CN101693674B - Oxime compound, preparation process and application thereof - Google Patents
Oxime compound, preparation process and application thereof Download PDFInfo
- Publication number
- CN101693674B CN101693674B CN200910233389.3A CN200910233389A CN101693674B CN 101693674 B CN101693674 B CN 101693674B CN 200910233389 A CN200910233389 A CN 200910233389A CN 101693674 B CN101693674 B CN 101693674B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- acid
- adds
- obtains
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- -1 Oxime compound Chemical class 0.000 title claims abstract description 32
- 150000002923 oximes Chemical class 0.000 claims abstract description 14
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 7
- 229940124589 immunosuppressive drug Drugs 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 43
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 229910015900 BF3 Inorganic materials 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 230000003068 static effect Effects 0.000 claims description 3
- 238000013019 agitation Methods 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 210000001744 T-lymphocyte Anatomy 0.000 abstract description 11
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 40
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 26
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 description 22
- 239000000843 powder Substances 0.000 description 18
- NAQQTJZRCYNBRX-UHFFFAOYSA-N n-pentan-3-ylidenehydroxylamine Chemical compound CCC(CC)=NO NAQQTJZRCYNBRX-UHFFFAOYSA-N 0.000 description 14
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 14
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 10
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- 229940079877 pyrogallol Drugs 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- IUJAAIZKRJJZGQ-UHFFFAOYSA-N 2-(2-chlorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1Cl IUJAAIZKRJJZGQ-UHFFFAOYSA-N 0.000 description 3
- ATPPNMLQNZHDOG-UHFFFAOYSA-N 2-fluoro-2-phenylacetic acid Chemical compound OC(=O)C(F)C1=CC=CC=C1 ATPPNMLQNZHDOG-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 210000001165 lymph node Anatomy 0.000 description 3
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- OTKCEEWUXHVZQI-UHFFFAOYSA-N 1,2-diphenylethanone Chemical class C=1C=CC=CC=1C(=O)CC1=CC=CC=C1 OTKCEEWUXHVZQI-UHFFFAOYSA-N 0.000 description 2
- CDPKJZJVTHSESZ-UHFFFAOYSA-N 4-chlorophenylacetic acid Chemical compound OC(=O)CC1=CC=C(Cl)C=C1 CDPKJZJVTHSESZ-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 238000011725 BALB/c mouse Methods 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229930003944 flavone Natural products 0.000 description 2
- 150000002213 flavones Chemical class 0.000 description 2
- 235000011949 flavones Nutrition 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- DGNVEKKAEPFSIH-UHFFFAOYSA-N 1-nitro-4-[2-(4-nitrophenoxy)ethoxy]benzene Chemical compound C1=CC([N+](=O)[O-])=CC=C1OCCOC1=CC=C([N+]([O-])=O)C=C1 DGNVEKKAEPFSIH-UHFFFAOYSA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NRPFNQUDKRYCNX-UHFFFAOYSA-N 4-methoxyphenylacetic acid Chemical compound COC1=CC=C(CC(O)=O)C=C1 NRPFNQUDKRYCNX-UHFFFAOYSA-N 0.000 description 1
- 108010013043 Acetylesterase Proteins 0.000 description 1
- NOIWGLZLVMRFSA-UHFFFAOYSA-N CCC(C=CC1(C)[O](C)C)=CC1c(c(CC)ccc1)c1OC Chemical compound CCC(C=CC1(C)[O](C)C)=CC1c(c(CC)ccc1)c1OC NOIWGLZLVMRFSA-UHFFFAOYSA-N 0.000 description 1
- ZRFJYAZQMFCUIX-UHFFFAOYSA-N CCc1cccc(Br)c1 Chemical compound CCc1cccc(Br)c1 ZRFJYAZQMFCUIX-UHFFFAOYSA-N 0.000 description 1
- NLJHXYJIUYVUIE-FOWTUZBSSA-N COc1ccc(C/C(/c(c(O)cc(O)c2)c2O)=N\O)cc1 Chemical compound COc1ccc(C/C(/c(c(O)cc(O)c2)c2O)=N\O)cc1 NLJHXYJIUYVUIE-FOWTUZBSSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 108010040476 FITC-annexin A5 Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 206010026865 Mass Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- HKVVMOWEYIGEGI-FOWTUZBSSA-N Oc(c(O)c1)ccc1/C(/Cc(cc1)ccc1Cl)=N/O Chemical compound Oc(c(O)c1)ccc1/C(/Cc(cc1)ccc1Cl)=N/O HKVVMOWEYIGEGI-FOWTUZBSSA-N 0.000 description 1
- IYTJONMOGHQFTF-LFIBNONCSA-N Oc1ccc(/C(/Cc2cc(F)ccc2)=N/O)c(O)c1O Chemical compound Oc1ccc(/C(/Cc2cc(F)ccc2)=N/O)c(O)c1O IYTJONMOGHQFTF-LFIBNONCSA-N 0.000 description 1
- DCTLJGWMHPGCOS-UHFFFAOYSA-N Osajin Chemical compound C1=2C=CC(C)(C)OC=2C(CC=C(C)C)=C(O)C(C2=O)=C1OC=C2C1=CC=C(O)C=C1 DCTLJGWMHPGCOS-UHFFFAOYSA-N 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- OUZCFMSJGDEXRT-UHFFFAOYSA-N Scandinone Natural products O=C1C=2C(OC)=C(CC=C(C)C)C=3OC(C)(C)C=CC=3C=2OC=C1C1=CC=C(O)C=C1 OUZCFMSJGDEXRT-UHFFFAOYSA-N 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- YCMFVOHPYCFMMI-RVDMUPIBSA-N [O-][N+](c1ccc(C/C(/c(ccc(O)c2O)c2O)=N\O)cc1)=O Chemical compound [O-][N+](c1ccc(C/C(/c(ccc(O)c2O)c2O)=N\O)cc1)=O YCMFVOHPYCFMMI-RVDMUPIBSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- XTCGYRFLVLFRGW-UHFFFAOYSA-N acronycidine Chemical compound COC1=C2C=COC2=NC2=C(OC)C(OC)=CC(OC)=C21 XTCGYRFLVLFRGW-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 231100000060 cardiovascular toxicity Toxicity 0.000 description 1
- 230000007681 cardiovascular toxicity Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 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
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- HDVRLUFGYQYLFJ-UHFFFAOYSA-N flamenol Chemical compound COC1=CC(O)=CC(O)=C1 HDVRLUFGYQYLFJ-UHFFFAOYSA-N 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 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
- 230000007056 liver toxicity Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000002331 protein detection Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Oxime compound is characterized in that the oxime compound is represented by the following general formula, wherein R1 is multi-hydroxyphenyl, and R2 is substituted benzyl. Oxime derivatives have obvious inhibition action on activated T cells and have weaker inhibition action on inactivated T cells, and then the oxime compound can be applied in preparation of immunosuppressive drug. Further, the invention discloses a process for preparing the oxime compound.
Description
Technical field
The present invention relates to oxime compounds and preparation method thereof and immunosuppressive drug.
Background technology
Immunosuppressor is a kind of important clinical medicine for medical procedure, and it is used for comprising treatment such as systemic lupus erythematous, rheumatoid arthritis and the psoriasis of graft-rejection and autoimmune disorder.The T lymphocyte has been brought into play indispensable effect in graft-rejection, make ciclosporin A (CsA), and tacrolimus (FK506's) and sirolimus (rapamycin) are shown one's talent as immunosuppressant treatment.Although immunosuppressive drug has been successfully used to the clinical treatment of organ transplantation and autoimmune disorder, its side effect comprises that liver toxicity, renal toxicity, malignant tumour, infection, Cardiovascular Toxicity etc. can not be ignored.Therefore, seek new adjusting immune response, and efficient, the immunosuppressive compounds of the potential novel species of low toxicity can clinical will never the stopping of medicine.
According to research reports, the compound of flavones and osajin has obvious restraining effect to the T cell proliferation in the immune response.The deoxybenzoin compounds is the precursor of flavonoid compound, and it has similarly significant active such as anticancer, antibiotic etc. with flavones a lot of aspect active.Therefore, as the derivative of deoxybenzoin class, its research aspect immunosuppression has larger potentiality equally.
Summary of the invention
The object of the present invention is to provide a class novel oxime compounds and their preparation method and purposes.
Technical scheme of the present invention is as follows:
One class oxime compounds is characterized in that it has following general formula:
In the formula: R
1-be:
Group;
R
2-be:
A kind of method for preparing above-mentioned oxime compounds, it is comprised of the following step:
Step 1. is in boron trifluoride ether solution, add the compound of corresponding phenol and the compound of corresponding toluylic acid class, the ratio of the amount of substance of the compound of the compound of phenol and toluylic acid class is about 1: 1, be heated with stirring to 80-84 ℃, cool off behind the reaction 2h, under agitation pour in the aqueous solution of sodium acetate, then static, filter out solid behind the 24h, the solid that obtains is dissolved in the dehydrated alcohol recrystallization purifies
Solid after the purification that step 2. obtains step 1 is dissolved in dehydrated alcohol, adds sodium acetate, adds the oxammonium hydrochloride of Isoequivalent weight again, be heated with stirring to 60 ℃, approximately use the thin layer chromatography detection reaction behind the 3h, until react completely, cooled and filtered, the filtrate decompression evaporate to dryness obtains the compound of oximes.
Above-mentioned method for making, in the described step 1, boron trifluoride ether solution is that mass percentage concentration is the 47.0-47.7% boron trifluoride ether solution, its consumption is that the compound of every mmole phenol adds 1.0-1.5ml.
Above-mentioned method for making, in the step 2 described in the described step 2, the consumption of dehydrated alcohol is that every mmole oxammonium hydrochloride adds 1.0-1.5ml.
Oxime compounds of the present invention is to the obvious restraining effect of T cell of activation, and to the restraining effect of non-activated T cell a little less than, therefore oxime compounds of the present invention can be used in the preparation immunosuppressive drug.
Embodiment
Embodiment one: (E)-and the preparation of 2-(4-bromophenyl)-1-(3,4 dihydroxy phenyl) ethyl ketone oxime (compound 1)
In the 100ml single necked round bottom flask, add pyrocatechol (10mmol) and to bromo-acid (10mmol), add again the boron trifluoride diethyl etherate (47.0-47.7%, in BF3, lower same) of 10ml.Stirring reaction is heated to 80-84 ℃ of back flow reaction and approximately cools off behind the 2h, adds in water (200ml) solution of sodium acetate (8g), and the limit edged stirs, and is then static, filters behind the 24h, obtains the solid of brown color.The product that obtains is put into the beaker of 100ml, added dehydrated alcohol to fully dissolving, then filter behind the recrystallization, obtain yellow lenticular material 2-(4-bromophenyl)-1-(3,4-dihydroxyl) Phenyl ethyl ketone.It is moved in the single necked round bottom flask of 100ml, sodium acetate and the oxammonium hydrochloride of the molar masss such as adding are dissolved in ethanol (10ml) again.Be heated with stirring to 60 ℃, reflux and approximately use the thin layer chromatography detection reaction behind the 3h, until react completely, cooled and filtered, the filtrate decompression evaporate to dryness obtains yellow particulate state compound, i.e. the target oxime compounds behind the recrystallization.Productive rate: 62%.Mp?144-145℃.
1H?NMR(300MHz，DMSO-d6)，3.99(s，2H)，6.67(d，J＝8.2Hz，1H)，6.92(dd，J＝8.22，2.2Hz，2H)，7.10(d，J＝2.2Hz，1H)，7.15(d，J＝8.4Hz，1H)，7.44(d，J＝8.4Hz，1H)，8.96(s，1H)，9.09(s，1H)，11.10(s，1H).ESI-MS：321.00([M+H]+).Anal.Calcd?for?C14H12BrNO3：C，52.20；H，3.75；Br，24.80；N，4.35；O，14.90％；found：C，52.11；H，3.70；Br，24.89；N，4.38；O，14.98％.
Embodiment two: (E)-and the preparation of 2-(4-bromophenyl)-1-(2,3,4-hydroxy phenyl) ethyl ketone oxime (compound 2)
The preparation method is with embodiment one.Replace pyrocatechol with pyrogallol, obtain brown particle shape target compound.Productive rate 63%.Mp?143-1145℃.
1H?NMR(300MHz，DMSO-d6)，4.14(s，2H)，6.24(s，1H)，6.39(d，J＝9Hz，1H)，6.90(d，J＝8Hz，2H)，7.08(d，J＝9Hz，2H)，7.88(d，J＝9Hz，1H)，8.71(s，1H)，9.45(s，1H)，10.11(s，1H)，12.45(s，1H).ESI-MS：336.99([M+H]+).Anal.Calcd?for?C14H12BrNO4：C，49.73；H，3.58；Br，23.63；N，4.14；O，18.93％；found：C，49.71；H，3.56；Br，23.65；N，4.15；O，18.97％.
Embodiment three: (E)-and the preparation of 2-(4-p-methoxy-phenyl)-1-(2,4,6-hydroxy phenyl) ethyl ketone oxime (compound 3)
The preparation method is with embodiment one.Replace pyrocatechol with Phloroglucinol monomethyl ether, replace bromo-acid with homoanisic acid, obtain brown ceramic powder shape target compound.Productive rate 60%.Mp?143-144℃.
1H?NMR(300MHz，DMSO-d6)，3.93(s，2H)，6.37(d，J＝9Hz，1H)，6.92(d，J＝8Hz，2H)，7.15(d，J＝8Hz，2H)，7.34(d，J＝9Hz，1H)，9.15(s，1H)，10.34(s，1H)，12.11(s，2H)，12.98(s，1H).ESI-MS：289.10([M+H]+).Anal.Calcd?for?C15H15NO5：C，62.28；H，5.23；N，4.84；O，27.65％；found：C，62.24；H，5.22；N，4.85；O，27.67％.
Embodiment four: (E)-and the preparation of 1-(2,4 dihydroxy phenyl)-2-(4-fluorophenyl) ethyl ketone oxime (compound 4)
The preparation method is with embodiment one.Replace bromo-acid with para-fluorophenylacetic acid, obtain brown ceramic powder shape target compound.Productive rate 58%.Mp?110-112℃.
1H?NMR(300MHz，DMSO-d6)，4.02(s，2H)，6.25(d，J＝7.32，2H)，7.10(t，J＝9Hz，2H)，7.28(t，J＝8.8，3H)，8.90(s，1H)，9.08(s，1H)，11.20(s，1H).ESI-MS：261.08([M+H]+).Anal.Calcd?for?C14H12FNO3：C，64.36；H，4.63；F，7.27；N，5.36；O，18.37％；found：C，64.34；H，4.60；F，7.29；N，5.39；O，18.38％.
Embodiment five: (E)-and the preparation of 2-(3-chloro-phenyl-)-1-(2,3,4-trihydroxy-phenyl) ethyl ketone oxime (compound 5)
The preparation method is with embodiment one.Replace bromo-acid with a chlorobenzene acetic acid, pyrogallol replaces pyrocatechol, obtains the white powder target compound.Productive rate 64%.Mp?115-117℃.
1H?NMR(300MHz，DMSO-d6)，4.17(s，2H)，6.29(d，J＝8.8，1H)，6.83(d，J＝8.8，1H)，7.23(t，J＝8.4，2H)，7.31(t，J＝7.7，2H)，8.21(s，1H)，9.25(s，1H)，11.54(s，1H)，11.63(s，1H).ESI-MS：293.05([M+H]+).Anal.Calcd?for?C14H12ClNO4：C，57.25；H，4.12；Cl，12.07；N，4.77；O，21.79％；fourd：C，57.22；H，4.11；Cl，12.09；N，4.74；O，21.81％.
Embodiment six: (E)-and the preparation of 2-(3-chloro-phenyl-)-1-(2,4-dihydroxy phenyl) ethyl ketone oxime (compound 6)
The preparation method is with embodiment one.Replace pyrocatechol with Resorcinol, replace bromo-acid with a chlorobenzene acetic acid, obtain the white powder target compound.Productive rate 62%.Mp?121-122℃.1H?NMR(300MHz，DMSO-d6)，4.18(s，2H)6.25(d，J＝1.29，1H)，6.26(s，1H)，6.41(d，J＝1.26，1H)，7.23(dd，J＝4.59，J＝9.15，1H)，7.30(d，J＝1.65，1H)，7.94(d，J＝5.31，1H)，8.16(s，1H)，11.54(s，1H)，11.63(s，1H)，12.37(s，1H).MS(ESI)：277.05([M+H]+).Anal.calc.for?C14H12ClNO3：C，60.55；H，4.36；Cl，12.77；N，5.04；O，17.28％；found：C，60.50；H，4.34；Cl，12.79；N，5.07；O，17.25％.
Embodiment seven: (E)-and the preparation of 2-(3-chloro-phenyl-)-1-(3,4-dihydroxy phenyl) ethyl ketone oxime (compound 7)
The preparation method is with embodiment one.Replace bromo-acid with a chlorobenzene acetic acid, obtain the white powder target compound.Productive rate 64%.Mp?120-122℃.
1H?NMR(300MHz，DMSO-d6)，4.10(s，2H)，6.68(d，J＝8.22，1H)，6.94(dd，J＝2.19，J＝8.22，1H)，7.12(d，J＝2.01，1H)，7.22(d，J＝5.31，2H)，7.37(d，J＝6.39，2H)，8.97(s，1H)，9.09(s，1H)，11.13(s，1H).MS(ESI)：277.05([M+H]
+).Anal.calc.for?C14H12ClNO3：C，60.55；H，4.36；Cl，12.77；N，5.04；O，17.28％；found：C，60.57；H，4.37；Cl，12.75；N，5.03；O，17.27％.
Embodiment eight: (E)-and the preparation of 2-(3-p-methoxy-phenyl)-1-(2,3,4-trihydroxy-phenyl) ethyl ketone oxime (compound 8)
The preparation method is with embodiment one.Replace pyrocatechol with pyrogallol, replace bromo-acid with the meta-methoxy toluylic acid, obtain yellow powder shape target compound.Productive rate 52%.Mp?120-121℃.
1H?NMR(300MHz，DMSO-d6)，3.70(s，3H)，4.07(s，2H)，6.27(d，J＝8.6，1H)，6.75(d，J＝7.1，1H)，6.82(d，J＝4.95，1H)，7.18(t，J＝7.68，3H)，8.19(s，1H)，9.15(s，1H)，11.44(s，1H)，11.73(s，1H).MS(ESI)：275.12([M+H]
+).Anal.calc.for?C15H17NO4：C，65.44；H，6.22；N，5.09；O，23.25％；found：C，65.47；H，6.20；N，5.07；O，23.26％.
Embodiment nine: (E)-and the preparation of 1-(2,4-dihydroxy phenyl)-2-(3-p-methoxy-phenyl) ethyl ketone oxime (compound 9)
The preparation method is with embodiment one.Replace pyrocatechol with Resorcinol, the meta-methoxy toluylic acid replaces bromo-acid, obtains yellow powder shape target compound.Productive rate 49%.Mp?153-156℃.
1H?NMR(500MHz，DMSO-d6)，3.70(s，3H)，4.13(s，2H)，6.24(s，1H)，6.25(d，J＝2.7，1H)，6.75(dd，J＝2.45，J＝8.25，1H)，6.81(s，1H)，6.83(d，J＝5.8，2H)，7.18(t，J＝7.65，1H)，7.27(d，J＝9.15，1H)，9.18(s，1H)，11.66(s，1H)，11.76(s，1H).MS(ESI)：273.10([M+H]
+).Anal.calc.for?C15H15NO4：C，65.92；H，5.53；N，5.13；O，23.42；found：C，65.94；H，5.54；N，5.18；O，23.41.
Embodiment ten: (E)-and the preparation of 1-(3,4-dihydroxy phenyl)-2-(3-p-methoxy-phenyl) ethyl ketone oxime (compound 10)
The preparation method is with embodiment one.Replace bromo-acid with the meta-methoxy toluylic acid, obtain yellow powder shape target compound.Productive rate 49%.Mp?153-156℃.
1H?NMR(500MHz，DMSO-d6)，3.70(s，3H)，4.13(s，2H)，6.24(s，1H)，6.25(d，J＝2.7，1H)，6.75(dd，J＝2.45，J＝8.25，1H)，6.81(s，1H)，6.83(d，J＝5.8，2H)，7.18(t，J＝7.65，1H)，7.27(d，J＝9.15，1H)，9.18(s，1H)，11.66(s，1H)，11.76(s，1H).MS(ESI)：273.10([M+H]
+).Anal.calc.forC15H15NO4：C，65.92；H，5.53；N，5.13；O，23.42％；found：C，65.94；H，5.54；N，5.18；O，23.41％.
Embodiment 11: (E)-and the preparation of 2-(3-bromophenyl)-1-(2,3,4-trihydroxy-phenyl) ethyl ketone oxime (compound 11)
The preparation method is with embodiment one.Replace pyrocatechol with pyrogallol, replace bromo-acid with a bromo-acid, obtain the white powder target compound.Productive rate 62%.Mp?126-127℃.
1H?NMR(300MHz，DMSO-d6)，4.09(s，2H)，6.29(d，J＝8.58，1H)，6.82(d，J＝8.76，1H)，7.23(t，J＝8.4，2H)，7.31(d，J＝7.7，1H)，7.47(d，J＝6.03，1H)，8.20(s，1H)，9.23(s，1H)，11.50(s，1H)，11.61(s，1H).MS(ESI)：336.99([M+H]
+).Anal.calc.for?C14H12BrNO4：C，49.73；H，3.58；Br，23.63；N，4.14；O，18.93％；found：C，49.75；H，3.60；Br，23.61；N，4.11；O，18.95％.
Embodiment 12: (E)-and the preparation of 2-(3-bromophenyl)-1-(3,4-dihydroxy phenyl) ethyl ketone oxime (compound 12)
The preparation method is with embodiment one.Replace bromo-acid with a bromo-acid, obtain the white powder target compound.Productive rate 64%.Mp?120-122℃.
1H?NMR(300MHz，DMSO-d6)，4.10(s，2H)，6.68(d，J＝8.22，1H)，6.94(dd，J＝2.19，J＝8.22，1H)，7.12(d，J＝2.01，1H)，7.22(d，J＝5.31，2H)，7.37(d，J＝6.39，2H)，8.97(s，1H)，9.09(s，1H)，11.13(s，1H).MS(ESI)：321.00([M+H]
+).Anal.calc.for?C14H12BrNO3：C，52.20；H，3.75；Br，24.80；N，4.35；O，14.90％；found：C，52.25；H，3.77；Br，24.77；N，4.32；O，14.88％.
Embodiment 13: (E)-and the preparation of 2-(3-bromophenyl)-1-(2,4-dihydroxy phenyl) ethyl ketone oxime (compound 13)
The preparation method is with embodiment one.Replace pyrocatechol with Resorcinol, a bromo-acid replaces bromo-acid, obtains the white powder target compound.Productive rate 53%.Mp?118-119℃.
1H?NMR(300MHz，DMSO-d6)，c4.17(s，2H)，6.25(s，1H)，7.25(d，J＝5.49，2H)，7.30(d，J＝8.97，2H)，7.38(d，J＝8.65，1H)，7.50(d，J＝5.31，1H)，9.71(s，1H)，11.61(s，1H)，11.50(s，1H).MS(ESI)：321.00([M+H]
+).Anal.calc.for?C14H12BrNO3：C，52.20；H，3.75；Br，24.80；N，4.35；O，14.90％；found：C，52.23；H，3.77；Br，24.82；N，4.30；O，14.88％.
Embodiment 14: (E)-and the preparation of 2-(4-chloro-phenyl-)-1-(2,3,4-trihydroxy-phenyl) ethyl ketone oxime (compound 14)
The preparation method is with embodiment one.Replace pyrocatechol with pyrogallol, 4-Chlorophenylacetic acid replaces bromo-acid, obtains the white powder target compound.Productive rate 53%.Mp?145-147℃.
1H?NMR(300MHz，DMSO-d6)，4.14(s，2H)，6.24(s，1H)，6.39(d，J＝9Hz，1H)，6.90(d，J＝8Hz，2H)，7.08(d，J＝9Hz，2H)，7.88(d，J＝9Hz，1H)，8.71(s，1H)，9.45(s，1H)，10.11(s，1H)，12.45(s，1H).MS(ESI)：293.05([M+H]
+).Anal.calc.for?C14H12ClNO4：C，57.25；H，4.12；C1，12.07；N，4.77；O，21.79％；found：C，57.26；H，4.13；Cl，12.08；N，4.73；O，21.80％.
Embodiment 15: (E)-and the preparation of 2-(4-chloro-phenyl-)-1-(3,4-dihydroxy phenyl) ethyl ketone oxime (compound 15)
The preparation method is with embodiment one.Replace bromo-acid with 4-Chlorophenylacetic acid, obtain the white powder target compound.Productive rate: 62%.Mp?144-145℃.
1H?NMR(300MHz，DMSO-d6)，3.99(s，2H)，6.67(d，J＝8.2Hz，1H)，6.92(dd，J＝8.22，2.2Hz，2H)，7.10(d，J＝2.2Hz，1H)，7.15(d，J＝8.4Hz，1H)，7.44(d，J＝8.4Hz，1H)，8.96(s，1H)，9.09(s，1H)，11.10(s，1H).ESI-MS：277.05([M+H]+).Anal.Calcd?for?C14H12ClNO3：C，60.55；H，4.36；Cl，12.77；N，5.04；O，17.28％；found：C，60.53；H，4.34；C1，12.78；N，5.05；O，17.30％.
Embodiment 16: (E)-and the preparation of 1-(3,4-dihydroxy phenyl)-2-(3-fluorophenyl) ethyl ketone oxime (compound 16)
The preparation method is with embodiment one.Replace bromo-acid with a fluorophenylacetic acid, obtain the white powder target compound.Productive rate 64%.Mp?120-122℃.
1H?NMR(300MHz，DMSO-d6)，4.10(s，2H)，6.68(d，J＝8.22，1H)，6.94(dd，J＝2.19，J＝8.22，1H)，7.12(d，J＝2.01，1H)，7.22(d，J＝5.31，2H)，7.37(d，J＝6.39，2H)，8.97(s，1H)，9.09(s，1H)，11.13(s，1H).MS(ESI)：261.08([M+H]
+).Anal.calc.for?C14H12FNO3：C，64.36；H，4.63；F，7.27；N，5.36；O，18.37％；found：C，64.35；H，4.64；F，7.23；N，5.35；O，18.39％.
Embodiment 17: (E)-and the preparation of 1-(2,4-dihydroxy phenyl)-2-(3-fluorophenyl) ethyl ketone oxime (compound 17)
The preparation method is with embodiment one.Replace pyrocatechol with Resorcinol, a fluorophenylacetic acid replaces bromo-acid, obtains the white powder target compound.Productive rate 53%.Mp?118-119℃.
1H?NMR(300MHz，DMSO-d6)，c4.17(s，2H)，6.25(s，1H)，7.25(d，J＝5.49，2H)，7.30(d，J＝8.97，2H)，7.38(d，J＝8.65，1H)，7.50(d，J＝5.31，1H)，9.71(s，1H)，11.61(s，1H)，11.50(s，1H).MS(ESI)：261.08([M+H]
+).Anal.calc.for?C14H12FNO3：C，64.36；H，4.63；F，7.27；N，5.36；O，18.37％；found：C，64.35；H，4.64；F，7.29；N，5.38；O，18.34％.
Embodiment 18: (E)-and the preparation of 2-(3-fluorophenyl)-1-(2,3,4-trihydroxy-phenyl) ethyl ketone oxime (compound 18)
The preparation method is with embodiment one.Replace pyrocatechol with pyrogallol, replace bromo-acid with a fluorophenylacetic acid, obtain the white powder target compound.Productive rate 62%.Mp?126-127℃.
1H?NMR(300MHz，DMSO-d6)，4.09(s，2H)，6.29(d，J＝8.58，1H)，6.82(d，J＝8.76，1H)，7.23(t，J＝8.4，2H)，7.31(d，J＝7.7，1H)，7.47(d，J＝6.03，1H)，8.20(s，1H)，9.23(s，1H)，11.50(s，1H)，11.61(s，1H).MS(ESI)：277.08([M+H]
+).Anal.calc.for?C14H12FNO4：C，60.65；H，4.36；F，6.85；N，5.05；O，23.08％；found：C，60.67；H，4.37；F，6.84；N，5.06；O，23.09％.
Embodiment 19: (E)-and the preparation of 2-(4-nitrophenyl)-1-(2,3,4-trihydroxy-phenyl) ethyl ketone oxime (compound 19)
The preparation method is with embodiment one.Replace pyrocatechol with pyrogallol, paranitrophenylacetic acid replaces bromo-acid, obtains the white powder target compound.Productive rate 53%.Mp?145-147℃.
1H?NMR(300MHz，DMSO-d6)，4.14(s，2H)，6.24(s，1H)，6.39(d，J＝9Hz，1H)，6.90(d，J＝8Hz，2H)，7.08(d，J＝9Hz，2H)，7.88(d，J＝9Hz，1H)，8.71(s，1H)，9.45(s，1H)，10.11(s，1H)，12.45(s，1H).MS(ESI)：304.07([M+H]
+).Anal.calc.for?C14H12N2O6：C，55.27；H，3.98；N，9.21；O，31.55％；found：C，55.26；H，3.99；N，9.20；O，31.53％.
Embodiment 20: (E)-and the preparation of 2-(4-nitrophenyl)-1-(2,3,4-trihydroxy-phenyl) ethyl ketone oxime (compound 20)
The preparation method is with embodiment one.Replace bromo-acid with paranitrophenylacetic acid, obtain the white powder target compound.Productive rate: 62%.Mp?144-145℃.
1H?NMR(300MHz，DMSO-d6)，3.99(s，2H)，6.67(d，J＝8.2Hz，1H)，6.92(dd，J＝8.22，2.2Hz，2H)，7.10(d，J＝2.2Hz，1H)，7.15(d，J＝8.4Hz，1H)，7.44(d，J＝8.4Hz，1H)，8.96(s，1H)，9.09(s，1H)，11.10(s，1H).ESI-MS：288.07([M+H]+).Anal.Calcd?for?C14H12N2O5：C，58.33；H，4.20；N，9.72；O，27.75％；found：C，58.32；H，4.22；N，9.73；O，27.77％.
Embodiment 21: the research of oxime compounds immunosuppressive activity
Adopt MTT[3-(4,5)-two methyl-2-thiazole-(2,5)-phenyl bromination tetrazole is blue] method measures oxime compounds to T cell and the non-activated T cell minimum inhibitory concentration (minimal inhibitoryconcentration, MIC) of activation.Adopt the method for flow cytometer and immunoblotting that the best compound of immunocompetence is carried out the mechanism of action detection.
(1) animal is prepared: available from the female BALB/c mouse in 6 to 8 ages in week of Jiangsu Province's Experimental Animal Center.Under 21 ± 2 ℃, mouse keep freely eating food and water, and kept for 12 little time/cycle secretly.Laboratory Animal Welfare and experimental arrangement are to carry out in strict accordance with treatment and laboratory animal guide (science and China, 200 years technical divisions) the ethics rules guide relevant with Nanjing University.Reduce to full capacity the misery of animal and reduce the quantity of using animal.
(2) cell is prepared with reagent: separate lymph-node cell from BALB/c mouse at 37 ℃, in the air of 5.0% carbonic acid gas humidification, cultivate in 1640 substratum that are aided with 10% foetal calf serum (foetal calf serum).Anti-CD3, anti-CD28 murine antibody is available from BD Pharmingen.Annexin V-FITC/PI test kit is available from the U.S. biotechnology of crystalline substance.Anti-caspase-3 antibody and the anti-PARP antibody of splitting is available from Santa Cruz biotech company.Anti-β-ribose antibody is available from Cell Signaling Technology, Inc..Every other chemical obtains Sigma chemical industry company limited.
(3) cell proliferation experiment: lymph-node cell is with 5 * 10
5The density of individual/plate is cultivated in 96 holes, with the compound of different concns with the anti-CD28 Co stituation of anti-CD3/, continue 72h.4h before cultivating end, every hole adds 20 μ l MTT, and the multiplicative stage begins.After the end, remove supernatant liquor after, add 20 μ l DMSO Rong Xie formazan crystallizations.With the absorbancy under the enzyme linked immunosorbent assay instrument test 540nm.
(4) cell toxicity test: with cell with 5 * 10
5The density in individual/hole adds in 96 orifice plates, and the compound that then adds gradient concentration is cultivated 72h.The every hole of 4h adds the MTT of 20 μ l before finishing cultivation.And then add the DMSO Rong Xie formazan crystal of 200 μ l.Survey at last the absorbance of 540nm.
(5) apoptosis detects: stimulate lymph-node cell with anti-CD3/anti-CD28 under the compound of different concns, continue 48 hours.Use again albumen V-fluorescence (fluorescein isothiocyanate) and propidium iodide (PI) to dye.With flow cytometer sample is analyzed at last.
(6) immunoblotting assay: after cultivating end, with phosphoric acid buffer and the lysate (Tris of 30mmol/L, pH value 7.5, the sodium-chlor of 150mmol/L, the phenylmethylsulfonyl fluoride of 1mmol/L, the sodium orthovanadate of 1mmol/L, 1%Nonidet P-40,10% glycerine and Phosphoric acid esterase and proteinase inhibitor) the washing lysing cell.The centrifugal 1O of 10,000 * g minute, use BCA
TMProtein detection kit (Pierce, Rockford, IL) is determined the content of the protein of supernatant liquor.Separate this protein with the 10%SDS-PAGE cracking again, be placed on subsequently and carry out the electricity conversion on the polyvinylidene fluoride film.Film at room temperature seals 2h with 5% skimmed milk.The film of sealing, then resists in conjunction with two with horseradish peroxidase and hatches at 4 ℃ of probe marks that spend the night in order to the primary antibodie of mark.With the LumiGLO chemical luminescence substrate system result is detected again.
(7) statistical study
All experiments have all repeated 3-5 time, all obtain similar result.These two experimental group P values are tested with two tail student t-checks.It is 0.05 that significance level fixes on the P value.If applicable, data report is mean+SD (SD).
The calculating of inhibiting rate: the inhibiting rate of Growth of Cells calculates according to following formula:
Growth inhibition ratio=(1-survival rate) * 100%=[1-(OD
Experiment-OD
Blank)/(OD
Contrast-OD
Empty In vain)] * 100% (OD
ExperimentThe average optical of expression testing drug group, OD
ContrastThe average optical of expression control group, OD
BlankThe average optical of expression control group).
Half-inhibition concentration (IC
50) be defined as the drug level when the survival of 50% tumour cell.According to the optical density(OD) (OD value) of measuring, make the typical curve of inhibitory rate of cell growth, try to achieve its corresponding drug level at typical curve.
The inhibition IC of T cell to activation of oxime compounds of the present invention
50Value sees Table 1, to the inhibition IC of non-activated T cell
50Value sees Table 2.
The inhibition IC of T cell to activation of the listed oxime compounds of table 1 the present invention
50Value (μ M)
The inhibition IC to non-activated T cell of the listed oxime compounds of table 2 the present invention
50Value (μ M)
Claims (5)
1. oxime compounds is characterized in that it has following general formula:
In the formula: R
1For:
R
2For:
2. method for preparing oxime compounds claimed in claim 1 is characterized in that it is comprised of the following step:
Step 1. is in boron trifluoride ether solution, add the compound of corresponding phenol and the compound of corresponding toluylic acid class, the ratio of the amount of substance of the compound of the compound of phenol and toluylic acid class is 1: 1, be heated with stirring to 80-84 ℃, cool off behind the reaction 2h, under agitation pour in the aqueous solution of sodium acetate, then static, filter out solid behind the 24h, the solid that obtains is dissolved in the dehydrated alcohol recrystallization purifies
Solid after the purification that step 2. obtains step 1 is dissolved in dehydrated alcohol, adds sodium acetate, adds the oxammonium hydrochloride of Isoequivalent weight again, is heated with stirring to 60 ℃, until react completely, and cooled and filtered, the filtrate decompression evaporate to dryness obtains the compound of oximes.
3. method for making according to claim 2, it is characterized in that: in the described step 1, boron trifluoride ether solution is that mass percentage concentration is the 47.0-47.7% boron trifluoride ether solution, and its consumption is that the compound of every mmole phenol adds 1.0-1.5ml.
4. method for making according to claim 2, it is characterized in that: in the described step 2, the consumption of dehydrated alcohol is that every mmole oxammonium hydrochloride adds 1.0-1.5ml.
5. oxime compounds claimed in claim 1 is used in the preparation immunosuppressive drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910233389.3A CN101693674B (en) | 2009-10-27 | 2009-10-27 | Oxime compound, preparation process and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910233389.3A CN101693674B (en) | 2009-10-27 | 2009-10-27 | Oxime compound, preparation process and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101693674A CN101693674A (en) | 2010-04-14 |
| CN101693674B true CN101693674B (en) | 2013-03-06 |
Family
ID=42092686
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910233389.3A Expired - Fee Related CN101693674B (en) | 2009-10-27 | 2009-10-27 | Oxime compound, preparation process and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101693674B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109772592B (en) * | 2019-03-13 | 2021-03-23 | 广东省科学院资源综合利用研究所 | Application of 2-hydroxy aronoxime compound as collecting agent in oxide ore flotation and flotation method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4029704A (en) * | 1972-08-25 | 1977-06-14 | Imperial Chemical Industries Limited | Oximes |
-
2009
- 2009-10-27 CN CN200910233389.3A patent/CN101693674B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4029704A (en) * | 1972-08-25 | 1977-06-14 | Imperial Chemical Industries Limited | Oximes |
Non-Patent Citations (5)
| Title |
|---|
| ACS.RN: 320741-23-9.《STN:REGISTRY》.2001, * |
| Huan-Qiu Li et al.Amines and oximes derived from deoxybenzoins as Helicobacter pylori urease inhibitors.《European Journal of Medicinal Chemistry》.2008,第44卷2246-2251. * |
| Medicinal Chemistry》.2007,第15卷3703-3710. * |
| Zhu-Ping Xiao et al.Polyphenols based on isoflavones as inhibitors of Helicobacter pylori urease.《Bioorganic & Medicinal Chemistry》.2007,第15卷3703-3710. |
| Zhu-Ping Xiao et al.Polyphenols based on isoflavones as inhibitors of Helicobacter pylori urease.《Bioorganic & * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101693674A (en) | 2010-04-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103102283A (en) | Preparation method of chalcone oxime compound and application of the same as novel immunosuppressant | |
| Fang et al. | EGCG inhibits proliferation, invasiveness and tumor growth by up-regulation of adhesion molecules, suppression of gelatinases activity, and induction of apoptosis in nasopharyngeal carcinoma cells | |
| CN103664932B (en) | One class indoles grafting thiazole hydrazone analog derivative and preparation method thereof and the inhibitory action to cancer cell tubulin polymerization | |
| CN106831383A (en) | Diarylheptanoids | |
| CN101693674B (en) | Oxime compound, preparation process and application thereof | |
| Viswanathan et al. | Battling Glioblastoma: A Novel Tyrosine Kinase Inhibitor with Multi-Dimensional Anti-Tumor Effect | |
| CN108530435B (en) | Quinoxaline-containing 1, 4-pentadiene-3-ketone derivative, preparation method and application | |
| CN101932331B (en) | Methods for in vitro maturation of ovarian follicles | |
| CN103102331B (en) | Pharmaceutical application of chalcone compound containing piperazine ring | |
| CN105884645B (en) | A kind of rhein compound and application thereof | |
| CN104529987A (en) | 4-hydroxyl bishydroxycoumarin compound and application thereof | |
| CN104447436B (en) | A kind of sulphur acylhydrazone, its preparation method and free radical resisting thereof or anti-tumor activity application | |
| CN103936772A (en) | Preparation method of binuclear copper complex with anti-tumor activity | |
| JP4939761B2 (en) | Ingredients of stone lotus flowers and their uses | |
| CN105646476B (en) | Biphenyl simultaneously [1,2,5] selenium oxadiazole derivative and its preparation method and application | |
| CN107496428A (en) | Calycosin derivative is preparing the application in promoting endothelial cell proliferation medicine | |
| CN104961707B (en) | Substituted thiazole ketone secretory protease inhibitors and preparation method thereof | |
| CN102093191A (en) | Resveratrol chalcone derivative and preparation method thereof | |
| CN114671917A (en) | Curcumin analogue, preparation method and application thereof in anti-cancer cell proliferation drugs | |
| Fu et al. | EDACO, a derivative of myricetin, inhibits the differentiation of Gaoyou duck embryonic osteoclasts in vitro | |
| CN104173325B (en) | Application of the palmitinic acid in preparation treatment liver cancer and anti-liver cancer and anti-diversion medicaments | |
| CN104910074A (en) | Hydroximic acid group-containing pyrazoles derivative, preparation method and purpose thereof | |
| CN106588581A (en) | Stilbenes derivative and application thereof | |
| CN104922125B (en) | 2- [3- cyano-[R1-R2-R3Azepine phenyl]-R4Thio-based compound and its pharmaceutical composition and its application | |
| CN106544399A (en) | The application of the high specific fluorescence probe of one class detection Cytochrome P450 1A1 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130306 Termination date: 20151027 |
|
| EXPY | Termination of patent right or utility model |