ES2325831T3 - Derivados de ciclohexano sustituidos con amino para el tratamiento de infecciones bacterianas. - Google Patents
Derivados de ciclohexano sustituidos con amino para el tratamiento de infecciones bacterianas. Download PDFInfo
- Publication number
- ES2325831T3 ES2325831T3 ES03747857T ES03747857T ES2325831T3 ES 2325831 T3 ES2325831 T3 ES 2325831T3 ES 03747857 T ES03747857 T ES 03747857T ES 03747857 T ES03747857 T ES 03747857T ES 2325831 T3 ES2325831 T3 ES 2325831T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- hydroxy
- alkenyl
- amino
- optionally substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- -1 AMINO Chemical group 0.000 title claims abstract description 361
- 208000035143 Bacterial infection Diseases 0.000 title claims description 7
- 208000022362 bacterial infectious disease Diseases 0.000 title claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 211
- 150000001875 compounds Chemical class 0.000 claims abstract description 208
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 94
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 87
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 74
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 64
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 60
- 150000002367 halogens Chemical class 0.000 claims abstract description 60
- 125000003118 aryl group Chemical group 0.000 claims abstract description 58
- 150000003839 salts Chemical class 0.000 claims abstract description 53
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims abstract description 51
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 claims abstract description 50
- 150000002148 esters Chemical class 0.000 claims abstract description 49
- 125000003277 amino group Chemical group 0.000 claims abstract description 44
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 42
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims abstract description 40
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims abstract description 40
- 239000001257 hydrogen Substances 0.000 claims abstract description 38
- 125000004429 atom Chemical group 0.000 claims abstract description 36
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 35
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 34
- 125000005137 alkenylsulfonyl group Chemical group 0.000 claims abstract description 30
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 30
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 28
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 27
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 27
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 26
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 25
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 22
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 22
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 21
- 125000001424 substituent group Chemical group 0.000 claims abstract description 21
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 20
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 17
- 125000006574 non-aromatic ring group Chemical group 0.000 claims abstract description 17
- 125000002252 acyl group Chemical group 0.000 claims abstract description 16
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 16
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract description 15
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 15
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 14
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 13
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract description 13
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 13
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims abstract description 13
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims abstract description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 11
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 10
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 10
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims abstract description 9
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims abstract description 8
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims abstract description 8
- 125000001414 1,2,4-triazol-5-yl group Chemical group [H]N1N=C([H])N=C1[*] 0.000 claims abstract description 7
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims abstract description 7
- 125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 7
- 125000005035 acylthio group Chemical group 0.000 claims abstract description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 6
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 4
- 125000004442 acylamino group Chemical group 0.000 claims abstract description 3
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims abstract description 3
- 125000005360 alkyl sulfoxide group Chemical group 0.000 claims abstract description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 claims abstract description 3
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims abstract description 3
- 125000005110 aryl thio group Chemical group 0.000 claims abstract description 3
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 3
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims abstract description 3
- 125000004468 heterocyclylthio group Chemical group 0.000 claims abstract description 3
- 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 claims abstract description 3
- 125000004549 quinolin-4-yl group Chemical group N1=CC=C(C2=CC=CC=C12)* 0.000 claims abstract description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 203
- 239000002253 acid Substances 0.000 claims description 128
- 150000001408 amides Chemical class 0.000 claims description 63
- 229910005965 SO 2 Inorganic materials 0.000 claims description 23
- 101100240517 Caenorhabditis elegans nhr-11 gene Proteins 0.000 claims description 18
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 16
- QURAWDWTNZXEDT-UHFFFAOYSA-N 2-methoxyquinolin-8-amine Chemical compound C1=CC=C(N)C2=NC(OC)=CC=C21 QURAWDWTNZXEDT-UHFFFAOYSA-N 0.000 claims description 11
- JHIAOWGCGNMQKA-UHFFFAOYSA-N 2-methyl-8-quinolinamine Chemical compound C1=CC=C(N)C2=NC(C)=CC=C21 JHIAOWGCGNMQKA-UHFFFAOYSA-N 0.000 claims description 11
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- 125000004043 oxo group Chemical group O=* 0.000 claims description 11
- DMBFCTCQROWGDZ-UHFFFAOYSA-N 8-aminoquinoline-2-carbonitrile Chemical compound C1=C(C#N)N=C2C(N)=CC=CC2=C1 DMBFCTCQROWGDZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 6
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 6
- 229910052727 yttrium Inorganic materials 0.000 claims description 6
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 5
- 150000003950 cyclic amides Chemical class 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 229910052721 tungsten Inorganic materials 0.000 claims description 5
- YJGLLSACEYQDLT-FBIMIBRVSA-N (1r,3r,4r)-3-hydroxy-4-[(3-oxo-4h-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino]cyclohexane-1-carboxylic acid Chemical compound O[C@@H]1C[C@H](C(O)=O)CC[C@H]1NCC1=CC=C(SCC(=O)N2)C2=N1 YJGLLSACEYQDLT-FBIMIBRVSA-N 0.000 claims description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 4
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000004553 quinoxalin-5-yl group Chemical group N1=CC=NC2=C(C=CC=C12)* 0.000 claims description 4
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000005948 methanesulfonyloxy group Chemical group 0.000 claims description 3
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 claims description 3
- JTNBYFVUXPHZIJ-UHFFFAOYSA-N 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-amine Chemical compound O1CCOC2=C1N=CC=C2N JTNBYFVUXPHZIJ-UHFFFAOYSA-N 0.000 claims description 2
- TXZGIJQANGIGSE-UHFFFAOYSA-N 3-methylquinoxalin-5-amine Chemical compound C1=CC=C(N)C2=NC(C)=CN=C21 TXZGIJQANGIGSE-UHFFFAOYSA-N 0.000 claims description 2
- RDZNOWLQQWAKKF-UHFFFAOYSA-N 6-[[[4-hydroxy-4-[2-(2-methoxyquinolin-8-yl)ethyl]cyclohexyl]amino]methyl]-4h-pyrido[3,2-b][1,4]oxazin-3-one Chemical compound O1CC(=O)NC2=NC(CNC3CCC(CC3)(O)CCC3=CC=CC4=CC=C(N=C43)OC)=CC=C21 RDZNOWLQQWAKKF-UHFFFAOYSA-N 0.000 claims description 2
- VUHCPMIDSUGHNO-UHFFFAOYSA-N 6-methoxy-1,5-naphthyridin-4-amine Chemical compound N1=CC=C(N)C2=NC(OC)=CC=C21 VUHCPMIDSUGHNO-UHFFFAOYSA-N 0.000 claims description 2
- 101100294102 Caenorhabditis elegans nhr-2 gene Proteins 0.000 claims description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
- 125000005605 benzo group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- CWXZEXZFHGYYCD-UHFFFAOYSA-N thieno[3,2-b]pyridin-7-amine Chemical compound NC1=CC=NC2=C1SC=C2 CWXZEXZFHGYYCD-UHFFFAOYSA-N 0.000 claims description 2
- PWHNTUSIPQQBCT-XFQXTVEOSA-N (1r,3r,4r)-n-(2-cyanoquinolin-8-yl)-3-hydroxy-4-[(3-oxo-4h-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino]cyclohexane-1-carboxamide Chemical compound C1=C(C#N)N=C2C(NC(=O)[C@H]3C[C@H]([C@@H](CC3)NCC=3N=C4NC(=O)CSC4=CC=3)O)=CC=CC2=C1 PWHNTUSIPQQBCT-XFQXTVEOSA-N 0.000 claims 2
- 101150020251 NR13 gene Proteins 0.000 claims 2
- PWHNTUSIPQQBCT-ZAAXVRCTSA-N (1s,3r,4s)-n-(2-cyanoquinolin-8-yl)-3-hydroxy-4-[(3-oxo-4h-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino]cyclohexane-1-carboxamide Chemical compound C1=C(C#N)N=C2C(NC(=O)[C@@H]3C[C@H]([C@H](CC3)NCC=3N=C4NC(=O)CSC4=CC=3)O)=CC=CC2=C1 PWHNTUSIPQQBCT-ZAAXVRCTSA-N 0.000 claims 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 claims 1
- CJIIYERJYXPGHA-UHFFFAOYSA-N 2-methylquinoxalin-5-amine Chemical compound NC1=CC=CC2=NC(C)=CN=C21 CJIIYERJYXPGHA-UHFFFAOYSA-N 0.000 claims 1
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 claims 1
- LRIOBKKSONRPSN-UHFFFAOYSA-N 3-methoxyquinolin-5-amine Chemical compound C1=CC=C(N)C2=CC(OC)=CN=C21 LRIOBKKSONRPSN-UHFFFAOYSA-N 0.000 claims 1
- ANDGDEKVTJNURV-UHFFFAOYSA-N 4-aminoquinoline-6-carbonitrile Chemical compound C1=C(C#N)C=C2C(N)=CC=NC2=C1 ANDGDEKVTJNURV-UHFFFAOYSA-N 0.000 claims 1
- PJDFSPWLDZBWIX-UHFFFAOYSA-N 5-methoxyquinolin-4-amine Chemical compound C1=CC(N)=C2C(OC)=CC=CC2=N1 PJDFSPWLDZBWIX-UHFFFAOYSA-N 0.000 claims 1
- ZZRDGWHDXUEJBL-HAQNSBGRSA-N OC(=O)[C@H]1CC[C@@H](CC1)NCc1ccc2SCC(=O)Nc2c1 Chemical compound OC(=O)[C@H]1CC[C@@H](CC1)NCc1ccc2SCC(=O)Nc2c1 ZZRDGWHDXUEJBL-HAQNSBGRSA-N 0.000 claims 1
- WWYLVEIKNRIFSD-UHFFFAOYSA-N n-(6-methoxy-1,5-naphthyridin-4-yl)cyclohexanecarboxamide Chemical compound C12=NC(OC)=CC=C2N=CC=C1NC(=O)C1CCCCC1 WWYLVEIKNRIFSD-UHFFFAOYSA-N 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 17
- 125000003302 alkenyloxy group Chemical group 0.000 abstract 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 abstract 1
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 abstract 1
- 125000005361 aryl sulfoxide group Chemical group 0.000 abstract 1
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 abstract 1
- 125000004966 cyanoalkyl group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 204
- 239000007787 solid Substances 0.000 description 188
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 182
- 239000000243 solution Substances 0.000 description 133
- 239000000203 mixture Substances 0.000 description 117
- 150000002500 ions Chemical class 0.000 description 115
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 113
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 105
- 238000006243 chemical reaction Methods 0.000 description 91
- 150000001299 aldehydes Chemical class 0.000 description 90
- 150000001412 amines Chemical class 0.000 description 82
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 80
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 70
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 65
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 49
- 238000004587 chromatography analysis Methods 0.000 description 49
- 235000019439 ethyl acetate Nutrition 0.000 description 45
- 239000000047 product Substances 0.000 description 41
- 239000000463 material Substances 0.000 description 40
- 235000019441 ethanol Nutrition 0.000 description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 35
- 239000012458 free base Substances 0.000 description 33
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
- 239000003921 oil Substances 0.000 description 29
- 235000019198 oils Nutrition 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000000284 extract Substances 0.000 description 27
- 239000000377 silicon dioxide Substances 0.000 description 27
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 26
- 239000002585 base Substances 0.000 description 23
- 230000008569 process Effects 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000001914 filtration Methods 0.000 description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- ZUMYZBZADRZJEV-IWSPIJDZSA-N (1r,3r,4r)-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]cyclohexane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(O)=O)C[C@H]1O ZUMYZBZADRZJEV-IWSPIJDZSA-N 0.000 description 17
- 239000003638 chemical reducing agent Substances 0.000 description 17
- 230000009467 reduction Effects 0.000 description 17
- 238000006722 reduction reaction Methods 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 17
- 235000017557 sodium bicarbonate Nutrition 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 235000011054 acetic acid Nutrition 0.000 description 14
- 238000005804 alkylation reaction Methods 0.000 description 14
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 238000005932 reductive alkylation reaction Methods 0.000 description 14
- CNQGYYKZRTYCLG-HSUXUTPPSA-N (1r,3r,4r)-4-amino-3-hydroxycyclohexane-1-carboxylic acid Chemical compound N[C@@H]1CC[C@@H](C(O)=O)C[C@H]1O CNQGYYKZRTYCLG-HSUXUTPPSA-N 0.000 description 13
- 230000029936 alkylation Effects 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 150000004702 methyl esters Chemical class 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 238000007796 conventional method Methods 0.000 description 10
- 238000005859 coupling reaction Methods 0.000 description 10
- 230000007062 hydrolysis Effects 0.000 description 10
- 238000006460 hydrolysis reaction Methods 0.000 description 10
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 10
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- 229960004979 fampridine Drugs 0.000 description 1
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- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
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- 125000005456 glyceride group Chemical group 0.000 description 1
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- 125000001188 haloalkyl group Chemical group 0.000 description 1
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- 239000004312 hexamethylene tetramine Substances 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011905 homologation Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
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- 238000006703 hydration reaction Methods 0.000 description 1
- XPXMKIXDFWLRAA-UHFFFAOYSA-N hydrazinide Chemical compound [NH-]N XPXMKIXDFWLRAA-UHFFFAOYSA-N 0.000 description 1
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
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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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- MHCFAGZWMAWTNR-UHFFFAOYSA-M lithium perchlorate Chemical compound [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 description 1
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- PLYATYNCZOQXBD-UHFFFAOYSA-N methyl 2-(6-methyl-4-nitropyridin-3-yl)oxyacetate Chemical compound COC(=O)COC1=CN=C(C)C=C1[N+]([O-])=O PLYATYNCZOQXBD-UHFFFAOYSA-N 0.000 description 1
- HYSFUNGLJWTDGA-UHFFFAOYSA-N methyl 2-(6-methylpyridin-3-yl)oxyacetate Chemical compound COC(=O)COC1=CC=C(C)N=C1 HYSFUNGLJWTDGA-UHFFFAOYSA-N 0.000 description 1
- QKSZKYBGCIPICZ-UHFFFAOYSA-N methyl 2-[6-(hydroxymethyl)-4-nitropyridin-3-yl]oxyacetate Chemical compound COC(=O)COC1=CN=C(CO)C=C1[N+]([O-])=O QKSZKYBGCIPICZ-UHFFFAOYSA-N 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- MKIJJIMOAABWGF-UHFFFAOYSA-N methyl 2-sulfanylacetate Chemical compound COC(=O)CS MKIJJIMOAABWGF-UHFFFAOYSA-N 0.000 description 1
- BRPREIDVQXJOJH-UHFFFAOYSA-N methyl 6-chloro-5-nitropyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(Cl)C([N+]([O-])=O)=C1 BRPREIDVQXJOJH-UHFFFAOYSA-N 0.000 description 1
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- 235000019799 monosodium phosphate Nutrition 0.000 description 1
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- 125000001624 naphthyl group Chemical group 0.000 description 1
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- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
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- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000001181 organosilyl group Chemical class [SiH3]* 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 150000004893 oxazines Chemical class 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 238000005949 ozonolysis reaction Methods 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
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- 230000035515 penetration Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PYNUOAIJIQGACY-UHFFFAOYSA-N propylazanium;chloride Chemical compound Cl.CCCN PYNUOAIJIQGACY-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004526 pyridazin-2-yl group Chemical group N1N(C=CC=C1)* 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000004260 quinazolin-2-yl group Chemical group [H]C1=NC(*)=NC2=C1C([H])=C([H])C([H])=C2[H] 0.000 description 1
- 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 description 1
- 125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 description 1
- VSGPVHSTVTXREH-UHFFFAOYSA-N quinolin-4-one Chemical compound C1=CC=C[C]2C(=O)C=CN=C21 VSGPVHSTVTXREH-UHFFFAOYSA-N 0.000 description 1
- 229930185107 quinolinone Natural products 0.000 description 1
- 125000004262 quinoxalin-2-yl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N=C1* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 150000004508 retinoic acid derivatives Chemical class 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- YHOBGCSGTGDMLF-UHFFFAOYSA-N sodium;di(propan-2-yl)azanide Chemical compound [Na+].CC(C)[N-]C(C)C YHOBGCSGTGDMLF-UHFFFAOYSA-N 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003440 styrenes Chemical class 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical class OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 150000003458 sulfonic acid derivatives Chemical class 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- WYVFPGFWUKBXPZ-UHFFFAOYSA-N tert-butyl n-(4-oxocyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(=O)CC1 WYVFPGFWUKBXPZ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- XJPANWOKBWZVHC-UHFFFAOYSA-N tetrazol-2-amine Chemical compound NN1N=CN=N1 XJPANWOKBWZVHC-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000004897 thiazines Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- MOSHKSKNWJKRQA-UHFFFAOYSA-N thieno[3,2-b]pyridin-7-amine dihydrochloride Chemical compound Cl.Cl.NC1=CC=NC2=C1SC=C2 MOSHKSKNWJKRQA-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000002827 triflate group Chemical class FC(S(=O)(=O)O*)(F)F 0.000 description 1
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- PGAJYUDRKAPMPA-UHFFFAOYSA-N trimethylsilyl n-ethylcarbamate Chemical compound CCNC(=O)O[Si](C)(C)C PGAJYUDRKAPMPA-UHFFFAOYSA-N 0.000 description 1
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- 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
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US39170002P | 2002-06-26 | 2002-06-26 | |
| US391700P | 2002-06-26 | ||
| US46096103P | 2003-04-07 | 2003-04-07 | |
| US460961P | 2003-04-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2325831T3 true ES2325831T3 (es) | 2009-09-21 |
Family
ID=30003201
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES03747857T Expired - Lifetime ES2325831T3 (es) | 2002-06-26 | 2003-06-25 | Derivados de ciclohexano sustituidos con amino para el tratamiento de infecciones bacterianas. |
Country Status (10)
| Country | Link |
|---|---|
| US (2) | US7622481B2 (https=) |
| EP (1) | EP1537123B1 (https=) |
| JP (1) | JP4522262B2 (https=) |
| AR (1) | AR040335A1 (https=) |
| AT (1) | ATE430154T1 (https=) |
| AU (1) | AU2003266949A1 (https=) |
| DE (1) | DE60327438D1 (https=) |
| ES (1) | ES2325831T3 (https=) |
| TW (1) | TW200406413A (https=) |
| WO (1) | WO2004002992A1 (https=) |
Families Citing this family (62)
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|---|---|---|---|---|
| GB0112834D0 (en) * | 2001-05-25 | 2001-07-18 | Smithkline Beecham Plc | Medicaments |
| US7312212B2 (en) | 2002-01-29 | 2007-12-25 | Glaxo Group Limited | Aminopiperidine derivatives |
| EP1470131A2 (en) | 2002-01-29 | 2004-10-27 | Glaxo Group Limited | Aminopiperidine compounds, process for their preparation, and pharmaceutical compositions containing them |
| AR040336A1 (es) | 2002-06-26 | 2005-03-30 | Glaxo Group Ltd | Compuesto de piperidina, uso del mismo para la fabricacion de un medicamento, composicion farmaceutica que lo comprende y procedimiento para preparar dicho compuesto |
| EP1560488B1 (en) | 2002-11-05 | 2010-09-01 | Glaxo Group Limited | Antibacterial agents |
| US7232832B2 (en) | 2002-11-05 | 2007-06-19 | Smithkline Beecham Corporation | Antibacterial agents |
| WO2004050036A2 (en) * | 2002-12-04 | 2004-06-17 | Glaxo Group Limited | Quinolines and nitrogenated derivatives thereof and their use as antibacterial agents |
| AR042486A1 (es) * | 2002-12-18 | 2005-06-22 | Glaxo Group Ltd | Compuesto de quinolina y naftiridina halosustituido en la posicion 3, procedimiento para preparar el compuesto, composicion farmaceutica que lo comprende y su uso para preparar dicha composicion . |
| WO2006002047A2 (en) | 2004-06-15 | 2006-01-05 | Glaxo Group Limited | Antibacterial agents |
| DE102004041163A1 (de) * | 2004-08-25 | 2006-03-02 | Morphochem Aktiengesellschaft für kombinatorische Chemie | Neue Verbindungen mit antibakterieller Aktivität |
| JP4887297B2 (ja) * | 2004-09-24 | 2012-02-29 | アクテリオン ファーマシューティカルズ リミテッド | 新規二環式抗生物質 |
| DE602005021133D1 (de) * | 2004-10-05 | 2010-06-17 | Actelion Pharmaceuticals Ltd | Neue piperidin-antibiotika |
| JP5314244B2 (ja) * | 2004-10-27 | 2013-10-16 | 富山化学工業株式会社 | 新規な含窒素複素環化合物およびその塩 |
| JP2008528598A (ja) * | 2005-01-25 | 2008-07-31 | グラクソ グループ リミテッド | 抗菌剤 |
| US7511035B2 (en) * | 2005-01-25 | 2009-03-31 | Glaxo Group Limited | Antibacterial agents |
| WO2006081182A2 (en) | 2005-01-25 | 2006-08-03 | Glaxo Group Limited | Antibacterial agents |
| JP2008528586A (ja) * | 2005-01-25 | 2008-07-31 | グラクソ グループ リミテッド | 抗菌剤 |
| EP1845995A4 (en) * | 2005-01-25 | 2010-03-03 | Glaxo Group Ltd | ANTIBACTERIAL AGENTS |
| MY150958A (en) | 2005-06-16 | 2014-03-31 | Astrazeneca Ab | Compounds for the treatment of multi-drug resistant bacterial infections |
| EP1900732A4 (en) * | 2005-06-24 | 2009-11-18 | Toyama Chemical Co Ltd | NEW NITROGENATED HETEROCYCLIC COMPOUND AND SALT THEREOF |
| WO2007016610A2 (en) * | 2005-08-02 | 2007-02-08 | Glaxo Group Limited | Antibacterial agents |
| ATE536351T1 (de) | 2006-01-26 | 2011-12-15 | Actelion Pharmaceuticals Ltd | Tetrahydropyran-antibiotika |
| ES2353829T3 (es) | 2006-02-15 | 2011-03-07 | Actelion Pharmaceuticals Ltd. | Derivados antibioticos de etanol o de 1,2-etanodiolciclohexilo. |
| WO2007118130A2 (en) * | 2006-04-06 | 2007-10-18 | Glaxo Group Limited | Antibacterial agents |
| EP2001887B1 (en) | 2006-04-06 | 2010-09-15 | Glaxo Group Limited | Pyrrolo-quinoxalinone derivatives as antibacterials |
| AU2007268749B2 (en) | 2006-05-26 | 2012-07-26 | Taisho Pharmaceutical Co., Ltd. | Novel heterocyclic compound or salt thereof and intermediate thereof |
| GB0613208D0 (en) | 2006-07-03 | 2006-08-09 | Glaxo Group Ltd | Compounds |
| EP1992628A1 (en) | 2007-05-18 | 2008-11-19 | Glaxo Group Limited | Derivatives and analogs of N-ethylquinolones and N-ethylazaquinolones |
| WO2008071962A1 (en) * | 2006-12-15 | 2008-06-19 | Astrazeneca Ab | Pteridines and pyrimidinopyridines as antibacterial agents |
| CL2007003693A1 (es) * | 2006-12-22 | 2008-06-27 | Actelion Pharmaceuticals Ltd | Compuestos derivados de pirido [3,2-b] [1,4] tiazina; composicion farmaceutica que contiene dichos compuestos; y su uso en el tratamiento de infecciones bacterianas. |
| CL2008001003A1 (es) | 2007-04-11 | 2008-10-17 | Actelion Pharmaceuticals Ltd | Compuestos derivados de oxazolidinona; composicion farmaceutica que comprende a dichos compuestos; y su uso para preparar un medicamento para tratar una infeccion bacteriana. |
| AU2008240764C1 (en) * | 2007-04-20 | 2011-10-20 | Glaxo Group Limited | Tricyclic nitrogen containing compounds as antibacterial agents |
| CN101874032B (zh) | 2007-11-26 | 2013-02-06 | 富山化学工业株式会社 | 二氮杂萘衍生物一水合物及其制备方法 |
| EP2080761A1 (en) | 2008-01-18 | 2009-07-22 | Glaxo Group Limited | Compounds |
| MX2010012855A (es) * | 2008-06-03 | 2010-12-21 | Actelion Pharmaceuticals Ltd | Derivados de [4-(1-amino-etil)-ciclohexil]-metil-amina y [6-(1-amino-etil)-tetrahidro-piran-3-il]-metil-amina como antibacterianos. |
| EP2352734A1 (en) | 2008-10-17 | 2011-08-10 | Glaxo Group Limited | Tricyclic nitrogen compounds used as antibacterials |
| WO2010045987A1 (en) * | 2008-10-23 | 2010-04-29 | Glaxo Group Limited | Substituted (aza) -1-methyl-1h-quin0lin-2-0nes as antibacterials |
| BRPI0921038A2 (pt) | 2008-11-17 | 2019-09-24 | Hoffmann La Roche | ácido naftilacéticos |
| US8318940B2 (en) | 2009-01-15 | 2012-11-27 | Glaxo Group Limited | Naphthyridin-2 (1 H)-one compounds useful as antibacterials |
| AU2010206161B2 (en) | 2009-01-21 | 2014-08-07 | Basilea Pharmaceutica Ag | Novel bicyclic antibiotics |
| AR076222A1 (es) * | 2009-04-09 | 2011-05-26 | Actelion Pharmaceuticals Ltd | Derivados 2-hidroxietil-1h-quinolin-ona y sus analogos azaisotericos con actividad antibacteriana y composiciones farmaceuticas que los contienen |
| US8394858B2 (en) | 2009-12-03 | 2013-03-12 | Novartis Ag | Cyclohexane derivatives and uses thereof |
| KR101891834B1 (ko) | 2009-12-18 | 2018-09-28 | 바실리어 파마슈티카 아게 | 트리시클릭 항생제 |
| EP2674430A4 (en) | 2011-02-07 | 2014-07-02 | Daiichi Sankyo Co Ltd | AMINO-GROUP-PYRROLIDINONE DERIVATIVES |
| JP2014517019A (ja) | 2011-06-17 | 2014-07-17 | バジリア ファルマスーチカ アーゲー | 三環式抗生物質 |
| US8470884B2 (en) | 2011-11-09 | 2013-06-25 | Hoffmann-La Roche Inc. | Alkenyl naphthylacetic acids |
| US9359275B2 (en) * | 2012-02-23 | 2016-06-07 | Children's Medical Center Corporation | Natural product antibiotics and analogs thereof |
| HK1220977A1 (en) * | 2013-03-29 | 2017-05-19 | Daiichi Sankyo Co., Ltd | Method for producing (1s,4s,5s)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one |
| CN103145709A (zh) * | 2013-04-12 | 2013-06-12 | 苏州科捷生物医药有限公司 | 一种4-氯-1,6-萘啶的合成工艺 |
| KR20150143720A (ko) | 2013-04-16 | 2015-12-23 | 액테리온 파마슈티칼 리미티드 | 항균성 이방향족 유도체 |
| WO2015193506A1 (en) * | 2014-06-20 | 2015-12-23 | Institut Pasteur Korea | Anti-infective compounds |
| US10702521B2 (en) | 2014-08-22 | 2020-07-07 | Glaxosmithkline Intellectual Property Development Limited | Methods for treating neisseria gonorrhoeae infection with substituted 1,2-dihydro-2A,5,8A-triazaacenaphthylene-3,8-diones |
| AR102256A1 (es) | 2014-10-15 | 2017-02-15 | Actelion Pharmaceuticals Ltd | Derivados biaromáticos básicos antibacterianos con sustitución de aminoalcoxi |
| DK3209655T3 (da) | 2014-10-24 | 2020-09-28 | Landos Biopharma Inc | Lanthioninsyntease C-lignende 2-baserede Therapeutica |
| TW201722965A (zh) | 2015-08-16 | 2017-07-01 | 葛蘭素史密斯克藍智慧財產發展有限公司 | 用於抗菌應用之化合物 |
| ES3057339T3 (en) * | 2017-08-10 | 2026-02-27 | Harvard College | Lincosamide antibiotics and uses thereof |
| WO2019032956A1 (en) | 2017-08-10 | 2019-02-14 | President And Fellows Of Harvard College | LINCONSAMIDE ANTIBIOTICS AND USES THEREOF |
| KR20200090873A (ko) | 2017-11-30 | 2020-07-29 | 란도스 바이오파마, 인크. | 란티오닌 c-유사 단백질 2 리간드 및 이와 함께 제조된 세포를 이용한 치료법 |
| CN108003100A (zh) * | 2017-12-20 | 2018-05-08 | 北京六合宁远科技有限公司 | 一种药物中间体含氮杂环的胺类化合物的合成方法 |
| KR20230026522A (ko) | 2019-12-20 | 2023-02-24 | 란도스 바이오파마, 인크. | 란티오닌 c-유사 단백질 2 리간드, 이로 제조된 세포, 및 이를 사용하는 치료법 |
| CN116102537B (zh) * | 2021-11-10 | 2024-10-01 | 四川大学 | 一种喹啉酮类衍生物及其制备方法和用途 |
| CN118451068A (zh) | 2021-12-30 | 2024-08-06 | 上海翰森生物医药科技有限公司 | 三并环类衍生物抑制剂、其制备方法和应用 |
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| CA2318842A1 (en) | 1998-01-26 | 1999-07-29 | Julie Dorothy Warrack | Quinoline derivatives as antibacterials |
| GB9822450D0 (en) | 1998-10-14 | 1998-12-09 | Smithkline Beecham Plc | Medicaments |
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| JP2002535323A (ja) | 1999-01-20 | 2002-10-22 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | プロテインキナーゼ阻害剤としてのピペリジニルキノリン |
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| GB9917406D0 (en) | 1999-07-23 | 1999-09-22 | Smithkline Beecham Plc | Compounds |
| GB9917408D0 (en) | 1999-07-23 | 1999-09-22 | Smithkline Beecham Plc | Compounds |
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| US6403610B1 (en) * | 1999-09-17 | 2002-06-11 | Aventis Pharma S.A. | Quinolylpropylpiperidine derivatives, their preparation and the compositions which comprise them |
| SI1249233T1 (sl) * | 1999-11-26 | 2009-02-28 | Shionogi & Co | Antagonisti NPYY5 |
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| WO2002024684A1 (en) | 2000-09-21 | 2002-03-28 | Smithkline Beecham P.L.C. | Quinoline derivatives as antibacterials |
| FR2816618B1 (fr) | 2000-11-15 | 2002-12-27 | Aventis Pharma Sa | Derives heterocyclylalcoyl piperidine, leur preparation et les compositions qui les contiennent |
| US6603005B2 (en) * | 2000-11-15 | 2003-08-05 | Aventis Pharma S.A. | Heterocyclylalkylpiperidine derivatives, their preparation and compositions containing them |
| GB0031086D0 (en) | 2000-12-20 | 2001-01-31 | Smithkline Beecham Plc | Medicaments |
| GB0031088D0 (en) | 2000-12-20 | 2001-01-31 | Smithkline Beecham Plc | Medicaments |
| GB0101577D0 (en) | 2001-01-22 | 2001-03-07 | Smithkline Beecham Plc | Compounds |
| MXPA03006522A (es) | 2001-01-24 | 2004-07-08 | Becton Dickinson Co | Recubrimiento lubricante para dispositivos medicos. |
| FR2822154B1 (fr) | 2001-03-13 | 2005-10-21 | Aventis Pharma Sa | Derives de la quinolyl propyl piperidine, leur preparation et les compositions qui les contiennent |
| US6602884B2 (en) * | 2001-03-13 | 2003-08-05 | Aventis Pharma S.A. | Quinolylpropylpiperidine derivatives, their preparation, and compositions containing them |
| GB0112834D0 (en) * | 2001-05-25 | 2001-07-18 | Smithkline Beecham Plc | Medicaments |
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| AR040336A1 (es) | 2002-06-26 | 2005-03-30 | Glaxo Group Ltd | Compuesto de piperidina, uso del mismo para la fabricacion de un medicamento, composicion farmaceutica que lo comprende y procedimiento para preparar dicho compuesto |
| FR2842807A1 (fr) | 2002-07-23 | 2004-01-30 | Aventis Pharma Sa | Derives de la quinolyl propyl piperidine, procede et intermediaires de preparation et compositions les renfermant |
| GB0217294D0 (en) | 2002-07-25 | 2002-09-04 | Glaxo Group Ltd | Medicaments |
| FR2844270B1 (fr) | 2002-09-11 | 2006-05-19 | Aventis Pharma Sa | Derives de la quinolyl propyl piperidine, leur procede et intermediaires de preparation et les compositions qui les contiennent |
| FR2844268B1 (fr) * | 2002-09-11 | 2004-10-22 | Aventis Pharma Sa | Derives de la quinolyl propyl piperidine, leurs procedes et intermediaires de preparation et les compositions qui les contiennent |
| EP1551829B1 (de) | 2002-10-10 | 2010-04-07 | Morphochem Aktiengesellschaft Für Kombinatorische Chemie | Neue verbindungen mit antibakterieller aktivität |
| EP1560488B1 (en) * | 2002-11-05 | 2010-09-01 | Glaxo Group Limited | Antibacterial agents |
| US7232832B2 (en) * | 2002-11-05 | 2007-06-19 | Smithkline Beecham Corporation | Antibacterial agents |
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| FR2849034A1 (fr) | 2002-12-20 | 2004-06-25 | Aventis Pharma Sa | Forme cristalline de l'acide (3r,4r)-4-(3-(s)-hydroxy-3- (6-methoxyquinolin-4-yl) propyl)-1-(2-(2-thienylthio) ethyl piperidine-3- carboxylique |
| TW200507841A (en) | 2003-03-27 | 2005-03-01 | Glaxo Group Ltd | Antibacterial agents |
| US7232833B2 (en) * | 2003-03-28 | 2007-06-19 | Novexel | 4-substituted quinoline derivatives, method and intermediates for their preparation and pharmaceutical compositions containing them |
| FR2852954B1 (fr) | 2003-03-28 | 2006-07-14 | Aventis Pharma Sa | Derives de quinoleines-4-substituees, leurs procede et intermediaires de preparation et les compositions pharmaceutiques qui les contiennent |
| DE10316081A1 (de) | 2003-04-08 | 2004-10-21 | Morphochem AG Aktiengesellschaft für kombinatorische Chemie | Neue Verbindungen mit antibakterieller Aktivität |
-
2003
- 2003-06-24 TW TW092117044A patent/TW200406413A/zh unknown
- 2003-06-24 AR ARP030102248A patent/AR040335A1/es not_active Application Discontinuation
- 2003-06-25 JP JP2004548887A patent/JP4522262B2/ja not_active Expired - Fee Related
- 2003-06-25 WO PCT/EP2003/006756 patent/WO2004002992A1/en not_active Ceased
- 2003-06-25 AU AU2003266949A patent/AU2003266949A1/en not_active Abandoned
- 2003-06-25 ES ES03747857T patent/ES2325831T3/es not_active Expired - Lifetime
- 2003-06-25 AT AT03747857T patent/ATE430154T1/de not_active IP Right Cessation
- 2003-06-25 US US10/518,653 patent/US7622481B2/en not_active Expired - Fee Related
- 2003-06-25 DE DE60327438T patent/DE60327438D1/de not_active Expired - Lifetime
- 2003-06-25 EP EP03747857A patent/EP1537123B1/en not_active Expired - Lifetime
-
2009
- 2009-11-17 US US12/620,129 patent/US20100081650A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| DE60327438D1 (de) | 2009-06-10 |
| AU2003266949A1 (en) | 2004-01-19 |
| JP4522262B2 (ja) | 2010-08-11 |
| US7622481B2 (en) | 2009-11-24 |
| EP1537123B1 (en) | 2009-04-29 |
| JP2005539087A (ja) | 2005-12-22 |
| TW200406413A (en) | 2004-05-01 |
| AR040335A1 (es) | 2005-03-30 |
| US20100081650A1 (en) | 2010-04-01 |
| WO2004002992A1 (en) | 2004-01-08 |
| ATE430154T1 (de) | 2009-05-15 |
| EP1537123A1 (en) | 2005-06-08 |
| US20060189604A1 (en) | 2006-08-24 |
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