CN101472922A - 新型苯并噻嗪酮衍生物及其作为抗菌剂的应用 - Google Patents
新型苯并噻嗪酮衍生物及其作为抗菌剂的应用 Download PDFInfo
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- CN101472922A CN101472922A CNA2006800551120A CN200680055112A CN101472922A CN 101472922 A CN101472922 A CN 101472922A CN A2006800551120 A CNA2006800551120 A CN A2006800551120A CN 200680055112 A CN200680055112 A CN 200680055112A CN 101472922 A CN101472922 A CN 101472922A
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- benzothiazine
- azaspiro
- oxa
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- trifluoromethyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
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- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
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- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
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- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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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
- A61P31/08—Antibacterial agents for leprosy
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
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Abstract
本发明涉及新的式(I)苯并噻嗪衍生物及其作为抗菌剂在由细菌引起的感染性疾病,特别是由分枝杆菌引起的肺结核(TB)及麻风病中的应用,其中R1和R2相互独立地为NO2、CN、CONR7R8、COOR9、CHO、卤素、NR7R8、SO2NR7R8、SR9、OCF3、单氟甲基、二氟甲基或三氟甲基;R3和R4相互独立地为H、具有1-7个链成员的饱和或不饱和的、直链或支链的脂肪族基团、具有3-6个碳原子的环烷基、苄基、SR9、OR9;R5和R6相互独立地为具有1-8个链成员的饱和或不饱和的、卤代或非卤代的、直链或支链的脂肪族基团、具有3-6个碳原子的环烷基、苯基,或R5和R6一起代表二价基团-(CR9 2)m-,或R5和R6一起代表二价基团式(II)或式(III),其中m是1-4,或代表具有杂原子N、S、O且被(R10)x取代的饱和或不饱和的单或多杂环二价基团,其中x是1-4。
Description
技术领域
本发明涉及新的苯并噻嗪衍生物及其作为抗菌剂在由细菌引起的哺乳动物(人和动物)的感染性疾病,特别是如由分枝杆菌(mycobacteria)引起的肺结核(TB)及麻风病的疾病中的应用。
背景技术
例如,AR 24 25 67 A1、AU 37 04 400 A1、CA 13 22 551 C1或EP 0 245901 B1中公开了噻嗪酮、其衍生物及其作为抗菌剂的应用,特别是抗分枝杆菌(TB)的应用。
众所周知,由对有效治疗产生抗性的分枝杆菌所引起的肺结核感染在世界范围内呈直线增长(B.R.Bloom,J.L.Murray,tuberculosis:commentary ona reemergent killer.Science 257,1992,1055-1064)。极其危险的是多药物抗性(MDR)分枝杆菌的发展。这些分枝杆菌不但至少对两种最具活性的肺结核药异烟肼和利福平具有抗性,而且也对链霉素、吡嗪酰胺(pyranzinamid)和乙胺丁醇具有抗性。在一些国家,MDR-TB的比例已经超过20%。通常,包括增长的TB疾病的数目,其每年在世界范围内导致约3,000,000人死亡。
对于所述疾病如TB或麻风病的治疗,迫切需要具有新的作用机制,特别是可以克服药物抗性和克服现有药物的已知的显著副作用的新型药物。
发明内容
本发明的目的在于制备作为潜在的新型肺结核药的具有抗分枝杆菌活性的新型化合物,以克服抗药性和耐药性的问题。
具体实施方式
通过提供式I的化合物来解决本发明目的
其中R1和R2相互独立地为NO2、CN、CONR7R8、COOR9、CHO、卤素、NR7R8、SO2NR7R8、SR9、OCF3、单氟甲基、二氟甲基或三氟甲基;
R3和R4相互独立地为H、具有1-7个链成员的饱和或不饱和的、直链或支链的脂肪族基团、具有3-6个碳原子的环烷基、苄基、SR9、OR9;
R5和R6相互独立地为具有1-8个链成员的饱和或不饱和的、卤代或非卤代的、直链或支链的脂肪族基团、具有3-6个碳原子的环烷基、苯基,或R5和R6一起代表二价基团-(CR9 2)m-,或R5和R6一起代表如下二价基团:
其中m是1-4,或代表具有杂原子N、S、O且被(R10)x取代的饱和或不饱和的单或多杂环二价基团,其中x是1-4;
R7、R8和R9相互独立地为H或具有1-7个链成员的饱和或不饱和的、卤代或非卤代的、直链或支链的脂肪族基团、单氟甲基、二氟甲基或三氟甲基、卤素、苯基,或R3和R4一起代表二价基团-(CH2)n-,其中n是2-7;
R10是H或具有1-7个链成员的饱和或不饱和的、卤代或非卤代的、直链或支链的脂肪族基团、NO2、NR7R8、CN、CONR7R8、COOR9、CHO、卤素、SO2NR7R8、SR9、OR9、OCF3、单氟甲基、二氟甲基或三氟甲基、苄基或苯基。
在优选的实施方案中,本发明涉及选自下组的式(I)的化合物:
2-(4-R5-4-R6-哌啶-1-基)-8-硝基-6-三氟甲基-1,3-苯并噻嗪-4-酮、
6-氰基-2-(4-R5-4-R6-哌啶-1-基)-8-硝基-1,3-苯并噻嗪-4-酮、
6-酰胺基-2-(4-R5-4-R6-哌啶-1-基)-8-硝基-1,3-苯并噻嗪-4-酮、
2-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-R1-6-R2-1,3-苯并噻嗪-4-酮、
2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-R1-6-R2-1,3-苯并噻嗪-4-酮、
2-[(2R)-2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基]-8-R1-6-R2-1,3-苯并噻嗪-4-酮、
2-[(2S)-2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基]-8-R1-6-R2-1,3-苯并噻嗪-4-酮、
2-[(2,3-二甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-R1-6-R2-1,3-苯并噻嗪-4-酮、
2-[(1,5-二氧杂-9-氮杂螺[5.5]十一-9-基)-8-R1-6-R2-1,3-苯并噻嗪-4-酮,其中R1、R2、R5和R6具有上述含义。
更具体地,本发明涉及选自下组的至少一种化合物:
2-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-6,8-二硝基-1,3-苯并噻嗪-4-酮、
2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-6,8-二硝基-1,3-苯并噻嗪-4-酮、
2-(4,4-二乙氧基哌啶-1-基)-6,8-二硝基-1,3-苯并噻嗪-4-酮、
7-甲基-2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-6,8-二硝基-1,3-苯并噻嗪-4-酮、
2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-6-(三氟甲基)-1,3-苯并噻嗪-4-酮、
2-(2,3-二甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-6-(三氟甲基)-1,3-苯并噻嗪-4-酮、
2-(1,5-二氧杂-9-氮杂螺[5.5]十一烷-9-基)-8-硝基-6-(三氟甲基)-1,3-苯并噻嗪-4-酮、
2-(1,5-二氧杂-9-氮杂螺[5.5]十一烷-9-基)-8-硝基-4-氧代-1,3-苯并噻嗪-6-腈、
2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-4-氧代-1,3-苯并噻嗪-6-腈、
8-氨基-2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-4-氧代-1,3-苯并噻嗪-6-腈和
8-氨基-2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-6-(三氟甲基)-1,3-苯并噻嗪-4-酮。
对于目标化合物的合成,我们开发出使用二硫代氨基甲酸酯衍生物作为中间体合成1,3-苯并噻嗪-4-酮的新方法(方法A)。也可使用使用硫氰酸盐合成1,3-苯并噻嗪-4-酮的传统方法。两种方法都示于下面的示意图中。
出人意料地,特别是对于分枝杆菌,本发明的化合物表现出强抗菌活性,对于快速生长的分枝杆菌,其最小抑菌浓度(MIC)的范围是0.23pg/mL至>10μg/mL,通过传统方法测得对结核分枝杆菌(M.tuberculosis,包括多抗性株)的MIC为0.195-1.56μg/mL,通过Alamar Blue法测得对结核分枝杆菌H37Rv的MIC为0.030μg/mL。出人意料地,本发明的化合物仅对分枝杆菌表现出高选择性,这极大地降低了潜在的副作用。
在SOS显色试验中,本发明的化合物在5mg/mL下不具有致突变性。
在肺结核感染的小鼠模型中,本发明的化合物的体内治疗活性优于作为阳性对照的主要抗结核药异烟肼。100%的大鼠存活。对照动物到第33天全部死亡。
在口服高至2000mg/kg的剂量后,本发明的化合物(特别是化合物2,即实施方案中的实施例1)是无毒的,服药后动物在第一小时及接下来的24小时内对化合物耐受良好。在7天的观察中,化合物2没有改变大鼠的一般状态和行为,没有影响其运动和反射能力、活动和休息周期(active andcalm cycle)、修饰行为(grooming)、食物消耗,且没有动物死亡的情况。化合物2的LD50大于2000mg/kg。
因此,本发明的化合物可用于人类和动物体内的结核感染和其他分枝杆菌感染的治疗。
因此,本发明涉及包含式I化合物的药物组合物。
此外,本发明还涉及式I化合物在治疗哺乳动物体内细菌感染的方法中的应用。在所述方法中优选使用的式I化合物是以上具体列出的化合物。
通过在药学可接受的水介质、有机介质或水介质-有机介质中制备稀溶液或混悬剂来将本发明的化合物配制使用,用于通过静脉注射、皮下注射或肌肉注射进行局部给药或非消化道给药或鼻内给药;或用常规的赋形剂制成片剂、胶囊剂或水混悬剂进行口服给药或作为栓剂。
本化合物可以0.001-1000mg/kg体重的剂量使用。
随后的实验部分中的实施例用于说明本发明,而不应被认为是对本发明的限制。
本发明的化合物的结构通过合成方式、元素分析、核磁共振和/或质谱,以及X-射线分析法确定。
具体实施方式
原料
化学药品和溶剂购自Lancaster Synthesis(Lancashire,England)或Aldrich(Sigma-Aldrich Company,St-Louis,US),且未经额外纯化直接用于合成。根据PB法测定熔点并未经修正(Electrothermal 9001,GB)。如分析仅由元素符号表示,则分析结果在理论值的±0.3%之内(Carlo-Erba 5500,Italy)。NMR光谱用Varian Unity Plus 400(USA)测定。1H NMR位移用由TMS(δ)向低场(downfield)的ppm表示。使用Finnigan SSQ-700(USA)装置直接注射获得质谱。通过使用Silicagel 60 F254铝片(Merck Co,Germany)进行TLC来控制反应和产物的纯度。
实施例1
2-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-6-三氟甲基-1,3-苯并噻嗪-4-酮,(化合物1)
方法A
在-20℃下,向50mL搅拌的25%氨水溶液中滴加5g 2-氯-3-硝基-5-三氟甲基苯甲酰氯(D.E Welch,R.R.Baron,B.A.Burton,J.Med,Chem.12;2;1969;299-303)的乙腈(10mL)溶液。十分钟后加入50mL的乙酸乙酯。分离有机相,用水洗涤两次,用Na2SO4干燥,并用活性炭处理,过滤并真空浓缩。粗产物通过自乙醇中结晶纯化。2-氯-3-硝基-5-三氟甲基苯甲酰胺的产率为92%,熔点为195-197℃(甲醇)。
分析计算值C8H4ClF3N2O3:C,35.78;H,1.50;N,10.43
实测值:C,36.01;H,1.53;N,10.39
将0.5g的2,2-氯-3-硝基-5-(三氟甲基)苯甲酰胺溶于25mL乙醇,反应混合物用0.5g1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-二硫代羧酸钠盐二水合物处理(Z.Ge,R.Li,T.Cheng,Synth.Commun.,29,18,1999,3191-3196),在室温下贮存18小时。然后将其倒入50mL冷水中并过滤得到的黄色沉淀,用乙醇通过两次重结晶后得到纯的终产物。2-(氨基羰基)-6-硝基-4-三氟甲基苯基-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-二硫代羧酸盐为淡黄色结晶固体,产率为0.47g%,熔点为138-140℃。
分析计算值:C11H12N4O2S2:C,42.57;H,3.57;N,9.31;S,14.21
实测值:C,42.61;H,3.67;N,9.22;S,14.30
将0.4g的2-(氨基羰基)-6-硝基-4-(三氟甲基苯基)-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-二硫代羧酸盐溶于25mL乙醇,反应混合物用0.32gNa2HPO4·12H2O处理并回流6小时。然后将其冷却并过滤得到的淡黄色沉淀,用30mL甲醇洗涤。用乙醇经过两次重结晶得到纯的终产物。2-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-6-三氟甲基)-1,3-苯并噻嗪-4-酮为淡黄色结晶固体,产率为0.47g%,熔点为211-212℃。
Rf(己烷-丙酮;2/1)-0.35
MS m/z 417(M+)。
1H NMR(DMSO-d6)δ 8.83和8.77(两个1H,两个s,2CH),3.80(8H,宽s,N(CH2CH2)2C),2.02(4H,宽s,OCH2CH2O)ppm.
分析计算值C16H14F3N3O5S:C,46.04;H,3.38;N,10.07;S,7.68
实测值:C,45.94;H,3.37;N,10.09;S,7.76
方法B
详细方法与J.Imrich,P Kristian,Coll.Czech.Chem.Commun.,47,1982,3268-3282;D.Koscik,P.Kristian,J.Gonda,E.Dandarova,Coll.Czech.Chem.Commun.,48,1983,3315-3328;D.Koscik,P.Kristian,O.Forgac,Coll.Czech.Chem.Commun.,48,1983,3427-3432;T.H.Cronin,H.-J.E.Hess,Pat.US 3522247中的描述相同。2-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-6-三氟甲基)-1,3-苯并噻嗪-4-酮的产率为0.21%,所述化合物的光谱数据与通过方法A合成的化合物相同。
实施例2
2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-6-(三氟甲基)-1,3-苯并噻嗪-4-酮,(化合物2)
按照实施例1的方法。淡黄色结晶固体。产率为54%。熔点为192-3℃。
Rf(己烷-丙酮;2/1)-0.30。
MS m/z 431(M+)。
1H NMR(DMSO-d6)δ 8.81和8.77(两个1H,两个s,2CH),4.24(1H,m,CH),4.11(1H,m,CH),4.06(4H,宽s,N(CH2)2),3,47(1H,t,CH),3.27(1H,s,CH),1.80(4H,宽d,C(CH2)2),1.23(3H,d,CH3)ppm。
分析计算值C17H16N3O5S:C,47.33;H,3.74;N,9.74;S,7.43
实测值:C,47.36;H,3.80;N,9.87;S,7.51
实施例3
2-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-6,8-二硝基-1,3-苯并噻嗪-4-酮,(化合物4)
用2-羟基-3,5-二硝基苯甲酸作为原料,按照实施例1的方法。淡黄色结晶固体。产率为43%。熔点为271-3℃(EtOH/DMF)。
Rf(己烷-丙酮;2/1)-0.25。
MS m/z 394(M+)。
1H NMR(DMSO-d6)δ 9.15和9.12(两个1H,两个s,2CH),3.86(8H,宽s,N(CH2CH2)2C),2.97(4H,宽s,OCH2CH2O)ppm。
分析计算值C15H14N4O7S:C,45.68;H,3.58;N,14.21;S,8.13
实测值:C,45.34;H,3.56;N,14.30;S,7.98
实施例4
2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸基)-6,8-二硝基-1,3-苯并噻嗪-4-酮,(化合物4)
用2-羟基-3,5-二硝基苯甲酸作为原料,按照实施例1的方法。黄色结晶固体。产率为57%。熔点为139-142℃(EtOH/DMF)。
Rf(己烷-丙酮;2/1)-0.50。
MS m/z 408(M+)。
1H NMR(DMSO-d6)δ 9.08和9.11(两个1H,两个s,2CH),4.23(1H,m,CH),4.10(1H,m,CH),4.06(4H,宽s,N(CH2)2),3.43(1H,t,CH),3.27(1H,s,CH),1.80(4H,宽d,C(CH2)2),1.20(3H,d,CH3)ppm。
分析计算值C16H16N4O7S:C,47.06;H,3.95;N,13.72;S,7.85
实测值:C,46.87;H,3.91;N,13.57;S,7.83
实施例5
2-(2,3-二甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-6-(三氟甲基)-1,3-苯并噻嗪-4-酮,(化合物5)
用2-羟基-3-硝基-5-三氟甲基苯甲酸作为原料,按照实施例1的方法。淡黄色结晶固体。产率为58%。熔点为205-207℃(EtOH/DMF)。
Rf(己烷-丙酮;2/1)-0.55。
MS m/z 44522(M+)。
1H NMR(DMSO-d6)δ 8.82和8.77(两个1H,两个s,2CH),3.86(4H,宽c,N(CH2)2),3,45-3.53(2H,m,2CH),2.41(4H,宽d,C(CH2)2),1.13-1.17(6H,m,2CH3)ppm。
分析计算值C18H18F3N3O5S:C,48.54;H,4.07;N,9.43;S,7.20
实测值:C,48.66;H,4.12;N,9.32;S,7.46
实施例6
2-(4,4-二乙氧基哌啶-1-基)-6,8-二硝基-1,3-苯并噻嗪-4-酮,(化合物6)
用2-羟基-3,5-二硝基苯甲酸作为原料,按照实施例1的方法。黄色结晶固体。产率为32%。熔点为179-181℃(i-PrOH)。
Rf(己烷-丙酮;2/1)-0.30。
MS m/z 424(M+)。
1H NMR(DMSO-d6)δ 9.08和9.11(两个1H,两个s,2CH),3.60-3.67(4H,m,N(CH2)2)2.11-2.08(4H,m,C(CH2)2),3.47和3.57(两个2H,q,2OCH2),1.16(6H,t,2CH3),ppm。
分析计算值C17H20N4O7S:C,48.11;H,4.75;N,13.20;S,7.56
实测值:C,48.12;H,4.73;N,13.41;S,7.67
实施例7
2-(7,12-二氧杂-3-氮杂螺[5.6]十二烷-3-基)-6,8-二硝基-1,3-苯并噻嗪-4-酮,(化合物7)
用2-羟基-3,5-二硝基苯甲酸作为原料,按照实施例1的方法。黄色结晶固体。产率为51%。熔点为193-195℃(i-PrOH/DMF)。
Rf(己烷-丙酮;2/1)-0.45。
MS m/z 422(M+)。
1H NMR(DMSO-d6)δ 8.97和9.16(两个1H,两个s,2CH),3.57-3.74(8H,m,4CH2),1.93-2.35(8H,m,4CH2)ppm。
分析计算值C17H18N4O7S:C,48.34;H,4.30;N,13.26;S,7.56实测值:C,48.21;H,4.43;N,13.30;S,7.66
实施例8
2-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-7-甲基-6,8-二硝基-1,3-苯并噻嗪-4-酮,(化合物8)
用2-羟基-4-甲基-3,5-二硝基苯甲酸作为原料,按照实施例1的方法。黄色结晶固体。产率为51%。熔点为207-210℃(i-PrOH/DMF)。
Rf(己烷-丙酮;2/1)-0.30。
MS m/z 408(M+)。
1H NMR(DMSO-d6)δ 8.77(1H,s,CH),3.86(8H,宽s,N(CH2CH2)2C),2.97(4H,宽c,OCH2CH2O),2.79(3H,s,CH3)ppm。
分析计算值C16H16N4O7S:C,47.06;H,3.95;N,13.72;S,7.85
实测值:C,47.12;H,4.01;N,13.69;S,7.94
实施例9
2-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-4-氧代-1,3-苯并噻嗪-6-腈,(化合物9)
向搅拌的5g(19mmol)2-羟基-5-碘代苯甲酸的50mL DMF溶液中加入2.5g(22mmol)的少量干燥的CuCN(I)。将反应混合物回流5小时,加入100mL水和50mL乙酸乙酯。将其进行浓缩后,在良好通风条件下小心地加入盐酸至pH约为3。分离有机相,用水洗涤两次,用Na2SO4干燥,用活性炭处理,过滤并真空浓缩。粗产物通过从水中结晶纯化。5-氰基-2-羟基苯甲酸的产率为71%。按照实施例1的方法。产率为44%。熔点为217-220℃(EtOH/DMF)。
Rf(己烷-丙酮;2/1)-0.50。
MS m/z 374(M+)。
1H NMR(DMSO-d6)δ 8.74和8.67(两个1H,两个s,2CH),3.41(8H,宽s,N(CH2CH2)2C),2.93(4H,宽s,OCH2CH2O)ppm。
分析计算值C16H14N4O5S:C,51.33;H,3.77;N,14.97;S,8.57
实测值:C,51.30;H,3.84;N,14.89;S,8.62
实施例10
2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-4-氧代-1,3-苯并噻嗪-6-腈,(化合物10)
按照实施例9的方法。黄色结晶固体。产率为34%。熔点为251-253℃(EtOH/DMF)。
Rf(己烷-丙酮;2/1)-0.40。
MS m/z 388(M+)。
1H NMR(DMSO-d6)δ 8.73和8.61(两个1H,两个s,2CH),4.23(1H,m,CH),4.11(1H,m,CH),4.07(4H,宽s,N(CH2)2),3.51(1H,t,CH),3.27(1H,s,CH),1.81(4H,宽d,C(CH2)2),1.22(3H,d,CH3)ppm。
分析计算值C17H16N4O5S:C,52.57;H,4.15;N,14.43;S,8.26
实测值:C,52.42;H,4.08;N,14.50;S,8.27
实施例11
2-(1,5-二氧杂-9-氮杂螺[5.5]十一烷-9-基)-8-硝基-4-氧代-1,3-苯并噻嗪-6-腈,(化合物11)
按照实施例9的方法合成,黄色结晶固体。产率为40%。熔点为230-232℃(EtOH/DMF)。
Rf(己烷-丙酮;2/1)-0.15。
MS m/z 388(M+)。
1H NMR(DMSO-d6)δ 8.74和8.61(两个1H,两个s,2CH),3.29-3.65(6H,m,3CH2),2.38(4H,宽s,2CH2),1.82-1.93(4H,m,2CH2)ppm。
分析计算值C17H16N4O5S:C,52.57;H,4.15;N,14.43;S,8.26
实测值:C,52.52;H,4.11;N,14.59;S,8.13
实施例12
测定本发明化合物对分枝杆菌的体外抑制活性。
根据NCCLS准则[National Committee for Clinical Laboratory Standards:Methods for dilution antimicrobial susceptibility tests for bacteria that growaerobically;5th Ed.;Villanova,Ed.;Approved standard Document M7-A5.NCCLS,(2000)],通过在Mueller-Hinton肉汤(Difco)中的微肉汤稀释法测定最小抑菌浓度(MIC)来测定本化合物对耻垢分枝杆菌(MycobacteriumsmegmatisSG 978)、金色分枝杆菌(M.aureum)SB66、母牛分枝杆菌(M.vaccae)IMET 1010670和偶发分枝杆菌(M.fortuitum)B的抗菌活性。
通过如下测定最小抑菌浓度(MIC)和最小杀菌浓度(MBC)的方法测定抗结核分枝杆菌H37Rv的活性:
在Lowenstein-Jensen培养基上接种菌株,21天后,用生长的培养物制备(5×108微生物细胞/mL)的接种物混悬液。使用0.2mL该混悬液,接种包含含有相应浓度(100.0-0.195mg/mL)的所研究的化合物的2mL液体Shkolnikova培养基的管。在37℃下培养14天后,将包含液体培养基的试管在3000RPM下离心15分钟。弃去上清液后,将得到的沉淀物在0.8mL的0.9%无菌NaCl中再悬浮。取0.1mL混悬液制备涂片,随后通过Ziehl-Neelsen法染色。将剩余的沉淀物以0.2mL的体积接种至3个包含不含药物的固体Lowenstein-Jensen培养基的管中以测定最小杀菌浓度(MBC)。在37℃下培养21-28天后得到实验结果。对照用未经所研究药物处理的测试菌株进行试管培养。
完全抑制分枝杆菌在固体培养基上的生长的药物浓度被视为药物的最小杀菌浓度(MBC)。抑菌效果(MIC)的特点在于涂片上仅出现单个分枝杆菌,且与对照相比菌落数明显减少。
结果见表1和表2。
表1:通过最小抑菌浓度MIC[μg/mL]测定的式I中化合物的抗微生物活性
化合物 | 耻垢分枝杆菌 | 母牛分枝杆菌 | 偶发分枝杆菌 |
1 | 12.5ng/mL | 3.12ng/mL | 12.5ng/mL |
2 | 1.56ng/mL | 0.76pg/mL | 0.023pg/mL |
3 | 0.2μg/mL | 0.0015μg/mL | 0.006μg/mL |
4 | 0.2μg/mL | 0.003μg/mL | 0.003μg/mL |
5 | 6.25ng/mL | 0.078ng/mL | 0.078ng/mL |
6 | >10μg/mL | 0.04μg/mL | 0.08μg/mL |
7 | 0.78μg/mL | 0.003μg/mL | 0.003μg/mL |
8 | 0.4μg/mL | 0.025μg/mL | 0.025μg/mL |
9 | 0.05μg/mL | 3.12ng/mL | 25ng/mL |
10 | 25ng/mL | 3.12ng/mL | 12.5ng/mL |
11 | 0.05μg/mL | 6.25ng/mL | 25ng/mL |
表2:通过最小抑菌浓度(MIC)和最小杀菌浓度(MBC)来测定式(I)的化合物对结核分枝杆菌H37Rv和临床分离菌株6341和6374的抗微生物活性
实施例13
在小鼠TB模型中测定本发明的化合物对结核分枝杆菌的体内抑制活性。
为测定化疗的疗效,使用患有实验性血行播散型肺结核的BALB/c系鼠。实验用鼠获自Central Animal Nursery of the Russian Academy of MedicalSciences。在实验中使用通过检疫的、标准体重(20-25g)的鼠,并仅使用雄性鼠。通过静脉(尾静脉)注射5×106CFU(菌落形成单位)的0.5mL盐水溶液的结核分枝杆菌H37Rv混悬液,对鼠进行2个星期的结核分枝杆菌H37Rv病原体感染。所有实验动物根据所用的治疗方案(表3)分组。实验药物的剂量根据文献和先前的研究结果选择。
表3
组编号 | 化合物 | 剂量(mg/kg) | 每组动物数量 |
3 | 2 | 12 | 10 |
4 | 2 | 25 | 10 |
5 | 异烟肼(INH) | 25 | 10 |
6 | 未治疗 | 10 |
在感染的次日开始治疗。该药物以包含少量PEG-400的羧甲基纤维素/水混悬剂口服给药。
每天进行一次化疗,每星期6次(星期日除外)。
实验动物用醚麻醉处死。为了测定每种治疗方案的疗效,记录鼠实质器官的宏观变化、来自固体培养基上病理物质的分枝杆菌的生长以及组织损伤的细菌视觉指数。对肝脏、脾脏和肺的宏观变化进行定性和定量分析,并计算出损伤指数(使用四分评分法)。
每种治疗方案的疗效的宏观评价由使用公式计算出的疗效指数表示。
微生物学检测包括用于测定实质性组织中的CFU的培养。为此,用6%硫酸分别将右肺和脾脏进行均质、离心、用水和盐水洗涤。用1.0mL盐水稀释产物(约0.5mL)并再次均质。实验器官的混悬液(0.5mL)用盐水稀释100和1000倍,并分散到固体Finn-2培养基上。培养物在37℃下培养1个月并从第10天开始每周计数。在28天后计算CFU。
实验中死亡的鼠的实质性器官的宏观检测和微生物检测的数据也计入实验结果的总体评估,数据见表4-6。
表4:小鼠器官损伤指数及疗效
组 | 药物 | 剂量(mg/kg) | 损伤指数 | 疗效指数(%) |
3 | 化合物2 | 12 | 2.1 | 44.7 |
4 | 化合物2 | 25 | 1.0 | 78 |
5 | INH,异烟肼 | 25 | 1.2 | 70.5 |
6 | 对照 | -- | 3.8 | -- |
表5:实验小鼠右肺和脾脏的微生物学检测结果(在培养基上接种42天后)
组 | 化合物 | 剂量(mg/kg) | 右肺培养,未稀释CFU | 脾脏培养,未稀释CFU |
3 | 2 | 12 | ~60 | ~60 |
4 | 2 | 25 | ~35 | ~35 |
5 | INH,异烟肼 | 25 | ~40 | ~40 |
6 | 对照 | -- | >120(总生长) | >120(总生长) |
表6:动物的存活
治疗天数 | 第3组化合物2 | 第4组化合物2 | 第5组异烟肼 | 第6组对照 |
1 | 10 | 10 | 10 | 10 |
2 | 10 | 10 | 10 | 10 |
3 | 10 | 10 | 10 | 10 |
4 | 10 | 10 | 10 | 10 |
5 | 10 | 10 | 10 | 10 |
6 | 10 | 10 | 10 | 10 |
7 | 10 | 10 | 10 | 10 |
8 | 10 | 10 | 10 | 10 |
9 | 10 | 10 | 10 | 10 |
10 | 10 | 10 | 10 | 10 |
11 | 10 | 10 | 10 | 10 |
12 | 10 | 10 | 10 | 10 |
13 | 10 | 10 | 10 | 9 |
14 | 10 | 10 | 10 | 9 |
15 | 10 | 10 | 10 | 9 |
16 | 10 | 10 | 10 | 9 |
17 | 10 | 10 | 10 | 9 |
18 | 10 | 10 | 10 | 9 |
19 | 10 | 10 | 10 | 9 |
20 | 10 | 10 | 10 | 8 |
21 | 10 | 10 | 10 | 8 |
22 | 10 | 10 | 10 | 8 |
23 | 10 | 10 | 10 | 8 |
24 | 10 | 10 | 10 | 8 |
25 | 10 | 10 | 10 | 5 |
26 | 10 | 10 | 10 | 4 |
27 | 100% | 100% | 100% | 40% |
对照组动物到第33天全部死亡。
Claims (11)
1.式I的化合物
其中R1和R2相互独立地为NO2、CN、CONR7R8、COOR9、CHO、卤素、NR7R8、SO2NR7R8、SR9、OCF3、单氟甲基、二氟甲基或三氟甲基;
R3和R4相互独立地为H、具有1-7个链成员的饱和或不饱和的、直链或支链的脂肪族基团、具有3-6个碳原子的环烷基、苄基、SR9、OR9;
R5和R6相互独立地为具有1-8个链成员的饱和或不饱和的、卤代或非卤代的、直链或支链的脂肪族基团、具有3-6个碳原子的环烷基、苯基,或R5和R6一起代表二价基团-(CR9 2)m-、或R5和R6一起代表如下二价基团:
其中m是1-4,或代表具有杂原子N、S、O且被(R10)x取代的饱和或不饱和的单或多杂环二价基团,其中x是1-4;
R7、R8和R9相互独立地为H或具有1-7个链成员的饱和或不饱和的、卤代或非卤代的、直链或支链脂肪族基团、单氟甲基、二氟甲基或三氟甲基、卤素、苯基,或R3和R4一起代表二价基团-(CH2)n-,其中n是2-7;
R10是H或具有1-7个链成员的饱和或不饱和的、卤代或非卤代的、直链或支链的脂肪族基团、NO2、NR7R8、CN、CONR7R8、COOR9、CHO、卤素、SO2NR7R8、SR9、OR9、OCF3、单氟甲基、二氟甲基或三氟甲基、苄基或苯基。
2.式I的化合物的盐。
3.如权利要求1所述的式(I)的2-(2,3-R5R6-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-6-(三氟甲基)-1,3-苯并噻嗪-4-酮,R1是NO2,R2是CF3,R3和R4是H,且R5和R6具有权利要求1中的定义。
4.如权利要求1所述的式(I)的2-(2,3-R5R6-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-4-氧代-1,3-苯并噻嗪-6-腈,R1是NO2,R2是CN,R3和R4是H,且R5和R6具有权利要求1中的定义。
5.如权利要求1所述的式(I)的2-(2,3-R5R6-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-6,8-二硝基-4-氧代-1,3-苯并噻嗪,R1和R2是NO2,R3和R4是H,且R5和R6具有权利要求1中的定义。
6.如权利要求1所述的式(I)的2-(2,3-R5R6-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-4-氧代-1,3-苯并噻嗪-6-脲,R1是NO2,R2是CONH2,R3和R4是H,且R5和R6具有权利要求1中的定义。
7.如权利要求1所述的式(I)的3,5-二硝基-2-R3R4-二硫代氨基甲酰基吡啶,其中X是式(II)的残基,R2是NO2,n是1,且R3和R4具有权利要求1中的定义,3,5-二硝基-2-二甲基-二硫代氨基甲酰基吡啶除外。
8.如权利要求1所述的式(I)的化合物,其选自下列化合物中:
2-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-6,8-二硝基-1,3-苯并噻嗪-4-酮、
2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-6,8-二硝基-1,3-苯并噻嗪-4-酮、
2-(4,4-二乙氧基哌啶-1-基)-6,8-二硝基-1,3-苯并噻嗪-4-酮、
7-甲基-2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-6,8-二硝基-1,3-苯并噻嗪-4-酮、
2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-6-(三氟甲基)-1,3-苯并噻嗪-4-酮、
2-(2,3-二甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-6-(三氟甲基)-1,3-苯并噻嗪-4-酮、
2-(1,5-二氧杂-9-氮杂螺[5.5]十一烷-9-基)-8-硝基-6-(三氟甲基)-1,3-苯并噻嗪-4-酮、
2-(1,5-二氧杂-9-氮杂螺[5.5]十一烷-9-基)-8-硝基-4-氧代-1,3-苯并噻嗪-6-腈、
2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-8-硝基-4-氧代-1,3-苯并噻嗪-6-腈、
8-氨基-2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-4-氧代-1,3-苯并噻嗪-6-腈和
8-氨基-2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-6-(三氟甲基)-1,3-苯并噻嗪-4-酮。
9.如权利要求1所述的式(I)的化合物,其选自R5和R6是烷基的化合物。
10.包含如权利要求1所述的式I的化合物的药物组合物。
11.式I的化合物,其用于治疗或预防性治疗哺乳动物肺结核感染或麻风病感染的方法,
其中R1和R2相互独立地为NO2、CN、CONR7R8、COOR9、CHO、卤素、NR7R8、SO2NR7R8、SR9、OCF3、单氟甲基、二氟甲基或三氟甲基;
R3和R4相互独立地为H、具有1-7个链成员的饱和或不饱和的、直链或支链的脂肪族基团、具有3-6个碳原子的环烷基、苄基、SR9、OR9;
R5和R6相互独立地为具有1-8个链成员的饱和或不饱和的、卤代或非卤代的、直链或支链的脂肪族基团、具有3-6个碳原子的环烷基、苯基,或R5和R6一起代表二价基团-(CR9 2)m-、或R5和R6一起代表如下二价基团:
其中m是1-4,或代表具有杂原子N、S、O且被(R10)x取代的饱和或不饱和的单或多杂环二价基团,其中x是1-4;
R7、R8和R9相互独立地为H或具有1-7个链成员的饱和或不饱和的、卤代或非卤代的、直链或支链脂肪族基团、单氟甲基、二氟甲基或三氟甲基、卤素、苯基,或R3和R4一起代表二价基团-(CH2)n-,其中n是2-7;
R10是H或具有1-7个链成员的饱和或不饱和的、卤代或非卤代的、直链或支链的脂肪族基团、NO2、NR7R8、CN、CONR7R8、COOR9、CHO、卤素、SO2NR7R8、SR9、OR9、OCF3、单氟甲基、二氟甲基或三氟甲基、苄基或苯基。
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