JP5400387B2 - 1−ベンゾイル−4−[2−[4−メトキシ−7−(3−メチル−1h−1,2,4−トリアゾール−1−イル)−1−[(ホスホノオキシ)メチル]−1h−ピロロ[2,3−c]ピリジン−3−イル]−1,2−ジオキソエチル]−ピペラジンの結晶形 - Google Patents
1−ベンゾイル−4−[2−[4−メトキシ−7−(3−メチル−1h−1,2,4−トリアゾール−1−イル)−1−[(ホスホノオキシ)メチル]−1h−ピロロ[2,3−c]ピリジン−3−イル]−1,2−ジオキソエチル]−ピペラジンの結晶形 Download PDFInfo
- Publication number
- JP5400387B2 JP5400387B2 JP2008545772A JP2008545772A JP5400387B2 JP 5400387 B2 JP5400387 B2 JP 5400387B2 JP 2008545772 A JP2008545772 A JP 2008545772A JP 2008545772 A JP2008545772 A JP 2008545772A JP 5400387 B2 JP5400387 B2 JP 5400387B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- crystal form
- ray diffraction
- methyl
- powder
- 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
Links
- SWMDAPWAQQTBOG-UHFFFAOYSA-N fostemsavir Chemical compound C1=2N(COP(O)(O)=O)C=C(C(=O)C(=O)N3CCN(CC3)C(=O)C=3C=CC=CC=3)C=2C(OC)=CN=C1N1C=NC(C)=N1 SWMDAPWAQQTBOG-UHFFFAOYSA-N 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims description 110
- 239000013078 crystal Substances 0.000 claims description 63
- 239000000203 mixture Substances 0.000 claims description 34
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 20
- 238000002411 thermogravimetry Methods 0.000 claims description 14
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 6
- 238000001144 powder X-ray diffraction data Methods 0.000 claims description 5
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000004689 octahydrates Chemical class 0.000 claims description 2
- 238000010586 diagram Methods 0.000 claims 1
- 238000001757 thermogravimetry curve Methods 0.000 claims 1
- 238000000034 method Methods 0.000 description 34
- 239000002904 solvent Substances 0.000 description 31
- 239000007787 solid Substances 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- 239000012453 solvate Substances 0.000 description 19
- 238000009472 formulation Methods 0.000 description 17
- -1 - amino Chemical group 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- 238000002425 crystallisation Methods 0.000 description 13
- 230000008025 crystallization Effects 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 13
- 239000003826 tablet Substances 0.000 description 12
- 125000004429 atom Chemical group 0.000 description 11
- 239000007884 disintegrant Substances 0.000 description 11
- 208000030507 AIDS Diseases 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000002441 X-ray diffraction Methods 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 239000002775 capsule Substances 0.000 description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000003765 sweetening agent Substances 0.000 description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 241000725303 Human immunodeficiency virus Species 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000007891 compressed tablet Substances 0.000 description 6
- 235000003599 food sweetener Nutrition 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 229940032147 starch Drugs 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000000346 sugar Nutrition 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000006073 displacement reaction Methods 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000011877 solvent mixture Substances 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- 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 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012296 anti-solvent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 229960000913 crospovidone Drugs 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 235000019426 modified starch Nutrition 0.000 description 3
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000003182 parenteral nutrition solution Substances 0.000 description 3
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 229920003109 sodium starch glycolate Polymers 0.000 description 3
- 239000008109 sodium starch glycolate Substances 0.000 description 3
- 229940079832 sodium starch glycolate Drugs 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 229960002555 zidovudine Drugs 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical group C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-p-benzoquinone Substances ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 2
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 2
- 208000031886 HIV Infections Diseases 0.000 description 2
- 208000037357 HIV infectious disease Diseases 0.000 description 2
- 102100034343 Integrase Human genes 0.000 description 2
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 239000004368 Modified starch Substances 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 2
- 229960004748 abacavir Drugs 0.000 description 2
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 229920006037 cross link polymer Polymers 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 2
- 229940038472 dicalcium phosphate Drugs 0.000 description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 2
- AJDPNPAGZMZOMN-UHFFFAOYSA-N diethyl (4-oxo-1,2,3-benzotriazin-3-yl) phosphate Chemical compound C1=CC=C2C(=O)N(OP(=O)(OCC)OCC)N=NC2=C1 AJDPNPAGZMZOMN-UHFFFAOYSA-N 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229960003804 efavirenz Drugs 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- CATSNJVOTSVZJV-UHFFFAOYSA-N heptan-2-one Chemical compound CCCCCC(C)=O CATSNJVOTSVZJV-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 230000006911 nucleation Effects 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000021092 sugar substitutes Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WYJIRAVZMKUVPC-UHFFFAOYSA-N 1,1-dichloroethane;methanol Chemical group OC.CC(Cl)Cl WYJIRAVZMKUVPC-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical group CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- IVVIEDLPSCBKIE-UHFFFAOYSA-N 1H-pyrrolo[2,3-b]pyridine 1H-pyrrolo[2,3-c]pyridine Chemical group N1C=CC2=CC=CN=C12.N1C=CC=2C1=CN=CC2 IVVIEDLPSCBKIE-UHFFFAOYSA-N 0.000 description 1
- PVXLGSWERQFDTC-UHFFFAOYSA-N 1H-pyrrolo[2,3-c]pyridine 1H-pyrrolo[3,2-c]pyridine Chemical group N1=CC=C2NC=CC2=C1.C1=NC=C2NC=CC2=C1 PVXLGSWERQFDTC-UHFFFAOYSA-N 0.000 description 1
- YXMSGIROUMWVRY-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical group C1=CC=C2NC=CC2=N1.C1=CC=C2NC=CC2=N1 YXMSGIROUMWVRY-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- OPJKGTJXHVPYIM-UHFFFAOYSA-N 2-methylprop-2-enamide;phenol Chemical compound CC(=C)C(N)=O.OC1=CC=CC=C1 OPJKGTJXHVPYIM-UHFFFAOYSA-N 0.000 description 1
- CDTYIDBYMWGJAI-UHFFFAOYSA-N 2-methylpropan-1-ol;pentan-3-ol Chemical compound CC(C)CO.CCC(O)CC CDTYIDBYMWGJAI-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- KKJHSACAMDNCJA-UHFFFAOYSA-N 2h-pyran;pyrrolidine Chemical compound C1CCNC1.C1OC=CC=C1 KKJHSACAMDNCJA-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- LHCOVOKZWQYODM-CPEOKENHSA-N 4-amino-1-[(2r,5s)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one;1-[(2r,4s,5s)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1.O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 LHCOVOKZWQYODM-CPEOKENHSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 0 C*C(C1CC2C3=CC3)C(C3CC3)C1C2C1(CC1)*=C Chemical compound C*C(C1CC2C3=CC3)C(C3CC3)C1C2C1(CC1)*=C 0.000 description 1
- ZLDOPRCGRXGVGY-UHFFFAOYSA-N CCO.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O Chemical compound CCO.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O ZLDOPRCGRXGVGY-UHFFFAOYSA-N 0.000 description 1
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 description 1
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- DOJXGHGHTWFZHK-UHFFFAOYSA-N Hexachloroacetone Chemical compound ClC(Cl)(Cl)C(=O)C(Cl)(Cl)Cl DOJXGHGHTWFZHK-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- OFFWOVJBSQMVPI-RMLGOCCBSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O.N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 OFFWOVJBSQMVPI-RMLGOCCBSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 101100189356 Mus musculus Papolb gene Proteins 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- NUDOTBNAOXZBQK-UHFFFAOYSA-N N1C=CC2=CN=CC=C12.N1C=CC2=NC=CC=C21 Chemical group N1C=CC2=CN=CC=C12.N1C=CC2=NC=CC=C21 NUDOTBNAOXZBQK-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010058874 Viraemia Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- GLWHPRRGGYLLRV-XLPZGREQSA-N [[(2s,3s,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](N=[N+]=[N-])C1 GLWHPRRGGYLLRV-XLPZGREQSA-N 0.000 description 1
- WMHSRBZIJNQHKT-FFKFEZPRSA-N abacavir sulfate Chemical compound OS(O)(=O)=O.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 WMHSRBZIJNQHKT-FFKFEZPRSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229960001830 amprenavir Drugs 0.000 description 1
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 229960003277 atazanavir Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940014461 combivir Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229960005319 delavirdine Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229960002656 didanosine Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 229940072253 epivir Drugs 0.000 description 1
- NGPZWOOKVNRELB-UHFFFAOYSA-N ethane-1,2-diol;methanol Chemical compound OC.OCCO NGPZWOOKVNRELB-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 229940112586 kaletra Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- ANYSGBYRTLOUPO-UHFFFAOYSA-N lithium tetramethylpiperidide Chemical compound [Li]N1C(C)(C)CCCC1(C)C ANYSGBYRTLOUPO-UHFFFAOYSA-N 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960004525 lopinavir Drugs 0.000 description 1
- 229940120922 lopinavir and ritonavir Drugs 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229940094933 n-dodecane Drugs 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229960000884 nelfinavir Drugs 0.000 description 1
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- VUNXBQRNMNVUMV-UHFFFAOYSA-N phenyl(piperazin-1-yl)methanone Chemical compound C=1C=CC=CC=1C(=O)N1CCNCC1 VUNXBQRNMNVUMV-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 229940064914 retrovir Drugs 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229940107904 reyataz Drugs 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000012306 spectroscopic technique Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229940054565 sustiva Drugs 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- MSXVEPNJUHWQHW-UHFFFAOYSA-N tertiary amyl alcohol Natural products CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940111527 trizivir Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229940098802 viramune Drugs 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229940087450 zerit Drugs 0.000 description 1
- 229940052255 ziagen Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本願は、2005年12月14日に出願された米国仮出願番号60/750,247の優先権の利益を主張する。
本発明は、一般に、1−ベンゾイル−4−[2−[4−メトキシ−7−(3−メチル−1H−1,2,4−トリアゾール−1−イル)−1−[(ホスホノオキシ)メチル]−1H−ピロロ[2,3−c]ピリジン−3−イル]−1,2−ジオキソエチル]−ピペラジンの結晶形に関する。本発明はまた、一般に、該結晶形を含む医薬組成物、並びにHIVおよび/またはAIDSの治療における該結晶形の使用方法、およびこのような結晶形を得る方法にも関する。
HIV−1(ヒト免疫不全ウイルス−1)感染は、重大な医療問題として残され、2002年の終わりには世界中で、推定4200万人が感染している。HIVおよびAIDS(後天性免疫不全症候群)の症例数は、急速に増加している。2002年において、〜500万の新たな感染が報告され、310万人がAIDSで亡くなった。HIVの治療のための現在利用可能な薬物には、
9種のヌクレオシド逆トランスクリプターゼ(RT)阻害薬または認可シングルピル併用:ジドブジンまたはAZT(またはレトロビル(登録商標))、ジダノシン(またはヴァイデックス(登録商標))、スタブジン(またはゼリット(登録商標))、ラミブジン(または3TCまたはエピビル(登録商標))、ザルシタビン(またはDDCまたはハイビッド(登録商標))、コハク酸アバカビル(またはザイアジェン(登録商標))、フマル酸テノホビルジソプロキシル(またはビリアード(登録商標))、コンビビル(登録商標)(AZTを加えた3TCを含有)、トリジビル(Trizivir)(登録商標)(アバカビル、ラミブジンおよびジドブジンを含有);
3種の非ヌクレオシド逆トランスクリプターゼ阻害薬:ネビラピン(またはビラミューン(登録商標))、デラビルジン(またはレスクリプター(登録商標))およびエファビレンツ(またはサスティバ(Sustiva)(登録商標));
8種のペプチド模倣プロテアーゼ阻害薬または認可製剤:サキナビル、インジナビル、リトナビル、ネルフィナビル、アンプレナビル、ロピナビル、カレトラ(登録商標)(ロピナビルおよびリトナビル)、およびアタザナビル(レイアタッツ(登録商標))が含まれる。これらの各薬物は、単独で用いるとウイルス複製を一時的にしか抑制できない。しかしながら併用した場合は、これらの薬物はウイルス血症および疾患進行に対し十分な効果を有する。実際、併用療法の広範囲にわたる適用の結果として、AIDS患者の中の死亡率の著しい減少が最近証明されてきた。しかし、これらの印象的な結果にもかかわらず、結局、30〜50%の患者が薬物併用療法に失敗している。不十分な薬効、非コンプライアンス、限られた組織浸透および特定細胞型内の薬物−特異的制限(たとえば、ほとんどのヌクレオシド類縁体は、休止細胞においてリン酸化され得ない)は、敏感なウイルス(sensitive virus)の不完全抑制の原因となりうる。さらに、変異の頻繁な取込みを兼ねたHIV−1の速い複製速度やすばやい代謝回転(turnover)は、準最適薬物濃度である場合に、薬剤耐性変異体の出現および処置ミスをもたらす(LarderおよびKemp ; Gulick ; Kuritzkes ; Morris−Jonesら;Schinaziら; Vaccaおよび Condra ; Flexner ; Berkhoutおよび Renら;(Ref. 6-14))。従って、より多くの治療の選択肢を提供するために、別個の耐性パターン、および好都合な薬物動態並びに安全性プロフィールを示す新規抗HIV薬が必要である。
Xは、CまたはNであるが、但し、XがNである場合、R1は存在せず;
Wは、CまたはNであるが、但し、WがNである場合、R2は存在せず;
Vは、Cであり;
R1は、水素、メトキシまたはハロゲンであり;
R2は、水素であり;
R3は、メトキシまたはヘテロアリールであり、その各々は独立して、Gから選択される一つの置換基で適宜置換されていてもよく;その中で、ヘテロアリールは、トリアゾリル、ピラゾリルまたはオキサジアゾリルであり;
Eは、水素またはその医薬的に許容されるモノもしくはジ塩であり;
Yは、
R10、R11、R12、R13、R14、R15、R16、R17は各々独立して、Hまたはメチルであるが、但し、R10−R17の多くて2つがメチルであり;
R18は、C(O)−フェニル、C(O)−ピリジニル、ピリジニル、ピリミジニル、キノリニル、イソキノリニル、キナゾリニル、キノキサリニル、ナフチリジニル、フタラジニル、アザベンゾフリルおよびアザインドリルからなる群より選択され、その各々は独立して、メチル、−アミノ、−NHMe、−NMe2、メトキシ、ヒドロキシメチルおよびハロゲンからなる群より選択される基の1〜2個で適宜置換されていてもよく;
Dは、シアノ、S(O2)R24、ハロゲン、C(O)NR21R22、フェニルおよびヘテロアリールからなる群より選択され;その中で、該フェニルまたはヘテロアリールは独立して、1〜3個の同一もしくは異なるハロゲンで、またはGから選択される1〜3個の同一もしくは異なる置換基で適宜置換されていてもよく;ヘテロアリールは、ピリジニルおよびオキサジアゾリルからなる群より選択され;
Aは、フェニル、ピリジニル、フリル、チエニル、イソキサゾリルおよびオキサゾリルからなる群より選択され、その中で、該フェニル、ピリジニル、フリル、チエニル、イソキサゾリルおよびオキサゾリルは独立して、1〜3個の同一もしくは異なるハロゲンで、またはGから選択される1〜3個の同一もしくは異なる置換基で適宜置換されていてもよく;
Gは、(C1-6)アルキル、(C1-6)アルケニル、フェニル、ヒドロキシ、メトキシ、ハロゲン、−NR23C(O)−(C1-6)アルキル、−NR24R25、−S(O)2NR24R25、COOR26および−CONR24R25からなる群より選択され;その中で、該(C1-6)アルキルは、ヒドロキシ、ジメチルアミノまたは1〜3個の同一もしくは異なるハロゲンで適宜置換されており;
R26は、水素および(C1-6)アルキルからなる群より選択され;
R20、R21、R22、R23、R24、R25は独立して、水素、(C1-6)アルキルおよび−(CH2)nNR27R28からなる群より選択され;
nは、0〜6であり;および
R27およびR28は各々独立して、Hまたはメチルである]
の化合物類(またはその医薬的に許容される塩)を開示する。
本発明は、1−ベンゾイル−4−[2−[4−メトキシ−7−(3−メチル−1H−1,2,4−トリアゾール−1−イル)−1−[(ホスホノオキシ)メチル]−1H−ピロロ[2,3−c]ピリジン−3−イル]−1,2−ジオキソエチル]−ピペラジン、その塩および溶媒和物の結晶形を提供する。これらの結晶形の態様には、本明細書で−01−H2−1型、−02−SA−1型、−03−E.5−1型、−03−SA−2型、および−03−DSA−2型等としての特徴を有するものが含まれる。特定の形態、例えば「−01−H2−1」等の特徴を有するように本明細書で用いられる名前は、類似または同一の物理的および化学的特徴を有するいずれの他の物質についても制限するものとみなされるべきではなく、むしろこれらの名称は、本明細書でも与えられる特徴情報に従って解釈されるべき識別子に過ぎないことが理解されるべきである。
によって記載される。
本開示は、少なくとも一部分において、化合物(I)、その塩および溶媒和物の結晶形を提供する。本開示はまた、一般に、該結晶形を含む医薬組成物、並びにHIVおよび/またはAIDSの治療における該結晶形の使用方法、およびこのような結晶形を得る方法にも関する。化合物(I)は、1−ベンゾイル−4−[2−[4−メトキシ−7−(3−メチル−1H−1,2,4−トリアゾール−1−イル)−1−[(ホスホノオキシ)メチル]−1H−ピロロ[2,3−c]ピリジン−3−イル]−1,2−ジオキソエチル]−ピペラジンである。本明細書で化合物(I)は、式(I):
によって記載される。
本明細書中で用いられるように、「多形」とは、同一の化学組成を有するが、結晶を形成する分子、原子、および/またはイオンの異なった空間配置を有する結晶形をいう。
(a)哺乳類、特に、症状にかかりやすいが、まだそれを有しているとは診断されていない哺乳類において、その症状が発生するのを予防すること;
(b)症状の抑制、すなわち、その進行の抑止;および/または
(c)症状の軽減、すなわち、症状の後退を引き起こすこと。
有機合成の当業者に周知の方法、並びにその全体が本明細書に引用されている共有(commonly owned)の米国非仮特許出願番号11/066,745(2005年2月25日に出願)に記載された方法を用いて、化合物(I)は製造されうる。
結晶形の製造方法は、当該技術分野で公知である。結晶形は様々な方法によって製造されうるが、それには、例えば、適当な溶媒からの結晶化または再結晶化、昇華、融解からの成長、固体以外から固体への状態変換、超臨界流体からの結晶化、および噴射スプレーが含まれる。溶媒混合物からの結晶形の結晶化または再結晶化のための技術には、例えば、溶媒の蒸発、溶媒混合物の温度の低下、分子および/または塩の過飽和溶媒混合物への種晶の付加、溶媒混合物の凍結乾燥、および溶媒混合物への貧溶媒(逆溶媒(countersolvent))の付加が含まれる。ハイスループット結晶化技術は、多形を含む結晶形の製造に用いられうる。
化合物(I)、その塩および溶媒和物の結晶形は、多数の方法、例えばこれらに限らないが、粉末X線回折(PXRD)、シミュレーションされた粉末X線パターン(Yin. S.; Scaringe, R. P.; DiMarco, J.; Galella, M. and Gougoutas, J. Z., American Pharmaceutical Review, 2003, 6,2, 80)、示差走査熱量測定(DSC)実験、固体C−13 NMR測定(W.L. Earl and D.L. VanderHart, J. Magn. Reson., 1982, 48, 35-54)、ラマン分光法、赤外分光法、吸湿等温線(VTI−−可変温度等温線(variable temperature isotherm))、および高温技術(hot stage technique)によって評価されうる。
化合物(I)、その塩および溶媒和物の結晶形は、単独または他の化合物と併用して、AIDSおよび/またはHIV感染を治療するのに用いられうる。
以下に示す略語(これらのほとんどは、当業者にとって周知の通常の略語である)を、本発明の説明および実施例を通じて使用する。使用する略語の幾つかは、以下の通りである。
h=時間
rt=室温
mol=モル
mmol=ミリモル
g=グラム
mg=ミリグラム
mL=ミリリットル
TFA=トリフルオロ酢酸
DCE=1,2−ジクロロエタン
CH2Cl2=ジクロロメタン
TPAP=過ルテニウム酸テトラプロピルアンモニウム
THF=テトラヒドロフラン
DEPBT=3−(ジエトキシホスホリルオキシ)−1,2,3−ベンゾトリアジン−4(3H)−オン
DMAP=4−ジメチルアミノピリジン
P−EDC=ポリマー支持1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド
EDC=1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド
DMF=N,N−ジメチルホルムアミド
ヒューニッヒ塩基=N,N−ジイソプロピルエチルアミン
mCPBA=メタ−クロロ過安息香酸
アザインドール=1H−ピロロ−ピリジン
4−アザインドール=1H−ピロロ[3,2−b]ピリジン
5−アザインドール=1H−ピロロ[3,2−c]ピリジン
6−アザインドール=1H−ピロロ[2,3−c]ピリジン
7−アザインドール=1H−ピロロ[2,3−b]ピリジン
PMB=4−メトキシベンジル
DDQ=2,3−ジクロロ−5,6−ジシアノ−1,4−ベンゾキノン
OTf=トリフルオロメタンスルホンオキシ
NMM=4−メチルモルホリン
PIP−COPh=1−ベンゾイルピペラジン
NaHMDS=ナトリウムヘキサメチルジシラジド
EDAC=1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド
TMS=トリメチルシリル
DCM=ジクロロメタン
DCE=ジクロロエタン
MeOH=メタノール
THF=テトラヒドロフラン
EtOAc=酢酸エチル
LDA=リチウムジイソプロピルアミド
TMP−Li=2,2,6,6−テトラメチルピペリジニルリチウム
DME=ジメトキシエタン
DIBALH=水素化ジイソブチルアルミニウム
HOBT=1−ヒドロキシベンゾトリアゾール
CBZ=ベンジルオキシカルボニル
PCC=クロロクロム酸ピリジニウム
Me=メチル
Ph=フェニル
01−H2−1型の化合物(I)は、実験式C25H26N7O8P1・2H2Oを有する二水和物である。01−H2−1型の単結晶は、表1で評価される。01−H2−1型における各原子(Hを除く)は、図3に従ってラベル付けされる。部分原子座標は、表2に記載されている。
02−SA−1型の化合物(I)は、C25H24N7O8P1Na2・8H2O・0.5C2H5OHの実験式を有する二ナトリウム塩のヘミエタノラート八水和物(hemiethanolate octahydrate of di-sodium salt)である。02−SA−1型の単結晶は、表3で評価される。02−SA−1型における各原子(Hを除く)は、図5に従ってラベル付けされる。部分原子座標は、表4に記載されている。
03−E.5−1型の化合物(I)は、C25H26N7O8P1・C4H11N1O3・0.5C2H5OHの実験式を有するモノトリス塩のヘミエタノラート(hemiethanolate of mono-TRIS salt)である。03−E.5−1型の単結晶は、表5で評価される。03−E.5−1型における各原子(Hを除く)は、図8に従ってラベル付けされる。部分原子座標は、表6に記載されている。
03−SA−2型の化合物(I)は、C25H26N7O8P1・C4H11N1O3・0.5H2O・0.5C3H6Oの実験式を有するモノトリス塩のヘミアセトナート半水和物(hemiacetonate hemihydrate of mono-TRIS salt)である。03−SA−2型の単結晶は、表7で評価される。03−SA−2型における各原子(Hを除く)は、図11に従ってラベル付けされる。部分原子座標は、表8に記載されている。
03−DSA−2型の化合物(I)は、03−SA−2型の脱水および脱溶媒和型(dehydrated and desolvated formo)であるモノトリス塩である。
U(eq)は、直交化されたUijテンソルのトレースの3分の1として定義される。
実施例1.1 01−H2−1型の化合物(I)
遊離酸(25mg)をMeOH(1mL)に溶解した。3つの開放型キャピラリー(open-ended capillary)をバイアル中に置いて、核形成および結晶化を促進するのに役立てた。室温でゆっくり蒸発させることによって、キャピラリー上に四角い板状結晶(square-like plate)と、ずっと小さな粒径の結晶性固形物を得た。
1. 化合物(I)の遊離酸(100mg、0.171mmol)をNaOH(1N、〜0.4mL、0.4mmol)と混合し、最終のpHは6.5であった。
2. IPA(3.5mL)を30〜35℃で透明な水溶液に加え、室温まで〜1時間ゆっくり冷却した。
3. 固形物を溶液からゆっくり晶出させた。
4. 懸濁液を室温で2時間攪拌し、固形物を濾過によって集めた。
5. 濾過ケーキをIPS(2×2.5mL)ですすいだ。
6. 生じた固形物を簡易の真空(house vacuo)で55℃で乾燥して、白色固形物を得た(72mg)。
7. 顕微鏡下で、それは半結晶性固形物であった。
8. 固形物を50〜55℃でEtOH(1.5mL)に溶解し、室温まで〜1時間ゆっくり冷却した。
9. 透明な溶液を室温で7日間静置し、顕微鏡下で毛のような結晶が観察された。
モノトリス塩(50mg)を室温で水(0.2mL)に溶解し、次いでEtOH(1.0mL)を加え、透明な溶液を得た。2つの開放型キャピラリーをバイアル中に置いて、核形成および結晶化を促進するのに役立て、バイアルをアルミホイルで覆った。2週間後、キャピラリー上に薄い板状結晶が形成された。
最初にモノトリス塩(50mg)を室温で水(0.2mL)に溶解し、次いでアセトン(1.0ml)を加えた。別のアセトン(0.6mL)を加えた後に、白色沈殿が生じた。透明な溶液が得られるまで、バイアルを80℃で加熱した。溶液を加熱から取り除き、自然に室温まで冷却した。2時間以内に長くて細い針状晶が観察された。
化合物(I)−ジトリスのジトリス塩(di-tris salt)の製造
1. 化合物(I)の遊離酸(0.50g)のH2O溶液(2mL、pH 1.02)を混合した。
2. トリスアミン水溶液(3M)を、pH 7.32になるまで遊離酸水溶液に加えた。
3. クルードの深紅色溶液を、セライトパッドを通して濾過し、H2O(3mL)を用いてセライトパッドをすすいだ。
4. アセトン(75mL)を室温で1時間かけて水溶液にゆっくりと加え、室温で種晶を入れた。
5. 室温で3時間攪拌した後、懸濁液を濾過によって集め、150:1 アセトン−水(2×5mL)ですすいだ。
6. 固形物を高真空で3時間乾燥し、窒素を出しながら(bleeding)、55℃で24時間、簡易の真空で乾燥した。
7. それによって生成物を得た(0.355g、SMに基づいて51%、SMの純度に基づいて60%)。
8. HPLCによってAP>99%が示され、母液は5〜10%の生成物を有する。
9. ジトリス塩(0.35g)のH2O溶液(3mL)を、pHが3.3になるまでTFA(50mg、1当量)に加え、反応液に種晶を入れ、37℃まで加熱し、40℃まで2時間ゆっくりと加熱した。アセトン(60mL)を溶液に加え、溶液を室温まで〜2時間ゆっくりと冷却し、白色固形物がゆっくりと現れた。
10. 室温で3時間攪拌した後、白色懸濁液をN2下で濾過によって集め、アセトン(2×10mL)ですすいだ。固形物を減圧乾燥して、生成物を得(0.241g、回収率80%、クルードの酸から49%)、HPLCによってAP>99%が示され、NMRによって529:トリス 1:10〜1.01が示された。
少なくとも下記の方法を用い、単結晶X線回折法を用いて、実施例1.1〜1.5で得られたいくつかのサンプルを評価した。シミュレーションされたPXRDもまたプロットする。結果を図1、4、6、9および12に示す。表9は、01−H2−1型、02−SA−1型、03−E.5−1型、03−SA−2型、および03−DSA−2型の化合物(I)を説明する選択されたPXRDピークを列挙する。
グラファイト単色(graphite-monochromated)Cu Kα照射(λ=1.54056Å)を備えているブルカー SMART 2K CCD回折計を用いて、室温で回折データを集めた。結晶−検出器間距離4.98cmで、2θの範囲にわたって、ωスキャンモードを用いて十分なデータセットを集めた。実験の吸収補正には、回折計(Bruker AXS. 1998, SMART and SAINTPLUS. Area Detector Control and Integration Software, Bruker AXS, Madison, Wisconsin, USA)に関するSADABSルーチンを利用した。最終的な単位格子パラメータを、全データセットを用いて決定した。
JPOWソフトウェア(Materials Data Inc. 2001. JPOWD. Powder Diffraction Simulation and Structure Display. Materials Data Inc, Livermore, California, USA)を用いることによって、すべてのシミュレーションされたPXRDパターンを、室温での結晶構造の精密化された原子座標から計算した。
少なくとも下記の方法を用い、DSCを用いて、実施例1.1〜1.5で得られたいくつかのサンプルを評価した。シミュレーションされたPXRDもまたプロットした。結果を図2、7、10および13に示す。
示差走査熱量測定(DSC)実験を、TAインスツルメント(TA Instruments)(登録商標)モデルQ1000または2920において行った。サンプル(約2〜6mg)を、小さい穴を有するオープンアルミニウム皿または密封皿(sealed pan)中で秤量し、ミリグラムの100分の1まで正確に記録し、DSCに移した。装置を50mL/分で、窒素ガスでパージした。加熱速度10℃/分で、室温と300℃の間でデータを集めた。下向きの吸熱ピークでプロットした。
少なくとも下記の方法を用い、TGAを用いて、実施例1.1〜1.5で得られたいくつかのサンプルを評価した。シミュレーションされたPXRDもまたプロットした。結果を図2、7、10および13に示す。
熱重量分析(TGA)実験を、TAインスツルメント(登録商標)モデルQ500または2950において行った。サンプル(約10〜30mg)を、あらかじめ風袋を量った白金皿中に置いた。サンプルの重量を正確に測定し、装置によってミリグラムの1000分の1まで記録した。炉(furnace)を100mL/分で、窒素ガスでパージした。加熱速度10℃/分で、室温と300℃の間でデータを集めた。
Claims (14)
- C25H24N7O8P1Na2・8H2O・0.5C2H5OHの実験式を有する二ナトリウム塩のヘミエタノラート八水和物である02−SA−1型を含む、化合物(I):
の結晶形であって、
約163Kから約183Kの温度で、4.3±0.2、6.7±0.2、7.4±0.2、8.5±0.2、10.0±0.2、11.8±0.2、12.9±0.2、13.5±0.2、14.1±0.2、14.8±0.2、15.5±0.2、16.0±0.2、16.5±0.2、17.1±0.2、および18.5±0.2からなる群より選択される4つまたはそれ以上の2θ値(CuKα λ=1.5418Å)を含む粉末X線回折パターンの特徴を有する、結晶形。 - 約163Kから約183Kの温度で、4.3±0.2、6.7±0.2、7.4±0.2、8.5±0.2、10.0±0.2、11.8±0.2、12.9±0.2、13.5±0.2、14.1±0.2、14.8±0.2、15.5±0.2、16.0±0.2、16.5±0.2、17.1±0.2、および18.5±0.2からなる群より選択される5つまたはそれ以上の2θ値(CuKα λ=1.5418Å)を含む粉末X線回折パターンの特徴をさらに有する、請求項1の結晶形。
- C25H26N7O8P1・C4H11N1O3・0.5C2H5OHの実験式を有するモノトリス塩のヘミエタノラートである03−E.5−1型を含む、化合物(I):
の結晶形であって、
約20℃から約25℃の温度で、5.0±0.2、5.8±0.2、7.2±0.2、8.1±0.2、10.0±0.2、11.0±0.2、11.6±0.2、12.0±0.2、13.2±0.2、16.1±0.2、17.0±0.2、17.5±0.2、19.0±0.2、20.4±0.2、および21.1±0.2からなる群より選択される4つまたはそれ以上の2θ値(CuKα λ=1.5418Å)を含む粉末X線回折パターンの特徴を有する、結晶形。 - 約20℃から約25℃の温度で、5.0±0.2、5.8±0.2、7.2±0.2、8.1±0.2、10.0±0.2、11.0±0.2、11.6±0.2、12.0±0.2、13.2±0.2、16.1±0.2、17.0±0.2、17.5±0.2、19.0±0.2、20.4±0.2、および21.1±0.2からなる群より選択される5つまたはそれ以上の2θ値(CuKα λ=1.5418Å)を含む粉末X線回折パターンの特徴をさらに有する、請求項6の結晶形。
- 組成物の重量に基づいて、少なくとも5重量%の請求項1の結晶形、および医薬的に許容される担体を含む組成物。
- 化合物(I)の塩が実質的に純粋である、請求項1の結晶形。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US75024705P | 2005-12-14 | 2005-12-14 | |
US60/750,247 | 2005-12-14 | ||
PCT/US2006/047571 WO2007070589A2 (en) | 2005-12-14 | 2006-12-13 | Crystalline forms of 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1h-1,2,4-triazol-1-yl)-1-[(phosphonooxy)methyl]-1h-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2009521414A JP2009521414A (ja) | 2009-06-04 |
JP2009521414A5 JP2009521414A5 (ja) | 2010-01-21 |
JP5400387B2 true JP5400387B2 (ja) | 2014-01-29 |
Family
ID=38163502
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008545772A Active JP5400387B2 (ja) | 2005-12-14 | 2006-12-13 | 1−ベンゾイル−4−[2−[4−メトキシ−7−(3−メチル−1h−1,2,4−トリアゾール−1−イル)−1−[(ホスホノオキシ)メチル]−1h−ピロロ[2,3−c]ピリジン−3−イル]−1,2−ジオキソエチル]−ピペラジンの結晶形 |
Country Status (17)
Country | Link |
---|---|
US (1) | US7851476B2 (ja) |
EP (1) | EP1963342A2 (ja) |
JP (1) | JP5400387B2 (ja) |
KR (1) | KR20080077010A (ja) |
CN (1) | CN101365708B (ja) |
AU (1) | AU2006326432B2 (ja) |
BR (1) | BRPI0619851A2 (ja) |
CA (1) | CA2635717A1 (ja) |
EA (1) | EA014706B1 (ja) |
GE (1) | GEP20125413B (ja) |
IL (1) | IL191769A (ja) |
MY (1) | MY144293A (ja) |
NO (1) | NO20082477L (ja) |
NZ (2) | NZ592684A (ja) |
UA (1) | UA94928C2 (ja) |
WO (1) | WO2007070589A2 (ja) |
ZA (1) | ZA200805063B (ja) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040110785A1 (en) * | 2001-02-02 | 2004-06-10 | Tao Wang | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
US7745625B2 (en) | 2004-03-15 | 2010-06-29 | Bristol-Myers Squibb Company | Prodrugs of piperazine and substituted piperidine antiviral agents |
WO2009158396A1 (en) * | 2008-06-25 | 2009-12-30 | Bristol-Myers Squibb Company | Diketopiperidine derivatives as hiv attachment inhibitors |
ES2462403T3 (es) | 2008-06-25 | 2014-05-22 | Bristol-Myers Squibb Company | Diceto azolopiperidinas y azolopiperazinas como agentes anti-VIH |
ATE550016T1 (de) * | 2008-09-04 | 2012-04-15 | Bristol Myers Squibb Co | Stabile pharmazeutische zusammensetzung zur optimierten abgabe eines hiv-attachment- inhibitors |
EP2646439B1 (en) | 2010-12-02 | 2016-05-25 | Bristol-Myers Squibb Company | Alkyl amides as hiv attachment inhibitors |
US8436168B2 (en) * | 2011-01-31 | 2013-05-07 | Bristol-Myers Squibb Company | Methods of making HIV attachment inhibitor prodrug compound and intermediates |
US8685982B2 (en) | 2011-04-12 | 2014-04-01 | Bristol-Myers Squibb Company | Thioamide, amidoxime and amidrazone derivatives as HIV attachment inhibitors |
ES2609579T3 (es) | 2011-08-29 | 2017-04-21 | VIIV Healthcare UK (No.5) Limited | Derivados espiro de diamina bicíclica como inhibidores de la unión del VIH |
EP2751119B1 (en) | 2011-08-29 | 2016-11-23 | VIIV Healthcare UK (No.5) Limited | Fused bicyclic diamine derivatives as hiv attachment inhibitors |
WO2013138436A1 (en) | 2012-03-14 | 2013-09-19 | Bristol-Myers Squibb Company | Cyclolic hydrazine derivatives as hiv attachment inhibitors |
WO2014025854A1 (en) | 2012-08-09 | 2014-02-13 | Bristol-Myers Squibb Company | Piperidine amide derivatives as hiv attachment inhibitors |
ES2616432T3 (es) | 2012-08-09 | 2017-06-13 | VIIV Healthcare UK (No.5) Limited | Derivados de alquenos tricíclicos como inhibidores de la unión del VIH |
RU2663466C1 (ru) * | 2017-03-20 | 2018-08-06 | Общество с ограниченной ответственностью "МБА-групп" | Композиция для профилактики и/или лечения вич-инфекции |
Family Cites Families (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB944443A (ja) | 1959-09-25 | 1900-01-01 | ||
GB8615562D0 (en) | 1986-06-25 | 1986-07-30 | Maggioni Farma | Aminoalcohols |
WO1990007926A1 (en) | 1989-01-20 | 1990-07-26 | Pfizer Inc. | 3-(1,2,5,6-tetrahydropyridyl)-pyrrolopyridines |
US5023265A (en) | 1990-06-01 | 1991-06-11 | Schering Corporation | Substituted 1-H-pyrrolopyridine-3-carboxamides |
IL99843A0 (en) | 1990-11-01 | 1992-08-18 | Merck & Co Inc | Synergistic combination of hiv reverse transcriptase inhibitors |
US5811432A (en) | 1990-11-09 | 1998-09-22 | Pfizer Inc | Azaoxindole derivatives |
US5192770A (en) | 1990-12-07 | 1993-03-09 | Syntex (U.S.A.) Inc. | Serotonergic alpha-oxoacetamides |
KR100236808B1 (ko) | 1991-07-03 | 2000-02-01 | 로렌스 티. 마이젠헬더 | 에이즈 치료약제로서의 치환된 인돌 |
US5124327A (en) | 1991-09-06 | 1992-06-23 | Merck & Co., Inc. | HIV reverse transcriptase |
WO1993005020A1 (en) | 1991-09-06 | 1993-03-18 | Merck & Co., Inc. | Indoles as inhibitors of hiv reverse transcriptase |
US5413999A (en) | 1991-11-08 | 1995-05-09 | Merck & Co., Inc. | HIV protease inhibitors useful for the treatment of AIDS |
IT1265057B1 (it) | 1993-08-05 | 1996-10-28 | Dompe Spa | Tropil 7-azaindolil-3-carbossiamidi |
US5424329A (en) | 1993-08-18 | 1995-06-13 | Warner-Lambert Company | Indole-2-carboxamides as inhibitors of cell adhesion |
GB9420521D0 (en) | 1994-10-12 | 1994-11-30 | Smithkline Beecham Plc | Novel compounds |
GB9600559D0 (en) | 1996-01-11 | 1996-03-13 | British Biotech Pharm | Use of chemokines |
AU4031697A (en) | 1996-08-29 | 1998-03-19 | Takeda Chemical Industries Ltd. | Cyclic ether compounds as sodium channel modulators |
DE19636150A1 (de) | 1996-09-06 | 1998-03-12 | Asta Medica Ag | N-substituierte Indol-3-glyoxylamide mit antiasthmatischer, antiallergischer und immunsuppressiver/immunmodulierender Wirkung |
WO1999024065A1 (en) | 1997-11-10 | 1999-05-20 | The Trustees Of Columbia University In The City Of New York | COMPOUNDS INHIBITING CD4-gp120 INTERACTION AND USES THEREOF |
JP2002515891A (ja) | 1997-12-19 | 2002-05-28 | スミスクライン・ビーチャム・コーポレイション | 新規なピペリジン含有化合物 |
PL343249A1 (en) | 1998-03-26 | 2001-07-30 | Shionogi & Co | Indole derivatives with antiviral activity |
DE19814838C2 (de) | 1998-04-02 | 2001-01-18 | Asta Medica Ag | Indolyl-3-glyoxylsäure-Derivate mit Antitumorwirkung |
US6384041B1 (en) | 1998-06-30 | 2002-05-07 | Eli Lilly And Company | Bicyclic sPLA2 inhibitors |
AU772477B2 (en) | 1998-08-28 | 2004-04-29 | Scios Inc. | Inhibitors of p38-alpha kinase |
GB9905010D0 (en) | 1999-03-04 | 1999-04-28 | Merck Sharp & Dohme | Therapeutic agents |
BR0011274A (pt) | 1999-05-21 | 2002-02-26 | Scios Inc | Derivados tipo indol como inibidores de p38 quinase |
US6469006B1 (en) | 1999-06-15 | 2002-10-22 | Bristol-Myers Squibb Company | Antiviral indoleoxoacetyl piperazine derivatives |
TWI269654B (en) | 1999-09-28 | 2007-01-01 | Baxter Healthcare Sa | N-substituted indole-3-glyoxylamide compounds having anti-tumor action |
US6476034B2 (en) | 2000-02-22 | 2002-11-05 | Bristol-Myers Squibb Company | Antiviral azaindole derivatives |
US20020061892A1 (en) | 2000-02-22 | 2002-05-23 | Tao Wang | Antiviral azaindole derivatives |
DK1299382T3 (da) | 2000-07-10 | 2006-01-16 | Bristol Myers Squibb Co | Præparat og antiviral virkning af substituerede indoloxoeddikesyrepiperazinderivater |
US6573262B2 (en) | 2000-07-10 | 2003-06-03 | Bristol-Myers Sqibb Company | Composition and antiviral activity of substituted indoleoxoacetic piperazine derivatives |
DE10037310A1 (de) | 2000-07-28 | 2002-02-07 | Asta Medica Ag | Neue Indolderivate und deren Verwendung als Arzneimittel |
US20030207910A1 (en) | 2001-02-02 | 2003-11-06 | Tao Wang | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
EP1363705B9 (en) | 2001-02-02 | 2012-11-07 | Bristol-Myers Squibb Company | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
US20040110785A1 (en) | 2001-02-02 | 2004-06-10 | Tao Wang | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
US6825201B2 (en) | 2001-04-25 | 2004-11-30 | Bristol-Myers Squibb Company | Indole, azaindole and related heterocyclic amidopiperazine derivatives |
US20040009990A1 (en) | 2001-11-09 | 2004-01-15 | Higgins Linda S. | Method to treat cystic fibrosis |
US20030236277A1 (en) | 2002-02-14 | 2003-12-25 | Kadow John F. | Indole, azaindole and related heterocyclic pyrrolidine derivatives |
AU2003215469A1 (en) | 2002-03-28 | 2003-10-13 | Procyon Biopharma Inc. | Pyridoxal-5-phosphate derivatives as hiv integrase inhibitors |
US7037913B2 (en) | 2002-05-01 | 2006-05-02 | Bristol-Myers Squibb Company | Bicyclo 4.4.0 antiviral derivatives |
US7348337B2 (en) | 2002-05-28 | 2008-03-25 | Bristol-Myers Squibb Company | Indole, azaindole and related heterocyclic 4-alkenyl piperidine amides |
US20040063744A1 (en) | 2002-05-28 | 2004-04-01 | Tao Wang | Indole, azaindole and related heterocyclic 4-alkenyl piperidine amides |
US20040106104A1 (en) | 2002-06-11 | 2004-06-03 | Pin-Fang Lin | Viral envelope mediated fusion assay |
US6900206B2 (en) | 2002-06-20 | 2005-05-31 | Bristol-Myers Squibb Company | Indole, azaindole and related heterocyclic sulfonylureido piperazine derivatives |
US20040063746A1 (en) | 2002-07-25 | 2004-04-01 | Alicia Regueiro-Ren | Indole, azaindole and related heterocyclic ureido and thioureido piperazine derivatives |
US20050075364A1 (en) | 2003-07-01 | 2005-04-07 | Kap-Sun Yeung | Indole, azaindole and related heterocyclic N-substituted piperazine derivatives |
KR20060037442A (ko) | 2003-08-14 | 2006-05-03 | 화이자 인코포레이티드 | Hiv 감염 치료용 피페라진 유도체 |
US20050124623A1 (en) | 2003-11-26 | 2005-06-09 | Bender John A. | Diazaindole-dicarbonyl-piperazinyl antiviral agents |
US7745625B2 (en) * | 2004-03-15 | 2010-06-29 | Bristol-Myers Squibb Company | Prodrugs of piperazine and substituted piperidine antiviral agents |
US20050215544A1 (en) | 2004-03-24 | 2005-09-29 | Pin-Fang Lin | Methods of treating HIV infection |
US20050215543A1 (en) | 2004-03-24 | 2005-09-29 | Pin-Fang Lin | Methods of treating HIV infection |
US7776863B2 (en) | 2004-03-24 | 2010-08-17 | Bristol-Myers Squibb Company | Methods of treating HIV infection |
US7449476B2 (en) | 2004-05-26 | 2008-11-11 | Bristol-Myers Squibb Company | Tetrahydrocarboline antiviral agents |
US7087610B2 (en) | 2004-06-03 | 2006-08-08 | Bristol-Myers Squibb Company | Benzothiazole antiviral agents |
WO2005121094A1 (en) | 2004-06-09 | 2005-12-22 | Pfizer Limited | Piperazine and piperidine derivatives as anti-hiv-agents |
US20060100432A1 (en) | 2004-11-09 | 2006-05-11 | Matiskella John D | Crystalline materials of 1-(4-benzoyl-piperazin-1-yl)-2-[4-methoxy-7-(3-methyl-[1,2,4]triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-ethane-1,2-dione |
US20060100209A1 (en) | 2004-11-09 | 2006-05-11 | Chong-Hui Gu | Formulations of 1-(4-benzoyl-piperazin-1-yl)-2-[4-methoxy-7-(3-methyl-[1,2,4]triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-ethane-1,2-dione |
US7183284B2 (en) | 2004-12-29 | 2007-02-27 | Bristol-Myers Squibb Company | Aminium salts of 1,2,3-triazoles as prodrugs of drugs including antiviral agents |
US7396830B2 (en) | 2005-10-04 | 2008-07-08 | Bristol-Myers Squibb Company | Piperazine amidines as antiviral agents |
US7501419B2 (en) | 2006-04-25 | 2009-03-10 | Bristol-Myers Squibb Company | 4-Squarylpiperazine derivatives as antiviral agents |
US7807671B2 (en) | 2006-04-25 | 2010-10-05 | Bristol-Myers Squibb Company | Diketo-piperazine and piperidine derivatives as antiviral agents |
-
2006
- 2006-12-11 US US11/636,755 patent/US7851476B2/en active Active
- 2006-12-13 CA CA002635717A patent/CA2635717A1/en not_active Abandoned
- 2006-12-13 EA EA200801529A patent/EA014706B1/ru not_active IP Right Cessation
- 2006-12-13 NZ NZ592684A patent/NZ592684A/en unknown
- 2006-12-13 NZ NZ568776A patent/NZ568776A/en unknown
- 2006-12-13 WO PCT/US2006/047571 patent/WO2007070589A2/en active Application Filing
- 2006-12-13 JP JP2008545772A patent/JP5400387B2/ja active Active
- 2006-12-13 EP EP06848592A patent/EP1963342A2/en not_active Withdrawn
- 2006-12-13 AU AU2006326432A patent/AU2006326432B2/en active Active
- 2006-12-13 KR KR1020087016884A patent/KR20080077010A/ko not_active Application Discontinuation
- 2006-12-13 UA UAA200809079A patent/UA94928C2/ru unknown
- 2006-12-13 BR BRPI0619851-1A patent/BRPI0619851A2/pt not_active Application Discontinuation
- 2006-12-13 CN CN2006800472167A patent/CN101365708B/zh active Active
- 2006-12-13 GE GEAP200610811A patent/GEP20125413B/en unknown
- 2006-12-13 MY MYPI20082090A patent/MY144293A/en unknown
-
2008
- 2008-05-27 IL IL191769A patent/IL191769A/en active IP Right Grant
- 2008-05-29 NO NO20082477A patent/NO20082477L/no not_active Application Discontinuation
- 2008-06-10 ZA ZA200805063A patent/ZA200805063B/xx unknown
Also Published As
Publication number | Publication date |
---|---|
ZA200805063B (en) | 2009-10-28 |
KR20080077010A (ko) | 2008-08-20 |
WO2007070589A3 (en) | 2007-09-27 |
CN101365708B (zh) | 2012-12-12 |
CA2635717A1 (en) | 2007-06-21 |
CN101365708A (zh) | 2009-02-11 |
US7851476B2 (en) | 2010-12-14 |
AU2006326432A1 (en) | 2007-06-21 |
MY144293A (en) | 2011-08-29 |
EA200801529A1 (ru) | 2009-02-27 |
IL191769A0 (en) | 2008-12-29 |
JP2009521414A (ja) | 2009-06-04 |
NO20082477L (no) | 2008-09-05 |
EP1963342A2 (en) | 2008-09-03 |
US20070155702A1 (en) | 2007-07-05 |
GEP20125413B (en) | 2012-03-12 |
NZ592684A (en) | 2012-07-27 |
NZ568776A (en) | 2011-06-30 |
IL191769A (en) | 2011-08-31 |
WO2007070589A2 (en) | 2007-06-21 |
AU2006326432B2 (en) | 2012-07-12 |
EA014706B1 (ru) | 2011-02-28 |
BRPI0619851A2 (pt) | 2011-10-25 |
UA94928C2 (en) | 2011-06-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5400387B2 (ja) | 1−ベンゾイル−4−[2−[4−メトキシ−7−(3−メチル−1h−1,2,4−トリアゾール−1−イル)−1−[(ホスホノオキシ)メチル]−1h−ピロロ[2,3−c]ピリジン−3−イル]−1,2−ジオキソエチル]−ピペラジンの結晶形 | |
JP6154473B2 (ja) | 第XIa因子阻害剤の結晶形 | |
US20200031784A1 (en) | Ozanimod addition salt crystal, preparation method, pharmaceutical composition, and uses | |
KR20160023879A (ko) | 결정질 형태의 다사티닙 염 | |
US7829711B2 (en) | Crystalline materials of 1-(4-benzoyl-piperazin-1-yl)-2-[4-methoxy-7-(3-methyl-[1,2,4]triazol-1-yl)-1H-pyrrolo[2,3-C]pyridine-3-yl]-ethane-1,2-dione | |
JP2018520188A (ja) | 呼吸器合胞体ウイルス(rsv)感染症の処置のためのn−[(3−アミノ−3−オキセタニル)メチル]−2−(2,3−ジヒドロ−1,1−ジオキシド−1,4−ベンゾチアゼピン−4(5h)−イル)−6−メチル−4−キナゾリンアミンの結晶形 | |
US7371864B2 (en) | Crystalline forms of a factor Xa inhibitor | |
US7723338B2 (en) | Crystalline forms of 1-benzoyl-4-[2-[4,7-dimethoxy-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-C]pyridin-3-yl]-1,2-dioxoethyl]-piperazine | |
JP2008514711A (ja) | ピラゾロ[3,4−c]ピリジンXA因子阻害剤の結晶フォーム | |
US9464086B2 (en) | Crystalline forms of N,N-dicyclopropyl-4-(1,5-dimethyl-1 H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-D]pyrrolo[2,3-B]pyridine-7-carboxamide for the treatment of myeloproliferative disorders | |
US9598413B2 (en) | Crystalline form of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-D]pyrrolo[2,3-B]pyridine-7-carboxamide for the treatment of myeloproliferative disorders | |
US9593116B2 (en) | Crystalline forms of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders | |
MX2008007297A (es) | Formas cristalinas de 1-benzoil-4-[2-[4-metoxi-7-(3-metil-1h-1,2,4-triazol-1-il)-1-[(fosfonoxi)metil]-1h-pirrolo[2,3-c]piridin-3-il]-1,2-dioxoetil]-piperazina | |
WO2022256550A1 (en) | Crystalline forms of an adenosine a2b receptor antagonist | |
AU2021233433A1 (en) | Crystal of imidazopyridinone compound or salt thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20091126 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20091126 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120529 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20120529 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20120828 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20120904 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20120926 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20121003 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20121003 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130402 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130409 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20131001 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20131025 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5400387 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |