(S)-2-tert-Butoxycarbonylamino-3-[4-(isopropylamino-methyl)-phenyl]-propionic acid | 845730-78-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-2-tert-Butoxycarbonylamino-3-[4-(isopropylamino-methyl)-phenyl]-propionic acid
• 英文别名: (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[4-[(propan-2-ylamino)methyl]phenyl]propanoic acid
• CAS: 845730-78-1
• 化学式: C₁₈H₂₈N₂O₄
• 分子量: 336.431
• InChiKey: WMIDUIHGVWVLBZ-HNNXBMFYSA-N

物化性质

• 沸点：
  489.4±45.0 °C(Predicted)
• 密度：
  1.107±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  24
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  87.7
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  氯甲酸苄酯 、 (S)-2-tert-Butoxycarbonylamino-3-[4-(isopropylamino-methyl)-phenyl]-propionic acid 以 四氢呋喃 、 水 为溶剂， 生成 L-N^α-Boc-N⁴-Cbz-4-<(isopropylamino)methyl>phenylalanine
  参考文献：
  名称：

  Gonadotropin-Releasing Hormone Antagonists: Novel Members of the Azaline B Family

  摘要：

  A series of antagonists of gonadotropin-releasing hormone (GnRH) homologous to azaline B ([Ac-DNal(1),DCpa(2),DPal(3),Aph(5)(Atz),DAph(6)(Atz),ILys(8),DAla(10)]GnRH) was synthesized, characterized, and tested in a rat antiovulatory assay (AOA). Selected analogues were also tested in both an in vitro dispersed rat pituitary cell culture assay for inhibition of GnRH-stimulated luteinizing hormone release and an in. vitro histamine release assay. The duration of action of some of the most potent and safest analogues in those assays was also determined in the castrated male rat in order to measure the extent (efficacy and duration of action) of inhibition of luteinizing hormone release. Structurally, this series of analogues has novel substitutions (X and Y) in the structure of the azaline B precursor: [Ac-DNal(1),DCpa(2),DPal(3),-Aph(5)(X),DAph(6)(Y),ILys(8),DAla(10)]GnRH. These substitutions were designed to confer increased hydrophilicity as compared to that of azaline B (determined by relative retention times on a C-18 reverse phase column using a triethylammonium phosphate buffer at pH 7.3) or to make them more easily accessible synthetically. Some bulky substituents were introduced in order to probe the spatial limitations of the receptor's cavity. These substitutions include acylated 4-aminophenylalanine at positions 5 and/or 6 (29 analogues), N-alpha-methylated backbone substitutions (six analogues), N-omega-isopropylaminophenylalanine at position 8, and hydrophilic amino acids at position 1. Out of 20 novel analogues tested for long duration position 8, and hydrophilic amino acids at position 1. Out of 20 novel analogues tested for long duration of action in this series, only seven ([Ac-DNal(1),DCpa(2),DPal(3),Aph(5),DAph(6),ILys(8),DAla(10)]GnRH, [Ac-DNal(1),DCpa(2),DPal(3), Aph(5)(For),DAph(6)(For), ILys(8),DAla(10)]GnRH, [Ac-DNal(1),DCpa(2),DPal(3),Aph(5)(Ac),DAph(6)(Ac),- ILys(8),DAla(10)]GnRH (acyline), [Ac-DNal(1),DCpa(2),DPal(3),Aph(5)(Pio),DAph(6)(Pio),ILys(8,)DAla(10)]GnRh, [Ac-DNal(1),DCpa(2),DPal(3),Aph(5)(Atz),DAph(6)(Ac),ILys(8),DAla(10)]GnRH, [Ac-DNalDCpa(2),DPal(3),Aph(5)(Atz-beta Ala),DAph(6)(Atz- beta Ala),ILys(8),DAla(10)]GnRH, [Ac-DNal(1),DCpa2,DPal(3),Aph(5)(Atz-Gab),DAph(6)(Atz-Gab),ILys(8),DAla(10)]GnRH) had relative potencies and/or duration of action comparable to those of azaline B. The others were one-half to one-tenth as effective as azaline B. N-alpha-Methylated backbone substitutions at position 5 yielded analogues that were significantly more hydrophilic presumably because of the breakage of the NH alpha-Tyr(5) to Arg(8)-CO hydrogen bond reported to stabilize a beta-turn encompassing residues 5-8 and which favored beta-sheet formation as shown earlier by Haviv et al.(2) This substitution resulted, however, in an increased potency in the histamine release assay and in significantly shorter duration of action.(3) Similarly, attempts at replacing isopropyllysine in position 8 by either isopropyl-4-aminophenylalanine or isopropyl-4(aminomethyl)phenylalanine resulted in loss of potency in the AOA.Changes in chirality at position 1 or 10 resulted in analogues that were one-tenth and one-half as potent, respectively, as acyline. Introduction of a relatively hydrophilic acetylated residue in position 1 (Ac-4-aminophenylalanine, Ac-2-quinolylalanine, Ac-3-quinolylalanine) also resulted in potent analogues in the AOA in the latter two cases (yet very short acting in the case of ([Ac-D2Qal(1),DCpa(2),DPal(3),Aph(5)(Atz),DAph(6)(Atz),ILys(8),DAla(10)]-GnRH). Introduction of either mesityl, (2-chlorophenyl)isourea, or (3-chlorophenyl)isourea as a substituent on the 4-amino function at residues 5 and 6 of the azaline B precursor was considerably less successful. In this article, we describe in details, improved synthetic protocols for all novel amino acis, N alpha-methylation of amino acids on the resin, and elimination of the undesired N omega-methylation of pyridylalanine at position 3 as the result of base treatment (piperidine or hydrazine) during the deprotection of the Fmoc group or formation of the triazole moiety in the presence of CH2Cl2.

  DOI：

  10.1021/jm00014a017
• 作为产物：
  描述：

  L-N-boc-4-[(三氯乙酰胺)甲基]苯丙氨酸 在 palladium on activated charcoal sodium hydroxide 、 4 A molecular sieve 、 氢气 作用下， 以 乙醇 为溶剂， 反应 26.5h， 生成 (S)-2-tert-Butoxycarbonylamino-3-[4-(isopropylamino-methyl)-phenyl]-propionic acid
  参考文献：
  名称：

  Gonadotropin-Releasing Hormone Antagonists: Novel Members of the Azaline B Family

  摘要：

  A series of antagonists of gonadotropin-releasing hormone (GnRH) homologous to azaline B ([Ac-DNal(1),DCpa(2),DPal(3),Aph(5)(Atz),DAph(6)(Atz),ILys(8),DAla(10)]GnRH) was synthesized, characterized, and tested in a rat antiovulatory assay (AOA). Selected analogues were also tested in both an in vitro dispersed rat pituitary cell culture assay for inhibition of GnRH-stimulated luteinizing hormone release and an in. vitro histamine release assay. The duration of action of some of the most potent and safest analogues in those assays was also determined in the castrated male rat in order to measure the extent (efficacy and duration of action) of inhibition of luteinizing hormone release. Structurally, this series of analogues has novel substitutions (X and Y) in the structure of the azaline B precursor: [Ac-DNal(1),DCpa(2),DPal(3),-Aph(5)(X),DAph(6)(Y),ILys(8),DAla(10)]GnRH. These substitutions were designed to confer increased hydrophilicity as compared to that of azaline B (determined by relative retention times on a C-18 reverse phase column using a triethylammonium phosphate buffer at pH 7.3) or to make them more easily accessible synthetically. Some bulky substituents were introduced in order to probe the spatial limitations of the receptor's cavity. These substitutions include acylated 4-aminophenylalanine at positions 5 and/or 6 (29 analogues), N-alpha-methylated backbone substitutions (six analogues), N-omega-isopropylaminophenylalanine at position 8, and hydrophilic amino acids at position 1. Out of 20 novel analogues tested for long duration position 8, and hydrophilic amino acids at position 1. Out of 20 novel analogues tested for long duration of action in this series, only seven ([Ac-DNal(1),DCpa(2),DPal(3),Aph(5),DAph(6),ILys(8),DAla(10)]GnRH, [Ac-DNal(1),DCpa(2),DPal(3), Aph(5)(For),DAph(6)(For), ILys(8),DAla(10)]GnRH, [Ac-DNal(1),DCpa(2),DPal(3),Aph(5)(Ac),DAph(6)(Ac),- ILys(8),DAla(10)]GnRH (acyline), [Ac-DNal(1),DCpa(2),DPal(3),Aph(5)(Pio),DAph(6)(Pio),ILys(8,)DAla(10)]GnRh, [Ac-DNal(1),DCpa(2),DPal(3),Aph(5)(Atz),DAph(6)(Ac),ILys(8),DAla(10)]GnRH, [Ac-DNalDCpa(2),DPal(3),Aph(5)(Atz-beta Ala),DAph(6)(Atz- beta Ala),ILys(8),DAla(10)]GnRH, [Ac-DNal(1),DCpa2,DPal(3),Aph(5)(Atz-Gab),DAph(6)(Atz-Gab),ILys(8),DAla(10)]GnRH) had relative potencies and/or duration of action comparable to those of azaline B. The others were one-half to one-tenth as effective as azaline B. N-alpha-Methylated backbone substitutions at position 5 yielded analogues that were significantly more hydrophilic presumably because of the breakage of the NH alpha-Tyr(5) to Arg(8)-CO hydrogen bond reported to stabilize a beta-turn encompassing residues 5-8 and which favored beta-sheet formation as shown earlier by Haviv et al.(2) This substitution resulted, however, in an increased potency in the histamine release assay and in significantly shorter duration of action.(3) Similarly, attempts at replacing isopropyllysine in position 8 by either isopropyl-4-aminophenylalanine or isopropyl-4(aminomethyl)phenylalanine resulted in loss of potency in the AOA.Changes in chirality at position 1 or 10 resulted in analogues that were one-tenth and one-half as potent, respectively, as acyline. Introduction of a relatively hydrophilic acetylated residue in position 1 (Ac-4-aminophenylalanine, Ac-2-quinolylalanine, Ac-3-quinolylalanine) also resulted in potent analogues in the AOA in the latter two cases (yet very short acting in the case of ([Ac-D2Qal(1),DCpa(2),DPal(3),Aph(5)(Atz),DAph(6)(Atz),ILys(8),DAla(10)]-GnRH). Introduction of either mesityl, (2-chlorophenyl)isourea, or (3-chlorophenyl)isourea as a substituent on the 4-amino function at residues 5 and 6 of the azaline B precursor was considerably less successful. In this article, we describe in details, improved synthetic protocols for all novel amino acis, N alpha-methylation of amino acids on the resin, and elimination of the undesired N omega-methylation of pyridylalanine at position 3 as the result of base treatment (piperidine or hydrazine) during the deprotection of the Fmoc group or formation of the triazole moiety in the presence of CH2Cl2.

  DOI：

  10.1021/jm00014a017

文献信息

• SSTR1-selective analogs
  申请人：Rivier E.F. Jean

  公开号：US20060155107A1

  公开（公告）日：2006-07-13

  Analogs of SRIF which are selective for SSTR1 in contrast to the other cloned SRIF receptors. These analogs are useful in determining the tissue and cellular expression of the receptor SSTR1 and its biological role in the endocrine, exocrine and nervous system, as well as in regulating tumor growth. SRIF analog peptides, such as des-AA 1,2,5 [D-Trp 8 , IAmp 9 , Tyr 11 ]-SRIF and counterparts incorporating Cbm at the N-terminus, as well as radioiodinated versions thereof, inhibit the binding of a universal SRIF radioligand to the cloned human receptor SSTR1, but they do not bind with significant affinity to human SSTR2, SSTR3, SSTR4 or SSTR5. By incorporating an iodinated tyrosine in position-2 or in position-11 in these SSTR1-selective SRIF analogs, a labeled compound useful in drug-screening methods is provided. The N-terminus accommodates bulky moieties without loss of selectivity, and a carbamoyl moiety or a conjugating agent that will accept a radioactive nuclide or will link to a cytotoxin may be present at the N-terminus.

  与其他克隆的 SRIF 受体相比，SRIF 的类似物对 SSTR1 具有选择性。这些类似物有助于确定 SSTR1 受体在组织和细胞中的表达，及其在内分泌、外分泌和神经系统中的生物学作用，以及在调节肿瘤生长方面的作用。SRIF 类似肽，如 des-AA 1,2,5 [D-Trp 8 、IAmp 9 ，Tyr 11 ]-SRIF 和在 N 端含有 Cbm 的对应物，以及它们的放射性碘化版本，可抑制通用 SRIF 放射性配体与克隆的人类受体 SSTR1 的结合，但它们与人类 SSTR2、SSTR3、SSTR4 或 SSTR5 的结合亲和力不强。通过在这些 SSTR1 选择性 SRIF 类似物的第 2 位或第 11 位加入一个碘化酪氨酸，提供了一种可用于药物筛选方法的标记化合物。N 端可容纳体积较大的分子而不会丧失选择性，N 端还可含有氨基甲酰基或可接受放射性核素或与细胞毒素连接的连接剂。
• RECEPTOR-SELECTIVE SOMATOSTATIN ANALOGS
  申请人：THE SALK INSTITUTE FOR BIOLOGICAL STUDIES

  公开号：EP0871666A1

  公开（公告）日：1998-10-21
• US7019109B2
  申请人：——

  公开号：US7019109B2

  公开（公告）日：2006-03-28
• [EN] RECEPTOR-SELECTIVE SOMATOSTATIN ANALOGS<br/>[FR] ANALOGUES DE LA STOMATINE A AFFINITE SELECTIVE POUR UN RECEPTEUR
  申请人：THE SALK INSTITUTE FOR BIOLOGICAL STUDIES

  公开号：WO1997014715A1

  公开（公告）日：1997-04-24

  (EN) Analogs of SRIF which are selective for SSTR1 in contrast to the other cloned SRIF receptors. These analogs are useful in determining the tissue and cellular expression of the receptor SSTR1 and its biological role in the endocrine, exocrine and nervous system, as well as in regulating tumor growth. SRIF analog peptides, such as des-AA1,2,5[D-Trp8, IAmp9]-SRIF inhibit the binding of [125I-Tyr11]SRIF to the cloned human receptor SSTR1 but do not bind to mouse SSTR2 and SSTR3, human SSTR4 or rat SSTR5. By incorporating an iodinated tyrosine in position-2 in these selective SRIF analogs, a labelled compound useful in drug-screening methods is provided.(FR) L'invention porte sur des analogues du SRIF présentant une affinité sélective pour le SSTR1 par contraste avec les autres récepteurs clonés du SRIF. Lesdits analogues s'avèrent utiles pour évaluer l'expression tissulaire et cellulaire du récepteur SSTR1 et son rôle biologique dans les systèmes endocrinien, exocrinien et nerveux, ainsi que dans la régulation de la croissance des tumeurs. Des peptides analogues du SRIF tels que le des-AA1,2,5 [D-Trp8, IAmp9]-SRIF inhibent la fixation du [125I-Tyr11]SRIF au récepteur SSTR1 cloné, mais ne se fixent pas aux SSTR2 et SSTR3 de la souris, ni au SSTR4 de l'homme, ni au SSTR5 du rat. En incorporant une tyrosine iodée en position-2 dans ces analogues sélectifs du SRIF, on obtient un composé marqué utilisable pour le dépistage des drogues.
• [EN] SSTR1-SELECTIVE ANALOGS<br/>[FR] ANALOGUES SÉLECTIFS POUR SSTR1
  申请人：SALK INST FOR BIOLOGICAL STUDI

  公开号：WO2010065572A1

  公开（公告）日：2010-06-10

  Short analogs of SRIF which are selective for SSTR1 in contrast to the other four SRIF receptors comprise a 6-member ring wherein D-Agl(NMe,2Np) and IAmp are flanked by residues having an aromatic side chain end wherein its C-terminus is amidated, inhibit the binding of a universal SRIF radioligand to the cloned human receptor SSTR1, but not to the other receptors. These short selective analogs of SRIF comprise the cyclic hexapeptide: formula (I) where X is H, 4Cl, 4F, 4NO2, 4NH2, 4NHCONH2, 4NHCONHOCH3, 4NHCONHOCH2-CH3 or 4NHCONHOH, where Xaa is Phe, Tyr or iodotyrosine (ITyr) and where the C-terminus is amidated. Radioactive iodinated tyrosine may be one of the two flanking residues, or at the N-terminus, which will also accommodate a conjugating agent or linkage to a cytotoxin.