Purinone derivative
Compounds represented by general formula (I) (all of the symbols in the formula conform to the definitions in the Description) are compounds that, in addition to having a Btk-selective inhibitory activity, exhibit an excellent metabolic stability and can avoid hepatotoxicity or the like, and as a consequence can provide safe therapeutic agents for diseases in which B cells or mast cells participate.
1. A method of treating a Btk-related disease selected from B-cell non-Hodgkin's lymphoma, lupus, systemic lupus erythematosus, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, and juvenile arthritis, comprising administering to a mammal in need thereof an effective amount of a compound represented by general formula (I):
(in the formula,
L represents (1) —O—, (2) —S—, (3) —SO—, (4) —SO 2 — (5) —NH—, (6) —C(O)—, (7) —CH 2 —O—, (8) —O—CH 2 —, (9) —CH 2 —, or (10) —CH(OH)—;
R 1 represents (1) a halogen atom, (2) a C 1-4 alkyl group, (3) a C 1-4 alkoxy group, (4) a C 1-4 haloalkyl group, or (5) a C 1-4 haloalkoxy group;
ring1 represents a benzene, cyclohexane, or pyridine ring, which may be substituted by from one to five substituents each independently selected from the group consisting of (1) halogen atoms, (2) C 1-4 alkyl groups, (3) C 1-4 alkoxy groups, (4) nitrile, (5) C 1-4 haloalkyl groups, and (6) C 1-4 haloalkoxy groups, wherein when two or more substituents are present on ring1, these substituents may form a 4- to 7-membered cyclic group together with the atoms in ring1 to which these substituents are bound;
ring2 represents a 4- to 6-membered nitrogenous saturated heterocycle, which is substituted by from one to three —K—R 2 ;
K represents —C(O)—, (wherein the bond on the left is bound to the ring2);
R 2 represents (1) a C 1-4 alkyl, (2) a C 2-4 alkenyl, or (3) a C 2-4 alkynyl group, each of which may be substituted by from one to five substituents each independently selected from the group consisting of (1) NR 3 R 4 , (2) halogen atoms, (3) CONR 5 R 6 , (4) CO 2 R 7 , and (5) OR 8 ;
R 3 and R 4 each independently represent (1) a hydrogen atom, or (2) a C 1-4 alkyl group which may be substituted by OR 9 or CONR 10 R 11 ;
R 3 and R 4 may, together with the nitrogen atom to which they are bound, form a 4- to 7-membered nitrogenous saturated heterocycle, which may be substituted by an oxo group or a hydroxyl group;
R 5 and R 6 each independently represent (1) a hydrogen atom, (2) a C 1-4 alkyl group, or (3) a phenyl group;
R 7 represents (1) a hydrogen atom or (2) a C 1-4 alkyl group;
R 8 represents (1) a hydrogen atom, (2) a C 1-4 alkyl group, (3) a phenyl group, or (4) a benzotriazolyl group;
R 9 represents (1) a hydrogen atom or (2) a C 1-4 alkyl group;
R 10 and R 11 each independently represent (1) a hydrogen atom or (2) a C 1-4 alkyl group;
n represents an integer from 0 to 4;
m represents an integer from 0 to 2; and
when n is two or more, the R 1 's may be the same as each other or may differ from one another), an optical isomer thereof or their mixture, a salt thereof, a solvate thereof, or an N-oxide thereof.
2. The method according to claim 1 , wherein R 2 is a C 2-4 alkenyl group or a C 2-4 alkynyl group, each of which may be substituted by from one to five substituents each independently selected from the group consisting of (1) NR 3 R 4 , (2) halogen atoms, (3) CONR 5 R 6 , (4) CO 2 R 7 , and (5) OR 8 .
3. The method according to claim 1 , wherein the 4- to 6-membered nitrogenous saturated heterocycle is an azetidine, pyrrolidine, or piperidine ring.
4. The method according to claim 1 , wherein the compound represented by general formula (I) is the compound represented by general formula (I-1)
(in the formula, ring1-1 represents a benzene, cyclohexane, or pyridine ring, each of which may be substituted by from one to five substituents each independently selected from the group consisting of (1) halogen atoms, (2) C 1-4 alkyl groups, (3) C 1-4 alkoxy groups, (4) nitrile, and (5) CF 3 , and ring2-1 represents a 4- to 6-membered nitrogenous saturated heterocycle, which is substituted by from one to three —K—R 2 , wherein the other symbols have the same definitions as above).
5. The method according to claim 4 , wherein R 2 is a C 2-4 alkenyl group or a C 2-4 alkynyl group, each of which may be substituted by from one to five substituents each independently selected from the group consisting of (1) NR 3 R 4 , (2) halogen atoms, (3) CONR 5 R 6 , (4) CO 2 R 7 , and (5) OR 8 .