DK149953B - ANALOGY PROCEDURE FOR THE PREPARATION OF PROSTAGLANDIN DERIVATIVES - Google Patents

Description

in 149953

The present invention relates to an analogy process for the preparation of novel prostaglandin derivatives of the general formula (I) as set forth in the preamble of claim 1, which is peculiar to the characterizing part of claim 1.

Prostaglandin endoperoxides (PGG2 and PGH2) are generated from arachidonic acid by a membrane-bound cyclooxygenase enzyme system described by D.H. Nugteren and E. Hazelhof (Biochem. Biophys. Acta, 326, 448-461, 1973) 10 and then converted to PGF2a, PGE2, PGD2 or Throm-boxan A2 which consists of contracting rabbit aortic strips and aggregating platelets.

It has now been found that microsomes originating from a variety of mammalian tissues catalyze the enzymatic conversion of the prostaglandin endoperoxides to a 9-deoxy-6,9a-epoxyprostaglandin Fβα derivative (hereinafter referred to as it contracts strips of rabbit aorta, but relaxes strips of rabbit peritoneal, mesenteric, and coronary arteries, has a strong anti-aggregative effect on platelets, is a strong vasodilator throughout animals, and has other properties described below. .

Prostacycline is unstable at room temperature in aqueous medium, having a half-life of approx.

10 minutes, but its anti-aggregatory action can be maintained for several days by dissolving the compound in aqueous base or in dry acetone and storing the solution 30 at -20 ° C. On average, Prostacycline is 10-40 times more effective as an anti-aggregator than PGE 2 and 5-20 times more effective than PGD2, itself a potent inhibitor of platelet aggregation. Prostacycline also interrupts and reverses the present platelet aggregation.

149953 2

Further studies have shown that Prostacycline has the chemical structure shown by Formula (I): 5 S ° 2 ° pt I / (I) 10 · Where H is hydrogen, (see Johnson et al., Prostaglandins, 12 / 6, 915-928, 1976).

In the process of this invention, compounds of formula (I) are prepared wherein R is hydrogen or a pharmacologically acceptable cation (hereinafter referred to as Prostacycline or its salts). Salts of Prostacycline include alkali metal salts, alkaline earth metal salts or salts of organic bases.

Prostacycline or its salts can be synthesized from a compound of formula (II) (see below) wherein R R is hydrogen, alkyl of 1-4 carbon atoms or a cation. Oxidative attack with iodine or potassium tri-iodide in the presence of a metal bicarbonate at the 5,6-double bond of a compound of formula (II) with simultaneous or subsequent cyclization comprising the 9-hydroxy group leads to a compound of formula (III) (see below) where is as defined above and X is iodine or bromine. This compound of formula (III) 30 is dehydrohalogenated by an alkali metal alkoxide in the process, resulting in the introduction of a 5,6 double bond (formula (IV), R = alkyl). This sequence of reactions is illustrated in the reaction scheme below. The resultant compound is then converted to the corresponding acid or a salt thereof with a pharmacologically acceptable cation (formula (I), R as defined herein).

3 U9S53 OH ^ / “" ^^^^ COOR1

(ID

OH hA / oh in COOR1 (lll) oh H * 0H: Ί r'ooc '^ Sy ^ l I / dv) OH Γ0Η 149953 4

The conversion of the ester compound obtained by the aforementioned dehydrohalogenation to a salt of Prostacycline can take place by treating the ester, for example the methyl ester, with a strong base such as sodium hydroxide 5 in a solvent and lyophilizing the resulting reaction mixture. Prostacycline itself may conveniently be prepared by base hydrolysis of the ester in the presence of an equivalent amount of a caustic alkali in an aqueous alcohol or aqueous tetrahydrofuran medium 10 and extracted into a low temperature organic solvent.

Prostacycline and its salts exhibit a strong anti-aggregatory effect on platelets and therefore have particular utility as anti-thrombotic agents in the treatment and / or prevention of mammals.

They are also useful in mammals, including humans, to reduce and control excessive gastric secretion, thereby reducing or avoiding gastrointestinal ulceration, and accelerating the healing of such ulcers and lesions already present in the gastrointestinal tract.

Furthermore, prostacyclin and its salts exhibit vasodilatory activity on blood vessels and therefore have a particular utility as antihypertensive agents in the treatment of high blood pressure in mammals, including humans. Platelets may be assimilated into the vascu- lar endothelium or even incorporated into endothelial cells. Biochemical cooperation between platelets and vascular endothelium in the production of Prostacyclin contributes to the healing of vascular endothelium, and prostacyclin and its salts have a further utility in promoting wound healing in mammals, including humans.

Prostacycline and its salts can be used, whenever desired, to inhibit platelet aggregation, to reduce the adherent nature of platelets, and to treat or prevent the formation of thrombi in mammals, including humans. They can be used, for example, in the treatment and prevention of myocardial infarction, in the treatment of peripheral vascular disease, to treat or prevent post-operative thrombosis, to promote the openness of vascular transplants after surgical procedures, and to treat complications of arteriosclerosis and the like. conditions such as atheroscleosis, blood coagulation defects caused by lipemia, and 10 other clinical conditions in which the underlying etiologiogia is associated with a lack of lipid balance or hyper-lipidemia.

They can also be used as blood additives, blood products, blood substitutes and other fluids used in artificial extra-corporal circulation and perfusion of isolated body parts, e.g. limbs and organs, whether attached to the body, removed and under preservation or preparation for transplantation or connected to a new body.

During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the circulatory system. This blockage is avoided in the presence of Prostacycline. For this purpose, Prostacycline or its salts may be added gradually or in 25 single or multiple portions to the circulating blood, to the donor animal's blood, to the flushed body portion, connected to or released from the recipient, or to two or all of them in a total equilibrium dose of 0.001 to 10 mg per liter of circulating fluid. It is particularly useful to use Prostacycline for laboratory animals, e.g. cats, dogs, rabbits, monkeys and rats, for the purpose of developing new methods and techniques for organ and limb transplants.

The amount of Prostacycline or salt thereof required (hereinafter referred to as the active ingredient) for therapeutic effect will vary with the route of use. Generally, a suitable dose for a mammal will be in the range of 0.01 to 200 mg per day. kg to body weight, conveniently 0.01 to 10 mg per kg.

Although it is possible to use the active ingredient as the raw chemical, it is preferred to use it as a pharmaceutical composition. Such compositions are preferably non-aqueous and non-hydroxylic in nature, but alkaline aqueous solutions may be used. Unit doses of a composition contain between 0.5 mg and 1.5 g of the active ingredient.

The process according to the invention will be described in more detail by the following examples.

Example 1

A stirred solution of PGF2α methyl ester (50 mg) in ether (1 ml) was treated with sodium bicarbonate (115.0 mg, 10 molecular equivalents) and water (1 ml) and then dropwise for 2 hours with aqueous potassium triiodide (0, 7 molar, 0.261 ml). After stirring overnight, the reaction mixture was shaken with ether and aqueous sodium thiosulfate. The ether phase was separated, washed with water, dried over magnesium sulfate and evaporated to give a yellow gum of 5ξ-iodo-9-deoxy-6ξ, 9α-epoxypro-staglandin F ^-methyl ester.

A solution of 5ξ-iodo-9-deoxy-6ξ, 9α-epoxy-prostaglandin F ^-methyl ester (1.00 mg) in methanolic sodium methoxide prepared from sodium (46 mg) and dry methanol (0.70 ml), was left under dry nitrogen for 5 hours and then freed of solvent in high vacuum. The amorphous solid obtained as evaporation residue was washed with benzene, left in atmospheric air overnight and stirred with 1N aqueous sodium hydroxide (0.5 ml) to give a suspension of colorless fine needles. The crystals were collected, washed with a few drops of 1N aqueous sodium hydroxide and dried in atmospheric air to give the sodium salt of 9-deoxy-6,9a-epoxy-A-prostaglandin. The inhibition of arachi-; Donic acid-induced aggregation of human platelets at a concentration of 0.2 ng / ml of said salt and its instability in water at acidic pH are compatible with the assignment of the configuration (5Z 2 -6,6-didehydro-9 6.9 <x-epoxyprostaglandin F, sodium salt.

13 The 1-0 high resolution C-NMR spectrum for a solution of the crystals in dimethylsulfoxide-dg showed the expected 20 resonances whose chemical shifts were fully consistent with the chemical structure determined for Prostacycline. No impurity tips were found.

Example 2 5ξ-Iodine-9-deoxy-δξ, 9α-epoxyprostaglandin-15 methyl ester (500 mg) was stirred with methanolic NaOCH ^, prepared from Na (0.23 g, 10 equivalents) and CH 3 OH (3.5 ml). , below ^ at room temperature overnight.

1N aqueous NaOH (2.5 mL) was added to the yellow reaction solution to provide hydrolysis of the ester moiety and after 2 hours the methanol was evaporated in vacuo at room temperature. The aqueous residue obtained as an evaporation residue spontaneously led to a mass of colorless fine needles of the desired sodium salt (formula (I): R = Na), which was cooled (0 ° C), collected, washed sparingly with 1N aqueous NaOH, air dried and stored in a plugged tube. This salt (383 mg) had vmax (KBr plate) 1692 cm 2 (0-C = C), and only 20 ° C resonances were observed (at 182.7 (Cl), 158.2 (C-6)). , 140.0 and 134.3 (C-13.14), 100.7 (C-5), 87.5 (C-15), 80.6 and 75.5 (C-9, 30 11), 58.0 (C-12), 49.0, 45.8, 42.4, 41.9, 37.5, 35.8 (C-18), 31.6, 29.9, 29.3, 26.7 (C-19) and 18.4 (C-20) ppm from TMS in DMSO-dg).

The product thus obtained, sodium (5 L) -5,6-dihydro-9-deoxy-6,9a-epoxyprostaglandin (Syn. Sodium Prostacycline), completely inhibited arachidonic acid induced platelet aggregation (human platelet plasma)

Claims (4)

149963 at 1 ng / ml, and its profile in terms of biological activity on rabbit aorta, rabbit abdominal artery, rat gastrointestinal tract and rat colon was consistent with the efficacy profile of sodium prostacyclin obtained by biosynthesis. After air drying, the salt had a coating of sodium carbonate (about 3.5% by weight) protecting the vinyl ether moiety from carbon dioxide-catalyzed hydrolysis. Prostacycline was injected intravenously and intravenously onto normotensive anesthetized rats and blood pressure and heart rate were noted. Results showed that Prostacycline is an effective vasodepressor with 5 times the strength of 15 Prostacycline was found to relax helical cut strips of coronary artery from bovine. The effect is dose-dependent and relaxation can be seen at doses as low as 20 nanograms per day. 5 ml bath. On isolated hearts from rabbits perfused at constant flow rate according to Langendorf technique, Prostacycline produced coronary vasodilation. Prostacycline relaxed strips of abdominal and mesenteric arteries, but was less effective than PGE2 · Prostacycline was found to inhibit the formation of 25 gastric lesions induced in rats with indomethacin at doses from 62.5 to 250yg / kg after subcutaneous injection. 1. Analogous Process for Preparation of Prostaglandine Derivatives of General Formula (I): r \ 35 r-f 111 Si