JP2002501072A5

JP2002501072A5 -

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Publication number: JP2002501072A5
Authority: JP; Japan
Prior art keywords: group; substituted; dihydro; chlorophenyl; brs
Prior art date: 1999-01-21
Legal status : Granted

Application number

JP2000528572A

Other languages

English (en)

Japanese (ja)

Other versions

JP4853934B2 (ja

JP2002501072A (ja

Filing date

1999-01-21

Publication date

2006-03-16

1998-09-04 Priority claimed from US09/148,823 external-priority patent/US6613905B1/en

1999-01-21 Application filed filed Critical

1999-01-21 Priority claimed from PCT/US1999/001266 external-priority patent/WO1999037651A1/en

2002-01-15 Publication of JP2002501072A publication Critical patent/JP2002501072A/ja

2006-03-16 Publication of JP2002501072A5 publication Critical patent/JP2002501072A5/ja

2012-01-11 Application granted granted Critical

2012-01-11 Publication of JP4853934B2 publication Critical patent/JP4853934B2/ja

2019-01-21 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

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150000001875 compounds Chemical class 0.000 description 263
125000001931 aliphatic group Chemical group 0.000 description 218
238000000034 method Methods 0.000 description 204
125000003118 aryl group Chemical group 0.000 description 179
238000005160 1H NMR spectroscopy Methods 0.000 description 168
-1 small molecule compounds Chemical class 0.000 description 118
125000006615 aromatic heterocyclic group Chemical group 0.000 description 89
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 74
239000000047 product Substances 0.000 description 62
LZAYOZUFUAMFLD-UHFFFAOYSA-N 4-(4-chlorophenyl)-4-hydroxypiperidine Chemical compound C=1C=C(Cl)C=CC=1C1(O)CCNCC1 LZAYOZUFUAMFLD-UHFFFAOYSA-N 0.000 description 57
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 57
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 55
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 53
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 48
239000002904 solvent Substances 0.000 description 48
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 47
239000000243 solution Substances 0.000 description 45
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 43
239000000203 mixture Substances 0.000 description 42
230000002829 reductive effect Effects 0.000 description 34
239000011541 reaction mixture Substances 0.000 description 31
239000011780 sodium chloride Substances 0.000 description 28
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
125000002252 acyl group Chemical group 0.000 description 27
229910052757 nitrogen Inorganic materials 0.000 description 27
239000007864 aqueous solution Substances 0.000 description 26
229920006395 saturated elastomer Polymers 0.000 description 26
229910052943 magnesium sulfate Inorganic materials 0.000 description 24
235000019341 magnesium sulphate Nutrition 0.000 description 24
125000004433 nitrogen atom Chemical group N* 0.000 description 24
239000012044 organic layer Substances 0.000 description 24
125000001072 heteroaryl group Chemical group 0.000 description 23
238000010898 silica gel chromatography Methods 0.000 description 23
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
102000019034 Chemokines Human genes 0.000 description 22
108010012236 Chemokines Proteins 0.000 description 22
238000001994 activation Methods 0.000 description 21
102100032367 C-C motif chemokine 5 Human genes 0.000 description 20
108010055166 Chemokine CCL5 Proteins 0.000 description 20
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
201000010099 disease Diseases 0.000 description 20
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 20
230000004913 activation Effects 0.000 description 19
210000000265 leukocyte Anatomy 0.000 description 19
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
239000005557 antagonist Substances 0.000 description 18
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210000004027 cell Anatomy 0.000 description 17
229910052736 halogen Inorganic materials 0.000 description 17
150000002367 halogens Chemical class 0.000 description 17
HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 17
DXNYSMPOOHDCMD-UHFFFAOYSA-N 11-(3-bromopropylidene)-5,6-dihydrodibenzo[2,1-b:2',1'-f][7]annulene Chemical compound C1CC2=CC=CC=C2C(=CCCBr)C2=CC=CC=C21 DXNYSMPOOHDCMD-UHFFFAOYSA-N 0.000 description 16
102000000013 Chemokine CCL3 Human genes 0.000 description 16
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QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
108700012434 CCL3 Proteins 0.000 description 15
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
238000010992 reflux Methods 0.000 description 15
238000002360 preparation method Methods 0.000 description 14
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
125000006575 electron-withdrawing group Chemical group 0.000 description 13
WAQHMFBPFLNJNQ-UHFFFAOYSA-N 7-methoxy-6h-[1]benzoxepino[2,3-b]pyridin-5-one Chemical compound O1C2=NC=CC=C2C(=O)CC2=C1C=CC=C2OC WAQHMFBPFLNJNQ-UHFFFAOYSA-N 0.000 description 12
229910052799 carbon Inorganic materials 0.000 description 12
125000004432 carbon atom Chemical group C* 0.000 description 12
230000007115 recruitment Effects 0.000 description 12
150000003839 salts Chemical class 0.000 description 12
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 11
LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 11
238000006243 chemical reaction Methods 0.000 description 11
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125000001424 substituent group Chemical group 0.000 description 11
230000002159 abnormal effect Effects 0.000 description 10
238000009739 binding Methods 0.000 description 10
ADEKJVNFIQUGRR-UHFFFAOYSA-N 4h-pyridin-3-one Chemical compound O=C1CC=CN=C1 ADEKJVNFIQUGRR-UHFFFAOYSA-N 0.000 description 9
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
125000004093 cyano group Chemical group *C#N 0.000 description 9
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 9
HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 9
JLAKCHGEEBPDQI-UHFFFAOYSA-N 4-(4-fluorobenzyl)piperidine Chemical compound C1=CC(F)=CC=C1CC1CCNCC1 JLAKCHGEEBPDQI-UHFFFAOYSA-N 0.000 description 8
230000027455 binding Effects 0.000 description 8
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
102100031172 C-C chemokine receptor type 1 Human genes 0.000 description 7
101710149814 C-C chemokine receptor type 1 Proteins 0.000 description 7
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
230000001404 mediated effect Effects 0.000 description 7
125000004076 pyridyl group Chemical group 0.000 description 7
125000006413 ring segment Chemical group 0.000 description 7
239000012312 sodium hydride Substances 0.000 description 7
229910000104 sodium hydride Inorganic materials 0.000 description 7
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
208000030507 AIDS Diseases 0.000 description 6
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
125000004429 atom Chemical group 0.000 description 6
239000002585 base Substances 0.000 description 6
125000000753 cycloalkyl group Chemical group 0.000 description 6
WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 6
230000000694 effects Effects 0.000 description 6
125000000623 heterocyclic group Chemical group 0.000 description 6
239000012528 membrane Substances 0.000 description 6
210000001616 monocyte Anatomy 0.000 description 6
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 6
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
239000002244 precipitate Substances 0.000 description 6
MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 5
102000001902 CC Chemokines Human genes 0.000 description 5
108010040471 CC Chemokines Proteins 0.000 description 5
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
241000124008 Mammalia Species 0.000 description 5
210000001744 T-lymphocyte Anatomy 0.000 description 5
230000035605 chemotaxis Effects 0.000 description 5
230000000770 proinflammatory effect Effects 0.000 description 5
BYOIMOJOKVUNTP-UHFFFAOYSA-N spiro[1h-2-benzofuran-3,4'-piperidine] Chemical compound C12=CC=CC=C2COC21CCNCC2 BYOIMOJOKVUNTP-UHFFFAOYSA-N 0.000 description 5
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
KSZKJGKTCSHPOS-UHFFFAOYSA-N 4-(4-chlorophenyl)-1-[3-(2-methoxy-6h-benzo[c][1]benzoxepin-11-ylidene)propyl]piperidin-4-ol Chemical compound C12=CC(OC)=CC=C2OCC2=CC=CC=C2C1=CCCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 KSZKJGKTCSHPOS-UHFFFAOYSA-N 0.000 description 4
102100032366 C-C motif chemokine 7 Human genes 0.000 description 4
101710155834 C-C motif chemokine 7 Proteins 0.000 description 4
241001465754 Metazoa Species 0.000 description 4
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125000002837 carbocyclic group Chemical group 0.000 description 4
239000002975 chemoattractant Substances 0.000 description 4
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DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical group C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 4
XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 4
IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 4
239000003814 drug Substances 0.000 description 4
239000003446 ligand Substances 0.000 description 4
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
125000000896 monocarboxylic acid group Chemical group 0.000 description 4
238000007911 parenteral administration Methods 0.000 description 4
239000008188 pellet Substances 0.000 description 4
YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 4
229910000027 potassium carbonate Inorganic materials 0.000 description 4
SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
MLCZLOSZWUXPEM-UHFFFAOYSA-N 5-(3-bromopropylidene)-7-methoxy-6h-[1]benzoxepino[2,3-b]pyridine Chemical group O1C2=NC=CC=C2C(=CCCBr)CC2=C1C=CC=C2OC MLCZLOSZWUXPEM-UHFFFAOYSA-N 0.000 description 3
BWBQQIJIIIGGAN-UHFFFAOYSA-N 5-[3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]propylidene]-6h-[1]benzoxepino[2,3-b]pyridin-7-ol Chemical compound C1C=2C(O)=CC=CC=2OC2=NC=CC=C2C1=CCCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 BWBQQIJIIIGGAN-UHFFFAOYSA-N 0.000 description 3
102100034871 C-C motif chemokine 8 Human genes 0.000 description 3
101710155833 C-C motif chemokine 8 Proteins 0.000 description 3
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BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 3
239000007995 HEPES buffer Substances 0.000 description 3
IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 3
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
238000005804 alkylation reaction Methods 0.000 description 3
235000019270 ammonium chloride Nutrition 0.000 description 3
229910002091 carbon monoxide Inorganic materials 0.000 description 3
239000003054 catalyst Substances 0.000 description 3
210000000170 cell membrane Anatomy 0.000 description 3
238000005119 centrifugation Methods 0.000 description 3
208000037893 chronic inflammatory disorder Diseases 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
125000000151 cysteine group Chemical class N[C@@H](CS)C(=O)* 0.000 description 3
LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
210000003979 eosinophil Anatomy 0.000 description 3
UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 3
239000008187 granular material Substances 0.000 description 3
229910052739 hydrogen Inorganic materials 0.000 description 3
239000001257 hydrogen Substances 0.000 description 3
230000004054 inflammatory process Effects 0.000 description 3
102000006495 integrins Human genes 0.000 description 3
108010044426 integrins Proteins 0.000 description 3
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AEUKDPKXTPNBNY-XEYRWQBLSA-N mcp 2 Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)C1=CC=CC=C1 AEUKDPKXTPNBNY-XEYRWQBLSA-N 0.000 description 3
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QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
239000002953 phosphate buffered saline Substances 0.000 description 3
NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
230000008569 process Effects 0.000 description 3
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
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229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
230000009870 specific binding Effects 0.000 description 3
239000007858 starting material Substances 0.000 description 3
238000011282 treatment Methods 0.000 description 3
MRXDGVXSWIXTQL-HYHFHBMOSA-N (2s)-2-[[(1s)-1-(2-amino-1,4,5,6-tetrahydropyrimidin-6-yl)-2-[[(2s)-4-methyl-1-oxo-1-[[(2s)-1-oxo-3-phenylpropan-2-yl]amino]pentan-2-yl]amino]-2-oxoethyl]carbamoylamino]-3-phenylpropanoic acid Chemical compound C([C@H](NC(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C=O)C1NC(N)=NCC1)C(O)=O)C1=CC=CC=C1 MRXDGVXSWIXTQL-HYHFHBMOSA-N 0.000 description 2
0 *C1CCNCC1 Chemical compound *C1CCNCC1 0.000 description 2
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CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
NGZLMMNFHIJKRL-UHFFFAOYSA-N methyl 11-[3-[2-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]propylidene]-6h-benzo[c][1]benzoxepine-1-carboxylate Chemical compound C1=2C(C(=O)OC)=CC=CC=2OCC2=CC=CC=C2C1=CCCN1CCC(O)CC1C1=CC=C(Cl)C=C1 NGZLMMNFHIJKRL-UHFFFAOYSA-N 0.000 description 1
LILBFDRUWNORGR-UHFFFAOYSA-N methyl 11-[3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]propylidene]-6h-benzo[c][1]benzoxepine-2-carboxylate Chemical compound C12=CC(C(=O)OC)=CC=C2OCC2=CC=CC=C2C1=CCCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 LILBFDRUWNORGR-UHFFFAOYSA-N 0.000 description 1
KUISDPUHRPZRFF-UHFFFAOYSA-N methyl 4-phenylpiperidine-4-carboxylate Chemical compound C=1C=CC=CC=1C1(C(=O)OC)CCNCC1 KUISDPUHRPZRFF-UHFFFAOYSA-N 0.000 description 1
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
229960004584 methylprednisolone Drugs 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
201000006417 multiple sclerosis Diseases 0.000 description 1
KCOHNRMFXQLTCW-UHFFFAOYSA-N n-(4-chlorophenyl)piperidin-4-amine Chemical compound C1=CC(Cl)=CC=C1NC1CCNCC1 KCOHNRMFXQLTCW-UHFFFAOYSA-N 0.000 description 1
PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
201000008383 nephritis Diseases 0.000 description 1
210000002569 neuron Anatomy 0.000 description 1
230000009871 nonspecific binding Effects 0.000 description 1
210000000056 organ Anatomy 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
229940037201 oris Drugs 0.000 description 1
125000004043 oxo group Chemical group O=* 0.000 description 1
ZDXPLBKUXYRHHM-UHFFFAOYSA-N oxolan-2-yl(diphenyl)phosphane Chemical compound C1COC(C1)P(c1ccccc1)c1ccccc1 ZDXPLBKUXYRHHM-UHFFFAOYSA-N 0.000 description 1
125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
208000012963 papular rash Diseases 0.000 description 1
UNEIHNMKASENIG-UHFFFAOYSA-N para-chlorophenylpiperazine Chemical compound C1=CC(Cl)=CC=C1N1CCNCC1 UNEIHNMKASENIG-UHFFFAOYSA-N 0.000 description 1
VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
210000005259 peripheral blood Anatomy 0.000 description 1
239000011886 peripheral blood Substances 0.000 description 1
125000001484 phenothiazinyl group Chemical class C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 1
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
125000003367 polycyclic group Chemical group 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000011591 potassium Substances 0.000 description 1
235000011056 potassium acetate Nutrition 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
229960004618 prednisone Drugs 0.000 description 1
XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
238000012746 preparative thin layer chromatography Methods 0.000 description 1
230000002265 prevention Effects 0.000 description 1
LJZPPWWHKPGCHS-UHFFFAOYSA-N propargyl chloride Chemical compound ClCC#C LJZPPWWHKPGCHS-UHFFFAOYSA-N 0.000 description 1
230000000069 prophylactic effect Effects 0.000 description 1
238000011321 prophylaxis Methods 0.000 description 1
125000006239 protecting group Chemical group 0.000 description 1
238000002731 protein assay Methods 0.000 description 1
125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
125000001453 quaternary ammonium group Chemical group 0.000 description 1
238000006268 reductive amination reaction Methods 0.000 description 1
230000001105 regulatory effect Effects 0.000 description 1
208000023504 respiratory system disease Diseases 0.000 description 1
206010039073 rheumatoid arthritis Diseases 0.000 description 1
238000003345 scintillation counting Methods 0.000 description 1
XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
239000002002 slurry Substances 0.000 description 1
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
239000007787 solid Substances 0.000 description 1
125000006850 spacer group Chemical group 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
235000011150 stannous chloride Nutrition 0.000 description 1
239000008223 sterile water Substances 0.000 description 1
238000003756 stirring Methods 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
239000007929 subcutaneous injection Substances 0.000 description 1
239000000126 substance Substances 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
238000007910 systemic administration Methods 0.000 description 1
239000003826 tablet Substances 0.000 description 1
BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
229960000278 theophylline Drugs 0.000 description 1
229940124597 therapeutic agent Drugs 0.000 description 1
AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
230000001052 transient effect Effects 0.000 description 1
238000002054 transplantation Methods 0.000 description 1
YLGRTLMDMVAFNI-UHFFFAOYSA-N tributyl(prop-2-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)CC=C YLGRTLMDMVAFNI-UHFFFAOYSA-N 0.000 description 1
ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
230000001960 triggered effect Effects 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1
238000010792 warming Methods 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1

JP2000528572A 1998-01-21 1999-01-21 ケモカイン受容体アンタゴニストおよびその使用方法 Expired - Fee Related JP4853934B2 (ja)