Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-06-06
1999-03-16
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514252, 514253, 544 8, 544239, A61K 3154, A01N 4358, C07D28516, C07D23700
Patent
active
058830901
DESCRIPTION:
BRIEF SUMMARY
This is a 371 application of PCT/EP96/04111, filed on Sep. 19, 1996.
The invention relates to compounds of the formula I ##STR2## in which Y is --C(R.sup.4 R.sup.4')C(R.sup.4 R.sup.4'), --CR.sup.4 .dbd.CR.sup.4' -- or C(R.sup.4 R.sup.4)S--, ##STR3## which is unsubstituted or mono- or disubstituted in the phenyl moiety by A, R.sup.3, OR.sup.4, NH.sub.2, NHA, NA.sub.2, NO.sub.2, CN, Hal, NHCOR.sup.4, NHSO.sub.2 R.sup.4, COOR.sup.4, COR.sup.4, CONHSO.sub.2 R.sup.6, O(CH.sub.2).sub.n R.sup.3, OPh, O(CH.sub.2).sub.n OR.sup.4 or S(O).sub.m R.sup.4 or ##STR4## which is unsubstituted or mono- or disubstituted in the cyclohexyldienyl moiety by A, R.sup.3, OR.sup.4, NH.sub.2 , NHA, NA.sub.2, NO.sub.2, CN, Hal, NHCOR.sup.4, NHSO.sub.2 R.sup.4, COOR.sup.4, COR.sup.4, CONHSO.sub.2 R.sup.6, O(CH.sub.2).sub.n R.sup.3, OPh, O(CH.sub.2).sub.n OR.sup.4 or S(O).sub.m R.sup.4, trisubstituted by A, OR.sup.5, NH.sub.2, NHA, NA.sub.2, NO.sub.2, CN or Hal, replaced by O or S atoms or by --CR.sup.4 .dbd.CR.sup.4, groups and also 1-7 H atoms can be replaced by F, or is benzyl, trisubstituted by A, OR.sup.4, NH.sub.2, NHA, NA.sub.2, NO.sub.2, CN, Hal, NHCOR.sup.4, NHSO.sub.2 R.sup.4, COOR.sup.4, COR.sup.4, CONHSO.sub.2 R.sup.6, O(CH.sub.2).sub.n R.sup.3, OPh, O(CH.sub.2).sub.n OR.sup.4 or S(O).sub.m R.sup.4, having 1 to 4 N, O and/or S atoms, bonded via N or C, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, R.sup.3, NH.sub.2, NHA, NA.sub.2, CN, NO.sub.2 and/or carbonyl oxygen,
Similar compounds having indan and indene parent structures are disclosed in WO 93/08799, those with indole systems are disclosed in WO 94/14434, pyrimidine derivatives are disclosed in EP 0 526 708 A1 and phenyl and naphthyl compounds are disclosed in EP 0 617 001 A.
The invention was based on the object of finding novel compounds having useful properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their salts have very useful pharmacological properties combined with good tolerability. In particular, they exhibit endothelin receptorantagonistic properties and can therefore be employed for the treatment of illnesses such as hypertension, cardiac insufficiency, coronary heart disease, renal, cerebral and myocardial ischaemia, renal insufficiency, cerebral infarct, subarachnoid haemorrhage, arteriosclerosis, pulmonary high blood pressure, inflammations, asthma, prostate hyperplasia, endotoxic shock and in complications after the administration of immunosuppressants, such as, for example, cyclosporin, which can produce renal vasoconstriction, as well as other illnesses associated with endothelin activities.
The compounds exhibit, inter alia, a high affinity for the endothelin subreceptors ET.sub.A and ET.sub.B. These actions can be determined by customary in vitro or in vivo methods, such as, for example, described by P. D. Stein et al., J. Med. Chem. 37, 1994, 329-331 and E. Ohlstein et al., Proc. Natl. Acad. Sci. USA 91, 1994, 8052-8056.
A suitable method for the determination of the hypertensive action is, for example, described by M. K. Brazil et al., J. Cardiovasc. Pharmacol. 22, 1993, 897-905 and J. Lange et al., Lab Animal 20, 1991, Appl. Note 1016.
The compounds of the formula I can be employed as pharmaceutical active compounds in human and in veterinary medicine, in particular for the prophylaxis and/or therapy of cardiac, circulatory and vascular diseases, especially of hypertension and cardiac insufficiency.
The invention relates to the compounds of the formula I and their salts, and to a process for the preparation of these compounds and their salts, characterized in that ##STR5## in which R.sup.1 and Y have the meaning indicated in Claim 1, ##STR6## in which Q is Cl, Br, I or a free or reactive functionally modified OH group and R.sup.2 and/or R.sup.3 are converted into one or more radicals R.sup.1, R.sup.2 and/or R.sup.3, by, for example,
In the above formulae, A has 1 to 6, preferably 1, 2, 3 or 4 carbon atoms. A is preferably methyl, fur
REFERENCES:
patent: 2832780 (1958-04-01), King et al.
Christadler Maria
Dorsch Dieter
Mederski Werner
Osswald Mathias
Schmitges Claus Jochen
Merck Patent Gesellschaft mit beschrankter Haftung
Ngo Tamthom T.
Raymond Richard L.
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