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Substituted quinazolinones as angiotensin II antagonists

  • US 5,240,928 A
  • Filed: 03/06/1991
  • Issued: 08/31/1993
  • Est. Priority Date: 07/03/1989
  • Status: Expired due to Fees
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Assignment
First Claim
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1. A compound of formula (I):

  • ##STR33## wherein;

    L is connected with J or K to form an aromatic ring as defined below;

    J is --C(═

    M)-- or J and L are connected together to form a 6 carbon aromatic ring substituted with R7a, R7b, R8a and R8b ;

    K is --C(═

    M)-- or K and L are connected together to form a 6 carbon aromatic ring substituted with R7a, R7b, R8a and R8b, provided that only one of J and K is --C(═

    M)--;

    M is O or NR22R1 is(a) --CO2 R4,(b) --SO3 R5,(c) --NHSO2 R23,(d) --PO(OR5)2,(e) --SO2 --NH--R23, ##STR34## (h) --SO2 NH--CO--R23, (i) --CH2 SO2 NH--CO--R23,(j) --CONH--SO2 R23,(k) --CH2 CONH--SO2 R23,(l) --NHSO2 NHCO--R23,(m) --NHCONHSO2 --R23, ##STR35## wherein heteroaryl is an unsubstituted, monosubstituted or disubstituted five or six membered aromatic ring which contains from 1 to 3 heteroatoms selected from the group consisting of O, N or S and wherein the substituents are members selected from the group consisting of --OH, --SH, --C1 -C4 -alkyl, --C1 -C4 -alkoxy, --CF3, Cl, Br, F, I, --NO2, --CO2 H, --CO2 --(C1 -C4 -alkyl), --NH2, --NH(C1 -C4 -alkyl) and --N(C1 -C4 -alkyl)2 ;

    R2a and R2b are each independently(a) H,(b) Cl, Br, I, or F,(c) NO2,(d) NH2,(e) C1 -C4 -alkylamino,(f) di(C1 -C4 -alkyl)amino,(g) SO2 NHR9,(h) CF3,(i) C1 -C6 -alkyl,(j) C1 -C6 -alkoxy,(k) C1 -C6 -alkyl-S-,(l) C2 -C6 -alkenyl,(m) C2 -C6 -alkynyl,(n) aryl,(o) aryl(C1 -C4 -alkyl), or(p) C3 -C7 -cycloalkyl;

    R3a is(a) H,(b) Cl, Br, I, or F,(c) C1 -C6 -alkyl,(d) C1 -C6 -alkoxy, or(e) C1 -C6 -alkoxyalkyl;

    R3b is(a) H,(b) Cl, Br, I, or F,(c) NO2,(d) C1 -C6 -alkyl,(e) C1 -C6 -acyloxy,(f) C3 -C7 -cycloalkyl,(g) C1 -C6 -alkoxy,(h) --NHSO2 R4,(i) hydroxy-(C1 -C4 -alkyl),(j) aryl-(C1 -C4 -alkyl),(k) C1 -C4 -alkylthio,(l) C1 -C4 -alkyl sulfinyl,(m) C1 -C4 -alkyl sulfonyl,(n) NH2,(o) C1 -C4 -alkylamino,(p) di(C1 -C4 alkyl)amino-,(q) fluoro-C1 -C4 -alkyl,(r) --SO2 --NHR9,(s) aryl,(t) furyl,(u) CF3,(v) C2 -C6 -alkenyl, or(w) C2 -C6 -alkynyl;

    wherein aryl is phenyl or naphthyl or substituted phenyl or naphthyl with one or two substituents selected from the group consisting of Cl, Br, I, F, N(R4)2, CO2 R4, C1- C4 -alkyl, C1- C4 -alkoxy, NO2, CF3, C1 -C4 -alkylthio, or OH;

    R4 is H, aryl, heteroaryl, C1 -C6 -alkyl, or aryl C1 -C6 alkyl;

    R4a is aryl, C1 -C6 -alkyl or aryl C1 -C6 alkyl;

    ##STR36## E is a single bond, --NR13 (CH2)s --, --S(O)x (CH2)s -- where x is 0 to 2 and s is 0 to 5, --CH(OH)--, --O--, or CO--;

    R6 is(a) phenyl or substituted phenyl with 1 or 2 substituents selected from the group consisting of Cl, Br, I, F, --O--C1 -C4 -alkyl, C1 -C4 -alkyl, --NO2, --CF3, --SO2 NR9 R10, --S--C1 -C4 -alkyl, --OH, --NH2, C3 -C7 -cycloalkyl, and C3 -C10 -alkenyl;

    (b) C1 -C6 -alkyl, C2 -C5 -alkenyl or C2 -C5 -alkynyl or substituted C1 -C6 alkyl, C2 -C6 alkenyl or C2 -C6 alkynyl with a substituent selected from the group consisting of aryl C3 -C7 -cycloalkyl, Cl, Br, I, F, --OR4, CF3, CF2 CF3, --NH2, --NH(C1 -C4 -alkyl), --N(C1 -C4 -alkyl)2, --NH--SO2 R4, --COOR4, and --SO2 NHR9 ;

    (c) an unsubstituted, monosubstituted or disubstituted heteroaromatic 5 or 6 membered cyclic ring which contains one or two members selected from the group consisting of N, O, S, and wherein the substituents are members selected from the group consisting of --OH, --SH, C1 -C4 -alkyl, C1 -C4 -alkyloxy --CF3, Cl, Br, I, F, or NO2,(d) C3 -C7 -cycloalkyl,(e) perfluoro-C1 -C4 -alkyl, or(f) H;

    R7a and R7b are independently(a) H,(b) C1 -C6 -alkyl, C2 -C6 -alkenyl or C2 -C6 -alkynyl,(c) Cl, Br, I, or F,(d) CF3, or(e) when R7a and R7b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring;

    R8a and R8b are independently(a) H,(b) C1 -C6 -alkyl or substituted C1 -C6 alkyl with a substituent selected from the group consisting of --OH, -guanidino, C1 -C4 -alkoxy, --N(R4)2, COOR4, --CON(R4)2, --O--COR4, --aryl, heteroaryl, --S(O)x --R23, -tetrazol-5-yl, --CONHSO2 R23, --SO2 NH-heteroaryl, --SO2 NHCOR23, --PO(OR4)2, --PO(OR4)R9, --SO2 NH--CN, --NR10 COOR23, morpholino, N--(C1 -C6 -alkyl)piperazine, or --COR4 ;

    (c) --CO-aryl,(d) --C3 -C7 -cycloalkyl,(e) --Cl, Br, I, or F,(f) --OH,(g) --OR23,(h) --C1 -C4 -perfluoroalkyl,(i) --S(O)x --R23,(j) --COOR4,(k) --SO3 H,(l) --NR4 R23,(m) --NHCOR23(n) --NH--CO2 R23,(O) --SO2 NR9 R10,(p) --NO2,(q) --NHSO2 R23,(r) --NHCONR4 R23, ##STR37## (t) aryl or -heteroaryl, (u) --NHSO2 CF3,(v) --SO2 NH--heteroaryl,(w) --SO2 NHCOR23,(x) --CONHSO2 R23,(y) --PO(OR4)2,(z) --PO(OR4)2,(aa) -tetrazol-5-yl,(bb) --CONH(tetrazol-5-yl),(cc) --COR4,(dd) --SO2 NHCN, ##STR38## (ff) --CO-heteroaryl, or (gg) --NHSO2 NR23 R9 ;

    R9 is H, C1 -C5 -alkyl, aryl, or arylmethyl;

    R10 is H, C1 -C4 -alkyl;

    R11 is H, C1 -C6 -alkyl, C1 -C4 -alkenyl, C1 -C4 -alkoxy alkyl, or ##STR39## R12 is --CN, --NO2, --CF3 or --CO2 R4 ;

    R13 is H, (C1 -C4 -alkyl)CO--, C1 -C6 -alkyl, allyl, C3 -C6 -cycloalkyl, aryl or arylmethyl;

    R14 is H, C1 -C8 -alkyl, C1 -C8 -perfluoroalkyl, C3 -C6 -cycloalkyl, aryl or arylmethyl;

    R15 is H, C1 -C6 -alkyl;

    R16 is H, C1 -C6 -alkyl, C3 -C6 -cycloalkyl, aryl or arylmethyl;

    R17 is --NR9 R10, --OR10, --NHCONH2, --NHCSNH2, ##STR40## R18 and R19 are independently C1 -C4 -alkyl or taken together are --(CH2)q -- where q is 2 or 3;

    R20 is H, --NO2, --NH2, --OH or --OCH3 ;

    R21 is H, aryl, C1 -C4 -alkyl or C1 -C4 -alkyl substituted with a aryl, --NH2, --NH(C1 -C4 -alkyl), --N(C1 -C4 -alkyl)2, --CO2 R4, --OH, --SO3 H, or --SO2 NH2 substituent;

    R22 is(a) aryl,(b) heteroaryl or,(c) C1 -C4 -alkyl or C1 -C4 alkyl substituted with a substituent selected from the group consisting of aryl, heteroaryl, --OH, --NH2, --NH(C1 -C4 -alkyl), --N(C1 -C4 -alkyl)2, --CO2 R4, Cl, Br, F, I, or --CF3 ;

    R23 is(a) aryl,(b) heteroaryl,(c) C3 -C7 -cycloalkyl,(d) C1 -C6 -alkyl or C1 -C6 alkyl substituted with a substituent selected from the group consisting of aryl, heteroaryl, --OH, --SH, C1 -C4 -alkyl, --O(C1 -C4 -alkyl), --S(C1 -C4 -alkyl), --CF3, Cl, Br, F, I, --NO2, --CO2 H, CO2 --C1 -C4 -alkyl, --NH2, --NH(C1 -C4 -alkyl), --N(C1 -C4 -alkyl)2, --PO3 H2, --PO(OH)(O--C1 -C4 -alkyl), or --PO (OR4)R9, or(e) perfluoro-C1 -C4 -alkyl;

    X is(a) a carbon-carbon single bond,(b) --CO--,(c) --O--,(d) --S--, ##STR41## (h) --OCH2 --, (i) --CH2 O--(j) --SCH2 --,(k) --CH2 S--,(l) --NHC(R9)(R10),(m) --NR9 SO2`--,(n) --SO2 NR9 --,(o) --C(R9)(R10)NH--,(p) --CH═

    CH--,(q) --CF═

    CF--,(r) --CH═

    CF--,(s) --CF═

    CH--,(t) --CH2 CH2 --,(u) --CF2 CF2 --, ##STR42## r is 1 or 2;

    or a pharmaceutically acceptable salt thereof.

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