GB2025972A - 20-methyl-13, 14-didehydro- PGl2 derivatives and process for their preparation - Google Patents

Abstract

20-Methyl-13, 14-didehydro- PGl2 derivatives of formula: <IMAGE> where R is hydrogen or methyl and M is hydrogen or a pharmaceutically acceptable cation have a greater effect than PGl2 or 20-methyl-PGl2 in disaggregating platelets in the bloodstream and in vasodilating action. They can be prepared by dehydrohalogenation of dihalo compounds of formula (II> <IMAGE> where R and M have the meanings given above and X1 and X2 are independently bromine, chlorine or iodine. A sodium or potassium alkoxide is the preferred dehydrohalogenating agent.

Description

SPECIFICATION 20-methyl-l 3,1 4-didehydro-PGI2 derivatives and process for their preparation This invention relates to 20-methyl-i 3,1 4-didehydro-PGl2 derivatives, their preparation, and pharmaceutical compositions containing them.

The above compounds have the following formula (I)

where R is hydrogen or methyl and M is hydrogen ora pharmaceutically acceptable cation. M is preferably the cation of an alkali metal, e.g. sodium or potassium. In the formulae in this specification the broken line (" " ') indicates that a substituent bound to a ring is in the a (or endo)-configuration and a substituent bound to a chain is in configuration S; the wavy line (0) indicates that a substituent bound to a ring can have either the a (or endo)-configuration or the ss (or exo)-configuration, and that a substituent bound to a chain can have either the S orR configuration.Both the individual configurational isomers, for instance, the individual 1 6S-methyl and 1 6R-methyl-epimers, and their mixtures, are included in formula (I). The compounds of formula i can be obtained by dehydrohalogenation of dihalo compounds of formula (II)

where R and M have the meanings given above and each of the groups X, and X2, which may be the same or different, is a halogen atom chosen from bromine, chlorine and iodine atoms, followed by optional salification of the obtained compound.

X2 is preferably a bromine atom. The dehydrohalogenation reaction is preferably carried out by reacting a compound of formula (il) with an excess of dehydrohalogenating agent chosen, for example, from a dimethylsulphinylcarbanion, an alkali metal, for instance sodium or potassium, alkoxide, preferably sodium or potassium methoxide, ethoxide, propoxide or butoxide, operating in an inert anhydrous solvent. The solvent is preferably a linear or branched alcohol containing from 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, butyl, or isopropyl alcohol, dimethylsulphoxide or hexamethylenephosphoramide. The reaction temperature can vary from room temperature to the boiiing point of the solvent, and the reaction time from a few minutes to several hours.The reaction is preferably carried out at temperatures of from 20 to 450C., with preferred reaction times of 2-3 hours.

At the end of the reaction the solvent can be evaporated off under vacuum and the compounds of formula (I) are crystallized, preferably from water or a mixture of water with an alcohol.

The optional salification (salt formation) step is carried out in a conventional way. Compounds of formula (il) are already known and can be synthesised, for example, by one of the processes described in German Offenlegungsschrift No. 27 57 919, or the corresponding Belgian Patent No. 862,514..

Prostacyclin or PGl2 (P rostaglandins, 12, G, December 1976, page 915) is a known vasodilating and anti-aggregating agent biosynthesised in the arteries and lungs of mammals and man, starting from arachidonic acid (Gryglewski et a/., Prostaglandins, 12, 658, 1976). PGl2 inhibits platelet aggregation and, even more important, disaggregates the platelet aggragates in the bloodstream. In man, a variable percentage of the total platelets circulates in the form of small aggregates and, statistically, their number is higher in atherosclerotic subjects, where it induces a high risk of infarctions (K.K. Wu and J.C.

Haak, Lancet, 2, 923-926, 1974).

Apart from the vasodilating action, prostacyclin is also able to disintegrate these aggregates in man (A. Szezezlik et a/., Pharmacol. Res. Comm., 1 9i8). The compounds of formula (I) exhibit this disaggregating activity predominantly and simultaneously with the 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 formula (I) are-totally free from prostaglandin-like activity and thromboxane-like activity; that is to say, they possess pure PGI2-like activity.

The PGI2-like activity of the compounds tested was evaluated on the basis of the capacity to relax a strip of bovine coronary artery and to inhibit platelet aggregation induced by ADP in platelet-rich rabbit plasma.

The prostaglandin-like activity, especially PGE2-like, was evaluated on the basis of the capacity to contract 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 compound 13,14-didehydro-20-methyl-PGI2 of formula (I) was compared with that of known compounds, such as PGI2, 20-methyl-PGI2, PGE2, the 11 ,9-epoxy-methano- analogue of PGH2 (E.M.A., U 46619, Upjohn Co.),. 6p- and 6a-20-methyl-PGI1,and with 6,B- and 6a-20- methyl,13,1 4-didehydro-PGI. Table I gives the data relative to the PGI2-, PGE2- and TXA2-like activity of the compounds mentioned above.

TABLE 1

PGI2-like activity PGE2-like activity TXA2-like activity Relaxation of a anti- Contraction of strip of bovine aggregating Contraction of rabbit mesenteric Compounds coronary artery action rat colon artery PGE2 0 0 100 0 E.M.A. 0 0 0 100 PGE2 100 100 0 0 20-methyl-PGI2 500 100 0 0 20-methyl-PGI2 (6ss) 0 1.5 5 1 20-methyl-PGE2 (6 &alpha;) 0 0 3 0.5 20-methyl-13,14-di-dehydro PGI1 (6ss) 5 2 2 0 20-methyl-13,14-di-dehydro PGE1 (6&alpha;) 0 0.1 0.5 0.4 20-methyl-13,14-di-dehydro PGI2 (formula I) 800 400 0 0 Comparison of the experiment data reported in Table I shows the importance of the triple bond in position 13,14, as far as the biological activity is concerned.In fact, in the compound of formula (I) 20-methyl-i 3,1 4-didehydro-PGI2,the pure PGI2-like activity is more potent even than that of the 20 methyl-PGI2 analogue.

Table 2 gives some experimental data relative to the vasodilator and anti-platelet aggregating activity in vitro, and the disaggregating action in vivo of compound 13,1 4-dehydro-20-methyl-PGl2 and the PGl2 and 20-methyl-PQI, analogues.

The vasodilating activity of said compounds in vitro was determined by evaluating in parallel their capacity to relax the bovine coronary artery and rabbit mesenteric artery; unlike the other two compounds, the 13,1 4-didehydro-derivatives are active on both vascular beds at the same doses.

The anti-platelet aggregating action was-assessed both on platelet-rich rabbit plasma and on heparinised cat blood according to Gryglewski's test (Naunym-Schmiedeberg's Arch. Pharmacol., 302, 25-30, 1978).

The disaggregating activity in vivo was determined on anaesthetised and heparinised cats, administering the compound under test by infusion, for instance (R.J. Qryglewski, R. Korbut, A.

Ocetkiewicz and J. Stachura, Naunya-Schmiedeberg's Arch. Pharmacol., 302,25-30, 1 978). TABLE 2

Vasoditating action Anti-platelet aggregating in vitro (ng/ml) activity in vitro (ng/ml) Disaggregating activity in Bovine Rabbit Platelet- Heparinised the cat in vivo (ng/Kg/min.) Coronary mesenteric rich rabbit cat Reversal of platelet artery artery plasma blood aggregation Compounds (TC)* (TC)* (IC50)** (IC50)** (ID50)*** PGI2 6.0 4.0 3.9 1.0 330 20-methyl-PGI2 1.2 1.0 4.0 7.2 330 20-methyl-13,14-di-dehydro-PGI2 (formula I) 0.7 0.7 1.0 2.5 100 *TC = minimum effective dose.

**IC50 = concentration evoking 50% of the maximum effect ***ID50 = dose evoking 50% of the maximum effect The compounds of formula (I) were tested in the form of their respective alkali metal salts but the figures given in Tables 1 and 2 refer to equimolecular quantities of the corresponding free acids. Table 2 indicates the superior vasodilating and anti-aggregating activities for the compounds of formula (I), with respect to PGl2 and its 20-methyl- derivative. Like natural prostacyclin and 20-methyl-prostacyclin, the compounds of the invention, moreover, do not form a substrate for 1 5-prnstaglanain dehydrogenase.In particular, the 16S- and 1 6R-methyl derivatives, which do not consititute a substrate for the enzyme 1 5-hydroxy-prostaglandin dehydrogenase, produce a platelet aggregation inhibiting effect 2 to 5 times greater than that of the corresponding compounds not substituted in position 16. Because of their vasodilating and anti-aggregating activity, the compounds of the invention are particularly useful in the treatment of acute myocardial infarction, in treating attacks of angina pectoris, in the prevention of platelet aggregation, whether or not associated with heparin-like substances, in the prevention of aggregation during haemodialysis, and during surgery with extracorporeal circulation of the blood. The toxicity of the compounds of formula (I) is quite negligible and therefore they can be safely used in therapy.

The compounds of formula (I) can be formulated as pharmaceutical compositions comprising an inert carrier and/or diluent and the active ingredient. The compounds or their compositions can be administered by the usual routes of administration, e.g. intravenous injection or infusion, subcutaneous or intramuscular injection, orally, sublingual absorption or rectally. In emergency situations, they are preferably administered by intravenous infusion, using for this purpose sterile buffers at pH 8.5-9 obtained from aqueous solutions containing the compounds at concentrations varying, for instance, from 0.0005 to 0.01%.In this case the administration can, for instance, be effected through an intravenous cannula fitted with a three-way tap and inserted, for example, into the left median cubital vein, for instance, by means of an automatic syringe, at the same time introducing a 5% dextrose solution into the right vein. In the case of intravenous infusion, the doses vary preferably from 0.2 to 25, especially from 0.5 to 2.0, ng (nanograms) per kilogram bodyweight per minute. The total daily dosage, either by injection or infusion, is preferably 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 administration. Sterile solutions of suspensions in aqueous or non-aqueous medium may be used for subcutaneous or intramuscular injection.Thus, for instance, the compound maybe dissolved in sterile water or in a solution of lidocaine hydrochloride (keeping the pH of the solution preferably between 8.5 and 9), or else in physiological saline or in any one of the usual solvents used for this type of administration. In such cases, the dosage varies preferably from about 0.05 to 50 mg daily. As already stated, other routes of administration can be used; for instance they can be administered orally, in the form of tablets, capsules or syrup, rectally, in the form of suppositories, or by sublingual absorption, in the form of tablets or sublingual lozenges.

The excipients and carriers usable for the various pharmaceutical formulations are the usual ones and can, for instance, be, in the case of oral administration for exampie, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, talc, calcium or magnesium stearate, glycols, starches, gum arabic, tragacanth, alginates, lecithin, or else polysorbates and lauryl sulphates, preferably of alkali or alkaline earth metals.

The following examples illustrate but do not limit the present invention in any way.

EXAMPLE 1 A solution of 0.58 g of 14-bromo-5(S,R)-iodo-6(S,R)-20-methyl-PGI1 in 4 ml of anhydrous dimethylsulphoxide and 0.34 g of sodium tert.-butoxide are left for 3 hours in an atmosphere of inert gas, with stirring. The solvents are evaporated under vacuum (0.2 mm Hg). The residue is taken up with a stoichiometric amount of 2N NaOH. Crystals of 13,1 4-dehydro-20-methyl-PGI2, sodium salt, [aj= + 100 (EtOH), are obtained on cooling the solution to OOC, (yield 80 ,ó) and then filtering.

EXAMPLE 2 A solution of 14,5(S,R)-dibromo-6(S,R)-20-methyl-PGI, (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 crystallised from 2N KOH/CH3OH/water, thus producing 1 3,14- dehydro-20-methyl-PGl2, potassium salt, [a]D= +1080 (EtOH), [yield 72%].

The same compound can be equally obtained by reaction with potassium tert.-butoxide in tert.butanol at 380C for 8 days.

EXAMPLE 3 A solution of 16S-methyl-14-bromo-5(5,R)-iodo-6(5,R)-20-methyl-PGI1 (0.3 g) and 0.35 g of sodium ethoxide in ethanol (4 ml) is kept at 500C for 1 5 days. The solvents are evaporated under vacuum and the residue is then diluted with 2N NaOH and cooled to OOC. On filtration, crystals of 13,1 4-didehydro-1 6S,20-dimethyl-PGl2, sodium salt, [a] D= + 11 (EtOH) are obtained.

13,1 4-Didehydro-1 6R,20-dimethyl-PGI2, sodium salt, [a]=+l 020 (EtOH) was obtained in the same way, from the corresponding 1 6R starting compound.

Claims (18)

1. A compound of formula (I)

where R is hydrogen or methyl and M is hydrogen or a pharmaceutically acceptable cation.

2.20-Methyl-13,14-didehydro-PGI2.

3. An alkali metal salt of 20-methyi- 3,14-didehydro-PGI2.

4. The sodium salt of 20-methyl- 13,1 4-didehydrn-PGl2.

5. The potassium salt of 20-methyl-13,1 4-didehydro-PGI2.

6. 13,14-Didehydro-16S,20-dimethyl-PGI2.

7. An alkali metal salt of 13,1 4-didehydro-1 6S,20-dimethyl-PGl2.

8. The sodium salt of 13,1 4-didehydro-1 6S,20-dimethyl-PGl2.

9. The potassium salt of 13,1 4^didehydro-1 6S,20-methyl-PGI2.

10. 13,14-Didehydro-16R,20-dimethyl-PGI2.

11. An alkali metal salt of 13,14-didehydro-16R,20-dimethyl-PGI2.

12. The sodium salt of 13,14-didehydro-16R,20-dimethyl-PGE2.

13. The potassium salt of 13,14-didehydro-16R,20-dimethyl-PGI2.

14. A process for the preparation of compounds claimed in claim 1, which comprises dehydrohalogenating a dihalo compound of formula (II)

where R and M have the meanings given in claim 1 and each of the groups X, and X2, which may be the same or different, is a bromine, chlorine or iodine atom, and, if the compound obtained is a free acid, optionally forming a salt thereof with a pharmaceutically acceptable cation.

1 5. A process according to claim 14 wherein a compound claimed in any one of claims 2 to 13 is prepared.

1 6. A process according to claim 14 substantially as described in any one of the Examples.

1 7. 20-Methyl- 13,14-didehydro-PGI2 derivatives according to claim 1 when prepared by a process claimed in claim 1 4, 1 5 or 16.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or claim 1 7, and a pharmaceutically acceptable carrier and/qr diluent