Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-01-17
1997-12-30
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530330, 530331, A61K 3800, C07K 500
Patent
active
057030502
DESCRIPTION:
BRIEF SUMMARY
This application is a 37, of PCT/EP 94/00713 filed Mar. 9, 1994.
FIELD OF THE INVENTION
The present invention relates to substituted ureas and thioureas, their preparation and their use as medicines, in particular as inhibitors of blood platelet aggregation.
DESCRIPTION OF THE RELATED ART
EP-A 449 079 and EP-A 530 505 describe hydantoin derivatives which have platelet aggregation-inhibiting effects. Structurally related urea derivatives are mentioned in WO-A 92 13552 and EP-A 512 829. Further investigations showed that the urea derivatives of the present invention are also potent inhibitors of blood platelet aggregation.
SUMMARY OF THE INVENTION
The present invention relates to urea derivatives of the general formula I ##STR2## in which r denotes an integer from 0 to 3; ; -C.sub.14)-aryl-(C.sub.1 -C.sub.8)-alkoxy, which can also be substituted in the aryl radical, optionally substituted (C.sub.6 -C.sub.14)-aryloxy, amino or mono- or di-((C.sub.1 -C.sub.18)-alkyl)amino; integer from 1 to 4, or ##STR3## in which n and p independently of one another stand for an integer from 0 to 4; integer from 1 to 4, or --NR.sup.b --CHR.sup.s --CO--, in which R.sup.s denotes an amino acid side chain, or ##STR4## in which n stands for an integer from 0 to 4, or ##STR5## in which s and t independently of one another can stand for an integer from 0 to 5, but the sum of s and t must be a number between 2 and 5. but where, if R stands for hydrogen, r denotes the number 1 and A stands for --(CH.sub.2).sub.k --NR.sup.a --, in which k stands for an integer from 2 to 4, or for ##STR6## in which p is other than 0, then B cannot simultaneously stand for --NR.sup.b --(CH.sub.2).sub.m --CO--, in which m stands for the numbers 1 or 2; (C.sub.1 -C.sub.18)-alkyl. (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.8)-alkyl, hydroxycarbonyl-(C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkoxycarbonyl-(C.sub.1 -C.sub.6)-alkyl, (C.sub.6 -C.sub.14)-aryloxycarbonyl-(C.sub.1 -C.sub.6)-alkyl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.6)-alkoxycarbonyl-(C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.28)-alkoxy, (C.sub.6 -C.sub.14)-aryloxy, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.8)-alkoxy, (C.sub.1 -C.sub.6)-alkylcarbonyloxy, (C.sub.1 -C.sub.6)-alkoxycarbonyloxy, (C.sub.6 -C.sub.14)-aryloxycarbonyloxy or (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.6)-alkoxycarbonyloxy, where the aryl radicals can also be substituted; -C.sub.6)-alkylcarbonyl, (C.sub.1 -C.sub.6)-alkoxycarbonyl, (C.sub.1 -C.sub.18)-alkylcarbonyloxy-(C.sub.1 -C.sub.6)-alkoxycarbonyl, optionally substituted (C.sub.6 -C.sub.14)-arylcarbonyl, optionally substituted (C.sub.6 -C.sub.14)-aryloxycarbonyl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.6)-alkoxycarbonyl, which can also be substituted in the aryl radical, cyano, hydroxyl, (C.sub.1 -C.sub.6)-alkoxy or amino or a radical of the formula II -C.sub.6)-alkyl, trifluoro-(C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkoxycarbonyl, (C.sub.1 -C.sub.6)-alkylcarbonyl, optionally substituted (C.sub.6 -C.sub.14)-arylcarbonyl, (C.sub.1 -C.sub.18)-alkylcarbonyloxy-(C.sub.1 -C.sub.6)-alkoxycarbonyl, optionally substituted (C.sub.6 -C.sub.14)-aryloxycarbonyl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.6)-alkoxycarbonyl, which can also be substituted in the aryl radical, cyano, hydroxyl, (C.sub.1 -C.sub.6)-alkoxy or amino; -C.sub.6)-alkynyl, phenyl or a mono- or bicyclic up to 8-membered heterocyclic ring, which can be aromatic, partially hydrogenated or completely hydrogenated and which can contain one, two or three identical or different heteroatoms from the series nitrogen, oxygen and sulphur, where the (C.sub.1 -C.sub.4)-alkyl and the phenyl can be unsubstituted or mono- or polysubstituted by identical or different radicals from the series hydroxyl, amino, (C.sub.1 -C.sub.4)-alkoxy, imidazolyl, indolyl, pyrrolidinyl, hydroxypyrrolidinyl, phenyl or halogen and the heterocyclic ring can be unsubstituted or mono- or poly-substituted by identical or different radicals from the series (C.sub.1 -C.sub.18)-alkyl, phenyl, phenyl-(C.sub.1 -C.s
REFERENCES:
patent: 5051405 (1991-09-01), Klein et al.
patent: 5053392 (1991-10-01), Klein et al.
patent: 5272162 (1993-12-01), Tjoeng et al.
patent: 5314902 (1994-05-01), Tjoeng et al.
patent: 5389614 (1995-02-01), Konig et al.
Effect of RGD Peptide on Cell Adhesion, by Kumagai et al., Biomedical and Biophysical Research Comm., vol. 177, No. 1 (1991), pp. 74-82.
A novel Arg-Gly-Asp Containing Peptide, etc, by Isoai et al., Cancer Letters, vol. 65, pp.255 to 263, (1992), Elsevier Pub. Ireland.
Modulation of Vitronectin Receptor-Mediated Osteoclast Adhesion, etc., Horton et al., Journal of Bone & Mineral Research, vol. 8, No. 2, pp. 239-247 (1993).
Synthetic Peptide Containing Arg-Gly-Asp Inhibits Bone Formation, etc., by Gronowicz et al., Journal of Bone & Mineral Research, vol. 9, No. 2, pp. 193 to 201 (1994).
Breipohl Gerhard
Jablonka Bernd
Just Melitta
Klingler Otmar
Knolle Jochen
Celsa Bennett
Hoechst Aktiengesellschaft
Tsang Cecilia J.
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