Patent EA-003264-B1 (EA)
Title: CRYSTALLINE FORMS OF EtO2 C-CH2-(R) Cgl-Aze-Pab-OH
Inventor: EDVARDSSON DANIEL
IPC: A61P7/02
Filed: 1999-09-02
Abstract: 1. A substantially crystalline form of EtO2 C-CH2-(R) Cgl-Aze-Pab-OH or a pharmaceutically acceptable salt. 2. A compound according to claim 1, which is in the form of an anhydrate. 3. A compound according to claim 2 is not in the form of salt. 4. A compound according to any of claims 1-3 contains no more than 2% (w/w) water. 5. A compound according to any of claims 1-4 characterized by a differential scanning calorimetric curve, at a heating rate of 5 degree C/min in a closed cup with a pinhole under flowing nitrogen, exhibiting an endotherm with an extrapolated onset temperature of about 150 degree C, a peak temperature of about 151 degree C, and an associated heat of about 113 J/gram, followed by an exotherm in the region 190-280 degree C.; and/or a X-ray powder diffraction pattern characterized by peaks with d-values at 12.0, 10.0, 8.2, 7.2, 6.0, 5.5, 5.0, 4.92, 4.85, 4.80, 4.42, 4.22, 4.11, 4.06, 3.99, 3.78, 3.72, 3.62, 3.34, 3.11, 3.10 and 3.03 angstrom and/or such as presented on the Fig. 1. 6. A compound according to any of claims 1-4, characterized by a differential scanning calorimetric curve, at a heating rate of 5 degree C/min in a closed cup with a pinhole under flowing nitrogen, exhibiting an endotherm with an extrapolated onset temperature of about 169 degree C, a peak temperature of about 170 degree C, and an associated heat of about 142 J/gram, followed by an exotherm in the region 180-280 degree C; and/or a X-ray powder diffraction pattern characterized by peaks with d-values at 12.0, 11.1, 8.8, 7.2, 6.8, 6.6, 6.5, 6.4, 6.0, 5.8, 5.6, 5.3, 5.2, 4.75, 4.52, 4.39, 4.31, 4.29, 4.25, 4.06, 4.00, 3.82, 3.73, 3.71, 3.69, 3.66, 3.59, 3.55, 3.41, 3.37, 3.34, 3.29, 3.25, 3.22, 3.10, 3.03, 3.00, 2.91, 2.78, 2.73, 2.62, 2.51, 2.46, 2.40, 2.38, 2.34, 2.29, 2.26 angstrom and/or such as presented on the Fig. 5. 7. A compound according to claim 1, which is in the form of a monohydrate. 8. A compound according to claim 7 is not in the form of salt. 9. A compound according to claim 7 or 8, characterized by a differential is scanning calorimetric curve, at a heating rate of 5 degree C/min in a closed cup with a pinhole under flowing nitrogen, exhibiting an endotherm with an extrapolated onset temperature of about 94 degree C., a peak temperature of about 109 degree C, and an associated heat of about 171 J/gram, followed by an exotherm in the region 170-290 degree C, and/or a X-ray powder diffraction pattern characterized by peaks with d-values at 16.4, 13.7, 9.4, 8.2, 7.1, 6.2, 5.5, 5.1, 4.98, 4.75, 4.68, 4.57, 4.48, 4.27, 4.21, 4.11, 4.04, 3.93, 3.89, 3.83, 3.68, 3.52, 3.47, 3.34, 3.26, 3.02, 2.61 and 2.42 angstrom and/or such as presented on the Fig. 2. 10. A compound according to any of claims 1,2 or 7, which is in the form of a hydro bromide. 11. A compound according to claim 10, characterized by a differential is scanning calorimetric curve, at a heating rate of 5 degree C/min in a closed cup with a pinhole under flowing nitrogen, exhibiting an endotherm with an extrapolated onset temperature of about 94 degree C, a peak temperature of about 166 degree C, and an associated heat of about 69 J/gram, followed by an exotherm in the region 170-220 degree C; and/or a X-ray powder diffraction pattern characterized by peaks with d-values at 12.0, 10.1, 9.5, 6.0, 5.7, 5.6, 5.2, 5.1, 4.95, 4.74, 4.57, 4.41, 4.35, 4.35, 4.17, 4.07, 4.03, 3.92, 3.82, 3.72, 3.69, 3.62, 3.51, 3.48, 3.38, 3.25, 3.06, 2.92, 2.86, 2.71, 2.53, and 2.33 angstrom and/or such as presented on the Fig. 3. 12. A compound according to any of claims 1,2 or 7, which is in the form of a methanesulphonate salt. 13. A compound according to claim 12, characterized by a differential scanning calorimetric curve, at a heating rate of 5 degree C/min in a closed cup with a pinhole under flowing nitrogen, exhibiting an endotherm with an extrapolated onset temperature of about 134 degree C., a peak temperature of about 137 degree C., and an associated heat of about 93 J/gram, followed by an exotherm in the region 140-220 degree C.; and/or a X-ray powder diffraction pattern characterized by peaks with d-values at 12.0, 11.7, 10.4, 10.2, 8.3, 7.8, 6.0, 5.6, 5.5, 5.2, 5.1, 5.0, 4.98, 4.90, 4.75, 4.63, 4.54, 4.46, 4,15, 4.06, 3.92, 3.84, 3.74, 3.65, 3.56, 3.47, 3.39, 3.22, 3.12, 2.95, 2.88, 2.76, 2.74, 2.69, 2.65, 2.54, 2.52, 2.49, 2.27, 2.21, 2.04 and 2.02 angstrom and/or such as presented on the Fig. 4. 14. A process for the production of a compound according to any of claims 1-13, comprising crystallizing EtO2 C-CH2-(R) Cgl-Aze-Pab-OH, or a pharmaceutically acceptable salt from a solvent, selected from the group consisting of acetates, lower alkyl alcohols, aliphatic and aromatic hydrocarbons, dialkyl ethers, dialkyl ketones, acetonitrile, aqueous solvents, and mixtures thereof. 15. A process as claimed in claim 14 wherein the solvent is selected from the group consisting of C1-6 alkyl acetates, linear or branched C1-6 alkyl alcohols, C6-12 aliphatic hydrocarbons, C6-10 aromatic hydrocarbons, di-C1-6 alkyl ethers, di-C1-6 alkyl ketones, acetonitrile, water, and mixtures thereof. 16. A process as claimed in claim 15 wherein the solvent is selected from the group consisting of ethyl acetate, butyl acetate, ethanol, iso-propanol, iso-octane, n-heptane, toluene, di-iso propyl ether, acetone, methyl isobutyl ketone, acetonitrile, water, and mixtures thereof. 17. A process for the production of a compound as claimed in claims 2-6, comprising a process as claimed in any of claims 14-16 wherein solvent is substantially free of water. 18 A process for the production of a compound as claimed in any of claims 2-4 or 6, comprising a process as claimed in any of claims 14 -16 wherein a solvent contains water. 19. A process for the production of a compound as claimed in any of claims 7 - 9, comprising a process as claimed in any of claims 14 -16 wherein a solvent contains water. 20. A compound obtainable by a process according to any of claims 14-19. 21. A compound according to any of claims 11-13 or 20 for use as a pharmaceutical treatment. 22. A compound according to any of claims 11-13 or 20 for use as a prodrug. 23. A compound according to any of claims 11-13 or 20 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 24. A use of compound according to any of claims 11-13 or 20 for production drug for the treatment of a condition where inhibition of thrombin is required or desired. 25. A method of treatment of a condition where inhibition of thrombin is required or desired which method comprises administering a therapeutically effective amount of a compound according to any of claims 11-13 or 20, to a patient in need of such treatment.