JP4870660B2 - Cxcr4アンタゴニストの合成プロセス - Google Patents
Cxcr4アンタゴニストの合成プロセス Download PDFInfo
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- JP4870660B2 JP4870660B2 JP2007503981A JP2007503981A JP4870660B2 JP 4870660 B2 JP4870660 B2 JP 4870660B2 JP 2007503981 A JP2007503981 A JP 2007503981A JP 2007503981 A JP2007503981 A JP 2007503981A JP 4870660 B2 JP4870660 B2 JP 4870660B2
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- 238000000034 method Methods 0.000 title claims description 77
- 230000008569 process Effects 0.000 title claims description 67
- 230000015572 biosynthetic process Effects 0.000 title description 15
- 238000003786 synthesis reaction Methods 0.000 title description 11
- 239000002576 chemokine receptor CXCR4 antagonist Substances 0.000 title description 2
- 229940121384 cxc chemokine receptor type 4 (cxcr4) antagonist Drugs 0.000 title description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 162
- 150000001875 compounds Chemical class 0.000 claims description 113
- 239000000243 solution Substances 0.000 claims description 82
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 78
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 63
- 239000000203 mixture Substances 0.000 claims description 62
- 239000002904 solvent Substances 0.000 claims description 40
- 150000002466 imines Chemical class 0.000 claims description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 29
- 239000003960 organic solvent Substances 0.000 claims description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 25
- -1 amino, carboxy Chemical group 0.000 claims description 25
- 238000002425 crystallisation Methods 0.000 claims description 24
- 230000008025 crystallization Effects 0.000 claims description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 21
- 150000001412 amines Chemical group 0.000 claims description 20
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 20
- 229940011051 isopropyl acetate Drugs 0.000 claims description 20
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical group CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 14
- 239000000741 silica gel Substances 0.000 claims description 12
- 229910002027 silica gel Inorganic materials 0.000 claims description 12
- 239000012535 impurity Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- 238000000746 purification Methods 0.000 claims description 10
- 150000003335 secondary amines Chemical class 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 239000013078 crystal Substances 0.000 claims description 9
- 150000003512 tertiary amines Chemical class 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 235000011054 acetic acid Nutrition 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 238000004821 distillation Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 229910052751 metal Chemical class 0.000 claims description 8
- 239000002184 metal Chemical class 0.000 claims description 8
- 150000007524 organic acids Chemical class 0.000 claims description 8
- 125000005543 phthalimide group Chemical group 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- SHQUNUAMNCPZNJ-UHFFFAOYSA-N 5,6,7,8-tetrahydroquinolin-2-amine Chemical group C1CCCC2=NC(N)=CC=C21 SHQUNUAMNCPZNJ-UHFFFAOYSA-N 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- 239000011592 zinc chloride Substances 0.000 claims description 7
- 235000005074 zinc chloride Nutrition 0.000 claims description 7
- JWYUFVNJZUSCSM-UHFFFAOYSA-N 2-aminobenzimidazole Chemical group C1=CC=C2NC(N)=NC2=C1 JWYUFVNJZUSCSM-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 239000012024 dehydrating agents Substances 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical group CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052987 metal hydride Inorganic materials 0.000 claims description 6
- 150000004681 metal hydrides Chemical class 0.000 claims description 6
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 5
- 125000006242 amine protecting group Chemical group 0.000 claims description 5
- 239000003610 charcoal Substances 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical group CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 4
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- WVLHHLRVNDMIAR-UHFFFAOYSA-N n'-(1h-benzimidazol-2-ylmethyl)-n'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine Chemical compound C1CCC2=CC=CN=C2C1N(CCCCN)CC1=NC2=CC=CC=C2N1 WVLHHLRVNDMIAR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 239000013557 residual solvent Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- WVLHHLRVNDMIAR-IBGZPJMESA-N AMD 070 Chemical compound C1CCC2=CC=CN=C2[C@H]1N(CCCCN)CC1=NC2=CC=CC=C2N1 WVLHHLRVNDMIAR-IBGZPJMESA-N 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000005015 aryl alkynyl group Chemical group 0.000 claims description 2
- 150000003857 carboxamides Chemical class 0.000 claims description 2
- 238000003818 flash chromatography Methods 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 238000010956 selective crystallization Methods 0.000 claims description 2
- 238000007614 solvation Methods 0.000 claims description 2
- 229940124530 sulfonamide Drugs 0.000 claims description 2
- 150000003456 sulfonamides Chemical class 0.000 claims description 2
- CWDABDQZCRPEJT-RUZDIDTESA-N 2-[4-[1h-benzimidazol-2-ylmethyl-[(8r)-5,6,7,8-tetrahydroquinolin-8-yl]amino]butyl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1CCCCN([C@H]1C2=NC=CC=C2CCC1)CC1=NC2=CC=CC=C2N1 CWDABDQZCRPEJT-RUZDIDTESA-N 0.000 claims 1
- CWDABDQZCRPEJT-VWLOTQADSA-N 2-[4-[1h-benzimidazol-2-ylmethyl-[(8s)-5,6,7,8-tetrahydroquinolin-8-yl]amino]butyl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1CCCCN([C@@H]1C2=NC=CC=C2CCC1)CC1=NC2=CC=CC=C2N1 CWDABDQZCRPEJT-VWLOTQADSA-N 0.000 claims 1
- RGWFFWNIIJWXKT-SFHVURJKSA-N 2-[4-[[(8s)-5,6,7,8-tetrahydroquinolin-8-yl]amino]butyl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1CCCCN[C@@H]1C2=NC=CC=C2CCC1 RGWFFWNIIJWXKT-SFHVURJKSA-N 0.000 claims 1
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims 1
- 230000000977 initiatory effect Effects 0.000 claims 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims 1
- 235000019341 magnesium sulphate Nutrition 0.000 claims 1
- WVLHHLRVNDMIAR-LJQANCHMSA-N n'-(1h-benzimidazol-2-ylmethyl)-n'-[(8r)-5,6,7,8-tetrahydroquinolin-8-yl]butane-1,4-diamine Chemical compound C1CCC2=CC=CN=C2[C@@H]1N(CCCCN)CC1=NC2=CC=CC=C2N1 WVLHHLRVNDMIAR-LJQANCHMSA-N 0.000 claims 1
- MGQNMYSRDBFUIR-UHFFFAOYSA-N nitro cyanoformate Chemical compound [O-][N+](=O)OC(=O)C#N MGQNMYSRDBFUIR-UHFFFAOYSA-N 0.000 claims 1
- NAYYNDKKHOIIOD-UHFFFAOYSA-N phthalamide Chemical compound NC(=O)C1=CC=CC=C1C(N)=O NAYYNDKKHOIIOD-UHFFFAOYSA-N 0.000 claims 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical group CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 claims 1
- 150000003573 thiols Chemical class 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 239000010410 layer Substances 0.000 description 31
- 238000005481 NMR spectroscopy Methods 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 22
- 235000011121 sodium hydroxide Nutrition 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
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- 239000002178 crystalline material Substances 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- YNZUHDHIWWRGOR-UHFFFAOYSA-N tert-butyl 2-(chloromethyl)benzimidazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C(CCl)=NC2=C1 YNZUHDHIWWRGOR-UHFFFAOYSA-N 0.000 description 10
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- 229960000583 acetic acid Drugs 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- JQGOUNFVDYUKMM-QMMMGPOBSA-N (8s)-5,6,7,8-tetrahydroquinolin-8-amine Chemical compound C1=CN=C2[C@@H](N)CCCC2=C1 JQGOUNFVDYUKMM-QMMMGPOBSA-N 0.000 description 8
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 8
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- 238000004042 decolorization Methods 0.000 description 7
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- 238000004128 high performance liquid chromatography Methods 0.000 description 7
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
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- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 4
- XCCUNWWBPDYJLY-UHFFFAOYSA-N 2-(2,2-dimethylpropanoyl)-2-ethyl-4,4-dimethyl-3-oxopentanal Chemical compound CC(C)(C)C(=O)C(C=O)(CC)C(=O)C(C)(C)C XCCUNWWBPDYJLY-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
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- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 4
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- SPMLMLQATWNZEE-UHFFFAOYSA-N 2-(chloromethyl)-1h-benzimidazole Chemical compound C1=CC=C2NC(CCl)=NC2=C1 SPMLMLQATWNZEE-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 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
- 239000002037 dichloromethane fraction Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
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- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 3
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D401/14—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 three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
-
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Description
本発明は、CXCR4ケモカインレセプターに結合する、薬学的複素環化合物を合成するためのプロセスに関する。
当業者により、純粋で安定した形態の薬学的化合物の、能率よく、信頼できる、合成経路を開発することが望まれる。例として、特許文献1で開示された、新しい複素環化合物は、標的細胞のヒト免疫不全ウイルス(HIV)による感染に対する、保護効果を示す。
本発明は、CXCR4ケモカインレセプターに結合する、薬学的複素環化合物を合成するプロセスを提供する。特定の実施形態において、本発明は、式I’:
a)必要に応じて置換された(R1)5,6,7,8−テトラヒドロキノリニルアミン((R)、(S)または(R,S))を、脱水剤を含むか、または含まない有機溶媒中で、フタルイミド保護基またはジ−tert−ブトキシカルボニル(ジ−BOC)保護基を有するアルキルアルデヒドと反応させ、イミンを生成することと;
b)有機酸または金属塩の存在下で、有機溶媒中のイミンを、金属水素化物還元剤を用いて還元し、第二級アミンを形成することと;
c)第二級アミンを、有機溶媒中で、ベンゾイミダゾールアミン保護基または他のアミン置換基を必要に応じて有する、必要に応じて置換された2−ハロメチルベンゾイミダゾールと反応させ、フタルイミドで保護された第三級アミン、またはジ−tert−ブトキシカルボニルで保護された第三級アミンを形成することと;そして
d)保護された第三級アミンを加水分解して、式IA’を有する化合物を得ることとを
包含する。
(a)式I’の化合物を、脱色炭およびシリカゲルを用いて処理して、不純物を除去する工程;ならびに、
(b)光学活性な式I’の化合物の場合には、選択的に結晶化するプロセスにより、結晶性物質((R)エナンチオマーまたは(S)エナンチオマーとして)として、N’−(1H−ベンゾイミダゾール−2−イルメチル)−N’−5,6,7,8−テトラヒドロキノリン−8−イル−アルキルジアミン(I’)を単離する工程
を包含し得る。
(a)非置換(5,6,7,8−テトラヒドロキノリンー8−イル)−アミン(S)を、金属炭酸塩の存在下で、有機溶媒中で1−(1,3−ジオキソ−1,3−ジヒドロイソインドール−2−イル)−ブタン−4−アールと反応させ、縮合によってイミンを生成し;
(b)有機溶媒中のイミンを、金属水素化物還元試薬、および有機酸または金属塩のいずれかを用いて還元し、N−{[1−(1,3−ジオキソ−1,3−ジヒドロイソインドール−2−イル)−ブタン−4−イル]−(5,6,7,8−テトラヒドロキノリン−8−イル)}−アミンを生成して;
(c)N−{[1−(1,3−ジオキソ−1,3−ジヒドロイソインドール−2−イル)−ブタン−4−イル]−(5,6,7,8−テトラヒドロキノリン−8−イル)}−アミンを、塩基性条件下、温度を上げ、有機溶媒中で、ベンゾイミダゾールアミン保護基として、ブトキシカルボニル部分を有する2−クロロメチルベンゾイミダゾールと反応させ、N−{[1−(1,3−ジオキソ−1,3−ジヒドロイソインドール−2−イル)−ブタン−4−イル]−[(ベンゾイミダゾール−2−イル)−メチル]−(5,6,7,8−テトラヒドロキノリン−8−イル)}−アミンを生成し;そして、
(d)順番に、または同時に、ベンゾイミダゾールアミン保護基、およびフタルイミド保護基を加水分解し、式Iに従う化合物を得ること
を包含する。
多くの薬学的化合物は、複数工程の化学合成を経て生成される。これらのプロセス中の各化学的工程は、純粋な化合物を効率よく誘導すべきである。この目的を達成するには、各工程を、実験的に最適化し、収量と生成物純度とを共に高めなければならない。潜在的に有害な副生成物または他の不純物を確実になくすために、合成の最後に、しばしば生物的に活性な薬学的化合物の最終精製が必要となる。
光学純度%=[α]観測値×100
[α]最大値
示すとおり、[α]観測値は、平面偏光の観測された回転角度であり、[α]最大値は、可能な最大回転である(単一のエナンチオマーに対し観測される回転)。この鏡像体過剰率はまた、絶対配置に関連し、次のとおり、1つのエナンチオマーの他のエナンチオマーに対する過剰率として評価される。
ee=[R]−[S]×100=%R−%S
[R]+[S]
キラルな薬物(chiral drug)のエナンチオマーは、大半が立体選択的である生物高分子と、影響し合うので、薬理学的効果および毒物学的効果が大きく異なるかもしれない(Drayer,Clin.Pharmacol.Ther.40:125(1986))。したがって、この薬物を単一のエナンチオマーとして純粋な形態で単離することが、当業者により、しばしば望まれている。8−アミノ−5,6,7,8−テトラヒドロキノリンの場合には、酵素の運動分解が、高い鏡像体純度(enantiopurity)(97%ee)で(S)−エナンチオマーを与える。(R)−エナンチオマーもまた、高い鏡像体純度で単離することができる。(国際公開第2003/022785号パンフレット参照)。
本発明は、スキーム5で示すとおり、式IIIのアルキルアルデヒドを用いた、式IIのアミノ置換5,6,7,8−テトラヒドロキノリンの能率的な形成プロセスを提供する。
本発明は、スキーム6に図示するとおり、イミン(式IV)を、化学還元して、還元された形態(式V)にするプロセスを提供する。
本発明は、アミンを保護された2−クロロメチルベンゾイミダゾール(式VI)を用いた、第二級アミン(式V)のアルキル化のプロセスを提供し、式VIIに従う第三級アミンを合成する。より詳細には、スキーム7は、アミン塩基および触媒量のヨウ化物の存在下、高温で、有機溶媒中での第二級アミン(式V)とアミンを保護された2−クロロメチルベンゾイミダゾール(式VI)との反応を示す。(Cookら,Tetrahedron,54:3999−4012(1998)も参照)。
さらに、本発明は、ブトキシカルボニル保護基(存在すれば)、およびフタルイミドアミン保護基を、式VIIの化合物から除去する手順を提供する。スキーム8は、脱保護の手順を図示している。
本発明はまた、次のとおり、式Iの化合物の精製および/または脱色のための任意的な追加的工程を提供する。1つの例では、式Iを有する化合物の水溶液は、脱色炭を用いて処理し、有色の不純物を除去することができる。別の例では、式Iを有する化合物を、有機溶媒を使用して抽出し、シリカゲルフラッシュクロマトグラフィを使用して精製することができる。
光学的に活性な式IIの化合物で開始され、したがって、光学的に活性な式Iの化合物を提供する合成経路に関し、本発明は、有機溶媒の混合物から式Iの化合物を結晶化するプロセスを提供する。1つの例では、本発明は、式Iを有する光学的に活性な化合物を生成するためのプロセスを提供し、このプロセスは:
a)有機溶媒の混合物(溶媒A)中で式Iを有する化合物を含有する溶液を濃縮し、予め決定された濃度の溶液を形成することと;
b)適当な結晶化溶媒または溶媒の混合物(溶媒B)を、a)中の溶液に加え、特定の温度で、共蒸留のプロセスにより予め決定された体積または濃度になるまで、残留する溶媒Aを必要に応じて除去することと;
c)適切な温度で、b)中の溶液に、少量の純粋な結晶状の(適切な形態のエナンチオマーの)式Iの化合物を加え、式Iを有する結晶が、自然に形成されるような制御条件下で、攪拌しながら混合物を冷却することと;
d)結晶状の物質を濾過し、そして乾燥させることとを
包含する。
(フタルイミド−置換アルキルアルデヒドからの(N’−(1H−ベンゾイミダゾール−2−イルメチル)−N’−5,6,7,8−テトラヒドロキノリン−8−イル−1,4−ブタンジアミンの合成)
化合物Iを、酢酸イソプロピル溶液を使用して、共蒸留(co−distillation)によりジクロロメタンを除去しながら、遊離塩基として結晶化することができる。CH2Cl2(50L)中のI(4.5kg、12.9mol)の溶液を、室温で8時間、無水Na2SO4(500g、3.5mol)と共に攪拌した。この混合物を、濾過して反応器へ移し、溶液を窒素雰囲気中に置いた。この混合物を、25℃に温めて真空中(約30mmHg)に置き、濃縮の間の溶液の温度を20℃と30℃との間に維持しながら、CH2Cl2を除去した。次いで、酢酸イソプロピル(32L)を加えた。
(tert−ブトキシカルボニル(BOC)置換アルキルアルデヒドからの(N’−(1H−ベンゾイミダゾール−2−イルメチル)−N’−5,6,7,8−テトラヒドロキノリン−8−イル−1,4−ブタンジアミンの合成)
(−(1H−ベンゾイミダゾール−2−イルメチル)−N’−5,6,7,8−テトラヒドロキノリン−8−イル−1,4−ブタンジアミンの大規模合成)
Claims (39)
- 式I’:
ここで、R、R1、R2およびR3は、独立して、水素、ハロ、ニトロ、シアノ、カルボン酸、アルキル(C1〜10)、アルケニル(C2〜10)、アルキニル(C2〜10)、シクロアルキル、ヒドロキシル、チオール、アミノ、カルボキシレート、カルボキサミド、スルホンアミド、芳香族基、複素環基、アリール(C5〜12)、アリールアルキル、アリールアルケニル、またはアリールアルキニルであり;
kは0〜3であり、
mは0〜4であり、そして
nは1〜6であり、該プロセスは、
(a) R1で必要に応じて置換された5,6,7,8−テトラヒドロキノリニルアミンを、フタルイミド保護基、またはジ−tert−ブトキシカルボニル保護基を有するアルキルアルデヒドと反応させて、イミンを生成することと;
(b) 金属水素化物還元試薬および、有機酸または金属塩のいずれかと共に、有機溶媒中でイミンを還元し、第二級アミンを形成することと;
(c) R3 で必要に応じて置換され、そしてベンゾイミダゾールアミン保護基あるいは他のアミン置換(R2)を必要に応じて有する2−ハロメチルベンゾイミダゾールと該第二級アミンを反応させ、フタルイミドで保護された第三級アミン、またはジ−tert−ブトキシカルボニルで保護された第三級アミンを形成することと;
(d)該保護された第三級アミンを加水分解することにより、式I’の化合物を得ることと
を含む、プロセス。 - 脱色炭またはシリカゲルを用いて、式Iの化合物を処理して、不純物を除去することをさらに包含する、請求項1に記載のプロセス。
- 前記5,6,7,8−テトラヒドロキノリニルアミンが、ラセミ混合物である、請求項1に記載のプロセス。
- 式I’の化合物が、ラセミ混合物である、請求項3に記載のプロセス。
- 結晶化溶媒中での選択的な結晶化によって、(R)エナンチオマーまたは(S)エナンチオマーを単離することをさらに包含する、請求項4に記載のプロセス。
- 前記5,6,7,8−テトラヒドロキノリニルアミンが、光学的に活性な(S)エナンチオマーである、請求項1に記載のプロセス。
- 式I’の化合物が、光学的に活性な(S)エナンチオマーである、請求項6に記載のプロセス。
- 前記5,6,7,8−テトラヒドロキノリニルアミンが、光学的に活性な(R)エナンチオマーである、請求項1に記載のプロセス。
- 式I’の化合物が、光学的に活性な(R)エナンチオマーである、請求項8に記載のプロセス。
- R、R1、R2、R3が、それぞれ水素である、請求項1に記載のプロセス。
- nが3である、請求項1に記載のプロセス。
- R、R1、R2、R3のうち少なくとも1つが、O、SおよびNからなる群から選択される、1つ以上のヘテロ原子を含む、請求項1に記載のプロセス。
- 前記アルキルアルデヒドが、エチルアルデヒド、プロピルアルデヒド、ブチルアルデヒドまたはペンチルアルデヒドである、請求項1に記載のプロセス。
- 工程(a)における脱水剤が、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム、または硫酸マグネシウムである、請求項1に記載のプロセス。
- 工程(b)における還元剤が、水素化ホウ素ナトリウムであり、前記有機酸が、酢酸、プロピオン酸、および塩化亜鉛からなる群から選択される、請求項1に記載のプロセス。
- 工程(b)が、−25℃〜−5℃の低温度で実施される、請求項1に記載のプロセス。
- 工程(c)における有機溶媒が、さらに、アミン塩基および触媒量のヨウ化物を含む、請求項1に記載のプロセス。
- 前記アミン塩基が、ジイソプロピルエチルアミンである、請求項17に記載のプロセス。
- 工程(c)において上昇した温度が40℃〜60℃である、請求項1に記載のプロセス。
- R2が、t−ブトキシカルボニルアミン保護基である、請求項1に記載のプロセス。
- 工程(d)におけるアミン保護基の除去が、水性条件下で、pH3で実行される、請求項20に記載のプロセス。
- 工程(d)におけるフタルイミド保護基の除去が、ヒドラジン、エチレンジアミン、n−ブチルアミン、またはメチルアミンを用いて実行される、請求項1に記載のプロセス。
- 式I’の化合物を精製するための精製工程をさらに包含する、請求項1に記載のプロセス。
- 式I’の化合物を、マイルドな酸性の水溶液に抽出し、続いて活性炭を用いて処理する、請求項23に記載のプロセス。
- 式I’の化合物の有機溶液を活性炭を用いて処理し、続いて濾過し、そしてマイルドな酸性の水溶液への抽出を行なう、請求項23に記載のプロセス。
- 前記精製工程が、式I’の化合物の塩基性水溶液の、ジクロロメタンを用いた抽出、続いてシリカゲルフラッシュクロマトグラフィを含む、請求項23に記載のプロセス。
- 前記精製工程が、水酸化ナトリウム水溶液を用いて、式I’の化合物のジクロロメタン溶液を抽出することにより、薬学的に受容可能なレベルにヒドラジンのレベルを下げることを含む、請求項23に記載のプロセス。
- 前記結晶化溶媒が酢酸イソプロピルである、請求項5に記載のプロセス。
- 前記結晶化溶媒が、酢酸エチル、テトラヒドロフラン、またはジクロロメタンである、請求項5に記載のプロセス。
- 残留したジクロロメタンのレベルを制御するための共蒸留手順をさらに包含する、請求項23に記載のプロセス。
- 式I’の化合物を、前記結晶化工程の前に濃縮乾固する工程をさらに包含する、請求項5に記載のプロセス。
- 前記結晶化溶媒が、酢酸イソプロピル、または酢酸エチルであり、かつ前記結晶化工程が、該結晶化溶媒との溶媒和を達成するために、50℃〜65℃の温度で実行される、請求項5に記載のプロセス。
- 前記結晶化工程が、式I’の化合物の溶液に、結晶性の式I’の化合物を種として加え、結晶化を開始させることをさらに包含する、請求項5に記載のプロセス。
- 式I’の化合物の溶液を攪拌して式I’の化合物の結晶粒子の大きさを制御しながら、前記結晶化工程が実行される、請求項5に記載のプロセス。
- 式I’の化合物の結晶を、真空オーブン中で乾燥させて、残留する溶媒のレベルを下げる、請求項5に記載のプロセス。
- 式I’の化合物が、(S)−N’−(1H−ベンゾイミダゾール−2−イルメチル)−N’−5,6,7,8−テトラヒドロキノリン−8−イル−1,4−ブタンジアミン;(R)−N’−(1H−ベンゾイミダゾール−2−イルメチル)−N’−5,6,7,8−テトラヒドロキノリン−8−イル−1,4−ブタンジアミン;および(R,S)−N’−(1H−ベンゾイミダゾール−2−イルメチル)−N’−5,6,7,8−テトラヒドロキノリン−8−イル−1,4−ブタンジアミンからなる群から選択される、請求項1に記載のプロセス。
- 前記フタルアミドで保護された第三級アミン化合物が、N−{[(ベンゾイミダゾール−2−イル)メチル−(1,3−ジオキソ−1,3−ジヒドロイソインドール−2−イル)−アルキル]−テトラヒドロキノリニル}アミン;(S)−2−{4−[(1H−ベンゾイミダゾール−2−イルメチル)−(5,6,7,8−テトラヒドロキノリン−8−イル)−アミノ]−ブチル}−イソインドール−1,3−ジオン;(R)−2−{4−[(1H−ベンゾイミダゾール−2−イルメチル)−(5,6,7,8−テトラヒドロキノリン−8−イル)−アミノ]−ブチル}−イソインドール−1,3−ジオン;または、(R,S)−2−{4−[(1H−ベンゾイミダゾール−2−イルメチル)−(5,6,7,8−テトラヒドロキノリン−8−イル)−アミノ]−ブチル}−イソインドール−1,3−ジオンである、請求項1に記載のプロセス。
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US (1) | US7332605B2 (ja) |
EP (1) | EP1730113B1 (ja) |
JP (1) | JP4870660B2 (ja) |
KR (1) | KR20060131899A (ja) |
CN (1) | CN1930127B (ja) |
AU (1) | AU2005224079A1 (ja) |
BR (1) | BRPI0508703B8 (ja) |
CA (1) | CA2558389C (ja) |
ES (1) | ES2614508T3 (ja) |
IL (1) | IL177511A (ja) |
NO (1) | NO20064200L (ja) |
RU (1) | RU2006136381A (ja) |
WO (1) | WO2005090308A1 (ja) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7354932B2 (en) | 2001-12-21 | 2008-04-08 | Anormed, Inc. | Chemokine receptor binding heterocyclic compounds with enhanced efficacy |
AR050522A1 (es) * | 2004-08-16 | 2006-11-01 | Smithkline Beecham Corp | Derivados de bencimidazol como moduladores de la actividad de los receptores de quimioquina; composiciones farmaceuticas que los contienen; metodos para su preparacion y su uso en la fabricacion de medicamentos para el tratamiento contra infecciones por hiv |
TW200619206A (en) * | 2004-09-29 | 2006-06-16 | Anormed Inc | Chemokine-binding heterocyclic compound salts, and methods of use thereof |
TW200738711A (en) * | 2006-01-25 | 2007-10-16 | Smithkline Beecham Corp | Chemical compounds |
JP2009524689A (ja) * | 2006-01-25 | 2009-07-02 | スミスクライン ビーチャム コーポレーション | 化合物 |
WO2008017025A2 (en) * | 2006-08-02 | 2008-02-07 | Genzyme Corporation | Combination therapy |
WO2008134326A1 (en) * | 2007-04-26 | 2008-11-06 | Dow Global Technologies Inc. | Novel aldehyde composition |
FR2934859B1 (fr) * | 2008-08-05 | 2010-08-13 | Servier Lab | Nouveau procede de synthese de l'agomelatine |
EA022623B1 (ru) | 2010-10-06 | 2016-02-29 | ГЛАКСОСМИТКЛАЙН ЭлЭлСи | Производные бензимидазола в качестве ингибиторов pi3-киназ |
WO2017106332A1 (en) | 2015-12-14 | 2017-06-22 | X4 Pharmaceuticals, Inc. | Methods for treating cancer |
ES2907489T3 (es) | 2015-12-14 | 2022-04-25 | X4 Pharmaceuticals Inc | Métodos para el tratamiento del cáncer |
CN108883091A (zh) | 2015-12-22 | 2018-11-23 | X4 制药有限公司 | 用于治疗免疫缺陷病的方法 |
GB201604213D0 (en) * | 2016-03-11 | 2016-04-27 | Proximagen Ltd | Drug combination and its use in therapy |
US11337969B2 (en) | 2016-04-08 | 2022-05-24 | X4 Pharmaceuticals, Inc. | Methods for treating cancer |
US10988465B2 (en) | 2016-06-21 | 2021-04-27 | X4 Pharmaceuticals, Inc. | CXCR4 inhibitors and uses thereof |
EP3808748A1 (en) | 2016-06-21 | 2021-04-21 | X4 Pharmaceuticals, Inc. | Substituted piperidines as cxcr4-inhibitors |
US11332470B2 (en) | 2016-06-21 | 2022-05-17 | X4 Pharmaceuticals, Inc. | CXCR4 inhibitors and uses thereof |
US10548889B1 (en) * | 2018-08-31 | 2020-02-04 | X4 Pharmaceuticals, Inc. | Compositions of CXCR4 inhibitors and methods of preparation and use |
WO2022113069A1 (en) | 2020-11-24 | 2022-06-02 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | E protein channel blockers and orf3 inhibitors as anti-covid-19 agents |
IL297852A (en) | 2020-05-01 | 2023-01-01 | Yissum Res Dev Co Of Hebrew Univ Jerusalem Ltd | E protein channel blockers, and orf3 inhibitors, against covid 19 |
WO2023059903A1 (en) * | 2021-10-07 | 2023-04-13 | X4 Pharmaceuticals, Inc. | Synthesis of mavorixafor and intermediates thereof |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9126677D0 (en) | 1991-12-16 | 1992-02-12 | Johnson Matthey Plc | Improvements in chemical compounds |
GB9400411D0 (en) | 1994-01-11 | 1994-03-09 | Johnson Matthey Plc | Improvements in chemical compounds |
GB9511357D0 (en) | 1995-06-06 | 1995-08-02 | Johnson Matthey Plc | Improved antiviral compounds |
TR199902923T2 (xx) * | 1997-06-02 | 2000-11-21 | Janssen Pharmaceutica N.V. | Yumu�ak kas h�cresi �o�almas� inhibit�rleri olarak (imidazol-5-il)metil-2-kuinolinon t�revleri. |
CA2368047A1 (en) | 1999-03-24 | 2000-09-28 | Anormed Inc. | Chemokine receptor binding heterocyclic compounds |
CN1457339A (zh) * | 2000-09-15 | 2003-11-19 | 阿诺麦德股份有限公司 | 趋化因子受体结合性杂环化合物 |
BR0113932A (pt) * | 2000-09-15 | 2003-06-24 | Anormed Inc | Compostos heterocìclicos que se ligam ao receptor da quimiocina |
CZ10903U1 (en) * | 2001-01-11 | 2001-02-19 | Oldrich Ing Cihak | Bladed water wheel |
US7354932B2 (en) * | 2001-12-21 | 2008-04-08 | Anormed, Inc. | Chemokine receptor binding heterocyclic compounds with enhanced efficacy |
RU2325387C2 (ru) * | 2001-12-21 | 2008-05-27 | Анормед Инк. | Гетероциклические соединения с повышенной эффективностью, связывающиеся с рецептором хемокина |
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- 2005-03-11 RU RU2006136381/04A patent/RU2006136381A/ru not_active Application Discontinuation
- 2005-03-11 AU AU2005224079A patent/AU2005224079A1/en not_active Abandoned
- 2005-03-11 CA CA2558389A patent/CA2558389C/en active Active
- 2005-03-11 JP JP2007503981A patent/JP4870660B2/ja active Active
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Also Published As
Publication number | Publication date |
---|---|
EP1730113A1 (en) | 2006-12-13 |
US7332605B2 (en) | 2008-02-19 |
KR20060131899A (ko) | 2006-12-20 |
RU2006136381A (ru) | 2008-04-27 |
WO2005090308A1 (en) | 2005-09-29 |
JP2007529526A (ja) | 2007-10-25 |
CN1930127B (zh) | 2012-11-21 |
BRPI0508703A (pt) | 2007-08-07 |
AU2005224079A1 (en) | 2005-09-29 |
NO20064200L (no) | 2006-09-15 |
CN1930127A (zh) | 2007-03-14 |
CA2558389A1 (en) | 2005-09-29 |
EP1730113A4 (en) | 2009-12-02 |
EP1730113B1 (en) | 2016-12-28 |
US20050209277A1 (en) | 2005-09-22 |
BRPI0508703B1 (pt) | 2020-11-24 |
CA2558389C (en) | 2013-10-08 |
BRPI0508703B8 (pt) | 2021-05-25 |
IL177511A0 (en) | 2006-12-10 |
IL177511A (en) | 2010-12-30 |
ES2614508T3 (es) | 2017-05-31 |
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