CS208668B2 - Method of making the derivatives of the 20-methyl-13,14-didehydro-pgi2 - 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

The present invention relates to a process for the preparation of 20-methyl-13, H-didebydro-JGIg derivatives

The compounds produced according to the invention are compounds of the general formula I (CH, L-cooM ⁾

(I) in which:

R represents a hydrogen atom; L represents a hydrogen atom or a Qeyl group; or a pharmaceutically acceptable cation.

pharmaceutical compositions comprising compounds of the general formula

The invention also includes Formula I. M is preferably an alkali metal cation such as sodium or potassium.

In the formula of the invention, the dashed line (>) means that the subssituent on the ring has a Z (or endo) configuration and the subssituent on the chain has a c-configuration S. The wavy line (zwwv) means that the subssituent on the ring can either be (or endo) or coitf The S (or exo) subs configuration of the subsSittent on the chain may have the S or R. R co-configuration. The present invention encompasses both individual co-configuration isomes, e.g.

The compounds of the formula I according to the invention are prepared by dehydrohalogenation of dihalogenated compounds of the formula II

in which

R and M are the same as above and

X 1 and X ₂ independently represent a halogen atom from the group consisting of bromine, chlorine and iodine, and optionally converting the obtained compound to its pharmaceutically acceptable salt.

X _2, E is preferably Br · dehydrohalogenation reaction is preferably carried out by treating compound II with an excess of a dehydrohalogenating agent, for example from the group consisting of dimetylsulfinylkarbaniontu, an alkali such as sodium or potassium alkoxide, and preferably sodium methoxide, ethoxide, propoxide or sodium or potassium butoxide. The treatment is carried out in an inert anhydrous solvent, preferably selected from the group consisting of a linear or branched alcohol having from 1 to 6 carbon atoms, e.g., methanol, ethyl alcohol, propyl alcohol, butyl alcohol, isopropyl alcohol, dimethylsulfoxide and hexamethylene phosphoramide.

The reaction temperature can range from room temperature to the boiling point of the solvent. The reaction time may range from a few minutes to several hours.

The reaction is preferably carried out at a temperature of 20 to 45 ° C for 2 to 3 hours.

At the end of the reaction, the solvent is evaporated in vacuo and the compounds of the invention crystallize, preferably from water or aqueous-alcoholic solutions.

Any salt production is carried out in a conventional manner:

The compounds of formula II are already known. They can be synthesized, for example, by any of the methods described in DOS No. 2,757,919 corresponding to Belgian Patent No. 862,514.

Prostacyclin or PGI ₂ (Prostaglandins 1.2 / 6 /, December 1976, p. 915) is a known vasodilator and antiplatelet agent that is biosynthesized in the arteries and lungs of mammals and humans. The starting material is arachidonic acid (Gryglewski et al., Prostaglandins 12, 658 (1976)).

PGI ₂ inhibits platelet aggregation, and even more importantly, it causes disintegration by platelet aggregation in the bloodstream. Of the total number of platelets, different amounts of platelets circulate in human bloodstream in the form of small aggregations. The number of aggregations is statistically higher for atherosclerotic objects where it leads to a high risk of heart attacks (K. K. Wu and JC Haak: Lancet 2, 923-926 (1974)).

In addition to its vasodilating effect, prostacyclin also has the ability to cause disintegration of these aggregations in humans (A. Szezeklik et al., Pharmacol. Res. Commun. 1978). The compounds of the invention are characterized by a predominance of this deaaggregation activity along with the ability to release coronary arteries. Both of these activities are enhanced when compared to POIg or its 20-methylated analog.

Like prostacyclin and 20-methylprostacycline, the compounds of the invention are completely free of prostaglandin and thromboxane activity. They can be said to have pure PGI? Activity.

The PGIg activity of the test compounds was evaluated on the basis of bovine coronary artery contraction relaxation capacity and inhibition of ADP-induced platelet aggregation in platelet-rich rabbit plasma.

Prostaglandin activity, particularly PGE2 activity, was evaluated as the contraction capacity of rat colon, whereas thromboxane activity, particularly TXAg activity, was determined as the contraction capacity of rabbit mesenteric artery.

The efficacy of the compounds of this invention, in particular of 13,14-didehydro-20-methyl-PGI ₂ , was compared with the efficacy of known compounds such as PGI ₂ , 20-methyl-PGI ₂ , PGE ₂ , 11,9-epoxy-methano analog PGH2 (U. M. A., U 46 619, Upjohn Co.), 6beta- and 6alpha-20-methyl-PGI ₁ and 6beta- and 6alpha-20-methyl-13,14-didehydro-PGI.

Table 1 gives the data relating to the PGI _{2 -} > HJEg- and TXA ₂ -activities of the above compounds.

Table 1

Compound PGI ₂ -activity PGE ₂ -activity Rat colonic contraction TXA ₂ -activity Rabbit mesenteric artery contraction Relaxation of coronary artery contraction Anti-aggregation efficacy poe ₂ 0 0 100 ALIGN! 0 Ε. M. A. 0 0 0 100 ALIGN! pgi ₂ 100 ALIGN! 100 ALIGN! 0 0 20-methyl-PG12 500 100 ALIGN! 0 0 20-Methyl-PGIj (óbeta) 0 1.5 5 1 20-Methyl-PGIj (6alfa) 0 0 3 0.5 20-methyl-13,14-didehydro-PGI (6beta) 5 2 2 0 20-Methyl-13,14-didehydro-PGI ₁ (6alpha) 0 0.1 0.5 0.4 20-methyl-13,14-didehydro-PGI ₂ 800 400 0 0

Comparison of the experimental data presented in Table 1 shows the importance of the triple bond at position 13,14 with respect to the biological activity of the compounds, the pure PG12 activity of the compound of the invention is 20-methyl-13,14-didehydro-PGI ₂ , even when compared with 20-methyl-PGI ₂ -analog.

Table 2 gives some experimental data on vasodilatory activity directed against platelet aggregation in vitro and in vivo disaggregation activity of 13,14-didehydro-20-methyl-PGI ₂ and PGI ₂ - and 20-methyl-PGI ₂ -analog.

206668

The in vitro vasodilatory activity of the compounds was determined by determining simultaneously their capacity to relax the contraction of the bovine coronary artery and the rabbit mesenteric artery. Unlike both compounds, the 13,14-didehydroderivative is effective on both vascular systems at the same dosage.

Efficacy against platelet aggregation was evaluated on both platelet-rich rabbit plasma and heparinized cat blood by the Gryglewski test (Naunym-Schmiedeberg® with Arch. Pharmacol. 302, 25 (1978)).

In vivo disaggregation activity was determined in anesthetized and heparinized cats, for example by infusion of the test compound (RJ Gryglewski, R. Korbutj, A. Ocetkiewicz, and J. Stachhur: Naunya-Schmiedeberg's Arch. Pharmacol. 302, 25 (1978)). .

Table 2

Compounds In vitro vasodilatory activity (ng / ml) Activity against platelet aggregation in vitro (ng / ml) In vivo desaggregation activity in cats (ng / kg / min). Degradation of platelet aggregation (ID ^ q) Bovine coronary artery (TC) ⁺ Rabbit mesenteric arteries (TC) ⁺ Platelet-rich rabbit plasma (IC ₅₀ ^{) +} He also steamed cat's blood (IC ₅₀ ) * ⁺ pgi ₂ 6.0 4.0 3.9 1.0 330 20-methyl-PGI ₂ 1.2 1.0 4.0 7.2 330 20-methyl-13,14-didehydro-PGI ₂ 0.7 OJ 1.0 2.5 100 ALIGN!

⁺ TC = minimum effective dose = concentration that produces the maximum effect of 50% ^x dose that produces the maximum effect of 50%

The compounds of the invention are tested in the form of their alkali metal salts, but the corresponding numbers in Table 1 and Table 2 indicate the equimolar amount of the corresponding free acid. Table 2 shows the vasodilating and anti-aggregating activities of the compounds of the invention with respect to PGI ₂ and its 20-methyl derivative. Similarly to prostacyclin and 20-methylprostacycline, the compounds of the invention do not form a substrate for 15-prostaglandin dehydrogenase. In particular, 16S- and 16R-methyl derivatives which do not form the substrate of the enzyme 15-hydroxyproetaglandin dehydrogenase have a platelet aggregation inhibitory effect two to five times greater than the corresponding compounds which are not substituted at the 16-position. Because of their vasodilator and anti-aggregation activity, the compounds of the invention are particularly useful in the treatment of acute myocardial infarction, in the treatment of angina pectoris, in preventing platelet aggregation alone or together with heparin-type agents, in preventing aggregation during hemodialysis and in extracorporeal blood circulation surgery. The toxicity of the compounds according to the invention is completely negligible. Thus, the compounds of the invention can be safely used in therapy.

The compounds of the invention are administered by conventional means, for example by intravenous injection or infusion, subcutaneous or intramuscular injection, orally, sublingual adsorption, rectal.

206668, etc. · In acute situations, the compounds are preferably administered by intravenous infusion for this purpose with sterile buffers of pH 8.5 to 9, which are prepared from an aqueous solution containing the compounds of the invention in concentrations ranging from, for example, 0, 0005 to 0.01 fc. In such a case, administration is effected, for example, by an intravenous cannula which is provided with a three-way tap and inserted, for example, into the left central elbow vein, for example by an automatic syringe; at the same time, a 5 $ dextrose solution was introduced into the right vein. In the case of intravenous infusion, the doses are preferably from 0.2 to 25, particularly preferably from 0.5 to 2.0 ng per kilogram of body weight per minute. The total daily dose, even when administered by injection or infusion, is preferably of the order of 0.05 to 20 mg / kg, the exact dose depending on the age, weight and condition of the patient as well as the route of administration.

Sterile solutions or suspensions in aqueous or non-aqueous media may be used for subcutaneous or intramuscular injection. For example, the compound may be dissolved in sterile water or lidocaine hydrochloride solution (the pH of the solution preferably being maintained at 8.5 to 9), in physiological saline or in any of the other conventional solvents used for this type of administration. In such cases, the dosage is preferably from about 0.05 to 50 mg per day. As mentioned above, other routes may be used to administer the compounds of the invention. For example, they may be administered orally in the form of tablets, capsules or syrup, rectally in the form of suppositories, or under the tongue in the form of sublingual lozenges. Excipients and carriers that are used in various pharmaceutical compositions are conventional excipients and carriers. They may be, for example, for oral administration of lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, talc, calcium stearate, magnesium stearate, glycols, starches, acacia, tragacanth, alginates, lecithin or other polysorbates and lauryl sulfates, preferably alkali metals. or alkaline earth metals.

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

He did

A solution of 0.58 g of 14-bromo-5 (S, R) -iodo-6 (S, R) -20-methyl-PGI in 4 ml of anhydrous dimethylsulfoxide and 0.34 g of sodium tert-butoxide was stirred for 3 hours in inert gas atmosphere. The solvent was evaporated in vacuo (27 Pa). The residue was treated with a stoichiometric amount of 2 N sodium hydroxide. After cooling the solution to 0 ° C, the crystals of 13,14-didehydro-20-methyl-PGI ₂ as the sodium salt, = 110 ° (ethanol) are filtered off in a yield of 80 ° C.

Example 2

Solution 14.5 (S, R) -dibromo-6 (S, R) -20-methyl-PGI (0.42 g) and potassium t-butoxide (0.45 g) in anhydrous methanol were allowed to stand at room temperature for 20 days. The solvent was evaporated in vacuo. The product was crystallized from 2 N potassium hydroxide-methane 1-water. There was obtained 13,14-didehydro-20-methyl-PGI ₂ as the potassium salt, [ _.alpha. ] _D = 108 DEG (ethanol) in 72% yield.

The same compound can also be produced by treatment with potassium tert-butoxide in tert-butanol at 38 ° C for 8 days.

Example 3

16S-Ethyl-14-bromo-5 (S, R) -Iodine-6 (S, R) -20-methyl-PGI solution | (0.3 g) and 0.35 g of sodium ethoxide in ethanol (4 ml) were allowed to stand at 50 ° C for 15 days. The solution was evaporated in vacuo. The residue was then diluted with 2 N sodium hydroxide and cooled to 0 ° C.

Filtration gave crystals of 13,14-didehydro-16S, 20-dimethyl-PG12 ⁱⁿ sodium salt, (CC) d = + 118 ° (ethanol).

In the same way, the sodium salt of 13,14-didehydro-16R, 20-dimethyl-PGI _{2 is obtained} , (0¾ = -H02 ° (ethanol)) ·

Claims (1)

SUBJECT OF THE INVENTION Process for the preparation of 20-methyl-13,14-didahydro-PGI2 formula I (CH _O), - COOM In which R is hydrogen or methyl and M represents a hydrogen atom or a pharmaceutically acceptable cation, characterized in that the compounds of the general formula (II) are dehydrohalogenated in which: R and M are the same as above, and wherein each of X ₁ and X _{2 is} independently halogen from bromine, chlorine, and iodine, and optionally converting the compound to its pharmaceutically acceptable salt.