EP1060167A1 - Nouveaux derives d'acide carboxylique substitues de fa on asymetrique, leur production et leur utilisation comme antagonistes de recepteurs et a?/et b? melanges - Google Patents

Nouveaux derives d'acide carboxylique substitues de fa on asymetrique, leur production et leur utilisation comme antagonistes de recepteurs et a?/et b? melanges

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Publication number
EP1060167A1
EP1060167A1 EP99906251A EP99906251A EP1060167A1 EP 1060167 A1 EP1060167 A1 EP 1060167A1 EP 99906251 A EP99906251 A EP 99906251A EP 99906251 A EP99906251 A EP 99906251A EP 1060167 A1 EP1060167 A1 EP 1060167A1
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Prior art keywords
phenyl
cooh
ome
meüiyl
alkyl
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German (de)
English (en)
Inventor
Wilhelm Amberg
Rolf Jansen
Dagmar Klinge
Hartmut Riechers
Stefan Hergenröder
Manfred Raschack
Liliane Unger
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Abbott GmbH and Co KG
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BASF SE
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    • C07—ORGANIC CHEMISTRY
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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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms

Definitions

  • New asymmetrically substituted carboxylic acid derivatives their preparation and use as mixed ET A / ET B receptor antagonists
  • the present invention relates to new carboxylic acid derivatives, their preparation and use.
  • Endothelin is a 21 amino acid peptide that is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following, "endothelin” or “ET” denotes one or all isoforms of endochelin. Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. This vasoconstriction is known to be caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 2-11, 440-444, 1988 and Biochem. Biophys. Res. Commun., 151, 868-875, 1988).
  • endothelin causes persistent vascular contraction in peripheral, renal, and cerebral blood vessels, which can lead to disease.
  • endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis and asthma (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 2-61, 2868 (1990), Nature 341, 114 (1990), N. Engl. J. Med. 32_2, 205 (1989), N. Engl. J. Med.
  • ET A and ET B receptor At least two endothelin receptor subtypes, ET A and ET B receptor, are currently described in the literature (Nature 348, 730 (1990), Nature ü, 732 (1990)). Therefore substances that inhibit the binding of endothelin to both receptors and antagonize physiological effects of endothelin should be valuable pharmaceuticals.
  • the object of the present invention was to provide so-called mixed endothelin receptor antagonists.
  • Mixed endothelin receptor antagonists bind to the E A and ET B receptors with approximately the same affinity. There is approximately the same affinity for the receptors if the quotient of the affinities ET A : ET B is greater than 0.05, preferably greater than 0.1, and less than 20, preferably less than 10.
  • the invention relates to carboxylic acid derivatives of the formula I.
  • Hydrogen the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically acceptable organic ammonium ion such as C 1 -C 4 alkyl ammonium or the ammonium ion;
  • R 7 may furthermore be a phenyl radical which one to five halogen atoms and / or can carry one to three of the following radicals: nitro, cyano, C 4 -alkyl, C 4 haloalkyl, hydroxy, C ⁇ -C 4 - Alkoxy, mercapto, C 1 -C 4 -alkylthio, amino, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 ;
  • a 5-membered heteroaromatic linked via a nitrogen atom such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one or two halogen atoms, or one or two C 1 -C 4 -alkyl or one or two CC 4 -alkoxy groups.
  • C ⁇ -C 4 alkyl C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C ⁇ -C 4 -haloalkyl, where these radicals a C ⁇ -C 4 alkoxy, C ⁇ ⁇ C 4 alkylthio and / or a phenyl radical as mentioned under c) can wear;
  • R 13 and R 14 may be the same or different and have the following meaning:
  • Hydrogen, -CC 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, benzyl, phenyl, the one to five halogen atoms and / or one to three of the following Residues can carry: nitro, cyano, C 1 -C 4 alkyl, -C-C 4 haloalkyl, hydroxy, C ⁇ -C 4 alkoxy, mercapto, C ⁇ -C 4 alkylthio, amino, NH (C ⁇ -C 4 - Alkyl), N (-CC 4 -alkyl) 2 ,
  • R 13 and R 14 together form a C 4 -C 7 alkylene chain which is closed to form a ring and which
  • alkylene group can be replaced by oxygen, sulfur or nitrogen
  • R 2 is hydrogen, hydroxy, NH 2 , H (-CC 4 alkyl), N (-C-C 4 alkyl) 2 , halogen, -C-alkyl, C 2 -C 4 alkenyl, C 2 -C -Alkinyl, -CC 4 -hydroxyalkyl, -C-C-haloalkyl, -C-C 4 alkoxy, C x -C 4 -haloalkoxy or -C-C 4 alkylthio, or CR 2 is with
  • Z is nitrogen or CR 10, wherein R 4 haloalkyl or C ⁇ -C 4 alkyl 10 is hydrogen, halogen, hydroxy, C ⁇ -C or CR 10 together with CR 2 or CR 3 a 5- or 6-membered alkylene or
  • Alkenylene ring which can be substituted by one or two -CC alkyl groups and in each case one or 5 several methylene groups can be replaced by oxygen, sulfur, -NH or N (-CC alkyl).
  • At least one of the ring members X, Y or Z is nitrogen.
  • R 3 is hydrogen, hydroxyl, NH 2 , H (C 1 -C 4 alkyl), N (C 1 -C alkyl) 2 , halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, -C-C 4 -haloalkyl, -C-C 4 -alkoxy, C ⁇ -C 4 -haloalkoxy, C ⁇ -C 4 -hydroxyalkyl, C ⁇ -C 4 -alkylthio, or CR 3 is with CR 10 as above indicated linked to a 5- or 6-membered ring.
  • R 4 Ci-Q-alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, which can be substituted by one or more of the following radicals: halogen, cyano, hydroxy, mercapto, C 1 -C 4 alkoxy , Phenoxy, carboxy, Cx ⁇ -haloalkoxy, -C-C-alkylthio, amino, NH (-C-C 4 alkyl), N (-C-C 4 alkyl) 2 or alkylcarbonyl.
  • R 5 phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, C 1 -C 4 -alkyl, C 2 -C alkenyl, C 1 -C 4 -hydroxyalkyl , C 2 -C alkynyl, -C-C 4 haloalkyl, C !
  • -C 4 -alkoxy phenoxy, carboxy, -C-C 4 -haloalkoxy, -C-C-alkylthio, amino, NH (-C-C-alkyl), N (-C-C 4 -alkyl) 2 or phenyl, the one or can be substituted several times, for example one to three times by halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C ! -C 4 alkoxy, -C -C haloalkoxy or C 1 -C 4 alkylthio; or
  • Phenyl or naphthyl which is ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group with R 4 ;
  • R 6 is C 3 -C 8 -cycloalkyl, where these radicals in each case may be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 4 -alkoxy, C 4 alkyl, C -C 2 -alkenyl, C 2 -C alkynyl, C 3 -C 6 alkenyloxy, CC oxy 6 alkynyl, C ⁇ -C 4 alkylthio, C ⁇ -C4-haloalkoxy, C ⁇ -C-Alkylcar-carbonyl, C 1 -C 4 alkoxycarbonyl, C 3 -C 8 alkylcarbonylalkyl,
  • Phenyl or naphthyl each of which can carry one or more of the following radicals: halogen, R 15 , nitro, mercapto, carboxy, cyano, hydroxy, amino, C 1 -C 4 -alkyl, C 2 -C alkenyl, C 2 -C 4 -alkynyl, C 3 -C 6 -alkenyloxy, -C-C 4 haloalkyl, C 3 -C 6 -alkynyloxy, C ⁇ -C 4 -alkylcarbonyl, C ⁇ -C 4 -alkoxycarbonyl, C ⁇ -C-alkoxy, C ⁇ -C 4 -haloalkoxy, phenoxy, -C-alkylthio, NH (-C-C 4 alkyl), N (-C 4 -alkyl) 2; Dioxomethylene, dioxoethylene or phenyl, which can be substituted one or more times, for example one to three times by
  • a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom which can carry one to four halogen atoms and / or one or two of the following radicals: -CC 4 alkyl, C 2 - C 4 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, phenyl or phenoxy, the phenyl radicals in turn having one to five halogen atoms and / or one to can carry three of the following radicals: -CC alkyl,
  • R 15 C 1 -C 4 alkyl, C 1 -C 4 alkylthio, C 1 -C alkoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (C 1 -C 4 alkyl), N (C ⁇ -C 4 alkyl) 2 , carboxamide or CON (C 1 -C 4 alkyl) 2 ;
  • Q is a spacer that corresponds in length to a C 2 -C chain.
  • the function of Q is to produce a defined distance between the groups R 6 and W in the compounds of the formula I. The distance should correspond to the length of a C 2 -C 4 alkyl chain.
  • radicals for example with C 2 -C alkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkynyl, -S-CH 2 -CH 2 -, -0-CH 2 -CH 2 -, -N-CO-CH 2 -, -CO-N-CH 2 -CH 2 -, -CO-N (C 1 -C 4 alkyl) -CH 2 -CH 2 -, S0 2 -N (-C-alkyl) -CH 2 -CH 2 -, S0 2 -NH-CH 2 -CH 2 -, where these radicals can be substituted one or more times by: halogen, hydroxy, mercapto, Cx- C ⁇ alkyl, C 2 -C 4 alkenyl, C 2 -C alkynyl, carboxy, nitro, cyano, C 1 -C alkoxy, C 3 -C 6 alkenyl
  • C ⁇ -C4-haloalkoxy C ⁇ -C 4 alkylcarbonyl, C ⁇ -C 4 alkoxy carbonyl, C 3 -C 8 -Alkylcarbonylalkyl, NH (C ⁇ -C alkyl), N (C ⁇ -C alkyl) 2, phenyl which may be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, C 4 -alkyl, C haloalkyl, C ⁇ -C 4 -alkoxy, C 4 -haloalkoxy or -C-C-alkylthio;
  • the spacer Q is part of a 5-7 membered ring, heterocyclic or carbocyclic, to which R 6 is fused.
  • An alkali metal is e.g. Lithium, sodium, potassium;
  • alkaline earth metal is e.g. Calcium, magnesium, barium;
  • C 3 -C 8 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
  • -C-C 4 haloalkyl can be linear or branched, such as
  • C 1 -C 4 -Halogenalkoxy can be linear or branched such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2, 2-difluoroethoxy, 1, 1, 2, 2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy , 2-chloro-l, 1, 2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
  • C 1 -C 4 -alkyl can be linear or branched, such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;
  • C 2 -C -Alkenyl can 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;
  • C 2 -C 4 alkynyl can be linear or branched, such as, for example, ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
  • C ⁇ ⁇ C 4 alkoxy can be linear or branched such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy; 8th
  • C 3 -C 6 alkenyloxy can be linear or branched, for example allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
  • C ⁇ -C 4 -hydroxyalkyl can be linear or branched, such as hydroxymethyl, l-hydroxyether-2-yl,
  • C 3 -C 6 alkynyloxy can be linear or branched, such as 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;
  • C 1 -C 4 -Alkylthio can be linear or branched such as, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1, 1-dimethylethylthio;
  • C 1 -C 4 -alkylcarbonyl can be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl;
  • C 1 -C 4 -alkoxycarbonyl can be linear or branched, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;
  • C 3 -C 8 -alkylcarbonylalkyl can be linear or branched, for example 2-oxo-prop-1-yl, 3-0xo-but-1-yl or 3-oxo-but-2-yl
  • C ! -C 8 alkyl can be linear or branched such as -CC 4 alkyl, pentyl, hexyl, heptyl or octyl;
  • Halogen is e.g. Fluorine, chlorine, bromine, iodine.
  • the invention further relates to those compounds from which the compounds of the formula I can be released (so-called prodrugs).
  • prodrugs in which the release takes place under conditions such as those in certain body compartments, e.g. in the stomach, intestines, bloodstream, liver, predominate.
  • the compounds and also the intermediates for their preparation, such as II, III and IV, can have one or more asymmetrically substituted carbon atoms.
  • Such compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof. Preference is given to using an enantiomerically pure or diastereomerically pure compound as the active ingredient.
  • the invention further relates to the use of the abovementioned carboxylic acid derivatives for the production of medicaments, in particular for the production of inhibitors for ET A and ET B receptors.
  • the compounds according to the invention are particularly suitable as mixed antagonists as defined at the outset.
  • Compounds of general formula III are either known or can e.g. can be synthesized by reducing the corresponding carboxylic acids or their esters, or by other generally known methods.
  • enantiomerically pure compounds of the formula IV can be obtained by carrying out a classic racemate resolution with suitable enantiomerically pure bases with racemic or diastereomeric compounds of the formula IV.
  • suitable bases are e.g. 4-chlorophenylethylamine and the bases mentioned in WO 96/11914.
  • R 11 is halogen or R 1 -S0 2 -, where R 12 can be C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or phenyl. Furthermore, at least one of the ring members X or Y or z is nitrogen.
  • the reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, ie a base which brings about a deprotonation of the intermediate IV, in a temperature range from room temperature to the boiling point of the solvent.
  • solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may optionally be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and Trichlorethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert.
  • chlorinated such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and Trichlorethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert.
  • nitriles such as, for example, acetonitrile and propionitrile
  • acid amides such as, for example, dirnethylformamide, dirnethylacetamide and N-methylpyrrolidone
  • sulfoxides and sulfones such as, for example, dimethyl sulfoxide and sulfolane.
  • an alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g. Sodium or potassium carbonate, an alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali amide such as lithium diisopropylamide or lithium amide.
  • Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie compounds of the formula I in which R 1 is COOH, and converting them first in the usual manner into an activated form such as an acid halide, an anhydride or Imidazolide transferred and then reacted with a corresponding Hydroxy1 compound H ⁇ R 7 .
  • This reaction can be carried out in the usual solvents 11 and often requires the addition of a base, the above being considered.
  • 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 water-releasing agent such as a carbodiimide.
  • compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, ie from compounds of the formula I in which R 1 is a COR group and R is OM, where M is an alkali metal cation or the equivalent of one Alkaline earth metal cation can be.
  • These salts can be reacted with many compounds of the formula RA, where A is a customary nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl or one other equivalent leaving group.
  • A is a customary nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl optionally substituted by halogen, alkyl or hal
  • carboxylic acid derivatives of the general formula I - both as pure enantiomers or pure diastereomers or as a mixture thereof - are preferred, in which the substituents have the following meaning:
  • R 2 is hydrogen, hydroxy, halogen, N (C ⁇ -C4 alkyl) 2, C ⁇ -C 4 -alkyl, C alkoxy, C ⁇ -C-alkylthio, C ⁇ -C4 haloalkyl, C ⁇ -C 4 - Haloalkoxy, or CR 2 is linked to CR 10 to a 5- or 6-membered ring as indicated below;
  • At least one of the ring members X, Y or Z is nitrogen.
  • R 3 is hydrogen, hydroxy, halogen, N (C 1 -C 4 alkyl) 2, C ⁇ -C alkyl, C ⁇ -C 4 -alkoxy, C alkylthio, C ⁇ -C haloalkyl; -C-C 4 haloalkoxy, or CR 3 is linked to CR 10 as stated above to form a 5- or 6-membered ring;
  • R 4 -C 4 alkyl or C 2 -C 4 alkenyl which can be substituted by one or more of the following radicals: halogen, cyano, hydroxy, mercapto, -C 4 alkoxy, phenoxy, carboxy, C ⁇ - C 4 -haloalkoxy, -C-alkylthio, amino, NH (-C-C 4 alkyl), N (-C-alkyl) 2 or C 1 -C alkylcarbonyl.
  • R 5 phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, C 1 -C 4 alkyl, C 2 -C alkenyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 -haloalkyl, -C-C 4 -haiogenalkoxy, -C-C-alkoxy, phenoxy, carboxy, C ⁇ -C 4 -alkylthio, amino,
  • NH C 1 -C 4 alkyl
  • N C ⁇ -C4 alkyl
  • phenyl which may be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, alkyl C , C ⁇ -C haloalkyl, C ⁇ ⁇ C 4 -alkoxy, C 4 -haloalkoxy or C ⁇ -C 4 alkylthio; or
  • R 6 is C 3 -C 8 cycloalkyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkynyl-oxy, -C-C 4 -alkylthio, -C-C 4 -haloalkoxy, -C-C 4 -Alkylcarbonyl, -CC 4 alkoxy-carbonyl, NH (-CC 4 alkyl), N (-C-alkyl) 2 or phenyl, which can be substituted one or more times, for example one to three times by halogen , Nitro, cyano, -CC alkyl, 13
  • Phenyl or naphthyl each of which can be substituted by one or more of the following radicals: halogen, ris,
  • a five- or six-membered heteroaromac containing one to three nitrogen atoms and / or a sulfur or oxygen atom which can carry one to four halogen atoms and / or one or two of the following radicals: -C 4 -alkyl, C ⁇ -C 4 - Haloalkyl, C 1 -C 4 alkoxy, trifluoromethoxy, C 1 -C 4 alkyl thio, phenyl or phenoxy, where the phenyl radicals in turn can carry one to five halogen atoms and / or one to three of the following radicals: C 1 -C 4 alkyl , -C-C 4 -haloalkyl, -C-C 4 alkoxy, -C-C-haloalkoxy and / or C 1. -C 4 alkylth.io;
  • R 15 is methyl, ethyl, methoxy or ethoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (-CC 4 alkyl), N (-C-alkyl) 2 , carboxamide or C0N (-C-C 4 alkyl) 2 ;
  • the one C ⁇ C ⁇ -C-C may be or polysubstituted, for example mono- to trisubstituted by halogen, cyano, -C-alkyl, 4 haloalkyl, 4 alkoxy, CC 4 -haloalkoxy or C ⁇ -C -alkylthio 14 or Q together with R 6 forms the following ring systems: indan-2-yl, indan-3-yl, 1, 2, 3, 4-tetrahydronaphth-2-yl, 1, 2, 3, 4-tetrahydronaphth-3-yl , where the phenyl rings can each be substituted by: halogen, hydroxy, mercapto,
  • R 2 trifluoromethyl, -CC 4 -alkyl, Cx-Cj-alkoxy, -C-C 4 alkylthio, or CR 2 is linked to CR 10 as stated below to form a 5- or 6-membered ring;
  • At least one of the ring members X, Y or Z is nitrogen
  • R3 trifluoromethyl, -CC 4 -alkyl, dC 4 -alkoxy, -C-C-alkylthio, or CR 3 is linked to CR 10 as stated above to form a 5- or 6-membered ring;
  • R 4 -CC alkyl which can be substituted by one or more of the following radicals: halogen, C ! -C 4 - lkoxy, -C-C 4 halo alkoxy.
  • R 5 is phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, amino, C ⁇ -C4 ⁇ alkyl, C ⁇ -C4 halo-alkyl, C 1 -C -Halogenalkoxy, -CC 4 alkoxy, phenoxy, -C-alkyl thio, NH (-C 4 -alkyl), N (-C 4 -alkyl) 2 or phenyl, which can be substituted one or more times can, for example, one to three times 15 by halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl,
  • Phenyl or naphthyl which is ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group with R 4 ;
  • R 6 cyclohexyl, which can be mono- or polysubstituted by: C 1 -C alkoxy, C 1 -C 4 -alkyl, halogen or phenyl, which can be mono- or polysubstituted, for example one to three times by halogen, C 1 -C C-alkyl, -CC 4 alkoxy;
  • R 15 methoxy or ethoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (C 1 -C 4 -alkyl), N (-C-C 4 -alkyl) 2 , carboxamide or CON (-C-C-alkyl ) 2 ;
  • Phenyl which can be mono- or polysubstituted, for example one to three times by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or Cx- alkylthio
  • the compounds of the present invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, chronic heart failure, angina pectoris, arrhythmia, acute / chronic kidney failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, asthma endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and by-pass surgery, benign prostate hyperplasia, ischemic and intoxication-related kidney failure or hypertension, metastasis and growth of mesenchymal tumors, contrast agent-induced kidney failure, pancreatitis gastrointestinal ulcers.
  • the compounds according to the invention partly show. also antagonistic effect on the neurokinin receptor.
  • NR R owns.
  • the invention further relates to combination preparations 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, above all, angiotensin converting enzyme (ACE) inhibitors.
  • ACE angiotensin converting enzyme
  • Another object of the invention are combination preparations from ß-blockers and the above. Endothelin receptor antagonists and from mixed ACE-neutral endopeptidase (NEP) inhibitors and the above Endothelin receptor antagonists.
  • NEP mixed ACE-neutral endopeptidase
  • the combination preparations can be presented in a single galenic form or in spatially separated forms.
  • the administration can be carried out simultaneously or at different times.
  • the dosage in the combination can be up to the maximum amount of the respective single dose. However, it is also possible to use lower doses than with the individual therapy. 17
  • the ET A or ET B receptor-expressing CHO cells were in DMEM NUT MIX F ⁇ 2 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022 ), 1 mM glutamine (Gibco No. 25030-024), 100 U / ml penicillin and 100 ⁇ g / ml streptomycin (Sigma No. P-0781). After 48 hours
  • the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 minutes at 37 ° C. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 x g.
  • the cells were adjusted to a concentration of 10 8 cells / ml buffer (50 mM Tris-HCl buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds / constant output 20).
  • the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl, 40 mg / ml bacitracin and 0.2% BSA)
  • test animals were given the test compounds i.v. 30 min before the ETI administration. injected (1 ml / kg). To determine the ET antagonistic properties, the blood pressure changes in the test animals were compared with those in the control animals.
  • big endothelin (20 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) or ETI (0.3 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) is given intravenously. Blood pressure and heart rate are continuously recorded over 30 minutes. The significant and persistent changes in blood pressure are calculated as the area under the curve (AUC).
  • AUC area under the curve
  • the AUC of the substance-treated animals is compared with the AUC of the control animals.
  • the compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). It can also be applied with vapors or sprays through the nasopharynx.
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • the daily dose of active substance is between approximately 0.5 and 50 mg / kg body weight when administered orally and between approximately 0.1 and 10 mg / kg body weight when administered parenterally.
  • the new compounds can be used in the customary pharmaceutical application forms in solid or liquid form, for example as tablets, film-coated tablets, capsules, powders, granules, coated tablets, 19
  • Suppositories, solutions, ointments, creams or sprays are manufactured in the usual way.
  • the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al. : Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1991).
  • the administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.
  • the alkaline phase was adjusted to pH 2 with 2N HCl and then extracted with ether.
  • the combined organic phases were dried over MgSO 4 , filtered, then the solvent was distilled off and the residue (1.25 g of yellow foam) was stirred in diisopropyl ether (1.1 g of product, diasteromerically pure).

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Abstract

L'invention concerne des dérivés d'acide carboxylique de la formule (I) où R1-R6, Q, W, Y et Z ont la signification donnée dans la description. L'invention concerne également leur production. Les nouveaux composés sont adaptés pour combattre des maladies.
EP99906251A 1998-03-04 1999-02-25 Nouveaux derives d'acide carboxylique substitues de fa on asymetrique, leur production et leur utilisation comme antagonistes de recepteurs et a?/et b? melanges Withdrawn EP1060167A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19809144A DE19809144A1 (de) 1998-03-04 1998-03-04 Neue unsymmetrisch substituierte Carbonsäurederivate, ihre Herstellung und Verwendung als gemischte ET¶LAMBDA¶/ET¶B¶-Rezeptorantagonisten
DE19809144 1998-03-04
PCT/EP1999/001208 WO1999044998A1 (fr) 1998-03-04 1999-02-25 Nouveaux derives d'acide carboxylique substitues de façon asymetrique, leur production et leur utilisation comme antagonistes de recepteurs eta/etb melanges

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DE19924892A1 (de) * 1999-06-01 2000-12-07 Basf Ag Neue Carbonsäurederivate mit arylsubstituierten Stickstoffheterocyclen, ihre Herstellung und Verwendung als Endothelin Rezeptorantagonisten
AU7912600A (en) * 1999-10-06 2001-05-10 Basf Aktiengesellschaft Inhibitors of the endothelin signalling pathway and alphavbeta3 integrin receptor antagonists for combination therapy

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DE19809144A1 (de) 1999-09-09
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CA2322541A1 (fr) 1999-09-10
TR200002545T2 (tr) 2000-11-21
CO5080805A1 (es) 2001-09-25
WO1999044998A1 (fr) 1999-09-10
NO20004351L (no) 2000-09-01
ZA991738B (en) 2000-10-11
SK11752000A3 (sk) 2001-05-10
JP2002505324A (ja) 2002-02-19
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HRP20000650A2 (en) 2001-06-30
HUP0101173A2 (hu) 2002-03-28
HUP0101173A3 (en) 2002-05-28

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