设计和合成喹唑啉乙酰胺的镇痛和抗炎活性外文翻译资料

Z. Naturforsch. 2015; aop

Veerachamy Alagarsamy*, Viswas Raja Solomon, Mohaideen Thasthagir Sulthana,

Meduri Satyasai Vijay and Bandi Narendhar

Design and synthesis of quinazolinyl acetamides

for their analgesic and anti-inflammatory

activities

DOI 10.1515/znb-2015-0035

Received February 17, 2015; accepted April 2, 2015

biosynthesis. However, this mechanism of action is also

responsible for their main undesirable effects, gastrointesti-

nal (GI) ulceration, and, less frequently, nephrotoxicity. The

increase in hospitalization and deaths due to GI-related dis-

Abstract: A variety of novel 2-(substituted)-N-(4-oxo- orders parallels the increased use of NSAIDs. Therefore, the

2-phenylquinazolin-3(3H)-yl)acetamides were synthesized discovery of new safer anti-inflammatory drugs represents

by the reaction of 2-chloro-N-(4-oxo-2-phenylquinazolin- a challenging goal for such a research area [1–4]. In our

3(3H)-yl)acetamide with various amines. The starting going medicinal chemistry research program, we found that

material,

2-chloro-N-(4-oxo-2-phenylquinazolin-3(3H)-yl) quinazolines and condensed quinazolines exhibit potent

acetamide, was synthesized from anthranilic acid by central nervous system activities including analgesic, anti-

the multistep process. The title compounds were inves- inflammatory [5–7], and anticonvulsant behavior [8]. Quina-

tigated for analgesic, anti-inflammatory, and ulcero- zolin-4(3H)-ones with C-2 and N-3 substitution are reported

genic index activities. Among those, the compound to possess significant analgesic, anti-inflammatory [9, 10],

2-(ethylamino)- N-(4-oxo-2-phenylquinazolin-3(3 H)-yl) and anticonvulsant activities [11]. Earlier we have docu-

acetamide (V9) showed most potent analgesic and anti- mented some lead 2-benzylamino-3-(2-subsituted amino)

inflammatory activities of the series and it is moderately quinazolin-4(3H)-one (Fig. 1,I) [12], 1-(2-phenylquinazolin-

morepotentcomparedtothereferencestandarddiclofenac 3-yl-4(3H)-one)-3-substituted thiourea (Fig. 1, II), 2,3-dis-

sodium. Interestingly, the test compounds showed only ubstituted quinazolines that exhibited good analgesic and

mild ulcerogenic potential compared to aspirin.

anti-inflammatory activities [5, 13, 14]. The present work is

an extension of our ongoing efforts towards the develop-

Keywords: analgesic; anti-inflammatory; quinazoline; ment and identification of new molecules for analgesic and

ulcer index.

anti-inflammatory activities with minimal gastrointestinal

ulceration side effects. With this background in the present

study, we have synthesized a series of 2-(substituted)-N-(4-

syn-

thesized compounds were tested for their analgesic,

anti-inflammatory, and ulcerogenic index behavior.

1 Introduction

oxo-2-phenylquinazolin-3(3H)-yl)acetamides.

The

Nonsteroidal anti-inflammatory drugs (NSAIDs) are com-

monly prescribed for the treatment of acute and chronic

inflammation, pain, and fever. The most of NSAIDs act via

inhibition of cyclooxygenase, thus preventing prostaglandin 2 Results and discussion

The synthetic route depicted in Scheme 1 outlines the

chemistry part of the present work. The key intermedi-

3-amino-2-phenylquinazoline-4-(3H)-one (4)

synthesized by a straightforward method; anthranilic

acid ( ) was treated with benzoyl chloride ( ) in the pres-

ence of pyridine to give benzoxazin-4-one (3) which was

condensed with hydrazine hydrate in ethanol to yield

*Corresponding author: Veerachamy Alagarsamy, Medicinal

Chemistry Research Laboratory, MNR College of Pharmacy, MNR

Nagar, Sangareddy-502 294, Telangana, India, Tel.: 91-8455-

230690, Fax: 91-8455-230555, E-mail: drvalagarsamy@gmail.com

Viswas Raja Solomon: Faculty of Pharmacy, The University of

Sydney, Sydney, NSW 2006, Australia

Mohaideen Thasthagir Sulthana, Meduri Satyasai Vijay and

Bandi Narendhar: Medicinal Chemistry Research Laboratory, MNR

College of Pharmacy, MNR Nagar, Sangareddy-502 294, Telangana,

India

ate

was

1

2

the

(4).

desired 3-amino-2-phenylquinazoline-4-(3H)-one

The 2-chloro-N-(4-oxo-2-phenylquinazolin-3(3H)-yl)

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2emsp;ensp;ensp;ensp;thinsp;emsp;V. Alagarsamy et al.: Quinazolinyl acetamide analogs

O

N

S

C

R1

O

N

R1

R2

O

N

O

C

R1

H

H

N

N

N N

CH2

N

N N

C

N

R2

R2

NHCH2

(I)

(II)

(III)

Fig. 1:ensp;Lead molecules of quinazolin-4-ones.

acetamide (6) was prepared by the reaction between4 and protons. The mass spectra of the title compounds showed

chloroacetyl chloride (5) in dry dioxane in the presence molecular ion peaks corresponding to their molecular

of triethylamine. The IR spectrum of 6 showed intense formulae. In the mass spectrum of compoundsV1–V10, a

peaks at 3189 cmminus;

(C = O), 1607 cmminus; for (C = N), and 700 cmminus;

H NMR spectrum of6 showed a singlet atdelta;  =  3.89 ppm

due to a CH2 group and for aromatic protons in the range the presence of a chlorine atom in the compounds. The

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设计和合成喹唑啉乙酰胺的镇痛和抗炎活性

摘 要

通过2-氯-N-(4-氧代-2-苯基喹唑啉-3(3H)-基)乙酰胺与多种胺的反应，合成了多种新型的2-(取代)-N-(4-氧代-2-苯基喹唑啉-3(3H)-基)乙酰胺。以邻氨基苯甲酸为原料，通过多步反应合成了2-氯-N-(4-氧代-2-苯基喹唑啉-3(3H)-基)乙酰胺。研究标题化合物的止痛、抗炎和溃疡指数活性。其中，化合物2-(乙基氨基)-N-(4-氧代-2-苯基喹唑啉-3(3H)-基)乙酰胺(V9)显示出该系列中最强的镇痛和抗炎活性，并且与参考标准双氯芬酸钠相比，它适度地更强。有趣的是，与阿司匹林相比，测试化合物仅显示出轻微的溃疡形成潜力。

关键词：镇痛药;抗炎;喹唑啉;溃疡指数。

1.介绍

非甾体抗炎药是治疗急性和慢性炎症、疼痛和发热的常用药物。大多数非甾体抗炎药通过抑制环氧合酶起作用，从而阻止前列腺素生物合成。由于胃肠相关疾病导致住院和死亡的增加与非甾体抗炎药的使用增加平行。因此，新的更安全的抗炎药物的发现对于这样的研究领域来说是一个具有挑战性的目标^[1-4]。在我们正在进行的药物化学研究项目中，我们发现喹唑啉和稠合喹唑啉显示出有效的中枢神经系统活性，包括镇痛、抗炎^[5-7]和抗惊厥行为^[8]。据报道，具有C2和n3取代的喹唑啉-4(3H)-酮具有显著的镇痛、抗炎^[9，10]和抗惊厥活性^[11]。早先我们已经报道了一些2-苄基氨基-3-(2-取代氨基)喹唑啉-4(3H)-酮(图1，ⅰ)^[12]，1-(2-苯基喹唑啉-3-基-4(3H)-酮)-3-取代硫脲(图1，ⅱ)，2，3-取代喹唑啉，它们显示出良好的镇痛和抗炎活性^{[5，13，14]}。目前的工作是我们正在努力开发和鉴定镇痛和抗炎活性的新分子，并将胃肠道溃疡副作用降至最低。在本研究的背景下，我们合成了一系列2-(取代)-N-(4-氧代-2-苯基喹唑啉-3(3H)-基)乙酰胺。测试合成化合物的镇痛、抗炎和溃疡指数行为。

2.结果和讨论

方案1中描述的合成路线概述了本工作的化学部分。通过简单的方法合成了关键的中间体3-氨基-2-苯基喹唑啉-4-(3H)-酮(4)；邻氨基苯甲酸(1)在吡啶存在下用苯甲酰氯(2)处理得到苯并噁嗪-4-酮(3)，苯并噁嗪-4-酮(3)在乙醇中与水合肼缩合得到所需的3-氨基-2-苯基喹唑啉-4-(3H)-酮(4)。2-氯-N-(4-氧代-2-苯基喹唑啉-3(3H)-基)

图1：喹唑啉-4-酮的铅分子。

乙酰胺(6)通过4和氯乙酰氯(5)在无水二恶烷中在三乙胺存在下反应制备。6的红外光谱显示在3189厘米(NH)、1689、1643厘米(羰基)(C = O)、1607厘米(C = N)和700厘米(碳-氯)处有强烈的峰值。6的氢核磁共振谱显示delta;= 3.89ppm处的单线态，这是由于CH2基团和delta;= 7.45-7.73ppm范围内的芳族质子。标题化合物2-(取代)-N-(4-氧代-2-苯基喹唑啉-3(3H)-基)乙酰胺V1-V10，通过用各种胺亲核取代6取代的氯化物，以相当好的收率获得，使用二恶烷作为溶剂。标题化合物的形成由起始材料的碳氯拉伸峰的消失和化合物红外光谱中3380，3360厘米处NH的出现来指示；核磁共振谱显示C-3处的物质的信号和由于NH引起的delta;= 8.5ppm附近的单线态，并且观察到芳族化合物在delta;= 7.12-7.78ppm处的多重态质子。标题化合物的质谱显示了与其分子式相对应的分子离子峰。在化合物V1-V10的质谱中，在m/z= 144处出现了对应于喹唑啉-4-酮部分的公共峰。化合物6的质谱中观察到氯/氯同位素峰，证实化合物中存在氯原子。与[M] 峰相比，这些氯/氯峰的相对强度为1∶3。元素(碳、氢、氮)分析令人满意地证实了合成化合物的元素组成和纯度。使用Wistar白化小鼠通过尾部浸没技术进行镇痛活性的评估(表1)。镇痛试验的结果表明，试验化合物在反应时间30分钟时表现出中等镇痛活性，在1小时时活性增加，在2小时时达到峰值水平，在3小时时观察到活性下降(表1)

方案1：2-（取代的）-N-（4-氧代-2-苯基喹唑啉-3（3H）-基）乙酰胺的合成。试剂和条件：（a）吡啶，室温，30分钟;（b）水合肼，乙醇回流，3小时;（c）氯乙酰氯（5）;（d）三乙胺，二恶烷，室温，30分钟，然后在回流温度下1小时。

表1：通过甩尾技术合成的化合物（V1-V10）的镇痛活性

复合	镇痛活性百分比
	0.5h	1h	2h	3h
V1	23plusmn;1.05b	24plusmn;1.53b	28plusmn;1.21b	26plusmn;1.53b
V2	21plusmn;1.46b	22plusmn;1.09b	25plusmn;1.43b	23plusmn;1.03b
V3	32plusmn;1.43b	35plusmn;1.17c	38plusmn;1.91c	29plusmn;1.15b
V4	34plusmn;1.62b	37plusmn;1.41c	40plusmn;1.91c	30plusmn;1.32b
V5	29plusmn;1.51b	31plusmn;1.30b	36plusmn;1.41c	28plusmn;1.32b
V6	28plusmn;1.13b	29plusmn;1.21b	32plusmn;1.06c	26plusmn;1.44b
V7	21plusmn;1.41b	23plusmn;1.62b	24plusmn;1.81b	21plusmn;1.14b
V8	25plusmn;1.11b	27plusmn;1.06b	30plusmn;1.20b	26plusmn;1.73b
V9	35plusmn;1.28c	41plusmn;1.42c	53plusmn;1.05c	31plusmn;1.53b
V10	30plusmn;1.51b	33plusmn;1.26c	36plusmn;1.51c	29plusmn;1.63b
控制	2plusmn;0.23	4plusmn;0.30	4plusmn;0.29	2plusmn;0.51
双氯芬酸	38plusmn;1.23c	43plusmn;1.42c	46plusmn;1.08c	35plusmn;1.15b

a数据表示为一式两份的六个不同实验的平均值plusmn;SD;显着性水平bp0.5和cplt;0.01与相应的对照相比;控制是指不进行治疗（仅限媒介物）。

表2：通过角叉菜胶诱导的大鼠爪水肿试验测定的合成化合物（V1-V10）的抗炎活性。

复合	百分比保护
	0.5h	1h	2h	3h
V1	211.31c	23plusmn;1.23c	25plusmn;1.21c	22plusmn;1.62b
V2	201.38c	21plusmn;1.54c	23plusmn;1.84d	20plusmn;1.26b
V3	311.26c	31plusmn;1.84d	34plusmn;1.04d	28plusmn;1.26b
V4	30plusmn;1.27b	35plusmn;1.48c	39plusmn;1.23c	29plusmn;1.23b
V5	26plusmn;1.72b	28plusmn;1.18c	32plusmn;1.53c	25plusmn;1.31b
V6	25plusmn;1.72b	26plusmn;1.32b	30plusmn;1.16c	23plusmn;1.42b
V7	20plusmn;1.12b	21plusmn;1.53b	21plusmn;1.27c	19plusmn;1.73b
V8	21plusmn;1.16b	22plusmn;1.42b	22plusmn;1.93b	20plusmn;1.53b
V9	33plusmn;1.16b	40plusmn;1.73b	42plusmn;1.52b	32plusmn;1.20b
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