DK169432B1 - Cyclodextrin clathrates of carbacyclin derivatives - Google Patents

Description

in DK 169432 B1

The present invention relates to novel cyclodextrin clathrates of carbacycline analogs.

From ΕΡ-Ά1-11,591 and EP-A1-119,949, carbacyclines, but not β-cyclodextrin clathrates of these carbacyclines are known.

DE-A-2,128,674 discloses clathrate compounds of prostaglandins and cyclodextrin analogs thereof. Thus, while β-cyclodextrin clathrates are mentioned, only monocyclic prostaglandins of type A, E and F are mentioned.

Japanese publication publication J 56 15 00 39 (cf.

Chem. Abstr., 1982, Vol. 96, 103964d) generally discloses carbacycline-cyclodextrin inclusion compounds. Carbacycline analogues are pharmacologically and medically valuable active substances, the preparation and use of which are described, for example, in DE Publication Nos. 28 45 770, 33 06 123, 32 26 15 550. These substances, in contrast to similar natural prostacyclin, have a significantly improved specificity and in particular a significantly longer effect at similar effect spectra.

The carbacycline analogs described in the aforementioned publications are often in non-crystalline form, which has limited the pharmaceutical use thereof. In addition, there is a further limited water solubility and dissolution rate.

It has now been found that inclusion compounds of these carbacycline analogs with cyclodextrins do not have the mentioned drawbacks, viz. their water solubility is improved, the dissolution rate is increased and the inclusion compounds are in crystalline form. In addition, their stability is increased, for example, against heat, light and oxygen, and poor galenic preparation (preparation of solutions or tablets) is facilitated.

The present invention relates to β-cyclodextrin clathrates of the following carbacycline analogs: (DK 169432 B1 2 1) (5E) - (16S) -13,14-didehydro-1,6,20-dimethyl-3-oxa-18,18,19 19-tetradehydro-6a-carba-prostaglandin-12 2) (5E) - (16S) -13,14-didehydro-1α, 1b-dihomo-16,20-dimethyl-3-oxa-18,18,19 , 19-tetradehydro-6a-carba-prostaglandin-I2 5 3) (5E) - (16S) -13,14,18,18,19,19-hexadehydro-16,20-dimethyl-6a-carbaprostaglandin-I2 4) (5E) - (16RS) -16-methyl-18,18,19,19-tetradehydro-6α-carba-prost aglandin-125 (5E) - (16S) -13,14-didehydro-1α, lb -dihomo-16,20-dimethyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I2.

Particularly preferred compounds of the invention are β-cyclodextrin clathrates of the aforementioned PGI2 derivatives 1-3 and 5, such as iloprost-β-cyclodextrin clathrate, which is not specifically mentioned in JA 56 15 00 39.

For the preparation of clathrates according to the invention, carbacycline analogs are dissolved in a pharmacologically acceptable solvent, e.g. an alcohol, preferably ethanol, a ketone, e.g. acetone or an ether, e.g. diethyl ether, and mixed with aqueous solutions of β-cyclodextrin, at 20-80 ° C, or the cyclodextrin added to the acids in the form of aqueous solution of their salts, e.g. the sodium or potassium salts, and after dissolving, the equivalent amount of an acid, e.g. hydrochloric or sulfuric acid.

Hereby, or after cooling, the corresponding 25 clathrates crystallize. Furthermore, the oily or crystalline carbacyclins can also be transferred to corresponding crystallates by stirring for a long time at room temperature with an aqueous solution of cyclodextrins. The clathrates can be isolated by suctioning and drying as solid, free-flowing crystals. By selecting the appropriate cyclodextrin and water quantities DK 169432 B1 3, clathrates in stoichiometric composition with a reproducible content of active substance can be obtained.

The clathrates prepared according to the invention are effective pharmaceutical compositions.

The clathrates may be used in anhydrous, hygroscopic form or in an aqueous, slightly hygroscopic form.

The novel carbacycline clathrates are present in stoichiometric ratios of carbacycline: -? - cyclodextrin = 1: 2 (3).

The dosage of the compound is 1-1500 µg / kg / day when administered 10 to humans. The unit dose is for the pharmaceutically acceptable carrier 0.01-100 mg.

The clathrates of the invention have a blood pressure lowering and bronchodilatory effect. Furthermore, they are suitable for inhibiting platelet aggregation. They act cytoprotectively in the stomach, intestine, heart, liver, kidneys and pancreas. Accordingly, the novel cyclodextrin clathrates of formula I are valuable pharmaceutically active substances. Furthermore, at similar effect spectra compared to similar prostaglandins, they exhibit a higher specificity and, in particular, a substantially longer effect. Compared to PGI2, they exhibit a higher stability. The high tissue specificity of the novel prostaglandins is evidenced by studies in smooth muscle organs such as e.g. in the guinea pig vein and in the isolated rabbit trachea, where significantly less stimulation is observed than 25 when using natural E, A or F type prostaglandins.

The novel carbacycline clathrates have the characteristics typical of prostacyclins such as e.g. reduction of peripheral arterial and coronary vascular resistance, inhibition of platelet aggregation and dissolution of platelet thrombi, myocardial cytoprotection, and consequent reduction of systemic blood pressure without simultaneously lowering stroke volume and coronary blood flow; stroke, prophylaxis and therapy for coronary heart disease, coronary thrombosis, myocardial infarction, peripheral artery disease, arteriosclerosis and thrombosis, prophylaxis and therapy of central nervous system ischemic attack, shock therapy, bronchoconstriction inhibition, inhibition of bronchoconstriction, inhibition of the gastrointestinal mucosa, cytoprotection in the liver, kidneys, heart and pancreas, and also by organic transplants. They exhibit antiallergic properties, decrease pulmonary vascular resistance and pulmonary blood pressure, increase renal hemorrhage, and may be used in place of heparin or as an adjuvant in the dialysis of hemofiltration, for preservation of blood plasma preserves, especially of platelet counts, for inhibition of food, for the treatment of pregnancy toxicity, for increasing cerebral blood circulation, etc. In addition, the novel carbacycline clathrates possess antiproliferate and anti-diarrheal properties.

The carbacycline clathrates of the invention can additionally be used in combination with e.g. / 3-blockers, diuretics, phosphodiesterase inhibitors, calcium antagonists, non-steroidal anti-inflammatory drugs, leukotriene synthesis inhibitors, leukotriene antagonists, thomboxane synthesis inhibitors or thromboxane antagonists.

The clathrates of the invention may be used in liquid or solid galenic formulations wherein the formulation may be administered enterally, parenterally, vaginally or rectally, or they may also be incorporated into surgical sewing material and plastics.

For the preparation of tablets, the prostaglandin cyclodextrin clathrate is mixed with carriers and excipients such as lactose, corn starch, polyvinylpyrrolidone and magnesium stearate.

5 DK 169432 B1

To prepare solutions for the enteral and parenteral use, the aqueous cyclodextrin clathrate solutions are lyophilized together with lactose. Then, the lyophilisates can be adjusted with physiological saline to the desired concentration.

The invention therefore encompasses pharmaceutical compositions and formulations containing a cyclodextrin clathrate of a carbacycline analogue as an active substance.

The invention is illustrated in the following Examples: Example 1

Dissolve 560 mg of β-cyclic odextrin in 4 ml of water at 80 ° C, cool to 60 ° C and drop this solution to a 60 ° C hot solution of 18 mg (5E) - (16R S) -16-methyl 18,18,19,19-tetradehydro-6α-carbaprostaglandin-1,2 in 0.3 ml of ethanol. The mixture is stirred for 4 hours at 60 ° C, 1 hour at 45 ° C and for 16 hours at 25 ° C. The precipitated solid is aspirated, washed with 20 ml of a mixture of water / ethanol (1: 1) and dried for 8 hours at 0.1 Torr and 25 ° C over phosphorus pentoxide. 340 mg of free-flowing crystals of the / 3-cycle odextrin clathrate of said carba-20 cyclin analog are obtained.

The content of the carbacycline analogue in the clathrate was determined by high pressure liquid chromatography and was 4.23%.

Example 2

Stir 1 g (5E) - (16S) -13,14-didehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I2 with 30.3 g of β-cyclodextrin in 214 ml of water for 48 hours at 25 ° C. The solid is aspirated, washed with 15 ml of a water / ethanol (1: 1) mixture and dried for 24 hours at 0.1 Torr and 25 ° C against phosphorus pentoxide. 22.45 g of free-flowing crystals of the β-cyclodextrin clathrate of the above carbacycline analog are obtained.

6 DK 169432 B1

The content of the carbacycline analog in the clathrate was determined by titration and amounted to 3.5%.

Example 3

41.75 g of β-cyclodextrin are dissolved in 298 ml of water at 80 ° C and a solution of 1.5 g of (5E) - (16S) -13,14-didehydro-1α-lb-dihomo-16,20 is added dropwise. -dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I2 in 24 ml of ethanol over 15 minutes. The mixture is stirred for 4 hours at 60 ° C and then allowed to cool overnight with stirring. The precipitated solid 10 is aspirated, washed with 50 ml of a water / ethanol (1: 1) mixture and dried for 24 hours at 0.1 Torr and 25 ° C over phosphorus pentoxide. 38 g of free flowing crystals of the β-cyclodex step clathrate of the above carbacycline analog are obtained.

The content of the carbacycline analog in the clathrate was determined by titration and amounted to 3.3%.

Example 4

0.5 g of (5E) - (16S) -13,14-didehydro-16,20-dimethyl-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I with 15 g of β-cyclodextrin are stirred in 110 ml. water for 50 hours at 25 ° C. The solid 20 is aspirated, washed with ca. 10 ml of a water-ethanol (1 + 1) mixture and dried for 24 hours at 0.1 Torr and 25 ° C over phosphorus pentoxide. 11 g of free-flowing crystals of the β-cyclodextrin clathrate of said carbacycline analog are obtained.

The content of the carbcycline analog in the clathrate was determined by titration and amounted to 3.6%.

Example 5

57.75 g of β-cyclodextrin are dissolved at 45 ° C in 1.53 L of water, a solution of 7.633 g (5E) - (16RS) - (16-methyl-18.18, 19,19-tetradehydro-6a- 7 DK 169432 B1 carbaprostaglandin-I2 in 45 ml of ethanol and rinse with 5 ml of ethanol, cool over 1 hour to 25 ° C, stir for 2 hours at this temperature and for 3 hours. The crystallization is suctioned off and washed with ice-cold water, acetone and again with water.

a) Dry in vacuo until the crystalline begins to absorb water from the air again at ambient temperature and humidity and allow the weight to remain constant. 56.01 g (93.9%) of free liquid crystallate are obtained, containing 6% water and 10.8% of the active substance determined by titration.

b) Dry under vacuum over phosphorus pentoxide to obtain 52.7 g of a free liquid hygroscopic crystallate having an active substance content of 13.6%, which was determined by titration.

Example 6

3,877 g of (5E) - (16S) -13,14-didehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin I2-tert are saponified. butyl ester with 11.7 ml of 1N sodium hydroxide solution, extract contaminants with diethyl ether and dilute with water to 660 ml of solution. 24.52 g / 3-cyclodextrin is added and heated with stirring to 26 ° C until a solution is obtained. Moon adds 11.7 ml of hydrochloric acid over 30 minutes and stirs for 90 minutes. It is heated to 55 ° C, cooled for 1 hour to 25 ° C and stirred for 1 hour at this temperature and 2.5 hours 25 in an ice bath. The crystallize is suctioned off, washed with ice water and dried as described in Example 4.

a) 22.53 g (89.2%) of a free liquid crystallate containing 7.2% water and 13.36% active substance, obtained by titration, are obtained.

Claims (4)

8 DK 169432 B1 b) 21.0 g of a free liquid hygroscopic crystal lysate containing 14.3% of active substance determined by titration is obtained. Example 7 Dissolve 14.30 g / 3-cyclodextrin at 50 ° C in 205 ml of water, drop over 30 minutes with stirring a solution of 1.456 g (5E) - (16S) -13,14-didehydro-1a, lb -dihomo-16,20-dimethyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I2 in 6 ml of ethanol and rinse with 1.2 ml of ethanol. It is cooled for 10 hours to 23 ° C, stirred for 2 hours at this temperature and for 18 hours in an ice bath. The crystallize is extracted, washed with ice-cold water and dried, as described in Example 4. a) 14.155 g (95.8%) of a free liquid crystalline containing 7.6% water and 9.9% are obtained substance which was determined by titration. b) 13.1 g of a free liquid hygroscopic crystal lysate containing 10.7% of active substance determined by titration is obtained. Example 8 Preparation of (5E) - (16S) -13,14,18,18,19,19-hexadehydro-16,2 O-dimethyl-6-carba-prostaglandin-I2-β-cyclodextrin chelate analogous to Example 1 out from (5E) - (16S) -13,14,18,18, -19,19-hexadehydro-16,20-dimethyl-6a-carba-prostaglandin-I2 and j6-cyclodextrin clathrate. 25 Patent claims. 1. (5E) - (16S) -13,14-didehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-12- / 3-cyclodextrin CLA thrat. DK 169432 B1 9 2. (5E) - (16S) -13,14-didehydro-1α, 1b-dihomo-16,20-dimethyl-3-oxa-18,18,19; 19-tetradehydro-6a-carba-prostaglandin-L2 / 3-cyclic-lodextrinclathrat. 3. (5E) - (16S) -13,14,18,18,19,19-hexadehydro-16,20-dimethyl-6a-5 carbaprostaglandin I2- [S-cyclodext: rinclathrate. 4. (5E) - (16RS) -16-methyl-18,18,19,19-tetradehydro-6α-carba-prostaglandin-1,2- cyclodextrin clathrate. 5. (5E) - (16S) -13,14-Didehydro-1α, 1b-dihomo-16,20-dimethyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-1,2,3-cyclodex - 10 step clathrate.