ES2894770T3 - Cristales de base libre - Google Patents
Cristales de base libre Download PDFInfo
- Publication number
- ES2894770T3 ES2894770T3 ES14812994T ES14812994T ES2894770T3 ES 2894770 T3 ES2894770 T3 ES 2894770T3 ES 14812994 T ES14812994 T ES 14812994T ES 14812994 T ES14812994 T ES 14812994T ES 2894770 T3 ES2894770 T3 ES 2894770T3
- Authority
- ES
- Spain
- Prior art keywords
- methyl
- pyrimidin
- pyrazolo
- solvate
- 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.)
- Active
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- 239000012458 free base Substances 0.000 title claims abstract description 134
- 239000013078 crystal Substances 0.000 title claims description 224
- 239000012453 solvate Substances 0.000 claims abstract description 93
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 69
- 229940126062 Compound A Drugs 0.000 claims abstract description 58
- 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 claims abstract description 58
- 239000010949 copper Substances 0.000 claims abstract description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 13
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052802 copper Inorganic materials 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims description 123
- 239000012044 organic layer Substances 0.000 claims description 59
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 57
- 238000000034 method Methods 0.000 claims description 38
- 239000000243 solution Substances 0.000 claims description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 26
- 150000003839 salts Chemical group 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 23
- -1 4-(6-fluoropyridin-2-yl)phenyl Chemical group 0.000 claims description 18
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 5
- 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 claims description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- 238000000113 differential scanning calorimetry Methods 0.000 description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 32
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 28
- 238000001914 filtration Methods 0.000 description 27
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 20
- 239000008096 xylene Substances 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 13
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 12
- 230000004907 flux Effects 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000010926 purge 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
- 239000011780 sodium chloride Substances 0.000 description 9
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 8
- 239000011521 glass Substances 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-Butanol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 8
- 238000002411 thermogravimetry Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 7
- 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 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 239000001530 fumaric acid Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 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
- UNRBJEOYYDGFGE-UHFFFAOYSA-N 2-[[4-(6-fluoropyridin-2-yl)phenyl]methyl]-5-methyl-1h-pyrazolo[3,4-d]pyrimidine-4,6-dione Chemical compound C1=C2C(=O)N(C)C(=O)NC2=NN1CC(C=C1)=CC=C1C1=CC=CC(F)=N1 UNRBJEOYYDGFGE-UHFFFAOYSA-N 0.000 description 3
- NINZAMOQCXMUNF-UHFFFAOYSA-N 6-chloro-1-[(4-methoxyphenyl)methyl]-3-methylpyrimidine-2,4-dione Chemical compound C1=CC(OC)=CC=C1CN1C(=O)N(C)C(=O)C=C1Cl NINZAMOQCXMUNF-UHFFFAOYSA-N 0.000 description 3
- KTTPPSPBNHDDGN-UHFFFAOYSA-N 6-hydrazinyl-1-[(4-methoxyphenyl)methyl]-3-methylpyrimidine-2,4-dione Chemical compound C1=CC(OC)=CC=C1CN1C(=O)N(C)C(=O)C=C1NN KTTPPSPBNHDDGN-UHFFFAOYSA-N 0.000 description 3
- 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 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- TYBWSXXWAKLUNF-UHFFFAOYSA-N OCc1ccc(cc1)-c1cccc(F)n1 Chemical compound OCc1ccc(cc1)-c1cccc(F)n1 TYBWSXXWAKLUNF-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 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
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 2
- KJOXOJKCGCJHGP-UHFFFAOYSA-N COc1ccc(Cn2c3nn(Cc4ccc(cc4)-c4cccc(F)n4)cc3c(=O)n(C)c2=O)cc1 Chemical compound COc1ccc(Cn2c3nn(Cc4ccc(cc4)-c4cccc(F)n4)cc3c(=O)n(C)c2=O)cc1 KJOXOJKCGCJHGP-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- YVPGMHIHOYONMU-RTBURBONSA-N Cn1c(N[C@@H]2CCC[C@H]2O)nc2nn(Cc3ccc(cc3)-c3cccc(F)n3)cc2c1=O Chemical compound Cn1c(N[C@@H]2CCC[C@H]2O)nc2nn(Cc3ccc(cc3)-c3cccc(F)n3)cc2c1=O YVPGMHIHOYONMU-RTBURBONSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 239000004353 Polyethylene glycol 8000 Substances 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N acetic acid;palladium Chemical compound [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229920003125 hypromellose 2910 Polymers 0.000 description 2
- 229940031672 hypromellose 2910 Drugs 0.000 description 2
- 229910052738 indium Inorganic materials 0.000 description 2
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 2
- 229960005235 piperonyl butoxide Drugs 0.000 description 2
- 229940085678 polyethylene glycol 8000 Drugs 0.000 description 2
- 235000019446 polyethylene glycol 8000 Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- ZFSXKSSWYSZPGQ-TYSVMGFPSA-N (1r,2r)-2-aminocyclopentan-1-ol;hydrochloride Chemical compound Cl.N[C@@H]1CCC[C@H]1O ZFSXKSSWYSZPGQ-TYSVMGFPSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
- JTBBWRKSUYCPFY-UHFFFAOYSA-N 2,3-dihydro-1h-pyrimidin-4-one Chemical compound O=C1NCNC=C1 JTBBWRKSUYCPFY-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- ZIDIKYIZXMYHAW-UHFFFAOYSA-N 2-bromo-6-fluoropyridine Chemical compound FC1=CC=CC(Br)=N1 ZIDIKYIZXMYHAW-UHFFFAOYSA-N 0.000 description 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
- SGLXGFAZAARYJY-UHFFFAOYSA-N 6-Chloro-3-methyluracil Chemical compound CN1C(=O)C=C(Cl)NC1=O SGLXGFAZAARYJY-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 1
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 101100243082 Caenorhabditis elegans pde-1 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 101001117086 Dictyostelium discoideum cAMP/cGMP-dependent 3',5'-cAMP/cGMP phosphodiesterase A Proteins 0.000 description 1
- 102000004076 Dopamine D1 Receptors Human genes 0.000 description 1
- 108090000511 Dopamine D1 Receptors Proteins 0.000 description 1
- 101001117089 Drosophila melanogaster Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1 Proteins 0.000 description 1
- 208000001914 Fragile X syndrome Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 208000005793 Restless legs syndrome Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 208000016620 Tourette disease Diseases 0.000 description 1
- PZRPBPMLSSNFOM-UHFFFAOYSA-N [4-(hydroxymethyl)phenyl]boronic acid Chemical compound OCC1=CC=C(B(O)O)C=C1 PZRPBPMLSSNFOM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 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
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- RKTYLMNFRDHKIL-UHFFFAOYSA-N copper;5,10,15,20-tetraphenylporphyrin-22,24-diide Chemical compound [Cu+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3[N-]2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 RKTYLMNFRDHKIL-UHFFFAOYSA-N 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 150000002500 ions Chemical class 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
- 239000011777 magnesium Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 201000003631 narcolepsy Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000000399 optical microscopy Methods 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
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 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
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000001931 thermography Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
Classifications
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361838105P | 2013-06-21 | 2013-06-21 | |
| US201361919424P | 2013-12-20 | 2013-12-20 | |
| PCT/US2014/043422 WO2014205354A2 (en) | 2013-06-21 | 2014-06-20 | Free base crystals |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2894770T3 true ES2894770T3 (es) | 2022-02-15 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES14812994T Active ES2894770T3 (es) | 2013-06-21 | 2014-06-20 | Cristales de base libre |
Country Status (13)
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|---|---|
| US (1) | US9630971B2 (enExample) |
| EP (2) | EP3010509B1 (enExample) |
| JP (2) | JP6865036B2 (enExample) |
| KR (2) | KR102430126B1 (enExample) |
| CN (3) | CN105658222A (enExample) |
| AU (1) | AU2014284224B2 (enExample) |
| BR (1) | BR112015032132B1 (enExample) |
| CA (1) | CA2916393C (enExample) |
| ES (1) | ES2894770T3 (enExample) |
| IL (2) | IL267331B2 (enExample) |
| MX (2) | MX2015017972A (enExample) |
| RU (1) | RU2675851C2 (enExample) |
| WO (1) | WO2014205354A2 (enExample) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| EP3010509B1 (en) | 2013-06-21 | 2021-07-28 | Intra-Cellular Therapies, Inc. | Free base crystals |
| US12410175B2 (en) | 2019-09-03 | 2025-09-09 | Intra-Cellular Therapies, Inc. | Compounds |
| US12435093B2 (en) | 2020-05-06 | 2025-10-07 | Intra-Cellular Therapies, Inc. | Free base crystals |
| WO2022026417A1 (en) * | 2020-07-26 | 2022-02-03 | Intra-Cellular Therapies, Inc. | Novel uses |
| JP2024531548A (ja) * | 2021-09-03 | 2024-08-29 | イントラ－セルラー・セラピーズ・インコーポレイテッド | 共結晶 |
| WO2023147484A1 (en) * | 2022-01-27 | 2023-08-03 | Intra-Cellular Therapies, Inc. | Novel compositions |
| WO2023147603A2 (en) * | 2022-01-31 | 2023-08-03 | Intra-Cellular Therapies, Inc. | Salt crystals |
| 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 |
| ATE496028T1 (de) * | 2002-02-08 | 2011-02-15 | Ono Pharmaceutical Co | Piperidinderivatverbindungen und arzneimittel, die diese verbindungen als wirkstoff enthalten |
| EP1613747A1 (en) | 2003-03-31 | 2006-01-11 | Pfizer Products Inc. | Crystal structure of 3 ,5 -cyclic nucleotide phosphodiesterase 1b (pde1b) and uses thereof |
| CN100457108C (zh) * | 2003-09-02 | 2009-02-04 | 默克公司 | 一种二肽基肽酶iv抑制剂的磷酸盐新晶体 |
| CN101031548B (zh) * | 2004-09-27 | 2011-04-06 | 阿卡蒂亚药品公司 | N-(4-氟苄基)-n-(1-甲基哌啶-4-基)-n'-(4-(2-甲基丙氧基)-苯基甲基)脲的盐及其制备 |
| WO2006133261A2 (en) | 2005-06-06 | 2006-12-14 | Intra-Cellular Therapies, Inc. | Organic compounds |
| WO2008063505A1 (en) | 2006-11-13 | 2008-05-29 | Intra-Cellular Therapies, Inc. | Organic compounds |
| WO2008070095A1 (en) | 2006-12-05 | 2008-06-12 | Intra-Cellular Therapies, Inc. | Novel uses |
| EP2939676A1 (en) * | 2007-12-06 | 2015-11-04 | Intra-Cellular Therapies, Inc. | Organic compounds |
| US20120070443A1 (en) | 2008-12-02 | 2012-03-22 | University Of Utah Research Foundation | Pde1 as a target therapeutic in heart disease |
| EA201170769A1 (ru) | 2008-12-06 | 2012-02-28 | Интра-Селлулар Терапиз, Инк. | Органические соединения |
| AU2009322903A1 (en) | 2008-12-06 | 2010-06-10 | Intra-Cellular Therapies, Inc. | Organic compounds |
| PE20110922A1 (es) * | 2008-12-06 | 2012-01-22 | Intra Cellular Therapies Inc | DERIVADOS DE PIRAZOLO[4,3-e]PIRIMIDIN COMO INHIBIDORES DE LA FOSFODIESTERASA 1 (PDE1) |
| WO2010098839A1 (en) | 2009-02-25 | 2010-09-02 | Intra-Cellular Therapies, Inc. | Pde 1 inhibitors for ophthalmic disorders |
| EP2434895A4 (en) | 2009-05-13 | 2013-08-07 | Intra Cellular Therapies Inc | ORGANIC CONNECTIONS |
| US8858911B2 (en) | 2009-10-08 | 2014-10-14 | Intra-Cellular Therapies, Inc. | Phosphodiesterase 1-targeting tracers and methods |
| TW201206937A (en) | 2010-05-31 | 2012-02-16 | Intra Cellular Therapies Inc | Organic compounds |
| US9763948B2 (en) | 2010-05-31 | 2017-09-19 | Intra-Cellular Therapies, Inc. | PDE1 inhibitory compounds and methods |
| 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 |
| EP3010509B1 (en) | 2013-06-21 | 2021-07-28 | Intra-Cellular Therapies, Inc. | Free base crystals |
-
2014
- 2014-06-20 EP EP14812994.3A patent/EP3010509B1/en active Active
- 2014-06-20 JP JP2016521847A patent/JP6865036B2/ja active Active
- 2014-06-20 US US14/900,589 patent/US9630971B2/en active Active
- 2014-06-20 CN CN201480046150.4A patent/CN105658222A/zh active Pending
- 2014-06-20 IL IL267331A patent/IL267331B2/en unknown
- 2014-06-20 EP EP20165092.6A patent/EP3702358A1/en active Pending
- 2014-06-20 WO PCT/US2014/043422 patent/WO2014205354A2/en not_active Ceased
- 2014-06-20 BR BR112015032132-1A patent/BR112015032132B1/pt active IP Right Grant
- 2014-06-20 MX MX2015017972A patent/MX2015017972A/es active IP Right Grant
- 2014-06-20 AU AU2014284224A patent/AU2014284224B2/en active Active
- 2014-06-20 CA CA2916393A patent/CA2916393C/en active Active
- 2014-06-20 KR KR1020217030964A patent/KR102430126B1/ko active Active
- 2014-06-20 KR KR1020167001273A patent/KR20160040522A/ko not_active Ceased
- 2014-06-20 CN CN201910526464.9A patent/CN110498800A/zh active Pending
- 2014-06-20 CN CN202110144523.3A patent/CN112851683A/zh active Pending
- 2014-06-20 RU RU2016101630A patent/RU2675851C2/ru active
- 2014-06-20 ES ES14812994T patent/ES2894770T3/es active Active
-
2015
- 2015-12-21 MX MX2020001628A patent/MX2020001628A/es unknown
- 2015-12-21 IL IL243269A patent/IL243269B/en active IP Right Grant
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2019
- 2019-06-04 JP JP2019104412A patent/JP2019189618A/ja active Pending
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