WO2008047655A1 - Derive d'uree destine a etre utilise dans la quantification de peroxyde d'hydrogene - Google Patents

Derive d'uree destine a etre utilise dans la quantification de peroxyde d'hydrogene Download PDF

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Publication number
WO2008047655A1
WO2008047655A1 PCT/JP2007/069799 JP2007069799W WO2008047655A1 WO 2008047655 A1 WO2008047655 A1 WO 2008047655A1 JP 2007069799 W JP2007069799 W JP 2007069799W WO 2008047655 A1 WO2008047655 A1 WO 2008047655A1
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WO
WIPO (PCT)
Prior art keywords
formula
hydrogen peroxide
urea derivative
group
present
Prior art date
Application number
PCT/JP2007/069799
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English (en)
Japanese (ja)
Inventor
Katsuya Noguchi
Eiji Watanabe
Munetaka Ishiyama
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Dojindo Laboratories
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Publication date
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Publication of WO2008047655A1 publication Critical patent/WO2008047655A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/26—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving oxidoreductase
    • C12Q1/28—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving oxidoreductase involving peroxidase
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
    • C07C309/15—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton the nitrogen atom of at least one of the amino groups being part of any of the groups, X being a hetero atom, Y being any atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
    • C07D279/30—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with acyl radicals attached to the ring nitrogen atom

Definitions

  • the present invention relates to a novel compound having a urea derivative structure, and is particularly suitable for use as a color reagent for quantifying hydrogen peroxide in the presence of peroxidase in clinical tests. It relates to new compounds.
  • a representative example of a color reagent for quantifying hydrogen peroxide in the presence of peroxidase is a compound having a urea derivative structure.
  • Patent Document 1 discloses a compound having a structure in which two substituted phenyl groups are bonded to urea.
  • Patent Document 2 proposes a compound having a urea derivative structure that has improved properties such as solubility in water compared to the compound described in Patent Document 1 above. Has been.
  • the compound described in Patent Document 2 has improved water solubility compared to the compound of Patent Document 1. It is still insufficient for use in clinical tests, and is not stable in aqueous solution. The problem remains.
  • Patent Document 1 Japanese Patent Publication No. 60-33479
  • Patent Document 2 Japanese Patent Publication No. 7-121901
  • the purpose of the present invention is to achieve solubility and stability in aqueous solutions corresponding to biological fluid samples. It is to provide a new substance that is excellent in use and suitable for use as a clinical reagent for the determination of hydrogen peroxide in the presence of peroxidase.
  • the present invention is a color reagent that comprises a urea derivative represented by the following general formula (I) and the urea derivative and is used for the determination of hydrogen peroxide in the presence of peroxidase.
  • R 1 represents an atomic group represented by the following general formula (R), and R 2 and R 3 each independently represents a 4-disubstituted aminoaryl group.
  • the aryl groups of R 2 and R 3 may be bonded to each other via a sulfur atom or an oxygen atom, and at least one of the aryl groups of R 2 and R 3 is an S sulfonic acid group. It ’s replaced!
  • n represents an integer of 1 to 4
  • X represents a hydrogen atom, sodium atom or potassium atom.
  • the compound of the present invention (urea derivative) has very high solubility in water, and also has very good stability in an aqueous solution. Therefore, the compounds of the present invention are used in clinical tests at high concentrations for the determination of hydrogen peroxide in the presence of peroxidase. It is particularly useful as a color reagent.
  • FIG. 1 shows a reaction scheme for synthesizing an example of a compound of the present invention (urea derivative).
  • FIG. 2A shows a calibration curve when hydrogen peroxide is quantified in the presence of peroxidase using the compound of the present invention and a comparative compound.
  • FIG. 2B shows a calibration curve when hydrogen peroxide is quantified in the presence of peroxidase using the compound of the present invention and a comparative compound.
  • FIG. 3A shows the stability in aqueous solutions measured for the compounds of the present invention and comparative compounds.
  • FIG. 3B shows the stability in aqueous solutions measured for the compounds of the present invention and comparative compounds.
  • Patent Document 2 discloses a compound represented by the following formulas (C 1) and (C 2), for example, as being extremely easily soluble in water.
  • the compound of the present invention (urea derivative) has a specific atomic group as R 1 of the formula (I), that is, an atomic group represented by the formula ( ⁇ ).
  • R 1 of the formula (I) an atomic group represented by the formula ( ⁇ ).
  • water solubility is higher than the compounds of the above formulas (C 1) and (C 2), and stability in aqueous solution is also good. Yes (see examples below).
  • n is a force that is an integer of;! To 4, preferably 2.
  • X represents a hydrogen atom, a sodium atom or a potassium atom, preferably a sodium atom.
  • R 2 and R 3 in formula (I) each independently represent a 4-disubstituted aminoaryl group, and the aryl groups of R 2 and R 3 are bonded to each other via a sulfur atom or an oxygen atom. Also good.
  • this embodiment which may be substituted with at least one S sulfonic acid group in the aryl group of R 2 and R 3 , includes the case where a sulfonic acid group is bonded to the substituted amino group.
  • a phenyl group is preferred as an aryl group.
  • the urea derivative of the present invention particularly preferred for constituting a color reagent represented by the formula (I) and used for the determination of hydrogen peroxide in the presence of peroxidase, the following formula ( Examples thereof include, but are not limited to, compounds represented by III) or (IV).
  • the urea derivative of the present invention represented by the formula (I) can be synthesized by the synthesis method found by the present inventors. That is, as illustrated in FIG. 1, a compound in which R 2 is CH C OONa in the formula (I) is used as a raw material (therefore, this raw material compound is a compound of the formula (C 1) or the formula (C 2). (This corresponds to the target compound of Patent Document 2), and this is reacted with an aminoalkanesulfonic acid such as taurine (2-aminoethanesulfonic acid) using a carpositimide such as dicyclohexylcarpositimide as a dehydrating condensing agent. (See examples below)
  • the compound of the present invention of the formula (III) was synthesized as follows. To 2.0 g of the compound of formula (C 1) was added 0.1N HCllOml and concentrated. 20ml THF to concentrate 3 ml of water and 3.27 g of dicyclohexyl carpositimide were added and stirred in an ice bath. After stirring for 30 minutes, 0.662 g of taurine and 0.444 g of sodium bicarbonate were dissolved in 3 ml of water and added to the reaction solution. -After stirring at room temperature, 2.18 g of dicyclohexyl carpositimide was further added. After 3 hours, stirring was stopped and the reaction solution was filtered and concentrated.
  • the compound of the present invention of the formula (IV) was synthesized as follows.
  • the compound l.Og of the formula (C2) was charged with 0.1N HCllOml and concentrated.
  • To the concentrate were added THFlOml, 3 ml of water and 2.16 g of dicyclohexyl carpositimide, and the mixture was stirred in an ice bath. After stirring for 30 minutes, 0.328 g of taurine and 0.213 g of sodium bicarbonate were dissolved in 3 ml of water and added to the reaction solution. After 3 hours, stirring was stopped and the reaction solution was filtered and concentrated.
  • the concentrate was purified by chromoform form and dried under reduced pressure to obtain 0.40 g of white powder.
  • the compounds (III) and (IV) of the present invention and the compounds (C 1) and (C 2) described in Patent Document 2 for comparison have a concentration of 0 ⁇ lmmol / U peroxidase at a concentration of 3.3 u / ml. Thus, it was dissolved in 50 mM MES [2 morpholinoethanesulfonic acid] sodium hydroxide buffer (pH 5.5).
  • the sample solution was added to 3 ml of the measurement solution 1.5, 3.0, 15 and 301 and heated at 37 ° C for 5 minutes, and then the absorbance at the maximum absorption wavelength was measured.
  • Figures 2A and 2B show the relationship between hydrogen peroxide concentration and absorbance. From FIG. 2A and FIG. 2B, the calibration curve of absorbance at the maximum absorption wavelength plotted against each hydrogen peroxide concentration M) showed quantitativeness.
  • the compounds (III) and (IV) of the present invention showed the same or better sensitivity than the comparative compounds (C 1) and (C 2).
  • the compounds (III) and (IV) of the present invention and the comparative compounds (C 1) and (C 2) were each dissolved in pure water at 25 ° C., and the solubility was determined.
  • Table 1 shows the solubilities of the compounds (III) and (IV) of the present invention and the comparative compounds (C 1) and (C 2).
  • the compounds (III) and (IV) of the present invention are more water-soluble than (C 1) and (C 2), respectively.
  • the compounds (III) and (IV) of the present invention and the comparative compounds (C 1) and (C 2) were each prepared with 50 mM MES sodium hydroxide buffer ( ⁇ 5 ⁇ 5) so as to be 10 mmol / l. Stored at 40 ° C, protected from light.
  • Figures 3A and 3B show the relationship between elapsed days and absorbance. As shown in FIGS. 3A and 3B, the compounds (III) and (IV) of the present invention have better stability than the comparative compounds (C 1) and (C 2).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne une nouvelle substance présentant d'excellentes solubilité et stabilité dans une solution aqueuse correspondant à un échantillon liquide biologique et pouvant être utilisée comme réactif clinique dans la quantification de peroxyde d'hydrogène, en présence d'une peroxydase. L'invention concerne en particulier un dérivé d'urée de formule (I) [dans laquelle R1 représente un groupe atomique de formule (II); R2 et R3 représentent indépendamment un groupe aminoaryle 4-disubstitué, à condition que le groupe aryle contenu dans R2 et le groupe aryle contenu dans R3 puissent être liés entre eux par l'intermédiaire d'un atome de soufre ou d'oxygène, et qu'au moins un site dans le groupe aryle dans R2 et R3 puisse être substitué par un groupe sulfonate; n représente un entier compris entre 1 et 4; et X représente un atome d'hydrogène, de sodium ou de potassium].
PCT/JP2007/069799 2006-10-16 2007-10-11 Derive d'uree destine a etre utilise dans la quantification de peroxyde d'hydrogene WO2008047655A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006280844A JP2010001217A (ja) 2006-10-16 2006-10-16 過酸化水素の定量に用いられる尿素誘導体
JP2006-280844 2006-10-16

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WO2008047655A1 true WO2008047655A1 (fr) 2008-04-24

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018159636A1 (fr) * 2017-02-28 2018-09-07 株式会社同仁化学研究所 Nouveau composé développable en couleur d'oxydation et réactif de développement de couleur d'oxydation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63246356A (ja) * 1986-07-01 1988-10-13 Wako Pure Chem Ind Ltd 新規な尿素誘導体及びこれを発色成分として用いる測定法
JPH01128797A (ja) * 1987-11-13 1989-05-22 Kyowa Medetsukusu Kk 酵素活性の定量法
JPH06289015A (ja) * 1993-03-30 1994-10-18 Sunstar Inc フェノチアジン系色源体安定化組成物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63246356A (ja) * 1986-07-01 1988-10-13 Wako Pure Chem Ind Ltd 新規な尿素誘導体及びこれを発色成分として用いる測定法
JPH01128797A (ja) * 1987-11-13 1989-05-22 Kyowa Medetsukusu Kk 酵素活性の定量法
JPH06289015A (ja) * 1993-03-30 1994-10-18 Sunstar Inc フェノチアジン系色源体安定化組成物

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018159636A1 (fr) * 2017-02-28 2018-09-07 株式会社同仁化学研究所 Nouveau composé développable en couleur d'oxydation et réactif de développement de couleur d'oxydation
US20190270888A1 (en) * 2017-02-28 2019-09-05 Dojindo Laboratories Novel oxidation color developable compound and oxidation color development reagent
US10787571B2 (en) 2017-02-28 2020-09-29 Dojindo Laboratories Oxidation color developable compound and oxidation color development reagent

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