WO2003006440A2 - Amide-containing compound having improved solubility and method of improving the solubility of an amide-containing compound - Google Patents
Amide-containing compound having improved solubility and method of improving the solubility of an amide-containing compound Download PDFInfo
- Publication number
- WO2003006440A2 WO2003006440A2 PCT/US2002/022526 US0222526W WO03006440A2 WO 2003006440 A2 WO2003006440 A2 WO 2003006440A2 US 0222526 W US0222526 W US 0222526W WO 03006440 A2 WO03006440 A2 WO 03006440A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- phenyl
- oxo
- optionally substituted
- methyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 142
- 238000000034 method Methods 0.000 title claims abstract description 58
- 150000001408 amides Chemical class 0.000 title claims abstract description 25
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims abstract description 43
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 462
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 421
- 125000000217 alkyl group Chemical group 0.000 claims description 306
- 229910052739 hydrogen Inorganic materials 0.000 claims description 206
- -1 phenyl- Chemical group 0.000 claims description 202
- 125000005843 halogen group Chemical group 0.000 claims description 95
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 79
- 125000003118 aryl group Chemical group 0.000 claims description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 53
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 52
- 229910052717 sulfur Inorganic materials 0.000 claims description 44
- 229910052731 fluorine Inorganic materials 0.000 claims description 40
- 229910052757 nitrogen Inorganic materials 0.000 claims description 37
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 33
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 28
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- DBTDEFJAFBUGPP-UHFFFAOYSA-N Methanethial Chemical compound S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 229910052727 yttrium Inorganic materials 0.000 claims description 13
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 10
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 9
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 150000001336 alkenes Chemical class 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 150000001768 cations Chemical class 0.000 claims description 5
- 125000005331 diazinyl group Chemical group N1=NC(=CC=C1)* 0.000 claims description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 5
- 125000005059 halophenyl group Chemical group 0.000 claims description 5
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 5
- CPRRHERYRRXBRZ-SRVKXCTJSA-N methyl n-[(2s)-1-[[(2s)-1-hydroxy-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CO)C[C@@H]1CCNC1=O CPRRHERYRRXBRZ-SRVKXCTJSA-N 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 150000002923 oximes Chemical class 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 5
- 125000004306 triazinyl group Chemical group 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 3
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims 4
- 229910003844 NSO2 Inorganic materials 0.000 claims 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims 2
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 101100440695 Dictyostelium discoideum corB gene Proteins 0.000 claims 1
- 125000001188 haloalkyl group Chemical group 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 180
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 167
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 136
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 107
- 125000004193 piperazinyl group Chemical group 0.000 description 104
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 87
- 238000002360 preparation method Methods 0.000 description 84
- 239000000203 mixture Substances 0.000 description 80
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 71
- WPZSAUFQHYFIPG-UHFFFAOYSA-N propanethioamide Chemical compound CCC(N)=S WPZSAUFQHYFIPG-UHFFFAOYSA-N 0.000 description 63
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 62
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 47
- 235000019439 ethyl acetate Nutrition 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 34
- 125000000160 oxazolidinyl group Chemical group 0.000 description 31
- IIPJWNFOLPDTEQ-UHFFFAOYSA-N cyclopropanecarbothioamide Chemical compound NC(=S)C1CC1 IIPJWNFOLPDTEQ-UHFFFAOYSA-N 0.000 description 29
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 26
- 239000000741 silica gel Substances 0.000 description 26
- 229910002027 silica gel Inorganic materials 0.000 description 26
- 239000011780 sodium chloride Substances 0.000 description 25
- 239000000047 product Substances 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- 229960000649 oxyphenbutazone Drugs 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- JKCJXAVMBWFTTC-UHFFFAOYSA-N thiazepine 1-oxide Chemical compound O=S1C=CC=CC=N1 JKCJXAVMBWFTTC-UHFFFAOYSA-N 0.000 description 21
- DYBINGBQLVCRNI-MRXNPFEDSA-N butyl (5r)-2-oxo-3-(4-thiomorpholin-4-ylphenyl)-1,3-oxazolidine-5-carboxylate Chemical compound O=C1O[C@@H](C(=O)OCCCC)CN1C1=CC=C(N2CCSCC2)C=C1 DYBINGBQLVCRNI-MRXNPFEDSA-N 0.000 description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 19
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 19
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 125000001841 imino group Chemical group [H]N=* 0.000 description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 229960004132 diethyl ether Drugs 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- 239000003242 anti bacterial agent Substances 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- UJKUGWXYPULWSS-UHFFFAOYSA-N thiazepine 1,1-dioxide Chemical compound O=S1(=O)C=CC=CC=N1 UJKUGWXYPULWSS-UHFFFAOYSA-N 0.000 description 12
- YHIIJNLSGULWAA-UHFFFAOYSA-N 1,4-thiazinane 1-oxide Chemical compound O=S1CCNCC1 YHIIJNLSGULWAA-UHFFFAOYSA-N 0.000 description 11
- 0 Cc1cc([N+])c(*)c(C)c1 Chemical compound Cc1cc([N+])c(*)c(C)c1 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- LMEZRNAEUMFZDX-UHFFFAOYSA-N acetic acid;ethanethioamide Chemical compound CC(O)=O.CC(N)=S LMEZRNAEUMFZDX-UHFFFAOYSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 238000011176 pooling Methods 0.000 description 10
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 7
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 7
- 239000012988 Dithioester Substances 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 239000012298 atmosphere Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 7
- 125000002757 morpholinyl group Chemical group 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 description 7
- JCSCLHOUNBXMEE-CYBMUJFWSA-N (5r)-3-[4-(3,6-dihydro-2h-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-carboxamide Chemical compound O=C1O[C@@H](C(=O)N)CN1C(C=C1F)=CC=C1C1=CCSCC1 JCSCLHOUNBXMEE-CYBMUJFWSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- FUHDWFAJHRGBNM-QGZVFWFLSA-N butyl (5r)-2-oxo-3-[4-(thian-4-yl)phenyl]-1,3-oxazolidine-5-carboxylate Chemical compound O=C1O[C@@H](C(=O)OCCCC)CN1C1=CC=C(C2CCSCC2)C=C1 FUHDWFAJHRGBNM-QGZVFWFLSA-N 0.000 description 6
- IIDDDIKGSSYACC-MRXNPFEDSA-N butyl (5r)-3-(3-fluoro-4-thiomorpholin-4-ylphenyl)-2-oxo-1,3-oxazolidine-5-carboxylate Chemical compound O=C1O[C@@H](C(=O)OCCCC)CN1C(C=C1F)=CC=C1N1CCSCC1 IIDDDIKGSSYACC-MRXNPFEDSA-N 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 description 6
- 238000001665 trituration Methods 0.000 description 6
- RQXQMUUSQGCLPL-UHFFFAOYSA-N 4-thiomorpholin-4-ylaniline Chemical compound C1=CC(N)=CC=C1N1CCSCC1 RQXQMUUSQGCLPL-UHFFFAOYSA-N 0.000 description 5
- 150000001414 amino alcohols Chemical class 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- WPLXTOVHRYJKSG-UHFFFAOYSA-N butanethioamide Chemical compound CCCC(N)=S WPLXTOVHRYJKSG-UHFFFAOYSA-N 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 125000004119 disulfanediyl group Chemical group *SS* 0.000 description 5
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 5
- JGRCHNVLXORPNM-UHFFFAOYSA-N 1,2-oxazol-4-one Chemical class O=C1CON=C1 JGRCHNVLXORPNM-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 4
- 206010008583 Chloroma Diseases 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- TTWOGACPCNPSNB-UHFFFAOYSA-N cyclobutanecarbothioamide Chemical compound NC(=S)C1CCC1 TTWOGACPCNPSNB-UHFFFAOYSA-N 0.000 description 4
- JMMKXVYQBRGGJF-UHFFFAOYSA-N cyclohexanecarbothioamide Chemical compound NC(=S)C1CCCCC1 JMMKXVYQBRGGJF-UHFFFAOYSA-N 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 150000003462 sulfoxides Chemical class 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- ZTAAKFXBCMVLOG-LLVKDONJSA-N (5r)-3-(3,5-difluoro-4-thiomorpholin-4-ylphenyl)-2-oxo-1,3-oxazolidine-5-carboxamide Chemical compound O=C1O[C@@H](C(=O)N)CN1C(C=C1F)=CC(F)=C1N1CCSCC1 ZTAAKFXBCMVLOG-LLVKDONJSA-N 0.000 description 3
- UQPYLSOHZOWISH-GFCCVEGCSA-N (5r)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidine-5-carboxylic acid Chemical compound O=C1O[C@@H](C(=O)O)CN1C(C=C1F)=CC=C1N1CCOCC1 UQPYLSOHZOWISH-GFCCVEGCSA-N 0.000 description 3
- FQPPEKCCNRMKBJ-GFCCVEGCSA-N (5r)-3-(3-fluoro-4-thiomorpholin-4-ylphenyl)-2-oxo-1,3-oxazolidine-5-carboxamide Chemical compound O=C1O[C@@H](C(=O)N)CN1C(C=C1F)=CC=C1N1CCSCC1 FQPPEKCCNRMKBJ-GFCCVEGCSA-N 0.000 description 3
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- GCDKJLDNOWCUSW-JTQLQIEISA-N n-[[(5s)-3-[3-fluoro-4-(5-sulfanylidene-4h-1,3,4-thiadiazin-2-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]ethanethioamide Chemical compound O=C1O[C@@H](CNC(=S)C)CN1C(C=C1F)=CC=C1C1=NNC(=S)CS1 GCDKJLDNOWCUSW-JTQLQIEISA-N 0.000 description 1
- RCXVRGFBFWUADC-QHGLUPRGSA-N n-[[(5s)-3-[3-fluoro-4-(6-fluoro-5-oxo-4h-1,3,4-thiadiazin-2-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1C1=NNC(=O)C(F)S1 RCXVRGFBFWUADC-QHGLUPRGSA-N 0.000 description 1
- AULNKVUZKVHAMK-LBPRGKRZSA-N n-[[(5s)-3-[3-fluoro-4-(9-oxo-5-thia-7,8-diazaspiro[3.5]non-6-en-6-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1C(S1)=NNC(=O)C11CCC1 AULNKVUZKVHAMK-LBPRGKRZSA-N 0.000 description 1
- FIQONJKJDNESKL-KCJUWKMLSA-N n-[[(5s)-3-[3-fluoro-4-[(6r)-6-methyl-5-oxo-4h-1,3,4-thiadiazin-2-yl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound N1C(=O)[C@@H](C)SC(C=2C(=CC(=CC=2)N2C(O[C@@H](CNC(C)=O)C2)=O)F)=N1 FIQONJKJDNESKL-KCJUWKMLSA-N 0.000 description 1
- SIMWTRCFFSTNMG-AWEZNQCLSA-N n-[[(5s)-3-[3-fluoro-4-[4-(2-hydroxyacetyl)piperazin-1-yl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCN(C(=O)CO)CC1 SIMWTRCFFSTNMG-AWEZNQCLSA-N 0.000 description 1
- QUDRRLWKRPLBKZ-HNNXBMFYSA-N n-[[(5s)-3-[3-fluoro-4-[4-(2-hydroxyacetyl)piperazin-1-yl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]azetidine-1-carbothioamide Chemical compound C1CN(C(=O)CO)CCN1C1=CC=C(N2C(O[C@@H](CNC(=S)N3CCC3)C2)=O)C=C1F QUDRRLWKRPLBKZ-HNNXBMFYSA-N 0.000 description 1
- GBGSQPWVUKYRIX-HNNXBMFYSA-N n-[[(5s)-3-[3-fluoro-4-[4-(2-hydroxyacetyl)piperazin-1-yl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]cyclopropanecarbothioamide Chemical compound C1CN(C(=O)CO)CCN1C1=CC=C(N2C(O[C@@H](CNC(=S)C3CC3)C2)=O)C=C1F GBGSQPWVUKYRIX-HNNXBMFYSA-N 0.000 description 1
- SYUFGFAMGWERAW-AWEZNQCLSA-N n-[[(5s)-3-[3-fluoro-4-[4-(2-hydroxyacetyl)piperazin-1-yl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]ethanethioamide Chemical compound O=C1O[C@@H](CNC(=S)C)CN1C(C=C1F)=CC=C1N1CCN(C(=O)CO)CC1 SYUFGFAMGWERAW-AWEZNQCLSA-N 0.000 description 1
- UJNMWSMZFJANHH-ZSOXZCCMSA-N n-[[(5s)-3-[3-fluoro-4-[6-(2-hydroxyethyl)-5-oxo-4h-1,3,4-thiadiazin-2-yl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1C1=NNC(=O)C(CCO)S1 UJNMWSMZFJANHH-ZSOXZCCMSA-N 0.000 description 1
- BRJOGFIIXKKPJF-NKUHCKNESA-N n-[[(5s)-3-[3-fluoro-4-[6-(hydroxymethyl)-5-oxo-4h-1,3,4-thiadiazin-2-yl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1C1=NNC(=O)C(CO)S1 BRJOGFIIXKKPJF-NKUHCKNESA-N 0.000 description 1
- MJNAUTAHUMVIHW-WMCAAGNKSA-N n-[[(5s)-3-[4-(1,1-dioxo-2-prop-2-enylthiazinan-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1C1CN(CC=C)S(=O)(=O)CC1 MJNAUTAHUMVIHW-WMCAAGNKSA-N 0.000 description 1
- CVQFRRKMNFSOMD-AWEZNQCLSA-N n-[[(5s)-3-[4-(1,1-dioxothian-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]ethanethioamide Chemical compound O=C1O[C@@H](CNC(=S)C)CN1C(C=C1F)=CC=C1C1CCS(=O)(=O)CC1 CVQFRRKMNFSOMD-AWEZNQCLSA-N 0.000 description 1
- XQEPAPIQLIHICJ-KFJBMODSSA-N n-[[(5s)-3-[4-(3,4-dihydro-2h-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]-2,2,2-trifluoroacetamide Chemical compound FC1=CC(N2C(O[C@@H](CNC(=O)C(F)(F)F)C2)=O)=CC=C1C1CCSC=C1 XQEPAPIQLIHICJ-KFJBMODSSA-N 0.000 description 1
- ATMCQIDBXGQRDF-PYMCNQPYSA-N n-[[(5s)-3-[4-(3,4-dihydro-2h-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1C1C=CSCC1 ATMCQIDBXGQRDF-PYMCNQPYSA-N 0.000 description 1
- BJTRRBPTEACDDA-PYMCNQPYSA-N n-[[(5s)-3-[4-(3,4-dihydro-2h-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]ethanethioamide Chemical compound O=C1O[C@@H](CNC(=S)C)CN1C(C=C1F)=CC=C1C1C=CSCC1 BJTRRBPTEACDDA-PYMCNQPYSA-N 0.000 description 1
- UMAKUQVGIFAKCF-HNNXBMFYSA-N n-[[(5s)-3-[4-(4-ethylsulfonylpiperazin-1-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]ethanethioamide Chemical compound C1CN(S(=O)(=O)CC)CCN1C1=CC=C(N2C(O[C@@H](CNC(C)=S)C2)=O)C=C1F UMAKUQVGIFAKCF-HNNXBMFYSA-N 0.000 description 1
- OWUQZVWHTKHNIS-HNNXBMFYSA-N n-[[(5s)-3-[4-(4-ethylsulfonylpiperazin-1-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]propanethioamide Chemical compound O=C1O[C@@H](CNC(=S)CC)CN1C(C=C1F)=CC=C1N1CCN(S(=O)(=O)CC)CC1 OWUQZVWHTKHNIS-HNNXBMFYSA-N 0.000 description 1
- UEVATOKHNCNOGX-KRWDZBQOSA-N n-[[(5s)-3-[4-(4-methylsulfonylpiperazin-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]cyclopropanecarbothioamide Chemical compound C1CN(S(=O)(=O)C)CCN1C1=CC=C(N2C(O[C@@H](CNC(=S)C3CC3)C2)=O)C=C1 UEVATOKHNCNOGX-KRWDZBQOSA-N 0.000 description 1
- YUFIIJSWUJNSKY-INIZCTEOSA-N n-[[(5s)-3-[4-(4-methylsulfonylpiperazin-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]ethanethioamide Chemical compound O=C1O[C@@H](CNC(=S)C)CN1C1=CC=C(N2CCN(CC2)S(C)(=O)=O)C=C1 YUFIIJSWUJNSKY-INIZCTEOSA-N 0.000 description 1
- GBOGUTSWIZWKAI-INIZCTEOSA-N n-[[(5s)-3-[4-(4-methylsulfonylpiperazin-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]propanethioamide Chemical compound O=C1O[C@@H](CNC(=S)CC)CN1C1=CC=C(N2CCN(CC2)S(C)(=O)=O)C=C1 GBOGUTSWIZWKAI-INIZCTEOSA-N 0.000 description 1
- RPXZUEUKEAJPRR-NSHDSACASA-N n-[[(5s)-3-[4-(6,6-dimethyl-5-oxo-4h-1,3,4-thiadiazin-2-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1C1=NNC(=O)C(C)(C)S1 RPXZUEUKEAJPRR-NSHDSACASA-N 0.000 description 1
- WBSBCGPRQDOKHP-ZSOXZCCMSA-N n-[[(5s)-3-[4-(6-ethyl-5-oxo-4h-1,3,4-thiadiazin-2-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound N1C(=O)C(CC)SC(C=2C(=CC(=CC=2)N2C(O[C@@H](CNC(C)=O)C2)=O)F)=N1 WBSBCGPRQDOKHP-ZSOXZCCMSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005071 nonynyl group Chemical group C(#CCCCCCCC)* 0.000 description 1
- HYDZPXNVHXJHBG-UHFFFAOYSA-N o-benzylhydroxylamine;hydron;chloride Chemical group Cl.NOCC1=CC=CC=C1 HYDZPXNVHXJHBG-UHFFFAOYSA-N 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 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
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005063 tetradecenyl group Chemical group C(=CCCCCCCCCCCCC)* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- OVRJVKCZJCNSOW-UHFFFAOYSA-N thian-4-one Chemical compound O=C1CCSCC1 OVRJVKCZJCNSOW-UHFFFAOYSA-N 0.000 description 1
- YGNGABUJMXJPIJ-UHFFFAOYSA-N thiatriazole Chemical compound C1=NN=NS1 YGNGABUJMXJPIJ-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000005040 tridecenyl group Chemical group C(=CCCCCCCCCCCC)* 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- YCBWXJZXFUKDPU-UHFFFAOYSA-N trimethyl(pyridin-4-yl)stannane Chemical group C[Sn](C)(C)C1=CC=NC=C1 YCBWXJZXFUKDPU-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
-
- 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
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Definitions
- the present invention is directed to amide- containing compounds having an improved water solubility and a method for improving the water-solubility of amide- containing compounds in general and, specifically, to oxazolidinone compounds having improved water solubility and a method of improving the water-solubility of oxazolidinone compounds.
- oxazolidinone derivatives containing an amide group are known to exhibit a variety of biological activities .
- Oxazolidinone derivatives have been shown to be inhibitors of monoamine oxidase-B, an enzyme implicated in Parkinson's disease. Ding et al . , J. Med. Chem . 36:3606-3610 (1993) .
- U.S. Patent 5,652,238 discloses carboxylic and phosphate esters of substituted-hydroxyacetyl piperazine phenyl oxazolidinones .
- U.S. Patent 5,688,792 discloses substituted oxazine and thiazine oxazolidinone useful as antibacticals.
- PCT International Publication WO 98/54161 discloses oxazolidinone antibacterial agents having a thiocarbonyl functionality.
- U.S. Patent 5,968,962 and PCT International Publication WO 99/29688 discloses phenyloxazolidinones having a C-C bond to 4-8 membered heterocyclic rings.
- U.S. Patent 5,952,324 discloses bicyclic oxazine and thiazine oxazolidinone useful as antibacticals.
- WO 00/10566 discloses isoxazolinones useful as antibacterial agents.
- U.S. Patent No. 5,880,118 discloses substituted oxazine and thiazine oxazolidinone antimocrobials .
- U.S. Patent No. 6,968,962 discloses phenyloxazolidinones having a C-C bond to 4-8 membered heterocyclic rings.
- U.S. Patent No. 5,981,528 discloses antibiotic oxazolidinone derivatives.
- U.S. Patent application Serial No. 60/236595 discloses N- ( ⁇ (5S) -3- [4- (1, l-dioxido-4-thiomorpholinyl) - 3, 5-difluorophenyl] -2-oxo-l, 3-oxazolidin-5- yl ⁇ methyl) acetamide .
- U.S. Patent Nos. 5,036,092; 5,036,093; 5,039,690; 5,032,605 and 4,965,268 disclose aminomethyl oxazolidinyl aza cycloalkylbenzene derivatives useful as antibacterial agents .
- U.S. Patent Nos. 5,792,765 and 5,684,023 disclose substituted isoxazolinones useful as antibacterial agents.
- International Publication No. WO 97/09328 discloses phenyloxazolidinones having a C-C bond to 4-8 membered heterocyclic rings useful as antimicrobial agents.
- PCT International Publication WO 93/23384 discloses oxazolidinones containing a substituted diazine moiety and their use as antimicrobials.
- PCT International Publication WO 95/07271 discloses substituted oxazine and thiazine oxazolidinones and their use as antimicrobials.
- amide-containing compounds have been shown to be extremely effective in the treatment of certain physiological disorders, some of these compounds have a low bioavailability due to their low water solubility and/or low permeability through biological barriers, such as the blood brain barrier and the intestinal barrier.
- prodrugs derivatize certain polar functional groups transiently and bioreversably to mask undesirable physical chemical characteristics of the groups without permanently altering the pharmacological properties of the molecules and have been used very successfully in cases where the prodrug derivatization involves converting a carboxyl or a hydroxyl functional group into an ester which can be readily hydrolyzed in vivo either chemically or enzymatically .
- this strategy has not been successfully used in the case of an amide group due to the chemical stability thereof.
- J is 0 or S
- R3 1 0 R 4io and R510 each independently are a) H, b) C 1 -4 alkyl, c) halogen, d) C 1 - 4 alkoxy, e) hydroxy, f) (CH 2 ) c OP(0) (OH) 2 , g) C 1 - 4 acyloxy, or h) C 1 - 4 alkyl substituted by halogen, hydroxy, acyloxy, NR ⁇ 2 ⁇ o i3io, or alkoxy;
- R ⁇ io R710 and R 8 ⁇ 0 each independently are a ) H , b ) CH 3 , or c ) C 2 H 5 ;
- R910 and R1010 each independently are a) H, b) CH 3 , c) C 2 H 5 , or d) combine to form a C 3 - 5 cycloalkyl;
- R 1 110 is H or C ⁇ - 6 alkyl
- R 12 10 and R1310 each independently are a) H, b) C 1 - 4 alkyl, or c) combine to form a heterocyclic ring;
- a is 0 or 1
- b is 0 or 1
- c is 0 or 1
- R 710 810 the proviso that when Q' is , b is 0 and a+b is 0 or 1;
- Ri is a) C1-4 alkyl, b) C 2 -4 alkenyl, c) OC 1 - 4 alkyl, d) C3-6 cycloalkyl, e) C 1 - 4 alkyl substituted with 1-3F, 1-2C1, CN, -COOC 1 - 4 alkyl or a C 3 _ 6 cycloalkyl; or f) H
- R 5 and Re at each occurrence are the same or different and are a) C ⁇ _ 2 alkyl, or b) R 5 and R 6 taken together are -(CH 2 ) k -;
- R 7 is C 1 - alkyl optionally substituted with one or more halos
- Rio and Rn at each occurrence are the same or different and are a) H, b) Ci_ 4 alkyl, or c) C 3 _ 8 cycloalkyl;
- R13 is a) H, or b) C1-4 alkyl;
- R 14 and R ⁇ 5 at each occurrence are the same or different and are a) Ci- 4 alkyl, or b) R 1 and R ⁇ 5 taken together are -(CH) ⁇ -;
- Ri 6 is a) H, b) Ci- alkyl, or c) C 3 - 8 cycloalkyl;
- R 17 is a) C 1 - 4 alkyl, or b) C3-8 cycloalkyl;
- Ris is a) H, b) Cl-4 alkyl, c) C 2 -4 alkenyl, d) C3- cycloalkyl, e) -OR13 or f) -NR21R22;
- R 19 is a) Cl, b) Br, or c) I;
- R 20 is a physiologically acceptable cation
- R 2 ⁇ and R 22 at each occurrence are the same or different and are a) H, b) C 1 - 4 alkyl, or c) -NR21R22 taken together are -(CH 2 ) m -; wherein R 23 and R 24 at each occurrence are the same or different and are a) H, b) F, c) Cl, d) C ⁇ -2 alkyl, e) CN f) OH, g) C ⁇ - 2 alkoxy, h) nitro, or i) amino;
- Z 1 is a) -CH 2 -, b) -CH(R 104 )-CH 2 -, c) -C(O)-, or d) -CH 2 CH 2 CH 2 -;
- Z is a) -O2S-, b) -0-, c) -N(R 107 )-, d) -OS-, e) -S-, or f) S(O) (NR190) ;
- Z 3 is a) -o 2 s-, b) -0-, c) -OS-, d) -S-, or e) S(O) (NR 190 wherein A 1 is a) H-, or b) CH 3 ;
- a 2 is a) H-, b) HO-, c) CH 3 -, d) CH 3 O-, e) R 102 O-CH 2 -C(O) -NH- f) R 103 O-C(O) -NH-, g) (Ci-C 2 )alkyl-0-C(0)-, h) HO-CH2-, i) CH 3 O-NH-, j) (Ci-C 3 )alkyl-0 2 C- k) CHa-CfO)-,
- R 102 is a) H-, b) CH 3 -, c) phenyl-CH 2 -, or d) CH 3 C(0)-;
- R 103 is a) (C 1 -C 3 ) alkyl-, or b) phenyl-;
- R 104 is a) H-, or b) HO-;
- R 106 is a) CH 3 -C(0)-, b) H-C(O)-, c) C1 2 CH-C(0)-, d) H0CH 2 -C(0)-, e) CH 3 S0 2 -,
- R 108 is a) H-, b) (C1-C4) alkyl, c) aryl -(CH 2 ) P , d) C1H 2 C-, e) CI 2 HC-, f) FH 2 C-, g) F 2 HC-, h) (C 3 -C 6 ) cycloalkyl, or i) CNCH 2 -.
- R 110 and R 111 are independently a) H-, b) CH 3 -; or
- R 112 is a) H-, b) CH 3 0-CH 2 0-CH 2 -, or c) HOCH 2 -;
- R 113 is a) CH 3 -, b) HOCH 2 -, c) (CH 3 ) 2 N-phenyl, or d) (CH 3 ) N-CH 2 -;
- R 114 is a) HO-, b) CH 3 O-, c) H 2 N-, d) CH 3 0-C(0)-0-, e) CH 3 -C(0)-0-CH 2 -C(0)-0-, f) phenyl-CH 2 -0-CH 2 -C(0) -0-, g) H0-(CH 2 ) 2 -0-, h) CH 3 0-CH 2 -0-(CH 2 ) 2 -0-, or i) CH 3 O-CH 2 -O-;
- R 115 is a) H-, or b) C1-;
- R 116 is a) HO- b) CH 3 O-, or c) F;
- R 150 and R 151 are each H or alkyl C1-C4 or R 150 and R 151 taken together with the nitrogen atom to which each is attached form a monocyclic heterocyclic ring having from 3 to 6 carbon atoms;
- R155 is a) H, b) F, c) C ⁇ - 4 alkyl, d) OC ⁇ _ 4 alkyl, e) SC ⁇ - 4 alkyl, or f) NHC ⁇ _ 4 alkyl;
- R 15 7 is a) -H, b) -F, c) -ci, d) -NH 2 , e) -OH, f) -CN, g) -C ⁇ - 4 alkyl, h) -OC ⁇ - 4 alkyl, i) -C ⁇ - 4 alkyl- -C ⁇ - 4 alkyl, j ) -NHC ⁇ - 4 alkyl, k) -(CH 2 )iC 3 - 6 cycloalkyl,
- Riei is a) H, or b) C ⁇ - 3 alkyl
- Ri 63 and R ⁇ 64 are independently a) H, or b) Ci- 8 alkyl, optionally substituted with one to three F, CI, OH, CN, or NH 2 ;
- Ri 65 is Ci- 4 alkyl, optionally substituted with 1-3 Ri ⁇ s;
- R170 is a) H, b) C 1 - 12 alkyl, optionally substituted with phenyl or CN, or c) C 2 _i 2 alkyl substituted with OH, SH, NH 2 , -OC ⁇ - 6 alkyl, -NHC ⁇ - 6 alkyl, -NHCOC ⁇ - 6 alkyl, -NHS0 2 C!_ 6 alkyl, -S(0) ⁇ C ⁇ - 6 alkyl, or one to three halo;
- Rl73 is a) H, or b) Ci-8 alkyl
- Rl74 is a) H, b) aryl, c) heti, e) Ci-8 alkyl;
- Rl75 is a) Ci-8 alkyl, b) aryl, or c) heti;
- Ri76 is a) aryl, b) heti, d) Ci-8 alkyl;
- R 177 and Ri 7 ⁇ are independently a) H, b) Ci-8 alkyl, or c) aryl; Ri 8 o and R 18 ⁇ taken together form C 3 - 5 cycloalkyl;
- R 1 8 2 is H, CH 3 or C 1 - 4 alkanoyl
- Ri 84 is C 1 - 4 alkyl, CH 2 OR ⁇ 86 , S-C1-4 alkyl, OC1-4 alkyl, or NR ⁇ 87 Ri88
- Ri 8 7 and Rse are independently H or C1-3 alkyl; or R 1 87 and Rise taken together form a 5- or 6-membered saturated heterocycle, wherein said saturated heterocycle may further contain one or two additional hetero-atoms selected from a group consisting of 0, S(0) n or NR ⁇ s 2 ;
- Ri 89 is H, CH 3 or benzyl
- R 193 is selected from the group consisting of null, H, C ⁇ _C 4 alkyl, C 3 -C 5 cycloalkyl, C ⁇ -C 4 haloalkyl, and halophenyl;
- R i94 is selected from the group consisting of H, alkyl, C ⁇ -C 2 alkoxy, halo, and haloalkoxy, or R ⁇ 93 and R ⁇ 94 can be taken together to form a 5- or 6-membered, optionally substituted, heteroalkyl or heteroaryl ring;
- R ⁇ 95 is H or F
- Ri 96 is selected from the group consisting of H, methyl, amino, and F;
- R 1 97 is H, CH 3 , or F
- B is an unsaturated 4-atom linker having one nitrogen and three carbons
- M is a) H, b) Ci-8 alkyl, c) C 3 - 8 cycloalkyl, d) -(CH 2 )mORi 3 , or e) -(CH 2 )h-NR 2 ⁇ R 22 ;
- Z is a) 0, b) S, or c) NM;
- Y is a) H, b) F, c) CI, d) Br, e) Ci- 3 alkyl, or f) N0 2 ;
- Yi is a) S(0)i, b) S(NR ⁇ 59 ), or c) S(NR 159 ) (0) ;
- Wi is 0 or S
- X 2 is 0 or NRi6 2
- X 3 is S(0) ⁇ or NR 1S6 ;
- Y 2 is a) 0 b) NH, c) CH 2 , or d) S(0)i;
- X 4 is a) O b) NR172, c) S(0) ⁇ , or d) S(O) (NR173) ;
- Y 3 is CH or N
- R 4 , R 5 R 6 , R7, R13, R ⁇ , Ri5f Ri 6 and R i7 are the same as defined above;
- R26 is a) R 28 , or b) NR2 NR28;
- R 27 and R 28 at each occurrence are the same or different and are a) H, b) Ci-8 alkyl, c) C 3 - 8 cycloalkyl, d) -(CH 2 ) m OR 13 , e) -(CH 2 ) h -NR 2 ⁇ R 22 , or f) R 27 and R 2 8 taken together are - (CH 2 ) 2 0 (CH 2 ) 2 -, -(CH 2 ) h CH(COR 7 )-, or - (CH 2 ) 2 N (CH 2 ) 2 (R 7 ) ;
- R38 is a) H, b) C1-6 alkyl, c) - (CH 2 ) q -aryl, or d) halo;
- R 4 o is a) H, b) C 1 - 6 alkyl optionally substituted with one or more OH, halo, or -CN, c) - (CH 2 ) q -aryl, or d) -(CH 2 ) q -OR 42 ;
- R 4 ⁇ is a) C ⁇ _ 6 alkyl optionally substituted with one or more OH, halo, or -CN, b) -(CH 2 ) q -aryl, or c) -(CH 2 ) q -OR 42 ;
- aryl is a) phenyl, b) pyridyl, or c) napthyl; a to c optionally substituted with one or more halo, -CN, OH, SH, C ⁇ - 6 alkyl, C ⁇ - S alkoxy, or C ⁇ _ 6 alkylthio;
- the present invention also provides an oxazolidinone derivative of Formula (II)
- the present invention also is directed to an oxazolidinone derivative of formula (VIII) having an improved solubility, wherein R is -CH 2 -G-A and Ri, G and A are as defined above.
- the present invention also is directed to a method of improving the solubility of an amide of Formula (III)
- the present invention also is directed to a method of improving the solubility of an amide of Formula (III) J R
- the present invention is also directed to an oxazolidinone derivative of formula (XIII)
- R is -G-A
- Ri' is a) H, b) OH, c) alkyl, d) alkoxy, e) alkenyl, f) amino, g) substituted alkyl, h) substituted alkoxy, i) substituted alkenyl, or ) substituted amino,
- R310, R410 and R510 each independently are a) H, b) C1-. 4 alkyl, c) halogen, d) C1- 4 alkoxy, e) hydroxy, f) (CH 2 ) c OP(0) (OH) 2 , g) C1- 4 acyloxy, or h) Ci_4 alkyl substituted by halogen, hydroxy, acyloxy, NR1210R1310 or alkoxy; and
- the present invention is also directed to a method of preparing an oxazolidinone derivative having an improved water solubility comprising the steps of providing an amide of formula (XVI) R'-tvJH 1
- R is -G-A and J, R' ⁇ , G, A and Pr are as described above .
- Ci- j defines the number of carbon atoms present from the integer "i" to the integer "j", inclusive.
- C1-4 alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof.
- C ⁇ - 2 alkyl refers to an alkyl group having one to two, one to three, one to four, one to five, one to six, one to eight, or one to sixteen carbon atoms respectively such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and their isomeric forms thereof.
- C2-4 alkenyl refers to at least one double bond alkenyl group having two to four, two to five, two to eight, two to fourteen, or two to sixteen carbon atoms, respectively such as, for example, ethenyl, propenyl, butenyl, pentenyl, pentdienyl, hexenyl, hexdienyl, heptenyl, heptdienyl, octenyl, octdienyl, octatrienyl, nonenyl, nonedienyl, nonatrienyl, undecenyl, undecdienyl, dodecenyl, tridecenyl, tetradecenyl and their isomeric forms thereof.
- C 2 . 5 alkynyl refers to at least one triple bond alkynyl group having two to five, two to eight, or two to ten carbon atoms respectively such as, for example, ethynyl, propynyl, butynyl, pentynyl, pentdiynyl, hexynyl, hexdiynyl, heptynyl, heptdiynyl, octynyl, octdiynyl, octatriynyl, nonynyl, nonediynyl, nonatriynyl and their isomeric forms thereof.
- C 3 . 4 cycloalkyl refers to a cycloalkyl having three to four, three to six, five to six, or three to eight carbon atoms respectively such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and their isomeric forms thereof.
- C 1 - 4 alkoxy refers to an alkyl group having one to four, one to six, or one to eight carbon atoms respectively attached to an oxygen atom such as, for example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy and their isomeric forms thereof.
- C ⁇ _ 5 alkylamino and “Ci-s alkylamino” refer to an alkyl group having one to six, or one to eight carbon atoms respectively attached to an amino moiety such as, for example, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino, or octoylamino and their isomeric forms thereof.
- C ⁇ _ s dialkylamino and “Ci-s dialkylamino” refer to two alkyl groups having one to six, or one to eight carbon atoms respectively attached to an amino moiety such as, for example, dimethylamino, methylethylamino, diethylamino, dipropylamino, methypropylamino, ethylpropylamino, dibutylamino, dipentylamino, dihexylamino, methylhecylamino, diheptylamino, or dioctoylamino and their isomeric forms thereof.
- C1-3 acyl refers to a carbonyl group having an alkyl group of one to three, one to four, one to five, one to six, one to eight, or two to eight carbon atoms.
- C1-4 alkoxycarbonyl refers to an ester group having an alkyl group of one to four, one to six, or one to eight carbon atoms.
- C ⁇ _ 8 alkyl phenyl refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one phenyl radical.
- C 2 -s alkenyl phenyl refers to a at least one double bond alkenyl group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one phenyl radical.
- C ⁇ - ⁇ alkyl pyridyl refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one pyridyl radical .
- C ⁇ _ 8 hydroxyl refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof attached to a hydroxy group.
- C ⁇ _ 8 alkylsulfonyl refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof attached to a S0 2 moiety.
- C1-6 alkylthio refers to an alkyl group having one to six carbon atoms and isomeric forms thereof attached to a sulfur atom.
- Het refers to 5 to 10 membered saturated, unsaturated or aromatic heterocyclic rings containing one or more oxygen, nitrogen, and sulfur forming such groups as, for example, pyridine, thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1- isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2- quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1- phthalazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4- imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3- pyr
- het 1 at each occurrence is independently a C-linked 5- or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring.
- het 2 at each occurrence is independently a N-linked 5- or 6-membered heterocyclic ring having 1 to 4 nitrogen and optionally having one oxygen or sulfur within the ring.
- Heti is a 5- or 6-membered heteroaromatic moiety having 1-3 N, 0 or S atoms, optionally substituted with the following: a) F, b) CI, c) Ci-3 alkoxy, d) C ⁇ _ 3 alkylthio, or e) CN.
- heti is a C-linked 5- or 6-membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, which is optionally fused to a benzene ring.
- halo refers to fluoro, chloro, bromo, or iodo.
- Pr refers to a suitable phosphate protecting group, such as benzyl, alkyl, tert-butyl, etc.
- the compounds of the present invention can be converted to their salts, where appropriate, according to conventional methods.
- pharmaceutically acceptable salts refers to acid addition salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, alate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate and the like. These salts may be in hydrated form.
- the dotted line in the heterocyclic ring means that this bond can be either single or double. In the case where the dotted line is a double bond, the R 39 group will not be present.
- the compounds of this invention contain a chiral center at C5 of the isoxazoline ring, and as such there exist two enantiomers or a racemic mixture of both.
- This invention relates to both the enantiomers, as well as mixtures containing both the isomers.
- additional chiral centers and other isomeric forms may be present in any of A or Ri group, and this invention embraces all possible stereoisomers and geometric forms in these groups.
- the compounds of this invention are useful for treatment of microbial infections in humans and other warm blooded animals, under both parenteral and oral administration.
- the inventive compounds have antibacterial activity against a number of human and veterinary pathogens including Gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci, Gram-negative organisms such as H. influenzae and M. ca tarrhalis, anaerobic organisms such as Bacteroides spp. and Clostridasppa , Mycobacteri um tuberculosis , M. avium and M. spp. and organisms such as Mycoplasma spp.
- Gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci
- Gram-negative organisms such as H. influenzae and M. ca tarrhalis
- anaerobic organisms such as Bacteroides spp. and Clostridasppa
- compositions of this invention may be prepared by combining the compounds of this invention with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques.
- Solid form compositions include powders, tablets, dispersible granules, capsules, cachets and suppositories.
- a solid carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent.
- Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like.
- Liquid form compositions include solutions, suspensions and emulsions.
- solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.
- the pharmaceutical composition is provided employing conventional techniques in unit dosage form containing effective or appropriate amounts of the active component, that is, the compound according to this invention.
- the quantity of active component that is the compound according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application, the potency of the particular compound, the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
- the compounds or pharmaceutical compositions thereof will be administered orally, parenterally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective.
- a concentration that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective.
- such antibacterially effective amount of dosage of active component will be in the range of about 0.1 to about 100, more preferably about 3.0 to about 50 mg/kg of body weight/day. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the bacterial infection being treated, and the particular compound being used.
- the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., 2-4 four times per day.
- compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound or a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3.5-6.
- a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection
- a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3.5-6.
- Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)- lysine and L (+) -arginine to name but a few representative buffering agents.
- the compound of this invention generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg/mL to about 400 mg/mL of solution.
- the resulting liquid pharmaceutical composition will be administered so as to obtain the above-mentioned antibacterially effective amount of dosage.
- the compounds according to this invention are advantageously administered orally in solid and liquid dosage forms.
- Formula I As a topical treatment an effective amount of Formula I is admixed in a pharmaceutically acceptable gel or cream vehicle that can be applied to the patient's skin at the area of treatment. Preparation of such creams and gels is well known in the art and can include penetration enhancers.
- the present invention improves the solubility and bioavailability of an amide of Formula III V 1
- the carboxylic acid derivative of Formula IV is prepared as described in M.G. Nicolaou, C.-S. Yuan and R.T. Borchardt, J. Med. Chem . 1996, 61, 8636-8641.
- Condensation of the amine of Formula V with the carboxylic acid of IV is accomplished by methods known in the art for amide or peptide bond formation.
- Examples include 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride and 4- (dimethylamino) - pyridine and solvents such as methylene chloride at reaction temperatures of 0 to 2 °C, 1- (3-dimethylamino- propyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole and solvents such as dimethylformamide at 0 to 24°C, and bis(2-oxo-3- oxazolidinyl)phosphinic chloride and triethylamine and solvents such as methylene chloride at 0 to 24°C.
- Step 2 of Scheme 1 the amide of VI undergoes an acylation reaction to give the compound of VII, wherein J is an oxygen atom.
- This reaction is conveniently carried out by allowing the compound of VI to react with an acid chloride in the presence of an efficient acid scavenger.
- Solvents such as methylene chloride, ethylene chloride or carbon tetrachloride at a temperature of from 24 °C to the reflux temperature of the solvent can be used.
- Acid scavengers such as 3 A units molecular sieves, propylene oxide, 1, 8-bis (dimethylamino) naphthalene and methyl trimethylsilylcarbamate are suitable for use in this reaction.
- Step 3 of Scheme 1 the phosphate esters of Formula VII are deprotected. This can be carried out by hydrogenolysis at atmospheric pressure and ambient temperature with a palladium catalyst. Solvents such as tetrahydrofuran, diethylether, or 1, 2-dimethoxyethane can be used for this reaction.
- Step 1 the acid (XIII) is converted to the acid chloride (XIV) with, for example, oxalyl chloride and dimethylformamide in a solvent, such as methylene chloride, at temperatures of from 0 to 30°C.
- Step 2 the compound of formula (XIV) is allowed to react with the compound of formula (III) in a solvent, such as methylene chloride, ethylene chloride or acetonitrile, in the presence of an efficient acid scavenger, such as methyl trimethylsilylcarbamate, at the reflux temperature of the solvent.
- Step 3 the phosphate protecting groups of the compound of formula (XV) is removed by methods known in the art.
- amides containing oxazolidinone groups that can be used in the present invention are shown below.
- the preparation of the following amides of Examples 1-434 are shown in United States Patent No. 6,362,189 Bl, the disclosure of which is herein incorporated by reference thereto.
- EXAMPLE 8 (S) -N- [ [3- [3-Fluoro-4- (4-morpholinyl) phenyl] ⁇ 2-oxo-5-oxazolidinyl]methyl] -thioformamide (7) .
- EXAMPLE 9 ( S) -N- [ [3- [3-Fluoro-4- (4-morpholinyl) phenyl] ⁇ 2-oxo-5-oxazolidinyl]methyl] thiopropion-amide (9) .
- EXAMPLE 10 (S) -N- [ [3- [3-Fluoro-4- (4- morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- chlorothioacetamide (11).
- EXAMPLE 16 (S) -N- [ [3- [3-Fluoro-4- (4- morpholinyl) phenyl] -2-oxo-5-oxazolidinyl]methyl] - - (methoxycarbonyl) thioacetamide (23) .
- EXAMPLE 17 (S) -N- [ [3- [4- [1- [1, 2 , 4 ] Triazolyl] phenyl] -2- oxo-5-oxazolidinyl]methyl] thioacetamide (25) .
- EXAMPLE 18 (S) -N- [ [3- [4- [1- [1, 2, 4 ] Triazolyl] phenyl] -2- oxo-5-oxazolidinyl]methyl] thioacetamide (25) .
- EXAMPLE 19 (S) -N- [ [3- [1- (Hydroxyacetyl) -5-indolinyl] -2- oxo-5-oxazolidinyl]methyl] thioacetamide (28) .
- EXAMPLE 20 (S) -N- [ [3- [3-Fluoro-4- [4- (hydroxyacetyl ) -1- piperazinyl] phenyl] -2-oxo-5- oxazolidinyl]methyl] thioacetamide (30) .
- Step 1 Preparation of (5R) - (-) -3- [3-fluoro-4- (4- morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxylic acid
- Step 2 Preparation of (5R) - (-) -3- [3-fluoro-4- (4- morpholinyl) phenyl] -2-oxo-5-oxazolidinecarboxamide
- Step 1 Preparation of (5R) - (-) -3- [3-fluoro-4- (4- morpholinyl) phenyl] -N-benzyloxy-2-oxo-5- oxazolidinecarboxamide
- Step 1 Preparation of (5R) - (-) -3- [3-fluoro-4- iodophenyl] -5-hydroxymethyl-2-oxazolidinone
- reaction mixture was then quenched with saturated aqueous ammonium chloride (20 mL) , diluted with water (20 mL) and the layers are separated.
- the aqueous phase was extracted with ethyl acetate (25 mL) , and the combined organic phase was washed with water (25 mL) and saline (25 mL) , dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
- Step 5 Preparation of (5R) - (-) -3- [4- (3-pyridyl) -3- fluorophenyl] -2-oxo-5-oxazolidinecarboxamide
- Step 1 Preparation of (5R) -3- [4- (trimethylstannyl) -3- fluorophenyl] -2-oxo-5-oxazolidinecarboxamide
- the resulting mixture was concentrated under reduced pressure to remove dioxane, diluted with methylene chloride (75 mL) , washed with saline (25 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure.
- Step 2 Preparation of (5R) - (-) -3- [4- (3, 6-dihydro-2H- pyran-4-yl) -3-fluorophenyl] -2-oxo-5-oxazolidine- carboxamide
- This intermediate (540 mg crude) was taken up in methanol (16 mL) , a drop of concentrated sulfuric acid was added, and the mixture was stirred at ambient temperature for 21 hours. Then, the reaction mixture was concentrated under reduced pressure and chromatographed on a Flash 40S 40g silica gel (32 - 63 n) cartridge, eluting with ethyl acetate/heptane (25/75) .
- Step 2 Preparation of (5R) - (-) -3- [4- (3, 6-dihydro-2H- thiopyran-4-yl) -3-fluorophenyl] -2-oxo-5- oxazolidinecarboxamide
- the catalyst was then removed by filtration through a pad of Celite, rinsing with methanol and tetrahydrofuran, and the filtrate was concentrated under reduced pressure and triturated with (5% methanol/methylene chloride) /diethyl ether. Filtration then provides the title compound, mp
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AU2002354579A AU2002354579A1 (en) | 2001-07-12 | 2002-07-12 | Amide-containing compound having improved solubility and method of improving the solubility of an amide-containing compound |
JP2003512212A JP2005520782A (en) | 2001-07-12 | 2002-07-12 | Amide-containing compound having improved water solubility and method for improving water solubility of amide-containing compound |
CA002452513A CA2452513A1 (en) | 2001-07-12 | 2002-07-12 | Amide-containing compound having improved solubility and method of improving the solubility of an amide-containing compound |
EP02752358A EP1451164A2 (en) | 2001-07-12 | 2002-07-12 | Amide derivatives having improved solubility |
MXPA04000357A MXPA04000357A (en) | 2001-07-12 | 2002-07-12 | Amide-containing compound having improved solubility and method of improving the solubility of an amide-containing compound. |
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Cited By (13)
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WO2003072553A1 (en) * | 2002-02-25 | 2003-09-04 | Pharmacia & Upjohn Company | N-aryl-2-oxazolidinone-5-carboxamides and their derivates and their use as antibacterials |
US7141588B2 (en) | 2002-02-25 | 2006-11-28 | Pfizer, Inc. | N-aryl-2-oxazolidinone-5-carboxamides and their derivatives |
US7304050B2 (en) | 2003-09-16 | 2007-12-04 | Pfizer Inc. | Antibacterial agents |
US7396847B2 (en) | 2001-09-11 | 2008-07-08 | Astrazeneca Ab | Oxazolidinone and/or isoxazoline as antibacterial agents |
DE102007032344A1 (en) | 2007-07-11 | 2009-01-15 | Bayer Healthcare Ag | Prodrug derivatives of 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4 -c] pyridine-3-carboxamide |
DE102007032347A1 (en) | 2007-07-11 | 2009-01-15 | Bayer Healthcare Ag | Aminoacyl prodrugs |
DE102007032345A1 (en) | 2007-07-11 | 2009-01-15 | Bayer Healthcare Ag | Aminoacyl prodrugs |
WO2009020616A1 (en) * | 2007-08-06 | 2009-02-12 | Micurx Pharmaceuticals, Inc. | Antimicrobial ortho-fluorophenyl oxazolidinones for treatment of bacterial infections |
JP2009526788A (en) * | 2006-02-16 | 2009-07-23 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | Aminoacyl prodrug derivatives and medicaments for the treatment of thromboembolic disorders |
US8362015B2 (en) | 2006-08-24 | 2013-01-29 | Bayer Intellectual Property Gmbh | Aminoacyl prodrug derivatives and medicaments for treatment of thromboembolic disorders |
US9382276B2 (en) | 2014-02-21 | 2016-07-05 | Micurx Pharmaceuticals, Inc. | Water-soluble O-carbonyl phosphoramidate prodrugs for therapeutic administration |
KR20180026491A (en) * | 2015-07-17 | 2018-03-12 | 더 글로벌 얼라이언스 포 티비 드러그 디벨롭먼트, 잉크. | Substituted phenyloxazolidinone for antimicrobial therapy |
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DE102007028319A1 (en) * | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituted oxazolidinones and their use |
DE102007028407A1 (en) * | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituted oxazolidinones and their use |
US8026232B2 (en) * | 2008-05-28 | 2011-09-27 | Toyama Chemical Co., Ltd. | Benzothiophene oxide derivative and salt thereof |
DE102010028362A1 (en) | 2010-04-29 | 2011-11-03 | Bayer Schering Pharma Aktiengesellschaft | manufacturing |
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DK0856002T3 (en) * | 1995-09-01 | 2002-02-11 | Upjohn Co | Phenyloxazolidinones with a C-C bond to 4-8-membered heterocyclic rings |
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2002
- 2002-07-12 CA CA002452513A patent/CA2452513A1/en not_active Abandoned
- 2002-07-12 EP EP02752358A patent/EP1451164A2/en not_active Withdrawn
- 2002-07-12 US US10/194,914 patent/US7049443B2/en not_active Expired - Fee Related
- 2002-07-12 JP JP2003512212A patent/JP2005520782A/en not_active Withdrawn
- 2002-07-12 WO PCT/US2002/022526 patent/WO2003006440A2/en not_active Application Discontinuation
- 2002-07-12 MX MXPA04000357A patent/MXPA04000357A/en unknown
- 2002-07-12 AU AU2002354579A patent/AU2002354579A1/en not_active Abandoned
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US20040014967A1 (en) | 2004-01-22 |
MXPA04000357A (en) | 2004-05-04 |
CA2452513A1 (en) | 2003-01-23 |
WO2003006440A8 (en) | 2003-07-10 |
EP1451164A2 (en) | 2004-09-01 |
AU2002354579A1 (en) | 2003-01-29 |
JP2005520782A (en) | 2005-07-14 |
US7049443B2 (en) | 2006-05-23 |
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