TWI823999B - 正性別構調節劑的鹽和結晶形式 - Google Patents
正性別構調節劑的鹽和結晶形式 Download PDFInfo
- Publication number
- TWI823999B TWI823999B TW108131297A TW108131297A TWI823999B TW I823999 B TWI823999 B TW I823999B TW 108131297 A TW108131297 A TW 108131297A TW 108131297 A TW108131297 A TW 108131297A TW I823999 B TWI823999 B TW I823999B
- Authority
- TW
- Taiwan
- Prior art keywords
- compound
- exhibits
- salt
- xrpd
- peaks
- Prior art date
Links
- 150000003839 salts Chemical group 0.000 title abstract description 128
- 239000013078 crystal Chemical group 0.000 title description 17
- 229940126027 positive allosteric modulator Drugs 0.000 title description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 382
- 238000001757 thermogravimetry curve Methods 0.000 claims description 138
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 92
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 66
- 239000000203 mixture Substances 0.000 claims description 36
- 239000010949 copper Substances 0.000 claims description 34
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 32
- 229910052802 copper Inorganic materials 0.000 claims description 32
- 230000005855 radiation Effects 0.000 claims description 32
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 abstract description 1359
- 238000000034 method Methods 0.000 abstract description 118
- 238000002360 preparation method Methods 0.000 abstract description 34
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 219
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 154
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 128
- 239000007787 solid Substances 0.000 description 115
- 239000000126 substance Substances 0.000 description 101
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 89
- 238000003756 stirring Methods 0.000 description 80
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 79
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 74
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 71
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 69
- 239000000725 suspension Substances 0.000 description 67
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 66
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 66
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 61
- 239000012458 free base Substances 0.000 description 58
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 description 56
- 239000002904 solvent Substances 0.000 description 54
- 239000012530 fluid Substances 0.000 description 52
- 238000012430 stability testing Methods 0.000 description 52
- 230000000968 intestinal effect Effects 0.000 description 51
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 51
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 50
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 50
- 230000002496 gastric effect Effects 0.000 description 50
- 238000012360 testing method Methods 0.000 description 50
- 238000002411 thermogravimetry Methods 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 47
- 239000000843 powder Substances 0.000 description 43
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 41
- 229940114119 gentisate Drugs 0.000 description 39
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 38
- 238000001179 sorption measurement Methods 0.000 description 36
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 35
- 230000004580 weight loss Effects 0.000 description 35
- 235000010323 ascorbic acid Nutrition 0.000 description 34
- 239000011668 ascorbic acid Substances 0.000 description 34
- 238000004255 ion exchange chromatography Methods 0.000 description 34
- 229940072107 ascorbate Drugs 0.000 description 32
- 239000002244 precipitate Substances 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 31
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethane-1,2-disulfonate Chemical compound [O-]S(=O)(=O)CCS([O-])(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 31
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 30
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 30
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 29
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 27
- 239000000047 product Substances 0.000 description 26
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 25
- 238000004458 analytical method Methods 0.000 description 25
- 229940109275 cyclamate Drugs 0.000 description 25
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical class C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 25
- 238000001907 polarising light microscopy Methods 0.000 description 25
- WUBBRNOQWQTFEX-UHFFFAOYSA-M 4-aminosalicylate(1-) Chemical compound NC1=CC=C(C([O-])=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-M 0.000 description 24
- 229910019142 PO4 Inorganic materials 0.000 description 24
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 24
- 239000010452 phosphate Substances 0.000 description 24
- 238000013112 stability test Methods 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 21
- 150000002690 malonic acid derivatives Chemical class 0.000 description 20
- 150000003891 oxalate salts Chemical class 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 238000005119 centrifugation Methods 0.000 description 18
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 17
- -1 cyclotenine Chemical compound 0.000 description 17
- 229940097042 glucuronate Drugs 0.000 description 16
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 15
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 11
- 238000013480 data collection Methods 0.000 description 11
- 229940113720 aminosalicylate Drugs 0.000 description 10
- 150000002688 maleic acid derivatives Chemical class 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 229940077388 benzenesulfonate Drugs 0.000 description 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- 239000000010 aprotic solvent Substances 0.000 description 8
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 8
- 229940120124 dichloroacetate Drugs 0.000 description 8
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 8
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 7
- 239000008186 active pharmaceutical agent Substances 0.000 description 7
- 239000012296 anti-solvent Substances 0.000 description 7
- 229940011051 isopropyl acetate Drugs 0.000 description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000003586 protic polar solvent Substances 0.000 description 7
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 6
- 229910052782 aluminium Inorganic materials 0.000 description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 6
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical class OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 6
- 230000008570 general process Effects 0.000 description 6
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 5
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical class O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 5
- 229960002303 citric acid monohydrate Drugs 0.000 description 5
- 239000006184 cosolvent Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000011888 foil Substances 0.000 description 5
- 239000001530 fumaric acid Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 5
- 150000003431 steroids Chemical class 0.000 description 5
- 229940095064 tartrate Drugs 0.000 description 5
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 201000009916 Postpartum depression Diseases 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 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 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical group 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 4
- 206010015037 epilepsy Diseases 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229960005219 gentisic acid Drugs 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 4
- 208000024714 major depressive disease Diseases 0.000 description 4
- 229940049920 malate Drugs 0.000 description 4
- 235000011090 malic acid Nutrition 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 4
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 230000000007 visual effect Effects 0.000 description 4
- 208000019901 Anxiety disease Diseases 0.000 description 3
- 208000020925 Bipolar disease Diseases 0.000 description 3
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical class [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 208000028552 Treatment-Resistant Depressive disease Diseases 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 229960004909 aminosalicylic acid Drugs 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 229960004106 citric acid Drugs 0.000 description 3
- 229960005215 dichloroacetic acid Drugs 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 3
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- 235000011007 phosphoric acid Nutrition 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000011877 solvent mixture Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- IAJILQKETJEXLJ-KKQCNMDGSA-N (2r,3r,4r,5s)-2,3,4,5-tetrahydroxy-6-oxohexanoic acid Chemical class O=C[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O IAJILQKETJEXLJ-KKQCNMDGSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical class OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 2
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 2
- YJUUZFWMKJBVFJ-UHFFFAOYSA-N 1,3-dimethylimidazolidin-4-one Chemical compound CN1CN(C)C(=O)C1 YJUUZFWMKJBVFJ-UHFFFAOYSA-N 0.000 description 2
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 2
- 229940044613 1-propanol Drugs 0.000 description 2
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 2
- 229940093475 2-ethoxyethanol Drugs 0.000 description 2
- GGDYAKVUZMZKRV-UHFFFAOYSA-N 2-fluoroethanol Chemical compound OCCF GGDYAKVUZMZKRV-UHFFFAOYSA-N 0.000 description 2
- KIPMDPDAFINLIV-UHFFFAOYSA-N 2-nitroethanol Chemical compound OCC[N+]([O-])=O KIPMDPDAFINLIV-UHFFFAOYSA-N 0.000 description 2
- 229910016860 FaSSIF Inorganic materials 0.000 description 2
- 229910005429 FeSSIF Inorganic materials 0.000 description 2
- DOJXGHGHTWFZHK-UHFFFAOYSA-N Hexachloroacetone Chemical compound ClC(Cl)(Cl)C(=O)C(Cl)(Cl)Cl DOJXGHGHTWFZHK-UHFFFAOYSA-N 0.000 description 2
- 239000001358 L(+)-tartaric acid Substances 0.000 description 2
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 2
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 2
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 2
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229940116298 l- malic acid Drugs 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 229940099690 malic acid Drugs 0.000 description 2
- 150000004701 malic acid derivatives Chemical class 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- MBHINSULENHCMF-UHFFFAOYSA-N n,n-dimethylpropanamide Chemical compound CCC(=O)N(C)C MBHINSULENHCMF-UHFFFAOYSA-N 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-L naphthalene-1,5-disulfonate(2-) Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1S([O-])(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-L 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 2
- ZLBLYGIIADHDKG-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid;tetrahydrate Chemical compound O.O.O.O.C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O ZLBLYGIIADHDKG-UHFFFAOYSA-N 0.000 description 2
- HKGOFWIZZIYCOS-UHFFFAOYSA-N naphthalene-2-sulfonic acid;hydrate Chemical compound O.C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 HKGOFWIZZIYCOS-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- DUHUCHOQIDJXAT-OLVMNOGESA-N 3-hydroxy-(3-α,5-α)-Pregnane-11,20-dione Chemical compound C([C@@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1=O DUHUCHOQIDJXAT-OLVMNOGESA-N 0.000 description 1
- AURFZBICLPNKBZ-FZCSVUEKSA-N 3beta-hydroxy-5alpha-pregnan-20-one Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 AURFZBICLPNKBZ-FZCSVUEKSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 229920002799 BoPET Polymers 0.000 description 1
- 206010054089 Depressive symptom Diseases 0.000 description 1
- PGTVWKLGGCQMBR-FLBATMFCSA-N Ganaxolone Chemical compound C([C@@H]1CC2)[C@](C)(O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 PGTVWKLGGCQMBR-FLBATMFCSA-N 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000005041 Mylar™ Substances 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- AURFZBICLPNKBZ-UHFFFAOYSA-N Pregnanolone Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 AURFZBICLPNKBZ-UHFFFAOYSA-N 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002577 cryoprotective agent Substances 0.000 description 1
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229950006567 ganaxolone Drugs 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 210000003750 lower gastrointestinal tract Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- MHCFHGFURSGVRK-UHFFFAOYSA-N methane;pentan-3-one Chemical compound C.CCC(=O)CC MHCFHGFURSGVRK-UHFFFAOYSA-N 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000000373 single-crystal X-ray diffraction data Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- HARRKNSQXBRBGZ-GVKWWOCJSA-N zuranolone Chemical compound O=C([C@H]1CC[C@H]2[C@H]3[C@@H]([C@H]4CC[C@@](C)(O)C[C@H]4CC3)CC[C@@]21C)CN1C=C(C#N)C=N1 HARRKNSQXBRBGZ-GVKWWOCJSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
-
- 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
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Pyridine Compounds (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Liquid Crystal Substances (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201862725805P | 2018-08-31 | 2018-08-31 | |
| US62/725,805 | 2018-08-31 | ||
| US16/517,369 | 2019-07-19 | ||
| US16/517,369 US10562930B1 (en) | 2018-08-31 | 2019-07-19 | Salts and crystal forms of GABAA positive allosteric modulator |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW202024108A TW202024108A (zh) | 2020-07-01 |
| TWI823999B true TWI823999B (zh) | 2023-12-01 |
Family
ID=69528249
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW108131297A TWI823999B (zh) | 2018-08-31 | 2019-08-30 | 正性別構調節劑的鹽和結晶形式 |
| TW112141287A TWI850138B (zh) | 2018-08-31 | 2019-08-30 | 正性別構調節劑的鹽和結晶形式 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW112141287A TWI850138B (zh) | 2018-08-31 | 2019-08-30 | 正性別構調節劑的鹽和結晶形式 |
Country Status (13)
| Country | Link |
|---|---|
| US (4) | US10562930B1 (https=) |
| EP (2) | EP3710465B1 (https=) |
| JP (3) | JP7199739B2 (https=) |
| KR (1) | KR102845326B1 (https=) |
| CN (1) | CN113473991B (https=) |
| AU (1) | AU2019333310B8 (https=) |
| BR (1) | BR112021003727A2 (https=) |
| CA (1) | CA3111193A1 (https=) |
| IL (1) | IL281143B2 (https=) |
| MA (1) | MA50921A (https=) |
| MX (1) | MX2021002382A (https=) |
| TW (2) | TWI823999B (https=) |
| WO (1) | WO2020047434A1 (https=) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117024501A (zh) * | 2014-10-16 | 2023-11-10 | 萨奇治疗股份有限公司 | 靶向cns障碍的组合物和方法 |
| US10562930B1 (en) | 2018-08-31 | 2020-02-18 | Praxis Precision Medicines, Inc. | Salts and crystal forms of GABAA positive allosteric modulator |
| MX2021006985A (es) * | 2018-12-14 | 2021-09-08 | Praxis Prec Medicines Inc | Metodos para el tratamiento de la depresión. |
| EP4125921A1 (en) | 2020-03-25 | 2023-02-08 | Sage Therapeutics, Inc. | Use of agents for treatment of respiratory conditions |
| WO2022006541A1 (en) * | 2020-07-02 | 2022-01-06 | Praxis Precision Medicines, Inc. | Methods for the treatment of adjustment disorder |
| EP4294819A4 (en) | 2021-02-18 | 2024-12-18 | Praxis Precision Medicines, Inc. | GABA-A POSITIVE ALLOSTERIC MODULATOR HEMI-CITRATE SALTS AND CORRESPONDING CRYSTALLINE FORM |
| WO2022177718A1 (en) | 2021-02-18 | 2022-08-25 | Sage Therapeutics, Inc. | Use of neuroactive steroid for treatment of sexual dysfunction |
| WO2022231309A1 (ko) | 2021-04-27 | 2022-11-03 | 경북대학교 산학협력단 | 저분자 콜라겐을 유효성분으로 포함하는 근감소증의 예방 또는 개선용 식품 조성물 및 약학적 조성물 |
| WO2023159035A1 (en) | 2022-02-16 | 2023-08-24 | Sage Therapeutics, Inc. | Neuroactive steroids for treatment of cns-related disorders |
| WO2023164386A1 (en) * | 2022-02-28 | 2023-08-31 | Sage Therapeutics, Inc. | Neuroactive steroids for treatment of gastrointestinal diseases or conditions |
| EP4514357A4 (en) * | 2022-04-26 | 2026-04-29 | Praxis Prec Medicines Inc | METHODS OF TREATING NEUROLOGICAL DISORDERS |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006131392A1 (en) * | 2005-06-09 | 2006-12-14 | Euro-Celtique S.A. | Pharmaceutical compositions of a neuroactive steroid and uses thereof |
Family Cites Families (41)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69435286D1 (de) * | 1993-05-24 | 2010-05-20 | Purdue Pharma Ltd | Verfahren und zusammensetzungen zum hervorrufen von schlaf |
| US5939545A (en) | 1994-02-14 | 1999-08-17 | Cocensys, Inc. | Method, compositions, and compounds for allosteric modulation of the gaba receptor by members of the androstane and pregnane series |
| ATE284895T1 (de) * | 1995-06-06 | 2005-01-15 | Euro Celtique Sa | Neuroaktive steroide der androstan- und pregnanreihe |
| US6780853B1 (en) | 1995-06-06 | 2004-08-24 | Euro-Celtique S.A. | Neuroactive steroids of the androstane and pregnane series |
| WO1998005337A1 (en) | 1996-08-01 | 1998-02-12 | Cocensys, Inc. | Use of gaba and nmda receptor ligands for the treatment of migraine headache |
| UA73736C2 (en) * | 1999-04-29 | 2005-09-15 | Euro Celtic S A | Method for alleviating or preventing insomnia and inducing anesthesia |
| CN1688288A (zh) * | 2002-08-05 | 2005-10-26 | 巴克斯特国际公司 | 具有多晶型控制的亚微米粒度颗粒的制备和新多晶型伊曲康唑 |
| WO2004072079A1 (en) | 2003-02-11 | 2004-08-26 | Pfizer Limited | Hydrated and anhydrous sildenafil hemi-citrate compound |
| WO2005007600A2 (en) | 2003-07-11 | 2005-01-27 | Eisai Co., Ltd. | Novel methods using aminobenzoic acid compounds |
| AU2004265101B2 (en) | 2003-08-14 | 2009-06-11 | F. Hoffmann-La Roche Ag | Gabanergic modulators |
| WO2005105822A2 (en) | 2004-04-23 | 2005-11-10 | Euro-Celtique S.A. | 3-alpha-hydroxy 21-n- heteroaryl-pregnane derivatives for modulation of brain excitability and a process for the production thereof |
| US20060074059A1 (en) | 2004-08-26 | 2006-04-06 | Goliber Philip A | Isomorphic crystalline habits of 3alpha-hydroxy-21-(1'-imidazolyl)-3beta-methoxymethyl-5alpha-pregnane-20-one |
| AU2006308889A1 (en) | 2005-10-31 | 2007-05-10 | Braincells, Inc. | GABA receptor mediated modulation of neurogenesis |
| AU2007229866A1 (en) | 2006-03-22 | 2007-10-04 | Mount Sinai School Of Medicine | Intranasal administration of ketamine to treat depression |
| US20090074677A1 (en) | 2007-01-08 | 2009-03-19 | Duke University | Neuroactive steroid compositions and methods of use therefor |
| MX2011011156A (es) * | 2009-04-23 | 2011-11-04 | Theravance Inc | COMPUESTOS DIAMIDA QUE TIENE ACTIVIDAD COMO ANTAGONISTAS DE LOS RECEPTORES MUSCARINICOS Y COMO AGONISTAS DE LOS RECEPTORES ANDRENERGICOS ß2. |
| CA2789654A1 (en) * | 2010-02-24 | 2011-09-01 | Ramot At Tel-Aviv University Ltd. | Crystalline forms of the tri-mesylate salt of perphenazine-gaba and process of producing the same |
| US20130252924A1 (en) * | 2010-11-11 | 2013-09-26 | Akron Molecules Gmbh | Compounds and Methods for Treating Pain |
| US20140315992A1 (en) | 2011-07-07 | 2014-10-23 | The Children's Hospital Of Philadelphia | Genetic Alterations Associated with Autism and the Autistic Phenotype and Methods of Use Thereof for the Diagnosis and Treatment of Autism |
| HRP20180487T1 (hr) | 2013-07-24 | 2018-05-04 | Commissariat à l'énergie atomique et aux énergies alternatives | Upotreba flekainida kao anti-koneksinskog sredstva i metoda za potenciranje učinaka psihotropnog lijeka |
| WO2016015653A1 (zh) * | 2014-08-01 | 2016-02-04 | 江苏豪森药业股份有限公司 | C-Met抑制剂结晶型游离碱或其结晶型酸式盐及其制备方法和应用 |
| JOP20200195A1 (ar) | 2014-09-08 | 2017-06-16 | Sage Therapeutics Inc | سترويدات وتركيبات نشطة عصبياً، واستخداماتها |
| CN117024501A (zh) | 2014-10-16 | 2023-11-10 | 萨奇治疗股份有限公司 | 靶向cns障碍的组合物和方法 |
| TWI728172B (zh) | 2016-08-18 | 2021-05-21 | 美商愛戴爾製藥股份有限公司 | 治療嗜伊紅性食道炎之方法 |
| US10391105B2 (en) | 2016-09-09 | 2019-08-27 | Marinus Pharmaceuticals Inc. | Methods of treating certain depressive disorders and delirium tremens |
| US10420773B2 (en) | 2017-09-26 | 2019-09-24 | Ovid Therapeutics Inc. | Methods of treating developmental disorders and/or seizure disorders with etifoxine |
| MY204493A (en) | 2017-11-10 | 2024-08-30 | Marinus Pharmaceuticals Inc | Ganaxolone for use in treating genetic epileptic disorders |
| US10562930B1 (en) | 2018-08-31 | 2020-02-18 | Praxis Precision Medicines, Inc. | Salts and crystal forms of GABAA positive allosteric modulator |
| MX2021006985A (es) | 2018-12-14 | 2021-09-08 | Praxis Prec Medicines Inc | Metodos para el tratamiento de la depresión. |
| MX2021007142A (es) | 2018-12-17 | 2021-08-11 | Intra Cellular Therapies Inc | Compuestos organicos. |
| US20220125803A1 (en) | 2019-03-04 | 2022-04-28 | Praxis Precision Medicines, Inc. | Methods for the treatment of perimenopause and menopause |
| WO2020185710A1 (en) | 2019-03-08 | 2020-09-17 | Alairion, Inc. | Method for treating sleep fragmentation disorders using neurosteroid positive allosteric modulators of the gabaa receptor |
| US20220265666A1 (en) | 2019-08-02 | 2022-08-25 | Praxis Precision Medicines, Inc. | Methods of treating substance abuse disorder, dyspnea, tinnitus, and child and adolescent depression |
| JP2022552808A (ja) | 2019-10-02 | 2022-12-20 | プラクシス プレシジョン メディシンズ， インコーポレイテッド | Ｇａｂａ－ａ受容体陽性アロステリック調節因子と、ｎｍｄａ拮抗薬、ｎｍｄａ陰性アロステリック調節因子、またはｎｍｄａ部分作動薬との組み合わせ |
| WO2021168106A1 (en) | 2020-02-18 | 2021-08-26 | Praxis Precision Medicines, Inc. | Deuterated neurosteroid |
| WO2022006541A1 (en) | 2020-07-02 | 2022-01-06 | Praxis Precision Medicines, Inc. | Methods for the treatment of adjustment disorder |
| JP2023539125A (ja) | 2020-08-20 | 2023-09-13 | イントラ－セルラー・セラピーズ・インコーポレイテッド | 有機化合物 |
| EP4294819A4 (en) | 2021-02-18 | 2024-12-18 | Praxis Precision Medicines, Inc. | GABA-A POSITIVE ALLOSTERIC MODULATOR HEMI-CITRATE SALTS AND CORRESPONDING CRYSTALLINE FORM |
| EP4329751A4 (en) | 2021-04-26 | 2025-03-19 | Praxis Precision Medicines, Inc. | Methods of treatment with neuroactive steroids |
| WO2023159094A2 (en) | 2022-02-16 | 2023-08-24 | Praxis Precision Medicines, Inc. | PROCESS OF MAKING 3α-HYDROXY-3β-METHOXYMETHYL-21-(1'- IMIDAZOLYL)-5α-PREGNAN-20-ONE |
| EP4514357A4 (en) | 2022-04-26 | 2026-04-29 | Praxis Prec Medicines Inc | METHODS OF TREATING NEUROLOGICAL DISORDERS |
-
2019
- 2019-07-19 US US16/517,369 patent/US10562930B1/en active Active
- 2019-08-30 CN CN201980071246.9A patent/CN113473991B/zh active Active
- 2019-08-30 MA MA050921A patent/MA50921A/fr unknown
- 2019-08-30 TW TW108131297A patent/TWI823999B/zh active
- 2019-08-30 EP EP19842855.9A patent/EP3710465B1/en active Active
- 2019-08-30 EP EP24194131.9A patent/EP4458357A3/en active Pending
- 2019-08-30 CA CA3111193A patent/CA3111193A1/en active Pending
- 2019-08-30 BR BR112021003727-6A patent/BR112021003727A2/pt unknown
- 2019-08-30 TW TW112141287A patent/TWI850138B/zh active
- 2019-08-30 KR KR1020217009437A patent/KR102845326B1/ko active Active
- 2019-08-30 MX MX2021002382A patent/MX2021002382A/es unknown
- 2019-08-30 JP JP2020517339A patent/JP7199739B2/ja active Active
- 2019-08-30 AU AU2019333310A patent/AU2019333310B8/en active Active
- 2019-08-30 WO PCT/US2019/049103 patent/WO2020047434A1/en not_active Ceased
- 2019-08-30 IL IL281143A patent/IL281143B2/en unknown
- 2019-11-27 US US16/698,057 patent/US10927141B2/en active Active
-
2021
- 2021-01-07 US US17/143,602 patent/US20220024967A1/en not_active Abandoned
-
2022
- 2022-12-14 JP JP2022199092A patent/JP2023036708A/ja active Pending
-
2023
- 2023-12-05 US US18/529,117 patent/US12404297B2/en active Active
-
2024
- 2024-10-03 JP JP2024174009A patent/JP2025020120A/ja active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006131392A1 (en) * | 2005-06-09 | 2006-12-14 | Euro-Celtique S.A. | Pharmaceutical compositions of a neuroactive steroid and uses thereof |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI823999B (zh) | 正性別構調節劑的鹽和結晶形式 | |
| US11434226B2 (en) | Salt and polymorph of benzopyrimidinone compound and pharmaceutical composition and use thereof | |
| TW201718516A (zh) | 組蛋白去乙醯酶抑制劑之晶形 | |
| HK40118203A (en) | Salts and crystal forms of gabaa positive allosteric modulator | |
| HK40037178B (en) | Salts and crystal forms of gabaa positive allosteric modulator | |
| HK40037178A (en) | Salts and crystal forms of gabaa positive allosteric modulator | |
| BR112020006051A2 (pt) | formas cristalinas de lenalidomida | |
| WO2026067446A1 (zh) | 一种大稠环化合物的盐、多晶型物及其应用 | |
| WO2024172778A1 (en) | Novel polymorph of ruxolitinib hemifumarate and method of preparation |