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
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- ES
- Spain
- Prior art keywords
- acetamide
- pyrimidin
- dioxo
- tetrahydro
- thiazol
- Prior art date
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- 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
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- 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
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- 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
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- 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
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- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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Classifications
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Landscapes
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| US300241P | 2010-02-01 | ||
| PCT/IB2010/000553 WO2010109287A1 (en) | 2009-03-23 | 2010-03-17 | Fused pyrimidine-dione derivatives as trpa1 modulators |
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| ES13005523.9T Active ES2551085T3 (es) | 2009-03-23 | 2010-03-17 | Proceso para preparar derivados de pirimidina-diona condensados, útiles como moduladores de TRPA1 |
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| EP2049520A4 (en) | 2006-08-07 | 2011-01-05 | Ironwood Pharmaceuticals Inc | indole compounds |
| EA023857B1 (ru) | 2009-03-23 | 2016-07-29 | Гленмарк Фармасеутикалс С.А. | Сочлененные производные пиримидиндионов в качестве модуляторов trpa1 |
| EP2655377B1 (en) * | 2010-12-20 | 2016-03-30 | Glenmark Pharmaceuticals S.A. | 2-amino-4-arylthiazole compounds as trpa1 antagonists |
| 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 |
| WO2012172475A1 (en) | 2011-06-13 | 2012-12-20 | Glenmark Pharmaceuticals S.A. | Treatment of respiratory disorders using trpa1 antagonists |
| WO2012176105A1 (en) | 2011-06-22 | 2012-12-27 | Glenmark Pharmaceuticals Sa | Pharmaceutical composition comprising a trpa1 antagonist and a leukotriene receptor antagonist |
| WO2012176143A1 (en) | 2011-06-22 | 2012-12-27 | Glenmark Pharmaceuticals Sa | Pharmaceutical composition comprising a trpa1 antagonist and a beta-2 agonist |
| WO2013014597A1 (en) | 2011-07-25 | 2013-01-31 | Glenmark Pharmaceuticals Sa | Pharmaceutical composition comprising a trpa1 antagonist and a steroid |
| MX2014001551A (es) | 2011-08-09 | 2014-09-15 | Hydra Biosciences Inc | Inhibicion de canal ionico del potencial receptor transitorio a1 (trpa1). |
| CA2857109A1 (en) | 2011-12-05 | 2013-06-13 | 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 |
| KR20150015488A (ko) | 2012-06-08 | 2015-02-10 | 그렌마크 파머수티칼스 에스. 아. | 2-아미노-4-아릴티아졸 화합물의 아미드 및 그의 염 |
| SI2903965T1 (sl) | 2012-10-01 | 2017-07-31 | Orion Corporation | Derivati n-prop-2-inil karboksamida in njihova uporaba kot antagonisti trpa1 |
| 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 |
| MX380546B (es) * | 2013-10-30 | 2025-03-12 | Shanghai hengrui pharmaceutical co ltd | Derivados de pirazolopirimidona o pirrolotriazona, metodo y preparacion de los mismos y aplicaciones farmaceuticas de los mismos. |
| 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 |
| EP3180342B1 (en) * | 2014-08-11 | 2019-06-26 | Hydra Biosciences, Inc. | Pyrrolo[3,2-d]pyrimidine-2,4(3h,5h)-dione derivatives |
| WO2016042501A1 (en) | 2014-09-16 | 2016-03-24 | Glenmark 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 |
| JP2020528060A (ja) * | 2017-07-28 | 2020-09-17 | 江蘇恒瑞医薬股▲ふん▼有限公司 | ピリミドンヘテロアリール誘導体の製造方法およびピリミドンヘテロアリール誘導体の中間体 |
| 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 |
| 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 |
| 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 |
| 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. |
| AU2003253165A1 (en) | 2002-08-13 | 2004-02-25 | 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 |
| WO2005077959A1 (en) * | 2004-02-11 | 2005-08-25 | Smithkline Beecham Corporation | Pth agonists |
| 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 |
| EP1847541A4 (en) | 2005-02-03 | 2009-12-30 | Takeda Pharmaceutical | CONDENSED PYRIMIDINE DERIVATIVE AND USE THEREOF |
| US20060291462A1 (en) * | 2005-06-28 | 2006-12-28 | Utstarcom, Inc. | Method and apparatus using multiple application cards to comprise multiple logical network entities |
| AU2006327181A1 (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 |
| CL2008000252A1 (es) | 2007-01-29 | 2008-03-14 | Xenon Pharmaceuticals Inc | Compuestos derivados de quinazolinona o pirimidinona; composicion farmaceutica que comprende a dichos compuestos; y su uso para tratar enfermedades mediadas por los canales de calcio, tales como dolor, depresion, enfermedades cardiovasculares, respir |
| CN101801362B (zh) | 2007-06-22 | 2014-01-22 | 海德拉生物科学公司 | 用于治疗病症的方法和组合物 |
| 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 |
| BRPI1009372A2 (pt) | 2009-03-23 | 2016-05-31 | Glenmark Pharmaceuticals Sa | compostos, composição farmacêutica e respectivos usos |
| EA023857B1 (ru) | 2009-03-23 | 2016-07-29 | Гленмарк Фармасеутикалс С.А. | Сочлененные производные пиримидиндионов в качестве модуляторов trpa1 |
| SG174398A1 (en) | 2009-03-23 | 2011-10-28 | 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. |
| EP2442653A2 (de) | 2009-06-18 | 2012-04-25 | Basf Se | Fungizide mischungen |
| IN2012DN02577A (enExample) | 2009-10-15 | 2015-08-28 | Pfizer | |
| 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 |
| US8163704B2 (en) | 2009-10-20 | 2012-04-24 | Novartis Ag | Glycoside derivatives and uses thereof |
| DK2483255T3 (da) | 2010-07-13 | 2014-01-20 | Novartis Ag | Oxazinderivater samt deres anvendelse ved behandling af neurologiske lidelser |
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