CA2389012A1 - 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

SODIUM 2- (4, 6-DIMETHYL-PYRIMIDIN-2-YLOXY) -3- (2- (3, 4-DIMETHOXYPHENYL)ETHOXY)-3,3-DIPHENYLPROPIONATE AND
USE THEREOF AS ENDOTHELIN ANTAGONIST
Description The present invention relates to a compound of formula (I) in solid crystalline form l0 COONa CH3 CH30 CHZ--CH2- 0-C- CH N ( I ) O
~ oar \
O N

WO 98/09953 describes azinyloxy- and phenoxy-diarylcarboxylic acid derivatives of the general formula (A) Y
R6-Q-~ I- IH ..-Q ~/ \ Z
X
R5 R1 \R3 and the use thereof as mixed ETAIETB endothelia rezeptor antagonists. Table 2 de-scribes a compound (I-445) having, as racemate and, in particular, as S-enantiomer, excellent ETA and ETB receptor affinities. The structure of I-445 is given by formula (B).

~3C
cooH cHs cH3o cHa--cH2- o-c- cH N (s>
~. o--.~~ . \
N

The synthesis of I-445 is described in Example 14. Purification of this substance in-volves dissolution of the free acid in ether and extraction with aqueous 1 M
NaOH, fol-lowed by reconversion to the free acid with 1M HCI and crystallization.
However, it has been found that this compound (1-445) is difficult to handle when pro-duced on an industrial scale, despite its excellent pharmacological action. It has not been possible to attain the high degree of purity of more than 99.5 % required for phar-maceutical purposes. Furthermore, the substance has been found to build up an excep-tionally high electrostatic charge during drying.
The object of the present invention is thus to provide a compound having a pharmacol-ogical endothelin-antagonistic efficacy similar to that shown by I-445 but without suffer-ing from its drawbacks with regard to 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 COONa CH3 CHgO O CHZ-CHZ- 0- C- CH
N
~ obi \

achieves this object.

The compound of formula (1) possesses the same receptor affinities in vitro toward the ETA and ETB receptors, as I-445. Here again, the S-form is the more effective enanti-omer and therefore constitutes a preferred embodiment of this invention.
Compound (I) is obtainable from the known compound I-445 by methods familiar to the person skilled in the art. Regarding the production of I-445 reference is made to docu-ment WO 98!09953, the contents of which are incorporated herein by reference.
Good results may be achieved by effecting deprotonation of the carboxylic acids with suitably strong bases by means of which sodium is introduced as counterion. Sodium hydroxide is particularly suitable. Alternatively, sodium alkoxides may be used with comparable results.
Well-suited 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 ether.
Salt formation can be carried out over a temperature range of from -20 ° to +100 °C, preferably from room temperature to 60 °C. Reaction temperatures outside this range do not enhance yield to any particular extent. Crystallization can then take place at tem-peratures between -20 °C and room temperature. Temperatures outside this range yield no special advantages.
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 galenical processing. The electrostatic charges found on the solid free acid (I-445) are not observed on this compound (I).
The invention also relates to the use of compound (I) as a pharmaceutical.
Thus effec-tive pharmaceuticals can be produced which are suitable for the treatment of diseases caused by endothelin.
Specifically, these are hypertonia, pulmonary high pressure, myocardial infarction, an-gina pectoris, arrhythmia, acutelchronic renal failure, chronic cardiac insufficiency, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, mi-graine, asthma, ateriosclerosis, endotoxic shock, endotoxin-induced failure of an organ, intravascular coagulation, restenosis following angioplasty and by-pass operations, be-nign prostatic hyperplasia, ischemic and toxine-induced renal insufficiency or hypertonia, carcinosis and the growth of mesenchymal tumors, contrast substance-induced renal insufficiency, pancreatitis, gastro-intestinal ulcers, and erectile dysfunction. The inven-tion further relates to combinations of endothelia receptor antagonists of formula I with inhibitors of the renin-angio-tensin system. Inhibitors of the renin-angio-tensin system are renin inhibitors, angio-tensin-II antagonists and angio-tensin converting enzyme (ACE) inhibitors. Preference is given to combinations of endothelia receptor antagonists of formula I with ACE inhibitors.
Compound (I) can be administered orally or parenterally in conventional manner. The dosage depends on the age, condition, and weight of the patient, and also on the method of administration used. Usually, the daily dose of the active component is be-tween approximately 0.5 and 50 mglkg of body weight for oral administration and be-tween approximately 0.1 and 10 mglkg of body weight for parenteral administration.
Compound (I) can be used for commonly employed methods of administration in solid or liquid form, eg, as tablets, film tablets, capsules, powders, granules, dragees, supposito-ries, solutions, ointments, creams, or sprays. These are produced in conventional man-ner. The active substances can be compounded with conventional galenic auxiliaries, such as tablet binders, fillers, preserving agents, tablet bursters, flow regulators, plasti-cizers, welters, dispersing agents, emulsifiers, solvents, retarding agents, antioxidants, and/or fuel gases (cf H. Sucker et al.: Pharmazeutische Technologie, Thieme Verlag, Stuttgart, 1991 ). The resulting administration forms normally contain the active sub-stance in a concentration of from 0.1 to 90 wt%.
Example In a boiler having a capacity of 400 L there 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
were added, the mixture being cooled to 10 °C.
To this solution there were added 3 kg of lithium amide over a period of 30 minutes at a temperature of 10-21 °C.

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

5 On completion of the reaction, the mixture was cooled to 10 °C, and 240 L of deminer-alized water were added.
To this solution there were added 70 L of MTB, followed by 40 L of 20 %
strength hydro-chloric acid. The pH of the aqueous phase was 2-3.
Following separation of the aqueous phase, the organic phase was again washed with 70 L of demineralized water and then discharged into a vat.
In a second boiler having a capaaty of 400 L, 3.2 kg of 50 % strength sodium hydroxide solution were added to 280 L of isopropanol, and the mixture was stirred for 2 hours at 50 °C. This mixture was then cooled to 20-25 °C.
The MTB phase in the aforementioned vat was then clarified by filtration through a frit prior to addition thereof to the above isopropanolic NaOH solution.
Stirring was effected for one hour at 20-25 °C, then for an hour at 45-50 °C, and finally for 13 hours at a temperature of 20-25 °C.
The product was isolated by filtration, the residue being washed on the filter with 50 L of isopropanol followed by drying on the filter with nitrogen at a jacket temperature of 50 °C.
There were obtained 19.2 kg of microcrystalline product having a purity of 99.7 % as determined by HPLC.

Claims (5)

claims

1. A compound of formula (I) in solid crystalline form

2. A compound as defined in claim 1, which is in the form of the S-enantiomer.

3. A method of using the compound as defined in claim 1 and claim 2 for the pro-duction of pharmaceuticals.

4. A method as defined in claim 3 for the production of pharmaceuticals for the treatment of asthma.

5. A pharmaceutical containing, as active substance, a compound as defined in claim 1 or claim 2.