Renal-selective biphenylalkyl 1h-substituted-1,2,4-triazole angiotensin ii antagonists for treatment of hypertension

Claim 2

A renal selective conjugate consisting of a first radical and a second radical, said first and second radicals connected together by a kidney-enzyme-cleavable amide bond, wherein said first radical is provided by a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound of Formula I ##STR571## wherein m is one; wherein R 1 is selected from amino, aminomethyl, aminoethyl, aminopropyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cycloalkylalkyl, carboxyl, carboxyalkyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1-dimethoxypropyl, 1,1-diemthoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, halo, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein R 2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, isopentyl, tert-butyl, n-pentyl and neopentyl; wherein one of R 5 and R 9 is COOH or ##STR572## wherein each of the remainder of R 3 through R 11 is independently selected from hydrido, amino, monoalkylamino and carboxylic acid; wherein said second radical is provided by a compound selected from a class of compounds of Formula II: ##STR573## wherein each of R 50 and R 51 may be independently selected from hydrido, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl and haloalkyl; and wherein G is selected from hydrido, hydroxyl, halo, mercapto, --OR 52 , --SR 53 and >NR 54 with each of R 52 , R 53 and R 54 independently selected from alkyl, and wherein each of R 53 and R 54 may be further independently selected from hybrido; with the proviso that said kidney-enzyme-cleavable amide bond is within an amide group formed between said first and second radicals, wherein said first radical has a primary or secondary amino moiety, wherein said first-radical amino moiety is provided by one of said R 1 through R 11 substituents of said Formula I compound or is provided by a linking moiety attached to a carbonyl group attached at one of said R 1 through R 11 substituents of said Formula I, and wherein said second radical has a carbonyl moiety attached at the gamma-position carbon of said Formula II compound, whereby said kidney-enzyme-cleavable amide bond is formed from said first-radical amino moiety and said second radical carbonyl moiety; and wherein said linking moiety is a divalent radical of Formula III: ##STR574## wherein each of R 200 and R 201 may be independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl and haloalkyl; and wherein n is a number selected from zero through six, inclusive; or a pharmaceutically-acceptable salt of said renal-selective conjugate.

Claim 3

Conjugate of claim 1 wherein said second residue forms a kidney-enzyme-cleavable amide bond with the radical of said angiotensin II antagonist compound.

Claim 4

Conjugate of claim 1 wherein each G substituent is hydroxy.

Claim 5

Conjugate of claim 3 wherein each G substituent is hydroxy; wherein R 50 is hydrido; and wherein R 51 is selected from ##STR575## wherein R 55 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and chloromethyl.

Claim 6

Conjugate of claim 1 wherein said second radical is ##STR576##

Claim 7

Conjugate of claim 1 wherein said first radical is a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound containing a primary or secondary amino moiety attached at one of said R 1 through R 11 positions of Formula I, said amino moiety selected from amino and linear or branched aminoalkyl moieties containing linear or branched alkyl groups selected from aminomethyl, aminoethyl, aminopropyl, aminosopropyl, aminobutyl, aminosedcbutyl, aminoiisobutyl, aminotertbutyl, aminopentyl, aminoisopentyl and aminoeopentyl.

Claim 8

Conjugate of claim 1 wherein each of R 200 and R 201 is hydrido.

Claim 9

Conjugate of claim 1 wherein said angiotensin II antagonist compound of Formula I is selected from compounds, and their pharmaceutically-acceptable salts, of the group consisting of methyl 4'-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylate; 4'-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; ' -[(5-butyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-secbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-isobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-tertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-phenyl-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-phenylmethyl-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; ' -[[5-butyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[3-5-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-dipropyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-disecbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-diisobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-ditertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-dipentyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-diisopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 5-[4'-[(5-butyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; and 5-[4'-[[3-butyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl)methyl]methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole.

Claim 10

Conjugate of claim 8 which is N-acetylglutamic acid, 5-[[4'-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]]carbonylhydrazide or a pharmaceutically-acceptable salt thereof.

Claim 11

Conjugate of claim 8 which is N 2 -acetyl-N-[[5-butyl-1-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-1H-1,2,4-triazol-3-yl]methyl]-L-glutamine or a pharmaceutically-acceptable salt thereof.

Claim 12

Conjugate of claim 8 which is N-acetyl-L-glutamic acid, 5-[5-butyl-1-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-1H-1,2,4-triazol-3-yl]acetylhydrazide or a pharmaceutically-acceptable salt thereof.

Claim 13

A pharmaceutical composition comprising one or more pharmaceutically-acceptable carriers or diluents and a therapeutically-effective amount of a renal-selective conjugate, said renal selective conjugate consisting of a first radical and a second radical, said first and second radicals connected together by a kidney-enzyme-cleavable amide bond, wherein said first radical is provided by a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound of Formula I ##STR577## wherein m is one; wherein R 1 is selected from amino, aminomethyl, aminoethyl, aminopropyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cycloalkylalkyl, carboxyl, carboxyalkyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1-dimethoxypropyl, 1,1-diemthoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, halo, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein R 2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, isopentyl, tert-butyl, n-pentyl and neopentyl; wherein one of R 5 and R 9 is COOH or ##STR578## wherein each of the remainder of R 3 through R 11 is independently selected from hydrido, amino, monoalkylamino and carboxylic acid; wherein said second radical is provided by a compound selected from a class of compounds of Formula II: ##STR579## wherein each of R 50 and R 51 may be independently selected from hydrido, alkylcarbonyl, alkoxycabonyl, alkoxyalkyl, hydroxyalkyl and haloalkyl; and wherein G is selected from hydrido, hydroxyl, halo, mercapto, --OR 52 , --SR 53 and >NR 54 with each of R 52 , R 53 and R 54 independently selected from alkyl, and wherein each of R 53 and R 54 may be further independently selected from hybrido; with the proviso that said kidney-enzyme-cleavable amide bond is within an amide group formed between said first and second radicals, wherein said first radical has a primary or secondary amino moiety, wherein said first-radical amino moiety is provided by one of said R 1 through R 11 substituents of said Formula I compound or is provided by a linking moiety attached to a carbonyl group attached at one of said R 1 through R 11 substituents of said Formula I, and wherein said second radical has a carbonyl moiety attached at the gamma-position carbon of said Formula II compound, whereby said kidney-enzyme-cleavable amide bond is formed from said first-radical amino moiety and said second radical carbonyl moiety; and wherein said linking moiety is a divalent radical of Formula III: ##STR580## wherein each of R 200 and R 201 may be independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkhyl, hydroxyalkyl and haloalkyl; and wherein n is a number selected from zero through six, inclusive; or a pharmaceutically-acceptable salt of said renal-selective conjugate.

Claim 14

A pharmaceutical composition comprising one or more pharmaceutically-acceptable carriers or diluents and a therapeutically-effective amount of a renal-selective conjugate, said renal selective conjugate consisting of a first radical and a second radical, said first and second radicals connected together by a kidney-enzyme-cleavable amide bond, wherein said first radical is provided by a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound of Formula I ##STR577## wherein m is one; wherein R 1 is selected from amino, aminomethyl, aminoethyl, aminopropyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cycloalkylalkyl, carboxyl, carboxyalkyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1-dimethoxypropyl, 1,1-diemthoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, halo, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein R 2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, isopentyl, tert-butyl, n-pentyl and neopentyl; wherein one of R 5 and R 9 is COOH or ##STR578## wherein each of the remainder of R 3 through R 11 is independently selected from hydrido, amino, monoalkylamino and carboxylic acid; wherein said second radical is provided by a compound selected from a class of compounds of Formula II: ##STR579## wherein each of R 50 and R 51 may be independently selected from hydrido, alkylcarbonyl, alkoxycabonyl, alkoxyalkyl, hydroxyalkyl and haloalkyl; and wherein G is selected from hydrido, hydroxyl, halo, mercapto, --OR 52 , --SR 53 and >NR 54 with each of R 52 , R 53 and R 54 independently selected from alkyl, and wherein each of R 53 and R 54 may be further independently selected from hybrido; with the proviso that said kidney-enzyme-cleavable amide bond is within an amide group formed between said first and second radicals, wherein said first radical has a primary or secondary amino moiety, wherein said first-radical amino moiety is provided by one of said R 1 through R 11 substituents of said Formula I compound or is provided by a linking moiety attached to a carbonyl group attached at one of said R 1 through R 11 substituents of said Formula I, and wherein said second radical has a carbonyl moiety attached at the gamma-position carbon of said Formula II compound, whereby said kidney-enzyme-cleavable amide bond is formed from said first-radical amino moiety and said second radical carbonyl moiety; and wherein said linking moiety is a divalent radical of Formula III: ##STR580## wherein each of R 200 and R 201 may be independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkhyl, hydroxyalkyl and haloalkyl; and wherein n is a number selected from zero through six, inclusive; or a pharmaceutically-acceptable salt of said renal-selective conjugate.

Claim 15

Conjugate of claim 12 wherein said second residue forms a kidney-enzyme-cleavable amide bond with the radical of said angiotensin II antagonist compound.

Claim 16

Conjugate of claim 12 wherein each G substituent is hydroxy.

Claim 17

Conjugate of claim 14 wherein each G substituent is hydroxy; wherein R 50 is hydrido; and wherein R 51 is selected from ##STR581## wherein R 55 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and chloromethyl.

Claim 18

Conjugate of claim 12 wherein said second radical is ##STR582##

Claim 19

Conjugate of claim 12 wherein said first radical is a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound containing a primary or secondary amino moiety attached at one of said R 1 through R 11 positions of Formula I, said amino moiety selected from amino and linear or branched aminoalkyl moieties containing linear or branched alkyl groups selected from aminomethyl, aminoethyl, aminopropyl, aminosopropyl, aminobutyl, aminosedcbutyl, aminoiisobutyl, aminotertbutyl, aminopentyl, aminoisopentyl and aminoeopentyl.

Claim 20

Conjugate of claim 12 wherein each of R 200 and R 201 is hydrido.

Claim 21

Conjugate of claim 12 wherein said angiotensin II antagonist compound of Formula I is selected from compounds, and their pharmaceutically-acceptable salts, of the group consisting of methyl 4'-[(3,5-dibutyl-1H-1,-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylate; 4'-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-secbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-isobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-tertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; ' -[(5-butyl-3-phenyl-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-phenylmethyl-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[3-5-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-dipropyl-1H-1,2,-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-isopropyl-1H-1,2-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-disecbutyl-1H-1,-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-diisobutyl-1H-1,-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-ditertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-dipentyl-1H-1,2,-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-diisopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 5-[4'-[(5-butyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; and 5-[4'-[[3-butyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl)methyl]methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole.

Claim 22

The composition of claim 19 wherein said angiotensin II antagonist compound of Formula I is N-acetylglutamic acid, 5-[[4'-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]]carbonylhydrazide or a pharmaceutically-acceptable salt thereof.

Claim 23

The composition of claim 19 wherein said angiotensin II antagonist compound of Formula I is N 2 -acetyl-N-[[5-butyl-1-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-1H-1,2,4-triazol-3-yl]methyl]-L-glutamine or a pharmaceutically-acceptable salt thereof.

Claim 24

The composition of claim 19 wherein said angiotensin II antagonist compound of Formula I is N-acetyl-L-glutamic acid, 5-[5-butyl-1-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-1H-1,2,4-triazol-3-yl]acetylhydrazide or a pharmaceutically-acceptable salt thereof.

Claim 27

The method of claim 23 wherein said second residue forms a kidney-enzyme-cleavable amide bond with the radical of said angiotensin II antagonist compound.

Claim 28

The method of claim 23 wherein each G substituent is hydroxy.

Claim 29

The method of claim 25 wherein each G substituent is hydroxy; wherein R 50 is hydrido; and wherein R 51 is selected from ##STR587## wherein R 55 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and chloromethyl.

Claim 30

The method of claim 23 wherein said second radical is ##STR588##

Claim 31

The method of claim 23 wherein said first radical is a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound containing a primary or secondary amino moiety attached at one of said R 1 through R 11 positions of Formula I, said amino moiety selected from amino and linear or branched aminoalkyl moieties containing linear or branched alkyl groups selected from aminomethyl, aminoethyl, aminopropyl, aminosopropyl, aminobutyl, aminosedcbutyl, aminoiisobutyl, aminotertbutyl, aminopentyl, aminoisopentyl and aminoeopentyl.

Claim 32

The method of claim 23 wherein each of R 200 and R 201 is hydrido.

Claim 33

The method of claim 23 wherein said angiotensin II antagonist compound of Formula I is selected from compounds, and their pharmaceutically-acceptable salts, of the group consisting of methyl 4'-[(3,5-dibutyl-1H-1,-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylate; 4'-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; ' -[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid, hydrazide; 4'-[(5-butyl-3-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-secbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-isobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-tertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-phenyl-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(5-butyl-3-phenylmethyl-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; ' -[[5-butyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[3-5-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[[5-butyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-dipropyl-1H-1,2,-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-isopropyl-1H-1,2-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-disecbutyl-1H-1,-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-diisobutyl-1H-1,-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-ditertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-dipentyl-1H-1,2,-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(3,5-diisopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 5-[4'-[(5-butyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; 5-[4'-[(5-butyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole; and 5-[4'-[[3-butyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl)methyl]methyl][1,1'-biphenyl]-2-yl]-1H-tetrazole.

Claim 34

The method of claim 30 wherein said angiotensin II antagonist compound of Formula I is N-acetylglutamic acid, 5-[[4'-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1'-biphenyl]-2-yl]]carbonylhydrazide or a pharmaceutically-acceptable salt thereof.

Claim 35

The method of claim 30 wherein said angiotensin II antagonist compound of Formula I is N 2 -acetyl-N-[[5-butyl-1-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-1H-1,2,4-triazol-3-yl]methyl]-L-glutamine or a pharmaceutically-acceptable salt thereof.

Claim 36

The method of claim 30 wherein said angiotensin II antagonist compound of Formula I is N-acetyl-L-glutamic acid, 5-[5-butyl-1-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-1H-1,2,4-triazol-3-yl]acetylhydrazide or a pharmaceutically-acceptable salt thereof.

Claim 37

The method of claim 23 wherein said circulatory disorder is a hypertensive-related disorder.

Claim 38

The method of claim 34 wherein said hypertensive-related disorder is chronic hypertension.

Claim 39

The method of claim 23 wherein said circulatory disorder is a sodium-retaining disorder.

Claim 40

The method of claim 36 wherein said sodium-retaining disorder is congestive heart failure.

Claim 41

The method of claim 36 wherein said sodium-retaining disorder is cirrhosis.

Claim 42

The method of claim 36 wherein said sodium-retaining disorder is nephrosis.