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Pyridazinone derivatives used for the treatment of pain

A technology of pyridazinone and its derivatives, applied in the field of pyridazinone derivatives and their salts

Inactive Publication Date: 2008-09-17
ASTELLAS PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The above facts indicate that, although of great interest for the future treatment of RA, these biological substances have fundamental disadvantages related to patient cost, production efficiency, limitations of subcutaneous or intravenous administration, etc.

Method used

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  • Pyridazinone derivatives used for the treatment of pain
  • Pyridazinone derivatives used for the treatment of pain
  • Pyridazinone derivatives used for the treatment of pain

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 123

[0316] 6-[(5S)-2-(4-fluorophenyl)-5-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl ]-2-(2-methylphenyl)pyridazine-3(2H)-one (Example 124)

Embodiment 125

[0318] 6-(5-isopropyl-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-(2-methylbenzene Yl)pyridazine-3(2H)-one (Example 130)

[0319] [III] Test results

[0320] Table 1: Inhibition of 100nM concentration on TNF-α production in THP-1 cells

[0321] Test compound (Example number)

% Inhibition rate of control

Example 1

88

Example 2

98

Example 6

80

Example 35

90

Example 37

94

Example 47

95

Example 55

98

Example 57

97

Example 85

88

Example 98

86

Example 107

90

Example 123

94

Example 124

94

Example 125

83

Example 130

70

[0322] Test 2: Inhibition of hind paw edema in rat arthritis induced by adjuvant

[0323] [I] Test method

[0324] Arthritis was induced by injecting 0.5 mg of Mycobacterium tuberculosis (Difco Laboratories, Detroit, Mich.) in 50 μL of liquid para...

Embodiment 132

[0335] [III] Test results

[0336] Table 2: Inhibition of hind paw edema in rat arthritis induced by adjuvant

[0337] Test compound (Example number)

Dose (mg / kg)

Medium-treated rats

%Inhibition rate

Example 1

0.3

51.2

Example 3

1

56.4

Example 18

1

46.1

Example 37

1

63.6

Example 63

1

39.5

Example 86

1

48.1

Example 100

0.5

40.2

Example 123

1

62.3

Example 124

1

50.6

Example 132

1

60.4

[0338] The compound (I) of the present invention and its salts can be used as inhibitors of cytokine production and its conversion, and by inhibiting p38αMAPK, they have pharmacological effects, such as analgesic effects, anti-inflammatory or anti-disruptive arthritis effects, etc., Therefore, it can be used to prevent and / or treat pain, rheumatoid arthritis, other diseases related t...

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PUM

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Abstract

A pyridazinone derivative compound shown by the following formula (I): wherein R1 is selected from hydrogen, etc.; R2 is selected from substituted or unsubstituted aryl, etc.; R3 is hydrogen, etc.;p is 0, 1 or 2; R4 and R5 are each hydrogen, etc.; R6 and R7 are taken together to form a group of the formula: wherein R8 is hydrogen; X is selected from oxygen, etc; R10 is selected from hydrogen, etc.; R11 is selected from hydrogen, etc.; R12 is selected from hydrogen, etc.; R13 is selected from hydrogen, etc.; R14 is selected from hydrogen, etc.; m and n are each 0, 1, or 2, or a pharmaceutically acceptable salt thereof, which is useful as a medicament.

Description

Technical field [0001] The present invention relates to pyridazinone derivatives and their salts, which can be used as medicines. Background technique [0002] Rheumatoid arthritis (RA) is a systemic inflammatory disease that mainly results in a lack of synovial fluid in the joints. Methotrexate (MTX) is currently a commonly used anti-rheumatoid drug (DMARD) for disease reduction, but its effect on inflammation or mutilating arthritis is still insufficient. On the other hand, the biology of targeted cytokines (TNF, IL-I, IL-6) has recently revealed their efficacy for RA and demonstrated the important role of these cytokines in RA characterization. Particularly worth mentioning is the monoclonal TNF antibody Remicade and the soluble TNF receptor fusion protein, which inhibit the function of TNF because of its unexpected effect on inflammatory response and mutilating arthritis. [0003] The above facts show that although they are of great significance for the treatment of RA in the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D487/20A61K31/495A61P29/00
CPCC07D487/04A61P1/04A61P17/06A61P19/02A61P25/00A61P25/02A61P29/00A61P43/00A61K31/495C07D487/20
Inventor 山崎齐笠原千义洼田浩一绀谷彻浅野亨水原日出一横本正治三隅启司木下智彦
Owner ASTELLAS PHARMA INC