DERIVADOS HETEROCICLICOS DE ACIDO CARBONICO SU PRODUCCION Y APLICACION COMO ANTAGONISTAS DE RECEPTORES DEENDOTELINA

    公开(公告)号:CO4930270A1

    公开(公告)日:2000-06-27

    申请号:CO97073662

    申请日:1997-12-17

    Applicant: BASF AG

    Abstract: Derivados de ácido carbónico de la fórmula I: CARACTERIZADOS porque R1 representa tetrazol o a un grupo en el que R tiene el siguiente significado: a) un residuo OR6 , en donde R6 significa: hidrógeno, el catión de un metal alcalino, el catión de metal alcalinotérreo, o un ión amonio fisiológicamente compatible; C3 -C8 cicloalquilo, C1 -C8 alquilo, CH2 -fenilo, que puede ser sustituido, un grupo C3 -C6 -alquenilo o C3 -C6 - alquinilo, que puede ser sustituido o fenilo, en caso dado, sustituido.b) un heteroaromático de 5 eslabones ligado con un átomo de nitrógeno, c) un grupo en el que k puede tomar los valores 0,1 y 2, p los valores 1, 2, 3 y 4 y R7 representa d) un residuo - 2 -donde R8 significa : C1 -C4 -alquilo, C3 -C8 -alquenilo, C3 -C8 -alquinilo, C3 -C8 -cicloalquilo, donde estos residuos pueden tener un residuo C1 -C4 -alcoxi, C1 -C4 -alquiltio y/o un residuo fenilo C1 -C4 -halogenalquilo o fenilo, en caso de ser necesario, sustituido; X nitrógeno o metino, con la condición de que si X = nitrógeno, entonces Z=nitrógeno y si X = metino, entonces por lo menos uno de los eslabones Y o Z son nitrógeno; Y nitrógeno o CR9 ; Z nitrógeno o CR10 , R2 C1 -C4 -alquilo, C2 -C4 -alquenilo, C2 -C4 -alquinilo, pudiendo estar estos residuos sustituidos; hidrógeno, halógeno, C1 -C4 -alcoxi, C1 -C4 -halogenalcoxi, C3 -C6 -alqueniloxi, C3 -C6 -alquiniloxi, C1 -C4 -alquiltio, C1 -C4 -alquilcarbonilo, C1 -C4 -coxicarbonilo, NH(C1 -C4 -alquilo) N(C1 -C4 -alquilo)2 , hidroxi, carboxi, ciano, amino; o CR2 junto con CR9 o CR10 forma un anillo de alquileno de 5 ó 6 eslabones o de alquenilo, que puede ser sustituido por uno o dos grupos C1 -C4 -alquilo y en donde uno o más grupos metilenos pueden ser sustituidos por oxígeno, azufre -NH o N(C1 -C4 -alquilo)2 . R3 y R4 (que pueden ser iguales o distintos) son: fenilo o naftilo, que pueden ser sustituidos fenilo o naftilo, que pueden estar unidos en posición orto por una unión directa a un grupo metileno, etileno o etenileno, a un átomo de oxígeno o azufre o a un grupo SO2 , NH- o N-alquilo; C3 -C8 -cicloalquilo, que puede ser sustituido; R5 hidrógeno, C1 -C8 alquilo, C3 -C8 -alquenilo o C3 -C8 -alquinilo, pudiendo estar estos residuos sustituidos; fenilo o naftilo, que pueden ser sustituidos; un heteroaromático de cinco a seis eslabones conteniendo de uno a tres átomos de nitrógeno y/o un átomo de azufre u oxígeno, el cual puede ser sustituido C3 -C8 -cicloalquilo, que puede ser sustituido R9 y R10 (que pueden ser iguales o diferentes) son:hidrógeno, hidroxi, NH2 , NH(C1 AND#8209;C4 AND#8209;alquilo), N(C1 AND#8209;C4 AND#8209;alquilo)2 , halógeno, C1 AND#8209;C4 alcoxi, C1 AND#8209;C4 AND#8209;halogenalcoxi o C1 AND#8209;C4 AND#8209;alquiltio; C1 AND#8209;C4 AND#8209;alquilo, C2 AND#8209;C4 AND#8209;alquenilo, C2 AND#8209;C4 AND#8209;alquinilo, pudiendo estos residuos estar sustituidos; o bien CR9 o CR10 está unido con CR2 como en R2 para dar un anillo de 5 o 6 eslabones;W es azufre, oxígeno o una unión simple; Q es oxígeno o nitrógeno, con la condición que en caso que Q = N, entonces W es una unión simple. así como las sales fisiológicamente compatibles y las formas enantiómeras y diastereómeras.

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

    公开(公告)号:DE19858779A1

    公开(公告)日:2000-06-21

    申请号:DE19858779

    申请日:1998-12-18

    Applicant: BASF AG

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

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