US005728842A United States Patent (19) 11 Patent Number: 5,728.842 Hill et al. 45) Date of Patent: Mar 17, 1998 54 SUBSTITUTED IMIDAZOLYL-ALKYLTHIO 4,808,607 2/1989 Wareiing, II ............................. 514/400 ALKANOIC ACDS 5,011,851 4/1991 Meanwell ................................ 514/400 75) Inventors: David Taylor Hill, North Wales; FOREIGN PATENT DOCUMENTS Joseph Weinstock, Phoenixville; John Gerald Gleason. Downingtown, all of 0427463 5/1991 European Pat. Off. ............... 54/400 Pa. 3306646 8/1984 Germany ............................... 514/400 73 Assignee: SmithKline Beecham Corporation, 62-265270 1 1/1987 Japan ..................................... 54/400 63-141969 6/1988 Japan ..................................... 514/400 Philadelphia, Pa. WO92/O2510 2/1992 WIPO ...... ... 548/319. (21) Appl. No.: 351,443 92-004330 3/1992 WIPO .................................... 514/400 22 PCT Filed: Jun. 30, 1993 WO94/00120 1/1994 WIPO ............................... 54.8/319.1 (86 PCT No.: PCT/US93/06246 Primary Examiner-Floyd D. Higel S371 Date: Feb. 22, 1995 Attorney, Agent, or Firm-Mary E. McCarthy; Stephen A. S 102(e) Date: Feb. 22, 1995 Venetianer; Edward T. Lentz 87 PCT Pub. No.: WO94/00120 57 ABSTRACT PCT Pub. Date:Jan. 6, 1994 Angiotensin II receptor antagonists having the formula: 30 Foreign Application Priority Data Jun. 30, 1992 GB United Kingdom ................... 92.13934 (51) Int. Cl' ..................... C07D 233/60; C07D 233/84; N (CH2) th S-Rs C07D 235/02; CO7D 403/06; C07D 403/04; A61K 31/415 R-X-( R' 52 U.S. C. ...................... 548/319.1; 514/397: 514/398; N R3 514/399; 514,400; 548/321.1; 548/341.5; 548/342.1; 548/342.5 (58) Field of Search ............................ 548/319.1, 321.1. which are useful in regulating hypertension and in the 548/341.5, 342.1, 342.5; 514/397, 398, treatment of congestive heart failure, renal failure, and 399, 400 glaucoma, pharmaceutical compositions including these antagonists, and methods of using these compounds to (56) References Cited produce angiotensin II receptor antagonism in mammals. U.S. PATENT DOCUMENTS 4,668,794 5/1987 Wareing, I .............................. 514/400 5 Claims, No Drawings 5,728,842 1 2 acids. Specifically, the discloser includes 1-benzyl-2-n- SUBSTITUTED MDAZOLYLALKYLTHO butyl-5-chloroimidazole-4-acetic acid and 1-benzyl-2- ALKANOIC ACDS phenyl-5-chloroimidazole-4-propanoic acid. This applicationis a 371 of PCT/U.S. 93/06246 filed Jun. Furukawa, et al., U.S. Pat. No. 4355.040 discloses sub 30, 1993. 5 stituted imidazole-5-acetic acid derivatives. A compound The present invention relates to new compounds which specifically disclosed is 1-(2-chlorobenzyl)-2-n-butyl-4- are angiotensin II receptor antagonists and are useful in chloroimidazole-5-acetic acid. regulating hypertension induced or exacerbated by angio Carini et al... in European Patent Application Number tensin II, and in the treatment of congestive heart failure, 253,310 disclose certain substituted inidazoles. An inter renal failure, and glaucoma. This invention also relates to 10 mediate described in this patent is ethyl 3-1-(4-nitrobenzyl) pharmaceutical compositions containing these compounds -2-butyl-4-chloroimidazol-5-yl)propenoate. and methods for using these compounds as antagonists of Carini et al., in European Patent Application Number angiotensin II, as antihypertensive agents and as agents for 324377 disclose substituted imidazoles and processes for treating congestive heart failure, renal failure, and glau their preparation. This application also relates to pharma COa. 15 ceutical compositions containing the substituted imidazoles alone and in conjunction with other drugs, particularly in BACKGROUND OF THE INVENTION conjunction with diuretics and non-steroidal antiinflamma The class of peptide pressor hormone known as angio tory drugs. tensin is responsible for a vasopressor action that is impli cated in the etiology of hypertension in man. Inappropriate DESCRIPTION OF THE INVENTION activity of the renin-angiotensin systems appears to be a key The compounds of the present invention that are blockers element in essential hypertension, congestive heart failure of angiotensin II receptors are represented by the following and in some forms of renal disease. In addition to a direct Formula (I): action on arteries and arterioles, angiotensin II (AII), being one of the most potent endogenous vasoconstrictors known, (CH2)-R (T) exerts stimulation on the release of aldosterone from the adrenal cortex. Therefore, the renin-angiotensin system, by N e -S-Rs virtue of its participation in the control of renal sodium R4 f handling, plays an important role in cardiovascular hemeo stasis. 30 --. Interruption of the renin-angiotensin system with convert in which: ing enzyme inhibitors, such as captopril, has proved to be R" is adamantyl, phenyl, biphenyl, or naphthyl, with each clinically useful in the treatment of hypertension and con phenyl, biphenyl, or naphthyl group being unsubsti gestive heart failure (Abrams, W. B., et al., (1984), Federa tuted or substituted by one to three substituents selected tion Proc., 43. 1314). The most direct approach towards 35 from Cl, Br, F, I, C-Calkyl. nitro, A-CO'R'. inhibition of the renin-angiotensin system would block the tetrazol-5-yl, C-Calkoxy, hydroxy, SC-alkyl, action of AI at the receptor. Compelling evidence suggests SONHR, NHSOR', SOH, CONR'R''. CN, that AI also contributes to renal vasoconstriction and SOC-Calkyl, NHSOR". PO(OR), NR'R'', sodium retention that is characteristic of a number of dis NR7COH, NR7COC-Calkyl. NR7 CONOR7), orders such as heart failure, cirrhosis and complications of NRCOY, Y, or SOY; pregnancy (Hollenberg, N. K., (1984), J. Cardiovas. R’ is C-Coalkyl, Ca-Coalkenyl, Ca-Coalkenyl, Pharmacol., 6. S176). In addition, recent animal studies C-C cycloalkyl, or (CH2)osphenyl unsubstituted or suggest that inhibition of the renin-angiotensin system may substituted by one to three substituents selected from be beneficial inhalting or slowing the progression of chronic 45 C-Calkyl, nitro, Cl, Br, F, I, hydroxy. C-Calkoxy. renal failure (Anderson, S., et al., (1985), J. Clin. Invest, 76. NR'R''. COR. CN, CONR'R''. Y, tetrazol-5-yl. 612). Also, a recent patent application (South African Patent NRCOC-Calkyl, NRCOY SC-Calkyl, S.O.Y. or Application No. 87101.653) claims that AI antagonists are SOC-Calkyl; useful as agents for reducing and controlling elevated X is a single bond, S, or O; intraocular pressure, especially glaucoma, in mammals. 50 The compounds of this invention inhibit, block and R is hydrogen, Cl, Br, F, L, CHO. hydroxymethyl, antagonize the action of the hormone AI, and are therefore COOR'R' CONR'R''. NO Y. CN. NR'R''. or phenyl: useful in regulating and moderating angiotensin induced Y is CF2:1; hypertension, congestive heart failure, renal failure and A is -(CH2)-, -CH=CH-, -O(CH2)- or other disorders attributed to the actions of AI. When com 55 -S(CH2); pounds of this invention are administered to mammals, the R is H. C.-Calkyl, or -S(CH2)COR; elevated blood pressure due to ADI is reduced and other t is 0 or 1; manifestations based on AI intercession are minimized and Ris-CHR(CH2)COR” or -(CH2).R'; controlled. Compounds of this invention are also expected to R is hydrogen, CO.R. C.-Calkyl, or -(CH2).R; exhibit diuretic activity. each mindependently is 1-3; Recognition of the importance of blocking and inhibiting the actions of AI has stimulated other efforts to synthesize each n independently is 1-3: antagonists of AII. The following references have disclosed each p independently is 0-4; imidazole derivatives which are described as having AI each q independently is 0-2; blocking activity and useful as hypotensive agents. 65 each R’ independently is hydrogen or C-Calkyl: Furukawa et al., U.S. Pat. No. 4340,598 discloses R is phenyl, naphthyl 2- or 3-thienyl, 2- or 3-thiazolyl, imidazol-5-yl-acetic acids and imidazol-5-yl-propanoic triazolyl, tetrazolyl pyrazolyl pyrrolyl, oxazolyl. or 5,728.842 3 4 isoxazolyl, with each R group being unsubstituted or 4-(2-n-butyl-5-[(2-carboxyphenyl)thiomethyl-1H substituted by C-Calkyl, C-Calkoxy, Cl, Br, F, L, imidazol-5-yl)methyl-1-naphthalenecarboxylic acid. NR'R''. CONR'R''. COR”. SOH, SONHR'. OH, methyl 4-(2-n-butyl-5-[(2-carbomethoxyphenyl)-thiol NO. Y. SO2C-C alkyl. SOY. SC-Calkyl methyl-1H-imidazol-5-yl)methyl)-1-naphthalene NRCOH, NRCOY, or NRCOC-Calkyl; and carboxylate, R is phenyl. naphthyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, S-(2-n-butyl-1-(4-carboxyphenyl)methyl-4-chloro 3-, or 4-pyridyl pyrimidyl, imidazolyl, thiazolyl, 1H-imidazol-5-yl)methylthiosalicylic acid. triazolyl, tetrazolyl pyrazolyl, pyrrolyl, oxazolyl, or S-(2-n-butyl-1-(4-carboxyphenyl)methyl)-1H isoxazolyl, with each R group being unsubstituted or imidazol-5-yl)methyl-4-thiobenzoic acid, substituted by C-Calkyl, C-Calkoxy, Cl, Br, F. I. 10 NR'R''. CO.R. CONR'R', SOH SONHR'. OH, S-(2-n-butyl-1-(4-carboxyphenyl)methyl)-1H NO, Y, SQC -Calkyl, SOY, SC-C alkyl. imidazol-5-yl)methyl)-3-thiobenzoic acid, NRCOH, NRCOY, or NRCOC-Calkyl; or a phar S-(2-n-butyl-1-(4-carbomethoxyphenyl)methyl)-1H maceutically acceptable salt thereof. imidazol-5-yl)methyl)-2-thioimidazole, Preferred compounds of this invention are represented by 15 5 S-(2-n-butyl-1-(4-carboxyphenyl)methyl-4-nitro Formula (I) when: 1H-imidazol-5-yl)methylthiosalicylic acid, R" is phenyl or naphthyl, with each phenyl or naphthyl S-(2-n-butyl-1-(4-carboxyphenyl)methyl-1H group being unsubstituted or substituted by one to three imidazol-5-yl)thiosalicylic