Pyridinylpyrazolopyrimidinone derivatives as pde 7 inhibitors

a technology of pyrazolopyrimidinone and derivatives, which is applied in the direction of antibacterial agents, immunological disorders, drug compositions, etc., can solve the problem that no curative medicines with pde 7 inhibiting effect as main pharmacological mechanism have developed up to now, and achieve significant pde 7 inhibiting

Inactive Publication Date: 2006-06-15
DAIICHI SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0115] The following compounds showed no more than 0.1 μM of IC50 values. Compounds NO. 16, 17, 18, 20, 21, 22, 25, 26, 27, 28, 29, 32, 33, 36, 37, 43, 44, 47, 48, 49.
[0118] Compound 32: IC50=0.00321 μM;
[0119] As described above, the compounds of the present invention showed significant PDE 7 inhibiting effect.
[0120] The compounds of the present invention selectively inhibit PDE 7 and their selectivities are more than 10 times compared to PDE 4 (phosphodiesterase IV), which is similar to the PDE 7. Therefore, it is expected that the side effect of the compounds of the present invention caused by PDE 4 to be less. The selectivity against PDE 4 (phosphodiesterase IV) of the compounds of the present invention was affirmed by means of the following Biological Test.
[0125] (4) IC50 was calculated as 50% inhibiting concentration of the metabolic activities of phosphodiesterase IV of the tested compound.
[0126] As the results of the mentioned above Biological Test 2, the IC50 of the compounds of the present invention was more than 10 times weaker than that of PDE 7 inhibiting effect.

Problems solved by technology

However, no curative medicines having PDE 7 inhibiting effect as main pharmacological mechanism have developed up to now.

Method used

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  • Pyridinylpyrazolopyrimidinone derivatives as pde 7 inhibitors

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examples

[0106] The present invention is illustrated in more detail by way of the following Biological Test and Examples, but it is to be noted that the present invention is not limited by those Examples in any way.

[0107] The synthesis of the compounds of the present invention and intermediate compounds to be used in the synthesis are illustrated in the Example mentioned later. Further, the physicochemical data and chemical structure of the compounds and intermediate compounds obtained by the Examples are summarized in the Tables mentions later.

[0108] The compound numbers in the Examples are identical to those in the Tables.

[0109] The PDE 7 (phosphodiesterase VII) inhibiting effect of the compounds of the present invention obtained in the later mentioned Examples was evaluated by mean of the following Biological Tests.

manufacturing examples and examples

[0134] The synthesis of the compounds of the present invention is illustrated in the following Examples.

[0135] The physicochemical data and chemical structure of the compounds are summarized in the Tables mentions later. The compound numbers in the Examples are identical to those in the Tables.

example 1

2-Cyclohexyl-5-Methyl-2,4-Dihydro-3H-Pyrazol-3-One

[0136] A mixture solution of 14.5 mL(0.134 mol) of methyl acetoacetate and 20.2 g (0.134 mol) of cyclohexylhydrazine hydrochloride was stirred for 2 hours at 120° C., and the mixture was cooled. Then, the reaction mixture was neutralized with 30 mL of 4M-sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was treated with hexane. The resulting precipitate was collected to give 19.0 g (79%) of the titled compound.

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Abstract

To provide the compounds inhibiting PDE 7 selectively, and therefore, enhance cellular cAMP level. Consequently, the compound is useful for treating various kinds of disease such as allergic disease, inflammatory disease or immunologic disease. The compound is pyridinylpyrazolopyrimidinone compound represented by the following formula (IA) or (IB): especially, R1 is cyclohexyl or cycloheptyl group, R2 is methyl; R3 is a group: —NR5R6 or —S(O)0-2R8; hydrogen atom; nitro group; cyano group; a halogen atom; heteroaryl group; and R4 is methoxy or ethoxy group.

Description

TECHNICAL FIELD [0001] The present invention relates to pyridinylpyrazolopyrimidinone compounds, pharmaceutically acceptable salts and solvates thereof, having selective PDE 7 (phosphodiesterase VII) inhibiting effect. These compounds are effective compounds for treating various kinds of disease such as allergic disease, inflammatory disease and immunologic disease. BACKGROUND ART [0002] A cyclic AMP (cAMP) or cyclic GMP (cGMP), which is an intracellular second messenger substance, is decomposed and inactivated by phosphodiesterase (PDE 1 to PDE 11). The PDE 7 selectively decomposes CAMP, and is characterized as an enzyme not decomposed by rolipram. Rolipram is a selective inhibitor of PDE 4 which decomposes CAMP. [0003] It is suggested that PDE 7 plays an important role for activating T cells (Beavo, et al., Science, 283, 848 (1999)), and well known that activating of T-cell is concerned with the exacerbation of allergic disease, inflammatory disease or immunologic disease. These d...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/519C07D487/02A61P29/00A61P37/00C07D487/04C07D519/00
CPCC07D487/04A61P1/00A61P1/04A61P1/16A61P1/18A61P9/00A61P9/10A61P11/00A61P11/02A61P11/06A61P17/00A61P17/06A61P19/02A61P25/00A61P27/02A61P27/14A61P27/16A61P29/00A61P31/04A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00
Inventor INOUE, HIDEKAZUMURAFUJI, HIDENOBUHAYASHI, YASUHIRO
Owner DAIICHI SANKYO CO LTD
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