HRP20010164A2 - New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists - Google Patents

Description

Endotelin je peptid izgrađen od 21 amino kiseline, kojeg sintetizira i oslobađa vaskularni endotel. Endotelin postoji u tri izomerna oblika, ET-1, ET-2 i ET-3. Kako se ovdje rabi, pojam “endotelin” ili “ET” odnosi se na jedan ili na sve izomerne oblike endotelina. Endotelin je jaki vazokonstriktor i snažno djeluje na tonus krvnih žila. Poznato je, da tu vazokonstrikciju uzrokuje vezanje endotelina na njegov receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 i Biochem. Biophys. Res. Commun., 154, (1988), 868-875). Endothelin is a peptide made of 21 amino acids, which is synthesized and released by the vascular endothelium. Endothelin exists in three isomeric forms, ET-1, ET-2 and ET-3. As used herein, the term “endothelin” or “ET” refers to one or all of the isomeric forms of endothelin. Endothelin is a strong vasoconstrictor and has a strong effect on blood vessel tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, (1988), 868 -875).

Povišeno ili nenormalno oslobađanje endotelina uzrokuje trajno sužavanje u perifernim, renalnim i cerebralnim krvnim žilama, koje može dovesti do zdravstvenih poremećaja. Iz literature je poznato da je endotelin uključen u brojne zdravstvene poremećaje. To su hipertenzija, akutni miokardijalni infarkt, plućna hipertenzija, Raynaudov sindrom, cerebralne vazospazme, udar kapi, benigna hipertrofija prostate, ateroskleroza, astma i rak prosta (J. Vascular Med. Biology 2, (1990) 207, J. Am. Med. Association 264, (1990) 2868, Nature 344, (1990) 114, N. Engl. J. Med. 322, (1989) 205, N. Engl. J. Med. 328, (1993) 1732, Nephron 66, (1994) 373, Stroke 25, (1994) 904, Nature 365, (1993) 759, J. Mol. Cell. Cardiol. 27, (1995) A234, Cancer Research 56, (1996) 663. Elevated or abnormal release of endothelin causes permanent narrowing in peripheral, renal and cerebral blood vessels, which can lead to health disorders. It is known from the literature that endothelin is involved in numerous health disorders. These are hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2, (1990) 207, J. Am. Med. Association 264, (1990) 2868, Nature 344, (1990) 114, N. Engl. J. Med. 322, (1989) 205, N. Engl. J. Med. 328, (1993) 1732, Nephron 66, ( 1994) 373, Stroke 25, (1994) 904, Nature 365, (1993) 759, J. Mol. Cell. Cardiol. 27, (1995) A234, Cancer Research 56, (1996) 663.

Zasada su u literaturi opisana najmanje dva podtipa endotelin-receptora, ETA i ETB receptori (Nature 348, (1990) 730, Nature 348, (1990) 732). Prema tome, tvari koje inhibiraju vezanje endotelina na jedan ili na obadva receptora, antagoniziraju fiziološke efekte endotelina i stoga predstavljaju dragocjene lijekove. So far, at least two subtypes of endothelin receptors, ETA and ETB receptors, have been described in the literature (Nature 348, (1990) 730, Nature 348, (1990) 732). Therefore, substances that inhibit the binding of endothelin to one or both receptors antagonize the physiological effects of endothelin and therefore represent valuable drugs.

Miješani endotelin receptor antagonisti su oni spojevi koji se vežu s približno jednakim afinitetom na ETA i na ETB receptore. Približno jednak afinitet za receptore postoji kad je omjer afiniteta ETA:ETB veći od 0,05, ponajprije veći od 0,1, i manji od 20, ponajprije manji od 10. Mixed endothelin receptor antagonists are those compounds that bind with approximately equal affinity to ETA and ETB receptors. Approximately equal receptor affinity exists when the ETA:ETB affinity ratio is greater than 0.05, preferably greater than 0.1, and less than 20, preferably less than 10.

U patentnoj prijavi DE 19636046.3 opisani su miješani ЕТA/ЕТB receptor antagonisti. Za te spojeve važna je skupina razmaka Q (vidi formulu XX), koja duljinom odgovara lancu C2-C4-alkila. Patent application DE 19636046.3 describes mixed ETA/ETB receptor antagonists. Important for these compounds is the spacing group Q (see formula XX), which corresponds in length to the C2-C4-alkyl chain.

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Miješani receptor antagonisti su također dobiveni sa skupinom razmaka Q = COCR7R8 (vidi formulu I). Mixed receptor antagonists have also been obtained with the spacer group Q = COCR7R8 (see formula I).

Zadatak izuma je identificirati spojeve koji se s približno jednakim afinitetom vežu na ЕТA i ЕТB receptor i koji imaju bolja svojstva u usporedbi s već poznatim miješanim endotelin receptor antagonistima. The task of the invention is to identify compounds that bind with approximately equal affinity to the ETA and ETB receptor and that have better properties compared to already known mixed endothelin receptor antagonists.

Izum se odnosi na derivate karboksilne kiseline formule I The invention relates to carboxylic acid derivatives of formula I

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u kojoj supstituenti imaju slijedeća značenja: in which the substituents have the following meanings:

R1 predstavlja tetrazol ili skupinu R1 represents a tetrazole or a group

[image] [image]

u kojoj where

R ima slijedeća značenja: R has the following meanings:

a) radikal OR9, gdje R9 predstavlja: a) radical OR9, where R9 represents:

vodik, kation alkalijskog metala, kation zemno alkalijskog metala ili fiziološki podnošljiv organski amonijev ion, kao što je tercijarni C1-C4-alkil-amonijev ili amonijev ion; hydrogen, an alkali metal cation, an alkaline earth metal cation, or a physiologically tolerable organic ammonium ion, such as a tertiary C1-C4-alkylammonium or ammonium ion;

C3-C8-cikloalkil, C1-C8-alkil, CH2-fenil, koji može biti supstituirani s jednim ili više slijedećih radikala: halogen, nitro, cijano, C1-C4-alkil, C1-C4-halogenalkil, hidroksi, C1-C4-alkoksi, merkapto, C1-C4-alkiltio, amino, NH(C1-C4-alkil), N(C1-C4-alkil)2; C3-C8-cycloalkyl, C1-C8-alkyl, CH2-phenyl, which may be substituted with one or more of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxy, C1-C4 -Alkoxy, mercapto, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;

C3-C6-alkenilnu ili C3-C6-alkinilnu skupinu, pri čemu te skupine, sa svoje strane, mogu nositi jedan do pet halogenih atoma; C3-C6-alkenyl or C3-C6-alkynyl group, whereby these groups, for their part, can carry one to five halogen atoms;

fenilni radikal koji može nositi jedan do pet halogenih atoma i/ili jedan do tri slijedeća radikala: nitro, cijano, C1-C4-alkil, C1-C4-halogenalkil, hidroksi, C1-C4-alkoksi, merkapto, C1-C4-alkiltio, amino, NH(C1-C4-alkil), N(C1-C4-alkil)2; a phenyl radical that can carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxy, C1-C4-alkoxy, mercapto, C1-C4-alkylthio , amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;

b) peteročlani heteroaromatski sistem koji je povezan preko dušikovog atoma, kao pirolil, pirazolil, imidazolil i triazolil, koji može nositi jedan ili dva halogena atoma, ili jednu ili dvije C1-C4-alkilne ili jednu ili dvije C1-C4-alkoksi skupine; b) a five-membered heteroaromatic system that is connected via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one or two halogen atoms, or one or two C1-C4-alkyl or one or two C1-C4-alkoxy groups;

c) skupina c) group

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u kojoj k može imati vrijednost 0, 1 i 2, p može biti 1, 2, 3 i 4 i R10 je where k can have the value 0, 1 and 2, p can be 1, 2, 3 and 4 and R10 is

C1-C4-alkil, C3-C8-cikloalkil, C3-C6-alkenil, C3-C6-alkinil ili fenil, koji može biti jednostruko ili višestruko, na primjer jednostruko do trostruko supstituiran sa slijedećim radikalima: C1-C4-alkyl, C3-C8-cycloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or phenyl, which can be mono- or multi-substituted, for example mono- to tri-substituted with the following radicals:

halogen, nitro, cijano, C1-C4-alkil, C1-C4-halogen-alkil, hidroksi, C1-C4-alkoksi, C1-C4-alkiltio, merkapto, amino, NH(C1-C4-alkil), N(C1-C4-alkil)2; halogen, nitro, cyano, C1-C4-alkyl, C1-C4-halogeno-alkyl, hydroxy, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, NH(C1-C4-alkyl), N(C1 -C4-alkyl)2;

d) radikal formule d) the radical of the formula

[image] [image]

u kojoj R11 je in which R11 is

C1-C4-alkil, C1-C4-halogenalkil, C3-C6-alkenil, C3-C6-alkinil, C3-C8-cikloalkil, pri čemu ovi radikali mogu nositi C1-C4-alkoksi, C1-C4-alkiltio i/ili fenilni radikal definiran kao pod c); C1-C4-alkyl, C1-C4-halogenoalkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl, wherein these radicals can carry C1-C4-alkoxy, C1-C4-alkylthio and/or phenyl radical defined as under c);

fenil, koji može biti supstituiran s jednim do tri slijedeća radikala: halogen, nitro, cijano, C1-C4-alkil, C1-C4-halogenalkil, hidroksi, C1-C4-alkoksi, C1-C4-alkiltio, merkapto, amino, NH(C1-C4-alkil), N(C1-C4-alkil)2; phenyl, which may be substituted with one to three of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl, hydroxy, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, NH (C1-C4-alkyl), N(C1-C4-alkyl)2;

R2 je vodik, hidroksi, NH2, NH(C1-C4-alkil), N(C1-C4-alkil)2, halogen, C1-C4-alkil, C2-C4-alkenil, C2-C4-alkinil, C1-C4-hidroksialkil, C1-C4-halogenalkil, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio, ili je CR2 povezan na CR12 kako je dolje prikazano za Z, tako da se dobije peteročlani ili šesteročlani prsten; R2 is hydrogen, hydroxy, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4 -hydroxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio, or CR2 is linked to CR12 as shown below for Z, to give a five- or six-membered ring;

X je dušik ili metin; X is nitrogen or methine;

Y je dušik ili metin; Y is nitrogen or methine;

Z je dušik ili CR12, gdje R12 predstavlja vodik, halogen, C1-C4-halogenalkil ili C1-C4-alkil, ili CR12 zajedno sa CR2 ili sa CR3 tvori 5- ili 6-člani alkilenski ili alkenilenski prsten koji može biti supstituiran s jednom ili dvije C1-C4-alkilne skupine i u kojem u svakom slučaju jedna ili više metilenskih skupina može biti zamijenjeno s kisikom, sumporom, -NH ili s N(C1-C4-alkilom), gdje barem jedan od članova prstena X, Y ili Z predstavlja dušik; Z is nitrogen or CR12, where R12 represents hydrogen, halogen, C1-C4-haloalkyl or C1-C4-alkyl, or CR12 together with CR2 or with CR3 forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted with one or two C1-C4-alkyl groups and in each case one or more methylene groups may be replaced by oxygen, sulfur, -NH or by N(C1-C4-alkyl), where at least one of the ring members X, Y or Z represents nitrogen;

R3 je vodik, hidroksi, NH2, NH(C1-C4-alkil), N(C1-C4-alkil)2, halogen, C1-C4-alkil, C2-C4-alkenil, C2-C4-alkinil, C1-C4-halogenalkil, C1-C4-alkoksi, , C1-C4-halogenalkoksi, C1-C4-hidroksialkil, C1-C4-alkiltio, ili je CR3 povezan na CR12 kako je gore navedeno za Z, tako se dobije 5- ili 6-člani prsten; R3 is hydrogen, hydroxy, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4 -haloalkyl, C1-C4-alkoxy, , C1-C4-haloalkyloxy, C1-C4-hydroxyalkyl, C1-C4-alkylthio, or CR3 is linked to CR12 as above for Z, thus giving a 5- or 6-membered a ring;

R4 i R5 (koji mogu biti jednaki ili različiti) predstavljaju: R4 and R5 (which can be the same or different) represent:

fenil ili naftil, od kojih svaki može biti supstituiran s jednim ili više slijedećih radikala: halogen, nitro, cijano, hidroksi, merkapto, C1-C4-alkil, C2-C4-alkenil, C2-C4-alkinil, C1-C4-halogenalkil, C1-C4-alkoksi, fenoksi, karboksi, C1-C4-halogenalkoksi, C1-C4-alkiltio, amino, NH(C1-C4-alkil), N(C1-C4-alkil)2 ili fenil, koji može biti jednostruko ili višestruko, na primjer jednostruko do trostruko supstituiran s halogenim, nitro, cijano, C1-C4-alkilom, C1-C4-halogenalkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; phenyl or naphthyl, each of which may be substituted with one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl . or multiply, for example singly to triply substituted with halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio;

fenil ili naftil koji su međusobno povezani u orto položaju preko izravne veze, metilenske, etilenske ili etenilne skupine, kisikovog ili sumpornog atoma ili SO2, NH ili N-alkilne skupine; phenyl or naphthyl linked to each other in the ortho position via a direct bond, methylene, ethylene or ethenyl group, oxygen or sulfur atom or SO2, NH or N-alkyl group;

C3-C8-cikloalkil; C3-C8-cycloalkyl;

R6 je C3-C8-cikloalkil, pri čemu ti radikali u svakom slučaju mogu biti jednostruko ili višestruko supstituirani sa slijedećim supstituentima: halogen, hidroksi, merkapto, karboksi, nitro, cijano, C1-C4-alkoksi, C1-C4-alkil, C2-C4-alkenil, C2-C4-alkinil, C2-C4-alkeniloksi, C3-C6-alkinil-oksi, C1-C4-alkiltio, C1-C4-halogenalkoksi, C1-C4-alkil-karbonil, C1-C4-alkoksikarbonil, C3-C8-alkilkarbonil, karboksamid, NH(C1-C4-alkil), N(C1-C4-alkil)2 ili fenil, koji može biti jednostruko ili višestruko, na primjer jednostruko do trostruko supstituiran s halogenim, nitro, cijano, C1-C4-alkilom, C1-C4-halogenalkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; R6 is C3-C8-cycloalkyl, whereby these radicals can in any case be singly or multiply substituted with the following substituents: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C1-C4-alkoxy, C1-C4-alkyl, C2 -C4-alkenyl, C2-C4-alkynyl, C2-C4-alkenyloxy, C3-C6-alkynyl-oxy, C1-C4-alkylthio, C1-C4-halogenalkoxy, C1-C4-alkyl-carbonyl, C1-C4-alkoxycarbonyl , C3-C8-alkylcarbonyl, carboxamide, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or phenyl, which can be mono- or multi-substituted, for example mono- to tri-substituted with halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio;

fenil ili naftil, od kojih svaki može biti supstituiran s jednim ili više slijedećih radikala: halogen, R15, nitro, merkapto, karboksi, cijano, hidroksi, amino, C1-C4-alkil, C2-C4-alkenil, C2-C4-alkinil, C3-C6-alkeniloksi, C1-C4-halogenalkil, C3-C6-alkiniloksi, C1-C4-alkilkarbonil, C1-C4-alkoksikarbonil, karboksamid, C1-C4-alkoksi, C1-C4-halogenalkoksi, fenoksi, C1-C4-alkiltio, NH(C1-C4-alkil), N(C1-C4-alkil)2, dioksometilen, diokso-etileln, ili fenil, koji može biti jednostruko ili višestruko, na primjer jednostruko do trostruko supstituiran s halogenim, nitro, cijano, C1-C4-alkilom, C1-C4-halogenalkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; phenyl or naphthyl, each of which may be substituted with one or more of the following radicals: halogen, R15, nitro, mercapto, carboxy, cyano, hydroxy, amino, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl . -alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, dioxomethylene, dioxo-ethylen, or phenyl, which can be mono- or multi-substituted, for example mono- to tri-substituted with halogen, nitro, cyano , C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio;

petero- ili šesteročlani heteroaromatski sistem koji sadrži jedan do tri dušikova atoma i/ili jedan sumporni ili kisikov atom, i koji može nositi jedan do četiri halogena atoma i/ili jedan do dva slijedeća radikala: C1-C4-alkil, C2-C4-alkenil, C1-C4-halogenalkil, C1-C4-alkoksi, C1-C4-halogenalkoksi, C1-C4-alkiltio, fenil ili fenoksi, pri čemu fenilni radikali sa svoje strane mogu nositi jedan do pet halogenih atoma i/ili jedan do tri slijedeća radikala: C1-C4-alkil, C1-C4-halogenalkil, C1-C4-alkoksi, C1-C4-halogen-alkoksi i/ili C1-C4-alkiltio; a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and/or one sulfur or oxygen atom, and which can carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C2-C4- alkenyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy, C1-C4-alkylthio, phenyl or phenoxy, whereby the phenyl radicals can carry one to five halogen atoms and/or one to three the following radicals: C1-C4-alkyl, C1-C4-halogenoalkyl, C1-C4-alkoxy, C1-C4-halo-alkoxy and/or C1-C4-alkylthio;

R7 i R8 (koji mogu biti jednaki ili različiti) predstavljaju: R7 and R8 (which may be the same or different) represent:

vodik, C1-C4-alkil; hydrogen, C1-C4-alkyl;

R15 je C1-C4-alkil, C1-C4-alkiltio, C1-C4-alkoksi, koji može nositi jedan ili više slijedećih radikala: hidroksi, karboksi, amino, NH(C1-C4-alkil), N(C1-C4-alkil)2, karboks-amid ili CON(C1-C4-alkil)2; R15 is C1-C4-alkyl, C1-C4-alkylthio, C1-C4-alkoxy, which can carry one or more of the following radicals: hydroxy, carboxy, amino, NH(C1-C4-alkyl), N(C1-C4- alkyl)2, carboxamide or CON(C1-C4-alkyl)2;

W je sumpor ili kisik. W is sulfur or oxygen.

Ovdje i u daljnjem tekstu vrijede slijedeće definicije: The following definitions apply here and in the following text:

Alkalijski metal je npr. litij, natrij, kalij. An alkali metal is, for example, lithium, sodium, potassium.

Zemno alkalijski metal je npr. kalcij, magnezij, barij. Alkaline earth metal is, for example, calcium, magnesium, barium.

C3-C8-cikloalkil je npr. ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheptil, ili ciklooktil; C3-C8-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl;

C1-C4-halogenalkil može biti linearan ili razgranat, kao npr. fluormetil, difluormetil, trifluormetil, klor-difluormetil, diklorfluormetil, triklormetil, 1-fluoretil, 2-fluoretil, 2,2-difluoretil, 2,2,2-trifluoretil, 2-klor-2,2-difluoretil, 2,2-diklor-2-fluoretil, 2,2,2-trikloretil ili pentafluoretil; C1-C4-haloalkyl can be linear or branched, such as fluoromethyl, difluoromethyl, trifluoromethyl, chloro-difluoromethyl, 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;

C1-C4-halogenalkoksi može biti linearan ili razgranat, kao npr. difluormetoksi, trifluormetoksi, klordifluor-metoksi, 1-fluoretoksi, 2,2-difluoretoksi, 1,1,2,2-tetra-fluoretoksi, 2,2,2-trifluoretoksi, 2-klor-1,1,2-trifluor-etoksi, 2-fluoretoksi ili pentafluoretoksi; C1-C4-halogenalkoxy can be linear or branched, such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2- trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;

C1-C4-alkil može biti linearan ili razgranat, kao npr. metil, etil, 1-propil, 2-propil, 2-metil-2-propil, 2-metil-1-propil, 1-butil ili 2-butil; C1-C4-alkyl 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-alkenil može biti linearan ili razgranat, kao npr. etenil, 1-propen-3-il, 1-propen-2-il, 1-propen-1-il, 2-metil-1-propenil, 1-butenil ili 2-butenil; C2-C4-alkenyl can 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-alkinil može biti linearan ili razgranat, kao npr. etinil, 1-propin-1-il, 1-propin-3-il, 1-butin-4-il ili 2-butin-4-il; C2-C4-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;

C1-C4-alkoksi može biti linearan ili razgranat, kao npr. metoksi, etoksi, propoksi, 1-metiletoki, butoksi, 1-metilpropoksi, 2-metilpropoksi ili 1,1-dimetiletoksi; C1-C4-Alkoxy can be linear or branched, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;

C3-C6-alkeniloksi može biti linearan ili razgranat, kao npr. aliloksi, 2-buten-1-iloksi ili 3-buten-2-iloksi; C3-C6-alkenyloxy can be linear or branched, such as allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;

C3-C6-alkiniloksi može biti linearan ili razgranat, kao npr. 2-propin-1-iloksi, 2-butin-1-iloksi ili 3-butin-2-iloksi; C3-C6-alkynyloxy can be linear or branched, such as 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;

C1-C4-alkiltio može biti linearan ili razgranat, kao npr. metiltio, etiltio, propiltio, 1-metiletiltio, butiltio, 1-metilpropiltio, 2-metilpropiltio ili 1,1-dimetiletiltio; C1-C4-alkylthio can be linear or branched, such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;

C1-C4-alkilkarbonil može biti linearan ili razgranat, kao npr. acetil, etilkarbonil ili 2-propilkarbonil; C1-C4-alkylcarbonyl may be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl;

C1-C4-alkoksikarbonil može biti linearan ili razgranat, kao npr. metoksikarbonil, etoksikarbonil, n-propoksikarbonil, i-propoksikarbonil ili n-butoksi-karbonil; C1-C4-Alkoxycarbonyl can be linear or branched, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;

C3-C8-alkilkarbonilalkil može biti linearan ili razgranat, kao npr. 2-okso-prop-1-il, 3-okso-but-1-il ili 3-okso-but-2-il; C3-C8-alkylcarbonylalkyl may be linear or branched, such as 2-oxo-prop-1-yl, 3-oxo-but-1-yl or 3-oxo-but-2-yl;

C1-C8-alkil može biti linearan ili razgranat, kao npr. C1-C4-alkil, pentil, heksil, heptil ili oktil; C1-C8-alkyl may be linear or branched, such as C1-C4-alkyl, pentyl, hexyl, heptyl or octyl;

halogen je npr. fluor, klor, brom, jod. halogen is, for example, fluorine, chlorine, bromine, iodine.

Daljnji predmet izuma su takovi spojevi iz kojih se mogu osloboditi spojevi formule I (takozvani pred-lijekovi). A further subject of the invention are such compounds from which the compounds of formula I can be released (so-called prodrugs).

Prednosni su takovi pred-lijekovi u kojima se oslobađanje odvija pod uvjetima koji vladaju u određenim dijelovima tijela, npr. u želucu, crijevima, krvotoku, jetri. Preferable are such prodrugs in which the release takes place under the conditions prevailing in certain parts of the body, eg in the stomach, intestines, bloodstream, liver.

Spojevi I i također intermedijati za njihovu proizvodnju, kao što su npr. II, III, IV, V i VI, mogu imati jedan ili više asimetrično supstituiranih ugljikovih atoma. Takovi spojevi mogu postojati kao čisti enantiomeri, odnosno kao čisti diastereomeri ili kao njihova smjesa. Pri upotrebi kao aktivne tvari, prednost se daje upotrebi enantiomerno čistog spoja. Compounds I and also intermediates for their production, such as II, III, IV, V and VI, may have one or more asymmetrically substituted carbon atoms. Such compounds can exist as pure enantiomers, i.e. as pure diastereomers or as a mixture thereof. When used as an active substance, preference is given to using an enantiomerically pure compound.

Izum se nadalje odnosi na upotrebu gore navedenih derivata karboksilnih kiselina za proizvodnju lijekova, posebno za proizvodnju inhibitora ETA i ETB receptora. Spojevi prema izumu posebno su prikladni kao miješani antagonisti kako su uvodno definirani. The invention further relates to the use of the above-mentioned carboxylic acid derivatives for the production of drugs, especially for the production of ETA and ETB receptor inhibitors. The compounds of the invention are particularly suitable as mixed antagonists as defined in the introduction.

Spojevi opće formule IV, u kojoj W predstavlja sumpor ili kisik, mogu se proizvesti, kako je opisano u WO 96/11914. Compounds of general formula IV, wherein W represents sulfur or oxygen, can be prepared as described in WO 96/11914.

U ovoj reakciji, posljednja keto skupina je zaštićena kao ciklički acetal; međutim, mogu se također zamisliti i druge zaštitne skupine, kao na primjer, dimetil acetal. In this reaction, the last keto group is protected as a cyclic acetal; however, other protecting groups are also conceivable, such as, for example, dimethyl acetal.

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Spojevi formule IV mogu se dobiti u enantiomerno čistom obliku počevši od enantiomerno čistih spojeva formule II i njihovom reakcijom sa spojevima formule III kako je opisano u WO 96/11914. Compounds of formula IV can be obtained in enantiomerically pure form starting from enantiomerically pure compounds of formula II and reacting them with compounds of formula III as described in WO 96/11914.

Daljnja mogućnost za dobivanje enantiomerno čistih spojeva formule IV je klasično rastavljanje s prikladno enantiomerno čistim bazama upotrebom racemičnih ili diastereomernih spojeva formule IV. Prikladne baze te vrste jesu, na primjer, 4-klorfeniletilamin i baze spomenute u WO 96/11914. A further possibility for obtaining enantiomerically pure compounds of formula IV is classical resolution with suitable enantiomerically pure bases using racemic or diastereomeric compounds of formula IV. Suitable bases of this type are, for example, 4-chlorophenylethylamine and the bases mentioned in WO 96/11914.

Pripravljanje spojeva opće formule II bilo je opisano u WO 96/11914, dok su spojevi opće formule III poznati ili se mogu sintetizirati općenito poznatim metodama, kao na primjer: The preparation of compounds of general formula II was described in WO 96/11914, while compounds of general formula III are known or can be synthesized by generally known methods, such as for example:

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Derivati karboksilnih kiselina opće formule IV mogu zatim reagirati sa spojevima opće formule V, pri čemu se dobije tvar tipa VI. Derivatives of carboxylic acids of the general formula IV can then react with compounds of the general formula V, whereby a substance of type VI is obtained.

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U formuli V, R16 je halogen ili R117-SO2-, gdje R17 može biti C1-C4-alkil, C1-C4-halogenalkil ili fenil. Osim toga, barem jedan od članova prstena X ili Y ili Z je dušik. Reakcija se odvija ponajprije u inertnom otapalu ili u sredstvu za razrjeđivanje, uz dodatak prikladne baze, tj. baze koja uzrokuje deprotoniranje intermedijarnog proizvoda IV, pri temperaturi u području od sobne temperature do vrelišta otapala. In formula V, R 16 is halogen or R 117 -SO 2 -, where R 17 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 takes place preferably in an inert solvent or diluent, with the addition of a suitable base, i.e. a base that causes deprotonation of the intermediate product IV, at a temperature in the range from room temperature to the boiling point of the solvent.

Spojevi tipa VI, gdje R1 predstavlja COOH, mogu se dobiti izravno tako da se intermedijat IV, u kojem R1 predstavlja COOH, deprotonira s dva ekvivalenta prikladne baze i reakcijom sa spojevima opće formule V. Ta se reakcija također odvija u inertnom otapalu i pri temperaturi u području od sobne temperature do vrelišta otapala. Compounds of type VI, where R1 is COOH, can be obtained directly by deprotonating intermediate IV, where R1 is COOH, with two equivalents of a suitable base and reacting with compounds of the general formula V. This reaction also takes place in an inert solvent and at temperature in the range from room temperature to the boiling point of the solvent.

Primjeri takovih otapala ili sredstava za razrjeđivanje jesu alifatski, aliciklički i aromatski ugljikovodici, od kojih svaki može biti kloriran, kao, na primjer, heksan, cikloheksan, petrol eter, ligroin, benzen, toluen, ksilen, metilen klorid, kloroform, tetraklorugljik, etil klorid i trikloretilen, eteri, kao na primjer diizopropil eter, dibutil eter, metil-terc-butil eter, propilen oksid, dioksan i tetrahidrofuran, nitrili kao npr. acetonitril i propionitril, kiselinski amidi, kao npr. dimetilformamid, dimetilacetamid i N-metilpirolidon, sulfoksidi i sulfoni, kao, na primjer, dimetil sulfoksid i sulfolan. Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, acid amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone , sulfoxides and sulfones, such as, for example, dimethyl sulfoxide and sulfolane.

Spojevi formule V su poznati, a neki od njih se mogu kupiti, ili se mogu proizvesti po opće poznatim metodama. Compounds of formula V are known, and some of them can be purchased, or can be prepared by generally known methods.

Kao baza može se upotrijebiti hidrid alkalijskog ili zemno alkalijskog metala, kao natrijev hidrid, kalijev hidrid ili kalcijev hidrid, karbonat kao karbonat alkalijskog metala, npr. natrijev ili kalijev karbonat, hidroksid alkalijskog ili zemno alkalijskog metala kao natrijev ili kalijev hidroksid, organometalni spoj kao butil-litij ili amid alkalijskog metala, kao litijev diizopropilamid ili litijev amid. Alkali or alkaline earth metal hydride, such as sodium hydride, potassium hydride or calcium hydride, carbonate such as alkali metal carbonate, e.g. sodium or potassium carbonate, alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide, organometallic compound such as butyllithium or an alkali metal amide, such as lithium diisopropylamide or lithium amide.

Spojevi prema izumu, u kojima supstituenti imaju značenja navedena pod općom formulom I, mogu se konačno proizvesti odstranjivanjem keto zaštitne skupine u spojevima formule VI. U slučaju etilene glikol acetala, to se može provesti kiselom hidrolizom. The compounds according to the invention, in which the substituents have the meanings given under the general formula I, can be finally produced by removing the keto protecting group in the compounds of the formula VI. In the case of ethylene glycol acetals, this can be done by acid hydrolysis.

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Spojevi tipa I mogu se, nadalje, sintetizirati preko spojeva koji imaju formulu VII Compounds of type I can also be synthesized via compounds of formula VII

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Spojevi opće formule VII mogu zatim reagirati s Grignardovim reagentima, čime se dobiju spojevi formule I Compounds of general formula VII can then be reacted with Grignard reagents to give compounds of formula I

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Spojevi formule I mogu se proizvesti također i tako da se pođe od odgovarajućih karboksilnih kiselina, tj. spojeva formule I u kojoj R1 predstavlja COOH, i oni se najprije na uobičajen način prevedu u aktivirani oblik, kao što je kiselinski halogenid, anhidrid ili imidazolid, a potonji zatim reagira s odgovarajućim hidroksilnim spojem HOR9. Ta reakcija se može provesti u uobičajenim otapalima i često je potreban dodatak baze, i u tom slučaju su prikladne gore spomenute. Ta dva stupnja mogu se također pojednostavniti, na primjer, tako da se karboksilnu kiselinu pusti djelovati na hidroksilni spoj u prisutnosti sredstva za dehidrataciju, kao što je karbodiimid. Compounds of formula I can also be produced by starting from the corresponding carboxylic acids, i.e. compounds of formula I in which R1 represents COOH, and they are first converted in the usual way into an activated form, such as an acid halide, anhydride or imidazolide, and the latter then reacts with the corresponding hydroxyl compound HOR9. This reaction can be carried out in common solvents and often requires the addition of a base, in which case those mentioned above are suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent, such as carbodiimide.

Osim toga, spojevi formule I mogu se također proizvesti i tako da se pođe od soli odgovarajućih karboksilnih kiselina, tj. spojeva formule I u kojoj R1 predstavlja skupinu COOM, pri čemu M može biti kation alkalijskog metala ili ekvivalent kationa zemno alkalijskog metala. Te soli mogu reagirati s mnogim spojevima formule R9-A, pri čemu A predstavlja uobičajenu nukleofilnu otpusnu skupinu, primjerice halogen, kao klor, brom, jod, ili aril- ili alkilsulfonil prema potrebi supstituiran s halogenim, alkilom ili s halogenalkilom, kao npr. toluensulfonil i metilsulfonil, ili s drugom ekvivalentnom otpusnom skupinom. Spojevi formule R9-A s reaktivnim supstituentom A su poznati ili se lako mogu dobiti na osnovi općeg stručnog znanja. Ta se reakcija može provesti u uobičajenim otapalima i odvija se prednosno uz dodatak baze, i u tom slučaju su prikladne gore navedene. In addition, the compounds of formula I can also be produced by starting from salts of the corresponding carboxylic acids, i.e. compounds of formula I in which R1 represents the group COOM, where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can react with many compounds of the formula R9-A, where A represents a common nucleophilic leaving group, for example halogen, such as chlorine, bromine, iodine, or aryl- or alkylsulfonyl optionally substituted with halogen, alkyl or haloalkyl, such as e.g. toluenesulfonyl and methylsulfonyl, or with another equivalent leaving group. Compounds of formula R9-A with a reactive substituent A are known or can be easily obtained based on general knowledge of the art. This reaction can be carried out in common solvents and takes place preferably with the addition of a base, in which case the above are suitable.

U nekim slučajevima za pripravljanje spojeva I prema izumu moraju se primijeniti općenito poznati postupci sa zaštitnim skupinama. Ako, na primjer, R6 predstavlja 4-hidroksifenil, tada se hidroksilnu skupinu može najprije zaštititi kao benzilni eter, koji se zatim odcjepljuje u prikladnom stupnju reakcije. In some cases, for the preparation of compounds I according to the invention, generally known procedures with protecting groups must be applied. If, for example, R 6 represents 4-hydroxyphenyl, then the hydroxyl group may first be protected as a benzyl ether, which is then cleaved off in an appropriate reaction step.

Spojevi formule I, u kojoj R1 predstavlja tetrazol, mogu se proizvesti kako je opisano u WO 96/11914. Compounds of formula I, wherein R 1 is tetrazole, can be prepared as described in WO 96/11914.

Što se tiče biološkog djelovanja, prednost se daje derivatima karboksilne kiseline formule I kao čistim enantiomerima, odnosno čistim diastereomerima ili kao njihovim smjesama, u kojima supstituenti imaju slijedeća značenja: As far as biological activity is concerned, preference is given to carboxylic acid derivatives of formula I as pure enantiomers, i.e. pure diastereomers or as their mixtures, in which the substituents have the following meanings:

R2 je vodik, N(C1-C4-alkil)2, C1-C4-alkil, C1-C4-alkoksi, C1-C4-alkiltio, C1-C4-halogenalkil, C1-C4-halogen-alkoksi ili je CR2 povezan na CR12 kako je navedeno za Z, čime se dobije 5- ili 6-člani prsten; R2 is hydrogen, N(C1-C4-alkyl)2, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkyl, C1-C4-halo-alkoxy or CR2 is linked to CR12 as indicated for Z, giving a 5- or 6-membered ring;

X je dušik ili metin; X is nitrogen or methine;

Y je dušik ili metin; Y is nitrogen or methine;

Z je dušik ili CR12, u kojem R12 predstavlja vodik, fluor, trifluormetil ili metil ili CR12 zajedno sa CR2 ili sa CR3 tvori 5- ili 6-člani alkilenski ili alkenilenski prsten koji može biti supstituiran s jednom ili dvije metilne skupine i u kojem u svakom slučaju jedna skupina može biti zamijenjene s kisikom ili sumporom, kao –CH2-CH2-O-, –CH2-CH2-CH2-O-, -CH=CH-O-, -CH=CH-CH2-O-, -CH(CH3)-CH(CH3)-O-, –CH=C(CH3)-O-, –C(CH3)=C(CH3)-O– ili -C(CH3)=C(CH3)-S; Z is nitrogen or CR12, in which R12 represents hydrogen, fluorine, trifluoromethyl or methyl or CR12 together with CR2 or with CR3 forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted with one or two methyl groups and in which in each case one group can be replaced by oxygen or sulfur, as –CH2-CH2-O-, –CH2-CH2-CH2-O-, -CH=CH-O-, -CH=CH-CH2-O-, -CH (CH3)-CH(CH3)-O-, –CH=C(CH3)-O-, –C(CH3)=C(CH3)-O– or -C(CH3)=C(CH3)-S;

barem jedan od članova prstena X, Y ili Z je dušik; at least one of the ring members X, Y or Z is nitrogen;

R3 je vodik, N(C1-C4-alkil)2, C1-C4-alkil, C1-C4-alkoksi, C1-C4-alkiltio, C1-C4-halogenalkil, C1-C4-halogen-alkoksi, ili je CR3 povezan na CR12 kako je gore navedeno za Z, tako se se dobije 5- ili 6-člani prsten; R 3 is hydrogen, 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 -C 4 -Halo-Alkoxy, or CR 3 is linked to CR12 as above for Z, giving a 5- or 6-membered ring;

R4 i R5 (koji mogu biti jednaki ili različiti) predstavljaju: R4 and R5 (which can be the same or different) represent:

fenil ili naftil, od kojih svaki može biti jednostruko do trostruko supstituiran s radikalom iz skupine koju čine: halogen, cijano, C1-C4-alkil, C1-C4-halogenalkil, C1-C4-alkoksi, fenoksi, C1-C4-alkiltio, NH(C1-C4-alkil) ili N(C1-C4-alkil)2 ili fenil, koji može biti jednostruko do trostruko supstituiran s halogenim, cijano, C1-C4-alkilom, C1-C4-halogenalkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; ili phenyl or naphthyl, each of which can be mono- to tri-substituted with a radical from the group consisting of: halogen, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl, C1-C4-alkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2 or phenyl, which may be mono- to tri-substituted with halogen, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl, C1-C4-alkoxy , C1-C4-halogenalkoxy or C1-C4-alkylthio; or

ili fenil ili naftil, koji mogu biti međusobno povezani u orto položaju preko izravne veze, metilenske, etilenske ili etenilne skupine, kisikov ili atoma sumpora, ili SO2, NH ili N-alkilne skupine; or phenyl or naphthyl, which may be connected to each other in the ortho position via a direct bond, methylene, ethylene or ethenyl group, oxygen or sulfur atom, or SO2, NH or N-alkyl group;

C5-C6-cikloalkil; C5-C6-cycloalkyl;

R6 je C3-C8-cikloalkil, pri čemu ti radikali u svakom slučaju mogu biti jednostruko do trostruko supstituirani sa slijedećim supstituentima: halogen, C1-C4-alkoksi, C1-C4-alkil, C1-C4-alkiltio, C1-C4-halogenalkoksi, C1-C4-alkoksi-karbonil ili fenil, koji može biti jednostruko do trostruko supstituiran s halogenim, C1-C4-alkilom, C1-C4-halogen-alkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; R6 is C3-C8-cycloalkyl, whereby these radicals can in any case be mono- to tri-substituted with the following substituents: halogen, C1-C4-alkoxy, C1-C4-alkyl, C1-C4-alkylthio, C1-C4-halogenalkoxy . -alkylthio;

fenil ili naftil, od kojih svaki može nositi jedan ili više slijedećih radikala: halogen, R15, cijano, hidroksi, C1-C4-alkil, C1-C4-halogenalkil, C1-C4-alkilkarbonil, C1-C4-alkoksikarbonil, C1-C4-alkoksi, C1-C4-halogenalkoksi, fenoksi, C1-C4-alkiltio, NH(C1-C4-alkil), N(C1-C4-alkil)2, dioksometilen, dioksoetilen, ili fenil, koji može biti jednostruko do trostruko supstituiran s halogenim, cijano, C1-C4-alkilom, C1-C4-halogenalkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; phenyl or naphthyl, each of which may carry one or more of the following radicals: halogen, R15, cyano, hydroxy, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4 -Alkoxy, C1-C4-halogenalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, dioxomethylene, dioxoethylene, or phenyl, which may be mono- to tri-substituted with halo, 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;

petero- ili šesteročlani heteroaromatski sistem koji sadrži jedan do tri dušikova atoma i/ili jedan sumporni ili kisikov atom, i koji može nositi jedan ili dva halogena atoma i/ili jedan ili dva slijedeća radikala: C1-C4-alkil, C1-C4-alkoksi, trifluormetoksi, C1-C4-alkiltio, fenil ili fenoksi, pri čemu fenilni radikali sa svoje strane mogu nositi jedan do pet halogenih atoma i/ili jedan do tri slijedeća radikala: C1-C4-alkil, C1-C4-alkoksi, i/ili C1-C4-alkiltio; a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and/or one sulfur or oxygen atom, and which may carry one or two halogen atoms and/or one or two of the following radicals: C1-C4-alkyl, C1-C4- alkoxy, trifluoromethoxy, C1-C4-alkylthio, phenyl or phenoxy, whereby the phenyl radicals can carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-alkoxy, and / or C1-C4-alkylthio;

R7 i R8 (koji mogu biti jednaki ili različiti) predstavljaju C1-C4-alkil; R7 and R8 (which may be the same or different) represent C1-C4-alkyl;

R15 je metil, etil, metoksi ili etoksi, od kojih svaki nosi jedan od slijedećih radikala: hidroksi, karboksi, amino, NH(C1-C4-alkil), N(C1-C4-alkil)2, karboksiamid ili CON(C1-C4-alkil)2; R15 is methyl, ethyl, methoxy or ethoxy, each of which carries one of the following radicals: hydroxy, carboxy, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, carboxyamide or CON(C1- C4-alkyl)2;

W je sumpor ili kisik. W is sulfur or oxygen.

Posebnu prednost daje se spojevima formule I kao čistim enantiomerima ili čistim diastereomerima ili kao njihovim smjesama, u kojima supstituenti imaju slijede}a značenja: Particular preference is given to compounds of formula I as pure enantiomers or pure diastereomers or as their mixtures, in which the substituents have the following meanings:

R2 je trifluormetil, C1-C4-alkil, C1-C4-alkoksi, C1-C4-alkiltio ili je CR2 povezan na CR12 kako je navedeno za Z, tako da se dobije 5- ili 6-člani prsten; R 2 is trifluoromethyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, or CR 2 is linked to CR 12 as indicated for Z, so as to form a 5- or 6-membered ring;

X je dušik ili metin; X is nitrogen or methine;

Y je dušik ili metin; Y is nitrogen or methine;

Z je dušik ili CR12, gdje R12 predstavlja vodik, fluor ili metil, ili CR12, zajedno sa CR2 ili CR3, tvori 5- ili 6-člani alkilenski ili alkenilenski prsten u kojem jedna metilenska skupina u svakom slučaju može biti zamijenjena s kisikom ili sumporom, kao –CH2-CH2-S-, -CH=CH-O-, –CH2-CH2-S-; Z is nitrogen or CR12, where R12 is hydrogen, fluorine or methyl, or CR12, together with CR2 or CR3, forms a 5- or 6-membered alkylene or alkenylene ring in which one methylene group in each case may be replaced by oxygen or sulfur , as –CH2-CH2-S-, -CH=CH-O-, –CH2-CH2-S-;

barem jedan od članova prstena X, Y ili Z je dušik; at least one of the ring members X, Y or Z is nitrogen;

R3 je trifluormetil, C1-C4-alkil, C1-C4-alkoksi, C1-C4-alkiltio ili je CR3 povezan na CR12 kako je gore prikazano za Z tako da se dobije 5- ili 6-člani prsten; R 3 is trifluoromethyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio or CR 3 is linked to CR 12 as shown above for Z to form a 5- or 6-membered ring;

R4 i R5 (koji mogu biti jednaki ili različiti) predstavljaju: R4 and R5 (which can be the same or different) represent:

fenil ili naftil, od kojih svaki može biti jednostruko do trostruko supstituiran sa slijedećim radikalima: halogen, C1-C4-alkil, C1-C4-alkoksi, fenoksi ili fenil, koji može biti jednostruko do trostruko supstituiran s halogenim, C1-C4-alkilom ili C1-C4-alkoksi; ili phenyl or naphthyl, each of which may be mono- to tri-substituted with the following radicals: halogen, C1-C4-alkyl, C1-C4-alkoxy, phenoxy or phenyl, which may be mono- to tri-substituted with halogen, C1-C4-alkyl or C1-C4-Alkoxy; or

ili fenil ili naftil, koji su međusobno povezani u orto položaju izravnom vezom, metilenskom, etilenskom ili etenilnom skupinom, ili sa SO2 skupinom; or phenyl or naphthyl, which are connected to each other in the ortho position by a direct bond, a methylene, ethylene or ethenyl group, or with an SO2 group;

cikloheksil; cyclohexyl;

R6 je cikloheksil koji može biti jednostruko do trostruko supstituiran sa slijedećim supstituentima: C4-alkoksi, C1-C4-alkil, halogen ili fenil, koji može biti jednostruko do trostruko supstituiran s halogenim, C1-C4-alkilom, C1-C4-alkoksi; R6 is cyclohexyl which can be mono- to tri-substituted with the following substituents: C4-Alkoxy, C1-C4-alkyl, halogen or phenyl, which can be mono- to tri-substituted with halogen, C1-C4-alkyl, C1-C4-Alkoxy;

fenil ili naftil, koji u svakom slučaju može biti jednostruko do trostruko supstituiran sa slijedećim radikalima: halogen, R15, C1-C4-alkil, C1-C4-halogenalkil, acetil, C1-C4-alkoksikarbonil, C1-C4-alkoksi, fenoksi, C1-C4-alkiltio, dioksometilen, dioksoetileln, ili fenil, koji može biti jednostruko do trostruko supstituiran s halogenim, C1-C4-alkilom, C1-C4-alkoksi ili C1-C4-alkiltio; phenyl or naphthyl, which in any case can be singly or triply substituted with the following radicals: halogen, R15, C1-C4-alkyl, C1-C4-haloalkyl, acetyl, C1-C4- alkoxycarbonyl, C1-C4- alkoxy, phenoxy, C1-C4-alkylthio, dioxomethylene, dioxoethylen, or phenyl, which may be mono- to tri-substituted with halogen, C1-C4-alkyl, C1-C4-alkoxy or C1-C4-alkylthio;

R7 i R8 (koji mogu biti jednaki ili različiti) predstavljaju: R7 and R8 (which may be the same or different) represent:

vodik, C1-C4-alkil; hydrogen, C1-C4-alkyl;

R15 je metoksi ili etoksi, od kojih svaka nosi jedan od slijedećih radikala: hidroksil, karboksil, karboksamid ili CON(C1-C4-alkil)2; R15 is methoxy or ethoxy, each of which carries one of the following radicals: hydroxyl, carboxyl, carboxamide or CON(C1-C4-alkyl)2;

W je sumpor ili kisik. W is sulfur or oxygen.

Spojevi predloženog izuma nude novu terapeutsku mogućnost za liječenje hipertenzije, visokog plućnog tlaka, miokardijalnog infarkta, angine pektoris, aritmije, akutnog/kroničnog otkazivanja bubrega, kronične srčane insuficijencije, insuficijencije bubrega, cerebralnih vazospazmi, cerebralne ishemije, subarahnoidnih krvarenja, migrene, astme, ateroskleroze, endotoksičkog šoka, otkazivanja organa induciranog endotoksinom, intravaskularne koagulacije, restenoze nakon angioplastije i by-pass operacija, benigne hiperplazije prostate, ishemijskog otkazivanja bubrega ili hipertenzije otkazivanja bubrega ili hipertenzije uzrokovane intoksikacijom, metastaziranja i rasta mezenhimalnih tumora, otkazivanja bubrega induciranog kontrastnim sredstvom, pankreatitisa, gastrointestinalnih čireva. The compounds of the proposed invention offer a new therapeutic option for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, acute/chronic renal failure, chronic heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis , endotoxic shock, organ failure induced by endotoxin, intravascular coagulation, restenosis after angioplasty and by-pass surgery, benign prostatic hyperplasia, ischemic renal failure or hypertension renal failure or hypertension caused by intoxication, metastasis and growth of mesenchymal tumors, renal failure induced by contrast media, pancreatitis , gastrointestinal ulcers.

Izum se nadalje odnosi na kombinacije koje sadrže endotelin receptor antagoniste formule I i inhibitore sistema renin-angiotenzin. Inhibitori sistema renin-angiotenzin su inhibitori renina, angiotenzin-II antagonisti i, posebno, inhibitori enzima koji pretvara angiotenzin (ACE) (e. Angiotensin-Converting-Enzyme). Prednost se daje kombinacijama endotelin receptora formule I i ACE inhibitora. The invention further relates to combinations containing 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, inhibitors of the enzyme that converts angiotensin (ACE) (e. Angiotensin-Converting-Enzyme). Preference is given to combinations of endothelin receptors of formula I and ACE inhibitors.

Izum se nadalje odnosi na kombinaciju endotelin receptor antagonista formule I i beta-blokera. The invention further relates to the combination of an endothelin receptor antagonist of formula I and a beta-blocker.

Izum se također odnosi na kombinacije endotelin receptor antagonista formule I i diuretika. The invention also relates to combinations of endothelin receptor antagonists of formula I and diuretics.

Izum se dalje odnosi na kombinacije endotelin receptor antagonista formule I i tvari koje blokiraju djelovanje VEGF-a (vaskularni endolijski faktor rasta, e. vascular endotelial growt factor). Takove tvari jesu, na primjer, antitijela usmjerena protiv VEGF-a ili specifični vezni proteini ili alternativno tvari niske molekulske mase koje mogu specifično inhibirati oslobađanje VEGF-a ili vezanje receptora. The invention further relates to combinations of endothelin receptor antagonists of formula I and substances that block the action of VEGF (vascular endothelial growth factor). Such substances are, for example, antibodies directed against VEGF or specific binding proteins or alternatively low molecular weight substances that can specifically inhibit VEGF release or receptor binding.

Gore spomenute kombinacije mogu se dati istovremena ili uzastopno. One se mogu primijeniti u jednostrukoj farmaceutskoj formulaciji ili alternativno u odvojenim formulacijama. Oblik davanja također može biti različit, na primjer endotelin receptor antagonisti se mogu dati oralno, a i VEGF inhibitori se mogu sati parenteralno. The combinations mentioned above can be given simultaneously or sequentially. They can be administered in a single pharmaceutical formulation or alternatively in separate formulations. The form of administration can also be different, for example endothelin receptor antagonists can be given orally, and VEGF inhibitors can be given parenterally.

Ti kombinirani pripravci su posebno prikladni za liječenje i prevenciju hipertenzije i njezinih posljedica, i za liječenje kardijalne insuficijencije. These combined preparations are particularly suitable for the treatment and prevention of hypertension and its consequences, and for the treatment of heart failure.

Izum se dalje odnosi na strukturni fragment formule The invention further relates to the structural fragment of the formula

[image] [image]

u kojoj radikali R1, R4, R5, R6, R7, R8 i W imaju gore spomenuto značenje. in which the radicals R1, R4, R5, R6, R7, R8 and W have the meaning mentioned above.

Takvi strukturni fragmenti su prikladni kao strukturni konstituenti endotelin receptor antagonista, posebno miješanih endotelin receptor antagonista. Such structural fragments are suitable as structural constituents of endothelin receptor antagonists, especially mixed endothelin receptor antagonists.

Izum se dalje odnosni na endotelin receptor antagoniste koji sadrže strukturni fragment formule The invention further relates to endothelin receptor antagonists containing a structural fragment of the formula

[image] [image]

u kojoj radikali R1, R2, R3, R4, R5, R7, R8, W, X, I i Z imaju gore navedena značenja, kovalentno povezan na skupinu koja ima molekulsku masu najmanje 40, ponajprije najmanje 77. in which the radicals R1, R2, R3, R4, R5, R7, R8, W, X, I and Z have the meanings given above, covalently linked to a group having a molecular weight of at least 40, preferably at least 77.

Dobar učinak spojeva može se pokazati pomoću slijedećih ispitivanja: The good performance of compounds can be demonstrated by means of the following tests:

Proučavanje vezanja receptora Study of receptor binding

Za proučavanje vezanja upotrijebljene su klonirane CHO-stanice koje umnažaju humani ETA- ili ETB-receptor. Cloned CHO cells amplifying the human ETA or ETB receptor were used for binding studies.

Priprava membrana Preparation of membranes

CHO-stanice, koje umnažaju ETA- ili ETB-receptor, rasle su u DMEM NUT MIX F12-mediju (Gibco, br. 21331-020) s 10% fetalnog telećeg seruma (PAA Laboratories GmbH, Linz, br. A15-022), 1 mM glutamina (Gibco br. 25030-024), 100 U/ml penicilina i 100 μg/ml streptomicina (Gibco, Sigma br. P-0781). Nakon 48 sati stanice su isprane s PBS-om i inkubirane 5 minuta pri 37oC s PBS-om koji je sadržavao 0,05% tripsina. Smjesa je zatim neutralizirana s medijem i stanice su skupljene centrifugiranjem pri 300 x g. CHO cells expressing the ETA or ETB receptor were grown in DMEM NUT MIX F12 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022). , 1 mM glutamine (Gibco No. 25030-024), 100 U/ml penicillin, and 100 μg/ml streptomycin (Gibco, Sigma No. P-0781). After 48 hours the cells were washed with PBS and incubated for 5 minutes at 37oC with PBS containing 0.05% trypsin. The mixture was then neutralized with medium and the cells were harvested by centrifugation at 300 x g.

Za pripravljanje membrana stanice su namještene na koncentraciju od 108 stanica/ml pufera (50 ml tris HCl pufer, pH 7,4) i zatim su dezintegrirane ultrazvukom (Branson Sonifier 250, 40-70 sekundi/konstatan učin 20). To prepare the membranes, cells were adjusted to a concentration of 108 cells/ml buffer (50 ml tris HCl buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds/constant power 20).

Ispitivanja vezanja Binding tests

Za ispitivanje vezanja ETA- i ETB-receptora membrane su suspendirane u puferu za inkubaciju (50 mM tris HCl, pH 7,4 s 5 mM MnCl2, 40 μg/ml bacitracina i 0,2% BSA) u koncentraciji od 50 μg proteina po ispitnoj smjesi i inkubiraju se pri 25oC s 25 pM 125J-ET1 (ispitivanje ETA-receptora) ili 25 pM 125J-ET3 (ispitivanje ETB-receptora) u prisutnosti ili odsutnosti ispitne tvari. Nespecifično vezanje određeno je s 10-7 M ET1. Nakon 30 minuta slobodan i vezani radioligand su rastavljeni filtriranjem kroz filtere od staklenih vlakana GF/B (Whatman, Engleska) na skupljaču stanica Skatron (Skatron, Lier, Norveška) i filteri su isprani s ledeno hladnim puferom tris HCl, pH 7,4 s 0,2% BSA. Radioaktivnost skupljena na filterima kvantitativno je utvrđena pomoću scintilacijskog brojača za tekućine Packard 2200 CA. To test the binding of ETA- and ETB-receptors, membranes were suspended in incubation buffer (50 mM Tris HCl, pH 7.4 with 5 mM MnCl2, 40 μg/ml bacitracin and 0.2% BSA) at a concentration of 50 μg protein per test mixture and are incubated at 25oC with 25 pM 125J-ET1 (ETA-receptor assay) or 25 pM 125J-ET3 (ETB-receptor assay) in the presence or absence of the test substance. Nonspecific binding was determined with 10-7 M ET1. After 30 min, free and bound radioligand were separated by filtration through GF/B glass fiber filters (Whatman, England) on a Skatron cell harvester (Skatron, Lier, Norway) and the filters were washed with ice-cold Tris HCl buffer, pH 7.4 for s 0.2% BSA. Radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Ispitivanje ET-antagonista in vivo Testing of ET-antagonists in vivo

Mužjaci SD štakora, težine 250 - 300 g, anestezirani su s amobarbitalom, priključeni na umjetno disanje, vagotomizirani i despinalizirani. Arteria carotis i vena jugularis bile su katetezirane. Male SD rats, weighing 250-300 g, were anesthetized with amobarbital, connected to artificial respiration, vagotomized and de-spinalized. The carotid artery and jugular vein were catheterized.

U skupini kontrolnih životinja intravensko davanje 1 μg/kg ET1 dovelo je do jasnog porasta krvnog tlaka, koji se je održao tijekom relativno duljeg vremena. In the group of control animals, intravenous administration of 1 μg/kg ET1 led to a clear increase in blood pressure, which was maintained for a relatively long time.

Pokusnim životinjama, 30 minuta prije davanja ET1, ubrizgani su ispitni spojevi i.v. (1 mg/kg). Za određivanje ET-antagonističkih svojstava porast krvnog tlaka pokusnih životinja bio je uspoređen s onim kod kontrolnih životinja. Experimental animals, 30 minutes before the administration of ET1, were injected with the test compounds i.v. (1 mg/kg). To determine the ET-antagonistic properties, the increase in blood pressure of experimental animals was compared with that of control animals.

Oralno ispitivanje miješanih ETA- i ETB-antagonista Oral testing of mixed ETA- and ETB-antagonists

Mužjaci normotenzivnih štakora (Sprague Dawley, Janvier) težine 250-350 g najprije su oralno primili ispitne tvari. 80 minuta kasnije životinje su anestezirane s uretanom, a arteria carotis (za mjerenje krvnog tlaka) kao i vena jugularis (aplikacija big endotelin/endotelin 1) su kateterizirane. Male normotensive rats (Sprague Dawley, Janvier) weighing 250-350 g first received test substances orally. 80 minutes later the animals were anesthetized with urethane, and the carotid artery (for blood pressure measurement) as well as the jugular vein (big endothelin/endothelin 1 application) were catheterized.

Nakon faze stabilizacije, intravenski je dat big endotelin (20 μg/kg, aplicirani volumen 0,5 ml/kg), odnosno ET1 (0,3 μg/kg, aplicirani volumen 0,5 ml/kg). Krvni tlak i srčana frekvencija registrirani su kontinuirano tijekom 30 minuta. Jasne i trajne promjene krvnog tlaka računate su kao površine ispod krivulje (AUC). Za određivanje antagonističkog djelovanja ispitnih tvari AUC životinja koje su primile ispitne tvari uspoređen je s AUC-om kontrolnih životinja. After the stabilization phase, big endothelin (20 μg/kg, applied volume 0.5 ml/kg) or ET1 (0.3 μg/kg, applied volume 0.5 ml/kg) was given intravenously. Blood pressure and heart rate were registered continuously for 30 minutes. Clear and persistent changes in blood pressure were calculated as area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the animals that received the test substances was compared with the AUC of the control animals.

Spojevi prema izumu mogu se davati na uobičajen način oralno ili parenteralno (subkutano, intravenski, intra-muskularno, intraperitonealno). Aplikacija se također može izvršiti s parama ili sprejevima kroz nos-ždrijelo. The compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). The application can also be performed with vapors or sprays through the nasopharynx.

Doziranje ovisi o starosti, stanju i težini pacijenta, te o načinu aplikacije. U pravilu, dnevna doza aktivnog spoja iznosi od približno 0,5 do 50 mg/kg tjelesne težine kod oralnog davanja i od približno 0,1 do 10 mg/kg tjelesne težine kod parenteralnog davanja. The dosage depends on the age, condition and weight of the patient, and on the method of application. As a rule, the daily dose of the active compound is from approximately 0.5 to 50 mg/kg of body weight for oral administration and from approximately 0.1 to 10 mg/kg of body weight for parenteral administration.

Novi spojevi mogu se dati u uobičajenim krutim ili tekućim farmaceutskim oblicima, npr. kao tablete, s filmom prevučene tablete, kapsule, prašak, granulat, dražeje, čepići, otopine, masti, kreme ili sprejevi. Oni se proizvode na uobičajen način. U tu svrhu aktivne tvari se mogu preraditi s uobičajenim farmaceutskim pomoćnim sredstvima kao što su veziva za tablete, punila, konzervansi, sredstva za dezintegraciju tableta, sredstva za regulaciju tečenja, omekšivači, sredstva za kvašenje, disperzanti, emulgatori, otapala, sredstva za usporeno oslobađanje aktivne tvari, antioksidanti i/ili potisni plinovi (usporedi H. Sucker et al.; Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). Tako dobiveni aplikacijski oblici sadrže aktivnu tvar obično količinom od 0,1 do 90 mas. %. The novel compounds may be provided in conventional solid or liquid pharmaceutical forms, eg as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. They are produced in the usual way. For this purpose, active substances can be processed with common pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow control agents, plasticizers, wetting agents, dispersants, emulsifiers, solvents, slow-release agents active substances, antioxidants and/or propellants (cf. H. Sucker et al.; Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). Application forms obtained in this way contain the active substance usually in an amount of 0.1 to 90 wt. %.

PRIMJERI SINTEZE EXAMPLES OF SYNTHESIS

Primjer 1 Example 1

Metil 2-hidroksi-3,3-difenil-3-(2-fenil-[l,3]-dioksolan-2-il-metoksi)propionat Methyl 2-hydroxy-3,3-diphenyl-3-(2-phenyl-[1,3]-dioxolan-2-yl-methoxy)propionate

p-toluensulfonsku kiselino (0,50 g, 0,27 mmola) doda se uz hlađenje ledom k otopini od 2-fenil-[1,3]-dioksolan-2-ilmetanola (1,98 g, 11,0 mmolova) i metil 3,3-difenil-2,3-epoksipropionata (4,71 g, 13,2 mmolova; čistoća prema HPLC: 71%) u bezvodnom diklormetanu (100 ml) i smjesu se miješa 15 minuta pri 0°C. Dobivenu otopinu se ispere s otopinom natrijevog hidrogen-karbonata otopina, i organsku fazu se odvoji i osuši preko magnezijevog sulfata. Kad se sredstvo za sušenje odfiltrira, otapalo se odstrani destilacijom; preostalo sirovo ulje (4,70 g) reagira dalje bez daljnjeg čišćenja. p-toluenesulfonic acid (0.50 g, 0.27 mmol) was added under ice-cooling to a solution of 2-phenyl-[1,3]-dioxolan-2-ylmethanol (1.98 g, 11.0 mmol) and of methyl 3,3-diphenyl-2,3-epoxypropionate (4.71 g, 13.2 mmol; HPLC purity: 71%) in anhydrous dichloromethane (100 ml) and the mixture was stirred for 15 min at 0°C. The resulting solution is washed with sodium hydrogen carbonate solution, and the organic phase is separated and dried over magnesium sulfate. When the desiccant is filtered off, the solvent is removed by distillation; the remaining crude oil (4.70 g) reacts further without further purification.

Primjer 2 Example 2

2-hidroksi-3,3-difenil-3-(2-fenil-[1,3]-dioksolan-2-il-metoksi)-propionska kiselina 2-hydroxy-3,3-diphenyl-3-(2-phenyl-[1,3]-dioxolan-2-yl-methoxy)-propionic acid

Metil 2-hidroksi-3-(2-fenil)-[1,3]-dioksolan-2-il-metoksi)-3,3-difenil propionat (4,60 g, sirov) otopi se u dioksan/vodi 2:1 (45 ml) i pomiješa s natrijevim hidroksidom (300 mg, 7,50 mmolova). Smjesu se zagrije na 40°C i miješa se 1 sat. Za obradu se razrijedi s vodom (150 ml) i ekstrahira dva puta s etil acetatom. Vodenu fazu se zakiseli s limunskom kiselinom i ekstrahira dva puta s etil acetatom. Ekstrakti dobiveni nakon zakiseljavanja se osuše preko magnezijevog sulfata i otapalo se odstrani destilacijom. Dobiveno je 4,00 g sirovog ulja koje dalje reagira bez daljnjeg čišćenja. Methyl 2-hydroxy-3-(2-phenyl)-[1,3]-dioxolan-2-yl-methoxy)-3,3-diphenyl propionate (4.60 g, crude) was dissolved in dioxane/water 2: 1 (45 ml) and mixed with sodium hydroxide (300 mg, 7.50 mmol). The mixture is heated to 40°C and stirred for 1 hour. For processing, it is diluted with water (150 ml) and extracted twice with ethyl acetate. The aqueous phase is acidified with citric acid and extracted twice with ethyl acetate. The extracts obtained after acidification are dried over magnesium sulfate and the solvent is removed by distillation. 4.00 g of crude oil was obtained, which reacted further without further purification.

Primjer 3 Example 3

2-(4-metoksi-6-metilpirimidin-2-iloksi)-3,3-difenil-3-(2-fenil-[1,3]-dioksolan-2-ilmetoksi)propionska kiselina 2-(4-Methoxy-6-methylpyrimidin-2-yloxy)-3,3-diphenyl-3-(2-phenyl-[1,3]-dioxolan-2-ylmethoxy)propionic acid

50%-tni natrijev hidrid (240 mg, 5,00 mmolova) doda se u 3 obroka tijekom 3 minute k otopini 2-hidroksi-3-(2-fenil-[1,3]-dioksolan-2-ilmetoksi)-3,3-difenilpropionske kiseline (1,00 g, 1,62 mmola čistoće prema HPLC od 68%) u bezvodnom DMF-u (15 ml). Smjesu se miješa 5 minuta i zatim se u obrocima doda 2-metansulfonil-4,6-dimetilpirimidin (421 mg, 2,00 mmola). Smjesu se miješa 16 sati pri sobnoj temperaturi. Za obradu, sadržaj tikvice se prelije na led, zatim se zakiseli s limunskom kiselinom i ekstrahira dva puta s eterom. Organski ekstrakti se osuše preko magnezijevog sulfata i otapalo se odstrani destilacijom. Preostane 1,75 g ulja koje se dalje očisti vakuumskom kromatografijom i zatim kristalizacijom iz eter/n-heksana. Naslovni spoj je dobiven kao bezbojna kruta tvar (750 mg, iskorištenje 85%). 50% sodium hydride (240 mg, 5.00 mmol) was added in 3 portions over 3 minutes to a solution of 2-hydroxy-3-(2-phenyl-[1,3]-dioxolan-2-ylmethoxy)-3 ,3-diphenylpropionic acid (1.00 g, 1.62 mmol HPLC purity of 68%) in anhydrous DMF (15 ml). The mixture was stirred for 5 minutes and then 2-methanesulfonyl-4,6-dimethylpyrimidine (421 mg, 2.00 mmol) was added in portions. The mixture is stirred for 16 hours at room temperature. For processing, the contents of the flask are poured onto ice, then acidified with citric acid and extracted twice with ether. The organic extracts are dried over magnesium sulfate and the solvent is removed by distillation. 1.75 g of oil remain, which is further purified by vacuum chromatography and then by crystallization from ether/n-hexane. The title compound was obtained as a colorless solid (750 mg, yield 85%).

1H-NMR (200 MHz, СDСl3): 7,5 - 7,7 ppm (2 H, m), 7,2 - 7,4 (13 H, m), 6,3 (1 H, s), 6,2 (1 H, s), 4,2 - 4,4 (2 H, m), 4,1 (1 H, d), 3,9 (3 H, s), 3,8 - 4,0 (2 H, m), 3,6 (1 H, d), 2,4 (3 H,s). 1H-NMR (200 MHz, SDSl3): 7.5 - 7.7 ppm (2 H, m), 7.2 - 7.4 (13 H, m), 6.3 (1 H, s), 6 ,2 (1 H, s), 4.2 - 4.4 (2 H, m), 4.1 (1 H, d), 3.9 (3 H, s), 3.8 - 4.0 (2 H, m), 3.6 (1 H, d), 2.4 (3 H, s).

Primjer 4 Example 4

2-(4-metoksi-6-metilpirimidin-2-iloksi)-3-(2-okso-2-feniletoksi)-3,3-difenilpropionska kiselina 2-(4-methoxy-6-methylpyrimidin-2-yloxy)-3-(2-oxo-2-phenylethoxy)-3,3-diphenylpropionic acid

p-toluenesulfonsku kiselinu (50 mg) doda se k otopini 2-(4-metoksi-6-metilpirimidin-2-iloksi)-3-(2-fenil-[1,3]-dioksolan-2-ilmetoksi)-3,3-difenilpropionske kiseline (600 mg, 1,11 mmola) u dioksan/vodi 1:1 (20 ml) i dobivenu smjesu se miješa 2 sata pri 80°C. Kad se ohladi, smjesu se razrijedi s vodom i ekstrahira dva puta s eterom. Sjedinjene organske faze se osuše preko magnezijevog sulfata i otapalo se odstrani destilacijom. Ostatak (550 mg) se očisti kristalizacijom iz eter/n-heksana, zatim vakuumskom kromatografijom i ponovno kristalizacijom iz eter/n-heksana. Naslovni spoj je dobiven kao kristalinična kruta tvar (163 mg, iskorištenje 30%). p-toluenesulfonic acid (50 mg) is added to a solution of 2-(4-methoxy-6-methylpyrimidin-2-yloxy)-3-(2-phenyl-[1,3]-dioxolan-2-ylmethoxy)-3, of 3-diphenylpropionic acid (600 mg, 1.11 mmol) in dioxane/water 1:1 (20 ml) and the resulting mixture was stirred for 2 hours at 80°C. When cooled, the mixture is diluted with water and extracted twice with ether. The combined organic phases are dried over magnesium sulfate and the solvent is removed by distillation. The residue (550 mg) was purified by crystallization from ether/n-hexane, then by vacuum chromatography and recrystallization from ether/n-hexane. The title compound was obtained as a crystalline solid (163 mg, yield 30%).

1H-NMR (200 MHz, CDCl3): 7,2 – 7,9 ppm (15 Н, m), 6,2 (2 H, s br), 5,1 (2 H, m), 3,7 (3 H, s), 2,2 (3 H, s). 1H-NMR (200 MHz, CDCl3): 7.2 – 7.9 ppm (15 N, m), 6.2 (2 H, s br), 5.1 (2 H, m), 3.7 ( 3 H, s), 2.2 (3 H, s).

ESI-MS : H+ = 498 ESI-MS: H+ = 498

Analogno su proizvedeni slijedeći spojevi: Analogously, the following compounds were produced:

Primjer 5 Example 5

2-(4,6-dimetilpirimidin-2-iloksi)-3-(2-okso-2-feniletoksi)-3,3-difenilpropionska kiselina 2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-oxo-2-phenylethoxy)-3,3-diphenylpropionic acid

1H-NMR (200 MHz, CDCl3): 7,8 ppm (2 H, d), 7,2 - 7,7 (13 H, m), 6,7 (1 H, s), 6,3 (1 H, s), 5,2 (I H, d), 4,9 (1 H, d), 2,3 (6 H, s). 1H-NMR (200 MHz, CDCl3): 7.8 ppm (2 H, d), 7.2 - 7.7 (13 H, m), 6.7 (1 H, s), 6.3 (1 H, s), 5.2 (1 H, d), 4.9 (1 H, d), 2.3 (6 H, s).

ESI-MS: M+ = 482 ESI-MS: M+ = 482

Primjer 6 Example 6

3-[2-(4-bromofenil)-2-oksoetoksi]-2 -(4,6-dimetilpirimidin-2-iloksi)-3,3-difenilpropionska kiselina* 3-[2-(4-bromophenyl)-2-oxoethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid*

1H-NMR (200 MHz, CDCl3): 7,7 ppm (2 H, d), 7,6 (2 H, d), 7,2 - 7,5 i (10 H, m), 6,7 (1 H, s), 6,2 (1 H, s), 5,1 (1 H, d), 4,9 (1 H, d), 2,3 (6 H, s). 1H-NMR (200 MHz, CDCl3): 7.7 ppm (2 H, d), 7.6 (2 H, d), 7.2 - 7.5 i (10 H, m), 6.7 ( 1 H, s), 6.2 (1 H, s), 5.1 (1 H, d), 4.9 (1 H, d), 2.3 (6 H, s).

ESI-MS: M+ = 560 ESI-MS: M+ = 560

Primjer 7 Example 7

3-[2-(4-bromofenil)-2-oksoetoksi]-2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3,3-difenilpropionska kiselina* 3-[2-(4-bromophenyl)-2-oxoethoxy]-2-(4-methoxy-6-methyl-pyrimidin-2-yloxy)-3,3-diphenylpropionic acid*

1H-NMR (200 MHz, CDCl3): 7,7 ppm (2 H, d), 7,6 (2 H, d), 7,2 - 7,5 (10 H, m), 6,2 (1 H, s), 6,0 (1 H, S), 5,2 (1 H, d), 4,9 (1 H, d), 3,7 (3 H, s), 2,2 (3 H, s). 1H-NMR (200 MHz, CDCl3): 7.7 ppm (2 H, d), 7.6 (2 H, d), 7.2 - 7.5 (10 H, m), 6.2 (1 H, s), 6.0 (1 H, S), 5.2 (1 H, d), 4.9 (1 H, d), 3.7 (3 H, s), 2.2 (3 H, s).

ESI-MS: M+ = 576 ESI-MS: M+ = 576

* U sintezi 4-bromofenil-supstituiranih derivata, za krajnje odcjepljenje acetala umjesto p-toluenesulfonske kiseline upotrijebljen je borov trifluorid eter. * In the synthesis of 4-bromophenyl-substituted derivatives, boron trifluoride ether was used instead of p-toluenesulfonic acid for the final separation of the acetal.

Primjer 8 Example 8

Benzil 2-hidroksi-3-[metoksimetilkarbamoil)metoksi]-3,3-difenilpropionat Benzyl 2-hydroxy-3-[methoxymethylcarbamoyl)methoxy]-3,3-diphenylpropionate

Borov trifluorid eter (0,10 ml) doda se polako k na -78°C ohlađenoj otopini 2-hidroksi-N-metoksi-N-metil-acet-amida (1,19 g, 10,0 mmolova) i benzil 3,3-difenil-2,3-epoksi-propionata (3,88 g, 11,0 mmolova; čistoća prema HPLC: 94%) u bezvodnom diklormetanu (100 ml). Smjesu se miješa dva sata i zatim se postupno zagrije na -20°C, i reakciju se zaustavi opreznim dodatkom vodene otopine natrijevog hidrogenkarbonata. Organsku fazu se ispere s otopinom natrijevog hidrogenkarbonaa i osuši preko magnezijevog sulfata. Sredstvo za sušenje se odfiltrira, otapalo se odstrani destilacijom; preostalo sirovo ulje (5,50 g) reagira dalje bez daljnjeg čišćenja. Boron trifluoride ether (0.10 ml) was added slowly to a -78°C cooled solution of 2-hydroxy-N-methoxy-N-methyl-acet-amide (1.19 g, 10.0 mmol) and benzyl 3, of 3-diphenyl-2,3-epoxy-propionate (3.88 g, 11.0 mmol; HPLC purity: 94%) in anhydrous dichloromethane (100 ml). The mixture was stirred for two hours and then gradually warmed to -20°C, and the reaction was stopped by the careful addition of an aqueous solution of sodium hydrogencarbonate. The organic phase is washed with sodium bicarbonate solution and dried over magnesium sulfate. The drying agent is filtered off, the solvent is removed by distillation; the remaining crude oil (5.50 g) reacts further without further purification.

Primjer 9 Example 9

Benzil 3-[(metoksimetilkarbamoil)metoksi]-2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3,3-difenilpropionat Benzyl 3-[(methoxymethylcarbamoyl)methoxy]-2-(4-methoxy-6-methyl-pyrimidin-2-yloxy)-3,3-diphenylpropionate

Otopinu benzil 2-hidroksi-3-[(metoksimetilkarbamoill-metoksi]-3,3-difenilpropionata (1,35 g, sirov) pomiješa se uz hlađenje ledom s kalijevim karbonatom (365 mg, 2,64 mmola) i, nakon 10 minuta, s 2-metanesulfonil-4-metoksi-6-metil-pirimidinom (320 mg, 1,45 mmola). Zatim se miješa 30 minuta pri 0°C i zatim 16 sati pri sobnoj temperaturi. Smjesu se razrijedi s vodom, zakiseli s limunskom kiselinom i ekstrahira dva puta s eterom. Sjedinjene organske faze se ponovno isperu s vodom i osuše preko magnezijevog sulfata. Nakon odstranjivanja otapala destilacijom zaostane pjena (1,60 g) koju se očisti vakuumskom kromatografijom i zatim kristalizacijom iz eter/n-heksana; dobiveno je 650 mg naslovnog spoja. A solution of benzyl 2-hydroxy-3-[(methoxymethylcarbamoyl-methoxy]-3,3-diphenylpropionate (1.35 g, crude) was mixed under ice-cooling with potassium carbonate (365 mg, 2.64 mmol) and, after 10 min , with 2-methanesulfonyl-4-methoxy-6-methyl-pyrimidine (320 mg, 1.45 mmol). It was then stirred for 30 minutes at 0°C and then for 16 hours at room temperature. The mixture was diluted with water, acidified with citric acid and extracted twice with ether. The combined organic phases were washed again with water and dried over magnesium sulfate. After removal of the solvent by distillation, a foam remained (1.60 g), which was purified by vacuum chromatography and then by crystallization from ether/n-hexane; 650 mg of the title compound were obtained.

Primjer 10 Example 10

Benzil 3-[2-(3,4-dimetoksifenil)-2-oksoetoksi]-2-(4-metoksi-6-metilpirimidin-2-iloksi)-3,3-difenilpropionat Benzyl 3-[2-(3,4-dimethoxyphenyl)-2-oxoethoxy]-2-(4-methoxy-6-methylpyrimidin-2-yloxy)-3,3-diphenylpropionate

1-molarnu otopinu 3,4-dimetoksifenilmagnezijevog bromida u tetrahidrofuranu (0,60 ml) doda se pri sobnoj temperaturi k otopini benzil 3-[(metoksimetilkarbamoil)-metoksi]-2-(4-metoksi-6-metilpirimidin-2-iloksi)-3,3-di-fenilpropionata (250 mg, 0,38 mmola, čstoća prena HPLC 86%) u bezvodnom tetrahidrofuranu (25 ml). Nakon 10 minuta miješanja opažena je samo djelomična pretvorba, pa se zbog toga ponovno doda kap po kap 1-molarnu otopinu 3,4-dimetoksifenilmagnezijevog bromida u tetrahidrofuranu (0,60 ml. Smjesu se miješa daljnjih 10 minuta, i zatim se otapalo ispari. Ostatak se preuzme u etil acetat/eter 1:2. Neotopljenu tvar se odfiltrira, otapalo se odstrani destilacijom i uljasti ostatak (400 mg) se očisti vakuumskom kromatografijom. Naslovni spoj se dobije kao pjena (125 mg, iskorištenje 49% čistoće prema HPLC od 95%). A 1-molar solution of 3,4-dimethoxyphenylmagnesium bromide in tetrahydrofuran (0.60 ml) was added at room temperature to a solution of benzyl 3-[(methoxymethylcarbamoyl)-methoxy]-2-(4-methoxy-6-methylpyrimidin-2-yloxy) )-3,3-di-phenylpropionate (250 mg, 0.38 mmol, purity by HPLC 86%) in anhydrous tetrahydrofuran (25 ml). After 10 minutes of stirring, only partial conversion was observed, so a 1-molar solution of 3,4-dimethoxyphenylmagnesium bromide in tetrahydrofuran (0.60 ml) was added dropwise again. The mixture was stirred for another 10 minutes, and then the solvent was evaporated. The residue was taken up in ethyl acetate/ether 1:2. The undissolved material was filtered off, the solvent was removed by distillation and the oily residue (400 mg) was purified by vacuum chromatography. The title compound was obtained as a foam (125 mg, yield 49% purity by HPLC from 95%).

1H-NMR (200 MHz, CDCl3): 7,5 – 7,7 ppm (4 H, m), 7,4 (2 H, d), 7,2 - 7,3 (9 H, m), 6,9 (2 H, d), 6,8 (1 H, d}, 6,3 (1 H, s), 6,2 (1 H, s), 5,4 (1 H, d), 5,0 (2 H, m), 4,7 (1 H, d), 3,9 (б Н, s), 3,7 (3 H, s), 2,3 (3 B, s). 1H-NMR (200 MHz, CDCl3): 7.5 – 7.7 ppm (4 H, m), 7.4 (2 H, d), 7.2 - 7.3 (9 H, m), 6 .9 (2 H, d), 6.8 (1 H, d}, 6.3 (1 H, s), 6.2 (1 H, s), 5.4 (1 H, d), 5 .0 (2 H, m), 4.7 (1 H, d), 3.9 (b N, s), 3.7 (3 H, s), 2.3 (3 B, s).

Spojevi navedeni u tablici I mogu se proizvesti analogno ili kako je opisano u općem dijelu. The compounds listed in Table I can be prepared analogously or as described in the general section.

Primjer 11 Example 11

Podaci vezanja receptora za dolje navedene spojeve izmjereni su gore opisanim ispitivanjem vezanja. Receptor binding data for the compounds listed below were measured using the binding assay described above.

Rezultati su prikazani u tablici 2. The results are presented in Table 2.

Tablica 2 Table 2

Podaci vezanja receptora (Ki vrijednosti) Receptor binding data (Ki values)

[image] [image]

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Claims (11)

1. Derivat karboksilne kiseline formule I [image] naznačen time, da supstituenti imaju slijedeća značenja: R1 predstavlja tetrazol ili skupinu [image] u kojoj R ima slijedeća značenja: a) radikal OR9 gdje R9 predstavlja: vodik, kation alkalijskog metala, kation zemno alkalijskog metala ili fiziološki podnošljiv organski amonijev ion; C3-C8-cikloalkil, C1-C8-alkil, C3-C6-alkenil, C3-C6-alkinil, CH2-fenil, od kojih svaki prema potrebi može biti supstituiran; b) peteročlani heteroaromatski sistem koji je povezan preko dušikovog atoma; c) skupina [image] u kojoj k može imati vrijednost 0, 1 i 2, p može biti 1, 2, 3 i 4 i R10 je C1-C4-alkil, C3-C8-cikloalkil, C3-C6-alkenil, C3-C6-alkinil ili prema potrebi supstituirani fenil, d) radikal formule [image] u kojoj R11 je C1-C4-alkil, C3-C6-alkenil, C3-C6-alkinil, C3-C8-ciklo-alkil, gdje ovi radikali mogu nositi C1-C4-alkoksi, C1-C4-alkiltio i/ili fenilni radikal; fenil, koji prema potrebi može biti supstituiran; R2 je vodik, hidroksi, NH2, NH(C1-C4-alkil), N(C1-C4-alkil)2, halogen, C1-C4-alkil, C2-C4-alkenil, C2-C4-alkinil, C1-C4-halogenalkil, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio, ili je CR2 povezan na CR12 kako je dolje prikazano tako da se dobije peteročlani ili šesteročlani prsten; X je dušik ili metin; Y je dušik ili metin; Z je dušik ili CR12, u kojem R12 predstavlja vodik, halogen, C1-C4-halogenalkil ili C1-C4-alkil, ili CR12 zajedno sa CR2 ili sa CR3 tvori 5- ili 6-člani alkilenski ili alkenilenski prsten koji prema potrebi može biti supstituiran, i u kojem u svakom slučaju jedna ili više metilenskih skupina može biti zamijenjeno s kisikom, sumporom, -NH ili s N(C1-C4-alkilom); R3 je vodik, hidroksi, NH2, NH(C1-C4-alkil), N(C1-C4-alkil)2, halogen, C1-C4-alkil, C2-C4-alkenil, C2-C4-alkinil, C1-C4-halogenalkil, C1-C4-alkoksi, C1-C4-halogenalkoksi, C1-C4-alkiltio, ili je CR3 povezan na CR12 kako je gore navedeno tako se dobije 5- ili 6-člani prsten; R4 i R5 (koji mogu biti jednaki ili različiti) predstavljaju: fenil ili naftil, od kojih svaki može biti supstituiran; fenil ili naftil koji su međusobno povezani u orto položaju preko izravne veze, metilenske, etilenske ili etenilne skupine, kisikovog ili sumpornog atoma ili SO2, NH ili N-alkilne skupine; C3-C8-cikloalkil, koji je prema potrebi supstituiran; R6 je prema potrebi supstituirani C3-C8-cikloalkil; fenil ili naftil, koji je prema potrebi supstituiran; petero- ili šesteročlani heteroaromatski sistem koji sadrži jedan do tri dušikova atoma i/ili jedan sumporni ili kisikov atom, i koji je prema potrebi supstituiran; R7 i R8 (koji mogu biti jednaki ili različiti) predstavljaju: vodik, C1-C4-alkil; W je sumpor ili kisik.1. Carboxylic acid derivative of formula I [image] indicated that the substituents have the following meanings: R1 represents a tetrazole or a group [image] where R has the following meanings: a) radical OR9 where R9 represents: hydrogen, an alkali metal cation, an alkaline earth metal cation, or a physiologically tolerable organic ammonium ion; C3-C8-cycloalkyl, C1-C8-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, CH2-phenyl, each of which may be optionally substituted; b) a five-membered heteroaromatic system connected through a nitrogen atom; c) group [image] where k can have the value 0, 1 and 2, p can be 1, 2, 3 and 4 and R10 is C1-C4-alkyl, C3-C8-cycloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or optionally substituted phenyl, d) the radical of the formula [image] in which R11 is C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cyclo-alkyl, where these radicals can carry a C1-C4-alkoxy, C1-C4-alkylthio and/or a phenyl radical; phenyl, which can be substituted if necessary; R2 is hydrogen, hydroxy, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4 -haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio, or CR2 is linked to CR12 as shown below to form a five- or six-membered ring; X is nitrogen or methine; Y is nitrogen or methine; Z is nitrogen or CR12, in which R12 represents hydrogen, halogen, C1-C4-haloalkyl or C1-C4-alkyl, or CR12 together with CR2 or with CR3 forms a 5- or 6-membered alkylene or alkenylene ring which, if necessary, can be substituted, and in which in each case one or more methylene groups may be replaced by oxygen, sulfur, -NH or by N(C1-C4-alkyl); R3 is hydrogen, hydroxy, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4 -haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy, C1-C4-alkylthio, or CR3 is linked to CR12 as mentioned above to give a 5- or 6-membered ring; R4 and R5 (which can be the same or different) represent: phenyl or naphthyl, each of which may be substituted; phenyl or naphthyl linked to each other in the ortho position via a direct bond, methylene, ethylene or ethenyl group, oxygen or sulfur atom or SO2, NH or N-alkyl group; C3-C8-cycloalkyl, which is optionally substituted; R 6 is optionally substituted C 3 -C 8 -cycloalkyl; phenyl or naphthyl, optionally substituted; a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and/or one sulfur or oxygen atom, and which is optionally substituted; R7 and R8 (which may be the same or different) represent: hydrogen, C1-C4-alkyl; W is sulfur or oxygen. 2. Farmaceutski pripravak, naznačen time, da sadrži barem jedan derivat karboksilne kiseline I prema zahtjevu 1.2. Pharmaceutical preparation, characterized in that it contains at least one carboxylic acid derivative I according to claim 1. 3. Upotreba derivata karboksilne kiseline prema zahtjevu 1, naznačena time, da se on koristi za liječenje bolesti.3. The use of a carboxylic acid derivative according to claim 1, characterized in that it is used for the treatment of diseases. 4. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi kao endotelin receptor antagonist.4. Use of compound I according to claim 1, characterized in that it is used as an endothelin receptor antagonist. 5. Upotreba derivata karboksilne kiseline I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijekova ili za liječenje bolesti kod kojih se pojavljuje povišena razina endotelina.5. Use of carboxylic acid derivative I according to claim 1, characterized in that it is used for the production of drugs or for the treatment of diseases in which an elevated level of endothelin occurs. 6. Upotreba prema zahtjevu 5, naznačena time, da se on koristi za liječenje kronične srčane insuficijencije, restenoze, visokog krvnog tlaka, visokog plućnog tlaka, akutnog/kroničnog otkazivanja bubrega, cerebralne ishemije, benigne hiperplazije prostate i raka prostate.6. Use according to claim 5, characterized in that it is used for the treatment of chronic heart failure, restenosis, high blood pressure, high pulmonary pressure, acute/chronic renal failure, cerebral ischemia, benign prostatic hyperplasia and prostate cancer. 7. Kombinirani farmaceutski pripravak, naznačen time, da sadrži derivat karboksilne kiseline prema zahtjevu 1 i inhibitor sistema renin-angiotenzina ili miješani ACE/neutralni inhibitor endopeptidaze (NEP) ili β-bloker.7. Combined pharmaceutical preparation, characterized in that it contains a carboxylic acid derivative according to claim 1 and an inhibitor of the renin-angiotensin system or a mixed ACE/neutral endopeptidase inhibitor (NEP) or β-blocker. 8. Upotreba spojeva formule IV [image] u kojoj radikali R1, R4, R5, R6, R7, R8 i W imaju značenja navedena u zahtjevu 1, naznačena time, da se oni koriste kao intermedijati za sintezu endotelin receptor antagonista.8. Use of compounds of formula IV [image] in which the radicals R1, R4, R5, R6, R7, R8 and W have the meanings specified in claim 1, indicated that they are used as intermediates for the synthesis of endothelin receptor antagonists. 9. Upotreba strukturnog fragmenta formule [image] u kojoj radikali R1, R4, R5, R6, R7, R8 i W imaju značenja navedena u zahtjevu 1, naznačena time, da se on koristi kao strukturni dio endotelin receptor antagonista.9. Use of the structural fragment of the formula [image] in which the radicals R1, R4, R5, R6, R7, R8 and W have the meanings stated in claim 1, indicated that it is used as a structural part of the endothelin receptor antagonist. 10. Upotreba strukturnog fragmenta formule [image] u kojoj radikali R1, R2, R3, R4, R5, R7, R8, W, X, Y i Z imaju značenja navedena u zahtjevu 1, naznačena time, da se on koristi kao strukturni dio u endotelin receptor antagonistu.10. Use of the structural fragment of the formula [image] in which the radicals R1, R2, R3, R4, R5, R7, R8, W, X, Y and Z have the meanings given in claim 1, indicated that it is used as a structural part in an endothelin receptor antagonist. 11. Spoj formule VIa [image] naznačen time, da u njoj radikali R1, R2, R3, R4, R5, R6, R7, R8, W, X, Y i Z imaju značenja navedena u zahtjevu 1, a R18 i R19 imaju slijedeća značenja: R18 i R19 (koji mogu biti jednaki ili različiti) predstavljaju; C1-C4-alkil ili R18, zajedno s R19, tvori etilenski ili propilenski most koji prema potrebi može biti supstituiran s jednom do četiri metilne skupine.11. Compound of formula VIa [image] characterized by the fact that in it the radicals R1, R2, R3, R4, R5, R6, R7, R8, W, X, Y and Z have the meanings specified in claim 1, and R18 and R19 have the following meanings: R18 and R19 (which may be the same or different) represent; C1-C4-alkyl or R18, together with R19, forms an ethylene or propylene bridge which can be substituted with one to four methyl groups as needed.