CH640522A5 - 20-METHYL-13,14-DIDEHYDRO-PGI (2) DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. - Google Patents

Description

The invention relates to new 20-methyl-13,14-didehydro-PGI2 derivatives, a process for their preparation and one in which R and M have the meanings given above and each of the groups Xj and X2, which can be identical or different , a halogen atom selected from the group bromine, chlorine and iodine, after which 60 if appropriate the compound obtained is converted into a salt.

X2 preferably means a bromine atom.

The dehydrohalogenation reaction is preferably carried out by reacting a compound of the formula (II) 65 with an excess of dehydrohalogenation agent which is selected, for example, from the group dimethylsulfinylcarbanion, alkali metal alkylate, preferably sodium or potassium alkylate, in particular sodium or potassium methylate,

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640522

ethylate, propylate or butylate can react, in an inert anhydrous solvent, preferably one selected from the group of linear or branched alcohols having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, , Butyl, isopropyl alcohol, dimethyl sulfoxide and hexamethylene phosphoramide, works. The reaction temperature can vary from room temperature to the boiling point of the solvent and the reaction time varies from a few minutes to several hours. The reaction is preferably carried out at temperatures within the range from 20 to 45 ° C. with reaction times of 2 to 3 hours.

After the reaction has ended, the solvent can be evaporated off under vacuum and the compounds according to the invention can be crystallized, preferably in aqueous or aqueous-alcoholic solutions.

The conversion into a salt which may be carried out can be carried out in a conventional manner.

The compounds of the formula (II) are already known and they can be prepared, for example, by one of the processes described in German Offenlegungsschrift 27 57 919, corresponding to Belgian Patent 862 514.

Prostacyclin or PGI2 (cf. "Prostaglandins", 12, December 6, 1976, p. 915) is a known vasodilator and anti-aggregation agent, which is biologically synthesized in the arteries and lungs of mammals and humans, starting from arachidonic acid (cf. Gryglewski et al in "Prostaglandins", 12, 658, 1976). PGI2 inhibits or prevents platelet aggregation and, more importantly, causes platelet aggregates to disaggregate in the blood stream. In humans, a variable percentage of whole platelets circulate in the bloodstream in the form of small aggregates, and statistically their number is higher in arteriosclerotic patients, where they represent a high risk of infarction [cf. K.K. Wu and J.C. Haak, Lancet, 2, 923-926 (1974)]. Apart from the vasodilatory effect, prostacyclin is also able to disintegrate these aggregates in humans (cf. A. Szezeklik et al, "Pharmacol. S Res. Comm.", 1978). The compounds according to the invention are characterized by a predominance of this disaggregation activity, while at the same time they have the ability to relax the coronary arteries, these two activities being present to a higher degree than with PGI2 or its 20-methyl analogue. In addition, the compounds according to the invention, such as prostacyclin and 20-methyl-prostacyclin, are completely free from a prostaglandin-like activity and a thromboxane-like activity, i.e. they have a pure PGI2-like activity.

The PGI2-like activity of the compounds tested was evaluated based on their ability to relax a strip of bovine coronary artery and to inhibit or prevent platelet aggregation caused by ADP in a platelet rich in platelets.

Prostaglandin-like activity, particularly PGE2-like activity, was evaluated based on their ability to contract a rat colon, while thromboxane-like activity, particularly TXA2-like activity, was examined for a streak contracting a rabbit mesentery artery.

The activity of the compounds according to the invention, in particular the compound 13-14-didehydro-20-methyl-PGI2, was compared with the activity of known compounds, such as PGI2, 20-methyl-PGI2, PGE2, the 11,9-epoxy-methano-- Analog of PGH2 (EMA, U 46619, Upjohn Co), 6β- and öa-20-methyl-PG ^ and 6ß- and 6a-20-methyl-13,14-di-dehydro-PGIj compared. Table I below shows the data relating to the PGI2, PGE2 and TXA2-like activity of the above-mentioned compounds.

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TABLE I

Compounds PGl2-like activity PGE2-like activity TXA2-like activity

Relaxation anti-aggregation contraction of a contraction of a streaking effect rat colon IC rabbit mesentery

a bovine coronary artery

PGE2 0

E.M.A. O

PGI2 100

20-methyl-PGI2 500

20-methyl-PGI2 (6β) 0

20-methyl-PGÏ! (a) 0

20-methyl-13,14-didehydro-

-PGIj (6ß) 5

20-methyl-13,14-didehy dro-

-PGIX (6a) 0

20-methyl-13,14-didehydro-

-PGI2 800

0 100 0

0 0 100

100 0 0

100 0 0

1.5 5 1

0 3 0.5

2 2 0

0.1 0.5 0.4

400 0 0

65 A comparison of the experimental data given in Table I shows the importance of the triple bond in position 13, 14 in terms of biological activity. Indeed, in the compound of the invention

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20-methyl-13,14-didehydro-PGI2 potentiates the pure PGI2-like activity also with regard to the 20-methyl-PGI2 analogue.

In the following Table II are some experimental data regarding the vasodilatory and anti-platelet aggregation activity in vitro and the disaggregation effect in vivo of the compound 13,14-dehydro-20-methyl-PGI2 and the PG ^ - and 20- Methyl PGI2 analogs indicated.

The vasodilatory activity of these compounds in io vitro was determined by parallel evaluation of their ability to relax a bovine coronary artery and a rabbit mesenteric artery; in contrast to the other two compounds, the 13,14-didehydro derivative is active in both vascular systems at the same doses. 15

The anti-platelet aggregation effect was investigated both in rabbit plasma rich in platelets and in heparinized cat blood using the Gryglewski test [cf. Naunym-Schmiede-berg, «Arch. Pharmacol. », 302, 25-30 (1978)]. 20th

The disaggregation activity in vivo was determined in anesthetized and heparinized cats by administration of the tested compound, for example by infusion [cf. R. J. Gryglewski, R. Korbut, A. Ocetkiewicz and J. Stachura, "Naunya-Schmiedeberg's Arch. Pharma- 25 col.", 302, 25-30 (1978)].

TABLE II

Compounds vasodilatory effect in vitro

(ng / ml)

Bovine Coronary Rabbit Mesopotomy (TC) * terium artery

(TC) *

Anti-platelet aggregation activity in vitro (ng / ml)

rabbit-rich plasma (IC50) ** feline blood on platelets

(IC50) **

Disaggregation activity in cats in vivo (ng / kg / min.) Reversal of platelet aggregation

(ID50) ***

PGI2 6.0

20-methyl-PGI2 1,2

20-methyl-13,14-

-didehydro-PGI2 0.7

4.0 1.0

0.7

3.9 4.0

1.0

1.0 7.2

2.5

330 330

100

* TC = minimum effective dose

** IC00 = concentration that produces 50% of the maximum effect

*** IDso = dose that produces 50% of the maximum effect

The compounds according to the invention were tested in the form of their respective alkali salts, but the numerical values given in Tables I and II relate to equimolar amounts of the corresponding free acids. Table II shows the potentiation of the vasodilatory and anti-aggregation activities of the compounds according to the invention in relation to PGI2 and its 20-methyl derivative. Like natural prostacyclin and 20-methyl-prostacyclin, the compounds according to the invention do not form a substrate for 15-prostaglandin dehydrogenase. In particular, the 16S and 16R-methyl derivatives, which are not a substrate for the enzyme 15-hydroxyprostagindine dehydrogenase, give a platelet aggregation inhibition effect which is two to five times greater than that of the corresponding compounds which are not in the 16-position tion are substituted. Because of their vasodilatory and anti-aggregation activity, the compounds according to the invention are particularly valuable for the treatment of acute myocardial infarction, for the elimination of angina pec-toris attacks, for the prevention of platelet aggregation, associated or not with heparin-like substances, 50 for the prevention of aggregation during the Hemodialysis and during surgery with extracorporeal blood circulation. The toxicity of the compounds according to the invention is negligibly low, and they can therefore be used safely in therapy. The compounds according to the invention can be administered in a customary manner, for example by intravenous injection or infusion, by subcutaneous or intramuscular injection, orally, by sublingual absorption, rectally and the like. In emergency situations, the compounds 60 are preferably administered by intravenous infusion, for this purpose Sterile buffers with a pH of 8.5 to 9, prepared from aqueous solutions which contain the compounds according to the invention in concentrations which vary, for example, from 0.0005 to 0.01%, are used. In this case, the administration can be carried out, for example, by means of an intravenous cannula which is provided with a 3-way cock and is inserted, for example, into the left median cupital vein

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for example by means of an automatic syringe with simultaneous introduction of a 5% dextrose solution into the right vein. In the case of intravenous infusion, the doses preferably vary from 0.2 to 25, in particular from 0.5 to 2.0 mg / kg body weight / min. The total daily dose when administered by injection or infusion is preferably in the order of 0.005 to 20 mg / kg, the exact doses depending on the age, weight and condition of the patient and on the type of administration. Sterile solutions or suspensions in aqueous or non-aqueous media can be used for subcutaneous or intramuscular injection. For example, the compound can be dissolved in sterile water or in a solution of lido-cain hydrochloride (the pH of the solution preferably being kept between 8.5 and 9), or in a physiological saline solution (saline solution) or in any of the common solvents used for this type of administration. In such cases, the dose preferably varies from about 0.05 to about 50 mg per day. As already stated, other routes of administration can also be used to administer the compounds according to the invention, for example they can be administered orally in the form of tablets, capsules or a syrup, rectally in the form of suppositories, or by sublingual absorption in the form of tablets or sublingual pastilles.

The excipients and carriers that can be used for the various pharmaceutical formulations are the usual ones, and in the case of oral administration they can be, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, talc, calcium - Or magnesium stearate, glycols, starches, gum arabic, tragacanth, alginates, lecithin, or also polysorbates and lauryl sulfates, preferably of alkali or alkaline earth metals.

The invention is illustrated by the following examples.

example 1

A solution of 0.58 g of 14-bromo-5 (S, R) -iodo-6 (S, R) -20-methyl-PGIj in 4 ml of anhydrous dimethyl sulfoxide and 0.34 g of sodium tert-butoxide was added Allow to stand for 3 hours in a 5 inert gas atmosphere with stirring. The solvents were evaporated in vacuo (0.2 mm Hg). The residue was taken up with a stoichiometric amount of 2N NaOH. After cooling the solution to 0 ° C. and then filtering, crystals of the sodium salt of 13,14-dehydro-20-methyl-PGI2 were obtained in a yield of 80%, [a] D = + 110 ° (EtOH ).

Example 2

A solution of 0.42 g of 14.5 (S, R) dibromo-6 (S, R) -20-me-15 thyl-PGIj and 0.45 g of potassium tert-butoxide in anhydrous methanol was kept for 20 days kept at room temperature. The solvents were evaporated in vacuo and the product was crystallized in 2N KOH / CH3OH / water to give the potassium salt of 13,14-dehydro-20-20-methyl-PGL in a yield of 72%, [a] D = + 108 ° (EtOH).

The same compound can be obtained by reaction with potassium tert-butoxide in tert-butanol at 38 ° C for a period of 8 days.

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Example 3

A solution of 0.3 g of 16S-methyl-14-bromo-5 (S, R) -iodo-6 (S, R) -20-methyl-PGI1 and 0.35 g of sodium ethylate in 4 ml of ethanol was used for 15 days kept at 50 ° C for a long time. The solvents were evaporated in vacuo and the residue was then diluted with a stoichiometric amount of 2N NaOH and cooled to 0 ° C. After filtering, crystals of the sodium salt of 13,14-di-dehydro-16S, 20-dimethyl-PGI2 were obtained in a yield of 88%, 35 [a] D = + 118 ° (EtOH).

The sodium salt of 13,14-didehydro-16R, 20-dimethyl-PGI2, [a] D = + 102 ° (EtOH) was obtained in the same way.

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Claims (11)

640522 2nd PATENT CLAIMS 1. 20-methyl-13,14-didehydro-PGI2 derivatives, characterized by the general formula: (I) (CHJ.-COOM {• 2 3 CH R C "CH-CH-CPH, 5H 5 11 wherein R is hydrogen or methyl and M is hydrogen or a pharmaceutically acceptable cation. 2. 20-methyl-13,14-didehydro-PGI2 as a compound according to claim 1. 3. alkali metal salts of 20-methyl-13,14-didehydro-PGI2 according to claim 2, preferably the sodium or potassium salt. 4. 13,14-Didehydro-16S, 20-dimethyl-PGI2 as a compound according to claim 1. 5. alkali metal salts of 13,14-didehydro-16S, 20-dimethyl-PGI2 according to claim 4, preferably the sodium or potassium salt. 6. 13,14-didehydro-16R, 20-dimethyl-PGI2 according to claim 1. 7. alkali metal salts of 13,14-didehydro-16R, 20-dimethyl-PGI2 according to claim 6, preferably the sodium or potassium salt. 8. A process for the preparation of 20-methyl-13,14-di-dehydro-PGI2 derivatives according to claim 1, characterized in that dihalogen compounds of the general formula: h y CH- (CH) -C00M / Cli - ° WCH2 X. pharmaceutical preparation containing these derivatives as an active substance. The compounds according to the invention have the general formula: 10th r (ch,) "- coom I 2 o t " a * CH, y * 15 R C <? % OH V ^ NCH-CH-C.H ~ 5 OH c 11 20 wherein R is hydrogen or methyl and M is hydrogen or a pharmaceutically acceptable cation. The compounds are conveniently used in the form of pharmaceutical agents. M preferably denotes the cation of an alkali metal, 25 such as e.g. Sodium or potassium. In the formulas given here, the broken line (11111) indicates that the binding of a substituent to a ring is in the a (or endo) configuration and the binding of a substituent to a chain is in the S configuration; the wavy line 30 (T) indicates that the binding of a substituent to a ring can be either in the a (or endo) configuration or in the β (or exo) configuration and that a substituent attached to a chain can either be the S -35 or the R configuration. The two individual configuration isomers, e.g. the individual 16S-methyl and 16R-methyl epimers and their mixtures also fall within the scope of the present invention. The compounds according to the invention are prepared by dehydrohalogenation of dihalogen compounds of the general formula (II) 45 wherein R and M have the meanings given in claim 1 and each of the groups and X2, which may be the same or different, denote a bromine, chlorine or iodine atom, dehydrohalogenated. 9. The method according to claim 8, characterized in that obtained compounds are converted into corresponding salts by reaction with a pharmaceutically acceptable salt-providing inorganic or organic base. 10. A pharmaceutical preparation which contains as an active ingredient a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 50 55 II