CN102180849A - Diaryl diene cyclic ketone derivatives, and preparation method and application thereof - Google Patents

Diaryl diene cyclic ketone derivatives, and preparation method and application thereof Download PDF

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CN102180849A
CN102180849A CN 201110071536 CN201110071536A CN102180849A CN 102180849 A CN102180849 A CN 102180849A CN 201110071536 CN201110071536 CN 201110071536 CN 201110071536 A CN201110071536 A CN 201110071536A CN 102180849 A CN102180849 A CN 102180849A
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formula
diaryl
containing
diene
compound
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CN 201110071536
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A·H·康尼
卢宇靖
张焜
徐学涛
方岩雄
杜志云
汤志恺
涂增清
莫容清
薛贵华
郑希
韦星船
黄华蓉
黄宝华
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广东工业大学
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Abstract

The invention discloses diaryl diene cyclic ketone derivatives, and a preparation method and application thereof. The chemical formula of the derivatives is shown as the formula (I). The diaryl diene cyclic ketone derivatives have a structure similar to that of natural curcumin, are more stable than the curumin, easy to synthesize and suitable for expanded production. The diaryl diene cyclic ketone derivatives have good inhibition effects on the proliferation growth of various tumor cells such as humanized prostatic cancer cells, pancreatic cancer cells, colon cancer cells and the like, low toxic and side effects and a prospect of being developed into a novel anti-tumor medicament.

Description

一种二芳基二烯环酮衍生物及其制备方法与应用 A two aryl rings diene derivative and its preparation method and application

技术领域 FIELD

[0001] 本发明涉及一种二芳基二烯环酮衍生物及其制备方法与应用。 [0001] The present invention relates to a cyclic diene diaryl ketone derivatives, preparation method and application. 背景技术 Background technique

[0002] 癌症是危及人类生存和健康的主要疾病之一。 [0002] Cancer is one of the major diseases threatening human survival and health. 抗癌新药一直是各国药物学家研究的热点,高效低毒的抗癌药物是抗肿瘤药物研究的主要方向之一。 Anti-cancer drugs has been the focus of national drug research scientists, efficiency and low toxicity of anticancer drugs is one of the main directions of research of anticancer drugs.

[0003] 二芳基二烯酮衍生物的天然产物代表是姜黄素,姜黄素是植物姜黄(Curcuma longa Linn)的主要成分,具有无毒及多种生物活性作用。 [0003] Representative natural product dienone derivatives diaryl curcumin, curcumin is turmeric (Curcuma longa Linn) is a main component, and a variety of non-toxic biological activity. 由于姜黄素对多种肿瘤细胞的增殖具有明显的抑制作用,姜黄素作为抗肿瘤药物的研究受到极大的关注。 Since curcumin significantly inhibited the proliferation of various tumor cells, curcumin as antitumor drugs is greatly concerned. 但由于姜黄素的生物利用度较低、稳定性差、对肿瘤细胞的抑制活性还有待提高等因素,在临床上的应用受到限制。 Because of the low bioavailability of curcumin, poor stability to be improved inhibitory activity of tumor cells and other factors, the clinical application is limited. 为了提高姜黄素类化合物的稳定性和抗肿瘤生物活性,研究其类似结构是主要的策略之一。 To enhance the stability and Antitumor activity of curcuminoids, study similar structure is one of the major strategies.

[0004] 二芳基二烯酮类化合物的结构特征主要由两边对称的芳香部分与中间的酮部分用双健连接。 [0004] The structural characteristics of the diaryl ketone diene compound mainly composed of bilaterally symmetrical aromatic ketone moiety with an intermediate portion connected to double bonds. 目前报道的这类化合物主要集中在中间为丙酮或C6及以下的脂环酮与两边为芳基取代物。 Such compounds are reported to date is mainly concentrated in the middle and below acetone or C6 alicyclic ketone with an aryl group substituted with two sides thereof. 含杂大环酮本身具有一定的抗肿瘤作用。 Hetero macroketone itself has some anti-tumor effect. 中间含0,S杂原子的C6及以上的大环酮,或C7及以上的不饱和的脂环酮,同时两边苯基含2个以上的烷基或烷氧基,或一边或两边为含N杂芳基等的该类化合物还未见报道;这类化合物对肿瘤作用的研究还未见报道。 Intermediate containing 0, C6 and above macroketone S heteroatom, or more unsaturated C7 and alicyclic ketones, and phenyl group containing at least two sides of the alkyl or alkoxy groups, or one or both sides containing such compounds N heteroaryl group has not been reported; Study action on tumors such compounds have not been reported.

发明内容 SUMMARY

[0005] 本发明的目的在于提供一种具有抗癌活性的二芳基二烯环酮衍生物。 [0005] The object of the present invention to provide a diaryl cyclic diene derivative having anticancer activity.

[0006] 本发明的另一个目的在于提供一种上述二芳基二烯环酮衍生物的制备方法。 [0006] Another object of the present invention is to provide a process for preparing the above-mentioned diaryl ketone derivatives of cyclic diene.

[0007] 本发明的另一个目的在于提供一种上述二芳基二烯环酮衍生物在制备抗肿瘤药物中的应用。 [0007] Another object of the present invention is to provide an application of the above cyclic dienes diaryl derivative in the manufacture of anti-tumor drugs.

[0008] 本发明上述目的是通过如下方案予以实现的: [0008] The object of the present invention is to be implemented by the following scheme:

本发明根据具有抗肿瘤作用的小分子二苯二烯酮类化合物(如姜黄素)的结构,设计合 The structure of the present invention is a small molecule diphenyl diene-based compounds (such as curcumin) having antitumor effects, the design co

成得到本发明的含杂二芳基二烯环酮衍生物。 To obtain the present invention heteroatom containing biaryl derivative cyclic diene. 其化学结构如式(I)所示: The chemical structure of formula (I) below:

ο ο

fki fki

m η m η

(I) (I)

其中: among them:

m = 0 〜4,η = 0 〜4,m+n 2 2 ;且X = 0、S、OCH2CH2O, OC (CH3) 2、CO2CH2, CONH、CH=CH 或C三C ; m = 0 ~4, η = 0 ~4, m + n 2 2; and X = 0, S, OCH2CH2O, OC (CH3) 2, CO2CH2, CONH, CH = CH and C or C;

4Y和Z同时或分别为式(II)所示化合物、式(III)所示化合物、式(IV)所示化合物、 式(V)所示化合物: 4Y and Z are simultaneously or formula (II) shown in FIG FIG compound of formula (V) a compound of formula (III) compound, of formula (IV) the compound:

Figure CN102180849AD00051

式(II)中R1, R2, R3, R4, R5有三个或以上取代基同时或分别为CV6烷基、Cp6烷氧基、 CV6含烷脂基、CV6含F烷基、CV6含F烷氧基,C1^6含F烷脂基、-F、 Formula (II), R1, R2, R3, R4, R5, or three or more substituents are simultaneously CV6 alkyl, Cp6 alkoxy, aliphatic alkyl group containing CV6, CV6 alkyl group containing F, CV6 alkoxy containing F group, C1 ^ 6 aliphatic alkyl group containing F, -F,

Figure CN102180849AD00052

,其余为H,R3 , The remainder being H, R3

可为0Η。 Can 0Η.

[0009]式(III)、式(IV)、式(V)中 & 为Cp6 烷基; In & [0009] Formula (III), Formula (IV), Formula (V) is Cp6 alkyl;

式(III)、式(IV)、式(V)中&为CV6烷基、Ch6烷氧基、CV6含F烷基、Ch6含F烷氧基。 Of formula (III), Formula (IV), Formula (V), as & CV6 alkyl, Ch6 alkoxy, CV6 alkyl group containing F, Ch6 F-containing alkoxy group.

[0010] 本发明含杂二芳基二烯环酮衍生物的制备方法根据式(I)所示的Y和Z的相同和不同,主要有两种制备方法: [0010] The present invention diaryl heteroatom containing cyclic diene derivative prepared according to formula (I) and different from the same, there are two main methods of preparation of Y and Z is as follows:

1.当式(I)中Y与Z为式(II)、式(III)、式(IV)、式(V)完全相同时,该方法包括如下步骤: 1. When the formula (I) wherein Y and Z are formula (II), Formula (III), Formula (IV), Formula (V) are identical, the method comprising the steps of:

将芳香醛与含0或S杂环酮或C7_12大环脂酮进行双边羟醛缩合反应,得到式(I)所示二芳基二烯环酮衍生物。 The aromatic aldehydes with heterocyclic ketones containing 0 or S or one C7_12 macrolide bilateral aldol condensation reaction to give the formula (I) represents a group of diaryl cyclic diene derivative.

[0011] 上述步骤中芳香醛与含0或S杂环酮或C7_12大环脂酮的摩尔比例为2〜3 :1,优选2 :1。 [0011] In the above step with an aromatic aldehyde molar ratio of 0, or S-containing heterocyclic ketones or ketone C7_12 macrolide is 2 or 3: 1, preferably 2: 1.

[0012] 上述步骤中采用质量百分比为5〜40%的NaOH溶液做催化剂,优选质量分数为15%。 [0012] The step of using the mass percentage of 5 ~ 40% NaOH solution as catalyst, preferably 15% mass fraction.

[0013] 上述步骤中可采用饱和HCl (g)的乙醇或乙酸溶液做催化剂. [0013] The above-described steps can be employed with saturated HCl (g) solution in ethanol or acetic acid as catalyst.

上述步骤根据芳香醛与酮的反应活性确定反应时间,一般反应时间为1〜2小时。 The above step of determining the reaction time and reactivity of aromatic aldehyde ketone, the reaction time is generally 1 ~ 2 hours.

[0014] 上述步骤中反应温度一般控制在室温,根据芳香醛与酮反应活性,可适当加热至摄氏50°C。 [0014] The reaction in the above step at room temperature control, according to the reactivity of aromatic aldehydes and ketones, can be properly heated to 50 ° C ° C.

[0015] 2.当式(I)中Y与Z为式(II)、式(III)、式(IV)、式(V)不完全相同时,该方法包括如下步骤: [0015] 2. When the formula (I) wherein Y and Z are formula (II), Formula (III), Formula (IV), Formula (V) is not exactly the same, the method comprising the steps of:

先将芳香醛与含0或S杂环酮单边羟醛缩合反应制备单边烯酮中间体,再与另一芳香醛反应,得到式(I)所示的不对称二芳基二烯环酮衍生物。 First of aromatic aldehydes with heterocyclic ketones containing 0 or S, prepared by reacting aldol condensation unilateral unilateral ketene intermediate, and then further reacted with an aromatic aldehyde of formula (I), asymmetric diaryl ring dienes derivatives.

[0016] 上述步骤中芳香醛与含0或S杂环酮或C7_12大环脂酮单边羟醛缩合反应的摩尔比例为1 :3〜10,优选1 :3。 [0016] The molar ratio of the step with an aromatic aldehyde or ketone 0 or S heterocyclic C7_12 macrolide containing one unilateral aldol condensation reaction is 1: 3~10, preferably 1: 3.

[0017] 上述步骤中单边羟醛缩合反应采用质量百分比为5〜40%的NaOH溶液做催化剂, 优选质量分数为10%。 [0017] The step aldol reaction using unilateral mass percentage of 5 ~ 40% NaOH solution as catalyst, preferably 10% mass fraction.

[0018] 上述步骤中单边羟醛缩合反应制备单边烯酮中间体,将芳香醛溶于THF (四氢呋喃)或乙醇中,滴加到酮的THF或乙醇溶液中,慢慢搅拌。 [0018] The aldol condensation step unilateral unilateral prepared by reacting ketene intermediate, an aromatic aldehyde was dissolved in THF (tetrahydrofuran) or ethanol, a ketone is added dropwise in THF or ethanol solution was slowly stirred. 根据芳香醛与酮的反应活性确定反应时间,一般反应时间为1〜2小时。 The reaction time is determined according to the reactivity of aromatic aldehydes and ketones, the reaction time is generally 1 ~ 2 hours. [0019] 上述步骤中进行第二个芳香醛羟醛缩合时,芳香醛与制备的单边烯酮中间体的摩尔比例为1〜2 :1,优选1 :1。 [0019] When a second aromatic aldehyde aldol condensation above step, the molar ratio of aromatic aldehyde unilateral enone intermediates for the preparation of ~ 2: 1, preferably 1: 1.

[0020] 上述步骤中进行第二个芳香醛羟醛缩合时采用质量百分比为5〜40%的NaOH溶液做催化剂,优选质量分数为10%。 When using a second aromatic aldehyde aldol condensation [0020] The mass percentage of Step 5 ~ 40% NaOH solution as catalyst, preferably 10% mass fraction.

[0021] 上述步骤中进行第二个芳香醛羟醛缩合时可采用饱和HCl (g)的乙醇或乙酸溶液做催化剂。 [0021] can be saturated HCl (g) solution in ethanol or acetic acid as the catalyst when the second aromatic aldehyde in the aldol condensation step above.

[0022] 本发明的二芳基二烯环酮衍生物经实验证实,对多种人癌细胞株的生长有显著的抑制作用,因此可用于制备抗癌药物。 [0022] diaryl cyclic diene derivative of the present invention confirmed by experiments, significantly inhibited the growth of a variety of human cancer cell lines, and thus can be used for the preparation of anticancer drugs.

[0023] 本发明的二芳基二烯环酮衍生物与药学上可以接收的助剂组合制备抗癌药物,抗癌药物为片剂、胶囊、丸剂、注射液、乳剂或悬浊液等。 [0023] The adjuvant composition cyclic dienes diaryl ketone derivatives of this invention and the preparation of pharmaceutically received anticancer drug, anticancer drug as tablets, capsules, pills, injections, emulsions, suspensions, or the like.

[0024] 与现有技术相比,本发明具有如下有益效果: [0024] Compared with the prior art, the present invention has the following advantages:

本发明的二芳基二烯环酮衍生物与天然产物姜黄素结构类似,比姜黄素稳定;同时,合成简单,易于扩大生产;对多种人癌细胞株的生长有显著的抑制作用和较低的毒副作用,具有发展成新型抗肿瘤药物的前景。 Cyclic dienes diaryl ketone derivatives and natural product-like structure of the present invention curcumin, curcumin stable than; the same time, the synthesis is simple and easy to expand production; on the growth of various human cancer cell lines have a more significant inhibition and low toxicity, has developed into the prospect of new anticancer drugs.

具体实施方式 detailed description

[0025] 以下通过具体实施例对本发明做进一步说明,但具体实施例并不对本发明做任何限定。 [0025] The following invention is further illustrated by the specific embodiments, specific embodiments of the present invention is not at all limited.

实施例1 :化合物1的合成 Synthesis of Compound 1: Example 1

Figure CN102180849AD00061

本实施例的过程的制备过程,包括如下步骤: Preparation process of the present embodiment, comprising the steps of:

将0.01 mol的3,4,5-三甲氧基苯甲醛与0.005 mol的四氢吡喃酮置于圆底烧瓶中, 加入20 mL饱和HCl (g)的冰醋酸溶液,于室温(25-30 °C)搅拌30 min后放置2天。 3,4,5-methoxybenzaldehyde 0.01 mol and 0.005 mol of tetrahydropyranone placed in a round bottom flask, 20 mL of saturated HCl (g) in glacial acetic acid at room temperature (25-30 after ° C) was stirred for 30 min for 2 days. 反应完全,于反应瓶中加入20 mL水,过滤沉淀得到粗产品,用乙醇重结晶,真空干燥得黄色粉末,即化合物1,本实例产率为90. 0%。 The reaction was complete, the reaction flask in 20 mL of water, the precipitate was filtered to give the crude product, recrystallized from ethanol, and dried in vacuo to give a yellow powder, i.e. compound 1, this Example yield of 90.0%.

[0026]熔点:248-250°C. 1HWR (CDCl3j 300 MHz) δ ppm :7. 76 (s, 2H, - CH=), 6. 55 (s, 4H, arom), 4. 97 (s, 4H, - CH2-O - CH2 - ) 3. 90 (s, 18H, -OCH3). ESI—MS (m/z): 457 (M+l) +· [0026] Melting point: 248-250 ° C 1HWR (CDCl3j 300 MHz) δ ppm:.. 7 76 (s, 2H, - CH =), 6. 55 (s, 4H, arom), 4. 97 (s, 4H, - CH2-O - CH2 -) 3. 90 (s, 18H, -OCH3) ESI-MS (m / z):. 457 (m + l) + ·

实施例2 :化合物2的合成 Example 2: Synthesis of Compound 2

Figure CN102180849AD00062

本实施例的过程的制备过程,包括如下步骤: Preparation process of the present embodiment, comprising the steps of:

将0.01 mol的3,4,5-三甲氧基苯甲醛与0.005 mol的四氢噻喃酮置于圆底烧瓶中,加入20 mL饱和HCl (g)的冰醋酸溶液,于室温(25-30 °C )搅拌30 min后放置2天。 3,4,5-methoxybenzaldehyde 0.01 mol and 0.005 mol of tetrahydrothiopyran-one was placed in a round bottom flask, 20 mL of saturated HCl (g) in glacial acetic acid at room temperature (25-30 after ° C) was stirred for 30 min for 2 days. 反应完全,于反应瓶中加入20 mL水,过滤沉淀得到粗产品,用乙醇重结晶,真空干燥得黄色粉末,即化合物2,本实例产率为85. 0%。 The reaction was complete, the reaction flask in 20 mL of water, the precipitate was filtered to give the crude product, recrystallized from ethanol, and dried in vacuo to give a yellow powder, i.e. Compound 2, this Example yield of 85.0%.

[0027]熔点:220-222 "C . 1HWR (CDC13, 300 MHz) δ (ppm) :7. 71 (s, 2H, - CH=), 6. 63 (s, 4H, arom), 3. 96 (s, 4H, - CH2—S - CH2 - ) ,3.89 (s, 18H, -0CH3). ESI-MSCm/ ζ): 473 (M+l) +. [0027] Melting point: 220-222 "C 1HWR (CDC13, 300 MHz) δ (ppm):.. 7 71 (s, 2H, - CH =), 6. 63 (s, 4H, arom), 3. 96 (s, 4H, - CH2-S - CH2 -), 3.89 (s, 18H, -0CH3) ESI-mSCm / ζ):. 473 (M + l) +.

实施例3 :化合物3的合成 Synthesis of Compound 3: Example 3

Figure CN102180849AD00071

本实施例的过程的制备过程,包括如下步骤: Preparation process of the present embodiment, comprising the steps of:

将0.01 mol的3,5-二甲氧基-4-羟基-苯甲醛与0.005 mol的四氢吡喃酮置于圆底烧瓶中,加入20 mLTHF溶液溶解,加入5mL20%Na0H水溶液,于室温(25-30 V )搅拌30 min后放置2天。 0.01 mol of the 3,5-dimethoxy-4-hydroxy - benzaldehyde and 0.005 mol of tetrahydropyranone round-bottom flask was dissolved 20 mLTHF, 5mL20% Na0H solution was added, at room temperature ( after 25-30 V) was stirred for 30 min for 2 days. 反应完全后,过滤沉淀得到粗产品,用乙醇洗涤,真空干燥得橙黄色粉末, 即化合物3,本实例产率为78. 0%。 After completion of the reaction, the precipitate was filtered to give the crude product washed with ethanol and dried in vacuo to give a yellow-orange powder, i.e. compound 3, the present example a yield of 78.0%.

[0028]熔点:2¾ - 228 "C . IH 匪R (DMS0_d6,300 MHz) δ (ppm) : 9. 03 (brs, 2H, -OH),7. 58 (s, 2H, - CH=),6. 70 (s, 4H, arom),4. 95 (s, 4H, - CH2-S _ CH2 -), 3.81 (s, 12H, -OCH3). ESI-MS (m/z) : 427 (MI) +· 实施例4 :化合物4的合成 [0028] Melting point: 2¾ - 228 "C IH bandit R (DMS0_d6,300 MHz) δ (ppm):.. 9. 03 (brs, 2H, -OH), 7 58 (s, 2H, - CH =), . 6. 70 (s, 4H, arom), 4 95 (s, 4H, - CH2-S _ CH2 -), 3.81 (s, 12H, -OCH3) ESI-MS (m / z):. 427 (MI ) + EXAMPLE 4: synthesis of compound 4

Figure CN102180849AD00072

本实施例的过程的制备过程,包括如下步骤: Preparation process of the present embodiment, comprising the steps of:

将0.01 mol的3,5-二甲氧基-4-羟基-苯甲醛与0.005 mol的四氢噻喃酮置于圆底烧瓶中,加入20 mLTHF溶液溶解,滴加5mL20%Na0H水溶液,于室温(25-30 V )搅拌30 min后放置2天。 0.01 mol of the 3,5-dimethoxy-4-hydroxy - benzaldehyde and 0.005 mol of tetrahydrothiopyran-one placed in a round bottom flask was added 20 mLTHF was dissolved, was added dropwise 5mL20% Na0H solution, at room temperature (25-30 V) placed stirred 30 min 2 days. 反应完全后,过滤沉淀得到粗产品,用乙醇洗涤,真空干燥得亮黄色粉末, 即化合物4,本实例产率为82. 0%。 After completion of the reaction, the precipitate was filtered to give the crude product washed with ethanol and dried in vacuo to give a light yellow powder, i.e. the compound 4, the present example a yield of 82.0%.

[0029]熔点:149-152 "C . 1H 匪R (DMS0_d6,300 MHz) δ (ppm) : 8.93 (brs, 2H, -OH),7. 53 (s, 2H, - CH=),6. 80 (s, 4H, arom),4. 03 (s, 4H, - CH2 - S - CH2 -), 3. 80 (s, 12H, -OCH3). ESI-MS (m/z) : 443 (MI)+. 实施例5 :化合物5的合成 [0029] Melting point: 149-152 "C 1H bandit R (DMS0_d6,300 MHz) δ (ppm):. 8.93 (brs, 2H, -OH), 7 53 (s, 2H, - CH =), 6. 80 (s, 4H, arom), 4 03 (s, 4H, - CH2 - S - CH2 -), 3. 80 (s, 12H, -OCH3) ESI-MS (m / z):.. 443 (MI synthesis of compound 5:) + Example 5.

Figure CN102180849AD00081

本实施例的过程的制备过程,包括如下步骤: Preparation process of the present embodiment, comprising the steps of:

将0.01 mol的2,4-二氟苯甲醛与0.005 mol的四氢吡喃酮置于圆底烧瓶中,加入40 mLTHF溶液溶解,滴加5mL10%Na0H水溶液,于室温(25-30 V )搅拌30 min后放置1天。 2,4-difluorobenzaldehyde 0.01 mol and 0.005 mol of tetrahydropyranone placed in a round bottom flask was added 40 mLTHF was dissolved, was added dropwise 5mL10% Na0H solution, stirred at room temperature (25-30 V) 30 min after placing 1 day. 反应完全后,过滤沉淀得到粗产品,用乙醇洗涤,真空干燥得浅黄色粉末,即化合物5,本实例产率为72. 0%。 After completion of the reaction, the precipitate was filtered to give the crude product washed with ethanol and dried in vacuo to give a pale yellow powder, i.e. compound 5, the present example 72.0% yield.

[0030]熔点:130-132 "C . 1HWR (CDCl3, 300 MHz) δ (ppm) :7. 93 (s, 2H, - CH=), 7. 13 (s, 2H, arom),6. 69-6. 63 (m, 4H, arom),3. 90 (s, 4H, - CH2-O - CH2 - ). ESI-MS (m/z) : 349 (M+1)+. [0030] Melting point: 130-132 "C 1HWR (CDCl3, 300 MHz) δ (ppm):... 7 93 (s, 2H, - CH =), 7. 13 (s, 2H, arom), 6 69 . -6 63 (m, 4H, arom), 3 90 (s, 4H, - CH2-O - CH2 -) ESI-MS (m / z):.. 349 (m + 1) +.

实施例6 :化合物6的合成 Example 6: Synthesis of Compound 6

Figure CN102180849AD00082

本实施例的过程的制备过程,包括如下步骤: Preparation process of the present embodiment, comprising the steps of:

将0.01 mol的2,4-三氟甲氧基苯甲醛与0.005 mol的四氢吡喃酮置于圆底烧瓶中, 加入40 mLTHF溶液溶解,滴加5mL15%Na0H水溶液,于室温(25-30 V )搅拌30 min后放置1天。 The 2,4-trifluoromethoxybenzaldehyde 0.01 mol and 0.005 mol of tetrahydropyranone placed in a round bottom flask was added 40 mLTHF was dissolved, was added dropwise 5mL15% Na0H solution, at room temperature (25-30 after V) was stirred for 30 min to stand for 1 days. 反应完全后,过滤沉淀得到粗产品,用乙醇洗涤,真空干燥得浅黄色粉末,即化合物6, 本实例产率为86. 0%。 After completion of the reaction, the precipitate was filtered to give the crude product washed with ethanol and dried in vacuo to give a pale yellow powder, i.e. compounds 6, in this example a yield of 86.0%.

[0031]熔点:180-182 "C . 1HWR (CDCl3, 300 MHz) δ (ppm) :7. 91 (s, 2H, - CH=), 6. 93 (s, 2H, arom),6. 28-6. 23 (m, 4H, arom),3. 91 (s, 4H, - CH2-O - CH2 - ) , 3. 89 (s, 18H, -OCH3). ESI-MS (m/z) : 613(M+1)+. 实施例7 :化合物7的合成 . [0031] Melting point: 180-182 "C 1HWR (CDCl3, 300 MHz) δ (ppm): 7 91 (s, 2H, - CH =), 6. 93 (s, 2H, arom), 6 28. .. -6 23 (m, 4H, arom), 3 91 (s, 4H, - CH2-O - CH2 -), 3. 89 (s, 18H, -OCH3) ESI-MS (m / z):. . 613 (M + 1) + Example 7: synthesis of compound 7

本实施例的过程的制备过程,包括如下步骤: Preparation process of the present embodiment, comprising the steps of:

Figure CN102180849AD00083

将0.01 mol的2-吡啶甲醛与0.005 mol的四氢吡喃酮置于圆底烧瓶中,加入20 mL 乙醇溶液溶解,滴加anL15%Na0H水溶液,于室温(25-30 °C )搅拌30 min后放置6 h。 A mixture of 2-pyridinecarboxaldehyde 0.01 mol and 0.005 mol of tetrahydropyranone placed in a round bottom flask, 20 mL of ethanol was dissolved, was added dropwise anL15% Na0H solution, stirred for 30 min at room temperature (25-30 ° C) after standing for 6 h. 反应完全后,过滤沉淀得到粗产品,用乙醇洗涤,真空干燥得浅黄色粉末,即化合物7,本实例产率为63. 0%。 After completion of the reaction, the precipitate was filtered to give the crude product washed with ethanol and dried in vacuo to give a pale yellow powder, i.e. the compound 7, the present example a yield of 63.0%.

[0032]熔点:200-202° C. 1HWR (CDCl3, 300 MHz) δ (ppm) : 8. 73-8.63 (m, 2H, arom), 7. 75-7. 65 (m, 2H, arom) , 7. 63 (s, 2H, -CH=), 7. 49-7. 41 (m, 2H, arom), 7. 23-7. 15 (m, 2H, arom),5. 31 (s, 4H, - H2C - O-CH2 - ). ESI-MS (m/z) : 279 (M+1)+·实施例8 :化合物8的合成 [0032] Melting point: 200-202 ° C. 1HWR (CDCl3, 300 MHz) δ (ppm):. 8. 73-8.63 (m, 2H, arom), 7. 75-7 65 (m, 2H, arom) , 7. 63 (s, 2H, -CH =), 7. 49-7. 41 (m, 2H, arom), 7. 23-7. 15 (m, 2H, arom), 5. 31 (s, 4H, - H2C - O-CH2 -) ESI-MS (m / z): 279 (m + 1) + · Example 8: synthesis of compound 8.

Figure CN102180849AD00091

本实施例的过程的制备过程,包括如下步骤: Preparation process of the present embodiment, comprising the steps of:

将0.01 mol的2-吡啶甲醛与0.005 mol的四氢噻喃酮置于圆底烧瓶中,加入20 mL 乙醇溶液溶解,滴加anL15%Na0H水溶液,于室温(25-30 °C )搅拌30 min后放置6 h。 A mixture of 2-pyridinecarboxaldehyde 0.01 mol and 0.005 mol of tetrahydrothiopyran-one was placed in a round-bottomed flask, dissolved 20 mL of ethanol was added dropwise anL15% Na0H solution, stirred for 30 min at room temperature (25-30 ° C) after standing for 6 h. 反应完全后,过滤沉淀得到粗产品,用乙醇洗涤,真空干燥得黄色粉末,即化合物8,本实例产率为68. 0%。 After completion of the reaction, the precipitate was filtered to give the crude product washed with ethanol and dried in vacuo to give a yellow powder, i.e. the compound 8, in this example a yield of 68.0%.

[0033]熔点:153-156 C. 1H NMR (CDCl3, 300 MHz) δ (ppm) : 8.94-8.83 (m ,2H arom),8. 70-8. 58 (m, 2H arom,), 7.96-7.87 (m, 2H, arom), 7. 62 (s, 2H, -CH=),7. 48-7. 39 (m, 2H, arom),3. 80 (s, 4H, - H2C - S-CH2 - ). ESI-MS (m/z) : 295 (M+1) +· [0033] Melting point: 153-156 C. 1H NMR (CDCl3, 300 MHz) δ (ppm):.. 8.94-8.83 (m, 2H arom), 8 70-8 58 (m, 2H arom,), 7.96- 7.87 (m, 2H, arom), 7. 62 (s, 2H, -CH =), 7 48-7 39 (m, 2H, arom), 3 80 (s, 4H, -... H2C - S- CH2 -) ESI-MS (m / z):. 295 (m + 1) + ·

实施例9 :化合物9的合成 Example 9: Synthesis of Compound 9

Figure CN102180849AD00092

本实施例的过程的制备过程,包括如下步骤: Preparation process of the present embodiment, comprising the steps of:

将0.01 mol的3,4,5-三甲氧基苯甲醛与0.005 mol的5-氧杂环辛酮置于圆底烧瓶中,加入30 mL饱和HCl (g)的冰醋酸溶液,用少量THF溶解原料,于室温(25-30 °C )搅拌30 min后放置5天。 3,4,5-methoxybenzaldehyde 0.01 mol and 0.005 mol of 5-oxo-octanone heterocyclic round-bottom flask was added 30 mL of saturated HCl (g) in glacial acetic acid, dissolved in a small amount of THF material at room temperature (25-30 ° C) was stirred for 30 min after placing five days. 反应完全,于反应瓶中加入5 mL水,过滤沉淀得到粗产品,用乙醇加热重结晶,真空干燥得黄色粉末,即化合物9,本实例产率为63. 0%。 The reaction was complete, the reaction flask 5 mL of water, the precipitate was filtered to give the crude product recrystallized from ethanol is heated to give a yellow powder and dried in vacuo, compound 9, the present example a yield of 63.0%. [0034]熔点:236-238° C. 1H 匪R (CDCl3j 300 MHz) δ ppm :7. 74 (s, 2H, - CH=), 6. 50 (s,4H, arom), 4. 95 (s, 4H, - CH2-O - CH2 - ) 3. 81 (s, 18H, -OCH3), 2. 24 (t, 4H, -CH2-). ESI-MS (m/z) : 485 (M+1) +. [0034] Melting point: 236-238 ° C. 1H bandit R (CDCl3j 300 MHz) δ ppm: 7 74 (s, 2H, - CH =), 6. 50 (s, 4H, arom), 4. 95 ( s, 4H, - CH2-O - CH2 -) 3. 81 (s, 18H, -OCH3), 2. 24 (t, 4H, -CH2-) ESI-MS (m / z):. 485 (m + 1) +.

实施例10 :化合物10的合成 Example 10: Synthesis of Compound 10

Figure CN102180849AD00093

本实施例的过程的制备过程,包括如下步骤: Preparation process of the present embodiment, comprising the steps of:

(1)将0.01 mol的3,4,5-三甲氧基苯甲醛和与0. 04 mol四氢噻喃酮置于圆底烧瓶中,溶于20 mLTHF中,均勻搅拌使其溶解,缓慢滴加浓度为10%的氢氧化钠水溶液10 mL, 控制滴速为2 d/s,滴毕室温搅拌反应15 h,析出固体,抽滤,乙醇重结晶,所得固体真空干燥至重量保持不变,得淡黄色粉末; (1) 3,4,5-methoxybenzaldehyde and 0.01 mol and 0. 04 mol tetrahydrothiopyran-one was placed in a round-bottomed flask, dissolved in 20 mLTHF and uniformly dissolved with stirring, slowly added dropwise add a concentration of 10% aqueous sodium hydroxide 10 mL, controlled drip rate of 2 d / s, the reaction was stirred dropwise at room temperature 15 h, the precipitated solid was filtered off with suction, recrystallized from ethanol, the resulting solid was dried under vacuum until the weight remains unchanged, light yellow powder;

(2)将取0. 005 mol的上述淡黄色粉末和4-三氟甲氧基_2_甲氧基苯甲醛0. 005mol 加入到IOmL饱和HCl (g)的冰醋酸溶液中,用DMSO溶解,于室温(25-30 V )搅拌30 min后放置2天。 (2) taking 0. 005 mol and the pale yellow powder _2_ 4-trifluoromethoxy-methoxybenzaldehyde was added to 0. 005mol IOmL saturated HCl (g) in glacial acetic acid, dissolved in DMSO after stirring for 30 min at room temperature (25-30 V) for 2 days. 反应完全,于反应瓶中加入10 mL水,过滤沉淀得到粗产品,用乙醇洗涤,真空干燥得亮黄色粉末,即化合物10,本实例总产率为52. 0%。 The reaction was complete, the reaction flask in 10 mL of water, the precipitate was filtered to give the crude product washed with ethanol and dried in vacuo to give a light yellow powder, i.e. compound 10, the present example a total yield of 52.0%.

[0035]熔点:2^-2¾ "C . 1HWR (CDCl3, 300 MHz) δ (ppm) : 7. 76 (s, 2H, - CH=), 6. 68 (s, 1H, arom), 6. 60 (s, 1H, arom),6. 20 (s. 2H, arom),3. 90 (s, 4H, -CH2-S-CH2-),3. 89-3. 93 (s, 12H, -OCH3). ESI-MS (m/z) : 497 (M+1) +· 实施例11 :化合物11的合成 [0035] Melting point: 2 ^ -2¾ "C 1HWR (CDCl3, 300 MHz) δ (ppm):. 7. 76 (s, 2H, - CH =), 6. 68 (s, 1H, arom), 6. . 60 (s, 1H, arom), 6 20 (s 2H, arom.), 3 90 (s, 4H, -CH2-S-CH2 -)., 3 89-3 93 (s, 12H,.. - synthesis of compound 11: OCH3) ESI-MS (m / z):. 497 (m + 1) + · Example 11

Figure CN102180849AD00101

本实施例的过程的制备过程,包括如下步骤: Preparation process of the present embodiment, comprising the steps of:

(1)将0.01 mol的3,4,5-三甲氧基苯甲醛和与0. 04 mol 5-硫杂环辛酮置于圆底烧瓶中,溶于20 mLTHF中,均勻搅拌使其溶解,缓慢滴加质量分数浓度为20%的氢氧化钠水溶液10mL,控制滴速为2 d/s,滴毕室温搅拌反应15 h,析出固体,抽滤,乙醇重结晶,所得固体真空干燥至重量保持不变,得淡黄色粉末; (1) 3,4,5-methoxybenzaldehyde and 0.01 mol and 0. 04 mol 5- thietanyl octanone was placed in a round-bottomed flask, dissolved in 20 mLTHF and uniformly dissolved with stirring, was slowly added dropwise fraction concentration of 20 mass% aqueous sodium hydroxide 10mL, controlled drip rate of 2 d / s, the reaction was stirred dropwise at room temperature 15 h, the precipitated solid was filtered off with suction, recrystallized from ethanol, the resulting solid was dried in vacuo to a weight holding constant, to obtain a pale yellow powder;

(2)将取0. 005 mol的上述淡黄色粉末和2,4- 二(三氟甲氧基)苯甲醛0. 005mol加入到10mL15%质量分数的NaOH溶液中,用5mL DMSO完全溶解,于室温(25-30 V )搅拌30 min后放置2天。 (2) taking 0. 005 mol, and the pale yellow powder of 2,4-bis (trifluoromethoxy) benzaldehyde was added to 0. 005mol 10mL15% by mass of NaOH solution, washed with 5mL DMSO was completely dissolved in room temperature (25-30 V) was stirred for 30 min for 2 days. 反应完全,于反应瓶中加入10 mL水,过滤沉淀得到粗产品,用乙醇洗涤, 真空干燥得亮黄色粉末,即化合物10,本实例总产率为59. 0%。 The reaction was complete, the reaction flask in 10 mL of water, the precipitate was filtered to give the crude product washed with ethanol and dried in vacuo to give a light yellow powder, i.e. compound 10, the present example a total yield of 59.0%.

[0036]熔点:206 - 208 ° C. 1H 匪R (DMS0_i/6,300 MHz) δ (ppm) : 7. 38 (s, 2H, -CH=), 6. 23-6. 28 (m, 5H, arom), 3.95 (s, 4H, -CH2-S-CH2-), 3.81 (s, 9H, -OCH3),2. 33-2. 40 (m, 4H, -CH2-). ESI-MS (m/z) : 579 (MI) +· 实施例12 :化合物12的合成 [0036] Melting point:. 206 - 208 ° C. 1H bandit R (DMS0_i / 6,300 MHz) δ (ppm): 7. 38 (s, 2H, -CH =), 6. 23-6 28 (m, 5H, arom), 3.95 (s, 4H, -CH2-S-CH2-), 3.81 (s, 9H, -OCH3), 2. 33-2. 40 (m, 4H, -CH2-). ESI-MS (m / z): synthesis of compound 12: 579 (MI) + · 12 Example

Figure CN102180849AD00102

本实施例的过程的制备过程,包括如下步骤: Preparation process of the present embodiment, comprising the steps of:

(1)将0.01 mol的3,4,5-三甲氧基苯甲醛和与0. 04 mol四氢吡喃酮置于圆底烧瓶中,溶于20 mLTHF中,均勻搅拌使其溶解,缓慢滴加浓度为10%的氢氧化钠水溶液10 mL, 控制滴速为2 d/s,滴毕室温搅拌反应15 h,析出固体,抽滤,乙醇重结晶,所得固体真空干燥至重量保持不变,得淡黄色粉末; (1) 3,4,5-methoxybenzaldehyde and 0.01 mol and 0. 04 mol tetrahydropyranone placed in a round bottom flask, was dissolved in 20 mLTHF and uniformly dissolved with stirring, slowly added dropwise add a concentration of 10% aqueous sodium hydroxide 10 mL, controlled drip rate of 2 d / s, the reaction was stirred dropwise at room temperature 15 h, the precipitated solid was filtered off with suction, recrystallized from ethanol, the resulting solid was dried under vacuum until the weight remains unchanged, light yellow powder;

(2)将取0.005 mol的上述淡黄色粉末和3,5-二(三氟甲氧基)苯甲醛0.00511101加入到10 mL10%质量分数的NaOH溶液中,用5mL DMSO完全溶解,于室温(25-30 °C )搅拌30 min后放置2天。 (2) taking the pale yellow powder was 0.005 mol and the 3,5-bis (trifluoromethoxy) benzaldehyde was added to the NaOH solution 0.00511101 10 mL10% mass fraction, the completely dissolved 5mL DMSO, at room temperature (25 -30 ° C) after stirring for 30 min for 2 days. 反应完全,于反应瓶中加入10 mL水,过滤沉淀得到粗产品,用乙醇洗涤, 真空干燥得亮黄色粉末,即化合物12,本实例总产率为56. 0%。 The reaction was complete, the reaction flask in 10 mL of water, the precipitate was filtered to give the crude product washed with ethanol and dried in vacuo to give a light yellow powder, i.e. Compound 12 of the present example a total yield of 56.0%.

[0037]熔点:202 - 204 ° C. 1H 匪R (DMS0_i/6,300 MHz) δ (ppm) : 7. 58 (s, 2H, -CH=), 6. 36 (s, 2H, arom), 6. 23 (s, 2H, arom), 6. 15 (s, 1H, arom), 4.05 (s, 4H, -CH2-S-CH2-), 3.81 (s, 9H, -OCH3). ESI-MS (m/z) : 535 (MI) +. [0037] Melting point: 202 - 204 ° C. 1H bandit R (DMS0_i / 6,300 MHz) δ (ppm): 7. 58 (s, 2H, -CH =), 6. 36 (s, 2H, arom) , 6. 23 (s, 2H, arom), 6. 15 (s, 1H, arom), 4.05 (s, 4H, -CH2-S-CH2-), 3.81 (s, 9H, -OCH3). ESI- MS (m / z): 535 (MI) +.

实施例13 :衍生物对肿瘤细胞生长的抑制作用 Example 13: Inhibition of tumor cell growth derivatives

本实施案例选择人前列腺癌细胞株(PC-3)、人胰腺癌细胞株(Panc-Ι)、人大肠癌细胞株(HT-29),对实施例制备得到的含杂二芳基二烯环酮衍生物进行抑制肿瘤细胞的生长实验。 Case present embodiment selection of human prostate cancer cell line (PC-3), human pancreatic cancer cell lines (Panc-Ι), human colon cancer cell line (HT-29), obtained in preparation Example hetero biaryl diene ring derivatives inhibit tumor cell growth experiments.

[0038] 采用MTT法进行体外细胞毒性测定:在96孔板上将肿瘤细胞种植到含0. 2 X IO5 cells/mL (0. 2 mL/孔)孵育M小时。 [0038] MTT assay in vitro cytotoxicity assay: Tumor cells in 96 well plates containing seeded into 0. 2 X IO5 cells / mL (0. 2 mL / well) were incubated for M hours. 把不同浓度的各测试样品作用癌细胞72小时。 The effect of different concentrations of each test sample of cancer cells for 72 hours. 分别计算抑制细胞生长达50%时的化合物浓度,以IC5tl表示,结果见表1 : Calculate the concentration of compound that inhibits cell growth by 50% to IC5tl expressed, results shown in Table 1:

Figure CN102180849AD00111

由表1可以看出,实施例所得化合物1-12均对体外三种癌细胞株有很强的抑制作用, 说明本发明的二芳基二烯环酮衍生物具有可用于抗癌药物的前景。 As can be seen from Table 1, the compound obtained in Example 1-12 were strong inhibitory effect on three kinds of cancer cell lines in vitro, cyclic dienes described diaryl ketone derivatives of this invention can be used for promising anticancer drug .

Claims (8)

  1. 1.本发明涉及的含杂原子的一种二芳基二烯环酮衍生物,其化学结构如式(I)所示: One kind of heteroatom-containing cyclic diene diaryl derivatives of the present invention is directed to 1. The chemical structure of formula (I) below:
    Figure CN102180849AC00021
    其中:m = 0 〜4,η = 0 〜4,m+n 2 2 ;且X = 0、S、OCH2CH2O, OC (CH3) 2、CO2CH2, CONH、CH=CH 或C三C ;Y和Z同时或分别为式(II)所示化合物、式(III)所示化合物、式(IV)所示化合物、 式(V)所示化合物: Wherein: m = 0 ~4, η = 0 ~4, m + n 2 2; and X = 0, S, OCH2CH2O, OC (CH3) 2, CO2CH2, CONH, CH = CH and C or C; the Y and Z simultaneously or respectively of formula (II) shown in FIG FIG compound of formula (V) a compound of formula (III) compound, of formula (IV) the compound:
    Figure CN102180849AC00022
    式(II)中R1, R2, R3, R4, R5有三个或以上取代基同时或分别为CV6烷基、Cp6烷氧基、 CV6含烷脂基、Cp6含F烷基、CV6含F烷氧基、Cp6含F烷脂基或-F Formula (II), R1, R2, R3, R4, R5, or three or more substituents are simultaneously CV6 alkyl, Cp6 alkoxy, CV6 aliphatic group containing alkyl, Cp6 alkyl group containing F, CV6 alkoxy containing F group, Cp6 F-containing aliphatic alkyl group or -F
    Figure CN102180849AC00023
    ,其余为H,R3 可为0H;式(III)、式(IV)、式(V)中&为CV6烷基;式(III)、式(IV)、式(V)中R7SCV6烷基、Cp6烷氧基、CV6含F烷基或CV6含F烷氧基。 , The remainder being H, R3 may 0H; of formula (III), the formula & (IV), Formula (V) is CV6 alkyl; of formula (III), Formula (IV), Formula (V), R7SCV6 alkyl, Cp6 alkoxy, F-containing CV6 CV6 alkyl or alkoxy group containing F.
  2. 2. —种权利要求1所述的二芳基二烯环酮衍生物的制备方法,其特征在于当式(I)中Y = Z时,该方法包括如下步骤:将芳香醛与含0或S杂环酮或C7_12大环脂酮进行双边羟醛缩合反应,得到式(I)所示二芳基二烯环酮衍生物。 2. - preparation of diaryl diene species cyclic ketone derivative according to claim 1, characterized in that when formula (I), when Y = Z, the method comprising the steps of: aromatic aldehydes containing 0 or S heterocyclic ketones or ketone C7_12 macrolide bilateral aldol condensation reaction to give the formula (I) represents a group of diaryl cyclic diene derivative.
  3. 3.根据权利要求2所述的制备方法,其特征在于:上述芳香醛与含0或S杂环酮或(:7_12 大环脂酮的摩尔比为2〜3:1。 3. The production method according to claim 2, wherein: the above-described aromatic aldehydes with heterocyclic ketones containing 0 or S, or (: lipid molar ratio of macrocyclic ketone 7_12 is 2 or 3: 1.
  4. 4.根据权利要求2所述的制备方法,其特征在于:上述反应采用质量百分比为5〜40% 的NaOH溶液做催化剂,或采用饱和HCl (g)的乙醇或乙酸溶液做催化剂。 4. The production method according to claim 2, characterized in that: the above reaction using the mass percentage of 5 ~ 40% NaOH solution as catalyst, or with saturated HCl (g) solution in ethanol or acetic acid as catalyst.
  5. 5. 一种权利要求1所述的二芳基二烯环酮衍生物的制备方法,其特征在于当式(I)中Y兴Z时,该方法包括如下步骤:先将芳香醛与含0或S杂环酮单边羟醛缩合反应,再与另一芳香醛反应,得到式(I)所2示的不对称二芳基二烯环酮衍生物。 Preparation of diaryl cyclic dienes 5. A derivative as claimed in claim 1, characterized in that when formula (I) wherein Y Xing Z, the method comprising the steps of: first and aromatic aldehydes containing 0 S or heterocyclic ketones unilateral aldol condensation reaction, then reacted with another aromatic aldehydes, to give formula (I), 72.8 diaryl ketone derivatives, cyclic dienes illustrated.
  6. 6.根据权利要求5所述的制备方法,其特征在于:上述芳香醛与含0或S杂环酮或(:7_12 大环脂酮单边羟醛缩合反应的摩尔比为1 :3〜10。 The production method according to claim 5, wherein: the above-described aromatic aldehydes with 0 or S-containing heterocyclic ketones or (: lipid molar ratio of macrocyclic ketones 7_12 unilateral aldol condensation is 1: 3~10 .
  7. 7.根据权利要求5所述的制备方法,其特征在于:上述第一步反应采用质量百分比为5〜40%的NaOH溶液做催化剂,第二步反应采用质量百分比为5〜40%的NaOH溶液做催化剂或采用饱和HCl (g)的乙醇或乙酸溶液做催化剂。 7. The production method according to claim 5, wherein: the above-described first step of the reaction mass percentage of 5 ~ 40% using NaOH solution as catalyst, using the second step the reaction mass percentage of 5 ~ 40% NaOH solution or as catalyst with a saturated HCl (g) solution in ethanol or acetic acid as catalyst.
  8. 8.权利要求1所述的二芳基二烯环酮衍生物在制备抗肿瘤药物中的应用。 Application of diaryl diene cyclic ketone derivative according to claim 1 in the preparation of anti-tumor drugs.
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WO2000047205A1 (en) * 1999-02-10 2000-08-17 The Trustees Of The University Of Pennsylvania Tyrosine kinase inhibitors and methods of using the same
WO2001040188A1 (en) * 1999-12-03 2001-06-07 Emory University Curcumin analogues for treating cancer
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