CN114524799B - 一种hdac抑制剂及其制备方法和用途 - Google Patents
一种hdac抑制剂及其制备方法和用途 Download PDFInfo
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- CN114524799B CN114524799B CN202210242078.9A CN202210242078A CN114524799B CN 114524799 B CN114524799 B CN 114524799B CN 202210242078 A CN202210242078 A CN 202210242078A CN 114524799 B CN114524799 B CN 114524799B
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- 239000003276 histone deacetylase inhibitor Substances 0.000 title claims abstract description 68
- 229940121372 histone deacetylase inhibitor Drugs 0.000 title claims abstract description 62
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- 238000006243 chemical reaction Methods 0.000 claims description 23
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- 125000000217 alkyl group Chemical group 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
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- 238000006268 reductive amination reaction Methods 0.000 claims description 6
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical group C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 5
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical group [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 5
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
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- 239000007864 aqueous solution Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- WYVFPGFWUKBXPZ-UHFFFAOYSA-N tert-butyl n-(4-oxocyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(=O)CC1 WYVFPGFWUKBXPZ-UHFFFAOYSA-N 0.000 claims description 4
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- 125000003118 aryl group Chemical group 0.000 claims description 3
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- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims description 3
- SXWRTZOXMUOJER-UHFFFAOYSA-N hydron;piperidin-4-one;chloride;hydrate Chemical compound O.Cl.O=C1CCNCC1 SXWRTZOXMUOJER-UHFFFAOYSA-N 0.000 claims description 3
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/02—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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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Abstract
一种HDAC抑制剂及其制备方法和用途,属于医药技术领域。该HDAC抑制剂,其结构通式如(I)所示,该HDAC抑制剂对HDAC具有良好的抑制活性以及抗肿瘤活性,可以作为HDAC抑制药物,用于治疗、预防肿瘤的抗肿瘤药物中的应用。优选于,抗肿瘤药物为治疗或预防结直肠癌、乳腺癌、白血病或多发性骨髓瘤等疾病的药物。结构通式(I)中的R1、R2、R3、R4、A、T、U、V、W、X、Y、Z如权利要求书和说明书所述。
Description
技术领域
本发明涉及医药技术领域,特别是制备抗肿瘤药物领域,具体是一种HDAC抑制剂及其 制备方法和用途。
背景技术
近些年来,恶性肿瘤的发病率逐年提升,成为仅次于心脑血管危害的人类健康以及生活 质量的疾病。目前除了常规的放化疗、激素治疗等,小分子靶向抑制药物逐渐展现出了强大 的治疗效果与研究前景。随着表观遗传学机制的深入研究,发现组蛋白去乙酰化酶(histone deacetylase inhibitor,HDAC)和组蛋白乙酰基转移酶(histone acetylase,HAT)在肿瘤的发生和发 展起到重要的调控作用。HDAC通过对乙酰化组蛋白赖氨酸残基去乙酰化,增强组蛋白DNA 与核小体的结合,增加染色质紧实度,从而调节基因的表达。而HAT与HDAC起到相反的 作用,肿瘤的发生通常与HAT与HDAC的失衡有关。在不同环境的肿瘤细胞中,会有不同 的HDAC亚型的过表达。对HDAC抑制后能明显抑制肿瘤细胞的增殖,诱导肿瘤细胞的凋 亡以及周期阻滞。
HDAC抑制剂与小分子抑制剂联用能够减少药物用量,改善肿瘤细胞耐药以及减轻药物 的毒副作用。目前被批准上市的HDAC抑制剂仅有5种,且也仅在恶性血液肿瘤的治疗中表 现出较好的活性。由于HDAC抑制剂在药物联用方向有着良好的前景,自身也拥有良好的特 异性的肿瘤靶向能力,研发新型,针对实体瘤能表现出较好活性的HDAC抑制剂非常的关键 和必要。
发明内容
本发明的目的是提供一种HDAC抑制剂及其制备方法和用途。该HDAC抑制剂对HDAC具有良好的抑制活性以及抗肿瘤活性,可以作为HDAC抑制药物,用于治疗、预防肿瘤的抗肿瘤药物中的应用。优选于,抗肿瘤药物为治疗或预防结直肠癌、乳腺癌、白血病或多发性骨髓瘤等疾病的药物。
本发明提供一种HDAC抑制剂,其结构通式如(I)所示:
其中,
R1为H,C1-C4烷基,酰基,甲基环丙基,甲基环丁基,甲基环戊基或苄基中的一种;
R2为H,C1-C4烷基,卤素,烷氧基,三氟甲基,氰基中的一种;
R3为在结构通式(I)中A环上4,5,6,7位置的无取代、单取代或者多取代的R3取代基, R3取代基为H,卤素,C1-C4烷基,烷氧基,硝基,氨基,氰基,甲酰胺,磺酰胺,取代或非 取代芳基中的一种或多种;
R4为芳环上的单取代或者多取代的R4取代基,R4取代基为H,卤素,C1-C4烷基,烷氧基,硝基,氨基,氰基中的一种或多种;
A环为苯环,喹啉环,异喹啉环,咔唑环、萘环中的一种;
X为-CH2-NH-,-CO-,-SO2-,-CH2-中的一种;
A环为无取代A环或有取代A环,有取代A环中,W,V,U,T分别独立表示为A环 上单取代或多取代氮原子;
Y为N或CH;
Z为N或CH。
本发明优选结构通式(I)所示的HDAC抑制剂及其药学上可接受的盐:
其中,
R1为H;
R2为H或甲基;
R3为H,单取代5-F,单取代6-F,单取代6-甲基中的一种或几种;
R4为单取代F;
A为苯环;
X为-CH2-NH-,-CO-中的一种;
Y为N或CH;
Z为CH;
W,V,U,T独立表示为H,即为A环为无取代A环。
本发明的HDAC抑制剂,优选如下结构的HDAC抑制剂:
本发明的HDAC抑制剂可与无机酸或有机酸反应形成药学上可接受的盐,其中,所述无 机酸为盐酸、氢溴酸、氢氟酸、硫酸、硝酸或磷酸中的一种或几种;所述的有机酸为甲酸、 乙酸、丙酸、柠檬酸、甲磺酸、乙磺酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、 苹果酸或酒石酸中的一种或几种。
本发明还提供了该HDAC抑制剂及其盐的制备方法,本发明提供的制备HDAC抑制剂及其盐的方法,合成步骤简便且易于操作。该类HDAC抑制剂具有非常好的抗肿瘤活性以及HDAC抑制活性,在HDAC抑制抗肿瘤药物领域具有重要的使用价值和应用前景。
本发明提供的结构通式(I)的HDAC抑制剂的制备方法,包括如下步骤:
S1:将结构通式(II)所示化合物与哌啶-4-酮盐酸盐水合物反应,得到结构通式(III)的化合 物;将结构通式(II)所示化合物与4-N-Boc-氨基环己酮反应,得到结构通式(IV)的化合物。
其中,结构通式(II)、(III)、(IV)中R1、R2、R3的定义同结构通式(I)中R1、R2、R3;
S2:将结构通式(V)的化合物与溴乙酸乙酯在碱性条件下反应,其中,R=H时,得到结构 通式(VI)的化合物;R=OH时,得到结构通式(VII)的化合物。
其中,结构通式(V)、(VI)、(VII)中R4、Z的定义同结构通式(I)中R4、Z;
S3:将第一反应物和第二反应物发生还原胺化反应或缩合反应,再与羟胺水溶液水解反 应,得到结构通式(I)所示化合物;
其中,第一反应物选择结构通式(III)的化合物与第二反应物选择结构通式(VI)或结构通式 (VII)的化合物反应;或者第一反应物选择结构通式(IV)的化合物与第二反应物选择结构通式 (VI)的化合物。
上述结构通式(I)的HDAC抑制剂的制备方法中,步骤S1中,结构通式(II)所示的化合物 与哌啶-4-酮盐酸盐水合物,或4-N-Boc-氨基环己酮反应的反应介质为冰醋酸或2mol/L氢氧 化钾的甲醇溶液,反应条件为70~100℃加热回流,反应时间为2-12小时:
所述的步骤S2中,所述取代反应介质为乙腈;所述碱性条件为反应体系中加入K2CO3; 其中,按摩尔比,K2CO3:结构通式(V)的化合物=(1.5-2):1,反应条件为70~100℃回流,反应 时间为4-6h。
所述的步骤S3中,所述还原胺化反应介质为甲醇,还原剂为氰基硼氢化钠,其中,按摩 尔比,氰基硼氢化钠:结构通式(VI)化合物=(1~6):1,催化剂优选冰醋酸,反应条件为室温, 反应时间为8-12小时。
所述的步骤S3中,缩合反应介质为DMF,缩合剂为HOBT(1-Hydroxybenzotriazole,HOBT),碱性条件为反应体系中加入K2CO3。
水解反应介质为1mol/L KOH的甲醇溶液,按摩尔比,羟胺:结构通式(VI)的化合物或结 构通式(VII)的化合物为(1~10):1,按体积比,羟胺水溶液:甲醇为1:(1~50),反应条件为室 温,反应时间为2~6h。
所述的结构通式(I)的HDAC抑制剂的制备方法中,根据反应的化学计量比,加入反应的 化合物。
本发明还提供了一种药物组合物,包含HDAC抑制剂及其药学上可接受的盐,还包括药 学上可接受的赋形剂。
一种HDAC抑制剂的用途,用于制备预防和/或治疗肿瘤的抗肿瘤药物中的应用。
一种药物组合物的用途,用于制备预防和/或治疗肿瘤的抗肿瘤药物中的应用。
所述的抗肿瘤药物为治疗和/或预防结直肠癌、乳腺癌、白血病或多发性骨髓瘤疾病的药 物。
本发明的一种HDAC抑制剂及其制备方法和用途,其有益效果为:
本发明的HDAC抑制剂具有较强的HDAC抑制活性,并且该类化合物具有反应原料易得,容易制备等优点,在制备抗肿瘤药物领域,可以用作抗肿瘤的治疗剂。
本发明的HDAC抑制剂,能够在多种肿瘤治疗中表现很高的活性,具有良好的特异性的 肿瘤靶向能力。
具体实施方式
下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和生物材料,如 无特殊说明,均为市售。
实施例1
本实施例的HDAC抑制剂为2-(3-氟-4-((4-(6-甲基-1H-吲哚-3-基)-3,6-二氢吡啶-1(2H)-基) 甲基)苯氧基)-N-羟基乙酰胺(DZ-1)
本实施例的HDAC抑制剂的制备方法,包括以下步骤:
步骤1)2-甲基-3-(1,2,3,6-四氢吡啶-4-基)-1H-吲哚的合成
于50mL圆底烧瓶,2-甲基-1H-吲哚1.3g(10mmol)溶于20mL冰醋酸中,加入哌啶-4-酮盐酸盐水合物3.5g(22.8mmol),80℃回流2小时,将反应液倒入冰的饱和碳酸氢钠溶液中, 然后用30mL乙酸乙酯萃取三次。有机层用饱和食盐水30mL清洗有机层2次,无水硫酸钠干燥过夜。浓缩有机层后得到2-甲基-3-(1,2,3,6-四氢吡啶-4-基)-1H-吲哚。(收率86.4%)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:10.86(s,1H),7.44(d,J=7.8,1H),7.23(d,J=7.9,1H), 6.99–6.95(m,1H),6.91(td,J=7.5,7.1,1.1,1H),5.65(p,J=1.7,1H),3.39(q,J=2.9,2H), 2.93(t,J=5.5,2H),2.50(p,J=1.8,2H),2.34(dt,J=5.5,2.8,2H).ESI-MS m/z:213.14[M+ H]+。
步骤2)2-(3-氟-4-甲酰苯氧基)乙酸乙酯的合成
于100mL圆底烧瓶中,2-氟-4-羟基苯甲醛1.12g(8.0mmol)溶于40mL乙腈中,加入1.6 g(12mmol)无水碳酸钾,加入1.6g(9.6mmol)溴乙酸乙酯,80℃回流6小时。旋干溶剂后,加入30mL水后,用30mL乙酸乙酯萃取三次。有机层用饱和食盐水30mL清洗有机层2次, 无水硫酸钠干燥过夜。浓缩有机层得到2-(3-氟-4-甲酰苯氧基)乙酸乙酯固体(产率74%)。
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:10.08(s,1H),7.79(t,J=8.5,1H),7.05(dd,J=12.8,2.4, 1H),6.97(dd,J=8.7,2.4,1H),4.97(s,2H),4.19(q,J=7.1,2H),1.22(t,J=7.1,3H).ESI-MS m/z:227.09[M+H]+。
步骤3)2-(3-氟-4-((4-(6-甲基-1H-吲哚-3-基)-3,6-二氢吡啶-1(2H)-基)甲基)苯氧基)-N-羟基 乙酰胺的合成
在50mL圆底烧瓶中,2-甲基-3-(1,2,3,6-四氢吡啶-4-基)-1H-吲哚(1.5mmol)和2-(3-氟-4- 甲酰苯氧基)乙酸乙酯(1.8mmol)溶于20mL甲醇中,加入催化量的冰醋酸,室温下搅拌约 30分钟,随后加入氰基硼氢化钠(3mmol)后,室温搅拌12小时。加20mL冰水淬灭反应, 后用30mL乙酸乙酯萃取三次。有机层用饱和食盐水30mL清洗有机层2次,无水硫酸钠干燥过夜。浓缩有机层后得到2-(3-氟-4-((4-(2-甲基-1H-吲哚-3-基)-3,6-二氢吡啶-1(2H)-基)甲基) 苯氧基)乙酸乙酯固体。
随后将所得固体干燥后溶解于20mL 1mol/L KOH的甲醇溶液,加入羟胺水溶液(6mmol in 10mL water)。室温反应2小时后,反应体系中加入20mL水,有固体析出。将固体收率后 烘干,得到2-(3-氟-4-((4-(6-甲基-1H-吲哚-3-基)-3,6-二氢吡啶-1(2H)-基)甲基)苯氧基)-N-羟基 乙酰胺固体。
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:10.89(s,1H),10.85(s,1H),9.00(s,1H),7.44(d,J=8.0, 1H),7.38(t,J=8.5,1H),7.23(d,J=8.0,1H),6.97(ddd,J=8.0,7.0,1.1,1H),6.90(ddd,J=8.0, 7.0,1.1,1H),6.85–6.79(m,2H),5.62(dq,J=3.4,1.7,1H),4.49(s,1H),3.62(s,2H),3.14(s, 2H),2.69(d,J=5.8,2H),2.49(s,1H),2.36(s,3H).13C NMR(150MHz,DMSO-d6)δ:164.45, 162.46,160.84,158.66,158.59,135.48,132.74,132.69,131.91,130.64,127.51,124.35,122.51, 122.17,120.54,119.05,119.01,113.70,111.15,110.97,102.62,102.45,66.55,54.49,52.82,49.97, 30.68,13.21.HR-ESI-MS:410.1875[M+H]+,(calcd for C23H24FN3O3,410.1874)。
实施例2
本实施例的HDAC抑制剂为2-(3-氟-4-((4-(5-氟-1H-吲哚-3-基)-3,6-二氢吡啶-1(2H)-基)甲 基)苯氧基)-N-羟基乙酰胺(DZ-5)
本实施例的HDAC抑制剂的制备方法基本同实施例1,其中,步骤1)的合成方式与实施 例1不同,具体为:
5-氟-2-甲基-3-(1,2,3,6-四氢吡啶-4-基)-1H-吲哚的合成
在50mL圆底烧瓶中,将5-氟-1H-吲哚1.1g(8mmol)在冰水浴的条件下加入20mL2mol/L 的氢氧化钾甲醇溶液,随后加入哌啶-4-酮盐酸盐水合物3.7g(24mmol)。在80℃下回流反应 12小时。反应结束后加入20mL水,用30mL乙酸乙酯萃取三次。有机层用饱和食盐水30mL 清洗有机层2次,无水硫酸钠干燥过夜。浓缩有机层后得到5-氟-2-甲基-3-(1,2,3,6-四氢吡啶 -4-基)-1H-吲哚。(收率56.2%)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:11.37(s,1H),7.66(dd,J=10.7,2.6,1H),7.58(s,1H), 7.51(dd,J=8.8,4.8,1H),7.09(td,J=9.1,2.6,1H),6.24(d,J=3.4,1H),3.61–3.48(m,2H), 3.32–3.14(m,2H),3.07(t,J=5.6,2H),2.64(p,J=1.8,1H).ESI-MS m/z:217.35[M+H]+
随后与实施例1制备方法一致,还原胺化,水解得到2-(3-氟-4-((4-(5-氟-1H-吲哚-3-基)-3,6- 二氢吡啶-1(2H)-基)甲基)苯氧基)-N-羟基乙酰胺。
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:11.21(s,1H),7.50(dd,J=12,2.5,1H),7.43(d,J=3.5, 1H),7.39–7.32(m,2H),6.94(td,J=12,2.5,1H),6.85–6.77(m,2H),6.05(d,J=3.5,1H),4.47 (s,2H),3.56(s,2H),3.10(q,J=2.9,2H),2.64(t,J=5.7,2H),2.49–2.46(m,2H).13C NMR (150MHz,DMSO-d6)δ:164.34,162.44,160.82,158.68,158.42,156.88,134.03,132.61,132.56, 129.63,125.20,125.14,125.07,118.19,116.59,116.56,113.09,113.02,111.14,109.86,109.69, 105.39,105.23,102.61,102.44,66.60,54.56,52.86,49.96,28.95.HR-ESI-MS:414.1631[M+H]+, (calcd for C22H21F2N3O3,414.1624)。
实施例3
本实施例的HDAC抑制剂为2-(3-氟-4-((4-(6-甲基-1H-吲哚-3-基)环己-3-烯-1-基)氨基)甲 基)苯氧基)-N-羟基乙酰胺(DZ-12)
本实施例的HDAC抑制剂的制备方法基本同实施例1,其中步骤3)中将步骤1)所得化合 物叔丁基(4-(2-甲基-1H-吲哚-3-基)环己-3-烯-1-基)氨基甲酸酯在1mol/L盐酸乙酸乙酯中脱去 Boc保护,后与2-(3-氟-4-甲酰苯氧基)乙酸乙酯进行反应,同实施例1,得到固体2-(3-氟 -4-((4-(6-甲基-1H-吲哚-3-基)环己-3-烯-1-基)氨基)甲基)苯氧基)-N-羟基乙酰胺。
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:10.82(s,1H),7.42(d,J=8.5,1H),7.41(d,J=7.5,1H), 7.22(d,J=8.0,1H),6.96(ddd,J=8.1,6.9,1.2,1H),6.90(ddd,J=8.1,6.9,1.2,1H),6.82–6.76 (m,2H),5.55(tq,J=2.7,1.4,1H),4.47(s,2H),3.77(s,2H),2.78(td,J=10.8,8.4,5.2,1H),2.49 –2.39(m,3H),2.34(s,3H),2.05–1.96(m,2H),1.52–1.49(m,1H).13C NMR(150MHz, DMSO-d6)δ:164.47,161.99,160.38,158.26,158.19,135.47,132.21,131.58,131.42,131.37, 127.66,123.21,120.45,119.06,118.86,114.73,111.10,110.91,102.58,102.41,66.58,52.19,43.06, 33.03,29.59,29.20,13.10.HR-ESI-MS:424.2029[M+H]+,(calcd for C24H26FN3O3,424.2031)。
实施例4
本实施例的HDAC抑制剂为2-(3-氟-4-((4-(5-氟-1H-吲哚-3-基)环己-3-烯-1-基)氨基)甲基) 苯氧基)-N-羟基乙酰胺(DZ-15)
本实施例的HDAC抑制剂的制备方法基本同实施例2,其中步骤3)中将步骤1)所得化合 物叔丁基(4-(5-氟-1H-吲哚-3-基)环己-3-烯-1-基)氨基甲酸酯,在1mol/L盐酸乙酸乙酯中脱去 Boc保护,后与2-(3-氟-4-甲酰苯氧基)乙酸乙酯进行反应,同实施例1,得到固体2-(3-氟 -4-((4-(5-氟-1H-吲哚-3-基)环己-3-烯-1-基)氨基)甲基)苯氧基)-N-羟基乙酰胺。
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:11.16(s,1H),7.49(dd,J=10.8,2.5,1H),7.42(d,J=2.5, 1H),7.39(d,J=9.3,1H),7.35(dd,J=10.8,4.8,1H),6.93(td,J=9.3,2.5,1H),6.81–6.76(m, 2H),6.02(dt,J=4.3,2.0,1H),4.47(s,2H),3.76(s,2H),2.74–2.67(m,1H),2.54(d,J=5.1,1H), 2.48(d,J=5.1,1H),2.42–2.32(m,1H),2.02–1.96(m,2H),1.51–1.44(m,1H).13C NMR(150 MHz,DMSO-d6)δ:164.46,161.98,160.37,158.36,158.23,158.15,156.83,133.99,131.41, 131.36,131.26,125.23,125.16,124.99,120.86,120.76,118.81,117.37,117.34,113.02,112.96, 111.08,109.75,109.58,105.40,105.24,102.56,102.39,66.57,52.16,43.06,32.95,29.38,27.57. HR-ESI-MS:428.1783[M+H]+,(calcd for C23H23F2N3O3,428.1780)。
选用其他的取代的苯酚或取代的苯甲酸,采用以上相同的制备方法,经过还原胺化或酰 胺缩合,最后水解得到结构通式(I)中其他产物。
实施例5
本实施例的HDAC抑制剂为2-(3-氟-4-((4-(5-氟-1H-吲哚-3-基)-3,6-二氢吡啶-1(2H)-基)甲 基)苯氧基)-N-羟基乙酰胺(DZ-9)
本实施例的HDAC抑制剂的制备方法基本同实施例2,选用其他的对甲氧基苯甲酸,采 用相同的制备方法,步骤3)在50mL圆底烧瓶中,2-甲基-3-(1,2,3,6-四氢吡啶-4-基)-1H-吲哚 和4-(2-乙氧基-2-氧乙氧基)苯甲酸溶于20mL DMF中,按照摩尔比,加入2-甲基-3-(1,2,3,6- 四氢吡啶-4-基)-1H-吲哚1.5倍的HOBT和1.5倍的无水碳酸钾,室温反应6小时。加水用 30mL乙酸乙酯萃取三次。有机层用饱和食盐水30mL清洗有机层2次,无水硫酸钠干燥过 夜。浓缩有机层后,得到固体按实施例1中水解步骤,得到2-(3-氟-4-((4-(5-氟-1H-吲哚-3- 基)-3,6-二氢吡啶-1(2H)-基)甲基)苯氧基)-N-羟基乙酰胺固体。
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:10.96(s,1H),7.50(s,1H),7.48–7.44(m,2H),7.25(d,J =8.0,1H),7.05–7.01(m,2H),7.01–6.97(m,1H),6.95–6.91(m,1H),5.74(s,1H),4.52(s,3H), 4.29–4.08(m,2H),3.60(br,2H),2.57(s,2H),2.39(s,3H).13C NMR(150MHz,DMSO-d6)δ: 164.49,159.21,135.51,132.25,131.40,129.42,129.33,127.31,121.06,120.71,119.15,119.07, 114.86,113.37,111.06,66.29,13.23.HR-ESI-MS:406.1758[M+H]+,(calcd for C23H23N3O4, 406.1761)。
选用不同的对羟基苯酚衍生物和吲哚衍生物,根据实施例1-5合成方法,即可得到如结 构通式(I)中其他产物
实施例6
本实施例的HDAC抑制剂为2-(4-((4-(2-甲基-1H-吲哚-3-基)-3,6-二氢吡啶-1(2H)-基)甲基) 苯氧基)-N-羟基乙酰胺(DZ-2)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:10.88(s,1H),7.44(d,J=7.8,1H),7.36(t,J=8.5,1H), 7.23(d,J=7.8,1H),6.99–6.95(m,1H),6.92–6.88(m,1H),6.85–6.79(m,2H),5.67–5.57(m, 1H),4.47(s,2H),3.58(s,2H),3.11(q,J=3.1,2H),2.65(t,J=5.6,2H),2.47(dq,J=6.6,3.6,3.1, 2H),2.35(s,3H).13C NMR(150MHz,DMSO-d6)δ:162.46,160.85,135.49,132.71,132.67, 131.90,130.64,127.51,122.53,120.54,119.06,119.01,113.71,111.16,110.97,102.61,102.43, 66.61,54.50,52.82,49.97,30.70,13.21.HR-ESI-MS:392.1776[M+H]+,(calcd for C23H25N3O3, 392.1896)。
实施例7
本实施例的HDAC抑制剂为2-(3-氟-4-((4-(6-甲基-1H-吲哚-3-基)-3,6-二氢吡啶-1(2H)-基) 甲基)苯氧基)-N-羟基乙酰胺(DZ-3)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:10.92(s,1H),7.65(d,J=8.2,1H),7.34(t,J=8.2,1H), 7.25(d,J=2.4,1H),7.14(s,1H),6.86–6.78(m,3H),6.07(d,J=3.8,1H),4.48(s,2H),3.55(s, 2H),3.10(d,J=3.3,2H),2.63(t,J=5.8,2H),2.49–2.45(m,2H),2.37(s,3H).13C NMR(150 MHz,DMSO-d6)δ:164.37,162.43,160.81,158.64,158.57,150.32,137.87,132.58,132.54, 130.66,130.17,130.14,123.07,122.52,121.43,120.28,117.69,117.64,116.16,111.99,111.15, 102.62,102.45,66.57,54.58,52.94,50.01,28.90,21.70.HR-ESI-MS:410.1878[M+H]+,(calcd for C23H24FN3O3,410.1874)。
实施例8
本实施例的HDAC抑制剂为2-(4-((4-(6-甲基-1H-吲哚-3-基)-3,6-二氢吡啶-1(2H)-基)甲基) 苯氧基)-N-羟基乙酰胺(DZ-4)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:11.00(s,1H),10.85(s,1H),8.98(s,1H),7.67(d,J=8.2, 1H),7.38–7.28(m,3H),7.16(s,1H),6.96(d,J=8.2,2H),6.86(dd,J=8.3,3.5,1H),6.09(d,J =3.5,1H),4.47(s,2H),3.76(br,2H),2.89(br,2H),2.58(br,2H),2.37(s,3H).13C NMR(150 MHz,DMSO-d6)δ:164.52,158.84,143.65,138.79,137.90,133.23,132.80,130.66,124.40, 122.94,122.63,121.73,120.21,120.03,115.72,114.98,113.39,112.08,111.12,66.31,66.21,61.38, 40.41,21.82,21.69,21.59.HR-ESI-MS:392.1975[M+H]+,(calcd for C23H25N3O3,392.1969)。
实施例9
本实施例的HDAC抑制剂为2-(4-((4-(5-氟-1H-吲哚-3-基)-3,6-二氢吡啶-1(2H)-基)甲基)苯 氧基)-N-羟基乙酰胺(DZ-6)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:11.37(s,1H),10.94(s,1H),8.99(s,1H),7.50(dd,J=10.8, 2.6,1H),7.45(d,J=2.6,1H),7.37(dd,J=9.1,4.8,1H),7.31(d,J=8.0,2H),6.94(tt,J=9.1, 3.4,3H),6.04(d,J=3.4,1H),4.46(s,2H),3.61(s,2H),3.14(s,2H),2.81–2.61(m,2H),2.58– 2.51(m,2H).13C NMR(150MHz,DMSO-d6)δ:163.67,157.75,157.30,156.37,155.77,142.68, 132.95,129.65,129.55,128.61,124.19,123.96,123.89,120.85,114.57,113.72,112.04,111.97, 108.71,108.54,104.23,104.07,65.11,64.97,51.66,48.76.HR-ESI-MS:396.1713[M+H]+,(calcd for C22H22FN3O3,396.1718)。
实施例10
本实施例的HDAC抑制剂为2-(3-氟-4-((4-(6-氟-1H-吲哚-3-基)-3,6-二氢吡啶-1(2H)-基)甲 基)苯氧基)-N-羟基乙酰胺(DZ-7)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:11.44(s,1H),11.07(s,1H),9.05(s,1H),7.77(dd,J=12, 6,1H),7.39(s,2H),7.16(dd,J=12,6,1H),6.95–6.77(m,3H),6.10(d,J=3.5,1H),4.53(s, 2H),3.64(s,2H),3.20(s,2H),2.80(s,2H).13C NMR(150MHz,DMSO-d6)δ:164.14,162.48, 160.84,160.76,160.68,160.52,158.94,151.64,144.00,138.66,133.96,132.73,129.82,124.45, 122.01,121.64,121.58,121.51,114.69,114.59,112.00,111.20,110.98,110.82,103.44,103.28, 99.92,99.75,66.38,56.11.HR-ESI-MS:414.1631[M+H]+,(calcd for C22H21F2N3O3,414.1624)。
实施例11
本实施例的HDAC抑制剂为2-(4-((4-(6-氟-1H-吲哚-3-基)-3,6-二氢吡啶-1(2H)-基)甲基)苯 氧基)-N-羟基乙酰胺(DZ-8)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:11.16(s,1H),10.83(s,1H),8.98(s,1H),7.77(dd,J=12, 6,1H),7.36(d,J=2.4,1H),7.26(d,J=8.2,2H),7.14(dd,J=12,6,1H),6.92(d,J=8.2,2H), 6.86(td,J=9.2,2.4,1H),6.09(d,J=3.6,1H),4.45(s,2H),3.51(s,2H),3.07(q,J=2.8,2H), 2.62(t,J=5.7,2H),2.47(d,J=6.3,2H).13C NMR(150MHz,DMSO-d6)δ:164.81,159.86, 158.31,157.29,137.40,137.32,131.62,130.39,129.77,123.77,123.75,122.02,121.60,121.54, 118.48,116.58,114.80,108.04,107.88,98.15,97.98,66.36,61.80,53.16,50.07,28.95. HR-ESI-MS:396.1712[M+H]+,(calcd for C22H22FN3O3,396.1718)。
实施例12
本实施例的HDAC抑制剂为2-(4-(4-(5-氟-1H-吲哚-3-基)-1,2,3,6-四氢吡啶-1-羰基)苯氧 基)-N-羟基乙酰胺(DZ-10)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:11.29(s,1H),9.01(s,1H),7.57(s,1H),7.52(s,1H),7.44 (d,J=8.5,2H),7.38(dd,J=8.8,4.7,1H),7.02(d,J=8.3,2H),6.96(dt,J=9.4,5.8,1H),6.12(s, 1H),4.52(s,2H),4.23(s,2H),3.88–3.52(m,2H),2.59(d,J=6.2,2H).13C NMR(150MHz, DMSO-d6)δ:164.48,159.25,158.52,156.99,134.08,130.29,129.35,125.66,125.02,124.96, 116.89,116.22,116.19,115.37,114.85,113.19,113.13,110.05,109.88,105.44,105.28,66.31. HR-ESI-MS:410.1509[M+H]+,(calcd forC22H20FN3O4,410.1511)。
实施例13
本实施例的HDAC抑制剂为2-(4-(4-(6-氟-1H-吲哚-3-基)-1,2,3,6-四氢吡啶-1-羰基)苯氧 基)-N-羟基乙酰胺(DZ-11)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:11.24(s,1H),10.87(s,1H),9.00(s,1H),7.81(s,1H),7.45 –7.42(m,3H),7.15(dd,J=9.8,6.0,1H),7.02(d,J=6.0,2H),6.88(s,1H),6.19(s,1H),4.53(s, 2H),4.22(s,2H),3.59(s,2H),2.60–2.55(m,2H).13C NMR(150MHz,DMSO-d6)δ:164.56, 159.93,159.22,158.37,137.46,137.38,131.72,130.41,129.36,124.27,121.86,121.61,121.55, 117.01,116.16,114.95,114.86,108.23,108.07,98.25,98.09,66.27.HR-ESI-MS:410.1498 [M+H]+,(calcd for C22H20FN3O4,410.1511)。
实施例14
本实施例的HDAC抑制剂为2-(4-((4-(2-甲基-1H-吲哚-3-基)环己-3-烯-1-基)氨基)甲基)苯 氧基)-N-羟基乙酰胺(DZ-13)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:10.82(s,1H),7.40(d,J=7.8,1H),7.31–7.28(m,2H),7.22(d,J=8.0,1H),6.96(ddd,J=8.1,6.6,1.2,1H),6.90(dd,J=8.1,6.6,3H),5.55(tq,J=2.7, 1.4,1H),4.43(s,2H),3.74(s,2H),2.82–2.72(m,1H),2.48–2.42(m,1H),2.42–2.37(m,2H), 2.33(s,3H),2.05–1.94(m,2H),1.54–1.48(m,1H).13C NMR(150MHz,DMSO-d6)δ:164.82, 156.98,135.47,134.53,132.19,131.55,129.47,129.42,127.67,123.36,120.44,119.05,118.86, 114.76,110.91,66.41,52.08,49.89,33.16,29.70,29.29,13.10.HR-ESI-MS:406.2120[M+H]+, (calcd for C24H27N3O3,406.2125)。
实施例15
本实施例的HDAC抑制剂为2-(3-氟-4-((4-(6-甲基-1H-吲哚-3-基)环己-3-烯-1-基)氨基)甲 基)苯氧基)-N-羟基乙酰胺(DZ-14)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:10.87(s,1H),7.65(d,J=8.3,1H),7.40(t,J=8.8,1H), 7.23(d,J=2.4,1H),7.14(s,1H),6.84(dd,J=8.3,1.5,1H),6.81–6.76(m,2H),6.06(dt,J=4.6, 2.4,1H),4.47(s,2H),3.76(s,2H),3.17(s,1H),2.74–2.69(m,1H),2.54(t,J=4.0,1H),2.48(d, J=5.1,1H),2.37(s,4H),2.02–1.97(m,J=12.0,2H),1.52–1.43(m,1H).13C NMR(150MHz, DMSO-d6)δ:164.42,161.99,160.38,158.28,158.21,137.82,131.78,131.46,131.42,130.54, 123.15,122.29,121.32,120.36,118.18,116.92,111.95,111.09,102.56,102.39,66.55,52.29,49.07, 43.02,32.90,29.35,27.49,21.70.HR-ESI-MS:424.2027[M+H]+,(calcd for C24H26FN3O3, 424.2031)。
实施例16
本实施例的HDAC抑制剂为2-(3-氟-4-((4-(6-氟-1H-吲哚-3-基)环己-3-烯-1-基)氨基)甲基) 苯氧基)-N-羟基乙酰胺(DZ-16)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:11.11(s,1H),7.75(dd,J=8.9,5.4,1H),7.40(t,J=8.9, 1H),7.33(d,J=2.4,1H),7.12(dd,J=10.0,2.5,1H),6.86(td,J=9.3,2.5,1H),6.80–6.75(m, 2H),6.07(dt,J=4.5,2.2,1H),4.46(s,2H),3.75(s,2H),2.73–2.68(m,1H),2.53(d,J=4.6,1H), 2.47(t,J=5.1,1H),2.42–2.31(m,1H),2.02–1.96(m,2H),1.51–1.44(m,1H).13C NMR(150 MHz,DMSO-d6)δ:164.45,161.97,160.36,159.81,158.25,158.22,158.14,137.33,137.25, 131.39,131.34,123.51,122.11,121.66,121.59,120.91,120.80,119.00,117.31,111.08,107.92, 107.76,102.55,102.38,98.07,97.90,66.57,52.14,43.07,33.01,29.41,27.54.HR-ESI-MS: 428.1769[M+H]+,(calcd forC23H23F2N3O3,428.1780)。
实施例17
本实施例的HDAC抑制剂为2-(3-氟-4-((4-(5-氟-2-甲基-1H-吲哚-3-基)环己-3-烯-1-基)氨 基)甲基)苯氧基)-N-羟基乙酰胺(DZ-17)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:10.96(s,1H),7.42(t,J=8.8,1H),7.20(dd,J=8.8,4.7, 1H),7.11(dd,J=10.5,2.6,1H),6.81(dd,J=9.0,2.6,2H),6.79(dd,J=3.5,2.1,1H),5.56–5.54 (m,1H),4.47(s,2H),3.78(s,2H),2.79(s,1H),2.46(dd,J=14.0,9.0,1H),2.42–2.36(m,2H), 2.33(s,3H),2.05–1.95(m,2H),1.56–1.48(m,1H).13C NMR(150MHz,DMSO-d6)δ:164.45, 162.01,160.39,158.33,158.25,158.03,156.50,133.99,132.08,131.78,131.47,131.43,127.85, 127.79,123.44,115.08,115.05,111.71,111.64,111.12,108.32,108.15,103.84,103.68,102.59, 102.42,66.57,52.15,43.00,32.84,29.40,28.93,13.22.HR-ESI-MS:442.1933[M+H]+,(calcd for C24H25F2N3O3,442.1937)。
实施例18
本实施例的HDAC抑制剂为2-(4-((4-(1H-吲哚-3-基)环己-3-烯-1-基)氨基)甲基)-3-氟苯氧 基)-N-羟基乙酰胺(DZ-18)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:11.04(s,1H),10.71(s,1H),8.98(s,1H),7.77(d,J=8.0, 1H),7.40(t,J=8.8,1H),7.35(d,J=8.1,1H),7.33(d,J=2.5,1H),7.07(t,J=7.5,1H),7.00(t, J=7.5,1H),6.81–6.76(m,2H),6.08(dt,J=4.7,2.1,1H),4.47(s,2H),3.77(s,2H),2.73(d,J=11.4,1H),2.53(t,J=14.0,2H),2.44–2.34(m,1H),2.03–1.99(m,2H),1.52–1.44(m,1H).13C NMR(150MHz,DMSO-d6)δ:164.42,162.00,160.39,158.32,158.24,137.34,131.70,131.50, 131.45,125.20,122.97,121.57,120.60,119.57,118.49,117.08,112.14,111.11,102.57,102.40, 66.54,52.30,42.99,32.85,29.30,27.63.HR-ESI-MS:410.1869[M+H]+,(calcd for C23H24FN3O3, 410.1874)。
实施例19
本实施例的HDAC抑制剂为2-(2-氟-4-((4-(2-甲基-1H-吲哚-3-基)环己-3-烯-1-基)氨基)甲 基)苯氧基)-N-羟基乙酰胺(DZ-19)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:10.85(s,1H),7.43(d,J=7.8,1H),7.29(dd,J=12.4,2.0, 1H),7.26–7.22(m,1H),7.14(dd,J=8.3,2.0,1H),7.06(t,J=8.5,1H),6.99(ddd,J=8.0,7.0, 1.1,1H),6.92(ddd,J=8.0,7.0,1.1,1H),5.59–5.57(m,1H),4.53(s,2H),3.78(s,2H),2.81– 2.77(m,1H),2.51–2.45(m,1H),2.45–2.41(m,2H),2.36(s,3H),2.09–1.98(m,2H),1.57– 1.51(m,1H).13C NMR(150MHz,DMSO-d6)δ:164.48,152.83,151.21,144.77,144.70,135.47, 132.20,131.56,127.67,124.17,123.28,120.44,119.06,118.86,116.05,115.93,115.36,114.75, 110.91,67.14,52.06,49.41,33.08,29.65,29.25,13.10.HR-ESI-MS:424.2021[M+H]+,(calcd for C24H26FN3O3,424.2031)。
实施例20
本实施例的HDAC抑制剂为4-(2-(羟胺基)-2-氧乙氧基)-N-(4-(2-甲基-1H-吲哚-3-基)环己 -3-烯-1-基)苯甲酰胺(DZ-20)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:10.87(s,2H),9.00(s,1H),8.21(d,J=7.7,1H),7.90–7.83(m,2H),7.46(d,J=7.9,1H),7.24(d,J=7.9,1H),7.05–7.01(m,2H),6.98(ddd,J=8.1, 7.0,1.2,1H),6.92(ddd,J=8.1,7.0,1.2,1H),5.62(br,1H),4.53(s,2H),4.20–4.11(m,1H),2.64 –2.53(m,1H),2.47(d,J=5.2,1H),2.38(s,3H),2.34–2.28(m,1H),2.03–1.94(m,1H),1.83– 1.77(m,1H).13C NMR(150MHz,DMSO-d6)δ:165.65,164.46,160.39,135.49,132.17,131.74, 129.50,128.17,127.66,123.23,120.51,119.07,118.93,114.55,110.96,66.32,45.75,32.14,29.78, 29.63,13.12.HR-ESI-MS:420.1910[M+H]+,(calcd for C24H25N3O4,420.1918)。
实施例21
本实施例的HDAC抑制剂为N-(4-(5-氟-1H-吲哚-3-基)环己-3-烯-1-基)-4-(2-(羟胺)-2-氧乙 氧基)苯甲酰胺(DZ-21)
结构确证数据如下:
1H NMR(600MHz,DMSO-d6)δ:11.21(s,1H),8.19(d,J=7.7,1H),7.85(d,J=8.7,2H), 7.54(dd,J=9.0,2.6,1H),7.47(d,J=2.1,1H),7.37(dd,J=8.8,4.8,1H),7.02(d,J=8.8,2H), 6.95(td,J=9.0,2.6,1H),6.10–6.05(m,1H),4.50(s,2H),4.12–4.09(m,1H),2.60(dt,J=17.9, 3.6,1H),2.56–2.51(m,2H),2.35–2.24(m,1H),2.03–1.95(m,1H),1.80–1.73(m,1H).13C NMR(150MHz,DMSO-d6)δ:165.63,158.42,156.88,134.01,131.15,129.49,125.25,125.19, 118.74,117.21,117.18,114.53,113.07,113.01,109.82,109.64,105.45,105.29,45.75,32.04,29.38, 28.08.HR-ESI-MS:424.1666[M+H]+,(calcdfor C23H22FN3O4,424.1667)。
活性测试实施例1
本实施例进行的为细胞毒性的评价
选取对数生长期的细胞,向96孔板中每个孔加入100μL细胞悬液(0.6×104)个细胞 (DMEM培养液),在培养箱中培养12小时。
利用DMEM将待测化合物稀释至所需浓度,在每个孔中加入100μL待测液。空白组只加入DMEM培养液,在培养箱中继续培养。
培养72小时后,每个孔中加入20μL MTT培养液(5mg/mL)。
在培养箱中继续培养4小时后,轻轻吸出培养基,每个孔中加入150μL DMSO溶解,摇 床震荡5分钟,使结晶紫完全溶解。
利用多功能酶标仪在490nm波长下读取OD值,计算存活率,绘制IC50曲线,其抑制活性见表1。
表1该类化合物对四种肿瘤细胞的抑制活性。
a实验平行重复三次结果均值。药物均作用于细胞72小时
“-”未进行测试
活性测试实施例2
本实施例进行的是HDAC抑制活性评价
制备1x分析缓冲液(改良Tris缓冲液)。
在100%DMSO中通过回声将化合物转移至96孔板。DMSO的最终浓度不大于1%。
对于HDAC1、HDAC2、HDAC3和HDAC6,在1x中添加胰蛋白酶和Ac肽底物。对于 HDAC8,在1x分析缓冲液中加入Ac肽底物,制成底物溶液。
将15μL酶溶液转移至分析板,或将15μL 1x转移至低对照板分析缓冲液。在室温下培 养15分钟。
向每个孔中加入10μL底物溶液以开始反应。对于HDAC1、HDAC2、HDAC3和HDAC6, 使用355nm激发,460nm发射。对于HDAC8,在RT下培养240分钟,然后添加胰蛋白酶 溶液并在RT下培养120分钟。
在Envison上读取平板,激发波长为355nm,发射波长为460nm。
使用公式(1)拟合Excel中的数据以获得抑制值
方程(1):Inh%=(最大信号)/(最大最小)*100
使用公式(2)对数据进行XL拟合,以获得IC50值
方程(2):Y=底部+(顶部-底部)/(1+(IC50/X)*斜率)
Y为%抑制,X为化合物浓度
表2化合物LZ1对5种HDAC亚型的活性。
通过酶活力与细胞毒性实验结果表明,本发明具有具有良好的抗肿瘤活性,其中对DZ-12 活性最好对HCT116的抑制达到了99nM,同时针对HDAC的抑制达到了1.6nM(HDAC1)。 该类药物为发现新的抗肿瘤HDAC抑制剂提供了理论依据。
Claims (10)
2.根据权利要求1所述的HDAC抑制剂,其特征在于,结构通式(I)所示的HDAC抑制剂及其药学上可接受的盐:
其中,
R1为H;
和/或,R2为H或甲基;
和/或,R3为H,单取代5-F,单取代6-F,单取代6-甲基中的一种或几种;
和/或,R4为单取代F;
和/或,A为苯环;
和/或,X为-CH2-NH-,-CO-中的一种;
和/或,Y为N或CH;
和/或,Z为CH。
4.根据权利要求2所述的HDAC抑制剂,其特征在于,HDAC抑制剂与无机酸或有机酸反应形成药学上可接受的盐,其中,所述无机酸为盐酸、氢溴酸、氢氟酸、硫酸、硝酸或磷酸中的一种或几种;所述的有机酸为甲酸、乙酸、丙酸、柠檬酸、甲磺酸、乙磺酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸或酒石酸中的一种或几种。
5.权利要求1~3任意一项所述的HDAC抑制剂的制备方法,其特征在于,包括如下步骤:
S1:将结构通式(II)所示化合物与哌啶-4-酮盐酸盐水合物反应,得到结构通式(III)的化合物;将结构通式(II)所示化合物与4-N-Boc-氨基环己酮反应,得到结构通式(IV)的化合物;
其中,结构通式(II)、(III)、(IV)中R1、R2、R3的定义同结构通式(I)中R1、R2、R3;
S2:将结构通式(V)的化合物与溴乙酸乙酯在碱性条件下反应,其中,R=H时,得到结构通式(VI)的化合物;R=OH时,得到结构通式(VII)的化合物;
其中,结构通式(V)、(VI)、(VII)中R4、Z的定义同结构通式(I)中R4、Z;
S3:将第一反应物和第二反应物发生还原胺化反应或缩合反应,再与羟胺水溶液水解反应,得到结构通式(I)所示化合物;
其中,第一反应物选择结构通式(III)的化合物与第二反应物选择结构通式(VI)或结构通式(VII)的化合物反应;或者第一反应物选择结构通式(IV)的化合物与第二反应物选择结构通式(VI)的化合物。
6.根据权利要求5所述的HDAC抑制剂的制备方法,其特征在于,步骤S1中,结构通式(II)所示的化合物与哌啶-4-酮盐酸盐水合物,或4-N-Boc-氨基环己酮反应的反应介质为冰醋酸或2mol/L氢氧化钾的甲醇溶液,反应条件为70~100℃加热回流,反应时间为2-12h;
和/或,所述的步骤S2中,所述取代反应介质为乙腈;所述碱性条件为反应体系中加入K2CO3;其中,按摩尔比,K2CO3:结构通式(V)的化合物=(1.5-2):1,反应条件为70~100℃回流,反应时间为4-6h。
7.根据权利要求5所述的HDAC抑制剂的制备方法,其特征在于,所述的步骤S3中,所述还原胺化反应介质为甲醇,还原剂为氰基硼氢化钠,其中,按摩尔比,氰基硼氢化钠:结构通式(VI)化合物=(1~6):1,催化剂为冰醋酸,反应条件为室温,反应时间为8-12h;
缩合反应介质为DMF,缩合剂为HOBT(1-Hydroxybenzotriazole,HOBT),碱性条件为反应体系中加入K2CO3;
水解反应介质为1mol/LKOH的甲醇溶液,按摩尔比,羟胺:结构通式(VI)的化合物或结构通式(VII)的化合物为(1~10):1,按体积比,羟胺水溶液:甲醇为1:(1~50),反应条件为室温,反应时间为2~6h。
8.一种药物组合物,其特征在于,包含权利要求1~4任意一项所述的HDAC抑制剂及其药学上可接受的盐,还包括药学上可接受的赋形剂。
9.权利要求1~4任意一项所述的HDAC抑制剂的用途和权利要求8所述的药物组合物的用途,用于制备预防和/或治疗肿瘤的抗肿瘤药物中的应用。
10.根据权利要求9所述的HDAC抑制剂的用途和药物组合物的用途,所述的抗肿瘤药物为治疗和/或预防结直肠癌、乳腺癌、白血病或多发性骨髓瘤疾病的药物。
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