DE19858779A1 - New 3-acylamino-propionic acid and 3-sulfonylamino-propionic acid derivatives useful as endothelin receptor antagonists in treatment of e.g. cardiovascular and renal disorders, migraine and cancer - Google Patents

Abstract

3-(Acylamino or sulfonylamino)-2-heteroaryloxy-propionic acid derivatives are new. The 3-(acylamino or sulfonylamino)-2-heteroaryloxy-propionic acid derivatives are compounds of formula (I) and their enantiomers, diastereoisomers and salts, excluding the compounds 2-(6-ethyl-2-methyl-pyrimidin-4-yloxy)-3-(4-methoxybenzoylamino)-3,3-d iphenylpropionic acid; 2-(2,6-dimethyl-pyrimidin-4-yloxy)-3-(4-methoxybenzoylamino)-3,3-diphe nylpropionic acid; 3-(4-methoxy-benzoylamino)-2-(6-methoxy-2-methyl-pyrimidin-4-yloxy)-3, 3-diphenylpropionic acid; 3-(4-methoxy-benzoylamino)-2-(6-methoxy-5-methyl-pyrazin-2-yloxy)--3,3 -diphenylpropionic acid; 3-(4-methoxy-benzoylamino)-2-(5-methoxy-6-methyl-(1,2,4)triazin-3-ylox y)-3,3-diphenylpropionic acid; 2-(4-ethyl-6-methyl-(1,3,5)triazin-2-yloxy)-3-(4-methoxy-benzoylamino) -3,3-diphenylpropionic acid; 3-(4-methoxy-benzoylamino)-2-(5-methoxy-6-methyl-pyridazin-3-yloxy)--3 ,3-diphenylpropionic acid; 2-(4,6-dimethyl-(1,3,5)triazin-2-yloxy)-3-(4-methoxy-benzoylamino)--3, 3-diphenylpropionic acid; 3-(4-methoxy-benzoyl amino)-2-(4-methoxy-6-methyl-(1,3,5)triazin-2-yloxy)-3,3-diphenylpropi onic acid; 3-(4-methoxy-benzoylamino)-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrim idin-2-yloxy)-3,3-diphenylpropionic acid; 3-(4-methoxy-benzoylamino)-2-(4-methoxy-5,6-dihydrofuro(2,3-d)pyrimidi n-2-yloxy)--3,3-diphenylpropionic acid; 2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-(4-methoxy-benzoylamino)-3,3-dip henylpropionic acid; 2-(4-ethyl-6-methyl-pyrimidin-2-yloxy)-3-(4-methoxy-benzoylamino)-3,3- diphenylpropionic acid; 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(4-methoxy-benzoylamino)-3,3-diph enylpropionic acid; 3-(4-methoxy-benzoylamino)-2-(4-methoxy-6-methyl-pyrimidin-2-yloxy)-3, 3-diphenylpropionic acid; 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(4-hydroxy-benzoylamino)--3,3-dip henylpropionic acid; 2-(4-methoxy-6-methyl-pyrimidin-2-yloxy)-3-(4-methylsulfanyl-benzoylam ino)--3,3-diphenylpropionic acid; 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(4-nitro-benzoylamino)-3,3-diphen ylpropionic acid; 3-(4-chloro-benzoylamino)-2-(4-ethyl-6-methyl-pyrimidin-2-yloxy)-3,3-d iphenylpropionic acid; 3-(4-ethyl-benzoylamino)-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimid in-2-yloxy)-3,3-diphenylpropionic acid; 3,3-bis(4-fluorophenyl)-3-(4-methoxy-benzoylamino)-2-(4-methoxy-5,6-di hydrofuro(2,3-d)pyrimidin-2-yloxy)-3,3-diphenylpropionic acid; 3-(4-chloro-benzoylamino)--2-(4,6-dimethyl-(1,3,5)triazin-2-yloxy)--3, 3-diphenylpropionic acid; 3-(3,4-dimethoxy-benzoylamino)-2-(4-methoxy-6-methyl-(1,3,5)triazin-2- yloxy)-3,3-diphenylpropionic acid; 3-(3,4-dimethoxy-benzoylamino)-2-(4-ethyl-6-methyl-(1,3,5)triazin-2-yl oxy)-3,3-diphenylpropionic acid; 3-(4-chloro-benzoylamino)-2-(5-methoxy-6-methyl-pyridazin-3-yloxy)-3,3 -diphenylpropionic acid; 3-(3,4-dichloro-benzoylamino)-2-(6-methoxy-5-methyl-pyrazin-2-yloxy)-3 ,3-diphenylpropionic acid; 3-(4-hydroxy-3-methoxy-benzoylamino)-2-(5-methoxy-6-methyl-(1,2,4)tria zin-3-yloxy)-3,3-diphenylpropionic acid; 3-(3-chloro-benzoylamino)-2-(2,6-dimethyl-pyrimidin-4-yloxy)-3,3-diphe nylpropionic acid; 3-(2-chloro-benzoylamino)-2-(6-methoxy-2-methyl-pyrimidin-4-yloxy)-3,3 -diphenylpropionic acid; and 2-(6-ethyl-2-methyl-pyrimidin-4-yloxy)-3-(4-nitro-benzoylamino)-3,3-di phenylpropionic acid. R1 = tetrazolyl, or C(O)R; R = OR6, N-bonded 5-membered heteroaryl; -O-(CH2)p-S(O)k-R7; or -NH-SO2-R8; R6 = H, or 3-8C cycloalkyl, 1-8C alkyl, benzyl, 3-8C alkenyl, 3-8C alkynyl, or phenyl (all optionally substituted); k = 0-2; p = 1-4; R7 = 1-4C alkyl; 3-8C cycloalkyl; 3-8C alkenyl; 3-8C alkynyl; or optionally substituted phenyl; R8 = 1-4C alkyl, 3-8C alkenyl, 3-8C alkynyl or 3-8C cycloalkyl (each optionally substituted with 1-4C alkoxy, 1-4C alkylthio and/or phenyl); 1-4C haloalkyl; or optionally substituted phenyl; X = N or CR9; Y = N or CR10; Q = N or CR11 (X = CR9 and Y = CR10 when Q = N); W and V = N or CH (Q = N when W = V = CH); R9 and R10 = H, halo, 1-4C alkoxy, 1-4C haloalkoxy, 3-6C alkenyloxy, 3-6C alkynyloxy, 1-4C alkylthio, 1-4C alkylcarbonyl, 1-4C alkoxycarbonyl, OH, NH2, NH(1-4C alkyl), N(1-4C alkyl)2, or 1-4C alkyl, 2-4C alkenyl or 2-4C alkynyl (each optionally substituted); or R9 or R10 together with R11 forms a 5-6 membered alkylene or alkenylene group in which 1 or more CH2 is replaced with O, S, NH or N(1-4 alkyl); R11 = H, halo, 1-4C alkoxy, 1-4C haloalkoxy, 3-6C alkenyloxy, 3-6C alkynyloxy, 1-4C alkylthio, 1-4C alkylcarbonyl, 1-4C alkoxycarbonyl, NH(1-4C alkyl), N(1-4C alkyl)2, OH, COOH, CN, NH2, SH, or 1-4C alkyl, 2-4C alkenyl or 2-4C alkynyl (each optionally substituted); R2 and R3 = phenyl or naphthyl (both optionally substituted or optionally bonded to one another via a bond, CH2, CH2CH2, CH=CH, O, S, SO2, NH or N-alkyl); or 5-6C cycloalkyl; R4 = C(O)R12 or SO2R13; R12 = phenyl, naphthyl or 5-6 membered heteroaryl containing 1-3 N and/or 1 O or S atom (each optionally substituted); R13 = 1-4C alkyl or 1-4C alkoxy (each optionally substituted with halo), 1-4C alkylthio, or phenyl or phenoxy (each optionally substituted); and R5 = H or 1-4C alkyl. Independent claims are also included for the following: (1) 3-(acylamino or sulfonamido)-2-hydroxy-propionic acid derivatives (II); (2) the use of (I) in combination with a renin angiotensin system inhibitor, e.g. renin inhibitor, angiotensin-II antagonist, especially an ACE inhibitor, mixed ACE/neutral endopeptidase (NEP) inhibitor or beta -blocker; and (3) a fragment of formula (A) as a structural element in an endothelial receptor antagonist.

Description

The present invention relates to new carboxylic acid derivatives, their manufacture 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. Hereinafter, "endothelin" or "ET" means one or all Isoforms of endothelin. Endothelin is a potent vasocone strict and has a strong effect on vascular tone. It it is known that this vasoconstriction depends on the binding of Endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 2311 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).

Increased or abnormal release of endothelin causes one persistent vascular contraction in peripheral, renal and cerebral Blood vessels that can lead to disease. As in literature Endothelin is reported to be involved in a number of diseases fourth. These include: hypertension, acute myocardial infarction, pulmonary Hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostate hypertrophy, atherosclerosis, asthma and prosta takrebs (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. As sociation 264, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med. 328, 1732 (1993), Nephron 66, 373 (1994), Stroke L. 904 (1994), Nature 365 759 (1993), J. Mol. Cell. Cardiol. 22. A234 (1995); Cancer Research 56, 663 (1996), Nature Medicine 1, 944, (1995)).

At least two endothelin receptor subtypes, ET _A and ET _B receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, substances that inhibit the binding of endothelin to one or both receptors should antagonize the physiological effects of endothelin and should therefore be valuable pharmaceuticals.

DE 197 26 146.9 describes the production of β-amino and β-azido carboxylic acid derivatives and their use as endothelin receptors rantagonists. Further investigations revealed found that related aromatic carboxamides and sulfona midderivate in terms of receptor affinity and receptor binding profile advantageous properties. Your manufacture and  Use is the subject of the present patent specification.

The invention relates to β-amido and β-sulfonamidocarboxylic acid derivatives of the formula I.

R ¹ stands for tetrazole or for a group

in which R has the following meaning:

• a) a radical OR ⁶ , in which R ⁶ denotes:
  Hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically compatible organic ammonium ion such as tertiary C ₁ -C ₄ -alkylammonium or the ammonium ion;
  C ₃ -C ₈ cycloalkyl, C ₁ -C ₈ alkyl, CH ₂ phenyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C ₁ -C ₄ alkyl, C ₁ - C ₄ haloalkyl, hydroxy, C ₁ -C ₄ alkoxy, mercapto, C ₁ -C ₄ alkylthio, amino, NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ ;
  A C ₃ -C ₈ alkenyl or a C ₃ -C ₈ alkynyl group, these groups in turn being able to carry one to five halogen atoms;
  R ⁶ can furthermore be a phenyl radical which can carry one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy, C ₁ - C ₄ alkoxy, mercapto, C ₁ -C ₄ alkylthio, amino, NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ ;
• b) a 5-membered heteroaromatic linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which carry one or two halogen atoms, or one or two C ₁ -C ₄ -alkyl or one or two C ₁ -C ₄ -alkoxy groups can.
• c) a group
  where k is 0, 1 and 2, p is 1, 2, 3 and 4 and R ^{7 is}
  C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ alkenyl, C ₃ -C ₈ alkynyl or phenyl, which is replaced by one or more, for. B. one to three of the following radicals can be substituted:
  Halogen, nitro, cyano, C ₁ -C ₄ alkyl, hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, amino, NH (C ₁ -C ₄ alkyl), N (C ₁ - C ₄ alkyl) ₂ , mercapto.
• d) a rest
  where R ⁸ means:
  C ₁ -C ₄ alkyl, C ₃ -C ₈ alkenyl, C ₃ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, these radicals being a C ₁ -C ₄ alkoxy, C ₁ -C ₄ -Alkylthio- and / or a phenyl radical as mentioned under c) can wear;
  C ₁ -C ₄ haloalkyl or phenyl, optionally substituted, in particular as mentioned under c).

The other substituents have the following meaning:
W and Z, which can be the same or different:
Nitrogen or methine; with the proviso that if W and Z = methine, then Q = nitrogen;
X nitrogen or CR ⁹ ;
Y is nitrogen or CR ¹⁰ ;
Q nitrogen or CR ¹¹ ; with the proviso that if Q = nitrogen, then X = CR ⁹ and Y = CR ¹⁰ ;
R ² and R ³ , which may be the same or different:
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 ₄ alkenyl, C ₂ -C ₄ alkynyl , C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, phenoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkylthio, amino, NH (C ₁ -C ₄ alkyl), N ( C ₁ -C ₄ alkyl) ₂ or phenyl, which can be mono- or polysubstituted, e.g. B. one to three times by halogen, nitro, cyano, C ₁ -C ₄ alkyl, C ₂ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or C ₁ -C ₄ -Alkylthio or
Phenyl or naphthyl which are 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;
C ₅ -C ₆ cycloalkyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ haloalkoxy;

R ⁴

• a) a rest
  with R ¹² phenyl, naphthyl or a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom, where the radicals mentioned can be substituted one or more times by: halogen, nitro, cyano, hydroxy, Mercapto, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ halo alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylcarbonyl, carboxy, C ₁ -C ₄ -Halogenalkoxy, C ₁ -C ₄ alkylthio, amino, NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ , H ₂ NSO ₂ , (C ₁ -C ₄ alkyl) NHSO ₂ , (C ₁ -C ₄ alkyl) ₂ NSO ₂ or phenoxy or phenyl, which can be mono- or polysubstituted, e.g. B. one to three times by halogen, nitro, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and / or C ₁ - C ₄ alkylthio
• b) a rest
  with R ¹³ C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or phenyl, where the phenyl radical in turn can carry one to five halogen atoms and / or one to three of the following radicals: C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and / or C ₁ -C ₄ alkylthio;
  R ^{5 is} hydrogen, C ₁ -C ₄ alkyl;
  R ⁹ and R ¹⁰ (which may be the same or different):
  Hydrogen, halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halo alkoxy, C ₃ -C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, C ₁ -C ₄ alkyl thio, C ₁ -C _4- alkylcarbonyl, C ₁ -C ₄ -alkoxycarbonyl, hydroxy, NH ₂ , NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ ;
  C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, where these radicals can be substituted by halogen, hydroxy, mercapto, carboxy, cyano;
  or CR ⁹ or CR ¹⁰ is linked to CR ¹¹ as stated under R ¹¹ to form a 5- or 6-membered ring;
  R ^{11 is} hydrogen, halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halo alkoxy, C ₃ -C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, C ₁ -C ₄ alkyl thio, C ₁ -C ₄ alkylcarbonyl, C ₁ -C ₄ alkoxycarbonyl, NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ , hydroxy, carboxy, cyano, amino, mercapto;
  C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, where these radicals can each be substituted one or more times by: halogen, hydroxy, mercapto, carboxy, cyano, amino, C ₁ -C ₄ alkoxy;
  or CR ¹¹ together with CR ⁹ or CR ¹⁰ forms a 5- or 6-membered alkylene or alkenylene ring, which may be substituted by one or two C ₁ -C ₄ alkyl groups, and in each case one or more methylene groups by oxygen, sulfur , -NH or -N (C ₁ -C ₄ alkyl) can be replaced;

The following definitions apply here and below:
An alkali metal is e.g. B. lithium, sodium, potassium;
An alkaline earth metal is e.g. B. calcium, magnesium, barium;
Organic ammonium ions are protonated amines such as B. ethanol amine, diethanolamine, ethylenediamine, diethylamine or piperazine;
C ₃ -C ₈ cycloalkyl is e.g. B. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
C ₁ -C ₄ haloalkyl can be linear or branched, such as. B. fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2.2 -Dichlor-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl;
C ₁ -C ₄ haloalkoxy can be linear or branched, such as. B. difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1, 2-trifluoroethoxy, 2- Fluoroethoxy or pentafluoroethoxy;
C ₁ -C ₄ alkyl can be linear or branched, such as. B. methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;
C ₂ -C ₄ alkenyl can be linear or branched, such as. B. 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. B. ethynyl, 1-propin-1-yl, 1-propin-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
C ₁ -C ₄ alkoxy can be linear or branched, such as. B. methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;
C ₃ -C ₆ alkenyloxy can be linear or branched, such as. B. allyl oxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
C ₃ -C ₆ alkynyloxy can be linear or branched, such as. B. 2-propin-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy; C ₁ -C ₄ alkylthio can be linear or branched, such as. B. methyl thio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;
C ₁ -C ₅ alkylcarbonyl can be linear or branched, such as. B. acetyl, ethylcarbonyl or 2-propylcarbonyl;
C ₁ -C ₈ alkyl can be linear or branched, such as. B. C ₁ -C ₄ alkyl, pentyl, hexyl, heptyl or octyl;
C ₃ -C ₈ alkenyl can be linear or branched such as. B. 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-buten-4-yl, 2-buten-3-y1, 1-penten-5-yl, 1-hexen-6-yl, 3-he xen-6-yl, 2-hepten-7-yl or 1-octen-8-yl;
C ₃ -C ₈ alkynyl can be linear or branched, such as. B. 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl, 2-butyn-4-yl, 2-pentyn-5-yl, 3-hexyn-6-yl, 3-heptin-7-yl, 2-octin-8-yl;

Halogen is e.g. B. fluorine, chlorine, bromine, iodine.

The invention further relates to compounds of this type, from which the compounds of formula I can be released (so-called prodrugs).

Those prodrugs in which the release is below are preferred such conditions expire in certain bodies compartments, e.g. B. in the stomach, intestines, bloodstream, liver, prevalence.

The compounds I and also the intermediates for their Manufacturing such. B. II and III can be one or more asymme have trically substituted carbon atoms. Such Compounds can be pure enantiomers or pure diastereo mers or as a mixture thereof. The is preferred Use of an enantiomerically pure compound as an active ingredient.

The invention further relates to the use of the above-mentioned carboxylic acid derivatives for the production of medicaments, in particular for the production of inhibitors for ET _A and / or ET _B receptors. The compounds according to the invention are suitable as antagonists as defined at the outset.

The preparation of the compounds according to the invention with the For mel I can be done in the ways described in DE 197 26 146.9.  

Alternatively, production via intermediates of the general formula III is possible; these derivatives can be synthesized either by reducing azides of the formula II (see DE 197 26 146.9) using generally known methods or by opening the oxazoline derivatives of the general formula IV described in WO 95/07 266.

The opening of the oxazoline derivatives of the formula IV can be done by Behan with aqueous solutions of strong acids such as salt acid, hydrobromic acid, sulfuric acid, perchloric acid, tri fluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or tri fluoromethanesulfonic acid in the presence of a suitable solvent ver by means of. For this purpose, everyone can use water miscible solvents are used insofar as they are opposite are inert to the reagents used.

Examples of such solubilizers are alcohols, such as Example methanol, ethanol, n-propanol, isopropanol; Ether like Tetrahydrofuran or dioxane; Nitriles such as aceto nitrile or propionitrile; Acid amides such as dimethyl formamide or dimethylacetamide; Sulfoxides and sulfones, such as Example dimethyl sulfoxide; Carboxylic acids, such as vinegar acid or propionic acid.

The reaction is preferably in a temperature range between 0 ° C and the boiling point of the solvent or solution medium mixture carried out.

The compounds according to the invention in which R ⁴ R ⁵ N denotes an aromatic or heteroaromatic carboxamide can, for example, be carried out by acylating III on the nitrogen or alternatively acylating both the amino and the hydroxyl group in III and subsequently the esters -Acyl group is split off using generally known methods. For this purpose, the compound of general formula III is reacted with the acylating reagent in a molar ratio of 1: 1 to 1: 6 in the presence of a suitable diluent. All solvents which are inert to the reagents used can be used for this purpose.

Examples of such solvents or diluents middle are aliphatic, alicyclic and aromatic coals Hydrogen, which may be chlorinated if necessary, such as hexane, cyclohexane, petroleum ether, ligroin, benzene, Toluene, xylene, methylene chloride, chloroform, ethyl chloride and tri chloroethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, dioxane and tetrahydrofuran, Nitriles such as acetonitrile and propionitrile, acid amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones such as Dimethyl sulfoxide and sulfolane.

The reaction is preferably in a temperature range between 0 ° C and the boiling point of the solvent or solution medium mixture carried out.

The presence of a reaction catalyst can be advantageous. Dimethylaminopyridine, for example, comes as a catalyst in question.

The resulting compounds of general formula V are converted into the β-amidocarboxylic acid derivatives according to the invention by reacting the compounds of general formula V with heterocycles of general formula VI.

In formula VI, R ^{14 is} halogen or R ¹⁵ -SO ₂ -, where R ^{15 can be} C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or phenyl, and for W, X, Y, Z and Q the conditions mentioned at the beginning apply. 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 V, in a temperature range from room temperature to the boiling point of the solvent.

Compounds of the formula VI are known, some are commercially available or can be prepared in a generally known manner.

If R ¹ in compounds of general form Ia is an ester, the ester group can be cleaved acidic, basic or hydrogenolytically to give the free carboxylic acids with R ¹ = COOH. Compounds of type Ia with R ¹ = COOH can, however, also be obtained directly if the intermediate V, in which R ¹ = COOH, is deprotonated with three equivalents of a suitable base and reacted with compounds of the general formula VI. Here too, the reaction takes place in an inert solvent and in a temperature range from room temperature to the boiling point of the solvent.

As a base, 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. B. 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. The compounds of the general formula I according to the invention in which R ⁴ R ⁵ N is a sulfonamide can be obtained from amines of the general formula VII, the preparation of which is described in DE 197 26 146.9. For this purpose, VII is reacted with sulfonic acid halides by generally known methods and subsequently, if R ^{1 is} an ester, the ester group is cleaved acidic, basic or hydrogenolytically.

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 to an activated form such as an acid halide, an anhydride or in the usual way Imidazolide transferred and then reacted with a corresponding hydroxyl compound HOR ⁶ or sulfonamide H ₂ NSO ₂ R ⁸ . This reaction can be carried out in the customary solvents and often requires the addition of a base, the above-mentioned being possible. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound or the sulfonamide in the presence of a water-releasing agent such as a carbodiimide.

In addition, 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 group COR and R is OM, where M is an alkali metal cation or can be the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula RD, where D is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or optionally substituted by halogen, alkyl or haloalkyl or aryl- or alkylsulfonyl such as. B. toluenesulfonyl and methylsulfonyl or another equivalent leaving group. Compounds of the formula RD with a reactive substituent D are known or are easy to obtain with the general specialist knowledge. This reaction can be carried out in the customary solvents and is advantageously carried out with the addition of a base, the abovementioned being considered.

Compounds of the formula I in which R ^{1 is} tetrazole can be prepared analogously to the methods described in WO 96/11 914, from the corresponding carboxylic acids (formula I with R ¹ = COOH).

In some cases, the use of generally known protective group techniques is required to prepare the compounds I according to the invention. If, for example, R ⁴ R ^{5 is} N = 4-HO-phenyl-CONH-, the hydroxyl group can first be protected as benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.

Compounds of the formula I and V can be in enantiomerically pure form can be obtained by using racemic or diastereomeric Compounds of formula I and V a classic resolution resolution with suitable enantiomerically pure bases, such as. B. the in WO 96/11 914, performed.

With regard to the biological action, 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 ¹ stands for tetrazole or for a group

in which R has the following meaning:

• a) a radical OR ⁶ , in which R ⁶ denotes:
  Hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically acceptable organic ammonium ion such as tertiary C ₁ -C ₄ -alkylammonium or the ammonium ion;
  C ₃ -C ₈ cycloalkyl, C ₁ -C ₈ alkyl, CH ₂ phenyl, which can be substituted by one or more of the following radicals: halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl , Hydroxy, C ₁ -C ₄ alkoxy, mercapto, C ₁ -C ₄ alkylthio, NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ ;
  A C ₃ -C ₈ alkenyl or a C ₃ -C ₈ alkynyl group, these groups in turn being able to carry one to five halogen atoms;
  R ⁶ can also be a phenyl radical which can carry one to five halogen atoms and / or one to three of the following radicals: C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy, C ₁ -C ₄ alkoxy , Mercapto, C ₁ -C ₄ alkylthio, NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ ;
• b) a 5-membered heteroaromatic linked via a nitrogen atom, such as 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 C ₁ -C ₄ -alkoxy groups .
• c) a group
  where k is 0, 1 and 2, p is 1, 2, 3 and 4 and R ^{7 is}
  C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ alkenyl, C ₃ -C ₈ alkynyl or phenyl, which is replaced by one or more, for. B. one to three of the following radicals can be substituted:
  Halogen, C ₁ -C ₄ alkyl, hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ , Mercapto.
• d) a rest
  where R ⁸ means:
  C ₁ -C ₄ alkyl, C ₃ -C ₈ alkenyl, C ₃ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, these radicals being a C ₁ -C ₄ alkoxy, C ₁ -C ₄ -Alkylthio- and / or wear a phenyl radical as mentioned under c);
  C ₁ -C ₄ haloalkyl or phenyl, optionally substituted, in particular as mentioned under c).
  W and Z (which can be the same or different):
  Nitrogen or methine; with the proviso that if W and Z = methine, then Q = nitrogen;
  X nitrogen or CR ⁹ ;
  Y is nitrogen or CR ¹⁰ ;
  Q nitrogen or CR ¹¹ ; with the proviso that if Q = nitrogen, then X = CR ⁹ and Y = CR10;
  R ² and R ³ (which may be the same or different):
  Phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, cyano, hydroxy, mercapto, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, phenoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkylthio, amino, NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ or phenyl, which can be substituted one or more times can, e.g. B. one to three times by halogen, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or C ₁ -C ₄ alkylthio ; or
  Phenyl or naphthyl which are 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;

R ⁴

• a) a rest
  with R ¹² phenyl, naphthyl or a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom, where the radicals mentioned can be substituted one or more times by: halogen, cyano, hydroxy, mercapto, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkyl thio, amino , NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ , H ₂ NSO ₂ , (C ₁ -C ₄ alkyl) NHSO ₂ , (C ₁ -C ₄ alkyl) ₂ NSO ₂ or phenoxy or phenyl, which can be substituted one or more times, for. B. one to three times by halogen, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and / or C ₁ -C ₄ -Alkylthio
• b) a rest
  with R ¹³ C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or phenyl, where the phenyl radical in turn can carry one to five halogen atoms and / or one to three of the following radicals: C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy;
  R ^{5 is} hydrogen, methyl;
  R ⁹ and R ¹⁰ (which may be the same or different):
  Hydrogen, halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkylthio, NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ ;
  C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, where these radicals can be substituted by halogen, hydroxy, mercapto, cyano;
  or CR ⁹ or CR ¹⁰ is linked to CR ¹¹ as stated under R ¹¹ to form a 5- or 6-membered ring;
  R ^{11 is} hydrogen, halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkylthio, NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ) ₂ , cyano;
  C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, where these radicals can each be mono- or polysubstituted by: halogen, cyano, C ₁ -C ₄ alkoxy;
  or CR ¹¹ together with CR ⁹ or CR ¹⁰ forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C _1-4 alkyl groups, and in which one or more methylene groups are each substituted by oxygen, sulfur, -NH or -N (C ₁ -C ₄ alkyl) can be replaced.

Such radicals R ⁴ with the meaning are also very suitable

with R ¹² naphthyl or a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom, where the radicals mentioned can be substituted one or more times by: halogen, nitro, cyano, hydroxy, mercapto, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylcarbonyl, carboxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkylthio, amino, NH (C ₁ -C ₄ alkyl) ₂ NSO ₂ or phenoxy or phenyl, which can be mono- or polysubstituted, e.g. B. one to three times by halogen, nitro, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and / or C ₁ - C ₄ -alkylthio or phenyl, which may be substituted one or more times by: fluorine, bromine, cyano, hydroxy at the 2- or 3-position, mercapto, methyl, propyl, butyl, C ₁ -C ₄ -hydroxyalkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkoxy, C ₁ -C ₄ alkylcarbonyl, carboxy, C ₁ -C ₄ haloalkoxy, C ₂ -C ₄ alkylthio, amino, NH (C ₁ -C ₄ Alkyl), N (C ₁ -C ₄ alkyl) ₂ , H ₂ NSO ₂ , (C ₁ -C ₄ alkyl) NHSO ₂ , (C ₁ -C ₄ alkyl) ₂ NSO ₂ or phenoxy or phenyl that can be substituted one or more times, e.g. B. one to three times by halogen, nitro, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and / or C ₁ - C ₄ alkyl thio.

Compounds of the formula I are particularly preferred - both as pure enantiomers or pure diastereomers or as a mixture thereof - in which the substituents have the following meaning:
R ¹ stands for tetrazole or for a group

in which R has the following meaning:

• a) a radical OR ⁶ , in which R ⁶ denotes:
  Hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or the ammonium ion;
  C ₁ -C ₈ alkyl, CH ₂ phenyl, which can be substituted by one or more of the following radicals: halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy ;
  R ⁶ can furthermore be a phenyl radical which can carry one to five halogen atoms and / or one to three of the following radicals: C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy;
• b) a 5-membered heteroaromatic linked via a nitrogen atom, such as imidazolyl and triazolyl, which can carry one or two halogen atoms, or one or two C ₁ -C ₄ -alkyl or one or two C ₁ -C ₄ -alkoxy groups.
• c) a group
  where k is 0, 1 and 2, p is 1, 2, 3 and 4 and R ^{7 is}
  C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl or phenyl, which is replaced by one or more, for. B. one to three of the following radicals can be substituted:
  Halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy;
• d) a rest
  where R ⁸ means:
  C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, where these radicals can carry a C ₁ -C ₄ alkoxy and / or a phenyl radical as mentioned under c);
  C ₁ -C ₄ haloalkyl or phenyl, optionally substituted, in particular as mentioned under c).
  W and Z (which can be the same or different):
  Nitrogen or methine; with the proviso that if W and Z = methine, then Q = nitrogen;
  X nitrogen or CR ⁹ ;
  Y is nitrogen or CR ¹⁰ ;
  Q nitrogen or CR ¹¹ ; with the proviso that if Q = nitrogen, then X = CR ⁹ and Y = CR ¹⁰ ;
  R ² and R ³ (which may be the same or different):
  Phenyl groups which can be substituted by one or more of the following radicals: halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, phenoxy, C ₁ -C ₄ alkylthio, NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ or phenyl, which can be mono- or polysubstituted, e.g. B. one to three times by halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylthio; or
  Phenyl groups which are 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;

R ⁴

• a) a rest
  with R ¹² phenyl or a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom, where the radicals mentioned can be substituted one or more times by: halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, phenoxy, C ₁ -C ₄ alkylthio, NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ , (C ₁ -C ₄ alkyl) NHSO ₂ , (C ₁ -C ₄ alkyl) ₂ NSO ₂ or phenyl, which can be substituted one or more times, for . B. one to three times by halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy and / or C ₁ -C ₄ haloalkoxy;
• b) a rest
  with R ¹³ C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or phenyl, where the phenyl radical in turn can carry one to five halogen atoms and / or one to three of the following radicals: C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy;
  R ^{5 is} hydrogen, methyl;
  R ⁹ and R ¹⁰ (which may be the same or different):
  Hydrogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, N (C ₁ -C ₄ alkyl) ₂ ;
  C ₁ -C ₄ alkyl, where these radicals can be substituted by halogen;
  or CR ⁹ or CR ¹⁰ is linked to CR ¹¹ as stated under R ¹¹ to form a 5- or 6-membered ring;
  R ^{11 is} hydrogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, cyano;
  C ₁ -C ₄ alkyl, where these radicals can each be substituted one or more times by halogen;
  or CR ¹¹ together with CR ⁹ or CR ¹⁰ forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C _1-4 alkyl groups, and in which one or more methylene groups are each substituted by oxygen, sulfur, -NH or -N (C ₁ -C ₄ alkyl) can be replaced;

The compounds of the present invention offer new the therapeutic potential for the treatment of hypertension, pulmo nalem high pressure, myocardial infarction, chronic heart failure, Angina pectoris, acute / chronic kidney failure, kidneys insufficiency, cerebral vasospasm, cerebral ischemia, Subarachnoid hemorrhage, migraine, asthma, atherosclerosis, endo toxic shock, endotoxin-induced organ failure, intravas culinary coagulation, restenosis after angioplasty, benign prosta ta hyperplasia, ischemic and intoxication Kidney failure or hypertension, cyclosporin-induced kidney fail erectile dysfunction, metastasis and growth mesenchymal tumors, cancer, prostate cancer, contrast medium indu graced kidney failure, pancreatitis, gastrointestinal ulcers.

Another object of the invention are combination preparations from endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system. Inhibitors of renin angiotensin Systems are renin inhibitors, angiotensin II antagonists and above all angiotensin converting enzyme (ACE) inhibitors.

These combination products are particularly suitable for treatment and prevention of hypertension and its complications, as well for the treatment of heart failure.

The good action of the compounds can be seen in the following Ver search show:

Receptor binding studies

Cloned human ET _A or ET _B receptor-expressing CHO cells were used for binding studies.

Membrane preparation

The ET _A or ET _B receptor-expressing CHO cells were in DMEM NUT MIX F ₁₂ 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 μg / ml streptomycin (Gibco, Sigma No. P-0781) increased. 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 × g.

For the membrane preparation, the cells were concentrated tration of 108 cells / ml buffer (50 mM Tris-HCL buffer, pH 7.4) adjusted and then disintegrated by ultrasound Branson Sonifier 250, 40-70 seconds / constant / output 20).

Binding tests

For the ET _A and ET _B receptor binding test, the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl ₂ , 40 mg / ml bacitracin and 0.2% BSA) in a concentration of 50 µg Protein suspended per test batch and incubated at 25 ° C with 25 pH [125J] -ET ₁ (ET _A receptor test) or 25 pH [125J] -ET ₃ (ET _B receptor test) in the presence and absence of test substance. The non-specific binding was determined with 10 ^-7 M ET ₁ . After 30 min, the free and bound radioligand was removed by filtration through GF / B glass fiber filters

(Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway) separated and the filters with ice-cold Tris-HCl buffer, pH 7.4 washed with 0.2% BSA. The collected on the filters Radioactivity was measured using a Packard 2200 CA liquid cintillation counter quantified.

Testing the ET antagonists in vivo

Male SD rats weighing 250-300 g were treated with amobarbital anesthetized, artificially ventilated, vagotomized and despinali siert. The carotid artery and jugular vein became catheter siert.

In control animals, intravenous administration of 1 mg / kg ET1 a significant increase in blood pressure over a long period of time space persists.  

The test animals were given the test compounds 30 minutes before the ET1 administration i.v. injected (1 ml / kg). To determine the ET antagonistic Characteristics were the blood pressure changes in the test animals compared to those in the control animals.

p.o. - Testing the ET receptor antagonists

Male normotonic rats weighing 250-350 g (Sprague Dawley, Janvier) are pretreated orally with the test substances. 80 Minutes later, the animals are anesthetized with urethane and the A. carotis (for measuring blood pressure) and the V. jugularis (Appli cation of big endothelin / endothelin 1) catheterized.

After a stabilization phase, big endothelin (20 µg / kg, Appl. Vol. 0.5 ml / kg) or ET1 (0.3 µg / kg, Appl. Vol. 0.5 ml / kg) given intravenously. Blood pressure and heart rate become continuous Registered over 30 minutes. The clear and long lasting Tending blood pressure changes are shown as the area under the curve (AUC) calculated. To determine the antagonistic effect of The AUC of the substance-treated animals is tested with the AUC of control animals compared.

The compounds according to the invention can be administered orally in the usual way or parenterally (subcutaneously, intravenously, intramuscularly, intrapero toneal). The application can also with vapors or sprays through the nasopharynx.

The dosage depends on the age, condition and weight of the patient as well as on the type of application. As a rule, the daily is active ingredient dose between about 0.5 and 50 mg / kg body weight with oral administration and between about 0.1 and 10 mg / kg body weight with parenteral administration.

The new compounds can be used in the usual galenic Application forms can be applied in solid or liquid form, e.g. B. as Tablets, film-coated tablets, capsules, powders, granules, coated tablets, Suppositories, solutions, ointments, creams or sprays. These will made in the usual way. The active ingredients can the usual pharmaceutical auxiliaries such as tablet binders, filling substances, preservatives, tablet disintegrants, flow regulating agents, plasticizers, wetting agents, dispersing agents, Emulsifiers, solvents, retardants, antioxidants and / or propellant gases are processed (see H. Sucker et al .: Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1991). The Application forms thus obtained contain the active ingredient usually in an amount of 0.1 to 90% by weight.  

Synthesis examples example 1 3-Amino-2-hydroxy-3,3-diphenylpropionic acid methyl ester

To a solution of methyl 3-azido-2-hydroxy-3,3-diphenylpropionate (5.71 g; 19.2 mmol) in methanol (100 ml) was added 0.2 g of a 10% palladium / carbon hydrogenation catalyst . The mixture was stirred for 48 hours at room temperature under a hydrogen atmosphere; the catalyst was then filtered off and the solvent was distilled off. The residue was taken up with 5% aqueous citric acid and the resulting solution was extracted with ether. The aqueous phase was then alkalized with dilute sodium hydroxide solution and extracted again with ether. The extracts obtained from the alkaline were dried over magnesium sulfate and the solvent was removed in vacuo. 4.03 g (14.9 mmol, 77% yield) of the pure amine were obtained.
¹ H NMR (200 MHz): 7.5 (m, 2 H); 7.2-7.4 (m, 8H), 5.0 (s, 1H); 4.2 (s br, 1H), 3.4 (s, 3H); 2.0-2.4 (s br, 2H).

Example 2 4-methoxy-benzoic acid 2- (4-methoxy-benzoylamino) -1-methoxy carbonyl-2,2-diphenyl ethyl ester

To a solution of 3-amino-2-hydroxy-3,3-diphenylpropionic acid methyl ester (2.00 g, 7.37 mmol) in dichloromethane (10 ml) was added successively pyridine (1.17 g; 14.7 mmol), a spatula tip Dimethylaminopyridine and para-methoxybenzoyl chloride (2.52 g, 14.7 mmol). The batch was run for 4 hours at room temperature stirred, then worked up with water and ether extracted. The combined organic phases were after Wash with aqueous citric acid and saturated saline dried over magnesium sulfate. Evaporation of the solvent in the Vacuum provided the crude bisacylation product, which without further ado Purification was used (1.37 g; 28% yield at 82% pure HPLC).  

Example 3 2-Hydroxy-3- (4-methoxy-benzoylamino) -3,3-diphenylpropionic acid methyl ester

4-methoxy-benzoic acid 2- (4-methoxy-benzoylamino) -1-methoxy carbonyl-2,2-diphenyl-ethyl ester (1.37 g; 2.08 mmol at 82% Purity) was dissolved in methanol (20 ml) and with potassium carbonate (863 mg, 6.25 mmol) was added. The resulting mixture turned 16 Stirred for hours at room temperature and then in vacuo from Free solvent. The residue was taken up in water and extracted with ether; a colorless solid precipitated out, which was isolated by filtration and with the title compound was identical. The aqueous phase was then again with Extracted ethyl acetate. The combined organic phases were combined, dried over magnesium sulfate and in vacuo from Free solvent. The crude product was by crystallization purified from dichloromethane / ether / n-hexane, a colorless one fell Solid on (503 mg; 60% yield).

Example 4 2-Hydroxy-3- (4-methoxy-benzoylamino) -3,3-diphenylpropionic acid benzyl ester

To a solution of 2-hydroxy-3- (4-methoxy-benzoylamino) -3,3-di phenyl-propionic acid methyl ester (503 mg; 1.24 mmol) in water / Tetrahydrofuran 1: 2 (50 ml) became 2.11 ml of a 1 molar Added sodium hydroxide solution and stirred for 60 hours at room temperature. After that, the starting material was largely implemented; for ver completion of the reaction was again 1 molar sodium hydroxide solution (2.11 ml) was added and stirring was continued for one hour. The approach was diluted with water, extracted with ether, with citric acid acidified and extracted again with ether. The one from the sour Extracts obtained were dried over magnesium sulfate and in Vacuum freed from the solvent. The residue (406 mg) was in Dimethylformamide (20 ml) was added and successively with potassium carbonate (179 mg; 1.30 mmol) and benzyl bromide (195 mg; 1.14 mmol) transferred. The resulting mixture was at 20 hours Stirred at room temperature and then with 5% aqueous citrus added acid. After dilution with water, dichlor methane and then with ether (product is only moderately soluble in ether) extracted. The combined organic extracts became thorough washed with water and then with saturated saline, dried over magnesium sulfate and in vacuo from the solvent exempted. Traces of benzyl bromide and dimethylformamide could be found by washing the residue with a little ether / n-hexane 1: 1 ent  be removed. 487 mg (79%) of the pure benzyl ester were obtained.

Example 5 2- (4,6-diethyl- [1,3,5] triazin-2-yloxy) -3- (4-methoxy-benzoyl amino) -3,3-diphenylpropionic acid benzyl ester

To a solution of 2-hydroxy-3- (4-methoxy-benzoylamino) -3,3- benzyl diphenylpropionate (139 mg, 0.29 mmol) in dimethyl formamide (15 ml) was sequentially potassium carbonate (80 mg; 0.58 mmol) and 2-chloro-4,6-diethyl- [1,3,5] triazine (74 mg; 0.43 mmol) given. It was heated to 60 ° C and 4 hours at this Temperature stirred. The reaction was by adding 5% Citric acid (10 ml) stopped. After dilution with water was extracted with ether and the combined organic Phases were washed with saturated saline as well dried over magnesium sulfate. The solvent was distilled off; the remaining residue was Chromatography (eluent: ethyl acetate in cyclohexane 30 → 50%) cleaned. 124 mg of the target compound fell in 90% Purity (according to HPLC) (63% yield).

Example 6 2- (4,6-diethyl- [1,3,5] triazin-2-yloxy) -3- (4-methoxy-benzoyla mino) -3,3-diphenylpropionic acid (I-4)

A solution of benzyl 2- (4,6-diethyl- [1,3,5] triazin-2-yloxy) -3- (4-methoxy-benzoylamino) -3,3-diphenylpropionate (124 mg, 0.18 mmol added 90% purity) in ethyl acetate (15 ml) was mixed with a 10% palladium / carbon hydrogenation catalyst (spatula tip) and stirred at room temperature for 3 hours under a hydrogen atmosphere. The catalyst was then filtered off and the solvent was distilled off in vacuo. The residue was crystallized from dichloromethane / ether / n-hexane, 99 mg (73% yield) of the pure carboxylic acid were obtained.
¹ H NMR (200 MHz): 7.8 (m, 3 H); 7.6 (dd, 2H); 7.1-7.4 (m, 8H); 6.9 (d, 2H); 6.6 (s, 1H); 3.8 (s, 3H); 2.7 (q, 4H); 1.2 (t, 6H).
ESI-MS: M ⁺ = 526.

Analogous were synthesized

2- (4,6-diethyl- [1,3,5] triazin-2-yloxy) -3- (3,5-dimethoxy-benzoyl amino) -3,3-diphenylpropionic acid (I-327)
¹ H NMR (200 MHz): 7.9 (s, 1 H); 7.6 (m, 2H), 7.2-7.5 (m, 8H); 6.9 (d, 2H); 6.7 (s, 1H), 6.6 (t, 1H); 3.8 (s, 6H); 2.7 (q, 4H); 1.2 (t, 6H).
ESI-MS: M ⁺ = 556.

3- (3,5-Dimethoxy-benzoylamino) -2- (4,6-dimethyl-pyrimidin-2-yl oxy) -3,3-diphenylpropionic acid (I-248)
¹ H NMR (200 MHz): 8.1 (s br, 1 H); 7.7 (m, 2H); 7.2-7.5 (m, 8H); 7.0 (d. 2H); 6.70 (s, 1H); 6.65 (s, 1H); 6.60 (t, 1H); 3.8 (s, 6H); 2.3 (s, 6H).
ESI-MS: M ⁺ = 527.

3-benzoylamino-2- (4,6-dimethyl-pyrimidin-2-yloxy) -3,3-diphenyl propionic acid (I-66)
¹ H NMR (200 MHz): 8.2 (s br, 1 H); 7.8 (m, 2H); 7.6 (m, 2H); 7.1-7.5 (m, 11H); 6.70 (s, 1H); 6.65 (s, 1H); 2.3 (s, 6H).
ESI-MS: M ⁺ = 467.

2- (4,6-dimethyl-pyrimidin-2-yloxy) -3- (4-methyl-benzoyla mino) -3,3-diphenylpropionic acid (I-199)
¹ H NMR (200 MHz): 8.0 (s br, 1 H); 7.7 (d. 2H); 7.6 (m, 2H); 7.1-7.5 (m, 10H); 6.7 (s, 2H); 2.4 (s, 3H); 2.3 (s, 6H).
ESI-MS: M ⁺ = 481.

2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (4-methoxy-benzoylamino) -3,3-diphenylpropionic acid
¹ H NMR (200 MHz): 8.0 (s br, 1 H); 7.8 (d. 2H); 7.7 (dd, 2H); 7.1-7.5 (m, 8H); 6.9 (d, 2H); 6.70 (s, 1H); 6.65 (s, 1H); 3.8 (s, 3H); 2.3 (s, 3H).
ESI-MS: M ⁺ = 497.

Example 7 Benzyl 2-methyl-4,4-diphenyl-4,5-dihydro-oxazole-5-carboxylate

To a solution of benzyl 3,3-diphenyl-oxirane-2-carboxylate (10.0 g; 28.3 mmol) in acetonitrile (100 ml) became careful Boron trifluoride etherate (8.04 g; 56.7 mmol) added. The mixture was stirred for one hour at room temperature and then on  Rotary evaporator concentrated. It was taken up in water saturated with sodium chloride and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and in Vacuum freed from solvent; the residue (13.5 g) used without cleaning.

Example 8 Benzyl 3-amino-2-hydroxy-3,3-diphenylpropionate

Benzyl 2-methyl-4,4-diphenyl-4,5-dihydro-oxazole-5-carboxylate (13.5 g; crude) was dissolved in a mixture of methanol (25 ml), water (50 ml) and concentrated hydrochloric acid ( 50 ml) stirred for 60 hours at room temperature. After that, the undissolved was decanted; the residue was stirred for another three hours in the above mixture. It was decanted again; the remaining residue was discarded. The two liquid phases were combined and adjusted to pH 8-9 with sodium hydroxide solution, whereupon crystallization began. The crystals were washed with ether and suction filtered; 4.65 g of the desired amino alcohol were obtained in 97% purity.
¹ H NMR (200 MHz): 7.4 (m, 2 H); 7.1-7.3 (m, 11H); , 7.0 (m, 2H); 5.0 (s, 1H); 4.9 (d. 1H); 4.7 (d. 1H); 1.9-2.5 (s br, 2H).

Example 9 2-Hydroxy-3,3-diphenyl-3- (4-trifluoromethyl-benzoylamino) -pro benzyl pionate

Pyridine (94 mg; 1.00 mmol), a spatula tip of dimethylaminopyridine, was added successively to a solution of benzyl 3-amino-2-hydroxy-3,3-diphenylpropionate (365 mg; 1.00 mmol) in dichloromethane (50 ml) and para-trifluoromethylbenzoyl chloride (215 mg, 1.00 mmol). The mixture was stirred at room temperature for 60 hours and then extracted with dilute citric acid for working up. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The residue (540 mg) was taken up in chloroform (50 ml), pyridine (36 mg, 0.45 mmol) and a few crystals of dimethylaminopyridine were added and the mixture was heated to boiling under reflux for 4 hours. After cooling, the mixture was extracted with dilute citric acid for working up. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was crystallized from ether / n-hexane; 235 mg (45% yield) of the pure product were obtained.
¹ H NMR (2G0 MHz): 7.7 (d, 2 H); 7.5 (d. 2H); 7.2-7.4 (m, 13H); 7.1 (d. 2H); 5.5 (d br, 1H); 5.0 (m, 2H); 4.6-4.8 (s br, 1H).

Example 10 2- (4,6-dimethyl-pyrimidin-2-yloxy) -3,3-diphenyl-3- (4-trifluorome benzyl thyl-benzoylamino) propionate

To a solution of 2-hydroxy-3,3-diphenyl-3- (4-trifluoromethyl benzoylamino) benzyl propionate (220 mg, 0.42 mmol) in Dimethylformamide (15 ml) was sequentially potassium carbonate (100 mg; 0.72 mmol) and 2-methylsulfonyl-4,6-dimethylpyrimidine (96 mg; 0.51 mmol). It was heated to 80 ° C and at an hour this temperature stirred. The reaction was started by adding diluted citric acid and water (200 ml) canceled. It was extracted with ether; the organic phase was over Magnesium sulfate dried and concentrated in vacuo. The residue was crystallized from ether / n-hexane; 158 mg (60%) fell the pure title connection.

Example 11 2- (4,6-dimethyl-pyrimidin-2-yloxy) -3,3-diphenyl-3- (4-trifluorome thyl-benzoylamino) propionic acid (I-201)

A solution of 2- (4,6-dimethyl-pyrimidin-2-yl oxy) -3,3-diphenyl-3- (4-trifluoromethyl-benzoylamino) propionic acid rebenzyl ester (150 mg, 0.24 mmol) in ethyl acetate ( 50 ml) was mixed with a 10% palladium / carbon hydrogenation catalyst (spatula tip) and stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was then filtered off and the solvent was distilled off in vacuo. The residue was crystallized from ether / n-hexane, 100 mg (78%) of the pure carboxylic acid were obtained.
¹ H-MR (200 MHz): 8.3 (s br, 1 H); 7.9 (d. 2H); 7.7 (m, 4H); 7.1-7.4 (m, 8H); 6.7 (s, 1H); 6.6 (S, 1H); 2, 3 (s, 6H).
ESI-MS: M ⁺ = 535.

Analog were made

3- (3,4-Dimethoxy-benzoylamino) -2- (4,6-dimethyl-pyrimidin-2-yl oxy) -3,3-diphenylpropionic acid (I-48)
¹ H NMR (200 MHz): 8.2 (s br, 1 H); 7.7 (m, 2H); 7.1-7.5 (m, 10H); 6.8 (d, 1H); 6.7 (s, 1H); 6.6 (s, 1H); 3.9 (s, 3H); 3.8 (s, 3H); 2.3 (s, 6H).
ESI-MS: M ⁺ = 527.

3- (3,4-difluorobenzoylamino) -2- (4,6-dimethyl-pyrimidin-2-yl oxy) -3,3-diphenylpropionic acid (I-340)
¹ H NMR (200 MHz): 8.2 (s br, 1 H); 7.5-7.8 (m, 5H); 7.1-7.4 (m, 8H); 6.7 (s, 1H); 6.6 (s, 1H); 2.3 (s, 6H).
ESI-MS: M ⁺ = 5 03.

2- (4,6-dimethyl-pyrimidin-2-yloxy) -3- (4-fluoro-benzoylamino) - 3,3-diphenylpropionic acid (I-170)
¹ H NMR (200 MHz): 8.2 (s br, 1 H); 7.8 (dd, 2H); 7.6 (m, 2H); 7.0-7.5 (m, 10H) 6.7 (s, 1H); 6.6 (s, 1H); 2.3 (s, 6H).
ESI-MS: M ⁺ = 485.

Example 12 2- (4,6-dimethoxypyrimidin-2-yloxy) -3-methanesulfonylamino-3,3- diphenylpropionic acid methyl ester

To a solution of 3-amino-2- (4,6-dimethoxy-pyrimidin-2-yl oxy) -3,3-diphenylpropionic acid methyl ester. (213 mg; 0.52 mmol) in Dichloromethane (15 ml) became methanesulfonyl chloride (83 mg, 0.73 mmol), Pyridine (82 mg; 1.04 mmol) and dimethylaminopyridine (Spatula tip). The mix was a week at room temperature stirred. Because of incomplete sales were still Add 0.20 mol equivalents of methanesulfonyl chloride and again stirred for three days at room temperature. To work up was the batch diluted with ether and successively with diluted Citric acid, sodium hydrogen carbonate solution and saturated Washed saline. The organic phase was over Magnesium sulfate dried and in vacuo from the solvent exempted. The citric acid extract was neutralized and with Extracted ether; the organic phases obtained therefrom were dried and evaporated as described above. The back stand (206 mg) was used without further processing.

Example 13 2- (4,6-Dimethoxypyrimidin-2-yloxy) -3-methanesulfonylamino-3,3-di phenylpropionic acid (I-156)

To a solution of methyl 2- (4,6-dimethoxypyrimidin-2-yloxy) -3-methanesulfonylamino-3,3-diphenylpropionate (181 mg, crude) in water / tetrahydrofuran 1: 2 (30 ml) 50 ml of a 1 molar sodium hydroxide solution were added and the mixture was stirred at room temperature for 5 days. To complete the reaction, a further 0.5 molar equivalents of 1 molar sodium hydroxide solution were added and the mixture was stirred for another 24 hours. It was diluted with water and extracted with ether; then the aqueous phase was acidified with citric acid and extracted again with ether. The extracts obtained from the acid were dried over magnesium sulfate and freed from the solvent in vacuo. Crystallization of the residue from dichloromethane / n-hexane gave the pure target compound (71 mg; 33% yield over two stages).
¹ H NMR (200 MHz): 7.6-7.7 (m, 2 H); 7.3-7.5 (m, 8H), 6.5 (s, 1H); 6.3 (s br, 1H), 5.8 (s, 1H); 3.9 (s, 6H); 2.2 (s, 3H).
ESI-MS: M ⁺ = 473.

The compounds listed in Table 1 can be prepared analogously or as described in the general part.

Example 14

According to the binding test described above, for the Compounds listed below measured receptor binding data. The results are shown in Table 2.

Table 2

Receptor binding data (K _i values)

Claims (10)

1. β-amido and β-sulfonamidocarboxylic acid derivatives of the formula I.
where the substituents have the following meaning:

• 1. R ¹ tetrazole or a group
  R:
• 2. a radical OR ⁶ , in which R ⁶ denotes:
  Hydrogen,
  C ₃ -C ₈ cycloalkyl, C ₁ -C ₈ alkyl, CH ₂ phenyl, where the radicals mentioned can be optionally substituted,
  C ₃ -C ₈ alkenyl or a C ₃ -C ₈ alkynyl group optionally substituted or
  Phenyl optionally substituted,
• 3. a 5-membered heteroaromatic linked via a nitrogen atom.
• 4. a group
  in which k can have the values 0, 1 and 2, p can have the values 1, 2, 3 and 4 and R ⁷ for
  C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ alkenyl, C ₃ -C ₈ alkynyl or optionally substituted phenyl,
• 5. a rest
• 6. wherein R ⁸ means:
  C ₁ -C ₄ alkyl, C ₃ -C ₈ alkenyl, C ₃ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, these radicals being a C ₁ -C ₄ alkoxy, C ₁ -C ₄ Can carry alkylthio and / or a phenyl radical,
  C ₁ -C ₄ haloalkyl or phenyl, optionally substituted,
  W and Z, which can be the same or different:
  Nitrogen or methine; with the proviso that if W and Z = methine, then Q = nitrogen;
  X nitrogen or CR ⁹ ;
  Y is nitrogen or CR ¹⁰ ;
  Q nitrogen or CR ¹¹ ; with the proviso that if Q = nitrogen, then X = CR ⁹ and Y = CR ¹⁰ ;
  R ² and R ³ , which may be the same or different:
  Phenyl or naphthyl, optionally substituted, or
  Phenyl or naphthyl which are 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
  C ₅ -C ₆ cycloalkyl optionally substituted;
• 7. R ⁴
  • a) a rest
    with R ¹² phenyl, naphthyl or a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom, it being possible for the said radicals to be substituted;
  • b) a rest
    with R ¹³ C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkylthio, phenyl or phenoxy, the phenyl radicals may optionally be substituted;
    R ^{5 is} hydrogen, C ₁ -C ₄ alkyl; R ⁹ and R ¹⁰ (which may be the same or different):
    Hydrogen, halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halo alkoxy, C ₃ -C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ -Alkylcarbonyl, C ₁ -C ₄ -alkoxy carbonyl, hydroxy, NH ₂ , NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ ,
    C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, where these radicals can optionally be substituted,
    or CR ⁹ or CR ¹⁰ is linked to CR ¹¹ to a 5- or 6-membered ring as indicated below;
    R ^{11 is} hydrogen, halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halo alkoxy, C ₃ -C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, C ₁ -C ₄ alkylthio, C ₁ - C ₄ alkylcarbonyl, C ₁ -C ₄ alkoxy carbonyl, NH (C ₁ -C ₄ alkyl), N (C ₁ -C ₄ alkyl) ₂ , hydroxy, carboxy, cyano, amino, mercapto,
    C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, it being possible for these radicals to be optionally substituted;
    or CR ¹¹ forms together with CR ⁹ or CR ¹⁰ a 5- or 6-membered alkylene or alkenylene ring, which may optionally be substituted, and in which in each case one or more methylene groups by oxygen, sulfur, -NH or -N (C ₁ -C ₄ alkyl), can be replaced,
• 8. mean, as well as the physiologically compatible salts, and the possible enantiomerically pure and diastereoisomerically pure forms, with the exception of the following compounds:
  2- (6-ethyl-2-methylpyrimidin-4-yloxy) -3- (4-methoxybenzoylamino) -3,3-diphenylpropionic acid
  2- (2,6-Dimethyl-pyrimidin-4-yloxy) -3- (4-methoxy-benzoyl axnino) -3,3-diphenylpropionic acid
  3- (4-methoxy-benzoylamino) -2- (6-methoxy-2-methyl-pyrimidine-4-yloxy) -3,3-diphenylpropionic acid
  3- (4-methoxy-benzoylamino) -2- (6-methoxy-5-methyl-pyrazin-2-yloxy) -3,3-diphenylpropionic acid
  3- (4-methoxy-benzoylamino) -2- (5-methoxy-6-methyl- [1,2,4] triazin-3-yloxy) -3,3-diphenylpropionic acid
  2- (4-Ethyl-6-methyl- [1,3,5] triazin-2-yloxy) -3- (4-methoxy benzoylamino) -3,3-diphenylpropionic acid
  3- (4-methoxy-benzoylamino) -2- (5-methoxy-6-methyl-pyrida zin-3-yloxy) -3,3-diphenylpropionic acid
  2- (4,6-Dimethyl- [1,3,5] triazin-2-yloxy) -3- (4-methoxy benzoylamino) -3,3-diphenylpropionic acid
  3- (4-methoxy-benzoylamino) -2- (4-methoxy-6-methyl- [1,3,5] triazin-2-yloxy) -3,3-diphenylpropionic acid
  3- (4-methoxy-benzoylamino) -2- (4-methoxy-6,7-dihydro-5H cyclopentapyrimidin-2-yloxy) -3,3-diphenylpropionic acid
  3- (4-methoxy-benzoylamino) -2- (4-methoxy-5,6-dihydro furo [2,3-d] pyrimidin-2-yloxy) -3,3-diphenylpropionic acid
  2- (4,6-Dimethoxy-pyrimidin-2-yloxy) -3- (4-methoxy-benzoyl amino) -3,3-diphenylpropionic acid
  2- (4-ethyl-6-methyl-pyrimidin-2-yloxy) -3- (4-methoxy benzoylamino) -3,3-diphenylpropionic acid
  2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (4-methoxy-benzoyl amino) -3,3-diphenylpropionic acid
  3- (4-methoxy-benzoylamino) -2- (4-methoxy-6-methyl-pyrimidine-2-yloxy) -3,3-diphenylpropionic acid
  2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (4-hydroxy-benzoyl amino) -3,3-diphenylpropionic acid
  2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (4-methylsul fanyl-benzoylamino) -3,3-diphenylpropionic acid
  2- (4,6-Dimethoxy-pyrimidin-2-yloxy) -3- (4-nitro-benzoyl amino) -3,3-diphenylpropionic acid
  3- (4-chloro-benzoylamino) -2- (4-ethyl-6-methyl-pyrimidine-2-yloxy) -3,3-diphenylpropionic acid
  3- (4-ethyl-benzoylamino) -2- (4-methoxy-6,7-dihydro-5H cyclopentapyrimidin-2-yloxy) -3,3-diphenylpropionic acid
  3,3-bis (4-fluoro-phenyl) -3- (4-methoxy-benzoyla mino) -2- (4-methoxy-5,6-dihydrofuro [2,3-d] pyrimidin-2-yl oxy ) propionic acid
  3- (4-chloro-benzoylamino) -2- (4,6-dimethyl- [1,3,5] tri azin-2-yloxy) -3,3-diphenylpropionic acid
  3- (3,4-Dimethoxy-benzoyla mino) -2- (4-methoxy-6-methyl- [1,3,5] triazin-2-yl oxy) -3,3-diphenylpropionic acid
  3- (3,4-Dimethoxy-benzoylamino) -2- (4-ethyl-6-methyl- [1,3,5] triazin-2-yloxy) -3,3-diphenylpropionic acid
  3- (4-chloro-benzoylamino) -2- (5-methoxy-6-methylpyridazin-3-yloxy) -3,3-diphenylpropionic acid
  3- (3,4-dichloro-benzoylamino) -2- (6-methoxy-5-methylpyrazin-2-yloxy) -3,3-diphenylpropionic acid
  3- (4-Hydroxy-3-methoxy-benzoylamino) -2- (5-methoxy-6-methyl- [1,2,4] triazin-3-yloxy) -3,3-diphenylpropionic acid
  3- (3-chloro-benzoylamino) -2- (2,6-dimethyl-pyrimidin-4-yl oxy) -3,3-diphenylpropionic acid
  3- (2-chloro-benzoylamino) -2- (6-methoxy-2-methyl-pyrimidine-4-yloxy) -3,3-diphenylpropionic acid
  2- (6-ethyl-2-methyl-pyrimidin-4-yloxy) -3- (4-nitrobenzoylamino) -3,3-diphenylpropionic acid.

2. Use of the β-amido and β-sulfonamidocarboxylic acid derivatives according to claim 1 for the treatment of diseases. 3. Use of the compounds I according to claim 2 as an endothe lin receptor antagonists. 4. Use of the β-amido and β-sulfonamidocarboxylic acid derivatives I according to claim 1 for the manufacture of medicaments for Treatment of diseases in which increased endothelin Mirrors occur. 5. Use of the β-amido and β-sulfonamidocarboxylic acid derivatives I according to claim 1 for the treatment of chronic heart failure efficiency, restenosis, high blood pressure, pulmonary high pressure, acute / chronic kidney failure, erectile dysfunction, cerebral ischemia, benign prostatic hyperplasia, and prostate takreb. 6. Use of the β-amido and β-sulfonamidocarboxylic acid derivatives I according to claim 1 in combination with: inhibitors of renin Angiotensin systems such as renin inhibitors, angiotensin II antagonists and especially angiotensin converting enzyme (ACE) inhibitor mer; mixed ACE / neutral endopeptidase (NEP) inhibitors; β-blockers. 7. Pharmaceutical preparations for oral, parenteral and intraperenteral use, containing per single dose, in addition to the usual pharmaceutical excipients, at least one Carboxylic acid derivative I according to claim 1.   8. Compounds of formula II
wherein the radicals R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meaning given in claim 1. 9. Use of compounds of the formula II,
wherein the radicals R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meaning given in claim 1, as a starting material for the synthesis of endothelin receptor antagonists. 10. A structural fragment of the formula
wherein the radicals R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meaning given in claim 1, as a structural element in an endothelin receptor antagonist.