Patent EA-002761-B1 (EA)
Title: Crystalline forms of 1s-[1alpha (2s<(>,3rs<(>, 9alpha]-6, 10-dioxo-n- 92-ethoxy-5-oxo-tetrahydro-3 -furanyl) -9-[[(1-isoquinolyl) carbonyl]-amino] octahydro-6h-piridazino[1,2-a][1,2] diazepin-1-carboxamide
Inventor: GODARD JEAN-YVES
IPC: A61P29/00
Filed: 1999-04-07
Abstract: 1. A crystalline form of anhydrous 1S-[1alpha(2S*,3R*)-9-alpha]-6,10-dioxo-N-(2-ethoxy-5-oxo-tetrahydro-3-furanyl)-9-[[(1-isoquinolyl)carbonyl]amino]octahydro-6H-piridazino [1,2-a] [1,2] diazepine-1-carboxamide (form A), which is a triclinic crystalline system and having the crystallinity degree alpha 91,38; beta 93,62; gamma 90,43 and a spatial group of symmetry P1; Z2. 2. A crystalline form of anhydrous 1S-[1alpha(2S*,3R*)-9-alpha]-6,10-dioxo-N-(2-ethoxy-5-oxo-tetrahydro-3-furanyl)-9-[[(1-isoquinolyl)carbonyl]amino]octahydro-6H-piridazino [1,2-a] [1,2] diazepine-1-carboxamide (form A) according to claim 1, having at least one the following characteristics: a) endothermic fusion from 168 degree C, b) infrared spectrum, having absorption characteristics about (liquid paraffin, cm<-1>): 3253; 1789; 1702; 1681; 1644; c) diffraction diagram of X rays, characteristic interlattice distances in which are (d,  angstrom ): 17,73; 8,87; 8,11; 7,50; 7,17; 6,31; 6,09; 5,81. 3. A crystalline form of anhydrous 1S-[1alpha(2S*,3R*)-9-alpha]-6,10-dioxo-N-(2-ethoxy-5-oxo-tetrahydro-3-furanyl)-9-[[(1-isoquinolyl)carbonyl]amino]octahydro-6H-piridazino [1,2-a] [1,2] diazepine-1-carboxamide (Form A) according to claim 2, having the a), b) and c) characteristics. 4. A crystalline form of anhydrous 1S-[1alpha(2S*,3R*)-9-alpha]-6,10-dioxo-N-(2-ethoxy-5-oxo-tetrahydro-3-furanyl)-9-[[(1-isoquinolyl)carbonyl]amino]octahydro-6H-piridazino [1,2-a] [1,2] diazepine-1-carboxamide (Form A) according to claim 2 or 3, having the infrared spectrum, substantially identical to the spectrum represented in fig.2A and the diffraction diagram of X rays substantially identical to the diagram represented in fig.3A. 5. A crystalline form of hydrated 1S-[1alpha(2S*,3R*)-9-alpha]-6,10-dioxo-N-(2-ethoxy-5-oxo-tetrahydro-3-furanyl)-9-[[(1-isoquinolyl)carbonyl]amino]octahydro-6H-piridazino [1,2-a] [1,2] diazepine-1-carboxamide (Form B), having at least one the following characteristics: a) endothermic dehydration between 50 degree C and 110 degree C and between 110 degree C and 130 degree C, endothermic fusion from 162 degree C, b) infrared spectrum, having absorption characteristics about (liquid paraffin, cm<-1>): 3569; 3447; 3322; 1778; 1682; 1660, c) diffraction diagram of X rays of (Form B), characteristic interlattice distances in which are (d,  angstrom ): 11,34; 10,80; 10,06; 7,59; 7,16; 6,71; 6,41; 6,11; 5,44. 6. A crystalline form of hydrated 1S-[1alpha(2S*,3R*)-9-alpha]-6,10-dioxo-N-(2-ethoxy-5-oxo-tetrahydro-3-furanyl)-9-[[(1-isoquinolyl)carbonyl]amino]octahydro-6H-piridazino [1,2-a] [1,2] diazepine-1-carboxamide (Form B) according to claim 5, having the a), b) and c) characteristics. 7. A crystalline form of hydrated 1S-[1alpha(2S*,3R*)-9-alpha]-6,10-dioxo-N-(2-ethoxy-5-oxo-tetrahydro-3-furanyl)-9-[[(1-isoquinolyl)carbonyl]amino]octahydro-6H-piridazino [1,2-a] [1,2] diazepine-1-carboxamide (Form B) according to claim 5 or 6, having the infrared spectrum, substantially identical to the spectrum represented in fig.2B and the diffraction diagram of X rays substantially identical to the diagram represented in fig.3B. 8. A method for preparing Form A or B according to any of claims 1 to 7, characterized in that amorphous 1S-[1alpha(2S*,3R*)-9-alpha]-6,10-dioxo-N-(2-ethoxy-5-oxo-tetrahydro-3-furanyl)-9-[[(1-isoquinolyl)carbonyl]amino]octahydro-6H-piridazino [1,2-a] [1,2] diazepine-1-carboxamide is dissolved in an appropriate organic solvent or a mixture thereof at a room temperature and further crystallize them to prepare Forms A and B. 9. The method for preparing Form A or B according to claim 8, characterized in that a solvent is an ether, in particular diisopropylic ether. 10. The method for preparing Form A or B according to claim 8, characterized in that a solvent is an alcohol, in particular n-butanol or isopropanol. 11. The method for preparing Form A or B according to claim 8, characterized in that the crystallization is effected from the mixture of alcohol and ether, in particular from the mixture of ethanol and diisopropylic ether. 12. The method for preparing Form A or B according to claim 8, characterized in that a solvent is toluene. 13. Use of the crystalline Form A according to claims 1 to 4 as a medicament. 14. Use of the crystalline Form B according to claims 5 to 7 as a medicament. 15. A pharmaceutical composition, comprising at least one compound according to one claims 1 to 7 and one or several pharmaceutically acceptable excipients, diluents or carriers. 16. Use of a crystalline compound according to any of claims 1 to 7 for preparing a medicament destined for inhibiting enzyme activities of 1-beta interleukine conversion.