EP0190299A1 - NOUVEAUX PEPTIDES DE p-PHENYLENEDIAMINE ET REACTIFS LES CONTENANT POUR DETERMINER DES PROTEINASES DU SYSTEME DE COAGULATION DU SANG - Google Patents

NOUVEAUX PEPTIDES DE p-PHENYLENEDIAMINE ET REACTIFS LES CONTENANT POUR DETERMINER DES PROTEINASES DU SYSTEME DE COAGULATION DU SANG

Info

Publication number
EP0190299A1
EP0190299A1 EP85904101A EP85904101A EP0190299A1 EP 0190299 A1 EP0190299 A1 EP 0190299A1 EP 85904101 A EP85904101 A EP 85904101A EP 85904101 A EP85904101 A EP 85904101A EP 0190299 A1 EP0190299 A1 EP 0190299A1
Authority
EP
European Patent Office
Prior art keywords
group
compound according
compound
aniline
phenylenediamine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP85904101A
Other languages
German (de)
English (en)
Inventor
Knut Bartl
Udo Becker
Herbert Von Der Eltz
Helmut Lill
Hans-Georg Batz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics GmbH
Original Assignee
Roche Diagnostics GmbH
Boehringer Mannheim GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Roche Diagnostics GmbH, Boehringer Mannheim GmbH filed Critical Roche Diagnostics GmbH
Publication of EP0190299A1 publication Critical patent/EP0190299A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C12Q1/56—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • C07K14/675—Beta-endorphins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • 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
    • C12Q2337/00—N-linked chromogens for determinations of peptidases and proteinases
    • C12Q2337/10—Anilides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/745—Assays involving non-enzymic blood coagulation factors
    • G01N2333/755—Factors VIII, e.g. factor VIII C [AHF], factor VIII Ag [VWF]

Definitions

  • proteases of the blood coagulation system is of considerable clinical and scientific importance, especially in the context of the determination and regulation of the ability of the blood to clot.
  • the invention is therefore based on the object of eliminating this disadvantage and of creating a substrate for the proteases of the blood coagulation system which does not adversely affect the coagulation cascade and others on the one hand forms a color during cleavage, the absorption maximum of which is longer-wave than 565 nm and thereby also enables determination in whole blood or in the presence of other interfering colored substances.
  • A the amino acid arginine or lysine
  • X is an N-terminal amino acid protecting group
  • D-amino acid Y is a single bond or a chain consisting of 1 to 3 amino acids
  • NR 1 R 2 is a group in the o- or p-position with R 1 and R 2 independently of one another in each case hydrogen or alkyl having 1 to 3 C atoms and R 3 represents a hydrogen atom, a carboxyl group, a halogen atom or an alkyl group having 1 to 3 C atoms.
  • the new compounds of the invention can be cleaved by the proteases of the blood coagulation system with the liberation of an o- or p-phenylenediamine derivative, which in the presence of an oxidizing agent with a suitable coupling partner, such as. B. N-methylanthranilic acid forms a color, the absorption maximum is longer than 565 mn.
  • the compounds according to the invention are particularly preferred Tos-Gly-Pro-Arg-p-phenylenediamine and H-D-PhePip-Arg-p-phenylenediamine.
  • the new compounds according to the invention can be prepared using the methods of peptide synthesis familiar to the person skilled in the art.
  • the preparation is preferably carried out by using a compound of the general formula II
  • the reduction of the compounds of the general formula II is preferably carried out by catalytic hydrogenation, for example using palladium / carbon as a catalyst in solvents customary for reductive hydrogenation, such as methanol / glacial acetic acid.
  • the compounds according to the invention are particularly suitable as chromophobic substrates for the determination of proteases, in particular proteases of the blood coagulation system, such as thrombin, plasmin, plasminogen, factor Xa, kallikrein, plasminogen activator etc.
  • proteases in particular proteases of the blood coagulation system, such as thrombin, plasmin, plasminogen, factor Xa, kallikrein, plasminogen activator etc.
  • they are also suitable as substrates for other proteases such as B. chymotrypsin, trypsin and the like.
  • the compounds according to the invention are cleaved by the respective protease to release the phenylenediamine or a phenylenediamine derivative, and this is oxidized in the presence of an oxidizing agent such as K 3 [Fe (CN) 6 ] with a suitable coupling component to give a dye with an absorption maximum greater than 565 nm.
  • an oxidizing agent such as K 3 [Fe (CN) 6 ]
  • a suitable coupling component to give a dye with an absorption maximum greater than 565 nm.
  • coagulation factors factors of the fibrinolytic system or the kallikrein-kinin system
  • Leukocyte-released proteolytic enzymes such as granulocyte elastase or cathepsin-G can be determined in body fluids with the aid of the compounds according to the invention.
  • These compounds also enable the analysis of entire enzyme cascades of the coagulation system, as is the case in the test systems of the prothrombin time method (PT or quick test) or the partial thromboplastin time method (PTT test).
  • the compounds according to the invention are also suitable for determining the inhibitors of certain active proteolytic enzymes by measuring the reduction in activity of these proteases.
  • An example of this is the measurement of the decrease in activity of thrombin due to the presence of antithrombin.
  • Aromatic amines or phenols are suitable as coupling components for this reaction.
  • Compounds of the formula II are particularly suitable
  • X is an NR 2 R 3 or -OR group
  • R 1 is hydrogen or chlorine, if R 4 and / or R 6 also
  • R 2 and R 3 are the same or different and are hydrogen, an alkyl, aralkyl or aryl group with up to 8 carbon atoms, which may also be hydroxyl, alkoxy with up to 5 carbon atoms, -CO 2 H , SO 3 H may be substituted.
  • R 4 and R 6 are hydrogen, low alkyl with up to 5 atoms of chlorine, bromine, iodine, -COOR 2 , SO 3 H 2 ,
  • R 5 and R 7 represent an alkyl group with up to 5 carbon atoms
  • R 4 and R 5 or R 6 and R 7 together with the benzene ring can also form a naphthyl and anthryl skeleton.
  • the alkyl groups in the above compounds have up to 6, preferably 1 to 3, carbon atoms.
  • the methyl group and ethyl group are particularly preferred.
  • N-methylanthrahilic acid preferred examples of this are xylenols such as 2,3-xylenol, dialkylmethanilic acids such as diethylmethanilic acid and their salts, N-alkyl- (3'sulfobenzyl) anilines, in particular the N-ethyl compound, N-alkyl N- (3'-sulfobenzyl) -3- toluidine, especially the methyl, ethyl and propyl compound and N-biscarboxybenzyl-3-anisidine in the form of the salts, especially the sodium salt.
  • xylenols such as 2,3-xylenol
  • dialkylmethanilic acids such as diethylmethanilic acid and their salts
  • N-alkyl- (3'sulfobenzyl) anilines in particular the N-ethyl compound, N-alkyl N- (3'-sulfobenzyl)
  • Another object of the invention is a reagent for determining the proteases of the blood coagulation system, which is characterized in that it contains a compound according to formula 1, an oxidizing agent, an aniline or phenol derivative which forms a dye with phenylenediamine and buffer.
  • the reagents according to the invention may also contain: compound according to general formula I, coupling component, oxidizing agent and buffer substance pH 6 to 10, activators (e.g. magnesium salts), wetting agents, stabilizing agents, thickeners and other customary auxiliaries.
  • activators e.g. magnesium salts
  • the reagent can be present either in dried form, dissolved in an aqueous solvent, or impregnated on an absorbent carrier (test strip).
  • Solution 1 10 ml Tris-HCl buffer, pH 8.1 are mixed with 4 ml thromboplastin (Boehringer Mannheim, Order No. 244252) and 1 ml substrate solution (6.83 mmol / l in water) and then 1:10 with a Tris buffer pH 8.1, which additionally contains 6 mmol / l CaCl 2 and 0.25 mol / l urea.
  • Solution 2 10 ml Tris-HCl buffer, pH 8.1 are mixed with 4 ml thromboplastin (Boehringer Mannheim, Order No. 244252) and 1 ml substrate solution (6.83 mmol / l in water) and then 1:10 with a Tris buffer pH 8.1, which additionally contains 6 mmol / l CaCl 2 and 0.25 mol / l urea.
  • Solution 2 10 ml Tris-HCl buffer, pH 8.1 are mixed with 4 ml thromboplastin (Boehringer Mannheim, Order No. 24
  • the recorder is started at the same time as the sample is added.
  • a PTT reagent such as is used for optically registering coagulation machines (e.g. actin, Dade or Neothromtin, Behring), is mixed with Tris / HCl buffer 0.1 mol / 1, pH 7.6 Diluted 1:10.
  • the recorder With the addition of solution 4, the recorder is started at the same time.
  • the type of reaction curve is the same as in Example 1.
  • the reaction time is the time from the start (addition of solution 4) to reaching an extinction difference of 0.1.
  • a reference curve for determining factor VIII is created as follows:
  • Citrate plasma from 10 normal donors is pooled and represents a factor VIII content of 100% of the
  • Citrate plasma from a donor with hereditary hamophilia A with a residual activity of less than 1% of the norm e.g. available from George King Biomedical, Overland Park, Kansas, USA.
  • Component 1 and 2 are mixed so that factor VIII activities of 100% (pure component 1), 50 (component 1 and 2 1 + 1 mixed), 25, 10 and 5% of the norm arise.
  • a PTT test analogous to Example 2 is carried out on these samples.
  • the reaction times listed in Table 1 are obtained. If the reaction times are plotted against the% factor VIII activity, a reference curve for factor VIII is obtained, from which the factor VIII content of this patient sample can be determined over the reaction time of a patient sample.
  • Solution A 1 g of N, N-dimethyl-2-bromo-4-nitro-aniline is dissolved in 120 ml of DMF, mixed with 0.1 g of Pd / C and hydrogenated until the calculated amount of hydrogen is absorbed in the shaker. The catalyst is then filtered off under nitrogen.
  • Solution B 2.2 g of Cbo-gly-pro- ( ⁇ -Boc) -lys are dissolved in 50 ml of DMF, treated with 1.3 ml of triethylamine and cooled to -20 ° C. 0.7 ml of xobutyl chloroformate are added and the mixture is stirred for 15 minutes.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Neurosurgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Analytical Chemistry (AREA)
  • Hematology (AREA)
  • Biotechnology (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Toxicology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

Dans de nouvelles compositions ayant la formule générale (I), A est l'acide aminé arginine ou lysine, X est un groupe d'acides aminés de protection à terminal N ou un acide aminé D, Y est une liaison simple ou une chaîne composée de 1 à 3 acides aminés, NR1R2 est un groupe en position o ou p où R1 et R2 sont indépendants l'un de l'autre et représentent de l'hydrogène ou de l'alcoyle ayant 1 à 3 atomes C et R3 est un atome d'hydrogène, un groupe carboxyle, un atome d'halogène ou un groupe alcoyle ayant 1 à 3 atomes C. Ces compositions sont utiles comme substrats chromogènes de protéinases. Elles sont obtenues par réduction et le cas échéant par alkylation des nitroanilides correspondantes. Un réactif correspondant pour déterminer des protéïnases du système de coagulation du sang comprend une composition ayant la formule (I), un agent d'oxydation, un dérivé d'aniline ou de phénol qui forme un colorant par oxydation avec de la phénylène-diamine et une substance tampon.
EP85904101A 1984-08-02 1985-07-31 NOUVEAUX PEPTIDES DE p-PHENYLENEDIAMINE ET REACTIFS LES CONTENANT POUR DETERMINER DES PROTEINASES DU SYSTEME DE COAGULATION DU SANG Withdrawn EP0190299A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3428543 1984-08-02
DE19843428543 DE3428543A1 (de) 1984-08-02 1984-08-02 Neue p-phenylendiamin-peptide und diese enthaltende reagenzien zur bestimmung von proteasen des blutgerinnungssystems

Publications (1)

Publication Number Publication Date
EP0190299A1 true EP0190299A1 (fr) 1986-08-13

Family

ID=6242223

Family Applications (1)

Application Number Title Priority Date Filing Date
EP85904101A Withdrawn EP0190299A1 (fr) 1984-08-02 1985-07-31 NOUVEAUX PEPTIDES DE p-PHENYLENEDIAMINE ET REACTIFS LES CONTENANT POUR DETERMINER DES PROTEINASES DU SYSTEME DE COAGULATION DU SANG

Country Status (6)

Country Link
EP (1) EP0190299A1 (fr)
JP (1) JPS61501635A (fr)
AU (1) AU564556B2 (fr)
DE (1) DE3428543A1 (fr)
WO (1) WO1986001209A2 (fr)
ZA (1) ZA855814B (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4717658A (en) * 1985-12-03 1988-01-05 Miles Inc. Gram negative bacteria screening method with horseshoe crab amebocyte lysate (LAL)
FI860043A (fi) * 1986-01-06 1987-07-07 Orion Yhtymae Oy Peptidsubstrat samt foerfarande foer kvantitativ analys av endotoxin.
SE8601327D0 (sv) * 1986-03-21 1986-03-21 Kabivitrum Ab Nya peptidderivat
SE461494B (sv) * 1986-03-21 1990-02-19 Thorsman & Co Ab Faestanordning foer en elektrisk kopplingsdosa
FR2644697B1 (fr) * 1989-03-24 1992-05-15 Poudres & Explosifs Ste Nale Composes anesthesiques a duree d'action controlee et compositions pharmaceutiques les contenant
ES2162025T3 (es) 1995-01-10 2001-12-16 Hendrik Coenraad Hemker Procedimientos para la determinacion del potencial de trombina endogena (etp) y sustratos de la trombina para su uso en esos procedimientos.
WO2000050446A1 (fr) * 1999-02-23 2000-08-31 Pentapharm Ag Derives d'oligopeptides pour la mesure electrochimique de l'activite de proteases
DE602005026035D1 (en) * 2004-10-12 2011-03-03 Hoffmann La Roche Festphasenpeptidsynthese

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2497798A1 (fr) * 1981-01-09 1982-07-16 Pharmindustrie Nouveaux peptides portant un fluorophore, procede pour leur preparation et leur application au dosage fluorimetrique des endotoxines
JPS57176940A (en) * 1981-04-25 1982-10-30 Wako Pure Chem Ind Ltd Novel color-developing peptide derivative
JPS58172354A (ja) * 1982-04-05 1983-10-11 Dai Ichi Pure Chem Co Ltd ペプチド誘導体
GB2118190B (en) * 1982-04-13 1985-05-01 Erba Farmitalia Peptides with sauvagine-like activity
DE3244030A1 (de) * 1982-11-27 1984-05-30 Behringwerke Ag, 3550 Marburg Chromogene verbindungen, verfahren zu ihrer herstellung und ihre verwendung
JPH08142597A (ja) * 1994-11-21 1996-06-04 Dainippon Printing Co Ltd 転写箔及びこれを用いた装飾ガラス

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8601209A2 *

Also Published As

Publication number Publication date
AU4723885A (en) 1986-03-07
WO1986001209A3 (fr) 1986-03-27
WO1986001209A2 (fr) 1986-02-27
AU564556B2 (en) 1987-08-13
DE3428543A1 (de) 1986-02-13
JPS61501635A (ja) 1986-08-07
ZA855814B (en) 1986-04-30

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