Bicyclic pyrimidine compounds and therapeutic use thereof

• US 6,951,866 B2
• Filed: 08/19/2002
• Issued: 10/04/2005
• 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: Tanaka, Hiroshi, Iwai, Kiyotaka, Fujita, Hitoshi, Kawakami, Hajime, Antoku, Fujio, Fujiwara, Norio
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US10/222,922
• Publication Number:
  US 20030105323A1
• Time in Patent Office: 1,142 Days
• Field of Search: 544/323, 544/324, 544/325, 514/275
• US Class Current: 514/275
• 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

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.

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_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)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 is hydrogen atom, or straight or branched C_1-10 alkyl, and

R³ 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

R¹¹ 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 R¹¹ is phenyl.

2. The pyrimidine compound or its pharmaceutical acceptable salt of claim 1, wherein R³ is straight or branched C_1-7 alkyl.

3. The pyrimidine compound or its pharmaceutically acceptable salt of claim 1, wherein R³ is the formula (4)

R¹¹—

(CH₂)_n—

 

 

(4)

wherein R¹¹ and n are the same as defined above.

4. The pyrimidine compound or its pharmaceutically acceptable salt of claim 1 or 3, wherein R¹¹ 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 R⁵ 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 R¹ is the formula (2)

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

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

wherein R⁵, R⁶, and R⁷ 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.