JP2008508357A - 化学的化合物 - Google Patents

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Publication number

JP2008508357A

JP2008508357A JP2007524853A JP2007524853A JP2008508357A JP 2008508357 A JP2008508357 A JP 2008508357A JP 2007524853 A JP2007524853 A JP 2007524853A JP 2007524853 A JP2007524853 A JP 2007524853A JP 2008508357 A JP2008508357 A JP 2008508357A

Authority

JP

Japan

Prior art keywords

methyl

tetrahydro

benzimidazol

quinolinamine

het

Prior art date

2004-08-02

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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• 150000001875 compounds Chemical class 0.000 title claims abstract description 227
• 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 claims abstract description 25
• 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims abstract description 25
• 208000031886 HIV Infections Diseases 0.000 claims abstract description 19
• 208000037357 HIV infectious disease Diseases 0.000 claims abstract description 19
• 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims abstract description 19
• 102000009410 Chemokine receptor Human genes 0.000 claims abstract description 17
• 108050000299 Chemokine receptor Proteins 0.000 claims abstract description 17
• 101710149870 C-C chemokine receptor type 5 Proteins 0.000 claims abstract description 13
• 102100035875 C-C chemokine receptor type 5 Human genes 0.000 claims abstract description 13
• -1 2-{[methyl (5,6,7,8-tetrahydro-8-quinolinyl) amino] methyl} -1H-benzimidazol-1-yl Chemical group 0.000 claims description 227
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 150
• 239000000203 mixture Substances 0.000 claims description 121
• 125000000217 alkyl group Chemical group 0.000 claims description 81
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 73
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 61
• 238000000034 method Methods 0.000 claims description 59
• 125000003342 alkenyl group Chemical group 0.000 claims description 56
• 125000000304 alkynyl group Chemical group 0.000 claims description 56
• 239000003814 drug Substances 0.000 claims description 35
• 150000003839 salts Chemical class 0.000 claims description 35
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 33
• 229910052736 halogen Inorganic materials 0.000 claims description 31
• 150000002367 halogens Chemical class 0.000 claims description 31
• 125000001188 haloalkyl group Chemical group 0.000 claims description 30
• 150000001412 amines Chemical class 0.000 claims description 29
• 201000010099 disease Diseases 0.000 claims description 28
• 239000012453 solvate Substances 0.000 claims description 24
• ICASOSHOAZDLCQ-CKOJHNACSA-N (8s)-n-methyl-n-[[1-[[(3s)-1-[[(2r)-1-methylpyrrolidin-2-yl]methyl]piperidin-3-yl]methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C([C@@H](C1)CN2C3=CC=CC=C3N=C2CN(C)[C@@H]2C3=NC=CC=C3CCC2)CCN1C[C@H]1CCCN1C ICASOSHOAZDLCQ-CKOJHNACSA-N 0.000 claims description 23
• 125000003118 aryl group Chemical group 0.000 claims description 23
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 23
• 125000001072 heteroaryl group Chemical group 0.000 claims description 23
• XHRXIYNWBWPAAC-AVRDEDQJSA-N (8s)-n-methyl-n-[[1-[[(3s)-piperidin-3-yl]methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound CN([C@@H]1C2=NC=CC=C2CCC1)CC1=NC2=CC=CC=C2N1C[C@H]1CCCNC1 XHRXIYNWBWPAAC-AVRDEDQJSA-N 0.000 claims description 22
• 229940079593 drug Drugs 0.000 claims description 22
• 239000008194 pharmaceutical composition Substances 0.000 claims description 22
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• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 20
• 150000003973 alkyl amines Chemical class 0.000 claims description 20
• 208000026935 allergic disease Diseases 0.000 claims description 20
• 125000000623 heterocyclic group Chemical group 0.000 claims description 20
• 125000002883 imidazolyl group Chemical group 0.000 claims description 19
• UPBCAKKETXMWBJ-UHFFFAOYSA-N n-[[1-(3-aminopropyl)benzimidazol-2-yl]methyl]-n-methyl-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CCC2=CC=CN=C2C1N(C)CC1=NC2=CC=CC=C2N1CCCN UPBCAKKETXMWBJ-UHFFFAOYSA-N 0.000 claims description 19
• VETGEHMWKIZMPG-UHFFFAOYSA-N n-methyl-n-[[1-[(1-methylpiperidin-3-yl)methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CCC2=CC=CN=C2C1N(C)CC1=NC2=CC=CC=C2N1CC1CCCN(C)C1 VETGEHMWKIZMPG-UHFFFAOYSA-N 0.000 claims description 19
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
• 206010061218 Inflammation Diseases 0.000 claims description 16
• 239000003795 chemical substances by application Substances 0.000 claims description 16
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
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• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
• 208000029523 Interstitial Lung disease Diseases 0.000 claims description 15
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
• 230000008569 process Effects 0.000 claims description 15
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• 206010047115 Vasculitis Diseases 0.000 claims description 14
• 150000001540 azides Chemical class 0.000 claims description 14
• OQMAUHRSKCHLHU-UHFFFAOYSA-N n-methyl-n-[[1-(pyridin-3-ylmethyl)benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CCC2=CC=CN=C2C1N(C)CC1=NC2=CC=CC=C2N1CC1=CC=CN=C1 OQMAUHRSKCHLHU-UHFFFAOYSA-N 0.000 claims description 14
• 238000006268 reductive amination reaction Methods 0.000 claims description 14
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 14
• 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 14
• VETGEHMWKIZMPG-CVDCTZTESA-N (8s)-n-methyl-n-[[1-[[(3s)-1-methylpiperidin-3-yl]methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound CN([C@@H]1C2=NC=CC=C2CCC1)CC1=NC2=CC=CC=C2N1C[C@H]1CCCN(C)C1 VETGEHMWKIZMPG-CVDCTZTESA-N 0.000 claims description 13
• 206010028980 Neoplasm Diseases 0.000 claims description 13
• 239000002253 acid Substances 0.000 claims description 13
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• 230000000694 effects Effects 0.000 claims description 13
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• 230000002265 prevention Effects 0.000 claims description 13
• 125000002947 alkylene group Chemical group 0.000 claims description 12
• 125000005724 cycloalkenylene group Chemical group 0.000 claims description 12
• 125000002993 cycloalkylene group Chemical group 0.000 claims description 12
• XHRXIYNWBWPAAC-GCJKJVERSA-N (8s)-n-methyl-n-[[1-[[(3r)-piperidin-3-yl]methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound CN([C@@H]1C2=NC=CC=C2CCC1)CC1=NC2=CC=CC=C2N1C[C@@H]1CCCNC1 XHRXIYNWBWPAAC-GCJKJVERSA-N 0.000 claims description 11
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 11
• 125000004450 alkenylene group Chemical group 0.000 claims description 11
• 125000004419 alkynylene group Chemical group 0.000 claims description 11
• ASCHSOKJVZUWMP-UHFFFAOYSA-N n-[[1-(3-aminopropyl)benzimidazol-2-yl]methyl]-n-ethyl-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CCC2=CC=CN=C2C1N(CC)CC1=NC2=CC=CC=C2N1CCCN ASCHSOKJVZUWMP-UHFFFAOYSA-N 0.000 claims description 11
• SIQJINIEOSWWSC-UHFFFAOYSA-N n-methyl-n-[[1-(piperidin-4-ylmethyl)benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CCC2=CC=CN=C2C1N(C)CC1=NC2=CC=CC=C2N1CC1CCNCC1 SIQJINIEOSWWSC-UHFFFAOYSA-N 0.000 claims description 11
• NTSBJKADBVYMSM-UHFFFAOYSA-N n-methyl-n-[[1-[(1-methylpyrrolidin-3-yl)methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CCC2=CC=CN=C2C1N(C)CC1=NC2=CC=CC=C2N1CC1CCN(C)C1 NTSBJKADBVYMSM-UHFFFAOYSA-N 0.000 claims description 11
• OVVVPNSGDFVCAW-HOFKKMOUSA-N (8s)-n-[[1-[[(3s)-1-propan-2-ylpiperidin-3-yl]methyl]benzimidazol-2-yl]methyl]-n-propyl-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound CCCN([C@@H]1C2=NC=CC=C2CCC1)CC1=NC2=CC=CC=C2N1C[C@H]1CCCN(C(C)C)C1 OVVVPNSGDFVCAW-HOFKKMOUSA-N 0.000 claims description 10
• QSKQVYGGIODIIN-BWKNWUBXSA-N (8s)-n-methyl-n-[[1-[[(3r)-1-propan-2-ylpiperidin-3-yl]methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1N(C(C)C)CCC[C@H]1CN1C2=CC=CC=C2N=C1CN(C)[C@@H]1C2=NC=CC=C2CCC1 QSKQVYGGIODIIN-BWKNWUBXSA-N 0.000 claims description 10
• SUVTXSXXZWCMHL-NVQXNPDNSA-N (8s)-n-methyl-n-[[1-[[(3s)-1-(2-methylpropyl)piperidin-3-yl]methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1N(CC(C)C)CCC[C@@H]1CN1C2=CC=CC=C2N=C1CN(C)[C@@H]1C2=NC=CC=C2CCC1 SUVTXSXXZWCMHL-NVQXNPDNSA-N 0.000 claims description 10
• JEPDGRCNPREMJT-UHFFFAOYSA-N n-[[1-[3-(dimethylamino)propyl]benzimidazol-2-yl]methyl]-n-methyl-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1=CC=C2N(CCCN(C)C)C(CN(C)C3C4=NC=CC=C4CCC3)=NC2=C1 JEPDGRCNPREMJT-UHFFFAOYSA-N 0.000 claims description 10
• IBMXMPNDZLRVME-UHFFFAOYSA-N n-methyl-n-[[1-[(1-methylazetidin-3-yl)methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CCC2=CC=CN=C2C1N(C)CC1=NC2=CC=CC=C2N1CC1CN(C)C1 IBMXMPNDZLRVME-UHFFFAOYSA-N 0.000 claims description 10
• QSKQVYGGIODIIN-PXDATVDWSA-N (8r)-n-methyl-n-[[1-[[(3r)-1-propan-2-ylpiperidin-3-yl]methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1N(C(C)C)CCC[C@H]1CN1C2=CC=CC=C2N=C1CN(C)[C@H]1C2=NC=CC=C2CCC1 QSKQVYGGIODIIN-PXDATVDWSA-N 0.000 claims description 9
• VETGEHMWKIZMPG-WMZHIEFXSA-N (8r)-n-methyl-n-[[1-[[(3s)-1-methylpiperidin-3-yl]methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound CN([C@H]1C2=NC=CC=C2CCC1)CC1=NC2=CC=CC=C2N1C[C@H]1CCCN(C)C1 VETGEHMWKIZMPG-WMZHIEFXSA-N 0.000 claims description 9
• MFZFCJAAAVWRCZ-OFVILXPXSA-N (8s)-n-[[1-[[(3s)-1-methylpiperidin-3-yl]methyl]benzimidazol-2-yl]methyl]-n-propyl-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound CCCN([C@@H]1C2=NC=CC=C2CCC1)CC1=NC2=CC=CC=C2N1C[C@H]1CCCN(C)C1 MFZFCJAAAVWRCZ-OFVILXPXSA-N 0.000 claims description 9
• VETGEHMWKIZMPG-XXBNENTESA-N (8s)-n-methyl-n-[[1-[[(3r)-1-methylpiperidin-3-yl]methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound CN([C@@H]1C2=NC=CC=C2CCC1)CC1=NC2=CC=CC=C2N1C[C@@H]1CCCN(C)C1 VETGEHMWKIZMPG-XXBNENTESA-N 0.000 claims description 9
• KNNLCWNQAVHYHR-FIPFOOKPSA-N (8s)-n-methyl-n-[[1-[[(3s)-1-(pyridin-2-ylmethyl)piperidin-3-yl]methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C([C@@H](C1)CN2C3=CC=CC=C3N=C2CN(C)[C@@H]2C3=NC=CC=C3CCC2)CCN1CC1=CC=CC=N1 KNNLCWNQAVHYHR-FIPFOOKPSA-N 0.000 claims description 9
• JSIVRGPWVYZZRY-RDPSFJRHSA-N 2-[[1-[[(3s)-1-methylpiperidin-3-yl]methyl]benzimidazol-2-yl]methyl-[(8s)-5,6,7,8-tetrahydroquinolin-8-yl]amino]ethanol Chemical compound C1N(C)CCC[C@@H]1CN1C2=CC=CC=C2N=C1CN(CCO)[C@@H]1C2=NC=CC=C2CCC1 JSIVRGPWVYZZRY-RDPSFJRHSA-N 0.000 claims description 9
• USAIXVIEVCGFRQ-NVQXNPDNSA-N 2-[[1-[[(3s)-1-propan-2-ylpiperidin-3-yl]methyl]benzimidazol-2-yl]methyl-[(8s)-5,6,7,8-tetrahydroquinolin-8-yl]amino]ethanol Chemical compound C1N(C(C)C)CCC[C@@H]1CN1C2=CC=CC=C2N=C1CN(CCO)[C@@H]1C2=NC=CC=C2CCC1 USAIXVIEVCGFRQ-NVQXNPDNSA-N 0.000 claims description 9
• PXSYBAMOAXOVKV-OFVILXPXSA-N 3-[[1-[[(3s)-1-methylpiperidin-3-yl]methyl]benzimidazol-2-yl]methyl-[(8s)-5,6,7,8-tetrahydroquinolin-8-yl]amino]propan-1-ol Chemical compound C1N(C)CCC[C@@H]1CN1C2=CC=CC=C2N=C1CN(CCCO)[C@@H]1C2=NC=CC=C2CCC1 PXSYBAMOAXOVKV-OFVILXPXSA-N 0.000 claims description 9
• 229910052739 hydrogen Inorganic materials 0.000 claims description 9
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• HEPWOFBXMDSUEO-UHFFFAOYSA-N n-[[1-(3-aminopropyl)benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1=CC=C2N(CCCN)C(CNC3C4=NC=CC=C4CCC3)=NC2=C1 HEPWOFBXMDSUEO-UHFFFAOYSA-N 0.000 claims description 9
• AMJRGYWDPGQUFD-SREVYHEPSA-N n-[[1-[(z)-4-(dimethylamino)but-2-enyl]benzimidazol-2-yl]methyl]-n-methyl-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1=CC=C2N(C\C=C/CN(C)C)C(CN(C)C3C4=NC=CC=C4CCC3)=NC2=C1 AMJRGYWDPGQUFD-SREVYHEPSA-N 0.000 claims description 9
• FFROZRURSWKTSQ-UHFFFAOYSA-N n-methyl-n-[[1-(1-methylpiperidin-4-yl)benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CCC2=CC=CN=C2C1N(C)CC1=NC2=CC=CC=C2N1C1CCN(C)CC1 FFROZRURSWKTSQ-UHFFFAOYSA-N 0.000 claims description 9
• GHZOBXUUQBAKHP-HOFKKMOUSA-N (8s)-n-methyl-n-[[1-[[(3s)-1-(3-methylbutyl)piperidin-3-yl]methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1N(CCC(C)C)CCC[C@@H]1CN1C2=CC=CC=C2N=C1CN(C)[C@@H]1C2=NC=CC=C2CCC1 GHZOBXUUQBAKHP-HOFKKMOUSA-N 0.000 claims description 8
• QSKQVYGGIODIIN-OFVILXPXSA-N (8s)-n-methyl-n-[[1-[[(3s)-1-propan-2-ylpiperidin-3-yl]methyl]benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1N(C(C)C)CCC[C@@H]1CN1C2=CC=CC=C2N=C1CN(C)[C@@H]1C2=NC=CC=C2CCC1 QSKQVYGGIODIIN-OFVILXPXSA-N 0.000 claims description 8
• LILSBXJJIIFDGR-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinolin-8-amine Chemical compound C1CCNC2=C1C=CC=C2N LILSBXJJIIFDGR-UHFFFAOYSA-N 0.000 claims description 8
• OGKYHMHLZSDZND-RDPSFJRHSA-N 2-[(3s)-3-[[2-[[methyl-[(8s)-5,6,7,8-tetrahydroquinolin-8-yl]amino]methyl]benzimidazol-1-yl]methyl]piperidin-1-yl]ethanol Chemical compound CN([C@@H]1C2=NC=CC=C2CCC1)CC1=NC2=CC=CC=C2N1C[C@H]1CCCN(CCO)C1 OGKYHMHLZSDZND-RDPSFJRHSA-N 0.000 claims description 8
• ZGXWKJJTZYBTPX-OFVILXPXSA-N 3-[(3s)-3-[[2-[[methyl-[(8s)-5,6,7,8-tetrahydroquinolin-8-yl]amino]methyl]benzimidazol-1-yl]methyl]piperidin-1-yl]propan-1-ol Chemical compound CN([C@@H]1C2=NC=CC=C2CCC1)CC1=NC2=CC=CC=C2N1C[C@H]1CCCN(CCCO)C1 ZGXWKJJTZYBTPX-OFVILXPXSA-N 0.000 claims description 8
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• CGEYSKSKPCRPDK-UHFFFAOYSA-N n-methyl-n-[[1-(2-piperidin-1-ylethyl)benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CCC2=CC=CN=C2C1N(C)CC1=NC2=CC=CC=C2N1CCN1CCCCC1 CGEYSKSKPCRPDK-UHFFFAOYSA-N 0.000 claims description 8
• CEZDJMFFDIZREC-UHFFFAOYSA-N n-methyl-n-[[1-(2-piperidin-2-ylethyl)benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CCC2=CC=CN=C2C1N(C)CC1=NC2=CC=CC=C2N1CCC1CCCCN1 CEZDJMFFDIZREC-UHFFFAOYSA-N 0.000 claims description 8
• LJLXFECAEZYHOF-UHFFFAOYSA-N n-methyl-n-[[1-(pyrrolidin-3-ylmethyl)benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CCC2=CC=CN=C2C1N(C)CC1=NC2=CC=CC=C2N1CC1CCNC1 LJLXFECAEZYHOF-UHFFFAOYSA-N 0.000 claims description 8
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