CA1183531A - 20-methyl-13,14-didehydro-pg1.sub.2 derivatives and process for their preparation - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates to a process for the preparation of a compound of formula (I) (I) where R is hydrogen or methyl and M is hydrogen or a pharmaceutically acceptable cation, characterized by subjecting to dehydrohalogenation dihalo compounds of formula (II) (II) where R and M have the meanings given in claim I and each of the groups XI and X2, which may be the same or different, is a halogen atom chosen from the bromine, chlorine and iodine group, and where a salt is required heating a compound of formula I with a base. The compounds of the invention are characterized by predominance of this disaggregating activity simultaneously with tha ability to relax the coronary arteries, and both these activities are at a higher level compared to PGI2 or its 20-methyl analogue. Moreover, like prostacyclin and 20-methyl prostacyclin, the compounds of the invention are totally free from prostaglandin-like activity and thromboxane-like activity;
that is to say, they possess pure PGI2-like activity.

Description

~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 .. . .. . . , . .. . ~ . .. _ .. .

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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).

~, . .

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~ 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.

Claims (20)

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

1. A process for the preparation of a compound of formula (I) (I) where R is hydrogen or methyl and M is hydrogen or a pharmaceutically accept-able cation characterized by subjecting to dehydrohalogenation dihalo compounds of formula (II) (II) where R and M have the meanings given above and each of the groups XI and X2, which may be the same or different, is a halogen atom chosen from the bromine, chlorine and iodine group, and where a salt is required heating compound of formula I with a base.

2. A compound of formula (I) (I) where R is hydrogen or methyl and M is hydrogen or a pharmaceutically acceptable cation whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process for the preparation of 13,14-dehydro-20-methyl-PGI2 or a pharmaceutically acceptable salt thereof which comprises reacting 14-bromo-5(S,R)-iodo-6(S,R)-20-methyl-PGI1 or 14,5(S,R)-dibromo-6(S,R)-20-methyl-PGI1 with a base having a pharmaceutically acceptable cation.

4. A process for the preparation the sodium salt of 13,14-dehydro-20-methyl-PGI1 which comprises reacting 14-bromo-5(S,R)-iodo-6(S,R)-20-methyl-PGI1 with sodium tert. butoxide.

5. A process for the preparation of the potassium salt of 13,14-dehy-dro-20-methyl-PGI2 which comprises reacting 14,5(S,R)-dibromo-6(S,R)-20-methyl-PGI1 with potassium tert. butoxide.

6. A process for the preparation of 13,14-didehydro-16S,20-dimethyl-PGI2, sodium salt which comprises reacting 16S-methyl-14-bromo- 5(S,R)-iodo-6(S,R)-20-methyl-PGI1 with sodium ethoxide.

7. An alkaline salt of 20-methyl-13,14-didehydro-PGI2, whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

8. The sodium salt of 13,14-dehydro-20-methyl-PGI2, whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

9. Potassium salt of 13,14-dehydro--20-methyl-PGI2, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

10. A process for the preparation of 13,14-didehydro-16S,20-dimethyl-PGI2 or a pharmaceutically acceptable salt thereof which comprises re-acting 16S-methyl-14-bromo-5(S,R)-iodo-6(S,R)-20-methyl-PGIl with a base having a pharmaceutically acceptable cation.

11. 13,14-didehydro-16S,20-dimethyl-PGI2, sodium salt. whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

12. A process according to claim 1 wherein the dehydro-halogenation is carried out by treatment of the compound of formula II with a base in which sodium or potassium is cation.

13. A process for the preparation of a pharmaceutically acceptable alkali metal salt of 13,14-dehydro-16S,20-dimethyl PGI2, which comprises reacting 16S-methyl-14-bromo-5(S,R)-iodo-6(S,R)-20-methyl PGIl with the ethoxide of a pharmaceutically acceptable alkali metal.

14. A pharmaceutically acceptable alkali metal salt of 13,14-dehydro-16S,20-dimethyl PGI2, whenever prepared by a process according to claim 13 or an obvious chemical equivalent thereof.

15. A process for preparing 13,14-dehydro-16R,20-dimethyl-PGI2 or a pharmaceutically acceptable salt thereof which comprises reacting 16R-methyl-14-bromo-5(S,R)-iodo-6(S,R)-20-methyl PGIl with a base having a pharmacautically acceptable cation.

16 A process for preparing 13,14-dehydro-16R,20-dimethyl PGI2 sodium salt which comprises reacting 16R-methyl-14-bromo-5(S,R)-iodo-6(S,R)-20-methyl PGIl with sodium ethoxide.

17. 13,14-Dehydro-16R,20-dimethyl PGI2 sodium salt when prepared by a process according to claim 16 or an obvious chemical equivalent thereof.

18. A process for preparing a pharmaceutically acceptable alkali metal salt of 13,14-dehydro-16R,20-dimethyl PGI2 wbich comprises reacting 16R-methyl-14-bromo-5(S,R)-iodo-6(S,R)-20-methyl PGIl with the ethoxide of a pharmaceutical-ly acceptable alkali metal.

19. A pharmaceutically acceptable alkali metal salt of 13,14-dehydro-16R,

20-dimethyl PGI2 whenever prepared by a process according to claim 18 or by an obvious chemical equivalent.