Title:
PRODRUG COMPOUNDS AND PROCESS FOR PREPARATION THEREOF
Document Type and Number:
WIPO Patent Application WO2000033888
Kind Code:
A3
Abstract:
The compound of the invention is a prodrug form of a therapeutic agent linked directly or indirectly to an oligopeptide, which in turn, is linked to a stabilizing group. More generally, the present invention may be described as a new prodrug compound of a therapeutic agent, especially prodrugs comprising an antitumor therapeutic agent, displaying improved therapeutic properties relative to the products of the prior art, especially improved therapeutic properties in the treatment of cancerous tumors and/or in the treatment of inflammatory reactions such as rheumatic diseases. Improved therapeutic properties include decreased toxicity and increased efficacy. Particularly desired are prodrugs which display a high specificity of action, a reduced toxicity, an improved stability in the serum and blood, and which do not move into target cells until activated by a target cell associated enzyme. Prodrug compounds of a marker enabling tumors to be characterized (diagnosis, progression of the tumor, assay of the factors secreted by tumor cells, etc.) are also contemplated. The present invention also relates to the pharmaceutical composition comprising the compound according to the invention and optionally a pharmaceutically acceptable adjuvant or vehicle. Further, a method of decreasing toxicity by modifying a therapeutic agent to create a prodrug is disclosed. Several processes for creating a prodrug of the invention are described. Compounds of the invention include the prodrugs, Suc-ssAla-Leu-Ala-Leu-Dox, Suc-ssAla-Leu-Ala-Leu-Dnr, and Glutaryl-ssAla-Leu-Ala-Leu-Dox. Additionally intermediate compounds, important to the process of preparation of the prodrugs of the invention are claimed.
Inventors:
LOBL THOMAS J (US)
DUBOIS VINCENT (BE)
FERNANDEZ ANNE-MARIE (BE)
GANGWAR SANJEEV (US)
LEWIS EVAN (US)
NIEDER MATTHEW H (US)
TROUET ANDRE (BE)
VISKI PETER (US)
YARRANTON GEOFFREY T (US)
DUBOIS VINCENT (BE)
FERNANDEZ ANNE-MARIE (BE)
GANGWAR SANJEEV (US)
LEWIS EVAN (US)
NIEDER MATTHEW H (US)
TROUET ANDRE (BE)
VISKI PETER (US)
YARRANTON GEOFFREY T (US)
Application Number:
PCT/US1999/030393
Publication Date:
November 08, 2001
Filing Date:
December 10, 1999
Export Citation:
Assignee:
COULTER PHARM INC (US)
LOBL THOMAS J (US)
DUBOIS VINCENT (BE)
FERNANDEZ ANNE MARIE (BE)
GANGWAR SANJEEV (US)
LEWIS EVAN (US)
NIEDER MATTHEW H (US)
TROUET ANDRE (BE)
VISKI PETER (US)
YARRANTON GEOFFREY T (US)
LOBL THOMAS J (US)
DUBOIS VINCENT (BE)
FERNANDEZ ANNE MARIE (BE)
GANGWAR SANJEEV (US)
LEWIS EVAN (US)
NIEDER MATTHEW H (US)
TROUET ANDRE (BE)
VISKI PETER (US)
YARRANTON GEOFFREY T (US)
International Classes:
A61K31/138; A61K31/165; A61K31/198; A61K31/337; A61K31/407; A61K31/437; A61K31/4745; A61K31/513; A61K31/519; A61K31/52; A61K31/5517; A61K31/555; A61K31/7004; A61K31/7028; A61K31/7048; A61K31/7064; A61K31/7068; A61K33/24; A61K47/42; A61K47/48; A61P29/00; A61P35/00; C07K5/10; C07K7/00; (IPC1-7): A61K47/48; A61P35/00
Domestic Patent References:
| WO1996005863A1 | 1996-02-29 | |||
| WO1998052966A1 | 1998-11-26 |
Foreign References:
| EP0037388A2 | 1981-10-07 | |||
| EP0475230A1 | 1992-03-18 | |||
| EP0640622A1 | 1995-03-01 |
Other References:
MASQUELIER, M. ET AL: "Incorporation and binding of anthracycline derivatives to low density lipoprotein: in vitro and in vivo studies on drug-LDL conjugates", RECENT ADV. CHEMOTHER., PROC. INT. CONGR. CHEMOTHER., 14TH, VOLUME ANTICANCER SECT. 1, PAGES 311-12. EDITOR(S): ISHIGAMI, JOJI. PUBLISHER: UNIV. TOKYO PRESS, TOKYO, JAPAN., XP000914544
KING, H. DALTON ET AL: "Synthesis and proteolytic cleavage of 3'-N- peptidyl -adriamycin prodrugs", PEPT.: CHEM., STRUCT. BIOL., PROC. AM. PEPT. SYMP., 11TH, MEETING DATE 1989, PAGES 137-9. EDITOR(S): RIVIER, JEAN E.;MARSHALL, GARLAND R. PUBLISHER: ESCOM SCI. PUB., LEIDEN, NETH., XP000914543
TROUET A ET AL: "A COVALENT LINKAGE BETWEEN DAUNORUBICIN AND PROTEINS THAT IS STABLE IN SERUM AND REVERSIBLE BY LYSOSOMAL HYDROLASES AS REQUIRED FOR A LYSOSOMOTROPIC DRUG CARRIER CONJUGATE IN-VITRO AND IN-VIVO STUDIES", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1982, vol. 79, no. 2, 1982, pages 626 - 629, XP002029566, ISSN: 0027-8424
UMEMOTO N ET AL: "PREPARATION AND IN-VITRO CYTOTOXICITY OF A METHOTREXATE-ANTI-MM46 MONOCLONAL ANTIBODY CONJUGATE VIA AN OLIGOPEPTIDE SPACER", INTERNATIONAL JOURNAL OF CANCER 1989, vol. 43, no. 4, 1989, pages 677 - 684, XP000120606, ISSN: 0020-7136
DE MARRE ANNE ET AL: "Evaluation of the hydrolytic and enzymatic stability of macromolecular Mitomycin C derivatives.", JOURNAL OF CONTROLLED RELEASE 1994, vol. 31, no. 1, 1994, pages 89 - 97, XP000456583, ISSN: 0168-3659
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MASQUELIER, M. ET AL: "Antitumor activity of daunorubicin linked to proteins: biological and antitumor properties of peptidic derivatives of daunorubicin used as intermediates", XP002139800, retrieved from STN Database accession no. 97:150635 HCA
MASQUELIER, MICHELE ET AL: "Amino acid and dipeptide derivatives of daunorubicin. 1. Synthesis, physicochemical properties, and lysosomal digestion", J. MED. CHEM., 1980, VOL. 23, NO. 11, PAGE(S) 1166-70, XP000914522
WALDMANN H ET AL: "ENZYMATIC PROTECTING GROUP TECHNIQUES", CHEMICAL REVIEWS,US,AMERICAN CHEMICAL SOCIETY. EASTON, vol. 94, no. 4, 1 June 1994 (1994-06-01), pages 911 - 937, XP000450393, ISSN: 0009-2665
ABOUD-PIRAK E ET AL: "CYTOTOXIC ACTIVITY OF DAUNORUBICIN OR VINDESINE CONJUGATED TO A MONOCLONAL ANTIBODY ON CULTURED MCF-7 BREAST CARCINOMA CELLS", BIOCHEMICAL PHARMACOLOGY 1989, vol. 38, no. 4, 1989, pages 641 - 648, XP000914578, ISSN: 0006-2952
KING, H. DALTON ET AL: "Synthesis and proteolytic cleavage of 3'-N- peptidyl -adriamycin prodrugs", PEPT.: CHEM., STRUCT. BIOL., PROC. AM. PEPT. SYMP., 11TH, MEETING DATE 1989, PAGES 137-9. EDITOR(S): RIVIER, JEAN E.;MARSHALL, GARLAND R. PUBLISHER: ESCOM SCI. PUB., LEIDEN, NETH., XP000914543
TROUET A ET AL: "A COVALENT LINKAGE BETWEEN DAUNORUBICIN AND PROTEINS THAT IS STABLE IN SERUM AND REVERSIBLE BY LYSOSOMAL HYDROLASES AS REQUIRED FOR A LYSOSOMOTROPIC DRUG CARRIER CONJUGATE IN-VITRO AND IN-VIVO STUDIES", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1982, vol. 79, no. 2, 1982, pages 626 - 629, XP002029566, ISSN: 0027-8424
UMEMOTO N ET AL: "PREPARATION AND IN-VITRO CYTOTOXICITY OF A METHOTREXATE-ANTI-MM46 MONOCLONAL ANTIBODY CONJUGATE VIA AN OLIGOPEPTIDE SPACER", INTERNATIONAL JOURNAL OF CANCER 1989, vol. 43, no. 4, 1989, pages 677 - 684, XP000120606, ISSN: 0020-7136
DE MARRE ANNE ET AL: "Evaluation of the hydrolytic and enzymatic stability of macromolecular Mitomycin C derivatives.", JOURNAL OF CONTROLLED RELEASE 1994, vol. 31, no. 1, 1994, pages 89 - 97, XP000456583, ISSN: 0168-3659
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MASQUELIER, M. ET AL: "Antitumor activity of daunorubicin linked to proteins: biological and antitumor properties of peptidic derivatives of daunorubicin used as intermediates", XP002139800, retrieved from STN Database accession no. 97:150635 HCA
MASQUELIER, MICHELE ET AL: "Amino acid and dipeptide derivatives of daunorubicin. 1. Synthesis, physicochemical properties, and lysosomal digestion", J. MED. CHEM., 1980, VOL. 23, NO. 11, PAGE(S) 1166-70, XP000914522
WALDMANN H ET AL: "ENZYMATIC PROTECTING GROUP TECHNIQUES", CHEMICAL REVIEWS,US,AMERICAN CHEMICAL SOCIETY. EASTON, vol. 94, no. 4, 1 June 1994 (1994-06-01), pages 911 - 937, XP000450393, ISSN: 0009-2665
ABOUD-PIRAK E ET AL: "CYTOTOXIC ACTIVITY OF DAUNORUBICIN OR VINDESINE CONJUGATED TO A MONOCLONAL ANTIBODY ON CULTURED MCF-7 BREAST CARCINOMA CELLS", BIOCHEMICAL PHARMACOLOGY 1989, vol. 38, no. 4, 1989, pages 641 - 648, XP000914578, ISSN: 0006-2952
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