AU650342B2 - Imidazobenzoquinones and composition for preventing or treating hypertension or congestive heart failure containing the same - Google Patents

Description

0 I 3 I Cl 2 PCr ANNOUNCEMENT OF THE LATER PUBLCATION OF INTERNATIONAL SEARCH REPORT INTERNAI IONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 92/19211 C07D 235/02, A61K 31/415 A3 C07D 235/08, 403/10, A61K 31/41 (43) International Publication Date: 12 November 1992 (12.11.92) C07D 235/08, 403/10, A61K 31/41 (21) International Application Number: PCT/US92/03440 30 April 1992 (30.04.92) (22) International Filing Date Priority data: S3/102639 /3/140057 /3/205879.

3/346283.

8 May 1991 (08.05.91) 12 June 1991 (12.06.91) 16 August 1991 (16.08.91) 27 December 1991 (27.12.91) (71) Applicant (for all designated States except US): THE UP- JOHN COMPANY [US/US]; 301 Henrietta Street, Kalamazoo, MI 49001 (US).

(72) Inventors; and Inventors/Applicants (for US only) KOH, Keiko [JP/JP]; 17-5, 3-chome Azuma, Tsukuba-shi, Ibaraki 305 (JP).

ITOH, Noriie [JP/JP]; 1346-48, Wakaguri, Ami-machi Inashiki-gun, Ibaraki 300-03 OZAWA, Kazunori (JP/JP]; 17-5, 3-chome Azuma, Tsukuba-shi, Ibaraki 305 KUSHIDA, Hiroshi [JP/JP]; 1305-157 Tamado, Shimodate-shi, Ibaraki 308 MCWHORTER, William, Jr. [US/US]; 349 Glendale Blvd., Kalamazoo, MI 49004 (US).

(74)Agent: WELCH, Lawrence, Corporate Patents Trademarks, The Upjohn Company, 301 Henrietta Street, KalamazoG, MI 49001 (US).

(81) Designated States: AT (European patent), AU, BB, BE (European patent), BF (OAPI patent), BG, BJ (OAPI patent), BR, CA, CF(OAPI patent), CG (OAPI patent), CH (European patent), CI (OAPI patent), CM (OAPI patent), CS, DE (European patent), DK (European patent), ES (European patent), FI, FR (European patent), GA (OAPI patent), GB (European patent), GN (OAPI patent), GR (European patent), HU, IT (European patent), JP, KP, KR, LK, LU (European patent), MC (European patent), MG, ML (OAPI patent), MN, MR (OA- PI patent), MW, NL (European patent), NO, PL, RO, RU, SD, SE (European patent), SN (OAPI patent), TD (OAPI pate T A ate S.

Published s. 4 With international search report.

Before the expiration of the time limit for amending the claims and to be republished in the event of the receipt of amendments.

(88) Date of publication of the international search report: 21 January 1993 (21.01.93) (54)Title: IMIDAZOBENZOQUINONES AND COMPOSITION FOR PREVENTING OR TREATING HYPERTENSION OR CONGESTIVE HEART FAILURE CONTAINING THE SAME (57) Abstract There are provided pharmacologically active compounds which are highly effective to treat hypertension or congestive heart failure, and are well absorbed into the body and have long-lasting action. Thus, the present invention provides a compound represented by general formula or a pharmacologically acceptable ester or salt thereof, and a pharmaceutical composition for preventing or treating hypertension or congestive heart failure which comprises the compound as an active ingredient.

WO 92/19211 PCr/US92/03440

-I-

IMIDAZOBENZOQUINONES AND COMPOSITION FOR PREVENTING OR TREATING HYPERTENSION OR CONGESTIVE HEART FAILURE CONTAINING THE SAME BACKGROUND OF THE INVENTION The present invention relates to a novel imidazobezoquinone or a pharmacologically acceptable ester or salt thereof and a pharmaceutical composition for preventing or treating hypertension or congestive heart failure which contains the same as an active ingredient.

It is widely known that Renin-Angiotensin-Aldosterone system is closely connected with hypertensive pathogeny or pathemia through control of blood pressure and amount of fluid or electrolyte. Prevention and treatment of hypertension (including essential hypertension) and further congestive heart failure by controlling this system have been studied for a long time.

As the controlling methods, there are i) inhibition of synthesis or secretion of renin which is thought to be situated at the most upstream position, ii) inhibition of a reaction between renin and a substrate of renin (angiotonsinogen) to decrease angiotensin which is a reaction product, iii) inhibition of an enzyme which converts angiotensin into angiotensin (II) having strong vasoconstriction action, aldosterone secretion stimulating action, sympathetic nerve function promoting action and the like (angiotensin converting enzyme: ACE), iv) inhibition of the action of the produced angiotensin (II) by blocking a receptor part thereof, v) activation of angiotensinase which rapidly degrades the produced angiotensin (II) and the like.

Among the agents active in this system, the study of ACE inhibitors is most advanced, and many such drugs are used for preventing or treating hypertension or congestive heart failure. However, since the ACE inhibitors are not selective and act toward other systems such as kalliklein-kinin system and the like, there is a clinical problem in that the side effects such as skin rash and dry cough occur more frequently. For this reason, many attempts to develop a renin inhibitor, which is thought to be more selective, have been tried, but have not successfully been marketed.

The putative peptidic Angiotensin II antagonist Saralasin has been available for over years. However, its therapeutic use has been severely limited by its partial agonistic action, short plasma half-life and lack of oral activity. Since the discovery of a "non-peptide" Angiotensin II antagonist by Takeda (Japan Kokai Patent 1979-148,788. 1981-71,073, 1982- 98,270, 1983-157,768), extensive efforts have been made to modify or optimize this prototype lead especially by Dupont. These are reported in EP-A0253310 and EP-A0291969, and the compound known as Dup753 is currently being clinically tested. The structure of Dup753 is set out below: WO 92/19211 PCT/US92/03440 -2- .C1 H N=N I However, since this compound is usually produced as 1:1 positional isomer upon Nalkylation, Dup753 can not be selectively synthesized unless a special process is used, and this is thought to be a problem for mass production. On the other hand, it was thought to be effective at that time that the 5-position of the imidazole should have a polar group for increasing the pharmacological activity. This thinking was compelled to be significantly modified by the finding of benzimidazoles shown in EP-A0392317 (also reported in EP- A0400835 and EP-A0399732 later). Further, this was developed into imidazopyridines (see EP-A0399731, EP-A0400974 and EP-A0415886). An example of such a structure is shown below:

N'

1 PROBLEMS TO BE SOLVED BY THE INVENTION From the above described point of view, and paying attention to Ang-II antagonist as an agent for preventing or treating hypertension or congestive heart failure, the present inventors have studied drugs which have higher activity, good absorbability into the body upon oral administration and long-lasting action, and as a result, we have found that certain imidazoquinones are effective, resulting in the present invention.

Common quinone structures in the present invention is similar to those of vitamin A, vitamin K, ubiquinone and the likes, and these are known to have the lipidperoxidation inhibiting action. This shows that having both of Ang-II antagonist and lipidperoxidation inhibiting action works more effectively on treatment of hypertension for a long perioc ,i time, taking into consideration that the lipidperoxidation inhibiting action is effective for inhibiting development of arterial sclerosis and there is the closer relationship between arterial sclerosis WO 92/19211 PCr/ US92/0340 -3and hypertension.

INFORMATION DISCLOSURE A number of imidazo containing moieties are disclosed as useful in the treatment of hypertension as described above, see, Japanese Kokai 78/148,788; 81/71,073; 82/98,270 and 83/157,768; published European patent applications EPA 253310; 291969; 392317; 400835; 399732; 399731; 400974; and 415886. EP 400974 discloses imidazoquinones among a wide variety of other possibilities.

SUMMARY OF THE INVENTION The present invention provides an imidazobenzoquinone represented by the general formula II R N X R 3 (CH )n wherein R 1 is hydrogen atom, a C 1

-C

8 alkyl group, a C 2

-C

8 alkenyl group, a C 2

-C

8 alkynyl group, -CF 3 group, an aryl group or an aralkyl group; X is oxygen atom or a group of the formula N-OR 6

N-NHR

5 or CR 7

R

8 Y is a 1H-tetrazol-5-yl group or an alkali metal salt thereof, a -CO2R 4 group, a CONR'R" group or a -CONHSO 2

R

5 group;

R

2 and R 3 are independently hydrogen atom, an optionally substituted C 1 -Cg alkyl group, a C 1 -Cg alkoxy group, -CN, a -C0 2

R

4 group, a -CONR'R" group or a -CONHSO 2

R

5 group, or R 2 and R 3 together form an optionally substituted aromatic or heterocyclic ring;

R

4 is hydrogen atom, alkali metal or a C 1

-C

8 alkyl group:

R

5 is a C 1 -Cg alkyl group, a C 3

-C

10 cycloalkyl group or an aryl group;

R

6 is hydrogen atom or a CI-C 8 alkyl group optionally substituted by Y;

R

7 and R 8 are independently hydrogen, CI-C 8 alkyl, C 2

-C

8 alkenyl, C 2

-C

8 alkynyl, CF3, aryl, or aralkyl, or R 7 and R 8 together form an alicyclic structure, R' and R" are independently hydrogen atom or a Cl-Cg alkyl group, or R' and R" together form an alicyclic structure; and WO 92/19211 PCT/US92/03440 -4n is 0, 1 or 2, or a pharmacologically acceptable ester or salt thereof, and a pharmaceutical composition for preventing or treating hypertension or congestive heart failure which omGprises, a ts active ingredient an imidazobenzoquinone of the general formula or pharmacologically acceptable ester or salt thereof.

EFFECT OF THE INVENTION According to the present invention, there is provided imidazobenzoqunones which have high activity to hypertension or congestive heart failure, are well abdsorbed into the body upon administration and have long-lasting action. Further, a pharmaceutical composition for preventing or treating hypertension or congestive heart failure containing the same.

The carbon atom content of the carbon containing moieties is indicated by a prefix "Ci- Cj" wherein i is the lowest number of carbon atoms nid j is the highest number of carbon atoms.

As the lower alkyl group represented by R 1 in the general formula there are an alkyi group having from 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like. As the lower alkenyl group, there are vinyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, 1-penteny!, 2-pentenyl, 1-hexenyl, 1-heptenyl, 1-octenyl and the like. As the lower alkynyl group, there are an acetylene group, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1pentynyl, 2-pentynyl, 1-hexynyl, 1-heptynyl, 1-octynyl and the like. As the aryl group or aralkyl group, there are those having from 6 to 10 carbon atoms, for example, phenyl, naphthyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl and the like. These aryl or aralkyl groups may be optionally substituted by substituents such as the lower alkyl group described above, or lower alkoxy group, a halogen atom, nitro group, cyano group and the like.

When Y is an alkali metal salt of the 1H-tetrazol-5-yl in the compound represented by the general formula examples of the alkali metal salt are sodium, potassium salt and the like. Examples of R 4 in the -CO 2

R

4 group are a hydrogen atom, an alkali metal, a lower alkyl group. Examples of the alkali metal salt are sodium, potassium salt and the like. Examples of the lower alkyl group are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, npentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like. Examples of NR'R" in the -CONR'R" group are amino, methylamino, dimethylamino, ethylamino, diethylamino. n-propylamino, di(npropyl)amino, diisopropylamino, dibutylamino, pyrrolidinyl, piperazino, morpholino and the like. And examples of R 5 in the -CONHSO 2

R

5 group are methyl, ethyl, n-propyl, n-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl and the like.

35 When R 2 or R 3 represents the lower alkyl group. the -C0 2

R

4 group, the -CONR'R" group or the -CONHSO 2

R

5 group, examples of them are the same as described above about 'J 1* r WO 92/19211 PCr/US92/03440

R

1

R

4 NR'R oR4 and R 5 When R 2 oR 3 is the substituted lower alkyl group, examples of them are hydroxymethyl, carboxymethyl, 2-carboxyethyl, 3-carboxy-n-propyl, 4-carboxy 'ibutyl, 2-hydroxyethyl, 3-hydroxy-n-propyl, 4-hydroxy-n-butyl and the like. Examples of the lower alkoxy are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like.

When R 2 and R 3 taken together represent the aromatic or heterocyclic ring, examples of the aromatic ring are benzene ring or naphthalene ring, and examples of the heterocyclic ring are pyridine ring, pyrimidine ring, fliran ring or thiophene ring. Thesp. aromatic and heterocyclic rings may be optionally substituted by a halogen atom, a lower alkyl group, CF 3 a lower alkoxy group, -CN, a -C0 2

R

4 group, a -COR'R" group, a -SO 3 H group or an alkali me!1 salt thereof, a -SO 2

NHR

5 group. Examples of these lower alkyl group, lower alkoxy gvoup, -C0 2

R

4 group, -CONHR'R" group, -CONHSO 2

R

5 group, -SO 2

NHR

5 group are the same as those described above,I Further, in the compound of the general formula examples of the lower alkyl group, the lower alkenyl group, the lower alkynyl group, the aryl group and the aralkyl group represented by Rl' as well as examples of the lower alkyl group represented by RT and RY are as described about R 1 Examples of the optionally substituted alkyl and lower alkoxy groups are as described about R 2 and R Particular examples of compounds represented by the general formula are as follows. The number described corresponds to the compound number.

1) 1-[(2'-Carboxybiphenyl-4-yl)methyl]-2-n-butyl- 1H-naphthimidazol-4,9-dione, 2) 1 -[(2'-t-Butoxycarbonylbiphenyl-4-yt)methyl]-2-n-butyl-1H-naphthimidazol-4,9dione, 3) 1 -[(2'-(Tetrazole-5-yl)biphenyl-4-yl)methyl]-2-n-butyl- 1H-naphthimidazol-4,9dione, 4) 1-[(2'-Carboxybiphenyl -4-yl)methyll-2-(1 -propen-1 -yl)-l H-naphthimidazol-4,9dione, 1-[2'-(Tetrazol -5-yl)biphenyl -4-yl)meth yl] -prop en- 1 1 H naphthimidazol-4,9-dione, 6) 1 -[(2'-Carboxybiphenyl-4-yl)methyl]-2-( 1-propyn- l-yl)- 1H-naphthimidazol-4,9dione, 7) 1 -[(2'-CTetrazol-5-yl)biphenyl-4-yl)methyl]-2-( I-propyn- l-yl)-lH naphthimidazol-4,9-dione, 8) 1-[(2'-Carboxybiphenyl-4-yl)methyl]-2-phenyl-1H-naphthimidazol-4,9-dione, 9) 1 (2'-(Tetrazol -5-yl)b iphenyl-4-yl)metnyl]I-2-phenyl-I H naphth imid azol -4,9dione, 1 '-Carboxybiphenyl-4-yl)methyl]-2-benzyl- I H -naphthimidazol -4 .9-di!one, WO 92/19211 PCT/US92/03440 -6- 11) 1-[(2'-(Tetrazol-5-yl)biphenyl-4-yl)methyl]-2-benzyl-1H-naphthimidazol-4,9dione, 12) 1-[(2'-Carboxybiphenyl-4-yI)methyl]-2-trifluoromethyl- 1H-naphthimidazol-4,9dione, 13) 1 -[(2'-(Tetrazol-5-yl)biphenyl-4-yI)methyl]-2-trifluoromethyl- IH-naphthiniidazol- 4,9-dione, 14) 1-[(2'-Carboxybiphenyl-4-yl)methyl]-2-methyl-1H-naphthimidazol-4,9-dione, 1-[(2'-(Tetrazol-5-yl)biphenyl-4-yl)methyl]-2-methyl- 1H-naphthimidazol-4,9dione, 16) 1 -[(2'-Carboxybiplnyl-4-yl)methy1]-2-ethylI- H-naphthimidazol-4,9-dione,, 17) 1 -[(2'-(Tetrazol-5-yl)biphenyl-4-yl)methyl]-2-ethyl- 1H-naphthirnidazol-4,9- 18) '-Carboxybiphenyl-4-yI)methyl j-2-n-propyl- I 11-naphth imid azol-4,9-d ione, 19) 1.4(2 '-(retrazol-5-yl)biphenyl-4-yl)inethyl]-2-n-propyl- 1H-naphthimidazol-4,9dione, 1-[(2'-Carboxybiphenyl-4-yl)rnethyl]-2-n-pentyl- 1 I{-naphthimidazol-4 ,9-d ione, 21) 1-[(2'-Cfetrazol-5-yl)biphenyl-4-yl)methyll-2-n-pentyl- 1 H-naphthimidazol -4,9dione, 22) 1-[(2'-(Tetrazol-5-yI)biphenyl -4-yl)methyl]-2-n-hexyl-1I H-naphthimidazol.-4,9dione, 23) 1 -[(2'-Carboxybiphenyl-4-yI)meth.y1]-2-n-butyI-5 ,8-d imethoxy-l1W naphthirnidazol-4,9-dione., 24) 1 '-Tetrazol-5-yl)biphenyl-4-yI)methyll '-2-n-buityI -6,7-d imethyl- I H naphthimidazol-4,9-dione, 25) 1-[(2'-Carboxybiphenyl-4-yl)methylj-2-n-butyl-1I H-benzimid azol-4,7-d ione, 26) 1-I(2'-Carboxybiphenyl-4-yI)methyll-2-n-butyl-5,6-dimethyl- 1 H-benzimidazol 4,7-dione, 27) 1-[(2'-(Tetrazol-5-yI)biphenyl-4-yl)methyll-2-n-butyl-5,6-dimethyl- 1 Hbenzimidazol-4,7-dione, 28) 1-[(2'-Carboxybiphenyl-4-yI)mediyl]-2-n-butyl -5,6-d imethoxy- 1 H-benzimidazol- 4,7-dione, 29) 1-('(erzl5y~ihnl--lm .yj2nbtl56dmtoy I H benzimidazol-4,7-dione, 1 -I(2'-Carboxybiphenyl-4-yl)methyl]-2-n-butyl-5 .6-dihydroxymethyI 1 H bentzimidazol-4,7-dione, 31) H-[(2'-(Tetrazol -5 -yl)biph env] -4-yI )methyl]1-2-n-butyl-5 .6-d ihvdroxymethyl- IH wo 92/19211 PCT/US92/03440 -7benzimidazol-4,7-dione, 32) 'A -[(2'-Carboxybiphenyl-4-yI)methyl]-2-n-butyl-5-methyl-6-carboxymethiyl- I1Hbenzimidazol-4,7-dione, 33) 1 -[(2'-(Tetrazol -5 -yl)biphenyl -4-yI)meth yl -2-n-butyl -5 nethyl -6-carboxym ethyl IH-benzimidazol-4,7-ciione, 34) 1 -[(2'-Carboxybiphenyl-4-yl)methyl]-2-n-butyl-5-carboxynethyl-6-methyl- I Hbenzimidazol-4,7-dione, 1 (2-(Tetrazol -5-yI)b iphenyl -4-yI)methyll)-2-n-butyl -5 -carboxymethyl -6-methyl IH-henzimidazol-4,7-dione, 36) 1-1(2 '-Carboxybiphenyl-4-yl)rnethyll-2-n-butyl-5-rnethyl-6-carboxy- I Hbenzimidazol-4,7-dione, 37) 1 -[(2'-(Tetrazol -5-yl)biphenyl-4-yl)methyl] -2-n-butyl -5-methyl -6-carboxy- 1iNbenzimidazol-4,7-dione, 38) 1 '-Carboxybiphenyl-4-yI)niethyl]-2-n-butyl-5-carboxy-6-methyl- 1 Hbenzimidazoi,-4,7-dione, 39) 1-1(2 '-(Tetrazol-5-yI)biphienyl-4-yl)methyl]-2-n-butyI -5-carboxy-6-methyl- 1 Hbenzimidazol-4,7-dione, 1-[(2'-Carboxybiphenyl-4-yI)methyl]-2-n-butyl-5-methyl-6-(N,Ndimethyl)carbamoyl-lH-benzimidazol-4,7-dione, 41) 1 -[(2'-(Tetrazol-5-yl)biphenyl-4-yI)methyl]-2-n-butyil-5-methyl-6-(N,Ndimethyl)carbamoyl-LH-benzimidazol-4,7-dione, 42) 1 -[(2'-Carboxybiphenyl-4-yl)methyl]-2-n-butyl-5-(N.N-dimethvl)carbamoyl -6methyl-1H-benzimidazol-4,7-dione, 43) 1-[(2'-(Tetrazol -5-yI)biphenyl -4-yI)methyl] -2-n-butyl dimethyl)carbarnoyl-6-methyl-1IH-benzimidazol-4,7-dione, 44) 1 '-Carboxybiphenyl-4-yl)methyl]-2-n-butyl-5-methyl -6-cyano- 1 H benzimidazol-4,7-dione, 1 -[(2'-(Tetrazol-5-yl)biphenyl-4-yI)methyl]-2-n-butyl -5-methyl-6-cyano- I Hbenzimidazol-4,7-dione, 46) 1 '-Carboxybiphenyl-4-y)methyl]-2-n-butyl-5-cvano-6-methyl- I Hbenzimidazol-4,7-dione, 47) 1 -[2'-CretrazoI-S-y1)biipheny1-4-yI)methy1I-2-n-buty1-5-cyano-6-methyI- 1 H- benzimidazol-4,7-dione, 48) 1 -[(2'-Carboxybiphenyl-4-yI)methyll-2-n-butyl-5,6-d icyano- 1 H-benzimidazol- 4,7-dione, 49) 1-1(2 '-CIetrazol-5-yl)biphenvl-4-yI)methyl]-2-n-butyl-5 .6-dicyano- 1 H wo 92119211 PCT/US92/03440 -8benzimidazol-4,7-dione, 1 -[(2'-Carboxybiphenyl-4-yl)methyll-2-n-butyl-5-methyl metlianesulfonyl)carbainoyl-1H-benzimidazol-4,7-dione, niethanesulfonyl)carbarnoyl-1 H-benzimidazol-4, 7-d ione, 52) 1 -[(2'-Carboxybipheny 4-y)methylI -2-n hutyl -5-methyl -6-(2-carboxy)ethyl -I Hbenzimidazol-4,7-dione, 53) 1 -[(2'-(Tetrazol-5-yI)biphenyl-4-yl)methyl- ,)-n-butyl-5-methyl.6-(2carboxy)ethyl-lH-benzimidazol-4,7-dione, 54) l-[ 2 '-Carboxybiphenyl-4-yl)methyl] -2-n-butyl-5-methyl -carboxy)propyl IH-benzimidazol-4,7-dione, 2 '-Cretrazol-5-yl)biphenyl -4-yl)meth yl )-2-n-butyl -5 methyl carboxy)propyl- I1H-benizimid azol -4,7 -d ione, 56) 1 '-CarboxybiphenylA-yl)methyl]-2-n-butyl-5-methyl-6-(4-carboxy)butyl- I ti benzimidazol-.4,7-dione, 57) 1 -[(2'-(Tetrazol-5-yl)biphenyl -4-yl)methyl]-2-n-butyl-5-methyI carboxy)butyl- 1H-benzimidazol-4,7-dione, 58) 1 -[(2'-Carboxybipheny.4-yl)methyI-2-n-butyl-5-methyl.6-(2-hyd roxyethyl)) 11benzimidazol-4,7-dione, 59) 1 Tetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-butyl-5-methyl-6-(2 hydroxyethyl)-1H-benzimidazol-4,7-dione, 1 -[(2'-Carboxyb iphenyl -4-yl) methyl] -2-n-butyl -5 -methyl -hyd roxypropyl)- 1H-benzimidazoI-4,7-dione, 61) I-[(2'-(Tetrazol-5-y)biphenyl-4-yi)rnethyl]-2-n-butyl-5-methyl-6-(3 hydroxypropy!)- IH-benzimidazol-4,7-dione, 62) 1 '-Carboxybiphenyl-4-yl)methyl j-2-n-butyl -5-methyl -6-(4-hyd roxybutyl)-1 benzimidazol-4,7-dione, 63) 1 -[(2'-(Tetrazol-5-yI)biphenyl-4-yl)methyl] -2-n-butyl-5-methyl-6-(4hydroxybutyl)-1H-benzimidazol-4,7-dione, 64) 1 -[(2'-(Tetrazol-5-yl)biphenyl-4-yi)methyll- 11--naphthimidazol-4,9-dione, 1-[(2'-(N-Methanesulfonyl)carbamoylbiphenyl-4-yl)methyll-2-n-butyl- I Hnaphthimidazol-4,9-dione, 66) 1 -[(2'-Cretrazol-5-yl)biphenyl-4-yl)methyl]-2-ethyl-5,6-dtimethyl-rnbenzimidazol-4,7-dione, 67) 1 '-Ci'etrazol-5-yl)biphenyl-4-y!)methylj-2-n-propyl-5,6-dimethvl-

H-

benzimidazo!-4,7-dione, WO 92/19211 PCY/US92/03440 -9- 68) 1 -[(2'-kTetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-pentyl.5 ,6-dimethyl- 1Hbenzimidazol-4,7-dione, 69) 1 -[(2'-(Tetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-hexyl-5,6-dimethyl- 1Hbenzimidazol-4,7-dione, 70) 1 -[(2'-(Tetrazol-5-yl)biphenyl-4-yl)methyl]-4-methoxyimino-2-n-propyl- 1Hnaphthimidazol-9-one, 71) 1-[(2'-(Tetrazol-5-yI)biphenyl-4-yl)methylI-2-n-buty-4-methoxyimino-1Hnaphthimidazol-9-one, 72) 1 -f(2'-(Tetrazol-5-yl)biphenyl-4-yl)methyl]-5,6-dimethyl-4-methoxyimino-2-npropyl-1H-benzimidazol-7-one, 73) 1 -[(2'-(Tetrazol. 3-yl)biphenyl-4-yi)methyl]-2-n-butyl-5 ,6-dimethyl-4methoxyimino-1H-benzimidazol-7-one.

Additional compoundc of this invention include: 74) 1 -[(2'-(Tetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-butyl-4-e thylidene- IHnaphtiznidazol-9-one, fetrazol-5-yl)biphenyl-4-yl)methyl] -2-n-butyl-4-benzyl idene- 1 Hnaphtimidazol-9-one, 76) 1-1(2 '-(Tetrazol-5-yl)biphenyl-4-yl)methyl)-2-n-butyl-4-(2 ,2dimethyl)propyl idene- 1H-naphtimidazol-9-one, 77) 1 -[(2'-(Tetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-butyl-4-ethyl idene-5,6-dimethy[- IH-benzimidazol-7-one, 78) 1-1(2' -(Tetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-butyl -4-benzyl idene-5-methyl -6- (2-carboxy)ethvl-1H-benzimidazol-7-one, d imethyl)propyl idene-5-methyl -6-(2-hydroxy)ethyl -I H-benzimidazol -7 -one, 1 -[(2'-(T.,trazol-5-yl)b iph enyl -4-yl)methyl] -2-n-buty I 11-naphti mid azol -4,9dione methyihydrazone, 81) 1-[(2'-(Tetrazol-5-yI)biphenyl-4-yl)methyl]-2-n-butyl-5,6-dimethyl- 1benzimidazol-4,7-dione phenyihydrazone.

The imidazobenzoquinones of the present invention can form a pharmacologically acceptable ester at a part of R 2 3 or y h general formula or at a part of XI or X 2 in the general formulas [I As examples of the formed esters, there are methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl or tbutoxycarbonyl.

Furthe,., imidazobenzuquin,)nes of the present invention can form a pharmacologically acceptable salt at a part of irnirU7l in the general formula [11 when Y is -CO-,R.

WO 92/19211 PCT/US92/03440 -CONR'R". As examples of such a salt, there are hydrochloride, h;'drobromide, hydroiodide, sulphate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, tartrate and the like. And when Y is the 1H-tetrazol-5-yl in the general formula they can form an alkali metal salt at a part of the 1H-. In both of cases, these salts may be in the form of a hydrate.

Imidazobenzoquinones represented by the general formula can be prepared, for example, according to the following scheme.

WO 92/19211 W0929211P/ US92/03440 -11- 0 X

H

2

N

c1 x 2 [3 a] 0

X

R

1

-C-NH

0 J ~9 I halo group halo C0 2

R

4 0 0 I D C 0 2

R

4 ydrolysis £1a] 0

X

n C0 2

H

[1 cl hydrolysis L' b 3 WO 92/19211 PC/ US92/03440 -12wherein X 1 and X 2 are a hydrogeiz atom, a halogen atom, a lower alkyl group, -CF 3 a lower alkoxy group, -CN, -C0 2

R

4 a -CONR'R" group, a -CONHSO 2

R

5 group, a -SO 3 H group or an alkali metal salt thereof, or a

SO

2

NHR

5 group, and R 4 R" and R 5 are as defined above.

The compound [2a] which is used in this process is synthesized according to the method reported by J. R. E. Hoover, A. R. Daty in J. Am. Chem. Soc., 76, 4151 (1954). That ia, after 2-amino-3-chloro-l,4-naphthoquinone [3a] is subjected to the conventional acylation reaction, a chloro atom is converted into an amino group by eating with ammmmonia gas at about 150 0 C, and further an intramolecular cyclization reaction is carried under the basic condition to obtain the compound [2a] at high yield.

An alternative process is as follows: WO 92/19211 PCT/US921 03440

QSO

2 Ph OSO 2 Ph Initration re&t&-i 0S0 2 Ph OSC2Ph jacylation 0 2 N 'K,2 OSO2Ph

C

5 a]I treduction o0 OSO 2 Ph 0 OOPh 0 2 N A

OSQ

2 ph

OSO

2 Ph [7 Ireduction

OSO

2 Ph 0 OS0 2 Ph H2N tkR-CN 2

H

2 R H 2

N):-R

OSO

2 Ph

OSO

2 Ph [81 orthoester thydrolysis; oxidation 0 0 R I 1

-CHN,

0 Ihalogenation 0 0 0 C3 b] amination 0 0 R'-CHN r2 0 9 OS0 2 Ph N2 H OSO 2 Ph hydrolysis; oxidation 6] hydrolysis oxidation 2 b]I WO 92/19211 PCT/US92/03440 -14- That is, in this process, the compound obtained by reacting a hydroquinone derivative and benzenesulfonyl chloride according to the process by E. M. Kampouris (J.

Chem. Soc. 1967, 1235) is used as a starting material. Benzyl chloride can be used as a protecting group for phenols instead of benzenesulfonyl chloride. However, a desirable protecting group must be selected in view of subsequent reactions and the like. That is, when benzenesulfonyl chloride is used, the protecting group is easily cleaved under alkaline conditions, and when benzyl chloride is used, the protecting group is easily cleaved under reductive conditions, while it is stable under alkaline conditions. As a representative example, the use of benzenesulfonyl chloride will be described below. The compound can be converted into the dinitro [5a] and/or mononitro [5b] compounds by reacting with fuming nitric acid according to the above-described method. The compound [5a] can be converted into a corresponding diamine by reduction using sodium dithionite, conventional catalytic reduction or reduction using a metal, for example, zinc-acetic acid, zinc-potassium chloride-ethanol/water.

The diamine can be converted into the compound according to the reaction by heating with an orthoester which is widely known as the imidazole synthesizing method. The compound [7] can be converted into the imidazoquinone [2b] by subjecting a conventional hydrolysis reaction into a corresponding hydroquinone with an alcoholic solution of sodium or potassium hydroxide, then subjecting to the oxidation reaction.

On the other hand, the above-described mononitro compound [5b] can be similarly converted into the compound by reduction reaction and acylating reaction, The compound can be converted into compound using again nitration reaction and reduction reaction, Alternatively, the compound can be synthesized also by acylating a diamine obtained by reducing the compound The compound can be converted into the diaminoquinone [9] by subjecting to hydrolysis reaction and then oxidation reaction, and the compound can be fused into an imidazole ring according to the nietho' by J. R. E. Hoover described above.

Also, the compound itself can he converted into the compound [3b] by halogenation reaction after hydrolysis and oxidation reaction into a monoaminoquinone. The synthesis of the imidazoquinone [2b] from the compound [3b] via the compound [91 may be carried out according to the method by J. R. E. Hoover.

Imidazobenzoquinones in the general formula wherein X is oxygen atom can be derived into a monooxime, for example, by heating with a hydrochloride of hydroxylamine.

alkoxyamine and the like in pyridine.

WO 92/19211 PMTUS92/03440 S R

NOR

6 N R 05 0 SH2 C The conversion of the diketone to compounds wherein X is N-NHR 5 or CR 7

R

8 is similarly undertaken using procedures well known in the art, analogous to those described herein.

Pharmacological activity test of the compound of the present invention is described hereinafter.

1) In vitro angiotensin II mesenteric artery receptor binding assay According to the method by Gunther et al., a membrane fraction was prepared from mesenteric artery of a male rat, 50 Ag protein equivalent thereof and 0.2 nM 125 1-Ang 11 as well as various concentrations of test compounds were incubated at 22 0 C for 90 min. in 200 Al reaction volume of incubation buffer (50 mM Tris-HC, 120 mM NaCI, 5 mM MgCI 2 0.25% bovine serum albumin, pH7.2). This was cooled, and the reaction was stopped by addition of ice-cooled phosphate buffer (10 mM phosphate, 140 mM NaCI, pH7.4, hereinafter referred to as PBS), and then the reaction sol ition was filtered through a glass fiber filter (Whatman CF/B), the filter was washed, dried, and then the radioactivity of captured 1251-angiotensin II which bound to the receptor was measured by y-counter. Non-specific binding amount was obtained from the reaction in the presence of 1 AM of unlabeled angiotensin II. The test compound was tested at the concentration of 0.01 to 1 iM, and those that inhibited more than of total specific binding amount at 1 /M was determined as an active compound, and inhibiting concentration (IC 50 was obtained [see Gunther, Gimbrone, M.A. and Alexander, Circ. Res., 17:278-286, 1980].

2) In vitro adrenal cortex angiotensin II rceptor binding assay According to the method by Capponi et al. angiotensin II receptor binding assay was carried out by preparing a membrane fraction from an adrenal cortex of a male rat and using this as a receptor material in the same manner as in the above-described pharmacological test 1) [see Capponi, A. M. and Catt, J. Biol. Chem. 254:5120-5127(1979)].

3) Antagonism to angiotensin II constriction in an isolated rabbit thoracic aorta A rectangular strip-like sample of thoracic aorta isolated from an anethetized rabbit war WO 92/19211 P(3T/US92/03440 -16prepared, and this was suspended at 2.0 g of loaded tension in a Magnus tube filled with Krebs- Henseleitoid nutrition solution which was well aerated with 95% 02-5% CO 2 and the constriction tension was measured using an isometric transducer. After the tension of the sample at rest became stable, accumulative administration of angiotensin II was carried out to obtain a concentration-action curve. Thereafter, the sample was washed with the same nutrition solution, and then 10 6 M test compound was treated for 20 min. to obtain again a concentration-action curve of angiotensin II. The results were obtained as followed: generated maximum tension at the first accumulative administration of angiotensin II was regarded as 100%, and the 50% effective concentration (ED 5 0 was obtained in the presence or absence of the test compound, and pA 2 value was calculated according to the following equations: pA 2 =-logKB C: concentration of the test compound (M)

ED

5 0 in the presence of test compound (M) A: ED 50 in the absence of the test compound (M) 4)Antagonism to blood pressure increasing by angiotensin II in a spine destroyed rat Wistar rat anesthetized with pentobarbital was fixed at dorsal position, and a cannula for measuring blood pressure was inserted into sinister arteria carotis communis, and a cannula for administration of the test compound into dexter external jugular vein and a cannula for administration of angiotensin II into sinister external jugular vein, ambilateral nervous vagus was cut, and artificial respiration was carried out. A thin bar made of metal was stabbed into spinal column through sininster orbita to destroy spine. Blood pressure was recorded on polygraph via pressure transducer from an arterial cannula. After blood pressure was stable for more than 30 min., 3 p/g/kg of angiotensin II was administered intravenously four times every min., and every 5 min. before the administration of angiotensin II from the second admininstration onward, a solvent, a lower dose of the test compound, and a higher dose of the test compound were admininstered intravenously in this order to observe the blood pressure increasing response by angiotensin II. ED 50 values were calculated from the inhibiting rate when the first blood pressure increase by angiotensin II was regarded as 100%.

In abov e tests, the compounds of the present invention showed high activity. For example, the compound No. 1 and No. 2 showed IC 50 =6.1x107 M or 5.0x10' 8 M in the test respectively. And the compound No. 1 showed IC 50 =5.4x10- 7 M, pA 2 =6.64, and the compound No. 2 showed IC 50 =4.8x10-8 M, pA 2 =7.60 in tests 2) and respectively.

Further, the compound No. 1 showed ED 50 value =22.6 mg/kg in the test 4).

The irfiidazobenzoquinones or pharmacologically acceptable esters or salts thereof can be formulated, by a conventional method, into a dosage unit forms such as tablets, capsules, pills, powders, granules, powder packet, cachets, sterile parenteral solutions or suspensions.

WO 92/19211 PC/US92/03440 -17eyedrops, solutions or suspensions, elixirs, suppositories, aerosols and emulsions which contains them in a predetermined amount.

For oral admininstration, solid or fluid unit dosage form can be prepared. For preparing solid composition, the active compound is mixed with an excipient or a carrier such as magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulphate, starch, lactose, acacia, methyl cellulose and the like. A capsule agent is prepared by mixing the compound of the present invention with an inert pharmaceutical excipient, filling the mixture into a hard gelatin capsule having suitable size. A soft gelatin capsule is prepared by machine capsulation of slurry composed of the compound, suitable vegetable oil, light petrolatum or other inert oil.

For preparing a fluid composition, the compound of the present invention is dissolved in aqueous vehicle together with sugar, aromatic flavor and preservative to obtain a syrup.

Elixirs are prepared using an alcoholic vehicle such as ethanol, a sweetener such as sugar and saccharin as well as a flavor. Suspensions are prepared using a suspending agent such as acacia, tragacanth or methyl cellulose and an aqueous vehicle.

For parenteral administration, a fluid unit dosage form is prepared using the compound of the present invention and a sterile vehicle. Depending upon a vehicle such as water, Ringer's solution, isotonic sodium chloride solution and the concentration to be used, the compound is suspended or dissolved in the vehicle. For preparing solutions, the compound is dissolved in water for injection, and this is sterile filtered, filled into a vial or an ampoule, and sealed. Advantageously, an adjuvant such as local anesthetic, preservative and buffer is dissolved in vehicle. Alternatively, a lyophilized powder having good shelf stability can be prepared. In the case of this formulation, the powder is reconstituted upon use. Parenteral suspensions can be similarly prepared using the compound of the present invention. In the case of this formulation, the compound of the present invention can be sterilized by exposure to ethylene oxide before suspended in a sterile vehicle. Advantageously, a surfactant or a wetting agent is added to facilitate dispersion of the compound.

Alternatively, the compound of the present invention can be formulated into a local dosage form in combination with a suitable carrier for local administration. Examples of a carrier to be used are cream, ointment, lotion, paste, jelly, spray, aerosol and the like.

Further, when other form can not be administered, suppositories can be prepared. Examples of a base are cacao butter, polyethylene glycol, polyethylene sorbitan monostearate and the like, Imidazobenzoquinones or pharmacologically acceptable esters or salts thereof are administered orally, parenterally by insufflation, rectally, locally. Parenteral administration includes subcutaneous, intravenous, intramuscular, intranasal adminstration or injection. Dose to be administered to an adult is in a range of 1 to 50 mg/day. The exact dose can be selected WO 92/19211 P(7/US92/03440 -18from the above range, taking into account the age of patient, weight, condition and route of administration into consideration. Frequency of administration is usually one to four times a day.

Additionally, no toxicity of the compound of the present invention or pharmacolog;cally acceptable esters or salts thereof was observed in the above-described dose range.

DETAILED DESCRIPTION OF THE INVENTION The following Examples further illustrate the present invention in detail but are not to be construed to limit the scope thereof.

Example 1 Preparation of 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-n-butyl-lH-naphthimidazol-4,9dione (Compound No. 1) 0 0 73 mg (0.29 mmol) of 2-n-Butyl-1H-naphthimidazol-4,9-dione which had been synthesized according to the known method in the reference Am. Chem. Soc., 76, 4151(1954)] was dissolved in 3 ml of dimethylformamide. After 0.35 mmol of sodium hydride was added at 15 to 20°C under the nitrogen atmosphere, 100 mg (0.29 mmol) of butoxycarbonylbiphenyl-4-yl)methyl bromide was added to react for 2.5 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with water and dried with magnesium sulphate. The solvent was distilled off under the reduced pressure, the residue was purified by silica gel column chromatography (CHCI 3 :MeOH=30:1) to obtain 99 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-n-butyl-lH-naphthimidazol- 4,9-dione (Compound No. NMR spectrum is as follows.

6 ppm (CDCI 3 1.00 (3H, t, J=7Hz), 1.26 (9H, 1.49 (2H, sextet, J=7Hz), 1.91 (2H, quintet, J=8Hz), 2.88 (2H, t, J=8Hz), 5.83 (2H, 7.22 (2P, d, J=8Hz), 7.31-7.37 (3H, 7.45 (1H, ddd, J=8, 8.2Hz), 7.53 (1H, ddd, J=8, 8.2Hz), 7.72-7.85 8.14-8.20 (1H, 8.29-8.35 (1H, m) 99 mg Of the compound was reacted at reflux for 3 hours under the nkrogen atmosphere in trifluoroacetic acid (2 ml)-chloroform (2 ml) solution. The solvent was distilled off under the reduced pressure, the residue was poured into water, extracted with methylene WO 92/19211 PCT/US92/03440 -19chloride, washed with a solution of sodium bicarbonate, dried with sodium sulphate. The solvent was distilled off under the reduced pressure, the residue was purified by silica gel column chromatography (developing solvent: CHCI 3 /MeOH =30/1) to obtain 65 mg of carboxybiphenyl-4-yl)methyl]-2-n-butyl-lH-naphthimidazol-4,9-dione (Compound No. 1: U- 93211), as pale yellow crystal. This has the following NMR spectrum.

6 ppm (CDC13): 0.90 (3H, t, J=7Hz), 1.39 (2H, sextet, J=7Hz), 1.77 (2H, quintet, J=8Hz), 2.84 (2H, t, J=8Hz), 5.81 (2H, 7.23 (2H, d, J=SHz), 7.40-7.33 (3H, 7.48 (1H, ddd, J=8, 8.1Hz), 7.60 (1H, ddd, 8.1Hz), 7.69-7.79 (2H, 8.01 (1H, dd, J=lHz), 8.13- 8.17 (1H, 8.25-8.29(1H, m) Example 2 Preparation of 1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-butyl-lH-naphthimidazol- 4,9-dione (Compound No. 3)

C!

According to the same manner as that described in Example 1, 122 mg (0.5 mmol) of 2-A-butyl-1H-naphthimidazol-4,9-dione and 0.58 mmol of sodium hydride were reacted in 3 ml of dimethylformamide under the nitrogen atmosphere, then 287 mg (0,5 mmol) of triphenylmehtyltetrazol-5-yl)biphenyl-4-yl)methyl bromide was reacted. After the reaction, the similar treatment was carried out, and purified by silica gel column chromatography to obtain 160 mg of l-[(2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-butyl-lHnaphthimidazol-4,9-dione. This has the following NMR spectrum.

6 ppm (CDCI 3 0.88 (3H, t, J=7Hz), 1.33 (2H, sextet, J=8Hz), 1.75 (2H, quintet, J=8Hz), 2.66 (2H, t, J=8Hz), 5.61 (2H, 6.89-6.93 (8H, 7.11 (2H, d, J=8Hz), 7.21-7.34 7.41-7.51 (2H, 7.65-7.76 (2H, 7.89-7.94 (1H. 8.05-8.11 (1H, 8.25-8.28 (1H, m) 160 mg Of the compound was reacted at room temperature for 5 hours in 10% aqueous hydrochloride (0.3 ml)-acetone (3 ml), then the mixture was extracted with chloroform, washed with sodium bicarbonate, and dried with sodium sulphate. The solvent was distilled off under the reduced pressuure, the residue was purified by Slica gel column chromatography (developing solvent: CHCI 3 /MeOH=30/1-10/1) to obtain 98 mg of WO 92/19211 PCT/US92/03440 yl)biphenyl-4-yl)methyl]-2-n-butYl- 1H-naphthimidazol-4,9-dione (Compound No. 3: U-93285) as pale yellow crystals. This has the following NMR spectrum., 6 ppm (CDCI 3 0.80 (3H, t, 1.29 (2H, sextet, J =811z), 1.61 quintet, J =8Hz), 2.66 (2H, t, 3=8Hz), 5.62 (2H, 7.01-7.09 (4H, in), 7,32 (1H, dd, J=8.2Hz), 7.41 (11H, ddd, 3=8, 8.2H1z), 7.49 (1H, ddd, 3=8, 8.2Hz), 7.61-7.67 (2H1, mn), 7.81 (IH1, dd, 1=8.1Hz), 7.98-8.08 (2H, mn) Examples 3 -toIlI According to the same manner as that described in Example 1, various 2-substituted 1H-naphthimidazol-4,9-diones were reacted with (2 '-t-butoxycarbonylbiphenyl-4-yl)methyl bromide and then subjected to hydrolysis to obtain 2-substituted 1-1(2'-carboxybiphenyl-4yl)methyl]-1H-naphthimidazol-4,9-diones, Results are shown in Tables I and 2. All reactions were carried out by using an equivalent molar amount of (2'-t-butoxycarbonylbiphenyl-4-yl)methy bromide relative to the compound [2a] (XI X 2 in the presence of 1.2 equivalent amount of sodium hydride, WO 92/19211 PCr/US92/03440 -21- TABLE 1 Example RI Yield MS(mele) NMR(6ppm) Comp. No, 3 Me 75.7 422 DMSO-d.

6 14 62,45(3H,s), .75(2H,s), 7.24-7.70(8H,m), 7.82-7. 89(2H 8.06-8. 16(2H,rn) 4 Et 77.3 436 DMSO-d 6 16 ai .22(3H,t,J 2.77(211,q,J 5.78(2H,s), 7.20-7.68(8H,m), 7.82-7.86(2H,m), 8.05-8.1 1(2H,mj nPr 71.0 450 CD 3 0D 18 6O.91(3H,t,J 1 .70(2H,sex.,J 2.74(2H,t,J 5.80(2H,s), 7.21-7 .36(5H 7.44(1H,t,J =7,3Hz), 7.54(1H,t,J =7,3Hz), 7.69(1H,t,J =7.8Hz), 7.81-7.88(2H,m), 8.03-8. 12(2H,m) WO 92/19211 PCr/US92/03440 -22- TABLE 2 Comp.

Example RI Yield MS(me/e) NMR(6ppm) No.

6 nPentyl 62.9 478 DMSO-d 6 &0.82(3H,t,J =7Hlz), 1.2 1-1.28(411,m), 1,62-1 ,68(2H,m), 2.76(3H,t,J 5.80(2H,s), 7.2 l-7.35(5H-,m), 7,44(1H,t,] =7,6Hz), 7.55(1H,t,J =7,6Hz), 7,70(IH,d,J ,1Hz), 7,83-7,88(214,m), 8,04-8, 12(2H,m) 7 CF, 63.8 476 12 9phenyl 54.8 484 8 (Ph) 9 benlzyl 29.1 498 DMSO-d 6 (PhCH 2 64.21(211,s), 5,82(2H,s), 7, 17-7.35(9H,m), 7,44(1J-,t,J =7,6Hz), 7.56(11-{,t,J =7.6Hz), 7.70(l H,d,J 7.6Hz), 7,81-7. 88(2H ,m 8,03-8. 12(2H,m)

CH

3 CH=CH- 32.9 448 i4

CH

3 C'mC- 28.6 1 6 Examples 12 Jom 16 According, to the same manner as that described in Example 2, various 2-substituted WO 92/19211 PCr/US92/03440 -23naphthimidazol-4,9-diones and -tripht-nylmethyltetrazoJ-5-yI)biphenyl-4-yl)niethyI bromide were reacted and then the deprotection reac>, a was carried out under strong acid conditions to synthesize 2-substituted 1-[(2'-(tetrazol-5-yI)bi 4'enyIA--yl)methyI])-- H -naph th imid azol -4,9d jones.

Results are shown in Table 3. All reactions were carried out by using an equivalent molar amount of (2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yI)methyl bromide relative to the compound [2a] (Xp=X 2 in the presence of 1,2 equivalent mole amount of sodium hydride, WO 92/19211 PCT/US92/03440 -24- TABLE 3 MS Comp.

Example RI (CA) (me/e) NMR(bppm) No.

12 Me 69.9 446 13 Et 72.2 460 17 14 nPr 39.7 474 CDCI 3 19 0.99(3H,t,J =7Hz), 1.77-1 .93(2H,sex.,J =7Hz), 2.77(2H,t,J =7Hz), 5.74(2H,s), 7. 18(2H,d,J Hz), 7.24(211,d,J 8Hz), 7,39(IH,dd,J =8Hz,J 2Hz), 1-7.59(2H,m), 7.68-7,74(2H,m), 8.09-8, 15(2H,m), 8. 19-8.24(1H,m) nPentyl 17.1 502 CDC1 3 21 0.84(3H,t,J =7Hz), 1 .20-1 .36(4H,m), 1.68-1 ,76(2H,m), 2,72(2H,t,J =8H~z), 5.68(211,s), 7. 10(2H,d,J=8Hz), 7,i6(211,d,J 7.36(1H~ddJ =7Hz,J =2H4z), 7,46-7.57(2H,m) 7.65-7,23(2H,m), 7.86(1HAdJ =84 8.04-8.09(111,m),, 8.14-8, 17(IH,m) 16 CF 3 73.9 500 1-1 13 WO 92/19211 PCT/US92/03440 Examplle 17 Preparation of 1 -1(2'-carboxybiphenyl-4-yl)methyl]-2-n-butyl-5 ,6-dimethyl -1 Hbenzimidazol-4,7-dione (Compound No. 26) 0

N

0 C0 2

P,

N

1000 ing (7.2 mmol) Of 2,3-dimethyl-p-hydroquinone was dissolved i.40 ml of ~etiU.ri~,to this were added 6998 mg (21.5 mmol) of cesium carbonate arJ 2574 mg (15.1 mmo.1) of benzyl broimide and the mixture was heated under reflux for 3.5 hours. After the reaction solution wa s cooled, the precipitate was filtered., and the filtrate was concentrated under the reduced pressure, to obta'in 2257 mg of 2,3-dimethylhydroquinone bisbenzyl ether as town solid (y~'eld 100%), TIhis has the following NMR spectrum, 6 ppm PC)Cl 3 2.24 (611, 5.01 (4H, 6.70 (2H, 7.31-7.46 (10H, m) 2257 mg (7.2 mmol) Of the b ,nzyl ether was suspended in 20 ml of acetic anhydride, and tiiis was cooled to V 0 C. After one drop of conc, sulfuric acid was added, 1.3 ml of nitric acid was added eiropwise, the reaction temperature was roswj to 50' and the rezction mixture was stirred for 22 hours. The reaction solution was cooled to O'C, and water was added to obtain a precipitate which was filtered, and was washed with water and dried under the reduced pressure tW obtain 1915 mg of 2,3,dinethyl-S,6-dlnitrohydroquinone btsbenzy] ether as brown powder (yield Trhis has the follov.ing NMR spectrum, 6 ppm (Cb~C1 3 2.32 (6H, 5.00 (4H, 7.39-7.44 O0H, mn) 1400 rag (3.4 mxnol) Of the diniltro, compound was suspended In 50 nil of methanol, and rther a suspension of 11.9 g (68,4 mmc/i) of sodium dithionite in 50 ml of methanol was added and the mixture was heated under reilux for 4 hours. The reaction mixture was concentrated under the reduced pressure, ice-water was added, anu a pre'lpitate formed was filtered, and this was wasried with water, and dried to obtain 815 mg of 2,3-dimetli:/l-5,6diaminohydroquinone bisbenzyl ether as brown powder (yield 69 Inj. This has the following NMR spectrum.

6 ppm (CDC1 3 2.18 (6H, 4.80 7.35-7.50 (1IOH, mn) To 934 mg (2.7 mmol) of the diamine was adde 457 mg (2,8 mmol) of trimethyl orthonvyalcrate, and the mixture was stireed for 25 mmn at 1000C. Drying under the reduced WO 92/19211 PCT/US92/03440 -26pressure after the reaction gave 1100 mg of 2-n-butyl-4,7-dibenzyloxy-5,6-dimethyl-lHbenzimidazole as brown solid (yield This has the following NMR spectrum.

6 ppm (CDCI 3 0.93 (3H, t, J=7Hz), 1.31-1.39 (2H, 1.59-1.65 (2H, 2.24 (6H, s), 2.72 (2H, t, J=8Hz), 5.24 (4H, bs), 7.34-7.42 (10H, m) 1100 mg (2.6 mmol) Of the benzimidazole was dissolved in 60 ml of methanol, and 150 mg of 10% palladium-carbon was added. The mixture was stirred at room temperature for 22 hours under the atmosphere of 2.2 kg/cm 2 hydrogen. The reaction mixtura was filtered, and the filtrate was stirred at room temperature for 30 min. under the atmospheric pressure, and concentrated under the reduced pressure to obtain 616 mg of 2-n-butyl-5,6-dimethyl-lHbenzimidazol-4,7-dione (Compound 72) as brown solid (yield 100%). This has the following NMR spectrum.

6 ppm (CDCI 3 0.90 (3H, t, J=7Hz), 1.34-1.42 (2H, 1,75-1.86 (2H, 2.07 (6H, s), 2.93 (2H, t, J= 8Hz) 340 mg (1.5 rmmol) Of the benzimidazol-4,7-dione was dissolved in 15 ml of dimehtylformamide, and this was cooled to 0°C. After 65 mg (1.6 mmol) of 60% sodium hydride was added and the mixture was stirred for 30 min. A solution of 503 mg (1.5 mmol) of (2'-t-butoxycarbonylbiphenyl-4-yl)methyl bromide in 2 ml of dimethylformamide was added dropwise and the mixture was stirred for 1 hour. To the reaction mixture was added an aqueous saturated solution of anm onium chloride, and this was extracted with ethyl acetate, The organic layer was washed with an aqueous saturated sodium chloride solution, and this was dried over anhydrous sodium sulphate, and the solvent was distilled off under the reduced pressure. The resultant crude product was purified by silica gel chromatography (ethyl acetate: n-hexane 5:1) to obtain 421 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-n-butyl- 5,6-dimthyl-1H-benzimidazol-4,7-dione as yellow oily material (Yield This has the following N'h4 spectrum.

6 p~oi ).91 (3H, t, J=7Hz), 1.21 (9H, 1.35-1.43 1.76-1.82 (2H, 2.04 (3H, 5.62 (2H, 7.10 (2H, d, J=8Hz), 7.27-7.30 (3H, 7,39-7.42 (1H, 7.45-7.48 (1H, 7.78 (11, dd, J=6, 1Hz) 420 mg (0.8 mmol) Of the ester was dissolved in 20 ml of chloroform, and to this was added 4 ml of trifluoroacetic acid and the mixture was heated under reflux for 2 hours. After the reaction mixture was cooled, an aqueous saturated solution of sodium bicarbonate was added to adjust pH to 8, The organic layer was washed with an aqueous saturated sal'ie solution and dried over anhydrous sodium sulphate, and the solvent was distilled off under the reduced pressure to obtain 370 mg of l-[(2'-carboxybiphenyl-4-yl)methyl]-2-n-butyl-5,6dimethyl-lH-benzimidazol-4,7-dione (Compound No, 26) as yellow powder (yield This has the following NMR spectrum.

WO 92/19211 PCr/US92/03440 -27a ppm (CDCl 3 0.83 (311, t, 3=7Hz), 1.27-1.35 mn), 1.57-1.70 (211, quintet), 2.04 (311, 2.09 (3H1, 2.71 (2H, t, J =8Hz), 5.61 (21H, 7.10 (2H, d, J3=811z), 7.31 (3H, d, J=8Hz), 7.40-7.46 (111, in), 7.55 (1H, dd, J=8, 1Hz), 7.95 (IH, dd, J=8, 1Hz) Example 18 Preparation of 1 '-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-butyl-5 ,6-dimethyl- IH benzimidazol-4,7-dior~e (Comound No, 27) 0

N

0 N=N N 1h 230 mng (1.0 mmol) Of 2-n-butyl-5,6-dimethyl-lH-benzimidazol-4,7-dione obtained according to the same manner as that described in Example 17 and 1.0 minol of sodium hydride were reacted in 18 ml of dimethylformainide at OTC and then 552 mg (1.0 minol) of (2 -triphenylmethyltetrazol -5-yl)biph enyl -4-yl)methyl bromide was reacted. TFhe reaction mixture was poured into water, and this was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulphate. The solvent was distilled off under the reduced pressure, the residue was puriffied by silica gel chromatograpl y (n-hexane:ethyl acetate 1) to obtain 350 mg of 1 1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl]-2-nbutyl-5,6-diinethyl-1H-benzimidazol-4,7-dione as yellow powder (yield This has the following NMR spectrum.

6 ppm (CDCI 3 0.86 (3H1, t, 1=711z), 1.23-1.34 (2H, mn), 1.64-1.72 (2H, in), 2.00 (3H1, s), 2.10 (3H1, 2.60 (2H1, t, J3=8Hz), 5.47 (2H1, 6.85 (2H, d, J3=811z), 6,90~-6.94 (6H, in), 7.10 (2H1, d, 3 =8Hz), 7.22-7.36 (1011, in), 7.42-7.49 (2H, in), 7.90-7.94 (1IH, in) 350 mg (0.5 iniol) Of the benzimidazol-4,7-dione was dissolved in a mixture of 6 ml of methanol and 7 ml of acetone, and to this was added 5 ml of 2N hydrochloric acid and the mixture was stirred at 40*C for 30 min. After the reaction mixture was cooled, this was neutralized with 2N sodium hydroxide to pH6. The reaction mixture was concentrated under the reduced pressure, and extracted with chloroform. After washed with water, this was dried over anhydrous sodiumx sulphate, the solvent was distilled off under the reduced pressure, and the residue was purified by silica gel chromatography (chloroform methanol 100: 1) to obtain 155 mng of '-(tetrazol-5-yl)biphenyl-4.yl)methyl]-2-n-butvl-5,6-dimethvl-IIbenzimidazol-4,7-dione (Compound No. 27) as yelluw powder (yield 6817c). This has the WO 92/19211 PCT/US92/03440 -28following NMR spectrum.

6 ppm (CDC1 3 0.85 (311, t, 1=7Hz), 1.28-1.36 (2H, in), 1.63-1.69 (2H, quintet), 2,03 (3H1, 2.05 (3H, 2.65 (211, t, J1=8Hz), 5.56 (2H1, 7.05 (2H, d, J3=8Hz), 7.15 (2H, d, J=8H1z), 7.37 (111, d, J=8Hz), 7.51-7.57 (2H, mn), 7.99 (IH, d, 3=8Hz) Examples 19 anci 2,3-Dimethyl-5,6-diaminohydroquinone bisbenlzyl ether obtained in Example 17 was reacted with various orthoester and then hydrogenated in the presence of 5% palladium-carbon catalyst. The reaction mixture was stirred in air to obtain the corresponding 2-substituted-5,6dimethyl-IH-benzimidazol-4,7-dione. The results are shown in Table 4.

TABLE 4 Comp. No.

Example R1 Yield MS(me/e) NMR(6ppm) 19 Et 100 204 1,k3tJ=81z,66 2. 09(6H 2.191(2H,q,J 8Hz) n-Pr 100 218 0.97(3H,t,=7Hz), 67 1 .80-1,89(2H,m), 2.07(6H,s), 2.90(2H,t,J =7Hz) 21 n-Pent 37 246 0.88(3H,t,J=7Hz), 68 1.30-1 .40(4H,m), 1 .78-1.83(2H,m), 2.05(6H,s), 2. 87(2H,t,J =7Hz) 22 n-Hex 39 260 0.84(3H,t,i=7H-z), 69 1.26-1 .32(6H,in), 1.79-1 .84(2H,m), 2. 08(6H 2.93(2H,t.J 8Hz) Examples 21 and 22 2,3 -Di'methyl-5,6-d iam inohyd roqu inone bisbenzyl ether obtained in Example 17 was reacted with various acid chlorides in the presence of triethylamine to obtain the corresponding WO 92/19211 PCF /US92/03440 -29monoacylated compound. The monoacylated compound was heated with phosphorous oxychloride in chloroform to obtain the corresponding 2-substiruted-5,6-dimethyl-Hbenzimidazol-4,7-bisbenzyl ether, which was hydrogenated in the presence of 5% palladiumcarbon. The reactioon mixture was stirred in air to obtain the corresponding 2-substituted-5,6dimethyl-lH-benzimidazol-4,7-dione. The results are shown in Table 4.

Example 23 Preparation of l-[(2'-tetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-butyl-5,6-dimethyl-4methoxyimino-1H-benzimidazol-7-one (Compound No. 73) 200 mg (0.43mmol) Of 1-[(2'-tetrazol-5-yl)biphenyl-4-yl)methyll-2-n-butyl-5,6dimethyl-1H-benzimidazol-4,7-dione obtained in Example 18 and 359 mg (0.43 mmol) of methoxylamine hydrochloride were heated and stirred in 3 ml of pyridine at 100°C for 80 min.

The solvent was distilled off under the reduced pressure, the residue was dissolved in chloroform, washed with water, and dried over sodium sulphate. The solvent was distilled off under the reduced pressure, the residue was purified by silica gel chromatography (developer: chloroform/MeOH =40/1) to obtain 196 mg of the titled compound as pale yellow powder (yield This has the following NMR spectrum, and is a mixture of isomers based on syn and anti of an oxime.

Compound Number: 73 6 ppm (CDC1 3 0.79 (3H, t, J=7Hz), 1.24 (2H, sextet, J=7Hz), 1.51 (2H, quintet, J=7Ez), 2.02, 2.07 (3H, two 2.26, 2.44 (3H, two 2.49 (2H, t, J=7Hz), 4.02, 4.04 (3H, c o s), 5.57, 5.65 (2H, two 6.8-7.1 (4H, 7.2-7.6 (3H, 7.9 (1H, m) Example 24 Preparation of 1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-4-methoxyimino-2-n-propyl- 1H-naphthimidazol-9-one (Compound No. According to the same manner as that described in Example 23, the titled compound was synthesized from 1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-propyl-lH-naphthimidazol- 4,9-dione (Compound No. 18) obtained in Example 5. This has the following NMR spectrum.

Compound Number: 6 ppm (CDCI 3 0.85 (3H, t, J=7Hz), 1.60 (2H, sextet, J=7Hz), 2.54 (21, t, J=7Hz), 4.07, 4.17 (3H, two 5.65, 5.73 (2H, two 6.8-8,0 (10H, 8.14, 8.28 (1H, two d, J=7Hz), 8.34, 9.00 (1H, two d, J=8Hz) Example Following the procedures of the preceding examples, the methods of the charts, and analogous procedures well-known to those of ordinary skill in the art, the following compounds are prepared: 29) 1-[(2'-(Tetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-butyl-5.6-dimetho:,y-

H-

WO 92/19211 PCF/US92/03440 benzimidazol-4,7-dione, 33) 1 -1(2V-(Tetrazol -5-y1)biphenyl-y-,l)methyl] -2-n-butyl -5-methyl -6-carboxymeth yl 1H-benzimidazol-4,7-dione, 37) 1 -[(2'-(Tetrazol-5-yI)biphenyl-4-y)methyl]-2-n-butyl-5-methyl-6-carboxy-lHbenzimidazol-4,7-dione, 41) 1 -[(2'-(Tetrazol-5-yI)biphenyl-4-yl)methyl]-2-n-butyl.5-methyl ,Ndimethyl)carbamoyl-1H-benzimidazol-4 ,7-d jone, 53) 1 '-(Tetrazol-5-yl)biphenyl -4-yI)methyl] -2-n-butyl-5-methyl-6-(2carboxy)ethyl-1H-benzimidazol-4,7-dione, 59) 1 -[(2'-(Tetrazol-5-yI)biphenyl -4-yI)methyl ]-2-n-butyl -5 -meth yl-6-(2 hydroxyethyl)-1IH-benzi mid azol-4,7-d ione, 74) 1 -[(2'-(Tetrazol -5-yl)biphenyl-4-yl)methyl)-2-n-butyl-4-ethyI idene- I1-H naphtimidazol-9-one, 1 -[(2'-(Tetrazol-5-yI)biphenyl-4-y)methyl]-2-n-butyl -4-benzylidene- I Hnaphtimidazol-9-one, 76) '-(Tetrazol-5-yI)biphenyl-4-y)methiyl]-2-n-buty-4-(2 ,2dimethyl)propyl idene- I1H-naphtimidazol -9 -one, 77) (2'-(Tetrazol-5-yI)b iph enyl -4-yI)meth yl] -2-n-butyl -4-eth yl idene-5 ,6-d imethyl 1H-benzimidazol-7-one, 78) 1 -[(2'-(Tetrazol -5-yI)b iphenyl -4-y)meth yl ]-2-n-butyl -4-benzyl id ene-5-methyl -6- (2-carboxy)ethyl -1I-1-benzimid azol -7-one, 79) 1 etrazol-5-yl)biphenyl-4-yl)methyl]-2-n-butyl-4-(2 .2dimethyl)propyl idene-5-methyl -6-(2-hydroxy) ethyl-I1 H-benzimidazol-7-one, 1-I(2'-Cretrazol-5-yI)biphenyl-4-yl)methyll-2-n-buty-1 H-naphtimidazol-4,9dione methyihydrazone, 81) 1-[(2'-(Tetrazol-5-yl)biphenyl-4-y)methyl]-2-n-butyl-5,6-dimethy--Ibenzimidazol-4,7-dione phenyihydrazone.

Claims (6)

1. An imidazobenzoquinone represented by the general formula X N R 2 N R 3 (H2)n 0 i\ o wherein R 1 is hydrogen atom, a Cj-C 8 alkyl group, a C 2 -C 8 alkenyl group, a C 2 -C 8 alkynyl group, -CF 3 group, an aryl group or an aralkyl group; X is oxygen atom or a group of the formula N-OR 6 N-NHR 5 or CR 7 R 8 Y is a 1H-tetrazol-5-yl group or an alkali metal salt thereof, a -C0 2 R 4 group, a CONR'R" group or a -CONHSO 2 R 5 group; R 2 and R 3 are independently hydrogen atom, an optionally substituted C 1 -C 8 alkyl group, a C 1 -C 8 alkoxy group, -CN, a -CO 2 R 4 group, a -CONR'R" group or a -CONHSO 2 R 5 group, or R 2 and R 3 together form an optionally substituted aromatic or heterocyclic ring; R 4 is hydrogen atom, alkali metal or a C 1 -C 8 alkyl group; R 5 is a C 1 -C 8 alkyl group, a C 3 -C 1 0 cycloalkyl group or an aryl group; R 6 is hydrogen atom or a C 1 -C 8 alky] group optionally substitue by Y; R 7 and R 8 are independently hydrogen, C 1 -Cg alkyl, C 2 -Cg alkenyl, C 2 -C 8 alkynyl, CF 3 aryl, or aralkyl, or R 7 and R 8 together form an alicyclic structure, R' and R" are independently hydrogen atom or a C 1 -C 8 alkyl group, or R' and R" together form an a'icyclic structure; and n is 0, 1 or 2, or a pharmacologically acceptable ester or salt thereof.

2. A composition for preventing or treating hypertension or congestive heart failure which mprneisas an active ingredient an imidazobenzoquinone represented by the general formula 11): i ^'8 WO 92/19211 PCF/US92/03440 -32- N R2 0~~f wherein RI is hydrogen atom, a CI-C 8 alkyl group, a C 2 -C 8 alkenyl group, a C 2 -C 8 alkynyl group, -CF 3 group, an aryl group or an aralkyl group; X is oxygen atom or N R6 gop Y is a 1H-tetrazol-5-yl group or an alkali metal salt thereof, a -C0 2 R 4 group, a CONR'R" group or a -CONHSO 2 R 5 group; R 2 and R 3 are independently hydrogen atom, an optionally substituted C 1 -C 8 alkyl group, a CI-CB alkoxy group, -CN, a -C0 2 R 4 group, a -CONR'R" group or a -CONHSO 2 R 5 group, or R 2 and R 3 together form an optionally substituted aromatic or heterocyclic ring; R 4 is hydrogen atom, alkali metal or a C 1 -C 8 alkyl group; R 5 is R Cl-C 8 "alkyl group, a C 3 -CIO cycloalkyl group or an aryl group; R 6 is hydrogen atom or a C 1 -C 8 alky, group optionally substituted by Y; R' and R" are independently hydrogen atom or a CI-C 8 alkyl group, or R' and R" together form an alicyclic structure; and n is 0, 1 or 2, or a pharmacologically acceptable ester or salt thereof.

3. A compound of Claim 1, selected from the group consisting of: 1) 1 -[(2'-Carboxybiphenyl-4-yl)methyll-2-n-butyl- 1H-naphthimidazol-4,9-dione, 2) 1 -[(2'-t-Butoxycarbonylbiphenyl-4-yl)methyl]-2-n-butyl- 1l--naphthimidazo1-4,9- dione, 3) 1 -[(2'-(Tetrazole-5-yl)biphenyl-4-yl)methyl]-2-n-buty- 1H-naphthimidazol-4,9- dione, 4) 1-1(2'-Carboxybiphenyl-4-yl)methyl]-2-(l -propen-1I-yl)-I H-naphthimidazol-4,9- dione, 5) 1 -[(2'-(T1etrazol-5-yl)biphenyl-4-yl)methylj-2-( 1-propen- 1 1H- naphthimidazol-4,9-dione, WO 92/19211 PCr/US92/03440 -33- 6) 1 -[(2'-Carboxybiphenyl-4-yl)methyl]-2-(1 -propyn-1-yI)-1H-naphthimidazol-4,9- dione, 7) 1-[(2'-(Tetrazol-5-yl)biphenyl-4-yI)methyl]-2-(- )ropyn- l-yl)- 1H- naphthimidazol-4,9-dGiorie, 8) 1-[(2'-Carboxybiphenyl-4-yl)methyl]-2-pheny]-IH-naphthimidazol-4,9-dione, 9) 1 -[(2'-(Tetrazol-5-yI)biphenyl-4-yI)methyl]-2-phenyl-1H-naphthimidazol-4,9- dione, 14[(2 '-Carboxybiphenyl-4-yl)methyl-2-benzyl- 1H-naphthimidazol-4,9-dione, 11) 1 -[(2'-(Tetrazol-5-yl)biphenyl-4-yI)methyl]-2-benzyl- 1H-naphthimidazol-4,9- dione, 12) 1 Carboxybiphenyl-4-yI)methyli-2-trifluoromethyl-1 H-naphthimidazol-4,9- dione, 13) 1 -[(2'-(Tetrazol-5-yI)biphenyl-4-yI)methyll-2-trifluoromethyl- 1H-naphthimidazol- 4,9-dione, is 14) 1 -[(2'-Carboxybiphenyl-4-yl)methyl]-2-methyl-1H-naphthimidazol-4,9-dione, 1-[(2'-(Tetrazo-5-y)biphenyl-4-yl)methyl]-2-methylI-H-naphthimidazol-4,9- dione, 16) 1-[(2'-CparboxybiplienyI-4-yl)methyl]-2-ethylI-H-naphthiniidazol-4,9-dione, 17) 14[(2'-(Tetrazol-5-yl)biphenyl-4-y)rnethyl]-2-ethyl- 1H-naphthirnildazol-4,9- dione, 18) 1 -[(2'-Carboxybiphenyl-4-y)methyl]-2-n-propyl-H-naphthinida.ol-4,9-dione, 19) 1-[(2'-(Tetrazo1-5-yI)biphenyI-4-yI)rnethyI]-2-n-propylI-H-naphiimidazoI-4,9- dione, 1-[(2'-Carboxybiphenyl-4-yl)methylj-2-n-pentyl- 1H-naphthimidazol-4,9-dione, 21) 1-I(2'-(1'etrazol-5-yl)biphenyl14-y)metw1]j-2-n-penty1- IH-naphthimidazol-4,9- dione, 22) 1 '-(Tetrazo1-5-yI)biphenyIA4-yI)methyI]-2-n-hexyl- 1H-naphthimidazol-4,9- dione, 23) 1 '-Carboxybiphenyl-4-yl)methyl]-2-n-butyl-5 ,8-dimethoxy- IH- naphthimidazol-4,9-dione, 24) 1-[(2'-Tetrazol-.5-yI)biphenyl-4-yl)methyl]-2-n-butyl-6,7-dimethyl-1 H- naphthimidazol-4,9-dione, 1 (2'-Carboxyb iphenyl -4-yl)methyl ]-2-n-butyl-I 1 H-benzi mid azol -4,7 -d ione, 26) 1 -[(2'-Carboxybiphenyl-4-yl)methyl]-2-n-butyl-5 ,6-dimethyl- 1I-benzimidazol- 4,7-dione, 27) 1 -[(2'-(Tetrazol-5-yI)biphenyl-4-y!)methyl]-2-n-butyl-5,6-dimethyl- IH WO 92/19211 PCT/US92/03440 -34- ben7zimidazol-4,7-dione, 28) 1 -[(2'-Carboxybiphenyl-4-yl)methyll-2-n-butyl -5,6-dirnethoxy- I1H-benzimidazol- 4,7-dione, 29) 1-[(2'-(TetrazoI-5-y1)biphenyl-4-yl)methyfl-2-n-butyI -5,6-d imethoxy- 1 H- benzimidazol-4,7-dione, 1 '-Carboxybiphenyl-4-yl)methyl] -2-n-butyl-5 ,6-dihydroxymethyl- ,H- 1benziiidazo-4,7-dione, 31) 1 etrazol-5-yl)biphenylA4-yI)methyl]-2-n-butyl-5 ,6-dihydroxymethyl- 1H- benzimidazol-4,7-dione, 32) 1 -[(2'-Carboxybiphenyl-4-yl)methyl]-2-n-butyl-5-methyl -6-carboxymethyl-1 H- benzimidazo1-4,7-dione, 33) 1-[(2'-(Tetrazol-5 -yl)b iphenyl -4-yI)methyl -n-bu tyl -5-methyl -6-carboxym ethyl[. 1H-benzimidazol-4,7-dione, 34) 1 -,(2'-Carboxybipheny-4-yl)methylJ-2-n-butyI-5-carboxymethyl-6-methyl- 1H- benzimidazol-4,7-dione, 1 -(Tetrazol-5-yl)biphenyl-4-yI)methyl]-2-n-butyl-5-carboxymethyl-6&rnethyl- IH-benziinidazoI-4,7-dione, 36) 1 -[(2'-Carboxybiphenyl-4-yl)methyII-2-n-butyl-5-methyl -6-carboxy- 1 benzimidazol-4,7-dione, 37) 1 d(2'-(Tetrazol-5-y)biphenyl-4-y)nlethyll-2-n-butyl-5-methyl-6-carboxy- iIH- benzimidazol-4,7-dione, 38) 1 '-Carboxybipheny-4-y)methy]-2-n-buty-5-carboxy-6-methyl- 1H- benzirnidazol-4,7--dione, 39) 1 '-(etrazol-5-yl)biphenyl-4-y)methyl]-2-n-butyl-5-carboxy-6-methyl- 1H- benzimiddazol-4,7-dione, 1 -Caxboxybiphenyl-4'y)methyI]-2-n-butyI-5-methyl-6-(N, N- dimethyl)carbarrnoyl-IH-benzimidazol-4,7-dione, 41) '-(Tetrazol-5-yI)biphenyl-4--y)methyfl-2-n-butyl-5-niethyl-6-(N,N- dimethyl)carbamoyl-1H-benzimidazol-4,7-dione, 42) 1-((2'-Carboxybiphenyl-4-yI)methyll-2-n-butyl-5-(N ,N-dimethyl)carbamoyl-6- methyl-1H-benzimidazol-4,7-dione, 43) 1 '-(Tetrazol-5-yl)biphenyl-4-yI)methyl]-2-n-butyl ,N dimethyl)carbanioyl-6-methyl-I H-benzimidazol-4,7-dione, 44) *1-[(2'-C.arboxybiphenyl-4y)methyl-2-i-butyl-5-methyl-6-cyano- 1- benzimidazol-4,7-d ion e, 1 '-(Tetrazol-3-yl)biplienyI-4-yl)meahyII-2-n-butyI-5-methy-6-cyano- 1H- WO 92/19211 PCr/US92/03440 benzimidazol-4,7-dione, 46) 1-[(2'-Carboxybiphenyl-4-yl)methyl]-2-n-butyl-5-cyano-6-methyl- H- benzimidazo1-4,7-dione, 47) 1 -[(2'-(Tetrazol-5-y!)biphenyl -4-yl)methyl]-2-n-butyl-5-cyano-6-methyl-l11- benzimidazol-4,7-dione, 48) 1-[(2'-Carboxybiphenyl-4-yI)methyll-2-n-butyl-5,6-dicyano-1 H-benzimidazol- 4,7-dione, 49) 1-[(2'-(-1etrazol-5-yI)biphenyl-4-yl)methyl]-2-n-butyl-5 ,6-dicyano- 1H- benzimidazol-4,7-dione, 50) 1 '-Carboxybiphenyl-4-yl)nethyfl-2-n-butyl-5-methyl-6-(N- methanesulfonyl)carbamoyl-1 H-benzimidazol-4,7-dione, 51) 1-[(2'-(Tetrazol-5-yI)biphenyI-4-y)methyl]-2-n-buty-5-methyI-6-(N- xnethanesulfonyl)carbamoyl-1H-benzimidazol-4,7-dione, 52) 1-[(2'-Carboxybiphenyl-4-yI)methyI]-2-n-buty-5-methy-6-(2-carboxy)ethyl- 11- benzimidazol-4,7-dione, 53) 1-[(2'-(Tetrazol-5-yI)biphenyl-4-yl)methyl]-2-n-butyl-5-methyl-6-(2- carboxy)ethyl-1H-benzimidazol-4,7-dione, 54) 1 '-Carboxybiphenyl-4-yI)methyl]-2-n-butyl-5-methyl-6-(3-carboxy)propyl- IH-benzimidazol-4,7-dione, 55) 1 -(Tetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-butyl-5-methyl-6-(3- carboxy)propyl-IH-benziniidazol-4,7-dione, 56) 1-1(2 '-Carboxybiphenyl -4-yl)mcthyl] -2-n-butyl -5-methyl-6-(4-carboxy)butyl-I1H- benzimidazol-4,7-dione, 57) 1 '-(Tetrazol-5-yl)biphienyl-4-yl)niethyl]-2-n-butyl-5-methyl-6-(4- carboxy)butyl-1H-benzimid.azol-4,7-dione, 58) 1-[(2'-Carboxybiphenyl-4-yl)methyl]-2-n-butyl-S-methyl-6-(2-hydroxyethyl)-IH- benzimidazol-4,7-dione, 59) 1-[(2'-(Tetrazol-5-yl)biphenyl-4-yI)methyl]-2-n-butyl-5-methyl-6-(2- hydroxyethyl)-1H-benzimidazol-4,7-dione, 60) 1-[(2'-Carboxybiphenyl-4-yI)methyl]-2-n-butyl-5-methyl-6-(3-hydroxypropyl)- 1H-benzimidazol-4,7-di!one, 61) 1. j(2'-(Tetrazol-5-yl)bipheny-4-yl)methyl-2-n-buty-5-methy-6-(3- hydroxypropyl)- 1H-benzimidazol-4,7-dione, 62) '-Carboxybiphenyl-4-yI)methyl]-2-n-butyl-5-methyl-6-(4-hydtoxybutyl)- 1H- bf.-nzimidazol-4,7-dione, 63) 1 -[(2'-(Tetrazol-5-yl)biphenyl-4-yI)methyfl-2-n-butyl-5-methyl-6-(4- WO 92/19211 PCr/US92/034e4O -36- hydroxybutyl)-iH-benzimidazol-4,7-dione, 64) 1-[(2'-(Tetrazol -5-yl)biphenyl-4-yI)methyl] 1 H-naphth imidazol ione, 1-[(2'-(N-Methanesulfonyl)carbamoylbiphenyl-4-y)methyl]-2-n -butyl- 1 H- naphthimidazol-4,9-dione, 66) 1-[(2'-(Tetrazol-5-yl)biphenyl-4--yl)methyl]-2-ethyl-5,6-d imethyl- I H- benziniidazol-4,7-d jone, 67) 1 -I(2'-Cretrazol -5-yI)biphenyl -4-yl)rnethyfl -2-n-p ropy] -5,6-dimethyl- 1 H- benzimidazol-4 ,7-dione, 68) 1-[(2'-(Tetrazol-5-yl)biphenyl -4-yI)methyl]-2-n-pentyl-5 ,6-d imethyl- I H benzimidazol-4,7-dione, 69) 1 -[(2'-(T-etrazol-5-yl)biphenyl-4-yl)metbyl]-2-n-hexyl-5,6-dimethyl-1H- benzimidazol-4,7-dione, 1-[K2'-Cfetrazol-5-yI)biphenyl-4-yI)methyll-4-rnetho7xyirniino-2-n-propyl- 1H- naphthimidazol-9-one, 71) '-t(2'-(Tetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-butyl-4-methoxyimino- 1H- naphthimidazol-9-one, 72) 1 -[(2'-(Tetrazol-5-yI)biphenyl-4-yI)methyl]-5,6-dimethyl-4-metboxyimino-2-n propyl-1H-benzimidazol-7-one, 73) 1-[(2'-(Tetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-butyl-5,6-dimethyl-4- methoxyimino-IH-benzirnidazol-7-one, 74) 1 -[(2'-(Tetrazol-5-yI)biphenyl-4-yl)methyl]-2-n-butyl-4-ethyl idene- 1H naphtimidazol-9-one, 1-f(2 '-(Tetrazol-5-yI)biphenyl-4-yl)methyl]-2-n-butyl-4-benzyl idene-1 H- naphtimidazol-9-one, 76) 14[(2-('erazol-5-y1)biphenyl-4-y1)methy1)-2-n-butyl-4-(2 ,2- dimethyl)propylidene-1H-naphtimidazol-9-one, '77) 1 -I(2'-{fetrazol-5-ylbiphenyl-4-yl)methyl]-2-n-butyl-4-ethyl idene-5 ,6-dimethyl- 1H-benzimidazol-7-one, 78) 1-[(2'-Cretrazol-5-yI)biphenyl-4-yI)methyl]-2-n-butyl-4-benzyl idene-$5-methyl-6- (2-carboxy)ethyl-IH-benzimidazol-7-one, 79) 1-[(2'-(Tetrazol-5-yi)b iphenyl-4-yI)m ethyl) -2-n-bu tyl d Imethyl)propyl idene-5 -methyl -6-(2-hydroxy)ethy -I 1H-benzitnid azo 1-7 -one, 1-[(2'-(Tetrazol-5-yI)biphenyl-4-yI)methyll-2-n-butyl- 1H-naphtimidazoI-4.9- dione methyihydrazone, aM~ 81) 1-f(2'-Cretrazol-5-yl)biphenyI-4-yI)methyII-2-n-buty-5,6-dimethy-I H- benzimidazol-4,7-dione phenyihydrazone. WO 92/19211 PCT/US92/03440 -37- C, fNs a

4. A composition of Claim 2, coempff"sifg-a compound of Claim A compound of Claim 1, wherein P1 is C 3 -C 7 alkyl; X is oxygen; Y is a IH-tetrazol-5-yl group or an alkali metal salt thereof or -Co 2 H; and n is 1,

6. A compound of Claim 5, selected from: 1-[(2'-(Tetrazol-5-yl)biphenyl-4-yl)methyl]-2-n-propyi 1IH-naphtimidazol-4,9-dione; 1-[(2'-(Tetrazol-5-yl)biphienyl-4-yl)methylj-2 -butyl-1 H-naphtimidazol-4,9-dione; 1-[(2'{retrazol-5-yl)biphenyl-4-yl)methyl]-2-n-butyl- 1H-5,6-dimet 1 -H-benzimidazol-

7-oine; and 14[(2 '-(Tetrazol-5-yl)biphenyl-4-yilmethyl]-2-n-pentyl- IH-S ,6-dimethyl -1H- benzimidazol-7-one, INTERNATIONAL SEARCH REPORT International Application No OCT/US 92/03440 I. QASSIFICATION a? SUBJECT NATTER (if saviazi cassification Symbols apply, indcate all)' According to Lnternullonal Patent assfcation (IC or to both National Cassilicatlon and WPC Int.Cl 5 C070235/02; A61K31/415; C1070235/08; C07D403/10 A61K31/41 HI. FIEWS SEAMCED Minimum Documentation S -Xchedl Classification System Classification Symbols Int.C1. 5 C07D A61K Documentation Searched other than Mlnimumn Docuwitno to the Extent that such Documents are Included In the Fields SearchedO MI. DOC1JMDETS CONSIDERED TO HE 7Z. Aif 1 Categoy 0 C itation of Document 11 0ith tadicaiton, where appropriate, of the relevant passages Relevant to Claim No 13 A EPA,fj 209 707 (DR. KARL THOMAE GMBH) 28 January 1987 A EP,A,0 400 835 (MERCK CO. INC.) December 1990 P,A EP,A,D 426 021 (FUJISAWA PHARMACEUTICAL CO.,LTD.) 8 May 1991 A EP,A,0 400 974 (NERCK CO. INC.) December 1990 cited in the application 1Speci categories of cited documents T lamgor document p i'afntor the lntemiaioa1 fiing (ate or priority date and not In conflict rith the application 'but document defIIg the general State Of A11e art Which IS not cited to M dustand the principle or theory WndWting the con~sidered to be of particular relevanve invention earlier document but publishei on at after the lnt.onational 'X document of particular reliwnce; the claimed Invention filing date cannot be considered siovel or cannot We considered to OL' documeent which may throw doubts on priortty clim(s) or Involve A Inventive step which Is cited to establish the publication date of anotlwe document of pirticuaW relevance; thr claimed inventlnn citation or other specal reason (as specified) cannot be coasidered to Involve a Inventive Step when the 'Oo document referring to an oral Eis~osurv, use, ehibition or document 4n comnbined with one or more other such docit- other mzans meats, such comblination Walg obvious to a pwAn sWiled TO1 document published prior to the international filing date but in the art later than the priority date claimed Wa document member of the same patent family 1 a~o th~h A~o of thc,1010rn4sdona.1 Search Date off Mafln u" thinternatiotial SearchReOMrt 06 N0VEMB6 t L-992,%i29 Intornational Searching AuthorMty [aw"u of Authorizedl omle" EUROPUAN PATENT OP111CE DE BUYSER I.A.F .r3 ifm MCIISAJ21O tmocn shoWI IJ 7 103) ANNEX TO THE INTERNATIONAL SEARCH REPORT 9 ON INTERNATIONAL PATENT APPLICATION NO. US 9203440 SA 64970 This annex Uts the patwnt family members relating to the patent documents cited in the above-mendtioned international sarch report. The o r.bers are as contain td in the European Patent Oficz EDP file on The Ei opean Patent Ofcce is in no way liable for these particlars which are merely given for the purpose of information. 06/11/92 Patent document Publication Patent family Publication cited in sear,;h report 'jate member(s) date EP-A-0209707 28-01-87 DE-A- 3522230 02-01-87 AU-A- 5893286 4L -12-86 JP-A- 62000471 (6-01-87 EP-A-0400835 05-12-90 CA-A- 2016710 15-11-90 JP-A- 3027362 05-02-91 EP-A-0426021 08-05-91 AU-A- 6560390 09-05-91 CN-A- 1051358 15-05-91 JP-A- 3188076 16-08-91 JP-A- 3184976 12-08-91 EP-A-0400974 05-12-90 AU-A- 5602490 06-12-90 CA-A- 2017773 30-11-90 CN-A- 1048546 16-01-91 JP-A- 3095181 19-04-91 US 5102880 07-04-92 0 or more detal about ts annex Of Joual of the oean PA Offi No. 1282 For more dtals about thsP uaex s!E Offil Journal of the EUro~ean Ftc"t. Office, No. 12/lIZ