Patent CA-1338238-C (CA)
Title: Angiotensin ii receptor blocking imidazoles and combinations thereof with diuretics and nsaids
Inventor: CARINI DAVID JOHN
IPC: C07F9/6558
Filed: 1988-12-22
Granted: 1996-04-09
Abstract: The present invention relates to substituted imidazoles, useful in pharmaceutical compositions, especially diuretics and non-steroidal anti-inflamatory drugs.  The imidazoles have the formula:       (I) wherein:            R1 is 4-CO2H;  4-CO2R9;      ;   -SO3H;      C(CF3)2OH;     ;  -PO3H;      ;   4-NHSO2CH3;  4-NHSO2CF3;    -CONHOR12;      SO2NH2;        ;        ;       ;      ;      ;                  ;      ;      ;       ;    4 - CONHNHS~F3;     ;                             (?-isomer)   ;        ;       ;                 ;        ;   ;   or             ;          R2 is H; Cl; Br; I; F; NO2; CN; alkyl of 1 to 4 carbon atoms, acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO2H; CO2R6; NHSO2CH3; NHSO2CF3;     CONHOR12; SO2NH2 ;    ; aryl; or furyl;         R3 is H; Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; R4 is CN, NO2 or CO2R11; R5 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms alkenyl or alkynyl of 2 to 4 carbon atoms; R6 is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO2R14; cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms; (CH2)sZ(CH2)mR5 optionally substituted with F or CO2R14; benzyl or benzrl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro; R7 is H, F, Cl, Br, I, NO2, CvF2v+1, where v =1-6, C6F5; CN;  ; straight or branched alkyl of 1 to 6 carbon atoms; phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms; or substituted phenyl or substituted phenylalkyl, where alkyl is 1 to 3 carbon atoms, substituted with one or two substituents selected from alkyl of 1 to 4 carbon atoms, F, Cl, Br, OH, OCH3, CF3, and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl; R8 is H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms; -(CH2)m-imidazol-1-yl; -(CH2)m-1,2,3-triazolyl optionally substituted with one or two groups selected from CO2CH3 or alkyl of 1 to 4 carbon atoms; -(CH2)s-tetrazolyl;        ;        ;    -(CH2)nSR15 ;        ;        ;     <IGM> ;        ;        ;        ;       ;        ;     ;  -(CH2)nNR11SO2R10 ;        ; -(CH2)mF ; -(CH2)mONO2; -CH2N3;     -(CH2)mNO2;   -CH=N-NR11R17;        ;         ;       ;         ;     ;        ;   or      ;     R9  is     ; R10 is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH2)pC6H5; R11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R12 is H methyl or benzyl; R13 is -CO2H; -CO2R ; -CH2CO2H, -CH2CO2R9;        ;    ; -SO3H;    -PO3H; -C(CF3)2OH; -NHSO2CH3; -NHSO2CF3; -NHCOCF3;    -CONHOR12; -SO2NH2;     ;     ;         ;         ;  -CONHNHSO2CF3 ;             ;  or     ;     R14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R15 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl; R16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH2)pC6H5, OR17, or NR18R19;     R17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R18 and R19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, .alpha.-methylbenzyl, or taken together with the nitrogen form a ring of the formula    ;         Q is NR20, O or CH2; R20 is H, alkyl of 1-4 carbon atoms, or phenyl; R21 is alkyl of 1 to 6 carbon atoms, -NR22R23, or   ;         R22 and R23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH2)u where u is 3-6; R24 is H, CH3 or -C6H5;       R25 is NR27R28, OR28, NHCONH2, NHCSNH2,         or         :         R26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl; R27 and R28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl; R29 and R30 are independently alkyl of 1-4 carbon atoms or taken together are -(CH2)q-; R31 is H, alkyl of 1 to 4 carbon atoms, -CH2CH=CH2 or -CH2C6H4R32; R32 is H, NO2, NH2, OH or OCH3;     X is a carbon-carbon sing-lo bond, -CO-, -CH2-, -O-, -S-, -NH-,  ,   ,   , -OCH2-, -CH2O-, -SCH2-, -CH2S-, -NHC(R27)(R28), -NR23SO2-, -SO2NR23-, -C(R27)(R28)NH-, -CH=CH-, -CF=CF-, -CH=CF-,  -CF=CH-. -CH2CH2-, -CF2CF2,  ,  ,   ,     or    ;            Y is 0 or S; Z is 0, NR11, or S; m is 1 to 5; n is 1 to 10; p is 0 to 3; q is 2 to 3; r is 0 to 2; s is 0 to 5; t is 0 or 1;   and pharmaceutically acceptable salts of these compounds; provided that: (1)  the R1 group is not in the ortho position;     (2)  when R1 is    ,  Y is a single bond, and R13 is CO2H, or     then R13 must be in the ortho or meta position; or when R1 and X are as above and R13 is NHSO2CF3 or NHSO2CH3, R13 must be ortho;     (3)  when R1 is   , and X is other than a single bond, then R13 must bo ortho except when X = NR23CO and R13 is NHSO2CF3 or NHSO2CH3, then R13 must be ortho or meta; (4)  when R1 is 4-CO2H or a salt thereof, R6 cannot be S-alkyl; (5)  when R1 is 4-CO2H or a salt theroof, the substituent on the 4-position of the imidazolo cannot be CH2OH, CH2OCOCH3, or CH2CO2H;       (6)  when R1  is      . X -OCH2-, and R13 is 2-CO2H,  nd R7 is h thcn R6 is not C2H5S;     (7)  when R1 is   , and R6 is n-hexyl then R7 and R8 are not both hydrogen;            (8)  when R1 is    , R6 is not methoxy-benzyl;     (9)  the R6 group is not       or CH2OH;             (10) when r=O, R1 is    , X is    R13 is 2-NHSO2CF3, and R6 is n-propyl, then R7 and R8 are not -CO2CH3;            (11) when r=O, R1 is   , X is  , R13 is 2-COOH, and R6 is n-propyl, then R7 and R8 are not -CO2CH3;            (12) when r=1, R1=    , X is a single bond, R7 is Cl, and R8 is -CHO, then R13 is not 3-(tetrazol-5-yl);            (13) when r=1, R1=    , X is a single bond, R7  is Cl, and R8 is -CHO, then R13 is not 4-(tetrazol-5-yl).