CA2548494A1 - Novel tricyclic spiroderivatives as modulators of chemokine receptor activity - Google Patents
Novel tricyclic spiroderivatives as modulators of chemokine receptor activity Download PDFInfo
- Publication number
- CA2548494A1 CA2548494A1 CA002548494A CA2548494A CA2548494A1 CA 2548494 A1 CA2548494 A1 CA 2548494A1 CA 002548494 A CA002548494 A CA 002548494A CA 2548494 A CA2548494 A CA 2548494A CA 2548494 A1 CA2548494 A1 CA 2548494A1
- Authority
- CA
- Canada
- Prior art keywords
- amino
- alkyl
- spiro
- benzofuran
- piperidin
- Prior art date
- 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.)
- Abandoned
Links
- 230000000694 effects Effects 0.000 title claims description 8
- 102000009410 Chemokine receptor Human genes 0.000 title claims description 4
- 108050000299 Chemokine receptor Proteins 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 128
- 238000000034 method Methods 0.000 claims abstract description 22
- 230000008569 process Effects 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 6
- -1 cyano, hydroxyl Chemical group 0.000 claims description 104
- 229910052736 halogen Inorganic materials 0.000 claims description 61
- 150000002367 halogens Chemical class 0.000 claims description 61
- 125000001424 substituent group Chemical group 0.000 claims description 52
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 51
- 229910052757 nitrogen Inorganic materials 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 45
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 33
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 31
- 239000012453 solvate Substances 0.000 claims description 27
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 25
- 125000004122 cyclic group Chemical group 0.000 claims description 23
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 229920006395 saturated elastomer Polymers 0.000 claims description 17
- 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
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 13
- 239000005864 Sulphur Chemical group 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 208000006673 asthma Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000004043 oxo group Chemical group O=* 0.000 claims description 7
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- 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
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- XOFHEEHNVZYWLO-UHFFFAOYSA-N [2-[3-amino-2-(5-chlorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]phenyl]urea;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.C1CC2(OC3=CC=C(Cl)C=C3C2)CCN1C(CN)COC1=CC=CC=C1NC(N)=O XOFHEEHNVZYWLO-UHFFFAOYSA-N 0.000 claims description 4
- HPNGOCWULGUIQG-UHFFFAOYSA-N [2-[3-amino-2-(5-fluorospiro[3h-1-benzofuran-2,4'-piperidine]-1'-yl)propoxy]phenyl]urea;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.C1CC2(OC3=CC=C(F)C=C3C2)CCN1C(CN)COC1=CC=CC=C1NC(N)=O HPNGOCWULGUIQG-UHFFFAOYSA-N 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- 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
- 238000002156 mixing Methods 0.000 claims description 3
- 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 2
- 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 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 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 2
- 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 2
- NTZZHSRUGUPATF-UHFFFAOYSA-N n-[2-[3-amino-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.OC(=O)C(F)(F)F.COC1=CC=C(NC(C)=O)C(OCC(CN)N2CCC3(OC4=CC=C(Cl)C=C4C3)CC2)=C1 NTZZHSRUGUPATF-UHFFFAOYSA-N 0.000 claims description 2
- ICYRNVQCNZOVAZ-UHFFFAOYSA-N n-[2-[3-amino-2-(5-fluorospiro[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.OC(=O)C(F)(F)F.COC1=CC=C(NC(C)=O)C(OCC(CN)N2CCC3(OC4=CC=C(F)C=C4C3)CC2)=C1 ICYRNVQCNZOVAZ-UHFFFAOYSA-N 0.000 claims description 2
- 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 1
- 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 1
- 229910006074 SO2NH2 Inorganic materials 0.000 claims 1
- 230000009286 beneficial effect Effects 0.000 claims 1
- HSYYNRXEWHZTGC-UHFFFAOYSA-N n-[2-(3-amino-2-spiro[3h-1-benzofuran-2,4'-piperidine]-1'-ylpropoxy)-4-methoxyphenyl]acetamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.COC1=CC=C(NC(C)=O)C(OCC(CN)N2CCC3(OC4=CC=CC=C4C3)CC2)=C1 HSYYNRXEWHZTGC-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 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 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 94
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 56
- 239000000203 mixture Substances 0.000 description 54
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 52
- 238000005160 1H NMR spectroscopy Methods 0.000 description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 49
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- 239000011541 reaction mixture Substances 0.000 description 42
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 37
- 239000003039 volatile agent Substances 0.000 description 31
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 24
- 229910002027 silica gel Inorganic materials 0.000 description 24
- 238000003818 flash chromatography Methods 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 20
- 229910017974 NH40H Inorganic materials 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 101150041968 CDC13 gene Proteins 0.000 description 14
- 125000003003 spiro group Chemical group 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 10
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 10
- 206010039083 rhinitis Diseases 0.000 description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 229910052731 fluorine Inorganic materials 0.000 description 8
- 239000011737 fluorine Substances 0.000 description 8
- 125000006413 ring segment Chemical group 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
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- 239000003480 eluent Substances 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- BDYDBRINEAMBRZ-UHFFFAOYSA-N 5-chlorospiro[3h-1-benzofuran-2,4'-piperidine] Chemical compound C1C2=CC(Cl)=CC=C2OC21CCNCC2 BDYDBRINEAMBRZ-UHFFFAOYSA-N 0.000 description 6
- 102000019034 Chemokines Human genes 0.000 description 6
- 108010012236 Chemokines Proteins 0.000 description 6
- 230000035605 chemotaxis Effects 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- QAJSCZSRUBMWMH-UHFFFAOYSA-N 5-fluorospiro[3h-1-benzofuran-2,4'-piperidine] Chemical compound C1C2=CC(F)=CC=C2OC21CCNCC2 QAJSCZSRUBMWMH-UHFFFAOYSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- AJHYUYMTAFGNRR-MRVPVSSYSA-N (2r)-2-[(5-methoxy-2-nitrophenoxy)methyl]oxirane Chemical compound COC1=CC=C([N+]([O-])=O)C(OC[C@@H]2OC2)=C1 AJHYUYMTAFGNRR-MRVPVSSYSA-N 0.000 description 4
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 4
- 229910015845 BBr3 Inorganic materials 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- LISFMEBWQUVKPJ-UHFFFAOYSA-N carbostyril Natural products C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
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Landscapes
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| US8796436B2 (en) | 2003-04-17 | 2014-08-05 | Alnylam Pharmaceuticals, Inc. | Modified iRNA agents |
| AU2004233092C9 (en) | 2003-04-17 | 2010-10-28 | Alnylam Pharmaceuticals, Inc. | Modified iRNA agents |
| US7723509B2 (en) | 2003-04-17 | 2010-05-25 | Alnylam Pharmaceuticals | IRNA agents with biocleavable tethers |
| US7851615B2 (en) | 2003-04-17 | 2010-12-14 | Alnylam Pharmaceuticals, Inc. | Lipophilic conjugated iRNA agents |
| US8017762B2 (en) | 2003-04-17 | 2011-09-13 | Alnylam Pharmaceuticals, Inc. | Modified iRNA agents |
| SE0303090D0 (sv) * | 2003-11-20 | 2003-11-20 | Astrazeneca Ab | Novel compounds |
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| TWI350168B (en) | 2004-05-07 | 2011-10-11 | Incyte Corp | Amido compounds and their use as pharmaceuticals |
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| US20080064884A1 (en) * | 2006-05-10 | 2008-03-13 | Astrazeneca Ab | Novel Process 1 |
| JP2009544609A (ja) * | 2006-07-18 | 2009-12-17 | アストラゼネカ・アクチエボラーグ | 置換２−アセチルアミノ−アルコキシフェニルの製造方法 |
| CN101553493B (zh) * | 2006-07-19 | 2012-07-04 | 阿斯利康(瑞典)有限公司 | 三环螺哌啶化合物、它们的合成和它们作为趋化因子受体活性调节剂的用途 |
| EP2120935A4 (en) * | 2007-02-23 | 2011-06-22 | Astrazeneca Ab | NOVEL COMBINATION OF COMPOUNDS FOR THE TREATMENT OF AIRWAY DISEASES, IN PARTICULAR CHRONIC OBSTRUCTIVE BRONCHOPNEUMOPATHY (COPD) AND ASTHMA |
| WO2009011654A1 (en) * | 2007-07-17 | 2009-01-22 | Astrazeneca Ab | Process for the preparation of cyclic spiropiperidines |
| WO2009011655A1 (en) * | 2007-07-17 | 2009-01-22 | Astrazeneca Ab | Splropiperidine compounds, a process of their preparation, pharmaceutical compositions containing them, and their use in the treatment of airway diseases, inflammatory diseases, copd or asthma |
| WO2009061881A1 (en) * | 2007-11-07 | 2009-05-14 | Glaxo Group Limited | Spirodihydrobenzofurans as modulators of chemokine receptors |
| RU2011153723A (ru) * | 2009-06-10 | 2013-07-20 | Суновион Фармасьютикалз Инк. | Обратные агонисты и антагонисты н3 рецепторов гистамина и способы их применения |
| EP3233799B1 (en) | 2014-12-19 | 2021-05-19 | The Broad Institute, Inc. | Dopamine d2 receptor ligands |
| EP3233077A4 (en) | 2014-12-19 | 2018-08-08 | The Broad Institute Inc. | Dopamine d2 receptor ligands |
| KR102869129B1 (ko) | 2021-02-08 | 2025-10-14 | 닛본 세이고 가부시끼가이샤 | 역입력 차단 클러치 |
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| US4166120A (en) * | 1978-04-14 | 1979-08-28 | American Hoechst Corporation | Analgesic and tranquilizing benzoylpropyl-spiro[dihydrobenzofuran]piperidines and pyrrolidines |
| US4166119A (en) | 1978-04-14 | 1979-08-28 | American Hoechst Corporation | Analgesic and tranquilizing spiro[dihydrobenzofuran]piperidines and pyrrolidines |
| US4263317A (en) * | 1979-09-06 | 1981-04-21 | Hoechst-Roussel Pharmaceuticals, Inc. | Spiro[cyclohexane-1,1'(3'H)-isobenzofuran]s |
| US5366986A (en) | 1988-04-15 | 1994-11-22 | T Cell Sciences, Inc. | Compounds which inhibit complement and/or suppress immune activity |
| DE3930262A1 (de) | 1989-09-11 | 1991-03-21 | Thomae Gmbh Dr K | Kondensierte diazepinone, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| US5576321A (en) | 1995-01-17 | 1996-11-19 | Eli Lilly And Company | Compounds having effects on serotonin-related systems |
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| JP2001508798A (ja) | 1997-01-21 | 2001-07-03 | メルク エンド カンパニー インコーポレーテッド | ケモカインレセプター活性のモジュレーターとしての３，３−二置換ピペリジン類 |
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| US6288083B1 (en) | 1998-09-04 | 2001-09-11 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| JP2003514777A (ja) | 1999-10-27 | 2003-04-22 | シーオーアール セラピューティクス インコーポレイテッド | フィブリノゲン依存性血小板凝集の阻害剤としてのピリジル含有スピロ環化合物 |
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| AR028948A1 (es) | 2000-06-20 | 2003-05-28 | Astrazeneca Ab | Compuestos novedosos |
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| AU2002363236A1 (en) | 2001-10-30 | 2003-05-12 | Millennium Pharmaceuticals, Inc. | Compounds, pharmaceutical compositions and methods of use therefor |
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| JP2006511500A (ja) | 2002-10-30 | 2006-04-06 | メルク エンド カムパニー インコーポレーテッド | γ−アミノアミド系のケモカイン受容体活性調節剤 |
| AU2003293129B2 (en) | 2002-11-27 | 2009-03-12 | Incyte Holdings Corporation | 3-aminopyrrolidine derivatives as modulators of chemokine receptors |
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2006
- 2006-05-25 IL IL175958A patent/IL175958A0/en unknown
- 2006-06-20 ZA ZA200605082A patent/ZA200605082B/en unknown
- 2006-07-19 NO NO20063355A patent/NO20063355L/no not_active Application Discontinuation
-
2009
- 2009-04-28 US US12/431,338 patent/US20090298861A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU2004303735A1 (en) | 2005-07-07 |
| US20090298861A1 (en) | 2009-12-03 |
| MXPA06007025A (es) | 2006-08-31 |
| US20070099945A1 (en) | 2007-05-03 |
| SE0303541D0 (sv) | 2003-12-22 |
| BRPI0417036A (pt) | 2007-02-06 |
| US7524856B2 (en) | 2009-04-28 |
| IL175958A0 (en) | 2006-10-05 |
| NO20063355L (no) | 2006-09-22 |
| WO2005061499A1 (en) | 2005-07-07 |
| KR20060117343A (ko) | 2006-11-16 |
| ZA200605082B (en) | 2007-11-28 |
| AR046992A1 (es) | 2006-01-04 |
| AU2004303735B2 (en) | 2007-09-20 |
| TW200604197A (en) | 2006-02-01 |
| UY28694A1 (es) | 2005-07-29 |
| JP2007515476A (ja) | 2007-06-14 |
| EP1699791A1 (en) | 2006-09-13 |
| CN1918160A (zh) | 2007-02-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |