CZ20021485A3 - Sodium 2-(4,6-dimethyl-pyrimidinyl-2-oxy)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-3,3-diphenylpropionate and its use as endothelin antagonist - Google Patents

Abstract

The invention relates to a compound of formula (I) in a solid crystalline form and use thereof as a mixed ETA/ ETB-endothelin receptor antagonist.

Description

Technical field

The invention relates to the field of organic chemistry and pharmacology, and in particular to sodium 2- (4,6-dimethylpyrimidinyl-2-oxy) -3- [2 - ((3,4-dimethoxyphenyl) ethoxy] -3,3-diphenylpropionate of the formula I

in a solid crystalline mold.

BACKGROUND OF THE INVENTION

WO 98/09953 discloses azinyloxydiarylcarboxylic acid and phenoxydiarylcarboxylic acid derivatives ⁱⁿ general terms.

R ^<1 _R 2 ^{R 6} -QWC CH-Q - (/ VI, IX ^{'R5 R1} Ή3 (A) and the use thereof as a mixed ETA / ETB endothelin receptor antagonist. Table II shows compounds (1-445) having as a racemate , particularly as the S-enantiomer, excellent ETa and ETb receptor affinities The structure of Compound 1-445 is given by the formula B.

(Β)

The preparation of 1-445 is described in Example 14. Purification of this compound involves dissolving the free acid in ether and extracting with an aqueous 1M sodium hydroxide solution followed by conversion to the free acid by adding 1M hydrochloric acid and crystallizing.

However, this compound 1-445 has been found to be difficult to handle when manufactured on an industrial scale, despite its excellent pharmacological action. It is not possible to maintain a degree of purity higher than 99.5% required for pharmaceutical purposes. In addition, the compound acquires an extremely high electrostatic charge upon drying.

SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a compound with pharmacological endothelin antagonist activity similar to 1-445, but without the known deficiencies in purity and handling.

SUMMARY OF THE INVENTION

The present invention provides sodium 2- (4,6-dimethylpyrimidinyl-2-oxy) -3- [2 - ((3,4-dimethoxyphenyl) ethoxy] -3,3-diphenylpropionate of formula I

· «Φ which surprisingly fulfills the task.

The compound of formula I has the same receptor affinities in vitro for ETα and ETb receptors as 1-445. The S-form is a more potent enantiomer and thus represents a preferred embodiment of the invention.

The compound of formula I is obtainable from compound 1-445 by methods similar to those known to those skilled in the art. The preparation method 1-445 is described in WO 98/09953. Good results are obtained by carrying out the deprotonation of carboxylic acids with suitable strong bases, thereby introducing sodium as an ion. A particularly suitable base is sodium hydroxide. However, sodium alcoholates may also be used with comparable results.

Well-suited solvents from which the sodium salt can be crystallized are alcohols to which other less polar solvents can be added, for example isopropanol in a mixture of MTB ether.

O

The salt formation can be carried out at a temperature of -20 to 100 ° C

preferably at room temperature up to 60 ° C. Reaction temperatures outside the art do not support the yield to any particular extent. Crystallization can then be carried out at a temperature of -20 ° C to room temperature. Temperatures outside this range do not lead to special advantages.

The compound of formula I is a crystalline solid which is easy to handle, is obtained in high purity and is highly suitable for galenic processing. The electrostatic charge, as determined in the case of 1-445, is not present in the compound of formula I.

The invention also relates to the use of a compound of formula I as a pharmaceutically active substance. Thus, it is possible to produce effective medicaments suitable for the treatment of diseases caused by endothelineffl.

In particular, the treatment of diseases such as hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, acute or chronic renal failure, chronic cardiac insufficiency, renal insufficiency, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhagia, migraine, asthma, atherosiosis , endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and surgical bypass, benign prostatic hyperplysia, renal insufficiency induced by ischemic or toxic or high pressure, carcinoma and mesenchymal tumor growth, renal insufficiency induced by contrast agent, pancreatic intestinal, pancreatic intestinal, ulcers and erectile dysfunction. The invention further relates to the combination of endothelin recombinant antagonists of formula I with inhibitors of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin-II antagonists and angiotensin converting enzyme (ACE) inhibitors. Combinations of endothelin receptor antagonists of formula I with ACE inhibitors are preferred.

The compound of formula I may be administered orally or parenterally in a manner known per se. The dosage depends on the age, condition and weight of the patient, as well as the route of administration chosen. As a rule, the dosage of active ingredient is about 0.5 to 50 mg / kg body weight for oral administration and about 0.1 to 10 mg / kg body weight for parenteral administration.

The compound of formula I may be used for oral administration in solid or liquid form, for example in the form of tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. Such compositions are produced by methods known per se. The active ingredients may be formulated with the usual galenic excipients such as tablet binders, fillers, preservatives, effervescent additives to tab5. ···················· years, flow regulators, emollients, wetting agents, dispersing agents, emulsifying agents, wetting agents, retarding agents, antioxidants and / or propellants (H. Sucker et al., Pharmazeutische Technologie, Thieme Verlag, Stuttgart, 1991). The form of administration obtained generally contains from 0.1 to 90% by weight of active ingredient.

The invention is illustrated by the following non-limiting example. Percentages are by weight unless otherwise indicated.

Examples

18.8 kg of S-2-hydroxy-3- (2 - ((3,4-dimethoxyphenyl) ethoxy] -3,3-diphenylpropionic acid) was added to a 400 L digester and 80 L of dimethylformamide was added. the mixture is cooled to 10 DEG C. 3 kg of lithium amide are added to the solution over a period of 30 minutes at a temperature of 10 DEG to 21 DEG C. Then 10 kg of 4,6-dimethylpyrimidine-2-methylsulfone are added and the mixture is stirred for β.

hours at 35 C. After completion of the reaction, the mixture is cooled e

240 l of demineralized water was added to 10 ° C. To this solution was added 70 L of MTB followed by 40 L of 10% hydrochloric acid. The pH of the aqueous phase is 2-3. After separation of the aqueous phase, the organic phase is washed again with 70 L of demineralized water and poured into a vat.

In a second 400 liter digester, 3.2 kg of 50% sodium hydroxide solution is added to 280 l of isopropanol and the mixture is

The mixture is stirred at 50 ° C for two hours. The mixture is cooled to 20-25 ° C.

The MTB phase in the vat is clarified by filtration through a frit prior to addition to the prepared isopropanolic sodium hydroxide solution. The mixture is stirred for one hour at 20 to 25 ° C, for one hour at 45 to 50 ° C, and finally for 13 hours at 20 to 25 ° C.

The product was collected by filtration, the filter residue was washed with 50 L of isopropanol, dried on the filter with a jacket temperature of 50 ° C. 19.2 kg of microcrystalline product, 99.7% pure according to HPLC chromatography, were sieved.

Industrial use

A process for the industrial production of highly pure sodium 2- (4,6-dimethylpyrimidinyl-2-oxy) -3- [2 - ((3,4-dimethoxyphenyl) ethoxy] -3,3-diphenylpropionate suitable for pharmaceutical purposes.

AOvOKMWi KANCgUŘ «• green calenian hamster

AND PARTNERS

120 00 řrsr.e 2, Haikova 2 Czech Republic

JUDr, Petr Katensky advokat

Claims (5)

PATENTOVÉ Claims ··· ·· · · · · ················· 1. Sodium 2- (4,6-dimethylpyrimidinyl-2-oxy) -3- [2- (1,3-dimethoxyphenyl) ethoxy] -3,3-diphenylpropionate of formula I CH ₃ (I) CH ₃ in solid crystalline form. Sodium 2- (4,6-dimethylpyrimidinyl-2-oxy) -3- [2 - ((3,4-dimethoxyphenyl) ethoxy] -3,3-diphenylpropionate) according to claim 1 in the form of the S-enantiomer. Use of sodium 2- (4,6-dimethylpyrimidinyl-2-oxy) -3- [2- ((3,4-dimethoxyphenyl) ethoxy] -3,3-diphenylpropionate) according to claims 1 and 2 for the manufacture of pharmaceutical compositions. Use of sodium 2- (4,6-dimethylpyrimidinyl-2-oxy) -3- [2 - ((3,4-dimethoxyphenyl) ethoxy] -3,3-diphenylpropionate) according to claim 3 for the manufacture of pharmaceutical compositions for the treatment of asthma. A pharmaceutical composition comprising as active ingredient 2- (4,6-dimethylpyrimidinyl-2-oxy) -3- [2 - ((3,4-dimethoxyphenyl) ethoxy] -3,3- Sodium di phenylpropionate of the formula I according to claim 1 or 2. JOINT LAW OFFICE ALL GREEN GREENHOUSE CALENDAR AND PARTNERS 120 00 Prague 2, Hůlková 2 Czech Republic