reaction times of 2-3 hours.
At the end o the reaction the solvent is evaporated o~f under
.. . .. . . , . .. . ~ . .. _ .. .
;3s~
vacuum and the compound~ ef th~ in~ention are cryetallized, pr~-
f~rably from watar or hydro-alcoholic eolutions.
The optional salification step is carried out in a ~onventional way.
Compounds of formula (II) ar~ already known and can be synth~sized, for
~a~ple, by one of the processes de~cribed in the Cerman Offenlegungss~hrift
No. 27 57 91g (Farmdoc 32160A~ 7 corresponding to ~elgian Patent ~o. 862751q.
Prostacyclin or PGI2 (Prostaglandins, I2, 6, December I976, page
9I5) is a known vasodilating and anti~aggregating agent biosynthesized
in the arteries and lun~s of mammals and man, starting from arachi
donic acid (Gryglewski et al., Prostaglandins, I2, 658, I976).
PGI2 inhibits platelet aggregation and, even more important, dis
aggregates the platele~ aggrega~es in the bloodstream. In man, a
variable percentage of ~he total platelets circulates in the form
of small aggregates and, statistically, ~heir number is higher in
atha~cl~rotio subjects7 where it induces a high risk of infarc
tions ~K.K. Wu and J.C. ~ak, Lancet, 2, 923-926, I974).
Apart from the vasodilating action, pros~acyclin is also able to
disintegrate these aggregates in man ~A. Szezeklik et al., Pharmacol.
Res. Comm., I978)~ The compounds of the invention are character
ized by predominance of this disaggre~a~ing activity simultaneous
ly with the ability to relax the coronary arteries, and
both the~e activities are at a highar level comp~red to PGI2 or its
20Lmethyl analogue.
Moreover, like prostacyclin and 20-methyl prostacyclin , the com
pounds of the invention are totally free from prostaglandin-like
activity and thromboxane-like activity; that is to say~ they possess
pure PGI2-like activity.
~ ~ ~ 3 S ~
The PGI2-like activity of the co~Dunds tested was evaluated on
the basis of the capacity to relax a strip of bovine coronary ar
tery and to inhibi~ platelet ag~regation induced by ADP in ~late
let-rich rabbit plasma.
The prostaglandin-like activity, especially PGE2-like, was evalu
ated on the basis of the capacity to con~ract rat colon, while
the thromboxane-like activity, especially TXA2-like, was assessed
on the capacity to contract a strip of rabbit mesenteric artery.
The activity of the compounds of the invention, especially of co_
pound I3,I4-didehydro-20-methyl-PGI2, was compared with the activity
of known compounds, such as PGI2, 20-methyl-PGI2, PGE2, the ~,9-
epoxy-methano- analogue of PGH2 (E.M.A., U 466I9, Upjohn C0.),
_~o-- _ g.~
6~- and 6~Fmethyl-PGII, and 6~- and 6~ methyl,I3,I4-didehydro-PCI1.
Table I gives the data rela~ive to the PGI2-, PGE2- and TXA2-like
activity of the compounds mentioned above.
33~3
--
~ ... . ___...... ....... .. .. ........ . .
~ .~
.. P ~ . . . . . . ... .. ..
...... 1 .. .~ ~ o o ~ o - o C~ ~ o
~ ~ 5~ . ~
....... ... , _ ` . ~ ~ ~ _ . ._._ .... .... .
... _._.. _._.~_.~... 'r~ _~_,._____ i .
.......... '... _ __ ~ .
............... ~ .. ~ . .. _ _ . . .... _. ... .. .
... ... __. ., _ +~ ~ ____ .. ._. _ .,._ _, ,., , ,,~ ~n .
P ~ o o o o ~ ~ ~ o ~
.. .. 4, .1 , ~4 .... -- --------- - -- ~
~1 ~
__ ~ . _ .. . . ' ~ c~ ~ O ~ . ~ . o o
.. _.~... ~ ~ ;~ ~ ~ ~ '~ .
P . __ _ _ ~
_ . - ~ ~
! ~ oP~ . ! .
~ ~ ~ 8 o . 8
_.. _ - ~ 1, ~ S-l h , . ~,~ ~ . _ .. _ -- - ------- j 00
. ~ ~ o
. _ ... j . _ .
~
--
.: . M ... .. _ .
L ~ ,. .. 7
......... , . .. ~ ~
~ 3S3~L ~
Comparison o ~he experimental data reported in table I shows
the importance of the triple bond in position I3,I4, as far as
the biological activity is concerned. In -fact, in the compound
of the invention 20-methyl-I3,I4-didehydr~pGI27 the pure PGI2-
like activity is potentiated ~ve~ with respect to the
20-methyl-PGI2 analogue.
Table 2 gives some experimental data relative to the vasodilator
and anti-platelet aggregating activi~y in vitro, and the disaggre
gating action in vivo of compound I3,I4-dehydro-20-methyl-PGI2
and the PGI2 and 20-methyl-PGI2 analogues.
The vasodilator activity of said compounds in vitro was determined
by evaluating in parallel their capacity ~o relax bovine coronary
artery and rabbit mesenteric artery; unlike the other two compounds,
the I3,I4-did~hYdr- derivative are aotiv~ on both v~_ -
cular beds at the same doses.
The anti-platelet aggregating action was assessed both on platelet-
rich rabbit plasma and on heparinized cat blood according to Gryg
- lewski's test (Naunym-Schmiedeberg's Arch. Pharmacol., 302, 25-30,
I978)
The disaggregating activity in vivo was determined on anaesthetized
and heparini7ed cats, administering the compound under test by in
fusion, for instance ~R.J.Gryglewski, R. Korbut, A. Ocetkiewicz and
J. Stachura, Naunya-Schmiedeberg's Arch. Pharmacol., 302, 25-30,
1978).
~, . .
53~
~ h ~ _
~ ~ ~D ~ ' ...._, . , _~_
,~ ~1 . ' . I
C ~ "c~ *~ O ~ ' O
~ O ,o
~ ~ ~ . '' . '
.; . I`D ~ ~ ~_
. ~ ~ ~ . ........ . '.
~ ~ D
.. , ~ ~ __
~ C~ . _.'.... ._. ~.. ~ .. _ '
. _.. ... , .. , ~ ~ a~ . ~ . .
0 ~ rl ~_ O C~
~D ~ :i O
. ~_ C~
8~ ~ O H .
t' a) rl '
7~ ~ ___
~ ~ ~ ~ o C~ O O
~1 ~ ~ r ~ Ll~ O ~ ~
~. ~ r1 C~ ) ~ ~ ~ _I
. . - : +' ~ l--i ~ _ .. ... . +~ .
.. .. . ~ _~_ _ Q.)
.. ._.. _ . .~ ~ .. . _ .. _ .. _, . .~
....... , E~ ~ ~ ~ ~ O ~ ~ '
~ ~i-,l ~ ~
, , . _
O ~ O . _........ ~ '
;, ~d ~ O C~
. ' , 1~ . ~ O
_~_ .
. .. . ~ ~ ~
' U~ ' _~ ~ c9
C --~ t9 ~ ~ O
. ~ O O ,~ ~ *
____ ~ .
.
1183531 8.
The compounds of the invention were tested in the form o-f their
respective alkaline salts but the figures given in tables I and
2 refer to equimolecular quantities of the corresponding free
acids. Table 2 indicates potentiation of the va~odilator ~d anti-
aggregating activities for the compounds of the invention, withre~ to PGI2 and its 20-methyl- derivative. Like natural pros
tacyclin and 20-methyl-prostacyclin , the compounds of the inven
~ion, moreover, ~o not form a substrate for I5-prostaglandin
dehydrogenase. In particular, the I6S- and I6R-methyl derivatives,
which do not constitute a substrate for the enzyme I5-hydroxy-
prostaglandin dehydrogenase, produce a platelet aggregation i_
hibi~ng effect 2 to 5 ~imes greater than that of the corTespond
ing terms not substituted in position I6.Because of their vaso
dilating and anti-aggregating activity, the compounds of the in
vention are particularly useful in the treatment of acute myocar
dial infarction, in resolving attacks of angina pectoris, in the
prevention of platelet aggregation, associated or not with heparin-
like substances, in the prevention of aggregation during haemo
dialysisg and during surgery with extracorporeal circulation of
the blood, ~he toxicity of th~ compounds of the inverltion is quite negligible
~and therefore they can b~ safely used in therapy.
j The compounds of tbe invention can be administered
by the usual routes of administration, for instance, by intravenous
injection or infusion, by subcutaneous or intramuscular injection,
orally, by sublingual absorption, rectally~ etc. In emergency situ
ations, the compounds are preferably administered by intravenous
infusion using for this purpose sterile buffers at pH 8.5 - 9
obtained from aqueous solutions containing the compounds of the
,
,.
3533~ 9.
invention at concentrations varying, for ins~ancea from 0.0005 to
O.OI~. In this case the administration can, for instance, be effected
through an intravenous cannula ~itted with a three-way tap and
inserted, for example, into the left median cubital vein, for i_
stance, by means of an automatic syringe, at the same time. intro
ducing a 5~ dextrose solution into the right vein. In the case of
intravenous infusion, the doses vary preerably from 0.2 to 25,
especially from 0.5 to 2.0, ng per kilogram bodyweight per minute.
The total daily dosa~e, either by injection or infusion, is pre
ferably of the order of 0.005-20 mg/Kg, the exact doses depending on
age, weight and condition of the patient, as well as on the route
of ~dministration. Sterile solutions or suspensions in aqueous or
non-aqueous medium may be used for subcutaneous or intramuscular
injection. Thus, for instance, the compound may be dissolved in
sterile water or in a solution of lidocaine hydrochloride (keeping
the pH of the solution p-raferably between 8.5 and 9), OT else in
physiological saline or in any one of the usual solvents used for
this type of administration. In such cases, the dosage varies pre
ferably from about 0.05 to 53 mg daily. As already stated, other
? routes of administration can be used for the compounds of the i_
~ention; for instance, they can be administered orally, in the
form of tablets, capsules or syrup, re~ally, in the form of suppos
itories, or by sublin~ual absorption,- in the form of tablets or
sublingual lozenges. The excipients and carriers used for the various
pharmaceutical formulations are the usual ones and can, for in
stance, be, in the case of oral administration for example, lactose~
~353~ IO.
dextrose, sucrose, mannitol, sorbitol, cellulose, talc, calcium
or magnesium stearate, glycols, starches, gum arabic, tragacanth,
alginates, lecithin, or else polysorbates and lauryl sulphates,
preferably o alkaline or alkaline earth metals.
The following examples illustrate but do not limit the present
invention in any way.
Example I
A solution of 0.58 g of I4-bromo-5~S,R)-iodo-6~S,R)-20-methyl-PGII
in 4 ml of anhydrous dimethylsulphoxide and 0.34 g of sodium tert.-
butGxide are left for 3 hours in an atmosphere o:E inert gas, with
stirring. The solvents are evaporated under vacuum (0.2 mm Hg).
a stoiohiome~ric amount of
The residue is taken up with/2N NaOH. Crystals of I3,I4-dehydro-
20-methyl-PGI2, sodium salt, /~-7D= ~ IIO (EtOH), are obtained
on cooling the solution to 0C~ (yield 801o) ~d then ~ilt0ring.
F.xample 2
A solution of I4,5(S,R)-dibromo-6(S,R)-20-methyl-PGII (0.42 g)
and potassium tert.-butoxide ~0.45 g) in anhydrous methanol is kept
- at room temperature for 20 days. The solvents are evaporated under
vacuum and the product is crys~allized from 2N KOH/CH30H/water,
obtaining I3,I4-dehydro-20-methyl-PGI2, potassium salt, _~ 7 D =
~I08 (EtOH)i Eyield 72~o].
The same compound can be equally obtained by reaction with potassium
;ert.-butoxide in tert.-butanol at 38C. for 8 days.
Exam~le 3
~1 5 A solution of I6S-methyl-I4-bromo-5~S,R)-iodo-6(S,R)-20-methyl-
(0.3 g) and 0.35 g of sodium ethoxide in ethanol (4 ml) is kept
353~
at 50C. for 15 days. The solvents are evaporated under vacuum and the
residue is then dilutcd with a stoichiometric amount of 2N NaOII and cooled
to 0C
On ~iltrati~n, crystals of 13, 14 didehydro-IGS,20-dimethyl-PGI2,
sodium salt, /~7D ~118 ~EtOH) are obtained, (yield 88%).
13,14-didehydro-16R,20-dimethyl-PGI2, sodium salt, /-~-/D= -~102
~EtOH) was obtained in the same way.
- 11 -
