Salts

摘要

The present invention relates to new crystalline salt forms of flibanserine which have valuable pharmacological properties, to a process for their manufacture, to pharmaceutical formulations containing them and to their use as medicament.

主权项

1. A salt of the compound 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one selected from the group consisting of:
I. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of Tfus (onset)=215±5° C. and characteristic peaks in the x-ray powder diffractogram of d=15.99±0.05 Å, 7.44±0.05 Å, 3.98±0.05 Å, and 3.44±0.05 Å; II. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one chloride having a melting point of Tfus (onset)=217±5° C. and characteristic peaks in the x-ray powder diffractogram of d=16.43±0.05 Å, 5.08±0.05 Å, 4.35±0.05 Å, 3.47±0.05 Å, and 7.66±0.05 Å; III. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one bromide having a melting point of Tfus (onset)=252±5° C. and by the peaks in the X-ray powder diffractogram which occur at d=3.48±0.05 Å, d=3.33±0.05 Å, d=4.28±0.05 Å, d=3.43±0.05 Å and d=16.03±0.05 Å; IV. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one bromide having a melting point of Tfus (onset)=252±5° C. and by the peaks in the X-ray powder diffractogram which occur at d=15.52±0.05 Å, d=5.15±0.05 Å, d=4.60±0.05 Å, d=4.36±0.05 Å and d=3.94±0.05 Å; V. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one edisylate having a melting point of Tfus (onset)=144±5° C.; VI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one tosylate having a melting point of Tfus (onset)=238±5° C.; VII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one mesylate having a melting point of Tfus (onset)=207±5° C.; VIII. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one besylate having a melting point of Tfus (onset)=247±5° C.; IX. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one oxalate having a melting point of Tfus (onset)=209±5° C.; X. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one oxalate having a melting point of Tfus (onset)=254±5° C.; XI. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one sacharinate having a melting point of Tfus (onset)=90±5° C.; XII. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one phosphate having a melting point of Tfus (onset)=182±5° C.; XIII a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one maleate having a melting point of Tfus (onset)=98±5° C.; XIV. a crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one maleate having a melting point of Tfus (onset)=172±5° C.; XV. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one ethansulfonate having a melting point of Tfus (onset)=207±5° C.; XVI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one camphorsulfonate having a melting point of Tfus (onset)=217±5° C.; XVII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one malonate having a melting point of Tfus (onset)=103±5° C.; XVIII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one malonate the following data:Empirical formulaC20H22F3N4O+•C3H3O4−2•2 C4H10OFw 642.71T [K] 120(2)λ[Å]  0.71073Crystal systemMonoclinicSpace groupP 21/cUnit cell dimensionsa [Å]  9.2650(3)b [Å]  24.2380(2)c [Å]  30.128(8)α [°]  90β [°] 101.620(2)γ [°]  90V [Å3] 6627.0(4)Z  8Dm [g/cm3]  1.288F(000) 2736Crystal size [mm3]0.25 × 0.1 × 0.08θ range [°]1.5 → 24Reflections collected22364Independent reflections10286 [Rint = 0.1143]S  1.093R [I > 2σ(I)]R1 = 0.1070, wR2 = 0.1271R indices (all data)R1 = 0.2167, wR2 = 0.1563 XIX. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one malonate, having the following characteristics:Empirical formulaC20H22F3N4O+•C3H3O4−2•H2OFw 530.50T [K] 120(2)λ[Å]  0.71073Crystal systemTriclinicSpace groupP −1Unit cell dimensionsa [Å]  7.8050(2)b [Å]  8.0730(2)c [Å]  20.1470(4)α [°]  80.0090(8)β [°]  87.4660(8)γ [°]  74.5320(9)V [Å3] 1204.92(3)Z  2Dm [g/cm3]  1.462F(000) 556Crystal size [mm3]0.3 × 0.25 × 0.1θ range [°]2 → 37Reflections collected14593Independent reflections12114 [Rint = 0.0408]S  1.062R [I > 2σ(I)]R1 = 0.0742, wR2 = 0.1389R indices (all data)R1 = 0.1184, wR2 = 0.1594 XX. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one salicylate the following data:Empirical formulaC20H22F3N4O+•C7H5O3−Fw 528.53T [K] 293(2)λ[Å]  0.71073Crystal systemMonoclinicSpace groupP 21/cUnit cell dimensionsa [Å]  16.3790(2)b [Å]  15.4410(4)c [Å]  10.1810(4)α [°]  90β [°]  98.1820(12)γ [°]  90V [Å3] 2548.6(2)Z  4Dm [g/cm3]  1.377F(000) 1104Crystal size [mm3]0.4 × 0.3 × 0.2θ range [°]2.5 → 26Reflections collected12472Independent reflections4948 [Rint = 0.0289]S  0.949R [I > 2σ(I)]R1 = 0.0565, wR2 = 0.1471R indices (all data)R1 = 0.0753, wR2 = 0.1647 XXI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one L-tartrate having a melting point of Tfus (onset)=151±5° C.; XXII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one hemifumarate having a melting point of Tfus (onset)=195±5° C.; XXIII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one fumarate having a melting point of Tfus (onset)=193±5° C.; XXIV. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one glycolate (form I) (=hydrate form) having a melting point of Tfus (onset)=139±5° C.; XXV. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one citrate having a melting point of Tfus (onset)=176±5° C.; XXVI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one mandelate having a melting point of Tfus (onset)=148±5° C.; XXVII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one L-malate having a melting point of Tfus (onset)=176±5° C.; XXVIII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one succinate the following data: XXIX. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one naphthalenesulfonate peaks in the X-ray powder diffractogram which occur at d=4.92±0.05 Å, d=3.43±0.05 Å, d=4.00±0.05 Å and d=3.96±0.05 Å;Empirical formula2 C20H22F3N4O+•C4H4O42−•2 H2OFw 934.94T [K] 293(2)λ[Å]  0.71073Crystal systemTriclinicSpace groupP −1Unit cell dimensionsa [Å]  9.5450(4)b [Å] 10.7120(5)c [Å] 11.7330(7)α [°] 97.597(2)β [°] 93.690(2)γ [°] 110.663(3)V [Å3]1104.6(1)Z  1Dm [g/cm3]  1.405F(000) 490Crystal size [mm3]0.3 × 0.3 × 0.2θ range [°]3.5 → 26Reflections collected6382Independent reflections4176 [Rint = 0.0194]S  1.036R [I > 2σ(I)]R1 = 0.0555, wR2 = 0.1386R indices (all data)R1 = 0.0649, wR2 = 0.1484 XXX. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one tosylate (form II) (=anhydrous form) having a melting point of Tfus (onset)=241±5° C.; XXXI. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one fumarate (form III) (=anhydrous form) having a melting point of Tfus (onset)=202±5° C.; XXXII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one camphorsulfonate (form II) (=anhydrous form) having a melting point of Tfus (onset)=231±5° C.; XXXIII. crystalline 1-[2-(4-(3-trifluoro-methyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one glycolate (form II) (=hydrate form) having a melting point of Tfus (onset)=231±5° C.