EP1228047A1 - 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
Sodium 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate and use thereof as endothelin antagonistInfo
- Publication number
- EP1228047A1 EP1228047A1 EP00974404A EP00974404A EP1228047A1 EP 1228047 A1 EP1228047 A1 EP 1228047A1 EP 00974404 A EP00974404 A EP 00974404A EP 00974404 A EP00974404 A EP 00974404A EP 1228047 A1 EP1228047 A1 EP 1228047A1
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- European Patent Office
- Prior art keywords
- compound
- sodium
- ethoxy
- yloxy
- pyrimidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions
- the present invention relates to a compound of formula (I] in solid crystalline form
- WO 98/09953 describes azinyloxy and phenoxy-diaryl-carboxylic acid derivatives of the general formula (A)
- Table 2 describes a compound (1-445) which has excellent ET A and ET B receptor affinities as a racemate and in particular as an S-enantiomer.
- the structure of 1-445 is shown in formula (B).
- Example 14 The preparation of 1-445 is described in Example 14. When this substance is purified, the free acid is dissolved in ether, extracted with aqueous IM NaOH and then converted back into the free acid with IM HC1 and crystallized out.
- this compound (1-445) proved to be difficult to handle despite its excellent pharmacological action.
- the high purity of more than 99.5% that was sought for pharmaceutical purposes could not be achieved.
- the substance experienced an extraordinarily strong electrical charge during drying.
- the object was therefore to provide a compound which has similarly good pharmacological activities with regard to endothelin antagonism as 1-445, but without having its disadvantages in terms of purification and handling.
- the compound of formula (I) has the same receptor affinities in vitro with respect to of the ET A and ET B receptor like 1-445. Again, the S form is the more effective enantiomer and therefore a preferred embodiment of this invention.
- the compound (I) can be prepared from the known compound 1-445 by processes familiar to the person skilled in the art. With regard to the production of 1-445, reference is made to document WO 98/09953, the content of which is hereby incorporated by reference. Good results can be achieved if suitably strong bases are used to deprotonate the carboxylic acids with which sodium is introduced as the counter ion. Sodium is particularly suitable hydroxide. However, sodium alcoholates can also be used in a comparable manner.
- Alcohols which in turn can be mixed with other non-polar solvents, for example isopropanol in a mixture with MTB ether, are particularly suitable as solvents from which the sodium salt can be crystallized.
- Salt formation can be carried out in a temperature range between -20 ° C to + 100 ° C, preferably at room temperature to 60 ° C. Reaction temperatures outside this range result in no particular advantages in terms of yield. The crystallization can then take place at temperatures between -20 to room temperature. Temperatures outside this range have no particular advantages.
- the compound (I) As a solid crystalline substance, the compound (I) is easy to handle, is already obtained in high purity and is excellently suitable for further galenical processing. The electrostatic charging of the solid which occurs with the free acid (1-445) is not observed with this compound (I).
- Another object of the invention is the use of compound (I) as a medicament. It can be used to produce effective drugs that are suitable for the treatment of diseases caused by endothelin.
- these are hypertension, pulmonary high pressure, myocardial infarction, angina pectoris, arrhythmia, acute / chronic renal failure, chronic heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis, endotoxin-induced shock, endotoxin-induced organism , intravascular coagulation, restenosis after angioplasty and by-pass operations, benign prostatic hyperplasia, ischemic and intoxication-caused kidney failure or hypertension, metastasis and growth of mesenchymal tumors, contrast-induced kidney failure, pancreatitis, gastrointestinal ulcer function, erectile dysfunction ,
- the invention further relates to combinations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system.
- Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and angiotensin converting enzyme (ACE) inhibitors. Combinations of endothelin receptor antagonists of the formula I and ACE inhibitors are preferred.
- the compound (I) can be administered orally or parenterally in a conventional manner. The dosage depends on the age, condition and
- the daily dose of active ingredient is between about 0.5 and
- the compound (I) can be used in the customary application forms in solid or liquid form, e.g. as tablets, film
- the active ingredients can be combined with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators,
- the mixture was first stirred at 20-25 ° C for one hour, then for one hour
- the product was filtered off through the filter, the residue was washed with 50 l of isopropanol and dried on the filter with nitrogen at a jacket temperature of 50 ° C.
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- Plural Heterocyclic Compounds (AREA)
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
2- (4, 6-Dimethyl-pyrimidin-2-yloxy) -3- (2- (3 , 4-dimethoxy- phenyl) ethoxy) -3 , 3-diphenylpropionsäure-Natriumsalz und seine Verwendung als Endothelinantagonist2- (4, 6-Dimethyl-pyrimidin-2-yloxy) -3- (2- (3, 4-dimethoxy-phenyl) ethoxy) -3, 3-diphenylpropionic acid sodium salt and its use as an endothelin antagonist
Beschreibungdescription
Die vorliegende Erfindung betrifft eine Verbindung der Formel (I] in fester kristalliner FormThe present invention relates to a compound of formula (I] in solid crystalline form
In WO 98/09953 werden Azinyloxy- und Phenoxy-diaryl-carbonsäure- derivate der allgemeinen Formel (A)WO 98/09953 describes azinyloxy and phenoxy-diaryl-carboxylic acid derivatives of the general formula (A)
beschrieben sowie deren Verwendung als gemischte ETA/ETB-Endothe- lin-rezeptorantagonisten. In Tabelle 2 wird eine Verbindung beschrieben (1-445), die als Racemat und insbesondere als S-Enan- tiomer ausgezeichnete ETA- und ETB-Rezeptoraffinitäten besitzt. Die Struktur von 1-445 ist in Formel (B) dargestellt.and their use as mixed ET A / ET B endothelin receptor antagonists. Table 2 describes a compound (1-445) which has excellent ET A and ET B receptor affinities as a racemate and in particular as an S-enantiomer. The structure of 1-445 is shown in formula (B).
Die Herstellung von 1-445 ist in Beispiel 14 beschrieben. Bei der Reinigung dieser Substanz wird die freie Säure in Ether gelöst, mit wäßriger IM NaOH extrahiert und anschließend mit IM HC1 wieder in die freie Säure überführt und auskristallisiert . The preparation of 1-445 is described in Example 14. When this substance is purified, the free acid is dissolved in ether, extracted with aqueous IM NaOH and then converted back into the free acid with IM HC1 and crystallized out.
Bei der Herstellung dieser Verbindung im technischen Maßstab erwies sich jedoch diese Verbindung (1-445) trotz ihrer ausgezeichneten pharmakologischen Wirkung als schlecht handhabbar. Die für pharmazeutische Zwecke angestrebte hohe Reinheit von größer 99,5 % konnte nicht erzielt werden. Desweiteren erfuhr die Substanz bei der Trocknung eine außerordentlich starke elektrische Aufladung.In the production of this compound on an industrial scale, however, this compound (1-445) proved to be difficult to handle despite its excellent pharmacological action. The high purity of more than 99.5% that was sought for pharmaceutical purposes could not be achieved. Furthermore, the substance experienced an extraordinarily strong electrical charge during drying.
Es bestand daher die Aufgabe, eine Verbindung bereitzustellen, die ähnlich gute pharmakologische Wirksamkeiten bezüglich Endo- thelinantagonismus besitzt wie 1-445, ohne jedoch deren Nachteile bei der Aufreinigung und in der Handhabbarkeit aufzuweisen.The object was therefore to provide a compound which has similarly good pharmacological activities with regard to endothelin antagonism as 1-445, but without having its disadvantages in terms of purification and handling.
Es wurde nun gefunden, daß die Verbindung der Formel (I) 2- (4, 6-Dimethyl-pyrimidin-2-yloxy)-3-(2-(3, 4-dimethoxy- phenyl) ethoxy)-3 , 3-diphenylpropionsäure-NatriumsalzIt has now been found that the compound of the formula (I) 2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (2- (3, 4-dimethoxy-phenyl) ethoxy) -3, 3- diphenylpropionic sodium salt
diese Aufgabe erfüllt.accomplishes this task.
Die Verbindung der Formel (I) besitzt die gleichen Rezeptoraffinitäten in vitro bzgl . des ETA und ETB Rezeptors wie 1-445. Auch hier ist die S-Form das wirksamere Enantiomer und deshalb eine bevorzugte Ausführungsform dieser Erfindung.The compound of formula (I) has the same receptor affinities in vitro with respect to of the ET A and ET B receptor like 1-445. Again, the S form is the more effective enantiomer and therefore a preferred embodiment of this invention.
Die Verbindung (I) ist aus der bekannten Verbindung 1-445 durch dem Fachmann geläufige Verfahren herstellbar. Bezüglich der Herstellung von 1-445 wird auf das Dokument WO 98/09953 verwiesen, dessen Inhalt hiermit in Bezug genommen wird. Gute Ergebnisse lassen sich erzielen, wenn geeignet starke Basen zum Deproto- nieren der Carbonsäuren, mit welchen Natrium als Gegenion eingeführt wird, genutzt werden. Besonders geeignet ist Natrium-
hydroxid. Vergleichbar können aber auch Natriumalkoholate eingesetzt werden.The compound (I) can be prepared from the known compound 1-445 by processes familiar to the person skilled in the art. With regard to the production of 1-445, reference is made to document WO 98/09953, the content of which is hereby incorporated by reference. Good results can be achieved if suitably strong bases are used to deprotonate the carboxylic acids with which sodium is introduced as the counter ion. Sodium is particularly suitable hydroxide. However, sodium alcoholates can also be used in a comparable manner.
Gut geeignet als Lösungsmittel, aus denen das Natriumsalz aus- kristallisiert werden kann, sind Alkohole, die wiederum mit weiteren unpolareren Lösungsmitteln versetzt sein können, beispielsweise Isopropanol im Gemisch mit MTB-Ether.Alcohols, which in turn can be mixed with other non-polar solvents, for example isopropanol in a mixture with MTB ether, are particularly suitable as solvents from which the sodium salt can be crystallized.
Die Salzbildung läßt sich in einem Temperaturbereich zwischen -20°C bis +100°C, vorzugsweise bei Raumtemperatur bis 60°C ausführen. Reaktionstemperaturen außerhalb dieses Bereichs ergeben keine besonderen Ausbeutevorteile. Die Kristallisation kann dann bei Temperaturen zwischen -20 bis Raumtemperatur erfolgen. Temperaturen außerhalb dieses Bereichs ergeben keine besonderen Vor- teile.Salt formation can be carried out in a temperature range between -20 ° C to + 100 ° C, preferably at room temperature to 60 ° C. Reaction temperatures outside this range result in no particular advantages in terms of yield. The crystallization can then take place at temperatures between -20 to room temperature. Temperatures outside this range have no particular advantages.
Die Verbindung (I) ist als fester kristalliner Stoff gut zu handhaben, fällt bereits in hoher Reinheit an und ist ausgezeichnet für die galenische Weiterverarbeitung geeignet. Die bei der freien Säure (1-445) auftretende elektrostatische Aufladung des Feststoffs wird bei dieser Verbindung (I) nicht beobachtet.As a solid crystalline substance, the compound (I) is easy to handle, is already obtained in high purity and is excellently suitable for further galenical processing. The electrostatic charging of the solid which occurs with the free acid (1-445) is not observed with this compound (I).
Ein weiterer Gegenstand der Erfindung ist die Verwendung der Verbindung (I) als Arzneimittel. Es lassen sich damit wirksame Arz- neimittel herstellen, die zur Behandlung von durch Endothelin verursachten Krankheiten geeignet sind.Another object of the invention is the use of compound (I) as a medicament. It can be used to produce effective drugs that are suitable for the treatment of diseases caused by endothelin.
Insbesondere sind dies Hypertonie, pulmonaler Hochdruck, Myokard- infarkt, Angina Pectoris, Arrhythmie, akutes/chronisches Nieren- versagen, chronische Herzinsuffizienz, Niereninsuffizienz, zerebrale Vasospasmen, zerebrale Ischämie, Subarachnoidalblutungen, Migräne, Asthma, Atherosklerose, endotoxischem Schock, Endotoxin- induziertes Organversagen, intravaskuläre Koagulation, Restenose nach Angioplastie und by-pass Operationen, benigne Prostata-Hy- perplasie, ischämisches und durch Intoxikation verursachtes Nie- renversagen bzw. Hypertonie, Metastasierung und Wachstum mesenchymaler Tumoren, Kontrastmittel-induziertes Nierenversagen, Pankreatitis, gastrointestinale Ulcera, erektile Dysfunktion. Ein weiterer Gegenstand der Erfindung sind Kombinationen aus Endothe- linrezeptorantagonisten der Formel I und Inhibitoren des Renin- Angiotensin Systems. Inhibitoren des Renin-Angiotensin-Systems sind Reninhemmer, Angiotensin-II-Antagonisten und Angiotensin- Converting-Enzyme (ACE) -Hemmer . Bevorzugt sind Kombinationen aus Endothelinrezeptorantagonisten der Formel I und ACE-Hemmern.
Die Verbindung (I) kann in üblicher Weise oral oder parenteral verabreicht werden. Die Dosierung hängt vom Alter, Zustand undIn particular, these are hypertension, pulmonary high pressure, myocardial infarction, angina pectoris, arrhythmia, acute / chronic renal failure, chronic heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis, endotoxin-induced shock, endotoxin-induced organism , intravascular coagulation, restenosis after angioplasty and by-pass operations, benign prostatic hyperplasia, ischemic and intoxication-caused kidney failure or hypertension, metastasis and growth of mesenchymal tumors, contrast-induced kidney failure, pancreatitis, gastrointestinal ulcer function, erectile dysfunction , The invention further relates to combinations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and angiotensin converting enzyme (ACE) inhibitors. Combinations of endothelin receptor antagonists of the formula I and ACE inhibitors are preferred. The compound (I) can be administered orally or parenterally in a conventional manner. The dosage depends on the age, condition and
Gewicht des Patienten sowie von der Applikationsart ab. In derWeight of the patient and the type of application. In the
Regel beträgt die tägliche Wirkstoffdosis zwischen etwa 0,5 undAs a rule, the daily dose of active ingredient is between about 0.5 and
5 50 mg/kg Körpergewicht bei oraler Gabe und zwischen etwa 0,1 und5 50 mg / kg body weight with oral administration and between about 0.1 and
10 mg/kg Körpergewicht bei parenteraler Gabe.10 mg / kg body weight with parenteral administration.
Die Verbindung (I) kann in den gebräuchlichen Applikationsformen fest oder flüssig angewendet werden, z.B. als Tabletten, Film-The compound (I) can be used in the customary application forms in solid or liquid form, e.g. as tablets, film
10 tabletten, Kapseln, Pulver, Granulate, Dragees, Suppositorien, Lösungen, Salben, Cremes oder Sprays. Diese werden in üblicher Weise hergestellt. Die Wirkstoffe können dabei mit den üblichen galenischen Hilfsmitteln wie Tablettenbindern, Füllstoffen, Konservierungsmitteln, Tablettensprengmitteln, Fließreguliermitteln,10 tablets, capsules, powders, granules, coated tablets, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way. The active ingredients can be combined with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators,
15 Weichmachern, Netzmitteln, Dispergiermitteln, Emulgatoren, Lösungsmitteln, Retardierungsmitteln, Antioxidantien und/oder Treibgasen verarbeitet werden (vgl. H. Sucker et al . : Pharmazeutische Technologie, Thieme Verlag, Stuttgart, 1991). Die so erhaltenen Applikationsformen enthalten den Wirkstoff normaler-15 plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants are processed (see H. Sucker et al.: Pharmaceutical Technology, Thieme Verlag, Stuttgart, 1991). The application forms thus obtained contain the active ingredient normally
20 weise in einer Menge von 0,1 bis 90 Gew.-%.20 wise in an amount of 0.1 to 90 wt .-%.
Beispielexample
In einem 400 1 Kessel wurden 18,8 kg der S-2-Hydroxy-3- (2- 25 (3 , 4-dimethoxyphenyl) ethoxy) -3 , 3-diphenylpropionsäure vorgelegt, 80 1 DMF zugefahren und auf 10°C abgekühlt.18.8 kg of the S-2-hydroxy-3- (2- 25 (3, 4-dimethoxyphenyl) ethoxy) -3, 3-diphenylpropionic acid were placed in a 400 1 kettle, 80 1 DMF were added and the mixture was cooled to 10 ° C. ,
Zu dieser Lösung wurden bei Temperaturen zwischen 10-21°C innerhalb einer halben Stunde 3 kg Lithiumamid zugegeben. 303 kg of lithium amide were added to this solution at temperatures between 10-21 ° C. within half an hour. 30
Anschließend wurden 10 kg des 4 , 6-Dimethylpyrimidin-2-methylsul- fons zugegeben und 23 Stunden bei 35°C gerührt.Then 10 kg of 4, 6-dimethylpyrimidine-2-methylsulfone were added and the mixture was stirred at 35 ° C. for 23 hours.
Nach Beendigung der Reaktion wurde auf 10°C abgekühlt und 240 1 35 VE-Wasser zugegeben.After the reaction had ended, the mixture was cooled to 10 ° C. and 240 1 35 DI water was added.
Zu der Lösung wurden erst 70 1 MTB und dann 40 1 20%ige Salzsäure gegeben. Der pH-Wert der wässrigen Phase betrug pH=2-3.First 70 1 MTB and then 40 1 20% hydrochloric acid were added to the solution. The pH of the aqueous phase was pH = 2-3.
40 Nach der Abtrennung der wässrigen Phase wurde die organische40 After the aqueous phase had been separated off, the organic
Phase nochmals mit 70 1 VE-Wasser gewaschen und dann in ein Faß abgelassen.Phase washed again with 70 l of demineralized water and then drained into a barrel.
In einem zweiten 400 1 Kessel wurden 280 1 Isopropanol mit 3,2 kg 45 50%iger Natronlauge versetzt und 2 Stunden bei 50°C gerührt. Anschließend wurde auf 20-25°C abgekühlt.
Zu dieser isopropanolischen NaOH-Lösung wurde die MTB-Phase aus dem vorher erwähnten Faß über eine Fritte klarfiltriert zugegeben.In a second 400 1 kettle, 3.2 kg 45 50% sodium hydroxide solution were added to 280 1 isopropanol and the mixture was stirred at 50 ° C. for 2 hours. The mixture was then cooled to 20-25 ° C. To this isopropanolic NaOH solution, the MTB phase from the above-mentioned barrel was added through a frit, filtered clearly.
Erst wurde eine Stunde bei 20-25°C gerührt , dann eine StundeThe mixture was first stirred at 20-25 ° C for one hour, then for one hour
45-50°C und anschließend nochmals 13 Stunden bei Temperaturen zwischen 20-25°C.45-50 ° C and then another 13 hours at temperatures between 20-25 ° C.
Das Produkt wurde über den Filter abfiltriert, der Rückstand mit 50 1 Isopropanol gewaschen und auf dem Filter mit Stickstoff bei einer Manteltemperatur von 50°C getrocknet.The product was filtered off through the filter, the residue was washed with 50 l of isopropanol and dried on the filter with nitrogen at a jacket temperature of 50 ° C.
Es wurden 19,2 kg feinkristallines Produkt mit einer Reinheit von 99,7 % nach HPLC isoliert.
19.2 kg of finely crystalline product with a purity of 99.7% were isolated by HPLC.
Claims
1. Verbindung der Formel (I) in fester kristalliner Form1. Compound of formula (I) in solid crystalline form
2. Verbindung nach Anspruch 1, dadurch gekennzeichnet, daß es sich um das S-Enantiomer handelt.2. Compound according to claim 1, characterized in that it is the S enantiomer.
3. Verwendung der Verbindung gemäß Anspruch 1 und 2 zur Herstel- lung von Arzneimittel .3. Use of the compound according to claims 1 and 2 for the manufacture of medicaments.
4. Verwendung nach Anspruch 3 zur Herstellung von Arzneimitteln zur Behandlung von Asthma und benigner Prostata Hyperplasie.4. Use according to claim 3 for the manufacture of medicaments for the treatment of asthma and benign prostatic hyperplasia.
5. Arzneimittel enthaltend als Wirkstoff eine Verbindung gemäß Anspruch 1 oder 2. 5. Medicament containing as active ingredient a compound according to claim 1 or 2.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19951671A DE19951671A1 (en) | 1999-10-27 | 1999-10-27 | 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 |
DE19951671 | 1999-10-27 | ||
PCT/EP2000/010202 WO2001030767A1 (en) | 1999-10-27 | 2000-10-17 | Sodium 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate and use thereof as endothelin antagonist |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1228047A1 true EP1228047A1 (en) | 2002-08-07 |
Family
ID=7927001
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP00974404A Withdrawn EP1228047A1 (en) | 1999-10-27 | 2000-10-17 | Sodium 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate and use thereof as endothelin antagonist |
Country Status (17)
Country | Link |
---|---|
EP (1) | EP1228047A1 (en) |
JP (1) | JP2003512460A (en) |
KR (1) | KR20020047301A (en) |
CN (1) | CN1384822A (en) |
AU (1) | AU1272701A (en) |
BG (1) | BG106700A (en) |
BR (1) | BR0015112A (en) |
CA (1) | CA2389012A1 (en) |
CZ (1) | CZ20021485A3 (en) |
DE (1) | DE19951671A1 (en) |
HU (1) | HUP0203476A3 (en) |
IL (1) | IL149312A0 (en) |
MX (1) | MXPA02004071A (en) |
NO (1) | NO20021986D0 (en) |
SK (1) | SK5962002A3 (en) |
TR (1) | TR200201169T2 (en) |
WO (1) | WO2001030767A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101006076B (en) | 2004-06-24 | 2010-09-29 | 沃泰克斯药物股份有限公司 | Modulators of ATP-binding cassette transporters |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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DE19636046A1 (en) * | 1996-09-05 | 1998-03-12 | Basf Ag | New carboxylic acid derivatives, their production and use as mixed ET¶A¶ / ET¶B¶ receptor antagonists |
-
1999
- 1999-10-27 DE DE19951671A patent/DE19951671A1/en not_active Withdrawn
-
2000
- 2000-10-17 MX MXPA02004071A patent/MXPA02004071A/en unknown
- 2000-10-17 TR TR2002/01169T patent/TR200201169T2/en unknown
- 2000-10-17 HU HU0203476A patent/HUP0203476A3/en unknown
- 2000-10-17 BR BR0015112-2A patent/BR0015112A/en not_active IP Right Cessation
- 2000-10-17 IL IL14931200A patent/IL149312A0/en unknown
- 2000-10-17 SK SK596-2002A patent/SK5962002A3/en unknown
- 2000-10-17 CA CA002389012A patent/CA2389012A1/en not_active Abandoned
- 2000-10-17 CZ CZ20021485A patent/CZ20021485A3/en unknown
- 2000-10-17 WO PCT/EP2000/010202 patent/WO2001030767A1/en not_active Application Discontinuation
- 2000-10-17 EP EP00974404A patent/EP1228047A1/en not_active Withdrawn
- 2000-10-17 KR KR1020027005457A patent/KR20020047301A/en not_active Application Discontinuation
- 2000-10-17 CN CN00814871A patent/CN1384822A/en active Pending
- 2000-10-17 JP JP2001533121A patent/JP2003512460A/en not_active Abandoned
- 2000-10-17 AU AU12727/01A patent/AU1272701A/en not_active Abandoned
-
2002
- 2002-04-26 NO NO20021986A patent/NO20021986D0/en not_active Application Discontinuation
- 2002-05-14 BG BG106700A patent/BG106700A/en unknown
Non-Patent Citations (1)
Title |
---|
See references of WO0130767A1 * |
Also Published As
Publication number | Publication date |
---|---|
KR20020047301A (en) | 2002-06-21 |
HUP0203476A3 (en) | 2003-07-28 |
MXPA02004071A (en) | 2002-10-11 |
CA2389012A1 (en) | 2001-05-03 |
SK5962002A3 (en) | 2002-09-10 |
WO2001030767A1 (en) | 2001-05-03 |
HUP0203476A2 (en) | 2003-05-28 |
CZ20021485A3 (en) | 2003-06-18 |
DE19951671A1 (en) | 2001-05-03 |
IL149312A0 (en) | 2002-11-10 |
BR0015112A (en) | 2002-10-29 |
NO20021986L (en) | 2002-04-26 |
JP2003512460A (en) | 2003-04-02 |
BG106700A (en) | 2003-02-28 |
CN1384822A (en) | 2002-12-11 |
AU1272701A (en) | 2001-05-08 |
TR200201169T2 (en) | 2002-09-23 |
NO20021986D0 (en) | 2002-04-26 |
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