Prodrugs their preparation and use as pharmaceuticals
First Claim
1. A compound of the formula I
in whichglycosyl 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 substituentsR are, independently or identically, H, methyl, methoxy, carboxyl, methyloxycarbonyl, CN, hydroxyl, nitro, fluorine, chlorine, bromine, sulfo, sulfamoyl or (C1-4)-alkylsulfamoyl andp is 0 or 1n is an integer,X is O, NH, methyleneoxy, methyleneamino or methylene(C1-4)-alkylamino andY is O or NH, anddrug 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.
Y)--X--!.sub.p --W(R).sub.n --X--C(═
Y)--drug(I)
1 Assignment
0 Petitions
Accused Products
Abstract
Glycosyl-spacer-drugs compounds (prodrugs), their preparation and their use as pharmaceuticals are described.
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Citations
16 Claims
- 1. A compound of the formula I
- space="preserve" listing-type="equation">glycosyl--Y --C(═
Y)--X--!.sub.p --W(R).sub.n --X--C(═
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 (C1-4)-alkylsulfamoyl and p is 0 or 1 n is an integer, X is O, NH, methyleneoxy, methyleneamino or methylene(C1-4)-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. - View Dependent Claims (2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16)
- 8. A pharmaceutical composition for the treatment of diseases in which intracellular enzymes are released or made accessible by cell damage comprising an effective amount of a compound as claimed in claim 1 and a pharmaceutically acceptable carrier.
- 9. The composition as claimed in claim 8, wherein the pharmaceutically acceptable carrier protein.
- 10. The composition as claimed in claim 8, wherein the composition further comprises a compound which breaks multiple drug resistance.
- 11. The composition as claimed in claim 9, wherein the carrier protein is human serum albumin or human acid alpha-1 glycoprotein.
- 12. The composition as claimed in claim 10, wherein the compound which breaks up multiple drug resistance is cyclosporin A, R-verapamil, pentoxifylline or rapamycin.
- 13. A compound as claimed in claim 5 wherein the drug is doxorubicin, 4'"'"'-epidoxorubicin, or 4- or 4'"'"' deoxydoxorubicin.
- 14. A compound as claimed in claim 1 wherein the drug is selected from the group consisting of etoposides, N,N-bis(2-chloroethyl)4-hydroxyaniline, 4-hydroxycyclophosphamide, vindesine, vinblastine, vincristine, terfenadine, terbutaline, fenoterol, salbutamol, muscarine, oxyphenbutazone, salicylic acid, p-aminosalicyclic acid, 5-fluorouracil, 5-fluorouridine, 5-fluorocytidine, methotrexate, diclofenac, flufenamic acid, 4-methylaminophenazone, theophylline, nifedipine, mitomycin C, mitoxantrone, camptothecin, m-AMSA, taxol, nocodazole, colchicine, cyclophosphamide, rachelmycin, cisplatin, melphalan, bleomycin, nitrogen mustard, phosphoramide mustard, verrucarin A, neocarcinostatin, calicheamicin, dynemicin, esperamicin A, quercetin, genistein, erbstatin, tyrphostin, rohitukin derivative, retinoic acid, butyric acid, phorbol ester, DMSO, aclacinomycin, progesterone, buserelin, tamoxifen, mifepristone, onapristone, N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide, pyridinyloxazol-2-one, quinolyl-, isoquinolyloxazol-2-one, staurosporine, ethanolamine, verapamil, forskolin, 1,9-dideoxyforskolin, quinine, quinidine, reserpine, methyl 18-O-(3,5-dimethoxy4-hydroxybenzoyl)reserpate, lonidamine, buthionine-sulfoximin, diethyl dithiocarbamate, cyclosporin A, rapamycin, azathioprine, chlorambucil, hydroxycrotonamide derivateive 2, 15-deoxyspergualine, FK 506, ibuprofen, indomethacin, aspirin, sulfasalazine, penicillamine, chloroquine, dexamethasone, prednisolone, mefenamic acid, paracetamol, 4-aminophenazone, muskosine, orciprenaline, isoprenaline, amiloride, p-nitrophenyl guanidinobenzoate and their derivatives additionally substituted by one or more hydroxyl, amino or imino groups, where the drug already has a hydroxyl, amino or imino group.
- 15. A method for the treatment of diseases in which intracellular enzymes are released or are made accessible by cell damage which comprises administering to a host in need of said treatment a pharmaceutical composition as claimed in claim 8.
- 16. A method for the treatment of diseases in which intracellular enzymes are released or are made accessible by cell damage which comprises administering to a host in need of said treatment an effective amount of a compound of the formula I as claimed in claim 1.
- space="preserve" listing-type="equation">glycosyl--Y --C(═
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7. 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)benzylaminocarbonyl!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!doxorubicin, 9-O- 4-beta-D-glucuronyloxy)-3-chlorobenzyloxycarbonyl)quinine and methyl 18-O- 3,5-dimethoxy4- 4-(beta-D-glucuronyloxy)-3-chlorobenzyloxycarbonyl!benzoyl!reserpate.
Specification