JP4369397B2 - プロテインキナーゼc阻害剤 - Google Patents
プロテインキナーゼc阻害剤 Download PDFInfo
- Publication number
- JP4369397B2 JP4369397B2 JP2005135900A JP2005135900A JP4369397B2 JP 4369397 B2 JP4369397 B2 JP 4369397B2 JP 2005135900 A JP2005135900 A JP 2005135900A JP 2005135900 A JP2005135900 A JP 2005135900A JP 4369397 B2 JP4369397 B2 JP 4369397B2
- Authority
- JP
- Japan
- Prior art keywords
- mmol
- added
- methyl
- protein kinase
- indol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 229940123924 Protein kinase C inhibitor Drugs 0.000 title description 12
- 239000003881 protein kinase C inhibitor Substances 0.000 title description 12
- 101710175516 14 kDa zinc-binding protein Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 117
- 108010044467 Isoenzymes Proteins 0.000 claims abstract description 73
- 108010024526 Protein Kinase C beta Proteins 0.000 claims abstract description 14
- 102000015766 Protein Kinase C beta Human genes 0.000 claims abstract description 14
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 10
- -1 monoalkylaminoalkyl Chemical group 0.000 claims description 71
- 239000001257 hydrogen Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000004480 active ingredient Substances 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 11
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 8
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 102000003923 Protein Kinase C Human genes 0.000 abstract description 59
- 108090000315 Protein Kinase C Proteins 0.000 abstract description 59
- 238000000034 method Methods 0.000 abstract description 18
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 16
- 239000003112 inhibitor Substances 0.000 abstract description 10
- 229940124639 Selective inhibitor Drugs 0.000 abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 171
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 78
- 239000000243 solution Substances 0.000 description 74
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 71
- 239000000203 mixture Substances 0.000 description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 238000006243 chemical reaction Methods 0.000 description 55
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 238000004519 manufacturing process Methods 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 28
- 238000003756 stirring Methods 0.000 description 28
- 238000002844 melting Methods 0.000 description 24
- 230000008018 melting Effects 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 22
- 239000013078 crystal Substances 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- 238000009472 formulation Methods 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 239000002585 base Substances 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 239000002244 precipitate Substances 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 230000001575 pathological effect Effects 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- RQEDXUKWSYJDPG-UHFFFAOYSA-N 1-piperidin-4-ylindole Chemical compound C1CNCCC1N1C2=CC=CC=C2C=C1 RQEDXUKWSYJDPG-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 description 9
- 239000012156 elution solvent Substances 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 9
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 9
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- 229920002472 Starch Polymers 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 239000008107 starch Substances 0.000 description 8
- 235000019698 starch Nutrition 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- 125000004442 acylamino group Chemical group 0.000 description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 description 7
- 244000309464 bull Species 0.000 description 7
- 239000002808 molecular sieve Substances 0.000 description 7
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 101710150593 Protein beta Proteins 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 235000001465 calcium Nutrition 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 229960005069 calcium Drugs 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 235000010980 cellulose Nutrition 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 125000001188 haloalkyl group Chemical group 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 150000001412 amines Chemical group 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 150000001982 diacylglycerols Chemical class 0.000 description 4
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 0 *[n]1c2ccccc2c(C(C(N2)=O)=C(c3c(C**4)[n]4c4c3cccc4)C2=O)c1 Chemical compound *[n]1c2ccccc2c(C(C(N2)=O)=C(c3c(C**4)[n]4c4c3cccc4)C2=O)c1 0.000 description 3
- LZZHKPRKLWCFSP-UHFFFAOYSA-N 1-(1-benzylpiperidin-4-yl)indole Chemical compound C1CC(N2C3=CC=CC=C3C=C2)CCN1CC1=CC=CC=C1 LZZHKPRKLWCFSP-UHFFFAOYSA-N 0.000 description 3
- HDBWSCPBUCTVMT-UHFFFAOYSA-N 1-(1-methylpiperidin-4-yl)indole Chemical compound C1CN(C)CCC1N1C2=CC=CC=C2C=C1 HDBWSCPBUCTVMT-UHFFFAOYSA-N 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000004945 acylaminoalkyl group Chemical group 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000003349 gelling agent Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 3
- 230000006303 immediate early viral mRNA transcription Effects 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 239000003039 volatile agent Substances 0.000 description 3
- MSVZMUILYMLJCF-UHFFFAOYSA-N (1-benzhydrylazetidin-3-yl) methanesulfonate Chemical compound C1C(OS(=O)(=O)C)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 MSVZMUILYMLJCF-UHFFFAOYSA-N 0.000 description 2
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 2
- PFDCSCAAZRVKEE-UHFFFAOYSA-N 1-(1-ethylpiperidin-4-yl)indole Chemical compound C1CN(CC)CCC1N1C2=CC=CC=C2C=C1 PFDCSCAAZRVKEE-UHFFFAOYSA-N 0.000 description 2
- PFGJVEXRRZRWQS-UHFFFAOYSA-N 1-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]indole Chemical compound C1CN(CC(F)(F)F)CCC1N1C2=CC=CC=C2C=C1 PFGJVEXRRZRWQS-UHFFFAOYSA-N 0.000 description 2
- QTUBHJUPHOYQPM-UHFFFAOYSA-N 1-[1-(2,2,3,3,4,4,4-heptafluorobutyl)piperidin-4-yl]indole Chemical compound C1CN(CC(F)(F)C(F)(F)C(F)(F)F)CCC1N1C2=CC=CC=C2C=C1 QTUBHJUPHOYQPM-UHFFFAOYSA-N 0.000 description 2
- MCZAQODBBXEFIV-UHFFFAOYSA-N 1-[1-(3-chloropropyl)piperidin-4-yl]indole Chemical compound C1CN(CCCCl)CCC1N1C2=CC=CC=C2C=C1 MCZAQODBBXEFIV-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- HHROFTMOYYXAAW-UHFFFAOYSA-N 2-indol-1-ylbutane-1,4-diol Chemical compound C1=CC=C2N(C(CO)CCO)C=CC2=C1 HHROFTMOYYXAAW-UHFFFAOYSA-N 0.000 description 2
- AMIQWFKUOQYSLF-UHFFFAOYSA-N 2-indol-1-ylbutyl methanesulfonate Chemical compound C1=CC=C2N(C(COS(C)(=O)=O)CC)C=CC2=C1 AMIQWFKUOQYSLF-UHFFFAOYSA-N 0.000 description 2
- IUAKPBZKBNOACJ-UHFFFAOYSA-N 3-(4-indol-1-ylpiperidin-1-yl)-n,n-dimethylpropan-1-amine Chemical compound C1CN(CCCN(C)C)CCC1N1C2=CC=CC=C2C=C1 IUAKPBZKBNOACJ-UHFFFAOYSA-N 0.000 description 2
- UMEVYDLODKYDQA-UHFFFAOYSA-N 3-indol-1-yloxolan-2-one Chemical compound O=C1OCCC1N1C2=CC=CC=C2C=C1 UMEVYDLODKYDQA-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- XJGOWXQXLXFCJX-UHFFFAOYSA-N 8,9-dihydro-7h-pyrido[1,2-a]indol-6-ylidenemethyl acetate Chemical compound C1=CC=C2N3C(=COC(=O)C)CCCC3=CC2=C1 XJGOWXQXLXFCJX-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 2
- 208000036566 Erythroleukaemia Diseases 0.000 description 2
- 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 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- XIFKOQYHTZVPDL-ZQTLJVIJSA-N [(2r,3s)-5-acetyloxy-2-(azidomethyl)oxolan-3-yl] acetate Chemical compound CC(=O)OC1C[C@H](OC(C)=O)[C@@H](CN=[N+]=[N-])O1 XIFKOQYHTZVPDL-ZQTLJVIJSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 208000021841 acute erythroid leukemia Diseases 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 208000029028 brain injury Diseases 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000001952 enzyme assay Methods 0.000 description 2
- IMLHEVKSJVHFFB-UHFFFAOYSA-N ethyl 4-indol-1-ylpiperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1N1C2=CC=CC=C2C=C1 IMLHEVKSJVHFFB-UHFFFAOYSA-N 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 210000002510 keratinocyte Anatomy 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000019254 respiratory burst Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229910001958 silver carbonate Inorganic materials 0.000 description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VJCXACABXTXLEE-UHFFFAOYSA-N tert-butyl 4-indol-1-ylpiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1C2=CC=CC=C2C=C1 VJCXACABXTXLEE-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000012049 topical pharmaceutical composition Substances 0.000 description 2
- 125000004954 trialkylamino group Chemical group 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- QGVLYPPODPLXMB-UBTYZVCOSA-N (1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-4a,7b,9,9a-tetrahydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-1,1a,1b,4,4a,7a,7b,8,9,9a-decahydro-5H-cyclopropa[3,4]benzo[1,2-e]azulen-5-one Chemical compound C1=C(CO)C[C@]2(O)C(=O)C(C)=C[C@H]2[C@@]2(O)[C@H](C)[C@@H](O)[C@@]3(O)C(C)(C)[C@H]3[C@@H]21 QGVLYPPODPLXMB-UBTYZVCOSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 description 1
- XRVPFRDAJLYBHY-NTSWFWBYSA-N (4s,5r)-6-azido-4,5-dihydroxyhexan-2-one Chemical compound CC(=O)C[C@H](O)[C@H](O)CN=[N+]=[N-] XRVPFRDAJLYBHY-NTSWFWBYSA-N 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- PFPUMJVBHFHMAN-UHFFFAOYSA-N 1-(1,4-diiodobutan-2-yl)indole Chemical compound C1=CC=C2N(C(CI)CCI)C=CC2=C1 PFPUMJVBHFHMAN-UHFFFAOYSA-N 0.000 description 1
- YYHDCZNNADMZDB-UHFFFAOYSA-N 1-(1-benzylpyrrolidin-3-yl)indole Chemical compound C1CC(N2C3=CC=CC=C3C=C2)CN1CC1=CC=CC=C1 YYHDCZNNADMZDB-UHFFFAOYSA-N 0.000 description 1
- RRJBXAZFCXOEIJ-UHFFFAOYSA-N 1-(1-propan-2-ylpiperidin-4-yl)indole Chemical compound C1CN(C(C)C)CCC1N1C2=CC=CC=C2C=C1 RRJBXAZFCXOEIJ-UHFFFAOYSA-N 0.000 description 1
- GMJLKDDVABMGCD-UHFFFAOYSA-N 1-[1-(cyclopropylmethyl)piperidin-4-yl]indole Chemical compound C1CC(N2C3=CC=CC=C3C=C2)CCN1CC1CC1 GMJLKDDVABMGCD-UHFFFAOYSA-N 0.000 description 1
- MMAJXKGUZYDTHV-UHFFFAOYSA-N 1-benzhydrylazetidin-3-ol Chemical compound C1C(O)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 MMAJXKGUZYDTHV-UHFFFAOYSA-N 0.000 description 1
- QYUAUAYVRBCXJK-UHFFFAOYSA-N 1-methyl-2-propan-2-ylindole Chemical compound C1=CC=C2N(C)C(C(C)C)=CC2=C1 QYUAUAYVRBCXJK-UHFFFAOYSA-N 0.000 description 1
- JXBKNJGOHKLWCK-UHFFFAOYSA-N 1-methyl-3-[4-[1-(1-methylpiperidin-4-yl)indol-3-yl]-1H-pyrrol-3-yl]indole Chemical compound C1CN(C)CCC1N1C2=CC=CC=C2C(C=2C(=CNC=2)C=2C3=CC=CC=C3N(C)C=2)=C1 JXBKNJGOHKLWCK-UHFFFAOYSA-N 0.000 description 1
- GREHKUAVLDCGGG-UHFFFAOYSA-N 2,2,2-trifluoro-1-(4-indol-1-ylpiperidin-1-yl)ethanone Chemical compound C1CN(C(=O)C(F)(F)F)CCC1N1C2=CC=CC=C2C=C1 GREHKUAVLDCGGG-UHFFFAOYSA-N 0.000 description 1
- WFELVFKXQJYPSL-UHFFFAOYSA-N 2,2,3,3,4,4,4-heptafluorobutanoyl chloride Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(Cl)=O WFELVFKXQJYPSL-UHFFFAOYSA-N 0.000 description 1
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 1
- UVACVUNPDBUNNE-UHFFFAOYSA-N 2-(1-methyl-2-propan-2-ylindol-3-yl)acetamide Chemical compound C1=CC=C2N(C)C(C(C)C)=C(CC(N)=O)C2=C1 UVACVUNPDBUNNE-UHFFFAOYSA-N 0.000 description 1
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 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
- KISWVXRQTGLFGD-UHFFFAOYSA-N 2-[[2-[[6-amino-2-[[2-[[2-[[5-amino-2-[[2-[[1-[2-[[6-amino-2-[(2,5-diamino-5-oxopentanoyl)amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)p Chemical compound C1CCN(C(=O)C(CCCN=C(N)N)NC(=O)C(CCCCN)NC(=O)C(N)CCC(N)=O)C1C(=O)NC(CO)C(=O)NC(CCC(N)=O)C(=O)NC(CCCN=C(N)N)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 KISWVXRQTGLFGD-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- JQGRMZUVGWRDIV-UHFFFAOYSA-N 3-(1-methylindol-3-yl)-4-[1-(1-methylpiperidin-4-yl)indol-3-yl]pyrrole-2,5-dione Chemical compound C1CN(C)CCC1N1C2=CC=CC=C2C(C=2C(NC(=O)C=2C=2C3=CC=CC=C3N(C)C=2)=O)=C1 JQGRMZUVGWRDIV-UHFFFAOYSA-N 0.000 description 1
- TZCVWFOZBOBEIU-UHFFFAOYSA-N 3-(1-methylindol-3-yl)-4-[1-(1-methylpiperidin-4-yl)indol-3-yl]pyrrole-2,5-dione;hydrochloride Chemical compound Cl.C1CN(C)CCC1N1C2=CC=CC=C2C(C=2C(NC(=O)C=2C=2C3=CC=CC=C3N(C)C=2)=O)=C1 TZCVWFOZBOBEIU-UHFFFAOYSA-N 0.000 description 1
- IFTMGQDZPAVXCG-UHFFFAOYSA-N 3-(1-methylindol-3-yl)-4-[1-(1-propylpiperidin-4-yl)indol-3-yl]pyrrole-2,5-dione Chemical compound C1CN(CCC)CCC1N1C2=CC=CC=C2C(C=2C(NC(=O)C=2C=2C3=CC=CC=C3N(C)C=2)=O)=C1 IFTMGQDZPAVXCG-UHFFFAOYSA-N 0.000 description 1
- WKAHWXDLLVBAFI-UHFFFAOYSA-N 3-(1-methylindol-3-yl)-4-[1-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]indol-3-yl]pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C(C(NC1=O)=O)=C1C(C1=CC=CC=C11)=CN1C1CCN(CC(F)(F)F)CC1 WKAHWXDLLVBAFI-UHFFFAOYSA-N 0.000 description 1
- INRSJRVWEVTFDV-UHFFFAOYSA-N 3-[1-(1-acetylpiperidin-4-yl)indol-3-yl]-4-(1-methylindol-3-yl)pyrrole-2,5-dione Chemical compound C1CN(C(=O)C)CCC1N1C2=CC=CC=C2C(C=2C(NC(=O)C=2C=2C3=CC=CC=C3N(C)C=2)=O)=C1 INRSJRVWEVTFDV-UHFFFAOYSA-N 0.000 description 1
- ARKNUCQRPYIUMU-UHFFFAOYSA-N 3-[1-(1-ethylpiperidin-4-yl)indol-3-yl]-4-(1-methylindol-3-yl)pyrrole-2,5-dione Chemical compound C1CN(CC)CCC1N1C2=CC=CC=C2C(C=2C(NC(=O)C=2C=2C3=CC=CC=C3N(C)C=2)=O)=C1 ARKNUCQRPYIUMU-UHFFFAOYSA-N 0.000 description 1
- YALPPWBBUWUINJ-UHFFFAOYSA-N 3-[1-(2-hydroxyethyl)indol-3-yl]-4-(1-methylindol-3-yl)furan-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C1=C(C=2C3=CC=CC=C3N(CCO)C=2)C(=O)OC1=O YALPPWBBUWUINJ-UHFFFAOYSA-N 0.000 description 1
- FUVJGBQDHCCGCD-UHFFFAOYSA-N 3-[1-(3-hydroxypropyl)indol-3-yl]-4-(1-methylindol-3-yl)pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C1=C(C=2C3=CC=CC=C3N(CCCO)C=2)C(=O)NC1=O FUVJGBQDHCCGCD-UHFFFAOYSA-N 0.000 description 1
- DIBQJDJFXJGVJC-UHFFFAOYSA-N 3-[1-(4-hydroxybutyl)indol-3-yl]-4-(1-methylindol-3-yl)pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C1=C(C=2C3=CC=CC=C3N(CCCCO)C=2)C(=O)NC1=O DIBQJDJFXJGVJC-UHFFFAOYSA-N 0.000 description 1
- BQZQRZSRZHVEPY-UHFFFAOYSA-N 3-[1-[1-(2,2,3,3,4,4,4-heptafluorobutyl)piperidin-4-yl]indol-3-yl]-4-(1-methylindol-3-yl)pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C(C(NC1=O)=O)=C1C(C1=CC=CC=C11)=CN1C1CCN(CC(F)(F)C(F)(F)C(F)(F)F)CC1 BQZQRZSRZHVEPY-UHFFFAOYSA-N 0.000 description 1
- VYXIZKJRRNWQAK-UHFFFAOYSA-N 3-[1-[1-(cyclopropylmethyl)piperidin-4-yl]indol-3-yl]-4-(1-methylindol-3-yl)pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C(C(NC1=O)=O)=C1C(C1=CC=CC=C11)=CN1C(CC1)CCN1CC1CC1 VYXIZKJRRNWQAK-UHFFFAOYSA-N 0.000 description 1
- NSVWVUUWIXBTIK-UHFFFAOYSA-N 3-[1-[3-(cyclopropylamino)propyl]indol-3-yl]-4-(1-methylindol-3-yl)pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C(C(NC1=O)=O)=C1C(C1=CC=CC=C11)=CN1CCCNC1CC1 NSVWVUUWIXBTIK-UHFFFAOYSA-N 0.000 description 1
- QMGUOJYZJKLOLH-UHFFFAOYSA-N 3-[1-[3-(dimethylamino)propyl]indol-3-yl]-4-(1h-indol-3-yl)pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(CCCN(C)C)C=C1C1=C(C=2C3=CC=CC=C3NC=2)C(=O)NC1=O QMGUOJYZJKLOLH-UHFFFAOYSA-N 0.000 description 1
- FRWXXAYVHFLWCV-UHFFFAOYSA-N 3-[8-(hydroxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methylindol-3-yl)pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C1=C(C=2C3=CC=CC=C3N3CCC(CO)CC3=2)C(=O)NC1=O FRWXXAYVHFLWCV-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- LFJJGHGXHXXDFT-UHFFFAOYSA-N 3-bromooxolan-2-one Chemical compound BrC1CCOC1=O LFJJGHGXHXXDFT-UHFFFAOYSA-N 0.000 description 1
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 1
- AZRRZGIBBLWSSQ-UHFFFAOYSA-N 4-ethyl-7-phenyl-3,5-diazabicyclo[2.2.2]octane-2,6-dione Chemical compound N1C(=O)C2C(=O)NC1(CC)CC2C1=CC=CC=C1 AZRRZGIBBLWSSQ-UHFFFAOYSA-N 0.000 description 1
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- KSKCIDPQFZJVQX-UHFFFAOYSA-N 7,9-dihydro-6h-pyrido[1,2-a]indole-8,8-dicarboxylic acid Chemical compound C1=CC=C2N3CCC(C(O)=O)(C(=O)O)CC3=CC2=C1 KSKCIDPQFZJVQX-UHFFFAOYSA-N 0.000 description 1
- RBWNDBNSJFCLBZ-UHFFFAOYSA-N 7-methyl-5,6,7,8-tetrahydro-3h-[1]benzothiolo[2,3-d]pyrimidine-4-thione Chemical compound N1=CNC(=S)C2=C1SC1=C2CCC(C)C1 RBWNDBNSJFCLBZ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- MSIHFIIEQBNJGX-WLYNEOFISA-N C(C)(=O)OC(C)=O.CC(=O)C[C@H](OC(C)=O)[C@H](O)CN=[N+]=[N-] Chemical compound C(C)(=O)OC(C)=O.CC(=O)C[C@H](OC(C)=O)[C@H](O)CN=[N+]=[N-] MSIHFIIEQBNJGX-WLYNEOFISA-N 0.000 description 1
- PGIHRAJLUCQBRX-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)N1CCC(CC1)N1C=CC2=CC=CC=C12 Chemical compound C(C1=CC=CC=C1)(=O)N1CCC(CC1)N1C=CC2=CC=CC=C12 PGIHRAJLUCQBRX-UHFFFAOYSA-N 0.000 description 1
- HWDWTZCCTONGQL-UHFFFAOYSA-N C=C(OC(=O)N1CCC(CC1)N1C=C(C2=CC=CC=C12)C=1C(NC(C1C1=CN(C2=CC=CC=C12)C)=O)=O)C Chemical compound C=C(OC(=O)N1CCC(CC1)N1C=C(C2=CC=CC=C12)C=1C(NC(C1C1=CN(C2=CC=CC=C12)C)=O)=O)C HWDWTZCCTONGQL-UHFFFAOYSA-N 0.000 description 1
- GFDUWGAPGIICHX-BYLMWILSSA-N CC(=O)C[C@H](O)[C@H](O)COS(=O)(=O)C1=CC=C(C)C=C1.CC(=O)C[C@H](O)[C@H](O)CN=[N+]=[N-] Chemical compound CC(=O)C[C@H](O)[C@H](O)COS(=O)(=O)C1=CC=C(C)C=C1.CC(=O)C[C@H](O)[C@H](O)CN=[N+]=[N-] GFDUWGAPGIICHX-BYLMWILSSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 125000000824 D-ribofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@]1([H])O[H] 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 101000619542 Homo sapiens E3 ubiquitin-protein ligase parkin Proteins 0.000 description 1
- 101001051767 Homo sapiens Protein kinase C beta type Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 102000047918 Myelin Basic Human genes 0.000 description 1
- 101710107068 Myelin basic protein Proteins 0.000 description 1
- YFGOWTPFKYJYIS-GHMBPFNYSA-N N(=[N+]=[N-])C[C@@H]1[C@H](C[C@H](O1)C(CCCN1C=C(C2=CC=CC=C12)C=1C(NC(C1C1=CN(C2=CC=CC=C12)C)=O)=O)O)O Chemical compound N(=[N+]=[N-])C[C@@H]1[C@H](C[C@H](O1)C(CCCN1C=C(C2=CC=CC=C12)C=1C(NC(C1C1=CN(C2=CC=CC=C12)C)=O)=O)O)O YFGOWTPFKYJYIS-GHMBPFNYSA-N 0.000 description 1
- DJNLOVULWGVVMW-ZDZKPJIOSA-N N-[[(2R,3S,5R)-3-hydroxy-5-[1-hydroxy-2-[3-[4-(1-methylindol-3-yl)-2,5-dioxopyrrol-3-yl]indol-1-yl]ethyl]oxolan-2-yl]methyl]acetamide Chemical compound C(C)(=O)NC[C@@H]1[C@H](C[C@@H](O1)C(CN1C=C(C2=CC=CC=C12)C=1C(NC(C=1C1=CN(C2=CC=CC=C12)C)=O)=O)O)O DJNLOVULWGVVMW-ZDZKPJIOSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 108010064785 Phospholipases Proteins 0.000 description 1
- 102000015439 Phospholipases Human genes 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100024923 Protein kinase C beta type Human genes 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- CSADFCXSDWSLTN-SFYZADRCSA-N [(2r,3s)-1-azido-2-hydroxy-5-oxohexan-3-yl] acetate Chemical compound CC(=O)C[C@H](OC(C)=O)[C@H](O)CN=[N+]=[N-] CSADFCXSDWSLTN-SFYZADRCSA-N 0.000 description 1
- VDCWSQVNYNQWNB-QWHCGFSZSA-N [(2r,3s)-2,3-dihydroxy-5-oxohexyl] 4-methylbenzenesulfonate Chemical compound CC(=O)C[C@H](O)[C@H](O)COS(=O)(=O)C1=CC=C(C)C=C1 VDCWSQVNYNQWNB-QWHCGFSZSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 125000003525 allosyl group Chemical group 0.000 description 1
- 125000003420 altrosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 229940031955 anhydrous lanolin Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 125000000089 arabinosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O)CO1)* 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- DCBDOYDVQJVXOH-UHFFFAOYSA-N azane;1h-indole Chemical compound N.C1=CC=C2NC=CC2=C1 DCBDOYDVQJVXOH-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000008238 biochemical pathway Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 229960003340 calcium silicate Drugs 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 108020001778 catalytic domains Proteins 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000023549 cell-cell signaling Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004966 cyanoalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- KQWGXHWJMSMDJJ-UHFFFAOYSA-N cyclohexyl isocyanate Chemical compound O=C=NC1CCCCC1 KQWGXHWJMSMDJJ-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-M ethanimidate Chemical compound CC([O-])=N DLFVBJFMPXGRIB-UHFFFAOYSA-M 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- NEMGGLUZJGBQRS-UHFFFAOYSA-N ethyl 4-(indol-1-ylmethylidene)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1=CN1C2=CC=CC=C2C=C1 NEMGGLUZJGBQRS-UHFFFAOYSA-N 0.000 description 1
- KMBJGGVKWSZREJ-UHFFFAOYSA-N ethyl 4-(methylsulfonyloxymethylidene)piperidine-1-carboxylate Chemical compound CCOC(=O)N1CCC(=COS(C)(=O)=O)CC1 KMBJGGVKWSZREJ-UHFFFAOYSA-N 0.000 description 1
- VRZVPALEJCLXPR-UHFFFAOYSA-N ethyl 4-methylbenzenesulfonate Chemical compound CCOS(=O)(=O)C1=CC=C(C)C=C1 VRZVPALEJCLXPR-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000002519 galactosyl group Chemical group C1([C@H](O)[C@@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 125000002951 idosyl group Chemical group C1([C@@H](O)[C@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002496 iodine Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-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
- 239000008101 lactose Substances 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 125000003796 lyxosyl group Chemical group C1([C@@H](O)[C@@H](O)[C@H](O)CO1)* 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000000311 mannosyl group Chemical group C1([C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 210000003593 megakaryocyte Anatomy 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000013081 microcrystal Substances 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 102000045222 parkin Human genes 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- QGVLYPPODPLXMB-QXYKVGAMSA-N phorbol Natural products C[C@@H]1[C@@H](O)[C@]2(O)[C@H]([C@H]3C=C(CO)C[C@@]4(O)[C@H](C=C(C)C4=O)[C@@]13O)C2(C)C QGVLYPPODPLXMB-QXYKVGAMSA-N 0.000 description 1
- 150000004633 phorbol derivatives Chemical class 0.000 description 1
- 239000002644 phorbol ester Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000006410 propenylene group Chemical group 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 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 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GCMMHBRAPKXXJF-UHFFFAOYSA-N tert-butyl n-carbamothioyl-n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)N(C(N)=S)C(=O)OC(C)(C)C GCMMHBRAPKXXJF-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 102000009310 vitamin D receptors Human genes 0.000 description 1
- 108050000156 vitamin D receptors Proteins 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 125000000969 xylosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)CO1)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- 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
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Neurosurgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Hematology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Obesity (AREA)
- Psychiatry (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
で示される基であり、
R2およびR2'は、独立して水素、アルキル、アルコキシアルキル、ヒドロキシアルキル、C1−C3アルキルチオ、S(0)C1−C3アルキル、もしくはCF3であるか、またはR1およびR2は、一緒になって−(CH2)r−X−CH2−を形成することができ、
R3は水素またはCH3COであり、
R4、R4'、R5、R5'、R6、R6'、R7、およびR7'は、独立して水素、ハロゲン、アルキル、ヒドロキシ、アルコキシ、−COO(C1−C3アルキル)、CF3、ニトロ、アミノ、アセチルアミノ、モノアルキルアミノ、ジアルキルアミノ、アルキルチオ、C1−C3アルキルチオ、またはS(0)C1−C3アルキルであり、
XはCHR8またはNR8であり、
R8は(CH2)sR9であり、
R9は水素、ヒドロキシ、アルコキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、トリアルキルアミノ、アジド、アシルアミノ、アルコキシカルボニル、シアノ、アミジノ、またはアミノカルボニルであり、
nは1、2、3、4、5、または6であり、
rは1、2、または3であり、
sは0、1、2、または3である]
で示される化合物の医薬的有効量を、そのような治療を必要とする哺乳動物に投与することを特徴とするプロテインキナーゼCβ−1およびβ−2アイソザイムを選択的に阻害する方法を提供するものである。
R2およびR2'は、独立して水素、アルキル、アルコキシアルキル、ヒドロキシアルキル、C1−C3アルキルチオ、S(0)C1−C3アルキル、またはCF3であり、R3は水素またはCH3CO−であり、
R4、R4'、R5、R5'、R6、R6'、R7、およびR7'は、独立して水素、ハロゲン、アルキル、ヒドロキシ、アルコキシ、−COO(C1−C3アルキル)、CF3、ニトロ、アミノ、アセチルアミノ、モノアルキルアミノ、ジアルキルアミノ、アルキルチオ、C1−C3アルキルチオ、またはS(0)C1−C3アルキルであり、R12は水素、アルキル、ハロアルキル、シクロアルキル、アセチル、アリール、−CH(アリール)2、アミノ、モノアルキルアミノ、ジアルキルアミノ、グアニジノ、−C(=N(アルコキシカルボニル))NH(アルコキシカルボニル)、アミジノ、ヒドロキシ、カルボキシ、アルコキシカルボニル、またはヘテロサイクリル基であり、
pおよびqは独立して1、2、3、または4であり、
sは0、1、2、または3であり、
tは1または2であり、uは0または1である]、
式III:
R2'は、水素、アルキル、アルコキシアルキル、ヒドロキシアルキル、C1−C3アルキルチオ、S(0)C1−C3アルキル、またはCF3であり、
R3は水素またはCH3CO−であり、
R4、R4'、R5、R5'、R6、R6'、R7、およびR7'は、独立して水素、ハロゲン、アルキル、ヒドロキシ、アルコキシ、−COO(C1−C3アルキル)、CF3、ニトロ、アミノ、アセチルアミノ、モノアルキルアミノ、ジアルキルアミノ、アルキルチオ、C1−C3アルキルチオ、またはS(0)C1−C3アルキルであり、XはCR8R9であり、
R8は(CH2)sR10であり、
R9は(CH2)sR11であり、
R10およびR11は、独立してヒドロキシ、アルコキシ、カルボキシ、アシルオキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、トリアルキルアミノ、アジド、アシルアミノ、アルコキシカルボニル、シアノ、アミジノ、またはアミノカルボニルであり、
rは1、2、または3であり、
sは0、1、2、または3である]、および
式IV:
R1'は水素、C1−C4アルキル、シクロプロピルメチル、アミノアルキル、モノアルキルアミノアルキル、またはジアルキルアミノアルキルであり、
R2およびR2'は、独立して水素、アルキル、アルコキシアルキル、ヒドロキシアルキル、C1−C3アルキルチオ、S(0)C1−C3アルキル、またはCF3であり、R3は水素またはCH3CO−であり、
R4、R4'、R5、R5'、R6、R6'、R7、およびR7'は、独立して水素、ハロゲン、アルキル、ヒドロキシ、アルコキシ、−COO(C1−C3アルキル)、CF3、ニトロ、アミノ、アセチルアミノ、モノアルキルアミノ、ジアルキルアミノ、アルキルチオ、C1−C3アルキルチオ、またはS(0)C1−C3アルキルであり、nは1、2、3、4、5、または6である]。
R1'は水素、C1−C4アルキル、アミノアルキル、モノアルキルアミノアルキル、またはジアルキルアミノアルキルであり、
R2は水素またはメチルである]、および
式Ib:
XはCR8R9またはNR8であり、
R8は(CH2)sR10であり、
R9は(CH2)sR11であり、
R10およびR11は、独立して水素、ヒドロキシ、モノアルキルアミノ、またはジアルキルアミノであり、
rは1、または2であり、
sは1である]。
R1'は水素またはC1−C4アルキルであり、
R12は水素またはC1−C4アルキルである]
で示される化合物である。
工程1
1)エステラーゼもしくはリパーゼによって開裂させることができるエステルもしくはアミド誘導体、
2)特異的または非特異的プロテアーゼによって認識可能なペプチド、あるいは3)プロドラッグ形もしくは修飾されたプロドラッグ形が膜選択性を介して作用部位に蓄積される誘導体、またはこれら1)〜3)のあらゆる組み合せ。適切なプロドラッグ誘導体を選択し、製造するための一般的方法は、例えば、H.Bundgaardの、Design of Profrugs(1985)に記載されている。
PKC酵素アッセイ
PKC酵素=α、βI、βII、γ、δ、ε、η、およびζ。
20mM HEPES緩衝液(Sigma,St.Louis,Missouri)(pH7.5)中、酵素活性を最大に活性化するのに十分なジアシルグリセロール(Avanti Polar Lipids)および120μg/mLのホスファチジルセリン(Avanti Polar Lipids)からなる小胞、α、βI、βII、およびγ酵素のみのアッセイ用として940μM塩化カルシウム(Sigma,St.Louis,Missouri)、全ての酵素について1mM EGTA、10mM塩化マグネシウム(Sigma,St.Louis,Missouri)、および30μM(γ−32P)ATP(DuPont)。全ての酵素についてヒストンHL型(Worthington)またはミエリン塩基性蛋白のいずれかを基質として使用した。プロテインキナーゼC酵素を加えてアッセイを開始し、30℃で10分間インキュベーションした後、冷トリクロロ酢酸(Amresco)0.5mL、次いで1mg/mLのウシ血清アルブミン(Sigma,St.Louis,Missouri)100μLを加えてアッセイを止めた。TOMTECTM濾過システムを用いてガラス線維フィルターで減圧濾過することによって沈降物を回収し、βシンチレーションカウンターでカウントすることによって定量した。
製造例2
2−(1−(1−N(H)−ピペリジン−4−イル)−インドール−3−イル)−酢酸エチルエステル
製造例3
1−(1−エチル−ピペリジン−4−イル)−1H−インドール
製造例4
1−[(1−N−シクロプロピルメチル)−ピペリジン−4−イル]−インドール
製造例5
1−N−[1−N−(3−クロロプロピル)−ピペリジン−4−イル]−インドール
製造例6
[3−(4−インドール−1−イル−ピペリジン−1−イル)−プロピル]− ジメチルアミン
製造例7
1−ベンゾイル−4−(1−インドリル)−ピペリジン
製造例8
1−t−ブトキシカルボニル−4−(1−インドリル)−ピペリジン
製造例9
4−(1−インドリル)−ピペリジン
製造例10
6,7,8,9−テトラヒドロピリド[1,2−a]インドール−8,8−ジカルボン酸ジエチルエーテル
製造例11
1−(1−メチル−ピペリジン−4−イル)−インドール
製造例12
4−(インドール−1−イル)−ピペリジン−1−カルボン酸エチルエステル
製造例13
1−N−(1−N−(シクロプロピルメチル)−ピペリジン−4−イル)−インドール
製造例14
製造例15
1−N−[1−N−(2,2,2−トリフルオロ−エチル)−ピペリジン−4−イル]−インドール
製造例16
1−N−(1−N−(トリフルオロアセチル)ピペリジン−4−イル)−インドール
製造例17
1−N−[1−N−(2,2,3,3,4,4,4−ヘプタフルオロ−ブチル)−ピペリジン−4−イル]−インドール
製造例18
1−N−[1−N−2,2,3,3,4,4,4−ヘプタフルオロ)ブチルアミド−ピペリジン−4−イル]−インドール
製造例19
[t−ブトキシカルボニルイミノ−(4−インドール−1−イル−ピペリジン−1−イル)−メチル]−カルバミン酸t−ブチルエステル
製造例20
1−N−(1−メチル−ピペリジン−4−イル)メチレン)−インドール
製造例21
4−(インドール−1−イル)メチレン−ピペリジン−1−カルボン酸エチルエステル
製造例22
2−(インドール−1−イル)ブチロラクトン
インドール(9g、78mモル)の氷冷乾燥DMF(80mL)溶液を、油を含まない水素化ナトリウム(2.25g、94mモル)で処理した。1時間後、2−ブロモブチロラクトン(14.6mL、78mモル)の乾燥THF(20mL)溶液を滴加した。周囲温度で一夜撹拌した後、混合物を砕いた氷に注ぎ、酢酸エチル(3×)で抽出し、乾燥して留去した。残留物を、ヘキサン/酢酸エチルグラジエント(9:1〜7:3)を用いるシリカゲルフラッシュクロマトグラフィーで精製した。溶離溶媒を留去して帯黄色油状物8g(理論値の52%)を得た。
製造例23
2−(インドール−1−イル)−ブタン−1,4−ジオール
製造例24
1,4−(ビス)メタンスルホニルオキシ−2−(インドール−1−イル)−ブタン
製造例25
1,4−ジイオド−2−インドール−1−イル−ブタン
製造例26
1−N−(1−ベンジル−ピロリジン−3−イル)−インドール
製造例27
1−N−(1−ベンズヒドリル−アゼチジン−3−イル)−インドール
2−[2−(1−ベンズヒドリル)−アゼチジン−3−イル)−2−アミノ)−フェニル]−エタノール(3.1g、0.01モル)の乾燥塩化メチレン(100mL)溶液を−5℃に冷却し、少量に分けたピロジニウムジクロメート(PDC)(9.3g)で処理した。混合物を徐々に周囲温度とし、さらにPDC(9.3g)を加えた。1時間後、混合物を乾燥シリカゲル層に通して濾過し、次いで黄色油状の溶離液(0.85g)を留去して塩化メチレンチエチルエーテルですすぎ、これをさらに精製することなく使用した(理論値の25%)。MS
製造例28
1−N−(1−N(ベンズヒドリル)−アゼチジン−3−イル)−2−(エタン−2−オール)−アナリン
乾燥トルエン(150mL)中のメタンスルホン酸 1−ベンズヒドリル−アゼチジン−3−イル エステル(14g、44.2mモル)、2−(エタン−2−オール)−アナリン(14g、44.2mモル)、および無水炭酸カリウムの(2.8g、50mモル)の混合物を4時間還流した。トルエンを留去して残留物を水と塩化メチレンに分配した。有機相を乾燥し、留去し、残る油状物をヘキサン/アセトングラジエント(90:10〜85:15)で溶離するシリカゲルカラムクロマトグラフィーで精製した。溶離溶媒を留去して無色油状物6g(理論値の44%)を得た。MS
製造例29
メタンスルホン酸 1−ベンズヒドリル−アゼチジン−3−イル エステル
1−ベンズヒドリル−アゼチジン−3−オール(50g、0.208モル)の乾燥ピリジン(500mL)溶液を5℃に冷却した。メタンスルホニルクロリド(16.2mL、0.208モル)を30分間かけて加えた。混合物を徐々に(12時間)周囲温度とし、さらに2時間撹拌し続けた。溶媒を、40〜50℃で減圧除去した。残留物を塩化メチレンに再溶解し、水洗(2×)して乾燥した。粗製物質をt−ブチルメチルエーテル/石油エーテル(15:85)溶液でトリチュレートして精製された生成物の結晶(53g、収率80%)を得た。融点:85〜87℃。MS
製造例30
メチル−2−デオキシ−5−O−トシル−D−リボース
メチル−2−デオキシ−5−D−リボース(8g、54mモル)をピリジン(60mL)に溶解した。この溶液にトシルクロリド(10.86g、57mモル)を、0℃で1時間かけて加えた。室温で14時間後、この溶液を濃縮し、氷水(250mL)で反応を止め、酢酸エチルで抽出した。抽出物を飽和NaHCO3および水で洗浄し、乾燥し、次いで濾過して濃縮した。残留物(13.6g、収量83.5%)を直接用いた。NMR
製造例31
メチル−5−アジド−2.5 ジデオキシ−D−リボース
メチル−2−デオキシ−5−O−トシル−D−リボース(13.6g、45mモル)のDMF(250mL)溶液にアジ化ナトリウム(4.4g、67mモル)を加えた。混合物を4時間還流し、次いで室温に冷却し、氷水(1.5mL)で反応を止めて酢酸エチルで抽出した。抽出物を水洗し、乾燥し、濃縮して油状物(6.2g、収率86%)を得た。NMR
製造例32
メチル−3−O−アセチル−5−アジド−2.5 ジデオキシ−D−リボース
無水酢酸(25mL)を、メチル−5−アジド−2.5−ジデオキシ−D−リボース(6.2g、38mモル)のピリジン(100mL)溶液に加えた。室温で4時間後、混合物を減圧下で濃縮した。残留物(6g)をヘキサンエチルアセテート(8:2)で溶離するフラッシュクロマトグラフィーで精製した。溶離する溶媒を留去し、油状の生成物(4.9g、収率60%)を得た。NMR
製造例33
3−O−アセチル−5−アジド−2,5−ジデオキシ−D−リボシルアセテート
製造例34
8,8−ビス(アセトキシメチレン)−6,7,8,9−テトラヒドロピリド[1,2−a]インドール
3−(1−[2−(5−アセトアミド−2,5−ジデオキシ−α−D−
リボピラノシル)ヒドロキシエチル]−3−インドリル)−4−
(1−メチル−3−インドリル)−1H−ピロール−2,5−ジオン
αアノマー 1H−NMR(CDCl3):1.9(3H,s,NAc)、2.2(2H,m,H−2ab)、3.8(2H,m,CH2)、3.85(3H,s,NCH3)、4.2(2H,m,CH2)、5.05(1H,d,H−1)、6.7−7.8(10H,インドール H)、8.4(1H,s,NH)。
質量分析。
1H−NMR(CDCl3、250MHz) δ 2.02−2.26(6H,m)、3.06(2H,m)、3.64(2H,s)、3.84(3H,2)、4.24(1H,m)、6.68(1H,m)、6.81(2H,m)、7.11(3H,m)、7.28(7H,m)、7.69(1H,s)、7.85(1H,s)、8.50(1H,bs)。
質量分析:515[M++H]、計算値 514 FW。
全収量:鮮やかな橙色の結晶210mg(理論値の16%)。
融点:238−245℃。
1H−NMR(CDCl3、250MHz) δ 1.49(18H,s)、2.02(2H,m)、2.02(4H,m)、3.09(2H,m)、3.86(3H,s)、5.29(3H,m)、6.66(2H,m)、6.91(1H,m)、7.16−7.36(5H,m)、7.48(1H,s)、7.75(1H,s)、10.18(1H,bs)。
質量分析:667[M++H]、計算値 666 FW。
1H−NMR(CDCl3、250MHz) δ 1.48(9H,s)、1.74(2H,m)、2.02(2H,m)、2.87(2H,m)、3.85(3H,s)、4.29(3H,m)、6.69(2H,d)、6.88(1H,t)、7.07−7.36(5H,m)、7.51(1H,s)、7.68(1H,s)、7.75(1H,bs)。
1H−NMR(CDCl3、250MHz) δ 1.49(9H,m)、1.79(2H,m)、2.02(2H,m)、2.88(2H,m)、4.27(3H,m)、6.74(1H,m)、6.85(2H,m)、7.07−7.35(5H,m)、7.59(1H,s)、7.62(1H,s)、7.74(1H,s)、8.67(1H,bs)。
質量分析:510[M+]、計算値 510 FW。
収率:理論値の11%。
融点:>250℃。
1H−NMR(DMSO−d6):1.9および2.3(2H,m,H−2'ab)、3.7(2H,m,CH2)、3.85(3H,s,NCH3)、3.9(3H,s,NCH3)、4.4(2H,m,CH2)、4.6−5.0(4H,m,糖 H)、6.6−7.9(10H,m,インドール H)、10.9(1H,s,NH)。
3−(1−[4−(2,5−ジデオキシ−5−アジド−α−D−
リボフラノシル)ヒドロキシブチル]−3−インドリル)−4−
(1−メチル−3−インドリル)−1H−ピロール−2,5−ジオン
および
3−(1−[4−(2,5−ジデオキシ−5−アジド−β−D−
リボフラノシル)ヒドロキシ−ブチル]−3−インドリル)−4−(1−メチル−
3−インドリル)−1H−ピロール−2,5−ジオン−ピロール−2,5−ジオン
αアノマー 1H−NMR(CDCl3):1.6(2H,m,CH3)、1.9(2H,m,CH2)、2.1(2H,m,H−2'ab)、3.7(2H,m,CH2)、3.8(3H,s,NCH3)、4.2(2H,m,CH2)、5.2(1H,d,H−1')、6.7−7.9(10H,インドール H)。
βアノマー 1H−NMR(CDCl3):1.6(2H,m,CH2)、1.9(2H,m,CH2)、2.1(m,1H−2'a)、2.2(1H,m,H−2'b)、3.8(2H,m,CH2)、3.9(3H,s,NCH3)、4.2(2H,m,CH2)、5.15(1H,d,H−1')、6.7−7.8(10H,インドール H)。
αアノマーの収量:320mg(30%)。
βアノマーの収量:410mg(39%)。
βアノマー 1H−NMR(CDCl3):1.6(2H,m,CH2)、1.9(2H,m,CH2)、2.1(m,1H,H−2'b)、2.2(1H,m,H−2'a)、3.8(2H,m,CH3)、3.85(3H,s,NCH3)、4.2(2H,m,CH3)、5.2(1H,d,H−1')、6.7−7.7(10H,インドール H)、8.5(1H,s,NH)。
3−(1−[2−(5−アセトアミド−2,5−ジデオキシ−β−D−
リボフラノシル)ヒドロキシエチル]−3−インドリル)−4−
(1−メチル−3−インドリル)−1H−ピロール−2,5−ジオン
βアノマー 1H−NMR(CDCl3):1.8(3H,s,NAc)、2.0(1H,m,H−2b)、2.2(m,1H,H−2a)、3.7(2H,m,CH2)、3.8(3H,s,NMe)、4.2(2H,m,CH2)、600(1H,d,H−1)、6.7−7.7(10H,インドール H)、9.1(1H,s,NH)。
融点:>293℃。
融点:247−252℃。
融点:>250℃。
融点:>250℃。
収量:赤色の粉末100mg(収率 6%)。
全収量:41.6g(理論値の54%)。
融点:316−318℃。
収量:70g(理論値の92%)。
融点:280−282℃。
実施例 44
3−[1−(1−カルボキシアミジン−ピペリジン−4−
イル)インドール−3−イル]−4−(1−メチル−インドール−3−
イル)−1−ピロール−2,5−ジオン
融点:>210℃(分解)。
収量:鮮やかな橙色の結晶160mg(理論値の49%)。
融点:>250℃。
3−{1−[1−(2,2,3,3,4,4,4−ヘプタフルオロ−
ブチル)ピペリジン−4−イル]インドール−3−イル}−4−
(1−メチル−インドール−3−イル)−1H−ピロール−2,5−ジオン
収量:鮮やかな橙色の結晶260mg(理論値の38%)。
融点:231−234℃。
収量:鮮やかな橙色の結晶210mg(理論値の25%)。
融点:228℃(分解)。
融点:104−106℃。
収量:理論値の6%。
質量分析:500(M+)、341、303、276、159、91(100%)。
収量:理論値の3%。
融点:102−105℃。
製剤例 1
量(mg/カプセル剤)
活性成分 250
デンプン,乾燥 200
ステアリン酸マグネシウム 10
合 計 460mg
上記成分を混合して、硬ゼラチンカプセルに460mg量を充填する。
製剤例 2
量(mg/錠剤)
活性成分 250
セルロース,微晶質 400
二酸化ケイ素,フュームド 10
ステアリン酸 5
合 計 665mg
各成分を混合し、圧縮して、各々の重量が665mgである錠剤を成形する。
製剤例 3
量(重量%)
活性成分 0.25
エタノール 29.75
プロペラント 22(クロロジフルオロメタン) 70.00
合 計 100.00
活性成分をエタノールと混合する。その混合物をプロペラント 22の一部に加え、−30℃まで冷却して、充填装置へ移す。次いで、必要量をステンレススチール製の容器に入れ、残りのプロペラントで希釈する。次いで、バルブ装置を容器に取り付ける。
製剤例 4
量(mg/錠剤)
活性成分 60mg
デンプン 45mg
微晶質セルロース 35mg
ポリビニルピロリドン(10%水溶液として) 4mg
カルボキシメチルデンプンナトリウム 4.5mg
ステアリン酸マグネシウム 0.5mg
タルク 1mg
合 計 150mg
活性成分、デンプンおよびセルロースを米国No.45メッシュの篩にかけて、完全に混合する。その結果得られた粉末とポリビニルピロリドン溶液とを混合した後、これを米国No.14メッシュの篩にかける。このようにして製造した顆粒を50℃で乾燥し、米国No.18メッシュの篩にかける。次いで、あらかじめ米国No.60メッシュの篩にかけておいたカルボキシメチルデンプンナトリウム、ステアリン酸マグネシウム、およびタルクを顆粒に加え、混合した後、打錠機で圧縮して、各々の重量が150mgである錠剤を得る。
製剤例 5
量(mg/カプセル剤)
活性成分 80mg
デンプン 59mg
微晶質セルロース 59mg
ステアリン酸マグネシウム 2mg
合 計 200mg
活性成分、セルロース、デンプンおよびステアリン酸マグネシウムを混合し、米国No.45メッシュの篩にかけて、硬ゼラチンカプセルに200mg量を充填する。
製剤例 6
量(mg/坐剤)
活性成分 225mg
飽和脂肪酸グリセリド 2,000mg
合 計 2,225mg
活性成分を米国No.60メッシュの篩にかけ、あらかじめ必要最小限の熱を用いて溶融しておいた飽和脂肪酸グリセリドに懸濁させる。次いで、その混合物を容量2gの坐薬型に注入して放冷する。
製剤例 7
量
活性成分 50mg
カルボキシメチルセルロースナトリウム 50mg
シロップ 1.25ml
安息香酸溶液 0.10ml
香料 適 量
着色料 適 量
精製水を加えて5.0mlとする
薬物を米国No.45メッシュの篩にかけ、カルボキシメチルセルロースナトリウムおよびシロップと混合して、滑らかなペーストとする。安息香酸溶液、香料、および着色料を少量の水で希釈して、撹拌しながら加える。次いで、十分水を加え、所望の容量とする。
製剤例 8
量
活性成分 250mg
等張生理食塩水 1000mg
先の成分の溶液を1分間につき約1mlの速度で処置を必要とする患者に静脈内投与する。
Claims (2)
- 式:
R1'は水素、C1−C4アルキル、シクロプロピルメチル、アミノアルキル、モノアルキルアミノアルキル、またはジアルキルアミノアルキルであり、
R2およびR2'は、独立して水素、アルキル、アルコキシアルキル、ヒドロキシアルキル、C1−C3アルキルチオ、S(O)C1−C3アルキル、またはCF3であり、
R3は水素またはCH3CO−であり、
R4、R4'、R5、R5'、R6、R6'、R7、およびR7'は、独立して水素、ハロゲン、アルキル、ヒドロキシ、アルコキシ、−COO(C1−C3アルキル)、CF3、ニトロ、アミノ、アセチルアミノ、モノアルキルアミノ、ジアルキルアミノ、アルキルチオ、C1−C3アルキルチオ、またはS(O)C1−C3アルキルであり、nは1、2、3、4、5、または6である]
で示される化合物またはその医薬的に許容される塩もしくは溶媒和物。 - 活性成分である請求項1に記載の化合物を、1またはそれ以上の医薬的に許容される担体、賦形剤もしくは希釈剤と一緒に含有する、プロテインキナーゼC β-1およびβ-2アイソザイム活性を選択的に阻害するための医薬製剤。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17374193A | 1993-12-23 | 1993-12-23 | |
US08/324,948 US5545636A (en) | 1993-12-23 | 1994-10-18 | Protein kinase C inhibitors |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP51747995A Division JP3998261B2 (ja) | 1993-12-23 | 1994-12-14 | プロテインキナーゼc阻害剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2005225896A JP2005225896A (ja) | 2005-08-25 |
JP4369397B2 true JP4369397B2 (ja) | 2009-11-18 |
Family
ID=26869484
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP51747995A Expired - Lifetime JP3998261B2 (ja) | 1993-12-23 | 1994-12-14 | プロテインキナーゼc阻害剤 |
JP2005135900A Expired - Lifetime JP4369397B2 (ja) | 1993-12-23 | 2005-05-09 | プロテインキナーゼc阻害剤 |
JP2005135896A Expired - Lifetime JP4365803B2 (ja) | 1993-12-23 | 2005-05-09 | プロテインキナーゼc阻害剤 |
JP2006198260A Expired - Lifetime JP4490400B2 (ja) | 1993-12-23 | 2006-07-20 | プロテインキナーゼc阻害剤 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP51747995A Expired - Lifetime JP3998261B2 (ja) | 1993-12-23 | 1994-12-14 | プロテインキナーゼc阻害剤 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2005135896A Expired - Lifetime JP4365803B2 (ja) | 1993-12-23 | 2005-05-09 | プロテインキナーゼc阻害剤 |
JP2006198260A Expired - Lifetime JP4490400B2 (ja) | 1993-12-23 | 2006-07-20 | プロテインキナーゼc阻害剤 |
Country Status (13)
Country | Link |
---|---|
US (3) | US5661173A (ja) |
EP (2) | EP0817627B1 (ja) |
JP (4) | JP3998261B2 (ja) |
AT (2) | ATE290378T1 (ja) |
AU (1) | AU1339895A (ja) |
CA (1) | CA2179650C (ja) |
DE (1) | DE69434294T2 (ja) |
DK (1) | DK0817627T3 (ja) |
ES (1) | ES2236702T3 (ja) |
HK (1) | HK1008183A1 (ja) |
PT (1) | PT817627E (ja) |
SI (1) | SI0817627T1 (ja) |
WO (1) | WO1995017182A1 (ja) |
Families Citing this family (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL126272A0 (en) * | 1996-03-20 | 1999-05-09 | Lilly Co Eli | Synthesis of indolylmaleimides |
US6232299B1 (en) * | 1996-05-01 | 2001-05-15 | Eli Lilly And Company | Use of protein kinase C inhibitors to enhance the clinical efficacy of oncolytic agents and radiation therapy |
SE9603283D0 (sv) * | 1996-09-10 | 1996-09-10 | Astra Ab | New compounds |
SE9603284D0 (sv) * | 1996-09-10 | 1996-09-10 | Astra Ab | New compounds |
SE9603285D0 (sv) * | 1996-09-10 | 1996-09-10 | Astra Ab | New compounds |
TW472045B (en) | 1996-09-25 | 2002-01-11 | Astra Ab | Protein kinase C inhibitor compounds, method for their preparation, pharmaceutical composition thereof and intermediate used for their preparation |
US5859261A (en) * | 1997-03-20 | 1999-01-12 | Eli Lilly And Company | Synthesis of indolylmaleimides |
AR017200A1 (es) | 1997-12-23 | 2001-08-22 | Astrazeneca Ab | Compuestos inhibidores de la proteina cinasa c, sales farmaceuticamente aceptables de los mismos, formulaciones farmaceuitcas que los comprenden, usode las mismas y proceso para la sintesis de dichos compuestos |
SE9800835D0 (sv) | 1998-03-13 | 1998-03-13 | Astra Ab | New Compounds |
DE69909068T2 (de) * | 1998-03-17 | 2004-05-06 | F. Hoffmann-La Roche Ag | Substituierte bisindolylmaleimide zur inhibierung der zellproliferation |
CA2330756C (en) | 1998-05-04 | 2007-10-02 | Asta Medica Aktiengesellschaft | Indole derivatives and their use for the treatment of malignant and other diseases based on pathological cell proliferation |
US6127401A (en) * | 1998-06-05 | 2000-10-03 | Cephalon, Inc. | Bridged indenopyrrolocarbazoles |
US6013646A (en) | 1998-07-02 | 2000-01-11 | Bayer Corporation | Indolocarbazole derivatives useful for the treatment of neurodegenerative diseases and cancer |
US6841567B1 (en) * | 1999-02-12 | 2005-01-11 | Cephalon, Inc. | Cyclic substituted fused pyrrolocarbazoles and isoindolones |
US6492406B1 (en) | 1999-05-21 | 2002-12-10 | Astrazeneca Ab | Pharmaceutically active compounds |
US6284783B1 (en) | 1999-06-09 | 2001-09-04 | The Uab Research Foundation | Use of bisindolylmaleimide compounds to induce Fas-mediated apoptosis |
US6346625B1 (en) | 1999-06-23 | 2002-02-12 | Astrazeneca Ab | Protein kinase inhibitors |
US6642228B1 (en) | 1999-06-24 | 2003-11-04 | Toray Industries, Inc. | α1b-adrenergic receptor antagonists |
US6399780B1 (en) | 1999-08-20 | 2002-06-04 | Cephalon, Inc. | Isomeric fused pyrrolocarbazoles and isoindolones |
US6743785B2 (en) | 1999-12-16 | 2004-06-01 | Eli Lilly And Company | Agents and methods for the treatment of proliferative diseases |
ES2220585T3 (es) * | 1999-12-16 | 2004-12-16 | Eli Lilly And Company | Agentes y procedimiento para el tratamiento de enfermedades proliferativas. |
US6867198B2 (en) | 1999-12-16 | 2005-03-15 | Eli Lilly And Company | Agents and methods for the treatment of proliferative diseases |
CZ296087B6 (cs) | 2000-05-11 | 2006-01-11 | Consejo Superior Investigaciones Cientificas | Farmaceutický prostredek pro lécbu nemoci, na nízse podílí heterocyklické inhibitory glykogensyntázakinázy GSK-3 |
ES2166328B1 (es) * | 2000-05-11 | 2003-09-16 | Consejo Superior Investigacion | Inhibidores heterociclicos del enzima gsk 3 utiles en el tratamiento de procesos neurodegenerativos e hiperproliferativos |
WO2002002094A2 (en) * | 2000-06-29 | 2002-01-10 | Eli Lilly And Company | Use of a protein kinase c inhibitor to enhance the clinical efficacy of anti-neoplastic chemotherapeutic agents and radiation therapy |
WO2002002116A2 (en) * | 2000-06-29 | 2002-01-10 | Eli Lilly And Company | Therapeutic treatment of cancer with a protein kinase c inhibitor |
RU2003117078A (ru) | 2000-12-08 | 2004-12-10 | Орто-Макнейл Фармасьютикал, Инк. (Us) | Индазолил-замещенные соединения пирролина в качестве ингибиторов киназы |
EP1513830A1 (en) | 2002-06-05 | 2005-03-16 | Janssen Pharmaceutica N.V. | Bisindolyl-maleimid derivatives as kinase inhibitors |
DE60323749D1 (de) | 2002-06-05 | 2008-11-06 | Janssen Pharmaceutica Nv | Substituierte pyrroline als kinase inhibitoren |
CA2393720C (en) * | 2002-07-12 | 2010-09-14 | Eli Lilly And Company | Crystalline 2,5-dione-3-(1-methyl-1h-indol-3-yl)-4-[1-(pyridin-2-ylmethyl)piperidin-4-yl]-1h-indol-3-yl]-1h-pyrrole mono-hydrochloride |
DE10244453A1 (de) | 2002-09-24 | 2004-04-01 | Phenomiques Gmbh | Hemmung der Proteinkinase C-alpha zur Behandlung von Krankheiten |
WO2005041953A1 (en) * | 2003-10-24 | 2005-05-12 | Eli Lilly And Company | Bisindolyl maleimides useful for treating prostate cancer and akt-mediated diseases |
US20080182801A1 (en) | 2003-12-22 | 2008-07-31 | Btg International Limited | Core 2 glcnac-t inhibitors |
GB0329667D0 (en) | 2003-12-22 | 2004-01-28 | King S College London | Core 2 GlcNAc-T inhibitor |
GB0513881D0 (en) | 2005-07-06 | 2005-08-10 | Btg Int Ltd | Core 2 GLCNAC-T Inhibitors III |
EP2277595A3 (en) | 2004-06-24 | 2011-09-28 | Novartis Vaccines and Diagnostics, Inc. | Compounds for immunopotentiation |
AU2006213890B2 (en) | 2005-02-09 | 2011-07-21 | Arqule Inc. | Meleimide derivatives, pharmaceutical compositions and methods for treatment of cancer |
WO2006108270A1 (en) * | 2005-04-11 | 2006-10-19 | Pharmagap Inc. | Inhibitors of protein kinases and uses thereof |
GB0513888D0 (en) | 2005-07-06 | 2005-08-10 | Btg Int Ltd | Core 2 GLCNAC-T Inhibitors II |
KR20080023732A (ko) * | 2005-07-11 | 2008-03-14 | 노파르티스 아게 | 인돌릴말레이미드 유도체 |
JO2660B1 (en) | 2006-01-20 | 2012-06-17 | نوفارتيس ايه جي | Pi-3 inhibitors and methods of use |
GB0605691D0 (en) * | 2006-03-21 | 2006-05-03 | Novartis Ag | Organic Compounds |
AR060358A1 (es) | 2006-04-06 | 2008-06-11 | Novartis Vaccines & Diagnostic | Quinazolinas para la inhibicion de pdk 1 |
US8304425B2 (en) | 2007-06-22 | 2012-11-06 | Arqule, Inc. | Pyrrolidinone, pyrrolidine-2,5-dione, pyrrolidine and thiosuccinimide derivatives, compositions and methods for treatment of cancer |
WO2009002808A2 (en) | 2007-06-22 | 2008-12-31 | Arqule, Inc. | Quinazolinone compounds and methods of use thereof |
EP2173748B1 (en) | 2007-06-22 | 2011-08-31 | ArQule, Inc. | Indolyl pyrrolidines for the treatment of cancer |
AR069798A1 (es) | 2007-12-20 | 2010-02-17 | Novartis Ag | Derivados de 1, 3-tiazol, metodos para su preparacion, composiciones farmaceuticas que los comprenden y su uso en la manufactura de medicamentos para el tratamiento de enfermedades mediadas por la fosfatidilinositol 3-cinasa. |
WO2010019225A1 (en) * | 2008-08-15 | 2010-02-18 | Robert Shorr | Pharmaceutical composition |
WO2010074936A2 (en) | 2008-12-15 | 2010-07-01 | Eli Lilly And Company | Enzastaurin for the treatment of cancer |
US8293753B2 (en) | 2009-07-02 | 2012-10-23 | Novartis Ag | Substituted 2-carboxamide cycloamino ureas |
BR112012024585A2 (pt) | 2010-03-30 | 2016-05-31 | Novartis Ag | inibidores de pkc para o tratamento de linfomade células b tendo sinalização do receptor de células b ativas crônicas |
AR082418A1 (es) | 2010-08-02 | 2012-12-05 | Novartis Ag | Formas cristalinas de 1-(4-metil-5-[2-(2,2,2-trifluoro-1,1-dimetil-etil)-piridin-4-il]-tiazol-2-il)-amida de 2-amida del acido (s)-pirrolidin-1,2-dicarboxilico |
WO2012104776A1 (en) | 2011-01-31 | 2012-08-09 | Novartis Ag | Novel heterocyclic derivatives |
EP2567959B1 (en) | 2011-09-12 | 2014-04-16 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
US8846712B2 (en) | 2011-09-12 | 2014-09-30 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
EA023935B1 (ru) | 2011-10-28 | 2016-07-29 | Новартис Аг | Производные пурина и их применение для лечения заболевания |
LT2825542T (lt) | 2012-03-16 | 2016-12-27 | Vitae Pharmaceuticals, Inc. | Kepenų x receptoriaus moduliatoriai |
US9006244B2 (en) | 2012-03-16 | 2015-04-14 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
EP2847191B1 (en) | 2012-05-09 | 2016-06-15 | Sanofi | Substituted 6-(4-hydroxy-phenyl)-1h-pyrazolo[3,4-b]pyridine derivatives as kinase inhibitors |
SG11201406550QA (en) | 2012-05-16 | 2014-11-27 | Novartis Ag | Dosage regimen for a pi-3 kinase inhibitor |
BR112015012497B1 (pt) | 2012-11-29 | 2022-05-17 | Novartis Ag | Combinações e composições farmacêuticas, seus usos, preparação combinada, e embalagem comercial |
WO2014174478A1 (en) | 2013-04-26 | 2014-10-30 | Novartis Ag | Pharmaceutical combinations of a pkc inhibitor and a c-met receptor tyrosine kinase inhibitor |
ES2899167T3 (es) | 2013-12-06 | 2022-03-10 | Novartis Ag | Régimen posológico para un inhibidor de fosfatidilinositol 3-cinasas selectivo para la isoforma alfa |
US20170216286A1 (en) | 2014-01-28 | 2017-08-03 | Mayo Foundation For Medical Education And Research | Killing senescent cells and treating senescence-associated conditions using a src inhibitor and a flavonoid |
JO3589B1 (ar) | 2014-08-06 | 2020-07-05 | Novartis Ag | مثبطات كيناز البروتين c وطرق استخداماتها |
CN104398508B (zh) * | 2014-11-28 | 2017-06-13 | 上海交通大学 | 双吲哚马来酰亚胺衍生物在制备治疗慢性粒细胞白血病药物中的应用 |
EP3370719A1 (en) | 2015-11-02 | 2018-09-12 | Novartis AG | Dosage regimen for a phosphatidylinositol 3-kinase inhibitor |
US10112924B2 (en) | 2015-12-02 | 2018-10-30 | Astraea Therapeutics, Inc. | Piperdinyl nociceptin receptor compounds |
EP3383390A4 (en) * | 2015-12-02 | 2019-11-20 | Astraea Therapeutics, LLC | PIPERIDINYL COMPOUNDS FOR NOCICEPTIN RECEPTOR |
CN106146475B (zh) * | 2016-06-01 | 2019-05-17 | 中国海洋大学 | 双吲哚马来酰亚胺衍生物及其制备方法和用途 |
CN110218206B (zh) * | 2016-06-01 | 2022-03-04 | 中国海洋大学 | 双吲哚马来酰亚胺衍生物及其制备方法和用途 |
JOP20190025A1 (ar) | 2016-09-01 | 2019-02-19 | Denovo Biopharma Llc | طرق وتركيبة لتوقع نشاط إنزاستورين |
WO2018060833A1 (en) | 2016-09-27 | 2018-04-05 | Novartis Ag | Dosage regimen for alpha-isoform selective phosphatidylinositol 3-kinase inhibitor alpelisib |
WO2019000224A1 (zh) * | 2017-06-27 | 2019-01-03 | 中国海洋大学 | 双吲哚马来酰亚胺衍生物及其制备方法和用途 |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4785085A (en) * | 1986-11-21 | 1988-11-15 | Bristol-Myers Company | Rebeccamycin analogs |
US4808613A (en) * | 1986-11-21 | 1989-02-28 | Bristol-Myers Company | Rebeccamycin derivative containing pharmaceutical composition |
US4923986A (en) * | 1987-03-09 | 1990-05-08 | Kyowa Hakko Kogyo Co., Ltd. | Derivatives of physiologically active substance K-252 |
DE3803620A1 (de) * | 1988-02-06 | 1989-08-17 | Goedecke Ag | Indolocarbazol-derivate, verfahren zu deren herstellung und diese enthaltende arzneimittel |
SK75289A3 (en) * | 1988-02-10 | 1998-05-06 | Hoffmann La Roche | Substituted pyrroles, their use for producing a drug, and the drug on their base |
MC2096A1 (fr) | 1989-02-23 | 1991-02-15 | Hoffmann La Roche | Pyrroles substitues |
DE3914764A1 (de) * | 1989-05-05 | 1990-11-08 | Goedecke Ag | Maleinimid-derivate und deren verwendung als arzneimittel |
DE3942991A1 (de) * | 1989-12-27 | 1991-07-04 | Goedecke Ag | Maleinimid-derivate und deren verwendung als arzneimittel |
PT93947B (pt) | 1989-05-05 | 1996-11-29 | Goedecke Ag | Processo para a preparacao de novos derivados de maleinimidas e de composicoes farmaceuticas que os contem |
US5380746A (en) * | 1989-05-05 | 1995-01-10 | Goedecke Aktiengesellschaft | Bis-(1H-indol-3-YL)-maleinimide derivatives, processes for the preparation thereof and pharmaceutical compositions containing them |
DE3942296A1 (de) * | 1989-12-21 | 1991-06-27 | Goedecke Ag | Indolocarbazol-derivate, verfahren zu deren herstellung und deren verwendung |
DE4005970A1 (de) * | 1990-02-26 | 1991-08-29 | Boehringer Mannheim Gmbh | Neue trisubstituierte maleinimide, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten |
DE4005969A1 (de) * | 1990-02-26 | 1991-08-29 | Boehringer Mannheim Gmbh | Neue trisubstituierte pyrrole, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten |
CA2046801C (en) * | 1990-08-07 | 2002-02-26 | Peter D. Davis | Substituted pyrroles |
US5292747A (en) * | 1990-08-07 | 1994-03-08 | Hoffman-La Roche Inc. | Substituted pyrroles |
WO1992016517A1 (en) * | 1991-03-22 | 1992-10-01 | Xenova Limited | Pharmaceutical xanthone derivatives |
GB9123396D0 (en) * | 1991-11-04 | 1991-12-18 | Hoffmann La Roche | A process for the manufacture of substituted maleimides |
EP0630241A1 (en) * | 1992-03-20 | 1994-12-28 | The Wellcome Foundation Limited | Indole derivatives with antiviral activity |
US5461146A (en) * | 1992-07-24 | 1995-10-24 | Cephalon, Inc. | Selected protein kinase inhibitors for the treatment of neurological disorders |
DE4243321A1 (de) * | 1992-12-21 | 1994-06-23 | Goedecke Ag | Aminosäurederivate von Heterocyclen als PKC-Inhibitoren |
AU678435B2 (en) * | 1993-05-10 | 1997-05-29 | F. Hoffmann-La Roche Ag | Substituted pyrroles |
US5481003A (en) * | 1994-06-22 | 1996-01-02 | Eli Lilly And Company | Protein kinase C inhibitors |
-
1994
- 1994-12-14 EP EP95904892A patent/EP0817627B1/en not_active Expired - Lifetime
- 1994-12-14 AT AT95904892T patent/ATE290378T1/de active
- 1994-12-14 DK DK95904892T patent/DK0817627T3/da active
- 1994-12-14 DE DE69434294T patent/DE69434294T2/de not_active Expired - Lifetime
- 1994-12-14 ES ES95904892T patent/ES2236702T3/es not_active Expired - Lifetime
- 1994-12-14 SI SI9430475T patent/SI0817627T1/xx unknown
- 1994-12-14 EP EP04102054A patent/EP1449529B1/en not_active Expired - Lifetime
- 1994-12-14 CA CA002179650A patent/CA2179650C/en not_active Expired - Lifetime
- 1994-12-14 AU AU13398/95A patent/AU1339895A/en not_active Abandoned
- 1994-12-14 AT AT04102054T patent/ATE456367T1/de not_active IP Right Cessation
- 1994-12-14 JP JP51747995A patent/JP3998261B2/ja not_active Expired - Lifetime
- 1994-12-14 WO PCT/US1994/014313 patent/WO1995017182A1/en active IP Right Grant
- 1994-12-14 PT PT95904892T patent/PT817627E/pt unknown
-
1995
- 1995-05-25 US US08/450,320 patent/US5661173A/en not_active Expired - Lifetime
- 1995-05-25 US US08/452,617 patent/US5668152A/en not_active Expired - Lifetime
- 1995-05-25 US US08/452,606 patent/US5672618A/en not_active Expired - Lifetime
-
1998
- 1998-07-14 HK HK98109161A patent/HK1008183A1/xx not_active IP Right Cessation
-
2005
- 2005-05-09 JP JP2005135900A patent/JP4369397B2/ja not_active Expired - Lifetime
- 2005-05-09 JP JP2005135896A patent/JP4365803B2/ja not_active Expired - Lifetime
-
2006
- 2006-07-20 JP JP2006198260A patent/JP4490400B2/ja not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
DK0817627T3 (da) | 2005-06-06 |
ATE290378T1 (de) | 2005-03-15 |
JP4490400B2 (ja) | 2010-06-23 |
JP2005225896A (ja) | 2005-08-25 |
EP0817627A1 (en) | 1998-01-14 |
EP0817627B1 (en) | 2005-03-09 |
ATE456367T1 (de) | 2010-02-15 |
US5661173A (en) | 1997-08-26 |
JPH09507066A (ja) | 1997-07-15 |
SI0817627T1 (ja) | 2005-08-31 |
JP4365803B2 (ja) | 2009-11-18 |
US5672618A (en) | 1997-09-30 |
EP1449529A1 (en) | 2004-08-25 |
DE69434294D1 (de) | 2005-04-14 |
EP1449529B1 (en) | 2010-01-27 |
JP2006316068A (ja) | 2006-11-24 |
CA2179650A1 (en) | 1995-06-29 |
US5668152A (en) | 1997-09-16 |
JP3998261B2 (ja) | 2007-10-24 |
CA2179650C (en) | 2007-10-30 |
PT817627E (pt) | 2005-07-29 |
DE69434294T2 (de) | 2005-12-29 |
WO1995017182A1 (en) | 1995-06-29 |
ES2236702T3 (es) | 2005-07-16 |
HK1008183A1 (en) | 1999-05-07 |
EP0817627A4 (en) | 2002-07-17 |
AU1339895A (en) | 1995-07-10 |
JP2005225895A (ja) | 2005-08-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4365803B2 (ja) | プロテインキナーゼc阻害剤 | |
US5545636A (en) | Protein kinase C inhibitors | |
US5491242A (en) | Protein kinase C inhibitors | |
EP1487822B1 (en) | Pyrrole-2,5-dione derivatives and their use as gsk-3 inhibitors | |
US5629430A (en) | Trifluoromethylpyrroloindolecarboxylic acid ester and process for production thereof | |
PL182124B1 (pl) | Nowe zwiazki oraz srodek farmaceutyczny przeznaczony do leczenia powiklan cukrzycowych lub do leczenia nowotworów PL PL PL PL PL PL PL PL | |
KR19990007863A (ko) | 혈소판 활성 인자 길항제로서의 인돌-3-카보닐 및 인돌-3-설포닐 유도체 | |
JP3235840B2 (ja) | プロテインキナーゼcのハロ置換阻害剤 | |
US5481003A (en) | Protein kinase C inhibitors | |
KR20100044816A (ko) | Parp-1 억제제로서의 프탈라지논 유도체 | |
CA2488798A1 (en) | Substituted pyrrolines as kinase inhibitors | |
WO2022159980A1 (en) | Pharmaceutical compounds and methods of making and using the same | |
CA2193703C (en) | Protein kinase c inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20090127 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20090427 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20090501 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090519 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20090811 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20090827 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120904 Year of fee payment: 3 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130904 Year of fee payment: 4 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
EXPY | Cancellation because of completion of term |