CN110013483B - 噻唑并[3,2-a]嘧啶-6-甲腈衍生物用于抗菌的用途 - Google Patents
噻唑并[3,2-a]嘧啶-6-甲腈衍生物用于抗菌的用途 Download PDFInfo
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- CN110013483B CN110013483B CN201910392457.4A CN201910392457A CN110013483B CN 110013483 B CN110013483 B CN 110013483B CN 201910392457 A CN201910392457 A CN 201910392457A CN 110013483 B CN110013483 B CN 110013483B
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- Prior art keywords
- thiazolo
- pyrimidine
- amino
- carbonitrile
- nmr
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- 230000000844 anti-bacterial effect Effects 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- -1 hydroxy, amino Chemical group 0.000 claims description 100
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 241000191967 Staphylococcus aureus Species 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229960003085 meticillin Drugs 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
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- 239000011630 iodine Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
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- 230000003115 biocidal effect Effects 0.000 abstract 1
- ZIEWSZYVEDTXGH-UHFFFAOYSA-N pyrimidine-4-carbonitrile Chemical class N#CC1=CC=NC=N1 ZIEWSZYVEDTXGH-UHFFFAOYSA-N 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 69
- 238000005481 NMR spectroscopy Methods 0.000 description 40
- 238000002844 melting Methods 0.000 description 23
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- 239000007787 solid Substances 0.000 description 23
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 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 9
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
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- 239000008194 pharmaceutical composition Substances 0.000 description 4
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- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 3
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 3
- WZWIQYMTQZCSKI-UHFFFAOYSA-N 4-cyanobenzaldehyde Chemical compound O=CC1=CC=C(C#N)C=C1 WZWIQYMTQZCSKI-UHFFFAOYSA-N 0.000 description 3
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 3
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- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 2
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- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000002608 ionic liquid Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
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- FMKMKBLHMONXJM-UHFFFAOYSA-N 5-methyl-2-phenylpyrazol-3-amine Chemical compound N1=C(C)C=C(N)N1C1=CC=CC=C1 FMKMKBLHMONXJM-UHFFFAOYSA-N 0.000 description 1
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- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
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- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
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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 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
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- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
本发明属于医疗领域，具体涉及式I化合物，噻唑并[3,2‑a]嘧啶‑6‑甲腈衍生物用于抗菌的用途，本发明提供的化合物对耐甲氧西林金黄色葡萄球菌有抑菌作用，且该化合物对五种细胞株均有抑制作用；
Description
技术领域
本发明属于医疗领域，具体涉及噻唑并[3,2-a]嘧啶-6-甲腈衍生物用于抗菌的用途。
背景技术
革兰氏阳性细菌感染为常见病和多发病，危害人类健康，近年来革兰氏阳性菌感染日见增多，耐甲氧西林金黄色葡萄球菌(MRSA)检出率上升，耐青霉素肺炎链球菌(PRSP)在许多国家与地区传播，耐糖肽和其他多种抗生素的耐万古霉素肠球菌(VRE)出现，也标志着抗菌药物的最后一道防线被攻破，因此，研究开发治疗革兰氏阳性菌感染的新型药物已成为当务之急。
发明内容
本发明的目的在于提供一种噻唑并[3,2-a]嘧啶-6-甲腈衍生物用于抗菌的用途。
本发明提供式I所示的化合物及其药学上可接受的盐在制备治疗抗菌剂的药物中的应用：
其中，R1为卤素，硝基，氰基，被一个或多个卤素、羟基、氨基取代或未被取代的C1-5的烷基，被一个或多个卤素、羟基、氨基取代或未被取代的C1-5的烷氧基；
R2为卤素，氰基，被一个或多个卤素、羟基、氨基取代或未被取代的C1-5的烷基，被一个或多个卤素、羟基、氨基取代或未被取代的C1-5的烷氧基。
在上述式I所示化合物中，其中，所述C1-5的烷基选自甲基、乙基、丙基、丁基或戊基；所述C1-5的烷氧基选自甲氧基、乙氧基、丙氧基、丁氧基或戊氧基。
在上述式I所示化合物中，其中，所述卤素选自氟、氯、溴或碘。
在上述式I所示化合物中，其中，所述的R1为甲基，氯，氰基，溴，硝基，甲氧基；R1为甲基，氯，氰基，溴，甲氧基。
本发明进一步优选的实施例方案中，所述C1-5的烷基选自正丙基(n-Pr、 -CH2CH2CH3)或异丙基((i-Pr、-CH(CH3)2)；所述丁基选自正丁基(n-Bu、 -CH2CH2CH2CH3)，异丁基(i-Bu、-CH2CH(CH3)2)，仲丁基(s-Bu、-CH(CH3)CH2CH3) 或叔丁基(t-Bu、-C(CH3)3)；所述戊基选自正戊基(-CH2CH2CH2CH2CH3)，2-戊基 (-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)， 3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)或2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)。
本发明进一步优选的实施例方案中，所述C1-5的烷氧基选自甲氧基(MeO、-OCH3)、乙氧基(EtO、-OCH2CH3)、1-丙氧基(n-PrO、n-丙氧基、-OCH2CH2CH3)、2-丙氧基 (i-PrO、i-丙氧基、-OCH(CH3)2)、1-丁氧基(n-BuO、n-丁氧基、-OCH2CH2CH2CH3)、 2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH2CH(CH3)2)、2-丁氧基(s-BuO、s-丁氧基、-OCH(CH3)CH2CH3)、2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH3)3)、1-戊氧基(n-戊氧基、-OCH2CH2CH2CH2CH3)、2-戊氧基(-OCH(CH3)CH2CH2CH3)、3-戊氧基 (-OCH(CH2CH3)2)、2-甲基-2-丁氧基(-OC(CH3)2CH2CH3)、3-甲基-2-丁氧基 (-OCH(CH3)CH(CH3)2)、3-甲基-l-丁氧基(-OCH2CH2CH(CH3)2)、2-甲基-l-丁氧基 (-OCH2CH(CH3)CH2CH3)。
本发明更优选的实施例方案中，所述C1-5的烷基优选自C1-3的烷基，所述C1-3的烷基选自甲基、乙基、正丙基(n-Pr、-CH2CH2CH3)或异丙基((i-Pr、-CH(CH3)2)。
本发明更优选的实施例方案中，所述C1-5的烷氧基优选自C1-3的烷氧基，所述 C1-3的烷氧基选自甲氧基(MeO、-OCH3)、乙氧基(EtO、-OCH2CH3)、1-丙氧基(n-PrO、 n-丙氧基、-OCH2CH2CH3)或2-丙氧基(i-PrO、i-丙氧基、-OCH(CH3)2)。
本发明优选的其他实施例方案中，所述式I所示的化合物的示例化合物如下所示：
本发明进一步提供式I所示的化合物、对映异构体的可药用的盐，所述可药用的盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐、酒石酸盐、马来酸盐、富马酸盐、甲磺酸盐、葡糖酸盐、糖二酸盐、苯甲酸盐、乙磺酸盐、苯磺酸盐或对甲苯磺酸盐。
另外，本发明提供一种药物组合物包含治疗有效量的，如权利要求1-中任一项所述的式I所示的化合物、对映异构体或其可药用的盐和医学上可接受的载体。
本发明优选的实施例方案中，药物组合物可以利用一种或多种可药用的载体按照常规的方式加以配制。因此，本发明的活性化合物可以被配制成口服、口腔含化给药、鼻内、肠胃外(例如静脉内、肌内或皮下)或直肠给药的剂型，或者适用于通过吸入或吹入给药的剂型。本发明的化合物也可以被配制成持续释放的剂型。
本发明优选的实施例方案中，有效剂量的本发明化合物可与如惰性稀释剂或某种载体一起口服。根据本发明的一些实施例，可将本发明的化合物包裹于明胶胶囊中或压制成片。为口服治疗的目的，本发明化合物可与赋形剂一起使用并以片剂、锭剂、胶囊、混悬剂、糖浆剂等形式使用。根据本发明的实施例，上述制剂应含有至少0.5％(w/w)的本发明的活性化合物，但可根据特定的剂型变化，其中占单位重量的4％至约70％是便利的。在这样的药物组合物中活性化合物的量应达到适当的剂量。
本发明提供的式I所示的化合物、对映异构体或其可药用的盐或所述的药物组合物在制备治疗抗菌药物中的用途。
另一方面，本发明提供一种制备式I所示的化合物、对映异构体或其可药用的盐的制备方法，该方法包括：将α-溴代苯乙酮与硫脲、丙二腈、芳香醛、催化剂2a和乙醇加入反应容器中，在80℃下充分反应至完全，制备式I化合物；反应式如下：
本发明有益的技术效果
本发明提供的化合物对耐甲氧西林金黄色葡萄球菌有抑菌作用，且该化合物对五种细胞株均有抑制作用，其中22对耐甲氧西林金黄色葡萄球菌有很好的抑制作用，尤其是对18H6、18I1具有非常好的抑制效果，其MIC均在5μg/mL，若继续研究其抑菌机制，有望将其发展为耐甲氧西林金黄色葡萄球菌的新药物。
实施例
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。除非另外指明，本文所指的比例、百分比等均以重量计。
实施例1：5,12-二甲基-3,10-二苯基-二甲基-1H-吡唑并[b，f]的[4,5]-1,5-二氮杂二环[3.3.1]-2,6-辛二烯(1)
干燥的250mL三颈烧瓶中加入吡啶(0.5mol，39.5g)、正丁基溴(0.55mol， 68g)和60mL二氯甲烷，先加热至60℃，沸腾提起，防止爆沸，溶液不沸以后将温度升高至80℃，加热回流5～6小时直至反应完全。然后在该体系中加入四氟硼酸钠(0.5mol，55g)，交换阴离子，80℃温度下加热回流12小时，过滤，用二氯甲烷洗涤，将滤液减压蒸馏，除去溶剂二氯甲烷，即可得到金黄色离子液体[Bpy]BF4。
25mL圆底烧瓶中加入1mL离子液体[Bpy]BF4、1mmol3-甲基-1-苯基-1H-吡唑 -5-胺、0.5mL甲醛水溶液(30％)和1mL三氟乙酸，室温下搅拌5～7小时，反应结束(TLC跟踪)后加入10mL蒸馏水，将混合物过滤，洗涤，干燥，得到粗产物，称量计算产率后，用无水乙醇重结晶得到纯净的产物2a:白色固体，熔点：266-267℃.1H NMR(400MHz,CDCl3)δ7.95-7.97(d,J＝8.4Hz,4H). 7.49-7.53(m,4H),7.30-7.32(t,J＝8.0Hz,2H),4.24-4.32(t,J＝7.2Hz,4H),3.59(d, J＝15.6Hz,2H),1.97(s,6H).13C NMR(100MHz,CDCl3)δ145.4,145.1,139.4,129.2,125.9,120.8,104.3,68.5,48.1,12.5.HRMS(ESI)m/z[M+H]+计算值 C23H22N6:383.1984；实验值:383.1969.
实施例2、5-氨基-3-(4-甲氧基苯基)-7-(对-甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(2)
反应式(1)
将4-甲氧基-溴代苯乙酮(1mmol)、硫脲(1.5mmol)、丙二腈(2mmol)、对甲基苯甲醛(1mmol)、催化剂2a(20mmol％)和乙醇(5mL)依次加入50mL圆底烧瓶中，80℃下充分反应至完全(TLC跟踪监测)。冷却至室温，用二氯甲烷萃取，收取有机相，经无水Na2SO4干燥，减压蒸馏，柱层析纯化的产物(V二氯甲烷：V甲醇＝80:1)。得到目标产物5-氨基-3-(4-甲氧基苯基)-7-(对-甲苯基)-7H-噻唑并[3,2-a]嘧啶 -6-甲腈：白色固体,熔点.108.6-109.4℃,1H NMR(400MHz,DMSO)δ7.43–7.30 (m,4H),7.25(d,J＝8.1Hz,4H),6.97(t,J＝12.3Hz,2H),5.64(d,J＝8.0Hz,1H),5.06 (d,J＝8.0Hz,1H),3.74(s,J＝35.8Hz,3H),2.31(s,3H).13C NMR(101MHz,)δ167.39, 159.45,150.22,138.09,135.60,130.30,130.14,127.96,127.58,115.09,114.35, 55.66,44.25,30.74,21.16.HRMS(ESI)m/z:计算值C21H19N4OS[M+H]+:375.1280；实验值:375.7574
实施例3、5-氨基-7-(4-氯苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(3)
用4-氯苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-氯苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(3)。
灰色固体,熔点:103.2-104.5℃,1H NMR(400MHz,DMSO)δ7.51(dd,J＝26.8,8.0Hz,4H),7.33(d,J＝6.2Hz,4H),6.99(d,J＝8.2Hz,2H),5.68(d,J＝7.9Hz,1H),5.17 (d,J＝16.1Hz,1H),3.78(s,3H).13C NMR(101MHz,)δ167.52,159.51,150.71, 137.60,133.48,130.31,130.06,129.62,127.45,114.38,114.18,113.75,113.59, 55.66,43.81,30.69.HRMS(ESI)m/z:计算值C20H15ClN4OS[M+H]+:395.0733；实验值:395.0728.
实施例4、5-氨基-7-(4-氰基苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6- 甲腈(4)
用对氰基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-氰基苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(4)
黄色固体,熔点：112.4-113.2℃,1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.9Hz,2H),7.47(d,J＝7.8Hz,2H),7.23(d,J＝8.2Hz,2H),6.90(d,J＝7.8Hz,2H),5.28(s,2H), 4.89(d,J＝8.2Hz,1H),4.13(d,J＝7.6Hz,1H),3.79(s,3H).13C NMR(101MHz, DMSO)δ167.64,159.52,143.73,133.51,130.30,129.14,127.02,118.82,114.34, 113.76,113.54,113.34,111.58,55.61,55.35,44.08,30.27.HRMS(ESI)m/z:计算值 C21H15N5OS[M+H]+:386.1076；实验值:386.1072
实施例5、5-氨基-3,7-双(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(5) 用对甲氧基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-3,7-双(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(5)
黄色固体,熔点：99.6-100.5℃,1H NMR(400MHz,CDCl3)δ7.36–7.23(m,4H),6.90(m,J＝6.3Hz,4H),5.48(s,2H),4.80(d,J＝8.0Hz,1H),4.08(d,J＝7.8Hz,1H),3.78(d, J＝10.8Hz,6H).13C NMR(101MHz,DMSO)δ167.23,159.35,149.95,130.37,130.20, 129.27,127.51,115.17,114.83,114.27,113.86,113.71,55.63,55.59,43.80, 30.85.HRMS(ESI)m/z:计算值C21H18N4O2S[M-NH2]-:375.1041；实验值:375.1208
实施例6、5-氨基-7-(4-溴苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(6)
用4-溴苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-溴苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(6)
灰色固体,熔点:132.5-133.6℃,1H NMR(400MHz,CDCl3)δ7.50(d,J＝7.9Hz,2H),7.24(d,J＝7.6Hz,2H),7.20(d,J＝7.7Hz,2H),6.89(d,J＝8.0Hz,2H),5.32(s,J＝73.8Hz,2H),4.79(d,J＝7.8Hz,1H),4.08(d,J＝7.8Hz,1H),3.78(s,3H).13C NMR(101MHz,)δ166.41,160.11,151.46,135.77,132.85,130.19,129.30,126.21,115.68,114.37,111.38,111.27,55.47,45.22,30.66.HRMS(ESI)m/z:计算值C20H15BrN4OS [M+H]+:439.0228；实验值:439.0217
实施例7、5-氨基-7-(4-氯苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(7)
用4-甲基-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-氯苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-氯苯基)-3-(对甲苯基)-7H- 噻唑并[3,2-a]嘧啶-6-甲腈(7)
灰色固体,熔点：114.8-115.6℃,1H NMR(400MHz,CDCl3)δ7.42(d,J＝7.5Hz,2H),7.34(d,J＝7.5Hz,2H),7.26(dd,J＝12.6,8.2Hz,4H),5.49(s,2H),4.89(d,J＝7.5Hz,1H),4.14(d,J＝7.2Hz,1H),2.39(d,J＝15.5Hz,3H).13C NMR(101MHz,)δ166.49, 139.03,135.23,135.20,129.88,129.65,129.03,128.77,116.21,111.36,111.26, 45.08,30.73,21.43.HRMS(ESI)m/z:计算值C20H15ClN4S[M+H]+:379.0784；实验值： 379.0784
实施例8、5-氨基-7-(4-氰基苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(8)
用4-甲基-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-氰基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-氰基苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(8)
黄色固体,熔点：182.3-183.4℃,1H NMR(400MHz,CDCl3)δ7.68(d,J＝7.7Hz,2H),7.46(d,J＝7.4Hz,2H),7.19(s,4H),5.40(s,2H),4.90(d,J＝7.5Hz,1H),4.17(d,J＝7.1Hz,1H),2.34(s,3H).13C NMR(101MHz,)δ167.81,143.84,137.97,133.59, 129.58,129.20,128.98,118.90,113.99,113.62,113.41,111.64,44.10,30.37,21.36. HRMS(ESI)m/z:计算值C21H15N5S[M+H]+:370.1125；实验值：370.1132
实施例9、5-氨基-7-(4-溴苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(9)
用4-甲基-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-溴苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-溴苯基)-3-(对甲苯基)-7H- 噻唑并[3,2-a]嘧啶-6-甲腈(9)
灰色固体,熔点：102.5-102.9℃,1H NMR(400MHz,CDCl3)δ7.51(d,J＝7.9Hz,2H),7.20(dd,J＝14.1,9.1Hz,6H),5.21(s,2H),4.81(d,J＝7.6Hz,1H),4.06(d,J＝7.7Hz,1H),2.34(s,3H).13C NMR(101MHz,)δ166.52,151.75,139.02,135.75,132.83, 130.94,129.65,129.30,128.76,123.34,116.08,111.35,111.25,45.15,30.64,21.44. HRMS(ESI)m/z:计算值C20H15BrN4S[M+H]+:423.0279；实验值:423.0257
实施例10、5-氨基-7-(3-氯苯基)-3-(4-氯苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(10)
用4-氯-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用3-氯苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(3-氯苯基)-3-(4-氯苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(10)
灰色固体,熔点：113.5-114.1℃,1HNMR(400MHz,CDCl3)δ7.40–7.31(m,6H),7.28(d,J＝8.5Hz,2H),5.34(s,1H),4.75(d,J＝7.7Hz,1H),4.12(d,J＝7.8Hz,1H).HRMS (ESI)m/z:计算值C31H31N6[M+H]+:383.0051；实验值:384.3076.
实施例11、5-氨基-3,7-双(4-氯苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(11)
用4-氯-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-氯苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-3,7-双(4-氯苯基)-7H-噻唑并[3,2-a] 嘧啶-6-甲腈(11)
黄色固体,熔点：92.7-94.2℃,1H NMR(400MHz,CDCl3)δ7.52(d,J＝7.7Hz,2H),7.35 (d,J＝7.4Hz,2H),7.26(d,J＝7.0Hz,2H),7.09(d,J＝8.7Hz,2H),5.20(s,2H),4.75(d, J＝8.2Hz,1H),4.08(d,J＝7.3Hz,1H).13C NMR(101MHz,)δ166.39,135.44,135.14,134.88,132.23,130.24,130.02,129.21,128.94,117.13,111.21,111.05,45.15,30.87,27.00.HRMS(ESI)m/z:计算值C16H11N6O2S[M+H]+:384.3081；实验值:374.3076
实施例12、5-氨基-7-(4-溴苯基)-3-(4-氯苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(12)
用4-氯-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-溴苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-溴苯基)-3-(4-氯苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(12)
灰色固体,熔点：121.7-122.1℃,1H NMR(400MHz,CDCl3)δ7.70(d,J＝7.7Hz,2H),7.45(d,J＝7.8Hz,2H),7.37(d,J＝7.6Hz,2H),7.25(d,J＝7.8Hz,2H),5.22(s,2H), 4.84(d,J＝7.7Hz,1H),4.13(d,J＝7.7Hz,1H).13C NMR(101MHz,)δ167.88,149.60, 137.78,133.84,133.19,132.57,130.85,130.36,129.06,127.75,122.17,115.94, 43.58,30.55.HRMS(ESI)m/z:计算值C17H13N6O2S[M+H]+:442.9733；实验值： 442.9725
实施例13、5-氨基-3-(4-氯苯基)-7-(4-氰基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(13)
用4-氯-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-氰基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-3-(4-氯苯基)-7-(4-氰基苯基) -7H-噻唑并[3,2-a]嘧啶-6-甲腈(13)
黄色固体,熔点：196.8-198.0℃,1H NMR(400MHz,CDCl3)δ7.70(d,J＝7.5Hz,2H),7.45(d,J＝7.7Hz,2H),7.36(d,J＝7.5Hz,2H),7.29–7.21(m,2H),5.20(s,2H),4.84 (d,J＝7.1Hz,1H),4.13(d,J＝7.6Hz,1H).13C NMR(101MHz,DMSO)δ167.95, 149.99,143.56,133.65,133.54,133.16,130.82,129.14,129.00,118.81,115.13, 113.52,113.29,111.62,43.80,30.22.HRMS(ESI)m/z:计算值C20H12ClN5S [M-H]-:388.0424；实验值:388.0499
实施例14、5-氨基-7-(4-氯苯基)-3-(4-氰基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(14)
用4-氰基-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-氯苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-氯苯基)-3-(4-氰基苯基) -7H-噻唑并[3,2-a]嘧啶-6-甲腈(14)
黄色固体,熔点：158.7-159.5℃,1H NMR(400MHz,CDCl3)δ7.67(d,J＝7.4Hz,2H),7.46(d,J＝7.6Hz,2H),7.39(d,J＝7.5Hz,2H),7.27(d,J＝7.7Hz,2H),5.17(s,2H), 4.76(d,J＝7.5Hz,1H),4.10(d,J＝8.0Hz,1H).HRMS(ESI)m/z:计算值C20H12ClN5S [M-H]-:388.0424；实验值:388.0492
实施例15、5-氨基-7-(3-氯苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(15)
用3-氯苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(3-氯苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(15)
黄色固体,熔点：126.1-126.5℃,1H NMR(400MHz,DMSO)δ7.66(s,1H),7.58(s,1H), 7.43(s,2H),7.32(d,J＝9.0Hz,4H),6.99(d,J＝7.8Hz,2H),5.71(d,J＝8.0Hz,1H),5.20(d,J＝7.9Hz,1H),3.79(s,3H).13C NMR(101MHz,DMSO)δ167.07,158.91, 150.35,140.41,133.57,130.85,129.75,128.22,127.33,126.52,113.56,113.27, 55.06,48.65,43.27,30.02.HRMS(ESI)m/z:计算值C20H15ClN4OS[M+H]+:395.0720；实验值:395.0733。
实施例16、5-氨基-7-(3-溴苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(16)
用3-溴苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(3-溴苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(16)
灰色固体,熔点：163.4-164.8℃,1H NMR(400MHz,DMSO)δ7.66(s,1H),7.58(s,1H), 7.43(s,2H),7.32(d,J＝9.0Hz,4H),6.99(d,J＝7.8Hz,2H),5.71(d,J＝8.0Hz,1H),5.20(d,J＝7.9Hz,1H),3.79(s,3H).13C NMR(101MHz,DMSO)δ167.49,160.29, 159.45,150.75,141.08,131.72,131.65,130.62,130.25,127.37,127.27,122.66, 114.32,113.84,55.61,43.78,30.50.HRMS(ESI)m/z:计算值C20H15BrN4OS [M+H]+:439.0228；实验值：439.0217。
实施例17、5-氨基-7-(3-硝基苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(17)
用4-甲基-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用3-硝基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(3-硝基苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(17)
黄色固体,熔点:199.6-200.3℃,1H NMR(400MHz,DMSO)δ8.35(s,1H),8.25(d,J＝7.8Hz,1H),7.90(d,J＝7.4Hz,1H),7.77(t,J＝7.8Hz,1H),7.37(s,2H),7.25(dd,J＝14.3,7.4Hz,4H),5.79(d,J＝7.8Hz,1H),5.40(d,J＝7.7Hz,1H),2.34(s,3H).13C NMR(101MHz,DMSO)δ168.05,158.47,149.62,127.79,126.78,113.76,99.29,55.02. HRMS(ESI)m/z:计算值C20H15N5O2S[M-H]-:388.0868；实验值:388.0753。
实施例18、5-氨基-3-(4-甲氧基苯基)-7-(3-硝基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(18)
用3-硝基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-3-(4-甲氧基苯基)-7-(3-硝基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(18)
黄色固体,熔点：132.9-133.2℃,1H NMR(400MHz,DMSO)δ8.36(s,1H),8.25(d,J＝7.8Hz,1H),7.90(d,J＝7.1Hz,1H),7.78(t,J＝7.9Hz,1H),7.35(s,2H),7.31(d,J＝7.4Hz,2H),6.98(d,J＝7.5Hz,2H),5.80(d,J＝7.7Hz,1H),5.41(d,J＝7.7Hz,1H),3.78(s,3H).13C NMR(101MHz,DMSO)δ172.70,167.61,159.52,148.53,147.39,140.53, 135.01,131.64,131.25,130.29,123.77,122.82,114.34,113.56,113.17,55.62,43.63,30.60.HRMS(ESI)m/z:计算值C20H15N5O3S[M+H]+:406.0974；实验值:406.0972。
实施例19、5-氨基-3-(4-氯苯基)-7-(3-硝基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(19)
用4-氯-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用3-硝基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-3-(4-氯苯基)-7-(3-硝基苯基) -7H-噻唑并[3,2-a]嘧啶-6-甲腈(19)
黄色固体,熔点：189.3-190.5℃,1H NMR(400MHz,DMSO)δ8.42–7.99(m,6H), 7.80(dd,J＝20.0,12.2Hz,2H),7.70(d,J＝7.0Hz,2H),5.72(d,J＝11.1Hz,1H),4.53 (d,J＝11.4Hz,1H).13C NMR(101MHz,DMSO)δ167.98,150.09,148.53,140.29, 135.02,133.59,133.23,131.26,130.82,130.00,129.00,128.65,123.82,122.82, 114.97,113.50,113.25,43.44,30.54,14.33,11.23.HRMS(ESI)m/z:计算值 C20H16ClN5O2S[M+H]+:410.0478；实验值：410.0472。
实施例20、5-氨基-7-(4-硝基苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(20)
用4-甲基-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-硝基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-硝基苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(20)
黄色固体,熔点：203.4-204.2℃,1H NMR(400MHz,DMSO)δ8.32(d,J＝7.5Hz,2H),7.71(d,J＝7.9Hz,2H),7.36(s,2H),7.25(d,J＝8.4Hz,4H),5.77(d,J＝7.1Hz,1H), 5.37(d,J＝7.9Hz,1H),2.34(s,3H).13C NMR(101MHz,DMSO)δ167.77,151.51, 147.67,145.63,137.92,132.01,129.56,129.51,128.90,124.71,113.80,113.52, 113.31,43.85,30.39,21.29.HRMS(ESI)m/z:计算值C20H15N5O2S[M+H]+:390.1025；
实验值390.1018。
实施例21、5-氨基-3-(4-甲氧基苯基)-7-(4-硝基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(21)
用4-硝基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-3-(4-甲氧基苯基)-7-(4-硝基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(21)
黄色固体,熔点：205.7-206.3℃,1H NMR(400MHz,DMSO)δ8.39(d,J＝7.8Hz,2H),7.78(d,J＝8.5Hz,2H),7.44(s,2H),7.38(d,J＝7.4Hz,2H),7.05(d,J＝7.7Hz,2H), 5.84(d,J＝7.6Hz,1H),5.44(d,J＝7.6Hz,1H),3.85(s,3H).13C NMR(101MHz, DMSO)δ167.64,159.48,151.23,147.66,145.70,130.26,129.58,127.24,124.71, 114.32,113.55,113.35,113.18,55.61,43.88,30.40.HRMS(ESI)m/z:计算值 C20H15N5O3S[M+H]+:406.0974；实验值：406.0972。
实施例22、5-氨基-3-(4-氯苯基)-7-(4-硝基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(22)
用4-氯-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-硝基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物-氨基-3-(4-氯苯基)-7-(4-硝基苯基)-7H -噻唑并[3,2-a]嘧啶-6-甲腈(22)
黄色固体,熔点：206.3-207.5℃,1H NMR(400MHz,DMSO)δ8.39(d,J＝7.5Hz,2H),7.77(d,J＝7.8Hz,2H),7.56(d,J＝7.1Hz,4H),7.46(d,J＝7.3Hz,2H),5.87(d,J＝8.1 Hz,1H),5.49(d,J＝7.4Hz,1H).13C NMR(101MHz,DMSO)δ167.47,149.50,147.26, 133.08,132.60,130.37,129.11,128.46,124.16,43.47,29.53.HRMS(ESI)m/z:计算值C20H16ClN5O2S[M+H]+:410.0478；实验值410.0472。
实施例23 5-氨基-7-(4-氯苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(23)
用4-甲基-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-氯苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-氯苯基)-3-(对甲苯基)-7H- 噻唑并[3,2-a]嘧啶-6-甲腈(23)
白色固体，熔点：92.7-94.2oC.1H NMR(400MHz,DMSO)δ7.50(d,J＝8.1Hz,2H),7.41(d,J＝8.3Hz,2H),7.37–7.28(m,4H),7.25(d,J＝7.6Hz,2H),5.65(d,J＝8.3Hz, 1H),5.11(d,J＝8.1Hz,1H),2.31(s,3H).13C NMR(101MHz,)δ167.71,149.09, 138.15,135.40,134.00,133.06,130.82,130.16,129.03,127.94,116.92,113.88, 113.69,43.90,30.69,21.17.HRMS(ESI)m/z:计算值C20H15BrN4S[M+H]+: 379.0784；实验值:379.0713。
实施例23、新型含多取代的5-氨基-3,7-二苯基-7H-噻唑并[3,2-a]嘧啶-6-甲腈衍生物抗菌活性试验：
通过临床分离的耐甲氧西林金黄色葡萄球菌对产物的抗菌活性进行筛选，具体实验步骤如下：
用甲醇将产物配置成10mg/Ml溶液,吸出6μL到新的离心管，待甲醇挥干留下定量的固体产物加入6μL DMSO及294μLLuria-Bertani(LB)溶液(保证最终 96孔板中的DMSO溶液少于2％)，由此将产物配成200μg/mL的样品再用LB 溶液按比例稀释成20μg/mL、2μg/mL，在96孔板的第一排各孔中加入50μL浓度为200μg/mL的药物溶液，第二排各孔加入50μL溶度为20μg/mL的药物溶液，第三排各孔加入50μL溶度为2μg/mL的药物溶液。吸取50μL单一菌液到各孔中并使药液和菌液混匀。在新的一块96孔板中只加菌液，作为负对照BO；加入美罗培南和菌液混合液作为正对照。把装有药物溶液和菌液的96孔板放在酶标仪下测其吸光度值为B1，之后将其放入37℃培养箱培养18-20h,后在测其吸光度值B2，并计算其抑制率。
抑制率(％)＝[1-(样品OD600增加量(B2-B1)/负对照OD600增加量 (B2-B1))]×100％
表1化合物对五种菌株的最低抑菌浓度
。
a最低抑菌浓度大于百分之50％的标记为“-”。
按照最低抑菌浓度大于50％为无效原则，七个化合物(4、6、9、10、12、 16、22)对耐甲氧西林金黄色葡萄球菌有抑菌作用，且该七个化合物对五种细胞株均有抑制作用，其中22对耐甲氧西林金黄色葡萄球菌有很好的抑制作用，尤其是对18H6、18I1具有非常好的抑制效果，其MIC均在5μg/mL，若继续研究其抑菌机制，有望将其发展为耐甲氧西林金黄色葡萄球菌的新药物。
Claims (4)
1.式I所示的化合物及其药学上可接受的盐在制备抗耐甲氧西林金黄色葡萄球菌的药物中的应用：
所述C1-5的烷基选自甲基、乙基、丙基、丁基或戊基；所述C1-5的烷氧基选自甲氧基、乙氧基、丙氧基、丁氧基或戊氧基。
2.根据权利要求1所述的应用，其特征在于，所述卤素选自氟、氯、溴或碘。
3.根据权利要求1所述的应用，其特征在于所述的R1为甲基，氯，氰基，溴，硝基，甲氧基；R2为甲基，氯，氰基，溴，甲氧基。
4.根据权利要求1所述的应用，其特征在于，所述式I所示的化合物选自：
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