Bicycle derivatives, their preparation and use

Details Bicycle derivatives, their preparation and use Bicycle derivatives, their preparation and use

1996-06-06

1997-12-02

Bond, Robert T.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514258, 544279, 544285, 540502, 540506, A61K 3155, A61K 31505, C07D48704, C07D47104

Patent

active

056936370

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP 94/03980, filed 30 Nov. 1994 which claims priority of German application P 43 41 6659 filed Dec. 7, 1993.
The present invention relates to novel bicycle derivatives, their preparation and use in therapy.
Endothelin is a peptide which is composed of 21 amino acids and is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. "Endothelin" or "ET" hereinafter means one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a powerful effect on vascular tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332, 411.gtoreq.415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).
Elevated or abnormal release of endothelin causes persistent vasoconstriction in peripheral, renal and cerebral blood vessels, which may lead to disorders. It has been reported in the literature that elevated endothelin levels have been found in the plasma of patients with hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, atherosclerosis and in the airways of asthmatics (Japan J. Hypertension, 12, 79 (1989), J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990)).
Accordingly, substances which specifically inhibit the binding of endothelin to the receptor ought also to antagonize the various abovementioned physiological effects of endothelin and therefore represent valuable drugs.
We have found that certain bicycle derivatives have good endothelin-antagonistic activity.
The invention relates to bicycle derivatives of the formula I ##STR2## where 2 of the radicals A, B, D and E are CH groups and the 2 other radicals are CH groups or nitrogen atoms, phenyl-C.sub.1-4 -alkyl, naphthyl or naphthyl-C.sub.1-6 -alkyl which is unsubstituted or substituted on the aromatic radical by C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, halogen, CF.sub.3, NO.sub.2 or CN, or C.sub.2-6 -alkenyl or C.sub.2-6 -alkynyl, C.sub.3-7 -cycloalkyl or one of the groups --NHR.sup.4, --NR.sup.4.sub.2, --OR.sup.4, --SO.sub.2 NHR.sup.4, --SO.sub.2 NR.sup.4.sub.2, --COR.sup.4 or --CO.sub.2 R.sup.4 (with R.sup.4 meaning C.sub.1-4 -alkyl, phenyl, phenyl-C.sub.1-4 -alkyl, naphthyl or naphthyl-C.sub.1-4 -alkyl), or ##STR3## (where Z.sup.3 has one of the meanings indicated for Z.sup.1, and M is a CH.sub.2 or NH group), C.sub.1-6 -alkyl, or a phenyl, benzyl, naphthyl or naphthylmethyl group which is unsubstituted or substituted in the aryl moiety by C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, halogen, CF.sub.3, NO.sub.2 or CN), ##STR4## L is an alkylene, alkenylene or alkynylene group with, in each case, up to 6 C atoms or one of the groups ##STR5## (with R.sup.3 meaning hydrogen, C.sub.1-4 -alkyl, benzyl or naphthylmethyl), ##STR6## (with Q meaning C.sub.1-6 -alkyl, aryl or CH.sub.2 --R.sup.7 where R.sup.7 is phenyl or hetaryl) or ##STR7## R.sup.1 is --CO.sub.2 R.sup.4 (with R.sup.4 meaning hydrogen, C.sub.1-4 -alkyl or benzyl), --CONR.sup.4.sub.2, --OR.sup.4, --SR.sup.4, --SO.sub.3 R.sup.4, --PO.sub.3 R.sup.4.sub.2 or tetrazolyl, and ##STR8## (with R.sup.5 and R.sup.6 meaning hydrogen, C.sub.1-4 -alkyl, --OR.sup.4 or --SR.sup.4) or hetaryl, acids.
Preferred compounds of the formula I are those where one or more of the moieties A, B, D, E, G, K, L, R.sup.1, R.sup.2, Z.sup.1 and Z.sup.2 have the following meanings: ##STR9## R.sup.1 --COOH R.sup.2 ##STR10## (R.sup.3 .dbd.H, C.sub.1-3 -alkyl, --CHO, --COO--C.sub.1-3 -alkyl), ##STR11## Z.sup.1 C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl, C.sub.2-6 -alkynyl, --NH--CO--C.sub.2-5 -alkyl ##STR12## which is linked to B and D and is substituted by one of the radicals mentioned as preferred for Z.sup.1.
The compounds of the formula I are obtained, if E is nitrogen, by the following route: with an amine of the formula III results firstly in IV. Ring closure with an activated derivative of carbonic acid affords the compounds of the formula V. Alkylation of the amide nitrogen leads to the comp

REFERENCES:
patent: 5403836 (1995-04-01), Blackburn et al.
JAMA, Dec. 12, 1990-vol. 264, No. 22.
J. Vascular Med. Bio. 2, 207, 1990.
Biochemical and Biophy. Res. Comm., vol. 154, No. 3, 1988, pp. 868-875.
Feb, vol. 231, No. 2, 440-444, Apr. 1988 Nature, vol. 332, Mar. 31, 1988.

Affiliated with

Also associated with

Rating

Bicycle derivatives, their preparation and use does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Bicycle derivatives, their preparation and use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bicycle derivatives, their preparation and use will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-801432