MXPA02004071A - Sodium 2(4, 6dimethylpyrimidin2yloxy)3(2(3, 4dimethoxyphenyl)ethoxy)3,3diphenylpropionate 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 ETBendothelin receptor antagonist.

Description

2- (4,6-DIMETHYL-PYRIMIDIN-2-ILOXI) -3- (2- (3, 4- DIMETOXYPHENYL) ETOXY) -3,3-DIPHENYL PROPIONATE OF SODIUM AND ITS USE AS AN ENDOGENINE ANTAGONIST The present invention relates to a compound of the formula (I) in a solid crystalline form: (I) WO 98/09953 describes the derivatives of azynyloxy- and phenoxy-diarylcarboxylic acid of the general formula (A): and the use of these as antagonists of IQS receptors for endothelin ETA / ETB mixed. Table 2 describes a compound (1-445) which has, as a racemate and, in In particular, as an S-enantiomer, excellent affinities for ^^^^ ij ^ u T the receivers ETA and ETB. The structure of 1-445 is given by the formula (B): The synthesis of 1-445 is described in Example 14. The purification of this substance includes the dissolution of free acid in ether and extraction with aqueous 1M NaOH, followed by reconversion to the free acid with 1M HCl and crystallization.

However, it has been found that this compound (1-445) is difficult to handle when produced on an industrial scale, despite its excellent pharmacological action. It has not been possible to achieve the high degree of purity of more than 99.5% necessary for pharmaceutical purposes. In addition, it has been found that the substance accumulates an exceptionally high electrostatic charge during drying.

Hli? I? Ü? Fft? T-irA "- - - - The aim of the present invention, in this way, is to provide a compound having a pharmacological efficacy as an endothelin antagonist similar to that shown by 1-445, but without presenting the disadvantages with respect to purification and handling.

We have found that the compound of the formula (I), sodium 2- (4, β-dimethylpyrimidinyl-2-oxy) -3- [2- (3, 4-dimethoxyphenyl) ethoxy] -3,3-diphenyl propionate: achieve this goal.

The compound of the formula (I) has the same affinities for the receptor in vi tro towards the ETA and ETB receptors, as 1-445. In this case also, the S-form is the most effective enantiomer and therefore constitutes a preferred embodiment of this invention.

The compound (I) can be obtained from the compound 1-445 known by the methods customary for the person skilled in the art. With respect to the production of 1-445 reference is made to WO 98/09953, the content of which is incorporated herein by reference. Good results can be achieved by effecting deprotonation of the carboxylic acids with suitably strong bases by means of which sodium is introduced as counter-ion. Sodium hydroxide is particularly suitable. Otherwise, it is possible to use sodium alkoxides with comparable results.

The very suitable solvents from which the sodium salt can be crystallized are the alcohols, to which other less polar solvents can be added, for example, isopropanol in mixture with MTB ether.

The formation of the salt can be carried out over a temperature range from -20 ° to + 100 ° C, preferably from room temperature to 60 ° C. Reaction temperatures outside this range do not improve the performance in any particular measure. The crystallization can then take place at temperatures between -20 ° C and room temperature. Temperatures outside this range do not produce special advantages.

The compound (I) is a solid crystalline material which is easy to handle, is obtained in a high degree of purity and is highly suitable for galenic processing. The electrostatic changes found in solid free acid (1-445) are not observed in this compound (I).

The invention also relates to the use of the compound (I) as a pharmaceutical. In this way it is possible to produce effective pharmaceuticals which are suitable for the treatment of diseases caused by endothelin.

Specifically, these are hypertonia, high pulmonary pressure, myocardial infarction, angina pectoris, arrhythmia, acute / chronic renal failure, chronic heart failure, renal insufficiency, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shoc, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and bypass operations, benign prostatic hyperplasia, ischemic and induced renal insufficiency by toxins or hypertonia, carcinosis and the growth of mesenchymal tumors, renal failure induced by contrast substances, pancreatitis, ^^^ | d m ^^ UM ^ A ^ gastrointestinal ulcers and erectile dysfunction. The invention further relates to combinations of endothelin receptor antagonists of formula I with inhibitors of the renin-angiotensin system. The inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists, and ACE inhibitors.

• Angiotensin converting enzyme (ACE). Preference is given to combinations of antagonists of 10 the endothelin receptors of the formula I with ACE inhibitors. flB Compound (I) can be administered orally or parenterally in a customary manner. The dosage 15 depends on the age, condition and weight of the patient, and also on the method of administration used. Typically, the daily dose of the active compound is between about 0.5 and 50 mg / kg of body weight for oral administration and between about 0.1 and 10 mg / kg of body weight for parenteral administration.

• Compound (I) can be used for administration methods commonly used in solid or liquid form such as tablets, film tablets, capsules, 25 powders, granules, dragees, suppositories, solutions, ^ á > ii *. ** ^. . ^^ .. ^^^^ a .. ^ ,. «-. ointments, creams or sprays. These occur in a usual way. The active substances may be composed of customary galenic auxiliaries, such as tablet binders, diluents, preserving agents, tablet burners, flow regulators, plasticizers, wetting agents, dispersing agents, emulsifiers, solvents, retarding agents, antioxidants and / or combustible gases ( see H. Sucker et al .: Pharmazeutische Technologie, Thieme Verlag, Stuttgart, 1991). The resulting administration forms normally contain the active substance in a concentration from 0.1 to 90% by weight.

Example In a kettle with a capacity of 400 L were placed 18.8 kg of S-2-hydroxy-3- [2- (3, 4-dimethoxyphenyl) ethoxy] -3,3-diphenylpropionic acid, to which 80 L of DMF, cooling the mixture to 10 ° C.

To this solution were added 3 kg of lithium amide for a period of 30 minutes at a temperature of 10-21 ° C.

Then 10 kg of 4,6-dimethylpyrimidin-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.

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

After the separation of the aqueous phase, the phase • Organic was again washed with 70 L of demineralized water and then discharged to a tub. In a second kettle with a capacity of 400 L, 3.2 kg of a 50% sodium hydroxide solution was added to 280 L of isopropanol, and the mixture was stirred for 2 hours at 50 ° C. This mixture was then cooled to 20 20-25 ° C. • The MTB phase in the aforementioned vat was then clarified by filtering through a frit before adding it to the isopropanolic NaOH solution 25 previous.

Agitation was carried out for one hour at 20-25 ° C, then for one hour at 45-50 ° C and finally for 13 hours at a temperature of 20-25 ° C.

The product was isolated by filtration by washing the residue on the filter with 50 L of isopropanol followed by drying on the filter with nitrogen at a temperature of • 50 ° C jacket. 10.2 kg of the microcrystalline product was obtained with a purity of 99.7% as determined by HPLC. •

Claims (4)

1. A compound of the formula (I) in solid crystalline form: • CH3 (I) 10
2. 2. The compound as defined in claim 1, • which is in the form of the S-enantiomer
3. 3. A method of using the compound as defined in claim 1 and claim 2 for the production of pharmaceuticals.
4. 4. The method as defined in claim 3 for the production of pharmaceuticals for treatment • of asthma. A pharmaceutical composition containing, as an active substance, a compound as defined in Claim 1 or Claim 2.