Insulin sensitivity with angiotensin II receptor blocking imidazoles

A method of improving insulin sensitivity alone or in conjunction with the treatment of hypertension using an angiotensin II antagonist of formula I:

• ##STR44## wherein:
• R.sup.1 is:
• 4-CO.sub.2 H;
• 4-CO.sub.2 R.sup.9 ;
• ##STR45## --SO.sub.3 H;
• --C(CF.sub.3).sub.2 OH;
• ##STR46## R.sup.2 is H;
• Cl;
• Br;
• I;
• F;
• NO.sub.2 ;
• CN;
• alkyl of 1 to 4 carbon atoms;
• acyloxy of 1 to 4 carbon atoms;
• alkoxy of 1 to 4 carbon atoms;
• CO.sub.2 H;
• CO.sub.2 R.sup.9 ;
• HNSO.sub.2 CH.sub.3 ;
• NHSO.sub.2 CF.sub.3 ;
• CONHOR.sup.12 ;
• SO.sub.2 NH.sub.2 ;
• ##STR47## aryl;
• or furyl;
• R.sup.3 is H;
• Cl, Br, I or F;
• alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;
• R.sup.4 is CN, NO.sub.2 or CO.sub.2 R.sup.11 ;
• R.sup.5 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;
• R.sup.6 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 CO.sub.2 R.sup.14 ;
• cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl, of 4 to 10 carbon atoms;
• cycloalkylalkenyl or cycloalkylalkynyl 5 to 10 carbon atoms;
• (CH.sub.2).sub.s Z(CH.sub.2).sub.m R.sup.5 optionally substituted with F or CO.sub.2 R.sup.14 ;
• benzyl 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;
• R.sup.7 is H, F, Cl, Br, I, NO.sub.2, C.sub..nu. F.sub.2.nu.+1, where v=1-6, C.sub.6 F.sub.5 ;
• CN;
• ##STR48## 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, OCH.sub.3, CF.sub.3, and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl;
• R.sup.8 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;
• --(CH.sub.2).sub.m -imidazol-1-yl;
• --(CH.sub.2).sub.m -1,2,3-triazolyl optionally substituted with one or two group selected from CO.sub.2 CH.sub.3 or alkyl of 1 to 4 carbon atoms;
• --(CH.sub.2).sub.s tetrazolyl;
• ##STR49## R.sup.9 is:
• ##STR50## R.sup.10 is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH.sub.2).sub.p C.sub.6 H.sub.5 ;
• R.sup.11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
• R.sup.12 is H, methyl or benzyl;
• R.sup.13 is --CO.sub.2 H;
• --CO.sub.2 R.sup.9 ;
• --CH.sub.2 CO.sub.2 H, --CH.sub.2 CO.sub.2 R.sup.9 ;
• ##STR51## --PO.sub.3 H.sub.2 ;
• --C(CF.sub.3).sub.2 OH;
• --NHSO.sub.2 CH.sub.3 ;--NHSO.sub.2 CF.sub.3 ;
• --NHCOCF.sub.3 ;
• --CONHOR.sup.12 ;
• --SO.sub.2 NH.sub.2 ;
• ##STR52## R.sup.14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
• R.sup.15 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;
• R.sup.16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH.sub.2).sub.p C.sub.6 H.sub.5, OR.sup.17, or NR.sup.18 R.sup.19 ;
• R.sup.17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
• R.sup.18 and R.sup.19 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 ##STR53## Q is NR.sup.20, O or CH.sub.2 ;
• R.sup.20 is H, alkyl of 1-4 carbon atoms, or phenyl;
• R.sup.21 is alkyl of 1 to 6 carbon atoms, --NR.sup.22 R.sup.23, or ##STR54## R.sup.22 and R.sup.23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH.sub.2).sub.u, where u is 3-6;
• R.sup.24 is H, CH.sub.3 or --C.sub.6 H.sub.5 ;
• R.sup.25 is NR.sup.27 R.sup.28, OR.sup.28, NHCONH.sub.2, NHCSNH.sub.2, ##STR55## R.sup.26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl;
• R.sup.27 and R.sup.28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl;
• R.sup.29 and R.sup.30 are independently alkyl of 1-4 carbon atoms or taken together are --(CH.sub.2).sub.q --;
• R.sup.31 is H, alkyl or 1 to 4 carbon atoms, --CH.sub.2 CH.dbd.CH.sub.2 or --CH.sub.2 C.sub.6 H.sub.4 R.sup.32 ;
• X is a carbon-carbon single bond, --CO--, --CH.sub.2 --, --O--, --S--, --NH--, ##STR56## --OCH.sub.2 --, --CH.sub.2 O--, --SCH.sub.2 --, --CH.sub.2 S--, --NHC(R.sup.27)(R.sup.28)--, --NR.sup.23 SO.sub.2 --, --SO.sub.2 NR.sup.23 --, --CH.dbd.CH--, --CF.dbd.CF--, --CH.dbd.CF--, --CF.dbd.CH--, --CH.sub.2 CH.sub.2 --, --C(R.sup.27)(R.sup.28)NH--, ##STR57## Y is O or S;
• Z is O, NR.sup.11, 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 R.sup.1 group is not in the ortho position;
• (2) when R.sup.1 is ##STR58## X is a single bond, and R.sup.13 is CO.sub.2 H, or ##STR59## then R.sup.13 must be in the ortho or meta position;
• or when R.sup.1 and X are as above and R.sup.13 is NHSO.sub.2 CF.sub.3 or NHSO.sub.2 CH.sub.3, R.sup.13 must be ortho;
• (3) when R.sup.1 is ##STR60## and X is other than a single bond, then R.sup.13 must be ortho except when X.dbd.NR.sup.23 CO and R.sup.13 is NHSO.sub.2 CF.sub.3 or NHSO.sub.2 CH.sub.3, then R.sup.13 must be ortho or meta;
• (4) when R.sup.1 is 4-CO.sub.2 H or a salt thereof, R.sup.6 cannot be S-alkyl;
• (5) when R.sup.1 is 4-CO.sub.2 H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH.sub.2 OH, CH.sub.2 OCOCH.sub.3, or CH.sub.2 CO.sub.2 H;
• (6) when R.sup.1 is ##STR61## X is --OCH.sub.2 --, and R.sup.13 is 2-CO.sub.2 H, and R.sup.7 is H then R.sup.6 is not C.sub.2 H.sub.5 S;
• (7) when R.sup.1 is ##STR62## and R.sup.6 is n-hexyl then R.sup.7 and R.sup.8 are not both hydrogen;
• (8) when R.sup.1 is ##STR63## R.sup.6 is not methoxybenzyl;
• (9) the R.sup.6 group is not ##STR64## or CH.sub.2 OH;
• (10) when r=0, R.sup.1 is ##STR65## X is ##STR66## R.sup.13 is 2-NHSO.sub.2 CF.sub.3, and R.sup.6 is n-propyl, then R.sup.7 and R.sup.8 are not --CO.sub.2 CH.sub.3 ;
• (11) when r=0, R.sup.1 is ##STR67## X is ##STR68## R.sup.13 is 2-COOH, and R.sup.6 is n-propyl, then R.sup.7 and R.sup.8 are not --CO.sub.2 CH.sub.3 ;
• (12) when r=1, R.sup.1 is ##STR69## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 3-(tetrazol-5-yl);
• (13) when r=1, R.sup.1 is ##STR70## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 4-(tetrazol-5-yl).