DE60037013T2 - Neurotropische substituierte pyrimidine - Google Patents

Info

Publication number

DE60037013T2

DE60037013T2 DE60037013T DE60037013T DE60037013T2 DE 60037013 T2 DE60037013 T2 DE 60037013T2 DE 60037013 T DE60037013 T DE 60037013T DE 60037013 T DE60037013 T DE 60037013T DE 60037013 T2 DE60037013 T2 DE 60037013T2

Authority

DE

Germany

Prior art keywords

amino

pyrimidine

chlorophenoxy

alkyl

trans

Prior art date

1999-04-08

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.)

Expired - Lifetime

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• 150000003230 pyrimidines Chemical class 0.000 title abstract description 5
• 230000002276 neurotropic effect Effects 0.000 title 1
• 238000002360 preparation method Methods 0.000 claims abstract description 19
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
• 210000003169 central nervous system Anatomy 0.000 claims abstract description 9
• 230000000626 neurodegenerative effect Effects 0.000 claims abstract description 9
• 208000012902 Nervous system disease Diseases 0.000 claims abstract description 8
• 208000025966 Neurological disease Diseases 0.000 claims abstract description 8
• 210000001428 peripheral nervous system Anatomy 0.000 claims abstract description 8
• -1 3-oxopiperidino Chemical group 0.000 claims description 121
• 125000000217 alkyl group Chemical group 0.000 claims description 99
• 150000001875 compounds Chemical class 0.000 claims description 74
• 150000003839 salts Chemical class 0.000 claims description 28
• 125000003118 aryl group Chemical group 0.000 claims description 27
• 125000001831 (C6-C10) heteroaryl group Chemical group 0.000 claims description 24
• 150000002148 esters Chemical class 0.000 claims description 23
• 229910052739 hydrogen Inorganic materials 0.000 claims description 23
• 150000001408 amides Chemical class 0.000 claims description 22
• 239000012453 solvate Substances 0.000 claims description 21
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 19
• 208000024827 Alzheimer disease Diseases 0.000 claims description 18
• 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims description 16
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 15
• 201000010099 disease Diseases 0.000 claims description 13
• 229910052736 halogen Inorganic materials 0.000 claims description 13
• 150000002367 halogens Chemical class 0.000 claims description 13
• 229910052757 nitrogen Inorganic materials 0.000 claims description 13
• 125000003545 alkoxy group Chemical group 0.000 claims description 12
• 229910052799 carbon Inorganic materials 0.000 claims description 11
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
• 229910052760 oxygen Inorganic materials 0.000 claims description 10
• 125000001424 substituent group Chemical group 0.000 claims description 10
• 125000003342 alkenyl group Chemical group 0.000 claims description 9
• 125000000304 alkynyl group Chemical group 0.000 claims description 9
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 9
• 206010039966 Senile dementia Diseases 0.000 claims description 8
• 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 8
• 125000005842 heteroatom Chemical group 0.000 claims description 8
• 229910052717 sulfur Inorganic materials 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 7
• 125000001072 heteroaryl group Chemical group 0.000 claims description 7
• 241000124008 Mammalia Species 0.000 claims description 6
• 208000027232 peripheral nervous system disease Diseases 0.000 claims description 6
• 125000005505 thiomorpholino group Chemical group 0.000 claims description 6
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
• 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
• 125000004104 aryloxy group Chemical group 0.000 claims description 4
• PQCHKBRHYRPMQA-UHFFFAOYSA-N 1-[2-amino-5-[(2-chloro-4-methylphenyl)methyl]pyrimidin-4-yl]piperidin-3-one Chemical compound ClC1=CC(C)=CC=C1CC1=CN=C(N)N=C1N1CC(=O)CCC1 PQCHKBRHYRPMQA-UHFFFAOYSA-N 0.000 claims description 3
• ZUHNCYXOCMYTBJ-UHFFFAOYSA-N 1-[[[2-amino-5-(4-chlorophenoxy)pyrimidin-4-yl]amino]methyl]cyclopropan-1-ol Chemical compound C1CC1(O)CNC1=NC(N)=NC=C1OC1=CC=C(Cl)C=C1 ZUHNCYXOCMYTBJ-UHFFFAOYSA-N 0.000 claims description 3
• VMKUHZBJUWCWOR-IUODEOHRSA-N 2-[(1r,2r)-2-[[2-amino-5-(4-chlorophenoxy)pyrimidin-4-yl]amino]cyclohexyl]ethanol Chemical compound N([C@H]1[C@H](CCCC1)CCO)C1=NC(N)=NC=C1OC1=CC=C(Cl)C=C1 VMKUHZBJUWCWOR-IUODEOHRSA-N 0.000 claims description 3
• 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 3
• MJNSSMVAEUKNKG-BXUZGUMPSA-N [(1s,2r)-2-[[2-amino-5-(4-chlorophenoxy)pyrimidin-4-yl]amino]cyclohexyl]methanol Chemical compound N([C@H]1[C@H](CCCC1)CO)C1=NC(N)=NC=C1OC1=CC=C(Cl)C=C1 MJNSSMVAEUKNKG-BXUZGUMPSA-N 0.000 claims description 3
• 238000011161 development Methods 0.000 claims description 3
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• 125000000464 thioxo group Chemical group S=* 0.000 claims description 3
• IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims description 2
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
• 125000004432 carbon atom Chemical group C* 0.000 claims description 2
• 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 2
• 229940079593 drug Drugs 0.000 claims description 2
• 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 2
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
• 125000005368 heteroarylthio group Chemical group 0.000 claims description 2
• 125000000623 heterocyclic group Chemical group 0.000 claims description 2
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 2
• 239000001257 hydrogen Substances 0.000 claims description 2
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
• 239000001301 oxygen Substances 0.000 claims description 2
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims 6
• DVQPRDGEQIHFRR-QFUJRKBSSA-N (1r,2r)-2-[[2-amino-5-(4-chlorophenoxy)pyrimidin-4-yl]amino]cyclohexan-1-ol;(1s,3s)-3-[[2-amino-5-(4-chlorophenoxy)pyrimidin-4-yl]amino]cyclohexan-1-ol Chemical compound N([C@@H]1C[C@@H](O)CCC1)C1=NC(N)=NC=C1OC1=CC=C(Cl)C=C1.N([C@H]1[C@@H](CCCC1)O)C1=NC(N)=NC=C1OC1=CC=C(Cl)C=C1 DVQPRDGEQIHFRR-QFUJRKBSSA-N 0.000 claims 1
• NSKRLHPZTXHKTO-MQSLJWAISA-N (1s,2s)-2-[[[2-amino-5-(4-chlorophenoxy)pyrimidin-4-yl]amino]methyl]cyclohexan-1-ol;(1r,3s)-3-[[[2-amino-5-(4-chlorophenoxy)pyrimidin-4-yl]amino]methyl]cyclohexan-1-ol Chemical compound C([C@@H]1C[C@H](O)CCC1)NC1=NC(N)=NC=C1OC1=CC=C(Cl)C=C1.C([C@H]1[C@H](CCCC1)O)NC1=NC(N)=NC=C1OC1=CC=C(Cl)C=C1 NSKRLHPZTXHKTO-MQSLJWAISA-N 0.000 claims 1
• 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims 1
• VMHGQVJUJVBTPM-UHFFFAOYSA-N 1-[2-amino-5-[(4-bromo-2-chlorophenyl)methyl]pyrimidin-4-yl]piperidin-3-one 1-[2-amino-5-[[2-chloro-4-(trifluoromethyl)phenyl]methyl]pyrimidin-4-yl]piperidin-3-one Chemical compound NC1=NC=C(C(=N1)N1CC(CCC1)=O)CC1=C(C=C(C=C1)C(F)(F)F)Cl.NC1=NC=C(C(=N1)N1CC(CCC1)=O)CC1=C(C=C(C=C1)Br)Cl VMHGQVJUJVBTPM-UHFFFAOYSA-N 0.000 claims 1
• VTSNHLYTVKXWGU-UHFFFAOYSA-N 4-[[2-amino-5-(4-chlorophenoxy)pyrimidin-4-yl]amino]-3-methylphenol [4-[[2-amino-5-(4-chlorophenoxy)pyrimidin-4-yl]amino]phenyl] acetate Chemical compound C(C)(=O)OC1=CC=C(NC2=NC(=NC=C2OC2=CC=C(C=C2)Cl)N)C=C1.NC1=NC=C(C(=N1)NC1=C(C=C(C=C1)O)C)OC1=CC=C(C=C1)Cl VTSNHLYTVKXWGU-UHFFFAOYSA-N 0.000 claims 1
• UFSPXXMLIZPAOR-UHFFFAOYSA-N 4-[[2-amino-5-(4-chlorophenoxy)pyrimidin-4-yl]amino]phenol Chemical compound C=1C=C(O)C=CC=1NC1=NC(N)=NC=C1OC1=CC=C(Cl)C=C1 UFSPXXMLIZPAOR-UHFFFAOYSA-N 0.000 claims 1
• IMLXLGZJLAOKJN-UHFFFAOYSA-N 4-aminocyclohexan-1-ol Chemical compound NC1CCC(O)CC1 IMLXLGZJLAOKJN-UHFFFAOYSA-N 0.000 claims 1
• REHKNLZJFYVCKC-UIUABNLFSA-N ClC1=C(OC=2C(=NC=NC2)N[C@@H]2CC[C@H](CC2)O)C=CC(=C1)Cl.C(C)C1=CC=C(OC=2C(=NC=NC2)N[C@@H]2CC[C@H](CC2)O)C=C1 Chemical compound ClC1=C(OC=2C(=NC=NC2)N[C@@H]2CC[C@H](CC2)O)C=CC(=C1)Cl.C(C)C1=CC=C(OC=2C(=NC=NC2)N[C@@H]2CC[C@H](CC2)O)C=C1 REHKNLZJFYVCKC-UIUABNLFSA-N 0.000 claims 1
• LMYCXDZHZVEFFL-JJQWWBAOSA-N ClC1=CC(=C(OC=2C(=NC=NC2)N[C@@H]2CC[C@H](CC2)O)C=C1)F.O[C@@H]1CC[C@H](CC1)NC1=NC=NC=C1OC1=CC=C(C=C1)C(F)(F)F Chemical compound ClC1=CC(=C(OC=2C(=NC=NC2)N[C@@H]2CC[C@H](CC2)O)C=C1)F.O[C@@H]1CC[C@H](CC1)NC1=NC=NC=C1OC1=CC=C(C=C1)C(F)(F)F LMYCXDZHZVEFFL-JJQWWBAOSA-N 0.000 claims 1
• NRFQBXGMMBISQV-ACMTZBLWSA-N ClC1=CC=C(OC=2C(=NC=NC2)NCCO)C=C1.ClC1=CC=C(OC=2C(=NC=NC2)NC[C@H]2[C@@H](C2)CO)C=C1 Chemical compound ClC1=CC=C(OC=2C(=NC=NC2)NCCO)C=C1.ClC1=CC=C(OC=2C(=NC=NC2)NC[C@H]2[C@@H](C2)CO)C=C1 NRFQBXGMMBISQV-ACMTZBLWSA-N 0.000 claims 1
• SGGJQOGKIOSERG-QVMLEOCLSA-N ClC1=CC=C(OC=2C(=NC=NC2)N[C@H]2[C@@H](CCC2)CO)C=C1.ClC1=CC=C(OC=2C(=NC=NC2)N[C@@H]2C[C@H](CC2)CO)C=C1 Chemical compound ClC1=CC=C(OC=2C(=NC=NC2)N[C@H]2[C@@H](CCC2)CO)C=C1.ClC1=CC=C(OC=2C(=NC=NC2)N[C@@H]2C[C@H](CC2)CO)C=C1 SGGJQOGKIOSERG-QVMLEOCLSA-N 0.000 claims 1
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