CN1291190A - 5-substituted pyrimidine-2-yloxy carboxylic acid derivatives, the production of the same and their utilization as endothelin antagonist - Google Patents

5-substituted pyrimidine-2-yloxy carboxylic acid derivatives, the production of the same and their utilization as endothelin antagonist Download PDF

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CN1291190A
CN1291190A CN99803037A CN99803037A CN1291190A CN 1291190 A CN1291190 A CN 1291190A CN 99803037 A CN99803037 A CN 99803037A CN 99803037 A CN99803037 A CN 99803037A CN 1291190 A CN1291190 A CN 1291190A
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W·安伯格
R·扬森
A·克林
D·克林格
H·里舍尔斯
S·赫尔根勒德尔
M·拉沙克
L·翁格尔
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Abstract

The invention relates to carboxylic acid derivatives of formula (I), wherein the substituents have the following meanings; R<1>= tetrazole or a group (1); R = a radical OR<7>(2), (3), a 5-membe red heteroaromatic bonded by a nitrogen atom such a pyrrolyl, pyrazolyl, imidazolyl and trizolyl; R<2>, R<3> = hydrogen, hydroxy, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-halogen alkyl, C1-C4-alkoxy, C1-C4-halogen alkoxy or C1-C4-alkythio; X = halogen, C1-C4-halogen alkyl, hydroxy; R<4> and R<5> = phenyl or naphthyl, C3-C7-cycloalkyl, phenyl or naphthyl which are bonded in ortho position by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2-NH or an N-alkyl group or a 5-membered or 6-membered heteroaromatic; R<6> = hydrogen, phenyl or naphthyl, a five or six-membered heteroaromatic, C1-C8-alkyl, C3-C6-alkenyl, C3-C6-alkinyl or C3-C8-cycloalkyl, whereby said radicals can be substituted once or many times, with the proviso that R<6> can only stand for hydrogen if Z does not represent a single bond; Z = sulfur, oxygen or a single bond, in addition to the physiologically compatible salts and the enantiomeric-pure and diastereomeric-pure forms. The novel compounds are suitable for combating diseases, especially as endothelin antagonists.

Description

Pyrimidine-2-yloxy carboxylic acid derivatives that 5-replaces and method for making thereof and as the purposes of endothelin antagonists
The present invention relates to novel carboxylic acid derivative with 5-substituted pyrimidines ring, with and its production and use.
The endothelium peptide is a kind of peptide of being made up of 21 amino acid, and the synthetic and release by blood vessel endothelium.The endothelium peptide exists with three kinds of isomeric form, i.e. ET-1, ET-2 and ET-3.Hereinafter, " endothelium peptide " or " ET " are meant a kind of of endothelium peptide or all isomer.The endothelium peptide is a kind of vasoconstrictor of brute force, and antiotasis is had strong effective function.Known this vasoconstriction effect causes (Nature, 332,411-415,1988 by the endothelium peptide with combining of its acceptor; FEBS Letters, 231,440-444,1988 and Biochem.Biophys.Res.Commun., 154.868-875,1988).
The release of endothelium peptide increases or improper release will cause peripheral blood vessel, kidney blood vessel and cerebrovascular lasting contraction, thereby causes the generation of disease.Reported in the document that the endothelium peptide relates to numerous disease, comprised hypertension, Acute Myocardial Infarction, pulmonary hypertension, Raynaud disease, cerebral vasospasm, apoplexy, benign prostatauxe, atherosis, asthma and prostate cancer.(J．Vascular?Med．Biology?2．207(1990)，J．Am．Med．Association264，2868(1990)，Nature?344．114(1990)，N．Engl．J．Med．322，205(1989)，N．Engl．J．Med．328，1732(1993)，Nephron?66，373(1994)，Stroke?25，904(1994)，Nature?365，759(1993)，J．Mol.Cell．Cardiol．27，A234(1995)；Cancer?Research?56，663(1996)，Nature?Medicine?1．944(1995))
At least two kinds of endothelium peptide receptor subtypes have been described, ETA and ETB acceptor (Nature 348,730 (1990), and Nature 348,732 (1990)) in the document at present.As a result, the material that suppresses endothelium peptide and one or both receptors bind can resist the physiological action of endothelium peptide, is valuable medicament therefore.
Carboxylic acid derivative and as the purposes such as the WO 95/26716 of endothelin antagonists, WO96/11914, WO 97/9294, and WO 97/12878, and WO 97/38980, and WO 97/38981 is described.These compounds have the group shown in a nitrogen-atoms or the following formula on 5 of heterocyclic In contrast, compound of the present invention has the group shown in the following formula on this
Figure 9980303700072
Wherein X is halogen, hydroxyl or C 1-C 4Haloalkyl.Compare with known endothelin antagonists, compound of the present invention is for example more favourable the human body metabolism.
The present invention relates to the carboxylic acid derivative shown in the formula I R wherein 1Be the group shown in tetrazolium or the following formula
Figure 9980303700074
Wherein R is:
(a) group OR 7, R wherein 7For
Hydrogen, alkali metal cation, alkaline earth metal cation, physiology capacitive organic ammonium ion are such as uncle C 1-C 4Alkylammonium or ammonium ion;
C 3-C 8Cycloalkyl, C 1-C 8Alkyl, CH 2-phenyl, it can be replaced by one or more following groups: halogen, nitro, cyano group, C 1-C 4Alkyl, C 1-C 4Haloalkyl, hydroxyl, C 1-C 4Alkoxyl group, sulfydryl, C 1-C 4Alkyl sulfenyl, amino, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2
C 3-C 6Alkenyl or C 3-C 6Alkynyl, these groups itself can be with 1～5 halogen atom; R in addition 7Can be for having the phenyl of 1～5 halogen atom and/or 1～3 following groups: nitro, cyano group, C 1-C 4Alkyl, C 1-C 4Haloalkyl, hydroxyl, C 1-C 4Alkoxyl group, sulfydryl, C 1-C 4Alkyl sulfenyl, amino, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2
(b) the five yuan of hetero-aromatic rings that connect through nitrogen-atoms such as pyrryl, pyrazolyl, imidazolyl and triazolyl, and this hetero-aromatic ring can have 1～2 halogen atom, 1～2 C 1-C 4Alkyl or 1～2 C 1-C 4Alkoxyl group.
(c) group shown in the following formula
Figure 9980303700081
Wherein k can be 0,1 or 2, and p can be 1,2,3 or 4, and
R 8Be C 1-C 4Alkyl, C 3-C 8Cycloalkyl, C 3-C 6Alkenyl, C 3-C 6Alkynyl or phenyl, they can be by one or more, and for example 1～3 following groups replaces:
Halogen, nitro, cyano group, C 1-C 4Alkyl, C 1-C 4Haloalkyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkyl sulfenyl, sulfydryl, amino, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2
D) oxygen of group shown in following formula base, C 1-C 4Alkyl sulfenyl, sulfydryl, amino, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2
Other substituting group is defined as follows:
R 2Be hydrogen, hydroxyl, NH 2, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl, C 1-C 4Hydroxyalkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy or C 1-C 4Alkyl sulfenyl, morpholine;
X is halogen, C 1-C 4Haloalkyl, hydroxyl;
R 3Be hydrogen, hydroxyl, NH 2, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl, C 1-C 4Hydroxyalkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy ,-NH-O-C 1-C 4Alkyl, C 1-C 4The alkyl sulfenyl;
R 4And R 5(can be identical or different) be:
Can be by the phenyl or naphthyl that one or more following groups replaced: halogen, nitro, cyano group, hydroxyl, C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, phenoxy group, sulfydryl, alkyl-carbonyl, alkoxy carbonyl, C 1-C 4Alkyl sulfenyl, amino, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2Or
Phenyl or naphthyl, it is at the direct key of ortho position warp, methylene radical, ethylidene or vinylidene, oxygen or sulphur atom or SO 2-, NH-or N-alkyl be interconnection; Or
Contain five yuan or six-membered Hetero-aromatic of 1～3 nitrogen-atoms and/or sulphur or Sauerstoffatom, it can have 1～4 halogen atom and/or 1～2 following groups: C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, C 1-C 4Alkyl sulfenyl, phenyl, phenoxy group or phenylcarbonyl group, wherein phenyl itself can have 1～5 halogen atom and/or 1～3 following groups: C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy and/or C 1-C 4The alkyl sulfenyl; Or C 3-C 7Cycloalkyl;
R 6For hydrogen,
C 1-C 8Alkyl, C 3-C 6Alkenyl, C 3-C 6Alkynyl or C 3-C 8Cycloalkyl, wherein these groups can be replaced by the following groups list or be polysubstituted: hydroxyl, sulfydryl, carboxyl, halogen, nitro, cyano group, C 1-C 4Alkoxyl group, C 3-C 6Alkenyloxy, C 3-C 6Alkynyloxy group, C 1-C 4Alkyl sulfenyl, C 1-C 4Halogenated alkoxy, C 1-C 4Alkyl-carbonyl, C 1-C 4Alkoxy carbonyl, C 3-C 8Alkyl-carbonyl alkyl, amino, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2, phenoxy group or phenyl, but wherein above-mentioned aryl coverlet or polysubstituted is for example replaced by following groups 1～3: halogen, nitro, cyano group, C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, sulfydryl, carboxyl, hydroxyl, amino, R 12, C 1-C 4Alkoxy carbonyl, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2, dioxo methylene radical, dioxo ethylidene or C 1-C 4The alkyl sulfenyl;
Phenyl or naphthyl, it can be replaced by one or more following groups separately: halogen, nitro, cyano group, hydroxyl, amino, C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, phenoxy group, C 1-C 4Alkyl sulfenyl, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2Or dioxo methylene radical or dioxo ethylidene;
Contain five yuan or six-membered Hetero-aromatic of 1～3 nitrogen-atoms and/or sulphur or Sauerstoffatom, it can have 1～4 halogen atom and/or 1～2 following groups: C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, C 1-C 4Alkyl sulfenyl, phenyl, phenoxy group or phenylcarbonyl group, wherein phenyl itself can have 1～5 halogen atom and/or 1～3 following groups: C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy and/or C 1-C 4The alkyl sulfenyl;
Condition is when the non-singly-bound of Z, R 6Can only be hydrogen;
R 12Be C 1-C 4Alkyl, C 1-C 4Alkyl sulfenyl, C 1-C 4Alkoxyl group, it can have a following groups: hydroxyl, carboxyl, amino, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2, methane amide or CON (C 1-C 4Alkyl) 2
Z is sulphur, oxygen or singly-bound.
Reach thereafter at this, adopt following definition:
Basic metal is, for example: lithium, sodium, potassium;
Alkaline-earth metal is, for example: calcium, magnesium, barium;
The organic ammonium ion is protonated amine such as thanomin, diethanolamine, quadrol, diethylamine or piperazine;
C 3-C 7Cycloalkyl is, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl;
C 1-C 4Haloalkyl is a straight or branched, such as, fluoro methyl, difluoromethyl, trifluoromethyl, a chlorodifluoramethyl-, dichloro one methyl fluoride, trichloromethyl, 1-fluoro ethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, 2-chloro-2,2-two fluoro ethyls, 2,2-two chloro-2-fluoro ethyls, 2,2,2-three chloroethyls or pentafluoroethyl group;
C 1-C 4Halogenated alkoxy is a straight or branched, such as, difluoro-methoxy, trifluoromethoxy, a chlorine difluoro-methoxy, 1-fluorine oxyethyl group, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoro oxyethyl group, 2,2,2-trifluoro ethoxy, 2-chloro-1,1,2-trifluoro ethoxy, 2-fluorine oxyethyl group or five fluorine oxyethyl groups;
C 1-C 4Alkyl is a straight or branched, such as, methyl, ethyl, 1-propyl group, 2-propyl group, 2-methyl-2-propyl group, 2-methyl isophthalic acid-propyl group, 1-butyl or 2-butyl;
C 2-C 4Alkenyl is a straight or branched, such as, vinyl, 1-propylene-3-base, 1-propylene-2-base, 1-propylene-1-base, 2-methyl isophthalic acid-propenyl, 1-butylene base or crotyl;
C 2-C 4Alkynyl is a straight or branched, such as, ethynyl, 1-propine-1-base, 1-propine-3-base, ethyl acetylene-4-base or 2-butyne-4-base;
C 1-C 4Alkoxyl group is a straight or branched, such as, methoxyl group, oxyethyl group, propoxy-, 1-methyl ethoxy, butoxy, 1-methyl propoxy-, 2-methyl propoxy-or 1,1-dimethyl oxyethyl group;
C 3-C 6Alkenyloxy is a straight or branched, such as, allyloxy, 2-butylene-1-oxygen base or 3-butene-2-oxygen base;
C 3-C 6Alkynyloxy group is a straight or branched, such as, 2-propine-1-oxygen base 2-butyne-1-oxygen base or 3-crotonylene-oxygen base;
C 1-C 4The alkyl sulfenyl is a straight or branched, such as, methylthio group, ethylmercapto group, rosickyite base, 1-methyl ethylmercapto group, butylthio, 1-methyl-prop sulfenyl, 2-methyl-prop sulfenyl or 1,1-dimethyl ethylmercapto group;
C 1-C 4Alkyl-carbonyl is a straight or branched, such as, ethanoyl, ethyl carbonyl or 2-propyl group carbonyl;
C 1-C 4Alkoxy carbonyl is a straight or branched, such as, methoxycarbonyl, ethoxy carbonyl, positive propoxy carbonyl, isopropoxy carbonyl or n-butoxy carbonyl;
C 3-C 8The alkyl-carbonyl alkyl is a straight or branched, such as, 2-oxo third-1-base, 3-oxo fourth-1-base or 3-oxo fourth-2-base;
C 1-C 8Alkyl is a straight or branched, such as, C 1-C 4Alkyl, amyl group, hexyl, heptan reach or octyl group;
Halogen is for example fluorine, chlorine, bromine, iodine.
The invention further relates to the compound (prodrug) of compound shown in those energy release type I.
Preferred prodrug is can be in certain zone of human body, for example in stomach, intestines, blood flow or the liver, and the compound that discharges under the condition that is often had.
This compound with and the preparation usefulness intermediate, such as II and IV, one or more asymmetric alternate c atoms can be arranged.This compounds can pure enantiomorph or pure diastereomer or the existence of its mixture.Preferably use the mapping pure compound to be active compound.
In addition, the present invention relates to the purposes that above-mentioned carboxylic acid derivative is used to prepare medicine, especially for the purposes of preparation endothelium peptide acceptor inhibitor.
Compound shown in the formula IV, wherein Z is that (IV a) can be prepared as described in WO 96/11914 for sulphur or oxygen.
Figure 9980303700121
Compound shown in the formula III or be known, or can be by for example, the reduction of corresponding carboxylic acid or its ester, or synthesize by other currently known methods.
Compound shown in the formula IV a can be by DE 19636046.3 described acid-catalyzed transesterification reactions, and the form pure with its mapping obtains.
In addition, the pure compound of the mapping shown in the formula IV a can split and obtains by using suitable mapping soda ash that the racemize shown in the formula IV a or non-mapping compound are carried out traditional racemize.Suitable alkali is 4-chloro-phenyl-ethamine and at the alkali described in the WO 96/11914 for example.
Compound shown in the formula IV, wherein Z is singly-bound (IV b), can obtain with racemize or enantiopure form as described in the WO 97/38981.
Compound of the present invention, wherein substituting group is suc as formula defining in the I, can be by for example, the substituting group compound shown in the carboxylic acid derivative shown in the formula IV and the formula V as defined above reacts and prepares.
Figure 9980303700123
In the formula V, R 10Be halogen or R 11-SO 2-, and R 11Be C 1-C 4Alkyl, C 1-C 4Haloalkyl or phenyl.Reaction is preferably carried out in inert solvent or thinner, and adds suitable alkali, can be to the alkali of intermediate IV deprotonation, and simultaneous temperature is room temperature～solvent boiling point.
Therefore, R 1For the compound of the type I of COOH can directly obtain, method is R 1For the intermediate IV of COOH behind two normal suitable alkali deprotonations, again with the compound reaction shown in the formula V.Reaction is also carried out in inert solvent, and temperature is room temperature～solvent boiling point.
The example of solvent or thinner is aliphatic hydrocarbon, alicyclic hydrocarbon and aromatic hydrocarbon, it can be replaced by chlorine in either case, such as, hexane, hexanaphthene, sherwood oil, V.M.. naphtha, benzene,toluene,xylene, methylene dichloride, chloroform, tetracol phenixin, monochloroethane and trieline; Ether, such as, Di Iso Propyl Ether, diisobutyl ether, methyl tertiary butyl ether, propylene oxide, diox and tetrahydrofuran (THF); Nitrile, such as, acetonitrile, propionitrile; Acid amides is such as dimethyl formamide, N,N-DIMETHYLACETAMIDE and N-Methyl pyrrolidone; Sulfoxide and sulfone are such as dimethyl sulfoxide (DMSO) and tetramethylene sulfone.
Formula V compound is known, and wherein some can obtain from commercial channels, or preparation in a well-known manner.
The hydride of basic metal or alkaline-earth metal is such as sodium hydride, potassium hydride KH or hydrolith; Carbonate, such as alkaline carbonate, for example yellow soda ash or salt of wormwood; Basic metal or alkaline earth metal hydroxides are such as sodium hydroxide or potassium hydroxide; Organometallic compound is such as butyllithium; Or alkali metal ammonia compound, as the di-isopropyl lithamide, all can be used as alkali.
Formula I compound also can be from the i.e. R wherein of corresponding carboxylic acid 1For the compound shown in the formula I of COOH prepares.At first this compounds is converted into activity form, as etheride, acid anhydrides or acyl imidazoles, then with suitable oxy-compound HOR with usual way 7Reaction.This reaction can be carried out in common solvent, and normal require to add alkali such as, triethylamine, pyridine, imidazoles or diazabicylo undecane.This two step also can be simplified to, and for example carboxylic acid is acted on the oxy-compound in the presence of such as the carbodiimide dehydrated reagent.
In addition, the compound shown in the formula I also can be from the i.e. R wherein of corresponding carboxylic acid salt 1For the compound shown in the formula I of COOM prepares, wherein M can be alkali metal cation or alkaline earth metal cation of equal value.This class salt can with formula R 7The reaction of chemical compound lot shown in the-A, A is freestone leaving group commonly used, halogen for example, such as chlorine, bromine, iodine, or aryl-or alkyl sulphonyl, for example tosyl group and methylsulfonyl, it can be replaced by halogen, alkyl or haloalkyl; Or other leaving group of equal value.The formula R that has reactive substituents A 7Compound shown in the-A is the known expertise acquisition commonly used of maybe can passing through.This reaction can be carried out in common solvent, and advantageously carries out when adding alkali, and this moment, above-mentioned alkali was suitable.
In some cases, must adopt known protecting group technology to prepare chemical compounds I of the present invention.If, R for example 6Be the 4-hydroxy phenyl, this hydroxyl can at first be protected with the form of benzyl oxide, and the suitable stage in reaction cuts then.
R wherein 1For the compound shown in the formula I of tetrazolium can be prepared as described in WO 96/11914.
Consider biological activity, preferred those substituting group carboxylic acid derivative shown in the formula I of giving a definition wherein, it can be pure enantiomorph or pure diastereomer or its mixture:
R 2Be hydrogen, hydroxyl, N (C 1-C 4Alkyl) 2, C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, C 1-C 4Alkyl sulfenyl, halogen;
X is halogen, trifluoromethyl;
R 3Be hydrogen, hydroxyl, N (C 1-C 4Alkyl) 2, C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, C 1-C 4Alkyl sulfenyl, halogen;
R 4And R 5For can be by one or more, 1-3 phenyl or naphthyl that following groups replaced for example: halogen, cyano group, hydroxyl, sulfydryl, amino, C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, C 1-C 4Alkyl sulfenyl, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2, C 1-C 4Alkyl-carbonyl, C 1-C 4Alkoxy carbonyl;
Phenyl or naphthyl, it is at the direct key of ortho position warp, methylene radical, ethylidene or vinylidene, oxygen or sulphur atom or SO 2-, NH or N (C 1-C 4Alkyl) interconnection;
Contain five yuan of hetero-aromatic rings of 1 or 2 nitrogen-atoms and/or sulphur or Sauerstoffatom, it has 1～2 halogen atom and/or 1～2 following groups: C 1-C 4Alkyl, C 1-C 4Alkoxyl group, phenyl itself can have 1～3 halogen atom and/or 1～3 following groups: C 1-C 4Alkyl, C 1-C 4Alkoxyl group or C 1-C 4The alkyl sulfenyl;
Or C 3-C 7Cycloalkyl;
R 6Be C 1-C 8Alkyl, C 3-C 6Alkenyl, C 3-C 6Alkynyl or C 3-C 8Cycloalkyl, wherein these groups can be replaced by the following groups list or be polysubstituted: halogen, hydroxyl, cyano group, C 1-C 4Alkoxyl group, C 3-C 6Alkenyloxy, C 3-C 6Alkynyloxy group, C 1-C 4Alkyl sulfenyl, C 1-C 4Halogenated alkoxy, C 1-C 4Alkyl-carbonyl, hydroxycarbonyl group, C 1-C 4Alkoxy carbonyl, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2, phenoxy group or phenyl, but wherein above-mentioned aryl coverlet or polysubstituted, for example 1～3 replaces, substituting group is halogen, C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, R 12, C 1-C 4Alkoxy carbonyl, dioxo methylene radical, dioxo ethylidene, C 1-C 4Alkyl sulfenyl, phenyl or phenoxy group;
Can be by the phenyl or naphthyl that one or more following groups replaced: halogen, nitro, cyano group, hydroxyl, amino, C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, phenoxy group, C 1-C 4Alkyl sulfenyl, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2
Contain five yuan or six-membered Hetero-aromatic of 1～3 nitrogen-atoms and/or sulphur or Sauerstoffatom, it can have 1～4 halogen atom and/or 1～2 following groups: C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, C 1-C 4Alkyl sulfenyl, phenyl, phenoxy group or phenylcarbonyl group.Wherein phenyl itself can have 1～5 halogen atom and/or 1～3 following groups: C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy and/or C 1-C 4The alkyl sulfenyl;
R 12Be C 1-C 4Alkyl, C 1-C 4Alkoxyl group, it has a following groups: hydroxyl, methane amide or CON (C 1-C 4Alkyl) 2
Z is sulphur, oxygen or singly-bound.
The special compound of preferred substituents shown in the formula I of giving a definition, it can be pure enantiomorph or pure diastereomer or its mixture.
R 2Be C 1-C 4Alkyl, C 1-C 4Alkoxyl group, particularly methyl, ethyl, methoxyl group, oxyethyl group, difluoro-methoxy, trifluoromethoxy;
X is fluorine, trifluoromethyl;
R 3Be C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Alkyl sulfenyl, particularly methyl, ethyl, methoxyl group, oxyethyl group, difluoro-methoxy, trifluoromethoxy;
R 4And R 5(identical or different) is can be by one or more, for example 1～3, and the phenyl that following groups replaced: halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4The alkyl sulfenyl or
R 4And R 5For at the ortho position through directly key, methylene radical, ethylidene or vinylidene, oxygen or sulphur atom or SO 2-, NH or N (C 1-C 4Alkyl) interconnected phenyl; Or
Thiazole, oxazole, thiophene or furans, wherein above-mentioned hetero-aromatic ring can be by halogen, C 1-C 4Alkyl, C 1-C 4The alkoxyl group list replaces or two replacements;
R 4And R 5Be cyclohexyl;
R 6Be C 1-C 8Alkyl, C 3-C 6Alkenyl or C 3-C 8Cycloalkyl, wherein these groups can be replaced by the following groups list or be polysubstituted: halogen, hydroxyl, cyano group, C 1-C 4Alkoxyl group, C 3-C 6Alkenyloxy, C 1-C 4Alkyl sulfenyl, phenoxy group or phenyl, but wherein above-mentioned aryl coverlet or polysubstituted, for example 1～3 replaces, and substituting group is C 1-C 4Alkyl, C 1-C 4Alkoxyl group, dioxo methylene radical, dioxo ethylidene, C 1-C 4The alkyl sulfenyl;
The phenyl or naphthyl that can be replaced by one or more following groups: halogen, nitro, cyano group, hydroxyl, amino, C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, phenoxy group, C 1-C 4Alkyl sulfenyl, C 1-C 4Alkylamino or C 1-C 4Dialkyl amido;
Contain five yuan or six-membered Hetero-aromatic of a nitrogen-atoms and/or sulphur or Sauerstoffatom, it can have 1～4 halogen atom and/or 1～2 following groups: C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Alkyl sulfenyl, phenyl, phenoxy group or phenylcarbonyl group, wherein phenyl itself can have 1～5 halogen atom and/or 1～3 following groups: C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group and/or C 1-C 4The alkyl sulfenyl;
Y is sulphur, oxygen or singly-bound.
Compound of the present invention provides a kind of novel medical potentiality, can be used for treating hypertension, pulmonary hypertension, myocardial infarction, stenocardia, irregular pulse, acute/chronic renal failure, chronic cardiac insufficiency, renal insufficiency, cerebral vasospasm, cerebrum ischemia, the film bleed bottom, migraine, asthma, atherosis, endotoxin shock, the function depletion that intracellular toxin causes, IC, vascular restenosis after angioplasty and the bypass, benign prostatauxe, hypertension that local asphyxia or poisoning cause or renal failure, the transfer of mesenchymoma and growth, the renal failure that contrast medium causes, pancreatitis, intestine gastric ulcer and erection problem.
The invention further relates to the combination of the inhibitor of endothelium peptide receptor antagonists shown in the formula I and renin-angiotensin system.The inhibitor of renin-angiotensin system is renin inhibitor, angiotensin and angiotensin-converting enzyme (ACE) inhibitor.The endothelium peptide receptor antagonists shown in the preferred formula I and the combination of ACE inhibitor.
In addition, the present invention relates to the endothelium peptide receptor antagonists shown in the formula I and the combination of Beta receptor blockers.
In addition, the present invention relates to the endothelium peptide receptor antagonists shown in the formula I and the combination of diuretic(s).
In addition, the present invention relates to the combination of the material of endothelium peptide receptor antagonists shown in the formula I and blocking VEGF (vascular endothelial growth factor) effect.This material for example directly suppresses the proteic antibody of VEGF or particular combination, perhaps can specifically suppress the low molecular weight substance of VEGF release or receptors bind.
Aforesaid combination can obey simultaneously into, or different time obey successively into.They can single medicine type or isolating dosage form take.Usage also can be different, and for example the endothelium peptide receptor antagonists can be oral, and the VEGF inhibitor is an administered parenterally.
These combination preparations are specially suitable for treatment and preventing hypertension and the disease that caused thereof, also are suitable for treating simultaneously cardiac insufficiency.
The high reactivity of The compounds of this invention can experimental results show that by following:
Receptors bind research clone's human body ET AOr ET BAcceptor-expression Chinese hamster ovary celI is used in conjunction with research.
Membrane prepare
ET AOr ET BAcceptor-expression Chinese hamster ovary celI is at DMEM NUT MIX F 12Growth (Gibco in the substratum, No.21331-020), contain 10% foetal calf serum (PAA laboratory GmbH in this substratum, Linz, No.A15-022), 1mM glutamine (Gibco No.25030-024), 100U/ml penicillin and 100 μ g/ml Streptomycin sulphates (Gibco, Sigma No.P-0781).After 48 hours, cell washs with PBS, and contains tryptic PBS 37 ℃ of cultivations 5 minutes with 0.05%.Mixture neutralizes with substratum then, and (collect with centrifugal by 300 * g) modes for cell.
Be the preparation film, it is 10 that cell dilution becomes concentration 8(the 50mMtris.HCl damping fluid pH7.4), decomposes 40-70 second/constant output 20 with the ultrasonic wave of Branson Sonifier 250 to the damping fluid of cell/ml then.
In conjunction with test
ET AAnd ET BIn the receptor binding assays, film is suspended in cultivates that (50mMTris-HCl damping fluid, pH7.4 contain 5mM MnCl in the damping fluid 2, 40mg/ml liver bacterium peptide and 0.2%BSA), its concentration is 50 μ g albumen/test mixing things, and at 25 ℃ and 25pM[ 125I] ET 1(ET AAcceptor is tested) or 25pM[ 125I] ET 3(ET BAcceptor test) cultivates being with or without under the situation of measured matter together.Non-specific binding is with 10 -7MET 1Measure.After 30 minutes, GF/B glass fibre filter in Skatron cell harvestor (Skatron, Lier, Norway) filters the filtrate of gained, obtain free and bonded radioligand by separating, filter pH is 7.4 the ice-cold Tris-HCl damping fluid washing that contains 0.2%BSA.The radioactivity that is collected in the filter is measured with Packard 2200 CA liquid phase scintillometer.
The endothelium peptide receptor antagonists is to the functionality test of blood vessel
Rabbit aorta slice initial tension is 2g, and relaxation is after 1 hour, with K in 37 ℃, the Krebs-Henseleit solution of pH7.3-7.4 +Cause and shrink.After cleaning, can draw to maximum endothelium peptide dosage-design sketch.
Before beginning to draw endothelium peptide dosage-design sketch 15 minutes, in other prepared product of same vascular specimen, add the potential endothelin antagonists.The effect of endothelium peptide is with K +The percentage of the contraction of-initiation recently calculates.Effectively endothelin antagonists makes endothelium peptide dosage-design sketch move to right-hand.
The in vivo test of ET antagonist:
Weight is that the male SD rat of 250～300g is anaesthetized with Amobarbital, and the artificial ventilation cuts off its vagus nerve and pith.Insert conduit at its carotid artery and jugular vein.
In control animal, intravenous injection 1 μ g/kg ET1 causes blood pressure obviously to rise, and keeps considerable time.
Tested animal the injection ET1 before 30 minutes, accept the tested compound of intravenous injection (1ml/kg).For measuring ET-antagonism, the blood pressure of contrast test animal and control animal.
Mix ET AAnd ET BThe oral test of antagonist:
Weight is normal male mouse (Sprague Dawley, Janvier) the oral in advance tested material of 250～350g.After 80 minutes, this animal is anaesthetized with urethane, and locates to insert conduit at carotid artery (mensuration blood pressure) and jugular vein (clothes are gone into big endothelium peptide/endothelium peptide 1).
After one period stationary phase, and the big endothelium peptide of intravenous injection (20 μ g/kg, Appl.Vol.0.5ml/kg) or ET1 (0.3 μ g/kg, Appl. Vol. 0.5ml/kg).Continuous blood pressure measuring and heart rate in 30 minutes.The significance of blood pressure and persistence change to be calculated with area under curve (AUC).For measuring the antagonism effectiveness of tested material, contrast AUC of the animal that this mass treatment crosses and the AUC of control animal.
Compound of the present invention can usual way oral or administered parenterally (subcutaneous, vein, intramuscular, intraperitoneal).Taking mode also can suck with gas or spray through the nasopharynx space.
Amount of application depends on patient's age, physical appearance and body weight and takes mode.The per daily dose of active substance is: oral is about 0.5～50mg/kg body weight, and administered parenterally is about 0.1～10mg/kg body weight.
This novel cpd can be traditional solid or liquid, medicinal form use for example not dressing or coated tablet, capsule, pulvis, granula, suppository, solution, ointment, emulsifiable paste or spray.These are all with ordinary method production.The active substance that is used for this purpose can be processed with traditional pharmaceutical adjuvant, such as tablet binder, weighting agent, sanitas, tablet with disintegrating agent, flowing regulator, softening agent, wetting agent, dispersion agent, emulsifying agent, solvent, sustained release dosage, oxidation inhibitor and/or impelling gas (referring to H.Sucker et al.:PharmazeutischeTechnologie, Thieme-Verlag, the Stuttgart, 1991).The formulation that this method obtains contains the active substance of 0.1～90% weight usually.
Synthetic embodiment
Embodiment 1:
2-(4,6-dimethoxy-5-fluorine pyrimidine-2-yloxy)-3-methoxyl group-3,3-diphenyl-propionic acid methyl esters
With 1. 0g (3.5mmol) 2-hydroxyl-3-methoxyl group-3,3-diphenyl-propionic acid methyl esters is dissolved among the DMF, drops to 0.18gNaH (4.2mmol, 55% in slab oil) in the suspension of 10mlDMF.Stirred the mixture under the room temperature 30 minutes, and sneaked into 4 of 830mg (4.8mmol) among the 10ml DMF then, 6-dimethoxy-5-fluoro-2-methanesulfonyl pyrimidine stirred 2 hours under the room temperature.Reaction mixture is inclined to ice-waterborne, and with extracted with diethyl ether three times.Ether removes down in decompression then and desolvates through the dried over mgso after-filtration.Brown resistates (1. 7g) obtains the required product of 1.3g through the MPLC purifying, and it can directly further react.
Embodiment 2:
2-(4,6-dimethoxy-5-fluorine pyrimidine-2-yloxy)-3-methoxyl group-3,3-diphenyl-propionic acid (A) and 2-(4-methoxyl group-5-fluoro-6-hydroxy pyrimidine-2-base oxygen base)-3-methoxyl group-3,3-diphenyl-propionic acid (B)
With 1.3g (2.9mmol) 2-(4,6-dimethoxy-5-fluorine pyrimidine-2-yloxy)-3-methoxyl group-3,3-diphenyl-propionic acid methyl esters is dissolved in the 10ml diox, and sneaks into the 1NKOH solution of 5.9ml.Mixture stirred 4 hours under refluxing.After adding entry, water ether extracting twice.With the ether extraction, distill to remove after dried over mgso and desolvate by organic phase behind 1N HCl acidified aqueous solution for water.Residual collection is in ether, and crystallization obtains the 100mg product B.Mother liquor obtains 400mg solid product A after sneaking into normal hexane.
A： 1H-NMR(CDCl 3，500MHz)：7．2-7．45(m，10H)；6．05(s，1H)；3．95(s，6H)；3．3(s，3H)
m．p．：168～170℃
B： 1H-NMR(DMSO，250MHz)：7．1-7．4(m，10H)；6．05(s，1H)；3．9(s，3H)；3．3(s，3H)
m．p．：115～117℃
Embodiment 3:
2-(4-morpholino-5-fluorine pyrimidine-2-yloxy)-3-methoxyl group-3,3-diphenylprop acid benzyl ester
With 3.3g (9mmol) 2-hydroxyl-3-methoxyl group-3,3-diphenylprop acid benzyl ester and 4-morpholino-5-fluoro-2-chloropyrimide is dissolved among the DMF, drops to 9.96g K 2CO 3(72mmol) in the suspension in 40ml DMF.Mixture stirred 3 hours at 90 ℃ earlier, stirred 3 hours at 130 ℃ subsequently.Reaction mixture is inclined to ice-waterborne, and with ethyl acetate extraction three times.Ester removes down in decompression then and desolvates with dried over mgso and filtration.Brown resistates (5.72g) can directly further react through the MPLC purifying.
Embodiment 4:
2-(4-morpholino-5-fluorine pyrimidine-2-yloxy)-3-methoxyl group-3, the 3-diphenyl-propionic acid
By the palladium on the 300mg activated carbon (10%), with 0.9g2-(4-morpholino-5-fluorine pyrimidine-2-yloxy)-3-methoxyl group-3, the solution of 3-diphenylprop acid benzyl ester in the 30ml ethyl acetate under room temperature, normal pressure with hydrogen hydrogenation 3 hours.Reaction mixture after filtration, concentrate after, gained resistates (900mg) is with the MPLC purifying.
1H?NMR(CDCl 3，500MHz)：8．95(d，1H)；7．2-7．5(m，10H)；6．05(s，1H)；3．8(s，8H)；3．3(s，3H)
m．p．：174～175℃
The compound that the table I is listed can prepare in the same way.
The table I
Figure 9980303700231
Figure 9980303700241
Figure 9980303700251
Figure 9980303700271
Figure 9980303700281
The table II
Figure 9980303700291
Embodiment 5:
Adopt above-mentioned combination test, following compounds has been measured its receptors bind data.
The result compiles in table 3.
Table 3
Receptors bind data (K iValue)
Compound ET A[nM] ET B[nM]
I-2 7．4 1200
I-121 61 ＞10000
I-168 4000 ＞7000

Claims (8)

1. the carboxylic acid derivative shown in the formula I
Wherein:
R 1Be the group shown in tetrazolium or the following formula
R is:
A) group OR 7, R wherein 7For
Hydrogen, alkali metal cation, alkaline earth metal cation, physiology capacitive organic ammonium ion or ammonium ion;
C 3-C 8Cycloalkyl, C 1-C 8Alkyl, CH 2-phenyl, it can be replaced by one or more following groups: halogen, nitro, cyano group, C 1-C 4Alkyl, C 1-C 4Haloalkyl, hydroxyl, C 1-C 4Alkoxyl group, sulfydryl, C 1-C 4Alkyl sulfenyl, amino, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2
C 3-C 6Alkenyl or C 3-C 6Alkynyl, these groups itself can have 1～5 halogen atom;
In addition, R 7Can be phenyl, it can have 1～5 halogen atom and/or 1～3 following groups: nitro, cyano group, C 1-C 4Alkyl, C 1-C 4Haloalkyl, hydroxyl, C 1-C 4Alkoxyl group, sulfydryl, C 1-C 4Alkyl sulfenyl, amino, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2
B) the five yuan of hetero-aromatic rings that connect by nitrogen-atoms such as pyrryl, pyrazolyl, imidazolyl and triazolyl, and this aromatic ring can have 1～2 halogen atom, 1～2 C 1-C 4Alkyl or 1～2 C 1-C 4Alkoxyl group;
C) group shown in the following formula
Figure 9980303700031
Wherein k can be 0,1 or 2, and p can be 1,2,3 or 4, and
R 8Be C 1-C 4Alkyl, C 3-C 8Cycloalkyl, C 3-C 6Alkenyl, C 3-C 6Alkynyl or phenyl, they can be by one or more, and for example 1～3 following groups replaces:
Halogen, nitro, cyano group, C 1-C 4Alkyl, C 1-C 4Haloalkyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkyl sulfenyl, sulfydryl, amino, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2
D) group shown in the following formula
Figure 9980303700032
R wherein 9For:
C 1-C 4Alkyl, C 3-C 6Alkenyl, C 3-C 6Alkynyl, C 3-C 8Cycloalkyl, wherein these groups can have a C 1-C 4Alkoxyl group, C 1-C 4Alkyl sulfenyl and/or a c) in mentioned phenyl;
Can be by 1～3 phenyl that following groups replaced:
Halogen, nitro, cyano group, C 1-C 4Alkyl, C 1-C 4Haloalkyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkyl sulfenyl, sulfydryl, amino, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2,
R 2Be hydrogen, hydroxyl, NH 2, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl, C 1-C 4Hydroxyalkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy or C 1-C 4Alkyl sulfenyl, morpholine;
X is halogen, C 1-C 4Haloalkyl, hydroxyl;
R 3Be hydrogen, hydroxyl, NH 2, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl, C 1-C 4Hydroxyalkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy ,-NH-O-C 1-C 4Alkyl, C 1-C 4The alkyl sulfenyl;
R 4And R 5(can be identical or different) be:
Can be by the phenyl or naphthyl that one or more following groups replaced: halogen, nitro, cyano group, hydroxyl, C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, phenoxy group, sulfydryl, alkyl-carbonyl, alkoxy carbonyl, C 1-C 4Alkyl sulfenyl, amino, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2Or
Phenyl or naphthyl, its at the ortho position by direct key, methylene radical, ethylidene or vinylidene, oxygen or sulphur atom or SO 2-, NH-or N-alkyl interconnect; Or
Contain five yuan or six-membered Hetero-aromatic of 1～3 nitrogen-atoms and/or sulphur or Sauerstoffatom, it can have 1～4 halogen atom and/or 1～2 following groups: C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, C 1-C 4Alkyl sulfenyl, phenyl, phenoxy group or phenylcarbonyl group, wherein phenyl itself can have 1～5 halogen atom and/or 1～3 following groups: C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy and/or C 1-C 4The alkyl sulfenyl;
Or C 3-C 7Cycloalkyl;
R 6For hydrogen,
C 1-C 8Alkyl, C 3-C 6Alkenyl, C 3-C 6Alkynyl or C 3-C 8Cycloalkyl, wherein these groups can be replaced by the following groups list or be polysubstituted: hydroxyl, sulfydryl, carboxyl, halogen, nitro, cyano group, C 1-C 4Alkoxyl group, C 3-C 6Alkenyloxy, C 3-C 6Alkynyloxy group, C 1-C 4Alkyl sulfenyl, C 1-C 4Halogenated alkoxy, C 1-C 4Alkyl-carbonyl, C 1-C 4Alkoxy carbonyl, C 3-C 8Alkyl-carbonyl alkyl, amino, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2But, coverlet or polysubstituted phenyl, for example by halogen, nitro, cyano group, C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy or C 1-C 4Phenyl or phenoxy group that alkyl sulfenyl 1～3 replaces;
Separately can be by the phenyl or naphthyl that one or more following groups replaced: halogen, nitro, cyano group, hydroxyl, amino, C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, phenoxy group, C 1-C 4Alkyl sulfenyl, NH (C 1-C 4Alkyl), N (C 1-C 4Alkyl) 2Or dioxo methylene radical or dioxo ethylidene;
Contain five yuan or six-membered Hetero-aromatic of 1～3 nitrogen-atoms and/or sulphur or Sauerstoffatom, it can have 1～4 halogen atom and/or 1～2 following groups: C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, C 1-C 4Alkyl sulfenyl, phenyl, phenoxy group or phenylcarbonyl group, wherein phenyl itself can have 1～5 halogen atom and/or 1～3 following groups: C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy and/or C 1-C 4The alkyl sulfenyl;
Condition is when the non-singly-bound of Z, R 6Can only be hydrogen;
Z is sulphur, oxygen or singly-bound,
With and physiology on admissible salt and the pure form of the pure and non-mapping of mapping.
2. the described carboxylic acid derivative I of claim 1 is in the purposes of treatment in the disease.
3. the described chemical compounds I of claim 1 is as the purposes of endothelium peptide receptor antagonists.
4. the described carboxylic acid derivative I of claim 1 is used to prepare the purposes of treatment and the medicine of endothelium peptide level rising diseases associated.
5. the described carboxylic acid derivative I of claim 1 is used to prepare the purposes of treatment by the medicine of the disease of endothelium peptide control development and/or progress.
6. the described carboxylic acid derivative I of claim 1 is used for the treatment of the purposes of chronic cardiac insufficiency, restenosis, hypertension, pulmonary hypertension, acute/chronic renal insufficiency, brain ischemic, asthma, benign prostatauxe and prostate cancer.
7. the combination of the described carboxylic acid derivative I of claim 1 and one or more active compounds, wherein said active compound are selected from inhibitor, mixing ACE/ neutral endopeptidase (NEP) inhibitor, beta blocker, diuretic(s), calcium antagonist and the VEGF-blocking-up material of the renin-angiotensin system such as renin inhibitor, angiotensin, angiotensin-converting enzyme (ACE) inhibitor.
8. for the pharmaceutical preparation of administration in oral, administered parenterally and the stomach, it removes to contain and uses always the medicament assistant agent in each dosage, also comprises the described carboxylic acid derivative I of at least a claim 1.
CN99803037A 1998-02-17 1999-02-05 5-substituted pyrimidine-2-yloxy carboxylic acid derivatives, the production of the same and their utilization as endothelin antagonist Pending CN1291190A (en)

Applications Claiming Priority (2)

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DE19806438A DE19806438A1 (en) 1998-02-17 1998-02-17 New pyrimidinyloxy-propionic acid derivatives useful as endothelin receptor antagonists in treatment of e.g. cardiac insufficiency, restenosis, hypertension, kidney failure, asthma and prostate cancer
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DE19924892A1 (en) * 1999-06-01 2000-12-07 Basf Ag New carboxylic acid derivatives with aryl-substituted nitrogen heterocycles, their production and use as endothelin receptor antagonists
US8217155B2 (en) 2007-07-31 2012-07-10 Gilead Colorado, Inc. Metabolites and derivatives of ambrisentan
ES2549379T3 (en) 2008-01-22 2015-10-27 Dow Agrosciences Llc 4-amino5-fluoropyrimidine derivatives as fungicides
CA2731332A1 (en) * 2008-08-01 2010-04-29 Zoltan L. Benko Use of 5-fluorocytosine as a fungicide

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