Bicyclic pyrimidine compounds and therapeutic use thereof

• US 6,458,798 B1
• Filed: 02/27/2001
• Issued: 10/01/2002
• Est. Priority Date: 08/27/1998
• Status: Expired due to Fees

• Current Assignee: Dainippon Sumitomo Pharma Company Limited (Sumitomo Chemical Company Limited)
• Original Assignee: Sumitomo Pharmaceuticals Company Limited (Sumitomo Chemical Company Limited)
• Inventors: Fujita, Hitoshi, Tanaka, Hiroshi, Kawakami, Hajime, Antoku, Fujio, Fujiwara, Norio, Iwai, Kiyotaka
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): RAO, DEEPAK R
• Application Number:
  US09/763,728
• Time in Patent Office: 581 Days
• Field of Search: 544/278, 544/291, 514/258, 514/260, 514/260.1, 514/266.4
• US Class Current: 514/260.1
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

Abstract

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.

Claims

1. A pyrimidine compound of the formula (1) or its salt

wherein R¹ 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

R⁴ 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 OR⁸, wherein R⁸ 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

R¹ is a formula (3)

wherein

R⁵ is straight or branched C_2-10 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;

C_3-8 cycloalkyl;

a 5 to 7 membered saturated heterocyclic ring having one or two oxygen atoms as heteroatoms;

or C(═

O)R⁹, wherein R⁹ 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 OR¹⁰, wherein R¹⁰ 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,

R⁶ 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

R⁷ is a hydrogen atom, or straight or branched C_1-10 alkyl, and

R² and R³ taken together are C_3-5 alkylene or said alkylene in which methylene is substituted by an O atom.

2. The pyrimidine compound or its pharmaceutically acceptable salt of claim 1, wherein R² and R³ taken together are trimethylene or tetramethylene.

3. The pyrimidine compound or its pharmaceutically acceptable salt of claim 1, wherein R¹ is the formula (2)

wherein ring A and R⁴ are the same as defined above.

4. The pyrimidine compound or its pharmaceutically acceptable salt of claim 1, wherein R¹ is the formula (3)

wherein R⁵, R⁶ and R⁷ are the same as defined above.

5. The pyrimidine compound or its pharmaceutically acceptable salt of claim 1 or 4, wherein R⁵ is straight C_3-5 alkyl or straight C_2-4 alkyl substituted by hydroxy.

6. A method for suppressing the immune response of type 2 helper T cells in a patient comprising administering an effective amount of the pyrimidine compound or its pharmaceutically acceptable salt of claim 1 as an active ingredient to said patient.

7. 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.

8. The method of claim 7, wherein the disease is an allergic disease.

9. The method of claim 8, wherein the alleregic disease is asthma, allergic rinitis, or allergic dermatitis.

10. A method for enhancing the immune response of type 1 helper T cells 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 enhancing the production of IFNγ

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.

12. A method for treating a patient with a disease wherein enhancing the immune response 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.

13. The method of claim 12, wherein the disease is viral or bacterial infectious disease.