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Pyrazolo[3,4-B] Pyridine Compounds and Their Use as Pde4 Inhibitors

a technology of pyridine compounds and pyridine, which is applied in the direction of antibacterial agents, drug compositions, immunological disorders, etc., can solve the problems of inability to disclose the use of pyrazolo[3,4-b]pyridine compounds by external topical administration and inability to inhal

Inactive Publication Date: 2008-11-06
GLAXO GRP LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to pyrazolobpyridine compounds and their use in therapy. The compounds have been found to inhibit phosphodiesterase type IV (PDE4) and to have anti-inflammatory and analgesic properties. They can be used to treat inflammatory and allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, allergic rhinitis, and atopic dermatitis. The invention also includes processes for preparing the compounds, pharmaceutical compositions containing them, and methods of using them in therapy.

Problems solved by technology

However, the use of the pyrazolo[3,4-b]pyridine compounds by external topical administration is not disclosed.
For treatment and / or prophylaxis of atopic dermatitis, inhaled administration is usually not suitable.

Method used

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  • Pyrazolo[3,4-B] Pyridine Compounds and Their Use as Pde4 Inhibitors
  • Pyrazolo[3,4-B] Pyridine Compounds and Their Use as Pde4 Inhibitors
  • Pyrazolo[3,4-B] Pyridine Compounds and Their Use as Pde4 Inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(2,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0544]

[0545]A solution of Intermediate 5 (0.066 mmol) in DMF (1 ml) was mixed with EDC (0.066 mmol), HOBT (0.066 mmol) and DIPEA (0.151 mmol) followed by 2,4-dimethyl benzylamine (0.066 mmol) (e.g. Trans World Chemicals Inc.). The reaction mixture was left to stand at room temperature overnight (e.g. for 16 h). The DMF was evaporated and the residue was partitioned between DCM (5 ml) and saturated aqueous NaHCO3 solution (2 ml). The organic layer was collected through a hydrophobic frit and evaporated. The residue was purified by mass directed autoprep. HPLC to give the title compound Example 1 as a gum (7.9 mg). LCMS showed MH+=450; TRET=2.8 min.

example 2

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0546]

[0547]A solution of Intermediate 5 (100 mg, 0.3 mmol) in dry DMF (e.g. can be about 1 ml) was treated with EDC (63 mg, 0.33 mmol), HOBT (45 mg, 0.33 mmol) and DIPEA (0.13 ml, 0.75 mmol). 10 minutes later, 3,4-dimethyl-benzylamine (47 microlitres, 0.33 mmol) (e.g. available from Trans World Chemicals Inc.) was added and the resulting solution was left to stand at room temperature overnight. The DMF was removed by evaporation and the residue was partitioned between DCM and saturated aqueous NaHCO3 solution. The organic layer was collected through a hydrophobic frit and was concentrated in vacuo to dryness. The residue was purified by passing through a 20 g silica SPE cartridge, using firstly a gradient of EtOAc and cyclohexane (increasing concentration of EtOAc) and then a step gradient of EtOAc and methanol as the eluent. The product was eluted in the fracti...

example 2a

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0550]

[0551]A mixture of Intermediate 9 (27 mg, 0.08 mmol), Intermediate 12 (16 mg, 0.088 mmol) and DIPEA (35 microlitres, 0.2 mmol) in MeCN (2 ml) was heated at reflux for 18 h. More of Intermediate 12 (0.5 mole equivalents, ca. 0.04 mmol, ca. 7 mg) was added. The reaction mixture was heated at reflux for a further 24 h, cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between DCM and water. The organic phase was collected through a hydrophobic frit and evaporated to dryness. LCMS indicated that there were two products of the same molecular weight.

[0552]Therefore, the residue was purified by mass directed autopreparative HPLC to give the title compound as Example 2A (4.4 mg); LCMS showed MH+=450 and TRET=2.79 min.

[0553]The other undesired product having the same molecular weight as Example 2A was also isolated from the mas...

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Abstract

The invention provides a compound of formula (I) or a salt thereof:wherein:R1 is C1-3alkyl, C1-3fluoroalkyl, or —CH2CH2OH;R2 is hydrogen, methyl or C1fluoroalkyl;R3 is of sub-formula (aa) or (bb):wherein Y is NCONH2 and n1 is 0 or 1;R4 is H; and R5 is a group of the sub-formula (x), (y), (y1) or (z):These compounds are PDE4 inhibitors.

Description

[0001]The present invention relates to pyrazolo[3,4-b]pyridine compounds or salts thereof, processes for their preparation, intermediates usable in these processes, and pharmaceutical compositions containing the compounds or salts. The invention also relates to the use of the pyrazolo[3,4-b]pyridine compounds or salts thereof in therapy, for example as inhibitors of phosphodiesterase type IV (PDE4) and / or for the treatment and / or prophylaxis of inflammatory and / or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, allergic rhinitis, psoriasis or atopic dermatitis.BACKGROUND TO THE INVENTION[0002]U.S. Pat. No. 3,979,399, U.S. Pat. No. 3,840,546, and U.S. Pat. No. 3,966,746 (E.R. Squibb & Sons) disclose 4-amino derivatives of pyrazolo[3,4-b]pyridine-5-carboxamides wherein the 4-amino group NR3R4 can be an acyclic amino group wherein R3 and R4 may each be hydrogen, lower alkyl (e.g. butyl), phenyl, etc.; NR3R4 can alternatively be a 3-...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/437C07D487/04A61P11/06
CPCC07D471/04A61P1/04A61P11/00A61P11/02A61P11/06A61P13/12A61P17/00A61P17/06A61P19/02A61P25/00A61P25/24A61P25/28A61P27/02A61P27/16A61P29/00A61P31/04A61P35/00A61P37/00A61P37/08A61P43/00A61P9/10C07D487/04
Inventor COOK, CAROLINE MARYDOWLE, MICHAEL DENNISEDLIN, CHRISTOPHER DAVIDJOHNSON, MARTIN REDPATHJONES, PAUL SPENCERLINDVALL, MIKA KRISTIANTRIVEDI, NAIMISHAREDGRAVE, ALISON JUDITH
Owner GLAXO GRP LTD