公开(公告)号：EP0681569B1

公开(公告)日：2001-03-21

申请号：EP94907200.3

申请日：1994-01-19

申请人： SCHERING CORPORATION

发明人： DUGAR, Sundeep ,  CLADER, John, W. ,  BURNETT, Duane, A. ,  BROWNE, Margaret, E. ,  DAVIS, Harry, R.

IPC分类号： C07D205/12 ,  C07D471/10 ,  A61K31/395

CPC分类号： C07D471/10 ,  C07D205/12

摘要： Novel compounds of formula (1) or a pharmaceutically acceptable salt thereof, wherein R1 is (A); R2 and R3 are independently selected from the group consisting of -CH2-, -CH(lower alkyl)-, -C(di-lower alkyl)-, -CH = CH- and -C(lower alkyl) = CH-; or R1 together with an adjacent R2, or R1 together with an adjacent R3, form a -CH = CH- or a -CH = C(lower alkyl)- group; u and v are independently 0, 1, 2 or 3, provided both are not zero; provided that when R2 is -CH = CH- or -C(lower alkyl) = CH-, v is 1; provided that when R3 is -CH = CH- or -C(lower alkyl) = CH-, u is 1; provided that when v is 2 or 3, the R2's can be the same or different; and provided that when u is 2 or 3, the R3's can be the same or different; R4 is B-(CH2)mC(O)-, wherein m is 0-5; B-(CH2)q-, wherein q is 0-6; B-(CH2)e-Z-(CH2)r-, wherein Z is -O-, -C(O)-, phenylene, -N(R8)- or -S(O)0-2-, e is 0-5 and r is 0-5, provided that the sum of e and r is 0-6; B-(C2-C6 alkenylene)-; B'-(C4-C6 alkadienylene)-; B-(CH2)t-Z-(C2-C6 alkenylene)-, wherein t is 0-3, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2-6; B-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6; B-(CH2)t-V-(C2-C6 alkenylene)- or B'-(C2-C6 alkenylene)-V-(CH2)t-, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6; B-(CH2)a-Z-(CH2)b-V-(CH2)d-, wherein a, b and d are independently 0-6, provided that the sum of a, b and d is 0-6; T-(CH2)s-, wherein T is cycloalkyl of 3-6 carbon atoms and s is 0-6; or R1 and R4 together form the group (A'); B is optionally-substituted phenyl, indanyl, indenyl, naphthyl, tetrahydronaphthyl or optionally substituted-heteroaryl; and R20 and R21 are independently optionally-substituted phenyl, optionally-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, optionally-substituted heteroaryl, optionally-substituted benzofused heteroaryl or cyclopropyl are disclosed, as well as pharmaceutical compositions comprising said compounds, the use of said compounds as hypocholesterolemic agents, processes for preparing the compounds, and the use of said compounds in combination with cholesterol biosynthesis inhibitors to treat or prevent atherosclerosis.

公开(公告)号：EP0869942A1

公开(公告)日：1998-10-14

申请号：EP95943048.0

申请日：1995-12-18

申请人： SCHERING CORPORATION

发明人： VACCARO, Wayne, D. ,  BURNETT, Duane, A. ,  CLADER, John, W.

IPC分类号： A61K31 ,  A61P3 ,  A61P9 ,  C07D205 ,  C07D401 ,  C07D403 ,  C07D413 ,  C07D491 ,  C07D521

CPC分类号： C07D231/12 ,  C07D205/08 ,  C07D205/12 ,  C07D233/56 ,  C07D249/08 ,  C07D403/12 ,  C07D413/10 ,  C07D491/08 ,  C07D491/10

摘要： 4-[(Heterocycloalkyl or heteroaromatic)-substituted phenyl]-2-azetidinone hypocholesterolemic agents of formula (I) or a pharmaceutically acceptable salt thereof, wherein: A is optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted benzofused heterocycloalkyl, or optionally substituted benzofused heteroaryl; Ar1 is optionally substituted aryl; Ar2 is optionally substituted aryl; Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the spiro group (a); and R1 is selected from the group consisting of -(CH¿2?)q-, wherein q is 2-6, provided that when Q is a spiro ring, q can also be 0 or 1; -(CH2)e-G-(CH2)r-, wherein G is -O-, -C(O)-, phenylene, -NR?8¿- or -S(O)¿0-2?-, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; alkenylene; and -(CH2)f-V-(CH2)g-, wherein V is cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6; R?5¿ is (b), (c), (d), (e), (f), (g) or (h); R?6 and R7¿ are -CH¿2?-, -CH(alkyl)-, -C(dialkyl), -CH=CH- or -C(alkyl)=CH-; or R?5¿ together with an adjacent R?6, or R5¿ together with an adjacent R7, form a -CH=CH- or a -CH=C(alkyl)- group; a and b are independently 0-3, provided both are not zero; and when Q is a bond, R1 also can be: (i), (j) or (k); M is -O-, -S-, -S(O)- or -S(O)¿2?-; X, Y and Z are -CH2-, -CH(alkyl)- or -C(dialkyl); R?10 and R12 -OR14¿, -O(CO)R14, -O(CO)OR16 or -O(CO)NR?14R15; R11 and R13¿ are H, alkyl or aryl; or R?10 and R11¿ together are =O, or R?12 and R13¿ together are =O; d is 1-3; h is 0-4; s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4; provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1, the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5; v is 0 or 1; j and k are independently 1-5, provided that the sum of j, k and v is 1-5; R8 is H, alkyl, arylalkyl, -C(O)R14 or -COOR14; R9 is H, alkyl, alkoxy, -COOH, NO¿2?, -NR?14R15¿, OH or halogeno; R?14 and R15¿ are H, alkyl, aryl and arylalkyl; R16 is alkyl or optionally substituted aryl; and R19 is H, OH or alkoxy are disclosed, as well as a method of lowering serum cholesterol by administering said compounds, pharmaceutical compositions containing them, and the combination of a substituted azetidinone and a cholesterol biosynthesis inhibitor for the treatment and prevention of atherosclerosis.

公开(公告)号：EP0792264A1

公开(公告)日：1997-09-03

申请号：EP95939677.0

申请日：1995-11-15

申请人： SCHERING CORPORATION

发明人： McKITTRICK, Brian, A. ,  DUGAR, Sundeep ,  BURNETT, Duane, A.

IPC分类号： A61K31 ,  A61P3 ,  A61P9 ,  C07D205 ,  C07D401 ,  C07D409

CPC分类号： C07D401/12 ,  C07D205/08 ,  C07D409/12

摘要： Sulfur-substituted azetidinone hypocholesterolemic agents of formula (I), or a pharmaceutically acceptable salt thereof, wherein: Ar1 is aryl, R10-substituted aryl or heteroaryl; Ar2 is aryl or R4-substituted aryl; Ar3 is aryl or R5-substituted aryl; X and Y are -CH¿2?-, -CH(lower alkyl)- or -C(dilower alkyl)-; R is -OR?6¿, -O(CO)R6, -O(CO)OR9 or -O(CO)NR6R7; R1 is hydrogen, lower alkyl or aryl; or R and R1 together are =0; q is 0 or 1; r is 0, 1 or 2; m and n are 0-5; provided that the sum of m, n and q is 1-5; R4 is selected from lower alkyl, -OR6, -O(CO)R6, -O(CO)OR9, -O(CH¿2?)1-5OR?6¿, -O(CO)NR?6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO¿2R?9, -COOR6, -CONR6R7, -COR6, -SO¿2NR6R7, S(O)¿0-2R?9, -O(CH¿2?)1-10-COOR?6¿, -O(CH¿2?)1-10CONR?6R7¿, -(lower alkylene)-COOR6 and -CH=CH-COOR6; R5 is selected from -OR6, -O(CO)R6, -O(CO)OR9, -O(CH¿2?)1-5OR?6¿, -O(CO)NR?6R7, -NR6?R?7 -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO¿2R?9, -COOR6, -CONR6R7, -COR6, -SO¿2NR6R7, S(O)¿0-2R?9, -O(CH¿2?)1-10-COOR?6¿, -O(CH¿2?)1-10CONR?6R7, -CF¿3, -CN, -NO2, halogen, -(lower alkylene)COOR6 and -CH=CH-COOR?6; R6, R7 and R8¿ are H, lower alkyl, aryl or aryl-substitued lower alkyl; R9 is lower alkyl, aryl or aryl-sybstituted lower alkyl; and R10 is selected from lower alkyl, -OR6, -O(CO)R6, -O(CO)OR9, -O(CH¿2?)1-5OR?6¿, -O(CO)NR?6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO¿2R?9, -COOR6, -CONR6R7, COR6, -SO¿2NR6R7, -S(O)¿0-2R?9, -O(CH¿2?)1-10-COOR?6¿, -O(CH¿2?)1-10CONR?6R7, -CF¿3, -CN, -NO2 and halogen; are disclosed, as well as pharmaceutical compositions containing them, and a method of lowering serum cholesterol by administering said compounds, alone or in combination with a cholesterol biosynthesis inhibitor.

摘要翻译： 式（I）的硫取代的氮杂环丁酮降血胆固醇剂或其药学上可接受的盐，其中：Ar 1是芳基，R 10取代的芳基或杂芳基; Ar 2是芳基或R 4取代的芳基; Ar3是芳基或R5-取代的芳基; X和Y是-CH 2 - ， - CH（低级烷基） - 或-C（低级烷基） - ; R是-OR 6，-O（CO）R 6，-O（CO）OR 9或-O（CO）NR 6 R 7; R1是氢，低级烷基或芳基; 或R和R1一起为= 0; q是0或1; r是0,1或2; m和n是0-5; 条件是m，n和q的和为1-5; R4选自低级烷基，-OR6，-O（CO）R6，-O（CO）OR9，-O（CH2-2）1-5OR6，-O（CO）NR6R7，-NR6R7 ，-NR6（CO）R7，-NR6（CO）OR9，-NR6（CO）NR7R8，-NR6SO2R9，-COOR6，-CONR6R7，-COR6，-SO2NR6R7，S（O） （低级亚烷基）-COOR 6和-CH = CH-COOR 6，-O（CH 2）2 -COOR 6，-O（CH 2 2）1-10 CONR 6 R 7， ; R5选自-OR6，-O（CO）R6，-O（CO）OR9，-O（CH2-2）1-5OR6，-O（CO）NR6R7，-NR6R5， （CO）R7，-NR6（CO）OR9，-NR6（CO）NR7R8，-NR6SO2R9，-COOR6，-CONR6R7，-COR6，-SO2NR6R7，S（O） 2（R 2）1-10 -COOR 6，-O（CH 2 2）1-10 CONR 6 R 7，-CF 3，-CN，-NO 2，卤素， - （ 低级亚烷基）COOR 6和-CH = CH-COOR 6; R6，R7和R8是H，低级烷基，芳基或芳基取代的低级烷基; R9是低级烷基，芳基或芳基 - 取代的低级烷基; （CO）R6，-O（CO）OR9，-O（CH2-2）1-5OR6，-O（CO）NR6R7， - NR6R7，-NR6（CO）R7，-NR6（CO）OR9，-NR6（CO）NR7R8，-NR6SO2R9，-COOR6，-CONR6R7，COR6，-SO2NR6R7，-S（O） -O（CH 2 2）1-10 -COOR 6，-O（CH 2 2）1-10 CONR 6 R 7，-CF 3，-CN，-NO 2和卤素; 以及含有它们的药物组合物以及通过单独或与胆固醇生物合成抑制剂组合给予所述化合物来降低血清胆固醇的方法。

公开(公告)号：EP0720599A1

公开(公告)日：1996-07-10

申请号：EP94928563.0

申请日：1994-09-14

申请人： SCHERING CORPORATION

发明人： ROSENBLUM, Stuart, B. ,  DUGAR, Sundeep ,  BURNETT, Duane, A. ,  CLADER, John, W. ,  MCKITTRICK, Brian, A.

IPC分类号： A61K31 ,  A61P3 ,  A61P7 ,  A61P9 ,  C07D205

CPC分类号： C07D205/08 ,  A61K9/2018 ,  A61K9/4858 ,  A61K31/21 ,  A61K31/35 ,  A61K31/395 ,  A61K31/40 ,  A61K45/06 ,  Y02P20/55 ,  Y10S514/824 ,  A61K2300/00

摘要： Hydroxy-substd. azetidinone derivs. of formula (I) and their salts are new. Ar1,Ar2 = aryl (opt. substd. by 1-5 gps. R4); Ar3 = aryl (opt. substd. by 1-5 gps. R5); X, Y, Z = CH2, CH(1-6C alkyl) or C(di(1-6C alkyl); R, R2 = OR6, OCOR6, OCOOR9 or OCONR6R7; R1, R3 = H, 1-6C alkyl or aryl; q, r = 0 or 1; m, n, p = 0-4, provided that i) at least one of q and r is 1, and the sum of m, n q and r is 1-6, and ii) when p is 0 and r is 1, the sum of m, q and n is 1-5; R4 = 1-6C alkyl, OR6, OCOR6, OCOR9, O(CH2)sOR6, OCONR6R7, NR6R7, NR6COR7, NR6COOR9, NR9, NR6CONR7R8, NR6CONR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)tR9, O(CH2)uCOOR6, O(CH2)uCONR6R7, lower alkylCOOR6, CH=CH-COOR6, CF3, CN, NO2 or halogen; R5 = OR6, OCOR6, O(CO)R9, O(CH2)vOR6, -O(CO)NR6R7, NR6R7, NR6COR7, NR6COOR9, NR6COOR9, NR6CONR7R8, NR6SO2R9, COOR6, CONR6R7, COR6, SO2NR6R7, S(O)tR9, -O(CH2)uCOOR6, O(CH2)uCONR6R7, lower alkylCOOR6 or -CH=CH-COOR6; s = 1-5; t = 0-2; u = 1-10; v = 1-5; R6, R7, R8 = H, 1-6C alkyl (opt.substd. with aryl) or aryl; and R9 = 1-6C alkyl (opt. substd. with aryl) or aryl.