Prodrugs their preparation and use as pharmaceuticals
AssigneesBehringwerke Aktiengesellschaft, Laboratories Hoechst S/A
InventorsKlaus Bosslet, Jorg Czech, Dieter Hoffmann, Cenek Kolar, Fran.cedilla.ois Tillequin, Jean-Claude Florent, Michel Azoulay, Claude Monneret, Jean-Claude Jacquesy, Jean-Pierre Gesson, Michel Koch
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Abstract
Glycosyl-spacer-drugs compounds (prodrugs), their preparation and their use as pharmaceuticals are described.
Claims16
A compound of the formula I
- glycosyl--Y--C(.dbd.Y)--X--!.sub.p --W(R).sub.n --X--C(.dbd.Y)--drug(I)
- in which
- glycosyl is a poly-, oligo- or monosaccharide which can be cleaved off enzymatically,
- W is an aromatic or heteroaromatic or aliphatic group with conjugated double bonds or an amino-acid derivative which cyclizes after elimination of the glycosyl radical, in which the substituents
- R are, independently or identically, H, methyl, methoxy, carboxyl, methyloxycarbonyl, CN, hydroxyl, nitro, fluorine, chlorine, bromine, sulfo, sulfamoyl or (C.sub.1-4)-alkylsulfamoyl and
- p is 0 or 1
- n is an integer,
- X is O, NH, methyleneoxy, methyleneamino or methylene(C.sub.1-4)-alkylamino and
- Y is O or NH, and
- drug is a compound which is linked via a hydroxyl, amino or imino group and has a biological effect, except anthracyclines linked via a 3'-amino group when p=0.
A compound selected from the group consisting of 4'-O-4-(Alpha-D-glucopyranosyloxy)phenylaminocarbonyl!etoposide, 4'-O-4-(beta-D-galactopyranoxyloxy)phenylaminocarbonyl!etoposide, 4'-O-4-(beta-D-glucuronyloxy)phenylaminocarbonyl!etoposide, 4'-O-(beta-D-glucuronyloxy)-3-nitrobenzylaminocarbonyl!etoposide, 4'-O-4'-(beta-D-glucuronyloxy)-3-chlorobenzylaminocarbonyl!etoposide, 1-N-4-(beta-D-gluocuronyloxy)benzyloxycarbonyl!mitomycin C, 14-O-4-(beta-D-glucuronyloxy)-3-nitrobenzylaminocarbonyl!doxorubicin, 4-O-4-(beta-D-glucuronyloxy)benzylaminocarbonyl!4-hydroxy-N, N-bis(2-chloroethyl)aniline,4-O-4-(beta-D-glucuronyloxy)benzylaminocarbon yl!terfenadine, 3'-O-4-(beta-D-glucuronyloxy)benzylaminocarbonyl!terbutaline, 3'-O-4-(beta-D-glucuronyloxy)benzylaminocarbonyl!fenoterol, 1"-O-4-(beta-D-glucuronyloxy)benzylaminocarbonyl!salbutamol, 3-O-4-(beta-D-glucuronyloxy)benzylaminocarbonyl!muscarine, 4'-O-4-(beta-D-glucuronyloxy)benzylaminocarbonyl!oxyphenbutazone, 2-O-4-(beta-D-glucuronyloxy)benzylaminocarbonyl!salicylic acid, N-4-(beta-D-glucuronyloxy)benzyloxycarbonyl!diclofenac, N-4-(beta-D-glucuronyloxy)benzyloxycarbonyl!flufenamic acid, 4-N-4-(beta-D-glucuronyloxy)benzyloxycarbonyl!-4-methylaminophenazone, 7-N-4-(beta-D-glucuronyloxy)benzyloxycarbonyl!theophylline, 1-N-4(beta-D-glucuronyloxy)benzyloxycarbonyl!nifedipine, 4-(beta-D-glucuronyl)-3-nitrobenzyl 2-1 -cyano-1-(N-4-trifluoromethylphenyl)carbamoyl!propen-1-yl carbonate, N-4-(Alpha-D-galactopyranosyloxy-carbonylamino)benzyloxycarbonyl!doxorubi cin, 9-O-4-beta-D-glucuronyloxy)-3-chlorobenzyloxycarbonyl)quinine and methyl 18-O-3,5-dimethoxy4-4-(beta-D-glucuronyloxy)-3-chlorobenzyloxycarbonyl!b enzoyl!reserpate.
Dependencies are inferred from the claim text.