CN106699690B - 一种具有酰基哌嗪基侧链的截短侧耳素衍生物及其制备方法和用途 - Google Patents
一种具有酰基哌嗪基侧链的截短侧耳素衍生物及其制备方法和用途 Download PDFInfo
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- CN106699690B CN106699690B CN201611115910.XA CN201611115910A CN106699690B CN 106699690 B CN106699690 B CN 106699690B CN 201611115910 A CN201611115910 A CN 201611115910A CN 106699690 B CN106699690 B CN 106699690B
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- hydrogen atom
- acid
- pleuromutilin
- compound
- solvent
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- -1 acyl piperazine Chemical compound 0.000 title claims abstract description 46
- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical class C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title abstract 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 73
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 10
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 241000894006 Bacteria Species 0.000 claims abstract description 7
- 241000282414 Homo sapiens Species 0.000 claims abstract description 7
- 241001465754 Metazoa Species 0.000 claims abstract description 7
- 241000204031 Mycoplasma Species 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 78
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 69
- 239000000203 mixture Substances 0.000 claims description 62
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 42
- 239000002904 solvent Substances 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 238000010438 heat treatment Methods 0.000 claims description 23
- 238000004440 column chromatography Methods 0.000 claims description 22
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 21
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 19
- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 claims description 17
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 16
- 239000000010 aprotic solvent Substances 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical class C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 10
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 8
- 150000001263 acyl chlorides Chemical class 0.000 claims description 8
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 235000009518 sodium iodide Nutrition 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 208000015181 infectious disease Diseases 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- PWZDJIUQHUGFRJ-UHFFFAOYSA-N 1-(2-chlorophenyl)piperazine Chemical compound ClC1=CC=CC=C1N1CCNCC1 PWZDJIUQHUGFRJ-UHFFFAOYSA-N 0.000 claims description 3
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 claims description 3
- WICKLEOONJPMEQ-UHFFFAOYSA-N 1-(2-methylphenyl)piperazine Chemical compound CC1=CC=CC=C1N1CCNCC1 WICKLEOONJPMEQ-UHFFFAOYSA-N 0.000 claims description 3
- YJRCDSXLKPERNV-UHFFFAOYSA-N 1-(2-nitrophenyl)piperazine Chemical compound [O-][N+](=O)C1=CC=CC=C1N1CCNCC1 YJRCDSXLKPERNV-UHFFFAOYSA-N 0.000 claims description 3
- VHFVKMTVMIZMIK-UHFFFAOYSA-N 1-(3-chlorophenyl)piperazine Chemical compound ClC1=CC=CC(N2CCNCC2)=C1 VHFVKMTVMIZMIK-UHFFFAOYSA-N 0.000 claims description 3
- PZIBVWUXWNYTNL-UHFFFAOYSA-N 1-(3-methoxyphenyl)piperazine Chemical compound COC1=CC=CC(N2CCNCC2)=C1 PZIBVWUXWNYTNL-UHFFFAOYSA-N 0.000 claims description 3
- JIWHIRLNKIUYSM-UHFFFAOYSA-N 1-(3-methylphenyl)piperazine Chemical compound CC1=CC=CC(N2CCNCC2)=C1 JIWHIRLNKIUYSM-UHFFFAOYSA-N 0.000 claims description 3
- LHHZRIYUOZPKSG-UHFFFAOYSA-N 1-(3-nitrophenyl)piperazine Chemical compound [O-][N+](=O)C1=CC=CC(N2CCNCC2)=C1 LHHZRIYUOZPKSG-UHFFFAOYSA-N 0.000 claims description 3
- ONEYFZXGNFNRJH-UHFFFAOYSA-N 1-(4-methylphenyl)piperazine Chemical compound C1=CC(C)=CC=C1N1CCNCC1 ONEYFZXGNFNRJH-UHFFFAOYSA-N 0.000 claims description 3
- VWOJSRICSKDKAW-UHFFFAOYSA-N 1-(4-nitrophenyl)piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1N1CCNCC1 VWOJSRICSKDKAW-UHFFFAOYSA-N 0.000 claims description 3
- AYGYICRITMSJOC-UHFFFAOYSA-N 3-piperazin-1-ylphenol Chemical compound OC1=CC=CC(N2CCNCC2)=C1 AYGYICRITMSJOC-UHFFFAOYSA-N 0.000 claims description 3
- GPEOAEVZTOQXLG-UHFFFAOYSA-N 4-piperazin-1-ium-1-ylphenolate Chemical compound C1=CC(O)=CC=C1N1CCNCC1 GPEOAEVZTOQXLG-UHFFFAOYSA-N 0.000 claims description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- MRDGZSKYFPGAKP-UHFFFAOYSA-N para-methoxyphenylpiperazine Chemical compound C1=CC(OC)=CC=C1N1CCNCC1 MRDGZSKYFPGAKP-UHFFFAOYSA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- UORNTHBBLYBAJJ-UHFFFAOYSA-N 2-piperazin-1-ylphenol Chemical compound OC1=CC=CC=C1N1CCNCC1 UORNTHBBLYBAJJ-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 230000003213 activating effect Effects 0.000 claims description 2
- 230000004913 activation Effects 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 2
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- UNEIHNMKASENIG-UHFFFAOYSA-N para-chlorophenylpiperazine Chemical compound C1=CC(Cl)=CC=C1N1CCNCC1 UNEIHNMKASENIG-UHFFFAOYSA-N 0.000 claims description 2
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- 238000001953 recrystallisation Methods 0.000 claims description 2
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- 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 2
- 241000191967 Staphylococcus aureus Species 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 5
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学领域,公开了一种具有酰基哌嗪基侧链的截短侧耳素类化合物及其制备方法和用途。该截短侧耳素衍生物是具有如式3、式4和式5所示结构的化合物及其可药用盐。其中,R1、R2、R3各自独立地选自氢原子、羟基、氨基、巯基、羟甲基、胺甲基、硝基、卤素、三卤代甲基、甲基、天然氨基酸酰氨基和碳原子数为1~6的烷氧基中的一种。本发明具有酰基哌嗪基侧链的截短侧耳素类化合物具有良好的抑制金黄色葡萄球菌和支原体活性,特别适合作为新型抗菌药物用于防治人或动物经支原体或多药耐药菌感染引起的感染性疾病。
Description
技术领域
本发明属于药物化学领域,特别涉及一种具有酰基哌嗪基侧链的截短侧耳素衍生物及其制备方法和用途。
背景技术
截短侧耳素(式1)是由高等真菌Pleurotusmutiliz(Fr.)Sacc.和PleurotusPasseckeranius Pilat产生的一种具有5-6-8三环二萜结构的化合物,该类化合物只选择性的抑制原核细胞蛋白质的合成,对真核细胞没有影响,也不与哺乳动物的核糖体相互作用,且不易与其他抗生素产生联合耐药性。自发现至今,研究人员通过对截短侧耳素进行结构改造,获得数以万计的截短侧耳素衍生物,其中在羟基被取代的其他截短侧耳素已经被开发,且不乏具有高效抗菌活性、低毒性的备选药物例如抗微生物剂。截止目前,截短侧耳素类抗菌药已有三种药物相继上市,分别为动物专用抗菌药沃尼妙林(Valnemulin)和泰妙菌素(Tiamulin),及2007年获FDA批准上市的第一个人用截短侧耳素类抗菌药瑞他妙林(Retapamulin)。
目前应用于临床的截短侧耳素类抗生素抗菌谱广,对革兰氏阳性菌有效,对支原体属和螺旋体属作用强,而对肠道菌属如大肠杆菌、沙门氏菌效力较低。
由于截短侧耳素类抗生素的这种独特的作用机理,这类药物和其他药物之间不会产生交叉耐药性,故针对截短侧耳素类抗菌药的耐药菌尚不多见。而且与其他类抗生素如青霉素类、头孢类、氨基糖苷类等相比,截短侧耳素类至今被成功开发的药物只有三种,我们有理由相信截短侧耳素类抗生素的开发潜力是巨大的。
发明内容
为了解决现有技术的缺点和不足之处,本发明的首要目的在于提供一种具有酰基哌嗪基侧链的截短侧耳素衍生物;
本发明的另一目的在于提供上述具有酰基哌嗪基侧链的截短侧耳素衍生物的制备方法;
本发明的再一个目的在于提供一种药物组合物,其包含上述具有酰基哌嗪基侧链的截短侧耳素衍生物作为活性成分;
本发明的又一个目的在于提供上述具有酰基哌嗪基侧链的截短侧耳素衍生物在制备治疗感染性疾病特别是多药耐药菌引起的感染性疾病的药物中的用途。
本发明目的通过以下技术方案实现:
一种具有酰基哌嗪基侧链的截短侧耳素衍生物,该截短侧耳素衍生物是具有如式3、式4和式5所示结构的化合物及其可药用盐:
其中,
R4为氯代特戊酰基、2-氯丙酰基、3-氯丙酰基、3-氯苯甲酰基、4-氯丁酰基中的一种。
R5为中的一种。
R1为氢原子、羟基、氨基、巯基、羟甲基、胺甲基、硝基、卤素、三卤代甲基、甲基、天然氨基酸酰氨基和碳原子数为1~6的烷氧基中的一种,优选为氢、羟基、氨基、羟甲基、胺甲基、氟、三氟甲基、硝基、三氟甲基、甲氧基、乙氧基、脯氨酰氨基和缬氨酰氨基中的一种。
R2为氢原子、羟基、氨基、巯基、羟甲基、胺甲基、硝基、卤素、三卤代甲基、甲基、天然氨基酸酰氨基和碳原子数为1~6的烷氧基中的一种,优选为氢、羟基、氨基、羟甲基、胺甲基、氟、三氟甲基、硝基、三氟甲基、甲氧基、乙氧基、脯氨酰氨基和缬氨酰氨基中的一种。
R3为氢原子、羟基、氨基、巯基、羟甲基、胺甲基、硝基、卤素、三卤代甲基、甲基、天然氨基酸酰氨基和碳原子数为1~6的烷氧基中的一种,氢、羟基、氨基、羟甲基、胺甲基、氟、三氟甲基、硝基、三氟甲基、甲氧基、乙氧基、脯氨酰氨基和缬氨酰氨基中的一种。
术语“卤素”表示氟、氯、溴、碘。
更加优选的:所述R1为氢原子,R2为氢原子,R3为氢原子;
或R1为硝基,R2为氢原子,R3为氢原子;
或R1为氢原子,R2为硝基,R3为氢原子;
或R1为氢原子,R2为氢原子,R3为硝基;
或R1为氯原子,R2为氢原子,R3为氢原子;
或R1为氢原子,R2为氯原子,R3为氢原子;
或R1为氢原子,R2为氢原子,R3为氯原子;
或R1为甲氧基,R2为氢原子,R3为氢原子;
或R1为氢原子,R2为甲氢基,R3为氢原子;
或R1为氢原子,R2为氢原子,R3为甲氧基;
或R1为羟基,R2为氢原子,R3为氢原子;
或R1为氢原子,R2为羟基,R3为氢原子;
或R1为氢原子,R2为氢原子,R3为羟基;
或R1为甲基,R2为氢原子,R3为氢原子;
或R1为氢原子,R2为甲基,R3为氢原子;
或R1为氢原子,R2为氢原子,R3为甲基;
上述优选方式也可以如表1、2、3所示:
表1本发明代表性化合物b-f结构式
表2本发明代表性化合物1a-1f结构式
表3本发明代表性化合物2a-17a,3b-17b,2c-17c,2d-17d,2e-17e,2f-17f结构式
所述可药用盐是具有如式3、式4和式5所示结构的化合物,与盐酸、氢溴酸、硫酸、硝酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、琥珀酸、柠檬酸、苹果酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、谷氨酸或天冬氨酸形成的盐。
优选地,本发明的通式3和式4所示的化合物中部分具有代表性的化合物的可药用盐结构式如表4所示:
表4部分化合物的可药用盐
上述具有酰基哌嗪基侧链的截短侧耳素衍生物的制备方法,包括以下操作步骤:
(1)将截短侧耳素与对甲苯磺酰氯反应,获取如下式所示结构的中间体Ⅰ;
(2)以中间体Ⅰ为原料,通过与碘化钠反应进一步活化,再与N-BOC-哌嗪(N-叔丁氧羰基-哌嗪)在碱性条件下反应,除去BOC(叔丁氧羰基)获得如式2所示结构的中间体Ⅱ;
(3)以中间体Ⅱ为原料,与酰氯反应,分别获得中间体IV或如式3所示结构的中间体Ⅲ;
(4)以中间体Ⅲ或中间体IV作为原料,与各取代苯基哌嗪反应,得到如式4或式5所示结构的具有酰基哌嗪基侧链的截短侧耳素类化合物。
步骤(1)所述反应是采用乙酸乙酯作为溶剂,在常温条件下反应3小时;所述截短侧耳素与对甲苯磺酰氯摩尔比为1:1.1。
步骤(2)所述反应是采用非质子溶剂作为溶剂,先将中间体Ⅰ溶于非质子溶剂中,溶剂用量为中间体Ⅰ质量的10倍,再加入无水碘化钠,加热回流1小时,其中中间体Ⅰ与无水碘化钠摩尔比为1:1.1;再将N-BOC-哌嗪、碱与活化所得产物一起加热回流2小时,其中中间体Ⅰ与N-BOC-哌嗪摩尔比为1:1.1,N-BOC-哌嗪与碱摩尔比为1:2;然后将上述反应所得产物加入到质量分数25%的三氟乙酸的二氯甲烷溶液,常温搅拌8h,获得中间体Ⅱ;所述碱为氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾或碳酸铯;所述非质子溶剂为乙腈。
步骤(3)所述反应采用非质子溶剂作为溶剂,加入酰氯及碱,与中间体Ⅱ在0℃进行反应3小时;其中中间体Ⅱ与酰氯摩尔比为1:1.1,酰氯与碱摩尔比为1:2;其中所述酰氯为氯乙酰氯、氯代特戊酰氯、2-氯丙酰氯、3-氯苯甲酰氯、4-氯丁酰氯或3-氯丙酰氯;所述非质子溶剂为乙腈。
步骤(4)所述反应采用非质子溶剂作为溶剂,加入取代苯基哌嗪及碱,与中间体Ⅲ或中间体IV一起加热回流3小时,即得目标产物,重结晶或柱层析纯化;其中中间体Ⅲ或中间体IV,与取代苯基哌嗪摩尔比为1:1.1,取代苯基哌嗪与碱摩尔比为1:2;其中,所述非质子溶剂为二氯甲烷、乙腈、乙酸乙酯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、吡啶;所述取代苯基哌嗪为1-甲基哌嗪、N-苯基哌嗪、2-甲基苯基哌嗪、3-甲基苯基哌嗪、4-甲基苯基哌嗪、2-甲氧基苯基哌嗪、3-甲氧基苯基哌嗪、4-甲氧基苯基哌嗪、2-硝基苯基哌嗪、3-硝基苯基哌嗪、4-硝基苯基哌嗪、2-羟基苯基哌嗪、3-羟基苯基哌嗪、4-羟基苯基哌嗪、2-氯苯基哌嗪、3-氯苯基哌嗪或4-氯苯基哌嗪。
上述制备方法的合成路线如下,可以合成出中间体Ⅱ、I I I、IV(式2、3化合物)和化合物1a-1f,2a-17a,2b-17b,2c-17c,2d-17d,2e-17e,2f-17f:
一种药物组合物,该药物组合物包含了上述具有酰基哌嗪基侧链的截短侧耳素衍生物作为活性成分。
上述的具有酰基哌嗪基侧链的截短侧耳素衍生物在制备治疗感染性疾病药物中的用途,所述感染性疾病为人或动物经支原体或多药耐药菌感染引起的感染性疾病。
上述具有酰基哌嗪基侧链的截短侧耳素衍生物用来制备抗感染药物时,可以单独使用,或者按照制药学上的常规方法,将其与可药用的赋形剂、稀释剂等混合,制成口服给药的片剂、胶囊剂、颗粒剂、糖浆剂、预混剂、微丸剂,或者制成非口服方式给药的搽剂或注射剂等。
与现有技术相比,本发明具有以下优点及有益效果:本发明提供的截短侧耳素类化合物是首次报道的具有全新结构的化合物;本发明人经过广泛而深入的研究,合成了大量化合物并进行了广泛的生物活性筛选,首次发现具有通式3、通式4及通式5结构的化合物具有良好的抑制金黄色葡萄球菌和支原体活性的抗菌活性,特别适合作为新兴抗菌药物用于动物或人全身系统感染,用于防治人或动物经支原体或多药耐药菌感染引起的感染性疾病。
附图说明
图1是MRSA感染小鼠死亡保护实验结果图。
具体实施方式
下面结合实施例对本发明作进一步详细的描述,但本发明的实施方式不限于此。下述实施例1-19所得化合物的编号如权利要求书中所示。
中间体Ⅰ制备实施例:
截短侧耳素10g(26.42mmol)溶于25ml乙酸乙酯,加入对甲苯磺酰氯5.5g(29.06mmol),冰浴至0℃左右,加入氢氧化钠溶液(氢氧化钠2.1g(52.84mmol)溶于10mL水)。常温搅拌反应3h后加入50mL水淬灭反应。将反应液倒入分液漏斗,先加30mL氯仿分层,除去水相,后再用水100mL洗涤有机相2次,最后用去离子水100mL洗涤有机相2次并用无水硫酸钠干燥。旋转蒸发干有机相,往残余固体中加入36mL异丙醇并加热溶解,冷却后析出大量白色粉末,减压抽滤,滤出物用异丙醇洗涤,产物白色粉末剩余液体自然挥发至干燥,得白色粉末即中间体Ⅰ12.0g,产率85.71%。
中间体Ⅱ制备实施例:
中间体Ⅰ1g(1.88mmol)溶于10mL乙腈,加入无水碘化钠0.31g(2.07mmol),70℃左右加热搅拌反应1h。取BOC哌嗪0.38g(2.07mmol),碳酸钾0.52g(3.76mmol),加入上述反应体系中,70℃左右加热搅拌反应2h。将反应液倒入分液漏斗中,加30mL氯仿萃取,50mL水洗涤两次,再经无水硫酸钠干燥,取有机相。所得有机相旋转蒸干得混合物加入二氯甲烷15mL复溶,再加入三氟乙酸5mL常温搅拌8h。将所得反应液旋转蒸干,用30mL氯仿复溶,再用饱和碳酸氢钠溶液萃取,得有机相至PH 7~8,经无水硫酸钠干燥,所得有机相旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,二氯甲烷:甲醇=5:1为流动相),得到产物如式2所示结构的中间体Ⅱ的纯品0.52g。产率61.9%。HR-MS(ESI):Calcd.for C26H43N2O4(M+H+):447.3217;Found:447.3201.tR=8.24min。
中间体Ⅲ制备实施例:
中间体Ⅲ1g(2.24mmol)溶于10mL二氯甲烷,冰盐浴条件下加入氯乙酰氯0.187mL(2.46mmol),碳酸钾0.619g(4.48mmol),常温搅拌2.5h。加反应液倒入分液漏斗中,加30mL氯仿萃取,50mL水洗涤两次,再经无水硫酸钠干燥,取有机相。所得有机相旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,石油醚:乙酸乙酯=1:1为流动相),得到产物如式3所示结构的中间体Ⅲ的纯品0.71g。产率60.7%。HR-MS(ESI):Calcd.for C28H44ClN2O5(M+H+):523.2933;Found:523.2938.tR=10.04min
实施例1:14-O-1-(4-(2-N-甲基哌嗪基乙酰基))哌嗪基妙林(化合物1a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),1-甲基哌嗪0.233mL(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(2-N-甲基哌嗪基乙酰基))哌嗪基妙林(化合物1a)的纯品。产率40.78%。HR-MS(ESI):Calcd.for C33H55N4O5(M+H+):587.4167;Found:665.41803。
实施例2:14-O-1-(4-(2-甲基苯基哌嗪基乙酰基))哌嗪基妙林(化合物2a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),2-甲基苯基哌嗪0.37g(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(2-甲基苯基哌嗪基乙酰基))哌嗪基妙林(化合物2a)的纯品。产率46.74%。HR-MS(ESI):Calcd.for C39H59N4O5(M+H+):663.4480;Found:663.4485。
实施例3:14-O-1-(4-(3-甲基苯基哌嗪基乙酰基))哌嗪基妙林(化合物3a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),3-甲基苯基哌嗪0.36mL(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(3-甲基苯基哌嗪基乙酰基))哌嗪基妙林(化合物3a)的纯品。产率60.56%。HR-MS(ESI):Calcd.for C39H59N4O5(M+H+):663.4480;Found:663.4470。
实施例4:14-O-1-(4-(4-甲基苯基哌嗪基乙酰基))哌嗪基妙林(化合物4a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),4-甲基苯基哌嗪0.37g(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(4-甲基苯基哌嗪基乙酰基))哌嗪基妙林(化合物4a)的纯品。产率48.92%。HR-MS(ESI):Calcd.for C39H59N4O5(M+H+):663.4480;Found:663.4488。
实施例5:14-O-1-(4-(2-甲氧基苯基哌嗪基乙酰基))哌嗪基妙林(化合物5a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),2-甲氧基苯基哌嗪0.4g(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(2-甲氧基苯基哌嗪基乙酰基))哌嗪基妙林(化合物5a)的纯品。产率43.75%。HR-MS(ESI):Calcd.for C39H59N4O6(M+H+):679.4429;Found:679.4409。
实施例6:14-O-1-(4-(3-甲氧基苯基哌嗪基乙酰基))哌嗪基妙林(化合物6a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),3-甲氧基苯基哌嗪0.36mL(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(3-甲氧基苯基哌嗪基乙酰基))哌嗪基妙林(化合物6a)的纯品。产率46.05%。HR-MS(ESI):Calcd.for C39H59N4O6(M+H+):679.4429;Found:679.4416。
实施例7:14-O-1-(4-(4-甲氧基苯基哌嗪基乙酰基))哌嗪基妙林(化合物7a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),4-甲氧基苯基哌嗪0.37g(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(4-甲氧基苯基哌嗪基乙酰基))哌嗪基妙林(化合物7a)的纯品。产率55.67%。HR-MS(ESI):Calcd.for C39H59N4O6(M+H+):679.4429;Found:679.4434。
实施例8:14-O-1-(4-(2-硝基苯基哌嗪基乙酰基))哌嗪基妙林(化合物8a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),2-硝基苯基哌嗪0.43g(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(2-硝基苯基哌嗪基乙酰基))哌嗪基妙林(化合物8a)的纯品。产率51.78%。HR-MS(ESI):Calcd.for C38H56N5O7(M+H+):694.4174;Found:694.4174。
实施例9:14-O-1-(4-(3-硝基苯基哌嗪基乙酰基))哌嗪基妙林(化合物9a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),3-硝基苯基哌嗪0.43g(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(3-硝基苯基哌嗪基乙酰基))哌嗪基妙林(化合物9a)的纯品。产率53.47%。HR-MS(ESI):Calcd.for C38H56N5O7(M+H+):694.4174;Found:694.4143。
实施例10:14-O-1-(4-(4-硝基苯基哌嗪基乙酰基))哌嗪基妙林(化合物10a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),4-硝基苯基哌嗪0.43g(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(4-硝基苯基哌嗪基乙酰基))哌嗪基妙林(化合物10a)的纯品。产率49.26%。HR-MS(ESI):Calcd.for C38H56N5O7(M+H+):694.4174;Found:694.4182。
实施例11:14-O-1-(4-(2-羟基苯基哌嗪基乙酰基))哌嗪基妙林(化合物11a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),2-羟基苯基哌嗪0.37g(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(2-羟基苯基哌嗪基乙酰基))哌嗪基妙林(化合物11a)的纯品。产率64.21%。HR-MS(ESI):Calcd.for C38H57N4O6(M+H+):665.4273;Found:665.4271。
实施例12:14-O-1-(4-(3-羟基苯基哌嗪基乙酰基))哌嗪基妙林(化合物12a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),3-羟基苯基哌嗪0.37g(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(3-羟基苯基哌嗪基乙酰基))哌嗪基妙林(化合物12a)的纯品。产率68.32%。HR-MS(ESI):Calcd.for C38H57N4O6(M+H+):665.4273;Found:665.4276。
实施例13:14-O-1-(4-(4-羟基苯基哌嗪基乙酰基))哌嗪基妙林(化合物13a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),4-羟基苯基哌嗪0.37g(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(4-羟基苯基哌嗪基乙酰基))哌嗪基妙林(化合物13a)的纯品。产率66.77%。HR-MS(ESI):Calcd.for C38H57N4O6(M+H+):665.4273;Found:665.4277。
实施例14:14-O-1-(4-(2-氯苯基哌嗪基乙酰基))哌嗪基妙林(化合物14a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),2-氯苯基哌嗪0.41g(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(2-氯苯基哌嗪基乙酰基))哌嗪基妙林(化合物14a)的纯品。产率55.76%。HR-MS(ESI):Calcd.for C38H56ClN4O5(M+H+):683.3934;Found:683.3933。
实施例15:14-O-1-(4-(3-氯苯基哌嗪基乙酰基))哌嗪基妙林(化合物15a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),3-氯苯基哌嗪0.35mL(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(3-氯苯基哌嗪基乙酰基))哌嗪基妙林(化合物15a)的纯品。产率52.92%。HR-MS(ESI):Calcd.for C38H56ClN4O5(M+H+):683.3934;Found:683.3940。
实施例16:14-O-1-(4-(4-氯苯基哌嗪基乙酰基))哌嗪基妙林(化合物16a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),4-氯苯基哌嗪二盐酸盐0.57g(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(4-氯苯基哌嗪基乙酰基))哌嗪基妙林(化合物16a)的纯品。产率63.71%。HR-MS(ESI):Calcd.for C38H56ClN4O5(M+H+):683.3934;Found:683.3939。
实施例17:14-O-1-(4-(2-N-苯基哌嗪基乙酰基))哌嗪基妙林(化合物17a)合成
中间体Ⅲ1g(1.91mmol)溶于10mL乙腈,加入碳酸钾0.53g(3.82mmol),N-苯基哌嗪0.32mL(2.1mmol),70℃左右加热搅拌反应3h,即得目标产物。所得混合溶液旋转蒸干得混合物经二氯甲烷复溶,加入100-200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析过柱提纯(200~300目硅胶粉为固定相,乙酸乙酯:甲醇=20:1为流动相),得到产物14-O-1-(4-(2-N-苯基哌嗪基乙酰基))哌嗪基妙林(化合物17a)的纯品。产率77.25%。HR-MS(ESI):Calcd.for C38H57N4O5(M+H+):649.4323;Found:649.4329。
实验实施例:体外抑菌实验
实验方法
采用琼脂二倍稀释法测定本发明所得的系列化合物的最小抑菌浓度(MIC),实验对照药物选用泰妙菌素、沃尼妙林、瑞他妙林为截短侧耳素类抗生素,是该类抗生素中目前经FDA批准使用的抗菌药(泰妙菌素及沃尼妙林为动物专用、瑞他妙林为人用抗菌药)。使用多点接种器将菌液接种在含不同浓度药物的培养皿中,接种菌量为106CFU/ml。37℃孵育24小时后观察结果,以不长菌的培养皿中的化合物浓度作为该化合物的最小抑菌浓度(MIC)。
实验中所用的菌株为大肠杆菌ATCC25922、金黄色葡萄球菌ATCC29213、耐甲氧西林金黄色葡萄球菌ATCC43300、金黄色葡萄球菌ATCC29212、粪肠球菌ATCC35667。
精密称取25.6mg所合成的目标化合物,置于10mL的容量瓶中,先用少量甲醇溶解后,再用甲醇定容至10mL,配成2560μg/mL的储备液。另精密称取25.6mg截短侧耳素、泰妙菌素、沃尼妙林、瑞他妙林,置于10ml容量瓶中,甲醇稀释并定容至10mL,配成2560μg/mL的对照储备液。
将储备液以倍比稀释法稀释在培养皿中,每个培养皿含药液1mL,以融化的MH琼脂稀释至20mL,使系列培养皿中受试化合物的终浓度分别为32,16,8,4,2,1,0.5,0.25,0.125,0.0625,0.03,0.015μg/ml。
下表5为MIC结果。
表5体外抑菌数据
全部目标化合物对金黄色葡萄球菌表现出较好的抗菌活性,化合物5a,6a,7a,8a对耐甲氧西林金黄色葡萄球菌抗菌活性强于目前临床上广泛使用的沃尼妙林及瑞他妙林,其中化合物3a,5a,8a对金黄色葡萄球菌抗菌活性均接近目前临床上广泛使用的沃尼妙林及瑞他妙林。
实验实施例:MRSA感染小鼠死亡保护实验
以MRSA ATCC43300构建ICR小鼠感染模型,选取化合物5a与市场上广泛应用的泰妙菌素为受试药物,比较5a与泰妙菌素对MRSA感染小鼠死亡保护作用。具体实验步骤如下:
实验动物:25-28g ICR鼠,雌雄各半,每组10只。
实验材料:环磷酰胺,DMSO,吐温80。
实验步骤:
建立小鼠免疫缺陷模型,连续三天给小鼠腹腔注射150mg/kg环磷酰胺,停一天,再腹腔注射100mg/kg的环磷酰胺,24h后进行腹腔攻毒,ATCC43300菌量为1x107CFU/mL。攻菌一小时后给药,药物用DMSO20%,吐温805%,生理盐水75%进行溶解。另做泰妙菌素为阳性对照组,与5a组的处理方式一致,每组10只老鼠。结果如图1所示。
图1结果显示,40mg/kg剂量下,5a对MRSA感染小鼠的死亡保护作用明显优于泰妙菌素。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (7)
1.一种具有酰基哌嗪基侧链的截短侧耳素衍生物,其特征在于:该截短侧耳素衍生物是具有如式5所示结构的化合物及其可药用盐:
所述R5为
所述R1为氢原子,R2为氢原子,R3为氢原子;
或R1为硝基,R2为氢原子,R3为氢原子;
或R1为氢原子,R2为硝基,R3为氢原子;
或R1为氢原子,R2为氢原子,R3为硝基;
或R1为氯原子,R2为氢原子,R3为氢原子;
或R1为氢原子,R2为氯原子,R3为氢原子;
或R1为氢原子,R2为氢原子,R3为氯原子;
或R1为甲氧基,R2为氢原子,R3为氢原子;
或R1为氢原子,R2为甲氧基,R3为氢原子;
或R1为氢原子,R2为氢原子,R3为甲氧基;
或R1为羟基,R2为氢原子,R3为氢原子;
或R1为氢原子,R2为羟基,R3为氢原子;
或R1为氢原子,R2为氢原子,R3为羟基;
或R1为甲基,R2为氢原子,R3为氢原子;
或R1为氢原子,R2为甲基,R3为氢原子;
或R1为氢原子,R2为氢原子,R3为甲基。
2.根据权利要求1所述的一种具有酰基哌嗪基侧链的截短侧耳素衍生物,其特征在于:所述可药用盐是具有如式5所示结构的化合物,与盐酸、氢溴酸、硫酸、硝酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、琥珀酸、柠檬酸、苹果酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、谷氨酸或天冬氨酸形成的盐。
3.根据权利要求1-2任一项所述的一种具有酰基哌嗪基侧链的截短侧耳素衍生物的制备方法,其特征在于包括以下操作步骤:
(1)将截短侧耳素与对甲苯磺酰氯反应,获取如下式所示结构的中间体Ⅰ;
(2)以中间体Ⅰ为原料,通过与碘化钠反应进一步活化,再与N-BOC-哌嗪在碱性条件下反应,除去叔丁氧羰基获得如式2所示结构的中间体Ⅱ;
(3)以中间体Ⅱ为原料,与氯乙酰氯反应,获得中间体IV;
(4)以中间体IV作为原料,与各取代苯基哌嗪反应,得到如式5所示结构的具有酰基哌嗪基侧链的截短侧耳素类化合物;所述取代苯基哌嗪为N-苯基哌嗪、2-甲基苯基哌嗪、3-甲基苯基哌嗪、4-甲基苯基哌嗪、2-甲氧基苯基哌嗪、3-甲氧基苯基哌嗪、4-甲氧基苯基哌嗪、2-硝基苯基哌嗪、3-硝基苯基哌嗪、4-硝基苯基哌嗪、2-羟基苯基哌嗪、3-羟基苯基哌嗪、4-羟基苯基哌嗪、2-氯苯基哌嗪、3-氯苯基哌嗪或4-氯苯基哌嗪。
4.根据权利要求3所述的制备方法,其特征在于:步骤(1)所述反应是采用乙酸乙酯作为溶剂,在常温条件下反应3小时;所述截短侧耳素与对甲苯磺酰氯摩尔比为1:1.1;
步骤(2)所述反应是采用非质子溶剂作为溶剂,先将中间体Ⅰ溶于非质子溶剂中,溶剂用量为中间体Ⅰ质量的10倍,再加入无水碘化钠,加热回流1小时,其中中间体Ⅰ与无水碘化钠摩尔比为1:1.1;再将N-BOC-哌嗪、碱与活化所得产物一起加热回流2小时,其中中间体Ⅰ与N-BOC-哌嗪摩尔比为1:1.1,N-BOC-哌嗪与碱摩尔比为1:2;然后将上述反应所得产物加入到质量分数25%的三氟乙酸的二氯甲烷溶液,常温搅拌8h,获得中间体Ⅱ;所述碱为氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾或碳酸铯;所述非质子溶剂为乙腈。
5.根据权利要求3所述的制备方法,其特征在于:步骤(3)所述反应采用非质子溶剂作为溶剂,加入酰氯及碱,与中间体Ⅱ在0℃进行反应3小时;其中中间体Ⅱ与酰氯摩尔比为1:1.1,酰氯与碱摩尔比为1:2;所述非质子溶剂为乙腈;
步骤(4)所述反应采用非质子溶剂作为溶剂,加入取代苯基哌嗪及碱,与中间体Ⅲ一起加热回流3小时,即得目标产物,重结晶或柱层析纯化;其中中间体Ⅲ与取代苯基哌嗪摩尔比为1:1.1,取代苯基哌嗪与碱摩尔比为1:2;其中,所述非质子溶剂为二氯甲烷、乙腈、乙酸乙酯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、吡啶。
6.一种药物组合物,其特征在于:该药物组合物包含了上述权利要求1-2任一项所述的具有酰基哌嗪基侧链的截短侧耳素衍生物作为活性成分。
7.根据权利要求1-2任一项所述的一种具有酰基哌嗪基侧链的截短侧耳素衍生物在制备治疗感染性疾病药物中的用途,其特征在于:所述感染性疾病为人或动物经支原体或多药耐药菌感染引起的感染性疾病。
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