ES2456515T3 - Derivados de pirimidindiona fusionados como moduladores de TRPA1 - Google Patents
Derivados de pirimidindiona fusionados como moduladores de TRPA1 Download PDFInfo
- Publication number
- ES2456515T3 ES2456515T3 ES10755503.9T ES10755503T ES2456515T3 ES 2456515 T3 ES2456515 T3 ES 2456515T3 ES 10755503 T ES10755503 T ES 10755503T ES 2456515 T3 ES2456515 T3 ES 2456515T3
- Authority
- ES
- Spain
- Prior art keywords
- acetamide
- pyrimidin
- dioxo
- tetrahydro
- thiazol
- 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
- 101000764872 Homo sapiens Transient receptor potential cation channel subfamily A member 1 Proteins 0.000 title claims description 6
- 102100026186 Transient receptor potential cation channel subfamily A member 1 Human genes 0.000 title claims description 5
- 150000008512 pyrimidinediones Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 210
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 69
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 34
- 239000001257 hydrogen Substances 0.000 claims abstract description 34
- 125000003118 aryl group Chemical group 0.000 claims abstract description 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 28
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 28
- 150000002367 halogens Chemical group 0.000 claims abstract description 28
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 26
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 26
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 25
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 25
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 21
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 16
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 15
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 14
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 13
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims abstract description 11
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims abstract description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 10
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims abstract description 10
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 9
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 8
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims abstract description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 6
- 150000003233 pyrroles Chemical class 0.000 claims abstract description 6
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims abstract description 6
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims abstract description 5
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims abstract description 5
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims abstract description 5
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229930192474 thiophene Natural products 0.000 claims abstract description 5
- BEWFIPLBFJGWSR-AONZOJHOSA-N butyl (z,12r)-12-acetyloxyoctadec-9-enoate Chemical group CCCCCC[C@@H](OC(C)=O)C\C=C/CCCCCCCC(=O)OCCCC BEWFIPLBFJGWSR-AONZOJHOSA-N 0.000 claims abstract description 3
- -1 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H -pyrrolo [3,2-d] pyrimidin-5-yl Chemical group 0.000 claims description 181
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 181
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 86
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 37
- 208000002193 Pain Diseases 0.000 claims description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 28
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 17
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 208000035475 disorder Diseases 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 11
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 208000000094 Chronic Pain Diseases 0.000 claims description 6
- 208000004296 neuralgia Diseases 0.000 claims description 6
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 5
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 208000024891 symptom Diseases 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 4
- 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims description 4
- 208000021722 neuropathic pain Diseases 0.000 claims description 4
- 201000001119 neuropathy Diseases 0.000 claims description 4
- 230000007823 neuropathy Effects 0.000 claims description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000001331 3-methylbutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 claims description 3
- 208000026935 allergic disease Diseases 0.000 claims description 3
- 230000003349 osteoarthritic effect Effects 0.000 claims description 3
- 208000009935 visceral pain Diseases 0.000 claims description 3
- 208000008035 Back Pain Diseases 0.000 claims description 2
- 206010058019 Cancer Pain Diseases 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
- 208000023890 Complex Regional Pain Syndromes Diseases 0.000 claims description 2
- 206010011224 Cough Diseases 0.000 claims description 2
- 201000004624 Dermatitis Diseases 0.000 claims description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 2
- 208000001640 Fibromyalgia Diseases 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 206010020751 Hypersensitivity Diseases 0.000 claims description 2
- 208000019695 Migraine disease Diseases 0.000 claims description 2
- 206010030216 Oesophagitis Diseases 0.000 claims description 2
- 206010036376 Postherpetic Neuralgia Diseases 0.000 claims description 2
- 208000004550 Postoperative Pain Diseases 0.000 claims description 2
- 208000003251 Pruritus Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 208000008765 Sciatica Diseases 0.000 claims description 2
- 208000007107 Stomach Ulcer Diseases 0.000 claims description 2
- 206010046543 Urinary incontinence Diseases 0.000 claims description 2
- 206010047700 Vomiting Diseases 0.000 claims description 2
- 230000002917 arthritic effect Effects 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 208000010668 atopic eczema Diseases 0.000 claims description 2
- 201000003146 cystitis Diseases 0.000 claims description 2
- 208000000718 duodenal ulcer Diseases 0.000 claims description 2
- 208000006881 esophagitis Diseases 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 201000005917 gastric ulcer Diseases 0.000 claims description 2
- 230000009610 hypersensitivity Effects 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 2
- 208000028867 ischemia Diseases 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 206010027599 migraine Diseases 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- MIQCXSCTXQXGMO-UHFFFAOYSA-N n-[4-[3,5-dichloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)acetamide Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2C=CN1CC(=O)NC(SC=1)=NC=1C1=CC(Cl)=C(OCC(C)(C)C)C(Cl)=C1 MIQCXSCTXQXGMO-UHFFFAOYSA-N 0.000 claims description 2
- ZVGKXJDRPSRLQF-UHFFFAOYSA-N n-[4-[4-(2,2-dimethylpropoxy)-3-fluorophenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)acetamide Chemical compound CC1=CC=2N(C)C(=O)N(C)C(=O)C=2N1CC(=O)NC(SC=1)=NC=1C1=CC=C(OCC(C)(C)C)C(F)=C1 ZVGKXJDRPSRLQF-UHFFFAOYSA-N 0.000 claims description 2
- RHMISVBJYQSDSS-UHFFFAOYSA-N n-[4-[4-(cyclopropylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)acetamide Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2C=CN1CC(=O)NC(SC=1)=NC=1C(C=C1F)=CC(F)=C1OCC1CC1 RHMISVBJYQSDSS-UHFFFAOYSA-N 0.000 claims description 2
- 230000004770 neurodegeneration Effects 0.000 claims description 2
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 2
- 208000023504 respiratory system disease Diseases 0.000 claims description 2
- 210000002784 stomach Anatomy 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 2
- PWFCNAOHVWWKNG-UHFFFAOYSA-N 2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)-n-[4-(2,3,4-trichlorophenyl)-1,3-thiazol-2-yl]acetamide Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2C=CN1CC(=O)NC(SC=1)=NC=1C1=CC=C(Cl)C(Cl)=C1Cl PWFCNAOHVWWKNG-UHFFFAOYSA-N 0.000 claims 1
- VJXIKTQSMMQMOO-UHFFFAOYSA-N 2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)-n-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2C=CN1CC(=O)NC(SC=1)=NC=1C1=CC=C(C(F)(F)F)C(F)=C1 VJXIKTQSMMQMOO-UHFFFAOYSA-N 0.000 claims 1
- HHGALMGKEXDRBM-UHFFFAOYSA-N 2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)-n-[4-[4-(2,2-dimethylpropoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2C=CN1CC(=O)NC(SC=1)=NC=1C1=CC(F)=C(OCC(C)(C)C)C(F)=C1 HHGALMGKEXDRBM-UHFFFAOYSA-N 0.000 claims 1
- ZVIQXFUBNNGOJY-UHFFFAOYSA-N 3-fluoro-4-(trifluoromethyl)benzaldehyde Chemical group FC1=CC(C=O)=CC=C1C(F)(F)F ZVIQXFUBNNGOJY-UHFFFAOYSA-N 0.000 claims 1
- 208000028389 Nerve injury Diseases 0.000 claims 1
- 230000002757 inflammatory effect Effects 0.000 claims 1
- 208000028774 intestinal disease Diseases 0.000 claims 1
- QKIWOLBTEJUIKO-UHFFFAOYSA-N n-[4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3,7-trimethyl-2,4-dioxopyrrolo[2,3-d]pyrimidin-5-yl)acetamide Chemical compound CN1C(=O)N(C)C(=O)C2=C1N(C)C=C2CC(=O)NC(SC=1)=NC=1C1=CC=C(F)C(C(F)(F)F)=C1F QKIWOLBTEJUIKO-UHFFFAOYSA-N 0.000 claims 1
- PNDMPMPPVJPCBO-UHFFFAOYSA-N n-[4-[3,5-dichloro-4-(cyclobutylmethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)acetamide Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2C=CN1CC(=O)NC(SC=1)=NC=1C(C=C1Cl)=CC(Cl)=C1OCC1CCC1 PNDMPMPPVJPCBO-UHFFFAOYSA-N 0.000 claims 1
- NLQAMAXKCHXKCL-UHFFFAOYSA-N n-[4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)acetamide Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2C=CN1CC(=O)NC(SC=1)=NC=1C1=CC(F)=C(OCC(F)(F)F)C(F)=C1 NLQAMAXKCHXKCL-UHFFFAOYSA-N 0.000 claims 1
- HMHDLTBMXATXHH-UHFFFAOYSA-N n-[4-[3,5-difluoro-4-(3-methylbutoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)acetamide Chemical compound C1=C(F)C(OCCC(C)C)=C(F)C=C1C1=CSC(NC(=O)CN2C=3C(=O)N(C)C(=O)N(C)C=3C=C2)=N1 HMHDLTBMXATXHH-UHFFFAOYSA-N 0.000 claims 1
- ZYQSASOLLSILBE-UHFFFAOYSA-N n-[4-[3,5-difluoro-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)acetamide Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2C=CN1CC(=O)NC(SC=1)=NC=1C(C=C1F)=CC(F)=C1OCC1=CC=C(C(F)(F)F)C=C1 ZYQSASOLLSILBE-UHFFFAOYSA-N 0.000 claims 1
- MPFSSCWDMILAOW-UHFFFAOYSA-N n-[4-[3-chloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)acetamide Chemical compound CC1=CC=2N(C)C(=O)N(C)C(=O)C=2N1CC(=O)NC(SC=1)=NC=1C1=CC=C(OCC(C)(C)C)C(Cl)=C1 MPFSSCWDMILAOW-UHFFFAOYSA-N 0.000 claims 1
- DVEXKZCKMAEQGO-UHFFFAOYSA-N n-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)acetamide Chemical compound CC1=CC=2N(C)C(=O)N(C)C(=O)C=2N1CC(=O)NC(SC=1)=NC=1C1=CC=C(C(F)(F)F)C(F)=C1 DVEXKZCKMAEQGO-UHFFFAOYSA-N 0.000 claims 1
- JPMLQKMNYAURPB-UHFFFAOYSA-N n-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3,7-trimethyl-2,4-dioxopyrrolo[2,3-d]pyrimidin-5-yl)acetamide Chemical compound CN1C(=O)N(C)C(=O)C2=C1N(C)C=C2CC(=O)NC(SC=1)=NC=1C1=CC=C(C(F)(F)F)C(F)=C1 JPMLQKMNYAURPB-UHFFFAOYSA-N 0.000 claims 1
- HYUWZKXSCQQPNU-UHFFFAOYSA-N n-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3,7-trimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)acetamide Chemical compound CN1C(=O)N(C)C(=O)C2=C1C(C)=CN2CC(=O)NC(SC=1)=NC=1C1=CC=C(C(F)(F)F)C(F)=C1 HYUWZKXSCQQPNU-UHFFFAOYSA-N 0.000 claims 1
- URFBKMSDRKBRGT-UHFFFAOYSA-N n-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(2,5,7-trimethyl-4,6-dioxopyrazolo[3,4-d]pyrimidin-3-yl)acetamide Chemical compound CN1N=C2N(C)C(=O)N(C)C(=O)C2=C1CC(=O)NC(SC=1)=NC=1C1=CC=C(C(F)(F)F)C(F)=C1 URFBKMSDRKBRGT-UHFFFAOYSA-N 0.000 claims 1
- RXOGCQYZCSVOKK-UHFFFAOYSA-N n-[4-[4-(cyclobutylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)acetamide Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2C=CN1CC(=O)NC(SC=1)=NC=1C(C=C1F)=CC(F)=C1OCC1CCC1 RXOGCQYZCSVOKK-UHFFFAOYSA-N 0.000 claims 1
- IAZLFUFODLEFKX-UHFFFAOYSA-N n-[4-[4-(difluoromethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)acetamide Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2C=CN1CC(=O)NC(SC=1)=NC=1C1=CC(F)=C(OC(F)F)C(F)=C1 IAZLFUFODLEFKX-UHFFFAOYSA-N 0.000 claims 1
- UZCBRKYSYQOZEM-UHFFFAOYSA-N n-[4-[4-chloro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)acetamide Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2C=CN1CC(=O)NC(SC=1)=NC=1C1=CC=C(Cl)C(C(F)(F)F)=C1 UZCBRKYSYQOZEM-UHFFFAOYSA-N 0.000 claims 1
- 230000008764 nerve damage Effects 0.000 claims 1
- 150000000177 1,2,3-triazoles Chemical class 0.000 abstract description 2
- 125000005343 heterocyclic alkyl group Chemical group 0.000 abstract description 2
- 238000000034 method Methods 0.000 description 204
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 146
- 239000000543 intermediate Substances 0.000 description 128
- 239000007787 solid Substances 0.000 description 124
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 121
- 239000000047 product Substances 0.000 description 118
- 238000005160 1H NMR spectroscopy Methods 0.000 description 109
- 238000010168 coupling process Methods 0.000 description 95
- 230000008878 coupling Effects 0.000 description 90
- 238000005859 coupling reaction Methods 0.000 description 90
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 70
- 229910000104 sodium hydride Inorganic materials 0.000 description 68
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 54
- 239000011541 reaction mixture Substances 0.000 description 41
- 239000000243 solution Substances 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 26
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- 235000019439 ethyl acetate Nutrition 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 14
- 238000003786 synthesis reaction Methods 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
- 125000003545 alkoxy group Chemical group 0.000 description 13
- 229910052794 bromium Inorganic materials 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000007832 Na2SO4 Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 150000001412 amines Chemical class 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- 238000013459 approach Methods 0.000 description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 9
- QVUUNTAJJXNRAP-UHFFFAOYSA-N 2-bromo-n-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=C(C(F)(F)F)C(F)=CC(C=2N=C(NC(=O)CBr)SC=2)=C1 QVUUNTAJJXNRAP-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 230000029936 alkylation Effects 0.000 description 8
- 238000005804 alkylation reaction Methods 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 8
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 230000006378 damage Effects 0.000 description 7
- 238000010992 reflux Methods 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 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZOJBYZNEUISWFT-UHFFFAOYSA-N allyl isothiocyanate Chemical compound C=CCN=C=S ZOJBYZNEUISWFT-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 239000012039 electrophile Substances 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 5
- 150000008062 acetophenones Chemical class 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 4
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 4
- WJVQAKXNHAFCTG-UHFFFAOYSA-N 2-bromo-n-[4-[4-(2,2-dimethylpropoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=C(F)C(OCC(C)(C)C)=C(F)C=C1C1=CSC(NC(=O)CBr)=N1 WJVQAKXNHAFCTG-UHFFFAOYSA-N 0.000 description 4
- QETLJJSSAJXEIO-UHFFFAOYSA-N 4-chloro-1,3-dimethyl-2,6-dioxopyrimidine-5-carbaldehyde Chemical compound CN1C(Cl)=C(C=O)C(=O)N(C)C1=O QETLJJSSAJXEIO-UHFFFAOYSA-N 0.000 description 4
- HZJOVZZMDMNJJT-UHFFFAOYSA-N 6-hydrazinyl-1,3-dimethylpyrimidine-2,4-dione Chemical compound CN1C(NN)=CC(=O)N(C)C1=O HZJOVZZMDMNJJT-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 4
- 208000001294 Nociceptive Pain Diseases 0.000 description 4
- 101150095096 TRPM2 gene Proteins 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 244000309464 bull Species 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 4
- 210000000929 nociceptor Anatomy 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- OSTDULKDQDIIKB-UHFFFAOYSA-N 1,3,6-trimethyl-5-nitropyrimidine-2,4-dione Chemical compound CC1=C([N+]([O-])=O)C(=O)N(C)C(=O)N1C OSTDULKDQDIIKB-UHFFFAOYSA-N 0.000 description 3
- UTZVSIXTYYWUOB-USJZOSNVSA-N 2-[(1s,2s,4as,8as)-2-hydroxy-2,5,5,8a-tetramethyl-3,4,4a,6,7,8-hexahydro-1h-naphthalen-1-yl]-n-methoxy-n-methylacetamide Chemical compound CC1(C)CCC[C@]2(C)[C@H](CC(=O)N(C)OC)[C@@](C)(O)CC[C@H]21 UTZVSIXTYYWUOB-USJZOSNVSA-N 0.000 description 3
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 3
- FTYAJPZNGIJJNX-UHFFFAOYSA-N 5-[3-fluoro-4-(trifluoromethyl)phenyl]-1h-imidazol-2-amine Chemical compound N1C(N)=NC(C=2C=C(F)C(=CC=2)C(F)(F)F)=C1 FTYAJPZNGIJJNX-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 108091006146 Channels Proteins 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 235000016720 allyl isothiocyanate Nutrition 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000002981 neuropathic effect Effects 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 235000011149 sulphuric acid Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 3
- 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 2
- LSOLGCXAMRBKTJ-UHFFFAOYSA-N 1,3,6-trimethyl-5h-pyrrolo[3,2-d]pyrimidine-2,4-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1C=C(C)N2 LSOLGCXAMRBKTJ-UHFFFAOYSA-N 0.000 description 2
- XLSXPKZIKMPZHK-UHFFFAOYSA-N 1,3-dimethyl-5h-pyrrolo[3,2-d]pyrimidine-2,4-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=C2 XLSXPKZIKMPZHK-UHFFFAOYSA-N 0.000 description 2
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical compound NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 2
- GAIZCKXXSFRGOK-UHFFFAOYSA-N 2-(1,3,7-trimethyl-2,4-dioxopyrrolo[2,3-d]pyrimidin-5-yl)acetic acid Chemical compound CN1C(=O)N(C)C(=O)C2=C1N(C)C=C2CC(O)=O GAIZCKXXSFRGOK-UHFFFAOYSA-N 0.000 description 2
- AACUYXPCLUSFMI-UHFFFAOYSA-N 2-bromo-n-(1,3-thiazol-2-yl)acetamide Chemical compound BrCC(=O)NC1=NC=CS1 AACUYXPCLUSFMI-UHFFFAOYSA-N 0.000 description 2
- KBEBWXCTYZDCRQ-UHFFFAOYSA-N 2-bromo-n-[4-[3,5-difluoro-4-(3-methylbutoxy)phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=C(F)C(OCCC(C)C)=C(F)C=C1C1=CSC(NC(=O)CBr)=N1 KBEBWXCTYZDCRQ-UHFFFAOYSA-N 0.000 description 2
- ARBYOYXVPPYGKL-UHFFFAOYSA-N 2-bromo-n-[4-[4-(2,2-dimethylpropoxy)-3-fluorophenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=C(F)C(OCC(C)(C)C)=CC=C1C1=CSC(NC(=O)CBr)=N1 ARBYOYXVPPYGKL-UHFFFAOYSA-N 0.000 description 2
- FLCKOUDUILBAEO-UHFFFAOYSA-N 2-bromo-n-[4-[4-(cyclobutylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]acetamide Chemical compound FC1=CC(C=2N=C(NC(=O)CBr)SC=2)=CC(F)=C1OCC1CCC1 FLCKOUDUILBAEO-UHFFFAOYSA-N 0.000 description 2
- ZSJKJFVVOWGCRP-UHFFFAOYSA-N 2-bromo-n-[4-[4-(difluoromethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=C(F)C(OC(F)F)=C(F)C=C1C1=CSC(NC(=O)CBr)=N1 ZSJKJFVVOWGCRP-UHFFFAOYSA-N 0.000 description 2
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 description 2
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 2
- CQTJFQYYLUTDME-UHFFFAOYSA-N 4,6-dimethyl-1h-pyrazolo[4,3-d]pyrimidine-5,7-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1NN=C2 CQTJFQYYLUTDME-UHFFFAOYSA-N 0.000 description 2
- OPHDOIKOSGCXPW-UHFFFAOYSA-N 4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=C(F)C(=CC=2)C(F)(F)F)=C1 OPHDOIKOSGCXPW-UHFFFAOYSA-N 0.000 description 2
- XOCOZIHOJCULLE-UHFFFAOYSA-N 5-(trifluoromethoxy)-1,3-benzothiazol-2-amine Chemical compound FC(F)(F)OC1=CC=C2SC(N)=NC2=C1 XOCOZIHOJCULLE-UHFFFAOYSA-N 0.000 description 2
- KPADHLBAZFIMTA-UHFFFAOYSA-N 5-amino-1,3-dimethylpyrimidine-2,4-dione Chemical compound CN1C=C(N)C(=O)N(C)C1=O KPADHLBAZFIMTA-UHFFFAOYSA-N 0.000 description 2
- SGLPRIIINMCHCW-UHFFFAOYSA-N 5h-pyrimidine-2,4-dione Chemical compound O=C1CC=NC(=O)N1 SGLPRIIINMCHCW-UHFFFAOYSA-N 0.000 description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- 101800004538 Bradykinin Proteins 0.000 description 2
- OYPRJOBELJOOCE-BKFZFHPZSA-N Calcium-45 Chemical compound [45Ca] OYPRJOBELJOOCE-BKFZFHPZSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 2
- 101000605625 Homo sapiens Polycystic kidney disease 2-like 1 protein Proteins 0.000 description 2
- 101000605623 Homo sapiens Polycystic kidney disease 2-like 2 protein Proteins 0.000 description 2
- 101001074439 Homo sapiens Polycystin-2 Proteins 0.000 description 2
- 101000844504 Homo sapiens Transient receptor potential cation channel subfamily M member 4 Proteins 0.000 description 2
- 101000844521 Homo sapiens Transient receptor potential cation channel subfamily M member 5 Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102100035792 Kininogen-1 Human genes 0.000 description 2
- 102100026502 Mucolipin-1 Human genes 0.000 description 2
- 102100030870 Mucolipin-2 Human genes 0.000 description 2
- 102100030868 Mucolipin-3 Human genes 0.000 description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-YYWVXINBSA-N N,N-dimethylformamide-d7 Chemical compound [2H]C(=O)N(C([2H])([2H])[2H])C([2H])([2H])[2H] ZMXDDKWLCZADIW-YYWVXINBSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 102100038330 Polycystic kidney disease 2-like 1 protein Human genes 0.000 description 2
- 102100038335 Polycystic kidney disease 2-like 2 protein Human genes 0.000 description 2
- 102100036142 Polycystin-2 Human genes 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 2
- 108060008646 TRPA Proteins 0.000 description 2
- 102000027549 TRPC Human genes 0.000 description 2
- 108060008648 TRPC Proteins 0.000 description 2
- 102000003564 TRPC7 Human genes 0.000 description 2
- 102000027545 TRPM Human genes 0.000 description 2
- 108091008847 TRPM Proteins 0.000 description 2
- 102000003617 TRPM1 Human genes 0.000 description 2
- 102000003615 TRPM2 Human genes 0.000 description 2
- 102000003620 TRPM3 Human genes 0.000 description 2
- 108060008547 TRPM3 Proteins 0.000 description 2
- 102000003618 TRPM4 Human genes 0.000 description 2
- 102000003611 TRPM7 Human genes 0.000 description 2
- 102000027544 TRPML Human genes 0.000 description 2
- 108091008846 TRPML Proteins 0.000 description 2
- 108060009332 TRPP Proteins 0.000 description 2
- 102000003563 TRPV Human genes 0.000 description 2
- 108060008564 TRPV Proteins 0.000 description 2
- 102000003566 TRPV1 Human genes 0.000 description 2
- 102000003565 TRPV2 Human genes 0.000 description 2
- 102000003568 TRPV3 Human genes 0.000 description 2
- 102000003570 TRPV5 Human genes 0.000 description 2
- 102000003569 TRPV6 Human genes 0.000 description 2
- 101150096736 TRPV6 gene Proteins 0.000 description 2
- 102100031215 Transient receptor potential cation channel subfamily M member 5 Human genes 0.000 description 2
- 101150033973 Trpc7 gene Proteins 0.000 description 2
- 101150016206 Trpv1 gene Proteins 0.000 description 2
- 101150077905 Trpv2 gene Proteins 0.000 description 2
- 101150043371 Trpv3 gene Proteins 0.000 description 2
- 101150034091 Trpv5 gene Proteins 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 208000005298 acute pain Diseases 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 150000005347 biaryls Chemical group 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- 230000006196 deacetylation Effects 0.000 description 2
- 238000003381 deacetylation reaction Methods 0.000 description 2
- 238000006392 deoxygenation reaction Methods 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- NGGXACLSAZXJGM-UHFFFAOYSA-N n-(diaminomethylidene)acetamide Chemical compound CC(=O)N=C(N)N NGGXACLSAZXJGM-UHFFFAOYSA-N 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Chemical group 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 230000001953 sensory effect Effects 0.000 description 2
- 230000000391 smoking effect Effects 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 208000037816 tissue injury Diseases 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- JVJFIQYAHPMBBX-FNORWQNLSA-N (E)-4-hydroxynon-2-enal Chemical compound CCCCCC(O)\C=C\C=O JVJFIQYAHPMBBX-FNORWQNLSA-N 0.000 description 1
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N 1,3,5-trimethylpyrrolo[3,2-d]pyrimidine-2,4-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- GRDXZRWCQWDLPG-UHFFFAOYSA-N 1,3,6-trimethylpyrimidine-2,4-dione Chemical compound CC1=CC(=O)N(C)C(=O)N1C GRDXZRWCQWDLPG-UHFFFAOYSA-N 0.000 description 1
- VVSASNKOFCZVES-UHFFFAOYSA-N 1,3-dimethyl-1,3-diazinane-2,4,6-trione Chemical compound CN1C(=O)CC(=O)N(C)C1=O VVSASNKOFCZVES-UHFFFAOYSA-N 0.000 description 1
- LHGAKKLQGHFLPQ-UHFFFAOYSA-N 1,3-dimethyl-2,4-dioxo-5h-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=C2C=O LHGAKKLQGHFLPQ-UHFFFAOYSA-N 0.000 description 1
- SDLBIQNBDPOOPJ-UHFFFAOYSA-N 1,3-dimethyl-5-nitropyrimidine-2,4-dione Chemical compound CN1C=C([N+]([O-])=O)C(=O)N(C)C1=O SDLBIQNBDPOOPJ-UHFFFAOYSA-N 0.000 description 1
- SKJJVYVZMFKWBP-UHFFFAOYSA-N 1,3-dimethyl-7h-pyrrolo[2,3-d]pyrimidine-2,4-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1C=CN2 SKJJVYVZMFKWBP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- NXQBONPKAOTSNA-UHFFFAOYSA-N 1-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=C(C(F)(F)F)C(F)=C1 NXQBONPKAOTSNA-UHFFFAOYSA-N 0.000 description 1
- CFENPPFMNOOCSZ-UHFFFAOYSA-N 1-acetyl-3,5,7-trimethylpyrazolo[3,4-d]pyrimidine-4,6-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1N(C(=O)C)N=C2C CFENPPFMNOOCSZ-UHFFFAOYSA-N 0.000 description 1
- 125000006083 1-bromoethyl group Chemical group 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- DTXASEKLDRHEQO-UHFFFAOYSA-N 2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)-n-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2C=CN1CC(=O)NC(SC=1)=NC=1C1=CC=C(F)C(C(F)(F)F)=C1 DTXASEKLDRHEQO-UHFFFAOYSA-N 0.000 description 1
- QEQUIPGNNNNDGO-UHFFFAOYSA-N 2-(2,5,7-trimethyl-4,6-dioxopyrazolo[3,4-d]pyrimidin-3-yl)acetic acid Chemical compound CN1C(=O)N(C)C(=O)C2=C(CC(O)=O)N(C)N=C21 QEQUIPGNNNNDGO-UHFFFAOYSA-N 0.000 description 1
- QEAJQJGPXFVEJA-UHFFFAOYSA-N 2-bromo-n-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]acetamide Chemical compound C1=CC(Cl)=CC=C1C1=CSC(NC(=O)CBr)=N1 QEAJQJGPXFVEJA-UHFFFAOYSA-N 0.000 description 1
- RXFZFVUMTSCASN-UHFFFAOYSA-N 2-bromo-n-[4-[3,5-dichloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=C(Cl)C(OCC(C)(C)C)=C(Cl)C=C1C1=CSC(NC(=O)CBr)=N1 RXFZFVUMTSCASN-UHFFFAOYSA-N 0.000 description 1
- AJPGNMMGQJWRPA-UHFFFAOYSA-N 2-bromo-n-[4-[3,5-dichloro-4-(cyclobutylmethoxy)phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound ClC1=CC(C=2N=C(NC(=O)CBr)SC=2)=CC(Cl)=C1OCC1CCC1 AJPGNMMGQJWRPA-UHFFFAOYSA-N 0.000 description 1
- QILKPVWUQNGMHJ-UHFFFAOYSA-N 2-bromo-n-[4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound FC1=C(OCC(F)(F)F)C(F)=CC(C=2N=C(NC(=O)CBr)SC=2)=C1 QILKPVWUQNGMHJ-UHFFFAOYSA-N 0.000 description 1
- SXXAHJARGBGQHJ-UHFFFAOYSA-N 2-bromo-n-[4-[3,5-difluoro-4-(2-methylpropoxy)phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=C(F)C(OCC(C)C)=C(F)C=C1C1=CSC(NC(=O)CBr)=N1 SXXAHJARGBGQHJ-UHFFFAOYSA-N 0.000 description 1
- QGBKVAWQTXNWEJ-UHFFFAOYSA-N 2-bromo-n-[4-[3-bromo-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=C(Br)C(OCC(F)(F)F)=CC=C1C1=CSC(NC(=O)CBr)=N1 QGBKVAWQTXNWEJ-UHFFFAOYSA-N 0.000 description 1
- PTJRZCTXEBUQTQ-UHFFFAOYSA-N 2-bromo-n-[4-[3-chloro-4-(2,2-dimethylpropoxy)-5-fluorophenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=C(Cl)C(OCC(C)(C)C)=C(F)C=C1C1=CSC(NC(=O)CBr)=N1 PTJRZCTXEBUQTQ-UHFFFAOYSA-N 0.000 description 1
- YGGBOTCLODTTJI-UHFFFAOYSA-N 2-bromo-n-[4-[3-chloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=C(Cl)C(OCC(C)(C)C)=CC=C1C1=CSC(NC(=O)CBr)=N1 YGGBOTCLODTTJI-UHFFFAOYSA-N 0.000 description 1
- AHIDPMFBUPTYSU-UHFFFAOYSA-N 2-bromo-n-[4-[4-(cyclopropylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]acetamide Chemical compound FC1=CC(C=2N=C(NC(=O)CBr)SC=2)=CC(F)=C1OCC1CC1 AHIDPMFBUPTYSU-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
- 125000006088 2-oxoazepinyl group Chemical group 0.000 description 1
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- ALWVPFIPTLPTEV-UHFFFAOYSA-N 2h-pyrazolo[4,3-d]pyrimidine-3,5-dione Chemical compound C1=NC(=O)N=C2C(=O)NN=C21 ALWVPFIPTLPTEV-UHFFFAOYSA-N 0.000 description 1
- DYEIQBYFEXTAAU-UHFFFAOYSA-N 3,4,6-trimethyl-2h-pyrazolo[4,3-d]pyrimidine-5,7-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1C(C)=NN2 DYEIQBYFEXTAAU-UHFFFAOYSA-N 0.000 description 1
- VSPRBFLKSINHLP-UHFFFAOYSA-N 3,5,7-trimethyl-2h-pyrazolo[3,4-d]pyrimidine-4,6-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1NN=C2C VSPRBFLKSINHLP-UHFFFAOYSA-N 0.000 description 1
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 1
- XVHGXRIOJOSLFN-UHFFFAOYSA-N 4,6,6-trimethyl-3-phenyl-1h-pyrimidine-2-thione Chemical compound CC1=CC(C)(C)NC(=S)N1C1=CC=CC=C1 XVHGXRIOJOSLFN-UHFFFAOYSA-N 0.000 description 1
- NDCSJUJQMRFHEX-UHFFFAOYSA-N 4-(3,4-difluorophenyl)-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=C(F)C(F)=CC=2)=C1 NDCSJUJQMRFHEX-UHFFFAOYSA-N 0.000 description 1
- DJGBSHUJYGXFQN-UHFFFAOYSA-N 4-(3,5-difluorophenyl)-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=C(F)C=C(F)C=2)=C1 DJGBSHUJYGXFQN-UHFFFAOYSA-N 0.000 description 1
- DWGWNNCHJPKZNC-UHFFFAOYSA-N 4-(4-chlorophenyl)-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=CC(Cl)=CC=2)=C1 DWGWNNCHJPKZNC-UHFFFAOYSA-N 0.000 description 1
- QFMNMDDKDKCKKW-UHFFFAOYSA-N 4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C(=C(F)C(=CC=2)C(F)(F)F)F)=C1 QFMNMDDKDKCKKW-UHFFFAOYSA-N 0.000 description 1
- UYSJHSJNYGOZHN-UHFFFAOYSA-N 4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C(=C(C(F)=CC=2)C(F)(F)F)F)=C1 UYSJHSJNYGOZHN-UHFFFAOYSA-N 0.000 description 1
- QTFIQKQWACKFHA-UHFFFAOYSA-N 4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C(=C(C=CC=2)C(F)(F)F)F)=C1 QTFIQKQWACKFHA-UHFFFAOYSA-N 0.000 description 1
- WTMCMRXAHVSYMO-UHFFFAOYSA-N 4-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C(=CC(=CC=2)C(F)(F)F)F)=C1 WTMCMRXAHVSYMO-UHFFFAOYSA-N 0.000 description 1
- FPIUGVQEXYOXEA-UHFFFAOYSA-N 4-[2-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C(=CC=C(C=2)C(F)(F)F)F)=C1 FPIUGVQEXYOXEA-UHFFFAOYSA-N 0.000 description 1
- XVMBKWVKVXOTCS-UHFFFAOYSA-N 4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=C(F)C(OCC(F)(F)F)=C(F)C=2)=C1 XVMBKWVKVXOTCS-UHFFFAOYSA-N 0.000 description 1
- VYRFEJAFSZHYEI-UHFFFAOYSA-N 4-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=C(OC(F)(F)F)C=CC=2)=C1 VYRFEJAFSZHYEI-UHFFFAOYSA-N 0.000 description 1
- ZZDBATBJNFVJCB-UHFFFAOYSA-N 4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=C(C=CC=2)C(F)(F)F)=C1 ZZDBATBJNFVJCB-UHFFFAOYSA-N 0.000 description 1
- VCMSBRUFWBYGNR-UHFFFAOYSA-N 4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=C(F)C(OC(F)(F)F)=CC=2)=C1 VCMSBRUFWBYGNR-UHFFFAOYSA-N 0.000 description 1
- OKZVSIANNZWQDU-UHFFFAOYSA-N 4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazole Chemical compound FC=1C=C(C=CC1C(F)(F)F)C=1N=CSC1 OKZVSIANNZWQDU-UHFFFAOYSA-N 0.000 description 1
- UKJQCMKGJGFQFQ-UHFFFAOYSA-N 4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=C(C=C(F)C=2)C(F)(F)F)=C1 UKJQCMKGJGFQFQ-UHFFFAOYSA-N 0.000 description 1
- OFXMYQNRJIWJHK-UHFFFAOYSA-N 4-[4-(2,2-dimethylpropoxy)-3,5-difluorophenyl]-1,3-thiazol-2-amine Chemical compound C1=C(F)C(OCC(C)(C)C)=C(F)C=C1C1=CSC(N)=N1 OFXMYQNRJIWJHK-UHFFFAOYSA-N 0.000 description 1
- QHFXFYBCBXWOGR-UHFFFAOYSA-N 4-[4-(2-methylpropyl)phenyl]-1,3-thiazol-2-amine Chemical compound C1=CC(CC(C)C)=CC=C1C1=CSC(N)=N1 QHFXFYBCBXWOGR-UHFFFAOYSA-N 0.000 description 1
- SDIUFDASQXZLBJ-UHFFFAOYSA-N 4-[4-(difluoromethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=C(F)C(OC(F)F)=C(F)C=2)=C1 SDIUFDASQXZLBJ-UHFFFAOYSA-N 0.000 description 1
- XFGFAEIZTOEDAN-UHFFFAOYSA-N 4-[4-(difluoromethoxy)-3-fluorophenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=C(F)C(OC(F)F)=CC=2)=C1 XFGFAEIZTOEDAN-UHFFFAOYSA-N 0.000 description 1
- HYAHAIVZFRFEBU-UHFFFAOYSA-N 4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=CC(=CC=2)C(F)(F)F)=C1 HYAHAIVZFRFEBU-UHFFFAOYSA-N 0.000 description 1
- KGPBNLSPHADRDS-UHFFFAOYSA-N 4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=C(C(F)=CC=2)C(F)(F)F)=C1 KGPBNLSPHADRDS-UHFFFAOYSA-N 0.000 description 1
- KTMMEWQJKQBEAK-UHFFFAOYSA-N 4-chloro-1,3-dimethyl-2,6-dioxopyrimidine-5-carbonitrile Chemical compound CN1C(Cl)=C(C#N)C(=O)N(C)C1=O KTMMEWQJKQBEAK-UHFFFAOYSA-N 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- YINDFUSXBDZGIH-UHFFFAOYSA-N 5-(4-bromophenyl)-1,2-oxazol-3-amine Chemical compound O1N=C(N)C=C1C1=CC=C(Br)C=C1 YINDFUSXBDZGIH-UHFFFAOYSA-N 0.000 description 1
- FDKLGFYAEDLCNA-UHFFFAOYSA-N 5-amino-1,3,6-trimethylpyrimidine-2,4-dione Chemical compound CC1=C(N)C(=O)N(C)C(=O)N1C FDKLGFYAEDLCNA-UHFFFAOYSA-N 0.000 description 1
- VFGRNTYELNYSKJ-UHFFFAOYSA-N 6-amino-1,3-dimethylpyrimidine-2,4-dione Chemical compound CN1C(N)=CC(=O)N(C)C1=O VFGRNTYELNYSKJ-UHFFFAOYSA-N 0.000 description 1
- LNDZXOWGUAIUBG-UHFFFAOYSA-N 6-aminouracil Chemical class NC1=CC(=O)NC(=O)N1 LNDZXOWGUAIUBG-UHFFFAOYSA-N 0.000 description 1
- VATQPUHLFQHDBD-UHFFFAOYSA-N 6-chloro-1,3-dimethylpyrimidine-2,4-dione Chemical compound CN1C(Cl)=CC(=O)N(C)C1=O VATQPUHLFQHDBD-UHFFFAOYSA-N 0.000 description 1
- PKUFNWPSFCOSLU-UHFFFAOYSA-N 6-chloro-1h-pyrimidine-2,4-dione Chemical class ClC1=CC(=O)NC(=O)N1 PKUFNWPSFCOSLU-UHFFFAOYSA-N 0.000 description 1
- ZTWVDTQCEOXUGL-UHFFFAOYSA-N 7-(diethylaminomethyl)-1,3-dimethyl-5h-pyrrolo[3,2-d]pyrimidine-2,4-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1C(CN(CC)CC)=CN2 ZTWVDTQCEOXUGL-UHFFFAOYSA-N 0.000 description 1
- XGIBUCRNAAADNS-UHFFFAOYSA-N 7-[(dimethylamino)methyl]-1,3-dimethyl-5h-pyrrolo[3,2-d]pyrimidine-2,4-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1C(CN(C)C)=CN2 XGIBUCRNAAADNS-UHFFFAOYSA-N 0.000 description 1
- DCSPXSBKVLCEGM-UHFFFAOYSA-N 7-bromo-1,3-dimethyl-5h-pyrrolo[3,2-d]pyrimidine-2,4-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=C2Br DCSPXSBKVLCEGM-UHFFFAOYSA-N 0.000 description 1
- 240000002234 Allium sativum Species 0.000 description 1
- 102100031366 Ankyrin-1 Human genes 0.000 description 1
- 101710191059 Ankyrin-1 Proteins 0.000 description 1
- 101100350964 Arabidopsis thaliana PANS1 gene Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 244000056139 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 101150076566 CMR1 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 244000223760 Cinnamomum zeylanicum Species 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 238000005618 Fries rearrangement reaction Methods 0.000 description 1
- JVJFIQYAHPMBBX-UHFFFAOYSA-N HNE Natural products CCCCCC(O)C=CC=O JVJFIQYAHPMBBX-UHFFFAOYSA-N 0.000 description 1
- 102100029100 Hematopoietic prostaglandin D synthase Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000988802 Homo sapiens Hematopoietic prostaglandin D synthase Proteins 0.000 description 1
- 101000844510 Homo sapiens Transient receptor potential cation channel subfamily M member 1 Proteins 0.000 description 1
- 101000844503 Homo sapiens Transient receptor potential cation channel subfamily M member 3 Proteins 0.000 description 1
- 101000844519 Homo sapiens Transient receptor potential cation channel subfamily M member 6 Proteins 0.000 description 1
- 101000844518 Homo sapiens Transient receptor potential cation channel subfamily M member 7 Proteins 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 101150091161 MCOLN1 gene Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102400001335 Mucolipin Human genes 0.000 description 1
- 101100520164 Mus musculus Pkdrej gene Proteins 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 206010029216 Nervousness Diseases 0.000 description 1
- 101100426589 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) trp-3 gene Proteins 0.000 description 1
- 229910004679 ONO2 Inorganic materials 0.000 description 1
- 101100047461 Rattus norvegicus Trpm8 gene Proteins 0.000 description 1
- 101100426590 Schizosaccharomyces pombe (strain 972 / ATCC 24843) trp2 gene Proteins 0.000 description 1
- 101100100680 Schizosaccharomyces pombe (strain 972 / ATCC 24843) trp4 gene Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229940123524 TRPA1 antagonist Drugs 0.000 description 1
- 102000003627 TRPC1 Human genes 0.000 description 1
- 101150017559 TRPC1 gene Proteins 0.000 description 1
- 102000003629 TRPC3 Human genes 0.000 description 1
- 102000003622 TRPC4 Human genes 0.000 description 1
- 102000003621 TRPC5 Human genes 0.000 description 1
- 101150042815 TRPC5 gene Proteins 0.000 description 1
- 102000003623 TRPC6 Human genes 0.000 description 1
- 102000003609 TRPM5 Human genes 0.000 description 1
- 101150059135 TRPM5 gene Proteins 0.000 description 1
- 102000003608 TRPM6 Human genes 0.000 description 1
- 101150045183 TRPM7 gene Proteins 0.000 description 1
- 108091008849 TRPN Proteins 0.000 description 1
- 108010004408 TRPP Cation Channels Proteins 0.000 description 1
- 102000003567 TRPV4 Human genes 0.000 description 1
- 101150098315 TRPV4 gene Proteins 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 102100031229 Transient receptor potential cation channel subfamily M member 3 Human genes 0.000 description 1
- 102100031228 Transient receptor potential cation channel subfamily M member 4 Human genes 0.000 description 1
- 102100031232 Transient receptor potential cation channel subfamily M member 7 Human genes 0.000 description 1
- 101710123694 Transient receptor potential cation channel subfamily M member 7 Proteins 0.000 description 1
- 108050001421 Transient receptor potential channel, canonical 6 Proteins 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 101150037542 Trpc3 gene Proteins 0.000 description 1
- 101150099990 Trpc4 gene Proteins 0.000 description 1
- 101150032671 Trpm1 gene Proteins 0.000 description 1
- 101150111943 Trpm4 gene Proteins 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- QPBNUBJVIBPFJM-UHFFFAOYSA-N acetic acid;1h-pyrimidine-2,4-dione Chemical compound CC(O)=O.OC1=CC=NC(O)=N1 QPBNUBJVIBPFJM-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 210000003766 afferent neuron Anatomy 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 150000003975 aryl alkyl amines Chemical class 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 150000001559 benzoic acids Chemical class 0.000 description 1
- 125000005872 benzooxazolyl group Chemical group 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 230000003185 calcium uptake Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000017803 cinnamon Nutrition 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 150000001945 cysteines Chemical class 0.000 description 1
- 125000005507 decahydroisoquinolyl group Chemical group 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229940009976 deoxycholate Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000001667 episodic effect Effects 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 235000004611 garlic Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 102000052408 human TRPA1 Human genes 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- XVKDDFFJMZYCHZ-UHFFFAOYSA-N n-(2-bromo-2h-1,3-thiazol-3-yl)acetamide Chemical compound CC(=O)NN1C=CSC1Br XVKDDFFJMZYCHZ-UHFFFAOYSA-N 0.000 description 1
- ADEAXEQTXHDIHA-UHFFFAOYSA-N n-(2-chlorophenyl)-1,3-thiazol-2-amine Chemical compound ClC1=CC=CC=C1NC1=NC=CS1 ADEAXEQTXHDIHA-UHFFFAOYSA-N 0.000 description 1
- XGDWUOTWCBUFBF-UHFFFAOYSA-N n-[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)acetamide Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2C=CN1CC(=O)NC(SC=1)=NC=1C1=CC=C(F)C=C1F XGDWUOTWCBUFBF-UHFFFAOYSA-N 0.000 description 1
- NRPHMVYNJXMSLW-UHFFFAOYSA-N n-[5-[3-fluoro-4-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]acetamide Chemical compound N1C(NC(=O)C)=NC(C=2C=C(F)C(=CC=2)C(F)(F)F)=C1 NRPHMVYNJXMSLW-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000003040 nociceptive effect Effects 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- BHMBVRSPMRCCGG-OUTUXVNYSA-N prostaglandin D2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)[C@@H](O)CC1=O BHMBVRSPMRCCGG-OUTUXVNYSA-N 0.000 description 1
- BHMBVRSPMRCCGG-UHFFFAOYSA-N prostaglandine D2 Natural products CCCCCC(O)C=CC1C(CC=CCCCC(O)=O)C(O)CC1=O BHMBVRSPMRCCGG-UHFFFAOYSA-N 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- ZSKGQVFRTSEPJT-UHFFFAOYSA-N pyrrole-2-carboxaldehyde Chemical compound O=CC1=CC=CN1 ZSKGQVFRTSEPJT-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- LGOOLCMGKKGBHW-UHFFFAOYSA-N pyrrolo[3,2-d]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C2=NC=CC2=N1 LGOOLCMGKKGBHW-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000006476 reductive cyclization reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000003238 somatosensory effect Effects 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 102000042565 transient receptor (TC 1.A.4) family Human genes 0.000 description 1
- 108091053409 transient receptor (TC 1.A.4) family Proteins 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 101150079396 trpC2 gene Proteins 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/06—Anti-spasmodics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Diabetes (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Cardiology (AREA)
- Immunology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Otolaryngology (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (21)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| INMU06652009 | 2009-03-23 | ||
| IN665MU2009 | 2009-03-23 | ||
| US17135509P | 2009-04-21 | 2009-04-21 | |
| US171355P | 2009-04-21 | ||
| INMU22112009 | 2009-09-23 | ||
| IN2211MU2009 | 2009-09-23 | ||
| INMU22122009 | 2009-09-23 | ||
| IN2212MU2009 | 2009-09-23 | ||
| US25194409P | 2009-10-15 | 2009-10-15 | |
| US251944P | 2009-10-15 | ||
| US25326309P | 2009-10-20 | 2009-10-20 | |
| US253263P | 2009-10-20 | ||
| IN2891MU2009 | 2009-12-15 | ||
| INMU28912009 | 2009-12-15 | ||
| IN2892MU2009 | 2009-12-15 | ||
| INMU28922009 | 2009-12-15 | ||
| US29446310P | 2010-01-12 | 2010-01-12 | |
| US294463P | 2010-01-12 | ||
| US30024110P | 2010-02-01 | 2010-02-01 | |
| US300241P | 2010-02-01 | ||
| PCT/IB2010/000553 WO2010109287A1 (en) | 2009-03-23 | 2010-03-17 | Fused pyrimidine-dione derivatives as trpa1 modulators |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2456515T3 true ES2456515T3 (es) | 2014-04-22 |
Family
ID=42780198
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES10755503.9T Active ES2456515T3 (es) | 2009-03-23 | 2010-03-17 | Derivados de pirimidindiona fusionados como moduladores de TRPA1 |
| ES13005523.9T Active ES2551085T3 (es) | 2009-03-23 | 2010-03-17 | Proceso para preparar derivados de pirimidina-diona condensados, útiles como moduladores de TRPA1 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES13005523.9T Active ES2551085T3 (es) | 2009-03-23 | 2010-03-17 | Proceso para preparar derivados de pirimidina-diona condensados, útiles como moduladores de TRPA1 |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US9000159B2 (enExample) |
| EP (2) | EP2411393B1 (enExample) |
| JP (1) | JP5657638B2 (enExample) |
| KR (1) | KR20110132575A (enExample) |
| CN (1) | CN102361873B (enExample) |
| AP (1) | AP3280A (enExample) |
| AU (1) | AU2010227245B2 (enExample) |
| BR (1) | BRPI1013559A2 (enExample) |
| CA (1) | CA2756518A1 (enExample) |
| CL (2) | CL2011002315A1 (enExample) |
| DK (1) | DK2411393T3 (enExample) |
| EA (1) | EA023857B1 (enExample) |
| ES (2) | ES2456515T3 (enExample) |
| IL (1) | IL215178A (enExample) |
| MX (1) | MX2011009824A (enExample) |
| PE (1) | PE20120774A1 (enExample) |
| PL (1) | PL2411393T3 (enExample) |
| PT (1) | PT2411393E (enExample) |
| SG (1) | SG174402A1 (enExample) |
| SI (1) | SI2411393T1 (enExample) |
| UA (1) | UA108069C2 (enExample) |
| WO (1) | WO2010109287A1 (enExample) |
| ZA (1) | ZA201107648B (enExample) |
Families Citing this family (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2009001327A (es) | 2006-08-07 | 2009-06-05 | Ironwood Pharmaceuticals Inc | Compuestos de indol. |
| WO2010109287A1 (en) | 2009-03-23 | 2010-09-30 | Glenmark Pharmaceuticals S.A. | Fused pyrimidine-dione derivatives as trpa1 modulators |
| MX336549B (es) | 2010-12-20 | 2016-01-22 | Glenmark Pharmaceuticals Sa | Compuestos de 2-amino-4-ariltiazol como antagonistas de trpa1. |
| AR084433A1 (es) | 2010-12-22 | 2013-05-15 | Ironwood Pharmaceuticals Inc | Inhibidores de la faah y composiciones farmaceuticas que los contienen |
| EP2520566A1 (en) | 2011-05-06 | 2012-11-07 | Orion Corporation | New Pharmaceutical Compounds |
| RU2014100744A (ru) | 2011-06-13 | 2015-07-20 | Гленмарк Фармасьютикалс С.А. | Лечение респираторных нарушений с помощью trpa1 антагонистов |
| JP2014517062A (ja) | 2011-06-22 | 2014-07-17 | グレンマーク ファーマシューティカルズ， エセ．アー． | ＴＲＰＡ１アンタゴニスト及びβ２アゴニストを含む医薬組成物 |
| WO2012176105A1 (en) | 2011-06-22 | 2012-12-27 | Glenmark Pharmaceuticals Sa | Pharmaceutical composition comprising a trpa1 antagonist and a leukotriene receptor antagonist |
| CA2841417A1 (en) | 2011-07-25 | 2013-01-31 | Glenmark Pharmaceuticals Sa | Pharmaceutical composition comprising a trpa1 antagonist and a steroid |
| BR112014002960A2 (pt) | 2011-08-09 | 2017-02-21 | Cubist Pharm Inc | inibição de canal de íons potencial receptor transiente trpa1 |
| US20140364445A1 (en) | 2011-12-05 | 2014-12-11 | Glenmark Pharmaceuticals S.A. | Pharmaceutical composition comprising a trpa1 antagonist and an anticholinergic agent |
| CN104203236A (zh) | 2012-01-17 | 2014-12-10 | 味之素株式会社 | 杂环酰胺衍生物和含有其的药物 |
| HK1207643A1 (en) | 2012-06-08 | 2016-02-05 | Glenmark Pharmaceuticals S.A. | Amides of 2-amino-4-arylthiazole compounds and their salts |
| EP2903965B1 (en) | 2012-10-01 | 2017-03-01 | Orion Corporation | N-prop-2-ynyl carboxamide derivatives and their use as trpa1 antagonists |
| US9394308B2 (en) | 2013-01-18 | 2016-07-19 | Merck Sharp & Dohme Corp. | Inhibiting the transient receptor potential A1 ion channel |
| RU2016115093A (ru) | 2013-10-15 | 2017-11-21 | Гленмарк Фармасьютикалс С.А. | Фармацевтическая композиция, содержащая антагонист trpa1 и анальгетический агент |
| BR112016008799B1 (pt) * | 2013-10-30 | 2023-02-23 | Shanghai Hengrui Pharmaceutical Co., Ltd. | Derivados de pirazolopirimidona ou pirrolotriazona, seus intermediários, seus usos, seus processos de preparação, e composição farmacêutica |
| CN103755705B (zh) * | 2014-02-17 | 2017-02-15 | 上海佰特因医药科技有限公司 | 一种天然产物四甲基尿酸的全合成方法 |
| JP6667092B2 (ja) * | 2014-08-11 | 2020-03-18 | ハイドラ・バイオサイエンシーズ・リミテッド・ライアビリティ・カンパニーＨｙｄｒａ Ｂｉｏｓｃｉｅｎｃｅｓ， ＬＬＣ | ピロロ［３，２−ｄ］ピリミジン−２，４（３Ｈ，５Ｈ）−ジオン誘導体 |
| US20190175599A1 (en) | 2014-09-16 | 2019-06-13 | Glemark Pharmaceuticals S.A. | Trpa1 antagonist for the treatment of pain associated to diabetic neuropathic pain |
| CN105001170A (zh) * | 2015-07-13 | 2015-10-28 | 佛山市赛维斯医药科技有限公司 | 末端腈基取代的三氮唑亚砜类化合物、其制备方法及其用途 |
| WO2017060488A1 (en) | 2015-10-09 | 2017-04-13 | Almirall, S.A. | New trpa1 antagonists |
| WO2017064068A1 (en) | 2015-10-14 | 2017-04-20 | Almirall, S.A. | New trpa1 antagonists |
| RU2741788C1 (ru) * | 2017-07-28 | 2021-01-28 | Цзянсу Хэнжуй Медицин Ко., Лтд. | Способ получения гетероарильного производного пиримидона и промежуточного соединения гетероарильного производного пиримидона |
| CN109422749B (zh) * | 2017-08-21 | 2023-01-24 | 重庆医药工业研究院有限责任公司 | 一种抑制单羧酸转运蛋白的嘧啶二酮衍生物 |
| US10710994B2 (en) | 2018-03-19 | 2020-07-14 | Genentech, Inc. | Oxadiazole transient receptor potential channel inhibitors |
| CN108558836A (zh) * | 2018-05-14 | 2018-09-21 | 东南大学 | 一类具有双重作用机制的dpp-4抑制剂及其用途 |
| WO2023096915A1 (en) * | 2021-11-24 | 2023-06-01 | Slap Pharmaceuticals Llc | Multicyclic compounds |
| CA3243510A1 (en) * | 2022-02-03 | 2023-08-10 | D.E. Shaw Research, Llc | N3-SUPPOSED URACIL COMPOUNDS AS TRPA1 INHIBITORS |
| KR20240161147A (ko) | 2022-03-14 | 2024-11-12 | 슬랩 파마슈티컬스 엘엘씨 | 다중 사이클릭 화합물 |
| CN114656480B (zh) * | 2022-04-27 | 2024-01-26 | 成都施贝康生物医药科技有限公司 | 噻吩并嘧啶类化合物、异构体或盐及其制备方法和用途 |
| CN114656473B (zh) * | 2022-04-27 | 2023-09-29 | 成都施贝康生物医药科技有限公司 | 吡咯并嘧啶类化合物、异构体或盐及其制备方法和用途 |
| CN114656472B (zh) * | 2022-04-27 | 2023-07-04 | 成都施贝康生物医药科技有限公司 | 吡唑并嘧啶类化合物、异构体或盐及其制备方法和用途 |
| CN118373832B (zh) * | 2023-01-20 | 2025-01-28 | 深圳晶蛋生物医药科技有限公司 | 大环类化合物、其药物组合物及其应用 |
| WO2025264860A2 (en) | 2024-06-18 | 2025-12-26 | Yale University | Methods of treating post-covid airway disease |
Family Cites Families (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2248231A1 (de) | 1972-10-02 | 1974-04-11 | Basf Ag | 3-aminoisothiazolo eckige klammer auf 3,4-d eckige klammer zu pyrimidine |
| SE9701398D0 (sv) * | 1997-04-15 | 1997-04-15 | Astra Pharma Prod | Novel compounds |
| ES2193839B1 (es) * | 2001-06-22 | 2005-02-16 | Almirall Prodesfarma, S.A. | Nuevos derivados de 6-fenildihidropirrolpirimidindiona. |
| WO2004014916A1 (en) | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | Pyrimidine fused bicyclic metalloproteinase inhibitors |
| AU2003290066A1 (en) | 2002-12-18 | 2004-07-09 | Novartis Ag | Anktm1, a cold-activated trp-like channel expressed in nociceptive neurons |
| JP2007522214A (ja) * | 2004-02-11 | 2007-08-09 | スミスクライン・ビーチャム・コーポレイション | Ｐｔｈアゴニスト |
| WO2005089206A2 (en) | 2004-03-13 | 2005-09-29 | Irm Llc | Modulators of ion channel trpa1 |
| MY140748A (en) | 2004-12-06 | 2010-01-15 | Astrazeneca Ab | Novel pyrrolo [3,2-d] pyrimidin-4-one derivatives and their use in therapy |
| WO2006083005A1 (ja) | 2005-02-03 | 2006-08-10 | Takeda Pharmaceutical Company Limited | 縮合ピリミジン誘導体およびその用途 |
| US20060291462A1 (en) * | 2005-06-28 | 2006-12-28 | Utstarcom, Inc. | Method and apparatus using multiple application cards to comprise multiple logical network entities |
| WO2007073505A2 (en) * | 2005-12-22 | 2007-06-28 | Hydra Biosciences, Inc. | Trpa1 inhibitors for treating pain |
| TW200800997A (en) | 2006-03-22 | 2008-01-01 | Astrazeneca Ab | Chemical compounds |
| AR065081A1 (es) | 2007-01-29 | 2009-05-13 | Xenon Pharmaceuticals Inc | Compuestos de quinazolinona y pirimidona fusionados y composicion farmaceutica |
| WO2009002933A1 (en) * | 2007-06-22 | 2008-12-31 | Hydra Biosciences, Inc. | Methods and compositions for treating disorders |
| WO2009158719A2 (en) * | 2008-06-27 | 2009-12-30 | Hydra Biosciences, Inc. | Methods and compositions for treating disorders |
| US8299077B2 (en) | 2009-03-02 | 2012-10-30 | Roche Palo Alto Llc | Inhibitors of Bruton's tyrosine kinase |
| WO2010109287A1 (en) | 2009-03-23 | 2010-09-30 | Glenmark Pharmaceuticals S.A. | Fused pyrimidine-dione derivatives as trpa1 modulators |
| EP2411397B1 (en) | 2009-03-23 | 2013-05-29 | Glenmark Pharmaceuticals S.A. | Isothiazolo-pyrimidinedione derivatives as trpa1 modulators |
| SG184767A1 (en) | 2009-03-23 | 2012-10-30 | Glenmark Pharmaceuticals Sa | Furopyrimidinedione derivatives as trpa1 modulators |
| AR076332A1 (es) | 2009-04-21 | 2011-06-01 | Boehringer Ingelheim Int | Derivados heterociclicos de 5-alquinil-piridinas, composiciones farmaceuticas que los comprenden y uso de los mismos para el tratamiento y/o prevencion del cancer, procesos inflamatorios, autoinmunes, y/o infecciones. |
| KR20120046175A (ko) | 2009-06-18 | 2012-05-09 | 바스프 에스이 | 살진균 혼합물 |
| US8404461B2 (en) | 2009-10-15 | 2013-03-26 | SK Biopharmaceutical Co. Ltd. | Method for preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester |
| AR078522A1 (es) | 2009-10-15 | 2011-11-16 | Lilly Co Eli | Compuesto de espiropiperidina, composicion farmaceutica que lo comprende, su uso para preparar un medicamento util para tratar diabetes y compuesto intermediario para su sintesis |
| EP2311844A1 (en) | 2009-10-15 | 2011-04-20 | Interquim, S.A. | Silyl polymeric benzoic acid ester compounds, uses, and compositions thereof |
| JP5629324B2 (ja) | 2009-10-15 | 2014-11-19 | ファイザー・インク | ピロロ［２，３−ｄ］ピリミジン化合物 |
| US8163704B2 (en) | 2009-10-20 | 2012-04-24 | Novartis Ag | Glycoside derivatives and uses thereof |
| NZ598137A (en) | 2010-07-13 | 2014-06-27 | Novartis Ag | Oxazine derivatives and their use in the treatment of neurological disorders |
-
2010
- 2010-03-17 WO PCT/IB2010/000553 patent/WO2010109287A1/en not_active Ceased
- 2010-03-17 UA UAA201111147A patent/UA108069C2/uk unknown
- 2010-03-17 PE PE2011001707A patent/PE20120774A1/es not_active Application Discontinuation
- 2010-03-17 EP EP10755503.9A patent/EP2411393B1/en not_active Not-in-force
- 2010-03-17 SI SI201030523T patent/SI2411393T1/sl unknown
- 2010-03-17 PL PL10755503T patent/PL2411393T3/pl unknown
- 2010-03-17 JP JP2012501401A patent/JP5657638B2/ja not_active Expired - Fee Related
- 2010-03-17 SG SG2011066487A patent/SG174402A1/en unknown
- 2010-03-17 ES ES10755503.9T patent/ES2456515T3/es active Active
- 2010-03-17 EP EP13005523.9A patent/EP2708538B1/en not_active Not-in-force
- 2010-03-17 MX MX2011009824A patent/MX2011009824A/es unknown
- 2010-03-17 EA EA201190143A patent/EA023857B1/ru not_active IP Right Cessation
- 2010-03-17 CN CN201080013471.6A patent/CN102361873B/zh not_active Expired - Fee Related
- 2010-03-17 PT PT107555039T patent/PT2411393E/pt unknown
- 2010-03-17 DK DK10755503.9T patent/DK2411393T3/da active
- 2010-03-17 ES ES13005523.9T patent/ES2551085T3/es active Active
- 2010-03-17 CA CA2756518A patent/CA2756518A1/en not_active Abandoned
- 2010-03-17 AP AP2011005887A patent/AP3280A/xx active
- 2010-03-17 BR BRPI1013559A patent/BRPI1013559A2/pt active Search and Examination
- 2010-03-17 KR KR1020117022612A patent/KR20110132575A/ko not_active Ceased
- 2010-03-17 AU AU2010227245A patent/AU2010227245B2/en not_active Ceased
-
2011
- 2011-09-15 IL IL215178A patent/IL215178A/en not_active IP Right Cessation
- 2011-09-20 CL CL2011002315A patent/CL2011002315A1/es unknown
- 2011-10-19 ZA ZA2011/07648A patent/ZA201107648B/en unknown
-
2013
- 2013-11-14 US US14/079,932 patent/US9000159B2/en not_active Expired - Fee Related
-
2014
- 2014-06-02 CL CL2014001447A patent/CL2014001447A1/es unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2456515T3 (es) | Derivados de pirimidindiona fusionados como moduladores de TRPA1 | |
| ES2424340T3 (es) | Derivados de isotiazolo-pirimidindiona como moduladores de TRPA1 | |
| ES2424341T3 (es) | Derivados de furopirimidinadiona como moduladores de TRPA1 | |
| US8623880B2 (en) | Fused pyrimidine-dione derivatives as TRPA1 modulators | |
| WO2010125469A1 (en) | Pyrimidinedione-fused heterocyclic compounds as trpa1 modulators | |
| HK1166075B (en) | Fused pyrimidine-dione derivatives as trpa1 modulators |