Analogs of adamantylureas as soluble epoxide hydrolase inhibitors

An alkyl, compound technology, applied in the field of analogs of adamantyl urea as a soluble epoxidase inhibitor, can solve the problems of low water solubility, lack of selectivity, chemical and metabolic instability, etc.

Inactive Publication Date: 2018-07-31
UNIV DE BARCELONA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some R&D limitations are: lack of selectivity, chemical and metabolic instability, and inappropriate physical properties, especially low aqueous solubility

Method used

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  • Analogs of adamantylureas as soluble epoxide hydrolase inhibitors
  • Analogs of adamantylureas as soluble epoxide hydrolase inhibitors
  • Analogs of adamantylureas as soluble epoxide hydrolase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1a

[0084] Example 1a: Preparation of 1-(2-oxaadamantan-1-yl)-3-(2,3,4-trifluorophenyl)urea, I a

[0085]

[0086] In a round bottom flask equipped with a stir bar, 1.2 eq. of (2-oxaadamantan-1-yl)amine hydrochloride was added to anh. dichloromethane (DCM) (-110 mM) under nitrogen atmosphere. To this suspension was added 1.0 eq. of 2,3,4-trifluorophenylisocyanate followed by 7 eq. of triethylamine (TEA). The reaction mixture was stirred overnight at room temperature. The solvent was then removed under vacuum and the resulting crude product (SiO 2 , hexane / ethyl acetate mixture), and evaporation of the appropriate fractions in vacuo afforded urea I as a white solid a(163 mg, 94% yield), mp 196-198°C. IR (ATR): 3300-2800 (3293, 3232, 3127, 2933, 2857), 1702, 1640, 1621, 1563, 1509, 1489, 1471, 1446, 1373, 1349, 1340, 1317, 1294, 1257, 1239, 1227, 1200, 1165, 1117, 1099, 1080, 1020, 996, 976, 963, 932, 912, 884, 840, 805, 788, 757, 683, 653cm -1 . MS(DIP), m / e(%): 179(11), ...

Embodiment 1b

[0087] Example 1b: Preparation of 1-(3-methyl-2-oxaadamantan-1-yl)-3-(2,3,4-trifluorophenyl)urea, I b

[0088]

[0089] Using (3-methyl-2-oxaadamantan-1-yl)amine in a procedure analogous to one of the examples 1a, the title compound was obtained in 93% yield. Mp 195-197°C. IR (ATR): 3300-2800 (3270, 3227, 3128, 2976, 2927, 2856), 1701, 1641, 1622, 1564, 1509, 1492, 1471, 1373, 1341, 1322, 1301, 1286, 1256, 1228, 1213, 1200, 1171, 1136, 1106, 1090, 1072, 1034, 1006, 991, 972, 959, 921, 899, 885, 804, 788, 755, 682, 670, 652cm -1 . MS(DIP), m / e(%): 172(13), 150(14), 149(100), 148(80), 147(25), 109(10), 108(14), 107(11 ), 95(10), 93(25). Analytical Computing C 17 h 19 f 3 N 2 o 2 0.05H 2 O: C 59.84, H 5.64, F 16.70, N 8.21. Found: C 59.91, H 5.90, F 16.52, N 8.22.

Embodiment Ic

[0090] Example Ic: Preparation of 1-(3-ethyl-2-oxaadamantan-1-yl)-3-(2,3,4-trifluorophenyl)urea, I c

[0091]

[0092] Using (3-ethyl-2-oxaadamantan-1-yl)amine in a procedure analogous to one of the examples 1a, the title compound was obtained in 96% yield. Mp 165-166°C. IR (ATR): 3300-2800 (3288, 3238, 3128, 2970, 2927, 2850), 1702, 1641, 1622, 1563, 1509, 1471, 1371, 1341, 1322, 1301, 1254, 1227, 1209, 1172, 1091, 1010, 996, 965, 939, 921, 896, 803, 788, 755, 669, 653cm -1 . MS (DIP), m / e (%): 354 (M ·+ , 5), 148(14), 146(100), 94(10), 93(10). Analytical Computing C 18 h 21 f 3 N 2 o 2 • 0.01 EtOAc: C 60.99, H 5.98, F 16.04, N 7.89. Found: C 60.97, H 6.06, F 16.23, N 7.84.

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Abstract

N-(2-oxaadamantan-1-yl)ureas of formula I, where R3 is H, C1-C3 alkyl, cyclohexyl or phenyl; R is -[CH2]n -Y; n is 0-15; in -[CH2]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 thoseof 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.

Description

[0001] The present invention relates to the field of pharmaceuticals for human and veterinary medicine, in particular to soluble cyclooxygenase (sEH) inhibitors and their therapeutic indications. Background technique [0002] A total of more than 100 patent publications have described multiple classes of sEH inhibitors based on different chemical structures, such as amides, thioamides, ureas, thioureas, carbamates, acylhydrazones, and chalcone oxides (see e.g. H.C. Shen , "Solubleepoxide hydrolase inhibitors: a patent review", Expert.Opin.Ther.Patents 2010, vol.20, pp.941-956, review with 149 references). sEH inhibition has been associated with various beneficial biological effects, which can be understood for hypertension, atherosclerosis, lung disease, kidney disease, stroke, pain, neuropathic pain, inflammation, pancreatitis, immune disorders, Eye disease, cancer, obesity, diabetes, metabolic syndrome, preeclampsia, anorexia nervosa, depression, erectile dysfunction, wound ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D311/96C07D405/12C07D413/12C07D417/12A61K31/352A61K31/453A61P9/12
CPCA61P9/10A61P9/12C07D311/96C07D405/12C07D405/14C07D413/12C07D417/12A61K31/35A61K31/453A61K31/352C07D493/08
Inventor S·巴兹克斯克鲁斯E·巴尔韦德穆里洛R·莱瓦马丁内斯M·巴兹克斯卡莱拉S·卡多尼格斯伯特
Owner UNIV DE BARCELONA
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