JP2003505377A - Novel carboxylic acid derivatives having 5,6-substituted pyrimidine rings, their preparation and their use as endothelin receptor antagonists - Google Patents

Abstract

(57) [Summary] Formula (I): Wherein the substituents are those described in the detailed description, and their use.

Description

Detailed Description of the Invention

[0001]   The present invention relates to novel carboxylic acid derivatives, their preparation and use.

Endothelin is a peptide composed of 21 amino acids that is synthesized and released by the vascular endothelium. Endothelin is ET-1, ET-2 and ET
-3 exist in three isoforms. In the following, "endothelin" or "E
T "means one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a potent effect on vascular tone. It is known to be caused by binding to (Nature, 332 , 411-415, 1988; FEBS Letters, 231 , 440-444,
1988 and Biochem. Biophys. Res. Commun., 154 , 868-875, 1988).

Increased or abnormal release of endothelin causes persistent vasoconstriction in peripheral, renal and cerebral blood vessels, which can lead to disease. As reported in the literature, endothelin is associated with a range of disorders; hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebrovascular spasm, stroke, benign prostatic hypertrophy, atherosclerosis. Includes arteriosclerosis, asthma and prostate cancer (J. Vascular Med. 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 , 90
4 (1994), Nature 365 , 759 (1993), J. Mol. Cell. Cardiol. 27 , A234 (1995); C
ancer Research 56 , 663 (1996), Nature Medicine 1 , 944, (1995)).

At least two endothelin receptor subtypes, ET _A and ET _B receptors, have recently been described in the literature (Nature 348 , 730 (1990), Nature 348 ,
732 (1990)). Thus, substances that inhibit the binding of one or both of the endothelins to their receptors antagonize the physiological effects of endothelin and are therefore valuable agents.

The production and use of endothelin receptor antagonists has already been described in WO95 / 2.
6716, WO96 / 11914, WO97 / 09294, WO97 / 1
2878, WO97 / 38980, WO97 / 38981, WO97 / 3
8982, WO98 / 099953, WO98 / 27070, DE1972
No. 6146.9, DE19748238.4, DE19755029.5,
DE 19806438.1, DE 19809144.3 and DE 1983
No. 6044.4. In a further investigation, it was found that the compounds used with 5,6-substituted pyrimidine rings have advantageous properties in receptor affinity and receptor binding profile. Its manufacture and use is the subject of this patent application.

[0006]   The subject of the present invention is the formula I

[0007]

[Chemical 5]

[Wherein R ¹ is a tetrazole or a group:

[0009]

[Chemical 6]

Wherein R represents the following: a) group: OR ⁷ , where R ⁷ is: hydrogen, an alkali metal cation, an alkaline earth metal cation, a physiologically tolerable organic Ammonium ions, for example tertiary C ₁ -C ₄ -alkylammonium or ammonium ions; C ₃ -C ₈ -cycloalkyl, C ₁ -C ₈ -alkyl, one or more of the following groups: 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} may be substituted by CH ₂ - phenyl; _C 3 _{~C 6} - alkenyl or _C 3 -C ₆ - alkyl Group, in that case these groups themselves, 1-5 may have a halogen atom; R ⁷ is further 1-5 halogen atoms and / or 1-3 of the following groups: nitro , Cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -halogenalkyl, hydroxy, C ₁ -C ₄ -alkoxy, mercapto, C ₁ -C ₄ -alkylthio, amino,
It may be a phenyl group which may have NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ ; b) is bound via a nitrogen atom and 2 halogen atoms or 1
5-membered heteroaromatics which may have two C ₁ -C ₄ -alkyl or 1-2 C ₁ -C ₄ -alkoxy groups, for example pyrrolyl, pyrazolyl, imidazolyl and triazolyl, c) Basis:

[0011]

[Chemical 7]

[0012] (In the formula, k may have the values 0, 1 and 2 and p may have the values 1, 2, 3 and 4.
And R⁸Is C₁~ C_Four-Alkyl, C_Three~ C₈-Cycloalkyl, C_Three~
C₆-Alkenyl, C_Three~ C₆-Alkynyl, or one or more, eg 1-3
The following groups: Halogen, nitro, cyano, C₁~ C_Four-Alkyl, C₁~ C_Four− Halogen
Kill, hydroxy, C₁~ C_Four-Alkoxy, C₁~ C_Four-Alkylthio, mel
Capto, amino, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl) _Two Phenyl optionally substituted by), d) Group:

[0013]

[Chemical 8]

[0014] (In the formula, R⁹Is C₁~ C_Four-Alkyl, C_Three~ C₆-Alkenyl, C_Three~ C₆-Archi
Nil, C_Three~ C₈-Cycloalkyl, wherein these radicals are C₁~ C_Four-A
Lucoxy group, C₁~ C_Four-Alkylthio groups and / or groups such as those mentioned under c).
May have a phenyl group; 1 to 3 groups: halogen, nitro, cyano, C₁~ C_Four-Alkyl, C₁ ~ C_Four-Halogenalkyl, hydroxy, C₁~ C_Four-Alkoxy, C₁~ C_Four -Alkylthio, mercapto, amino, NH (C₁~ C_Four-Alkyl), N (C ₁ ~ C_Four-Alkyl)_TwoIs phenyl optionally substituted by)]
It is a boric acid derivative.

[0015]   Other substituents represent:   R^TwoIs hydroxy, NH_Two, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four -Alkyl)_Two, C₁~ C_Four-Alkyl, C_Two~ C_Four-Alkenyl, C_Two~ C_Four -Alkynyl, C₁~ C_Four-Hydroxyalkyl, C₁~ C_Four-Halogen alk
Le, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogenalkoxy or C₁~ C _Four -Alkylthio or CR^TwoIs CR^Three5 members or
Forming a 6-membered alkylene ring or alkenylene ring, wherein the ring is 1 or 2
C₁~ C_Four-May be substituted by an alkyl group, and in that case,
One or more methylene groups are oxygen, sulfur, -NH or -N (C₁~ C_Four-Alkyl
).

R ³ is hydroxy, NH ₂ , NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ , halogen, C ₁ -C ₄ -alkyl, C ₂ -C ₄ — Alkenyl,
C ₂ -C ₄ - _alkynyl, C 3 ~C ₆ - _alkenyloxy, C 1 ~C ₄ - _{alkylcarbonyl,} C 1 ~C ₄ - alkoxycarbonyl _C 1 -C ₄ - _{hydroxyalkyl,} C 1 ~C ₄ - halogen _alkyl, C 1 _{~C 4} - _alkoxy, C 1 _{~C 4} -
Halogenalkoxy, —NH—O—C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylthio, or CR ³ together with CR ² as described for R ² is 5
Form a six-membered or six-membered ring.

R ⁴ and R ⁵ (which may be the same or different) are one or more of the following groups: halogen, nitro, cyano, hydroxy, C ₁ -C ₄ -alkyl, C ₁ -C ₄ —. _{halogenalkyl,} C 1 -C ₄ - _alkoxy, C 1 -C ₄ - -haloalkoxy, _phenoxy, C 1 -C ₄ - alkylthio, amino, NH _(C 1 ~C ₄ - alkyl), _{N (C} 1 ~C ₄ - alkyl) is either a or phenyl or naphthyl optionally substituted by _2; or a direct bond to each other, a methylene group, an ethylene group or an ethenylene group, an oxygen atom or a sulfur atom or a SO 2, _-, an NH- or N- alkyl phenyl or naphthyl bound ortho via; or C ₃ -C 7 _- cycloalkyl.

[0018]   R⁶Is hydrogen, C₁~ C₈-Alkyl, C_Three~ C₆-Alkenyl, C_Three~ C₆-Alkynyl
Is C_Three~ C₈-Cycloalkyl, where each of these groups is
Xy, mercapto, carboxyl, halogen, nitro, cyano, C₁~ C_Four-A
Lucoxy, C_Three~ C₆-Alkenyloxy, C_Three~ C₆-Alkynyloxy, C ₁ ~ C_Four-Alkylthio, C₁~ C_Four-Halogenalkoxy, C₁~ C_Four-Al
Kircarbonyl, C₁~ C_Four-Alkoxycarbonyl, (C₁~ C_Four-Alkyl
) NH carbonyl, (C₁~ C_Four-Alkyl)_TwoN carbonyl, C_Three~ C₈-A
Rukylcarbonylalkyl, amino, NH (C₁~ C_Four-Alkyl), N (C₁ ~ C_Four-Alkyl)_Two, Mono- or multi-positioned with phenoxy or phenyl
May be substituted, in which case the above aryl groups are mono- or polysubstituted.
May be, for example, halogen, nitro, cyano, C₁~ C_Four-Alkyl, C₁~
C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four− Halogen
Coxy, mercapto, carboxy, hydroxy, amino, R¹⁰, C₁~ C_Four−
Alkoxycarbonyl, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four-Al
kill)_Two, Dioxomethylene, dioxoethylene or C₁~ C_Four-Alkyl
Phenyl or phenoxy mono- or tri-substituted by o,
Well; One or more of the following groups: halogen, nitro, cyano, hydroxy, amino, C₁~
C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C ₁ ~ C_Four-Halogenalkoxy, phenoxy, C₁~ C_Four-Alkylthio, NH
(C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl)_TwoOr dioxomethy
Phenyl or phenyl, each of which may be substituted by len or dioxoethylene.
Or naphthyl; Has 1 to 3 nitrogen atoms and / or 1 sulfur atom or oxygen atom, or
1 to 4 halogen atoms and / or 1 to 2 groups: C₁~ C_Four-A
Rukiru, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four -Halogenalkoxy, C₁~ C_Four-Alkylthio, phenyl, phenoxy
Or may have phenylcarbonyl, where the phenyl group is itself 1-5
Halogen atoms and / or 1 to 3 groups of the following: C₁~ C_Four-Alkyl, C ₁ ~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogen
Alkoxy and / or C₁~ C_Four-Up to 5 members, which may have alkylthio
Or a 6-membered heteroaromatic.

[0019]   R¹⁰Is C₁~ C_Four-Alkyl, C₁~ C_Four-Alkylthio, C₁~ C_Four−
Alkoxy, which may have one of the following groups: hydroxy, cal
Boxy, amino, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl) _Two , Carboxamide or CON (C₁~ C_Four-Alkyl)_Two.

[0020]   Z is sulfur or oxygen.

[0021]   In this case, and below, the following definitions apply: Alkali metals are, for example, lithium, sodium, potassium; Alkaline earth metals are, for example, calcium, magnesium, barium; Organic ammonium ions are protonated amines such as ethanolamine, diene
Tanolamine, ethylenediamine, diethylamine or piperazine; C_Three~ C₇-Cycloalkyl means for example cyclopropyl, cyclobutyl, cyclo
Lopentyl, cyclohexyl or cycloheptyl; C₁~ C_Four-Halogenalkyl may be straight-chain or branched,
For example, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluor
Chloromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl,
2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroe
Chill, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluor
Is ethyl, 2,2,2-trichloroethyl or pentafluoroethyl,
Often; C₁~ C_Four-Halogenalkoxy may be straight-chain or branched,
For example, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1
-Fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetraf
Luoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2
-Trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy
May be; C₁~ C_Four-Alkyl may be straight-chain or branched, for example methyl,
Ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl
May be -1-propyl, 1-butyl or 2-butyl; C_Two~ C_Four-Alkenyl may be straight-chain or branched, for example ethenyl.
1-propen-3-yl, 1-propen-2-yl, 1-propen-1-y
, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl.
Ku; C_Two~ C_Four-Alkynyl may be straight-chain or branched, e.g.
1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl
Or may be 2-butyn-4-yl; C₁~ C_Four-Alkoxy can be straight-chain or branched, for example
Ci, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy
May be xy, 2-methylpropoxy or 1,1-dimethylethoxy; C_Three~ C₆-Alkenyloxy may be straight or branched, eg
Allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy
May be; C_Three~ C₆-Alkynyloxy may be straight or branched, eg
2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butynyl
May be 2-yloxy; C₁~ C_Four-Alkylthio may be straight-chain or branched, e.g.
Ruthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-
Methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio
May be o; C₁~ C_Four-Alkylcarbonyl may be straight-chain or branched,
May be acetyl, ethylcarbonyl or 2-propylcarbonyl; C₁~ C_Four-Alkoxycarbonyl may be straight-chain or branched,
For example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i
-Propoxycarbonyl or n-butoxycarbonyl; C_Three~ C₈-Alkylcarbonylalkyl may be linear or branched.
, For example 2-oxo-prop-1-yl, 3-oxobut-1-yl or 3
-Oxobut-2-yl; C₁~ C₈-Alkyl may be straight-chain or branched, eg C₁~ C _Four -May be alkyl, pentyl, hexyl, heptyl or octyl; Halogen is, for example, fluorine, chlorine, bromine, iodine.

Another subject of the invention is a compound capable of releasing a compound of formula I (a so-called prodrug).

Preference is given to prodrugs whose release takes place under conditions predominant in certain compartments of the body, for example in the stomach, intestines, bloodstream or liver.

The compounds and intermediates for their preparation, eg II and IV, may have one or more asymmetrically substituted carbon atoms. Such compounds may exist as pure enantiomers or pure diastereomers, or mixtures thereof. It is advantageous to use enantiomerically pure compounds as active substances.

A subject of the present invention is also the use of the carboxylic acid derivatives described above for the manufacture of a medicament, in particular for the manufacture of an inhibitor of the endothelin receptor.

Compounds (IV) of formula IV wherein Z is sulfur or oxygen can be prepared as described in WO 96/11914.

[0027]

[Chemical 9]

The compounds of general formula III are known or they can be synthesized, for example by reduction of the corresponding carboxylic acids or their esters, or other generally known methods.

The compound of formula IV can be obtained in enantiomerically pure form by an acid-catalyzed transesterification reaction as described in WO 98/099953.

Furthermore, enantiomerically pure compounds of formula IV are obtained by carrying out a classical racemic resolution in a racemic or diastereomeric compound of formula IV using a suitable enantiomerically pure base. You can Suitable bases are, for example, 4-chlorophenylethylamine and the bases described in WO 96/11914.

The compounds according to the invention in which the substituents are as defined in the general formula I can be prepared, for example, by reacting a carboxylic acid derivative of the general formula IV in which the substituents represent the above with a compound of the general formula V. .

[0032]

[Chemical 10]

[0033]   In formula V, R¹¹Is halogen or R¹²-SO_Two−, Where R ¹² Is C₁~ C_Four-Alkyl, C₁~ C_Four-With a halogenalkyl or phenyl
It may be. Advantageously, the reaction is carried out by deprotonation of a suitable base, namely intermediate IV.
Boiling at room temperature or in an inert solvent or diluent with the addition of a base that affects
Conduct in the temperature range of the spot.

When R ¹ is an ester, compounds having R ¹ = COOH can be prepared by acidic, basic or catalytic separation of ester groups.

Compounds of the type I with R ¹ ═COOH are further prepared by deprotonating intermediate IV with R ¹ ═COOH with 2 equivalents of a suitable base and reacting with a compound of general formula V You can get it directly. Here too, the reaction is carried out in an inert solvent and in the temperature range from room temperature to the boiling point of the solvent.

Examples of such solvents or diluents are aliphatic, cycloaliphatic and aromatic hydrocarbons, which in each case may be chlorinated, for example hexane, cyclohexane, petroleum ether, ligroin, Benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichlorethylene,
Ethers such as diisopropyl ether, diisobutyl ether, methyl
t-Butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, acid amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones such as dimethylsulfoxide and sulfolane.

The compounds of formula V are known, and some are commercially available or can be prepared by generally known methods.

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 carbonate or potassium carbonate, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide or potassium hydroxide, organometallic compounds such as Butyllithium, or alkali metal amides such as lithium diisopropylamide can be used as a base.

The compounds of the formula I start from the corresponding carboxylic acids, ie the compounds of the formula I in which R ¹ is COOH, which is first converted into the activated form, eg the halide, anhydride or imidazolide, in a conventional manner. Converted, and then with the appropriate hydroxy compound H
It can also be produced by reacting with OR ⁷ . The reaction can be carried out in conventional solvents and often requires the addition of a base such as triethylamine, pyridine, imidazole or diazabicycloundecane. Both of these steps can also be facilitated, for example by reacting the carboxylic acid with a hydroxy compound in the presence of a dehydrating agent such as carbodiimide.

[0040]   Furthermore, the compounds of formula I can be prepared from the corresponding carboxylic acid salts, ie R¹Is a COOM
And M is an alkali metal cation or an equivalent alkaline earth metal cation
It can also be prepared by starting from a compound of formula I which may be present. These salts have the formula R ⁷ -A can be reacted with a number of compounds, in which A is a conventional nucleofugal leaving group, for example
Halogen, such as chlorine, bromine, iodine or arylsulfonyl or ar
By a sulfonyl, such as halogen, alkyl or halogenalkyl.
Optionally substituted arylsulfonyl or alkylsulfonyl,
For example, toluenesulfonyl and methylsulfonyl, or another equivalent leaving group.
. Formula R having a reactive substituent A⁷Compounds of -A are known or common
It can be easily obtained with specialized knowledge. The reaction can be carried out in conventional solvents and is advantageously
Is carried out with the addition of a base, the abovementioned bases being suitable.

In some cases it is necessary to use generally known protecting group techniques for the preparation of the compounds I according to the invention. For example, if R ⁶ = 4-hydroxyphenyl, the hydroxy group can be protected as a benzyl ether, which can then be separated at a suitable step in the reaction sequence.

Compounds of formula I wherein R ¹ is tetrazole can be prepared as described in WO 96/11914.

[0043]   From a biological standpoint, the substituents are: R^TwoIs hydroxy, N (C₁~ C_Four-Alkyl)_Two, C₁~ C_Four-Alkyl-
, C₁~ C_Four-Halogenalkyl-, C₁~ C_Four-Alkoxy-, C₁~ C_Four−
Halogenalkoxy-, C₁~ C_Four-Alkylthio or CR^TwoIs C
R^ThreeForm a 5- or 6-membered alkylene ring or alkenylene ring together with
With one or two Cs₁~ C_Four-Substituted by an alkyl group
And at that time one or more methylene groups are each oxygen, sulfur, --NH or
Is -N (C₁~ C_Four-Alkyl), R^ThreeIs hydroxy, N (C₁~ C_Four-Alkyl)_Two, C₁~ C_Four-Alkyl-
, C₁~ C_Four-Halogenalkyl-, C₁~ C_Four-Alkoxy-, C₁~ C_Four−
Halogenalkoxy-, C₁~ C_Four-Alkylthio, halogen, or
CR^ThreeIs R^TwoCR as described in^TwoForm a 5- or 6-membered ring with
Then R^FourAnd R⁵Is one or more, for example 1 to 3, the following groups: halogen, cyano
, Hydroxy, mercapto, amino, C₁~ C_Four-Alkyl, C₁~ C_Four-Halo
Genalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogenalkoxy, C ₁ ~ C_Four-Alkylthio, NH (C₁~ C_Four-Alkyl)_Two, N (C₁~ C_Four−
Alkyl)_Two, C₁~ C_Four-Alkylcarbonyl, C₁~ C_Four-Alkoxycar
Phenyl or naphthyl optionally substituted by bonyl; Direct bond, methylene group, ethylene group or ethenylene group, oxygen or sulfur atom
Or SO_TwoGroup, NH group or N (C₁~ C_Four-Alkyl) groups with one another
Ortho-bonded phenyl or naphthyl, Or C_Three~ C₇-Cycloalkyl, R⁶Is C₁~ C₈-Alkyl, C_Three~ C₆-Alkenyl, C_Three~ C₆-Arkini
Le or C_Three~ C₈-Cycloalkyl, wherein these groups are the respective
In cases: halogen, hydroxy, cyano, C₁~ C_Four-Alkoxy, C_Three ~ C₆-Alkenyloxy, C_Three~ C₆-Alkynyloxy, C₁~ C_Four-Al
Kircio, C₁~ C_Four-Halogenalkoxy, C₁~ C_Four-Alkylcarbonyl
, Hydroxycarbonyl, C₁~ C_Four-Alkoxycarbonyl, NH (C₁~ C _Four -Alkyl)_Two, N (C₁~ C_Four-Alkyl)_Two, Phenoxy or phenyl
May be mono- or poly-substituted by, wherein the aryl group is
Halogen, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁~ C_Four -Alkoxy, C₁~ C_Four-Halogenalkoxy, R¹⁰, C₁~ C_Four-Arco
Xycarbonyl, dioxomethylene, dioxoethylene, C₁~ C_Four-Alkyl
Mono- or polysubstituted by thio, phenyl or phenoxy, eg monosubstituted
Or may be tri-substituted, One or more of the following groups: halogen, nitro, cyano, hydroxy, amino, C₁~
C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C ₁ ~ C_Four-Halogenalkoxy, phenoxy, C₁~ C_Four-Alkylthio, NH
(C₁~ C_Four-Alkyl)_Two, N (C₁~ C_Four-Alkyl)_TwoReplaced by
Optional phenyl or naphthyl; Having 1 to 3 nitrogen atoms and / or sulfur or oxygen atoms, and 1 to
4 halogen atoms and / or 1 to 2 groups: C₁~ C_Four-Alkyl
, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halo
Genalkoxy, C₁~ C_Four-Alkylthio, phenyl, phenoxy or phenoxy
5 or 6-membered heteroaromatics which may have nilcarbonyl, in which case
The phenyl group may itself be 1 to 5 halogen atoms and / or 1 to 3 groups:
C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Arukoki
Shi, C₁~ C_Four-Halogenalkoxy and / or C₁~ C_Four-Alkylthio
May have R¹⁰Is one of the following groups: hydroxy, carboxamide or CON (C₁~
C_Four-Alkyl)_TwoWith C₁~ C_Four-Alkyl, C₁~ C_Four-With alkoxy
Yes, Z is sulfur or oxygen , Either as a pure enantiomer or as a pure diastereomer?
Preference is given to the carboxylic acid derivatives of the general formula I, or as a mixture thereof.

[0044]   The substituents are: R^TwoIs C₁~ C_Four-Alkyl, C₁~ C_Four-Alkoxy, especially methyl, ethyl
, Methoxy, ethoxy, difluoromethoxy, trifluoromethoxy,
Or CR^TwoIs CR^ThreeTogether with a 5- or 6-membered alkylene ring or
It forms a lukenylene ring, and the mating ring is one or two C₁~ C_FourBy an alkyl group
May be substituted, and in that case, one or more methylene groups are each oxygen,
Sulfur, -NH or -N (C₁~ C_Four-Alkyl)
, R^ThreeIs C₁~ C_Four-Alkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four-Archi
Ruthio, especially methyl, ethyl, methoxy, ethoxy, difluoromethoxy, tri
Fluoromethoxy or CR^ThreeIs R^TwoCR as described in^TwoAnd one
Forming a five-membered ring, R^FourAnd R⁵Is one or more, for example 1 to 3, the following groups: halogen, hydroxy
Shi, C₁~ C_Four-Alkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four-Alkyl
Phenyl (same or different) optionally substituted by o, or
R^FourAnd R⁵Is a direct bond, methylene, ethylene or ethenylene group, oxygen atom
Or sulfur atom or SO_Two, NH or N (C₁~ C_Four-Alkyl) group
Phenyl, ortho-bonded to each other via R^FourAnd R⁵Is cyclohexyl, R⁶Is C₁~ C₈-Alkyl, C_Three~ C₆-Alkenyl or C_Three~ C₈−
Cycloalkyl, where these radicals are in each case: halogen
N, hydroxy, cyano, C₁~ C_Four-Alkoxy, C_Three~ C₆-Alkenyl
Kish, C₁~ C_Four-Also monosubstituted by alkylthio, phenoxy or phenyl
It may be poly-substituted, wherein the aryl group is C₁~ C_Four-Archi
Le, C₁~ C_Four-Alkoxy, dioxomethylene, dioxoethylene, C₁~ C _Four -Mono- or poly-substituted by alkylthio, for example mono- or tri-substituted
May be done; One or more of the following groups: halogen, nitro, cyano, hydroxy, amino, C₁~
C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C ₁ ~ C_Four-Halogenalkoxy, phenoxy, C₁~ C_Four-Alkylthio, C₁ ~ C_Four-Alkylamino or C₁~ C_Four-Substituted by dialkylamino
Optional phenyl or naphthyl; Having a nitrogen atom and / or a sulfur atom or an oxygen atom, and having 1 to 4 halo.
Gen atom and / or one or two of the following groups: C₁~ C_Four-Alkyl, C₁~ C _Four -Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four-Alkylthio,
5 members, which may have phenyl, phenoxy or phenylcarbonyl
Is a 6-membered heteroaromatic, the phenyl group itself being 1-5 halogen atoms.
A child and / or one to three of the following groups: C₁~ C_Four-Alkyl, C₁~ C_Four-C
Rogen alkyl, C₁~ C_Four-Alkoxy and / or C₁~ C_Four-Alkyl
May have thio, Y is sulfur, oxygen or a single bond Or both as a pure enantiomer and a pure diastereomer,
Compounds of formula I, as a mixture thereof, or are particularly preferred.

The compounds of the present invention are effective for hypertension, pulmonary hypertension, myocardial infarction, angina, arrhythmia, acute / chronic renal failure, chronic heart failure, renal failure, cerebrovascular spasm, cerebral ischemia, subarachnoid hemorrhage, migraine headache. , Asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, endovascular coagulation, restenosis after angioplasty and bypass surgery, benign prostatic hypertrophy, cirrhosis, erectile dysfunction, ischemia It also offers novel therapeutic potential for the treatment of renal failure or hypertension caused by poisoning, metastasis and growth of mesenchymal tumors, renal failure induced by contrast agents, pancreatitis, especially acute pancreatitis, gastrointestinal ulcer.

Another subject of the invention relates to the combination of an endothelin receptor antagonist of formula I and an inhibitor of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin-II antagonists and angiotensin converting enzyme (ACE) inhibitors. A combination of an endothelin receptor antagonist of formula I and an ACE inhibitor is advantageous.

Another subject of the invention is a combination of an endothelin receptor antagonist of formula I and a beta blocker.

Another subject of the invention is a combination of an endothelin receptor antagonist of formula I and a diuretic.

The subject matter of the present invention further comprises endothelin receptor antagonists of formula I and VEG
It relates to a combination of substances that block the action of F (vascular endothelial growth factor). Such a substance is, for example, an antibody against VEGF or a protein that specifically binds, or a low molecular weight substance that specifically inhibits VEGF release or receptor binding.

The combinations described above may be applied simultaneously or one and the other may be applied at different times. They can be used both in single pharmaceutical formulations and in separate formulations. The application form may also be different, for example the endothelin receptor antagonist may be applied orally and the VEGF inhibitor may be applied parenterally.

These combination preparations are particularly suitable for the treatment and prevention of hypertension and the diseases caused thereby and the treatment of heart failure.

[0052] can be demonstrated by the following test good effect of the compounds were used: CHO cells expressing the receptors ET _A or ET _B human and binding studies cloned receptors for binding studies.

Membrane Preparation CHO cells expressing ET _A or ET _B receptors were treated with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022), 1 mM glutamine (Gi.
bco No. 25030-024), 100 U / ml penicillin and 100 μg / ml streptomycin (Gibco, Sigma No. P0781) in DMEM NUT M.
It was grown in IX F ₁₂ medium (Gibco, No. 21331-020). After 48 hours, cells were washed with PBS and incubated with PBS containing 0.05% trypsin for 5 minutes at 37 ° C. The mixture was then neutralized with medium and cells were harvested by centrifugation at 300 xg.

For membrane preparation, cells were adjusted to a concentration of 10 ⁸ cells / ml (50 mM Tris-HCl buffer, pH 7.4) and then a Branson sonic generator (
Branson Sonifier 250) was used to sonicate for 40-70 seconds / constant power of 20.

Binding Assay For binding assay of ET _A or ET _B receptors, membranes were incubated with incubation buffer (5 mM MnCl ₂ , 40 mg / ml bacitracin and 0.2%.
Suspended in 50 mM Tris-HCl pH 7.4 with BSA of 50 μg protein per test batch and at 25 ° C. 25 pM [125 I] ET ₁ (25 μM).
ET _A receptor test) or 25 pM [125 I] ET ₃ (ET _B receptor test) in the presence and absence of test substance. Non-specific binding 1
0 ^{- 7} was measured using the ET ₁ of M. Thirty minutes later, filtration with a GF / B glass fiber filter (Whatman, England) was performed in a Skatron cell collector (Skatron, Lier, Norway) to separate free and bound radioligand, and The filters were washed with ice cold Tris-HCl buffer (pH 7.4) containing 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200CA liquid scintillation counter.

Functional Vascular Assay of Endothelin Receptor Antagonist A segment of rabbit aorta was treated with 2 g of Krebs-Henseleit solution at 37 ° C.
After an initial tension of 1 h and a relaxation time of 1 h, K ⁺ contractions were first induced. After washing off, an endothelin dose-effect curve up to the maximum was generated.

An effective endothelin antagonist was applied to another preparation of the same vessel 15 minutes before the start of the endothelin dose-effect curve. The effect of endothelin was calculated as% of K ⁺ -induced contraction. Effective endothelin antagonists result in a rightward shift in the endothelin dose-effect curve.

In Vivo Testing of ET Antagonists Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially oxygenated, vagus nerve transected and spinal cord removed. Catheter was inserted into the carotid artery and jugular vein.

In control animals, intravenous application of ₁ μg / kg of ET ₁ resulted in a significant increase in blood pressure, which was relatively long-lasting.

Test animals were treated with test compound i.p. 30 minutes before ET ₁ application. v. Injection (1 ml / k
g). Changes in blood pressure in test animals were compared to those in control animals to determine ET-antagonistic properties.

Oral study of mixed ET _A and ET _B antagonists Male normotensive rats weighing 250-350 g (Sprague Dawley, Janvier
) Was orally pretreated with the test substance. After 80 minutes, the animals were anesthetized with urethane and the carotid artery (for blood pressure measurement) and jugular vein (large endothelin / endothelin 1).
Catheter).

After stable phase, large endothelin (20 μg / kg, application volume 0.5 ml / kg)
Alternatively, ET ₁ (0.3 μg / kg, application volume 0.5 ml / kg) was applied intravenously. Blood pressure and heart rate were recorded continuously for 30 minutes. A significant and lasting change in blood pressure was calculated as the area under the curve (AUC). To determine the antagonism of a test substance, the AUC of the animal treated with the substance is compared with the AUC of the control animal.
Compared with.

The compounds according to the invention are orally or parenterally (subcutaneous, intravenous,
It can be applied intramuscularly, intraperitoneally). Application can also be carried out by steam or spray through the nasopharyngeal area.

The dose depends on the age, condition and weight of the patient and the mode of application. In general, the daily dose of the active substance is about 0.5 to 50 mg / kg (body weight) for oral application and about 0.1 to 10 mg / kg (body weight) for parenteral application.

The novel compounds are customary solid or liquid pharmaceutical application forms, for example tablets or film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions,
It can be used as an ointment, cream or spray. These can be manufactured by a conventional method. In this case, the active substances are incorporated into customary pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow control agents, plasticizers, wetting agents, dispersants, emulsifiers, solvents, delayed-release agents, oxidation agents. Inhibitors and / or propellants (H. Zucker et al .: Pharmaceutical Technology, Thieme Publishing, Stuttgart, 19
It may be processed in 91). The application forms obtained as described above usually contain the active substance in a concentration of 0.
It is contained in an amount of 1 to 90% by mass.

Synthetic Examples Example 1 2-Methylsulfanyl-6,7-dihydro-5H-cyclopentapyrimidine Solution consisting of 16.4 g (119 mmol) potassium carbonate and 42.3 g (152 mmol) S-methylisothiourea sulphate. 2 dissolved in 100 ml of water
4.9 g (44 mmol) of -oxo-cyclopentanecarbaldehyde were added within 1 hour, stirred at room temperature overnight and then heated to 65 ° C for 6 hours. The aqueous solution is extracted with pentane, the organic phase is concentrated and the residue is chromatographed on silica gel (heptane / acetic acid ester 8: 1), whereby 0.93 g of the expected compound is obtained as a solid.

Example 2 2-Methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine 2-Methylsulfanyl-6,7-dihydro-5H- in 20 ml of methanol.
Alternatingly at 0 ° C. into a solution of 0.85 g (5.1 mmol) cyclopentapyrimidine,
The pH value was adjusted to 2-3 by adding a solution of 9.9 g (16.1 mmol) of Oxone in 70 ml of water and a 4M sodium hydroxide solution. After the addition was complete, the batch was post-stirred for 2 hours at room temperature, then extracted with acetic ester, the organic phase was dried over sodium sulphate and rotary evaporated. The solid residue (0.93g) was used without further purification.

Example 3 2- (6,7-Dihydro-5H-cyclopentapyrimidin-2-yl-oxy-
) -3-Methoxy-3,3-diphenyl-propionic acid benzyl ester 0.1 g NaH in 10 ml DMF (3.3 mmol, 80 in white oil).
%) 2-hydroxy-3-methoxy-3 dissolved in DMF at 0 ° C.
, 3-Diphenyl-propionic acid benzyl ester 0.6 g (1.6 mmol)
Was dripped. After stirring for 30 minutes, to the mixture was added a mixture containing 420 mg (2.1 mmol) of 2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine in 10 ml of DMF and stirred at room temperature overnight. The batch was poured into ice water and extracted 3 times with diethyl ether. The ethereal phase was dried over magnesium sulphate, subsequently filtered and the solvent was distilled off under vacuum. Yellow residue (0.54 g
) Is chromatographed on silica gel, whereby the desired product 24
3 mg could be isolated.

MS (API): 503 (M + Na) ⁺ .

Example 4 2- (6,7-Dihydro-5H-cyclopentapyrimidin-2-yloxy)-
3-Methoxy-3,3-diphenyl-propionic acid (I-136) 2- (6,7-dihydro-5) in 15 ml of 2: 1 acetate / methanol.
H-Cyclopentapyrimidin-2-yl-oxy) -3-methoxy-3,3-diphenylpropionic acid benzyl ester 0.23 g was treated with hydrogen using 60 mg of palladium (10%) on activated carbon with hydrogen. 24 hours at room temperature under standard pressure
Hydrogenated. The batch was filtered, concentrated and the residue (177 mg) was stirred in diethyl ether, filtered and then dried. 95 mg was isolated from the desired product.

¹ H-NMR (d ₆ -DMSO, 200 MHz): 8.3 (s, 1H); 7.2
~ 7.4 (m, 10H); 6.15 (s, 1H); 3.3 (s, 3H); 2.8
(M, 4H), 2.1 (m, 2H).

Example 5 2-Chloro-4-methoxy-5-methylpyrimidine A solution of 25 g 2,4-dichloro-5-methylpyrimidine in methanol at 0 ° C.
After cooling, 28.5 ml of sodium methylate solution (30% in methanol) were added and stirred first at 0 ° C. for 1 hour and then at room temperature for 2 hours. The solvent was subsequently removed from the resulting suspension, taken up in water and extracted with ether. The organic phase is dried over sodium sulphate, filtered, concentrated and the residue thus obtained is chromatographed on silica gel, whereby 11.4 g of the expected compound are obtained.

Example 6 2- (4-Methoxy-5-methylpyrimidin-2-yloxy) -3-isopropoxy-3,3-diphenyl-propionic acid (I-5) 0.23 g sodium hydride in 20 ml DMF ( 0.76 g (2.5 mmol) 2-hydroxy-3-isopropoxy-3,3-diphenyl-propionic acid dissolved in DMF at 0 ° C. in a suspension of 7.6 mmol, 80% in white oil). Was added dropwise. After stirring for 30 minutes, the mixture was treated with 2-chloro-4- in 10 ml DMF.
0.6 g (3.8 mmol) of methoxy-5-methylpyrimidine were added, then first stirred overnight at room temperature and subsequently at 40 ° C. for 8 hours. The batch was poured into ice water, brought to pH 1 with 2N HCl and extracted 3 times with diethyl ether. The ether phase is extracted with 1N KOH and the alkaline aqueous phase is renewed with 2N HCl to pH 1
And extracted again with ether. The ether phase thus obtained is dried over magnesium sulphate, filtered and the solvent is distilled off under vacuum. The yellowish residue (0.8 g) was chromatographed on silica gel, which allowed the isolation of 0.19 g of the desired product.

¹ H-NMR (CDCl ₃ , 200 MHz): 8.0 (s, 1H); 7.5-7
． 6 (m, 2H); 7.2-7.4 (m, 8H); 6.3 (s, 1H); 3.9
(M, 1H); 3.9 (s, 3H); 2.0 (s, 3H), 1.1 (m, 6H)
.

MS (API): 423 (M + H) ⁺ .

Example 7 2-Methylsulfanyl-4-methoxy-5-methylpyrimidine To a solution of 14.8 g (93 mmol) 2-chloro-4-methoxy-5-methyl-pyrimidine in 100 ml acetonitrile is added sodium thiomethylate. 7.2
g (102 mmol) was added and the suspension thus obtained was heated at reflux for 4 hours. The solvent was subsequently removed, taken up in water and extracted with ether. The organic phase is dried with sodium sulphate, filtered, concentrated and the residue obtained (
13.4 g) was reacted without further purification.

Example 8 2-Methylsulfonyl-4-methoxy-5-methylpyrimidine To a solution of 13.3 g (78.1 mmol) 2-methylsulfanyl-4-methoxy-5-methylpyrimidine in 80 ml of methanol at 0 ° C. Oxon 6 in the water
2.4 g (101 mmol) of solution and 4M sodium hydroxide solution (about 40
ml) was added to maintain the pH value at 2-3. After the addition is complete, the batch is allowed to stand at room temperature for 2
After stirring for a period of time, the methanol was removed and then extracted with acetic ester, the organic phase was dried with sodium sulphate and rotary evaporated. Solid residue (14.
7 g) was stirred in diethyl ether for 2 hours, then filtered and dried, which gave 13.5 g of pure target product.

Example 9 2- (4-Methoxy-5-methylpyrimidin-2-yloxy) -3-benzyloxy-3,3-diphenylpropionic acid (I-47) 0.27 g (9) of sodium hydride in 20 ml of DMF. 1.0 g (2.5 mmol) of 2-hydroxy-3-benzyloxy-3,3-diphenyl-propionic acid dissolved in DMF at 0 ° C. was added dropwise to a suspension of 80 mmol), 80% in white oil). Added After stirring for 30 minutes, 0.79 g (3.9 mmol) of 2-methylsulfonyl-4-methoxy-5-methylpyrimidine in 10 ml of DMF was added to the mixture and then stirred at room temperature overnight. Pour the batch into ice water and add 2N HCl to pH 1
And extracted 3 times with diethyl ether. The ethereal phase was extracted with 1N KOH, the alkaline aqueous phase was renewed with 2N HCl to pH 1 and again extracted with ether. The ether phase thus obtained is dried over magnesium sulphate, filtered and the solvent is distilled off under vacuum. 10 ml of diethyl ether were added to the yellowish residue (1.2 g), the mixture was stirred at room temperature for 3 hours, and the precipitated solid was suction filtered and dried, whereby 0.6 g of the target compound was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz): 8.0 (s, 1H); 7.2-7
． 45 (m, 10H); 6.2 (s, 1H); 4.7 (d, 1H); 4.55 (
d, 1H); 3.85 (s, 3H); 2.1 (s, 3H).

MS (API): 471 (M + H) ⁺ .

Example 10 2- (4-Methoxy-5-methylpyrimidin-2-yloxy) -3-hydroxy-3,3-diphenyl-propionic acid (I-29) 2- (4-methoxy in 20 ml acetic acid ester -5-methyl-pyrimidine-2
-Yloxy) -3-benzyloxy-3,3-diphenyl-propionic acid 44
0 mg (0.94 mmol) solution to 80 mg palladium on activated carbon (10%)
Was hydrogenated under standard pressure at room temperature for 3 days. The batch was filtered, concentrated and the residue (430 mg) was chromatographed on silica gel, whereby 39 mg of the desired target product could be isolated.

¹ H-NMR (d ₆ -DMSO, 200 MHz): 8.0 (s, 1H); 7.6
(M, 2H); 7.0-7.5 (m, 8H); 5.6 (s, 1H); 3.8 (m
3H); 1.9 (s, 3H).

Example 11 (S) -2- (4-Methoxy-5-methylpyrimidin-2-yloxy) -3-
Methoxy-3,3-diphenyl-propionic acid (I-2) A suspension of 3.3 g of sodium hydride (110 mmol, 80% in white oil) in 40 ml of DMF was dissolved in 40 ml of DMF at 0 ° C (S). 2-Hydroxy-3-methoxy-3,3-diphenyl-propionic acid 10 g (36.7 mmol) was added dropwise. After stirring for 60 minutes, the mixture was charged with 2-methylsulfonyl-4-methoxy-5-methylpyrimidine 9.6 (47.7 mmol) in 20 ml DMF.
Was added and then stirred overnight at room temperature. The batch was poured into ice water, brought to pH 1 with 2N HCl and extracted 3 times with diethyl ether. The ether phase is extracted with 1N KOH and the alkaline aqueous phase is renewed with 2N HCl to pH.
1 and extracted again with ether. The ether phase thus obtained is dried over sodium sulphate, filtered and the solvent is distilled off under vacuum. Residue (17.
1 g) was stirred in diethyl ether overnight, filtered and dried. The solid thus obtained (12.1 g) was chromatographed on silica gel, which made it possible to isolate 11.4 g of the desired product.

¹ H-NMR (CDCl ₃ , 270 MHz): 8.0 (s, 1H); 7.2-
7.45 (m, 10H); 6.1 (s, 1H); 3.85 (s, 3H); 3.3
(S, 3H); 2.0 (s, 3H).

Melting point: 134 ° C (decomposition) MS (ESI): 394 (M + H) ⁺ .

[0086]   The following compounds were made similarly to the above example.

Example 12 3-Ethoxy-2- (4-methoxy-5-methyl-pyrimidin-2-yloxy) -3,3-diphenyl-propionic acid (I-4) ¹ H-NMR (CDCl ₃ , 200 MHz) : 8.0 (s, 1H); 7.1-
7.5 (m, 10H); 6.2 (s, 1H); 3.9 (s, 3H); 3.5 (m
, 2H); 2.0 (s, 3H); 1.1 (t, 3H).

MS (API): 409 (M + H) ⁺ .

Example 13 3- [2- (3,4-Dimethoxy-phenyl) -ethoxy] -2- (4-methoxy-5-methyl-pyrimidin-2-yloxy) -3,3-diphenyl-propionic acid ¹ H-NMR (CDCl ₃ , 200 MHz): 8.0 (s, 1H); 7.1-
7.4 (m, 10H); 6.6 to 6.8 (m, 3H); 6.3 (s, 1H); 3
． 9 (s, 3H); 3.8 (m, 7H); 3.5-3.65 (m, 1H);
7-2.9 (m, 2H); 2.0 (s, 3H); 1.1 (t, 3H).

MS (ESI): 555 (M + H) ⁺ .

Example 14 3- [2- (3,4-Dimethoxy-phenyl) -ethoxy] -2- (9-methyl-9H-purin-2-yl-oxy) -3,3-diphenyl-propionic acid ( I
-150) ¹ H-NMR (CDCl ₃ , 200 MHz): 8.2 (s, 1H); 7.9 (
s, 1H); 7.1-7.4 (m, 10H); 6.6-6.8 (m, 3H); 6
． 3 (s, 1H); 3.9 (s, 3H); 3.8 (m, 7H); 3.5-3.6.
5 (m, 1H); 2.7 to 2.9 (m, 2H); 2.0 (s, 3H); 1.1 (
t, 3H).

MS (ESI): 555 (M + H) ⁺ .

Example 15 3,3-Bis- (4-fluoro-phenyl) -3-methoxy-2- (4-methoxy-5-methyl-pyrimidin-2-yloxy) -propionic acid (I-61) ¹ H _{-NMR (CDCl 3, 400MHz):} 8.0 (s, 1H); 7.4~
7.5 (m, 2H); 7.25 to 7.35 (m, 2H); 6.9 to 7.0 (m,
4H); 6.05 (s, 1H); 3.9 (s, 3H); 3.3 (s, 3H); 2
． 05 (s, 3H).

MS (API): 431 (M + H) ⁺ .

Example 16 3- (3,4-Dimethyl-benzyloxy) -2- (4-methoxy-5-methyl-pyrimidin-2-yloxy) -3,3-diphenyl-propionic acid (I-1
49) ¹ H-NMR (CDCl ₃ , 200 MHz): 8.0 (s, 1H); 7.1-
7.5 (m, 10H); 6.2 (s, 1H); 4.6 (d, 1H); 4.4 (d
, 1H); 3.85 (s, 3H); 2.2 (s, 6H); 2.0 (s, 3H).

MS (API): 498 (M + H) ⁺ .

[0097]   Similarly, the compounds listed in Table 1 can be prepared.

Example 17 Receptor binding data was measured for the compounds described below as described in the binding studies above and the results are set forth in Table 2.

[0099]

[Table 1]

[0100]

[Table 2]

[0101]

[Table 3]

[0102]

[Table 4]

[0103]

[Table 5]

[0104]

[Table 6]

[0105]

[Table 7]

[0106]

[Table 8]

[0107]

[Table 9]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 5/16 A61P 5/16 9/04 9/04 9/10 9/10 9/12 9/12 11 / 06 11/06 13/12 13/12 35/00 35/00 43/00 111 43/00 111 C07D 239/47 C07D 239/47 Z 239/52 239/52 239/56 239/56 239/80 239 / 80 401/12 401/12 405/12 405/12 409/12 409/12 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE , IT, LU, MC, NL, PT, SE), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, G D, GE, GH, GM, HR, H , ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA , ZWF F term (reference) 4C063 AA01 BB08 CC29 CC79 CC95 DD16 DD29 EE01 4C086 AA01 AA02 AA03 BC42 BC46 GA02 GA04 GA07 MA01 MA04 NA14 ZA02 ZA15 ZA36 ZA42 ZA59 ZA66 ZA81 ZB26 ZC06 ZC42

Claims (8)

[Claims] 1. Formula I     [Chemical 1] [In the formula, R¹Is a tetrazole or group:     [Chemical 2] (In the formula, R represents: a) group: OR⁷, Then R⁷Is: Hydrogen, alkali metal cations, alkaline earth metal cations, physiologically acceptable
Organic ammonium ions, such as tertiary C₁~ C_Four-Alkylammoniu
Or ammonium ion; C_Three~ C₈-Cycloalkyl, C₁~ C₈-Alkyl, CH_Two-Phenyl, this
Is one or more of the following groups: halogen, nitro, cyano, C₁~ C_Four-Alkyl, C ₁ ~ C_Four-Halogenalkyl, hydroxy, C₁~ C_Four-Alkoxy, mercap
G, C₁~ C_Four-Alkylthio, amino, NH (C₁~ C_Four-Alkyl), N (
C₁~ C_Four-Alkyl)_TwoMay be replaced by; C_Three~ C₆-Alkenyl group or C_Three~ C₆-Alkynyl groups, in which case these
The group may itself have from 1 to 5 halogen atoms; R⁷Is further 1 to 5 halogen atoms and / or 1 to 3 of the following groups: nitro
, Cyano, C₁~ C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, hydroxy
, C₁~ C_Four-Alkoxy, mercapto, C₁~ C_Four-Alkylthio, amino,
NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl)_TwoHave
A phenyl group; b) bound through a nitrogen atom and having 1-2 halogen atoms or 1-
2 C₁~ C_Four-Alkyl or 1-2 C₁~ C_Four-Has an alkoxy group
Optionally a 5-membered heteroaromatic group such as pyrrolyl, pyrazolyl, imidazolyl or
And triazolyl, c) group:     [Chemical 3] (In the formula, k may have the values 0, 1 and 2 and p may have the values 1, 2, 3 and 4.
And R⁸Is C₁~ C_Four-Alkyl, C_Three~ C₈-Cycloalkyl, C_Three~
C₆-Alkenyl, C_Three~ C₆-Alkynyl, or one or more, eg 1-3
The following groups: Halogen, nitro, cyano, C₁~ C_Four-Alkyl, C₁~ C_Four− Halogen
Kill, hydroxy, C₁~ C_Four-Alkoxy, C₁~ C_Four-Alkylthio, mel
Capto, amino, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl) _Two Phenyl optionally substituted by), d) Group:     [Chemical 4] (In the formula, R⁹Is C₁~ C_Four-Alkyl, C_Three~ C₆-Alkenyl, C_Three~ C₆-Archi
Nil, C_Three~ C₈-Cycloalkyl, wherein these radicals are C₁~ C_Four-A
Lucoxy group, C₁~ C_Four-Alkylthio groups and / or groups such as those mentioned under c).
May have a phenyl group; 1 to 3 groups: halogen, nitro, cyano, C₁~ C_Four-Alkyl, C₁ ~ C_Four-Halogenalkyl, hydroxy, C₁~ C_Four-Alkoxy, C₁~ C_Four -Alkylthio, mercapto, amino, NH (C₁~ C_Four-Alkyl), N (C ₁ ~ C_Four-Alkyl)_TwoPhenyl optionally substituted by), R^TwoIs hydroxy, NH_Two, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four−
Alkyl)_Two, C₁~ C_Four-Alkyl, C_Two~ C_Four-Alkenyl, C_Two~ C_Four−
Alkynyl, C₁~ C_Four-Hydroxyalkyl, C₁~ C_Four-Halogen alkyl
, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogenalkoxy or C₁~ C_Four -Alkylthio or CR^TwoIs CR^Three5 or 6 together with
Membered alkylene ring or alkenylene ring is formed, and the ring has 1 or 2
C₁~ C_Four-May be substituted by alkyl groups and in each case 1
One or more methylene groups are oxygen, sulfur, -NH or -N (C₁~ C_Four-Alkyl
) May be substituted, R^ThreeIs hydroxy, NH_Two, NH (C₁~ C_Four-Alkyl), N (C₁~ C_Four -Alkyl)_Two, Halogen, C₁~ C_Four-Alkyl, C_Two~ C_Four-Alkenyl,
C_Two~ C_Four-Alkynyl, C_Three~ C₆-Alkenyloxy, C₁~ C_Four-Archi
Lecarbonyl, C₁~ C_Four-Alkoxycarbonyl, C₁~ C_Four-Hydroxya
Rukiru, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four -Halogenalkoxy, -NH-O-C₁~ C_Four-Alkyl, C₁~ C_Four-Al
Kirthio or CR^ThreeIs R^TwoCR as described in^TwoBe with
Form a 5- or 6-membered ring, R^FourAnd R⁵(These may be the same or different) is one or more of the following
Groups: halogen, nitro, cyano, hydroxy, C₁~ C_Four-Alkyl, C₁~
C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four− Halogen
Coxy, phenoxy, C₁~ C_Four-Alkylthio, amino, NH (C₁~ C_Four−
Alkyl), N (C₁~ C_Four-Alkyl)_TwoMay be replaced by Pheny
Is le or naphthyl; or Direct bond with each other, methylene group, ethylene group, or ethenylene group, if oxygen atom
Cu sulfur atom or SO_TwoOrtho position via-, NH- or N-alkyl group
Phenyl or naphthyl linked together by; C_Three~ C₇-Cycloalkyl, R⁶Is hydrogen, C₁~ C₈-Alkyl, C_Three~ C₆-Alkenyl, C_Three~ C₆-Alkynyl
Is C_Three~ C₈-Cycloalkyl, where each of these groups is
Xy, mercapto, carboxyl, halogen, nitro, cyano, C₁~ C_Four-A
Lucoxy, C_Three~ C₆-Alkenyloxy, C_Three~ C₆-Alkynyloxy, C ₁ ~ C_Four-Alkylthio, C₁~ C_Four-Halogenalkoxy, C₁~ C_Four-Al
Kircarbonyl, C₁~ C_Four-Alkoxycarbonyl, (C₁~ C_Four-Alkyl
) NH carbonyl, (C₁~ C_Four-Alkyl)_TwoN carbonyl, C_Three~ C₈-A
Rukylcarbonylalkyl, amino, NH (C₁~ C_Four-Alkyl), N (C₁ ~ C_Four-Alkyl)_Two, Mono- or multi-positioned with phenoxy or phenyl
May be substituted, in which case the above aryl groups are mono- or polysubstituted.
Well; One or more of the following groups: halogen, nitro, cyano, hydroxy, amino, C₁~
C_Four-Alkyl, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C ₁ ~ C_Four-Halogenalkoxy, phenoxy, C₁~ C_Four-Alkylthio, NH
(C₁~ C_Four-Alkyl), N (C₁~ C_Four-Alkyl)_TwoOr dioxomethy
Phenyl or phenyl, each of which may be substituted by len or dioxoethylene.
Or naphthyl; Has 1 to 3 nitrogen atoms and / or 1 sulfur atom or oxygen atom, or
1 to 4 halogen atoms and / or 1 to 2 groups: C₁~ C_Four-A
Rukiru, C₁~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four -Halogenalkoxy, C₁~ C_Four-Alkylthio, phenyl, phenoxy
Or may have phenylcarbonyl, where the phenyl group is itself 1-5
Halogen atoms and / or 1 to 3 groups of the following: C₁~ C_Four-Alkyl, C ₁ ~ C_Four-Halogenalkyl, C₁~ C_Four-Alkoxy, C₁~ C_Four-Halogen
Alkoxy and / or C₁~ C_Four5 members which may have alkylthio
Is a 6-membered heteroaromatic; Z is sulfur or oxygen] and its physiologically tolerable salts, tautomers
Isomers and pure enantiomeric and diastereomeric forms. 2. Use of compound I according to claim 1 for treating a disease. 3. Use of compound I according to claim 1 as an endothelin receptor antagonist. 4. Use of compound I according to claim 1 for the manufacture of a medicament for the treatment of diseases in which elevated endothelin levels are manifested. 5. Use of compound I according to claim 1 for the manufacture of a medicament for the treatment of diseases in which endothelin contributes to its development and / or progression. 6. A method for treating chronic heart failure, restenosis, hypertension, pulmonary hypertension, acute / chronic renal failure, cerebral ischemia, asthma, benign thyroid hypertrophy, prostate cancer and acute pancreatitis. Use of Compound I of. 7. A compound I according to claim 1 and an inhibitor of the renin-angiotensin system, such as a renin inhibitor, an angiotensin-II-antagonist, an angiotensin converting enzyme (ACE) inhibitor, a mixed ACE / neutral endopeptidase ( NEP) inhibitors, β-blockers, diuretics, calcium antagonists and V
A combination with one or more agents selected from EGF-blockers. 8. Pharmaceutical preparation for oral and parenteral application, which contains at least one compound I according to claim 1 in addition to the customary pharmaceutical auxiliaries per dose.