CA2085584C - Treatment of chronic renal failure with imidazole angiotensin-ii receptor antagonists - Google Patents

Treatment of chronic renal failure with imidazole angiotensin-ii receptor antagonists Download PDF

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CA2085584C
CA2085584C CA002085584A CA2085584A CA2085584C CA 2085584 C CA2085584 C CA 2085584C CA 002085584 A CA002085584 A CA 002085584A CA 2085584 A CA2085584 A CA 2085584A CA 2085584 C CA2085584 C CA 2085584C
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carbon atoms
alkyl
phenyl
benzyl
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CA2085584A1 (en
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David John Carini
John Jonas Vytautas Duncia
Pancras Chor-Bun Wong
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EIDP Inc
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EI Du Pont de Nemours and Co
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

Substituted imidazoles such as 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole and 2-butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole and pharmaceutically acceptable salts thereof are useful for treating chronic renal failure, mediated by angiotensin-II.

Description

T i fi~
Treatment of Chronic Rensl Failure With. Imidazole Angiotensin-II Receptor Antagonists Ei .e1_d ef~he Invent This invention relates to a method of treating chronic renal~failure and, in particular, to a method which utilizes imidazole angiotens3n-II (AII) receptor antagonists to treat chronic renal failure mediated by angiotensin-II.
Hask_Qr,~~nd a ' th _ Im,~~ en Angiotensin converting enzyme inhibitors may have beneficial effects over other antihypertensive agents in progressive renal disease of various origins including diabetic nephropathy, essential hypertension and other intrinsic renal diseases (See, e.g., Hypertension:
Pathophysiology, Diagnosis, and Management ed. by J. H.
Laragh and 8. M. Bienner, vol. 1, pp. 1163-1176, Ravew Press, Ltd., New York, 1990: hypertension:
Pathophysiology, Diagnosis, and Management, ed. by J. H.
Zaragh and 8. M. Hrenner, vol. 2, pp. 1677-1687, Raven Press, Ltd., New York, 1990). For instance, in partially~nephrectomized rats, glomerular capillary hypertension in the remnant kidney is associated with progressive proteinuria, focal glomerular sclerosis, and moderate hypertension. Angiotensin converting enzyme inhibitors, which lower systemic arterial pressure. and W~ 92/00067 ;~~°.~'P'°~'."r ~ PCT/US91/03906 ';«L9~3~~
glomerular capillary pressure, limit the progression of glomerular injury.
There are other antihypertensive agents which lower systemic arterial blood pressure to a similar extent, but fail to reduce glomerular capillary pressure. Such agents do not prevent the progression of glomerular injury. It is speculated that in these rats intrarenal generation of angiotensin-II constricts the renal efferent arteriole and causes an increase in glomerular hydraulic pressure. Glomerular hyperfiltration, hyperperfusion and/or hypertension may then initiate and induce glomerular lesions. Thus, blockade of the intrarenal formation of angiotensin-II by angiotensin converting enzyme inhibitors may retard the.
deterioration of renal failure.
Although the partially nephrectomized rat is associated with moderate hypertension, systemic hypertension does not appear to be necessary for the acceleration of zenal disease. In the insulin-treated rat with streptozocin-induced diabetes, systemic arterial pressure is normal but glomerular capillary pressure is high. Similar to the partially nephrectomized rat model, angiotensin converting enzyme inhibitors are beneficial in limiting the glomerular structural lesions, suggesting that glomerular capillary hypertension but not systemic arterial hypertension play a critical role in rats with progressive renal failure.
Nonpeptide angiotensin-II receptor antagonists are believed to be more efficacious than angiotensin converting enzyme inhibitors in treating chronic renal failure because the nonpeptide angiotensin-II receptor antagonists may block the renal effect of angiotensin-II
more completely irrespective of the source of angiotensin-TI. In contrast, angiotensin converting enzyme inhibitors selectively block kininase II and, w0 92/00067 ~1,~~ ~ ~~~ 1'CT/IJ591/03906 thus, may not inhibit totally the local formation of angiotensin-II in the kidney. Other types of peptidyl dipeptidase may also be responsible for the formation of angiotensin-II. (Wong, P. C. and Zimmerman, B. G.: Role of Extrarenal and Intrarenal Converting Enzyme Inhibition in Renal Vasodilator Response to Intravenous Captopril.
Life Sci. 27: 1291, 1980; Schmidt M., Giesen-Crouse, E. M., Krieger, J. P., Welsch, C. and Imbs, J. L.: Effect of angiotensin converting enzyme inhibitors on the 20 vasoconstrictor action of angiotensin I on isolated rat kidney. J. Cardiovasc. Pharmacol. 8 (Suppl. 10): 5100, 1986) ) .
In clinical renal artery stenosis, the usefulness of angiotensin converting enzyme inhibitors may be limited by a reversible loss of filtration in the stenotic kidney. It is possible that nonpeptide angiotensin II
receptor antagonists may have a similar renal effect in the stenotic kidney.
K. Matsumura, et al., in U.S. Patent 4,207,324 issued June 10, 1980 discloses 1,2-disubstituted-9 haloimidazole-5-acetic acid derivatives of the formula:
X
R2 ~N ~'CH2COOR3 R~
wherein R1 is hydrogen, nitro or amino; R2 is phenyl, furyl or thienyl optionally substituted by halogen, lower WO 92/00067 P~T/US91/03906 °~.~ '!~ !-' r u~~~~<~ 4 alkyl, lower alkoxy or di-lower alkylamino; R~ is hydrogen or lower alkyl and X is halogen; and their physiologically acceptable salts. These compounds have diuretic and hypotensive actions.
Furukawa, et al., in U.S. Patent 9,355,090 issued October 19, 1982 discloses hypot:ensive imidazole-5-acetic acid derivatives having the formula:
Y
R1 'N 'CH2C92R2 CHZ
XI~~Io\~3 wherein R1 is lower alkyl, cycloalkyl, or phenyl optionally substituted; X1, Xz, and X3 are each hydrogen, halogen, nitro, amino, lower alkyl, lower alkoxy, benzyloxy, or hydroxy; Y is halogen and R2 is hydrogen or lower alkyl; and salts thereof.
Furukawa, et al., in U.S. Patent 9,390,598, issued July 20, 1982, discloses hypotensive imidazole derivatives of the formula:

R2 'N ~R4 2o Rt WO 92/00067 ~~,,~.0'.~~~;f-u~ PCT/gJ891/03906 ._.-wherein R1 is lower alkyl or, phenyl C1_2 alkyl optionally substituted with halogen or nitro; RZ is lower alkyl, cycloalkyl or phenyl optionally substituted;
one of R3 and R9 is -(CH2)nCORS where RS is amino, lower 5 alkoxyl or hydroxyl and n is 0, 1, 2 and the other of R3 and R4 is hydrogen or halogen; provided that R1 is lower alkyl or phenethyl when R3 is hydrogen, n=1 and R5 is lower alkoxyl or hydroxyl; and salts thereof.
Furukawa et al., in European Patent Application 103,647 discloses 4-chloro-2-phenylimidazole-5-acetic acid derivatives useful for treating edema and hypertension of the formula:
/CI

R
OH
where R represents lower alkyl and salts thereof.
The metabolism and disposition of hypotensive agent 4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenyl-imidazole-5-acetic acid is discloses by H. Torii in Takeda Kenkyushoho, 91, I~o 3l4, 180-191 (1982).
Frazee et al., in European Patent Application 125,033-A discloses 1-phenyl(alkyl)-2-.(alkyl)-thioimidazole derivatives which are inhibitors of dopamine-A-hydroxylase and are useful as antihypertensives, diuretics and cardiotonics.

WO 92100067 PC'f/US91/03906 K~~ 4:a1 ,r...K...~~
6 , European Patent Application 146,228 filed October 16,1984 by S. S. L. Parhi discloses a process for the preparation of 1-substituted-5-hydroxymethyl-2-mercaptoimidazoles.
A number of references disclose 1-benzyl-imidazoles such as U.S. Patent 9,948,781 to Cross and Dickinson (issued May 15, 1984); U.S. Patent 4,226,878 to Ilzuka et al. (issued October 7, 1980); U.S. Patent 3,772,315 to Regel et al. (issued November 13, 1973); U.S. Patent 4,379,927 to Vorbriiggen et al. (issued April 12, 1983);
amongst others.
Pals et al., Circulation Research, 29, 673 (1971) describe the introduction of a sarcosin residue in position 1 and alanine in position 8 of the endogenous vasoconstrictor hormone All to yield an (octa)peptide that blocks the effects of ATI on the blood pressure of pithed rats. This analog, [Sari, Alaa] AII, initially called "P-113" and subsequently "Saralasin", was found to be one of the most potent competitive antagonists of the actions of AII, although, like most of the so-called peptide-AII-antagonists, it also possesses agonistic actions of its own. Saralasin has been demonstrated to lower arterial pressure in mammals and man when the (elevated) pressure is dependent on circulating All (Pals et al., Circulation Research, 29, 673 (1971);
Stre.eten and Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of Antihypertensive Drugs, A. E.
Doyle (Editor), Elsevier Science Publishers B. V., p.
246 (1984)). However, due to its agonistic character, saralasin generally elicits pressor effects when the pressure is not sustained by AII. Being a peptide, the pharmacological effects to saralasin are relatively short-lasting and are only manifest after parenteral administration, oral doses being ineffective. Although the therapeutic uses of peptide AII-blockers, like saralasin, are severely limited due to their oral ineffectiveness and short duration of action, their major utility is as a pharmaceutical standard.
$~m»~y of ~h~ I nv n - i on According to the present invention there is provided a method of treating chronic rena3. failure mediated by All in a mammal comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition having the formula (I), and the use of a pharmaceutical compound for treating chronic renal failure mediated by angiotensin-II (AII) in a mammal, wherein the pharmaceutical compound is in a form suitable for administration to the mammal, and wherein the pharmaceutical compound comprises formula (I):
wherein R1 is 9-CO~H: 9-COZRg;
. O . O
~ 9 ~ ~ 3~2 ~ ~ , ~3 2~ H .~ -OH, -O-S-OH' -SO H' -C CF OH' -O-P-OH' -P H - -N -O OH OH
9-NHS02CH3; -9-NHS02CF3; -CONHOR12;

vr.~~ .f.1 ._.I,.--. f...
a4,, ''fll~~ ~, ~ i M V
WO 92/00067 Pt,T/jJS91/03906 OH C~ N°N
-S02NH~; - i -i ~-OH;

H
N~N R~s F F
/ ti . ,/
. ~ 3 ; 4 -)( F .
N \ ~~r R \ ~ ' H R2 R~3 F
O
(~
-HNC
4 X ~ ~
HOC R~3 ~ ; X13 N-°N C02H
/ 1' ; 4-CONHNHSO2CF3; 4-CONH-CNCH2CsH5 (I-isomer);
4-CONH~ iN
N
H ' HOZC R11 CF
I-isomer 4-CO-N ~ ( ?, ~.~ R» N
H
CO2H X13 p 13 _ R
N N ' ~ -N '~~ 3 4--< ~NH ~ ~_~ . J R ;
C , o R2 .
O R2o or -C-NHSO2-(CH~)S

'VSO 92/00067 ~~~ ~~ ~y p~'f/U~9~/03906 R2 is H; C1; Br; I; F; N02; CN; alkyl of 1 to ~ carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; C02H; C02R9; NHS02CH3;
N-N
\N
N~
NHS02CF3; CONHOR12; S02:NH2; H .
aryl; or furyl;
R3 is H; C1, Br, I or F; alkyl of 1 to 9 carbon atoms or alkoxy of 1 to 4 carbon atoms;
R~ is CN, N02 or C02R11;
R5 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 ZO to 6 carbon atoms, alkenyl or alkynyl of 2 to 9 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 C02R14; 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 C02R19; benzyl or 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;
R7 is H, F, C1, Br, I, N02, CvF2v+1. where v = 1-6;
O
C6F5: CN; -~R~s ; 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, C1, Br, OH, OCH3, CF3, and COOR, where R is H, alkyl of 1 to 9 carbon atoms, or phenyl;

~~t:'t'9i.s~° C.
IVVO 92/i~0067 PCT/US91/039~6 vinyl; alkynyl of 2-10 carbon atoms;
phenylalkynyl where the alkynyl portion is 2-6 carbon atoms; heteroaryl selected from 2- and thienyl, 2- and 3-furyl, 2-, 3-, and 9-pyridyl, 5 2-pyrazinyl, 2-, 4-, and 5-pyrimidinyl, 3- and pyridazinyl, 2-, 9- and 5-thiazolyl, 2-, 4-, and 5-selenazolyl, 2-, 4-, a:nd 5-oxazolyl; 2- or pyrrolyl, 3-, 4- or 5-pyrazolyl, and 2-, 9-or 5-imidazolyl; o-, m- or p-biphenylyl; o-, m- or p-10 phenoxyphenyl; substituted phenylalkynyl, heteroaryl, biphenyl or phenoxyphenyl as defined above substituted on ring carbon with 1 or 2 substituents selected from halogen, alkoxy of carbon atoms, alkyl of 1-5 carbon atoms, -N02, -CN, -CF3, -COR16, -CH20R1~
-NHCOR1~

r , , S(O)rRl7, and S02NR1~R19; pyrrolyl, pyrazolyl or imidazolyl as defined above substituted on ring nitrogen with alkyl of 1-5 carbon~atoms or benzyl; or substituted alkyl, alkenyl, or alkynyl of 1 to 10 carbon atoms substituted with a substituted or unsubstituted heteroaryl, biphenylyl or phenoxyphenyl group as defined above; any of the foregoing polycyclic aryl groups substituted with 1 or 2 substituents selected from halogen, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, -N02, -CN, -CF3, -COR16, -CH20R1~
-NHCOR1~

~
, , S(0)rRl~. and S02NR18R19; the anhydride of 9,5-dicarboxyl-1- or 2-naphthyl; or substituted alkyl of 1 to l0 carbon atoms, alkenyl or alkynyl of 2 o to 10 carbon atoms substituted with a substituted or unsubstituted polycyclic aryl group as defined above;

W~ 92/00067 11 ,q~ ~-_-e- Pi'f/~L1S91/0390b ~~~'~.f~:s~i~
Rg 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 ~ carbon atoms;
-(CH2)m-imidazol-1-yl; °-(CH2)m-1,2,3-triazolyl optionally substituted with one or two groups selected from C02CH3 or alkyl of 1 to 4 carbon atoms; -(CH2)s-tetrazolyl;
C) -(CH2)n-1 H-R11~ _{CH~)nOCIRI4o -(CH2)n~RlSe OR
R1~ O
-CH=CH(CH2)S~HOR15; -CH=CH(CH2)SCR16; -CRIB;
O O
II
-CH--CH(CH2)sOCRlI; -{CH2)s-~I-I-COR16; -(CH2)nCRl6;

Y Y
-(CH~)nOCNHR1°; -{CH2)nNRIICOR1°;
O
II
-(CH2)nNRIICNHR1°; -{CH2)nNRlls~2R1°°, Y
-{CHa)nNR11CR1°. -(CH2)m~~ -{CH2)mON02; -CH~N3;

W~ 92/00067 ~.~~ 4~ ,~~,~ PCT/US91/03906 O
-(CHz)mNOz; -CH=N-NR11 Rt~~ _(CH2)m N
N= ; N-N O
-(CH2)~ ~ NH'_(CH ) ~ ~ ' z S N C; F3 Ra H
O
-(CH2)S N N ; -(CHz)»_'_~_N~ ;

N
-CH~N-NH-SOz ~ ~ ; -CH=N-NH~
N
H
Rza O
R9 -CH-OC,R21 is R10 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 (CH2)pC6H5;
Rll 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 -C02H; -C02R9; -CH2C02H, -CH2C02R~;
O O O
-O-SI-OH; -O-P~-OH; -S03H; -NHPI-OH;
pl OH OH

WO 92/00067 °?~ n ~-r_-a"~';,.~,~b~~~, P~.T/US91/0390t -P03H2; -CSCF3)20H; -NHS02CH3; -NHS02CF3;
-NHCOCF3; °-CONHOR12; -S02NH2;
N-o e\
P-OH ; ~ N
~27 ~ Nr P OH
~a~
-CONHNH -/N . SO2CF3 .
-CH2 /N , -CONH
N NH
H
N~N N~N
NH or CFA

O R2o -C-NHS02-(CH2)s 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, hlkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH2)pCSHS, OR17, or NR18R19;
R1~ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R18 and Rlg independently are H, alkyl of 1 to 4 carbon.atoms, phenyl, benzyl, a-methylbenzyl, or ?.1 ,r'°,!"" o o.,, ' -'~'.~:e~>~~"~. 14 pLT/US91/03906 W~ 92/00057 taken together with the nitrogen form a ring of the formula ~N~ ~ \~2~t .Q
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 -CHCH2C02CH3;
I

R22 and R23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH2)u where a is 3-6;
R24 is H, CH3 or -C6H5;
R25 is NR27R2~, OR28, NHCONH2, NHCSNH2, -NHS02 ~ ~ CH3 or -NHS02 R26 is hydrogen, alkyl with. from 1 to 6 carbon atoms, benzyl, or allyl;
R2~ and R28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl;
R29 and R30 are independently alkyl of 1-9 carbon atoms or taken together are -(CH2)q-;
R31 is H, alkyl of 1 to 4 carbon atoms, -CH2CH=CH2 ar -CH2C6H4R32;
R32 1S H, N02, NH2, OH Or OCH3;
X is a carbon-carbon single bond, -CO-, -CH2_, _0 -S-, -NH°, -, -CO ~ -, -NCO-, l WO 92/00067 15 ~~'~ ~~,~-",°. ~~, 1~ g~/U591/03906 -OCH2-', -CH20-, -SCH2-, -CH2S-, -NHC(R2~) (R2$)-, -NR23SC)2-, -S02NR23_~ __C (R2~) (R28) NH-, -CH=CH-, -CF=CF-, -CH=CF-, -CF=t;H-, -CH2CH2-, -CF2CF2-, R14~ CoF117, ~~~5 R29~ OR30 or _ -CH- H-Y is O or S;
Z is t), NRll, 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;
or a pharmaceutically acceptable salt thereof;
provided that:
(I) the Rl group is not in the ortho position;
(2) when R1 is _X
~~R3 X is a single bond, and R13 is C02H, or (~~N
~N
H

WO 92/00067 ac~;y ~ '~ ~~ PCT/iJS91/03906 then R13 must be in the ortho or meta position; or when R1 and X are as above and R13 is NHS02CF3 or NHS02CH3, R13 must be ortho;
(3) when R1 is and X is other than a single bond, then R13 must be ortho except when X = NR23C0 and R13 is NHS02CF3 or NHS02CH3, then R13 must be ortho or meta;
(9) when R1 is 4-C02H or a salt thereof, R6 cannot be S-alkyl;
(5) when R1 is 9-C02H or a salt thereof, the substituent on the 9-position of the imidazole cannot be CH20H, CH20COCH3, or CH2C02H;
25 (6) when R1 is I~~.R3 X is -OCH2-, and R13 is 2-C02H, and R~ is H then R6 is not C2H5S;
(7j when R1 is C~3SO2HN
-COi~H
and R6 is n-hexyl, then R~ and R8 are not both hydrogen;
(8) when R1 is 17 ~'~~'z'L i3c~
WO 92/00067 PGT/US9y/03906 CF3S~2H~
-NHCO
R6 is not methoxybenzyl;
(9) the R6 group is not -CHFCH2GH2CHg or CH20H;
(10) when r=0, R1 is 'x ~~~~R3 X is -NH-CO-, R13 is 2-NHS02CF3, and R6 is n-propyl, then R~ and R8 are not -C02CH3;
(11) when r=0, R1 is -X
'~ ~~\~3 X is -NH-CO-, R13 is 2-COOH, and R6 is n-propyl, then R~
and R8 are not -C02CH3;
(12) when r=1, R1=

_x. ~ ~'f$3 ~2 R
X is a single bond, R~ is C1, and R8 is -CHO, then R13 is not 3-(tetrazol-5-yl);
(13) when r=1, R1=

s X is a single bond, R~ is Cl, and R8 is -CHO, then R13 is not 4-(tetrazol-5-yl).
5 Preferred in the use of this invention are compounds having the formula iII):
R~
8~ 8 R N R

R~
wherein Rl is -C02Ii; -NHSOZCFg;

p ~x'T, ~.~.,._rt_, ,~
1 7 lirJ a./~ ~ 2~~ i ~ Lr WO 92/00067 P~'/i.JS91/03~06 R' N°°N
-~~ ~
N.
H
or ~ ~ ~ ~ , R6 is alkyl of 3 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, benzyl substituted on the phenyl ring with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, and vitro;
R8 i5 O
-(CH2)g-tetrazolyl, -(CH2)nOR~l; -(CH2)nOCRl4;
O Raa -CH=CH(CH2)sCRls, -CH=CH(CH2)9CHOR15;
O O
- (CH2) nCRl6; - (CH2) nNHCORl~; - (CH2) nNHS02R1~; .
O
-(CHZ)mE'; or -CR16;

WO 92/000f>7 ~,~,,~,~,j~r, PCT/US91l03906 'v~v~a.9e..9~C~.
phenylalkenyl wherein the aliphatic portion is 2 to 4 carbon atoms: -(CH2)m imidazol-1-yl; or -(CH2)m-1,2,3-triazolyl optionally substituted with one two groups selected from -C02CH3 or S alkyl or 1 to 9 carbon atoms;
Rl3is -C02H, -C02R9, NHS02CF3; S03H; or N-IN
~i ,N
Ne Ri6 is H, alkyl or 1 to 5 carbon atoms, OR~7, or NR18R19:
X is carbon-carbon single bond, -CO-, -CH2CH2-, -CON-, -NCO-, -OCH2-, -CH20-, -O-, -SCH2-, -CH2S-, -NH-CH2-, -CH2NH- or -CH=CH-; and pharmaceutically acceptable salts of these compounds.
More preferred in the process of the invention are compounds of the preferred scope where:
R2 is H, alkyl of 1 to 9 carbon atoms, halogen, or alkoxy or 1 to 4 carbon atoms;
R6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms;
R~ is heteroaryl selected from 2- and 3-thienyl, 2-and 3-furyl, 2-, 3-, and 4-pyridyl, p-biphenylyl; H, C1, Br, I; CvF2v+1. where v=1-3;
O
°CR1~; straight or branched chain alkyl of 1 to 6 carbon atoms; or phenyl;

21 ~?'y~'~''°r.', V'WLSO~
WO 92/00067 ~~CT/~iJS91/03906 Ra is II I
-(CH2)~OR11; -(CH2)mOCRa4; -CH=CH-CHOR15;
O O
II Il -(CH2)mCR~6; -CH2NHCOR1~; -(CH2)mNHS02R1~;
N-°N
-CH ~ ~N

or -CORas;
R1~ is Cr~3, alkyl or 1 to 6 carbon atoms or phenyl;
R11 is H, or alkyl or 1 to 4 carbon atoms;
R13 is C02H; C02CH20COC(CH3)3; NHS02CF3;
N-"N
'N
N~
H
R14 is H, or alkyl of 1 to 4 carbon atoms;
R15 is H, alkyl or 1 to 9 carbon atoms, or acyl or 1 to 4 carbon atoms;
R16 is H, alkyl or 1 to 5 carbon atoms; OR17; or °N O
m is.1 to 5;
3C = single bond, -O-; -CO-; -NHCO-; or -OCHZ-; and pharmaceutically acceptable salts.

More preferred in the use of the invention are compounds of Formula II, wherein Rl is ~2 and X is a single bond; and pharmaceutically suitable salts thereof.
Most preferred in the use of the invention are compounds of formula II selected from the following, and pharmaceutically acceptable salts thereof:
~ 2-Hutyl-9-chloro-1-[ (2'-(1FI-tetrazol-5-yl)biphenyl-9-yl)methyl]-5-(hydroxymethyl)imidazole ~ 2-Butyl-9-chloro-1-[(2'-carboxybiphenyl-9-yl)-methyl]-5-(hydroxymethyl)imidazole ~ 2-Butyi-4-chloro-1-[(2'-carboxybiphenyl-4-yl)-methyl]-5-[(methoxycarbonyl)aminomethyl] imidazole ~ 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-9-yl)-methyl]-5-((propoxycarbonyl)aminomethyl] imidazole ~ 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-9-yl)methyl]imidazole-5-carboxaldehyde ~ 2-Butyl-1-[(2'-carboxybiphenyl-9-yl)methyl]-imidazole-5-carboxaldehyde ~ 2-(lE=8utenyl)-4-chloro-1-((2'-carboxybiphenyl-9-yl)methyl]-5-(hydroxymethyl)imidazole ~ 2-(lE-Butenyl)-9-chloro-1-[(2'-carboxybiphenyl-9-yl)methyl]imidazole-5-carboxaldehyde ~ 2-Propyl-9-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-9-yl)methyl]-5-(hydroxymethyl)imidazole ~ 2-Propyl-9-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl.-4-yl)methyl]imidazole-5-carboxaldehyde ~ 2-Hutyl-9-chloro-1- [2' - (1H-tetrazol-5-yl ) bipbenyl-9-yl)methyl]imidazole-5-carboxaldehyde W~ 92/00067 PCT/US91/03906 2-(lE-Butenyl)-9-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5--hydroxymethyl)imidazole ~ 2-(lE-Butenyl)-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-9-yl)methyl]imidazole-5-carboxaldehyde ~ 2-Butyl-4,-chloro-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole-5-carboxylic acid ~ 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole-5-carboxylic acid ~ 2-Propyl-~-trifluoromethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-9-yl)methyl]imidazole-5-carboxylic acid ~ 2-Propyl-4-trifluoromethyl-1-[(2°-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxylmethyl)-imidazole 2-Butyl-9-trifluoromethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-9-yl)methyl]imidazole-5-carboyxlic acid ~ 2-Propyl-9-trifluoromethyl-1-[(2'-(carboxybiphenyl-9-yl)methyl]imidazole-5-carboxaldehyde ~ 2-Propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole ~ 2-Propyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-9-yl)methyl]imidazole-4,5-dicarboxylic acid 2-Propyl-9-pentafluoroethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-9-yl)methyl]imidazole-5-carboxylic acid ~ 2-Propyl-4-pentafluoroethyl-[(2'-(1H-tetrazol-5-yl)biphenyl-9-yl)methyl]imidazole--5-carboxaldehyde ° 1-[(2'-(1H-Tetrazol-5-yl)biphenyl-4-yl)methyl]-9-phenyl-2-propylimidazole-5-carboxaldehyde ~ 1-[(2'-Carboxybiphenyl-4-yl)methyl]-4-phenyl-2-propylimidazole-5-carboxaldehyde Note that throughout the text when an alkyl substituent is mentioned, the normal alkyl structure is meant (i,e., butyl is g-butyl) unless otherwise specified.
Pharmaceutically suitable salts include both the metallic (inorganic) salts and organic salts; a list of which is given in Remington's Pharmaceutical Sciences, 17th Edition, pg. 1918 (1985). It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hydroscopicity and solubility. Preferred salts of this invention for the reasons cited above include potassium, sodium, calcium and ammonium salts.
Also within the scope of this invention are uses of pharmaceutical compositions comprising a suitable pharmaceutical carrier and a compound of Formula (I), to treat chronic renal failure. The pharmaceutical compositions can optionally contain one or more other therapeutic agents. It should be noted in the foregoing structural formula, when a radical Can be a substituent in more than one previously defined radical, that first radical can be selected independently in each previously defined radical. For example, R1, R2 and R3 can each be CONHOR12. R12 need not be the same substituent in each of R1, R2 and R3 but can be selected independently fox each of them.
The compounds of Formula (I) useful in this invention are~described in and prepared by methods set forth in European Patent Application EPA 0 324 377, published 7!19/89, (page 17, line 5 through page 212, line.32), European Patent Application EPA 0 253,310, published 1/20/88 (page 15, line 26, through page 276) and U.S. Patent No. 5,354,867.
It is believed that the compounds described herein are efficacious in the treatment of most~chronic renal failure cases mediated by AII. While it is not clear, 25 ~~;~La~~~
WO 92/00067 PCTlU591/0390b there is a possibility that the efficacy of these compounds may be limited in the treatment of renal artery stenosis due to a reversible loss of filtration in the stenotic kidney.
The following illustrate the use of nonpeptide All receptor antagonists to treat chronic renal failure mediated by angiotensin-II:
par i al ~ Y~phr omi . .d a Rats are subjected to five-sixths renal ablation by surgically removing the right kidney and infarction of about two-thirds of the left kidney by ligation of two or three branches of the left renal artery as described by Anderson et al. in J. Clin. Invest., Vol. 76, pages 612-619 (August 1985). Rats are fed standard rat chow cantaining about 24% protein by weight and are separated into two groups. The rats in Group I are not treated.
The rats in Group II are treated over a period of four weeks using one of the compounds described above. Renal hemodynamics and glomerular injury are monitored in both groups of rats after four weeks.
It is expected that the rats in Group I (no treatment) would have high blood pressure, protein urea and glomerular structural lesions whereas the rats in Group II (treatment with the test compound) would have normal blood pressure, less protein urea and fewer glomerular lesions.
nto2oto~in-Ind~d Diabeti Ra s This procedure is described by Zatz et al, in Proc.
Natl. Acad. Sci. USA 82: 5963-5967 (September 1985).
Rats are studied two to ten weeks after being injected once with streptozotocin (60 mg/kg i.v.). In additian, ultralente insulin is given to maintain the blood glucose level between 200-400 mg/dl. Rats are WO 92/00067 ~ .~~ ~'~~~ PCI°/US91/03906 maintained on diet containing about 50~ protein by weight. The rats are then separated into two groups.
The rats in Group I are not treated. The Group II rats are treated for about four to :five weeks after streptozotocin injection using one of the compounds described above. Renal hemodynamics and glomerular injury are monitored in both groups of rats.
It is expected that the rats in Group I (no treatment) would have normal brood pressure, protein urea, and glomerular structural lesions whereas the rats in Group II (treatment with the test compound) would have slightly lower blood pressure, less protein urea and fewer glomerular lesions.
DOSAS,~ ORMS
The compounds of this invention can be administered for the treatment of AII-mediated chronic renal failure according to the invention by any means that effects contact of the active ingredient compound with the site of action. For example, administration can be parenteral, i.e., subcutaneous, intravenous, intramuscular, or intraperitoneal. Alternatively, or concurrently, in some cases administration can be by the oral route.
The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.

wo 9z/ooos~
PCf/U~91/039a6 The dosage administered will be dependent on the age, health and weight of.the recipient, the extent of disease, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired.
Usually, a daily dosage of active ingredient compound will be from about 1-500 milligrams per day. Ordinarily, from 10 to 100 milligrams per day in one or more applications is effective to obtain desired results.
The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained.release products to provide for continuous release of medication over a period of hours.
Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium _ 2 8 PCT/US9I /03906 a,J \J~ W 2J i-:~
bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
Also used are citric acid and its salts and sodium EDTA.
In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.
Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
.~aias,~ ~;
A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft , la in a~S~~lg~s;
A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.
Tablg~;
A large number. of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams. of starch and 98.8 milligrams of lactose.
Appropriate coatings may be applied to increase palatability or delay absorption.

~n~~~,ra_h1e: 2oa55a4 A parenteral composition suitable for administration by injection is prepared by stirring 1.5%
by Weight of active ingredient in 10% by volume propylene glycol. The solution is made to volume with water for injection and sterilized.
~nens;on:
An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.
The same dosage forms can generally be used when the compounds of this invention are administered stepwise in conjunction with another therapeutic agent.
when the drugs are administered in physical combination, the dosage form and administration route should be selected far compatibility with both drugs.
.......k.. ... ,.,."... . ...... ,.

Claims (31)

What is claimed is:
1. The use of a pharmaceutical compound for treating chronic renal failure mediated by angiotensin-II
(AII) in a mammal, wherein the pharmaceutical compound is in a form suitable for administration to the mammal, and wherein the pharmaceutical compound comprises formula (I):

wherein R1 is 4-CO2H; 4-CO2R9;

-SO3H; -C(CF3)2OH; 4-NHSO2CH3; -4-NHSO2CF3; -CONHOR12;

-SO2NH2; 4-CONHNHSO2CF3;

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; CO2R9; 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 9 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms;
(CH2)s Z(CH2)m R5 optionally substituted with F or CO2R14; benzyl or 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;
R7 is H, F, Cl, Br, I, NO2, C v F2v+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;
vinyl; alkynyl of 2-10 carbon atoms:

phenylalkynyl where the alkynyl portion is 2-6 carbon atoms; heteroaryl selected from 2- and 3-thienyl, 2- and 3-furyl, 2-, 3-, and 4-pyridyl, 2-pyrazinyl, 2-, 4-, and 5-pyrimidinyl, 3- and 9-pyridazinyl, 2-. 4- and 5-thiazolyl, 2-, 4-, and 5-selenazolyl, 2-, 4-, and 5-oxazolyl; 2- or 3-pyrrolyl, 3-, 4- or 5-pyrazolyl, and 2-, 4- or 5-imidazolyl; o-, m- or p-biphenylyl; o-, m- or p-phenoxyphenyl; substituted phenylalkynyl, heteroaryl, biphenyl or phenoxyphenyl substituted on ring carbon with 1 or 2 substituents selected from halogen, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, -NO2, -CN, -CF3, -COR16, -CH2OR17, -NHCOR17, CONR18R19, S(O)r R17, and SO2NR18R19; pyrrolyl, pyrazolyl or imidazolyl substituted on ring nitrogen with alkyl of 1-5 carbon atoms or benzyl; or substituted alkyl, alkenyl, or alkynyl of 1 to 10 carbon atoms substituted with a substituted or unsubstituted heteroaryl, biphenylyl or phenoxyphenyl group;
any of the foregoing polycyclic aryl groups substituted with 1 or 2 substituents selected from halogen, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, -NO2, -CN, -CF3, -COR15, -CH2OR17, -NHCOR17, CONR18R19, S(O)r R17, and SO2NR18R19; the anhydride of 4,5-dicarboxyl-1- or 2-naphthyl; or substituted alkyl of 1 to 10 carbon atoms, alkenyl or alkynyl of 2 to 10 carbon atoms substituted with a substituted or unsubstituted polycyclic aryl group;
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 fi carbon atoms:
-(CH2)m-imidazol-1-yl; -(CH2)m-1,2,3-triazolyl optionally substituted with one or two groups selected from CO2CH3 and alkyl of 1 to 4 carbon atoms: -(CH2)s-tetrazolyl:

-(CH2)n SR15;

-(CH2)n NR11SO2R10;

-(CH2)m F; -(CH2)m ONO2; -CH2N3;

-(CH2)m NO2; -CH~N-NR11R17; R9 is R10 is alkyl of 1 to fi carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH2)p C6H5;
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; -CO2R9; -CH2CO2H, -CH2CO2R9:
-SO3H; -PO3H2; -C(CF3)2OH; -NHSO2CH3; -NHSO2CF3;
-NHCOCF3; -CONHOR12; -SO2NH2:

; -CONHNHSO2CF3:

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, or phenacyl;
R16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH2)p C6H5, 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 a is 3-6:
R24 is H, CH3 or -C6H5:
R25 is NR27R28, OR28, NHCONH2, NHCSNH2, 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 single 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-, Y is O or S:
Z is O, 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 salt of these compounds:
provided that:
(1) the R1 group is not in the ortho position:
(2) when R1 is X 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 be 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 thereof, the substituent on the 4-position of the imidazole cannot be CH2OH, CH2OCOCH3, or CH2CO2H:
(6) when R1 is X is -OCH2-, and R13 is 2-CO2H, and R7 is H then 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 methoxybenzyl:
(9) the R6 group is not -CHFCH2CH2CH3 or CH2OH;
(10) when r=O, R1 is X is -NH-CO-, R13 is 2-NHSO2CF3, and R6 is n-propyl, then R7 and R8 are not -CO2CH3:
(11) when r=0, R1 is X is -NH-CO-, R13 is 2-COON, and R6 is n-propyl, then R7 and R8 are not -CO2CH3:

(12) when r=1, R1=
X is a single bond, R7 is C1, and R8 is -CHO, then R13 is not 3-(tetrazol-5-yl);
(13) when r=1, R1=
X is a single bond, R7 is C1, and R8 is -CHO, then R13 is not 4-(tetrazol-5-yl).
2. The use according to claim 1 wherein, in the compound of formula I is a compound of formula II:
wherein R1 is R6 is alkyl of 3 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, benzyl substituted on the phenyl ring with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, and nitro;
R8 is phenylalkenyl wherein the aliphatic portion is 2 to 4 carbon atoms: -(CH2)m-imidazol-1-yl; or -(CH2)m-1,2,3-triazolyl optionally substituted with one or two groups selected from -CO2CH3 and alkyl of 1 to 4 carbon atoms;

R13 is -CO2H, -CO2R9, NHSO2CF3; SO3H; or R16 is H, alkyl of 1 to 5 carbon atoms, OR17, or X is carbon-carbon single bond, -CO-, -CH2CH2-, -OCH2-, -CH2O-, -O-, -SCH2-, -CH2S-, -NH-CH2-, -CH2NH-or -CH=CH-; or a pharmaceutically acceptable salt thereof.
3. The use according to claim 2 wherein the compound of formula II is a compound wherein:
R2 is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms:
R6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms:
R7 is heteroaryl selected from 2- and 3-thienyl, 2- and 3-furyl, 2-, 3-, and 9-pyridyl, p-biphenylyl; H, Cl, Br, I: C vF2 v+1, where v=1- ~
3; straight or branched chain alkyl of 1 to 6 carbon atoms: or phenyl;

R8 is R10 is CF3, alkyl of 1 to 6 carbon atoms or phenyl:
R11 is H, or alkyl of 1 to 4 carbon atoms:
R13 is CO2H; CO2CH2OCOC(CH3)3: NHSO2CF3;
R14 is H, or alkyl of 1 to 4 carbon atoms;
R15 is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms;
R16 is H, alkyl of 1 to 5 carbon atoms: OR17; or m is 1 to 5;
X = single bond, -O-; -CO-; -NHCO-; or -OCH2-; or a pharmaceutically acceptable salt thereof.
4. The use according to claim 3 wherein the compound of formula II is a compound wherein R1 is and X is a single bond; or a pharmaceutically suitable salt thereof.
5. The use according to claim 4 wherein the compound of formula II is 2-Butyl-9-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole or a pharmaceutically acceptable salt thereof.
6. The use according to claim 4 wherein the compound of formula II is 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole or a pharmaceutically acceptable salt thereof.
7. The use according to claim 4 wherein the compound of formula II is 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-[(methoxycarbonyl)aminomethyl]imidazole or a pharmaceutically acceptable salt thereof.
8. The use according to claim 4 wherein the compound of formula II is 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-[(propoxycarbonyl)aminomethyl]imidazole or a pharmaceutically acceptable salt thereof.
9. The use according to claim 4 wherein the compound of formula II is 2-Butyl-9-chloro-1-((2'-carboxybiphenyl-9-yl)methyl]imidazole-5-carboxaldehyde or a pharmaceutically acceptable salt thereof.
10. The use according to claim 4 wherein the compound of formula II is 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde or a pharmaceutically acceptable salt thereof.
11. The use according to claim 4 wherein the compound of formula II is 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole or a pharmaceutically acceptable salt thereof.
12. The use according to claim 4 wherein the compound of formula II is 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde or a pharmaceutically acceptable salt thereof.
13. The use according to claim 4 wherein the compound of formula II is 2-Propyl-9-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl) imidazole or a pharmaceutically acceptable salt thereof.
14. The use according to claim 4 wherein the compound of formula II is 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-cazboxaldehyde or a pharmaceutically acceptable salt thereof.
15. The use according to claim 4 wherein the compound of formula II is 2-Butyl-4-chloro-1-[2'-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde or a i pharmaceutically acceptable salt thereof.
16. The use according to claim 4 wherein the compound of formula II is 2-(1E-Butenyl)-9-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-9-yl)methyl]-5-hydroxymethyl)imidazole or a pharmaceutically acceptable salt thereof.
17. The use according to claim 4 wherein the compound of formula II is 2-(1E-Butenyl)-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)imidazole-5-carboxaldehyde or a pharmaceutically acceptable salt thereof.
18. The use according to claim 4 wherein the compound of formula II is 2-Butyl-4-chloro-1-[(2'-1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.
19. The use according to claim 4 wherein the compound of formula II is 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.
20. The use according to claim 4 wherein the compound of formula II is 2-Propyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.
21. The use according to claim 4 wherein the compound of formula II is 2-Propyl-4-trifluoromethyl-1-[(2'-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxylmethyl)-imidazole or a pharmaceutically acceptable salt thereof.
22. The use according to claim 4 wherein the compound of formula II is 2-Butyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.
23. The use according to claim 4 wherein the compound of formula II is 2-Propyl-4-trifluoromethyl-1-((2'-(carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde or a pharmaceutically acceptable salt thereof.
24. The use according to claim 4 wherein the compound of formula II is 2-Propyl-4-pentafluoroethyl-1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole or a pharmaceutically acceptable salt thereof.
25. The use according to claim 4 wherein the compound of formula II is 2-Propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.
26. The use according to claim 4 wherein the compound of formula II is 2-Propyl-4-pentafluoroethyl-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde or a pharmaceutically acceptable salt thereof.
27. The use according to claim 4 wherein the compound of formula II is 1-[(2'-(1H-Tetrazol-5-yl)biphenyl-4-yl)methyl]-4-phenyl-2-propylimidazole-5-carboxaldehyde or a pharmaceutically acceptable salt thereof.
28. The use according to claim 4 wherein the compound of formula II is 1-[(2'-Carboxybiphenyl-4-yl)methyl]-4-phenyl-2-propylimidazole-5-carboxaldehyde or a pharmaceutically acceptable salt thereof.
29. The use of a pharmaceutical compound for treating chronic renal failure mediated by angiotensin-II (AII) in a mammal, wherein the pharmaceutical compound is in a form suitable for administration to the mammal, and wherein the pharmaceutical compound comprises formula (I):
wherein R1 is 4-CO2H; 4-CO2R9;
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: CO2R9: 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)~Z(CH2)m R5 optionally substituted with F or CO2R14; benzyl or 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;
R7 is H, F, Cl, Br, I, NO2, C v F2v+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)m NO2; -CH=N-NR11R17; ;
~
R9 is ;
R10 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 (CH2)p C6H5;
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; -CO2R9; -CH2CO2H, -CH2CO2R9;
-PO3H2; -C(CF3)2OH; -NHSO2CH3; -NHSO2CF3;
-NHCOCF3; -CONHOR12; -SO2NH2;
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, or phenacyl;
R16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH2)p C6H5, OR17, or NR18R19;
R17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 5 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 5 carbon atoms, benzyl, or are taken together as (CH2)u where a is 3-6;
R24 is H, CH3 or -C6H5:
R25 is NR27R28, OR28, NHCONH2, NHCSNH2, 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 single 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-, Y is O or S:
Z is O, 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;
or a pharmaceutically acceptable salt thereof:
provided that:
(1) the R1 group is not in the ortho position;
(2) when R1 is X 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 be 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 thereof, the substituent on the 4-position of the imidazole cannot be CH2OH, CH2OCOCH3, or CH2CO2H;
(6) when R1 is X is -OCH2-, and R13 is 2-CO2H, and R7 is H then 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 methoxybenzyl;
(9) the R6 group is not -CHFCH2CH2CH3 or CH2OH;
(10) when r=0, R1 is X is -NH-CO-, R13 is 2-NHSO2CF3, and R6 is n-propyl, then R7 and R8 are not -CO2CH3;
(11) when r=0, R1 is X is NH-CO-, 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).
30. The use of a pharmaceutical compound for treating chronic renal failure mediated by angiotensin-II
(AII) in a mammal, wherein the pharmaceutical compound is in a form suitable for administration to the mammal, and wherein the pharmaceutical compound comprises formula (I):

wherein R1 is 4-CO2H; 9-CO2R9:

4-NHSO2CH3; -4-NHSO2CF3; -CONHOR12;

R2 is H; Cl; Br; I; F; NO2; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO2H; CO2R9; NHSO2CH3;
NHSO2CF3; CONHOR12; SO2NH2; aryl; or furyl; or R7 is H, F, Cl, Br, I, NO2, C v F2v+1, where v = 1-6;
C6F5; or CN;
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)m- .
tetrazolyl;

X is a carbon-carbon single bond, -CO-, -O-, -S-, -NH-, -NR26-, -CONR23-, -NR23CO-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -NHC (R27) (R28)-, -NR23SO2-, SO2NR23-, C(R27) (R28)NH-, -CH=CH-, -CF=CF-, -CH=CF-, -CF=CH-, -CH2CH2-, -CF2CF2-, or a pharmaceutically suitable salt thereof.
31. The use of a pharmaceutical compound for treating chronic renal failure mediated by angiotensin-II
(AII) in a mammal, wherein the pharmaceutical compound is in a form suitable for administration to the mammal, and wherein the pharmaceutical compound comprises formula (I):

wherein R1 is 4-CO2H; 4-CO2R9;

4-NHSO2CH3; -4-NHSO2CF3; -CONHOR12;

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; CO2R9: 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)s Z(CH2)m R5 optionally substituted with F or CO2R14; benzyl or 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;
R7 is vinyl; alkynyl of 2-10 carbon atoms;
phenylalkynyl where the alkynyl portion is 2-6 carbon atoms; heteroaryl selected from 2- and 3-thienyl, 2- and 3-furyl, 2-, 3-, and 4-pyridyl, 2-pyrazinyl, 2-, 4-, and 5-pyrimidinyl, 3- and 4-pyridazinyl, 2-, 4- and 5-thiazolyl, 2-, 4-, and 5-selenazolyl, 2-, 4-, and 5-oxazolyl; 2- or 3-pyrrolyl, 3-, 4- or 5-pyrazolyl, and 2-, 4- or 5-imidazolyl; o-, m- or p-biphenylyl; o-, m- or p-phenoxyphenyl; substituted phenylalkynyl, heteroaryl, biphenyl or phenoxyphenyl substituted with 1 or 2 substituents selected from halogen, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, -NO2, -CN, -CF3, -COR16, -CH2OR17, -NHCOR17, CONR18R19, S(O)r R17, and SO2NR18R19; pyrrolyl, pyrazolyl or imidazolyl as defined above substituted on ring nitrogen with alkyl of 1-5 carbon atoms or benzyl; or substituted alkyl, alkenyl, or alkynyl of 1 to 10 carbon atoms substituted with a substituted or unsubstituted heteroaryl, biphenylyl or phenoxyphenyl group;
R8 is R10 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 (CH2)p C6H5;
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; -CO2R9; -CH2CO2H, -CH2CO2R9;

-PO3H2; -C(CF3)2OH; -NHSO2CH3; -NHSO2CF3;
-NHCOCF3; -CONHOR12; -SO2NH2;

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, or phenacyl;

R16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH2)p C6H5, 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, 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 single 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-, Y is O or S:
Z is O, 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;
or a pharmaceutically acceptable salt thereof;
provided that:
(1) the R1 group is not in the ortho position:
(2) when R1 is X 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 be ortho except when X = NR23CO and R13 is NHSO2CF3 or NHSO2CH3, then R13 must be ortho or meta:
(4) when R1 is 9-CO2H or a salt thereof, R6 cannot be S-alkyl:
(5) when R1 is 9-CO2H or a salt thereof, the substituent on the 9-position of the imidazole cannot be CH2OH, CH2OCOCH3, or CH2CO2H;
(6) when R1 is R6 is not methoxybenzyl;

(7) the R6 group is not -CHCH2CH2CH3 or CH2OH.
¦
F
CA002085584A 1990-06-22 1991-06-07 Treatment of chronic renal failure with imidazole angiotensin-ii receptor antagonists Expired - Lifetime CA2085584C (en)

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