JP2007515476A - ケモカイン受容体活性のモジュレーターとしての新規三環式スピロ誘導体 - Google Patents
ケモカイン受容体活性のモジュレーターとしての新規三環式スピロ誘導体 Download PDFInfo
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- JP2007515476A JP2007515476A JP2006546906A JP2006546906A JP2007515476A JP 2007515476 A JP2007515476 A JP 2007515476A JP 2006546906 A JP2006546906 A JP 2006546906A JP 2006546906 A JP2006546906 A JP 2006546906A JP 2007515476 A JP2007515476 A JP 2007515476A
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- Prior art keywords
- amino
- alkyl
- spiro
- benzofuran
- piperidin
- Prior art date
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- 230000000694 effects Effects 0.000 title claims description 5
- 102000009410 Chemokine receptor Human genes 0.000 title claims description 4
- 108050000299 Chemokine receptor Proteins 0.000 title claims description 4
- 125000003003 spiro group Chemical group 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 125
- 238000000034 method Methods 0.000 claims abstract description 26
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 5
- -1 cyano, hydroxyl Chemical group 0.000 claims description 133
- 229910052736 halogen Inorganic materials 0.000 claims description 61
- 150000002367 halogens Chemical class 0.000 claims description 61
- 229910052757 nitrogen Inorganic materials 0.000 claims description 58
- 150000003839 salts Chemical class 0.000 claims description 42
- 125000001424 substituent group Chemical group 0.000 claims description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 34
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
- 239000012453 solvate Substances 0.000 claims description 26
- 125000004122 cyclic group Chemical group 0.000 claims description 25
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 18
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 17
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 239000001301 oxygen Chemical group 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- 208000006673 asthma Diseases 0.000 claims description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 11
- 229910052717 sulfur Chemical group 0.000 claims description 11
- 239000011593 sulfur Chemical group 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 6
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 6
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 5
- DUIPHYMVNRMZCO-KRWDZBQOSA-N 5-[(2s)-2-amino-3-(5-fluorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]-4h-1,4-benzoxazin-3-one Chemical compound C1C2=CC(F)=CC=C2OC1(CC1)CCN1C[C@H](N)COC1=CC=CC2=C1NC(=O)CO2 DUIPHYMVNRMZCO-KRWDZBQOSA-N 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- QGFUMASBDBAAFV-IBGZPJMESA-N n-[2-[(2s)-2-amino-3-(5-chlorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]-4-methoxyphenyl]acetamide Chemical compound COC1=CC=C(NC(C)=O)C(OC[C@@H](N)CN2CCC3(OC4=CC=C(Cl)C=C4C3)CC2)=C1 QGFUMASBDBAAFV-IBGZPJMESA-N 0.000 claims description 5
- SMTZBQWTZXYYTH-UHFFFAOYSA-N 5-chloro-2-[2-chloro-3-(5-chlorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]-4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC(Cl)=C(O)C=C1OCC(Cl)CN1CCC2(OC3=CC=C(Cl)C=C3C2)CC1 SMTZBQWTZXYYTH-UHFFFAOYSA-N 0.000 claims description 4
- NPRRMRYPBGEKBY-IBGZPJMESA-N 8-[(2s)-2-amino-3-(5-fluorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]-1h-quinolin-2-one Chemical compound C1C2=CC(F)=CC=C2OC1(CC1)CCN1C[C@H](N)COC1=CC=CC2=C1NC(=O)C=C2 NPRRMRYPBGEKBY-IBGZPJMESA-N 0.000 claims description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- VJDQUMOMMQQPTR-IBGZPJMESA-N n-[2-[(2s)-2-amino-3-(5-fluorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]-4-methoxyphenyl]acetamide Chemical compound COC1=CC=C(NC(C)=O)C(OC[C@@H](N)CN2CCC3(OC4=CC=C(F)C=C4C3)CC2)=C1 VJDQUMOMMQQPTR-IBGZPJMESA-N 0.000 claims description 4
- VNNNTNKEXAIYHX-IBGZPJMESA-N n-[2-[(2s)-2-amino-3-spiro[3h-1-benzofuran-2,4'-piperidine]-1'-ylpropoxy]-4-methoxyphenyl]acetamide Chemical compound COC1=CC=C(NC(C)=O)C(OC[C@@H](N)CN2CCC3(OC4=CC=CC=C4C3)CC2)=C1 VNNNTNKEXAIYHX-IBGZPJMESA-N 0.000 claims description 4
- RYSFHZIQDZFYOE-UHFFFAOYSA-N n-[2-[2-chloro-3-(5-chlorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]-4-hydroxyphenyl]acetamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CC(=O)NC1=CC=C(O)C=C1OCC(Cl)CN1CCC2(OC3=CC=C(Cl)C=C3C2)CC1 RYSFHZIQDZFYOE-UHFFFAOYSA-N 0.000 claims description 4
- NCIQBQOFFXPCCQ-UHFFFAOYSA-N n-[2-[3-amino-2-(5-chlorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]-4-methoxyphenyl]acetamide Chemical compound COC1=CC=C(NC(C)=O)C(OCC(CN)N2CCC3(OC4=CC=C(Cl)C=C4C3)CC2)=C1 NCIQBQOFFXPCCQ-UHFFFAOYSA-N 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- DUVLVEWJJZCDBT-UHFFFAOYSA-N 2-[2-amino-3-(5-chlorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]-5-chloro-4-hydroxybenzoic acid Chemical compound C1CC2(OC3=CC=C(Cl)C=C3C2)CCN1CC(N)COC1=CC(O)=C(Cl)C=C1C(O)=O DUVLVEWJJZCDBT-UHFFFAOYSA-N 0.000 claims description 3
- ACTJKGJMWUVTGT-UHFFFAOYSA-N 5-chloro-2-[3-(5-chlorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)-2-(dimethylamino)propoxy]-4-hydroxybenzoic acid Chemical compound C1CC2(OC3=CC=C(Cl)C=C3C2)CCN1CC(N(C)C)COC1=CC(O)=C(Cl)C=C1C(O)=O ACTJKGJMWUVTGT-UHFFFAOYSA-N 0.000 claims description 3
- JLACTVLWRWQQEI-UHFFFAOYSA-N 5-chloro-2-[3-(5-chlorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)-2-(methylamino)propoxy]-4-hydroxybenzoic acid Chemical compound C1CC2(OC3=CC=C(Cl)C=C3C2)CCN1CC(NC)COC1=CC(O)=C(Cl)C=C1C(O)=O JLACTVLWRWQQEI-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- SKXZQBTWCWIBOO-UHFFFAOYSA-N n-[2-(3-amino-2-spiro[3h-1-benzofuran-2,4'-piperidine]-1'-ylpropoxy)-4-methoxyphenyl]acetamide Chemical compound COC1=CC=C(NC(C)=O)C(OCC(CN)N2CCC3(OC4=CC=CC=C4C3)CC2)=C1 SKXZQBTWCWIBOO-UHFFFAOYSA-N 0.000 claims description 3
- QKIBSNRBRFMBRL-NRFANRHFSA-N n-[2-[(2s)-2-acetamido-3-(5-fluorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]-4-methoxyphenyl]acetamide Chemical compound COC1=CC=C(NC(C)=O)C(OC[C@H](CN2CCC3(OC4=CC=C(F)C=C4C3)CC2)NC(C)=O)=C1 QKIBSNRBRFMBRL-NRFANRHFSA-N 0.000 claims description 3
- JSAUQHHZESPOHK-NTEVMMBTSA-N n-[2-[(2s)-2-amino-3-(5-fluorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]-4-hydroxyphenyl]acetamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.CC(=O)NC1=CC=C(O)C=C1OC[C@@H](N)CN1CCC2(OC3=CC=C(F)C=C3C2)CC1 JSAUQHHZESPOHK-NTEVMMBTSA-N 0.000 claims description 3
- MXOCRMMYDODNPI-NTEVMMBTSA-N n-[2-[(2s)-2-amino-3-spiro[3h-1-benzofuran-2,4'-piperidine]-1'-ylpropoxy]-4-hydroxyphenyl]acetamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.CC(=O)NC1=CC=C(O)C=C1OC[C@@H](N)CN1CCC2(OC3=CC=CC=C3C2)CC1 MXOCRMMYDODNPI-NTEVMMBTSA-N 0.000 claims description 3
- NFBNWWPIDPGKLT-UHFFFAOYSA-N n-[2-[2-(5-chlorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]-4-methoxyphenyl]acetamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.COC1=CC=C(NC(C)=O)C(OCC(C)N2CCC3(OC4=CC=C(Cl)C=C4C3)CC2)=C1 NFBNWWPIDPGKLT-UHFFFAOYSA-N 0.000 claims description 3
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- 229940124530 sulfonamide Drugs 0.000 claims description 3
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- CHWGHHXWLQXCBC-UHFFFAOYSA-N [2-[3-amino-2-(5-chlorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]phenyl]urea Chemical compound C1CC2(OC3=CC=C(Cl)C=C3C2)CCN1C(CN)COC1=CC=CC=C1NC(N)=O CHWGHHXWLQXCBC-UHFFFAOYSA-N 0.000 claims description 2
- VDJQXVBVSWTOOX-UHFFFAOYSA-N [2-[3-amino-2-(5-fluorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]phenyl]urea Chemical compound C1CC2(OC3=CC=C(F)C=C3C2)CCN1C(CN)COC1=CC=CC=C1NC(N)=O VDJQXVBVSWTOOX-UHFFFAOYSA-N 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
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- HJCWYBWMEZOYTF-NTEVMMBTSA-N n-[2-[(2s)-2-amino-3-(5-chlorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]-4-hydroxyphenyl]acetamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.CC(=O)NC1=CC=C(O)C=C1OC[C@@H](N)CN1CCC2(OC3=CC=C(Cl)C=C3C2)CC1 HJCWYBWMEZOYTF-NTEVMMBTSA-N 0.000 claims description 2
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Classifications
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Applications Claiming Priority (2)
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| SE0303541A SE0303541D0 (sv) | 2003-12-22 | 2003-12-22 | New compounds |
| PCT/SE2004/001938 WO2005061499A1 (en) | 2003-12-22 | 2004-12-20 | Novel tricyclic spiroderivatives as modulators of chemokine receptor activity |
Publications (2)
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| JP2007515476A true JP2007515476A (ja) | 2007-06-14 |
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| SE0202133D0 (sv) | 2002-07-08 | 2002-07-08 | Astrazeneca Ab | Novel compounds |
| US8017762B2 (en) | 2003-04-17 | 2011-09-13 | Alnylam Pharmaceuticals, Inc. | Modified iRNA agents |
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- 2004-12-20 CN CNA200480042013XA patent/CN1918160A/zh active Pending
- 2004-12-20 BR BRPI0417036-9A patent/BRPI0417036A/pt not_active IP Right Cessation
- 2004-12-20 MX MXPA06007025A patent/MXPA06007025A/es unknown
- 2004-12-20 CA CA002548494A patent/CA2548494A1/en not_active Abandoned
- 2004-12-20 TW TW093139699A patent/TW200604197A/zh unknown
- 2004-12-20 JP JP2006546906A patent/JP2007515476A/ja active Pending
- 2004-12-20 AU AU2004303735A patent/AU2004303735B2/en not_active Ceased
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| EP1699791A1 (en) | 2006-09-13 |
| AU2004303735B2 (en) | 2007-09-20 |
| AU2004303735A1 (en) | 2005-07-07 |
| NO20063355L (no) | 2006-09-22 |
| US20090298861A1 (en) | 2009-12-03 |
| ZA200605082B (en) | 2007-11-28 |
| WO2005061499A1 (en) | 2005-07-07 |
| TW200604197A (en) | 2006-02-01 |
| KR20060117343A (ko) | 2006-11-16 |
| SE0303541D0 (sv) | 2003-12-22 |
| US20070099945A1 (en) | 2007-05-03 |
| BRPI0417036A (pt) | 2007-02-06 |
| AR046992A1 (es) | 2006-01-04 |
| IL175958A0 (en) | 2006-10-05 |
| CN1918160A (zh) | 2007-02-21 |
| UY28694A1 (es) | 2005-07-29 |
| MXPA06007025A (es) | 2006-08-31 |
| CA2548494A1 (en) | 2005-07-07 |
| US7524856B2 (en) | 2009-04-28 |
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