JP2003512460A - 2- (4,6-dimethyl-pyrimidin-2-yloxy) -3- (2- (3,4-dimethoxyphenyl) ethoxy) -3,3-diphenylpropionic acid-sodium salt and its use as an endothelin antagonist - Google Patents

Abstract

(57) Abstract: Compounds of formula (I), especially the (S) -enantiomer, in solid crystalline form, and their use as mixed ET _A / ET _B -endothelin receptor antagonists. Embedded image

Description

Detailed Description of the Invention

[0001]   The present invention relates to compounds of formula (I) in solid crystalline form:

[0002]

[Chemical 2]

[0003]   In WO 98/099953, the general formula (A):

[0004]

[Chemical 3]

[0005] The Ajiniruokishi - and phenoxy - diaryl - carboxylic acid derivatives, and mixtures ET _A / ET B _- endothelin - their use as receptor antagonists. Table 2 describes compounds (I-445) which have excellent ET _A -and ET _B -receptor affinity as racemates and especially as S-enantiomers. The structure of I-445 is represented by formula (B):

[0006]

[Chemical 4]

The preparation of I-445 is described in Example 14. During purification of this material, the free acid was dissolved in ether and extracted with aqueous 1M NaOH, followed by 1MH.
It is converted to the free acid again with Cl and crystallized.

However, during the production of this compound on an industrial scale, this compound (I-4
It has been found that 45) has poor handleability despite its excellent pharmacological action effect. High purities above 99.5%, which have been sought to be obtained for pharmaceutical purposes, have not been achieved. Furthermore, this material was very strongly charged when it dried.

[0009] There was therefore the problem of providing compounds which have a good pharmacological effect similar to I-445 in terms of endothelin antagonism, but which do not have the drawbacks during purification and in their handling.

By the way, the compound of formula (I) 2- (4,6-dimethyl-pyrimidin-2-yloxy) -3- (2- (3,4-dimethoxyphenyl) ethoxy) -3,3-diphenylpropionic acid -Sodium salt:

[0011]

[Chemical 5]

[0012] Found to satisfy this challenge.

The compounds of formula (I), in vitro, with respect to ET _A and ET _B receptors I-
It has the same receptor affinity as 445. Again, the S-form is the effective enantiomer and is therefore a preferred embodiment of this invention.

Compound (I) can be produced from known compound I-445 by a method known to those skilled in the art. The production of I-445 is described in the publication WO 98/099953, the content of which is related thereto. Good results can be achieved when utilizing a suitable strong base, which introduces sodium as a counterion, for the deprotonation of the carboxylic acid. Sodium hydroxide is particularly preferred. However, sodium alcoholate can also be used with comparable results.

As a solvent from which the sodium salt can be crystallized, very suitable are alcohols to which other non-polar solvents can be added, for example isopropanol mixed with MTB-ether.

Salt formation can be carried out in the temperature range from −20 ° C. to + 100 ° C., preferably room temperature to 60 ° C. Reaction temperatures outside this range do not give rise to particular yield advantages. Crystallization can then be carried out at temperatures between -20 and room temperature. Temperatures outside this range produce no particular advantage.

The compound (I) has good handleability as a solid crystalline substance, is already obtained in high purity, and is extremely suitable for further pharmaceutical processing. Free acid (I-4
The electrostatic charge of this solid, which appears in the case of 45), is not observed with compound (I).

Another subject of the invention is the use of compound (I) as a medicament. It can be used to produce effective pharmaceuticals that are suitable for the treatment of endothelin-based diseases.

In particular, the diseases are: hypertension, pulmonary hypertension, myocardial infarction, angina,
Arrhythmia, acute / chronic renal failure, chronic heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atheroma, endotoxic shock, endotoxin-induced organ weakness, intravascular coagulation, angiogenesis Restenosis after surgery and bypass surgery, benign prostatic hyperplasia, renal failure or hypertension due to ischemia and intoxication, metastasis and growth of mesenchymal tumors,
Contrast-induced renal weakness, pancreatitis, gastrointestinal ulcer, erectile dysfunction. Another subject of the invention is the combination of an endothelin receptor antagonist of the formula I with an inhibitor of the renin-angiotensin-system. Inhibitors of the renin-angiotensin-system are renin inhibitors, angiotensin-II-antagonists and angiotensin-converting-enzyme (ACE) -inhibitors. A combination of an endothelin receptor antagonist of formula I and an ACE-inhibitor is preferred.

Compound (I) can usually be applied orally or parenterally. The dose will depend on the age, condition and weight of the patient and the method of application. Usually, a daily dosage of active substance is about 0.5 to 50 mg / kg body weight for oral application and about 0.1 to 10 mg / kg body weight for parenteral application.

The compounds (I) are solid or liquid within the customary application forms, for example tablets, membrane tablets,
It can be used as a capsule, powder, granule, dragee, suppository, solution, ointment, cream or spray. These are manufactured by a conventional method. In this case, the active substances are the customary formulation auxiliaries, such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, softeners, wetting agents, dispersants, emulsifiers, solvents, retarders. Can be applied with agents, antioxidants and / or propellants (H. Sucker et al.,: Pharmazeutisch
e Technologie, Thieme Verlag, Stuttgart, 1991). The application forms thus obtained usually contain the active substance in an amount of 0.1 to 90% by weight.

Example In a 400-liter tank, 18.8 kg of S-2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethoxy) -3,3-diphenylpropionic acid was charged in advance and DMF80 was used. 1 liter was introduced and 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.

Subsequently, 10 kg of 4,6-dimethylpyrimidine-2-methylsulfone was added, and 3
The mixture was stirred at 5 ° C for 23 hours.

After the completion of this reaction, the mixture was cooled to 10 ° C. and VE-water (demineralized water) 240 was added.
Added liters.

To this solution was first added 70 liters of MTB and then 40 liters of 20% hydrochloric acid. The pH value of the aqueous phase was pH = 2-3.

After separation of the aqueous phase, the organic phase was washed again with 70 l of VE-water and then poured into a barrel.

50% to 280 liters of isopropanol in a second 400 liter tank
3.2 kg of a caustic soda solution was added, and the mixture was stirred at 50 ° C for 2 hours. 20 to 2
Allowed to cool to 5 ° C.

To this isopropanolic NaOH-solution was added the MTB-phase from the barrel described above,
It was added by clear filtration through a frit.

First, the mixture was stirred at 20 to 25 ° C. for 1 hour, then at 45 to 50 ° C. for 1 hour, and then again at a temperature of 20 to 25 ° C. for 13 hours.

The product was filtered through a filter, the residue was washed with 50 liters of isopropanol and dried on this filter with nitrogen at a jacket temperature of 50 ° C.

19.2 kg of a microcrystalline product having a purity of 99.7% by HPLC were isolated.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Coat (Reference) A61P 9/00 A61P 9/00 9/04 9/04 9/06 9/06 9/10 9/10 103 103 9/12 9/12 11/00 11/00 11/06 11/06 13/08 13/08 13/12 13/12 15/10 15/10 25/06 25/06 35/00 35/00 35 / 04 35/04 37/00 37/00 // C07M 7:00 C07M 7:00 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK , LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZWF F terms (reference) 4C086 AA01 AA02 AA03 BC42 MA01 MA04 MA13 MA17 MA28 MA35 MA36 MA37 MA41 MA43 MA52 MA59 MA60 MA63 MA66 NA14 ZA08 ZA29 ZA36 ZA40 ZA42 ZA59 ZA66 ZA68 ZA81 ZB07 ZC41 (54) [Title of Invention] 2- (4,6-dimethyl - 2-yloxy) -3- (2- (3,4 Jimetokishifu Eniru) ethoxy) -3,3-di-phenylpropionic acid - its use as the sodium salt and endothelin Anta agonist

Claims (5)

[Claims] 1. Formula (I) in solid crystalline form: Compound of. 2. The compound according to claim 1, which is the S-enantiomer. 3. Use of a compound according to claim 1 or 2 for the manufacture of a medicament. 4. Use according to claim 3 for the manufacture of a medicament for the treatment of asthma and benign prostatic hyperplasia. 5. A compound according to claim 1 or 2 is contained as an active substance,
Medicine.