L-天冬氨酸,4-(9H-芴-9-基甲基)酯 | 135928-47-1

• 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
• 中文名称: L-天冬氨酸,4-(9H-芴-9-基甲基)酯
• 英文名称: L-aspartic β-9-fluorenylmethyl ester
• 英文别名: (2S)-2-amino-4-(9H-fluoren-9-ylmethoxy)-4-oxobutanoic acid
• CAS: 135928-47-1
• 化学式: C₁₈H₁₇NO₄
• 分子量: 311.337
• InChiKey: FDNQJSUPJXCUFZ-INIZCTEOSA-N

物化性质

• 沸点：
  542.1±50.0 °C(Predicted)
• 密度：
  1.310±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  89.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  二碳酸二叔丁酯 、 L-天冬氨酸,4-(9H-芴-9-基甲基)酯 以 1,4-二氧六环 、 水 为溶剂， 以87%的产率得到BOC-L-天门冬氨酸Β-9-芴甲氧羰酰甲酯
  参考文献：
  名称：

  天冬氨酸和谷氨酸的ω-9-芴基甲基酯的一步合成

  摘要：

  摘要 9-芴基甲酯的碱不稳定性使该基团在与 tBoc 方法结合用于制备环肽时可用于固相肽合成。我们描述了天冬氨酸和谷氨酸的 9-芴基甲酯的简单一步合成。

  DOI：

  10.1080/00397919208019289
• 作为产物：
  描述：

  L-天门冬氨酸 、 9-芴甲醇 在 四氟硼酸-二乙醚络合物 、 sodium sulfate 作用下， 以 四氢呋喃 为溶剂， 反应 12.0h， 以40%的产率得到L-天冬氨酸,4-(9H-芴-9-基甲基)酯
  参考文献：
  名称：

  天冬氨酸和谷氨酸的ω-9-芴基甲基酯的一步合成

  摘要：

  摘要 9-芴基甲酯的碱不稳定性使该基团在与 tBoc 方法结合用于制备环肽时可用于固相肽合成。我们描述了天冬氨酸和谷氨酸的 9-芴基甲酯的简单一步合成。

  DOI：

  10.1080/00397919208019289

文献信息

• CYCLIC TETRAMER COMPOUNDS AS PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) INHIBITORS FOR THE TREATMENT OF METABOLIC DISORDERS
  申请人：NOVARTIS AG

  公开号：US20200164024A1

  公开（公告）日：2020-05-28

  The disclosure relates to inhibitors of PCSK9 useful in the treatment of cholesterol lipid metabolism, and other diseases in which PCSK9 plays a role, having the Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof, wherein R 1 , R 1 , R 1 , R 1 , R 1 , R 1 , R 1 , R 1 , R 1 , X 1 , X 2 , and X 3 are described herein.

  该披露涉及对PCSK9的抑制剂，用于治疗胆固醇脂质代谢以及其他PCSK9发挥作用的疾病，其化学式为(I)： 或其药用可接受的盐、水合物、溶剂合物、前药、立体异构体、N-氧化物或互变异构体，其中R1、R2、R3、R4、R5、R6、R7、R8、R9、X1、X2和X3如本文所述。
• [EN] FUSED 1,4-OXAZEPINES AND RELATED ANALOGS AS BET BROMODOMAIN INHIBITORS<br/>[FR] 1,4-OXAZEPINES CONDENSÉES ET LEURS ANALOGUES ASSOCIÉS EN TANT QU'INHIBITEURS DE BROMODOMAINE BET
  申请人：UNIV MICHIGAN REGENTS

  公开号：WO2017142881A1

  公开（公告）日：2017-08-24

  The present disclosure provides fused 1,4-oxazepines and related analogs represented by Formula (I) and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R1, R2a, R2b, R3a, R3b, R4, R5, A, and Y are as defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula (I) to treat a condition or disorder responsive to inhibition of BET bromodomains such as cancer.

  本发明公开了式(I)表示的融合1,4-噁嗪和相关类似物及其药学上可接受的盐、水合物和溶剂化物，其中R1、R2a、R2b、R3a、R3b、R4、R5、A和Y的定义如说明书中所述。本发明还涉及式(I)化合物用于治疗对BET溴结构域抑制有反应的病症或疾病，如癌症的用途。
• [EN] 1-(2-(4-CYCLOPROPYL-1H-1,2,3-TRIAZOL-1-YL)ACETYL)-4-HYDROXY-N-(BENZYL)PYRROLIDIN E-2-CARBOXAMIDE DERIVATIVES AS VHL INHIBITORS FOR THE TREATMENT OF ANEMIA AND CANCER<br/>[FR] DÉRIVÉS DE 1-(2-(4-CYCLOPROPYL-1H-1,2,3-TRIAZOL-1-YL)ACÉTYL)-4-HYDROXY-N-(BENZYL)PYRROLIDIN E-2-CARBOXAMIDE UTILISÉS EN TANT QU'INHIBITEURS DE VHL POUR LE TRAITEMENT DE L'ANÉMIE ET DU CANCER
  申请人：GENENTECH INC

  公开号：WO2022103411A1

  公开（公告）日：2022-05-19

  The present disclosure relates to 1-(2-(4-cyclopropyl-1H-l,2,3- triazol-l-yl)acetyl)-4-hydroxy-N-(benzyl)pyrrolidine-2-carboxamide derivatives and structurally related compounds as VHL inhibitors for the treatment of e.g. anemia (e.g. chronic anemia or anemia associated with chronic kidney disease, dialysis or cancer chemotherapy), ischemia, stroke or damage to the cardiovascular system during ischemia, or for enhancing wound healing, reducing scarring, or enhancing angiogenesis or arteriogenesis, and cancer. Exemplary compounds are e.g.: N-(3-([l,l'-biphenyl]-4-yl)-l-amino-l-oxopropan-2-yl)-l-(2- (4-cyclopropyl-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl)-4- hydroxypyrrolidine-2-carboxamide; N-(3-([l,l'-biphenyl]-4-yl)-l-amino-l-oxopropan-2-yl)-l-(2-(4- cyclopropyl-lH-l,2,3-triazol-l-yl)propanoyl)-4-hydroxypyrrolidine-2- carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-l-amino-l-oxopropan-2-yl)-1-(2- (4-cyclopropyl-1H-l,2,3-triazol-l-yl)-3,3-dimethylbutanoyl)-4- hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-l-amino-1-oxopropan-2-yl)-1-(2-cyclobutyl-2- (4-cyclopropyl-1H-1,2,3-triazol-l-yl)acetyl)-4-hydroxypyrrolidine-2- carboxamide; 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4- hydroxy-N-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide; 1-(2-cyclohexyl-2-(4-cyclopropyl-1H-1,2,3-triazol-l-yl)acetyl)-4- hydroxy-N-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide; 1-(2-(adamantan-1-yl)-2-(4-cyclopropyl-1H-1,2,3-triazol-l-yl)acetyl) -4-hydroxy-N-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide; l-(2-(4-cyclopropyl-lH-l,2,3-triazol-l-yl)-3,3-dimethylpentanoyl)-4- hydroxy-N-(l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide.

  本公开涉及1-(2-(4-环丙基-1H-1,2,3-三唑-1-基)乙酰基)-4-羟基-N-(苄基)吡咯烷-2-羧酰胺衍生物和结构相关化合物，作为VHL抑制剂，用于治疗贫血（例如慢性贫血或与慢性肾病、透析或癌症化疗相关的贫血）、缺血、中风或缺血期间对心血管系统的损伤，或用于增强伤口愈合、减少瘢痕形成或增强血管生成或动脉生成，以及癌症。示例化合物包括：N-(3-([1,1'-联苯]-4-基)-1-氨基-1-氧丙酰基)-1-(2-(4-环丙基-1H-1,2,3-三唑-1-基)-3-甲基丁酰基)-4-羟基吡咯烷-2-羧酰胺；N-(3-([1,1'-联苯]-4-基)-1-氨基-1-氧丙酰基)-1-(2-(4-环丙基-1H-1,2,3-三唑-1-基)丙酰基)-4-羟基吡咯烷-2-羧酰胺；N-(3-([1,1'-联苯]-4-基)-1-氨基-1-氧丙酰基)-1-(2-(4-环丙基-1H-1,2,3-三唑-1-基)-3,3-二甲基丁酰基)-4-羟基吡咯烷-2-羧酰胺；N-(3-([1,1'-联苯]-4-基)-1-氨基-1-氧丙酰基)-1-(2-环丁基-2-(4-环丙基-1H-1,2,3-三唑-1-基)乙酰基)-4-羟基吡咯烷-2-羧酰胺；1-(2-(4-环丙基-1H-1,2,3-三唑-1-基)-3,3-二甲基丁酰基)-4-羟基-N-(1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-羧酰胺；1-(2-环己基-2-(4-环丙基-1H-1,2,3-三唑-1-基)乙酰基)-4-羟基-N-(1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-羧酰胺；1-(2-(金刚烷-1-基)-2-(4-环丙基-1H-1,2,3-三唑-1-基)乙酰基)-4-羟基-N-(1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-羧酰胺；1-(2-(4-环丙基-1H-1,2,3-三唑-1-基)-3,3-二甲基戊酰基)-4-羟基-N-(1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-羧酰胺。
• ANTIPROTOZOAL COMPOUNDS
  申请人：Bacoba AG

  公开号：EP3345917A1

  公开（公告）日：2018-07-11

  The present invention relates to a compound of formula (I) wherein --A-- represents a peptide chain, wherein said peptide chain consists of 5 to 7 amino acids, wherein said amino acids are selected from any amino acid, wherein at least two, preferably at least three of said 5 to 7 amino acids are α-aminoisobutyric acid (Aib), leucine (Leu) or alanine (Ala); R1 is wherein X is N or CH; R5 is selected from H, C1-C16alkyl, C1-C16alkenyl, C(O)-C1-C16alkyl, C(O)-C1-C16alkenyl, (wherein said C1-C16alkyl, C1-C16alkenyl, C(O)-C1-C16alkyl, C(O)-C1-C16alkenyl are) independently optionally substituted with halogen, NR11R12, -[O-C2H4]n-OCH3 wherein n=2-20; C(O)-R8, C(O)-C1-C3alkylene-R8, N(H)C(O)-R8, or S(O)2-R9, wherein R8 is independently at each occurrence selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, each independently optionally substituted with C1-C4alkyl, halogen, CF3, OR10, NR11R12, C6H5 and C6H5 substituted with halogen, C1-C3alkyl, OR10, NR11R12; wherein R10, R11, R12 are independently at each occurrence H, C1-C3alkyl; R9 is independently at each occurrence selected from C1-C4alkyl, aryl, heteroaryl, each independently optionally substituted with C1-C4alkyl, halogen, CF3, OR13, NR14R15; wherein R13, R14, R15 are independently at each occurrence H, C1-C3alkyl; R6, R7 are independently at each occurrence selected from H, C1-C4alkyl, C1-C4alkenyl, C(O)-C1-C3alkyl, C(O)-C1-C4alkenyl, (wherein said C1-C4alkyl, C1-C4alkenyl, C(O)-C1-C3alkyl, C(O)-C1-C4alkenyl are) independently optionally substituted with halogen, NR11R12; or R6 and R7 together with the X-C to which they are attached form independently at each occurrence an aryl, heteroaryl, cycloalkyl, heterocyclyl, each independently optionally (further) substituted with C1-C4alkyl, halogen, CF3, OR10, NR11R12, C6H5 and C6H5 substituted with halogen, C1-C3alkyl, OR10, NR11R12; wherein R10, R11, R12 are independently at each occurrence H, C1-C3alkyl; and wherein the arrow indicates the attachment to the NH-moiety depicted in formula (I); R2 is selected from C1-C14alkyl, C2-C14alkyl optionally substituted with OH, C2-C14alkoxy, C2-C14alkenyl optionally substituted with OH; C1-C8alkylene-R23, wherein in alkylene one or two -CH2- moieties are optionally replaced by -CH(NR24R25)-,-CH(OH)-, -C(=O)-, -NR24R25- or -CH(CH3)- moieties, wherein there are no adjacent-C(=O)- moieties or adjacent -NR24R25- moieties, and wherein R23 is independently at each occurrence selected from hydrogen; aryl, heteroaryl, cycloalkyl, heterocyclyl, each independently optionally substituted with C1-C4alkyl, OR26, NR27R28; wherein R26, R27, R28 are independently at each occurrence H, halogen, CF3, C1-C3alkyl; and wherein R24 and R25 are independently at each occurrence H, C1-C3alkyl; with the proviso that R2 is not -CH2CH(CH3)CH2CH(OH)CH2C(O)C2H5, -CH2CH(CH3)CH2CH=CHC(O)C2H5, -CH2CH(CH3)CH2CH2CH2C(O)C2H5, -CH2CH(CH3)(CH2)3CH(OH)C2H5, -CH2CH(CH3)CH2CH(OCH3)CH2C(O)C2H5; R3 is selected from C2-C12alkyl optionally substituted with OH, C2-C12alkoxy, C2-C12alkenyl optionally substituted with OH, C1-C8alkylene-R29, wherein in alkylene one or two -CH2- moieties are optionally replaced by -CH(NR30R31)-, -CH(OH)-, -C(=O)-, -NR30R31- or -CH(CH3)- moieties, wherein there are no adjacent -C(=O)- moieties or adjacent -NR30R31- moieties, and wherein R29 is independently at each occurrence selected from hydrogen; aryl, heteroaryl, cycloalkyl, heterocyclyl, each independently optionally substituted with C1-C4alkyl, OR32, NR33R34; wherein R32, R33, R34 are independently at each occurrence H, halogen, CF3, C1-C3alkyl; and wherein R30 and R31 are independently at each occurrence H, C1-C3alkyl; R4 is wherein R35 is independently selected from hydrogen and C1-C3-alkyl; R36 is independently at each occurrence selected from -cycloalkyl-NR41R42, wherein said cycloalkyl moiety is optionally substituted by C1-C4alkyl, hydroxyl, halogen, OR43; -C3-C6alkylene-NR41R42, wherein said C3-C6alkylene moiety is optionally substituted by hydroxyl, OR43, halogen; cycloalkyl optionally substituted with C1-C4alkyl, halogen, OR43; or wherein R35 and R36 together with the nitrogen atom to which they are attached form independently at each occurrence a heteroaryl, a heterocyclyl or a heterocyclic spiranyl, each independently optionally substituted with C1-C4alkyl, halogen, OR43, NR44R45, wherein R43, R44, R45 are independently at each occurrence H, C1-C4alkyl; and wherein R37, R38, R39 and R40 are independently at each occurrence H or C1-C3alkyl, preferably H or methyl, or independently at each occurrence two of said R37, R38, R39 and R40 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring, preferably a carbocyclic ring, and wherein R41 and R42 are independently of each other H or C1-C4alkyl optionally substituted with halogen, hydroxyl or C3-C6cycloalkyl; or together with the nitrogen atoms to which they are attached form independently at each occurrence a heteroaryl or a heterocyclyl, each independently optionally substituted with halogen, C1-C4alkyl, OR43, NR44R45; wherein the arrow indicates the attachment to the C(O)-moiety depicted in formula (I); and pharmaceutically acceptable salts of said compound of formula (I). The present invention further relates to pharmaceutical compositions comprising said compounds and to the use of said compounds in a method of treatment of a protozoan disease, wherein preferably said protozoan disease is selected from malaria, human African trypanosomiasis, Chagas disease or leishmaniasis.

  本发明涉及式(I)的化合物，其中--A--表示一条肽链，所述肽链由5至7个氨基酸组成，其中所述氨基酸选自任何氨基酸，其中所述5至7个氨基酸中至少有两个、优选至少三个为α-氨基异丁酸(Aib)、亮氨酸(Leu)或丙氨酸(Ala)； R1是： 其中，X为N或CH； R5选自H、C1-C16烷基、C1-C16烯基、C(O)-C1-C16烷基、C(O)-C1-C16烯基(其中所述C1-C16烷基、C1-C16烯基、C(O)-C1-C16烷基、C(O)-C1-C16烯基)各自可独立地被卤素、NR11R12、-[O-C2H4]n-OCH3(其中n=2-20)取代；C(O)-R8、C(O)-C1-C3亚烷基-R8、N(H)C(O)-R8、或S(O)2-R9，其中： R8在每次出现时独立地选自芳基、杂芳基、环烷基、杂环基，各自独立地可被C1-C4烷基、卤素、CF3、OR10、NR11R12、C6H5和被卤素、C1-C3烷基、OR10、NR11R12取代的C6H5取代；其中R10、R11、R12在每次出现时独立地为H、C1-C3烷基； R9在每次出现时独立地选自C1-C4烷基、芳基、杂芳基，各自独立地可被C1-C4烷基、卤素、CF3、OR13、NR14R15取代；其中R13、R14、R15在每次出现时独立地为H、C1-C3烷基； R6、R7在每次出现时独立地选自H、C1-C4烷基、C1-C4烯基、C(O)-C1-C3烷基、C(O)-C1-C4烯基(其中所述C1-C4烷基、C1-C4烯基、C(O)-C1-C3烷基、C(O)-C1-C4烯基)各自独立地可被卤素、NR11R12取代；或R6和R7与所连接的X-C基团共同形成独立地在每次出现时为芳基、杂芳基、环烷基、杂环基，各自独立地可被C1-C4烷基、卤素、CF3、OR10、NR11R12、C6H5和被卤素、C1-C3烷基、OR10、NR11R12取代的C6H5取代；其中R10、R11、R12在每次出现时独立地为H、C1-C3烷基；其中箭头指示连接至式(I)中所示的NH基团； R2选自C1-C14烷基、C2-C14烷基可选地被OH、C2-C14烷氧基、C2-C14烯基可选地被OH取代；C1-C8亚烷基-R23，其中亚烷基中的一或两个-CH2-基团可选地被-CH(NR24R25)-、-CH(OH)-、-C(=O)-、-NR24R25-或-CH(CH3)-基团取代，且不存在相邻的-C(=O)-基团或相邻的-NR24R25-基团，且其中： R23在每次出现时独立地选自氢；芳基、杂芳基、环烷基、杂环基，各自独立地可被C1-C4烷基、OR26、NR27R28取代；其中R26、R27、R28在每次出现时独立地为H、卤素、CF3、C1-C3烷基；且其中R24和R25在每次出现时独立地为H、C1-C3烷基； 条件是R2不为-CH2CH(CH3)CH2CH(OH)CH2C(O)C2H5、-CH2CH(CH3)CH2CH=CHC(O)C2H5、-CH2CH(CH3)CH2CH2CH2C(O)C2H5、-CH2CH(CH3)(CH2)3CH(OH)C2H5、-CH2CH(CH3)CH2CH(OCH3)CH2C(O)C2H5； R3选自C2-C12烷基可选地被OH、C2-C12烷氧基、C2-C12烯基可选地被OH取代，或C1-C8亚烷基-R29，其中亚烷基中的一或两个-CH2-基团可选地被-CH(NR30R31)-、-CH(OH)-、-C(=O)-、-NR30R31-或-CH(CH3)-基团取代，且不存在相邻的-C(=O)-基团或相邻的-NR30R31-基团，且其中： R29在每次出现时独立地选自氢；芳基、杂芳基、环烷基、杂环基，各自独立地可被C1-C4烷基、OR32、NR33R34取代；其中R32、R33、R34在每次出现时独立地为H、卤素、CF3、C1-C3烷基；且其中R30和R31在每次出现时独立地为H、C1-C3烷基； R4为： 其中R35独立地选自氢和C1-C3烷基； R36在每次出现时独立地选自-环烷基-NR41R42的环烷基部分可选地被C1-C4烷基、羟基、卤素、OR43取代；-C3-C6亚烷基-NR41R42的C3-C6亚烷基部分可选地被羟基、OR43、卤素取代；环烷基可选地被C1-C4烷基、卤素、OR43取代；或R35和R36与所连接的氮原子共同形成独立地在每次出现时为杂芳基、杂环基或杂环螺旋基，各自独立地可被C1-C4烷基、卤素、OR43、NR44R45取代，其中R43、R44、R45在每次出现时独立地为H、C1-C4烷基；且其中： R37、R38、R39和R40在每次出现时独立地为H或C1-C3烷基，优选H或甲基，或在每次出现时R37、R38、R39和R40中的两个与所连接的碳原子共同形成碳环或杂环环，优选为碳环，且其中： R41和R42彼此独立地为H或C1-C4烷基(可选地被卤素、羟基或C3-C6环烷基取代)；或与所连接的氮原子共同形成独立地在每次出现时为杂芳基或杂环基，各自独立地可被卤素、C1-C4烷基、OR43、NR44R45取代；其中 箭头指示连接至式(I)中所示的C(O)基团；以及式(I)化合物的药学上可接受的盐。 本发明还涉及包含所述化合物的药物组合物，以及所述化合物在治疗原虫病的方法中的用途，其中优选所述原虫病选自疟疾、人类非洲锥虫病、查加斯病或利什曼病。
• Cyclic tetramer compounds as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for the treatment of metabolic disorders
  申请人：NOVARTIS AG

  公开号：US11026993B2

  公开（公告）日：2021-06-08

  The disclosure relates to inhibitors of PCSK9 useful in the treatment of cholesterol lipid metabolism, and other diseases in which PCSK9 plays a role, having the Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof, wherein R1, R1, R1, R1, R1, R1, R1, R1, R1, X1, X2, and X3 are described herein.

  本公开涉及可用于治疗胆固醇脂质代谢和 PCSK9 在其中起作用的其他疾病的 PCSK9 抑制剂，其具有式 (I)： 或其药学上可接受的盐、水合物、溶液剂、原药、立体异构体、N-氧化物或同系物，其中 R1、R1、R1、R1、R1、R1、R1、X1、X2 和 X3 在本文中描述。