Spirocycloalkyl-substituted azetidinones useful as hypocholesterolemic agents (hypocholesterolemic agents useful as hypocholesterolemic agents)

摘要

The present invention relates to the use of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof, an anticholinergic pharmaceutical composition, a use of the compound as a hypocholesterolemic agent, a method for producing the compound and atherosclerosis To the use of the combination of the compound and a cholesterol biosynthesis inhibitor.;Wherein R_Onesilver;And R₂And R₃Is independently-CH₂-,-CH (lower alkyl)-,-C (di-lower alkyl)-,-CH =₃Together with-CH = CH-or-CH = C (lower alkyl)-group, u and V are independently 0, 1, 2 or 3,₂Is-CH = CH-or-C (lower alkyl) = CH-, then v is 1 and R₃Is-CH = CH-or-C (lower alkyl) = CH-, when u is 1 and v is 2 or 3, all R₂May be the same or different, and when u is 2 or 3, all R₃May be the same or different, and R₄(CH₂)_mC (O)-, wherein m is 0, 1, 2, 3, 4 or 5, B-(CH₂)_q-(wherein q is 0, 1, 2, 3, 4, 5 or 6), B-(CH₂)_e-Z-(CH₂)_r-, wherein Z is-O-,-C (O)-, phenylene,-N (R₈)-or-S (O)_0-2E is 0, 1, 2, 3, 4 or 5 and r is 0, 1, 2, 3, 4 or 5, provided that the sum of e and r is 0, 1, 2, 5, with the proviso that the sum of e and r is 0, 1, 2, 3, 4, 5 or 6, B-(C₂-C₆Alkenylene)-, B-(C₄-C₆Alkadienylene)-, B-(CH₂)_t-Z-(C₂-C₆Alkenylene)-, wherein Z is as defined above and t is 0, 1, 2, or 3, provided that the sum of t and the number of carbon atoms of the alkenylene chain is 2, 3, 4, 5 or 6, B-(CH₂)_t-V-(CH₂)_g-wherein V is C₃-C₆F is 1, 2, 3, 4 or 5 and g is 0, 1, 2, 3, 4 or 5, provided that the sum of f and g is 0, 1, 2, 3, 4, 5 or 6), B-(CH₂)_t-V-(C₂-C₆Alkenylene) or B '-(C₂-C₆Alkenylene)-V-(CH₂)_t-, wherein V and t are as defined above, provided that the sum of t and the number of carbon atoms of the alkenylene chain is 2, 3, 4, 5 or 6, B-(CH₂)_a-Z-(CH₂)_b-V-(CH₂)_dB and d are independently 0, 1, 2, 3, 4, 5 or 6, provided that the sum of a, b and d is 0, 1, 2 , 3, 4, 5 or 6), T-(CH₂)_s-wherein T is cycloalkyl of 3 to 6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6, or R_OneAnd R₄Group together;Wherein B is indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl wherein the heteroaryl is pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, Thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, in the case of nitrogen-containing heteroaryl it is an N-oxide thereof) or;W is a substituent on a ring carbon atom and is independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino) Lower alkyl lower alkanedioyl, allyloxy,-CF₃-, OCF₃, Benzyl, R₇-benzyl, benzyloxy, R_7-Benzyloxy, phenoxy, R₇-phenoxy, dioxolanyl, NO₂,-N (R₈) (R₉), N (R₈) (R₉)-lower alkylene-, N (R₈) (R₉)-lower alkylenedioxy-, OH, halogeno,-CN,-N₃,-NHC (O) OR₁₀,-NHC (O) R₁₀M R₁₁O₂SNH-, (R₁₁O₂S)₂N-,-S (O)₂NH₂,-S (O)_0-2R₈, Tert-butyldimethylsilyloxymethyl,-C (O) R₁₂,-COOR₁₉,-CON (R₈) (R₉),-CH = CHC (O) R₁₂,-lower alkylene-C (O) R₁₂, R₁₀C (O) (lower alkylenedioxy)-, N (R₈) (R₉) C (O) (lower alkylenedioxy)-and-;Lower alkyl, lower alkoxy,-C (O) OR RTI ID = 0.0 ₁₀,-C (O) R ₀, OH, N (R₈) (R₉)-lower alkylene-, N (R₈) (R₉)-lower alkyleneoxy-,-S (O)₂NH₂And 2-(trimethylsilyl)-ethoxymethyl, wherein R RTI ID = 0.0 ₇Is independently selected from the group consisting of lower alkyl, lower alkoxy,-COOH, NO₂,-N (R₈) (R₉), OH or halogeno, R 3 ₈And R₉Is independently H or lower alkyl, R₁₀Is lower alkyl, phenyl, R₇-phenyl, benzyl or R₇-benzyl, R₁₁Is OH, lower alkyl, phenyl, benzyl, R₇-phenyl or R₇-benzyl, R₁₂Is H, OH, alkoxy, phenoxy, benzyloxy,;-N (R₈) (R₉), Lower alkyl, phenyl or R₇-phenyl, R₁₃Is-O-,-CH₂-,-NH-,-N (lower alkyl)-or-NC (O) R₁₉And R₁₅, R₁₆And R₁₇Are independently selected from the group consisting of the groups defined for H and W, or R₁₅Is hydrogen, R₁₆And R₁₇Together with the adjacent carbon atoms form a dioxolanyl ring, R₁₉Is H, lower alkyl, phenyl or lower alkyl, and R₂₀And R₂₁Are independently phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzo fused heteroaryl , W-substituted benzo-fused heteroaryl, and cyclopropyl, wherein the heteroaryl is as defined above.