JP2012509903A - Mlk阻害剤および使用方法 - Google Patents
Mlk阻害剤および使用方法 Download PDFInfo
- Publication number
- JP2012509903A JP2012509903A JP2011537733A JP2011537733A JP2012509903A JP 2012509903 A JP2012509903 A JP 2012509903A JP 2011537733 A JP2011537733 A JP 2011537733A JP 2011537733 A JP2011537733 A JP 2011537733A JP 2012509903 A JP2012509903 A JP 2012509903A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- optionally substituted
- phenyl
- mmol
- pyrrolo
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 77
- 239000003112 inhibitor Substances 0.000 title claims description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 318
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 70
- 239000003814 drug Substances 0.000 claims abstract description 65
- 201000010099 disease Diseases 0.000 claims abstract description 47
- 238000011282 treatment Methods 0.000 claims abstract description 37
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 26
- 230000005764 inhibitory process Effects 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 5
- -1 C 1 -C 3 alkoxy Chemical group 0.000 claims description 116
- 125000000217 alkyl group Chemical group 0.000 claims description 49
- 125000001072 heteroaryl group Chemical group 0.000 claims description 45
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 44
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 43
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 36
- 102100025207 Mitogen-activated protein kinase kinase kinase 11 Human genes 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 102100025184 Mitogen-activated protein kinase kinase kinase 13 Human genes 0.000 claims description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
- 230000000694 effects Effects 0.000 claims description 29
- 210000004027 cell Anatomy 0.000 claims description 27
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 125000004429 atom Chemical group 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 125000002619 bicyclic group Chemical group 0.000 claims description 17
- 208000035475 disorder Diseases 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- SCMLRESZJCKCTC-KMYQRJGFSA-N gtpl8173 Chemical group C12=CC=C(CSCC)C=C2C2=C(CNC3=O)C3=C3C4=CC(CSCC)=CC=C4N4C3=C2N1[C@]1(C)[C@@](O)(C(=O)OC)C[C@H]4O1 SCMLRESZJCKCTC-KMYQRJGFSA-N 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 230000001404 mediated effect Effects 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 239000011737 fluorine Substances 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims description 12
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims description 12
- 230000001629 suppression Effects 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 206010061218 Inflammation Diseases 0.000 claims description 11
- 150000001408 amides Chemical class 0.000 claims description 11
- 230000006378 damage Effects 0.000 claims description 11
- 230000004054 inflammatory process Effects 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 230000004083 survival effect Effects 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 230000006870 function Effects 0.000 claims description 9
- 210000002865 immune cell Anatomy 0.000 claims description 9
- 230000002093 peripheral effect Effects 0.000 claims description 9
- 230000035755 proliferation Effects 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 230000004766 neurogenesis Effects 0.000 claims description 8
- 125000004450 alkenylene group Chemical group 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 7
- 201000001119 neuropathy Diseases 0.000 claims description 7
- 230000007823 neuropathy Effects 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 208000024827 Alzheimer disease Diseases 0.000 claims description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims description 6
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 6
- 206010011878 Deafness Diseases 0.000 claims description 6
- 206010020772 Hypertension Diseases 0.000 claims description 6
- 201000001431 Hyperuricemia Diseases 0.000 claims description 6
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 230000010370 hearing loss Effects 0.000 claims description 6
- 231100000888 hearing loss Toxicity 0.000 claims description 6
- 208000016354 hearing loss disease Diseases 0.000 claims description 6
- 210000003494 hepatocyte Anatomy 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 210000000274 microglia Anatomy 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 210000000653 nervous system Anatomy 0.000 claims description 6
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 6
- 208000020016 psychiatric disease Diseases 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 6
- 208000008960 Diabetic foot Diseases 0.000 claims description 5
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 5
- 201000005569 Gout Diseases 0.000 claims description 5
- 206010022489 Insulin Resistance Diseases 0.000 claims description 5
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 5
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 5
- 208000028389 Nerve injury Diseases 0.000 claims description 5
- 208000012902 Nervous system disease Diseases 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 5
- 206010030113 Oedema Diseases 0.000 claims description 5
- 208000017442 Retinal disease Diseases 0.000 claims description 5
- 206010038923 Retinopathy Diseases 0.000 claims description 5
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 5
- 208000025865 Ulcer Diseases 0.000 claims description 5
- 208000027418 Wounds and injury Diseases 0.000 claims description 5
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 5
- 230000006735 deficit Effects 0.000 claims description 5
- 210000002064 heart cell Anatomy 0.000 claims description 5
- 201000001421 hyperglycemia Diseases 0.000 claims description 5
- 230000006872 improvement Effects 0.000 claims description 5
- 208000014674 injury Diseases 0.000 claims description 5
- 210000002540 macrophage Anatomy 0.000 claims description 5
- 210000001616 monocyte Anatomy 0.000 claims description 5
- 210000005036 nerve Anatomy 0.000 claims description 5
- 230000008764 nerve damage Effects 0.000 claims description 5
- 230000003959 neuroinflammation Effects 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 208000028173 post-traumatic stress disease Diseases 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- 230000002207 retinal effect Effects 0.000 claims description 5
- 210000000225 synapse Anatomy 0.000 claims description 5
- 230000009529 traumatic brain injury Effects 0.000 claims description 5
- 231100000397 ulcer Toxicity 0.000 claims description 5
- 230000001720 vestibular Effects 0.000 claims description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- 230000001154 acute effect Effects 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 208000006454 hepatitis Diseases 0.000 claims description 4
- 231100000283 hepatitis Toxicity 0.000 claims description 4
- 230000003451 hyperinsulinaemic effect Effects 0.000 claims description 4
- 201000008980 hyperinsulinism Diseases 0.000 claims description 4
- 208000017169 kidney disease Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 208000030159 metabolic disease Diseases 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 208000020925 Bipolar disease Diseases 0.000 claims description 3
- 206010011903 Deafness traumatic Diseases 0.000 claims description 3
- 208000002946 Noise-Induced Hearing Loss Diseases 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- 210000003027 ear inner Anatomy 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 claims description 3
- 231100000331 toxic Toxicity 0.000 claims description 3
- 230000002588 toxic effect Effects 0.000 claims description 3
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 2
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 claims description 2
- 208000025966 Neurological disease Diseases 0.000 claims description 2
- 108091000080 Phosphotransferase Proteins 0.000 claims description 2
- 208000016097 disease of metabolism Diseases 0.000 claims description 2
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 2
- 102000020233 phosphotransferase Human genes 0.000 claims description 2
- 229940124530 sulfonamide Drugs 0.000 claims description 2
- 150000003456 sulfonamides Chemical class 0.000 claims description 2
- 230000000007 visual effect Effects 0.000 claims description 2
- 101001005602 Homo sapiens Mitogen-activated protein kinase kinase kinase 11 Proteins 0.000 claims 4
- 230000001737 promoting effect Effects 0.000 claims 4
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims 1
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 1
- 238000011084 recovery Methods 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 54
- 108090001035 mitogen-activated protein kinase kinase kinase 12 Proteins 0.000 abstract description 23
- 102100025180 Mitogen-activated protein kinase kinase kinase 12 Human genes 0.000 abstract 3
- 239000000203 mixture Substances 0.000 description 114
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 94
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 83
- 238000002360 preparation method Methods 0.000 description 54
- 238000004128 high performance liquid chromatography Methods 0.000 description 50
- 235000019439 ethyl acetate Nutrition 0.000 description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 238000005481 NMR spectroscopy Methods 0.000 description 43
- 230000014759 maintenance of location Effects 0.000 description 43
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 38
- 238000010898 silica gel chromatography Methods 0.000 description 35
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 34
- 239000012044 organic layer Substances 0.000 description 34
- 229940079593 drug Drugs 0.000 description 33
- 238000009472 formulation Methods 0.000 description 33
- 239000000243 solution Substances 0.000 description 33
- 239000000651 prodrug Substances 0.000 description 31
- 229940002612 prodrug Drugs 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 108010041596 mitogen-activated protein kinase kinase kinase 11 Proteins 0.000 description 30
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 28
- 239000011734 sodium Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- HXITXNWTGFUOAU-UHFFFAOYSA-N dihydroxy-phenylborane Natural products OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 18
- RULQUTYJXDLRFL-UHFFFAOYSA-N (3,4,5-trimethoxyphenyl)boronic acid Chemical compound COC1=CC(B(O)O)=CC(OC)=C1OC RULQUTYJXDLRFL-UHFFFAOYSA-N 0.000 description 16
- 238000002953 preparative HPLC Methods 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 241000725303 Human immunodeficiency virus Species 0.000 description 14
- 239000004480 active ingredient Substances 0.000 description 14
- 125000005842 heteroatom Chemical group 0.000 description 14
- 239000000843 powder Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 238000013268 sustained release Methods 0.000 description 14
- 239000012730 sustained-release form Substances 0.000 description 14
- 230000001225 therapeutic effect Effects 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 229910052717 sulfur Inorganic materials 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- 125000000623 heterocyclic group Chemical group 0.000 description 11
- 238000002347 injection Methods 0.000 description 11
- 239000007924 injection Substances 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 210000004556 brain Anatomy 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 238000001990 intravenous administration Methods 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 206010012289 Dementia Diseases 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 6
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000013270 controlled release Methods 0.000 description 6
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 210000002569 neuron Anatomy 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 5
- 108010025020 Nerve Growth Factor Proteins 0.000 description 5
- 102000007072 Nerve Growth Factors Human genes 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- YWLUQJOZTNNPPH-UHFFFAOYSA-N 3-(1-methylindol-5-yl)-5-(3,4,5-trimethoxyphenyl)-1h-imidazo[4,5-b]pyrazin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2N=C3N(C=4C=C5C=CN(C)C5=CC=4)C(=O)NC3=NC=2)=C1 YWLUQJOZTNNPPH-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 230000008499 blood brain barrier function Effects 0.000 description 4
- 210000001218 blood-brain barrier Anatomy 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 230000003111 delayed effect Effects 0.000 description 4
- 238000000105 evaporative light scattering detection Methods 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 4
- 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 4
- 238000007918 intramuscular administration Methods 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 230000000324 neuroprotective effect Effects 0.000 description 4
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 4
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 125000004149 thio group Chemical group *S* 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- FVEOJPCOQYXPSY-UHFFFAOYSA-N 1-[4-[3-(1h-indol-5-yl)-1h-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-n,n-dimethylmethanamine Chemical compound C1=CC(CN(C)C)=CC=C1C1=CN=C(NC=C2C=3C=C4C=CNC4=CC=3)C2=C1 FVEOJPCOQYXPSY-UHFFFAOYSA-N 0.000 description 3
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-UHFFFAOYSA-N 0.000 description 3
- ZCBIFHNDZBSCEP-UHFFFAOYSA-N 1H-indol-5-amine Chemical compound NC1=CC=C2NC=CC2=C1 ZCBIFHNDZBSCEP-UHFFFAOYSA-N 0.000 description 3
- XPNPPOQHYUISHS-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-7-(1h-indol-5-yl)-5h-pyrrolo[2,3-b]pyrazine Chemical compound C1=C(OC)C(OC)=CC=C1C1=CN=C(NC=C2C=3C=C4C=CNC4=CC=3)C2=N1 XPNPPOQHYUISHS-UHFFFAOYSA-N 0.000 description 3
- MUMJRQNVMWXASS-UHFFFAOYSA-N 3,3,5-tribromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-2-one Chemical compound BrC1=CN=C2N(COCC[Si](C)(C)C)C(=O)C(Br)(Br)C2=C1 MUMJRQNVMWXASS-UHFFFAOYSA-N 0.000 description 3
- DTLBKXRFWUERQN-UHFFFAOYSA-N 3,5-dibromopyrazin-2-amine Chemical compound NC1=NC=C(Br)N=C1Br DTLBKXRFWUERQN-UHFFFAOYSA-N 0.000 description 3
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 3
- VQIIIUZXKBIBAJ-UHFFFAOYSA-N 3-(cyclopropylmethyl)-5-(3,4,5-trimethoxyphenyl)-1h-imidazo[4,5-b]pyrazine-2-thione Chemical compound COC1=C(OC)C(OC)=CC(C=2N=C3N(CC4CC4)C(=S)NC3=NC=2)=C1 VQIIIUZXKBIBAJ-UHFFFAOYSA-N 0.000 description 3
- RPXBKGNKBJMYOG-UHFFFAOYSA-N 5-(3,4,5-trimethoxyphenyl)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3CC(=O)NC3=NC=2)=C1 RPXBKGNKBJMYOG-UHFFFAOYSA-N 0.000 description 3
- GQPZZEHVDIALIE-UHFFFAOYSA-N 5-(3,5-dimethylphenyl)-3-(1-methylindol-5-yl)-1h-imidazo[4,5-b]pyrazin-2-one Chemical compound CC1=CC(C)=CC(C=2N=C3N(C=4C=C5C=CN(C)C5=CC=4)C(=O)NC3=NC=2)=C1 GQPZZEHVDIALIE-UHFFFAOYSA-N 0.000 description 3
- DBDKPUREOHXHQA-UHFFFAOYSA-N 5-(3,5-dimethylphenyl)-3-(1h-indol-5-yl)-1h-imidazo[4,5-b]pyrazin-2-one Chemical compound CC1=CC(C)=CC(C=2N=C3N(C=4C=C5C=CNC5=CC=4)C(=O)NC3=NC=2)=C1 DBDKPUREOHXHQA-UHFFFAOYSA-N 0.000 description 3
- BSQNVHKKUPVJOP-UHFFFAOYSA-N 5-(4-hydroxyphenyl)-3-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2-one Chemical compound C1=CC(O)=CC=C1C1=CN=C(NC(=O)N2C=3C=C4C=CNC4=CC=3)C2=N1 BSQNVHKKUPVJOP-UHFFFAOYSA-N 0.000 description 3
- CPRJNAUANBWOEN-UHFFFAOYSA-N 5-bromo-1-(2-trimethylsilylethoxymethyl)-3h-pyrrolo[2,3-b]pyridin-2-one Chemical compound BrC1=CN=C2N(COCC[Si](C)(C)C)C(=O)CC2=C1 CPRJNAUANBWOEN-UHFFFAOYSA-N 0.000 description 3
- SKIWCHGADZGKSB-UHFFFAOYSA-N 5-bromo-3-(1h-indol-5-yl)-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=C(Br)C=C2C(C=2C=C3C=CNC3=CC=2)=C1 SKIWCHGADZGKSB-UHFFFAOYSA-N 0.000 description 3
- RNPRNNYUHMYADJ-UHFFFAOYSA-N 5-bromo-3-iodo-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=C(Br)C=C2C(I)=C1 RNPRNNYUHMYADJ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 208000030507 AIDS Diseases 0.000 description 3
- 206010065040 AIDS dementia complex Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 3
- 102000001253 Protein Kinase Human genes 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 125000004423 acyloxy group Chemical group 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000004419 alkynylene group Chemical group 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 229910052796 boron Inorganic materials 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 125000001589 carboacyl group Chemical group 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 206010014599 encephalitis Diseases 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 125000004438 haloalkoxy group Chemical group 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 3
- 229920001223 polyethylene glycol Polymers 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
- 235000011056 potassium acetate Nutrition 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 108060006633 protein kinase Proteins 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 238000007910 systemic administration Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- 238000011200 topical administration Methods 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
- 230000037317 transdermal delivery Effects 0.000 description 3
- DJGHSJBYKIQHIK-UHFFFAOYSA-N (3,5-dimethylphenyl)boronic acid Chemical compound CC1=CC(C)=CC(B(O)O)=C1 DJGHSJBYKIQHIK-UHFFFAOYSA-N 0.000 description 2
- FQWUBDDFDBNOPL-IUXPMGMMSA-N (3z)-3-(pyridin-4-ylmethylidene)-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(=C/C=4C=CN=CC=4)/C(=O)NC3=NC=2)=C1 FQWUBDDFDBNOPL-IUXPMGMMSA-N 0.000 description 2
- COIQUVGFTILYGA-UHFFFAOYSA-N (4-hydroxyphenyl)boronic acid Chemical compound OB(O)C1=CC=C(O)C=C1 COIQUVGFTILYGA-UHFFFAOYSA-N 0.000 description 2
- CGKLYWOFLUIKCX-UHFFFAOYSA-N 1,3-dihydroimidazo[4,5-b]pyrazin-2-one Chemical class C1=CN=C2NC(=O)NC2=N1 CGKLYWOFLUIKCX-UHFFFAOYSA-N 0.000 description 2
- IYZNLFXYLPTBST-UHFFFAOYSA-N 1-(1h-indol-5-yl)-6-(3,4,5-trimethoxyphenyl)-3h-imidazo[4,5-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3N(C=4C=C5C=CNC5=CC=4)C(=O)NC3=NC=2)=C1 IYZNLFXYLPTBST-UHFFFAOYSA-N 0.000 description 2
- ZUWGSRAZBKRISU-UHFFFAOYSA-N 1-[4-[4-[3-(1h-indol-5-yl)-1h-pyrrolo[2,3-b]pyridin-5-yl]benzoyl]piperazin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCN1C(=O)C1=CC=C(C=2C=C3C(C=4C=C5C=CNC5=CC=4)=CNC3=NC=2)C=C1 ZUWGSRAZBKRISU-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- PGTSGPCXPIFQEL-UHFFFAOYSA-N 1-methylindol-5-amine Chemical compound NC1=CC=C2N(C)C=CC2=C1 PGTSGPCXPIFQEL-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- VHADYSUJZAPXOW-UHFFFAOYSA-N 1h-indol-5-ylboronic acid Chemical compound OB(O)C1=CC=C2NC=CC2=C1 VHADYSUJZAPXOW-UHFFFAOYSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- KVZBCDAJVSPXSP-UHFFFAOYSA-N 2-bromo-7-(1h-indol-5-yl)-5-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyrazine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=C(Br)N=C2C(C=2C=C3C=CNC3=CC=2)=C1 KVZBCDAJVSPXSP-UHFFFAOYSA-N 0.000 description 2
- QONWBLJGJMTBKI-UHFFFAOYSA-N 2-bromo-7-iodo-5-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyrazine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=C(Br)N=C2C(I)=C1 QONWBLJGJMTBKI-UHFFFAOYSA-N 0.000 description 2
- JIZQQDVOJUWOEI-UHFFFAOYSA-N 3,3-dimethyl-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(C)(C)C(=O)NC3=NC=2)=C1 JIZQQDVOJUWOEI-UHFFFAOYSA-N 0.000 description 2
- NMMATNQHSAAIGY-UHFFFAOYSA-N 3-(1h-indol-5-yl)-5-(3,4,5-trimethoxyphenyl)-1h-imidazo[4,5-b]pyrazin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2N=C3N(C=4C=C5C=CNC5=CC=4)C(=O)NC3=NC=2)=C1 NMMATNQHSAAIGY-UHFFFAOYSA-N 0.000 description 2
- OFDLUROFHFYRIA-UHFFFAOYSA-N 3-(1h-indol-5-yl)-5-(3,4,5-trimethoxyphenyl)imidazo[4,5-b]pyrazine Chemical compound COC1=C(OC)C(OC)=CC(C=2N=C3N(C=4C=C5C=CNC5=CC=4)C=NC3=NC=2)=C1 OFDLUROFHFYRIA-UHFFFAOYSA-N 0.000 description 2
- QKKIWEILHCXECO-UHFFFAOYSA-N 3-(1h-indol-5-yl)-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1h-pyrrolo[2,3-b]pyridine Chemical compound C1CN(C)CCN1CC1=CC=C(C=2C=C3C(C=4C=C5C=CNC5=CC=4)=CNC3=NC=2)C=C1 QKKIWEILHCXECO-UHFFFAOYSA-N 0.000 description 2
- CSDCPKXPWNJTLY-UHFFFAOYSA-N 3-[[2-oxo-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-3-ylidene]methyl]benzonitrile Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(=CC=4C=C(C=CC=4)C#N)C(=O)NC3=NC=2)=C1 CSDCPKXPWNJTLY-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- AJUHCVAZMDGWQB-UHFFFAOYSA-N 4-[5-[3-(4-acetylpiperazine-1-carbonyl)phenyl]-1h-pyrrolo[2,3-b]pyridin-3-yl]benzamide Chemical compound C1CN(C(=O)C)CCN1C(=O)C1=CC=CC(C=2C=C3C(C=4C=CC(=CC=4)C(N)=O)=CNC3=NC=2)=C1 AJUHCVAZMDGWQB-UHFFFAOYSA-N 0.000 description 2
- PRGMHVZMKYMIJG-UHFFFAOYSA-N 4-[5-[3-(piperazine-1-carbonyl)phenyl]-1h-pyrrolo[2,3-b]pyridin-3-yl]benzamide Chemical compound C1=CC(C(=O)N)=CC=C1C1=CNC2=NC=C(C=3C=C(C=CC=3)C(=O)N3CCNCC3)C=C12 PRGMHVZMKYMIJG-UHFFFAOYSA-N 0.000 description 2
- NDQATEXYJSNSRD-UHFFFAOYSA-N 4-[5-[3-[(4-methylpiperazin-1-yl)methyl]phenyl]-1h-pyrrolo[2,3-b]pyridin-3-yl]benzamide Chemical compound C1CN(C)CCN1CC1=CC=CC(C=2C=C3C(C=4C=CC(=CC=4)C(N)=O)=CNC3=NC=2)=C1 NDQATEXYJSNSRD-UHFFFAOYSA-N 0.000 description 2
- YAEZGCXSMFMCKO-UHFFFAOYSA-N 4-[5-[4-[(4-acetylpiperazin-1-yl)methyl]phenyl]-1h-pyrrolo[2,3-b]pyridin-3-yl]benzamide Chemical compound C1CN(C(=O)C)CCN1CC1=CC=C(C=2C=C3C(C=4C=CC(=CC=4)C(N)=O)=CNC3=NC=2)C=C1 YAEZGCXSMFMCKO-UHFFFAOYSA-N 0.000 description 2
- RRUKYRBIYOLONU-UHFFFAOYSA-N 4-[5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1h-pyrrolo[2,3-b]pyridin-3-yl]benzamide Chemical compound C1CN(C)CCN1CC1=CC=C(C=2C=C3C(C=4C=CC(=CC=4)C(N)=O)=CNC3=NC=2)C=C1 RRUKYRBIYOLONU-UHFFFAOYSA-N 0.000 description 2
- VUISIWLXFTZVKU-UHFFFAOYSA-N 4-[[2-oxo-5-(3,4,5-trimethoxyphenyl)-1,3-dihydropyrrolo[2,3-b]pyridin-3-yl]methyl]benzamide Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(CC=4C=CC(=CC=4)C(N)=O)C(=O)NC3=NC=2)=C1 VUISIWLXFTZVKU-UHFFFAOYSA-N 0.000 description 2
- NQUBJOHNOXIWBP-UHFFFAOYSA-N 4-[[4-[3-(1h-indol-5-yl)-1h-pyrrolo[2,3-b]pyridin-5-yl]phenyl]methyl]-1-methylpiperazin-2-one Chemical compound C1C(=O)N(C)CCN1CC1=CC=C(C=2C=C3C(C=4C=C5C=CNC5=CC=4)=CNC3=NC=2)C=C1 NQUBJOHNOXIWBP-UHFFFAOYSA-N 0.000 description 2
- WZWIQYMTQZCSKI-UHFFFAOYSA-N 4-cyanobenzaldehyde Chemical compound O=CC1=CC=C(C#N)C=C1 WZWIQYMTQZCSKI-UHFFFAOYSA-N 0.000 description 2
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 2
- QGRWEFHVAHCGQH-UHFFFAOYSA-N 5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridine Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C=CNC3=NC=2)=C1 QGRWEFHVAHCGQH-UHFFFAOYSA-N 0.000 description 2
- NAVNICSNKNRXON-UHFFFAOYSA-N 5-(3,4,5-trimethoxyphenyl)spiro[1h-pyrrolo[2,3-b]pyridine-3,1'-cyclopentane]-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C4(CCCC4)C(=O)NC3=NC=2)=C1 NAVNICSNKNRXON-UHFFFAOYSA-N 0.000 description 2
- ZUMBBARLJHSZAM-UHFFFAOYSA-N 5-(4-hydroxyphenyl)-3-(1-methylindol-5-yl)-1H-imidazo[4,5-b]pyrazin-2-one Chemical compound C=1C=C2N(C)C=CC2=CC=1N(C(NC1=NC=2)=O)C1=NC=2C1=CC=C(O)C=C1 ZUMBBARLJHSZAM-UHFFFAOYSA-N 0.000 description 2
- QITXIHCDCBZEMF-UHFFFAOYSA-N 5-bromo-3-(1-methylindol-5-yl)-1h-imidazo[4,5-b]pyrazin-2-one Chemical compound C12=NC(Br)=CN=C2NC(=O)N1C1=CC=C2N(C)C=CC2=C1 QITXIHCDCBZEMF-UHFFFAOYSA-N 0.000 description 2
- SQZXFMCDIDWEGL-UHFFFAOYSA-N 5-bromo-3-(1h-indol-5-yl)-1h-imidazo[4,5-b]pyrazin-2-one Chemical compound C1=C2NC=CC2=CC(N2C(=O)NC3=NC=C(N=C32)Br)=C1 SQZXFMCDIDWEGL-UHFFFAOYSA-N 0.000 description 2
- CZWFHBMRVMLUGV-UHFFFAOYSA-N 7-(1h-indol-5-yl)-2-(3,4,5-trimethoxyphenyl)-5h-pyrrolo[2,3-b]pyrazine Chemical compound COC1=C(OC)C(OC)=CC(C=2N=C3C(C=4C=C5C=CNC5=CC=4)=CNC3=NC=2)=C1 CZWFHBMRVMLUGV-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 208000002249 Diabetes Complications Diseases 0.000 description 2
- 206010012655 Diabetic complications Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 102100039289 Glial fibrillary acidic protein Human genes 0.000 description 2
- 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 description 2
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 208000031886 HIV Infections Diseases 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101001092197 Homo sapiens RNA binding protein fox-1 homolog 3 Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 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 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 102100023174 Methionine aminopeptidase 2 Human genes 0.000 description 2
- 108090000192 Methionyl aminopeptidases Proteins 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 2
- 102000007339 Nerve Growth Factor Receptors Human genes 0.000 description 2
- 108010032605 Nerve Growth Factor Receptors Proteins 0.000 description 2
- 208000027089 Parkinsonian disease Diseases 0.000 description 2
- 206010034010 Parkinsonism Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 108700023400 Platelet-activating factor receptors Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 102100035530 RNA binding protein fox-1 homolog 3 Human genes 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 241000534944 Thia Species 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 125000005011 alkyl ether group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000005012 alkyl thioether group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000003435 aroyl group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 230000035578 autophosphorylation Effects 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 2
- 230000009702 cancer cell proliferation Effects 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 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 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000006003 dichloroethyl group Chemical group 0.000 description 2
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 2
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 2
- 125000006001 difluoroethyl group Chemical group 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 125000004982 dihaloalkyl group Chemical group 0.000 description 2
- 208000037765 diseases and disorders Diseases 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 208000024714 major depressive disease Diseases 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
- 239000011159 matrix material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 125000006682 monohaloalkyl group Chemical group 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- BJLLVMRHGCCXOV-UHFFFAOYSA-N n-[5-bromo-3-(2-trimethylsilylethynyl)pyrazin-2-yl]acetamide Chemical compound CC(=O)NC1=NC=C(Br)N=C1C#C[Si](C)(C)C BJLLVMRHGCCXOV-UHFFFAOYSA-N 0.000 description 2
- KUCQMLFHLSDMKS-UHFFFAOYSA-N n-methyl-4-[5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1h-pyrrolo[2,3-b]pyridin-3-yl]benzamide Chemical compound C1=CC(C(=O)NC)=CC=C1C1=CNC2=NC=C(C=3C=CC(CN4CCN(C)CC4)=CC=3)C=C12 KUCQMLFHLSDMKS-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 230000004112 neuroprotection Effects 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003791 organic solvent mixture Substances 0.000 description 2
- 231100000199 ototoxic Toxicity 0.000 description 2
- 230000002970 ototoxic effect Effects 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 102000030769 platelet activating factor receptor Human genes 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 125000006684 polyhaloalkyl group Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000000946 synaptic effect Effects 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- TXWQPIPDZDRBOV-UHFFFAOYSA-N tert-butyl 4-[3-[3-(4-carbamoylphenyl)-1h-pyrrolo[2,3-b]pyridin-5-yl]benzoyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1=CC=CC(C=2C=C3C(C=4C=CC(=CC=4)C(N)=O)=CNC3=NC=2)=C1 TXWQPIPDZDRBOV-UHFFFAOYSA-N 0.000 description 2
- QPYOLSJFOCIOHK-UHFFFAOYSA-N tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1=CC=C(B2OC(C)(C)C(C)(C)O2)C=C1 QPYOLSJFOCIOHK-UHFFFAOYSA-N 0.000 description 2
- SRQMKJGIFHMHKI-UHFFFAOYSA-N tert-butyl 4-[4-[3-(4-carbamoylphenyl)-1h-pyrrolo[2,3-b]pyridin-5-yl]benzoyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1=CC=C(C=2C=C3C(C=4C=CC(=CC=4)C(N)=O)=CNC3=NC=2)C=C1 SRQMKJGIFHMHKI-UHFFFAOYSA-N 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- 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 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229910052727 yttrium Inorganic materials 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-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
- RCVDPBFUMYUKPB-UHFFFAOYSA-N (3,4-dimethoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1OC RCVDPBFUMYUKPB-UHFFFAOYSA-N 0.000 description 1
- FQWUBDDFDBNOPL-CAOOACKPSA-N (3e)-3-(pyridin-4-ylmethylidene)-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(=C\C=4C=CN=CC=4)/C(=O)NC3=NC=2)=C1 FQWUBDDFDBNOPL-CAOOACKPSA-N 0.000 description 1
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 1
- BBUAHHOMTDMBPX-NVMNQCDNSA-N (3z)-3-benzylidene-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(=C/C=4C=CC=CC=4)/C(=O)NC3=NC=2)=C1 BBUAHHOMTDMBPX-NVMNQCDNSA-N 0.000 description 1
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 1
- POPHMOPNVVKGRW-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7-octahydronaphthalene Chemical compound C1CCC2CCCCC2=C1 POPHMOPNVVKGRW-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 description 1
- IGERFAHWSHDDHX-UHFFFAOYSA-N 1,3-dioxanyl Chemical group [CH]1OCCCO1 IGERFAHWSHDDHX-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ROUYUBHVBIKMQO-UHFFFAOYSA-N 1,4-diiodobutane Chemical compound ICCCCI ROUYUBHVBIKMQO-UHFFFAOYSA-N 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- XRYFFCUHEFROCI-UHFFFAOYSA-N 1-(cyclopropylmethyl)-6-(3,4,5-trimethoxyphenyl)-3h-imidazo[4,5-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3N(CC4CC4)C(=O)NC3=NC=2)=C1 XRYFFCUHEFROCI-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- IBZLPDSAIOZFSV-UHFFFAOYSA-N 1-[4-[[4-[3-(1h-indol-5-yl)-1h-pyrrolo[2,3-b]pyridin-5-yl]phenyl]methyl]piperazin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCN1CC1=CC=C(C=2C=C3C(C=4C=C5C=CNC5=CC=4)=CNC3=NC=2)C=C1 IBZLPDSAIOZFSV-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- CYEYLYGHCOHIDC-UHFFFAOYSA-N 1-methyl-4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine Chemical group C1CN(C)CCN1CC1=CC=C(B2OC(C)(C)C(C)(C)O2)C=C1 CYEYLYGHCOHIDC-UHFFFAOYSA-N 0.000 description 1
- PLRACCBDVIHHLZ-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 1
- LXFQSRIDYRFTJW-UHFFFAOYSA-M 2,4,6-trimethylbenzenesulfonate Chemical compound CC1=CC(C)=C(S([O-])(=O)=O)C(C)=C1 LXFQSRIDYRFTJW-UHFFFAOYSA-M 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- ABLIMXXAJWRGPB-UHFFFAOYSA-N 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1h-imidazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(C=2NC=CN=2)C=C1 ABLIMXXAJWRGPB-UHFFFAOYSA-N 0.000 description 1
- CBUOGMOTDGNEAW-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(CBr)C=C1 CBUOGMOTDGNEAW-UHFFFAOYSA-N 0.000 description 1
- MLPIPCKQZXPCSX-UHFFFAOYSA-N 2-[4-[3-(1h-indol-5-yl)-1h-pyrrolo[2,3-b]pyridin-5-yl]-2-methoxyphenoxy]-n,n-dimethylethanamine Chemical compound C1=C(OCCN(C)C)C(OC)=CC(C=2C=C3C(C=4C=C5C=CNC5=CC=4)=CNC3=NC=2)=C1 MLPIPCKQZXPCSX-UHFFFAOYSA-N 0.000 description 1
- KTKMLXBEBKGQGL-UHFFFAOYSA-N 2-bromo-5h-pyrrolo[2,3-b]pyrazine Chemical compound BrC1=CN=C2NC=CC2=N1 KTKMLXBEBKGQGL-UHFFFAOYSA-N 0.000 description 1
- ULGMTONBTOMHOK-UHFFFAOYSA-N 2-bromo-7-iodo-5h-pyrrolo[2,3-b]pyrazine Chemical compound BrC1=CN=C2NC=C(I)C2=N1 ULGMTONBTOMHOK-UHFFFAOYSA-N 0.000 description 1
- PELIJVQFPYPWOG-UHFFFAOYSA-N 2-carbonoperoxoylbenzoic acid;magnesium Chemical compound [Mg].OOC(=O)C1=CC=CC=C1C(O)=O PELIJVQFPYPWOG-UHFFFAOYSA-N 0.000 description 1
- WFSJROCEOJANPD-UHFFFAOYSA-N 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol Chemical compound C1=C(O)C(OC)=CC(B2OC(C)(C)C(C)(C)O2)=C1 WFSJROCEOJANPD-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- WRXNJTBODVGDRY-UHFFFAOYSA-N 2-pyrrolidin-1-ylethanamine Chemical compound NCCN1CCCC1 WRXNJTBODVGDRY-UHFFFAOYSA-N 0.000 description 1
- PXEBCKJMBGGJJQ-UHFFFAOYSA-N 3,3-bis(cyclopropylmethyl)-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(CC4CC4)(CC4CC4)C(=O)NC3=NC=2)=C1 PXEBCKJMBGGJJQ-UHFFFAOYSA-N 0.000 description 1
- BEXIBVAXBFVLJP-UHFFFAOYSA-N 3,3-dibenzyl-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(CC=4C=CC=CC=4)(CC=4C=CC=CC=4)C(=O)NC3=NC=2)=C1 BEXIBVAXBFVLJP-UHFFFAOYSA-N 0.000 description 1
- UQHKXSZPEUNUDH-UHFFFAOYSA-N 3-(1h-indol-5-yl)-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridine Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(C=4C=C5C=CNC5=CC=4)=CNC3=NC=2)=C1 UQHKXSZPEUNUDH-UHFFFAOYSA-N 0.000 description 1
- BDKQHXVYBFXYNY-UHFFFAOYSA-N 3-(1h-indol-5-yl)-5-[3-methoxy-4-(2-piperazin-1-ylethoxy)phenyl]-1h-pyrrolo[2,3-b]pyridine Chemical compound COC1=CC(C=2C=C3C(C=4C=C5C=CNC5=CC=4)=CNC3=NC=2)=CC=C1OCCN1CCNCC1 BDKQHXVYBFXYNY-UHFFFAOYSA-N 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- KDUPSKIOLZENPU-UHFFFAOYSA-N 3-(cyclopropylmethyl)-5-(3,4,5-trimethoxyphenyl)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(CC4CC4)C(=O)NC3=NC=2)=C1 KDUPSKIOLZENPU-UHFFFAOYSA-N 0.000 description 1
- FKXOORRMAHPCMI-UHFFFAOYSA-N 3-(pyridin-3-ylmethyl)-5-(3,4,5-trimethoxyphenyl)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(CC=4C=NC=CC=4)C(=O)NC3=NC=2)=C1 FKXOORRMAHPCMI-UHFFFAOYSA-N 0.000 description 1
- SJQKLWBZTHZVPG-UHFFFAOYSA-N 3-(pyridin-3-ylmethylidene)-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(=CC=4C=NC=CC=4)C(=O)NC3=NC=2)=C1 SJQKLWBZTHZVPG-UHFFFAOYSA-N 0.000 description 1
- LDTTYRLLPSXUQB-UHFFFAOYSA-N 3-(pyridin-4-ylmethyl)-5-(3,4,5-trimethoxyphenyl)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(CC=4C=CN=CC=4)C(=O)NC3=NC=2)=C1 LDTTYRLLPSXUQB-UHFFFAOYSA-N 0.000 description 1
- FQWUBDDFDBNOPL-UHFFFAOYSA-N 3-(pyridin-4-ylmethylidene)-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(=CC=4C=CN=CC=4)C(=O)NC3=NC=2)=C1 FQWUBDDFDBNOPL-UHFFFAOYSA-N 0.000 description 1
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
- SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 1
- FQKKTEOYMUTPDC-UHFFFAOYSA-N 3-[4-(1h-imidazol-2-yl)phenyl]-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridine Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(C=4C=CC(=CC=4)C=4NC=CN=4)=CNC3=NC=2)=C1 FQKKTEOYMUTPDC-UHFFFAOYSA-N 0.000 description 1
- BODYCSYFOVDCON-UHFFFAOYSA-N 3-[[2-oxo-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-3-ylidene]methyl]benzamide Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(=CC=4C=C(C=CC=4)C(N)=O)C(=O)NC3=NC=2)=C1 BODYCSYFOVDCON-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
- WVNHJGNBMUWNDT-UHFFFAOYSA-N 3-benzyl-5-(3,4,5-trimethoxyphenyl)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(CC=4C=CC=CC=4)C(=O)NC3=NC=2)=C1 WVNHJGNBMUWNDT-UHFFFAOYSA-N 0.000 description 1
- BBUAHHOMTDMBPX-UHFFFAOYSA-N 3-benzylidene-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(=CC=4C=CC=CC=4)C(=O)NC3=NC=2)=C1 BBUAHHOMTDMBPX-UHFFFAOYSA-N 0.000 description 1
- AYYCJLDODRZCOB-UHFFFAOYSA-N 3-formylbenzamide Chemical compound NC(=O)C1=CC=CC(C=O)=C1 AYYCJLDODRZCOB-UHFFFAOYSA-N 0.000 description 1
- HGZJJKZPPMFIBU-UHFFFAOYSA-N 3-formylbenzonitrile Chemical compound O=CC1=CC=CC(C#N)=C1 HGZJJKZPPMFIBU-UHFFFAOYSA-N 0.000 description 1
- SJYRAFSTKJKANU-UHFFFAOYSA-N 3-iodo-1-(4-methylphenyl)sulfonyl-5-(3,4,5-trimethoxyphenyl)pyrrolo[2,3-b]pyridine Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(I)=CN(C3=NC=2)S(=O)(=O)C=2C=CC(C)=CC=2)=C1 SJYRAFSTKJKANU-UHFFFAOYSA-N 0.000 description 1
- BNUYPQOBSWQDMG-UHFFFAOYSA-N 3-iodo-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridine Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(I)=CNC3=NC=2)=C1 BNUYPQOBSWQDMG-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ANQUZKPKKVNPTD-UHFFFAOYSA-N 4-[3-(1h-indol-5-yl)-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridin-5-yl]benzaldehyde Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=C(C=3C=CC(C=O)=CC=3)C=C2C(C=2C=C3C=CNC3=CC=2)=C1 ANQUZKPKKVNPTD-UHFFFAOYSA-N 0.000 description 1
- ZCYXAIOCALMGOI-UHFFFAOYSA-N 4-[4-[3-(4-carbamoylphenyl)-1h-pyrrolo[2,3-b]pyridin-5-yl]benzoyl]piperazine-1-carboxylic acid Chemical compound C1=CC(C(=O)N)=CC=C1C1=CNC2=NC=C(C=3C=CC(=CC=3)C(=O)N3CCN(CC3)C(O)=O)C=C12 ZCYXAIOCALMGOI-UHFFFAOYSA-N 0.000 description 1
- KFPRSPRIHQMUJC-UHFFFAOYSA-N 4-[5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-3-yl]benzamide Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(C=4C=CC(=CC=4)C(N)=O)=CNC3=NC=2)=C1 KFPRSPRIHQMUJC-UHFFFAOYSA-N 0.000 description 1
- KGRHWBRNFKQGRZ-UHFFFAOYSA-N 4-[5-[4-(piperazine-1-carbonyl)phenyl]-1h-pyrrolo[2,3-b]pyridin-3-yl]benzamide Chemical compound C1=CC(C(=O)N)=CC=C1C1=CNC2=NC=C(C=3C=CC(=CC=3)C(=O)N3CCNCC3)C=C12 KGRHWBRNFKQGRZ-UHFFFAOYSA-N 0.000 description 1
- CGBCMHRCPRQCCE-UHFFFAOYSA-N 4-[5-bromo-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridin-3-yl]-n-methylbenzamide Chemical compound C1=CC(C(=O)NC)=CC=C1C1=CN(S(=O)(=O)C=2C=CC(C)=CC=2)C2=NC=C(Br)C=C12 CGBCMHRCPRQCCE-UHFFFAOYSA-N 0.000 description 1
- IPKZJXIJURRFII-UHFFFAOYSA-N 4-[[2-oxo-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-3-ylidene]methyl]benzamide Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(=CC=4C=CC(=CC=4)C(N)=O)C(=O)NC3=NC=2)=C1 IPKZJXIJURRFII-UHFFFAOYSA-N 0.000 description 1
- WCXQFXJVCJRVLE-UHFFFAOYSA-N 4-[[2-oxo-5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-3-ylidene]methyl]benzonitrile Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(=CC=4C=CC(=CC=4)C#N)C(=O)NC3=NC=2)=C1 WCXQFXJVCJRVLE-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- LBUNNMJLXWQQBY-UHFFFAOYSA-N 4-fluorophenylboronic acid Chemical compound OB(O)C1=CC=C(F)C=C1 LBUNNMJLXWQQBY-UHFFFAOYSA-N 0.000 description 1
- QWDCXCRLPNMJIH-UHFFFAOYSA-N 4-formylbenzamide Chemical compound NC(=O)C1=CC=C(C=O)C=C1 QWDCXCRLPNMJIH-UHFFFAOYSA-N 0.000 description 1
- 125000001054 5 membered carbocyclic group Chemical group 0.000 description 1
- SORLHSCKIMGUFM-UHFFFAOYSA-N 5-(1h-indol-5-yl)pyrazine-2,3-diamine Chemical compound N1=C(N)C(N)=NC=C1C1=CC=C(NC=C2)C2=C1 SORLHSCKIMGUFM-UHFFFAOYSA-N 0.000 description 1
- RAOZYYPRJSSMQE-UHFFFAOYSA-N 5-(3,4,5-trimethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-3h-pyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3CC(=O)N(COCC[Si](C)(C)C)C3=NC=2)=C1 RAOZYYPRJSSMQE-UHFFFAOYSA-N 0.000 description 1
- MNDWDBWIHDIYCI-UHFFFAOYSA-N 5-(3,4-dimethoxyphenyl)-3-(1h-indol-5-yl)-1h-pyrrolo[2,3-b]pyridine Chemical compound C1=C(OC)C(OC)=CC=C1C1=CN=C(NC=C2C=3C=C4C=CNC4=CC=3)C2=C1 MNDWDBWIHDIYCI-UHFFFAOYSA-N 0.000 description 1
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 1
- DHPKTHROZFIEJK-UHFFFAOYSA-N 5-bromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound BrC1=CN=C2NC(=O)CC2=C1 DHPKTHROZFIEJK-UHFFFAOYSA-N 0.000 description 1
- LPTVWZSQAIDCEB-UHFFFAOYSA-N 5-bromo-1h-pyrrolo[2,3-b]pyridine Chemical compound BrC1=CN=C2NC=CC2=C1 LPTVWZSQAIDCEB-UHFFFAOYSA-N 0.000 description 1
- INZKTAOMHJCPFQ-UHFFFAOYSA-N 5-bromo-3-(1h-indol-5-yl)imidazo[4,5-b]pyrazine Chemical compound C1=C2NC=CC2=CC(N2C=NC3=NC=C(N=C32)Br)=C1 INZKTAOMHJCPFQ-UHFFFAOYSA-N 0.000 description 1
- LQJGZEFWBXJKJI-UHFFFAOYSA-N 5-bromo-3-(2-trimethylsilylethynyl)pyrazin-2-amine Chemical compound C[Si](C)(C)C#CC1=NC(Br)=CN=C1N LQJGZEFWBXJKJI-UHFFFAOYSA-N 0.000 description 1
- RAAKRWOQXGMFBM-UHFFFAOYSA-N 5-bromo-3-(4-fluorophenyl)-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=C(Br)C=C2C(C=2C=CC(F)=CC=2)=C1 RAAKRWOQXGMFBM-UHFFFAOYSA-N 0.000 description 1
- GIPGJYARDOQGDJ-UHFFFAOYSA-N 5-bromo-3-iodo-1h-pyrrolo[2,3-b]pyridine Chemical compound BrC1=CN=C2NC=C(I)C2=C1 GIPGJYARDOQGDJ-UHFFFAOYSA-N 0.000 description 1
- SEJWVDCVNSZQJS-UHFFFAOYSA-N 5-bromo-3-n-(1h-indol-5-yl)pyrazine-2,3-diamine Chemical compound NC1=NC=C(Br)N=C1NC1=CC=C(NC=C2)C2=C1 SEJWVDCVNSZQJS-UHFFFAOYSA-N 0.000 description 1
- YRGMYJUKFJPNPD-UHFFFAOYSA-N 5-bromopyridine-2,3-diamine Chemical compound NC1=CC(Br)=CN=C1N YRGMYJUKFJPNPD-UHFFFAOYSA-N 0.000 description 1
- RKUCGDPUOWGALR-UHFFFAOYSA-N 5-chloro-1-(cyclopropylmethyl)-6-(3,4,5-trimethoxyphenyl)-3h-imidazo[4,5-b]pyrazin-2-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C(=NC=3NC(=O)N(CC4CC4)C=3N=2)Cl)=C1 RKUCGDPUOWGALR-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 1
- 125000004008 6 membered carbocyclic group Chemical group 0.000 description 1
- JYVRKTJNPZAMNN-UHFFFAOYSA-N 6-bromo-1-(cyclopropylmethyl)-3h-imidazo[4,5-b]pyridin-2-one Chemical compound C12=CC(Br)=CN=C2NC(=O)N1CC1CC1 JYVRKTJNPZAMNN-UHFFFAOYSA-N 0.000 description 1
- 125000001960 7 membered carbocyclic group Chemical group 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-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- ILSUDFIYVUJJHY-UHFFFAOYSA-N B1(OC(C(O1)(C)C)(C)C)C2=CC(=CC=C2)C(=O)C3CNCCN3C(=O)OC(C)(C)C Chemical compound B1(OC(C(O1)(C)C)(C)C)C2=CC(=CC=C2)C(=O)C3CNCCN3C(=O)OC(C)(C)C ILSUDFIYVUJJHY-UHFFFAOYSA-N 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- YUGYIWRAZSXSJM-UHFFFAOYSA-N CN(C=CC1=C2)C1=CC=C2N(C(C1N2)=NC=CN1O)C2=O Chemical compound CN(C=CC1=C2)C1=CC=C2N(C(C1N2)=NC=CN1O)C2=O YUGYIWRAZSXSJM-UHFFFAOYSA-N 0.000 description 1
- HHBAYPCXATXKFD-UHFFFAOYSA-N COC1=C(OC)C(OC)=CC(C=2C=C3C(C=4C=CC(=CC=4)C(N)=O)=CN=C3N(O)C=2)=C1 Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C3C(C=4C=CC(=CC=4)C(N)=O)=CN=C3N(O)C=2)=C1 HHBAYPCXATXKFD-UHFFFAOYSA-N 0.000 description 1
- IOAYNTIXBBKJJY-UHFFFAOYSA-N COC1=CC(=CC(=C1OC)OC)C2=CC3=C(NC(=O)C3=CC4=CC(=CC=C4)C(=N)N)N=C2 Chemical compound COC1=CC(=CC(=C1OC)OC)C2=CC3=C(NC(=O)C3=CC4=CC(=CC=C4)C(=N)N)N=C2 IOAYNTIXBBKJJY-UHFFFAOYSA-N 0.000 description 1
- MCHRLOQCAAZBLA-UHFFFAOYSA-N COC1=CC(=CC(=C1OC)OC)C2=CC3=C(NC(=O)C3=CC4=CC=C(C=C4)C(=N)N)N=C2 Chemical compound COC1=CC(=CC(=C1OC)OC)C2=CC3=C(NC(=O)C3=CC4=CC=C(C=C4)C(=N)N)N=C2 MCHRLOQCAAZBLA-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000020446 Cardiac disease Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000011068 Cdc42 Human genes 0.000 description 1
- 108050001278 Cdc42 Proteins 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 229920002307 Dextran Polymers 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
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 208000037487 Endotoxemia Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical group CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 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
- 108091007911 GSKs Proteins 0.000 description 1
- 102000013446 GTP Phosphohydrolases Human genes 0.000 description 1
- 108091006109 GTPases Proteins 0.000 description 1
- 102000053171 Glial Fibrillary Acidic Human genes 0.000 description 1
- 102000004103 Glycogen Synthase Kinases Human genes 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 101000958409 Homo sapiens Mitogen-activated protein kinase kinase kinase 10 Proteins 0.000 description 1
- 101001055085 Homo sapiens Mitogen-activated protein kinase kinase kinase 9 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 239000012825 JNK inhibitor Substances 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 208000004852 Lung Injury Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027452 Metastases to bone Diseases 0.000 description 1
- 102100038243 Mitogen-activated protein kinase kinase kinase 10 Human genes 0.000 description 1
- 102100026909 Mitogen-activated protein kinase kinase kinase 9 Human genes 0.000 description 1
- SOWBFZRMHSNYGE-UHFFFAOYSA-N Monoamide-Oxalic acid Natural products NC(=O)C(O)=O SOWBFZRMHSNYGE-UHFFFAOYSA-N 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 125000005855 N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl group Chemical group 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 102100031455 NAD-dependent protein deacetylase sirtuin-1 Human genes 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- 102000008763 Neurofilament Proteins Human genes 0.000 description 1
- 108010088373 Neurofilament Proteins Proteins 0.000 description 1
- 101710138657 Neurotoxin Proteins 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 230000010718 Oxidation Activity Effects 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 102100031538 Phosphatidylcholine-sterol acyltransferase Human genes 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical group CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 125000005631 S-sulfonamido group Chemical group 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- 101000761953 Schizosaccharomyces pombe (strain 972 / ATCC 24843) Protein kinase byr2 Proteins 0.000 description 1
- 102000011990 Sirtuin Human genes 0.000 description 1
- 108050002485 Sirtuin Proteins 0.000 description 1
- 108010041191 Sirtuin 1 Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 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
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- 241000282887 Suidae Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010069363 Traumatic lung injury Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 108010021119 Trichosanthin Proteins 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 102100035071 Vimentin Human genes 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 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 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000005042 acyloxymethyl group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000005018 aryl alkenyl group Chemical group 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 125000005015 aryl alkynyl group Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 1
- 201000005008 bacterial sepsis Diseases 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 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
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- MKCBRYIXFFGIKN-UHFFFAOYSA-N bicyclo[1.1.1]pentane Chemical compound C1C2CC1C2 MKCBRYIXFFGIKN-UHFFFAOYSA-N 0.000 description 1
- LPCWKMYWISGVSK-UHFFFAOYSA-N bicyclo[3.2.1]octane Chemical compound C1C2CCC1CCC2 LPCWKMYWISGVSK-UHFFFAOYSA-N 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 150000001715 carbamic acids Chemical class 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000005854 carbamoyl-(C1-C2)alkyl group Chemical group 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000004653 carbonic acids Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004617 chromonyl group Chemical group O1C(=CC(C2=CC=CC=C12)=O)* 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229910052570 clay Inorganic materials 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000009225 cognitive behavioral therapy Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 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
- IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 229940124447 delivery agent Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 125000005852 di-N,N—(C1-C2)alkylamino(C2-C3)alkyl group Chemical group 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- LMEDOLJKVASKTP-UHFFFAOYSA-N dibutyl sulfate Chemical group CCCCOS(=O)(=O)OCCCC LMEDOLJKVASKTP-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- LTVOKYUPTHZZQH-UHFFFAOYSA-N difluoromethane Chemical group F[C]F LTVOKYUPTHZZQH-UHFFFAOYSA-N 0.000 description 1
- 125000005433 dihydrobenzodioxinyl group Chemical group O1C(COC2=C1C=CC=C2)* 0.000 description 1
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000005045 dihydroisoquinolinyl group Chemical group C1(NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000004655 dihydropyridinyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 125000005805 dimethoxy phenyl group Chemical group 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- GAFRWLVTHPVQGK-UHFFFAOYSA-N dipentyl sulfate Chemical compound CCCCCOS(=O)(=O)OCCCCC GAFRWLVTHPVQGK-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000010228 ex vivo assay Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000004612 furopyridinyl group Chemical group O1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229940114119 gentisate Drugs 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000004995 haloalkylthio group Chemical group 0.000 description 1
- 125000000232 haloalkynyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- 125000005241 heteroarylamino group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000004295 hippocampal neuron Anatomy 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000008206 lipophilic material Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 231100000515 lung injury Toxicity 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 210000001259 mesencephalon Anatomy 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 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
- 230000007388 microgliosis Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 125000005858 morpholino(C2-C3)alkyl group Chemical group 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UQEIFYRRSNJVDO-UHFFFAOYSA-N n,n-dibenzyl-2-phenylethanamine Chemical compound C=1C=CC=CC=1CN(CC=1C=CC=CC=1)CCC1=CC=CC=C1 UQEIFYRRSNJVDO-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- FUJGYWFWHBPESW-UHFFFAOYSA-N n-methyl-4-[5-(3,4,5-trimethoxyphenyl)-1h-pyrrolo[2,3-b]pyridin-3-yl]benzamide Chemical compound C1=CC(C(=O)NC)=CC=C1C1=CNC2=NC=C(C=3C=C(OC)C(OC)=C(OC)C=3)C=C12 FUJGYWFWHBPESW-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 210000005155 neural progenitor cell Anatomy 0.000 description 1
- 230000007372 neural signaling Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 210000005044 neurofilament Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000007996 neuronal plasticity Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 238000002732 pharmacokinetic assay Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 125000005856 piperidino(C2-C3)alkyl group Chemical group 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 125000001042 pteridinyl group Chemical class N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 125000005857 pyrrolidino(C2-C3)alkyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 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
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 210000003594 spinal ganglia Anatomy 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000009168 stem cell therapy Methods 0.000 description 1
- 238000009580 stem-cell therapy Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 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
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 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
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity 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
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- JYIGYTWAYATZEO-UHFFFAOYSA-N trimethyl-[2-(pyrrolo[2,3-b]pyridin-1-ylmethoxy)ethyl]silane Chemical compound C1=CN=C2N(COCC[Si](C)(C)C)C=CC2=C1 JYIGYTWAYATZEO-UHFFFAOYSA-N 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 210000005048 vimentin Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 125000005853 β-dimethylaminoethyl group Chemical group 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- 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
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
- A61P3/06—Antihyperlipidemics
-
- 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
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- 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
- A61P7/10—Antioedematous agents; Diuretics
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
-
- 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
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- 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
- 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
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Cardiology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Heart & Thoracic Surgery (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Physical Education & Sports Medicine (AREA)
- Psychiatry (AREA)
- Endocrinology (AREA)
- Immunology (AREA)
- Emergency Medicine (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Vascular Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Psychology (AREA)
- Ophthalmology & Optometry (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
【選択図】なし
Description
本発明を、例示的目的で提供され、いずれの方法によっても本発明を制限することを意図しない、以下の実施例によってさらに説明する。当業者は、本質的に同一の結果を得るために変化または修正され得る、多種多様の重大でないパラメータを容易に認識するであろう。
実施例1
スキーム1
5−(3,4−ジメトキシフェニル)−3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン(化合物D)の調製
N−(4−(3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル)フェニル)アセトアミド(化合物E)の調製
5−(3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル)ピリジン−2−アミン(化合物F)の調製
4−(3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル)−2−メトキシアニリン(化合物G)の調製
3−(1H−インドール−5−イル)−5−(6−メトキシピリジン−3−イル)−1H−ピロロ[2,3−b]ピリジン(化合物H)の調製
3−(1H−インドール−5−イル)−5−(2−(4−メチルピペラジン−1−イル)ピリジン−4−イル)−1H−ピロロ[2,3−b]ピリジン(化合物I)の調製
4−(3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル)アニリン(化合物J)の調製
5−(3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル)ピリミジン−2−アミン(化合物K)の調製
3−(1H−インドール−5−イル)−5−(6−(ピペラジン−1−イル)ピリジン−3−イル)−1H−ピロロ[2,3−b]ピリジン(化合物L)の調製
N−(4−(3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル)フェニル)メタンスルホンアミド(化合物M)の調製
3,5−ジ(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン(化合物N)の調製
5−(3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル)−N,N−ジメチルピリジン−2−アミン(化合物O)の調製
3−(1H−インドール−5−イル)−5−フェニル−1H−ピロロ[2,3−b]ピリジン(化合物P)の調製
4−(5−(3,4,5−トリメトキシフェニル)−1H−ピロロ[2,3−b]ピリジン−3−イル)アニリン(化合物Q)の調製
N−(4−(5−(3,4,5−トリメトキシフェニル)−1H−ピロロ[2,3−b]ピリジン−3−イル)フェニル)アセトアミド(化合物R)の調製
5−(5−(3,4,5−トリメトキシフェニル)−1H−ピロロ[2,3−b]ピリジン−3−イル)ピリミジン−2−アミン(化合物S)の調製
5−(5−(3,4,5−トリメトキシフェニル)−1H−ピロロ[2,3−b]ピリジン−3−イル)ピリジン−2−アミン(化合物T)の調製
N,N−ジメチル−5−(5−(3,4,5−トリメトキシフェニル)−1H−ピロロ[2,3−b]ピリジン−3−イル)ピリジン−2−アミン(化合物U)の調製
5,5’−(1H−ピロロ[2,3−b]ピリジン−3,5−ジイル)ジピリミジン−2−アミン(化合物W)の調製
5,5’−(1H−ピロロ[2,3−b]ピリジン−3,5−ジイル)ビス(N,N−ジメチルピリジン−2−アミン)(化合物X)の調製
5−(3−(3−クロロ−4−フルオロフェニル)−1H−ピロロ[2,3−b]ピリジン−5−イル)−N,N−ジメチルピリジン−2−アミン(化合物Y)の調製
5−(3−(4−アミノフェニル)−1H−ピロロ[2,3−b]ピリジン−5−イル)ピリジン−2−アミン(化合物Z)の調製
3−(1−メチル−1H−インドール−5−イル)−5−(3,4,5−トリメトキシフェニル)−1H−ピロロ[2,3−b]ピリジン(化合物AA)の調製
4−(5−(3,4,5−トリメトキシフェニル)−1H−ピロロ[2,3−b]ピリジン−3−イル)ベンズアミド(化合物AB)の調製
4−(5−(3,4−ジメトキシフェニル)−1H−ピロロ[2,3−b]ピリジン−3−イル)ベンズアミド(化合物AC)の調製
4−(5−(4−アミノ−3−メトキシフェニル)−1H−ピロロ[2,3−b]ピリジン−3−イル)ベンズアミド(化合物AD)の調製
4−(5−(6−アミノピリジン−3−イル)−1H−ピロロ[2,3−b]ピリジン−3−イル)ベンズアミド(化合物AE)の調製
5−(3−(3−クロロ−4−フルオロフェニル)−1H−ピロロ[2,3−b]ピリジン−5−イル)ピリジン−2−アミン(化合物AF)の調製
スキーム2
5−(3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル)−N−(2−(ピロリジン−1−イル)エチル)ピリジン−2−アミン(化合物AI)の調製
スキーム3
1−(4−(3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル)フェニル)−N,N−ジメチルmエタンアミン(化合物AL)の調製
スキーム4
2−(4−(3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル)−2−メトキシフェノキシ)−N,N−ジメチルエタンアミン(化合物AP)の調製
スキーム5
2−(3,4−ジメトキシフェニル)−7−(1H−インドール−5−イル)−5H−ピロロ[3,2−b]ピラジン(化合物AX)の調製
4−(7−(1H−インドール−5−イル)−5H−ピロロ[3,2−b]ピラジン−2−イル)−2−メトキシアニリン(化合物AY)の調製
4−(2−(4−(7−(1H−インドール−5−イル)−5H−ピロロ[3,2−b]ピラジン−2−イル)−2−メトキシフェノキシ)エチル)モルホリン(化合物AZ)の調製
スキーム6
1−(1−メチル−1H−インドール−5−イル)−6−(3,4,5−トリメトキシフェニル)−1H−イミダゾ[4,5−b]ピラジン−2(3H)−オン(化合物BE)の調製
6−(4−ヒドロキシフェニル)−1−(1−メチル−1H−インドール−5−イル)−1H−イミダゾ[4,5−b]ピラジン−2(3H)−オン(化合物BF)の調製
6−(3,5−ジメチルフェニル)−1−(1−メチル−1H−インドール−5−イル)−1H−イミダゾ[4,5−b]ピラジン−2(3H)−オン(化合物BG)の調製
1−(1H−インドール−5−イル)−6−(ピリジン−4−イル)−1H−イミダゾ[4,5−b]ピラジン−2(3H)−オン(化合物BH)の調製
6−(4−ヒドロキシフェニル)−1−(1H−インドール−5−イル)−1H−イミダゾ[4,5−b]ピラジン−2(3H)−オン(化合物BI)の調製
6−(3,5−ジメチルフェニル)−1−(1H−インドール−5−イル)−1H−イミダゾ[4,5−b]ピラジン−2(3H)−オン(化合物BJ)の調製
スキーム7
スキーム8
EtOH(3.5mL)中、3,5−ジブロモピラジン−2−アミン(3.48g、13.7mmol)および対応するアルキルアミン、アリールアミン、またはヘテロアリールアミン(15.0mmol)の撹拌懸濁液に、ジイソプロピルエチルアミン[DIEA](2.60mL、15.0mmol)を添加した。得られた混合物を80℃で48時間撹拌し、その後、EtOAcとH2Oとの間に分配させた。有機層を分離し、その後、ブラインで洗浄し、Na2SO4で乾燥させ、濾過し、真空内で蒸発させて残渣を得、1:1のEtOAc:ヘキサンで溶出する自動中圧シリカゲルクロマトグラフィーで精製して、無定形固体として中間体を得た。
中間体2BB(0.450g、1.5mmol)をTHF(5mL)中に溶解し、カルボニルジイミダゾール(1.20g、7.40mmol)で処置した。得られた混合物を65℃で48時間加熱し、その後、真空内で濃縮し、EtOAcとH2Oとの間に分配させた。有機層を分離し、MgSO4で乾燥させ、濾過し、真空内で濃縮して残渣を得、ヘキサン/EtOAcで溶出する自動シリカゲルクロマトグラフィーによって精製して、無定形固体として中間体2BCを得た。
Personal Chemistryマイクロ波反応バイアル内で、CH3CN(1mL)中、中間体2BC(0.08mmol)の個々の溶液に、対応するボロン酸(0.08mmol)、ビス(トリフェニルホスフィン)−二塩化パラジウム(II)(6.0mg、0.008mmol)、および1M Na2CO3(1mL)を添加した。得られた混合物をArで10分間脱気し、その後、Personal Chemistry Optimizer内で、150℃で10分間加熱した。有機層を分離し、濾過し、真空内で濃縮した。残渣を分取HPLCで精製し、無定形固体として、表2の表題化合物を得た。
5−クロロ−1−(シクロプロピルメチル)−6−(3,4,5−トリメトキシフェニル)−1H−イミダゾ[4,5−b]ピラジン−2(3H)−オンの調製
スキーム8
スキーム9
1−(シクロプロピルメチル)−6−(3,4,5−トリメトキシフェニル)−1H−イミダゾ[4,5−b]ピリジン−2(3H)−オンの調製
スキーム10
1−(シクロプロピルメチル)−6−(3,4,5−トリメトキシフェニル)−1H−イミダゾ[4,5−b]ピラジン−2(3H)−チオン(化合物BX)の調製
スキーム11
(E)−および(Z)−3−ピリジン−4−イルメチレン−5−(3,4,5−トリメトキシ−フェニル)−1,3−ジヒドロ−ピロロ[2,3−b]ピリジン−2−オンの調製
3−ベンジリデン−5−(3,4,5−トリメトキシ−フェニル)−1,3−ジヒドロ−ピロロ[2,3−b]ピリジン−2−オンの調製
4−[2−オキソ−5−(3,4,5−トリメトキシ−フェニル)−1,2−ジヒドロ−ピロロ[2,3−b]ピリジン−3−イリデンメチル]−ベンズアミドの調製
3−[2−オキソ−5−(3,4,5−トリメトキシ−フェニル)−1,2−ジヒドロ−ピロロ[2,3−b]ピリジン−3−イリデンメチル]−ベンズアミドの調製
スキーム12
3−[2−オキソ−5−(3,4,5−トリメトキシ−フェニル)−1,2−ジヒドロ−ピロロ[2,3−b]ピリジン−3−イリデンメチル]−ベンゾニトリルの調製
スキーム13
3−ピリジン−4−イルメチル−5−(3,4,5−トリメトキシ−フェニル)−1,3−ジヒドロ−ピロロ[2,3−b]ピリジン−2−オンの調製
スキーム14
4−[2−オキソ−5−(3,4,5−トリメトキシ−フェニル)−2,3−ジヒドロ−1H−ピロロ[2,3−b]ピリジン−3−イルメチル]−ベンズアミドの調製
3,3−ジベンジル−5−(3,4,5−トリメトキシ−フェニル)−1,3−ジヒドロ−ピロロ[2,3−b]ピリジン−2−オンの調製
1−(4−{4−[3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル]−ベンジル}−ピペラジン−1−イル)−エタノンの調製
4−{4−[3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル]−ベンジル}−1−メチル−ピペラジン−2−オンの調製
4−{4−[3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル]−ベンジル}−ピペラジン−2−オンの調製
4−{3−[3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル]−ベンジル}−1−メチル−ピペラジン−2−オンの調製
4−{4−[3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル]−ベンジル}−ピペラジン−1−カルボン酸tert−ブチルエステルの調製
スキーム15
1−(4−{4−[3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル]−ベンゾイル}−ピペラジン−1−イル)−エタノンの調製
{3−[3−(1H−インドール−5−イル)−1H−ピロロ[2,3−b]ピリジン−5−イル]−フェニル}−(4−メチル−ピペラジン−1−イル)−メタノンの調製
スキーム16
4−{5−[4−(ピペラジン−1−カルボニル)−フェニル]−1H−ピロロ[2,3−b]ピリジン−3−イル}−ベンズアミド、塩酸塩の調製
4−{5−[4−(4−アセチル−ピペラジン−1−カルボニル)−フェニル]−1H−ピロロ[2,3−b]ピリジン−3−イル}−ベンズアミドの調製
4−{3−[3−(4−カルバモイル−フェニル)−1H−ピロロ[2,3−b]ピリジン−5−イル]−ベンゾイル}−ピペラジン−1−カルボン酸tert−ブチルエステルの調製
4−{5−[3−(ピペラジン−1−カルボニル)−フェニル]−1H−ピロロ[2,3−b]ピリジン−3−イル}−ベンズアミド、塩酸塩の調製
4−{5−[3−(4−アセチル−ピペラジン−1−カルボニル)−フェニル]−1H−ピロロ[2,3−b]ピリジン−3−イル}−ベンズアミドの調製
4−[7−オキシ−5−(3,4,5−トリメトキシ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−イル]−ベンズアミドの調製
4−{5−[4−(4−メチル−ピペラジン−1−イルメチル)−フェニル]−1H−ピロロ[2,3−b]ピリジン−3−イル}−ベンズアミドの調製
4−{5−[3−(4−メチル−ピペラジン−1−イルメチル)−フェニル]−1H−ピロロ[2,3−b]ピリジン−3−イル}−ベンズアミドの調製
4−{5−[4−(4−アセチル−ピペラジン−1−イルメチル)−フェニル]−1H−ピロロ[2,3−b]ピリジン−3−イル}−ベンズアミドの調製
4−{5−[4−(4−メチル−3−オキソ−ピペラジン−1−イルメチル)−フェニル]−1H−ピロロ[2,3−b]ピリジン−3−イル}−ベンズアミドの調製
スキーム17
2−フェニル−N−{4−[5−(3,4,5−トリメトキシ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−イル]−ベンジル}−アセトアミドの調製
3−フェニル−N−{4−[5−(3,4,5−トリメトキシ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−イル]−ベンジル}−プロピオンアミドの調製
スキーム18
5−(1H−インドール−5−イル)−3−[4−(4−メチル−ピペラジン−1−イルメチル)−フェニル]−1H−ピロロ[2,3−b]ピリジンの調製
スキーム19
N−メチル−4−{5−[4−(4−メチル−ピペラジン−1−イルメチル)−フェニル]−1H−ピロロ[2,3−b]ピリジン−3−イル}−ベンズアミドの調製
スキーム20
スキーム21
200ng(130nM)のMLK3(Dundee、DU8313)を、2μM冷ATP(Km)および0.5μCi/アッセイ33P ATPの存在下、ならびに化合物の適切な濃度で、1μM不活性MKK7b(Dundee、DU703)とともにインキュベートした。20分間のインキュベート後、反応物を濾板によって洗浄し、シンチレーションカウンター上で読み取った。結果は以下の表4に示され、+++は、<0.1μMを示し、++は、>0.1μMおよび<1μMを示し、+は、>1μMを示す。
吸収、分布、代謝、および排出パラメータを決定するために、本明細書に開示される化合物を、薬物動態アッセイおよびモデルで評価することができる。インビトロおよびエクスビボアッセイならびにインビボモデルの選択および調整は、投与/製剤の経路、研究中の適応症、試験化合物の特性等によって、ならびに費用、科学技術および資源の利用可能性等によって変化する。このようなパラメータは、薬理学および薬剤開発の分野でよく知られている。そのような研究を設計および実行すること、またはそれを能力のある第三者に外注することは、当業者の能力の範囲内である。
本明細書に開示されるいくつかの化合物を、標準的マウス薬物動態モデルで評価した。適度な溶解度および代謝的安定性、低分子量に基づく良好な予測される血液脳関門透過、水素結合供与体の低下、2〜4の範囲内のlogD、ならびに低極性表面積を示した化合物を選択した。
本明細書に開示される化合物は、MLK3阻害が治療的役割を果たし得る疾病のために、任意の数の周知の、および公的に入手可能な動物有効性モデルにおいて試験され得る。そのようなモデルを選択および調整することは、当業者の能力の範囲内である。
例えば、本明細書に開示される化合物を、NeuroAids(D.Eggert,The Journal of Immunology,in press,November2009)に関連するマウスモデルにおいて、インビボ効力についてランク付けすることができる。選択された試験化合物は、脳内のMLK3効力および好ましい曝露に基づいて優先順位を付けられるが、これは絶対条件ではない。4週齢の雄のCB−17/IcrCrl−SCIDbr(CB17/SCID)マウスは、Charles River Laboratoryから購入することができる。HIV−1ADA感染MDM(5mL中、0.1のMOIで感染された1.5×105細胞)を、ウイルス感染の1日後に定位的に頭蓋内に注入し、HIVEマウスと称する。試験化合物を、次いで、0.5mg/kg/日、1.0mg/kg/日、1.5mg/kg/日、5.0mg/kg/日、および15.0mg/kg/日の投与量で、7日間、毎日腹腔内に投与する(例えば、n=4マウス/治療群)。媒体のみは、対照としての機能を果たす。CB17/SCIDマウスは、培地の頭蓋内(i.c.)注入(疑似手術)を受け、さらなる対照とされる。動物を、頭蓋内注入1日後から、MDM注入および試験化合物治療後7日間、媒体または試験化合物(すなわち、本明細書に開示される化合物)で治療する。投与パラメータ、群毎の数等は、必要に応じて変化してもよく、そのような変化は、当業者の技能の範囲内である。
脳組織を剖検で収集し、4%のリン酸緩衝パラホルムアルデヒドで固定し、パラフィン内に包埋する。ヒトMDMの注入部位が確認されるまで、パラフィンブロックを切断する。HIV−1 p24 Ag(cloneKal−1、Dako、カリフォルニア州カーピンテリア)を、ウイルス感染したヒトMDMを試験するために使用する。各マウスにおいて、30〜100の連続切片(5mmの厚さ)を注入部位から切除し、3から7の切片(10切片離れた)を分析する。ビメンチン中間径フィラメント(クローンVIM 3B4、Boehringer Mannheim、インディアナ州インディアナポリス)に対する抗体を、マウス脳内のヒト細胞の検出のために使用する。Iba−1(日本国大阪所在、和光純薬工業)に対する抗体によってマウス小膠細胞を検出し、グリア細胞繊維性酸性タンパク質([GFAP]Dako)への抗体によって星状膠細胞を検出する。NeuN、MAP−2(ともにChemicon Internationalから)、および重鎖(200kDa)ニューロフィラメント(Dako)を、ニューロンの検出のために使用する。全ての切片を、マイヤーヘマトキシリンで対比染色する。多ヒトMDMおよびHIV−1 p24 Ag陽性細胞の数を、Nikon Microphot−FXA顕微鏡で計数する。入手した全ての画像を、GFAP、Iba−1、MAP−2、およびNeuN陽性染色の面積(%)を定量化するために、Image−Pro Plus、バージョン4.0(Media Cybernetics,メリーランド州シルバースプリング)に取り込む。効果的なMLK阻害剤は、対照動物に対して小膠細胞症における用量依存的抑制および正常なシナプス構築を示す。本明細書に開示される化合物を、本方法に従って試験することができ、同様の結果を示すことが予測される。
Claims (71)
- 構造式II
破線は、第2の結合が代替的に存在しても、なくてもよいことを示し、
X1は、CHおよびNから選択され、
X2は、CおよびNから選択され、
Y1、Y2、およびY3は独立して、結合、低級アルキル、低級カルボキシル、および低級ヘテロアルキルから選択され、
Y4は、−(CH2)m、C(O)、−(CH2)mO−、および−(CH2)mN−から選択され、
mは、0〜2の整数であり、
R1、R2、およびR3は独立して、低級アルキル、低級アルケニル、低級アルキニル、低級ハロアルキル、低級シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アシル、アミド、アミノ、アルコキシ、ヒドロキシ、シアノ、およびニトロから選択され、それらのいずれも、任意で置換されてもよいか、あるいはR1およびR2は、それぞれさらにヘテロアルキルであってもよく、かつR1およびR2がともに、3〜5個の原子を含むアルキレン、アルケニレン、もしくはヘテロアルキル架橋を形成するように、ともに接合されてもよく、これは任意で置換されてもよく、
R4は、水素、(O)、および(S)から選択され、
R5は、水素、ヒドロキシ、シアノ、低級アルキル、低級シクロアルキル、および低級アルコキシから選択され、それらのいずれも、任意で置換されてもよく、
R13は、水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、低級アルキル、低級シクロアルキル、低級シクロアルキルアルキル、および低級アルコキシから選択され、それらのいずれも、任意で置換されてもよく、かつさらに、R13およびR3がともに接合して、3〜6個の原子を含む低級スピロ−シクロアルキルまたはスピロ−フェニルを形成してもよく、これは任意で置換されてもよく、
R14は、不在、低級シクロアルキル、低級ヘテロシクロアルキル、フェニル、および低級ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよい、化合物またはその塩。 - R4は(O)であり、R4と融合二環式コアとを結合する第2の結合が存在し、かつ前記融合二環式コアの5員部分の第2の結合が存在しない、請求項1に記載の化合物。
- R4は水素であり、R4と融合二環式コアとを結合する第2の結合が存在せず、かつ前記融合二環式コアの5員部分の第2の結合が存在する、請求項1に記載の化合物。
- 化合物が構造式III
破線は、第2の結合が代替的に存在しても、なくてもよいことを示し、
X1およびX2は独立して、CHおよびNから選択され、
Y3は、結合、低級アルキル、低級カルボキシル、および低級ヘテロアルキルから選択され、
Y4は、C(O)、−(CH2)m−、−(CH2)mO−、および−(CH2)mN−から選択され、
mは、0〜1の整数であり、
R2およびR3は独立して、低級シクロアルキル、ヘテロシクロアルキル、低級アリール、および低級ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよく、
R4は、水素、(O)、および(S)から選択され、
R14は、不在、低級シクロアルキル、低級ヘテロシクロアルキル、フェニル、および低級ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよい、請求項1に記載の化合物。 - 式IVおよび式V
X1およびX2は独立して、CHおよびNから選択され、
Y3は、結合、低級アルキル、低級カルボキシル、および低級ヘテロアルキルから選択され、
Y4は、C(O)、−(CH2)m−、−(CH2)mO−、および−(CH2)mN−から選択され、
mは、0〜1の整数であり、
R2およびR3は独立して、低級シクロアルキル、低級ヘテロシクロアルキル、低級アリール、および低級ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよく、
R14は、不在、低級シクロアルキル、低級ヘテロシクロアルキル、フェニル、および低級ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよい、請求項4に記載の化合物またはその塩。 - Y3は、結合、C(O)、および低級アルキルから選択される、請求項5に記載の化合物。
- R3は、低級シクロアルキル、フェニル、および低級ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよい、請求項6に記載の化合物。
- R2は、フェニルおよび低級ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよい、請求項7に記載の化合物。
- R2は、フェニル、6員の単環式ヘテロアリール、および5/6融合二環式ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよい、請求項7に記載の化合物。
- R2は、フェニル、ピリジニル、ピリミジニル、およびインドリルから選択され、それらのいずれも、任意で置換されてもよい、請求項9に記載の化合物。
- R2は、ハロゲン、ヒドロキシ、低級アミノ、C1−C3アルコキシ、およびC1−C3アルキルから選択される1つ以上の置換基で置換される、請求項10に記載の化合物。
- R2は、フッ素、ヒドロキシ、NH2、NH(CH3)、N(CH3)2、メトキシ、およびメチルから選択される1つ以上の置換基で置換される、請求項11に記載の化合物。
- 化合物が式VI、式VII、式VIII、および式IX
Y3は、結合、低級アルキル、低級カルボキシル、および低級ヘテロアルキルから選択され、
Y4は、C(O)、−(CH2)m−、−(CH2)mO−、および−(CH2)mN−から選択され、
mは、0〜1の整数であり、
R2は、フェニル、6員の単環式ヘテロアリール、および5/6融合二環式ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよく、
R3は、低級シクロアルキル、フェニル、および低級ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよく、
R14は、不在、低級シクロアルキル、低級ヘテロシクロアルキル、フェニル、および低級ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよい、請求項9に記載の化合物またはその塩。 - R2は、フェニル、ピリジニル、ピリミジニル、およびインドリルから選択され、それらのいずれも、任意で置換されてもよい、請求項13に記載の化合物。
- Y4は、C(O)、O、N、および−CH2−から選択される、請求項14に記載の化合物。
- R2は、
uは、0〜3の整数であり、
Y4は、C(O)、−(CH2)m−、−(CH2)mO−、および−(CH2)mN−から選択され、
mは、0〜1の整数であり、
R14は、不在、低級シクロアルキル、低級ヘテロシクロアルキル、フェニル、および低級ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよく、
各R15は独立して、ハロゲン、ヒドロキシ、シアノ、C1−C4アルキル、C2−C4アルケニル、C2−C4アルキニル、C1−C4ハロアルキル、C1−C3アルコキシ、C1−C3ハロアルコキシ、低級アミノ、低級アミド、低級スルホンアミド、および低級スルホニルから選択される、請求項13に記載の化合物。 - R14は、不在、低級ヘテロシクロアルキル、フェニル、および単環式低級ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよい、請求項16に記載の化合物。
- Y4は−(CH2)m−であり、
mは0であり、
R14は存在せず、
uは、1〜3の整数であり、
各R15は独立して、フッ素、ヒドロキシ、NH2、NH(CH3)、N(CH3)2、NS(O)2CH3、メトキシ、およびメチルから選択される、請求項17に記載の化合物。 - Y4は−(CH2)m−であり、
mは1であり、
R14は、不在、低級シクロアルキル、低級ヘテロシクロアルキル、フェニル、および低級ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよく、
uは、0〜2の整数であり、
各R15は独立して、フッ素、ヒドロキシ、NH2、NH(CH3)、N(CH3)2、NS(O)2CH3、メトキシ、およびメチルから選択される、請求項17に記載の化合物。 - 各R15は独立して、ハロゲン、ヒドロキシ、低級アミノ、C1−C3アルコキシ、およびC1−C3アルキルから選択される、請求項17に記載の化合物。
- Y4は、C(O)、O、N、および−CH2−から選択される、請求項20に記載の化合物。
- Y3は、結合および低級アルキルから選択される、請求項21に記載の化合物。
- R14は、不在および低級ヘテロシクロアルキルから選択され、それらのいずれも、任意で置換されてもよい、請求項22に記載の化合物。
- Y3は、結合およびメチルから選択される、請求項23に記載の化合物。
- R3は、ハロゲン、ヒドロキシ、低級アミノ、低級アミド、低級フェニルアミド、低級フェニルアルキルアミド、低級ヘテロシクロアルキル、低級ヘテロシクロアルキル、低級アルキルヘテロシクロアルキル、C1−C3アルコキシ、およびC1−C3アルキルから選択される1つ以上の置換基で置換される、請求項24に記載の化合物。
- Y4は−CH2−である、請求項25に記載の化合物。
- R3は、ベンゾチアゾリル、ピロロピリジニル、インダニル、シクロプロピル、シクロペンチル、フェニル、ピリジニル、ピリミジニル、およびインドリルから選択され、それらのいずれも、任意で置換されてもよい、請求項26に記載の化合物。
- Y3は結合である、請求項27に記載の化合物。
- 各R15は独立して、フッ素、ヒドロキシ、NH2、NH(CH3)、N(CH3)2、メトキシ、およびメチルから選択される、請求項28に記載の化合物。
- R3は、フッ素、塩素、ヒドロキシ、NH2、NH(CH3)、N(CH3)2、C(O)NH2、C(O)NHCH3、モルホリノ、ピペラジニル、メチルピペラジニル、アセトアミド、メチルアセトアミド、メチルプロピオンアミド、フェニルアセトアミドメチレン、ベンズアミドメチレン、フェニルプロパンアミドメチレン、メトキシ、およびメチルから選択される1つ以上の置換基で置換される、請求項29に記載の化合物。
- 構造式III
破線は、第2の結合が代替的に存在しても、なくてもよいことを示し、
X1およびX2は独立して、CHおよびNから選択され、
Y3は結合であり、
Y4は、C(O)、CH2、CHF、およびCF2から選択され、
R2は、フェニルおよび6員の単環式ヘテロアリールから選択され、それらのいずれも、任意で置換されてもよく、
R3は、任意で置換された二環式ヘテロアリールであり、
R4は、水素、(O)、および(S)から選択され、
R14は、任意で置換された単環式ヘテロシクロアルキルである、化合物またはその塩。 - R3は、任意で置換された5/6融合二環式ヘテロアリールである、請求項31に記載の化合物。
- Y4はCH2である、請求項32に記載の化合物。
- R14は、任意で置換されたピペラジニルである、請求項33に記載の化合物。
- 実施例1〜167から選択される、化合物。
- 薬物として使用するための、請求項1に記載の化合物。
- MLK媒介性疾患の治療のための薬物として使用するための、請求項1に記載の化合物。
- MLK3媒介性疾患の治療のための薬物として使用するための、請求項37に記載の化合物。
- 前記疾患は、真性糖尿病、高血糖、網膜症、腎症、ニューロパチー、潰瘍、微小血管障害および大血管障害、痛風および糖尿病性足部疾患、インスリン抵抗性、メタボリックシンドローム、高インスリン血症、高血圧、高尿酸血症、肥満、浮腫、脂質異常症、慢性心不全、アテローム性動脈硬化、末梢性炎症、癌、ならびに肝炎から選択される、請求項38に記載の化合物。
- MLK媒介性疾患の治療のための薬物の製造における、請求項1に記載の化合物の使用。
- 前記MLKはMLK3である、請求項40に記載の使用。
- 前記疾患は、真性糖尿病、高血糖、網膜症、腎症、ニューロパチー、潰瘍、微小血管障害および大血管障害、痛風および糖尿病性足部疾患、インスリン抵抗性、メタボリックシンドローム、高インスリン血症、高血圧、高尿酸血症、肥満、浮腫、脂質異常症、慢性心不全、アテローム性動脈硬化、末梢性炎症、癌、ならびに肝炎から選択される、請求項41に記載の使用。
- 請求項1に記載の化合物を薬学的に許容される担体とともに含む、薬学的組成物。
- 請求項43に記載の化合物を薬学的に許容される担体とともに含む、薬学的組成物。
- MLKを請求項1に記載の化合物と接触させることを含む、MLKの阻害の方法。
- 前記MLKはMLK3である、請求項45に記載の方法。
- 前記阻害は、他のキナーゼよりも選択的である、請求項46に記載の方法。
- MLK媒介性疾患の治療の方法であって、それを必要とする患者への、治療有効量の請求項1に記載の化合物の投与を含む、方法。
- 前記疾患は、炎症性疾患または代謝性疾患である、請求項48に記載の方法。
- 前記疾患は、真性糖尿病、高血糖、網膜症、腎症、ニューロパチー、潰瘍、微小血管障害および大血管障害、痛風および糖尿病性足部疾患、インスリン抵抗性、メタボリックシンドローム、高インスリン血症、高血圧、高尿酸血症、肥満、浮腫、脂質異常症、慢性心不全、アテローム性動脈硬化、ならびに末梢性炎症から選択される、請求項49に記載の方法。
- 前記疾患は自己免疫疾患である、請求項50に記載の方法。
- 前記疾患は、癌および肝炎から選択される、請求項51に記載の方法。
- MLK媒介性疾患の治療の方法であって、
a.治療有効量の請求項1に記載の化合物、および
b.別の治療薬の投与を含む、方法。 - 患者への治療有効量の請求項1に記載の化合物の前記投与を含む、患者において効果を達成する方法であって、前記効果は、
心臓細胞の生存の増加、
神経炎症または末梢性炎症の抑制、
免疫細胞の活性の抑制、
損傷後の肝細胞の増殖の抑制、および
癌細胞の増殖の抑制から選択される、方法。 - 前記免疫細胞は、単球、マクロファージ、および小膠細胞から選択される、請求項54に記載の方法。
- 患者における精神神経障害の治療の方法であって、前記患者にMLK阻害剤を投与するステップを含む、方法。
- 前記MLKはMLK3である、請求項56に記載の方法。
- 患者における精神神経障害の治療の方法であって、前記患者に請求項1に記載の化合物を投与するステップを含む、方法。
- 前記障害は心理的障害である、請求項58に記載の方法。
- 前記疾患は、鬱病、双極性障害、および心的外傷後ストレス障害(PTSD)から選択される、請求項59に記載の方法。
- 前記疾患は外傷性脳損傷である、請求項58に記載の方法。
- 前記外傷性脳損傷は脳卒中である、請求項61に記載の方法。
- 前記疾患は、アルツハイマー病(AD)、パーキンソン病、およびHIV関連神経認知障害(HAND)から選択される、請求項58に記載の方法。
- 前記疾患は、聴覚または視覚の神経疾患である、請求項58に記載の方法。
- 前記疾患は、中毒性難聴、難聴、内耳の急性損傷、音響外傷、および発破音に起因する損傷から選択される、請求項64に記載の方法。
- 第2の治療薬の投与をさらに含む、請求項2に記載の方法。
- 前記第2の治療薬は、選択的セロトニン再摂取阻害剤(SSRI)である、請求項66に記載の方法。
- 前記第2の治療薬はCEP1347である、請求項66に記載の方法。
- 患者への治療有効量の請求項1に記載の化合物の投与を含む、患者において効果を達成する方法であって、前記効果は、
神経系の細胞、蝸牛細胞、前庭細胞、または網膜細胞の生存の増加、
神経発生の促進、
シナプス形成の促進、
神経損傷の予防または低減、および
神経機能の回復または向上から選択される、方法。 - 患者への治療有効量の請求項1に記載の化合物の投与を含む、患者において効果を達成する方法であって、前記効果は、
神経系の細胞、蝸牛細胞、前庭細胞、または網膜細胞の生存の増加、
心臓細胞の生存の増加、
神経発生の促進、
シナプス形成の促進、
神経損傷の予防または低減、
神経機能の回復または向上、
神経炎症または末梢性炎症の抑制、
免疫細胞の活性の抑制、
損傷後の肝細胞の増殖の抑制、および
癌細胞の増殖の抑制から選択される、方法。 - 前記免疫細胞は、単球、マクロファージ、および小膠細胞から選択される、請求項70に記載の方法。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11795008P | 2008-11-25 | 2008-11-25 | |
US61/117,950 | 2008-11-25 | ||
US14877809P | 2009-01-30 | 2009-01-30 | |
US14875509P | 2009-01-30 | 2009-01-30 | |
US61/148,755 | 2009-01-30 | ||
US61/148,778 | 2009-01-30 | ||
PCT/US2009/065878 WO2010068483A2 (en) | 2008-11-25 | 2009-11-25 | Mlk inhibitors and methods of use |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014232195A Division JP5873544B2 (ja) | 2008-11-25 | 2014-11-14 | Mlk阻害剤および使用方法 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2012509903A true JP2012509903A (ja) | 2012-04-26 |
JP2012509903A5 JP2012509903A5 (ja) | 2013-01-17 |
JP5930278B2 JP5930278B2 (ja) | 2016-06-08 |
Family
ID=42243278
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2011537733A Active JP5930278B2 (ja) | 2008-11-25 | 2009-11-25 | Mlk阻害剤および使用方法 |
JP2014232195A Active JP5873544B2 (ja) | 2008-11-25 | 2014-11-14 | Mlk阻害剤および使用方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014232195A Active JP5873544B2 (ja) | 2008-11-25 | 2014-11-14 | Mlk阻害剤および使用方法 |
Country Status (8)
Country | Link |
---|---|
US (4) | US8877772B2 (ja) |
EP (2) | EP2379561B1 (ja) |
JP (2) | JP5930278B2 (ja) |
CN (1) | CN102264743B (ja) |
AU (1) | AU2009324894B2 (ja) |
CA (1) | CA2744498C (ja) |
ES (1) | ES2554375T3 (ja) |
WO (1) | WO2010068483A2 (ja) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014181813A1 (ja) * | 2013-05-10 | 2014-11-13 | 武田薬品工業株式会社 | 複素環化合物 |
JP2015052009A (ja) * | 2008-11-25 | 2015-03-19 | ユニバーシティー オブ ロチェスター | Mlk阻害剤および使用方法 |
JP2019530695A (ja) * | 2016-10-06 | 2019-10-24 | ヤンセン ファーマシューティカ エヌ.ベー. | 置換1H−イミダゾ[4,5−b]ピリジン−2(3H)−オン及びGLUN2B受容体調節因子としてのそれらの使用 |
JP2021518856A (ja) * | 2018-03-01 | 2021-08-05 | ザ トラスティーズ オブ コロンビア ユニバーシティー イン ザ シティー オブ ニューヨーク | 有毒な小胞体ストレスを抑制するための化合物、組成物、および方法 |
JP2022547436A (ja) * | 2019-08-30 | 2022-11-14 | ティーエスディー ライフ サイエンス カンパニー リミテッド | イミダゾピリジン誘導体及びこれを有効成分として含有する薬学的組成物 |
JP7486478B2 (ja) | 2018-09-19 | 2024-05-17 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | スピロ環状2,3-ジヒドロ-7-アザインドール化合物およびその使用 |
Families Citing this family (102)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8227603B2 (en) | 2006-08-01 | 2012-07-24 | Cytokinetics, Inc. | Modulating skeletal muscle |
PT2583970E (pt) | 2006-08-02 | 2016-02-08 | Cytokinetics Inc | Certas entidades químicas, composições e métodos compreendendo imidazopirimidinas |
US8299248B2 (en) | 2006-08-02 | 2012-10-30 | Cytokinetics, Incorporated | Certain 1H-imidazo[4,5-b]pyrazin-2(3H)-ones and 1H-imidazo[4,5-b]pyrazin-2-ols and methods for their use |
KR20140104060A (ko) | 2006-10-19 | 2014-08-27 | 시그날 파마소티칼 엘엘씨 | 헤테로아릴 화합물, 이들의 조성물 그리고 단백질 키나아제 억제제로서의 이들의 용도 |
EP2244711A4 (en) | 2008-02-04 | 2011-08-24 | Cytokinetics Inc | CERTAIN CHEMICAL ENTITIES, COMPOSITIONS AND METHODS |
US7998976B2 (en) | 2008-02-04 | 2011-08-16 | Cytokinetics, Inc. | Certain chemical entities, compositions and methods |
MY153606A (en) | 2008-08-05 | 2015-02-27 | Daiichi Sankyo Co Ltd | Imidazopyridin-2-one derivatives |
RU2011123647A (ru) | 2008-11-10 | 2012-12-20 | Вертекс Фармасьютикалз Инкорпорейтед | Соединения, полезные в качестве ингибиторов atr киназы |
CA3013000C (en) | 2008-12-19 | 2022-12-13 | Vertex Pharmaceuticals Incorporated | Pyrazine derivatives useful as inhibitors of atr kinase |
RU2557242C2 (ru) | 2009-10-26 | 2015-07-20 | СИГНАЛ ФАРМАСЬЮТИКАЛЗ, ЭлЭлСи | Способы получения и очистки гетероарильных соединений |
SG185524A1 (en) | 2010-05-12 | 2012-12-28 | Vertex Pharma | Compounds useful as inhibitors of atr kinase |
EP2568984A1 (en) | 2010-05-12 | 2013-03-20 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
EP2569287B1 (en) | 2010-05-12 | 2014-07-09 | Vertex Pharmaceuticals Inc. | Compounds useful as inhibitors of atr kinase |
CA2798760A1 (en) | 2010-05-12 | 2011-11-17 | Vertex Pharmaceuticals Incorporated | 2-aminopyridine derivatives useful as inhibitors of atr kinase |
EP2569286B1 (en) | 2010-05-12 | 2014-08-20 | Vertex Pharmaceuticals Inc. | Compounds useful as inhibitors of atr kinase |
WO2011143419A1 (en) | 2010-05-12 | 2011-11-17 | Vertex Pharmaceuticals Incorporated | Pyrazines useful as inhibitors of atr kinase |
EP2576549A4 (en) * | 2010-05-24 | 2013-12-18 | Univ Rochester | Bicyclic Heteroarylkinase Inhibitors and Methods of Use |
EP2585468A1 (en) * | 2010-06-23 | 2013-05-01 | Vertex Pharmaceuticals Incorporated | Pyrrolo- pyrazine derivatives useful as inhibitors of atr kinase |
DE102010049877A1 (de) | 2010-11-01 | 2012-05-03 | Merck Patent Gmbh | 7-((1,2,3)Triazol-4-yl)-pyrrolo(2,3) pyrazinderivate |
EP2487159A1 (en) * | 2011-02-11 | 2012-08-15 | MSD Oss B.V. | RorgammaT inhibitors |
JP2014510151A (ja) | 2011-04-05 | 2014-04-24 | バーテックス ファーマシューティカルズ インコーポレイテッド | Atrキナーゼ(trakinase)阻害剤として有用なアミノピラジン化合物 |
JP2014522818A (ja) | 2011-06-22 | 2014-09-08 | バーテックス ファーマシューティカルズ インコーポレイテッド | Atrキナーゼ阻害剤として有用な化合物 |
US8822469B2 (en) | 2011-06-22 | 2014-09-02 | Vertex Pharmaceuticals Incorporated | Pyrrolo[2,3-B]pyrazines useful as inhibitors of ATR kinase |
EP2723746A1 (en) | 2011-06-22 | 2014-04-30 | Vertex Pharmaceuticals Inc. | Compounds useful as inhibitors of atr kinase |
EA201791043A1 (ru) | 2011-07-13 | 2017-09-29 | Сайтокинетикс, Инк. | Комбинированная терапия бокового амиотрофического склероза |
EP2751088B1 (en) | 2011-09-30 | 2016-04-13 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
CA2850564A1 (en) | 2011-09-30 | 2013-04-04 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
CA2850491C (en) | 2011-09-30 | 2020-10-27 | Vertex Pharmaceuticals Incorporated | Treating pancreatic cancer and non-small cell lung cancer with atr inhibiors |
WO2013049726A2 (en) | 2011-09-30 | 2013-04-04 | Vertex Pharmaceuticals Incorporated | Processes for making compounds useful as inhibitors of atr kinase |
US8853217B2 (en) | 2011-09-30 | 2014-10-07 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
CA2852921C (en) | 2011-10-19 | 2023-10-10 | Signal Pharmaceuticals, Llc | Treatment of cancer with tor kinase inhibitors |
US8841450B2 (en) | 2011-11-09 | 2014-09-23 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
JP2015502925A (ja) | 2011-11-09 | 2015-01-29 | バーテックス ファーマシューティカルズ インコーポレイテッドVertex Pharmaceuticals Incorporated | Atrキナーゼの阻害剤として有用なピラジン化合物 |
EP2776429A1 (en) | 2011-11-09 | 2014-09-17 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
WO2013071088A1 (en) | 2011-11-09 | 2013-05-16 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
WO2013071090A1 (en) | 2011-11-09 | 2013-05-16 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
BR112014013332B1 (pt) | 2011-12-02 | 2022-09-06 | Signal Pharmaceuticals, Llc | Composições farmacêuticas de 7-(6-(2-hidroxi-propan-2-il)piridin-3-il)-1-((trans)-4- metoxicicloexil)-3,4-diidropirazino [2,3-b]pirazin-2(1h)-ona, uma forma sólida dessa e métodos de seu uso |
AU2013202305B2 (en) | 2012-02-24 | 2015-03-12 | Signal Pharmaceuticals, Llc | Methods for treating cancer using TOR kinase inhibitor combination therapy |
CN102627646A (zh) * | 2012-03-19 | 2012-08-08 | 苏州四同医药科技有限公司 | 一种3-碘-5-溴-4,7-二氮杂吲哚的制备方法 |
MX358818B (es) | 2012-04-05 | 2018-09-05 | Vertex Pharma | Compuestos utiles como inhibidores de cinasa ataxia telangiectasia mutada y rad3 relacionados (atr) y terapias de combinacion de estos. |
WO2014026327A1 (en) | 2012-08-15 | 2014-02-20 | Merck Sharp & Dohme Corp. | 4-heteroaryl substituted benzoic acid compounds as rorgammat inhibitors and uses thereof |
WO2014026329A1 (en) | 2012-08-15 | 2014-02-20 | Merck Sharp & Dohme Corp. | N-alkylated indole and indazole compounds as rorgammat inhibitors and uses thereof |
WO2014026330A1 (en) | 2012-08-15 | 2014-02-20 | Merck Sharp & Dohme Corp. | 3-AMINOCYCLOALKYL COMPOUNDS AS RORgammaT INHIBITORS AND USES THEREOF |
WO2014055756A1 (en) | 2012-10-04 | 2014-04-10 | Vertex Pharmaceuticals Incorporated | Method for measuring atr inhibition mediated increases in dna damage |
US8912198B2 (en) | 2012-10-16 | 2014-12-16 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
AU2013203714B2 (en) | 2012-10-18 | 2015-12-03 | Signal Pharmaceuticals, Llc | Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity |
US9073878B2 (en) | 2012-11-21 | 2015-07-07 | Zenith Epigenetics Corp. | Cyclic amines as bromodomain inhibitors |
WO2014080291A2 (en) | 2012-11-21 | 2014-05-30 | Rvx Therapeutics Inc. | Biaryl derivatives as bromodomain inhibitors |
EP2925319B1 (en) * | 2012-11-30 | 2019-01-09 | University Of Rochester | Mixed lineage kinase inhibitors for hiv/aids therapies |
ES2946360T3 (es) | 2012-12-07 | 2023-07-17 | Vertex Pharma | Pirazolo[1,5-a]pirimidinas útiles como inhibidores de ATR quinasa para el tratamiento de enfermedades de cáncer |
US9260426B2 (en) | 2012-12-14 | 2016-02-16 | Arrien Pharmaceuticals Llc | Substituted 1H-pyrrolo [2, 3-b] pyridine and 1H-pyrazolo [3, 4-b] pyridine derivatives as salt inducible kinase 2 (SIK2) inhibitors |
CA2895905A1 (en) | 2012-12-21 | 2014-06-26 | Zenith Epigenetics Corp. | Novel heterocyclic compounds as bromodomain inhibitors |
CA2897985A1 (en) | 2013-01-16 | 2014-07-24 | Signal Pharmaceuticals, Llc | Substituted pyrrolopyrimidine compounds, compositions thereof, and methods of treatment therewith |
WO2014138692A1 (en) * | 2013-03-07 | 2014-09-12 | Califia Bio, Inc. | Mixed lineage kinase inhibitors and method of treatments |
WO2014143240A1 (en) | 2013-03-15 | 2014-09-18 | Vertex Pharmaceuticals Incorporated | Fused pyrazolopyrimidine derivatives useful as inhibitors of atr kinase |
CN105392499B (zh) | 2013-04-17 | 2018-07-24 | 西格诺药品有限公司 | 用于治疗癌症的包含tor激酶抑制剂和胞苷类似物的组合疗法 |
NZ629469A (en) | 2013-04-17 | 2017-05-26 | Signal Pharm Llc | Methods for treating cancer using dihydropyrazino-pyrazine compound combination therapy |
CN105339008A (zh) | 2013-04-17 | 2016-02-17 | 西格诺药品有限公司 | 用于治疗癌症的包括tor激酶抑制剂和n-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯基氨基)嘧啶-4-基氨基)苯基)丙烯酰胺的组合疗法 |
CA2908353C (en) | 2013-04-17 | 2021-11-02 | Signal Pharmaceuticals, Llc | Treatment of cancer with dihydropyrazino-pyrazines |
TWI656875B (zh) | 2013-04-17 | 2019-04-21 | 美商標誌製藥公司 | 藉二氫吡并吡治療癌症 |
ES2744198T3 (es) | 2013-04-17 | 2020-02-24 | Signal Pharm Llc | Formulaciones farmacéuticas, procesos, formas sólidas y procedimientos de uso relacionados con 1-etil-7-(2-metil-6-(1H-1,2,4-triazol-3-il)piridin-3-il)-3, 4 dihidropirazino[2,3-b]pirazin-2(1H)-ona |
CA2909625C (en) | 2013-04-17 | 2021-06-01 | Signal Pharmaceuticals, Llc | Combination therapy comprising a tor kinase inhibitor and a 5-substituted quinazolinone compound for treating cancer |
US9604939B2 (en) | 2013-05-29 | 2017-03-28 | Signal Pharmaceuticals, Llc | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-YL)pyridin-3-YL)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-B]pyrazin-2(1H)-one, a solid form thereof and methods of their use |
US9636328B2 (en) | 2013-06-21 | 2017-05-02 | Zenith Epigenetics Ltd. | Substituted bicyclic compounds as bromodomain inhibitors |
BR112015031073B1 (pt) | 2013-06-21 | 2022-11-29 | Zenith Epigenetics Ltd | Compostos inibidores bicíclicos de bromodomínio e composição farmacêutica contendo os referidos compostos |
KR20160038008A (ko) | 2013-07-31 | 2016-04-06 | 제니쓰 에피제네틱스 코포레이션 | 브로모도메인 억제제로서 신규 퀴나졸리논 |
RU2687276C2 (ru) | 2013-12-06 | 2019-05-13 | Вертекс Фармасьютикалз Инкорпорейтед | Соединения, пригодные для использования в качестве ингибиторов atr киназы |
US9718824B2 (en) | 2014-04-16 | 2017-08-01 | Signal Pharmaceuticals, Llc | Solid forms comprising 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, and a coformer, compositions and methods of use thereof |
ES2823756T3 (es) | 2014-04-16 | 2021-05-10 | Signal Pharm Llc | Métodos para tratar el cáncer usando terapia de combinación de inhibidores de quinasa TOR |
US9512129B2 (en) | 2014-04-16 | 2016-12-06 | Signal Pharmaceuticals, Llc | Solid forms comprising 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one and a coformer |
NZ714742A (en) | 2014-04-16 | 2017-04-28 | Signal Pharm Llc | Solid forms of 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one, compositions thereof and methods of their use |
LT3152212T (lt) | 2014-06-05 | 2020-05-11 | Vertex Pharmaceuticals Inc. | Radioaktyviai žymėti 2-amino-6-fluor-n-[5-fluor-piridin-il]- pirazolo[1,5-a]pirimidin-3-karboksamido junginio dariniai, naudingi kaip atr kinazės inhibitoriai, minėto junginio gamybos būdas ir jo skirtingos kietos formos |
SG11201610500WA (en) | 2014-06-17 | 2017-01-27 | Vertex Pharma | Method for treating cancer using a combination of chk1 and atr inhibitors |
NZ629796A (en) | 2014-07-14 | 2015-12-24 | Signal Pharm Llc | Amorphous form of 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7h-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-n-methylbenzamide, compositions thereof and methods of their use |
CA2955009A1 (en) | 2014-07-14 | 2016-01-21 | Signal Pharmaceuticals, Llc | Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof |
US10155727B2 (en) | 2014-08-15 | 2018-12-18 | Janssen Pharmaceuticals, Inc. | Pyrazoles |
EP3180329B1 (en) | 2014-08-15 | 2020-03-18 | Janssen Pharmaceuticals, Inc. | Triazoles as nr2b receptor inhibitors |
US10710992B2 (en) | 2014-12-01 | 2020-07-14 | Zenith Epigenetics Ltd. | Substituted pyridinones as bromodomain inhibitors |
US10179125B2 (en) | 2014-12-01 | 2019-01-15 | Zenith Epigenetics Ltd. | Substituted pyridines as bromodomain inhibitors |
WO2016092375A1 (en) | 2014-12-11 | 2016-06-16 | Zenith Epigenetics Corp. | Substituted heterocycles as bromodomain inhibitors |
US10231953B2 (en) | 2014-12-17 | 2019-03-19 | Zenith Epigenetics Ltd. | Inhibitors of bromodomains |
EP3256450B1 (en) | 2015-02-11 | 2020-12-02 | Merck Sharp & Dohme Corp. | Substituted pyrazole compounds as ror-gamma-t inhibitors and uses thereof |
WO2016164641A1 (en) * | 2015-04-08 | 2016-10-13 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
WO2017007938A1 (en) | 2015-07-09 | 2017-01-12 | Janssen Pharmaceutica Nv | Substituted 4-azaindoles and their use as glun2b receptor modulators |
CA3000684A1 (en) | 2015-09-30 | 2017-04-06 | Vertex Pharmaceuticals Incorporated | Method for treating cancer using a combination of dna damaging agents and atr inhibitors |
US10584121B2 (en) | 2015-10-27 | 2020-03-10 | Merck Sharp & Dohme Corp. | Heteroaryl substituted benzoic acids as RORgammaT inhibitors and uses thereof |
EP3368516B1 (en) | 2015-10-27 | 2020-07-15 | Merck Sharp & Dohme Corp. | SUBSTITUTED BICYCLIC PYRAZOLE COMPOUNDS AS RORgammaT INHIBITORS AND USES THEREOF |
KR20180070697A (ko) | 2015-10-27 | 2018-06-26 | 머크 샤프 앤드 돔 코포레이션 | Ror감마t 저해제로서의 치환된 인다졸 화합물 및 이의 용도 |
CN109071488B (zh) | 2016-02-10 | 2021-08-13 | 詹森药业有限公司 | 取代的1,2,3-三唑作为nr2b-选择性nmda调节剂 |
ES2959860T3 (es) | 2017-06-22 | 2024-02-28 | Celgene Corp | Tratamiento del carcinoma hepatocelular caracterizado por la infección por el virus de la hepatitis B |
EP3774732A4 (en) | 2018-04-04 | 2022-02-09 | Janssen Pharmaceutica NV | PYRIDINE AND SUBSTITUTED PYRIMIDINES AND THEIR USE AS GLUN2B RECEPTOR MODULATORS |
AU2020293642A1 (en) | 2019-06-14 | 2022-01-20 | Janssen Pharmaceutica Nv | Substituted pyrazolo[4,3-b]pyridines and their use as GluN2B receptor modulators |
PE20220386A1 (es) | 2019-06-14 | 2022-03-18 | Janssen Pharmaceutica Nv | Amidas de pirazolo-piridina sustituidas y su uso como moduladores del receptor glun2b |
MX2021015500A (es) | 2019-06-14 | 2022-02-10 | Janssen Pharmaceutica Nv | Pirazolo-pirazinas sustituidas y su uso como moduladores del receptor glun2b. |
CN114007691A (zh) | 2019-06-14 | 2022-02-01 | 詹森药业有限公司 | 吡啶氨基甲酸酯及其作为GluN2B受体调节剂的用途 |
JOP20210330A1 (ar) | 2019-06-14 | 2023-01-30 | Janssen Pharmaceutica Nv | مركبات بيرازولو-بيريدين عطرية غير متجانسة مستبدلة واستخدامها كمعدِّلات لمستقبل الغلوتومات "glun2b" |
JP2022538795A (ja) | 2019-06-14 | 2022-09-06 | ヤンセン ファーマシューティカ エヌ.ベー. | ピラジンカルバメート及びGluN2B受容体調節因子としての使用 |
WO2023050323A1 (en) * | 2021-09-30 | 2023-04-06 | Citrix Systems, Inc. | Automated transfer of peripheral device operations |
US11661409B1 (en) * | 2022-01-31 | 2023-05-30 | Pioneura Corporation | Acid addition salts, compositions, and methods of treating |
US11479541B1 (en) | 2022-01-31 | 2022-10-25 | Pioneura Corporation | Acid addition salts, compositions, and methods of treating thereof |
WO2023207911A1 (zh) * | 2022-04-24 | 2023-11-02 | 上海医药集团股份有限公司 | 一种双环杂环化合物、药物组合物和应用 |
CN117447392A (zh) * | 2023-09-13 | 2024-01-26 | 广州大学 | 一种荧光材料及其制备方法和应用 |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2400101A (en) * | 2003-03-28 | 2004-10-06 | Biofocus Discovery Ltd | Compounds capable of binding to the active site of protein kinases |
JP2006521336A (ja) * | 2003-03-06 | 2006-09-21 | エーザイ株式会社 | Jun阻害剤 |
US20070043068A1 (en) * | 2004-07-27 | 2007-02-22 | Sgx Pharmaceuticals, Inc. | Pyrrolo-pyridine kinase modulators |
JP2007504252A (ja) * | 2003-09-04 | 2007-03-01 | バーテックス ファーマシューティカルズ インコーポレイテッド | プロテインキナーゼのインヒビターとして有用な組成物 |
JP2007516180A (ja) * | 2003-07-02 | 2007-06-21 | スゲン,インコーポレイティド | c−Met阻害薬としてのアリールメチルトリアゾロおよびイミダゾピラジン類 |
JP2008508303A (ja) * | 2004-07-27 | 2008-03-21 | エスジーエックス ファーマシューティカルズ、インコーポレイテッド | ピロロ−ピリジンキナーゼモジュレーター |
WO2008051493A2 (en) * | 2006-10-19 | 2008-05-02 | Signal Pharmaceuticals, Llc | Heteroaryl compounds, compositions thereof, and their use as protein kinase inhibitors |
JP2008514628A (ja) * | 2004-09-24 | 2008-05-08 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 蛋白質キナーゼ類のイミダゾ{4,5−b}ピラジノン阻害剤 |
US20080146561A1 (en) * | 2006-08-02 | 2008-06-19 | Alex Muci | Certain chemical entities, compositions and methods |
JP2008523085A (ja) * | 2004-12-08 | 2008-07-03 | スミスクライン・ビーチャム・コーポレイション | 1h−ピロロ[2,3−b]ピリジン |
WO2008124849A2 (en) * | 2007-04-10 | 2008-10-16 | Sgx Pharmaceuticals, Inc. | Pyrrolo-pyridine kinase modulators |
WO2010016490A1 (ja) * | 2008-08-05 | 2010-02-11 | 第一三共株式会社 | イミダゾピリジン-2-オン誘導体 |
Family Cites Families (66)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4933438A (en) | 1984-02-29 | 1990-06-12 | University Of Florida | Brain-specific analogues of centrally acting amines |
US6150354A (en) | 1987-01-15 | 2000-11-21 | Bonnie Davis | Compounds for the treatment of Alzheimer's disease |
US5133974A (en) | 1989-05-05 | 1992-07-28 | Kv Pharmaceutical Company | Extended release pharmaceutical formulations |
DK0584185T3 (da) | 1991-05-14 | 2000-02-07 | Ernir Snorrason | Behandling af træthedssyndrom med cholinesteraseinhibitorer |
IT1250421B (it) | 1991-05-30 | 1995-04-07 | Recordati Chem Pharm | Composizione farmaceutica a rilascio controllato con proprieta' bio-adesive. |
US6537579B1 (en) | 1993-02-22 | 2003-03-25 | American Bioscience, Inc. | Compositions and methods for administration of pharmacologically active compounds |
FR2710265B1 (fr) | 1993-09-22 | 1995-10-20 | Adir | Composition pharmaceutique bioadhésive pour la libération contrôlée de principes actifs. |
US5618819A (en) | 1994-07-07 | 1997-04-08 | Adir Et Compagnie | 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one and oxazolo[4,5-b]pyridin-2-(3H)-one compounds |
US6548084B2 (en) | 1995-07-20 | 2003-04-15 | Smithkline Beecham Plc | Controlled release compositions |
US6245347B1 (en) | 1995-07-28 | 2001-06-12 | Zars, Inc. | Methods and apparatus for improved administration of pharmaceutically active compounds |
DE19541260A1 (de) | 1995-11-06 | 1997-05-07 | Lohmann Therapie Syst Lts | Therapeutische Zubereitung zur transdermalen Applikation von Wirkstoffen durch die Haut |
US6512010B1 (en) | 1996-07-15 | 2003-01-28 | Alza Corporation | Formulations for the administration of fluoxetine |
AU9062998A (en) | 1997-09-11 | 1999-03-29 | Nycomed Danmark A/S | Modified release multiple-units compositions of non-steroid anti-inflammatory drug substances (nsaids) |
US6624200B2 (en) | 1998-08-25 | 2003-09-23 | Columbia Laboratories, Inc. | Bioadhesive progressive hydration tablets |
US6607751B1 (en) | 1997-10-10 | 2003-08-19 | Intellipharamaceutics Corp. | Controlled release delivery device for pharmaceutical agents incorporating microbial polysaccharide gum |
GB9721437D0 (en) | 1997-10-10 | 1997-12-10 | Glaxo Group Ltd | Heteroaromatic compounds and their use in medicine |
US6403597B1 (en) | 1997-10-28 | 2002-06-11 | Vivus, Inc. | Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation |
US6248864B1 (en) | 1997-12-31 | 2001-06-19 | Adherex Technologies, Inc. | Compounds and methods and modulating tissue permeability |
US6613358B2 (en) | 1998-03-18 | 2003-09-02 | Theodore W. Randolph | Sustained-release composition including amorphous polymer |
US6312717B1 (en) | 1998-07-07 | 2001-11-06 | Bristol-Myers Squibb Company | Method for treatment of anxiety and depression |
US20020009478A1 (en) | 1998-08-24 | 2002-01-24 | Douglas Joseph Dobrozsi | Oral liquid mucoadhesive compositions |
SE9802864D0 (sv) | 1998-08-27 | 1998-08-27 | Pharmacia & Upjohn Ab | Transdermally administered tolterodine as antimuscarinic agent for the treatment of overactive bladder |
CN1406126A (zh) | 1998-10-01 | 2003-03-26 | 诺瓦提斯公司 | 新型缓释口服制剂 |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
GB9904933D0 (en) | 1999-03-04 | 1999-04-28 | Glaxo Group Ltd | Compounds |
GB9904995D0 (en) | 1999-03-04 | 1999-04-28 | Glaxo Group Ltd | Substituted aza-oxindole derivatives |
US6498176B1 (en) | 1999-03-04 | 2002-12-24 | Smithklinebeecham Corporation | 3-(anilinomethylene) oxindoles as protein tyrosine kinase and protein serine/threonine kinase inhibitors |
US6624171B1 (en) | 1999-03-04 | 2003-09-23 | Smithkline Beecham Corporation | Substituted aza-oxindole derivatives |
FR2792527B1 (fr) | 1999-04-22 | 2004-08-13 | Ethypharm Lab Prod Ethiques | Microgranules de ketoprofene, procede de preparation et compositions pharmaceutiques |
US6541020B1 (en) | 1999-07-09 | 2003-04-01 | Trimeris, Inc. | Methods and compositions for administration of therapeutic reagents |
CN1361779A (zh) | 1999-07-21 | 2002-07-31 | 阿斯特拉曾尼卡有限公司 | 新化合物 |
US6562375B1 (en) | 1999-08-04 | 2003-05-13 | Yamanouchi Pharmaceuticals, Co., Ltd. | Stable pharmaceutical composition for oral use |
CA2383220C (en) | 1999-09-02 | 2009-11-03 | Nostrum Pharmaceuticals, Inc. | Controlled release pellet formulation |
US6544548B1 (en) | 1999-09-13 | 2003-04-08 | Keraplast Technologies, Ltd. | Keratin-based powders and hydrogel for pharmaceutical applications |
US6080736A (en) | 1999-10-27 | 2000-06-27 | Janus Pharmaceuticals, Inc. | Methods and compositions for treating and preventing anxiety and anxiety disorders using optically pure (R) tofisopam |
US6461631B1 (en) | 1999-11-16 | 2002-10-08 | Atrix Laboratories, Inc. | Biodegradable polymer composition |
WO2001047501A1 (en) | 1999-12-29 | 2001-07-05 | Nanodelivery, Inc. | Drug delivery system exhibiting permeability control |
US6589549B2 (en) | 2000-04-27 | 2003-07-08 | Macromed, Incorporated | Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles |
US6524621B2 (en) | 2000-05-01 | 2003-02-25 | Aeropharm Technology Inc. | Core formulation |
US6482440B2 (en) | 2000-09-21 | 2002-11-19 | Phase 2 Discovery, Inc. | Long acting antidepressant microparticles |
US6524615B2 (en) | 2001-02-21 | 2003-02-25 | Kos Pharmaceuticals, Incorporated | Controlled release pharmaceutical composition |
WO2002070662A2 (en) | 2001-03-02 | 2002-09-12 | Gpc Biotech Ag | Three hybrid assay system |
US20030187026A1 (en) | 2001-12-13 | 2003-10-02 | Qun Li | Kinase inhibitors |
ATE508129T1 (de) * | 2004-03-30 | 2011-05-15 | Vertex Pharma | Als inhibitoren von jak und anderen proteinkinasen geeignete azaindole |
US20060011139A1 (en) | 2004-07-16 | 2006-01-19 | Applied Materials, Inc. | Heated substrate support for chemical vapor deposition |
CN101027302B (zh) * | 2004-07-27 | 2011-05-11 | Sgx药物公司 | 吡咯并吡啶激酶调节剂 |
US7626021B2 (en) | 2004-07-27 | 2009-12-01 | Sgx Pharmaceuticals, Inc. | Fused ring heterocycle kinase modulators |
CA2585544A1 (en) | 2004-10-27 | 2006-05-11 | Janssen Pharmaceutica N.V. | Pyridine imidazoles and aza-indoles as progesterone receptor modulators |
JP2008530212A (ja) | 2005-02-16 | 2008-08-07 | シェーリング コーポレイション | Cxcr3アンタゴニスト活性を有するピペラジン−ピペリジン |
BRPI0611863B1 (pt) * | 2005-06-22 | 2021-11-23 | Plexxikon, Inc | Composto, bem como composição e kit compreendendo o mesmo, composto intermediário na preparação do mesmo, método para tratamento e uso do mesmo |
JP2007108926A (ja) | 2005-10-12 | 2007-04-26 | Denso Corp | 運転支援装置及びプログラム |
CN101317091A (zh) | 2005-12-08 | 2008-12-03 | Irm责任有限公司 | 抑制人类免疫缺陷病毒(hiv)感染的方法和组合物 |
ATE477331T1 (de) | 2006-05-05 | 2010-08-15 | George Mason Intellectual Prop | Verfahren zum nachweis einer hiv-infektion |
CN101448827A (zh) * | 2006-05-22 | 2009-06-03 | 阿斯利康(瑞典)有限公司 | 吲哚衍生物 |
US7732447B2 (en) | 2006-06-22 | 2010-06-08 | Cephalon, Inc. | Fused [d]pyridazin-7-ones |
GB0706168D0 (en) | 2007-03-29 | 2007-05-09 | Glaxo Group Ltd | Compounds |
AU2008237019A1 (en) | 2007-04-10 | 2008-10-16 | Sgx Pharmaceuticals, Inc. | Fused ring heterocycle kinase modulators |
EP2143724B1 (en) | 2007-04-18 | 2013-12-11 | Kissei Pharmaceutical Co., Ltd. | Nitrogenated fused ring derivative, pharmaceutical composition comprising the same, and use of the same for medical purposes |
AU2008317406B2 (en) | 2007-10-25 | 2013-07-18 | Merck Sharp & Dohme Corp. | Therapeutic compounds |
CA2713710A1 (en) | 2008-02-25 | 2009-09-03 | F. Hoffmann-La Roche Ag | Pyrrolopyrazine kinase inhibitors |
US8592448B2 (en) * | 2008-11-20 | 2013-11-26 | OSI Pharmaceuticals, LLC | Substituted pyrrolo[2,3-b]-pyridines and -pyrazines |
AU2009324894B2 (en) * | 2008-11-25 | 2015-04-09 | University Of Rochester | MLK inhibitors and methods of use |
US8846096B2 (en) | 2008-12-12 | 2014-09-30 | Creighton University | Nanoparticles and methods of use |
EP2576549A4 (en) | 2010-05-24 | 2013-12-18 | Univ Rochester | Bicyclic Heteroarylkinase Inhibitors and Methods of Use |
AU2011323458B2 (en) | 2010-11-02 | 2017-02-23 | Board Of Regents Of The University Of Nebraska | Compositions and methods for the delivery of therapeutics |
EP2925319B1 (en) | 2012-11-30 | 2019-01-09 | University Of Rochester | Mixed lineage kinase inhibitors for hiv/aids therapies |
-
2009
- 2009-11-25 AU AU2009324894A patent/AU2009324894B2/en active Active
- 2009-11-25 CA CA2744498A patent/CA2744498C/en active Active
- 2009-11-25 JP JP2011537733A patent/JP5930278B2/ja active Active
- 2009-11-25 EP EP09832359.5A patent/EP2379561B1/en active Active
- 2009-11-25 EP EP15186751.2A patent/EP3037421A3/en not_active Withdrawn
- 2009-11-25 WO PCT/US2009/065878 patent/WO2010068483A2/en active Application Filing
- 2009-11-25 ES ES09832359.5T patent/ES2554375T3/es active Active
- 2009-11-25 CN CN200980152665.1A patent/CN102264743B/zh active Active
- 2009-11-25 US US13/131,193 patent/US8877772B2/en active Active
-
2014
- 2014-10-07 US US14/508,566 patent/US9181247B2/en active Active
- 2014-11-14 JP JP2014232195A patent/JP5873544B2/ja active Active
-
2015
- 2015-10-06 US US14/876,345 patent/US20160024087A1/en not_active Abandoned
-
2016
- 2016-06-03 US US15/172,355 patent/US9814704B2/en active Active
Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006521336A (ja) * | 2003-03-06 | 2006-09-21 | エーザイ株式会社 | Jun阻害剤 |
GB2400101A (en) * | 2003-03-28 | 2004-10-06 | Biofocus Discovery Ltd | Compounds capable of binding to the active site of protein kinases |
JP2007516180A (ja) * | 2003-07-02 | 2007-06-21 | スゲン,インコーポレイティド | c−Met阻害薬としてのアリールメチルトリアゾロおよびイミダゾピラジン類 |
JP2007504252A (ja) * | 2003-09-04 | 2007-03-01 | バーテックス ファーマシューティカルズ インコーポレイテッド | プロテインキナーゼのインヒビターとして有用な組成物 |
JP2008508303A (ja) * | 2004-07-27 | 2008-03-21 | エスジーエックス ファーマシューティカルズ、インコーポレイテッド | ピロロ−ピリジンキナーゼモジュレーター |
US20070043068A1 (en) * | 2004-07-27 | 2007-02-22 | Sgx Pharmaceuticals, Inc. | Pyrrolo-pyridine kinase modulators |
JP2008514628A (ja) * | 2004-09-24 | 2008-05-08 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 蛋白質キナーゼ類のイミダゾ{4,5−b}ピラジノン阻害剤 |
JP2008523085A (ja) * | 2004-12-08 | 2008-07-03 | スミスクライン・ビーチャム・コーポレイション | 1h−ピロロ[2,3−b]ピリジン |
WO2007106236A2 (en) * | 2006-02-27 | 2007-09-20 | Sgx Pharmaceuticals, Inc. | Pyrrolo-pyridine kinase modulators |
US20080146561A1 (en) * | 2006-08-02 | 2008-06-19 | Alex Muci | Certain chemical entities, compositions and methods |
WO2008051493A2 (en) * | 2006-10-19 | 2008-05-02 | Signal Pharmaceuticals, Llc | Heteroaryl compounds, compositions thereof, and their use as protein kinase inhibitors |
WO2008124849A2 (en) * | 2007-04-10 | 2008-10-16 | Sgx Pharmaceuticals, Inc. | Pyrrolo-pyridine kinase modulators |
WO2010016490A1 (ja) * | 2008-08-05 | 2010-02-11 | 第一三共株式会社 | イミダゾピリジン-2-オン誘導体 |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2015052009A (ja) * | 2008-11-25 | 2015-03-19 | ユニバーシティー オブ ロチェスター | Mlk阻害剤および使用方法 |
WO2014181813A1 (ja) * | 2013-05-10 | 2014-11-13 | 武田薬品工業株式会社 | 複素環化合物 |
JP2019530695A (ja) * | 2016-10-06 | 2019-10-24 | ヤンセン ファーマシューティカ エヌ.ベー. | 置換1H−イミダゾ[4,5−b]ピリジン−2(3H)−オン及びGLUN2B受容体調節因子としてのそれらの使用 |
JP7001682B2 (ja) | 2016-10-06 | 2022-01-19 | ヤンセン ファーマシューティカ エヌ.ベー. | 置換1H-イミダゾ[4,5-b]ピリジン-2(3H)-オン及びGLUN2B受容体調節因子としてのそれらの使用 |
JP2021518856A (ja) * | 2018-03-01 | 2021-08-05 | ザ トラスティーズ オブ コロンビア ユニバーシティー イン ザ シティー オブ ニューヨーク | 有毒な小胞体ストレスを抑制するための化合物、組成物、および方法 |
JP7487170B2 (ja) | 2018-03-01 | 2024-05-20 | ザ トラスティーズ オブ コロンビア ユニバーシティー イン ザ シティー オブ ニューヨーク | 毒性小胞体ストレスを抑制するための化合物、組成物および方法 |
JP7486478B2 (ja) | 2018-09-19 | 2024-05-17 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | スピロ環状2,3-ジヒドロ-7-アザインドール化合物およびその使用 |
JP2022547436A (ja) * | 2019-08-30 | 2022-11-14 | ティーエスディー ライフ サイエンス カンパニー リミテッド | イミダゾピリジン誘導体及びこれを有効成分として含有する薬学的組成物 |
JP7345220B2 (ja) | 2019-08-30 | 2023-09-15 | ティーエスディー ライフ サイエンス カンパニー リミテッド | イミダゾピリジン誘導体及びこれを有効成分として含有する薬学的組成物 |
Also Published As
Publication number | Publication date |
---|---|
US9814704B2 (en) | 2017-11-14 |
JP5930278B2 (ja) | 2016-06-08 |
CA2744498C (en) | 2017-10-24 |
CN102264743A (zh) | 2011-11-30 |
EP2379561A4 (en) | 2012-10-03 |
US20150105401A1 (en) | 2015-04-16 |
US20160317509A1 (en) | 2016-11-03 |
WO2010068483A2 (en) | 2010-06-17 |
CN102264743B (zh) | 2015-02-11 |
AU2009324894A1 (en) | 2011-11-24 |
US20160024087A1 (en) | 2016-01-28 |
CA2744498A1 (en) | 2010-06-17 |
ES2554375T3 (es) | 2015-12-18 |
AU2009324894B2 (en) | 2015-04-09 |
EP3037421A1 (en) | 2016-06-29 |
EP2379561A2 (en) | 2011-10-26 |
EP2379561B1 (en) | 2015-11-04 |
US8877772B2 (en) | 2014-11-04 |
WO2010068483A3 (en) | 2010-09-30 |
JP2015052009A (ja) | 2015-03-19 |
EP3037421A3 (en) | 2016-11-30 |
US9181247B2 (en) | 2015-11-10 |
JP5873544B2 (ja) | 2016-03-01 |
US20120053175A1 (en) | 2012-03-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5873544B2 (ja) | Mlk阻害剤および使用方法 | |
JP6086326B2 (ja) | 二環式ヘテロアリールキナーゼ阻害剤および使用方法 | |
US11932643B2 (en) | Substituted heterocyclic inhibitors of PTPN11 | |
EP2925319B1 (en) | Mixed lineage kinase inhibitors for hiv/aids therapies | |
US11058688B2 (en) | Imidazopiperazine inhibitors of transcription activating proteins | |
CA3142239A1 (en) | Anticancer combination therapy | |
US11046649B2 (en) | Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase | |
US20190135793A1 (en) | Heterocyclic inhibitors of kdm5 for the treatment of disease | |
CN116261454A (zh) | 转录激活蛋白的咪唑并哌嗪抑制剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20121121 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20121122 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140205 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20140206 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20140502 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20140513 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140520 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20140714 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20141114 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20150202 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20150220 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160215 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20160420 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5930278 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |