ES2477583T3 - Compuestos de carboxamida y su uso como inhibidores de calpaína IV - Google Patents

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Publication number

ES2477583T3

ES2477583T3 ES10798323.1T ES10798323T ES2477583T3 ES 2477583 T3 ES2477583 T3 ES 2477583T3 ES 10798323 T ES10798323 T ES 10798323T ES 2477583 T3 ES2477583 T3 ES 2477583T3

Authority

ES

Spain

Prior art keywords

phenyl

alkyl

dioxo

pyrazol

pyridin

Prior art date

2009-12-22

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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• -1 Carboxamide compounds Chemical class 0.000 title claims abstract description 2815
• 108010079785 calpain inhibitors Proteins 0.000 title description 28
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 96
• 125000001424 substituent group Chemical group 0.000 claims abstract description 72
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 69
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 66
• 125000003118 aryl group Chemical group 0.000 claims abstract description 64
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 59
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 51
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 39
• 150000002367 halogens Chemical class 0.000 claims abstract description 39
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 35
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 23
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 16
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims abstract description 13
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 12
• 125000000000 cycloalkoxy group Chemical group 0.000 claims abstract description 9
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 6
• 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims abstract description 6
• 125000006771 (C1-C6) haloalkylthio group Chemical group 0.000 claims abstract description 5
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims abstract description 3
• 125000005865 C2-C10alkynyl group Chemical group 0.000 claims abstract description 3
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract 8
• 150000003254 radicals Chemical class 0.000 claims description 121
• 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 67
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 42
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 36
• 238000011282 treatment Methods 0.000 claims description 35
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 32
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 31
• 229910052757 nitrogen Inorganic materials 0.000 claims description 30
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 28
• 150000003839 salts Chemical class 0.000 claims description 25
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 24
• 208000035475 disorder Diseases 0.000 claims description 24
• 125000003545 alkoxy group Chemical group 0.000 claims description 23
• 239000000651 prodrug Substances 0.000 claims description 23
• 229940002612 prodrug Drugs 0.000 claims description 23
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 22
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 22
• 229910052739 hydrogen Inorganic materials 0.000 claims description 21
• 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 20
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 20
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 19
• DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 19
• 150000004677 hydrates Chemical class 0.000 claims description 19
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 18
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 16
• 125000005842 heteroatom Chemical group 0.000 claims description 16
• 229910052717 sulfur Inorganic materials 0.000 claims description 15
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 13
• 239000001257 hydrogen Substances 0.000 claims description 13
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
• 235000005152 nicotinamide Nutrition 0.000 claims description 11
• 229910052799 carbon Inorganic materials 0.000 claims description 10
• 229910052801 chlorine Inorganic materials 0.000 claims description 10
• 229910052731 fluorine Inorganic materials 0.000 claims description 10
• 239000011570 nicotinamide Substances 0.000 claims description 10
• 230000006378 damage Effects 0.000 claims description 9
• 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 9
• 125000000586 2-(4-morpholinyl)ethoxy group Chemical group [H]C([H])(O*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 8
• DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 claims description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
• 125000004414 alkyl thio group Chemical group 0.000 claims description 8
• 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 8
• 125000000623 heterocyclic group Chemical group 0.000 claims description 8
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 8
• 125000003342 alkenyl group Chemical group 0.000 claims description 7
• 125000000304 alkynyl group Chemical group 0.000 claims description 7
• 210000003734 kidney Anatomy 0.000 claims description 7
• 201000004792 malaria Diseases 0.000 claims description 7
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 7
• VLSSILIYHTYHQV-BPGUCPLFSA-N (2r)-n-[4-(cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl]-1-[(2-fluorophenyl)methyl]-5-oxopyrrolidine-2-carboxamide Chemical compound FC1=CC=CC=C1CN1C(=O)CC[C@@H]1C(=O)NC(C(=O)C(=O)NC1CC1)CC1=CC=CC=C1 VLSSILIYHTYHQV-BPGUCPLFSA-N 0.000 claims description 6
• JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 6
• 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 6
• 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 6
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
• VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 5
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
• 208000002177 Cataract Diseases 0.000 claims description 4
• 102000000589 Interleukin-1 Human genes 0.000 claims description 4
• 108010002352 Interleukin-1 Proteins 0.000 claims description 4
• 206010027476 Metastases Diseases 0.000 claims description 4
• 206010028980 Neoplasm Diseases 0.000 claims description 4
• 201000005485 Toxoplasmosis Diseases 0.000 claims description 4
• 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 4
• 206010015037 epilepsy Diseases 0.000 claims description 4
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 4
• 201000006938 muscular dystrophy Diseases 0.000 claims description 4
• 208000031225 myocardial ischemia Diseases 0.000 claims description 4
• OWMNFLDCTWHKQI-UHFFFAOYSA-N n-[3,4-dioxo-1-phenyl-4-(2-phenylethylamino)butan-2-yl]-2-[3-(4-fluorophenyl)pyrazol-1-yl]pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C1=NN(C=2C(=CC=CN=2)C(=O)NC(CC=2C=CC=CC=2)C(=O)C(=O)NCCC=2C=CC=CC=2)C=C1 OWMNFLDCTWHKQI-UHFFFAOYSA-N 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 238000002560 therapeutic procedure Methods 0.000 claims description 4
• 208000003890 Coronary Vasospasm Diseases 0.000 claims description 3
• 208000029549 Muscle injury Diseases 0.000 claims description 3
• 238000002399 angioplasty Methods 0.000 claims description 3
• 125000005018 aryl alkenyl group Chemical group 0.000 claims description 3
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
• 125000005605 benzo group Chemical group 0.000 claims description 3
• 210000004204 blood vessel Anatomy 0.000 claims description 3
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 230000003683 cardiac damage Effects 0.000 claims description 3
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
• 208000002780 macular degeneration Diseases 0.000 claims description 3
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 208000037803 restenosis Diseases 0.000 claims description 3
• 210000002027 skeletal muscle Anatomy 0.000 claims description 3
• VLSSILIYHTYHQV-LBAQZLPGSA-N (2s)-n-[4-(cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl]-1-[(2-fluorophenyl)methyl]-5-oxopyrrolidine-2-carboxamide Chemical compound FC1=CC=CC=C1CN1C(=O)CC[C@H]1C(=O)NC(C(=O)C(=O)NC1CC1)CC1=CC=CC=C1 VLSSILIYHTYHQV-LBAQZLPGSA-N 0.000 claims description 2
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
• 125000001845 4 membered carbocyclic group Chemical group 0.000 claims description 2
• 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 2
• 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 2
• 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 2
• 206010003225 Arteriospasm coronary Diseases 0.000 claims description 2
• 238000002512 chemotherapy Methods 0.000 claims description 2
• 208000020832 chronic kidney disease Diseases 0.000 claims description 2
• 201000011634 coronary artery vasospasm Diseases 0.000 claims description 2
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 2
• 208000001286 intracranial vasospasm Diseases 0.000 claims description 2
• 230000035755 proliferation Effects 0.000 claims description 2
• 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 2
• 210000000329 smooth muscle myocyte Anatomy 0.000 claims description 2
• 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims 1
• 208000010362 Protozoan Infections Diseases 0.000 claims 1
• 230000009401 metastasis Effects 0.000 claims 1
• 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
• 125000004429 atom Chemical group 0.000 abstract 1
• 125000001309 chloro group Chemical group Cl* 0.000 description 921
• 150000001875 compounds Chemical class 0.000 description 249
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 151
• 108010032088 Calpain Proteins 0.000 description 86
• 102000007590 Calpain Human genes 0.000 description 86
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 86
• 238000006243 chemical reaction Methods 0.000 description 79
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 72
• 239000000203 mixture Substances 0.000 description 37
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
• 238000005160 1H NMR spectroscopy Methods 0.000 description 33
• 230000005764 inhibitory process Effects 0.000 description 29
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
• 210000004185 liver Anatomy 0.000 description 23
• 238000000034 method Methods 0.000 description 22
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• 239000003814 drug Substances 0.000 description 20
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• 239000000243 solution Substances 0.000 description 18
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 16
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 16
• 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 15
• 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 15
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 15
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 15
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• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 15
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• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 15
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
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• 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 15
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• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 14
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