KR20090122218A - ５-(２,４-디히드록시-５-이소프로필-페닐)-４-(４-모르폴린-４-일메틸-페닐)-이속사졸-３-카르복실산 에틸아미드의 산 부가염, 수화물 및 다형체, 및 이들 형태를 포함하는 제제 - Google Patents
５-(２,４-디히드록시-５-이소프로필-페닐)-４-(４-모르폴린-４-일메틸-페닐)-이속사졸-３-카르복실산 에틸아미드의 산 부가염, 수화물 및 다형체, 및 이들 형태를 포함하는 제제 Download PDFInfo
- Publication number
- KR20090122218A KR20090122218A KR1020097018126A KR20097018126A KR20090122218A KR 20090122218 A KR20090122218 A KR 20090122218A KR 1020097018126 A KR1020097018126 A KR 1020097018126A KR 20097018126 A KR20097018126 A KR 20097018126A KR 20090122218 A KR20090122218 A KR 20090122218A
- Authority
- KR
- South Korea
- Prior art keywords
- phenyl
- dihydroxy
- isopropyl
- ylmethyl
- isoxazole
- 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.)
- Ceased
Links
- NDAZATDQFDPQBD-UHFFFAOYSA-N luminespib Chemical class CCNC(=O)C1=NOC(C=2C(=CC(O)=C(C(C)C)C=2)O)=C1C(C=C1)=CC=C1CN1CCOCC1 NDAZATDQFDPQBD-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 150000003839 salts Chemical class 0.000 title claims abstract description 25
- 239000000203 mixture Substances 0.000 title claims abstract description 19
- 238000009472 formulation Methods 0.000 title claims abstract description 17
- 239000002253 acid Substances 0.000 title claims description 10
- 150000004677 hydrates Chemical class 0.000 title abstract description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 23
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 claims abstract description 17
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 claims abstract description 17
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 13
- 239000007864 aqueous solution Substances 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 208000035475 disorder Diseases 0.000 claims abstract description 9
- 230000001404 mediated effect Effects 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- 239000011521 glass Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- -1 2,4-dihydroxy-5-isopropyl-phenyl Chemical group 0.000 claims description 55
- JLLYLQLDYORLBB-UHFFFAOYSA-N 5-bromo-n-methylthiophene-2-sulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(Br)S1 JLLYLQLDYORLBB-UHFFFAOYSA-N 0.000 claims description 14
- ZMAQNODASNQSRR-UHFFFAOYSA-N 5-(2,4-dihydroxy-5-propan-2-ylphenyl)-N-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-oxazole-3-carboxamide methanesulfonic acid Chemical compound CS(O)(=O)=O.CCNC(=O)C1=NOC(C=2C(=CC(O)=C(C(C)C)C=2)O)=C1C(C=C1)=CC=C1CN1CCOCC1 ZMAQNODASNQSRR-UHFFFAOYSA-N 0.000 claims description 13
- 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 claims description 12
- 239000008103 glucose Substances 0.000 claims description 12
- PMJKKPCMQNUNMH-UHFFFAOYSA-N 5-(2,4-dihydroxy-5-propan-2-ylphenyl)-N-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-oxazole-3-carboxamide hydrochloride Chemical compound Cl.CCNC(=O)C1=NOC(C=2C(=CC(O)=C(C(C)C)C=2)O)=C1C(C=C1)=CC=C1CN1CCOCC1 PMJKKPCMQNUNMH-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- ATWDUWYFCBVNET-UHFFFAOYSA-N ethylammonium methanesulfonate Chemical compound CC[NH3+].CS([O-])(=O)=O ATWDUWYFCBVNET-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 7
- OKRBMTVAQNIMIB-UHFFFAOYSA-N 2,3-dihydroxybutanedioic acid 5-(2,4-dihydroxy-5-propan-2-ylphenyl)-N-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-oxazole-3-carboxamide Chemical compound OC(=O)C(O)C(O)C(O)=O.CCNC(=O)C1=NOC(C=2C(=CC(O)=C(C(C)C)C=2)O)=C1C(C=C1)=CC=C1CN1CCOCC1 OKRBMTVAQNIMIB-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- BTCJJPNMEPEHHK-UHFFFAOYSA-N 5-(2,4-dihydroxy-5-propan-2-ylphenyl)-N-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-oxazole-3-carboxamide phosphoric acid Chemical compound OP(O)(O)=O.CCNC(=O)C1=NOC(C=2C(=CC(O)=C(C(C)C)C=2)O)=C1C(C=C1)=CC=C1CN1CCOCC1 BTCJJPNMEPEHHK-UHFFFAOYSA-N 0.000 claims description 4
- AFHJZDKGISEZGR-UHFFFAOYSA-N N-ethyl-1,2-oxazole-3-carboxamide methanesulfonic acid Chemical compound CS(O)(=O)=O.CCNC(=O)c1ccon1 AFHJZDKGISEZGR-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- ARPJZLLWCWXWJQ-UHFFFAOYSA-N dihydrogen phosphate;ethylazanium Chemical compound CCN.OP(O)(O)=O ARPJZLLWCWXWJQ-UHFFFAOYSA-N 0.000 claims description 2
- FAXCUWWHBDEGMM-UHFFFAOYSA-N C(C)OC(=O)C1=NOC(=C1C1=CC=C(C=C1)CN1CCOCC1)C1=C(C=C(C(=C1)C(C)C)O)O Chemical compound C(C)OC(=O)C1=NOC(=C1C1=CC=C(C=C1)CN1CCOCC1)C1=C(C=C(C(=C1)C(C)C)O)O FAXCUWWHBDEGMM-UHFFFAOYSA-N 0.000 claims 3
- 241001465754 Metazoa Species 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 12
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 abstract description 4
- 238000001990 intravenous administration Methods 0.000 abstract description 4
- 229910019142 PO4 Inorganic materials 0.000 abstract description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 3
- 239000010452 phosphate Substances 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 229940095064 tartrate Drugs 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 239000012458 free base Substances 0.000 description 15
- 239000000725 suspension Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- AYUNIORJHRXIBJ-TXHRRWQRSA-N tanespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 7
- VJZBSHKIQOPPRU-UHFFFAOYSA-N 5-(2,4-dihydroxy-5-propan-2-ylphenyl)-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-oxazole-3-carboxylic acid Chemical group C1=C(O)C(C(C)C)=CC(C2=C(C(C(O)=O)=NO2)C=2C=CC(CN3CCOCC3)=CC=2)=C1O VJZBSHKIQOPPRU-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000008351 acetate buffer Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 229950005069 luminespib Drugs 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 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 3
- 239000003708 ampul Substances 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 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 3
- 239000000872 buffer Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 150000003460 sulfonic acids Chemical class 0.000 description 3
- 150000003892 tartrate salts Chemical class 0.000 description 3
- 108091006112 ATPases Proteins 0.000 description 2
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108010006519 Molecular Chaperones Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000013011 aqueous formulation Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000007979 citrate buffer Substances 0.000 description 2
- 238000002845 discoloration Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 230000008482 dysregulation Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 2
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000003797 solvolysis reaction Methods 0.000 description 2
- SWDZPNJZKUGIIH-QQTULTPQSA-N (5z)-n-ethyl-5-(4-hydroxy-6-oxo-3-propan-2-ylcyclohexa-2,4-dien-1-ylidene)-4-[4-(morpholin-4-ylmethyl)phenyl]-2h-1,2-oxazole-3-carboxamide Chemical compound O1NC(C(=O)NCC)=C(C=2C=CC(CN3CCOCC3)=CC=2)\C1=C1/C=C(C(C)C)C(O)=CC1=O SWDZPNJZKUGIIH-QQTULTPQSA-N 0.000 description 1
- KDJOYLAIVOVSNG-UHFFFAOYSA-N 4-[4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-oxazol-5-yl]-6-propan-2-ylbenzene-1,3-diol Chemical compound OC1=C(C=C(C(=C1)O)C(C)C)C1=C(C=NO1)C1=CC=C(C=C1)CN1CCOCC1 KDJOYLAIVOVSNG-UHFFFAOYSA-N 0.000 description 1
- 102000021527 ATP binding proteins Human genes 0.000 description 1
- 108091011108 ATP binding proteins Proteins 0.000 description 1
- 101100011744 Dictyostelium discoideum grp94 gene Proteins 0.000 description 1
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 1
- 108010033152 HSP90 Heat-Shock Proteins Proteins 0.000 description 1
- 102000007011 HSP90 Heat-Shock Proteins Human genes 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 102000005431 Molecular Chaperones Human genes 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 108010085012 Steroid Receptors Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 231100000230 acceptable toxicity Toxicity 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 150000002545 isoxazoles Chemical class 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VYGYNVZNSSTDLJ-HKCOAVLJSA-N monorden Natural products CC1CC2OC2C=C/C=C/C(=O)CC3C(C(=CC(=C3Cl)O)O)C(=O)O1 VYGYNVZNSSTDLJ-HKCOAVLJSA-N 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- JZWQGHAERZIZGM-UHFFFAOYSA-N n-ethyl-1,2-oxazole-3-carboxamide Chemical compound CCNC(=O)C=1C=CON=1 JZWQGHAERZIZGM-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- AECPBJMOGBFQDN-YMYQVXQQSA-N radicicol Chemical compound C1CCCC(=O)C[C@H]2[C@H](Cl)C(=O)CC(=O)[C@H]2C(=O)O[C@H](C)C[C@H]2O[C@@H]21 AECPBJMOGBFQDN-YMYQVXQQSA-N 0.000 description 1
- 229930192524 radicicol Natural products 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP07103346.8 | 2007-03-01 | ||
| EP07103346 | 2007-03-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20090122218A true KR20090122218A (ko) | 2009-11-26 |
Family
ID=38134307
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020097018126A Ceased KR20090122218A (ko) | 2007-03-01 | 2008-02-28 | ５-(２,４-디히드록시-５-이소프로필-페닐)-４-(４-모르폴린-４-일메틸-페닐)-이속사졸-３-카르복실산 에틸아미드의 산 부가염, 수화물 및 다형체, 및 이들 형태를 포함하는 제제 |
Country Status (40)
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8563842B2 (en) | 2010-09-27 | 2013-10-22 | Electronics And Telecommunications Research Institute | Method and apparatus for separating musical sound source using time and frequency characteristics |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200922595A (en) * | 2007-10-12 | 2009-06-01 | Novartis Ag | Organic compounds |
| TWI450898B (zh) * | 2008-07-04 | 2014-09-01 | Sigma Tau Res Switzerland Sa | 具有抗腫瘤活性之芳基異唑化合物 |
| US8309578B2 (en) | 2008-11-25 | 2012-11-13 | Nerviano Medical Sciences S.R.L. | Bicyclic pyrazole and isoxazole derivatives as antitumor and antineurodegenerative agents |
| WO2011089234A2 (en) * | 2010-01-21 | 2011-07-28 | Aprea Ab | Method and composition |
| CN102753546A (zh) * | 2010-02-17 | 2012-10-24 | 日东制药株式会社 | 新型5-元杂环衍生物及其制备方法 |
| WO2013015661A2 (en) * | 2011-07-28 | 2013-01-31 | Ildong Pharm Co.,Ltd. | Novel prodrugs of 5-(2,4-dihydroxy-5-isopropylphenyl)-n-ethyl-4-(5-methyl1-1,2,4-oxadiazol-3-yl)isoxazole-3-carboxamide |
| FR3039401B1 (fr) * | 2015-07-31 | 2018-07-13 | Les Laboratoires Servier | Nouvelle association entre le 3-[(3-{[4-(4-morpholinylmethyl)-1h-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1h-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione et un inhibiteur de la tyr kinase du egfr |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101166749B1 (ko) * | 2003-02-11 | 2012-07-27 | 베르날리스(캠브리지)리미티드 | 열쇼크 단백질 저해제로서의 이소옥사졸 화합물 |
| US20060070405A1 (en) * | 2004-10-06 | 2006-04-06 | Anheuser-Busch, Inc. | Method for the production of amber glass with reduced sulfur-containing emissions |
| CA2677651A1 (en) | 2007-02-15 | 2008-08-21 | Novartis Ag | Combinations of therapeutic agents for treating cancer |
| WO2010069458A1 (de) | 2008-12-17 | 2010-06-24 | Merck Patent Gmbh | Hexahalochromat(lll)-komplexe |
-
2008
- 2008-02-28 ES ES08717228T patent/ES2384906T3/es active Active
- 2008-02-28 US US12/529,090 patent/US8163747B2/en active Active
- 2008-02-28 SI SI200830688T patent/SI2131845T1/sl unknown
- 2008-02-28 BR BRPI0807992-7A2A patent/BRPI0807992A2/pt not_active IP Right Cessation
- 2008-02-28 EP EP08717228A patent/EP2131845B1/en active Active
- 2008-02-28 CN CN201110226727.8A patent/CN102302500A/zh active Pending
- 2008-02-28 PT PT08717228T patent/PT2131845E/pt unknown
- 2008-02-28 HR HRP20120535AT patent/HRP20120535T1/hr unknown
- 2008-02-28 EP EP11192158.1A patent/EP2545921A3/en not_active Withdrawn
- 2008-02-28 AT AT08717228T patent/ATE552836T1/de active
- 2008-02-28 KR KR1020097018126A patent/KR20090122218A/ko not_active Ceased
- 2008-02-28 UY UY30943A patent/UY30943A1/es not_active Application Discontinuation
- 2008-02-28 JP JP2009551218A patent/JP2010520176A/ja active Pending
- 2008-02-28 PL PL08717228T patent/PL2131845T3/pl unknown
- 2008-02-28 GE GEAP200811444A patent/GEP20115309B/en unknown
- 2008-02-28 RS RS20120263A patent/RS52351B/sr unknown
- 2008-02-28 CN CN200880005490.7A patent/CN101636162A/zh active Pending
- 2008-02-28 UA UAA200908592A patent/UA101950C2/ru unknown
- 2008-02-28 AU AU2008220800A patent/AU2008220800B2/en not_active Ceased
- 2008-02-28 DK DK08717228.4T patent/DK2131845T3/da active
- 2008-02-28 NZ NZ578854A patent/NZ578854A/en not_active IP Right Cessation
- 2008-02-28 AR ARP080100831A patent/AR065519A1/es not_active Application Discontinuation
- 2008-02-28 CA CA002678043A patent/CA2678043A1/en not_active Abandoned
- 2008-02-28 WO PCT/EP2008/052443 patent/WO2008104595A1/en not_active Ceased
- 2008-02-28 EA EA200901141A patent/EA017075B1/ru not_active IP Right Cessation
- 2008-02-28 MX MX2009009233A patent/MX2009009233A/es active IP Right Grant
- 2008-02-29 TW TW097107239A patent/TW200844102A/zh unknown
- 2008-02-29 PE PE2008000418A patent/PE20090166A1/es not_active Application Discontinuation
- 2008-02-29 PA PA20088771101A patent/PA8771101A1/es unknown
- 2008-02-29 CL CL200800618A patent/CL2008000618A1/es unknown
-
2009
- 2009-08-03 ZA ZA200905417A patent/ZA200905417B/xx unknown
- 2009-08-13 IL IL200401A patent/IL200401A0/en unknown
- 2009-08-21 CR CR10989A patent/CR10989A/es not_active Application Discontinuation
- 2009-08-28 NI NI200900161A patent/NI200900161A/es unknown
- 2009-08-28 EC EC2009009602A patent/ECSP099602A/es unknown
- 2009-08-28 TN TNP2009000357A patent/TN2009000357A1/fr unknown
- 2009-08-31 GT GT200900236A patent/GT200900236A/es unknown
- 2009-08-31 DO DO2009000209A patent/DOP2009000209A/es unknown
- 2009-08-31 MA MA32191A patent/MA31204B1/fr unknown
- 2009-09-01 CO CO09092694A patent/CO6210828A2/es not_active Application Discontinuation
- 2009-09-30 SM SM200900080T patent/SMAP200900080A/it unknown
-
2012
- 2012-03-08 US US13/415,268 patent/US8487095B2/en not_active Expired - Fee Related
- 2012-07-09 CY CY20121100610T patent/CY1113805T1/el unknown
-
2013
- 2013-07-10 US US13/938,659 patent/US20130296556A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8563842B2 (en) | 2010-09-27 | 2013-10-22 | Electronics And Telecommunications Research Institute | Method and apparatus for separating musical sound source using time and frequency characteristics |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8487095B2 (en) | Acid addition salts, hydrates and polymorphs of 5-(2,4-dihydroxy-5-iso-propyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide and formulations comprising these forms | |
| JP6946194B2 (ja) | キナーゼを調節する化合物の固体形態 | |
| ES2618891T3 (es) | N,N'-diariltioureas y N,N¿-diarilureas cíclicas como antagonistas del receptor de andrógenos, agente anticanceroso, método para producirlo y usarlo | |
| JP2021517902A (ja) | 置換ピロロトリアジン系化合物およびその医薬組成物並びにそれらの使用 | |
| JPWO2004037812A1 (ja) | 複素環式化合物及びそれを有効成分とする抗腫瘍剤 | |
| ES2548881T3 (es) | Dihidroetorfinas y su preparación | |
| TW201831191A (zh) | 一種新的硼酸衍生物及其藥物組合物 | |
| KR20240099193A (ko) | Erbb 억제제로서의 다형체 | |
| DK2151439T3 (en) | Nitrogenated AROMATIC 6-membered RINGDERIVAT, AND THIS pharmaceutical composition comprising | |
| RU2709810C2 (ru) | ПРОИЗВОДНЫЕ ПИРАЗОЛО[3,4-с]ПИРИДИНА | |
| CN102807575B (zh) | 3-芳基-5-噻吩基-5H-噻唑并[3,2-a]嘧啶类衍生物及其应用 | |
| ES2285474T3 (es) | Dicetopiperazinas sustituidas y su uso como antagonistas de oxitocina. | |
| TWI338687B (enExample) | ||
| WO2021037198A1 (zh) | 氘代化合物及其在治疗癌症方面的应用 | |
| WO2021037183A1 (zh) | 一类前药化合物及其在治疗癌症方面的应用 | |
| SK152095A3 (en) | Crystalline (+) l-hydrogentartrate, preparation method thereof, pharmaceutical composition containing its and its use | |
| JP5959617B2 (ja) | オタミキサバンの安息香酸塩 | |
| CA3067271A1 (en) | Crystalline forms of ponatinib hydrochloride | |
| HK1139073B (en) | 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide mesylate, hydrates and polymorphs thereof, and formulations comprising these forms | |
| US6071968A (en) | Phenylenediamine derivative radical scavenger, brain-infarction depressant, and brain-edema depressant | |
| EP2048138A1 (en) | Salt or solvate of 5-methyl-2-(piperazin-1-yl)benzenesulfonic acid | |
| BRPI0611096A2 (pt) | (5z)-5-(6-quinoxalinilmetilideno)-2-[(2,6-diclorofenil)a mino]-1,3-tiazol-4(5h)-ona | |
| HK1162358A (en) | Acid addition salts, hydrates and polymorphs of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide and formulations comprising these forms |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PA0105 | International application |
Patent event date: 20090831 Patent event code: PA01051R01D Comment text: International Patent Application |
|
| PG1501 | Laying open of application | ||
| A201 | Request for examination | ||
| PA0201 | Request for examination |
Patent event code: PA02012R01D Patent event date: 20130222 Comment text: Request for Examination of Application |
|
| E902 | Notification of reason for refusal | ||
| PE0902 | Notice of grounds for rejection |
Comment text: Notification of reason for refusal Patent event date: 20140227 Patent event code: PE09021S01D |
|
| E601 | Decision to refuse application | ||
| PE0601 | Decision on rejection of patent |
Patent event date: 20140602 Comment text: Decision to Refuse Application Patent event code: PE06012S01D Patent event date: 20140227 Comment text: Notification of reason for refusal Patent event code: PE06011S01I |