CN112062763B - 羟基吡啶酮并[1,2-b][1,2,5]三氮卓平衍生物及制备和应用 - Google Patents
羟基吡啶酮并[1,2-b][1,2,5]三氮卓平衍生物及制备和应用 Download PDFInfo
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- CN112062763B CN112062763B CN202010947492.0A CN202010947492A CN112062763B CN 112062763 B CN112062763 B CN 112062763B CN 202010947492 A CN202010947492 A CN 202010947492A CN 112062763 B CN112062763 B CN 112062763B
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- triazepine
- hydroxy
- tetrahydropyrido
- dione hydrochloride
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- NMIUQIUOECJAJO-UHFFFAOYSA-N OC=1C=NC=C2N(N1)C=CC=N2 Chemical class OC=1C=NC=C2N(N1)C=CC=N2 NMIUQIUOECJAJO-UHFFFAOYSA-N 0.000 title claims description 10
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 claims abstract description 10
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 claims abstract description 10
- 241000712431 Influenza A virus Species 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 82
- -1 benzhydryl group Chemical group 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 30
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
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- 239000003814 drug Substances 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 229940125773 compound 10 Drugs 0.000 claims description 6
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- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 4
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- 239000007858 starting material Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 2
- 230000001590 oxidative effect Effects 0.000 claims 2
- 125000006239 protecting group Chemical group 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 238000006264 debenzylation reaction Methods 0.000 claims 1
- 150000007857 hydrazones Chemical class 0.000 claims 1
- 150000003840 hydrochlorides Chemical class 0.000 claims 1
- NGGPLHHTRNJSDT-UHFFFAOYSA-N methylmaltol Natural products COC1=C(C)OC=CC1=O NGGPLHHTRNJSDT-UHFFFAOYSA-N 0.000 claims 1
- UOAZKTDJBZTDNC-UHFFFAOYSA-N n-amino-n-[(2-methylpropan-2-yl)oxy]formamide Chemical compound CC(C)(C)ON(N)C=O UOAZKTDJBZTDNC-UHFFFAOYSA-N 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 125000004434 sulfur atom Chemical group 0.000 claims 1
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- 229940122277 RNA polymerase inhibitor Drugs 0.000 abstract description 2
- UXIVXGFGVAWZCH-UHFFFAOYSA-N 2h-triazepine Chemical class N1N=CC=CC=N1 UXIVXGFGVAWZCH-UHFFFAOYSA-N 0.000 abstract 2
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Abstract
本发明公开了羟基吡啶酮并[1,2‑b][1,2,5]三氮卓平衍生物及制备和应用。经实验证明,所述羟基吡啶酮并[1,2‑b][1,2,5]三氮卓平衍生物(通式I)对甲型流感病毒RNA聚合酶活性具有较好抑制作用,可作为流感病毒RNA聚合酶抑制剂,治疗流感病毒引起的感冒。结构通式I如下:
Description
技术领域
本发明属于制药领域,具体涉及一种羟基吡啶酮并[1,2-b][1,2,5]三氮卓平衍生物及制备方法和应用。
背景技术
流行性感冒(Influenza),简称为流感,是在流感病毒入侵机体后引起机体发生急性呼吸道感染性疾病。流感病毒,即流行性感冒病毒(Influenza virus),是正粘病毒科(Orthomyxoviridae)的代表种,分为甲(A)、乙(B)、丙(C)、丁(D)四种类型,其中甲型流感病毒(Influenza A virus)比较容易发生抗原变异,一般会在每隔10-15年造成一次流感大流行;乙型流感病毒引起的乙型流感规模较小,在人群中传播较局限;丙型流感病毒引起的丙型流感具有散发性流行的特点,引起机体的病情较轻;丁型流感病毒主要影响部分动物,对人类不具有致病性。通常情况下流感病毒的扩散会引起季节性流感或者流感大流行,其中老人与小孩为易感人群。流感具有高致病率与高致死率的特点,据统计,在全球范围内,流感的流行会造成每年约300-500万例的重症病例数,以及约 29-65万例的与呼吸道疾病相关的死亡病例数。因此,寻找安全高效的方法去应对流感的流行是目前临床上以及药学研究领域热门的话题。
目前流感疫苗(Influenza Vaccines)是预防和控制流感的主要方法之一,已有的流感疫苗是由三种病毒组成的流感病毒灭活疫苗,使用时间已超过60年。但是由于甲型流感病毒易发生抗原变异,通过新流行的流感病毒株制成相应的疫苗需要的时间较长,往往需要依靠抗流感病毒药物去控制流感。目前的流感治疗试剂主要包括三类:M2离子通道抑制剂、神经氨酸酶(NA)抑制剂和RNA 聚合酶抑制剂,但M2离子通道抑制剂以及神经氨酸酶(NA)抑制剂这两类试剂在使用过程中流感病毒对其产生了耐药性,这限制了这两类抑制剂的临床使用。
RNA聚合酶是目前研究较热门的抗流感病毒靶点,这一类酶是异源三聚体复合物,只存在于流感病毒中,结构高度保守,能够催化流感病毒RNA(vRNA) 的复制和转录。主要由酸性聚合酶(PA)、碱性聚合酶1(PB1)和碱性聚合酶 2(PB2)组成,其中PA具有序列选择性核酸内切酶活性,能够将宿主的RNA 链切开成包含10-13个核苷酸的短链,PB2与宿主pre-mRNA 5’端的7-甲基GTP 帽端结构域结合,PB1能够使用PA酶切的核苷酸短链增长病毒的RNA链。目前报道出的RNA聚合酶抑制剂包括广谱抗RNA病毒药物法匹拉韦(已上市)、 PB2抑制剂匹莫迪韦(VX-787,临床三期)、以及PA核酸内切酶抑制剂巴洛沙韦 (在日本已上市)。但是由于法匹拉韦具有致畸性和胚胎毒性,只适用于对其他抗流感药物无效或者疗效不够的新型流感患者或者重新出现的大流行患者;匹莫迪韦在2a期临床试验中出现了匹莫迪韦耐药流感病毒突变体,这些都限制了药物的临床使用。PA核酸内切酶抑制剂巴洛沙韦虽然已在日本上市,在我国国内已经获批开展临床试验,但是这个化合物的专利被其他国家持有,开展针对流感病毒RNA聚合酶这一靶点的自主药物研发极为迫切。
发明内容
本发明所要解决的技术问题是提供一种羟基吡啶酮并[1,2-b][1,2,5]三氮卓平衍生物,具有以下结构式I:
其中:
R1是氢、低级烷基、含杂原子的低级烷基、低级烷基芳基、低级烷基芳杂基、芳基、芳杂基,其中低级烷基选自C1-C4烷烃,芳基选自苯基、烷基取代苯基、羟基取代苯基、卤素取代苯基,芳杂基选自吡啶基、呋喃基、噻吩基、嘧啶基、吲哚基。
R2是氢、CY1Y2,Y1和Y2独立地选自氢、取代的芳基、取代的杂芳基或Y1和 Y2在一起形成取代的三环的环烯基、取代的三环的杂环基,其中所述的取代选自氢、卤素、甲基、甲氧基。
*是R构型或S构型;
及其药学上可接受的盐。
所述的羟基吡啶酮并[1,2-b][1,2,5]三氮卓平衍生物,选自如下任一化合物:
(R)-3-苄基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-1),
(S)-3-苄基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-2),
(S)-11-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,11,12,12a-六氢吡啶并[1,2-b]吡咯并[1,2-e][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-3),
(S)-11-二苯甲基-6-羟基-1,2,3,11,12,12a-六氢吡啶并[1,2-b]吡咯并 [1,2-e][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-4),
(S)-3-异丙基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-5),
(S)-3-异丁基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-6),
(S)-3-(1-甲基正丙基)-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基 -1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-7),
(S)-3-甲硫乙基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-8),
(S)-3-异丙基-1-二苯甲基-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平 -5,7-二酮盐酸盐(Ⅰ-9),
(S)-3-苄基-1-二苯甲基-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-10),
(R)-3-苯基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-11),
(R)-3-异丁基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-12)。
本发明的另一个目的是提供所述的羟基吡啶酮并[1,2-b][1,2,5]三氮卓平衍生物制备方法,其中,萃取、纯化等只要进行通常有机化合物的实验中进行的处理即可。原料化合物可以使用市售的化合物、本说明书中记载的化合物和其他公知化合物。在常规的合成法以及实施例中,各缩写的意思如以下所示:
DMF:N,N-二甲基甲酰胺,
DBU:1,8-二氮杂二环十一碳-7-烯,
DMA:N,N-二甲基乙酰胺,
HATU:2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯,
T3P:1-丙基磷酸酐。
合成路线如下:
步骤1
将市售的苄基麦芽酚1溶于95%乙醇,再加入苄氯和氢氧化钠水溶液,使其在60℃下反应6-18小时,TLC跟踪反应完成后,45℃减压蒸馏除去乙醇,加二氯甲烷萃取,分液所得的二氯甲烷层用4%氢氧化钠溶液洗涤,再加饱和食盐水洗涤,45℃减压蒸干得到的粗品再加乙酸乙酯和石油醚重结晶,由此可以得到化合物2。
步骤2
将步骤1所得的中间体2溶于溴苯,再加入二氧化硒固体,使其在回流状态下反应6-10小时,TLC跟踪反应完成后,将反应体系抽滤,滤液80℃减压蒸馏除去溴苯,柱层析分离纯化得到化合物3。
步骤3
将步骤2所得的化合物3溶于丙酮与水的混合溶剂中,再加入氨基磺酸固体,冰浴下往反应中分批加入亚氯酸钠固体,继续冰浴反应半小时,再转移至室温反应3-6小时,TLC跟踪反应完成后,反应体系在45℃减压蒸馏除去丙酮,待冷至室温,抽滤,弃去滤液,滤饼50℃烘干,由此可以得到化合物4。
步骤4
将步骤3所得的化合物4溶于DMF,冰浴下滴加碘甲烷,待碘甲烷滴加完毕,再接着在冰浴下滴加DBU,继续冰浴反应半小时,再转移至室温反应3-5 小时,TLC跟踪反应完成后,反应体系加乙酸乙酯与水萃取,乙酸乙酯层加水洗涤3次,再加饱和食盐水洗涤一次,45℃减压蒸馏除去乙酸乙酯,柱层析分离纯化得到化合物5。
步骤5
将步骤4所得的化合物5溶于DMA,再加入对甲苯磺酸吡啶盐和肼基甲酸叔丁酯,55℃反应6-12小时,TLC跟踪反应完成后,反应体系加二氯甲烷与水萃取,二氯甲烷层加水洗涤3次,再加饱和食盐水洗涤一次,45℃减压蒸馏除去二氯甲烷,柱层析分离纯化得到化合物6。
步骤6
将步骤5所得的化合物6置于三颈瓶中,冰浴下滴加三氟醋酸,继续冰浴反应半小时,转移至室温反应2-4小时,TLC跟踪反应完成后,反应体系40℃减压蒸馏除去三氟醋酸,再加饱和碳酸氢钠溶液调节体系PH到7,加二氯甲烷萃取,分液,弃去水层,二氯甲烷层45℃减压蒸干,柱层析分离纯化得到化合物7。
步骤7
将市售的R构型或S构型的N-Boc保护氨基酸8溶于无水二氯甲烷,再加入三乙胺,冰浴下分批加入HATU,待HATU投料完成,再冰浴下分批加入 N,O-二甲基羟胺盐酸盐,继续冰浴反应半小时,转移至室温反应6-12小时,TLC 跟踪反应完成后,反应体系加二氯甲烷与水萃取,分液,弃去水层,二氯甲烷层45℃减压蒸干,柱层析分离纯化得到化合物9。
步骤8
将步骤7所得的化合物9溶于无水四氢呋喃,再在冰浴下分批加入氢化铝锂,继续冰浴反应半小时,转移至室温反应2-3小时,TLC跟踪反应完成后,反应体系倒入到冰水中,再用稀盐酸调节反应体系与冰水的混合体系的PH到 4-5,加乙酸乙酯萃取,分液,乙酸乙酯层45℃减压蒸干,由此可以得到化合物 10,并直接投下一步反应。
步骤9
将步骤6所得的化合物7溶于甲苯与甲醇的混合溶剂中,再加入步骤8所得的化合物10、催化量的醋酸以及无水硫酸钠,55℃反应12-24小时,TLC跟踪反应完成后,抽滤,滤液55℃减压蒸干,柱层析离纯化得到化合物11。
步骤10
将步骤9所得的化合物11溶于甲醇中,加入醋酸调节体系pH到3-4,再转移至冰浴,分批加入氰基硼氢化钠,继续冰浴反应半小时,转移至室温反应 3-12小时,TLC跟踪反应完成后,反应体系加二氯甲烷与饱和碳酸氢钠溶液萃取,分液,弃去水层,二氯甲烷层再加饱和碳酸氢钠溶液洗涤3次,45℃减压蒸干,由此可以得到化合物12。
步骤11
将步骤10所得的化合物12置于三颈瓶中,冰浴下滴加三氟醋酸,继续冰浴反应半小时,转移至室温反应2-4小时,TLC跟踪反应完成后,反应体系40℃减压蒸馏除去三氟醋酸,再加饱和碳酸氢钠溶液调节体系PH到7,加乙酸乙酯萃取,分液,弃去水层,乙酸乙酯层50℃减压蒸干,柱层析分离纯化得到化合物13。
步骤12
将步骤11所得的化合物13溶于无水甲醇中,冰浴下分批加入甲醇钠,继续冰浴反应半小时,转移至室温反应2-12小时,TLC跟踪反应完成后,反应体系倒入到冰水中,再加乙酸乙酯萃取,分液,弃去水层,乙酸乙酯层50℃减压蒸干,柱层析分离纯化得到化合物14。
步骤13
将步骤12所得的化合物14溶于50%T3P的乙酸乙酯溶液,加入R2取代的醇,110℃下在封管中反应1-3小时,TLC跟踪反应完成后,反应体系加乙酸乙酯与水萃取,分液,弃去水层,乙酸乙酯层50℃减压蒸干,用乙酸乙酯与石油醚体系重结晶得到化合物15。
步骤14
将步骤13所得的化合物体15溶于DMA,加入氯化锂,80℃反应24-36 小时,TLC跟踪反应完成后,反应体系加二氯甲烷与水萃取,分液,弃去水层,二氯甲烷层加0.5M盐酸洗涤10次,再加饱和食盐水洗涤1次,45℃减压蒸干,加乙酸乙酯与石油醚固化,加入盐酸乙醚得到终产物Ⅰ。
本发明的再一个目的是提供所述羟基吡啶酮并[1,2-b][1,2,5]三氮卓平衍生物在制备抗甲型流感病毒RNA聚合酶活性药物中的应用。
本发明提供羟基吡啶酮并[1,2-b][1,2,5]三氮卓平衍生物,经实验证明,对甲型流感病毒RNA聚合酶活性具有一定的抑制作用,可作为流感病毒RNA聚合酶抑制剂,治疗流感病毒引起的感冒。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中,下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1(R)-3-苄基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基 -1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐;
原料1:商业可获得。
步骤1:2-甲基-3-苄氧基-4H-吡喃-4-酮的制备:
将100g市售的苄基麦芽酚溶于80mL 95%乙醇,再加入83mL苄氯和 115mL 30%氢氧化钠水溶液,使其在60摄氏度下反应6-18小时,TLC跟踪反应完成后,45℃减压蒸馏除去乙醇,加300mL二氯甲烷萃取,分液所得的二氯甲烷层用30mL 4%氢氧化钠溶液洗涤,再加30mL饱和食盐水洗涤,45℃减压蒸干得到的粗品再加60mL乙酸乙酯和120mL石油醚重结晶,由此可以得到 145.3g化合物2(收率为84%)。淡黄色固体,m.p.49.4-50.4℃.1H NMR(500MHz) δ7.59(d,J=5.5Hz,1H),7.39-7.38(m,2H),7.35-7.29(m,3H),6.36(d,J=5.5Hz, 1H),5.15(s,2H),2.08(s,3H).HRMS(ESI):m/z calcd for(C13H12O3+H)+:217.0859;found:217.0850。
步骤2:3-苄氧基-4-氧代-4H-吡喃-2-甲醛的制备:
将10g步骤1所得的中间体2溶于30mL溴苯,再加入15.4g二氧化硒固体,使其在回流状态下反应6-10小时,TLC跟踪反应完成后,将反应体系抽滤,滤液80℃减压蒸馏除去溴苯,柱层析(PET:AcOEt=2:1)分离纯化得到9 g化合物3(收率为85%)。黄色粘状液体.1HNMR(500MHz)δ9.84(s,1H),8.24 (d,J=5.5Hz,1H),7.45-7.42(m,2H),7.39-7.36(m,3H),6.62(d,J=5.5Hz,1H), 5.35(s,2H).HRMS(ESI):m/z calcd for(C13H10O4+CH4O+H)+:263.0914;found: 263.0905。
步骤3:3-苄氧基-4-氧代-4H-吡喃-2-甲酸的制备:
将8.5g步骤2所得的中间体3溶于30mL丙酮与30mL水的混合溶剂中,再加入3.8g氨基磺酸固体,冰浴下往反应中分批加入5.9g亚氯酸钠固体,继续冰浴反应半小时,再转移至室温反应3-6小时,TLC跟踪反应完成后,反应体系在45℃减压蒸馏除去丙酮,待冷至室温,抽滤,弃去滤液,滤饼50℃烘干,由此可以得到8g化合物4(收率为88%)。类白色固体,m.p.149.5-150.4℃.1H NMR(500MHz)δ14.14(s,1H),8.22(d,J=5.5Hz,1H),7.45-7.43(m,2H), 7.38-7.32(m,3H),6.56(d,J=5.5Hz,1H),5.12(s,2H).HRMS(ESI):m/z calcd for(C13H10O5+Na)+:269.0420;found:269.0412。
步骤4:3-苄氧基-4-氧代-4H-吡喃-2-甲酸甲酯的制备:
将7g步骤3所得的中间体4溶于14mL DMF,冰浴下滴加3.2mL碘甲烷,待碘甲烷滴加完毕,再接着在冰浴下滴加6.4mL DBU,继续冰浴反应半小时,再转移至室温反应3-5小时,TLC跟踪反应完成后,反应体系加42mL乙酸乙酯与42mL水萃取,乙酸乙酯层加42mL水洗涤3次(42mL×3),再加 12mL饱和食盐水洗涤一次,45℃减压蒸馏除去乙酸乙酯,柱层析(PET:AcOEt =4:1)分离纯化得到6.66g化合物5(收率为90%)。浅黄色固体,m.p.56.7-57.6℃.1H NMR(500MHz)δ8.24(d,J=6.0Hz,1H),7.44-7.41(m,2H),7.39-7.31(m,3H), 6.59(d,J=6.0Hz,1H),5.15(s,2H),3.81(s,3H).HRMS(ESI):m/z calcd for (C14H12O5+H)+:283.0577;found:283.0585。
步骤5:1-(叔丁氧羰基氨基)-3-苄氧基-4-氧代-1,4-二氢吡啶-2-甲酸甲酯的制备:
将6g步骤4所得的中间体5溶于24mL DMA,再加入17.4g对甲苯磺酸吡啶盐和3.7g肼基甲酸叔丁酯,55℃反应6-12小时,TLC跟踪反应完成后,反应体系加48mL二氯甲烷与48mL水萃取,二氯甲烷层加48mL水洗涤3次 (48mL×3),再加12mL饱和食盐水洗涤一次,45℃减压蒸馏除去二氯甲烷,柱层析(PET:AcOEt=1:1)分离纯化得到3.8g化合物6(收率为44%)。类白色固体,m.p.153.9-154.9℃.1H NMR(500MHz)δ8.18(s,1H),7.40-7.38(m,2H),7.36-7.29(m,3H),7.27(d,J=4.5Hz,1H),6.39(d,J=8.0Hz,1H),5.25(s,2H), 3.76(s,3H),1.45(s,9H).HRMS(ESI):m/z calcd for(C19H22N2O6+H)+:375.1551; found:375.1556。
步骤6:1-氨基-3-苄氧基-4-氧代-1,4-二氢吡啶-2-甲酸甲酯的制备:
将3.5g步骤5所得的中间体6置于三颈瓶中,冰浴下滴加10mL三氟醋酸,继续冰浴反应半小时,转移至室温反应2-4小时,TLC跟踪反应完成后,反应体系40℃减压蒸馏除去三氟醋酸,加入10mL水溶解,再加饱和碳酸氢钠溶液调节体系PH到7,加20mL二氯甲烷萃取,分液,弃去水层,二氯甲烷层 45℃减压蒸干,柱层析(CH2Cl2:MeOH=20:2)分离纯化得到2.44g化合物7 (收率为95%)。类白色固体,m.p.99.5-100.2℃.1H NMR(500MHz)δ7.59(d,J=8.0Hz,1H),7.38-7.30(m,5H),6.53(s,2H),6.24(d,J=7.5Hz,1H),5.11(s,2H), 3.77(s,3H).HRMS(ESI):m/z calcd for(C14H14N2O4+H)+:275.1026;found: 275.1032。
中间体8:商业可获得。
步骤7:(N-甲基-N-甲氧基-3-苯基丙酰胺-2-基)氨基甲酸叔丁酯的制备:
将10g市售的Boc-D-苯丙氨酸溶于60mL无水二氯甲烷,再加入10.3mL 三乙胺,冰浴下分批加入17.2g HATU,待HATU投料完成,再冰浴下分批加入 4.05g N,O-二甲基羟胺盐酸盐,继续冰浴反应半小时,转移至室温反应6-12小时,TLC跟踪反应完成后,反应体系加20mL二氯甲烷与40mL水萃取,分液,弃去水层,二氯甲烷层45℃减压蒸干,柱层析(PET:AcOEt=1:1)分离纯化得到10.5g化合物9(收率为91%)。白色固体,m.p.141.2-141.8℃.1HNMR(500 MHz)δ7.29-7.26(m,2H),7.23(t,J=7.5Hz,1H),7.17(d,J=7.5Hz,2H),5.18(d,J=9.0Hz,1H),4.97-4.92(m,1H),3.65(s,3H),3.16(s,3H),3.07(dd,J=13.5,6.0 Hz,1H),2.89(dd,J=13.5,7.5Hz,1H),1.38(s,9H).HRMS(ESI):m/z calcd for (C16H24N2O4+Na)+:331.1628;found:331.1619。
步骤8:(3-苯基丙醛-2-基)氨基甲酸叔丁酯的制备:
将10g步骤7所得的中间体9溶于50mL无水四氢呋喃,再在冰浴下分批加入1.4g氢化铝锂,继续冰浴反应半小时,转移至室温反应2-3小时,TLC 跟踪反应完成后,反应体系倒入到50mL冰水中,再用稀盐酸调节反应体系与冰水的混合体系的PH到4-5,加50mL乙酸乙酯萃取,分液,乙酸乙酯层45℃减压蒸干,由此可以得到7.4g化合物10粗品(收率为93%),并直接投下一步反应。
步骤9:(R)-1-(2-叔丁氧羰基氨基-3-苯基)亚丙基氨基-3-苄氧基-4-氧代-2- 甲酸甲酯的制备:
将2g步骤6所得的中间体7溶于10mL甲苯与2mL甲醇的混合溶剂中,再加入3.6g步骤8所得的中间体10、催化量的冰醋酸以及12g无水硫酸钠, 55℃反应12-24小时,TLC跟踪反应完成后,抽滤,滤液55℃减压蒸干,柱层析(CH2Cl2:MeOH=50:1)分离纯化得到2.6g化合物11(收率为70%)。黄色粘状液体.1H NMR(500MHz,DMSO)δ8.34(d,J=8.0Hz,1H),8.21(d,J=4.0 Hz,1H),7.37-7.32(m,5H),7.29(t,J=7.5Hz,2H),7.25-7.18(m,4H),6.41(d,J=7.5Hz,1H),5.15(s,2H),4.51-4.46(m,1H),3.75(s,3H),3.05(dd,J=14.0,5.0Hz, 1H),2.83(dd,J=14.0,10.0Hz,1H),1.31(s,9H).HRMS(ESI):m/z calcd for (C28H31N3O6+H)+:506.2286;found:506.2295。
步骤10:(R)-1-(2-叔丁氧羰基氨基-3-苯基)丙基氨基-3-苄氧基-4-氧代-2-甲酸甲酯的制备:
将2.5g步骤9所得的中间体11溶于10mL甲醇中,加入冰醋酸调节体系 PH到3-4,再转移至冰浴,分批加入0.9g氰基硼氢化钠,继续冰浴反应半小时,转移至室温反应3-12小时,TLC跟踪反应完成后,反应体系加20mL二氯甲烷与10mL饱和碳酸氢钠溶液萃取,分液,弃去水层,二氯甲烷层再加10mL饱和碳酸氢钠溶液洗涤3次(10mL×3),45℃减压蒸干,由此可以得到2.3g 化合物12粗品(收率为92%),并直接投下一步反应。
步骤11:(R)-1-(3-苯基-2-氨基)丙基氨基-3-苄氧基-4-氧代-2-甲酸甲酯的制备:
将2.2g步骤10所得的中间体12置于三颈瓶中,冰浴下滴加7mL三氟醋酸,继续冰浴反应半小时,转移至室温反应2-4小时,TLC跟踪反应完成后,反应体系40℃减压蒸馏除去三氟醋酸,再加5mL水溶解,加饱和碳酸氢钠溶液调节体系PH到7,再加10mL乙酸乙酯萃取,分液,弃去水层,乙酸乙酯层50℃减压蒸干,柱层析(CH2Cl2:MeOH=5:1)分离纯化得到1.5g化合物13(收率为85%)。黄色粘状液体.1H NMR(500MHz,DMSO)δ8.02(s,2H),7.82(d,J=7.5Hz,1H),7.38-7.29(m,7H),7.28-7.19(m,4H),6.31(d,J=8.0Hz,1H), 5.12-5.07(m,2H),3.74(s,3H),3.41-3.35(m,1H),3.18-3.09(m,2H),2.91-2.81(m, 2H).HRMS(ESI):m/zcalcd for(C23H25N3O4+H)+:408.1918;found:408.1913。
步骤12:(R)-3-苄基-6-苄氧基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平 -5,7-二酮的制备:
将1.4g步骤11所得的中间体13溶于3mL无水甲醇中,冰浴下分批加入 0.3g甲醇钠,继续冰浴反应半小时,转移至室温反应2-12小时,TLC跟踪反应完成后,反应体系倒入到10mL冰水中,再加10mL乙酸乙酯萃取,分液,弃去水层,乙酸乙酯层50℃减压蒸干,柱层析(CH2Cl2:MeOH=10:1)分离纯化得到1.1g化合物14(收率为85%)。类白色粉末,m.p.250.8-251.7℃.1H NMR (500MHz,DMSO)δ8.54(d,J=6.5Hz,1H),7.58(d,J=7.5Hz,1H),7.43(dd,J= 9.0,3.5Hz,1H),7.38-7.35(m,2H),7.33-7.23(m,7H),7.21-7.16(m,1H),6.17(d,J =7.5Hz,1H),5.16(d,J=10.5Hz,1H),4.88(d,J=10.5Hz,1H),3.33-3.28(m,1H), 3.17-3.12(m,1H),2.82-2.66(m,3H).HRMS(ESI):m/z calcd for(C22H21N3O3+H)+: 376.1656;found:376.1650。
步骤13:(R)-3-苄基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-苄氧基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮的制备:
将0.2g步骤12所得的中间体14溶于2mL 50%T3P的乙酸乙酯溶液,加入0.13g 10,11-二氢-5H-二苯并[a,d][7]环-5-醇,110℃下在封管中反应1-3小时,TLC跟踪反应完成后,反应体系加5mL乙酸乙酯与5mL水萃取,分液,弃去水层,乙酸乙酯层50℃减压蒸干,用1mL乙酸乙酯与6mL石油醚体系重结晶得到0.24g化合物15(收率为80%)。类白色粉末,m.p.260.1-260.9℃.1H NMR(500MHz,DMSO)δ8.60(s,1H),7.34-7.10(m,19H),6.02(s,1H),5.66(s, 1H),4.97(d,J=11.0Hz,1H),4.87(d,J=11.0Hz,1H),3.90-3.84(m,1H), 3.68-3.62(m,1H),3.29-3.22(m,1H),3.12-3.02(m,1H),2.89-2.83(m,1H), 2.79-2.74(m,1H),2.63-2.50(m,3H).HRMS(ESI):m/z calcd for(C37H33N3O3+H)+: 568.2595;found:568.2594。
步骤14:目标化合物(R)-3-苄基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5- 基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(I-1)的制备:
将0.15g步骤13所得的中间体15溶于3mL DMA,加入0.33g氯化锂, 80℃反应24-36小时,TLC跟踪反应完成后,反应体系加18mL二氯甲烷与9mL 水萃取,分液,弃去水层,二氯甲烷层加9mL 0.5M盐酸洗涤10次,再加9mL 饱和食盐水洗涤1次,45℃减压蒸干,加1mL乙酸乙酯与6mL石油醚固化,加入盐酸乙醚得到0.066g终产物I-1(收率为52%)。类白色粉末,m.p. 180.1-180.5℃.1H NMR(500MHz,DMSO)δ8.47(s,1H),7.91(s,1H),7.34(d,J=7.0Hz,1H),7.27-7.09(m,13H),5.93(s,1H),5.67(s,1H),3.91-3.85(m,1H), 3.69-3.64(m,1H),3.46-3.37(m,1H),3.19-3.15(m,1H),2.89-2.83(m,1H), 2.79-2.73(m,1H),2.63-2.57(m,3H).13C NMR(125MHz,DMSO)δ170.6,162.6, 140.0,139.2,138.0,136.2,135.7,131.4,131.1,130.8,128.9,128.8,128.7,128.3, 126.9,126.5,125.9,109.9,65.0,52.5,35.7,31.5,30.5,15.2.HRMS(ESI):m/z calcd for(C30H27N3O3+H)+:478.2125;found:478.2134。
实施例2(S)-3-苄基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基 -1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐
参照实施例1的方法,只是将Boc-D-苯丙氨酸换成Boc-L-苯丙氨酸,类白色粉末,m.p.245.1-246.0℃.1H NMR(500MHz,DMSO)δ8.54(s,1H),8.06(s, 1H),7.36(d,J=7.5Hz,1H),7.31-7.09(m,13H),6.11(s,1H),5.71(s,1H), 3.90-3.83(m,1H),3.78(s,1H),3.69-3.63(m,1H),3.46-3.40(m,1H),3.22-3.17(m, 1H),2.89-2.83(m,1H),2.79-2.73(m,1H),2.64-2.58(m,3H).13C NMR(125MHz, DMSO)δ162.3,140.0,139.2,137.9,136.0,135.5,131.4,131.1,130.8,129.0,128.9, 128.8,128.3,126.5,126.0,110.1,52.4,35.7,31.5,30.5.HRMS(ESI):m/z calcd for (C30H27N3O3+H)+:478.2125;found:478.2131。
实施例3(S)-11-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基 -1,2,3,11,12,12a-六氢吡啶并[1,2-b]吡咯并[1,2-e][1,2,5]三氮卓平-5,7-二酮盐酸盐
参照实施例1的方法,只是将Boc-D-苯丙氨酸换成Boc-L-脯氨酸,类白色粉末,m.p.276.6-277.5℃.1H NMR(500MHz,CHCl3)δ7.31(td,J=7.5,1.5Hz, 1H),7.23-7.18(m,2H),7.16(d,J=7.0Hz,1H),7.11(td,J=7.5,1.5Hz,1H),7.05 (d,J=7.0Hz,1H),7.00(t,J=7.5Hz,2H),6.9(t,J=7.5Hz,1H),5.91(d,J=7.5 Hz,1H),5.39(s,1H),4.06-3.98(m,2H),3.95-3.88(m,1H),3.72-3.66(m,1H), 3.64-3.58(m,1H),3.40(dd,J=14.0,5.0,1H),3.30(s,1H),3.03-2.95(m,2H), 2.88-2.83(m,1H),2.09-2.02(m,1H),2.01-1.95(m,1H),1.74-1.64(m,1H), 1.56-1.52(m,1H).13C NMR(125MHz,CHCl3)δ171.5,160.6,148.4,141.1,141.0, 138.7,135.9,135.1,131.4,131.2,131.2,131.1,129.5,129.1,126.9,126.6,125.9, 110.0,77.6,55.9,55.3,46.5,32.6,31.9,28.7,22.8.HRMS(ESI):m/zcalcd for (C26H25N3O3+H)+:428.1969;found:428.1961。
实施例4(S)-11-二苯甲基-6-羟基-1,2,3,11,12,12a-六氢吡啶并[1,2-b]吡咯并[1,2-e][1,2,5]三氮卓平-5,7-二酮盐酸盐
参照实施例1的方法,只是将Boc-D-苯丙氨酸换成Boc-L-脯氨酸以及10, 11-二氢-5H-二苯并[a,d][7]环-5-醇换成二苯甲醇,类白色粉末,m.p.271.0-271.5℃. 1H NMR(500MHz,CHCl3)δ7.43(d,J=7.5Hz,2H),7.38(d,J=7.5Hz,2H),7.32 (t,J=7.5Hz,3H),7.24-7.18(m,3H),7.16(t,J=7.0Hz,1H),6.02(d,J=6.5Hz, 1H),5.47(s,1H),3.97-3.93(m,2H),3.70-3.64(m,1H),3.41(dd,J=13.0,4.5Hz, 1H),3.25(s,1H),3.02(t,J=12.0Hz,1H),2.13-2.04(m,1H),2.01-1.95(m,1H), 1.76-1.66(m,1H),1.63-1.59(m,1H).13C NMR(125MHz,CHCl3)δ171.2,160.3, 147.2,139.4,138.7,138.6,129.4,129.0,128.6,128.4,128.0,127.2,126.4,110.2, 74.4,58.6,55.1,46.1,28.8,22.8.HRMS(ESI):m/zcalcd for(C24H23N3O3+H)+: 402.1812;found:402.1820。
实施例5(S)-3-异丙基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基 -1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐
参照实施例1的方法,只是将Boc-D-苯丙氨酸换成Boc-L-缬氨酸,类白色粉末,m.p.279.9-280.3℃.1H NMR(500MHz,DMSO)δ8.41(s,1H),7.86(s, 1H),7.32(d,J=7.5Hz,1H),7.25-7.05(m,8H),5.97(s,1H),5.66(s,1H),3.89-3.83 (m,1H),3.70-3.64(m,1H),3.21(dd,J=13.0,5.0Hz,1H),3.01-2.93(m,1H), 2.88-2.82(m,1H),2.79-2.73(m,1H),2.63-2.54(m,1H),1.58-1.50(m,1H),0.83(d, J=7.0Hz,3H),0.72(d,J=6.5Hz,3H).13CNMR(125MHz,DMSO)δ170.4, 162.8,139.2,136.1,135.8,131.2,131.2,130.9,130.7,128.7,125.9,109.9,56.1,31.4, 30.6,29.0,19.5,18.7.HRMS(ESI):m/z calcd for(C26H27N3O3+H)+:430.2125; found:430.2133。
实施例6(S)-3-异丁基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基 -1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐
参照实施例1的方法,只是将Boc-D-苯丙氨酸换成Boc-L-亮氨酸,类白色粉末,m.p.242.1-242.8℃.1H NMR(500MHz,DMSO)δ8.44(s,1H),7.93(s, 1H),7.33(d,J=7.5Hz,1H),7.29-7.06(m,8H),6.01(s,1H),5.66(s,1H),3.89-3.83 (m,1H),3.68-3.62(m,1H),3.22-3.11(m,2H),2.88-2.81(m,1H),2.78-2.73(m,1H), 2.47-2.42(m,1H),1.64-1.57(m,1H),1.27-1.22(m,1H),1.04-0.99(m,1H),0.78(d, J=6.5Hz,3H),0.70(d,J=6.5Hz,3H).13C NMR(125MHz,DMSO)δ170.3, 162.6,140.0,139.2,136.1,135.7,131.3,131.1,130.8,130.8,128.8,128.7,127.5, 125.9,110.0,48.6,38.4,31.5,30.5,24.2,22.8,21.3.HRMS(ESI):m/z calcd for (C27H29N3O3+H)+:444.2282;found:444.2290。
实施例7(S)-3-(1-甲基正丙基)-1-(10,11-二氢-5H-二苯并[a,d][7]环-5- 基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐
参照实施例1的方法,只是将Boc-D-苯丙氨酸换成Boc-L-异亮氨酸,类白色粉末,m.p.269.4-270.2℃.1H NMR(500MHz,DMSO)δ8.41(s,1H),7.89(s, 1H),7.32(d,J=7.5,1H),7.26-7.07(m,8H),5.99(s,1H),5.66(s,1H),3.89-3.83(m, 1H),3.70-3.64(m,1H),3.21-3.14(m,1H),3.04-2.91(m,1H),2.88-2.82(m,1H), 2.79-2.73(m,1H),2.64-2.53(m,1H),1.41-1.29(m,2H),1.14-1.05(m,1H),0.72(t, J=7.0Hz,3H),0.66(d,J=7.0Hz,3H).13C NMR(125MHz,DMSO)δ170.3, 162.7,139.2,136.1,135.8,131.3,131.2,130.9,130.7,128.8,125.9,110.0,54.4,35.1, 31.4,30.6,25.4,14.6,10.5.HRMS(ESI):m/z calcd for(C27H29N3O3+H)+:444.2282; found:444.2280。
实施例8(S)-3-甲硫乙基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐
参照实施例1的方法,只是将Boc-D-苯丙氨酸换成Boc-L-甲硫氨酸,类白色粉末,m.p.153.7-154.7℃.1H NMR(500MHz,DMSO)δ8.50(s,1H),7.94(s, 1H),7.32-7.30(m,1H),7.28-7.24(m,1H),7.23-7.17(m,2H),7.16-7.08(m,5H), 6.03(s,1H),5.67(s,1H),3.88-3.82(m,2H),3.68-3.60(m,2H),3.52(s,1H), 3.35-3.27(m,1H),3.23-3.17(m,1H),3.14-3.08(m,1H),2.88-2.82(m,1H), 2.79-2.73(m,1H),2.48-2.46(m,1H),2.43-2.36(m,1H),1.94(s,3H),1.55-1.49 (m,1H).13C NMR(125MHz,DMSO)δ170.2,162.6,143.0,139.1,136.1,135.7, 131.3,131.1,130.8,130.7,129.4,128.8,128.7,128.4,126.8,126.0,124.9,110.0, 49.4,34.9,31.4,31.4,30.5,29.7,29.5,14.5.HRMS(ESI):m/z calcd for(C26H27N3O3S+H)+:462.1846;found:462.1851。
实施例9(S)-3-异丙基-1-二苯甲基-6-羟基-1,2,3,4-四氢吡啶并 [1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐
参照实施例1的方法,只是将Boc-D-苯丙氨酸换成Boc-L-缬氨酸以及10, 11-二氢-5H-二苯并[a,d][7]环-5-醇换成二苯甲醇,类白色粉末,m.p. 313.5-314.3℃.1H NMR(500MHz,DMSO)δ8.28(d,J=7.3Hz,1H),7.89(d,J=7.5Hz,1H),7.48(d,J=7.5Hz,2H),7.42(d,J=7.5Hz,2H),7.35(t,J=7.5Hz, 2H),7.26-7.21(m,3H),7.13(t,J=7.5Hz,1H),5.93(d,J=7.5Hz,1H),5.85(s, 1H),3.14(dd,J=11.0,4.5Hz,1H),2.89-2.82(m,1H),2.71(t,J=11.0Hz,1H), 1.62-1.55(m,1H),0.87(d,J=6.5Hz,3H),0.73(d,J=6.5Hz,3H).HRMS(ESI): m/z calcd for(C24H25N3O3+H)+:404.1969;found:404.1977。
实施例10(S)-3-苄基-1-二苯甲基-6-羟基-1,2,3,4-四氢吡啶并 [1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐
参照实施例1的方法,只是将Boc-D-苯丙氨酸换成Boc-L-苯丙氨酸以及10,11-二氢-5H-二苯并[a,d][7]环-5-醇换成二苯甲醇,类白色粉末,m.p. 297.1-298.3℃.1H NMR(500MHz,DMSO)δ8.41(d,J=7.5Hz,1H),7.90(d,J= 8.0Hz,1H),7.49(d,J=7.5Hz,2H),7.43(d,J=7.5Hz,2H),7.37(t,J=7.5Hz, 2H),7.29-7.15(m,8H),7.14(t,J=7.5Hz,1H),5.91(d,J=7.5Hz,1H),5.87(s, 1H),3.42-3.34(m,1H),3.14(dd,J=11.5,5.0Hz,1H),2.75(t,J=11.5Hz,1H), 2.64(d,J=7.0Hz,2H).13C NMR(125MHz,DMSO)δ170.6,163.1,144.6,140.5, 140.3,138.1,134.5,129.1,129.0,128.7,128.3,128.1,128.0,127.7,127.5,126.5, 126.5,110.3,70.1,59.7,52.6,35.8.HRMS(ESI):m/z calcd for(C28H25N3O3+H)+: 452.1969;found:452.1966。
实施例11(R)-3-苯基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基 -1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐
参照实施例1的方法,只是将Boc-D-苯丙氨酸换成Boc-D-苯甘氨酸,类白色粉末,m.p.191.8-192.5℃.1H NMR(500MHz,DMSO)δ8.91(s,1H),7.75(s, 1H),7.46(d,J=7.5Hz,1H),7.30-7.16(m,12H),7.05-7.02(m,1H),5.95(s,1H), 5.75(s,1H),4.61-4.50(m,1H),3.93-3.87(m,1H),3.76-3.70(m,1H),3.37(dd,J= 13.0,5.0Hz,1H),2.92-2.86(m,2H),2.81-2.76(m,1H).13C NMR(125MHz, DMSO)δ170.9,162.6,140.3,139.3,136.1,135.9,135.6,131.4,131.3,130.9,130.7, 128.9,128.8,128.6,128.3,127.5,126.7,126.2,125.9,110.0,54.6,31.5,30.8.HRMS (ESI):m/z calcd for(C29H25N3O3+H)+:464.1960;found:464.1968。
实施例12(R)-3-异丁基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基 -1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐
参照实施例1的方法,只是将Boc-D-苯丙氨酸换成Boc-D-亮氨酸,类白色粉末,m.p.264.7-265.6℃.1H NMR(500MHz,DMSO)δ8.42(s,1H),7.89(s, 1H),7.32(d,J=7.5Hz,1H),7.27-7.06(m,8H),5.98(s,1H),5.65(s,1H),3.89-3.83 (m,1H),3.68-3.62(m,1H),3.50(s,1H),3.22-3.11(m,2H),2.88-2.81(m,1H), 2.78-2.73(m,1H),2.47-2.39(m,1H),1.64-1.58(m,1H),1.27-1.21(m,1H), 1.04-0.99(m,1H),0.78(d,J=7.0Hz,3H),0.69(d,J=6.5Hz,3H).13C NMR(125 MHz,DMSO)δ170.4,162.6,140.0,139.2,136.2,135.7,131.3,131.1,130.8,130.8, 128.8,128.7,127.4,125.9,110.0,48.6,38.4,31.5,30.5,24.2,22.8,21.3.HRMS (ESI):m/z calcd for(C27H29N3O3+H)+:444.2282;found:444.2289。
实施例13:甲型流感病毒RNA聚合酶抑制活性
通过报告质粒转染细胞后检测Luciferin底物荧光强度以反映Luciferase表达量的方法,检测基因调控作用,先以荧光素为底物检测萤火虫荧光素酶,后以肠腔素为底物检测海肾荧光素酶,同时抑制Firefly Luciferase的催化反应,实现双荧光素酶报告基因检测。Rennilla Luciferase作用为校正转染效率的内参,以消除孔间细胞数量和转染效率的差异,Firefly luciferase催化Luciferin发光波长为560nm,Renilla luciferase催化Coelenterazine发光波长为465nm.
实验结果显示,实施例1-4对甲型流感病毒RNA聚合酶抑制活性较好,可以达到75%(表1)。
表1
化合物编号 | 10μM浓度下的抑制率/% |
I-1 | 67.63 |
I-2 | 58.55 |
I-3 | 74.57 |
I-4 | 48.02 |
I-5 | 28.31 |
I-6 | 30.33 |
I-7 | 9.80 |
I-8 | 28.84 |
I-9 | 7.70 |
I-10 | 13.00 |
I-11 | 27.77 |
I-12 | 8.55 |
Claims (4)
2.根据权利要求1所述的羟基吡啶酮并[1,2-b][1,2,5]三氮卓平衍生物,其特征在于,所述的化合物I为如下任一化合物:
(R)-3-苄基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-1),
(S)-3-苄基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-2),
(S)-11-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,11,12,12a-六氢吡啶并[1,2-b]吡咯并[1,2-e][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-3),
(S)-11-二苯甲基-6-羟基-1,2,3,11,12,12a-六氢吡啶并[1,2-b]吡咯并[1,2-e][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-4),
(S)-3-异丙基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-5),
(S)-3-异丁基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-6),
(S)-3-(1-甲基正丙基)-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-7),
(S)-3-甲硫乙基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-8),
(S)-3-异丙基-1-二苯甲基-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-9),
(S)-3-苄基-1-二苯甲基-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-10),
(R)-3-苯基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-11),
(R)-3-异丁基-1-(10,11-二氢-5H-二苯并[a,d][7]环-5-基)-6-羟基-1,2,3,4-四氢吡啶并[1,2-b][1,2,5]三氮卓平-5,7-二酮盐酸盐(Ⅰ-12)。
3.根据权利要求1或2所述的羟基吡啶酮并[1,2-b][1,2,5]三氮卓平衍生物的制备方法,其特征在于,通过以下步骤实现:
以甲基麦芽酚1为起始原料,将羟基用苄基保护得到苄基麦芽酚2,再用二氧化硒氧化得到化合物3,接着用亚氯酸钠氧化得到化合物4,用碘甲烷将羧基反应成甲酯得到化合物5,再用叔丁氧基甲酰肼取代母核上的氧得到化合物6,化合物6进一步脱Boc保护基得到化合物7,构象固定的N-Boc保护氨基酸8与N,O-二甲基羟胺盐酸盐缩合得到化合物9,再经氢化铝锂还原得到化合物10,化合物7与化合物10在醋酸催化下形成腙11,再经氰基硼氢化钠还原得到化合物12,接着用三氟醋酸脱Boc保护基得到化合物13,再在甲醇钠作用下自身环合得到化合物14,接着化合物14与醇脱水得到化合物15,最后一步脱苄基成盐得到目的化合物I;反应式:
取代基定义同权利要求1。
4.根据权利要求1或2所述的羟基吡啶酮并[1,2-b][1,2,5]三氮卓平衍生物在制备抗甲型流感病毒RNA聚合酶的活性药物中的应用。
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