Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1994-04-22
1995-08-15
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544238, 544240, 548254, C07D23726, C07D23732, C07D25704
Patent
active
054420628
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of international application PCT/US92/08584, filed 14 Oct. 1992, which claims the benefit of Japanese Patent Application Ser. No. 216809/92, filed 14 Aug. 1992, Japanese Patent Application Ser. No. 095191/92, filed 15 Apr. 1992, Japanese Patent Application Ser. No. 323474/91, filed 7 Dec. 1991, and Japanese Patent Application Ser. No. 277537/91, filed 24 Oct. 1991.
FIELD OF THE INVENTION
The present invention relates to a novel imidazole derivative or a pharmacologically acceptable ester or salt thereof and a pharmaceutical composition for preventing or treating hypertension, congestive heart failure, renal failure, glaucoma or hyperuricemia which contains the same as an active ingredient.
BACKGROUND OF THE INVENTION
It is widely known that Renin-Angiotensin-Aldosterone system is closely connected with hypertensive pathogenesis through control of blood pressure and the water/electrolyte balance. 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 of the system, ii) renin-inhibition of the conversion of the renin substrate (angiotensinogen) to angiotensin (I), iii) inhibition of the angiotensin converting enzyme (ACE) which converts angiotensin (I) into angiotensin (II) having strong vasoconstriction action, aldosterone secretion stimulating action, sympathetic nerve function promoting action and the like, iv) blockade of angiotensin (II) receptor, v) activation of angiotensinase to accelerate the degradation of the produced angiotensin (II).
Among them, the study of ACE inhibitors is most advanced, and many drugs have been 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 side effects such as skin rash and dry cough occur frequently. For this reason, many attempts to develop a renin inhibitor which is thought to be more selective have been tried but none have been successfully marketed.
On the other hand, since salarasin obtained by modifying the terminal part of angiotensin (II) has been found to have the antagonism to the receptor of angiotensin (II) by D. T. Pals et al., the study on a receptor antagonist (hereinafter referred to as Ang-II antagonist) has begun. Studies are directed to search for a nonpeptidic compound without partial agonist activity which can be administered orally, and has long-lasting action. The first reports are found in JP-A 54-148788, JP-A 56-71073, JP-A 57-98270 and JP-A 58-157768, but the pharmacological activity is about 1/10000 of the practical level. An increase in this activity to a practical level was first reported in EP-A 0253310 and EP-A 0291969, and the compound called as Dup753 is currently in clinical tests. ##STR2##
However, since this compound is usually produced as a mixture of regio-isomers (where the ratio depends on the reaction conditions), 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 has been recognized that an addition of a hydrophilic group on the 5-position of the imidazole ring is effective for increasing the pharmacological activity. This working hypothesis was compelled to be significantly modified by the finding of benzimidazoles shown in EP-A 039231717 (also reported in EP-A 0400835 and EP-A 0399732 later) and imidazopyridines (see EP-A 0399731, EP-A 0400974 and EP-A 01415886). ##STR3##
In addition, the present inventors have found that imidazobenzoquinones shown by the following formula have higher angiotensin (II) antagonist action and also have the vasodepressor activity in vivo tests, and filed a patent application (Japanese patent application No
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Fujita Yoshiji
Itoh Noriie
Koh Keiko
Kunihara Mineo
Kushida Hiroshi
Lambkin Deborah
Raymond Richard L.
The Upjohn Company
Welch Lawrence T.
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