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WO1999048903A1 - Derive d'adenosine - Google Patents

Derive d'adenosine Download PDF

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Publication number
WO1999048903A1
WO1999048903A1 PCT/JP1999/001459 JP9901459W WO9948903A1 WO 1999048903 A1 WO1999048903 A1 WO 1999048903A1 JP 9901459 W JP9901459 W JP 9901459W WO 9948903 A1 WO9948903 A1 WO 9948903A1
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WO
WIPO (PCT)
Prior art keywords
receptor
adenosine
receptors
adenine
group
Prior art date
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Ceased
Application number
PCT/JP1999/001459
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English (en)
Japanese (ja)
Inventor
Akira Matsuda
Hiroyasu Nakata
Yoshiko Saitoh
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Application filed by Individual filed Critical Individual
Publication of WO1999048903A1 publication Critical patent/WO1999048903A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel adenosine derivatives. More specifically, the present invention relates to an adenosine derivative capable of binding to a purine receptor 3-like substance.
  • Conventional technology relates to novel adenosine derivatives. More specifically, the present invention relates to an adenosine derivative capable of binding to a purine receptor 3-like substance.
  • Adenosine 5'-triphospate (ATP) is a substance that is a source of energy in living organisms, and its biochemical importance in cells. Sex has been recognized for many years. In addition to its intracellular activity, knowledge of extracellular actions via its receptor on its cell surface has been accumulating in recent decades (NY Acad. Sci. 603, 1-17, 1990).
  • ATP exerts its physiological actions through purine receptors (Receptor & Channel, 3, 283-289, 1995).
  • the receptor is classified into P1 receptor and P2 receptor, both of which are said to bind extracellular adenine nucleotides.
  • P1 receptors are usually called adenosine receptors, selectively bind to adenosine, and are classified into subclasses of Al, A2, and A3.
  • A1 and A3 receptors bind to GI / G0 proteins and are involved in suppressing adenylate cyclase activity.
  • A2 receptor stimulates adenylate cyclase activity by binding to GS protein.
  • P2 receptors are classified into purine receptor families of P2X (ligand gated), P2Y, U and Z (G protein binding) (Pharmacol, rev. 46, 143-156, 1994).
  • P2X ligand gated
  • P2Y P2Y
  • U and Z G protein binding
  • ATP acts on the P2x subtype of purine receptors and increases ion transport to a wide range of cells, including neurons and smooth muscle cells (Trends. Pharmacol. Sci. 16, 168-174).
  • six types of P2x receptors have been The p2x purine receptor subtype has been cloned.
  • purine receptors are roughly classified into P1 receptors and P2 receptors, and are further subdivided.
  • P1 receptor particularly an adenosine antagonist
  • adenosine antagonist as a therapeutic agent for anti-Parkinson's disease and a therapeutic agent for renal failure.
  • P2 receptors for example, the binding of P2X receptors to ATP is deeply involved in sympathetic transmission in neurons.
  • P2X1 is involved in the above-mentioned transmission between neurons and smooth muscle. Therefore, nervous system diseases, pollakiuria, analgesics, etc. are considered as clinical applications of the ligand.
  • P3-like receptor purine receptor 3-like substance
  • an object of the present invention is to provide a substance that can bind to a P3-like receptor. Disclosure of the invention
  • the substance capable of binding to the P3-like receptor according to the present invention is an adenosine derivative represented by the following general formula.
  • R 1 and R 2 represent a hydroxyl group or a lower alkynyl group. However, when one of R 1 and R 2 is a lower alkynyl group, the other is a hydroxyl group; and one of R 1 and R 2 Is a hydroxyl group and the other is a lower alkynyl group)
  • preferred compounds are those represented by the following general formula (4).
  • a compound in which one of R 1 and R 2 is a hydroxyl group and the other is an ethynyl group or an 11-hexynyl group is preferable.
  • the method for screening a purine receptor 3-like substance of the present invention is characterized by using an adenosine derivative represented by the above general formula.
  • the adenosine derivative of the present invention is represented by the above general formula, and examples of the lower alkynyl group represented by R 1 and R 2 include an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, and a hexynyl group. , Preferably eti Examples thereof include a phenyl group and a 1-hexynyl group.
  • the compound of the present invention has optical isomers based on an asymmetric carbon in the molecule, and such isomers and mixtures thereof are all included in the scope of the present invention.
  • the adenosine derivatives of the present invention include salts thereof, and examples of such salts include acid addition salts such as hydrochloride, nitrate, and phosphate.
  • the adenosine derivative of the present invention represented by the above general formula can be obtained by various methods. For example, as shown in Examples described later, it can be synthesized by a method represented by the following reaction scheme. .
  • R 1 , R 2 Co C (CH 2 ) 3 CH 3 or OH 3c, d;, R 2 -C ⁇ C (CH 2 ) 3 CH 3 or OH
  • R 1 C ⁇ CH
  • R 2 GH
  • R 1 OH
  • R 2 C C (CH 2 ) 3 CH 3
  • the screening method for a purine receptor 3-like substance of the present invention is characterized by using an adenosine derivative represented by the above general formula. More specifically, the method described in Test Examples described later is used. It can be implemented according to. Industrial applicability
  • the adenosine derivative of the present invention can selectively bind to a P3-like receptor as shown in the test examples described below, it can be used for screening for a P3-like receptor and a substance having the action. It is useful for studying the pharmacological, biochemical and physiological actions and mechanisms of purine receptors. Further, the adenosine derivative of the present invention can be expected to be applied as a medicine (for example, a hypotensive agent or the like).
  • a medicine for example, a hypotensive agent or the like.
  • EtMgBr (3 M THF solution, 5.62 mL) was added to a THF solution (20 mL) containing trimethylsilyl acetylene (2.54 mL) at 10 ° C under an argon atmosphere, and the mixture was stirred at the same temperature for 2 hours.
  • An aqueous NH 4 C1 solution (1 M) was added to the reaction solution, extracted with ethyl acetate, and the organic layer was dried over Na 2 SO 4 . The organic layer was concentrated to dryness and the residue was purified by a silica gel column. 2a (1.24 g), 2b (461 mg) and a mixture of 2a and 2b (282 mg) were converted to a white foam. I got it.
  • a rat brain membrane fraction was prepared in the same manner as described in (1989), and 10 volumes of 0.4% CHAPS at 0 ° C.
  • the membrane proteins were solubilized by mixing with 5 OmM Tris acetate buffer ( ⁇ 7.2) containing After centrifugation at 40,000 ⁇ g for 1 hour, the supernatant was collected and applied to a hydroxyapatite column pre-equilibrated with 50 mM Tris acetate buffer (pH 7.2) containing 0.1 M sodium chloride and 0.1% CHAPS.
  • the purine receptor binding inhibition experiment of the compound of the present invention was performed by the following method.
  • (1) The inhibitory effect of the test compound on the NEC3-binding activity of the P3-like receptor was examined according to the method described in Biochem. Biophys. Res. Commun., 219, 469-474 (1996). That is, it contains 0.1% CHAPS, 4 mM magnesium chloride, test compounds of various concentrations (1 ⁇ -100 ⁇ ) (the compound of the present invention represented by the general formula (4a), the same applies hereinafter), and 32 nM tritium-labeled NECA.
  • 0.12 pinol of the purified P3-like receptor was added to 50 mM Tris acetate buffer (pH 7.2), and incubated at 0 ° C for 15 hours.
  • the reaction was terminated by filtering the reaction mixture through a filter (Whatman GF / B) pretreated with 0.3% polyethyleneimine.
  • the filter was washed three times with 50 mM Tris acetate buffer (pH 7.2), transferred to a vial, added with 5 ml of Aquasol, and the tritium count was measured with a liquid scintillation counter.
  • K i values were calculated using the Graph Pad Prism of the combi- ter program.
  • the K i of the test compound for the NECA binding activity of the P 3 -like receptor was determined to be 19 nM.
  • the membrane fraction of rat brain prepared by the method described in J. Biol. Chem., 264, 16545-16551 (1989) was used. Was used. A membrane fraction of 0.18 mg was used to measure the activity of the A1 adenosine receptor, and 0.55 mg was used to measure the activity of the A2a adenosine receptor.
  • A1 adenosine receptor ligands include 2. OnM tritium-labeled DP CPX
  • A2a adenosine receptor has 5.9n tritium-labeled CGS 2 1680
  • the binding activity was measured in the same manner as above.
  • the test compound does not inhibit the DPCP X binding activity of A1 adenosine receptor at concentrations below ⁇ . ⁇ (Ki; 12 ⁇ ), and the CGS 21680 binding activity of A2a adenosine receptor is only inhibited by about 40% even at ⁇ Did not.
  • VA VA-13 cells were used to measure A2b adenosine receptor activity, and the change in intracellular cAMP concentration when the test compound was added was examined.
  • Cells were cultured in 24-well plates at a concentration of 100,000 cells / ⁇ l for 2 days, and the cells were treated with 118 mM sodium chloride, 4.7 mM potassium chloride, 1.2 mM magnesium chloride, 1.5 mM calcium chloride, 1.2 mM potassium dihydrogen phosphate, The plate was washed with a 20 mM HEPES buffer (pH 7.4) containing 0.5 mM EDTA and 10 mM glucose.
  • O.lmM R 0-20-1724 and 2 units / m1 containing adenosine deaminase After pre-incubator adipate 1 0 minutes at 37 ° C for the addition of buffer, the ink Yube and Bok 1 0 min at 37 a C added to the same buffer containing test compound at various concentrations (0-100 ⁇ ). The buffer was removed and the reaction was stopped by adding 0.1 M hydrochloric acid. After neutralization with 1 M sodium hydroxide, the mixture was extracted twice with ice-cooled 65% (v / v) ethanol, dried, and cAMP was quantified by Enzymimnoassay. The test compound did not induce an increase in cAMP levels by the A2b adenosine receptor at any concentration. In addition, it did not inhibit the increase in cAMP concentration caused by A2b adenosine receptor agonist (NECA).
  • NECA A2b adenosine receptor agonist
  • the compound of the present invention is a substance that can specifically bind to a P3-like receptor.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé d'adénosine agissant de manière sélective sur un récepteur de type P3 (substance de récepteur de purine de type 3). Etant donné que ce dérivé peut se lier de manière sélective à un récepteur de type P3, on peut l'utiliser pour cribler un récepteur de type P3 et des substances ayant une action sur celui-ci et pour étudier les effets pharmacologiques, biochimiques et physiologiques ainsi que les mécanismes des récepteurs de purine.
PCT/JP1999/001459 1998-03-24 1999-03-23 Derive d'adenosine Ceased WO1999048903A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/96799 1998-03-24
JP10096799A JPH11279193A (ja) 1998-03-24 1998-03-24 アデノシン誘導体

Publications (1)

Publication Number Publication Date
WO1999048903A1 true WO1999048903A1 (fr) 1999-09-30

Family

ID=14174682

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/001459 Ceased WO1999048903A1 (fr) 1998-03-24 1999-03-23 Derive d'adenosine

Country Status (2)

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JP (1) JPH11279193A (fr)
WO (1) WO1999048903A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002055521A1 (fr) * 2001-01-10 2002-07-18 Vernalis Research Limited Dérivés puriniques et leur utilisation comme antagonistes des récepteurs purinergiques
US7285550B2 (en) 2003-04-09 2007-10-23 Biogen Idec Ma Inc. Triazolotriazines and pyrazolotriazines and methods of making and using the same
US7674791B2 (en) 2003-04-09 2010-03-09 Biogen Idec Ma Inc. Triazolopyrazines and methods of making and using the same
US7834014B2 (en) 2003-04-09 2010-11-16 Biogen Idec Ma Inc. A2a adenosine receptor antagonists
CN106589026A (zh) * 2016-10-27 2017-04-26 浙江诚意药业股份有限公司 一种核糖结晶残液中废弃物α‑四乙酰核糖的利用方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MATSUDA A., ET AL.: "NUCLEOSIDES AND NUCLEOTIDES. 177. 9-(6,7-DIDEOXY-BETA-D-ALLO-HEPT-5-YNOFURANOSYL)ADENINE: A SELECTIVE AND POTENT LIGAND FOR P3 PURINOCEPTOR-LIKE PROTEIN.", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 41., no. 15., 16 July 1998 (1998-07-16), US, pages 2676 - 2678., XP002920989, ISSN: 0022-2623, DOI: 10.1021/jm9802822 *
SHINOZUKA K., BJUR R. A., WESTFALL D. P.: "CHARACTERIZATION OF PREJUNCTIONAL PURINOCEPTORS ON ADRENERGIC NERVES OF THE RAT CAUDAL ARTERY.", NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, SPRINGER, DE, vol. 338., 1 January 1988 (1988-01-01), DE, pages 221 - 227., XP002920990, ISSN: 0028-1298, DOI: 10.1007/BF00173391 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002055521A1 (fr) * 2001-01-10 2002-07-18 Vernalis Research Limited Dérivés puriniques et leur utilisation comme antagonistes des récepteurs purinergiques
JP2004517874A (ja) * 2001-01-10 2004-06-17 バーナリス リサーチ リミテッド プリン作動性レセプターアンタゴニストとしてのプリン誘導体
US7452894B2 (en) 2001-01-10 2008-11-18 Vernalis Research Limited Purine derivatives as purinergic receptor antagonists
US7285550B2 (en) 2003-04-09 2007-10-23 Biogen Idec Ma Inc. Triazolotriazines and pyrazolotriazines and methods of making and using the same
US7674791B2 (en) 2003-04-09 2010-03-09 Biogen Idec Ma Inc. Triazolopyrazines and methods of making and using the same
US7834014B2 (en) 2003-04-09 2010-11-16 Biogen Idec Ma Inc. A2a adenosine receptor antagonists
CN106589026A (zh) * 2016-10-27 2017-04-26 浙江诚意药业股份有限公司 一种核糖结晶残液中废弃物α‑四乙酰核糖的利用方法
CN106589026B (zh) * 2016-10-27 2019-09-10 浙江诚意药业股份有限公司 一种核糖结晶残液中废弃物α-四乙酰核糖的利用方法

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Publication number Publication date
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