JP2010503682A - レニン阻害剤としてのピペリジン誘導体 - Google Patents

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Publication number

JP2010503682A

JP2010503682A JP2009528319A JP2009528319A JP2010503682A JP 2010503682 A JP2010503682 A JP 2010503682A JP 2009528319 A JP2009528319 A JP 2009528319A JP 2009528319 A JP2009528319 A JP 2009528319A JP 2010503682 A JP2010503682 A JP 2010503682A

Authority

JP

Japan

Prior art keywords

methyl

tert

butyl

carboxylate

pyran

Prior art date

2006-09-18

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.)

Withdrawn

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• 239000002461 renin inhibitor Substances 0.000 title description 16
• 229940086526 renin-inhibitors Drugs 0.000 title description 16
• 150000003053 piperidines Chemical class 0.000 title 1
• 150000003839 salts Chemical class 0.000 claims abstract description 51
• 238000000034 method Methods 0.000 claims abstract description 47
• 108091005502 Aspartic proteases Proteins 0.000 claims abstract description 22
• 102000035101 Aspartic proteases Human genes 0.000 claims abstract description 22
• 230000001404 mediated effect Effects 0.000 claims abstract description 9
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
• -1 methyl compound Chemical class 0.000 claims description 113
• 150000001875 compounds Chemical class 0.000 claims description 63
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 52
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 50
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
• 125000000217 alkyl group Chemical group 0.000 claims description 16
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 14
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 14
• 239000003795 chemical substances by application Substances 0.000 claims description 13
• 229910052801 chlorine Inorganic materials 0.000 claims description 12
• 208000035475 disorder Diseases 0.000 claims description 12
• 229910052731 fluorine Inorganic materials 0.000 claims description 12
• 239000005541 ACE inhibitor Substances 0.000 claims description 10
• 206010020772 Hypertension Diseases 0.000 claims description 10
• 108090000783 Renin Proteins 0.000 claims description 10
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 10
• 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 10
• 229910052794 bromium Inorganic materials 0.000 claims description 9
• KNTZCGBYFGEMFR-UHFFFAOYSA-N (propan-2-ylazaniumyl)formate Chemical compound CC(C)NC(O)=O KNTZCGBYFGEMFR-UHFFFAOYSA-N 0.000 claims description 8
• 102100028255 Renin Human genes 0.000 claims description 8
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• 229940125364 angiotensin receptor blocker Drugs 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• 125000001188 haloalkyl group Chemical group 0.000 claims description 7
• 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 6
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
• 239000003085 diluting agent Substances 0.000 claims description 6
• 230000009977 dual effect Effects 0.000 claims description 6
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 6
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 5
• FZBZOIXHKQUVBU-KGLIPLIRSA-N 2-trimethylsilylethyl n-[(2s)-2-amino-3-[(3r)-oxan-3-yl]propyl]-n-methylcarbamate Chemical compound C[Si](C)(C)CCOC(=O)N(C)C[C@@H](N)C[C@H]1CCCOC1 FZBZOIXHKQUVBU-KGLIPLIRSA-N 0.000 claims description 5
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• YNTOKMNHRPSGFU-UHFFFAOYSA-N n-Propyl carbamate Chemical compound CCCOC(N)=O YNTOKMNHRPSGFU-UHFFFAOYSA-N 0.000 claims description 4
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• 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 claims description 2
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• 108010010369 HIV Protease Proteins 0.000 claims description 2
• 208000012902 Nervous system disease Diseases 0.000 claims description 2
• 229940030600 antihypertensive agent Drugs 0.000 claims description 2
• ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 claims description 2
• 230000029142 excretion Effects 0.000 claims description 2
• 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
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• 108010064733 Angiotensins Proteins 0.000 claims 2
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• 208000025966 Neurological disease Diseases 0.000 claims 1
• 230000008485 antagonism Effects 0.000 claims 1
• 230000001452 natriuretic effect Effects 0.000 claims 1
• 239000003696 aspartic proteinase inhibitor Substances 0.000 abstract description 86
• 229940092160 Aspartic protease inhibitor Drugs 0.000 abstract description 43
• OVIFHFRAOKPVPC-UHFFFAOYSA-N aspartic protease inhibitor Natural products CC(N)C(=O)NCC(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CC(O)=O)C(=O)NC(CC(O)=O)C(=O)NC(CC(O)=O)C(=O)NC(CC(O)=O)C(=O)N1CCCC1C(=O)N1C(C(=O)NC(CCC(O)=O)C(O)=O)CCC1 OVIFHFRAOKPVPC-UHFFFAOYSA-N 0.000 abstract description 43
• 239000000243 solution Substances 0.000 description 206
• 239000000203 mixture Substances 0.000 description 165
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 103
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
• 239000000460 chlorine Substances 0.000 description 92
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 76
• 239000011734 sodium Substances 0.000 description 75
• 239000011541 reaction mixture Substances 0.000 description 56
• 238000006243 chemical reaction Methods 0.000 description 52
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 51
• 235000019439 ethyl acetate Nutrition 0.000 description 50
• 239000012267 brine Substances 0.000 description 49
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 46
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• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 41
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• 239000012043 crude product Substances 0.000 description 32
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• DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 29
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• 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 23
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• CEMFUCYZRBNMRO-AEFFLSMTSA-N tert-butyl (3r)-3-[(r)-(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]piperidine-1-carboxylate Chemical compound C([C@H]1[C@@H](OCCNC(=O)OC)C=2C=C(Cl)C=CC=2)CCN(C(=O)OC(C)(C)C)C1 CEMFUCYZRBNMRO-AEFFLSMTSA-N 0.000 description 12
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