NZ535365A - Phosphate prodrugs of fluorooxindoles - Google Patents
Phosphate prodrugs of fluorooxindolesInfo
- Publication number
- NZ535365A NZ535365A NZ535365A NZ53536503A NZ535365A NZ 535365 A NZ535365 A NZ 535365A NZ 535365 A NZ535365 A NZ 535365A NZ 53536503 A NZ53536503 A NZ 53536503A NZ 535365 A NZ535365 A NZ 535365A
- Authority
- NZ
- New Zealand
- Prior art keywords
- chloro
- fluoro
- ester
- oxo
- indol
- Prior art date
Links
- 229910019142 PO4 Inorganic materials 0.000 title description 18
- 239000000651 prodrug Substances 0.000 title description 14
- 229940002612 prodrug Drugs 0.000 title description 14
- 239000010452 phosphate Substances 0.000 title description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 115
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
- 208000035475 disorder Diseases 0.000 claims abstract description 22
- 239000001257 hydrogen Substances 0.000 claims abstract description 21
- 102000016469 Large-Conductance Calcium-Activated Potassium Channels Human genes 0.000 claims abstract description 20
- 108010092555 Large-Conductance Calcium-Activated Potassium Channels Proteins 0.000 claims abstract description 20
- 239000012453 solvate Substances 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 15
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 15
- 125000004185 ester group Chemical group 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 208000028867 ischemia Diseases 0.000 claims abstract description 10
- 208000006673 asthma Diseases 0.000 claims abstract description 8
- 206010015037 epilepsy Diseases 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 69
- 150000002148 esters Chemical class 0.000 claims description 64
- 238000006243 chemical reaction Methods 0.000 claims description 56
- -1 methyl- 2,3-dihydro-indol-1-yl methyl Chemical group 0.000 claims description 51
- 229910001868 water Inorganic materials 0.000 claims description 45
- 238000005160 1H NMR spectroscopy Methods 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 39
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 18
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 17
- 230000009529 traumatic brain injury Effects 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- 238000004679 31P NMR spectroscopy Methods 0.000 claims description 13
- 238000004293 19F NMR spectroscopy Methods 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 10
- CWIOUIVULUFRSB-INIZCTEOSA-N [(3s)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indol-1-yl]methyl dihydrogen phosphate Chemical compound COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2N(COP(O)(O)=O)C1=O CWIOUIVULUFRSB-INIZCTEOSA-N 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 201000009941 intracranial hypertension Diseases 0.000 claims description 9
- 150000004702 methyl esters Chemical class 0.000 claims description 8
- 208000020431 spinal cord injury Diseases 0.000 claims description 8
- 208000001408 Carbon monoxide poisoning Diseases 0.000 claims description 7
- 206010010904 Convulsion Diseases 0.000 claims description 7
- 208000019695 Migraine disease Diseases 0.000 claims description 7
- 206010046543 Urinary incontinence Diseases 0.000 claims description 7
- 230000036461 convulsion Effects 0.000 claims description 7
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 7
- 206010027599 migraine Diseases 0.000 claims description 7
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 5
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 5
- 239000007983 Tris buffer Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 229940005657 pyrophosphoric acid Drugs 0.000 claims description 3
- HNLLHFDPAMMLNM-SFHVURJKSA-N 2-phosphonooxyethyl (3s)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indole-1-carboxylate Chemical compound COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2N(C(=O)OCCOP(O)(O)=O)C1=O HNLLHFDPAMMLNM-SFHVURJKSA-N 0.000 claims description 2
- VOWFZWMTQQCJHH-SFHVURJKSA-N [(3s)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indol-1-yl]methyl 2-phosphonooxyacetate Chemical compound COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2N(COC(=O)COP(O)(O)=O)C1=O VOWFZWMTQQCJHH-SFHVURJKSA-N 0.000 claims description 2
- RWCHRIFSGHWHPF-IBGZPJMESA-N [(3s)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indol-1-yl]methyl n-(2-phosphonooxyethyl)carbamate Chemical compound COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2N(COC(=O)NCCOP(O)(O)=O)C1=O RWCHRIFSGHWHPF-IBGZPJMESA-N 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 3
- 238000004821 distillation Methods 0.000 claims 2
- FBOONKKJAFGFGT-JLNKLDRZSA-N 2-phosphonooxypropyl (3s)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indole-1-carboxylate Chemical compound COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2N(C(=O)OCC(C)OP(O)(O)=O)C1=O FBOONKKJAFGFGT-JLNKLDRZSA-N 0.000 claims 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims 1
- UTIHTXLQUMTDIC-IBGZPJMESA-N [(3s)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indol-1-yl]methyl 3-phosphonooxypropanoate Chemical compound COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2N(COC(=O)CCOP(O)(O)=O)C1=O UTIHTXLQUMTDIC-IBGZPJMESA-N 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- HGJMXJABQKRULV-UHFFFAOYSA-K tetrabutylazanium;phosphate Chemical compound [O-]P([O-])([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC HGJMXJABQKRULV-UHFFFAOYSA-K 0.000 claims 1
- 208000006011 Stroke Diseases 0.000 abstract description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
- 239000002253 acid Substances 0.000 description 32
- 238000000034 method Methods 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
- 239000002904 solvent Substances 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
- 239000000843 powder Substances 0.000 description 25
- 239000011347 resin Substances 0.000 description 22
- 229920005989 resin Polymers 0.000 description 22
- 208000014674 injury Diseases 0.000 description 20
- 108091006146 Channels Proteins 0.000 description 19
- 208000027418 Wounds and injury Diseases 0.000 description 17
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 17
- 238000001819 mass spectrum Methods 0.000 description 17
- 235000021317 phosphate Nutrition 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 230000006378 damage Effects 0.000 description 15
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 229940079593 drug Drugs 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 12
- 239000006260 foam Substances 0.000 description 12
- 238000006073 displacement reaction Methods 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- 102000004257 Potassium Channel Human genes 0.000 description 10
- 238000009527 percussion Methods 0.000 description 10
- 108020001213 potassium channel Proteins 0.000 description 10
- 229910001424 calcium ion Inorganic materials 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 9
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- 239000012530 fluid Substances 0.000 description 8
- 239000003456 ion exchange resin Substances 0.000 description 8
- 229920003303 ion-exchange polymer Polymers 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 7
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 7
- 239000011575 calcium Substances 0.000 description 7
- 229910052791 calcium Inorganic materials 0.000 description 7
- 230000003834 intracellular effect Effects 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
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- 230000001404 mediated effect Effects 0.000 description 6
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- 230000001105 regulatory effect Effects 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 102000005702 Calcium-Activated Potassium Channels Human genes 0.000 description 5
- 108010045489 Calcium-Activated Potassium Channels Proteins 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 150000003863 ammonium salts Chemical class 0.000 description 5
- 210000001168 carotid artery common Anatomy 0.000 description 5
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- 238000002347 injection Methods 0.000 description 5
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000011007 phosphoric acid Nutrition 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- 201000006474 Brain Ischemia Diseases 0.000 description 4
- UTIBPSUPFVPALO-UHFFFAOYSA-N C1C2=C(C=C(C=C2)C(F)(F)F)N(C1=O)F Chemical compound C1C2=C(C=C(C=C2)C(F)(F)F)N(C1=O)F UTIBPSUPFVPALO-UHFFFAOYSA-N 0.000 description 4
- 206010008120 Cerebral ischaemia Diseases 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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- VDNVVLOBNHIMQA-UHFFFAOYSA-N iberiotoxin Chemical compound C1SSCC(C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(O)=O)NC(=O)C(CCCNC(N)=N)NC(=O)C1NC(=O)C(CCCCN)NC(=O)C(CCCCN)NC(=O)CNC(=O)C(CCSC)NC(=O)C(NC(=O)C(CCCCN)NC(=O)CNC(=O)C(CCCNC(N)=N)NC(=O)C(CC(O)=O)NC(=O)C(C(C)C)NC(=O)CNC(=O)C(CC=1C=CC=CC=1)NC(=O)C(CC(C)C)NC(=O)C(CC(O)=O)NC(=O)C(CCCCN)NC1=O)CSSCC1NC(=O)C(C(C)C)NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(NC(=O)C(CCC(O)=O)NC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(C(C)C)NC(=O)C(CO)NC1=O)CSSCC1NC(=O)C(CC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(O)=O)NC(=O)C(C(C)O)NC(=O)C(NC(=O)C1NC(=O)CC1)CC1=CC=CC=C1 VDNVVLOBNHIMQA-UHFFFAOYSA-N 0.000 description 4
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- 229910052708 sodium Inorganic materials 0.000 description 4
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- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 3
- ULYONBAOIMCNEH-UHFFFAOYSA-N 3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-1h-indol-2-one Chemical compound COC1=CC=C(Cl)C=C1C1(F)C2=CC=C(C(F)(F)F)C=C2NC1=O ULYONBAOIMCNEH-UHFFFAOYSA-N 0.000 description 3
- MXIRBQGJHHAAIX-UHFFFAOYSA-N 3-fluoro-1,3-dihydroindol-2-one Chemical class C1=CC=C2C(F)C(=O)NC2=C1 MXIRBQGJHHAAIX-UHFFFAOYSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- 239000004254 Ammonium phosphate Substances 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 241000209761 Avena Species 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 206010030113 Oedema Diseases 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 235000019289 ammonium phosphates Nutrition 0.000 description 3
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Classifications
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- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
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- 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 Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Landscapes
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- Reproductive Health (AREA)
- Endocrinology (AREA)
- Gynecology & Obstetrics (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US36601002P | 2002-03-20 | 2002-03-20 | |
| PCT/US2003/008613 WO2003080047A1 (en) | 2002-03-20 | 2003-03-20 | Phosphate prodrugs of fluorooxindoles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ535365A true NZ535365A (en) | 2006-07-28 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ535365A NZ535365A (en) | 2002-03-20 | 2003-03-20 | Phosphate prodrugs of fluorooxindoles |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US6930100B2 (OSRAM) |
| EP (1) | EP1485085A4 (OSRAM) |
| JP (1) | JP4359150B2 (OSRAM) |
| KR (1) | KR100951499B1 (OSRAM) |
| CN (1) | CN100384820C (OSRAM) |
| BR (1) | BR0308737A (OSRAM) |
| CA (1) | CA2479256A1 (OSRAM) |
| CO (1) | CO5611143A2 (OSRAM) |
| GE (1) | GEP20074230B (OSRAM) |
| HR (1) | HRP20040853A2 (OSRAM) |
| IL (2) | IL164022A0 (OSRAM) |
| IS (1) | IS7456A (OSRAM) |
| MX (1) | MXPA04008999A (OSRAM) |
| NO (1) | NO20044442L (OSRAM) |
| NZ (1) | NZ535365A (OSRAM) |
| PL (1) | PL372413A1 (OSRAM) |
| RS (1) | RS81904A (OSRAM) |
| RU (1) | RU2312857C2 (OSRAM) |
| UA (1) | UA77296C2 (OSRAM) |
| WO (1) | WO2003080047A1 (OSRAM) |
| ZA (1) | ZA200407337B (OSRAM) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
| IL166241A0 (en) | 2002-07-29 | 2006-01-15 | Rigel Pharmaceuticals Inc | Method of treating or preventing autoimmune diseases with 2,4-pyrimidinedinediamine compounds |
| US6916937B2 (en) * | 2003-02-03 | 2005-07-12 | Bristol-Myers Squibb Company | Carbohydrate prodrugs of fluorooxindoles |
| RS53109B (sr) | 2003-07-30 | 2014-06-30 | Rigel Pharmaceuticals Inc. | Jedinjenja 2,4 pirimidindiamina za upotrebu u tretmanu ili prevenciji autoimunih bolesti |
| US7169803B2 (en) * | 2004-03-15 | 2007-01-30 | Bristol-Myers Squibb Company | N-substituted prodrugs of fluorooxindoles |
| US7253167B2 (en) | 2004-06-30 | 2007-08-07 | Bristol-Myers Squibb Company | Tricyclic-heteroaryl compounds useful as kinase inhibitors |
| NZ555947A (en) | 2005-01-19 | 2010-11-26 | Rigel Pharmaceuticals Inc | Prodrugs of 2,4-pyrimidinediamine compounds and their uses |
| US8227455B2 (en) * | 2005-04-18 | 2012-07-24 | Rigel Pharmaceuticals, Inc. | Methods of treating cell proliferative disorders |
| US20090114877A1 (en) * | 2005-09-13 | 2009-05-07 | Eisai R&D Management Co., Ltd. | Composition Containing Stability-Improved Chloromethyl Phosphate Derivatve and Process for Producing Same |
| TWI385169B (zh) | 2005-10-31 | 2013-02-11 | Eisai R&D Man Co Ltd | 經雜環取代之吡啶衍生物及含有彼之抗真菌劑 |
| TW200841879A (en) * | 2007-04-27 | 2008-11-01 | Eisai R&D Man Co Ltd | Pyridine derivatives substituted by heterocyclic ring and phosphonoamino group, and anti-fungal agent containing same |
| US8513287B2 (en) * | 2007-12-27 | 2013-08-20 | Eisai R&D Management Co., Ltd. | Heterocyclic ring and phosphonoxymethyl group substituted pyridine derivatives and antifungal agent containing same |
| EP2249833B1 (en) * | 2008-02-05 | 2012-10-17 | Merck Sharp & Dohme Corp. | Prodrugs of cgrp receptor antagonist |
| US8188119B2 (en) * | 2008-10-24 | 2012-05-29 | Eisai R&D Management Co., Ltd | Pyridine derivatives substituted with heterocyclic ring and γ-glutamylamino group, and antifungal agents containing same |
| HUE033442T2 (en) * | 2009-06-25 | 2017-11-28 | Alkermes Pharma Ireland Ltd | Heterocyclic compounds for the treatment of neurological and psychological disorders |
| EP2445343B1 (en) * | 2009-06-25 | 2021-08-04 | Alkermes Pharma Ireland Limited | Prodrugs of nh-acidic compounds |
| JP5848761B2 (ja) * | 2010-06-24 | 2016-01-27 | アルカーメス ファーマ アイルランド リミテッド | Ｎｈ酸性化合物のプロドラッグ：エステル、カルボネート、カルバメートおよびホスホネートの誘導体 |
| IL293770B2 (en) | 2015-07-06 | 2023-07-01 | Gilead Sciences Inc | Modulators of cot and methods of using them |
| KR20200121800A (ko) | 2018-01-05 | 2020-10-26 | 싸이브렉사 1, 인크. | 산성 또는 저산소성 질환에 걸린 조직에 관련된 질환의 치료를 위한 화합물, 조성물 및 방법 |
| CA3093234A1 (en) * | 2018-03-05 | 2019-09-12 | Teon Therapeutics, Inc. | Adenosine receptor antagonists and uses thereof |
| CA3092335A1 (en) | 2018-03-05 | 2019-09-12 | Alkermes Pharma Ireland Limited | Aripiprazole dosing strategy |
| TWI770527B (zh) | 2019-06-14 | 2022-07-11 | 美商基利科學股份有限公司 | Cot 調節劑及其使用方法 |
| US11555019B2 (en) | 2019-07-10 | 2023-01-17 | Cybrexa 3, Inc. | Peptide conjugates of microtubule-targeting agents as therapeutics |
| CN114341162B (zh) | 2019-07-10 | 2025-10-17 | 赛博克萨2公司 | 作为治疗剂的细胞毒素的肽缀合物 |
| JP2023520650A (ja) | 2020-03-30 | 2023-05-18 | ギリアード サイエンシーズ， インコーポレイテッド | （Ｓ）－６－（（（１－（ビシクロ［１．１．１］ペンタン－１－イル）－１Ｈ－１，２，３－トリアゾール－４－イル）２－メチル－１－オキソ－１，２－ジヒドロイソキノリン－５－イル）メチル）））アミノ）８－クロロ－（ネオペンチルアミノ）キノリン－３－カルボニトリルＣｏｔ阻害剤化合物の固体形態 |
| CN119390681A (zh) | 2020-04-02 | 2025-02-07 | 吉利德科学公司 | 用于制备cot抑制剂化合物的方法 |
| EP3912625A1 (en) | 2020-05-20 | 2021-11-24 | Kaerus Bioscience Limited | Novel maxi-k potassium channel openers for the treatment of fragile x associated disorders |
| WO2025233532A1 (en) | 2024-05-10 | 2025-11-13 | Les Laboratoires Servier | Maxi-k potassium channel openers and therapeutic applications thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU749063A1 (ru) * | 1979-01-29 | 1996-09-10 | Военно-медицинская академия им.С.М.Кирова | 3-(4-карбэтокси)-фенилимино-2-оксоиндолин, повышающий устойчивость организма к повторной черепно-мозговой травме |
| US5234947A (en) | 1991-11-07 | 1993-08-10 | New York University | Potassium channel activating compounds and methods of use thereof |
| US5187173A (en) | 1991-12-27 | 1993-02-16 | Sterling Winthrop Inc. | 2-saccharinylmethyl and 4,5,6,7-tetrahydro-2-saccharinylmethyl phosphates, phosphonates and phosphinates useful as proteolytic enzyme inhibitors and compositions and method of use thereof |
| US5565483A (en) * | 1995-06-07 | 1996-10-15 | Bristol-Myers Squibb Company | 3-substituted oxindole derivatives as potassium channel modulators |
| DE69822514T2 (de) | 1997-12-31 | 2005-03-24 | The University Of Kansas, Lawrence | Wasserlösliche pro-pharmaka von arzneistoffen, die ein tertiäres amin enthalten, und verfahren zu ihrer herstellung |
| CA2318817A1 (en) * | 1998-01-29 | 1999-08-05 | Bristol-Myers Squibb Company | Phosphate derivatives of diaryl 1,3,4-oxadiazolone |
-
2003
- 2003-03-20 NZ NZ535365A patent/NZ535365A/en not_active IP Right Cessation
- 2003-03-20 KR KR1020047014626A patent/KR100951499B1/ko not_active Expired - Fee Related
- 2003-03-20 UA UA20041109513A patent/UA77296C2/uk unknown
- 2003-03-20 IL IL16402203A patent/IL164022A0/xx active IP Right Grant
- 2003-03-20 EP EP03711659A patent/EP1485085A4/en not_active Withdrawn
- 2003-03-20 US US10/393,031 patent/US6930100B2/en not_active Expired - Lifetime
- 2003-03-20 GE GEAP8458A patent/GEP20074230B/en unknown
- 2003-03-20 HR HRP20040853 patent/HRP20040853A2/xx not_active Application Discontinuation
- 2003-03-20 BR BR0308737-9A patent/BR0308737A/pt not_active IP Right Cessation
- 2003-03-20 JP JP2003577875A patent/JP4359150B2/ja not_active Expired - Fee Related
- 2003-03-20 PL PL03372413A patent/PL372413A1/xx not_active Application Discontinuation
- 2003-03-20 CN CNB038109778A patent/CN100384820C/zh not_active Expired - Fee Related
- 2003-03-20 WO PCT/US2003/008613 patent/WO2003080047A1/en not_active Ceased
- 2003-03-20 RS YUP-819/04A patent/RS81904A/sr unknown
- 2003-03-20 RU RU2004131201/04A patent/RU2312857C2/ru not_active IP Right Cessation
- 2003-03-20 CA CA002479256A patent/CA2479256A1/en not_active Abandoned
- 2003-03-20 MX MXPA04008999A patent/MXPA04008999A/es active IP Right Grant
-
2004
- 2004-09-12 IL IL164022A patent/IL164022A/en not_active IP Right Cessation
- 2004-09-13 ZA ZA200407337A patent/ZA200407337B/en unknown
- 2004-09-17 IS IS7456A patent/IS7456A/is unknown
- 2004-09-20 CO CO04093294A patent/CO5611143A2/es not_active Application Discontinuation
- 2004-10-19 NO NO20044442A patent/NO20044442L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| RU2004131201A (ru) | 2005-05-10 |
| US6930100B2 (en) | 2005-08-16 |
| JP2005526097A (ja) | 2005-09-02 |
| US20030195169A1 (en) | 2003-10-16 |
| KR100951499B1 (ko) | 2010-04-07 |
| IL164022A (en) | 2008-04-13 |
| CA2479256A1 (en) | 2003-10-02 |
| UA77296C2 (en) | 2006-11-15 |
| IS7456A (is) | 2004-09-17 |
| ZA200407337B (en) | 2006-02-22 |
| EP1485085A1 (en) | 2004-12-15 |
| PL372413A1 (en) | 2005-07-25 |
| RU2312857C2 (ru) | 2007-12-20 |
| JP4359150B2 (ja) | 2009-11-04 |
| IL164022A0 (en) | 2005-12-18 |
| HRP20040853A2 (en) | 2004-12-31 |
| CN1652769A (zh) | 2005-08-10 |
| AU2003215017A1 (en) | 2003-10-08 |
| CN100384820C (zh) | 2008-04-30 |
| NO20044442L (no) | 2004-10-19 |
| RS81904A (sr) | 2007-02-05 |
| EP1485085A4 (en) | 2007-03-14 |
| KR20040106293A (ko) | 2004-12-17 |
| GEP20074230B (en) | 2007-11-12 |
| MXPA04008999A (es) | 2004-12-07 |
| BR0308737A (pt) | 2005-01-11 |
| WO2003080047A1 (en) | 2003-10-02 |
| CO5611143A2 (es) | 2006-02-28 |
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Legal Events
| Date | Code | Title | Description |
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| PSEA | Patent sealed | ||
| RENW | Renewal (renewal fees accepted) | ||
| RENW | Renewal (renewal fees accepted) | ||
| LAPS | Patent lapsed |