PRODRUG COMPOUNDS AND PROCESS FOR PREPARATION THEREOF

• Main Authors: LOBL, THOMAS, J, VISKI, PETER, TROUET, ANDRE, YARRANTON, GEOFFREY, T, NIEDER, MATTHEW, H, DUBOIS, VINCENT, FERNANDEZ, ANNE-MARIE, GANGWAR, SANJEEV, LEWIS, EVAN
• Format: Patent
• Language: English; French
• Published: 15.06.2000
• Edition: 7
• Subjects: CHEMISTRY; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PEPTIDES; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

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. The prodrug of the invention is a modified form of a therapeutic agent and comprises a therapeutic agent, an oligopeptide, a stabilizing group and, optionally, a linker group. The prodrug is cleavable by the enzyme trouase. Also disclosed are processes for making the prodrug compounds. La présente invention concerne un promédicament constituant une forme modifiée d'un agent thérapeutique et comprenant un agent thérapeutique, un oligopeptide, un groupe de stabilisation et, en option, un groupe de liaison. Ce promédicament est clivable par l'enzyme trouase. L'invention concerne également des procédés de fabrication des composés à base du promédicament.