trans-(+)-6-acetyl-4R-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3S-ol, hemihydrate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: trans-(+)-6-acetyl-4R-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3S-ol, hemihydrate
• 英文别名: SB-204268；N-[(3S,4R)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-4-fluorobenzamide
• 化学式: C₂₀H₂₀FNO₄
• 分子量: 357.382
• InChiKey: RCLXAPJEFHPYEG-MSOLQXFVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1-((1aS,7bS)-2,2-dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]-chromen-6-yl)ethan-1-one 在 氨 、 三乙胺 作用下， 以 乙醇 为溶剂， 生成 trans-(+)-6-acetyl-4R-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3S-ol, hemihydrate
  参考文献：
  名称：

  新型反式-4-（取代的苯甲酰胺基）-3,4-二氢-2H-苯并[b]-吡喃-3-醇衍生物的合成作为潜在的具有独特结合特征的抗惊厥药。

  摘要：

  DOI：

  10.1021/jm960535w

文献信息

• Benzopyrans and their use as therapeutic agents
  申请人：SMITHKLINE BEECHAM PLC

  公开号：EP1114821A1

  公开（公告）日：2001-07-11

  Compounds selected from the group consisting of: trans-6-Acetyl-4S-(3,5-difluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, trans-6-Acetyl-4S-(2,3,4-trifuorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, trans-6-Acetyl-4S-(5-fluoro-2-methylbenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, and trans-7-Acetyl-4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol are useful in the treatment and/or prophylaxis of anxiety, mania, depression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable or preventable with anti-convulsive agents; such as epilepsy; Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease, schizophrenia and/or aggression.

  选自以下组别的化合物 反式-6-乙酰基-4S-(3,5-二氟苯甲酰氨基)-3,4-二氢-2,2-二甲基-2H-1-苯并吡喃-3R-醇、 反式-6-乙酰基-4S-(2,3,4-三氟苯甲酰氨基)-3,4-二氢-2,2-二甲基-2H-1-苯并吡喃-3R-醇、 反式-6-乙酰基-4S-(5-氟-2-甲基苯甲酰氨基)-3,4-二氢-2,2-二甲基-2H-1-苯并吡喃-3R-醇，和 反式-7-乙酰基-4-(4-氟苯甲酰氨基)-3,4-二氢-2,2-二甲基-2H-1-苯并吡喃-3-醇可用于治疗和/或预防焦虑症、躁狂症、抑郁症、与蛛网膜下腔出血或神经休克有关的失调症、与可卡因、尼古丁、酒精和苯二氮卓等滥用药物戒断有关的影响，以及可使用抗惊厥剂治疗或预防的失调症；如癫痫、帕金森病、精神病、偏头痛、脑缺血、老年痴呆症、精神分裂症和/或攻击行为。
• Trans-6-Acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol
  申请人：SMITHKLINE BEECHAM PLC

  公开号：EP1108718A2

  公开（公告）日：2001-06-20

  Compounds of formula (I) or pharmaceutically acceptable salts thereof: wherein: Y is C-R1 where R1 is methyl; R2 is hydrogen; R3 and R4 are each methyl; R5 is hydroxy; R6, R8 and R9 are each hydrogen; R7 is 4-fluorophenyl; the R8-N-CO-R7 group being trans to the R5 group; and X is oxygen are useful in the treatment and/or prophylaxis of anxiety and/or mania, and/or depression and/or the effects associated wit withdrawal from substances of above, and/or disorders treatable and/or preventable with anti-convulsive agents.

  式 (I) 的化合物或其药学上可接受的盐： 其中 Y为C-R1，其中R1为甲基；R2为氢；R3和R4各自为甲基；R5为羟基；R6、R8和R9各自为氢；R7为4-氟苯基；R8-N-CO-R7基团与R5基团反式；以及X为氧，可用于治疗和/或预防焦虑症和/或躁狂症，和/或抑郁症和/或与戒断上述物质相关的影响，和/或可使用抗惊厥剂治疗和/或预防的紊乱。
• Pharmaceutical composition containing bicyclic type compounds
  申请人：SmithKline Beecham p.l.c.

  公开号：US20010021780A1

  公开（公告）日：2001-09-13

  A compound of formula (I) or pharmaceutically acceptable salt thereof: 1 wherein: either Y is N and R 2 is hydrogen, or Y is C—R 1 where: either one of R 1 and R 2 is hydrogen and the other is selected from the class of hydrogen, C 3-8 cycloalkyl, C 1-6 alkyl optionally interrupted by oxygen or substituted by hydroxy, C 1-6 alkoxy or substituted aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, CF 3 S, or a group CF 3 —A—, where A is —CF 2 —, —CO—, —CH 2 —, CH(OH), SO 2 , SO, CH 2 —O, or CONH, or a group CF 2 H—A′-where A′ is oxygen, sulphur, SO, SO 2 , CF 2 , or CFH; trifluoromethoxy, C 1-6 alkylsulphinyl, perfluoro C 2-6 alkylsulphonyl, C 1-6 alkylsulphonyl, C 1-6 alkoxysulphinyl, C 1-6 alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulphinyl, heterarylsulphinyl, arylsulphonyl, heteroarylsulphonyl in which any aromatic moiety is optionally substituted, C 1-6 alkylcarbonylamino, C 1-6 alkoxycarbonylamino, C 1-6 alkyl-thiocarbonyl, C 1-6 alkoxy-thiocarbonyl, C 1-6 alkyl-thiocarbonyloxy, 1-mercapto C 2-7 alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C 1-6 alkyl groups, or C 1-6 alkylsulphinylamino, C 1-6 alkylsulphonylamino, C 1-6 alkoxysulphinylamino or C 1-6 alkoxysulphonylamino, or ethylenyl terminally substituted by C 1-6 alkylcarbonyl, nitro or cyano, or —C(C 1-6 alkyl)NOH or —C(C 1-6 alkyl)NNH 2 , or one of R 1 and R 2 is nitro, cyano or C 1-3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C 1-6 alkyl or by C 2-7 alkanoyl; or R 1 and R 2 together are —(CH 2 ) 4 — or —CH═CH—CH═CH—, or form an optionally substituted triazole or oxadiazole ring; one of R 3 and R 4 is hydrogen or C 1-4 alkyl and the other is C 1-4 alkyl, CF 3 or CH 2 X a where X a is fluoro, chloro, bromo, iodo, C 1-4 alkoxy, hydroxy, C 1-4 alkylcarbonyloxy, —S—C 1-4 alkyl, nitro, amino optionally substituted by one or two C 1-4 alkyl groups; cyano or C 1-4 alkoxycarbonyl or R 3 and R 4 together are C 2-5 polymethylene optionally substituted by C 1-4 alkyl; R 5 is C 1-6 alkylcarbonyloxy, benzoyloxy, ONO 2 , benzyloxy, phenyloxy or C 1-6 alkoxy and R 6 and R 9 are hydrogen or R 5 is hydroxy and R 6 is hydrogen or C 1-2 alkyl and R 9 is hydrogen; R 7 is heteroaryl or phenyl; both of which are optionally substituted one or more times independently with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, amino optionally substituted once or twice by C 1-4 alkyl, cyano, azido, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethoxy and trifluoromethyl; R 8 is hydrogen; C 1-6 alkyl, OR 9 or NHCOR 10 wherein R 9 is hydrogen, C 1-6 alkyl, formyl, C 1-6 alkanoyl, aroyl or aryl-C 1-6 alkyl and R 10 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, mono or di C 1-6 alkyl amino, amino, amino-C 1-6 alkyl, hydroxy-C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 acyloxy-C 1-6 alkyl, C 1-6 alkoxycarbonyl-C 1-6 -alkyl, aryl or heteroaryl; the R 8 —N—CO—R 7 group being cis to the R 5 group; and X is oxygen or NR 10 where R 10 is hydrogen or C 1-6 alkyl with the proviso that the compound is not racemic cis-4-benzoylamino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol.

  式 (I) 的化合物或其药学上可接受的盐： 1 其中 Y 是 N 且 R 2 是氢，或 Y 是 C-R 1 其中 R 1 和 R 2 中的一个为氢，另一个选自氢、C 3-8 环烷基 1-6 烷基，可选择被氧打断或被羟基取代，C 1-6 烷氧基或取代的氨基羰基，C 1-6 烷羰基、C 1-6 烷氧羰基、C 1-6 烷基羰氧基，C 1-6 烷氧基、硝基、氰基、卤代、三氟甲基、CF 3 S，或一个基团 CF 3 -A-，其中 A 是-CF 2 -、-CO-、-CH 2 -、CH（OH）、SO 2 、SO、CH 2 -O，或 CONH，或一个基团 CF 2 H-A′-其中 A′为氧、硫、SO、SO 2 、CF 2 或 CFH；三氟甲氧基，C 1-6 烷基亚磺酰基、全氟 C 2-6 烷基磺酰基、C 1-6 烷基磺酰基，C 1-6 烷氧基亚磺酰基，C 1-6 烷氧基磺酰基、芳基、杂芳基、芳基羰基、杂芳基羰基、膦酰基、芳基羰酰氧基、杂芳基羰酰氧基、芳基亚砜基、杂芳基亚砜基、芳基磺酰基、杂芳基磺酰基（其中任何芳香族基团均被任选取代）、C. 1-6 烷基羰基氨基、C 1-6 烷氧羰基氨基、C 1-6 烷基硫代羰基，C 1-6 烷氧基硫代羰基，C 1-6 烷基硫代羰氧基，1-巯基 C 2-7 烷基、甲酰基或氨基亚磺酰基、氨基磺酰基或氨基羰基，其中任何氨基可选择被一个或两个 C 1-6 烷基或 C 1-6 烷基亚磺酰氨基、C 1-6 烷基磺酰氨基、C 1-6 烷氧基亚磺酰氨基或 C 1-6 烷氧基磺酰基氨基，或被 C 1-6 烷基羰基、硝基或氰基取代的乙烯基，或-C(C 1-6 烷基）NOH 或-C（C 1-6 烷基）NNH 2 或 R 1 和 R 2 是硝基、氰基或 C 1-3 烷基羰基，另一个是甲氧基或氨基，任选被一个或两个 C 1-6 烷基或 C 2-7 烷酰基取代；或 R 1 和 R 2 一起是-(CH 2 ) 4 - 或-CH═CH-CH═CH-，或形成任选取代的三唑或噁二唑环； R 3 和 R 4 是氢或 C 1-4 烷基，另一个是 C 1-4 烷基、CF 3 或 CH 2 X a 其中 X a 是氟、氯、溴、碘、C 1-4 烷氧基、羟基、C 1-4 烷基羰氧基、-S-C 1-4 烷基、硝基、被一个或两个 C 1-4 烷基；氰基或 C 1-4 烷氧羰基或 R 3 和 R 4 一起是 C 2-5 可选择被 C 1-4 烷基取代； R 5 是 C 1-6 烷基羰氧基、苯甲酰氧基、ONO 2 、苄氧基、苯氧基或 C 1-6 烷氧基和 R 6 和 R 9 为氢或 R 5 是羟基，R 6 是氢或 C 1-2 烷基，R 9 是氢； R 7 是杂芳基或苯基；二者均可任选被选自氯、氟、溴、碘、硝基的基团或原子一次或多次独立取代，这些基团或原子可任选被 C 1-4 烷基、氰基、叠氮基、C 1-4 烷基、C 1-4 烷氧基、三氟甲氧基和三氟甲基； R 8 是氢；C 1-6 烷基、OR 9 或 NHCOR 10 其中 R 9 是氢、C 1-6 烷基、甲酰基、C 1-6 烷酰基、芳基或芳基-C 1-6 烷基和 R 10 是氢、C 1-6 烷基 1-6 烷氧基、单或双 C 1-6 烷基氨基、氨基、氨基-C 1-6 烷基、羟基-C 1-6 烷基、卤代-C 1-6 烷基、C 1-6 酰氧基-C 1-6 烷基、C 1-6 烷氧基羰基-C 1-6 -烷基、芳基或杂芳基； R 8 -N-CO-R 7 基团与 R 5 基团的顺式； X 是氧或 NR 10 其中 R 10 是氢或 C 1-6 烷基，但该化合物不是外消旋顺式-4-苯甲酰基氨基-6-氰基-3,4-二氢-2,2-二甲基-2H-苯并[b]吡喃-3-醇。
• Use of benzopyranols to treat neurological disorders
  申请人：——

  公开号：US20020010209A1

  公开（公告）日：2002-01-24

  Benzopyran derivatives and analogs are disclosed as useful for the treatment and/or prophylaxis of degenerative diseases such as Huntingdon's chorea, schizophrenia, neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction.

  已公开的苯并吡喃衍生物和类似物可用于治疗和/或预防退行性疾病，如亨廷顿舞蹈症、精神分裂症、与艾滋病相关的神经功能缺损、睡眠障碍（包括昼夜节律紊乱、失眠和嗜睡症）、抽搐（如Giles de la Tourette综合征）、创伤性脑损伤、耳鸣、神经痛（尤其是三叉神经痛）、神经病理性疼痛、牙痛、癌痛、颅内压增高、颅内压增高、颅内压增高、颅内压增高和颅内压增高。神经痛（尤其是三叉神经痛）、神经性疼痛、牙痛、癌痛、糖尿病、多发性硬化症和运动神经元病等疾病引起的神经元活动失调导致的神经紧张、共济失调、肌肉僵硬（痉挛）、颞下颌关节功能障碍。
• Wet milling process
  申请人：——

  公开号：US20040089753A1

  公开（公告）日：2004-05-13

  A process for preparing a finely divided preparation of a drug substance comprising wet milling a suspension of the drug substance in a mill having at least one chamber and agitation means, said chamber(s) and/or said agitation means comprising nylon, wherein the nylon comprises one or more internal lubricants results in finely divided preparations of a drug substance in which the level of grinding media contamination and process contamination are reduced.

  一种用于制备药物细化制剂的工艺，包括在具有至少一个腔室和搅拌装置的磨机中对药物悬浮液进行湿磨，所述腔室和/或所述搅拌装置包括尼龙，其中尼龙包括一种或多种内部润滑剂，从而制备出药物细化制剂，在这种制剂中，研磨介质污染和工艺污染的程度都会降低。