FORM 2 CRYSTALLINE POLYMORPH OF A SALT OF N-[1-6-(ETHYNYL-3-OXO-HEXAHYDRO-FURO[3,2-B]PYRROLE-4-CARBONYL)-3-METHYL-BUTYL]-4-[5-FLUORO-2-(4-METHYL-PIPERAZINYL)THIAZOL-4-YL]-BENZAMIDE USEFUL AS CYSTEINE PROTEASE INHIBITOR

• Main Authors: DIAZ PEREZ, VICTOR M, CARR, ANDREW, GRABOWSKA, URSZULA, SALVADORE-ODEN, LOURDES
• Format: Patent
• Language: English; French
• Published: 15.06.2021
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

Abstract The cathepsin K inhibitor of the formula: N 0 hl 14' 0 N ¨N 0 S F has improved pharmaceutical properties as regards to crystallinity, moisture and thermal stability and solubility, and thereby utility in the oral treatment of osteoporosis, osteoarthritis and rheumatoid arthritis, when prepared as the Form 2 crystalline polymorph defined by N-[1-6-(ethynyl-3-oxo-hexahydro-furo[3,2-b]pyrrole-4-carbonyl)-3-methyl-butyl]-4-[5-fluoro-2-(4-methyl-piperazin-1-yl)thiazol-4-yl]-benzamide monohydrochloride and N41-6-(ethynyl-3-oxo-hexahydro-furo[3,2-b]pyrrole-4-carbonyl)-3-methyl-butyl]-445-fluoro-2-(4-methyl-piperazin-1-yl)thiazol-4-yl]-benzamide hydrate monohydrochloride with XRPD peaks including at least three peaks selected from 6.8, 14.9, 17.8, 24.1, 24.6 and 24.8 ( 0.2 degrees, 2-theta values). The Form 2 crystalline polymorph can be prepared from the free base by reaction with HCI in the presence of a solvent selected from acetone, IPA, IPAc, Et0Ac, THF or MEK, and crystallisation by seeding or antisolvent addition. Date Recue/Date Received 2020-08-10 L'invention porte sur la forme cristalline polymorphe 2 constituée de monochlorhydrate de N-[1-6-(éthynyl-3-oxo-hexahydrofuro[3,2-b]pyrrole-4-carbonyl)-3-méthylbutyl]-4-[5-fluoro-2-(4-méthylpipérazin-1-yl)thiazol-4-yl]benzamide et de monochlorhydrate de N-[1-6-(éthynyl-3-oxo-hexahydrofuro[3,2-b]pyrrole-4-carbonyl)-3-méthylbutyl]-4-[5-fluoro-2-(4-méthylpipérazin-1-yl)thiazol-4-yl]benzamide hydraté, sur son utilisation en tant que médicament et sur des procédés pour sa préparation.