CN105601649B - 噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物及其应用 - Google Patents
噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物及其应用 Download PDFInfo
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- CN105601649B CN105601649B CN201610142014.6A CN201610142014A CN105601649B CN 105601649 B CN105601649 B CN 105601649B CN 201610142014 A CN201610142014 A CN 201610142014A CN 105601649 B CN105601649 B CN 105601649B
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- triazine
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- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 13
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 7
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 6
- 125000005936 piperidyl group Chemical group 0.000 claims abstract description 6
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 58
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 18
- 241000894006 Bacteria Species 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 10
- -1 N- methyl Piperazinyl Chemical group 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 150000002240 furans Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 241000192125 Firmicutes Species 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 claims description 3
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 claims description 2
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 abstract description 19
- 229940079593 drug Drugs 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 238000006467 substitution reaction Methods 0.000 abstract description 6
- QUHYUSAHBDACNG-UHFFFAOYSA-N acerogenin 3 Natural products C1=CC(O)=CC=C1CCCCC(=O)CCC1=CC=C(O)C=C1 QUHYUSAHBDACNG-UHFFFAOYSA-N 0.000 abstract description 5
- URLVCROWVOSNPT-QTTMQESMSA-N desacetyluvaricin Natural products O=C1C(CCCCCCCCCCCC[C@@H](O)[C@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 URLVCROWVOSNPT-QTTMQESMSA-N 0.000 abstract description 5
- 125000005079 alkoxycarbonylmethyl group Chemical group 0.000 abstract description 3
- URLVCROWVOSNPT-XOTOMLERSA-N (2s)-4-[(13r)-13-hydroxy-13-[(2r,5r)-5-[(2r,5r)-5-[(1r)-1-hydroxyundecyl]oxolan-2-yl]oxolan-2-yl]tridecyl]-2-methyl-2h-furan-5-one Chemical compound O1[C@@H]([C@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCCCCC=2C(O[C@@H](C)C=2)=O)CC1 URLVCROWVOSNPT-XOTOMLERSA-N 0.000 abstract 3
- 125000005843 halogen group Chemical group 0.000 abstract 2
- 230000003115 biocidal effect Effects 0.000 abstract 1
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- 238000002360 preparation method Methods 0.000 description 30
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- 238000000034 method Methods 0.000 description 22
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical class Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 17
- 230000008859 change Effects 0.000 description 16
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
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- 238000006243 chemical reaction Methods 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
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- 229920000137 polyphosphoric acid Polymers 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
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- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
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- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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- 229960003165 vancomycin Drugs 0.000 description 3
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- 238000005406 washing Methods 0.000 description 3
- PDWZJMKDSKSWMD-UHFFFAOYSA-N 6-methyl-2h-1,2,4-triazin-5-one Chemical compound CC1=NNC=NC1=O PDWZJMKDSKSWMD-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
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- 235000014469 Bacillus subtilis Nutrition 0.000 description 2
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
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- 238000002474 experimental method Methods 0.000 description 2
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- 150000002576 ketones Chemical class 0.000 description 2
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- KDDNKZCVYQDGKE-UHFFFAOYSA-N (2-chlorophenyl)methanamine Chemical class NCC1=CC=CC=C1Cl KDDNKZCVYQDGKE-UHFFFAOYSA-N 0.000 description 1
- HMTSWYPNXFHGEP-UHFFFAOYSA-N (4-methylphenyl)methanamine Chemical class CC1=CC=C(CN)C=C1 HMTSWYPNXFHGEP-UHFFFAOYSA-N 0.000 description 1
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 description 1
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- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域,涉及噻唑并[3,2‑b]‑1,2,4‑三嗪‑3‑乙酸衍生物及其在制备抗菌药物中的应用。噻唑并[3,2‑b]‑1,2,4‑三嗪‑3‑乙酸衍生物及该类化合物的立体异构体和药学上适用的盐,其结构通式如下:Y为C1‑C6烷氧基,‑OH,‑NR’(OR’’),其中R’、R’’独立地选自C1~C6的烷基,‑NHR’,‑NR’’R’’’,其中R’选自C1‑C6烷基;卤素取代的C1‑C6烷基;未取代或C1‑C6烷基或卤素取代的苄基,2‑呋喃甲基,4‑(烷氧基羰基甲基)‑2‑噻唑基,其中烷氧基选自C1‑C6烷氧基;R’’、R’’’独立地选自C1~C6的烷基,或R’’、R’’’与它们相连的氮原子一起组成吡咯烷基,哌啶基,吗啉基,N‑甲基哌嗪基,N‑取代(或不取代)苯基哌嗪基。噻唑并[3,2‑b]‑1,2,4‑三嗪‑3‑乙酸衍生物以及该类化合物药学上适用的酸加成的盐具有明显的抗菌活性,可用于制备抗菌方面的药物。
Description
技术领域:
本发明属于医药技术领域,更具体地,涉及一种噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物、制备方法及其在制备抗菌药物中的用途。
背景技术:
抗菌药物是目前临床应用范围广泛、品种繁多的一大类治疗致病菌感染的药物,多年来随着抗菌药物在全球的普及和应用,存在严重的滥用情况,随着多种耐药菌株的出现。其中,耐药性的革兰氏阳性菌尤为严重,如甲氧西林葡萄球菌(methicillin-resistantStaphylococcus,MRS)、甲氧西林的金黄色葡萄球菌(methicillinresistantStaphylococcus aureus,MRSA)、异质性万古霉素中介金黄色葡萄球菌(heterogeneousvancomycin-intermediate Staphylococcus aureus,hVISA)、万古霉素耐药金黄色葡萄球菌(vancomycin-resistant Staphylococcus aureus,VRSA)以及青霉素的肺炎链球菌(penicillin-resistant Streptococcus pneumoniae,PRSP)等是当前临床上存在的主要问题。经过80余年发展,抗菌药物的研发已经从针对各种普通细菌转向针对耐药细菌。目前设计合成具有全新结构类型的和全新作用机制的抗菌药物已成为抗菌药物研究的重要方向。
噻唑并[3,2-b]-1,2,4-三嗪类衍生物作为嘌呤结构类似物而具有潜在的生物活性,近几年来该骨架化合物因其在抗癌、抑菌、抗病毒等生物活性方面而备受关注。
发明内容:
本发明的第一个目的在于提供一种新型结构噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物。
本发明的第二个目的在于提供一种新型噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物的制备方法。此制备方法合成收率高,后处理简单,适用于大量生产。
本发明的第三个目的在于提供一种新型噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物的作为抗菌药物的应用。
为达到上述第一个目的,本发明采用下述技术方案:
本发明涉及的噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物及其药学上可接受的盐。
其中
Y为C1-C6烷氧基,-OH,-NR’(OR”),其中R’、R”独立地选自C1~C6的烷基,-NHR’,-NR”R”’,其中R’选自C1-C6烷基;卤素取代的C1-C6烷基;未取代或C1-C6烷基或卤素取代的苄基,2-呋喃甲基,4-(烷氧基羰基甲基)-2-噻唑基,其中烷氧基选自C1-C6烷氧基;R”、R”’独立地选自C1~C6的烷基,或R”、R”’与它们相连的氮原子一起组成吡咯烷基,哌啶基,吗啉基,N-甲基哌嗪基,N-取代(或不取代)苯基哌嗪基。
优选地,Y为C1-C4烷氧基,-OH,-NR’(OR”),其中R’、R”独立地选自C1~C4的烷基,-NHR’,-NR”R”’,其中R’选自C1-C4烷基;卤素取代的C1-C4烷基;未取代或C1-C4烷基或卤素取代的苄基,2-呋喃甲基,4-(烷氧基羰基甲基)-2-噻唑基,其中烷氧基选自C1-C4烷氧基;R”、R”’独立地选自C1~C4的烷基,或R”、R”’与它们相连的氮原子一起组成吡咯烷基,哌啶基,吗啉基,N-甲基哌嗪基,N-取代(或不取代)苯基哌嗪基。
更优选地,Y选自-OCH2CH3,-OH,-N(CH3)(OCH3),-NHR’,-NR”R”’,其中R’选自-CH2CH2CH2CH3;2-氯乙基;未取代或甲基或卤素取代的苄基,2-呋喃甲基,4-(乙氧基羰基甲基)-2-噻唑基;R”、R”’独立地选自C1~C4的烷基,或R”、R”’与它们相连的氮原子一起组成吡咯烷基,哌啶基,吗啉基,N-甲基哌嗪基,N-取代(或不取代)苯基哌嗪基。
“取代的”,除非另外说明,指取代基可以在一个或多个位置存在,取代基独立地选自具体地选项。
为达到上述第二个目的,本发明采用下述技术方案:
一种新型噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物的制备方法,包括如下步骤如下列反应式所示:
a)将1,2,4-三嗪类化合物,加到KOH的水溶液中,搅拌下加入4-氯乙酰乙酸乙酯的有机溶液,室温反应后,抽滤,用水洗涤,乙酸乙酯洗涤,干燥。
b)将硫醚类衍生物和多聚磷酸(PPA)混合,100-130℃加热反应。反应结束后降至室温,加冰水,搅拌均匀后,抽滤,用水洗涤,干燥,乙酸乙酯重晶,得到粉末固体,即2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪基)乙 酸乙酯。
c)将NaOH溶液加到上步得到的2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪基)乙酸乙酯的甲醇溶液中,室温搅拌反应至结束,加水,减压蒸馏除甲醇,余物降温后用HCl调pH=2,有大量浅黄色晶体析出,冰浴、抽滤、干燥,乙酸乙酯重结晶,得到粉状固体。
d)将上步得到的2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪基)乙酸和各种胺加到有机溶剂中,然后再加入HOBt、EDC·HCl和三乙胺,反应室温搅拌反应,反应后反应混合物先后使用HCl溶液洗涤、饱和NaHCO3溶液洗涤、饱和NaCl溶液洗涤,有机层Na2SO4干燥,减压蒸馏,柱层析得粉末固体。
步骤b)中所述硫醚类衍生物与PPA的质量比为1:1-1:10,PPA的含量为(以P2O5含量计)≥80%。
为达到上述第三个目,本发明提供了噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物及其药学上可接受的盐在制备抗菌药物中的应用。
优选地,所述菌为革兰氏阳性菌或革兰氏阴性菌。
本发明还涉及一种抗菌药用组合物,该组合物含有上述结构通式中衍生物或其立体异构体或其药学上适用的酸加成盐以及药学上适用的载体。
具体实施方式:
为了更清楚地说明本发明,下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解,下面所具体描述的内容是说明性的而非限制性的,不应以此限制本发明的保护范围。
实施例1:N,N-二甲基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪-3-基)乙酰胺(PB01)的制备
步骤1):4-[(6-甲基-5-氧代-2,5-二氢-1,2,4-三嗪-3-基)硫基]-3-氧代丁酸乙酯(MA)的制备
将0.01mol(1.43g)3,4-二氢-6-甲基-3-硫代-1,2,4-三嗪-5(2H)-酮加到5mL DMF中,搅拌下加入10%KOH溶液5.6ml,然后滴加0.01mol(1.64g)4-氯乙酰乙酸乙酯4ml乙醇溶液,室温反应30min后,加冰水稀释,有大量晶体释出,抽滤,用水洗涤,干燥,乙酸乙酯重结晶,得到白色细沙状粉末,收率38%。
ESI-MS(m/z):272.04(M+H)+。
步骤2):2-[6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪基]乙酸乙酯(MB)的制备
将4.0g 4-[(6-甲基-5-氧代-2,5-二氢-1,2,4-三嗪-3-基)硫基]-3-氧代丁酸乙酯加入到120℃8.0g 85%PPA中,搅拌反应30min。反应结束后降至室温,加入15ml冰水,搅拌均匀后,抽滤,用水洗涤,干燥,乙酸乙酯重结晶,得白色粉末固体,收率44%。
IR(KBr):υ3103,2990,2965,2926,1742,1476,1229,1192cm-11;H NMR(400MHz,Chloroform-d)δ6.82(s,1H),4.26(q,J=7.1Hz,2H),3.87(d,J=1.0Hz,2H),2.44(s,3H),1.29(dt,J=19.4,7.1Hz,3H);ESI-MS(m/z):253.9 (M+H)+。
步骤3):2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪基)乙酸(MC)的制备
将6mL 2mol/L NaOH加到0.004mol(1.01g)2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪基)乙酸乙酯的20mL甲醇溶液中,室温反应2h,加入40m水,再减压蒸馏除醇,余物降温后用1mol/L HCl调pH=2,有大量浅黄色晶体析出,抽滤,干燥,乙酸乙酯重结晶,得到浅黄色固体状粉末,收率65%。
IR(KBr):υ2990,1713,1321,1259,941cm-1;1H NMR(600MHz,DMSO-d6)δ12.80(s,1H),7.24(s,1H),3.86(s,2H),2.23(s,3H);ESI-MS(m/z):226.0.0(M+H)+。
步骤4):N,N-二甲基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪-3-基)乙酰胺(PB01)的制备
2.38mmol(0.19g)二甲胺盐酸盐和2.38mmol(0.54g)2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪基)乙酸加到24.0ml CH2Cl2中,然后再向溶液中加入2.62mmol(0.35g)HOBt、2.62mmol(0.50g)EDC盐酸盐和三乙胺10mmol(1.01g)。反应室温搅拌10h以上。反应液5%HCl(3×30.0ml)、5%NaHCO3溶液(40.0ml)、H2O(40.0ml)、饱和NaCl(40.0ml),然后Na2SO4干燥,柱层析(CH2Cl2/MeOH,50:1)得白色固体,收率54%。
IR(KBr):υ3117,2956,1634,1487,1385cm-1;1H NMR(400MHz,Chloroform-d)δ6.81(s,1H),3.89(s,2H),3.20(s,3H),3.05(s,3H),2.44(s,3H);ESI-MS(m/z):253.0(M+H)+。
实施例2:N-(呋喃-2-基甲基)-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪-3-基)乙酰胺(PB02)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成2-呋喃甲胺,收率49%。
IR(KBr):υ3306,3103,2953,2920,2851,1661,1551,1468,1385,1364,743cm-1;1HNMR(600MHz,DMSO-d6)δ8.57(t,J=5.8Hz,1H),7.56(d,J=1.8Hz,1H),7.20(s,1H),6.38(t,J=2.5Hz,1H),6.23(d,J=3.1Hz,1H),4.27(d,J=5.7Hz,2H),3.75(s,2H),2.20(s,3H);ESI-MS(m/z):305.3(M+H)+。
实施例3:N-(呋喃-2-基甲基)-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪-3-基)乙酰胺(PB03)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成二乙胺,收率56%。
IR(KBr):υ3115,2968,2920,2876,1632,1485,1449,1377cm-1;1H NMR(600MHz,DMSO-d6)δ7.16(s,1H),3.91(s,2H),3.41(q,J=7.1Hz,2H),3.27(q,J=7.0Hz,2H),2.20(s,3H),1.20(t,J=7.1Hz,3H),1.01(t,J=7.0Hz,3H);ESI-MS(m/z):281.3(M+H)+。
实施例4:N,N-二正丁基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪-3-基)乙酰胺(PB04)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成二正丁 胺,收率51%。
IR(KBr):υ3109,2961,2922,2870,1641,1479,1449,1379cm-1;1H NMR(400MHz,Chloroform-d)δ6.77(s,1H),3.86(d,J=0.9Hz,2H),3.42–3.33(m,4H),2.40(s,3H),1.69(dq,J=9.3,7.5Hz,2H),1.61–1.49(m,2H),1.42(dt,J=14.8,7.4Hz,2H),1.38–1.24(m,2H),0.97(dt,J=31.0,7.3Hz,6H);ESI-MS(m/z):337.4(M+H)+。
实施例5:N,N-二异丙基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪-3-基)乙酰胺(PB07)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成二异丙胺,收率54%。
IR(KBr):υ3117,2992,2965,2930,2872,1641,1483,1447,1381cm-1;1H NMR(400MHz,Chloroform-d)δ6.73(s,1H),4.05(p,J=6.7Hz,1H),3.84(d,J=1.0Hz,2H),3.61(s,1H),2.41(s,3H),1.41(d,J=6.7Hz,6H),1.34(d,J=6.7Hz,6H);ESI-MS(m/z):309.13(M+H)+。
实施例6:6-甲基-3-[2-氧代-2-(哌啶-1-基)乙基]-7H-噻唑并[3,2-b][1,2,4]三嗪-7-酮(PB08)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成哌啶,收率48%。
IR(KBr):υ3105,2934,2855,1641,1481,1445,1382cm-1;1H NMR(400MHz,Chloroform-d)δ6.79(d,J=1.0Hz,1H),3.88(d,J=1.0Hz,2H),3.57(dt,J=27.2,5.3Hz,4H),2.42(s,3H),1.78–1.58(m,6H);ESI-MS(m/z):293.1(M+H)+。
实施例7:6-甲基-3-(2-吗啉基-2-氧代乙基)-7H-噻唑并[3,2-b][1,2,4]三嗪-7-酮(PB09)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成吗啉,收率55%。
IR(KBr):υ3103,2959,2922,1630,1485,1456,1385cm-1;1H NMR(400MHz,Chloroform-d)δ6.82(s,1H),3.89(d,J=1.0Hz,2H),3.71(ddt,J=45.2,19.6,4.7Hz,8H),2.43(s,3H);ESI-MS(m/z):295.2(M+H)+。
实施例8:6-甲基-3-[2-(4-甲基哌嗪-1-基)-2-氧代乙基]-7H-噻唑并[3,2-b][1,2,4]三嗪-7-酮(PB10)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成甲基哌嗪,收率43%。
IR(KBr):υ3113,2936,2845,1641,1481,1450,1381cm-1;1H NMR(400MHz,Chloroform-d)δ6.80(d,J=1.1Hz,1H),3.89(d,J=1.0Hz,2H),3.66(dt,J=24.0,5.1Hz,4H),2.51(t,J=5.1Hz,2H),2.44(d,J=6.2Hz,5H),2.36(s,3H);ESI-MS(m/z):308.4(M+H)+。
实施例9:6-甲基-3-[2-氧代-2-(吡咯烷-1-基)乙基]-7H-噻唑并[3,2-b][1,2,4]三嗪-7-酮(PB11)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成四氢吡咯, 收率44%。
IR(KBr):υ3107,2963,2931,2882,1632,1437,1381cm-1;1H NMR(400MHz,Chloroform-d)δ6.87(d,J=1.1Hz,1H),3.85–3.80(m,2H),3.63(t,J=6.8Hz,2H),3.54(t,J=6.9Hz,2H),2.43(s,3H),2.14–2.02(m,2H),2.01–1.89(m,2H);ESI-MS(m/z):279.3(M+H)+。
实施例10:6-甲基-3-[2-氧代-2-(4-苯基哌嗪-1-基)乙基]-7H-噻唑并[3,2-b][1,2,4]三嗪-7-酮(PB12)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成苯基哌嗪,收率54%。
IR(KBr):υ3117,2959,2918,2855,1647,1599,1462,1382,760,689cm-1; 1H NMR(400MHz,Chloroform-d)δ7.38–7.28(m,2H),6.97(dd,J=8.3,7.2Hz,3H),6.83(d,J=1.1Hz,1H),3.95(d,J=1.0Hz,2H),3.83(dt,J=23.2,5.2Hz,4H),3.31(d,J=10.4Hz,1H),3.30(s,1H),3.24(t,J=5.3Hz,2H),2.43(s,3H);ESI-MS(m/z):370.3(M+H)+。
实施例11:N-异丙基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪-3-基)乙酰胺(PB14)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成异丙胺,收率58%。
IR(KBr):υ3281,3073,2970,2874,1657,1576,1558,1495,1425,1379cm-1;1H NMR(400MHz,Chloroform-d)δ6.85(d,J=1.1Hz,1H),5.95(s,1H),4.11(dp,J=7.9,6.5Hz,1H),3.70(d,J=1.1Hz,2H),2.43(s,3H),1.21(d,J=6.6Hz,6H);ESI-MS(m/z):267.1(M+H)+。
实施例12:N-环丙基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪-3-基)乙酰胺(PB15)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成环丙胺,收率52%。
IR(KBr):υ3226,3103,2959,2924,1655,1576,1549,1487,1429,1381cm-1;1H NMR(400MHz,Chloroform-d)δ6.87(s,1H),6.09(s,1H),3.70(d,J=1.0Hz,2H),2.77(dq,J=7.1,3.5Hz,1H),2.44(s,3H),0.89–0.76(m,2H),0.60–0.51(m,2H);ESI-MS(m/z):265.1(M+H)+。
实施例13:N-(2-氯苄基)-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪-3-基)乙酰胺(PB16)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成2-氯苄胺,收率48%。
IR(KBr):υ3049,2957,1711,1612,1508,1476,1423,1381,1354,1286,921,779,764cm-1;1H NMR(400MHz,Chloroform-d)δ7.44–7.36(m,2H),7.33–7.21(m,1H),6.84(s,1H),6.44(s,1H),4.57(d,J=5.1Hz,2H),3.77(s,2H),2.32(s,3H),1.28(s,1H);ESI-MS(m/z):348.7(M+H)+。
实施例14:2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪-3-基)-N-(4-甲基苄基)乙酰胺(PB17)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成4-甲基苄胺,收率52%。
IR(KBr):υ3242,3090,3028,2922,1682,1612,1593,1514,1466,1431,1381,820cm-1;1H NMR(600MHz,DMSO-d6)δ8.54(t,J=6.0Hz,1H),7.23–7.20(m,1H),7.12(q,J=7.9Hz,4H),4.23(d,J=5.9Hz,2H),3.77(s,2H),2.26(s,3H),2.22(d,J=1.0Hz,3H);ESI-MS(m/z):329.3(M+H)+。
实施例15:N-(4-氟苄基)-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪-3-基)乙酰胺(PB18)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成4-氟苄胺,收率48%。
IR(KBr):υ3294,3103,2955,2922,1661,1616,1545,1510,1425,1383,820cm-1;1HNMR(600MHz,DMSO-d6)δ8.60(t,J=6.1Hz,1H),7.31–7.25(m,2H),7.22(s,1H),7.13(t,J=8.7Hz,2H),4.26(d,J=5.9Hz,2H),3.78(s,2H),2.20(s,3H);ESI-MS(m/z):333.3(M+H)+。
实施例16:3-{2-[4-(4-氯苯基)哌嗪-1-基]-2-氧代乙基}-6-甲基-7H-噻唑并[3,2-b][1,2,4]三嗪-7-酮(PB21)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成1-(4-氯苯基)哌嗪,收率45%。
IR(KBr):υ3117,2955,2891,1649,1595,1578,1495,1458,1383,818cm-1; 1H NMR(400MHz,Chloroform-d)δ7.40(ddd,J=9.0,5.3,3.5Hz,2H),7.30–7.21(m,2H),5.60(s,1H),4.32(s,2H),2.54(s,3H),1.28(d,J=6.5Hz,8H);ESI-MS(m/z):404.2(M+H)+。
实施例17:3-{2-[4-(2,6-二甲基苯基)哌嗪-1-基]-2-氧代乙基}-6-甲基-7H-噻唑并[3,2-b][1,2,4]三嗪-7-酮(PB22)的制备
按照实施例1方法,区别在于,将步骤4)中二甲胺盐酸盐换成1-(2,6-二甲基苯基)哌嗪,收率55%。
IR(KBr):υ3103,2997,2922,2812,1655,1580,1473,1445,1381,773cm-1; 1H NMR(400MHz,Chloroform-d)δ7.09–6.97(m,3H),6.84(s,1H),3.96(d,J=1.1Hz,2H),3.80(t,J=5.0Hz,2H),3.72(t,J=4.9Hz,2H),3.22(t,J=4.9Hz,2H),3.15(t,J=5.0Hz,2H),2.46(s,3H),2.36(s,6H);ESI-MS(m/z):397.8(M+H)+。
实施例18:N,N-二甲基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪-3-基)乙酰胺(PB01)的制备
按照实施例1方法,区别在于,将步骤2)中的PPA的量换为4g,收率37%。
实施例19:N,N-二甲基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪-3-基)乙酰胺(PB01)的制备
按照实施例1方法,区别在于,将步骤2)中的PPA的量换为40g,收率48%。
实施例20:N,N-二甲基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪 -3-基)乙酰胺(PB01)的制备
按照实施例1方法,区别在于,将步骤2)的反应条件换为“100℃搅拌反应1h”,收率39%。
实施例21:N,N-二甲基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b][1,2,4]三嗪-3-基)乙酰胺(PB01)的制备
按照实施例1方法,区别在于,将步骤2)的反应条件换为“130℃搅拌反应20min”,收率42%。
实施例22:噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物抗菌活性测定
本发明化合物作为抗菌和抗结核抑制剂的活性可以按许多标准的生物学试验或药理学试验测定。
应用琼脂稀释法测定实验化合物的MIC(μg/ml)值。
抗菌药物原液的配制:甲醇溶解后配制成2mg/mL溶液,用滤过法除菌。
含药琼脂原液的配制:用稀释法将原液稀释成多个梯度浓度。分别取1ml加入到已作好标记的内径90mm的平板孔内。再取已灭菌的50℃的M-H琼脂19ml到平板孔内,混菌后冷却。
接种:用接种器在平板孔内逐个接种,每次接种量为1~2μL(含菌量约为5×105CFU/ml)。最后接种不含药物的生长对照板,以检查整个实验过程中测试菌种的存活状态。
孵育:平板置于37℃孵育24h。
结果判断:菌落完全生长被完全抑制的最低药物浓度为该化合物对检测菌种的MIC。单一菌落生长可忽略不计。
噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物抗菌活性测定结果
结果表明,噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物对大肠杆菌(E.coli),铜绿假单胞菌(P.aeruginosa),金黄色葡萄球菌(S.aureus)和枯草芽孢杆菌(B.subtilis)都有不同程度的抑制作用。
显然,本发明的上述实施例仅仅是为清楚地说明本发明所作的举例,而并非是对本发明的实施方式的限定,对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动,这里无法对所有的实施方式予以穷举,凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。
Claims (8)
1.噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物及其药学上可接受的盐:
其中:
Y为C1-C6烷氧基;-NR’(OR”),其中R’独立地选自C1~C6的烷基,R”独立地选自C1~C6的烷基;-NHR’,其中R’选自C1-C6烷基、卤素取代的C1-C6烷基、苄基、C1-C6烷基取代的苄基、卤素取代的苄基、2-呋喃甲基;-NR”R”’,其中R”独立地选自C1~C6的烷基,R”’独立地选自C1~C6的烷基,或R”、R”’与它们相连的氮原子一起组成吡咯烷基、哌啶基、吗啉基、N-甲基哌嗪基、N-苯基哌嗪基。
2.如权利要求1所述的噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物及其药学上可接受的盐:
其中:Y为C1-C4烷氧基;-NR’(OR”),其中R’独立地选自C1~C6的烷基,R”独立地选自C1~C6的烷基;-NHR’,其中R’选自C1-C4烷基、卤素取代的C1-C4烷基、苄基、C1-C4烷基取代的苄基、卤素取代的苄基、2-呋喃甲基;-NR”R”’,R”独立地选自C1~C4的烷基,R”’独立地选自C1~C4的烷基,或R”和R”’与它们相连的氮原子一起组成吡咯烷基、哌啶基、吗啉基、N-甲基哌嗪基、N-苯基哌嗪基。
3.如权利要求1或2所述的噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物及其药学上可接受的盐:
其中:Y选自-OCH2CH3;-N(CH3)(OCH3);-NHR’,其中R’选自-CH2CH2CH2CH3、2-氯乙基、苄基、甲基取代的苄基、卤素取代的苄基、2-呋喃甲基;-NR”R”’,其中R”独立地选自C1~C4的烷基,R”’独立地选自C1~C4的烷基,或R”和R”’与它们相连的氮原子一起组成吡咯烷基、哌啶基、吗啉基、N-甲基哌嗪基、N-苯基哌嗪基。
4.噻唑并[3,2-b]-1,2,4-三嗪-3-乙酸衍生物及其药学上可接受的盐,选自:N,N-二甲基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪-3-基)乙酰胺;
N-(呋喃-2-基甲基)-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪-3-基)乙酰胺;
N-(呋喃-2-基甲基)-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪-3-基)乙酰胺;
N,N-二正丁基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪-3-基)乙酰胺;
N,N-二异丙基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪-3-基)乙酰胺;
6-甲基-3-[2-氧代-2-(哌啶-1-基)乙基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;6-甲基-3-(2-吗啉基-2-氧代乙基)-7H-噻唑并[3,2-b]-1,2,4--三嗪-7-酮;
6-甲基-3-[2-(4-甲基哌嗪-1-基)-2-氧代乙基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-甲基-3-[2-氧代-2-(吡咯烷-1-基)乙基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-甲基-3-[2-氧代-2-(4-苯基哌嗪-1-基)乙基]-7H-噻唑并[3,2-b]-1,2,4--三嗪-7-酮;
N-异丙基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪-3-基)乙酰胺;
N-环丙基-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪-3-基)乙酰胺;
N-(2-氯苄基)-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪-3-基)乙酰胺;
2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4-三嗪-3-基)-N-(4-甲基苄基)乙酰胺;
N-(4-氟苄基)-2-(6-甲基-7-氧代-7H-噻唑并[3,2-b]-1,2,4--三嗪-3-基)乙酰胺;
3-{2-[4-(4-氯苯基)哌嗪-1-基]-2-氧代乙基}-6-甲基-7H-噻唑并[3,2-b]-1,2,4--三嗪-7-酮;
3-{2-[4-(2,6-二甲基苯基)哌嗪-1-基]-2-氧代乙基}-6-甲基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮。
5.一种药用组合物,该组合物含有权利要求1-4任何一项所述的衍生物及其药学上可接受的盐,及其药学上可接受的载体。
6.权利要求1-4任何一项所述的衍生物及其药学上可接受的盐在制备抗菌药物中的应用。
7.权利要求5所述的药物组合物在制备抗菌药物中的应用。
8.如权利要求6或7所述的应用,其特征在于:所述菌为革兰氏阳性菌或革兰氏阴性菌。
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