Title:
HIV PRODRUGS CLEAVABLE BY CD26
Document Type and Number:
WIPO Patent Application WO2004099135
Kind Code:
A3
Abstract:
The present invention provides new prodrugs which are conjugates of a therapeutic compound and a peptide wherein the conjugate is cleavable by dipeptidyl-peptidases, more preferably by CD26, also known as DPPIV (dipeptidyl aminodipeptidase IV). The present prodrugs have the formula (I), the stereoisomeric forms and salts thereof, wherein n is I to 5; Y is proline, alanine, hydroxyproline, dihydroxyproline, thiazolidinecarboxylic acid (thioproline), dehydroproline, pipecolic acid (L-homoproline), azetidinecarboxylic acid, aziridinecarboxylic acid, glycine, serine, valine, leucine, isoleucine and threonine; X is selected from any amino acid in the D- or L-configuration; X and Y in each repeat of [Y-X] are chosen independently from one another and independently from other repeats; Z is a direct bond or a bivalent straight or branched saturated hydrocarbon group having from 1 to 4 carbon atoms; R<1> is an aryl, heteroaryl, aryloxy, heteroaryloxy, aryloxyC1-4alkyl, heterocycloalkyloxy, heterocycloalkylC1-4akloxy, heteroaryloxyC1-4alkyl, heteroarylC1-4alkyloxy; R<2> is arylC1-4alkyl; R<3> is C1-10alkyl, C2-6alkenyl or C3-7cycloalkyIC1-4alkyl; R<4> is hydrogen or C1-4alkyl. The present invention furthermore provides the use of said prodrugs as medicines as well as a method of producing said prodrugs.
Inventors:
DE KOCK HERMAN AUGUSTINUS (BE)
WIGERINCK PIET TOM BERT PAUL (BE)
BALZARINI JAN (BE)
WIGERINCK PIET TOM BERT PAUL (BE)
BALZARINI JAN (BE)
Application Number:
PCT/EP2004/050753
Publication Date:
February 17, 2005
Filing Date:
May 10, 2004
Export Citation:
Assignee:
TIBOTEC PHARM LTD (IE)
DE KOCK HERMAN AUGUSTINUS (BE)
WIGERINCK PIET TOM BERT PAUL (BE)
BALZARINI JAN (BE)
DE KOCK HERMAN AUGUSTINUS (BE)
WIGERINCK PIET TOM BERT PAUL (BE)
BALZARINI JAN (BE)
International Classes:
A61K47/48; C07D493/04; C07H15/252; C07K5/06; C07K5/062; C07K5/065; C07K5/068; C07K5/072; C07K5/083; C07K5/103; C07K5/11; C07K5/113; C07K7/06; C07K9/00; A61K38/00; (IPC1-7): A61K47/48; C07D473/00; C07H15/252
Domestic Patent References:
| WO1997045117A1 | 1997-12-04 | |||
| WO2000071571A2 | 2000-11-30 | |||
| WO1999067278A1 | 1999-12-29 | |||
| WO2003048190A2 | 2003-06-12 | |||
| WO1999067254A2 | 1999-12-29 |
Foreign References:
| US5962216A | 1999-10-05 |
Other References:
BALAJTHY Z ET AL: "SYNTHESIS AND FUNCTIONAL EVALUATION OF A PEPTIDE DERIVATIVE OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 35, no. 18, 1992, pages 3344 - 3349, XP002939110, ISSN: 0022-2623
TROUET A ET AL: "Extracellularly tumor - activated prodrugs fo the selective chemotherapy of cancer: application to doxorubicin and preliminary in vitro and in vivo studies", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, BALTIMORE, MD, US, vol. 61, no. 7, 1 April 2001 (2001-04-01), pages 2843 - 2846, XP002204750, ISSN: 0008-5472
MASQUELIER M ET AL: "AMINO ACID AND DIPEPTIDE DERIVATIVES OF DAUNORUBICIN. 1. SYNTHESIS,PHYSICOCHEMICAL PROPERTIES, AND LYSOSOMAL DIGESTION", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 23, no. 11, 1980, pages 1166 - 1170, XP000914522, ISSN: 0022-2623
ANAND BANMEET ET AL: "Novel dipeptide prodrugs of acyclovir for ocular herpes infections: Bioreversion, antiviral activity and transport across rabbit cornea.", CURRENT EYE RESEARCH. 2003 MAR-APR, vol. 26, no. 3-4, March 2003 (2003-03-01), pages 151 - 163, XP009036464, ISSN: 0271-3683
AUGUSTYNS K ET AL: "THE UNIQUE PROPERTIES OF DIPEPTIDYL-PEPTIDASE IV (DPP IV/CD26) AND THE THERAPEUTIC POTENTIAL OF DPP IV INHIBITORS", CURRENT MEDICINAL CHEMISTRY, BENTHAM SCIENCE PUBLISHERS BV, BE, vol. 6, no. 4, 1999, pages 311 - 327, XP000870290, ISSN: 0929-8673
YARON A ET AL: "PROLINE-DEPENDENT STRUCTURAL AND BIOLOGICAL PROPERTIES OF PEPTIDES AND PROTEINS", CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY, CRC PRESS, BOCA RATON, FL, US, vol. 28, no. 1, 1993, pages 31 - 81, XP000925565, ISSN: 1040-9238
DE MEESTER I ET AL: "CD26, let it cut or cut it down", IMMUNOLOGY TODAY, ELSEVIER PUBLICATIONS, CAMBRIDGE, GB, vol. 20, no. 8, 1 August 1999 (1999-08-01), pages 367 - 375, XP004177365, ISSN: 0167-5699
BOONACKER EMIL ET AL: "The multifunctional or moonlighting protein CD26/DPPIV.", EUROPEAN JOURNAL OF CELL BIOLOGY, vol. 82, no. 2, February 2003 (2003-02-01), pages 53 - 73, XP002302224, ISSN: 0171-9335
OHTSUKI TAKASHI ET AL: "Good or evil: CD26 and HIV infection", JOURNAL OF DERMATOLOGICAL SCIENCE, vol. 22, no. 3, April 2000 (2000-04-01), pages 152 - 160, XP002302250, ISSN: 0923-1811
TROUET A ET AL: "Extracellularly tumor - activated prodrugs fo the selective chemotherapy of cancer: application to doxorubicin and preliminary in vitro and in vivo studies", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, BALTIMORE, MD, US, vol. 61, no. 7, 1 April 2001 (2001-04-01), pages 2843 - 2846, XP002204750, ISSN: 0008-5472
MASQUELIER M ET AL: "AMINO ACID AND DIPEPTIDE DERIVATIVES OF DAUNORUBICIN. 1. SYNTHESIS,PHYSICOCHEMICAL PROPERTIES, AND LYSOSOMAL DIGESTION", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 23, no. 11, 1980, pages 1166 - 1170, XP000914522, ISSN: 0022-2623
ANAND BANMEET ET AL: "Novel dipeptide prodrugs of acyclovir for ocular herpes infections: Bioreversion, antiviral activity and transport across rabbit cornea.", CURRENT EYE RESEARCH. 2003 MAR-APR, vol. 26, no. 3-4, March 2003 (2003-03-01), pages 151 - 163, XP009036464, ISSN: 0271-3683
AUGUSTYNS K ET AL: "THE UNIQUE PROPERTIES OF DIPEPTIDYL-PEPTIDASE IV (DPP IV/CD26) AND THE THERAPEUTIC POTENTIAL OF DPP IV INHIBITORS", CURRENT MEDICINAL CHEMISTRY, BENTHAM SCIENCE PUBLISHERS BV, BE, vol. 6, no. 4, 1999, pages 311 - 327, XP000870290, ISSN: 0929-8673
YARON A ET AL: "PROLINE-DEPENDENT STRUCTURAL AND BIOLOGICAL PROPERTIES OF PEPTIDES AND PROTEINS", CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY, CRC PRESS, BOCA RATON, FL, US, vol. 28, no. 1, 1993, pages 31 - 81, XP000925565, ISSN: 1040-9238
DE MEESTER I ET AL: "CD26, let it cut or cut it down", IMMUNOLOGY TODAY, ELSEVIER PUBLICATIONS, CAMBRIDGE, GB, vol. 20, no. 8, 1 August 1999 (1999-08-01), pages 367 - 375, XP004177365, ISSN: 0167-5699
BOONACKER EMIL ET AL: "The multifunctional or moonlighting protein CD26/DPPIV.", EUROPEAN JOURNAL OF CELL BIOLOGY, vol. 82, no. 2, February 2003 (2003-02-01), pages 53 - 73, XP002302224, ISSN: 0171-9335
OHTSUKI TAKASHI ET AL: "Good or evil: CD26 and HIV infection", JOURNAL OF DERMATOLOGICAL SCIENCE, vol. 22, no. 3, April 2000 (2000-04-01), pages 152 - 160, XP002302250, ISSN: 0923-1811
Download PDF:
Previous Patent: GLUTAMINYL BASED DP IV-INHIBITORS
Next Patent: SYSTEM AND METHOD FOR OBJECT CHARACTERIZATION OF TOBOGGAN-BASED CLUSTERS
Next Patent: SYSTEM AND METHOD FOR OBJECT CHARACTERIZATION OF TOBOGGAN-BASED CLUSTERS