Bicyclic pyrimidine compounds and therapeutic use thereof
View Patent ↗1. A pyrimidine derivative of the formula (1) or a salt thereof; has an inhibitory activity of production of Th2 type cytokines such as IL-4, IL-5, etc., and is useful as an therapeutic agent for allergic diseases, autoimmune diseases such as systemic lupus erythemathosus, etc., and acquired immunodeficiecy syndrome (AIDS) and so on.
1. A pyrimidine compound of the formula (1) or its salt
wherein R 1 is a formula (2)
wherein
ring A is substituted or unsubstituted C 3-10 cycloalkane, substituted or unsubstituted C 5-10 cycloalkene, substituted or unsubstituted C 7-10 bicycloalkane, or substituted or unsubstituted heterocyclic ring having an O atom or a S atom as a heteroatom, and said S atom may form sulfinyl or sulfonyl together with one or two oxygen atoms, and
R 4 is straight or branched C 1-10 alkyl, C 2-6 alkenyl, C 3-6 alkinyl, C 3-6 cycloalkyl, C 4-10 cycloalkyl-alkyl, or OR 8 , wherein R 8 is straight or branched C 1-10 alkyl, C 3-6 alkenyl, C 3-6 alkinyl, C 3-6 cycloalkyl or C 4-10 cycloalkyl-alkyl, or
R 1 is a formula (3)
wherein
R 5 is straight or branched C 1-10 alkyl; C 2-6 alkenyl; C 3-6 alkinyl; straight or branched C 1-10 alkyl substituted by hydroxy, halogen atom or C 1-4 alkoxy; phenyl; C 3-8 cycloalkyl; a 5 to 7 membered saturated heterocyclic ring having one or two oxygen atoms as heteroatoms; or C(═O)R 9 , wherein R 9 is straight or branched C 1-10 alkyl, C 2-6 alkenyl, C 3-6 alkinyl, C 3-6 cycloalkyl, C 4-10 cycloalkyl-alkyl, or OR 10 , wherein R 10 is straight or branched C 1-10 alkyl, C 2-6 alkenyl, C 3-6 alkinyl, C 3-6 cycloalkyl or C 4-10 cycloalkyl-alkyl,
R 6 is a hydrogen atom, straight or branched C 1-10 alkyl, C 6-10 aryl, halogen atom, C 6-10 aryl substituted by C 1-4 alkoxy or C 1-4 alkyl, carbamoyl, or hydroxymethyl, and
R 7 is a hydrogen atom, or straight or branched C 1-10 alkyl, and
R 2 is hydrogen atom, or straight or branched C 1-10 alkyl, and
R 3 is straight or branched C 1-10 alkyl; C 3-6 cycloalkyl; straight or branched C 1-10 alkyl substituted by C 1-2 alkylcarbamoyl, C 2-4 dialkylcarbamoyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, C 3-6 cycloalkyl, hydroxy, C 1-4 alkylcarbonyloxy, halogen atom, amino, C 2-4 acyl-substituted amino, C 1-4 alkyl-substituted sulfonylamino or C 1-5 alkoxycarbonylamino; a formula (4)
wherein
R 11 is phenyl, pyridyl, thienyl, or furyl and each of them may be substituted by one or more substituents selected from the group consisting of: a halogen atom, cyano, carbamoyl, C 1-4 alkoxy, or C 1-4 alkyl;
n is an integer of 0-4, provided that n is an integer of 1-4 when R 11 is phenyl.
2. The pyrimidine compound or its pharmaceutical acceptable salt of claim 1 , wherein R 3 is straight or branched C 1-7 alkyl.
3. The pyrimidine compound or its pharmaceutically acceptable salt of claim 1 , wherein R 3 is the formula (4)
R 11 —(CH 2 ) n — (4)
wherein R 11 and n are the same as defined above.
4. The pyrimidine compound or its pharmaceutically acceptable salt of claim 1 or 3 , wherein R 11 of the formula (4) is pyridyl, thienyl or furyl.
5. The pyrimidine compound or its pharmaceutically acceptable salt of claim 1 , 2 , or 3 , wherein n of the formula (4) is an integer of 2-4.
6. The pyrimidine compound or its pharmaceutically acceptable salt of claim 1 , 2 , or 3 , wherein R 5 is straight C 2-4 alkyl or straight C 2-4 alkyl substituted by hydroxy.
7. The pyrimidine compound or its pharmaceutically acceptable salt of claim 1 , 2 , or 3 , wherein R 1 is the formula (2)
wherein ring A and R 4 are the same as defined above.
8. The pyrimidine compound or its pharmaceutically acceptable salt of claim 1 , 2 , or 3 , wherein R 1 is the formula (3)
wherein R 5 , R 6 , and R 7 are the same as defined above.
9. A method for treating a patient with a disease wherein suppressing the immune response of type 2 helper T cells that are abnormally enhanced is necessary to overcome said disease, comprising administering an effective amount of the pyrimidine compound or its pharmaceutically acceptable salt of claim 1 to said patient.
10. A method for enhancing the production of IFN-γ in a patient comprising administering an effective amount of the pyrimidine compound or its pharmaceutically acceptable salt of claim 1 to a patient in need thereof.
11. A method for treating a patient with a disease wherein enhancing the immune responses of type 1 helper T cells is necessary to overcome said disease, comprising administering an effective amount of the pyrimidine compound or its pharmaceutically acceptable salt of claim 1 to said patient.
12. The method according to claim 9 wherein the disease is an allergic disease.
13. The method according to claim 12 wherein the allergic disease is asthma, allergic rhinitis, or allergic dermatitis.