SK11752000A3 - Novel unsymmetrically substituted carboxylic acid derivatives, method for producing them, and their use as mixed eta/etb-receptor antagonists - Google Patents

Novel unsymmetrically substituted carboxylic acid derivatives, method for producing them, and their use as mixed eta/etb-receptor antagonists Download PDF

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SK11752000A3
SK11752000A3 SK1175-2000A SK11752000A SK11752000A3 SK 11752000 A3 SK11752000 A3 SK 11752000A3 SK 11752000 A SK11752000 A SK 11752000A SK 11752000 A3 SK11752000 A3 SK 11752000A3
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phenyl
alkoxy
alkylthio
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Wilhelm Amberg
Rolf Jansen
Dagmar Klinge
Hartmut Riechers
Stefan Hergenr�Der
Manfred Raschack
Liliane Unger
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Basf Aktiengesellschaft
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Abstract

The invention relates to carboxylic acid derivatives of formula (I), wherein R<1>-R<6>, Q, W, X, Y and Z have the meanings given in the description. The novel compounds are suitable for combating diseases.

Description

Predložený vynález sa týka nových derivátov karboxylových kyselín, ich prípravy a použitia.The present invention relates to novel carboxylic acid derivatives, their preparation and use.

Doterajší stav technikyBACKGROUND OF THE INVENTION

Endotelín je peptid, ktorý pozostáva z 21 aminokyselín a syntetizuje sa uvoľňuje sa vaskulárnym endotelom. Endotelín jestvuje v troch izoformách, ET-1, ET-2 a ET-3. „Endotelín“ alebo „ET“ v ďalšom označuje jeden alebo všetky izoformy endotelínu. Endotelín je účinným vazokonštriktorom a vykazuje silný účinok na tonus ciev. Je známe, že táto vazokonštrikcia je spôsobená naviazaním endotelínu ku jeho receptoru (Náture, 332. 411-415,1988; FEBS Letters, 231, 440444, 1988 a Biochem. Biophys. Res. Commun., 154. 868-875,1988).Endothelin is a peptide consisting of 21 amino acids and synthesized by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. "Endothelin" or "ET" hereinafter refers to one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a potent effect on vascular tone. This vasoconstriction is known to be due to the binding of endothelin to its receptor (Nature, 332. 411-415, 1988; FEBS Letters, 231, 440444, 1988 and Biochem. Biophys. Res. Commun., 154. 868-875, 1988) .

Zvýšené alebo nadmerné uvoľňovanie endotelínu spôsobuje vytrvalú vazokonštrikciu v periférnych, renálnych a mozgových krvných cievach, ktorá môže viesť k ochoreniam. Ako bolo publikované v literatúre, endotelín sa podieľa na celom rade ochorení. Tieto ochorenia zahrňujú hypertenziu, akútny infarkt myokardu, pulmonálnu hypertenziu, Raynaudov syndróm, cerebrálny angiospazmus, mŕtvicu, benígnu hypertrofiu prostaty, aterosklerózu a astmu (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Náture 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), Náture 365. 759 (1993), J. Mol. Celí. Cardiol. 27, A234 (1995); Cancer Research 56, 663 (1996)).Increased or excessive release of endothelin causes persistent vasoconstriction in peripheral, renal and cerebral blood vessels, which can lead to diseases. As reported in the literature, endothelin is involved in a variety of diseases. Such diseases include hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral angiospasm, stroke, benign prostate hypertrophy, atherosclerosis and asthma (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, 904 (1994), Nature 365. 759 (1993), J. Mol Cell, Cardiol 27, A234 (1995), Cancer Research 56, 663 (1996)).

Najmenej dva podtypy endotelínových receptorov, ETÄ a ETB receptory, boli opísané v literatúre (Náture 348, 730 (1990), Náture 348, 732 (1990)). V súlade s tým, látky, ktoré inhibujú viazanie endotelínu k týmto dvom receptorom by teda mohli antagonizovať fyziologické účinky endotelínu a mohli by byť preto hodnotnými liečivami.At least two endothelin receptor subtypes, ET A and ET B receptors, have been described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, agents that inhibit endothelin binding to these two receptors could therefore antagonize the physiological effects of endothelin and could therefore be valuable therapeutics.

WO 95/26716 opisuje zlúčeniny vzorca XX ako antagonisty endotelínového receptora.WO 95/26716 discloses compounds of formula XX as endothelin receptor antagonists.

Na rozdiel od toho, predmetom predloženého vynálezu je poskytnúť takzvané zmesné antagonisty endotelínového receptora. Zmesné antagonisty endotelínového receptora sa viažu približne s rovnakou afinitou ku ETA a ETB receptorom. Jestvuje tu približne rovnaká afinita pre receptory, ak pomer afinít ETA : ETB je väčší ako 0.05, výhodne väčší ako 0,1, a menší ako 20, výhodne menší ako 10.In contrast, it is an object of the present invention to provide so-called mixed endothelin receptor antagonists. Mixed endothelin receptor antagonists bind with approximately the same affinity for ET A and ET B receptors. There is approximately the same affinity for the receptors if the ratio of ET A : ET B affinities is greater than 0.05, preferably greater than 0.1, and less than 20, preferably less than 10.

Dokument DE 196364046.3 opisuje deriváty karboxylových kyselín, ktoré sa viažu s vysokou afinitou ku ETA receptoru a ku ETB receptoru. Jednou charakteristikou týchto zlúčenín je napríklad symetrická substitúcia s dvomi fenylovými kruhmi na β centrum. Teraz sme zistili, celkom prekvapujúco, že zmesné antagonisty receptora sa môžu získať dokonca pomocou nesymetrickej substitúcie β centra (napríklad metyl/fenyl).DE 196364046.3 discloses carboxylic acid derivatives that bind with high affinity to the ET A receptor and to the ET B receptor. For example, one characteristic of these compounds is the symmetric substitution with two phenyl rings at the β center. We have now found, quite surprisingly, that mixed receptor antagonists can be obtained even by asymmetric β-center substitution (e.g. methyl / phenyl).

Podstata vynálezuSUMMARY OF THE INVENTION

Vynález sa týka derivátov karboxylových kyselín všeobecného vzorca IThe invention relates to carboxylic acid derivatives of the general formula I

(D, kde substituenty majú nasledujúce významy:(D, wherein the substituents have the following meanings:

R1 znamená tetrazolyl alebo skupinuR 1 represents tetrazolyl or a group

kde R predstavujewherein R represents

a) zvyšok OR7, v ktorom R7 znamená:(a) a residue of OR 7 in which R 7 represents:

-3vodík, katión alkalického kovu, katión kovu alkalických zemín, fyziologicky prijateľný organický amóniový ión, ako je Ci-C4-alkylamónium alebo amóniový ión;-Hydrogen, an alkali metal cation, an alkaline earth metal cation, a physiologically acceptable organic ammonium ion, such as a C 1 -C 4 -alkylammonium or an ammonium ion;

C3-C8-cykloalkylovú skupinu, Ci-C8-alkylovú skupinu, CH2-fenylovú skupinu, ktorá môže byť substituovaná jedným alebo viacerými z nasledujúcich zvyškov, ako je: halogén, nitroskupina, kyanoskupina, Ci-C4-alkylová skupina, Ci-C4-halogénalkylová skupina, hydroxylová skupina, Ci-C4-alkoxylová skupina, merkaptoskupina, Ci-C4-alkyltioskupina, aminoskupina, karboxylová skupina, NH(Ci-C4-alkyl), N(Ci-C4alkyl)2;C 3 -C 8 -cycloalkyl, C 1 -C 8 -alkyl, CH 2 -phenyl which may be substituted by one or more of the following radicals, such as: halogen, nitro, cyano, C 1 -C 4 -alkyl, Ci-C 4 -haloalkyl, hydroxyl, Ci-C 4 -alkoxy, mercapto, C 4 -alkylthio, amino, carboxy, NH (Ci-C4 alkyl), N (Ci-C4 alkyl ) 2 ;

C3-C6-alkenylovú alebo C3-Ce-alkinylovú skupinu, pričom tieto skupiny môžu samotné niesť jeden až päť atómov halogénu;A C 3 -C 6 -alkenyl or C 3 -C 6 -alkynyl group, which groups may themselves carry one to five halogen atoms;

R7 môže tiež znamenať fenylový zvyšok, ktorý môže niesť jeden až päť atómov halogénu a/alebo jeden až tri z nasledujúcich zvyškov, ako je: nitroskupina, kyanoskupina, CrC4-alkylová skupina, Ci-C4-halogénalkylová skupina, hydroxylová skupina, Ci-C4-alkoxylová skupina, merkaptoskupina, Ci-C4-alkyltioskupina, aminoskupina, NH(Ci-C4-alkyl), N(Ci-C4-alkyl)2;R 7 may also be a phenyl radical which may carry one to five halogen atoms and / or one to three of the following radicals, such as: 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-členný heteroaromatický systém, ako je pyrolyl, pyrazolyl, imidazolyl a triazolyl, ktorý je viazaný prostredníctvom atómu dusíka a ktorý môže niesť jeden až dva atómy halogénu alebo jednu až dve Ci-C4-alkylovú skupiny alebo jednu až dve Ci-C4-alkoxylové skupiny;b) a 5-membered heteroaromatic system, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which is bonded via a nitrogen atom and which may carry one to two halogen atoms or one to two C 1 -C 4 -alkyl groups or one to two C 1 -C 4 -alkyl groups C 4 -alkoxy groups;

c) skupinu ‘fl’*.(c) the 'fl' group *.

“O“ (CH2)~S_ r , v ktorej k predstavuje hodnoty 0,1 a 2, p znamená hodnoty 1, 2, 3 a 4, a R8 predstavuje"O" (CH 2 ) - S - r in which k represents values of 0,1 and 2, p represents values of 1, 2, 3 and 4, and R 8 represents

Ci-C4-alkylovú skupinu, C3-C8-cykloalkylovú skupinu, C3-C6-alkenylovú skupinu, C3-C6-alkinylovú skupinu alebo fenylovú skupinu, ktorá môžeC 1 -C 4 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl or phenyl which may be

-4byť substituovaná jedným alebo viacerými, napríklad jedným až tromi z nasledujúcich zvyškov ako je: halogén, nitroskupina, kyanoskupina, Ci-C4-alkylová skupina, Ci-C4-halogénalkylová skupina, hydroxylová skupina, Ci-C4-alkoxylová skupina, Ci-C4-alkyltioskupina, merkaptoskupina, aminoskupina, karboxylová skupina, NH(C1-C4-alkyl), N(C;-C4alkyl)2;- be substituted with one or more, for example one to three, of the following radicals: halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, hydroxyl, C 1 -C 4 -alkoxy, C -C 4 -alkylthio, mercapto, amino, carboxy, NH (C 1 -C 4 alkyl), N (C, -C 4 alkyl) 2;

d) zvyšok o(d) the remainder by

—N“S”RN "S" R

H nH n

O v ktorom R9 znamená:O in which R 9 means:

Ci-C4-alkylovú skupinu, C3-C6-alkenylovú skupinu, C3-C6-alkinylovú skupinu, C3-C8-cykloalkylovú skupinu, Ci-C4-halogénalkylovú skupinu, pričom tieto zvyšky môžu niesť Ci-C4-alkoxylovú skupinu, Ci-C4-alkyltioskupinu a/alebo fenylový zvyšok, ako je uvedené pod c);Ci-C 4 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, C 4 -haloalkyl, where the radicals can carry a C-C A 4- alkoxy group, a C 1 -C 4 -alkylthio group and / or a phenyl radical as mentioned under c);

fenylovú skupinu, ktorá je prípadne substituovaná, ako je podrobne uvedené vyššie,a phenyl group optionally substituted as detailed above,

e) skupinu(e) the group

kde R13 a R14 môžu byť rovnaké alebo rozdielne a majú nasledujúce významy:wherein R 13 and R 14 may be the same or different and have the following meanings:

vodík, Ci-C8-alkylová skupina, C3-C8-cykloalkylová skupina, C3-C8alkenylová skupina, C3-C8-alkinylová skupina, benzylová skupina, fenylová skupina, ktorá môže niesť jeden až päť atómov halogénu a/alebo jeden až tri z nasledujúcich zvyškov, ako je: nitroskupina, kyanoskupina, Ci-C4-alkylová skupina, Ci-C4-halogénalkylová skupina, hydroxylová skupina, CrC4-alkoxylová skupina, merkaptoskupina, Cr C4-alkyltioskupina, aminoskupina, NH(CrC4-alkyl), N(Ci-C4-alkyl)2l hydrogen, C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 alkenyl, C 3 -C 8 -alkynyl, benzyl, phenyl, which may bear one to five halogen atoms and / or one to three of the following radicals: nitro, Ci-C 4 -alkyl, C 4 -haloalkyl, hydroxyl, -C 4 -alkoxy, mercapto, C r C 4 -alkylthio , amino, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 21

-5alebo R13 a R14 spolu tvoria C4-C7-alkylénový reťazec, ktorý je uzatvorený do kruhu a môže byť substituovaný Ci-C4-alkylovou skupinou a v ktorom môže byť jedna alkylénová skupina nahradená kyslíkom, sírou alebo dusíkom, ako je -(CH2)4-, -(CH2)5-, -(CH2)6-, (CH2)2-O-(CH2)2-, -(CH2)7-, -CH2-S-(CH2)2-, -CH2-NH-(CH2)2-, -(CH2)2-N(CH2)2-;-5 or R 13 and R 14 together form a C 4 -C 7 -alkylene chain which is ring-closed and may be substituted with a C 1 -C 4 -alkyl group and in which one alkylene group may be replaced by oxygen, sulfur or nitrogen, such as - (CH 2 ) 4 -, - (CH 2 ) 5 -, - (CH 2 ) 6 -, (CH 2 ) 2 -O- (CH 2 ) 2 -, - (CH 2 ) 7 -, -CH 2 - S- (CH 2 ) 2 -, -CH 2 -NH- (CH 2 ) 2 -, - (CH 2 ) 2 -N (CH 2 ) 2 -;

R2 znamená vodík, hydroxylovú skupinu, NH2, NH(CrC4-alkyl), N(CrC4alkyl)2, halogén, CrC^alkylovú skupinu, C2-C4-alkenylovú skupinu, C2C4-alkinylovú skupinu, Ci-C4-hydroxyalkylovú skupinu, Ci-C4-halogénalkylovú skupinu, Ci-C4-alkoxylovú skupinu, Ci-C4-halogénalkoxylovú skupinu alebo Ci-C4-alkyltioskupinu, alebo CRZ je viazaný ku CR10 ako je uvedené nižšie, za vzniku 5- alebo 6-členného kruhu;R 2 is H, OH, NH2, NH (Ci-C4 alkyl), N (Ci-C4 alkyl) 2, halo, -C ^ alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl , C 4 -hydroxyalkylovú group, a Ci-C 4 -haloalkyl, C 4 -alkoxy, C 4 -halogénalkoxylovú group or a Ci-C4 alkylthio, or CR, Z is linked to CR 10 as shown below to form a 5- or 6-membered ring;

X predstavuje dusík alebo metín;X represents nitrogen or methine;

Y znamená dusík alebo metín;Y is nitrogen or methine;

Z predstavuje dusík alebo skupinu CR10, v ktorom R10 znamená vodík, halogén, hydroxylovú skupinu, Ci-C4-halogénalkylovú skupinu alebo CiC4-alkylovú skupinu, alebo CR10 tvorí spolu s CR2 alebo CR35- alebo 6členný alkylénový alebo alkenylénový kruh, ktorý môže byť substituovaný jednou alebo dvomi Ci.C4.alkylovými skupinami a v ktorom v každom prípade jedna alebo viac metylénových skupín môže byť nahradených kyslíkom, sírou, skupinou -NH alebo N(Ci-C4-alkyl);Z represents nitrogen or CR 10 in which R 10 represents hydrogen, halogen, hydroxyl, C 1 -C 4 -haloalkyl or C 1 -C 4 -alkyl, or CR 10 together with CR 2 or CR 3 forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted one to two Ci.C 4 .alkylovými groups and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, -NH or N (C-C4 alkyl);

najmenej jeden z členov kruhu X, Y alebo Z znamená dusík;at least one of the ring members X, Y or Z is nitrogen;

R3 predstavuje vodík, hydroxylovú skupinu, NH2t NHíC^C^alkyl), N(CrC4alkyl)2, halogén, Ci-C4-alkylovú skupinu, C2-C4-alkenylovú skupinu, C2C4-alkinylovú skupinu, CrC4-halogénalkylovú skupinu, Ci-C4-alkoxylovú skupinu, Ci-C4-halogénalkoxylovú skupinu, Ci-C4-hydroxyalkylovú skupinu, Ci-C4-alkyltioskupinu alebo CR3 je viazaný ku CR10 ako je uvedené vyššie, za vzniku 5- alebo 6-členného kruhu;R 3 is H, OH, NH 2 t NHíC C ^ alkyl), N (C r C 4 alkyl) 2, halogen, Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 C 4 -alkynyl, C r C 4 -haloalkyl, C 4 -alkoxy, C 4 -halogénalkoxylovú group, C 4 -hydroxyalkylovú group, a Ci-C 4 alkylthio, or CR3 is linked to CR10 as above, to form a 5- or 6-membered ring;

R4 znamená Ci-C4-alkylovú skupinu, C2-C4-alkenylovú skupinu alebo C2-C4alkinylovú skupinu, ktorá môže byť substituovaná jedným aleboR 4 represents a C 1 -C 4 -alkyl group, a C 2 -C 4 -alkenyl group or a C 2 -C 4 alkynyl group which may be substituted by one or more

-6viacerými z nasledujúcich zvyškov, ako je: halogén, kyanoskupina, hydroxylová skupina, merkaptoskupina, C1-C4-alkoxylová skupina, fenoxyskupina, karboxylová skupina, Ci-C4-halogénalkoxylová skupina,-6more of the following moieties such as: halogen, cyano, hydroxyl, mercapto, C 1 -C 4 -alkoxy, phenoxy, carboxyl, C 1 -C 4 -haloalkoxy,

CrC4-alkyltio-skupina, aminoskupina, NH(Ci-C4-alkyl), N(CrC4-alkyl)2 alebo alkylkarbonylová skupina;C 1 -C 4 -alkylthio, amino, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 or alkylcarbonyl;

Ci-C4-alkylovú skupinu, C2-C4-alkenylovú skupinu alebo C2-C4alkinylovú skupinu, ktorá je pripojená k R5 pomocou priamej väzby, metylénovej, etylénovej alebo etenylénovej skupiny, atóm kyslíka alebo síry alebo SO2, NH alebo N-alkylovú skupinu;A C 1 -C 4 -alkyl group, a C 2 -C 4 -alkenyl group or a C 2 -C 4 alkynyl group which is attached to R 5 by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or SO 2 , NH or N-alkyl;

R5 predstavuje fenylovú alebo naftylovú skupinu, z ktorých každá môže byť substituovaná jedným alebo viacerými z nasledujúcich zvyškov, ako je: halogén, nitroskupina, kyanoskupina, hydroxylová skupina, merkaptoskupina, Ci-C4-alkylová skupina, C2-C4-alkenylová skupina, C1-C4hydroxyalkylová skupina, C2-C4-alkinylová skupina, Ci-C4-halogénalkylová skupina, Ci-C4-alkoxylová skupina, fenoxyskupina, karboxylová skupina, Ci-C4-halogénalkoxylová skupina, Ci-C4-alkyltioskupina, aminoskupina, NH(Ci-C4-alkyl), N(Ci-C4-alkyl)2 alebo fenylová skupina, ktorá môže byť substituovaná, jedenkrát alebo viackrát, napríklad jedenkrát až trikrát, substituentom, ako je: halogén, nitroskupina, kyanoskupina, Ci-C4-alkylová skupina, Ci-C4-halogénalkylová skupina, CrC4-alkoxylová skupina, CrC4-halogénalkoxylová skupina alebo Cr C4-alkyltioskupina; alebo fenylovú alebo naftylovú skupinu, ktorá je pripojená v orto-polohe ku R4 pomocou priamej väzby, metylénovej, etylénovej alebo etenylénovej skupiny, atómu kyslíka alebo síry alebo SO2, NH alebo N-alkylovej skupiny;R 5 represents a phenyl or naphthyl group, each of which may be substituted by one or more of the following radicals, such as: halogen, nitro, cyano, hydroxyl, mercapto, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl C 1 -C 4 -hydroxyalkyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, phenoxy, carboxyl, 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 a phenyl group which may be substituted one or more times, for example one to three times, with a substituent such as: 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 -alkylthio; or a phenyl or naphthyl group which is attached at the ortho-position to R 4 by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group;

C3-C8-cykloalkylovú skupinu;C 3 -C 8 -cycloalkyl;

R6 znamená C3.C8.cykloalkylovú skupinu, pričom tieto zvyšky môžu byť v každom prípade substituované, jedenkrát alebo viackrát, substituentom, ako je: halogén, hydroxylová skupina, merkaptoskupina,R 6 represents a C 3 -C 8 cycloalkyl group, which radicals may in each case be substituted, one or more times, with a substituent such as: halogen, hydroxyl, mercapto,

-7karboxylová skupina, nitroskupina, kyanoskupina, Ci-C4-alkoxylová skupina, Ci-C4-alkylová skupina, C2-C4-alkenylová skupina, C2-C4alkinylová skupina, C3-C6-alkenyloxylová skupina, C3-C6-alkinyloxylová skupina, Ci-C4-alkyltio-skupina, Ci-C4-halogénalkoxylová skupina, Cr C4-alkylkarbonylová skupina, Ci-C4-alkoxykarbonylová skupina, C3-C8alkylkarbonylalkylová skupina, NH(Ci-C4-alkyl), N(Ci-C4-alkyl)2, alebo fenylová skupina, ktorá môže substituovaná, jedenkrát alebo viackrát, napríklad jedenkrát až trikrát substituentom, ako je: halogén, nitroskupina, kyanoskupina, Ci-C4-alkylová skupina, Ci-C4-halogénalkylová skupina, Ci-C4-alkoxylová skupina, Ci-C4-halogénalkoxylová skupina alebo Ci-C4-alkyltioskupina;-7karboxylová, nitro, cyano, Ci-C4 alkoxy group, Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 -alkenyloxylová group, C 3 -C 6 -alkyloxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 3 -C 8 alkylcarbonylalkyl, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 , or a phenyl group which may be substituted one or more times, for example one to three times with a substituent such as: halogen, nitro, cyano, C 1 -C 4 4 -alkyl, C 4 -haloalkyl group, a Ci-C 4 -alkoxy, C 4, or C -halogénalkoxylová -C 4 -alkylthio;

fenylovú alebo naftylovú skupinu, z ktorých každá môže niesť jeden alebo viac z nasledujúcich zvyškov, ako je: halogén, R15, nitroskupina, merkaptoskupina, karboxylová skupina, kyanoskupina, hydroxylová skupina, aminoskupina, CrC4-alkylová skupina, C2-C4-alkenylová skupina, C2-C4-alkinylová skupina, C3-C6-alkenyloxylová skupina, Ci-C4halogénalkylová skupina, C3-C6-alkinyloxylová skupina, CrC^alkylkarbonylová skupina, Ci-C4-alkoxykarbonylová skupina, Ci-C4alkoxylová skupina, CrC4-halogénalkoxylová skupina, fenoxyskupina, Ci-C4-alkyltioskupina, NH(Ci-C4-alkyl), N(Ci-C4-alkyl)2, metyléndioxylová skupina, etyléndioxylová skupina alebo fenylová skupina, ktorá môže byť substituovaná, jedenkrát alebo viackrát, napríklad jedenkrát až trikrát, substituentom ako je: halogén, nitroskupina, kyanoskupina, Cr C4-alkylová skupina, CrC4-halogénalkylová skupina, CrC4-alkoxylová skupina, Ci-C4-halogénalkoxylová skupina alebo Ci-C4-alkyltioskupina, pod podmienkou, že ak R6 znamená nesubstituovaný fenylový zvyšok, R2 a R3 nemôžu obidva znamenať OCH3;a phenyl or naphthyl group, each of which may bear one or more of the following radicals such as: halogen, R 15 , nitro, mercapto, carboxyl, cyano, hydroxyl, amino, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl , C2-C4-alkynyl, C3-C6-alkenyloxy, C1-C4haloalkyl, C3-C6-alkynyloxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4alkoxy, C1-C4-haloalkoxy, phenoxy , C1-C4-alkylthio, NH (C1-C4-alkyl), N (C1-C4-alkyl) 2, methylenedioxyl, ethylenedioxyl or phenyl, which may be substituted one or more times, for example one to three times, by a substituent such as: 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 -alkylthio, below the number provided that when R 6 is an unsubstituted phenyl radical, R 2 and R 3 cannot both represent OCH 3;

päť- alebo šesť-členný heteroaromatický systém, ktorý obsahuje jeden až tri atómy dusíka a/alebo jeden atóm síry alebo kyslíka a ktorý môže niesť jeden až štyri atómy halogénu a/alebo jeden až dva z nasledujúcich zvyškov, ako je: Ci-C4-alkylová skupina, C2-C4alkenylová skupina, CrC4-halogénalkylová skupina, Ci-C4-alkoxylováa five- or six-membered heteroaromatic system which contains one to three nitrogen atoms and / or one sulfur or oxygen atom and which may bear one to four halogen atoms and / or one to two of the following residues, such as: C 1 -C 4 -alkyl, C 2 -C 4 alkenyl group, -C 4 -haloalkyl group, a C 4 -alkoxy-C

-8skupina, Ci-C4-halogén-alkoxylová skupina, Ci-C4-alkyltioskupina, fenylová skupina alebo fenoxyskupina, pričom fenylové zvyšky môžu samotné niesť jeden až päť atómov halogénu a/alebo jeden až tri z nasledujúcich zvyškov, ako je: Ci-C4-alkylová skupina, Ci-C4-halogénalkylová skupina, Ci-C4-alkoxylová skupina, Ci-C4-halogénalkoxylová skupina a/alebo Ci-C4-alkyltioskupina;-8skupina, C -C 4 -halo-alkoxy, Ci-C4 -alkylthio, phenyl or phenoxy, where the phenyl radicals in turn to carry one to five halogen atoms and / or one to three of the following radicals: C -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and / or C 1 -C 4 -alkylthio;

R15 predstavuje Ci-C4-alkylovú skupinu, Ci-C4-alkyltioskupinu, Ci-C4alkoxylovú skupinu, ktoré nesú jeden z nasledujúcich zvyškov, ako je: hydroxylová skupina, karboxylová skupina, aminoskupina, NH(Ci-C4alkyl), N(Ci-C4-alkyl)2, karbamoylová skupina alebo CON(Ci-C4-alkyl)2;R 15 represents a C 1 -C 4 -alkyl group, a C 1 -C 4 -alkylthio group, a C 1 -C 4 alkoxy group bearing one of the following radicals such as: hydroxyl, carboxyl, amino, NH (C 1 -C 4 alkyl) ), N (Ci-C4 alkyl) 2, carboxamide or CON (Ci-C4 alkyl) 2;

W predstavuje síru alebo kyslík;W represents sulfur or oxygen;

Q znamená spacer, ktorý svojou dĺžkou zodpovedá C2.C4-reťazcu.Q is a spacer, which in length corresponds to C 2 .C 4 -reťazcu.

Funkciou Q je vytvoriť definovanú vzdialenosť medzi skupinami R6 a W v zlúčeninách vzorca I. Vzdialenosť by mala zodpovedať dĺžke C2-C4alkylového reťazca. Toto sa dá dosiahnuť s veľkým počtom chemických zvyškov, napríklad so zvyškami, ako je C2-C4-alkylén, C3-C4-alkenylén, C3-C4-alkinylén, -S-CH2-CH2-, -O-CH2-CH2-, -N-CO-CH2-, -CO-N-CH2CH2-, -CO-N(Ci-C4-alkyl)-CH2-CH2-, SO2-N(Ci-C4-alkyl)-CH2-CH2-, SO2NH-CH2-CH2-, pričom tieto zvyšky môžu byť v každom prípade substituované, jedenkrát alebo viackrát, substituentom, ako je: halogén, hydroxylová skupina, merkaptoskupina, Ci-C4-alkylová skupina, C2-C4alkenylová skupina, C2-C4-alkinylová skupina, karboxylová skupina, nitroskupina, kyanoskupina, CrC4-alkoxylová skupina, C3-C6-alkenyloxyskupina, C3-C6-alkinyloxylová skupina, Ci-C4-alkyltio-skupina, Ci-C4halogénalkoxylová skupina, Ci-C4-alkylkarbonylová skupina, Ci-C4alkoxykarbonylová skupina, C3-C8-alkylkarbonylalkylová skupina, NH(Ci-C4-alkyl), N(C1-C4-alkyl)2, fenylová skupina, ktorá môže byť substituovaná, jedenkrát alebo viackrát, napríklad jedenkrát až trikrát, substituentom, ako je: halogén, nitroskupina, kyanoskupina, Ci-C4alkylová skupina, CrC4-halogénalkylová skupina, Ci-C4-alkoxylová skupina, Ci-C4-halogénalkoxylová skupina alebo CrC4-alkyltioskupina;The function of Q is to create a defined distance between the groups R 6 and W in the compounds of formula I. The distance should correspond to the length of the C 2 -C 4 alkyl chain. This can be achieved with a large number of chemical radicals, for example, with groups such as C 2 -C 4 alkylene, C 3 -C 4 alkenylene, C 3 -C 4 -alkinylén, -S-CH 2 -CH 2 -, -O-CH 2 -CH 2 -, -N-CO-CH 2 -, -CO-N-CH 2 CH 2 -, -CO-N (C 1 -C 4 -alkyl) -CH 2 -CH 2 -, SO 2 -N (C 1 -C 4 -alkyl) -CH 2 -CH 2 -, SO 2 NH-CH 2 -CH 2 -, wherein these radicals may in each case be substituted, one or more times, with a substituent such as: halogen, hydroxyl, mercapto, C 1 -C 4 -alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, carboxyl, nitro, cyano, C 1 -C 4 -alkoxy, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkynyloxy, C 1 -C 4 -alkylthio, C 1 -C 4 haloalkoxy, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, C 3 -C 8 -alkylcarbonylalkyl, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 , a phenyl group which may be substituted once or several times, for example one to three times, with a substituent such as: halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or CrC 4 - alkylthio;

-9alebo spacer Q predstavuje časť 5-7-členného kruhu, heterocyklického alebo karbocyklického, ku ktorému je R6 kondenzované.-9alebo spacer Q is part of a 5-7 membered ring, heterocyclic or carbocyclic, to which R6 is fused.

Pre tieto a v ďalšom uvedené platia nasledujúce definície:The following definitions apply to these and the following:

alkalickým kovom je napríklad lítium, sodík, draslík;an alkali metal is, for example, lithium, sodium, potassium;

kovom alkalickej zeminy je napríklad vápnik, horčík, bárium;an alkaline earth metal is, for example, calcium, magnesium, barium;

C3-C8-cykloalkylovou skupinou je napríklad cyklopropyl, cyklobutyl, cyklopentyl, cyklohexyl, cykloheptyl alebo cyklooktyl;C 3 -C 8 -cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;

Ci-C4-halogénalkylová skupina môže byť lineárna alebo rozvetvená, ako je napríklad fluórmetyl, difluórmetyl, trifluórmetyl, chlórdifluórmetyl, dichlórfluórmetyl, trichlórmetyl, 1-fluóretyl, 2-fluóretyl, 2,2-difluóretyl, 2,2,2-trifluóretyl, 2-chlór-2,2difluóretyl, 2,2-dichlór-2-fluóretyl, 2,2,2-trichlóretyl alebo pentafluóretyl;Ci-C 4 -haloalkyl can be linear or branched such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl;

Ci-C4-halogénalkoxylová skupina môže byť lineárna alebo rozvetvená, ako je napríklad difluórmetoxy, trifluórmetoxy, chlórdifluórmetoxy, 1-fluóretoxy, 2,2difluóretoxy, 1,1,2,2-tetrafluóretoxy, 2,2,2-trifluóretoxy, 2-chlór-1,1,2-trifluóretoxy, 2-f luóretoxy alebo pentafluóretoxy;The C 1 -C 4 -haloalkoxy group may be linear or branched, such as, for example, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2- chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;

Ci-C4-alkylová skupina môže byť lineárna alebo rozvetvená, ako je napríklad metyl, etyl, 1-propyl, 2-propyl, 2-metyl-2-propyl, 2-metyl-1-propyl, 1-butyl alebo 2butyl;The C 1 -C 4 -alkyl group may be linear or branched, such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;

C2-C4-alkenylová skupina môže byť lineárna alebo rozvetvená, ako je napríklad etenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-metyl-1-propenyl, 1-butenyl alebo 2-butenyl;C 2 -C 4 -alkenyl group may be linear or branched, such as ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl , 1-butenyl or 2-butenyl;

C2-C4-alkinylová skupina môže byť lineárna alebo rozvetvená, ako je napríklad etinyl, 1-propin-1-yl, 1-propin-3-yl, 1-butin-4-yl alebo 2-butin-4-yl;C 2 -C 4 -alkynyl can be linear or branched such as ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl ;

Ci-C4-alkoxylová skupina môže byť lineárna alebo rozvetvená, ako je napríklad metoxy, etoxy, propoxy, 1-metyletoxy, butoxy, 1-metylpropoxy, 2-metylpropoxy alebo 1,1-dimetyletoxy;The C 1 -C 4 -alkoxy group may be linear or branched, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;

C3-C6-alkenyloxylová skupina môže byť lineárna alebo rozvetvená, ako je napríklad alyloxy, 2-buten-1-yloxy alebo 3-buten-2-yloxy;The C 3 -C 6 -alkenyloxy group may be linear or branched, such as allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;

-10Ci-C4-hydroxyalkylová skupina môže byť lineárna alebo rozvetvená, ako je napríklad hydroxymetyl, 2-hydroxyetyl;The -10C 1 -C 4 -hydroxyalkyl group may be linear or branched, such as hydroxymethyl, 2-hydroxyethyl;

C3-C6-alkinyloxylová skupina môže byť lineárna alebo rozvetvená, ako je napríklad 2-propin-1-yloxy, 2-butin-1-yloxy alebo 3-butin-2-yloxy;The C 3 -C 6 -alkynyloxy group may be linear or branched, such as 2-propyn-1-yloxy, 2-butin-1-yloxy or 3-butin-2-yloxy;

Ci-C4-alkyltioskupina môže byť lineárna alebo rozvetvená, ako je napríklad metyltio, etyltio, propyltio, 1-metyletyItio, butyltio, 1-metylpropyltio, 2-metylpropyltio alebo 1,1 -d imety lety Itio;The C 1 -C 4 -alkylthio group may be linear or branched, such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethyl Itio;

Ci-C4-alkylkarbonylová skupina môže byť lineárna alebo rozvetvená, ako je napríklad acetyl, etylkarbonyl alebo 2-propylkarbonyl;The C 1 -C 4 -alkylcarbonyl group may be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl;

Ci-C4-alkoxykarbonylová skupina môže byť lineárna alebo rozvetvená, ako je napríklad metoxykarbonyl, etoxykarbonyl, n-propoxykarbonyl, /-propoxykarbonyl alebo n-butoxykarbonyl;The C 1 -C 4 -alkoxycarbonyl group may be linear or branched, such as, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-propoxycarbonyl or n-butoxycarbonyl;

C3-C8-alkylkarbonylalkylová skupina môže byť lineárna alebo rozvetvená, ako je napríklad 2-oxo-1-propyl, 3-oxo-1-butyl alebo 3-oxo-2-butyl;The C 3 -C 8 -alkylcarbonylalkyl group may be linear or branched, such as 2-oxo-1-propyl, 3-oxo-1-butyl or 3-oxo-2-butyl;

CrCs-alkylová skupina môže byť lineárna alebo rozvetvená, ako je napríklad Cr C4-alkyl, pentyl, hexyl, heptyl alebo oktyl;CRCs-alkyl can be linear or branched such as C r C 4 alkyl, pentyl, hexyl, heptyl or octyl;

Halogénom je napríklad fluór, chlór, bróm, jód.Halogen is, for example, fluorine, chlorine, bromine, iodine.

Vynález sa ďalej týka takých zlúčenín, z ktorých sa zlúčeniny vzorca I môžu uvoľňovať (takzvané prekurzory).The invention further relates to such compounds from which the compounds of formula I can be released (so-called precursors).

Výhodné sú také prekurzory, v ktorých uvoľňovanie nastáva pri podmienkach, ktoré prevažujú v určitých častiach tela, napríklad v žalúdku, v črevách, v krvnom riečišti alebo v pečeni.Preferred are those precursors in which release occurs under conditions that predominate in certain parts of the body, for example, in the stomach, intestines, bloodstream, or liver.

Zlúčeniny a tiež medziprodukty na ich prípravu, ako sú napríklad zlúčeniny vzorca II, III a IV, môžu obsahovať jeden alebo viac asymetricky substituovaných atómov uhlíka. Zlúčeniny tohto typu môžu jestvovať ako čisté enantioméry alebo čisté diastereoizoméry alebo ako ich zmes. Výhodné je použitie enantiomérne čistej alebo diastereoizomérne čistej zlúčeniny ako účinnej zložky.The compounds as well as intermediates for their preparation, such as compounds of formulas II, III and IV, may contain one or more asymmetrically substituted carbon atoms. Compounds of this type may exist as pure enantiomers or pure diastereoisomers or as a mixture thereof. The use of an enantiomerically pure or diastereomerically pure compound as an active ingredient is preferred.

-11 Príprava takýchto zlúčenín je opísaná v príkladoch.The preparation of such compounds is described in the Examples.

Vynález sa ďalej týka použitia vyššie uvedených derivátov karboxylových kyselín na prípravu liečiv, predovšetkým na prípravu inhibítorov pre ETA a ETB receptory. Zlúčeniny podľa predloženého vynálezu sú predovšetkým vhodné ako zmesné antagonisty, ako je definované v úvode.The invention further relates to the use of the aforementioned carboxylic acid derivatives for the preparation of medicaments, in particular for the preparation of inhibitors for ET A and ET B receptors. The compounds of the present invention are particularly useful as mixed antagonists as defined in the introduction.

Zlúčeniny všeobecného vzorca IV, v ktorom W znamená síru alebo kyslík, sa môžu pripraviť tiež v enantiomérne čistej forme, ako je opísané v dokumentoch WO 96/11914 alebo DE 19636046.3.Compounds of formula IV in which W is sulfur or oxygen can also be prepared in enantiomerically pure form as described in WO 96/11914 or DE 19636046.3.

Zlúčeniny všeobecného vzorca III sú buď známe alebo sa môžu syntetizovať napríklad redukciou zodpovedajúcich karboxylových kyselín alebo ich esterov alebo s použitím Ďalších všeobecne známy metód.Compounds of formula (III) are either known or can be synthesized, for example, by reduction of the corresponding carboxylic acids or esters thereof, or using other generally known methods.

R—Q-W (IV)R - Q - W (IV)

RR

HH

--C-‘OH 1 1--C - OH 1 1

R RR R

Ďalšou možnosťou na získanie enantiomérne čistých zlúčenín vzorca IV je uskutočnenie klasického racemického rozlíšenia s racemickými alebo diastereoizomérnymi zlúčeninami vzorca IV s použitím vhodných enantiomérne čistých zásad. Vhodnými zásadami tohto typu sú napríklad 4-chlórfenyletylamín a zásady uvedené v dokumente WO 96/11914.Another possibility to obtain enantiomerically pure compounds of formula IV is to perform classical racemic resolution with racemic or diastereomeric compounds of formula IV using suitable enantiomerically pure bases. Suitable bases of this type are, for example, 4-chlorophenylethylamine and those disclosed in WO 96/11914.

Zlúčeniny podľa predloženého vynálezu, v ktorých substituenty majú významy uvedené definované pod všeobecným vzorcom I, sa môžu pripraviť napríklad reakciou derivátov karboxylových kyselín vzorca IV, v ktorom substituenty majú definované významy, so zlúčeninami všeobecného vzorca V.The compounds of the present invention in which the substituents have the meanings defined in the general formula I can be prepared, for example, by reacting the carboxylic acid derivatives of the formula IV in which the substituents have the defined meanings with the compounds of the general formula V.

(1)( 1 )

-12Vo vzorci V, R11 znamená halogén alebo R12-SO2-, pričom R12 môže predstavovať Ci-C4-alkylovú, Ci-C4-halogénalkylovú alebo fenylovú skupinu. Okrem toho, najmenej jeden z členov kruhu X alebo Y alebo Z znamená dusík. Reakcia sa výhodne uskutočňuje v inertnom rozpúšťadle alebo riedidle s prídavkom vhodnej zásady, t.j. zásady, ktorá deprotónuje medziprodukt vzorca IV, pri teplote v rozsahu od laboratórnej teploty po teplotu varu rozpúšťadla.In formula V, R 11 is halogen or R 12 -SO 2 -, wherein R 12 can be C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl or phenyl. In addition, at least one of the ring members X or Y or Z is nitrogen. The reaction is preferably carried out in an inert solvent or diluent with the addition of a suitable base, i.e. a base which deprotonates the intermediate of formula IV, at a temperature ranging from room temperature to the boiling point of the solvent.

Zlúčeniny typu I, kde R1 = COOH, sa okrem toho môžu získať priamo, ak sa medziprodukt vzorca IV, v ktorom R1 znamená COOH, deprotónuje s dvomi ekvivalentmi vhodnej zásady a nechá sa reagovať so zlúčeninami všeobecného vzorca V. Táto reakcia sa taktiež uskutočňuje v inertnom rozpúšťadle a pri teplote v rozsahu od laboratórnej teploty po teplotu varu rozpúšťadla.The compounds of type I where R1 = COOH can furthermore be obtained directly if the intermediate of formula IV in which R1 is COOH is deprotonated with two equivalents of a suitable base and reacted with compounds of the formula V. This reaction also The reaction is carried out in an inert solvent and at a temperature ranging from room temperature to the boiling point of the solvent.

Príkladmi takýchto rozpúšťadiel alebo riedidiel sú alifatické, alicyklické a aromatické uhľovodíky, z ktorých každý môže byť prípadne chlórovaný, ako je napríklad hexán, cyklohexán, petroléter, nafta, benzén, toluén, xylén, metylénchlorid, chloroform, tetrachlorid uhličitý, etylchlorid a trichlóretylén, étery, ako je diizopropyléter, dibutyléter, metylterc-butyléter, propylénoxid, dioxán a tetrahydrofurán, nitrily, ako je acetonitril a propionitril, amidy, ako je dimetylformamid, dimetylacetamid a N-metylpyrolidón, sulfoxidy a sulfóny, ako je dimetylsulfoxid a sulfolán.Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may optionally be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichlorethylene, etichlorethylene such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones such as dimethylsulfoxide and sulfol.

Zlúčeniny vzorca V sú známe, niektoré z nich sú komerčne dostupné alebo sa môžu pripraviť všeobecne známym spôsobom.The compounds of formula (V) are known, some of which are commercially available or can be prepared in a manner known per se.

Ako zásada sa môže použiť hydrid alkalického kovu alebo kovu alkalickej zeminy, ako je hydrid sodný, hydrid draselný alebo hydrid vápenatý, uhličitan, ako je uhličitan alkalického kovu, napríklad uhličitan sodný alebo draselný, hydroxid alkalického kovu alebo kovu alkalickej zeminy, ako je hydroxid sodný alebo hydroxid draselný, organokovová zlúčenina, ako je butyllítium alebo amid alkalického kovu, ako je diizopropylamid lítny alebo amid lítny.As the base, an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as an alkali metal carbonate such as sodium or potassium carbonate, an alkali metal or an alkaline earth metal hydroxide such as sodium hydroxide can be used. or potassium hydroxide, an organometallic compound such as butyllithium or an alkali metal amide such as lithium diisopropylamide or lithium amide.

Zlúčeniny vzorca I sa môžu tiež pripraviť tak, že sa vychádza zo zodpovedajúcich karboxylových kyselín, t.j. zlúčenín vzorca I, v ktorom R1 znamenáCompounds of formula I may also be prepared starting from the corresponding carboxylic acids, ie compounds of formula I, wherein R 1 is

COOH, a najskôr sa konvertujú zvyčajným spôsobom na aktivovanú formu, ako je halogenid kyseliny, anhydrid kyseliny alebo imidazolid kyseliny, a táto sa potomCOOH, and first converted in the usual manner to an activated form such as an acid halide, acid anhydride or acid imidazolide, and this is then

-13nechá reagovať s vhodnou hydroxylovou zlúčeninou HOR7. Táto reakcia sa môže uskutočňovať v konvenčných rozpúšťadlách a často vyžaduje pridanie zásady, pričom v takomto prípade sú vhodné vyššie uvedené zásady. Tieto dva kroky sa môžu tiež zjednodušiť, napríklad tak, že sa na karboxylovú kyselinu nechá pôsobiť hydroxylová zlúčenina v prítomnosti dehydratačného činidla, ako je karbodiimid.13 does not react with the appropriate hydroxyl compound HOR 7 . This reaction can be carried out in conventional solvents and often requires the addition of a base, in which case the abovementioned bases are suitable. These two steps can also be simplified, for example by treating the carboxylic acid with a hydroxyl compound in the presence of a dehydrating agent such as carbodiimide.

Ďalej je tiež možné pripraviť zlúčeniny vzorca I tak, že sa vychádza zo solí zodpovedajúcich karboxylových kyselín, t.j. zo zlúčenín vzorca I, v ktorých R1 znamená skupinu COOM, kde M môže predstavovať katión alkalického kovu alebo ekvivalent katiónu kovu alkalickej zeminy. Tieto soli sa môžu reagovať s mnohými zlúčeninami vzorca R-A, kde A znamená konvenčnú nukleofúgnu odstupujúcu skupinu, napríklad halogén, ako je chlór, bróm, jód, alebo ak je to vhodné, halogénom, alkylom alebo halogénalkylom substituovaný arylsulfonyl alebo alkylsulfonyl, ako je napríklad toluénsulfonyl a metylsulfonyl, alebo iná ekvivalentná odstupujúca skupina. Zlúčeniny vzorca R-A, ktoré obsahujú reaktívny substituent A, sú známe alebo sa môžu ľahko pripraviť s použitím poznatkov, ktoré sú pre odborníkov všeobecne známe. Táto reakcia sa môže uskutočňovať v konvenčných rozpúšťadlách a výhodne sa uskutočňuje s pridaním zásady, pričom v takomto prípade sú vhodné vyššie uvedené zásady.Furthermore, it is also possible to prepare compounds of formula I starting from salts of the corresponding carboxylic acids, ie compounds of formula I in which R 1 represents a COOM group, where M may be an alkali metal cation or an alkaline earth metal cation equivalent. These salts can be reacted with a number of compounds of formula RA, wherein A is a conventional nucleofusion leaving group, for example, halogen such as chlorine, bromine, iodine or, where appropriate, halogen, alkyl or haloalkyl substituted arylsulfonyl or alkylsulfonyl such as toluenesulfonyl and methylsulfonyl, or another equivalent leaving group. Compounds of formula RA which contain a reactive substituent A are known or can be readily prepared using the knowledge generally known to those skilled in the art. This reaction can be carried out in conventional solvents and preferably is carried out with the addition of a base, in which case the abovementioned bases are suitable.

V niektorých prípadoch je potrebné použiť na prípravu zlúčenín vzorca I podľa vynálezu všeobecne známe metódy s použitím chrániacich skupín. Napríklad ak R6 znamená 4-hydroxyfenyl, hydroxylová skupina sa môže na začiatku chrániť ako benzyléter, ktorý sa potom vo vhodnom stupni reakčného postupu odštiepi.In some cases, it is necessary to use generally known methods using protecting groups for the preparation of the compounds of formula I according to the invention. For example, when R 6 is 4-hydroxyphenyl, the hydroxyl group may initially be protected as a benzyl ether, which is then cleaved off at a suitable stage in the reaction process.

Zlúčeniny vzorca I, v ktorom R1 znamená tetrazol, sa môžu pripraviť ako je opísané v dokumente WO 96/11914.Compounds of formula I wherein R 1 is tetrazole can be prepared as described in WO 96/11914.

Z hľadiska biologického účinku, výhodnými derivátmi karboxylových kyselín všeobecného vzorca I, buď ako čisté enantioméry alebo ako čisté diastereoizoméry alebo ich zmesi, sú také deriváty, v ktorých substituenty majú nasledujúce významy:In terms of biological activity, preferred derivatives of the carboxylic acids of formula I, either as pure enantiomers or as pure diastereoisomers or mixtures thereof, are those derivatives in which the substituents have the following meanings:

-14R2 znamená vodík, hydroxylovú skupinu, halogén, N(Ci-C4-alkyl)2, Ci-C4alkyl, Ci-C4-alkoxylovú skupinu, Ci-C4-alkyltioskupinu, Ci-C4-halogénalkylovú skupinu, Ci-C4-halogénalkoxylovú skupinu alebo CR2 je pripojený ku CR10, ako je uvedené nižšie, za vzniku 5- alebo 6-členného kruhu;-14R 2 is H, OH, halogen, N (Ci-C4 alkyl) 2, Ci-C4 alkyl, Ci-C 4 -alkoxy, C 4 alkylthio, C 4 -haloalkyl C 1 -C 4 -haloalkoxy or CR 2 is attached to CR 10 as shown below to form a 5- or 6-membered ring;

X predstavuje dusík alebo metín;X represents nitrogen or methine;

Y znamená dusík alebo metín;Y is nitrogen or methine;

Z predstavuje dusík alebo skupina CR10, v ktorom R10 znamená vodík, halogén, Ci-C4-halogénalkylovú skupinu alebo CrC4-alkylovú skupinu, alebo CR10 tvorí, spolu s CR2 alebo CR3, 5- alebo 6-členný alkylénový alebo alkenylénový kruh, ktorý môže byť substituovaný jedným alebo dvomi metylovými skupinami, a v ktorom v každom prípade metylénová skupina môže byť nahradená kyslíkom alebo sírou, ako je -CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH=CH-O-, -CH=CH-CH2O-, -CH(CH3)-CH(CH3)-O-, -CH=C(CH3)-0-, -C(CH3)=C(CH3)-O- alebo -C(CH3)=C(CH3)-S;Z represents nitrogen or CR 10 in which R 10 represents hydrogen, halogen, C 1 -C 4 -haloalkyl or C 1 -C 4 -alkyl, or CR 10 forms, together with CR 2 or CR 3 , a 5- or 6-membered an alkylene or alkenylene ring which may be substituted by one or two methyl groups and in which case in any case the methylene group may be replaced by oxygen or sulfur, such as -CH 2 -CH 2 -O-, -CH 2 -CH 2 -CH 2 -O-, - CH = CH-O-, -CH = CH-CH 2 O-, -CH (CH 3 ) -CH (CH 3 ) -O-, -CH = C (CH 3 ) -O-, -C (CH 3) I = C (CH 3 ) -O- or -C (CH 3 ) = C (CH 3 ) -S;

pričom najmenej jeden z členov kruhu X, Y alebo Z znamená dusík;wherein at least one of the ring members X, Y or Z is nitrogen;

R3 predstavuje vodík, hydroxylovú skupinu, halogén, N(Ci-C4-alkyl)2, Ci-C4alkylovú skupinu, Ci-C4-alkoxylovú skupinu, Ci-C4-alkyltioskupinu, C1C4-halogénalkylovú skupinu, Ci-C4-halogénalkoxylovú skupinu alebo C R3 je pripojený ku C R10, ako je uvedené vyššie, za vzniku 5- alebo 6členného kruhu;R 3 is hydrogen, hydroxyl, halogen, N (C 1 -C 4 -alkyl) 2 , C 1 -C 4 alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkyl, C 1 A -C 4 -haloalkoxy group or CR 3 is attached to CR 10 as above to form a 5- or 6-membered ring;

R4 znamená Ci-C4-alkylovú skupinu alebo C2-C4-alkenylovú skupinu, ktorá môže byť substituovaná jedným alebo viacerými z nasledujúcich zvyškov, ako je: halogén, kyanoskupina, hydroxylová skupina, merkaptoskupina, Ci-C4-alkoxylová skupina, fenoxyskupina, karboxylová skupina, Ci-C4-halogénalkoxylová skupina, Ci-C4-alkyltioskupina, aminoskupina, NH(Ci-C4-alkyl), N(Ci-C4-alkyl)2 alebo Ci-C4-alkylkarbonylová skupina;R 4 is C 1 -C 4 -alkyl or C 2 -C 4 -alkenyl, which may be substituted by one or more of the following radicals, such as: halogen, cyano, hydroxyl, mercapto, C 1 -C 4 -alkoxy , phenoxy, carboxyl, Ci-C 4 -halogénalkoxylová group, a Ci-C 4 -alkylthio, amino, NH (Ci-C4 alkyl), N (Ci-C 4 -alkyl) 2 or C -C 4 -alkylcarbonyl group;

R5 predstavuje fenylovú alebo naftylovú skupinu, z ktorých každá môže byť substituovaná jedným alebo viacerými z nasledujúcich zvyškov, ako je:R 5 represents a phenyl or naphthyl group, each of which may be substituted by one or more of the following radicals, such as:

halogén, nitroskupina, kyanoskupina, hydroxylová skupina, merkapto-15skupina, Ci-C4-alkýlová skupina, C2-C4-alkenylová skupina, Ci-C4-hydroxyalkylová skupina, Ci-C4-halogénalkylová skupina, CrC4-halogénalkoxylová skupina, CrC4-alkoxylová skupina, fenoxyskupina, karboxylová skupina, Ci-C4-alkyltioskupina, aminoskupina, NH(Ci-C4-alkyl), N(CrC4alkyl)2 alebo fenylová skupina, ktorá môže byť substituovaná jedenkrát alebo viackrát, napríklad jedenkrát až trikrát, substituentom ako je halogén, nitroskupina, kyanoskupina, Ci-C4-alkylová skupina, Ci-C4halogénalkylová skupina, Ci-C4-alkoxylová skupina, Ci-C4-halogénalkoxylová skupina alebo Ci-C4-alkyltioskupina; alebo C3-C8-cykloalkylovú skupinu;halogen, nitro, cyano, hydroxyl, mercapto-15, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy a group, C 1 -C 4 -alkoxy, phenoxy, carboxyl, C 1 -C 4 -alkylthio, amino, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 alkyl) 2 or a phenyl group which may be substituted one or more times , for example one to three times, a substituent such as 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 -alkylthio; or a C 3 -C 8 -cycloalkyl group;

R6 znamená C3-C8-cykloalkylovú skupinu, pričom tieto zvyšky môžu byť v každom prípade substituované jedenkrát alebo viackrát, substituentom, ako je: halogén, hydroxylová skupina, merkaptoskupina, karboxylová skupina, nitroskupina, kyanoskupina, Ci-C4-alkoxylová skupina, Ci-C4-alkylová skupina, C2-C4-alkenylová skupina, C2-C4alkinylová skupina, C3-C6-alkenyloxylová skupina, C3-C6-alkinyloxylová skupina, Ci-C4-alkyltioskupina, Ci-C4-halogénalkoxylová skupina, Ci-C4alkyl-karbonylová skupina, CrC4-alkoxykarbonylová skupina, NH(Ci-C4alkyl), N(Ci-C4-alkyl)2 alebo fenylová skupina, ktorá môže byť substituovaná, jedenkrát alebo viackrát, napríklad jedenkrát až trikrát, substituentom ako je: halogén, nitroskupina, kyanoskupina, Ci-C4alkylová skupina, Ci-C4-halogénalkylová skupina, Ci-C4-alkoxylová skupina, Ci-C4-halogén-alkoxylová skupina alebo Ci-C4-alkyltioskupina;R 6 represents a C 3 -C 8 -cycloalkyl group, which radicals may in each case be substituted one or more times with a substituent such as: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C 1 -C 4 -alkoxy group, a Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 -alkenyloxylová group, a C 3 -C 6 -alkinyloxylová group, a Ci-C 4 -alkylthio. C 1 -C 4 -haloalkoxy, C 1 -C 4 alkyl-carbonyl, C 1 -C 4 -alkoxycarbonyl, NH (C 1 -C 4 alkyl), N (C 1 -C 4 -alkyl) 2 or a phenyl group which may be substituted , one or more times, for example one to three times, with a substituent such as: halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -halo- alkoxy or C 1 -C 4 -alkylthio;

fenylovú alebo naftylovú skupinu, z ktorých každá môže byť substituovaná jedným alebo viacerými z nasledujúcich zvyškov, ako je: halogén, R15, nitroskupina, merkaptoskupina, karboxylová skupina, kyanoskupina, hydroxylová skupina, amino skupina, Ci-C4-alkylová skupina, C2-C4-alkenylová skupina, C2-C4-alkinylová skupina, C3-C6alkenyloxylová skupina, Ci-C4-halogénalkylová skupina, C3-C6-alkinyloxylová skupina, Ci-C4-alkylkarbonylová skupina, Ci-C4-alkoxykarbonylová skupina, Ci-C4-alkoxylová skupina, Ci-C4-halogénalkoxylová skupina, fenoxyskupina, CrC4-alkyltioskupina, NH(C1-C4 phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, R 15 , nitro, mercapto, carboxyl, cyano, hydroxyl, amino, C 1 -C 4 -alkyl, C C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 3 -C 6 alkenyloxy, C 1 -C 4 -haloalkyl, C 3 -C 6 -alkyloxy, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkyloxy -C 4 -alkoxycarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenoxy, C 1 -C 4 -alkylthio, NH (C 1 -C 4)

-16alkyl), N(Ci-C4-alkyl)2, metyléndioxylová, etyléndioxylová alebo fenylová skupina, ktorá môže byť substituovaná jedenkrát alebo viackrát, napríklad jedenkrát až trikrát, substituentom, ako je halogén, nitroskupina, kyanoskupina, Ci-C4-alkylová skupina, Ci-C4-halogénalkylová skupina, Ci-C4-alkoxylová skupina, Ci-C4-halogénalkoxylová skupina alebo Ci-C4-alkyltioskupina, pod podmienkou, že ak R6 znamená nesubstituovaný fenylový kruh, potom CR10 musí tvoriť spolu s C R2 alebo CR3 5-členný alkylénový kruh, v ktorom jedna alebo dve metylénové skupiny môžu byť nahradené O alebo S;-16alkyl), N (C 1 -C 4 -alkyl) 2 , methylenedioxyl, ethylenedioxyl or phenyl, which may be substituted one or more times, for example one to three times, with a substituent such as 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 -alkylthio, provided that when R 6 represents an unsubstituted phenyl ring, then CR 10 must form together with CR 2 or CR 3 a 5-membered alkylene ring in which one or two methylene groups may be replaced by O or S;

päť- alebo šesť-členný heteroaromatický systém, ktorý obsahuje jeden až tri atómy dusíka a/alebo jeden atóm síry alebo kyslíka a ktorý môže niesť jeden až štyri atómy halogénu a/alebo jeden až dva z nasledujúcich zvyškov, ako je: Ci-C4-alkylová skupina, CrC4halogénalkylová skupina, Ci-C4-alkoxylová skupina, trifluórmetoxyskupina, CrC4-alkyltioskupina, fenylová skupina alebo fenoxyskupina, pričom fenylové zvyšky môžu samotné niesť jeden až päť atómov halogénu a/alebo jeden až tri z nasledujúcich zvyškov, ako je: Ci-C4alkylová skupina, Ci-C4-halogén-alkylová skupina, Ci-C4-alkoxylová skupina, Ci-C4-halogénalkoxylová skupinu a/alebo Ci-C4-alkyltio skupina;a five- or six-membered heteroaromatic system which contains one to three nitrogen atoms and / or one sulfur or oxygen atom and which may bear one to four halogen atoms and / or one to two of the following residues, such as: C 1 -C 4 -alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 -alkoxy, trifluoromethoxy, C 1 -C 4 -alkylthio, phenyl or phenoxy, wherein the phenyl radicals may themselves carry one to five halogen atoms and / or one to three of the following radicals, such as: C 1 -C 4 alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and / or C 1 -C 4 -alkylthio;

R15 predstavuje metylovú skupinu, etylovú skupinu, metoxyskupinu alebo etoxyskupinu, ktoré môžu niesť jeden z nasledujúcich zvyškov, ako je: hydroxylová skupina, karboxylová skupina, aminoskupina, NH(Ci-C4alkyl), N(Ci-C4-alkyl)2, karbamoylová skupina alebo CON(CrC4-alkyl)2;R 15 represents a methyl group, an ethyl group, a methoxy group or an ethoxy group which may carry one of the following radicals, such as: hydroxyl, carboxyl, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 -alkyl) 2 , carbamoyl or CON (C 1 -C 4 -alkyl) 2 ;

W znamená síru alebo kyslík;W is sulfur or oxygen;

Q predstavuje C2-C3-alkylén, C3-alkenylén, -S-CH2-CH2., -O-CH2-CH2-, pričom tieto zvyšky môžu byť v každom prípade substituované, jedenkrát alebo viackrát, substituentom, ako je: halogén, hydroxylová skupina, merkaptoskupina, kyanoskupina, Ci-C4-alkylová skupina, Ci-C4alkoxylová skupina, Ci-C4-alkyltioskupina, Ci-C4-halogénalkoxylová skupina, Ci-C4-alkoxykarbonylová skupina, NH(Ci-C4-alkyl), N(Ci-C4 Q represents C 2 -C 3 -alkylene, C 3 -alkenylene, -S-CH 2 -CH 2 , -O-CH 2 -CH 2 -, which residues may in each case be substituted, one or more times, with a substituent such as is halogen, hydroxyl, mercapto, cyano, Ci-C 4 -alkyl, C 4 alkoxy, C 4 -alkylthio, C 4 -halogénalkoxylová group, a Ci-C 4 -alkoxycarbonyl, NH (Ci-C 4 alkyl), N (C 4 -C

-17alkyl)2 alebo fenylová skupina, ktorá môže byť substituovaná, jedenkrát alebo viackrát, napríklad jedenkrát až trikrát, substituentom ako je:-17alkyl) 2 or phenyl, which is optionally substituted one or more times, for example one to three, substituents such as:

halogén, kyanoskupina, Ci-C4-alkylová skupina, Ci-C4-halogénalkylová skupina, Ci-C4-alkoxylová skupina, Ci-C4-halogénalkoxylová skupina alebo Ci-C4-alkyltioskupina;halogen, cyano, Ci-C 4 -alkyl, C 4 -haloalkyl group, a Ci-C 4 -alkoxy, C 4, or C -halogénalkoxylová -C 4 -alkylthio;

alebo Q tvorí spolu s R6 nasledujúce kruhové systémy: 2-indanyl, 1indanyl, 1,2,3,4-tetrahydro-2-naftyl, 1,2,3,4-tetrahydro-1-naftyl, pričom tieto fenylové kruhy môžu byť v každom prípade substituované substituentom ako je: halogén, hydroxylová skupina, merkaptoskupina, karboxylová skupina, nitroskupina, kyanoskupina, CrC4-alkoxylová skupina, Ci-C4-alkylová skupina, C2-C4-alkenylová skupina, C2-C4alkinylová skupina, C3-C6-alkenyloxylová skupina, C3-C6-alkinyloxylová skupina, Ci-C4-alkyltio-skupina, Ci-C4-halogénalkoxylová skupina, Cr C4-alkylkarbonylová skupina, Ci-C4-alkoxykarbonylováý skupina, aminoskupina, NH(Ci-C4-alkyl), N(Ci-C4-alkyl)2 alebo fenylová skupina.or Q together with R 6 form the following ring systems: 2-indanyl, 1-indanyl, 1,2,3,4-tetrahydro-2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, which phenyl rings may in each case substituted by a substituent such as: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 alkenyloxy, C 3 -C 6 -alkinyloxylová group, a Ci-C 4 alkylthio group, C 4 -halogénalkoxylová group, a Cr C 4 -alkylcarbonyl, C 4 -alkoxykarbonylováý , amino, NH (Ci-C4 alkyl), N (Ci-C 4 -alkyl) 2 or phenyl.

Predovšetkým výhodnými zlúčeninami všeobecného vzorca I, buď ako čisté enantioméry alebo ako čisté diastereoizoméry alebo ich zmesi, sú také zlúčeniny, v ktorých substituenty majú nasledujúce významy:Particularly preferred compounds of formula I, either as pure enantiomers or as pure diastereoisomers or mixtures thereof, are those wherein the substituents have the following meanings:

R2 znamená trifluórmetylovú skupinu, Ci-C4-alkylovú skupinu, Ci-C4alkoxylovú skupinu, Ci-C4-alkyltioskupinu, alebo CR2 je pripojené ku CR10 ako je uvedené nižšie, za vzniku 5- alebo 6-členného kruhu;R 2 is trifluoromethyl, C 1 -C 4 -alkyl, C 1 -C 4 alkoxy, C 1 -C 4 -alkylthio, or CR 2 is attached to CR 10 as below to form a 5- or 6-membered ring ;

X predstavuje dusík alebo metín;X represents nitrogen or methine;

Y znamená dusík alebo metín;Y is nitrogen or methine;

Z predstavuje dusík alebo skupinu CR10, v ktorej R10 znamená vodík, fluór alebo metyl, alebo CR10 tvorí spolu s CR2 alebo CR3 5- alebo 6-členný alkylénový alebo alkenylénový kruh, ktorý môže byť substituovaný jednou alebo dvomi metylovými skupinami a v ktorom v každom prípade môže byť jedna metylénová skupina nahradená kyslíkom alebo sírou, ako je skupina -CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH=CH-O-, -CH=CH- 18CH2O-, -CH(CH3)-CH(CH3)-O-, -CH=C(CH3)-O-, -C(CH3)=C(CH3)-O-, alebo -C(CH3)=C(CH3)-S;Z represents nitrogen or CR 10 in which R 10 represents hydrogen, fluoro or methyl, or CR 10 together with CR 2 or CR 3 forms a 5- or 6-membered alkylene or alkenylene ring which may be substituted by one or two methyl groups and in which case one methylene group may be replaced by oxygen or sulfur, such as -CH 2 -CH 2 -O-, -CH 2 -CH 2 -CH 2 -O-, -CH = CH-O-, - CH = CH-18CH 2 O-, -CH (CH 3) -CH (CH 3 ) -O-, -CH = C (CH 3 ) -O-, -C (CH 3 ) = C (CH 3 ) -O -, or -C (CH 3 ) = C (CH 3 ) -S;

najmenej jeden z členov kruhu X, Y alebo Z znamená dusík;at least one of the ring members X, Y or Z is nitrogen;

R3 znamená trifluórmetylovú skupinu, Ci-C4-alkylovú skupinu, Ci-C4alkoxylovú skupinu, Ci-C4-alkyltioskupinu, alebo CR3 je pripojené ku CR10 ako je uvedené vyššie, za vzniku 5- alebo 6-členného kruhu;R 3 is trifluoromethyl, C 1 -C 4 -alkyl, C 1 -C 4 alkoxy, C 1 -C 4 -alkylthio, or CR 3 is attached to CR 10 as above to form a 5- or 6-membered ring ;

R4 predstavuje Ci-C4-alkylovú skupinu, ktorá môže byť substituovaná jedným alebo viacerými z nasledujúcich zvyškov, ako je: halogén, CrC4alkoxylová skupina, Ci-C4-halogénalkoxylová skupina;R 4 represents a C 1 -C 4 -alkyl group which may be substituted by one or more of the following radicals, such as: halogen, C 1 -C 4 alkoxy, C 1 -C 4 -haloalkoxy;

R5 znamená fenylovú alebo naftylovú skupinu, z ktorých každá môže byť substituovaná, jedným alebo viacerými z nasledujúcich zvyškov, ako je: halogén, nitroskupina, kyanoskupina, hydroxylová skupina, merkaptoskupina, aminoskupina, Ci-C4-alkylová skupina, Ci-C4-halogénalkylová skupina, CrC4-halogénalkoxylová skupina, Ci-C4-alkoxyskupina, fenoxyskupina, CrC4-alkyltioskupina, NH(Ci-C4-alkyl), N(Ci-C4-alkyl)2 alebo fenylová skupina, ktorá môže byť substituovaná, jedenkrát alebo viackrát, napríklad jedenkrát až trikrát, substituentom, ako je: halogén, nitroskupina, kyanoskupina, Ci-C4-alkylová skupina, Ci-C4-halogénalkylová skupina, Ci-C4-alkoxylová skupina, Ci-C4-halogénalkoxylová skupina alebo Ci-C4-alkyltioskupina; alebo fenylovú alebo naftylovú skupinu, ktoré sú pripojené v orto-polohe ku R4 pomocou priamej väzby, metylénovej, etylénovej alebo etenylénovej skupiny, atómu kyslíka alebo síry alebo SO2, NH alebo N-alkylovej skupiny;R 5 represents a phenyl or naphthyl group, each of which may be substituted, with one or more of the following radicals such as: halogen, nitro, cyano, hydroxyl, mercapto, amino, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl group, -C 4 -halogénalkoxylová group, a Ci-C 4 -alkoxy, phenoxy, -C 4 -alkylthio, NH (Ci-C4 alkyl), N (Ci-C 4 -alkyl) 2 or phenyl, which may be substituted, one or more times, for example one to three times, with a substituent such as: halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 4- haloalkoxy or C 1 -C 4 -alkylthio; or a phenyl or naphthyl group, which are attached at the ortho-position to R 4 by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group;

cyklohexylovú skupinu;a cyclohexyl group;

R6 predstavuje cyklohexylovú skupinu, ktorá môže byť substituovaná, jedenkrát alebo viackrát, substituentom, ako je: Ci-C4-alkoxylová skupina, Ci-C4-alkylová skupina, halogén alebo fenylová skupina, ktorá môže byť substituovaná, jedenkrát alebo viackrát, napríklad jedenkrát až trikrát, halogénom, Ci-C4-alkylovou skupinou, Ci-C4-alkoxylovou skupinou;R 6 represents a cyclohexyl group which may be substituted, one or more times, with a substituent such as: C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl, halogen or a phenyl group which may be substituted one or more times, for example, one to three times, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy;

-19fenylovú alebo naftylovú skupinu, z ktorých každá môže byť substituovaná jedným alebo viacerými z nasledujúcich zvyškov, ako je: halogén, R15, Ci-C4-alkylová skupina, Ci-C4-halogénalkylová skupina, acetylová skupina, Ci-C4-alkoxykarbonylová skupina, CrC4-alkoxylová skupina, fenoxyskupina, Ci-C4-alkyltioskupina, NH(Ci-C4-alkyl), N(Ci-C4alkyl)2, metyléndioxylová skupina, etyléndioxylová skupina alebo fenylová skupina, ktorá môže byť substituovaná, jedenkrát alebo viackrát, napríklad jedenkrát až trikrát, substituentom, ako je: halogén, kyanoskupina, Ci-C4-alkylová skupina, Ci-C4-alkoxylová skupina alebo Ci-C4-alkyltioskupina, pod podmienkou, že ak Q znamená -CH2-CH2- a W predstavuje O, fenylový kruh musí obsahovať najmenej jeden substituent odlišný od vodíka;-19phenyl or naphthyl, each of which may be substituted by one or more of the following radicals, such as: halogen, R 15 , C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, acetyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkoxy, phenoxy, C 1 -C 4 -alkylthio, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 alkyl) 2 , methylenedioxyl, ethylenedioxyl or phenyl, which may be substituted, one or more times, for example one to three, with a substituent such as: halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or C 1 -C 4 -alkylthio, provided that if Q is -CH 2 -CH 2 - and W represents O, the phenyl ring must contain at least one substituent other than hydrogen;

R15 znamená metoxyskupinu alebo etoxyskupinu, ktorá nesie jeden z nasledujúcich zvyškov, ako je: hydroxylová skupina, karboxylová skupina, aminoskupina, NH(CrC4-alkyl), N(Ci-C4-alkyl)21 karbamoylová skupina alebo CON(Ci-C4-alkyl)2;R 15 represents methoxy or ethoxy, which carry one of the following radicals: hydroxyl, carboxyl, amino, NH (C r C 4 alkyl), N (Ci-C4 alkyl) carbamoyl group 21 or CON ( C 1 -C 4 -alkyl) 2 ;

W predstavuje síru alebo kyslík;W represents sulfur or oxygen;

Q znamená C2-C3-alkylén, -S-CH2.CH2., -O-CH2-CH2-, pričom tieto zvyšky môžu byť v každom prípade substituované jedenkrát alebo viackrát substituentom ako je: halogén, Ci-C4-alkylová skupina, Ci-C4-alkoxylová skupina, Ci-C4-alkyltioskupina alebo fenylová skupina, ktorá môže byť substituovaná jedenkrát alebo viackrát, napríklad jedenkrát až trikrát, substituentom, ako je: halogén, Ci-C4-alkylová skupina, Ci-C4alkoxylová skupina alebo Ci-C4-alkyltioskupina;Q is C 2 -C 3 -alkylene-S-CH 2 .CH 2., -O-CH2 CH2 -, where the radicals may in each case be substituted one or more times with substituents: halogen, C C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio or phenyl, which may be substituted one or more times, for example one to three times, with a substituent such as: halogen, C 1 -C 4 -alkyl C 1 -C 4 alkoxy or C 1 -C 4 -alkylthio;

alebo Q tvorí spolu s R6 nasledujúce kruhové systémy: 2-indanyl, 1indanyl, 1,2,3,4-tetrahydro-2-naftyl, 1,2,3,4-tetrahydro-1-naftyl, pričom tieto fenylové kruhy môžu byť v každom prípade substituované substituentom, ako je: halogén, hydroxylová skupina, merkaptoskupina, karboxylová skupina, kyanoskupina, Ci-C4-alkoxylová skupina, Ci-C4alkylová skupina, C2-C4-alkenylová skupina, C2-C4-alkinylová skupina, C3-C6-alkenyloxylová skupina, C3-C6-alkinyloxylová skupina, Ci-C4-20alkyltioskupina, Ci-C4-halogénalkoxylová skupina, Ci-C4-alkoxykarbonylová skupina, NH(Ci-C4-alkyl), N(Ci-C4-alkyl)2 alebo fenylová skupina.or Q together with R 6 form the following ring systems: 2-indanyl, 1-indanyl, 1,2,3,4-tetrahydro-2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, which phenyl rings may in each case substituted by a substituent such as: halogen, hydroxyl, mercapto, carboxyl, cyano, C 1 -C 4 -alkoxy, C 1 -C 4 alkyl, C 2 -C 4 -alkenyl, C 2 -C 4- alkynyl, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkyloxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkoxycarbonyl, NH (C 1 -C 4 -alkoxy) C 4 alkyl), N (Ci-C 4 -alkyl) 2 or phenyl.

Zlúčeniny podľa predloženého vynálezu poskytujú nové terapeutické možnosti na liečenie hypertenzie, pulmonálnej hypertenzie, infarktu myokardu, chronického zlyhania srdca, angíny pectoris, arytmie, akútneho/chronického zlyhania obličiek, chronickej srdcovej nedostatočnosti, renálnej nedostatočnosti, cerebrálneho angiospazmu, cerebrálnej ischémie, subarachnoidálnej hemorágie, migrény, astmy, aterosklerózy, endotoxického šoku, endotoxínom vyvolaného zlyhania orgánov, intravaskulárnej koagulácie, restenózy po angioplastii a bypassových operáciách, benígnej hyperplázii prostaty, hypertenzii alebo zlyhania obličiek spôsobeného ischémiou alebo intoxikáciou, metastáz a rastu mezenchymálnych nádorov, zlyhania obličiek spôsobeného kontrastným činidlom, pankreatitídy, gastrointestinálnych vredov.The compounds of the present invention provide novel therapeutic options for the treatment of hypertension, pulmonary hypertension, myocardial infarction, chronic heart failure, angina pectoris, arrhythmia, acute / chronic renal failure, chronic cardiac insufficiency, renal insufficiency, cerebral angiospasm, cerebral angiospasm, cerebral angiospasm, cerebral angiospasm, cerebral angiospasm, cerebral angiospasm, cerebral angiospasm , asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and bypass surgery, benign prostatic hyperplasia, hypertension or kidney failure due to ischemia or intoxication, contraindications, metastasis and tumor growth gastrointestinal ulcers.

Zlúčeniny podľa vynálezu v niektorých prípadoch prekvapujúco vykazujú tiež antagonistický účinok na neurokinínový receptor.Surprisingly, the compounds of the invention also in some cases also exhibit neurokinin receptor antagonistic activity.

Toto platí predovšetkým pre zlúčeniny vzorca I, v ktorom R1 má významThis is especially true for compounds of formula I in which R 1 is as defined above

NR RNR R

Vynález sa ďalej týka kombinácie produktov obsahujúcich antagonisty endotelínového receptora vzorca I a inhibítorov renín-angiotenzínového systému. Inhibítormi renín-angiotenzínového systému sú inhibíitory renínu, antagonisty angiotenzínu II a predovšetkým inhibítory angiotenzín konvertujúceho enzýmu (ACE).The invention further relates to the combination of products comprising endothelin receptor antagonists of formula I and inhibitors of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists, and in particular angiotensin converting enzyme (ACE) inhibitors.

Vynález sa ďalej týka kombinácie produktov obsahujúcich β-blokátory a vyššie uvedené antagonisty endotelínového receptora a kombinácií, ktoré obsahujú zmesné inhibítory ACE/neutrálnej endopeptidázy (NEP) a vyššie uvedených antagonistov endotelínového receptora.The invention further relates to a combination of products comprising β-blockers and the above mentioned endothelin receptor antagonists and combinations comprising mixed ACE / neutral endopeptidase (NEP) inhibitors and the above endothelin receptor antagonists.

-21 Kombinácie produktov sa môžu podávať v jednoduchej farmaceutickej forme alebo tiež v oddelených formách. Podávanie sa môže uskutočňovať súbežne alebo následne.Combinations of products can be administered in a simple pharmaceutical form or also in separate forms. Administration may be concurrent or sequential.

Dávka kombinácie sa môže v každom prípade rozšíriť až do maximálneho množstva jednoduchej dávky. Avšak je taktiež možné použiť menšie dávky ako pre príslušnú monoterapiu.The dose of the combination may in any case be extended up to the maximum single dose. However, it is also possible to use smaller doses than for the respective monotherapy.

Tieto kombinácie produktov sú predovšetkým vhodné na liečenie a prevenciu hypertenzie a jej následkov a na liečenie zlyhania srdca.These product combinations are particularly suitable for the treatment and prevention of hypertension and its consequences and for the treatment of heart failure.

Dobrý účinok zlúčenín sa môže demonštrovať v nasledujúcich testoch: Štúdie väzby receptoraThe good effect of the compounds can be demonstrated in the following assays: Receptor Binding Studies

Na štúdie väzby receptora sa použili klonované ľudské ETA alebo ETB receptor exprimujúce CHO bunky.Cloned human ET A or ET B receptor expressing CHO cells were used for receptor binding studies.

Príprava membránPreparation of membranes

ETa or ETb receptor-exprimujúce CHO bunky sa kultivovali v DMEM NUT MIX F12 médiu (Gibco, No. 21331-020) obsahujúcom 10 % fetálneho teľacieho séra (PAA Laboratories GmbH, Linz, No. A15-022), 1 mM glutamínu (Gibco No. 25030024), 100U/ml penicilínu a 100pg/ml streptomycínu (Sigma No. P-0781). Po 48 hodinách sa bunky premyli s PBS a inkubovali sa s 0,05% PBS obsahujúceho trypsín pri teplote 37 °C počas 5 minút. Zmes sa potom neutralizovala s médiom a bunky sa zachytili centrifúgovaním pri 300 x g.ET and or ET b receptor-expressing CHO cells were cultured in DMEM NUT MIX F12 medium (Gibco, No. 21331-020) containing 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022), 1 mM glutamine. (Gibco No. 25030024), 100U / ml penicillin and 100µg / ml streptomycin (Sigma No. P-0781). After 48 hours, cells were washed with PBS and incubated with 0.05% trypsin-containing PBS at 37 ° C for 5 minutes. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 x g.

Na prípravu membrány sa bunky zriedili na koncentráciu 108 buniek/ml pufra (50 mM tris HCI pufer, pH 7,4) a potom sa dezintegrovali pomocou ultrazvuku (Branson Sonifier 250, 40 až 70 sekúnd/konštantný výkon 20).For membrane preparation, cells were diluted to a concentration of 10 8 cells / ml buffer (50 mM Tris HCl buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds / constant 20).

Skúšky väzbovostiBonding tests

Pre ETa and ETB skúšky väzbovosti receptora sa membrány suspendovali v inkubačnom pufre (50 mM tris-HCI, pH 7,4 s 5 mM MnCI2, 40 mg/ml bacitracínu aFor ET and and ET B receptor binding assays, membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7.4 with 5 mM MnCl 2 , 40 mg / ml bacitracin and

0,2 % BSA) pri koncentrácii 50 pg proteínu na zmes vzorky a inkubovali sa pri teplote 25 °C s 25 pM [125J] ETi (ETA vzorka receptora) alebo 25 pM [125J] ET3 (ETB 0.2% BSA) at 50 µg protein per sample mixture and incubated at 25 ° C with 25 µM [ 125 J] ETi (ETA receptor sample) or 25 µM [ 125 J] ET3 (ET B

-22vzorka receptora) v prítomnosti a bez prítomnosti testovanej zlúčeniny. Nešpecifická väzba sa stanovila s použitím 10'7M ETi. Po 30 minútach sa uskutočnila filtrácia cez GF/B filtre so skleneným vláknom (Whatman, Anglicko) v kolektore buniek Skatron (Skatron, Lier, Nórsko), aby sa oddelili voľné a viazané rádioligandy a filtre sa premyli s ľadovo chladným tris-HCI pufrom, pH 7,4, obsahujúcim 0,2 % BSA. Rádioaktivita zachytená na filtroch sa kvantifikovala s použitím kvapalného scintilačného počítača Packard 2200 CA.-22 receptor pattern) in the presence and absence of the test compound. Non-specific binding was determined using 10 ' 7 M ETi. After 30 minutes filtration through GF / B glass fiber filters (Whatman, England) was performed in a Skatron cell collector (Skatron, Lier, Norway) to separate free and bound radioligands and the filters were washed with ice-cold tris-HCl buffer, pH 7.4, containing 0.2% BSA. The radioactivity retained on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Testovanie ET antagonistov in vivo:In vivo testing of ET antagonists:

Samce SD potkanov s hmotnosťou 250 až 300 gramov sa anestetizovali s amobarbitalom, umelo sa ventilovali, vagotomizovali a usmrtili sa. Krčná artéria a jugulárna žila sa katetrizovali.Male SD rats weighing 250-300 grams were anesthetized with amobarbital, artificially ventilated, vagotomized and sacrificed. The carotid artery and jugular vein were catheterized.

U kontrolných zvierat intravenózne podávanie 1 mg/kg ET1 viedlo k jednoznačnému zvýšeniu krvného tlaku, ktorý pretrvával počas relatívne dlhého obdobia.In control animals, intravenous administration of 1 mg / kg ET1 resulted in a clear increase in blood pressure that persisted over a relatively long period.

Testované zvieratá dostali intravenóznu injekciu testovanej zlúčeniny (1 ml/kg) 30 minút pred podaním ET1. Na stanovenie ET-antagonistických vlastností sa zmeny v krvnom tlaku pri testovaných zvieratách porovnali s hodnotami pre kontrolné zvieratá.Test animals received an intravenous injection of test compound (1 ml / kg) 30 minutes prior to ET1 administration. To determine ET-antagonistic properties, changes in blood pressure in the test animals were compared with the values for the control animals.

Orálne testovanie zmesných antagonistov ETA a ETB:Oral testing of mixed ET A and ET B antagonists:

Samce potkanov s hmotnosťou 250 až 350 g s normálnym tonusom (Sprague Dawley, Janvier) sa predošetrili orálne s testovanými látkami. O 80 minút neskôr sa zvieratá anestetizovali s uretánom a krčná artéria (na meranie tlaku krvi) a jugulárna žila (podávanie veľkého množstva endotelin/endotelin 1) sa katetrizovali.Male rats weighing 250-350 g with normal tone (Sprague Dawley, Janvier) were pretreated orally with test substances. 80 minutes later, the animals were anesthetized with urethane and the carotid artery (for measuring blood pressure) and the jugular vein (administration of large amounts of endothelin / endothelin 1) were catheterized.

Po fáze stabilizácie, veľké množstvo endotelínu (20 pg/kg, aplikovaný objemAfter the stabilization phase, a large amount of endothelin (20 pg / kg, applied volume)

0,5 ml/kg) alebo ET1 (0,3 mg/kg, aplikovaný objem. 0,5 ml/kg) sa podávalo intravenózne. Krvný tlak a srdcová frekvencia sa kontinuálne zaznamenávali počas obdobia 30 minút. Zreteľné a pretrvávajúce zmeny krvného tlaku sa vypočítali ako oblasť pod krivkou (AUC). Na stanovenie antagonistického účinku testovaných0.5 ml / kg) or ET1 (0.3 mg / kg, applied volume. 0.5 ml / kg) was administered intravenously. Blood pressure and heart rate were continuously recorded for a period of 30 minutes. Obvious and persistent changes in blood pressure were calculated as the area under the curve (AUC). To determine the antagonistic effect of the test subjects

-23látok sa AUC zvierat, ktoré sa ošetrili s látkou, porovnalo s AUC kontrolných zvierat.-23 Substance, the AUC of the treated animals was compared to that of the control animals.

Zlúčeniny podľa predloženého vynálezu sa môžu podávať bežným spôsobom orálne alebo parenterálne (subkutánne, intravenózne, intramuskulárne, intraperitoneálne). Podávanie sa môže tiež uskutočniť pomocou pár alebo sprejov cez nosohltanovú dutinu.The compounds of the present invention may be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) by conventional means. Administration can also be by vapor or spray through the nasopharynx cavity.

Dávka závisí od veku, stavu a hmotnosti pacienta a od spôsobu podávania. Denná dávka účinnej látky zvyčajne predstavuje približne 0,5 až 50 mg/kg telesnej hmotnosti pri orálnom podávaní a približne 0,1 až 10 mg/kg telesnej hmotnosti pri parenterálnom podávaní.The dose depends on the age, condition and weight of the patient and the route of administration. The daily dose of active ingredient is usually about 0.5 to 50 mg / kg body weight for oral administration and about 0.1 to 10 mg / kg body weight for parenteral administration.

Nové zlúčeniny sa môžu použiť v konvenčných pevných alebo kvapalných farmaceutických formách podávania, napríklad ako nepoťahované alebo (filmom) poťahované tablety, kapsule, prášky, granule, čipky, roztoky, masti, krémy alebo spreje. Tieto sa pripravia zvyčajným spôsobom. Účinné zložky sa na tento účel môžu spracovať s konvenčnými farmaceutickými pomocnými látkami, ako sú spojivá tabliet, plnidlá, konzervačné látky, dezintegrátory tabliet, regulátory tečenia, plastifikátory, zmáčacie činidlá, dispergačné činidlá, emulgátory, rozpúšťadlá, činidlá spomaľujúce uvoľňovanie, antioxidanty a/alebo hnacie plyny (porovnaj H. Sucker a kol.: Pharmazeutische Technológie, Thieme-Verlag, Stuttgart, 1991). Formy podávania, získané týmto spôsobom, zvyčajne obsahujú od 0,1 do 90 % hmotnostných účinnej zložky.The novel compounds can be used in conventional solid or liquid pharmaceutical forms of administration, for example, as uncoated or (film) coated tablets, capsules, powders, granules, lace, solutions, ointments, creams or sprays. These are prepared in the usual manner. For this purpose, the active ingredients may be formulated with conventional pharmaceutical excipients such as tablet binders, fillers, preservatives, tablet disintegrators, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release retarding agents, antioxidants and / or propellants (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way usually contain from 0.1 to 90% by weight of active ingredient.

Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION

Príklady syntézySynthesis examples

Príklad 1Example 1

Metylester kyseliny 2-hydroxy-3-(2-(4-chlórfenyl)etoxy)-3-fenylbutánovej (diastereo-izomér I, podľa všetkého 2s,3r) kvapiek dietyléterátu fluoridu boritého sa pri laboratórnej teplote pridalo k zmesi 5 g (26 mmol) metylesteru kyseliny trans-2,3-epoxy-3-fenylbutánovej a 4.0 g (26 mmol) 2-(4-chlórfenyl)etanolu a zmes sa miešala pri teplote 30 až 35 °C2-Hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutanoic acid methyl ester (diastereoisomer I, presumably 2s, 3r) drops of boron trifluoride diethyl etherate was added to a mixture of 5 g (26 mmol) at room temperature. of methyl trans-2,3-epoxy-3-phenylbutanoate and 4.0 g (26 mmol) of 2- (4-chlorophenyl) ethanol and stirred at 30-35 ° C.

-24počas 2,5 hodín (chloroform sa prípadne môže použiť ako rozpúšťadlo). Na ukončenie reakcie sa potom pridali ďalšie 3 kvapky dietyléterátu fluoridu boritého a v miešaní sa pokračovalo pri teplote 30 až 35 °C počas ďalšej hodiny. Zmes sa nakoniec vytrepala do éteru a trikrát sa extrahovala s 2 N NaOH, organická fáza sa vysušila nad MgSO4 a prefiltrovala sa a potom sa rozpúšťadlo oddestilovalo. Zvyšok: 8,7 g nažltlého oleja, ktorý sa okamžite použil v ďalšej reakcii.24 hours (chloroform may optionally be used as solvent). An additional 3 drops of boron trifluoride diethyl etherate was then added to complete the reaction and stirring was continued at 30-35 ° C for an additional hour. The mixture was finally taken up in ether and extracted three times with 2 N NaOH, the organic phase was dried over MgSO 4 and filtered, and then the solvent was distilled off. The residue: 8.7 g of a yellowish oil which was used immediately in the next reaction.

Príklad 2Example 2

Kyselina 2-hydroxy-3-(2-(4-chlórfenyl)etoxy)-3-fenylbutánová (diastereoizomér I, podľa všetkého 2s,3r)2-Hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutanoic acid (diastereoisomer I, presumably 2s, 3r)

8,7 g metylesteru kyseliny (2s,3r)-2-hydroxy-3-(2-(4-chlórfenyl)etoxy)-3fenylbutánovej (surový produkt z príkladu 1) sa rozpustil v 50 ml dioxánu a, po pridaní 75 ml 1 M NaOH, sa zmes miešala pri laboratórnej teplote počas troch hodín. K zmesi sa potom pridala voda a vodná fáza sa extrahovala s éterom. Vodná fáza sa okyslila s kyselinou chlorovodíkovou a extrahovala sa s etylacetátom a organická fáza sa vysušila nad síranom hoŕečnatým. Po odstránení rozpúšťadla destiláciou sa izolovalo 7,0 g oleja, ktorý sa bezprostredne použil ďalej. Diastereoizomérna zmes (2s,3r/2s,3s 80:20).8.7 g of (2s, 3r) -2-hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutanoic acid methyl ester (crude product of Example 1) was dissolved in 50 ml dioxane and, after addition of 75 ml 1 M NaOH, the mixture was stirred at room temperature for three hours. Water was then added to the mixture and the aqueous phase was extracted with ether. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate. After removal of the solvent by distillation, 7.0 g of an oil were isolated and used immediately. Diastereomeric mixture (2s, 3r / 2s, 3s 80:20).

Príklad 3Example 3

Kyselina 2-(4,6-dimetyl-2-pyrimidinyloxy)-3-(2-(4-chlórfenyl)etoxy)-3-fenylbutánová (diastereoizomér I, podľa všetkého 2s,3r)2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutanoic acid (diastereoisomer I, presumably 2s, 3r)

0,28 g NaH (9 mmol, 80 % v bielom oleji) sa predložilo do 10 ml DMF pod dusíkom, po kvapkách sa pridal 1 g kyseliny 2-hydroxy-3-(2-(4-chlórfenyl)etoxy)-3fenylbutánovej (surový produkt z príkladu 2) rozpustenej v 5 ml DMF a po 10 minútach sa pridalo 640 mg 2-chlór-4,6-dimetylpyrimidínu. Zmes sa potom miešala pri laboratórnej teplote počas štyroch dní. K reakčnej zmesi sa pridala voda a hodnota pH sa adjustovala na 2 s použitím 2 N HCI. Vodná fáza sa extrahovala s éterom. Spojené organické fázy sa trikrát vytrepali s 2 N NaOH a organická fáza sa vyradila. Alkalická fáza sa adjustovala na hodnotu pH 2 s použitím 2 N HCI a potom sa extrahovala s éterom. Spojené organické fázy sa vysušili nad MgSO4 a prefiltrovali sa, potom sa rozpúšťadlo oddestilovalo a zvyšok (1,1 g žltej peny) sa0.28 g of NaH (9 mmol, 80% in white oil) was added to 10 mL of DMF under nitrogen, and 1 g of 2-hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutanoic acid (1 mL) was added dropwise. the crude product of Example 2) dissolved in 5 ml of DMF and after 10 minutes 640 mg of 2-chloro-4,6-dimethylpyrimidine was added. The mixture was then stirred at room temperature for four days. Water was added to the reaction mixture and the pH was adjusted to 2 using 2 N HCl. The aqueous phase was extracted with ether. The combined organic phases were shaken three times with 2 N NaOH and the organic phase was discarded. The alkaline phase was adjusted to pH 2 using 2 N HCl and then extracted with ether. The combined organic phases were dried over MgSO 4 and filtered, then the solvent was distilled off and the residue (1.1 g of yellow foam) was removed.

-25prečistil pomocou chromatografie (metylénchlorid/metanol 9:1). Dve frakcie: 187 mg zmesi dvoch diastereoizomérov (2s,3r/2s,3s 84 : 16); 400 mg zmesi dvoch diastereoizomérov (2s,3r/2s,3s 75:25).Purified by chromatography (methylene chloride / methanol 9: 1). Two fractions: 187 mg of a mixture of two diastereoisomers (2s, 3r / 2s, 3s 84: 16); 400 mg of a mixture of two diastereoisomers (2s, 3r / 2s, 3s 75:25).

ESI-MS: M+ = 440ESI-MS: M &lt; + &gt; = 440

Príklad 4Example 4

Metylester kyseliny 2-hydroxy-3-(2-(4-chlórfenyl)etoxy)-3-fenylbutánovej (diastereo-izomér II, podľa všetkého 2s,3s) kvapiek dietyléterátu fluoridu boritého sa pri laboratórnej teplote pridalo k zmesi 5 g (26 mmol) metylesteru kyseliny cis-2,3-epoxy-3-fenylbutánovej a 4,0 g (26 mmol) 2-(4-chlórfenyl)etanolu a zmes sa miešala pri teplote 30 až 35 °C počas 2,5 hodín (chloroform sa prípadne môže použiť ako rozpúšťadlo). Na dokončenie reakcie sa potom pridalo ďalších 9 kvapiek dietyléterátu fluoridu boritého a vmiešaní sa pokračovalo pri teplote 30 až 35 °C počas troch hodín. Zmes sa nakoniec vytrepala do éteru a trikrát sa extrahovala s 2 N NaOH, organická fáza sa vysušila nad MgSO4 a prefiltrovala sa a rozpúšťadlo sa potom oddestilovalo. Zvyšok: 8,1 g nažltlého oleja, ktorý sa okamžite použil ďalej.2-Hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutanoic acid methyl ester (diastereoisomer II, presumably 2s, 3s) drops of boron trifluoride diethyl etherate was added to a mixture of 5 g (26 mmol) at room temperature. cis-2,3-epoxy-3-phenylbutanoate and 4.0 g (26 mmol) of 2- (4-chlorophenyl) ethanol and stirred at 30-35 ° C for 2.5 hours (chloroform optionally as a solvent). A further 9 drops of boron trifluoride diethyl etherate were then added to complete the reaction and stirring was continued at 30-35 ° C for three hours. The mixture was finally taken up in ether and extracted three times with 2 N NaOH, the organic phase was dried over MgSO 4 and filtered and the solvent was then distilled off. The residue: 8.1 g of a yellowish oil which was used immediately.

Príklad 5Example 5

Kyselina 2-hydroxy-3-(2-(4-chlórfenyl)etoxy)-3-fenylbutánová (diastereoizomér II, podľa všetkého 2s,3s)2-Hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutanoic acid (diastereoisomer II, presumably 2s, 3s)

8,1 g metylesteru kyseliny (2s,3s)-2-hydroxy-3-(2-(4-chlórfenyl)etoxy)-3fenylbutánovej (surový produkt z príkladu 4) sa rozpustilo v 50 ml dioxánu a po pridaní 69 ml 1 M NaOH sa zmes miešala pri laboratórnej teplote počas štyroch hodín. K reakčnej zmesi sa potom pridala voda a vodná fáza sa extrahovala s éterom. Vodná fáza sa okyslila s kyselinou chlorovodíkovou a extrahovala sa s etylacetátom a organická fáza sa vysušila nad síranom horečnatým. Po oddestilovaní rozpúšťadla sa izolovalo 5,8 g oleja (diastereoizomérna zmes 2s,3s/2s,3r 87:13). Tento surový produkt sa miešal v malom množstve diizopropyléteru cez noc. Výsledná zrazenina sa odfiltrovala a po odstránení rozpúšťadla (2,3 g bielej pevnej látky, diastereoizomérne čistej, teplota topenia. 94 až 95 °C) sa nechala reagovať ďalej v príklade 6.8.1 g of (2s, 3s) -2-hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutanoic acid methyl ester (crude product of Example 4) was dissolved in 50 ml of dioxane and after addition of 69 ml of 1 M NaOH was stirred at room temperature for four hours. Water was then added to the reaction mixture and the aqueous phase was extracted with ether. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate. After distilling off the solvent, 5.8 g of an oil were isolated (diastereomeric mixture 2s, 3s / 2s, 3r 87:13). This crude product was stirred in a small amount of diisopropyl ether overnight. The resulting precipitate was filtered off and after removal of the solvent (2.3 g of white solid, diastereomerically pure, mp. 94-95 ° C) was reacted further in Example 6.

-26Prí klad 6-26Example 6

Kyselina 2-(4,6-dimetyl-2-pyrimidinyloxy)-3-(2-(4-chlórfenyl)etoxy)-3-fenylbutánová (diastereoizomér II, podľa všetkého 2s,3s)2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutanoic acid (diastereomer II, presumably 2s, 3s)

0,28 g NaH (9 mmol, 80 % v bielom oleji) sa predložilo do 10 ml DMF pod dusíkom, po kvapkách sa pridal 1 g kyseliny 2-hydroxy-3-(2-(4-chlórfenyl)etoxy)-3fenylbutánovej (3 mmol z príkladu 5) rozpustenej v 5 ml DMF a po 10 minútach sa pridalo 640 mg 2-chlór-4,6-dimetylpyrimidínu. Reakčná zmes sa potom miešala pri laboratórnej teplote cez noc. K reakčnej zmesi sa pridala voda a hodnota pH sa adjustovala na 2 s použitím 2 N HCI. Vodná fáza sa extrahovala s éterom. Spojené organické fázy sa trikrát vytrepali s 2 N NaOH a organická fáza sa vyradila. Alkalická fáza sa adjustovala na hodnotu pH 2 s použitím 2 N HCI a potom sa extrahovala s éterom. Spojené organické fázy sa vysušili nad MgSO4 a prefiltrovali sa a potom sa rozpúšťadlo oddestilovalo a zvyšok (1,25 g žltej peny) sa miešal v diizopropylétere (1,1 g produktu, diasteroizomérne čistý).0.28 g of NaH (9 mmol, 80% in white oil) was added to 10 mL of DMF under nitrogen, and 1 g of 2-hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutanoic acid (1 mL) was added dropwise. 3 mmol of Example 5) dissolved in 5 ml of DMF and after 10 minutes 640 mg of 2-chloro-4,6-dimethylpyrimidine were added. The reaction mixture was then stirred at room temperature overnight. Water was added to the reaction mixture and the pH was adjusted to 2 using 2 N HCl. The aqueous phase was extracted with ether. The combined organic phases were shaken three times with 2 N NaOH and the organic phase was discarded. The alkaline phase was adjusted to pH 2 using 2 N HCl and then extracted with ether. The combined organic phases were dried over MgSO 4 and filtered and then the solvent was distilled off and the residue (1.25 g of a yellow foam) was stirred in diisopropyl ether (1.1 g of product, diastereomerically pure).

1H NMR (270 MHz, DMSO): 12,5 -13,0 ppm (1H, br); 7,15 - 7,4 (9H, m); 6,85 (1H, s); 5,15 (1H, s); 3,50 - 3,65 (1 H, m); 3,2 - 3,4 (1 H, m); 2,7 - 2,85 (2H, m), 2,25 (6H, s); 1,65 (3H, s). 1 H NMR (270 MHz, DMSO): 12.5 -13.0 ppm (1H, br); 7.15 - 7.4 (9H, m); 6.85 (1 H, s); 5.15 (1 H, s); 3.50 - 3.65 (1H, m); 3.2-3.4 (1H, m); 2.7-2.85 (2H, m), 2.25 (6H, s); 1.65 (3 H, s).

ESI-MS: M* = 440,ESI-MS: M + = 440;

Nasledujúce zlúčeniny sa pripravili analogicky k vyššie uvedeným príkladom.The following compounds were prepared in analogy to the above examples.

Príklad 7Example 7

Kyselina 2-(4-metoxy-6-metyl-2-pyrimidinyloxy)-3-(2-(4-metylfenyl)etoxy)-3-fenylbutánová (diastereoizomér I, podľa všetkého 2s,3r) 1H NMR (200 MHz, CDCI3): 7,0 - 7,5 ppm (9H, m); 6,25 (1H, s); 5,3 (1H, s); 3,9 (3H, d); 3,65 - 3,8 (1H, m); 3,4 - 3,6 (1H, m); 2,8 - 3,0 (2H, m) 2,3 (3H, s), 1,8 (3H, m).2- (4-methoxy-6-methyl-2-pyrimidinyloxy) -3- (2- (4-methylphenyl) ethoxy) -3-phenylbutyric acid (diastereomer I, presumably 2s, 3r) 1H NMR (200 MHz, CDCl 3 ): 7.0 - 7.5 ppm (9H, m); 6.25 (1 H, s); 5.3 (1 H, s); 3.9 (3 H, d); 3.65 - 3.8 (1H, m); 3.4-3.6 (1H, m); 2.8-3.0 (2H, m); 2.3 (3H, s); 1.8 (3H, m).

Príklad 8Example 8

Kyselina 2-(4-metoxy-6-metyl-2-pyrimidinyloxy)-3-(2-(4-metylfenyl)etoxy)-3-fenylbutánová (diastereoizomér II, podľa všetkého 2s,3s)2- (4-Methoxy-6-methyl-2-pyrimidinyloxy) -3- (2- (4-methylphenyl) ethoxy) -3-phenylbutanoic acid (diastereoisomer II, presumably 2s, 3s)

-271H NMR (250 ΜΗζ, CDCI3): 7,0 - 7,5 ppm (9H, m); 6,1 (1H, s); 5,5 (1 H, s); 3,9 (3H,-27 1 H NMR (250 ΜΗζ, CDCl 3 ): 7.0-7.5 ppm (9H, m); 6.1 (1 H, s); 5.5 (1H, s); 3.9 (3H,

d); 3,65 - 3,8 (1H, m); 3,4 - 3,6 (1H, m); 2,8 - 3,0 (2H, m) 2,3 (3H, s), 2,2 (6H, s);d); 3.65 - 3.8 (1H, m); 3.4-3.6 (1H, m); 2.8-3.0 (2H, m); 2.3 (3H, s); 2.2 (6H, s);

1,8 (3H, m).1.8 (3 H, m).

Príklad 9Example 9

Kyselina 2-(4,6-dimetyl-2-pyrimidinyloxy)-3-(2-(4-metylfenyl)etoxy)-3-fenylbutánová (diastereoizomér I, podľa všetkého 2s,3r) 1H NMR (200 MHz, DMSO): 12 -13,5 ppm (1H, br); 7,0 - 7,3 (9H, m); 6,8 (1H, s);2- (4,6-dimethyl-2-pyrimidinyloxy) -3- (2- (4-methylphenyl) ethoxy) -3-phenylbutyric acid (diastereomer I, presumably 2s, 3r) 1H NMR (200 MHz, DMSO) : 12-13.5 ppm (1 H, br); 7.0 - 7.3 (9H, m); 6.8 (1 H, s);

5,3 (1 H, s); 3,4 - 3,7 (2H, m); 2,7 - 2,9 (2H, m); 2,25 (6H, s); 2,2 (3H, s); 1,7 (3H, s). ESI-MS: M+ = 4205.3 (1H, s); 3.4-3.7 (2H, m); 2.7-2.9 (2H, m); 2.25 (6 H, s); 2.2 (3H, s); 1.7 (3H, s). ESI-MS: M &lt; + &gt; = 420

Príklad 10Example 10

Kyselina 2-(4,6-dimetyl-2-pyrimidinyloxy)-3-(3-fenylpropoxy)-3-fenylbutánová (diastereoizomér I, podľa všetkého 2s,3r) 1H NMR (200 MHz, DMSO): 12 -13,5 ppm (1H, br); 7,1 - 7,4 (9H, m); 6,8 (1H, s);2- (4,6-dimethyl-2-pyrimidinyloxy) -3- (3-phenyl-propoxy) -3-phenylbutyric acid (diastereomer I, presumably 2s, 3r) 1H NMR (200 MHz, DMSO): 12 -13, Δ ppm (1 H, br); 7.1-7.4 (9H, m); 6.8 (1 H, s);

5.3 (1H, s); 3,2 - 3,6 (2H, m); 2,5 - 2,7 (2H, m); 2,25 (6H, s); 1,7 (3H. s); 1,ľ - 1,9 (2H, m).5.3 (1 H, s); 3.2-3.6 (2H, m); 2.5-2.7 (2H, m); 2.25 (6 H, s); 1.7 (3H, s); 1.1-1.9 (2H, m).

ESI-MS: M* = 420ESI-MS: M <+> = 420

Príklad 11Example 11

Kyselina 2-(4,6-dimetyl-2-pyrimidinyloxy)-3-(2-(2-naftyl)etoxy)-3-fenylbutánová (diastereoizomér I, podľa všetkého 2s,3r)2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (2- (2-naphthyl) ethoxy) -3-phenylbutanoic acid (diastereoisomer I, presumably 2s, 3r)

H NMR (250 MHz, DMSO): 12 -13,5 ppm (1H, br); 7,7 - 7,9 (4H, m); 7,1 - 7,5 (8H, m): 6,9 (1H, s); 5,3 (1H, s); 3,6 - 3,8 (1H, m); 3,4 - 3,6 (1H, m); 2,9 - 3,1 (2H, m);1 H NMR (250 MHz, DMSO): δ -13.5 ppm (1H, br); 7.7 - 7.9 (4H, m); 7.1-7.5 (8H, m); 6.9 (1H, s); 5.3 (1 H, s); 3.6-3.8 (1 H, m); 3.4-3.6 (1H, m); 2.9-3.1 (2H, m);

2.3 (6H, s); 1,7 (3H, s).2.3 (6 H, s); 1.7 (3H, s).

ESI-MS: M* = 456ESI-MS: M &lt; + &gt; = 456

Príklad 12Example 12

Kyselina 2-(4,6-dimetyl-2-pyrimidinyloxy)-3-(3-(4-chlórfenyl)propoxy)-3-fenyl-butánová (diastereoizomér I, podľa všetkého 2s,3r)2- (4,6-dimethyl-2-pyrimidinyloxy) -3- (3- (4-chlorophenyl) propoxy) -3-phenylbutyric acid (diastereoisomer I, presumably 2s, 3r)

-281H NMR (270 MHz, DMSO): 12,5 -13,0 ppm (1H, br); 7,15 - 7,5 (9H, m); 6,9 (1H, s); 5,2 (1H, s); 3,3 - 3,5 (1H, m); 3,1 - 3,3 (1H, m); 2,55 - 2,7 (2H, m); 2,3 (6H, s); 1,7 (3H, s); 1,65-1,9 (2H, m).-28 1 H NMR (270 MHz, DMSO): 12.5 -13.0 ppm (1 H, br); 7.15 - 7.5 (9H, m); 6.9 (1 H, s); 5.2 (1 H, s); 3.3-3.5 (1H, m); 3.1-3.3 (1H, m); 2.55 - 2.7 (2H, m); 2.3 (6H, s); 1.7 (3H, s); 1.65-1.9 (2 H, m).

ESI-MS: M+ = 454ESI-MS: M &lt; + &gt; = 454

Príklad 13Example 13

Kyselina 2-(4,6-dimetyl-2-pyrimidinyloxy)-3-(2-(4-fluórfenyl)etoxy)-3-fenylbutánová (diastereoizomér I, podľa všetkého 2s,3r) 1H NMR (200 MHz, DMSO): 12,0 -13,0 ppm (1H, br); 7,0 - 7,4 (9H, m); 6,8 (1H, s); 5,2 (1 H, s); 3,5 - 3,7 (1 H, m); 3,3 - 3,5 (1 H, m); 2,7 - 2,85 (2H, m); 2,3 (6H, s); 1,7 (3H, s).2- (4,6-dimethyl-2-pyrimidinyloxy) -3- (2- (4-fluorophenyl) ethoxy) -3-phenylbutyric acid (diastereomer I, presumably 2s, 3r) 1H NMR (200 MHz, DMSO) : 12.0-13.0 ppm (1 H, br); 7.0 - 7.4 (9H, m); 6.8 (1 H, s); 5.2 (1H, s); 3.5-3.7 (1H, m); 3.3-3.5 (1H, m); 2.7 - 2.85 (2H, m); 2.3 (6H, s); 1.7 (3H, s).

ESI-MS: M+ = 424ESI-MS: M &lt; + &gt; = 424

Príklad 14Example 14

Kyselina 2-(4,6-dimetyl-2-pyrimidinyloxy)-3-(2-(4-fluórfenyl)etoxy)-3-fenylbutánová (diastereoizomér II, podľa všetkého 2s,3s) 1H NMR (200 MHz, DMSO): 12,5 -13,0 ppm (1H, br); 7,0 - 7,4 (9H, m); 6,8 (1H, s); 5,1 (1 H, s); 3,5 -3,7 (1 H, m); 3,2 - 3,4 (1 H, m); 2,7 - 2,85 (2H, m); 2,3 (6H, s); 1,65 (3H, s).2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (2- (4-fluorophenyl) ethoxy) -3-phenylbutanoic acid (diastereomer II, presumably 2s, 3s) 1 H NMR (200 MHz, DMSO) 12.5 -13.0 ppm (1 H, br); 7.0 - 7.4 (9H, m); 6.8 (1 H, s); 5.1 (1H, s); 3.5-3.7 (1H, m); 3.2-3.4 (1H, m); 2.7 - 2.85 (2H, m); 2.3 (6H, s); 1.65 (3 H, s).

ESI-MS: M+ = 424ESI-MS: M &lt; + &gt; = 424

Príklad 15Example 15

Kyselina 2-(4,6-dimetyl-2-pyrimidinyloxy)-3-(2-(4-metoxyfenyl)etoxy)-3-fenylbutánová (diastereoizomér I, podľa všetkého 2s,3r) 1H NMR (200 MHz, DMSO): 12,0 -13,0 ppm (1H, br); 7,2 - 7,4 (5H, m); 7,1 (2H, d);2- (4,6-dimethyl-2-pyrimidinyloxy) -3- (2- (4-methoxyphenyl) ethoxy) -3-phenylbutyric acid (diastereomer I, presumably 2s, 3r) 1H NMR (200 MHz, DMSO) : 12.0-13.0 ppm (1 H, br); 7.2 - 7.4 (5H, m); 7.1 (2 H, d);

6,9 (1H, s); 6,75 (2H, d); 5,2 (1H, s); 3,7 (3H, s); 3,4 - 3,6 (1H, m); 3,2 - 3,4 (1H, m); 2,7 - 2,85 (2H, m); 2,3 (6H, s); 1,7 (3H, s).6.9 (1 H, s); 6.75 (2 H, d); 5.2 (1 H, s); 3.7 (3 H, s); 3.4-3.6 (1H, m); 3.2-3.4 (1H, m); 2.7 - 2.85 (2H, m); 2.3 (6H, s); 1.7 (3H, s).

ESI-MS: M* = 436ESI-MS: M &lt; + &gt; = 436

Príklad 16Example 16

Kyselina 2-(4,6-dimetyl-2-pyrimidinyloxy)-3-(3-(4-metoxyfenyl)propoxy)-3-fenylbutánová (diastereoizomér I, podľa všetkého 2s,3r)2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (3- (4-methoxyphenyl) propoxy) -3-phenylbutanoic acid (diastereomer I, presumably 2s, 3r)

-29Teplota topenia.: 153 až 156 °C-29 Melting point: 153-156 ° C

ESI-MS: M+ = 450ESI-MS: M &lt; + &gt; = 450

Zlúčeniny zosumarizované v tabuľke 1 sa môže pripraviť analogicky alebo ako je opísané vo všeobecnej sekcii.The compounds summarized in Table 1 can be prepared analogously or as described in the general section.

o COo CO

Tabuľka 1Table 1

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First f F Φ 2 Φ 2 - - 1 1 1 1 1 1 1 1 Φ Φ Φ Φ Φ Φ Φ Φ £ £ 1 1 Φ s Φ p Φ 2 Φ 2 £ £ LL LL Φ Φ Φ Φ Q Q 1 1 2 2 2 2 t T Y Y a and UJ UJ UJ UJ UJ UJ Q Q a and a and 2 2 2 2 2 2 2 2 O ABOUT UJ UJ LU LU O ABOUT Φ Φ 2 2 2 2 > > Q Q x x O ABOUT O ABOUT o about o about c C c Φ c Φ ω ω O ABOUT O l Tf ABOUT l Tf O ABOUT 4 4 ’M· The M · 4 4 O ABOUT O ABOUT O 4 Tf ABOUT 4 Tf O ABOUT 2 > 2 > o about O ABOUT ω ω ω ω 2 > 2 > 2 2 4 4 4 4 c C uS uS m m υ υ u at c C C C O ABOUT cô what A A A A CO WHAT x x x x CO WHAT 4 4 4 4 4 4 co’ what' co what co what ώ ώ co what 4 4 o about 4 4 Tf tf 4 4 4 4 □ □ 4 4 « « co’ what' x x co’ what' co’ what' 4 4 x x x x 4 4 k x o k x o 1 CM T o 1 CM T o k T O to T O k T o k T o N x o N x o k x o k x o k X o to X o k X O k X O k T o to T o k X □ k X □ k x o k x o k X o k X o k X o to X o k X o to X o k X o to X o k X o k X o 1 (N X o 1 (N X o k X o 1 x o k X o 1 x o k X o k X o k X o k X o k X □ k X □ 1 CM x o 1 CM x o k to k to k to k to k to k to k to k to k to k to k to k to k to k to CM CM k to k to k to k to k to k to k to k to x x x x x x x x x x x x x x x x x x x x x x I I I I x x x x x x x x x x x x x x I I I I x x x x x x I I x x x x x x x x x x X X I I I I o about o about o about o about o about o about o about o about o about o about o about u at o about o about o about o about o about o k OK ω ω o about o about υ υ υ υ o about o about υ υ υ k υ k c C o about υ υ υ υ o about o about u at u at k to k to II II II II k to k to II II k to k to k to k to II II II II II II k to k to k to II II k to k to k to k to II II II II k to Φ Φ k to k to II II II II I I x x I I x x x x x x x x I I I I x x I I I I I I I I x x x x x x I I x x I I I I x x I I X X I I I I x x LL LL I I I I x x x x I I x x I I o about o about o about o 1 about 1 o 1 about 1 o about o about o about o about o t o t o 4 about 4 o about o about o about o 1 about 1 υ i υ and o about o about υ 4 υ 4 o 1 about 1 o 1 about 1 o 1 about 1 o 1 about 1 o about o 1 about 1 o about o 1 about 1 o 1 about 1 o about o 1 about 1 o about o about o 1 about 1 o about o about <o <o (0 x (0 x (0 x (0 x CO I CO I x x o about o about o about o about k to k to x x x x X X x x o about o about o about > > > > Q Q >. >. >» > » > > > > >> >> 0 0 >» > » > > 5> 5> ό ό >> >> >. >. >, >. > > ô about >» > » > > T. T. >1 > 1 k to k to Φ Φ Φ Φ h> h> Φ Φ CD CD T O 1 T O 1 Φ Φ Φ Φ b b b b uľ already Φ Φ Φ Φ Φ Φ Φ Φ Φ Φ b b b b φ φ -f -f Φ Φ b b b b φ φ b b b b X X b b φ φ b b Φ Φ Φ Φ Φ Φ I I Φ Φ 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 o about 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 o about 2 2 2 2 2 2 2 2 2 2 2 2 O ABOUT 2 2 2 2 2 2 2 2 2 2 2 2 o about 2 2 > > > > > > > > > > > > > > > > > > > > > > >. >. > > C C c C C C c C c C c C c C c C c C c C c C n n c C c C r r c C Φ Φ φ φ 14-F-Fer 14-F-Fer Φ Φ φ φ φ φ Φ Φ φ φ φ φ φ φ φ φ Φ Φ Φ Φ φ φ Φ Φ Φ Φ Φ Φ L L E E x x x x | Fenyl | phenyl | Fenyl | phenyl | Fenyl | phenyl x x x x x x x x | Fenyl | phenyl | Fenyl | phenyl | Fenyl | phenyl x x x x x x x x 1 Fenyl 1 Phenyl Fenyl phenyl x x x x I Fenyl I Phenyl x x x x Fenyl phenyl x x x x Fenyl phenyl Φ Φ Φ Φ Ô 1 ’M· ABOUT 1 ’M · 1 o 4 1 o 4 C Φ x C Φ x 4-a- 4-a- ϋ 4 ϋ 4 ó 1 'M· about 1 'M · 4-CI- 4-Cl 1 o 4 1 o 4 i o 4 i o 4 ó 4 ’M- about 4 'M- 4-CI- 4-Cl | Fény | driers 4-CI- 4-Cl 4-CI- 4-Cl |Feny | Bitches 1 υ 4 1 υ 4 4-CI-i 4-Cl-i J. 9 J. 9 1 o 4 1 o 4 Fenyl phenyl 4-F-F 4-F-F 4-F-F 4-F-F Fenyl phenyl x x I I x x x x x x x x I I x x x x I I X X φ 2 φ 2 x x x x x x x x I I X X x x x x x x X X I I x x x x x x X X I I x x I I x x x x T T X X T T o about o about O ABOUT O ABOUT O ABOUT O ABOUT o about o about o about o about o about O ABOUT O ABOUT O ABOUT o about o about o about o about O ABOUT O ABOUT O ABOUT O ABOUT O ABOUT O ABOUT o about o about O ABOUT O ABOUT 0 0 o about O ABOUT O ABOUT O ABOUT O ABOUT O ABOUT o about o about o about o about O ABOUT O ABOUT o about o about o about O ABOUT o about O ABOUT o about o about o about o about O ABOUT o about o about o about o about O ABOUT o about o about o about o about o about o about o about O ABOUT o about o about O ABOUT O ABOUT o about u at υ υ o about o about ϋ ϋ O ABOUT o about o about υ υ O ABOUT o about O ABOUT o about o about o about o about O ABOUT ϋ ϋ o about o about o about O ABOUT o about o about o about o about Q Q O ABOUT o about O ABOUT υ υ O ABOUT O ABOUT O ABOUT o about m m CO WHAT b- b- oo oo 0) 0) o about CM CM CO WHAT 'M' The M U) U) CO WHAT b- b- oo oo a> a> o about Q Q CO WHAT Tf tf 3 3 CO WHAT b- b- CO WHAT CD CD o about M“ M " CM CM 5? 5? ’M· The M · ιο ιο co what b- b- s? with? 0> 0> CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM cm cm CM CM co what CO WHAT co what CO WHAT M M CO WHAT CO WHAT CO WHAT CO WHAT Tf tf Tf tf b- 1 b- 1 b- 1 b- 1 b- 1 b- 1 b- 1 b- 1 b- b- b- 1 b- 1 b- 1 b- 1 b- b- b- b- b- b- b- 1 b- 1 b- 1 b- 1 b- b- b- 1 b- 1 b- b- b. 1 b. 1 b. 1 b. 1 b- 1 b- 1 b. 1 b. 1 b- 1 b- 1 b* i b * i b· 1 b · 1 h- h- b. 1 b. 1 b- 1 b- 1 b- 1 b- 1 b- 1 b- 1 T T b. 1 b. 1 b· 1 b · 1 b* 1 b * 1 b· i b · and b- 1 b- 1 b- 1 b- 1

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-53Príklad 17-53Example 17

Údaje väzby receptora sa merali s použitím skúšky väzbovosti opísanej vyššie pre uvedené zlúčeniny.Receptor binding data was measured using the binding assay described above for the compounds.

Výsledky sú znázornené v tabuľke 2.The results are shown in Table 2.

Tabuľka 2 > Údaje väzby receptora (hodnoty K,)Table 2> Receptor Binding Data (K-Values)

Príklad Example ETA[nM]ET A [nM] ETb [n M]ET b [n M] 3 3 20 20 70 70 6 6 95 95 780 780 7 7 35 35 70 70 8 8 72 72 580 580 9 9 36 36 75 75 10 10 700 700 1000 1000 11 11 95 95 100 100 12 12 90 90 850 850 13 13 350 350 930 930 14 14 100 100 145 145 15 15 45 45 140 140 16 16 40 40 230 230

f /fäT-f / fäT-

Claims (9)

PATENTOVÉ NÁROKYPATENT CLAIMS 1. Derivát karboxylovej kyseliny všeobecného vzorca I kde substituenty majú nasledujúce významy: R1 znamená tetrazolyl alebo skupinu kde R predstavujeA carboxylic acid derivative of the formula I wherein the substituents have the following meanings: R 1 represents tetrazolyl or a group wherein R represents a) zvyšok OR7, v ktorom R7 znamená:(a) a residue of OR 7 in which R 7 represents: vodík, katión alkalického kovu, katión kovu alkalických zemín alebo fyziologicky prijateľný organický amóniový ión;hydrogen, an alkali metal cation, an alkaline earth metal cation, or a physiologically acceptable organic ammonium ion; C3-C8-cykloalkylovú skupinu, Ci-C8-alkylovú skupinu,C 3 -C 8 -cycloalkyl, C 1 -C 8 -alkyl, CH2-fenylovú skupinu, ktorá môže byť prípadne substituovaná, aleboCH 2 -phenyl, which may be optionally substituted, or C3-C6-alkenylovú alebo C3-C6-alkinylovú skupinu, ktoré môžu byť prípadne substituované, alebo fenyl, ktorý môže byť prípadne substituovaný;A C 3 -C 6 -alkenyl or C 3 -C 6 -alkynyl group which may be optionally substituted, or a phenyl which may be optionally substituted; b) 5-členný heteroaromatický systém, ktorý je viazaný prostredníctvom atómu dusíka;b) a 5-membered heteroaromatic system which is bonded via a nitrogen atom; c) skupinu (fl’\ —O”(CH2)~S_R , v ktorej k predstavuje hodnoty 0, 1 a 2, p znamená hodnoty 1, 2, 3 a 4, a R8 predstavujec) a (fi '\ O' (CH2) ~ _ S R, which is a value of 0, 1 and 2, the value of p is 1, 2, 3 and 4, and R 8 is -55Ci-C4-alkylskupinu, C3-C8-cykloalkylskupinu, C3-C6.alkenylskupinu, C3Ce-alkinylskupinu alebo prípadne substituovanú fenylovú skupinu;-55C 1 -C 4 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 -alkynyl or optionally substituted phenyl; d) zvyšok o(d) the remainder by v ktorom R9 znamenáwherein R 9 is Ci-C4-alkylovú skupinu, C3-C6-alkenylovú skupinu, C3-C6-alkinylovú skupinu, C3-C8-cykloalkylovú skupinu, pričom tieto zvyšky môžu niesť Ci-C4-alkoxylskupinu, Ci-C4-alkyltioskupinu a/alebo fenylový zvyšok;C 1 -C 4 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, which residues may carry C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl 4- alkylthio and / or phenyl; fenylovú skupinu, ktorá je prípadne substituovaná,phenyl optionally substituted, e) zvyšok(e) the rest Λ ' 1414 R kde R13 a R14 môžu byť rovnaké alebo rozdielne a majú nasledujúce významy vodík, Ci-Ce-alkylskupina, C3-C8-cykloalkylskupina, C3-C8-alkenyl skupina;Wherein R 13 and R 14 may be the same or different and have the following meanings hydrogen, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -alkenyl; C3-C8-alkinylová skupina, benzylová skupina, fenylová skupina, ktorá je prípadne substituovaná, alebo R13 a R14 spolu tvoria C4-C7-alkylénový reťazec, ktorý je uzatvorený do kruhu a môže obsahovať heteroatóm;C 3 -C 8 -alkynyl, benzyl, phenyl optionally substituted, or R 13 and R 14 taken together form a C 4 -C 7 -alkylene ring which is ring-closed and may contain a heteroatom; R2 znamená vodík, hydroxyskupinu, NH2, NH(CrC4-alkyl), N(Ci-C4-alkyl)2, halogén, CrC4-alkylskupinu, C2-C4-alkenylskupinu, C2-C4-alkinylskupinu, CrC4-halogénalkylskupinu, Ci-C4-alkoxylskupinu, Ci-C4-halogénalkoxylovú skupinu alebo Ci-C4-alkyltioskupinu, alebo CR2 je viazaný ku CR10 ako je uvedené nižšie, za vzniku 5- alebo 6-členného kruhu;R 2 is H, OH, NH2, NH (Ci-C4 alkyl), N (Ci-C4 alkyl) 2, halo, -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 - alkynyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 1 -C 4 -alkylthio, or CR 2 is bound to CR 10 as below to form a 5- or 6-membered ring; X predstavuje dusík alebo metín;X represents nitrogen or methine; -56Y znamená dusík alebo metín;-56Y means nitrogen or methine; Z predstavuje dusík alebo skupinu CR10, v ktorom R10 znamená vodík, halogén, hydroxylovú skupinu, CrC4-halogénalkylovú skupinu alebo Ci-C4-alkylovú skupinu, alebo CR10 tvorí spolu s CR2 alebo CR3 5alebo 6-členný alkylénový alebo alkenylénový kruh, ktorý môže byť prípadne substituovaný a v ktorom v každom prípade jedna alebo viac metylénových skupín môže byť nahradených kyslíkom, sírou, -NH alebo skupinou -N(CrC4-alkyl);Z represents nitrogen or CR 10 in which R 10 represents hydrogen, halogen, hydroxyl, C 1 -C 4 -haloalkyl or C 1 -C 4 -alkyl, or CR 10 together with CR 2 or CR 3 forms a 5 or 6-membered alkylene or an alkenylene ring which may be optionally substituted and in which case one or more methylene groups may in each case be replaced by oxygen, sulfur, -NH or -N (C 1 -C 4 -alkyl); R3 predstavuje vodík, hydroxylovú skupinu, NH2, NH(Ci-C4-alkyl), N(Ci-C4alkyl)2, halogén, Ci-C4-alkylovú skupinu, C2-C4-alkenylovú skupinu, C2C4-alkinylovú skupinu, Ci-C4-hydroxyalkylovú skupinu, Ci-C4-halogénalkylovú skupinu, Ci-C4-alkoxylovú skupinu, Ci-C4=-halogénalkoxylovú skupinu, Ci-C4-alkyltioskupinu alebo CR3 je viazaný ku CR10 ako je uvedené vyššie, za vzniku 5- alebo 6-členného kruhu;R 3 represents hydrogen, hydroxyl, 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 1 -C 4 -hydroxyalkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 = -haloalkoxy, C 1 -C 4 -alkylthio or CR 3 is bonded to CR 10 as above to form a 5- or 6-membered ring; R4 znamená Ci-C4-alkylovú skupinu, C2-C4-alkenylovú skupinu alebo C2C4-alkinylovú skupinu, ktoré môžu byť prípadne substituované;R 4 is C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl or C 2 -C 4 -alkynyl which may be optionally substituted; R5 predstavuje fenylovú alebo naftylovú skupinu, z ktorých každá môže byť prípadne substituovaná; alebo fenylovú alebo naftylovú skupinu, ktorá je pripojená v orto-polohe ku R4 pomocou priamej väzby, metylénovej, etylénovej alebo etenylénovej skupiny, atómu kyslíka alebo síry alebo SO2, NH alebo N-alkylovej skupiny;R 5 represents a phenyl or naphthyl group, each of which may be optionally substituted; or a phenyl or naphthyl group which is attached at the ortho-position to R 4 by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group; C3-C8-cykloalkylovú skupinu, ktorá je prípadne substituovaná;C 3 -C 8 -cycloalkyl optionally substituted; R6 znamená prípadne substituovanú Cs-Ce-cykloalkylovú skupinu;R 6 represents an optionally substituted C 3 -C 6 -cycloalkyl group; fenylovú alebo naftylovú skupinu, z ktorých každá môže niesť jeden alebo viac z nasledujúcich zvyškov, ako je halogén, R15, nitroskupina, merkaptoskupina, karboxylová skupina, kyanoskupina, hydroxylová skupina, aminoskupina, CrC4-alkylová skupina, C2-C4-alkenylová skupina, C2-C4-alkinylová skupina, C3-C6alkenyloxylová skupina, Cr C4-halogénalkylová skupina, C3-C6.alkinyloxylová skupina, CrC4-57alkylkarbonylová skupina, Ci-C4-alkoxykarbonylová skupina, Ci-C4alkoxylová skupina, Ci-C4-halogénalkoxylová skupina, fenoxyskupina,phenyl or naphthyl, each of which may bear one or more of the following radicals such as halogen, R 15 , nitro, mercapto, carboxyl, cyano, hydroxyl, amino, C 1 -C 4 -alkyl, C 2 -C 4 - alkenyl, C 2 -C 4 -alkynyl, C 3 -C 6 alkenyloxy group, a C r C 4 -haloalkyl group, a C 3 -C 6 .alkinyloxylová group, a C r C 4 -57alkylkarbonylová group, a Ci-C 4 - alkoxycarbonyl, C 1 -C 4 alkoxy, C 1 -C 4 -haloalkoxy, phenoxy, Ci-C4-alkyltioskupina, NH(Ci-C4-alkyl), N(Ci-C4-alkyl)2, metyléndioxylová skupina, etyléndioxylová skupina alebo fenylová skupina, ktorá môže byť substituovaná, jedenkrát alebo viackrát, napríklad * jedenkrát až trikrát, substituentom ako je halogén, nitroskupina, kyanoskupina, Ci-C4-alkylová skupina, C1-C4-halogénalkylová skupina, * Ci-C4-alkoxylová skupina, Ci-C4-halogénalkoxylová skupina alebo Cr C4-alkyltioskupina, pod podmienkou, že ak R6 znamená nesubstituovaný fenylový zvyšok, R2 a R3 nemôžu obidva predstavovať OCH3;C -C 4 -alkylthio, NH (Ci-C4 alkyl), N (Ci-C4 alkyl) 2, methylenedioxy, ethylenedioxy, or phenyl which may be substituted one or more times, for example once to * three times, by halogen, nitro, cyano, Ci-C 4 -alkyl, C 1 -C 4 -haloalkyl group, a C * -C 4 -alkoxy, C 4 -halogénalkoxylová, or C r C 4 - alkylthio, provided that when R 6 is an unsubstituted phenyl radical, R 2 and R 3 cannot both represent OCH 3 ; päť- alebo šesť-členný heteroaromatický systém, ktorý obsahuje jeden až tri atómy dusíka a/alebo jeden atóm síry alebo kyslíka a ktorý môže niesť jeden až štyri atómy halogénu a/alebo jeden až dva z nasledujúcich zvyškov, ako je Ci-C4-alkylová skupina, C2-C4alkenylová skupina, Ci-C4-halogénalkylová skupina, Ci-C4-alkoxylová skupina, Ci-C4-halogén-alkoxylová skupina, Ci-C4-alkyltioskupina, fenylová skupina alebo fenoxyskupina, pričom fenylové zvyšky môžu samotné niesť jeden až päť atómov halogénu a/alebo jeden až tri z nasledujúcich zvyškov, ako je CrC4-alkylová skupina, Ci-C4-halogénalkylová skupina, Ci-C4-alkoxylová skupina, CrC4-halogénalkoxylová skupina a/alebo Ci-C4-alkyltio-skupina;a five- or six-membered heteroaromatic system which contains one to three nitrogen atoms and / or one sulfur or oxygen atom and which may bear one to four halogen atoms and / or one to two of the following radicals, such as C 1 -C 4 - alkyl, C 2 -C 4 alkenyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, phenyl or phenoxy, wherein: the phenyl radicals in turn to carry one to five halogen atoms and / or one to three of the following radicals: C r C 4 -alkyl, C 4 -haloalkyl group, a Ci-C 4 -alkoxy, -C 4 -halogénalkoxylová a group and / or a C 1 -C 4 -alkylthio group; R15 predstavuje Ci-C4-alkylovú skupinu, Ci-C4-alkyltioskupinu, Ci-C4alkoxylovú skupinu, ktoré nesú jeden z nasledujúcich zvyškov, ako je * hydroxylová skupina, karboxylová skupina, aminoskupina, NH(Ci-C4alkyl), N(Ci-C4-alkyl)2, karbamoylová skupina alebo CON(Ci-C4-alkyl)2;R 15 is C 1 -C 4 -alkyl, C 1 -C 4 -alkylthio, C 1 -C 4 alkoxy bearing one of the following radicals such as * hydroxyl, carboxyl, amino, NH (C 1 -C 4 alkyl) ), N (Ci-C4 alkyl) 2, carboxamide or CON (Ci-C4 alkyl) 2; LL W predstavuje síru alebo kyslík;W represents sulfur or oxygen; Q znamená spacer, ktorý svojou dĺžkou zodpovedá C2.C4-reťazcu;Q is a spacer, which in length corresponds to C 2 .C 4 -reťazcu; a ich fyziologicky prijateľné soli a enantiomérne čisté a diastereoizomérne čisté formy.and their physiologically acceptable salts and enantiomerically pure and diastereoisomerically pure forms. 2. Farmaceutický prípravok na orálne, parenterálne alebo intraperitoneálne použitie, vyznačujúci sa tým, že obsahuje najmenej jeden derivát karboxylovej kyseliny vzorca I, podľa nároku 1 okrem konvenčných farmaceutických pomocných látokPharmaceutical preparation for oral, parenteral or intraperitoneal use, characterized in that it comprises at least one carboxylic acid derivative of the formula I according to claim 1 in addition to conventional pharmaceutical excipients 3. Použitie derivátu karboxylovej kyseliny podľa nároku 1 na liečenie ochorení.Use of a carboxylic acid derivative according to claim 1 for the treatment of diseases. 4. Použitie zlúčeniny vzorca I podľa nároku 1, ako antagonistu endotelínového receptora.Use of a compound of formula I according to claim 1 as an endothelin receptor antagonist. 5. Použitie derivátu karboxylovej kyseliny vzorca I podľa nároku 1, na prípravu liečiv na liečenie ochorení, pri ktorých sa vyskytujú zvýšené hladiny endotelínu.Use of a carboxylic acid derivative of the formula I according to claim 1 for the preparation of medicaments for the treatment of diseases in which elevated endothelin levels occur. 6. Použitie derivátu karboxylovej kyseliny vzorca I podľa nároku 1, na liečenie chronického zlyhania srdca, infarktu myokardu, aterosklerózy, arytmie, angíny pectoris, restenózy, vysokého krvného tlaku, pulmonálnej hypertenzie, akútneho/chronického zlyhania obličiek, renálnej nedostatočnosti, cerebrálnej ischémie, astmy, benígnej hyperplázie prostaty a karcinómu prostaty.Use of a carboxylic acid derivative of the formula I according to claim 1, for the treatment of chronic heart failure, myocardial infarction, atherosclerosis, arrhythmia, angina pectoris, restenosis, high blood pressure, pulmonary hypertension, acute / chronic renal failure, renal insufficiency, astebral ischemia , benign prostate hyperplasia and prostate cancer. 7. Použitie derivátu karboxylovej kyseliny vzorca I podľa nároku 1, v kombinácii s inhibítormi renín-angiotenzínového systému, zmesnými inhibítormi ACE/neutrálnej endopeptidázy (NEP), β-blokátormi.Use of a carboxylic acid derivative of the formula I according to claim 1, in combination with inhibitors of the renin-angiotensin system, mixed ACE / neutral endopeptidase (NEP) inhibitors, β-blockers. 8. Použitie zlúčenín vzorca IVUse of compounds of formula IV R—Q—WR-Q-W RR H --C—OHH - C - OH 5 115 11 R R (IV) , v ktorom zvyšky R1, R4, R5, R6, Q a W majú významy definované v nároku 1, ako východiskového materiálu na syntézu zmesných antagonistov ETA/ETB receptora.RR (IV), wherein the residues R 1 , R 4 , R 5 , R 6 , Q and W have the meanings defined in claim 1 as a starting material for the synthesis of mixed ET A / ET B receptor antagonists. 9. Štruktúrny fragment vzorca9. Structural fragment of the formula R—Q—WR-Q-W RR H * tr°t R R v ktorom zvyšky R1, R4, Rs, R6, Q a W majú významy definované v nároku 1, ako štruktúrny element zmesného antagonistu ETa/ETb receptora.H * t tr ° RR in which the radicals R 1, R 4, R s, R 6, Q and W are as defined in claim 1, as structural element of the mixed ETA antagonist / ET B receptors.
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