Oligopeptide derivatives for the electrochemical measurement...

Details Oligopeptide derivatives for the electrochemical measurement... Oligopeptide derivatives for the electrochemical measurement...

2001-11-21

2002-12-17

Russel, Jeffrey E. (Department: 1653)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving blood clotting factor

C205S777500, C435S023000, C530S331000, C530S345000

Reexamination Certificate

active

06495336

ABSTRACT:

The present invention relates to oligopeptide derivatives of the formula (I)
in which
R
1
is
(a) a hydrogen atom, a C
2-8
-alkanoyl group optionally having an amino group in the &ohgr; position, a phenyl-C
2-4
-alkanoyl group whose phenyl radical is optionally substituted in the p position by an amino group; or
(b) a cyclohexylcarbonyl group which is optionally substituted in the 4 position by an aminomethyl radical, a benzoyl group which is optionally substituted in the o or p position by methyl, amino or halogen, a C
1-8
-alkoxycarbonyl group, a benzyloxycarbonyl group which is optionally substituted in the p position by methoxy, methyl or chlorine; or
(c) a radical of the formula —SO
2
—R
5
where R
5
can be a C
1-6
-alkyl radical, an optionally substituted aryl or heteroaryl radical or a radical of a bicyclic terpene derivative; or
(d) a group of the formula —CO—CH(R
6
)—NH—R
7
, where R
6
is hydrogen, a C
1-6
-alkyl radical, a 1- or 2-hydroxyethyl radical, a methylmercaptoethyl radical, an aminobutyl radical, a guanidinopropyl radical, a carboxy-C
1-4
-alkyl radical, a carboxamido-C
1-4
-alkyl radical, a phenyl-C
1-4
-alkyl radical whose phenyl radical is optionally substituted by OH, halogen, C
1-4
-alkyl or methoxy, or a cyclohexyl or cyclohexylmethyl radical whose ring is optionally substituted by OH, halogen, C
1-4
-alkyl or methoxy, or a nitrogen-containing heteroaryl-C
1-4
-alkyl radical with 3 to 8 carbon atoms in the heterocyclic system, where the group —CO—CH(R
6
)—NH—R
7
may be racemic or have the D or L configuration, and R
7
can be a group of type (a), (b) or (c); or
(e) a group of the formula
where R
7
has the above meaning, m can be 1 or 2, and one of the methylene groups can be substituted by hydroxyl, carboxyl, C
1-4
-alkyl or aryl-C
1-4
-alkyl;
R
2
is hydrogen, C
1-6
-alkyl, C
1-2
-hydroxyalkyl, C
1-4
-alkoxy-C
1-6
-alkyl, benzyloxy-C
1-2
-alkyl, an &ohgr;-carboxy-C
1-3
-alkyl radical, an &ohgr;-C
1-4
-alkoxycarbonyl-C
1-3
-alkyl radical, an &ohgr;-benzyloxycarbonyl-C
1-3
-alkyl radical or a cyclohexyl, cyclohexylmethyl, 4-hydroxycyclohexylmethyl, phenyl, benzyl, 4-hyroxybenzyl or imidazolyl-4-methyl radical;
R
3
is
(a) hydrogen or C
1-4
-alkyl and R
3′
is hydrogen; or
(b) together with R
3′
a tri- or tetramethylene group, where one of the methylene groups can be substituted by hydroxyl, carboxyl, C
1-4
-alkyl or aryl-C
1-4
-alkyl; and
R
4
is
(a) an aniline residue of the formula
where R
8
can be hydroxyl or amino and R
9
can be hydrogen, halogen, amino, nitro, C
1-4
-alkyl, C
1-4
-alkoxy or C
1-4
-alkanoyl; or
(b) a quinoline residue of the formula
where one of R
10
, R
11
and R
12
is an —NH group via which the quinoline residue is linked to the Arg residue, a second one can be hydroxyl or amino, and the third one can be hydrogen, hydroxyl or amino;
and the salts thereof.
These oligopeptide derivatives and the salts are novel. They are cleaved by enzymes of the peptide hydrolase enzyme class (E.C. 3.4.), in particular proteinases (E.C. 3.4.21-99) and inhibitors thereof, of the blood coagulation system, of the fibrinolytic system and of complement, in particular of thrombin. They thus serve as substrates for the quantitative and qualitative determination of the abovementioned enzymes, in particular thrombin, in complex sample liquids, in particular capillary blood.
The present invention relates to novel oligopeptide derivatives of the formula (I) and salts thereof, to the preparation of these oligopeptide derivatives and salts, and to a method for the quantitative determination of a protease or antiprotease, in particular of the blood coagulation system, of the fibrinolytic system or of complement, in particular thrombin, which is carried out by means of the novel oligopeptide derivatives or salts thereof.
The term “alkyl” used in this description designates, on its own or in combinations such as “hydroxyalkyl” or “benzyloxyalkyl”, straight-chain or branched saturated hydrocarbon radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. The term “alkoxy” designates an alkyl radical within the meaning of the above definition of “alkyl”, which is linked via an oxygen bridge. The term “alkanoyl” designates the acyl radical of an alkylcarboxylic acid which may be straight-chain or branched, such as acetyl, propionyl and the like. The term “aryl” designates the radical of an aromatic hydrocarbon and comprises radicals such as phenyl, naphthyl and the like. The term “heteroaryl” designates the radical of an aromatic heterocyclic system such as imidazolyl, indolyl, quinolinyl, isoquinolinyl and the like.
If R
1
in formula (I) is a radical of the formula —SO
2
R
5
, then R
5
can be, for example, methyl, isopropyl, phenyl, tert-butylphenyl, 4-methylphenyl, 2,4,6-trimethylphenyl, 2,4,6-triisopropylphenyl, 4-methoxy-2,3,6-trimethylphenyl, anthraquinoyl, 1- or 2-naphtyl, quinolyl or isoquinolyl or a radical derived from camphor. If, in formula (I), R
1
is a group of the formula —CO—CH(R
6
)—NH—R
7
and R
6
is heteroarylalkyl, then R
6
can be, for example, imidazolylmethyl or indolylmethyl.
If the N-terminal amino acid in the molecule carries a protective group, then this protective group is expediently tert-butoxycarbonyl (“Boc”), p-toluenesulfonyl (“Tos”), tert-butylphenylsulfonyl (“t-Bups”), methylsulfonyl (“Mes”), naphthylsulfonyl (“Naps”), benzoyl (“Bzo”), benzyloxycarbonyl (“Z”), isopropylsulfonyl or camphorsulfonyl.
If R
4
is an aniline residue, then expediently R
8
is hydroxyl in the o- or p position and R
9
is halogen in the m position or R
8
is hydroxyl in the o, m or p position and R
9
is nitro or C
1-4
-alkanoyl in the m or p position. The radical R
4
is preferably derived from 2-amino-4-nitrophenol, 4-amino-2-nitrophenol, 4-amino-3-nitrophenol, 2-amino-5-nitrophenol, 2,4-diaminotoluene, 2,4-diaminophenol, 4-amino-m-cresol, 2,5-diaminoanisole, 4-nitro-o-phenylenediamine, 2-amino-4-chlorophenol, 4-amino-2-chlorophenol, 4-amino-3-chlorophenol, 4-fluoro-2-aminophenol, 2-fluoro-4-aminophenol, 5-fluoro-2-aminophenol, 5-amino-8-hydroxyquinoline or 2-amino-8-hydroxyquinoline.
The oligopeptide derivatives of the formula (I) contain L-arginine (“Arg”) as C-terminal amino acid. Further amino acids which may be present in the molecule are, for example, 2-aminobutyric acid, alanine, 3-cyclohexylalanine, 2-cyclohexylglycine, phenylalanine, pipecolic acid, proline and valine, it being possibe for these amino acids to be in the L, D or DL form, and glycine; preference is given in this connection to L-alanine (“Ala”), L-2-aminobutyric acid (“Abu”), D-3-cyclohexylalanine (“D-Cha”), D-2-cyclohexylglycine (“D-Chg”), glycine (“Gly”) and L-proline (“Pro”).
Representative examples of oligopeptide derivatives of the formula (I) are:
H-(D)-Chg-Gly-Arg 3-chloro-4-hydroxyanilide;
Boc-(D)-Chg-Gly-Arg 3-chloro-4-hydroxyanilide;
Tos-(D)-Chg-Gly-Arg 3-chloro-4-hydroxyanilide;
t-Bups-(D)-Chg-Gly-Arg 3-chloro-4-hydroxyanilide;
Mes-(D)-Chg-Gly-Arg 3-chloro-4-hydroxyanilide;
Naps-2-(D)-Chg-Gly-Arg 3-chloro-4-hydroxyanilide;
Z-(D)-Chg-Gly-Arg 3-chloro-4-hydroxyanilide;
H-(D)-Cha-Gly-Arg 3-chloro-4-hydroxyanilide;
Boc-(D)-Cha-Gly-Arg 3-chloro-4-hydroxyanilide;
H-Gly-Pro-Arg 3-chloro-4-hydroxyanilide;
Boc-Gly-Pro-Arg 3-chloro-4-hydroxyanilide;
Tos-Gly-Pro-Arg 3-chloro-4-hydroxyanilide;
t-Bups-Gly-Pro-Arg 3-chloro-4-hydroxyanilide;
Mes-Gly-Pro-Arg 3-chloro-4-hydroxyanilide;
isopropylsulfonyl-Gly-Pro-Arg 3-chloro-4-hydroxyanilide;
Naps-2-Gly-Pro-Arg 3-chloro-4-hydroxyanilide;
(−)-camphorsulfonyl-Gly-Pro-Arg 3-chloro-4-hydroxyanilide;
H-(D)-Cha-Pro-Arg 3-chloro-4-hydroxyanilide;
Boc-(D)-Cha-Pro-Arg 3-chloro-4-hydroxyanilide;
H-(D)-Cha-Ala-Arg 3-chloro-4-hydroxyanilide;
Boc-(D)-Cha-Ala-Arg 3-chloro-4-hydroxyanilide;
Boc-(D)-Cha-Abu-Arg 3-chloro-4-hydroxyanilide;
Z-Gly-Pro-Arg 2-chloro-4-hydroxyanilide;
Z-Gly-Pro-Arg 5-chloro-2-hydroxyanilide;
Z-Gly-Pro- Arg 8-hydroxyquinolin-5-ylamide;
Boc-(D)-Chg-Gly-Pro-Arg 3-chloro-4-hydroxyanilide;
H-(D)-Chg-Gly-Pro-Arg 3-chloro-4-hydroxyanilide; and
t-Bups-(D)-

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