AU2013294920B2 - Derivatives of azaindazole or diazaindazole type for treating pain - Google Patents
Derivatives of azaindazole or diazaindazole type for treating pain Download PDFInfo
- Publication number
- AU2013294920B2 AU2013294920B2 AU2013294920A AU2013294920A AU2013294920B2 AU 2013294920 B2 AU2013294920 B2 AU 2013294920B2 AU 2013294920 A AU2013294920 A AU 2013294920A AU 2013294920 A AU2013294920 A AU 2013294920A AU 2013294920 B2 AU2013294920 B2 AU 2013294920B2
- Authority
- AU
- Australia
- Prior art keywords
- charom
- group
- optionally substituted
- pain
- alkyl
- 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.)
- Active
Links
- 208000002193 Pain Diseases 0.000 title claims abstract description 112
- 230000036407 pain Effects 0.000 title claims abstract description 102
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical class C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 title description 6
- VQNDBXJTIJKJPV-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyridine Chemical compound C1=CC=NC2=NNN=C21 VQNDBXJTIJKJPV-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 140
- 239000000203 mixture Substances 0.000 claims abstract description 63
- 238000011282 treatment Methods 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 239000012453 solvate Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims description 149
- 125000000217 alkyl group Chemical group 0.000 claims description 73
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 59
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 47
- DBTDEFJAFBUGPP-UHFFFAOYSA-N Methanethial Chemical compound S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 claims description 40
- 229910052717 sulfur Inorganic materials 0.000 claims description 40
- 125000000623 heterocyclic group Chemical group 0.000 claims description 37
- 229910052757 nitrogen Inorganic materials 0.000 claims description 33
- -1 S(0)2CH2 Chemical group 0.000 claims description 30
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 25
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 22
- 125000005843 halogen group Chemical group 0.000 claims description 20
- 101100073357 Streptomyces halstedii sch2 gene Proteins 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 125000001188 haloalkyl group Chemical group 0.000 claims description 15
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 13
- 230000002265 prevention Effects 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 101100212791 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) YBL068W-A gene Proteins 0.000 claims description 10
- 208000004296 neuralgia Diseases 0.000 claims description 10
- 208000021722 neuropathic pain Diseases 0.000 claims description 10
- 206010065390 Inflammatory pain Diseases 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 208000001294 Nociceptive Pain Diseases 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 208000028389 Nerve injury Diseases 0.000 claims description 4
- 230000008764 nerve damage Effects 0.000 claims description 4
- 208000025747 Rheumatic disease Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000001107 psychogenic effect Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 183
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 143
- 239000000243 solution Substances 0.000 description 140
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 118
- 238000005481 NMR spectroscopy Methods 0.000 description 95
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 93
- 239000007787 solid Substances 0.000 description 90
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 88
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 75
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 74
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 70
- 239000012429 reaction media Substances 0.000 description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 69
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 65
- 239000002904 solvent Substances 0.000 description 64
- 238000006243 chemical reaction Methods 0.000 description 61
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 59
- 239000012074 organic phase Substances 0.000 description 58
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- 239000011541 reaction mixture Substances 0.000 description 48
- 238000010586 diagram Methods 0.000 description 46
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 37
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 34
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 235000019341 magnesium sulphate Nutrition 0.000 description 33
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 32
- 238000003756 stirring Methods 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 24
- 239000002798 polar solvent Substances 0.000 description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 23
- 239000000047 product Substances 0.000 description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 22
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 22
- 238000010898 silica gel chromatography Methods 0.000 description 22
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 239000000843 powder Substances 0.000 description 19
- 239000002244 precipitate Substances 0.000 description 19
- 239000007795 chemical reaction product Substances 0.000 description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
- 229910052739 hydrogen Inorganic materials 0.000 description 17
- 239000000543 intermediate Substances 0.000 description 17
- 229910000027 potassium carbonate Inorganic materials 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- 108010025020 Nerve Growth Factor Proteins 0.000 description 15
- 150000007529 inorganic bases Chemical class 0.000 description 15
- 150000007530 organic bases Chemical class 0.000 description 15
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 14
- 102000015336 Nerve Growth Factor Human genes 0.000 description 14
- 229940053128 nerve growth factor Drugs 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 238000005755 formation reaction Methods 0.000 description 13
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 description 12
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 11
- 208000004454 Hyperalgesia Diseases 0.000 description 11
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 11
- 101150111783 NTRK1 gene Proteins 0.000 description 11
- 229910052786 argon Inorganic materials 0.000 description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 11
- 239000013078 crystal Substances 0.000 description 11
- 239000003480 eluent Substances 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- 101150056950 Ntrk2 gene Proteins 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 10
- 230000003197 catalytic effect Effects 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 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 9
- 239000002253 acid Substances 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 9
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 8
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
- 108091000080 Phosphotransferase Proteins 0.000 description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 8
- 230000000202 analgesic effect Effects 0.000 description 8
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 8
- 238000005859 coupling reaction Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 238000007254 oxidation reaction Methods 0.000 description 8
- 102000020233 phosphotransferase Human genes 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical compound C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 7
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 7
- 208000000094 Chronic Pain Diseases 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 230000009471 action Effects 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- 239000002038 ethyl acetate fraction Substances 0.000 description 7
- 230000002757 inflammatory effect Effects 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000000377 silicon dioxide Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- FYHRQFFVACXNTB-UHFFFAOYSA-N 2-chloro-5-iodopyridine-3-carbonitrile Chemical class ClC1=NC=C(I)C=C1C#N FYHRQFFVACXNTB-UHFFFAOYSA-N 0.000 description 6
- 206010005949 Bone cancer Diseases 0.000 description 6
- 208000018084 Bone neoplasm Diseases 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 6
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 239000011591 potassium Substances 0.000 description 6
- 235000011181 potassium carbonates Nutrition 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 150000003462 sulfoxides Chemical class 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 5
- DDZGQYREBDXECY-UHFFFAOYSA-N 1h-pyrazolo[3,4-b]pyrazine Chemical class C1=CN=C2C=NNC2=N1 DDZGQYREBDXECY-UHFFFAOYSA-N 0.000 description 5
- QDHZJXAAFQGWIY-UHFFFAOYSA-N 3-amino-6-iodopyrazine-2-carboxamide Chemical class NC(=O)C1=NC(I)=CN=C1N QDHZJXAAFQGWIY-UHFFFAOYSA-N 0.000 description 5
- FDNXQCAFVGNIPT-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)-2-[oxan-4-yl-(2,2,2-trifluoroacetyl)amino]benzoic acid Chemical compound C1CN(C)CCN1C1=CC=C(C(O)=O)C(N(C2CCOCC2)C(=O)C(F)(F)F)=C1 FDNXQCAFVGNIPT-UHFFFAOYSA-N 0.000 description 5
- BYEUNDASYOFKIW-UHFFFAOYSA-N 5-iodo-2h-pyrazolo[3,4-b]pyridin-3-amine Chemical class C1=C(I)C=C2C(N)=NNC2=N1 BYEUNDASYOFKIW-UHFFFAOYSA-N 0.000 description 5
- XVIHGTRTKQZJAC-UHFFFAOYSA-N 6-chloro-3-nitropyridine-2-carbonitrile Chemical compound [O-][N+](=O)C1=CC=C(Cl)N=C1C#N XVIHGTRTKQZJAC-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 208000035154 Hyperesthesia Diseases 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 230000001154 acute effect Effects 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 229940050390 benzoate Drugs 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 229910052742 iron Inorganic materials 0.000 description 5
- 239000012038 nucleophile Substances 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 230000002269 spontaneous effect Effects 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- GPYNAAUDGBICPV-UHFFFAOYSA-N 3-amino-n-(3,5-difluorophenyl)-2h-pyrazolo[3,4-b]pyridine-5-sulfonamide Chemical compound C1=C2C(N)=NNC2=NC=C1S(=O)(=O)NC1=CC(F)=CC(F)=C1 GPYNAAUDGBICPV-UHFFFAOYSA-N 0.000 description 4
- SSNUTEUZXZIYTB-UHFFFAOYSA-N 5-bromo-2h-pyrazolo[3,4-b]pyridin-3-amine Chemical compound N1=CC(Br)=CC2=C(N)NN=C21 SSNUTEUZXZIYTB-UHFFFAOYSA-N 0.000 description 4
- KAXIYYPIORYZLB-UHFFFAOYSA-N 5-hydroxypyridine-3-carbonitrile Chemical class OC1=CN=CC(C#N)=C1 KAXIYYPIORYZLB-UHFFFAOYSA-N 0.000 description 4
- JWRYNLANQMKICK-UHFFFAOYSA-N 6-(2,4-difluoroanilino)-2-methylsulfanylpyridine-3-carbonitrile Chemical compound C1=C(C#N)C(SC)=NC(NC=2C(=CC(F)=CC=2)F)=C1 JWRYNLANQMKICK-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [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 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 102000001253 Protein Kinase Human genes 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 208000005298 acute pain Diseases 0.000 description 4
- 239000000730 antalgic agent Substances 0.000 description 4
- 239000012223 aqueous fraction Substances 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 230000006399 behavior Effects 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 150000003857 carboxamides Chemical class 0.000 description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 229910052802 copper Inorganic materials 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 230000000763 evoking effect Effects 0.000 description 4
- 210000002683 foot Anatomy 0.000 description 4
- 210000000548 hind-foot Anatomy 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 239000012454 non-polar solvent Substances 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 108060006633 protein kinase Proteins 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 235000010288 sodium nitrite Nutrition 0.000 description 4
- 150000003457 sulfones Chemical class 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- XMRKFDSPGSPFGE-UHFFFAOYSA-N (5-cyano-6-methylsulfanylpyridin-2-yl) trifluoromethanesulfonate Chemical compound CSC1=NC(OS(=O)(=O)C(F)(F)F)=CC=C1C#N XMRKFDSPGSPFGE-UHFFFAOYSA-N 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- UVKBAINRDCMDIE-UHFFFAOYSA-N 2,2,2-trichloro-1-[4-(4-methylpiperazin-1-yl)phenyl]ethanol Chemical compound C1CN(C)CCN1C1=CC=C(C(O)C(Cl)(Cl)Cl)C=C1 UVKBAINRDCMDIE-UHFFFAOYSA-N 0.000 description 3
- LFCADBSUDWERJT-UHFFFAOYSA-N 2,6-dichloropyridine-3-carbonitrile Chemical compound ClC1=CC=C(C#N)C(Cl)=N1 LFCADBSUDWERJT-UHFFFAOYSA-N 0.000 description 3
- JPGXJOYWNKSCGX-UHFFFAOYSA-N 2-[(4,4-difluorocyclohexyl)-(2,2,2-trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoic acid Chemical compound C1CN(C)CCN1C1=CC=C(C(O)=O)C(N(C2CCC(F)(F)CC2)C(=O)C(F)(F)F)=C1 JPGXJOYWNKSCGX-UHFFFAOYSA-N 0.000 description 3
- UQNVAKOELHOJFN-UHFFFAOYSA-N 2-[4-(4-methylpiperazin-4-ium-1-yl)phenyl]acetate Chemical compound C1CN(C)CCN1C1=CC=C(CC(O)=O)C=C1 UQNVAKOELHOJFN-UHFFFAOYSA-N 0.000 description 3
- UAFHMAWFIOXXQI-NSHDSACASA-N 2-[oxan-4-yl-(2,2,2-trifluoroacetyl)amino]-4-[(3s)-3-[(2,2,2-trifluoroacetyl)amino]pyrrolidin-1-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(N2C[C@H](CC2)NC(=O)C(F)(F)F)C=C1N(C(=O)C(F)(F)F)C1CCOCC1 UAFHMAWFIOXXQI-NSHDSACASA-N 0.000 description 3
- VVKFXPRMHQRBGL-UHFFFAOYSA-N 2-amino-5-cyano-6-methylsulfanylpyridine-3-carboxylic acid Chemical compound CSC1=NC(N)=C(C(O)=O)C=C1C#N VVKFXPRMHQRBGL-UHFFFAOYSA-N 0.000 description 3
- PLERTPJDYXYVTI-UHFFFAOYSA-N 2-chloro-5-[(3,5-difluorophenyl)methoxy]pyridine-3-carbonitrile Chemical compound FC1=CC(F)=CC(COC=2C=C(C(Cl)=NC=2)C#N)=C1 PLERTPJDYXYVTI-UHFFFAOYSA-N 0.000 description 3
- MCPVFSJAPYCXMS-UHFFFAOYSA-N 2-chloro-5-[(3,5-difluorophenyl)sulfamoyl]pyridine-3-carboxamide Chemical compound N1=C(Cl)C(C(=O)N)=CC(S(=O)(=O)NC=2C=C(F)C=C(F)C=2)=C1 MCPVFSJAPYCXMS-UHFFFAOYSA-N 0.000 description 3
- IHWZCGMZILLKFD-UHFFFAOYSA-N 2-methoxypyridine-3-carbonitrile Chemical compound COC1=NC=CC=C1C#N IHWZCGMZILLKFD-UHFFFAOYSA-N 0.000 description 3
- MOUURCSKHKVYPB-UHFFFAOYSA-N 2-methylsulfanyl-6-oxo-1h-pyridine-3-carbonitrile Chemical compound CSC1=NC(O)=CC=C1C#N MOUURCSKHKVYPB-UHFFFAOYSA-N 0.000 description 3
- WUAWAZWIWVBBEM-UHFFFAOYSA-N 3-amino-6-iodopyrazine-2-carbonitrile Chemical compound NC1=NC=C(I)N=C1C#N WUAWAZWIWVBBEM-UHFFFAOYSA-N 0.000 description 3
- UFTSPZWLJMPOKT-UHFFFAOYSA-N 3-chloro-6-iodopyrazine-2-carbonitrile Chemical compound ClC1=NC=C(I)N=C1C#N UFTSPZWLJMPOKT-UHFFFAOYSA-N 0.000 description 3
- DYUMBFTYRJMAFK-UHFFFAOYSA-N 3-cyano-2-pyridone Chemical compound OC1=NC=CC=C1C#N DYUMBFTYRJMAFK-UHFFFAOYSA-N 0.000 description 3
- UVSUWPMFLDLVMI-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzaldehyde Chemical compound C1CN(C)CCN1C1=CC=C(C=O)C(NC2CCOCC2)=C1 UVSUWPMFLDLVMI-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-O 4-methylmorpholin-4-ium Chemical compound C[NH+]1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-O 0.000 description 3
- XNMSAEOZDVATJK-UHFFFAOYSA-N 5-(3,5-difluorophenyl)sulfanyl-2h-pyrazolo[3,4-b]pyridin-3-amine Chemical compound C1=C2C(N)=NNC2=NC=C1SC1=CC(F)=CC(F)=C1 XNMSAEOZDVATJK-UHFFFAOYSA-N 0.000 description 3
- BMYJZWWKUPNCNN-UHFFFAOYSA-N 5-[(3,5-difluorophenyl)methoxy]-1-oxidopyridin-1-ium-3-carbonitrile Chemical compound N#CC1=C[N+]([O-])=CC(OCC=2C=C(F)C=C(F)C=2)=C1 BMYJZWWKUPNCNN-UHFFFAOYSA-N 0.000 description 3
- JVIGDQVFRFSUKJ-UHFFFAOYSA-N 5-[(3,5-difluorophenyl)methoxy]-2h-pyrazolo[3,4-b]pyridin-3-amine Chemical compound C1=C2C(N)=NNC2=NC=C1OCC1=CC(F)=CC(F)=C1 JVIGDQVFRFSUKJ-UHFFFAOYSA-N 0.000 description 3
- ABNOQRUXVJFBSN-UHFFFAOYSA-N 5-[(3,5-difluorophenyl)methoxy]pyridine-3-carbonitrile Chemical compound FC1=CC(F)=CC(COC=2C=C(C=NC=2)C#N)=C1 ABNOQRUXVJFBSN-UHFFFAOYSA-N 0.000 description 3
- FRKLCMNRGGZZTQ-UHFFFAOYSA-N 5-bromo-2-methoxypyridine-3-carbonitrile Chemical compound COC1=NC=C(Br)C=C1C#N FRKLCMNRGGZZTQ-UHFFFAOYSA-N 0.000 description 3
- DHWIFHCOMJIINQ-UHFFFAOYSA-N 5-cyano-6-methylsulfanyl-2-oxo-1h-pyridine-3-carboxylic acid Chemical compound CSC=1NC(=O)C(C(O)=O)=CC=1C#N DHWIFHCOMJIINQ-UHFFFAOYSA-N 0.000 description 3
- VGWDPJMGTMXJIJ-UHFFFAOYSA-N 5-iodo-2-methylsulfanyl-6-oxo-1h-pyridine-3-carbonitrile Chemical compound CSC1=NC(O)=C(I)C=C1C#N VGWDPJMGTMXJIJ-UHFFFAOYSA-N 0.000 description 3
- DHNUUSNUUZTHEN-UHFFFAOYSA-N 5-iodo-2-oxo-1h-pyridine-3-carbonitrile Chemical compound IC1=CNC(=O)C(C#N)=C1 DHNUUSNUUZTHEN-UHFFFAOYSA-N 0.000 description 3
- XXMSBZGWGCYUDN-UHFFFAOYSA-N 5-iodo-2h-pyrazolo[3,4-b]pyrazin-3-amine Chemical compound C1=C(I)N=C2C(N)=NNC2=N1 XXMSBZGWGCYUDN-UHFFFAOYSA-N 0.000 description 3
- OYXUUECJEFKKLG-UHFFFAOYSA-N 5-iodo-2h-pyrazolo[3,4-b]pyridine-3,6-diamine Chemical compound NC1=C(I)C=C2C(N)=NNC2=N1 OYXUUECJEFKKLG-UHFFFAOYSA-N 0.000 description 3
- CNTGLVVONIKHSF-UHFFFAOYSA-N 5-iodo-6-methoxy-2-methylsulfanylpyridine-3-carbonitrile Chemical compound COC1=NC(SC)=C(C#N)C=C1I CNTGLVVONIKHSF-UHFFFAOYSA-N 0.000 description 3
- IOCCJZXMIMJYOD-UHFFFAOYSA-N 6-(2,4-difluorophenyl)sulfanyl-2h-pyrazolo[3,4-b]pyridin-3-amine Chemical compound C=1C=C2C(N)=NNC2=NC=1SC1=CC=C(F)C=C1F IOCCJZXMIMJYOD-UHFFFAOYSA-N 0.000 description 3
- HSSNFLZQIPOZRO-UHFFFAOYSA-N 6-(3,5-dichlorophenyl)sulfanyl-3-nitropyridine-2-carbonitrile Chemical compound N1=C(C#N)C([N+](=O)[O-])=CC=C1SC1=CC(Cl)=CC(Cl)=C1 HSSNFLZQIPOZRO-UHFFFAOYSA-N 0.000 description 3
- WDUYGQZRZXAAGJ-UHFFFAOYSA-N 6-amino-2-methylsulfanylpyridine-3-carbonitrile Chemical compound CSC1=NC(N)=CC=C1C#N WDUYGQZRZXAAGJ-UHFFFAOYSA-N 0.000 description 3
- ONGQTMGRJGAOHG-UHFFFAOYSA-N 6-amino-5-iodo-2-methylsulfanylpyridine-3-carbonitrile Chemical compound CSC1=NC(N)=C(I)C=C1C#N ONGQTMGRJGAOHG-UHFFFAOYSA-N 0.000 description 3
- ODCXTIKFDHBSQN-UHFFFAOYSA-N 6-amino-5-iodo-2-methylsulfinylpyridine-3-carbonitrile Chemical compound CS(=O)C1=NC(N)=C(I)C=C1C#N ODCXTIKFDHBSQN-UHFFFAOYSA-N 0.000 description 3
- IMSRXABOKDAELG-UHFFFAOYSA-N 6-chloro-5-cyano-n-(3,5-difluorophenyl)pyridine-3-sulfonamide Chemical compound FC1=CC(F)=CC(NS(=O)(=O)C=2C=C(C(Cl)=NC=2)C#N)=C1 IMSRXABOKDAELG-UHFFFAOYSA-N 0.000 description 3
- JUVQPYNYLHZBKI-UHFFFAOYSA-N 6-n-(2,4-difluorophenyl)-2h-pyrazolo[3,4-b]pyridine-3,6-diamine Chemical compound C=1C=C2C(N)=NNC2=NC=1NC1=CC=C(F)C=C1F JUVQPYNYLHZBKI-UHFFFAOYSA-N 0.000 description 3
- APASLXZZEDBGED-UHFFFAOYSA-N 6-n-(2,4-difluorophenyl)-6-n-methyl-2h-pyrazolo[3,4-b]pyridine-3,6-diamine Chemical compound C=1C=C2C(N)=NNC2=NC=1N(C)C1=CC=C(F)C=C1F APASLXZZEDBGED-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- 208000001640 Fibromyalgia Diseases 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 101150117329 NTRK3 gene Proteins 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 238000000297 Sandmeyer reaction Methods 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 3
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 3
- VMMMYBOZMXKJMU-UHFFFAOYSA-N [4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)phenyl]methanol Chemical compound C1CN(C)CCN1C1=CC=C(CO)C(NC2CCOCC2)=C1 VMMMYBOZMXKJMU-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 229960004365 benzoic acid Drugs 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 150000001805 chlorine compounds Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 238000007033 dehydrochlorination reaction Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000012954 diazonium Substances 0.000 description 3
- 229940043279 diisopropylamine Drugs 0.000 description 3
- PFNXTASHNOUFCN-UHFFFAOYSA-N ethyl 2-amino-5-cyano-6-methylsulfanylpyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC(C#N)=C(SC)N=C1N PFNXTASHNOUFCN-UHFFFAOYSA-N 0.000 description 3
- UCDROSIPSKGDQH-UHFFFAOYSA-N ethyl 5-cyano-6-methylsulfanyl-2-oxo-1h-pyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC(C#N)=C(SC)N=C1O UCDROSIPSKGDQH-UHFFFAOYSA-N 0.000 description 3
- 210000003414 extremity Anatomy 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 150000002429 hydrazines Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 3
- 230000026045 iodination Effects 0.000 description 3
- 238000006192 iodination reaction Methods 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000012948 isocyanate Substances 0.000 description 3
- 150000002513 isocyanates Chemical class 0.000 description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 3
- FDLARAKNPMCCKJ-UHFFFAOYSA-N methyl 3-amino-6-iodopyrazine-2-carboxylate Chemical compound COC(=O)C1=NC(I)=CN=C1N FDLARAKNPMCCKJ-UHFFFAOYSA-N 0.000 description 3
- DDDZNRSTGCSUJP-UHFFFAOYSA-N n'-(3-cyano-5-iodopyrazin-2-yl)-n,n-dimethylmethanimidamide Chemical compound CN(C)C=NC1=NC=C(I)N=C1C#N DDDZNRSTGCSUJP-UHFFFAOYSA-N 0.000 description 3
- JDPQOPNYABKMJI-UHFFFAOYSA-N n-(6-chloro-5-cyanopyridin-3-yl)-3,5-difluorobenzenesulfonamide Chemical compound FC1=CC(F)=CC(S(=O)(=O)NC=2C=C(C(Cl)=NC=2)C#N)=C1 JDPQOPNYABKMJI-UHFFFAOYSA-N 0.000 description 3
- 229910052759 nickel Inorganic materials 0.000 description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 3
- 229940005483 opioid analgesics Drugs 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 150000005229 pyrazolopyridines Chemical class 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 229910000367 silver sulfate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- GHERUNYLCLILIJ-UHFFFAOYSA-N tert-butyl 2-[(4,4-difluorocyclohexyl)amino]-4-(4-methylpiperazin-1-yl)benzoate Chemical compound C1CN(C)CCN1C1=CC=C(C(=O)OC(C)(C)C)C(NC2CCC(F)(F)CC2)=C1 GHERUNYLCLILIJ-UHFFFAOYSA-N 0.000 description 3
- DIFVPEGUJIXKOC-UHFFFAOYSA-N tert-butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate Chemical compound C1CN(C)CCN1C1=CC=C(C(=O)OC(C)(C)C)C(N)=C1 DIFVPEGUJIXKOC-UHFFFAOYSA-N 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- NMEPLWZDUIIAAC-UHFFFAOYSA-N 1h-pyrazolo[4,3-c]pyridazine Chemical class C1=NN=C2C=NNC2=C1 NMEPLWZDUIIAAC-UHFFFAOYSA-N 0.000 description 2
- WCXFPLXZZSWROM-UHFFFAOYSA-N 1h-pyrazolo[4,3-c]pyridine Chemical compound C1=NC=C2C=NNC2=C1 WCXFPLXZZSWROM-UHFFFAOYSA-N 0.000 description 2
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 2
- YFTHTJAPODJVSL-UHFFFAOYSA-N 2-(1-benzothiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(SC=C2)C2=C1 YFTHTJAPODJVSL-UHFFFAOYSA-N 0.000 description 2
- PTDOCINOKMDHSU-UHFFFAOYSA-N 2-chloro-6-(2,4-difluorophenyl)sulfanylpyridine-3-carbonitrile Chemical compound FC1=CC(F)=CC=C1SC1=CC=C(C#N)C(Cl)=N1 PTDOCINOKMDHSU-UHFFFAOYSA-N 0.000 description 2
- JAUPUQRPBNDMDT-UHFFFAOYSA-N 2-chloropyridine-3-carbonitrile Chemical compound ClC1=NC=CC=C1C#N JAUPUQRPBNDMDT-UHFFFAOYSA-N 0.000 description 2
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 2
- KQOIBXZRCYFZSO-UHFFFAOYSA-N 3,5-difluoroaniline Chemical compound NC1=CC(F)=CC(F)=C1 KQOIBXZRCYFZSO-UHFFFAOYSA-N 0.000 description 2
- NUEYBFIIUBXAHT-UHFFFAOYSA-N 3-amino-6-(3,5-dichlorophenyl)sulfanylpyridine-2-carbonitrile Chemical compound N1=C(C#N)C(N)=CC=C1SC1=CC(Cl)=CC(Cl)=C1 NUEYBFIIUBXAHT-UHFFFAOYSA-N 0.000 description 2
- PAUUZIXIERHUHC-UHFFFAOYSA-N 3-amino-6-(3,5-difluoroanilino)pyridine-2-carbonitrile Chemical compound N1=C(C#N)C(N)=CC=C1NC1=CC(F)=CC(F)=C1 PAUUZIXIERHUHC-UHFFFAOYSA-N 0.000 description 2
- WRQYZMAMPGGLGG-UHFFFAOYSA-N 3-amino-6-[(3,5-difluorophenyl)methylsulfanyl]pyridine-2-carbonitrile Chemical compound N1=C(C#N)C(N)=CC=C1SCC1=CC(F)=CC(F)=C1 WRQYZMAMPGGLGG-UHFFFAOYSA-N 0.000 description 2
- OXQLRGICXLDZGZ-UHFFFAOYSA-N 3-amino-6-[(3,5-difluorophenyl)methylsulfanyl]pyridine-2-carboxamide Chemical compound C1=C(N)C(C(=O)N)=NC(SCC=2C=C(F)C=C(F)C=2)=C1 OXQLRGICXLDZGZ-UHFFFAOYSA-N 0.000 description 2
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 2
- WKPKXPORUZFLMM-UHFFFAOYSA-N 4-(1-methylpiperidin-4-yl)-2-[oxan-4-yl-(2,2,2-trifluoroacetyl)amino]benzoic acid Chemical compound C1CN(C)CCC1C1=CC=C(C(O)=O)C(N(C2CCOCC2)C(=O)C(F)(F)F)=C1 WKPKXPORUZFLMM-UHFFFAOYSA-N 0.000 description 2
- PFODEVGLOVUVHS-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)benzaldehyde Chemical compound C1CN(C)CCN1C1=CC=C(C=O)C=C1 PFODEVGLOVUVHS-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- XDBOLUQMQARCQO-UHFFFAOYSA-N 5-(3,5-dichlorophenyl)sulfanyl-1h-pyrazolo[4,3-b]pyridin-3-amine Chemical compound N1=C2C(N)=NNC2=CC=C1SC1=CC(Cl)=CC(Cl)=C1 XDBOLUQMQARCQO-UHFFFAOYSA-N 0.000 description 2
- RKJLJEWNXQZBIX-UHFFFAOYSA-N 5-(3,5-difluorophenyl)sulfonyl-2h-pyrazolo[3,4-b]pyridin-3-amine Chemical compound C1=C2C(N)=NNC2=NC=C1S(=O)(=O)C1=CC(F)=CC(F)=C1 RKJLJEWNXQZBIX-UHFFFAOYSA-N 0.000 description 2
- VGYONHCACXTVFA-UHFFFAOYSA-N 5-[(3,5-difluorophenyl)methylsulfanyl]-1h-pyrazolo[4,3-b]pyridin-3-amine Chemical compound N1=C2C(N)=NNC2=CC=C1SCC1=CC(F)=CC(F)=C1 VGYONHCACXTVFA-UHFFFAOYSA-N 0.000 description 2
- RGFRMTNTNUBPQX-UHFFFAOYSA-N 5-[(3,5-difluorophenyl)sulfamoyl]pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=CC(S(=O)(=O)NC=2C=C(F)C=C(F)C=2)=C1 RGFRMTNTNUBPQX-UHFFFAOYSA-N 0.000 description 2
- DZGYLSFTOFCXFZ-UHFFFAOYSA-N 5-iodo-6-methoxy-2h-pyrazolo[3,4-b]pyridin-3-amine Chemical compound C1=C(I)C(OC)=NC2=C1C(N)=NN2 DZGYLSFTOFCXFZ-UHFFFAOYSA-N 0.000 description 2
- ZEXJVDQSKVHQKM-UHFFFAOYSA-N 5-n-(3,5-difluorophenyl)-1h-pyrazolo[4,3-b]pyridine-3,5-diamine Chemical compound N1=C2C(N)=NNC2=CC=C1NC1=CC(F)=CC(F)=C1 ZEXJVDQSKVHQKM-UHFFFAOYSA-N 0.000 description 2
- YYBIEWNTHVYNHE-UHFFFAOYSA-N 6-(2,4-difluoro-n-methylanilino)-2-methylsulfanylpyridine-3-carbonitrile Chemical compound C1=C(C#N)C(SC)=NC(N(C)C=2C(=CC(F)=CC=2)F)=C1 YYBIEWNTHVYNHE-UHFFFAOYSA-N 0.000 description 2
- BJVTVMIGYUTGED-UHFFFAOYSA-N 6-[(3,5-difluorophenyl)methylsulfanyl]-3-nitropyridine-2-carbonitrile Chemical compound N1=C(C#N)C([N+](=O)[O-])=CC=C1SCC1=CC(F)=CC(F)=C1 BJVTVMIGYUTGED-UHFFFAOYSA-N 0.000 description 2
- XHSOTQAXOCJEBS-UHFFFAOYSA-N 6-chloro-3-nitropyrazine-2-carbonitrile Chemical class [O-][N+](=O)C1=NC=C(Cl)N=C1C#N XHSOTQAXOCJEBS-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 241000400611 Eucalyptus deanei Species 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010050296 Intervertebral disc protrusion Diseases 0.000 description 2
- 208000008930 Low Back Pain Diseases 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 208000031264 Nerve root compression Diseases 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [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 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 206010037779 Radiculopathy Diseases 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- KTFXBCVLEMBPGH-UHFFFAOYSA-M [Cl-].FC1=CC(F)=CC(C[Zn+])=C1 Chemical compound [Cl-].FC1=CC(F)=CC(C[Zn+])=C1 KTFXBCVLEMBPGH-UHFFFAOYSA-M 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- WFKAJVHLWXSISD-UHFFFAOYSA-N anhydrous dimethyl-acetamide Natural products CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000002051 biphasic effect Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 150000001879 copper Chemical class 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
- 230000006378 damage Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- KEXGUJMBPOYKBG-UHFFFAOYSA-N ethyl 2-chloro-5-chlorosulfonylpyridine-3-carboxylate Chemical class CCOC(=O)C1=CC(S(Cl)(=O)=O)=CN=C1Cl KEXGUJMBPOYKBG-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 150000002540 isothiocyanates Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- INCSQLZZXBPATR-UHFFFAOYSA-N methyl 3-aminopyrazine-2-carboxylate Chemical class COC(=O)C1=NC=CN=C1N INCSQLZZXBPATR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- FMLZEDJKDLHEAY-UHFFFAOYSA-N n-(3-amino-2h-pyrazolo[3,4-b]pyridin-5-yl)-3,5-difluorobenzenesulfonamide Chemical compound C1=C2C(N)=NNC2=NC=C1NS(=O)(=O)C1=CC(F)=CC(F)=C1 FMLZEDJKDLHEAY-UHFFFAOYSA-N 0.000 description 2
- BYDOOCPUDCJBNN-UHFFFAOYSA-N n-[5-[2-(3,5-difluorophenyl)ethynyl]-2h-pyrazolo[3,4-b]pyridin-3-yl]-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide Chemical compound C1CN(C)CCN1C(C=C1NC2CCOCC2)=CC=C1C(=O)NC1=NNC2=NC=C(C#CC=3C=C(F)C=C(F)C=3)C=C12 BYDOOCPUDCJBNN-UHFFFAOYSA-N 0.000 description 2
- 230000003040 nociceptive effect Effects 0.000 description 2
- 210000000929 nociceptor Anatomy 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229940127240 opiate Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 150000002940 palladium Chemical class 0.000 description 2
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 2
- 229910001958 silver carbonate Inorganic materials 0.000 description 2
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
- 235000011150 stannous chloride Nutrition 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000565 sulfonamide group Chemical group 0.000 description 2
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical class CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- DFSGLWKPJNAHSD-UHFFFAOYSA-N tert-butyl 2-amino-4-(1-methylpiperidin-4-yl)benzoate Chemical compound C1CN(C)CCC1C1=CC=C(C(=O)OC(C)(C)C)C(N)=C1 DFSGLWKPJNAHSD-UHFFFAOYSA-N 0.000 description 2
- ZHNMVTLHFLSTHK-UHFFFAOYSA-N tert-butyl 2-nitro-4-pyridin-4-ylbenzoate Chemical compound C1=C([N+]([O-])=O)C(C(=O)OC(C)(C)C)=CC=C1C1=CC=NC=C1 ZHNMVTLHFLSTHK-UHFFFAOYSA-N 0.000 description 2
- JNHYZIQVZUSMAB-UHFFFAOYSA-N tert-butyl 4-(1-methylpiperidin-4-yl)-2-(oxan-4-ylamino)benzoate Chemical compound C1CN(C)CCC1C1=CC=C(C(=O)OC(C)(C)C)C(NC2CCOCC2)=C1 JNHYZIQVZUSMAB-UHFFFAOYSA-N 0.000 description 2
- PBUSFCZVNOIGLX-UHFFFAOYSA-N tert-butyl 4-(1-methylpiperidin-4-yl)-2-[oxan-4-yl-(2,2,2-trifluoroacetyl)amino]benzoate Chemical compound C1CN(C)CCC1C1=CC=C(C(=O)OC(C)(C)C)C(N(C2CCOCC2)C(=O)C(F)(F)F)=C1 PBUSFCZVNOIGLX-UHFFFAOYSA-N 0.000 description 2
- FEWNHXSFBOSNBZ-UHFFFAOYSA-M tert-butyl 4-(1-methylpyridin-1-ium-4-yl)-2-nitrobenzoate;iodide Chemical compound [I-].C1=C[N+](C)=CC=C1C1=CC=C(C(=O)OC(C)(C)C)C([N+]([O-])=O)=C1 FEWNHXSFBOSNBZ-UHFFFAOYSA-M 0.000 description 2
- PNTUIHOIJCQTSU-UHFFFAOYSA-N tert-butyl 4-(4-methylpiperazin-1-yl)-2-nitrobenzoate Chemical compound C1CN(C)CCN1C1=CC=C(C(=O)OC(C)(C)C)C([N+]([O-])=O)=C1 PNTUIHOIJCQTSU-UHFFFAOYSA-N 0.000 description 2
- NCKQAMFTBRWGFK-UHFFFAOYSA-N tert-butyl n-[2-isocyanato-5-(4-methylpiperazin-1-yl)phenyl]carbamate Chemical compound C1CN(C)CCN1C1=CC=C(N=C=O)C(NC(=O)OC(C)(C)C)=C1 NCKQAMFTBRWGFK-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000005309 thioalkoxy group Chemical group 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 229910052718 tin Inorganic materials 0.000 description 2
- 239000011135 tin Substances 0.000 description 2
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- HYAVEDMFTNAZQE-UHFFFAOYSA-N (benzyldiselanyl)methylbenzene Chemical compound C=1C=CC=CC=1C[Se][Se]CC1=CC=CC=C1 HYAVEDMFTNAZQE-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- DBXNGZCLOOGZEW-UHFFFAOYSA-N 1-(2-bromo-2-phenylethyl)-3,5-difluorobenzene Chemical compound FC1=CC(F)=CC(CC(Br)C=2C=CC=CC=2)=C1 DBXNGZCLOOGZEW-UHFFFAOYSA-N 0.000 description 1
- POXVFBFTIHUAOP-UHFFFAOYSA-N 1-(3,5-difluorophenyl)sulfanylpyrazolo[3,4-b]pyridin-3-amine Chemical compound C12=NC=CC=C2C(N)=NN1SC1=CC(F)=CC(F)=C1 POXVFBFTIHUAOP-UHFFFAOYSA-N 0.000 description 1
- KVSVNRFSKRFPIL-UHFFFAOYSA-N 1-(bromomethyl)-3,5-difluorobenzene Chemical compound FC1=CC(F)=CC(CBr)=C1 KVSVNRFSKRFPIL-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- JKEWHRKMGKQITN-UHFFFAOYSA-N 1-[1-tert-butyl-5-(3,5-difluorophenyl)sulfanylpyrazolo[3,4-b]pyridin-3-yl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC(=O)NC(C1=C2)=NN(C(C)(C)C)C1=NC=C2SC1=CC(F)=CC(F)=C1 JKEWHRKMGKQITN-UHFFFAOYSA-N 0.000 description 1
- AWNXKZVIZARMME-UHFFFAOYSA-N 1-[[5-[2-[(2-chloropyridin-4-yl)amino]pyrimidin-4-yl]-4-(cyclopropylmethyl)pyrimidin-2-yl]amino]-2-methylpropan-2-ol Chemical compound N=1C(NCC(C)(O)C)=NC=C(C=2N=C(NC=3C=C(Cl)N=CC=3)N=CC=2)C=1CC1CC1 AWNXKZVIZARMME-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
- MJEPPEQNLZSPAP-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridin-3-amine Chemical class C1=CN=C2C(N)=NNC2=C1 MJEPPEQNLZSPAP-UHFFFAOYSA-N 0.000 description 1
- FVJBHWZOURTPME-UHFFFAOYSA-N 1h-pyrazolo[4,3-c]pyridazin-3-amine Chemical class C1=NN=C2C(N)=NNC2=C1 FVJBHWZOURTPME-UHFFFAOYSA-N 0.000 description 1
- FJRPOHLDJUJARI-UHFFFAOYSA-N 2,3-dihydro-1,2-oxazole Chemical compound C1NOC=C1 FJRPOHLDJUJARI-UHFFFAOYSA-N 0.000 description 1
- BICHBFCGCJNCAT-UHFFFAOYSA-N 2,4-difluorobenzenethiol Chemical compound FC1=CC=C(S)C(F)=C1 BICHBFCGCJNCAT-UHFFFAOYSA-N 0.000 description 1
- SHCWQWRTKPNTEM-UHFFFAOYSA-N 2,6-dichloro-3-nitropyridine Chemical class [O-][N+](=O)C1=CC=C(Cl)N=C1Cl SHCWQWRTKPNTEM-UHFFFAOYSA-N 0.000 description 1
- OUHBWOIKQHDTAD-UHFFFAOYSA-N 2-(2-fluoroethoxy)-4-(4-methylpiperazin-1-yl)benzoic acid Chemical compound C1CN(C)CCN1C1=CC=C(C(O)=O)C(OCCF)=C1 OUHBWOIKQHDTAD-UHFFFAOYSA-N 0.000 description 1
- IXJUKNQCZOUQQC-UHFFFAOYSA-N 2-(2-fluoroethoxy)-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]benzoic acid Chemical compound C1CN(C)CCC1N1CCN(C=2C=C(OCCF)C(C(O)=O)=CC=2)CC1 IXJUKNQCZOUQQC-UHFFFAOYSA-N 0.000 description 1
- SIGRPFDCVORHOW-UHFFFAOYSA-N 2-(4-aminophenyl)-n-[5-(3,5-difluorophenyl)sulfanyl-2h-pyrazolo[3,4-b]pyridin-3-yl]acetamide Chemical compound C1=CC(N)=CC=C1CC(=O)NC(C1=C2)=NNC1=NC=C2SC1=CC(F)=CC(F)=C1 SIGRPFDCVORHOW-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
- LGJSPTFUIMJKTA-UHFFFAOYSA-N 2-[(3,5-difluorophenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1CC1=CC(F)=CC(F)=C1 LGJSPTFUIMJKTA-UHFFFAOYSA-N 0.000 description 1
- QKYVZDRYXYVJBZ-UHFFFAOYSA-N 2-[2-fluoroethyl-(2,2,2-trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoic acid Chemical compound C1CN(C)CCN1C1=CC=C(C(O)=O)C(N(CCF)C(=O)C(F)(F)F)=C1 QKYVZDRYXYVJBZ-UHFFFAOYSA-N 0.000 description 1
- WBWGUECQZSTJSY-UHFFFAOYSA-N 2-[4-(4-methylpiperazin-1-yl)-2-nitrophenyl]acetic acid Chemical compound C1CN(C)CCN1C1=CC=C(CC(O)=O)C([N+]([O-])=O)=C1 WBWGUECQZSTJSY-UHFFFAOYSA-N 0.000 description 1
- YCNQPAVKQPLZRS-UHFFFAOYSA-N 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical class O1C(C)(C)C(C)(C)OB1CC1=CC=CC=C1 YCNQPAVKQPLZRS-UHFFFAOYSA-N 0.000 description 1
- PXRFWOKUSRKWBQ-UHFFFAOYSA-N 2-chloro-5-(phenylsulfamoyl)pyridine-3-carboxamide Chemical class N1=C(Cl)C(C(=O)N)=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 PXRFWOKUSRKWBQ-UHFFFAOYSA-N 0.000 description 1
- CJMKBNLIAVFWJM-UHFFFAOYSA-N 2-chloro-5-(phenylsulfamoyl)pyridine-3-carboxylic acid Chemical class N1=C(Cl)C(C(=O)O)=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 CJMKBNLIAVFWJM-UHFFFAOYSA-N 0.000 description 1
- LPZQFYVQHSUQNF-UHFFFAOYSA-N 2-chloro-5-[(3,5-difluorophenyl)sulfamoyl]pyridine-3-carboxylic acid Chemical compound N1=C(Cl)C(C(=O)O)=CC(S(=O)(=O)NC=2C=C(F)C=C(F)C=2)=C1 LPZQFYVQHSUQNF-UHFFFAOYSA-N 0.000 description 1
- LZTZZRPMYAKSFU-UHFFFAOYSA-N 2-chloro-5-chlorosulfonylpyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC(S(Cl)(=O)=O)=CN=C1Cl LZTZZRPMYAKSFU-UHFFFAOYSA-N 0.000 description 1
- YPSYBQCVDAJOAM-UHFFFAOYSA-N 2-chloro-6-[(3,5-difluorophenyl)methyl]pyridine-3-carbonitrile Chemical compound FC1=CC(F)=CC(CC=2N=C(Cl)C(C#N)=CC=2)=C1 YPSYBQCVDAJOAM-UHFFFAOYSA-N 0.000 description 1
- BHPYMZQTCPRLNR-UHFFFAOYSA-N 2-cyanoethanethioamide Chemical compound NC(=S)CC#N BHPYMZQTCPRLNR-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- BJEFCZACIRKVLJ-UHFFFAOYSA-N 2h-pyrazolo[3,4-b]pyridine-3,6-diamine Chemical compound NC1=CC=C2C(N)=NNC2=N1 BJEFCZACIRKVLJ-UHFFFAOYSA-N 0.000 description 1
- AOCSJJIMCMXDDG-UHFFFAOYSA-N 3,5-dichloro-2-nitropyrazine Chemical class [O-][N+](=O)C1=NC=C(Cl)N=C1Cl AOCSJJIMCMXDDG-UHFFFAOYSA-N 0.000 description 1
- WRXIPCQPHZMXOO-UHFFFAOYSA-N 3,5-dichlorobenzenethiol Chemical compound SC1=CC(Cl)=CC(Cl)=C1 WRXIPCQPHZMXOO-UHFFFAOYSA-N 0.000 description 1
- LFYVNHDFVIPZHV-UHFFFAOYSA-N 3,5-difluorobenzenethiol Chemical compound FC1=CC(F)=CC(S)=C1 LFYVNHDFVIPZHV-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-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
- FHHKMGLAIOHCQY-UHFFFAOYSA-N 3-nitro-6-sulfanylidene-1h-pyridine-2-carbonitrile Chemical compound [O-][N+](=O)C=1C=CC(=S)NC=1C#N FHHKMGLAIOHCQY-UHFFFAOYSA-N 0.000 description 1
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 1
- JHVKFHDSZWQIFF-UHFFFAOYSA-N 4,4,5,5-tetramethyl-3-(4,4,5,5-tetramethyldioxaborolan-3-yl)dioxaborolane Chemical compound CC1(C)C(C)(C)OOB1B1C(C)(C)C(C)(C)OO1 JHVKFHDSZWQIFF-UHFFFAOYSA-N 0.000 description 1
- NYYSPVRERVXMLJ-UHFFFAOYSA-N 4,4-difluorocyclohexan-1-one Chemical compound FC1(F)CCC(=O)CC1 NYYSPVRERVXMLJ-UHFFFAOYSA-N 0.000 description 1
- UXJJKFGTQCOPTI-NSHDSACASA-N 4-[(3s)-3-aminopyrrolidin-1-yl]-2-(oxan-4-ylamino)benzoic acid Chemical compound C1[C@@H](N)CCN1C1=CC=C(C(O)=O)C(NC2CCOCC2)=C1 UXJJKFGTQCOPTI-NSHDSACASA-N 0.000 description 1
- JCXMURUUBWONEA-SFHVURJKSA-N 4-[(3s)-3-aminopyrrolidin-1-yl]-n-[5-(3,5-difluorophenyl)sulfanyl-2h-pyrazolo[3,4-b]pyridin-3-yl]-2-(oxan-4-ylamino)benzamide Chemical compound C1[C@@H](N)CCN1C(C=C1NC2CCOCC2)=CC=C1C(=O)NC(C1=C2)=NNC1=NC=C2SC1=CC(F)=CC(F)=C1 JCXMURUUBWONEA-SFHVURJKSA-N 0.000 description 1
- FKERHSPGYLZIDP-UHFFFAOYSA-N 4-[3-(dimethylamino)propyl-methylamino]-2-[2-fluoroethyl-(2,2,2-trifluoroacetyl)amino]benzoic acid Chemical compound CN(C)CCCN(C)C1=CC=C(C(O)=O)C(N(CCF)C(=O)C(F)(F)F)=C1 FKERHSPGYLZIDP-UHFFFAOYSA-N 0.000 description 1
- LPTRHISTMVJAGX-UHFFFAOYSA-N 4-[3-(dimethylamino)propyl-methylamino]-2-[oxan-4-yl-(2,2,2-trifluoroacetyl)amino]benzoic acid Chemical compound CN(C)CCCN(C)C1=CC=C(C(O)=O)C(N(C2CCOCC2)C(=O)C(F)(F)F)=C1 LPTRHISTMVJAGX-UHFFFAOYSA-N 0.000 description 1
- JZUHRPMBVSKAQQ-UHFFFAOYSA-N 4-methylsulfanyl-6-oxo-1h-pyridazine-3-carbonitrile Chemical class CSC1=CC(O)=NN=C1C#N JZUHRPMBVSKAQQ-UHFFFAOYSA-N 0.000 description 1
- SVSBNSLUTSGNME-UHFFFAOYSA-N 4-methylsulfanyl-6-oxo-1h-pyridine-3-carbonitrile Chemical compound CSC1=CC(O)=NC=C1C#N SVSBNSLUTSGNME-UHFFFAOYSA-N 0.000 description 1
- SIRWWTJTGFJUNU-UHFFFAOYSA-N 5-(3,5-difluorophenyl)sulfanyl-n-[[4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)phenyl]methyl]-1h-pyrazolo[3,4-b]pyridin-3-amine Chemical compound C1CN(C)CCN1C(C=C1NC2CCOCC2)=CC=C1CNC(C1=C2)=NNC1=NC=C2SC1=CC(F)=CC(F)=C1 SIRWWTJTGFJUNU-UHFFFAOYSA-N 0.000 description 1
- ANCBPIWGSUPBAJ-UHFFFAOYSA-N 5-(3,5-difluorophenyl)sulfinyl-2h-pyrazolo[3,4-b]pyrazin-3-amine Chemical compound N1=C2C(N)=NNC2=NC=C1S(=O)C1=CC(F)=CC(F)=C1 ANCBPIWGSUPBAJ-UHFFFAOYSA-N 0.000 description 1
- BEWMMXCZNODTAZ-UHFFFAOYSA-N 5-[(3,5-difluorophenyl)methyl]-1h-pyrazolo[4,3-b]pyridin-3-amine Chemical compound N1=C2C(N)=NNC2=CC=C1CC1=CC(F)=CC(F)=C1 BEWMMXCZNODTAZ-UHFFFAOYSA-N 0.000 description 1
- YEFREPQOEYTXHU-UHFFFAOYSA-N 5-[(3,5-difluorophenyl)methyl]-2h-pyrazolo[3,4-b]pyridin-3-amine Chemical compound C1=C2C(N)=NNC2=NC=C1CC1=CC(F)=CC(F)=C1 YEFREPQOEYTXHU-UHFFFAOYSA-N 0.000 description 1
- YXWLEUCOZAOKNX-UHFFFAOYSA-N 5-benzyl-2-nitropyridine-3-carbonitrile Chemical class C1=C(C#N)C([N+](=O)[O-])=NC=C1CC1=CC=CC=C1 YXWLEUCOZAOKNX-UHFFFAOYSA-N 0.000 description 1
- GUSUHJNWILBQNV-UHFFFAOYSA-N 5-chloro-2-nitropyridine-3-carbonitrile Chemical compound [O-][N+](=O)C1=NC=C(Cl)C=C1C#N GUSUHJNWILBQNV-UHFFFAOYSA-N 0.000 description 1
- DMQTXELGRVDQPY-UHFFFAOYSA-N 5-cyano-6-methylsulfanylpyridine-3-carboxylic acid Chemical group CSC1=NC=C(C(O)=O)C=C1C#N DMQTXELGRVDQPY-UHFFFAOYSA-N 0.000 description 1
- KSGXFRBLXNHRNM-UHFFFAOYSA-N 5-iodo-6-methoxy-2-methylsulfinylpyridine-3-carbonitrile Chemical compound COC1=NC(S(C)=O)=C(C#N)C=C1I KSGXFRBLXNHRNM-UHFFFAOYSA-N 0.000 description 1
- YKRKKFQQFSQVCW-UHFFFAOYSA-N 5-iodo-6-methoxy-2-methylsulfonylpyridine-3-carbonitrile Chemical compound COC1=NC(S(C)(=O)=O)=C(C#N)C=C1I YKRKKFQQFSQVCW-UHFFFAOYSA-N 0.000 description 1
- DMLPQTWDFZCDTJ-UHFFFAOYSA-N 5-methoxypyridine-3-carbonitrile Chemical compound COC1=CN=CC(C#N)=C1 DMLPQTWDFZCDTJ-UHFFFAOYSA-N 0.000 description 1
- MZRUFMBFIKGOAL-UHFFFAOYSA-N 5-nitro-1h-pyrazole Chemical class [O-][N+](=O)C1=CC=NN1 MZRUFMBFIKGOAL-UHFFFAOYSA-N 0.000 description 1
- YRFSPIXYUZDAAR-UHFFFAOYSA-N 6-(3,5-difluoro-n-methylanilino)-2-methylsulfanylpyridine-3-carbonitrile Chemical compound C1=C(C#N)C(SC)=NC(N(C)C=2C=C(F)C=C(F)C=2)=C1 YRFSPIXYUZDAAR-UHFFFAOYSA-N 0.000 description 1
- IQPPCENBKPZGQL-UHFFFAOYSA-N 6-(3,5-difluoroanilino)-3-nitropyridine-2-carbonitrile Chemical compound N1=C(C#N)C([N+](=O)[O-])=CC=C1NC1=CC(F)=CC(F)=C1 IQPPCENBKPZGQL-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- PLRDSYYAKHJRON-UHFFFAOYSA-N 6-[(3,5-difluorophenyl)methyl]-2h-pyrazolo[3,4-b]pyridin-3-amine Chemical compound C=1C=C2C(N)=NNC2=NC=1CC1=CC(F)=CC(F)=C1 PLRDSYYAKHJRON-UHFFFAOYSA-N 0.000 description 1
- WGUBQNSZEHNKFH-UHFFFAOYSA-N 6-[(3,5-difluorophenyl)methyl]-3-nitropyridine-2-carbonitrile Chemical compound N1=C(C#N)C([N+](=O)[O-])=CC=C1CC1=CC(F)=CC(F)=C1 WGUBQNSZEHNKFH-UHFFFAOYSA-N 0.000 description 1
- LMRYVMLKXMJWNL-UHFFFAOYSA-N 6-amino-5-iodo-2-methylsulfonylpyridine-3-carbonitrile Chemical compound CS(=O)(=O)C1=NC(N)=C(I)C=C1C#N LMRYVMLKXMJWNL-UHFFFAOYSA-N 0.000 description 1
- AOMBSGDJMMMUNI-UHFFFAOYSA-N 6-benzyl-3-nitropyrazine-2-carbonitrile Chemical class N1=C(C#N)C([N+](=O)[O-])=NC=C1CC1=CC=CC=C1 AOMBSGDJMMMUNI-UHFFFAOYSA-N 0.000 description 1
- SCZZEMIFQWCCGY-UHFFFAOYSA-N 6-benzyl-3-nitropyridine-2-carbonitrile Chemical class N1=C(C#N)C([N+](=O)[O-])=CC=C1CC1=CC=CC=C1 SCZZEMIFQWCCGY-UHFFFAOYSA-N 0.000 description 1
- ZGCFHYKQHHBJJZ-UHFFFAOYSA-N 6-chloro-1h-pyrazolo[4,3-c]pyridin-3-amine Chemical class ClC1=NC=C2C(N)=NNC2=C1 ZGCFHYKQHHBJJZ-UHFFFAOYSA-N 0.000 description 1
- BDVONVNKANKJHV-UHFFFAOYSA-N 6-chloro-3-nitropyridine-2-carbonitrile 2,6-dichloro-3-nitropyridine Chemical compound ClC1=NC(=CC=C1[N+](=O)[O-])Cl.ClC1=CC=C(C(=N1)C#N)[N+](=O)[O-] BDVONVNKANKJHV-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000006820 Arthralgia Diseases 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
- 102100035080 BDNF/NT-3 growth factors receptor Human genes 0.000 description 1
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 206010051290 Central nervous system lesion Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006509 Congenital Pain Insensitivity Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 241000870659 Crassula perfoliata var. minor Species 0.000 description 1
- 208000011231 Crohn disease Diseases 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 206010013142 Disinhibition Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- YSWHPLCDIMUKFE-QWRGUYRKSA-N Glu-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 YSWHPLCDIMUKFE-QWRGUYRKSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 description 1
- 101000596896 Homo sapiens BDNF/NT-3 growth factors receptor Proteins 0.000 description 1
- 101000596894 Homo sapiens High affinity nerve growth factor receptor Proteins 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000003618 Intervertebral Disc Displacement Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 240000006240 Linum usitatissimum Species 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 206010027603 Migraine headaches Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- NXWFYDFNTNZIGI-UHFFFAOYSA-N OBOCC1=CC=CC=C1 Chemical compound OBOCC1=CC=CC=C1 NXWFYDFNTNZIGI-UHFFFAOYSA-N 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 208000003076 Osteolysis Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- 208000008765 Sciatica Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000006619 Stille reaction Methods 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- SAQSTQBVENFSKT-UHFFFAOYSA-M TCA-sodium Chemical compound [Na+].[O-]C(=O)C(Cl)(Cl)Cl SAQSTQBVENFSKT-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 102000005937 Tropomyosin Human genes 0.000 description 1
- 108010030743 Tropomyosin Proteins 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 206010048010 Withdrawal syndrome Diseases 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- 150000000475 acetylene derivatives Chemical class 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 150000001503 aryl iodides Chemical class 0.000 description 1
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 208000037738 autosomal recessive channelopathy-associated congenital insensitivity to pain Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical class BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- KGLYSXGHNGYWSL-UHFFFAOYSA-N chloromethylbenzene;zinc Chemical compound [Zn].ClCC1=CC=CC=C1 KGLYSXGHNGYWSL-UHFFFAOYSA-N 0.000 description 1
- LIQBAAKGMWRWPS-UHFFFAOYSA-M chlorozinc(1+);methanidylbenzene Chemical compound [Zn+]Cl.[CH2-]C1=CC=CC=C1 LIQBAAKGMWRWPS-UHFFFAOYSA-M 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000009519 contusion Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- MKNXBRLZBFVUPV-UHFFFAOYSA-L cyclopenta-1,3-diene;dichlorotitanium Chemical compound Cl[Ti]Cl.C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 MKNXBRLZBFVUPV-UHFFFAOYSA-L 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical group C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- XEDHNTPQPKCZSF-UHFFFAOYSA-N diethyl 2-(4-fluoro-2-nitrophenyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)C1=CC=C(F)C=C1[N+]([O-])=O XEDHNTPQPKCZSF-UHFFFAOYSA-N 0.000 description 1
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 1
- PGFWCWVVIAJUKT-UHFFFAOYSA-N diethyl 2-[4-(4-methylpiperazin-1-yl)-2-nitrophenyl]propanedioate Chemical compound C1=C([N+]([O-])=O)C(C(C(=O)OCC)C(=O)OCC)=CC=C1N1CCN(C)CC1 PGFWCWVVIAJUKT-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000004582 dihydrobenzothienyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- VTIIJXUACCWYHX-UHFFFAOYSA-L disodium;carboxylatooxy carbonate Chemical compound [Na+].[Na+].[O-]C(=O)OOC([O-])=O VTIIJXUACCWYHX-UHFFFAOYSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 1
- KNTPUWHHNMODOA-UHFFFAOYSA-N ethyl 5-cyano-6-methylsulfanylpyridine-3-carboxylate Chemical class CCOC(=O)C1=CN=C(SC)C(C#N)=C1 KNTPUWHHNMODOA-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- UEXCJVNBTNXOEH-OUBTZVSYSA-N ethynylbenzene Chemical class [13CH]#CC1=CC=CC=C1 UEXCJVNBTNXOEH-OUBTZVSYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 125000000524 functional group Chemical class 0.000 description 1
- ZYXBIOIYWUIXSM-UHFFFAOYSA-N furo[2,3-c]pyridine Chemical compound C1=NC=C2OC=CC2=C1 ZYXBIOIYWUIXSM-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 231100000640 hair analysis Toxicity 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000037584 hereditary sensory and autonomic neuropathy Diseases 0.000 description 1
- 201000000887 hereditary sensory and autonomic neuropathy type 5 Diseases 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 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
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 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
- 229960002725 isoflurane Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- GRHBQAYDJPGGLF-UHFFFAOYSA-N isothiocyanic acid Chemical compound N=C=S GRHBQAYDJPGGLF-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 230000009191 jumping Effects 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HNQIVZYLYMDVSB-NJFSPNSNSA-N methanesulfonamide Chemical compound [14CH3]S(N)(=O)=O HNQIVZYLYMDVSB-NJFSPNSNSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000004702 methyl esters Chemical group 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000037230 mobility Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- IMCCZKHIPVEUEI-UHFFFAOYSA-N n,n-difluoroaniline Chemical compound FN(F)C1=CC=CC=C1 IMCCZKHIPVEUEI-UHFFFAOYSA-N 0.000 description 1
- DSWNRHCOGVRDOE-UHFFFAOYSA-N n,n-dimethylmethanimidamide Chemical group CN(C)C=N DSWNRHCOGVRDOE-UHFFFAOYSA-N 0.000 description 1
- VNTDGIJKOWGCGP-UHFFFAOYSA-N n-(5-iodo-1-tritylpyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide Chemical compound C1CN(C)CCN1C(C=C1NC2CCOCC2)=CC=C1C(=O)NC1=NN(C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C2=NC=C(I)C=C12 VNTDGIJKOWGCGP-UHFFFAOYSA-N 0.000 description 1
- RQOOJWGFSPUOKJ-UHFFFAOYSA-N n-(5-iodo-2h-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide Chemical compound C1CN(C)CCN1C(C=C1NC2CCOCC2)=CC=C1C(=O)NC1=NNC2=NC=C(I)C=C12 RQOOJWGFSPUOKJ-UHFFFAOYSA-N 0.000 description 1
- ZQKDPKODEFRUEN-UHFFFAOYSA-N n-[5-(3,5-difluoroanilino)-1-tritylpyrazolo[3,4-b]pyridin-3-yl]-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide Chemical compound C1CN(C)CCN1C(C=C1NC2CCOCC2)=CC=C1C(=O)NC(C1=C2)=NN(C(C=3C=CC=CC=3)(C=3C=CC=CC=3)C=3C=CC=CC=3)C1=NC=C2NC1=CC(F)=CC(F)=C1 ZQKDPKODEFRUEN-UHFFFAOYSA-N 0.000 description 1
- QLTWJYWRIYEPDI-UHFFFAOYSA-N n-[5-(3,5-difluoroanilino)-2h-pyrazolo[3,4-b]pyridin-3-yl]-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide Chemical compound C1CN(C)CCN1C(C=C1NC2CCOCC2)=CC=C1C(=O)NC(C1=C2)=NNC1=NC=C2NC1=CC(F)=CC(F)=C1 QLTWJYWRIYEPDI-UHFFFAOYSA-N 0.000 description 1
- KCHLSEMOIQITKI-UHFFFAOYSA-N n-[5-(3,5-difluorophenyl)sulfanyl-2h-pyrazolo[3,4-b]pyrazin-3-yl]-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide Chemical compound C1CN(C)CCN1C(C=C1NC2CCOCC2)=CC=C1C(=O)NC1=C2N=C(SC=3C=C(F)C=C(F)C=3)C=NC2=NN1 KCHLSEMOIQITKI-UHFFFAOYSA-N 0.000 description 1
- JGPJNEQDNBDCOJ-UHFFFAOYSA-N n-[5-(3,5-difluorophenyl)sulfanyl-2h-pyrazolo[3,4-b]pyridin-3-yl]-2-(4-nitrophenyl)acetamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1CC(=O)NC(C1=C2)=NNC1=NC=C2SC1=CC(F)=CC(F)=C1 JGPJNEQDNBDCOJ-UHFFFAOYSA-N 0.000 description 1
- ZGGJRARKGWGFIA-UHFFFAOYSA-N n-[5-(3,5-difluorophenyl)sulfanyl-2h-pyrazolo[3,4-b]pyridin-3-yl]-4-(4-methylpiperazin-1-yl)-2-[oxan-4-yl-(2,2,2-trifluoroacetyl)amino]benzamide Chemical compound C1CN(C)CCN1C(C=C1N(C2CCOCC2)C(=O)C(F)(F)F)=CC=C1C(=O)NC(C1=C2)=NNC1=NC=C2SC1=CC(F)=CC(F)=C1 ZGGJRARKGWGFIA-UHFFFAOYSA-N 0.000 description 1
- QPQVPVSYRKEUAZ-UHFFFAOYSA-N n-[5-(3,5-difluorophenyl)sulfanyl-6-oxo-1,2-dihydropyrazolo[3,4-b]pyridin-3-yl]-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide Chemical compound C1CN(C)CCN1C(C=C1NC2CCOCC2)=CC=C1C(=O)NC(C1=C2)=NNC1=NC(O)=C2SC1=CC(F)=CC(F)=C1 QPQVPVSYRKEUAZ-UHFFFAOYSA-N 0.000 description 1
- RUAZKOVTMSAJDH-UHFFFAOYSA-N n-[5-[(3,5-difluorophenyl)sulfamoyl]-2h-pyrazolo[3,4-b]pyridin-3-yl]-4-(4-methylpiperazin-1-yl)-2-[oxan-4-yl-(2,2,2-trifluoroacetyl)amino]benzamide Chemical compound C1CN(C)CCN1C(C=C1N(C2CCOCC2)C(=O)C(F)(F)F)=CC=C1C(=O)NC1=NNC2=NC=C(S(=O)(=O)NC=3C=C(F)C=C(F)C=3)C=C12 RUAZKOVTMSAJDH-UHFFFAOYSA-N 0.000 description 1
- GTJRZXUZLSBJFN-UHFFFAOYSA-N n-[5-[2-(3,5-difluorophenyl)ethyl]-2h-pyrazolo[3,4-b]pyridin-3-yl]-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide Chemical compound C1CN(C)CCN1C(C=C1NC2CCOCC2)=CC=C1C(=O)NC(C1=C2)=NNC1=NC=C2CCC1=CC(F)=CC(F)=C1 GTJRZXUZLSBJFN-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229940121367 non-opioid analgesics Drugs 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 230000000010 osteolytic effect Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- JMJRYTGVHCAYCT-UHFFFAOYSA-N oxan-4-one Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- UEXCJVNBTNXOEH-UHFFFAOYSA-N phenyl acethylene Natural products C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 210000002248 primary sensory neuron Anatomy 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 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 group 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- 229940045872 sodium percarbonate Drugs 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229950008160 tanezumab Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- NQMFPYVTERZDFF-UHFFFAOYSA-N tert-butyl 2-(2-fluoroethoxy)-4-(4-methylpiperazin-1-yl)benzoate Chemical compound C1CN(C)CCN1C1=CC=C(C(=O)OC(C)(C)C)C(OCCF)=C1 NQMFPYVTERZDFF-UHFFFAOYSA-N 0.000 description 1
- KICZPQRODBCGGU-UHFFFAOYSA-N tert-butyl 2-[(4,4-difluorocyclohexyl)-(2,2,2-trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoate Chemical compound C1CN(C)CCN1C1=CC=C(C(=O)OC(C)(C)C)C(N(C2CCC(F)(F)CC2)C(=O)C(F)(F)F)=C1 KICZPQRODBCGGU-UHFFFAOYSA-N 0.000 description 1
- ZKSDSZOFDODWLF-UHFFFAOYSA-N tert-butyl 2-[2-fluoroethyl-(2,2,2-trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoate Chemical compound C1CN(C)CCN1C1=CC=C(C(=O)OC(C)(C)C)C(N(CCF)C(=O)C(F)(F)F)=C1 ZKSDSZOFDODWLF-UHFFFAOYSA-N 0.000 description 1
- WFQHGCOHRFRRHU-UHFFFAOYSA-N tert-butyl 4-bromo-2-nitrobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(Br)C=C1[N+]([O-])=O WFQHGCOHRFRRHU-UHFFFAOYSA-N 0.000 description 1
- LFMQLGMABWQOAM-UHFFFAOYSA-N tert-butyl 4-fluoro-2-(2-fluoroethoxy)benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(F)C=C1OCCF LFMQLGMABWQOAM-UHFFFAOYSA-N 0.000 description 1
- JLGPJOUWLXCECT-UHFFFAOYSA-N tert-butyl 4-fluoro-2-nitrobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(F)C=C1[N+]([O-])=O JLGPJOUWLXCECT-UHFFFAOYSA-N 0.000 description 1
- DQQJBEAXSOOCPG-ZETCQYMHSA-N tert-butyl n-[(3s)-pyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCNC1 DQQJBEAXSOOCPG-ZETCQYMHSA-N 0.000 description 1
- WACDXCHIIXEODU-UHFFFAOYSA-N tert-butyl n-[2-amino-5-(4-methylpiperazin-1-yl)phenyl]carbamate Chemical compound C1CN(C)CCN1C1=CC=C(N)C(NC(=O)OC(C)(C)C)=C1 WACDXCHIIXEODU-UHFFFAOYSA-N 0.000 description 1
- ZJQJFBQLRHEQMS-UHFFFAOYSA-N tert-butyl n-[2-isothiocyanato-5-(4-methylpiperazin-1-yl)phenyl]carbamate Chemical compound C1CN(C)CCN1C1=CC=C(N=C=S)C(NC(=O)OC(C)(C)C)=C1 ZJQJFBQLRHEQMS-UHFFFAOYSA-N 0.000 description 1
- NAYIMYIHMQMARV-UHFFFAOYSA-N tert-butyl n-[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]carbamate Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(NC(=O)OC(C)(C)C)=C1 NAYIMYIHMQMARV-UHFFFAOYSA-N 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000002303 tibia Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical class FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 108010064884 trkA Receptor Proteins 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 108010002164 tyrosine receptor Proteins 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229940087652 vioxx Drugs 0.000 description 1
- 238000005303 weighing Methods 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
- A61K31/495—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
- A61K31/435—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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP12305922.2A EP2689778A1 (en) | 2012-07-27 | 2012-07-27 | Derivatives of azaindoles or diazaindoles for treating pain |
| EP12305922.2 | 2012-07-27 | ||
| PCT/EP2013/065907 WO2014016433A1 (en) | 2012-07-27 | 2013-07-29 | Derivatives of azaindazole or diazaindazole type for treating pain |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2013294920A1 AU2013294920A1 (en) | 2015-03-12 |
| AU2013294920B2 true AU2013294920B2 (en) | 2017-08-24 |
Family
ID=48948392
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2013294920A Active AU2013294920B2 (en) | 2012-07-27 | 2013-07-29 | Derivatives of azaindazole or diazaindazole type for treating pain |
Country Status (28)
| Country | Link |
|---|---|
| US (1) | US9381195B2 (OSRAM) |
| EP (2) | EP2689778A1 (OSRAM) |
| JP (2) | JP6456823B2 (OSRAM) |
| KR (1) | KR102120505B1 (OSRAM) |
| CN (1) | CN104684554B (OSRAM) |
| AU (1) | AU2013294920B2 (OSRAM) |
| BR (1) | BR112015001502B1 (OSRAM) |
| CA (1) | CA2879595C (OSRAM) |
| CY (1) | CY1118478T1 (OSRAM) |
| DK (1) | DK2877177T3 (OSRAM) |
| ES (1) | ES2612349T3 (OSRAM) |
| HR (1) | HRP20170104T1 (OSRAM) |
| HU (1) | HUE032919T2 (OSRAM) |
| IL (1) | IL236917A (OSRAM) |
| LT (1) | LT2877177T (OSRAM) |
| MA (1) | MA37866B1 (OSRAM) |
| MX (1) | MX363605B (OSRAM) |
| MY (1) | MY183398A (OSRAM) |
| NZ (1) | NZ705253A (OSRAM) |
| PL (1) | PL2877177T3 (OSRAM) |
| PT (1) | PT2877177T (OSRAM) |
| RS (1) | RS55646B1 (OSRAM) |
| RU (1) | RU2640046C2 (OSRAM) |
| SI (1) | SI2877177T1 (OSRAM) |
| TN (1) | TN2015000034A1 (OSRAM) |
| UA (1) | UA116107C2 (OSRAM) |
| WO (1) | WO2014016433A1 (OSRAM) |
| ZA (1) | ZA201501209B (OSRAM) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT2725028T (pt) | 2008-10-22 | 2016-08-31 | Array Biopharma Inc | Compostos de pirazolo[1,5-]pirimidina substituídos como intermediários na síntese de inibidores de cinase trk |
| AR077468A1 (es) | 2009-07-09 | 2011-08-31 | Array Biopharma Inc | Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa |
| HUE044025T2 (hu) | 2010-05-20 | 2019-09-30 | Array Biopharma Inc | Makrociklusos vegyületek mint TRK-kináz inhibitorok |
| EP2689778A1 (en) * | 2012-07-27 | 2014-01-29 | Pierre Fabre Medicament | Derivatives of azaindoles or diazaindoles for treating pain |
| WO2015143652A1 (en) * | 2014-03-26 | 2015-10-01 | Merck Sharp & Dohme Corp. | TrkA KINASE INHIBITORS,COMPOSITIONS AND METHODS THEREOF |
| CN107106546A (zh) | 2014-10-06 | 2017-08-29 | 弗拉特利发现实验室有限责任公司 | 三唑并吡啶化合物和用于治疗囊性纤维化的方法 |
| FI3699181T3 (fi) | 2014-11-16 | 2023-03-28 | Array Biopharma Inc | Kiteinen muoto (s)-n-(5-((r)-2-(2,5-diluorifenyyli)-pyrrolidin-1-yyli)-pyratsolo[1,5-a]pyrimidin-3-yyli)-3-hydroksipyrrolidiini-1-karboksamidivetyysulfaatista |
| WO2016096709A1 (en) | 2014-12-16 | 2016-06-23 | Eudendron S.R.L. | Heterocyclic derivatives modulating activity of certain protein kinases |
| EP3368039A1 (en) | 2015-10-26 | 2018-09-05 | The Regents of The University of Colorado, A Body Corporate | Point mutations in trk inhibitor-resistant cancer and methods relating to the same |
| US10045991B2 (en) | 2016-04-04 | 2018-08-14 | Loxo Oncology, Inc. | Methods of treating pediatric cancers |
| RS65987B1 (sr) | 2016-04-04 | 2024-10-31 | Loxo Oncology Inc | Tečne formulacije (s)-n-(5-((r)-2-(2,5-difluorofenil)-pirolidin-1-il)-pirazolo[1,5-]pirimidin-3-il)-3-hidroksipirolidin-1-karboksamida |
| EP3800189B1 (en) | 2016-05-18 | 2023-06-28 | Loxo Oncology, Inc. | Preparation of (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide |
| US10246462B2 (en) | 2016-09-09 | 2019-04-02 | Flx Bio, Inc. | Chemokine receptor modulators and uses thereof |
| JOP20190092A1 (ar) | 2016-10-26 | 2019-04-25 | Array Biopharma Inc | عملية لتحضير مركبات بيرازولو[1، 5-a]بيريميدين وأملاح منها |
| WO2018079759A1 (ja) * | 2016-10-31 | 2018-05-03 | 塩野義製薬株式会社 | ＴｒｋＡ阻害活性を有する縮合複素環および縮合炭素環誘導体 |
| JOP20190213A1 (ar) | 2017-03-16 | 2019-09-16 | Array Biopharma Inc | مركبات حلقية ضخمة كمثبطات لكيناز ros1 |
| CA3098988A1 (en) * | 2018-05-02 | 2019-11-07 | Jw Pharmaceutical Corporation | Heterocycle derivative |
| KR102129114B1 (ko) | 2018-07-26 | 2020-07-02 | 주식회사 온코파마텍 | TrkA 저해 활성을 갖는 화합물 및 이를 유효성분으로 함유하는 통증의 예방 또는 치료용 약학적 조성물 |
| EP3725777A1 (en) * | 2019-04-17 | 2020-10-21 | Rottapharm Biotech S.r.l. | Benzo- and pyrido-pyrazoles as protein kinase inhibitors |
| CN110105356B (zh) * | 2019-05-31 | 2022-04-01 | 四川国康药业有限公司 | 一种氮杂吲哚类化合物及其制备方法和用途 |
| TW202448883A (zh) * | 2023-05-24 | 2024-12-16 | 大陸商長春金賽藥業有限責任公司 | Ｆｇｆｒ２／３選擇性抑制劑、藥物組合物及其用途 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012101239A1 (en) * | 2011-01-27 | 2012-08-02 | Pierre Fabre Medicament | Derivatives of azaindazole or diazaindazole type as medicament |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2202827T3 (es) * | 1997-03-19 | 2004-04-01 | ABBOTT GMBH & CO. KG | Pirrolo(2,3-d)pirimidinas y su uso como inhibidores de la tirosina kinasa. |
| EP1215208B1 (en) | 1997-10-27 | 2006-07-12 | Agouron Pharmaceuticals, Inc. | 4-Aminothiazole derivatives, their preparation and their use as inhibitors of cyclin-dependent kinases |
| WO2001098284A1 (en) | 2000-06-22 | 2001-12-27 | Pfizer Limited | Process for the preparation of pyrazolopyrimidinones |
| SE0301906D0 (sv) * | 2003-06-26 | 2003-06-26 | Astrazeneca Ab | New compounds |
| DE102004061288A1 (de) * | 2004-12-14 | 2006-06-29 | Schering Ag | 3-Amino-Pyrazolo[3,4b]pyridine als Inhibitoren von Proteintyrosinkinasen, deren Herstellung und Verwendung als Arzneimittel |
| JP2009506006A (ja) * | 2005-08-25 | 2009-02-12 | エフ．ホフマン−ラ ロシュ アーゲー | ｐ３８ＭＡＰキナーゼ阻害剤およびその使用方法 |
| WO2008010964A1 (en) | 2006-07-17 | 2008-01-24 | Merck & Co., Inc. | 1-hydroxy naphthyridine compounds as anti-hiv agents |
| EA017852B1 (ru) * | 2006-12-20 | 2013-03-29 | НЕРВИАНО МЕДИКАЛ САЙЕНСИЗ С.р.л. | Производные замещенных индазолов, активные в качестве ингибиторов киназ |
| US20080194557A1 (en) * | 2007-01-18 | 2008-08-14 | Joseph Barbosa | Methods and compositions for the treatment of pain, inflammation and cancer |
| WO2008112695A2 (en) * | 2007-03-12 | 2008-09-18 | Irm Llc | Pyrazolo [3,4-d] pyrimidines and 1, 2, 5, 6-tetraaza- as- indacenes as protein kinase inhibitors for cancer treatment |
| US8299057B2 (en) | 2007-07-20 | 2012-10-30 | Nerviano Medical Sciences S.R.L. | Substituted indazole derivatives active as kinase inhibitors |
| JP5580332B2 (ja) * | 2008-12-18 | 2014-08-27 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | キナーゼ阻害剤として活性な置換インダゾール誘導体 |
| EP2689778A1 (en) * | 2012-07-27 | 2014-01-29 | Pierre Fabre Medicament | Derivatives of azaindoles or diazaindoles for treating pain |
-
2012
- 2012-07-27 EP EP12305922.2A patent/EP2689778A1/en not_active Withdrawn
-
2013
- 2013-07-29 MX MX2015001009A patent/MX363605B/es unknown
- 2013-07-29 LT LTEP13745813.9T patent/LT2877177T/lt unknown
- 2013-07-29 RS RS20170095A patent/RS55646B1/sr unknown
- 2013-07-29 PT PT137458139T patent/PT2877177T/pt unknown
- 2013-07-29 EP EP13745813.9A patent/EP2877177B1/en active Active
- 2013-07-29 WO PCT/EP2013/065907 patent/WO2014016433A1/en not_active Ceased
- 2013-07-29 BR BR112015001502-6A patent/BR112015001502B1/pt active IP Right Grant
- 2013-07-29 NZ NZ705253A patent/NZ705253A/en unknown
- 2013-07-29 PL PL13745813T patent/PL2877177T3/pl unknown
- 2013-07-29 AU AU2013294920A patent/AU2013294920B2/en active Active
- 2013-07-29 CN CN201380049411.3A patent/CN104684554B/zh active Active
- 2013-07-29 HR HRP20170104TT patent/HRP20170104T1/hr unknown
- 2013-07-29 HU HUE13745813A patent/HUE032919T2/hu unknown
- 2013-07-29 CA CA2879595A patent/CA2879595C/en active Active
- 2013-07-29 UA UAA201501614A patent/UA116107C2/uk unknown
- 2013-07-29 MY MYPI2015700206A patent/MY183398A/en unknown
- 2013-07-29 RU RU2015106434A patent/RU2640046C2/ru active
- 2013-07-29 JP JP2015523576A patent/JP6456823B2/ja active Active
- 2013-07-29 US US14/417,507 patent/US9381195B2/en active Active
- 2013-07-29 DK DK13745813.9T patent/DK2877177T3/en active
- 2013-07-29 ES ES13745813.9T patent/ES2612349T3/es active Active
- 2013-07-29 KR KR1020157004735A patent/KR102120505B1/ko active Active
- 2013-07-29 SI SI201330496A patent/SI2877177T1/sl unknown
-
2015
- 2015-01-23 TN TNP2015000034A patent/TN2015000034A1/fr unknown
- 2015-01-25 IL IL236917A patent/IL236917A/en active IP Right Grant
- 2015-02-23 MA MA37866A patent/MA37866B1/fr unknown
- 2015-02-23 ZA ZA2015/01209A patent/ZA201501209B/en unknown
-
2017
- 2017-01-23 CY CY20171100091T patent/CY1118478T1/el unknown
-
2018
- 2018-10-24 JP JP2018200317A patent/JP6732855B2/ja active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012101239A1 (en) * | 2011-01-27 | 2012-08-02 | Pierre Fabre Medicament | Derivatives of azaindazole or diazaindazole type as medicament |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2013294920B2 (en) | Derivatives of azaindazole or diazaindazole type for treating pain | |
| AU2012210467B2 (en) | Derivatives of azaindazole or diazaindazole type as medicament | |
| US9428510B2 (en) | Derivatives of azaindazole or diazaindazole type for treating a cancer overexpressing Trk | |
| HK1207302B (en) | Derivatives of azaindazole or diazaindazole type for treating pain | |
| OA17324A (en) | Derivatives of azaindazole or diazaindazole type for treating pain. | |
| OA16493A (en) | Derivatives of azaindazole or diazaindazole type as medicament. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) |