ES2427999T3 - Compuestos heterocíclicos 2-cianofenil-condensados y composiciones y usos de los mismos - Google Patents

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Publication number

ES2427999T3

ES2427999T3 ES08742430T ES08742430T ES2427999T3 ES 2427999 T3 ES2427999 T3 ES 2427999T3 ES 08742430 T ES08742430 T ES 08742430T ES 08742430 T ES08742430 T ES 08742430T ES 2427999 T3 ES2427999 T3 ES 2427999T3

Authority

ES

Spain

Prior art keywords

pyrimidin

pyrido

dihydro

benzonitrile

methyl

Prior art date

2007-04-17

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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• 239000000203 mixture Substances 0.000 title description 181
• 150000002391 heterocyclic compounds Chemical class 0.000 title description 22
• 150000001875 compounds Chemical class 0.000 claims abstract description 303
• -1 cycloheteroalkyl Chemical group 0.000 claims abstract description 253
• 125000003118 aryl group Chemical group 0.000 claims abstract description 90
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 71
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 59
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 33
• 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims abstract description 28
• XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims abstract description 27
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 17
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract description 16
• 229910052731 fluorine Inorganic materials 0.000 claims abstract description 14
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 13
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims abstract description 13
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 12
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 12
• 229910052794 bromium Inorganic materials 0.000 claims abstract description 10
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims abstract description 10
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims abstract description 10
• JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims abstract description 9
• 108010081348 HRT1 protein Hairy Proteins 0.000 claims abstract description 9
• 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims abstract description 9
• 229910006074 SO2NH2 Inorganic materials 0.000 claims abstract description 9
• 229910006069 SO3H Inorganic materials 0.000 claims abstract description 9
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims abstract description 9
• 125000005945 imidazopyridyl group Chemical group 0.000 claims abstract description 9
• 125000001041 indolyl group Chemical group 0.000 claims abstract description 9
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 9
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 9
• 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims abstract description 9
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 8
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims abstract description 8
• MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims abstract description 7
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims abstract description 7
• 125000006217 methyl sulfide group Chemical group [H]C([H])([H])S* 0.000 claims abstract description 7
• 238000000034 method Methods 0.000 claims description 119
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 86
• 125000000217 alkyl group Chemical group 0.000 claims description 75
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 47
• 208000002193 Pain Diseases 0.000 claims description 42
• 238000011282 treatment Methods 0.000 claims description 38
• 229910052739 hydrogen Inorganic materials 0.000 claims description 35
• 239000001257 hydrogen Substances 0.000 claims description 35
• 239000008194 pharmaceutical composition Substances 0.000 claims description 35
• 201000010099 disease Diseases 0.000 claims description 33
• 230000036407 pain Effects 0.000 claims description 33
• 125000003545 alkoxy group Chemical group 0.000 claims description 32
• 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 claims description 30
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 27
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 27
• 150000003839 salts Chemical class 0.000 claims description 25
• 125000002252 acyl group Chemical group 0.000 claims description 24
• 125000004442 acylamino group Chemical group 0.000 claims description 20
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 20
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 20
• 239000012453 solvate Substances 0.000 claims description 20
• 125000003282 alkyl amino group Chemical group 0.000 claims description 17
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 17
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 17
• 125000004104 aryloxy group Chemical group 0.000 claims description 16
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 16
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
• 208000035475 disorder Diseases 0.000 claims description 14
• 230000000155 isotopic effect Effects 0.000 claims description 14
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
• 208000023275 Autoimmune disease Diseases 0.000 claims description 11
• 125000000623 heterocyclic group Chemical group 0.000 claims description 11
• 230000001404 mediated effect Effects 0.000 claims description 11
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 11
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
• 125000004414 alkyl thio group Chemical group 0.000 claims description 10
• 150000002148 esters Chemical class 0.000 claims description 10
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 9
• 208000004296 neuralgia Diseases 0.000 claims description 9
• 125000003107 substituted aryl group Chemical group 0.000 claims description 9
• 206010019233 Headaches Diseases 0.000 claims description 8
• 206010000891 acute myocardial infarction Diseases 0.000 claims description 8
• 208000006673 asthma Diseases 0.000 claims description 8
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 8
• 208000037765 diseases and disorders Diseases 0.000 claims description 8
• 231100000869 headache Toxicity 0.000 claims description 8
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 8
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 8
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 7
• 206010065390 Inflammatory pain Diseases 0.000 claims description 7
• 230000001154 acute effect Effects 0.000 claims description 7
• 125000001475 halogen functional group Chemical group 0.000 claims description 7
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• 208000019901 Anxiety disease Diseases 0.000 claims description 6
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• 150000002632 lipids Chemical class 0.000 claims description 6
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• 201000000980 schizophrenia Diseases 0.000 claims description 6
• IUVDXBRGFXCMBT-UHFFFAOYSA-N 2-[4-[1-(4-chloro-3-methylsulfonylphenyl)ethylamino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound C=1C=C(Cl)C(S(C)(=O)=O)=CC=1C(C)NC(C=1C2)=NC=NC=1CCN2C1=CC=C(C)C=C1C#N IUVDXBRGFXCMBT-UHFFFAOYSA-N 0.000 claims description 5
• ONLFWKIEMKGZBZ-UHFFFAOYSA-N 5-bromo-2-[4-[[6-(trifluoromethyl)pyridin-3-yl]methylamino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]benzonitrile Chemical compound C1=NC(C(F)(F)F)=CC=C1CNC1=NC=NC2=C1CN(C=1C(=CC(Br)=CC=1)C#N)CC2 ONLFWKIEMKGZBZ-UHFFFAOYSA-N 0.000 claims description 5
• 206010061218 Inflammation Diseases 0.000 claims description 5
• 208000008589 Obesity Diseases 0.000 claims description 5
• 206010046543 Urinary incontinence Diseases 0.000 claims description 5
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 5
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
• 230000002757 inflammatory effect Effects 0.000 claims description 5
• 230000004054 inflammatory process Effects 0.000 claims description 5
• 235000020824 obesity Nutrition 0.000 claims description 5
• 201000008482 osteoarthritis Diseases 0.000 claims description 5
• 125000004076 pyridyl group Chemical group 0.000 claims description 5
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
• IUVDXBRGFXCMBT-MRXNPFEDSA-N 2-[4-[[(1r)-1-(4-chloro-3-methylsulfonylphenyl)ethyl]amino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound N([C@H](C)C=1C=C(C(Cl)=CC=1)S(C)(=O)=O)C(C=1C2)=NC=NC=1CCN2C1=CC=C(C)C=C1C#N IUVDXBRGFXCMBT-MRXNPFEDSA-N 0.000 claims description 4
• PFTSILFRTYLFOO-INIZCTEOSA-N 2-[4-[[(1s)-1-(1,3-benzodioxol-5-yl)ethyl]amino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound N([C@@H](C)C=1C=C2OCOC2=CC=1)C(C=1C2)=NC=NC=1CCN2C1=CC=C(C)C=C1C#N PFTSILFRTYLFOO-INIZCTEOSA-N 0.000 claims description 4
• HDTMYJRQEISETD-HXUWFJFHSA-N 2-[4-[[(1s)-2-hydroxy-1-(2-methylpyrimidin-5-yl)ethyl]amino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound N#CC1=CC(C)=CC=C1N1CC2=C(N[C@H](CO)C=3C=NC(C)=NC=3)N=CN=C2CC1 HDTMYJRQEISETD-HXUWFJFHSA-N 0.000 claims description 4
• VFJLLZUKLXBDGQ-UHFFFAOYSA-N 5-bromo-2-[4-[(6-methoxypyridin-3-yl)methylamino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]benzonitrile Chemical compound C1=NC(OC)=CC=C1CNC1=NC=NC2=C1CN(C=1C(=CC(Br)=CC=1)C#N)CC2 VFJLLZUKLXBDGQ-UHFFFAOYSA-N 0.000 claims description 4
• DFGOJQUEWDGMKI-UHFFFAOYSA-N 5-chloro-2-[4-[(6-methoxypyridin-3-yl)methylamino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]benzonitrile Chemical compound C1=NC(OC)=CC=C1CNC1=NC=NC2=C1CN(C=1C(=CC(Cl)=CC=1)C#N)CC2 DFGOJQUEWDGMKI-UHFFFAOYSA-N 0.000 claims description 4
• FJEGDSNOOKRLRP-UHFFFAOYSA-N 5-methyl-2-[4-(1-quinoxalin-6-ylethylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]benzonitrile Chemical compound C=1C=C2N=CC=NC2=CC=1C(C)NC(C=1C2)=NC=NC=1CCN2C1=CC=C(C)C=C1C#N FJEGDSNOOKRLRP-UHFFFAOYSA-N 0.000 claims description 4
• FJEGDSNOOKRLRP-QGZVFWFLSA-N 5-methyl-2-[4-[[(1r)-1-quinoxalin-6-ylethyl]amino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]benzonitrile Chemical compound N([C@H](C)C=1C=C2N=CC=NC2=CC=1)C(C=1C2)=NC=NC=1CCN2C1=CC=C(C)C=C1C#N FJEGDSNOOKRLRP-QGZVFWFLSA-N 0.000 claims description 4
• NMFJPJCALUOMRM-UHFFFAOYSA-N 5-methyl-2-[4-[[6-(trifluoromethyl)pyridin-3-yl]methylamino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]benzonitrile Chemical compound N#CC1=CC(C)=CC=C1N1CC2=C(NCC=3C=NC(=CC=3)C(F)(F)F)N=CN=C2CC1 NMFJPJCALUOMRM-UHFFFAOYSA-N 0.000 claims description 4
• 208000030814 Eating disease Diseases 0.000 claims description 4
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• 206010043269 Tension headache Diseases 0.000 claims description 4
• 208000008548 Tension-Type Headache Diseases 0.000 claims description 4
• 201000011510 cancer Diseases 0.000 claims description 4
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
• 235000014632 disordered eating Nutrition 0.000 claims description 4
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• XPCVTIPTPXJKOD-UHFFFAOYSA-N 2-[4-(1,3-benzodioxol-5-ylmethylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound N#CC1=CC(C)=CC=C1N1CC2=C(NCC=3C=C4OCOC4=CC=3)N=CN=C2CC1 XPCVTIPTPXJKOD-UHFFFAOYSA-N 0.000 claims description 3
• XSSBBWWYALHHHM-UHFFFAOYSA-N 2-[4-(1,3-benzoxazol-5-ylmethylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound N#CC1=CC(C)=CC=C1N1CC2=C(NCC=3C=C4N=COC4=CC=3)N=CN=C2CC1 XSSBBWWYALHHHM-UHFFFAOYSA-N 0.000 claims description 3
• BEWVSTIRWSWSRV-UHFFFAOYSA-N 2-[4-(1h-indol-6-ylmethylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound N#CC1=CC(C)=CC=C1N1CC2=C(NCC=3C=C4NC=CC4=CC=3)N=CN=C2CC1 BEWVSTIRWSWSRV-UHFFFAOYSA-N 0.000 claims description 3
• QYKQWICOAQCEFR-UHFFFAOYSA-N 2-[4-(imidazo[1,2-a]pyridin-7-ylmethylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound N#CC1=CC(C)=CC=C1N1CC2=C(NCC3=CC4=NC=CN4C=C3)N=CN=C2CC1 QYKQWICOAQCEFR-UHFFFAOYSA-N 0.000 claims description 3
• UZBQPRXVKUBNPY-UHFFFAOYSA-N 2-[4-[(5-cyclopropylpyridin-2-yl)methylamino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound N#CC1=CC(C)=CC=C1N1CC2=C(NCC=3N=CC(=CC=3)C3CC3)N=CN=C2CC1 UZBQPRXVKUBNPY-UHFFFAOYSA-N 0.000 claims description 3
• RVOHPYXQEZNVMH-UHFFFAOYSA-N 2-[4-[(6-methoxypyridin-3-yl)methylamino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound C1=NC(OC)=CC=C1CNC1=NC=NC2=C1CN(C=1C(=CC(C)=CC=1)C#N)CC2 RVOHPYXQEZNVMH-UHFFFAOYSA-N 0.000 claims description 3
• PFTSILFRTYLFOO-UHFFFAOYSA-N 2-[4-[1-(1,3-benzodioxol-5-yl)ethylamino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound C=1C=C2OCOC2=CC=1C(C)NC(C=1C2)=NC=NC=1CCN2C1=CC=C(C)C=C1C#N PFTSILFRTYLFOO-UHFFFAOYSA-N 0.000 claims description 3
• PFTSILFRTYLFOO-MRXNPFEDSA-N 2-[4-[[(1r)-1-(1,3-benzodioxol-5-yl)ethyl]amino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound N([C@H](C)C=1C=C2OCOC2=CC=1)C(C=1C2)=NC=NC=1CCN2C1=CC=C(C)C=C1C#N PFTSILFRTYLFOO-MRXNPFEDSA-N 0.000 claims description 3
• OSQOURHXWJQPNS-OAHLLOKOSA-N 2-[4-[[(1r)-1-(2-methoxypyrimidin-5-yl)ethyl]amino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound C1=NC(OC)=NC=C1[C@@H](C)NC1=NC=NC2=C1CN(C=1C(=CC(C)=CC=1)C#N)CC2 OSQOURHXWJQPNS-OAHLLOKOSA-N 0.000 claims description 3
• OMDXBHIZMDEQDL-CYBMUJFWSA-N 5-bromo-2-[4-[[(1r)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl]amino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]benzonitrile Chemical compound N([C@H](C)C=1C=NC(=CC=1)C(F)(F)F)C(C=1C2)=NC=NC=1CCN2C1=CC=C(Br)C=C1C#N OMDXBHIZMDEQDL-CYBMUJFWSA-N 0.000 claims description 3
• YSDMEQRYDFBWMF-UHFFFAOYSA-N 5-chloro-2-[4-[[6-(trifluoromethyl)pyridin-3-yl]methylamino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]benzonitrile Chemical compound C1=NC(C(F)(F)F)=CC=C1CNC1=NC=NC2=C1CN(C=1C(=CC(Cl)=CC=1)C#N)CC2 YSDMEQRYDFBWMF-UHFFFAOYSA-N 0.000 claims description 3
• CTSWGKHAONRRHA-UHFFFAOYSA-N 5-methyl-2-[4-(quinoxalin-6-ylmethylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]benzonitrile Chemical compound N#CC1=CC(C)=CC=C1N1CC2=C(NCC=3C=C4N=CC=NC4=CC=3)N=CN=C2CC1 CTSWGKHAONRRHA-UHFFFAOYSA-N 0.000 claims description 3
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• LJLPOPGWBVSIFR-UHFFFAOYSA-N 2-[4-[(2-methoxypyrimidin-5-yl)methylamino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound C1=NC(OC)=NC=C1CNC1=NC=NC2=C1CN(C=1C(=CC(C)=CC=1)C#N)CC2 LJLPOPGWBVSIFR-UHFFFAOYSA-N 0.000 claims description 2
• OQZFQIHVHFJDIX-UHFFFAOYSA-N 2-[4-[(3,5-dichloropyridin-2-yl)methylamino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound N#CC1=CC(C)=CC=C1N1CC2=C(NCC=3C(=CC(Cl)=CN=3)Cl)N=CN=C2CC1 OQZFQIHVHFJDIX-UHFFFAOYSA-N 0.000 claims description 2
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• AFYIVHVQSPKIIO-UHFFFAOYSA-N 2-[4-[(3-iodo-4-methylphenyl)methylamino]-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-methylbenzonitrile Chemical compound N#CC1=CC(C)=CC=C1N1CC2=C(NCC=3C=C(I)C(C)=CC=3)N=CN=C2CC1 AFYIVHVQSPKIIO-UHFFFAOYSA-N 0.000 claims description 2
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