公开(公告)号：WO2020193448A1

公开(公告)日：2020-10-01

申请号：PCT/EP2020/057914

申请日：2020-03-23

Applicant: UNIVERSITAT DE BARCELONA

Inventor： MUÑOZ-TORRERO LÓPEZ-IBARRA, Diego ,  VÁZQUEZ CRUZ, Santiago ,  PONT MASANET, Caterina ,  CODONY GISBERT, Sandra

IPC: A61K31/4706 ,  A61P25/28 ,  C07D215/46 ,  C07D401/12

Abstract: The invention provides compounds of formula I wherein: m is 0, 1 or 2; n is 2, 3, 4 or 5; R 0 and R 1 are both H, or they form a bridge -CH 2 -C(R 4 )=CH-, R 4 being CH 3 or CH 2 CH 3 ; R 2 and R 3 independently are H, F, Cl or (C 1 -C 4 )-alkyl; R 5 is H, F, Cl, Br, I, OCH 3 , OCF 3 , SF 5 , SO 2 F, SO 2 CH 3 , NO 2 , CF 3 or (C 1 -C 4 )-alkyl; R 6 and R 7 independently are H, F, Cl, CH 3 or CF 3 ; and optionally R 5 and R 6 form a bridge -O-CH 2 -O-, R 7 being H, in vitro assays show that compounds I are simultaneously inhibitors of acetylcholinesterase and inhibitors of soluble epoxide hydrolase, and that they have a good blood-brain barrier permeability. Thus, compounds I are multitarget active pharmaceutical ingredients for the treatment of Alzheimer's disease in humans.

公开(公告)号：WO2017017048A1

公开(公告)日：2017-02-02

申请号：PCT/EP2016/067620

申请日：2016-07-25

Applicant: UNIVERSITAT DE BARCELONA

Inventor： VÁZQUEZ CRUZ, Santiago ,  VALVERDE MURILLO, Elena ,  LEIVA MARTÍNEZ, Rosana ,  VÁZQUEZ CARRERA, Manuel ,  CODONY GISBERT, Sandra

IPC: C07D405/14 ,  C07D311/96 ,  C07D405/12 ,  C07D413/12 ,  C07D417/12 ,  A61K31/352 ,  A61K31/453 ,  A61P9/12

CPC classification number: C07D311/96 ,  C07D405/12 ,  C07D405/14 ,  C07D413/12 ,  C07D417/12

Abstract: N-(2-oxaadamantan-1-yl)ureas of formula I, where R3 is H, C 1 -C 3 alkyl, cyclohexyl or phenyl; R is -[CH 2 ] n -Y; n is 0-15; in -[CH 2 ] n - 0-n/3 of the methylene groups are optionally replaced by non adjacent oxygen atoms; and Y is a 3- or 4-substituted phenyl, a 3- or 4-substituted cyclohexyl, a N-substituted piperidin-4-yl, a N-substituted piperidin-3-yl, a di- or tri-fluorosubstituted phenyl, 4-chloro-3-trifluoromethylphenyl, 3-chloro-4-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, or 3-fluoro-4-trifluoromethylphenyl; have epoxide hydrolase (sEH) inhibitory activities similar to those of their N-(adamantan-1-yl)urea analogs. Thus, compounds I are useful as API for the treatment of sEH mediated diseases. Besides, in general, compounds (I) have higher water solubilities and lower melting points, what make them more promising from the point of view of pharmacokinetics and formulation.

Abstract translation: 式I的N-（2-氧杂金刚烷-1-基）脲，其中R 3是H，C 1 -C 3烷基，环己基或苯基; R是 - [CH 2] n -Y; n为0-15; 亚甲基的 - [CH 2] n -O-N / 3任选被不相邻的氧原子取代; 并且Y是3-或4-取代的苯基，3-或4-取代的环己基，N-取代的哌啶-4-基，N-取代的哌啶-3-基，二或三氟取代的苯基， 4-氯-3-三氟甲基苯基，3-氟-4-三氟甲基苯基或3-氟-4-三氟甲基苯基; 具有与其N-（金刚烷-1-基）脲类似物类似的环氧化物水解酶（sEH）抑制活性。 因此，化合物I可用作治疗sEH介导的疾病的API。 此外，通常化合物（I）具有较高的水溶性和较低的熔点，从药代动力学和制剂的观点来看，它们更有希望。