C - Chemistry – Metallurgy – 07 – D
Patent
C - Chemistry, Metallurgy
07
D
167/208, 260/300
C07D 233/54 (2006.01) A61K 31/415 (2006.01) C07D 233/68 (2006.01) C07D 233/70 (2006.01) C07D 233/84 (2006.01) C07D 233/90 (2006.01) C07D 401/06 (2006.01) C07D 403/04 (2006.01) C07D 403/06 (2006.01) C07D 403/10 (2006.01) C07D 403/14 (2006.01) C07D 405/06 (2006.01) C07D 405/10 (2006.01) C07D 409/10 (2006.01) C07D 521/00 (2006.01) C07F 9/6506 (2006.01)
Patent
CA 1338238
The present invention relates to substituted imidazoles, useful in pharmaceutical compositions, especially diuretics and non-steroidal anti-inflamatory drugs. The imidazoles have the formula: Image (I) wherein: R1 is 4-CO2H; 4-CO2R9; Image ; -SO3H; C(CF3)2OH; Image ; -PO3H; Image ; 4-NHSO2CH3; 4-NHSO2CF3; -CONHOR12; SO2NH2; Image ; Image ; Image ; Image ; Image ; Image ; Image ; Image ; Image ; 4 - CONHNHS~F3; Image ; (?-isomer) Image ; Image ; Image ; Image ; Image ; Image ; or Image ; 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 ; Image ; 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; Image ; 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; Image ; Image ; -(CH2)nSR15 ; Image ; Image ; <IGM> ; Image ; Image ; Image ; Image ; Image ; Image ; -(CH2)nNR11SO2R10 ; Image ; -(CH2)mF ; -(CH2)mONO2; -CH2N3; -(CH2)mNO2; -CH=N-NR11R17; Image ; Image ; Image ; Image ; Image ; Image ; or Image ; R9 is Image ; 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; Image ; Image ; -SO3H; Image -PO3H; -C(CF3)2OH; -NHSO2CH3; -NHSO2CF3; -NHCOCF3; -CONHOR12; -SO2NH2; Image ; Image ; Image ; Image ; -CONHNHSO2CF3 ; Image ; or Image ; 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 Image ; 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 Image ; 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, Image or Image : 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-, Image , Image , Image , -OCH2-, -CH2O-, -SCH2-, -CH2S-, -NHC(R27)(R28), -NR23SO2-, -SO2NR23-, -C(R27)(R28)NH-, -CH=CH-, -CF=CF-, -CH=CF-, -CF=CH-. -CH2CH2-, -CF2CF2, Image , Image , Image , Image or Image ; 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 Image , Y is a single bond, and R13 is CO2H, or Image 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 Image , 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 Image . X -OCH2-, and R13 is 2-CO2H, nd R7 is h thcn R6 is not C2H5S; (7) when R1 is Image , and R6 is n-hexyl then R7 and R8 are not both hydrogen; (8) when R1 is Image , R6 is not methoxy- benzyl; (9) the R6 group is not Image or CH2OH; (10) when r=O, R1 is Image , X is Image R13 is 2-NHSO2CF3, and R6 is n-propyl, then R7 and R8 are not -CO2CH3; (11) when r=O, R1 is Image , X is Image , R13 is 2-COOH, and R6 is n-propyl, then R7 and R8 are not -CO2CH3; (12) when r=1, R1= Image , 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= Image , X is a single bond, R7 is Cl, and R8 is -CHO, then R13 is not 4-(tetrazol-5-yl).
586904
Carini David John
Duncia John Jonas Vytautas
Wong Pancras Chor Bun
E.i. Du Pont de Nemours And Company
Sim & Mcburney
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