CN1367778A - Novel carboxylic acid derivatives with 5,6 substitutedpyrimidine ring, their production and utilization thereof as endothelin receptor antagonists - Google Patents

Novel carboxylic acid derivatives with 5,6 substitutedpyrimidine ring, their production and utilization thereof as endothelin receptor antagonists Download PDF

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CN1367778A
CN1367778A CN00810533A CN00810533A CN1367778A CN 1367778 A CN1367778 A CN 1367778A CN 00810533 A CN00810533 A CN 00810533A CN 00810533 A CN00810533 A CN 00810533A CN 1367778 A CN1367778 A CN 1367778A
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W·安伯格
G·科特斯乔
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Abstract

The invention relates to compounds of formula (I), whereby the substituents have the meaning cited in the description. The invention also relates to the utilization of said derivatives.

Description

Novel carboxylic acid derivative, its preparation method and as the purposes of endothelin receptor antagonists with 5,6 substituted pyrimidines rings
The present invention relates to novel carboxylic acid derivative, Preparation Method And The Use.
Endothelin is a kind of peptide that is made up by 21 amino acid, and it is synthetic and release by blood vessel endothelium.Endothelin exists with three kinds of obform body forms, i.e. ET-1, ET-2 and ET-3.Below " endothelin " or " ET " be a kind of or whole obform body of endothelin.Endothelin is a kind of effective vasoconstrictor and antiotasis is had potent.Well-known vasoconstriction is that the combination by endothelin on its acceptor causes (Nature, 332,411-415,1988; FEBS Letters, 231,440-444,1988 and Biochem.Biophys.Res.Commun., 154,868-875,1988).
Interior plain skin increases or unusual release causes successive vasoconstriction in tip, kidney and the cerebral blood vessel, and this can be diseases induced.As what report in the document, endothelin has been brought a series of disease.To this, what can mention is: hypertension, Acute Myocardial Infarction, pulsation hypertension, hemiplegia alternans abducens, cerebri cerebral vasospasm, apoplexy, benign prostatauxe, atherosclerosis, asthma and prostate cancer (J.Vascular Med.Biology2,207 (1990), J.Ami.Med.Association 264,2868 (1990), Nature344,114 (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), and NatureMedicine 1,944, (1995)).
So far, at least two kinds of endothelin receptor hypotypes, i.e. ET have been described in the document A-acceptor and ET B-acceptor (Nature348,730 (1990), Nature 348,732 (1990)).Therefore, suppressing endothelin is combined on the acceptor or the material on two acceptors should have antagonistic action to the physiological effect of endothelin and therefore prepare of great value medicine.
The preparation of endothelin receptor antagonists and application have been disclosed among WO95/26716, WO96/11914, WO97/09294, WO97/12878, WO97/38980, WO97/38981, WO97/38982, WO98/09953, WO98/27070, DEl9726146.9, DEl9748238.4, DEl9750529.5, DEl9806438.1, DEl9809144.3 and the DEl9836044.4.The same compounds of group that further evidence has 5,6 substituted pyrimidines rings has favourable characteristic aspect receptor affinity and the receptors bind spectrum.Preparation Method And The Use is the theme of patent specification.
Theme of the present invention is the carboxylic acid derivative of formula I
Figure A0081053300071
In the formula: R 1Represent tetrazyl or group
Figure A0081053300072
R wherein has following definition:
A) group OR 7, R wherein 7Representative:
Hydrogen, alkali metal cation, alkaline earth metal cation, the acceptable organic ammonium ion of physiology be uncle C for example 1-4-alkylammonium or ammonium ion;
C 3-8-cycloalkyl, C 1-8Alkyl, CH 2-phenyl, they can be replaced by one or more following groups: halogen, nitro, cyano group, C 1-4-alkyl, C 1-4-haloalkyl, hydroxyl, C 1-4-alkoxyl group, sulfydryl, C 1-4-alkyl sulfide, amino, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2
C 3-6-alkenyl-or C 3-6-alkynyl wherein can have 1-5 halogen atom on this group;
In addition, R 7Can be phenyl, can have 1-5 halogen atom and/or 1-3 following groups on it: nitro, cyano group, C 1-4-alkyl, C 1-4-haloalkyl, hydroxyl, C 1-4-alkoxyl group, sulfydryl, C 1-4-alkyl sulfide, amino, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2
B) 5 yuan of heteroaromaticss that connect by a nitrogen-atoms, for example pyrryl, pyrazolyl, imidazolyl and triazolyl can have 1-2 halogen atom on it, or 1-2 C 1-4A-alkyl or 1-2 C 1-4-alkoxyl group;
C) group
Figure A0081053300073
Wherein k represents 0,1 and 2 numerical value, and p represents 1,2,3 and 4 numerical value and R 8Represent C 1-4-alkyl, C 3-8-cycloalkyl, C 3-6-alkenyl, C 3-6-alkynyl group or phenyl, it can be replaced by one or more for example 1-3 following groups;
Halogen, nitro, cyano group, C 1-4-alkyl, C 1-4-haloalkyl, hydroxyl, C 1-4-alkoxyl group, C 1-4-alkyl sulfide, sulfydryl, amino, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2
D) group
Figure A0081053300081
R wherein 8Representative:
C 1-4-alkyl, C 3-6-alkenyl, C 3-6-alkynyl, C 3-8-cycloalkyl, wherein this group can have C 1-4-alkoxyl group-, C 1-4-alkyl sulfide-and/or phenyl is as c) in listed;
Phenyl can be replaced by 1-3 following groups: halogen, nitro, cyano group, C 1-4-alkyl, C 1-4-haloalkyl, hydroxyl, C 1-4-alkoxyl group, C 1-4-alkyl sulfide, sulfydryl, amino, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2
Remaining substituting group has following definition:
R 2Representation hydroxy, NH 2, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2, C 1-4-alkyl, C 2-4-alkenyl, C 2-4-alkynyl, C 1-4-hydroxyalkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy or C 1-4-alkyl sulfide, or CR 2With CR 3Form 5 yuan or 6 yuan of alkylene basic rings or alkylene group ring together, this ring can be by one or two C 1-4-alkyl replace and one or more methylene radical respectively can by oxygen, sulphur ,-NH or-N (C 1-4-alkyl) replaces.
R 3Representation hydroxy, NH 2, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2, halogen, C 1-4-alkyl, C 2-4-alkenyl, C 2-4-alkynyl, C 3-6-alkenyloxy, C 1-4-alkyl-carbonyl, C 1-4-alkoxy carbonyl, C 1-4-hydroxyalkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy ,-NH-O-C 1-4-alkyl, C 1-4-alkyl sulfide, or CR 3As R 2Shown the same and CR 2Form 5 yuan or 6 yuan of rings together
R 4And R 5(can be identical or different) representative:
Phenyl or naphthyl, this group can be replaced by one or more following groups: halogen, nitro, cyano group, hydroxyl, C 1-4Alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy, phenoxy group, C 1-4-alkyl sulfide, amino, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2Or
Phenyl or naphthyl, this group pass through Direct Bonding, methylene radical, ethylidene or vinylidene, oxygen or sulphur atom or SO at the ortho position 2-, NH-or N-alkyl be connected to each other;
Or C 3-7-cycloalkyl;
R 6Represent hydrogen.
C 1-8-alkyl, C 3-6-alkenyl, C 3-6-alkynyl or C 3-6-cycloalkyl, wherein this group can be replaced by the following groups one or many respectively: hydroxyl, sulfydryl, carboxyl, halogen, nitro, cyano group, C 1-4-alkoxyl group, C 3-6-alkenyloxy, C 3-6-alkynyloxy group, C 1-4-alkyl sulfide, C 1-4-halogenated alkoxy, C 1-4-alkyl-carbonyl, C 1-4-alkoxy carbonyl, (C 1-4-alkyl) NH carbonyl, (C 1-4Alkyl) 2N carbonyl, C 3-8-alkyl-carbonyl alkyl, amino, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2, phenoxy group or phenyl, wherein said aryl can be replaced by one or many, for example by halogen, nitro, cyano group, C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy, sulfydryl, carboxyl, hydroxyl, amino, R 10, C 1-4-alkoxy carbonyl, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2, dioxy methylene radical, dioxy ethylidene, C 1-4-alkyl sulfide replaces the phenyl or the phenoxy group of one or many;
Phenyl or naphthyl, this group can be replaced by one or more following groups: halogen, nitro, chloro, hydroxyl, amino, C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy, phenoxy group, C 1-4-alkyl sulfide, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2Or dioxy methylene radical or dioxy ethylidene;
5 or 6 yuan heteroaromatics contains 1-3 nitrogen-atoms and/or sulphur or Sauerstoffatom, and they can have 1-4 halogen atom and/or 1-2 following groups: C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy, C 1-4-alkyl sulfide, phenyl, phenoxy group or phenylcarbonyl group, wherein phenyl can have 1-5 halogen atom and/or 1-3 following groups: C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy and/or C 1-4-alkyl sulfide;
R 10Represent C 1-4-alkyl, C 1-4-alkyl sulfide, C 1-4-alkoxyl group, this group can have arbitrary group of following groups: hydroxyl, carboxyl, amino, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2, Carboxylamide or CON (C 1-4-alkyl) 2
Z represents sulphur or oxygen.
Be suitable for following definitions in this case with under other situations:
Basic metal for example is lithium, sodium, potassium;
Alkaline-earth metal for example is calcium, magnesium, barium;
The organic ammonium ion is a protonated amines, for example thanomin, diethanolamine, quadrol, diethylamine or piperazine;
C 3-7-cycloalkyl for example is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl;
C 1-4-haloalkyl can be a straight or branched, for example fluoro methyl, difluoromethyl, trifluoromethyl, chlorodifluoramethyl-, dichlorofluoromethyl, 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 1-4-halogenated alkoxy can be a straight or branched, for example difluoro-methoxy, trifluoromethoxy, chlorine difluoro-methoxy, 1-fluoro-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 1-4-alkyl can be a straight or branched, for example 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 2-4-alkenyl can be a straight or branched, for example vinyl, 1-propylene-3-base, 1-propylene-2-base, 1-propylene-1-base, 2-methyl isophthalic acid-propenyl, 1-butylene base or crotyl;
C 2-4-alkynyl can be a straight or branched, for example ethynyl, 1-propine-1 base, 1-propine-3-base, ethyl acetylene-4-base or 2-butyne-4-base;
C 1-4-alkoxyl group can be a straight or branched, for example methoxyl group, oxyethyl group, propoxy-, 1-methyl ethoxy, butoxy, 1-methyl propoxy-, 2-methyl propoxy-or 1,1-dimethyl oxyethyl group;
C 3-6-alkenyloxy can be a straight or branched, for example allyloxy, 2-butylene-1 oxygen base or 3-butene-2-oxygen base;
C 3-6-alkynyloxy group can be a straight or branched, for example 2-propine-1-base oxygen base, 2-butyne-1-base oxygen base or 3-crotonylene-Ji oxygen base;
C 1-4-alkyl sulfide can be a straight or branched, for example methyl sulphur, ethyl sulphur, propylthio, 1-methylethyl sulphur, butyl sulphur, 1-methyl-propyl sulphur, 2-methyl-propyl sulphur or 1,1-dimethyl ethyl sulphur;
C 1-4-alkyl-carbonyl can be a straight or branched, for example ethanoyl, ethyl carbonyl or 2-propyl group carbonyl;
C 1-4-alkoxy carbonyl can be a straight or branched, for example methoxycarbonyl, ethoxy carbonyl, just-propoxycarbonyl, different-propoxycarbonyl or just-butoxy carbonyl;
C 3-8-alkyl-carbonyl alkyl can be a straight or branched, for example 2-oxygen-third-1-base, 3-oxygen-Ding-1-base or 3-oxygen-Ding-2-base;
C 1-8-alkyl can be straight or branched, for example C 1-4-alkyl, amyl group, hexyl, heptyl or octyl group; Halogen for example is fluorine, chlorine, bromine, iodine.
Other themes of the present invention are such compounds, can be discharged the compound (so-called prodrug) of formula I by this compound.
This prodrug is preferred, wherein this prodrug as them at some body part, for example stomach, intestines, blood circulation, the residing certain condition of liver release down.
This compound and be used to prepare its intermediate product, for example formula II and IV can have the carbon atom of one or more asymmetric replacements.This compound can exist with the form of pure enantiomer or pure diastereomer or its mixture.The compound that preferably uses enantiomeric pure is as active substance.
Theme of the present invention comprises that also above-mentioned carboxylic acid derivative prepares the purposes of medicine, especially prepares the inhibitor that endothelin receptor is used.
Preparation with compound of general formula I V can be undertaken by the description of WO96/11914, and wherein Z represents sulphur or oxygen.
Figure A0081053300111
The compound of general formula III is known, or can be for example synthetic by the reduction of corresponding carboxylic acid or its ester, or synthetic by other common known methods.
The formula IV compound of enantiomeric pure form can obtain by acid catalyzed etherification reaction again, as describing among the WO98/09953.
In addition, can adopt the alkali of suitable enantiomeric pure to carry out the compound that conventional racemize cracking obtains the enantiomeric pure of formula IV by adopting the formula IV compound of racemize and/or diastereomer.Suitable alkali for example is the alkali of enumerating among 4-chloro-phenyl-ethamine and the WO96/11914.
Compound of the present invention, wherein substituting group has the implication described in the general formula I, and for example can be by the preparation of following method: make the carboxylic acid derivative of general formula I V, wherein substituting group has described implication, reacts with the compound of general formula V.
Figure A0081053300112
Among the formula V, R 11Represent halogen or R 12-SO 2-, R wherein 12Can be C 1-4-alkyl, C 1-4-haloalkyl or phenyl.Reaction preferred in a kind of inert solvent or thinner adding a kind of suitable alkali, promptly cause in the alkali of intermediate product IV deprotonation, carry out to the temperature of solvent boiling point in room temperature.
If R 1Be a kind of ester, R so 1The compound of=COOH can be by acid, alkali or the catalytic pyrolysis preparation of ester group.
In addition, when with the suitable alkali deprotonation intermediate product IV of 2 equivalents (R wherein 1Represent COOH) and when reacting, just can directly obtain R with the compound of general formula V IThe I type compound of=COOH.Here, reaction also can be carried out to the temperature of solvent boiling point in room temperature in a kind of inert solvent.
The example of this solvent or thinner is aliphatic, alicyclic and aromatic hydrocarbons, this hydrocarbon can be distinguished chlorination where necessary, for example hexane, hexanaphthene, sherwood oil, volatile oil, benzene, toluene, xylol, methylene dichloride, chloroform, tetracol phenixin, ethyl chloride and trieline, ether, for example diisopropyl ether, dibutyl ether, methyl-uncle-butyl ether, propylene oxide, dioxan and tetrahydrofuran (THF), nitrile, for example acetonitrile and propionitrile, acid amides, for example dimethyl formamide, N,N-DIMETHYLACETAMIDE and N-Methyl pyrrolidone, sulfoxide and sulfone, for example dimethyl sulfoxide (DMSO) and tetramethylene sulfone.
The compound of formula V is known, and sometimes can buy maybe can be by common known method preparation.
Operable alkali is alkalimetal hydride or alkaline earth metal hydride, for example sodium hydride, potassium hydride KH or hydrolith, carbonate, alkaline carbonate for example, for example yellow soda ash or salt of wormwood, alkali metal hydroxide or alkaline earth metal hydroxides, for example sodium hydroxide or potassium hydroxide, organometallics, for example butyllithium or alkali amide, for example two different phenyl amino lithiums.
The compound of formula I also can be by the preparation of following method: adopt corresponding carboxylic acid, i.e. R wherein 1The formula I compound of representing COOH is a raw material, is converted into activated form for example acyl halide, acid anhydride or imidazoles at first according to a conventional method, makes itself and corresponding oxy-compound HOR then 7Reaction.This reaction can be carried out in common solvent and usually need to add a kind of alkali.For example triethylamine, pyridine, imidazoles or diazabicylo undecane.This two step for example also can simplify in the following manner, promptly in the presence of such as carbodiimide class dewatering agent carboxylic acid is had an effect to oxy-compound.
In addition, the compound of formula I also can prepare by following method: adopt the salt of corresponding carboxylic acid, i.e. R 1The formula I compound of representing the COOM group is a raw material, and wherein M can be the equivalent of a kind of alkali metal cation or alkaline earth metal cation.Make this salt and formula R 7Numerous compounds of-A react; wherein A represents common nucleofuge leavings group; halogen for example is as chlorine, bromine, iodine or the aryl or the alkyl sulphonyl that are replaced by halogen, alkyl or haloalkyl in case of necessity, for example tosyl group and methyl sulphonyl or other suitable leavings groups.Formula R with reactive substituents A 7-A compound is known or is easy to obtain by general expertise.This reaction can be carried out in common solvent and preferably carry out under the situation of adding a kind of alkali, wherein adopts the above-mentioned alkali of mentioning.
In some cases, in order to prepare Compound I of the present invention, in general need to adopt is known blocking group technology.For instance, if R 6=4-hydroxy phenyl, oh group at first can be subjected to the protection of dibenzyl ether so, cleavedly in reaction process in proper step then falls.
R wherein 1Represent the formula I compound of tetrazyl to prepare by the method that WO96/11914 describes.
Consider biological action, the carboxylic acid derivative of general formula I is preferred, both can be pure enantiomer or diastereomeric form, or their mixture, and wherein substituting group has following implication:
R 2Representation hydroxy, N (C 1-4-alkyl) 2, C 1-4-alkyl-, C 1-4-haloalkyl-, C 1-4-alkoxyl group-, C 1-4-halogenated alkoxy-, C 1-4-alkyl sulfide or CR 2With CR 3Form 5 yuan or 6 yuan of alkylene basic rings or alkylene group ring together, they can be by one or two C 1-4-alkyl group replaces, and wherein one or more methylene groups can by oxygen, sulphur ,-NH or-N (C 1-4-alkyl) replaces;
R 3Representation hydroxy, N (C 1-4Alkyl) 2, C 1-4-alkyl-, C 1-4-haloalkyl-, C 1-4-alkoxyl group-, C 1-4-halogenated alkoxy-, C 1-4-alkyl sulfide or CR 3As R 2Shown the same and CR 3Form 5 yuan or 6 yuan of rings together;
R 4And R 5Represent phenyl or naphthyl, this group can be replaced by one or more for example 1-3 following groups: halogen, cyano group, hydroxyl, sulfydryl, amino, C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy, C 1-4-alkyl sulfide, NH (C 1-4-alkyl) 2, N (C 1-4-alkyl) 2, C 1-4-alkyl-carbonyl, C 1-4-alkoxy carbonyl;
Phenyl or naphthyl, this group pass through Direct Bonding, methylene radical, ethylidene or vinylidene, oxygen or sulphur atom or SO at the ortho position 2-, NH-or N (C 1-4-alkyl) group is connected to each other;
Or C 3-7-cycloalkyl;
R 6Represent C 1-8-alkyl, C 3-6-alkenyl, C 3-6-alkynyl or C 3-8-cycloalkyl, wherein this group can be replaced by the following groups one or many respectively: halogen, hydroxyl, cyano group, C 1-4-alkoxyl group, C 3-6-alkenyloxy, C 3-6-alkynyloxy group, C 1-4-alkyl sulfide, C 1-4-halogenated alkoxy, C 1-4-alkyl-carbonyl, hydroxycarbonyl group, C 1-4-alkoxy carbonyl, NH (C 1-4-alkyl) 2, N (C 1-4-alkyl) 2, phenoxy group or phenyl, wherein said aryl can be replaced by one or many, for example by halogen, C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy, R 10, C 1-4-alkoxy carbonyl, dioxy methylene radical, dioxy ethylidene, C 1-4-alkyl sulfide replaces once or three times phenyl or phenoxy group;
Phenyl or naphthyl, this group can be replaced by one or more following groups: halogen, nitro, cyano group, hydroxyl, amino, C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy, phenoxy group, C 1-4-alkyl sulfide, NH (C 1-4-alkyl) 2, N (C 1-4-alkyl) 2
5 or 6 yuan heteroaromatics contains 1-3 nitrogen-atoms and/or sulphur or Sauerstoffatom, and they can have 1-4 halogen atom and/or 1-2 following groups: C 1-4Alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy, C 1-4-alkyl base, phenyl, phenoxy group or phenylcarbonyl group, wherein phenyl itself can have 1-5 halogen atom and/or 1-3 following groups: C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy and/or C 1-4-alkyl sulfide;
R 10Represent C 1-4-alkyl, C 1-4-alkoxyl group, this group can have arbitrary group of following groups: hydroxyl, carboxylic acid amides or CON (C 1-4-alkyl) 2
Z represents sulphur or oxygen.
Particularly preferably be the formula I compound of pure enantiomer or pure diastereomeric form or its mixture, wherein substituting group has following meanings:
R 2Represent C 1-4-alkyl, C 1-4-alkoxyl group, especially methyl, ethyl, methoxyl group, oxyethyl group, difluoro-methoxy, trifluoromethoxy or CR 2With CR 3Form 5 yuan or 6 yuan of alkylene basic rings or alkylene group ring together, they can be replaced by one or two methyl group, and wherein one or more methylene groups can be replaced by oxygen or sulphur respectively;
R 3Represent C 1-4-alkyl-, C 1-4-alkoxyl group, C 1-4-alkyl sulfide, especially methyl, ethyl, methoxyl group, oxyethyl group, difluoro-methoxy, trifluoromethoxy or CR 3As R 2Shown the same and CR 2Form 5 yuan of rings together;
R 4And R 5Represent phenyl (identical or different), this group can be replaced by one or more for example 1-3 following groups: halogen, hydroxyl, C 1-4-alkyl, C 1-4-alkoxyl group, C 1-4-alkyl sulfide or
R 4And R 5Represent phenyl, this group passes through Direct Bonding, methylene radical, ethylidene or vinylidene, oxygen or sulphur atom or SO at the ortho position 2-, NH-or N (C 1-4-alkyl) group is connected to each other; Or
R 4And R 5Represent cyclohexyl;
R 6Represent C 1-8-alkyl, C 3-6-alkenyl or C 3-8-cycloalkyl, wherein this group can be replaced by the following groups one or many respectively: halogen, hydroxyl, cyano group, C 1-4-alkoxyl group, C 3-6-alkenyloxy, C 1-4-alkyl sulfide, phenoxy group or phenyl, wherein said aryl can be replaced by one or many, for example by C 1-4-alkyl, C 1-4-alkoxyl group, dioxy methylene radical, dioxy ethylidene, C 1-4-alkyl sulfide replaces one or many;
Phenyl or naphthyl, this group can be replaced by one or more following groups: halogen, nitro, cyano group, hydroxyl, amino, C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy, phenoxy group, C 1-4-alkyl sulfide, C 1-4-alkylamino or C 1-4-dialkyl amido;
5 or 6 yuan heteroaromatics contains 1 nitrogen-atoms and/or sulphur or Sauerstoffatom, and they can have 1-4 halogen atom and/or 1-2 following groups: C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-alkyl sulfide, phenyl, phenoxy group or phenylcarbonyl group, wherein phenyl itself can have 1-5 halogen atom and/or 1-3 following groups: C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group and/or C 1-4-alkyl sulfide;
Z represents sulphur or oxygen;
Compound of the present invention has novel treatment potential, is used for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina cordis, irregular pulse, acute/depletion of chronic renal function, chronic cardiac insufficiency, renal insufficiency, cerebri cerebral vasospasm, cerebrum ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis, endotoxin shock, the organ failure of endotaxin induction, disseminated inravascular coagulation, restenosis (Restenose) after angioplasty and the coronary artery bypass grafting treatment, benign prostate histocyte morbid state increases, the liver hardening, erection is obstructed, no blood and the kidney function that causes because of poisoning are depleted or overstretched, between materialization metastases and growth, contrast medium inductive renal failure, chronic pancreatitis, especially acute pancreatitis, intestine gastric ulcer.
Another theme of the present invention is the combination of formula I endothelin receptor antagonists and rasied.The inhibitor of renin-angiotensin system is renin inhibitor, Angiotensin-II-antagonistic and angiotensin transferase (ACE) inhibitor.The preferably combination of formula I endothelin receptor antagonists and ACE inhibitor.
Another theme of the present invention is the combination of formula I endothelin receptor antagonists and beta-blocker.
Another theme of the present invention is the combination of formula I endothelin receptor antagonists and hydragog(ue) (Diuretika).
Further theme of the present invention is the combination of formula I endothelin receptor antagonists and the material that stops VEGF (vascular endothelial growth factor) to work.This material for example is at the antibody of VEGF or binding proteins specific matter or comprises that also the energy specificity suppresses the lower-molecular substance of VEGF release or receptors bind.
The combination of above-mentioned substance can while or administration in batches successively.The dosage form that they both can have been made by prescription individually uses, and also can use with the dosage form that separates.Type of service also can be different, for example can oral endothelin receptor antagonists and intestines external administration VEGF inhibitor.
This combination preparation at first is suitable for treatment and preventing hypertension and secondary disease, and the treatment cardiac insufficiency.
By following evidence the excellent effect of compound:
Receptors bind research
Clone's human body ET A-or ET BThe Chinese hamster ovary celI of expression of receptor is used to carry out combination research.
Membrane prepare
With ET A-or ET BThe Chinese hamster ovary celI breeding of-expression of receptor is containing 10% fetal bovine serum (PAA laboratory GmbH, Linz, A15-022 number), 1mM glutamine (Gibco 25030-024 number), the DMEM NUT MIXF of 100E/ml penicillin and 100 μ g/ml Streptomycin sulphates (Gibco, Sigma P-0781 number) 12In the medium (Gibco, 21331-020 number).After 48 hours, use the PBS washed cell, and with containing 0.05% tryptic PBS 37 ℃ of following incubations 5 minutes.Afterwards, with medium neutralization, centrifugation collecting cell under 300xg.
In order to prepare film, it is 10 that cell is adjusted to concentration 8The cells/ml damping fluid (50mM TrisHCl damping fluid, pH7.4), then by ultrasonic division (Branson Sonifier 250,40-70 second/constant/output 20).
In conjunction with test
For ET A-or ET B-receptor binding assays is suspended in film that (50mM Tris-HCl, pH7.4 contain 5mM MnCl in the incubation buffering liquid 2, 40mg/ml bacitracin and 0.2%BSA), concentration is 50 μ g protein/test additives, under 25 ℃, uses 25pM[125J]-ET 1(ET A-acceptor is tested) or 25pM[125J]-ET 3(ET B-acceptor test) be with or without substances in the presence of carry out incubation.With 10 -7MET 1Measure non-specific binding.After 30 minutes, with GF/B glass fibre filter (Whatman, Britain) free and bonded radioligand are filtered at a Skatron cell harvestor (Skatron, Lier, Norway) in, separate, be 7.4, contain the Tris-HCl damping fluid washing filter of 0.2%BSA with ice-cold pH.With the radioactive activity of Packard 2200 CA liquid-zintillation counter quantitative assay with the strainer collection.
The functional blood vessel test of endothelin receptor antagonists
At the prestress that applies 2g with after being 1 hour time of relaxation, at first cause K for enjoying in the gram Er Shi solution of 7.3-7.4 in the aorta disjunction rabbit 37 ℃ of following pH values +-contracture.After washing, drafting reaches peaked endothelin-dose curve.
Before beginning to draw endothelin-dose curve, potential endothelin antagonistic is applied on other samples of same blood vessel and reaches 15 minutes.Calculate and press K +The endothelin activity of-contracture meter (%).To the endothelin antagonistic correction endothelin-dosage activity curve that works.
In vivo test ET-antagonistic:
Endomorphy type SD-mouse, artificial respiration, the vagus nerve male with Amobarbital anesthesia 250-300g cut off and go spinal cord despinalisiert.Carotid artery and jugular vein are carried out catheterization.
In control animal, intravenous administration 1 μ g/kg ET1 obviously rises blood pressure, and this process continues long period of time.
Before administration ET1, test injection compound (1ml/kg) is 30 minutes in the experimental animal body.In order to measure the antagonistic properties of ET, the blood pressure change of simultaneous test animal and control animal.
Mix ET A-and ET BThe oral test of-antagonistic
With the mouse of the tension force of the male obesity of substances oral administration 250-350g normal (normotone) (Sprague Dawley, Janvier).After 80 minutes, anaesthetize this animal, carotid artery (measurement blood pressure) and jugular vein (applying heavy dose of endothelin/endothelin 1) are carried out catheterization with urethane.
After the steady stage, endothelium of intravenous administration heavy dose (20 μ g/kg, administration volume are 0.5ml/kg) or ET1 (0.3 μ g/kg, administration volume are 0.5ml/kg).The continuous 30 minutes recording blood pressures and the rhythm of the heart.The area of pressing under the curve (AUC) calculates tangible and persistent blood pressure change.For the antagonistic activity of determination test material, will compare through AUC of the animal of material treatment and the AUC of control animal.
Oral according to a conventional method or parenteral (subcutaneous, intravenously, intramuscular, intraperitoneal) administration compound of the present invention.Also can pass through nose-larynx administration by steam or spraying.
Dosage is according to patient's age, situation and body weight and administering mode and decide.In general, the active substance dosage of every day is about the 0.5-50mg/kg body weight when oral, is about the 0.1-10mg/kg body weight during administered parenterally.
In Galenic method of application commonly used, compound that can this is novel uses with solid-state or liquid form, for example tablet, coated tablet, capsule, powder, particle, drageeing, suspension, solution, ointment, emulsifiable paste or spray.They prepare in the usual way.The Galenic auxiliary agent of available routine for example tablet binder, filler, sanitas, tablet disintegrant, flowing regulator, softening agent, wetting agent, dispersion agent, emulsifying agent, solvent, sustained release dosage, antioxidant and/or whipping agent is handled this active substance (referring to people such as H.Sucker: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991).
So contained active matter quality is generally 0.1-90% (weight) in the form of medication that obtains.
Synthetic embodiment
Embodiment 1
2-methyl sulfane base (sulfanyl)-6,7-dihydro-5H-cyclopenta pyrimidine
Will be by 16.4g salt of wormwood (119 mmole) and the different thio urea vitriol of 42.3g S-methyl (152 mmole) solution of forming and 4.9g (44 mmole) 2-oxygen-pentamethylene formaldehyde that is dissolved in 100 ml waters, mixed 1 hour, at room temperature stir and spend the night, then 65 ℃ of heating 6 hours.Extract this aqueous solution with pentane, concentrate organic phase, chromatographic separation resistates on silica gel (heptane/ethyl acetate 8: 2) obtains the solid-state title compound of 0.93g.
Embodiment 2
2-methyl sulphonyl-6,7-dihydro-5H-cyclopenta pyrimidine
Under 0 ℃, with 0.85g (5.1 mmole) 2-methyl sulfane base-6, the solution of 20 ml methanol of 7-dihydro-5H-cyclopenta pyrimidine alternately so mixes with the solution of 9.9g (16.1 mmole) oxone (oxone) in 70 ml waters and 4M sodium hydroxide solution, makes the pH value remain on 2-3.After add finishing, at room temperature the restir mixture is 2 hours, uses ethyl acetate extraction then, dry organic phase and be rotated concentrated on sodium sulfate.Solid-state resistates (0.93g) need not further purification and can use.
Embodiment 3
2-(6,7-dihydro-5H-cyclopenta pyrimidine-2-base-oxygen)-3-methoxyl group-3,3-phenylbenzene-benzyl propionate
Under 0 ℃, in the suspension of 0.1g NaH (3.3 mmoles, 80%, in paraffin oil) in 10 milliliters of DMF, drip 0.6g (1.6 mmole) 2-hydroxyl-3-methoxyl group-3 that is dissolved among the DMF, 3-phenylbenzene-benzyl propionate.Stir after 30 minutes, with mixture and 420 milligrams of (2.1 mmole) 2-methyl sulphonyls-6, the solution of 7-dihydro-5H-cyclopenta pyrimidine and 10 milliliters of DMF mixes, and at room temperature stirs and spends the night.Mixture is poured in the frozen water, with diethyl ether extraction three times.With dried over mgso ether phase, then filter, remove in the vacuum and desolvate.The resistates of chromatogram separating yellow (0.54g) on silica gel separablely in the case goes out the required product of 243mg.
MS(API)：503(M+Na) +
Embodiment 4
2-(6,7-dihydro-5H-cyclopenta pyrimidine-2-base oxygen)-3-methoxyl group-3,3-phenylbenzene-propionic acid (I-136)
Under the situation of using palladium (10%) on the 60mg charcoal, under standard pressure and room temperature, with hydrogen hydrogenase 10 .23g2-(6,7-dihydro-5H-cyclopenta pyrimidine-2-base oxygen)-3-methoxyl group-3, the solution of 3-phenylbenzene-benzyl propionate in 15 milliliters of ethyl acetate/methanol 2: 1, hydrogenation time is 24 hours.Filtration, enriched mixture, (177mg) is stirred in the diethyl ether with resistates, filters, and carries out drying then.Isolate the title product of 95mg.
1H-NMR(d 6-DMSO，200MHz)：8.3(s，1H)，7.2-7.4(m，10H)；6.15(s，1H)；3.3(s，3H)；2.8(m，4H)；2.1(m，2H)。
Embodiment 5
2-chloro-4-methoxyl group-5-methylpyrimidine
With 25g 2, the methanol solution of 4-two chloro-5-methylpyrimidines is cooled to 0 ℃, mixes with 28.5 ml methanol sodium solutions (30%, in methyl alcohol), stirs 1 hour down at 0 ℃ earlier, at room temperature stirs then 2 hours.Then isolate the solvent in the suspension of formation, it is dissolved in the water, and uses extracted with diethyl ether.Resistates organic phase is dry on sodium sulfate, that filter, concentrate and will form thus carries out silica gel chromatography to be separated, and obtains the title compound of 11.4g.
Embodiment 6
2-(4-methoxyl group-5-methylpyrimidine-2-base oxygen)-3-isopropoxy-3,3-phenylbenzene-propionic acid (I-5)
Under 0 ℃, in the suspension of 20 milliliters of DMF of 0.23g sodium hydride (7.6 mmoles, 80%, in paraffin oil), drip 0.76g (2.5 mmole) and be dissolved in 2-hydroxyl-3-isopropoxy-3 among the DMF, 3-phenylbenzene-propionic acid.Stir after 30 minutes, the solution of mixture with 10 milliliters of DMF of 0.6g (3.8 mmole) 2-chloro-4-methoxyl group-5-methylpyrimidine is mixed, at room temperature stir earlier then and spend the night, stirred 8 hours down at 40 ℃ then.Mixture is poured on the frozen water, is adjusted to pH1, with diethyl ether extraction three times with 2N HCl.With 1N KOH extraction ether phase, with 2N HCl the water of alkalescence is adjusted to pH1 again, use extracted with diethyl ether again.Thus obtained ether is dry on sal epsom, filter and solvent removed in vacuo.Xanchromatic resistates (0.8g) is carried out silica gel chromatography separate, separablely go out the required product of 0.19g.
1H-NMR(CDCl 3，200MHz)：8.0(s，1H)；7.5-7.6(m，2H)；7.2-7.4(m，8H)；6.3(s，1H)；3.9(m，1H)；3.9(s，3H)；2.0(s，3H)；1.1(m，6H)。
MS(API)：423(M+H) +
Embodiment 7
2-methyl sulfane base-4-methoxyl group-5-methylpyrimidine
The solution of 100 milliliters of acetonitriles of 14.8g (93 mmole) 2-chloro-4-methoxyl group-5-methylpyrimidine is mixed the thus obtained suspension of reflux 4 hours with 7.2g (102 mmole) sulfo-sodium methylate.Then isolate solvent, be dissolved in the water and use extracted with diethyl ether.Organic phase is dry on sodium sulfate, filter, concentrate, the resistates of acquisition (13.4g) need not further purification, directly reacts.
Embodiment 8
2-methyl sulphonyl-4-methoxyl group-5-methylpyrimidine
Under 0 ℃, the solution of 80 ml methanol of 13.3g (78.1 mmole) 2-methyl sulfane base-4-methoxyl group-5-methylpyrimidine is mixed (about 40 milliliters) with the solution of 62.4g (101 mmole) oxone in water and 4M sodium hydroxide solution, make the pH value be 2-3.After adding end, at room temperature the restir mixture is 2 hours, isolates methyl alcohol, uses ethyl acetate extraction then, with organic phase dry and rotation on sodium sulphate.Solid-state resistates (14.7g) was stirred 2 hours in diethyl ether, filter then and drying, thereby obtain the pure title product of 13.5g.
Embodiment 9
2-(4-methoxyl group-5-methylpyrimidine-2-base oxygen)-3-benzyloxy-3,3-phenylbenzene-propionic acid (I-47)
Under 0 ℃, in the suspension of 20 milliliters of DMF of 0.27g sodium hydride (9 mmoles, 80%, in paraffin oil), drip 1.0g (2.5 mmole) and be dissolved in 2-hydroxyl-3-benzyloxy-3 among the DMF, 3-phenylbenzene-propionic acid.Stir after 30 minutes, the solution of mixture with 10 milliliters of DMF of 0.79g (3.9 mmole) 2-methyl sulphonyl-4-methoxyl group-5-methylpyrimidine is mixed, at room temperature spend the night then.Mixture is poured on the frozen water, is adjusted to pH1, with diethyl ether extraction three times with 2N HCl.With 1N KOH extraction ether phase, with 2N HCl the water of alkalescence is adjusted to pH1 again, use extracted with diethyl ether again.Thus obtained ether is dry on sal epsom, filter and solvent removed in vacuo.Xanchromatic resistates (1.2g) is mixed with 10 milliliters of diethyl ether and at room temperature stirred 3 hours, and then sucking-off precipitated solid and carry out drying obtains the 0.6g title compound.
1H-NMR(CDCl 3，200MHz)：8.0(s，1H)；7.2-7.45(m，10H)；6.2(s，1H)；4.7(d，1H)；4.55(d，1H)；3.85(s，3H)；2.1(s，3H).
MS(API)：471(M+H) +
Embodiment 10
2-(4-methoxyl group-5-methylpyrimidine-2-base oxygen)-3-hydroxyl-3,3-phenylbenzene-propionic acid (I-29)
Under the situation of using palladium (10%) on the 80mg charcoal, under standard pressure and room temperature, with hydrogen hydrogenation 440mg (0.94 mmole) 2-(4-methoxyl group-5-methylpyrimidine-2-base oxygen)-3-benzyloxy-3, the solution of 20 milliliters of ethyl acetate of 3-phenylbenzene-propionic acid, hydrogenation time are 3 days.Filter, enriched mixture, resistates (430mg) is carried out silica gel chromatography separates, separablely go out the required title product of 39mg.
1H-NMR(d 6-DMSO，200MHz)：8.0(s，1H)，7.6(m，2H)；7.0-7.5(m，8H)；5.6(s，1H)；3.8(s，3H)；1.9(s，3H)。
Embodiment 11
(S)-and 2-(4-methoxyl group-5-methylpyrimidine-2-base oxygen)-3-methoxyl group-3,3-phenylbenzene-propionic acid (I-2)
Under 0 ℃, in the suspension of 40 milliliters of DMF of 3.3g sodium hydride (110 mmoles, 80%, in paraffin oil), drip 10g (36.7 mmole) and be dissolved in (S)-2-hydroxyl-3-methoxyl group-3 among 40 milliliters of DMF, 3-phenylbenzene-propionic acid.Stir after 60 minutes, the solution of mixture with 20 milliliters of DMF of 9.6g (47.7 mmole) 2-methyl sulphonyl-4-methoxyl group-5-methylpyrimidine is mixed, at room temperature spend the night then.Mixture is poured on the frozen water, is adjusted to pH1, with diethyl ether extraction three times with 2N HCl.With 1NKOH extraction ether phase, with 2N HCl the water of alkalescence is adjusted to pH1 again, use extracted with diethyl ether again.Thus obtained ether is dry on sodium sulfate, filter and solvent removed in vacuo.Resistates (17.1g) stirred in diethyl ether spend the night, filter and dry.Thus obtained solid (12.1g) is carried out silica gel chromatography separate, separablely go out the required product of 11.4g.
1H-NMR(CDCl 3，270MHz)：8.0(s，1H)；7.2-7.45(m，10H)；6.1(s，1H)；3.85(s，3H)；3.3(s，3H)；2.0(s，3H)。
Fusing point: 134 ℃ (decomposition)
MS(ESI)：394(M+H) +
Prepare following compounds by method similar to the above embodiments.
Embodiment 12
3-oxyethyl group-2-(4-methoxyl group-5-methyl-pyrimidine-2-base oxygen)-3,3-phenylbenzene-propionic acid (I-4)
1H-NMR(CDCl 3，200MHz)：8.0(s，1H)；7.1-7.5(m，10H)；6.2(s，1H)；3.9(s，3H)；3.5(m，2H)；2.0(s，3H)；1.1(t，3H)。
MS(API)：409(M+H) +
Embodiment 13
3-[2-(3,4-dimethoxy-phenyl) oxyethyl group]-2-(4-methoxyl group-5-methyl-pyrimidine-2-base oxygen)-3,3-phenylbenzene-propionic acid
1H-NMR(CDCl 3，200MHz)：8.0(s，1H)；7.1-7.4(m，10H)；6.6-6.8(m，3H)；6.3(s，1H)；3.9(s，3H)；3.8(m，7H)；3.5-3.65(m，1H)；2.7-2.9(m，2H)；2.0(s，3H)；1.1(t，3H)。
MS(ESI)：555(M+H) +
Embodiment 14
3-[2-(3,4-dimethoxy-phenyl)-oxyethyl group]-2-(9-methyl-9H-purine-2-base oxygen)-3,3-phenylbenzene-propionic acid (I-150)
1H-NMR(CDCl 3，200MHz)：8.2(s，1H)；7.9(s，1H)；7.1-7.4(m，10H)；6.6-6.8(m，3H)；6.3(s，1H)；3.9(s，3H)；3.8(m，7H)；3.5-3.65(m，1H)；2.7-2.9(m，2H)；2.0(s，3H)；1.1(t，3H)。
MS(ESI)：555(M+H) +
Embodiment 15
3,3-pair-(4-fluoro-phenyl)-3-methoxyl group-2-(4-methoxyl group-5-methyl-pyrimidine-2-base oxygen)-propionic acid (I-61)
1H-NMR(CDCl 3，400MHz)：8.0(s，1H)；7.4-7.5(m，2H)；7.25-7.35(m，2H)；6.9-7.0(m，4H)；6.05(s，1H)；3.9(s，3H)；3.3(s，3H)；2.05(s，3H)。
MS(API)：431(M+H) +
Embodiment 16
3-(3,4-dimethyl-benzyloxy)-2-(4-methoxyl group-5-methyl-pyrimidine-2-base oxygen)-3,3-phenylbenzene-propionic acid (I-149)
1H-NMR(CDCl 3，200MHz)：8.0(s，1H)；7.1-7.5(m，10H)；6.2(s，1H)；4.6(d，1H)；4.4(d，1H)；3.85(s，3H)；2.2(s，6H)；2.0(s，3H)。
MS(API)：498(M+H) +
Prepare the listed compound of table 1 by similar method.
Embodiment 17
In conjunction with test, measure the receptors bind data of following compounds according to above-mentioned.
The results are shown in the table 2.
Table 2 receptors bind data (K i-value)
Compound ????ET A[nM]
????I-2 ????0.6
????I-4 ????1.8
????I-5 ????3
????I-29 ????175
????I-47 ????8.7
????I-61 ????3.1
????I-136 ????22
????I-149 ????5
????I-150 ????2200
Table I
Figure A0081053300231
??Nr. ????R 1 ????R 4，R 5 ????R 6 ????R 2 ????R 3 ????Z
????I-1 ????COOCH 3 Phenyl Methyl ????Me ????OMe ????O
????I-2 ????COOH Phenyl Methyl ????Me ????OMe ????O
????I-3 ????COOH Phenyl ????CH 3-S-CH 2-CH 2- ????Me ????OMe ????O
????I-4 ????COOH Phenyl Ethyl ????Me ????OMe ????O
????I-5 ????COOH Phenyl Different-propyl group ????Me ????OMe ????O
????I-6 ????COONa Phenyl Phenyl ????Me ????Me ????S
????I-7 ????COOH Phenyl 3,4-two-OMe-phenyl-CH 2-CH 2- ????Me ????Me ????O
????I-8 ????COOH Phenyl ????(CH 3) 2-CH-SO 2-CH 2-CH 2- ????Me ????Et ????O
????I-9 ????COOH Phenyl ????CH 3-S-CH 2-CH 2- ????Me ????Et ????O
????I-10 ????COONa Phenyl Methyl ????Me ????OMe ????O
????I-11 ????COOH Phenyl ????(CH 3) 2-CH-SO 2-CH 2-CH 2- ????Et ????NH-OMe ????O
????I-12 ????COOH Phenyl Just-propyl group ????Et ????OMe ????O
????I-13 ????COOCH 3 Phenyl Just-propyl group ????Et ????Et ????O
????I-14 ????COOH Phenyl Methyl ????Me The O propyl group ????S
??I-15 ????COOH Phenyl Just-propyl group ????Me The O propyl group ????O
??I-16 ????COOH Phenyl Just-butyl ????Me O-is different-propyl group ????O
??I-17 ????COOH Phenyl Different-butyl ????OMe ????OMe ????O
??I-18 ????COOH Phenyl Different-butyl ????Me ????Me ????O
??I-19 ????COOH Phenyl 3,4-two-OMe-phenyl-CH 2-CH 2- ????Me ????NH-Me ????O
??I-20 ????COOH Phenyl Tert-butyl ????Et ????N-(Me) 2 ????O
??I-21 ????COOH Phenyl Cyclopropyl-CH 2- ????Me ????OMe ????O
??I-22 ????COOH Phenyl Cyclopentyl ?????????-CH 2-CH 2-CH 2 ????O
??I-23 ????COOH Phenyl Cyclohexyl ????NH-Me ????Me ????O
??I-24 ????COOH Phenyl ????(CH 3) 3-C-CH 2-CH 2 ????Et ????OEt ????O
??I-25 ????COOH Phenyl 3,4-oxygen methylene radical-benzyl ????Et ????OMe ????S
??I-26 ????COOH Phenyl ????(CH 3) 2CH-CH 2-CH 2-CH 2- ????CF 3 ????OMe ????O
??I-27 ????COOH Phenyl ????HO 2C-(CH 2) 2- ????Et ????Et ????O
??I-28 ????COOH Phenyl The cyclopropyl methylene radical ????Me ????Me ????O
??I-29 ????COOH Phenyl ????H ????Me ????OMe ????O
??I-30 ????COOH Phenyl Phenyl ????OMe O-is different-propyl group ????O
??I-31 ????COOH Phenyl 3,4-two-OMe-phenyl-CH 2-CH 2- ????OMe ????Me ????O
??I-32 ????COOCH 3 Phenyl Phenyl ????Me ????Me ????O
??I-33 ????COOH Phenyl 4-sec.-propyl-phenyl ????Me ????OMe ????O
??I-34 ????COOH Phenyl The 4-SMe-phenyl ????Me ????Me ????O
??I-35 ????COOH Phenyl The 4-OMe-phenyl ????Me ????Et ????O
??I-36 ????COOH Phenyl The 3-Et-phenyl ????CF 3 ????CF 3 ????O
??I-37 ????COOH Phenyl The 2-Me-phenyl ????Me ????CF 3 ????O
??I-38 ????COOH Phenyl The 2-Cl-phenyl ????Me ????NH-OMe ????O
??I-39 ????COOH The 2-Me-phenyl Methyl ????Et ????Et ????S
??I-40 ????COOH Phenyl The 3-Br-phenyl ????-CH 2-CH 2-CH 2- ????O
??I-41 ????COOH Phenyl ????3-NO 2-phenyl ????Me ????OMe ????O
??I-42 ????COOH Phenyl The 2-HO-phenyl ????Me The O-propyl group ????O
??I-43 ????COOH Phenyl 3,4-two-OMe-phenyl ????Me ????SMe ????O
??I-44 ????COOH Phenyl 3,4-dioxy methylene radical-phenyl ????Me ????N-(Me) 2 ????O
??I-45 ????COOH Phenyl Methyl ????Et ????Et ????S
??I-46 ????COOH Phenyl 3,4,5-three-OMe-phenyl ????Me ????Me ????O
??I-47 ????COOH Phenyl Benzyl ????Me ????OMe ????O
??I-48 ????COOH Phenyl The 2-Cl-benzyl ????SMe ????Me ????O
??I-49 ????COOH Phenyl The 3-Br-benzyl ????Me ????CF 3 ????S
??I-50 ????COOH Phenyl The 4-F-benzyl ????Me ????OMe ????O
??I-51 ????COOH Phenyl The 2-Me-benzyl ????-CH 2-CF 3 ????OMe ????O
??I-52 ????COOH Phenyl The 2-Me-benzyl ????Me ????OMe ????O
??I-53 ????COOH Phenyl 3,4-two-Me-phenyl-CH 2-CH 2- ????Me ????Me ????O
??I-54 ????COOH Phenyl The 3-Et-benzyl ????Me ????N-(Me) 2 ????O
??I-55 ????COOH Phenyl 4-is different-propyl group-benzyl ????Me ????Me ????O
??I-56 ????COOH Phenyl 2,6-two-OMe-phenyl-CH 2-CH 2 ????Me The O-allyl group ????O
??I-57 ????COOH Phenyl 4-OMe-3-propyl group-benzyl ????Me ????Et ????O
??I-58 ????COOH Phenyl 2-Me-5-propyl group-benzyl ????Me ????OMe ????O
??I-59 ????COOH Phenyl 2-Me-5-propyl group-benzyl ????Et ????Et ????O
??I-60 ????COOH Phenyl 4-Me-2-propyl group-benzyl ????Me ????OMe ????O
??I-61 ????COOH The 4-F-phenyl Methyl ????Me ????OMe ????O
??I-62 ????COOCH 3 The 4-F-phenyl Methyl ????Et ????Et ????O
??I-63 ????COOH The 4-Cl-phenyl Methyl ????Me ????OMe ????O
??I-64 ????COOH The 4-Me-phenyl Methyl ????Me ????OMe ????O
??I-65 ????COOH The 4-Ome-phenyl Ethyl ????Me ????NH-OMe ????O
??I-66 ????COOH The 4-Me-phenyl Methyl ????Me ????Me ????O
??I-67 ????COOH Phenyl 3,4-two-OMe-phenyl-CH 2-CH 2- ????Et ????Et ????O
??I-68 ????COOH ??3-CF 3-phenyl Just-propyl group ????Me ????OMe ????O
??I-69 ????COOH Phenyl 3,4-two-OMe-phenyl-CH 2-CH 2- ????Et ????Me ????O
??I-70 ????COOH The 4-F-phenyl Ethyl ????Me ????Me ????O
??I-71 ????COOH Phenyl 3-OMe-phenyl-CH 2-CH 2- ????Et ????Me ????O
??I-72 ????COOCH 3 Phenyl Methyl ????Me ????OMe ????S
??I-73 ????OOOH The 3-Cl-phenyl Ethyl ????Me ????OEt ????O
??I-74 ????COOH The 2-F-phenyl Methyl ????Me ????OEt ????O
??I-75 ????COOH The 2-F-phenyl Methyl ????Me Propyl group ????O
??I-76 ????COOH The 2-Me-phenyl Methyl ????Me Propyl group ????O
??I-77 ????COOH Phenyl 3,4-two-Cl-phenyl-CH 2-CH 2- ????Me Propyl group ????O
??I-78 ????COOH Phenyl 3,4-two-Cl-phenyl-CH 2-CH 2- ????Me The O-propyl group ????O
??I-79 ????COOH ????4-CF 3-phenyl Methyl ????OMe ????OMe ????O
??I-80 ????COOH Phenyl Methyl ????Me The O-propyl group ????O
??I-81 ????COOH Phenyl 2,6-two-Cl-phenyl-CH 2-CH 2- ????Et Allyl group ????S
??I-82 ????COOCH 3 Phenyl Methyl ????Me The O-sec.-propyl ????O
??I-83 ????COOH ????4-OCF 3-phenyl Just-propyl group ????Me ????OCF 3 ????O
??I-84 ????COOH Phenyl Propyl group ????Me ????OCF 3 ????S
??I-85 ????COOH Phenyl Methyl ????Et ????CF 3 ????O
??I-86 ????COOH The 4-F-phenyl Benzyl ????Me ????Me ????O
??I-87 ????COOH Phenyl 3-Cl-phenyl-CH 2-CH 2- ????Et ????Me ????O
??I-88 ????COOH Phenyl 4-Cl-phenyl-CH 2-CH 2- ????Me ????OMe ????O
??I-89 ????COOH The 4-phenyl 3,4-two-Cl-phenyl-CH 2-CH 2- ????Et ????Me ????O
??I-90 ????COOH The 4-phenyl 3,4 two-Cl-phenyl-CH 2-CH 2- ????Me ????OMe ????O
??I-91 ????COOH Phenyl 3,5-two-Cl-phenyl-CH 2-CH 2- ????Et ????Et ????O
??I-92 ????COOH Phenyl 3,5-two-OMe-phenyl-CH 2-CH 2- ????Et Propyl group ????O
??I-93 ????COOH Phenyl Phenyl ????Me Sec.-propyl ????S
??I-94 ????COOH Phenyl 3,4-two-Cl-phenyl-CH 2-CH 2- ????Me Just-butyl ????S
??I-95 ????COOH Phenyl 3,4-two-OMe-phenyl-CH 2-CH 2- ????Me Just-butyl ????O
??I-96 ????COOH Phenyl 3,4-two-Me-phenyl-CH 2-CH 2- ????Et ????Me ????O
??I-97 ????COOH Phenyl 2,5-two-Cl-phenyl-CH 2-CH 2- ????Me Ethynyl ????O
??I-98 ????COOH Phenyl 3,4-two-Et-phenyl-CH 2-CH 2- ????Me Sec.-propyl ????O
??I-99 ????COOH The 4-F-phenyl ????H ????Me ????OMe ????O
??I-100 ????COOH Phenyl 3,4-two-Me-phenyl-CH 2-CH 2- ????Et ????Me ????S
??I-101 ????COOH Phenyl 4-sec.-propyl-phenyl-CH 2-CH 2- ????Me ????Me ????O
??I-102 ????COOH The 4-F-phenyl 3,4-two-Me-phenyl-CH 2-CH 2- ????Me ????OMe ????O
??I-103 ????COOH Phenyl Methyl ????Me ????N-(Me) 2 ????O
??I-104 ????COOH Phenyl Methyl ????Me Isobutyl- ????O
??I-105 ????COOH Cyclohexyl Methyl ????Me ????OMe ????O
??I-106 ????COOCH 3 Phenyl Methyl ????Me ????OH ????O
??I-107 ????COOCH 3 Phenyl Sec.-propyl ????Me ????OMe ????O
??I-108 ????COOC 2H 5 Phenyl Sec-butyl ????Me ????Cl ????O
??I-109 ???CONHSO 2Phenyl ????3-CF 3-phenyl Methyl ????Me ????Cl ????O
??I-110 ????COOH Phenyl 2,3-two-Cl-phenyl-CH 2-CH 2- ????Et ????OH ????O
??I-111 ????COOH The 4-Cl-phenyl 3,4-two-Me-phenyl-CH 2-CH 2- ????Me The O-propyl group ????O
??I-112 ????COOH Phenyl 3,4-two-Et-phenyl-CH 2-CH 2- ????Me Vinyl ????O
??I-113 ????COOC 2H 5 Phenyl Trifluoroethyl ????Me ????OMe ????O
??I-114 ????COOH Phenyl ????HO-CH 2-(HO-CH)-CH 2- ????Me ????OMe ????O
??I-115 ????COOH Phenyl ????HO-CH 2-CH 2-CH 2- ????Et ????Me ????S
??I-116 ????COOH Phenyl ????HO-CH 2-CH 2-CH 2- ????Me ????OMe ????O
??I-117 ????COOH Phenyl ????HO-CH 2-CH 2-CH 2- ????Et ????OMe ????O
??I-118 ????COOH Phenyl The 3-Cl-phenyl ????Me ????SMe ????S
??I-119 ????COOH Phenyl ????HO-CH 2-CH 2- ????Me ????SEt ????O
??I-120 ????COOH Phenyl Phenyl ????Me Allyl group ????O
??I-121 ????COOH Phenyl Phenyl ????Me The O-allyl group ????O
??I-122 ????COOH Phenyl Phenyl ????CF 3 ????CF 3 ????O
??I-123 ????COOH Phenyl Phenyl ????Et ????OMe ????O
??I-124 ????COOH Phenyl Phenyl ????Et ????Et ????O
??I-125 ????COOH Phenyl The 2-thiazolyl ????Me ????OMe ????O
??I-126 ????COOC 2H 5 The 3-Cl-phenyl Phenyl ????Me O-is different-propyl group ????O
??I-127 ????COOC 2H 5 Phenyl The 4-thiazolyl ????Me ????Cl ????O
??I-128 ????COOH The 4-F-phenyl Methyl Ethyl ????OMe ????O
??I-129 ????CONSO 2Phenyl The 4-F-phenyl Phenyl ????Me ????OMe ????O
??I-130 ????COOC 2H 5 Phenyl The 4-imidazolyl ????Me ????CF 3 ????O
??I-131 ???CONHSO 2Phenyl ????4-CF 3-phenyl Phenyl ????Me ????Cl ????O
??I-132 ????COOCH 3 Phenyl The 4-F-phenyl ????Me ????OCF 3 ????O
??I-133 ????COOC 2H 5 Phenyl The 2-dimethylaminophenyl ????Me ????Me ????O
??I-134 ????COOH Phenyl N-pentyl ????Me ????Me ????O
??I-135 ????COOH Hexamethylene Methyl ????Me The O-propyl group ????O
??I-136 ????COOH Phenyl Methyl ????-CH 2-CH 2-CH 2- ????O
??I-137 ????COOH Phenyl Phenyl ????Me ????Me ????S
??I-138 ????COOH The 3-F-phenyl Methyl ????Me ????SMe ????O
??I-139 ????COOH The 3-OMe-phenyl Methyl ????Me ????SMe ????O
??I-140 ????COOH Phenyl Methyl ????Et ????CF 3 ????O
?I-141 ????COOH The 3-F-phenyl Methyl ????Me ????Me ????O
?I-142 ????CONHSO 2Phenyl Phenyl Methyl ????Me ????OMe ????O
?I-143 ????CONHSO 2CH 3 Phenyl Methyl ????Me ????Et ????O
?I-144 ????COONa Phenyl Methyl ????Me ????OMe ????O
?I-145 ????CONHSO 2CH 3 Phenyl Methyl ????Me ????OMe ????O
?I-146 Tetrazyl Phenyl Methyl ????Me ????OMe ????O
?I-147 ????COOH The 3-Me-phenyl Methyl ????OMe ????OMe ????O
?I-148 ????COOH The 4-F-phenyl Methyl ????Me ????SMe ????O
?I-149 ????COOH Phenyl 3,4-two-Me-benzyl ????Me ????OMe ????O
?I-150 ????COOH Phenyl 3,4-two-OMe-phenyl-CH 2-CH 2- ????-N＝CH-N(CH 3)- ????O
Table II
Figure A0081053300311
??Nr. ????R 1 ????A ????R 6 ????R 2 ????R 3 ????Z
??II-1 ????COOH Key Methyl ????Me ????OMe ????O
??II-2 ????COOH ????CH 2 Methyl ????Me ????OMe ????O
??II-3 ????COOH ????CH 2-CH 2 Methyl ????Me ????OMe ????O
??II-4 ????COOH ????CH＝CH Methyl ????Me ????OMe ????O
??II-5 ????COOH ????O Methyl ????Me ????OEt ????O
??II-6 ????COOH ????S Methyl ????Me ????OMe ????O
??II-7 ????COOH ????NH(CH 3) Methyl ????Me ????OMe ????O
??II-8 ????COOH Key Sec.-propyl ????Me ????OMe ????O
??II-9 ????COOH Key The p-isopropyl phenyl ????Me ????OMe ????O
??II-10 ????COOH Key Benzyl ????Me ????SMe ????O
??II-11 ????COOH ????CH＝CH Ethyl ????Me ????OMe ????O
??II-12 ????COOH ????CH＝CH ???(CH 3) 2-CH 2-CH 2- ????Me ????OMe ????O
??II-13 ????COOH ????CH＝CH Cyclopropyl-CH 2- ????Me ????OMe ????O

Claims (8)

1. the compound of formula I
Figure A0081053300021
In the formula: R 1Represent tetrazyl or group
R wherein has following definition:
A) group OR 7, R wherein 7Representative:
Hydrogen, alkali metal cation, alkaline earth metal cation, the acceptable organic ammonium ion of physiology be uncle C for example 1-4-alkylammonium or ammonium ion;
C 3-8-cycloalkyl, C 1-8-alkyl, CH 2-phenyl, they can be replaced by one or more following groups: halogen, nitro, cyano group, C 1-4-alkyl, C 1-4-haloalkyl, hydroxyl, C 1-4-alkoxyl group, sulfydryl, C 1-4-alkyl sulfide, amino, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2
C 3-6-alkenyl-or C 3-6-alkynyl wherein can have 1-5 halogen atom on this group;
In addition, R 7Can be phenyl, can have 1-5 halogen atom and/or 1-3 following groups on it: nitro, cyano group, C 1-4-alkyl, C 1-4-haloalkyl, hydroxyl, C 1-4-alkoxyl group, sulfydryl, C 1-4-alkyl sulfide, amino, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2
B) 5 yuan of heteroaromaticss that connect by a nitrogen-atoms, for example pyrryl, pyrazolyl, imidazolyl and triazolyl can have 1-2 halogen atom on it, or 1-2 C 1-4A-alkyl or 1-2 C 1-4-alkoxyl group;
C) group
Figure A0081053300023
Wherein k represents 0,1 and 2 numerical value, and p represents 1,2,3 and 4 numerical value and R 8Represent C 1-4Alkyl, C 3-8-cycloalkyl, C 3-6-alkenyl, C 3-6-alkynyl group or phenyl, it can be replaced by one or more for example 1-3 following groups;
Halogen, nitro, cyano group, C 1-4-alkyl, C 1-4-haloalkyl, hydroxyl, C 1-4-alkoxyl group, C 1-4-alkyl sulfide, sulfydryl, amino, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2
D) group
R wherein 9Representative;
C 1-4-alkyl, C 3-6Alkenyl, C 3-6Alkynyl, C 3-6-cycloalkyl, wherein this group can have a C 1-4-alkoxyl group-, C 1-4-alkyl sulfide-and/or phenyl is as c) in listed;
Phenyl can be replaced by 1-3 following groups: halogen, nitro, cyano group, C 1-4-alkyl, C 1-4-haloalkyl, hydroxyl, C 1-4Alkoxyl group, C 1-4-alkyl base, sulfydryl, amino, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2
R 2Representation hydroxy, NH 2, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2, C 1-4-alkyl, C 2-4-alkenyl, C 2-4-alkynyl, C 1-4-hydroxyalkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy or C 1-4-alkyl sulfide, or CR 2With CR 3Form 5 yuan or 6 yuan of alkylene basic rings or alkylene group ring together, this ring can be by one or two C 1-4-alkyl replace and one or more methylene radical respectively can by oxygen, sulphur ,-NH or-N (C 1-4-alkyl) replaces;
R 3Representation hydroxy, NH 2, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2, halogen, C 1-4-alkyl, C 2-4-alkenyl, C 2-4-alkynyl, C 3-6-alkenyloxy, C 1-4-alkyl-carbonyl, C 1-4-alkoxy carbonyl, C 1-4-hydroxyalkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy ,-NH-O-C 1-4-alkyl, C 1-4-alkyl sulfide, or CR 3As R 2Shown the same and CR 2Form 5 yuan or 6 yuan of rings together;
R 4And R 5(can be identical or different) representative:
Phenyl or naphthyl, this group can be replaced by one or more following groups: halogen, nitro, cyano group, hydroxyl, C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy, phenoxy group, C 1-4-alkyl sulfide, amino, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2Or
Phenyl or naphthyl, this group pass through Direct Bonding, methylene radical, ethylidene or vinylidene, oxygen or sulphur atom or SO at the ortho position 2-, NH-or N-alkyl be connected to each other;
Or C 3-7-cycloalkyl;
R 6Represent hydrogen.
C 1-8Alkyl, C 3-6Alkenyl, C 3-6-alkynyl or C 3-8Cycloalkyl, wherein this group can be replaced by the following groups one or many respectively: hydroxyl, sulfydryl, carboxyl, halogen, nitro, cyano group, C 1-4-alkoxyl group, C 3-6-alkenyloxy, C 3-6-alkynyloxy group, C 1-4-alkyl base, C 1-4-halogenated alkoxy, C 1-4-alkyl-carbonyl, C 1-4-alkoxy carbonyl, (C 1-4-alkyl) NH carbonyl, (C 1-4-alkyl) 2N carbonyl, C 3-8-alkyl-carbonyl alkyl, amino, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2, phenoxy group or phenyl, wherein said aryl can be replaced by one or many;
Phenyl or naphthyl, this group can be replaced by one or more following groups: halogen, nitro, cyano group, hydroxyl, amino, C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy, phenoxy group, C 1-4-alkyl sulfide, NH (C 1-4-alkyl), N (C 1-4-alkyl) 2Or dioxy methylene radical or dioxy ethylidene;
5 or 6 yuan heteroaromatics contains 1-3 nitrogen-atoms and/or sulphur or Sauerstoffatom, and they can have 1-4 halogen atom and/or 1-2 following groups: C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy, C 1-4-alkyl sulfide, phenyl, phenoxy group or phenylcarbonyl group, wherein phenyl can have 1-5 halogen atom and/or 1-3 following groups: C 1-4-alkyl, C 1-4-haloalkyl, C 1-4-alkoxyl group, C 1-4-halogenated alkoxy and/or C 1-4-alkyl sulfide;
Z represents sulphur or oxygen
And physiologically acceptable salt, the form that tautomeric forms and enantiomer-pure and diastereomer are pure.
2. the purposes of claim 1 Compound I is used for the treatment of disease.
3. the purposes of claim 1 Compound I is used as endothelin receptor antagonists.
4. the purposes of claim 1 Compound I is used to prepare the medicine that the disease of level of ET rising appears in treatment.
5. the purposes of claim 1 Compound I is used to prepare the medicine for the treatment of disease, wherein helps endothelin to form and/or development.
6. the purposes of claim 1 Compound I is used for the treatment of chronic cardiac insufficiency, restenosis, hypertension, pulmonary hypertension, acute/depletion of chronic renal function, cerebrum ischemia, asthma, the abnormal increase of benign prostate histocyte, prostate cancer and acute pancreatitis.
7. the composition of claim 1 Compound I and one or more active substances, this active substance is selected from the inhibitor of renin-angiotensin system, as the material of renin inhibitor, Angiotensin-II-antagonistic and angiotensin transferase (ACE) inhibitor, blended ACE/ neutral endopeptidase (NEP) inhibitor, beta-Blocking agent, diuretic(s), calcium antagonists and retardance VEDF.
8. the pharmaceutical preparation of oral and administered parenterally except containing conventional pharmaceutical auxiliary agent, contains the Compound I of at least a claim 1 in every dose of medicine.
CN00810533A 1999-07-20 2000-07-05 Novel carboxylic acid derivatives with 5,6 substitutedpyrimidine ring, their production and utilization thereof as endothelin receptor antagonists Pending CN1367778A (en)

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