JP2008510006A - 化合物 - Google Patents

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Publication number

JP2008510006A

JP2008510006A JP2007527895A JP2007527895A JP2008510006A JP 2008510006 A JP2008510006 A JP 2008510006A JP 2007527895 A JP2007527895 A JP 2007527895A JP 2007527895 A JP2007527895 A JP 2007527895A JP 2008510006 A JP2008510006 A JP 2008510006A

Authority

JP

Japan

Prior art keywords

methyl

tetrahydro

benzimidazol

het

alkyl

Prior art date

2004-08-16

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.)

Pending

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 278
• 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 claims abstract description 24
• 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims abstract description 24
• 208000031886 HIV Infections Diseases 0.000 claims abstract description 21
• 208000037357 HIV infectious disease Diseases 0.000 claims abstract description 21
• 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims abstract description 21
• 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 cyano Nitro Chemical class 0.000 claims description 169
• 125000000217 alkyl group Chemical group 0.000 claims description 164
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 119
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 84
• 150000001412 amines Chemical class 0.000 claims description 78
• 125000003342 alkenyl group Chemical group 0.000 claims description 74
• 125000000304 alkynyl group Chemical group 0.000 claims description 74
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 66
• 125000001188 haloalkyl group Chemical group 0.000 claims description 62
• 239000002253 acid Substances 0.000 claims description 45
• 239000000203 mixture Substances 0.000 claims description 41
• 238000011282 treatment Methods 0.000 claims description 41
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 39
• 150000003839 salts Chemical class 0.000 claims description 39
• 238000000034 method Methods 0.000 claims description 38
• 229910052736 halogen Inorganic materials 0.000 claims description 33
• 150000002367 halogens Chemical class 0.000 claims description 33
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 33
• 239000000126 substance Substances 0.000 claims description 33
• 229910052739 hydrogen Inorganic materials 0.000 claims description 32
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 30
• 208000026935 allergic disease Diseases 0.000 claims description 28
• 206010020751 Hypersensitivity Diseases 0.000 claims description 27
• 201000010099 disease Diseases 0.000 claims description 26
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
• 150000003973 alkyl amines Chemical class 0.000 claims description 22
• 239000008194 pharmaceutical composition Substances 0.000 claims description 22
• 230000009610 hypersensitivity Effects 0.000 claims description 21
• 206010061218 Inflammation Diseases 0.000 claims description 19
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
• 230000004054 inflammatory process Effects 0.000 claims description 19
• 201000004624 Dermatitis Diseases 0.000 claims description 18
• 150000001540 azides Chemical class 0.000 claims description 18
• 125000002993 cycloalkylene group Chemical group 0.000 claims description 17
• 125000000623 heterocyclic group Chemical group 0.000 claims description 17
• LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 16
• 125000002947 alkylene group Chemical group 0.000 claims description 16
• 150000002148 esters Chemical class 0.000 claims description 16
• 238000006268 reductive amination reaction Methods 0.000 claims description 16
• 208000029523 Interstitial Lung disease Diseases 0.000 claims description 15
• 125000005724 cycloalkenylene group Chemical group 0.000 claims description 15
• 239000003814 drug Substances 0.000 claims description 15
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• 125000004450 alkenylene group Chemical group 0.000 claims description 14
• 125000004419 alkynylene group Chemical group 0.000 claims description 14
• 125000001072 heteroaryl group Chemical group 0.000 claims description 14
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• 206010028980 Neoplasm Diseases 0.000 claims description 13
• 125000003545 alkoxy group Chemical group 0.000 claims description 13
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• 230000000694 effects Effects 0.000 claims description 13
• AIVVNDNIWAQWOH-UHFFFAOYSA-N n-methyl-n-[(4-piperazin-1-yl-1h-benzimidazol-2-yl)methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CCC2=CC=CN=C2C1N(C)CC(NC1=CC=C2)=NC1=C2N1CCNCC1 AIVVNDNIWAQWOH-UHFFFAOYSA-N 0.000 claims description 13
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
• 238000004519 manufacturing process Methods 0.000 claims description 12
• 239000003112 inhibitor Substances 0.000 claims description 11
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 11
• 206010047115 Vasculitis Diseases 0.000 claims description 10
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
• FTIUDAIKGCFJLJ-UHFFFAOYSA-N (3-aminopyrrolidin-1-yl)-[2-[[methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl]-1h-benzimidazol-4-yl]methanone Chemical compound C1CCC2=CC=CN=C2C1N(C)CC(NC1=CC=C2)=NC1=C2C(=O)N1CCC(N)C1 FTIUDAIKGCFJLJ-UHFFFAOYSA-N 0.000 claims description 9
• 125000003282 alkyl amino group Chemical group 0.000 claims description 9
• 230000007815 allergy Effects 0.000 claims description 9
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
• 125000003107 substituted aryl group Chemical group 0.000 claims description 9
• NACDDZQXTMQNSA-UHFFFAOYSA-N (4-aminopiperidin-1-yl)-[2-[[methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl]-1h-benzimidazol-4-yl]methanone Chemical compound C1CCC2=CC=CN=C2C1N(C)CC(NC1=CC=C2)=NC1=C2C(=O)N1CCC(N)CC1 NACDDZQXTMQNSA-UHFFFAOYSA-N 0.000 claims description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
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• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 8
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• XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 7
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• 206010018364 Glomerulonephritis Diseases 0.000 claims description 7
• 208000009329 Graft vs Host Disease Diseases 0.000 claims description 7
• 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 7
• 241000238631 Hexapoda Species 0.000 claims description 7
• 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 7
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• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 7
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• 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 7
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• 208000022362 bacterial infectious disease Diseases 0.000 claims description 7
• 238000002512 chemotherapy Methods 0.000 claims description 7
• 201000005311 drug allergy Diseases 0.000 claims description 7
• 201000009580 eosinophilic pneumonia Diseases 0.000 claims description 7
• 208000024908 graft versus host disease Diseases 0.000 claims description 7
• 230000011132 hemopoiesis Effects 0.000 claims description 7
• 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 7
• 230000001404 mediated effect Effects 0.000 claims description 7
• 206010028417 myasthenia gravis Diseases 0.000 claims description 7
• RSCQVCDQCNRTNS-UHFFFAOYSA-N n-[2-(1h-imidazol-5-yl)ethyl]-1-methyl-2-[[methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl]benzimidazole-4-carboxamide Chemical compound C1CCC2=CC=CN=C2C1N(C)CC(N(C1=CC=C2)C)=NC1=C2C(=O)NCCC1=CNC=N1 RSCQVCDQCNRTNS-UHFFFAOYSA-N 0.000 claims description 7
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• 230000029663 wound healing Effects 0.000 claims description 7
• JEHABMXQHSEKPF-NRFANRHFSA-N (8s)-n-[[1-ethyl-7-(4-methylpiperazin-1-yl)benzimidazol-2-yl]methyl]-n-methyl-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C=12N(CC)C(CN(C)[C@@H]3C4=NC=CC=C4CCC3)=NC2=CC=CC=1N1CCN(C)CC1 JEHABMXQHSEKPF-NRFANRHFSA-N 0.000 claims description 6
• GJJZPHWMEXPWCE-MHZLTWQESA-N (8s)-n-benzyl-n-[[1-ethyl-7-(4-methylpiperazin-1-yl)benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound N=1C2=CC=CC(N3CCN(C)CC3)=C2N(CC)C=1CN([C@@H]1C2=NC=CC=C2CCC1)CC1=CC=CC=C1 GJJZPHWMEXPWCE-MHZLTWQESA-N 0.000 claims description 6
• WMXSCDKRBQLQHT-QFIPXVFZSA-N (8s)-n-ethyl-n-[[1-ethyl-7-(4-methylpiperazin-1-yl)benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound CCN([C@@H]1C2=NC=CC=C2CCC1)CC(N(C1=2)CC)=NC1=CC=CC=2N1CCN(C)CC1 WMXSCDKRBQLQHT-QFIPXVFZSA-N 0.000 claims description 6
• UQUSGFGEARIPEG-IBGZPJMESA-N (8s)-n-methyl-n-[(1-methyl-7-piperazin-1-ylbenzimidazol-2-yl)methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound CN([C@@H]1C2=NC=CC=C2CCC1)CC(N(C1=2)C)=NC1=CC=CC=2N1CCNCC1 UQUSGFGEARIPEG-IBGZPJMESA-N 0.000 claims description 6
• JKAGHWHIEIKQQE-FQEVSTJZSA-N (8s)-n-methyl-n-[[1-methyl-7-(4-methylpiperazin-1-yl)benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound CN([C@@H]1C2=NC=CC=C2CCC1)CC(N(C1=2)C)=NC1=CC=CC=2N1CCN(C)CC1 JKAGHWHIEIKQQE-FQEVSTJZSA-N 0.000 claims description 6
• BDERNNFJNOPAEC-UHFFFAOYSA-N 1-propanol Substances CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
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• 206010052779 Transplant rejections Diseases 0.000 claims description 6
• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 6
• WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 claims description 6
• 201000009564 autosomal recessive limb-girdle muscular dystrophy type 2A Diseases 0.000 claims description 6
• 210000001185 bone marrow Anatomy 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
• WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 claims description 6
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• DWASOSKRUBULNA-UHFFFAOYSA-N n-(2-aminoethyl)-2-[[methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl]-1h-benzimidazole-4-carboxamide Chemical compound C1CCC2=CC=CN=C2C1N(C)CC1=NC2=C(C(=O)NCCN)C=CC=C2N1 DWASOSKRUBULNA-UHFFFAOYSA-N 0.000 claims description 6
• UOGDWUJAQURVRZ-UHFFFAOYSA-N n-(cyclopropylmethyl)-n-[[1-methyl-7-(4-methylpiperazin-1-yl)benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CN(C)CCN1C1=CC=CC2=C1N(C)C(CN(CC1CC1)C1C3=NC=CC=C3CCC1)=N2 UOGDWUJAQURVRZ-UHFFFAOYSA-N 0.000 claims description 6
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• VLMHVPDHRBQBED-UHFFFAOYSA-N n-[2-(1h-imidazol-5-yl)ethyl]-2-[[methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino]methyl]-1h-benzimidazole-4-carboxamide Chemical compound C1CCC2=CC=CN=C2C1N(C)CC(NC1=CC=C2)=NC1=C2C(=O)NCCC1=CNC=N1 VLMHVPDHRBQBED-UHFFFAOYSA-N 0.000 claims description 6
• PHRYNVIBEQXSSX-UHFFFAOYSA-N n-[[1-methyl-7-(4-methylpiperazin-1-yl)benzimidazol-2-yl]methyl]-n-propyl-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CCC2=CC=CN=C2C1N(CCC)CC(N(C1=2)C)=NC1=CC=CC=2N1CCN(C)CC1 PHRYNVIBEQXSSX-UHFFFAOYSA-N 0.000 claims description 6
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• HOTFDACOUFWRFX-UHFFFAOYSA-N n-methyl-n-[[4-(piperazin-1-ylmethyl)-1h-benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CCC2=CC=CN=C2C1N(C)CC(NC1=CC=C2)=NC1=C2CN1CCNCC1 HOTFDACOUFWRFX-UHFFFAOYSA-N 0.000 claims description 6
• NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 claims description 6
• NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
• JKAGHWHIEIKQQE-HXUWFJFHSA-N (8r)-n-methyl-n-[[1-methyl-7-(4-methylpiperazin-1-yl)benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound CN([C@H]1C2=NC=CC=C2CCC1)CC(N(C1=2)C)=NC1=CC=CC=2N1CCN(C)CC1 JKAGHWHIEIKQQE-HXUWFJFHSA-N 0.000 claims description 5
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• TYTCWJIKJIONKI-QFIPXVFZSA-N (8s)-n-(cyclopropylmethyl)-n-[[4-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]methyl]-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1CN(C)CCN1C1=CC=CC2=C1N=C(CN(CC1CC1)[C@@H]1C3=NC=CC=C3CCC1)N2 TYTCWJIKJIONKI-QFIPXVFZSA-N 0.000 claims description 4
• XILRUNRCEGYBHT-QFIPXVFZSA-N (8s)-n-[[4-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]methyl]-n-propan-2-yl-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound CC(C)N([C@@H]1C2=NC=CC=C2CCC1)CC(NC1=CC=C2)=NC1=C2N1CCN(C)CC1 XILRUNRCEGYBHT-QFIPXVFZSA-N 0.000 claims description 4
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