CN115667244B - 3-氮杂二环烷基衍生物及包含其的药物组合物 - Google Patents
3-氮杂二环烷基衍生物及包含其的药物组合物 Download PDFInfo
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- CN115667244B CN115667244B CN202180036112.0A CN202180036112A CN115667244B CN 115667244 B CN115667244 B CN 115667244B CN 202180036112 A CN202180036112 A CN 202180036112A CN 115667244 B CN115667244 B CN 115667244B
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- Prior art keywords
- azabicyclo
- methylazetidin
- compound
- acetic acid
- heptan
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- 150000002367 halogens Chemical class 0.000 claims abstract description 7
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- -1 (S) -7-methyl-2- ((S) -2-methylazetidin-1-yl) -5, 7-dihydrofuro [3,4-d ] pyrimidin-4-yl Chemical group 0.000 claims description 58
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Classifications
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- C07D401/00—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
- C07D401/14—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 three or more hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- 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
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D403/14—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 three or more hetero rings
-
- 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
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- 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
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
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- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及:化学式1的化合物或其药学上可接受的盐或其异构体,以及包含其作为活性成分的用于治疗或预防代谢疾病的药物组合物。[化学式1]在化学式1中,R1表示未经取代的或经C1至C5烷基取代的含有一至三个N原子的C3至C7杂环烷基,R2和R3独立地表示氢、卤素或C1至C5烷基,R4表示‑(CH2)mCO2H,m、p和q各自独立地表示0至2的整数,X表示N或C‑CN,Y表示CH2或O,并且Z表示CH2或单键。
Description
技术领域
本发明涉及一种具有己酮糖激酶(KHK)抑制活性的新型3-氮杂二环烷基衍生化合物和含有该化合物作为活性成分的药物组合物。
背景技术
众所周知,代谢性疾病之一的非酒精性脂肪性肝炎(NASH)的病因主要包括脂肪肝的产生、炎症增加和细胞死亡。作为一种慢性疾病,NASH可能会逐渐发展为肝纤维化、肝硬化和肝癌。
同时,己酮糖激酶(KHK)是一种参与果糖代谢的酶,且是一种用于果糖代谢中果糖磷酸化的激酶。与葡萄糖代谢不同,由于果糖代谢不依从能量依赖性抑制,会导致快速脂肪堆积,并影响脂肪肝的生成。因此,当KHK被抑制时,可以期待抑制脂肪肝生成(为NASH原因之一)的效果。
在动物试验模型中,当KHK活性被抑制时,观察到代谢疾病的整体指标得到改善,KHK敲除小鼠的表型与正常小鼠没有区别,因此预期没有因KHK抑制而产生的严重副作用。
然而,由于KHK用于使用ATP进行磷酸化的事实,因KHK抑制可能抑制不同类型的激酶,故对于将KHK用作慢性病治疗剂的安全性存在甚多疑虑。因此,重要的是KHK抑制剂对不同的激酶没有选择性。
目前对KHK抑制剂的研究正在积极进行,但仍然需要开发一种可以有效地用于预防或治疗如糖尿病、糖尿病并发症、肥胖症、NASH或脂肪性肝炎等代谢疾病的治疗剂。
相关现有技术文献
(专利文献1)美国专利9,809,579号
发明内容
技术问题
本发明旨在提供一种具有己酮糖激酶(KHK)抑制活性的新型化合物或其药学上可接受的盐或异构体。
此外,本发明旨在提供一种用于预防或治疗代谢疾病的药物组合物,所述药物组合物包括上述化合物或其药学上可接受的盐或异构体。
此外,本发明旨在提供一种预防或治疗代谢疾病的方法,其包括将上述化合物或其药学上可接受的盐或异构体施用于受试者。
技术解决方案
本发明提供了下述化学式1的化合物或其药学上可接受的盐或异构体。
[化学式1]
在化学式1中,
R1为未经取代的或经C1至C5烷基取代的具有一至三个N原子的C3至C7杂环烷基,
R2和R3各自独立地为氢、卤素或C1至C5烷基,
R4为-(CH2)mCO2H,
m、p和q各自独立地为0至2的整数,
X为N或C-CN,
Y为CH2或O,并且
Z为CH2或单键。
此外,本发明提供一种用于抑制KHK的药物组合物,所述药物组合物包括上述化合物或其药学上可接受的盐或异构体,和药学上可接受的载体。
此外,本发明提供一种用于预防或治疗代谢性疾病的药物组合物,所述药物组合物包含上述化合物或其药学上可接受的盐或异构体,和药学上可接受的载体。
具体实施方式
在下文中,将更详细地描述本发明以帮助理解本发明。在此,说明书和申请专利范围中使用的术语和词语不应被解释为限于一般或字典术语的含义,而应当基于发明人已经为了用最好的方式来描述本发明而适当地定义术语的概念的原则,根据本发明的技术思想来解释含义和概念。
本发明提供了下述化学式1的化合物或其药学上可接受的盐或异构体。
[化学式1]
在化学式1中,
R1为未经取代的或经C1至C5烷基取代的具有一至三个N原子的C3至C7杂环烷基,
R2和R3各自独立地为氢、卤素或C1至C5烷基,
R4为-(CH2)mCO2H,
m、p和q各自独立地为0至2的整数,
X为N或C-CN,
Y为CH2或O,并且
Z为CH2或单键。
在整个说明书中,为了定义化学式1的化合物,使用如下定义的概念。除非另有特别说明,以下定义也适用于在整个说明书中单独使用或作为大群组的一部分使用的术语。除非另有定义,本文中使用的术语和缩写具有其原始含义。
术语“烷基”是指直链或支链烃基,且优选具有1至5、1至4或1至3个碳原子的直链或支链饱和或不饱和烃基。此外,烷基的每个碳原子可以任选地被一个或多个卤素取代。例如,经烷基或卤素取代的烷基可以是甲基、乙基、正丙基、异丙基、正丁基、叔丁基、戊基、氟甲基、三氟甲基、氟乙基或氟丙基,但本发明不限于此。
术语“杂环烷基”是指包括一个或多个选自N、O和S的杂原子作为环原子并构成单环或稠环的部分或完全饱和的烃。优选地,可以有1、1至2或1至3个杂原子。优选地,杂环烷基是具有一至三个N原子的C3至C7杂环烷基。例如,杂环烷基为氮杂环丁烷基、吡咯烷基、哌啶基、吗啉基、咪唑啉基或哌嗪基,但本发明不限于此。
术语“卤素”是指选自氟、氯、溴和碘的取代基。除非另有定义,本文中使用的其他术语和缩写具有其原始含义。
根据本发明的化学式1的化合物可以形成药学上可接受的盐。药学上可接受的盐包括由酸形成的酸加成盐,用以形成含有药学上可接受的阴离子的无毒酸加成盐的酸例如无机酸(如盐酸、磺酸、硝酸、磷酸、氢溴酸或氢碘酸),有机酸(如酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富马酸、马来酸或水杨酸),或磺酸(如甲磺酸、乙磺酸、苯磺酸或对甲苯磺酸)。
此外,药学上可接受的羧酸盐包括如由锂、钠、钾、钙或镁形成的碱金属或碱土金属盐,如赖氨酸、精氨酸或胍的氨基酸盐,以及如二环己胺、N-甲基-D-葡萄糖胺、三(羟甲基)甲胺、二乙醇胺、胆碱或三乙胺的有机盐。本发明的化学式1的化合物可以通过常规方法转化为其盐。
由于根据本发明的化合物具有不对称碳中心和不对称轴或不对称平面,它们可以存在为E或Z异构体、R或S异构体、外消旋物、非对映异构体的混合物或单独的非对映异构体,以及所有异构体及其混合物均包括在本发明的范围内。
下文中,除非另有说明,为方便起见,化学式1的化合物是指所有化学式1的化合物、其药学上可接受的盐及其异构体。
本发明的代表性化学式1的化合物可包括以下化合物,但本发明不限于此:
2-((1R,5S,6S)-3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;
2-((1R,5S,6S)-3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢异喹啉-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;
2-(3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-6,7,8,9-四氢-5H-环庚并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;
2-((1R,5S,6S)-3-(5-氰基-6-((S)-2-甲基氮杂环丁-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-8-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;
2-(3-(7,7-二甲基-2-((S)-2-甲基氮杂环丁-1-基)-5,7-二氢呋喃并[3,4-d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;
2-((1R,5S,6S)-3-((S)-7-甲基-2-((S)-2-甲基氮杂环丁-1-基)-5,7-二氢呋喃并[3,4-d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;
2-((1R,5S,6S)-3-((S)-7-甲基-2-((S)-2-甲基氮杂环丁-1-基)-5,7-二氢呋喃并[3,4-d]嘧啶-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸;
2-((1R,5S,6S)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;
2-((1R,5S,6S)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸;
2-((1R,5S,6S)-3-(8,8-二氟-2-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;
2-((1R,5S,6S)-3-(8,8-二氟-2-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸;和
2-((1R,5S,6S)-3-(8,8-二氟-2-(吡咯烷-1-基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸。
本发明的化学式1的化合物或其药学上可接受的盐或异构体具有己酮糖激酶(KHK)抑制活性。
本发明提供用作KHK抑制剂的化合物或其药学上可接受的盐或异构体。
本发明提供一种用于预防或治疗代谢疾病,特别是KHK相关代谢疾病的化合物或其药学上可接受的盐或异构体。
本发明的化学式1的化合物或其药学上可接受的盐或异构体适用于预防或治疗与KHK相关的代谢疾病。
本发明提供了一种用于KHK抑制剂的药物组合物,所述药物组合物包括化学式1的化合物或其药学上可接受的盐或异构体,和药学上可接受的载体。
此外,根据目的在体内转化为化学式1的化合物的各种类型的前药也包括在本发明的范围内。
本发明的药物组合物可用于预防或治疗与KHK相关的代谢疾病。KHK相关代谢疾病可以是糖尿病、糖尿病并发症、肥胖症、非酒精性脂肪性肝炎(NASH)或脂肪性肝炎,但本发明不限于此。优选地,根据本发明的药物组合物可用于预防或治疗NASH。
此外,本发明提供一种制备用于预防或治疗与KHK相关的代谢疾病,特别是糖尿病、糖尿病并发症、肥胖症、NASH或脂肪性肝炎的药物组合物的方法,所述方法包括将作为活性成分的化学式1的化合物或其药学上可接受的盐或异构体与药学上可接受的载体混合。
此外,本发明提供了化学式1的化合物或其药学上可接受的盐或异构体在制备用于治疗KHK相关代谢疾病的药物中的用途。KHK相关代谢疾病为糖尿病、糖尿病并发症、肥胖症、NASH或脂肪性肝炎,但本发明不限于此。
此外,“药物组合物”可以包括本发明的化合物和其他化学成分,例如稀释剂和载体。因此,药物组合物中可根据需要包括药学上可接受的载体、稀释剂或赋形剂或其组合。药物组合物有助于将化合物施用到生物体中。化合物的施用技术有多种,包括口服施用、注射、气雾剂施用、肠胃外施用和局部施用,但本发明不限于此。
术语“载体”是指有助于使化合物进入细胞或组织的化合物。例如,二甲基亚砜(DMSO)是一种常规载体,有助于使许多有机化合物进入生物体的细胞或组织。
术语“稀释剂”定义为不仅稳定目标化合物的生物活性形式,而且在水中稀释以溶解该化合物的化合物。溶解在缓冲液中的盐在本领域中用作稀释剂。常用的缓冲液是磷酸盐缓冲盐水,其模拟人类溶液的盐形式。由于缓冲盐可以在低浓度下控制溶液的pH值,因此缓冲稀释剂很少改变化合物的生物活性。
本文使用的术语“药学上可接受的”是指不损害化合物的生物活性和物理性质的性质。
本发明的化合物可以根据目的配制成各种药物剂型。在制备根据本发明的药物组合物时,具体上将作为活性成分的化学式1的化合物或其药学上可接受的盐或异构体,与可根据要制备的制剂选择出的各种药学上可接受的载体混合。例如,本发明的药物组合物可以根据目的配制成注射制剂或口服制剂。
本发明的化合物可以通过已知方法使用已知的药物载体和赋形剂来制备,并且可以包含在单位剂量形式或多剂量容器中。制剂的形式可以是在油或水性介质中的溶液、悬浮液或乳液,并且可以含有常规的分散剂、悬浮剂或稳定剂。此外,例如,该制剂可以为于使用前溶解在无菌无热原水中而使用的干粉。本发明的化合物也可以使用如可可脂或其他甘油酯的常规栓剂基质以制备成栓剂。用于口服施用的固体剂型可以是胶囊剂、片剂、丸剂、粉剂或颗粒剂,特别是胶囊剂和片剂均适用。片剂和丸剂优选用肠溶包衣剂制备。固体剂型可以通过将本发明的化合物与一种或多种如蔗糖、乳糖和淀粉的惰性稀释剂以及如润滑剂(如硬脂酸镁)、崩解剂和粘合剂的载体混合来制备。根据需要,本发明的化合物或包含其的药物组合物可以与其他药物,例如其他糖尿病治疗剂联合施用。
此外,本发明提供一种预防或治疗代谢疾病的方法,包括施用化学式1的化合物或其药学上可接受的盐或异构体;或向受试者施用包含其的药物组合物。
受试者可以是需要治疗或预防代谢疾病的人或人以外的哺乳动物,且代谢疾病可以是与KHK相关的代谢疾病。代谢性疾病的代表性实例可包括糖尿病、糖尿病并发症、肥胖症、NASH和脂肪性肝炎,但本发明不限于此,而优选为NASH。
本文使用的术语“治疗”是指当药物用于显示疾病症状的受试者时,中止、延迟或减缓疾病的进展,而“预防”是指当药物用于未显示疾病症状但具有高发病风险的受试者时,能中止、延迟或减缓疾病的发作。
本发明的化学式1的化合物或其药学上可接受的盐或异构体的剂量由医生根据患者的体重、年龄以及疾病的具体性质和严重程度所开具的处方来决定。然而,根据施用频率和强度,成人治疗所需的剂量通常在每天约1至500mg的范围内。当以肌肉内或静脉内方式施用给成人时,通常以分次日剂量施用大约每天1至300mg的本发明的化学式1的化合物的总剂量即已足够,但是对于一些患者,更高的日剂量可能是优选的。
本发明还提供制备化学式1的化合物的方法。以下,为帮助理解本发明,将以示例性反应方案叙述制备化学式1的化合物的方法。然而,本发明所属技术领域中的普通技术人员可以基于化学式1的结构通过不同方法制备化学式1的化合物,并且这些方法应理解为包括在本发明的范围内。即,化学式1的化合物可以通过将说明书中叙述的或相关领域中公开的不同合成方法任意组合来制备,其将理解为包括在本发明的范围内,并且制备该化学式1的化合物的方法不限于以下叙述。
制备本发明化合物时,可适当改变反应顺序。即,可以预先进行一个工序或者可以插入改变任何取代基的工序,并且根据需要,可以使用除示例试剂之外的任何其他试剂。各工序中得到的化合物可以通过重结晶、蒸馏、硅胶柱等常规方法进行分离或纯化。此外,可以在不分离或纯化每个工序中获得的化合物的情况下进行后续的工序。
在以下反应方案中,除非另有定义,所有取代基均与上述定义相同。试剂和起始材料可以很容易地自市面上取得。余者则可通过以下制备例和实施例中叙述的合成方法以及结构类似于本发明的已知化合物的合成方法制备。除非特别说明制备方法,否则作为起始材料的化合物是已知化合物,或者可为由已知化合物通过已知合成方法或其类似方法合成的化合物。
以下,参照制备例和实施例对本发明作进一步详细说明,但本发明的范围不限于此。
[制备例1]1,3-二氯-6,7-二氢-5H-环戊并[c]吡啶-4-甲腈的制备
通过以下步骤A和B制备制备例1的化合物。
(步骤A)1,3-二羟基-6,7-二氢-5H-环戊并[c]吡啶-4-甲腈的制备
将2-氧代环戊烷-1-甲酸乙酯(4.0g,25.6mmol)、2-氰基乙酰胺(2.15g,25.6mmol)和氢氧化钾(1.58g,28.2mmol)溶于甲醇(100ml)中,回流搅拌12小时。减压浓缩反应溶液后,加入1N盐酸溶液。将生成的固体过滤、水洗、氮气干燥,得到1,3-二羟基-6,7-二氢-5H-环戊并[c]吡啶-4-甲腈(1.5g,8.51mmol,33%)。
(步骤B)1,3-二氯-6,7-二氢-5H-环戊并[c]吡啶-4-甲腈的制备
步骤A得到的1,3-二羟基-6,7-二氢-5H-环戊并[c]吡啶-4-甲腈(1.5g,8.51mmol)、芐基三乙基氯化铵(3.6g,15.9mmol)和三氯化磷(3.7ml,39.7mmol)在100℃的反应温度下反应5小时。减压浓缩反应溶液后,加入水,再用乙酸乙酯萃取。有机层用氯化钠水溶液、碳酸氢钠水溶液和水洗涤,再以无水硫酸镁干燥,然后过滤。减压浓缩滤液后,用柱色谱法(乙酸乙酯/己烷=1/5)纯化,得到1,3-二氯-6,7-二氢-5H-环戊并[c]吡啶-4-甲腈(1.0g,4.69mmol,55%)。
1H-NMR(500MHz,CDCl3)δ3.23(t,J=7.8Hz,2H),3.06(t,J=7.6Hz,2H),2.30(t,J=7.6Hz,2H)
[制备例2]1,3-二氯-5,6,7,8-四氢异喹啉-4-甲腈的制备
通过制备例1中叙述的方法,使用2-氧代环己烷-1-甲酸乙酯(5.0g,29.4mmol)代替2-氧代环戊烷-1-甲酸乙酯以得到1,3-二氯-5,6,7,8-四氢异喹啉-4-甲腈(1.0g,4.40mmol,15%)。
1H-NMR(500MHz,CDCl3)δ2.99(d,J=5.6Hz,2H),2.77(t,J=5.6Hz,2H),1.89(d,J=5.5Hz,4H)
[制备例3]1,3-二氯-6,7,8,9-四氢-5H-环庚并[c]吡啶-4-甲腈的制备
通过制备例1中描述的方法,使用2-氧代环庚烷-1-甲酸甲酯(2.0g,11.8mmol)代替2-氧代环戊烷-1-甲酸乙酯以得到1,3-二氯-6,7,8,9-四氢-5H-环庚并[c]吡啶-4-甲腈(660mg,2.74mmol,23%)。
1H-NMR(500MHz,CDCl3):δ3.15(t,J=5.5Hz,2H),3.08(t,J=5.5Hz,2H),1.92(q,J=5.9Hz,2H),1.83-1.72(m,2H),1.72-1.61(m,2H)
[制备例4]6,8-二氯-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-甲腈的制备
通过制备例1中描述的方法,使用4-氧代四氢-2H-吡喃-3-甲酸乙酯(2.0g,11.6mmol)代替2-氧代环戊烷-1-甲酸乙酯以得到6,8-二氯-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-甲腈(200mg,0.87mmol,7.5%)。
1H-NMR(500MHz,CDCl3)δ4.73(s,2H),4.08-3.96(2H),3.06(t,J=5.5Hz,2H)
[制备例5](S)-2,4-二氯-7-甲基-5,7-二氢呋喃并[3,4-d]嘧啶的制备
通过以下步骤A、B、C和D制备制备例5的化合物。
(步骤A)(5S)-5-甲基-4-氧代四氢呋喃-3-甲酸甲酯的制备
将(S)-2-羟基丙酸甲酯(42.0g,38.4mmol)和氢化钠(1.54g,60%,38.4mmol)溶于四氢呋喃(100ml)中,于0℃下搅拌30分钟,再减压浓缩。
将丙烯酸甲酯(3.46ml,38.4mmol)和二甲基亚砜(30ml)加入至该浓缩物中,于室温搅拌12小时以完成反应。于所得反应溶液中加入1N盐酸溶液,再用乙酸乙酯萃取。所得萃取液用饱和氯化钠洗涤,再以无水硫酸镁干燥后,过滤,然后减压蒸馏所得滤液。将所得产物以柱色谱法(乙酸乙酯/己烷=1/5)纯化,从而获得(5S)-5-甲基-4-氧代四氢呋喃-3-甲酸甲酯(2.0g,12.7mmol,33%)。
1H-NMR(400MHz,CDCl3)δ4.61-4.56(0.3H),4.52(d,J=9.2Hz,0.7H),4.38-4.23(m,1H),3.98(d,J=6.7Hz,0.3H),3.91(d,J=7.0Hz,0.7H),3.85-3.74(3H),3.62-3.47(m,1H),1.35(dd,J=6.9,2.3Hz,3H)
(步骤B)(S)-5-甲基-4-脲基-2,5-二氢呋喃-3-甲酸甲酯的制备
将步骤A得到的(5S)-5-甲基-4-氧代四氢呋喃-3-甲酸甲酯(4.0g,25.3mmol)、尿素(7.6g,126mmol)和浓硫酸(1.35ml,25.3mmol)溶解在甲醇(100ml)中,再于回流下搅拌8小时。减压浓缩所得反应溶液后,加入过量的水以沉淀出固体。然后,过滤沉淀出的固体,再以氮气干燥,从而获得(S)-5-甲基-4-脲基-2,5-二氢呋喃-3-甲酸甲酯(2.0g,9.99mmol,40%)。
1H-NMR(400MHz,DMSO-D6)δ9.19-9.03(m,1H),6.97(s,2H),5.59(t,J=5.2Hz,1H),4.66-4.44(m,2H),3.68(d,J=6.4Hz,3H),2.51(s,1H),1.37-1.15(3H)
(步骤C)(S)-7-甲基-5,7-二氢呋喃并[3,4-d]嘧啶-2,4-二醇的制备
将步骤B得到的(S)-5-甲基-4-脲基-2,5-二氢呋喃-3-甲酸甲酯(2.0g,9.99mmol)溶于28%氨水(20ml)中,再于60℃下搅拌12小时。反应完成后,进行减压浓缩。于浓缩物中加入1N盐酸溶液后,用乙酸乙酯萃取。所得萃取液用饱和氯化钠洗涤,再以无水硫酸镁干燥,过滤后,减压蒸馏所得滤液。所得产物通过柱色谱法(甲醇/二氯甲烷=1/9)纯化,从而获得(S)-7-甲基-5,7-二氢呋喃并[3,4-d]嘧啶-2,4-二醇(1.0g,5.95mmol,60%)。
1H-NMR(400MHz,DMSO-D6)δ11.40(s,1H),11.02(s,1H),5.06-4.93(m,1H),4.78-4.67(1H),4.63(dd,J=10.5,2.6Hz,1H),3.32(s,2H),2.57-2.45(4H),1.36(d,J=6.4Hz,4H)
(步骤D)(S)-2,4-二氯-7-甲基-5,7-二氢呋喃并[3,4-d]嘧啶的制备
将步骤C得到的(S)-7-甲基-5,7-二氢呋喃并[3,4-d]嘧啶-2,4-二醇(1.0g,5.95mmol)、芐基三乙基氯化铵(1.4g,5.95mmol)和三氯化磷(8.3ml)溶于二氯乙烷(20ml)中,于100℃下反应8小时。减压浓缩反应溶液后,加入水,再以乙酸乙酯萃取。以饱和氯化钠水溶液、碳酸氢钠水溶液和水洗涤有机层,再以无水硫酸镁干燥并过滤。减压浓缩滤液,通过柱色谱法(乙酸乙酯/己烷=1/5)纯化,即得到(S)-2,4-二氯-7-甲基-5,7-二氢呋喃并[3,4-d]嘧啶(1.0g,4.88mmol,82%)。
1H-NMR(400MHz,CDCl3)δ5.25(td,J=4.4,2.2Hz,1H),5.12(ddd,J=32.0,13.7,2.1Hz,2H),1.58(d,J=6.4Hz,3H)
[制备例6]4-氯-7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊并[d]嘧啶
通过以下步骤A、B、C、D、E和F制备制备例6的化合物。
(步骤A)6-乙氧基-5,6-二氧代己酸的制备
将2-氧代环戊烷-1-甲酸乙酯(4.0g,25.6mmol)和氢化钠(1.0g,60%,25.6mmol)溶于四氢呋喃(100ml)中,于0℃下搅拌30分钟,然后在减压下浓缩。于反应溶液中加入亚硝基苯(2.88g,26.9mmol),再于0℃下搅拌30分钟以完成反应。于所得反应溶液中加入1N盐酸溶液,再以乙酸乙酯萃取。将所得萃取液以饱和氯化钠水溶液洗涤后以无水硫酸镁干燥,再减压蒸馏所得滤液,从而获得6-乙氧基-5,6-二氧代己酸(3.6g,19.1mmol)。所得物质不经纯化用于以下反应。
1H-NMR(400MHz,CDCl3)δ4.31(q,J=7.2Hz,2H),2.94(t,J=7.1Hz,2H),1.96(t,J=6.8Hz,2H),1.36(t,J=7.2Hz,2H)
(步骤B)2-氧代己二酸1-乙基-6-甲基酯的制备
将步骤A得到的6-乙氧基-5,6-二氧代己酸(3.6g,19.1mmol)溶解于乙醚(100ml)中,然后在0℃下缓慢滴加0.15M的重氮甲烷醚溶液(127ml,19.1mmol)。减压浓缩所得反应溶液,通过柱色谱法(乙酸乙酯/己烷=1/2)纯化,从而获得2-氧代己二酸1-乙基-6-甲基酯(2.7g,13.4mmol,52%,2-步骤得率)。
1H-NMR(500MHz,CDCl3)δ4.34(q,2H),3.69(s,3H),2.95(t,2H),2.41(t,2H),1.99(m,2H),1.39(t,3H)
(步骤C)2,2-二氟己二酸1-乙基-6-甲基酯的制备
将步骤B得到的2-氧代己二酸1-乙基-6-甲基酯(2.8g,13.4mmol)和二乙胺基三氟化硫(6.7g,41.5mmol)溶于氯仿(150ml)中,于0℃下搅拌3小时。于所得反应溶液中加入过量的水,再以乙酸乙酯进行萃取。用氯化钠水溶液、碳酸氢钠水溶液和水洗涤有机层后,以无水硫酸镁干燥并过滤。减压浓缩滤液,通过柱色谱法(乙酸乙酯/己烷=1/10)纯化,从而获得2,2-二氟己二酸1-乙基-6-甲基酯(0.9g,4.01mmol,30%)。
1H-NMR(500MHz,CDCl3)δ4.35(q,2H),3.69(s,3H),2.42(m,2H),2.14(m,2H),1.86(m,2H),1.38(t,3H)
(步骤D)2-乙氧基-3,3-二氟-2-羟基环戊烷-1-甲酸甲酯的制备
将步骤C得到的2,2-二氟己二酸1-乙基-6-甲基酯(0.9g,4.01mmol)和叔丁醇钾(473mg,4.21mmol)溶于四氢呋喃(100ml)中,于室温搅拌8小时。于所得反应溶液中加入1N盐酸溶液,再以乙酸乙酯萃取。用氯化钠水溶液、碳酸氢钠水溶液和水洗涤有机层后,用无水硫酸镁干燥并过滤。减压浓缩滤液,从而获得2-乙氧基-3,3-二氟-2-羟基环戊烷-1-甲酸甲酯。所得材料不经纯化用于后续反应。
(步骤E)7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊并[d]嘧啶-4-醇的制备
将步骤D得到的2-乙氧基-3,3-二氟-2-羟基环戊烷-1-甲酸甲酯(540mg,2.41mmol)、甲基异硫脲半硫酸盐(672mg,4.82mmol)和碳酸钠(767mg,7.24mmol)溶于水(50ml),于室温搅拌12小时。于所得反应溶液中加入过量的水,再以乙酸乙酯进行萃取。用氯化钠水溶液洗涤有机层后,用无水硫酸镁干燥,再经过滤后,减压浓缩滤液,再以柱色谱法纯化(乙酸乙酯/己烷=1/1),得到7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊并[d]嘧啶-4-醇(250mg,1.15mmol,48%)。
1H-NMR(400MHz,CDCl3)δ10.92(s,1H),2.84(m,2H),2.68(s,3H),2.50-2.63(m,2H)
(步骤F)4-氯-7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊并[d]嘧啶的制备
步骤E得到的7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊并[d]嘧啶-4-醇(200mg,1.15mmol)、三氯化磷(1.1ml,11.5mmol))和三乙胺(0.3ml,2.3mmol)溶于二氯乙烷(30ml),120℃反应2小时。减压浓缩反应溶液后,加入水,用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥并过滤后。滤液减压浓缩,以柱色谱法纯化(甲醇/二氯甲烷=1/19),得到4-氯-7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊并[d]嘧啶(130mg,0.55mmol,48%)。
1H-NMR(400MHz,CDCl3)δ2.95-3.00(m,2H),2.58-2.68(m,2H),2.65(s,3H)
[制备例7]4-氯-8,8-二氟-2-(甲硫基)-5,6,7,8-四氢喹唑啉的制备
通过以下程序制备制备例7的化合物。
通过制备例6的步骤A至E所述的方法,使用2-氧代环己烷-1-甲酸乙酯(20.0g,117.5mmol)代替2-氧代环戊烷-1-甲酸乙酯以得到8,8-二氟-2-(甲硫基)-5,6,7,8-四氢喹唑啉-4-醇(6.25g,26.9mmol,23%,4步骤)。
将8,8-二氟-2-(甲硫基)-5,6,7,8-四氢喹唑啉-4-醇(3.0g,12.9mmol)、三氯化磷(12.8ml,129.2mmol)和三乙胺(0.89ml,6.45mmol)溶于二氯乙烷(200ml),于100℃下反应1小时。减压浓缩反应溶液后,加入水,再用乙酸乙酯萃取。用饱和氯化钠水溶液洗涤有机层,再以无水硫酸镁干燥并过滤。减压浓缩滤液,通过柱色谱法(己烷/乙酸乙酯=2/1)纯化,得到4-氯-8,8-二氟-2-(甲硫基)-5,6,7,8-四氢喹唑啉(2.43g,9.72mmol,75%)。
1H-NMR(500MHz,CDCl3)δ2.85-2.71(m,2H),2.60(s,3H),2.43-2.24(m,2H),2.04(tt,J=9.4,3.2Hz,2H)
制备例7合成相关中间体的NMR结果如下:
7-乙氧基-6,7-二氧代庚酸:1H-NMR(400MHz,CDCl3)δ4.40-4.25(m,2H),3.49(t,J=1.5Hz,1H),2.87(t,J=6.1Hz,2H),2.46-2.32(m,2H),1.77-1.61(m,4H),1.44-1.30(m,3H)
2-氧代庚二酸1-乙基-7-甲基酯:1H-NMR(400MHz,CDCl3)δ4.33(qd,J=7.1,1.0Hz,2H),3.68(d,J=1.2Hz,3H),2.88(d,J=5.2Hz,2H),2.36(s,2H),1.76-1.61(5H),1.38(td,J=7.1,1.0Hz,3H)
2,2-二氟庚二酸1-乙基-7-甲基酯:1H-NMR(400MHz,CDCl3)δ4.34(q,J=7.1Hz,2H),3.69(s,3H),2.35(t,J=7.5Hz,2H),2.09(t,J=8.2Hz,2H),1.71(t,J=7.6Hz,2H),1.53(t,J=8.1Hz,2H),1.37(t,J=7.0Hz,3H)
8,8-二氟-2-(甲硫基)-5,6,7,8-四氢喹唑啉-4-醇:1H-NMR(400MHz,DMSO-D6)δ2.50(s,3H),2.46-2.35(2H),2.23(t,J=6.4Hz,2H),1.80(t,J=6.3Hz,2H)
[实施例1]
2-((1R,5S,6S)-3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸
通过以下步骤A、B和C制备实施例1的化合物。
(步骤A)2-(3-(3-氯-4-氰基-6,7-二氢-5H-环戊并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯的制备
将制备例1得到的1,3-二氯-6,7-二羟基-5H-环戊并[c]吡啶-4-甲腈(100mg,0.47mmol)、2-(3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯盐酸盐(97mg,0.47mmol)和二异丙基乙胺(0.33ml,1.88mmol)溶解在二烷(10ml)中,于50℃下搅拌8小时。反应完成后,加入1N盐酸水溶液,再以乙酸酯萃取。用氯化钠水溶液、碳酸氢钠水溶液和水洗涤有机层后,用无水硫酸镁干燥,再过滤。减压浓缩滤液后,以柱色谱法(乙酸乙酯/己烷=1/5)纯化,得到2-(3-(3-氯-4-氰基-6,7-二氢-5H-环戊并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯(60mg,0.17mmol,37%)。
(步骤B)2-(3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯的制备
将步骤A得到的2-(3-(3-氯-4-氰基-6,7-二氢-5H-环戊并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯(60mg,0.17mmol)、(S)-2-甲基氮杂环丁烷盐酸盐(27mg,0.26mmol)和碳酸钾(94mg,0.68mmol)溶解在N-甲基吡咯烷(4ml)中,于100℃下搅拌12小时。反应结束后,加入1N盐酸水溶液,再用乙酸酯萃取。用氯化钠水溶液、碳酸氢钠水溶液和水洗涤有机层后,用无水硫酸镁干燥,再过滤。减压浓缩滤液后,通过柱色谱法(乙酸乙酯/己烷=1/5)纯化,从而获得2-(3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯(35mg,0.092mmol,54%)。
(步骤C)2-((1R,5S,6S)-3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸的制备
将步骤B得到的2-(3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯(35mg,0.092mmol)和氢氧化锂一水合物(15mg,0.37mmol)溶解在20%四氢呋喃溶液(5ml)中后,在室温搅拌10小时。反应结束后,加入1N盐酸水溶液,再用乙酸酯萃取。用氯化钠水溶液洗涤有机溶液后,以无水硫酸镁干燥,再过滤。减压浓缩滤液后,用柱色谱法(乙酸乙酯/己烷=1/2)纯化,得到2-((1R,5S,6S)-3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸(10mg,0.027mmol,29%,极性相对较大的化合物)和2-((1R,5S,6R)-3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸(极性相对较小的化合物)。
1H-NMR(500MHz,CDCl3)δ4.58(q,J=6.7Hz,1H),4.41(td,J=8.4,4.5Hz,1H),4.15-3.86(m,5H),3.24-3.10(2H),2.85(t,J=7.6Hz,2H),2.73(d,J=7.9Hz,2H),2.48-2.28(m,4H),2.14(dd,J=13.1,7.6Hz,1H),2.07-1.93(m,3H),1.58-1.39(m,4H)
[实施例2]
2-((1R,5S,6S)-3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢异喹啉-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸
通过实施例1所述的方法,使用制备例2中得到的1,3-二氯-5,6,7,8-四氢异喹啉-4-甲腈(100mg,0.44mmol)来代替1,3-二氯-6,7-二羟基-5H-环戊并[c]吡啶-4-甲腈,以得到2-((1R,5S,6S)-3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢异喹啉-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸(11mg,0.029mmol 7%,3步骤)。
1H-NMR(500MHz,CDCl3)δ4.58(q,J=6.8Hz,1H),4.42(td,J=8.5,4.6Hz,1H),4.09-3.94(m,3H),3.89(dd,J=11.3,4.9Hz,2H),2.80(dd,J=15.4,6.9Hz,2H),2.73(d,J=7.9Hz,2H),2.63-2.49(m,2H),2.44-2.25(m,4H),2.26-2.12(m,1H),1.98(t,J=9.5Hz,1H),1.77(t,J=6.4Hz,2H),1.71-1.57(m,2H),1.52(dd,J=8.8,5.5Hz,1H),1.48(d,J=6.1Hz,3H)
[实施例3]
2-(3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-6,7,8,9-四氢-5H-环庚并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸
通过实施例1所述的方法,使用制备例3中得到的1,3-二氯-6,7,8,9-四氢-5H-环庚并[c]吡啶-4-甲腈(80mg,0.21mmol)来代替1,3-二氯-6,7-二羟基-5H-环戊并[c]吡啶-4-甲腈,以得到2-(3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-6,7,8,9-四氢-5H-环庚并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸(9.4mg,0.05mmol 24%,3步骤)。
1H-NMR(400MHz,CDCl3)δ4.56(q,J=6.9Hz,1H),4.41(td,J=8.7,4.6Hz,1H),4.08-3.92(m,2H),3.82(dd,J=16.9,11.9Hz,2H),3.71(d,J=11.4Hz,1H),2.87(dd,J=11.4,6.9Hz,2H),2.69(d,J=7.8Hz,2H),2.64(q,J=5.9Hz,2H),2.43-2.31(m,1H),2.30-2.22(m,3H),2.17(dd,J=13.3,8.2Hz,1H),2.04-1.90(m,1H),1.79(t,J=3.0Hz,2H),1.74-1.50(m,5H),1.44(d,J=5.9Hz,3H)
[实施例4]
2-((1R,5S,6S)-3-(5-氰基-6-((S)-2-甲基氮杂环丁-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-8-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸
通过实施例1所述的方法,使用制备例4中得到的6,8-二氯-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-甲腈(100mg,0.44mmol)来代替1,3-二氯-6,7-二羟基-5H-环戊并[c]吡啶-4-甲腈,以得到2-((1R,5S,6S)-3-(5-氰基-6-((S)-2-甲基氮杂环丁-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-8-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸(11mg,0.029mmol 7%,3步骤)。
1H-NMR(500MHz,CDCl3)δ4.71(s,2H),4.60(q,J=6.8Hz,1H),4.43(td,J=8.5,4.8Hz,1H),4.05(q,J=8.2Hz,2H),4.00-3.77(m,8H),2.88(t,J=5.8Hz,2H),2.73(d,J=7.9Hz,2H),2.48-2.26(m,5H),2.15(dd,J=13.1,7.6Hz,1H),1.99(t,J=9.6Hz,1H),1.56-1.39(m,5H)
[实施例5]
2-(3-(7,7-二甲基-2-((S)-2-甲基氮杂环丁-1-基)-5,7-二氢呋喃并[3,4-d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸
通过实施例1所述的方法,使用2,4-二氯-7,7-二甲基-5,7-二氢呋喃并[3,4-d]嘧啶(参考JMC,54(9),3426,2011中提出的合成方法;130mg,0.59mmol)来代替1,3-二氯-6,7-二羟基-5H-环戊并[c]吡啶-4-甲腈,以得到2-(3-(7,7-二甲基-2-((S)-2-甲基氮杂环丁-1-基)-5,7-二氢呋喃并[3,4-d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸(6mg,0.016mmol 3%,3步骤)。
1H-NMR(500MHz,CDCl3):δ5.24(d,J=7.0Hz,2H),4.49-4.36(1H),4.10-3.98(m,1H),3.98-3.91(m,1H),3.90-3.71(m,4H),2.72(d,J=7.9Hz,1H),2.65(s,0H),2.58(t,J=5.5Hz,1H),2.47-2.28(m,4H),2.20-2.06(m,1H),2.03-1.89(m,1H),1.51(d,J=6.1Hz,3H),1.48-1.37(m,7H)
[实施例6]
2-((1R,5S,6S)-3-((S)-7-甲基-2-((S)-2-甲基氮杂环丁-1-基)-5,7-二氢呋喃并[3,4-d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸
通过实施例1所述的方法,使用制备例5中得到的(S)-2,4-二氯-7-甲基-5,7-二氢呋喃并[3,4-d]嘧啶(63mg,0.31mmol)来代替1,3-二氯-6,7-二羟基-5H-环戊并[c]吡啶-4-甲腈,以得到2-((1R,5S,6S)-3-((S)-7-甲基-2-((S)-2-甲基氮杂环丁-1-基)-5,7-二氢呋喃并[3,4-d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸(30mg,0.8mmol 26%,3步骤)。
1H-NMR(400MHz,CDCl3)δ5.73-5.35(m,2H),5.27(ddd,J=31.8,10.1,2.1Hz,2H),5.10-4.92(m,1H),4.45(dd,J=8.5,5.7Hz,1H),4.16-4.01(1H),4.01-3.92(1H),3.91-3.67(m,4H),2.70(d,J=8.2Hz,2H),2.45-2.27(m,4H),2.24-2.06(m,1H),2.04-1.89(1H),1.58-1.46(3H),1.42(dd,J=14.2,5.9Hz,4H)
[实施例7]
2-((1R,5S,6S)-3-((S)-7-甲基-2-((S)-2-甲基氮杂环丁-1-基)-5,7-二氢呋喃并[3,4-d]嘧啶-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸
通过实施例1所述的方法,使用制备例5中得到的(S)-2,4-二氯-7-甲基-5,7-二氢呋喃并[3,4-d]嘧啶(78mg,0.38mmol)来代替1,3-二氯-6,7-二羟基-5H-环戊并[c]吡啶-4-甲腈,且使用2-((1R,5S,6S)-3-氮杂二环[3.1.0]己烷-6-基)乙酸乙酯(78mg,0.57mmol)来代替2-(3-氮杂二环[3.1.1]庚烷-6-基)乙酸甲酯盐酸盐,以得到2-((1R,5S,6S)-3-((S)-7-甲基-2-((S)-2-甲基氮杂环丁-1-基)-5,7-二氢呋喃并[3,4-d]嘧啶-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸(13mg,0.04mmol 11%,3步骤)。
1H-NMR(400MHz,CDCl3):δ5.25-5.06(m,2H),4.97(t,J=6.3Hz,1H),4.48-4.34(m,1H),4.02(td,J=8.6,4.5Hz,1H),3.94(q,J=7.9Hz,1H),3.81(d,J=25.3Hz,2H),3.65-3.48(m,2H),2.44-2.28(m,3H),1.96(t,J=9.0Hz,1H),1.60-1.48(m,5H),1.43(d,J=6.4Hz,3H),1.01(d,J=2.7Hz,1H)
[实施例8]
2-((1R,5S,6S)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸
通过以下步骤A、B、C和D制备实施例8的化合物。
(步骤A)2-(3-(7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯的制备
将制备例6得到的4-氯-7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊并[d]嘧啶(130mg,0.55mmol)、2-(3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯盐酸盐(121mg,0.55mmol)和二异丙基乙胺(0.29ml,1.65mmol)溶解在二烷(10ml)中,在50℃下搅拌8小时。反应完成后,加入1N盐酸水溶液,再以乙酸酯萃取。用氯化钠水溶液、碳酸氢钠水溶液和水洗涤有机层后,用无水硫酸镁干燥,再过滤。减压浓缩滤液后,通过柱色谱法(乙酸乙酯/己烷=1/3)纯化,从而获得2-(3-(7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯(170mg,0.44mmol,81%)。
(步骤B)2-(3-(7,7-二氟-2-(甲基磺酰基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯的制备
将步骤A中得到的2-(3-(7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯(170mg,0.44mmol)和3-氯苯过氧酸(248mg,1.11mmol)溶解在二氯甲烷(50ml)中,在室温下搅拌3小时。反应完毕后,加入碳酸氢钠水溶液,再以二氯甲烷萃取。用氯化钠水溶液洗涤有机层后,用无水硫酸镁干燥,再过滤。减压浓缩滤液后,以柱色谱纯化(乙酸乙酯/己烷=1/2),得到2-(3-(7,7-二氟-2-(甲基磺酰基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯(180mg,0.43mmol,98%)。
(步骤C)2-(3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯的制备
将步骤B得到的2-(3-(7,7-二氟-2-(甲基磺酰基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯(180mg,0.43mmol)、(S)-2-甲基氮杂环丁烷盐酸盐(70mg,0.65mmol)和碳酸钾(180mg,1.30mmol)溶解在N-甲基吡咯烷(15ml)中,在120℃下搅拌4小时。反应完成后,加入1N盐酸水溶液,再用乙酸酯萃取。用氯化钠水溶液、碳酸氢钠水溶液和水洗涤有机层后,用无水硫酸镁干燥,再过滤。减压浓缩滤液后,通过柱色谱法(乙酸乙酯/己烷=1/2)纯化,得到2-(3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯(60mg,0.15mmol,34%)。
(步骤D)2-((1R,5S,6S)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸的制备
将步骤C得到的2-(3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸乙酯(60mg,0.15mmol)和氢氧化锂一水合物(27mg,0.64mmol)溶解在20%四氢呋喃溶液(5ml)中,于室温搅拌10小时。反应结束后,加入1N盐酸水溶液,再用乙酸酯萃取。用氯化钠水溶液洗涤有机层后,以无水硫酸镁干燥,再过滤。减压浓缩滤液后,通过柱色谱法(乙酸乙酯/己烷=1/2)纯化,得到2-((1R,5S,6S)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸(25mg,0.066mmol,45%,极性相对较高的化合物)和2-((1R,5S,6R)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸(极性相对较低的化合物)。
1H-NMR(400MHz,CDCl3)δ4.42(q,J=6.7Hz,1H),4.15-3.76(m,6H),3.14(q,J=4.1Hz,2H),2.70(d,J=7.8Hz,2H),2.52-2.25(6H),2.11(dd,J=13.0,8.0Hz,1H),1.97-1.83(m,1H),1.48(d,J=6.4Hz,3H),1.41(q,J=4.9Hz,1H)
[实施例9]
2-((1R,5S,6S)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸
通过以下步骤A、B、C和D制备实施例9的化合物。
(步骤A)4-氯-7,7-二氟-2-(甲基磺酰基)-6,7-二氢-5H-环戊并[d]嘧啶的制备
将制备例6得到的4-氯-7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊并[d]嘧啶(1.67g,6.97mmol)溶于二氯甲烷中,再加入70wt%mCPBA(4.30g,17.43mmol),然后在室温下搅拌2小时。于反应完成后,加入饱和焦亚硫酸钠溶液,搅拌30分钟,再加入饱和碳酸氢钠,然后以二氯甲烷萃取。用氯化钠水溶液洗涤有机层后,用无水硫酸镁干燥,再过滤以进行浓缩。浓缩后获得的化合物(1.74g,6.48mmol)无需单独纯化工序即可用于后续反应。
1H-NMR(400MHz,CDCl3)δ3.45(s,3H),3.20(m,2H),2.75-2.86(m,2H)
(步骤B)2-((1R,5S,6S-3-(7,7-二氟-2-(甲基磺酰基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸乙酯的制备
将步骤A中得到的化合物(1.74g,6.48mmol)溶解在1,4-二烷中、将2-((1R,5S,6S)-3-氮杂二环[3.1.0]己烷-6-基)乙酸乙酯盐酸盐(1.6g,7.78mmol)加入1,4-二/>烷溶液中,再加入DIPEA(2.26ml,12.97mmol)。反应物在室温下搅拌18小时。反应完成后,进行减压浓缩。浓缩的化合物与乙酸乙酯和饱和氯化铵溶液混合用于萃取。用氯化钠溶液洗涤有机层后,用无水硫酸镁干燥,再过滤,然后减压浓缩。最后,通过柱色谱法(庚烷/乙酸乙酯=1/1)纯化浓缩的化合物,从而获得2-((1R,5S,6S-3-(7,7-二氟-2-(甲基磺酰基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸乙酯(1.327g,51%)。
1H-NMR(400MHz,CDCl3)δ4.16(m,4H),3.73-4.02(m,2H),3.30-3.40(m,3H),3.22-3.30(m,2H),2.57-2.68(m,2H)),2.24-2.41(m,2H),1.65(s,2H),1.26-1.33(m,3H),0.95-1.01(m,1H)
(步骤C)2-((1R,5S,6S)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸乙酯的制备
将步骤B中得到的化合物(1.32g,3.29mmol)溶解在NMP中,再加入碳酸钾(2.272g,16.44mmol),将(S)-甲基氮杂环丁烷盐酸盐溶解在NMP中后加入。在120℃下搅拌反应物4小时。反应结束后,降温至室温,再加入氯化铵水溶液和乙酸乙酯,然后搅拌数分钟,再进行萃取。用氯化铵水溶液和氯化钠水溶液洗涤有机层后,用无水硫酸镁干燥,再过滤。减压浓缩滤液后,将浓缩物以柱色谱法纯化(庚烷/乙酸乙酯=1/1),得到2-((1R,5S,6S)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸乙酯(770mg,59%)。
(步骤D)2-((1R,5S,6S)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸的制备
将步骤C得到的化合物(305mg,0.77mmol)溶解在四氢呋喃(8ml)中,再加入氢氧化锂一水合物(65mg,1.55mmol)。依次加入水(4ml)和甲醇(2ml)后,搅拌反应物18小时。反应完成后,加入1.5ml 1N HCl,再加入氯化铵水溶液和乙酸乙酯以进行萃取。用氯化钠洗涤有机层后,用无水硫酸镁干燥,然后过滤。减压浓缩滤液后,将浓缩后的化合物以柱色谱法(MC/MeOH=10/1)纯化,得到2-((1R,5S,6S)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸(262mg,93%)。
1H-NMR(400MHz,CDCl3)δ4.39(dt,J=20.4,6.3Hz,1H),4.10-3.86(m,4H),3.71-3.52(m,2H),3.46(d,J=16.9Hz,1H),3.07-2.90(m,2H),2.51-2.24(m,5H),1.97-1.83(m,1H),1.58-1.43(m,5H),1.03-0.88(m,1H)
[实施例10]
2-((1R,5S,6S)-3-(8,8-二氟-2-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸
通过实施例8所述的方法,使用制备例7中得到的4-氯-8,8-二氟-2-(甲硫基)-5,6,7,8-四氢喹唑啉(150mg,0.60mmol)得到2-((1R,5S,6S)-3-(8,8-二氟-2-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸(18mg,0.046mmol,8%,4步骤)和2-((1R,5S,6R)-3-(8,8-二氟-2-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸。
1H-NMR(400MHz,CDCl3)δ5.07-4.47(1H),4.39(t,J=6.6Hz,1H),4.12-3.99(m,2H),3.94(q,J=8.1Hz,3H),3.87(d,J=11.0Hz,1H),2.84-2.58(m,4H),2.31(d,J=8.2Hz,4H),2.26-2.14(m,2H),2.11(d,J=5.5Hz,1H),1.91(t,J=8.9Hz,1H),1.80(t,J=5.7Hz,2H),1.47(d,J=5.9Hz,3H),1.44-1.35(m,1H)
[实施例11]
2-((1R,5S,6S)-3-(8,8-二氟-2-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸
通过以下步骤A、B、C和D制备实施例11的化合物。
(步骤A)4-氯-8,8-二氟-2-(甲基磺酰基)-5,6,7,8-四氢喹唑啉的制备
将4-氯-8,8-二氟-2(甲硫基)-5,6,7,8-四氢喹唑啉(500mg,2.00mmol)和3-氯苯过氧酸(862mg,5.00mmol)溶解在二氯甲烷(30ml)中,再于室温下搅拌18小时。反应完成后,加入焦亚硫酸钠水溶液,再以二氯甲烷萃取。用碳酸氢钠水溶液洗涤有机层后,用无水硫酸镁干燥,再过滤。减压浓缩滤液后,用柱色谱法(乙酸乙酯/己烷=1/2)纯化,得到4-氯-8,8-二氟-2-(甲基磺酰基)-5,6,7,8-四氢喹唑啉(527mg,1.86mmol,93%)。
1H-NMR(500MHz,CDCl3)δ3.41(s,3H),3.03-2.89(m,2H),2.52-2.33(m,2H),2.22-2.07(m,2H)
(步骤B)2-((1R,5S,6S)-3-(8,8-二氟-2-(甲基磺酰基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸乙酯的制备
将步骤A中得到的化合物(2.03g,7.18mmol)溶解在1,4-二烷、将2-((1R,5S,6S)-3-氮杂二环[3.1.0]己烷-6-基)乙酸乙酯盐酸盐(1.6g,7.78mmol)加入到1,4-二/>烷溶液中,再加入DIPEA(2.5ml,14.36mmol),然后将反应物在室温下搅拌18小时。反应完成后,进行减压浓缩。浓缩的化合物与乙酸乙酯和饱和氯化铵溶液混合以进行萃取。用氯化钠溶液洗涤有机层后,加入无水硫酸镁以干燥,再过滤,然后减压浓缩。通过柱色谱法(庚烷/乙酸乙酯=1/1)纯化浓缩的化合物,从而获得2-((1R,5S,6S)-3-(8,8-二氟-2-(甲基磺酰基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸乙酯(2.360g,79%)。
1H-NMR(400MHz,CDCl3)δ4.13-4.24(m,4H),3.80-3.83(m,2H),3.33(s,3H),2.90(m,2H),2.27-2.39(m,4H),1.94-1.97(m,2H),1.60-1.63(m,2H),1.28(t,J=6.8Hz,2H),0.94-0.97(m,1H)
(步骤C)2-((1R,5S,6S)-3-(8,8-二氟-2-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸乙酯的制备
将步骤B中得到的化合物(2.36g,5.68mmol)溶解在NMP(20ml)中,再加入碳酸钾(3.93g,28.4mmol),然后将(S)-2-甲基氮杂环丁烷盐酸盐(1.22g,11.36mmol)溶于NMP(8ml)中后添加入,反应物在120℃下搅拌4小时。反应完成后,降温至室温,再加入氯化铵水溶液和乙酸乙酯,搅拌几分钟后进行萃取。用氯化铵水溶液和氯化钠水溶液洗涤有机层后,加入无水硫酸镁干燥,再过滤。减压浓缩滤液后,将浓缩后的化合物以柱色谱法(庚烷/乙酸乙酯=1/1)纯化,得到2-((1R,5S,6S)-3-(8,8-二氟-2-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸乙酯(974mg,42%)。
1H-NMR(500MHz,CDCl3)δ4.39-4.44(m,1H),4.15-4.20(m,2H),4.02-4.07(m,2H),3.92-3.99(m,2H),3.56(m,2H),2H),2.65(d,J=5.8Hz,2H),2.32-2.38(m,1H),2.30(d,J=7.0Hz,2H),2.20-2.26(m,2H),1.92-1.98(m,1H),1.82-1.87(m,2H),1.50(t,J=6.4Hz,5H),1.29(t,J=7.2Hz,3H)
(步骤D)2-((1R,5S,6S)-3-(8,8-二氟-2-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸的制备
将步骤C得到的化合物(221mg,0.544mmol)溶解在四氢呋喃(6ml)中,加入氢氧化锂一水合物(46mg,1.08mmol),加入水(3ml)和甲醇(1.5ml),然后搅拌18小时。反应完成后,加入1.0ml 1N HCl,然后加入氯化铵水溶液和乙酸乙酯萃取。用氯化钠洗涤有机层后,以无水硫酸镁干燥,再过滤。减压浓缩滤液后,将浓缩后的化合物以柱色谱法(MC/MeOH=10/1)纯化,得到2-((1R,5S,6S)-3-(8,8-二氟-2-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸(82mg,40%)。
1H-NMR(400MHz,CDCl3)δ4.37(dt,J=20.4,6.3Hz,1H),4.07-3.86(m,4H),3.62-3.46(3H),2.61(t,J=5.9Hz,2H),2.38-2.27(m,3H),2.27-2.13(m,2H),1.97-1.86(m,1H),1.86-1.75(m,2H),1.52-1.43(5H),1.06-0.94(1H)
[实施例12]
2-((1R,5S,6S)-3-(8,8-二氟-2-(吡咯烷-1-基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸
通过实施例11所述的方法,使用吡咯烷来代替(S)-2-甲基氮杂环丁烷盐酸盐,以得到2-((1R,5S,6S)-3-(8,8-二氟-2-(吡咯烷-1-基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.0]己烷-6-基)乙酸(17mg,0.044mmol,54%,2步骤)。
1H-NMR(400MHz,CDCl3)δ4.01(d,J=11.0Hz,2H),3.54(m,6H),3.48(s,1H),2.61(m,2H),2.33(d,J=7.3Hz,2H),2.22(m,2H),1.91(m,4H),1.80-1.85(m,2H),1.48(s,2H),0.98-1.03(m,1H)
[实验例]KHK抑制剂体外活性测定
KHK在大肠杆菌(E.coli)中表达,并使用His标签进行纯化。为了测量纯化的KHK的活性,使用BellBrook Labs的Transcreener ADP2 TR-FRET Red测定试剂盒。TranscreenerADP2 TR-FRET Red测定试剂盒是在适当浓度的KHK和ATP与含果糖的溶液反应15分钟后使用TR-FRET测量产生的ADP的量的方法。为了测量KHK抑制剂的活性,先将KHK与适当浓度的抑制剂反应30分钟,然后与含有KHK底物的溶液反应15分钟。此外,在TR-FRET反应1小时后,使用PerkinElmer的Envision装置测量荧光。Envision装置的设定值根据BellBrook Labs公布的TR-FRET优化程序确定。
每种KHK抑制剂浓度的所得值由665-nm波长与615-nm波长的比率确定。在此,基于ADP标准曲线将665/615比率转换为ADP浓度,且使用统计软件(Prizm)中的莫里森方程获得抑制活性、Ki值。
通过实验得到的实施例化合物的Ki值如表1所示。
[表1]
实施例1 | 实施例2 | 实施例3 | 实施例4 | 实施例5 | 实施例6 | |
Ki | D | D | D | D | C | C |
实施例7 | 实施例8 | 实施例9 | 实施例10 | 实施例11 | 实施例12 | |
Ki | C | D | D | D | D | C |
(A≥10μM,B≥1μM,C=1至0.1μM,D≤0.1μM)
Ki值是表示抑制剂与酶的结合亲和力的值,Ki值越低,抑制活性越高。因此,从结果可以证实,本发明实施例的化合物表现出优异的抑制活性。
工业适用性
本发明的化学式1的3-氮杂二环烷基衍生化合物具有KHK抑制活性,可有效用于预防或治疗糖尿病、糖尿病并发症、肥胖症、非酒精性脂肪性肝炎或脂肪性肝炎等代谢性疾病。
Claims (11)
1.一种下述化学式1的化合物或其药学上可接受的盐或异构体:
[化学式1]
在化学式1中,
R1为未经取代的或经C1至C5烷基取代的具有一至三个N原子的C3至C7杂环烷基,
R2和R3各自独立地为氢、卤素或C1至C5烷基,
R4为-(CH2)mCO2H,
m、p和q各自独立地为0至2的整数,
X为N或C-CN,
Y为CH2或O,并且
Z为CH2。
2.根据权利要求1所述的化合物,其中所述化合物是选自以下的化合物或其药学上可接受的盐或异构体:
2-((1R,5S,6S)-3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;
2-((1R,5S,6S)-3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢异喹啉-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;
2-(3-(4-氰基-3-((S)-2-甲基氮杂环丁-1-基)-6,7,8,9-四氢-5H-环庚并[c]吡啶-1-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;
2-((1R,5S,6S)-3-(5-氰基-6-((S)-2-甲基氮杂环丁-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-8-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;
2-(3-(7,7-二甲基-2-((S)-2-甲基氮杂环丁-1-基)-5,7-二氢呋喃并[3,4-d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;
2-((1R,5S,6S)-3-((S)-7-甲基-2-((S)-2-甲基氮杂环丁-1-基)-5,7-二氢呋喃并[3,4-d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;
2-((1R,5S,6S)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁-1-基)-6,7-二氢-5H-环戊并[d]嘧啶-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸;和
2-((1R,5S,6S)-3-(8,8-二氟-2-((S)-2-甲基氮杂环丁-1-基)-5,6,7,8-四氢喹唑啉-4-基)-3-氮杂二环[3.1.1]庚烷-6-基)乙酸。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐或异构体在制备用于抑制己酮糖激酶(KHK)的药物中的用途。
4.根据权利要求1或2所述的化合物或其药学上可接受的盐或异构体在制备用于预防或治疗代谢疾病的药物中的用途。
5.一种用于抑制己酮糖激酶(KHK)的药物组合物,包括:
根据权利要求1或2所述的化合物或其药学上可接受的盐或异构体,以及药学上可接受的载体。
6.一种用于预防或治疗己酮糖激酶(KHK)相关代谢疾病的药物组合物,包括:
根据权利要求1或2所述的化合物或其药学上可接受的盐或异构体,以及药学上可接受的载体。
7.根据权利要求6所述的药物组合物,其中所述代谢疾病选自糖尿病、糖尿病并发症、肥胖症和脂肪性肝炎。
8.根据权利要求6所述的药物组合物,其中所述代谢疾病是非酒精性脂肪性肝炎。
9.一种制备用于预防或治疗己酮糖激酶(KHK)相关代谢疾病的药物组合物的方法,包括:
将作为活性成分的根据权利要求1或2所述的化合物或其药学上可接受的盐或异构体与药学上可接受的载体混合。
10.根据权利要求9所述的方法,其中所述代谢疾病选自糖尿病、糖尿病并发症、肥胖症和脂肪性肝炎。
11.根据权利要求9所述的方法,其中所述代谢疾病是非酒精性脂肪性肝炎。
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CN113999212B (zh) * | 2020-07-28 | 2023-07-28 | 山东轩竹医药科技有限公司 | 己酮糖激酶抑制剂的盐、晶型及其用途 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107001377A (zh) * | 2014-12-08 | 2017-08-01 | 爱尔兰詹森科学公司 | 对呼吸道合胞病毒(rsv)的复制具有抑制活性的哌啶取代的吡唑并[1,5‑a]嘧啶衍生物 |
CN108473469A (zh) * | 2015-12-29 | 2018-08-31 | 辉瑞公司 | 作为己酮糖激酶抑制剂的被取代的3-氮杂双环[3.1.0]己烷 |
CN113412260A (zh) * | 2019-01-29 | 2021-09-17 | 山东轩竹医药科技有限公司 | 己酮糖激酶抑制剂及其用途 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107001377A (zh) * | 2014-12-08 | 2017-08-01 | 爱尔兰詹森科学公司 | 对呼吸道合胞病毒(rsv)的复制具有抑制活性的哌啶取代的吡唑并[1,5‑a]嘧啶衍生物 |
CN108473469A (zh) * | 2015-12-29 | 2018-08-31 | 辉瑞公司 | 作为己酮糖激酶抑制剂的被取代的3-氮杂双环[3.1.0]己烷 |
CN113412260A (zh) * | 2019-01-29 | 2021-09-17 | 山东轩竹医药科技有限公司 | 己酮糖激酶抑制剂及其用途 |
Non-Patent Citations (3)
Title |
---|
Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK);Kim Huard 等;ACS Medicinal Chemistry Letters;第60卷;第7835−7849页 * |
Impact of Physicochemical and Structural Properties on the Pharmacokinetics of a Series of α1L-Adrenoceptor Antagonists;Alison Betts 等;DRUG METABOLISM AND DISPOSITION;第35卷;第1435-1445页 * |
Inhibitors of Ketohexokinase: Discovery of Pyrimidinopyrimidines with Specific Substitution that Complements the ATP-Binding Site;Bruce E. Maryanoff 等;ACS Medicinal Chemistry Letters;第2卷;第538–543页 * |
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EP4134366A4 (en) | 2023-10-11 |
TW202202492A (zh) | 2022-01-16 |
EP4134366A1 (en) | 2023-02-15 |
JP2023522725A (ja) | 2023-05-31 |
WO2021215765A1 (ko) | 2021-10-28 |
TWI810550B (zh) | 2023-08-01 |
US20230203008A1 (en) | 2023-06-29 |
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CN115667244A (zh) | 2023-01-31 |
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