CN113387916A - 一种尿石素类pde2抑制剂化合物及其制备方法 - Google Patents
一种尿石素类pde2抑制剂化合物及其制备方法 Download PDFInfo
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Classifications
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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
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
-
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 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
- 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
Abstract
本发明提供了一种尿石素类PDE2抑制剂化合物及其制备方法，属于药物化学领域。本发明通过两步简单地反应得到两类化合物，共得到22个全新的PDE2抑制剂化合物；本发明合成此类化合物方法简单、方便，且节能环保；本发明第一步反应简单，无需柱层析，且纯度高，收率高，总收率在54％以上；第二步在室温下反应，且无副产物生成，大大提高了目标产品的纯度和收率，得到的化合物HPLC纯度高，达到97％以上，总收率高，达到30.0％以上。
Description
技术领域
本发明属于药物化学领域，具体涉及一种尿石素类PDE2抑制剂化合物及其制备方法。
背景技术
羟基取代的苯并[c]苯并吡喃-6-酮衍生物，也称为尿石素，是鞣花酸的肠道代谢物。到目前为止，已发现数十种尿石素代谢产物(图1)。尿石素可通过减少晚期糖基化终产物形成，诱导自噬细胞起到保护大脑海马体的作用，在治疗进行性神经退行性疾病，如典型的阿尔茨海默病(AD)和帕金森病(PD)，表现出了巨大的治疗潜力。
磷酸二酯酶2(PDE2)主要分布在脑和心脏细胞中，通过PDE2催化的环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP)水解，在维持细胞内第二信使cAMP和cGMP的水平方面起着重要作用，制药届广泛认可针对PDE2的选择性抑制剂在改善内皮细胞的通透性和记忆方面、干预甚至逆转AD进程方面具有重要意义和价值。但是，由于种种原因，并没有上市的PDE2抑制剂，因此，如果能研创出高效且副作用低的尿石素衍生物PDE2抑制剂，将有着广泛的社会和经济效益。
发明内容
本发明要解决的问题：为了克服现有抑制剂存在的不足，没有上市的PDE2抑制剂等问题，研创尿石素类PDE2抑制剂，满足社会用药需求，本发明提供一种尿石素类PDE2抑制剂化合物及其制备方法。
为了实现本发明目的，本发明所采用的技术方案如下：
一种尿石素类PDE2抑制剂化合物通式如下：
具体的，式(Ⅰ)中，R1为氢或甲氧基，R2为正己烷、正丁烷、2-乙基四氢呋喃、2-丙基噻吩、2-乙基呋喃、乙苯、乙基环己烷、2-乙基-5-甲基呋喃、1-氯-3-乙基-5-氟苯、(丙氧基甲基)苯、2-乙基吡嗪、2-丙基吡啶、1-丙基哌啶、甲基环己烷、2-乙基苯酚、2-乙基-4H-硫代吡喃、乙基环丁烷、1-乙基-3，5-二氟苯或庚烷。
进一步地，尿石素类PDE2抑制剂化合物包括尿石素B酰胺衍生物和甲氧基尿石素A酰胺衍生物两类，各自的结构式为：
尿石素B酰胺衍生物(1a-1m)：
甲氧基尿石素A酰胺衍生物(2a-2i)：
本发明所述的一种尿石素类PDE2抑制剂化合物的制备方法，步骤如下：
步骤如下：
当式(Ⅰ)中，R1为氢时，制备得到的产物是尿石素B酰胺衍生物，当式(Ⅰ)中，R1为甲氧基时，制备得到的产物是甲氧基尿石素A酰胺衍生物；
尿石素B酰胺衍生物的制备过程如下：
步骤(1)，用溶剂充分溶解尿石素B与溴乙酸，加入催化剂和缚酸剂。加热反应，用TLC跟踪反应。反应结束后，将反应液倒入蒸馏水中，溶液澄清透明后呈淡黄色。用浓盐酸调pH至酸性，有固体析出，抽滤，固体用大量的水洗涤，烘干，得到中间产物2-((6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酸。
步骤(2)，室温(25-35℃)下将步骤(1)所得固体2-((6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酸溶于溶剂中，依次加入EDCl(1乙基(3二甲基氨基丙基)碳酰二亚胺盐酸盐)、HOBt(1羟基苯并***)和DIEA(N，N-二异丙基乙胺)，搅拌活化，然后加入R2NH2，搅拌反应，用TLC跟踪反应。反应结束后，将反应液滴加到饱和NaHCO3水溶液中，有絮状固体生成，静置后过滤，固体用大量水洗涤，干燥，得尿石素B酰胺衍生物，用甲醇与二氯甲烷柱层析，纯化得到产物。
步骤(1)反应溶剂为丙酮；
步骤(1)催化剂为碘化钾；
步骤(1)缚酸剂为碳酸钾；
步骤(1)中：添加尿石素B、溴乙酸、碳酸钾、碘化钾的物质的量之比为：n(尿石素B):n(溴乙酸):n(碳酸钾):n(碘化钾)＝1:4-6:4-6:1-1.2；
步骤(1)中反应时间为15-22h，反应温度为55℃-65℃；pH值范围为2-3；
步骤(2)反应溶剂为DMF；反应温度为25℃-35℃
步骤(2)中：2-((6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酸、EDCl、HOBt、DIEA、R2NH2的物质的量之比为：n(固体):n(EDCL):n(HOBT):n(DIEA):n(伯胺)＝1:1.0-1.2:1.0-1.2:1.0-1.2:1.0-1.2。
步骤(2)中活化时间为1h，搅拌反应时间20h-25h。
甲氧基尿石素A酰胺衍生物的制备过程如下：
步骤(A)，用溶剂充分溶解甲氧基尿石素A与溴乙酸，加入催化剂和缚酸剂。加热反应，用TLC跟踪反应。反应结束后，将反应液倒入蒸馏水中，溶液澄清透明后呈淡黄色。用浓盐酸调pH至酸性，有固体析出，抽滤，固体用大量的水清洗，烘干，得到中间产物2-((8-甲氧基-6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酸。
步骤(B)，室温下加入溶剂，加入R2NH2、DIPEA(N,N-二异丙基乙胺)、PyBOP(六氟磷酸苯并***-1-基-氧基三吡咯烷基磷)、DMAP(4-二甲氨基吡啶)，随后缓慢滴加溶于二氯甲烷的2-((8-甲氧基-6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酸溶液。搅拌反应，用TLC跟踪反应，反应结束后，反应液用饱和NaCl水溶液洗涤，旋蒸得到固体化合物，再经过甲醇与二氯甲烷柱层析，比例为1:500，纯化得到甲氧基尿石素A酰胺衍生物。
步骤(A)反应溶剂为丙酮；
步骤(A)催化剂为碘化钾；
步骤(A)缚酸剂为碳酸钾；
步骤(A)中：添加甲氧基尿石素A、溴乙酸、碳酸钾、碘化钾的物质的量之比为：n(尿石素):n(溴乙酸):n(碳酸钾):n(碘化钾)＝1:4-6:4-6:1-1.2；
步骤(A)中反应时间为15-22h，反应温度为25℃-35℃；调节pH范围为2～3；
步骤(B)中：反应溶剂为二氯甲烷；反应温度为30℃-40℃；
步骤(B)中：R2NH2、DIPEA、PyBOP、DMAP、2-((8-甲氧基-6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酸的物质的量之比为n(固体):n(DIPEA):n(py.bop):n(DMAP):n(伯胺)＝1:0.5-0.6:0.5-0.6:0.5-0.6:1。
步骤(B)中搅拌反应时间为2-5h，最佳为4h。
本发明的有益效果：
本发明公开了一种尿石素类PDE2抑制剂化合物及其制备方法，有益效果如下：(1)两步简单地反应得到两类化合物，共得到22个全新的PDE2抑制剂化合物；(2)合成此类化合物方法简单、方便，且节能环保；(3)第一步反应简单，无需柱层析，且纯度高，收率高，总收率在54％以上；第二步在室温下反应，且无副产物生成，大大提高了目标产品的纯度和收率，得到的化合物HPLC纯度高，达到97％以上，总收率高，达到30.0％以上。
具体实施方式
下面将结合实施例对本发明的技术方案进行详细的描述。下列实施例用于说明而非限定通式化合物的合成方法。实施方式中，所述尿石素类类化合物包括如下所示的化合物：
实施例1：
(1-1)2-((6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酸
在500ml圆底烧瓶中加入粉白色固体粉末尿石素B(1mmol)与溴乙酸(5mmol)，催化剂碳酸钾(5mmol)与碘化钾(1mmol)，加入足够量的丙酮溶剂使得化合物溶解。在油浴锅60℃的条件下冷凝回流，反应约20h，用TLC检测反应是否结束，其中展开剂为：甲醇：二氯甲烷＝1:5；反应结束后，将反应液倒入蒸馏水中至溶液澄清透明，溶液呈淡黄色。用浓盐酸将PH值调节至3，淡黄色固体析出，抽滤，用大量的水清洗固体，烘干，得到中间产物2-((6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酸。
2-((6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酸(1-1)：白色固体，收率：59.4％；M.p.>300℃；1H NMR(300MHz,DMSO-d6)δ8.32(dd,J＝15.0,9.0Hz,2H),8.22(d,J＝9.0Hz,1H),7.93(t,J＝7.5Hz,1H),7.62(t,J＝7.5Hz,1H),7.03-7.00(m,2H),4.85(s,2H).13C NMR(75MHz,DMSO-d6)δ170.29,160.97,160.10,152.36,135.91,135.08,130.19,128.76,125.29,122.53,119.77,113.05,111.62,102.73,65.23.
(1-2)2-((8-甲氧基-6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酸
2-((8-甲氧基-6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酸(1-2):白色固体，收率：54％；M.p.>300℃；1H NMR(400MHz,DMSO-d6)δ13.16(s,1H),8.29(d,J＝8.0Hz,1H),8.21(d,J＝12.0Hz,1H),7.63(d,J＝4.0Hz,1H),7.53(dd,J＝12.0,2.9Hz,1H),7.02-6.99(m,2H),4.83(s,2H),3.91(s,3H).13C NMR(75MHz,DMSO-d6)δ170.31,160.84,159.41,159.31,151.42,128.47,124.61,124.48,124.44,120.97,113.00,111.78,111.44,102.68,65.27,56.11.
实施例2：
(2-1)尿石素B酰胺衍生物的合成(1a—1m)
室温下将上步所得固体(1-1)溶于20mLDMF中，依次加入EDCl、HOBt、DIEA搅拌。活化1h后，滴加R2NH2，搅拌一定时间，用TLC跟踪反应，反应结束后，将反应液中滴加到饱和NaHCO3水溶液，有絮状固体生成，静置后过滤，固体用大量水洗，干燥，得尿石素B酰胺衍生物。用甲醇/二氯甲烷纯化，体积比例为1：400。
化合物的1HNMR和13C NMR测试结果:
N-己基-2-(6-氧-6H-苯[c]苯并吡喃-3-yl)氧)乙酰胺(1a)：棕色固体，收率：27％，M.p.134.2℃～135.6℃.1H NMR(300MHz,DMSO-d6)δ8.34-8.14(m,4H),7.95-7.89(m,1H),7.61(t,J＝7.5Hz,1H),7.05(dd,J＝6.0,3.0Hz,1H),6.99(d,J＝3.0Hz,1H),4.61(s,2H),3.13(q,J＝6.0Hz,2H),1.30-1.10(m,8H),0.86(m,3H).13CNMR(75MHz,DMSO-d6)δ167.36,160.89,160.06,152.34,135.86,135.09,130.19,128.74,125.26,122.52,119.80,113.27,111.71,102.95,67.73,38.78,31.46,29.51,26.50,22.51,14.32.
正丁基-2-((6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酰胺(1b)：黄色固体，收率:67.8％,M.p.>300℃.1H NMR(300MHz,DMSO-d6)δ8.37-8.17(m,4H),7.95-7.87(m,1H),7.65-7.55(m,1H),7.08-7.01(m,2H),4.61(s,2H),3.15(t,J＝6.0,2H),1.48-1.38(m,2H),1.33-1.23(m,2H),0.86(t,J＝6.0,3H).13C NMR(75MHz,DMSO-d6)δ167.35,160.61,152.36,135.88,135.12,130.21,128.76,125.28,122.55,119.83,113.25,111.72,102.98,67.72,38.47,31.66,19.98,14.12.
2-((6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)-N-((四氢呋喃-2-基)甲基)乙酰胺(1c):白色固体，收率：46％，M.p.139.1℃～142℃.1H NMR(300MHz,DMSO-d6)δ8.34-8.19(m,4H),7.95-7.88(m,1H),7.60(td,J＝7.6,1.0Hz,1H),7.06-6.99(m,2H),4.65(s,2H),3.93-3.85(m,1H),3.78-3.71(m,1H),3.65-3.58(m,1H),3.22(m,2H),1.92-1.72(m,3H),1.57-1.46(m,1H).13C NMR(75MHz,DMSO-d6)δ167.69,160.90,160.05,152.34,135.85,135.07,130.18,128.73,125.26,122.52,119.80,113.21,111.68,102.88,77.41,67.61,67.54,42.84,28.89,25.58.
2-((6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)-N-(2-(噻吩-2-基)乙基)乙酰胺(1d):棕色固体，收率：69％，M.p.189.4℃～191.3°.1H NMR(400MHz,DMSO-d6)δ8.39-8.30(m,3H),8.23(dd,J＝8.0,1.4Hz,1H),7.94(td,J＝8.0,4.0Hz,1H),7.63(t,J＝8.0,1H),7.33(dd,J＝5.1,1.3Hz,1H),7.05(dd,J＝8.8,2.6Hz,1H),7.01(d,J＝2.5Hz,1H),6.94(dd,J＝5.1,3.4Hz,1H),6.89(dd,J＝3.4,1.1Hz,1H),4.64(s,2H),3.42(t,J＝4.0Hz，2H),3.00(t,J＝4.0Hz,2H).13C NMR(75MHz,DMSO-d6)δ167.63,160.93,160.01,152.37,141.73,135.89,135.11,130.22,128.78,127.43,125.69,125.31,124.52,122.56,119.84,113.23,111.78,103.02,67.66,29.65.N-(呋喃-2-基甲基)-2-(6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酰胺(1e):淡黄色固体，收率：76％，M.p.183.6℃～186.1℃.1H NMR(400MHz,DMSO-d6)δ8.64(t,J＝6.0Hz,1H),8.24(dd,J＝16.0,8.0Hz,2H),8.14(dd,J＝8.0,1.4Hz,1H),7.85(td,J＝8.0,4.0Hz,1H),7.56-7.52(m,2H),6.99(dd,J＝8.0,4.0Hz,1H),6.93(t,J＝4.0,1H),6.33(dd,J＝3.2,1.9Hz,1H),6.19(d,J＝4.0Hz,1H),4.61(s,2H),4.30(d,J＝4.0Hz,2H).13C NMR(75MHz,DMSO-d6)δ167.59,160.92,160.03,152.45,152.35,142.58,135.86,135.10,130.20,128.75,125.27,122.54,119.83,113.24,111.74,110.93,107.44,102.97,67.56,35.73.
n-苄基-2-((6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酰胺(1f):淡黄色固体，收率38％，M.p.171.2℃～173.5℃.1H NMR(300MHz,DMSO-d6)δ8.76(t,J＝4.5Hz,1H),8.33(dd,J＝12.0,9.0Hz,2H),8.23(dd,J＝9.0,3.0Hz,1H),7.93(td,J＝9.0,1.5Hz,1H),7.63(td,J＝7.6,1.0Hz,1H),7.34-7.21(m,5H),7.10-7.04(m,2H),4.72(s,2H),4.38(d,J＝6.0Hz,2H).13C NMR(75MHz,DMSO-d6)δ167.72,160.91,160.02,152.35,139.69,135.87,135.09,130.20,128.72,127.71,127.28,125.28,122.53,119.82,113.29,111.75,103.00,67.68,42.31.
N-(环己基甲基)-2-(6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酰胺(1g):黄色固体，收率：85％，M.p.157.9℃～160.1℃.1H NMR(400MHz,DMSO-d6)δ8.36(dd,J＝16.0,8.0Hz,2H),8.27-8.20(m,2H),7.97(td,J＝8.0,1.4Hz,1H),7.66(t,J＝8.0Hz,1H),7.10(dd,J＝8.0,2.6Hz,1H),7.05(d,J＝4.0Hz,1H),4.68(s,2H),3.04(t,J＝8.0Hz,2H),1.70-1.63(m,5H),1.49-1.46(m,1H),1.27-1.12(m,3H),0.94-0.86(m,2H).13C NMR(75MHz,DMSO-d6)δ167.45,160.90,160.11,152.35,135.88,135.11,130.20,128.75,125.26,122.54,119.80,113.33,111.69,102.95,67.70,44.98,37.94,30.81,26.45,25.85.
N-((5-甲基呋喃-2-基)甲基)-2-(6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酰胺(1h)：黄色固体，收率：80％，M.p.179.1℃～180.4℃.1H NMR(300MHz,DMSO-d6)δ8.70(t,J＝6.0Hz,1H),8.31-8.18(m,3H),7.90(t,J＝7.5Hz,1H),7.59(t,J＝7.5Hz,1H),7.04-6.97(m,2H),6.12(d,J＝3.0Hz,1H),5.97(d,J＝3.1Hz,1H),4.66(s,2H),4.30(d,J＝6.0Hz,2H),2.21(s,3H).13C NMR(75MHz,DMSO-d6)δ167.50,160.91,160.02,152.32,151.16,150.58,135.86,135.07,130.18,128.73,125.24,122.52,119.79,113.26,111.69,108.31,106.82,102.88,67.51,35.75,13.72.
N-(3-氯-5-氟苄基)-2-(6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酰胺(1i)：黄色固体，收率：80％，M.p.202.7℃～204.8℃.1H NMR(400MHz,DMSO-d6)δ8.88(t,J＝6.0Hz,1H),8.41-8.35(m,2H),8.28(dd,J＝8.0,1.4Hz,1H),7.99(dd,J＝8.0,1.4Hz,1H),7.69-7.62(m,2H),7.40-7.27(m,2H),7.18-7.08(m,2H),4.81(s,2H),4.42(d,J＝4.0Hz,2H).13C NMR(75MHz,DMSO-d6)δ168.18,160.88,159.90,152.35,144.55,135.86,135.09,134.26,130.19,128.77,125.33,123.62,122.54,119.84,114.91,113.52,113.33,111.87,103.00,70.25,67.67,41.50.
N-(2-(苄氧基)乙基)-2-(6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酰胺(1j):淡黄色固体，收率：83％，M.p.182.1℃～184.2℃.1H NMR(400MHz,DMSO-d6)δ8.28-8.19(m,3H),8.14(dd,J＝8.0,1.4Hz,1H),7.85(td,J＝8.0,1.5Hz,1H),7.58-7.52(m,1H),7.27-7.16(m,5H),6.99-6.93(m,2H),4.57(s,2H),4.41(s,2H),3.43(t,J＝6.0Hz,2H),3.31(t,J＝6.0Hz,2H).13C NMR(75MHz,DMSO-d6)δ167.70,160.05,152.37,138.80,135.87,135.10,130.20,128.65,127.98,127.86,125.29,122.54,119.84,113.22,111.76,102.98,72.31,68.65,67.65,38.83.
2-((6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)-N-(吡嗪-2-基甲基)乙酰胺(1k):淡黄色固体，收率：53.4％，M.p.182.9℃～183.1℃.1H NMR(300MHz,DMSO-d6)δ8.86(t,J＝6.0Hz,1H),8.54-8.47(m,3H),8.27-8.13(m,3H),7.84(t,J＝7.5Hz,1H),7.54(t,J＝7.5Hz,1H),7.02-6.97(m,2H),4.69(s,2H),4.47(d,J＝6.0Hz,2H).13CNMR(75MHz,DMSO-d6)δ168.23,160.90,159.96,154.31,152.34,144.35,143.83,143.68,135.84,135.06,130.18,128.74,125.26,122.53,119.81,113.26,111.76,103.02,67.61,42.43.
2-((6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)-N-(2-(吡啶-2-基)乙基)乙酰胺(1l):淡黄色固体，收率：44％，M.p.189.7℃～190.5℃.1H NMR(300MHz,DMSO-d6)δ8.55(d,J＝3.0Hz,1H),8.42-8.28(m,4H),8.02-7.97(m,1H),7.76-7.67(m,2H),7.32-7.24(m,2H),7.10(dd,J＝6.0,3.0Hz,1H),7.05(d,J＝3.0Hz,1H),4.67(s,2H),3.58(q,J＝6.0Hz,2H),2.99(t,J＝3.0Hz,2H).13C NMR(75MHz,DMSO-d6)δ167.51,160.91,159.97,159.42,152.33,149.51,136.94,135.85,135.08,130.19,128.74,125.27,123.60,122.52,121.97,119.82,113.19,111.74,102.93,67.66,38.70,37.56.
2-((6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)-N-(2-(哌啶-1-基)乙基)乙酰胺(1m):黄色固体，收率：55％，M.p.127.9℃～129.1℃.1H NMR(300MHz,DMSO-d6)δ8.27-8.13(m,3H),7.97(t,J＝6.0Hz,1H),7.88-7.82(m,1H),7.57-7.52(m,1H),7.00-6.93(m,2H),4.56(s,2H),3.19(q,J＝6.0Hz,2H),2.31-2.24(m,6H),1.42-1.15(m,6H).13C NMR(75MHz,DMSO-d6)δ167.41,160.88,159.97,152.35,135.86,135.06,130.19,128.75,125.29,122.52,119.80,113.21,111.77,102.97,67.69,57.88,54.43,36.39,26.00,24.47.
(2-2)甲氧基尿石素A酰胺衍生物的合成(2a—2i)
在25ml的圆底烧瓶中加入一定量的R2NH2，加入15mL二氯甲烷作为溶剂、以及一定量的DIPEA、PyBOP、DMAP，随后缓慢滴加溶于5mL二氯甲烷的(1-2)溶液。一定温度下反应一段时间，TLC跟踪反应，展开剂为甲醇：二氯甲烷＝1:10，待原料反应完全后，反应液用饱和NaCl水溶液洗涤，旋蒸得到固体化合物，再经过柱层析得到目标产物。甲醇/二氯甲烷＝1：500。
化合物的1HNMR和13C NMR测试结果:
N-环己基-2-((8-甲氧基-6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酰胺(2a):淡黄色固体，收率：42.5％，M.p.192.7℃～193.6℃.1H NMR(300MHz,DMSO-d6)δ8.24(dd,J＝21.0,9.0Hz,2H),7.99(d,J＝9.0Hz,1H),7.62(d,J＝30Hz,1H),7.52(dd,J＝9.0,3.0Hz,1H),7.04-6.97(m,2H),4.57(s,2H),3.90(s,3H),3.63(m,1H),1.74-1.68(m,4H),1.57(d,J＝12.0Hz,1H),1.26-1.06(m,5H).13C NMR(75MHz,DMSO-d6)δ166.50,160.85,159.41,159.34,151.37,128.47,124.59,124.45,120.97,113.17,111.80,111.44,102.84,67.66,56.11,47.98,32.73,25.61,25.12.
N-(2-羟基苄基)-2-((8-甲氧基-6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酰胺(2b):淡黄色固体，收率：39.9％，M.p.247.5℃～249.0℃.1H NMR(300MHz,DMSO-d6)δ8.84(t,J＝6.0Hz,1H),8.26(dd,J＝18.0,9.0Hz,2H),7.63(d,J＝3.0Hz,1H),7.53(dd,J＝9.0,3.0Hz,1H),7.38(dd,J＝5.0,1.4Hz,1H),7.05-6.95(m,5H),4.66(s,2H),4.52(d,J＝6.0Hz,2H),3.91(s,3H).13C NMR(75MHz,DMSO-d6)δ167.95,160.83,159.44,159.22,151.37,151.15,150.60,128.47,124.61,124.51,120.98,113.25,111.87,111.45,108.29,106.82,102.86,67.56,56.12,37.75,13.72.
N-(环丁基甲基)-2-((8-甲氧基-6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酰胺(2c):淡黄色固体，收率：49.5％，M.p.168℃～169.2℃.1H NMR(300MHz,DMSO-d6)δ8.30-8.14(m,3H),7.62(d,J＝3.0Hz,1H),7.52(dd,J＝9.0,3.0Hz,1H),7.04-6.98(m,2H),4.60(s,2H),3.90(s,3H),3.18(t,J＝6.0Hz,2H),2.47-2.39(m,1H),1.98-1.59(m,6H).13C NMR(75MHz,DMSO-d6)δ167.63,160.83,159.44,159.26,151.37,128.46,124.61,124.51,120.97,113.21,111.85,111.45,102.90,67.70,56.12,43.82,35.16,25.53,18.16.
N-苄基-2-((8-甲氧基-6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酰胺(2d)：淡黄色固体，收率：58.2％，M.p.218.1℃～219.3℃.1H NMR(300MHz,DMSO-d6)δ8.74(t,J＝6.0Hz,1H),8.26(dd,J＝21.0,9.0Hz,2H),7.63(d,J＝3.0Hz,1H),7.53(dd,J＝9.0,3.0Hz,1H),7.33-7.19(m,5H),7.07-7.02(m,2H),4.69(s,2H),4.37(d,J＝6.0Hz,2H),3.91(s,3H).13C NMR(75MHz,DMSO-d6)δ167.78,160.83,159.45,159.19,151.39,139.70,128.71,128.47,127.70,127.27,124.64,124.52,120.99,113.27,111.91,111.47,102.95,67.69,56.12,42.30.
2-((8-甲氧基-6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)-N-((5-甲基呋喃-2-基)甲基)乙酰胺(2e):淡黄色固体，收率：62.4％，M.p.181.5℃～182.1℃.1H NMR(300MHz,DMSO-d6)δ8.63(t,J＝6.0Hz,1H),8.25(dd,J＝18.0,9.0Hz,2H),7.64-7.51(m,2H),7.05-6.98(m,2H),6.11(d,J＝3.0Hz,1H),5.97(dd,J＝3.0,1.1Hz,1H),4.65(s,2H),4.29(d,J＝6.0Hz,2H),3.91(s,3H),2.22(s,3H).13C NMR(75MHz,DMSO-d6)δ167.54,160.80,159.41,159.19,151.35,151.15,150.60,128.43,124.57,124.46,124.42,120.95,113.21,111.85,111.42,108.29,106.81,102.83,67.55,56.09,35.75,13.71.
2-((8-甲氧基-6-氧代-6H-苯并[c]苯并吡喃-3-基)氧)-N-(吡嗪-2-基甲基)乙酰胺(2f):淡黄色固体，收率：52.4％，M.p.217.0℃～218.3℃.1H NMR(300MHz,DMSO-d6)δ8.88(t,J＝5.9Hz,1H),8.60(t,J＝3.0Hz,2H),8.53(d,J＝2.2Hz,1H),8.27(dd,J＝18.0,9.0Hz,2H),7.63(d,J＝3.0Hz,1H),7.53(dd,J＝9.0,3.0Hz,1H),7.08-7.04(m,2H),4.73(s,2H),4.53(d,J＝6.0Hz,2H),3.91(s,3H).13CNMR(75MHz,DMSO-d6)δ168.29,160.84,159.45,159.16,154.32,151.39,144.35,143.82,143.68,128.46,124.64,124.53,124.47,121.00,113.27,111.95,111.47,103.00,67.65,56.12,42.42.
N-(3，5-二氟苄基)-2-(8-甲氧基-6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酰胺(2g):淡黄色固体，收率：35.2％，M.p.215.4℃～216.3℃.1H NMR(300MHz,DMSO-d6)δ8.80(t,J＝6.0Hz,1H),8.26(dd,J＝18.0,9.0Hz,2H),7.63(d,J＝3.0Hz,1H),7.53(dd,J＝9.0,3.0Hz,1H),7.09-7.02(m,3H),6.96-6.90(m,2H),4.74(s,2H),4.37(d,J＝6.0Hz,2H),3.91(s,3H).13C NMR(75MHz,DMSO-d6)δ168.23,160.81,159.46,159.08,151.38,144.60,128.45,124.67,124.51,124.46,121.00,113.31,111.99,111.45,110.66,110.33,102.95,102.60,67.6,56.12,41.60.
2-((8-甲氧基-6-氧代-6H-苯并[c]苯并吡喃-3-基)氧)-N-(2-(吡啶-2-基)乙基)乙酰胺(2h):淡黄色固体，收率：39.8％，M.p.167.8℃～168.4℃.1H NMR(300MHz,DMSO-d6)δ8.49(dd,J＝6.0,3.0Hz,1H),8.31-8.20(m,3H),7.70-7.63(m,2H),7.55-7.51(dd,J＝9.0,3.0Hz,1H),7.25-7.17(m,2H),7.03-6.93(m,2H),4.59(s,2H),3.91(s,3H),3.51(t,J＝6.0Hz,2H),2.92(t,J＝7.5Hz,2H).13C NMR(75MHz,DMSO-d6)δ167.57,160.83,159.44,159.15,151.37,149.51,136.95,128.46,124.63,124.50,123.60,121.97,120.99,113.16,111.91,111.45,102.87,67.67,56.12,38.68,37.55.
N-己基-2-((8-甲氧基-6-氧代-6H-苯并[c]苯并吡喃-3-基)氧基)乙酰胺(2i):淡黄色固体，收率：42.4％，M.p.149.8℃～151.3℃.1H NMR(300MHz,DMSO-d6)δ8.25(dd,J＝21.0,9.0Hz,2H),8.14(t,J＝6.0Hz,1H),7.62(d,J＝3.0Hz,1H),7.52(dd,J＝9.0,3.0 Hz,1H),7.05-6.98(m,2H),4.59(s,2H),3.90(s,3H),3.13(q,J＝6.0 Hz,2H),1.25-1.15(m,7H),0.80(t,J＝7.5 Hz,4H).13C NMR(75 MHz,DMSO-d6)δ167.42,160.82,159.44,159.23,151.38,124.62,124.47,120.98,113.24,111.87,111.45,102.89,67.74,56.12,38.77,31.46,29.51,26.49,22.51,14.33.
Claims (9)
1.一种尿石素类PDE2抑制剂化合物，其特征在于，所述的尿石素类PDE2抑制剂化合物通式如下：
具体的，式(Ⅰ)中，R1为氢或甲氧基，R2为正己烷、正丁烷、2-乙基四氢呋喃、2-丙基噻吩、2-乙基呋喃、乙苯、乙基环己烷、2-乙基-5-甲基呋喃、1-氯-3-乙基-5-氟苯、(丙氧基甲基)苯、2-乙基吡嗪、2-丙基吡啶、1-丙基哌啶、甲基环己烷、2-乙基苯酚、2-乙基-4H-硫代吡喃、乙基环丁烷、1-乙基-3，5-二氟苯或庚烷。
2.根据权利要求1所述的一种尿石素类PDE2抑制剂化合物，其特征在于，尿石素类PDE2抑制剂化合物包括尿石素B酰胺衍生物和甲氧基尿石素A酰胺衍生物两类，各自的结构式为：
尿石素B酰胺衍生物1a-1m：
1a：
1b：
1c：
1d：
1e：
1f：
1g：
1h：
1i：
1j：
1k：
1l：
1m：
甲氧基尿石素A酰胺衍生物2a-2i)：
2a：
2b：
2c：
2d：
2e：
2f：
2g：
2h：
2i：
3.权利要求1-2任一所述的一种尿石素类PDE2抑制剂化合物的制备方法，其特征在于，反应式如下：
具体步骤如下：
当式(Ⅰ)中，R1为氢时，制备得到的产物是尿石素B酰胺衍生物，当式(Ⅰ)中，R1为甲氧基时，制备得到的产物是甲氧基尿石素A酰胺衍生物；
尿石素B酰胺衍生物的制备过程如下：
步骤(1)，用溶剂充分溶解尿石素B与溴乙酸，加入催化剂和缚酸剂；加热反应，用TLC跟踪反应；反应结束后，将反应液倒入蒸馏水中，溶液澄清透明后呈淡黄色；用浓盐酸调pH至酸性，有固体析出，抽滤，固体用大量的水清洗，烘干，得到中间产物2-((6-氧代-6H-苯并[c]色烯-3-基)氧基)乙酸；
步骤(2)，室温下将步骤(1)所得固体2-((6-氧代-6H-苯并[c]色烯-3-基)氧基)乙酸溶于溶剂中，依次加入EDCl、HOBt和DIEA，搅拌活化，然后加入R2NH2，搅拌反应，用TLC跟踪反应；反应结束后，将反应液中滴加到饱和NaHCO3水溶液中，有絮状固体生成，静置后过滤，固体用大量水洗涤，干燥，得尿石素B酰胺衍生物，用甲醇与二氯甲烷柱层析，体积比例为1：400，纯化得到尿石素B酰胺衍生物；
甲氧基尿石素A酰胺衍生物的制备过程如下：
步骤(A)，用溶剂充分溶解甲氧基尿石素A与溴乙酸，加入催化剂和缚酸剂；加热反应，用TLC跟踪反应；反应结束后，将反应液倒入蒸馏水中，溶液澄清透明后呈淡黄色；用浓盐酸调pH至酸性，有固体析出，抽滤，固体用大量的水洗涤，烘干，得到中间产物2-((8-甲氧基-6-氧代-6H-苯并[c]色烯-3-基)氧基)乙酸；
步骤(B)，室温下加入溶剂，加入R2NH2、DIPEA、PyBOP、DMAP，随后缓慢滴加溶于二氯甲烷的2-((8-甲氧基-6-氧代-6H-苯并[c]色烯-3-基)氧基)乙酸溶液；搅拌反应，用TLC跟踪反应，反应结束后，反应液用饱和NaCl水溶液洗涤，旋蒸得到固体化合物，再经过甲醇与二氯甲烷柱层析，体积比例为1:500，纯化得到甲氧基尿石素A酰胺衍生物。
4.根据权利要求3所述的一种尿石素类PDE2抑制剂化合物的制备方法，其特征在于，步骤(1)、步骤(A)的反应溶剂为丙酮；步骤(1)、步骤(A)的催化剂为碘化钾；步骤(1)、步骤(A)的缚酸剂为碳酸钾。
5.根据权利要求4所述的一种尿石素类PDE2抑制剂化合物的制备方法，其特征在于，步骤(1)中：添加尿石素B、溴乙酸、碳酸钾、碘化钾的物质的量之比为：n(尿石素B):n(溴乙酸):n(碳酸钾):n(碘化钾)＝1:4-6:4-6:1-1.2；步骤(A)中：添加甲氧基尿石素A、溴乙酸、碳酸钾、碘化钾的物质的量之比为：n(尿石素):n(溴乙酸):n(碳酸钾):n(碘化钾)＝1:4-6:4-6:1-1.2。
6.根据权利要求3、4或5所述的一种尿石素类PDE2抑制剂化合物的制备方法，其特征在于，步骤(1)中反应时间为15-22h，反应温度为55℃-65℃；pH值范围为2-3；步骤(A)中反应时间为15-22h，反应温度为25℃-35℃；调节pH范围为2-3。
7.根据权利要求3、4或5所述的一种尿石素类PDE2抑制剂化合物的制备方法，其特征在于，步骤(2)反应溶剂为DMF；反应温度为25℃-35℃；步骤(B)中：反应溶剂为二氯甲烷；反应温度为30℃-40℃。
8.根据权利要求3、4或5所述的一种尿石素类PDE2抑制剂化合物的制备方法，其特征在于，步骤(2)中：2-((6-氧代-6H-苯并[c]色烯-3-基)氧基)乙酸、EDCl、HOBt、DIEA、R2NH2的物质的量之比为：n(固体):n(EDCL):n(HOBT):n(DIEA):n(伯胺)＝1:1.0-1.2:1.0-1.2:1.0-1.2:1.0-1.2；步骤(B)中：R2NH2、DIPEA、PyBOP、DMAP、2-((8-甲氧基-6-氧代-6H-苯并[c]色烯-3-基)氧基)乙酸的物质的量之比为n(固体):n(DIPEA):n(py.bop):n(DMAP):n(伯胺)＝1:0.5-0.6:0.5-0.6:0.5-0.6:1。
9.根据权利要求3、4或5所述的一种尿石素类PDE2抑制剂化合物的制备方法，其特征在于，步骤(2)中活化时间为1h，搅拌反应时间20h-25h；步骤(B)中搅拌反应时间为2-5h，最佳为4h。
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