5-amino-3-(3-nitrophenyl)-1H-pyrazole-4-carbonitrile | 183739-73-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-amino-3-(3-nitrophenyl)-1H-pyrazole-4-carbonitrile
• 英文别名: 5-amino-3-(3-nitro-phenyl)-1H-pyrazole-4-carbonitrile；3-amino-5-(3-nitrophenyl)-1H-pyrazole-4-carbonitrile
• CAS: 183739-73-3
• 化学式: C₁₀H₇N₅O₂
• 分子量: 229.198
• InChiKey: XYWSZKIAWRHUDV-UHFFFAOYSA-N

物化性质

• 沸点：
  618.8±55.0 °C(Predicted)
• 密度：
  1.55±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  124
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5-amino-3-(3-nitrophenyl)-1H-pyrazole-4-carbonitrile 以 甲醇 、 甲苯 为溶剂， 反应 22.0h， 生成 4-(3-chloro-phenylamino)-3-(3-nitro-phenyl)-1H-pyrazolo[3,4-d]pyrimidine
  参考文献：
  名称：

  Use of a Pharmacophore Model for the Design of EGF-R Tyrosine Kinase Inhibitors:  4-(Phenylamino)pyrazolo[3,4-d]pyrimidines

  摘要：

  In the course of the random screening of a pool of CIBA chemicals, the two pyrazolopyrimidines 1 and 2 have been identified as fairly potent inhibitors of the EGF-R tyrosine kinase. Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGF-R protein tyrosine kinase (PTK), the class of the pyrazolo[3,4-d]pyrimidines was then optimized in an interactive process leading to a series of 4-(phenylamino)-1H-pyrazolo[3,4-d]-pyrimidines as highly potent inhibitors of the EGF-R tyrosine kinase. The most potent compounds 13, 14, 15, 17, 19, 22, 26, 28, and 30 of this series inhibited the EGF-R PTK with IC50 values below 10 nM. High selectivity toward a panel of nonreceptor tyrosine kinases (c-Src, upsilon-Abl) and serine/threonine kinases (PKC alpha, CDK1) was observed. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by compounds 13, 15, 19, 22, and 23 at IC50 values below 50 nM, whereas PDGF-induced tyrosine phosphorylation was not affected by concentrations up to 10 mu M, thus indicating high selectivity for the inhibition of the ligand-activated EGF-R signal transduction pathway. Compounds 15 and 19 inhibited proliferation of the EGF-dependent MK cell line with IC50 values below 0.5 mu M. In addition, two compounds, 9 and 11, showing satisfactory oral bioavailability in mice after oral administration, exhibited good in vivo efficacy at doses of 12.5 and 50 mg/kg in a nude mouse tumor model using xenografts of the EGF-R overexpressing A431 cell line. From SAR studies, a binding mode for 4-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidines, especially for compound 15, at the ATP-binding site of the EGF-R tyrosine kinase is proposed. 4-(Phenylamino)-1H-pyrazolo[3,4-d]pyrimidines represent a new class of highly potent tyrosine kinase inhibitors which preferentially inhibit the EGF-mediated signal transduction pathway and have the potential for further evaluation as anticancer agents.

  DOI：

  10.1021/jm970124v
• 作为产物：
  描述：

  3-nitro-dithiobenzoic acid methyl ester 在 一水合肼 作用下， 以 甲醇 、 甲苯 为溶剂， 反应 2.0h， 生成 5-amino-3-(3-nitrophenyl)-1H-pyrazole-4-carbonitrile
  参考文献：
  名称：

  Use of a Pharmacophore Model for the Design of EGF-R Tyrosine Kinase Inhibitors:  4-(Phenylamino)pyrazolo[3,4-d]pyrimidines

  摘要：

  In the course of the random screening of a pool of CIBA chemicals, the two pyrazolopyrimidines 1 and 2 have been identified as fairly potent inhibitors of the EGF-R tyrosine kinase. Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGF-R protein tyrosine kinase (PTK), the class of the pyrazolo[3,4-d]pyrimidines was then optimized in an interactive process leading to a series of 4-(phenylamino)-1H-pyrazolo[3,4-d]-pyrimidines as highly potent inhibitors of the EGF-R tyrosine kinase. The most potent compounds 13, 14, 15, 17, 19, 22, 26, 28, and 30 of this series inhibited the EGF-R PTK with IC50 values below 10 nM. High selectivity toward a panel of nonreceptor tyrosine kinases (c-Src, upsilon-Abl) and serine/threonine kinases (PKC alpha, CDK1) was observed. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by compounds 13, 15, 19, 22, and 23 at IC50 values below 50 nM, whereas PDGF-induced tyrosine phosphorylation was not affected by concentrations up to 10 mu M, thus indicating high selectivity for the inhibition of the ligand-activated EGF-R signal transduction pathway. Compounds 15 and 19 inhibited proliferation of the EGF-dependent MK cell line with IC50 values below 0.5 mu M. In addition, two compounds, 9 and 11, showing satisfactory oral bioavailability in mice after oral administration, exhibited good in vivo efficacy at doses of 12.5 and 50 mg/kg in a nude mouse tumor model using xenografts of the EGF-R overexpressing A431 cell line. From SAR studies, a binding mode for 4-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidines, especially for compound 15, at the ATP-binding site of the EGF-R tyrosine kinase is proposed. 4-(Phenylamino)-1H-pyrazolo[3,4-d]pyrimidines represent a new class of highly potent tyrosine kinase inhibitors which preferentially inhibit the EGF-mediated signal transduction pathway and have the potential for further evaluation as anticancer agents.

  DOI：

  10.1021/jm970124v

文献信息

• Pyrazole derivatives and processes for the preparation thereof
  申请人：Novartis AG

  公开号：US05981533A1

  公开（公告）日：1999-11-09

  4-Amino-1H-pyrazolo[3,4-d]pyrimidine derivatives of formula I ##STR1## wherein the symbols are as defined in claim 1, and intermediates for their manufacture are described. The compounds of formula I inhibit especially the tyrosine kinase activity of the receptor for epidermal growth factor and can be used, for example, in the case of epidermal hyperproliferation (psoriasis) and as anti-tumor agents.

  公式I的4-氨基-1H-吡唑并[3,4-d]嘧啶衍生物如下所示：其中符号如权利要求1中所定义，并描述了其制备的中间体。公式I的化合物特别抑制表皮生长因子受体的酪氨酸激酶活性，例如，在表皮过度增生（银屑病）和作为抗肿瘤剂中可以使用。
• Design, Synthesis and Biological Evaluation of 5-Amino-1H-pyrazole-4- carboxamide Derivatives as Potential Antitumor Agents
  作者：Baowei Yang、Wukun Liu、Yicheng Mei、Dandan Huang、Hai Qian、Wenlong Huang、Ronald Gust

  DOI：10.2174/1570180811666140115234123

  日期：2014.5.31

  Adenosine deaminase (ADA) inhibitors have been found to have antitumor activities. Here, thirteen potential adenosine deaminase inhibitors 5-amino-1H-pyrazole-4-carboxamide derivatives were designed, synthesized and screened for antitumor activities. Compound 8e exhibited strong growth-inhibitory effects which showed selectivity toward the estrogen receptor positive breast cancer cells (MCF-7) compared to other 5-amino-1H-pyrazole-4-carboxamide derivatives. In addition, it also exhibited appropriate (μM) adenosine deaminase inhibitory potency. Preliminary structure-activity relationships indicated that the incorporation of long chain branching on nitrogen atoms at pyrazole moiety was responsible for their activity.

  已发现腺苷脱氨酶（ADA）抑制剂具有抗肿瘤活性。本文设计、合成了 13 种潜在的腺苷脱氨酶抑制剂 5-氨基-1H-吡唑-4-甲酰胺衍生物，并对其进行了抗肿瘤活性筛选。与其他 5-氨基-1H-吡唑-4-甲酰胺衍生物相比，化合物 8e 对雌激素受体阳性的乳腺癌细胞（MCF-7）具有很强的生长抑制作用和选择性。 此外，它还表现出适当的（μM）腺苷脱氨酶抑制效力。初步的结构-活性关系表明，在吡唑分子的氮原子上加入长链分支是这些衍生物具有活性的原因。
• Novel biocompatible glucose-based deep eutectic solvent as recyclable medium and promoter for expedient multicomponent green synthesis of diverse three and four substituted pyrazole-4-carbonitrile derivatives
  作者：Reza Aryan、Hamid Beyzaei、Masoomeh Nojavan、Meysam Rezaei

  DOI：10.1007/s11164-017-2908-5

  日期：2017.8

  A novel biocompatible glucose-based deep eutectic solvent (DES) is reported for the first time in the multicomponent synthesis of diverse three and four substituted pyrazole-4-carbonitrile derivatives under catalyst-free condition without using any harmful organic solvent even for purification of the products. The desired products were obtained with high degree of diversity from the reaction of malononitrile

  首次报道了一种新型的生物相容性的基于葡萄糖的深共熔溶剂（DES），该多组分合成是在无催化剂的条件下不使用任何有害有机溶剂甚至无需纯化任何三价或四价取代的吡唑-4-腈衍生物而进行的多组分合成。产品。从丙二腈，芳族醛和各种肼衍生物作为氮源，在室温下，在较短的反应时间内，以良好的产率获得了具有高度多样性的所需产物。还将深的低共熔溶剂再循环并重复使用至少四次，而效率仅有一点损失。还提出了一个合理的机制，表明DES氢键在反应促进中的作用。
• [EN] PYRAZOLE DERIVATIVES AND PROCESSES FOR THE PREPARATION THEREOF<br/>[FR] DERIVES DE PYRAZOLE ET LEURS PROCEDES DE PREPARATION
  申请人：NOVARTIS AG

  公开号：WO1996031510A1

  公开（公告）日：1996-10-10

  (EN) 4-Amino-1H-pyrazolo[3,4-d]pyrimidine derivatives of formula (I) wherein the symbols are as defined in claim (1), and intermediates for their manufacture are described. The compounds of formula (I) inhibit especially the tyrosine kinase activity of the receptor for epidermal growth factor and can be used, for example, in the case of epidermal hyperproliferation (psoriasis) and as anti-tumour agents.(FR) La présente invention décrit des dérivés de 4-amino-1H-pyrazolo[3,4-d]pyrimidine de formule (I), dans laquelle les symboles sont tels que définis dans la revendication (1), ainsi que les intermédiaires pour leur fabrication. Les composés de formule (I) inhibent tout particulièrement l'activité de tyrosine-kinase du récepteur du facteur de croissance épidermique et peuvent être utilisés, par exemple, dans le cas d'une hyperprolifération épidermique (psoriasis) et comme agents anti-tumoraux.

  本发明涉及4-氨基-1H-吡唑并吡啶衍生物，其通用化学式为(I)，其中各符号按权利要求1所定义。描述了相应的中间体，用于合成这些分子。分子的结构式为： 4-氨基-1H-吡唑并吡啶衍生物的通用化学式为： 这些化合物的表现特性可以在权利要求1中找到详尽解释。这些化合物可以通过特定的方法合成。它们的进步特性尤其是其对表皮生长因子受体的靶向抑制能力，这使得它们对治疗某些皮肤疾病（如光面性 enabled conditions，即银Haschick氏病（Psoriasis））以及某些癌症具有潜在的用途。
• [EN] FUSED PYRAZOLE DERIVATIVES AND PROCESSES FOR THEIR PREPARATION<br/>[FR] DERIVES DE PYRAZOLE CONDENSES ET PROCEDES POUR LEUR PREPARATION
  申请人：NOVARTIS AG

  公开号：WO1998014449A1

  公开（公告）日：1998-04-09

  (EN) 4-Amino-1H-pyrazolo[3,4-d]pyrimidine derivatives of formula (I) in which m, n and v are each, independently of one another, 0 or 1, R is hydrogen or methyl, R1 is chlorine or methyl which is in each case located in position 3 of the phenyl radical, X is the group NH(CH-R7)t in which t is 0, 1 or 2 and R7 is hydrogen, or the group (C[R3]-R4)q, in which q is 0, and R2 is nitro, cyano, amino, dimethylamino-lower-alkyleneamino, 4-pyridylcarbonylamino, 2-methylpropanoylamino, tert-butyloxycarbonylamino, or methyl which is substituted by amino, C1-C5-alkanoylamino, tert-butyloxycarbonylamino or benzoylamino, with the exception of 3-(3-aminobenzylamino)-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine are described. The compounds of formula (I) inhibit in particular the tyrosine kinase activity of the receptor for epidermal growth factor and can be used, for example, for epidermal hyperproliferation (psoriasis) and as antitumor agents.(FR) L'invention concerne des dérivés de 4-amino-1H-pyrazolo(3,4-d)pyrimidine présentant la formule (I). Dans cette dernière, m, n et v sont chacun indépendamment l'une de l'autre égal à O ou 1. R représente hydrogène ou méthyle, R1 représente du chlore ou méthyle qui est dans chaque cas placé en position 3 du radical phényle, X est le groupe NH(CH-R7)t dans lequel t est égal à 0, 1 ou 2, et R7 représente hydrogène, ou le groupe (C(R3)-R4)q dans lequel q est égal à 0, et R2 est égal à nitro, cyano, amino, diméthylamino-alkylèneamino inférieur, 4-pyridylcarbonylamino, 2-méthylpropanoylamino, tert-butyloxycarbonylamino, ou méthyle qui est substitué par amino-alcanoylamino C1-C5, tert-butyloxycarbonylamino ou benzoylamino, à l'exception de 3-(3-aminobenzylamino)-4-(3-chlorophénylamino)-1H-pyrazolo (3,4-d)pyrimidine . Les composés selon la formule (I) inhibent en particulier l'activité de la tyrosine kinase du récepteur du facteur de croissance épidermique, et peuvent être utilisés, par exemple, pour l'hyperprolifération épidermique (psoriasis) et comme agents anti-tumoraux.

  本发明涉及一种4-氨基-1H-吡咯[3,4-d]吡咯衍生物，其化学式为(I)，化学式(I)中的m、n和v各自独立地取0或1。R为氢或甲基，R1为氯或甲基，其在每个情况下位于苯基基团的位置3。X为氨基-CH(R7)t基团，其中t为0、1或2，R7为氢；或为基团(C(R3])-R4)q，其中q为0，R2为硝基、羰基、氨基、二甲基氨基-下端乙基氨基、4-吡啶酰胺、2-甲基丙酰胺基、 tert-butyl-O-acet酰胺基、或甲基，后者被氨基-C1-C5-烯基酰胺基、 tert-butyl-O-acet酰胺基或苯酰酰胺基取代。除3-(3-氨基-苯基氨基)-4-(3-氯ophenty)氨基-1H-吡咯[3,4-d]吡咯外，所述化合物抑制酪氨酸激酶活性，特别地，它们可以用于角化素增多症(如光屑症)的治疗以及抗肿瘤用途。