KR20020047301A - 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 present invention relates to compounds of formula (I) in solid crystal form and their use as mixed ET _A / ET _B endothelin receptor antagonists.

<Formula I>

Description

Sodium 2- (4,6-dimethyl-pyrimidin-2-yloxy) -3- (2- (3,4-dimethoxyphenyl) ethoxy) -3,3-diphenylpropionate and endothelin antagonist Sodium 2- (4,6-Dimethyl-Pyrimidin-2-yloxy) -3- (2- (3,4-Dimethoxyphenyl) ethoxy) -3,3-Diphenylpropionate and Use Thereof as Endothelin Antagonist}

The present invention relates to compounds of formula (I) in solid crystalline form.

WO 98/09953 describes azinyloxy- and phenoxy-diarylcarboxylic acid derivatives of formula A, and their use as mixed ET _A / ET _B endothelin receptor antagonists.

Table 2 of this document describes compound I-445, which has good ET _A and ET _B receptor affinity as racemates, in particular S-enantiomers. The structure of compound I-445 is shown in formula B below.

The synthesis of I-445 is described in Example 14 of that document. Purification of this material includes dissolving the free acid in ether, extracting with aqueous 1M NaOH, followed by reconversion with the free acid using 1M HCl, and crystallization.

However, compound I-445 is known to be difficult to handle when produced on an industrial scale despite its good pharmacology. Prior to the present invention it was not possible to achieve high purity above 99.5% required for pharmaceutical purposes. It is also known that this material exhibits very high electrostatic charge during drying.

Accordingly, it is an object of the present invention to provide compounds which have pharmacological endothelin-antagonist efficacy similar to that exhibited by I-445 but no drawbacks in purification and handling.

The inventors have provided compounds of formula (I), ie sodium 2- (4,6-dimethylpyrimidinyl-2-oxy) -3- [2- (3,4-dimethoxyphenyl) ethoxy] -3,3- The above object has been achieved by diphenylpropionate to complete the present invention.

<Formula I>

Compounds of formula (I) have the same receptor affinity as I-445 for ET _A and ET _B receptors in vitro. In addition, the S-forms of the compounds of formula (I) are more effective enantiomers and thus constitute a preferred embodiment of the present invention.

Compound I can be obtained from known compound I-445 by methods known to those skilled in the art. For the preparation of I-445, reference is made to document WO 98/09953, the contents of which are incorporated herein by reference. By introducing sodium into the counterion, the carboxylic acid can be deprotonated appropriately with a strong base to achieve good results. Sodium hydroxide is particularly suitable. Alternatively, sodium alkoxide can be used to obtain comparable results.

Suitable solvents in which the sodium salt can be crystallized include alcohols, in which a less polar solvent such as isopropanol can be added in admixture with the MTB ether.

Salt formation can be carried out in a temperature range of -20 ° C to + 100 ° C, preferably room temperature to 60 ° C. Reaction temperatures outside this range do not increase the yield to any particular extent. Crystallization may then occur at temperatures between -20 ° C and room temperature. Temperatures outside this range have no particular advantage.

Compound I is a solid crystalline material that is easy to handle, is obtained in high purity and is very suitable for herbal processing. The electrostatic charge present in solid free acid I-445 is not observed in this compound I.

The invention also relates to the use of compound I as a medicament. Thus, an effective medicament suitable for the treatment of diseases caused by endothelin can be prepared.

Specifically, such diseases include hypertonia, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, sudden / chronic renal failure, chronic heart failure, renal failure, cerebrovascular spasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis, Endotoxin shock, endotoxin-induced organ failure, endovascular coagulation, restenosis after angioplasty and bypass surgery, benign prostatic hyperplasia, ischemic and toxin-induced renal failure or hypertension, carcinoma and mesenchymal tumor proliferation, contrast agent-induced Sexual renal failure, pancreatitis, gastrointestinal ulcers and erectile dysfunction. The present invention also relates to a combination of an endothelin receptor antagonist of formula (I) with a renin-angiotensin-based inhibitor. Renin-angiotensin-based inhibitors include renin inhibitors, angiotensin-II antagonists, and angiotensin converting enzyme (ACE) inhibitors. Preference is given to a complex of an endothelin receptor antagonist of formula I with an ACE inhibitor.

Compound I can be administered orally or parenterally in conventional manner. Dosage depends on the age, symptoms and weight of the patient and also on the method of administration used. In general, the daily dosage of the 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.

Compound I can be used in solid or liquid form, for example, in tablets, capsule tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays by conventionally used methods of administration. They are prepared in the usual way. The active substance is mixed with conventional herbal supplements such as tablet binders, fillers, preservatives, tablet bursters, rheology modifiers, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or fuel gases. (See Sucker et al., Pharmazeutische Technologie, Thieme Verlag, Suttgart, 1991). The resulting dosage form typically contains an active substance at a concentration of 0.1 to 90% by weight.

18.8 kg of S-2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethoxy] -3,3-diphenylpropionic acid was added to a 400 L boiler, and 80 L of DMF was added thereto. The mixture was cooled to 10 ° C.

3 kg of lithium amide was added to this solution at a temperature of 10 to 21 ° C. over 30 minutes.

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

At the end of the reaction, the mixture was cooled to 10 ° C. and 240 L of demineralized water were added.

70 L MTB was added to the solution, followed by 40 L hydrochloric acid at 20% concentration. The pH of the aqueous phase was 2-3.

The aqueous phase was separated and the organic phase was washed again with 70 L of demineralised water and then discharged into a vat.

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

The above mentioned MTB phases in the vat were then filtered through frit to clear and added to the isopropanol NaOH solution.

Stirred at a temperature of 20-25 ° C. for 1 hour, then at 45-50 ° C. for 1 hour, and finally at 20-25 ° C. for 13 hours.

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

As measured by HPLC, 19.2 kg of microcrystalline product having a purity of 99.7% was obtained.

Claims (5)

A compound of formula I in solid crystalline form. <Formula I> The compound of claim 1, which is in the form of S-enantiomer. A method for preparing a medicament using a compound as defined in claim 1. The method of claim 3, wherein the medicament is for treating asthma. A pharmaceutical agent containing the compound as defined in claim 1 as an active ingredient.