Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-06-20
1998-10-27
Lambkin, Deborah C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514406, 5462754, 5463641, 548119, 548252, 5483741, 5483751, A01K 3144, C07D40100, C07D75700, C07F 906
Patent
active
058278630
DESCRIPTION:
BRIEF SUMMARY
This application is a national stage application based on PCT/EP95/03086, which was filed on Aug. 2, 1995.
FIELD OF THE INVENTION
The present invention relates to new pyrazole derivatives which are potent angiotensin II antagonists. The invention also relates to a process for their preparation, to the pharmaceutical compositions containing them and to their use for the manufacture of medicaments for the treatment or prevention of hypertension, congestive heart failure, elevated intraocular pressure and other diseases or medical conditions in which the action of angiotensin II is implicated.
DESCRIPTION OF THE PRIOR ART
The renin-angiotensin system (RAS) plays a key role in the regulation of blood pressure and volume homeostasis. Activation of the renin-angiotensin cascade begins with renin secretion from the juxtaglomerular apparatus of the kidney and culminates in the formation of the octapeptide angiotensin II.
Angiotensin II exerts its biological effects via interactions with specific receptors present in many tissues. Two basic types of angiotensin II receptors have been characterized so far, both with a broad distribution: the AT.sub.1 receptors, responsible for the majority of effects attributed to this peptide, and the AT.sub.2 receptors, the functional role of which has not yet been identified.
The main effects of angiotensin II are the regulation of blood pressure through vasoconstriction thereby effecting an increase in vascular resistances, the regulation of volemia through the stimulation of the release of vasopressin and particularly aldosterone, which induces saline retention, and the regulation of the adrenocorticotropic hormone (ACTH). Angiotensin II can act as a neuropeptide at the central nervous system and can play a modulating function in the release of other neurotransmiters.
Furthermore, it has been described that the administration of angiotensin II to either the rat brain dorsal neostriatum or the lateral ventricle produces alterations in the rat cognitive responses. This fact suggests that probably angiotensin II is involved in several cerebral processes related with the learning function, memory and the like.
One of the possible modes of interfering with the RAS is to block the action of angiotensin II at the receptor level. Although several peptidic analogues of angiotensin II having greater affinity for its receptors than angiotensin II itself have been discovered, their therapeutic use has been severely limited by their lack of bioavailability and short duration of action.
More recently, several nonpeptide angiotensin II receptor antagonists have been reported in the literature. Patent applications EP 253310 and WO 93/05025 disclose compounds related to those described in the present invention.
DESCRIPTION OF THE INVENTION
The present invention relates to novel pyrazoles of general formula I: ##STR2## wherein: R.sub.1 represents hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, aryl, or --(CH.sub.2).sub.m COR.sub.5 ; C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4 alkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxyC.sub.1-4 alkyl, aryl or arylC.sub.1-4 alkyl; --(CH.sub.2).sub.p COR.sub.7 ; the remaining groups represent CR, wherein each R independently represents hydrogen, halogen, C.sub.1-4 alkyl, hydroxy, C.sub.1-4 alkoxy, nitro, amino, C.sub.1-4 alkylamino or C.sub.1-4 dialkylamino; tetrazol-5-ylmethyl; --CONH(tetrazol-5-yl); --CONHSO.sub.2 R.sub.9 ; --CONHSO.sub.2 --Het; --CONHOR.sub.8 ; --CONH.sub.2 ; --CONR.sub.8 R.sub.9 ; --COCH.sub.2 COR.sub.8 ; --COCH.sub.2 CO.sub.2 R.sub.8 ; --CONHNHSO.sub.2 R.sub.9 ; --CONHNHCONH.sub.2 ; --CH.sub.2 NHSO.sub.2 R.sub.9 ; --CH.sub.2 CO.sub.2 R.sub.8 ; --CH.sub.2 SO.sub.2 NHCOR.sub.8 ; --CH.sub.2 SO.sub.2 NHCONHR.sub.8 ; --CH.sub.2 CONHSO.sub.2 R.sub.9 ; --CH.sub.2 SO.sub.2 NH--Het; --CH.sub.2 NHCOR.sub.8 ; --NHSO.sub.2 R.sub.9 ; --NHCOR.sub.8 ; --NHCONHSO.sub.2 R.sub.9 ; --NHSO.sub.2 NHCOR.sub.8 ; --SO.sub.3 H; --SO.sub.2 NHR.sub.8 ; --SO.sub.2 NHCONH.sub.2 ; --SO.sub.2 NHCONR.sub.8 R.sub.9 ; --SO.sub.2 NHCO
REFERENCES:
patent: 5298519 (1994-03-01), Binder et al.
patent: 5389659 (1995-02-01), Ross et al.
Middlemiss et al., "C-Linked Pyrazole Biaryl Tetrazoles as Antagonists of Angiotensin II," Bioorganic & Medicinal Chemistry Letters, vol. 2, No. 10, pp. 1243-1246, 1992.
Almansa Carmen
Batroli Javier
Carceller Elena
Gonzalez Concepcion
Torres M. Carmen
J. Uriach & Cia S.A.
Lambkin Deborah C.
Murray Joseph
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