USOO5614519A United States Patent (19) 11) Patent Number: 5,614,519 Hauel et al. (45) Date of Patent: Mar 25, 1997 54) (1-(2,3 OR4-N-MORPHOLINOALKYL)- 56) References Cited IMIDAZOL-4-YL)-BENIZIMIDAZOL-1- YL-METHYL-BIPHENYLS USEFUL AS U.S. PATENT DOCUMENTS ANGOTENSIN-HANTAGONSTS 3,929,814 12/1975 Narayanan et al. ................... 514/365 4,492,708 1/1985 Spitzer .................................... 548/181 75 Inventors: Norbert Hauel, Schemmerhofen; 5,171,748 12/1992 Roberts et al. ... 514/381 Berthold Narr, deceased, late of 5,189,048 2/1993 Carini et al. .... ... 514/359 Biberach, by Elisabeth Narr, legal 5,190,942 3/1993 Poss ... 548/306.1 representive; Uwe Ries, Biberch; 5,194,435 3/1993 Kees ........... ... 514/249 Jacobus C. Antonius van Meel, 5,200,422 4/1993 Olesen et al. ... 54,387 Mittelbiberach; Wolfgang Wienen, 5,28,125 6/1993 Chen et al. ..... ... 54/252 Biberach/Rissegg; Michael Entzeroth, 5,250,554 10/1993 Naka et al. ... ... 54/.381 Warthausen, all of Germany 5,254,546 10/1993 Ardecky et al. ..................... 514/325.4 FOREIGN PATENT DOCUMENTS (73) Assignee: Karl Thomae GmbH, Biberach an der 2047496 2/1992 Canada .................................. 548/254 Riss, Germany 0426021 5/1991 European Pat. Off. ... ... 548/254 0468470 1/1992 European Pat. Off. ... ... 548,254 21 Appl. No.: 457,069 0495626 7/1992 European Pat. Off. ... ... 548/252 0512314 9/1992 European Pat. Off. ... 548/306.1 22 Filed: Jun. 1, 1995 92-04343 3/1992 WIPO .................................... 548,254 Related U.S. Application Data Primary Examiner-Floyd D. Higel Attorney, Agent, or Firm-Robert P. Raymond; Alan R. 60 Division of Ser. No. 385,936, Feb. 9, 1995, which is a Stempel; Wendy E. Rieder continuation-in-part of Ser. No. 201,139, Feb. 24, 1994, abandoned, Ser. No. 257,608, Jun. 9, 1994, abandoned, Ser. No. 237,477, May 3, 1994, abandoned, and Ser. No. 94,835, 57) ABSTRACT Jul. 20, 1993, abandoned, said Ser. No. 201,139, is a continuation of Ser. No. 832,193, Feb. 6, 1992, abandoned, Angiotensin-II antagonists of the formula said Ser. No. 257,608, is a continuation of Ser. No. 7,315, Jan. 21, 1993, abandoned, said Ser. No. 237,477, is a continuation of Ser. No. 40,778, Mar. 31, 1993, abandoned. 30) Foreign Application Priority Data Feb. 6, 1991 IDE) Germany .......................... 41 03492.9 May 25, 1991 DEI Germany .......................... 4 17 12.7 Nov. 16, 1991 DEI Germany .......................... 4 37 812.1 Jan. 22, 1992 DE Germany .......................... 42 O1554.5 Apr. 11, 1992 (DE) Germany .......................... 42 12 250.3 Jun. 17, 1992 (DE) Germany .......................... 42 19782.1 Jul. 22, 1992 DE Germany .......................... 42 24 1332 wherein R is, other than hydrogen and, inter alia, halogen, Jul. 27, 1992 (DE) Germany .......................... 42 24 752.7 lower alkyl or cycloalkyl; R is, inter alia, optionally sub Aug. 4, 1992 DE Germany .......................... 42 25 756.5 stituted benzimidazol-2-yl, 5,6,7,8-tetrahydro-imidazol,2- apyridin-2-yl, butanesultan-1-yl, imidazol-4-yl, and tet (51 Int. Cl. ..................... A61K 31/535; CO7D 413/06; rahydobenzimidazol-2-yl; R is, inter alia, lower alkyl; and, CO7D 413/14 R is an acidic group, such as carboxyl or tetrazolyl. An 52 U.S. C. ....................... 514/235.8: 514/365; 514/367; exemplary compound is: 4'-(2-n-propyl-4-methyl-6-(1-(2- 514/397; 514/398; 514/399; 548/181: 548/252; N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)- 548/306.1; 548/306.4; 54.4/139 methyl)-biphenyl-2-carboxylic acid. 58) Field of Search ..................................... 548/181, 252, 548/254, 306.1, 306.4; 514/367, 397, 398, 399, 235.8, 365; 54.4/139 8 Claims, No Drawings 5,614,519 1. 2 (1-(2,3 OR an acylamino group optionally substituted at the nitrogen 4-N-MORPHOLINOALKYL)-IMDAZOL atom by a C-alkyl group or by a phenyl, cycloalkyl, 4-YL)-BENIZIMDAZOL-1-YL-METHYL phenylalkyl, cycloalkylalkyl, bicyclohexyl or biphenyl BPHENYLS USEFUL AS ANGOTENSIN-II group, in which the acyl group is a C-alkanoyl group, a ANTAGONSTS C (alkoxycarbonyl) group, a C-alkylsulphonyl group, a benzoyl, benzenesulphonyl, phenylalkanesulphonyl, naph thalenesulphonyl, cycloalkylcarbonyl, phenylalkanoyl or RELATED APPLICATIONS cycloalkylalkanoyl group, in which the above-mentioned This application is a division of Ser. No. 08/385,936, filed phenyl nuclei may each be mono- or disubstituted by a on Feb. 9, 1995, now allowed, which is a continuation-in 10 fluorine, chlorine or bromine atom or by a methyl or part of the following four prior applications: methoxy group and the substituents may be identical or (A) Ser. No. 08/201,139, filed on Feb. 24, 1994, which is different, a continuation of Ser. No. 07/832,193, filed on Feb. 6, a phthalimino, homophthalimino, 2-carboxyphenylcarbo 1992, both now abandoned; nyl-amino or 2-carboxyphenylmethylamino group, in which 15 a carbonyl group in a phthalimino group may be replaced by (B) Ser. No. 08/257,608, filed on Jun. 9, 1994, which is a a methylene, alkylmethylene or dialkyl-methylene group, continuation of Ser. No. 08/007,315, filed on Jan. 21, and a methylene group in a homophthalimino group may be 1993, both now abandoned; substituted by one or two alkyl groups, and additionally the (C) Ser. No. 08/237,477, filed on May 3, 1994, which is above-mentioned phenyl nuclei may be mono- or disubsti a continuation of Ser. No. 08/040,778, filed on Mar. 31, 20 tuted by alkyl or alkoxy groups, whilst the substituents may 1993, both now abandoned; and be identical or different, and at the same time may be totally (D) Ser. No. 08/094,835, filed on Jul. 20, 1993, now or partially hydrogenated, abandoned. a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group optionally substituted by one or two alkyl groups or 25 by a tetramethylene or pentamethylene group, in which a FIELD OF THE INVENTION methylene group may be replaced by a carbonyl or sulpho The invention relates to certain novel benzimidazoles and nyl group, their use as medicaments. a bicycloalkane-2,3-dicarboxylic acid imino or bicy cloalkene-2,3-dicarboxylic acid imino group, wherein the 30 bicycloalkane and bicycloalkene moieties may each contain BACKGROUND AND BRIEF DESCRIPTION OF 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl THE INVENTION groups and may have an endomethylene group replaced by EP-A-0 392 317 has already described benzimidazoles an oxygen atom, which are valuable angiotensin antagonists. an amidino group optionally substituted by one or two It has now been found that the new benzimidazoles of 35 C1-alkyl groups, formula I described below are even more useful as angio a glutaric acid imino group wherein the n-propylene tensin antagonists, particularly angiotensin-II antagonists. group may be perfluorinated, or may be substituted by one or two alkyl groups or by a tetramethylene or pentamethyl ene group, DETALED DESCRIPTION OF THE 40 a maleic acid imido group optionally mono- or di-substi INVENTION tuted by an alkyl or phenyl group, whilst the substituents may be identical or different, A first aspect of the invention comprises compounds of a 5-membered heteroaromatic ring bound via a carbon the formula I atom or via an imino group and containing an imino group, (I) 45 an oxygen or sulphur atom, or an imino group and an oxygen, Sulphur or nitrogen atom, or R may represent a 6-membered heteroaromatic ring bound via a carbon atom and containing 1 or 2 nitrogen atoms, whilst the abovemen tioned heteroaromatic rings may be substituted in the carbon 50 structure by a C alkyl or by a phenylalkyl group, and an n-propylene, n-butylene or 1,3-butadienyl group may be linked to both the 5-membered and 6-membered heteroaro matic rings via two adjacent carbon atoms or an n-butylene wherein R, R, R and Ra are defined as set forth in options or 1,3-butadienyl group is linked thereto via an imino group A, B, C or D, as follows: 55 and an adjacent carbon atom and, in an anellated pyridine Option A ring thus formed, a methine group may be replaced by a R in the 4-position represents a fluorine, chlorine or nitrogen atom and a vinylene group in the 3-, 4-position bromine atom, a C -alkyl, a cycloalkyl, fluoromethyl, relative to the nitrogen atom of the pyridine ring formed may difluoromethyl or trifluoromethyl group and be replaced by a sulphur atom or in an anellated phenyl ring R represents a Cis-alkoxy group substituted in the 3-, 4 60 thus formed, one or two methine groups may be replaced by or 5-position by an imidazolyl group, or R2 may represent a N-atoms, whilst additionally the above-mentioned fused Cs-alkoxy group substituted in the 2-, 3-, 4- or 5-position aromatic or heteroaromatic rings may be monosubstituted in by a benzimidazolyl or tetrahydrobenzimidazolyl group, or, the carbon structure by a fluorine, chlorine or bromine atom if R represents a 1H-tetrazolyl group, R may also represent or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, a 2-(imidazol-1-yl)-ethoxy group, 65 alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, a C -alkylsulphonyloxy group, a benzenesulphonyloxy alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, or phenylalkanesulphonyloxy group, dialkylaminocarbonyl, fluoromethyl, difluoromethyl, trif 5,614,519 3 4 luoromethyl, alkanoyl, aminosulphonyl, alkylaminosulpho by fluorine or chlorine atoms or by methyl, methoxy or nyl or dialkylaminosulphonyl group or may be disubstituted hydroxy groups, and two methyl substituents in the 1,2- by fluorine or chlorine atoms or by methyl, methoxy or position relative to each other