CN108929329A - 2-氮杂环-5-三氟甲基-8-硝基苯并(硫代)吡喃-4-酮类化合物 - Google Patents
2-氮杂环-5-三氟甲基-8-硝基苯并(硫代)吡喃-4-酮类化合物 Download PDFInfo
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- CN108929329A CN108929329A CN201810092333.XA CN201810092333A CN108929329A CN 108929329 A CN108929329 A CN 108929329A CN 201810092333 A CN201810092333 A CN 201810092333A CN 108929329 A CN108929329 A CN 108929329A
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- substituted
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- compound
- alkyl
- trifluoromethyl
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Classifications
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- 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
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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- A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D417/12—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 linked by a chain containing hetero atoms as chain links
-
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Abstract
本发明公开了2‑氮杂环‑5‑三氟甲基‑8‑硝基苯并(硫代)吡喃‑4‑酮类化合物、其制备方法及在治疗和/或预防结核分枝杆菌引起的感染性疾病药物中的应用。具体地说,本发明涉及式(I)所示化合物及其异构体,其药学可接受的盐以及包含本发明化合物的药物组合物,其中X、Y、R1、R2、n如说明书所述。本发明旨在制备具有抗结核分枝杆菌活性的新化合物,其作为潜在的新药物,可用于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)疾病的治疗或预防性治疗,同时可用于克服与结核分枝杆菌耐药相关的问题。
Description
技术领域
本发明属于医药技术领域。特别涉及通式(I)所示的2-氮杂环-5-三氟甲基-8-硝基苯并(硫代)吡喃-4-酮类化合物,其制备方法,以该化合物为活性成分的药物组合物,以及它们在治疗和/或预防由结核分枝杆菌引起的感染性疾病中的应用。
背景技术
结核病(tuberculosis,TB)是由结核分枝杆菌引起的一种慢性致死性疾病,是危害人类健康和导致人类死亡的重大传染性疾病,结核病与艾滋病一样,成为全世界主要死亡原因之一。据世界卫生组织(WHO)估计(Global tuberculosis report2016),2015年全世界新发结核病数量约为1040万例,其中590万为男性(占56%),350万为女性(占34%),100万为儿童(占10%)。120万新发结核病例为艾滋病毒感染者(占11%),据估计有140万人死于结核病,还有40万艾滋病毒感染者死于结核病。
化学治疗是结核病治疗的主要手段。1944年链霉素的使用,开创了抗结核药物治疗的新时代,随着异烟肼、利福平、吡嗪酰胺的相继出现,使得治疗结核病疗程缩短到6个月,进入了“短程化疗时代”。尽管如此,长期药物联合治疗,使患者产生不良反应,难以坚持规律用药,加之所用药物多诞生于上世纪五六十年代,长期、广泛及不规范使用使得耐药菌发展日趋严重,出现多药耐药结核(MDR-TB)、广泛耐药结核(XDR-TB)与全部耐药结核(TDR-TB)。面对耐药结核,需使用价格昂贵且毒性较大的二线甚至三线抗结核药物。因此,研发具有新型骨架、新颖作用机制的抗结核药物以治疗与控制结核病,尤其是耐药结核尤为迫切。抗结核新药需要具有高效力、低毒性以及能够缩短治疗时间等特点。
发明内容
本发明要解决的技术问题是提供一种结构新颖并具有强抗结核分枝杆菌活性的2-氮杂环-5-三氟甲基-8-硝基苯并(硫代)吡喃-4-酮类化合物。本发明发现,2-氮杂环-5-三氟甲基-8-硝基苯并(硫代)吡喃-4-酮类化合物具有强的抗结核分枝杆菌作用,可用于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)疾病的治疗或预防性治疗,同时可用于克服与耐药性有关的问题。本发明基于以上发现而得以完成。
发明概述
为此,本发明第一方面提供通式(I)所示的化合物及其异构体、或其药学上可接受的盐,
其中,
X为O或S;
Y为C或N;
R1为H、C1-C3烷基、C1-C3烷氧基、F、Cl、Br、CN、OH、(=O)、(=S);
n为0、1或2;
R2为F、取代或未取代的C3-C6环烷基、取代或未取代的C3-C6杂环基、取代或未取代的C6-C10芳基、取代或未取代的C2-C9杂芳基、或和共同连接的碳原子一起表示含有3-8个碳原子的取代或未取代的环烷基或含1-3个选自氧、硫的杂原子的取代或未取代的4-6元杂环基;
所述C3-C6元杂环基、C2-C9杂芳基至少含有一个选自N、O、S中的杂原子;
所述R2中取代或未取代的取代基可任选自以下基团:F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基。
在一优选例中,所述化合物结构式如(II)所示:
其中,Y、R1、R2、n定义同本发明第一方面所述。
在另一优选例中,所述化合物结构式如(III)所示:
其中,Y、R1、R2、n定义同本发明第一方面所述。
在一些方面,式(I)化合物选自式(II-a)化合物:
其中,
R1为H、C1-C3烷基、F、Cl或(=O);
n为0或1;
R2为F、取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、或和共同连接的碳原子一起表示取代或未取代的环戊基或含1-2个选自氧、硫的杂原子的取代或未取代的5元杂环基;
所述R2中取代或未取代的取代基可任选自以下基团:F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基。
在一些方面,式(I)化合物选自式(II-b)化合物:
其中,
R1为H、C1-C3烷基、F、Cl或(=O);
n为0或1;
R2为取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基;
所述R2中取代或未取代的取代基可任选自以下基团:F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基;
在一些方面,式(I)化合物选自式(III-a)化合物:
其中,
R1为H、C1-C3烷基、F、Cl或(=O);
n为0或1;
R2为F、取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、或和共同连接的碳原子一起表示取代或未取代的环戊基或含1-2个选自氧、硫的杂原子的取代或未取代的5元杂环基;
所述R2中取代或未取代的取代基可任选自以下基团:F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基;
在一些方面,式(I)化合物选自式(III-b)化合物:
其中,
R1为H、C1-C3烷基、F、Cl或(=O);
n为0或1;
R2为取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基;
所述R2中取代或未取代的取代基可任选自以下基团:F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基;
在式(II)和(III)方案中,
n优选为0、1或2;
R1优选H、C1-C3烷基、C1-C3烷氧基、F、Cl、Br、CN、OH、(=O)或(=S);
当Y为C时,
R2优选为F、
当Y为N时,
R2优选为
Rx为F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基;
本发明中所述的药学上可接受的盐为本发明化合物与选自下列的酸形成的盐:盐酸、对甲苯磺酸、酒石酸、马来酸、乳酸、甲磺酸、硫酸、磷酸、柠檬酸、乙酸或三氟乙酸。优选为盐酸、对甲苯磺酸或三氟乙酸。
根据本发明第一方面任一项的化合物,其为实施例制备的本发明目标化合物(以结构式表示的或以***命名描述的)及其异构体,其药学可接受的盐。
根据本发明第一方面任一项化合物,其为选自下列的化合物:
本发明第二方面提供了制备本发明第一方面任一项所述化合物的方法,其包括以下步骤:
化合物A在合适的溶剂(例如二氯甲烷、四氢呋喃、乙腈,优选二氯甲烷)中,与胺类化合物B,在缩合试剂(例如CDI、DCC、EDCI\HOBT、HATU,优选DCC)的作用下,在空气或惰性气体(Ar或N2)保护下,置于-10℃-50℃反应1-24小时,其中优选室温反应8-15小时,得到式C所示化合物;
式C所示化合物在适当的溶剂(例如DMF、DMSO,优选DMF)中,在碱性条件(例如碳酸钠、碳酸钾或碳酸铯,优选碳酸钾)下,在惰性气体(Ar或N2)保护下,于20-140℃下反应0.5-12小时,优选110℃条件下反应1-5小时,得到式(II)化合物。
本发明中的化合物A参考现有出版物中已知的方法即可容易制得,例如(J.Med.Chem.2007,50,3369-3379)。
化合物D与二硫化碳在合适的溶剂(例如甲苯、丙酮、四氢呋喃、DMF、DMSO,优选DMSO)中,在碱性条件(例如NaH、氢氧化钠、甲醇钠、乙醇钠、叔丁醇钾、叔丁醇钠,优选氢氧化钠)下,在空气或惰性气体(Ar或N2)保护下,于-10-30℃下反应10-60分钟,优选15-25℃下反应15-30分钟,随后在15-25℃下加入MeI,反应30-60分钟,得到化合物E;
化合物E与胺类化合物B,在合适的溶剂(例如叔丁醇、异丙醇、乙二醇、乙二醇二甲醚、DMF、DMSO,优选异丙醇)中,在空气或惰性气体(Ar或N2)保护下,于80-160℃下反应1-48小时,优选120-140℃反应20-25小时,得到式(III)化合物。
将式(III)化合物于室温或加热条件下,溶解或混悬在合适的溶剂(例如二氯甲烷、四氢呋喃、甲醇、乙醇、异丙醇,优选乙醇、异丙醇)中,在空气或惰性气体(Ar或N2)保护下,加入相应的酸溶液(例如盐酸、硫酸、盐酸乙醇,优选盐酸乙醇),于室温或加热条件下搅拌1-48小时,优选室温下搅拌2小时,经过滤,相应溶剂洗涤,干燥后得到式(III)化合物相应的盐。
本发明第三方面提供了一种药用组合物,其包括治疗有效量的本发明第一方面任一项所述化合物及其药学可接受的盐,以及任选的一种或多种药学可接受的辅料。
本发明第四方面提供了本发明第一方面任一项所述化合物及其药学可接受的盐,或者本发明第三方面任一项所述药物组合物在制备治疗和/或预防结核分枝杆菌引起的感染性疾病药物中的应用。
前面所述内容只概述了本发明的某些方面,但并不限于这方面。这些方面及其他的方面内容将在下面做更加具体完整的描述。
发明详述
下面对本发明的各个方面和特点作进一步的描述。
本发明所引述的所有文献,它们的全部内容通过引用并入本文,并且如果这些文献所表达的含义与本发明不一致时,以本发明的表述为准。此外,本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。下面是本发明所用多种术语的定义,这些定义适用于本申请整个说明书中所用的术语,除非在具体情况中另作说明。
一般而言,术语“取代或未取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明,一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构始终不只有一个位置能被选自具体基团得一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。
Ci-Cj表示具有整数“i”(包含i)至整数“j”(包含j)个碳原子的部分。因此,例如C1-C3烷基指具有1至3个(包含1和3)碳原子的烷基。例如C2-C9杂芳基指具有2至9个(包含2和9)碳原子的杂芳基,包含四氮唑基、三氮唑基、噻吩基、吡啶基、嘧啶基、喹啉基。
如本文所述的,术语“烷基”是指具有指定数目碳原子数的烷基,其为直链或支链的烷基,并且其可包括其子基团,例如提及“C1-C3烷基”时,其还可以包括C1-C2烷基表示的子范围的基团,以及具体基团例如甲基、乙基、正丙基、异丙基。
如本文所述的,术语“烷氧基”和“烷胺基”属于惯用表达,是指分别通过一个氧原子或胺基连接到分子的其余部分的烷基基团,其中的烷基如本发明所述。
如本文所述的,术语“卤代烷基”表示烷基基团上的氢被一个或多个卤素原子所取代,这样的实例包含,但并不限于,单氟甲基、单氟甲氧基等。
如本文所述的,术语“环烷基”是指具有指定数目环碳原子数的环状烷基,并且其可包括其子基团,例如提及“C3-C6环烷基”时,其还可以包括C3-C5环烷基、C4-C6环烷基等表示的子范围的基团,以及具体基团例如环丙基、环丁基、环戊基、环己基。
如本文所述的,术语“C3-C6杂环烷基”,除另有说明或限定外,是指包含3-6个环碳原子的饱和或部分不饱和的单环、双环或三环体系,其中至少一个环原子选自氮、硫和氧原子。除非另外说明,杂环基可以是碳基或氮基,且-CH2-基团可以任选地被羰基替代。环的硫原子可以任选地被氧化成S-氧化物。杂环基包括但不限于氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢吡咯基、四氢噻唑基、哌啶基、哌嗪基、吗啉基、硫代吗啉、高哌嗪基等。
如本文所述的,术语“C6-C10芳基”表示含有6个环原子或6-10个环原子的单环和双环的碳环体系,其中,至少一个环是芳香族的,其中每一个环包含3-6个原子组成的环,且环体系中有一个或多个附着点与分子的其余部分相连。芳香基团可以包括苯基和萘基。
如本文所述的,术语“C2-C9杂芳基”在本文中指具有1至3个杂原子作为环原子,其余的环原子为碳的芳香基团,杂原子包括氧、硫和氮。杂芳基的实例包括但不限于吡啶基、哒嗪基、三氮唑基、四氮唑基、噁唑基、异噁唑基、嘧啶基、咪唑基、呋喃基、噻吩基、吡嗪基等。
如本文所述的,术语“环”表示被取代或未被取代的环烷基、被取代或未被取代的杂环基、被取代或未被取代的芳基或被取代或未被取代的杂芳基。所谓的环包括稠环。环上原子的数目通常被定义为环的元数,例如“C3-C6环”是指环绕排列3-6个原子。
如本文所述的,术语“杂原子”是指O、S、N,包括N、S的任何氧化态的形式;伯、仲、叔胺和季铵盐的形式;或者杂环中氮原子上的氢被取代的形式。
如本文所述的,术语“卤素”、“卤代”等表示氟(F)、氯(Cl)或溴(Br)。
本发明中“室温”指的是温度由10℃到40℃。在一些实施例中,“室温”指的是温度由20℃到30℃;在另一些实施例中,室温指的是25℃。
如本文所述的,术语“有效量”是指可在受试者中实现所期望的治疗本发明所述疾病或病症的药物用量。
如本文所述的,术语“药学可接受的”例如在描述“药学可接受的盐”时,表示该盐不但是受试者生理学上可接受,而且还可指在药学上有使用价值的合成物质。
如本文所述的,术语“药物组合物”,其还可以是指“组合物”,其可用于在受试者特别是哺乳动物中实现治疗本发明所述疾病或病症。
疾病的“治疗”包括:
(1)预防该疾病,即,使暴露至或易感染该疾病但未经历或显示该疾病症状的哺乳动物不发生该疾病的临床症状,
(2)抑制该疾病,即,阻止或减少该疾病或其临床症状的进展,
(3)减轻该疾病,即,引起该疾病或其临床症状的复原。
“治疗有效量”指为了治疗疾病向哺乳动物施用时足以实现对该疾病的治疗的化合物的量。治疗有效量将根据化合物、待治疗的疾病及其严重性以及哺乳动物的年龄、体重、性别等因素而变化。治疗有效量还可指足以实现所需的有益效果的化合物的任何量,该有益效果包括如以上(1)-(3)所述的预防疾病、抑制疾病或减轻疾病。例如化合物的量可以介于0.1-250mg/kg,或优选地,0.5-100mg/kg,或更优选地,1-50mg/kg,或甚至更优选地,2-20mg/kg。优选地,所述量的化合物每天两次向哺乳动物施用。更优选地,所述量的化合物每天一次向哺乳动物施用。
如本文所述的,术语“疾病和/或病症”是指所述受试者的一种身体状态,该身体状态与本发明所述疾病和/或病症有关。例如,本发明所述疾病和/或病症指结核杆菌感染性疾病。
如本文所述的,术语“受试者”可以指患者或者其它接受本发明式I化合物或其药物组合物以治疗本发明所述疾病或病症的动物,特别是哺乳动物,例如人、狗、猴、牛、马等。
本发明再一方面还涉及以本发明中的化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。
本发明中的化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、***、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药***。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助溶剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、***胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助溶剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助溶剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助溶剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
有益技术效果
本申请的发明人经过广泛的研究,合成了一系列化合物,并通过MABA(Microplatealamar blue assay)法以M.tuberculosis H37Rv菌株进行最低抑菌浓度MIC(Minimuminhibitory concentration)测定,显示出较好的抗结核分枝杆菌活性,其中获得MIC<0.5μg/mL的化合物14个,13个化合物的MIC达到10-8g/mL,与抗结核一线药物异烟肼相当,此外对Vero细胞毒性低(IC50大于64μg/mL)显示出良好的安全性,并且在HepG2细胞毒性测试中显示出相较苯并噻嗪酮类化合物PBTZ169(EMBO Mol.Med.2014,6,372-383)更高的安全性。本发明中部分化合物在肝微粒体及肝细胞代谢稳定性试验中均显示出较PBTZ169具有更优的代谢性质。小鼠体内药代动力学结果显示,化合物11具有较优于PBTZ169的体内药代动力学性质。本发明提供了一类结构新颖、体内抗结核活性强、药代性质良好的新化合物,其母核结构为苯并吡喃酮或苯并硫代吡喃酮结构,可用于由细菌引起的感染性疾病,特别是由结核分枝杆菌引起的结核病的治疗或预防性治疗,同时也可用于克服与耐药性有关的问题。
具体实施方式
通过下面的实施例可以对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进是显而易见的。
对于以下全部实施例,可使用本领域技术人员已知的标准操作和纯化方法。除非另有说明,所有温度以℃(摄氏度)表示。化合物的结构是通过核磁共振谱(NMR)来确定的。
制备实施例部分
化合物的结构是通过核磁共振氢谱(1H NMR)来确定的。核磁共振氢谱及碳谱位移(δ)以百万分之一(ppm)的单位给出。耦合常数(J)以赫兹(Hz)为单位。核磁共振谱用Mercury-400型核磁共振仪测定,氘代氯仿(CDCl3)作溶剂,四甲基硅烷(TMS)为内标。
电子天平采用日本Yanaco LY-300型电子天平。
柱层析一般使用200~300目硅胶为载体。
无水溶剂均通过标准方法处理。其它试剂均为市售分析纯。
本发明采用下述缩略词:
CDI为羰基二咪唑。
DCC为二环己基碳二亚胺。
DMF为N,N-二甲基甲酰胺。
DMSO为二甲基亚砜。
EDCI为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
HOBT为1-羟基苯并***。
HATU为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
实施例
实施例1
(S)-2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)-6-三氟甲基-8-硝基-苯并吡喃-4-酮
路线:
实验步骤:
第一步(S)-1-(2-氯-3-硝基-5-(三氟甲基)苯基)-3-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)丙烷-1,3-二酮B-1的制备
于25mL反应瓶中,将化合物3-(2-氯-3-硝基-5-(三氟甲基)苯基)-3-氧代丙酸A(311mg,1.0mmol)、DCC(201mg,1.0mmol)溶于干燥二氯甲烷中(5mL),Ar气保护,加入(S)-2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷(157mg,1.0mmol),室温下搅拌12小时。过滤掉不溶固体,浓缩,硅胶(200-300目)柱色谱分离,乙酸乙酯-石油醚(V:V=5~15:100)混合液为洗脱剂。得中间体B-1,浅黄色固体250mg,收率55.5%。
1H NMR(400MHz,CDCl3)δ:15.64(brs,1H),8.01(s,1H),8.00(s,1H),5.72(s,1H),4.30-4.13(m,1H),4.12-4.08(m,1H),3.75-3.47(m,5H),1.79-1.75(m,4H),1.30(m,3H).
第二步(S)-2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)-6-三氟甲基-8-硝基-苯并吡喃-4-酮II-1(化合物1)的制备
于10mL反应瓶中,将化合物(S)-1-(2-氯-3-硝基-5-(三氟甲基)苯基)-3-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)丙烷-1,3-二酮B-1(90mg,0.2mmol)、碳酸钾(28mg,0.2mmol)溶于DMF中(2mL),Ar气保护,升温至110℃反应1小时。蒸干溶剂,加入25mL二氯甲烷,依次用水和盐水洗,无水硫酸钠干燥,过滤,浓缩,硅胶(200-300目)柱色谱分离,甲醇-二氯甲烷(V:V=1:100)混合液为洗脱剂。得化合物II-1(化合物1),浅黄色固体58mg,收率69.9%。
1H NMR(400MHz,CDCl3)δ:8.74(s,1H),8.51(s,1H),5.66(s,1H),4.32-4.27(m,1H),4.14-4.10(m,1H),3.77-3.71(m,4H),3.53-3.49(m,1H),1.88-1.85(m,4H),1.31(d,J=6.0Hz,3H).
实施例2
2-(4-(环己基甲基)哌嗪-1-基)-6-三氟甲基-8-硝基-苯并吡喃-4-酮
路线:
实验步骤:
第一步1-(2-氯-3-硝基-5-三氟甲基苯基)-3-(4-(环己基甲基)哌嗪-1-基)丙烷-1,3-二酮B-2的制备
以1-(环己基甲基)哌嗪(182mg,1.0mmol)为原料,采用实施例1中第一步相似操作步骤,得到中间体B-2,浅黄色固体272mg,收率57.1%。
1H NMR(400MHz,CDCl3)δ:15.62(brs,1H),8.01(s,1H),8.00(s,1H),5.67(s,1H),3.73-3.49(m,4H),2.45(m,4H),2.17(m,2H),1.79-1.71(m,5H),1.26-1.20(m,4H),0.90-0.87(m,2H).
第二步2-(4-(环己基甲基)哌嗪-1-基)-6-三氟甲基-8-硝基-苯并吡喃-4-酮II-2(化合物2)的制备
以1-(2-氯-3-硝基-5-三氟甲基苯基)-3-(4-(环己基甲基)哌嗪-1-基)丙烷-1,3-二酮(95mg,0.2mmol)为原料,采用实施例1中第二步相似操作步骤,得到化合物II-2(化合物2),浅黄色固体46mg,收率52.3%。
1H NMR(400MHz,CDCl3)δ:8.74(d,J=2.0Hz,1H),8.50(d,J=2.0Hz,1H),5.59(s,1H),3.65(m,4H),2.55(m,4H),2.20(m,2H),1.80-1.62(m,5H),1.28-1.19(m,4H),0.91-0.86(m,2H).
实施例3
2-(4-(环己基甲基)哌嗪-2-酮-1-基)-6-三氟甲基-8-硝基-苯并吡喃-4-酮
以1-(环己基甲基)哌嗪-2-酮(39mg,0.2mmol)为原料,采用实施例2中相似操作步骤,得到化合物II-3(化合物3),浅黄色固体42mg,收率46.4%。
1H NMR(400MHz,CDCl3)δ:8.76(d,J=2.0Hz,1H),8.55(d,J=2.0Hz,1H),5.54(s,1H),4.14(s,2H),3.98-3.96(m,2H),3.58-3.56(m,2H),3.34(d,J=7.2Hz,2H),1.77-1.66(m,5H),1.29-1.19(m,4H),1.02-0.99(m,2H).
实施例4
2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮
路线
实验步骤:
第一步2-甲硫基-8-硝基-6-(三氟甲基)-4H-硫代色烯-4-酮D的制备
于50mL反应瓶中,将NaOH(800mg,20mmol)溶于DMSO(5mL),在20℃下加入二硫化碳(2.34g,30mmol),将2-氯-3-硝基-5-三氟甲基苯乙酮(2.67g,10mmol)分次加入其中,15分钟后,在20℃的温度下加入碘甲烷(10mmol),反应30分钟。加入100mL乙酸乙酯,依次用100mL水和盐水洗,无水硫酸钠干燥,过滤,浓缩,硅胶(200-300目)柱色谱分离,乙酸乙酯-石油醚(V:V=7:100)混合液为洗脱剂。得中间体D,浅黄色固体1.83g,收率60.0%。
1H NMR(400MHz,CDCl3)δ:9.12(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,1H),6.91(s,1H),2.70(s,3H).
第二步(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮III-1(化合物4)的制备
于25mL反应瓶中,将2-甲硫基-8-硝基-6-(三氟甲基)-4H-硫代色烯-4-酮(64mg,0.2mmol)、(S)-2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷(157mg,1.0mmol)溶于异丙醇(5mL),Ar保护下,于140℃反应24小时,得到化合物III-1(化合物4),浅黄色固体57mg,收率66.3%。
1H NMR(300MHz,CDCl3)δ:9.13(s,1H),8.77(s,1H),6.45(s,1H),4.28(m,1H),4.12(m,1H),3.82(m,4H),3.51(m,1H),1.88(m,4H),1.32(d,J=6Hz,3H).
实施例5
2-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮
以1,4-二氧杂-8-氮杂螺[4.5]癸烷(143mg,1.0mmol)为原料,采用实施例4中第二步相似操作步骤,得到化合物III-2(化合物5),浅黄色固体60mg,收率72.2%。
1H NMR(400MHz,CDCl3)δ:9.13(s,1H),8.76(s,1H),6.41(s,1H),4.03(s,4H),3.81(m,4H),1.88(m,4H).
实施例6
2-(1,4-二硫杂-8-氮杂螺[4.5]癸烷-8-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮
以1,4-二硫杂-8-氮杂螺[4.5]癸烷(175mg,1.0mmol)为原料,采用实施例4中第二步相似操作步骤,得到化合物III-3(化合物6),浅黄色固体70mg,收率77.8%。
1H NMR(400MHz,CDCl3)δ:9.12(d,J=1.6Hz,1H),8.78(d,J=1.6Hz,1H),6.54(s,1H),3.83(m,4H),3.39(s,4H),2.28(m,4H).
实施例7
2-(1-氧杂-4-硫杂-8-氮杂螺[4.5]癸烷-8-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮
以1-氧杂-4-硫杂-8-氮杂螺[4.5]癸烷(159mg,1.0mmol)为原料,采用实施例4中第二步相似操作步骤,得到化合物III-4(化合物7),浅黄色固体52mg,收率60.5%。
1H NMR(400MHz,CDCl3)δ:9.13(s,1H),8.80(s,1H),6.78(s,1H),4.23(m,2H),3.86(m,4H),3.16(m,2H),2.17(m,4H).
实施例8
2-(4-(环己基甲基)-3-氧代-哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮
以1-(环己基甲基)-哌嗪-2-酮(196mg,1.0mmol)为原料,采用实施例4中第二步相似操作步骤,得到化合物III-5(化合物8),浅黄色固体61mg,收率64.8%。
1H NMR(400MHz,CDCl3)δ:9.16(s,1H),8.80(s,1H),6.19(s,1H),4.24(m,2H),3.90(m,2H),3.59(m,2H),3.36(m,2H),1.73-1.66(m,6H),1.26-1.21(m,3H),1.02-1.00(m,2H).
实施例9
2-(4,4-二氟哌啶-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮
以4,4-二氟哌啶(121mg,1.0mmol)为原料,采用实施例4中第二步相似操作步骤,得到化合物III-6(化合物9),浅黄色固体63mg,收率79.7%。
1H NMR(400MHz,CDCl3)δ:9.13(s,1H),8.80(s,1H),6.41(s,1H),3.83(m,4H),2.20(m,4H).
实施例10
2-(4-(噻唑-2-基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮
以(哌嗪-1-基)噻唑(169mg,1.0mmol)为原料,采用实施例4中第二步相似操作步骤,得到化合物III-7(化合物10),浅黄色固体43mg,收率48.9%。
1H NMR(400MHz,CDCl3)δ:9.14(s,1H),8.80(s,1H),7.28(d,J=3.6Hz,1H),6.70(d,J=3.6Hz,1H),6.31(s,1H),3.84(m,8H).
实施例11
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮
以1-(环己基甲基)哌嗪(182mg,1.0mmol)为原料,采用实施例4中第二步相似操作步骤,得到化合物III-8(化合物11),橙色固体66mg,收率72.5%。
1H NMR(400MHz,CDCl3)δ:9.12(s,1H),8.75(s,1H),6.25(s,1H),3.66(m,4H),2.56(m,4H),2.20(m,2H),1.80-1.67(m,5H),1.51(m,1H),1.26-1.16(m,3H),0.94-0.88(m,2H).
实施例12
2-(4-(环己基甲基)-3-甲基-哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮
以1-(环己基甲基)-2-甲基哌嗪(196mg,1.0mmol)为原料,采用实施例4中第二步相似操作步骤,得到化合物III-9(化合物12),浅黄色固体67mg,收率71.3%。
1H NMR(400MHz,CDCl3)δ:9.12(s,1H),8.74(s,1H),6.24(s,1H),3.80-3.77(m,2H),3.47(m,1H),3.19(m,1H),2.95(m,1H),2.58(m,1H),2.50(m,1H),2.36(m,1H),2.01(m,1H),1.87(m,1H),1.71(m,4H),1.46(m,1H),1.25-1.11(m,6H),0.91-0.88(m,2H).
实施例13
2-(4-(苄基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮
以N-苄基哌嗪(176mg,1.0mmol)为原料,采用实施例4中第二步相似操作步骤,得到化合物III-10(化合物13),浅黄色固体55mg,收率61.1%。
1H NMR(400MHz,CDCl3)δ:9.12(s,1H),8.75(s,1H),7.35(m,5H),6.24(s,1H),3.68(m,4H),3.60(s,2H),2.63(m,4H).
实施例14
2-(4-苄基-3-甲基-哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮
以1-苄基-2-甲基哌嗪(190mg,1.0mmol)为原料,采用实施例4中第二步相似操作步骤,得到化合物III-11(化合物21),浅黄色固体47mg,收率50.7%。
1H NMR(400MHz,CDCl3)δ:9.12(s,1H),8.75(s,1H),7.35-7.26(m,5H),6.23(s,1H),4.06(d,J=13.2Hz,1H),3.84(t,J=15.2Hz,2H),3.40(t,J=9.6Hz,1H),3.27-3.20(m,2H),2.85(d,J=12.4Hz,1H),2.71(brs,1H),2.32(t,J=9.2Hz,1H),1.26(d,J=6.0Hz,3H).
实施例15
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮盐酸盐
将2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮(46mg,0.1mmol)置于5mL乙醇中,加热至溶解,搅拌下滴加1N的盐酸乙醇溶液0.1mL,滴加完毕后搅拌2小时,冷却过滤,少量冷乙醇洗,干燥得到化合物III-12(化合物22),黄色固体47mg,收率95.6%。
1H NMR(400MHz,DMSO-d6)δ:10.48(brs,1H),8.87(s,1H),8.86(s,1H),6.44(s,1H),4.31-4.28(m,2H),3.77-3.70(m,2H),3.61-3.58(m,2H),3.19-3.17(m,2H),2.99(brs,2H),1.83-1.80(m,3H),1.70-1.67(m,2H),1.64-1.60(m,1H),1.26-1.12(m,3H),0.98-0.95(m,2H).
实施例16
2-(4-(苄基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮盐酸盐
将2-(4-(苄基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮(45mg,0.1mmol)置于5mL乙醇中,加热至溶解,搅拌下滴加1N的盐酸乙醇溶液0.1mL,滴加完毕后搅拌2小时,冷却过滤,少量冷乙醇洗,干燥得到化合物III-13(化合物26),黄色固体46mg,收率94.7%。
1H NMR(400MHz,DMSO-d6)δ:11.3(brs,1H),8.88(s,1H),8.85(s,1H),7.58(brs,2H),7.47(brs,3H),6.42(s,1H),4.37-4.33(m,4H),3.66-3.60(m,2H),3.41-3.39(m,2H),3.23-3.21(m,2H).
生物活性测试
1、体外抗结核活性测试
测定方法:Microplate Alamar Blue Assay(MABA)法测定体外抗结核活性。
实验原理:Alamar Blue加入培养基可作为氧化还原指示剂,颜色由蓝色向红色转变,反映所研究的微生物对氧分子的消耗。Alamar Blue的颜色改变可用光度计测定,其发射波长为590nm。
实验方法:无菌96孔板(Falcon3072;Becton Dickinson,Lincoln Park,N.J.),实验化合物以DMSO溶解,制成浓度为5mg/mL的初溶液,最高浓度孔加入199μL 7H9培养基,1μL化合物初溶液,混合均匀后,向其余各孔依次2倍稀释,化合物终浓度为:25、12.5、6.25、3.125、1.56、0.78、0.39、0.2、0.1、0.05、0.025μg/mL。选取结核分枝杆菌H37Rv(或临床分离耐药菌株)培养2~3周的培养物制成菌悬液,接种到含0.05%吐温80、10%ADC的7H9培养基中,37℃静止培养1~2周,生长至浊度为McFarland 1(相当于107CFU/mL)时,1:20稀释后,加入各孔100μL,菌液的终浓度为106CFU/mL。每板上均设2个不含抗菌药的生长对照孔,96孔板于37℃孵育。7天后加入生长对照孔20μL 10×Alamar Blue和5%Tween80 50μL的混合液,37℃孵育24小时,如果颜色从蓝色变为粉色,则在各实验药物的孔内加入上述量的Alamar Blue和Tween 80混合液,37℃孵育24小时记录各孔的颜色,并应用酶标仪测定590nm荧光值,计算MIC90。
表1、本发明部分化合物体外抗结核分枝杆菌H37Rv活性
表2、本发明部分化合物体外抗耐药结核分枝杆菌活性
a耐异烟肼,利福平,链霉素,乙胺丁醇,利福喷丁,利福布丁和苯甲酰氨基水杨酸。
b耐异烟肼,乙胺丁醇,利福平,利福喷丁,利福布丁,阿米卡星和卷曲霉素。
由表1及表2数据可知,本发明中的化合物具有很强的体外抗结核敏感菌和耐药菌的活性。
2、细胞毒性测试
测定方法:MTT法
实验原理:细胞活性通过线粒体内脱氢酶(如琥珀酸脱氢酶)将氧化态的3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐(商品名:噻唑蓝)/MTT[3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide]还原为难溶的蓝色甲臜(formazan)化合物,经DMSO溶解后显色来测定,转化量与活细胞数量呈正性相关。
实验方法:1.细胞悬液的制备。将已培养至对数生长期的Vero/HepG2细胞用0.25%胰酶消化2~3min,吸弃消化液,加入适量培养液,混匀后取20μL用血球计数仪在显微镜下计数,配制成合适浓度的细胞悬液,备用。同时用PBS(phosphate bufferedsolution)配制5g/L的MTT溶液,过滤除菌,备用。2.药物配制与细胞毒性检测。将受试药物溶于DMSO中,以培养基稀释50倍,制成受试的最高浓度,然后用培养基在96孔板上按1∶3进行系列稀释,每个化合物设6个浓度,最高浓度64μg/mL,每个浓度设6个平行孔,50μL/孔。将制备好的细胞悬液接种于96孔板内,50μL/孔,细胞浓度4×105个/mL.。同时设不含药的细胞对照孔及培养基空白对照孔。培养48小时后,加入MTT 10μL/孔,继续培养4小时。取出培养板,小心弃去孔内培养基,每孔加DMSO100μL,振荡至甲臜颗粒完全溶解后,用酶联免疫检测仪在570nm波长处测定其光密度值(OD570)。3.数据处理。细胞抑制百分率(%)=[(细胞对照OD570值-加药组OD570值)/(细胞对照OD570值-空白OD570值)]×100%。用Origin7.0软件进行剂量-反应关系曲线拟合,计算各种化合物对细胞抑制率50%时的浓度(IC50)。
表3、本发明部分化合物Vero细胞毒性
表4、本发明部分化合物HepG2细胞毒性
由表3,表4数据可知,本发明的化合物的细胞毒性低,表现出了较阳性药PBTZ169具有更高的安全性。
3、肝微粒体代谢稳定性测试
实验方法:
选取目标化合物进行肝微粒体(混合的人源(Bioreclamation))的代谢稳定性研究,具体方法如下:分别取合成的目标化合物配制成1μM测试液。微粒体蛋白浓度为1mg/mL。通过添加NADPH(1mM)来引发反应,并将样品在振荡培养箱中于37℃孵育至多60分钟。通过添加含内标的冰冷的乙腈/甲醇(50:50)使反应终止于0,5,15和30分钟。分别于0,5,15,30和60分钟取出等份试样的反应混合物,然后加入含内标的冰冷的乙腈/甲醇(50:50,v/v)。将样品在4℃离心15分钟(4,000转/分),并通过LC-MS/MS分析上清液。色谱条件:色谱柱:KinetexC18 100A(30mm×3.0mm,2.6μm);柱温:室温,流动相:乙腈-水(含0.1%甲酸)梯度;流速:0.9mL/min。通过测量在有或没有NADPH辅因子的情况下化合物的残余量来评估化合物的代谢稳定性。
表5、本发明部分化合物的人源肝微粒体代谢稳定性数据
由表5数据可知,本发明的化合物具有较高的肝微粒体代谢稳定性。
4、肝细胞代谢稳定性测试
实验方法:
使用来自混合的CD-1小鼠(Bioreclamation IVT),混合的SD大鼠(Bioreclamation IVT),混合的雄性狗(Bioreclamation IVT),混合的雄性食蟹猴(RILD)和混合的人(Bioreclamation IVT)的肝细胞进行测定。在1μM浓度下测试化合物(化合物11和PBTZ169),最终肝细胞浓度为1百万个细胞/mL。通过向化合物溶液(2μM)中加入预热的肝细胞溶液(200万细胞/mL)来引发反应。将反应混合物在100转/分钟的CO2培养箱中于37℃孵育120分钟。在预定的时间点(0,15,30,60,90和120分钟),取出30μL反应混合物,通过加入200μL含内标的冰冷的ACN/MeOH(50:50)终止反应。将样品充分混合,在4℃离心15分钟(4,000转/分),并通过LC-MS/MS分析上清液。色谱条件:色谱柱:Kinetex C18100A(30mm×3.0mm,2.6μm);柱温:室温,流动相:乙腈-水(含0.1%甲酸)梯度;流速:0.9mL/min。通过测定化合物的剩余量来评估化合物在肝细胞中的代谢稳定性。
表6、化合物11和PBTZ169的肝细胞代谢稳定性
由表6数据可知,本发明的化合物11较阳性对照药PBTZ169在五种种属肝细胞中具有更长的半衰期,代谢稳定性显著优于PBTZ169。
5、化合物11,化合物22和PBTZ169小鼠体内药代动力学试验
实验方法:
每组采用三只重量为22-23克的Balb/c小鼠(雄性)进行化合物11,化合物22和PBTZ169的药代动力学研究。将化合物11以0.5%羧甲基纤维素和0.5%吐温80配制成2.5mg/mL悬液,化合物22以0.5%羧甲基纤维素配制成2.5mg/mL悬液,PBTZ169以0.5%羧甲基纤维素和4摩尔当量的1N盐酸配制成2.5mg/mL悬液,所有化合物给予25mg/kg的剂量。在口服给药后5,15,30分钟,以及1,2,4,7,24小时收集血浆样本。收集的血浆样本储存在-80℃直到用于分析。血浆样本用含有特非那丁内标的乙腈进行提取,提取剂与血浆比率为20:1。通过LC/TSQQuantum Access质谱仪(AB Sciex 5500)进行分析物定量。色谱条件:色谱柱:Kinetex C18 100A(30mm×3.0mm,2.6μm);柱温:室温,流动相:乙腈/水(80:20,v/v)(含0.1%甲酸);流速:0.8mL/min。质谱仪上的化合物检测以电喷雾正离子化模式进行。MRM方式检测m/z 456.17/359.80(化合物11),456.17/359.80(化合物22),m/z 457.16/344.20(PBTZ169)。应用WinNonlin软件(6.3Pharsight Corporation,Mountain View,USA)计算药代动力学参数。
表7小鼠口服化合物11,化合物22及PBTZ169后血浆药代动力学参数
由表7可知本发明的化合物11和化合物22较PBTZ169在小鼠体内具有更长的半衰期,其药代动力学性质优于PBTZ169,预示在临床使用时可以减少给药次数,从而提高患者用药的依从性。
6、化合物11,化合物22和PBTZ169稳定性考察
采用HPLC考察化合物11,化合物22和PBTZ169在光照、高温、高湿条件下放置10天的稳定性,结果如表8所示。
表8化合物11,化合物22和PBTZ169稳定性考察结果
采用Waters e2695-PDA HPLC***检测化合物纯度。色谱条件:色谱柱:KromasilC18(250mm×4.6mm,5μm);柱温:30℃,流动相:乙腈/水(84:16,v/v)等梯度;流速:1.0mL/min。由表8可知本发明的化合物11和化合物22在光照条件下的稳定性显著好于PBTZ169。相比PBTZ169,化合物11和化合物22具有更优的理化性质。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (13)
1.如式(I)所示的化合物及其异构体、或其药学上可接受的盐:
其中,
X为O或S;
Y为C或N;
R1为H、C1-C3烷基、C1-C3烷氧基、F、Cl、Br、CN、OH、(=O)或(=S);
n为0、1或2;
R2为F、取代或未取代的C3-C6环烷基、取代或未取代的C3-C6杂环基、取代或未取代的C6-C10芳基、取代或未取代的C2-C9杂芳基、或和共同连接的碳原子一起表示含有3-8个碳原子的取代或未取代的环烷基或含1-3个选自氧、硫的杂原子的取代或未取代的4-6元杂环基;
所述的C3-C6杂环基、C2-C9杂芳基至少含有一个选自N、O、S中的杂原子;
所述R2中取代或未取代的取代基可任选自以下基团:F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基。
2.根据权利要求1所述的化合物及其异构体、或其药学上可接受的盐,所述的化合物由通式(II)所示;
其中,
Y为C或N;
R1为H、C1-C3烷基、C1-C3烷氧基、F、Cl、Br、CN、OH、(=O)或(=S);
n为0、1或2;
R2为F、取代或未取代的C3-C6环烷基、取代或未取代的C3-C6杂环基、取代或未取代的C6-C10芳基、取代或未取代的C2-C9杂芳基、或和共同连接的碳原子一起表示含有3-8个碳原子的取代或未取代的环烷基或含1-3个选自氧、硫的杂原子的取代或未取代的4-6元杂环基;
所述的C3-C6杂环基、C2-C9杂芳基至少含有一个选自N、O、S中的杂原子;
所述R2中取代或未取代的取代基可任选自以下基团:F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基。
3.根据权利要求1所述的化合物及其异构体、或其药学上可接受的盐,所述的化合物由通式(III)所示;
其中,
Y为C或N;
R1为H、C1-C3烷基、C1-C3烷氧基、F、Cl、Br、CN、OH、(=O)或(=S);
n为0、1或2;
R2为F、取代或未取代的C3-C6环烷基、取代或未取代的C3-C6杂环基、取代或未取代的C6-C10芳基、取代或未取代的C2-C9杂芳基、或和共同连接的碳原子一起表示含有3-8个碳原子的取代或未取代的环烷基或含1-3个选自氧、硫的杂原子的取代或未取代的4-6元杂环基;
所述的C3-C6杂环基、C2-C9杂芳基至少含有一个选自N、O、S中的杂原子;
所述R2中取代或未取代的取代基可任选自以下基团:F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基。
4.根据权利要求1或2所述的化合物及其异构体、或其药学上可接受的盐,所述的化合物由通式(II-a)所示:
其中,
R1为H、C1-C3烷基、F、Cl或(=O);
n为0或1;
R2为F、取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、或和共同连接的碳原子一起表示取代或未取代的环戊基或含1-2个选自氧、硫的杂原子的取代或未取代的5元杂环基;
所述R2中取代或未取代的取代基可任选自以下基团:F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基。
5.根据权利要求1或2所述的化合物及其异构体、或其药学上可接受的盐,所述的化合物由通式(II-b)所示:
其中,
R1为H、C1-C3烷基、F、Cl或(=O);
n为0或1;
R2为取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基或取代或未取代的噻唑基;
所述R2中取代或未取代的取代基可任选自以下基团:F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基。
6.根据权利要求1或3所述的化合物及其异构体、或其药学上可接受的盐,所述的化合物由通式(III-a)所示:
其中,
R1为H、C1-C3烷基、F、Cl或(=O);
n为0或1;
R2为F、取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、或和共同连接的碳原子一起表示取代或未取代的环戊基或含1-2个选自氧、硫的杂原子的取代或未取代的5元杂环基;
所述R2中取代或未取代的取代基可任选自以下基团:F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基。
7.根据权利要求1或3所述的化合物及其异构体、或其药学上可接受的盐,所述的化合物由通式(III-b)所示:
其中,
R1为H、C1-C3烷基、F、Cl或(=O);
n为0或1;
R2为取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基;
所述R2中取代或未取代的取代基可任选自以下基团:F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基。
8.根据权利要求2所述的化合物及其异构体、或其药学上可接受的盐,
其中,
R1为H、C1-C3烷基、C1-C3烷氧基、F、Cl、Br、CN、OH、(=O)或(=S);
n为0、1或2;
当Y为C时,
R2为F、
当Y为N时,
R2为
Rx为F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基。
9.根据权利要求3所述的化合物及其异构体、或其药学上可接受的盐,
其中,
R1为H、C1-C3烷基、C1-C3烷氧基、F、Cl、Br、CN、OH、(=O)或(=S);
n为0、1或2;
当Y为C时,
R2为F、
当Y为N时,
R2为
Rx为F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基或C1-C3烷胺基。
10.根据权利要求1至9任一项的化合物及其异构体,或其药学上可接受的盐,其选自下列化合物:
11.制备权利要求1至10任一项所述化合物的方法,其包括以下步骤:
(1)
化合物A与氮杂环侧链B经缩合得到式C化合物,然后在碱性条件下关环得到式(II)所示化合物;
或(2)
化合物D先与二硫化碳在碱性条件下反应,然后经甲基化得到化合物E,随后与氮杂环侧链B发生取代反应得到式(III)所示化合物,式(III)所示化合物可在已知的合适溶剂中用相应的酸处理,转化为药学上可接受的盐,其中,可接受的盐选自盐酸盐、对甲苯磺酸盐、酒石酸盐、马来酸盐、乳酸盐、甲磺酸盐、硫酸盐、磷酸盐、柠檬酸盐、乙酸盐或三氟乙酸盐,
其中,Y、R1、R2、n定义同权利要求1-9中任一项。
12.一种药物组合物,其包括治疗和/或预防有效量的权利要求1至10任一项所述的化合物及其异构体,或其药学上可接受的盐以及任选的一种或多种药学上可接受的载体、赋形剂、稀释剂、辅料和媒介物。
13.权利要求1-10任一项所述化合物及其异构体或其药学可接受的盐或者权利要求12所述组合物在制备治疗和/或预防由结核分枝杆菌引起的感染性疾病的药物中的应用。
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CN112694461A (zh) * | 2019-10-23 | 2021-04-23 | 中国医学科学院药物研究所 | 色满酮类化合物及其制备方法和用途 |
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