MXPA96004072A - Derivatives of oxazolidinone and pharmaceutical compositions that contains them - Google Patents
Derivatives of oxazolidinone and pharmaceutical compositions that contains themInfo
- Publication number
- MXPA96004072A MXPA96004072A MXPA/A/1996/004072A MX9604072A MXPA96004072A MX PA96004072 A MXPA96004072 A MX PA96004072A MX 9604072 A MX9604072 A MX 9604072A MX PA96004072 A MXPA96004072 A MX PA96004072A
- Authority
- MX
- Mexico
- Prior art keywords
- per
- met
- uoro
- compound
- oxo
- Prior art date
Links
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 title description 4
- 239000000203 mixture Substances 0.000 claims abstract description 74
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000011780 sodium chloride Substances 0.000 claims abstract description 16
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 18
- 125000004429 atoms Chemical group 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- LCZDCKMQSBGXAH-AWEZNQCLSA-N 3-[[3-[(2S)-2-amino-2-carboxyethyl]-5-methyl-2,6-dioxopyrimidin-1-yl]methyl]-5-phenylthiophene-2-carboxylic acid Chemical compound O=C1C(C)=CN(C[C@H](N)C(O)=O)C(=O)N1CC1=C(C(O)=O)SC(C=2C=CC=CC=2)=C1 LCZDCKMQSBGXAH-AWEZNQCLSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 229940079593 drugs Drugs 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-Aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 8
- 150000004702 methyl esters Chemical class 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 5
- 241000009298 Trigla lyra Species 0.000 claims description 4
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 claims description 4
- VYZAMTAEIAYCRO-UHFFFAOYSA-N chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052804 chromium Inorganic materials 0.000 claims description 4
- 239000011651 chromium Substances 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims description 3
- 230000001105 regulatory Effects 0.000 claims description 3
- IAKOZHOLGAGEJT-UHFFFAOYSA-N 1,1,1-trichloro-2,2-bis(p-methoxyphenyl)-Ethane Chemical compound C1=CC(OC)=CC=C1C(C(Cl)(Cl)Cl)C1=CC=C(OC)C=C1 IAKOZHOLGAGEJT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 230000003115 biocidal Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 240000003670 Sesamum indicum Species 0.000 claims 3
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 claims 2
- YWSOBIMUIPVQQM-UHFFFAOYSA-N 7-chloro-3-ethoxy-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(OCC)N=C1C1=CC=CC=C1 YWSOBIMUIPVQQM-UHFFFAOYSA-N 0.000 claims 1
- 241001553178 Arachis glabrata Species 0.000 claims 1
- 241001649081 Dina Species 0.000 claims 1
- 101710045227 ELAVL1 Proteins 0.000 claims 1
- 206010022000 Influenza Diseases 0.000 claims 1
- GWFRSQBGIGLMFD-BBKOCAQVSA-N N-[9-[(2R,3R,4S,5R)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-3,4-dihydroxyoxolan-2-yl]purin-6-yl]-2-phenoxyacetamide Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC(OC)=CC=1)(C=1C=CC=CC=1)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C3=NC=NC(NC(=O)COC=4C=CC=CC=4)=C3N=C2)O1 GWFRSQBGIGLMFD-BBKOCAQVSA-N 0.000 claims 1
- 101700011774 PEPD Proteins 0.000 claims 1
- 241000283080 Proboscidea <mammal> Species 0.000 claims 1
- 241000822135 Ula Species 0.000 claims 1
- 229910052770 Uranium Inorganic materials 0.000 claims 1
- 241000625014 Vir Species 0.000 claims 1
- IJTHCTQNQZKJIY-UHFFFAOYSA-N XKN9029GHL Chemical group OC1=CC=C2C=CC3=CC=CC4=C3C2=C1O4 IJTHCTQNQZKJIY-UHFFFAOYSA-N 0.000 claims 1
- 235000019876 cocoa butter improver Nutrition 0.000 claims 1
- 230000001419 dependent Effects 0.000 claims 1
- 229950008597 drug INN Drugs 0.000 claims 1
- 230000002500 effect on skin Effects 0.000 claims 1
- 239000011521 glass Substances 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 230000003301 hydrolyzing Effects 0.000 claims 1
- 101700037660 ina-1 Proteins 0.000 claims 1
- 101700057654 lmn-1 Proteins 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 150000007978 oxazole derivatives Chemical class 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000011593 sulfur Substances 0.000 claims 1
- 230000000845 anti-microbial Effects 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 description 133
- 239000000243 solution Substances 0.000 description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 65
- 239000002904 solvent Substances 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
- -1 heptylthio Chemical group 0.000 description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- 239000012267 brine Substances 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 14
- 150000002500 ions Chemical class 0.000 description 14
- 150000002148 esters Chemical class 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000008079 hexane Substances 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 238000007792 addition Methods 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
- 235000019256 formaldehyde Nutrition 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 201000008827 tuberculosis Diseases 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 5
- 230000002829 reduced Effects 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 241000606125 Bacteroides Species 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- 239000004599 antimicrobial Substances 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 4
- 125000004432 carbon atoms Chemical group C* 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 4
- 201000009910 diseases by infectious agent Diseases 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- 150000002828 nitro derivatives Chemical class 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000001187 sodium carbonate Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N AI2O3 Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000002131 composite material Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000000813 microbial Effects 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 230000000699 topical Effects 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-Toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- KISPTSIXDBWEIX-UHFFFAOYSA-N 9-ethyl-3-[2-(1-methylquinolin-1-ium-2-yl)ethenyl]carbazole Chemical compound C1=CC=CC2=[N+](C)C(/C=C/C=3C=C4C5=CC=CC=C5N(C4=CC=3)CC)=CC=C21 KISPTSIXDBWEIX-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N Acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 206010060945 Bacterial infection Diseases 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N Benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 210000004369 Blood Anatomy 0.000 description 2
- 108060001688 COA3 Proteins 0.000 description 2
- 241001112696 Clostridia Species 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M Lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N Morphine Chemical group O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N Nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 241000295644 Staphylococcaceae Species 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-N VANCOMYCIN Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 2
- 229960003165 Vancomycin Drugs 0.000 description 2
- 108010059993 Vancomycin Proteins 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- RYPWQHONZWFXBN-UHFFFAOYSA-N dichloromethyl(methylidene)-$l^{3}-chlorane Chemical compound ClC(Cl)Cl=C RYPWQHONZWFXBN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- 150000004673 fluoride salts Chemical group 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 125000005842 heteroatoms Chemical group 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000011368 organic material Substances 0.000 description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000001681 protective Effects 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
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Abstract
The present invention relates to novel oxazolidinone derivatives represented by the chemical formula: or pharmaceutically acceptable salts thereof, as well as antimicrobial compositions containing as active ingredients, said derivatives or the salts thereof.
Description
?, DERIVATIVES OF OXAZOLIDINONE AND PHARMACEUTICAL COMPOSITIONS CONTAINING BACKGROUND OF THE INVENTION The present invention relates to novel derivatives of o? Azo] idinone or I \ > therapeutically acceptable salts of the same, and < ige t.e fa miar ics that contain them in the form of an ingredient * »ari, wis for the prevention or treatment of illnesses ínfect HISH'Í, More espp < If it is a lover, the present invention relates to useful agents which are effective against a number of atherogens *, humans and veterinarians, including staphylococci and multiple resistance organisms, as well as organisms. anae * rob.} co * »such as the bacteroides and clostrid a. ot and iis smaß resistant to acids such as Mvcobacter .um tub r 1t J ur> xs and Mycobacteriu aviu. The International Public Information No. W093 / 23384 describes axazole that inhibits a substituted portion of diazine (piper pn) and its use as an antimicrobial. "International Publication No. WD9" V09103 describes oololins with substituted sugar and IMI 33 -f. L ~ ?! < a.l i ns that are useful as anti-microbial agents, International Publication No. W090 / 02744 describes the? -3 mlol im l-5ß-am? domet and loxazol idi nanas, 3-fen?] - < can fnio ring «&ubs j tu? do) ~ 5ß- am? domet i loxa ^ ol idi nonas, 3- phenyl-ith nitrógono substido) -5ß ~ am? .domet and loxazole donuts, which are useful as antibac bepane agents. Oira iipíprences describing different oxazol i di nones include, U.S. Patent 4,801,600, J.
Med. Chem. 32, pages 1673 to 1681 U989); J. Med. Chem. 33, pages 2569 to 1578 (1990); They ahedron you. 45, pages 1323 to 1326
< 1989) -, and J. Med. Ch. 35, page 1156 (1992). The Publ J will fall under European Patent No. 352,781, discloses axazol id i nona ft-rulo with fula and substituted pipdila. The Patent Publication Furopea Na. 316,594 describes .xazal idinones with 3 substituted styrenes. European Patent Publication No. "'12, 000 describes oxazole, phenyl, phenylmethyl, and pyridine, 3] or substituted.
SUMMARY OF THE INVENTION Problems to be Solved by the Invention The object of the present invention is to provide novel derivatives of oi-azole and the pharmaceutically acceptable salts of the same, which have high microbial activities, and antimicrobial compositions that contain them in the form of active ingredients. Means for Solving the Problems The present inventors carried out intensive studies in order to achieve the object mentioned above. As a result of said studies, useful and novel derivatives of a? Azole were discovered and the present invention has been made based on said discovery. The present invention provides an oxazolidinone derivative represented by the general formula (I).
where. R is < a > as hydrogen, < b > alkyl Cj. ~ Ce ?, < c) c iclo lquilo CS-CA, < d) ami a, < e > lquil ino C_ ~ Ca, < f) d: i a 1 qu i 1 am i no C x ~ C®, (g) Ci-Cta alkoxy, or < h) has 1ogeno 1 cycloC t-Ca; R1 and R3 are each independently (a) hydrogen atom, (b) halogen atom, (c) Ci-C alkyl, < d) ci loalqu lo Cs-C,.,; (e) < CHa) rB-0R1", or (f) -Ci ^ O-R * 1; X and Y are each and independently (a) hydrogen atom, or < b) halogen atom;
R * and R * are each and independently (a) hydrogen atom, (b) alkyl C? -Cβ, < d) alkylthio C? -Cβ, (e) < CH?.) M-aRßl, () -a ~ < CHSÍ) m-0Rtsl, (g) -MR «93, < h) •• -N ---- CH ~ NR «'' - RS- *, -" - • (i) ~ -C (= 0) - NR ^ aRß: 2, or < j > < CHa.) MC < = A) -R '* i, or can be co-joined together to form < k) = 0, < 1 > - • = NR «3, (m)« = S - (n) = CR ** Re *. or (o) an optionally substituted, unsaturated or saturated 5- or 6- membered hetero ring having from 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, R11 and R? a are each independently of the halogen atom, (b) to 1k, C-Ce, or () methox imet ilo; R "* 1 is < a > hydrogen atom, < b) - < CHa) m-OH,. (t:) Ct-Cß alkyl, < e) -0 - CHa-0-C < -0) -R1: l, or 5 < f > ~ < CHa) m-C < = 0) -OR11;
< a) hydrogen atom, < c > a] chyl C_ ~ Cß, 10 -r ^ (d) r < -p) - p "-1, (.or <u> -MP1 'R *, (; * • - fr; H ^) -f ^ m 3o, or puwileii I' Lii? i? l? ipi'1'i-. juid 'i. -.?-.i form a group μ i rru ¡idi no, 15 a group pi p * - »ri di m >, a y, -upo p 3 por; - 1 no, one morphine group, or one group IUW G foj .1 m-, p. I - - and substi- tuted each un-t of 3 as rudlfi? By i3c | i! J 3 '!? - Cβ or - CHCH-a) m -OH;
. "* W J ía) i lomo de h.dróyc» uo,?. ('< b) iv,
< p) --íCH »)», - f •• * (• * ¡3o, f) -Ni < 4'-iR - * '"i', 25 iy) NH-C <-NHi-NHa, (li) f 1,?, 1] trj«;: £ il-4- 33o, or (i) 1 - 1 1 no i, (, R * ñon < ana? > • * i ndi-'pt id i í "i i-ii I« - * (a)? ') r, (0' -f? "1, or < d) • ípiv f? -. ?? _oj es ía) i lomo de li i drrt» MÍO ((.) • i li-j i lu Cj .-Cß, subsumed by one or more--, < d) Ü 1 that i I or pa-Cß) lial yenoa 3 qu J 3 O C _, - Cß, (f) < Q > - < CHa) m- - (-n »R" 1, (i) l>?] O;
(a) -i \ orno de, f yeito, > > (! &) i or l < • *] • > 11 I f- to; . .. p. > my eiile .. > - * l h? i- * > ? un > 'n3a': o. ". rn J 3 JO; I? I '> are set one .-> in¡ I» > pond io'? n J, 1? ns O or 1; p 'are given an oi nd>' in place 1, 2, I ', or 4; and J i li / Cf-Cfi, u¡? rada n.? of the f? nic? one = a rioras, μ ij e -. I nd a »- * ?? • l > - ^ ¡M ~,» II ÍHII > > > • «> •• > ni > -il J tuj gives by * un »!>) more <. > ub-. > l? luyon I o. > -or I? > ? o? a »lo. > s μ «.rl, i r d» - 3 ru or > on - > J of an atom d > * ha3 t »nn, ¡n ^ h i d r **; i 3 o, a group alc oxi lo C_ -CB, ui! group a i lii! i 3o f! j -f! «, an y-group, an alkylamine group > no Ct-C », uri y group -CN and a group ca bü J 3 o, or a salt f arma." • ** »I lóenl at op lab] e of 3 same. μ? v '>? jn > > > - invention also provides an antimicrobial agent for the active substance, the derivative of i uoni or a pharmaceutically active agent. acceptable »Jel mt lithium 3 ayetd» - iiiiLinpi ni, ??? o? ue that contains the active ingredient of l.? pro n in - iu ón can be used for the, -i va lam i enlu » j p ^ s *. ???????????????????????
"u sa tíft the iirt'ít'nu 'de > t vi pp c'iit, ol t rmma" t? * atam i "KJGU fn ci dii .1 or total of 3 symptoms.-, of a disease> 1e the i n-? L pad »» ». -.- a μai. Irinle, cinto se-.1 usa > -n st described i μ > "s on the l i no no" foresee ", ion" sigin-f on the fact of avoiding, partial or tota 1 mon lo, 3 o = > J i n hills of. a disease in a patient, who, »him. ? u .- »rdu > On the day of a ductor, can -? uf? i r 1-t »-» ?? f * • = > T hese and a re lated I ndiction with the same, unless - * • > tomón I HS measures μrovent 3 vas suitable. r the pre ~ > e?, l in ^ nf ion provide derivatives? USVÜS of o; < a; cj3 i d J nona, 1 > • < < ui3e- > They are useful. »I do not know how to do it. or t, póul i ». or > for infectious diseases. Compounds »le pt. Eid in en», on have 3 m on crob 3 ana ew the en > > ? ni goes v < ? r? ». s? -t l úono- > human and vetc »ri nar j os, including the stanhy lococc and the multiple-resistance streotococci, as well as anaerobic oryaviruses such as the bacteroid and alien species, and plant-resistant organisms such as Mycobac tepum tuberculosis and Mvcoba terium avium .
or the use of a number of various portions of the drug "."? b? v D-- > > * i n > J J r ad »> pot- an if-fi jc > that der-jyna the number ipimo and »* 3 > tt 'uro ue al al MHI »je? arbono in the p > For example, "3 pref i i u" "i-r_» l »-f i ue l the number of carbon atoms pri'sen e., de > of whole ol "4" Insta o3 whole "" 3in lusive. For what reason, X ". >» -.? Ei? Gold to rent from! To? R? G?; of carbon Inc lusive, or m ^ i l io, etj? o, μropi lo o 3 -.oprop ¡305 alqui l »f-Cfa».-_ • = > I put it, > .-,? lo, propi Jn, butyl, peulj lo, hííila, h pli lo, o- IJ lo _, i a • > ferma 1 '- mei-i »- > -, of 3 or - same. > I rent . • '"' fe- **? T the general formula (T) par-i 1> JS composed of the foot-, nte if.ven.- juu, - > (_ ref iere a motilo, eti lo , propyl, bul ilo, nor 11, hes,? lo, hepli lo, í ti ti and the isometc forms of my- "a". ", Jyiii pref fi ectly meti, eti lo, prop i lo, huí jln, peí.1 1 lo, he;: 1 lo y { >? - > ftiritid's i oméri s de 3 'JS same »>; tia.> pt * fyt» ntemente methyl, ethyl, propyl, butyl, and the 1-form thereof, of the same group, wherein the 1-C-B group may be subst 3, or cpt 3, 1 by 1. 1 ttá: »-ubst J uents selected from the group • read group 1 -_ •> of a halogen atom, a hydrophilic group, group < > ho hoo 3o fj- Ha, > jrupo a »i loi'i lo Ci-C ©», a yt-upo a ino, grupo alqui l ~ mino C.-CK », yrtipo di a 3 qu j 3 am mo CfCß, grupo - CN and a group • arijo-ile, said groups Ci-Cß alkyl subtypes iití II II 1 - 1"3 oropra p 13 o, 1 - f luoroprop 1 lo, 2- c 3 nroprap J Jo, 7 ~ f luoi'oprop 311 -, hj dro, 1 e 113 o, 7- h 1 shot :, 1 rop 11 o, 2 , 3-d 1 hidroí, i prop 11 o, I - hi dro *, i bu t 13 > _ > , 2-h idro;, i bul i read, 1 ™ ms-; t jí, 1 prop 11 o, 1 o < . { i 1 o ,,? pt op 13 o, 1 - a. e to: ', 1 proμ 1 lo, 1- am 1 n > i rop 13 o, I - MU I 1 > * .m I 1 I o, 1 - bu l i 1 a 1 no rop 11, 1, 1- dibut i 3 ami nopi)) i I o, 1- »i a i? but .1 or, 1 - r «box i but 31 o and the
, i l r e. f "ll,.? no lqueiu what pa-Cp means vi or lo, 1- propeni lo,? -pr opem 3 o, I --inet j J -1 --propen i lo, l-buter lo, 2- buteni lo, 1 -pen tni I > >, 7- p uten i 3 o, 1 - he ,, em 1 o, - 1-hepte? U 3 CD, 1-- or teru lo yls I was a - > isonn-st u .i &mt; m, pre < eren lomen tcj a group alqueni que qn > · ti 'íe of 1 to 5 atoms »of carbon, and more preferably a gi upo alqueru what has from 2 to 4 carbon atoms or not - "" F? termi no. 1 obufc i 1, cjc I open ti I oo cu lohe:, j 1 o. Fl termi no alqui la no C _ -C < B means a portion that does not contain an alk ion tjUe it has from 1 to 8 rarbono atoms, and "1 lormi uo di al qui 3 ai no C _.- ~ Cß" means an ammo portion that (one has two alkyl portions having from 1 to R atom. " , e < -n liuii. For example, the two terms cover prop i 3 - tu no yd J μrop i 3 am i no, re.- > Pect i va, they mean preferably * i qu i 1 m i no y d i a Iq i 3 am mcj that contain a port a n a3qu? l < ) qn < > 1-to-6 carbon atoms, and more preferably, to the 1-amino-1 and 2-alkylaryln that contain an alkyl portion that binds carbon atoms. Hl tt-jr i no alkoxyl Ct-Cra s? Cjrt3f3ca meto:; 3 lo, eto? Lo, propoM lo, bulo; i l > , put to; < i 3 o, he: - 13 CD :, I what, hep 113 or ?? 3 o, o ti lo; - i lo y 3a > shapes ? »What are the same, pref erently», a, and an alcove that has from 1 to 6 volumes of carbon, and that you have a group at the same time; 1 to 4 atoms of r di bone Alqui lo! 10 Ct- «sjgru fji met í I tio, ethylthio, propilliu, buiíltio, pentillio, hexiltio, heptylthio,
'> c 133 I 10 and la., f-e-t, go-is they themselves, preferably a group rent from tarmac, and more preferably n, yi ue alllio that l lene de 1 a 4 atoms of
carbon. F.3 halogen atom -uyiufu a fluoride atom, an atom < 3oruro, an 'in') ln or uro or a volume iodide. The preferred halogen atom pai to X and Y is a fluoride atom. The term h < * l ogonoa 3 c | u 3 o C _-- CB means a group? ^ l CJU i 3 u d -Cß in > 1 1 ua I the atoms of hl dróy are not s bs ituidos by the atom of b'lóg np de-finido utc - 1 ot * men be, this e- > pt efererite eitte a group alqui lo iim & I replaced child who has > ie 1 to 6 alomo i d i. -ii-hono, m. • > f pr of 1 and 4 atoms of rbonu, F.l has 1 geno 1 qu i 1 o Cj.-C__ can be 5 e je p 11 f i < . (1 uoromet i lo, tr if luorome 113 o, 1 -f 1 uoroet 11 o, 2-t 1 ro t 3 J o, 1,1,1 I rif I uoree li 1 o y 2, u-ri if 1 uaroprop i 1 o.! "" An i 11 *) do 5- a? - members n Unsaturated .-, or saturated that will be formed by R ** and R5 when they are taken together and
Xl which has d 1,? "-, heteroa l" we selected from the 0 group c nsistianl "» »a" I orne of ni ', óyí-ino, an atom of o:, Iyeno and an atom of arufi »» , Which can be exemplified by heterograms such as "I, T h -an, fl," (hü!, Olano (ceta! Et 1 ene), im 311a or 1 idji ta, \ 1, "', 1 > I i I Hilann, TI,"', 1; lila no,:; a, vo 3 idi na y
2, r.-di hi drot ia, "? 3 e.F. heturoan I 3 o can,? R replaced optima on 3ly poi gtique dc * o aretiJo, which can be replaced up < i a moni e by one or more hero groups: c? Jo, and one of said hydropile 1 - > ub_.13 l ls can be si? t J luí d ?; > ori on- > i Mieid e poi a I uilo C j. - fX, meto; ' i met i 3 o, ester and the ßiila in, F. ii tome e nitrogen that forms the heteroarullo can? t «n» ¡r a »jvup» »prole» 'er such a group acetilo ohi dr ».v,? Aret i 1 o. A he '- or your 31 or pr f in io within dt» the definition is the {Iridie o3.-uto • t eta I read 11 eno.) Fn where - > or m.ni f le-.ilan two variables in which certain portions are "ca" my "» - - independently ", means that each occurrence of c i- 'mw of the variables., pueri». - »- >; er the same or eferent and be * s | *. »< > u dress from the portions that are found in the list. Fl tormino - f H __) μ, - i eni l? Siyntfica preferably a group ben ».- i 3 or where p is 1, I CJS com? e-, 1 o- > The present invention can be converted to > u- > (According to the methods er * convenc 3 ona 3 is "The term" -ale, pharmaceutically "acceptable", means salts of riit ion, which are useful for the < l? ni strat i ón de | ot ompue • >! _ »> -, of» the present invention and these include the orhi va t »>, bt mli i tlr ato, sulfate, phosphate, acetate, or propionatt), laclólo , mesylate, maleate, - »uc c mato, tartrate, citr-ato, su] fo? t: i! > 2-h? Ri? O * ¡ethyl, fumara te- and similar ones, when it is re ent uo yr upo ha - > i < or,. C-.s salts can be in the form h i dra l ad-i. Some articles of the present invention may be used to describe the present invention. There are many salts of 5-»» »..,,,,,,,,,,,,, potassium, al al» y y y y y y y y y y y i i i se se............................................... The v.onf i gurac 3 on ab: > Preferred in the C-5 position of artillo o:, a, v > , I nia nona of the 'ompue, .tos claimed in this IIIVPIK JÓ? e, i.omu is represented in the structure of the Formula (T). E > 1 i tcití igura, absolute ion is called < S) ba or the system of numen »latina d Cabn- C? Ty» -) l d-Prelog. This is wl cnarrl, i omero (S) ¡jl »ual is ai. ivo armai al? gi camente. The racemic mixture is the same as the first and for the same purpose as the putative enantiomer (S): the difference is that the racemic material d > It must be u.ulo, as much as twice, to produce "the same efe", tp ant i ba "" ter a year. "Depending on the substi tuyentes," "• • the composites > J > In the present invention, there may be geometric shapes, other isomeric shapes, and the present invention incorporated here, which is the same as the example. The derivatives of the derivatives of; &t t t id id id id id id id id id id id id id representa representa representa representa representa representa representa id id id id id id id id Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es. (S) ~ l- -CS- (acet 3 lamí riómeti lo) -2 - o, -í "? /, A.-u I ul i na 3- i 3 oH - 2- f 1 uoro- phen 3 lo > - ~ p? per idi na-4- c rbo¡ 1 ic, s "2) (S) -N 17, (fluoto 4- pipen d3 na-1 - 1 lo-feru 3 o) ~ 2 - o; '. c.- o;, idr id 3 na- - i 3 met i 1 o "I -acet to ida, 35 (G) -N --- 3- f - fluoro 4-- (4- hl dro;, i - pipeí 'dj na -1 - ilo) - fe.ru 3 o] - 2 - o: -, o - o¡ a ol? d? na-5--? imetj Jo 3 -acelamide, 4) (S) -MI-! ". ', - l" 3- f 3 u > . > ro ---? ~ (4-h d: sim € -.}. t i l ~ p? id id - l-i lo) - feru loH-2- o: - 'o-o;: a. ] uh na 5- 33 met i 3 c > > ~ -a < - e? tam3 da, 5) (S) - IM- C - T4 (4 - di benc 1 ai no pi per * id 3 na-- i- 1 lo) -3- f 1 uoro- f at 31 o3--2-, > ? - O;, a;, O] I d? Na-5--? 3 met? Lu3-acetaítuda, 6) < S) -N-f. ' I "4 (4- ai no-pi per i di na- 1 ~ -? Lo) -3-f luaro-? Eni 3 o3- ~ o;, o -».), C¡.? 3 i ti i na 5- i 3 met i 1 o? -ac c-> the day, 7) (S) -N - ',' go "rf 3 uoro-4 - < 4"? O - pi pep d 3 na-l ~ 3 lo) -feni 3 ol- 2-axo-o ro 3 i di na -5- i 3 m» * li 3 3 - a \ fm, da , 8) Acid (c3) -1- r4 l * 5 - (ac t 31 to my non-met i lo) -2-o¡ o - ox zol 3 d¡ n -3- 13 ol- 2- f 3 uoro-- fen 3 lo > - pi per i di na- 4- c rboxi 11 co,
9) < S) -N-C3- 14 (4 -ac et i 1 anp rto-pi pep d? Na-l ~? 1 o) -3-f In? Opht? Lt) "- 2-oxo-o; 'a; * oJ idi na ~ 5--? Imeti 3 o3 -ateUirtída, 10) (S) - N (1 - f 4-T5 - (ac o 111 anu no-met i lo) ~ 2-o oo;; a ol id i a - '* - * • * '- i 1 o3 ~ 2- f 1 uoro- fen i, oí-pi per i di na --4- 31 o) - 2-lt i drox i -acet ida,
11) < 3) - -r 'r3-f3uoro-4- (4 -hi dro i 3 mi no-p iper id i na-1 - i lo) - f eni lo3 -2- o:, o ~ o:, a, or i i ti i na- 5-- 11 met i lo} -ace lick, 12) (S) - - (7 ~ f3 11 uor o- 4- T4- (2-?! '? - prop? 11 deno) -p? per i di na- 1- i 3 or 3 - fe i 1 o3 -2 oi-o or iidi na- 5- 3 li 3o) -ac etamida, 13) (S) - N-- f 3- I 4 (4-ac el i 3 --p iper idi na- 1- 11 o) -3-f 3 uoro-f eni 1 oi-2-oxo-axa cl t ti i? ta-5- i i met i 1 o3-a », ela i da, 14 ) (S) -N-- (3- f3- fi uoro-4- l "4- (2- hi r xj - acet i lo) -piper id na- li 1o3-fen3 lo.} -2- o; < o- o: ro! 3 d 3 na ¡1 mwt 11 o) --ac etamida, ~? s ^ 5) < S) ~ N ~ .3- TV- f luot * o- 4-- < 4-oxo-a / epan ~ 1-j lo) -feni 1 o3-2- axo-oxa..ol? c na-5- 1 I ei 3 o3 - ac etami da, 16) ( 5 > -N- f, "J -? - f 1 UOI? - 4- (4-1300; • op 3 perid 1 nale) lo) ~ feni 3 ol 2 ~ o:, o -o. id 1 na -5- 11 met 11 o3 -at e tam 1 da, 17) (5) -N-- 1 --Í 3,5- if J uor - - (4- o; - o- pip r id ina-I - i 3 o) - feni lo --- 2-o: ío - o¡'a.vo I idina 5 1 lmei 13 o3 -aretami da, 18) (B) -N- "3 f3- f 3 un-4- (3-f3-uoro-4-oxo-p iper id na-l-3 lo) -phen33 ol-2-oxo-o; d 1 na - 5 - 11 niel 11 o3 - acetami cJa, 19) < ?)) - -! "" - f "'f I uero- 4- (3- me li 3 o -4- o, o ~ p? per 3 di na- 1- i lo) - Te ni 3? > l- - o * "i -o *, * -o I uJ i na-" * - i 3 mu li I o3 - ac e mi da, 2 < "¡5 (?) -U '7' r "'- f luor o- 4 (3- I tid co: i mot i 1 -5-me 11 l- 4-o:; o - pje idi na-. - lo) f MU luí 2 - OXO - O: ring! 3 d 1 n -.- 5-? 3 me 11 lo3 - acet rtu tía, 21) < S) - N- '"" - rr- luoro 4- (4-met i 1- p 1 per id 1 nale 1 o) - f eru 1 or "l- 2- u;, u- o¡ to I 1 d 1 na- 5- 1] mei 31 o3 --ac eta 1 da, 22) (E) -N- 1 13- f 1 uoro -4- (4-me lox -p 3 pep d? Na-1- 11 o) - f eni lol -2 -oxo- or xa ol uluti- - 11 met 1 lo3 ~ a »~ e lick, r__? ) (B) -M-C3- l 3- f 1 u-ro- 4 - (4 me 111 sul fan 13 op 1 per i di na- 1 - 1J0) - phen 31 ol-2-o.) • o , a; ro 31 di na-5-1 l et 1 lo -ac etam 3 da, 24) < S) - N "" ', L4- (4- d 1 m »* t 11 to my non-p 1 but di na-1- 1 lo) -3-f 1 uoro-fem 1 U1--2- -OR:? -t); a. '»> 31 d 1 n- > - 5- 13 d 33 o? - to the am 1 da, 2 '") amide d> - acula (F5) - l- C4 - C5- (at et 1 lamí no-met 3 lo) ~ 2-axo-oxa / ol KJ IIB-3- J io "I ~ 7 - fi uor-o- f in 13? L-p3 for 1 di-ta-4-c rboxi 1 ico, 26) (3) ~ f 3 f" 'í I u 'M' a -4 - (-h íclrc-x 3 met 13 ími no-piper i di na- 1- 33 o) - f em io 1-2- o. O - »,;, a, *»? l uli na - 5- 13 met 13 o -at et pu da, 27) (S) -M- 17 f 1 utjro -4- (4- met 113 i no- iper id 1 na-li 3 o) - SK. If niloü-? Oxo-o, '-. Ol j> l 1 ita * - 13-met 11 o3 -ac etami da, 28) (3) - M-! 3 -r * .- fluoro- 4 - (3-h idro;,? -4- oxo- p 3 per id 3 na-1 - 3 lo) - f in 31 ol- 2- c 0-0, a, lii na- 5- 11 me t 11 or "¡a ~ etanti da, 29) (3'1 N! ', F3 f lnorc > -4- (4-methox urtotox i-piper 1 d 1 na- 1 - i lo) - fen 11 ol- 2- o ,, o- or "a." ?, 31 d \ na- 5- 11 et 1 lt) 3 -are the same, 3ó) (S) -N- '- [1 p, 4 -d? o "a -a.-a -> 1 r-oí 4.5 Idet -R - 3 I o) -3- f luoro- f eni 3 ol 2 e ,, e ~ o,, ..? 13 d 1 na- 5- 13 met 3 la3 - ~ ar etamicla, 31) < S) --N í 3 - I, '- f I ur * o- 4-- (4- me o;, 13 i no-iper id 1 na- 1-j 3 u) - f in 33 or 1-2-oxo-ox. .. ol ul 1 ua -5- 1 J me I.11 o! -a ce la í da, 32) (S) -N '', í "< í luoro-4- (4- meto;, u.arboni lapu no-p iper id pa-ii 1 o) ~ f eru 1 or 2 o, o -o ,, a.? I ti I na -5- i 1 m tí 1 o3 ™ ac elami, 3,3) (S) -N- f3 13-fluoro- 4- (4 ~ metox 3 carboni Ih? Ra nno ~ pi per J di na- 1 - 33 o) - 1 eiu I ol 2 ~ oo ~ o :, c >] j di na-5- J lmet i lo} - ctm 3 d, 34) () - - (3 f ', - f J novo- 4- í 4- (2-me ti l- T í, 31d j axolano- 2- 33 mel i 3 o) -pi per un na 1- i 3 ol-- f eru 1 o.}. 2 - o; >) -o;, k * o 13 di na-5- 13 met i 1 o) - at- 'i? i >; »Li, 3l"?) (S) - N < 7 '", fluorine» »4 M- (2-o;, o - prop i lo 5 -p 3 pericl i na- 1-' -i 3 olf eni 3? 3 - 2- oooa; o3 idi? Ta-5- i 3 met i 1 o) - ae lamí tía, 36) Estet mel? '3 it.o acid (3) - 8- -C4- T5- (acet 3 lapu non-met? 1o) -2 oxo-o, < -. »Ol idi na -." .-? Lol-2 f 1 uoro ~ f eru J o3 - 1, 4 ~ d? Oxa-R-- a-'a- e - =. P 3 roF4.51 of »year -6 tarboxi lo, 375 Methalic acid ester (3) - 1 - C4 - C5- (accel i lamí no-met i lo) -2 - ox or -o,: a.tol idi - 3- i 1> g - 2- f 1 uoro-feni 1 o. ~. ~ 4 ~ oxo ~ p ipor na-3- 'a i'ln »íl nn, 3R) (3) N C '.- Í;' - f 3nt) io-4- < 4 - o, ^) - 4H ~ pir *? D uta - 1- i 3 o) ~ f eru 3 ol- 2-?) "O-oxa. * Ol i rh na r" - i I mu ti ti3 -ai etamida, 395 (f!) -N- (',' "f luor o- 'l-r4- (2-mel? 1 - C 1, 33d loxol an-2-? 1 o) - p iper d irta- 1 - i 3 olfeni 3 e -2-o o-üxa2Ol i di na- - 33 met lo) - at etarpi da , 40) (3) - Í3- T - (4-at et i] - ~ p? Per ich na- 1- 3 lo) -3- f luoro- f eni 3 ol ~ 2 -oxo-o; a »or I i th na 5- i J met i lo3 - ar etarru da, 41) S) - N-f3 13 - f 3 uor o - - 3 - hi clrox J met i 3 -4-oxo-p iperi di na- 1 - 13 o) - f eru 3 ol - 2- »i o- o ,, a. * t > 3 id na -5--? 1 met i 1 or 3 - ac etam id a, 42) (3) - N- '"' r"; fluorine o- 4- (4-me tox i c arboiu lox i mi no- p ipop th n,? - 1- i lo) - f -M? 1 ol- 2- o; < o- oxazole i d i na 5-? lmet? l? 3- ac etam i d? , 43) (3) -N--! "", - C3 f 3 uora-4- (4-seftu c arbazono-piper? D? Na-1- / Lo) - fen 3 or 1-2- o, o- o; a 3 i di n -5- ilj lo3-ac etamida, 44) (3) - (3-C3-f3ut) t * o ~ 4-r4- (morfo3? no-4-13 imma) - pi per ich na -1-i 3 olflu 1 or -2-oxo-oxazo3 i di na-5-? l et i lo) - acetami dd, O (3) N \ 7- (3- 13uoro-4- C4 r (2-hj drox i -et i lo > ~ h? drazanal- iper id i na - l -i 3 o.} - faith or lo) - 2-axc * - oxa ol ídi na-5-? lmet i lo - acetam id., 46) < S) -N-! 3- l "3-13 uoro- - (4-am? Di noh i drazana-pi per'id? Na-1-fX *, lo) ~ fpni 3 ol-2-oxo-o .'t ) 3 id J na-5-? Lmi lo3 -ac tam i da, 47) (S) - - 13 - f "'fluaro-4- (4-ace tox i ace toxi imino-pipepdina- 1-i lo) --f eni 1 ol-2-? i, o -oxa ol u na- 5 - 33 met i 1 o3-ace tarto da, 48) < 3) ~ N- (3-f 3- f luor * o-4-í.4- (2- hi drox imet 11-C 1, 31d? Oxol ano- 2 ~? 1 o) -p per id i na - 1 - i 1 or 1 - fen i lo.} -2-oo ~ o azol id ina -5 -i lmet i lo) - acetamicla, 49) (3) -N-- C3- C3 -11 nnro- 4- (4-bent: 13 oxyacetox i-piper itl i na- 3 -i 3 o) - feíu 3 ol - 2 - o o - oxa; 'ol i di na-- 5- 3 lmet L 1Q} ~ aceta 3 da, "xd) (3) - - - i 3- f luoru - s4-- (4- hi clra: -one ~ p? p6» r idi rta-1- 13 o) - feni 3 r) l-2-oxo-oxa-; ol id x na-5-ilet 3 o3 -acetarru dd, 51) Methyl ester of acid (35- < 3) - C4-C5- (acet i la irta- met 315 -2-oxcD ~ oxa.-Ol id na -3-13 ol-2 -13 uoro-feru lo.}. -p? Pepd3 na-4- 111 denoami noox 1 lo) - ai ico, 525 < S) -N- (3- f3-f luoru-- - (A- < 2-hi clr-ox i-etox i? M? No) ~ pi per 3 cr? A-1 - J 1 ol - feíu 1 ol- 2- oxo- t) xa: - ol i cl 3 na-5 ~? 3 metí 3 o) - acelamide, 53) (3) -N- C - (3- f 3uor * o-4 ~ C4- [4- <2-h? D oxi -et i lo) - ^ i per zi ua- 1 - 13 oí ni i no -p iper id 3 na- li 3 o.}. - fc- ^ ni 3 o) -2- o o- o? a / o 3 idi na - 5 - i 3 me ti 1 or 1 - a> etching, 54) (S) -Nl "3- (-.- fluoro- 4- f 4-? (2-hrr or -cel i lo) - hydr ono -pi per idi na- 1 - i 3 o3 - feíu 1 o) - 2-oxu-oi'a ol id ina - 5- i lmet 31 ol -ac elat »la, 55) (S) - N- (3- C3-f luoro 4-T4 <l 1, 2, 41 tr 3 azol-4-? 1 OJ ÍTU no) - p3 per 3 di na-1 -i 1 ol -fon.1 o3 2 ~ o / o- axaro3 id i na-5- 3 lmet i lo) - acetami d, - ^) (3) -N ~ f3 f3-fluoro-4 (2-h 3 dro:; imet 11-1, 4-d? oxa-8-aza-e p i r * C 4. dee -8- 11 o > ~ fon i 1 ol -2-axo ~ -c.xa._o] id i na-5- i Im t i lo} - acetamide, 57) (8) -N- (3- 3 - f 1 uoro-4-T4- (2-metho-metho-etane ii mi no) - pi in di na- 1- i 1 ol feru 1 '* 3 - 2 - oxo-oxazole i dina- 5- i 1 meth i io) - acetami? , 58) (S) -M- (3- C "', - f 1 LIDIO- 4- T 4- (2- hi drox i -acet i lo) - 1 -oxa-4, 8-diaza-espi ror4 , 5 M t R ~~ i lol- feni 1 o3 -2-oxo-oxa / ol? D? Na-5- 11 met i 1 o) ~ ac e tam i da,?) <; S > -N- C - C4 - (4-c L no 3 m? Uo ~ p3per? D? Na-1-? Lo) -3-f luoro-f pin 3 o - 2-o oo? -iJ? » 31 n -5-- 13 met 33 o > ~ a (etairu da, 60) Ester etili or of acid (3) - (1- C4-C5- (ati laminóme ti lo) - 2 ~ axo ~ oxa. l 3 d 3 na 3-- i lol-2- f luoro - f em lo.} -pipen di na- - i 1 ideiiahi ra and inora rbon i 1 o) -at eth i co, 61) (S) ~ N ~ (3-f3- fluoro- 4- 12- (me to imethox i-me 11 o) -1, 4- di oxa-S-ar -espi r - »- > r." E < - -3--13 ol-- f eru 1 or 3 -2-oo-oxazole 3 di na-5- 3 lmet i lo) - acre tam ida, 62 (S) - N-! 3 - T4 - (4 - a 111 o-; 3 ii uo -p 3 per * id na-1 -i la) -3 ~ f 3 uoro-f eru 3 ol-2 - oxt) -oxa. "t) 3 i tli? ta-5- i Im ti! or 3 -ac tarru da, 1R 63) (8) ~ N-C3-r3 fl \ or. > 4 4-me lox I ai non-p? Per-? D? Na-1- i 1 o) ~, m 1? L-2 ~ o -oxa, vol idi ua- 5- i 3 mol i 3 o3 -ae lam da, 64) < 8) -N f3-L "3 f 3 HHGÜ- 4- (4-methox imethoxy-i-p iper? D? Na- 1- i lo) - faith ni 3 C> 1-2 ~ > VÍO- -O ', < -or 3 i di na -5- i 3 me 113 o) -ac the ami da, 65) Ester de á? I rit) tol ueno- -su] f ón? C: a ( S) -l ~ f4-C5- (acetyl-no-me 131 > -2- uo -oxazol 3 di na- 3- i lo! -2- f luoro- pheni lo > -66) ( 3 > -N- (3- [4- T4 - (2, v3-d 3! N dr * ox? -propox 3 m? No) -p? Per idina- 1 -i 3 or 3- 3- f 1 LIOGD- feni l 3 7 o: O ~ ox ol 3 di na- 5- 1 lmet i lo) -acetam? Da, - "". 7) (8) ~ N- (3- [3- f 1 uoro - 4- C4- (t 3 azol ~ 2-? Lam? Na) ~ p? Per idina- 3 -i 3 a -f in 331 > 3 -2 - oxo-o; 'azol 3 d? Na- 5- 33 met 33 o) -ac tam da, 68) < S) ~? N- (3- f3- fluoro- 4- C4- (2 ~ me tox í-et i lamí no) - piper id 3 na -1 ~? Lo3-feni 3 or 3"2 ~ oxo ~ oxa; .o3 id 3 na- - i lmeti la) - acetam, 69) < S) -N- (3- C4-T4- (at-ethoxy-3-methoxy-3 -carbonyl-lane) -piper-id-na-1 -i3-ol -3-fluoro-phe-1-one. ~ oxooxazole id 3 na-5 ~? lmet i lo) -acetamid, 70) (S) -N ~ Ü3-T3 - f 1 uoro- 4- (4-me 13 li non-p iper id i na- 1-i lo) - s '"em 1 o3-2-oxo-oxazol id na - 5 ~' 3 Imet i I. C. Tar, 71) (85-N - f 3; - [4- (4-d? Met 3 the i no-p iper id i na-1-? Lo) -3- f 1 uoraf fi 1 ol ~ 2 - oxo-oxa "vo3 i th nß.- 5-- 3 Imet i 3 o3 -acetamide, 72) (S) -N- C3 - C - (4- di me li la nomet 11 enaamino- i per di na- 1- i lo) -3- f 1 uoro - fen i 1 or 1-2- or "t) ~ oxa¿ül idi na- 5- i lmet i lo." -aceta 3 da,
73) (S5-2- f 3 uoro- N- C3- C3-f 3 uoro-4- (4-or op? Per id i na-1- 1 lo) - feru 3 o3 -2-axo-oxa. vol uhna-5- il eti lo3 -acre lamida and 74) (S) -N ~ C3- T3 - f luoro 4- (4-morph ol I no-4- 3 lo-piper id? na ~ 1 - i 1 o) -f in 3 lo3"2-axo-o, ', a"'] uli na- 5-? 3 met? 3o3-acetam? Da.
It '. »Fompue =, lu. represented by the general formula (I) can be prepared by means of the method of the reaction scheme 1. The method of the synthesis is described below, with respect to \ n ~ > piperuhnas subst 3 your da, which are compounds of the general formula (I) where n - 0. Without embaryo, it should be noted that the '* azepano.-. -ñubs 11 tu i dos where n - 1 can also be checked by similar methods.
; ^.
SCHEME 1
• r
As -repeatedly, the subinstitute lapi pen of the structure 1 or 4- hi tlr * t) - 1 pi pth na is reactivated with nitrobenzene 2 (Y ~ h lógeno otif 3 uot orn lanosul fon to) in the presence of a suitable base, such blunt N, N di i sopropi let i lam. na, hydride of sadia or h3 dichroic acid dichrophosphate, and in a suitable solvent such as acetoni ti * i lo, letralu drofuran (THF), ethyl acetate sulfoxide dimeti Jo (DMSR) or dimethyl far am da (DMF) to the ambient temperature or reflux temperature, in order to provide the adreto 3. When necessary, the "lateral chains of R%, R7!, R" and Ra can be protected with a group or groups protec lore * - *, I * .1 as a benzyl group or others that are described in "Prtd rti Group 3i? Organic Synthysis" (Protective Groups in 8 í nle- *? - "* Qr» .ján? Ca) of T.. Greene and P. G. M. Wuts, 2a. Edition, 5 Tohp Wi Law Z < Sons; New Yorl (1991), being removed, opt for the protection groups, after the synthesis. The nitro group of structure 3 is then reduced by hydranation in the presence of a suitable catalyst, such as palladium) in carbon or < Attachment I. Irides in a solvent - suitable, such as ethyl acetate, THF, methane, methylene chloride, chloroform, or a mixture thereof (hydrogen is supplied in the form of a) - or indirectly by means of ammonium format). l.a aniline 4 e then converted to its benzyl < R * - CH ^ pH) 1. methyl (R *** - CH3) derived from urethane 5, using the standard ion of Schotten-Bau ann or other known means potlo. experts in art. The urethane 5 is distilled post lei-1 or-meute by the action of a suitable base such as n-buli lithium or li io bi (tp met 1 J i 11 lo) a ida in a suitable solvent, such " rno THF or DMF at a suitable temperature in the range of - 7R a - 40ß f! to produce a lithiated intermediate which is treated after on but: while (-) - (R) -Gl ici di lo, which can be achieved in the erx do. The enta i nto at room temperature provides the room 6, which is the enant lor e of. the axazol irh nona ton h 3 rlrox urtet 31 or "substituted." Compound 6 is converted to J.3 mesylate corresponding (R '-methansul fon j 1 o) or sulfonated aryl (R ~ ArSOa, by example, p-tol uenosul foiu 1 o) by re,? r? _? nnn ^ for example, chloride of Hano & iil foru lo / p 1 r id i na or chloride of meta osu1 fon 31o / r * 1 ethyl me na / d 31 lorornetane or methanesul furan 1 lo / tr ie 111 arrn n / DMSO or mp ~ tal ueno & ul funí 1 o / p 1 n > .h na. Resulting sulfone to 7 is then reactivated with sodium azide to potassium azide or the like, in a solvent such as DMF or 1-met 11-2-p-1-1-one-1-one, or 3-on-one, in the pre .. i) of a taster 3 such as 18-crown-6 at a temperature of 50 ° C to produce the azide B (R «_. N3). 1 gives e-> reduced later by means of, idrogenac 1? N 011 pal '.di in 1. i-bond, catalyst Llndlar or a so-called 1, -ad? R of platinum in an appropriate solvent, such as ethyl acetate, methanol, methylene chloride, chloroform or a mixture thereof, to produce the amine R rrespandiertte (Rw -IMH__). AI ternat 1 vamenlo, the a: may be reduced by reaction with a trivalent phosphorus compound, such chromium trifenphosphine in a suitable solvent such as THF followed by the addition of water. At the third 3 month, the month or the full year your aplo can be displaced with trt I knot of potassium and by means of reflux in acetom tr *? the ulrp.olventa adei.uado. The phthalamide 8 (Rß-1 amide) is deprived and 3 gives rise to the addition of methylation to <; end reflux of c-itanol, to produce amine 8 (Rß ~ NHM). the amine R Í-Í < > a »bundle poster 1 or eute, using the methods known by lu. experts in the art, to produce the oxazol ich nonas of structure 9. For example, amine can be reactivated in a lorur? acid to anhydride in a basic solvent, such as pyrichne in a temperature range from -30 to 30 ° C to provide the acrylic compound 9 (R = alkylaubstituted as 1 ona I moni "e). A subst 3 receptor such as amine, ether, 33 a, ester or carbonyl group in R ** or R * can be converted to the corresponding derivative, such as alkylaryl, ether, carboxyl group, hydroxyl group 1 or, by means of the known methods, therefore, "in art." Those skilled in the art will appreciate that "the scope of the present invention, other group," can be easily linked to amine 8 (R ** - HM), by means of standard acylation techniques, for example, highlighted by J. March in "Advancí.d drganic Chemislry" (Chemistry ÜT-gámca Avanzada), T & rc < ar < L Edition * - John iley Z < Son-- .. New York, 1 85; pages 370 to 375, to provide additional examples of compound 9. Any protecting group linked to In the side chains of R1, R * 55, R * and Rβ in the pipenchno ring, it may be removed using the appropriate conditions, such as those described by 1". W. Greene, P. G. M. uts in "Prolective Groups in Organic Syntehsis". Second Fd 1 < ? '111, lohn iley Sana! New York (1991). The compounds of structure 9, represent the examples of the agents an an o robix of ozaxol 3 ch nona with pipepdina sz < bst 1 of the Formula (C), which are the subject of the present invention These 1 ompue-. What is useful for the treatment of microbial infections in humans and other warm-blooded animals, by * atlrn 1 ni * trac ion and? be parenteral, oral or topical. The pharmaceutical compositions of the present invention can be prepared by means of the combination of the compounds of Formula (I) of the present invention, with an acceptable base, and optionally with adjuvant; and pharmaceutically acceptable excipients, employing standard and conventional techniques. The compositions in this form include powders, tablets, granules, and capsules. A solid vehicle may be, at least one substance, which may also function as a diluent, as a carrier, as a carrier, as a lubricant, as a suspending agent, or as a carrier. a zador, antidegrading agent of tablets, agent of ene apsul c.1 ón »The inert solid vehicles contain magnesium carbonate, magnesia stearate, talc, sugar, lactose, petrol, dextpna, starch, gelatin, materials cellulose, with a low melting temperature, low temperature, to cocoa, and the surtí lar-es. Compounds 1 and 1 in liquid form include solutions, solutions, emulsions and emulsions. For example, ions of the compounds of the present invention can be provided loose in a * * a a * * of ayua and water-glical prapilena and water-glycol pol? Et? wood, containing a liquid agent, agent13 * -.border and zantor. , tabilizers and thickeners conven ». u »nah- *» Prefepenlem > ii? You, or prupor * ionan the pharmaceutical compositions using the convention techniques ls in the form of unitary unit, that (ontieiten effective or appropriate ant idades of active t empunt- nto, that H, C .1 composed of
Formula (I) according t.on 1 < *. pr senle invention. "* the amount of the active component, which is the compound of]? formula (1) of a», according to the present invention, in composition 3? u farmat ul p and a dosage form 13 un ion cat ion of - - "Xa herself, may be virided or adjusted widely, depending on t- > ] particular dw method, the potency of the particular compound and the i mu enters 'u' > n fle.et. . Normally, the amount of the bordering active component within the range of 0.5% to 90% per per 3 composition, in the therapeutic range for treatment or to combat infection, bacterial in lov. humans and other animals that have been diagitosii? ca »lo £ > with bacterial infections, the compounds or the > t ompos 1.1 one.-. pharmaceuticals thereof, can be- admiiti > trado = * by vi < < . oral, parenteral and / or topical, in a dose to obtain and maintain a concentration, or .U-, a quantity, or level in the blood of the active component, which is effective as an ... »ter i anus in the animal subjected to the treatment. Fiber 3, said effective dosage amount of the active component of the active component, in the range of approximately O.I ha.-, ta af > rox? 100 m Ag, more preferably from > of apro; approximately 3.0 ha'.ta approximately 5o iiuj / ly ».le pe < > or of the body porday ,. It should be understood uncle that 1, dosage may vary depending on -o1., Require mu et? T > > . »1 > The patient, the severity of the bacterial infection that is being treated, and the particular compound that is being treated. ! Should it be understood that the dosage nm such ath MU is brought, can be increased beyond the above mentioned level, in order to quickly achieve the desired level in the blood of the compound or, losifi 3? The initial dose may be smaller than the optimum and the daily dosage may be increased progressively during the course of treatment, depending on the particular situation. To be divided into multiple doses for administration, for example, two times four times per day, the compounds of the formula (I) according to the present invention are parenterally initiated, for example, by irmlia d > - an injection, either an intravenous injection or by other routes of parenteral administration.Firmary compositions for parenteral administration will contain 1mg a pharmaceutically acceptable quantity of I agree with Formula (I) in the form of a soluble salt (acid addition salt or base salt) dissolved in an acceptable liquid carrier such as, for example, water-para-i nyec ri on and a suitably regulated isotonic solution, for example, having a pH of about 3.5 to 6. The suitable regulating agents include, for example, or tofosfa to trisor uo, bu arboite to sodium, sodium citrate, N-met i 1 gl uc ai na, l (+) - l? ? na and L (+) ar ?? t? na, to name a few. The compound according to 3rd Formula (I) generally
_- < and will dissolve in the vehicle in an amount sufficient to provide a pharmaceutically acceptable injectable injectable drug in the range of about 1 mg / ml to about 10%. "* m / ttl the resulting pharmaceutical liquid composition will be admixed to obtain the effective amount previously in the package, as well as in the dosage in the dosage. of the Formula (I) according to the present invention are optionally administered orally in liquid and liquid dosage forms. As a topical treatment, an effective amount of the compound of the formula (T) is mixed in a vehicle in the form of an acceptable gel or cream, which can be applied to the skin of the patient in the treatment area. The preparation of said; * cream-, and gels, is well known in the art and can include ion penetration enhancers. The compounds of the present invention are useful antimicrobial agents which are effective against a number of human and veterinary pathogens, including stapbylococci and multiple resistance streptococci, as well as anaerobic organisms such as bacteroid and clostridia. and acid resistant organisms such as Mvcobacterium tubercul osis and Mvcabactepum avium. Next, the test methods used to verify the microbial action of the compounds within the scope of the present invention are examined. The compounds of the present invention were subjected to vain tests of antimicrobial activity, in which they exhibited antimrotational immunity against staphylococci and multiple resistance streptococci, as well as anaerobic organisms such chromium bacteroides and clostr idia species and acid-resistant organisms such as Mvcobacterium tuberculosis and Mvcobacterium avium beds MIC (minimum inhibitory concentration) for the compounds of the present invention against typical organisms were determined by means of the MIC test method , which will be described below and the Resolutions are shown in Table 1. The anti-icrobin action of the compounds of the present invention was also verified by the Murine Assay procedure (in vivo) which will be described below. compounds with numbers 7, 11, 30 and 31 had ED a values of 8.1 mg / kg, 8.2 mg / kg, 2.8 mg / kg and 5.0 mg / kg, respectively. in oral administration, therefore, they were as effective as control Vancomycin.
Test method MIC test. MICs (minimal inhibitory concentrations) of the test compounds were determined by the standard method of agar dilution. A solution of the drug of each analog was prepared in the preferred solvent, usually DMS0.Ha0
(1: 3) Dilutions of 2-colonies in series of each sample were made, using aliquots of 1.0 ml of sterile distilled water. To each aliquot of 1.0 of the drug, 9 ml of Mueller Hintan c rretida agar medium was added. The agar supplemented with the drug was mixed and poured into 15 x 100 mm petri dishes, and allowed to dry and dried before drying. I or 'bottle', each of the test organisms remained congregating, in the vapor phase of a liquid nitrogen freezer. the test tedues grew dur-ante the night at 7u * C, in the appropriate medium for each arganism »... The colonies * e rec ol» *? Washed with a sterile stopper, and the cell suspensions prepared in a Soya Tnticasa (TSB) broth to equal the turbid,? a standard McFarland 0.5. It was made a d i 3 ue ton of 1:20 of each suspension in TSB. The plates that < vintenian the agar. = > up 1 crate crart the drug was inoculated with a g * -) t, a of 0.001 ml of a cell suspension using a Steers duplicator, producing approximately 10 ** to 10 * cells per * drop. I a-, plates were incubated overnight at a temperature of 35"C. De * puó = > ^ the incubation, was read and recorded, the Minimum Inhibitor Concertation (MIC pg / l), the lower concentration of the dre »ja that inhibits the visible growth of the orga- Jute I + valuomic ina included in the assay and serves as a comparator and a control compound for the environment as a means to validate the ion of the test, the result of the control compound against the leniency of the test was compared with the previous and / or published MIC test results.
TABLE 1 Minimum Inhibitory Concentrations
Compue to s -___. M. No. aureus epid rmidis pyoQenes tuberculosis
8 * e * 8 4 8 6 > 64 7 0.5 9 1 10 16 11 1 29 8 8 30 8 4 31 4 4
0. 5 34 16 4 35 8 2 16 4 4 37 16 4 4 38 1 0.5 TABLE I (Cont.)
Compound S. s, HE. üi. No. aureus epidermidis pyoaenes tuberculosis
39 8 40 4 41 8 42 0.5 10 43 0.5 44 4 0.5 45 4 0.5 1 46 8 *? 0.5 47 4 0.5 1 15 48 1 2 24 49 D 0.5 50 0.5 51 8 A 8 1 ¿0 53 4 0.5 54 1 4 55 4 1 56 16 *? 4 57 1 4 '• *? R 58 16 4 4 60 4 1 2 1 16 4 8 TABLE I (Cont.) * X
Compound _____ _L_ s_. M. No. aureus epidermidis pyoaenes tuberculosis
62 8 63 4 64 8 65 8 8 ~~ - 66 8 67 16 68 69 '8 1 0.5 71 7 2 1 VVaannccaammiicc iinnaa 11 2 0.5
S. aureus: Staph lococcus aureus (UC 9213, *: UC 9218) -L. epidermidis: Staphylococcus epidermidis (UC 12084) S. Fyaqena * .; Streo acoccus Pyoqenes (UC 152) M. tuberculus is: Mycabacterium tuberculum Female mice (six mice of 18 to 20 grams each) were injected with rats and with Staphylococcus auerus bacteria (UC 9213), which were thawed just before use and suspended in an infusion of heart-brain with yeast from 1 to 4Vi - "* tap | -? lococ us aureus) to heart-brain infusion (Streptococcus species). Based on antibiotics at six dosage levels per drug (compound) after one hour and five hours of infection, either by oral intubation or subcutaneously.Survival was observed daily for six days. Mortality ratios were calculated using the "prsbit" analysis.The tested compounds were compared
against vancomycin that was used as a control. Here it should be noted that no toxicity was found to cause any problem in any of the compounds of the present invention, nor in the pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples are provided to illustrate broadly the present invention and, therefore, should not be taken as limiting the same.
EXAMPLE 1 Preparation of (S) -N-C3- (3-f-Luaro-4-piperidine-1-phenyl) -2-axo-ox-zol-idine-5-methyl) -acetamide (Compound
No. 2) To a solution of piperidine (5.77 g) in ethyl acetate (70 ml), di isopropi letila ina was added successively.
(15. and mi) and 3,4-cli f luorani trobenzene (5.0 ml) and the mixture was stirred at room temperature for two days. Water was added to the reaction solution and the separation layer of ethyl acetate was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to produce a nitro compound (10.1 g) in a yield of 100 '/ ». Palladium on carbon (10%, 1.0 g>) was added to a solution of the nitro compound (10.1 g) in ethyl acetate (101 ml) and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. The carbon palladium was extracted by filtration and the filtrate was concentrated under vacuum to yield an amine (8.75 g, 100%). To a solution of the amine (8.75 g) in tetrahydrofuran (THF) (100 ml) was added. Sodium hydrogencarbonate (5.0 g) and benzyloxycarbanyl chloride (8.4 ml) were added in succession, and the mixture was stirred at room temperature for 14 hours, water was added to the reaction solution and the THF separation layer was added. it was washed with water and brine, and dried over anhydrous sodium sulfate.The solvent was evaporated and the residue was purified by means of silica gel column chromatography (ethyl acetate / hexane / chlorofarma solvents - 1/6 / 4) to produce a carbamate benzylate (14.5 g) in a yield of 98%. To a solution of carbamate benzyl (2.75 g) in THF (24 ml), lithium butyl (1.6 M solution in hexane: 5.2 ml) was added at a temperature of -78 * C and the mixture was stirred for 5 minutes. At the same temperature, butyrate (R) ~ (-) - glycid (1.25 ml) was added to the stirred solution and the mixture was stirred for 14 hours while the temperature was slowly raised to room temperature. Water was added to the reaction solution and the THF separation layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate / hexane * 3.1 solvents) to yield an alcohol (2.20 g) in 89% yield. To a solution of the alcohol (2.20 g) in pyridine (8 ml) was added tosyl chloride (2.85 g) and the mixture was stirred at room temperature for 6 hours. Water (32 ml) was added to the reaction solution and the mixture was stirred for 1 hour. The resulting precipitate was collected by filtration and washed with water, followed by drying under vacuum at room temperature to produce a tasi laten (3.28 g) in a yield of 98%. To a solution of the tasilate (3.28 g) in dimethylformamide (DMF) (23 ml), sodium azide (3.80 g) was added at room temperature and the mixture was stirred at 65 ° C for 5.5 hours. After the reaction mixture was cooled to room temperature, water was added thereto and the mixture was extracted with ethyl acetate; the organic layer was concentrated under vacuum. The resulting residue was dissolved in ethyl acetate and washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (solvent: ethyl acetate / hexane = 1/1) to yield an azide (2.29 g) in 94% yield. To a solution of the azide (2.20 g) in ethyl acetate (19 ml) were added acetic anhydride (0.65 ml) and pyridine (10 ml) at room temperature, after the addition of palladium on carbon (10%). 0.22 a? • >), the mixture was stirred at room temperature for 6 hours under a 1 atm hydrogen atmosphere. The palladium on carbon was removed by filtration and the filtrate was washed with water and brine and dried over anhydrous ammonium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (acetone / hexane solvents = 1/1) to yield the titled compound (1.47 g) in a 64% yield.
"Example 2. Preparation of (S) -N-C3-C3-f luoro-4- (4-hydra? imet i 1- piper idina-1-i la) -feni lo3-2 ~ oxo- or azol idina -5-lmethyl.} - acetamide (Compound No. 4): Using ethyl ester of piperidine-4-carboxylic acid commercially available, the ethyl ester of (S) -1-C4-C5- acid was synthesized. (Aceti lamina-met i lo) ~ 2-oxo-oxazole idina-3-i lo] -2- ~ fl-phenyl.}. -piperid i na-4-carbo-1-yl.
, f (Composed Na. 1), using the same method described in
Example 1. To a solution of this compound (661 m) in THF (6.6 ml), lithium chloride (275 mg), sodium borohydride (2.45 mg) and ethanol (4.5) were successively added and the mixture was stirred at room temperature. the room temperature for 14 hours. A solution of saturated aqueous ammonium chloride was added to the reaction solution and the reaction mixture was extracted with methylene chloride; the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (chlorofar or / methanol solvents = 25/1 - 15/1) to yield the titled compound (402 mg) in 68% yield.
Example 1 3 Preparation of (S) -N-C3-C3-f luoro-4- (4-oxo-piper idine ~ l- i lo) -pheni-2-oxo-a zal idine ~ 5-i Imet i lo > -acetamide (Compound No. 7): Using 1,4-dioxa-8-aza-spiraC4.53decano, the (S) -N- C3-C4- (1, -dioxa-aza-spiraC4.53dec) was synthesized. 8-i lo) -3- fluaro-f nilo3 ~ 2-axo-oxazole idina-5-i lmet i lo > -acetamide (Compound
No. 30), following the method described in Example No. 1 .. To a solution of this cc_upuesta (3.79 g) in acetone (70 ml), were added successively, water (20 ml) and acid mohshidrato p toluene sulfonic acid (3.66 g) and the mixture was heated under reflux for 3 hours. Then the reaction mixture was cooled to room temperature- »and the acetone was distilled and the aqueous layer was
^ neutralized with triet i lamina. The solution was extracted with methylene chloride and the organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (solvent: chlorofarm / methanal = 50/1 - 25/1) to yield the titled compound (3.05 g) in a yield of
91%
Tp
What is 4 P reparation of (S) -N ~ 3- C4- (4 ~ ai i no-p iper id i n- i lo) -3- f luoro- fen i] .o3 ~ 2- oxa-a a ol id i na-5- i lmet i lo} -acetamide (Compound No. 6) s To a solution of ethyl ester (4-amino-piperidine-1-yl) -acetic acid in acetonitrile (80 ml), sodium carbonate was added in succession ( 18.1 g) and benzyl bromide (10.0 ml) and the mixture was stirred at room temperature for 14 hours. The reaction solution was filtered and the filtrate was concentrated under vacuum. The residue was dissolved in methylene chloride and washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate / hexane solvents = 1/6) to produce a dibenzyl compound (8.24 g) in an 82% yield. To a solution of the dibenzyl compound (8.24 g) of ethylene glycol (170 ml) was added potassium hydroxide (34 g) and the mixture was
"Stirred for 15 min. Subsequently, hydrazine monohydrate (5.7 ml) was added and the mixture was heated under reflux for 2 hours. After what. the reaction mixture was cooled to room temperature, water was added to the reaction solution and the precipitated crystal was collected by filtration and washed with water, followed by drying under vacuum at room temperature to produce the dibenc piperidine-4-ylamine (6.43 g) in a yield of 98%. Using the amino compound, the (S) -N-C3-C4- (4-d ibenc i 1 mi non-p iper id i na- 1- i 1o) -3-f 1uoro-phenyl 3-2- was synthesized. oxo- xazole idine-5-yl eti lo -cretamide (Compound No. 5), following the same method described in Example 1. To a solution of this compound (5.28 g) in methanol (200 ml) was added Hydrated from palladium on carbon (20%, 3.3 g) and the mixture was stirred at ambient temperature under a hydrogen atmosphere of 3 atm. The hydroxide of palladium on carbon was removed by filtration and the filtrate was concentrated under vacuum to yield the titled compound (3.48 g) in 100% yield.
•"re. The preparation of (S) -N-C3-C3-f luoro-4- (4-hydroxyimine-piperidine-1-yl) -phenyla3-2-axo-oxazole idine ~ 5-i1 eti la > - ida aceta (Composite No. 11): To a solution of 2.00 g of (S) -N - C3} -C3-f luoro-4- (4-oxo-piperidine-1-phenyl) -phenyl-2-oxa-axa or idine-5-ylmethyl} Acetamide (Compound No. 7) in methanol-methylene claride (10-10 ml), synthesized in Example 3, was added successively
»Sodium icetata (517 m) and hydroxylamina hydrochloride (219 mg), and the mixture was stirred at room temperature for 2 days. The solvent was evaporated and the residue was dissolved in methanol, followed by the addition of silica gel (8 g). The methanal was evaporated and the residue was purified by silica gel column chromatography (solvent: chloroform / methanol: - 50/1 - 25/1) to yield the titled compound (852 mg) in an 82% yield.
4C) y- E._ ju io 6 Preparation of (S) -N ~ -.3-l.3-fluoro-4- (4-meto ic rbani lhidrazana - l-iperidina ~ li la-feni lo3-2 -oxo-axazole idine-5-imetime and acetamide (Compound No. 33): To a solution of 500 mg of the (S) ~ N - [3-C3 ~ f-luaro-4- ( or "o-piperidine-l-ylcr") ~ phenyl] -2-cr »xa ~ axazalidin-5-ylmethyl-acetamide (Compound No. 7) synthesized in Example 3, in methanol-methylene chloride (5-4) mi) was added ticilic carbacinate (135 mg) and the mixture was stirred at room temperature for 14 hours.The solvent was evaporated and the residue was purified by column chromatography of silica gel (solvent: chlorofar or / methanal ~ 50/1) to yield the titled compound (487 mg) in an 81% yield.
EXAMPLE 7 Preparation of (s) -N- (3 ~ -3-fluoro-4 - [.4 ~ (2-methylo-C 1, 3-di-xal-no-2-i 1m-ti-1) -p -peridine- 1-i 1o3-pheny1o) -2-oxa-oxazole idine-5-imetho-lo) -acetamide (Compound No. 34): To a solution of potassium hydroxide (0.93 g) in ethanal (14 ml) ), dimethyl (2-oxopropyl) phosphate (2.85 ml) and N-benzyl-4-piperidone (3.00 g) were successively added, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution and the mixture was extracted with ether, washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel 0DS column chromatography (solvent: methanol / water ~ 2/1 - 4/1) to yield an enone (2.07 g) in 57% yield. To a solution is the dwarf
(3.69 g) in benzene (50 ml), ethylene glycol (4.49 ml) and p-toluenesulfonic acid monohydrate (3.37 g) were added successively and the mixture was refluxed for 5 hours under heating with a Dean apparatus. -Stark: After the reaction mixture was cooled to room temperature, saturated aqueous sodium carbonate solution was added and the mixture was extracted with ethyl acetate, washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated
X'Xóara produce a benzyl ketal compound (4.20 g) in a 95% yield. To a solution of the benzyl ketal compound (4.20 g) in methanol (42 ml), palladium hydroxide on carbon (0.42 g) was added and the mixture was stirred for two days under a 3 atm hydrogen atmosphere. . The palladium hydroxide on carbon was extracted by filtration and the filtrate was concentrated under vacuum to produce a ketal compound (2.80 g) in a yield of 98%. Using this compound, the
^ procedure described in Example 1 to produce the titled compound.
EXAMPLE 8 Preparation of the (S) -8- C4-C5-acetyl lamethyl-methyl ester) 2-oxo-oxazal idine-3-i lo3-2-f luorophenyl > -l, 4-dioxo-8-aza-spiroC4.53decano-6-carb? í < Ethyl (Compound No. 36) To a solution of 3-carbomethyl hydrochloride i-4- piperidone (3.43 g) in dichloromethane (40 ml), was added successively diisopropyl leti (7.71 ml) and then chloride of oxygen and loxycarboni (3.0 ml) at a temperature of 0 ° C, - and the mixture was stirred at room temperature for 14 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 7/3) to yield an N-benzyl carba binding (4.57 g) in 79% yield. Carbamate benzyl, p-toluenesulfonic acid hydrate (2.45 g) and ethylene glycol (8.69 g) were added to benzene (100 ml) and the mixture was refluxed for 6 hours under heating with water being continuously removed with a separator. of water. After being cooled to room temperature, the reaction solution was washed, first with saturated aqueous sodium hydrogencarbonate, and then with water; the organic layer was dried and concentrated under vacuum to yield a benzyl ketalletylene carbamate (4.89 g) in 94% yield. This compound was dissolved in a mixed solvent consisting of
^ diclaromethane (20 ml) and methanal (50 ml). The solution is
'I added palladium hydroxide to carbon (20%, 500 mg > and the mixture was stirred at room temperature for 14 hours under a 3 atm hydrogene atmosphere.) Palladium hydroxide on carbon was removed by filtration and the filtrate was concentrated in vacuo to yield a ketalethylene compound (3.44 g) in 100% yield Using this compound, the procedure described in Example 1 was repeated to produce the titled compound.
EisffljaÍQ_2. Preparation of methyl ester of acid (S) -1-Í4-C5- (acetyl mine-methylo) -2-oxo- or zol idine-3-i lo3-2-f luarafeni lo > -4-oxo ~ pipe idine-3-carboxy 1 ica (Compound No. 37): Using 400 mg of the methyl ester of (S) -8-C4-C5- (acet il mi no-met i lo) -2 ~ axa-ox zol id i na-3 ~ i lo3-2-f luoro-phenyl > 1, 4-diaxa-8-aza-spiro (4.) decane-6-carboxylic acid (Compound No. 36) synthesized in Example 8, the progress described in Example 3 was repeated to produce the compound titled (49 * - >
EXAMPLE 10 Preparation of (S) -N-Í3- i3-f1uoro-4- (4-oxo-4H-pi-ridine-1-ylo) -phenylo3-2-oxo-oxo-olin-S-ilmethyl-J -acetamide (Compound No. 38): To a solution of 4-hydroxypyridine (3.28 g) in dimethylhydrate and anhydrous drug (DMF) (50 ml), sodium hydride (1.88 g) was added at a temperature of 0 * C and the mixture was stirred for 30 minutes. Subsequently, 3,4-difluoroanth trobenzene (5.0 g) was added at the same temperature and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution and the solvent was evaporated. Toluene was added and the water was removed by azeotropia and the residue was suspended in dichloromethane (100 ml). The insolubles were rejected by filtration through Celite and the filtrate was concentrated under vacuum. The residue was purified by silica gel column cracking ~ N_. . { . { Light: methanol / dichloromethane - 5/95) to produce a nitro compound (4.89 g) in a 66% yield. The nitro compound was catalytically reduced with a Lindlar catalyst and subsequently treated with benzyloxycarbonyl chloride to produce a carbamate Jrienci lo (1.71 g) in u? 24% yield To a solution of the carbamate benzylate (1.22 g) in DMF (20 ml) was added lithium amide bis / trimeti Isi 1 i) 1M solution of THF; 4.0 ml), at a temperature of -78 ° C and the mixture was stirred for 5 minutes. At the same temperature, is it added? butyrate (R) ~ (-) - glycoid (0.56 ml) to the stirred solution and the mixture was stirred for 14 hours while the temperature was slowly raised to room temperature, stirring continued for three to more days at the room temperature. Water was added to the reaction solution and the solvent was evaporated. A dichloromethane soluble portion was produced for dehydration and the salt was extracted according to the same procedure described above and was
• ^ • Hirif icadcn par chroma tag raf iVa of silica gel column
(solvent: methanal / dichloromethane = 7/93) to produce an alcohol (745 mg). To the solution of alcohol 540 m) in dimethyl sulphonate (10 ml) was added triethylamine (0.4 ml) and then methanesulfanyl chloride (0.2 ml), at a temperature of 0 ° C and the rock was stirred at the temperature environment for 18 hours. The solvent was evaporated and the residue was dissolved in DMF (10 ml). To the solution was added sodium azide (160 ml) at room temperature and the mixture was stirred at 6 ° C for 14 hours. After the reaction mixture was cooled to room temperature, the insalubles were extracted by
filtration and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (methanol / dichloromethane solvents = 5/95) to yield an azide of (149 m) in 26% yield. To a solution of the azide in anhydrous THF (4 mL) was added trifenylphosphate (137 m) at room temperature and the mixture was stirred for 2 hours. Water (0.1 ml) was added to the reaction mixture followed by stirring at a temperature of 40 ° C for 4 hours., and - josteriarmente, for 14 hours at room temperature. The solvent was evaporated and the residue was dehydrated by azeotherapy in toluene. The resulting residue was suspended in dichloromethane (10 ml) and, after the addition of pyridine (0.8 ny) and acetic anhydride (1.0 ml) at a temperature of 0 ° C, the mixture was stirred at room temperature for 6 hours. .
The solvent was evaporated and the residue was purified by silica gel column chromatography (solvents
/ ^ "Tetanol / dichloromethane ~ 7/93} to produce the compound titled
(167 mg) in a 100% yield.
Example 11 Preparation of (S) -N- (3 - f3-f luaro ~ 4-C4- (2-met i la- [.1, 3 d iaxolano-2-i lo) -p iper idirta-1 -i lo3-phenyi-2-oxo-oxazole idine-5-imethox) acetamide (Compound No. 39): To a solution of ethyl isonipetoate (5.99 g) in acetanitrile (80 ml), successively added potassium carbonate (5.27 g) and benzyl bromide (3.97 ml), and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate / hexane-1/2 solvents) to yield a benzylated compound (7.03 g) in 89% yield. To a solution of lithium di isopropylidemide
(1.5M solution of hexane, 17.5 ml) in THF (10 ml) was added dropwise a solution of the benzyl compound (5.00 g) in THF (25 ml), at a temperature of -78 ° C and the mixture was stirred for 15 minutes. At the same temperature, a solution of acetyl chloride (2.15 ml) in THF (20 ml) was added dropwise and the mixture was stirred at -78 ° C for 30 minutes and then for 14 hours while the temperature was elevated at room temperature. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution and the
- mixture was extracted with ethyl acetate, washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate / hexane solvents = 1/2) to yield a crude acetyl ester compound (5.05 g). To a solution of the crude acetyl ester compound (5.05 g> in THF (20 mL) was added a 12% solution of aqueous sodium hydroxide (20 mL), and the mixture was stirred at a temperature of 60 °. C for 14 hours After the reaction mixture was cooled to room temperature, the THF was evaporated and the resulting aqueous solution was adjusted to a pH of
"4 by the addition of concentrated hydrochloric acid and the mixture was stirred at a temperature of 120 ° C for 30 minutes. After being cooled to room temperature, the reaction mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried anhydrous sodium sulfate sulfate. The solvent was evaporated to yield an acetyl compound (2.15 g> in a yield of 49% (by means of a one-step process) to a solution of the acetyl compound (2.15 g) in benzene (30 ml) was added. successively glycol ethylene (2.76 ml) and monah idrata of p-toluenesulfonic acid (2.07 g) and the mixture was subjected to re fl ux for 5 hours by heating it with a Dean-Stark apparatus After the reaction mixture was cooled to room temperature , a solution of saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate, washed with water and
,, brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to yield a benzyl ketal compound (2.59 g) in a yield of d3l. 100% To a solution of the benzyl compound ketal (2.59 g) in methanal (26 ml), palladium hydroxide on carbon (0.26 g) was added and the mixture was stirred for two hours under a hydrogen atmosphere of 3 atm. The palladium hydroxide on carbon was removed by filtration and the filtrate was concentrated under vacuum to yield a ketal compound (1.69 g> 100% yield.) Using this ketal compound, the procedure described in Example 1 was repeated. to produce the compound - Titled.
Example 12 Preparation of < S) -N-C3-C3-f luoro-4- (3-hydroxymethyl-1-4-oxo-piperidine-1-ylo) -pheni lo3-2-oxa-axazole idine-5-i eti lo > acetamide (Compound No. 41) s Using 600 mg of the methyl ester of (S) -8-C4-C5- (acet i lami no-met i lo) ~ 2-cnxo-oxazole id i na-3-i lo3-2-f luora-feni lo > - "i, 4-dioxa-8 ~ aza-espi roC4.53decano-6-carboxy 1 ico (Compound No.
36) synthesized in Example 8, the reduction was carried out by repeating the procedure described in Example 2, thereby producing an alcohol. (361 mg) in a yield of 66%.
Using 302 mg of the alcohol, the procedure described in Example 3 was repeated to yield the titled mixture (155 mg) in a yield of 1 58%.
Example 13 Preparation of (S) - ~ N- ~ (3 ~ -C3-f luora-4-C4- (2-hydroxymethyl-1, 33d io? Al no-2-i len) -p -peridine- 1-i lo-phenylo> -2-axo-axazole idine-5- imetime) acetamide (Compound No. 48) s A chalk compound 1 was synthesized by repeating the procedure described in Example 11, except that The acetyl chloride as a supply material was replaced by benzylchloride. Using this chalk 1, the procedure described in Example 1 was repeated to synthesize a compound, from which the protective benzyl group was removed to prepare the t i tulated compound.
E x p lo p 14 P reparae ion of (S) -N - C3 - í3 - f 1uorcn-4- (2-hi drox imet i 1 - 1, 4- d io? A-8-aza-esp iroC4. 5 dec-8 ~ i lo) -feni lo3-2-axa-oxazal idi na-5- i lmet i lo > ~ Acetamide (Tax No. 56): To a suspension of 500 mg of the (S) -N-C3-C3-f-luara-4- (4-oxa-piperidine-1-y1) -phenylo3- 2-oxo-ox ol idine-5-lmethyl ilo > -acetamide (Camp? estcn No. 7), which was synthesized in the üjempla 3, in benzene (10 ml), were added successively para-tcnluenosulfónico monahidrate (299 mg) and glycerol
(0.21 ml), and the mixture was heated under reflux for 4 hours, the water being continuously removed by means of a water separator. After the reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate solution was added thereto and the mixture was stirred. The solution was then extracted with methylene chloride and the organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (senlvente: chloraforma / methanol = 50/1 -25/1) to yield the titled compound (510 m) in an 84% yield.
üj malo 15 Preparation of (S) ~ N ~ (3 --- C3-f luora-4-C4- (2-hidroxi-acet i lo) - lo a-4,8 ~ diaza-espi oC4-5 dec- 8-i lo -feni lo > -2-oxo-oxazole idine-5-i lmet i lo) -acetamide (Compound No. 58): To a suspension of 600 mg of the (S) -N-C3- C3-f luoro-4- (4 ~ enxcn-piper idina-1- i lo) -pheni-lcn ~ 2-oxo-ox or idina-5-i Imet i lo} acetamide (Compound No. 7), which was synthesized in Example 3, in benzene (10 ml), ethanolamine (0.31 ml) was added and the mixture was heated under reflux for 2 hours, being * - After the reaction mixture was cooled to room temperature, the resulting crystals were collected by filtration, washed with benzene and dried under vacuum at room temperature to produce 671 mg of water. an oxazalidine compound To a solution of the oxazalidine compound (671 mg) in methylene chloride (5 ml), 0.17 ml of pyridine and 0.30 ml of benzyl loxative chlorine were successively added and the mixture was stirred to the ambient temperature for 48 hours After the addition of methanol, the mixture was stirred for 30 minutes and the solvent was evaporated.The residue was purified by silica gel column combustion (chloroform / methanol solvents - 50/1 ) to produce a benzyloxyacet lo compound (574 m) in a yield of 62%. To a solution of the benzyloxyacetyl compound (574 mg) in methanol-methylene chloride (8-4 ml), 57 mg of palladium on carbon was added and the mixture was stirred at room temperature for 14 hours under one atmosphere of hydrogen of 3 atm.
Depil s s the c l aller was extracted by fptration, the solvent was ovaporated and f- * l i > The duu was purified by column chromatography on a gel column (solvents c 1 oroform / methanol - 50/1 - 25/1 - 10/1) HGJ pr * oduc the title compound (148 mg) in a "reíith look at it from 31%.
Preparation of (S) ~ N-C3-C-f luorcn ~ 4- (4-m tcnx? Artunap by i di na- 1 - i 1 o) ~ fen? 1 or ~ 2 ~ cnxo- ~ o? za3? d na-5-j lmet i lo > - 10 '> arel amide (Compound No. 63) s I a (S) N- £ 3- C3-f 1 uaro-4- (4-me to i imi no-pi per 3 di na- 1- 3 lo) - ff. 1 O "J-2-CJ! IO-oxool 3 d3 na-5- i 1 met J-acetamtda (Compound No. 31), was synthesized using the (S) -N- C3 ~ l73 ~ f 1 uoro ~ 4- (4- oxo-pi per * J i na- 1- i lo) - feru la3-2 ~ oxa-a? Azol J d? Na ~ 5- i 1 met 11 o >- 1 r Iiketa ida (Compound No. 7), which was synthesized in Fes 3. a sol ion of Compound 31 (594 mg) in methane! (mi), * < - * * added 0.69 ml of borana complex -pipdin (8 M) at a temperature * -> or "C and the mixture was stirred for 5 minutes. After, . < • * you will add R mi of * 1% HC1 and the mixture
'' 'Stir at room temperature for 15 minutes *, additional, De = * pu - <of the neutralization with sodium carbonate, the solution was added to the metal chloride in the layer The organic material was washed with water and brine and dried over anhydrous sodium sulfate, the solvent was evaporated under vacuum and the residue was evaporated.
It was purified by column chromatography of silica gel (solvents i 1 orofor iiio / mnal - 50/1) to produce the titled compound (399 m) cj? t a d &] 67% yield.
P repa ii crt (S) --N- (- f 4-- 1"4- (2, 3- d ih 3 ci rox 3 -p ropox iii no) - p per itl j na- 1 - i 1 or 3- 3-f 3 uoro-f in J 1?> -2-a or -oxazole id na- 5- i 1 me t J 1 o) -a (otanu da (Compound No. 66) : () -N- C3 ~ - ÍA - (4 -al i] ox 3 ii no-iper id? na-1 -i lo) -3- f 1 uoro-phen 31 in -2- in Í -oxazc l id 3 na- - 13 I put the .acetamide (Compound No. 62) u ** smt? - »ii .'ada using the (S) -N- C3-C3- f luoro-4 - (4- o; io-p 3 per ii na- 1-j lo) - phen 1 or -2-ox »j-oxazole idi na- 5- 33 mt 3 lo. - acetarruda (Compound No. 7) , which was synthesized in the example 3. To a vulvation of Compound No. 62 (715 mg) in acetic acid-water (20 -2 ml), 0.5 ml of the troxidium * osmium was added successively ( tert-butanol solution 2.5% by weight) and 0.34 ml <- N- et ll morf o] inen-n-oxide (solution is 60% by weight) and the mixture was stirred at room temperature during 5 hours A solution of tj was added The sodium saturation was saturated and the mixture was stirred for 30 minutes, the solution was extruded with chlorine and methane and was then stirred. The organic material was washed on brine and brine and dried on anhydrous sodium sulfate. The solvent was evaporated under vacuum and the residue was purified by silica gel column chromatography (solvent: t 1 gold form / methanol = 25/1 - 10/1) to produce the tulad compound. ) (582 m) in a yield of 75%.
F j emp lo 18 P rep rei i i de (S) - N- C 3- - f 3 uoro-4- (A - m 111 mi no pi per i cl i na-1 - i 1 o) ~ f eiu 3 o3- ~ 2 ~ oxo-o a ol i di na-5-? Ime i lo > - acetamide (Compound No. 70): ^ To a -solu, i n of *? > (, (j of (S ~ N- f3-i-3-f 1 uoro-4- (4- uxo-p J per i ti i ua - 1 -i lo) - ff.ru 1 o3 -2- ?!, o -ox ol jdi na-5- i lmet 11 o> - acetarruda (Compound No. 7), which was synthesized in Example 3, in methanol-methylene chloride (20-20 ml), hydrochloride of mol i 1 aia (0.46 g) and palladium on carbon (0.20 g) were added, and the e was stirred at room temperature for 14 hours under a 2 atm hydrogenated atmosphere. The mixture was stirred for 10 minutes, then the catcher was removed by filtration and the solvent was evaporated under vacuum, the residue was purified by chromatography. of alumina column (solvents < rofmo / melanol = 100/1 - 30/1) to yield the compound titled 900 mg in 43% yield.
Example 19 Preparation of (S) - N- C3- C4- (4-d? Met i lamina-piper id? Na ~ l- i 1 o) - 3 -f 1 uoro-phen31 or3-2 ~ oxo -o zal id 3 na -5- 11 met i lo > - s ^ c tenmela (Compound Ncj: 71). To a suspension of 400 mg of the (S) -N- C3-T3- f luora-4- (4-me 13 lam i no-pi per * id 3 na-1- 11 o) -feni lo3-2- oxo ~ ox zol? d? na-5- lmet i 3 o > ~ ac t * tam3 da (Ccnmpuestcn No. 70), which was detected in Example 18, in acetone (3 ml), it was added in a timely manner (aqueous solution .3 37%, 0.4 ml) and sodium hydride of < The noboron (138 mg) was added, and the mixture was stirred at room temperature for 48 hours. Methanal was added and the mixture was stirred for 10 minutes. Pcnster J, alumina (5 »j) was added and the residue was evaporated under watt. The 51"Re iduo was purified or by alumina column chromatography,?, Ol sales chloroform / methane! - "1 0/1" to produce the titled compound (363 m) in a yield of 87%.
Example 1 Preparation of (S) - N-- (3- _3 ™ f 1-uoro-4-C4-t-azol-2-alamino) - pi peru d? Na-1 - i 1 al- phen 3 or > -2-axa-/ ul i d? Na-5-? 3 met i lo) - aceta ida (Compound No. 67) s To a -: »ur ur ion of 500 mg of the (S) -N-- C3-C4- (4-am no-! 'Jii er idi ? ta - 1 - 3 lo) --3- lúor -fyru 1 o -2-o "o ~ cnxazcnl i di na ~ 5- i lmet i lo > acetamide (Compound No. 6), which was detected in the
Example 4, in i i and 31 form (5 ml), SE * added carbonate and potassium (296 rtuj) and 2-bromot 3 azole (258 m), and the mixture was stirred at a temperature of 100 °. C for 2 days. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum and the residue was purified by column chromatography on silica gel.
(di r 1 or methanol / methanol - 97/3 - 4/1) to produce the titled compound (73 mg) and a yield of 12%.
repair of (S) -N ~ f -r4 ~ < 4-c? antmmi na-p per? d na-1-i lo) -3-f-1-chloro-phenyl-3-o-2-o-O-ole na-5-? 1 met i la > -acetamide (Compound No. 59): To benzene (70 ml), cyanoamide (601 mg) and 500 mg of (S) -N- C3- 3-f luaro-4- (4-) were added. oxo-p? per? d? na? 1-? lo) - fsii] 1 o3-2 ~ axo-ax zol idi na -5- i 3 et? lo > -acetamide (Compound No.
7), which was synthesized in Example 3, and the mixture was heated under reflux for 2 hours, being continuously removed. Water pair average of a water separator. The reaction mixture was "cooled to room temperature and the resulting crystal was collected by filtration. After having been washed with water, the crystal was dried overnight at 40 ° C and then left empty to produce the titled centrate (423 mg) in a yield of 79%.
J Bad 22 Prep ration of (S) -N-C3 ~ C4- (4-dimet i lami nomet lenoamina- p iper id ina-li lo) -3-f luoro-feni lo3-2-cnxcn-ol id ina- »5-Imeti la-acetamide (Centrate No. 72): To toluene (10 ml), dimethyl ether N, N-dimethylformamide (0.8 ml) and 1.0 g of (S) ~ N- were added. C3-C4- (4-amino-piper id ina-li lo) -3-f luora-pheny the -2-ox enl idina-5-i lmet i lo > - acetamide (Compound Na. 6), which was synthesized in the
^ Example 4, and the mixture was heated under reflux for 24 hours. The reaction mixture was cooled to room temperature, and concentrated lower to empty. The residue was washed with hexane to remove excessive dimethyl ether. The resulting precipitate was suspended in dichloromethane and the insolubles were separated by filtration. The filtrate was concentrated low empty to produce the titled chromatid (985 mg) in an 84% yield.
rep ect ion of (S) -2-f1 utnro-N- C3-C3- f luaro-4- (4-cnxcn- pipep d 3 na- 1 -i 1 o) - m 1 or -2- axo ~ or] d? na-5-? lmethy } - acetamycin (Ct) mpuesto No. 73): Beginning with 3- (1,4-d? 8-aza-esp? raC4-53dec- 8-? 1 o) -3-fluoro- phen i 1 en3- 5-h 3 drax í et 11 -ol? d? α-2-one, which was formed by an intermediate in Example 3, the procedure described in Example 1 was repeated to produce an azide compound in a 90% yield. The compound azide 11.5 g) was reduced with tp f or 1 phosphine / tetrahydrofurane / water s3gu3c, with the same method as described in Example 10 for priming a primary amide compound. The amine compound and tetylamine (1.2 ml) were added to dry dichloromethane.
(2.0 ml) and subsequently chloride was added to
The reaction mixture was stirred overnight at ambient temperature * and the resultant precipitate was removed by filtration.
The filtrate was t onc on low vacuum and the residue was purified by. Attenuation of the silica gel column
"" (methanol / di c) gold ethane - 5/95) to produce a benzylloxyallar compound (2.7 g) in a yield of 100%. The benz 3 compound (1.9 g) was dissolved in a mixed solvent consisting of methane! (30 mi) and di c 3 aramet no (5 mi).
To the solution was added hydrated of paladia in carbon 3 10%
"" "* (340 m) and the ntezv was stirred for 2 days under a hydrogen atmosphere of 2 atm.The hydroxide in the palladium was removed by filtration and the filtrate was concentrated under vacuum.
The residue was puri fi ed by rome ogr fí c | e co? Umn? L of Qe? of silica (m tano! / the 113th grade - 7/93) to produce an o-hydroxy acid compound (780 m) in a yield of 49%. To a solution of the α-hydroxyacetamine (530 mg) in tetrahydrofurana (10 ml), fluoride was added to either 3 (450 μm) and tetrabutylammonium fluoride (1.0 M solution). tetralu dro furan; 3.3 ml), and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and concentrated to low vacuum. He
1 < The residue was put through a column chromatography of silica gel (I ano ano-2/3) to produce a monofluoro compound (562 m) in 100% yield • To a solution of the compound menno-f luoroacetamide in 10 ml of an acetone, p-toluenesulfonic acid monohydrate was added.
(580 m) and water < 3 ml), and the mixture was heated under reflux for 2.5 hours. The reaction mixture was cooled to room temperature, neutralized with solid so-called hydrogen carbonate, and concentrated under vacuum. The water was removed by azeotropic with tolut-i? and the residue was purified by
"'< • silica gel column chromatography (hexane / acetone = 1/1) to produce the titled composite (408 m) in an 81% yield.
It was found that the compounds prepared in the second samples from 1 to 23, thus concentrating several compounds that were synthesized by similar methods, have the following data (H * -RMN) nuclear magnetic resonance spectrum: - ~ c Compound No. 1
H * - NMR (COCÍ ») £ pprns 1.2.7 (3H, t, J = 7.2 Hz), 1.86 - 2.07 (4H, ^ T), 2.02 (3H, s), 2.37 - 2.48 (1H, m) , 2"68 - 2.77 (2H, m), 3.34 - 3.41 (2.H, m), 3.55 - 3.76 (3H, m), 4.01 (1H, dd, J» 8.9, 8.9 Hz), 4.16 ( 2H, q, J = 7.2 Hz), 4.71 - 4.81 (1H, m), 6.12 < 1H, br s), 6.92 < 1H, dd, J = 8.9, 8.9 Hz), 7.06 (1H, ddd, J «2.4, 2.4, 8.9 Hz), 7.40 (1H, dd, J = 2.4, 13.8 Hz) .. i, '.» Compencn Nen . 2s
H »-RMN (CDCla) S ppm: 1.52 - 1.62 (2H, m), 1.65 - 1.78 (4H, m), 2.02 (3H, s), 2.96 - 3.00 (4H,), 3.55 - 3.77 (3H, m ), 4.01 (1H, dci, J «8.9, 8.9 Hz), 4.71 - 4.80 (1H, m), 6.28 (1H, br s), 6.93 < 1H, cid, J * 8.9, 8.9 H), 7.05 (1H, ddd, J = 2.4, 2.4, 8.9 Hz),
7. 38 (1H, dd 4, 14.3 Hz).
'ompueslu No,
H * -RMN (CDCI3) F. pp s 1.69 - 1.82 < 2H, m), 1.99 - 2.07 (2H, m),
/ * .02 (H, - *), 2.78 - 2.87 (2H,), 3.28 - 3.35 (2H, m), 3.54 - 3.76 (3H, nor), 3.81 - 3.90 (1H, m) 4.02 (1H, cid , J = 8.9, 8.9 H), 4.71 - *. 1 (1H, 111), 6.08 (1H, t, J = 5.9 Hz), 6.94 (1H, dd, J = 8.9, 8.9 Hz), 7.0 (1H, ddd, J = 2.2, 2.2, 8.9 Hz) , 7.41 (1H, dd, J-2.2, 14.3 Hz). Cmpnmpue = * l? No. 4
H »-RMN (DMSO-d *,) r, ppms 1, 22 - 1.36 < 2H, m), 1.41 - 1.53 (1H, m), 1.73 - 1.77 (2H,), 1.83 (3H, s), 2.55 - 2.63 (2H, m), 3.25 - 3.34 (4H, m), 3.39 < 2H, dd, T = 5.4, 5.4 Hz), 3.69 (1H, dd, J = 6.5, 8.9 Hz), 4.07 < 1H, »id, T = 8.9, 8.9 Hz), 4.48 (1H, t, T = • - 5.4 Hz), 4.65 - 4.74 < 1H, m), 7.05 (1H, dd, J * 9.2, 9.2 Hz), 7.13 < 1H,, J • - 2.7, 9.2 HJG), 7.43 (1H, d, J "2.2, 14.9 H¿>, 8.23 (1H, t, J •• 5.9 Hr).
i '»- or pue- * I or Nt)" 5;
J * -PMN (CDCI JS) S pp.nü 1.84 - 1.92 (4H, m), 2. 0 (3H, s), 2.49 - 2.68 (3H, m), 3.40 - 3.46 (2H, m), 3.53 - 3.74 (3H,), 3.69 (sys, 2H and 2H), 7.98 (1H, clrl,, T = - 9.2, 9.2 Hz), 4.69 - 4.78 (1H, m),
6. 26 (1H, i, f 5.9 Hz), 6. R7 (1H, d, J Hz), 7.01
(1H, .id, J '"^ ^ H., 7.16-7.40 (11H,) Compound No. 6
H * -RMN (DMBO-c-)? ppm: 1.55 - 1.69 (2H,), 1.84 (3H, s), 1.92 - 1.99 (2H, m), 2.65 - 2.74 (2H,), 2"98 - 3.07 (1H,). 3.28 - 3.33 (2H,),. "ÍO - 3.74 (3H, m), 4.0R (1H, dd, J = 9.2, 9.2 Hz), 4.66 - 4.75 (1H,), 7.07 (1H, dd, 1 - 9.2, 9.2 Hz), 7.17 (1H , dd, J - 2.4, 9.2 Hz), 7.47 (1H, dd, J * 2.4, 14.9 Hz), 8.28 (1H, t, J 5.7 H, -).
Compound No. 7
H * -RMN (CDCI3) S pp? 2.03 (3H, s), 2.60 ~ 2.65 (4H,), 3.35 -5.40 < 4H, m), 3.57 - 3.79 (3H, m), 4.03 (1H, dd, J * 8.9, 8.9 Hz), 4.73 - 4.82 (1H, m), 6.14 (1H, t, J = 5.9 Hz), 6.97 (1H, dd, J = 9.2, 9.2 Hz), 7.09 (1H, ddd, J = 2.2, 2.2, 9.2 Hz), 7.41 (1H, dd, J = 2.2, 14.0 Hz> Compuestcn No. 8s
H »-NMR (DMSO-d *,) S ppms 1.60 - 1.74 (2.H,), 1.83 - 1.97 (3H, m), 1.84 (3H, s), 2.57 - 2.65 (2H, m), 3.19 - - 3.25 (2H, m), 3.36 -3.41 (.2H,), 3.73 (1H, dd, J «- 6.5, 8.9 Hz), 4.07 (1H, dei,, T - ~ -8.9, 8.9 Hz), 4.65 - • 4.74 (1H,), 7.03 UH, dd, J = 9.2, 9.2 Hz), 7.14 (1H, dd,, T = 2.4, 9.2 Hz), 7.44 < 1H, dd, J - 2.4, 14.9 Hz), 8.39 (1H, t, J •: • - 5.7 Hz).
• ^ Compues or No. 9
H * -RMN (DMSO-d *) K ppms 1.45 - 1.60 (2H,), 1.76 - 1.90 (2H, m),
1. 81 (3H, s), 1.83 ¿3H, s), 2.67 - 2.75 (2H,), 3.22 - 3.29 (2H, "* ', 3.38 - 3.42 (211,), 3.61 - 3.73 (2H,) ,, 4.08 í_H, díi, T = 9.2, 9.2 Hz), 4. A / - 4.75 (1H, m), 7.07 (1H, d, J * 9.2, 9.2 Hz), 7.16 (1H, dd,, - 2.4, 9.2 Hz ), 7.47 <1 H, dd, J-2.4, 14.9 Hz), 7.85 (1 H, d, i 8.1 H), 8.24 (1 H, L. J-5.7 H) Compound No. 1 r >
H * -RMN (DMSQ-d *,) K ppms 1.71 - 1.87 (4H, m), 1.92 (3H, s), 2.76 - 2.84 (2H, m), 3"32 - 3.39 (2H, nt), 3.47 - 3.51 (2H, m), 3.76 - 3.86 (2H, m), 3.90 (2H, ci, J - 5.9 Hz), 4.16 (1H, dd, J == 8.9, R.9 Hr), 4.74 - 4.83 < 1H,), 5.52 (1H, t, J = 5.9 Hz), 7.15 (1H, dd, J - 9.2, 9.2 H "), 7.24 UH, dd, J - 1.8, 9.2 Hz), 7.55 UH, d, J »1.0, 14.9 \ i, '), 7.74 UH, d, J * 7.8 H_), 8.32 UH, t, J - 5.7 Hz).
H * -RMN (DMSC-d?),? | t. " t.83 (3H, s>, 2.25 - 2.38 (2H,), 2.61 - 2.65 (? H,), 3.0o - 3.31 (4H,), 3.38 - 3.42 (2H, m), 3.70 UH,
, 'd,, T - 6.5, 9.2 Hz), 4.08 UH, dd, J - = 9.2, 9.2 Hz), 4.64 - 4.75 UH, rtt), 7.9 (XH, dd,, - 8.9, 8.9 Hz), 7.17 UH, dd,, T - 2.2,
8. 9 HU, 7.49 UH, dci,, T - 2.2, 14.9 H. '), 8.24 UH, t, J - 4.9
Hz), 1 .42 UH, s). Compound No. 29 s r »
H * -RMN (CDCla) S ppm. 1.71 - 1.88 (2H,), 2.00 - 2.10 (2H,), 2.02 (3H, '. »), 2.79 - 2.88 (2H, m), 3.26 - 3.37 (2H, m), 3.40 (3H, s) , 3.55 - 3.77 (4H,), 4.01 UH, dci,, T = - 8.9, 8.9 Hz), 4.70 - 4.81 UH, nt), 4.73 (? H, s), 6.22 UH, br s), 6.94 UH , cid, J 9.2, 9.2 Hr), 7.05 UH, ddd, J • * = 1.5, 1.5, 8.9 H =), 7.40 UH, dd, T = • 2.4, 14.3 Hz).
61 -Comp e - > t or f "30:
H'-NMR (DCI?) S ppnt: 1"87 - 1.91 (4H,), 2.02 (3H, s), 3.11 - .15 (? H, nt), 3.56 - 3.78 (3H,), 4.00 (4H , s), 4.01 (ÍH, t, J = 8.9 Hz), 4.72 - 4.RJ (Ul,), 6.49 UH, t, J * 6.2 Hz), 6.94 UH,, J 8.9, 8.9 H.-i, 7.04 UH, -Id, J - 3.0, 8.9 Hz), 7.39 UH, dti, J = 2.6, 14.2 Mr). You compete t Mo. 31 s
H * -RMN (CD 1,5) S ppnv. 2.02 (31-1, s), 2.48 - 2.52 (2H, m), 2.72 -2.77 (21-1, m), 3. - 3.13 C "?, nt >, 3.16 - 3.20 (2H, m), 3.56 -3.69 <? H, m), 3.75 UH, dd, J - 6"8, 9.2 \ i.-), 3.86 (3H, s), 4.02 UH, dd, í --- 9.2, 9.2 Hz) , 4.72 - 4.82 UH, m), 6.25 UH, br s), 6.92 UH, dd, 3 - = 8.9, 8"9 Hz), 7.06 UH, d, J • = 2.6, 8.8 Hz), 7.43 UH , dd, J - 2.4, 14.3 Hz).
Compound No.
H * - NMR (DNSC-c) j? jjpm? 1.49 - 1.61 (2H,), 1.80 - 1.90 (2H, m), *, 8 (311, - »), 2.66 - 2.73 (? H, ftt), 3" 23 - 3.31 (2H, m), 3.38 - - 3.42 (2H, rtt), 3.53 (3H,), 3.69 UH, dd, J == 6.5, 8.9 Hz), 4.07
(ÍH I), O Hz), 4.65 - 4.73 (1 H,), 7.07 U H, del
9. 5, H •) (.U ?, Hz), 7.46 (\ H, dd,
2. 4, 14.9 Hz), 8.23 (1 H, t, J = - 5.7 Hz) Compound No. 33 s
H1- NMR (DMSp-d *) S ppm: 1.83 (3H, s), 2.42-2.46 (2H, m), 2.56 -2.60 < 2H,), 3.03 - 3. o7 (2H,), 3"tO - 3.15 (2H,), 3.38 -3.42 (2H, m), 3.70 UH, dd, T-6.3, 0.8 U), 4.08 UH, cid , T = 8.9, 8.9 Hz), 4.66 - 4.75 UH, m) 7.09 UH, cid, J = 9.0, 9.0 Hz), 7.17 UH, dd, J ~ - ~ 2.4, 8.9 Hz), 7.49 UH, d, J = • 2.4, 14.6 Hz), 8"23 UH, l, J - '5.R Hz).
__ ompue No. 3 1
Hl -ppp (ip I, 1 '¡in- 1.35 (3H, S), 1.40 - 1.75 (5H, m), 1.90 (2H, d, J * 12.2 H), 2.02 (3H, *), 2.60 - 2.68 (2H, m), 3.33 - L 3.38 (.? Y,), 3.55 - 3.77 (3H,), 3.90 - 3.96 < 4H, m), 4.01 UH, dd,, T - 8.8, 8.8 H . > , 4.71 - 4.80 UH, m), 6.34 UH, br s), 6.92 UH, dd, J 8.9, 8.9 Hr), 7.05 UH, br d, J - 8.9 Hz), 7.38 UH, dd, J 2.4, 14.6 H ). Nen compound 35 Ír-
H? rr *, f '•',. 1.36 - 1.51 (2H, nt), 1.77 - 1.82 (2H, m), 1.91 -. 5 UH, nt), 2.02 < 3H, s), 2.16 (3H, s), 2.43 (2H, cl, J = - 6.8 Hz), 2.63 - 2.72 (2H,), 3.34 - 3"38 (2H, m), 3.55 - 3.77 ( 3H,), 4.01 UH, »id, J - 9.0, 9.0 Hz), 4.72 - 4.81 UH, m), 6.28 UH, br -,), 6.92 UH, dd, J - 9.0, 9.0 Hz), 7.05 (ÍH) , ddd, J = 1.5, 1.5, 8.9 Hz), 7.39 (1H, dd, J - 2.3, 14.2 Hz).
(. ~ 7 (V ^ m ursst No »36:
n * m.p T ^ I., 'f-, », or, 1.66 - 1.92 UH, m), 1.93 (3H, S), 2.02 -. 9 (1H, m), 2.97 - 3.12 (2H, m), 3.23 UH,), 3.39 (2H, d, J = 6.8 Hz), 3.57 - 3.77 (3H,), 3.74 (3H, s), 4.02 ( 5H, m), 4.77 UH, m), 6.2 UH, t, J - 5.9 Hz), 6.95 UH, t, J - 8.6 Hz), 7.05 UH, dd, T - 2.4, R.6 Hz), 7.41 UH , dd, 3 --- 2.4, 13.8 Hz). Ccnmpues-t or No. 37:
Hl -HnM MV - J - "M i 2.02 (3H, s), 2.49 - 2.74 (2H, m), 3.27 -3.39 (2H,), 3.57 3.71 (4H, m), 3.73 ( 2H, d, J - 6.8 Hz), 3.78 (3H, s), 4.02 (.X, t, J - 8.9 Hz), 4.7R UH,), 6.45 UH, broad), 6.97 UH, t , J --- 8.6 H), 7.06 UH, dd, J ~ 2.4, 8.6 Hz), 7.43 UH, dd, J = 2.4, 13.8 Hz).
f.P, -Compue '-. to No, 381
II1 rl 'U "? V» |, - ,,, ", .04 (3H, S), 3.68 (2H, t, J - 5.7 Hz)," "89 UH, dd, i - 6.8, 9.5 Hz ), 4.11 UH, t. J • - 9.5 Hz), 4.85
UH, m), 6. o (2H, 7.8 Hz) 15 UH, b. 5.9 Hz), 7.34
(] H, dd, J - 2.4, 8.6 Hr), 7.38 < \, t, J - 8.6 Hz), 7.47 (2H, d, J - 7.8 Hz), 7.74 (1H, dd, = 2.4, 13.8 Hz). Compound No. 39:
H * -I 1N íp l 'p ... n: 1.3o (3H, s), 1. - 1.88 (5H, m), 2.02 (3H, =.,), 2.55 - 2.64 (2H, rn), 3.44 - 3.48 (7H,), 3.55 - 3.77 (3H, rtt), 3.89 - 4.04 < 5H, m), 4.72 - 4.81 UH, m), 6.39 UH, br s), 6.92 UH, dd, T ~ - 9.0, 9.0 Hz), 7.05 UH, dd, J - 2.2 , 9.2 Hz), 7.38 UH, dd, 1 - 2.8, 14.2 H).
Compue to No. 401
H-PMN 'Cl > r_lß '> PP-.W 1.76 - 2.00 (4H,), 2.02 (3H, s), 2.19
~~ H, s), 2.38 - 2.49 UH, m), 2.66 - 2.76 (2H,), 3.40 - 3.44
(2H, m), 3.56 - 3.77 (3H, m), 4.01 UH, dd, J - 8.8, 8.8 Hz), 4.72 - 4.81 UH, m), 6.35 UH, br s), 6.92 UH, cid, J - 8.9, 8.9
Hz), 7.05 UH, broad, f - 8.9 H), 7.39 UH, dd, J = 2.2, 14.6 Hz). Compound No. 41
H t -RMN 'VV < r | ? \ v,, .. "» _ 2.02 < 3H, ni), 2. '54 (1 H,), 2.64 - 2, 92 (2H, m), 3.05 - 3.2? (2H, m), 3.57 - 4.06 (7H, m), 4.03 UH, t, J - = 9.2 Hz), 4.78 (.XH, rtt), 6.2.7 (XH, br »*), 6.98 UH, t , T = 8.6 Hz), 7.08 dd, - 2.4, 8.6 Hz), 7.47 UH, dd, J = 2.4, 13.8 Hz).
? o Competes 1st No. 42
Hl pr-IN pm 2"02 (3H, S), 2.66 - 2.70 (2H, m), 2.84 -2.88 (2H,), 3.1 - 3.19 (2H, m), 3.23 3.27 (2H, m ), 3.56 - .78 (3H, nt), 3.9? (3H, s), 4.02 (1H, di \, J = 9.0, 9.0 H), 4.73 - 4.82 UH,), 6.1b UH, br s), 6.93 UH, dd, J = 9.0, 9.0 Hz), 7.07 UH, ddd, J 1 1, 1.1, 8.9 Hz), 7.46 UH, dl, J = - 2.6, 14.2
Hz). Compound No. 43 s
H
H »-RMN ín 'O, 1," * ,,,,, 1, 1.R3 (3H, s), 2.42 - 2.46 (2H, m), 2.55 - 2.60 (2H, m), 3.03 - 3.07 (2H, ni), 3.10 - 3.14 <2H, m), 3.38 - 3.42 (2H, m), 3.70 (Ui, dd, J - 6.2, 9.2 H.?), 3.90 (3H, s), 4.08
UH, dd, r - 9.0, 9.0 Hz), 4.66 - 4.73 UH,), 6.23 (2H, s),
7. 09 UH, dd,, 7 - R. *, 8.9 H), 7.17 UH, dd, J == 2.4, 8.9 Hz),
7. 49 UH, dd, J = 2.4, 14.6 H.), 8.23 UH, t, J - 5.7 Hz), 9.25 (1 H, s).
i Compound No, 44 s
H * -RMh í, '- "ppn. 1.83 (3H, s), 2.41 (2H, t, J - 5.9 Hz)
2. 62 (4H, m), 2.73 (? H, t, J = 5.9 Hz), 3.06 (2H, t, J »5.9 Hz). - X.12 (2H, t, J - 5.9 Hr), 3.40 (2H, t, J »5.4 H), 3.66 (5H, m)
4. 08 (ÍH, l, T - 8 ,, - V Hz), 4.70 UH, m), 7.09 UH, t, J = 9.2 H)
7. 17 UH, cid Hz), 7.49 UH, dd, T - 2.2 14.9 Hz)
8. 23 UH, i, J = 5.7 Hz). Compound No. 45
"* (; 111 -RMN 'Df'T) u.,%' I p. 1.83 (3H, s), 2.35 (2H, t, J * 5.7 Hz) 2.43 (2H, t, T - = 5.7 Hz), 3.06 (6H, m), 3.40 (2H, t J - = 5.9 Hz) 3.50 (2H, tld, J = 5.9, 11.9 Hr), 3.70 (XH, del, T * 6.5, 8.9 Hz) 4.08 UH, l, T - 8.9 Hz), 4.67 UH, t, J = - 5.4 H), 4.71 UH, m) 5.77 (IH, l ", 1 - 4,9 llz), 7 . "7 (1H, t, J - 9.2 H), 7.16 UH, dci T - = 2.4, 9.2 H /), • ', 8 UH, d, J - 2.2, 14.9 Hz), 8.23 UH, t. J - = 5.7 Hz).
/ Compound No. 46:
IP-RMN < EM < , - dA) ", ,, n 1.83 (3H, s), 2.42 - 2.47 (2H, m), 2.73 - 2.77 (2.H,), 3.01 - 3.05 (2H,), 3.09 - 3.12 (2H, m ), 3.38 - ^ .42 (2H,), 3.71 (\, d, J - 6.2, 9.5 H), 4.08 UH, dd, J = 9.0, 9.0 Hz), 4.66 - 4.75 UH, pt > , 5.88 (3H, br s), 7.09 UH, dd,
J »9.3, 9.3 \ -), 7.16 d, cid, T - 2.4, 8.6 Hz), 7.49 UH, dd, J * 2.3, 1 .7 Hz), 8.25 UH, l, J - 5 , 7 Hz). Com ue to No. 47 s
Y*
H1 -RMN ü.pri, "?> 2.02 (3H, s), 2.19 (3H, s), 2.65 - 2.69 <2H,), 2.81 - 2.86 (2H,), 3.16 - 3.20 (2H, m), 3.23 - 3.27 (2H, m), 3.57 - 3. '< - > (J, \\, ni), 4.02 UH, d, J - 9"?, 9.0 Hz), 4.73 - 4.82 UH, m), 4.79 (? H, s), 6.25 UH, l, J = 6.3 Hz), 6.93 UH, vid,, T - 8.9, 8.9 Hz), 7.08 UH, ddd, J - 1.2, 1.2, 8.8 Hz), 7.46 UH, dd, T - 2.4, 1.0 H).
and? om? . < , t or N o, r
H1 Tti "I 1.4: 1.54 (2H, m), 1.72 - 1.89 (3H, m)
^ .83 (3H, ",), 2.51 2.59 (2H,), 3.32 - 3.42 (4H, m), 3.69 UH, dd, J - 6.6, 9.0 Hz'1, V. 82 - 3.96 (4H,>, 4.07 UH, dd, J - 9.0, 9.0 Hz), 4.65 - 4.75 H, m), 4.75 UH, t, J == 6.1 Hz), 7.04 UH, cid, J - 9.3 , 9.3 H.), 7.14 UH, dd, T - 2.4, 8.6 H), 7.45 UH, dd,, T - 2.4, 15.1 H, X 8.23 UH, t, J = - 5.8 Hz.). Comp ue "to N. 4 s
ll'-UMN i, '2"02 (3H, s), 2.65 - 2.70 (2H,), 2.80 - 2.84 < 2H, iti 3.13 3.18 (2.H, m), 3.22 - 3.26 (2H, m), 3.56 - 3.79 (3H, ni), 4.01 (, dd, J 9.0, 9. Hz), 4.27 (2.H, ,), 4.69 (2H, _t), 4.72 - 4.82 UH, m), 6.33 UH, l, J 6.3 Hz), 6.92 UH, dd, J = - 9.0, 9.UH / l, 7.07 (1H, dd, T - 2., 8.8 Hz), 7.29 - 7.48 < 6H,, n) "('^" Sto No. 5:
l-P- MM vnH'Tl u? > '.., .11 1.83 (3H, s), 2.54 (2H, t.T = 5.4 Hz), _ / > _69 (2H, t J - 5.4 H, >), 3.06 (2H, t.J 5.4 Hz), 3.18 (2H, t,
T -. 5.4 Hz), 3.40 (2H, t, J = 5.4 Hz), 3.71 U, dd, J = 6.2, 8.6 Hv), 4.08 UH, t, 1 8.6 H), 4.70 UH, m), 7.11 (1H, t , J * 9.2
Hz), 7.17 UH, dd, r 2.4, 9.2 Hz), 7.49 (XH, dd,, T - 2.2, 14.9 Hz), 8.23 UH, t, J - 5.9 H), Compound Ncn. 51 s
lP -UMN ÍCD IA '02 (3H, s), 2.48 - 2.52 (2H, m), 2.81 -2.86 (2H, m), 3.13, 23 (4H,), 3.56 - 3.78 (3H, m ), 3.77 (3H,
< = > ), 4.05 UH, »! D, r - 8.4, 8.4 Hz), 4.61 (2H, s), 4.73 - 4.82
UH,) (IH 5.8 Hz.), 6.93 UH, dd, J - 9.0, 9.0
Hz), 7.06 i \ H vid, I 1.5, 8.8 Hz), 7"43 (dd, 1H, T =» 2.6, 14,
Hz).
Comp e to No,
Hl-HMN íí * t > Ci 1 I '(H,, 48 - 2.53 (2H,), 2.76
* ~ i.80 < H,), 3.11 - 3.21 (4H,), 3.56 - 3.78 (3H, m), 3.87 -, 92 < 2H, irt), 4.02 UH, del, J = - 9.0, 9.0, Hz), 4.16 - 4.19 (2H,), 4. '4.82 < .] \ h > 6.1 UH, 6.1 Hz), 6.93 (1H, dd,
J "9., 9.0 .- 7.09 UH, cid, J = 1.4, 8.6 Hz), 7.44 (dd, 1H,, 1 == 2.6 - 13.9 Hz) Compound Nt), 53 s
H3 KMN "_ * J) r ', 1 P' 2.02 (3H, s), 2.54 - 2.84 U4H, m), 3.14
(2H, t, J 5.7 H.-), 3.22 (2H, t, J «• 5.7 Hz), 3.61 (4H, m), 3.75
UH, dd,, T - 6.2, P.6 Hz), 4.02 UH, t, T - 8.6 Hz), 4.78 UH, m), 6.13 UH, br - * 5, 6.93 UH, t, J = 8.6 Hz) , 7.07 UH, d, J = 2.4, 8.6 Hz), 7.44 C \ H, dd,, T - 2.4, 13.8 Hz).
Compound No. 54
\ < > i1 NMR (Hl ^ n ^ '"u |? i" 1.83 (3H, s), 2.55 (4H, m), 3.03 (2H, m),
3. 19 (2H,), 3.40 (2H, m), 3.70 UH, m), 4.08 UH, t. J * 9.2 b -), 4.12 (2H, s), 4.71 UH,), 7.13 (2H,), 7.48 UH, cid, J = 2.2, J .9 Hz), 8.23 UH, t, J = 5.7 Hz). Compueslen No. 55 s
IP-PMM U "Pp ,, i- 't rT'o ppm 2.02 (3H,»), 2.63 - 2.68 < 2H,),
2. 85 - 2.89 (2H, m), 3.18 - 3.22 (2H,), 3.35 - 3.40 (2H, m), 3.54 - 3.80 (3H, ni), 4.04 UH, dd, J - 9.0, 9.0 Hz), 4.73 - 4.82 UH, m), 6.96 UH, vine, I = 9., 9.0 Hz), 7.10 UH, ddd, J --- 1.2, 1.2, 8.6 Hz), 7.3 UH, br s), 7.47 UH, dd, J = 2.4, 14.0 Hz), 8.22 (2H, s).
/ Compound No. 56
H1 m \ i (DITT .- > *,) ,,) "t, 64 - 1.70 (4H, m), 1.83 (3H, s), 2.98 -! ? .,. 07 (4H, tu), 3.38 - 3. '31 (4H, m), 3.67 - 3.74 (2H, m), 3.99 - 4.14 (3H,), 4.67 - 4. / 2 UH, m), 4.84 UH, t, J - 5.5 Hz) 7.05 - 7.18 (2H, m), 7.46 UH, vid, J - 2.4, 14.6 Hz), 8.23 UH, t, J - 5.8 ^, Compound Ncn. 57 I I
I-'1 -RMN < r.T) r] ?? pp? > 2.02 (3H, s), 2.48 - 2.53 (2H, m), 2.77 - 2.81 (2H,), 3. 9 3.2 »(4H, m), 3.38 (3H, s), 3.56 - 3.81 (5H,), 4.02 UH, dd, T = 9.0, 9.0 Hz), 4.21 - 4.25 UH, m), 4.68 (2H, s), 4.72 - 4.82 (HH,), 6.22 UH, t, J = 6.2 Hz) , 6.92 UH, dd, J = • 9.0, 9.0 Hz), 7.07 UH, dd, J - 2.2, 9.5 Hz), 7.43 UH, dd '.4, 14.0 H.
Compue * to No. 58!
MH i, id tun - i, Pil 1.57 (7H,), 1.83 (3H, s), 2.73 -, 92 (H, ni), ~ 3r. 3.26 (2H, m), 3.38 - 3.42 (2H, m), 3.51 -3.58 (2H, m), 3.67 3.73 UH, m), 3"97 - 4.12 (5H, m), 4.62 -4.75 (2H, m), 7.05 7.18 (2H, m), 7.47 UH, cid, J-2.4, 15.1 Hz), 8.23 UH, t, T 5.8 Hz) Compound No. 59;
H'- RM? P? '?? »L") r ppn, 1.83 (3H, s), 1.78 - 2.18 < 4H, m), 3.10 -3.21 (4H, m), 3.38 (2H, m), 3.70 UH, dd, J = 6.2, 9.2 Hz), 4.08 UH,. = 9.2 Hz), 4.71 UH, m), 7.00 - 7.20 (2H, m), 7.48 UH, dd, J - 2.4, 14.0 Hz), 8.23 UH, t, J - 5.9 Hz).
Compu si o No "60
H1 1.27 and 1.32 (cade *, one, t, J = 7.0 H, tcntal
JH), 2.o2 (3H, s), 2.54 - 2.75 (4H,), 3, 15 - 3.16 < 4H, m), 3.63 - 3.71 (2H, nt), 3, 76 UH, dd "J • - 6.8, 9.3 Hz), 4.02 UH, t, I - 9.3 Hz), 4" 21 and .25 (ond one ?, J - 7.0 Hz, total 2H), 4.77
(.ÍH,), 6, UH, br s), 6.93 UH, t, J - 8.9 Hz), 7.07 UH, d,
, 1 - 2.4, 8.9 Hz), 7.45 UH, dd, J - 2.4, 14.0 H) I i Compound No. 61 s
'I1 -!?! 1 (i'-ldv t 1.85 - 1.97 (4H, m), 2.02 (3H, -__), 3.09 - 3, 18 (4H,), 3.38 C', H, - *), 3.54 - 3.84 I / _H, m), 4.01 UH, dd, 3 = 9.0, 9.0 Hz), 4.12 UH, dd, J == 6.5, 8.4 Hz.), 4.31 - 4.40 UH, m), 4"67 22H, s), 4.72 - 4.82 UH, m), 6.15 UH, br? ), 6.94 UH, dd, T-9.0, 9.0 H,), 7.05 < XH, dd, J - = 1.9, 8.9 He), 7.40 UH, dd, J - 2.6, 14.2 Hz).
Compue .lo No "6"
--RMN p * '*? , *. 1. or: (, 3H,: .4C 53 <2H,) .77 - 2.81 (2H, m), 3.1 3.23 (4H,), 3, .56 - 3.78 < 3H, m), 4.02 UH, dd, f - 8.6, 8.6 Hz), 4.56 (? H, d,, T - = 1.6, 5.9 Hz), 4.72 - 4.82 UH, m), 5.22 UH, d, , T 1.4, 10.8 Hz), 5.3 UH, dd, J - 1.4,
18. 9 H / 5, 5.94 - 6"08 (1 H, m), 6" 30 (1 H, t, J = 6.3 Hz), 6.92 UH, cid,, T - 9.0, 9. H), 7.06 UH, dd, J = • 2.4, 8.6 Hz), 7.43 UH, id, J - 2.4, 1 .0 H). Compile? ~ I or No, 63 i
I -tlMIl ", r¡.tl '-1, - 1.54 - 1.68 (2H, nt), 1.96 - 2.01 (2H,), 2.02 (3H, s), 2.69 - 2.78 (2.H,), 2.96 - 3.07 UH, m), 3.37 -3.42 <2H, nor!, 3.57 <3H, - *), 3.60 - 3.77 (31-1, m), 4.01 UH, dd, J - 9.0, 9.0 Hz), 4.'T - 4.81 UH, m), 6.22 UH, t, J - 5.8 H), x6.94 UH, del, J - 9, or, 9.0 H; 7.05 (I, dd, 9.0 Hz .) 7.39 (U, cid,, T at 14.2 Hz) Compound Na. 64
, PMfl "Tí *, '?> 2.02 (3H, a), 2.52 - 2.57 (2H, >, 2.79 - 2.83 (2H,? N), 3.11 - 3.22 < 4H, m), 3.44 (3H, s), 3.56 - 3.78 (3H,), 4.02 (- \, dd, i - 8.9, 8.9 Hz), 4.72 - 4.82 UH,), 5.09
(2H, -,), 6.23 UH, t, J • = 6.3 Hz), 6.93 UH, dci, J = 9.3, 9.3 Hz), 7.07 (III, ddd, T - 1.5, 1.5, 8.6 Hz), 7.44 UH, dd, J = - 2.4, 1, 0 Hz). Cenmpue to Ncn, 65 s
H1- PI Tivi., I pp .. 1.91 - 2.02 (4H, m), 1.99 (3H, s), 2.46 (3H, ". *), 2.85 - 2.94 (2H,), 3.15 - 3.23 ( 2H, m), 3.56 - 3.68 (2H, m>, 3.74 UH, vid, J * 6.8, 9.3 Hz), 4.O0 UH, t, T - ~~ 9.3 Hz), 7.04 UH, dd, f - 2.4, 9.5 HJC), 7.32 (2H, d, J .- 6.5 Hz), 7.40 UH, del, J - 2, 4, 14.0 Hz), 7.87 (2H, d, J • - 6.5 Hz).
Co pu to No. 66
W tr i 1, 83 (3H, s), 2.37 - 2.41 (2H,), 2.64 - 2.68 (2H, ni), 3.0 3.13 (4H, nt), 3.34 - 3.42 (4H, m) , 3.67 - X73 (2H, m>, 3.86 UH, cid,, T 6.3, 10.7 Hz). 3.98 UH, cid, J - 5.0, 1 (i.7 Hz), 4"í] UH. dd,, 1 9.0, 9.0 Hz), 4.53 UH, t, 1 =
. 7 Hz), 4.68 - 4.75 (2H,), 7.06 - 7.19 < 2H, m), 7.49 UH, tid, J = 1.9, 14.6 Hz), 8.23 UH, t, J = 5.8). Compound No »67.
Hl-NMR (DMSO-d *) J? ppms 1.54 - 1.60 (2H, m), 1.83 (3H, s), 1.80 2.00 (2H, m), 2.73 (? H, m), 3.16 - 3.34 (3H, m), 3.40 (2H, t, J 5.4 Hz), 3.7 UH, d »i, J - 6.2, 9.2 Hz), 4.08 UH, t, J - = 9. Hz.), 4.70 < XH, m), 7.07 UH, t, J - 9.5 Hz), 7.16 (U d, J 2.4, 9.5), 7.47 UH, dd,, T - 2.4, 14.6 Hz.), 7.97 UH, ti, J 9.7 Hz), 8.11 UH d, - 9.7 Hz), 8.23 UH, t, J = 5.9 Hz).
incompue or No. 681
H * NMR (DM80- d, ") < z ppnts 1, 32 - 1.43 (2H, m), 1.83 (3H, s), 1.86 - '.90 (2H,), 2.4- * - 2.54 UH, nt), 2.62 - 2.70 (2H , m), 3.23 - 3.42 (6H, ni), 3.33 (3H, =,), 3.69 UH, d, T - 6.3, 9.3 H), 4.07 (XH, dd, 1 - 8, 9, H.9 Hz), 4.65 - 4.74 UH, m), 7.02 - 7.17 (2H, m), 7.45 UH, dd, r - 2.4, 15.1 H), 8.23 (1H, t, J = 5.5 H ). Compue - 1 or No, 695
H * -RMN (DMSp-d *) r, ppms 1.51 - 1.63 (2H, m), 1.82 - 1.87 (2H, m), 1"83 and 3H, -,), 2, 06 (1-1, s 5, 2.6 - 2- .74 (2H, m), 3.24 - 3.2.8 (2H, ni), 3.38 - 3.50 (3H, m), 3.66 - 3.72 UH, m >, 4.07 UH, dd , I 9.0, 9.0 Hz), 4.65 - 4.74 (m > 5.63 (2H, s), 7.03 - 7.17
(2H, ni), 7.46 (XH, dd, J2.3, 15.0 .-), 7.65 UH, d, J - 7.8
Hz. > , 8.23 C H, t,) 5.7 Hz).
"Tax No. 70 s
H-t-NMR (DMñn-d *) £ ppms 1.31 - 1.45 < 2H, m), 1.83 (3H, s), 1.84 -1.90 < 2H, m), 2.29 < ", H, s), 2.31 - 2.44 UH, m), 2.62 - 2.70 (2H,), 3.23 - 3.2.8 (2H, m), 3.20 - 3.40 UH,), 3.38 - 3.42 (2H, t), 3.69 UH, dd, J - 6.3, 8.8 Hz), 4.07 UH, dd, J - 8.8, 8.8 Hz), 4.65 - 4.74 UH,), 7.02 - 7.17 < 2H,) , 7.45 UH, dd, J = 2.4, 15.1 Hz), 8.23 UH, t, J = - 5.9 Hz) Compound No. 71 s
H »-NMR (DMRO-d *) R pptn 1.46 - 1.59 (2H,), 1.83 - 1.89 (2H, m), 1, 88 (3H, < • >), 2.13 2.20 UH,), 2.19 (? H, - = -), 2.58 - 2.66 (2H, m), 3.28 - 3.35 (2H, m), 3.37 - 3.42 (2H, m), 3.69 (H, dd, J -6.3, 9.3 Hz), 4.07 UH, el, J - 8.8, 8.8 Hz), 4.65 - 4.74 UH, m), 7.01 - 7. I7 (2H, m), 7.45 UH, dd, J - 2.6, 14.7 Hz), 8.22 UH, t, J = - 5.9? "-_: Oft? Well, tt) No,
H * -RMN (CDCIj) F. |) p? Rií 1.74 - 1.86 (4H,), 2.02 (3H, s), 2.71 - "i.80 (21-1,), 2.85 (? H, s ), 3.05 UH,), 3.40 - 3.45 (2H, m),
3. 6 - 3.76 (3H, nt), 4.01 UH, i. J '- 9.2 Hz), 4.77 UH, m), 6.23
UH, br -,), 6.94 UH, t, T - 8.9 Hz), 7.05 UH, cid, J = 2.4, 8.9
Hz) UH, of 14.0 Hz), 7.38 UH, s) ompue *? L > ? Do not
H * -RMN (DC1.5) flfUltS, (-T <4H.t 5.7 Hz) .8 (4H, 5.7 Hz), 89 (3H,), 4.07 UH. t,, 1 Hz), 4.74 UH, vi, J) !?), 4.8o UH,), 4.92 UH, d, J = 1.6 Hz), 6.81 UH, br '._ > , A "El { X ^, t, T - 9.2 Hz), 7.10 UH, vid, T .4, 9 Hz.), 7.46 UH, í \ d, J - 2.4, 1 .0 H).
fl *, ^ -ompue ^ i or N ») ,, 74 i
H »-NMR (DMSO-d *) F, ppms 1.54 - 1.61 (2H, m), 1.83 (3H, s), 1.80 - 2.00 < 2H, m), 2.09 - 2.68 (8H,), 3.30 UH, m), 3.38 (2H, m),: .50 - 3.58 (4H, m), 3.69 UH, dci,, 1 == 6.8, 9.2 Hz), 4.0 UH, t,,! 9.2 H), 4.70 (\\ i, ni), 7.05 UH, t, J • = 9.5 H), 7, 14 UH, rivl, J = - 2.4, 9.5 Hz 1, 7.45 UH, dd, J - 2.4, 14.6 H), 8.23 UH, t, - 5.9 H)
Claims (1)
1.lítti). EXCERPT OF THE INVENTION The present invention provides agents that have a high anti-biotic activity for the prevention and treatment of infirm diseases. From e-> Thus, the present invention provides new derivatives of oligoaldiin represented by the chemical formula; or the salts far ai v'-pt 11 c menté - acceptable to them, as well as chromium-containing compositions, nor robes containing active ingredients, dermal chemises or the lens salts themselves.
Applications Claiming Priority (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6-43949 | 1994-03-15 | ||
| JP4394994 | 1994-03-15 | ||
| JP6-146565 | 1994-06-28 | ||
| JP14656594 | 1994-06-28 | ||
| JP6/43949 | 1994-09-29 | ||
| JP6/235167 | 1994-09-29 | ||
| JP6235167A JPH0873455A (en) | 1994-03-15 | 1994-09-29 | Oxazolidinone derivative and medicine composition containingit as effective component |
| JP6/146565 | 1994-09-29 | ||
| JP6-235167 | 1994-09-29 | ||
| PCT/US1995/002972 WO1995025106A1 (en) | 1994-03-15 | 1995-03-14 | Oxazolidinone derivatives and pharmaceutical compositions containing them |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MX9604072A MX9604072A (en) | 1997-09-30 |
| MXPA96004072A true MXPA96004072A (en) | 1998-07-03 |
Family
ID=
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