MXPA00006621A - Novel aromatic amides, preparation method and application as medicines - Google Patents
Novel aromatic amides, preparation method and application as medicinesInfo
- Publication number
- MXPA00006621A MXPA00006621A MXPA/A/2000/006621A MXPA00006621A MXPA00006621A MX PA00006621 A MXPA00006621 A MX PA00006621A MX PA00006621 A MXPA00006621 A MX PA00006621A MX PA00006621 A MXPA00006621 A MX PA00006621A
- Authority
- MX
- Mexico
- Prior art keywords
- methyl
- radical
- formula
- compounds
- product
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 25
- 239000003814 drug Substances 0.000 title claims description 12
- 229940079593 drugs Drugs 0.000 title claims description 4
- 150000008430 aromatic amides Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 125000004432 carbon atoms Chemical group C* 0.000 claims abstract description 39
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 239000001301 oxygen Substances 0.000 claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 7
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- -1 alkyl radical Chemical class 0.000 claims description 136
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 80
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 40
- 150000003254 radicals Chemical class 0.000 claims description 39
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl radical Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 7
- WCYWZMWISLQXQU-UHFFFAOYSA-N Methyl radical Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 125000005842 heteroatoms Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 150000002829 nitrogen Chemical group 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- 239000002981 blocking agent Substances 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000004434 sulfur atoms Chemical group 0.000 claims description 2
- 125000004429 atoms Chemical group 0.000 claims 2
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims 2
- XMQOBGDXGQSRID-UHFFFAOYSA-N 2-oxochromene-3-carboxamide Chemical compound C1=CC=C2OC(=O)C(C(=O)N)=CC2=C1 XMQOBGDXGQSRID-UHFFFAOYSA-N 0.000 claims 1
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N Ethyl radical Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims 1
- PNUUMNMNQPEBBR-UHFFFAOYSA-N N-(2-morpholin-4-ylethyl)-2-oxochromene-3-carboxamide Chemical compound C=1C2=CC=CC=C2OC(=O)C=1C(=O)NCCN1CCOCC1 PNUUMNMNQPEBBR-UHFFFAOYSA-N 0.000 claims 1
- 101710026780 alc2 Proteins 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 16
- 239000001257 hydrogen Substances 0.000 abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 7
- 230000003115 biocidal Effects 0.000 abstract description 2
- 150000002431 hydrogen Chemical group 0.000 abstract 4
- 150000002367 halogens Chemical class 0.000 abstract 3
- 125000000304 alkynyl group Chemical group 0.000 abstract 2
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 239000000047 product Substances 0.000 description 228
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 219
- 239000000243 solution Substances 0.000 description 162
- 239000000203 mixture Substances 0.000 description 123
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 114
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 96
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 92
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 74
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 70
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 55
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 48
- 235000019341 magnesium sulphate Nutrition 0.000 description 48
- 239000012074 organic phase Substances 0.000 description 44
- 238000003756 stirring Methods 0.000 description 44
- 239000012429 reaction media Substances 0.000 description 39
- 229910052786 argon Inorganic materials 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 239000000377 silicon dioxide Substances 0.000 description 35
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 33
- 239000007864 aqueous solution Substances 0.000 description 31
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 31
- 235000019799 monosodium phosphate Nutrition 0.000 description 31
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 26
- 239000000725 suspension Substances 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- 125000001841 imino group Chemical group [H]N=* 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 19
- 239000012043 crude product Substances 0.000 description 17
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M Sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000008079 hexane Substances 0.000 description 15
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 15
- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 14
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- PSHKMPUSSFXUIA-UHFFFAOYSA-N N,N-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 239000008346 aqueous phase Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 9
- AYJRCSIUFZENHW-UHFFFAOYSA-L Barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 8
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N Coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 8
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 8
- 229910000397 disodium phosphate Inorganic materials 0.000 description 8
- 235000019800 disodium phosphate Nutrition 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000012267 brine Substances 0.000 description 7
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 7
- 239000011777 magnesium Substances 0.000 description 7
- 229910052749 magnesium Inorganic materials 0.000 description 7
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical group CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N Diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- FQRJNFFRZHSEHW-UHFFFAOYSA-N N-prop-2-ynylhydroxylamine;hydrochloride Chemical compound Cl.ONCC#C FQRJNFFRZHSEHW-UHFFFAOYSA-N 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M Potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000002808 molecular sieve Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (NE)-N-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- RGZRSLKIOCHTSI-UHFFFAOYSA-N hydron;N-methylhydroxylamine;chloride Chemical compound Cl.CNO RGZRSLKIOCHTSI-UHFFFAOYSA-N 0.000 description 5
- 229940072033 potash Drugs 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N Pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- HELHAJAZNSDZJO-UHFFFAOYSA-L Sodium tartrate Chemical compound [Na+].[Na+].[O-]C(=O)C(O)C(O)C([O-])=O HELHAJAZNSDZJO-UHFFFAOYSA-L 0.000 description 4
- 229960002167 Sodium tartrate Drugs 0.000 description 4
- AKEJUJNQAAGONA-UHFFFAOYSA-N Sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 4
- UDYFLDICVHJSOY-UHFFFAOYSA-N Sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 229960000956 coumarin Drugs 0.000 description 4
- 235000001671 coumarin Nutrition 0.000 description 4
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- GFHFNPNDTKMWNE-UHFFFAOYSA-N prop-2-ynoxycarbamic acid Chemical compound OC(=O)NOCC#C GFHFNPNDTKMWNE-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000001433 sodium tartrate Substances 0.000 description 4
- 235000011004 sodium tartrates Nutrition 0.000 description 4
- PANBYUAFMMOFOV-UHFFFAOYSA-N sodium;sulfuric acid Chemical compound [Na].OS(O)(=O)=O PANBYUAFMMOFOV-UHFFFAOYSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- BUDQDWGNQVEFAC-UHFFFAOYSA-N 3,4-dihydro-2H-pyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N Carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- MHCFAGZWMAWTNR-UHFFFAOYSA-M Lithium perchlorate Chemical compound [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 description 3
- 241000295644 Staphylococcaceae Species 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- AVFUHBJCUUTGCD-UHFFFAOYSA-M [Br-].[Mg+]C Chemical compound [Br-].[Mg+]C AVFUHBJCUUTGCD-UHFFFAOYSA-M 0.000 description 3
- 230000001154 acute Effects 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 3
- 229940043279 diisopropylamine Drugs 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- MVFGXYPEQHIKIX-UHFFFAOYSA-M heptane;acetate Chemical compound CC([O-])=O.CCCCCCC MVFGXYPEQHIKIX-UHFFFAOYSA-M 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 229910001486 lithium perchlorate Inorganic materials 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- LOVPHSMOAVXQIH-UHFFFAOYSA-M (4-nitrophenyl) carbonate Chemical compound [O-]C(=O)OC1=CC=C([N+]([O-])=O)C=C1 LOVPHSMOAVXQIH-UHFFFAOYSA-M 0.000 description 2
- GXYPITRJSPDNLU-UHFFFAOYSA-M (4-nitrophenyl)chloranuidylformate Chemical compound [O-]C(=O)[Cl-]C1=CC=C([N+]([O-])=O)C=C1 GXYPITRJSPDNLU-UHFFFAOYSA-M 0.000 description 2
- ZRSKKRWCHNPOPE-UHFFFAOYSA-N 1,1-dibromobutane Chemical compound CCCC(Br)Br ZRSKKRWCHNPOPE-UHFFFAOYSA-N 0.000 description 2
- AORMDLNPRGXHHL-UHFFFAOYSA-N 3-Ethylpentane Chemical compound CCC(CC)CC AORMDLNPRGXHHL-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina pectoris Diseases 0.000 description 2
- 101700067048 CDC13 Proteins 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N Methyl acetate Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M Perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 2
- 210000003491 Skin Anatomy 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- ITLHXEGAYQFOHJ-UHFFFAOYSA-N [diazo(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(=[N+]=[N-])C1=CC=CC=C1 ITLHXEGAYQFOHJ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 244000052616 bacterial pathogens Species 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- 201000009910 diseases by infectious agent Diseases 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- MOTRZVVGCFFABN-UHFFFAOYSA-N hexane;2-propan-2-yloxypropane Chemical compound CCCCCC.CC(C)OC(C)C MOTRZVVGCFFABN-UHFFFAOYSA-N 0.000 description 2
- 238000009114 investigational therapy Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- FWNSUQXHIZZNRM-UHFFFAOYSA-R palladium;triphenylphosphane;triphenylphosphanium Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 FWNSUQXHIZZNRM-UHFFFAOYSA-R 0.000 description 2
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
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- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 2
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- RWIVICVCHVMHMU-UHFFFAOYSA-N N-Aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
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- 239000000205 acacia gum Substances 0.000 description 1
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- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
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- 239000002775 capsule Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
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- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- ZFSLLTDUMPOMSX-UHFFFAOYSA-N dibutylalumanylium;hydride Chemical compound [H-].CCCC[Al+]CCCC ZFSLLTDUMPOMSX-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
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- 239000002270 dispersing agent Substances 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N dodecane-1-sulfonic acid Chemical class CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
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- 239000003995 emulsifying agent Substances 0.000 description 1
- KXADNVGOYKYAHQ-UHFFFAOYSA-N ethyl 7-hydroxy-8-methyl-2-oxo-4-phenylmethoxychromene-3-carboxylate Chemical compound C12=CC=C(O)C(C)=C2OC(=O)C(C(=O)OCC)=C1OCC1=CC=CC=C1 KXADNVGOYKYAHQ-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- LTZZYVWUGIPISL-UHFFFAOYSA-N ethyl(hydroxy)azanium;chloride Chemical compound [Cl-].CC[NH2+]O LTZZYVWUGIPISL-UHFFFAOYSA-N 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
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- 239000008187 granular material Substances 0.000 description 1
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- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;O-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 1
- 230000003211 malignant Effects 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
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- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
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- 239000002674 ointment Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- BHXXDGNDIDLJKA-UHFFFAOYSA-N pentane;2-propan-2-yloxypropane Chemical compound CCCCC.CC(C)OC(C)C BHXXDGNDIDLJKA-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical group ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L phosphate Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
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- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003527 tetrahydropyrans Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
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Abstract
The invention concerns compounds of formula (I), in which Y is oxygen, N-Nalc1 or NOalc2;X represents hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, CONOR or NRcRd, Rc and Rd being hydrogen or alkyl;Z represents hydrogen, halogen or free, etherified or esterified OH;R2 hydrogen or halogen;R3 hydrogen, alkyl or halogen;R hydrogen or alkyl;R1 hydrogen, alkyl, alkenyl or alkynyl;R5 hydrogen or O-alkyl;R6 alkyl or CH2-O-alkyl and R7 hydrogen or alkyl;or R6 and R7 form with the carbon atom which bears them a cyclic radical containing up to 8 carbon atoms. The compounds of formula (I) have antibiotic properties.
Description
NEW AROMATIC AMIDAS, ITS PROCEDURE FOR PREPARATION AND ITS APPLICATION AS MEDICINES
The present invention concerns new aromatic amides, their preparation process and their application as medicaments.
The subject of the invention is the compounds of formula (I):
in which
Y represents an oxygen atom, or an N-Nalcí or Noalc radical in the alkyla and al represent an alkyl radical, which contains up to 12 carbon atoms eventually interrupted by one or more oxygen atoms, REF. 121424 of sulfur or nitrogen optionally substituted by one or more halogen atoms, by an aryl radical optionally substituted by one or more halogen atoms, by a heterocyclic radical, by one or several radicals Ra N 'Rb
in which Ra and Rb identical or different from one another represent a hydrogen atom, an alkyl radical containing up to 8 carbon atoms optionally substituted, or Ra and Rb form together with the nitrogen atom to which a heterocycle is attached which can also contain another heteroatom selected from oxygen, sulfur or nitrogen,
X represents a hydrogen atom, a hydroxyl radical, an alkyl, alkenyl or alkynyl radical optionally interrupted by one or more oxygen, sulfur and nitrogen atoms, linear, branched or cyclic containing up to 12 carbon atoms, optionally substituted by one or more halogen atoms, by a heterocyclic radical, one or several free or esterified OH radicals, C = N, N02,
Ra N- • Rb
In which Ra and Rb, identical or different, represent a hydrogen atom, an alkyl radical enclosing up to 8 carbon atoms, or Ra and Rb form with the nitrogen atom to which a heterocycle that eventually encloses another selected heteroatom is bound between nitrogen, sulfur or oxygen, or X represents an alkoxy radical or a radical
OR
-C-NORe
wherein Re represents an alkyl radical containing up to 8 carbon atoms, optionally substituted by one or more of the substituents indicated above,
or X represents a radical NRcRd in which Rc and Rd identical or different, represent a hydrogen atom or an alkyl radical containing up to 12 carbon atoms, optionally substituted by one or more of the substituents indicated above, or Rc and Rd form together with the nitrogen atom to which a heterocycle is attached which optionally encloses another heteroatom selected from nitrogen, sulfur or oxygen,
- Z represents a hydrogen or halogen atom or a free, etherified or esterified OH radical,
R2 represents a hydrogen or halogen atom,
- R3 represents a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or a halogen atom,
- R, represents a hydrogen atom or an alkyl radical that contains up to 4 carbon atoms,
Ri represents a hydrogen atom, a linear, branched or cyclic alkyl, alkenyl or alkynyl radical containing up to 8 carbon atoms, optionally substituted by one or more halogen atoms, a C = N radical, an aryl radical that encloses up to 14 carbon atoms,
- R5 represents a hydrogen atom, an O-alkyl radical that contains up to 4 carbon atoms,
- or R6 represents an alkyl or CH2-0-alkyl radical, in which alkyl represents an alkyl radical containing up to 8 carbon atoms,
- R7 represents a hydrogen atom or an alkyl radical that contains up to 8 carbon atoms,
- or R6 and R7 form, with the carbon atom containing them, a cycle containing up to 8 carbon atoms, as well as the salts of the compound of formula (I), when the compounds of formula (I)) have a function basic As examples of salts, mention may also be made of the salts formed with acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, paratoluensulphonic, hydrochloric, hydrobromic, hydrodiolic, sulfuric, phosphoric acids and especially stearic, ethylsuccinic or laurylsulphonic acids.
In the definition of substituents:
the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl or cyclohexyl radical,
- halogen is preferably fluorine or chlorine, or bromine,
- the aryl radical is preferably the phenyl radical,
the heterocyclic radical is preferably the pyrrolyl, pyrrolidinyl, pyridyl, pyrazinyl, pyrimidyl, piperidinyl, piperazinyl, quinuclidinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, imidazolyl, benzimidazolyl, triazolyl, thiazolyl, azotidinyl, aziridinyl radical.
The subject of the invention is more particularly the compounds of formula (I) in which Y represents an oxygen atom, those in which Y represents a NO-alkyl radical in which the alkyl radical contains up to 4 carbon atoms, for example those in which Y represents the radical NOC2H5.
Among the preferred compounds of the invention, mention may be made of the compounds of formula (I) in which X represents an alkyl radical containing up to 4 carbon atoms and in particular the radical CH, or even those in which X represents an NH 2 radical, or even those in which X represents the radical:
Among the preferred compounds of the invention, mention may be made of the compounds of formula (I) in which Ri represents a radical:
-HC = C-CH2- those in which R represents a hydrogen atom, or even those in which R3 represents a methyl radical, or even those in which Z represents a hydrogen atom, or even those in which R2 represents a hydrogen atom, or even those in which R5 represents a radical OCH3, or even those in which R6 represents a methyl radical, or even those in which R7 represents a methyl radical, those in which R represents a radical ethyl, those in which Re and R: form with the carbon that contains them a cyclopentyl radical.
Among the preferred compounds of the invention, mention may be made of the compounds whose preparation is given below in the experimental part and very particularly the compounds 1, 2, 3, 4, 5 and 9.
The products of general formula (I) possess a very good antibiotic activity on gram bacteria such as staphylococci, streptococci, pneumococci, enterococci, listeria, anaerobes.
The compounds of the invention can then be used as medicaments in the treatment of infections of sensitive germs and, particularly, those of staphylococcus, such as septicemia of staphylococci, malignant staphylococci of the face or skin, pyoderma, septic or suppurating sores, boils, carbuncles, eriphyse and acne, staphylococcus such as acute or post-acute acute angina, bronchopneumonia, pulmonary suppurations, streptococcias such as acute angina, otitis, sinusitis, scarlet fever, pneumococcal pneumonia , bronchitis and diphtheria. The products of the present invention are also active against infections due to germs such as Haemofilus influenciae.
The invention then has as its object the compounds of formula (I) in the title of medicaments.
The invention is more particularly intended for the purpose of medicaments, the compounds indicated above as preferred compounds.
The subject of the invention is also pharmaceutical compositions comprising at least one of the drugs defined above as an active ingredient.
These compositions can be administered orally, rectally, parenterally or locally via topical application on the skin and mucous membranes, but the preferred route of administration is the buccal or injectable route.
They can be solid or liquid and be presented under the pharmaceutical forms currently used in human medicine, as for example, simple or grage-dried tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels / are prepared according to the usual methods. The active ingredient (s) can be incorporated into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
These compositions can also be in the form of a powder intended to be dissolved extemporaneously in a suitable vehicle, for example sterile pyrogen-free water.
The administered dose is variable according to the poorly treated, the drug in question, the route of administration and the product considered. It can be for example, between 50 mg and 3000 mg per day by oral or injectable route, in the adult for the preferred products.
The subject of the invention is also a process for the preparation of the compounds of formula (I), characterized in that a compound of formula (II) is subjected to:
in which the radicals R2, R3, Z, R5, R6 and R7 retain their previous meaning, OW represents a blocked hydroxyl group and W 'represents an alkyl or O-alkyl radical containing up to four carbon atoms, - to the action of a agent capable of introducing the radical
O R
or a series of operations likely to introduce the radical
0 R
C-N-ORi
R and Ri retain their previous meaning,
- to the action of an agent capable of releasing the hydroxyl radical of the OW radical,
- the eventual action of an agent capable of replacing W with the radical X other than alkyl or O-alkyl,
to the eventual action of an agent capable of introducing the radical Y different from oxygen,
- to the eventual action of a salification agent.
The products of formula (II) used at the beginning of the process of the invention are new products, the preparation of certain products of formula (II) is given below in the experimental part.
The other products of formula (II) can be synthesized by analogy with the procedures described in the experimental part.
The subject of the invention is more particularly the compounds of formula (II) whose preparation is given in the experimental part.
In a preferred embodiment:
The introduction of the radical.
O R
C-N-OR1 It is made in several stages, first action of a phenylchloroformate substituted or not, then action of a compound of formula R { ONHR
In which Ri and R retain their previous meaning,
the OH group is blocked in the form of a tetrahydropyran,
the hydrolysis is released by acid hydrolysis, for example by the action of paratoluenesulfonic acid,
the eventual transformation of the radical W into radical X and the transformation of the radical Y is done according to the classical procedures. For radical Y, it is particularly the action of an amine.
Another subject of the invention is a process characterized in that the product of formula (II) is prepared by the action of a compound of formula (III)
In which R5 / R6 and R? retain their previous meaning on a compound of formula (IV)
In which R2, R3 and Z retain their previous meaning, then a blocking agent of the free hydroxyl radical.
The following compounds of formula (III) are new and are themselves an object of the present invention, namely:
The following examples illustrate the invention without limiarta in any way.
Preparation 1: 7- [[6-Deoxy-5-C-methyl-4-O-methyl-2-O- (terahydro-2H-pyran-2-yl) -alpha-L-lixo-hexapyranosyl] oxy] - 4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-ethyl carboxylate
STAGE A: 7- [(6- deoxy-5- C-methyl-4-O-methyl-alpha-L-lixo-hexopyranosyl) oxy] -8-methyl-2-oxo-4- (enylmethoxy) -2H- 1- ethyl benzopyran-3-carboxylate
A solution containing 80 g of ethyl 7- hydroxy-8-methyl-2-oxo-4- (phenylmethoxy) -2H-1-benzopyran-3-carboxylate in 1200 ml of methylene chloride is stirred under an argon atmosphere. 52.07 g of 6- deoxy-5- C-methyl-4-O-methyl-L-lixo-hexopyranose and 71.22 g of triphenylphosphine are added at 0 ° C.
A diisopropyl nitrocarboxylate is introduced at 0 ° C, 54.78 ml. After an hour of reaction at room temperature, 34 g of triphenylphosphine and 25.6 ml of diisopropyl nitrocarboxylate are again added. Stir 16 hours at room temperature. Evaporate by half, filter the suspension eluting with the toluene / isopropyl alcohol mixture (95-5). When the product begins to pass, a mixture of 6% isopropyl alcohol is continued. It is obtained after filling in 700 ml of hexane / ethyl acetate mixture (4-1), 64.4 g of investigated product which is used as such in the next step.
STAGE B: 7- [(6-deoxy-5-C-methyl-4-O-methyl-3-O- (triethylsilyl) -alpha-L-lixo-hexopyranosyl) oxy] -8-methyl- 2- oxo- 4- (phenylmethoxy) .- 2H- 1-benzopyran-3-ethyl carboxylate
50 g of a solution of step A in 500 ml of methylene chloride are stirred under an argon atmosphere at room temperature. 42 ml of diisopropylethylamine and 9.66 g of imidazole are added. The solution is stirred for 15 minutes or cooled to 0 ° C, 20.64 ml of triethylchlorosilane are added dropwise in 30 minutes and stirred for 2 hours at 0 ° C. The reaction medium is poured into a molar solution of sodium dihydrogen phosphate. It is extracted to methylene chloride. It dries and evaporates to dryness. 66.27 g of product that is purified on silica is collected eluting with a mixture of methylene chloride or 0.75% acetone. When the product is practically isolated, it is eluted with a 1% methylene chloride solution of acetone. After filling in a hexane / ethyl acetate (9-1) mixture, 41.04 g of the investigated product are obtained.
RíLN? E (300 MHz, CDC13, ppm)
0. 73 (q, 6H), 1.04 (t, 9H), 1.04 (s, 3H), 1.30 (s, 3H), 1.40 (t, 3H), 2.24 (s, 3H), 2.74 (d, J = l Hz , 1H mobile), 3.28 (d, 1H, J = 9), 3.53 (s, 3H), 4.05 (m, 1H), 4.27 (dd, 1H, J = 3.5 and 9 Hz), 4.43 (q, 2H) , 5.31 (s, 2H), 5.62 (d, 1H, J = 2 Hz), 7.12 (d, 1H, J = 9 Hz), 7.43 (, 5H), 7.63 (d, 1H, J = 9 Hz).
STAGE C: 7- [[6-deoxy-5-C-methyl-4-O-methyl-2-O- (tetrahydro-2H-pyran-2-yl) -3- O- (triethylsilyl) -alpha-L - lixo-hexopyranosyl] oxy] - 8-methyl-2-oxo-4- (phenylmethoxy) -2H-1-benzopyran-3-carboxylic acid ethyl ester
A solution containing 40.9 g of product from the preceding step in 400 ml of methylene chloride at room temperature is stirred under argon. Add a few drops of paratoluenesulfonic acid, then 11.54 ml of dihydropyran.
Stir 2 hours at room temperature. 6 g of sodium bicarbonate is added. The suspension is stirred for 15 minutes. It is diluted with 1000 ml of a hexane / ethyl acetate (2-1) mixture and poured into water. Decant, dry the organic phase over sodium sulphate and evaporate to dryness. 54.67 g of product is obtained which is purified by eluting with a hexane / ethyl acetate (4-1) mixture. This gives 36.83 g. of product.
. STAGE D: 7- [[6-deoxy-5-C-methyl-4-O-methyl-2-O- (tetrahydro-2H-pyran-2-yl) -3- O- (triethylsilyl) -alpha-L - lixo-hexopyranosyl] oxy] - 4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-carboxylic acid ethyl ester
18 g of product prepared in the preceding step are hydrogenated in solution in 360 ml of tetrahydrofuran in the presence of 0.240 g of palladium on carbon. It is filtered. The catalyst is washed with a little tetrahydrofuran. 100 ml of solvent is evaporated and a solution is obtained which is used as such in the next step.
STAGE E: 7- [[6-deoxy-5-C-methyl-4-O-methyl-2-O- (tetrahydro-2H-pyran-2-yl) -alpha-L-lixo-hexopyranosyl] oxy] - 4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-ethyl carboxylate
A solution containing 15.31 g of product from the preceding step in 250 ml of tetrahydrofuran is cooled under argon at 0 ° C. 31 ml of tetrabutylammonium fluoride (1M in THF) is added dropwise. The reaction medium is diluted with 400 ml of a hexane / ethyl acetate (1-2) mixture. 300 ml of a 10% solution of sodium hydrogensulfate and decant are added. It dries and evaporates to dryness. The crude product obtained is solubilized in 20 ml of ethyl ether. Cool to -10 ° C and add 80 ml of pentane under stirring. The suspension obtained is stirred at -20 ° C, filtered at -16 ° C. The product obtained is washed with pentane and dried. 9.4 g of the investigated product are obtained.
Preparation 2: 3-Acetyl-7- [[6-deoxy-5-C-methyl-4-O-methyl-2-O- (tetrahydro-2H-pyran-2-yl) -alpha-L-lixo-hexopyranosyl ] oxy] -4-hydroxy-8-methyl-2H-1-benzopyran- 2-ketone
STAGE A: 4- (Di-enylmethoxy) -8-methyl-7- (tetrahydro-2H-pyran-2-yl) -2H-1-benzopyran-2-ketone
55 g of 4-hydroxy-8- eyil- 7- (tetrahydro- 2H- pyran-2- yl) is introduced - 2H- 1- benzopyran-2-ketone in 250 ml of anhydrous dimethylformamide heated to 40 ° C, and added drop by drop, a solution of 58.3 g of diphenyldiazomethane in 250 ml of dimethyl formamide. The addition is made in 3 hours keeping the temperature at 40 ° C.
Again several portions of 3 g of diphenyldiazomethane are added and stirred for one hour at 40 ° C.
The reaction medium is poured onto 2 1 of sulfuric ether. The organic solution is washed with an aqueous solution of sodium bicarbonate, with a solution of soda (0.1 M), in water and in brine. It evaporates to dryness. The residue is stirred in a mixture of isopropyl ether-hexane (1-2). The insoluble dries and dries. You get 20.5 g of product investigated.
CCM CH2Cl2-AcOEt (95-5), Rf = 0.44.
STAGE B: 4- (diphenylmethoxy) -7-hydroxy-8-methyl-2H-1-benzopyran-2- -onene
ml of a solution of 0.9 M hydrochloric acid in methanol is added in a solution containing a mixture of 20 g of product from step A, 100 ml of dichloromethane and 100 ml of methanol. Stir 2 hours at room temperature and evaporate the solvents. The residue is taken in absolute ethanol cooled to 0 ° C. The insoluble is drained and rinsed in ice-cold alcohol then in sulfuric ether. Dry and collect 15.53 g of product which is taken up again in ether, drained and dried. 14.54 g of the investigated product are obtained.
NMR * H (300 MHz, CDC13, ppm)
2. 31 (s, 3H9, 5.62 (s, 1H), 6.35 (s, 1H), 6.78 (d, 1H, J = _ Hz), 7.75 (d, 1H, J = _ Hz), 6.99 to 7.10 (, _H ), 7.30 to 7.42 (m, _H).
STAGE C: 7- [(6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lixo-hexapyranosyl) oxy] -4- (diphenylmethoxy) -8-methyl-2H-1-benzopyran- 2- setona
A mixture of 91.13 g of product from step B, 58.6 g of 6- deoxy-5- C-methyl-4- 0-methyl-L-lixo-hexopyranose and 80 g of triphenylphosphine in 900 ml of water is cooled to 0 ° C. dichloromethane. 60 ml of diisopropylazodicarboxylate is added dropwise. It is stirred for 1 hour at room temperature.
34 g of triphenylphosphine and 25 ml of diisopropylazodicarboxylate are added. Stir 1 hour at room temperature. 34 g of triphenylphosphine and 25 ml of diisopropylazodicarboxylate are added and stirred for 12 hours at room temperature. It is concentrated under reduced pressure. Chromatograph eluting with a toluene / isopropyl alcohol mixture (95-5). After run of the fractions and evaporation of the solvents, it is collected after recrystallization from isopropyl ether, 86.83 g of the investigated product.
NMR aH (300 MHz, CDClj, ppm)
1. 13 (s, 3H), 1.37 (s, 3H), 2.24 (s, 3H), 2.69 (s,
1H), 2.79 (s, 1H), 3.38 (d, 1H, J = 10 Hz), 3.60 (s,
3H), 4.24 (m, 1H), 4.28 (m, 1H), 5.56 (s, 1H), 5.64 (d,
1H, J = 1.5 Hz), 6.35 (s, 1H), 7.18 (d, 1H), 7.81 (d, 1H), 7.39 (m, 10H).
STAGE D: 7- [[6-deoxy-5- C-methyl-4-O-methyl-3-O- (triethylsilyl) -alpha-L-lixo-hexopyranosyl] oxy] -4- (diphenylmethoxy) - 8-methyl-2H-1-benzopyran-2-ketone
26.6 g of imidazole and 70.15 ml of diisopropyl ethylamine are added in a solution cooled to 0 ° C, containing 80 g of the product of the preceding step and 600 ml of dichloromethane. 33.5 ml of triethylsilyl chloride is added dropwise. Stir 1 hour at room temperature. It is washed with an aqueous solution of sodium dihydrogen phosphate (1M), in water and in brine. Dry over magnesium sulfate, filter and concentrate. 97.58 g of product are collected and purified by chromatography on silica eluting with the dichloromethane acetone mixture (from 0.8 to 1%). 46.5 g of product are obtained.
H-NMR (300 MHz, CDCl3-d6, ppm)
0. 60 (q, _H, J = _Hz), 0.74 q, _H, J = _Hz), 0.97
(t, _H, J = _Hz), 1.00 (t, _H, J = _Hz), 1.10 (s, 3H),
1. 32 (s, 3H), 2.24 (s, 2H), 2.74 (s, 1H), 3.31 (d, 1H,
J = _Hz), 3.54 (s, 3H), 4.07 (m, 1H), 4.29 (dd, 1H, J =
Hz), 5.50 (s, 1H), 5.64 (d, 1H, J = Hz, 6.35 (s, 1H), 7.28 (d, 1H, J = _Hz), 7.81 (d, 1H, J = _Hz), 7.40 (m).
STAGE E: 7- [[6-deoxy-5-C-methyl-4-O-methyl-2-O-tetrahydro-2H-pyran-2-yl) -3- O- (triethylsilyl) -alpha- L-lixo-hexopyranosyl] oxy] -4- (diphenylmethoxy) -8-methyl-2H-1-benzopyran- 2-ketone
19 ml of dihydropyran and 400 mg of paratoluene sulfonic acid (APTS) are added in a solution containing 67 g of product from the preceding step and 1 1 of dichloromethane. It is stirred for 40 minutes at room temperature, 300 mg of APTS is added. After 30 minutes, 100 mg of APTS, then 100 g of APTS are added. Stir for an additional 20 minutes, then introduce finely ground sodium hydrogencarbonate. Stir for 10 minutes, dilute the reaction mixture with a hexane / ethyl acetate (1-2) mixture, wash with water and with brine. It dries. It filters and evaporates the solvents. The product obtained is chromatographed eluting with the heptane / ethyl acetate (4-1) mixture. 77.9 g of investigated product are collected.
NMR XH (300 MHz, DMSO-d6, ppm) 0.64 (q, _H, J = _Hz), 0.73 (q, _H, J = Hz), 0.95 to 1. 32 (?), 2.25 (s, _H), 2.27 (s, _H), 3.30 (d, __H, J = _Hz), 3.4 (d, _H, J = _Hz), 3.50 (m, 2H), 3.93 ( m, 2H), 3.53 (s, _H), 3.54 (s, _H), 4.04 to 4.15, 4.36 (dd, _H, J = _Hz), 4.94 (1), 4.96 (1), 5.550 (if, _H) , 5.65 (if), 6.37 (s, 1H), 7.15 (d, _H, J = _Hz), 7.19 (d, _H, J = _Hz), 7.81 (, 1H), 7.30 to 7.44, 1.47 to 2.00.
STAGE F: 7- [[6- deoxy-5- C-methyl-4-O-methyl-2-O-tetrahydro-2H-pyran-2-yl) -3- O- (trimethylsilyl) -alpha-L- lixo-hexopyranosyl] oxy] -4-hydroxy-8-methyl-2H-1-benzopyran- 2-ketone
Hydrogenate in the presence of palladium on charcoal (2 g, 10%), 15 g of the product of the preceding step in 150 ml of absolute ethanol. The catalyst is removed by filtration and the solvents are evaporated to dryness.
14.4 g of product are obtained.
. STAGE G: 3- Acetyl- 7- [[6-deoxy-5-C-methyl-4-O-methyl-2-O- (tetrahydro-2H-pyran-2-yl) -3- O- (triethylsilyl)) - alpha-L- lixo-hexopyranosyl] oxy] -4-hydroxy-8-methyl-2H-1-benzopyran-2-ketone It is added in a solution containing 14.37 g of product from the preceding step and 150 ml of dichloromethane, 6.52 g of dimethylaminopyridine. 2.72 ml of acetic anhydride is introduced dropwise. It is stirred at room temperature under argon for 1 hour. Dilute with 200 ml of dichloromethane, wash with an aqueous solution of sodium dihydrogen phosphate. Dry over magnesium sulfate, filter and concentrate. 14.9 g of the investigated product is obtained.
STAGE H: 3- Acetyl- 7- [[6-deoxy-5-C-methyl-4-methyl-2-O- (tetrahydro-2H-pyran-2-yl) -alpha-L-lixo-hexopyranosyl) ] oxy] -4-hydroxy-8-methyl-2H-1-benzopyran- 2-ketone
A mixture of 1M solution of tetrabutylammonium fluoride in tetrahydrofuran, in a solution containing 15.2 ml of product from the preceding step in 250 ml of THF, is introduced dropwise at 0 ° C. It is stirred under argon for 48 hours at ambient temperature. The medium is diluted with the ethyl acetate / hexane mixture, washed with water and with brine. It dries, filters and concentrates to dryness. You get 13 g of a product that is crushed in pentane, the supernatant is eliminated and the operation is repeated several times. The product is maintained at + 4 ° C, the crushed in the presence of pentane, it filters the insoluble rinses and dries. 6.99 g of the investigated product is obtained.
NMR? E (300 MHz, CDCl3-d6, ppm)
1. 09 (s, 3H), 1.11 (s, 3H), 1.35 (s, 3H), 1.36 (s, 1H), 1.50 to 1.90 (m, 8), 2.23 (s, 3H), 2.24 (3, 3H) , 2.76 (s, 3H), 3.28 (d, 1H, J = _Hz), 3.33 (d, 1H, J = Hz), 3. 63 (s, 3H), 3. 64 (s, 3H), 3. 54 (m), 3. 97 (m), 4. 07 (m), 4. 20 to 4. 30 (, 2H), 4.59 (m, _H), 4.82 (m, _H), 5.63 (if, _H ), 5.85 (if, _H), 7.20 * (d, 1H, J = _Hz), 7.88 (, __H).
EXAMPLE 1: 3- ([2-Deoxy-5- C-methyl-4-O-methyl-alpha-L-lixo-hexopyranosyl] oxy] -4-hydroxy acid 3- (3-propynyloxy) -carbamic acid ester 8-methyl-2-oxo-2H-1-benzopyran-3-carboxamide
STAGE A: 3- (4-nitrophenylcarbonate) of 7- [[6-deoxy-5-C-methyl-4-O-methyl-2-O- (tetrahydro-2H-piaran-2-yl) -alpha-L] - lixo-hexopyranosyl] oxy] -4- hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-carboxylic acid ethyl ester. It is dissolved in argon in 80 ml of methylene chloride, 4 g of the product of Generation 1. 2.15 g of dimethylaminopyridine is added at 0 ° C, 2 g of 4-nitrophenylchloroformate. Stir for 1 hour at 0 ° C. The methylene chloride is evaporated and the investigated product is obtained.
STAGE B: 7- [[6- deoxy-5- C-methyl-4-O-methyl-3- O - [[(2-propynyloxy) amino (carbonyl] -2-tetrahydro-2H-pyran-2) - il) - alpha-L- lixo-hexopyranosyl] oxy] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-ethyl carboxylate
1,215 g of 0-propargylhydroxylamine hydrochloride in solution are added to 40 ml of dimethylformamide.
At 0 ° C, 0.392 g of sodium hydride (50% oil) is added and stirred for one hour at this temperature. 4 ml of solution of the product prepared in the preceding step in dimethylformamide and 940 mg of dimethylaminopyridine are introduced at 0 ° C in this suspension. Stir for 1 hour at 0 ° C. It is diluted with a hexane / ethyl acetate (1-2) mixture. The organic solution is washed with 400 ml of 10% sodium hydrogen phosphate solution, dried over sodium sulphate and evaporated to dryness. 7.87 g of gross investigated product is obtained.
STAGE C: 3- ([6-Deoxy-5- C-methyl-4-O-methyl-2-O-tetrahydro-2H-pyran-2-yl] 3-ester acid - alpha-L- lixo-hexopyranosyl] oxy] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-carboxamide
50 g of tetrahydrofuran is added to solution in 2 ml of product from the preceding step. The solution obtained is saturated with ammonia at 0 ° C for 10 minutes and stirred for 48 hours at room temperature. It is diluted with 100 ml of a hexane / ethyl acetate (1-1) mixture. The organic solution is washed with 100 ml of a 1M sodium dihydrogen phosphate solution, then dried over magnesium sulphate and evaporated to dryness. 2 g of the investigated product are obtained.
STAGE D: 3- ([2-Deoxy-5- C-methyl-4-O-methyl-alpha-L-lixo-hexopyranosyl] oxy] - 4-hydroxy acid (2- propynyloxy) -carbamic acid 3'-ester - 8-methyl-2-oxo-2H-1-benzopyran-3-carboxamide
g of the product of the preceding step and 200 mg of p-toluenesulfonic acid are dissolved in 20 ml of methanol. Stir for 1 hour. It is diluted with 100 ml of hexane / ethyl acetate (1-1) mixture. It is washed with a saturated solution of sodium dihydrogen phosphate, dry and leads to dryness. 1.6 g of the product is obtained which is purified by eluting with a mixture of methylene chloride / 8% methanol. It is packed with a mixture of ethyl ether / pentane. 0.574 g of the product under investigation is obtained.
NMR "H (300 MHz, DMSO-d6, ppm)
1. 04, (s, 3H), 1.26 (s, 3H), 2.20 (s, 3H), 3.45,
(s, 3H), 3.52 (d, 1H), 3.56 (m, 1H), 4.14 (, 1H), 4.46
(m, 2H), 5.20 (, 1H), 5.59 (yes, 1H), 5.77 (d, 1H mobile), 7.22 (d, 1Hz), 7.83 (d, 1H), 8.71 (m) and 8.96
(m) (2H mobile).
EXAMPLE 2: Acid (2- propynyloxy) -carbamiso 3'-ester of 7- [(6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lixo-hexopyranosyl) oxy] -4-hydroxy - 8-methyl-N- [2- (4-morpholinyl) ethyl] -2-oxo-2H-1-benzopyran-3-carboxamide
STAGE A: 3- (2- propynyloxy) -carbamic acid 3'-7- [[6-deoxy-5- C-methyl-4-O-methyl-2-O- (tetrahydro-2H-pyran-2-yl) ester ) - alpha-L- lixo-hexopyranosyl) oxy] -4-hydroxy-8-methyl- N- [2- (4-morpholinyl) ethyl] -2-oxo-2H-1-benzopyran-3-carboxamide
7.5 ml of 2- (4-morpholino) ethylamine is introduced into a solution containing 1 g of product from step B of example 1 in 4 ml of tetrahydrofuran. It is stirred 24 hours at room temperature. It is diluted with 100 ml of hexane / ethyl acetate / tetrahydrofuran (1-4-1). It is washed with a saturated solution of sodium dihydrogen phosphate, dried over magnesium sulphate and evaporated to dryness. 1 g of the investigated product is obtained.
STAGE B: 3- (D-Deoxy-5- C-methyl-4-O-methyl-alpha-L-lixo-hexopyranosyl) oxy] - 4-hydroxy acid (2- propynyloxy) -carbamic acid 3'-ester - 8- ethyl- N- [2- (4-morpholinyl) ethyl] -2-oxo-2H-1-benzopyran-3-carboxamide
0.97 mmol of the product from the preceding step are placed in solution in 10 ml of methanol. 100 mg of p-toluenesulfonic acid is added. It is stirred for 1 hour at room temperature. 80 mg of p-toluenesulfonic acid is added again. Stir for 3 hours. It is diluted with 50 ml of hexane / ethyl acetate (1-3) mixture. It is washed with 75 ml of a 1M solution of sodium dihydrogen phosphate, dried over magnesium sulphate and evaporated to dryness. The product is purified by chromatographing on silica eluting with the methylene chloride / methanol mixture (91-9). The product obtained is mixed in an ethyl ether / pentane mixture. 0.150 g of the investigated product is obtained.
XH NMR (300 MHz, DMSO-d6, ppm)
1. 03 (s, 3H), 1.27 (s, 3H), 2.21 (s, 3H), 2.50 (simulated, 4H), 2.57 (t, 2H), 3.45 (s, 3H), from 3.40 to 3.69 (m, 4H) ), 4.13 (m, 1H), 4.47 (d, 2H, J = 2.5 Hz), 5.20 (dd, 1H, J = 3 and 10 Hz), 5.60 (d, 1H, J = 2 Hz), 5.77 (d , 1H, J = 5 Hz), 7.21 (d, 1H, J - 9 Hz), 7.84 (d, 1H, H = 9 Hz), 9.45 (t, mobile 1H), 10.72 (, mobile 1H).
EXAMPLE 3: 3- (3-propynyloxy) -carbamic acid 3'-7- [[6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lixo-hexopyranosyl] oxy] -4-hydroxy ester 3- [1- (methoxyimino) ethyl] -8-methyl-2H-1-benzopyran-2-ketone STAGE A: 7- [6-deoxy-5-C-methyl-4-O-ethyl-2-O- (tetrahydro-2H-pyran-2-yl) -alpha-L-lixo-hexopyranosyl] oxy] -4-hydroxy-3- [1- (methoxyimino) ethyl] -8-methyl-2H-1-benzopyran-2-ketone
It is heated at 40 ° C in the presence of 0.597 g of potassium acetate and 0.407 mg of 0-methylhydroxylamine hydrochloride, a solution containing 1.2 g of the product of preparation 2. it is stirred for one and a half hours at 40 ° C the reaction medium, diluted with a mixture of ethyl acetate / hexane (4-1), washed with 150 ml of sodium hydrogen phosphate solution. It is rinsed with water, dried, filtered and evaporated to dryness.
STAGE B: 3- (4-nitrophenylcarbonate) of 7- [[6-deoxy-5-C-methyl-4-O-methyl-2-O- (tetrahydro-2H-pyran-2-yl) -alpha-L - lixo-hexopyranosyl] oxy] -4- hydroxy-3- [1- (methoxyimino) ethyl] -8-methyl-2H-benzopyran-2-ketone
0.390 g of dimethylaminopyridine is added in a solution containing 1.28 mmol of the product of the preceding step and 12 ml of dichloromethane. 0.319 g of 4-nitrophenyl chloroformate is added. Stir 30 minutes at 0 ° C. The methyl chloride is evaporated and the product obtained dried. Thus 1.218 mmoles of the investigated product is obtained.
STAGE C: (2-propynyloxy) -carbamisic acid 3'-7- [[6-deoxy-5- C-methyl-4-O-methyl-2-O- (tetrahydro-2H-pyran-2-yl) ester ) - alpha-L-lixo-hexopyranosyl] oxy] -4-hydroxy-3- [1- (methoxyimino) ethyl] -8-methyl-2H-1-benzopyran-2-ketone
To a solution cooled to 0 ° C of 0.655 g of 0-propargylhydroxylamine hydrochloride in 6 ml of dimethylformamide is added 0.240 g of sodium hydride (55% of mineral oil). It is stirred for 30 minutes at 0 ° C and poured into a solution containing 1.218 mmol of the product of the preceding step and 6 ml of DMF in the presence of 0.150 g of dimethylaminopyridine. After one hour at 0 ° C, the reaction mixture was poured into a 20% ethyl acetate / hexane mixture, washed with a 10% sodium hydrogensulfate solution, with water and with brine. It dries and evaporates the solvents to dryness. 0.865 g of the investigated product is obtained.
STAGE D: (2- propynyloxy) -carbamic acid 3 '- [[6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lixo-hexopyranosyl] oxy] -4-hydroxy- ester 3- [1- (methoxyimino) ethyl] -8-methyl-2H-1-benzopyran-2-ketone
To a solution containing 1218 mmoles of the product of the preceding step and 12 ml of methanol, 150 mg of APTS is added. Stir one hour at room temperature. Dilute with a mixture of ethyl acetate / hexane (1-1) and wash with an aqueous solution of 1M sodium dihydrogenphosphate, then with brine. The organic phase is dried over magnesium sulfate. The solvents are evaporated to dryness. The product obtained is chromatographed eluting with the dichloromethane / acetone mixture (85-15), and it collects 0.394 g of product which redissolves in ether and precipitates with pentane. Insoluble is isolated by filtration and dried under reduced pressure. Thus, 0.380 g of the investigated product is obtained.
EXAMPLE 4: 2- (6- Deoxy-5- C-methyl-4-O-methyl-alpha-L-lixo-hexopyranosyl] oxy] -3- [3- (3-propynyloxy) -carbamic acid 3-ester. 1- (Ethoxyimino) ethyl] -4-hydroxy-8-methyl-2H-1-benzopyran-2-ketone By working as above, the product under investigation has been obtained.
NMR CDCI3, ppm
1. 17 (s) - 1.38 (s): 2 CH3 Gem; 1.38 (t): CH3CH20;
1. 61 (s); 4 mobile, 2.25 (s) - 2.53 (s); 2CH3- C-;
2. 57 (t); J = 2.5 h-C C-; 2.64 (yes) OH-CH; 3.54 (s);
OCH3; 3.61 (d); J = 9.5 H4 rex; 4.23 (q) CH3-CH2-0 in light failure, 4.43 (if): H2 eq; 4.57 (d): 2H 0CH2-C CH;
. 46 (dd); J = 2.5 and 9.5 H3 ox; 5.61 (d); J = 2.5 Hl eq; 7.12 (d); H '6; 7.77 (d); H'5; H mobile 7.78; 14.15 and 15.11
Absorption along the spectrum
2. 05 (acetone), 4.13, 4.75 - 4.60 - 15.67
EXAMPLE 5: [7R- (7. alpha, 8.beta., 9.beta., 10 alpha.)] - (2-propynyloxy) -carbamic acid of 8-hydroxy- 7- [4- hydroxy- 3- [ 1- (methoxyimino) ethyl] -8-methyl-2-oxo-2H-1-benzopyran-7-yl] -10-methoxy-6-oxaspiro [4.5] decans- 9 ^ yl
The preparation of this product and that of the applied starting products can be outlined as follows:
Preparation 3: [8R- (8.alpha, 9.lpha, 10.beta)] - 10-methoxy-6-oxaspiro [4.5] decane- 7, 8, 9-triol
STAGE A: [4S- C4.alfa., 5.alfa. (S *)]] - 2, 2-dimethyl-5- [(1-hydroxycyclopentyl) methoxymethyl] -1,3, dioxolane-4-methanol
ml of a dibromobutane solution (106 ml of dibromobutane in 200 ml of THF) are introduced into a mixture containing 43 g of magnesium, 100 ml of THF and a crystal of iodine. 1.7 1 THF is added. The rest of the dibromed solution is added. The stirring is maintained for 2 hours 30. A solution containing 80.37 g of 2-O-methyl-3-4- (1-methylethylidene) -L-arabononic acid-1-delta-lactone is added at 17 ° C. liter of THF. It will stir approximately 5 hours at room temperature. Cool to 0 ° C, add a saturated solution in ammonium chloride. Decant, extract the organic phase, extract with a solution of ethyl acetate at 20% heptane. It is washed, dried and evaporated to dryness. 111.85 g of the investigated product are obtained.
E APA B: [3'aS- (3'a.alpha., 7 '.alpha. 7'a.beta.]] - 1' - methoxy-dihydro-spiro [skypentane- 1, 6'- [6H] -1, 3- dioxolo [4, 5 c] - 4 '(3aH) - ketone
221 g of pyridine sulfur trioxide (PyS03) is added in a solution containing 11 g of the product prepared in step A and a mixture of one liter of methylene chloride, 1 liter of DMSO, 0.607 1 of triethylamine. Stir 2 hours at room temperature. It is poured onto an aqueous solution of sodium hydrogen phosphate, extracted with a mixture of ethyl acetate, heptane (1-1). It dries, filters and evaporates to dryness. 57.7 g of the investigated product are obtained.
STAGE C: [8R-] (8. alpha, 9. alpha, 10.beta)] - 10 methoxy-6-oxaspiro [4.5] decane- 7, 8, 9-triol
To -5 ° C, 157 ml of a 1.5 M solution of dibutylaluminum hydride in toluene in a solution containing 56 g of the product of the preceding step and 300 ml of THF is added. Stir at -3 ° C for 1 hour. 1 liter of a 1 M solution of double sodium tartrate and potassium is added. Stir 15 minutes at room temperature. The reaction medium is extracted with a mixture of ethyl acetate-heptane 1- 1. It is washed with water, with brine, dried and evaporated to dryness.
The residue obtained is stirred at 70 ° C in the presence of 150 ml of a 0.1 N sulfuric acid solution and 150 ml of water for 2.5 hours. It is cooled to room temperature, added dibium carbonate, and stirred for 1 hour at room temperature. It is filtered, and evaporated to dryness. 49 g of the investigated product are obtained.
EXAMPLE 5: [7R- (7. alpha, 8.beta., 9.beta.,
. alpha)] - (2-propynyloxy) -carbamic acid of 8-hydroxy-7- [4-hydroxy-3- [1-methoxyimino) ethyl] -8-methyl-2-oxo-2H-1-benzopyran-7-yl ] - 10- methoxy- 6- oxaspiro
[4.5] decan- 9- ilo
STAGE A: [7R- (7. alpha, 8. eta., 9.beta., 10. alpha)] - 7- [(8,9-dihydroxy-10-methoxy-6-oxaspiro [4.5] decan- 9-yl) oxy] -4- (diphenylmethoxy) -8-methyl-2H-1-benzopyran- 2-ketone
45.30 g of diisopropylazodicarboxylate (DIAD) is added dropwise at 0 ° C in a mixture of 49 g of the preparation product 3.73 g of the product from step B of preparation 2 namely 4- (diphenylmethoxy) 7-hydroxy-8-methyl-2H-1-benzopyran-2-ketone and 59 g of triphenylphosphine. One hour and a half is stirred at room temperature. One equivalent of triphenylphosphine and DIAD is added to O ° C. The solvents are evaporated, taken back into ether and the investigated product is obtained.
STAGE B: [7R- (7. alpha, 8.beta., 9.beta., 10.alpha)] - 4- (diphenylmethoxy) - 7- [[8-hydroxy-10-ethoxy- 9- [( triethylsilyl) oxy] -6-oxaspiro [4.5] decan-7-yl) oxy] -8-methyl-2H-1-benzopyran- 2-ketone
.21 g of imidazole, 40.1 ml of diisopropylamine and 18.75 g of triethylsilane chloride are added at 0 ° C in a solution containing 48 g of the product from the preceding step and 400 ml of methylene chloride. It is stirred for 1 hour at 0 ° C, washed with a 1 M solution of sodium acid phosphate and rinsed with water. It dries. The product obtained is chromatographed on silica eluting with the methylene chloride / acetone 99-1 mixture then with the toluene / tert-butyl methyl ether mixture. 28.37 g of the investigated product are obtained.
STAGE C: [7R- (7 alpha, 8 beta, 9 beta, 10 alpha)] - 4 - (diphenylmethoxy) - 7- [[10-methoxy-8- [(tetrahydro-2H - pyran-2-yl) oxy] - [(triethylsilyl) oxy] -6-oxaspiro [4. 5] decan-7-yl) oxy] -8-methyl-2H-1-benzopyran-2-ketone 7.57 ml of 3,4-dihydropyran and 400 mg of paratoluene sulphonic acid are added in a solution containing 28.1 g of the product of the preceding step and 250 ml of dichloromethane. Stir 1 hour at room temperature. Add baking soda and stir 20 minutes at room temperature. Wash with water, dry the organic phases over sodium sulfate. The product obtained is chromatographed on silica eluting with the heptane-ethyl acetate 4.1 mixture. 16.81 g of the investigated product is obtained.
STAGE D: [7R- (7. alpha, 8.beta., 9.beta.,
. alf a)] - 4-hydroxy-7- [[10-methoxy-8- [(tetrahydro-2H-pyran-2-yl) oxy] -9- [(triethylsilyl) oxy] -6-oxaspiro [4 .5 ] decan-7-yl) oxy] -8-methyl-2H-1-benzopyran- 2 -onene
A solution of 16.19 g of the product of the preceding step, 150 ml of THF, is stirred under a hydrogen atmosphere in the presence of 810 mg of palladium on carbon. Filter and obtain 15.1 g of the investigated product.
STAGE E: [7R- (7. alpha, 8.beta., 9.beta.
. alpha)] - 3-acetyl-4-hydroxy-7- [[10-methoxy-8- [(tetrahydro-2H-pyran-2-yl) oxy] -9- [(triethylsilyl) oxy] -6-oxaspiro [ 4.5] desan-7-yl) oxy] -8-methyl-2H-1-benzopyran- 2-ketone
2.28 ml of acetic anhydride is added in a mixture containing 13.8 g of product from the preceding step and 150 ml of methylene chloride and 5.94 g of dimethylaminopyridine (DMAP). It is stirred for one hour at room temperature. It is treated with a molar solution of sodium hydrogen phosphate, extracted with methylene chloride, washed with water and dried. Obtained 16.21 g of investigated product used as such in the next stage.
STAGE F: [7R- (7.alfa., 8.beta., 9.beta., 10.alpha)] - 3-acetyl-4- hydroxy- 7- [[9-hydroxy-10-methoxy- 8- [(Tetrahydro-2H-pyran-2-yl) oxy] -6-oxaspiro [4.5] decan-7-yl) oxy] -8-methyl-2H-1-benzopyran-2-ketone
Add at 0 ° C, 1.5 equivalent of a 1M solution in the THF of tetrabutylammonium fluoride, in a solution containing the product of the preceding step and 200 ml of THF. The reaction mixture is kept under stirring at room temperature for 15 hours. The reaction mixture was poured into the heptane-ethyl acetate 30-70 mixture. It was washed with water, filtered and dried. A product is obtained that is used as such in the next stage.
STAGE G: [7R- (7.alfa., '8.beta., 9.beta., 10.alpha)] - 4-hydroxy- 7- [[9-hydroxy-10-methoxy- 8- [(tetrahydro -. 2H-pyran-2-yl) oxy] -6-oxaspiro [4.5] decan-7-yl) oxy] -3- [1- (methoxyimino) ethyl] -8-methyl-2H-1-benzopyran- 2 - ketone
4.6 g of potassium acetate and 3.12 g of O-methylhydroxylamine hydrochloride are added in a solution containing 18.69 mmoles of product from the preceding step and 100 ml of ethanol. It is stirred for an hour and a half at room temperature. It is poured onto a 1M solution of sodium hydrogen phosphate, extracted with a heptane / ethyl acetate 30-70 mixture. It is washed with water, dried and evaporated to dryness. The product obtained is chromatographed with a heptane-ethyl acetate (1: 1) mixture. 6.54 g of the investigated product is obtained.
STAGE H: [7R- (7. alpha, 8.beta., 9.beta., 10. alpha)] - (2-propynyloxy) -carbamic acid of 8-hydroxy-7- [4- hydroxy- 3- [ 1- (methoxyimino) ethyl] -8-methyl-2-oxo-2H-1-benzopyran-7-yl] -10-methoxy-6-oxaspiro [4.5] decan-9-yl
1) 3.70 g of DMAP and 3.05 g of para-nitrobenzene chloro formate are introduced at 0 ° C in a solution containing 6.37 g of product from the preceding step and 70 ml of dichloromethane. Stir 1 hour at 0 ° C.
2) 2.3 g of sodium hydride is added at 0 ° C in a solution containing 6.26 g of propargylhydroxylamine hydrochloride and 50 ml of DMF. Stir 1 hour at 0 ° C. The solution (1) is concentrated to dryness. The residue obtained is put into solution in 50 ml of DMF. 1.42 g of DMAP is added. The solution is added at 0 ° C
(2) in the solution thus obtained. Stir 1 hour at 0 ° C. It is treated with sodium acid phosphate, washed with water, dried and concentrated to dryness. The residue obtained is placed in solution in 100 ml of methanol. 2.1 g of APTS is added and stirred at room temperature. The product obtained is chromatographed eluting with toluene and then with a toluene-isopropyl ether mixture 92-8. The product is dispersed under ultrasound in a mixture of isopropyl ether-pentane. The investigated product is obtained. NMR spectrum: CDC1 ppm 1.3 to 2.00 CH2 cycle
2. 20 (s) C6H5-Me 2.50 (s) N = C-Me 2.56 (t) 0-CH2-C = CH
4. 57 (d) t 3.55 (s) C-Ome 3.65 (d, J = H4ax 4.00 (s) = N-OMe 4.38 (if) H2eq 5.37 (dd) H3ax 5.51 (d) Hieq 7.00 (d)
7. 66 (d) H5 '
19 (yes) NH
Preparation 4
STAGE A:
.4 g of 2- 0-methyl-3-, 4-- (1-methylethyledene) L arabinose in 200 ml of tetrahydrofuran is placed under solution under argon. It is added at 0 ° C. under argon, 200 ml of 2M allylmagnesium bromide solution in tetrahydrofuran. The solution is stirred for 1 hour at 0 ° C. The reaction medium is cooled to -15 ° C and is diluted with 100 ml of heptane. To neutralize the excess magnesium, 300 ml of an aqueous solution of 10% sodium hydrogen sulfate is added dropwise. The organic phase is separated and the aqueous phase is extracted with a mixture of heptane 1 / ethyl acetate 1. The organic phases are combined, dried over magnesium sulphate and evaporated to dryness.
22.96 g of the investigated product is obtained.
Performance: 94%
STAGE B:
It is placed in solution under argon atmosphere, 22.96 g of the product of the preceding step in 175 ml of dimethylformamide. 14.88 g of imidazole are then added at 0 ° C under argon, dropwise over 30 minutes, 23.31 ml of diphenylbutylsilyl chloride. The solution is stirred 30 minutes at 0 ° C. The reaction medium is diluted with 400 ml of heptane 1 / ethyl acetate 2 mixture. The organic phase is washed with twice 200 ml of an aqueous solution of 1 M sodium dihydrogenphosphate, dried over magnesium sulphate and evaporated to dryness. 45 g of resin product is obtained which is purified by chromatography on silica eluting with the mixture heptane 4 / ethyl acetate 1. It is obtained: 39.5 g of product investigated.
Performance 85%
STAGE C:
.1 g of pyridinium chlorochromate in 200 ml of methylene chloride are suspended. 53.8 g of molecular sieves 4 A ° are then added. To this suspension, 39.5 g of product from the preceding step in solution in 100 ml of methylene chloride are introduced in one go. Stir for 3 hours. The suspension is filtered. Elute with a methylene chloride 3% methanol mixture. The filtrate is evaporated to dryness. The residue obtained (35 g) is filtered on silica eluting with the heptane 4 / ethyl acetate 1 mixture.
32.9 g of the investigated product are obtained.
Performance 87%
STAGE D:
32.5 g of product of the preceding step are placed in solution in 250 ml of tertrahydrofuran. Under argon, at -5 ° C, 60 ml of methylmagnesium bromide solution in ether (3M) is added dropwise. It is stirred for 1 hour at room temperature. At 0 ° C, the excess magnesium is neutralized with an aqueous solution of 10% sodium hydrogen sulfate. 200 ml of a mixture of heptanol / ethyl acetate 2 is added. The organic phase is washed with 200 ml of an aqueous solution of sodium dihydrogen phosphate (M), dried over magnesium sulphate and evaporated to dryness. The product obtained is pasted in 200 ml of pentane / ether. 16.9 g of the investigated product is obtained.
Performance: 64%
STAGE E:
16.9 g of product from the preceding step are placed in solution in 150 ml of tetrahydrofuran. Under argon, at 0 ° C, 68 ml of tetrabutylammonium fluoride in tetrahydrofuran molar solution is added dropwise. It is stirred for 30 minutes at room temperature. 200 ml of a mixture of heptane 1 / ethyl acetate 2 is added. The organic phase is washed with 200 ml of an aqueous solution of molar sodium dihydrogen phosphate, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by chromatography on silica eluting with the mixture methylene chloride 95 / methanol 5. s obtained 10.1 g of product investigated.
STAGE F:
.15 g of product from the preceding step are placed in solution in 103 ml of methylene chloride. Under argon, at room temperature, 55 ml of triethylamine and 103 ml of dimethylsulfoxide stored on molecular sieves are added. The solution is cooled to about 5 ° C with a bath of ice water and added by fraction, 19.77 g of epiridine sulfur trioxide without the temperature exceeding 15 ° C. Stir for 1 hour. The reaction medium is poured into 1 liter of aqueous solution of molar sodium dihydrogen phosphate, the aqueous phase is extracted twice with a heptane 1 / ethyl acetate 2 mixture. The organic phase is washed with water, dried over magnesium sulfate and evaporated. to dryness. The crude product is crystallized and is packed in pentane. 6.8 g of the investigated product is obtained.
Performance: 68%
STAGE G:
.3 g of the product from the preceding step are dissolved in 30 ml of tetrahydrofuran. Under argon, at -6 ° C, 13.85 ml of DIBAL is added. After 1 and a half hours of stirring at 0 ° C, the reaction is terminated. The reaction medium is poured into 100 ml of 1M sodium tartrate double potassium solution; The aqueous phase is extracted with a heptane 1 / ethyl acetate 2 mixture. The organic phase is washed with 150 ml of 10% aqueous sodium hydrogen phosphate solution, dried over magnesium sulphate and evaporated to dryness.
You get 5.5 g of product investigated.
Performance: Quantitative
STAGE H:
.5 g of the product of the preceding step are placed in solution in 32 ml of 0.05 N sulfuric acid solution. After 1 hour and a half of heating at 70 ° C, the reaction is terminated. It is allowed to return to room temperature and the reaction medium is neutralized with 0.6 g of barium carbonate. The suspension is stirred one hour at room temperature (pH = 7), then filtered and evaporated to dryness. To dry the product, two trays are made in toluene. Dry and obtain 4.4 g of the investigated product.
Performance: 96%
EXAMPLE 6:
7 - [[6- deoxy-4- O-methyl-5- C- (2-propenyl) -3-O - [[(2-propynyloxy) amino] carbonyl] -, beta.- D-gulopyranosyl] oxy] - 4-hydroxy-8-methyl-3- [1- [(2-propynyloxy) imino] ethyl] -2H- 1-benzopyran- 2-ketone Y
7 - [[6- deoxy-4- O-methyl-5- C- (2-propenyl) -3-O - [[(2-propynyloxy) amino] carbonyl] -, beta.- D-gulopyranosyl] oxy] - 4-hydroxy-3- [1-methoxyimino) ethyl] -8-methyl-2H-1-benzopyran- 2-ketone
STAGE A:
4.4 g of the product of preparation 4 in solution are placed in 100 ml of methylene chloride. At room temperature, under argon, 7.33 g of coumarin (7- hydroxy-3- [(methoxyimino) methyl] -8-methyl-4- (2-propenyloxy) -2H-1-benzopyran-2-ketone) is added. as indicated in the preparation 8 of the international patent application WO 9747634 and 6.29 g of triphenylphosphine. The suspension is cooled to 0 ° C. 3.73 ml of DEAD is added dropwise. The suspension is stirred 1 hour at room temperature. 6.06 g of triphenylphosphine are added again and at 3.degree. C. 3.11 ml of DEAD. After one hour of stirring at room temperature, 50 ml of pentane is added to precipitate the reduced DEAD. The suspension is filtered, the filtrate is evaporated to dryness and purified on silica with the eluant mixture 3% toluene then 6% isopropyl alcohol. 7.1 g of product is obtained. The product is filtered on silica 60 eluting with an ether / heptane mixture then with ether. 6.13 g of the investigated product is obtained.
STAGE B: 6 g of product from the preceding stage are placed in solution in 75 ml of tatrahydrofuran. 3.86 g of carbonyldiimidazole is added and the reaction is heated at reflux for 1 hour. The reaction medium is diluted with 100 ml of heptane 1 / ethyl acetate 2 mixture. The organic phase is washed with an aqueous solution of 10% sodium hydrogen phosphate, dried over magnesium sulphate and evaporated to dryness.
4.94 g of the investigated product is obtained.
STAGE C:
4.94 g of product from the preceding step are placed in solution in 120 ml of tetrahydrofuran. Add 8.44 ml of diisopropylamine at 0 ° C, 1.05 g of palladium tetrakistriphenyl-phosphine. It is stirred for 20 minutes at 0 ° C. The reaction medium is diluted with 50 ml of heptane 1 / ethyl acetate 2 mixture. The organic phase is washed with an aqueous solution of 10% sodium hydrogensulfate, dried over magnesium sulphate and evaporated to dryness. 5.5 g of crude product is obtained which is purified on silica by eluting with the mixture 2% acetone methylene chloride.
You get 3.1 g of product investigated,
STAGE D:
0.65 g of the product of the preceding step is put into solution in 6.5 ml of dried pyridine over potash. At room temperature, 1.5 g of propargylhydroxylamine hydrochloride and 0.149 g of lithium eperchlorate are added.
It is stirred at room temperature for 48 hours. It is diluted with a heptane 1 / ethyl acetate 2 mixture and the organic phase is washed with a 10% sodium hydrogensulfate solution, dried over magnesium sulfate. 1.8 g of product is obtained which is purified by chromatography on silica eluting with the eluent mixture 80 methylene chloride / tert-butyl methyl ether 20.
There is obtained 200 mg of investigated isomer product in 3 and 500 mg of the isomer in 2.
STAGE E:
0.5 g of the isomer in 2 obtained in the preceding step are placed in solution under argon atmosphere in 10 ml of methylene chloride. 100 μl of DNU is added. Stir 24 hours at room temperature. Dilute in 50 ml of heptane 1 / ethyl acetate 3 mixture and wash the organic phase with a 1 M sodium dihydrogen sulphate solution, dry over magnesium sulphate and evaporate to dryness. The product obtained above is put into solution in 5 ml of ethanol. At room temperature, 0.72 g of methylhydroxylamine hydrochloride and 0.94 g of sodium acetate are added. The reaction medium is stirred for 5 hours at room temperature. Dilute in 50 ml of heptane 1 / ethyl acetate 3 mixture and wash the organic phase with a 1M sodium dihydrogen sulphate solution, dry over magnesium sulphate and evaporate to dryness. 0.45 g of crude product is obtained which is purified by chromatography on silica with the eluent mixture 80/20 methylene chloride tertiary methyl ethyl ester 20.
100 mg of the investigated product is obtained.
Preparation 5
STAGE A:
.4 g of 2-O-methyl-3, 4, -O (1-methylethylidene) L-arabinose are placed in solution under argon in 200 ml of tetrahydrofuran. Add at 0 ° C under argon, 100 ml of 1 M vinylmagnesium bromide solution in tetrahydrofuran then 200 ml of 1.7 M magnesium chloride solution in tetrahydrofuran; 0.34 moles). The solution is stirred for 1 hour at room temperature. The reaction medium is cooled to -15 ° C and is diluted with 100 ml of heptane. To neutralize the excess magnesium, 300 ml of a 20% mixture of an aqueous solution of molar sodium dihydrogen phosphate in tetrahydrofuran is added dropwise. The magnesium salts precipitate. 200 ml of heptane 1 / ethyl acetate 2 and 150 mnl of a 10% solution of sodium hydrogen sulfate are added. The organic solution is dried over magnesium sulphate and evaporated to dryness. 19.3 g of the investigated product are obtained.
Performance: 83%
STAGE B:
19.3 g of the product of the preceding step are placed in solution in 150 ml of dimethylformamide. 10.8 g of imidazole is then added at 0 ° C under argon, dropwise over 30 minutes 23.4. ml of diphenyl tert-butylsilyl chloride. The solution is stirred 30 minutes at 0 ° C. The reaction medium is diluted with 400 ml of heptane 1 / ethyl acetate 2 mixture.
The organic phase is washed with an aqueous solution of 1M sodium dihydrogen phosphate dried over magnesium sulphate and evaporated to dryness. 30.2 g of resin product is obtained which is purified by chromatography on silica eluting with the mixture heptane 4: ethyl acetate 1. 30.2 g of the investigated product is obtained. Performance: 77%.
STAGE C:
19.1 g of pyridinium chlorochromate in 250 ml of methylene chloride are placed in solution. 40 g of molecular sieves of 4 A ° are then added. To this suspension, 28.19 g of product from the preceding step in solution in 100 ml of methylene chloride are introduced in one go. After 4 hours of stirring at room temperature, the reaction is terminated. It is filtered. The filtrate is evaporated to dryness. The product obtained is chromatographed on silica eluting with the heptane / ethyl acetate mixture 6- 1. 10.5 g of the investigated product are obtained. Yield 36%.
STAGE D:
g of product from the preceding step are placed in solution in 100 ml of tetrahydrofuran. Under argon, at -5 ° C, 14 ml of methylmagnesium bromide solution in 3M ether is added dropwise. It is stirred 30 minutes at 0 ° C, neutralizes the excess magnesium with an aqueous solution of sodium hydrogen sulfate. to 10%. 200 ml of heptane 1 / ethyl acetate 2 mixture is added. The organic phase is washed with 200 ml of an aqueous solution of molar sodium dihydrogen phosphate, dried over magnesium sulphate and evaporated to dryness. The crude product is purified on silica eluting with the heptane 4 / ethyl acetate 1 mixture. The product obtained is pentane packed. 2.76 g of the investigated product is obtained.
Performance: 27
STAGE E:
2.79 g of the product of the preceding step is placed in solution in 15 ml of tetrahydrofuran. Under argon, at 0 ° C, 11.8 ml of tetrabutylammonium fluoride in tetrahydrofuran is added dropwise. Stir 1 hour at room temperature. 200 ml of a mixture of heptane 1 / ethyl acetate 2 is added. The organic phase is washed with 200 ml of an aqueous solution of molar sodium dihydrogen phosphate, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by silica chromatography eluting with the mixture 5% methylene chloride in methanol. 1.2 g of investigated product is obtained.
Performance: 86%
STAGE F:
1.2 g of the product from the preceding step are dissolved in 12.5 ml of methylene chloride. Under argon, at room temperature, 6.67 ml of triethylamine and 12.5 ml of dimethylsulfoxide stored on molecular sieves are added. The solution is cooled to approximately 5 ° C with a bath of ice water and 2.39 g of pyridine sulfotrioxide is added per fraction without the temperature exceeding 15 ° C. After 1 hour of stirring at room temperature, the reaction is terminated. Stir 1 hour at room temperature. The reaction medium is poured into 100 ml of sodium morphine dihydrogen phosphate broth solution, the aqueous phase is extracted twice with a heptane 1 / ethyl acetate 2 mixture. The organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness. The product obtained in pentane is pasted. 0.75 g of the investigated product is obtained.
Performance: 59%
STAGE G:
0.73 g of product from the preceding step is placed in solution in 30 ml of tetrahydrofuran. Under Argon, a-6 Stir 1 and a half hours at -6 ° C. the reaction medium is poured into a 1M solution of sodium and potassium double tartrate; The aqueous phase is extracted with a heptane-1 / ethyl acetate 2 mixture. The organic phase is washed with an aqueous solution of 10% sodium hydrogensulfate, dried over magnesium sulphate and evaporated to dryness. The product obtained in pentane is pasted. 0.95 g of the investigated product is obtained.
Quantitative performance.
STAGE H:
0.9 g of product from the preceding step is placed in an emulsion in 5 ml of 0.05 N sulfuric acid. After 1 hour of heating at 70 ° C, the reaction is terminated. Let it return to room temperature; the reaction medium is extracted with pentane and the aqueous phase is neutralized with 0.1 g of barium carbonate (the suspension is stirred one hour at room temperature (pH = 7), then filtered and evaporated to dryness. two trays with toluene, then it is solubilized in methylene chloride, the solution is dried over magnesium sulphate and evaporated to dryness 0.5 g of the investigated product is obtained.
Yield 86%.
EXAMPLE 7:
7- [[6- deoxy-5- C-ethenyl-4-O-methyl-3- O - [[(2-propynyloxy) amino] carbonyl] -. Beta-D-gulopyranosyl] oxy] -4-hydroxy 3- [1- (methoxyimino) ethyl] -8-methyl-2H-1-benzopyran-2-ketone.
STAGE A:
0.5 g of product from preparation 5 is dissolved in 17 ml of methylene chloride. At room temperature, under argon, 0.89 g of coumarin prepared as indicated in the international patent application W09747634 and 0.76 g of triphenylphosphine are added. The suspension is cooled to 0 ° C, 0.45 ml of DEAD is added dropwise. The suspension is stirred 1 hour at room temperature. Again add 0.63 g of triphenylphosphine and at 0 ° C, 0.37 ml of DEAD. A yellow solution is obtained. After 1 hour of stirring at room temperature, 10 ml of pentane is added to precipitate the reduced DEAD. The suspension is filtered, the filtrate is evaporated to dryness and purified by chromatography on silica with the eluent mixture toluene 97 / isopropyl alcohol 3 (elution is terminated with 6%). The product obtained in the mixture is then filtered on silica 60 eluting with the mixture heptane 1 / ether 2 then ether. 0.55 g of white crystals is obtained. Performance: 47
STAGE B:
A solution of o.55 g of the product from the preceding step is placed in solution of 7 ml of tetrahydrofuran. 0.364 g of carbonyl diimidazole is added and the reaction mixture is heated at reflux for 1 hour. The reaction medium is diluted with 40 ml of heptane 1 / ethyl acetate 2 mixture. The organic phase is washed with 50 ml of an aqueous solution of 10% sodium hydrogensulfate, dried over magnesium sulphate and evaporated to dryness. 0.5 g of the investigated product is obtained.
Performance: 88%
STAGE C:
0.5 g of product from the preceding step is placed in solution in 12 ml of tetrahydrofuran. 0.82 ml of diisopropylamine is added and at 0 ° C, 0.11 g of palladium tetrakistriphenylphosphine (0.1 equivalent). It is stirred for 20 minutes at 0 ° C. The reaction medium is diluted with 50 ml of heptane 1 / ethyl acetate 2 mixture. The organic phase is washed with 50 ml of 10% sodium hydrogen sulfate solution, dried over magnesium sulphate and evaporated to dryness. 0.58 g of crude product is obtained which is purified by chromatography on silica eluting with the mixture heptane 3 / ethyl acetate 1. 0.257 g of product investigated is obtained.
Performance: 57% STAGE D:
0.257 g of the product from the preceding step is dissolved in 2.5 ml of dried pyridine over potash. At room temperature, 0.58 g of propargylhydroxylamine hydrochloride and 0.057 g of lithium perchlorate are added. The reaction medium is stirred 48 hours at room temperature. It is diluted with a heptane 1 / ethyl acetate 2 mixture and the organic phase is washed with a 10% sodium hydrogensulfate solution, dried over magnesium sulfate. 0.28 -g of the investigated product is obtained. The obtained crude product is put into solution in 5 ml of ethanol, 0.45 g of methylhydroxylamine hydrochloride and 0.58 g of acetate are added. The reaction medium is stirred for 5 hours at room temperature. It is diluted with a heptane 1 / ethyl acetate 2 mixture and the organic phase is washed with a solution of sodium dihydrogen phosphate (1M), dried over magnesium sulphate and evaporated to dryness. 0.3 g of crude product is obtained which is purified by chromatography on silica eluting with the mixture methylene chloride 80 / ethyl acetate 19 / acetic acid 1. 0.90 g of the investigated product is obtained.
Performance: 31%.
Preparation 6:
STAGE A:
.5 g is placed in solution in 110 ml of tetrahydrofuran. Under argon, at -6 ° C, 329 ml of zinc tetraborohydride solution at 0.135 M in ether is added. Allow to stir for 30 minutes without ice bath, the reaction is then finished. A solution of sodium dihydrogen phosphate (M) is added. The aqueous phase is extracted with a heptane 1 / ethyl acetate 2 mixture. The organic phase is dried over magnesium sulphate and evaporated to dryness. 10.5 g of the investigated product is obtained, which is purified by chromatography eluting with the mixture heptane 4 / ethyl acetate 1. 8.75 g of the investigated product is obtained.
Performance: 83%
STAGE B:
8.75 g of product from the preceding step are placed in solution in 100 ml of tetrahydrofuran. Under argon, at 0 ° C, 37 ml of molar solution of tetrabutylammonium fluoride in tetrahydrofuran is added. After 30 minutes of stirring at 0 ° C, 200 ml of a mixture of heptane 1 / ethyl acetate 2 is added. The organic phase is washed with 200 ml of an aqueous solution of molar sodium dihydrogen phosphate, dried over magnesium sulfate. and evaporated to dryness. The crude product (10.5 g) is purified by chromatography eluting on silica the 20% acetone methylene chloride mixture. 3.6 g of the investigated product is obtained.
Performance: 78%
STAGE C:
3.57 g of product from the preceding step are placed in 38 ml of methylene chloride. Under argon, at room temperature, 20.5 ml of triethylamine and 38 ml of dimethylsulfoxide are added. The solution is cooled to ca.5 and 7.5 g of sulfur trioxide and pyrimidine are added without the temperature exceeding 15 ° C. It is stirred for 2 hours. The reaction medium is poured into 500 ml of aqueous solution of molar sodium dihydrogen phosphate, the aqueous phase is extracted twice with a heptane 1 / ethyl acetate 2 mixture. The organic phase is washed with twice 500 ml of water, dried over Magnesium sulphate and evaporated to dryness. The crude product crystallizes and is bound in pentane. 1.92 g of the investigated product is obtained.
Performance: 56%
STAGE D:
1.9 g of product from the preceding step are dissolved in 10 ml of tetrahydrofuran. Under argon, at 0 ° C, 6.66 ml of 1.5 M solution of DIBAL in toluene is added. It is stirred for 1 hour and a half. The reaction medium is poured into 100 ml of 1M sodium tartrate double potassium solution; The aqueous phase is extracted with a heptane 1 / ethyl acetate 2 mixture.
The organic phase is washed with 150 ml of 10% aqueous sodium hydrogen phosphate solution, dried over magnesium sulphate and evaporated to dryness.
1.9 g of the investigated product is obtained.
Performance: Quantitative
STAGE E:
1.95 g of the product of the preceding step is put into emulsion in 11.5 ml of 0.05 N sulfuric acid solution. It is heated for 1 hour and measured at 70 ° C. it is allowed to return to room temperature and the reaction medium is neutralized with 0.3 g of barium carbonate. The suspension is stirred one hour at room temperature (pH = 7), then filtered and evaporated to dryness. To dry the product, two trays are made with toluene. After drying (one night at 40 ° C in the presence of P205), 1.2 g of the investigated product are obtained.
Performance: Quantitative
EXAMPLE 8:
7- [(6-deoxy-6-methyl-4-O-methyl-3-O [[(2-propynyloxy) -amino] carbonyl] - .alpha.-L-mannopyranosyl) oxy] -4- hydroxy-8-methyl-3- [1- [(2-propynyloxy) imino] ethyl] -2H-1-benzopyran-3-yl] -2-acetone
7- [(6-deoxy-6-methyl-4-O-methyl-3- O - [[(2-propynyloxy) -amino] sarbonyl] - .alpha.-L-mannopyranosyl) or? I] ~ 4- hydroxy-3- [1- (methoxyimino) -ethyl] -8-methyl-2H-1-benzopyran-3-yl] -2-ketone
E APA A:
1.16 g of the product of Preparation 6 are dissolved in 25 ml of methylene chloride. At room temperature, under argon, 2.19 g of coumarin 7- hydroxy-3- [(methoxyimino) methyl] -8-ethyl-4- (2-propenyloxy) -2H-1-benzopyran-2-ketone prepared as indicated in the international patent application W09747634 and 1.89 g of triphenylphosphine. The suspension is cooled to 0 ° C, 1.12 ml of DEAD is added dropwise. The suspension is stirred 1 hour at room temperature. Another 1.58 g of triphenylphosphine is added at 0 ° C, 0.93 ml of DEAD. After 1 hour of stirring at room temperature, 50 ml of pentane is added to precipitate the reduced DEAD. The suspension is filtered, the filtrate is evaporated to dryness and purified by chromatography on silica eluting with the mixture toluene at 3% isopropyl alcohol. 0.870 g of white crystals and 0.850 g of mixture containing traces of reduced DEAD are obtained. The product is filtered rapidly over 100 g of silica 60 eluting with ether. 0.4 g of the investigated product is obtained.
Total weight: 1.27.g. Performance: 44 STAGE B:
1.27 g of the product of the preceding step are placed in solution in 10 ml of tetrahydrofuran. 0.85 g of carbonyldiimidazole is added and heated at reflux for 1 hour. The reaction medium is diluted with 50 ml of heptane 1 / ethyl acetate 2 mixture. The organic phase is washed twice with 50 ml of an aqueous solution of 10% sodium hydrogensulfate, dried over magnesium sulphate and evaporated to dryness. You get 1.41 g of product investigated.
Performance: Quantitative
STAGE C:
0.6 g of the product from the preceding step is placed in solution in 6.5 ml of dried pyridine over potash. At room temperature, 1.5 g of the propargylhydroxylamine hydrochloride and 0.149 of lithium perchlorate are added. It is stirred for 48 hours at room temperature. It is diluted with a heptane 1 / ethyl acetate 2 mixture and the organic phase is washed with a 10% sodium hydrogensulfate solution, dried over magnesium sulfate. 1.8 g of product is obtained which is chromatographed on silica eluting with the mixture methylene chloride 80 / ethyl acetate 19 / acetic acid 1. 186 mg of the isomer product is obtained in 3, 400 mg of isomer in 2.
Yield: 74 _ carbonate opening of which 30% isomer in 3.
STAGE D:
0.4 g of product from the preceding step (isomer in 2) is dissolved in 10 ml of methylene chloride. 100 μl of DBU is added. It is stirred for 24 hours at room temperature. It is diluted with a heptane 1 / ethyl acetate 2 mixture and the organic phase is washed with a 1M sodium dihydrogen phosphate solution, dried over magnesium sulphate and evaporated to dryness. In a 100 ml balloon, 0.4 g of the mixture obtained above is put into solution in 10 ml of ethanol. At room temperature, 0.59 g of methylhydroxylamine hydrochloride and 0.76 g of sodium acetate are added. The reaction medium is stirred for 5 hours at room temperature. It is diluted with a heptane 1 / ethyl acetate 2 mixture and the organic phase is washed with a 1M sodium dihydrogen phosphate solution, dried over magnesium sulphate and evaporated to dryness. 0.45 g of crude product is obtained which is purified on silica with the eluent mixture methylene chloride 80 / ethyl acetate 19 / acetic acid 1. only the expected isomer is isolated. 0.140 g of the investigated product is obtained.
Performance: 37%
Preparation 7
STAGE A.
26.2 g of low product argon in 250 ml of tetrahydrofuran are added to the solution. At 0 ° C under argon, dropwise, 400 ml of 1 M ethylmagnesium bromide solution in tetrahydrofuran is added. The solution is stirred 2 hours at room temperature. The reaction medium is cooled to 0 ° C and diluted with 100 ml of heptane. To neutralize the excess magnesium, 300 ml of an aqueous solution of dihydrogen phosphate is added dropwise. of sodium molar. The magnesium salts precipitate. 200 ml of a mixture of heptane 1 / ethyl acetate 2 and 150 ml of a 10% solution of sodium hydrogen sulfate are added. The organic solution is dried over magnesium sulphate and evaporated to dryness.
29 g of product is obtained which is chromatographed on silica eluting with the heptane 1 / ethyl acetate 4 mixture. 17 g of the investigated product are obtained. Yield 52%
STAGE B:
16.7 g of the product of the preceding step are placed in solution under argon in 150 ml of dimethylformamide. 10.07 g of imidazole are then added at 0 ° C under argon, dropwise over 30 minutes, 19.23 ml of diphenyl tert-butylsilyl chloride.
The solution is stirred 1 hour and a half at room temperature.
The reaction medium is diluted with 400 ml of heptane 1 / ethyl acetate 2 mixture. The organic phase is washed with an aqueous solution of molar sodium dihydrogen phosphate, dried over magnesium sulphate and evaporated to dryness.
38 g of product is obtained which is purified by chromatography on silica eluting with the mixture methylene chloride at 10% acetone. You get: 33.23 g of product investigated.
Performance: Quantitative
STAGE C:
22.57 g of 0.104 mol pyridinium chlorocromate in 300 ml of methylene chloride are suspended. 110 g of molecular sieves 4 A ° is then added. To this suspension, 33 g of product of the preceding step in solution in 100 ml of methylene chloride is introduced. After 3 hours of stirring at room temperature, the suspension is filtered. The filtrate is evaporated to dryness. The residue obtained (35 g) is purified on silica with the eluent mixture heptane 4 / ethyl acetate 1. 27 g of the investigated product is obtained.
Performance: 83%
STAGE D:
16.5 g of product from the preceding step are placed in solution in 150 ml of tetrahydrofuran. Under argon, at -5 ° C, 17.52 ml of solution (3M) of methylmagnesium bromide in ether is added dropwise. Stir 1 hour at room temperature. At 0 ° C, the excess magnesium is neutralized with an aqueous solution of 1 M sodium dihydrogen phosphate. 200 ml of a mixture of heptane 1 / ethyl acetate 2 is added. The organic phase is washed with 200 ml of an aqueous solution. of sodium dihydrogen phosphate molar, dried over magnesium sulphate and evaporated to dryness. The product obtained is pentane packed.
Obtained 14.85 g of product investigated.
Performance: 87%
STAGE E:
14.85 g of product from the preceding step are placed in solution in 150 ml of tetrahydrofuran. Under argon, at 0 ° C, 33 ml of tetrabutylammonium fluoride in tetrahydrofuran molar solution is added dropwise. After 30 minutes of stirring at room temperature, the reaction is terminated. 200 ml of a mixture of heptane 1 / ethyl acetate 2 is added. The organic phase is washed with 200 ml of an aqueous solution of molar sodium dihydrogen phosphate, dried over magnesium sulphate and evaporated to dryness. The crude product is purified on silica eluting with the mixture methylene chloride 15% acetone then 30% acetone. 7.85 g of the investigated product are obtained.
Performance: Quantitative
STAGE F:
7.85 g of the product from the preceding step are dissolved in 82.5 ml of methylene chloride. Under argon, at room temperature, 44.5 ml of triethylamine and 82.5 ml of dimethylsulfoxide stored in molecular sieves are added. The solution is cooled to approximately 5 ° C with a bath of ice water and 15.8 g of pyridine sulfur trioxide are added per fraction without the temperature exceeding 15 ° C. Stir for 1 hour. The reaction medium is poured into 1 liter of aqueous solution of molar sodium dihydrogen phosphate.
The aqueous phase is extracted with a mixture of heptane 1 / ethyl acetate 4. The organic phase is washed with water dried over magnesium sulfate and evaporated to dryness.
The product obtained is pasted in pentane.
You get 5.77 g of product investigated
Performance: 80%
STAGE G:
.46 g of product from the preceding step are placed in solution in 25 ml of tetrahydrofuran. Under argon, at 0 ° C, 16.7 ml of 1.5 M solution of DIBAL in toluene is added.
It is stirred for an hour and a half at 0 ° C. The reaction medium is poured into 250 ml of 1M solution of double sodium tartrate and potassium; The aqueous phase is extracted with a heptane 1 / ethyl acetate 2 mixture.
The organic phase is washed with 150 ml of 10% aqueous sodium sulfate solution, dried over magnesium sulphate and evaporated to dryness. You get 5.5 g of product investigated. Performance: Quantitative
STAGE H:
.5 g of the product from the preceding step are put into emulsion in 32 ml of 0.05 N sulfuric acid solution. After one and a half hours of heating at 70 ° C, the reaction is terminated. It is allowed to return to room temperature and the reaction medium is neutralized with 0.6 g of barium carbonate; the suspension is stirred one hour at room temperature
(pH = 7), then filtered on milipore filter paper evaporated to dryness. To dry the product, two trays are made with toluene. It is dried at 40 ° C in the presence of P205, 4.8 g of white gummy residue is obtained.
Quantitative performance.
EXAMPLE 9
Acid (2- propynyloxy) - sarbámiso 3 'ester of 7. [(6-deoxy-5-C-ethyl-4-O-methyl- etha-D-gulopyranosyl) oxy] -4-hydroxy-8-methyl - 3- [1- [(2-propynyloxy) imino] ethyl] -2H-1-benzopyran-2-ketone.
3- (3-propynyloxy) -carbamic acid 3- [(6-deoxy-5-C-ethyl-4-O-methyl-β-beta-D-gulopyranosyl) oxy] -4-hydroxy-3- [1-ester - (methoxyimino) ethyl] -8-methyl-2H-1-benzopyran-2-ketone.
Acid (2- propynyloxy) - carbamic 3 'ester of 7.
[(6- deoxy-5- C-ethyl-4-O-methyl-β-beta-D-gulopyranosyl) oxy] -3- [1- (ethoxyimino) ethyl] -4-hydroxy-8-methyl-2H- 1- benzopyran- 2- ketone.
STAGE A:
4.8 g of product of preparation 7 is dissolved in 100 ml of methylene chloride. At room temperature, under argon, 9.98 g of coumarin and 7.23 g of triphenylphosphine are added. The suspension is cooled to 0 ° C, 4.34 ml of DEAD is added dropwise. The slightly yellow suspension is stirred 1 hour at room temperature. 6 g of triphenylphosphine are again added and at 3.5 ° C 3.57 ml of DEAD. A yellow solution is obtained. After 1 hour of stirring at room temperature, 50 ml of pentane is added to precipitate the reduced DEAD. The suspension is filtered, the filtrate is evaporated to dryness and purified over 1750 kg of silica 60 with the eluent mixture toluene 3% then 6% isopropyl alcohol. 10 g of white crystals containing traces of reduced DEAD are obtained. The product is filtered rapidly over silica 60 with the eluent mixture heptane 1 / ethyl acetate 2 to remove the reduced DEAD, then with the mixture methylene chloride 95 / methanol 5 to obtain 7.3 g of expected product. Performance: 58%
STAGE B:
7.2 g of the product of the preceding step is introduced into 100 ml of THF. 4.41 g of diimidazole carbonate is added and it is heated at reflux for one hour. Pour into 150 ml of 10% hydrogen phosphate solution and extract with a mixture of hexane ethyl acetate. Dry and obtain 7.1 g of product investigated.
STAGE C:
7.1 g of product are placed in solution in 100 ml of tetrahydrofuran. 0.7 g of palladium on carbon is added and put under a hydrogen atmosphere. After 3 hours of stirring, the reaction is complete. The reaction medium is filtered and the filtrate is evaporated to dryness. The product is recrystallized from an ether / pentane mixture.
4.75 g of the investigated product is obtained.
Performance: 95%
STAGE D:
1.5 g of product obtained in the preceding step are placed in solution in 25 ml of methylene chloride. 0.99 g of dimethylaminopyridine is added and under argon, at 0
° C, dropwise, 0.38 ml of acetic anhydride After 30 minutes of stirring at 0 ° C, 95 μl of acetic anhydride and 0.225 g of dimethylaminopyridine are added. It is stirred 45 minutes. The reaction medium is diluted with
100 ml of heptane 1 / ethyl acetate 2 mixture. The organic phase is washed twice with 150 ml of a 1M sodium dihydrogenphosphate aqueous solution, dried over magnesium sulphate and evaporated to dryness. The expected product is isolated. You get 1.56 g of product investigated.
Performance: 93% STAGE E:
1.5 g of the product of the preceding step is placed in solution in 15 ml of dried pyridine over potash. At room temperature, 3.6 g of the propargyl-hydroxylamine hydrochloride and 0.36 g of lithium perchlorate are added. The reaction medium is stirred 48 hours at room temperature. It is diluted with a heptane 1 / ethyl acetate 2 mixture and the organic phase is washed with a 10% sodium dihydrogen sulphate solution, dried over magnesium sulfate.
1.8 g of the investigated product are obtained, 200 mg of this crude product is purified on silica with the eluent mixture methylene chloride 80 / terbutilmethylether 20. 90 mg of the investigated product is obtained, isomer in 3 and 75 mg of isomer in 2.
Yield: 77% 55/45 in isomer 3
STAGE F:
0.5 g of product from the preceding step is placed in solution in 5 ml of ethanol. At room temperature, 0.85 g of methylhydroxylamine hydrochloride and 0.94 g of potassium acetate are added. The reaction medium is stirred for 5 hours at room temperature. It is diluted with a mixture of heptane 1 / ethyl acetate 2 and the organic phase is washed with a 1M sodium dihydrogen phosphate solution, dried over magnesium sulphate and evaporated to dryness. A crude product is obtained which is purified on silica with the eluent mixture 20% methylene chloride of tert-butyl methyl ether.
You get: 0.095 g of product investigated.
STAGE G:
It is operated as indicated in step F using
0. 85 g of ethyl hydroxylamine hydrochloride. 0.104 g of the expected product isomer is obtained in 3.
EXAMPLE 10
3- (3-propynyloxy) -carbamic acid 3 '- 7 - [(6-deoxy-5-C-ethyl-4-O-methyl-β-beta-D-gulopyranosyl) oxy] -3- [1- ( methoxyimino) propyl] -4-hydroxy-8-methyl-2H-1-benzopyran- 2-ketone STAGE A:
0.6 g of the product obtained as in step C of example 9 is placed in solution in 15 ml of methylene chloride. 0.36 g of dimethylaminopyridine is added and under argon, at 0 ° C, dropwise, 0.20 g of propionic anhydride. It is stirred 30 minutes at 0 ° CC and then one hour at room temperature. The reaction medium is diluted with 100 ml of heptane 1 / ethyl acetate 2 mixture. The organic phase is washed with an aqueous solution of 1M sodium dihydrogen phosphate, dried over magnesium sulphate and evaporated to dryness. 0.6 g of investigated product is obtained.
Performance: 68%
STAGE B:
0.6 g of the product from the preceding step is placed in solution in 6 ml of dried pyridine over potash. At room temperature, 1.39 g of the propargylhydroxylamine hydrochloride and 0.13 g of perchlorate d elite are added. The reaction medium is stirred 48 hours at room temperature. It is diluted with a heptane 1 / ethyl acetate 2 mixture and the organic phase is washed with a 10% sodium dihydrogen sulphate solution, dried over magnesium sulfate. 0.56 g of product is obtained which is put into solution in 10 ml of ethanol, 1.07 g of methylhydroxylamine hydrochloride and 1.39 g of sodium acetate are added. The reaction medium is stirred for 5 hours at room temperature. It is diluted with a heptane 1 / ethyl acetate 2 mixture and the organic phase is washed with a 1M sodium dihydrogen phosphate solution, dried over magnesium sulphate and evaporated to dryness. 0.45 g of crude product is obtained which is purified by chromatography on silica eluting with the mixture 20% methylene chloride of tert-butyl methyl ether. Obtained 0.170 g of product investigated.
Operating as before, the products that respond to the formula have also been prepared:
R 0 (CHa) 2Br
OCH 2 ^
OC v
twenty
H Operating as previously has been obtained the following products that respond to the formula (I):
Operating as before, the following products have been prepared:
3- (3- [1- [[(5-Chloro-1,2,3-thiadiazol-4-yl) methoxy] imino] ethyl] -7- [(6-propynyloxy) -carbamic acid 3- (3-ester) - deoxy-5- C-methyl-4-O-methyl-, alpha-L-lixo-hexopyranosyl) oxy] -4-hydroxy-8-methyl-2H-1-benzopyran- 2-ketone
3- (1- [[[(Cyanomethoxy] imino] ethyl] -7- [(6-deoxy-5- C-methyl-4-O-methyl-alpha-) 3- (3- propynyloxy) -carbamic acid ester L- lixo-hexopyranosyl) oxy] -4- hydroxy-8-methyl-2H-1-benzopyran- 2-ketone
3 - [1- [[(2-Aminoethoxy] imino] ethyl] -7- [(6-deoxy-5- C-methyl-4-O-methyl- 3- (3-propynyloxy) -carbamic acid 3'- ester alpha-L-lixo-hexopyranosyl) oxy] -4- hydroxy-8-methyl-2H-1-benzopyran-2-ketone (7-[(6-deoxy-5-deoxy) -3- (3-propynyloxy) -carbamic acid - C-Methyl-4,0-methyl-alpha-L-lixo-hexopyranosyl) oxy] -4-hydroxy-8-methyl-3 [1- [1- [(2-hydroxyethoxy) imino] ethyl] -2H- 1- benzopyran- 2- ketone
Acid (2- propynyloxy) -carbamic 3'- ester of 7 - [(6-deoxy-5-C-methyl-4-methyl-alpha-L-lixo-hexopyranosyl) oxy] -4- hydroxy- 8- methyl- 3- [1- [[1- [3-piperidinyl) oxy] imino] ethyl] -2H- 1-benzopyran-2-ketone (isomer B)
Acid (2- propynyloxy) -carbamic 3'- ester of 7 - [(6-deoxy-5-C-methyl-4-methyl-alpha-L-lixo-hexopyranosyl) oxy] -4- hydroxy- 8- methyl- 3- [1- [[1- [3-piperidinyl) oxy] imino] ethyl] -2H-1-benzopyran-2-ketone (isomer A)
Acid (2- propynyloxy) -carbamic 3'- ester of 7 - [(6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lixo-hexopyranosyl) oxy] -4- hydroxy- 8- methyl-3- [1- [1-methylethoxy) imino] ethyl] -2H-1-benzopyran- 2-ketone
3- (3- [1- [(Cyclobutyloxy) imino] ethyl] -7- [(6-deoxy-5-C-methyl-4-O-methyl-alpha-L) -3- (3-propynyloxy) -carbamic acid - lixo-hexopyranosyl) oxy] -4-hydroxy-8-methyl-2H-1-benzopyran-2-ketone
Acid (2- propynyloxy) -carbamic 3'- ester of 7 - [(6-deoxy-5-C-methyl-4-methyl-alpha-L-lixo-hexopyranosyl) oxy] -4- hydroxy- 8- methyl-2H-1-benzopyran- 2-ketone
Acid (2- propynyloxy) -carbamic 3'- ester of 7 - [(6-deoxy-5-C-methyl-4-O-methyl-α-alpha-L-lixo-hexopiranssyl) oxy] -4-hydroxy- 8- methyl- 3- [1- [2, 2,
2, -trifluoroethoxy) imino] ethyl] -2H-1-benzopyran-2-ketone
Acid (2- propynyloxy) -carbamic 3'- ester of 7- [(6-deoxy-5- C-methyl-4-methyl-methyl-L-lixo-hexopyranosyl) oxy] -4-hydroxy- 8-methyl-3- [1 - [[(pentafluorophenyl) methoxy] imino] ethyl] -2H-1-benzopyran- 2-ketone
Acid (2- propynyloxy) -carbamic 3'- ester of 7 - [(6-deoxy-5- C-methyl-4-methyl-methyl-L-lixo-hexopyranosyl) oxy] -4-hydroxy- 8-methyl-3- [1- [[3- [4- (3-pyridyl) -1H-imidazol-1-yl] -propoxy] imino] ethyl] -2H- 1-benzopyran-2-ketone Acid (2- propynyloxy) -carbamic 3'- ester of 7- [(6-deoxy-5- C-methyl-4-methyl-methyl-L-lixo-hexopyranosyl) oxy] -4-hydroxy-8-methyl- 3- [1- [[2- (1-piperidinyl) -ethoxy] -imino] ethyl] -2H-1-benzopyran- 2-ketone
Acid (2- propynyloxy) -carbamic 3'- ester of 7- [(6-deoxy-5- C-methyl-4-methyl-methyl-L-lixo-hexopyranosyl) oxy] -4-hydroxy- 8-methyl-3- [1- [[2- (4-raorpholinyl) -ethoxy] -imino] ethyl] -2H-1-benzopyran- 2-ketone
Acid (2- propynyloxy) -carbamic 3'- ester of 7- [(6-deoxy-5-C-methyl-4-O-methyl-α-alpha-L-lixo-hexopyranosyl) oxy] -4-hydroxy- 8-methyl-3- [1- (methoxyimino) propyl] -2H-1-benzopyran- 2-ketone
Acid (2- propynyloxy) -carbamic 3'- ester of 7- [(6-deoxy-5-C-methyl-4-methyl-α-alpha-L-lixo- • hexopyranosyl) oxy] -4-hydroxy - 8- methyl- 3- [1- [(2,
2, 2- trifluoroethoxy) imino) propyl] -2H- 1-benzopyran- 2-ketone
Acid (2- propynyloxy) -carbamic 3'- ester of 7 - [(6-deoxy-5-C-methyl-4-O-methyl-α-alpha-L-lixo-hexopyranosyl) oxy] -4-hydroxy- 8-methyl-3- [1- (propoxyiminium) propyl] -2H-1-benzopyran- 2-ketone
Acid (2- propynyloxy) -carbamic 3'- ester of 7 - [(6-deoxy-5-C-methyl-4-O-methyl-α-alpha-L-lixo-hexopyranosyl) oxy] -3- [1 - (ethoxyimino) propyl] -4-hydroxy-8-methyl-2H-1-benzopyran- 2-ketone
7- [(6- deoxy-5- C-methyl-4-O-methyl-3- {- [[(2-propynyloxy) amino] carbonyl] - .alpha.- L- lixo-hexopyranosyl) oxy] - 3 - [1- (ethoxymethoxy) imino] -4-hydroxy-8-methyl-2H-1-benzopyran- 2-ketone
7- [(6-Desxy-5- C-methyl-4-O-methyl-3- {- [[(2-propynyloxy) propynyloxy) amino] carbonyl] -. alpha.-L- lixo-hexopyranosyl) oxy] -4-hydroxy-8-methyl-3 - [[(2-methyl-4-thiazolyl) methoxy] imino] ethyl] -2H-1-benzopyran- 2-ketone
Acid (2- propynyloxy-carbamic 3'-ester of 7 - [(6-deoxy-5-C-methyl-4-O-methyl-α-alpha-L-lixo-hexopyranosyl) oxy] -4-hydroxy- - methyl-3- [1- [[(2-thiazolyl) methoxy] imino] ethyl] -2H-1-benzopyran-2-ketone Acid (2- propynyloxycarbamic 3'- 7- [(6-deoxy) ester - 5- C-methyl-4- 0-methyl-. Alpha.- L- lixo-hexopyranosyl) oxy] -4-hydroxy-8-methyl-3- [1- [[(3-furanyl) methoxy] imino] ethyl] -2H- 1-benzopyran-2-ketone
Acid (2-propynyloxy-carbamic 3'-ester of 7- [(6-deoxy-5-C-methyl-4-methyl-1-alpha-L-lixo-hexopyranosyl) oxy] -4-hydroxy- - methyl-3- [1- [[(3-thienyl) methoxy] imino] ethyl] -2H-1-benzopyran-2-ketone
Acid (2- propynyloxy-carbamic 3'-ester of 7 - [(6-deoxy-5-C-methyl-4-methyl-1-alpha-L-lixo-hexopyranosyl) oxy] -4-hydroxy-3-ester - [1- [[(2-furanylmethoxy) imino] ethyl] -8-methyl-2H-1-benzopyran- 2-ketone
Acid (2- propynyloxy-carbamic 3'-ester of 7 - [(6-deoxy-5-C-methyl-4-O-methyl-α-alpha-L-lixo-hexopyranosyl) oxy] -4-hydroxy-3-ester - [1- [[(3,5-Dimethyl-isoxazol-4-yl) methoxy) imino] ethyl] -8-methyl-2H-1-benzopyran-2-ketone (2-propynyloxycarbamic acid 3'-ester) of 7 - [(6-deoxy-5- C-methyl-4-o-methyl- .alpha.-L-lixo-hexopyranosyl) oxy] -4-hydroxy-8-methyl-3- [1- (phenoxyimino) ethyl] -2H- 1-benzopyran- 2-ketone
[[[1- [7- [[6- deoxy-5- C-methyl-4- 0-methyl-3-0 - '[[(2-propynyloxy) amino] carbonyl] - .alpha.- L- lixo -hexopyranosyl) oxy] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] ethylidene] amino] oxy] methyl acetate.
EXAMPLES OF PHARMACEUTICAL COMPOSITIONS
It has been prepared tablets containing:
Product of example 1 150 mg
Excipient c.b.p. i g
Detail of the excipient: starch. Talcum, magnesium stearate
Product of example 5 150 mg
Excipient c.b.p. i g Detail of the excipient: starch, talc, magnesium stearate.
Injectable solutions have also been prepared from the salified products.
PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION
A- Method of dilutions in liquid medium
A series of tubes has been prepared in which the same amount of sterile nutrient medium was distributed. Increasing amounts of the product to be studied are distributed in each tube, then each tube is filled with a bacterial strain. After incubation for 24 hours in the oven at 37 ° C, the inhibition of growth is appreciated by transillumination which allows to determine the minimum inhibitory concentrations (C.M. I.) expressed in micrograms / cm3.
In vitro activity
CM1 in μg / ml On the following strains: Ex.l Ex.2 Ex.3 Ex.4
Staph. Aureus 011HT18 0.04 0.04 0.04 0.04
Staph. epidermidis 0126042 0.04 0.04 0.04 0.15
Staph. Coag. Negative 012HTS 0.3 0.04 0.15 0.15
Strepto. Piogen 02A1UC1 0.6 0.3 0.6 0.6
Strepto, pneumoniae 030BI2 0.04 0.08 0.08 0.15
Integer faeciu 02D3IP2 0.08 0.6 1.2 1.2
Entero faecalis 02D2UC5 0.3 1.2 1.2 1.2
B. Inhibition of gyrase B
The products are gyrase B inhibitors; the 50% dose of over-development of DNA is less than 5 μg / ml.
It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.
Having described the invention as above, it is claimed as property in the following:
Claims (26)
- (I), when the compounds of formula (I) have a basic function.
- 2) The compounds of formula (I) defined in claim 1, which are characterized in that Y represents an oxygen atom.
- 3) The compounds of formula (I) which are characterized in that Y represents a non-alkyl radical in which the alkyl radical contains up to 4 carbon atoms.
- 4) The compounds of formula (I) defined in claim 3, characterized in that Y represents the radical N0C2H5.
- 5) The compounds of formula (I) defined in any one of claims 1 to 4 which are characterized in that X represents an alkyl radical containing up to 4 carbon atoms and particularly the radical CH 3.
- 6) The compounds of formula (I) defined in any one of claims 1 to 4, characterized in that X represents an NH2 radical.
- 7) The compounds of formula (I) defined in any one of claims 1 to 4 which are characterized in that X represents the radical:
- 8) The compounds of formula (I) defined in any one of claims 1 to 7 which are characterized in that Ri represents a radical: HC = C-CH2-
- 9) The compounds of formula (I) defined in any one of claims 1 to 8 which are characterized in that R represents a hydrogen atom.
- 10) The compounds of formula (I) defined in any one of claims 1 to 9 which are characterized in that R 3 represents a methyl radical.
- 11) The compounds of formula (I) defined in any one of claims 1 to 10 which are characterized in that Z represents a hydrogen atom.
- 12) The compounds of formula (I) defined in any one of claims 1 to 11 which are characterized in that R 2 represents a hydrogen atom.
- 13) The compounds of formula (I) defined in any one of claims 1 to 12 which are characterized in that R 5 represents an OCH 3 radical.
- 14) The compounds of formula (I) defined in any one of claims 1 to 13 which are characterized in that R6 represents a methyl radical.
- 15) The compounds of formula (I) defined in any one of claims 1 to 14 which are characterized in that R7 represents a methyl radical.
- 16) The compounds of formula (I) defined in any one of claims 1 to 14 which are characterized in that R7 represents an ethyl radical.
- 17) The compounds of formula (I), defined in any one of claims 1 to 13, characterized in that R6 and R7 form, with the carbon atom containing them, a cyclopentyl radical.
- 18) The compounds of formula (I) defined in claim 1 which are characterized in that they are the following: - 7 - [[6-Deoxy-5- C-methyl-4-methyl-alpha-L-lixo-hexopyranosyl] oxy] -4-hydroxy-8-methyl- (3-propynyloxy) carbamic acid ester 2- oxo-2H-1-benzopyran-3-carboxamide - 7 - [[6-Deoxy-5- C-methyl-4-O-methyl-alpha-L-lixo-hexopyranosyl] oxy] -4-hydroxy-8-methyl- (3-propynyloxy) carbamic acid ester N- [2- (4-morpholinyl) ethyl] -2-oxo-2H-1-benzopyran-3-carboxamide - 3- (3-propynyloxy) -carbamic acid 3 'ester of 7 - [[6-deoxy-5- C-methyl-4-methyl-α-L-lixo-hexopyranosyl] oxy] -4-hydroxy- 3- [1- (methoxyimino) ethyl] -8-methyl-2H-1-benzopyran-2-ketone. Acid (2- propynyloxy) -carbamic 3'-ester of 7- [[6-deoxy-5-C-methyl-4-methyl-0-alpha-L-lixo-hexopyranosyl] oxy] -3- [1- (ethoxyimino) ethyl] -4-hydroxy-8-methyl-2H-1-benzopyran-2-ketone.
- 19) The compounds of formula (I) which are characterized because they are the following: 3- (3-propynyloxy) -carbamic acid 7 - [[6-deoxy-5-C-ethyl- 4-methyl-β-beta-D-gulopyranosyl) oxy] -4-hydroxy-3-ester - [1-methoxyimino) ethyl] -8-methyl-2H-1-benzopyran-2-ketone. - [7R- (7. alpha, 8.beta., 9.beta., 10. alpha.,)] - (2-propynyloxy) -carbamic acid of 8-hydroxy- 7- [4-hydroxy- 3- [ 1- (methoxyimino) and yl] -8-methyl-2-oxo-2H-1-benzopyran-7-yl] -10-methoxy-6-oxaspiro [4.5] decan-9-yl.
- 20) With the use of medicaments, the compounds of formula (I) defined in any one of claims 1 to 18 as well as their pharmaceutically acceptable salts.
- 21. The compounds of formula (I) defined in claim 19 as well as their pharmaceutically acceptable salts are referred to as medicaments.
- 22) Pharmaceutical compositions that are characterized in that they contain as a principle actiwo at least one drug defined in claim 20 or 21.
- 23. Process for the preparation of the compounds of formula (I) defined in any one of claims 1 to 19, characterized in that a compound of formula (II) is subjected to in which the radicals R2, R3, Z, R5, R6 and R7 retain their previous meaning, OW represents a blocked hydroxyl group and W 'represents an alkyl or O-alkyl radical containing up to 4 carbon atoms, to the action of an agent capable of introducing the radical O R C-N-ORi Or a series of operations likely to introduce the radical O R C-N-ORi R and Ri retain their previous meaning, - to the action of an agent capable of releasing the hydroxyl radical of the OW radical, - to the eventual action of an agent capable of replacing W 'by the radical X other than alkyl or O-alkyl, - to the eventual action of an agent capable of introducing the radical Y other than oxygen, - to the eventual action of a salification agent.
- 24) For the purpose of new chemical products, the compounds of formula (II) defined in claim 23.
- 25) Process according to claim 23, characterized in that the product of formula (II) is prepared by the action of a compound of formula (III). Sn which R5, R6 and R? retain their previous meaning on a compound of formula (IV) In which R2, R3 and Z retain their previous meaning, then a blocking agent of the free hydroxyl radical.
- 26) By way of new chemical products, the compounds of formula (III) defined in claim 25 below:
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR98/00116 | 1998-01-08 | ||
FR98/12936 | 1998-10-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA00006621A true MXPA00006621A (en) | 2001-07-09 |
Family
ID=
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