CN105777464A - Hydroxamic acid derivative, and preparation method and application thereof - Google Patents
Hydroxamic acid derivative, and preparation method and application thereof Download PDFInfo
- Publication number
- CN105777464A CN105777464A CN201410855187.3A CN201410855187A CN105777464A CN 105777464 A CN105777464 A CN 105777464A CN 201410855187 A CN201410855187 A CN 201410855187A CN 105777464 A CN105777464 A CN 105777464A
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- Prior art keywords
- compound
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- hydroxyl
- base
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 239000002253 acid Substances 0.000 title abstract description 21
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title abstract description 14
- 241000894006 Bacteria Species 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 149
- 238000000034 method Methods 0.000 claims description 81
- -1 nitro, cyano, mercapto Chemical group 0.000 claims description 79
- 239000000203 mixture Substances 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical group 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 231100000419 toxicity Toxicity 0.000 claims description 5
- 230000001988 toxicity Effects 0.000 claims description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 230000012010 growth Effects 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- 230000007918 pathogenicity Effects 0.000 claims description 3
- 208000035143 Bacterial infection Diseases 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims 3
- 125000006239 protecting group Chemical group 0.000 claims 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims 1
- 208000022362 bacterial infectious disease Diseases 0.000 claims 1
- 230000007921 bacterial pathogenicity Effects 0.000 claims 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims 1
- 208000027096 gram-negative bacterial infections Diseases 0.000 claims 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims 1
- PEMCNQCXITULJN-KRWDZBQOSA-N n-[(2s)-3-amino-1-(hydroxyamino)-1-oxopropan-2-yl]-4-[2-[4-[2-(hydroxyamino)-2-oxoethoxy]phenyl]ethynyl]benzamide Chemical compound C1=CC(C(=O)N[C@@H](CN)C(=O)NO)=CC=C1C#CC1=CC=C(OCC(=O)NO)C=C1 PEMCNQCXITULJN-KRWDZBQOSA-N 0.000 claims 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical group [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 7
- 238000011282 treatment Methods 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 238000011321 prophylaxis Methods 0.000 abstract 1
- 239000002585 base Substances 0.000 description 180
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 153
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 122
- 239000007787 solid Substances 0.000 description 69
- 239000002904 solvent Substances 0.000 description 60
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 59
- 238000005160 1H NMR spectroscopy Methods 0.000 description 58
- 239000001301 oxygen Substances 0.000 description 51
- 229910052760 oxygen Inorganic materials 0.000 description 51
- 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 50
- 239000002994 raw material Substances 0.000 description 49
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 47
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 45
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 44
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 40
- JGFBQFKZKSSODQ-UHFFFAOYSA-N Isothiocyanatocyclopropane Chemical compound S=C=NC1CC1 JGFBQFKZKSSODQ-UHFFFAOYSA-N 0.000 description 40
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 40
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 37
- 239000000243 solution Substances 0.000 description 34
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 20
- 239000001273 butane Substances 0.000 description 20
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 20
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 10
- 239000004698 Polyethylene Substances 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 10
- 239000002798 polar solvent Substances 0.000 description 10
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 6
- 239000002158 endotoxin Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 229920006008 lipopolysaccharide Polymers 0.000 description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 5
- 0 C*C(C)c1ccc(C(C)C)cc1 Chemical compound C*C(C)c1ccc(C(C)C)cc1 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 5
- 230000003385 bacteriostatic effect Effects 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- QXSAKPUBHTZHKW-UHFFFAOYSA-N para-hydroxybenzamide Natural products NC(=O)C1=CC=C(O)C=C1 QXSAKPUBHTZHKW-UHFFFAOYSA-N 0.000 description 5
- XPXXXQZNUQAFQY-UHFFFAOYSA-N 3-methylsulfonylpropan-1-ol Chemical compound CS(=O)(=O)CCCO XPXXXQZNUQAFQY-UHFFFAOYSA-N 0.000 description 4
- VSMDINRNYYEDRN-UHFFFAOYSA-N 4-iodophenol Chemical compound OC1=CC=C(I)C=C1 VSMDINRNYYEDRN-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 230000004907 flux Effects 0.000 description 4
- 230000012447 hatching Effects 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
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- 229940123346 LpxC inhibitor Drugs 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
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- 230000015572 biosynthetic process Effects 0.000 description 3
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
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- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- RJWUMFHQJJBBOD-UHFFFAOYSA-N 2-methylheptadecane Chemical compound CCCCCCCCCCCCCCCC(C)C RJWUMFHQJJBBOD-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 2
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
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- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
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- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- LDLDJEAVRNAEBW-UHFFFAOYSA-N Methyl 3-hydroxybutyrate Chemical compound COC(=O)CC(C)O LDLDJEAVRNAEBW-UHFFFAOYSA-N 0.000 description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
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- 239000004305 biphenyl Substances 0.000 description 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
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- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
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- 229940126214 compound 3 Drugs 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- FFYDXIRYINVCCL-UHFFFAOYSA-N ethynylbenzene formic acid Chemical compound C(=O)O.C1(=CC=CC=C1)C#C FFYDXIRYINVCCL-UHFFFAOYSA-N 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
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- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
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- 150000002333 glycines Chemical class 0.000 description 1
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- 125000005843 halogen group Chemical group 0.000 description 1
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 229960000201 isosorbide dinitrate Drugs 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
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- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
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- 238000010369 molecular cloning Methods 0.000 description 1
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- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910052756 noble gas Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
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- 210000000664 rectum Anatomy 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
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- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开一种异羟肟酸衍生物及其制备方法和应用，本发明的异羟肟酸衍生物的结构如式I所示，其中R1、m、n、X和R2的定义如说明书和权利要求书所述。本发明的异羟肟酸衍生物，能够抑制LpxC脱乙酰酶的活性，具有抑菌活性，尤其是能够抑制革兰氏阴性菌，特别适用于制备预防和/或治疗革兰氏阴性菌引起的相关疾病的药物。 The invention discloses a hydroxamic acid derivative and its preparation method and application. The structure of the hydroxamic acid derivative of the present invention is shown in formula I, wherein the definitions of R 1 , m, n, X and R 2 are as follows described in the specification and claims. The hydroxamic acid derivatives of the present invention can inhibit the activity of LpxC deacetylase, have antibacterial activity, especially can inhibit Gram-negative bacteria, and are especially suitable for the preparation of prophylaxis and/or treatment of gram-negative bacteria. Drugs for related diseases.
Description
Technical field
The invention belongs to medical compounds field.Specifically, the present invention relates to the hydroxamic acid derivs that a class is novel, or its enantiomer, diastereomer, racemic modification or its mixture, and pharmaceutically acceptable salt, and the preparation method of above-claimed cpd and above-claimed cpd as bioactive substance for preparing the purposes of medicine.
Background technology
Widely using along with antibacterials, occurs in that substantial amounts of fastbacteria clinically, and bacterial resistance sex chromosome mosaicism becomes the major issue threatening mankind's publilc health.For gram positive bacterial infection, the disease particularly caused by escherichia coli (E.coli), Pseudomonas aeruginosa (P.aeruginosa) and Acinetobacter bauamnnii (A.baumannii), medicine is extremely limited.
The outer layer of Gram-negative bacterial cell film is made up of lipopolysaccharide (LPS), it is possible to prevent antibiotic from entering inside antibacterial as a permeability barrier.Biological study shows, lipopolysaccharide is most important to bacterial cell growth, play an important role in the folding process of memebrane protein [TheJournalofBiologicalChemistry, 274 (8), 1999,5114-5119].Each lipopolysaccharide molecule is mainly made up of three major parts: O-type antigen, core polysaccharide and class matter A.Wherein lipoid A is the tie connecting lipopolysaccharide and adventitia, is the key structure [JLipidRes, 46 (5), 2005,839-861] maintaining cell membrane stability.Class matter A is under the catalysis of the enzyme of high conservative nine kinds single-minded, synthesis in Cytoplasm on the inner surface of inner membrance.The first step is to UDPG fatty acid acyl, is a step reversible reaction.Second step is then by the deacetylation of LpxC [UDP-3-O-(R-3-hydroxymyristoyl)-N-Acetyl-D-glucosamine deacetylase] catalysis, is the rate constants of biosynthesis lipoid A.If the activity of LpxC deacetylase can be suppressed, it is possible to blocking the synthesis of lipoid A, thus destroying the integrity of bacteria lipopolysaccharide, causing bacterial death.
LpxC deacetylase is a kind of zinc ion protease, and increasing or reduce its content is all fatal for antibacterial, and is widely present in gram negative bacteria, does not have common sequence with mammiferous protein component, is not likely to produce side effect.These advantages have made it the important target spot of novel against gram-negative bacteria medicine.
Document has reported multiple LpxC inhibitor [CurrentMedicinalChemistry, 2012,19,2038-2050], although major part antibacterial activity in vitro is better, but because druggability is poor, seldom has compound to enter clinical research.Only the ACHN-975 of Achaogen company entered a phase clinic in 2012, but injection site goes wrong and terminates research [Bioorganic&MedicinalChemistryLetters24 (2014) 3,683 3689] when 2013 because of drug administration by injection.
Summary of the invention
It is an object of the invention to provide a kind of LpxC inhibitor.
A first aspect of the present invention, it is provided that a kind of compound of formula I, its enantiomer, diastereomer, racemic modification or its mixture, or pharmaceutically acceptable salt,
In formula, R1For unsubstituted or substituted C1-C6Alkyl, described replacement refers to the substituent group having selected from lower group: hydroxyl, amino, halogen, nitro, cyano group, sulfydryl；
M is the integer of 0～2, is 0,1 or 2；
N is the integer of 0～1；
X is-O-,-S-,-NH-,-NHCO-or-CONH-；
R2For the C replaced1-C6Alkyl, described replacement refers to the substituent group having selected from lower group: hydroxyl, sulfydryl, nitro, cyano group ,-SO2(halo C1-C3Alkyl) ,-SO2(C1-C3Alkyl) ,-CONHOH,
Condition is, compound of formula I is not following compound:
Double; two [N-[(1S, 2R)-2-hydroxyl-1-[(hydroxyl amino) acyl group] propyl group] Benzoylamide of 4,4'-(1,3-diacetylene-1,4-two base)；
N-[(1S; 2R)-2-hydroxyl-1-[(hydroxyl amino) acyl group] propyl group]-N'-[(1R; 2R)-2-hydroxyl-1-[(hydroxyl amino) acyl group] propyl group]-[1,1'-biphenyl]-4,4'-diformamide；
N-[(1S)-1-(amino methyl)-2-(hydroxyl amino)-2-oxoethyl]-4-[2-[4-[2-(hydroxyl amino)-2-oxoethoxy] phenyl] acetenyl]-Benzoylamide.
In another preference, R1, m, n, X and R2Defined as described above, condition is X when being-CONH-or-NHCO-, R2On when there is two substituent groups, substituent group is not hydroxyl and-CONHOH；When X is-O-, R2On substituent group be not-CONHOH.
In another preference, described in be substituted by monosubstituted or polysubstituted.In another preference, described in be substituted by monosubstituted, two replace, three replace or four replacements.In another preference, described polysubstituted, two replace, three replace or four replace refer to that there is identical or different substituent group.
In another preference, C1-C6Alkyl has 1,2,3 or 4 substituent groups.
In another preference, in compound of formula I, the configuration of each chiral carbon atom independently be R type or S type.
In another preference, R1For the C that hydroxyl or amino replace1-C4Alkyl.
In another preference, R2For the C replaced1-C6Alkyl, described replacement refers to the substituent group having selected from lower group: hydroxyl ,-SO2CH3、-SO2CF3、-CONHOH、
In another preference, R2For the C replaced1-C4Alkyl, wherein C1-C4Substituent group on alkyl is selected from: hydroxyl ,-SO2CH3、-SO2CF3、-CONHOH、
In another preference, described compound of formula I is any one in embodiment in the compound 1-20 of preparation.
In another preference, described pharmaceutically acceptable salt is hydrochlorate, hydrobromate, sulfate, nitrate, phosphate, citrate, mesylate, trifluoroacetate, acetate, oxalates, succinate, malate, toluene fulfonate, tartrate, fumarate, glutamate, Glu, glucuronate, lactate, glutarate, arginine salt or maleate.
A second aspect of the present invention, it is provided that the preparation method of the compound of formula I described in first aspect, m is 1 or 2；When n is 1, said method comprising the steps of:
A () Formulas I-1 compound and Formulas I-2 compound condensation obtain Formulas I-3 compound；
B () Formulas I-3 compound and Formulas I-4 compound are obtained by reacting Formulas I-5 compound；
C () Formulas I-5 compound and azanol reaction obtain compound of formula I,
In various, X's is defined as described above,
M is 0；N is 0 or 1, X when being-O-or-S-, said method comprising the steps of:
I () Formula II-1 compound and Formula II-2 compound condensation obtain Formula II-3 compound, q is 1 or 2；
(ii) Formula II-3 compound and R2OH is obtained by reacting Formula II-4 compound；
(iii) Formula II-4 compound and azanol reaction obtain compound of formula I,
In various, R1For C protected or unprotected, unsubstituted or substituted1-C6Alkyl；
R2C for protected or unprotected replacement1-C6Alkyl；
Y is acetenyl or halogen；
Each described replacement refers to that the group being selected from lower group replaces independently: hydroxyl, amino, halogen, nitro, cyano group ,-SO2CH3、-CONHOH、
And work as R1For C protected, unsubstituted or substituted1-C6Alkyl and/or R2C for protected replacement1-C6During alkyl; described method also includes the step removing protection base, and described protection base is selected from: tertbutyloxycarbonyl, methoxy-benzyl, benzhydryl, benzyl, t-Butyldimethylsilyl, tert-butyl diphenyl is silica-based, pi-allyl, methoxy, methylthiomethyl, methoxvethoxvmethvl, benzyloxymethyl.
In another preference, R1For C protected, unsubstituted or substituted1-C6During alkyl, after Formula II-4 compound deprotection group, obtain compound of formula I with azanol reaction.
In another preference, R2C for protected replacement1-C6During alkyl, after Formula II-4 compound and azanol reaction, deprotection group obtains compound of formula I.
A third aspect of the present invention, it is provided that a kind of pharmaceutical composition, comprises:
Compound of formula I described in first aspect, its enantiomer, diastereomer, racemic modification or its mixture, or pharmaceutically acceptable salt；And
Pharmaceutically acceptable carrier.
A fourth aspect of the present invention, it is provided that the purposes of the compound of formula I described in first aspect or the pharmaceutical composition described in the third aspect, is used for:
(1) preparation suppresses the medicine of LpxC deacetylase；
(2) medicine that preparation prevention and/or treatment antibacterial infect；
(3) medicine of bacteria growing inhibiting is prepared；
(4) LpxC deacetylase inhibitors.
In another preference, described antibacterial is gram negative bacteria.
In another preference, described gram negative bacteria is selected from: escherichia coli, Pseudomonas aeruginosa, Acinetobacter bauamnnii.
A fifth aspect of the present invention, it is provided that a kind of method reducing Pathogenicity of Bacteria or toxicity, including step:
Antibacterial is contacted with the compound of formula I described in first aspect 1 or the pharmaceutical composition described in the third aspect, thus reducing Pathogenicity of Bacteria or toxicity.
In another preference, described antibacterial is gram negative bacteria.
In another preference, described gram negative bacteria is selected from: escherichia coli, Pseudomonas aeruginosa, Acinetobacter bauamnnii.
In another preference, the described curative method of method right and wrong.
In another preference, described method is curative method.
In another preference, described contact causes that the content of LpxC deacetylase in antibacterial increases or reduces.
A sixth aspect of the present invention, it is provided that a kind of method suppressing LpxC deacetylase, to required object or to the pharmaceutical composition used in environment described in the compound of formula I of safe and effective amount or the third aspect.
A seventh aspect of the present invention, it is provided that a kind of antibiotic method, to required object or to the pharmaceutical composition used in environment described in the compound of formula I of safe and effective amount or the third aspect.
A eighth aspect of the present invention, it is provided that a kind of for treat antibacterial infect method, comprise the following steps: to the object being infected by bacterial grant safe and effective amount compound of formula I or the third aspect described in pharmaceutical composition.
In another preference, compound of formula I or the pharmaceutical composition described in the third aspect contact with antibacterial and act on a period of time, thus reducing the pathogenic of antibacterial and/or toxicity.
In the present invention, the object of described needs includes people or non-human mammal, it is preferred that, for people, mice or rat.
In the present invention, the mode granted to described object has no particular limits, and includes but not limited to be administered orally, injection, sucks, and local uses.
In the present invention, " safe and effective amount " refers to: the amount of active component (compound of formula I) is enough to be obviously improved the state of an illness, and is unlikely to produce serious side effect.
The hydroxamic acid derivs of the present invention, it is possible to suppress the activity of LpxC deacetylase, have bacteriostatic activity, especially can suppress gram negative bacteria, is particularly useful for making prevention and/or treats the medicine of the relevant disease that antibacterial especially gram negative bacteria causes.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus constituting new or preferred technical scheme.As space is limited, this is no longer going to repeat them.
Detailed description of the invention
Present inventor, through extensively and in depth studying, develops the LpxC deacetylase inhibitors of a kind of novel structure, first for hydroxamic acid derivs.The hydroxamic acid derivs of the present invention, has bacteriostatic activity, especially can suppress gram negative bacteria.On this basis, the present invention is completed.
Hydroxamic acid derivs
In the present invention, the compound shown in hydroxamic acid derivs, compound of formula I, Formulas I has identical implication, each means the compound being structured with:
Wherein, R1, m, n, X and R2Defined as described above.
In the present invention, term " C1-C6Alkyl " refer to the straight or branched alkyl with 1 to 6 carbon atom, include methyl, ethyl, propyl group, isopropyl and butyl etc. without limitation.In the present invention, term " halogen " refers to fluorine, chlorine, bromine, iodine.
Preparation method
The compounds of this invention can be prepared by following method, but the condition of the method, for instance reactant, solvent, acid, alkali, the amount of compound used therefor, reaction temperature, response time etc. are not limited to description below.The combination of various synthetic method that describe in this manual or well known by persons skilled in the art can also optionally prepare the compound of the present invention easily, and those skilled in the art in the invention can easily carry out combinations thereof.
Route one: m is 1 or 2；When n is 1, said method comprising the steps of:
Route two: m is 0；When n is 0 or 1, said method comprising the steps of:
In various, X, R1、R2, Y, m, n defined as described above.
In a preferred embodiment, Formulas I-1 compound in polar solvent with Formulas I-2 compound under condensing agent and organic base exist, react 4-16 hour under room temperature condition, obtain Formulas I-3 compound.Described condensing agent can be 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (HATU), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) and I-hydroxybenzotriazole (HOBT).Described organic base can be triethylamine, diisopropyl ethyl amine；Polar solvent can be dichloromethane, N,N-dimethylformamide.
In a preferred embodiment; Formulas I-3 compound and Formulas I-4 compound (Y is acetenyl) are under the catalysis containing metallic copper catalyst; in the mixed solvent of alkali condition, react 12-24 hour under room temperature to 40 DEG C condition under inert gas shielding, obtain Formulas I-4 compound.Described can be Schweinfurt green containing metallic copper catalyst, and the mixed solvent of alkali condition can be the mixed solvent of pyridine and methanol.
In a preferred embodiment; Formulas I-3 compound and Formulas I-4 compound (Y is halogen) are under the catalysis containing metal palladium catalyst; in alkali condition and polar aprotic solvent, react 2-12 hour under room temperature to 40 DEG C condition under inert gas shielding, obtain Formulas I-5 compound.Described can be two (triphenylphosphine) palladium chloride and Hydro-Giene (Water Science) .s containing metal palladium catalyst.The alkali that described alkali condition uses can be: triethylamine, diisopropyl ethyl amine, pyridine.Described polar aprotic solvent may is that Isosorbide-5-Nitrae-dioxane, dimethylformamide, oxolane.Described noble gas can be nitrogen or argon.
In a preferred embodiment, Formula II-1 compound in polar solvent with Formula II-2 compound under condensing agent and organic base exist, react 4-16 hour under room temperature condition, obtain Formula II-3 compound.Described condensing agent can be 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (HATU), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) and I-hydroxybenzotriazole (HOBT).Described organic base can be triethylamine, diisopropyl ethyl amine；Polar solvent can be dichloromethane, N,N-dimethylformamide.
In a preferred embodiment, Formula II-3 compound in polar solvent with R2OH diethyl azodiformate (DEAD), triphenylphosphine existence under, under room temperature condition react 0.5-2 hour, obtain Formula II-4 compound.Polar solvent can be oxolane, N,N-dimethylformamide.
In a preferred embodiment, Formulas I-5 compound or Formula II-4 compound and aqueous hydroxylamine solution (such as 50%), in polar solvent, react 3-18 hour in room temperature to 40 DEG C, obtain compound of formula I.Described polar solvent can be the mixed solution of methanol and dichloromethane.In a preferred embodiment, part of compounds is absent from deprotection process, and azanol is directly end-product after replacing methyl ester.
In a preferred embodiment, R2There is Formulas I-5 compound or the R of blocking group2There is the product after Formula II-4 compound of blocking group and azanol reaction in acid flux material, in room temperature reaction 3-12 hour, deprotection base, obtain compound of formula I.Described acid flux material can be the mixed solution of trifluoroacetic acid and dichloromethane.
In a preferred embodiment, R1There is Formulas I-5 compound or the R of blocking group (such as tertbutyloxycarbonyl)1There is Formula II-4 compound of blocking group (such as tertbutyloxycarbonyl) in acid flux material after deprotection, then with aqueous hydroxylamine solution (such as 50%) in polar solvent, react 3-18 hour in room temperature to 40 DEG C, obtain compound of formula I.Described acid flux material can be 1,4-dioxane solution or the ethyl acetate solution of hydrogen chloride.Described polar solvent can be the mixed solution of methanol and dichloromethane.
Pharmaceutical composition
The compound of formula I of the present invention, it is possible to suppress the activity of LpxC deacetylase, there is bacteriostatic activity, especially can suppress gram negative bacteria.
Pharmaceutical composition provided by the invention, contained I or its pharmaceutically acceptable salt are as active component；And pharmaceutically acceptable carrier.
Generally, pharmaceutical composition contains 1-2000mg active component/agent, more preferably, containing 10-200mg active component/agent.It is preferred that described " potion " is a tablet.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solid or liquid filler or gelatinous mass, and they are suitable for people and use and it is necessary to have enough purity and of a sufficiently low toxicity.Active component that " compatibility " referred to herein as in compositions each component energy and the present invention and they between mutually admix, and significantly reduce the drug effect of active component.Pharmaceutically acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethyl cellulose, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, Talcum, kollag (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as Oleum Glycines, Oleum sesami, Oleum Arachidis hypogaeae semen, Fructus Canarii albi wet goods), polyhydric alcohol (such as propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifying agent (such as tween), wetting agent (such as sodium lauryl sulphate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, apirogen water etc..
The active component of the present invention or the method for application of pharmaceutical composition are not particularly limited, and representational method of application includes (but being not limited to): be administered orally, tumor is interior, rectum, parenteral (intravenous, intramuscular or subcutaneous) etc..
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.
In these solid dosage formss, active component mixes with at least one conventional inert excipients (or carrier), such as sodium citrate or dicalcium phosphate, or mixes with following compositions: (a) filler or bulking agent, such as, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) binding agent, for instance, hydroxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and arabic gum；(c) wetting agent, for instance, glycerol；(d) disintegrating agent, for instance, agar, calcium carbonate, potato starch or tapioca, alginic acid, some composition silicate and sodium carbonate；(e) retarding solvent, for instance paraffin；F () absorbs accelerator, for instance, quaternary ammonium compound；(g) wetting agent, for instance spermol and glyceryl monostearate；(h) adsorbent, for instance, Kaolin；(i) lubricant, for instance, Talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and pill, dosage form also can comprise buffer agent.
Described solid dosage forms also can adopt coating and shell material to prepare, such as casing and other material well known in the art.They can comprise opacifying agent, and, in this compositions, the release of active component can release in the part of certain in digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material and Wax.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except active component, liquid dosage form can comprise the conventional inert diluent adopted in this area, such as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture etc. of ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethylformamide and oil, particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, maize embryo oil, olive oil, Oleum Ricini and Oleum sesami or these materials.Except these inert diluents, compositions also can comprise auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, sweeting agent, correctives and spice.
Except active component, suspension can comprise suspending agent, for instance, the mixture etc. of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, microcrystalline Cellulose, aluminium methoxide and agar or these materials.
Compositions for parenteral injection can comprise physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or emulsion, and for being again dissolved into the sterilized powder of aseptic Injectable solution or dispersion liquid.Moisture and the nonaqueous carrier, diluent, solvent or the excipient that are suitable for include water, ethanol, polyhydric alcohol and suitable mixture thereof.
The compounds of this invention can be individually dosed, or with other treatment administered in combination.
When making pharmaceutical composition, it it is the mammal (such as people) that the formula I of safe and effective amount is applicable to treatment, when wherein using, dosage is the effective dosage pharmaceutically thought, for the people of 60kg body weight, day dosage is generally 1～2000mg, it is preferable that 20～500mg.Certainly, concrete dosage is it is also contemplated that the factor such as route of administration, patient health situation, and these are all within skilled practitioners skill.
The features described above that the present invention mentions, or the feature that embodiment is mentioned can be in any combination.The disclosed all features of this case description can with any composition forms use, each feature disclosed in description, it is possible to identical by any offer, impartial or similar purpose alternative characteristics replaces.Therefore except having special instruction, disclosed feature to be only impartial or similar features general example.
The invention have benefit that:
(1) the invention provides the hydroxamic acid derivs with new structure.
(2) preparation method that the invention provides hydroxamic acid derivs, technique is simply efficient.
(3) present invention firstly discovers that the new application of hydroxamic acid derivs, it is possible to be used for preparing antibacterials, suppress the medicine of gram negative bacteria especially for preparation.
Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate the present invention rather than restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally conventionally condition such as Sambrook et al., molecular cloning: laboratory manual (NewYork:ColdSpringHarborLaboratoryPress, 1989) condition described in, or according to manufacturer it is proposed that condition.Unless otherwise indicated, otherwise percentage ratio and number are calculated by weight.
Unless otherwise defined, the same meaning that all specialties used in literary composition are familiar with one skilled in the art with scientific words.Additionally, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that preferably implementation described in literary composition and material only present a demonstration.
In all embodiments,1H-NMR VarianMercury300 or AVANCEIII400 nuclear magnetic resonance analyser record, chemical shift represents with δ (ppm)；Separation silica gel, undeclared is 200-300 order, and the proportioning of eluent is volume ratio.
Preparation embodiment
Embodiment 1:N-((2S, 3R)-3-hydroxyl-1-(azanol base)-1-oxygen-containing butane-2-base) preparation of-4-((4-(3-(methylsulfonyl) propoxyl group) phenyl) 1,3-diacetylene base-) aniline (compound 1)
The iodo-4-of (a) 1-(3-(methylsulfonyl) propoxyl group) benzene
Under argon shield; by 3-methylsulfonyl propanol (200mg; 1.447mmol) with 4-iodophenol (382mg; 1.737mmol) it is dissolved in the anhydrous oxolane of 10ml; it is sequentially added into triphenylphosphine (569mg under 0 DEG C of stirring; 2.171mmol) with diethyl azodiformate (378mg; 2.171mmol); reaction 1h; it is complete that TLC (PE/EA=2/1) detects raw material reaction, is spin-dried for solution, column chromatography (PE/EA=5/1-2/1); obtain white solid 400mg, yield 81.3%.
1HNMR (400MHz, Chloroform-d) δ 7.56 (d, J=9.1Hz, 2H), 6.66 (d, J=9.0Hz, 2H), 4.08 (t, J=5.8Hz, 2H), 3.28-3.18 (m, 2H), 2.95 (s, 3H), 2.40 2.28 (m, 2H).
MS(ESI)m/z:[(M+Na)+,263.0].
(b) trimethyl ((4-(3-(methylsulfonyl) propoxyl group) phenyl) acetenyl) silane
Under argon shield; the iodo-4-of compound 1-(3-(methylsulfonyl) propoxyl group) benzene (400mg prepared by above-mentioned (a); 1.176mmol) with trimethylsilyl acetylene (173mg; 1.765mmol) it is dissolved in the anhydrous oxolane of 10ml, adds Ph (PPh3)2Cl2(42mg, 0.059mmol) and CuI (12mg, 0.059mmol), Et3N (238mg, 2.352mmol), is stirred at room temperature 12h.TLC (PE/EA=2/1) detects raw material and disappears, and is spin-dried for by solvent, after again dissolving by ethyl acetate, then washs with saturated aqueous ammonium chloride and saturated sodium-chloride water solution successively, and anhydrous sodium sulfate dries.Cross and filter anhydrous sodium sulfate, then solution is spin-dried for column chromatography (PE/EA=5/1-2/1), obtain yellow solid 330mg, yield 90.5%.
1HNMR (400MHz, Chloroform-d) δ 7.40 (d, J=8.7Hz, 2H), 6.80 (d, J=8.8Hz, 2H), 4.11 (t, J=5.8Hz, 2H), 3.31-3.16 (m, 2H), 2.95 (s, 3H), 2.35 (dq, J=11.4,6.0Hz, 2H), 0.23 (s, 9H).
MS(ESI)m/z:[(M+Cl)-,344.8].
(c) 1-acetenyl-4-(3-(methylsulfonyl) propoxyl group) benzene
Compound trimethyl ((4-(3-(methylsulfonyl) propoxyl group) phenyl) acetenyl) silane (330mg prepared by above-mentioned (b), 1.063mmol) it is dissolved in 10ml anhydrous tetrahydro furan, it is cooled to 0 DEG C, it is slowly added to tetra-n-butyl amine fluoride (1M, 1.3ml), rise to room temperature, reaction 1h, TLC (PE/EA=2/1) monitors reaction, after question response completes, adding 10ml water and 30ml ethyl acetate, separatory takes ethyl acetate layer, washing with saturated sodium-chloride water solution, anhydrous sodium sulfate dries.Cross and filter anhydrous sodium sulfate, then solution is spin-dried for column chromatography (PE/EA=5/1-2/1), obtain white solid 228mg, yield 90.0%.
1HNMR(400MHz,CDCl3) δ 7.43 (d, J=8.9Hz, 2H), 6.82 (d, J=8.9Hz, 2H), 4.12 (t, J=5.8Hz, 2H), 3.25 (dd, J=8.7,6.7Hz, 2H), 3.01 (s, 1H), 2.96 (s, 3H), 2.36 (ddt, J=11.6,7.6,5.7Hz, 2H) .MS (ESI) m/z:[(M+Na)+,263.0].
MS(ESI)m/z:[(M+Na)+,261.1].
(d) (2S, 3R)-3-hydroxyl-2-(4-((4-(3-(methylsulfonyl) propoxyl group) phenyl)-1,3-diacetylene-1-base) benzamido) methyl butyrate
nullCompound 1-acetenyl-4-(3-(methylsulfonyl) propoxyl group) benzene (228mg prepared by above-mentioned (c)，0.957mmol) with (2S,3R)-2-(4-acetylenylbenzene formamido group)-3-hydroxybutyrate methyl ester [Bioorganic&MedicinalChemistry19 (2011) 852 860] (500mg，1.914mmol)，It is dissolved in the mixed solvent of 8ml absolute methanol and 8ml pyridine，Schweinfurt green (348mg is added under argon shield，1.914mmol)，It is stirred at room temperature，Reaction 24h，TLC (PE/EA=2/1) monitors reaction，After question response completes，Add 40ml acetic acid ethyl dissolution，The pyridine in solvent is washed away with dilute hydrochloric acid (1M)，Wash with saturated sodium-chloride water solution again，Anhydrous sodium sulfate dries.Cross and filter anhydrous sodium sulfate, then solution is spin-dried for column chromatography (PE/EA=5/1-2/1), obtain white solid 195mg, yield 40.1%.
1HNMR(400MHz,CDCl3) δ 7.84 (d, J=8.3Hz, 2H), 7.62 (d, J=8.4Hz, 2H), 7.51 (d, J=8.8Hz, 2H), 6.92 (d, J=8.8Hz, 1H), 6.87 (d, J=8.8Hz, 2H), 4.84 (dd, J=8.8,2.2Hz, 1H), 4.50 (s, 1H), 4.16 (t, J=5.8Hz, 2H), 3.83 (s, 3H), 3.38 3.22 (m, 2H), 2.99 (s, 3H), 2.39 (dt, J=15.5,5.9Hz, 2H), 1.32 (d, J=6.4Hz, 3H).
MS(ESI)m/z:[(M+Na)+,520.1].
(e) N-((2S, 3R)-3-hydroxyl-1-(azanol base)-1-oxygen-containing butane-2-base)-4-((4-(3-(methylsulfonyl) propoxyl group) phenyl) 1,3-diacetylene base-) aniline
Compound (2S prepared by above-mentioned (d), 3R)-3-hydroxyl-2-(4-((4-(3-(methylsulfonyl) propoxyl group) phenyl)-1,3-diacetylene-1-base) benzamido) methyl butyrate (195mg, 0.392mmol) it is dissolved in the mixed solution of 5ml dichloromethane and 10ml methanol, the aqueous hydroxylamine solution (1ml) of 50% is dripped at 0 DEG C, 12h, TLC (CH is stirred at room temperature2Cl2/ MeOH=20/1) detect raw material disappearance.Being spin-dried for by solution, dichloromethane is pulled an oar three times and is obtained sterling, for off-white color solid 98mg, yield 50.1%.
1nullHNMR(400MHz,DMSO)δ10.70(s,1H),8.88(s,1H),8.22(d,J=8.4Hz,1H),7.95(d,J=8.4Hz,2H),7.71(d,J=8.4Hz,2H),7.59(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),4.91(d,J=6.4Hz,1H),4.25(dd,J=8.4,5.6Hz,1H),4.15(t,J=6.3Hz,2H),4.08–3.97(m,1H),3.31–3.26(m,2H),3.03(s,3H),2.20–2.11(m,2H),1.09(d,J=6.3Hz,3H).
MS(ESI)m/z:[(M-H)-,497.0].
Embodiment 2:N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base) preparation of-4-((4-(((S)-3 hydroxyl-1-(azanol)-1-propoxyl group-2-base) carbamyl) phenyl)-1,3-diacetylene-1-base) Benzoylamide (compound 2)
(a) (S)-3-hydroxyl-2-amino-propanoate hydrochlorate
L-threonine (1.0g, 9.443mmol) is suspended in 20ml methanol, adds thionyl chloride (1.3g, 10.86mmol) at 0 DEG C, 24h is stirred at room temperature, is spin-dried for obtain jelly 1.47g, yield 100%.
1HNMR (400MHz, DeuteriumOxide) δ 4.17 (t, J=3.7Hz, 1H), 4.00 (dd, J=12.6,4.2Hz, 1H), 3.89 (dd, J=12.3,3.2Hz, 1H), 3.75 (s, 3H).
(b) (S)-2-(4-acetylenylbenzene formoxyl)-3-hydroxybutyrate methyl ester
Compound (S)-3-hydroxyl-2-amino-propanoate hydrochlorate (256mg prepared by above-mentioned (a); 1.642mmol) with 4-acetylenylbenzene formic acid (200mg; 1.369mmol) it is dissolved in 10mlN; in dinethylformamide; argon shield; 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (315mg it is sequentially added at 0 DEG C; 1.642mmol), I-hydroxybenzotriazole (222mg; 1.642mmol), diisopropyl ethyl amine (708mg, 5.476mmol).20h, TLC detection is stirred at room temperature and reacts complete (CH2Cl2/ MeOH=20/1), add 40ml ethyl acetate, then wash with saturated aqueous ammonium chloride and saturated sodium-chloride water solution successively, anhydrous sodium sulfate dries.Cross and filter anhydrous sodium sulfate, then solution is spin-dried for column chromatography (CH2Cl2/ MeOH=100/1-80/1), obtain yellow solid 165mg, yield 44.0%.
1HNMR (400MHz, Chloroform-d) δ 7.82 (d, J=8.0Hz, 2H), 7.58 (d, J=8.0Hz, 2H), 7.15 (d, J=7.2Hz, 1H), 4.89 (dt, J=7.1,3.3Hz, 1H), 4.10 (qd, J=11.3,5.5Hz, 2H), 3.85 (s, 3H), 3.24 (s, 1H), 2.63 (t, J=5.8Hz, 1H).
MS(ESI)m/z:[(M+H)+,248.0].
(c) (2S; 3R)-3-hydroxyl-2-(4-((4-(((S)-3-hydroxyl-1-methoxy-1-propoxyl group-2-base) carbamoyl) phenyl)-1,3-diacetylene-1-base) benzamido) methyl butyrate
Compound (S)-2-(4-acetylenylbenzene formoxyl)-3-hydroxybutyrate methyl ester (160mg prepared by above-mentioned (b); 0.647mmol) with (2S; 3R)-2-(4-acetylenylbenzene formamido group)-3-hydroxybutyrate methyl ester (254mg; 0.971mmol); it is dissolved in the mixed solvent of 8ml absolute methanol and 8ml pyridine; Schweinfurt green (348mg is added under argon shield; 1.914mmol); it is stirred at room temperature; reaction 24h, TLC (CH2Cl2/ MeOH=20/1) monitoring reaction, after question response completes, add 40ml acetic acid ethyl dissolution, wash away the pyridine in solvent with dilute hydrochloric acid (1M), then wash with saturated sodium-chloride water solution, anhydrous sodium sulfate dries.Cross and filter anhydrous sodium sulfate, then solution is spin-dried for column chromatography (CH2Cl2/ MeOH=80/1-20/1), obtain white solid 110mg, yield 33.6%.
1HNMR(400MHz,DMSO-d6) δ 8.78 (d, J=7.4Hz, 1H), 8.47 (d, J=8.2Hz, 1H), 7.96 (d, J=8.0Hz, 4H), 7.76 (d, J=7.4Hz, 4H), 5.08 (t, J=6.2Hz, 1H), 4.99 (d, J=7.3Hz, 1H), 4.58 4.48 (m, 2H), 4.19 (h, J=6.8Hz, 1H), 3.80 (t, J=5.8Hz, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 1.15 (d, J=6.4Hz, 3H).
MS(EI)m/z:(M+,506).
(d) N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-propoxyl group-2-base)-4-((4-(((S)-3 hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) carbamyl) phenyl)-1,3-diacetylene-1-base) Benzoylamide
Compound (2S prepared by above-mentioned (c); 3R)-3-hydroxyl-2-(4-((4-(((S)-3-hydroxyl-1-methoxy-1-oxygen-containing butane-2-base) carbamoyl) phenyl)-1; 3-diacetylene-1-base) benzamido) methyl butyrate (110mg; 0.216mmol) it is dissolved in the mixed solution of 5ml dichloromethane and 10ml methanol; the aqueous hydroxylamine solution (1ml) of 50% is dripped at 0 DEG C; 12h, TLC (CH is stirred at room temperature2Cl2/ MeOH=20/1) detect raw material disappearance.Being spin-dried for by solution, dichloromethane is pulled an oar three times and is obtained sterling, for off-white color solid 100mg, yield 91.0%.
1HNMR(400MHz,DMSO-d6) δ 10.72 (s, 1H), 10.71 (s, 1H), 8.89 (s, 1H), 8.87 (s, 1H), 8.49 (d, J=7.9Hz, 1H), 8.24 (d, J=8.4Hz, 1H), 8.02 7.91 (m, 4H), 7.81 7.70 (m, 4H), 4.99 (t, J=5.8Hz, 1H), 4.91 (d, J=6.3Hz, 1H), 4.42 (q, J=6.6Hz, 1H), 4.26 (dd, J=8.4,5.6Hz, 1H), 4.09 3.97 (m, 1H), 3.69 (hept, J=5.3Hz, 2H), 1.10 (d, J=6.3Hz, 3H).
MS(ESI)m/z:[(M+H)+,508.9].
The preparation of embodiment 3:4,4'-(1,2-acetenyl) two (N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide) (compound 3)
(a) (2S, 3R)-3-hydroxyl-2-(4-iodobenzoyl) methyl butyrate
By the hydrochlorate (168mg of threonine methyl; 0.991mmol) with 4-iodo-benzoic acid (205mg; 0.826mmol) it is dissolved in 10mlN; in dinethylformamide; argon shield, is sequentially added into 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (190mg, 0.991mmol), I-hydroxybenzotriazole (134mg at 0 DEG C; 0.991mmol), diisopropyl ethyl amine (427mg, 3.304mmol).20h, TLC detection is stirred at room temperature and reacts complete (CH2Cl2/ MeOH=20/1), add 40ml ethyl acetate, then wash with saturated aqueous ammonium chloride and saturated sodium-chloride water solution successively, anhydrous sodium sulfate dries.Cross and filter anhydrous sodium sulfate, then solution is spin-dried for column chromatography (CH2Cl2/ MeOH=100/1-80/1), obtain yellow solid 140mg, yield 38.9%.
1HNMR (400MHz, Chloroform-d) δ 7.81 (d, J=8.4Hz, 2H), 7.57 (d, J=8.5Hz, 2H), 6.88 (d, J=8.8Hz, 2H), 4.80 (dd, J=8.8,2.4Hz, 1H), 4.47 (ddd, J=6.7,4.5,2.4Hz, 1H), 3.81 (s, 3H), 2.14 (d, J=4.7Hz, 1H), 1.29 (d, J=6.4Hz, 3H).
MS(ESI)m/z:[(M+H)+,386.0].
(b) (2S, 2'S, 3R, 3'R)-2,2'-((4,4'-(1,2-acetenyl) two (benzoyl)) two (3-hydroxybutyrate methyl ester)
Compound (2S prepared by above-mentioned (a), 3R)-3-hydroxyl-2-(4-iodobenzoyl) methyl butyrate (140mg, 0.386mmol) with (2S, 3R)-2-(4-acetylenylbenzene formamido group)-3-hydroxybutyrate methyl ester (121mg, 0.463mmol) it is dissolved in the anhydrous tetrahydrofuran solution of 15ml, under argon shield, it is sequentially added into triethylamine (78mg, 0.772mmol), two (triphenylphosphine) palladium chloride (14mg, 0.019mmol) with Hydro-Giene (Water Science). (4mg, 0.019mmol), 12h is reacted under 40 DEG C of conditions, complete (CH is reacted in TLC detection2Cl2/ MeOH=20/1), add 40ml ethyl acetate, then wash with saturated aqueous ammonium chloride and saturated sodium-chloride water solution successively, anhydrous sodium sulfate dries.Cross and filter anhydrous sodium sulfate, then solution is spin-dried for column chromatography (CH2Cl2/ MeOH=100/1-80/1), obtain yellow solid 90mg, yield 47.0%.
1HNMR(400MHz,DMSO-d6) δ 8.43 (d, J=8.1Hz, 2H), 7.98 (d, J=8.1Hz, 4H), 7.73 (d, J=8.1Hz, 4H), 4.99 (d, J=7.5Hz, 2H), 4.52 (dd, J=8.2,4.2Hz, 2H), 4.20 (td, J=6.9,4.4Hz, 2H), 3.67 (s, 6H), 1.14 (s, 3H) 1.18 (s, 3H).
MS(EI)m/z:(M+,496).
(c) 4,4'-(1,2-acetenyl) two (N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide)
Compound (2S prepared by above-mentioned (b), 2'S, 3R, 3'R)-2,2'-((4,4'-(1,2-acetenyl) two (benzoyls)) two (3-hydroxybutyrate methyl ester) (90mg, 0.216mmol) are dissolved in the mixed solution of 5ml dichloromethane and 10ml methanol, drip the aqueous hydroxylamine solution (1ml) of 50% at 0 DEG C, 12h, TLC (CH is stirred at room temperature2Cl2/ MeOH=20/1) detect raw material disappearance.Being spin-dried for by solution, dichloromethane is pulled an oar three times and is obtained sterling, for off-white color solid 80mg, yield 88.5%.
1HNMR(400MHz,DMSO-d6) δ 10.69 (s, 2H), 8.87 (s, 2H), 8.19 (d, J=8.5Hz, 2H), 7.97 (d, J=8.0Hz, 4H), 7.70 (d, J=8.0Hz, 4H), 4.92 (d, J=6.3Hz, 2H), 4.27 (dd, J=8.4,5.5Hz, 2H), 4.03 (q, J=6.0Hz, 2H), 1.10 (d, J=6.3Hz, 6H).
MS(ESI)m/z:[(M+H)+,521.1].
The preparation of embodiment 4:N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base)-4-((4-(3-(methylsulfonyl) propoxyl group) phenyl) acetenyl) Benzoylamide (compound 4)
(a) (2S, 3R)-3-hydroxyl-2-(4-((4-(3-(methylsulfonyl) propoxyl group) phenyl) acetenyl) benzoyl) methyl butyrate
With the iodo-4-of compound 1-(3-(methylsulfonyl) propoxyl group) benzene (product of embodiment 1 step (a)) (237mg, 0.498mmol), (2S, 3R)-2-(4-acetylenylbenzene formamido group)-3-hydroxybutyrate methyl ester (130mg, 0.696mmol), triethylamine (126mg, 1.245mmol), two (triphenylphosphine) palladium chloride (17mg, 0.025mmol) with Hydro-Giene (Water Science). (5mg, 0.025mmol), anhydrous tetrahydro furan is as solvent, according to (b) described method in embodiment 3, obtain yellow solid 200mg, yield 84.9%.
1HNMR(400MHz,CDCl3) δ 7.83 (d, J=8.6Hz, 2H), 7.58 (d, J=8.6Hz, 2H), 7.49 (d, J=8.9Hz, 2H), 6.94 6.80 (m, 3H), 4.83 (d, J=11.1Hz, 1H), 4.56 4.41 (m, 1H), 4.15 (t, J=5.8Hz, 2H), 3.80 (s, 3H), 3.27 (dd, J=9.2,6.1Hz, 2H), 2.97 (s, 3H), 2.42 2.33 (m, 2H), 2.10 (d, J=4.4Hz, 1H), 1.31 (d, J=6.4Hz, 3H).
MS(ESI)m/z:[(M+H)+,496.2].
(b) N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base)-4-((4-(3-(methylsulfonyl) propoxyl group) phenyl) acetenyl) Benzoylamide
With compound (2S prepared by above-mentioned (a); 3R)-3-hydroxyl-2-(4-((4-(3-(methylsulfonyl) propoxyl group) phenyl) acetenyl) benzoyl) methyl butyrate (80mg; 0.169mmol) for raw material; dichloromethane and methanol are solvent; according to the method described in (e) in embodiment 1; obtain white solid 30mg, yield 37.4%.
1HNMR(400MHz,DMSO-d6null)δ10.70(s,1H),8.88(s,1H),8.16(d,J=8.5Hz,1H),7.94(d,J=8.4Hz,2H),7.63(d,J=8.4Hz,2H),7.54(d,J=8.7Hz,2H),7.02(d,J=8.8Hz,2H),4.92(d,J=6.4Hz,1H),4.26(dd,J=8.5,5.5Hz,1H),4.14(t,J=6.2Hz,2H),4.03(q,J=6.2Hz,1H),3.33–3.26(m,2H),3.03(s,3H),2.21–2.11(m,2H),1.10(d,J=6.3Hz,3H).
MS(ESI)m/z:[(M+H)+,475.0].
The preparation of embodiment 5:N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base)-4-((4-(2-(methylsulfonyl) ethyoxyl) phenyl) acetenyl) Benzoylamide (compound 5)
The iodo-4-of (a) 1-(2-(methylsulfonyl) ethyoxyl) benzene
With compound 3-methylsulfonyl ethanol (200mg, 1.610mmol) with 4-iodophenol (425mg, 1.932mmol), triphenylphosphine (633mg, 2.415mmol) with diethyl azodiformate (420mg, 2.415mmol) for raw material, with anhydrous oxolane for solvent, according to the method described in (a) in embodiment 1, obtain white solid 411mg, yield 78.3%.
1HNMR (400MHz, Chloroform-d) δ 7.60 (d, J=9.0Hz, 2H), 6.69 (d, J=9.0Hz, 2H), 4.41 (t, 2H), 3.44 (t, J=5.3Hz, 2H), 3.05 (s, 3H).
MS(ESI)m/z:[(M+Cl)-,360.5].
(b) (2S, 3R)-3-hydroxyl-2-(4-((4-(2-(methylsulfonyl) ethyoxyl) phenyl) acetenyl) benzoyl) methyl butyrate
With the iodo-4-of compound 1-(3-(methylsulfonyl) ethyoxyl) benzene (411mg prepared by above-mentioned (a), 0.984mmol), (2S, 3R)-2-(4-acetylenylbenzene formamido group)-3-hydroxybutyrate methyl ester (280mg, 1.073mmol), triethylamine (298mg, 2.952mmol), two (triphenylphosphine) palladium chloride (35mg, 0.049mmol) with Hydro-Giene (Water Science). (10mg, 0.049mmol), anhydrous tetrahydro furan is as solvent, according to (b) described method in embodiment 3, obtain yellow solid 328mg, yield 72.5%.
1HNMR (400MHz, Chloroform-d) δ 7.85 (d, J=8.3Hz, 2H), 7.61 (d, J=8.2Hz, 2H), 7.54 (d, J=8.7Hz, 2H), 6.93 (d, J=8.8Hz, 2H), 4.86 (dd, J=8.7,2.4Hz, 1H), 4.65 4.36 (m, 3H), 3.84 (s, 3H), 3.49 (t, J=5.3Hz, 2H), 3.11 (s, 1H), 1.33 (d, J=6.4Hz, 3H).
MS(ESI)m/z:[(M+H)+,459.9].
(c) N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base)-4-((4-(2-(methylsulfonyl) ethyoxyl) phenyl) acetenyl) Benzoylamide
With compound (2S prepared by above-mentioned (b); 3R)-3-hydroxyl-2-(4-((4-(3-(methylsulfonyl) ethyoxyl) phenyl) acetenyl) benzoyl) methyl butyrate (100mg; 0.217mmol) for raw material; dichloromethane and methanol are solvent; according to the method described in (e) in embodiment 1; obtain white solid 30mg, yield 30.0%.
1nullHNMR(400MHz,DMSO)δ10.69(s,1H),8.87(s,1H),8.15(d,J=8.5Hz,1H),7.94(d,J=8.4Hz,2H),7.63(d,J=8.4Hz,2H),7.55(d,J=8.8Hz,2H),7.07(d,J=8.9Hz,2H),4.92(d,J=6.4Hz,1H),4.40(t,J=5.7Hz,2H),4.26(dd,J=8.4,5.6Hz,1H),4.03(dd,J=12.2,6.1Hz,1H),3.65(t,J=5.6Hz,2H),3.09(s,3H),1.09(d,J=6.3Hz,3H).
MS(ESI)m/z:[(M+H)+,460.8].
Embodiment 6:(S) preparation of-N-(3-amino-1-(azanol)-3-methyl isophthalic acid-oxygen-containing butane-2-base)-4-((4-(2-(methylsulfonyl) ethyoxyl) phenyl) acetenyl) Benzoylamide (compound 6)
(a) (S)-3-((tertbutyloxycarbonyl) amino)-3-methyl-2-(4-((4-(2-(methylsulfonyl) ethyoxyl) phenyl) acetenyl) Benzoylamide) methyl butyrate
With the iodo-4-of compound 1-(3-(methylsulfonyl) ethyoxyl) benzene (product of embodiment 5 step (a)) (209mg, 0.641mmol), (S)-3-((tertbutyloxycarbonyl) amino)-2-(4-acetylenylbenzene Methanamide)-3 Methylbutanoic acid methyl ester (WO2013170030A1) (200mg, 0.534mmol), triethylamine (162mg, 1.602mmol), two (triphenylphosphine) palladium chloride (37mg, 0.053mmol) with Hydro-Giene (Water Science). (10mg, 0.053mmol), anhydrous tetrahydro furan is as solvent, according to (b) described method in embodiment 3, obtain yellow solid 280mg, yield 91.6%.
1HNMR (400MHz, Chloroform-d) δ 9.13 (s, 1H), 7.98 7.87 (m, 2H), 7.65 7.55 (m, 2H), 7.54 7.47 (m, 2H), 6.90 (d, J=8.8Hz, 2H), 4.74 (d, J=8.0Hz, 1H), 4.70 (s, 1H), 4.48 (dd, J=5.8,4.9Hz, 2H), 3.75 (s, 3H), 3.49 3.42 (m, 2H), 3.08 (d, J=0.8Hz, 3H), 1.53 (s, 3H), 1.49 (s, 3H), 1.46 (s, 9H).
MS(ESI)m/z:[(M+H)+,572.7].
(b) (S)-3-amino-3-methyl-2-(4-((4-(2-(methylsulfonyl) ethyoxyl) phenyl) acetenyl) Benzoylamide) methyl butyrate
Compound (S)-3-((tertbutyloxycarbonyl) amino)-3-methyl-2-(4-((4-(2-(methylsulfonyl) ethyoxyl) phenyl) acetenyl) Benzoylamide) methyl butyrate (280mg prepared by above-mentioned (a), 0.489mmol) it is dissolved in the 1 of 10ml, in 4-dioxane solution, the 1 of dropping 5ml, 4-dioxane hydrogen chloride solution, 5h is stirred at room temperature, TLC (PE/EA=2/1) detection reaction is complete, 40ml acetic acid ethyl dissolution is added after being spin-dried for solvent, saturated sodium bicarbonate aqueous solution washes away the acid of remnants, wash with saturated sodium-chloride water solution again, ethyl acetate layer anhydrous sodium sulfate dries.Filtration is spin-dried for obtain solid 185mg, yield 80.1%.
1HNMR (400MHz, DMSO-d6) δ 8.41 (s, 1H), 7.91 (d, J=8.1Hz, 2H), 7.64 (d, J=8.0Hz, 2H), 7.56 (d, J=8.4Hz, 2H), 7.07 (d, J=8.5Hz, 2H), 4.42 (s, 1H), 4.40 (d, J=5.2Hz, 2H), 3.66 (s, 3H), 3.64 (d, 2H), 3.09 (s, 3H), 1.15 (s, 3H), 1.13 (s, 3H).
MS(ESI)m/z:[(M+H)+,473.1]
(c) (S)-N-(3-amino-1-(azanol)-3-methyl isophthalic acid-oxygen-containing butane-2-base)-4-((4-(2-(methylsulfonyl) ethyoxyl) phenyl) acetenyl) Benzoylamide
With compound (S)-3-amino-3-methyl-2-(4-((4-(2-(methylsulfonyl) ethyoxyl) phenyl) acetenyl) Benzoylamide) methyl butyrate (185mg prepared by above-mentioned (b), 0.391mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (e) in embodiment 1, obtain white solid 60mg, yield 32.4%.
1HNMR(400MHz,DMSO-d6) δ 11.19 (s, 1H), 9.26 (s, 1H), 8.63 (d, J=9.3Hz, 1H), 7.99 (d, J=8.2Hz, 2H), 7.65 (d, J=8.0Hz, 2H), 7.55 (d, J=8.7Hz, 2H), 7.07 (d, J=8.8Hz, 2H), 4.70 (d, J=9.3Hz, 1H), 4.40 (t, J=5.6Hz, 2H), 3.65 (s, 2H), 3.09 (s, 3H), 1.35 (s, 3H), 1.31 (s, 3H).
MS(ESI)m/z:[(M+H)+,474.1]
Embodiment 7:(S) preparation of-N-(3-amino-1-(azanol)-3-methyl isophthalic acid-oxygen-containing butane-2-base)-4-((4-(3-(methylsulfonyl) propoxyl group) phenyl) acetenyl) Benzoylamide (compound 7)
(a) (S)-3-((tertbutyloxycarbonyl) amino)-3-methyl-2-(4-((4-(2-(methylsulfonyl) propoxyl group) phenyl) acetenyl) Benzoylamide) methyl butyrate
With the iodo-4-of 1-(3-(methylsulfonyl) propoxyl group) benzene (product of embodiment 5 step (a)) (218mg, 0.641mmol), (S)-3-((tertbutyloxycarbonyl) amino)-2-(4-acetylenylbenzene Methanamide)-3 Methylbutanoic acid methyl ester (200mg, 0.534mmol), triethylamine (162mg, 1.602mmol), two (triphenylphosphine) palladium chloride (37mg, 0.053mmol) with Hydro-Giene (Water Science). (10mg, 0.053mmol), anhydrous tetrahydro furan is as solvent, according to (b) described method in embodiment 3, obtain yellow solid 260mg, yield 82.9%.
1HNMR (400MHz, Chloroform-d) δ 9.13 (s, 1H), 7.94 (d, J=8.1Hz, 2H), 7.61 (d, J=8.1Hz, 2H), 7.51 (d, J=8.4Hz, 2H), 6.89 (d, J=8.4Hz, 2H), 4.82 4.67 (m, 2H), 4.17 (t, J=5.8Hz, 2H), 3.77 (s, 3H), 3.42 3.15 (m, 2H), 2.99 (s, 3H), 2.44 2.34 (m, 2H), 1.55 (s, 3H), 1.51 (s, 3H), 1.48 (s, 9H).
MS(ESI)m/z:[(M+Na)+,609.2].
(b) (S)-3-amino-3-methyl-2-(4-((4-(2-(methylsulfonyl) propoxyl group) phenyl) acetenyl) Benzoylamide) methyl butyrate
(S)-3-((tertbutyloxycarbonyl) amino)-3-methyl-2-(4-((4-(2-(methylsulfonyl) propoxyl group) phenyl) acetenyl) Benzoylamide) methyl butyrate (260mg prepared by above-mentioned (a), 0.443mmol) it is dissolved in the 1 of 10ml, in 4-dioxane solution, the 1 of dropping 5ml, 4-dioxane hydrogen chloride solution, 5h is stirred at room temperature, TLC (PE/EA=2/1) detection reaction is complete, 40ml acetic acid ethyl dissolution is added after being spin-dried for solvent, saturated sodium bicarbonate aqueous solution washes away the acid of remnants, wash with saturated sodium-chloride water solution again, ethyl acetate layer anhydrous sodium sulfate dries.Filtration is spin-dried for obtain solid 170mg, yield 78.9%.
1HNMR (400MHz, DMSO) δ 8.54 (s, 1H), 7.93 (d, J=8.3Hz, 2H), 7.64 (d, J=8.4Hz, 2H), 7.54 (d, J=8.8Hz, 2H), 7.02 (d, J=8.8Hz, 2H), 4.53 (d, J=3.2Hz, 1H), 4.14 (t, J=6.2Hz, 2H), 3.67 (s, 3H), 3.31 3.23 (m, 2H), 3.03 (s, 3H), 2.26 2.08 (m, 2H), 1.20 (s, 3H), 1.19 (s, 3H).
MS(ESI)m/z:[(M+H)+,487.0].
(c) (S)-N-(3-amino-1-(azanol)-3-methyl isophthalic acid-oxygen-containing butane-2-base)-4-((4-(2-(methylsulfonyl) propoxyl group) phenyl) acetenyl) Benzoylamide
With (S)-3-amino-3-methyl-2-(4-((4-(2-(methylsulfonyl) propoxyl group) phenyl) acetenyl) Benzoylamide) methyl butyrate (170mg prepared by above-mentioned (b), 0.349mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (e) in embodiment 1, obtain white solid 60mg, yield 35.3%.
1nullHNMR(300MHz,DMSO-d6)δ11.24(d,J=5.2Hz,1H),9.28(d,J=13.9Hz,1H),8.55(d,J=9.4Hz,1H),8.04(s,2H),7.95(d,J=8.1Hz,2H),7.63(d,J=8.0Hz,2H),7.52(d,J=8.1Hz,2H),7.00(d,J=9.2Hz,2H),4.69(d,J=9.1Hz,1H),4.32–3.97(m,2H),3.25(d,J=8.2Hz,2H),3.01(s,3H),2.11(s,2H),1.33(s,3H),1.28(s,3H).
MS(ESI)m/z:[(M+H)+,488.0].
Embodiment 8:N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base) preparation of-4-((4-((5-hydroxyl-4-oxa--1,4-dihydropyridine-2-base) methyl ester) phenyl) acetenyl) Benzoylamide (compound 8)
(a) 2-((4-iodophenyl) methylene)-4,5-two ((4-methoxybenzyl) oxygen base) pyridine
With (4,5-bis-((4-methoxybenzyl) oxygen base)-2-pyridine radicals) methanol (WO2013150296A1) (500mg, 1.311mmol) with 4-iodophenol (346mg, 1.573mmol), triphenylphosphine (516mg, 1.967mmol) with diethyl azodiformate (343mg, 1.967mmol) for raw material, with anhydrous oxolane for solvent, according to the method described in (a) in embodiment 1, obtain white solid 400mg, yield 52.3%.
1HNMR (400MHz, Chloroform-d) δ 8.11 (s, 1H), 7.53 (d, J=9.1Hz, 2H), 7.33 7.28 (m, 4H), 7.04 (s, 1H), 6.88 (d, J=2.3Hz, 2H), 6.86 (d, J=2.3Hz, 2H), 6.71 (d, J=8.9Hz, 2H), 5.10 (s, 2H), 5.08 (s, 2H), 5.03 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H).
MS(ESI)m/z:[(M+H)+,584.4].
(b) (2S, 3R)-2-(4-((4-((4,5-bis-((4-methoxybenzyl) oxygen base)-2-pyridine radicals) methoxyl group) phenyl) acetenyl) Benzoylamide)-3-hydroxybutyrate methyl ester
Compound 2-((4-iodophenyl) methylene)-4 with above-mentioned (a), 5-bis-((4-methoxybenzyl) oxygen base) pyridine (400mg, 0.686mmol), (2S, 3R)-2-(4-acetylenylbenzene formamido group)-3-hydroxybutyrate methyl ester (215mg, 0.823mmol), triethylamine (208mg, 2.058mmol), two (triphenylphosphine) palladium chloride (24mg, 0.034mmol) with Hydro-Giene (Water Science). (7mg, 0.034mmol), anhydrous tetrahydro furan is as solvent, according to (b) described method in embodiment 3, obtain yellow solid 300mg, yield 61.0%.
1HNMR(400MHz,CDCl3) δ 8.13 (s, 1H), 7.82 (d, J=8.3Hz, 2H), 7.58 (d, J=8.3Hz, 2H), 7.47 (d, J=8.7Hz, 2H), 7.31 (t, J=8.9Hz, 4H), 7.06 (s, 1H), 6.92 (d, J=8.8Hz, 2H), 6.87 (m, 5H), 5.11 (s, 2H), 5.10 (s, 4H), 4.83 (dd, J=8.6,2.1Hz, 1H), 4.52 4.43 (m, 1H), 3.81 (s, 9H), 1.25 (d, J=2.5Hz, 3H).
MS(ESI)m/z:[(M+H)+,739.4].
(c) 4-((4-((4,5-bis-((4-methoxybenzyl) oxygen base)-2-pyridine radicals) methoxyl group) phenyl) acetenyl)-N-((2S, 3R)-3 hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide
With compound (2S prepared by above-mentioned (b), 3R)-2-(4-((4-((4,5-bis-((4-methoxybenzyl) oxygen base)-2-pyridine radicals) methoxyl group) phenyl) acetenyl) Benzoylamide)-3-hydroxybutyrate methyl ester (300mg, 0.419mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (e) in embodiment 1, obtain white solid 200mg, yield 66.5%.
1nullHNMR(400MHz,DMSO)δ10.71(s,1H),8.87(s,1H),8.20(s,1H),8.16(d,J=8.3Hz,1H),7.94(d,J=8.4Hz,2H),7.63(d,J=8.4Hz,2H),7.53(d,J=9.0Hz,2H),7.35(dd,J=10.4,8.2Hz,4H),7.30(s,1H),7.08(d,J=8.1Hz,2H),6.93(dd,J=8.7,4.2Hz,4H),5.14(s,2H),5.10(s,2H),5.08(s,2H),4.28–4.24(m,1H),4.06–4.00(m,1H),3.76(s,3H),3.75(s,3H),1.10(d,J=6.0Hz,3H).
MS(ESI)m/z:[(M+H)+,718.0].
(d) N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base)-4-((4-((5-hydroxyl-4-oxa--1,4-dihydropyridine-2-base) methyl ester) phenyl) acetenyl) Benzoylamide
Compound 4-((4-((4 prepared by above-mentioned (c), 5-bis-((4-methoxybenzyl) oxygen base)-2-pyridine radicals) methoxyl group) phenyl) acetenyl)-N-((2S, 3R)-3 hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide (200mg, 0.279mmol) it is dissolved in the 10ml dichloromethane dried, 0.2ml trifluoroacetic acid is dripped at 0 DEG C, finish to move to and 5h, TLC (CH is stirred at room temperature2Cl2/ MeOH=10:1) detect and react complete, it is spin-dried for, ethyl acetate is pulled an oar three times, obtains solid, yield 82.7%.
1HNMR(400MHz,DMSO-d6) δ 10.70 (s, 1H), 8.15 (d, J=8.4Hz, 1H), 7.95 (d, J=8.1Hz, 2H), 7.65 (s, 1H), 7.63 (d, J=8.1Hz, 2H), 7.56 (d, J=8.3Hz, 3H), 7.09 (d, J=8.5Hz, 2H), 6.65 (s, 1H), 5.07 (s, 2H), 4.32 4.23 (m, 1H), 4.09 3.99 (m, 1H), 1.10 (d, J=6.2Hz, 3H).
MS(ESI)m/z:[(M+H)+,478.0].
Embodiment 9:4-((4-((1,5-dihydroxy-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) phenyl) acetenyl) preparation of-N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide (compound 9)
(a) 1,5-bis-(benzhydryl oxygen base)-2-((4-iodine phenoxy group) methyl) pyridine-4 (1H)-one
With compound 1,5-bis-(benzhydryl oxygen base)-2-(methylol) pyridine-4 (1H)-one [JournalofMedicinalChemistry56 (2013) 5541-5552] (500mg, 1.021mmol) with 4-iodophenol (270mg, 1.225mmol), triphenylphosphine (402mg, 1.532mmol) with diethyl azodiformate (267mg, 1.532mmol) for raw material, with anhydrous oxolane for solvent, according to the method described in (a) in embodiment 1, obtain white solid 390mg, yield 55.2%.
1HNMR (400MHz, Chloroform-d) δ 7.75 7.26 (m, 20H), 7.19 7.15 (m, 2H), 6.98 (s, 1H), 6.43 (d, J=3.2Hz, 2H), 6.40 (s, 1H), 6.22 (s, 1H), 5.88 (s, 1H), 4.50 (s, 2H).
MS(ESI)m/z:[(M+H)+,714.2].
(b) (2S, 3R)-2-(4-((4-((1,5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) phenyl) acetenyl) benzamido)-3-hydroxybutyrate methyl ester
Compound 1 with above-mentioned (a), 5-bis-(benzhydryl oxygen base)-2-((4-iodine phenoxy group) methyl) pyridine-4 (1H)-one (390mg, 0.564mmol), (2S, 3R)-2-(4-acetylenylbenzene formamido group)-3-hydroxybutyrate methyl ester (177mg, 0.677mmol), triethylamine (171mg, 1.692mmol), two (triphenylphosphine) palladium chloride (20mg, 0.028mmol) with Hydro-Giene (Water Science). (6mg, 0.028mmol), anhydrous tetrahydro furan is as solvent, according to (b) described method in embodiment 3, obtain yellow solid 300mg, yield 64.5%.
1nullHNMR(400MHz,Chloroform-d)δ7.96(d,J=8.3Hz,2H),7.79(d,J=8.3Hz,1H),7.55(d,J=8.3Hz,2H),7.48–7.25(m,20H),7.19–7.16(m,2H),6.96(s,1H),6.66(d,J=8.7Hz,2H),6.45(s,1H),6.02(s,1H),5.88(s,1H),4.78(dd,J=8.2,3.2Hz,1H),4.60–4.50(m,2H),4.47(dd,J=6.5,3.3Hz,1H),3.80(s,3H),1.29(d,J=6.4Hz,3H).
MS(ESI)m/z:[(M+H)+,825.0].
(c) 4-((4-((1,5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) phenyl) acetenyl)-N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide
With compound (2S prepared by above-mentioned (b), 3R)-2-(4-((4-((1,5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) phenyl) acetenyl) benzamido)-3-hydroxybutyrate methyl ester (300mg, 0.363mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (e) in embodiment 1, obtain white solid 200mg, yield 66.7%.
1HNMR(400MHz,DMSO-d6null)δ10.70(s,1H),8.88(s,1H),8.16(d,J=8.4Hz,1H),7.95(d,J=8.4Hz,2H),7.85(s,1H),7.64(d,J=8.4Hz,2H),7.48(d,J=8.7Hz,2H),7.44–7.30(m,16iH),7.24–7.21(m,4H),6.78(d,J=8.9Hz,2H),6.47(s,1H),6.39(s,1H),6.02(s,1H),4.92(d,J=6.3Hz,1H),4.76(s,2H),4.27(dd,J=8.5,5.5Hz,1H),4.12(q,J=5.3Hz,1H),4.03(q,J=6.1Hz,1H),3.17(d,J=5.2Hz,3H),1.10(d,J=6.3Hz,3H).
MS(ESI)m/z:[(M-H)-,824.2].
(d) 4-((4-((1,5-dihydroxy-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) phenyl) acetenyl)-N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide
With compound 4-((4-((1 prepared by above-mentioned (c), 5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) phenyl) acetenyl)-N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base) Benzoylamide (200mg, 0.242mmol) for raw material, dichloromethane is solvent, trifluoroacetic acid is de-benzhydryl reagent, according to (d) described method in embodiment 8, obtain solid 110mg, yield 82.7%.
1HNMR (600MHz, DMSO) δ 10.72 (s, 1H), 8.90 (s, 1H), 8.18 (d, J=8.1Hz, 1H), 7.95 (d, J=7.8Hz, 2H), 7.92 (s, 1H), 7.64 (d, J=7.7Hz, 2H), 7.56 (d, J=7.8Hz, 2H), 7.10 (d, J=8.1Hz, 2H), 6.93 (s, 1H), 5.22 (s, 2H), 4.28 4.25 (m, 1H), 4.06 4.00 (m, 1H), 1.10 (d, J=5.7Hz, 3H).
MS(ESI)m/z:[(M+H)+,494.1].
Embodiment 10:4-((4-((1,5-dihydroxy-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) phenyl)-1,3-diacetylene base-1-base) preparation of-N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide (compound 10)
(a) 1,5-bis-(benzhydryl oxygen base)-2-((4-((trimethylsilyl) acetenyl) phenoxy group) methylene) pyridine-4 (1H)-one
With compound 1, 5-bis-(benzhydryl oxygen base)-2-((4-iodine phenoxy group) methyl) pyridine-4 (1H)-one (product of embodiment 9 step (a)) (390mg, 0.564mmol), trimethylsilyl acetylene (66mg, 0.677mmol), triethylamine (171mg, 1.692mmol), two (triphenylphosphine) palladium chloride (20mg, 0.028mmol) with Hydro-Giene (Water Science). (6mg, 0.028mmol), anhydrous tetrahydro furan is as solvent, according to (b) described method in embodiment 3, obtain yellow solid 300mg, yield 80.4%.
1HNMR (400MHz, Chloroform-d) δ 7.75 7.26 (m, 20H), 7.19 7.15 (m, 2H), 6.98 (s, 1H), 6.43 (d, J=3.2Hz, 2H), 6.40 (s, 1H), 6.22 (s, 1H), 5.88 (s, 1H), 4.50 (s, 2H), 0.23 (s, 9H).
MS(ESI)m/z:[(M+H)+,662.2].
(b) 1,5-bis-(benzhydryl oxygen base)-2-((4-acetenyl phenoxy group) methylene) pyridine-4 (1H)-one
With above-mentioned (a) compound 1,5-bis-(benzhydryl oxygen base)-2-((4-((trimethylsilyl) acetenyl) phenoxy group) methylene) pyridine-4 (1H)-one (300mg, 0.453mmol) for raw material, tetra-n-butyl amine fluoride (1M, 0.6ml) for de-trimethylsilyl reagent, oxolane is solvent, according to (c) described method in embodiment 1, obtain white solid 240mg, yield 89.8%.
1HNMR (400MHz, Chloroform-d) δ 7.75 7.26 (m, 20H), 7.19 7.15 (m, 2H), 6.98 (s, 1H), 6.43 (d, J=3.2Hz, 2H), 6.40 (s, 1H), 6.22 (s, 1H), 5.88 (s, 1H), 4.50 (s, 2H), 3.01 (s, 1H).
MS(ESI)m/z:[(M+H)+,662.2].
(c) (2S, 3R)-2-(4-((4-((1,5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) phenyl)-1,3-diacetylene-1-base) Benzoylamide)-3-hydroxybutyrate methyl ester
With compound 1 prepared by above-mentioned (b), 5-bis-(benzhydryl oxygen base)-2-((4-acetenyl phenoxy group) methylene) pyridine-4 (1H)-one (240mg, 0.407mmol), (2S, 3R)-2-(4-acetylenylbenzene formamido group)-3-hydroxybutyrate methyl ester (213mg, 0.813mmol), Schweinfurt green (122mg, 0.813mmol) for raw material, methanol and pyridine are mixed solvent, according to (d) described method in embodiment 1, obtain white solid 138mg, yield 40.0%.
1HNMR (400MHz, Chloroform-d) δ 7.84 (d, J=8.3Hz, 2H), 7.75 7.26 (m, 22H), 7.19 7.15 (m, 2H), 6.98 (s, 1H), 6.43 (d, J=3.2Hz, 2H), 6.40 (s, 1H), 6.22 (s, 1H), 5.88 (s, 1H), 4.84 (dd, J=8.8,2.2Hz, 1H), 4.60 (s, 1H), 4.50 (s, 2H), 3.83 (s, 3H), 1.32 (d, J=6.4Hz, 3H).
MS(ESI)m/z:[(M+H)+,849.3].
(d) 4-((4-((1,5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) phenyl)-1,3-diacetylene-1-base)-N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide
With compound (2S prepared by above-mentioned (c), 3R)-2-(4-((4-((1,5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) phenyl)-1,3-diacetylene-1-base) Benzoylamide)-3-hydroxybutyrate methyl ester (138mg, 0.163mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (e) in embodiment 1, obtain white solid 120mg, yield 87.0%.
1HNMR(400MHz,DMSO-d6null)δ10.70(s,1H),8.88(s,1H),8.16(d,J=8.4Hz,1H),7.85(d,J=8.4Hz,2H),7.85(s,1H),7.66(d,J=8.4Hz,2H),7.48(d,J=8.7Hz,2H),7.44–7.30(m,16H),7.24–7.21(m,4H),6.78(d,J=8.9Hz,2H),6.47(s,1H),6.39(s,1H),6.02(s,1H),4.92(d,J=6.3Hz,1H),4.76(s,2H),4.27(dd,J=8.5,5.5Hz,1H),4.12(q,J=5.3Hz,1H),4.03(q,J=6.1Hz,1H),3.17(d,J=5.2Hz,3H),1.10(d,J=6.3Hz,3H).
MS(ESI)m/z:[(M+H)+,850.3].
(e) 4-((4-((1,5-dihydroxy-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) phenyl)-1,3-diacetylene base-1-base)-N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide
With compound 4-((4-((1 prepared by above-mentioned (d), 5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) phenyl)-1,3-diacetylene-1-base)-N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base) Benzoylamide (120mg, 0.141mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (d) in embodiment 8, obtain white solid 58mg, yield 80.2%.
1HNMR (600MHz, DMSO) δ 10.72 (s, 1H), 8.90 (s, 1H), 8.18 (d, J=8.1Hz, 1H), 7.95 (d, J=7.8Hz, 2H), 7.92 (s, 1H), 7.66 (d, J=7.7Hz, 2H), 7.56 (d, J=7.8Hz, 2H), 7.10 (d, J=8.1Hz, 2H), 6.93 (s, 1H), 5.22 (s, 2H), 4.28 4.25 (m, 1H), 4.06 4.00 (m, 1H), 1.10 (d, J=5.7Hz, 3H) .MS (ESI) m/z:[(M+H)+,494.1].
MS(ESI)m/z:[(M+H)+,518.1].
Embodiment 11:N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base)-4-((4-((5-hydroxyl-4-oxa--1,4-dihydropyridine-2-yl) methoxyl group) phenyl)-1,3-diacetylene-1-base) preparation of Benzoylamide (compound 11)
(a) 4,5-bis-((4-methoxybenzyl) oxygen base)-2-((4-((trimethylsilyl) acetenyl) phenoxy group) methylene) pyridine
With compound 2-((4-iodophenyl) methylene)-4,5-bis-((4-methoxybenzyl) oxygen base) pyridine (product of embodiment 8 step (a)) (420mg, 0.720mmol), trimethylsilyl acetylene (106mg, 1.080mmol), triethylamine (218mg, 2.160mmol), two (triphenylphosphine) palladium chloride (25mg, 0.036mmol) with Hydro-Giene (Water Science). (7mg, 0.036mmol), anhydrous tetrahydro furan is as solvent, according to (b) described method in embodiment 3, obtain yellow solid 350mg, yield 87.8%.
1HNMR (400MHz, Chloroform-d) δ 8.13 (s, 1H), 7.40 (d, J=8.4Hz, 2H), 7.34 (d, J=8.4Hz, 2H), 7.31 (d, J=8.3Hz, 2H), 7.06 (s, 1H), 6.94 6.84 (m, 6H), 5.12 (s, 2H), 5.11 (s, 2H), 5.09 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 0.26 (s, 9H).
MS(ESI)m/z:[(M+H)+,554.0].
(b) 2-((4-ethynyl phenyl) methylene)-4,5-two ((4-methoxybenzyl) oxa-) pyridine
With above-mentioned (a) compound 4,5-bis-((4-methoxybenzyl) oxygen base)-2-((4-((trimethylsilyl) acetenyl) phenoxy group) methylene) pyridine (350mg, 0.632mmol) for raw material, tetra-n-butyl amine fluoride (1M, 0.8ml) for de-trimethylsilyl reagent, oxolane is solvent, according to (c) described method in embodiment 1, obtain white solid 270mg, yield 88.8%.
1HNMR (400MHz, Chloroform-d) δ 8.15 (s, 1H), 7.43 (d, J=8.5Hz, 2H), 7.33 (dd, J=10.5,8.5Hz, 4H), 7.07 (s, 1H), 6.89 (d, J=8.1Hz, 6H), 5.13 (s, 2H), 5.11 (s, 2H), 5.10 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.03 (s, 1H).
MS(ESI)m/z:[(M+H)+482.0].
(c) (2S, 3R)-2-(4-((4-((4,5-bis-((4-methoxybenzyl) oxygen base) pyridine-2-base) methoxyl group) phenyl)-1,3-diacetylene-1-base) Benzoylamide)-3-hydroxybutyrate methyl ester
With compound 2-((4-ethynyl phenyl) methylene)-4 prepared by above-mentioned (b), 5-bis-((4-methoxybenzyl) oxa-) pyridine (270mg, 0.561mmol), (2S, 3R)-2-(4-acetylenylbenzene formamido group)-3-hydroxybutyrate methyl ester (293mg, 1.121mmol), Schweinfurt green (168mg, 1.121mmol) for raw material, methanol and pyridine are mixed solvent, according to (d) described method in embodiment 1, obtain white solid 162mg, yield 38.9%.
1HNMR(300MHz,DMSO-d6null)δ8.41(d,J=8.1Hz,1H),8.17(s,1H),7.92(d,J=8.4Hz,2H),7.70(d,J=8.3Hz,2H),7.56(d,J=8.7Hz,2H),7.33(dd,J=8.6,7.7Hz,4H),7.27(s,1H),7.06(d,J=8.8Hz,2H),6.91(dd,J=8.7,3.2Hz,4H),5.12(s,2H),5.07(s,4H),4.96(d,J=7.4Hz,1H),4.48(dd,J=8.2,4.2Hz,1H),4.21–4.13(m,1H),3.74(s,3H),3.73(s,3H),3.64(s,3H),1.13(d,J=6.4Hz,3H).
MS(ESI)m/z:[(M+H)+,741.0].
(d) 4-((4-((4,5-bis-((4-methoxybenzyl) oxygen base) pyridine-2-base) methoxyl group) phenyl)-1,3-diacetylene-1-base)-N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide
With compound (2S prepared by above-mentioned (c), 3R)-2-(4-((4-((4,5-bis-((4-methoxybenzyl) oxygen base) pyridine-2-base) methoxyl group) phenyl)-1,3-diacetylene-1-base) Benzoylamide)-3-hydroxybutyrate methyl ester (162mg, 0.219mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (e) in embodiment 1, obtain white solid 138mg, yield 85.0%.
1HNMR(400MHz,DMSO-d6null)δ10.69(s,1H),8.87(s,1H),8.22–8.18(m,2H),7.95(d,J=8.0Hz,2H),7.71(d,J=8.1Hz,2H),7.58(d,J=8.4Hz,2H),7.35(dd,J=10.2,8.3Hz,4H),7.29(s,1H),7.08(d,J=8.5Hz,2H),6.97–6.89(m,4H),5.14(s,2H),5.09(s,4H),4.90(d,J=6.7Hz,1H),4.26(dd,J=8.5,5.5Hz,1H),4.03(q,J=6.2Hz,1H),3.76(s,3H),3.75(s,3H),1.09(d,J=6.3Hz,3H).
MS(ESI)m/z:[(M+H)+,742.1].
(e) N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base)-4-((4-((5-hydroxyl-4-oxa--1,4-dihydropyridine-2-yl) methoxyl group) phenyl)-1,3-diacetylene-1-base) Benzoylamide
With compound 4-((4-((4 prepared by above-mentioned (d), 5-bis-((4-methoxybenzyl) oxygen base) pyridine-2-base) methoxyl group) phenyl)-1,3-diacetylene-1-base)-N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base) Benzoylamide (138mg, 0.186mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (d) in embodiment 8, obtain white solid 65mg, yield 69.7%.
1HNMR (400MHz, DMSO-d6) δ 10.70 (s, 1H), 8.21 (d, J=8.4Hz, 1H), 7.98 (s, 1H), 7.95 (d, J=8.1Hz, 2H), 7.71 (d, J=8.0Hz, 2H), 7.63 (d, J=8.2Hz, 2H), 7.11 (d, J=8.5Hz, 2H), 7.08 (s, 1H), 5.24 (s, 2H), 4.26 (dd, J=8.4,5.5Hz, 1H), 4.10 3.94 (m, 1H), 1.09 (d, J=6.2Hz, 3H).
MS(ESI)m/z:[(M+H)+,502.1].
The preparation of embodiment 12:N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base)-4-(3-(methylsulfonyl) propoxyl group) Benzoylamide (compound 12)
(a) (2S, 3R)-3-hydroxyl-2-(4-hydroxybenzamide) methyl butyrate
With P-hydroxybenzoic acid (114mg, 0.826mmol), threonine methyl ester hydrochloric salt (168mg, 0.991mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (190mg, 0.991mmol), I-hydroxybenzotriazole (134mg, 0.991mmol), diisopropyl ethyl amine (427mg, 3.304mmol) for raw material, N-N-dimethylformamide is solvent, according to the described method of embodiment 2 (b), obtain white solid 157mg, yield 75.2%.
1HNMR(300MHz,CD3OD) δ 7.78 (d, J=8.4Hz, 2H), 6.85 (d, J=8.4Hz, 2H), 4.66 (d, J=3.3Hz, 1H), 4.37 (dq, J=3.3,6.6Hz, 1H), 3.75 (s, 3H), 1.22 (d, J=6.6Hz, 3H)；
MS(ESI)m/z:[(M-H)-,252.0].
(b) (2S, 3R)-3-hydroxyl-2-(4-(3-(methylsulfonyl) propoxyl group) Benzoylamide) methyl butyrate
With compound (2S prepared by above-mentioned (a), 3R)-3-hydroxyl-2-(4-hydroxybenzamide) methyl butyrate (157mg, 0.620mmol), 3-methylsulfonyl propanol (129mg, 0.930mmol) and, triphenylphosphine (325mg, 1.240mmol), diethyl azodiformate (216mg, 1.240mmol), for raw material, anhydrous tetrahydro furan is solvent, according to the described method of embodiment 1 (a), obtain white solid 160mg, yield 69.1%.
1HNMR (400MHz, Chloroform-d) δ 7.82 (d, J=8.7Hz, 2H), 6.99 (d, J=8.7Hz, 1H), 6.90 (d, J=8.8Hz, 2H), 4.80 (dd, J=8.7,2.5Hz, 1H), 4.50 4.38 (m, 1H), 4.15 (t, J=5.8Hz, 2H), 3.79 (s, 3H), 3.32 3.22 (m, 2H), 2.98 (s, 3H), 2.86 (d, J=5.2Hz, 1H), 2.44 2.31 (m, 2H), 1.28 (d, J=6.4Hz, 3H).
MS(ESI)m/z:[(M+H)+,374.0].
(c) N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base)-4-(3-(methylsulfonyl) propoxyl group) Benzoylamide
With compound (2S prepared by above-mentioned (b), 3R)-3-hydroxyl-2-(4-(3-(methylsulfonyl) propoxyl group) Benzoylamide) methyl butyrate (160mg, 0.428mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (e) in embodiment 1, obtain white solid 138mg, yield 86.0%.
1HNMR(400MHz,DMSO-d6) δ 10.65 (s, 1H), 8.84 (s, 1H), 7.93 7.80 (m, 3H), 7.03 (d, J=8.5Hz, 2H), 4.89 (d, J=6.3Hz, 1H), 4.25 (dd, J=8.4,5.3Hz, 1H), 4.16 (t, J=6.2Hz, 2H), 4.02 (q, J=6.1Hz, 1H), 3.32 3.26 (m, 2H), 3.03 (s, 3H), 2.21 2.11 (m, 2H), 1.08 (d, J=6.3Hz, 3H).
MS(ESI)m/z:[(M-H)-,373.1].
The preparation of embodiment 13:N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base)-4-(3-(methylsulfonyl) ethyoxyl) Benzoylamide (compound 13)
(a) (2S, 3R)-3-hydroxyl-2-(4-(3-(methylsulfonyl) ethyoxyl) Benzoylamide) methyl butyrate
With compound (2S, 3R)-3-hydroxyl-2-(4-hydroxybenzamide) methyl butyrate (product of embodiment 12 step (a)) (157mg, 0.620mmol), 3-methylsulfonyl ethanol (154mg, 1.240mmol) and, triphenylphosphine (325mg, 1.240mmol), diethyl azodiformate (216mg, 1.240mmol), for raw material, anhydrous tetrahydro furan is solvent, according to the described method of embodiment 1 (a), obtain white solid 150mg, yield 67.3%.
1HNMR (400MHz, Chloroform-d) δ 7.86 (d, J=8.8Hz, 2H), 6.96 (d, J=8.7Hz, 2H), 6.91 (d, J=8.8Hz, 1H), 4.83 (dd, J=8.7,2.4Hz, 1H), 4.55 4.44 (m, 3H), 3.82 (s, 3H), 3.50 (t, J=5.3Hz, 2H), 3.10 (s, 3H), 1.31 (d, J=6.4Hz, 3H).
MS(ESI)m/z:[(M+Cl)-,393.9].
(b) N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base)-4-(3-(methylsulfonyl) ethyoxyl) Benzoylamide
With compound (2S prepared by above-mentioned (a), 3R)-3-hydroxyl-2-(4-(3-(methylsulfonyl) ethyoxyl) Benzoylamide) methyl butyrate (150mg, 0.417mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (e) in embodiment 1, obtain white solid 120mg, yield 79.8%.
1HNMR(400MHz,DMSO-d6) δ 10.65 (s, 1H), 8.85 (s, 1H), 7.98 7.83 (m, 3H), 7.08 (d, J=8.8Hz, 2H), 4.90 (d, J=6.2Hz, 1H), 4.42 (t, J=5.7Hz, 2H), 4.26 (dd, J=8.5,5.4Hz, 1H), 4.02 (q, J=6.0Hz, 1H), 3.66 (t, J=5.7Hz, 2H), 3.09 (s, 3H), 1.08 (d, J=6.3Hz, 3H).
MS(ESI)m/z:[(M-Cl)-,358.9].
Embodiment 14:N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base) preparation of-4'-(3-(methylsulfonyl) propoxyl group)-[1,1'-biphenylyl]-4-Methanamide (compound 14)
(a) (2S, 3R)-3-hydroxyl-2-(4'-hydroxyl-[1,1'-biphenylyl]-4-formoxyl) methyl butyrate
With 4'-hydroxyl-[1,1'-biphenylyl]-4-carboxylic acid (177mg, 0.826mmol), threonine methyl ester hydrochloric salt (168mg, 0.991mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (190mg, 0.991mmol), I-hydroxybenzotriazole (134mg, 0.991mmol), diisopropyl ethyl amine (427mg, 3.304mmol) for raw material, N-N-dimethylformamide is solvent, according to the described method of embodiment 2 (b), obtain white solid 180mg, yield 66.2%.
1HNMR (400MHz, DMSO) δ 9.70 (s, 1H), 8.25 (d, J=8.2Hz, 1H), 7.95 (d, J=8.3Hz, 2H), 7.72 (d, J=8.3Hz, 2H), 7.59 (d, J=8.6Hz, 2H), 6.88 (d, J=8.6Hz, 2H), 5.00 (d, J=7.8Hz, 1H), 4.52 (dd, J=8.2,4.1Hz, 1H), 4.24 4.15 (m, 1H), 3.67 (s, 3H), 1.16 (d, J=6.4Hz, 3H).
MS(ESI)m/z:[(M+H)+,330.0]
(b) (2S, 3R)-3-hydroxyl-2-(4'-(3-methylsulfonyl) propoxyl group)-[1,1'-biphenylyl]-4-formoxyl) methyl butyrate
With compound (2S prepared by above-mentioned (a); 3R)-3-hydroxyl-2-(4'-hydroxyl-[1; 1'-biphenylyl]-4-formoxyl) methyl butyrate (180mg; 0.547mmol), 3-methylsulfonyl propanol (151mg; 1.094mmol) and, triphenylphosphine (287mg; 1.094mmol), diethyl azodiformate (191mg; 1.094mmol); for raw material; anhydrous tetrahydro furan is solvent; according to the described method of embodiment 1 (a), obtain white solid 150mg, yield 61.0%.
1nullHNMR(400MHz,Chloroform-d)δ7.92(d,J=8.3Hz,2H),7.63(d,J=8.3Hz,2H),7.56(d,J=8.7Hz,1H),7.01(d,J=8.7Hz,2H),6.99(d,J=8.7Hz,2H),4.87(dd,J=8.7,2.4Hz,1H),4.49(td,J=6.9,3.5Hz,1H),4.18(t,J=5.8Hz,2H),3.83(s,3H),3.37–3.26(m,2H),3.00(s,3H),2.45(d,J=3.7Hz,1H),2.43–2.36(m,2H),1.33(d,J=6.4Hz,3H).
MS(ESI)m/z:[(M+H)+,449.9].
(c) N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base)-4'-(3-(methylsulfonyl) propoxyl group)-[1,1'-biphenylyl]-4-Methanamide
With compound (2S prepared by above-mentioned (b); 3R)-3-hydroxyl-2-(4'-(3-methylsulfonyl) propoxyl group)-[1; 1'-biphenylyl]-4-formoxyl) methyl butyrate (150mg; 0.334mmol) for raw material; dichloromethane and methanol are solvent; according to the method described in (e) in embodiment 1, obtain solid 100mg, yield 66.7%.
1HNMR(400MHz,DMSO-d6null)δ10.69(s,1H),8.87(s,1H),8.04(d,J=8.3Hz,1H),7.97(d,J=8.4Hz,2H),7.75(d,J=8.4Hz,2H),7.71(d,J=8.7Hz,2H),7.07(d,J=8.7Hz,2H),4.93(d,J=6.5Hz,1H),4.29(dd,J=8.5,5.3Hz,1H),4.16(t,J=6.2Hz,2H),4.04(h,J=6.1Hz,1H),3.34–3.27(m,2H),3.04(s,3H),2.22–2.12(m,2H),1.10(d,J=6.3Hz,3H).
MS(ESI)m/z:[(M-H)-,448.9].
Embodiment 15:N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base) preparation of-4'-(3-(methylsulfonyl) ethyoxyl)-[1,1'-biphenylyl]-4-Methanamide (compound 15)
(a) (2S, 3R)-3-hydroxyl-2-(4'-(3-methylsulfonyl) ethyoxyl)-[1,1'-biphenylyl]-4-formoxyl) methyl butyrate
With compound (2S; 3R)-3-hydroxyl-2-(4'-hydroxyl-[1; 1'-biphenylyl]-4-formoxyl) methyl butyrate (product of embodiment 16 step (a)) (204mg; 0.620mmol), 3-methylsulfonyl ethanol (154mg; 1.240mmol) and, triphenylphosphine (325mg; 1.240mmol), diethyl azodiformate (216mg; 1.240mmol); for raw material; anhydrous tetrahydro furan is solvent; according to the described method of embodiment 1 (a), obtain white solid 190mg, yield 70.4%.
1nullHNMR(400MHz,Chloroform-d)δ7.92(d,J=8.3Hz,2H),7.63(d,J=8.3Hz,2H),7.56(d,J=8.7Hz,1H),7.01(d,J=8.7Hz,2H),6.99(d,J=8.7Hz,2H),4.87(dd,J=8.7,2.4Hz,1H),4.49(td,J=6.9,3.5Hz,1H),4.42(t,J=5.7Hz,2H),3.83(s,3H),3.66(t,J=5.7Hz,2H),3.00(s,3H),2.45(d,J=3.7Hz,1H),1.33(d,J=6.4Hz,3H).
MS(EI)m/z:(M+,435).
The preparation of (b) N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base)-4'-(3-(methylsulfonyl) ethyoxyl)-[1,1'-biphenylyl]-4-Methanamide
With compound (2S prepared by above-mentioned (b); 3R)-3-hydroxyl-2-(4'-(3-methylsulfonyl) ethyoxyl)-[1; 1'-biphenylyl]-4-formoxyl) methyl butyrate (190mg; 0.436mmol) for raw material; dichloromethane and methanol are solvent; according to the method described in (e) in embodiment 1, obtain solid 120mg, yield 63.1%.
1HNMR(400MHz,DMSO-d6) δ 10.69 (s, 1H), 8.87 (s, 1H), 8.04 (d, J=8.3Hz, 1H), 7.97 (d, J=8.4Hz, 2H), 7.75 (d, J=8.4Hz, 2H), 7.71 (d, J=8.7Hz, 2H), 7.07 (d, J=8.7Hz, 2H), 4.93 (d, J=6.5Hz, 1H), 4.42 (t, J=5.7Hz, 2H), 4.29 (dd, J=8.5,5.3Hz, 1H), 4.04 (h, J=6.1Hz, 1H), 3.66 (t, J=5.7Hz, 2H), 3.04 (s, 3H), 1.10 (d, J=6.3Hz, 3H).
MS(EI)m/z:(M+,436).
Embodiment 16:(S) preparation of-N-(3-amino-1-(azanol)-3-methyl isophthalic acid-oxygen-containing butane-2-base)-4'-(3-(methylsulfonyl) propoxyl group)-[1,1'-biphenylyl]-4-Methanamide (compound 16)
(a) (S)-3-((tertbutyloxycarbonyl) amino)-2-(4'-hydroxyl-[1,1'-biphenylyl]-4-formamido)-3 Methylbutanoic acid methyl ester
With 4'-hydroxyl-[1, 1'-biphenylyl]-4-carboxylic acid (177mg, 0.826mmol), (S)-2-amino-3-((tertbutyloxycarbonyl) amino)-3-methyl butyrate (WO201231298A2) (244mg, 0.991mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (190mg, 0.991mmol), I-hydroxybenzotriazole (134mg, 0.991mmol), diisopropyl ethyl amine (427mg, 3.304mmol) for raw material, N-N-dimethylformamide is solvent, according to the described method of embodiment 2 (b), obtain white solid 200mg, yield 54.7%.
1HNMR (400MHz, Chloroform-d) δ 9.07 (s, 1H), 7.99 (d, J=8.4Hz, 2H), 7.64 (d, J=8.4Hz, 2H), 7.57 (d, J=8.7Hz, 2H), 6.97 (d, J=8.7Hz, 2H), 4.78 (d, J=8.3Hz, 1H), 4.72 (s, 1H), 3.74 (s, 3H), 1.53 (s, 3H), 1.49 (s, 3H), 1.46 (s, 9H).
MS(EI)m/z:(M+,442)
(b) (S)-3-((tertbutyloxycarbonyl) amino)-3-methyl-2-(4'-(3-(methylsulfonyl) propoxyl group)-[1,1'-biphenylyl]-4-formamido) methyl butyrate
With compound (S)-3-((tertbutyloxycarbonyl) amino)-2-(4'-hydroxyl-[1 prepared by above-mentioned (a), 1'-biphenylyl]-4-formamido)-3 Methylbutanoic acid methyl ester (200mg, 0.452mmol), 3-methylsulfonyl propanol (151mg, 1.094mmol) with triphenylphosphine (287mg, 1.094mmol), diethyl azodiformate (191mg, 1.094mmol), for raw material, anhydrous tetrahydro furan is solvent, according to the described method of embodiment 1 (a), obtain white solid 180mg, yield 70.8%.
1nullHNMR(400MHz,Chloroform-d)δ9.07(s,1H),7.99(d,J=8.4Hz,2H),7.64(d,J=8.4Hz,2H),7.57(d,J=8.7Hz,2H),6.97(d,J=8.7Hz,2H),4.78(d,J=8.3Hz,1H),4.72(s,1H),4.16(t,J=5.8Hz,2H),3.74(s,3H),3.36–3.11(m,2H),2.97(s,J=0.7Hz,3H),2.43–2.16(m,2H),1.53(s,3H),1.49(s,3H),1.46(s,9H).
MS(ESI)m/z:[(M+Na)+,585.2].
(c) (S)-3-amino-3-methyl-2-(4'-(3-(methylsulfonyl) propoxyl group)-[1,1'-biphenylyl]-4-Methanamide) methyl butyrate
With compound (S)-3-((tertbutyloxycarbonyl) amino)-3-methyl-2-(4'-(3-(methylsulfonyl) propoxyl group)-[1 prepared by above-mentioned (b), 1'-biphenylyl]-4-formamido) methyl butyrate (180mg, 0.320mmol) for raw material, the 1 of hydrogen chloride, 4-dioxane is solvent, according to the described method of embodiment 7 (b), obtain solid 126mg, yield 85.0%.
1HNMR (400MHz, Chloroform-d) δ 7.89 (d, J=8.2Hz, 2H), 7.61 (d, J=8.2Hz, 2H), 7.54 (d, J=8.7Hz, 2H), 7.46 (d, J=8.4Hz, 1H), 7.05 6.83 (m, 2H), 4.59 (d, J=8.3Hz, 1H), 4.16 (t, J=5.8Hz, 2H), 3.78 (d, J=0.8Hz, 3H), 3.38 3.16 (m, 2H), 2.97 (s, 3H), 2.43 2.16 (m, 3H), 1.26 (s, 3H), 1.23 (s, 3H).
MS(ESI)m/z:[(M+H)+,463.1].
(d) (S)-N-(3-amino-1-(azanol)-3-methyl isophthalic acid-oxygen-containing butane-2-base)-4'-(3-(methylsulfonyl) propoxyl group)-[1,1'-biphenylyl]-4-Methanamide
With compound (S)-3-amino-3-methyl-2-(4'-(3-(methylsulfonyl) propoxyl group)-[1 prepared by above-mentioned (c), 1'-biphenylyl]-4-Methanamide) methyl butyrate (126mg, 0.320mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (e) in embodiment 1, obtain solid 80mg, yield 63.5%.
1HNMR (400MHz, DMSO) δ 8.12 (s, 1H), 7.93 (d, J=7.9Hz, 2H), 7.73 (d, J=8.0Hz, 2H), 7.69 (d, J=8.9Hz, 2H), 7.06 (d, J=8.2Hz, 2H), 6.29 (s, 2H), 4.36 (s, 1H), 4.15 (t, J=6.2Hz, 2H), 3.30 (s, 2H), 3.03 (s, 3H), 2.17 (t, J=7.8Hz, 2H), 1.14 (s, 3H), 1.06 (s, 3H).
MS(ESI)m/z:[(M+H)+,464.0].
Embodiment 17:N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base) preparation of-4-((5-hydroxyl-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) Benzoylamide (compound 17)
(a) (2S, 3R)-2-(4-((4,5-bis-((4-methoxybenzyl) oxygen base) pyridine-2-base) methoxyl group) benzoyl)-3-hydroxybutyrate methyl ester
With compound (2S, 3R)-3-hydroxyl-2-(4-hydroxybenzamide) methyl butyrate (product of embodiment 12 step (a)) (157mg, 0.620mmol), (4, 5-bis-((4-methoxybenzyl) oxygen base)-2-pyridine radicals) methanol (WO2013150296A1) (354mg, 0.930mmol), triphenylphosphine (325mg, 1.240mmol), diethyl azodiformate (216mg, 1.240mmol), for raw material, anhydrous tetrahydro furan is solvent, according to the described method of embodiment 1 (a), obtain white solid 300mg, yield 78.5%.
1HNMR (400MHz, DMSO) δ 8.19 (s, 1H), 8.07 (s, 1H), 7.88 (d, J=8.8Hz, 2H), 7.36 (d, J=13.0Hz, 5H), 7.11 (d, J=8.8Hz, 2H), 6.92 (s, 4H), 5.14 (s, 2H), 5.10 (d, J=5.3Hz, 4H), 4.94 (s, 1H), 4.48 (s, 1H), 4.16 (s, 1H), 3.74 (s, 6H), 3.65 (s, 3H), 1.13 (s, 3H).
MS(ESI)m/z:[(M+H)+,617.1]
(b) 4-((4,5-bis-((4-methoxybenzyl) oxygen base) pyridine-2-base) methoxyl group)-N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide
With compound (2S prepared by above-mentioned (a); 3R)-2-(4-((4; 5-bis-((4-methoxybenzyl) oxygen base) pyridine-2-base) methoxyl group) benzoyl)-3-hydroxybutyrate methyl ester (300mg; 0.486mmol) for raw material; dichloromethane and methanol are solvent; according to the method described in (e) in embodiment 1, obtain solid 240mg, yield 80.0%.
1HNMR(400MHz,DMSO-d6) δ 10.63 (s, 1H), 8.83 (s, 1H), 8.19 (s, 1H), 7.86 (t, J=9.0Hz, 1H), 7.42 7.27 (m, 4H), 7.09 (d, J=8.8Hz, 2H), 6.92 (dd, J=8.6,5.2Hz, 4H), 5.13 (s, 2H), 5.09 (s, 4H), 4.88 (s, 1H), 4.23 (s, 1H), 4.01 (s, 1H), 3.74 (s, 6H), 1.08 (s, 3H).
MS(ESI)m/z:[(M+H)+,618.0].
(c) N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base)-4-((5-hydroxyl-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) Benzoylamide
With compound 4-((4 prepared by above-mentioned (b), 5-bis-((4-methoxybenzyl) oxygen base) pyridine-2-base) methoxyl group)-N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base) Benzoylamide (240mg, 0.389mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (d) in embodiment 8, obtain white solid 100mg, yield 68.2%.
1HNMR(400MHz,DMSO-d6) δ 10.64 (s, 1H), 8.85 (s, 1H), 7.97 (s, 1H), 7.89 (s, 3H), 7.11 (d, J=8.8Hz, 3H), 5.25 (s, 2H), 4.25 (s, 1H), 4.01 (s, 1H), 1.99 (d, J=7.4Hz, 1H), 1.06 (s, 3H).
MS(ESI)m/z:[(M+H)+, 378.0].
Embodiment 18:4-((1,5-dihydroxy-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) preparation of-N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide (compound 18)
(a) (2S, 3R)-2-(4-((1,5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) Benzoylamide)-3-hydroxybutyrate methyl ester
With compound (2S, 3R)-3-hydroxyl-2-(4-hydroxybenzamide) methyl butyrate (product of embodiment 12 step (a)) (157mg, 0.620mmol), 1, 5-bis-(benzhydryl oxygen base)-2-(methylol) pyridine-4 (1H)-one [JournalofMedicinalChemistry56 (2013) 5541-5552] (607mg, 1.240mmol), triphenylphosphine (325mg, 1.240mmol), diethyl azodiformate (216mg, 1.240mmol) for raw material, anhydrous tetrahydro furan is solvent, according to the described method of embodiment 1 (a), obtain white solid 350mg, yield 77.9%.
1HNMR(400MHz,DMSO-d6null)δ8.11(d,J=8.2Hz,1H),7.85–7.79(m,3H),7.46–7.33(m,14H),7.30(dq,J=6.5,3.6,2.9Hz,2H),7.24–7.19(m,4H),6.83(d,J=8.8Hz,2H),6.46(s,1H),6.38(s,1H),6.03(s,1H),5.76(s,1H),4.94(d,J=7.6Hz,1H),4.77(s,2H),4.47(dd,J=8.2,4.1Hz,1H),4.17(ddd,J=7.7,6.3,4.1Hz,1H),3.65(s,3H),1.14(d,J=6.3Hz,2H).
MS(ESI)m/z:[(M+H)+,725].
(b) 4-((1,5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group)-N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide
With compound (2S prepared by above-mentioned (a), 3R)-2-(4-((1,5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) Benzoylamide)-3-hydroxybutyrate methyl ester (350mg, 0.482mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (e) in embodiment 1, obtain solid 250mg, yield 71.4%.
1HNMR(400MHz,DMSO-d6) δ 10.64 (s, 1H), 8.85 (s, 1H), 7.96 7.73 (m, 4H), 7.45 7.34 (m, 13H), 7.33 7.28 (m, 2H), 7.25 7.17 (m, 4H), 6.81 (d, J=8.8Hz, 2H), 6.46 (s, 1H), 6.39 (s, 1H), 6.02 (s, 1H), 4.88 (d, J=6.4Hz, 1H), 4.77 (s, 2H), 4.25 (dd, J=8.5,5.4Hz, 1H), 4.02 (q, J=6.1Hz, 1H), 1.08 (d, J=6.3Hz, 3H).
MS(ESI)m/z:[(M+Na)+,748.1].
(c) 4-((1,5-dihydroxy-4-oxa--1,4-dihydropyridine-2-base) methoxyl group)-N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base) Benzoylamide
With compound 4-((1 prepared by above-mentioned (b), 5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group)-N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base) Benzoylamide (250mg, 0.344mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (d) in embodiment 8, obtain white solid 100mg, yield 73.9%.
1HNMR(400MHz,DMSO-d6) δ 10.66 (s, 1H), 10.24 (d, J=2.5Hz, 2H), 8.84 (s, 4H), 8.03 7.81 (m, 2H), 7.11 (d, J=8.7Hz, 1H), 6.95 (s, 1H), 5.25 (s, 2H), 4.23 (s, 1H), 4.02 (s, 1H), 1.07 (s, 3H).
MS(ESI)m/z:[(M+H)+,394.0].
Embodiment 19:N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base)-4'-((5-hydroxyl-4-oxa--1,4-dihydropyridine-2-base) methoxyl group) preparation of-[1,1'-biphenylyl]-4-Methanamide (compound 19)
(a) (2S; 3R)-2-(4'-((4; 5-bis-((4-methoxybenzyl) oxygen base) pyridine-2-base) methoxyl group)-[1,1'-biphenylyl]-4-base formoxyl)-3-hydroxybutyrate methyl ester
With compound (2S, 3R)-3-hydroxyl-2-(4'-hydroxyl-[1, 1'-biphenylyl]-4-formoxyl) methyl butyrate (product of embodiment 16 step (a)) (204mg, 0.620mmol), (4, 5-bis-((4-methoxybenzyl) oxygen base)-2-pyridine radicals) methanol (354mg, 0.930mmol), triphenylphosphine (325mg, 1.240mmol), diethyl azodiformate (216mg, 1.240mmol) for raw material, anhydrous tetrahydro furan is solvent, according to the described method of embodiment 1 (a), obtain white solid 310mg, yield 72.2%.
1nullHNMR(400MHz,DMSO)δ8.27(d,J=8.2Hz,1H),8.20(s,1H),7.97(d,J=8.4Hz,2H),7.77(d,J=8.4Hz,2H),7.70(d,J=8.8Hz,2H),7.37(d,J=8.6Hz,2H),7.34(d,J=8.6Hz,2H),7.31(s,1H),7.13(d,J=8.8Hz,2H),6.92(dd,J=8.6,2.0Hz,4H),5.14(s,2H),5.10(d,J=7.6Hz,4H),4.99(d,J=7.7Hz,1H),4.52(dd,J=8.2,4.1Hz,1H),4.25–4.14(m,1H),3.74(s,3H),3.72(s,3H),3.67(s,3H),1.16(d,J=6.4Hz,3H).
MS(ESI)m/z:[(M+H)+,692.9].
(b) 4'-((4,5-bis-((4-methoxybenzyl) oxygen base) pyridine-2-base) methoxyl group)-N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base)-[1,1'-biphenylyl]-4-Benzoylamide
With compound (2S prepared by above-mentioned (a); 3R)-2-(4'-((4; 5-bis-((4-methoxybenzyl) oxygen base) pyridine-2-base) methoxyl group)-[1; 1'-biphenylyl]-4-base formoxyl)-3-hydroxybutyrate methyl ester (310mg; 0.447mmol) for raw material; dichloromethane and methanol are solvent; according to the method described in (e) in embodiment 1; obtain solid 270mg, yield 87.1%.
1HNMR(400MHz,DMSO-d6null)δ10.68(s,1H),8.86(s,1H),8.19(s,1H),8.02(d,J=8.6Hz,1H),7.96(d,J=8.5Hz,2H),7.75(d,J=8.4Hz,2H),7.69(d,J=8.8Hz,2H),7.37(d,J=8.7Hz,2H),7.34(d,J=8.7Hz,2H),7.31(s,1H),7.12(d,J=8.8Hz,2H),6.92(dd,J=8.7,2.0Hz,4H),5.14(s,2H),5.09(s,4H),4.92(d,J=6.4Hz,1H),4.29(dd,J=8.5,5.3Hz,1H),4.04(q,J=6.1Hz,1H),3.74(s,3H),3.72(s,3H),1.10(d,J=6.3Hz,3H).
MS(ESI)m/z:[(M+H)+,694.1].
(c) N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base)-4'-((5-hydroxyl-4-oxa--1,4-dihydropyridine-2-base) methoxyl group)-[1,1'-biphenylyl]-4-Methanamide
With compound 4'-((4 prepared by above-mentioned (b), 5-bis-((4-methoxybenzyl) oxygen base) pyridine-2-base) methoxyl group)-N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base)-[1,1'-biphenylyl]-4-Benzoylamide (270mg, 0.389mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (d) in embodiment 8, obtain white solid 100mg, yield 68.2%.
1HNMR (400MHz, DMSO) δ 10.69 (s, 1H), 8.04 (d, J=8.5Hz, 1H), 7.98 (d, J=8.1Hz, 2H), 7.94 (s, 1H), 7.75 (t, J=7.8Hz, 4H), 7.16 (d, J=8.6Hz, 2H), 7.05 (s, 1H), 5.24 (s, 2H), 4.29 (dd, J=8.4,5.5Hz, 1H), 4.08 4.02 (m, 1H), 1.11 (d, J=6.2Hz, 3H).
MS(ESI)m/z:[(M+H)+,454.2].
Embodiment 20:4'-((1,5-dihydroxy-4-oxa--1,4-dihydropyridine-2-base) methoxyl group)-N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base) preparation of-[1,1'-biphenylyl]-4-Methanamide (compound 20)
(a) (2S, 3R)-2-(4'-((1,5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group)-[1,1'-biphenylyl]-4-yl-benzamide base)-3-hydroxybutyrate methyl ester
With compound (2S, 3R)-3-hydroxyl-2-(4'-hydroxyl-[1, 1'-biphenylyl]-4-formoxyl) methyl butyrate (product of embodiment 16 step (a)) (304mg, 0.620mmol), 1, 5-bis-(benzhydryl oxygen base)-2-(methylol) pyridine-4 (1H)-one (607mg, 1.240mmol), triphenylphosphine (325mg, 1.240mmol), diethyl azodiformate (216mg, 1.240mmol) for raw material, anhydrous tetrahydro furan is solvent, according to the described method of embodiment 1 (a), obtain white solid 350mg, yield 69.4%.
1HNMR(400MHz,CDCl3null)δ8.02(d,J=8.3Hz,2H),7.76(d,J=8.3Hz,1H),7.58(d,J=8.4Hz,2H),7.43(d,J=8.7Hz,2H),7.33(d,J=8.7Hz,2H),7.17(s,1H),7.06(d,J=8.7Hz,2H),6.89(d,J=8.7Hz,2H),6.85(d,J=8.7Hz,2H),6.75(d,J=8.7Hz,2H),6.48(s,1H),4.99(s,2H),4.98(s,2H),4.83(dd,J=8.5,3.0Hz,1H),4.62(s,2H),4.53–4.46(m,1H),3.80(s,3H),3.78(s,3H),3.77(s,3H),1.34(d,J=6.4Hz,3H).
MS(ESI)m/z:[(M+Na)+,731.2].
(b) 4'-((1,5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group)-N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base)-[1,1'-biphenylyl]-4-Methanamide
With compound (2S prepared by above-mentioned (a), 3R)-2-(4'-((1,5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group)-[1,1'-biphenylyl]-4-yl-benzamide base)-3-hydroxybutyrate methyl ester (350mg, 0.436mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (e) in embodiment 1, obtain solid 280mg, yield 80.1%.
1nullHNMR(400MHz,DMSO)δ10.68(s,1H),8.86(s,1H),8.11(s,1H),8.03(d,J=8.4Hz,1H),7.98(d,J=8.3Hz,2H),7.76(d,J=8.4Hz,2H),7.71(d,J=8.3Hz,2H),7.39(d,J=7.0Hz,4H),7.05(d,J=8.5Hz,2H),6.98(d,J=5.6Hz,2H),6.96(d,J=5.7Hz,2H),6.19(s,1H),5.28(s,2H),5.05(s,2H),4.96(s,2H),4.92(d,J=6.4Hz,1H),4.30(dd,J=8.2,5.6Hz,1H),4.09–4.02(m,1H),3.77(s,3H),3.76(s,3H),1.11(d,J=6.3Hz,3H).
MS(ESI)m/z:[(M-H)-,708.0]
(c) 4'-((1,5-dihydroxy-4-oxa--1,4-dihydropyridine-2-base) methoxyl group)-N-((2S, 3R)-3-hydroxyl-1-(azanol)-1-oxygen-containing butane-2-base)-[1,1'-biphenylyl]-4-Methanamide
With compound 4'-((1 prepared by above-mentioned (b), 5-bis-(benzhydryl oxygen base)-4-oxa--1,4-dihydropyridine-2-base) methoxyl group)-N-((2S, 3R) the oxygen-containing butane of-3-hydroxyl-1-(azanol)-1--2-base)-[1,1'-biphenylyl]-4-Methanamide (280mg, 0.349mmol) for raw material, dichloromethane and methanol are solvent, according to the method described in (d) in embodiment 8, obtain white solid 100mg, yield 61.0%.
1HNMR (400MHz, DMSO) δ 10.69 (s, 1H), 8.03 (d, J=8.5Hz, 1H), 7.97 (d, J=7.9Hz, 2H), 7.80 (s, 1H), 7.75 (d, J=8.2Hz, 2H), 7.71 (d, J=8.3Hz, 2H), 7.12 (d, J=8.4Hz, 2H), 6.84 (s, 1H), 5.20 (s, 2H), 4.34 4.25 (m, 1H), 4.09 3.98 (m, 1H), 1.11 (d, J=6.2Hz, 3H).
MS(ESI)m/z:[(M-H)-,468.1].
Biological activity test
1. bacteriostatic experiment
Test method: MIC (Minimuminhibitoryconcentration, the minimal inhibitory concentration) value of each compound is all adopt following methods to test three times.
The process employs 96 orifice plates and the LB culture medium containing 5%DMSO.The variable concentrations being made into by compound, takes 100 μ L and is placed on 96 orifice plates (CorningCostar3596, flat band lid, polystyrene well).In twice dilution series, scope is 0.0005-1 μ g/mL, 0.0025-5 μ g/mL and 0.014-5 μ g/mL.Bacterial cell, grows to OD600=0.6, dilutes 100 times by fresh LB culture medium, then is joined in each hole by the cell of the dilution of 100 μ L.The plate that these are inoculated is placed in 37 DEG C of environment hatching 22h.After hatching terminates, add 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt (MTT) of the 1mg/mL of 50uL, then plank is continued hatching 3h.MIC value is as the criterion not having the least concentration of obvious variable color (black by xanthochromia).
Positive control drug is CHIR-090, is classical LpxC inhibitor, it is possible to effective suppression bacillus pyocyaneus and colibacillary growth.
From the data in table 2, it can be seen that the compounds of this invention has good biological activity, vitro inhibition bacillus pyocyaneus and colibacillary activity such as compound 4,5,6,7 are very strong, and particularly compound 4, its bacteriostatic activity is substantially better than positive drug CHIR-090.
Table 2. part of compounds is to bacillus pyocyaneus and colibacillary inhibitory activity data (unit: μ g/ml)
2. the Vitro hepatic Microsomal Stability experiment of the present invention
Test method: this experiment uses SD rat liver microsomes and ICR Mouse Liver Microsomes.Incubation method is as follows: be placed in by microsome in 0.1M tri-(methylol) aminomethane/hydrochloride buffer (pH7.4), and final concentration of 0.33mg/ml microsomal protein is subsequently added cofactor MgCl2(5mM), test-compound (final concentration of 0.1 μM, cosolvent is 0.01%DMSO, 0.005%BSA) and NADPH (1mM), hatch 60min in 37 DEG C.When adding hepatomicrosome, test-compound or NADPH, namely start reaction.Sample when hatching 0,7,17,30 and 60min, and make albumen precipitation terminate enzyme reaction by adding methanol.After centrifugal, LC/MS/MS is adopted to analyze sample.The method evaluates its metabolic stability by the vitro half-lives and hepatomicrosome clearance rate detecting test-compound.
Data in table 3 part of compounds hepatomicrosome stability experiment in vitro
From the data in table 3, it can be seen that the compounds of this invention 4 and 5 hepatomicrosome stability experiment in vitro has good stability, hence it is evident that be better than comparison medicine CHIR-090.
The all documents mentioned in the present invention are incorporated as reference all in this application, are individually recited as reference such just as each section of document.In addition, it is to be understood that after the above-mentioned teachings having read the present invention, the present invention can be made various changes or modifications by those skilled in the art, these equivalent form of values fall within the application appended claims limited range equally.
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