Adenosine derivatives, method for the synthesis thereof, and the pharmaceutical compositions for the prevention and treatment of the inflammatory diseases containing the same as an active ingredient
Inventors
Jeong, Lak Shin • Kim, Hea Ok • Jacobson, Kenneth A. • Choe, Seung Ah
Assignees
Future Medicine Co Ltd • US Department of Health and Human Services • Office of Technology Transfer
Publication Number
US-9018371-B2
Publication Date
2015-04-28
Expiration Date
2027-03-07
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Abstract
Disclosed are adenosine derivatives, methods for the synthesis thereof, and pharmaceutical compositions for the prevention and treatment of inflammatory diseases, comprising the same as an active ingredient. The adenosine derivatives have high binding affinity and selectivity for adenosine receptors, especially for A3 adenosine receptors and act as A3 adenosine receptor antagonists, and exhibit anti-inflammatory activity. Thus, the adenosine derivatives are useful in the prevention and treatment of inflammatory diseases.
Core Innovation
The invention discloses novel adenosine derivatives, methods for their synthesis, and pharmaceutical compositions comprising these derivatives as active ingredients for the prevention and treatment of inflammatory diseases. These adenosine derivatives exhibit high binding affinity and selectivity particularly for A3 adenosine receptors and act as A3 adenosine receptor antagonists, demonstrating anti-inflammatory activity.
The problem addressed is that previous adenosine receptor-targeting compounds lacked tissue-specific activation, limiting their therapeutic efficacy and commercialization. Although functions of A1 and A2 adenosine receptors are well studied, the role of A3 receptors was unclear, and existing antagonists based on non-purinergic heterocyclic compounds had weak or ineffective activity in animal models. There was a need for selective A3 adenosine receptor antagonists with nucleoside skeletons that maintain high affinity and selectivity across species, enabling their evaluation and use in animal tests and potential clinical applications.
The inventors discovered that adenosine derivatives lacking an N-methylcarbamoyl group at the 5-position of the sugar moiety but substituted with arylamino or alkylamino groups at the 6-position of the purine moiety are strong candidates for A3 adenosine receptor antagonists. The invention provides such derivatives with a general chemical formula involving specific substitutions (A as O or S; R and Y as defined) along with synthesis methods converting starting materials into these derivatives through multi-step reactions involving Lewis acid catalysis and amine substitution.
Claims Coverage
The patent includes claims covering a synthesis method, the A3 adenosine receptor antagonist compounds themselves, and pharmaceutical compositions containing said compounds. The claims specify inventive features related to chemical structures, synthesis steps, catalysts, and pharmaceutical uses.
Method for synthesizing a selective A3 adenosine receptor antagonist
A three-step synthesis involving (1) reaction of a starting material of Chemical formula 2 with a silylated purine derivative of Chemical formula 5 using a Lewis acid catalyst to produce a β-anomer (Chemical formula 3), (2) addition of HCl to yield a diol compound (Chemical formula 4), and (3) reaction of the diol with an amine compound in the presence of a base catalyst to obtain the A3 adenosine receptor antagonist. The method produces specific tetrahydrothiophen based adenosine derivatives listed in the claim.
Use of specific solvents and catalysts in synthesis steps
Conducting the first step in solvents such as dichloroethane, chloroform, acetonitrile, or dichloromethane, with trimethylsilyl trifluoromethanesulfonate as the Lewis acid catalyst.
Preparation of silylated purine compound
The silylated purine compound is prepared by reacting a purine compound of Chemical formula 5 with hexamethyldisilazane in the presence of ammonium sulfate as a catalyst.
Catalysts for the amine reaction step
Use of bases such as triethylamine, pyridine, N,N-dimethylaminopyridine, and 1,4-dioxane as catalysts in the reaction of the diol compound with the amine.
Starting material synthesis route involving D-mannose
Preparation of the starting material (Chemical formula 2a) via sequential steps starting from D-mannose: acid-catalyzed reaction with 2,2-dimethoxypropane to form diacetonide, ring opening with a reducing agent, mesylation to a dimesyl compound, cyclization to a thiosugar, selective hydrolysis to a diol, and conversion to an acetate compound in the presence of a catalyst.
Use of specific reagents and conditions in starting material synthesis
Use of acids (concentrated sulfuric acid, HCl, or p-toluene sulfonic acid) in Step a1, reducing agents (sodium borohydride, lithium aluminum hydride, sodium sulfite) in Step a2, methanesulfonyl chloride as mesylating agent in Step a3, solvents such as ethyl ether, petroleum ether, dichloromethane, tetrahydrofuran, and N,N-dimethylformamide in Step a4, and acid catalysts (acetic acid, sulfuric acid, hydrochloric acid, p-toluene sulfonic acid) in Step a5.
A3 adenosine receptor antagonist compounds themselves
Compounds comprising a (2R,3R,4S) tetrahydrothiophen based adenosine derivative or pharmaceutically acceptable salt thereof, selected from a defined group of specific chemical entities characterized by substitutions on the purine and sugar moieties as detailed in the claim.
Pharmaceutical composition for treatment of inflammatory diseases
Compositions containing the specified (2R,3R,4S) tetrahydrothiophen based adenosine derivatives or pharmaceutically acceptable salts thereof as active ingredients, formulated for preventing or treating inflammatory diseases such as exudative, purulent, hemorrhagic, and hyperplastic inflammation.
The claims disclose a comprehensive method for synthesizing selective A3 adenosine receptor antagonists, specific antagonist compounds defined by precise chemical substitutions, and pharmaceutical compositions for treating inflammatory diseases using these antagonists. The synthesis involves defined catalysts, solvents, and reaction steps, enabling production of compounds with high specificity and therapeutic efficacy.
Stated Advantages
The adenosine derivatives exhibit high binding affinity and selectivity for A3 adenosine receptors, minimizing off-target effects on A1 and A2 receptors.
The derivatives act as A3 adenosine receptor antagonists with significant anti-inflammatory activity, making them suitable therapeutic agents for inflammatory diseases.
Nucleoside skeleton-based A3 antagonists maintain high affinity and selectivity independent of species, facilitating effective evaluation in animal models.
The compounds can be formulated in various dosage forms for systemic or topical administration, providing flexibility in therapeutic use.
The compounds have demonstrated safety in toxicity assays with no observed deaths or adverse effects in animal models.
Documented Applications
Use of the adenosine derivatives as A3 adenosine receptor antagonists for the prevention and treatment of inflammatory diseases.
Treatment of acute and chronic inflammatory conditions including ulcerative, exudative, purulent, hemorrhagic, and hyperplastic inflammation.
Pharmaceutical compositions formulated for systemic or topical administration for therapeutic applications involving inflammation.
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