N'-(2,4-difluorophenyl)-N-(3,3-dimethyl-5-hydroxypentyl)-N-heptylurea | 139878-67-4

• 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'-(2,4-difluorophenyl)-N-(3,3-dimethyl-5-hydroxypentyl)-N-heptylurea
• 英文别名: 3-(2,4-difluorophenyl)-1-heptyl-1-(5-hydroxy-3,3-dimethylpentyl)urea
• CAS: 139878-67-4
• 化学式: C₂₁H₃₄F₂N₂O₂
• 分子量: 384.51
• InChiKey: JZCWGFHZHSQRMP-UHFFFAOYSA-N

物化性质

• 沸点：
  507.8±50.0 °C(Predicted)
• 密度：
  1.097±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  27
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  52.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N'-(2,4-difluorophenyl)-N-(3,3-dimethyl-5-hydroxypentyl)-N-heptylurea 在 四溴化碳 、 sodium hydride 、 三苯基膦 作用下， 以 二氯甲烷 为溶剂， 反应 5.0h， 生成 N'-(2,4-difluorophenyl)-N-<3,3-dimethyl-5-<(4,5-diphenyl-1H-imidazol-2-yl)thio>pentyl>-N-heptylurea
  参考文献：
  名称：

  酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂：一系列新的三取代咪唑的合成及结构活性关系研究。

  摘要：

  已经合成了一系列的4,5-二芳基-2-（取代硫代）-1H-咪唑，并被证明是酰基辅酶A：胆固醇酰基转移酶（ACAT）的有效抑制剂。本文报道了该系列的设计，合成和结构活性关系。该系列的化合物之一，N'-（2,4-二氟苯基）-N- [5-[（4,5-二芳基-1H-咪唑-2-基）硫代]戊基] -N-庚基脲（DuP 128）被选作肠道活性ACAT抑制剂进行开发。DuP 128是一种有效的体外和体内ACAT抑制剂，可抑制大鼠肝微粒体中的ACAT，IC50 = 10 nM，并且在体内具有有效的抗高胆固醇血症活性。

  DOI：

  10.1021/jm00047a009
• 作为产物：
  描述：

  4,4-dimethyl-tetrahydro-pyran-2-one 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 、 二氯甲烷 、 甲苯 为溶剂， 反应 37.0h， 生成 N'-(2,4-difluorophenyl)-N-(3,3-dimethyl-5-hydroxypentyl)-N-heptylurea
  参考文献：
  名称：

  酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂：一系列新的三取代咪唑的合成及结构活性关系研究。

  摘要：

  已经合成了一系列的4,5-二芳基-2-（取代硫代）-1H-咪唑，并被证明是酰基辅酶A：胆固醇酰基转移酶（ACAT）的有效抑制剂。本文报道了该系列的设计，合成和结构活性关系。该系列的化合物之一，N'-（2,4-二氟苯基）-N- [5-[（4,5-二芳基-1H-咪唑-2-基）硫代]戊基] -N-庚基脲（DuP 128）被选作肠道活性ACAT抑制剂进行开发。DuP 128是一种有效的体外和体内ACAT抑制剂，可抑制大鼠肝微粒体中的ACAT，IC50 = 10 nM，并且在体内具有有效的抗高胆固醇血症活性。

  DOI：

  10.1021/jm00047a009

文献信息

• Use of imidazoles for the treatment of atherosclerosis
  申请人：Du Pont Merck Pharmaceutical Company

  公开号：US05166214A1

  公开（公告）日：1992-11-24

  This invention relates to imidazoles as inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT), processes for their preparation, and their use as antihypercholesterolemic agents or antiatherosclerotic. The compounds for use in the described method are compounds of Formula (I): ##STR1## wherein R.sup.1 and R.sup.2 are selected independently from H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl, phenyl optionally substituted with 1 to 3 groups selected from F, Cl, Br, OH, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, CH.sub.3 S(O).sub.r, NO.sub.2, CF.sub.3, or NR.sup.7 R.sup.8 ; R.sup.3 is H, C.sub.1 -C.sub.6 alkyl, allyl, benzyl, or phenyl optionally substituted with F, Cl, CH.sub.3, CH.sub.3 O, or CF.sub.3 ; R.sup.4 is straight chain C.sub.1 -C.sub.8 alkyl optionally substituted with F; C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 aralkyl where the aryl group is optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; C.sub.3 -C.sub.6 alkenyl or alkynyl, C.sub.1 -C.sub.3 perfluoroalkyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.1 -C.sub.4, alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NCOR.sup.7 ; pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; 2-, 3-, or 4- or pyrindinyl, pyrimidinyl, or biphenyl; R.sup.5 is H, C.sub.1 -C.sub.6 alkyl, or benzyl; R.sup.6 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.8 alkenyl of alkynyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; R.sup.7 and R.sup.8 are selected independently from H or C.sub.1 -C.sub.4 alkyl; A is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 branched alkyl, C.sub.3 -C.sub.10 alkenyl, or C.sub.3 -C.sub.10 alkynyl; Y is O; Z is NHR.sup.4, OR.sup.4, or R.sup.4 ; r is 0-2, or a pharmaceutically acceptable salt thereof.

  本发明涉及咪唑类化合物作为酰基辅酶A：胆固醇酰基转移酶（ACAT）的抑制剂，其制备方法以及它们作为抗高胆固醇和抗动脉粥样硬化剂的用途。所述方法中使用的化合物为式（I）的化合物：其中R.sup.1和R.sup.2独立选择自H，C.sub.1-C.sub.8烷基，C.sub.3-C.sub.8支链烷基，C.sub.3-C.sub.7环烷基，C.sub.4-C.sub.10环烷基烷基，C.sub.7-C.sub.14 araalkyl，苯基，可选地被1到3个选自F，Cl，Br，OH，C.sub.1-C.sub.4烷氧基，C.sub.1-C.sub.4烷基，C.sub.3-C.sub.8支链烷基，CH.sub.3S（O）.sub.r，NO.sub.2，CF.sub.3或NR.sup.7R.sup.8的基团取代；R.sup.3为H，C.sub.1-C.sub.6烷基，烯丙基，苄基或可选地被F，Cl，CH.sub.3，CH.sub.3O或CF.sub.3取代的苯基；R.sup.4为直链C.sub.1-C.sub.8烷基，可选地被F取代的C.sub.3-C.sub.8支链烷基，C.sub.3-C.sub.7环烷基，C.sub.4-C.sub.10环烷基烷基，C.sub.7-C.sub.14 aralkyl，其中芳基基团可选地被1到3个选自C.sub.1-C.sub.4烷基或烷氧基，F，Br，Cl，NH.sub.2，OH，CN，CO.sub.2H，CF.sub.3，NO.sub.2，C.sub.1-C.sub.4羧烷氧基，NR.sup.7R.sup.8或NCOR.sup.7的基团取代；C.sub.3-C.sub.6烯基或炔基，C.sub.1-C.sub.3全氟烷基，可选地被1到3个选自C.sub.1-C.sub.4烷基，C.sub.3-C.sub.8支链烷基，C.sub.1-C.sub.4烷氧基，F，Br，Cl，NH.sub.2，OH，CN，CO.sub.2H，CF.sub.3，NO.sub.2，C.sub.1-C.sub.4羧烷氧基，NR.sup.7R.sup.8或NCOR.sup.7的基团取代的苯基；五氟苯基，可选地被1到3个选自C.sub.1-C.sub.4烷基或烷氧基，F，Br，Cl，NH.sub.2，OH，CN，CO.sub.2H，CF.sub.3，NO.sub.2，C.sub.1-C.sub.4羧烷氧基，NR.sup.7R.sup.8或NCOR.sup.7的基团取代的苄基；2-，3-或4-吡啶基，嘧啶基或联苯基；R.sup.5为H，C.sub.1-C.sub.6烷基或苄基；R.sup.6为C.sub.1-C.sub.8烷基，可选地被C.sub.3-C.sub.8支链烷基，C.sub.3-C.sub.7环烷基，C.sub.3-C.sub.8烯基或炔基，可选地被1到3个选自C.sub.1-C.sub.4烷基或烷氧基，F，Br，Cl，NH.sub.2，OH，CN，CO.sub.2H，CF.sub.3，NO.sub.2，C.sub.1-C.sub.4羧烷氧基，NR.sup.7R.sup.8或NCOR.sup.7的基团取代的苯基，五氟苯基，可选地被1到3个选自C.sub.1-C.sub.4烷基或烷氧基，F，Br，Cl，NH.sub.2，OH，CN，CO.sub.2H，CF.sub.3，NO.sub.2，C.sub.1-C.sub.4羧烷氧基，NR.sup.7R.sup.8或NCOR.sup.7的基团取代的苄基；R.sup.7和R.sup.8独立选择自H或C.sub.1-C.sub.4烷基；A为C.sub.2-C.sub.10烷基，C.sub.3-C.sub.10支链烷基，C.sub.3-C.sub.10烯基或C.sub.3-C.sub.10炔基；Y为O；Z为NHR.sup.4，OR.sup.4或R.sup.4；r为0-2，或其药学上可接受的盐。
• Imidazoles for the treatment of atherosclerosis
  申请人：The Du Pont Merck Pharmaceutical Company

  公开号：US05318984A1

  公开（公告）日：1994-06-07

  Disclosed are compounds of the formula ##STR1## wherein R.sup.1 and R.sup.2 are selected independently from H, C.sub.1 -C.sub.8 unbranched alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl, 2-, 3- or 4-pyridinyl, 2-thienyl, 2-furanyl, phenyl optionally substituted with 1 to 3 groups selected from F, Cl, Br, OH, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, CH.sub.3 S(O).sub.r, NO.sub.2, CF.sub.3, or NR.sup.7 R.sup.8 ; or ##STR2## where L is O, O(CH.sub.2).sub.m+1 O, or (CH.sub.2).sub.m where m is 0-4; R.sup.3 is H, C.sub.1 -C.sub.6 alkyl, allyl, benzyl, or phenyl optionally substituted with F, Cl, CH.sub.3, CH.sub.3 O, or CF.sub.3 ; R.sup.4 is straight chain C.sub.1 -C.sub.8 alkyl optionally substituted with F; C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl where the aryl group is optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; C.sub.3 --C.sub.6 alkenyl or alkynyl, C.sub.1 -C.sub.3 perfluoroalkyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.1 -C.sub.4 alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NCOR.sup.7 ; pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, pyrimidinyl, or biphenyl; R.sup.5 is H, C.sub.1 -C.sub.6 alkyl, or benzyl; R.sup.6 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.8 alkenyl or alkynyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; R.sup.7 and R.sup.8 are selected independently from H or C.sub.1 -C.sub.4 alkyl; X is S(O).sub.r, O, NR.sup.5, CH.sub.2 ; A is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 branched alkyl, C.sub.3 -C.sub.10 alkenyl, or C.sub.3 -C.sub.10 alkynyl; Y is O, S, H.sub.2, or NH; Z is NHR.sup.4, OR.sup.4, or R.sup.4 ; r is 0-2, or a pharmaceutically acceptable salt thereof and their use as antihypercholesterolemic agents or antiatherosclerotic agents.

  本发明涉及的化合物的结构式为：##STR1##其中R.sup.1和R.sup.2独立选择自H，C.sub.1-C.sub.8直链烷基，C.sub.3-C.sub.8支链烷基，C.sub.3-C.sub.7环烷基，C.sub.4-C.sub.10环烷基烷基，C.sub.7-C.sub.14 araalkyl，2-、3-或4-吡啶基，2-噻吩基，2-呋喃基，苯基，其可选地被1至3个选自F、Cl、Br、OH、C.sub.1-C.sub.4烷氧基、C.sub.1-C.sub.4烷基、C.sub.3-C.sub.8支链烷基、CH.sub.3S(O).sub.r、NO.sub.2、CF.sub.3或NR.sup.7R.sup.8的基取代；或##STR2##其中L为O、O(CH.sub.2).sub.m+1O或(CH.sub.2).sub.m，其中m为0-4；R.sup.3为H、C.sub.1-C.sub.6烷基、烯丙基、苄基或其可选地被F、Cl、CH.sub.3、CH.sub.3O或CF.sub.3取代的苯基；R.sup.4为直链C.sub.1-C.sub.8烷基，其可选地被F取代；C.sub.3-C.sub.8支链烷基，C.sub.3-C.sub.7环烷基，C.sub.4-C.sub.10环烷基烷基，C.sub.7-C.sub.14 araalkyl，其中芳基基团可选地被1至3个选自C.sub.1-C.sub.4烷基或烷氧基、F、Br、Cl、NH.sub.2、OH、CN、CO.sub.2H、CF.sub.3、NO.sub.2、C.sub.1-C.sub.4羧烷氧基、NR.sup.7R.sup.8或NCOR.sup.7的基取代；C.sub.3-C.sub.6烯基或炔基，C.sub.1-C.sub.3全氟烷基，其可选地被1至3个选自C.sub.1-C.sub.4烷基、C.sub.3-C.sub.8支链烷基、C.sub.1-C.sub.4烷氧基、F、Br、Cl、NH.sub.2、OH、CN、CO.sub.2H、CF.sub.3、NO.sub.2、C.sub.1-C.sub.4羧烷氧基、NR.sup.7R.sup.8或NCOR.sup.7的基取代的苯基；五氟苯基，其可选地被1至3个选自C.sub.1-C.sub.4烷基或烷氧基、F、Br、Cl、NH.sub.2、OH、CN、CO.sub.2H、嘧啶基或联苯基的基取代的苄基；R.sup.5为H、C.sub.1-C.sub.6烷基或苄基；R.sup.6为C.sub.1-C.sub.8烷基，C.sub.3-C.sub.8支链烷基，C.sub.3-C.sub.7环烷基，C.sub.3-C.sub.8烯基或炔基，其可选地被1至3个选自C.sub.1-C.sub.4烷基或烷氧基、F、Br、Cl、NH.sub.2、OH、CN、CO.sub.2H、CF.sub.3、NO.sub.2、C.sub.1-C.sub.4羧烷氧基、NR.sup.7R.sup.8或NCOR.sup.7的基取代的苯基；五氟苯基，其可选地被1至3个选自C.sub.1-C.sub.4烷基或烷氧基、F、Br、Cl、NH.sub.2、OH、CN、CO.sub.2H、CF.sub.3、NO.sub.2、C.sub.1-C.sub.4羧烷氧基、NR.sup.7R.sup.8或NCOR.sup.7的基取代的苄基；R.sup.7和R.sup.8独立选择自H或C.sub.1-C.sub.4烷基；X为S(O).sub.r、O、NR.sup.5、CH.sub.2；A为C.sub.2-C.sub.10烷基，C.sub.3-C.sub.10支链烷基，C.sub.3-C.sub.10烯基或C.sub.3-C.sub.10炔基；Y为O、S、H.sub.2或NH；Z为NHR.sup.4、OR.sup.4或R.sup.4；r为0-2或其药学上可接受的盐，以及它们作为抗高胆固醇药物或抗动脉粥样硬化药物的用途。
• US5166214A
  申请人：——

  公开号：US5166214A

  公开（公告）日：1992-11-24
• US5318984A
  申请人：——

  公开号：US5318984A

  公开（公告）日：1994-06-07
• [EN] IMIDAZOLES FOR THE TREATMENT OF ATHEROSCLEROSIS
  申请人：THE DU PONT MERCK PHARMACEUTICAL COMPANY

  公开号：WO1991018885A1

  公开（公告）日：1991-12-12

  (EN) This invention relates to imidazoles as inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT), processes for their preparation, and their use as antihypercholesterolemic agents or antiatherosclerotic.(FR) Cette invention se rapporte aux imidazoles comme inhibiteurs d'acyle-CoA: acyl transférase de cholestérol (ACAT), des procédés de préparation de ces imidazoles, et leur utilisation comme agents anti-hypercholestérolémiques ou antiathérosclérotiques.