Patent EP-0924209-A1 (EP)
Title: Hypoglycemic imidazoline compounds
Inventor: JIROUSEK MICHAEL ROBERT
IPC: A61K31/4164
Filed: 1998-12-18
Abstract: This invention relates to certain novel imidazoline compounds and
analogues thereof, to their use for the treatment of diabetes, diabetic complications,
metabolic disorders, or related diseases where impaired glucose disposal is present, to
pharmaceutical compositions comprising them, and to processes for their preparation. 
     The compounds have the following formula:
 
wherein
   X is -O-, -S-, or -NR 5 -,   R 5  is hydrogen, C 1-8  alkyl, or an amino protecting group;   R 1 , R 1' , R 2 , and R 3  are independently hydrogen or C 1-8  alkyl;   R 1  and R 2  optionally together form a bond and R 1'  and R 3  are independently
hydrogen or C 1-8  alkyl;   R 1  and R 2  optionally combine together with the carbon atoms to which they
are attached form a C 3-7  carbocyclic ring and R 1'  and R 3  are independently hydrogen
or C 1-8  alkyl;   R 1  and R 1'  together with the carbon atom to which they are attached
optionally combine to form a C 3-7  spirocarbocyclic ring and R 2  and R 3  are
independently hydrogen or C 1-8  alkyl;    R 2  and R 3  together with the carbon atom to which they are attached
optionally combine to form a C 3-7  spirocarbocyclic and R 1  and R 1'  are independently
hydrogen or C 1-8  alkyl;   n is 0, 1, or 2;   m is 0, 1 or 2;   m' is 0, 1, or 2;   q' is 0,1,2,3,4, or 5;   R 4  is
 
     Y is -O-, -S-, or -NR 8 -;   Y' is -O- or -S-;   R 6  and R 7  are independently hydrogen, C 1-8  alkyl, C 3-7  cycloalkyl, C 1-8 
alkoxy, C 1-8  alkylthio, halo C 1-8  alkylthio, C 1-8  alkylsulfinyl, C 1-8  alkylsulfonyl,
C 3-7  cycloalkoxy, aryl-C 1-8  alkoxy, halo, halo-C 1-8  alkyl, halo- C 1-8  alkoxy, nitro,
-NR 10 R 11 , -CONR 10 R 11 , aryl C 1-8  alkyl, optionally substituted heterocyclyl,
optionally substituted phenyl, optionally substituted naphthyl, optionally halo
substituted acylamino, cyano, hydroxy, COR 12 , halo C 1-8  alkylsulfinyl, or halo C 1-8 
alkylsulfonyl, or alkoxyalkyl of the formula
 CH 3 (CH 2 ) p -O-(CH 2 ) q -O-;  
where   p is 0, 1, 2, 3, or 4; and   q is 1, 2, 3, 4, or 5;   R 12  is C 1-8  alkyl or optionally substituted phenyl;   R 8  is hydrogen, C 1-8  alkyl, halo-C 1 _ 8  alkyl, optionally substituted phenyl,
optionally substituted heterocyclyl, COO C 1-8  alkyl, optionally substituted COaryl,
COC 1-8  alkyl, SO 2 C 1-8  alkyl, optionally substituted SO 2  aryl, optionally substituted
phenyl-C 1-8  alkyl, CH 3 (CH 2 ) p -O-(CH 2 ) q -O-;   R 9  is hydrogen, halo, C 1-8  alkyl, halo C 1-8  alkyl, C 1-8  alkylthio, halo C 1-8 
alkylthio, C 3-7  cycloalkylthio, optionally substituted arylthio or heteroarylthio, C 1-8 
alkoxy, C 3-7  cycloalkoxy, optionally substituted aryloxy, optionally substituted
heteroaryloxy, or optionally substituted aryl or heteroaryl, C 3-7  cycloalkyl, halo C 3-7 
cycloalkyl, C 3-7  cycloalkenyl, cyano, COOR 10 ,CONR 10 R 11  or NR 10 R 11 , C 2-6 
alkenyl, optionally substituted heterocyclyl, optionally substituted aryl C 1-8  alkyl,
optionally substituted heteroaryl C 1-8  alkyl in which the alkyl group can be substituted
by hydroxy, or C 1-8  alkyl substituted by hydroxy,   R 10  and R 11  are independently hydrogen, C 1-8  alkyl, optionally substituted
aryl C 1-8  alkyl, optionally substituted phenyl, or R 10  and R 11  together with the
nitrogen atom to which they are attached may combine to form a ring with up to six
carbon atoms which optionally may be substituted with up to two C 1-8  alkyl groups or
one carbon atom may be replaced by oxygen or sulfur;   R 14  and R 16  are independently hydrogen, halo, C 1-8  alkyl, C 3-7  cycloalkyl,
C 3-7  cycloalkoxy, C 3-7  cycloalkylC 1-8  alkoxy, halo-C 1-8  alkyl, halo-C 1-8  alkoxy,
C 1-8  alkoxy, carbo(C 1-8 )alkoxy, optionally substituted aryl, or optionally substituted
heteroaryl;    R 15  and R 17  are independently hydrogen, halo, C 1-8  alkoxy, C 3-7 -cycloalkyl,
C 3-7  cycloalkylC 1-8  alkoxy, C 1-8  alkyl, C 3-7  cycloalkoxy, hydroxy, halo C 1-8 
alkoxy, carbo(C 1-8 )alkoxy, optionally substituted phenyl, optionally substituted phenyl-C 1-8 
alkyl, optionally substituted phenyloxy, optionally substituted phenyl-C 1-8 
alkoxy, (tetrahydropyran-2-yl)methoxy, C 1-8  alkyl-S(O) m -, optionally substituted aryl-C 1-8 
alkyl-S(O) m' -, CH 3 (CH 2 ) p -Z 1 -(CH 2 ) q -Z 2 -, or Z 3 -(CH 2 )q'-Z 2 -;   Z 1  and Z 2  are independently a bond, O, S, SO, SO 2 , sulphoximino, or NR 10 ;
and   Z 3  is hydroxy, protected hydroxy, NR 10  R 11 , protected amino, SH or
protected SH;   provided that when R 1 , R 1' , R 2  and R 3  are all hydrogen; n is 0; R 4  is naphthyl;
and R 14 , R 15  and R 16 , or R 15 , R 16  and R 17  are all hydrogen, then R 17  or R 14 ,
respectively, is other than halo, methoxy, or C1-6 alkyl.   or a pharmaceutically acceptable salt or ester thereof.