SK5962002A3 - Sodium 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(3,4- dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate and use thereof 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

The present invention relates to a compound of formula I, sodium 2- (4,6-dimethylpyrimidinyl-2oxy) -3- [2- (3,4-dimethoxyphenyl) ethoxy] -3,3-diphenylpropionate in solid crystalline form and its use as endothelin antagonist.

BACKGROUND OF THE INVENTION

WO 98/09953 discloses azinyloxy- and phenoxy-diarylcarboxylic derivatives of the general formula A

R 2

R4

R6-Q-W-C-CH-Q

R5 R1

R3 (A) and their use as mixed endothelin receptor antagonists ETVETb. Table 2 describes the compound (I-445) which has excellent ET _A and ET _B receptor affinities as a racemate and in particular as a Senantiomer. The structure of I-445 is given by Formula B.

Synthesis 1-445 is described in Example 14. This material is purified by dissolving the free acid in ether and extracting with 1 M aqueous NaOH followed by conversion to the free acid with 1 M HCl and crystallization.

However, it has been found that this compound (I-445) is difficult to handle when produced on an industrial scale despite its excellent pharmacological action. It was not possible to achieve the high degree of purity of more than 99.5% required for pharmaceutical purposes. Moreover, it has been found that this substance produces an exceptionally high electrostatic charge during drying.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a compound with pharmacological endothelin-antagonistic activity similar to that of I445, but without the drawbacks of purification and handling.

We have now found that the compound of formula I, sodium 2- (4,6-dimethylpyrimidinyl-2-oxy) -3- [2- (-3,4-dimethoxyphenyl) ethoxy] -3,3-diphenylpropionate

CH ₃ O

CH ₃ O

CH ₂ —CH ₂ —OC-

(O achieves this goal.

The compound of formula I has the same receptor affinities in vitro for ET _a and ET _b receptors as 1-445. Here too, the S form is a more potent enantiomer and therefore represents a preferred embodiment of the invention.

Compound I can be obtained from known compound 1-445 by methods known to those skilled in the art. WO 98/09953 is incorporated herein by reference, the contents of which are hereby incorporated by reference. Good results can be obtained by carrying out the deprotonation of the carboxylic acids with suitably strong bases, by means of which sodium is introduced as a contraion. Sodium hydroxide is particularly suitable. Alternatively, sodium alkoxides can be used with comparable results.

Suitable solvents from which the sodium salt can be crystallized are alcohols to which other less polar solvents may be added, for example isopropanol in admixture with MTB.

The salt formation can be carried out in a temperature range of -20 ^° to +100 ° C, preferably room temperature to 60 ° C. Reaction temperatures outside this range do not significantly increase the yield. Crystallization can be carried out at temperatures between -20 ^° C and room temperature. Temperatures outside this range offer no particular advantages.

Compound I is a crystalline solid that is easy to handle, is obtained in a high degree of purity and is highly suitable for galenic processing.

Electrostatic charges occurring in solid free acid (1-445) are not observed with this compound I.

The invention also relates to the use of compound I as a pharmaceutical. Thus, effective pharmaceuticals that are useful in the treatment of endothelin-related diseases can be produced.

Specifically, these include: hypertonia, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, acute / chronic renal failure, chronic cardiac insufficiency, renal insufficiency, cerebral vasospasm, cerebral ischemia, subarachnoid haemorrhage, endotoxic, asthma, asthma, asthma, asthma, asthma, asthma endotoxin-induced organ failure, intravascular coagulation, restenosis following angioplasty and bypass surgery, benign prostatic hyperplasia, ischemic and toxin-induced renal insufficiency or hypertonia, carcinoma and growth of mesenchymal tumors, renal insufficiency induced by contrast agent, gastrointestinal dementia, pancreatitis, pancreatitis. The invention further relates to combinations of endothelin receptor antagonists of formula I and reninangiotensin system inhibitors. Inhibitors of the renin-angiotenin 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.

Compound I may be administered orally or parenterally by a conventional route. The dosage depends on the age, condition and weight of the patient as well as the route of administration used. The daily dose of the active ingredient is usually between about 0.5 and 50 mg / kg body weight on oral administration and between about 0.1 and 10 mg / kg body weight on parenteral administration.

Compound I can be used for commonly used methods of administration in solid or liquid form, such as tablets, film-coated tablets, capsules, powders, granules, dragees, supositories, solutions, ointments, creams or sprays. These are produced in a conventional manner. The active ingredients may be combined with conventional galenic excipients such as tablet binders, fillers, preservatives, tablet disintegrators, flow regulators, plasticizers, wetting agents, dispersing agents, emulsifiers, solvents, retardants, antioxidants and / or dispensing gases (see H. Sucker) et al., Pharmazeutische Technologie, Thieme Verlag, Stuttgart, 1991). The dosage forms obtained usually contain the active ingredient in a concentration of from 0.1 to 90% by weight.

DETAILED DESCRIPTION OF THE INVENTION

In a 400 L reactor, 18.8 kg of S-2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethoxy] -3,3-diphenylpropionic acid was charged to which 80 L DMF was added while the mixture was cooled to 10 ° C.

To this solution was added 3 kg of lithium amide over 30 minutes at 10-21 ° C.

Then, 10 kg of 4,6-dimethylpyrimidine-2-methylsulfone was added and the mixture was stirred at 35 ° C for 23 hours.

After completion of the reaction, the mixture was cooled to 10 ° C and 240 L of demineralized water was added.

To this solution was added 70 L of MTB followed by 40 L of 20% hydrochloric acid. The pH of the aqueous phase was 2-3.

After separation of the aqueous phase, the organic phase was washed again with 70 L of demineralized water and then poured into a vat.

To a second 400 L reactor was added 3.2 kg of 50% sodium hydroxide solution to 280 L of isopropanol and stirred at 50 ° C for 2 hours. This mixture was then cooled to 20-25 ° C.

The MTB phase in the above mentioned caddy was then clarified by filtration through a frit prior to its addition to the above isopropanolic NaOH solution.

The mixture was stirred at 20-25 ° C for one hour, then at 45-50 ° C for one hour and finally at 20-25 ° C for 13 hours.

The product was isolated by filtration, the residue was washed on a 50 L isopropanol filter and dried on the filter with nitrogen at a jacket temperature of 50 ° C.

19.2 kg of microcrystalline product were obtained with a purity of 99.7% according to

HPLC.

Claims (5)

A compound of formula I in solid crystalline form A compound according to claim 1, which is in the form of the S enantiomer. A method of using a compound as defined in claim 1 and claim 2 in the manufacture of pharmaceuticals. The method of claim 3 for the manufacture of a medicament for the treatment of asthma. Pharmaceutical, characterized in that it contains, as active substance, a compound as defined in claim 1 or 2.