JP2019511575A - (S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミドの液体製剤 - Google Patents
(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミドの液体製剤 Download PDFInfo
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- JP2019511575A JP2019511575A JP2019502549A JP2019502549A JP2019511575A JP 2019511575 A JP2019511575 A JP 2019511575A JP 2019502549 A JP2019502549 A JP 2019502549A JP 2019502549 A JP2019502549 A JP 2019502549A JP 2019511575 A JP2019511575 A JP 2019511575A
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- trka
- citrate
- cancer
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- -1 5-((R) -2- (2,5-difluorophenyl) -pyrrolidin-1-yl) -pyrazolo [1,5-a] pyrimidin-3-yl Chemical group 0.000 title claims description 99
- 238000002360 preparation method Methods 0.000 title claims description 41
- 239000007788 liquid Substances 0.000 title claims description 23
- LCDCPQHFCOBUEF-UHFFFAOYSA-N pyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCCC1 LCDCPQHFCOBUEF-UHFFFAOYSA-N 0.000 title description 4
- 239000012669 liquid formulation Substances 0.000 claims abstract description 279
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 208
- 201000011510 cancer Diseases 0.000 claims abstract description 161
- 150000003839 salts Chemical class 0.000 claims abstract description 89
- 238000011282 treatment Methods 0.000 claims abstract description 74
- 101100517381 Rattus norvegicus Ntrk1 gene Proteins 0.000 claims description 210
- 101100261976 Drosophila melanogaster trk gene Proteins 0.000 claims description 188
- 101100537955 Schizosaccharomyces pombe (strain 972 / ATCC 24843) trk1 gene Proteins 0.000 claims description 188
- 150000001875 compounds Chemical class 0.000 claims description 126
- 238000000034 method Methods 0.000 claims description 114
- 108090000623 proteins and genes Proteins 0.000 claims description 106
- 230000014509 gene expression Effects 0.000 claims description 82
- 239000000203 mixture Substances 0.000 claims description 82
- 101150111783 NTRK1 gene Proteins 0.000 claims description 74
- 230000008482 dysregulation Effects 0.000 claims description 73
- 239000002904 solvent Substances 0.000 claims description 71
- 230000000694 effects Effects 0.000 claims description 70
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 70
- 239000003765 sweetening agent Substances 0.000 claims description 65
- 235000003599 food sweetener Nutrition 0.000 claims description 63
- 239000000796 flavoring agent Substances 0.000 claims description 49
- 238000009472 formulation Methods 0.000 claims description 46
- 101150056950 Ntrk2 gene Proteins 0.000 claims description 40
- 230000035772 mutation Effects 0.000 claims description 40
- 229920000858 Cyclodextrin Polymers 0.000 claims description 37
- 238000003556 assay Methods 0.000 claims description 37
- 235000019658 bitter taste Nutrition 0.000 claims description 36
- 239000006068 taste-masking agent Substances 0.000 claims description 33
- 208000019505 Deglutition disease Diseases 0.000 claims description 32
- 235000019634 flavors Nutrition 0.000 claims description 32
- 229960000999 sodium citrate dihydrate Drugs 0.000 claims description 27
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 23
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 22
- 229930006000 Sucrose Natural products 0.000 claims description 22
- 108020001507 fusion proteins Proteins 0.000 claims description 22
- 102000037865 fusion proteins Human genes 0.000 claims description 22
- 239000005720 sucrose Substances 0.000 claims description 22
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 21
- 230000001404 mediated effect Effects 0.000 claims description 19
- 235000013355 food flavoring agent Nutrition 0.000 claims description 17
- DOMVYDBGOVLUEL-UHFFFAOYSA-N 2-hydroxypyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCCC1O DOMVYDBGOVLUEL-UHFFFAOYSA-N 0.000 claims description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 16
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical group O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- 239000008123 high-intensity sweetener Substances 0.000 claims description 14
- 235000013615 non-nutritive sweetener Nutrition 0.000 claims description 14
- 230000004913 activation Effects 0.000 claims description 13
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 13
- WWGLWWZONFOWQE-UHFFFAOYSA-N n-hydroxypyrrolidine-1-carboxamide Chemical compound ONC(=O)N1CCCC1 WWGLWWZONFOWQE-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 229960004853 betadex Drugs 0.000 claims description 11
- 239000001116 FEMA 4028 Substances 0.000 claims description 10
- SOQQBSNVBABHLO-UHFFFAOYSA-K O.O.O.O.O.O.C(CC(O)(C(=O)[O-])CC(=O)[O-])(=O)[O-].[K+].[K+].[K+] Chemical compound O.O.O.O.O.O.C(CC(O)(C(=O)[O-])CC(=O)[O-])(=O)[O-].[K+].[K+].[K+] SOQQBSNVBABHLO-UHFFFAOYSA-K 0.000 claims description 10
- HEOQUHKWXFSWFM-UHFFFAOYSA-H O.O.O.O.O.O.O.[Ca++].[Ca++].[Ca++].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O Chemical compound O.O.O.O.O.O.O.[Ca++].[Ca++].[Ca++].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O HEOQUHKWXFSWFM-UHFFFAOYSA-H 0.000 claims description 10
- PBPOTMMPWKHFDJ-UHFFFAOYSA-K O.O.O.O.O.O.[Na+].[Na+].[Na+].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O Chemical compound O.O.O.O.O.O.[Na+].[Na+].[Na+].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O PBPOTMMPWKHFDJ-UHFFFAOYSA-K 0.000 claims description 10
- MLDABNPMJHISIF-UHFFFAOYSA-H O.O.O.O.O.[Ca++].[Ca++].[Ca++].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O Chemical compound O.O.O.O.O.[Ca++].[Ca++].[Ca++].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O MLDABNPMJHISIF-UHFFFAOYSA-H 0.000 claims description 10
- 230000003321 amplification Effects 0.000 claims description 10
- 235000011187 glycerol Nutrition 0.000 claims description 10
- 238000003199 nucleic acid amplification method Methods 0.000 claims description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 10
- PJAHUDTUZRZBKM-UHFFFAOYSA-K potassium citrate monohydrate Chemical compound O.[K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PJAHUDTUZRZBKM-UHFFFAOYSA-K 0.000 claims description 10
- 229940050931 potassium citrate monohydrate Drugs 0.000 claims description 10
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 10
- OHGJCWABWSRBNC-UHFFFAOYSA-H tricalcium;2-hydroxypropane-1,2,3-tricarboxylate;hydrate Chemical compound O.[Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O OHGJCWABWSRBNC-UHFFFAOYSA-H 0.000 claims description 10
- SJYANGXRYLBKSA-UHFFFAOYSA-K tripotassium 2-hydroxypropane-1,2,3-tricarboxylate heptahydrate Chemical compound O.O.O.O.O.O.O.[K+].[K+].[K+].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O SJYANGXRYLBKSA-UHFFFAOYSA-K 0.000 claims description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 10
- PKIDNTKRVKSLDB-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;hydrate Chemical compound O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PKIDNTKRVKSLDB-UHFFFAOYSA-K 0.000 claims description 10
- NKFYBRSYSOPDCZ-UHFFFAOYSA-K O.O.O.O.O.[K+].[K+].[K+].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O Chemical compound O.O.O.O.O.[K+].[K+].[K+].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O NKFYBRSYSOPDCZ-UHFFFAOYSA-K 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical group OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 9
- 230000002018 overexpression Effects 0.000 claims description 9
- 239000001488 sodium phosphate Substances 0.000 claims description 9
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 9
- 235000011008 sodium phosphates Nutrition 0.000 claims description 9
- 235000000346 sugar Nutrition 0.000 claims description 9
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 9
- DVBIMNUZCMCPRL-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O DVBIMNUZCMCPRL-UHFFFAOYSA-K 0.000 claims description 9
- POZPMIFKBAEGSS-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;trihydrate Chemical compound O.O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O POZPMIFKBAEGSS-UHFFFAOYSA-K 0.000 claims description 9
- TUMCWFMHZOUPDA-UHFFFAOYSA-N 2-ethylsulfanyl-1,3-benzothiazol-6-amine Chemical compound C1=C(N)C=C2SC(SCC)=NC2=C1 TUMCWFMHZOUPDA-UHFFFAOYSA-N 0.000 claims description 8
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
- LADSWJKRZCQPTH-UHFFFAOYSA-K O.O.O.O.[K+].[K+].[K+].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O Chemical compound O.O.O.O.[K+].[K+].[K+].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O LADSWJKRZCQPTH-UHFFFAOYSA-K 0.000 claims description 8
- VNWBMIOGMIMEAL-UHFFFAOYSA-K O.O.O.O.[Na+].[Na+].[Na+].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O Chemical compound O.O.O.O.[Na+].[Na+].[Na+].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O VNWBMIOGMIMEAL-UHFFFAOYSA-K 0.000 claims description 8
- 229960004106 citric acid Drugs 0.000 claims description 8
- 235000015165 citric acid Nutrition 0.000 claims description 8
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- 238000013519 translation Methods 0.000 claims description 8
- MCWYAHIQJSBPDX-UHFFFAOYSA-K tripotassium 2-hydroxypropane-1,2,3-tricarboxylate trihydrate Chemical compound O.O.O.[K+].[K+].[K+].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O MCWYAHIQJSBPDX-UHFFFAOYSA-K 0.000 claims description 8
- OBKARMSLSGWHQK-UHFFFAOYSA-K tripotassium;2-hydroxypropane-1,2,3-tricarboxylate;dihydrate Chemical compound O.O.[K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O OBKARMSLSGWHQK-UHFFFAOYSA-K 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 7
- 239000001632 sodium acetate Substances 0.000 claims description 7
- 235000017281 sodium acetate Nutrition 0.000 claims description 7
- BYGHBKRGJLNJFU-UHFFFAOYSA-H tricalcium 2-hydroxypropane-1,2,3-tricarboxylate dihydrate Chemical compound O.O.[Ca++].[Ca++].[Ca++].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O BYGHBKRGJLNJFU-UHFFFAOYSA-H 0.000 claims description 7
- PVNSIYAUPJNAMQ-UHFFFAOYSA-K trisodium 2-hydroxypropane-1,2,3-tricarboxylate heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PVNSIYAUPJNAMQ-UHFFFAOYSA-K 0.000 claims description 7
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 6
- 235000011092 calcium acetate Nutrition 0.000 claims description 6
- 239000001639 calcium acetate Substances 0.000 claims description 6
- 229960005147 calcium acetate Drugs 0.000 claims description 6
- 229940001447 lactate Drugs 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- 229940074404 sodium succinate Drugs 0.000 claims description 6
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 claims description 6
- 229940095064 tartrate Drugs 0.000 claims description 6
- UCCRMEIIRRVQNN-UHFFFAOYSA-H tricalcium 2-hydroxypropane-1,2,3-tricarboxylate hexahydrate Chemical compound O.O.O.O.O.O.C(CC(O)(C(=O)[O-])CC(=O)[O-])(=O)[O-].[Ca+2].C(CC(O)(C(=O)[O-])CC(=O)[O-])(=O)[O-].[Ca+2].[Ca+2] UCCRMEIIRRVQNN-UHFFFAOYSA-H 0.000 claims description 6
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 claims description 5
- QAUJGNZFUUOOAF-UHFFFAOYSA-K [Li+].[Li+].[Li+].O.O.O.O.O.O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O Chemical compound [Li+].[Li+].[Li+].O.O.O.O.O.O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O QAUJGNZFUUOOAF-UHFFFAOYSA-K 0.000 claims description 5
- FMEZOJFOJAGTSX-UHFFFAOYSA-K [Li+].[Li+].[Li+].O.O.O.O.O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O Chemical compound [Li+].[Li+].[Li+].O.O.O.O.O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O FMEZOJFOJAGTSX-UHFFFAOYSA-K 0.000 claims description 5
- RVZWOOMUSWEJCM-UHFFFAOYSA-K [Li+].[Li+].[Li+].O.O.O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O Chemical compound [Li+].[Li+].[Li+].O.O.O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O RVZWOOMUSWEJCM-UHFFFAOYSA-K 0.000 claims description 5
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 claims description 5
- 239000001527 calcium lactate Substances 0.000 claims description 5
- 235000011086 calcium lactate Nutrition 0.000 claims description 5
- 229960002401 calcium lactate Drugs 0.000 claims description 5
- 239000001506 calcium phosphate Substances 0.000 claims description 5
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 5
- 235000011010 calcium phosphates Nutrition 0.000 claims description 5
- GUPPESBEIQALOS-UHFFFAOYSA-L calcium tartrate Chemical compound [Ca+2].[O-]C(=O)C(O)C(O)C([O-])=O GUPPESBEIQALOS-UHFFFAOYSA-L 0.000 claims description 5
- 239000001427 calcium tartrate Substances 0.000 claims description 5
- 235000011035 calcium tartrate Nutrition 0.000 claims description 5
- PBUBJNYXWIDFMU-UHFFFAOYSA-L calcium;butanedioate Chemical compound [Ca+2].[O-]C(=O)CCC([O-])=O PBUBJNYXWIDFMU-UHFFFAOYSA-L 0.000 claims description 5
- 239000013078 crystal Substances 0.000 claims description 5
- JCCYXJAEFHYHPP-OLXYHTOASA-L dilithium;(2r,3r)-2,3-dihydroxybutanedioate Chemical compound [Li+].[Li+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O JCCYXJAEFHYHPP-OLXYHTOASA-L 0.000 claims description 5
- PMUKAEUGVCXPDF-UAIGNFCESA-L dilithium;(z)-but-2-enedioate Chemical compound [Li+].[Li+].[O-]C(=O)\C=C/C([O-])=O PMUKAEUGVCXPDF-UAIGNFCESA-L 0.000 claims description 5
- SHPKCSFVQGSAJU-UAIGNFCESA-L dipotassium;(z)-but-2-enedioate Chemical compound [K+].[K+].[O-]C(=O)\C=C/C([O-])=O SHPKCSFVQGSAJU-UAIGNFCESA-L 0.000 claims description 5
- CVOQYKPWIVSMDC-UHFFFAOYSA-L dipotassium;butanedioate Chemical compound [K+].[K+].[O-]C(=O)CCC([O-])=O CVOQYKPWIVSMDC-UHFFFAOYSA-L 0.000 claims description 5
- MSJMDZAOKORVFC-UAIGNFCESA-L disodium maleate Chemical compound [Na+].[Na+].[O-]C(=O)\C=C/C([O-])=O MSJMDZAOKORVFC-UAIGNFCESA-L 0.000 claims description 5
- 235000013399 edible fruits Nutrition 0.000 claims description 5
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 5
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 claims description 5
- 229910001386 lithium phosphate Inorganic materials 0.000 claims description 5
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Abstract
Description
本出願は、2016年4月4日に出願された米国特許仮出願第62/318,041号;2016年4月15日に出願された同第62/323,452号;および2016年4月29日に出願された同第62/329,561号に対する優先権を主張する。これらの特許仮出願のそれぞれは、参照によりその全体が本明細書に組み込まれる。
本開示は、(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド(式I)、薬学的に許容可能なその塩、またはこれらの組み合わせの液体製剤と、疼痛、炎症、癌、および特定の感染症の処置における該液体製剤の使用とに関する。
Trkは、ニューロトロフィン(NT)と呼ばれる可溶性成長因子群により活性化される高親和性受容体チロシンキナーゼである。Trk受容体ファミリーには、3種のメンバー、TrkA、TrkB、およびTrkCがある。ニューロトロフィンには、(i)TrkAを活性化する神経成長因子(NGF)、(ii)TrkBを活性化する脳由来神経栄養因子(BDNF)、およびNT−4/5、ならびに(iii)TrkCを活性化するNT3がある。Trkは神経組織中に広範囲に発現し、神経細胞の維持、シグナル伝達および生存に関与している(Patapoutian,A.et al.,Current Opinion in Neurobiology,2001,11,272−280)。
本明細書で提供されるのは、可溶化剤および式(I):
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせを含む液体製剤である。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせを含む液体製剤である。また、液体製剤は、可溶化剤および緩衝液を含む。液体製剤は、約2.5〜約5.5のpHを有する。式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせは、液体製剤中で、約15mg/mL〜約35mg/mLの濃度を有する。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせを含む液体製剤である。また、液体製剤は、可溶化剤および塩基を含む。液体製剤は、約2.5〜約5.5のpHを有する。いくつかの実施形態では、塩基は、クエン酸塩(例えば、クエン酸ナトリウム)を含む。式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせは、液体製剤中で、約15mg/mL〜約35mg/mLの濃度を有する。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせを含む液体製剤である。また、液体製剤は、可溶化剤、緩衝液、甘味料、苦味マスキング剤、および香味料を含む。液体製剤は、約3〜約4のpHを有する。式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせは、液体製剤中で、約15mg/mL〜約35mg/mLの濃度を有する。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせを含む液体製剤である。液体製剤は、可溶化剤、塩基、甘味料、苦味マスキング剤、および香味料を含む。液体製剤は、約3〜約4のpHを有する。いくつかの実施形態では、塩基は、クエン酸塩(例えば、クエン酸ナトリウム)を含む。式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせは、液体製剤中で、約15mg/mL〜約35mg/mLの濃度を有する。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせを含む液体製剤である。液体製剤は、約5重量%〜約35重量%の量で存在する可溶化剤および約0.1重量%〜約5重量%の量で存在する緩衝液を含む。液体製剤は、約2.5〜約5.5のpHを有する。式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせは、液体製剤中で、約20mg/mL〜約30mg/mLの濃度を有する。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせを含む液体製剤である。液体製剤は、約5重量%〜約35重量%の量で存在する可溶化剤;約0.1重量%〜約5重量%の量で存在する緩衝液;約30重量%〜約70重量%の量で存在する甘味料;約0.2重量%〜約0.5重量%の量で存在する苦味マスキング剤;および約0.01重量%〜約2重量%の量で存在する香味料を含む。液体製剤は、約2.5〜約5.5のpHを有する。式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせは、液体製剤中で、約20mg/mL〜約30mg/mLの濃度を有する。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせを含む液体製剤である。液体製剤は、約5重量%〜約35重量%の量で存在する可溶化剤;約0.1重量%〜約5重量%の量で存在する塩基;約30重量%〜約70重量%の量で存在する甘味料;約0.2重量%〜約0.5重量%の量で存在する苦味マスキング剤;および約0.01重量%〜約2重量%の量で存在する香味料を含む。液体製剤は、約2.5〜約5.5のpHを有する。式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせは、液体製剤中で、約20mg/mL〜約30mg/mLの濃度を有する。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせを含む液体製剤である。液体製剤は、約5重量%〜約35重量%の量で存在する可溶化剤を含む。液体製剤は、約0.1重量%〜約5重量%の量で存在するクエン酸ナトリウム二水和物を含む緩衝液も含む。液体製剤はまた、約30重量%〜約70重量%の量で存在するショ糖を含む甘味料も含む。液体製剤はまた、約0.2重量%〜約0.5重量%の量で存在する苦味マスキング剤も含む。液体製剤はまた、約0.01重量%〜約2重量%の量で存在する香味料も含む。液体製剤は、約3〜約4のpHを有する。式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせは、液体製剤中で、約20mg/mL〜約30mg/mLの濃度を有する。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせを含む液体製剤である。液体製剤は、約5重量%〜約35重量%の量で存在する可溶化剤を含む。液体製剤はまた、約0.1重量%〜約5重量%の量で存在するクエン酸ナトリウム二水和物を含む塩基も含む。液体製剤はまた、約30重量%〜約70重量%の量で存在するショ糖を含む甘味料も含む。液体製剤はまた、約0.2重量%〜約0.5重量%の量で存在する苦味マスキング剤も含む。液体製剤はまた、約0.01重量%〜約2重量%の量で存在する香味料も含む。液体製剤は、約3〜約4のpHを有する。式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせは、液体製剤中で、約20mg/mL〜約30mg/mLの濃度を有する。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせを含む液体製剤である。液体製剤は、約5重量%〜約35重量%の量で存在する可溶化剤を含む。液体製剤はまた、約0.1重量%〜約5重量%の量で存在するクエン酸ナトリウム二水和物も含む。液体製剤はまた、約30重量%〜約70重量%の量で存在するショ糖を含む甘味料も含む。液体製剤はまた、約0.2重量%〜約0.5重量%の量で存在する苦味マスキング剤も含む。液体製剤はまた、約0.01重量%〜約2重量%の量で存在する香味料も含む。液体製剤は、約3〜約4のpHを有する。式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせは、液体製剤中で、約20mg/mL〜約30mg/mLの濃度を有する。
本開示は、(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせの液体製剤と、疼痛、炎症、癌、および特定の感染症の処置における該液体製剤の使用とに関する。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせを含む液体製剤である。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ、可溶化剤および緩衝液を含む液体製剤である。いくつかの実施形態では、製剤は、約2.5〜約5.5のpHを有する。いくつかの実施形態では、式(I)の化合物は、約15mg/mL〜約35mg/mLの濃度を有する。いくつかの実施形態では、製剤は、約3〜約4のpHを有し、式(I)の化合物、もしくは薬学的に許容可能なその塩、またはこれらの組み合わせは、液体製剤中で、約15mg/mL〜約35mg/mLの濃度で存在する。緩衝液は、クエン酸ナトリウム二水和物を含み得る。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ、可溶化剤および塩基を含む液体製剤である。いくつかの実施形態では、製剤は、約2.5〜約5.5のpHを有する。いくつかの実施形態では、式(I)の化合物は、約15mg/mL〜約35mg/mLの濃度を有する。いくつかの実施形態では、製剤は、約3〜約4のpHを有し、式(I)の化合物、もしくは薬学的に許容可能なその塩、またはこれらの組み合わせは、液体製剤中で、約15mg/mL〜約35mg/mLの濃度で存在する。塩基は、クエン酸ナトリウム二水和物を含み得る。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ、可溶化剤、緩衝液、甘味料、苦味マスキング剤、および香味料を含む液体製剤である。いくつかの実施形態では、製剤は、約3〜約4のpHを有し、式(I)の化合物、もしくは薬学的に許容可能なその塩、またはこれらの組み合わせは、液体製剤中で、約15mg/mL〜約35mg/mLの濃度で存在する。いくつかの実施形態では、緩衝液は、クエン酸ナトリウム二水和物を含む。いくつかの実施形態では、甘味料は、ショ糖を含む。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ、可溶化剤、塩基、甘味料、苦味マスキング剤、および香味料を含む液体製剤である。いくつかの実施形態では、製剤は、約3〜約4のpHを有し、式(I)の化合物、もしくは薬学的に許容可能なその塩、またはこれらの組み合わせは、液体製剤中で、約15mg/mL〜約35mg/mLの濃度で存在する。いくつかの実施形態では、塩基は、クエン酸ナトリウム二水和物を含む。いくつかの実施形態では、甘味料は、ショ糖を含む。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ、可溶化剤、緩衝液、甘味料、苦味マスキング剤、および香味料を含む液体製剤であり、製剤は約3〜約4のpHを有する。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ、可溶化剤、塩基、甘味料、苦味マスキング剤、および香味料を含む液体製剤であり、製剤は約3〜約4のpHを有する。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ、可溶化剤、緩衝液、甘味料、苦味マスキング剤、および香味料を含む液体製剤であり、式(I)の化合物は、液体製剤中で、約15mg/mL〜約35mg/mLの濃度を有する。
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ、可溶化剤、塩基、甘味料、苦味マスキング剤、および香味料を含む液体製剤であり、式(I)の化合物は、液体製剤中で、約15mg/mL〜約35mg/mLの濃度を有する。
(a)式(I):
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ;
(b)約5重量%〜約35重量%の量で存在する可溶化剤;および
(c)約0.1重量%〜約5重量%の量で存在する緩衝液
を含む液体製剤である。いくつかの実施形態では、緩衝液は、クエン酸ナトリウム脱水物を含む。いくつかの実施形態では、製剤はまた、約30重量%〜約70重量%の量で存在する甘味料を含む。いくつかの実施形態では、甘味料は、ショ糖を含む。いくつかの実施形態では、製剤はまた、約0.2重量%〜約0.5重量%の量で存在する苦味マスキング剤を含む。いくつかの実施形態では、製剤はまた、約0.01重量%〜約2重量%の量で存在する香味料を含む。いくつかの実施形態では、製剤は、約3〜約4のpHを有する。いくつかの実施形態では、式(I)の化合物は、液体製剤中で、約20mg/mL〜約30mg/mLの濃度を有する。
(a)式(I):
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ;
(b)約5重量%〜約35重量%の量で存在する可溶化剤;および
(c)約0.1重量%〜約5重量%の量で存在する塩基
を含む液体製剤である。いくつかの実施形態では、塩基は、クエン酸ナトリウム脱水物を含む。いくつかの実施形態では、製剤はまた、約30重量%〜約70重量%の量で存在する甘味料を含む。いくつかの実施形態では、甘味料は、ショ糖を含む。いくつかの実施形態では、製剤はまた、約0.2重量%〜約0.5重量%の量で存在する苦味マスキング剤を含む。いくつかの実施形態では、製剤はまた、約0.01重量%〜約2重量%の量で存在する香味料を含む。いくつかの実施形態では、製剤は、約3〜約4のpHを有する。いくつかの実施形態では、式(I)の化合物は、液体製剤中で、約20mg/mL〜約30mg/mLの濃度を有する。
(a)式(I):
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ;
(b)約5重量%〜約35重量%の量で存在する可溶化剤(例えば、ヒドロキシプロピル−β−シクロデキストリンなどのシクロデキストリン);および
(c)約0.1重量%〜約5重量%の量で存在する緩衝液(例えば、クエン酸ナトリウムなどのクエン酸緩衝液);
(d)約30重量%〜約70重量%の量で存在する甘味料(例えば、ショ糖または高甘味度甘味料を含む甘味料);
(e)約0.2重量%〜約0.5重量%の量で存在する苦味マスキング剤;および
(f)約0.01重量%〜約2重量%の量で存在する香味料
を含む液体製剤である。いくつかの実施形態では、製剤は、約3〜約4のpHを有する。いくつかの実施形態では、式(I)の化合物は、液体製剤中で、約20mg/mL〜約30mg/mLの濃度を有する。
(a)式(I):
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ;
(b)約5重量%〜約35重量%の量で存在する可溶化剤(例えば、ヒドロキシプロピル−β−シクロデキストリンなどのシクロデキストリン);および
(c)約0.1重量%〜約5重量%の量で存在する塩基(例えば、クエン酸ナトリウムなどのクエン酸塩);
(d)約30重量%〜約70重量%の量で存在する甘味料(例えば、ショ糖または高甘味度甘味料を含む甘味料);
(e)約0.2重量%〜約0.5重量%の量で存在する苦味マスキング剤;および
(f)約0.01重量%〜約2重量%の量で存在する香味料
を含む液体製剤である。いくつかの実施形態では、製剤は、約3〜約4のpHを有する。いくつかの実施形態では、式(I)の化合物は、液体製剤中で、約20mg/mL〜約30mg/mLの濃度を有する。
(a)式(I):
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ;
(b)約5重量%〜約35重量%の量で存在するヒドロキシプロピル−β−シクロデキストリン;および
(c)約0.1重量%〜約5重量%の量で存在するクエン酸ナトリウム;
(d)約30重量%〜約70重量%の量で存在するショ糖または高甘味度甘味料;
(e)約0.2重量%〜約0.5重量%の量で存在する苦味マスキング剤;および
(f)約0.01重量%〜約2重量%の量で存在する香味料
を含む液体製剤である。いくつかの実施形態では、製剤は、約3〜約4のpHを有する。いくつかの実施形態では、式(I)の化合物は、液体製剤中で、約20mg/mL〜約30mg/mLの濃度を有する。
(a)式(I):
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ;
(b)約5重量%〜約35重量%の量で存在するヒドロキシプロピル−β−シクロデキストリン;および
(c)約0.1重量%〜約5重量%の量で存在するクエン酸ナトリウム二水和物;
(d)約30重量%〜約70重量%の量で存在するショ糖または高甘味度甘味料;
(e)約0.2重量%〜約0.5重量%の量で存在する苦味マスキング剤;および
(f)約0.01重量%〜約2重量%の量で存在する香味料
を含む液体製剤である。いくつかの実施形態では、製剤は、約3〜約4のpHを有する。いくつかの実施形態では、式(I)の化合物は、液体製剤中で、約20mg/mL〜約30mg/mLの濃度を有する。
本明細書で考察したように、液体製剤は、結晶形の(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド(式I)、薬学的に許容可能なその塩、またはこれらの組み合わせから調製できる。いくつかの実施形態では、この結晶形は、結晶形(I−HS)である。
ACreancier et al.,Cancer Lett.365(1):107−111,2015.J
B米国特許出願公開第2015/0315657号。
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A基準TrkA配列は、UniProtKB/Swiss−Prot:P04629.4であり、URL:www.ncbi.nlm.nih.gov/protein/94730402?report=genbank&log$=protalign&blast_rank=0&RID=0(配列番号1)で見つけることができる。
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(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド約1グラムを、最小量の水に溶解し、約−26℃の温度に冷却した後、凍結乾燥機で24時間乾燥させる。凍結乾燥機から得られた非晶質材料約20mgをバイアルに入れて秤量し、それに5体積分割量の適切な溶媒系を添加した。混合物を、溶解について調べ、溶解が認められなかった場合には約40℃に加熱し、再び調べた。この手順を、溶解が観察されるまで、または100体積の溶媒が添加されるまで継続した。凍結乾燥実験から得られた非晶質材料のXRPDパターンを、図7に示す。
(a)濃硫酸を、(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミドのEtOH中溶液に添加し、(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミドの硫酸水素塩を形成するステップと、
(b)ステップ(a)の溶液にヘプタンを添加して、スラリーを形成するステップと、
(c)スラリーを濾過して、(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド硫酸水素塩を単離するステップと、
(d)前記(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド硫酸水素塩を、水/2−ブタノンの5:95w/w溶液と混合するステップと、
(e)エタノールの重量パーセントが約0.5%になり、(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド硫酸水素塩の結晶形のスラリーを形成するまで、ステップ(d)由来の混合物を、撹拌しながら約65〜70℃で加熱するステップと、
(f)結晶形の(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド硫酸水素塩を、濾過により単離するステップと
を含む。
(a)5−クロロ−3−ニトロピラゾロ[1,5−a]ピリミジンを、塩基の存在下で(R)−2−(2,5−ジフルオロフェニル)−ピロリジン(R)−2−ヒドロキシスクシネートと反応させて、(R)−5−(2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−3−ニトロピラゾロ[1,5−a]ピリミジンを形成するステップと、
(b)前記(R)−5−(2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−3−ニトロピラゾロ[1,5−a]ピリミジンを、Znおよび塩酸で処理して、(R)−5−(2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−アミンを形成するステップと、
(c)前記(R)−5−(2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−アミンを、塩基およびクロロギ酸フェニルで処理して、フェニル(R)−(5−(2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)カルバメートを形成するステップと、
(d)前記フェニル(R)−(5−(2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)カルバメートを、(S)−ピロリジン−3−オ−ルと反応させて、(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミドを形成するステップと、
(e)硫酸を、前記(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミドに添加して、(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド硫酸水素塩を形成するステップと、
(f)結晶形の(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド硫酸水素塩を単離するステップと
を含む。
5−クロロ−3−ニトロピラゾロ[1,5−a]ピリミジンの調製
ステップA.ナトリウムピラゾロ[1,5−a]ピリミジン−5−オレエートの調製:
1H−ピラゾール−5−アミンおよび1,3−ジメチルピリミジン−2,4(1H,3H)−ジオン(1.05当量)の溶液を、機械撹拌装置、蒸気ポット、還流冷却器、J−Kem温度プローブおよびN2陽圧制御のためのN2アダプターを備えた丸底フラスコに充填した。機械的撹拌下で、固形物を、窒素雰囲気下で4体積(4mL/g)の無水EtOHに懸濁させ、次に2.1当量のNaOEt(EtOH中21wt%溶液)を充填し、その後1体積(1mL/g)の無水EtOHでラインリンスを行った。スラリーを約75℃に温め、TRK1PM1 HPLCによって、1.5面積%未満の1H−ピラゾール−5−アミンが観察されるまで穏やかに還流させながら撹拌し、脱イオン水4mLで希釈した20μLのスラリーおよび5μLの注入用いて、220nmで反応の進行を追跡した。
風袋を差し引いた丸底フラスコにナトリウムピラゾロ[1,5−a]ピリミジン−5−オレエートを加え、40〜45℃で3.0体積(3.0mL/g)の脱イオン水に溶解した後、65℃の水浴中、高真空下のロータリーエバポレーターを用いて、出発材料の2.4倍の重量が観察されるまで濃縮した(1.4体積/1.4mL/g脱イオン水含量)。残留EtOH(MeOH約1mLに溶解した溶液30μL)をガスクロマトグラフィー(GC)で検出した結果、100ppm未満であることが示され、後でHNO3を添加すると微量の硝酸エチル煙霧が下部で観察された。いくつかのケースでは、元の溶液に追加の1.5体積(1.5mL/g)の脱イオン水を加え、その後、65℃の水浴を用い、高真空下のロータリーエバポレーターで出発材料の2.4倍の重量が観察されるまで濃縮した(1.4体積/1.4mL/g脱イオン水含量)。残留EtOH(MeOH約1mLに溶解させた溶液30μL)をガスクロマトグラフで検出した結果、<<100ppmの残留EtOHが示され、後にHNO3を添加しても下部で硝酸エチル煙霧は観察されなかった。
3−ニトロピラゾロ[1,5−a]ピリミジン−5(4H)−オンを、機械撹拌装置、加熱マントル、還流冷却器、J−Kem温度プローブおよびN2陽圧制御のためのN2アダプターを備えた丸底フラスコに加えた。機械的に撹拌しながら、固体を、8体積(8mL/g)のCH3CNに懸濁させ、次に2,6−ルチジン(lutitine)(1.05当量)を加えた後、スラリーを約50℃に温めた。均圧添加漏斗を使用し、混合物に0.33当量のPOCl3を滴加した。この充填によって、粘度が高い三量体のベージュ色スラリーが得られ、それを、半流動性の密集体が観察されるまで、撹拌しながらホモジナイズした。温度を安定化させながら追加の1.67当量のPOCl3を混合物に加えた後、反応混合物を温めて、穏やかに還流させた(78℃)。混合物を温めるといくらか煙霧が観察されたが、後に粘度が高いスラリーが希薄になるにつれて消失した。
(R)−2−(2,5−ジフルオロフェニル)−ピロリジン(R)−2−ヒドロキシスクシネートの調製
ステップA.tert−ブチル(4−(2,5−ジフルオロフェニル)−4−オキソブチル)−カルバメートの調製:
2−ブロモ−1,4−ジフルオロベンゼン(1.5当量)を、4体積のTHF(tert−ブチル 2−オキソピロリジン−1−カルボキシレートの重量を基準にして)に溶解させ、約5℃に冷却した。2.0MのiPrMgClのTHF(1.4当量)中溶液を、反応温度を25℃未満に維持しながら2時間かけて混合物に添加した。その溶液を約5℃に冷却し、1時間撹拌した(GC分析によって、グリニャール形成が確認された)。tert−ブチル 2−オキソピロリジン−1−カルボキシレート(1.0当量)の1体積のTHF中の溶液を、反応温度を25℃未満に維持しながら約30分かけて添加した。反応物を約5℃で90分間撹拌した(tert−ブチル 2−オキソピロリジン−1−カルボキシレートは、HPLCによって、0.5面積%未満であることが確認された)。反応温度を45℃未満に維持しながら、5体積の2M HCl水溶液で反応をクエンチした。次に、反応物を分液漏斗に移し、10体積のヘプタンを添加し、水層を除去した。有機層を、4体積の飽和NaCl水溶液で洗浄した後、2x1体積の飽和NaCl水溶液を添加した。有機層では、約7体積の最小蒸留体積で添加される2x4体積のヘプタンのために、蒸留温度35〜55℃および蒸留圧力100〜200mmHgにおいて、溶媒をヘプタンに切り替えた(<1%wtのTHFがGCにより確認された)。次に混合物を、約55℃に加熱しながらヘプタンで10体積まで希釈し、混合物を室温で一晩冷却して、より粘度が高い固形物を得た。スラリーを5℃未満に冷却し、ポリプロピレン濾布で濾過した。湿潤ケーキを、2x2体積のヘプタンで洗浄した。重量が一定になるまで、固形物を55℃の真空下で乾燥させると、tert−ブチル(4−(2,5−ジフルオロフェニル)−4−オキソブチル)−カルバメートが白色固体として理論的収率約75%〜85%で得られた。
tert−ブチル(4−(2,5−ジフルオロフェニル)−4−オキソブチル)−カルバメートを、5体積のトルエンに溶解し、2.2当量の12M HClを添加すると穏やかな発熱およびガスの発生が観察された。反応物を65℃で12〜24時間加熱し、HPLCによりモニターした。完了すると、反応物を氷/水浴で15℃未満に冷却した。pHを、3当量の2M NaOH水溶液(4.7体積)で約14に調整した。反応物を室温で1〜2時間撹拌した。混合物を、トルエンと共に分液漏斗に移した。水層を除去し、有機層を3体積の飽和NaCl水溶液で洗浄した。有機層を、油状物になるまで濃縮し、1.5体積のヘプタンに再溶解させた。得られた懸濁液を、GF/F濾紙で濾過し、濃縮して、5−(2,5−ジフルオロフェニル)−3,4−ジヒドロ−2H−ピロールの淡黄色油を理論的収率90%〜100%で得た。
クロロ−1,5−シクロオクタジエンイリジウム二量体(0.2mol%)および(R)−2−(2−(ジフェニルホスフィノ)フェニル)−4−イソプロピル−4,5−ジヒドロオキサゾール(0.4mol%)を、5体積のMTBE(5−(2,5−ジフルオロフェニル)−3,4−ジヒドロ−2H−ピロールを基準にして)に室温で懸濁させた。混合物を1時間撹拌すると、固体の大部分が溶解して、溶液が暗赤色に変化した。触媒の形成を、HPLC/PDA検出器を用いてモニターした。反応物を5℃未満に冷却し、5−(2,5−ジフルオロフェニル)−3,4−ジヒドロ−2H−ピロール(1.0当量)を、0.5体積のMTBEすすぎ液を用いて添加した。ジフェニルシラン(1.5当量)を、反応温度を10℃未満に維持しながら約20分かけて添加した。反応物を10℃未満で30分間撹拌した後、室温に温めた。反応物を室温で一晩撹拌した。HPLCにより反応の完了を確認した後、5℃未満に冷却した。温度を20℃未満に維持しながら、5体積の2M HCl水溶液で反応をクエンチした。10分後に氷/水浴を取り外し、2時間撹拌しながら反応温度を室温に上昇させた。混合物を、3体積のMTBEと共に分液漏斗に移した。水層を3.5体積のMTBEで洗浄した後、5体積のMTBEを水層に添加すると同時に、0.75体積の50%NaOH水溶液を添加することによりpHを約14に調整した。有機層を、5体積の飽和NaCl水溶液で洗浄した後、油状物になるまで濃縮し、3体積のMTBEで希釈した。溶液をポリプロピレン濾布で濾過し、1体積のMTBEですすいだ。濾液を濃縮して、(R)−2−(2,5−ジフルオロフェニル)−ピロリジンの油を理論的収率95%〜100%および75〜85%eeで得た。
(R)−2−(2,5−ジフルオロフェニル)−ピロリジン(1.0当量)を、15体積(効力について補正済)のEtOH(200プルーフ)を充填した丸底フラスコに移した。D−リンゴ酸(1.05当量)を添加し、混合物を65℃に加熱した。固形物のすべてが約64℃で溶解した。溶液をRTに冷却した。約55℃で、その溶液に(R)−2−(2,5−ジフルオロフェニル)−ピロリジン(R)−2−ヒドロキシ−スクシネート(約50mg、>97%ee)をシード添加し、室温で一晩撹拌した。その後、懸濁液をポリプロピレン濾布で濾過し、2x1体積のEtOH(200プルーフ)で洗浄した。固形物を、真空下、55℃で乾燥させると、(R)−2−(2,5−ジフルオロフェニル)−ピロリジン(R)−2−ヒドロキシ−スクシネートが理論的収率75%〜90%および>96%eeで得られた。
化合物II(5−クロロ−3−ニトロピラゾロ[1,5−a]ピリミジン)およびIII((R)−2−(2,5−ジフルオロフェニル)−ピロリジン(R)−2−ヒドロキシスクシネート、1.05当量)を、機械撹拌装置、J−Kem温度プローブおよびN2陽圧制御のためのN2アダプターを備えた丸底フラスコに加えた。4:1のEtOH:THF(10mL/gの化合物II)溶液を添加し、その後トリエチルアミン(NEt3、3.50当量)を添加漏斗を介して加えると、添加中に温度が約40℃に達した。添加が完了すると、反応混合物を50℃に加熱し、0.5〜3時間撹拌して化合物IVを得た。
結晶形(I−HS)の調製(方法1)
(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド(0.500g、1.17mmol)をEtOH(2.5mL)に溶解させ、約5℃に冷却した。濃硫酸(0.0636mL、1.17mmol)を冷却溶液に添加し、室温に温めながら約10分間撹拌した。メチルtert−ブチルエーテル(MTBE)(2mL)を、混合物にゆっくり添加すると、生成物がゴム状化した。次に、EtOH(2.5mL)を混合物に添加し、すべての固形物が溶解するまで、ほとんど還流状態で加熱した。室温に冷却し、約1時間撹拌すると、いくつかの固形物が形成された。約5℃に冷却した後、固形物を濾過し、MTBEで洗浄した。濾過し、約15分間風乾させた後、(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド硫酸水素塩を固体として単離した。
結晶形(I−HS)の調製(方法2)
濃硫酸(392mL)を、3031gの(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミドの18322mLのEtOH中溶液に添加し、硫酸水素塩を形成した。この溶液に、2gの(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド硫酸水素塩をシード添加し、この溶液を室温で少なくとも2時間撹拌し、硫酸水素塩のスラリーを形成した。ヘプタン(20888g)を添加し、スラリーを室温で少なくとも60分間撹拌した。スラリーを濾過し、濾過ケーキを1:1のヘプタン/EtOHで洗浄した。次に、固形物を真空下、周囲温度で乾燥させた(オーブン温度を15℃に設定)。
非晶質形AM(HS)の調製
(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド(9.40g、21.94mmol)のMeOH(220mL)中溶液に、急速に撹拌しながら、硫酸(MeOH中0.1M、219.4mL、21.94mmol)を周囲温度でゆっくり添加した。30分後、最初に反応物をロータリーエバポレーターによって、乾燥状態近くまで濃縮し、次に高真空状態で48時間乾燥し、非晶質形の(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド硫酸塩を得た(11.37g、21.59mmol、収率98.43%)。LCMS(apci m/z 429.1、M+H)。
式Iの結晶質HCl塩の調製
EtOH(6mL、200プルーフ)中の(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド(0.554g、1.29mmol)およびMTBE(10mL)の混合物を、撹拌しながら50℃に加熱して溶液を得、その後、塩化水素(濃)(0.108mL、1.29mmol)を一度に添加した。その後、反応混合物を最初に周囲温度に冷却し、次に氷水浴中で撹拌しながら約5℃に冷却して、結晶化を誘導した。懸濁液を、氷水浴中で4時間撹拌した後、真空濾過し、濾過ケーキをMTBEですすぎ、真空下、55℃で一定重量まで乾燥させて、結晶質(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド塩酸塩(0.534g、収率89%)が得られた。LCMS(apci m/z 429.2、M+H)。
EtOH(6mL、200プルーフ)中の(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド(0.505g、1.18mmol)およびMTBE(10mL)の混合物を、撹拌しながら50℃に加熱して溶液を得、その後、臭化水素(33%水溶液)(0.213mL、1.18mmol)を一度に添加した。反応混合物を加熱還流させると、ほぼ透明な溶液が得られ、反応容器のガラス壁上に少量の油状残留物が認められた。周囲温度に冷却すると、沈殿が現れ、油状残留物が固化した。混合物を再び50℃に加熱した後、室温に冷却し、一晩撹拌した。懸濁液を真空濾過し、濾過ケーキをMTBEですすぎ、真空下、55℃で一定重量になるまで乾燥させ、結晶質(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド臭化水素酸塩(0.51g、収率85%)が得られた。LCMS(apci m/z 429.3、M+H)。
EtOH(2.7mL、200プルーフ)中(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド(0.532g、1.24mmol)およびMTBE(5.3mL)の混合物を、撹拌しながら50℃に加熱して溶液を得、その後、メタンスルホン酸(0.076mL、1.24mmol)を一度に添加した。反応混合物を加熱還流させて、ほとんど透明な溶液を少量の微粒子と共に得た。周囲温度に冷却すると、沈殿が、若干の油状残留物と共に現れた。追加のEtOH(0.5mL、200プルーフ)およびメタンスルホン酸(0.010mL)を添加して、溶液を得た。反応混合物を再び50℃に加熱した後、室温に冷却し、1時間撹拌した。懸濁液を真空濾過し、濾過ケーキをMTBEですすぎ、真空下、55℃で一定重量になるまで乾燥させ、結晶質(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミドメタンスルホン酸塩(0.51g、収率78%)が得られた。LCMS(apci m/z 429.4、M+H)。
EtOH(3mL、200プルーフ)中の(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド(0.500g、1.17mmol)およびS−(+)−カンファースルホン酸(0.271g、1.17mmol)ならびにMTBE(5mL)の混合物を、撹拌しながら加熱還流させて、溶液を得た。周囲温度に冷却すると、沈殿が現れた。懸濁液を一晩室温で撹拌した後、真空濾過し、濾過ケーキをMTBEですすぎ、真空下、55℃で一定重量になるまで乾燥させ、結晶質(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド((1S,4R)−7,7−ジメチル−2−オキソビシクロ[2.2.1]ヘプタン−1−イル)メタンスルホン酸塩が得られた。
(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミドの液体製剤による処置が成功したNTRK3−ETV6融合体を有する乳児型線維肉腫
材料および方法
進行性固形腫瘍または原発性CNS腫瘍の患者の多施設小児第1相用量漸増試験を、2015年12月に開始し(ClinicalTrials.gov Identifier:NCT02637687)、化合物I−HS(すなわち、(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミドの硫酸水素塩)の安全性および耐容性を評価した。適格規準には、年齢1〜21歳(既知のTRK変化の存在に関係なく)、ならびに既知のNTRK融合体を有し、乳児型線維肉腫または先天性間葉芽腎腫(congential mesoblastic nephroma)の診断を受けている生後1ヶ月またはそれを超える年齢の患者を含めた。カプセル剤を嚥下できない患者のために、化合物I−HSの経口液体製剤を開発した。Simcyp(登録商標)Pediatric Simulation modeling(CERTARA,Princeton,New Jersey)を、患者の年齢、化合物I−HSを排出するクリアランス経路の個体発生学、および体表面積(BSA)を考慮した投与のための薬物動態学的手法を確立するために用いた。最初のコホートに対して選択された小児投与量は、推奨されている第2相の成人の投与量である100mgのBID投与量を服用する成人患者で達成される曝露に等しくなることが想定された。サイクルは28日毎に増やす連続投与で測定した。適切な画像診断法による応答の評価が8週毎に実施されるようにスケジュールされる。患者に対し、疾患進行または耐えられない毒性まで治療が継続される。
他の部位は健康な、顔面まで伸びる大きな右側頸部血管腫瘤を有する女児が誕生した。この腫瘤は、最初は、急性退縮性先天性血管腫として診断、処置された。生後6ヶ月時に、腫瘤は急速に成長し、外科的切除/大部分の除去によりIFSが明らかになり、蛍光インサイツハイブリダイゼーション(FISH)を用いて、ETV6転座によりIFSの診断が確証された。術後の最初の7日以内に、腫瘍が急速に進行し、口腔に侵入した。ビンクリスチン、アクチノマイシン−Dおよびシクロホスファミドを用いた化学療法が開始されたが、患者は1サイクル中に疾患進行を経験した。イホスファミドおよびドキソルビシン(ID)からなる新しい化学療法計画が、病変の大部分の除去手術と同時に開始され、口咽頭の障害物のために、気管開口術を実施した。2つの追加のコースのIDおよび4つのコースのイホスファミドおよびエトポシドは、腫瘍に対し、最小限の影響しか与えなかった。腫瘍は、頭蓋底、乳様突起および頸部脈管構造を含むまでに進行した。学際的外科医のチームにより、2015年10月に大規模外科的切除が実施されたが、無傷の外科的マージンは達成され得なかった。
(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミドの液体製剤
(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミドの液体製剤を表16に記載の成分を用いて調製した。
(1)API補正係数0.8137を含む。計算:遊離塩基分子量/塩式量=428.44/526.51。液体製剤の密度は1.2mg/mLである。
(2)ラベル表示=3,518.8gの塩型APIx0.8137/171,648g合計製剤*1.2g/mL密度*1,000mg/g。
(3)必要に応じ、pH調節のために製剤に加えられた追加の合計量の5%のクエン酸ナトリウムを含む。
Claims (71)
- 式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせが、約0.5重量%〜約7重量%の量で存在する、請求項1に記載の液体製剤。
- 式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせが、約1.5重量%〜約2.5重量%の量で存在する、請求項1または2に記載の液体製剤。
- 式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせが、前記液体製剤中で、約5mg/mL〜約50mg/mLの濃度を有する、請求項1〜3のいずれか一項に記載の液体製剤。
- 式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせが、前記液体製剤中で、約15mg/mL〜約35mg/mLの濃度を有する、請求項1〜4のいずれか一項に記載の液体製剤。
- 式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせが、前記液体製剤中で、約20mg/mLの濃度を有する、請求項1〜5のいずれか一項に記載の液体製剤。
- 前記可溶化剤が、シクロデキストリン、グリコール、グリセロール、およびこれらの組み合わせからなる群より選択される、請求項1〜6のいずれか一項に記載の液体製剤。
- 前記可溶化剤が、シクロデキストリンを含む、請求項1〜7のいずれか一項に記載の液体製剤。
- 前記可溶化剤が、β−シクロデキストリン誘導体、γ−シクロデキストリン、およびこれらの組み合わせからなる群より選択される、請求項1〜8のいずれか一項に記載の液体製剤。
- 前記可溶化剤が、ヒドロキシアルキル−γ−シクロデキストリンを含む、請求項1〜9のいずれか一項に記載の液体製剤。
- 前記可溶化剤が、ヒドロキシアルキル−β−シクロデキストリン、スルホアルキルエーテル−β−シクロデキストリン、およびこれらの組み合わせからなる群より選択されるβ−シクロデキストリンを含む、請求項1〜10のいずれか一項に記載の液体製剤。
- 前記可溶化剤が、ヒドロキシプロピル−β−シクロデキストリンを含む、請求項1〜11のいずれか一項に記載の液体製剤。
- 前記可溶化剤が、約5重量%〜約35重量%の量で存在する、請求項1〜12のいずれか一項に記載の液体製剤。
- 前記可溶化剤が、約13重量%〜約17重量%の量で存在する、請求項1〜13のいずれか一項に記載の液体製剤。
- 塩基をさらに含む、請求項1〜14のいずれか一項に記載の液体製剤。
- 前記塩基が、クエン酸塩、乳酸塩、リン酸塩、マレイン酸塩、酒石酸塩、コハク酸塩、酢酸塩、炭酸塩、または水酸化物のうちの少なくとも1種を含む、請求項15に記載の液体製剤。
- 前記塩基が、乳酸リチウム、乳酸ナトリウム、乳酸カリウム、乳酸カルシウム、リン酸リチウム、リン酸ナトリウム、リン酸カリウム、リン酸カルシウム、マレイン酸リチウム、マレイン酸ナトリウム、マレイン酸カリウム、マレイン酸カルシウム、酒石酸リチウム、酒石酸ナトリウム、酒石酸カリウム、酒石酸カルシウム、コハク酸リチウム、コハク酸ナトリウム、コハク酸カリウム、コハク酸カルシウム、酢酸リチウム、酢酸ナトリウム、酢酸カリウム、酢酸カルシウム、炭酸ナトリウム、炭酸カリウム、炭酸カルシウム、重炭酸ナトリウム、重炭酸カリウム、重炭酸カルシウム、水酸化ナトリウム、水酸化カリウム、または水酸化カルシウムのうちの少なくとも1種を含む、請求項15に記載の液体製剤。
- 前記塩基がクエン酸塩である、請求項15に記載の液体製剤。
- 前記クエン酸塩が、クエン酸リチウム一水和物、クエン酸ナトリウム一水和物、クエン酸カリウム一水和物、クエン酸カルシウム一水和物、クエン酸リチウム二水和物、クエン酸ナトリウム二水和物、クエン酸カリウム二水和物、クエン酸カルシウム二水和物、クエン酸リチウム三水和物、クエン酸ナトリウム三水和物、クエン酸カリウム三水和物、クエン酸カルシウム三水和物、クエン酸リチウム四水和物、クエン酸ナトリウム四水和物、クエン酸カリウム四水和物、クエン酸カルシウム四水和物、クエン酸リチウム五水和物、クエン酸ナトリウム五水和物、クエン酸カリウム五水和物、クエン酸カルシウム五水和物、クエン酸リチウム六水和物、クエン酸ナトリウム六水和物、クエン酸カリウム六水和物、クエン酸カルシウム六水和物、クエン酸リチウム七水和物、クエン酸ナトリウム七水和物、クエン酸カリウム七水和物、またはクエン酸カルシウム七水和物のうちの少なくとも1種を含む、請求項18に記載の液体製剤。
- 前記塩基が、クエン酸ナトリウム一水和物、クエン酸カリウム一水和物、クエン酸カルシウム一水和物、クエン酸ナトリウム二水和物、クエン酸カリウム二水和物、クエン酸カルシウム二水和物、クエン酸ナトリウム三水和物、クエン酸カリウム三水和物、クエン酸カルシウム三水和物、クエン酸ナトリウム四水和物、クエン酸カリウム四水和物、クエン酸カルシウム四水和物、クエン酸ナトリウム五水和物、クエン酸カリウム五水和物、クエン酸カルシウム五水和物、クエン酸ナトリウム六水和物、クエン酸カリウム六水和物、クエン酸カルシウム六水和物、クエン酸ナトリウム七水和物、クエン酸カリウム七水和物、またはクエン酸カルシウム七水和物のうちの少なくとも1種を含む、請求項18に記載の液体製剤。
- 前記塩基がクエン酸ナトリウム二水和物を含む、請求項15に記載の液体製剤。
- 前記塩基が、約0.1重量%〜約5重量%の量で存在する、請求項15〜21のいずれか一項に記載の液体製剤。
- 約2〜約7のpHを有する、請求項1〜22のいずれか一項に記載の液体製剤。
- 約3〜約4のpHを有する、請求項1〜23のいずれか一項に記載の液体製剤。
- 約3.5のpHを有する、請求項1〜24のいずれか一項に記載の液体製剤。
- 甘味料をさらに含む、請求項1〜25のいずれか一項に記載の液体製剤。
- 前記甘味料が糖を含む、請求項26に記載の液体製剤。
- 前記糖がショ糖を含む、請求項27に記載の液体製剤。
- 前記甘味料が高甘味度甘味料を含む、請求項26に記載の液体製剤。
- 前記高甘味度甘味料がスクラロースを含む、請求項29に記載の液体製剤。
- 前記甘味料が、約30重量%〜約70重量%の量で存在する、請求項26〜30のいずれか一項に記載の液体製剤。
- 前記甘味料が、約45重量%〜約55重量%の量で存在する、請求項26〜30のいずれか一項に記載の液体製剤。
- 苦味マスキング剤をさらに含む、請求項1〜32のいずれか一項に記載の液体製剤。
- 前記苦味マスキング剤が、約0.01重量%〜約2重量%の量で存在する、請求項33に記載の液体製剤。
- 前記苦味マスキング剤が、約0.2重量%〜約0.5重量%の量で存在する、請求項33または34に記載の液体製剤。
- 香味料をさらに含む、請求項1〜35のいずれか一項に記載の液体製剤。
- 前記香味料が、天然香味料、天然果実香味料、人工香味料、人工果実香味料、またはフレーバー強化剤のうちの少なくとも1種を含む、請求項36に記載の液体製剤。
- 前記香味料が、約0.01重量%〜約2重量%の量で存在する、請求項36または37に記載の液体製剤。
- 前記香味料が、約0.01重量%〜約0.1重量%の量で存在する、請求項36〜38のいずれか一項に記載の液体製剤。
- 着色料をさらに含む、請求項1〜39のいずれか一項に記載の液体製剤。
- 前記式(I)の化合物の薬学的に許容可能な塩から調製される、請求項1〜40のいずれか一項に記載の液体製剤。
- 前記式(I)の化合物の硫酸水素塩から調製される、請求項1〜40のいずれか一項に記載の液体製剤。
- 式(I)の化合物の結晶形から調製される、請求項1〜42のいずれか一項に記載の液体製剤。
- 約3〜約4のpHを有する、請求項45に記載の液体製剤。
- 前記塩基がクエン酸ナトリウム二水和物を含む、請求項45または請求項46に記載の液体製剤。
- 前記塩基が、クエン酸ナトリウム二水和物を含む、請求項48に記載の液体製剤。
- 前記甘味料が、ショ糖を含む、請求項48または49に記載の液体製剤。
- 式(I):
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ;
約5重量%〜約35重量%の量で存在する可溶化剤;
約0.1重量%〜約5重量%の量で存在する塩基;
約30重量%〜約70重量%の量で存在する甘味料;
約0.2重量%〜約0.5重量%の量で存在する苦味マスキング剤;および
約0.01重量%〜約2重量%の量で存在する香味料
を含む液体製剤であって、
約2.5〜約5.5のpHを有し、
式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせが、液体製剤中で、約20mg/mL〜約30mg/mLの濃度を有する、液体製剤。 - 式(I):
を有する(S)−N−(5−((R)−2−(2,5−ジフルオロフェニル)−ピロリジン−1−イル)−ピラゾロ[1,5−a]ピリミジン−3−イル)−3−ヒドロキシピロリジン−1−カルボキサミド、薬学的に許容可能なその塩、またはこれらの組み合わせ;
約5重量%〜約35重量%の量で存在する可溶化剤;
約0.1重量%〜約5重量%の量で存在するクエン酸ナトリウム二水和物を含む塩基;
約30重量%〜約70重量%の量で存在するショ糖を含む甘味料;
約0.2重量%〜約0.5重量%の量で存在する苦味マスキング剤;および
約0.01重量%〜約2重量%の量で存在する香味料
を含む液体製剤であって、
約3〜約4のpHを有し、
式(I)の化合物、薬学的に許容可能なその塩、またはこれらの組み合わせが、液体製剤中で、約20mg/mL〜約30mg/mLの濃度を有する、液体製剤。 - 前記結晶形が、18.4±0.2、20.7±0.2、23.1±0.2、および24.0±0.2の位置にXRPD回折ピーク(2θ度)を有することを特徴とする、請求項54に記載の液体製剤。
- 前記結晶形が、10.7±0.2、18.4±0.2、20.7±0.2、23.1±0.2、および24.0±0.2の位置にXRPD回折ピーク(2θ度)を有することを特徴とする、請求項54に記載の液体製剤。
- 前記結晶形が、10.7±0.2、18.4±0.2、19.2±0.2、20.2±0.2、20.7±0.2、21.5±0.2、23.1±0.2、および24.0±0.2の位置にXRPD回折ピーク(2θ度)を有することを特徴とする、請求項54に記載の液体製剤。
- 前記結晶形が、10.7±0.2、15.3±0.2、16.5±0.2、18.4±0.2、19.2±0.2、19.9±0.2、20.2±0.2、20.7±0.2、21.5±0.2、22.1±0.2、23.1±0.2、24.0±0.2、24.4±0.2、25.6±0.2、26.5±0.2、27.6±0.2、28.2±0.2、28.7±0.2、30.8±0.2、および38.5±0.2の位置にXRPD回折ピーク(2θ度)を有することを特徴とする、請求項54に記載の液体製剤。
- 必要としている患者において癌を処置する方法であって、
(a)処置を必要としている嚥下障害を有する患者を特定する工程;および
(b)請求項1〜58のいずれか一項に記載の液体製剤を治療有効量で前記患者に投与する工程
を含む、方法。 - 必要としている患者において癌を処置する方法であって、
(a)処置を必要としている嚥下障害を有する患者を特定する工程;
(b)前記癌が、Trkキナーゼにより媒介されているかどうかを判定する工程;および
(c)前記癌が、Trkキナーゼにより媒介されていると判定される場合、請求項1〜58のいずれか一項に記載の液体製剤を治療有効量で前記患者に投与する工程
を含む、方法。 - 必要としている患者において癌を処置する方法であって、請求項1〜58のいずれか一項に記載の液体製剤を治療有効量で前記患者に投与する工程を含む、方法。
- 前記癌が、頭頸部癌、喉頭癌、食道癌、またはこれらの組み合わせからなる群から選択される、請求項61に記載の方法。
- 前記患者が、乳幼児、子供、青年、または高齢患者である、請求項61または62に記載の方法。
- 必要としている対象において癌を処置するための方法であって、
(a)前記癌が、Trkキナーゼの過剰発現、活性化、増幅、および変異のうちの1つまたは複数に関連しているかどうかを判定する工程;ならびに
(b)前記癌が、Trkキナーゼの過剰発現、活性化、増幅および変異の1つまたは複数に関連すると判定される場合、請求項1〜58のいずれか一項に記載の液体製剤を治療有効量で前記対象に投与する工程
を含む、方法。 - 必要としている対象において癌を処置するための方法であって、
(a)前記癌が、Trkキナーゼにより媒介されているかどうかを判定する工程;および
(b)前記癌が、Trkキナーゼにより媒介されていると判定される場合、請求項1〜58のいずれか一項に記載の液体製剤を治療有効量で前記対象に投与する工程
を含む、方法。 - 対象を処置する方法であって、
(a)前記対象から得た試料でアッセイを実施し、前記対象がNTRK遺伝子、Trkタンパク質、またはその発現もしくはレベルの調節不全を有するかどうかを判定する工程;および
(b)NTRK遺伝子、Trkタンパク質、またはその発現もしくは活性もしくはレベルの調節不全を有すると判定された対象に、請求項1〜58のいずれか一項に記載の液体製剤を治療有効量で投与する工程
を含む、方法。 - NTRK遺伝子、Trkタンパク質、またはその発現もしくはレベルの前記調節不全が、Trk融合タンパク質の翻訳をもたらす染色体翻訳である、請求項66に記載の方法。
- 前記Trk融合タンパク質が、TP53−TrkA、LMNA−TrkA、CD74−TrkA、TFG−TrkA、TPM3−TrkA、NFASC−TrkA、BCAN−TrkA、MPRIP−TrkA、TPR−TrkA、RFWD2−TrkA、IRF2BP2−TrkA、SQSTM1−TrkA、SSBP2−TrkA、RABGAP1L−TrkA、C18ORF8−TrkA、RNF213−TrkA、TBC1D22A−TrkA、C20ORF112−TrkA、DNER−TrkA、ARHGEF2−TrkA、CHTOP−TrkA、PPL−TrkA、PLEKHA6−TrkA、PEAR1−TrkA、MRPL24−TrkA、MDM4−TrkA、LRRC71−TrkA、GRIPAP1−TrkA、EPS15−TrkA、DYNC2H1−TrkA、CEL−TrkA、EPHB2−TrkA、TGF−TrkA、NACC2−TrkB、QKI−TrkB、AFAP1−TrkB、PAN3−TrkB、SQSTM1−TrkB、TRIM24−TrkB、VCL−TrkB、AGBL4−TrkB、DAB2IP−TrkB、ETV6−TrkC、BTBD1−TrkC、LYN−TrkC、RBPMS−TrkC、EML4−TrkC、HOMER2−TrkC、TFG−TrkC、FAT1−TrkC、およびTEL−TrkCからなる群から選択される、請求項67に記載の方法。
- NTRK遺伝子、Trkタンパク質、またはその発現もしくは活性の前記調節不全が、前記遺伝子の1つまたは複数の点変異である、請求項66に記載の方法。
- 前記NTRK遺伝子が、NTRK1遺伝子であり、前記NTRK1遺伝子の前記1つまたは複数の点変異が、アミノ酸位置:33、336、337、324、420、444、517、538、649、682、683、702、および1879のうちの1つまたは複数に置換を有するTrkAタンパク質の翻訳をもたらす、請求項69に記載の方法。
- 前記NTRK1遺伝子の前記1つまたは複数の点変異が、アミノ酸置換:R33W、A336E、A337T、R324Q、R324W、V420M、R444Q、R444W、G517R、G517V、K538A、R649W、R649L、R682S、V683G、R702C、およびC1879Tのうちの1つまたは複数を有するTrkAタンパク質の翻訳をもたらす、請求項69に記載の方法。
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