N-α-(1-carboxy-3-phenylpropyl)-L-ornithyl-L-proline | 85955-67-5

• 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: N-α-(1-carboxy-3-phenylpropyl)-L-ornithyl-L-proline
• 英文别名: (2S)-1-[(2S)-5-amino-2-[(1-carboxy-3-phenylpropyl)amino]pentanoyl]pyrrolidine-2-carboxylic acid
• CAS: 85955-67-5
• 化学式: C₂₀H₂₉N₃O₅
• 分子量: 391.467
• InChiKey: OZPFXIPKGLHUDK-QRFGZVGRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.2
• 重原子数：
  28
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  133
• 氢给体数：
  4
• 氢受体数：
  7

文献信息

• Process for preparation of carboxyalkyldipeptide derivatives
  申请人：Merck & Co., Inc.

  公开号：EP0079521A1

  公开（公告）日：1983-05-25

  A process for the preparation of carboxyalkyldipeptide compounds of the Formula is described wherein R6 is hydroxy, loweralkoxy, or amino; R, R2 and R7 are hydrogen or loweralkyl; R3 is, e.g., hydrogen, or loweralkyl, R' is, e.g., hydrogen, or alkyl of from 1 to 20 carbon atoms, R4 is hydrogen or loweralkyl, R5 is, e.g., hydrogen, or loweralkyl, and, R4 and R5 may be connected together to form an alyklene bridge of from 2 to 4 carbon atoms. The process comprises reacting a compound of the Formula with a dipeptide (or protected dipeptide) of the Formula and an alkali metal cyanide or a trimethylsilycyanide, to form an amino nitrile compound of the Formula followed by hydrolysis. These compounds are useful as converting enzyme inhibitors and as antihypertensive agents.

  描述了一种制备Formula的羧基烷基二肽化合物的过程，其中R6为羟基、低烷氧基或氨基；R、R2和R7为氢或低烷基；R3为氢、低烷基等；R'为氢、1-20碳原子的烷基等；R4为氢或低烷基；R5为氢、低烷基等，R4和R5可以连接在一起形成2-4个碳原子的烷基桥。该过程包括将Formula的化合物与Formula的二肽（或保护的二肽）和碱金属氰化物或三甲基硅氰化物反应，形成Formula的氨基腈化合物，然后进行水解。这些化合物可用作转化酶抑制剂和降压剂。
• Prostaglandin antagonists
  申请人：MERCK FROSST CANADA INC.

  公开号：EP0140784A2

  公开（公告）日：1985-05-08

  This invention deals with the compounds of the formulae: wherein Z is thio, sulfinyl, or sulfonyl; R1 and R2 are independently hydrogen, halogen, amino, C1 to C4 alkyl, C1 to C4 alkylthio, C1 to C4 alkoxy, thiol, C, to C4 alkylsulfinyl, C1 to C4 alkylsulfonyl, trifluoromethyl, trifluoromethylthio, cyano, nitro, aralkyl, hydroxyalkyl, C1 to C4 alkylamino, dialkylamino wherein each alkyl group has 1 to 4 carbons, or R1 and R2 are joined together to form a polymethylene chain of 3 or 4 carbon atoms, with or without a hydroxy or keto functionality; X is O, N-R3, wherein R3 is hydrogen, C1 to C4 alkyl, aryl, hydroxy, C1 to C4 alkoxy, C1 to C5 acyloxy, amino, C1 to C4 alkylamino or dialkylamino wherein each alkyl group has 1 to 4 carbons; or a group of the formula: wherein each Y is independently O or S or NR6 wherein R6 is H, C1 to C4 alkyl, lower alkanoyl, benzoyl, trifluoroacetyl or CN; and R4 and R5 are each independently hydrogen or C1 to C4 alkyl and the broken line between R4 and R5 represents an optional bond when R4 and R5 are not hydrogen; and the pharmaceutically acceptable salts thereof. These compounds are useful for antagonizing the activity of prostaglandins in a mammal.

  本发明涉及式中的化合物： 式中 Z 是硫代、亚砜基或磺酰基； R1 和 R2 独立地为氢、卤素、氨基、C1 至 C4 烷基、C1 至 C4 烷硫基、C1 至 C4 烷氧基、硫醇、C, 至 C4 烷基亚磺酰基、C1 至 C4 烷基磺酰基、三氟甲基、三氟甲基硫代、氰基、硝基、芳烷基、羟基烷基、C1 至 C4 烷基氨基、二烷基氨基，其中 C1 至 C4 烷基为卤素、羟烷基、C1 至 C4 烷基氨基、二烷基氨基，其中每个烷基具有 1 至 4 个碳原子，或 R1 和 R2 连接在一起形成 3 或 4 个碳原子的多亚甲基链，具有或不具有羟基或酮官能团； X 是 O、N-R3，其中 R3 是氢、C1 至 C4 烷基、芳基、羟基、C1 至 C4 烷氧基、C1 至 C5 乙酰氧基、氨基、C1 至 C4 烷基氨基或二烷基氨基（其中每个烷基具有 1 至 4 个碳原子）；或式中的基团： 其中每个 Y 独立地为 O 或 S 或 NR6，其中 R6 为 H、C1 至 C4 烷基、低级烷酰基、苯甲酰基、三氟乙酰基或 CN；R4 和 R5 独立地为氢或 C1 至 C4 烷基，当 R4 和 R5 不是氢时，R4 和 R5 之间的断线代表任选键；及其药学上可接受的盐。 这些化合物可用于拮抗哺乳动物体内前列腺素的活性。
• Cardiovascular composition
  申请人：MERCK FROSST CANADA INC.

  公开号：EP0166257A2

  公开（公告）日：1986-01-02

  A cardiovascular composition is disclosed which comprises a dibenzo-thiepin compound having the formula wherein: X is a C1-C4 hydrocarbon group, optionally containing O, N or CO; Z is S, SO, S02, CO, CR4R5 wherein R4 and R5 taken together form the group =O or =CHR6 wherein R6 is hydrogen or phenyl; R1 is, e.g., 5-tetrazolyl, 5-tetrazolylmethyl, and wherein m is an integer of from 0 to 4 and R7 is, e.g., hydroxy or loweralkoxy; R2 and R3 can each independently be hydrogen, halogen (F, Cl, Br or I), nitro, loweralkyl, amino, N-loweralkylamino, N,N-diloweralkylamino, loweralkanoyl, hydroxy, loweralkoxy, lower acyloxy, loweralkylthio, trifluoromethylthio, loweralkylsulfinyl, loweralkylsulfonyl, trifluoromethyl, or R2 and R3, when bonded to adjacent carbon atoms, can be joined to form a 5- or 6-membered hydrocarbon ring which can optionally contain a double bond, a carbonyl group, or a hydroxyl group; or a pharmaceutically acceptable salt thereof. The composition can additionally comprise an angiotensin converting enzyme (ACE) inhibitor. These compositions represent a novel therapeutic approach to thromboembolic diseases in man.

  本发明公开了一种心血管组合物，该组合物包含一种二苯并噻吩化合物，其式为 其中X是C1-C4烃基，可选含有O、N或CO； Z是S、SO、S02、CO、CR4R5，其中R4和R5共同形成基团=O或=CHR6，其中R6是氢或苯基； R1是5-四唑基、5-四唑甲基，以及 其中 m 是 0 至 4 的整数，R7 是，例如、羟基或低级烷氧基；低级烷基磺酰基、三氟甲基，或 R2 和 R3 与相邻碳原子结合时可形成 5 或 6 元烃环，该环可选择含有双键、羰基或羟基；或其药学上可接受的盐。组合物还可以包含血管紧张素转换酶（ACE）抑制剂。这些组合物代表了一种治疗人类血栓栓塞性疾病的新方法。
• Indole-2-alkanoic acids and their use as prostaglandin antagonists
  申请人：MERCK FROSST CANADA INC.

  公开号：EP0166591A2

  公开（公告）日：1986-01-02

  Compounds of the formula I where R1 is H or alkyl of 1 to 6 carbons or R1 and R8 taken together form a group (CH2)v wherein v is 1 to 7; R2 is where each R8 is independently H, OH, C1 to C4-O-alkyl or alkyl of 1 to 4 carbons; or an R1 and an R8 taken together form a group (CH2)v wherein v is 1 to 7, R9 is COOR1; CH2OH; CHO; tetrazole; NHSO2R10 wherein R10 is OH, alkyl or alkoxy of 1 to 6 carbons, perhaloalkyl of 1 to 6 carbons, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbons, halogen, hydroxy, COOH, CN, formyl or acyl of 1 to 6 carbons; CONHSO2R10; hydroxymethylketone; CN; or CON(R8)2; X is O; S; SO; S02; NR11 wherein R11 is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons, CN; CR1R8; or the unit wherein the dotted line represents an optical triple bond and in which the R1 and R8 substituents are absent when a triple bond is present; r and q are each independently 0 to 5 and p is 0 or 1 provided that the total of p, q and r is 2 to 6; R3 is H, alkyl of 1 to 6 carbons; phenyl or phenyl substituted by R4; or C1 to C4 alkylphenyl or C1 to C4 alkylphenyl in which the phenyl is substituted by R4; R4, R5, R6 and R7 are each independently selected from: (1) hydrogen; (2) alkyl having 1 to 6 carbon atoms; (3) alkenyl having 2 to 6 carbon atoms; (4) -(CH2)nM wherein n is 0 to 3 and M is a) OR12; b) halogen; c) CF3; d) SR12; e) phenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of R12; f) COOR13; g) h) tetrazole; i) wherein R15 is C1 to C6 alkyl, benzyl or phenyl; j) -NR13R13; k) -NHSO2R16 wherein R16 is C1 to C6 alkyl, phenyl, or CF3; I) m) -SOR12; n) -CON13R13; o) -SO2NR13R13; p) -SO2R12; q) N02; r) s) t) u) CN; each R12 independently is H; C1 to C6 alkyl; benzyl; phenyl or substituted phenyl wherein the substituents are C1 to C3 alkyl, halogen, CN, CF3, COOR13, CH2COOR13, C1 to C3 alkoxy, or C1 to C4 perfluoroalkyl; each R13 is independently H, phenyl or C1 to C6 alkyl; and, each R14 independently is H, (CH2)nCOOR13 wherein n is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein substituted phenyl is as defined above in the definition of R12; and their pharmaceutically acceptable salts are useful as prostaglandin antagonists and are made into pharmaceutical compositions. Certain of the compounds are novel.

  式 I 的化合物 式中 R1 是 H 或 1 至 6 个碳原子的烷基，或 R1 和 R8 共同组成一个基团 (CH2)v，其中 v 为 1 至 7； R2 是 其中 每个 R8 独立地为 H、OH、C1 至 C4-O 烷基或 1 至 4 碳原子的烷基；或一个 R1 和一个 R8 共同形成一个基团 ( )v，其中 v 为 1 至 7、 R9 是 COOR1； OH；CHO；四唑；NHSO2R10，其中 R10 是 OH、1-6 碳原子的烷基或烷氧基、1-6 碳原子的全卤代烷基、苯基或被 1-3 碳原子的烷基或烷氧基取代的苯基、卤素、羟基、COOH、CN、1-6 碳原子的甲酰基或酰基；CONHSO2R10；羟甲基酮；CN 或 CON(R8)2； X 是 O；S；SO；S02；NR11，其中 R11 是 H、1-6 碳原子的烷基、1-6 碳原子的酰基、CN；CR1R8； 或单元 其中虚线代表光学三键，当存在三键时，R1 和 R8 取代基不存在； r 和 q 各自独立地为 0 至 5，p 为 0 或 1，条件是 p、q 和 r 的总和为 2 至 6； R3 是 H、1 至 6 碳原子的烷基；苯基或被 R4 取代的苯基；或 C1 至 C4 烷基苯基或苯基被 R4 取代的 C1 至 C4 烷基苯基； R4、R5、R6 和 R7 各自独立地选自以下各项： (1) 氢 (2) 具有 1 至 6 个碳原子的烷基 (3) 具有 2 至 6 个碳原子的烯基； (4) -( )nM 其中 n 为 0 至 3，M 为 a) OR12 b) 卤素 c) CF3 d) SR12 e) 苯基或取代苯基，其中取代苯基的定义见下文 R12 的定义； f) COOR13 g) h) 四氮唑 i) 其中 R15 为 C1 至 C6 烷基、苄基或苯基； j) -NR13R13 k) -NHSO2R16 其中 R16 是 C1 至 C6 烷基、苯基或 ； I) m) -SOR12 n) -CON13R13 o) -SO2NR13R13； p) -SO2R12 q) N02； r) s) t) u) CN； 每个 R12 独立地为 H、C1-C6 烷基、苄基、苯基或取代苯基，其中取代基为 C1-C3 烷基、卤素、CN、 、COOR13、 COOR13、C1-C3 烷氧基或 C1-C4 全氟烷基； 每个 R13 独立地是 H、苯基或 C1 至 C6 烷基；以及 每个 R14 独立地是 H、( )nCOOR13（其中 n 为 0 至 4）、C1 至 C6 烷基、 、苯基或取代的苯基（其中取代的苯基如上文 R12 定义中所定义）； 及其药学上可接受的盐类可用作前列腺素拮抗剂并制成药物组合物。某些化合物是新型的。
• Process for preparing carboxyalkyl dipeptides
  申请人：Merck & Co., Inc.

  公开号：EP0168769A2

  公开（公告）日：1986-01-22

  A process is disclosed for preparing a carboxyalkyl dipeptide compound which comprises: (a) protecting a peptide with a protecting group which is an a-fluorinated acyl group represented by the general formula: wherein: Z is, e.g., C1-C12 alkyl, aryl of C6 or C10, or heterocyclic groups of up to C7 containing an 0, N or S heteroatom; (b) coupling said protected peptide or amino acid with another peptide or amino acid to obtain a protected dipeptide; (c) reductively alkylating said protected dipeptide with a keto acid or keto ester; and, (d) hydrolyzing said reductively alkylated dipeptide to simultaneously remove said protecting group therefrom and recover said carboxyalkyl dipeptide compound. The protecting groups employed in this process permit them to be removed concurrently with obtaining the desired dipeptide compounds thereby avoiding the need for step-wise removal of such groups in separate reactions before the desired dipeptide compounds can be obtained.

  本发明公开了一种制备羧烷基二肽化合物的工艺，该工艺包括 (a) 用保护基团保护肽，该保护基团是由通式表示的a-氟化酰基： 其中Z是例如C1-C12烷基、C6或C10芳基或含有0、N或S杂原子的C7以下杂环基团； (b) 将所述受保护的肽或氨基酸与另一种肽或氨基酸偶联，得到受保护的二肽； (c) 用酮酸或酮酯还原烷基化所述受保护二肽；以及 (d) 水解所述还原烷基化二肽，同时从其中去除所述保护基团并回收所述羧基烷基二肽化合物。 该工艺中使用的保护基团可在获得所需二肽化合物的同时去除，从而避免了在获得所需二肽化合物之前在单独反应中分步去除这些基团的需要。