CA2321182A1 - 5-substituted pyrimidine-2-yloxy carboxylic acid derivatives, the production of the same and their utilization as endothelin antagonists - Google Patents
5-substituted pyrimidine-2-yloxy carboxylic acid derivatives, the production of the same and their utilization as endothelin antagonists Download PDFInfo
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to carboxylic acid derivatives of formula (I), wherein the substituents have the following meanings; R1= tetrazole or a group (1); R
= a radical OR7(2), (3), a 5-membe red heteroaromatic bonded by a nitrogen atom such a pyrrolyl, pyrazolyl, imidazolyl and trizolyl; R2, R3 = 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; R4 and R5 = 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; R6 =
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 R6 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.
= a radical OR7(2), (3), a 5-membe red heteroaromatic bonded by a nitrogen atom such a pyrrolyl, pyrazolyl, imidazolyl and trizolyl; R2, R3 = 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; R4 and R5 = 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; R6 =
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 R6 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
DERIVATIVES, THE PRODUCTION OF THE SAME AND THEIR
UTILIZATION AS ENDOTHELIN ANTAGONISTS
The present invention relates to novel carboxylic acid derivatives having a 5-substituted pyrimidine ring, to their preparation and use.
Endothelia is a peptide which is composed of 21 amino acids and is synthesized and released by the vascular endothelium.
Endothelia exists in three isoforms, ET-l, ET-2 and ET-3. In the following text, "endothelia" or "ET" signifies one or all isoforms of endothelia. Endothelia is a potent vasoconstrictor and has a potent effect on vessel tone. It is known that this vasoconstriction is caused by binding of endothelia to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 1~4, 868-875, 1988).
Increased or abnormal release of endothelia causes persistent vasoconstriction in the peripheral, renal and cerebral blood vessels, which may lead to disorders. It has been reported in the literature that endothelia is involved in a number of disorders;
these include hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's disease, cerebral vasospasms, stroke, benign prostatic hypertrophy, ateriosclerosis, asthma and cancer of the prostate (J. Vascular Med. Biology 2, 207 (1990), J. Am.
Med. Association 264, 2868 (1990), Nature 344, I14 (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 endothelia receptor subtypes, the ETA and ETB
receptors, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (I990)). Consequently, substances which inhibit binding of endothelia to one or both receptors should antagonize physiological effects of endothelia and should therefore be valuable drugs.
Carboxylic acid derivatives and their use as endothelia antagonists are described in WO 95/26716, WO 96/11914, Wp 97/9294, WO 97/12878, WO 97/38980, WO 97/38981. These compounds carry a nitrogen atom or a group /C-H
~
, CA 02321182 2000-08-14 ,_ , , , 0050/48785 at the 5-position of the heterocycle.
In contrast, the compounds according to the invention have in this position a group /C-X
where X is halogen, hydroxyl or C1-Ca-haloalkyl. Compared to the known endothelin antagonists, the compounds according to the invention are, for example, metabolized more favorably in the body.
The present invention relates to carboxylic acid derivatives of the formula I
a R
R N
I
R6 Z-C-C-O-~~ ~ R
Rs Ri N -where R1 is tetrazole or a group O
C-R
in which R is:
a) a radical ORS, where R~ is:
hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerable organic ammonium ion such as tertiary C1-C4-alkylammonium or the ammonium ion;
C3-CB-cycloalkyl, C1-C8-alkyl, CH2-phenyl which may be substituted by one or more of the following radicals:
halogen, nitro, cyano, C1-C4-alkyl, CI-C4-haloalkyl, hydroxyl, Ci-C4-alkoxy, mercapto, C1-CQ-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)z;
a C3-C6-alkenyl or a C3-C6-alkynyl group, it being possible for these groups for their part to carry one to five halogen atoms;
,. , , 0050/48785 R~ may furthermore be a phenyl radical which may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, Cl-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;
b) a 5-membered heteroaromatic such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl which is attached via a nitrogen atom and which may carry one to two halogen atoms, or one to two C1-C4-alkyl or one to two C1-C4-alkoxy groups.
c) a group (o)k_ -O-(CHZ)p-S-R8 in which k may be 0, 1 or 2, p may be 1, 2, 3 or 4 and Rg is C1-C4-alkyl, C3-C$-cycloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or phenyl which may be substituted by one or more, for example by one to three, of the following radicals:
halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-CQ-alkoxy, C1-C4-alkylthio, mercapto, amino, NH(C1-C4-alkyl), N(C1-Cq-alkyl)2.
d) a radical O
H
O
where R9 is:
C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-Cg-cycloalkyl, where these radicals may carry a C1-C4-alkoxy, C1-C4-alkylthio and/or a phenyl radical as mentioned under c);
phenyl which may be substituted by one to three of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-CQ-haloalkyl, hydroxyl, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, NH(C1-Cq-alkyl), N(C1-Cq-alkyl)Z, The other substituents are as defined below:
R2 is hydrogen, hydroxyl, NH2, NH(C~-C4-alkyl), N(Ci-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C~-C4-alkynyl, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio, morpholine;
X is halogen, C1-C4-haloalkyl, hydroxyl;
R3 is hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)z, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, -NH-0-C1-C4-alkyl, C1-C4-alkylthio;
R4 and R5 (which may be identical or different) are:
phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, mercapto, alkylcarbonyl, alkoxycarbonyl, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)Z; or phenyl or naphthyl which are ortho-linked with each other via a direct bond, a methylene, ethylene, or ethenylene group, an oxygen or sulfur atom or an S02-, NH- or N-alkyl group; or a five- or six-membered heteroaromatic containing one to three nitrogen atoms and/or one sulfur or oxygen atom which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, Cl-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals for their part may carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
or C3-C7-cycloalkyl;
R6 is hydrogen, C1-C8-alkyl, C3-C6-alkenyl, C3-C6-alkinyl or C3-Ce-cycloalkyl, where these radicals may in each case be mono- or polysubstituted by: hydroxyl, mercapto, carboxyl, halogen, vitro, cyano, C1-C4-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C3-C$-alkylcarbony-lalkyl, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)z, phenoxy or phenyl where the abovementioned aryl radicals may be mono- or polysubstituted, for example phenyl or phenoxy mono- to trisubstituted by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, mercapto, 5 carboxyl, hydroxyl, amino, R12, C1-C4-alkoxycarbonyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)Z, dioxomethylene, dioxoethylene or C1-C4-alkylthio;
phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl , N(Ci-C4-alkyl)z or dioxomethylene or dioxoethylene;
a five- or six-membered heteroaromatic containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-CQ-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals for their part may carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
with the proviso that R6 can only be hydrogen if Z is not a single bond;
R12 is Cl-C4-alkyl, C1-C4-alkylthio, C1-C4-alkoxy, which may carry one of the following radicals: hydroxyl, carboxyl, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)Z, carboxamide or CON(C1-C4-alkyl)2;
Z is sulfur, oxygen or a single bond.
For this and further below, the following definitions apply:
an alkali metal is, for example, lithium, sodium, potassium;
an alkaline earth metal is, for example, calcium, magnesium, barium;
organic ammonium ions are protonated amines such as, for example, ethanolamine, diethanolamine, ethylenediamine, diethylamine or piperazine;
,~, 0050/48785 C3-C~-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
C1-C4-haloalkyl may be linear or branched, such as, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoro-ethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl;
C1-C4-haloalkoxy may be linear or branched, such as, for example, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
C1-C4-alkyl may be linear or branched, such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;
CZ-C4-alkenyl may be linear or branched, such as, for example, ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl;
CZ--C4-alkynyl may be linear or branched, such as, for example, ethynyl, 1-propin-1-yl, 1-propin-3-yl, 1-butin-4-yl or 2-butin-4-yl;
C1-C4-alkoxy may be linear or branched, such as, for example, methoxy, ethoxy, propoxy, 1 methylethoxy, butoxy, 1 methyl-propoxy, 2-methylpropoxy or l,l~iimethylethoxy;
C3~6-alkenyloxy may be linear or branched, such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
C3-C6-alkynyloxy may be linear or branched, such as, for example, 2-propin-1-yloxy, 2-butin-1-yloxy or 3-butin-2-yloxy;
C1-C4-alkylthio may be linear or branched, such as, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2 methylpropylthio or 1,1-dimethylethylthio;
C1-CQ-alkylcarbonyl may be linear or branched, such as, for example, acetyl, ethylcarbonyl or 2-propylcarbonyl;
w , 0050/48785 io C1-C4-alkoxycarbonyl may be linear or branched, such as, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;
5 C3-Cg-alkylcarbonylalkyl may be linear or branched, such as, for example, 2-oxoprop-1-yl, 3-oxobut-1-yl or 3-oxobut-2-yl;
C1-CB-alkyl may be linear or branched, such as, for example, C1-C4-alkyl, pentyl, hexyl, heptyl or octyl;
halogen is, for example, fluorine, chlorine, bromine, iodine.
The invention further relates to those compounds from which the compounds of the formula I can be released (prodrugs).
Preference is given to those prodrugs where the release occurs under the conditions which prevail in certain compartments of the body, for example in the stomach, the intestine, the bloodstream or the liver.
The compounds and also the intermediates for their preparation, such as, for example, II and IV, may have one or more asym-metrically substituted carbon atoms. Such compounds may be present as pure enantiomers or pure diastereomers or as mixtures thereof. Preference is given to the use of an enantiomerically pure compound as active compound.
The invention furthermore relates to the use of the above-mentioned carboxylic acid derivatives for preparing drugs, in particular for preparing inhibitors for endothelin receptors.
The compounds of the formula IV in which Z is sulfur or oxygen (IVa) can be prepared as described in WO 96/11914.
O I
R R + R6-Z-H ~ R6_Z~C--OH
Rs R5 R1 II III IVa Compounds of the formula III are either known or can be synthesized, for example, by reduction of the corresponding carboxylic acids or esters thereof, or by other generally known methods.
,. , ~, 0050/48785 CA o232iis2 Zooo-os-i4 Compounds of the formula IVa can be obtained in enantiomerically pure form by an acid-catalyzed transetherification, as described in DE 19636046.3.
Furthermore, enantiomerically pure compounds of the formula IVa can be obtained by carrying out a classic racemate separation on racemic or diastereomeric compounds of the formula IVa using suitable enantiomerically pure bases. Suitable bases are, for example, 4-chlorophenylethylamine and the bases which are mentioned in WO 96/11914.
The compounds of the formula IV in which Z is a single bond (IVb) can be prepared both racemically and in enantiomerically pure form, as described in WO 97/38981.
R6--~--C=O ~' R6~C-OH
RS H ~ s a R R
V IVb The compounds according to the invention in which the substi-tuents are as defined in the formula I can be prepared, for example, by reacting the carboxylic acid derivatives of the formula IV in which the substituents are as defined with compounds of the formula V.
Rz IV + Rl~ --~/ ~ X ~ I
X-In the formula V, Rlo is halogen or R11-SOz-, and R11 can be C1-C4-alkyl, C1-C4-haloalkyl or phenyl. The reaction is preferably carried out in an inert solvent or diluent with addition of a suitable base, i.e. a base which effects a deprotonation of intermediate IV, in a temperature range of from room temperature to the boiling point of the solvent.
Compounds of type I where R1 = COON can furthermore be obtained directly when the intermediate IV in which R1 is COON is deprotonated with two equivalents of a suitable base and reacted with compounds of the formula V. The reaction is again carried out in an inert solvent and in a temperature range of from room temperature to the boiling point of the solvent.
Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, which may in each case be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloro-ethylene, ethers, such as, for example, diisopropyl ether, diisobutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles, such as, for example, acetonitrile and propionitrile, acid amides, such as, for example, dimethylformamide, dimethylacetamide and N methylpyrrolidone, sulfoxides and sulfones, such as, for example, dimethyl sulfoxide and sulfolane. .
Compounds of the formula V are known, and some of them are commercially available, or they can be prepared in a generally known manner.
An alkali metal or alkaline earth metal hydride, such as sodium hydride, potassium hydride or calcium hydride, a carbonate, such as an alkali metal carbonate, for example sodium carbonate or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or potassium hydroxide, an organometallic compound, such as butyllithium, or an alkali metal amide, such as lithium diisopropylamide, may serve as base.
Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, i.e. compounds of the formula I in which R1 is COON, and initially converting these in a customary manner into an activated form, such as an acyl halide, an anhydride or imidazolide, and then reacting this with an appropriate hydroxyl compound HORS. This reaction can be carried out in the customary solvents and often requires addition of a base, such as, for example, triethylamine, pyridine, imidazole or diazabicycloundecane. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent, such as a carbodiimide.
Moreover, compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, i.e. from compounds of the formula I in which R1 is a group COOM
in which M may be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R~-A, A being a customary nucleofugic ,', 0050/48785 leaving group, for example halogen, such as chlorine, bromine, iodine or aryl- or alkylsulfonyl, such as, for example, toluene-sulfonyl and methylsulfonyl, which may be substituted by halogen, alkyl or haloalkyl, or another equivalent leaving group.
5 Compounds of the formula R~-A having a reactive sub~stituent A are known or can easily be obtained with general expert knowledge.
This reaction can be carried out in the customary solvents and is advantageously carried out with the addition of a base, in which case those mentioned above are suitable.
In some cases, generally known protective group techniques have to be employed for the preparation of the compounds I according to the invention. If, for example, R6 = 4-hydroxyphenyl, the hydroxyl group can initially be protected as benzyl ether which is then cleaved at a suitable stage of the reaction sequence.
Compounds of the formula I in which R1 is tetrazole can be prepared as described in WO 96/11914.
With a view to biological activity, preference is given to those carboxylic acid derivatives of the formula I - both as pure enantiomers or pure diastereomers or as mixtures thereof - in which the substituents are as defined below:
RZ is hydrogen, hydroxyl, N(C1-C4-alkyl)Z, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, halogen;
X is halogen, trifluoromethyl;
R3 is hydrogen, hydroxyl, N(C1-C4-alkyl)Z, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, halogen;
R4 and RS are phenyl or naphthyl which may be substituted by one or more, for example by one to three, of the following radicals: halogen, cyano, hydroxyl, mercapto, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, NH(C1-C4-alkyl)Z, N(C1-CQ-alkyl)2, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl;
phenyl or naphthyl which are ortho-linked to each other via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SOZ, NH or N(C1-C4-alkyl) group ,. ,~, 0050/48785 a five-membered heteroaromatic containing one or two nitrogen atoms and/or a sulfur or oxygen atom, which may carry one to two halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-alkoxy, phenyl which for its part may carry one to three halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-alkoxy or C1-C4-alkylthio;
or C3-C~-cycloalkyl;
R6 is CI-CB-alkyl, C3-C6-alkenyl, C3-C6-alkynyl or C3-Cg-cycloalkyl where these radicals may in each case be mono- or polysubstituted by: halogen, hydroxyl, cyano, C1-C4-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-CQ-alkyl-thio, C1-C4-haloalkoxy, C1-Cq-alkylcarbonyl, hydroxycarbonyl, C1-C4-alkoxycarbonyl, NH(C1-C9-alkyl)z, N(C1-C4-alkyl)z, phenoxy or phenyl, where the abovementioned aryl radicals may be mono- or polysubstituted, for example mono- to trisubstituted, by halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, Rlz, C1-C4-alkoxycarbonyl, dioxomethylene, dioxoethylene, C1-C4-alkylthio, phenyl or phenoxy;
phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-Cq-alkyl)z, N ( C1--C4-alkyl ) z:
a five- or six-membered heteroaromatic containing one to three nitrogen atoms and/or a sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, Cz-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals for their part may carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
R1z is C1-C4-alkyl, C1-C4-alkoxy, which carry one of the following radicals: hydroxyl, carboxamide or CON(C1-C4-alkyl)Z;
Z is sulfur, oxygen or single bond.
.~, 0050/48785 Particular preference is given to compounds of the formula I -both as pure enantiomers and pure diastereomers or as mixtures thereof - where the substituents are as defined below:
R2 is C1-C4-alkyl, C1-C4-alkoxy, in particular methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;
X is fluorine, trifluoromethyl;
R3 is C1-C4-alkyl, C1~4-alkoxy, C1-C4-alkylthio, in particular methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;
R4 and RS are phenyl (identical or different) which may be substituted by one or more, for example by one to three, of the following radicals: halogen, hydroxyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio or R4 and R5 are phenyl groups which are ortho-linked to each other via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2, NH or N(C1-C4-alkyl) group; or thiazole, oxazole, thiophene or furan, where the above-mentioned heteroaromatics may be mono- to disubstituted by:
halogen, C1-C4-alkyl, C1-C4-alkoxy;
R4 and RS are cyclohexyl;
R6 is C1-CB-alkyl, C3-C6-alkenyl or C3-Cg-cycloalkyl, where these radicals may in each case be mono- or polysubstituted by:
halogen, hydroxyl, cyano, C1-C4-alkoxy, C3-C6-alkenyloxy, C1-C4-alkylthio, phenoxy or phenyl, where the abovementioned aryl radicals may be mono- or polysubstituted, for example mono- to trisubstituted, by C1-C9-alkyl, C1-C4-alkoxy, dioxomethylene, dioxoethylene, C1-C4-alkylthio;
phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, C1-C4-alkylamino or C1-C4-dialkylamino;
a five- or six-membered heteroaromatic, containing a nitrogen atom and/or a sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, .. , , 0050/48785 ., C1-CQ-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals for their part may carry one to five halogen atoms and/or one to three of the following radicals:
C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and/or C1-C4-alkylthio;
Y is sulfur, oxygen or a single bond.
The compounds of the present invention provide a novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, arrhythmia, acute/chronic kidney failure, chronic cardiac insufficiency, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorhages, migraine, asthma, aterio-sclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and bypass operations, benign prostatic hyperplasia, hypertension or kidney failure caused by ischemia or intoxication, metastasis and growth of mesenchymal tumors, contrast-agent-induced kidney failure, pancreatitis, gastro-intestinal ulcers and erectile dysfunction.
The invention further relates to combinations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin-II antagonists and angiotensin converting enzyme (ACE) inhibitors. Preference is given to combinations of endothelin receptor antagonists of the formula I and ACE inhibitors.
The invention furthermore relates to combinations of endothelin receptor antagonists of the formula I and beta blockers.
The invention furthermore relates to combinations of endothelin receptor antagonists of the formula I and diuretics.
The invention furthermore relates to combinations of endothelin receptor antagonists of the formula I and substances which block the action of VEGF (vascular endothelial growth factor). Such substances are, for example, antibodies directed against VEGF or specific binding proteins or else low-molecular-weight substances which are able to inhibit VEGF release or receptor binding specifically.
The abovementioned combinations can be administered simul-taneously or one after the other at different times. They can be used both in a single pharmaceutical formulation and in separate ,, ooso~4s~s5 formulations. The application forms may also differ, for example the endothelin receptor antagonists may be administered orally and the VEGF inhibitors parenterally.
These combination preparations are suitable in particular for the treatment and prevention of hypertension and disorders resulting therefrom, and also for the treatment of cardiac insufficiency.
The high activity of the compounds can be demonstrated by the following experiments:
Receptor binding studies Cloned human ETA or ET$ receptor-expressing CHO cells were used for the binding studies.
Membrane preparation The ETA or ETB receptor-expressing CHO cells were grown in a DMEM
NUT MIX F12 medium (Gibco, No. 21331-020) containing 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022), 1 mM
glutamine (Gibco No. 25030-024), 100 U/ml penicillin and 100 wg/ml streptomycin (Gibco, Sigma No. P-0781). After 48 hours, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS at 37°C for 5 minutes. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 x g.
For the membrane preparation, the cells were diluted to a concentration of 108 cells/ml of buffer (50 mM tris~HC1 buffer, pH 7.4) and then disintegrated by ultrasound using a Branson Sonifier 250, for 40-70 seconds/constant output 20.
Binding assays For the ETA and ETB receptor binding assay, the membranes were suspended in an incubation buffer (50 mM tris-HC1, pH 7.4 with 5 mM MnCl2, 40 mg/ml of bacitracin and 0.2% BSA) at a concen-tration of 50 ~g of protein per assay mixture and incubated at 25~C with 25 pM [125I~ ET1 (ETA receptor assay) or 25 pM [125I) ET3 (ETB receptor assay) in the presence and absence of test substance. The nonspecific binding was determined using 10-~ M
ET1. After 30 min, filtration through GF/B glass fiber filters (Whatman, England) in a Skatron cell collector (Skatron, Lier, Norway) was carried out to separate free and bound radioligand, and the filters were washed with ice-cold tris-HC1 buffer, pH 7.4, containing 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.
Functional test on vessels for endothelia receptor antagonists Segments of rabbit aorta are, after an initial tension of 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37°C and pH 7.3-7.4, first induced to contract with K+. After washing out, an endothelia dose-effect plot up to the maximum is constructed.
Potential endothelia antagonists are administered to other preparations of the same vessel 15 minutes before starting the endothelia dose-effect plot. The effects of the endothelia are calculated as ~ of the K+-induced contraction. Effective endothelia antagonists effect a shift to the right in the endothelia dose-effect plat.
Testing of ET antagonists in vivo:
Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed. The carotid artery and jugular vein were catheterized.
In control animals, intravenous administration of l~.g/kg ET1 leads to a distinct rise in blood pressure which persists for a relatively long period.
The test animals received an i.v. injection of the test compounds (1 ml/kg) 30 min before the administration of ET1. To determine the ET-antagonistic properties, the changes in blood pressure in the test animals were compared with those in the control animals.
Oral testing of the mixed ETA and ETH antagonists:
Male normotone rats weighing 250-350 g (Sprague Dawley, Janvier) are pretreated orally with the test substances. 80 minutes later, the animals are anesthetized with urethan and the A. carotis (for measuring blood pressure) and the V. jugularis (administration of big endothelin/endothelin 1) are catheterized.
After a stabilization phase, big endothelia (20 ~,g/kg, Appl. Vol.
0.5 ml/kg) or ET1 (0.3 ~,g/kg, appl. vol. 0.5 ml/kg) are adminis-tered intravenously. Blood pressure and heart frequency are con-tinuously recorded over a period of 30 minutes. The distinct and persistent changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the animals which have been .. , , 0050/48785 treated with the substance is compared with the AUC of the con-trol animals.
The compounds according to the invention can be administered in a customary manner orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally).
Administration can also take place with vapors or sprays through the nasopharyngeal space.
The dosage depends on the age, condition and weight of the patient and on the mode of administration. The daily dose of active substance is about 0.5-50 mg/kg of body weight on oral administration and about 0.1-10 mg/kg of body weight on parenteral administration.
The novel compounds can be used in the conventional solid or liquid pharmaceutical administration forms, for example as uncoated or film-coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active substances can for this purpose be processed with conventional pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellent gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way usually contain from 0.1 to 90$ by weight of the active substance.
Synthesis examples Example 1:
Methyl 2-(4,6-dimethoxy-5-fluoropyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate 1.0 g (3.5 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate, dissolved in DMF, was added dropwise to a suspension of 0.18 g of NaH (4.2 mmol, 55$ in white mineral oil) in 10 ml of DMF. The mixture was stirred at room temperature for 30 minutes and then admixed with 830 mg (4.8 mmol) of 4,6-dime-thoxy-5-fluoro-2-methylsulfonylpyrimidine in 10 ml of DMF and stirred at room temperature for 2 hours. The reaction mixture was poured onto ice-water and extracted three times with diethyl ether. The ether phases were dried with magnesium sulfate and subsequently filtered, and the solvent was removed under reduced ,, 0050/48785 pressure. The brown residue (1.7 g) was purified by MPLC, giving 1.3 g of the desired product which was directly reacted further.
Example 2:
2-(4,6-dimethoxy-5-fluoropyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid (A) and 2-(4-methoxy-5-fluoro-6-hydroxypyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid (B) 1.3 g (2.9 mmol) of methyl 2-(4,6-dimethoxy-5-fluoropyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate were dissolved in 10 ml of dioxane and admixed with 5.9 ml of 1 N KOH solution. The mixture was stirred at reflux for four hours. Water was added to the reaction mixture, and the aqueous phase was extracted twice with ether. The aqueous phase was acidified with 1 N aqueous HCl and extracted with ether, the organic phase was dried over magnesium sulfate and the solvent was distilled off. The residue was taken up in ether, and 100 mg of product B crystallized out.
The mother liquor was admixed with n-hexane, giving 400 mg of product A as a solid.
A: 1H NMR (CDC13, 500 MHz): 7.2-7.45 (m, lOH); 6.05 (s, 1H); 3.95 (s, 6H); 3.3 (s, 3H) m.p.: 168-170°C
B: 1H NMR (DMSO, 250 MHz): 7.1-7.4 (m, lOH); 6.05 (s, 1H); 3.9 (s, 3H); 3.3 (s, 3H) m.p. : 115-117°C
Example 3:
Benzyl 2-(4-morpholino-5-fluoropyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate 3.3 g (9 mmol) of benzyl 2-hydroxy-3-methoxy-3,3-diphenyl-propionate and 4-morpholino-5-fluoro-2-chloropyrimidine, dissolved in DMF, were added dropwise to a suspension of 9.96 g of KZC03 (72 mmol) in 40 ml of DMF. The mixture was stirred initially at 90°C for 3 hours and subsequently at 130°C for 3 hours. The reaction mixture was poured onto ice-water and extracted three times with ethyl acetate. The ethyl acetate phases were dried using magnesium sulfate and subsequently filtered, and the solvent was removed under reduced pressure. The ., , 0050/48785 brown residue (5.72 g) was purified by MPLC and directly reacted further.
Example 4:
2-(4-Morpholino-5-fluoropyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid Using 300 mg of palladium on activated carbon (10$), a solution of 0.9 g of benzyl 2-(4-morpholino-5-fluoropyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate in 30 ml of ethyl acetate was hydrogenated with hydrogen under atmospheric pressure at room temperature over a period of 3 hours. The reaction mixture was filtered and concentrated and the residue (900 mg) was purified by MPLC.
1H NMR (CDC13, 500 MHz): 8.95 (d, 1H); 7.2-7.5 (m, lOH); 6.05 (s, 1H); 3.8 (s, 8H); 3.3 (s, 3H) m.p.: 174-175°C
The compounds listed in Table I can be prepared in a similar manner.
N O O O I O O vaO O O O I O O O
~Cw w w w w w w w w w w w w w U
a a~a~w a~a a~ a~d a~a~~ a a~
~ 0 0 0 0 0 0 ~ o o ~ o o z o 0 oao 0 0 0 0 0 0 0 0 0 0 ~ 0 0 0 x a I x s ~ s~
~ U x U
U
c x x x C
~' ~' x~ ix ~ ~ a ~
_ o ~,q ~ ~ ~ ~,~ T T
L1.' U 04' ~ ' ~ ~ Z O a ~ a a I ,ca~v U ~ s ~ s V U ~ E ~ . c ~ E E E a c ~ . a c~
N
N
T T >,T T T T T T T >,?,>.T T
C C C C C C C C C C C C C C C
N N ~ C.7N N N N ~ N N N N N C.7 Git t t t t t t .Ct t t t t t t G
. G.G G G G G.G.d 2 d.G G G G.
z ~ x U z s z z s z x x x s z s x U
_ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 C;
i-.i U U U U U U U U U U U U U U U
N
O --~N M ~ V1 .L~ p .-aN M ~ V~~Dt~00O~~ .-w.r..r..r.r H
N cn O O O O O O O I O O O ~n O O O O O O O I O O O O O
~G w w w w w w w w w w w w w w w w w w w w w w w w w w O O O O ~ ~ ~ O U O ~ O O O O W O ~ O ~ U ~ ~ O ~ U
a~ a~ a d a~ a~ a~ a~ a~ a a~ a~ a~ a~
ri O O O O ~ ~ O ~ O O ~ O O O O W O ~ O O U ~ O O ~ U
x x U
Z a x a~
U .n C U
T ~ ~ C x N T
x a~ V >, ° C
t ~.~,' V T e~ ~ t L
G. V ~ ~ ~ x ~ ~ C. d C C
x s v ~' z ~, ~ ~, ~ s >, q y o ° ~ U X U = ~ ~ ~ a ~' ~ s d ~ ~ y C a, ~. t ''' ~ ~' 2 G. a o ~_os o o~ '~., N C
y c -c~ p ~ v a a~ v v x ~ x d O c~ °~ ~ a~ ~ ~ c~
C: ~ C C .~ M ~ U ~ U U U M ~ x x U ~.. d M ~ d h ~/ 7, 9, ?~ T T 7, T >, >, >, T T i, T 7, T T ?. >, i, >, >, T T T 7~
C C C C C C C C C C C C C C C C C C C C C C C C C C
a) N 5,7 47 C) N N ~ Cl d d O~ N a) ~ ~ N dI N N ~ G7 N C~ N N
t L t t t t t t t t t t t t t t t L L t .C t t .= t a c. a a c. a a n. a a a a a o. a o. n a a c a a a a n. a.
Z
x x x " x x x x x x x x x x x x x x x x U x x x x O O O O O O O O O O O O O O O O O O O O O O O O O O
O O O O O O O O O O O O O O O O O O O O O O O O O O
.o ~ ;~c a o -~ N ~ c ~wc c~ oo a o ~ N M ~~ ~wc ~ 00 a o N N N N N N N N N N M M M M M M N) M M M V ~t i y i ~ i ~ i i i i ~ i ~ i i i i ~ i ~ ~ ~ ~ ~ i i ~. .. .. .~ .. r. .. ~..
N O O v~ 0 0 0 I O O O O O ~n 0 0 0 0 0 0 I 0 0 0 0 0 0 7G w u. w w w w w w w w w w w w w w w v w w w w w w w w ci: O O O O O ~ ~ O O O O ~ fi7 O O ~ U O O W O ~ O ~ O O
~ N ~ C) N N C7 ~ ~ ~ ~ ~ w y ~ N N
nii!O OOOO',~mO~"OO~wOOOOOUW.~OO~O
a, t T
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o, o c. o~ °s' ~ ~ a °, a ~ ~ ~_ ~ ~ c C ~ ~ G a r~
v °' >, a' o. c a, y O d ~ o ~' "~ ~'' ~ '~ ~ >' ~ ~ a ~ a uhw~'~Z..~I ~~~a v acv ~wI~ ~~~w ~~o N N E M ~ ~ E ~ M N M M E M .D N M ~ N E N M M ~ ~ N
>, C
a _ _ _ _ _ _ _ _ _ T T y >, T T >, T T T T T T T T T T T T T T T ~, T T T
C C C C C G C C C G C C C C G G C C C C C C C C C
v o~ ~ a~ a~ a~ a> a~ a~ a a a~ a~ a a~ a~ a~ a> a~ a~ o~ a~ a a~ a~ n~
s I s s s s s s s s s s s s s s s s s s s s .~ s s c a N a a a a a a a a a a a a a a a a a a a o. a a a Z .T. T Z Z Z Z Z Z ~ Z Z Z Z ~ ~ Z Z Z Z Z Z T ~
O O O O O O O O O O O O O O O O O O O O O O O O O O
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c-n M v v; ~.o ~ x a o ~-~ m M er we ~ ~ a o -~ N M ~r v, vo o v ~ ~ v ~ ~ ~r ~r ~mn ~n v~ v~ vmn vmn v~ .o vc ~o vo vo ~o vo vo i i i y" .!. ..~ ~ i i ~ ~ i i ~ i i ~ i i i i ~ i i i ... .. ... .. ~. .r r. ..
N O O O O O I O O O O O O O O cnO O O O O O O I O O O
k w w w w w w w w w w w w w w w w w u,~.w w w w w w w a v a~a~a a~ a~ d a~a~a d a~ a~v ~ ~ w w x ~ o o ~ 0 0 0 0 ~ w o ~ o ~ 0 0 0 0 0 ~ o o ~ o o z o o o 0 0 0 o o o 0 0 0 o o o ~ 0 0 0 ~ w ~ w ~ w w U U
x U U
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c a T T ~ U U
v v c c G T G ~
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L t L s L L a ~ ~ w ~ v ~ 5 v v a~a~a s a~ ~ ~ a~T v a~v a~ a~.
s s .1 v ,cI I E E E E E a~E M I M ~ ~ E n,E E E M M E ~ E E
sy'N ~ C a~
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C s C N T C T T C
C C y ~ Q ry- L C y C C = 1.
v a~s a W o. a~ s ~ a~p, n.
a s a ~ , y o > > ' a L v a a y > a a >
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v u.ts.U v ~ O ~ o~C.~o~w c~a U tr..w ~ v o~U a~v a a~
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v x x v x x x x x x x x x z v x x x x x z x x x x U U U U U U U U U U U U U U U U U U U U U U U U U U
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m .o~ ~ ~ ~ t~t~~ n ~ t~0000000000000oao00000,a.ovo.
~ i i i i i i i i i i i ~ i i i i i ~ i i i i i i i N o ~ I o 0 0 0 0 0 0 0 ~ ~ 0 0 0 0 ~ 0 0 0 0 0 o I o M
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ric :' ti:O O ~ U ~ ~ O ~ O ~ O O ~ O ~ O ~ ~ O ~ O ~ W ~ U
v a~ a~ a~ a~ a~v a~ a a~ a~ a a~d O O ~ O ~ W O W O W O O W O W O O W O W O ~ W ~ O O
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s s ~ s L a> L p 1 I . I I
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I I I i H
Example 5 Using the binding assay described above, receptor binding data were measured for the compounds listed below.
The results are compiled in Table 3.
Table 3 Receptor binding data (Ki values) Compound ETA [nM] ETB [nM]
I-2 7.4 1200 I-121 61 > 10000 I-168 4000 > 7000
UTILIZATION AS ENDOTHELIN ANTAGONISTS
The present invention relates to novel carboxylic acid derivatives having a 5-substituted pyrimidine ring, to their preparation and use.
Endothelia is a peptide which is composed of 21 amino acids and is synthesized and released by the vascular endothelium.
Endothelia exists in three isoforms, ET-l, ET-2 and ET-3. In the following text, "endothelia" or "ET" signifies one or all isoforms of endothelia. Endothelia is a potent vasoconstrictor and has a potent effect on vessel tone. It is known that this vasoconstriction is caused by binding of endothelia to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 1~4, 868-875, 1988).
Increased or abnormal release of endothelia causes persistent vasoconstriction in the peripheral, renal and cerebral blood vessels, which may lead to disorders. It has been reported in the literature that endothelia is involved in a number of disorders;
these include hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's disease, cerebral vasospasms, stroke, benign prostatic hypertrophy, ateriosclerosis, asthma and cancer of the prostate (J. Vascular Med. Biology 2, 207 (1990), J. Am.
Med. Association 264, 2868 (1990), Nature 344, I14 (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 endothelia receptor subtypes, the ETA and ETB
receptors, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (I990)). Consequently, substances which inhibit binding of endothelia to one or both receptors should antagonize physiological effects of endothelia and should therefore be valuable drugs.
Carboxylic acid derivatives and their use as endothelia antagonists are described in WO 95/26716, WO 96/11914, Wp 97/9294, WO 97/12878, WO 97/38980, WO 97/38981. These compounds carry a nitrogen atom or a group /C-H
~
, CA 02321182 2000-08-14 ,_ , , , 0050/48785 at the 5-position of the heterocycle.
In contrast, the compounds according to the invention have in this position a group /C-X
where X is halogen, hydroxyl or C1-Ca-haloalkyl. Compared to the known endothelin antagonists, the compounds according to the invention are, for example, metabolized more favorably in the body.
The present invention relates to carboxylic acid derivatives of the formula I
a R
R N
I
R6 Z-C-C-O-~~ ~ R
Rs Ri N -where R1 is tetrazole or a group O
C-R
in which R is:
a) a radical ORS, where R~ is:
hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerable organic ammonium ion such as tertiary C1-C4-alkylammonium or the ammonium ion;
C3-CB-cycloalkyl, C1-C8-alkyl, CH2-phenyl which may be substituted by one or more of the following radicals:
halogen, nitro, cyano, C1-C4-alkyl, CI-C4-haloalkyl, hydroxyl, Ci-C4-alkoxy, mercapto, C1-CQ-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)z;
a C3-C6-alkenyl or a C3-C6-alkynyl group, it being possible for these groups for their part to carry one to five halogen atoms;
,. , , 0050/48785 R~ may furthermore be a phenyl radical which may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, Cl-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;
b) a 5-membered heteroaromatic such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl which is attached via a nitrogen atom and which may carry one to two halogen atoms, or one to two C1-C4-alkyl or one to two C1-C4-alkoxy groups.
c) a group (o)k_ -O-(CHZ)p-S-R8 in which k may be 0, 1 or 2, p may be 1, 2, 3 or 4 and Rg is C1-C4-alkyl, C3-C$-cycloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or phenyl which may be substituted by one or more, for example by one to three, of the following radicals:
halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-CQ-alkoxy, C1-C4-alkylthio, mercapto, amino, NH(C1-C4-alkyl), N(C1-Cq-alkyl)2.
d) a radical O
H
O
where R9 is:
C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-Cg-cycloalkyl, where these radicals may carry a C1-C4-alkoxy, C1-C4-alkylthio and/or a phenyl radical as mentioned under c);
phenyl which may be substituted by one to three of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-CQ-haloalkyl, hydroxyl, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, NH(C1-Cq-alkyl), N(C1-Cq-alkyl)Z, The other substituents are as defined below:
R2 is hydrogen, hydroxyl, NH2, NH(C~-C4-alkyl), N(Ci-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C~-C4-alkynyl, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio, morpholine;
X is halogen, C1-C4-haloalkyl, hydroxyl;
R3 is hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)z, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, -NH-0-C1-C4-alkyl, C1-C4-alkylthio;
R4 and R5 (which may be identical or different) are:
phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, mercapto, alkylcarbonyl, alkoxycarbonyl, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)Z; or phenyl or naphthyl which are ortho-linked with each other via a direct bond, a methylene, ethylene, or ethenylene group, an oxygen or sulfur atom or an S02-, NH- or N-alkyl group; or a five- or six-membered heteroaromatic containing one to three nitrogen atoms and/or one sulfur or oxygen atom which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, Cl-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals for their part may carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
or C3-C7-cycloalkyl;
R6 is hydrogen, C1-C8-alkyl, C3-C6-alkenyl, C3-C6-alkinyl or C3-Ce-cycloalkyl, where these radicals may in each case be mono- or polysubstituted by: hydroxyl, mercapto, carboxyl, halogen, vitro, cyano, C1-C4-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C3-C$-alkylcarbony-lalkyl, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)z, phenoxy or phenyl where the abovementioned aryl radicals may be mono- or polysubstituted, for example phenyl or phenoxy mono- to trisubstituted by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, mercapto, 5 carboxyl, hydroxyl, amino, R12, C1-C4-alkoxycarbonyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)Z, dioxomethylene, dioxoethylene or C1-C4-alkylthio;
phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl , N(Ci-C4-alkyl)z or dioxomethylene or dioxoethylene;
a five- or six-membered heteroaromatic containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-CQ-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals for their part may carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
with the proviso that R6 can only be hydrogen if Z is not a single bond;
R12 is Cl-C4-alkyl, C1-C4-alkylthio, C1-C4-alkoxy, which may carry one of the following radicals: hydroxyl, carboxyl, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)Z, carboxamide or CON(C1-C4-alkyl)2;
Z is sulfur, oxygen or a single bond.
For this and further below, the following definitions apply:
an alkali metal is, for example, lithium, sodium, potassium;
an alkaline earth metal is, for example, calcium, magnesium, barium;
organic ammonium ions are protonated amines such as, for example, ethanolamine, diethanolamine, ethylenediamine, diethylamine or piperazine;
,~, 0050/48785 C3-C~-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
C1-C4-haloalkyl may be linear or branched, such as, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoro-ethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl;
C1-C4-haloalkoxy may be linear or branched, such as, for example, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
C1-C4-alkyl may be linear or branched, such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;
CZ-C4-alkenyl may be linear or branched, such as, for example, ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl;
CZ--C4-alkynyl may be linear or branched, such as, for example, ethynyl, 1-propin-1-yl, 1-propin-3-yl, 1-butin-4-yl or 2-butin-4-yl;
C1-C4-alkoxy may be linear or branched, such as, for example, methoxy, ethoxy, propoxy, 1 methylethoxy, butoxy, 1 methyl-propoxy, 2-methylpropoxy or l,l~iimethylethoxy;
C3~6-alkenyloxy may be linear or branched, such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
C3-C6-alkynyloxy may be linear or branched, such as, for example, 2-propin-1-yloxy, 2-butin-1-yloxy or 3-butin-2-yloxy;
C1-C4-alkylthio may be linear or branched, such as, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2 methylpropylthio or 1,1-dimethylethylthio;
C1-CQ-alkylcarbonyl may be linear or branched, such as, for example, acetyl, ethylcarbonyl or 2-propylcarbonyl;
w , 0050/48785 io C1-C4-alkoxycarbonyl may be linear or branched, such as, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;
5 C3-Cg-alkylcarbonylalkyl may be linear or branched, such as, for example, 2-oxoprop-1-yl, 3-oxobut-1-yl or 3-oxobut-2-yl;
C1-CB-alkyl may be linear or branched, such as, for example, C1-C4-alkyl, pentyl, hexyl, heptyl or octyl;
halogen is, for example, fluorine, chlorine, bromine, iodine.
The invention further relates to those compounds from which the compounds of the formula I can be released (prodrugs).
Preference is given to those prodrugs where the release occurs under the conditions which prevail in certain compartments of the body, for example in the stomach, the intestine, the bloodstream or the liver.
The compounds and also the intermediates for their preparation, such as, for example, II and IV, may have one or more asym-metrically substituted carbon atoms. Such compounds may be present as pure enantiomers or pure diastereomers or as mixtures thereof. Preference is given to the use of an enantiomerically pure compound as active compound.
The invention furthermore relates to the use of the above-mentioned carboxylic acid derivatives for preparing drugs, in particular for preparing inhibitors for endothelin receptors.
The compounds of the formula IV in which Z is sulfur or oxygen (IVa) can be prepared as described in WO 96/11914.
O I
R R + R6-Z-H ~ R6_Z~C--OH
Rs R5 R1 II III IVa Compounds of the formula III are either known or can be synthesized, for example, by reduction of the corresponding carboxylic acids or esters thereof, or by other generally known methods.
,. , ~, 0050/48785 CA o232iis2 Zooo-os-i4 Compounds of the formula IVa can be obtained in enantiomerically pure form by an acid-catalyzed transetherification, as described in DE 19636046.3.
Furthermore, enantiomerically pure compounds of the formula IVa can be obtained by carrying out a classic racemate separation on racemic or diastereomeric compounds of the formula IVa using suitable enantiomerically pure bases. Suitable bases are, for example, 4-chlorophenylethylamine and the bases which are mentioned in WO 96/11914.
The compounds of the formula IV in which Z is a single bond (IVb) can be prepared both racemically and in enantiomerically pure form, as described in WO 97/38981.
R6--~--C=O ~' R6~C-OH
RS H ~ s a R R
V IVb The compounds according to the invention in which the substi-tuents are as defined in the formula I can be prepared, for example, by reacting the carboxylic acid derivatives of the formula IV in which the substituents are as defined with compounds of the formula V.
Rz IV + Rl~ --~/ ~ X ~ I
X-In the formula V, Rlo is halogen or R11-SOz-, and R11 can be C1-C4-alkyl, C1-C4-haloalkyl or phenyl. The reaction is preferably carried out in an inert solvent or diluent with addition of a suitable base, i.e. a base which effects a deprotonation of intermediate IV, in a temperature range of from room temperature to the boiling point of the solvent.
Compounds of type I where R1 = COON can furthermore be obtained directly when the intermediate IV in which R1 is COON is deprotonated with two equivalents of a suitable base and reacted with compounds of the formula V. The reaction is again carried out in an inert solvent and in a temperature range of from room temperature to the boiling point of the solvent.
Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, which may in each case be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloro-ethylene, ethers, such as, for example, diisopropyl ether, diisobutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles, such as, for example, acetonitrile and propionitrile, acid amides, such as, for example, dimethylformamide, dimethylacetamide and N methylpyrrolidone, sulfoxides and sulfones, such as, for example, dimethyl sulfoxide and sulfolane. .
Compounds of the formula V are known, and some of them are commercially available, or they can be prepared in a generally known manner.
An alkali metal or alkaline earth metal hydride, such as sodium hydride, potassium hydride or calcium hydride, a carbonate, such as an alkali metal carbonate, for example sodium carbonate or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or potassium hydroxide, an organometallic compound, such as butyllithium, or an alkali metal amide, such as lithium diisopropylamide, may serve as base.
Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, i.e. compounds of the formula I in which R1 is COON, and initially converting these in a customary manner into an activated form, such as an acyl halide, an anhydride or imidazolide, and then reacting this with an appropriate hydroxyl compound HORS. This reaction can be carried out in the customary solvents and often requires addition of a base, such as, for example, triethylamine, pyridine, imidazole or diazabicycloundecane. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent, such as a carbodiimide.
Moreover, compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, i.e. from compounds of the formula I in which R1 is a group COOM
in which M may be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R~-A, A being a customary nucleofugic ,', 0050/48785 leaving group, for example halogen, such as chlorine, bromine, iodine or aryl- or alkylsulfonyl, such as, for example, toluene-sulfonyl and methylsulfonyl, which may be substituted by halogen, alkyl or haloalkyl, or another equivalent leaving group.
5 Compounds of the formula R~-A having a reactive sub~stituent A are known or can easily be obtained with general expert knowledge.
This reaction can be carried out in the customary solvents and is advantageously carried out with the addition of a base, in which case those mentioned above are suitable.
In some cases, generally known protective group techniques have to be employed for the preparation of the compounds I according to the invention. If, for example, R6 = 4-hydroxyphenyl, the hydroxyl group can initially be protected as benzyl ether which is then cleaved at a suitable stage of the reaction sequence.
Compounds of the formula I in which R1 is tetrazole can be prepared as described in WO 96/11914.
With a view to biological activity, preference is given to those carboxylic acid derivatives of the formula I - both as pure enantiomers or pure diastereomers or as mixtures thereof - in which the substituents are as defined below:
RZ is hydrogen, hydroxyl, N(C1-C4-alkyl)Z, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, halogen;
X is halogen, trifluoromethyl;
R3 is hydrogen, hydroxyl, N(C1-C4-alkyl)Z, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, halogen;
R4 and RS are phenyl or naphthyl which may be substituted by one or more, for example by one to three, of the following radicals: halogen, cyano, hydroxyl, mercapto, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, NH(C1-C4-alkyl)Z, N(C1-CQ-alkyl)2, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl;
phenyl or naphthyl which are ortho-linked to each other via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SOZ, NH or N(C1-C4-alkyl) group ,. ,~, 0050/48785 a five-membered heteroaromatic containing one or two nitrogen atoms and/or a sulfur or oxygen atom, which may carry one to two halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-alkoxy, phenyl which for its part may carry one to three halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-alkoxy or C1-C4-alkylthio;
or C3-C~-cycloalkyl;
R6 is CI-CB-alkyl, C3-C6-alkenyl, C3-C6-alkynyl or C3-Cg-cycloalkyl where these radicals may in each case be mono- or polysubstituted by: halogen, hydroxyl, cyano, C1-C4-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-CQ-alkyl-thio, C1-C4-haloalkoxy, C1-Cq-alkylcarbonyl, hydroxycarbonyl, C1-C4-alkoxycarbonyl, NH(C1-C9-alkyl)z, N(C1-C4-alkyl)z, phenoxy or phenyl, where the abovementioned aryl radicals may be mono- or polysubstituted, for example mono- to trisubstituted, by halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, Rlz, C1-C4-alkoxycarbonyl, dioxomethylene, dioxoethylene, C1-C4-alkylthio, phenyl or phenoxy;
phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-Cq-alkyl)z, N ( C1--C4-alkyl ) z:
a five- or six-membered heteroaromatic containing one to three nitrogen atoms and/or a sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, Cz-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals for their part may carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
R1z is C1-C4-alkyl, C1-C4-alkoxy, which carry one of the following radicals: hydroxyl, carboxamide or CON(C1-C4-alkyl)Z;
Z is sulfur, oxygen or single bond.
.~, 0050/48785 Particular preference is given to compounds of the formula I -both as pure enantiomers and pure diastereomers or as mixtures thereof - where the substituents are as defined below:
R2 is C1-C4-alkyl, C1-C4-alkoxy, in particular methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;
X is fluorine, trifluoromethyl;
R3 is C1-C4-alkyl, C1~4-alkoxy, C1-C4-alkylthio, in particular methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;
R4 and RS are phenyl (identical or different) which may be substituted by one or more, for example by one to three, of the following radicals: halogen, hydroxyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio or R4 and R5 are phenyl groups which are ortho-linked to each other via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2, NH or N(C1-C4-alkyl) group; or thiazole, oxazole, thiophene or furan, where the above-mentioned heteroaromatics may be mono- to disubstituted by:
halogen, C1-C4-alkyl, C1-C4-alkoxy;
R4 and RS are cyclohexyl;
R6 is C1-CB-alkyl, C3-C6-alkenyl or C3-Cg-cycloalkyl, where these radicals may in each case be mono- or polysubstituted by:
halogen, hydroxyl, cyano, C1-C4-alkoxy, C3-C6-alkenyloxy, C1-C4-alkylthio, phenoxy or phenyl, where the abovementioned aryl radicals may be mono- or polysubstituted, for example mono- to trisubstituted, by C1-C9-alkyl, C1-C4-alkoxy, dioxomethylene, dioxoethylene, C1-C4-alkylthio;
phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, C1-C4-alkylamino or C1-C4-dialkylamino;
a five- or six-membered heteroaromatic, containing a nitrogen atom and/or a sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, .. , , 0050/48785 ., C1-CQ-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals for their part may carry one to five halogen atoms and/or one to three of the following radicals:
C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and/or C1-C4-alkylthio;
Y is sulfur, oxygen or a single bond.
The compounds of the present invention provide a novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, arrhythmia, acute/chronic kidney failure, chronic cardiac insufficiency, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorhages, migraine, asthma, aterio-sclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and bypass operations, benign prostatic hyperplasia, hypertension or kidney failure caused by ischemia or intoxication, metastasis and growth of mesenchymal tumors, contrast-agent-induced kidney failure, pancreatitis, gastro-intestinal ulcers and erectile dysfunction.
The invention further relates to combinations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin-II antagonists and angiotensin converting enzyme (ACE) inhibitors. Preference is given to combinations of endothelin receptor antagonists of the formula I and ACE inhibitors.
The invention furthermore relates to combinations of endothelin receptor antagonists of the formula I and beta blockers.
The invention furthermore relates to combinations of endothelin receptor antagonists of the formula I and diuretics.
The invention furthermore relates to combinations of endothelin receptor antagonists of the formula I and substances which block the action of VEGF (vascular endothelial growth factor). Such substances are, for example, antibodies directed against VEGF or specific binding proteins or else low-molecular-weight substances which are able to inhibit VEGF release or receptor binding specifically.
The abovementioned combinations can be administered simul-taneously or one after the other at different times. They can be used both in a single pharmaceutical formulation and in separate ,, ooso~4s~s5 formulations. The application forms may also differ, for example the endothelin receptor antagonists may be administered orally and the VEGF inhibitors parenterally.
These combination preparations are suitable in particular for the treatment and prevention of hypertension and disorders resulting therefrom, and also for the treatment of cardiac insufficiency.
The high activity of the compounds can be demonstrated by the following experiments:
Receptor binding studies Cloned human ETA or ET$ receptor-expressing CHO cells were used for the binding studies.
Membrane preparation The ETA or ETB receptor-expressing CHO cells were grown in a DMEM
NUT MIX F12 medium (Gibco, No. 21331-020) containing 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022), 1 mM
glutamine (Gibco No. 25030-024), 100 U/ml penicillin and 100 wg/ml streptomycin (Gibco, Sigma No. P-0781). After 48 hours, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS at 37°C for 5 minutes. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 x g.
For the membrane preparation, the cells were diluted to a concentration of 108 cells/ml of buffer (50 mM tris~HC1 buffer, pH 7.4) and then disintegrated by ultrasound using a Branson Sonifier 250, for 40-70 seconds/constant output 20.
Binding assays For the ETA and ETB receptor binding assay, the membranes were suspended in an incubation buffer (50 mM tris-HC1, pH 7.4 with 5 mM MnCl2, 40 mg/ml of bacitracin and 0.2% BSA) at a concen-tration of 50 ~g of protein per assay mixture and incubated at 25~C with 25 pM [125I~ ET1 (ETA receptor assay) or 25 pM [125I) ET3 (ETB receptor assay) in the presence and absence of test substance. The nonspecific binding was determined using 10-~ M
ET1. After 30 min, filtration through GF/B glass fiber filters (Whatman, England) in a Skatron cell collector (Skatron, Lier, Norway) was carried out to separate free and bound radioligand, and the filters were washed with ice-cold tris-HC1 buffer, pH 7.4, containing 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.
Functional test on vessels for endothelia receptor antagonists Segments of rabbit aorta are, after an initial tension of 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37°C and pH 7.3-7.4, first induced to contract with K+. After washing out, an endothelia dose-effect plot up to the maximum is constructed.
Potential endothelia antagonists are administered to other preparations of the same vessel 15 minutes before starting the endothelia dose-effect plot. The effects of the endothelia are calculated as ~ of the K+-induced contraction. Effective endothelia antagonists effect a shift to the right in the endothelia dose-effect plat.
Testing of ET antagonists in vivo:
Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed. The carotid artery and jugular vein were catheterized.
In control animals, intravenous administration of l~.g/kg ET1 leads to a distinct rise in blood pressure which persists for a relatively long period.
The test animals received an i.v. injection of the test compounds (1 ml/kg) 30 min before the administration of ET1. To determine the ET-antagonistic properties, the changes in blood pressure in the test animals were compared with those in the control animals.
Oral testing of the mixed ETA and ETH antagonists:
Male normotone rats weighing 250-350 g (Sprague Dawley, Janvier) are pretreated orally with the test substances. 80 minutes later, the animals are anesthetized with urethan and the A. carotis (for measuring blood pressure) and the V. jugularis (administration of big endothelin/endothelin 1) are catheterized.
After a stabilization phase, big endothelia (20 ~,g/kg, Appl. Vol.
0.5 ml/kg) or ET1 (0.3 ~,g/kg, appl. vol. 0.5 ml/kg) are adminis-tered intravenously. Blood pressure and heart frequency are con-tinuously recorded over a period of 30 minutes. The distinct and persistent changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the animals which have been .. , , 0050/48785 treated with the substance is compared with the AUC of the con-trol animals.
The compounds according to the invention can be administered in a customary manner orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally).
Administration can also take place with vapors or sprays through the nasopharyngeal space.
The dosage depends on the age, condition and weight of the patient and on the mode of administration. The daily dose of active substance is about 0.5-50 mg/kg of body weight on oral administration and about 0.1-10 mg/kg of body weight on parenteral administration.
The novel compounds can be used in the conventional solid or liquid pharmaceutical administration forms, for example as uncoated or film-coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active substances can for this purpose be processed with conventional pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellent gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way usually contain from 0.1 to 90$ by weight of the active substance.
Synthesis examples Example 1:
Methyl 2-(4,6-dimethoxy-5-fluoropyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate 1.0 g (3.5 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate, dissolved in DMF, was added dropwise to a suspension of 0.18 g of NaH (4.2 mmol, 55$ in white mineral oil) in 10 ml of DMF. The mixture was stirred at room temperature for 30 minutes and then admixed with 830 mg (4.8 mmol) of 4,6-dime-thoxy-5-fluoro-2-methylsulfonylpyrimidine in 10 ml of DMF and stirred at room temperature for 2 hours. The reaction mixture was poured onto ice-water and extracted three times with diethyl ether. The ether phases were dried with magnesium sulfate and subsequently filtered, and the solvent was removed under reduced ,, 0050/48785 pressure. The brown residue (1.7 g) was purified by MPLC, giving 1.3 g of the desired product which was directly reacted further.
Example 2:
2-(4,6-dimethoxy-5-fluoropyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid (A) and 2-(4-methoxy-5-fluoro-6-hydroxypyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid (B) 1.3 g (2.9 mmol) of methyl 2-(4,6-dimethoxy-5-fluoropyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate were dissolved in 10 ml of dioxane and admixed with 5.9 ml of 1 N KOH solution. The mixture was stirred at reflux for four hours. Water was added to the reaction mixture, and the aqueous phase was extracted twice with ether. The aqueous phase was acidified with 1 N aqueous HCl and extracted with ether, the organic phase was dried over magnesium sulfate and the solvent was distilled off. The residue was taken up in ether, and 100 mg of product B crystallized out.
The mother liquor was admixed with n-hexane, giving 400 mg of product A as a solid.
A: 1H NMR (CDC13, 500 MHz): 7.2-7.45 (m, lOH); 6.05 (s, 1H); 3.95 (s, 6H); 3.3 (s, 3H) m.p.: 168-170°C
B: 1H NMR (DMSO, 250 MHz): 7.1-7.4 (m, lOH); 6.05 (s, 1H); 3.9 (s, 3H); 3.3 (s, 3H) m.p. : 115-117°C
Example 3:
Benzyl 2-(4-morpholino-5-fluoropyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate 3.3 g (9 mmol) of benzyl 2-hydroxy-3-methoxy-3,3-diphenyl-propionate and 4-morpholino-5-fluoro-2-chloropyrimidine, dissolved in DMF, were added dropwise to a suspension of 9.96 g of KZC03 (72 mmol) in 40 ml of DMF. The mixture was stirred initially at 90°C for 3 hours and subsequently at 130°C for 3 hours. The reaction mixture was poured onto ice-water and extracted three times with ethyl acetate. The ethyl acetate phases were dried using magnesium sulfate and subsequently filtered, and the solvent was removed under reduced pressure. The ., , 0050/48785 brown residue (5.72 g) was purified by MPLC and directly reacted further.
Example 4:
2-(4-Morpholino-5-fluoropyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid Using 300 mg of palladium on activated carbon (10$), a solution of 0.9 g of benzyl 2-(4-morpholino-5-fluoropyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate in 30 ml of ethyl acetate was hydrogenated with hydrogen under atmospheric pressure at room temperature over a period of 3 hours. The reaction mixture was filtered and concentrated and the residue (900 mg) was purified by MPLC.
1H NMR (CDC13, 500 MHz): 8.95 (d, 1H); 7.2-7.5 (m, lOH); 6.05 (s, 1H); 3.8 (s, 8H); 3.3 (s, 3H) m.p.: 174-175°C
The compounds listed in Table I can be prepared in a similar manner.
N O O O I O O vaO O O O I O O O
~Cw w w w w w w w w w w w w w U
a a~a~w a~a a~ a~d a~a~~ a a~
~ 0 0 0 0 0 0 ~ o o ~ o o z o 0 oao 0 0 0 0 0 0 0 0 0 0 ~ 0 0 0 x a I x s ~ s~
~ U x U
U
c x x x C
~' ~' x~ ix ~ ~ a ~
_ o ~,q ~ ~ ~ ~,~ T T
L1.' U 04' ~ ' ~ ~ Z O a ~ a a I ,ca~v U ~ s ~ s V U ~ E ~ . c ~ E E E a c ~ . a c~
N
N
T T >,T T T T T T T >,?,>.T T
C C C C C C C C C C C C C C C
N N ~ C.7N N N N ~ N N N N N C.7 Git t t t t t t .Ct t t t t t t G
. G.G G G G G.G.d 2 d.G G G G.
z ~ x U z s z z s z x x x s z s x U
_ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 C;
i-.i U U U U U U U U U U U U U U U
N
O --~N M ~ V1 .L~ p .-aN M ~ V~~Dt~00O~~ .-w.r..r..r.r H
N cn O O O O O O O I O O O ~n O O O O O O O I O O O O O
~G w w w w w w w w w w w w w w w w w w w w w w w w w w O O O O ~ ~ ~ O U O ~ O O O O W O ~ O ~ U ~ ~ O ~ U
a~ a~ a d a~ a~ a~ a~ a~ a a~ a~ a~ a~
ri O O O O ~ ~ O ~ O O ~ O O O O W O ~ O O U ~ O O ~ U
x x U
Z a x a~
U .n C U
T ~ ~ C x N T
x a~ V >, ° C
t ~.~,' V T e~ ~ t L
G. V ~ ~ ~ x ~ ~ C. d C C
x s v ~' z ~, ~ ~, ~ s >, q y o ° ~ U X U = ~ ~ ~ a ~' ~ s d ~ ~ y C a, ~. t ''' ~ ~' 2 G. a o ~_os o o~ '~., N C
y c -c~ p ~ v a a~ v v x ~ x d O c~ °~ ~ a~ ~ ~ c~
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C C C C C C C C C C C C C C C C C C C C C C C C C C
a) N 5,7 47 C) N N ~ Cl d d O~ N a) ~ ~ N dI N N ~ G7 N C~ N N
t L t t t t t t t t t t t t t t t L L t .C t t .= t a c. a a c. a a n. a a a a a o. a o. n a a c a a a a n. a.
Z
x x x " x x x x x x x x x x x x x x x x U x x x x O O O O O O O O O O O O O O O O O O O O O O O O O O
O O O O O O O O O O O O O O O O O O O O O O O O O O
.o ~ ;~c a o -~ N ~ c ~wc c~ oo a o ~ N M ~~ ~wc ~ 00 a o N N N N N N N N N N M M M M M M N) M M M V ~t i y i ~ i ~ i i i i ~ i ~ i i i i ~ i ~ ~ ~ ~ ~ i i ~. .. .. .~ .. r. .. ~..
N O O v~ 0 0 0 I O O O O O ~n 0 0 0 0 0 0 I 0 0 0 0 0 0 7G w u. w w w w w w w w w w w w w w w v w w w w w w w w ci: O O O O O ~ ~ O O O O ~ fi7 O O ~ U O O W O ~ O ~ O O
~ N ~ C) N N C7 ~ ~ ~ ~ ~ w y ~ N N
nii!O OOOO',~mO~"OO~wOOOOOUW.~OO~O
a, t T
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o, o c. o~ °s' ~ ~ a °, a ~ ~ ~_ ~ ~ c C ~ ~ G a r~
v °' >, a' o. c a, y O d ~ o ~' "~ ~'' ~ '~ ~ >' ~ ~ a ~ a uhw~'~Z..~I ~~~a v acv ~wI~ ~~~w ~~o N N E M ~ ~ E ~ M N M M E M .D N M ~ N E N M M ~ ~ N
>, C
a _ _ _ _ _ _ _ _ _ T T y >, T T >, T T T T T T T T T T T T T T T ~, T T T
C C C C C G C C C G C C C C G G C C C C C C C C C
v o~ ~ a~ a~ a~ a> a~ a~ a a a~ a~ a a~ a~ a~ a> a~ a~ o~ a~ a a~ a~ n~
s I s s s s s s s s s s s s s s s s s s s s .~ s s c a N a a a a a a a a a a a a a a a a a a a o. a a a Z .T. T Z Z Z Z Z Z ~ Z Z Z Z ~ ~ Z Z Z Z Z Z T ~
O O O O O O O O O O O O O O O O O O O O O O O O O O
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c-n M v v; ~.o ~ x a o ~-~ m M er we ~ ~ a o -~ N M ~r v, vo o v ~ ~ v ~ ~ ~r ~r ~mn ~n v~ v~ vmn vmn v~ .o vc ~o vo vo ~o vo vo i i i y" .!. ..~ ~ i i ~ ~ i i ~ i i ~ i i i i ~ i i i ... .. ... .. ~. .r r. ..
N O O O O O I O O O O O O O O cnO O O O O O O I O O O
k w w w w w w w w w w w w w w w w w u,~.w w w w w w w a v a~a~a a~ a~ d a~a~a d a~ a~v ~ ~ w w x ~ o o ~ 0 0 0 0 ~ w o ~ o ~ 0 0 0 0 0 ~ o o ~ o o z o o o 0 0 0 o o o 0 0 0 o o o ~ 0 0 0 ~ w ~ w ~ w w U U
x U U
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L t L s L L a ~ ~ w ~ v ~ 5 v v a~a~a s a~ ~ ~ a~T v a~v a~ a~.
s s .1 v ,cI I E E E E E a~E M I M ~ ~ E n,E E E M M E ~ E E
sy'N ~ C a~
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C C y ~ Q ry- L C y C C = 1.
v a~s a W o. a~ s ~ a~p, n.
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m .o~ ~ ~ ~ t~t~~ n ~ t~0000000000000oao00000,a.ovo.
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ric :' ti:O O ~ U ~ ~ O ~ O ~ O O ~ O ~ O ~ ~ O ~ O ~ W ~ U
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_ _ z z z z z z z z z s z z z z z z z z z x x z z 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o z o ''tiU U U U U U U U U U U U U U U U U U U U U U U U U
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N O O O O cnO O O I O O O O cn O O O O I O O O O cnO O
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a a a ofa v aJa~a~a~
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7,7, C C
L L
a a O~O ' a x x s ~~ ' x s U U x U V x x x ~ x x x x x z ~ x .~x ~ ~ x x x 0 0 0 0 0 0 o z z o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 ~ 0 0 0 0 0 0 N M ~ ~!Sv0t~00CvO .-~N M ~ W O l~00O,O ~ N M ~ ~
V ~ ~ V
c c c N N N N c N N M M M M M r:M M M M ~ ~ ~ ~ et~t -~d J rrrr.--~.r~ rr..-n.r.r r - r -~
.--.-r . . ~ r . . ~ ..r,H ~r.~.w i t ~ i ~ y i i i i y i i i r i ~ ~ t i ~ ~ ~ .:,.~,.:
rw.. ~ r ~.
cnO O O O O O O O O O O t O O O O O O t O O O ~nO O O
w w ~:.w w u.w w w w w w w w w w w w w w w w w w w w w v ~ v ~ L ~ ~ ~ ~ v ~ ~ ~ i U v ~ v ~ i ~ ~
G L L C
O ~ O U O w O O O ~ U O O O U U O ~ O ~ O x U O O U
a, e_ ~
o s v v a~a> a~a~a~a~ a~a a> a a n~
O O ~ ~ U w w O O O O O O ~ O O O ~ ~ ~ ~ O E U O ~ w >, a s a t c r~
j,U T T
v I _T y , O
r, c N ~..ni . s a~
I CJT T T T T ~ T T ~_ T >,~ T d E ~,C T T T T T >, U t v ~ ~ ~ ~ s ~ ~ CGs _ L ~ ~ ~ ti -T
I ~ t t L L I L t L ~ t .C. ~ I ~ ~ .C
i c ~ ~ E ~ ~
r;. c. a a.a c~a a e a~ c.e a c~a c E E a E E E
>, T C
c a c s a,s = v a~a~ a T
s ac T 7,T T T T T ?,d a T >,~,d O-T ~ T T T T 0 T >,G.'~>, v ~ ~ v ~ ~ ~ ci._ ~ ~ ~ citi~ U ~ u ~ u v ~ ~ G:O
U
G G G d G G d N ~ a n n . . a ~ c a o o n a ~ ~
~ ~
G. r . . . . . . v . . c e a T T
c c N N
.C t a o.
r~ t x ,-,x o ~ r ,~,x x O
T "'x x Z x ~ U U U U x x Z U Z U U x x x x x x x x c o 0 0 0 0 0 0 0 0 0 0 0 o z o z o 0 0 0 0 0 0 0 0 0 ~ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 U U U U U U U U U U U U U U U U U U U U U U U U U U U
w.~ r a o --m ~ m n ~ t~000,o --~cnr~~ Two t~00ovo - c~
-.r~ ~ -~~;V;w_:~m ~_nv v~v~~Ow e vc~n~ ~ ~ ~Dv0t~t~r ...~..,.-.1~ _,..,~ ...~. , . _ ....~..,.~.-,,...
!._..__'.,!..!.' r:~: ' ' .!,_'.' .!,' ' ' ' ";.:.:..:.:' ~:' .~
O i O O O O O i i O O
c~.r~.,ciu.cLw u,w w w U.
O O
U ~ ~ ~ ~ W O
v v o~ w a a~
O O ~ ~ W LidO W O O O
T t ~ s S t t d ~ .C.G
L ~ GJN ~ O i~O O O N
E c E E E E E c n E E
. .
_ T _ T y T
C
d G T _ T T T T 7,T
T
L v ~ ~ ~ ~ ~ ~ ~ ~ Li .
% c n n m r . c . . o.o.n.a ;
T
C r n U U
c.
O O O
tnf/~r.VJ
O O O O O O O O O O
' U U U U U U ~ U U U U
~fV'7v0l~x O~O - N M
~ c~~ ~ ~ r x x x x -.....~
i i i i i i i i i i i N O O O O O O O O O O O O O
>Cw w w w w w w w w w w w w r~O O O O O O O O O O O O O
Ca;O O O O O O O O O O O O O
I
x" x T
O
/ \
ix- ~ z x x a U U
i >, ~ a, N - ~ o ~ O
>,> > > > > > >
, , , . , , o o , ~ o r N T
n _ ~
.
E E E E E E E .~b.a o V v ~, ...
Z
~'z z s = ~ _ ~ z z Q .nU U U O v)Z . o ~ U U U
a .
Z z Z Z z Z Z ~ Z ~ Z 2 2 O O O O O O O O O O O O O
O O O
O O O O O O O O O O
N
O -~N t~
"Q Q ~~N M v t~ O~~ .~.-,~-r I 1 I : I I
I I I i H
Example 5 Using the binding assay described above, receptor binding data were measured for the compounds listed below.
The results are compiled in Table 3.
Table 3 Receptor binding data (Ki values) Compound ETA [nM] ETB [nM]
I-2 7.4 1200 I-121 61 > 10000 I-168 4000 > 7000
Claims (8)
1. A carboxylic acid derivative of the formula I
where:
R1 is tetrazole or a group R is a) a radical OR7, where R7 is:
hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerable organic ammonium ion or ammonium ion;
C3-C8-cycloalkyl, C1-C8-alkyl, CH2-phenyl which may be substituted by one or more of the following radicals:
halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;
a C3-C6-alkenyl or a C3-C6-alkynyl group, it being possible for these groups for their part to carry one to five halogen atoms;
R7 may furthermore be a phenyl radical which may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;
b) a 5-membered heteroaromatic such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl which is attached via a nitrogen atom and which may carry one to two halogen atoms, or one to two C1-C4-alkyl or one to two C1-C4-alkoxy groups.
c) a group in which k may be 0, 1 or 2, p may be 1, 2, 3 or 4 and R8 is C1-C4-alkyl, C3-C8-cycloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or phenyl which may be substituted by one or more, for example by one to three, of the following radicals:
halogen, vitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2.
d) a radical where R9 is:
C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl, where these radicals may carry a C1-C4-alkoxy, C1-C4-alkylthio and/or a phenyl radical as mentioned under c);
phenyl which may be substituted by one to three of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 R2 is hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio, morpholine;
X is halogen, C1-C4-haloalkyl, hydroxyl;
R3 is hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, -NH-O-C1-C4-alkyl, C1-C4-alkylthio;
R4 and R5 (which may be identical or different) are:
phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, mercapto, alkylcarbonyl, alkoxycarbonyl, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2; or phenyl or naphthyl which are ortho-linked with each other via a direct bond, a methylene, ethylene, or ethenylene group, an oxygen or sulfur atom or an SO2-, NH- or N-alkyl group; or a five- or six-membered heteroaromatic containing one to three nitrogen atoms and/or one sulfur or oxygen atom which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C2-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals for their part may carry one to five halogen atoms and/or one to three of the following radicals:
C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
or C3-C7-cycloalkyl;
R6 is hydrogen, C1-C8-alkyl, C3-C6-alkenyl, C3-C6-alkynyl or C3-C8-cycloalkyl, where these radicals may in each case be mono- or polysubstituted by: hydroxyl, mercapto, carboxyl, halogen, nitro, cyano, C1-C4-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C3-C8-alkylcarbonylalkyl, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, phenyl which may be mono- or polysubstituted, for example phenyl or phenoxy which may be mono- to trisubstituted by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or dioxomethylene or dioxoethylene;
a five- or six-membered heteroaromatic containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals for their part may carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
with the proviso that R6 can only be hydrogen if Z is not a single bond;
Z is sulfur, oxygen or a single bond, and the physiologically tolerable salts, and the enantiomerically pure and also the diastereomerically pure forms.
where:
R1 is tetrazole or a group R is a) a radical OR7, where R7 is:
hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerable organic ammonium ion or ammonium ion;
C3-C8-cycloalkyl, C1-C8-alkyl, CH2-phenyl which may be substituted by one or more of the following radicals:
halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;
a C3-C6-alkenyl or a C3-C6-alkynyl group, it being possible for these groups for their part to carry one to five halogen atoms;
R7 may furthermore be a phenyl radical which may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;
b) a 5-membered heteroaromatic such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl which is attached via a nitrogen atom and which may carry one to two halogen atoms, or one to two C1-C4-alkyl or one to two C1-C4-alkoxy groups.
c) a group in which k may be 0, 1 or 2, p may be 1, 2, 3 or 4 and R8 is C1-C4-alkyl, C3-C8-cycloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or phenyl which may be substituted by one or more, for example by one to three, of the following radicals:
halogen, vitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2.
d) a radical where R9 is:
C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl, where these radicals may carry a C1-C4-alkoxy, C1-C4-alkylthio and/or a phenyl radical as mentioned under c);
phenyl which may be substituted by one to three of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 R2 is hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio, morpholine;
X is halogen, C1-C4-haloalkyl, hydroxyl;
R3 is hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, -NH-O-C1-C4-alkyl, C1-C4-alkylthio;
R4 and R5 (which may be identical or different) are:
phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, mercapto, alkylcarbonyl, alkoxycarbonyl, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2; or phenyl or naphthyl which are ortho-linked with each other via a direct bond, a methylene, ethylene, or ethenylene group, an oxygen or sulfur atom or an SO2-, NH- or N-alkyl group; or a five- or six-membered heteroaromatic containing one to three nitrogen atoms and/or one sulfur or oxygen atom which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C2-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals for their part may carry one to five halogen atoms and/or one to three of the following radicals:
C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
or C3-C7-cycloalkyl;
R6 is hydrogen, C1-C8-alkyl, C3-C6-alkenyl, C3-C6-alkynyl or C3-C8-cycloalkyl, where these radicals may in each case be mono- or polysubstituted by: hydroxyl, mercapto, carboxyl, halogen, nitro, cyano, C1-C4-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C3-C8-alkylcarbonylalkyl, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, phenyl which may be mono- or polysubstituted, for example phenyl or phenoxy which may be mono- to trisubstituted by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or dioxomethylene or dioxoethylene;
a five- or six-membered heteroaromatic containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals for their part may carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
with the proviso that R6 can only be hydrogen if Z is not a single bond;
Z is sulfur, oxygen or a single bond, and the physiologically tolerable salts, and the enantiomerically pure and also the diastereomerically pure forms.
2. The use of the carboxylic acid derivatives I as claimed in claim 1 for treating disorders.
3. The use of the compounds I as claimed in claim 1 as endothelin receptor antagonists.
4. The use of the carboxylic acid derivatives I as claimed in claim 1 for preparing drugs for the treatment of disorders which are associated with increased endothelin levels.
5. The use of the carboxylic acid derivatives I as claimed in claim 1 for preparing drugs for the treatment of disorders in which endothelia contributes to the development and/or progression.
6. The use of the carboxylic acid derivatives I as claimed in claim 1 for the treatment of chronic cardiac insufficiency, restenosis, high blood pressure, pulmonary hypertension, acute/chronic kidney failure, cerebral ischemia, asthma, benign prostatic hyperplasia and cancer of the prostate.
7. A combination of carboxylic acid derivatives of the formula I
as claimed in claim 1 and one or more active compounds, selected from inhibitors of the renin-angiotensin system such as renin inhibitors, angiogensin-II antagonists, angiotensin converting enzyme (ACE) inhibitors, mixed ACE/neutral endopeptidase (NEP) inhibitors, .beta.-blockers, diuretics, calcium antagonists and VEGF-blocking substances.
as claimed in claim 1 and one or more active compounds, selected from inhibitors of the renin-angiotensin system such as renin inhibitors, angiogensin-II antagonists, angiotensin converting enzyme (ACE) inhibitors, mixed ACE/neutral endopeptidase (NEP) inhibitors, .beta.-blockers, diuretics, calcium antagonists and VEGF-blocking substances.
8. A drug preparation for oral, parenteral and intra- parenteral administration which comprises per individual dose, in addition to the customary drug auxiliaries, at least one carboxylic acid derivative I as claimed in claim 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19806438.1 | 1998-02-17 | ||
| 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 |
| PCT/EP1999/000776 WO1999042453A1 (en) | 1998-02-17 | 1999-02-05 | 5-substituted pyrimidine-2-yloxy carboxylic acid derivatives, the production of the same and their utilization as endothelin antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2321182A1 true CA2321182A1 (en) | 1999-08-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002321182A Abandoned CA2321182A1 (en) | 1998-02-17 | 1999-02-05 | 5-substituted pyrimidine-2-yloxy carboxylic acid derivatives, the production of the same and their utilization as endothelin antagonists |
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| Country | Link |
|---|---|
| EP (1) | EP1066268A1 (en) |
| JP (1) | JP2002503726A (en) |
| KR (1) | KR20010086247A (en) |
| CN (1) | CN1291190A (en) |
| AR (1) | AR014960A1 (en) |
| AU (1) | AU3027199A (en) |
| BG (1) | BG104577A (en) |
| BR (1) | BR9907911A (en) |
| CA (1) | CA2321182A1 (en) |
| DE (1) | DE19806438A1 (en) |
| HR (1) | HRP20000602A2 (en) |
| HU (1) | HUP0100957A3 (en) |
| IL (1) | IL137038A0 (en) |
| NO (1) | NO20004075D0 (en) |
| PL (1) | PL342311A1 (en) |
| SK (1) | SK11512000A3 (en) |
| TR (1) | TR200002376T2 (en) |
| TW (1) | TW579376B (en) |
| WO (1) | WO1999042453A1 (en) |
| ZA (1) | ZA991214B (en) |
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| US9174970B2 (en) | 2008-01-22 | 2015-11-03 | Dow Agrosciences Llc | 5-fluoro pyrimidine derivatives |
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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 |
| EP2183223A2 (en) * | 2007-07-31 | 2010-05-12 | Gilead Colorado, Inc. | Metabolites and derivatives of ambrisentan |
| CN104521977A (en) * | 2008-08-01 | 2015-04-22 | 陶氏益农公司 | Use of 5-fluorocytosine as a fungicide |
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| DE4411225A1 (en) * | 1994-03-31 | 1995-10-05 | Basf Ag | Use of carboxylic acid derivatives as a drug |
| DE19533023B4 (en) * | 1994-10-14 | 2007-05-16 | Basf Ag | New carboxylic acid derivatives, their preparation and use |
| DE19614534A1 (en) * | 1996-04-12 | 1997-10-16 | Basf Ag | New carboxylic acid derivatives, their production and use |
| DE19614533A1 (en) * | 1996-04-12 | 1997-10-16 | Basf Ag | New alpha-hydroxy acid derivatives, their production and use |
| BR9714047A (en) * | 1996-12-18 | 2000-05-09 | Basf Ag | Carboxylic acid derivatives, use thereof, combination of these with one or more active compounds, preparation of drugs for oral and parenteral administration, and endothelin receptor antagonist |
| DE19726146A1 (en) * | 1997-06-19 | 1998-12-24 | Basf Ag | New ß-amino and ß-azidopcarboxylic acid derivatives, their preparation and use as endothelin receptor antagonists |
| TR200001182T2 (en) * | 1997-10-31 | 2000-11-21 | Basf Aktiengesellschaft | New carbonic acid derivatives, their production and uses. |
-
1998
- 1998-02-17 DE DE19806438A patent/DE19806438A1/en not_active Withdrawn
-
1999
- 1999-02-05 IL IL13703899A patent/IL137038A0/en unknown
- 1999-02-05 HU HU0100957A patent/HUP0100957A3/en unknown
- 1999-02-05 TR TR2000/02376T patent/TR200002376T2/en unknown
- 1999-02-05 BR BR9907911-9A patent/BR9907911A/en not_active IP Right Cessation
- 1999-02-05 EP EP99911657A patent/EP1066268A1/en not_active Withdrawn
- 1999-02-05 SK SK1151-2000A patent/SK11512000A3/en unknown
- 1999-02-05 KR KR1020007008925A patent/KR20010086247A/en not_active Application Discontinuation
- 1999-02-05 CN CN99803037A patent/CN1291190A/en active Pending
- 1999-02-05 JP JP2000532405A patent/JP2002503726A/en active Pending
- 1999-02-05 WO PCT/EP1999/000776 patent/WO1999042453A1/en not_active Application Discontinuation
- 1999-02-05 AU AU30271/99A patent/AU3027199A/en not_active Abandoned
- 1999-02-05 CA CA002321182A patent/CA2321182A1/en not_active Abandoned
- 1999-02-05 PL PL99342311A patent/PL342311A1/en unknown
- 1999-02-10 TW TW088102031A patent/TW579376B/en active
- 1999-02-16 AR ARP990100634A patent/AR014960A1/en not_active Application Discontinuation
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2000
- 2000-07-04 BG BG104577A patent/BG104577A/en unknown
- 2000-08-15 NO NO20004075A patent/NO20004075D0/en not_active Application Discontinuation
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US9174970B2 (en) | 2008-01-22 | 2015-11-03 | Dow Agrosciences Llc | 5-fluoro pyrimidine derivatives |
| US9204653B2 (en) | 2008-01-22 | 2015-12-08 | Dow Agrosciences Llc | 5-fluoro pyrimidine derivatives |
Also Published As
| Publication number | Publication date |
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| IL137038A0 (en) | 2001-06-14 |
| BR9907911A (en) | 2000-10-24 |
| WO1999042453A1 (en) | 1999-08-26 |
| DE19806438A1 (en) | 1999-08-19 |
| HUP0100957A3 (en) | 2002-03-28 |
| JP2002503726A (en) | 2002-02-05 |
| NO20004075L (en) | 2000-08-15 |
| HRP20000602A2 (en) | 2001-06-30 |
| TR200002376T2 (en) | 2000-12-21 |
| TW579376B (en) | 2004-03-11 |
| PL342311A1 (en) | 2001-06-04 |
| KR20010086247A (en) | 2001-09-10 |
| SK11512000A3 (en) | 2001-04-09 |
| ZA991214B (en) | 2000-08-16 |
| NO20004075D0 (en) | 2000-08-15 |
| CN1291190A (en) | 2001-04-11 |
| AR014960A1 (en) | 2001-04-11 |
| AU3027199A (en) | 1999-09-06 |
| HUP0100957A2 (en) | 2002-02-28 |
| BG104577A (en) | 2001-03-30 |
| EP1066268A1 (en) | 2001-01-10 |
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