N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide hydrochloride | 956901-23-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide hydrochloride
• 英文别名: (R)-N-[4-(1-aminoethyl)-2,6-difluorophenyl]methanesulfonamide hydrochloride；(R)-N-(4-aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide hydrochloride；[(1R)-1-[3,5-difluoro-4-(methanesulfonamido)phenyl]ethyl]azanium;chloride
• CAS: 956901-23-8
• 化学式: C₉H₁₂F₂N₂O₂S*ClH
• 分子量: 286.73
• InChiKey: XGTMJUVUJJEZAD-NUBCRITNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.78
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  80.6
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-溴-2-糠酸 、 N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide hydrochloride 在 N-甲基吗啉 、 4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 以50%的产率得到5-bromo-furan-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide
  参考文献：
  名称：

  [EN] NOVEL COMPOUNDS, ISOMER THEREOF, OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF AS VANILLOID RECEPTOR ANTAGONIST AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
  [FR] NOUVEAUX COMPOSÉS, ISOMÈRE CORRESPONDANT OU SELS PHARMACEUTIQUEMENT ACCEPTABLES CORRESPONDANTS EN TANT QU'ANTAGONISTE DU RÉCEPTEUR VANILLOÏDE ET COMPOSITIONS PHARMACEUTIQUES LES CONTENANT

  摘要：

  公开号：

  WO2010002209A3
• 作为产物：
  描述：

  4-溴-2,6-二氟苯胺 在 1,3-双(二苯基膦)丙烷 、 palladium diacetate 吡啶 、 盐酸 、 titanium(IV) tetraethanolate 、 sodium tetrahydroborate 、 potassium carbonate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 54.5h， 生成 N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide hydrochloride
  参考文献：
  名称：

  AMIDE DERIVATIVES AS ION-CHANNEL LIGANDS AND PHARMACEUTICAL COMPOSITIONS AND METHODS OF USING THE SAME

  摘要：

  披露了具有以下公式表示的化合物：公式（I）。这些化合物可以制备为药物组合物，并可用于预防和治疗包括人类在内的哺乳动物的各种疾病，例如疼痛、炎症、创伤性损伤等。

  公开号：

  US20120088746A1

文献信息

• Substituted sulfonylaminoarylmethyl cyclopropanecarboxamide as VR1 receptor antagonists
  申请人：Hanazawa Takeshi

  公开号：US20060211741A1

  公开（公告）日：2006-09-21

  This invention provides a compound of the formula (I): wherein A and B are independently CR 12 or N; D and E are each independently CR 9 or N; R 1 represents (C 1 -C 6 )alkyl; R 2 represents hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl; R 3 , R 4 , R 5 , R 6 , R 10 and R 11 each independently represent hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl; or R 3 and R 4 are taken together with the carbon atom to which they are attached to form a 3- to 7-membered carbocyclic ring or heterocyclic ring in which one or two non-adjacent carbon atoms are optionally replaced by an oxygen atom, a sulfur atom or NH; R 7 and R 9 each independently represent hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, NH 2 , [(C 1 -C 6 )alkyl]NH—, [(C 1 -C 6 )alkyl] 2 N—, H 2 N—(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-NH—(C 1 -C 6 )alkoxy, [(C 1 -C 6 )alkyl] 2 N(C 1 -C 6 )alkoxy; H 2 N—(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, (C 1 C 6 )alkyl-NH—(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, [(C 1 -C 6 )alkyl] 2 N(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl or 5- or 6-membered heterocyclic ring containing at least one nitrogen atom; R 8 represents halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkylsulfonyl, halo(C 1 -C 6 )alkylsulfinyl, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkylthio, [(C 1 -C 6 )alkyl]NH— or [(C 1 -C 6 )alkyl] 2 N—; or R 7 and R 8 , when E is CR 9 , are taken together with the carbon atoms to which they are attached form a 5-8 membered carbocyclic or heterocyclic ring, in which one or two non-adjacent carbon atoms are optionally replaced by oxygen, sulfur, N or NH groups, wherein the carbocyclic ring or the heterocyclic ring is unsubstituted or substituted with one or more substituents each independently selected from the group consisting of hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and hydroxy(C 1 -C 6 )alkyl; and R 12 represents hydrogen, halogen, (C 1 -C 6 )alkyl or hydroxy(C 1 -C 6 )alkyl; or a pharmaceutically acceptable salt or solvate thereof. These compounds are useful for the treatment of disease conditions caused by overactivation of VR1 receptor such of pain, or the like in mammalian. This invention also provides a pharmaceutical composition comprising the above compound.

  这项发明提供了一个化合物的结构式(I)：其中A和B分别独立地为CR12或N；D和E分别独立地为CR9或N；R1代表(C1-C6)烷基；R2代表氢、卤素、羟基、(C1-C6)烷基、卤代(C1-C6)烷基、羟基(C1-C6)烷基、(C1-C6)氧烷基或(C1-C6)氧烷基-(C1-C6)烷基；R3、R4、R5、R6、R10和R11分别独立地代表氢、卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C1-C6)氧烷基、羟基(C1-C6)烷基或(C1-C6)氧烷基-(C1-C6)烷基；或者R3和R4一起与它们连接的碳原子形成一个3-至7-成员的碳环或杂环，其中一个或两个非相邻的碳原子可以选择性地被氧原子、硫原子或NH取代；R7和R9分别独立地代表氢、卤素、(C1-C6)烷基、卤代(C1-C6)烷基、羟基(C1-C6)烷基、(C1-C6)氧烷基、羟基(C1-C6)氧烷基、(C1-C6)氧烷基-(C1-C6)烷基、(C1-C6)氧烷基-(C1-C6)氧烷基、(C1-C6)烷基硫、(C1-C6)烷基亚硫基、(C1-C6)烷基磺基、NH2、[(C1-C6)烷基]NH—、[(C1-C6)烷基]2N—、H2N—(C1-C6)氧烷基、(C1-C6)烷基-NH—(C1-C6)氧烷基、[(C1-C6)烷基]2N(C1-C6)氧烷基；H2N—(C1-C6)氧烷基-(C1-C6)烷基、(C1C6)烷基-NH—(C1-C6)氧烷基-(C1-C6)烷基、[(C1-C6)烷基]2N(C1-C6)氧烷基-(C1-C6)烷基或含有至少一个氮原子的5-或6-成员杂环，R8代表卤素、(C1-C6)烷基、卤代(C1-C6)烷基、羟基(C1-C6)烷基、(C1-C6)氧烷基、羟基(C1-C6)氧烷基、(C1-C6)氧烷基-(C1-C6)烷基、(C1-C6)氧烷基-(C1-C6)氧烷基、卤代(C1-C6)烷基磺基、卤代(C1-C6)烷基亚硫基、卤代(C1-C6)烷基氧基、卤代(C1-C6)烷基硫基、[(C1-C6)烷基]NH—或[(C1-C6)烷基]2N—；或者当E为CR9时，R7和R8一起与它们连接的碳原子形成一个5-8成员的碳环或杂环，其中一个或两个非相邻的碳原子可以选择性地被氧、硫、N或NH基团取代，其中碳环或杂环未取代或取代有一个或多个取代基，每个取代基独立地选自羟基、(C1-C6)烷基、(C1-C6)氧烷基和羟基(C1-C6)烷基；R12代表氢、卤素、(C1-C6)烷基或羟基(C1-C6)烷基；或其药学上可接受的盐或溶剂。这些化合物对于治疗由VR1受体过度激活引起的疾病状况，如哺乳动物中的疼痛等，是有用的。这项发明还提供了包含上述化合物的药物组合物。
• CHIRAL RESOLUTION METHOD OF N-[4-(1-AMINOETHYL)-PHENYL]-SULFONAMIDE DERIVATIVES
  申请人：AMOREPACIFIC CORPORATION

  公开号：US20170342027A1

  公开（公告）日：2017-11-30

  The present specification relates to a chiral resolution method of a stereoisomer mixture, comprising a step of mixing a stereoisomer mixture of compounds, in which an amine group is bound to an asymmetric carbon atom, with a chiral auxiliary and salt-forming auxiliary compound, wherein the chiral auxiliary is an O,O′-diacyltartaric acid derivative, more specifically, a 2,3-dibenzoyl-tartaric acid or O,O′-di-p-toluoyl tartaric acid, the salt-forming auxiliary compound is mandelic acid or camphorsulfonic acid, and an optical isomer having a high level of optical purity can be obtained by using the method. Therefore, according to one aspect of the present invention, the method can be useful in pharmaceutical or cosmetic field when preparing an optical isomer having a high optical purity.

  本规范涉及一种手性分离方法，包括以下步骤：将含有胺基与不对称碳原子结合的化合物的立体异构物混合物与手性辅助剂和盐形成辅助剂混合，其中手性辅助剂是O,O′-二酰基酒石酸衍生物，更具体地说是2,3-二苯乙酰酒石酸或O,O′-二对甲苯酰酒石酸，盐形成辅助剂是苯甲酸或藿香磺酸，通过使用该方法可以获得具有高光学纯度的光学异构体。因此，根据本发明的一个方面，在制备具有高光学纯度的光学异构体时，该方法在制药或化妆品领域中可能是有用的。
• METHOD FOR PREPARING (R)-N-[4-(1-AMINO-ETHYL)-2,6-DIFLUORO-PHENYL]-METHANESULFONAMIDE
  申请人：AMOREPACIFIC CORPORATION

  公开号：US20200031766A1

  公开（公告）日：2020-01-30

  Disclosed in the present specification is a method capable of preparing N-[4-[(1R)-1-[[(R)-(1,1-dimethylethyl)sulfinyl]amino]ethyl]-2,6-difluorophenyl]-methanesulfonamide (INT028-2) with high optical purity, through the selection of Ellman-chiral auxiliaries and the re-crystallization and separation of optical isomers. According to the above method, high-purity N-[4-[(1R)-1-[[(R)-(1,1-dimethylethyl)sulfinyl]amino]ethyl]-2,6-difluorophenyl]-methanesulfonamide with excellent quality can be produced at room temperature by improving cryogenic process conditions necessary for realizing high optical purity, and thus the trimming due to the process failure rate can be remarkably reduced.

  本说明书公开了一种方法，通过选择Ellman手性辅助剂和光学异构体的重结晶和分离，能够制备具有高光学纯度的N-[4-[(1R)-1-[[(R)-(1,1-二甲基乙基)亚磺酰基]氨基]乙基]-2,6-二氟苯基]-甲磺酰胺（INT028-2）。根据上述方法，在改善实现高光学纯度所必需的低温过程条件的情况下，可以在室温下生产具有优异质量的高纯度N-[4-[(1R)-1-[[(R)-(1,1-二甲基乙基)亚磺酰基]氨基]乙基]-2,6-二氟苯基]-甲磺酰胺，从而可以显着降低由于工艺失效率而导致的修剪。
• SUBSTITUTED SULFONYLAMINOARYLMETHYL CYCLOPROPANECARBOXAMIDE AS VR1 RECEPTOR ANTAGONISTS
  申请人：HANAZAWA TAKESHI

  公开号：US20100035880A1

  公开（公告）日：2010-02-11

  This invention provides a compound of the formula (I): wherein A and B are independently CR 12 or N; D and E are each independently CR 9 or N; R 1 represents (C 1 -C 6 )alkyl; R 2 represents hydrogen, halogen, hydroxy, (C 1 -C 6 ) alkyl, halo(C 1 -C 6 ) alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl; R 3 , R 4 , R 5 , R 6 , R 10 and R 11 each independently represent hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl; or R 3 and R 4 are taken together with the carbon atom to which they are attached to form a 3- to 7-membered carbocyclic ring or heterocyclic ring in which one or two non-adjacent carbon atoms are optionally replaced by an oxygen atom, a sulfur atom or NH; R 7 and R 9 each independently represent hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, NH 2 , [(C 1 -C 6 )alkyl]NH—, [(C 1 -C 6 )alkyl] 2 N—, H 2 N—(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-NH—(C 1 -C 6 )alkoxy, [(C 1 -C 6 )alkyl] 2 N(C 1 -C 6 )alkoxy; H 2 N—(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-NH—(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, [(C 1 -C 6 )alkyl] 2 N(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl or 5- or 6-membered heterocyclic ring containing at least one nitrogen atom; R 8 represents halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkoxy, (C 1 -C 8 )alkoxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkylsulfonyl, halo(C 1 -C 6 )alkylsulfinyl, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkylthio, [(C 1 -C 6 )alkyl]NH— or [(C 1 -C 6 )alkyl] 2 N—; or R 7 and R 8 , when E is CR 9 , are taken together with the carbon atoms to which they are attached form a 5-8 membered carbocyclic or heterocyclic ring, in which one or two non-adjacent carbon atoms are optionally replaced by oxygen, sulfur, N or NH groups, wherein the carbocyclic ring or the heterocyclic ring is unsubstituted or substituted with one or more substituents each independently selected from the group consisting of hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and hydroxy(C 1 -C 6 )alkyl; and R 12 represents hydrogen, halogen, (C 1 -C 6 )alkyl or hydroxy(C 1 -C 6 )alkyl; or a pharmaceutically acceptable salt or solvate thereof. These compounds are useful for the treatment of disease conditions caused by overactivation of VR1 receptor such of pain, or the like in mammalian. This invention also provides a pharmaceutical composition comprising the above compound.

  本发明提供了一种公式（I）的化合物：其中A和B分别独立表示CR12或N; D和E分别独立表示CR9或N; R1表示（C1-C6）烷基; R2表示氢，卤素，羟基，（C1-C6）烷基，卤代（C1-C6）烷基，羟基（C1-C6）烷基，（C1-C6）氧烷基或（C1-C6）氧烷基-（C1-C6）烷基; R3、R4、R5、R6、R10和R11分别独立表示氢，卤素，（C1-C6）烷基，卤代（C1-C6）烷基，（C1-C6）氧烷基，羟基（C1-C6）烷基或（C1-C6）氧烷基-（C1-C6）烷基; 或R3和R4与它们所附着的碳原子一起形成3-至7-成员的碳环或杂环，其中一个或两个非相邻的碳原子可以选择地被氧原子，硫原子或NH代替; R7和R9分别独立表示氢，卤素，（C1-C6）烷基，卤代（C1-C6）烷基，羟基（C1-C6）烷基，（C1-C6）氧烷基，羟基（C1-C6）氧烷基，（C1-C6）氧烷基-（C1-C6）烷基，（C1-C6）氧烷基-（C1-C6）氧烷基，（C1-C6）烷基硫，（C1-C6）烷基亚磺酰基，（C1-C6）烷基磺酰基，NH2，[(C1-C6)烷基] NH-，[(C1-C6)烷基] 2N-，H2N-（C1-C6）氧烷基，（C1-C6）烷基-NH-（C1-C6）氧烷基，[(C1-C6)烷基] 2N（C1-C6）氧烷基; H2N-（C1-C6）氧烷基-（C1-C6）烷基，（C1-C6）烷基-NH-（C1-C6）氧烷基-（C1-C6）烷基，[(C1-C6)烷基] 2N（C1-C6）氧烷基-（C1-C6）烷基或含有至少一个氮原子的5-或6-成员杂环，R8表示卤素，（C1-C6）烷基，卤代（C1-C6）烷基，羟基（C1-C6）烷基，（C1-C6）氧烷基，羟基（C1-C6）氧烷基，（C1-C8）氧烷基-（C1-C6）烷基，（C1-C6）氧烷基-（C1-C6）氧烷基，卤代（C1-C6）烷基磺酰基，卤代（C1-C6）烷基亚磺酰基，卤代（C1-C6）氧烷基，卤代（C1-C6）烷基硫，[(C1-C6)烷基] NH-或[(C1-C6)烷基] 2N-; 或者当E为CR9时，R7和R8与它们所附着的碳原子一起形成5-8成员的碳环或杂环，其中一个或两个非相邻的碳原子可以选择地被氧，硫，N或NH基团代替，其中碳环或杂环未被取代或被一个或多个取代基取代，每个取代基独立地选择自羟基，（C1-C6）烷基，（C1-C6）氧烷基和羟基（C1-C6）烷基; R12表示氢，卤素，（C1-C6）烷基或羟基（C1-C6）烷基; 或其药学上可接受的盐或溶剂。这些化合物对于治疗由VR1受体过度激活引起的疾病状况，如哺乳动物中的疼痛等非常有用。本发明还提供了包含上述化合物的药物组成物。
• NOVEL COMPOUNDS, ISOMER THEREOF, OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF AS VANILLOID RECEPTOR ANTAGONIST; AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
  申请人：Amorepacific Corporation

  公开号：US20140011881A1

  公开（公告）日：2014-01-09

  This present disclosure relates to novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor (Vanilloid Receptor 1; VR1; TRPV1) antagonist; and a pharmaceutical composition containing the same. The present disclosure provides a pharmaceutical composition for preventing or treating a disease such as pain, migraine, arthralgia, neuralgia, neuropathies, nerve injury, skin disorder, urinary bladder hypersensitiveness, irritable bowel syndrome, fecal urgency, a respiratory disorder, irritation of skin, eye or mucous membrane, stomach-duodenal ulcer, inflammatory diseases, ear disease, heart disease and so on.

  本公开涉及新化合物、其异构体或其药学上可接受的盐作为vanilloid受体（Vanilloid Receptor 1；VR1；TRPV1）拮抗剂；以及含有相同化合物的药物组合物。本公开提供了一种用于预防或治疗疾病的药物组合物，例如疼痛、偏头痛、关节痛、神经痛、神经病、神经损伤、皮肤疾病、膀胱过敏、肠易激综合征、粪便紧急情况、呼吸系统疾病、皮肤、眼睛或粘膜刺激、胃十二指肠溃疡、炎症性疾病、耳病、心脏疾病等等。