CN114081890B - 嘧啶酮类衍生物在抗结核杆菌感染中的应用 - Google Patents
嘧啶酮类衍生物在抗结核杆菌感染中的应用 Download PDFInfo
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- CN114081890B CN114081890B CN202111404552.5A CN202111404552A CN114081890B CN 114081890 B CN114081890 B CN 114081890B CN 202111404552 A CN202111404552 A CN 202111404552A CN 114081890 B CN114081890 B CN 114081890B
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- dione
- pyrimidine
- dihydropyrido
- propanethiol
- mmol
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 230000002829 reductive effect Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
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- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
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- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 208000036979 totally drug-resistant tuberculosis Diseases 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种嘧啶酮类衍生物在抗结核杆菌感染中的应用,本发明的嘧啶酮类衍生物结构如式I所示,其中R1、m、X、Y、Z、R2和R3的定义如说明书和权利要求书所述。实验证明,本发明的嘧啶酮类衍生物具有明显的抗结核杆菌的活性,特别适用于制备预防和/或治疗结核杆菌引起的相关疾病的药物。
Description
分案说明
本案是申请日为2020年7月4日,申请号为202010633523.5,发明名称为“嘧啶酮类衍生物及其制备方法和在抗结核杆菌感染中的应用”的专利申请的分案申请。
技术领域
本发明属于药物化合物领域。具体地,本发明涉及一类嘧啶酮类衍生物,或其对映异构体、非对映异构体、外消旋体或其混合物,及其药学上可接受的盐在抗结核杆菌中的用途。
背景技术
结核病(tuberculosis,TB)是由结核分枝杆菌(Mycobacterium tuberculosis,MTB)感染导致的一种非常古老的传染病。该疾病通常由结核分枝杆菌感染所引起并破坏人体的肺脏及其他系统和器官,形成结核结节、浸润、干酪样变或空洞,常见临床表现包括长期低热、咳痰、咯血等[Wang Y,Luan S,Zhou X,Fan S,Research progress on anti-tuberculosis drugs,Clinical Medication Journal,2018,16(4),9-13]。
结核病是目前传播范围最广、感染性最强和致死性最为严重的疾病之一,每年新增TB感染病例上千万,死亡超百万[CampanicoA,Moreira R,Lopes F,Drug discovery intuberculosis.New drug targets and antimycobacterial agents,Eur.J.Med.Chem.2018,150,525-545]。耐药TB(DR-TB)、耐多药TB(MDR-TB,治愈率为40-80%)、广泛耐药TB(XDR-TB)和完全耐药TB(TDR-TB)及TB与HIV双重感染的出现和广泛传播,导致全球TB防控形势日益严峻。
2018年9月18日世界卫生组织在纽约联合国总部宣布的《2018年全球结核病报告》中说,2017年,全球估计有1000万人感染结核病,其中160万人因结核病死亡。2013年至2017年,全球结核病新增病例年均下降2%,2017年患病和死亡人数均为近年来低点,但结核病仍是全球最致命的传染病。报告指出,世卫组织所估计的1000万患者中,仅有640万在国家报告系统中有记录。报告还说,耐药结核病是全球卫生邻域一大难题,耐多药结核病的治愈率仅有55%[World Health Organization,Global Tuberculosis Report,2018,http://www.who.int/tb/]。
全球结核病的状况非常严峻,以目前趋势来看,难以实现联合国2030年可持续发展议程所设定的目标,即2030年前消灭结核病。为改变这一状况,除了健全结核病报告机制,主要是增强对耐药结核病的治疗,并加大研发投入以生产出更有效的抗结核药物。
近半个世纪仅研发获得三款新药,与拥挤的PD-1等抗肿瘤药赛道相比,抗结核药研发管线几近枯竭,新药可及性偏低,仿制药企业积极性也不高,这是包括中国在内的结核高负担国家面临的公共健康挑战。结核病已经成为全球性的公共卫生问题,其治疗亟需研发出疗效确切、依从性更好的新型抗结核药。针对目前结核耐药的严峻形势,开发具有新结构类型或具有新的作用机制的抗结核药物同样十分迫切。
发明内容
本发明的目的在于提供一类嘧啶酮类衍生物在抗结核杆菌感染中的应用。
为了达到上述目的,本发明采用了以下技术手段:
本发明提供了一种如式I所示的化合物,其对映异构体、非对映异构体、外消旋体或其混合物,或药学上可接受的盐的用途,其特征在于,用于:
(1)制备预防和/或治疗结核感染的药物;
(2)制备预防和/或治疗耐药结核感染的药物;或
(3)制备抑制结核杆菌生长的药物;
式中,R1为饱和烃基、不饱和烃基、羧基、羟基、C1-C6的烷氧基、取代或未取代氨基、卤素、硝基、氰基、取代或未取代酰胺基;其中所述取代氨基中的取代基选自以下:氢、C1-C6的烷基、羧基、羟基、氨基、C1-C6的烷氧基、硝基、氰基或三氟甲基;
m为0,1或2;
X为硫或氧;
当Y和Z之间为单键时,Y为-CH2-或-N(R)-,所述R选自以下:氢、饱和烃基、不饱和烃基、羧基、羟基、C1-C6的烷氧基、取代或未取代氨基、卤素、硝基、氰基、取代或未取代酰胺基;Z为或-CH2-;其中所述取代氨基中的取代基选自以下:氢、C1-C6的烷基、羧基、羟基、氨基、C1-C6的烷氧基、硝基、氰基或三氟甲基;当Y和Z之间为双键时,Y为N,Z为CH;
R2为氢、饱和烃、不饱和烃、羧基、羟基、C1-C6的烷氧基、取代或未取代氨基、卤素、硝基、氰基、取代或未取代酰胺基;其中取代氨基中的取代基选自以下:氢、C1-C6的烷基、羧基、羟基、氨基、C1-C6的烷氧基、硝基、氰基或三氟甲基;
R3为氢、取代或未取代C1-C6的烷基、C1-C6的烷氧基、羧基、硝基、卤素、三氟甲基、氰基、保护基保护或未保护的羟基、保护基保护或未保护的氨基、取代或未取代苯基或稠环基、取代或未取代的杂环基;其中所述取代烷基中的取代基选自以下:羧基、羟基、氨基、卤素、硝基、氰基或巯基;其中所述取代苯基或稠环基具有1、2、3、4或5个取代基,取代基选自以下:氢、C1-C6的烷基、羧基、羟基、氨基、C1-C6的烷氧基、硝基、氰基或三氟甲基;其中所述的杂环基为三元环、四元环、五元环杂环基;杂原子为O、S、N;所述的杂环基具有1或多个取代基时,取代基选自以下:氢、C1-C6的烷基、羧基、羟基、氨基、C1-C6的烷氧基、硝基、氰基或三氟甲基;其中所述保护基选自以下:叔丁氧羰基、对甲氧基苄基、二苯甲基、苄基、叔丁基二甲基硅基、叔丁基二苯基硅基、烯丙基、甲氧基甲基、甲硫基甲基、甲氧基乙氧基甲基或苄氧基甲基。
其中,优选的,式I所示的化合物中各手性碳的构型独立地为R构型或S构型。
其中,优选的,所述药学上可接受的盐为盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、柠檬酸盐、加磺酸盐、三氟乙酸盐、乙酸盐、草酸盐、丁二酸盐、苹果酸盐、甲苯磺酸盐、酒石酸盐、富马酸盐、谷氨酸盐、葡萄醛酸盐、乳酸盐、戊二酸盐、精氨酸盐或马来酸盐。
其中,优选的,式中,R1为甲基或乙烯基;
m为0,1或2;
X为硫;
R2为氢;
R3为4-丙氧基苯基、3-羟基-4-甲氧基苯基、3,4-二羟基苯基、3,4,5-三甲氧基苯基、3,4-二甲氧基苯基、3-硝基-4氯苯基、4-硝基苯基、2-羟基-4甲氧基苯基、4-羟基苯基、2,6-二甲基苯基、3-硝基苯基、2,4-二羟基苯基、4-丙氧基苯基、4-碘苯基、4-甲氧基苯基、2,3-二羟基-4-甲氧基苯基、3-羟基-4-丙氧基苯基、4-溴苯基、4-氟苯基、2-羟基-4-丙氧基苯基、4-苄氧基苯基、4-苯氧基苯基、3,4,5-三羟基苯基、4-三氟甲氧基苯基、4-乙氧基苯基、4-甲氧基-3-硝基苯基、4-甲氧基-2-硝基苯基、3-甲氧基苯基、2-甲氧基苯基、3-羟基苯基、3-氰基苯基、2-硝基苯基、4-羟基-3-硝基苯基、苯基、喹啉-4-基、喹啉-5-基、喹啉-6-基或4-甲氧基苯基。
其中,优选的,所述式I所示的化合物为:
2-丙巯基-5-(4-丙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-甲巯基-5-(4-丙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3-羟基-4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-甲巯基-5-(3-羟基-4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3,4-二羟基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-甲巯基-5-(3,4,5-三甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3,4,5-三甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3,4-二甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3-硝基-4-氯苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-甲巯基-5-(4-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-甲巯基-5-(2-羟基-4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(2-羟基-4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-羟基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-甲巯基-5-(2,6-二甲基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(2,6-二甲基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-甲巯基-5-(3-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(2,4-二羟基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-烯丙巯基-5-(4-丙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-烯丙巯基-5-(3-羟基-4-氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-烯丙巯基-5-(2-羟基-4-丙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-烯丙巯基-5-(3,4-二甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-碘苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(2,3-二羟基-4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3-羟基-4-丙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-溴苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-氟苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(2-羟基-4-丙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-苄氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-苯氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3,4,5-三羟基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-三氟甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(喹啉-6-基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-甲基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-三氟甲基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-乙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3-硝基-4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(2-硝基-4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(2-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3-羟基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3-氰基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(2-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3-硝基-4-羟基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-苯基-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(喹啉-4-基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(喹啉-5-基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-甲氧基苯基)-吡啶骈[2,3-d]嘧啶-4(3H)-酮;
2-丙巯基-5-(喹啉-6-基)-吡啶骈[2,3-d]嘧啶-4(3H)-酮;
2-丙巯基-5-(4-甲氧基苯基)-吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮。
进一步的,本发明还提出了所述的化合物的制备方法,本发明化合物可通过如下的方法制得,然而该方法的条件,例如反应物、溶剂、酸、碱、所用化合物的量、反应温度、反应时间等不限于以下的描述。还可以任选将本说明书中描述的或本领域技术人员已知的各种合成方法的组合来方便地制得本发明的化合物,本发明所属领域的技术人员可以容易地进行上述组合。
所述方法包括以下步骤:
(a)氰基乙酸乙酯与式I-1化合物反应得到式I-2化合物;
(b)式I-2化合物与R1取代的卤化物反应得到式I-3化合物;
(c)式I-3化合物与甲醇、乙醇、卤代烷烃、卤代不饱和烷烃、溴化氰、N-氯代琥珀酰亚胺、N-溴代琥珀酰亚胺、1-氰基-1-甲基硝酸乙酯、脲、异氰酸甲酯、氯胺反应得到式I-4化合物;
(d)式I-4化合物与2,2-二甲基-1,3-二氧六环-4,6-二酮、式I-5化合物“一锅煮”反应得到式I-6化合物,其中R3为氢、取代或未取代C1-C6的烷基、羧基、硝基、卤素、三氟甲基、取代或未取代苯基或稠环基、取代或未取代的杂环基;
步骤(d)得到的化合物进一步依次通过羟基化、还原、氰基化、氰基水解反应得到式I-6所示的化合物,其中R3为羟基、氨基、氰基、酰胺基;
(e)式I-6化合物经过取代反应得到式I所示的化合物;
式中X、m、R1、R2、R以及取代基的定义同前;或者
所述方法包括以下步骤:
(a)(b)(c)步骤同上面所示,反应得到式I-4化合物;
(d)式I-4化合物与式I-7化合物反应得到式I-8化合物;其中R3为氢、取代或未取代C1-C6的烷基、羧基、硝基、卤素、三氟甲基、取代或未取代苯基或稠环基、取代或未取代的杂环基;
步骤(d)得到的化合物进一步依次通过羟基化、还原、氰基化、氰基水解反应得到式I-8所示的化合物,其中R3为羟基、氨基、氰基、酰胺基;
(e)式I-8化合物经过取代反应得到式I所示的化合物;
式中X、m、R1、R2、R以及取代基的定义同前。
当Y为N;Z为CH时,也就是所述I化合物为:
所述方法包括以下步骤:
(a)(b)(c)如前面所示反应得到式I-4化合物;
(d)N,N-二甲基甲酰胺二甲基缩醛(DMFDMA)与式I-9化合物反应得到式I-10化合物;
(e)式I-4化合物中与式I-10化合物反应得到式I化合物,其中R3为氢、取代或未取代C1-C6的烷基、羧基、硝基、卤素、三氟甲基、取代或未取代苯环基或稠环基、取代或未取代的杂环基;
步骤(e)得到的化合物进一步依次通过羟基化、还原、氰基化、氰基水解反应得到式I所示的化合物,其中R3为羟基、氨基、氰基、酰胺基;
式中X、m、R1、R2、R以及取代基的定义同前。
在一优选实施方式中,氰基乙酸乙酯在极性溶剂中和式I-1化合物在碱性条件下加热回流2-5小时得到式I-2化合物。碱可以为金属钠、甲醇钠、乙醇钠、钠氢,后处理调节pH值7-9;
在一优选实施方式中,式I-2化合物在极性溶剂中和R1取代的卤化物,在碱性条件下加热回流5-10小时得到式I-3化合物。碱可以为氢氧化钠、氢氧化钾;
在一优选实施方式中,式I-3化合物在极性溶剂中和含R2基团的相应试剂,在碱性条件下室温或加热反应2-5小时得到式I-4化合物。碱可以为氢氧化钠、氢氧化钾,氨水,三乙胺,二乙胺,氢化钠,N,N-二异丙基乙胺。
在一优选实施方式中,式I-4化合物、丙二酸亚异丙酯以及式I-5化合物在高沸点的溶剂中,170-210℃温度下加热反应1-8小时,得到式I-6化合物。高沸点溶剂可以为硝基苯,乙二醇;
在一优选实施方式中,式I-6化合物在极性溶剂中和含R基团的相应试剂,在碱性条件下室温或加热反应2-5小时得到式I化合物二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮类。碱可以为氢氧化钠、氢氧化钾,氨水,三乙胺,二乙胺,氢化钠,N,N-二异丙基乙胺。
在一优选实施方式中,式I-4化合物与R3取代丙烯酸乙酯式I-7化合物在靶催化剂,对甲苯磺酸水合物,过硫酸钠,乙酸酐的催化下,在甲苯溶剂中加热回流12-36小时得到式I-8化合物。靶催化剂可以为醋酸钯等。
在一优选实施方式中,式I-8化合物在极性溶剂中和含R基团的相应试剂,在碱性条件下室温或加热反应2-5小时得到式I化合物吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮类。碱可以为氢氧化钠、氢氧化钾,氨水,三乙胺,二乙胺,氢化钠,N,N-二异丙基乙胺。
在一优选实施方式中,N,N-二甲基甲酰胺二甲基缩醛(DMFDMA)与R3取代的甲基酮式I-9化合物在极性溶剂中加热回流1-5小时,得到式I-10化合物。极性溶剂常为二氧六环、苯。
在一优选实施方式中,式I-4化合物与式I-10化合物在冰醋酸中加热1-5小时得到式I化合物吡啶骈[2,3-d]嘧啶-4(3H)-酮类。
一种降低结核杆菌致病性或毒性的方法,包括以下步骤:
将结核杆菌与安全有效量的本发明所述的化合物,其对映异构体、非对映异构体、外消旋体或混合物,或药学上可接受的盐或本发明所述的药物组合物进行接触,从而降低结核杆菌致病性或毒性。
本发明中向所述对象施与的方式没有特别的限制,包括但不限于口服,注射,吸入,局部使用。
本发明中,“安全有效量”指的是:活性成分(式I化合物)的量足以明显改善病情,而不至于产生严重的副作用。
本发明中,嘧啶酮类衍生物、式I化合物、式I所示的化合物具有相同的含义,均是指具有如下结构的化合物:
其中,R1、m、X、Y、Z、R2和R3的定义如前所述。
在本发明中,术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基,非限制性的包括甲基、乙基、丙基、异丙基和丁基等。本发明中,术语“卤素”是指氟、氯、溴、碘。
通常,药物组合物含有1-2000mg活性成分/剂,更佳地,含有10-200mg活性成分/剂。较佳地,所述的“一剂”为一个药片。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组分能和本发明的活性成分以及它们之间相互掺和,而不明显减低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润滑剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的活性成分或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
在这些固体剂型中,活性成分与至少一种常规惰性赋型剂(或载体)混合,如柠檬酸钠或磷酸儿钙,或与下述成分混合:(a)填料或增溶剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、碳酸钠;(e)缓溶剂,例如,石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如,鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;(i)润滑剂,例如,滑石,硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
所述的固体剂型还可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。
用于口服给的液体剂型包括药学上可以接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其他溶剂,增溶剂和乳化剂,例如,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋型剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他治疗药物联合给药。
使用药物组合物时,是将安全有效量的本发明式I化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常1-2000mg,优选20-500mg。当然,具体剂量还要考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明提到的上述特征,或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用,说明书中所揭示的各个特征,可以被任何提供相同、均等或相似目的的替代性特征取代。因此除有特别说明,所揭示的特征仅为均等或相似特征的一般性例子。
本发明的有益之处在于:
(1)本发明提供了具有新型的嘧啶酮类结构衍生物。
(2)本发明提供了嘧啶酮类衍生物的制备方法,工艺简单高效。
(3)本发明首次发现了嘧啶酮类衍生物的新用途,可以用于制备抗结核药物。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
所有实施例中,薄层分析用薄层硅胶板检测(Merck,TLC Silica gel 60F254);柱层析所用硅胶(200-300目)为购自青岛海洋化工,柱层析所用到的石油醚沸程为60-90℃;实验中所有试剂除有特殊说明外均购自(北京)百灵威科技公司和上海毕得医药科技有限公司,为分析纯或化学纯,未经进一步处理。各化合物进行生物活性测试之前都采用HPLC进行纯度分析,分析中均使用色谱纯有机溶剂和屈臣氏纯净水。1H-NMR,13C-NMR用400M或600M核磁共振仪记录,化学位移以δ(ppm)表示。
制备实施例
6-氨基-2-硫脲嘧啶的制备:
将氰基乙酸乙酯(6.40mL,60.0mmol)和硫脲(4.56g,60.0mmol)加入到溶有乙醇钠(4.29g,63.0mmoL)的乙醇溶液中(44mL),油浴下加热回流2小时,有棕色不溶物析出。将反应液浓缩后,加入到适量的冰水中,用10%的冰醋酸调pH值,类白色固体逐渐析出。室温下,搅拌,静置过夜,过滤,得白色固体6.0g,产率70%。
2-丙巯基-6-氨基嘧啶-4(3H)-酮的制备:
6-氨基-2-硫脲嘧啶(1.43g,10.0mmol),1-溴丙烷(0.93mL,10.0mmol)以及氢氧化钠(0.4g,10.0mmol)溶于50毫升水和10毫升的异丙醇的混合溶液中,加热回流10小时,TLC检测原料几乎反应完全。冷却至室温后,有大量白色沉淀析出。将反应液过滤,用大量清水洗涤,滤饼即为产物,干燥,得到1.10g白色粉末,产率:59.5%。
1HNMR(DMSO-d6,400MHz)δ(ppm)11.46(1H,s),6.42(2H,s),4.88(1H,s),3.04(2H,t,J=7.2Hz),1.58-1.68(2H,m),0.96(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,101MHz)δ(ppm)164.60,163.96,162.70,81.70,31.65,22.79,13.65;
MS(ESI+)m/z 186.2[M+H]+.
2-甲巯基-6-氨基嘧啶-4(3H)-酮的制备:
6-氨基-2-硫脲嘧啶(1.43g,10.0mmol),碘甲烷(0.62mL,10.0mmol)以及氢氧化钠(0.4g,10.0mmol)溶于50毫升水和10毫升的异丙醇的混合溶液中,加热回流8小时,TLC检测原料几乎反应完全。冷却至室温后,有大量白色沉淀析出。将反应液过滤,用大量清水洗涤,滤饼即为产物,干燥,得到1.16g白色粉末,产率:73.9%。
1HNMR(DMSO-d6,400MHz)δ(ppm)11.49(1H,s),6.44(2H,s),4.90(1H,s),2.42(3H,s);
13CNMR(DMSO-d6,101MHz)δ(ppm)164.68,163.99,163.33,81.63,13.02;
MS(ESI+)m/z 158.0[M+H]+.
2-烯丙巯基-6-氨基嘧啶-4(3H)-酮的制备:
6-氨基-2-硫脲嘧啶(1.43g,10.0mmol),3-溴丙烯(0.87mL,10.0mmol)以及氢氧化钠(0.4g,10.0mmol)溶于50毫升水和10毫升的异丙醇的混合溶液中,加热回流5小时,TLC检测原料几乎反应完全。冷却至室温后,有大量白色沉淀析出。将反应液过滤,用大量清水洗涤,滤饼即为产物,干燥,得到0.74g白色粉末,产率:40.4%。
1HNMR(DMSO-d6,400MHz)δ(ppm)11.52(1H,s),6.46(2H,s),5.87-5.94(1H,m),5.31(1H,dd,J=16.8,1.8Hz),5.10(1H,dd,J=10.2,1.2Hz),4.93(1H,s),3.74(2H,d,J=7.2Hz);
13CNMR(DMSO-d6,101MHz)δ(ppm)134.28,118.47,81.78,32.56;
MS(ESI+)m/z 184.0[M+H]+.
3-二甲基氨基-1-(4-甲氧基苯基)-2-丙烯-1-酮的制备:
将对甲氧基苯乙酮(150mg,1.0mmol)和N,N-二甲基甲酰胺二甲基缩醛(DMFDMA)(476mg,4.0mmol)溶于约5.0毫升的DMF中,加热回流约3.5小时,TLC检测原料几乎反应完全。将反应液浓缩得到黄色样固体205毫克,产率100%。
1HNMR(DMSO-d6,600MHz)δ(ppm)7.87(2H,d,J=9.0Hz),7.66(1H,d,J=12Hz),6.95(2H,d,J=9.0Hz),5.80(1H,d,J=12Hz),3.80(3H,s),3.12(3H,s),2.90(3H,s);
13CNMR(DMSO-d6,150MHz)δ(ppm)185.20,161.90,154.12,133.26,129.60×2,113.78×2,55.74,44.88,37.55;
MS(ESI+)m/z 206.1[M+H]+.
3-二甲基氨基-1-(喹啉-6-基)-2-丙烯-1-酮的制备:
将6-乙酰基喹啉(171mg,1.0mmol)和N,N-二甲基甲酰胺二甲基缩醛(DMFDMA)(476mg,4.0mmol)溶于约5.0毫升的DMF中,油浴加热回流约3.5小时,TLC检测原料几乎反应完全。将反应液浓缩得到黄色样固体226毫克,产率100%。
1HNMR(DMSO-d6,600MHz)δ(ppm)8.95(1H,dd,J=4.2,1.8Hz),8.57(1H,d,J=1.2Hz),8.49(1H,d,J=7.8Hz),8.24(1H,dd,J=8.4,1.8Hz),8.04(1H,d,J=8.4Hz),7.80(1H,d,J=12Hz),7.59(1H,q),6.01(1H,d,J=12Hz),3.18(3H,s),2.98(3H,s);
MS(ESI+)m/z 227.1[M+H]+.
实施例1:
2-丙巯基-5-(4-丙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-7-30)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-丙氧基苯甲醛(0.158mL,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约2小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:40%)得纯品50mg,产率:13.4%。
1HNMR(DMSO-d6,400MHz)δ(ppm)12.57(1H,s),10.52(1H,s),7.05(2H,dd,J=8.4,2.0Hz),6.83(2H,dd,J=8.4,1.8Hz),4.14(1H,d,J=7.2Hz),3.87(2H,t,J=6.8Hz),3.05-3.17(2H,m),3.01(1H,q),2.49(1H,d,J=16.2Hz),1.63-1.74(4H,m),0.97(3H,t,J=7.2Hz),0.95(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,101MHz)δ(ppm)171.04,157.93,134.70,127.92×2,114.97×2,69.33,38.71,32.63,31.95,22.83,22.48,13.63,10.87;
MS(ESI+)m/z 374.1[M+H]+.
实施例2:
2-甲巯基-5-(4-丙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮的制备(LSL-7-36)
将2-甲巯基-6-氨基嘧啶-4(3H)-酮(157mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-丙氧基苯甲醛(0.158mL,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约1.5小时,TLC(石油醚/乙酸乙酯=2/3)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:55%)得纯品43mg,产率:12.4%。
1HNMR(DMSO-d6,400MHz)δ(ppm)12.59(1H,s),10.52(1H,s),7.05(2H,d,J=8.4Hz),6.83(2H,d,J=8.4Hz),4.14(1H,d,J=7.2Hz),3.86(2H,t,J=6.8Hz),2.99(1H,q),2.50(3H,s),2.49(1H,d,J=16.0Hz),1.64-1.74(2H,m),0.95(3H,t,J=7.6Hz);13CNMR(DMSO-d6,101MHz)δ(ppm)171.00,157.93,134.65,127.93×2,114.96×2,69.34,38.75,32.62,22.48,13.17,10.87;
MS(ESI+)m/z 368.1[M+Na]+.
实施例3:
2-丙巯基-5-(3-羟基-4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-7-38)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3-羟基-4-甲氧基苯甲醛(152mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约2.5小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:50%)得纯品70mg,产率:19.3%。
1HNMR(DMSO-d6,400MHz)δ(ppm)12.56(1H,s),10.50(1H,s),8.91(1H,s),6.80(1H,d,J=8.4Hz),6.58(1H,d,J=2.0Hz),6.53(1H,dd,J=8.4,2.0Hz),4.06(1H,d,J=7.6Hz),3.70(3H,s),3.87(2H,t,J=6.8Hz),3.05-3.17(2H,m),2.97(1H,q),2.47(1H,d,J=16.4Hz),1.63-1.72(2H,m),0.98(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,101MHz)δ(ppm)171.05,146.93,146.89,135.57,117.42,114.30,112.99,56.15,38.76,32.78,31.94,22.84,13.63;
MS(ESI+)m/z 362.1[M+H]+.
实施例4:
2-甲巯基-5-(3-羟基-4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-7-39)的制备
将2-甲巯基-6-氨基嘧啶-4(3H)-酮(157mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3-羟基-4-甲氧基苯甲醛(152mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约3小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:50%)得纯品85mg,产率:25.5%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.58(1H,s),10.48(1H,s),8.88(1H,s),6.80(1H,d,J=8.4Hz),6.57(1H,d,J=1.8Hz),6.53(1H,dd,J=8.4,1.8Hz),4.06(1H,d,J=7.8Hz),3.70(3H,s),2.96(1H,q),2.50(3H,s),2.46(1H,d,J=16.8Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.00,146.96,146.91,135.55,117.45,114.33,113.04,56.19,38.81,32.80,13.17;
MS(ESI+)m/z 334.1[M+H]+.
实施例5:
2-丙巯基-5-(3,4-二羟基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-7-42)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3,4-二羟基苯甲醛(138mg,1.0mmol)溶于约5mL的乙二醇中,油浴170℃下加热反应约5小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:60%)得纯品95mg,产率:27.4%。
1HNMR(DMSO-d6,400MHz)δ(ppm)12.53(1H,s),10.46(1H,s),8.81(1H,s),8.68(1H,s),6.61(1H,d,J=8.4Hz),6.52(1H,d,J=1.8Hz),6.41(1H,dd,J=8.4,1.8Hz),4.02(1H,d,J=7.2Hz),3.05-3.10(2H,m),2.94(1H,q),2.44(1H,d,J=16.8Hz),1.63-1.70(2H,m),0.97(3H,t,J=7.8Hz);
13CNMR(DMSO-d6,101MHz)δ(ppm)171.10,145.56,144.48,133.76,117.63,116.04,114.33,38.90,32.77,31.96,22.85,13.63;
MS(ESI+)m/z 348.1[M+H]+.
实施例6:
2-甲巯基-5-(3,4,5-三甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-7-43)的制备
将2-甲巯基-6-氨基嘧啶-4(3H)-酮(157mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3,4,5-三甲氧基苯甲醛(196mg,1.0mmol)溶于约5mL的乙二醇中,油浴170℃下加热反应约3小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:70%)得纯品78mg,产率:20.7%。
1HNMR(DMSO-d6,400MHz)δ(ppm)12.61(1H,s),10.52(1H,s),6.47(2H,s),4.16(1H,d,J=7.8Hz),3.69(8H,s),3.61(3H,s),3.00(1H,q),2.56(1H,d,J=16.8Hz),2.51(3H,s);
13CNMR(DMSO-d6,101MHz)δ(ppm)171.14,153.34×2,138.78,136.96,104.44×2,60.42,56.34×2,38.40,33.63,14.02;
MS(ESI+)m/z 378.1[M+H]+.
实施例7:
2-丙巯基-5-(3,4,5-三甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-7-44)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3,4,5-三甲氧基苯甲醛(196mg,1.0mmol)溶于约5mL的乙二醇中,油浴170℃下加热反应约2.5小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:50%)得纯品102mg,产率:25.2%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.58(1H,s),10.52(1H,s),6.48(2H,s),4.16(1H,d,J=7.8Hz),3.69(8H,s),3.61(3H,s),3.06-3.16(2H,m),3.00(1H,q),2.56(1H,d,J=16.2Hz),1.63-1.69(2H,m),0.96(3H,t,J=7.8Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.17,153.37×2,138.80,136.96,104.43×2,60.42,56.31×2,38.34,33.60,31.99,22.84,13.57;
MS(ESI+)m/z 406.1[M+H]+.
实施例8:
2-丙巯基-5-(3,4-二甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-7-46)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3,4-二甲氧基苯甲醛(166mg,1.0mmol)溶于约5mL的乙二醇中,油浴170℃下加热反应约3小时,TLC(石油醚/乙酸乙酯=1/3)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:50%)得纯品100mg,产率:26.7%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.57(1H,s),10.49(1H,s),6.88(1H,d,J=1.8Hz),6.82(1H,d,J=8.4Hz),6.54(1H,dd,J=8.4,1.8Hz),4.15(1H,d,J=7.2Hz),3.70(3H,s),3.69(3H,s),3.06-3.15(2H,m),2.98(1H,q),2.54(1H,d,J=16.8Hz),1.63-1.69(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.11,149.30,148.18,135.38,118.03,112.36,111.66,56.01,55.90,38.60,32.99,31.97,22.84,13.61;
MS(ESI+)m/z 376.1[M+H]+.
实施例9:
2-丙巯基-5-(3-硝基-4氯苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-7-48)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3-硝基-4-氯苯甲醛(185mg,1.0mmol)溶于约5mL的乙二醇中,油浴170℃下加热反应约3小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:50%)得纯品125mg,产率:31.7%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.66(1H,s),10.56(1H,s),7.88(1H,d,J=1.8Hz),7.69(1H,d,J=8.4Hz),7.45(1H,dd,J=8.4,1.8Hz),4.31(1H,d,J=7.8Hz),3.07-3.14(2H,m),3.06(1H,q),2.58(1H,d,J=16.2Hz),1.63-1.70(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.40,148.10,132.37,132.30,124.31,113.56,100.00,37.93,33.03,32.01,22.86,13.66;
MS(ESI+)m/z 395.1[M+H]+.
实施例10:
2-甲巯基-5-(4-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-7-49)的制备
将2-甲巯基-6-氨基嘧啶-4(3H)-酮(157mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-硝基苯甲醛(151mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约2.5小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:50%)得纯品85mg,产率:25.6%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.68(1H,s),10.65(1H,s),8.16(2H,d,J=8.4Hz),7.44(2H,d,J=8.4Hz),4.36(1H,d,J=7.8Hz),3.12(1H,q),2.57(1H,d,J=16.8Hz),2.52(3H,s);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.43,146.90,128.40×2,124.36×2,88.48,38.01,33.63,13.19;
MS(ESI+)m/z 333.1[M+H]+.
实施例11:
2-丙巯基-5-(4-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-7-50)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-硝基基苯甲醛(151mg,1.0mmol)溶于约5mL的乙二醇中,油浴210℃下加热反应约1小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:60%)得纯品92mg,产率:25.6%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.67(1H,s),10.58(1H,s),8.16(2H,d,J=9.0Hz),7.44(2H,d,J=8.4Hz),4.35(1H,d,J=7.8Hz),3.08-3.15(2H,m),3.07(1H,q),2.56(1H,d,J=16.2Hz),1.63-1.70(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)168.36,149.05,144.74,126.28×2,122.21×2,35.91,31.59,29.89,20.74,11.53;
MS(ESI+)m/z 361.1[M+H]+.
实施例12:
2-甲巯基-5-(2-羟基-4甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-1)的制备
将2-甲巯基-6-氨基嘧啶-4(3H)-酮(157mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及2-羟基-4-甲氧基苯甲醛(152mg,1.0mmol)溶于约5mL的乙二醇中,油浴210℃下加热反应约2.5小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:60%)得纯品60mg,产率:18.0%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.33(1H,s),10.31(1H,s),6.57(1H,d,J=8.4Hz),6.37(1H,d,J=1.8Hz),6.23(1H,dd,J=8.4,1.8Hz),4.28(1H,d,J=8.4Hz),3.64(3H,s),2.88(1H,q),2.47(3H,s),2.45(1H,d,J=16.8Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.34,134.59,129.16,127.04,104.52,102.61,100.00,55.35,37.56,27.97,13.26;
MS(ESI+)m/z 356.1[M+Na]+.
实施例13:
2-丙巯基-5-(2-羟基-4甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-2)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及2-羟基-4-甲氧基苯甲醛(152mg,1.0mmol)溶于约5mL的乙二醇中,油浴210℃下加热反应约3.5小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:50%)得纯品96mg,产率:26.6%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.57(1H,s),10.44(1H,s),9.71(1H,s),6.52(1H,d,J=8.4Hz),6.40(1H,d,J=2.4Hz),6.25(1H,dd,J=8.4,2.4Hz),4.30(1H,d,J=7.8Hz),3.64(3H,s),3.08-3.17(2H,m),2.88(1H,q),2.46(1H,d,J=16.2Hz),1.65-1.71(2H,m),0.98(3H,t,J=7.8Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.21,159.53,156.09,127.28,120.55,104.51,102.32,55.35,37.56,31.99,27.89,22.86,13.64;
MS(ESI+)m/z 362.1[M+H]+.
实施例14:
2-丙巯基-5-(4-羟基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-6)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及对羟基苯甲醛(122mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约2小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:1.5%)得纯品130mg,产率:39.3%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.61(1H,s),10.37(1H,s),9.26(1H,s),6.93(2H,dt,J=8.4,1.8Hz),6.65(1H,dt,J=8.4,1.8Hz),4.08(1H,d,J=7.8Hz),3.03-3.12(2H,m),2.94(1H,q),2.46(1H,d,J=16.2Hz),1.62-1.69(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.10,156.52,133.26,127.88×2,115.69×2,38.92,32.71,31.96,22.90,13.65;
MS(ESI+)m/z 332.1[M+H]+.
实施例15:
2-甲巯基-5-(2,6-二甲基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-7)的制备
将2-甲巯基-6-氨基嘧啶-4(3H)-酮(157mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及2,6-二甲氧基苯甲醛(166mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约2.5小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:60%)得纯品78mg,产率:22.5%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.16(1H,s),10.21(1H,s),7.11(1H,t,J=8.4Hz),6.57(2H,d,J=8.4Hz),4.78(1H,d,J=9.0Hz),3.66(8H,s),2.93(1H,q),2.46(3H,s),2.06(1H,d,J=16.8Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.47,158.44,128.01×2,121.24,105.15×2,56.06×2,36.74,24.22,13.17;
MS(ESI+)m/z 370.1[M+Na]+.
实施例16:
2-丙巯基-5-(2,6-二甲基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-8)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及2,6-二甲氧基苯甲醛(166mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约2小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:60%)得纯品130mg,产率:34.7%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.10(1H,s),10.23(1H,s),7.11(1H,t,J=8.4Hz),6.57(2H,d,J=8.4Hz),4.77(1H,d,J=9.6Hz),3.66(8H,s),3.02-3.13(2H,m),2.94(1H,q),2.06(1H,d,J=16.8Hz),1.61-1.68(2H,m),0.96(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.50,158.44,128.02×2,121.22,105.18×2,56.04×2,38.75,31.91,24.24,22.94,13.61;
MS(ESI+)m/z 398.1[M+Na]+.
实施例17:
2-甲巯基-5-(3-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-9)的制备
将2-甲巯基-6-氨基嘧啶-4(3H)-酮(157mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3-硝基苯甲醛(151mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约2.5小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:55%)得纯品110mg,产率:33.1%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.74(1H,s),10.56(1H,s),8.09(1H,dd,J=7.8,1.8Hz),8.03(1H,d,J=1.8Hz),7.64(1H,dd,J=7.8,1.8Hz),7.60(1H,t,J=7.8Hz),4.37(1H,d,J=7.8Hz),3.06-3.11(1H,q),2.61(1H,d,J=16.2Hz),2.49(3H,s);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.57,148.45,145.61,133.82,130.69,122.27,121.68,38.06,33.39,13.23;
MS(ESI+)m/z 333.1[M+H]+.
实施例18:
2-丙巯基-5-(3-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-10)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3-硝基苯甲醛(151mg,1.0mmol)溶于约5mL的乙二醇中,油浴210℃下加热反应约1小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:60%)得纯品138mg,产率:38.3%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.68(1H,s),10.59(1H,s),8.08(1H,dd,J=8.4,1.8Hz),8.03(1H,d,J=1.8Hz),7.59-7.65(2H,m),4.37(1H,d,J=7.8Hz),3.07-3.15(2H,m),3.07(1H,q),2.61(1H,d,J=16.2Hz),1.63-1.70(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.60,148.46,145.55,133.79,130.72,122.29,121.69,37.99,33.36,32.01,22.86,13.64;
MS(ESI+)m/z 361.1[M+H]+.
实施例19:
2-丙巯基-5-(2,4-二羟基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-12)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及2,4-二羟基苯甲醛(138mg,1.0mmol)溶于约5mL的乙二醇中,油浴210℃下加热反应约1.5小时,TLC(石油醚/乙酸乙酯=1/3)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:1.5-2.0%)得纯品100mg,产率:28.8%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.50(1H,s),10.26(1H,s),9.00(1H,s),6.44(1H,d,J=8.4Hz),6.24(1H,d,J=3.0Hz),6.06(1H,dd,J=8.4,3.0Hz),4.22(1H,d,J=8.4Hz),3.02-3.11(2H,m),2.85(1H,q),2.45(1H,d,J=16.2Hz),1.62-1.69(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.47,163.22,157.43,126.89,122.18,106.20,100.00,37.69,31.95,27.89,22.97,13.68;
MS(ESI+)m/z 348.1[M+H]+.
实施例20:
2-烯丙巯基-5-(4-丙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-14)的制备
将2-烯丙巯基-6-氨基嘧啶-4(3H)-酮(183mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-丙氧基苯甲醛(164mg,1.0mmol)溶于约5mL的乙二醇中,油浴210℃下加热反应约3小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:65%)得纯品70mg,产率:18.9%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.56(1H,s),10.53(1H,s),7.04(2H,d,J=8.4Hz),6.83(2H,d,J=8.4Hz),5.89-5.97(1H,m),5.39(1H,d,J=16.8Hz),5.13(1H,d,J=9.6Hz),4.14(1H,d,J=7.8Hz),3.86(2H,t,J=6.6Hz),3.77-3.84(2H,m),3.00(1H,q),2.49(1H,d,J=16.8Hz),1.65-1.72(2H,m),0.95(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.03,157.96,134.69,133.77,127.92×2,119.22,115.00×2,69.37,38.68,32.79,32.65,22.49,10.86;
MS(ESI+)m/z 372.1[M+H]+.
实施例21:
2-烯丙巯基-5-(3-羟基-4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-15)的制备
将2-烯丙巯基-6-氨基嘧啶-4(3H)-酮(183mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3-羟基-4-甲氧基苯甲醛(152mg,1.0mmol)溶于约5mL的乙二醇中,油浴210℃下加热反应约2小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:1.5%)得纯品95mg,产率:26.5%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.58(1H,s),10.50(1H,s),8.89(1H,s),6.80(1H,d,J=8.4Hz),6.57(1H,d,J=1.8Hz),6.52(1H,dd,J=8.4,1.8Hz),5.89-5.97(1H,m),5.39(1H,d,J=16.8Hz),5.13(1H,d,J=9.6Hz),4.06(1H,d,J=7.8Hz),3.77-3.85(2H,m),3.70(3H,s),2.97(1H,q),2.47(1H,d,J=16.8Hz).
13CNMR(DMSO-d6,150MHz)δ(ppm)169.96,145.88,145.85,134.48,130.91,128.05,116.34,113.25,111.95,55.10,39.47,37.65,31.72;
MS(ESI+)m/z 360.1[M+H]+.
实施例22:
2-烯丙巯基-5-(2-羟基-4-丙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-15)的制备
将2-烯丙巯基-6-氨基嘧啶-4(3H)-酮(183mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及2-羟基-4-甲氧基苯甲醛(152mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约2.5小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:1.5%)得纯品103mg,产率:28.7%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.60(1H,s),10.46(1H,s),9.71(1H,s),6.51(1H,d,J=7.8Hz),6.40(1H,d,J=2.4Hz),6.24(1H,dd,J=8.4,2.4Hz),5.91-5.98(1H,m),5.40(1H,d,J=16.8Hz),5.14(1H,d,J=10.2Hz),4.30(1H,d,J=7.2Hz),3.79-3.87(2H,m),3.64(3H,s),2.89(1H,q),2.47(1H,d,J=16.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.13,158.46,155.01,130.92,128.06,126.21,119.42,103.42,101.23,54.28,39.52,36.47,31.73;
MS(ESI+)m/z 360.1[M+H]+.
实施例23:
2-烯丙巯基-5-(3,4-二甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-17)的制备
将2-烯丙巯基-6-氨基嘧啶-4(3H)-酮(183mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3,4-二甲氧基苯甲醛(166mg,1.0mmol)溶于约5mL的乙二醇中,油浴170℃下加热反应约2.5小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:65%)得纯品108mg,产率:29.0%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.60(1H,s),10.52(1H,s),6.87(1H,d,J=1.8Hz),6.82(1H,d,J=8.4Hz),6.53(1H,dd,J=7.8,1.8Hz),5.89-5.96(1H,m),5.39(1H,d,J=16.2Hz),5.13(1H,d,J=10.2Hz),4.15(1H,d,J=7.8Hz),3.78-3.85(2H,m),3.70(3H,s),3.69(3H,s),2.99(1H,q),2.54(1H,d,J=16.8Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.03,148.23,147.12,134.25,132.69,128.06,116.96,111.29,110.55,54.93,54.83,39.47,37.47,31.92;
MS(ESI+)m/z 374.1[M+H]+.
实施例24:
2-丙巯基-5-(4-碘苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-19)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-碘基苯甲醛(233mg,1.0mmol)溶于约5mL的乙二醇中,油浴210℃下加热反应约2.5小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:65%)得纯品235mg,产率:53.2%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.92(1H,s),10.28(1H,s),7.62(2H,d,J=8.4Hz),6.97(2H,d,J=8.4Hz),4.14(1H,d,J=7.8Hz),3.69(3H,s),3.00-3.08(2H,m),2.97(1H,q),2.47(1H,d,J=16.2Hz),1.60-1.67(2H,m),0.96(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.78,155.17,143.53,137.85×2,129.52×2,97.93,92.64,38.50,33.37,31.93,22.99,13.72;
MS(ESI+)m/z 442.0[M+H]+.
实施例25:
2-丙巯基-5-(4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-21)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-甲氧基苯甲醛(173mg,1.0mmol)溶于约5mL的乙二醇中,油浴210℃下加热反应约3小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:65%)得纯品71mg,产率:20.6%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.70(1H,s),10.39(1H,s),7.06(2H,d,J=9.0Hz),6.83(2H,d,J=9.0Hz),4.13(1H,d,J=7.2Hz),3.69(3H,s),3.03-3.12(2H,m),2.97(1H,q),2.48(1H,d,J=16.8Hz),1.62-1.69(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.03,158.46,127.96×2,114.41×2,100.00,55.51,38.80,32.73,31.96,22.90,13.65;
MS(ESI+)m/z 346.1[M+H]+.
实施例26:
2-丙巯基-5-(2,3-二羟基-4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-23)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及2,3-二羟基-4-甲氧基苯甲醛(168mg,1.0mmol)溶于约5mL的乙二醇中,油浴210℃下加热反应约3小时,TLC(石油醚/乙酸乙酯=1/3)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:70%)得纯品120mg,产率:31.8%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.56(1H,s),10.38(1H,s),9.02(1H,s),8.39(1H,s),6.31(1H,d,J=8.4Hz),6.09(1H,d,J=8.4Hz),4.32(1H,d,J=8.4Hz),3.69(3H,s),3.05-3.14(2H,m),2.89(1H,q),2.47(1H,d,J=16.8Hz),1.63-1.70(2H,m),0.98(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.32,147.69,143.93,135.10,115.54,103.40,100.00,56.27,37.57,31.99,28.01,22.90,13.65;
MS(ESI+)m/z 378.1[M+H]+.
实施例27:
2-丙巯基-5-(3-羟基-4-丙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-25)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3-羟基-4-丙氧基苯甲醛(152mg,1.0mmol)溶于约5mL的乙二醇中,油浴180℃下加热反应约3.5小时,TLC(石油醚/乙酸乙酯=1/3)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:2.5%)得纯品110mg,产率:28.3%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.55(1H,s),10.40(1H,s),8.78(1H,s),6.78(1H,d,J=8.4Hz),6.58(1H,d,J=2.4Hz),6.51(1H,dd,J=8.4,2.4Hz),4.04(1H,d,J=7.8Hz),3.84(2H,t,J=6.6Hz),3.03-3.14(2H,m),2.94(1H,q),2.45(1H,d,J=16.2Hz),1.62-1.72(4H,m),0.97(3H,t,J=7.2Hz),0.95(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.04,147.27,146.11,135.78,117.49,114.47,100.00,70.50,38.83,32.86,31.96,22.89,22.62,13.65,10.88;
MS(ESI+)m/z 390.1[M+H]+.
实施例28:
2-丙巯基-5-(4-溴苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-26)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-溴苯甲醛(185mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约2.5小时,TLC(石油醚/乙酸乙酯=1/3)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:65%)得纯品135mg,产率:34.4%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.63(1H,s),10.48(1H,s),7.47(2H,dt,J=8.4,1.8Hz),7.11(2H,dt,J=8.4,1.8Hz),4.18(1H,d,J=7.8Hz),3.04-3.14(2H,m),3.02(1H,q),2.50(1H,d,J=16.2Hz),1.62-1.69(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.74,142.63,131.91×2,129.28×2,120.15,38.35,33.11,31.99,22.87,13.65;
MS(ESI+)m/z 394.0[M+H]+.
实施例29:
2-丙巯基-5-(4-氟苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-27)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-氟苯甲醛(124mg,1.0mmol)溶于约5mL的乙二醇中,油浴180℃下加热反应约2.5小时,TLC(石油醚/乙酸乙酯=1/3)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:65%)得纯品125mg,产率:37.5%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.59(1H,s),10.48(1H,s),7.17-7.21(2H,m),7.08-7.12(2H,m),4.20(1H,d,J=7.8Hz),3.04-3.14(2H,m),3.02(1H,q),2.51(1H,d,J=16.8Hz),1.63-1.69(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.84,160.66,139.29,(128.85,128.80,JC-F=7.95Hz)×2,(115.80,115.66,JC-F=2.10Hz)×2,38.61,32.85,31.98,22.86,13.64;
MS(ESI+)m/z 334.1[M+H]+.
实施例30:
2-丙巯基-5-(2-羟基-4-丙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-29)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及2-羟基-4-丙氧基苯甲醛(152mg,1.0mmol)溶于约5mL的乙二醇中,油浴185℃下加热反应约5小时,TLC(石油醚/乙酸乙酯=1/3)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:2%)得纯品120mg,产率:30.8%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.48(1H,s),10.36(1H,s),9.96(1H,s),6.53(1H,d,J=8.4Hz),6.37(1H,d,J=1.8Hz),6.23(1H,dd,J=8.4,1.8Hz),4.28(1H,d,J=7.8Hz),3.79(2H,t,J=6.6Hz),3.04-3.14(2H,m),2.88(1H,q),2.46(1H,d,J=16.2Hz),1.63-1.70(4H,m),0.98(3H,t,J=7.2Hz),0.93(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.29,158.90,105.49,105.15,103.27,102.97,102.12,69.22,37.57,31.98,27.93,22.91,22.49,13.66,10.86;
MS(ESI+)m/z 390.1[M+H]+.
实施例31:
2-丙巯基-5-(4-苄氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-31)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-苄氧基苯甲醛(212mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约2.5小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:50%)得纯品70mg,产率:19.3%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.14(1H,s),10.07(1H,s),7.87(2H,dt,J=9.0,1.8Hz),7.47(2H,d,J=7.2Hz),7.41(2H,t,J=7.2Hz),7.35(1H,t,J=7.2Hz),7.21(2H,dt,J=9.0,1.8Hz),5.03(2H,s),4.09(1H,d,J=7.8Hz),2.95-3.01(2H,m),2.86(1H,q),2.45(1H,d,J=16.8Hz),1.59-1.66(2H,m),0.95(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.76,163.77,136.80,132.27×2,130.28,128.99×2,128.55,128.32×2,115.78×2,70.15,38.47,33.22,31.86,23.09,13.78;
MS(ESI+)m/z 422.1[M+H]+.
实施例32:
2-丙巯基-5-(4-苯氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-32)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-苯氧基苯甲醛(212mg,1.0mmol)溶于约5mL的乙二醇中,油浴190℃下加热反应约7小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:65%)得纯品120mg,产率:28.5%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.14(1H,s),10.07(1H,s),7.35(2H,t,J=8.4Hz),7.18(2H,d,J=8.4Hz),7.10(1H,t,J=7.6Hz),6.95(2H,d,J=7.8Hz),6.90(2H,d,J=8.4Hz),4.17(1H,d,J=7.8Hz),2.98-3.04(2H,m),2.93(1H,q),2.50(1H,d,J=16.8Hz),1.59-1.66(2H,m),0.95(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.03,157.41,130.43×2,128.65×2,123.59,119.22×2,118.67×2,114.17,100.00,38.47,33.22,31.86,23.09,13.78;
MS(ESI+)m/z 408.1[M+H]+.
实施例33:
2-丙巯基-5-(3,4,5-三羟基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-33)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3,4,5-三羟基苯甲醛(154mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约3小时,TLC(石油醚/乙酸乙酯=1/3)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:5%)得纯品50mg,产率:13.8%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.50(1H,s),10.43(1H,s),8.70(2H,s),7.89(1H,s),6.07(2H,s),3.94(1H,d,J=7.8Hz),3.04-3.17(2H,m),2.92(1H,q),2.42(1H,d,J=16.2Hz),1.63-1.70(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.07,146.42×2,133.00,132.20,105.71×2,38.97,32.97,31.96,22.86,13.64;
MS(ESI+)m/z 364.1[M+H]+.
实施例34:
2-丙巯基-5-(4-三氟甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-35)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-三氟甲氧基苯甲醛(190mg,1.0mmol)溶于约5mL的乙二醇中,油浴210℃下加热反应约6小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:60%)得纯品130mg,产率:32.6%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.58(1H,s),10.18(1H,s),7.28(2H,d,J=8.4Hz),7.25(2H,d,J=8.4Hz),4.20(1H,d,J=7.8Hz),2.99-3.06(2H,m),2.97(1H,q),2.50(1H,d,J=16.8Hz),1.60-1.66(2H,m),0.95(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.81,147.33,128.90×2,121.50×2,100.00,97.94,38.68,33.32,31.89,23.06,13.76;
MS(ESI+)m/z 400.1[M+H]+.
实施例35:
2-丙巯基-5-(喹啉-6-基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-36)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及6-醛基喹啉(157mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约2小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:2.3%)得纯品60mg,产率:16.4%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.59(1H,s),10.60(1H,s),8.84(1H,dd,J=4.2,1.2Hz),8.31(1H,d,J=7.8Hz),7.97(1H,d,J=8.4Hz),7.65(1H,dd,J=3.0,1.2Hz),7.62(1H,s),7.47-7.50(1H,q),4.41(1H,d,J=7.8Hz),3.12-3.19(2H,m),3.09(1H,q),2.66(1H,d,J=16.8Hz),1.65-1.72(2H,m),0.98(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.80,150.71,147.38,141.16,136.33,129.98,129.64,128.20,124.89,122.09,38.46,33.62,32.03,22.83,13.65;
MS(ESI+)m/z 367.1[M+H]+.
实施例36:
2-丙巯基-5-(4-甲基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-37)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-甲基苯甲醛(120mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约6小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:60%)得纯品70mg,产率:19.3%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.44(1H,s),10.19(1H,s),7.06(2H,d,J=8.4Hz),7.03(2H,d,J=7.8Hz),4.13(1H,d,J=7.2Hz),2.99-3.08(2H,m),2.94(1H,q),2.47(1H,d,J=16.2Hz),1.62-1.66(2H,m),0.96(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.03,135.91,129.42×2,126.90×2,38.89,33.31,31.90,23.00,21.02,13.72;
MS(ESI+)m/z 330.1[M+H]+.
实施例37:
2-丙巯基-5-(4-三氟甲基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-38)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-三氟甲基苯甲醛(174mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约6小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(石油醚/乙酸乙酯:60%)得纯品104mg,产率:27.2%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.63(1H,s),10.62(1H,s),7.66(2H,d,J=8.4Hz),7.38(2H,d,J=8.4Hz),4.30(1H,d,J=7.8Hz),3.09-3.16(2H,m),3.08(1H,q),2.55(1H,d,J=16.2Hz),1.64-1.70(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.63,147.86,127.87×2,126.07,38.17,33.51,32.00,22.81,13.62;
MS(ESI+)m/z 384.1[M+H]+.
实施例38:
2-丙巯基-5-(4-乙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-39)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-乙氧基苯甲醛(150mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约6小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:2%)得纯品50mg,产率:13.9%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.54(1H,s),10.49(1H,s),7.04(2H,d,J=8.4Hz),6.82(2H,d,J=7.8Hz),4.13(1H,d,J=7.2Hz),3.96(2H,q),3.06-3.15(2H,m),2.99(1H,q),2.50(1H,d,J=16.2Hz),1.63-1.72(2H,m),1.29(3H,t,J=6.6Hz),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.04,157.78,134.73,127.93×2,114.95×2,63.41,38.71,32.64,31.99,22.84,15.11,13.62;
MS(ESI+)m/z 360.1[M+H]+.
实施例39:
2-丙巯基-5-(4-甲氧基-3-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-40)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-甲氧基-3-硝基苯甲醛(181mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约5小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:1.5%)得纯品70mg,产率:17.9%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.62(1H,s),10.60(1H,s),7.65(1H,d,J=2.4Hz),7.42(1H,dd,J=8.4,1.8Hz),7.30(1H,d,J=8.4Hz),4.248(1H,d,J=7.8Hz),3.88(3H,s),3.05-3.16(2H,m),3.05(1H,q),2.56(1H,d,J=16.8Hz),1.63-1.70(2H,m),0.97(3H,t,J=7.8Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.66,151.34,139.56,135.40,132.83,123.29,115.22,57.16,38.18,32.40,32.02,22.81,13.62;
MS(ESI+)m/z 391.1[M+H]+.
实施例40:
2-丙巯基-5-(4-甲氧基-2-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-41)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-甲氧基-2-硝基苯甲醛(181mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约2小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:1.3%)得纯品50mg,产率:12.8%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.60(1H,s),10.70(1H,s),7.49(1H,d,J=2.4Hz),7.21(1H,dd,J=8.4,2.4Hz),7.02(1H,d,J=8.4Hz),4.48(1H,d,J=8.4Hz),3.81(3H,s),3.20(1H,q),3.07-3.17(2H,m),2.43(1H,d,J=16.8Hz),1.65-1.72(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.14,158.82,149.67,129.35,128.74,120.50,110.06,56.40,38.34,32.04,29.24,22.82,13.64;
MS(ESI+)m/z 391.1[M+H]+.
实施例41:
2-丙巯基-5-(3-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-47)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3-甲氧基苯甲醛(136mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约4小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:1.5%)得纯品100mg,产率:29.0%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.57(1H,s),10.51(1H,s),7.19(1H,t,J=8.4Hz),6.78(1H,dd,J=8.4,1.8Hz),6.73(1H,t,J=1.8Hz),6.70(1H,d,J=7.8Hz),4.17(1H,d,J=7.8Hz),3.70(3H,s),3.06-3.15(2H,m),3.02(1H,q),2.52(1H,d,J=16.8Hz),1.63-1.70(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.96,159.89,144.62,130.16,118.89,113.32,112.09,55.41,38.45,33.45,32.00,22.83,13.61;
MS(ESI+)m/z 346.1[M+H]+.
实施例42:2-丙巯基-5-(2-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-48)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及2-甲氧基苯甲醛(136mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约5小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:1.3%)得纯品70mg,产率:20.3%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.53(1H,s),10.45(1H,s),7.21(1H,td,J=7.8,1.8Hz),7.00(1H,d,J=8.4Hz),6.81(1H,t,J=7.8Hz),6.72(1H,d,J=7.2Hz),4.41(1H,d,J=8.4Hz),3.83(3H,s),3.08-3.18(2H,m),2.95(1H,q),2.39(d,J=16.8Hz),1.65-1.72(2H,m),0.99(3H,t,J=7.8Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.86,157.05,129.65,128.55,126.87,120.66,111.59,55.76,37.54,32.01,28.62,22.86,13.65;
MS(ESI+)m/z 346.1[M+H]+.
实施例43:
2-丙巯基-5-(3-羟基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-9-49)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3-羟基苯甲醛(122mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约5小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:3%)得纯品70mg,产率:22.4%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.57(1H,s),10.51(1H,s),9.31(1H,s),7.06(1H,t,J=7.8Hz),6.60(1H,d,J=7.8Hz),6.58(1H,dd,J=7.8,2.4Hz),6.53(1H,t,J=2.4Hz),4.10(1H,d,J=7.8Hz),3.06-3.17(2H,m),3.00(1H,q),2.48(1H,d,J=16.8Hz),1.63-1.70(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.96,157.94,144.46,130.03,117.67,114.09,113.72,38.61,33.43,31.98,22.85,13.63;
MS(ESI+)m/z 332.1[M+H]+.
实施例44:
2-丙巯基-5-(3-氰基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-10-02)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及3-氰基苯甲醛(131mg,1.0mmol)溶于约5mL的乙二醇中,油浴210℃下加热反应约2小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:2.0%)得纯品40mg,产率:11.8%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.62(1H,s),10.61(1H,s),7.70(1H,d,J=7.2Hz),7.62(1H,s),7.52(1H,t,J=7.2Hz),7.48(1H,d,J=7.8Hz),4.28(1H,d,J=7.8Hz),3.10-3.17(2H,m),3.07(1H,q),2.58(1H,d,J=16.2Hz),1.64-1.70(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.58,144.63,131.92,131.13,130.78,130.47,119.22,112.04,38.11,33.24,32.04,22.80,13.63;
MS(ESI+)m/z 341.1[M+H]+.
实施例45:
2-丙巯基-5-(2-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-10-03)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及2-硝基苯甲醛(151mg,1.0mmol)溶于约5mL的乙二醇中,油浴200℃下加热反应约3小时,TLC(石油醚/乙酸乙酯=1/2)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:1.5%)得纯品100mg,产率:27.8%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.61(1H,s),10.73(1H,s),7.95(1H,d,J=8.4Hz),7.63(1H,d,J=7.2Hz),7.50(1H,t,J=7.2Hz),7.15(1H,d,J=7.2Hz),4.58(1H,d,J=8.4Hz),3.25(1H,q),3.08-3.18(2H,m),2.47(1H,d,J=16.8Hz),1.67-1.71(2H,m),0.99(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.02,149.09,131.92,137.14,134.38,128.88,128.38,125.31,38.11,32.05,29.84,22.81,13.65;
MS(ESI+)m/z 361.1[M+H]+.
实施例46:
2-丙巯基-5-(4-羟基-3-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-10-04)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-羟基-3硝基苯甲醛(167mg,1.0mmol)溶于约5mL的乙二醇中,油浴210℃下加热反应约3小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:2.2%)得纯品60mg,产率:16.0%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.61(1H,s),10.85(1H,s),10.59(1H,s),7.64(1H,d,J=2.4Hz),7.35(1H,dd,J=8.4,2.4Hz),7.07(1H,d,J=8.4Hz),4.20(1H,d,J=7.8Hz),3.06-3.16(2H,m),3.03(1H,q),2.55(1H,d,J=16.2Hz),1.63-1.70(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.71,151.45,136.92,134.13,134.04,123.04,120.03,38.16,32.35,32.02,22.81,13.62;
MS(ESI+)m/z 377.1[M+H]+.
实施例47:
2-丙巯基-5-苯基-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-10-05)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及苯甲醛(106mg,1.0mmol)溶于约5mL的乙二醇中,油浴170℃下加热反应约2小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:2.5%)得纯品80mg,产率:25.4%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.58(1H,s),10.53(1H,s),7.27-7.33(2H,m),7.18-7.21(1H,m),7.10-7.16(2H,m),4.20(1H,d,J=6.0Hz),3.10-3.16(2H,m),3.05(1H,q),2.53(1H,d,J=16.2Hz),1.65-1.71(2H,m),0.97(3H,t,J=6.0Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.94,143.04,129.09×2,127.17,126.93×2,38.58,33.49,31.99,22.84,13.83;
MS(ESI+)m/z 316.1[M+H]+.
实施例48:
2-丙巯基-5-(喹啉-4-基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-10-06)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及4-喹啉甲醛(157mg,1.0mmol)溶于约5mL的乙二醇中,油浴170℃下加热反应约2小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:3.5%)得纯品80mg,产率:21.9%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.64(1H,s),10.68(1H,s),8.75(1H,d,J=4.8Hz),8.34(1H,d,J=8.4Hz),8.07(1H,d,J=8.4Hz),7.81(1H,td,J=7.2,0.6Hz),7.71(1H,td,J=7.2,0.6Hz),6.96(1H,d,J=4.8Hz),5.06(1H,d,J=9.0Hz),3.30(1H,q),3.12-3.22(2H,m),2.46(1H,d,J=16.8Hz),1.69-1.76(2H,m),1.01(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.07,150.97,148.75,147.64,130.52,129.83,127.42,126.13,124.03,118.21,38.20,32.09,29.68,22.85,13.67;
MS(ESI+)m/z 367.1[M+H]+.
实施例49:
2-丙巯基-5-(喹啉-5-基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-10-07)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol),2,2-二甲基-1,3-二氧六环-4,6-二酮(173mg,1.2mmol)以及5-喹啉甲醛(157mg,1.0mmol)溶于约5mL的乙二醇中,油浴170℃下加热反应约0.5小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,有絮状沉淀生成,过滤,得到粗产物。后经flash柱分离纯化(二氯甲烷/甲醇:4.0%)得纯品154mg,产率:42.1%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.60(1H,s),10.64(1H,s),8.95(1H,dd,J=4.2,1.8Hz),8.75(1H,d,J=8.4Hz),7.91(1H,d,J=8.4Hz),7.63(1H,d,J=7.2Hz),7.62(1H,dd,J=8.4,3.6Hz),7.06(1H,d,J=7.2Hz),5.05(1H,d,J=8.4Hz),3.24(1H,q),3.12-3.21(2H,m),2.42(1H,d,J=16.8Hz),1.69-1.75(2H,m),1.01(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)170.36,150.71,149.10,138.91,132.33,129.56,128.91,125.94,123.41,121.97,38.97,32.07,29.50,22.86,13.68;
MS(ESI+)m/z 367.1[M+H]+.
实施例50:
2-丙巯基-5-(4-甲氧基苯基)-吡啶骈[2,3-d]嘧啶-4(3H)-酮(LSL-11-02)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol)和3-二甲基氨基-1-(4-甲氧基苯基)-2-丙烯-1-酮(205mg,1.0mmol)溶于约10毫升的冰醋酸中,油浴下加热回流约2小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液倒入适量冰水中,溶液呈悬浊液,乙酸乙酯萃取三次,有机相合并后分别用清水和饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩后经flash柱分离纯化(石油醚/乙酸乙酯:25%)得纯品120mg,产率:37%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.75(1H,s),8.39(1H,d,J=7.8Hz),8.18(2H,d,J=8.4Hz),7.95(1H,d,J=8.4Hz),7.10(2H,d,J=9.0Hz),3.85(3H,s),3.28(2H,t,J=6.6Hz),1.72-1.79(2H,m),1.03(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)162.04,161.73,161.71,160.64,158.55,136.94,130.49,129.55×2,117.73,114.79×2,113.61,55.84,32.14,22.42,13.67;
MS(ESI+)m/z 328.1[M+H]+.
实施例51:
2-丙巯基-5-(喹啉-6-基)-吡啶骈[2,3-d]嘧啶-4(3H)-酮(LSL-11-08)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol)和3-二甲基氨基-1-(喹啉-6-基)-2-丙烯-1-酮(171mg,1.0mmol)溶于约10毫升的冰醋酸中,油浴下加热回流约2小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液浓缩后倒入适量冰水中,有黄色固体生成,过滤得粗产物,后经flash柱分离纯化(二氯甲烷/甲醇:3.0%)得纯品130mg,产率:37.4%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.85(1H,s),8.99(1H,dd,J=4.2,1.8Hz),8.87(1H,d,J=1.8Hz),8.57-8.61(2H,m),8.53(1H,d,J=8.4Hz),8.20(1H,d,J=8.4Hz),8.18(1H,d,J=9.0Hz),7.63(1H,q),3.31(2H,t,J=6.6Hz),1.75-1.81(2H,m),1.05(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)152.14,148.80,137.71,137.48,135.98,129.93,128.72,128.36,128.21,122.06,118.91,32.20,22.40,13.68;
MS(ESI+)m/z 349.1[M+H]+.
实施例52:
2-丙巯基-5-(4-甲氧基苯基)-吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮(LSL-11-09)的制备
将2-丙巯基-6-氨基嘧啶-4(3H)-酮(185mg,1.0mmol)和乙酸酐(204mg,2.0mmol)溶于约5毫升的甲苯中。室温下,搅拌约5分钟后,对甲苯磺酸一水合物(190mg,1.0mmol),对甲氧基肉桂酸乙酯(1.03g,5.0mmol),过硫酸钠(714mg,3.0mmol)以及醋酸钯(22.45mg,0.1mmol)一次性加入到上述反应液中,油浴下加热回流36小时,TLC(石油醚/乙酸乙酯=1/1)检测原料点消失。将反应液过滤,加入适量冰水中,乙酸乙酯萃取三次,有机相合并后分别用清水和饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩后经flash柱分离纯化(石油醚/乙酸乙酯:25%)得纯品50mg,产率:14.6%。
1HNMR(DMSO-d6,600MHz)δ(ppm)12.70(1H,s),10.39(1H,s),7.06(2H,d,J=9.0Hz),6.83(2H,d,J=9.0Hz),4.13(1H,s),3.69(3H,s),3.03-3.12(2H,m),1.62-1.69(2H,m),0.97(3H,t,J=7.2Hz);
13CNMR(DMSO-d6,150MHz)δ(ppm)171.03,158.46,133.5,127.96×2,115.1,114.41×2,100.00,55.51,31.96,22.90,13.65;
MS(ESI+)m/z 344.1[M+H]+.
实验例1生物活性测试:
抑菌实验
菌株MTB H37Rv(ATCC 27294)由首都医科大学附属北京胸科医院&北京市结核病胸部肿瘤研究所细菌免疫室保存。培养分枝杆菌的培养基7H9、7H10及其添加剂OADC购自BD。
采用接种环蘸取保存于-80℃的MTB H37Rv于7H10固体培养基(含10%OADC)划线,37℃静置培养直至长出单菌落;挑取单菌落接种于5mL 7H9培养基(含10%OADC和0.05%Tween80),静置培养10~14d至对数后期。
采用二倍稀释法在96孔板中测定化合物对Mtb H37Rv的最低抑制浓度(minimuminhibitory concentrations,MIC)。第1排和第8排加入200μL 7H9培养基以防止干燥。对数期菌株接种至新鲜7H9培养基至终浓度OD600为0.005。测试样品浓度最高为64μg/mL,最低为0.125μg/mL(3个平行)。溶剂DMSO为阴性对照,INH(异烟肼)为阳性对照。将96孔板置于培养箱37℃静置培养10d左右,观察菌株生长情况,以培养液光吸收不见明显变化的药物浓度为最低抑菌浓度。
表1.部分化合物对结核分枝杆菌的抑制活性数据MIC(单位:μg/mL)
由表1数据可知,本发明化合物具有很好的抗结核活性,如化合物LSL-7-30,LSL-9-2,LSL-9-21,LSL-9-29,LSL-9-36,LSL-11-02,LSL-11-08以及LSL-11-09,尤其是LSL-9-21和LSL-9-36,抗结核杆菌的MIC和阳性对照药INH相当。
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (4)
1.一种如式I所示的化合物或其药学上可接受的盐的用途,其特征在于,用于:
(1)制备预防和/或治疗由结核杆菌感染引起的疾病的药物;或
(2)制备抑制结核杆菌生长的药物;
式中,R1为甲基或乙烯基;
m为0,1或2;
X为硫;
R2为氢;
R3为4-丙氧基苯基、3-羟基-4-甲氧基苯基、3,4-二羟基苯基、3,4,5-三甲氧基苯基、3,4-二甲氧基苯基、4-硝基苯基、4-羟基苯基、3-硝基苯基、4-甲氧基苯基、4-溴苯基、4-氟苯基、4-三氟甲氧基苯基、4-甲基苯基、4-三氟甲基苯基、4-乙氧基苯基、3-甲氧基苯基、2-甲氧基苯基、3-羟基苯基、2-硝基苯基或苯基。
2.如权利要求1所述的用途,其特征在于,式I所示的化合物中各手性碳的构型独立地为R构型或S构型。
3.如权利要求1所述的用途,其特征在于,所述药学上可接受的盐为盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、柠檬酸盐、加磺酸盐、三氟乙酸盐、乙酸盐、草酸盐、丁二酸盐、苹果酸盐、甲苯磺酸盐、酒石酸盐、富马酸盐、谷氨酸盐、葡萄醛酸盐、乳酸盐、戊二酸盐、精氨酸盐或马来酸盐。
4.如权利要求1所述的用途,其特征在于,所述式I所示的化合物为:
2-丙巯基-5-(4-丙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3-羟基-4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3,4-二羟基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-甲巯基-5-(3,4,5-三甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3,4,5-三甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3,4-二甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-甲巯基-5-(4-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-羟基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-甲巯基-5-(3-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-烯丙巯基-5-(4-丙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-烯丙巯基-5-(3-羟基-4-氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-烯丙巯基-5-(3,4-二甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-溴苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-氟苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-甲基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-三氟甲基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(4-乙氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(2-甲氧基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(3-羟基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-(2-硝基苯基)-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮;
2-丙巯基-5-苯基-5,6-二氢吡啶骈[2,3-d]嘧啶-4,7(3H,8H)-二酮。
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