ES2527849T3 - Derivados de ciclohexilamida como antagonistas del receptor de CRF - Google Patents
Derivados de ciclohexilamida como antagonistas del receptor de CRF Download PDFInfo
- Publication number
- ES2527849T3 ES2527849T3 ES11701824.2T ES11701824T ES2527849T3 ES 2527849 T3 ES2527849 T3 ES 2527849T3 ES 11701824 T ES11701824 T ES 11701824T ES 2527849 T3 ES2527849 T3 ES 2527849T3
- Authority
- ES
- Spain
- Prior art keywords
- chloro
- trans
- methyl
- cyclohexyl
- ylmethyl
- 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.)
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- 229940044551 receptor antagonist Drugs 0.000 title description 19
- 239000002464 receptor antagonist Substances 0.000 title description 19
- 108010056643 Corticotropin-Releasing Hormone Receptors Proteins 0.000 title description 5
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical class NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 200
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 62
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 61
- 239000001257 hydrogen Substances 0.000 claims abstract description 46
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 24
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 22
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 15
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 14
- 239000011737 fluorine Substances 0.000 claims abstract description 14
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 12
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000002367 halogens Chemical group 0.000 claims abstract description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000460 chlorine Substances 0.000 claims abstract description 8
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 7
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 7
- 125000005605 benzo group Chemical group 0.000 claims abstract description 5
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims abstract description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 4
- 125000005059 halophenyl group Chemical group 0.000 claims abstract description 3
- -1 4 - ((4- (4-chlorophenyl) -5-methyl-1 H -pyrazol-3-ylamino) methyl) cyclohexyl Chemical group 0.000 claims description 164
- 238000000034 method Methods 0.000 claims description 91
- 150000003839 salts Chemical group 0.000 claims description 71
- 238000011282 treatment Methods 0.000 claims description 45
- 239000002253 acid Substances 0.000 claims description 36
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 34
- 201000010099 disease Diseases 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 19
- 102400000739 Corticotropin Human genes 0.000 claims description 15
- 101800000414 Corticotropin Proteins 0.000 claims description 15
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 claims description 15
- 229960000258 corticotropin Drugs 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 239000005557 antagonist Substances 0.000 claims description 13
- 230000001965 increasing effect Effects 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 125000004494 ethyl ester group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 6
- 229910052805 deuterium Inorganic materials 0.000 claims description 6
- MRZCTSJNLTVOQB-UHFFFAOYSA-N 2-chloro-n-[4-[[4-chloro-3-(hydroxymethyl)pyrazol-1-yl]methyl]cyclohexyl]-5-(trifluoromethyl)benzamide Chemical compound C1=C(Cl)C(CO)=NN1CC1CCC(NC(=O)C=2C(=CC=C(C=2)C(F)(F)F)Cl)CC1 MRZCTSJNLTVOQB-UHFFFAOYSA-N 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 239000011570 nicotinamide Substances 0.000 claims description 5
- 229960003966 nicotinamide Drugs 0.000 claims description 5
- SIVDZRMKCXLRPY-CZIWCDLHSA-N CC1=NC=C(Cl)C=C1C(=O)N[C@@H]1CC[C@@H](CN2C=3CCCC=3C=N2)CC1 Chemical compound CC1=NC=C(Cl)C=C1C(=O)N[C@@H]1CC[C@@H](CN2C=3CCCC=3C=N2)CC1 SIVDZRMKCXLRPY-CZIWCDLHSA-N 0.000 claims description 4
- UVKGWNIRLPNREG-CZIWCDLHSA-N CC1=NC=C(Cl)C=C1C(=O)N[C@@H]1CC[C@@H](CN2N=C3CCCC3=C2)CC1 Chemical compound CC1=NC=C(Cl)C=C1C(=O)N[C@@H]1CC[C@@H](CN2N=C3CCCC3=C2)CC1 UVKGWNIRLPNREG-CZIWCDLHSA-N 0.000 claims description 4
- 230000002074 deregulated effect Effects 0.000 claims description 4
- SUUSNFSQMHCMDE-UHFFFAOYSA-N 2-chloro-n-[4-[[3-(4-methoxyphenyl)-5-methylpyrazol-1-yl]methyl]cyclohexyl]-5-(trifluoromethyl)benzamide Chemical compound C1=CC(OC)=CC=C1C1=NN(CC2CCC(CC2)NC(=O)C=2C(=CC=C(C=2)C(F)(F)F)Cl)C(C)=C1 SUUSNFSQMHCMDE-UHFFFAOYSA-N 0.000 claims description 3
- GSQGCFTWOSTTHY-UHFFFAOYSA-N 5-chloro-2-methyl-n-[4-[(3,4,5-trimethylpyrazol-1-yl)methyl]cyclohexyl]pyridine-3-carboxamide Chemical compound CC1=C(C)C(C)=NN1CC1CCC(NC(=O)C=2C(=NC=C(Cl)C=2)C)CC1 GSQGCFTWOSTTHY-UHFFFAOYSA-N 0.000 claims description 3
- YFGJKTCILASHFF-UHFFFAOYSA-N 5-chloro-n-[4-[(3,5-diethylpyrazol-1-yl)methyl]cyclohexyl]-2-methylpyridine-3-carboxamide Chemical compound N1=C(CC)C=C(CC)N1CC1CCC(NC(=O)C=2C(=NC=C(Cl)C=2)C)CC1 YFGJKTCILASHFF-UHFFFAOYSA-N 0.000 claims description 3
- KQQMWFWXNSJHJA-UHFFFAOYSA-N 5-chloro-n-[4-[[(5-ethyl-4-methyl-1h-pyrazol-3-yl)amino]methyl]cyclohexyl]-2-methylpyridine-3-carboxamide Chemical compound CC1=C(CC)NN=C1NCC1CCC(NC(=O)C=2C(=NC=C(Cl)C=2)C)CC1 KQQMWFWXNSJHJA-UHFFFAOYSA-N 0.000 claims description 3
- CVWWTNXFLUGTDI-ZHTAKFGLSA-N CC(C(O)=O)c1ccc(NC[C@H]2CC[C@@H](CC2)NC(=O)c2cc(ccc2Cl)C(F)(F)F)cc1 Chemical compound CC(C(O)=O)c1ccc(NC[C@H]2CC[C@@H](CC2)NC(=O)c2cc(ccc2Cl)C(F)(F)F)cc1 CVWWTNXFLUGTDI-ZHTAKFGLSA-N 0.000 claims description 3
- DLODGACIEXJIID-KOMQPUFPSA-N CC(C)(C)c1ccn(C[C@H]2CC[C@@H](CC2)NC(=O)c2cc(ccc2Cl)C(F)(F)F)n1 Chemical compound CC(C)(C)c1ccn(C[C@H]2CC[C@@H](CC2)NC(=O)c2cc(ccc2Cl)C(F)(F)F)n1 DLODGACIEXJIID-KOMQPUFPSA-N 0.000 claims description 3
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Classifications
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- C07D491/04—Ortho-condensed systems
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-
2011
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- 2011-01-31 CN CN201180007786.4A patent/CN102753527B/zh not_active Expired - Fee Related
- 2011-01-31 ES ES11701824.2T patent/ES2527849T3/es active Active
- 2011-01-31 WO PCT/EP2011/051293 patent/WO2011095450A1/en not_active Ceased
- 2011-01-31 US US13/576,040 patent/US8835444B2/en not_active Expired - Fee Related
- 2011-01-31 EP EP11701824.2A patent/EP2531490B1/en not_active Not-in-force
Also Published As
| Publication number | Publication date |
|---|---|
| EP2531490A1 (en) | 2012-12-12 |
| US8835444B2 (en) | 2014-09-16 |
| JP5748777B2 (ja) | 2015-07-15 |
| WO2011095450A1 (en) | 2011-08-11 |
| US20120316185A1 (en) | 2012-12-13 |
| CN102753527B (zh) | 2014-12-24 |
| CN102753527A (zh) | 2012-10-24 |
| EP2531490B1 (en) | 2014-10-15 |
| JP2013518845A (ja) | 2013-05-23 |
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