(+/-) SKB20206 | 151433-82-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 奎宁环
• 英文名称: (+/-) SKB20206
• 英文别名: sabcomeline；[R-(Z)]-α-(methoxyimino)-α-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile；(+/-) α-(methoxyimino)-α-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile；(3Z)-N-methoxy-1-azabicyclo[2.2.2]octane-3-carboximidoyl cyanide
• CAS: 151433-82-8
• 化学式: C₁₀H₁₅N₃O
• 分子量: 193.249
• InChiKey: IQWCBYSUUOFOMF-ZRDIBKRKSA-N

物化性质

• 沸点：
  278.1±42.0 °C(Predicted)
• 密度：
  1.25±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  14
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  48.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (+/-) SKB20206 生成 沙可美林
  参考文献：
  名称：

  Design of [R-(Z)]-(+)-α-(Methoxyimino)-1-azabicyclo[2.2.2]octane-3-acetonitrile (SB 202026), a Functionally Selective Azabicyclic Muscarinic M1 Agonist Incorporating the N-Methoxy Imidoyl Nitrile Group as a Novel Ester Bioisostere

  摘要：

  Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of muscarinic receptors located on nerve terminals while postsynaptic muscarinic M1 receptors appear to remain largely intact. Muscarinic agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic muscarinic agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisostere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile R-(+)-(Z)-5g which is a functionally selective muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)-(Z)-5g can be rationalized in terms of the relative affinity of the compound at muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.

  DOI：

  10.1021/jm9702903
• 作为产物：
  描述：

  奎宁环-3-羧酸 在 吡啶 、 四氯化碳 、 氯化亚砜 、 三苯基膦 作用下， 以 二氯甲烷 、 氯仿 、 二甲基亚砜 、 乙腈 为溶剂， 反应 13.33h， 生成 (+/-) SKB20206
  参考文献：
  名称：

  Design of [R-(Z)]-(+)-α-(Methoxyimino)-1-azabicyclo[2.2.2]octane-3-acetonitrile (SB 202026), a Functionally Selective Azabicyclic Muscarinic M1 Agonist Incorporating the N-Methoxy Imidoyl Nitrile Group as a Novel Ester Bioisostere

  摘要：

  Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of muscarinic receptors located on nerve terminals while postsynaptic muscarinic M1 receptors appear to remain largely intact. Muscarinic agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic muscarinic agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisostere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile R-(+)-(Z)-5g which is a functionally selective muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)-(Z)-5g can be rationalized in terms of the relative affinity of the compound at muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.

  DOI：

  10.1021/jm9702903

文献信息

• Synthesis and properties of [R-(Z)]-(+)-α-(1-azabicyclo[2.2.2]oct-3-yl)-α-(methoxyimino)acetonitrile, a novel functionally selective muscarinic partial agonist
  作者：Steven M. Bromidge、Frederick Cassdiy、Michael S. G. Clark、Drake S. Eggeleston、Barry S. Oriek

  DOI：10.1039/c39940002189

  日期：——

  The (Z)-N-methoxy imidoyl nitrile functionality is a novel methyl ester bioisostere, which, when substituted onto the quinuclidine ring system gives the title compound 1, a stable, brain penetrant and fuctionally selective muscarinic partial agonist; X-ray studies confirm the configurational assignment and reveal that the imino and cyano bond lengths are consistent with those expected for formal double and triple bonds, respectively.

  (Z)-N-甲氧基酰亚胺腈官能团是一种新型的甲酯生物异构体，将其取代到喹烯酮环系统上后，就得到了标题化合物 1，这是一种稳定、脑穿透力强且具有诱导选择性的毒蕈碱类部分激动剂；X 射线研究证实了该化合物的构型分配，并发现其酰亚胺键和氰键的长度分别与正式双键和三键的预期长度一致。
• [EN] PROCESS FOR THE PREPARATION OF AZABICYCLIC DERIVATIVES<br/>[FR] PROCEDE DE PREPARATION DE DERIVES AZABICYCLIQUES
  申请人：SMITHKLINE BEECHAM PLC

  公开号：WO1995031456A1

  公开（公告）日：1995-11-23

  (EN) A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 represents (a) in which r represents an integer of 2 to 4, s represents 1 or 2 and t represents 0 or 1; R2 is a group OR4, where R4 is C1-4alkyl, C2-4alkenyl or C2-4alkynyl or a group OCOR5 where R5 is hydrogen or R4; and R3 is CN; said process comprising reacting a compound of formula (II) wherein R1' is R1 or a group convertible thereto, and R3' is an electron withdrawing group, with a source of nitrous acid, and thereafter converting the resulting =NOH group to =NR2 wherein R2 is as defined in formula (I), converting R1' and R3' when other than R1 and R3 to R1 and R3, and thereafter optionally forming a pharmaceutically acceptable salt.(FR) Procédé de préparation d'un composé répondant à la formule (I), ou de son sel pharmaceutiquement acceptable. Dans ladite formule (I), R1 représente (a), où r est un nombre entier compris entre 2 et 4, s vaut 1 ou 2 et t vaut 0 ou 1; R2 représente un groupe OR4, où R4 représente alkyle C1-4, alcényle C2-4 ou alcynyle C2-4, ou un groupe OCOR5, où R5 représente hydrogène ou R4; et R3 représente CN. Ledit procédé consiste à faire réagir un composé répondant à la formule (II), dans laquelle R1' représente R1 ou un groupe apte à être transformé en celui-ci, et R3' représente un groupe électroaccepteur, avec une source d'acide nitreux, puis à transformer le groupe =NOH ainsi obtenu en =NR2, où R2 est tel que défini dans la formule (I), à transformer R1' et R3' en R1 et R3 au cas où ils ne représenteraient pas déjà R1 et R3, et éventuellement à former un sel pharmaceutiquement acceptable.

  一种制备公式（I）化合物或其药学上可接受的盐的方法，其中R1表示（a），其中r表示2至4的整数，s表示1或2，t表示0或1；R2是OR4基团，其中R4是C1-4烷基，C2-4烯基或C2-4炔基或OCOR5基团，其中R5是氢或R4；R3是CN；所述方法包括将公式（II）化合物与一种亚硝酸源反应，其中R1'是R1或可转化为其的基团，R3'是电子吸引基团，然后将得到的=NOH基团转化为=NR2，其中R2如公式（I）中所定义，将R1'和R3'转化为R1和R3，然后选择性地形成药学上可接受的盐。
• Derivatives of quinuclidine n-oxide as muscarinic receptor ligands
  申请人：SmithKline Beecham p.l.c.

  公开号：US05675007A1

  公开（公告）日：1997-10-07

  A compound of formula (I) or a pharmaceutically acceptable salt thereof (I) wherein R.sub.1 represents (a), R.sub.2 is a group OCH.sub.3, and R.sub.3 is cyano, for use in the treatment and/or prophylaxis of dementia in mammals.

  公式（I）的化合物或其药学上可接受的盐（I），其中R.sub.1代表（a），R.sub.2是OCH.sub.3基团，R.sub.3是氰基，用于哺乳动物的痴呆症的治疗和/或预防。
• Formulation for the treatment and/or prophylaxis of dementia
  申请人：SmithKline Beecham p.l.c.

  公开号：US20020127271A1

  公开（公告）日：2002-09-12

  A pharmaceutical composition for administration to the skin, which comprises [R-(Z)]-&agr;-(methoxyimino)-&agr;-(1-azabicyclo[2.2.2]oct-3-yl)acentonitrile or a pharmaceutically acceptable salt thereof together with a suitable pharmaceutically acceptable carrier, for the treatment or prophylaxis of dementia.

  一种用于皮肤给药的药物组合物，它包含[R-(Z)]-&agr;-(甲氧基亚氨基)-&agr;-(1-氮杂双环[2.2.2]辛-3-基)戊腈或其药学上可接受的盐，以及合适的药学上可接受的载体，用于治疗或预防痴呆症。
• Method of treatment
  申请人：SmithKline Beecham Corporation & SmithKline Beecham p.l.c.

  公开号：US20020156093A1

  公开（公告）日：2002-10-24

  The use of [R-(Z)]-&agr;-(methoxyimino)-&agr;-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile or a pharmaceutically acceptable salt thereof for the treatment of psychosis or other neuropsychiatric symptoms.

  将[R-(Z)]-&agr;-(甲氧基亚氨基)-&agr;-(1-氮杂双环[2.2.2]辛-3-基)乙腈或其药学上可接受的盐用于治疗精神病或其他神经精神症状。