KR20020016926A - 케모카인 수용체 길항제 및 이들의 사용 방법 - Google Patents
케모카인 수용체 길항제 및 이들의 사용 방법 Download PDFInfo
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- KR20020016926A KR20020016926A KR1020027001177A KR20027001177A KR20020016926A KR 20020016926 A KR20020016926 A KR 20020016926A KR 1020027001177 A KR1020027001177 A KR 1020027001177A KR 20027001177 A KR20027001177 A KR 20027001177A KR 20020016926 A KR20020016926 A KR 20020016926A
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- substituted
- aromatic
- aliphatic group
- ring
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- 238000000034 method Methods 0.000 title claims abstract description 314
- 229940122444 Chemokine receptor antagonist Drugs 0.000 title description 6
- 239000002559 chemokine receptor antagonist Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 487
- 230000004913 activation Effects 0.000 claims abstract description 24
- 210000000265 leukocyte Anatomy 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
- 201000010099 disease Diseases 0.000 claims abstract description 21
- 238000011084 recovery Methods 0.000 claims abstract description 16
- 230000002159 abnormal effect Effects 0.000 claims abstract description 15
- -1 R 22 compound Chemical class 0.000 claims description 294
- 125000001931 aliphatic group Chemical group 0.000 claims description 280
- 125000003118 aryl group Chemical group 0.000 claims description 197
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 171
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 68
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 65
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 43
- 229910052757 nitrogen Inorganic materials 0.000 claims description 40
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 35
- 125000000623 heterocyclic group Chemical group 0.000 claims description 33
- 125000002252 acyl group Chemical group 0.000 claims description 32
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 15
- 125000004429 atom Chemical group 0.000 claims description 11
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- VHVGFEDTMPYCSX-UHFFFAOYSA-N [1-[[2,2-dimethyl-3-[[4-(oxoazaniumylmethylidene)pyridin-1-yl]methoxy]propoxy]methyl]pyridin-4-ylidene]methyl-oxoazanium;dichloride Chemical compound [Cl-].[Cl-].C1=CC(=C[NH+]=O)C=CN1COCC(C)(C)COCN1C=CC(=C[NH+]=O)C=C1 VHVGFEDTMPYCSX-UHFFFAOYSA-N 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 125000006413 ring segment Chemical group 0.000 claims description 7
- 125000005750 substituted cyclic group Chemical group 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 235
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 219
- 239000000047 product Substances 0.000 description 197
- 239000000243 solution Substances 0.000 description 179
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- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 143
- 239000000203 mixture Substances 0.000 description 115
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 100
- 238000003786 synthesis reaction Methods 0.000 description 98
- 230000015572 biosynthetic process Effects 0.000 description 97
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 93
- 239000002904 solvent Substances 0.000 description 89
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 86
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 81
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 80
- 235000019439 ethyl acetate Nutrition 0.000 description 80
- 230000002829 reductive effect Effects 0.000 description 76
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 71
- 206010057190 Respiratory tract infections Diseases 0.000 description 70
- 239000011541 reaction mixture Substances 0.000 description 70
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
- 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 55
- 229920006395 saturated elastomer Polymers 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- 239000012044 organic layer Substances 0.000 description 52
- 238000010898 silica gel chromatography Methods 0.000 description 51
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 49
- 238000006243 chemical reaction Methods 0.000 description 45
- 125000005605 benzo group Chemical group 0.000 description 43
- 239000011780 sodium chloride Substances 0.000 description 41
- 239000000460 chlorine Substances 0.000 description 40
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 40
- 235000019341 magnesium sulphate Nutrition 0.000 description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 37
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 36
- 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 32
- 238000002360 preparation method Methods 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 28
- 238000010992 reflux Methods 0.000 description 28
- 239000000741 silica gel Substances 0.000 description 28
- 229910002027 silica gel Inorganic materials 0.000 description 28
- 102000019034 Chemokines Human genes 0.000 description 25
- 108010012236 Chemokines Proteins 0.000 description 25
- 239000005557 antagonist Substances 0.000 description 23
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- 102000009410 Chemokine receptor Human genes 0.000 description 20
- 108050000299 Chemokine receptor Proteins 0.000 description 20
- 238000010586 diagram Methods 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 17
- 239000010410 layer Substances 0.000 description 17
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 15
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 14
- PBEGUZILPWUYGX-UHFFFAOYSA-N [1]benzoxepino[2,3-b]pyridine Chemical compound C1=CC2=CC=CN=C2OC2=CC=CC=C21 PBEGUZILPWUYGX-UHFFFAOYSA-N 0.000 description 14
- 235000011114 ammonium hydroxide Nutrition 0.000 description 14
- 238000009739 binding Methods 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- MTJLFBYYTSWTBO-UHFFFAOYSA-N 1-fluoropiperidine Chemical compound FN1CCCCC1 MTJLFBYYTSWTBO-UHFFFAOYSA-N 0.000 description 13
- 101710151805 Mitochondrial intermediate peptidase 1 Proteins 0.000 description 13
- 239000000908 ammonium hydroxide Substances 0.000 description 13
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 13
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 230000027455 binding Effects 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- FTERNUIABLBPER-UHFFFAOYSA-N 4-amino-3H-pyridin-4-ol Chemical compound NC1(CC=NC=C1)O FTERNUIABLBPER-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- ADEKJVNFIQUGRR-UHFFFAOYSA-N 4h-pyridin-3-one Chemical compound O=C1CC=CN=C1 ADEKJVNFIQUGRR-UHFFFAOYSA-N 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- MJUVRTYWUMPBTR-MRXNPFEDSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-n-[1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide Chemical compound FC=1C=C2N(C[C@@H](O)CO)C(C(C)(CO)C)=CC2=CC=1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 MJUVRTYWUMPBTR-MRXNPFEDSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- 229940049706 benzodiazepine Drugs 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000001404 mediated effect Effects 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 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 8
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 7
- 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
- QPJORFLSOJAUNL-UHFFFAOYSA-N dibenzo[a,d][7]annulene Chemical compound C1=CC2=CC=CC=C2CC2=CC=CC=C21 QPJORFLSOJAUNL-UHFFFAOYSA-N 0.000 description 7
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 6
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 6
- 239000012346 acetyl chloride Substances 0.000 description 6
- 125000002837 carbocyclic group Chemical group 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 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
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
- 108700012434 CCL3 Proteins 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 5
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- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical group CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 5
- 150000003053 piperidines Chemical class 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 5
- HGRWHBQLRXWSLV-DEOSSOPVSA-N (4s)-3'-(3,6-dihydro-2h-pyran-5-yl)-1'-fluoro-7'-(3-fluoropyridin-2-yl)spiro[5h-1,3-oxazole-4,5'-chromeno[2,3-c]pyridine]-2-amine Chemical compound C1OC(N)=N[C@]21C1=CC(C=3COCCC=3)=NC(F)=C1OC1=CC=C(C=3C(=CC=CN=3)F)C=C12 HGRWHBQLRXWSLV-DEOSSOPVSA-N 0.000 description 4
- 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
- NCFPUGGDCATCPI-UHFFFAOYSA-N 3-chloro-3-(4-chlorophenyl)propan-1-ol Chemical compound OCCC(Cl)C1=CC=C(Cl)C=C1 NCFPUGGDCATCPI-UHFFFAOYSA-N 0.000 description 4
- WROWOTAYCAHVMR-UHFFFAOYSA-N 4-(4-chlorophenyl)-4-methylpiperidine Chemical compound C=1C=C(Cl)C=CC=1C1(C)CCNCC1 WROWOTAYCAHVMR-UHFFFAOYSA-N 0.000 description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-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
- 102000001902 CC Chemokines Human genes 0.000 description 4
- 108010040471 CC Chemokines Proteins 0.000 description 4
- CDEMHJCJMMOFMB-UHFFFAOYSA-M ClC1=CC=C([Mg]Br)C=C1 Chemical compound ClC1=CC=C([Mg]Br)C=C1 CDEMHJCJMMOFMB-UHFFFAOYSA-M 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 4
- 230000035605 chemotaxis Effects 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- 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 4
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
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- GQONLASZRVFGHI-UHFFFAOYSA-M phenylmagnesium chloride Chemical compound Cl[Mg]C1=CC=CC=C1 GQONLASZRVFGHI-UHFFFAOYSA-M 0.000 description 1
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- 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
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridine hydrochloride Substances [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
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- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
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- 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
- 230000019491 signal transduction Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
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- 229960001967 tacrolimus Drugs 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
- ZUCCFQYHVLRASO-UHFFFAOYSA-N tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1(O)C1=CC=C(Cl)C=C1 ZUCCFQYHVLRASO-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 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 group 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
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 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
- SYUVAXDZVWPKSI-UHFFFAOYSA-N tributyl(phenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=C1 SYUVAXDZVWPKSI-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 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
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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| MXPA04004826A (es) * | 1998-09-04 | 2004-08-11 | Millenium Pharmaceuticals Inc | Antagonista del receptor de quimioquinas y metodos para su uso. |
| US6919313B2 (en) * | 2001-03-30 | 2005-07-19 | President & Fellows Of Harvard College | Protein waving a PDZ and a RGS domain |
| US7541365B2 (en) * | 2001-11-21 | 2009-06-02 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| NZ596484A (en) * | 2001-11-21 | 2013-05-31 | Millennium Pharm Inc | Chemokine receptor antagonists and methods of use thereof |
| US20060019977A1 (en) * | 2002-10-18 | 2006-01-26 | Ono Pharmaceutical Co., Ltd. | Spiroheterocyclic derivative compounds and drugs comprising the compound as the active ingredient |
| TWI291467B (en) * | 2002-11-13 | 2007-12-21 | Millennium Pharm Inc | CCR1 antagonists and methods of use therefor |
| CA2520660C (en) * | 2003-03-28 | 2013-08-20 | Sigmoid Biotechnologies Limited | Solid oral dosage form containing seamless microcapsules |
| CN100526301C (zh) * | 2003-12-26 | 2009-08-12 | 卫材R&D管理有限公司 | 1,2-二(环式基)取代苯化合物 |
| MY140489A (en) * | 2003-12-26 | 2009-12-31 | Eisai R&D Man Co Ltd | 1,2-di (cyclic) substituted benzene compounds |
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| US7410971B2 (en) * | 2003-12-26 | 2008-08-12 | Eisai R&D Management Co., Ltd. | 1,2-di(cyclic)substituted benzene compounds |
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| ATE553761T1 (de) | 2004-12-17 | 2012-05-15 | Millennium Pharm Inc | Solide formen eines chemokin-rezeptorantagonisten und anwendungsverfahren dafür |
| EP1832580A4 (en) | 2004-12-20 | 2009-03-11 | Eisai R&D Man Co Ltd | 1-CYCLOPROPYLMETHYL-4-Ý2- (3,3,5,5) -TETRAMETHYLCYCLOHEXYL) PHENYL PIPERAZINE CRYSTAL AND SALT |
| MY144974A (en) * | 2005-06-14 | 2011-11-30 | Eisai R&D Man Co Ltd | 1,2-di(cyclic) substituted benzene derivatives |
| EP2079456B1 (en) | 2007-04-04 | 2012-12-05 | Sigmoid Pharma Limited | Pharmaceutical cyclosporin compositions |
| EP2586428B1 (en) * | 2007-04-26 | 2023-11-08 | Sublimity Therapeutics Limited | Manufacture of multiple minicapsules |
| CA2685591A1 (en) * | 2007-05-01 | 2008-11-06 | Sigmoid Pharma Limited | Pharmaceutical nimodipine compositions |
| US20090286823A1 (en) * | 2007-12-17 | 2009-11-19 | Millennium Pharmaceuticals Inc. | CCR1 Inhibitors useful for the treatment of multiple myeloma and other disorders |
| ES2649112T3 (es) | 2009-05-18 | 2018-01-10 | Sigmoid Pharma Limited | Composición que comprende gotas de aceite |
| CN107582526A (zh) | 2009-08-12 | 2018-01-16 | 希格默伊德药业有限公司 | 包含聚合物基质和油相的免疫调节组合物 |
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| GB201020032D0 (en) | 2010-11-25 | 2011-01-12 | Sigmoid Pharma Ltd | Composition |
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| EP3881829A1 (en) | 2014-11-07 | 2021-09-22 | Sublimity Therapeutics Limited | Compositions comprising cyclosporin |
| CN115389659B (zh) * | 2022-08-23 | 2024-07-16 | 浙江中医药大学 | 一种细胞膜键合磁性碳球复合材料及其制备方法和应用 |
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-
1999
- 1999-07-28 US US09/362,837 patent/US6509346B2/en not_active Expired - Lifetime
-
2000
- 2000-07-28 JP JP2001514341A patent/JP4903333B2/ja not_active Expired - Fee Related
- 2000-07-28 CA CA002391267A patent/CA2391267A1/en not_active Abandoned
- 2000-07-28 DE DE60041336T patent/DE60041336D1/de not_active Expired - Lifetime
- 2000-07-28 AU AU63914/00A patent/AU6391400A/en not_active Abandoned
- 2000-07-28 WO PCT/US2000/020732 patent/WO2001009138A2/en not_active Ceased
- 2000-07-28 CN CNA008131481A patent/CN1471536A/zh active Pending
- 2000-07-28 KR KR1020027001177A patent/KR20020016926A/ko not_active Withdrawn
- 2000-07-28 EP EP00950880A patent/EP1204665B1/en not_active Expired - Lifetime
- 2000-07-28 IL IL14785200A patent/IL147852A0/xx unknown
- 2000-07-28 AT AT00950880T patent/ATE420090T1/de not_active IP Right Cessation
- 2000-07-28 HK HK02104294.3A patent/HK1044333A1/zh unknown
- 2000-07-28 HU HU0202202A patent/HUP0202202A3/hu unknown
- 2000-07-28 ES ES00950880T patent/ES2321798T3/es not_active Expired - Lifetime
- 2000-07-28 BR BR0013065-6A patent/BR0013065A/pt not_active Application Discontinuation
- 2000-07-28 EA EA200200194A patent/EA200200194A1/ru unknown
- 2000-07-28 MX MXPA02000978A patent/MXPA02000978A/es unknown
-
2002
- 2002-08-13 US US10/217,865 patent/US20030045516A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101102335B1 (ko) * | 2011-09-06 | 2012-01-03 | (주)칠칠공사 | 수영 연습용 가변형 풀 |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0202202A2 (hu) | 2002-11-28 |
| JP4903333B2 (ja) | 2012-03-28 |
| EA200200194A1 (ru) | 2002-08-29 |
| ES2321798T3 (es) | 2009-06-12 |
| CA2391267A1 (en) | 2001-02-08 |
| ATE420090T1 (de) | 2009-01-15 |
| MXPA02000978A (es) | 2002-08-12 |
| BR0013065A (pt) | 2002-07-30 |
| WO2001009138A3 (en) | 2001-09-13 |
| DE60041336D1 (de) | 2009-02-26 |
| US20030045516A1 (en) | 2003-03-06 |
| EP1204665A2 (en) | 2002-05-15 |
| HK1044333A1 (zh) | 2002-10-18 |
| AU6391400A (en) | 2001-02-19 |
| US6509346B2 (en) | 2003-01-21 |
| HUP0202202A3 (en) | 2003-05-28 |
| IL147852A0 (en) | 2002-08-14 |
| WO2001009138A2 (en) | 2001-02-08 |
| JP2003506377A (ja) | 2003-02-18 |
| CN1471536A (zh) | 2004-01-28 |
| US20020119973A1 (en) | 2002-08-29 |
| EP1204665B1 (en) | 2009-01-07 |
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