4-[4-[1-butyl-3(R)-[1(R)-cyclohexyl-1-hydroxymethyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-ylmethyl]phenoxy]benzoic acid hydrochloride

• 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-[4-[1-butyl-3(R)-[1(R)-cyclohexyl-1-hydroxymethyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-ylmethyl]phenoxy]benzoic acid hydrochloride
• 英文别名: 4-{[4-({(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenyl]oxy}benzoic acid hydrochloride；aplaviroc；Aplaviroc hydrochloride；[3H]-Aplaviroc hydrochloride；(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride；(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride；4-[4-(((3R)-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl)methyl)phenoxy]benzoic acid hydrochloride；4-[4-[[(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzoic acid;hydron;chloride
• 化学式: C₃₃H₄₃N₃O₆*ClH
• 分子量: 614.182
• InChiKey: QNNBMSGFNQRUEH-PQQSRXGVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.0
• 重原子数：
  43
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  119
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-[4-[1-butyl-3(R)-[1(R)-cyclohexyl-1-hydroxymethyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-ylmethyl]phenoxy]benzoic acid hydrochloride 、 (1-methoxy-1-methylethyl)hydroxyamine 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 盐酸 作用下， 以 DMF (N,N-dimethyl-formamide) 、 水 、 甲醇 、 乙酸乙酯 为溶剂， 反应 1.25h， 生成 (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(N-hydroxycarbamoyl)phenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride
  参考文献：
  名称：

  EP1378509

  摘要：

  公开号：
• 作为产物：
  描述：

  3-cyclohexylacrylic acid 在 titanium(IV) isopropylate 、 盐酸 、 sodium chlorite 、 sodium dihydrogenphosphate 、 2-甲基-2-丁烯 、 D-(-)-酒石酸二乙酯 、 过氧化氢异丙苯 、 硫酸 、 20 % Pd(OH)2/C 、 氢气 、 三氧化硫吡啶 、 三乙酰氧基硼氢化钠 、 二异丁基氢化铝 、 溶剂黄146 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 生成 4-[4-[1-butyl-3(R)-[1(R)-cyclohexyl-1-hydroxymethyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-ylmethyl]phenoxy]benzoic acid hydrochloride
  参考文献：
  名称：

  Spirodiketopiperazine-based CCR5 antagonist: Discovery of an antiretroviral drug candidate

  摘要：

  Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate. (c) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.12.109

文献信息

• Triazaspiro[5.5]undecane derivative and pharmaceutical composition comprising the same as active ingredient
  申请人：Ono Pharmaceutical Co., Ltd.

  公开号：US07262193B2

  公开（公告）日：2007-08-28

  Triazaspiro[5.5]undecane derivatives of the formula (I), quaternary ammonium salts thereof, N-oxides thereof, non-toxic salts thereof, or pharmaceutical compositions comprising them, as active ingredients (wherein R1 is formula (II) or formula (III); R2 is alkyl or alkynyl etc.; R3, R4 is H, (substituted) alkyl etc., or R3 and R4 together to form formula (IV); R5 is H or alkyl). Therefore the compounds of the formula (I) regulate the effect of chemokine/chemokine receptor, they are used for prevention and treatment of various inflammatory diseases, asthma, atopic dermatitis, urticaria, allergic diseases, nephritis, nephropathy, hepatitis, arthritis or rheumatoid arthritis etc.

  公式（I）的Triazaspiro [5.5] undecane衍生物，其季铵盐，N-氧化物，非毒性盐或包含它们的制药组合物作为活性成分（其中R1为公式（II）或公式（III）; R2为烷基或炔基等; R3，R4为H，（取代的）烷基等，或R3和R4结合形成公式（IV）; R5为H或烷基）。因此，公式（I）的化合物调节趋化因子/趋化因子受体的作用，它们用于预防和治疗各种炎症性疾病，哮喘，特应性皮炎，荨麻疹，过敏性疾病，肾炎，肾病，肝炎，关节炎或类风湿性关节炎等。
• Triazaspiro[5.5]undecane derivatives and drugs containing the same as the active ingredient
  申请人：——

  公开号：US20040082584A1

  公开（公告）日：2004-04-29

  Triazaspiro[5.5]undecane derivatives of the formula (I), quaternary ammonium salts thereof, N-oxides thereof, non-toxic salts thereof, or pharmaceutical compositions comprising them, as active ingredients (wherein R 1 is formula (II) or formula (III); R 2 is alkyl or alkynyl etc.; R 3 , R 4 is H, (substituted) alkyl etc., or R 3 and R 4 together to form formula (IV); R 5 is H or alkyl). 1 Therefore the compounds of the formula (I) regulate the effect of chemokine/chemokine receptor, they are used for prevention and treatment of various inflammatory diseases, asthma, atopic dermatitis, urticaria, allergic diseases, nephritis, nephropathy, hepatitis, arthritis or rheumatoid arthritis etc.

  化合物的公式（I）是Triazaspiro[5.5]十一烷衍生物，其季铵盐，N-氧化物，非毒性盐，或以其为活性成分的制药组合物（其中R1是公式（II）或公式（III）; R2是烷基或烷炔基等; R3，R4是H，（取代）烷基等，或R3和R4一起形成公式（IV）; R5是H或烷基）。因此，公式（I）的化合物调节趋化因子/趋化因子受体的作用，它们用于预防和治疗各种炎症性疾病，哮喘，特应性皮炎，荨麻疹，过敏性疾病，肾炎，肾病，肝炎，关节炎或类风湿性关节炎等。
• Triazaspiro[5.5]undecane derivatives and drugs comprising the same as the active ingredient
  申请人：Takaoka Yoshikazu

  公开号：US20050267114A1

  公开（公告）日：2005-12-01

  Compounds represented by formula (I) (wherein all of the symbols have the same meanings as defined in specification.), quaternary ammonium salts thereof, N-oxides thereof or salts thereof. The compounds represented by formula (I) are used for prevention and/or treatment of various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis, arthritis, chronic rheumatoid arthritis, rhinitis, conjunctivitis, ulcerative colitis and the like), immunologic diseases (autoimmune diseases, transplant rejection, immunosuppression, psoriasis, multiple sclerosis and the like), human immunodeficiency virus (acquired immunodeficiency syndrome and the like), allergic diseases (atopic dermatitis, nettle rash, allergic bronchopulmonary aspergillosis, allergic eosinophilic gastroenteritis and the like), ischemia-reperfusion injury, acute respiratory distress syndrome, shock accompanied by bacterial infection, diabetes mellitus, or metastasis and the like.

  化合物的化学式为(I)（其中所有符号的含义与规范中定义的相同），以及其季铵盐、N-氧化物或盐。式(I)所代表的化合物用于预防和/或治疗各种炎症性疾病（哮喘、肾炎、肾病、肝炎、关节炎、慢性类风湿性关节炎、鼻炎、结膜炎、溃疡性结肠炎等）、免疫性疾病（自身免疫疾病、移植排斥、免疫抑制、银屑病、多发性硬化症等）、人类免疫缺陷病毒（获得性免疫缺陷综合症等）、过敏性疾病（特应性皮炎、荨麻疹、过敏性支气管肺曲霉病、过敏性嗜酸性胃肠炎等）、缺血再灌注损伤、急性呼吸窘迫综合症、伴有细菌感染的休克、糖尿病或转移等。
• Drugs containing triazaspiro[5.5]undecane derivatives as the active ingredient
  申请人：——

  公开号：US20040106619A1

  公开（公告）日：2004-06-03

  A pharmaceutical composition for prevention and/or treatment for HIV infection or AIDS induced by the infection which comprises, as an active ingredient, a triazaspiro[5.5]undecane derivative, a quaternary ammonium salt thereof, an N-oxide thereof, or a non-toxic salt thereof, and if necessary, it may be combined with at least one member of other agents for prevention and/or treatment for HIV infection (wherein all symbols are as defined in the specification.). 1 The triazaspiro[5.5]undecane derivatives, the quaternary ammonium salts thereof or the N-oxides thereof, or the non-toxic salts thereof are useful in preventing and/or treating HIV infection and AIDS induced by the infection.

  一种用于预防和/或治疗由HIV感染引起的艾滋病的药物组合物，其作为活性成分包括三氮杂螺[5.5]十一烷衍生物、其季铵盐、其N-氧化物或其非毒性盐，如有必要，还可以与其他预防和/或治疗HIV感染的药物组合使用（其中所有符号均如规范中定义） 。1三氮杂螺[5.5]十一烷衍生物、其季铵盐或其N-氧化物，或其非毒性盐在预防和/或治疗HIV感染和由该感染引起的艾滋病中有用。
• TRIAZASPIRO 5.5]UNDECANE DERIVATIVES AND DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT
  申请人：ONO PHARMACEUTICAL CO., LTD.

  公开号：EP1378510A1

  公开（公告）日：2004-01-07

  Triazaspiro[5.5]undecane derivatives of the formula (I), quaternary ammonium salts thereof, N-oxides thereof, non-toxic salts thereof, or pharmaceutical compositions comprising them, as active ingredients (wherein R1 is formula (II) or formula (III); R2 is alkyl or alkynyl etc.; R3, R4 is H, (substituted) alkyl etc., or R3 and R4 together to form formula (IV); R5 is H or alkyl). Therefore the compounds of the formula (I) regulate the effect of chemokine/chemokine receptor, they are used for prevention and treatment of various inflammatory diseases, asthma, atopic dermatitis, urticaria, allergic diseases, nephritis, nephropathy, hepatitis, arthritis or rheumatoid arthritis etc.

  作为活性成分的式(I)的三氮杂螺[5.5]十一烷衍生物、其季铵盐、其N-氧化物、其无毒盐或由其组成的药物组合物（其中R1为式(II)或式(III)；R2为烷基或炔基等；R3、R4为H、（取代的）烷基等，或R3和R4共同组成式(IV)；R5为H或烷基）。 因此，式（I）化合物可调节趋化因子/趋化因子受体的作用，用于预防和治疗各种炎症性疾病、哮喘、特应性皮炎、荨麻疹、过敏性疾病、肾炎、肾病、肝炎、关节炎或类风湿性关节炎等。