(4-Methyl-piperidin-1-yl)-acetonitrile | 847574-01-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (4-Methyl-piperidin-1-yl)-acetonitrile
• 英文别名: (4-Methylpiperidin-1-yl)acetonitrile；2-(4-methylpiperidin-1-yl)acetonitrile
• CAS: 847574-01-0
• 化学式: C₈H₁₄N₂
• mdl: MFCD09027193
• 分子量: 138.213
• InChiKey: JPCZNTKWDQCTTC-UHFFFAOYSA-N

物化性质

• 沸点：
  213.0±23.0 °C(Predicted)
• 密度：
  0.930±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  10
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.875
• 拓扑面积：
  27
• 氢给体数：
  0
• 氢受体数：
  2

安全信息

• 海关编码：
  2933399090

反应信息

• 作为反应物：
  描述：

  (4-Methyl-piperidin-1-yl)-acetonitrile 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 生成 2-(4-甲基-1-哌啶)-乙胺
  参考文献：
  名称：

  5-(2-Aminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones:  Variation of N-Alkyl Substituents Modulates Sensitivity to Efflux Transporters Associated with Multidrug Resistance

  摘要：

  5H-8,9-Dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo [c, h]-[1,6]naphthyridin-6-one (ARC-111) has potent TOP1-targeting activity and pronounced antitumor activity. Several analogues of ARC-111 were synthesized with NH2, N-alkyl, N,N-dialkyl, pyrrolidinyl, piperidinyl, and piperazinyl substituents at the 2-position of the 5-ethyl group. The relative TOP1-targeting activity and cytotoxicity of these structural analogues were assessed in RPMI8402 and P388 tumor cells and their camptothecin-resistant variants CPT-K5 and P388/CPT45, respectively. Potent TOP1-targeting activity was retained within a series of mono N-alkyl analogues that included NHCH2CH3, NHCH(CH3)(2), and NHC(CH3)(3). TOP1-targeting activity was diminished by the presence of a N-benzyl moiety. In a comparison of a series of N-alkyl-N-isopropyl analogues, activity decreased in the order CH3 > CH2CH3 > CH(CH3)(2). Cytotoxicity in RPMI8402 and P388 did correlate with TOP1-targeting activity. Cytotoxic activity was also determined in KB3-1 cells and its variants KB/V-1 and KBH5.0. As KB/V-1 cells overexpress MDR1 and KBH5.0 cells overexpress BCRP, decreased cytotoxicity in these cell lines relative to the parent cell line is indicative of compounds that are substrates for these efflux transporters. In view of their diminished cytotoxicity in KB/V-1 cells, it appears that the likely demethylated metabolites of ARC-111, i.e., where NH2 or NHCH3 replaces the N(CH3)(2) at the 2-position of the 5-ethyl substituent, are substrates for MDR1. In contrast, no significant difference in cytotoxicity among these three cell lines was observed with other N-alkyl analogues, including NHC2H5, NHCH(CH3)(2), NHC(CH3)(3), N(CH3)(2), N(CH2CH3)(2), NCH3(CH(CH)(3))(2)), and either the pyrrolidinyl or the piperidinyl analogues. The 2-(piperazinyl) analogues were associated with diminished cytotoxicity in KB/V-1 cells, suggesting that the second basic amino substituent is associated with their recognition as substrates by MDR1. Comparative studies on the antitumor activity of ARC-111 and its N-demethylated derivatives (the NHCH3 and NH2 analogues) against SJ-BT45 medulloblastoma xenografts in scid mice revealed that the secondary amine metabolite is at least as active as ARC-111 in vivo, although the primary amine derivative was significantly less potent.

  DOI：

  10.1021/jm049447z
• 作为产物：
  描述：

  4-甲基哌啶 、 alkaline earth salt of/the/ methylsulfuric acid 在 potassium carbonate 、 sodium iodide 作用下， 以 乙腈 为溶剂， 生成 (4-Methyl-piperidin-1-yl)-acetonitrile
  参考文献：
  名称：

  5-(2-Aminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones:  Variation of N-Alkyl Substituents Modulates Sensitivity to Efflux Transporters Associated with Multidrug Resistance

  摘要：

  5H-8,9-Dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo [c, h]-[1,6]naphthyridin-6-one (ARC-111) has potent TOP1-targeting activity and pronounced antitumor activity. Several analogues of ARC-111 were synthesized with NH2, N-alkyl, N,N-dialkyl, pyrrolidinyl, piperidinyl, and piperazinyl substituents at the 2-position of the 5-ethyl group. The relative TOP1-targeting activity and cytotoxicity of these structural analogues were assessed in RPMI8402 and P388 tumor cells and their camptothecin-resistant variants CPT-K5 and P388/CPT45, respectively. Potent TOP1-targeting activity was retained within a series of mono N-alkyl analogues that included NHCH2CH3, NHCH(CH3)(2), and NHC(CH3)(3). TOP1-targeting activity was diminished by the presence of a N-benzyl moiety. In a comparison of a series of N-alkyl-N-isopropyl analogues, activity decreased in the order CH3 > CH2CH3 > CH(CH3)(2). Cytotoxicity in RPMI8402 and P388 did correlate with TOP1-targeting activity. Cytotoxic activity was also determined in KB3-1 cells and its variants KB/V-1 and KBH5.0. As KB/V-1 cells overexpress MDR1 and KBH5.0 cells overexpress BCRP, decreased cytotoxicity in these cell lines relative to the parent cell line is indicative of compounds that are substrates for these efflux transporters. In view of their diminished cytotoxicity in KB/V-1 cells, it appears that the likely demethylated metabolites of ARC-111, i.e., where NH2 or NHCH3 replaces the N(CH3)(2) at the 2-position of the 5-ethyl substituent, are substrates for MDR1. In contrast, no significant difference in cytotoxicity among these three cell lines was observed with other N-alkyl analogues, including NHC2H5, NHCH(CH3)(2), NHC(CH3)(3), N(CH3)(2), N(CH2CH3)(2), NCH3(CH(CH)(3))(2)), and either the pyrrolidinyl or the piperidinyl analogues. The 2-(piperazinyl) analogues were associated with diminished cytotoxicity in KB/V-1 cells, suggesting that the second basic amino substituent is associated with their recognition as substrates by MDR1. Comparative studies on the antitumor activity of ARC-111 and its N-demethylated derivatives (the NHCH3 and NH2 analogues) against SJ-BT45 medulloblastoma xenografts in scid mice revealed that the secondary amine metabolite is at least as active as ARC-111 in vivo, although the primary amine derivative was significantly less potent.

  DOI：

  10.1021/jm049447z

文献信息

• Cinnoline compounds
  申请人：——

  公开号：US20030212055A1

  公开（公告）日：2003-11-13

  The invention relatest to compounds of the formula (I) wherein either any one of G 1 , G 2 , G 3 , G 4 and G 5 is nitrogen and the other four are —CH—, or G 1 , G 2 , G 3 , G 4 and G 5 are all —CH—; Z is —O—, —NH—, —S—, —CH 2 — or a direct bond; Z is linked to any one of G 1 , G 2 , G 3 and G 4 which is a free carbon atom; n is an integer from 0 to 5; any of the substitutents R 1 may be attached at any free carbon atom of the indole, azaindole or indazole group; m is an integer from 0 to 3; R a represents hydrogen; R b represents hydrogen or another value as defined herein; R 1 represents hydrogen, oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy, C 1-4 -alkyl, aminoC 1-4 alkyl, C 1-3 alkylaminoC 1-4 alkyl, di(C 1-3 alkyl)aminoC 1-4 alkyl, —C 1-5 alkyl(ring B) wherein ring B is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinly, N-ethylpiperazinyl, morpholino and thiomorpholino; R 2 represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 aklylsulphanyl, —NR 3 R 4 (wherein R 3 and R 4 , which may be the same or different, each represents hydrogen or C 1-3 alkyl), or R 5 X 1 — (wherein R 5 and X 1 are as defined herein) and salts thereof, processes for the preparation of such compounds, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient and the use of a compound of formula I in the manufacture of medicament for the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals. The compounds of formula I and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

  该发明涉及以下式(I)的化合物，其中G1、G2、G3、G4和G5中的任何一个是氮，其他四个是—CH—，或者G1、G2、G3、G4和G5都是—CH—；Z是—O—、—NH—、—S—、—CH2—或直接键；Z与G1、G2、G3和G4中的任何一个自由碳原子相连；n是从0到5的整数；R1的任何取代基可能连接到吲哚、氮杂吲哚或吲唑基团的任何自由碳原子；m是从0到3的整数；Ra代表氢；Rb代表氢或本文中定义的另一个值；R1代表氢、氧代、羟基、卤代、C1-4烷基、C1-4烷氧基、C1-4烷氧基、C1-4烷基、氨基C1-4烷基、C1-3烷基氨基C1-4烷基、二(C1-3烷基)氨基C1-4烷基、—C1-5烷基(环B)，其中环B选自氮杂环丙烷基、吡咯烷基、哌啶基、哌嗪基、N-甲基哌嗪基、N-乙基哌嗪基、吗啉和硫代吗啉；R2代表氢、羟基、卤代、氰基、硝基、三氟甲基、C1-3烷基、C1-3烷氧基、C1-3烷基硫基、—NR3R4(其中R3和R4，可能相同也可能不同，各自代表氢或C1-3烷基)，或R5X1—(其中R5和X1如本文所定义)及其盐，制备这类化合物的方法，含有式I的化合物或其药学上可接受的盐作为活性成分的药物组合物，以及利用式I的化合物制备药物，用于在温血动物中产生抗血管生成和/或血管通透性降低作用。式I的化合物及其药学上可接受的盐抑制VEGF的作用，这是治疗多种疾病状态的有价值特性，包括癌症和类风湿性关节炎。
• [EN] QUINAZOLINE DERIVATIVES AS ANGIOGENESIS INHIBITORS<br/>[FR] DERIVES DE QUINAZOLINE EN TANT QU'INHIBITEURS D'ANGIOGENESE
  申请人：ASTRAZENECA AB

  公开号：WO2005014582A1

  公开（公告）日：2005-02-17

  The present invention relates to compounds of the Formula (I): wherein: ring C is an 8, 9, 10, 12 or 13-membered bicyclic or tricyclic moiety which moiety may be saturated or unsaturated, which may be aromatic or non-aromatic, and which optionally may contain 1-3 heteroatoms selected independently from O, N and S; is -O- -NH- or -S-; is 0, 1, 2, 3, 4 or 5; is 0, 1, 2 or 3; and R2 and R1 are as defined herein; and salts thereof; their use in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm blooded animals; processes for the preparation of such compounds; pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof and methods of treating disease states involving angiogenesis by administering a compound of formula I or a pharmaceutically acceptable salt thereof. The compounds of Formula (I) inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

  本发明涉及以下式（I）的化合物：其中：环C是一个8、9、10、12或13成员的双环或三环基团，该基团可以是饱和的或不饱和的，可以是芳香的或非芳香的，并且可以选择性地包含1-3个从O、N和S中独立选择的杂原子；是-O-、-NH-或-S-；是0、1、2、3、4或5；是0、1、2或3；R2和R1如本文所定义；及其盐；它们在制造用于在温血动物中产生抗血管生成和/或血管通透性降低作用的药物中的用途；制备这种化合物的方法；含有式（I）的化合物或其药学上可接受的盐的药物组合物以及通过给予式（I）的化合物或其药学上可接受的盐来治疗涉及血管生成的疾病状态的方法。式（I）的化合物抑制VEGF的作用，在治疗包括癌症和类风湿性关节炎在内的多种疾病状态中具有价值的特性。
• Quinoline derivatives having vegf inhibiting activity
  申请人：——

  公开号：US20030199491A1

  公开（公告）日：2003-10-23

  The invention relates to compounds of formula (I) wherein: either any one of G 1 , G 2 , G 3 , G 4 and G 5 is nitrogen and the other four are —CH—, or G 1 , G 2 , G 3 , G 4 and G 5 are all —CH—; Z is —O—, —NH—, —S—, —CH 2 — or a direct bond; Z is linked to any one of G 1 , G 2 , G 3 and G 4 ; n is an integer from 0 to 5; m is an integer from 0 to 3; R a represents hydrogen or fluoro; R b , R 1 and R 2 are defined herein and salt thereof, process for the preparation so such compounds, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient and the use of a compound of formula I in the manufacture of a medicament for the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blodded animals. The compounds of formula I and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of diseases states including cancer and rheumatoid arthritis.

  该发明涉及以下式（I）的化合物：其中：G1、G2、G3、G4和G5中的任意一个是氮，其他四个是—CH—，或者G1、G2、G3、G4和G5都是—CH—；Z是—O—、—NH—、—S—、—CH2—或直接键；Z与G1、G2、G3和G4中的任意一个相连；n是从0到5的整数；m是从0到3的整数；R代表氢或氟；Rb、R1和R2在此处定义，并且其盐，制备这种化合物的方法，含有式I的化合物或其药学上可接受的盐作为活性成分的药物组合物，以及利用式I的化合物制造用于在温血动物中产生抗血管生成和/或血管通透性降低作用的药物的用途。式I的化合物及其药学上可接受的盐抑制VEGF的作用，这是治疗多种疾病状态的有价值的特性，包括癌症和类风湿性关节炎。
• Chemical compounds
  申请人：——

  公开号：US20030207878A1

  公开（公告）日：2003-11-06

  The invention relates to compounds of the formula (I): wherein: ring C is 9 or 10-membered bicyclic heteroaromatic group containing at least one nitrogen atom in the ring attached to Z and optionally containing a further 1-3 heteroatoms, selected independently from O, S, and N, with the proviso that ring C is not a quinazoline, quinoline or cinnoline group; either any one of G 1 , G 2 , G 3 , G 4 and G 5 is nitrogen and the other four are —CH—; or G 1 , G 2 , G 3 , G 4 and G 5 are all —CH—; Z is —O—, NH—, —S—, CH 2 — or a direct substituents R 1 may be attached at any free carbon atom of the indole, azaindole or indazole group; m is an integer from 0 to 2; R b represents hydrogen or another value as defined herein; R 1 represents hydrogen, hydroxy, halogeno, C 1-4 alkyl, or any other value as defined herein; R 2 represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylsulphanyl, —NR 3 R 4 (wherein R 3 and R 4 , which may be the same or different, each represents hydrogen or C 1-3 alkyl), or R 5 X 1 — (wherein R 5 and X 1 are as defined herein) and salts thereof, processes for the preparation of such compounds, pharmaceutical compositions

  本发明涉及具有以下化学式（I）的化合物：其中：环C是9或10元杂环脂环芳烃基团，至少含有一个氮原子连接到Z，并可选地含有另外1-3个杂原子，独立选择自O、S和N，条件是环C不是喹唑啉、喹啉或茴香啉基团；G1、G2、G3、G4和G5中的任何一个是氮，其他四个是—CH—；或者G1、G2、G3、G4和G5都是—CH—；Z是—O—、NH—、—S—、CH2—或直接取代基，R1可以连接到吲哚、氮杂吲哚或吲唑基团的任何自由碳原子处；m是0到2的整数；Rb代表氢或本文中定义的另一个值；R1代表氢、羟基、卤代基、C1-4烷基或本文中定义的任何其他值；R2代表氢、羟基、卤代基、氰基、硝基、三氟甲基、C1-3烷基、C1-3烷氧基、C1-3烷基硫基、—NR3R4（其中R3和R4，可能相同也可能不同，各自代表氢或C1-3烷基），或R5X1—（其中R5和X1如本文所定义），以及其盐，以及制备此类化合物的方法，制备药物组合物。
• [EN] TRICYCLIC PYRAZINONE COMPOUNDS, COMPOSITIONS AND METHODS OF USE THEREOF AS JANUS KINASE INHIBITORS<br/>[FR] COMPOSÉS PYRAZINONES TRICYCLIQUES, LEURS COMPOSITIONS ET LEURS PROCÉDÉS D'UTILISATION EN TANT QU'INHIBITEURS DE JANUS KINASE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2012085176A1

  公开（公告）日：2012-06-28

  The invention provides novel compounds of formula I having the general formula (I) wherein X, R1, R2, R3 and R5 are as described herein. Accordingly, the compounds may be provided in pharmaceutically acceptable compositions and used for the treatment of immunological or hyperproliferative disorders.

  该发明提供了一种具有通式（I）的新化合物，其通式为（I），其中X、R1、R2、R3和R5如本文所述。因此，这些化合物可以以药学上可接受的组合物形式提供，并用于治疗免疫性或过度增殖性疾病。