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Purine derivatives as immunomodulators

a technology of purine derivatives and immunomodulators, applied in the field of compounds, can solve the problems of inability to show a sustained viral response and inability to control viral load

Inactive Publication Date: 2010-05-13
SMITHKLINE BECKMAN CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The patent describes compounds that can induce human interferon, a protein that has various uses in treating disorders such as infectious diseases, cancer, and allergic diseases. These compounds have improved potency and can be used as vaccine adjuvants and in the treatment of inflammatory conditions. The compounds are also easier to manufacture and have a better safety profile compared to other inducers of interferon."

Problems solved by technology

However, many patients fail to show a sustained viral response and in these patients viral load is not controlled.
Additionally, therapy with injected interferon may be associated with a number of unwanted adverse effects which are shown to affect compliance (Dudley T, O'Donnell K, Haydon G, Mutimer D.

Method used

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  • Purine derivatives as immunomodulators
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  • Purine derivatives as immunomodulators

Examples

Experimental program
Comparison scheme
Effect test

example 1

6-Amino-2-butoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-7,9-dihydro-8H-purin-8-one

[1591]

[1592]2-Butoxy-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (0.22 g) was dissolved in methanol (10 mL) and treated with 4N hydrogen chloride in 1,4-dioxane (1 mL). The reaction was stirred at room temperature 16 hours and stripped to give a solid that was suspended in water (2 mL) before sufficient methanol was added until a solution was obtained. 2N Sodium hydroxide solution was added to bring to pH 7, and the solution concentrated until a suspension formed. The white solid was filtered and washed with water (2 mL, twice to complete transfer and wash). This was dried under suction and then under vacuum at 50° C. to give the title compound as a white solid (0.189 g).

[1593]MS calcd for (C15H23N5O3)+=321

[1594]MS found (electrospray): (M+H)+=322

[1595]1H NMR ((CD3)2SO): 9.86 (1H, s), 6.41 (2H, s), 4.14 (2H, t), 3.81 (2H, m), 3.55 (2H, d), 3.22 (2H, m), 2.03 (1H, m), 1.64 (2H, m), 1.49-1....

example 2

6-Amino-2-butoxy-9-(tetrahydro-2H-pyran-2-ylmethyl)-7,9-dihydro-8H-purin-8-one

[1596]

[1597]2-Butoxy-8-methoxy-9-(tetrahydro-2H-pyran-2-ylmethyl)-9H-purin-6-amine (6 mg, ˜85% pure) was dissolved in methanol (1 mL), treated with 4N hydrogen chloride in 1,4-dioxane (0.5 mL) and stirred for 5 hours at room temperature. The mixture was stripped to dryness to give the title compound (77.8:10.8 by LCMS) as a colourless gum (8 mg).

[1598]MS calcd for (C15H23N5O3)+=321

[1599]MS found (electrospray): (M+H)+=322

[1600]1H NMR (CD3OD): 4.54 (2H, t), 4.06-3.65 (5H, overlapping m), 1.87-1.83 (3H, overlapping m), 1.69 (1H, d), 1.52 (4H, overlapping m), 1.35 (2H, m), 1.01 (3H, t) (NH2 & NH protons exchanged).

example 3

6-Amino-2-butoxy-9-(tetrahydrofuran-2-ylmethyl)-7,9-dihydro-8H-purin-8-one

[1601]

[1602]To 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.20 g) in dry DMF (5 mL) was added anhydrous potassium carbonate (0.315 g). This was heated to 60° C. for 1 hour and then cooled to room temperature. Tetrahydrofurfuryl bromide (65 uL) was added and the reaction mixture was then heated to 50° C. overnight. The reaction was quenched with water and extracted with ethyl acetate (twice). The organic phase was separated, combined and dried by passing through a hydrophobic frit. Evaporation of the organic phase and purification of the oil so formed by silica chromatography (40 g) (ISCO) eluting with 0-100% ethyl acetate:cyclohexane and then 0-10% methanol:ethyl acetate then methanol gave a gum. This gum was dissolved in methanol (5 mL) and treated with 4N hydrogen chloride in 1,4-dioxane (1 mL) and stirred overnight at room temperature. The reaction mixture was stripped to dryness to give a g...

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Abstract

Compounds of formula (I):whereinR1 is C1-8alkylamino, C1-8alkoxy, C3-7cycloalkylC1-6alkylamino, C3-7cycloalkylC1-6alkoxy, C1-3alkoxyC2-3alkoxy, or Hetb-C1-3alkoxy;Hetb is a 5- or 6-membered saturated aliphatic heterocycle containing one oxygen atom;R2 is —(CH2)n-Het;n is an integer having a value of 1 to 4;Het is a 5- or 6-membered saturated aliphatic heterocycle containing one oxygen heteroatom, which heterocycle may be substituted by one or two C1-4alkyl groups, and salts and solvates thereof, are inducers of human interferon and may be useful in the treatment of various disorders in particular infectious diseases, cancer, and allergic diseases and other inflammatory conditions for example allergic rhinitis and asthma, and as vaccine adjuvants.

Description

BACKGROUND OF THE INVENTION[0001]The present invention relates to compounds, processes for their preparation, compositions containing them, to their use in the treatment of various disorders in particular infectious diseases, cancer, and allergic diseases and other inflammatory conditions for example allergic rhinitis and asthma, and as vaccine adjuvants.[0002]Vertebrates are constantly threatened by the invasion of microorganisms and have evolved mechanisms of immune defence to eliminate infective pathogens. In mammals, this immune system comprises two branches; innate immunity and acquired immunity. The first line of host defence is the innate immune system, which is mediated by macrophages and dendritic cells. Acquired immunity involves the elimination of pathogens at the late stages of infection and also enables the generation of immunological memory. Acquired immunity is highly specific, due to the vast repertoire of lymphocytes with antigen-specific receptors that have undergo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/522C07D473/18A61P35/00A61P29/00A61P11/06
CPCC07D473/18C07D473/16A61P11/02A61P11/06A61P29/00A61P31/00A61P35/00A61P35/04A61P37/00A61P37/04A61P37/08
Inventor LAZARIDES, LINOSSMITH, STEPHEN ALLANSTOCKER, RICHARDTHEOBALD, COLIN JACK
Owner SMITHKLINE BECKMAN CORP
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