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
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 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
- 230000001413 cellular effect Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 208000029028 brain injury Diseases 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 239000004568 cement Substances 0.000 description 4
- 206010008118 cerebral infarction Diseases 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000004064 dysfunction Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000002102 hyperpolarization Effects 0.000 description 4
- 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
- 108010068927 iberiotoxin Proteins 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000008733 trauma Effects 0.000 description 4
- 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
- 230000037005 anaesthesia Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000007428 craniotomy Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000005342 ion exchange Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 230000010291 membrane polarization Effects 0.000 description 3
- 210000003657 middle cerebral artery Anatomy 0.000 description 3
- 210000000287 oocyte Anatomy 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- ZIRHWDZZCPGYMG-INIZCTEOSA-N (3s)-3-(5-chloro-2-methoxyphenyl)-1-(chloromethyl)-3-fluoro-6-(trifluoromethyl)indol-2-one Chemical compound COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2N(CCl)C1=O ZIRHWDZZCPGYMG-INIZCTEOSA-N 0.000 description 2
- OFKCSEIZYJOIQG-INIZCTEOSA-N (3s)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-1-(hydroxymethyl)-6-(trifluoromethyl)indol-2-one Chemical compound COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2N(CO)C1=O OFKCSEIZYJOIQG-INIZCTEOSA-N 0.000 description 2
- ULYONBAOIMCNEH-HNNXBMFYSA-N (3s)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-1h-indol-2-one Chemical compound COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2NC1=O ULYONBAOIMCNEH-HNNXBMFYSA-N 0.000 description 2
- SCRXASNUPJPFGP-UHFFFAOYSA-N 1-fluoro-3h-indol-2-one Chemical class C1=CC=C2N(F)C(=O)CC2=C1 SCRXASNUPJPFGP-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- ZIRHWDZZCPGYMG-UHFFFAOYSA-N 3-(5-chloro-2-methoxyphenyl)-1-(chloromethyl)-3-fluoro-6-(trifluoromethyl)indol-2-one Chemical compound COC1=CC=C(Cl)C=C1C1(F)C2=CC=C(C(F)(F)F)C=C2N(CCl)C1=O ZIRHWDZZCPGYMG-UHFFFAOYSA-N 0.000 description 2
- NNOCVDAKOTUHKZ-UHFFFAOYSA-N 3-(5-chloro-2-methoxyphenyl)-3-fluoro-1-(methylsulfanylmethyl)-6-(trifluoromethyl)indol-2-one Chemical compound COC1=CC=C(Cl)C=C1C1(F)C2=CC=C(C(F)(F)F)C=C2N(CSC)C1=O NNOCVDAKOTUHKZ-UHFFFAOYSA-N 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 235000005781 Avena Nutrition 0.000 description 2
- 102000034573 Channels Human genes 0.000 description 2
- 208000012184 Diffuse Brain injury Diseases 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical class CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 206010061216 Infarction Diseases 0.000 description 2
- 206010022773 Intracranial pressure increased Diseases 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- 235000014443 Pyrus communis Nutrition 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- IMGDSFKRBWXNRP-SFHVURJKSA-N [(3s)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indol-1-yl]methyl 2-hydroxyacetate Chemical compound COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2N(COC(=O)CO)C1=O IMGDSFKRBWXNRP-SFHVURJKSA-N 0.000 description 2
- ZNZSSUYAXDBLHX-UHFFFAOYSA-N [2,2,3,5,5-pentamethylhexan-3-yl(propan-2-yl)amino]phosphonous acid Chemical compound CC(C)N(C(C)(CC(C)(C)C)C(C)(C)C)P(O)O ZNZSSUYAXDBLHX-UHFFFAOYSA-N 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 230000006931 brain damage Effects 0.000 description 2
- 231100000874 brain damage Toxicity 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 238000005251 capillar electrophoresis Methods 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 238000004130 chiral capillary electrophoresis Methods 0.000 description 2
- JYWJULGYGOLCGW-UHFFFAOYSA-N chloromethyl chloroformate Chemical compound ClCOC(Cl)=O JYWJULGYGOLCGW-UHFFFAOYSA-N 0.000 description 2
- 239000010779 crude oil Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 2
- 235000011180 diphosphates Nutrition 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- YEWZQCDRZRYAEB-UHFFFAOYSA-N ditert-butyl hydrogen phosphate Chemical compound CC(C)(C)OP(O)(=O)OC(C)(C)C YEWZQCDRZRYAEB-UHFFFAOYSA-N 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 150000002333 glycines Chemical class 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 230000007574 infarction Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000028161 membrane depolarization Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000003961 neuronal insult Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 150000005623 oxindoles Chemical class 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000008024 pharmaceutical diluent Substances 0.000 description 2
- VGEREEWJJVICBM-UHFFFAOYSA-N phloretin Chemical compound C1=CC(O)=CC=C1CCC(=O)C1=C(O)C=C(O)C=C1O VGEREEWJJVICBM-UHFFFAOYSA-N 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 150000003148 prolines Chemical class 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000011369 resultant mixture Substances 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- VKFFEYLSKIYTSJ-UHFFFAOYSA-N tetraazanium;phosphonato phosphate Chemical compound [NH4+].[NH4+].[NH4+].[NH4+].[O-]P([O-])(=O)OP([O-])([O-])=O VKFFEYLSKIYTSJ-UHFFFAOYSA-N 0.000 description 2
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- LOXDAHJPYOUDMW-INIZCTEOSA-N (3s)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indole-1-carboxylic acid Chemical compound COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2N(C(O)=O)C1=O LOXDAHJPYOUDMW-INIZCTEOSA-N 0.000 description 1
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- ZWTDXYUDJYDHJR-UHFFFAOYSA-N (E)-1-(2,4-dihydroxyphenyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one Natural products OC1=CC(O)=CC=C1C=CC(=O)C1=CC=C(O)C=C1O ZWTDXYUDJYDHJR-UHFFFAOYSA-N 0.000 description 1
- UUDAMDVQRQNNHZ-UHFFFAOYSA-N (S)-AMPA Chemical compound CC=1ONC(=O)C=1CC(N)C(O)=O UUDAMDVQRQNNHZ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- LNDRIXJOWGDIQL-GPZGZDFJSA-N 2-[bis[(2-methylpropan-2-yl)oxy]phosphoryloxy]propyl (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)(OC(C)(C)C)OC(C)(C)C)C1=O LNDRIXJOWGDIQL-GPZGZDFJSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical compound OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 1
- ACQYZSFXPXXIHL-UHFFFAOYSA-N 2-phenylmethoxycarbonyl-3,4-dihydro-1h-isoquinoline-1-carboxylic acid Chemical compound C1CC2=CC=CC=C2C(C(=O)O)N1C(=O)OCC1=CC=CC=C1 ACQYZSFXPXXIHL-UHFFFAOYSA-N 0.000 description 1
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- YYNOKZZRWQDXLF-UHFFFAOYSA-N 3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indole-1-carbonyl chloride Chemical compound COC1=CC=C(Cl)C=C1C1(F)C2=CC=C(C(F)(F)F)C=C2N(C(Cl)=O)C1=O YYNOKZZRWQDXLF-UHFFFAOYSA-N 0.000 description 1
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 description 1
- WHNNUZIGIVYACR-UHFFFAOYSA-N 3-fluoro-6-(trifluoromethyl)-1,3-dihydroindol-2-one Chemical compound FC(F)(F)C1=CC=C2C(F)C(=O)NC2=C1 WHNNUZIGIVYACR-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- LZPKWQOLOCLSBO-UHFFFAOYSA-N 6-(trifluoromethyl)-1,3-dihydroindol-2-one Chemical compound FC(F)(F)C1=CC=C2CC(=O)NC2=C1 LZPKWQOLOCLSBO-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 235000007319 Avena orientalis Nutrition 0.000 description 1
- ULYONBAOIMCNEH-OAHLLOKOSA-N BMS 204352 Chemical compound COC1=CC=C(Cl)C=C1[C@]1(F)C2=CC=C(C(F)(F)F)C=C2NC1=O ULYONBAOIMCNEH-OAHLLOKOSA-N 0.000 description 1
- 238000006418 Brown reaction Methods 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 206010057671 Female sexual dysfunction Diseases 0.000 description 1
- 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 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- VLSMHEGGTFMBBZ-OOZYFLPDSA-M Kainate Chemical compound CC(=C)[C@H]1C[NH2+][C@H](C([O-])=O)[C@H]1CC([O-])=O VLSMHEGGTFMBBZ-OOZYFLPDSA-M 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010057672 Male sexual dysfunction Diseases 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910017974 NH40H Inorganic materials 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- YQHMWTPYORBCMF-UHFFFAOYSA-N Naringenin chalcone Natural products C1=CC(O)=CC=C1C=CC(=O)C1=C(O)C=C(O)C=C1O YQHMWTPYORBCMF-UHFFFAOYSA-N 0.000 description 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 229920005372 Plexiglas® Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 229910020169 SiOa Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 241000269370 Xenopus <genus> Species 0.000 description 1
- 241000269368 Xenopus laevis Species 0.000 description 1
- CWIOUIVULUFRSB-MRXNPFEDSA-N [(3r)-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-MRXNPFEDSA-N 0.000 description 1
- FIHWWVIYVVVLKI-IBGZPJMESA-N [(3s)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indol-1-yl]methyl 3-hydroxypropanoate Chemical compound COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2N(COC(=O)CCO)C1=O FIHWWVIYVVVLKI-IBGZPJMESA-N 0.000 description 1
- BMTUFQKYWWLCLC-UHFFFAOYSA-K [hydroxy(oxido)phosphoryl] phosphate;tetrabutylazanium Chemical compound OP([O-])(=O)OP([O-])([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC BMTUFQKYWWLCLC-UHFFFAOYSA-K 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- ZRIUUUJAJJNDSS-UHFFFAOYSA-N ammonium phosphates Chemical class [NH4+].[NH4+].[NH4+].[O-]P([O-])([O-])=O ZRIUUUJAJJNDSS-UHFFFAOYSA-N 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003918 blood extract Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 1
- XQPRBTXUXXVTKB-UHFFFAOYSA-M caesium iodide Chemical compound [I-].[Cs+] XQPRBTXUXXVTKB-UHFFFAOYSA-M 0.000 description 1
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Inorganic materials [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 description 1
- 230000003185 calcium uptake Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000006727 cell loss Effects 0.000 description 1
- 230000009134 cell regulation Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- YBZSHUAKOJGWRT-UHFFFAOYSA-M cesium;propanoate Chemical compound [Cs+].CCC([O-])=O YBZSHUAKOJGWRT-UHFFFAOYSA-M 0.000 description 1
- JWMLCCRPDOIBAV-UHFFFAOYSA-N chloro(methylsulfanyl)methane Chemical compound CSCCl JWMLCCRPDOIBAV-UHFFFAOYSA-N 0.000 description 1
- JIKSKOXEWAHMRJ-UHFFFAOYSA-N chloromethyl dihydrogen phosphate Chemical compound OP(O)(=O)OCCl JIKSKOXEWAHMRJ-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000009519 contusion Effects 0.000 description 1
- 210000005226 corpus cavernosum Anatomy 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012045 crude solution Substances 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical class NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000002999 depolarising effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- VRQDXVDLJIBJPV-UHFFFAOYSA-N ditert-butyl [3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indol-1-yl]methyl phosphate Chemical compound COC1=CC=C(Cl)C=C1C1(F)C2=CC=C(C(F)(F)F)C=C2N(COP(=O)(OC(C)(C)C)OC(C)(C)C)C1=O VRQDXVDLJIBJPV-UHFFFAOYSA-N 0.000 description 1
- ZMBZPMVMLZIOPS-UHFFFAOYSA-M ditert-butyl phosphate;tetrabutylazanium Chemical compound CC(C)(C)OP([O-])(=O)OC(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC ZMBZPMVMLZIOPS-UHFFFAOYSA-M 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000004387 flavanoid group Chemical group 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 210000002064 heart cell Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- HXJZHJLLMIGFCM-UHFFFAOYSA-N hydroxy-imino-di(propan-2-yloxy)-$l^{5}-phosphane Chemical compound CC(C)OP(N)(=O)OC(C)C HXJZHJLLMIGFCM-UHFFFAOYSA-N 0.000 description 1
- 230000003116 impacting effect Effects 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- QTJQYZNOEKJHSL-UHFFFAOYSA-N iodomethyl 3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indole-1-carboxylate Chemical compound COC1=CC=C(Cl)C=C1C1(F)C2=CC=C(C(F)(F)F)C=C2N(C(=O)OCI)C1=O QTJQYZNOEKJHSL-UHFFFAOYSA-N 0.000 description 1
- XLLBTSILSOJMTH-UHFFFAOYSA-N iodomethyl carbamate Chemical class NC(=O)OCI XLLBTSILSOJMTH-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000001457 metallic cations Chemical class 0.000 description 1
- 238000005649 metathesis reaction Methods 0.000 description 1
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 210000003666 myelinated nerve fiber Anatomy 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- CATWEXRJGNBIJD-UHFFFAOYSA-N n-tert-butyl-2-methylpropan-2-amine Chemical class CC(C)(C)NC(C)(C)C CATWEXRJGNBIJD-UHFFFAOYSA-N 0.000 description 1
- 230000001423 neocortical effect Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007248 oxidative elimination reaction Methods 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 230000001936 parietal effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000008375 physiological alteration Effects 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 150000003109 potassium Chemical class 0.000 description 1
- 108010083133 potassium channel protein I(sk) Proteins 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000011472 radical prostatectomy Methods 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000003134 recirculating effect Effects 0.000 description 1
- 230000002336 repolarization Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 230000005477 standard model Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical class [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
Classifications
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
-
- 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
-
- 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
- A61K31/40—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
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Psychiatry (AREA)
- Gynecology & Obstetrics (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
ID=28454740
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 (https=) |
| EP (1) | EP1485085A4 (https=) |
| JP (1) | JP4359150B2 (https=) |
| KR (1) | KR100951499B1 (https=) |
| CN (1) | CN100384820C (https=) |
| BR (1) | BR0308737A (https=) |
| CA (1) | CA2479256A1 (https=) |
| CO (1) | CO5611143A2 (https=) |
| GE (1) | GEP20074230B (https=) |
| HR (1) | HRP20040853A2 (https=) |
| IL (2) | IL164022A0 (https=) |
| IS (1) | IS7456A (https=) |
| MX (1) | MXPA04008999A (https=) |
| NO (1) | NO20044442L (https=) |
| NZ (1) | NZ535365A (https=) |
| PL (1) | PL372413A1 (https=) |
| RS (1) | RS81904A (https=) |
| RU (1) | RU2312857C2 (https=) |
| UA (1) | UA77296C2 (https=) |
| WO (1) | WO2003080047A1 (https=) |
| ZA (1) | ZA200407337B (https=) |
Families Citing this family (28)
| 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 |
| ES2445208T3 (es) | 2002-07-29 | 2014-02-28 | Rigel Pharmaceuticals, Inc. | Compuestos de 2,4-pirimidindiamina para uso en métodos para tratar o prevenir enfermedades autoinmunitarias |
| US6916937B2 (en) * | 2003-02-03 | 2005-07-12 | Bristol-Myers Squibb Company | Carbohydrate prodrugs of fluorooxindoles |
| BRPI0413018B8 (pt) | 2003-07-30 | 2021-05-25 | Rigel Pharmaceuticals Inc | composto, e, uso de um composto |
| 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 |
| DE602006010979D1 (de) | 2005-01-19 | 2010-01-21 | Rigel Pharmaceuticals Inc | Prodrugs aus 2,4-pyrimidindiamin-verbindungen und ihre verwendungen |
| US8227455B2 (en) | 2005-04-18 | 2012-07-24 | Rigel Pharmaceuticals, Inc. | Methods of treating cell proliferative disorders |
| JP4981673B2 (ja) * | 2005-09-13 | 2012-07-25 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 安定性が改善されたクロロメチルフォスフェイト誘導体を含む組成物およびその製造方法 |
| 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 |
| AU2009212514A1 (en) * | 2008-02-05 | 2009-08-13 | 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 |
| CA2937222C (en) * | 2009-06-25 | 2019-06-04 | Alkermes Pharma Ireland Limited | Prodrugs of nh-acidic compounds |
| LT2445502T (lt) | 2009-06-25 | 2017-09-25 | Alkermes Pharma Ireland Limited | Heterocikliniai junginiai, skirti neurologinių ir fiziologinių susirgimų gydymui |
| AU2011270701B2 (en) | 2010-06-24 | 2015-05-14 | Alkermes Pharma Ireland Limited | Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives |
| KR101974793B1 (ko) | 2015-07-06 | 2019-05-02 | 길리애드 사이언시즈, 인코포레이티드 | Cot 조정제 및 그의 사용 방법 |
| 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 |
| EP3761983A1 (en) | 2018-03-05 | 2021-01-13 | Alkermes Pharma Ireland Limited | Aripiprazole dosing strategy |
| ES2975753T3 (es) * | 2018-03-05 | 2024-07-12 | Teon Therapeutics Inc | Antagonistas del receptor de adenosina y usos de los mismos |
| 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 |
| TW202116356A (zh) | 2019-07-10 | 2021-05-01 | 美商斯布雷克薩三號公司 | 作為治療劑之微管靶向藥劑之肽結合物 |
| 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 |
| AU2021249010B2 (en) | 2020-03-30 | 2024-09-26 | Gilead Sciences, Inc. | Solid forms of (S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)2-methyl-1-oxo-1,2- dihydroisoquinolin-5-yl)methyl)))amino)8-chloro-(neopentylamino)quinoline-3-carb onitrile a cot inhibitor compound |
| JP7446475B2 (ja) | 2020-04-02 | 2024-03-08 | ギリアード サイエンシーズ， インコーポレイテッド | Ｃｏｔ阻害剤化合物を調製するためのプロセス |
| 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 |
| KR20010033811A (ko) | 1997-12-31 | 2001-04-25 | 토마스 안 빅토리아 | 2차 및 3차 아민을 함유하는 약제의 물에 용해가능한프로드럭 및 그것의 제조방법 |
| PT1056754E (pt) * | 1998-01-29 | 2004-03-31 | Bristol Myers Squibb Co | Derivados fosfatados de 1,3,4-oxadiazolona de diarilo |
-
2003
- 2003-03-20 HR HRP20040853 patent/HRP20040853A2/xx not_active Application Discontinuation
- 2003-03-20 NZ NZ535365A patent/NZ535365A/en not_active IP Right Cessation
- 2003-03-20 UA UA20041109513A patent/UA77296C2/uk unknown
- 2003-03-20 CA CA002479256A patent/CA2479256A1/en not_active Abandoned
- 2003-03-20 BR BR0308737-9A patent/BR0308737A/pt not_active IP Right Cessation
- 2003-03-20 IL IL16402203A patent/IL164022A0/xx active IP Right Grant
- 2003-03-20 RU RU2004131201/04A patent/RU2312857C2/ru not_active IP Right Cessation
- 2003-03-20 GE GEAP8458A patent/GEP20074230B/en unknown
- 2003-03-20 RS YUP-819/04A patent/RS81904A/sr unknown
- 2003-03-20 MX MXPA04008999A patent/MXPA04008999A/es active IP Right Grant
- 2003-03-20 JP JP2003577875A patent/JP4359150B2/ja not_active Expired - Fee Related
- 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 KR KR1020047014626A patent/KR100951499B1/ko not_active Expired - Fee Related
- 2003-03-20 PL PL03372413A patent/PL372413A1/xx not_active Application Discontinuation
- 2003-03-20 WO PCT/US2003/008613 patent/WO2003080047A1/en not_active Ceased
- 2003-03-20 CN CNB038109778A patent/CN100384820C/zh not_active Expired - Fee Related
-
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 |
|---|---|
| EP1485085A4 (en) | 2007-03-14 |
| PL372413A1 (en) | 2005-07-25 |
| RU2004131201A (ru) | 2005-05-10 |
| BR0308737A (pt) | 2005-01-11 |
| NO20044442L (no) | 2004-10-19 |
| US6930100B2 (en) | 2005-08-16 |
| IL164022A (en) | 2008-04-13 |
| HRP20040853A2 (en) | 2004-12-31 |
| CO5611143A2 (es) | 2006-02-28 |
| IS7456A (is) | 2004-09-17 |
| UA77296C2 (en) | 2006-11-15 |
| CN1652769A (zh) | 2005-08-10 |
| AU2003215017A1 (en) | 2003-10-08 |
| JP2005526097A (ja) | 2005-09-02 |
| JP4359150B2 (ja) | 2009-11-04 |
| GEP20074230B (en) | 2007-11-12 |
| CA2479256A1 (en) | 2003-10-02 |
| KR100951499B1 (ko) | 2010-04-07 |
| RS81904A (sr) | 2007-02-05 |
| MXPA04008999A (es) | 2004-12-07 |
| CN100384820C (zh) | 2008-04-30 |
| EP1485085A1 (en) | 2004-12-15 |
| US20030195169A1 (en) | 2003-10-16 |
| RU2312857C2 (ru) | 2007-12-20 |
| KR20040106293A (ko) | 2004-12-17 |
| IL164022A0 (en) | 2005-12-18 |
| ZA200407337B (en) | 2006-02-22 |
| WO2003080047A1 (en) | 2003-10-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6930100B2 (en) | Phosphate prodrugs of fluoroxindoles | |
| KR0171570B1 (ko) | N-헤테로사이클릭프로필리덴-1,1-비스포스폰산,이의제조방법및약제학적조성물 | |
| WO1987003598A1 (en) | Novel bisphosphonic derivatives, a method for their production and a pharmaceutical composition | |
| US7169803B2 (en) | N-substituted prodrugs of fluorooxindoles | |
| EP1056754B1 (en) | Phosphate derivatives of diaryl 1,3,4-oxadiazolone | |
| EP1303527B1 (en) | Matrix metalloproteinase inhibitors | |
| AU2003215017B2 (en) | Phosphate prodrugs of fluorooxindoles | |
| US6916937B2 (en) | Carbohydrate prodrugs of fluorooxindoles | |
| US5977150A (en) | Amino acid derivatives of diaryl 1,3,4-oxadiazolone | |
| EP0328834A1 (en) | Novel aspartate transcarbamylase inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PSEA | Patent sealed | ||
| RENW | Renewal (renewal fees accepted) | ||
| RENW | Renewal (renewal fees accepted) | ||
| LAPS | Patent lapsed |