2-[3-(Phenylmethoxycarbonylamino)propanoylamino]benzoic acid | 205063-47-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-[3-(Phenylmethoxycarbonylamino)propanoylamino]benzoic acid
• CAS: 205063-47-4
• 化学式: C₁₈H₁₈N₂O₅
• 分子量: 342.351
• InChiKey: NXTJGCIGOPEKOS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  25
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  105
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-[3-(Phenylmethoxycarbonylamino)propanoylamino]benzoic acid 在 palladium on activated charcoal 氢气 、 N,N'-羰基二咪唑 作用下， 以 甲醇 、 乙酸乙酯 为溶剂， 25.0~30.0 ℃ 、101.33 kPa 条件下， 反应 31.0h， 生成 1-(4-Bromo-phenyl)-3-{2-[3-(3-isopropoxy-phenyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-ethyl}-urea
  参考文献：
  名称：

  Novel Nonpeptide CCK-B Antagonists:  Design and Development of Quinazolinone Derivatives as Potent, Selective, and Orally Active CCK-B Antagonists

  摘要：

  We have designed a novel series of CCK-B receptor antagonists by combining key pharmacophores, an arylurea moiety of 1 and a quinazolinone ring of 3, from two known series. Our earlier studies showed that compounds with methylene linkers in our "target" produced moderate binding affinity and selectivity for CCK-B receptors, whereas its higher and lower homologues resulted in loss of affinity. Introduction of -NH- as a linker dramatically enhanced binding affinity and selectivity for CCK-B receptors, thus providing several compounds with single-digit nanomolar binding affinity and excellent selectivity. Analogous to the earlier studies of the series of quinazolinone derivatives 3, we also found 3-isopropoxyphenyl as a preferred substitution on the N-3 quinazolinone. Electron-withdrawing substitutions on the urea terminal phenyl ring enhanced the CCK-B potency. Representative compounds of this series were tested in the functional assay and showed pure antagonist profiles. Compounds 51 and 61 were orally active in the elevated rat X-maze test. These compounds were also evaluated for their pharmacokinetic profile. The absolute oral bioavailability of compound 61 was 22% in rats.

  DOI：

  10.1021/jm970373j
• 作为产物：
  描述：

  N-CBZ-beta-丙氨酸 在 lithium hydroxide 、 N,N'-羰基二咪唑 作用下， 以 1,4-二氧六环 为溶剂， 反应 49.0h， 生成 2-[3-(Phenylmethoxycarbonylamino)propanoylamino]benzoic acid
  参考文献：
  名称：

  Novel Nonpeptide CCK-B Antagonists:  Design and Development of Quinazolinone Derivatives as Potent, Selective, and Orally Active CCK-B Antagonists

  摘要：

  We have designed a novel series of CCK-B receptor antagonists by combining key pharmacophores, an arylurea moiety of 1 and a quinazolinone ring of 3, from two known series. Our earlier studies showed that compounds with methylene linkers in our "target" produced moderate binding affinity and selectivity for CCK-B receptors, whereas its higher and lower homologues resulted in loss of affinity. Introduction of -NH- as a linker dramatically enhanced binding affinity and selectivity for CCK-B receptors, thus providing several compounds with single-digit nanomolar binding affinity and excellent selectivity. Analogous to the earlier studies of the series of quinazolinone derivatives 3, we also found 3-isopropoxyphenyl as a preferred substitution on the N-3 quinazolinone. Electron-withdrawing substitutions on the urea terminal phenyl ring enhanced the CCK-B potency. Representative compounds of this series were tested in the functional assay and showed pure antagonist profiles. Compounds 51 and 61 were orally active in the elevated rat X-maze test. These compounds were also evaluated for their pharmacokinetic profile. The absolute oral bioavailability of compound 61 was 22% in rats.

  DOI：

  10.1021/jm970373j

文献信息

• Methods of synthesis for 9-substituted hypoxanthine derivatives
  申请人：Glasky J. Alvin

  公开号：US20050014943A1

  公开（公告）日：2005-01-20

  An improved method of synthesis of a 9-substituted hypoxanthine derivative comprises the steps of: (1) reacting aminocyanacetamide with triethyl orthoformate to form an imidoester derivative of aminocyanacetamide; (2) forming a compound having a reactive amino group on a hydrocarbyl moiety, the hydrocarbyl moiety being linked through an amide group to a physiologically active moiety or an esterified derivative of a physiologically active moiety including therein an esterified benzoyl group; (3) reacting the imidoester with the compound having the reactive amino group on the hydrocarbyl moiety to form a derivative of 5-aminoimidazole-4-carboxamide substituted at the 1-position with a hydrocarbyl moiety linked through an amide group to a physiologically active moiety including therein an optionally esterified benzoyl group; (4) forming the six-membered heterocyclic ring of the purine moiety of the hypoxanthine by reacting the derivative of 5-aminoimidazole-4-carboxamide formed in step (3) with triethyl orthoformate to form a 9-substituted hypoxanthine compound substituted at the 9-position with a hydrocarbyl moiety linked through an amide group to a physiologically active moiety including therein an optionally esterified benzoyl group; and (5) hydrolyzing the ester of the optionally esterified benzoyl group if present.

  一种改进的合成9-取代次黄嘌呤衍生物的方法，包括以下步骤：（1）将氨基氰乙酰胺与三乙基正甲酸酯反应，形成氨基氰乙酰胺的亚甲基酯衍生物；（2）形成一个具有在烃基残基上具有反应性氨基基团的化合物，该烃基残基通过酰胺基与生理活性残基或生理活性残基的酯化衍生物相连，其中包括酯化苯甲酰基团；（3）将亚甲基酯与具有在烃基残基上具有反应性氨基基团的化合物反应，形成5-氨基咪唑-4-羧酰胺的衍生物，其在1-位上取代了一个通过酰胺基与生理活性残基相连的烃基残基，其中包括可选的酯化苯甲酰基团；（4）通过将步骤（3）中形成的5-氨基咪唑-4-羧酰胺衍生物与三乙基正甲酸酯反应形成次黄嘌呤的嘌呤基团的六元杂环环，形成一个在9-位上取代了一个通过酰胺基与生理活性残基相连的烃基残基的9-取代次黄嘌呤化合物，其中包括可选的酯化苯甲酰基团；（5）水解可选的酯化苯甲酰基团的酯。
• Design and synthesis of novel nonpeptide CCK-B receptor antagonists
  作者：J.K. Padia、H. Chilvers、P. Daum、R. Pinnock、N. Suman-Chauhan、L. webdale、B.K. Trivedi

  DOI：10.1016/s0960-894x(97)00108-x

  日期：1997.1

  A novel hybrid series of nonpeptide CCK-B receptor antagonists has been designed from two known series derived from asperlicin. An efficient synthesis of 2-aminoquinazolinone, an intermediate for the synthesis of a targeted analog, has been developed. (C) 1997 Elsevier Science Ltd.
• METHODS OF SYNTHESIS FOR 9-SUBSTITUTED HYPOXANTHINE DERIVATIVES
  申请人：Neotherapeutics, Inc.

  公开号：EP1294722A2

  公开（公告）日：2003-03-26
• [EN] IMPROVED METHODS OF SYNTHESIS FOR 9-SUBSTITUTED HYPOXANTHINE DERIVATIVES<br/>[FR] METHODES AMELIOREES DE SYNTHESE DE DERIVES D'HYPOXANTHINE 9-SUBSTITUES
  申请人：NEOTHERAPEUTICS INC

  公开号：WO2002000659A2

  公开（公告）日：2002-01-03

  An improved method of systhesis of a 9-substituted hypoxanthine derivative comprises the steps of: (1) reacting aminocyanacetamide with triethyl orthoformate to form an imidoester derivative of aminocyanacetamide; (2) forming a compound having a reactive amino group on a hydrocarbyl moiety, the hydrocarbyl moiety being linked through an amide group to a physiologically active moiety or an esterified derivative of a physiologically active moiety including therein an esterified benzoyl group; (3) reacting the imidoester with the compound having the reactive amino group on the hydrocarbyl moiety to form a derivative of 5-aminoimidazole-4-carboxamide substituted at the 1-position with a hydrocarbyl moiety linked through an amide group to a physiologically active moiety including therein an optionally esterified benzoyl group; (4) forming the six-membered heterocyclic ring of the purine moiety of the hypoxanthine by reacting the derivative of 5-aminoimidazole-4-carboxamide formed in step (3) with triethyl orthoformate to form a 9-substituted hypoxanthine compound substituted at the 9-position with a hydrocarbyl moiety linked through an amide group to a physiologically active moiety including therein an optionally esterified benzoyl group; and (5) hydrolyzing the ester of the optionally esterified group if present.
• Novel Nonpeptide CCK-B Antagonists:  Design and Development of Quinazolinone Derivatives as Potent, Selective, and Orally Active CCK-B Antagonists
  作者：Janak K. Padia、Mark Field、Joanna Hinton、Ken Meecham、Julius Pablo、Rob Pinnock、Bruce D. Roth、Lakhbir Singh、Nirmala Suman-Chauhan、Bharat K. Trivedi、Louise Webdale

  DOI：10.1021/jm970373j

  日期：1998.3.1

  We have designed a novel series of CCK-B receptor antagonists by combining key pharmacophores, an arylurea moiety of 1 and a quinazolinone ring of 3, from two known series. Our earlier studies showed that compounds with methylene linkers in our "target" produced moderate binding affinity and selectivity for CCK-B receptors, whereas its higher and lower homologues resulted in loss of affinity. Introduction of -NH- as a linker dramatically enhanced binding affinity and selectivity for CCK-B receptors, thus providing several compounds with single-digit nanomolar binding affinity and excellent selectivity. Analogous to the earlier studies of the series of quinazolinone derivatives 3, we also found 3-isopropoxyphenyl as a preferred substitution on the N-3 quinazolinone. Electron-withdrawing substitutions on the urea terminal phenyl ring enhanced the CCK-B potency. Representative compounds of this series were tested in the functional assay and showed pure antagonist profiles. Compounds 51 and 61 were orally active in the elevated rat X-maze test. These compounds were also evaluated for their pharmacokinetic profile. The absolute oral bioavailability of compound 61 was 22% in rats.