JP6865036B2 - 遊離塩基結晶 - Google Patents
遊離塩基結晶 Download PDFInfo
- Publication number
- JP6865036B2 JP6865036B2 JP2016521847A JP2016521847A JP6865036B2 JP 6865036 B2 JP6865036 B2 JP 6865036B2 JP 2016521847 A JP2016521847 A JP 2016521847A JP 2016521847 A JP2016521847 A JP 2016521847A JP 6865036 B2 JP6865036 B2 JP 6865036B2
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- JP
- Japan
- Prior art keywords
- methyl
- crystals
- pyrazolo
- fluoropyridin
- free base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000013078 crystal Substances 0.000 title claims description 296
- 239000012458 free base Substances 0.000 title claims description 166
- 239000000203 mixture Substances 0.000 claims description 131
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 103
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 97
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 81
- 239000012453 solvate Substances 0.000 claims description 75
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 73
- 238000000034 method Methods 0.000 claims description 68
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 66
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 claims description 62
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 60
- 239000012044 organic layer Substances 0.000 claims description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
- 150000003839 salts Chemical class 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- 239000002904 solvent Substances 0.000 claims description 43
- -1 (6-fluoropyridin-2-yl) phenyl Chemical group 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 150000004712 monophosphates Chemical class 0.000 claims description 23
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 21
- 238000004519 manufacturing process Methods 0.000 claims description 21
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 18
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 10
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
- 239000001530 fumaric acid Substances 0.000 claims description 8
- 229910019142 PO4 Inorganic materials 0.000 claims description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- HCZCZIVEWQQNFZ-UHFFFAOYSA-N P(=O)(O)(O)O.N1NC=C2C(N=CN=C21)=O Chemical compound P(=O)(O)(O)O.N1NC=C2C(N=CN=C21)=O HCZCZIVEWQQNFZ-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- JTBBWRKSUYCPFY-UHFFFAOYSA-N 2,3-dihydro-1h-pyrimidin-4-one Chemical compound O=C1NCNC=C1 JTBBWRKSUYCPFY-UHFFFAOYSA-N 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims 3
- 230000008018 melting Effects 0.000 claims 3
- 239000000126 substance Substances 0.000 claims 3
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical class C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 description 73
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 73
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 65
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 32
- 238000001914 filtration Methods 0.000 description 31
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 28
- 239000010949 copper Substances 0.000 description 27
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 23
- 235000019439 ethyl acetate Nutrition 0.000 description 22
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 21
- 239000008096 xylene Substances 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 229910052802 copper Inorganic materials 0.000 description 18
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 13
- BBIPVJCGIASXJB-PKTZIBPZSA-N (11R,15S)-5-anilino-4-[[4-(6-fluoropyridin-2-yl)phenyl]methyl]-8-methyl-1,3,4,8,10-pentazatetracyclo[7.6.0.02,6.011,15]pentadeca-2,5,9-trien-7-one Chemical compound N1([C@H]2CCC[C@H]2N=C1N(C(C1=C2NC=3C=CC=CC=3)=O)C)C1=NN2CC(C=C1)=CC=C1C1=CC=CC(F)=N1 BBIPVJCGIASXJB-PKTZIBPZSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000010926 purge Methods 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 238000002411 thermogravimetry Methods 0.000 description 10
- 229910052782 aluminium Inorganic materials 0.000 description 9
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 9
- 238000007254 oxidation reaction Methods 0.000 description 9
- 230000035945 sensitivity Effects 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 8
- 238000002788 crimping Methods 0.000 description 8
- 239000011521 glass Substances 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 235000021317 phosphate Nutrition 0.000 description 6
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 5
- 238000007614 solvation Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- ZQJUAPPNCFBJJW-UHFFFAOYSA-N 1,3,4,8,10-pentazatricyclo[7.3.0.02,6]dodeca-2,4,6,8,10-pentaene Chemical compound C1=C2C=NN=C2N2CC=NC2=N1 ZQJUAPPNCFBJJW-UHFFFAOYSA-N 0.000 description 3
- RHNXMQLPXJSMON-UHFFFAOYSA-N 2-[4-(chloromethyl)phenyl]-6-fluoropyridine Chemical compound FC1=CC=CC(C=2C=CC(CCl)=CC=2)=N1 RHNXMQLPXJSMON-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
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- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
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- 239000008194 pharmaceutical composition Substances 0.000 description 3
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- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- YSCXUVDHFWPGFP-SJORKVTESA-N (6ar,9as)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-2-(4-(6-fluoro-pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2h)-one Chemical compound N1([C@H]2CCC[C@H]2N=C1N(C(C1=C2Cl)=O)C)C1=NN2CC(C=C1)=CC=C1C1=CC=CC(F)=N1 YSCXUVDHFWPGFP-SJORKVTESA-N 0.000 description 2
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- XMMHSXURCPJTAF-UHFFFAOYSA-N 5-anilino-4-[[4-(6-fluoropyridin-2-yl)phenyl]methyl]-8-methyl-1,3,4,8,10-pentazatetracyclo[7.6.0.02,6.011,15]pentadeca-12,14-dien-7-one Chemical compound CN1C2N(C3C(C1=O)C(N(N3)CC1=CC=C(C=C1)C1=NC(=CC=C1)F)NC1=CC=CC=C1)C=1C(N2)C=CC=1 XMMHSXURCPJTAF-UHFFFAOYSA-N 0.000 description 1
- JVYBHXSIAJRNGN-UHFFFAOYSA-N 7-[(4-methoxyphenyl)methyl]-5-methyl-1h-pyrazolo[3,4-d]pyrimidine-4,6-dione Chemical compound C1=CC(OC)=CC=C1CN1C(=O)N(C)C(=O)C2=C1NN=C2 JVYBHXSIAJRNGN-UHFFFAOYSA-N 0.000 description 1
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- 208000006289 Rett Syndrome Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
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- 239000008186 active pharmaceutical agent Substances 0.000 description 1
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
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- 238000012512 characterization method Methods 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- 230000008020 evaporation Effects 0.000 description 1
- 229940051164 ferric oxide yellow Drugs 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
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- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
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- 239000002198 insoluble material Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 201000003631 narcolepsy Diseases 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000000646 scanning calorimetry Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000012032 thrombin generation assay Methods 0.000 description 1
- 208000014903 transposition of the great arteries Diseases 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本発明は、(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基の結晶およびこのような遊離塩基結晶の製造法および使用法に関する。
化合物(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンはWO2009/075784(米国公開番号2010/0273754)に開示されている。この化合物は、PDE1発現細胞における低レベルのcAMPおよび/またはcGMPおよび/またはドーパミンD1受容体シグナル伝達活性低下により特徴付けられる障害(例えば、パーキンソン病、トゥーレット症候群、自閉症、脆弱X症候群、ADHD、レストレスレッグ症候群、うつ病、統合失調症の認知機能障害、ナルコレプシー);および/またはプロゲステロンシグナル伝達の増強により軽減し得る何らかの疾患または状態の処置または予防に有用な強力かつ選択的ホスホジエステラーゼ1(PDE1)阻害剤であることが判明している。この障害の一覧は例示的であり、網羅的であることを意図しない。
24種の異なる溶媒と、熟成、温度循環、蒸発、クラッシュ・クーリング、貧溶媒添加、湿気誘発結晶化、アニーリングおよび超音波促進結晶化法の組み合わせを使用して、遊離塩基形態の化合物(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン(“化合物A”)が、多くの溶媒系中で非晶質固体または油状物として存在するが、驚くべきことに、特定の溶媒系および方法を使用したときに、結晶形態で単離できることが判明した。これらの遊離塩基結晶は安定であり、該化合物Aのモノリン酸塩結晶の製造に特に有利であり、該塩の製造においては化合物A対酸比1:1を形成するためには、極めて高度に制御された化学量論量のリン酸を一般に必要とする。いかなる特定の理論にも拘束されないが、遊離塩基結晶形態の化合物Aは、非晶質形態と比較して含まれる不純物が極めて小量であり、化合物Aのモノリン酸付加塩の製造のためのリン酸の量が正確に決定され、それによりモノリン酸塩結晶を効率的に、安定して、かつ再現性よく製造することを可能にする。それゆえに、先ず、第一の面において、本発明は次のものを提供する。
(1) 非溶媒和物または溶媒和物形態の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基(化合物A)の結晶、すなわち、化合物Aの遊離塩基結晶を溶媒に溶解し;
(2) 工程(1)で得られた溶液に、所望により溶媒中の酸を添加し、そして
(3) 工程(2)で得られた混合物を撹拌して、目的の塩を得る
ことを含む、方法を提供する。
(1) 非溶媒和物または溶媒和物形態の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基の結晶(すなわち、化合物Aの遊離塩基結晶)を溶媒に溶解し;
(2) 工程(1)で得られた溶液に溶媒中のリン酸を添加し、そして
(3) 工程(2)で得られた混合物を撹拌して、目的のモノリン酸塩結晶を得る
ことを含む、方法を提供する。
(1)(6aR,9aS)−3−クロロ−2−(4−(6−フルオロピリジン−2−イル)ベンジル)−5−メチル−5,6a,7,8,9,9a−ヘキサヒドロシクロペンタ[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンを溶媒中、塩基、アニリン、パラジウム触媒およびリガンドの存在下で撹拌し、次いで有機層を分離し;
(2)工程(1)において得た有機層に目的の溶媒和物形態に対応する溶媒を添加する
ことを含む、方法である。
(1)(6aR,9aS)−3−クロロ−2−(4−(6−フルオロピリジン−2−イル)ベンジル)−5−メチル−5,6a,7,8,9,9a−ヘキサヒドロシクロペンタ[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンを溶媒中、塩基、アニリン、パラジウム触媒およびリガンドの存在下で撹拌し、次いで有機層を分離し;
(2)工程(1)において得た有機層に非溶媒和物形態の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基の種晶を添加する
ことを含む、方法である。
(1) 非溶媒和物または溶媒和物形態の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン(化合物A)の塩結晶(すなわち、化合物Aの塩結晶)を有機溶媒、水および塩基水溶液の混合物に溶解し;
(2) 有機層を分離し;
(3) 工程(2)に溶媒を添加して、目的の溶媒和物を形成させ;
(4) 工程(3)で得られた混合物を撹拌して、目的の結晶を得る
ことを含む、方法を提供する。
(a) 非溶媒和物または溶媒和物形態のヘミフマル酸塩の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン(化合物A)の塩結晶を有機溶媒と塩基性水溶液の混合物に溶解し;
(b) 有機層を分離し;
(c) 工程(b)で得られた有機溶媒溶液にエタノールを添加し;
(d) 工程(c)で得られた混合物を撹拌して、目的の結晶を得て;
(e) 工程(d)で得られた結晶を単離し;
(f) 工程(e)で得られた結晶を溶解し;
(g) 工程(f)で得られた溶液に溶媒中のリン酸(例えば、化合物Aの遊離塩基結晶の0.5〜2.0当量、好ましくは0.8〜1.2当量、より好ましくは、0.9〜1.1当量の量)を添加し;そして
(h) 工程(g)で得られた混合物を撹拌して、目的の塩を得る
ことを含む、方法を提供する。
(4−(6−フルオロピリジン−2−イル)フェニル)メタノール
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基モノエタノール溶媒和物の結晶
1H NMR (500 MHz, DMSO-d6) δ 0.98-1.13 (m, 3H), 1.34-1.52 (m, 1H), 1.54-1.83 (m, 4H), 2.03-2.17 (m, 1H), 3.11 (s, 3H), 3.39-3.54 (m, 2H), 4.29-4.43 (m, 1H), 4.51-4.60 (m, 1H), 4.60-4.70 (m, 1H), 5.15-5.35 (m, 2H), 6.71-6.88 (m, 3H), 7.05-7.29 (m, 5H), 7.81-7.93 (m, 1H), 7.94-8.11 (m, 3H), 8.67 (s, 1H)
チューブアノード:Cu
発生機電圧:30kV
チューブ電流:15mA
波長α1:1.5406Å
波長α2:1.5444Å
開始角度[2θ]:3
終了角度[2θ]:40
走査速度6.000°/分
走査ステップサイズ:0.02
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基モノエタノール溶媒和物の結晶
チューブアノード:Cu
発生機電圧:40kV
チューブ電流:40mA
波長α1:1.5406Å
波長α2:1.5444Å
開始角度[2θ]:4
終了角度[2θ]:40
ステップあたりの時間:2.5秒
走査ステップサイズ:0.016
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基モノ−n−プロパノール溶媒和物の結晶
1H NMR (500 MHz, DMSO-d6) δ 0.74-0.92 (m, 3H), 1.31-1.50 (m, 3H), 1.54-1.83 (m, 4H), 1.98-2.21 (m, 1H), 3.11 (s, 3H), 3.25-3.42 (m, 2H), 4.29-4.43 (m, 1H), 4.51-4.60 (m, 1H), 4.60-4.70 (m, 1H), 5.15-5.35 (m, 2H), 6.71-6.88 (m, 3H), 7.05-7.29 (m, 5H), 7.81-7.93 (m, 1H), 7.94-8.11 (m, 3H), 8.66 (s, 1H)
チューブアノード:Cu
発生機電圧:30kV
チューブ電流:15mA
波長α1:1.5406Å
波長α2:1.5444Å
開始角度[2θ]:3
終了角度[2θ]:40
走査速度6.000°/分
走査ステップサイズ:0.02
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基モノイソプロパノール溶媒和物の結晶
1H NMR (500 MHz, DMSO-d6) δ 1.04 (d, 6H, J=5.99 Hz), 1.30-1.50 (m, 1H), 1.51-1.83 (m, 4H), 1.99-2.20 (m, 1H), 3.11 (s, 3H), 3.72-3.88 (m, 1H), 4.28-4.40 (m, 1H), 4.50-4.60 (m, 1H), 4.60-4.70 (m, 1H), 5.15-5.32 (m, 2H), 6.71-6.91 (m, 3H), 7.01-7.30 (m, 5H), 7.84-7.94 (m, 1H), 7.94-8.12 (m, 3H), 8.65 (s, 1H)
チューブアノード:Cu
発生機電圧:30kV
チューブ電流:15mA
波長α1:1.5406Å
波長α2:1.5444Å
開始角度[2θ]:3
終了角度[2θ]:40
走査速度6.000°/分
走査ステップサイズ:0.02
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基非溶媒和物の結晶
1H NMR (500 MHz, DMSO-d6) δ 1.32-1.51 (m, 1H), 1.53-1.83 (m, 4H), 1.97-2.20 (m, 1H), 3.11 (s, 3H), 4.49-4.60 (m, 1H), 4.60-4.69 (m, 1H), 5.13-5.37 (m, 2H), 6.70-6.90 (m, 3H), 7.04-7.31 (m, 5H), 7.82-7.93 (m, 1H), 7.93-8.12 (m, 3H), 8.67 (s, 1H)
チューブアノード:Cu
発生機電圧:30kV
チューブ電流:15mA
波長α1:1.5406Å
波長α2:1.5444Å
開始角度[2θ]:3
終了角度[2θ]:40
走査速度6.000°/分
走査ステップサイズ:0.02
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基非溶媒和物の結晶
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基モノメタノール溶媒和物の結晶
1H NMR (500 MHz, DMSO-d6) δ 1.34-1.51 (m, 1H), 1.52-1.80 (m, 4H), 2.02-2.16 (m, 1H), 3.12 (s, 3H), 3.18 (d, 3H, J=5.36 Hz), 4.10 (q, 1H, J= 5.36 Hz), 4.52-4.59 (m, 1H), 4.60-4.69 (m, 1H), 5.14-5.32 (m, 2H), 6.74-6.85 (m, 3H), 7.08-7.27 (m, 5H), 7.85-7.93 (m, 1H), 7.93-8.10 (m, 3H), 8.65 (s, 1H)
チューブアノード:Cu
発生機電圧:30kV
チューブ電流:15mA
波長α1:1.5406Å
波長α2:1.5444Å
開始角度[2θ]:3
終了角度[2θ]:40
走査速度6.000°/分
走査ステップサイズ:0.02
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基モノ−n−ブタノール溶媒和物の結晶
1H NMR (500 MHz, DMSO-d6) δ 0.87 (t, J=7.4 Hz, 3H), 1.25-1.48 (m, 5H), 1.54-1.78 (m, 4H), 2.00-2.20 (m, 1H), 3.11 (s, 3H), 3.30-3.42 (m, 2H), 4.29-4.32 (m, 1H), 4.51-4.60 (m, 1H), 4.60-4.70 (m, 1H), 5.19-5.30 (m, 2H), 6.71-6.90 (m, 3H), 7.05-7.25 (m, 5H), 7.81-7.93 (m, 1H), 7.94-8.10 (m, 3H), 8.64 (s, 1H)
チューブアノード:Cu
発生機電圧:30kV
チューブ電流:15mA
波長α1:1.5406Å
波長α2:1.5444Å
開始角度[2θ]:3
終了角度[2θ]:40
走査速度6.000°/分
走査ステップサイズ:0.02
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンモノリン酸塩
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンモノリン酸塩
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンモノリン酸塩
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンモノリン酸塩
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンヘミフマル酸塩0.5酢酸エチル0.3アセトン溶媒和物の塩結晶
1H NMR (500 MHz, DMSO-d6) δ 1.18 (t, J = 7.09 Hz, 1.5H), 1.38-1.52 (m, 1H), 1.56-1.80 (m, 4H), 2.00 (s, 1.5 H), 2.05-2.16 (m, 3H), 3.12 (s, 3H), 4.04 (q, J = 6.94 Hz, 1H), 4.54-4.61 (m, 1H), 4.62-4.71 (m, 1H), 5.20-5.31 (m, 2H), 6.62 (s, 1H), 6.77-6.84 (m, 3H), 7.12-7.24 (m, 5H), 7.89-7.92 (m, 1H), 7.98-8.10 (m, 3H), 8.69 (s, 1H)
チューブアノード:Cu
発生機電圧:30kV
チューブ電流:15mA
波長α1:1.5406Å
波長α2:1.5444Å
開始角度[2θ]:3
終了角度[2θ]:40
走査速度6.000°/分
走査ステップサイズ:0.02
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基モノエタノール溶媒和物の結晶
(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンモノ安息香酸塩結晶
1H NMR (500 MHz, DMSO-d6) δ 1.37-1.50 (m, 1H), 1.58-1.76 (m, 4H), 2.06-2.13 (m, 1H), 3.12 (s, 3H), 4.54-4.60 (m, 1H), 4.62-4.67 (m, 1H), 5.20-5.29 (m, 2H), 6.77-6.84 (m, 3H), 7.11-7.24 (m, 5H), 7.49-7.53 (m, 2H), 7.60-7.65 (m, 1H), 7.89-7.92 (m, 1H), 7.93-7.97 (m, 2H), 7.97-8.02 (m, 2H), 8.02-8.09 (m, 1H), 8.67 (s, 1H), 12.95 (bro, 1H)
チューブアノード:Cu
発生機電圧:30kV
チューブ電流:15mA
波長α1:1.5406Å
波長α2:1.5444Å
開始角度[2θ]:3
終了角度[2θ]:40
走査速度6.000°/分
走査ステップサイズ:0.02
化合物Aのモノリン酸塩結晶を含む医薬組成物
結合剤溶液を、ヒドロキシプロピルセルロース(157.5g)を精製水(2468g)に溶解することにより調製する。化合物Aのモノリン酸塩結晶(1232g)、マンニトール(2996g)、微結晶セルロース(367.5g)およびデンプングリコール酸ナトリウム(262.5g)を、流動層造粒装置に入れる。入れた粉末(5016g)を、結合剤溶液(2626g)を流動層造粒装置中で噴霧することにより増収する。顆粒を流動層造粒装置中で乾燥させる。乾燥顆粒を、1.5mmΦパンチングスクリーンを備えたパワーミルを使用して粉砕する。粉砕顆粒(4299g)を、拡散混合器中で微結晶セルロース(135.0g)およびステアリン酸マグネシウム(66.00g)と混合する。混合顆粒(4200g)を、7mmΦのパンチを備えた打錠機を使用して、150mgの荷重で錠剤に圧縮する。錠剤(3000g)を、プレミックス1(ヒプロメロー2910/ポリエチレングリコール8000/二酸化チタン/酸化第二鉄赤色=9/2/1/0.2)およびプレミックス2(ヒプロメロー2910/ポリエチレングリコール8000/二酸化チタン/酸化第二鉄黄色=9/2/1/0.2)を含む水性フィルムコーティング溶液で被覆する。
Claims (19)
- 107℃〜108℃の吸熱ピークを含む示差走査熱量測定(DSC)融解吸熱パターンまたは図1−Aに示される示差走査熱量測定(DSC)パターンを示す、請求項1に記載の結晶。
- 97℃の吸熱ピークを含む示差走査熱量測定(DSC)融解吸熱パターンまたは図3−Aに示される示差走査熱量測定(DSC)パターンを示す、請求項3に記載の結晶。
- 84℃〜85℃の吸熱ピークを含む示差走査熱量測定(DSC)融解吸熱パターンまたは図5−Aに示される示差走査熱量測定(DSC)パターンを示す、請求項5に記載の結晶。
- (6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンの塩の製造法であって、
(1) 非溶媒和物または溶媒和物形態の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基の結晶を溶媒に溶解し;
(2) 工程(1)で得られた溶液に、所望により溶媒中の酸を添加し、そして
(3) 工程(2)で得られた混合物を撹拌して、(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンの塩を得る
ことを含む、方法。 - 該塩が塩結晶である、請求項7に記載の方法。
- 該塩結晶がフマル酸塩、リン酸塩、1−ヒドロキシ−2−ナフトエ酸塩、メタンスルホン酸塩または安息香酸塩の結晶から選択される、請求項8に記載の方法。
- 工程(2)の酸がフマル酸、リン酸、酒石酸、メタンスルホン酸および安息香酸から選択される、請求項8に記載の方法。
- 工程(1)および/または(2)の溶媒がメタノール、アセトニトリル、アセトンまたはそれらの混合物である、請求項7〜9のいずれかに記載の方法。
- (6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンのモノリン酸塩結晶の製造法であって、
(1) 非溶媒和物または溶媒和物形態の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基の結晶を溶媒に溶解し;
(2) 工程(1)で得られた溶液に溶媒中のリン酸を添加し、そして
(3) 工程(2)で得られた混合物を撹拌して、(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンのモノリン酸塩結晶を得る
ことを含む、方法。 - 工程(1)における溶媒がアセトンおよびアセトニトリルから選択される、請求項12に記載の方法。
- 工程(2)における溶媒がアセトンまたはアセトニトリルから選択される、請求項12または13に記載の方法。
- 工程(2)で添加すべきリン酸の量が工程(1)の非溶媒和物形態または溶媒和物形態の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン遊離塩基の結晶の量と等モル量である、請求項12〜14のいずれかに記載の方法。
- 工程(2)においてさらに水を添加する、請求項12〜15のいずれかに記載の方法。
- 工程(3)において混合物を20〜70℃で撹拌する、請求項12〜16のいずれかに記載の方法。
- 混合物を50℃、32℃、38℃または39℃で撹拌する、請求項17に記載の方法。
- (6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンのモノリン酸塩結晶の製造法であって、
(a) 非溶媒和物または溶媒和物形態のヘミフマル酸塩の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンの塩結晶を有機溶媒と塩基性水溶液の混合物に溶解し;
(b) 有機層を分離し;
(c) 工程(b)で得られた有機溶液にエタノールを添加し;
(d) 工程(c)で得られた混合物を撹拌して、対応する結晶を得て;
(e) 工程(d)で得られた結晶を単離し;
(f) 工程(e)で得られた結晶を溶解し;
(g) 工程(f)で得られた溶液に溶媒中のリン酸を添加し;そして
(h) 工程(g)で得られた混合物を撹拌して、(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オンのモノリン酸塩結晶を得る
ことを含む、方法。
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EP2717877B1 (en) | 2011-06-10 | 2017-11-08 | Intra-Cellular Therapies, Inc. | Organic compounds |
AR091507A1 (es) | 2012-06-21 | 2015-02-11 | Intra Cellular Therapies Inc | SALES DE (6aR,9aS)-5,6a,7,8,9,9a-HEXAHIDRO-5-METIL-3-(FENILAMINO)-2-((4-(6-FLUOROPIRIDIN-2-IL)FENIL)METIL)-CICLOPENT[4,5]IMIDAZO[1,2-a]PIRAZOLO[4,3-e]PIRIMIDIN-4(2H)-ONA |
RU2675851C2 (ru) | 2013-06-21 | 2018-12-25 | Интра-Селлулар Терапиз, Инк. | Кристаллические формы свободного основания |
JP2022546710A (ja) | 2019-09-03 | 2022-11-07 | イントラ-セルラー・セラピーズ・インコーポレイテッド | 新規化合物 |
WO2021226407A1 (en) * | 2020-05-06 | 2021-11-11 | Intra-Cellular Therapies, Inc. | Free base crystals |
WO2023034965A2 (en) * | 2021-09-03 | 2023-03-09 | Intra-Cellular Therapies, Inc. | Co-crystals |
WO2023147484A1 (en) * | 2022-01-27 | 2023-08-03 | Intra-Cellular Therapies, Inc. | Novel compositions |
WO2023233410A1 (en) * | 2022-06-02 | 2023-12-07 | Biosight Ltd. | Crystalline form of aspacytarabine intermediate |
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GB9412571D0 (en) | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
US5471001A (en) * | 1994-12-15 | 1995-11-28 | E. I. Du Pont De Nemours And Company | Crystallization of adipic acid |
GB9624615D0 (en) | 1996-11-26 | 1997-01-15 | Zeneca Ltd | Chrystallisation process |
TWI265925B (en) | 1999-10-11 | 2006-11-11 | Pfizer | Pyrazolo[4,3-d]pyrimidin-7-ones useful in inhibiting type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterases(cGMP PDE5), process and intermediates for their preparation, their uses and composition comprising them |
NZ534523A (en) | 2002-02-08 | 2006-10-27 | Ono Pharmaceutical Co | Piperidine derivative compounds and drugs containing the compounds as the active ingredient |
EP1613747A1 (en) | 2003-03-31 | 2006-01-11 | Pfizer Products Inc. | Crystal structure of 3 ,5 -cyclic nucleotide phosphodiesterase 1b (pde1b) and uses thereof |
US20060287528A1 (en) | 2003-09-02 | 2006-12-21 | Wenslow Robert M | Novel crystalline forms of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor |
US7732615B2 (en) * | 2004-09-27 | 2010-06-08 | Acadia Pharmaceuticals Inc. | N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms |
JP5084725B2 (ja) | 2005-06-06 | 2012-11-28 | 武田薬品工業株式会社 | 有機化合物 |
WO2008063505A1 (en) | 2006-11-13 | 2008-05-29 | Intra-Cellular Therapies, Inc. | Organic compounds |
JP5837278B2 (ja) | 2006-12-05 | 2015-12-24 | イントラ−セルラー・セラピーズ・インコーポレイテッドIntra−Cellular Therapies, Inc. | 新規使用 |
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WO2010065617A1 (en) | 2008-12-02 | 2010-06-10 | University Of Utah Research Foundation | Pde1 as a target therapeutic in heart disease |
MX2011005936A (es) | 2008-12-06 | 2011-12-16 | Intra Cellular Therapies Inc | Compuestos organicos. |
EP2358723B1 (en) | 2008-12-06 | 2015-05-13 | Intra-Cellular Therapies, Inc. | 4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine compounds as PDE1 inhibitors |
AU2009322901A1 (en) | 2008-12-06 | 2010-06-10 | Intra-Cellular Therapies, Inc. | Organic compounds |
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JP2013507360A (ja) | 2009-10-08 | 2013-03-04 | イントラ−セルラー・セラピーズ・インコーポレイテッド | ホスホジエステラーゼ1−標的トレーサーおよび方法 |
EP2576551A4 (en) | 2010-05-31 | 2014-04-16 | Intra Cellular Therapies Inc | ORGANIC COMPOUNDS |
TW201206937A (en) | 2010-05-31 | 2012-02-16 | Intra Cellular Therapies Inc | Organic compounds |
EP2717877B1 (en) | 2011-06-10 | 2017-11-08 | Intra-Cellular Therapies, Inc. | Organic compounds |
AR091507A1 (es) * | 2012-06-21 | 2015-02-11 | Intra Cellular Therapies Inc | SALES DE (6aR,9aS)-5,6a,7,8,9,9a-HEXAHIDRO-5-METIL-3-(FENILAMINO)-2-((4-(6-FLUOROPIRIDIN-2-IL)FENIL)METIL)-CICLOPENT[4,5]IMIDAZO[1,2-a]PIRAZOLO[4,3-e]PIRIMIDIN-4(2H)-ONA |
RU2675851C2 (ru) | 2013-06-21 | 2018-12-25 | Интра-Селлулар Терапиз, Инк. | Кристаллические формы свободного основания |
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