JP2002533330A - Novel β-amide and β-sulfonamidocarboxylic acid derivatives, their preparation and their use as endothelin receptor antagonists - Google Patents

Abstract

(57) The present invention relates to a compound of the formula (I) wherein the substituents have the following meanings: R ¹ is a tetrazole or group (a); W and Z may be the same or different , Nitrogen or methine, provided that when W and Z are methine, Q is nitrogen; X is nitrogen or CR ⁹ ; Y is nitrogen or CR ¹⁰ ; Q is nitrogen or CR ¹¹ ; When Q is nitrogen, X is CR ⁵ and Y is CR ¹⁰ ; R ² and R ³ are the same or different and are optionally substituted phenyl or naphthyl or a direct bond at the ortho position, methylene or an ethylene group, an oxygen or sulfur atom or SO 2 _-, NH- or N- alkyl C ₅ -C 6 substituted by groups or _- phenyl or naphthyl which is connected via a cycloalkyl And R ⁴ is (b) or (c); and R ⁵ is hydrogen, C ₁ -C ₄ -alkyl]. The invention further relates to their preparation and their use as endothelin receptor antagonists. The invention also relates to compounds of the formula (II) and structural fragments of the formula (d), wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meaning of claim 1 and these As a structural element in endothelin receptor antagonists.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel carboxylic acid derivatives, their production and use.

[0002] Endothelin is a peptide consisting of 21 amino acids and is produced and released by the vascular endothelium. Endothelin has three isoforms, RT-1,
Present as ET-2 and ET-3. Hereafter, "endothelin" or "ET
"Refers to one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a significant 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, 213, 440-444, 1988 and Bi).
ochem. Biophys. Res. Commun., 154, 868-875, 1988).

[0003] High or abnormal release of endothelin causes persistent vascular tone in the peripheral, renal and cerebral blood vessels, which can lead to disease. As reported in the literature, endothelin has been implicated in a number of diseases. These include hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Me
d. Biology 2, 207, (1990), J. Am. Med. Association 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 25, 904, (1994)
), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995), Canc.
er Research 56, 663 (1996), Nature Medicine 1, 944, (1995)).

[0004] At least two endothelin receptor subtypes, ET _A and ET _B receptors, have recently been reported in the literature (Nature 348, 730 (1990); Nature 348, 732 (199).
0)). Thus, substances that inhibit the binding of endothelin to one or both of the receptors should have an antagonistic effect on the physiological actions of endothelin, and are therefore valuable drugs.

[0005] German Patent Application (DE) 197 26 146.9 describes the preparation of β-amino and β-azidocarboxylic acid derivatives and their use as endothelin receptor antagonists. Subsequent studies have revealed that related aromatic carboxamide and sulfonamide derivatives have advantageous properties in relation to receptor affinity and receptor binding profile. This patent relates to their manufacture and use.

The present invention provides compounds of formula I

[0007]

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Wherein R ¹ is tetrazolyl or a group

[0009]

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(Wherein, R represents the following.

A) a group OR ⁶ , wherein R ⁶ is hydrogen, an alkali metal cation, an alkaline earth metal cation or a physiologically acceptable organic ammonium ion, such as quaternary C ₁ -C ₄ - alkylammonium, or ammonium ion, _C 3 -C ₈ - _cycloalkyl, C 1 -C ₈ - alkyl, CH ₂ - phenyl, which may optionally be substituted with one or more of the following groups: halogen , nitro, _cyano, C 1 -C ₄ - _alkyl, C 1 -C ₄ - haloalkyl, hydroxyl,
C ₁ -C ₄ - alkoxy, _mercapto, C 1 -C ₄ - alkylthio, amino, N
H (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ ; C ₃ -C ₈ -alkenyl or C ₃ -C ₈ -alkynyl groups; R ⁶ may be a phenyl group which may further have 1 to 5 halogen atoms and / or 1 to 3 groups: nitro, cyano, C ₁ -C ₄ - _alkyl, C 1 -C ₄ - haloalkyl, _hydroxyl, 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) 5-membered heteroaromatic systems linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, one or two of which halogen atoms or one or two _C 1 -C ₄ - alkyl or one or two _C 1 -C ₄ - may have an alkoxy group, c) group

[0012]

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Where k can take the values 0, 1 and 2, p can take the values 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 one of the following groups or more, for example optionally substituted with 1 to 3 phenyl it is: halogen, nitro, _cyano, C 1 -C ₄ - alkyl, _hydroxyl, 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) group

[0014]

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(Wherein R ⁸ is C ₁ -C ₄ -alkyl, C ₃ -C ₈ -alkenyl, C ₃ -C ₈ -alkynyl, C ₃ -C ₈ -cycloalkyl, and these groups are ₁ -C ₄ - _alkoxy, C 1 -C ₄ - alkylthio and / or c) may have a phenyl group as described in claim, _C 1 -C ₄ - haloalkyl or unsubstituted or, especially the c ) Is phenyl substituted as described in section)))).

A β-amide or β-sulfonamidocarboxylic acid derivative of

Other substituents have the following meanings: W and Z may be the same or different, nitrogen or methine, provided that when W and Z are methine, Q is nitrogen, and X Is nitrogen or CR ⁹ , Y is nitrogen or CR ¹⁰ , Q is nitrogen or CR ¹¹ , provided that when Q = nitrogen, X = CR ⁹ and Y =
CR ¹⁰ and R ² and R ³ may be the same or different and each is phenyl or naphthyl optionally substituted by one or more of the following groups: halogen, nitro, cyano, hydroxyl , _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 one or more, for example 1 to 3 times, halogen, nitro, _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 -
Phenyl optionally substituted by alkylthio, or phenyl or naphthyl linked together at the ortho position by 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, these groups, halogen, hydroxyl, mercapto, carboxyl, nitro, _cyano, C 1 -C ₄ - _alkyl, C 2 -C ₄ - _alkenyl, C 2 -C ₄ - alkynyl, May be substituted in each case 1 to 3 times by C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₄ -haloalkoxy, R ⁴ is a) group

[0018]

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(Wherein R¹²Is phenyl, naphthyl or 1 to 3 nitrogen atoms and / or
A 5- or 6-membered heteroaromatic system containing one sulfur or oxygen atom, wherein said group is
May be substituted one or more times by the following groups: halogen, nitro
, Cyano, hydroxyl, mercapto, C₁~ C₄-Alkyl, C₁~ C₄-H
Droxyalkyl, C₁~ C₄-Haloalkyl, C₁~ C₄-Alkoxy, C₁ ~ C₄-Alkylcarbonyl, carboxyl, C₁~ C₄-Haloalkoxy, C ₁ ~ C₄-Alkylthio, amino, NH (C₁~ C₄-Alkyl), N (C₁~
C₄-Alkyl)₂, H₂NSO₂, (C₁~ C₄-Alkyl) NHSO₂, (
C₁~ C₄-Alkyl)₂NSO₂, Or all halogen, nitro, cyano
, C₁~ C₄-Alkyl, C₁~ C₄-Haloalkyl, C₁~ C₄-Alkoxy
, C₁~ C₄-Haloalkoxy and / or C₁~ C₄-By alkylthio
Phenoxy or phenyl optionally substituted one or more times, for example 1-3 times
Enyl) b) group

[0020]

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(Where R¹³Is C₁~ C₄-Alkyl, C₁~ C₄-Haloalkyl or
And the phenyl group further comprises 1 to 5 halogen atoms and / or 1 to 3 halogen atoms.
May have the following groups: C₁~ C₄-Alkyl, C₁~ C₄-Haloa
Luquil, C₁~ C₄-Alkoxy, C₁~ C₄-Haloalkoxy and / or
C₁~ C₄-Alkylthio), R⁵Is hydrogen, C₁~ C₄-Alkyl, R⁹And R¹⁰(Which may be the same or different) are hydrogen, halogen, C₁~ C₄-Alkoxy, C₁~ C₄-Haloalkoxy, C₃ ~ C₆-Alkenyloxy, C₃~ C₆Alkynyloxy, C₁~ C₄-Al
Kircio, C₁~ C₄-Alkylcarbonyl, C₁~ C₄-Alkoxycarboni
, Hydroxyl, NH₂, NH (C₁~ C₄-Alkyl), N (C₁~ C₄−
Alkyl)₂, C₁~ C₄-Alkyl, C₂~ C₄-Alkenyl, C₂~ C₄Alkynyl
Thus, these groups are halogen, hydroxyl, mercapto, carboxyl,
Or R⁹And R¹⁰Is R¹¹CR as described in¹¹Connected with 5 members
Becomes a 6-membered ring, R¹¹Is hydrogen, halogen, C₁~ C₄-Alkoxy, C₁~ C₄-Halo Alco
Kissi, C₃~ C₆-Alkenyloxy, C₃~ C₆Alkynyloxy, C₁~
C₄-Alkylthio, C₁~ C₄-Alkylcarbonyl, C₁~ C₄-Alkoki
Cicarbonyl, NH (C₁~ C₄-Alkyl), N (C₁~ C₄-Alkyl)₂ , Hydroxyl, carboxyl, cyano, amino, mercapto, C₁~ C₄-Alkyl, C₂~ C₄-Alkenyl, C₂~ C₄Alkynyl
Therefore, these groups are halogen, hydroxyl, mercapto, carboxyl,
Ano, amino, C₁~ C₄-Substituted one or more times by alkoxy
Or CR¹¹Is R⁹Or R¹⁰Together with one or two C ₁ ~ C₄-5- or 6-membered alkylene optionally substituted by an alkyl group
Or forms an alkenylene ring and in each case one or more
Is a further methylene group, oxygen, sulfur, -NH or -N (C₁~ C₄-Al
Kill) can be exchanged.

The definitions applied herein and thereafter are as follows:

The alkali metals are, for example, lithium, sodium, potassium. The alkaline earth metals are, for example, calcium, magnesium, barium.

The organic ammonium ion is a protonated amine such as ethanolamine, diethanolamine, ethylenediamine, diethylamine or piperazine.

C ₃ -C ₈ -Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

C ₁ -C ₄ -Haloalkyl may be linear or branched, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl , 2
, 2-Difluoroethyl, 2,2,2-trifluoropropyl, 2-chloro-2
, 2-Difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2
-It can be trichloroethyl or pentafluoroethyl.

C ₁ -C ₄ -Haloalkoxy may be linear or branched, for example difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2, 2-tetrafluoroethoxy, 2
, 2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy.

C ₁ -C ₄ -alkyl may be linear or branched, for example methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1- It can be butyl or 2-butyl.

C ₂ -C ₄ -Alkenyl may be linear or branched, for example ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl- It can be 1-propenyl, 1-butenyl or 2-butenyl.

C ₂ -C ₄ -Alkynyl may be linear or branched, for example ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn- It can be 4-yl.

C ₁ -C ₄ -Alkoxy may be linear or branched, for example methoxy, ethoxy,
It can be propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.

C ₃ -C ₆ -Alkenyloxy can be linear or branched, for example allyloxy,
It can be 2-buten-1-yloxy or 3-buten-2-yloxy.

C ₃ -C ₆ -Alkynyloxy can be linear or branched, for example 2-propyne-
It can be 1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy.

C ₁ -C ₄ -alkylthio may be linear or branched, for example methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1- It can be dimethylethylthio.

The C ₁ -C ₅ -alkylcarbonyl can be linear or branched, for example acetyl, ethylcarbonyl or 2-propylcarbonyl.

[0036] C ₁ -C ₈ - alkylcarbonyl, linear or branched, for example _C 1 -C ₄ -
It can be alkyl, pentyl, hexyl, heptyl or octyl.

C ₃ -C ₈ -Alkenyl may be linear or branched, for example 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-. Propenyl, 1-buten-4-yl, 2-buten-3-yl, 1-penten-5-yl, 1-hexen-6-yl, 3-hexen-6-yl, 2-hepten-7-yl or It can be 1-octen-8-yl.

C ₃ -C ₈ -Alkynyl may be linear or branched, for example 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl, 2-butyn-4-yl. Il,
2-pentyn-5-yl, 3-hexyn-6-yl, 3-heptin-7-yl,
It can be 2-octin-8-yl.

Halogen is, for example, fluorine, chlorine, bromine, iodine.

The present invention further relates to compounds from which compounds of the formula I can be released (called prodrugs).

Advantageous prodrugs include certain compartments of the body, such as the stomach, digestive tract, blood circulatory system,
Release occurs under normal conditions in the liver.

Compound I and intermediates for preparing them, such as II and III,
It may have one or more asymmetrically substituted carbon atoms. Compounds of this type can exist as pure enantiomers or pure diastereomers or as mixtures thereof. It is advantageous to use enantiomerically pure compounds as active ingredients.

The invention further relates to the preparation of a medicament, in particular the use of a carboxylic acid derivative as described above for preparing an inhibitor of the ET _A and / or ET _B receptor. The novel compounds are suitable as antagonists as defined at the outset.

The compounds according to the invention having the formula I are described in German Patent (DE) 19726146
. No. 9 can be produced via the route described in the specification.

A possible alternative to this is the preparation via intermediates of general formula III. These derivatives can be prepared by reduction of the azide of the formula II by a general method (German Patent (D
E) see 197 26146.9) or by rings of oxazoline derivatives of the general formula IV described in WO 95/07266.

[0046]

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The oxazoline derivative of the formula IV can be used to solubilize aqueous solutions of strong acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid. The ring can be opened by treating in the presence of All water-miscible solvents can be used for this purpose, as long as they are inert to the reagents used.

Examples of such solubilizers are alcohols such as methanol, ethanol, n
-Propanol, isopropanol; ethers, such as tetrahydrofuran or dioxane; nitriles, such as acetonitrile or propionitrile; amides, such as dimethylformamide or dimethylacetamide; sulfoxides and sulfones, such as dimethylsulfoxide; carboxylic acids such as acetic acid or propionic acid.

The reaction in this case is preferably carried out at a temperature between 0 ° C. and the boiling point of the solvent or solvent mixture.

Compounds according to the invention wherein R ⁴ R ⁵ N is an aromatic or heteroaromatic carboxamide can be obtained, for example, by acylation of III on nitrogen or, alternatively, the amino group in III by using generally known methods. It can be prepared by acylation of both the group and the hydroxyl group and subsequent elimination of the ester acyl group. For this purpose, a compound of the general formula III is reacted with an acylating agent in a molar ratio in the range from 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.

[0051]

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Examples of such solvents or diluents are, in each case, optionally chlorinated aliphatic, cycloaliphatic and aromatic hydrocarbons, for example hexane, cyclohexane, petroleum ether, naphtha, Benzene, toluene, xylene, methylene chloride, chloroform, ethyl chloride and trichloroethylene, ethers such as diisopropyl ether, dibutyl ether, methyl-t-butyl ether, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, amides such as dimethylformamide, Dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones, such as dimethylsulfoxide and sulfolane.

The reaction in this case is advantageously carried out at a temperature between 0 ° C. and the boiling point of the solvent or solvent mixture.

The presence of a reaction catalyst may be advantageous. A suitable catalyst in this case is, for example, dimethylaminopyridine.

The resulting compound of the general formula V is converted into a β-amidocarboxylic acid derivative according to the invention by reacting a compound of the general formula V with a heterocyclic compound of the compound of the general formula VI.

[0056]

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R in Formula VI¹⁴Is halogen or R^Fifteen-SO₂-[Where R^FifteenIs C₁~ C ₄ -Alkyl, C₁~ C₄-Haloalkyl or phenyl)
And the definitions of W, X, Y, Z and Q are given at the outset. The reaction is
Deprotonation of a suitable base, ie, intermediate V, in an inert solvent or diluent
The reaction is carried out at a temperature in the range from room temperature to the boiling point of the solvent with the addition of the base to be converted.

The compounds of the formula VI are known and some of them can be purchased or they can be prepared by generally known methods.

When R ^{1 in} the compound of general formula Ia is an ester, the ester group can be cleaved using an acid or a base or by hydrogenolysis to give a free carboxylic acid with R ¹ ＝ COOH. However, compounds of the form Ia with R ¹ = COOH are
Intermediate V where R ¹ = COOH can also be directly obtained by deprotonating with 3 equivalents of a suitable base and reacting with a compound of general formula VI. Again, the reaction is carried out in a solvent at a temperature in the range from room temperature to the boiling point of the solvent.

Bases which can be used are alkali metal or alkaline earth metal hydrides, such as sodium hydride, potassium hydride or calcium hydride, carbonates, such as alkali metal carbonates, such as sodium or potassium carbonate, alkali. Metal or alkaline earth metal hydroxides, such as sodium or potassium hydroxide, organometallic compounds, such as butyllithium or alkali metal amides, such as lithium diisopropylamide or lithium amide. The compounds according to the invention of the general formula I in which R ⁴ R ⁵ N is a sulphonamide can be obtained from amines of the general formula VII and can be prepared as described in German Patent Application (DE) 197 26 146.9. Can be manufactured. For this purpose, VII is reacted with a sulfonyl halide in a manner known ^per se in general for isocyanates and, if R ¹ is an ester, the ester group is cleaved with an acid or base or by hydrogenolysis.

[0061]

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The compounds of formula I are also suitable carboxylic acids, ie of formula I wherein R ¹ is COOH
From the compounds of formula (I) are first converted in a conventional manner to their activated forms, for example acid halides, anhydrides or imidazolides, and the latter are then converted to the appropriate hydroxyl compounds HOR ⁶ or sulfonamides H ₂ NSO ₂ R ⁸ It can also be produced by reacting. The reaction can be carried out in conventional solvents and often requires the addition of a base, in which case the above are preferred. These two steps can also be simplified, for example, by acting a carboxylic acid on a hydroxyl compound or a sulfonamide in the presence of a dehydrating agent, for example a carbodiimide.

Starting from a salt of a suitable carboxylic acid, ie from a compound of formula I, wherein R ¹ is the group COOM, wherein M can be an equivalent of an alkali metal cation or an alkaline earth metal cation. Thus, it is also possible to prepare compounds of the formula I. These salts have the formula RD wherein D is a conventional nucleofugic leaving group, for example halogen, such as chlorine, bromine, iodine or optionally halogen, alkyl or haloalkyl substituted. Arylsulfonyl or alkylsulfonyl, for example toluenesulfonyl and methylsulfonyl or other equivalent leaving groups]. Compounds of the formula R-D having a reactive substituent D are known or can easily be obtained using the knowledge of the general expert. The reaction can be carried out in conventional solvents and is advantageously carried out in the presence of a base, the ones mentioned being preferred.

Compounds of formula I wherein R ¹ is tetrazolyl can be prepared from the corresponding carboxylic acid (formula I with R ¹ = COOH) according to the methods described in WO 96/11914.

In some cases, it is necessary to use generally known protecting group techniques to prepare compounds I according to the present invention. For example, R ⁴ R ⁵ N = 4-HO-phenyl-CO
If NH-, the hydroxyl group can be protected initially as a benzyl ether, which can then be cleaved at an appropriate stage in the reaction sequence.

Compounds of formulas I and V can be prepared by performing conventional racemic resolution methods using a suitable enantiomerically pure base, such as those described in WO 96/11914. And V can be obtained in enantiomerically pure form.

X In terms of biological effects, the preferred carboxylic acid derivatives of the general formula I (both pure enantiomers or pure diastereomers and mixtures thereof) are those in which the substituents have the following meanings It is.

R ¹ is tetrazolyl or a group

[0069]

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[Wherein, R has the following meaning.

A) Group OR⁶(Where R⁶Is hydrogen, alkali metal cation, alkaline earth metal cation, physiologically acceptable
Organic ammonium ions such as quaternary C₁~ C₄-Alkylammonium
Or ammonium ion, C₃~ C₈-Cycloalkyl, C₁~ C₈-Alkyl, CH₂-Phenyl, this
Can be substituted with one or more of the following groups: halogen,
C₁~ C₄-Alkyl, C₁~ C₄-Haloalkyl, hydroxyl, C₁~ C₄ -Alkoxy, mercapto, C₁~ C₄-Alkylthio, NH (C₁~ C₄-A
Lucil), N (C₁~ C₄-Alkyl)₂C₃~ C₈-Alkenyl or C₃~ C₈Alkynyl groups, these groups are furthermore
May have 1 to 5 halogen atoms.⁶Has 1 to 5 halogen atoms and / or 1 to 3 groups shown below.
Can be a phenyl group that can be: C₁~ C₄-Alkyl, C₁ ~ C₄-Haloalkyl, hydroxyl, C₁~ C₄-Alkoxy, mercapto,
C₁~ C₄-Alkylthio, NH (C₁~ C₄-Alkyl), N (C₁~ C₄−
Alkyl)₂B) 5-membered heteroaromatic systems linked via a nitrogen atom, for example pyrazolyl, imimi
Dazolyl and triazolyl, which are one or two halogen atoms
Or one or two C₁~ C₄-Alkyl or one or two C₁~ C ₄ A c) group which may have an alkoxy group;

[0072]

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Where k can take the values 0, 1 and 2 and p is the value 1, 2, 3 and
And 4 and R⁷Is C₁~ C₄-Alkyl, C₃~ C₈-Shiku
Lower alkyl, C₃~ C₈-Alkenyl, C₃~ C₈Alkynyl or the following groups
Phenyl which can be substituted with one or more, for example 1 to 3,
Is: halogen, C₁~ C₄-Alkyl, hydroxyl, C₁~ C₄-Alkoxy, C ₁ ~ C₄-Alkylthio, NH (C₁~ C₄-Alkyl), N (C₁~ C₄-A
Lequil)₂, Mercapto), d) group

[0074]

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Wherein R ⁸ is C ₁ -C ₄ -alkyl, C ₃ -C ₈ -alkenyl, C ₃ -C ₈ -alkynyl, C ₃ -C ₈ -cycloalkyl, and these groups are ₁ -C ₄ - _alkoxy, C 1 -C ₄ - alkylthio and / or c) may have a phenyl group as described in claim, _C 1 -C ₄ - haloalkyl or optionally, in particular the c) W and Z (which may be the same or different) are nitrogen or methine, provided that when W and Z are methine, Q is X is nitrogen or CR ⁹ , Y is nitrogen or CR ¹⁰ , Q is nitrogen or CR ¹¹ , provided that when Q = nitrogen, X = CR ⁹ and Y =
CR ¹⁰ and R ² and R ³ , which may be the same or different, are each phenyl or naphthyl optionally substituted by one or more of the following groups: halogen, cyano, hydroxyl, _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 one or more, for example 1 to 3 times, 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 - group in an alkylthio Or phenyl or naphthyl linked together at the ortho position by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or a SO ₂ , NH or N-alkyl group; ⁴ is a) group

[0076]

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Wherein R ¹² is phenyl, naphthyl or a 5- or 6-membered heteroaromatic system containing 1 to 3 nitrogen atoms and / or one sulfur or oxygen atom; May be substituted one or more times by groups: halogen, cyano,
Hydroxyl, _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 - 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 both halogen, _cyano, C 1 -C ₄ - _alkyl, C 1 -C ₄ - _haloalkyl, C 1 -C ₄ - _alkoxy, C 1 -C ₄ - haloalkoxy and / Or a phenoxy or phenyl] b) group which may be substituted one or more times, for example 1 to 3 times, by C ₁ -C ₄ -alkylthio.

[0078]

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(Wherein R ¹³ is C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl or phenyl, and the phenyl group further has 1 to 5 halogen atoms and / or 1 to 3
Number of groups may have the _following: 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) are 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 - a alkenyl, these groups halogen, hydroxyl, mercapto, optionally substituted with cyano be good or ^{R 9} and ^{R 10, is} connected to the ^{CR 11} becomes 5-membered or 6-membered ring as described in ^{R 11, R 11} is hydrogen, _halogen, C 1 -C ₄ - alkoxy, C _{1 ~C 4} - _{Roarukokishi,} 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, these groups, halogen, _cyano, C 1 -C ₄ - substituted one or more times by alkoxy at best, or, ^{CR 11} together with ^{R 9} or ^{R 10,} 1 to 2 amino _C 1 -C ₄ -
Form a 5- or 6-membered alkylene or alkenylene ring which may be substituted by an alkyl group, and in each case one or more methylene groups are oxygen, sulfur, -NH or -N - it can be replaced by _(C 1 -C ₄ alkyl).

Particularly advantageous compounds I of the formula I, both as pure enantiomers or pure diastereomers and as mixtures thereof, are those in which the substituents have the following meanings:

R ¹ is tetrazolyl or a group

[0082]

Embedded image

[Wherein, R represents the following.

A) a group OR ⁶ , wherein R ⁶ is hydrogen, a cation of an alkali metal, a cation or an ammonium ion of an alkaline earth metal, C ₁ -C ₈ -alkyl, CH ₂ -phenyl, R ⁶ can be optionally substituted with one or more of the following groups: halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy; It can also be a phenyl group optionally having 1 to 5 halogen atoms and / or 1 to 3 groups: C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C _1. -C 4 _- alkoxy) b) a nitrogen atom linked via a to which 5-membered heteroaromatic system, for example it is a imidazolyl and triazolyl, which are also one or two halogen atoms One or two _C 1 -C ₄ - alkyl or one or two _C 1 -C ₄ - may have an alkoxy group, c) group

[0085]

Embedded image

Where k can take the values 0, 1 and 2 and p can take the values 1, 2, 3 and 4 and R ⁷ is C ₁ -C ₄ − _alkyl, C 3 _{~C 8} - 1 or more cycloalkyl or the following groups, for example by phenyl which may be substituted with 1-3 _halogen, C 1 -C ₄ - _{alkyl, C} 1 ~ C ₄ - alkoxy), d) group

[0087]

Embedded image

Wherein R ⁸ is C ₁ -C ₄ -alkyl, C ₃ -C ₈ -cycloalkyl, and these groups are C ₁ -C ₄ -alkoxy and / or c) A phenyl group, which may be C ₁ -C ₄ -haloalkyl or optionally phenyl, in particular substituted as described in c))), W and Z (same or different) May be nitrogen or methine, provided that when W and Z are methine, Q is nitrogen; X is nitrogen or CR ⁹ ; Y is nitrogen or CR ¹⁰ ; Q is nitrogen Or CR ¹¹ , provided that when Q = nitrogen, X = CR ⁹ and Y =
CR ¹⁰ and R ² and R ³ (which may be the same or different) are phenyl optionally substituted by one or more of the following groups: 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 1 or more times, for example 1 to 3 times, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy or C ₁ -C 4 _- or a phenyl, optionally substituted alkylthio, in the ortho-position, a direct bond, methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO ₂ group, together with the NH group or an N- alkyl A linked phenyl group, R ⁴ is a) group

[0089]

Embedded image

[Wherein, R¹²Is phenyl or 1 to 3 nitrogen atoms and / or sulfur or
A 5- or 6-membered heteroaromatic system containing one oxygen atom, wherein the group is
May be substituted one or more times: halogen, hydroxyl, C ₁ ~ C₄-Alkyl, C₁~ C₄-Haloalkyl, C₁~ C₄-Alkoxy, C ₁ ~ C₄Haloalkoxy, phenoxy, C₁~ C₄-Alkylthio, NH (C ₁ ~ C₄-Alkyl), N (C₁~ C₄-Alkyl)₂, (C₁~ C₄-Archi
Le) NHSO₂, (C₁~ C₄-Alkyl)₂NSO₂Or halogen, C₁ ~ C₄-Alkyl, C₁~ C₄-Haloalkyl, C₁~ C₄-Alkoxy and
/ Or C₁~ C₄One or more times by haloalkoxy, C₁~ C₄−
Phenyl which may be substituted 1-3 times) b) group

[0091]

Embedded image

[Wherein, R ¹³ is C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl or phenyl, and the phenyl group further has 1 to 5 halogen atoms and / or 1 to 3 halogen atoms.
Number of groups may have the _following: 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} (or different these same) is _hydrogen, C 1 -C ₄ - _alkoxy, C 1 -C ₄ - alkylthio, _{N (C} 1 ~C ₄ -
Alkyl) ₂ , C ₁ -C ₄ -alkyl, wherein these groups are optionally substituted by halogen, or R ⁹ and R ¹⁰ are linked to CR ¹¹ as described for R ¹¹ to form a 5-membered Or a 6-membered ring, wherein R ¹¹ is hydrogen, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, cyano, C ₁ -C ₄ -alkyl, and these groups are in each case substituted by halogen It may be substituted one or more times, or, ^{CR 11} together with ^{R 9} or ^{R 10,} 1 to 2 amino _C 1 -C ₄ -
Form a 5- or 6-membered alkylene or alkenylene ring which may be substituted by an alkyl group, and in each case one or more methylene groups are oxygen, sulfur, -NH or -N - it can be replaced by _(C 1 -C ₄ alkyl).

The compounds of the present invention may be used for treating hypertension, pulmonary hypertension, myocardial infarction, chronic heart failure, angina, acute / chronic renal failure, renal dysfunction, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, Asthma, atherosclerosis, endotoxin shock, endotoxin-induced organ failure, intravascular coagulation,
Restenosis after angioplasty, benign prostatic hypertrophy, ischemia and poisoning-induced renal failure or hypertension, cyclosporine-induced renal failure, erectile dysfunction, metastasis and growth of mesenchymal tumors, cancer, prostate cancer, contrast-induced kidney It provides a new possible treatment for insufficiency, pancreatitis, gastrointestinal ulcer.

The present invention further relates to a combination product comprising an endothelin receptor antagonist of formula I and an inhibitor of the renin-angiotensin system. Inhibitors of the renin-angiotensin system include renin inhibitors, angiotensin II antagonists, and
In particular, angiotensin converting enzyme (ACE) inhibitors.

These composite products are particularly suitable for the treatment and prevention of hypertension and its sequelae, and for the treatment of heart failure.

The favorable effects of the compounds can be demonstrated in the tests described below.

[0097] Using the human ET _A and ET _B receptors expressing CHO cells were receptor binding assay Cloning the binding assay.

[0098] Membrane Preparation ET _A or ET _B receptor - expression CHO cells, 10% fetal calf serum (PAA
Laboratory Co., Ltd. (PAA Laboratories GmbH, Linz) No. A15-022),
1 mM glutamine (Gibco number 25030-024), 100 U / ml
Penicillin and 100 μm / ml streptomycin (Sigma number P
DMEM NUT MIX _{F 12} medium containing -0781) (Gibco No. 213
31-020). Forty-eight hours later, cells were washed with PBS.
Incubation was carried out at 37 ° C. for 5 minutes using PBS containing 05% trypsin.
The medium was then neutralized, and the cells were harvested by centrifugation at 300 × g.

For membrane preparation, cells were harvested at 10 ⁸ (cells) / ml [buffer (50 mM Tris-H
Cl buffer, pH 7.4)] and then micronized with ultrasound (Branson Sonifier 250, 40-70 sec / constant output 2).
0).

Binding Assay ET_AAnd ET_BIncubate membrane for receptor-binding assay
Buffer (50 mM Tris-HCl buffer, pH 7.4, 5 mM MnCl₂, 4
0 μg / ml bacitracin and 0.2% BSA) in a concentration of 50 μg (tan
(Protein) / (assay mixture) and 25 pM [¹²⁵I] -ET₁[ET _A Receptor assay] or 25 pM [¹²⁵I] -ET₃[ET_BReceptor ass
Incubation at 25 ° C in the presence or absence of a test substance using
did. Non-specific binding is 10^{- 7}M ET₁It measured using. 30 minutes later,
GF / B in Skatron cell harvester (Skatron, Lier, Norway)
Free by filtration through a glass fiber filter (Whatman, England)
The bound radioligand is separated and the filter is then ice-cold with 0.2% BSA.
Washed with Tris-HCl buffer, pH 7.4. Collect on filter
The radioactivity into a Packard 2200CA liquid scintillation counter
Quantification was carried out using a thermometer.

In Vivo Testing of ET Antagonists Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, subjected to vagal transection, and killed by spinal cord transection. A catheter was inserted into the carotid artery and jugular vein.

In control animals, intravenous injection of 1 mg / ml ET1 resulted in a significant increase in blood pressure, which was prolonged.

Test animals are injected intravenously (1 ml / kg) of test compound 30 minutes prior to ET1 administration.
) Received. To determine ET antagonist properties, blood pressure changes in test animals were compared to those of control animals.

Oral Study of ET Receptor Antagonists Male normotensive rats weighing 250-350 g (Sprague Dawley)
Dawley, Janvier)) were pretreated by oral administration of the test substances. Eighty minutes later, the animals were anesthetized with urethane and catheters were inserted into the carotid artery (for measuring blood pressure) and the jugular vein (administering big endothelin / endothelin 1).

After the stabilization period, big endothelin (20 μg / kg, dose volume 0.5 ml
/ ET) (0.3 μg / kg, dose volume 0.5 ml / kg) was administered intravenously. Blood pressure and heart rate were recorded continuously for 30 minutes. Significantly long-lasting changes in blood pressure were calculated from the area under the curve (AUC). To determine the antagonism of the test substances, the AUC of animals treated with the substance was compared to the AUC of control animals.

The novel compounds can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional manner. Administration can also be by vapor or spray through the nasopharyngeal cavity.

The dose will vary depending on the age, physical condition and weight of the patient and the mode of administration. Generally, the daily dose of the active ingredient is about 0.5-50 mg / kg (body weight) for oral administration and about 0.1-10 mg / kg (body weight) for parenteral administration.

The novel compounds can be administered in conventional solid or liquid dosage forms, such as uncoated or (film) coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. . These can be manufactured by a conventional method. The active ingredient is formulated for this purpose in conventional pharmaceutical auxiliaries, such as tablet binders, bulking agents.
agents, preservatives, disintegrants, flow modifiers, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained release agents, antioxidants and / or propellants (H. Soccer et al. "Drug Technology" (H. Sucker et al. Pharmazeutische Technologie, Thiem
e-Verlag, Stuttgart, 1991)). The dosage form obtained by this method usually contains 0.1 to 90% by mass of the active ingredient.

Synthetic Examples Example 1 Methyl 3-amino-2-hydroxy-3,3-diphenylpropionate 10% palladium / 0.2 g of hydrogenation catalyst on methyl 3-azido-2 in methanol (100 ml) -Hydroxy-3,3-diphenylpropionate (5
. (71 g, 19.2 mmol). The mixture was stirred under a hydrogen atmosphere at room temperature for 48 hours. Then the catalyst was filtered off and the solvent was distilled off. The residue was taken up in a 5% aqueous citric acid solution and the resulting solution was extracted with ether. The aqueous phase was then made alkaline with dilute sodium hydroxide solution and then extracted again with ether. The extract obtained from the alkaline phase was dried over magnesium sulfate, and the solvent was removed in vacuo. 4.03 g of pure amine (14.9
Mmol, 77% yield).

[0110]

[Outside 1]

Example 2 2- (4-methoxybenzoylamino) -1-methoxycarbonyl-2,2-diphenylethyl-4-methoxybenzoate pyridine (1.17 g, 14.7 mmol), dimethylaminopyridine 1 spatula (s
patula tip), and para-methoxybenzoyl chloride (2.52 g, 14.
(7 mmol) was added in sequence to a solution of methyl 3-amino-2-hydroxy-3,3-diphenylpropionate (2.00 g, 7.37 mmol) in dichloromethane (10 ml). The mixture was stirred at room temperature for 4 hours, then mixed with water for treatment and extracted with ether. The combined organic phases were washed with aqueous citric acid and saturated brine, and then dried over magnesium sulfate. Removal of the solvent in vacuo yielded the crude bisacylated product which was used without further purification (1.37 g, 28% yield, 82% purity by HPLC).

Example 3 Methyl 2-hydroxy-3- (4-methoxybenzoylamino) -3,3-diphenylpropionate 2- (4-methoxybenzoylamino) -1-methoxycarbonyl-2,2-diphenylethyl -4-methoxybenzoate (1.37 g, 2.08 mmol,
(Purity 82%) in methanol (20 ml) and potassium carbonate (863 mg).
, 6.25 mmol). The resulting mixture was stirred at room temperature for 16 hours, then the solvent was removed in vacuo. The residue was taken up in water and extracted with ether. A colorless solid precipitated during this time and was isolated by filtration, consistent with the title compound.
The aqueous phase was then extracted again using ethyl acetate. The organic phases were combined, dried over magnesium sulfate and the solvent was removed in vacuo. The crude product was crystallized from dichloromethane / ether / n-hexane to give a colorless solid (503 mg, yield 6).
0%).

Example 4 Benzyl 2-hydroxy-3- (4-methoxybenzoylamino) -3,3-
2.11 ml of a 1 molar sodium hydroxide solution of diphenylpropionate was added to 1: 2 water / tetrahydrofuran (
A solution of methyl 2-hydroxy-3- (4-methoxybenzoylamino) -3,3-diphenylpropionate (503 mg, 1.24 mmol) in 50 ml) was stirred at room temperature for 60 hours. The starting material is subsequently converted substantially,
To complete the reaction, a 1 molar sodium hydroxide solution (2.11 ml) was added again and stirring was continued for 1 hour. The mixture was diluted with water, extracted with ether, acidified with citric acid and extracted again with ether. The extract obtained from the acidic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The residue (406 mg) was taken up in dimethylformamide (20 ml), then potassium carbonate (179 mg, 1.30 mmol) and benzyl bromide (195 mg,
1.14 mmol) were added in order. The resulting mixture was stirred at room temperature for 20 hours,
Then, a 5% strength aqueous citric acid solution was added. After dilution with water, extraction was carried out with dichloromethane and then with ether (the product only dissolved moderately in ether). The combined organic extracts were washed thoroughly with water, then with brine, dried over magnesium sulfate and the solvent was removed in vacuo. Traces of benzyl bromide and dimethylformamide were removed by washing the residue with a small amount of 1: 1 ether / n-hexane. 487 mg (79%) of pure benzyl ether
was gotten.

Example 5 Benzyl 2- (4,6-diethyl [1.3.5] triazin-2-yloxy) -3- (4-methoxybenzoylamino) -3,3-diphenylpropionate Potassium carbonate ( 80 mg, 0.58 mmol) and 2-chloro-4,6-diethyl- [1.3.5] triazine (74 mg, 0.43 mmol) were treated with benzyl 2-hydroxy-3- in dimethylformamide (15 ml). (4-methoxybenzoylamino) -3,3-diphenylpropionate (139 mg, 0.2
(9 mmol). The mixture was heated to 60 ° C. and stirred at this temperature for 4 hours. The reaction was stopped by adding a 5% aqueous citric acid solution (10 ml). After dilution with water, extraction was carried out with ether and the combined organic phases were washed with saturated brine and then dried over magnesium sulfate. The solvent was distilled off. The residue was purified by flash chromatography (eluent: ethyl acetate in cyclohexane 30-50%). 124 mg of the target compound is 90% pure
(By HPLC) (63% yield).

Example 6 2- (4,6-diethyl [1.3.5] triazin-2-yloxy) -3- (
4-Methoxybenzoylamino) -3,3-diphenylpropionic acid (I-4) 10% palladium / carbon hydrogenation catalyst (1 spatula) was treated with benzyl 2- (4,6-diethyl-) in ethyl acetate (15 ml). [1.3.5] Triazin-2-yloxy) -3- (4-methoxybenzoylamino) -3,3-diphenylpropionate (124 mg, 0.18 mmol, 90% purity) and then added The mixture was stirred at room temperature in a hydrogen atmosphere for 3 hours. The catalyst was then filtered off and the solvent was distilled off in vacuo. The residue was crystallized from dichloromethane / ether / n-hexane to give 99 mg of pure carboxylic acid (yield 73%).

[0116]

[Outside 2]

The following was synthesized in the same manner.

2- (4,6-diethyl [1.3.5] triazin-2-yloxy) -3- (
3,5-dimethoxybenzoylamino) -3,3-diphenylpropionic acid (I
-327)

[0119]

[Outside 3]

3- (3,5-dimethoxybenzoylamino) -2- (4,6-dimethyl-2-
Pyrimidinyloxy) -3,3-diphenylpropionic acid (I-248)

[0121]

[Outside 4]

3-benzoylamino-2- (4,6-dimethyl-2-pyrimidinyloxy)-
3,3-diphenylpropionic acid (I-66)

[0123]

[Outside 5]

2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (4-methylbenzoylamino) -3,3-diphenylpropionic acid (I-199)

[0125]

[Outside 6]

Example 7 Benzyl 2-methyl-4,4-diphenyl-4,5-dihydrooxazole-
5-Carboxylate Boron trifluoride etherate (8.04 g, 56.7 mmol) was added to benzyl 3,3-diphenyloxirane-2-carboxylate (10.0 g, 28.3 mmol) in acetonitrile (100 ml). The solution was added carefully. The mixture was stirred at room temperature for 1 hour and then concentrated in a tumble dryer. The residue was taken up in water, saturated with sodium chloride and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The residue (13.5 g
) Was used without further purification.

Example 8 Benzyl 3-amino-2-hydroxy-3,3-diphenylpropionate Benzyl 2-methyl-4,4-diphenyl-4,5-dihydrooxazole-
5-Carboxylate (13.5 g, crude) was stirred in a mixture of methanol (25 ml), water (50 ml) and concentrated hydrochloric acid (50 ml) at room temperature for 60 hours.
The solution was then decanted to remove undissolved material. The residue was again stirred in the above mixture for 3 hours. Decantation was performed again. The remaining residue was discarded. When the two liquid phases were combined and adjusted to pH 8-9 with sodium hydroxide solution, crystallization started. The crystals were washed with ether, suctioned and filtered. 4.65 g of the required amino alcohol are obtained with a purity of 97%.

[0128]

[Outside 7]

Example 9 Benzyl 2-hydroxy-3,3-diphenyl-3- (4-trifluoromethylbenzoylamino) -propionate pyridine (94 mg, 1.00 mmol), dimethylaminopyridine 1 spatula, and para-tri Fluoromethylbenzoyl chloride (215 mg, 1.00 mmol) was added sequentially to a solution of benzyl 3-amino-2-hydroxy-3,3-diphenylpropionate (365 mg, 1.00 mmol) in dichloromethane (50 ml). added. The mixture was stirred at room temperature for 60 hours and then extracted and worked up with dilute citric acid. 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), and after adding pyridine (36 mg, 0.45 mmol) and several crystals of dimethylaminopyridine, the mixture was refluxed for 4 hours. After cooling, it was extracted and treated with dilute citric acid. 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 of pure product (yield 4
5%).

[0130]

[Outside 8]

Example 10 Benzyl 2- (4,6-dimethyl-2-pyrimidinyloxy) -3,3-diphenyl-3- (4-trifluoromethylbenzoylamino) propionate Potassium carbonate (100 mg, 0.72 mmol) And 2-methylsulfonyl-4,6-dimethylpyrimidine (96 mg, 0.51 mmol) were converted to benzyl 2-hydroxy-3,3-diphenyl- in dimethylformamide (15 ml).
3- (4-trifluoromethylbenzoylamino) -propionate (220 m
g, 0.42 mmol). The mixture was heated to 80 ° C. and stirred at this temperature for 1 hour. The reaction was stopped by adding dilute citric acid and water (200 ml). After extraction with ether, the organic phase was dried over magnesium sulfate and then concentrated in vacuo. The residue was crystallized from ether / n-hexane. 158 mg (60%) of the pure title product were obtained.

Example 11 2- (4,6-dimethyl-2-pyrimidinyloxy) -3,3-diphenyl-3
-(4-Trifluoromethylbenzoylamino) propionic acid (I-201) 10% palladium / carbon hydrogenation catalyst (1 spatula) was treated with benzyl 2- (4,6-dimethyl-2-) in ethyl acetate (50 ml). Pyrimidinyloxy) -3,3-diphenyl-3- (4-trifluoromethylbenzoylamino) propionate (1
50 mg, 0.24 mmol) and the mixture was stirred at room temperature under a hydrogen atmosphere at room temperature.
Stirred for hours. The catalyst was then filtered off and the solvent was distilled off in vacuo. The residue was crystallized from ether / n-hexane to give 100 mg (78%) of pure carboxylic acid.

[0133]

[Outside 9]

The following was obtained in a similar manner.

3- (3,4-Dimethoxybenzoylamino) -2- (4,6-dimethyl-2-
Pyrimidinyloxy) -3,3-diphenylpropionic acid (I-48)

[0136]

[Outside 10]

3- (3,4-difluorobenzoylamino) -2- (4,6-dimethyl-2-
Pyrimidinyloxy) -3,3-diphenylpropionic acid (I-340)

[0138]

[Outside 11]

2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (4-fluorobenzoylamino) -3,3-diphenylpropionic acid (I-170)

[0140]

[Outside 12]

Example 12 Methyl 2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-methanesulfonylamino-3,3-diphenylpropionate methanesulfonyl chloride (83 mg, 0.73 mmol), pyridine ( 82
mg, 1.04 mmol) and dimethylaminopyridine (1 spatula) were added to methyl 3-amino-2- (4,6-dimethoxy-2) in dichloromethane (15 ml).
-Pyrimidinyloxy) -3,3-diphenylpropionate (213 mg, 0
. 52 mmol). The mixture was stirred at room temperature for 1 week. Since the conversion was incomplete, another 0.20 molar equivalent of methanesulfonyl chloride was added, and the mixture was further stirred at room temperature for 3 days. For treatment, the mixture was diluted with ether and washed with dilute citric acid, sodium bicarbonate solution and saturated saline solution in that order.
The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The citric acid extract was neutralized and extracted with ether. The organic phase obtained from this was dried and evaporated as described above. The residue (206 mg) was used in the next step without further purification.

Example 13 2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-methanesulfonylamino-3,3-diphenylpropionic acid (I-156) 0.50 ml of a 1 molar sodium hydroxide solution was added. Methyl 2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-methanesulfonylamino-3,3-diphenylpropionate (181) in 1: 2 water / tetrahydrofuran (30 ml).
mg, crude product) and the mixture was stirred at room temperature for 5 days. To complete the reaction, a further 0.5 molar equivalent of a 1 molar sodium hydroxide solution was added and the mixture was again stirred for 24 hours. After dilution with water and extraction with ether, the aqueous phase was acidified with citric acid and extracted again with ether. The extract obtained from the acidic phase was dried over magnesium sulfate and the solvent was removed in vacuo. Crystallization of the residue from dichloromethane / n-hexane gave pure target compound (71 mg, 33% yield over two steps).

[0143]

[Outside 13]

The compounds shown in Table 1 can be prepared analogously or as described in the common part.

Example 14 Receptor binding data was measured using the binding assay described above for the following compounds.

The results are shown in Table 2.

Table 2 Receptor binding data (K _i values)

[0148]

[Table 1]

[0149]

[Table 2]

[0150]

[Table 3]

[0151]

[Table 4]

[0152]

[Table 5]

[0153]

[Table 6]

[0154]

[Table 7]

[0155]

[Table 8]

[0156]

[Table 9]

[0157]

[Table 10]

[0158]

[Table 11]

[0159]

[Table 12]

[0160]

[Table 13]

[0161]

[Table 14]

[0162]

[Table 15]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/10 A61P 9/10 9/12 9/12 13/08 13/08 13/12 13/12 15 / 10 15/10 35/00 35/00 43/00 111 43/00 111 C07C 229/34 C07C 229/34 233/87 233/87 235/52 235/52 C07D 251/24 C07D 251/24 401/12 401/12 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA ( BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, M , RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE , ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT , TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Georg Kettschau Germany Ludwigshafen Saarburger Strasse 29 (72) Inventor Hartmut Lichers Germany Neustadt, Germany St. Müller-Turgau-Weg 5 (72) Inventor Ernst Baumann Germany Düdenhofen Falkenstraße 6a (72) Inventor Stephan Helgenrader Germany Mainz Hans-Beckler-Strasse 108 (72) Inventor Manfred Laschack Weisenheim Donnersbergstrasse 7 Germany (72) Inventor Liliane Unger Ludwigshafen Germany Wolstrasse 129 F-term (reference) 4C063 AA01 BB07 CC29 DD12 EE01 4C086 AA01 AA02A BC42 BC64 GA07 GA08 MA01 MA02 MA03 MA04 MA05 MA52 MA55 MA56 NA14 ZA36 ZA42 ZA81 ZB26 ZC02 ZC17 ZC20 ZC41 ZC75 4H006 AA02 AA03 AB20 AB23 AB25 AB28 BJ50 BN10 BT12 BT16 BU32 BU38

Claims (10)

[Claims] 1. A compound of the formula I Wherein the substituents have the following meanings: R ¹ is tetrazolyl or a group R: a) a group OR ⁶ , wherein R ⁶ is hydrogen, C ₃ -C ₈ -cycloalkyl, C ₁ -C ₈ -alkyl, CH ₂ -phenyl, wherein said groups are optionally substituted well, if C ₃ substituted by -C 8 _- alkenyl or C ₃ -C 8 _- alkynyl, or optionally a substituted phenyl) b) 5-membered heteroaromatic linked via a nitrogen atom System, c) group Wherein k can take the values 0, 1 and 2 and p can take the values 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 - is phenyl substituted alkynyl or optionally), d) groups embedded image (Wherein R ⁸ is C ₁ -C ₄ -alkyl, C ₃ -C ₈ -alkenyl, C ₃ -C ₈ -alkynyl, C ₃ -C ₈ -cycloalkyl, and these groups are represented by C ₁ -C ₈ -alkyl). ₄ -alkoxy, C ₁ -C ₄ -alkylthio and / or phenyl groups, optionally substituted C ₁ -C ₄ -haloalkyl or phenyl) W and Z are the same or May be different, nitrogen or methine, provided that when W and Z are methine, Q is nitrogen, X is nitrogen or CR ⁹ , Y is nitrogen or CR ¹⁰ , Q is nitrogen Or CR ¹¹ , provided that when Q = nitrogen, X = CR ⁹ and Y =
CR ¹⁰ and R ² and R ³ may be the same or different and are optionally substituted phenyl or naphthyl, or a direct bond at the ortho position, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom Or phenyl or naphthyl linked together by an SO ₂ , NH or N-alkyl group, optionally substituted C ₅ -C ₆ -cycloalkyl, R ⁴ is a group of the formula Wherein R ¹² is phenyl, naphthyl or a 5- or 6-membered heteroaromatic system containing 1 to 3 nitrogen atoms and / or one sulfur or oxygen atom, wherein said groups are optionally substituted B) group embedded image (Wherein, R ¹³ is 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,
R ⁵ is hydrogen, C ₁ -C ₄ -alkyl, R ⁹ and R ¹⁰ , which may be the same or different, are phenyl or phenoxy, wherein the phenyl group is optionally substituted , hydrogen, _halogen, C 1 -C ₄ - _alkoxy, C 1 -C ₄ - _haloalkoxy, C 3 -C ₆ - _alkenyloxy, C 3 -C ₆ - _alkynyloxy, C 1 -C ₄ - alkylthio, _{C 1} -C ₄ - _{alkylcarbonyl,} C 1 -C ₄ - alkoxycarbonyl, _{hydroxyl, NH 2, NH (C 1} ~C 4 - _{alkyl), N (C 1 ~C 4} -
_Alkyl) 2, _C 1 which may be optionally substituted -C ₄ - _alkyl, C 2 -C ₄ - _alkenyl, C 2 -C ₄ - a alkynyl, or CR ⁹ and ^{CR 10} are as follows in conjunction with a ^{CR 11} 5-membered or 6
R ¹¹ is hydrogen, halogen, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, C ₃ -C ₆ -alkenyloxy, C ₃ -C ₆ -alkynyloxy, C _1-
C ₄ - _alkylthio, C 1 -C ₄ - _{alkylcarbonyl,} C 1 -C ₄ - alkoxycarbonyl, NH _(C 1 ~C ₄ - _{alkyl), N (C 1 ~C 4} - _{alkyl) 2,} hydroxyl, carboxyl, together alkynyl, or, ^{CR 11} and CR ⁹ or ^{CR 10} - cyano, amino, mercapto, if _C 1 substituted by -C ₄ - _alkyl, C 2 -C ₄ - _alkenyl, C 2 -C ₄ To form an optionally substituted 5- or 6-membered alkylene or alkenylene ring, and in each case one or more methylene groups are oxygen, sulfur , -NH or -N (C ₁ -C ₄ -alkyl).] Acid derivatives, and physiologically acceptable salts, and possible enantiomerically pure and diastereomerically pure forms, except for the following compounds: 2- (6-ethyl-2) -Methyl-4-pyrimidinyloxy) -3- (4-methoxybenzoylamino) -3,3-diphenylpropionic acid, 2- (2,6-dimethyl-4-pyrimidinyloxy) -3- (4-methoxybenzoylamino ) -3,3-Diphenylpropionic acid, 3- (4-methoxybenzoylamino) -2- (6-methoxy-2-methyl-4)
-Pyrimidinyloxy) -3,3-diphenylpropionic acid, 3- (4-methoxybenzoylamino) -2- (6-methoxy-5-methyl-2)
-Pyrazinyloxy) -3,3-diphenylpropionic acid, 3- (4-methoxybenzoylamino) -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-methoxybenzoylamino) -3,3-diphenylpropionic acid, 3- (4-methoxybenzoylamino) -2- (5-methoxy-6-methyl-3
-Pyridazinyloxy) -3,3-diphenylpropionic acid, 2- (4,6-dimethyl [1.3.5] triazin-2-yloxy) -3- (
4-methoxybenzoylamino) -3,3-diphenylpropionic acid, 3- (4-methoxybenzoylamino) -2- (4-methoxy-6-methyl [1
. 3.5] triazin-2-yloxy) -3,3-diphenylpropionic acid,
3- (4-methoxybenzoylamino) -2- (4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3,3-diphenylpropionic acid, 3- (4-methoxybenzoyl) Amino) -2- (4-methoxy-5,6-dihydrofluoro [2,3-d] pyrimidin-2-yloxy) -3,3-diphenylpropionic acid, 2- (4,6-dimethoxy-2-pyrimidinyl Oxy) -3- (4-methoxybenzoylamino) -3,3-diphenylpropionic acid, 2- (4-ethyl-6-methyl-2-pyrimidinyloxy) -3- (4-methoxybenzoylamino) -3, 3-diphenylpropionic acid, 2- (4,6-dimethyl-2-pyrimidinyloxy) -3- (4-methoxybenzoylamino) -3,3-diph Nirupuropion acid, 3- (4-methoxybenzoyl) -2- (4-methoxy-6-methyl-2
-Pyrimidinyloxy) -3,3-diphenylpropionic acid, 2- (4,6-dimethyl-2-pyrimidinyloxy) -3- (4-hydroxybenzoylamino) -3,3-diphenylpropionic acid, 2- (4 -Methoxy-6-methyl-2-pyrimidinyloxy) -3- (4-methylsulfanylbenzoylamino) -3,3-diphenylpropionic acid, 2- (4,6-dimethoxy-2-pyrimidinyloxy) -3- ( 4-nitrobenzoylamino) -3,3-diphenylpropionic acid, 3- (4-chlorobenzoylamino) -2- (4-ethyl-6-methyl-2-pyrimidinyloxy) -3,3-diphenylpropionic acid, 3- (4-ethylbenzoylamino) -2- (4-methoxy-6,7-dihydro-5H-cyclopentapyrimidine 2-yloxy) -3,3-diphenylpropionic acid, 3,3-bis- (4-fluorophenyl) -3- (4-methoxy-benzoylamino) -2- (4-methoxy-5,6-dihydrofluoro [2,3-d] pyrimidin-2-yloxy) -propionic acid 3- (4-chlorobenzoylamino) -2- (4,6-dimethyl [1.3.5]
Triazin-2-yloxy) -3,3-diphenylpropionic acid, 3- (3,4-dimethoxybenzoylamino) -2- (4-methoxy-6-methyl [1.3.5] triazin-2-yloxy) -3,3-diphenylpropionic acid, 3- (3,4-dimethoxybenzoylamino) -2- (4-ethyl-6-methyl [1.3.5] triazin-2-yloxy) -3,3-diphenyl Propionic acid, 3- (4-chlorobenzoylamino) -2- (5-methoxy-6-methyl-3-
Pyridazinyloxy) -3,3-diphenylpropionic acid, 3- (3,4-dichlorobenzoylamino) -2- (6-methoxy-5-methyl-2-pyrazinyloxy) -3,3-diphenylpropionic acid 3- (4-hydroxy-3-methoxybenzoylamino) -2- (5-methoxy-6-methyl [1.2.4] triazin-3-yloxy) -3,3-diphenylpropionic acid, 3- ( 3-chlorobenzoylamino) -2- (2,6-dimethyl-4-pyrimidinyloxy) -3,3-diphenylpropionic acid, 3- (2-chlorobenzoylamino) -2- (6-methoxy-2-methyl) -4-
-Pyrimidinyloxy) -3,3-diphenylpropionic acid, 2- (6-ethyl-2-methyl-4-pyrimidinyloxy) -3- (4-nitrobenzoylamino) -3,3-diphenylpropionic acid. 2. A pharmaceutical preparation comprising the β-amide and β-sulfonamidocarboxylic acid derivative according to claim 1 for treating a disease. 3. A pharmaceutical preparation of compound I according to claim 2 as an endothelin receptor antagonist. 4. Use of the β-amide and β-sulfonamidocarboxylic acid derivative I according to claim 1 for the manufacture of a medicament for the treatment of a disease in which high endothelin levels occur. 5. The β-amide of claim 1 for the treatment of chronic heart failure, restenosis, hypertension, pulmonary hypertension, acute / chronic renal failure, erectile dysfunction, cerebral ischemia, benign prostatic hypertrophy and prostate cancer. A pharmaceutical preparation comprising β-sulfonamidocarboxylic acid derivative I. 6. Inhibitors of the renin-angiotensin system, such as renin inhibitors, angiotensin II antagonists and especially angiotensin converting enzyme (ACE) inhibitors, mixed ACE / neutral endopeptidase (NEP) inhibitors.
The β-amide and β-amide according to claim 1, in combination with a β-blocker.
A pharmaceutical preparation comprising a sulfonamidocarboxylic acid derivative I. 7. Pharmaceutical formulation for oral, parenteral and intraperitoneal administration, which comprises at least one carboxylic acid derivative I according to claim 1 in a single dose, and also conventional pharmaceutical auxiliaries. 8. A compound of the formula II A compound of the formula wherein the groups R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meaning according to claim 1. 9. A compound of formula II Use of a compound of the formula wherein the groups R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meaning of claim 1 as starting material for the synthesis of endothelin receptor antagonists. 10. The formula: A structural fragment as a structural element within an endothelin receptor antagonist, wherein the groups R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meaning of claim 1.