Amino acid derivatives and anti-inflammatory agents

Details Amino acid derivatives and anti-inflammatory agents Amino acid derivatives and anti-inflammatory agents

1999-04-02

2003-04-22

Davis, Brian (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S559000, C514S562000, C514S567000, C514S618000, C514S620000, C548S349100, C560S012000, C560S040000, C564S162000, C564S165000

Reexamination Certificate

active

06552061

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an anti-inflammatory agents that is useful for preventing, improving or treating inflammatory skin injuries or diseases, and skin external products and toiletries containing the same.
2. Description of the Related Art
In recent years, the causes of various skin injuries and diseases have been increasingly studied. For example, it is known that with respect to the causes of senescence, canceration, pigmentation and inflammation, inflammatory cytoklines such as IL-1&agr; and TNF-&agr; and extracellular matrix decomposition enzymes such as collagenase deeply participate therein (for example, “Oxidative Stress in Dermatology”, Marcel Dekker, Inc., pp. 187-205, 1993). The expression of genes encoding these proteins is mainly controlled at a gene transcription level. Regarding the inflammatory proteins such as inflammatory cytokines and extracellular matrix decomposition enzymes, the expression thereof is controlled by transcription control factors such as NF-&kgr;B and AP-1 (for example, “Active Oxygen and Signal Transfer”, Kodansha Scientific. pp. 37-46, 1996). Accordingly, when the expression of inflammatory proteins or the activation of transcription control factors participating therein can be inhibited, it is expected to prevent skin injuries and diseases.
For example, it is indicated that sulfur-containing antioxidants such as N-acetyl-L-cysteine and pyrrolidine dithiocarbamate inhibit NF-&kgr;B activation (for example, “Active Oxygen and Signal Transfer”, Kodansha Scientific, pp. 37-46, 1996). N-acetyl-L-cysteine is reported to inhibit also AP-1 activation (for example, FEBS Letters, vol. 384, pp. 92-96, 1996). These compounds are however problematic in the feeling upon use owing to a peculiar odor derived from a sulfur atom present in the molecular structure thereof. Besides the sulfur-containing antioxidants, AP-1 activation and expression of extracellular matrix decomposition enzymes by retinoic acid (for example, Nature, vol. 379, pp. 335-339, 1996) and inhibition of NF-&kgr;B activation by a steroidal anti-inflammatory drug or a non-steroidal anti-inflammatory drug (for example, Bio Essays, vol. 18, pp. 371-378, 1996) have been reported. Nevertheless, retinoic acid has a side effect such as skin peeling, and a steroidal anti-inflammatory drug has a side effect such as steroidal dermatosis. Accordingly, the use thereof is limited. Although a non-steroidal anti-inflammatory drug is free from a systemic side effect encountered in the steroidal anti-inflammatory drug, a local side effect thereof has to be improved, and further, an effect of inhibiting inflammatory factor activation is unsatisfactory.
SUMMARY OF THE INVENTION
It is an object of the invention to provide an anti-inflammatory agents which inhibits expression of an Inflammatory protein and activation of a gene transcription control factor participating therein and which exhibits a good feeling upon use and a safety.
The present inventors have assiduously conducted investigations to achieve the object, and have consequently found that the object is achieved by using amino acid derivatives represented by the following formula (I) or salts thereof as an active ingredient. This finding has led to the completion of the invention.
That is, the invention relates to an anti-inflammatory agents containing, as an active ingredient, at least one selected from amino acid derivatives represented by formula (I)
wherein
Ar represents an optionally substituted 2-hydroxyaryl group,
n is 0 or 1.
R
2
represents a hydrogen atom or a side chain of an &agr;-amino acid or a &bgr;-amino acid,
X represents —O— or —NH—,
R
1
represents a hydrogen atom or a group that forms, together with R
2
and an adjacent atoms, a cyclic structure of pyroglutamic acid, and
R
3
represents a hydrogen atom, an alkyl group having from 1 to 22 carbon atoms or an alkenyl group having from 2 to 22 carbon atoms,
and salts thereof.
Further, the invention relates to an agent for preventing or treating inflammatory diseases, especially ultraviolet induction inflammatory diseases which agent contains at least one of the amino acid derivatives represented by formula (I) and the salts thereof.
Still further, the invention relates to a toiletry additive which is added as a toiletry component, this toiletry additive being composed of at least one of the amino acid derivatives represented by formula (I) and the salts thereof.
Furthermore, the invention relates to toiletries or skin external products containing at least one selected from the amino acid derivatives represented by formula (I) and the salts thereof. The toiletries of the invention are useful for preventing or improving inflammatory skin injuries, and the skin external products of the invention are useful for preventing or treating inflammatory diseases.
Of the compounds represented by formula (I), the compounds represented by formula (II) are novel compounds undescribed in the literature or publication.
wherein
Ar may be substituted with 2-hydroxyaryl group,
m is 0 or 1,
R
5
represents a side chain selected from the group of alanine, phenylalanine, serine, cysteine. aspartic acid, cysteic acid, homocysteic acid, ornithine or histidine when m is 0 and , R
5
represents hydrogen atom when m is 1,
R
4
represents a hydrogen atom or a group that forms, together with R
5
and adjacent atoms, a cyclic structure of pyroglutamic acid, and
Y represents —OR
6
, —NHR
6
or —NH
2
, and
R
6
represents alkyl group having from 1 to 7 carbon atoms.
DETAILED DESCRIPTION OF THE INVENTION
The present invention will be explained in detail as follows.
In the compounds represented by formula (I), n is an Integer of 0 or 1. When n is 0, the compounds represented by formula (I) are &bgr;-amino acid derivatives. When n is 1, the compounds represented by formula (I) are &bgr;-amino acid derivatives.
When n is 0, R
2
in the amino acid derivatives represented by formula (I) is a hydrogen atom or a side chain of an &agr;-amino acid. Examples of the side chain of the &agr;-amino acid include side chain of acidic amino acids such as glutamic acid, aspartic acid, cysteic acid and homocysteic acid, neutral amino acids such as glycine, alanines valine, leucine, isoleucine, phenylalanine, tryptophan, threonine, serine, homoserine,tyrosine, dopa, cysteine, methionine, glutamine and asparagine, and basic amino acids such as lysine, ornithine, arginine and histidine. Side chains of neutral amino acids are preferable.
Further, when n is 1, R
2
may be a hydrogen atom or a side chain of a &bgr;-amino acid. As the &bgr;-amino acid, &bgr;-alanine is preferable.
In the amino acid derivatives represented by formula (I), R
1
is usually a hydrogen atom. However, R
1
can also form, together with R
2
and an adjacent atom, a cyclic structure: As the cyclic structure, a 2-pyrrolidone ring is preferable.
In this case, the compounds represented by formula (I) are pyroglutamic acid derivatives.
When an asymmetric carbon atom is present in the amino acid residue, the compounds may be either optically active compounds or racemic compounds.
The alkyl group in R
3
of formula (I) is a linear or branched alkyl group having from 1 to 22 carbon atoms, preferably from 1 to 18 carbon atoms, and it may have an unsaturated group in a part of a carbon chain. Examples of the alkyl group in the invention include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-amyl, sec-amyl, tert-amyl, isoamyl, n-hexyl, cyclohexyl, n-heptyl, n-octyl, 2-ethylhexyl, nonyl, isononyl, decyl, isodecyl, undecyl, lauryl, tridecyl, isotridecyl, myristyl, cetyl, isocetyl, stearyl, isostearyl, behenyl groups and so on.
Further, the alkenyl group is a linear or branched alkenyl group having from 2 to 22 carbon atoms, preferably from 2 to 18 carbon atoms, more preferably from 5 to 18 carbon atoms which group may have at least one of carbon-carbon double bonds or carbon-carbon triple bonds as required. An alkenyl group derived from unsaturated fatty acids, such as an oleyl gr

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