Boronic acid or borinic acid derivatives as enzyme stabilizers

Details Boronic acid or borinic acid derivatives as enzyme stabilizers Boronic acid or borinic acid derivatives as enzyme stabilizers

1996-01-25

1998-11-24

Fries, Kery

Cleaning compositions for solid surfaces, auxiliary compositions

Cleaning compositions or processes of preparing

Enzyme component of specific activity or source

510530, 510465, 435188, C11D 3386

Patent

active

058406778

DESCRIPTION:

BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT/DK94/00249 filed Jun. 22, 1994, which is incorporated herein by reference.


FIELD OF INVENTION

This invention relates to a liquid composition containing an enzyme and an improved enzyme stabilizer.


BACKGROUND OF THE INVENTION

Storage stability problems are well known with liquids containing enzyme(s). Especially in enzyme-containing liquid detergents a major problem, in particular if the detergent contains protease, is that of ensuring enzyme activity over time.
The prior art has dealt extensively with improving the storage stability, for example by adding a protease inhibitor.
Boric acid and boronic acids are known to reversibly inhibit proteolytic enzymes. A discussion of the inhibition of one serine protease, subtilisin, by boronic acid is provided in Molecular & Cellular Biochemistry 51, 1983, pp. 5-32.
Boronic acids have very different capacities as subtilisin inhibitors. Boronic acids containing only alkyl groups such as methyl, butyl or 2-cyclohexylethyl are poor inhibitors with methylboronic acid as the poorest inhibitor, whereas boronic acids bearing aromatic groups such as phenyl, 4-methoxyphenyl or 3,5-dichlorophenyl are very good inhibitors with 3,5-dichlorophenylboronic acid as a particularly effective one (see Keller et al, Biochem. Biophys. Res. Com. 176, 1991, pp. 401-405).
It is also claimed that aryl boronic acids which have a substitution at the 3-position relative to boron are unexpectedly good reversible protease inhibitors. Especially, acetamidobenzene boronic acid is claimed to be a superior inhibitor of proteolytic enzymes (see WO 92/19707).
The inhibition constant (K.sub.i) is ordinarily used as a measure of capacity to inhibit enzyme activity, with a low K.sub.i indicating a more potent inhibitor. However, it has earlier been found that the K.sub.i values of boronic acids do not always tell how effective inhibitors they are (see for instance WO 92/19707).


SUMMARY OF THE INVENTION

In this invention it is surprisingly found that some special boronic and borinic acid derivatives have extraordinary good capacities as enzyme stabilizers.
Accordingly, the present invention relates to a liquid composition comprising an enzyme and a boronic acid or a borinic acid derivative enzyme stabilizer of the following formula: ##STR1## where R.sub.1 is an optionally substituted fused aromatic ring structure containing 14 or 18 carbon atoms in the ring, or an optionally substituted monocyclic or fused aromatic heterocyclic ring structure containing up to 17 carbon atoms in the ring, or an optionally substituted monocyclic or fused quinonoid ring structure containing up to 18 carbon atoms in the ring; ##STR2## where X is the same or different and selected from hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, aryl, substituted aryl, hydroxy, hydroxyl derivative, halogen, amine, alkylated amine, amine derivative, nitro, thiol, thiol derivative, aldehyde, acid, acid salt, ester, sulfonate or phosphonate, and o,p and q may be the same or different and may each be 0,1 or 2; m and n may be the same or different and may each be 0 or 1; R.sub.3 is the same or different as R.sub.1 and selected from R.sub.1, or R.sub.3 is a hydroxyl group, or R.sub.1 and R.sub.3 are both optionally substituted monocyclic or dicyclic aromatic ring structures.
In this context optionally substituted ring structures mean that the substituents on the ring structure are freely chosen, but they are preferably selected from hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, aryl, substituted aryl, hydroxy, hydroxyl derivative, halogen, amine, alkylated amine, amine derivative, nitro, thiol, thiol derivative, aldehyde, acid, acid salt, ester, sulfonate or phosphonate.


DETAILED DISCLOSURE OF THE INVENTION

Boronic and borinic acid derivatives may be prepared using methods well known to those skilled in the art, for example by using one of the following methods:
a) Hydroboration of unsaturated materials, i.

REFERENCES:
patent: 5039446 (1991-08-01), Estell
patent: 5354491 (1994-10-01), Bjorkquist et al.
patent: 5422030 (1995-06-01), Panandiker et al.
patent: 5431842 (1995-07-01), Panandiker et al.
patent: 5472628 (1995-12-01), Panandiker et al.
patent: 5476608 (1995-12-01), Boyer et al.
patent: 5488157 (1996-01-01), Bjorkquist et al.
Phillip and Marpuri "Inhibition of Subtilisin by Substituted Arylboronic Acids" FEBS Letters (1981).

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