3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzaldehyde | 159017-85-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzaldehyde
• 英文别名: 3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzaldehyde；3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde
• CAS: 159017-85-3
• 化学式: C₁₈H₁₅NO₃
• 分子量: 293.322
• InChiKey: LBIXKXAJNZFWRA-UHFFFAOYSA-N

物化性质

• 沸点：
  486.1±55.0 °C(Predicted)
• 密度：
  1.205±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  52.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzaldehyde 在 盐酸羟胺 、 sodium acetate 作用下， 以 乙醇 为溶剂， 生成 3-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzaldehyde oxime
  参考文献：
  名称：

  Antihyperglycemic activity of new 1,2,4-oxadiazolidine-3,5-diones

  摘要：

  A series of 1,2,4-oxadiazolidine-3,5-diones was synthesized and evaluated as oral antihyperglycemic agents in the obese insulin resistant db/db and ob/ob mouse - the two models for Type 2 diabetes mellitus. The majority of the prepared methoxy- and ethoxy-linked oxazole 1,2,4-oxadiazolidine-3,5-diones normalized plasma glucose levels at the 100 mg kg(-1) oral dose in the db/db diabetic mouse model, and several amongst them reduced the glucose levels at the 20 mg kg(-1) oral dose. The most potent compounds in the db/db mouse model were also active in the ob/ob mouse model normalizing the plasma glucose levels at the 20 mg kg(-1) oral dose. The trifluoromethoxy analog 32 was the most active compound of the series, reducing significantly the plasma glucose levels at the 5 mg kg(-1) oral dose. Oxadiazole-tailed 1,2,4-oxadiazolidine-3,5-diones were also active in both the db/db and ob/ob diabetic mouse models normalizing plasma glucose levels at the 100 mg kg(-1) oral dose. (C) 2001 Editions scientifiques et medicales Elsevier SAS.

  DOI：

  10.1016/s0223-5234(00)01191-0
• 作为产物：
  描述：

  4,5-dimethyl-2-phenyl-oxazole 3-oxide 在 potassium carbonate 、 三氯氧磷 作用下， 以 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzaldehyde
  参考文献：
  名称：

  偶氮苯氧基羟基脲作为5-脂氧合酶的选择性和口服活性抑制剂。

  摘要：

  唑类苯氧基羟基脲是一类新的5-脂氧合酶（5-LO）抑制剂。结构-活性关系研究表明，恶唑尾巴的2-苯基部分的负电取代基增加了这些抑制剂的离体效能。噻唑类似物上的类似取代对离体活性仅有很小的贡献。三氟甲基取代的恶唑24是离体（6 h预处理大鼠）和体内（3 h预处理大鼠）RPAR测定中最佳恶唑系列化合物，ED50值分别约为1和3.6 mg / kg，但在过敏性豚鼠试验中的活性较弱。恶唑50在RPAR和豚鼠体内模型中均具有同等活性，与齐留通相似。未取代的噻唑52是噻唑系列中最好的化合物，在口服剂量为10 mg / kg的情况下，通过抑制RPAR分析（预处理3小时的大鼠）中白三烯B4的生物合成为99％，而在静脉注射剂量为10 mg / kg的情况下，对变应性豚鼠的支气管收缩作用抑制了50％公斤。在体外测定中，恶唑24表现出高选择性的5-LO抑制活性，IC50值范围从小鼠巨噬细胞中的0.08 microM到人外周单核细胞中的0

  DOI：

  10.1021/jm950363n

文献信息

• Novel 5-Substituted 2,4-Thiazolidinedione and 2,4-Oxazolidinedione Derivatives as Insulin Sensitizers with Antidiabetic Activities
  作者：Yu Momose、Tsuyoshi Maekawa、Tohru Yamano、Mitsuru Kawada、Hiroyuki Odaka、Hitoshi Ikeda、Takashi Sohda

  DOI：10.1021/jm010490l

  日期：2002.3.1

  Two novel classes of 2,4-thiazolidinediones and 2,4-oxazolidinediones with an omega-(azolylalkoxyphenyl)alkyl substituent at the 5-position were prepared and their antidiabetic effects were evaluated in two genetically obese and diabetic animal models, KKA(y) mice and Wistar fatty rats. A large number of the 2,4-thia(oxa)zolidinediones showed potent glucose- and lipid-lowering activities. The antidiabetic

  制备了在5位具有ω-（偶氮基烷氧基苯基）烷基取代基的两类新的2,4-噻唑烷二酮和2,4-恶唑烷二酮，并在两个遗传性肥胖和糖尿病动物模型KKA（y）中评估了它们的抗糖尿病作用小鼠和Wistar脂肪大鼠。大量的2,4-硫杂恶唑烷二酮显示出有效的降糖和降脂活性。2,4-恶唑烷二酮的抗糖尿病活性优于2,4-噻唑烷二酮的抗糖尿病活性。在这些化合物中，5- [3- [4- [2-（2-呋喃基）-5-甲基-4-恶唑基甲氧基] -3-甲氧基苯基]丙基] -2，4-恶唑烷二酮的两种对映体（64）就活性而言，最有趣的化合物是通过使用固定化脂肪酶对相应的α-羟基戊酸酯（26）进行不对称O-乙酰化合成的，然后将恶唑烷二酮环环化。（R）-（+）-64比（S）-（-）-64（ED25> 1.5 mg / kg / d）表现出更强的降糖活性（有效剂量（ED）25 = 0.561 mg / kg / d） ）或吡格列酮（ED25
• Oxazolidinedione derivatives and their use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US05665748A1

  公开（公告）日：1997-09-09

  Novel 2,4-oxazolidinedione compounds of the formula: ##STR1## wherein R is a hydrocarbon residue or a heterocyclic group each of which may be substituted; Y is --CO--, --CH(OH)-- or --NR.sup.3 -- (wherein R.sup.3 is an alkyl group which may be substituted); m is 0 or 1; n is 0, 1 or 2; X is CH or N; A is bivalent straight or branched hydrocarbon chain residue having 1 to 7 carbon atoms; R.sup.1 and R.sup.2 each are hydrogen or an alkyl group, or R.sup.1 and R.sup.2 are combined with each other to form a 5- to 6-membered heterocyclic group optionally containing nitrogen; L and M each are hydrogen, or L and M are combined with each other to form a bond, or pharmaceutically acceptable salts thereof, having excellent hypoglycemic and hypolipidemic activities and are useful as anti-diabetics or hypolipidemic agents.

  2,4-噁唑烷二酮类化合物的化学式如下：##STR1## 其中R是一个烃残基或一个杂环基，每个都可以被取代；Y是--CO--，--CH(OH)--或--NR.sup.3--（其中R.sup.3是一个可以被取代的烷基）；m为0或1；n为0, 1或2；X是CH或N；A是具有1至7个碳原子的二价直链或支链烃基残基；R.sup.1和R.sup.2分别是氢或烷基，或R.sup.1和R.sup.2结合在一起形成一个含氮的5至6元杂环基；L和M分别是氢，或L和M结合在一起形成一个键，或其药用盐，具有出色的降糖和降脂活性，并可用作抗糖尿病或降脂药物。
• Oxyiminoalkanoic acid derivatives with hypoglycemic and hypolipidemic activity
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US06251926B1

  公开（公告）日：2001-06-26

  This invention provides a novel oxyiminoalkanoic acid derivative which has excellent hypoglycemic and hypolipidemic actions and which is used for the treatment of diabetes mellitus, hyperlipemia, insulin insensitivity, insulin resistance and impaired glucose tolerance.

  本发明提供了一种新颖的氧亚氨基烷酸衍生物，该衍生物具有优异的降糖和降脂作用，用于治疗糖尿病、高脂血症、胰岛素不敏感、胰岛素抵抗和葡萄糖耐量受损。
• Novel 5-Substituted-1H-tetrazole Derivatives as Potent Glucose and Lipid Lowering Agents.
  作者：Yu Momose、Tsuyoshi Maekawa、Hiroyuki Odaka、Hitoshi Ikeda、Takashi Sohda

  DOI：10.1248/cpb.50.100

  日期：——

  A series of 5-(4-alkoxyphenylalkyl)-1H-tetrazole derivatives, containing an oxazole-based group at the alkoxy moiety, was prepared and their antidiabetic effects were evaluated in two genetically obese and diabetic animal models, KKAy mice and Wistar fatty rats. Syntheses were performed by cyclization of the corresponding nitriles reacting with azide compounds. A large number of the 5-(4-alkoxyphenylalkyl)-1H-tetrazoles showed potent glucose and lipid lowering activities in KKAy mice. In particular, 5-[3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridyl]propyl]-1H-tetrazole had potent glucose lowering activity (ED25=0.0839 mg⋅kg−1⋅d−1), being 72 times more active than pioglitazone hydrochloride (ED25=6.0 mg⋅kg−1⋅d−1). This compound also showed strong glucose lowering (ED25=0.0873 mg⋅kg−1⋅d−1) and lipid lowering effects (ED25=0.0277 mg⋅kg−1⋅d−1) in Wistar fatty rats. The antidiabetic effects of this compound are considered to be due to its potent agonistic activity for peroxisome proliferator-activated receptor γ (PPARγ) (EC50=6.75 nM).

  合成了一系列含有噁唑基团的5-(4-烷氧基苯基烷基)-1H-四唑衍生物，并在两种遗传性肥胖和糖尿病动物模型（KKAy小鼠和Wistar肥胖大鼠）中评估了它们的抗糖尿病效果。合成是通过相应的腈与叠氮化合物反应环化进行的。大量的5-(4-烷氧基苯基烷基)-1H-四唑在KKAy小鼠中显示出强大的降血糖和降脂活性。特别是5-[3-[6-(5-甲基-2-苯基-4-噁唑基甲氧基)-3-吡啶基]丙基]-1H-四唑显示出强大的降血糖活性（ED25=0.0839 mg⋅kg−1⋅d−1），比盐酸吡格列酮（ED25=6.0 mg⋅kg−1⋅d−1）活性高出72倍。该化合物在Wistar肥胖大鼠中也显示出强大的降血糖（ED25=0.0873 mg⋅kg−1⋅d−1）和降脂效果（ED25=0.0277 mg⋅kg−1⋅d−1）。该化合物的抗糖尿病效果被认为是因为它对过氧化物酶体增殖物激活受体γ（PPARγ）具有强大的激动活性（EC50=6.75 nM）。
• Studies on Non-Thiazolidinedione Antidiabetic Agents. 2. Novel Oxyiminoalkanoic Acid Derivatives as Potent Glucose and Lipid Lowering Agents.
  作者：Hiroshi Imoto、Yasuo Sugiyama、Hiroyuki Kimura、Yu Momose

  DOI：10.1248/cpb.51.138

  日期：——

  We previously reported that (Z)-2-4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino}-2-(4-phenoxyphenyl)acetic acid (3) showed potent glucose and lipid lowering effects in genetically obese and diabetic mice, KKAy. This compound also showed transcriptional activity for peroxisome proliferator-activated receptor (PPAR)-γ. We expanded on the structure–activity relationships of oxyiminoalkanoic acid derivatives based on this transcriptional activity (in vitro). Insertion of a carbon chain between the imino carbon and the carboxyl moiety of (Z)-2-4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino}-2-phenylacetic acid (2) resulted in a marked increase in transcriptional activity at PPARγ. In vivo potencies of synthesized compounds, which showed strong functional activity at PPARγ, were tested using KKAy mice. Among these compounds, (E)-4-4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino}-4-phenylbutyric acid (27) exhibited marked glucose and lipid lowering activity while showing no significant body weight gain. Compound (27) (TAK-559) showed favorable pharmacokinetic properties with good absorption and duration, and was considered as an attractive candidate for further evaluation.

  我们之前报道过，(Z)-2-4-[(5-甲基-2-苯基-1,3-恶唑-4-基)甲氧基]苄氧亚胺}-2-(4-苯氧基苯基)乙酸 (3) 在基因肥胖和糖尿病小鼠 KKAy 中表现出显著的降糖和降脂效果。该化合物还显示出对过氧化物酶体增殖物激活受体 (PPAR)-γ 的转录活性。我们基于这种转录活性（体外）扩展了氧亚胺烷酸衍生物的结构—活性关系。在 (Z)-2-4-[(5-甲基-2-苯基-1,3-恶唑-4-基)甲氧基]苄氧亚胺}-2-苯基乙酸 (2) 的亚胺碳与羧基之间插入碳链，显著提高了 PPARγ 的转录活性。合成化合物在 KKAy 小鼠中进行了体内效能测试，这些化合物在 PPARγ 上显示出强的功能活性。在这些化合物中，(E)-4-4-[(5-甲基-2-苯基-1,3-恶唑-4-基)甲氧基]苄氧亚胺}-4-苯基丁酸 (27) 展示了显著的降糖和降脂活性，同时未显示出明显的体重增加。化合物 (27) (TAK-559) 显示出良好的药代动力学特性，具备良好的吸收和持续时间，因此被认为是进一步评估的有吸引力的候选者。