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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Applications Claiming Priority (21)
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| INMU06652009 | 2009-03-23 | ||
| IN665MU2009 | 2009-03-23 | ||
| US17135509P | 2009-04-21 | 2009-04-21 | |
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| US25326309P | 2009-10-20 | 2009-10-20 | |
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| 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)
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| ES2456515T3 true ES2456515T3 (es) | 2014-04-22 |
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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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| 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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Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008019357A2 (en) | 2006-08-07 | 2008-02-14 | Ironwood Pharmaceuticals, Inc. | Indole compounds |
| EA023857B1 (ru) | 2009-03-23 | 2016-07-29 | Гленмарк Фармасеутикалс С.А. | Сочлененные производные пиримидиндионов в качестве модуляторов trpa1 |
| JP5694560B2 (ja) | 2010-12-20 | 2015-04-01 | グレンマーク ファーマシューティカルズ， エセ．アー． | Ｔｒｐａ１アンタゴニストとしての２−アミノ−４−アリールチアゾール化合物 |
| 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 |
| CN103826637A (zh) | 2011-06-13 | 2014-05-28 | 格兰马克药品股份有限公司 | 使用trpa1拮抗剂治疗呼吸疾患 |
| US20140107113A1 (en) | 2011-06-22 | 2014-04-17 | Glenmark Pharmaceuticals S.A. | Pharmaceutical composition comprising a trpa1 antagonist and a beta-2 agonist |
| WO2012176105A1 (en) | 2011-06-22 | 2012-12-27 | Glenmark Pharmaceuticals Sa | Pharmaceutical composition comprising a trpa1 antagonist and a leukotriene receptor antagonist |
| WO2013014597A1 (en) | 2011-07-25 | 2013-01-31 | Glenmark Pharmaceuticals Sa | Pharmaceutical composition comprising a trpa1 antagonist and a steroid |
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