Prodrugs their preparation and use as pharmaceuticals

• US 5,955,100 A
• Filed: 05/24/1995
• Issued: 09/21/1999
• Est. Priority Date: 10/27/1992
• Status: Expired due to Term

• Current Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Original Assignee: Laboratories Hoechst S A, Behringwerke Aktiengesellschaft (Sanofi )
• Inventors: Bosslet, Klaus, Florent, Jean-Claude, Monneret, Claude, Koch, Michel, Czech, Jorg, Jacquesy, Jean-Claude, Kolar, Cenek, Hoffmann, Dieter, Gesson, Jean-Pierre, Azoulay, Michel, Tillequin, Fran.cedilla.ois
• Primary Examiner(s): Peselev, Elli
• Application Number:
  US08/449,021
• Time in Patent Office: 1,581 Days
• Field of Search: 536/6.4, 536/18.1, 536/1.1, 536/4.1, 536/6.5, 549/266, 530/322, 514/25, 514/34, 514/23, 514/2, 514/8, 424/450
• US Class Current: 424/450
• CPC Class Codes: A61K 47/50 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 13/08 having the esterifying carboxyl radicals directly attached to carbocyclic rings
• CPC Class Codes: C07H 13/12 by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
• CPC Class Codes: C07H 15/203 Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Glycosyl-spacer-drugs compounds (prodrugs), their preparation and their use as pharmaceuticals are described.

Claims

1. A compound of the formula I

View Dependent Claims (2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16)

2. A compound as claimed in claim 1, wherein

W is an aromatic or heteroaromatic group or an aliphatic group with conjugated double bonds or an amino-acid derivative residue which cyclizes after elimination of the glycosyl radical and has 5-20 carbon atoms and 0-4 heteroatoms, where heteroatom means N, O or S, to which substituents can be bonded, and

R, p, n, X, Y and drugs are as defined in claim 1.

3. A compound as claimed in claim 1, wherein

W is a phenyl radical or a polysubstituted phenyl 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_1-4) alkylsulfamoyl,

n is 1 to 4 and

p, X, Y and drugs are as defined in claim 1.

4. (Amended) A compound as claimed in claim 3, wherein

W is a phenyl radical or a monosubstituted phenyl radical in which one of the substituents

R is methoxy, methyloxycarbonyl, CN, hydroxyl, nitro, fluorine, chlorine, bromine, sulfo or sulfamoyl, and the others are hydrogen.

5. A compound as claimed in claim 1, wherein the drug is an anthracycline which is not linked by 3'"'"'-amino groups when p=0 .

6. A process for the preparation of a compound according to formula I in claim 1, which comprises reacting a phenyl glycoside of the formula II

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.

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.