CN116490498A - 嘧啶并环类化合物及其用于制备治疗疼痛、脊髓损伤药物中的用途 - Google Patents
嘧啶并环类化合物及其用于制备治疗疼痛、脊髓损伤药物中的用途 Download PDFInfo
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- CN116490498A CN116490498A CN202280007273.1A CN202280007273A CN116490498A CN 116490498 A CN116490498 A CN 116490498A CN 202280007273 A CN202280007273 A CN 202280007273A CN 116490498 A CN116490498 A CN 116490498A
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
- C07D255/04—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 condensed with carbocyclic rings or ring systems
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- C07—ORGANIC CHEMISTRY
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- C07D405/12—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 linked by a chain containing hetero atoms as chain links
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Abstract
一种如式(I)所示的化合物、其立体异构体、互变异构体或其药学上可接受的盐,以及其用于制备治疗疼痛、脊髓损伤药物中的用途。
Description
本申请属于化学医药领域,具体涉及一种嘧啶并环类化合物及其用于制备治疗疼痛、脊髓损伤药物中的用途。
疼痛是身体痛苦和痛苦的一种常见形式,也是患者向医生报告的最常见原因之一。它可以形式(伤害性或神经性)、持续时间(慢性或急性)和程度(轻度、中度或重度)区分。通常,伤害性疼痛是急性的,由损伤引起,如烧伤、扭伤、烧伤、骨折或炎症(炎症性疼痛,包括骨关节炎和类风湿性关节炎)。另一方面,国际疼痛研究协会将神经病理性疼痛定义为一种由神经系统病变或功能障碍引起的慢性疼痛。通常,神经性疼痛是由糖尿病神经病变、HIV感染和带状疱疹后神经痛引起的。与神经病理性疼痛相关的其他疾病包括复杂的局部疼痛综合征、三叉神经痛、腰痛、坐骨神经痛、幻肢痛、冲击痛、纤维肌痛和其他导致慢性疼痛的疾病(见Jensen,European Journal of Pain,2002年)。
K
+-Cl
-协同转运蛋白KCC2负责维持中枢神经系统(CNS)神经元的低Cl
-浓度,这是通过GABAA和甘氨酸受体进行突触后抑制所必需的。虽然没有中枢神经系统疾病与KCC2突变相关,但这种转运体活性的丧失已成为一些神经和精神疾病的关键机制,包括癫痫、运动性痉挛、压力、焦虑、精神分裂症、吗啡引起的痛觉过敏和慢性疼痛。研究表明,增强KCC2活性可能是在涉及受损Cl
-转运的病理条件下恢复抑制和正常功能的有利治疗策略(Gagnon,Martin.et al.Nature Medicine(2013),19(11),1524-1528)。
现有研究还表明,KCC2激动剂通过选择性表达KCC2在交错脊髓损伤之间和周围的抑制性中间神经元中进行模拟,使得脊髓损伤的小鼠恢复了步进能力。从机制上讲,这些治疗方法将损伤引起的脊髓回路功能障碍转变为功能状态,促进脑源性指令向腰脊髓的传递。因此,KCC2激动剂有希望成为促进脊髓损伤后功能恢复的治疗方法(Bo Chen,Yi Li.et al.Cell(2018),174(3),521-535)。
发明内容
本申请公开了一种嘧啶并环类化合物,其可作为潜在的KCC2激动剂,以及用于制备治疗疼痛、脊髓损伤药物中的用途。
一方面,本申请提供了式(I)化合物、其立体异构体、互变异构体或其药学上可接受的盐:
其中,环A为含有0-4个杂原子、5-14个环原子的环烷基、杂环基、芳基或杂芳基;
环B为含有0-2个杂原子、5-7个环原子的环烷基、杂环基、芳基或杂芳基;
X为C或N;
R
1各自独立地选自氢、C
1-C
6烷基、C
3-C
6环烷基、C
2-C
6烯基、C
2-C
6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;
R
2各自独立地选自氢、C
1-C
6烷基、C
3-C
6环烷基、C
2-C
6烯基、C
2-C
6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;
m、n、n’选自0、1、2或3;以及
代表单键或双键。
在某些实施方案中,式(I)是式(Ia):
其中,环A为含有1-4个杂原子、5-14个环原子的杂环基或杂芳基;
环B为含有0-2个杂原子、5-7个环原子的环烷基、杂环基、芳基或杂芳基;
X为C或N;
R
1各自独立地选自氢、C
1-C
6烷基、C
3-C
6环烷基、C
2-C
6烯基、C
2-C
6炔基、 卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;
R
2各自独立地选自氢、C
1-C
6烷基、C
3-C
6环烷基、C
2-C
6烯基、C
2-C
6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;
m、n选自0、1、2或3;以及
代表单键或双键。
在某些实施方案中,式(I)是式(Ib):
其中,环A为含有1-3个杂原子、5-7个环原子的杂环基或杂芳基;
环B为含有0-2个杂原子、5-7个环原子的环烷基或杂环基;
R
1各自独立地选自氢、C
1-C
6烷基、C
3-C
6环烷基、C
2-C
6烯基、C
2-C
6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;
R
2各自独立地选自氢、C
1-C
6烷基、C
3-C
6环烷基、C
2-C
6烯基、C
2-C
6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;以及
m、n选自0、1、2或3。
在某些实施方案中,式(I)是式(Ic)或(Id):
其中,环B为含有0-2个杂原子、5-7个环原子的环烷基或杂环基;
R
1各自独立地选自氢、C
1-C
6烷基、C
3-C
6环烷基、C
2-C
6烯基、C
2-C
6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;
R
2各自独立地选自氢、C
1-C
6烷基、C
3-C
6环烷基、C
2-C
6烯基、C
2-C
6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;以及
m、n选自0、1、2或3。
在某些实施方案中,式(I)所示的化合物,其选自:
在某些实施方案中,其结构为:
在某些实施方案中,其结构为:
在某些实施方案中,其结构为:
前述化合物中任一位置的H可以为氘。
另一方面,本申请还提供一种药物组合物,其包含治疗有效量的前述的化合物,或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体;以及药学上可接受的载体或赋形剂。
另一方面,本申请还提供前述化合物,或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体用于制备KCC2激动剂药物中的用途。
另一方面,本申请还提供前述化合物,或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体用于制备治疗脊髓损伤药物中的用途。
另一方面,本申请还提供前述化合物,或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体用于制备镇痛药物中的用途。
术语:
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。
术语“异构体”包括给定结构的对映异构形式、非对映异构形式和几何(或构象)异构形式。例如,本申请包括每个不对称中心的R和S构型、Z和E双键异构体、Z和E构象异构体、单一立体化学异构体及对映异构体、非对映异构体和几何(或构象)异构体混合物。
术语“药学上可接受的盐”指,诸如其酸加成盐和/或碱盐。合适的酸加成盐由酸形成,其形成无毒盐,例如盐酸盐/氯化物。合适的碱盐由碱形成,其形成无毒盐,例如钙盐和钠盐。还可形成酸和碱的半盐,例如半硫酸盐和半钙盐。
术语“治疗有效量”是指本申请化合物的以下量,其(i)治疗具体的疾病、病症或障碍;(ii)减轻、缓解或消除具体的疾病、病症或障碍的一种或多种症状;或(iii)预防或延迟本申请所述具体的疾病、病症或障碍的一种或多种症状的发作。
术语“药学上可接受的载体或赋形剂”是指不破坏用其配制的化合物的药理活性的无毒载体、辅料或媒介物。
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至12个碳原子的烷基,更优选含有1至6个碳原子的烷基。含有1至6个碳原子的低级烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。
术语“烯基”指具有至少一个碳-碳双键的脂族烃,包括具有至少一个碳-碳双键的直链和支链。在一些实施方案中,烯基基团具有2至20个碳原子、2至10个碳原子、2至6个碳原子、3至6个碳原子或2至4个碳原子。例如,术语“C
2-6烯基”包括2至6个碳原子的直链或支链不饱和基团(具有至少一个碳-碳双键),包括但不限于乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基等。
术语“炔基”指具有至少一个碳-碳三键的脂族烃,包括具有至少一个碳-碳三键的直链和支链。在一些实施方案中,炔基基团具有2至20个碳原子、2至10个碳原子、2至6个碳原子、或3至6个碳原子。例如,“C
2-6炔基”包括2至6个碳原子的直链或支链不饱和基团(具有至少一个碳-碳三键)。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基),其中烷基如上所定义。烷氧基的非限制性实例包括:甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,优选包含3至12个碳原子,更优选包含3至6个碳原子(例如3、4、5或6个碳原子),最优选包含5至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等;多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多 环基团,其可以含有一个或多个双键,但每个环均不具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基,优选为单螺环烷基和双螺环烷基,更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。
术语“稠环烷基”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团,其中一个或多个环可以含有一个或多个双键,但每个环均不具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环烷基。
术语“桥环烷基”指5至20元,任意两个环共用两个不直接连接的碳原子的全碳多环基团,其可以含有一个或多个双键,但每个环均不具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,优选为双环、三环或四环,更优选为双环或三环。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1~4个是杂原子;更优选包含3至8个环原子,其中1~3个是杂原子;最优选包含5至6个环原子,其中1~2或1~3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等,优选四氢吡喃基、哌啶基、吡咯烷基。多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。其可以含有一个或多个双键,但每个环均不具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单螺杂环基和双螺杂环基,更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。
术语“稠杂环基”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个环可以含有一个或多个双键,但每个环均不具有完全共轭的π电子系统,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基,优选为双环或三环,更优选为5元/5元或5元/6元双环稠杂环基。
术语“桥杂环基”指5至14元,任意两个环共用两个不直接连接的原子的多环杂环基团,其可以含有一个或多个双键,但每个环均不具有完全共轭的π电子系统,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基,优选为双环、三环或四环,更优选为双环或三环。
所述杂环基包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基,其非限制性实例包括:
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至10元,例如苯基和萘基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。杂芳基优选为5至10元,含1至3个杂原子;更优选为5元或6元,含1至2个杂原子;优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基和哒嗪基等。
所述杂芳基包括如上所述的杂芳基稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,其非限制性实例包括:
术语“羟烷基”指被羟基取代的烷基,其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代,其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代,其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代,其中烷基如上所定义。
术语“氘代烷氧基”指烷氧基被一个或多个氘原子取代,其中烷氧基如上所定义。
术语“环烷基烷基”指烷基被一个或多个环烷基取代,其中环烷基和烷基如上所定义。
术语“环烷基氧基”指-O-环烷基,其中环烷基如上所定义。
术语“杂环基烷基”指烷基被一个或多个杂环基取代,其中杂环基和烷基如上所定义。
术语“芳基烷基”指烷基被一个或多个芳基取代,其中芳基和烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH
2。
术语“氰基”指-CN。
术语“硝基”指-NO
2。
术语“羧基”指-C(O)OH。
图1是实施例5化合物对SNI神经损伤模型的后爪机械性触诱发痛的效应。
图2是实施例4化合物对SNI神经损伤模型的后爪机械性触诱发痛的效应。
图3是实施例2化合物对SNI神经损伤模型的后爪机械性触诱发痛的效应。
中间体制备
中间体1.1的制备:4-(溴甲基)-3,5-二氯吡啶
步骤一:(3,5-二氯吡啶-4-基)甲醇的制备。3,5-二氯吡啶-4-甲醛(20.0g,113.63mmol,1.0eq.)硼氢化钠(6.44g,170.45mmol,1.5eq.)加入到MeOH(200mL)中,25℃反应12小时,反应结束后旋干,用EA(200mL)和水(200mL)萃取,有机相用饱和氯化钠洗一次,有机相用硫酸镁干燥,过滤,制砂,EA:PE=1:8柱层析得到标题化合物(15.1g,收率75.5%)。MS(m/z)=179[M+H]
+。
步骤二:4-(溴甲基)-3,5-二氯吡啶的制备。(3,5-二氯吡啶-4-基)甲醇(5.0g,28.08mmol,1.0eq.)三苯基膦(11.05g,42.13mmol,1.5eq.)四溴化碳(13.96g,42.13mmol,1.5eq.)加入到DCM(200mL)中,20℃反应12小时,反应结束后旋干,制砂,EA:PE=1:20柱层析得到标题化合物(5.6g,收率83.58%)。MS(m/z)=242[M+H]
+。
实施例1:2-(((3,5-二氯吡啶-4-基)甲基)硫)吡咯并[2,1-f][1,2,4]三嗪-4(3H)-酮
步骤一:1-氨基-1H-吡咯-2-羧酸乙酯的制备。0℃下,NaH(60%,3.73g,93.41mmol,1.3eq.)加入到DMF(100mL)中,氮气保护下加入1H-吡咯-2-羧酸乙酯(10.0g,71.86mmol,1.0eq.)和O-(2,4-二硝基-苯基)-羟胺(21.45g,107.79mmol,1.5eq.),25℃反应12小时,反应结束后旋干,将体系泼入水(200mL)中,用EA:甲叔醚=1:1(100mL)萃取两次,有机相用饱和氯化钠洗一次,有机相用硫酸镁干燥,过滤,制砂,EA:PE=1:8柱层析得到标题化合物(10g,收率85.4%)。MS(m/z)=155[M+H]
+。
步骤二:1-(3-苯甲酰基硫脲基)-1H-吡咯-2-羧酸乙酯的制备。1-氨基-1H-吡咯-2-羧酸乙酯(10.0g,64.86mmol,1.0eq.)加入到THF(100mL)中,然后加入苯甲酰异硫氰酸酯的THF(100mL)溶液(10.58g,64.86mmol,1.0eq.), 25℃反应12小时,反应结束后旋干,用PE:甲叔醚=9:1打浆,过滤,滤饼烘干,直接用于下一步。MS(m/z)=318[M+H]
+。
步骤三:2-硫代-2,3-二氢吡咯并[2,1-f][1,2,4]三嗪-4(1H)-酮的制备。1-(3-苯甲酰基硫脲基)-1H-吡咯-2-羧酸乙酯(18.86g,59.47mmol,1.0eq.)加入到2N的氢氧化钠溶液(118mL,4.0eq.)中,加热至85℃,反应1.5小时,降至室温后,加入乙醇(35mL),降温至0℃,加入乙酸(14.46g,240.85mmol,4.05eq.),25℃反应12小时,反应结束后析出的固体过滤烘干,直接用于下一步。MS(m/z)=168[M+H]
+。
步骤四:2-(((3,5-二氯吡啶-4-基)甲基)硫)吡咯并[2,1-f][1,2,4]三嗪-4(3H)-酮的制备。2-硫代-2,3-二氢吡咯并[2,1-f][1,2,4]三嗪-4(1H)-酮(660.9mg,3.95mmol,1.0eq.),4-(溴甲基)-3,5-二氯吡啶(1.0g,4.15mmol,1.05eq.)和三乙胺(599.5mg,5.92mmol,1.5eq.)加入到乙醇(10mL)中,25℃反应12小时,反应结束后析出的固体过滤,溶于THF中,制砂,THF:PE=1:1柱层析,得到标题化合物(1.4g,收率100%)。MS(m/z)=328[M+H]
+。
1H NMR(400MHz,DMSO)δ12.21(s,1H),8.66(s,2H),7.55-7.56(m,1H),6.87-6.88(m,1H),6.51-6.52(m,1H),4.63(s,2H)。
实施例2:2-(3,5-二氯吡啶-4-基甲基硫烷基)-3,5,6,7-四氢环戊嘧啶-4-酮
步骤一:2-硫代-1,2,3,5,6,7-六氢-4H-环戊[d]嘧啶-4-酮的制备。2-氧代环戊烷-1-羧酸乙酯(5.0g,32.42mmol,1.0eq.),硫脲(3.70g,48.63mmol,1.5eq.),DBU(7.40g,48.63mmol,1.5eq.)加入到乙腈(50mL)中,95℃反应12小时,反应结束后降至0℃,搅拌30分钟,析出的固体过滤,放入50mL水中,用2N盐酸调pH至1,过滤,烘干直接用于下一步。MS(m/z)=242[M+H]
+。
步骤二:2-(3,5-二氯吡啶-4-基甲基硫烷基)-3,5,6,7-四氢环戊嘧啶-4-酮的制备。2-硫代-1,2,3,5,6,7-六氢-4H-环戊[d]嘧啶-4-酮(6.31g,35.72mmol,1.0eq.),4-(溴甲基)-3,5-二氯吡啶(8.6g,37.50mmol,1.05eq.)和三乙胺(5.42g,53.53mmol,1.5eq.)加入到乙醇(100mL)中,25℃反应12小时,反应结束后析出的固体 过滤,固体用乙醇50mL打浆两次,烘干,得到标题化合物(7.6g,收率64.95%)。MS(m/z)=329[M+H]
+。
1H NMR(400MHz,DMSO)δ12.69(s,1H),8.66(s,2H),4.67(s,2H),2.77-2.80(m,2H),2.59-2.61(d,2H),1.94-2.01(m,2H)。
实施例3:2-((3,5-二氯吡啶-4-基)甲基)硫代)-5,7-二氢呋喃[3,4-d]嘧啶-4(3H)-酮
步骤一:2-氯-5,7-二氢呋喃[3,4-d]嘧啶-4-醇的制备。2,4-二氯-5,7-二氢呋喃[3,4-d]嘧啶(2.0g,10.47mmol,1.0eq.),3N的氢氧化钠溶液(17mL,52.35mmol,5.0eq.)加入到THF(20mL)中,50℃反应12小时,用3N盐酸调pH至6,加入EA(20mL)和水(20mL)萃取,有机相干燥,旋干,用EA(5mL)打浆,过滤,烘干,直接用于下一步。MS(m/z)=174[M+H]
+。
步骤二:2-巯基5,7-二氢呋喃[3,4-d]嘧啶-4-醇的制备。2-氯-5,7-二氢呋喃[3,4-d]嘧啶-4-醇(0.5g,2.89mmol,1.0eq.),硫氢化钠(0.19mg,3.47mmol,1.2eq.)加入到DMAc(5mL)中,100℃反应12小时,反应结束后,将体系泼入水中,析出的固体,过滤,烘干,直接用于下一步。MS(m/z)=171[M+H]
+。
步骤三:2-(((3,5-二氯吡啶-4-基)甲基)硫基)-5,7-二氢呋喃[3,4-d]嘧啶-4-醇的制备。2-巯基5,7-二氢呋喃[3,4-d]嘧啶-4-醇(0.213g,1.25mmol,1.0eq.),4-(溴甲基)-3,5-二氯吡啶(0.361g,1.501mmol,1.2eq.)和三乙胺(0.379g,3.75mmol,3.0eq.)加入到乙醇(10mL)中,25℃反应12小时,反应结束后析出的固体过滤,固体用乙醇(10mL)打浆两次,烘干,得到标题化合物(396mg,收率95%)。MS(m/z)=331[M+H]
+。
1H NMR(400MHz,DMSO)δ13.05(s,1H),8.67(s,2H),4.84-4.86(t,4H),4.68(s,2H)。
实施例4:2-((嘧啶-5-基甲基)硫基)-3,5,6,7-四氢-4H-环戊[d]嘧啶-4-酮
2-硫代-1,2,3,5,6,7-六氢-4H-环戊[d]嘧啶-4-酮(0.194g,1.15mmol,1.0eq.),5-氯甲基嘧啶(0.2g,1.211mmol,1.05eq.)和DIPEA(0.372g,2.88mmol,2.5eq.)加入到乙醇(10mL)中,80℃反应48小时,反应结束后旋干,固体用甲醇(5mL)打浆两次,烘干,得到标题化合物(120mg,收率40%)。MS(m/z)=261[M+H]
+。
1H NMR(400MHz,DMSO)δ12.61(s,1H),9.05(s,1H),8.86(s,2H)4.37(s,2H),2.74-2.77(m,2H),2.56-2.59(m,2H),1.93-1.97(m,2H)。
实施例5:2-(((3,5-二氯吡啶-4-基)甲基)硫基)-3,5,6,7-四氢-4H-吡咯并[3,4-d]嘧啶-4-酮盐酸盐
步骤一:4-氧代-2-硫代-1,2,3,4,5,7-六氢-6H-吡咯并[3,4-d]嘧啶-6-羧酸叔丁酯的制备。1-(叔丁基)3-乙基2-氧吡咯烷-1,3-二羧酸酯(20.00g,77.74mmol,1eq.)和硫脲(8.88g,116.60mmol,1.5eq.)在室温下加入到乙腈(300mL)中,加入DBU(17.75g,116.60mmol,1.5eq.)后加热到80℃反应16小时。反应液蒸干乙腈,加水溶解后用2N盐酸调pH=4~5,析出大量白色固体,过滤,滤饼水洗至中性,烘干得到标题化合物(17.20g,收率82.16%)。
步骤二:2-(((3,5-二氯吡啶-4-基)甲基)硫基)-4-氧代-3,4,5,7-四氢-6H-吡咯并[3,4-d]嘧啶-6-羧酸叔丁酯的制备。将4-氧代-2-硫代-1,2,3,4,5,7-六氢-6H-吡咯并[3,4-d]嘧啶-6-羧酸叔丁酯(9.50g,35.27mmol,1eq.)溶于EtOH(100mL)中,室温下加入4-(溴甲基)-3,5-二氯吡啶(12.75g,52.91mmol,1.5eq.)和TEA (5.35g,52.91mmol,1.5eq.),加完在室温下反应12小时。反应液中析出的固体直接过滤,滤饼用乙醇(20mL)洗涤,烘干得到标题化合物(11.35g,收率74.9%)。
步骤三:2-(((3,5-二氯吡啶-4-基)甲基)硫基)-3,5,6,7-四氢-4H-吡咯并[3,4-d]嘧啶-4-酮盐酸盐的制备。将2-(((3,5-二氯吡啶-4-基)甲基)硫基)-4-氧代-3,4,5,7-四氢-6H-吡咯并[3,4-d]嘧啶-6-羧酸叔丁酯(11.35g,26.44mmol,1eq.)溶于1,4-二氧六环(100mL)中,室温下加入HCl的二氧六环溶液(9.64g,264.37mmol,10eq.),加完在室温下反应8小时。反应液中析出的固体直接过滤,滤饼用二氧六环(50mL)洗涤,EA(50mL)洗涤,烘干滤饼得到标题化合物(7.90g,收率90.7%)。MS(m/z)=367[M+H]
+。
1H NMR(400MHz,DMSO-d6)δ=10.29(brs,2H),8.67(d,2H),4.68(s,2H),4.34(m,2H),4.26(m,2H)。
实施例6:2-(((3,5-二氯吡啶-4-基)甲基)硫基)-6-甲基-3,5,6,7-四氢-4H-吡咯并[3,4-d]嘧啶-4-酮
2-(((3,5-二氯吡啶-4-基)甲基)硫基)-3,5,6,7-四氢-4H-吡咯并[3,4-d]嘧啶-4-酮盐酸盐(100mg,0.303mmol,1.0eq.),多聚甲醛(40mg,0.455mmol,1.5eq.),硼氢化钠(17mg,0.455mmol,1.5eq.)加入到甲醇(5mL)中,70℃反应14小时。反应结束后,旋干加入水(10mL)打浆过滤,滤饼用甲醇(5mL)打浆过滤,固体烘干,得到标题化合物(20mg,收率19.23%)。MS(m/z)=344[M+H]
+。
1H NMR(400MHz,DMSO)δ12.59(s,1H),8.67(s,2H),4.68(s,2H),4.35(s,2H),4.17(s,2H),3.23-3.28(m,3H)。
实施例7:2-(((3,5-二氯吡啶-4-基)甲基)硫基)-3,5,6,7,8,9-六氢-4H-嘧啶[4,5-d]氮杂环庚烷-4-酮盐酸盐
参考实施例5的制备方法,得到标题化合物。MS(m/z)=393[M+H]
+。
1H NMR(400MHz,DMSO-d6)δ=9.64(brs,2H),8.66(s,2H),4.68(s,2H),3.23(t,2H),3.14(m,4H),2.94(t,2H)。
实施例8:2-((嘧啶-5-基甲基)硫代)-3,5,6,7,8,9-六氢-4H-嘧啶基[4,5-d]氮杂-4-酮盐酸盐
参考实施例5的制备方法,得到标题化合物。MS(m/z)=326[M+H]
+。
1H NMR(400MHz,DMSO-d6)δ=9.64(brs,2H),9.08(s,1H),8.92(s,2H),4.37(s,2H),3.19(t,2H),3.11(m,4H),2.90(t,2H)。
实施例9:2-(((3,5-二氯吡啶-4-基)甲基)硫基)-5,6,7,8-四氢喹唑啉-4(3H)-酮
参考实施例2的制备方法,得到标题化合物。MS(m/z)=343[M+H]+。
1H NMR (400MHz,DMSO)δ12.64(s,1H),8.65(s,2H),4.67(s,2H),2.55(s,2H),2.30(s,2H),1.64-1.71(m,4H)。
实施例10:2-(((四氢-2H-吡喃-4-基)甲基)硫基)-3,5,6,7-四氢-4H-环戊[d]嘧啶-4-酮
参考实施例4的制备方法,得到标题化合物。MS(m/z)=267[M+H]+。
1H NMR(400MHz,DMSO)δ12.53(s,1H),3.81-3.85(m,2H),3.22-3.28(m,2H)3.08-3.10(d,2H),2.70-2.74(m,2H),2.55-2.59(m,2H),1.90-1.98(m,2H),1.82-1.83(m,1H),1.63-1.66(d,2H),1.19-1.29(m,2H)。
实施例11:2-(((3,5-二氯吡啶-4-基)甲基)硫基)-7-(甲基磺酰基)-3,5,6,7,8,9-六氢-4H-嘧啶基[4,5-d]氮杂-4-酮
步骤一:2-(((3,5-二氯吡啶-4-基)甲基)硫基)-3,7-双(甲基磺酰基)-3,5,6,7,8,9-六氢-4H-嘧啶[4,5-d]氮杂-4-酮的制备。将2-(((3,5-二氯吡啶-4-基)甲基)硫基)-3,5,6,7,8,9-六氢-4H-嘧啶[4,5-d]氮杂环庚烷-4-酮盐酸盐(2.50g,7.00mmol,1eq.)加入DCM(50mL)中,室温下加入TEA(4.25g,41.99mmol,6.0eq.),原料溶解后用冰水浴冷却到0~5℃,滴加氯(甲基)二亚甲基-λ
6-亚砜的二氯甲烷溶液(3.21g,27.99mmol,4.0eq.),加完反应4小时。反应液加水(20mL)淬灭,分液,有机相蒸干得到粗品直接投入下一步反应。
步骤二:2-(((3,5-二氯吡啶-4-基)甲基)硫基)-7-(甲基磺酰基)-3,5,6,7,8,9-六氢-4H-嘧啶基[4,5-d]氮杂-4-酮的制备。将2-(((3,5-二氯吡啶-4-基)甲基)硫基)-3,7-双 (甲基磺酰基)-3,5,6,7,8,9-六氢-4H-嘧啶[4,5-d]氮杂-4-酮(3.59g,6.99mmol,1eq.)加入MeOH(35mL)中,室温下加K
2CO
3(1.93g,13.98mmol,2.0eq),加完反应12小时。粗品经100~200目硅胶柱分离纯化(洗脱剂:DCM:MeOH=30:1~10:1)得到标题化合物(650.0mg,收率:21.35%)。MS(m/z)=436.35[M+H]
+。
1H NMR(400MHz,DMSO-d6)δ=8.60(s,2H),4.47(s,2H),3.27(t,2H),3.17(t,2H),2.84(s,3H),2.72(t,2H),2.66(t,2H)
.。
实施例12:2-(((3,5-二氯吡啶-4-基)甲基)硫基)-7-甲基-3,5,6,7,8,9-六氢-4H-嘧啶基[4,5-d]氮杂-4-酮
步骤一:将2-硫代-1,2,3,5,6,7,8,9-八氢-4H-嘧啶[4,5-d]氮杂环庚烷-4-酮(990.0mg,5.02mmol,1eq.)加入MeOH(15mL)中,室温下加入(226.04mg,7.53mmol,1.5eq.)甲醛水溶液,加完搅拌1~2小时后,加入三乙酰氧基硼氢化钠STAB(2.13g,10.04mmol,2.0eq.)并反应2小时。反应液加水(10mL)淬灭,用碳酸钠固体调pH至碱性,过滤不溶固体,滤液蒸干后加乙醇溶解产品,过滤除去无机盐,滤液直接投入下一步反应。
步骤二:2-(((3,5-二氯吡啶-4-基)甲基)硫基)-7-甲基-3,5,6,7,8,9-六氢-4H-嘧啶基[4,5-d]氮杂-4-酮的制备。参考实施例2得到标题化合物。MS(m/z)=372.28[M+H]
+。
1H NMR(400MHz,DMSO-d6)δ=8.66(s,2H),4.68(s,2H),2.84~2.87(t,2H),2.67~2.70(t,2H),2.53~2.55(t,2H),2.43~2.46(t,2H),2.30(s,3H)。
实验例1 小鼠坐骨神经分支选择性神经损伤模型检测待试化合物的镇痛作用
实验所使用的成年雄性C57BL/6J小鼠,购于上海灵畅生物科技有限公司(8周龄鼠,体重约为21-23g)。实验动物饲养在SPF级(温度为21.0±2℃,湿度为40-70%,12/12小时明暗交替,3-5只/笼)的屏障环境。实验前适应饲养环境5-7天,允许自由进食与饮水。在动物实验执行过程中所涉及的相关操作流程遵循国际实验动物关爱与使用委员会的指导方针执行。所测化合物以及溶媒对照 每组动物数量为10只。采用腹腔给药,给药剂量为100mg/kg。所采用溶媒为含10%DMSO的20%HPCD溶液。所有待测化合物配制成5mg/mL母液,存储于4℃待用。
阳性对照CLP290结构:
给予C57BL/6J小鼠肌肉注射舒泰(
20mg/kg),待其完全麻醉后剃除左侧后腿及臀部毛发。用酒精和碘伏反复消毒皮肤,使用手术刀在切开小鼠后腿部皮肤,并用止血钳向下钝性分离皮下组织和肌肉,暴露坐骨神经分支。在保证保持腓肠神经完整性的前提下用6-0丝线结扎腓神经和胫神经,并从结扎处沿脚端剪除约1mm腓神经和胫神经分支。完毕后用生理盐水和棉签反复清洗创口,并手术缝合肌肉和皮肤,然后将实验小鼠放置于恒温箱内并待其苏醒。
实验所进行的冯弗雷纤毛机械痛敏测试所有行为学测试均遵循双盲准则。参考文献报道的50%缩爪阈值测试与计算方法(Chaplan et al.,1994),采用手动冯弗雷纤毛(von Frey filaments,North Coast Medical Inc.,USA)测量SNI造模小鼠给药前后不同时间点的缩爪阈值变化,用以评价待测化合物对机械痛敏的潜在镇痛作用。测试前先将C57BL/6J小鼠放置在金属铁丝网格支架上的单个透明有机玻璃容器65*85*60mm)中直至其停止明显的探索活动并处于趴伏不动的安静状态(约90-100分钟)。从0.008g力度冯弗雷纤毛开始施加不同强度的触觉刺激。透过金属网格空隙接触小鼠鼠后爪足底跖面,然后给予足够的力度促使其明显弯曲并持续2-3秒。每一相同力度刺激的冯弗雷纤毛重复测试3次,间隔大于5秒。如果10次刺激中出现缩爪阳性反应(迅速撤足、舔舐后爪、爪子退缩或者逃避刺激)低于6次,则换用力度较大的纤毛,相反其缩爪阳性反应≥6次,则换用力度较小的纤毛,如此重复测量直到其反应模式可用以计算出50%缩爪阈值。
通过各时间点的小鼠缩爪阈值变化取平均值进行归类整合。根据实验设计分组对数据采用GraphPad Prism 8软件进行作图及统计分析。实验数据表达为平均值±标准差(Mean±SEM)。采用重复测量双因素方差分析后邦费尼罗多重比较检验方法,当P<0.05时,对应的实验结果被视为具有显著统计差异。
采用手动冯弗雷纤毛(von Frey)测试小鼠后足的缩爪阈值(PWT)来评估机械性触诱发痛,其相应的测试时间点为待测化合物给药前、给药后0.5小时、1小时和2小时。图1、图2和图3显示,与溶媒对照组相比较,实施例2、实施例4以及实施例5的化合物在给药后0.5小时、1小时和2小时对机械性缩爪阈值有显著的逆转效应。在给药后0.5小时、1小时优于阳性化合物CLP290。
Claims (12)
- 一种如下式(I)所示的化合物、其立体异构体、互变异构体或其药学上可接受的盐:其中,环A为含有0-4个杂原子、5-14个环原子的环烷基、杂环基、芳基或杂芳基;环B为含有0-2个杂原子、5-7个环原子的环烷基、杂环基、芳基或杂芳基;X为C或N;R 1各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;R 2各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;m、n、n’选自0、1、2或3;以及代表单键或双键。
- 根据权利要求1所述的化合物,其中式(I)是式(Ia):其中,环A为含有1-4个杂原子、5-14个环原子的杂环基或杂芳基;环B为含有0-2个杂原子、5-7个环原子的环烷基、杂环基、芳基或杂芳基;X为C或N;R 1各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;R 2各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、 卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;m、n选自0、1、2或3;以及代表单键或双键。
- 根据权利要求1所述的化合物,其中式(I)是式(Ib):其中,环A为含有1-3个杂原子、5-7个环原子的杂环基或杂芳基;环B为含有0-2个杂原子、5-7个环原子的环烷基或杂环基;R 1各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;R 2各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;以及m、n选自0、1、2或3。
- 根据权利要求1所述的化合物,其中式(I)是式(Ic)或(Id):其中,环B为含有0-2个杂原子、5-7个环原子的环烷基或杂环基;R 1各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、 卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;R 2各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基;以及m、n选自0、1、2或3。
- 根据权利要求1所述的式(I)所示的化合物,其选自:
- 根据权利要求1所述的式(I)所示的化合物,其结构为:
- 根据权利要求1所述的式(I)所示的化合物,其结构为:
- 根据权利要求1所述的式(I)所示的化合物,其结构为:
- 一种药物组合物,其包含治疗有效量的权利要求1所述的化合物,或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体;以及药学上可接受的载体或赋形剂。
- 权利要求1所述的化合物,或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体用于制备KCC2激动剂药物中的用途。
- 权利要求1所述的化合物,或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体用于制备治疗脊髓损伤药物中的用途。
- 权利要求1所述的化合物,或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体用于制备镇痛药物中的用途。
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EP3356345B1 (en) * | 2015-09-30 | 2023-11-08 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Heteroaryl derivatives as sepiapterin reductase inhibitors |
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2022
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