Patent EP-1229034-A1 (EP)
Inventor: CHAMBERS ROBERT J
IPC: A61K31/443
Filed: 2002-01-11
Abstract: Compounds useful as inhibitors of PDE4 in the treatment of diseases regulated by
the activation and degranulation of eosinophils, especially asthma, chronic bronchitis, and
chronic obstructive pulmonary disease, of the formula:
 
wherein  j  is 0 or 1,  k  is 0 or 1,  m  is 0, 1, or 2;
 n  is 1 or 2; A is is selected from the partial
Formulas:
 
where  q  is 1, 2, or 3,  W 3    is -O-;
-N(R 9 )-; or -OC(=O)-;  R 7    is selected from -H;
-(C 1 -C 6 )alkyl, -(C 2 -C 6 )alkenyl, or -(C 2 -C 6 )alkynyl substituted by 0 to 3 substituents R 10 ;
-(CH 2 ) u -(C 3 -C 7 ) cycloalkyl where u is 0, 1 or 2, substituted by 0 to 3 R 10 ; and phenyl or benzyl
substituted by 0 to 3 R 14 ;  R 8    is tetrazol-5-yl; 1,2,4-triazol-3-yl; 1,2,4-triazol-3-on-5-yl; 1,2,3-triazol-5-yl;
imidazol-2-yl; imidazol-4-yl; imidazolidin-2-on-4-yl; 1,3,4-oxadiazolyl; 1,3,4-oxadiazol-2-on-5-yl;
1,2,4-oxadiazol-3-yl; 1,2,4-oxadiazol-5-on-3-yl; 1,2,4-oxadiazol-5-yl;
1,2,4-oxadiazol-3-on-5-yl; 1,2,5-thiadiazolyl; 1,3,4-thiadiazolyl; morpholinyl; parathiazinyl;
oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; pyrrolyl; pyrazolyl; succinimidyl; glutarimidyl;
pyrrolidonyl; 2-piperidonyl; 2-pyridonyl; 4-pyridonyl; pyridazin-3-onyl; pyridyl; pyrimidinyl;
pyrazinyl; pyridazinyl; indolyl; indolinyl; isoindolinyl; benzo[ b ]furanyl; 2,3-dihydrobenzofuranyl;
1,3-dihydroisobenzofuranyl; 2 H -1-benzopyranyl; 
2- H -chromenyl; chromanyl; benzothienyl;
1 H -indazolyl; benzimidazolyl; benzoxazolyl; benzisoxazolyl; benzothiazolyl; benzotriazolyl;
benzotriazinyl; phthalazinyl; 1,8-naphthyridinyl; quinolinyl; isoquinolinyl; quinazolinyl;
quinoxalinyl; pyrazolo[3,4- d ]pyrimidinyl; pyrimido[4,5- d ]pyrimidinyl; imidazo[1,2- a ]pyridinyl;
pyridopyridinyl; pteridinyl; or 1 H -purinyl; or A is selected from phosphorous and sulfur acid
groups; W is ―O―; ―S(=O) t ―, where t is 0, 1, or 2; or -N(R 3 )―; Y is C(R 1   a )―, or
-[N□(O) k ] where k is 0 or 1; R 4 ,
R 5  and R 6  are  (1) ―H;
provided that R 5  and R 6  are not both
-H at the same time, ―F; ―Cl; -(C 2 -C 4 )
alkynyl; -R 16 ; ―OR 16 ;
-S(=O) p R 16 ; ―C(=O)R 16 ,
-C(=O)OR 16 ; -OC(=O)R 16 ; -CN; -NO 2 ;
-C(=O)NR 16 R 17 ; -OC(=O)NR 16 R 17 ;
―NR 12   a C(=O)NR 16 R 17 ;
-NR 12   a C(=NR 12 )NR 16 R 17 ;
-NR 12   a C(=NCN)NR 15 R 16 ;
-NR 12   a C(=N-NO 2 )NR 15 R 16 ;
-C(=NR 12   a )NR 15 R 16 ;
-CH 2 C(=NR 12   a )NR 16 R 17 ;
―OC(=NR 12   a )NR 16 R 17 ;
―OC(=N―NO 2 )NR 16 R 17 ;
-NR 16 R 17 ; -CH 2 NR 16 R 17 ;
-NR 12   a C(=O)R 16 ;
-NR 12   a C(=O)OR 16 ; =NOR 16 ;
―NR 12   a S(=O) p R 17 
-S(=O) p NR 16 R 17 ; and
―CH 2 C(=NR 12   a )NR 16 R 17 ;
 (2)  -(C 1 -C 4 ) alkyl including dimethyl
and -(C 1 -C 4 ) alkoxy substituted with 0 to 3 substituents
―F or ―Cl; or 0 or 1 substituent
(C 1 -C 2 ) alkoxycarbonyl―,
(C 1 -C 2 ) alkylcarbonyl―, or
(C 1 -C 2 ) alkylcarbonyloxy―;
or  (3)  an aryl or heterocyclic moiety; or  (4) 
R 5  and R 6  are taken
together to form a moiety of partial Formulas (1.3.1) through (1.3.15):
 
 B 1    and  B 2   
is a moiety comprising a saturated or
unsaturated carbon ring system that is 3- to 7-membered monocyclic, or
that is 7- to 12-membered, fused or discontinuous, polycyclic; wherein
optionally one carbon atom thereof may be replaced by a heteroatom
selected from N, O and S; and where N is selected, optionally a second
carbon atom thereof may be replaced by a heteroatom selected from N, O,
or S; 
or a pharmaceutically acceptable salt thereof.