Ectoin and ectoin derivatives as moisturizers in cosmetics

Details Ectoin and ectoin derivatives as moisturizers in cosmetics Ectoin and ectoin derivatives as moisturizers in cosmetics

1999-10-25

2001-07-31

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Cosmetic, antiperspirant, dentifrice

C424S401000, C514S398000, C514S399000

Reexamination Certificate

active

06267973

ABSTRACT:

It is known that (S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid (ectoin) is found in extremely halophilic microorganisms and that it plays a role in the osmoregulation of these organisms (E. A. Galinski et al., Eur. J. Biochem., 149 (1985) pages 135-139).
A major task of cosmetics is the preservation or restoration of the normal state of the skin. In addition to other criteria, stabilizing the moisture content of the skin plays an important role. Under normal conditions, the skin itself is capable of regulating its moisture content. A change in the external environment, such as, for example, a cold dry atmosphere, very rapidly results in the state in which the skin surface is dried out. The surface of the skin turns flaky and tends to chap slightly. The skin is highly sensitive to chemical and physical factors. In patients suffering from atopy, these skin symptoms are observed irrespectively of the age, while, in healthy humans, the dry skin condition becomes more pronounced as they grow older (B. Idson, Cosmetics & Toiletries, 107 (1992), pages 69-78). This skin condition can be prevented as well as counteracted by using suitable moisturizing preparations.
The ingredients used for this purpose in moisturizing preparations differ with regard to two, different principles of action. The occlusive substances (for example paraffin oils) form a barrier on the skin surface which is impermeable to water vapor, whereby they prevent trans-epidermal water loss (TEWL) of the skin. In contrast, intradermal substances such as glycerol bind the water in the skin.
It has now been found that cosmetic preparations comprising at least one compound of the formula Ia or Ib improve and stabilize the hydration of the human skin.
The invention relates to the use of at least one compound of the formula Ia or Ib
and/or a physiologically acceptable salt of the compound of the formula Ia or Ib and/or a stereoisomeric form of the compound of the formula Ia or Ib for the preparation of cosmetic products; R
1
being defined as follows:
a) a hydrogen atom or
b) (C
1
-C
4
)-alkyl,
R
2
being defined as follows:
a) a hydrogen atom,
b) —COOH,
in which R
5
is
1) a hydrogen atom,
2) (C
1
-C
4
)-alkyl,
3) an amino acid radical,
4) a dipeptide radical or
5) a tripeptide radical,
R
3
and R
4
independently of one another being defined as follows:
a) a hydrogen atom or
b) —OH, and
n is the number 1, 2 or 3.
The compounds of the formula Ia or Ib can be present in the cosmetic products in the form of the optical isomers, diastereomers, racemates, zwitterions, cations or in the form of a mixture of these.
Preferred is the use of at least one compound of the formula Ia or Ib, R
1
being defined as follows:
a) a hydrogen atom or
b) methyl,
R
2
being defined as follows:
a) a hydrogen atom or
b) —COOH,
R
3
and R
4
independently of one another being defined as follows:
a) a hydrogen atom or
b) —OH, and
n is the number 2.
The invention furthermore relates to cosmetic products comprising (S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid and/or (S,S)-1,4,5,6-tetrahydro-5-hydroxy-2-methyl-4-pyrimidinecarboxylic acid.
The invention furthermore relates to processes for the preparation of the compound of the formula Ia or Ib which comprise
A) reacting a compound of the formula II
in which R
1
is as in formula Ia,
with a compound of the formula III
in the presence of an alcohol to give a compound of the formula Ia or Ib,
R
3
, R
4
and n being defined as in formula Ia and R
2
being a hydrogen atom or —COOH, or
B) reacting a compound of the formula Ia or Ib in which R
2
is —COOH with an alkyl halide to give the corresponding carboxylic esters of the compound of the formula Ia or Ib, or
C) reacting a compound of the formula Ia or Ib in which R
2
is an activated carboxylic ester with an amine of the formula NH
2
—R
5
to give the corresponding carboxamide of the compound of the formula Ia or Ib.
The term “amino acid” is to be understood as meaning the stereoisomeric forms, for example the D and L forms of the following compounds:
asparagine, arginine, aspartic acid, glutamine, glutamic acid, &bgr;-alanine, &ggr;-aminobutyrate, N&egr;-acetyllysine, N&dgr;-acetylornithine, N&ggr;-acetyldiaminobutyrate, N&agr;-acetyldiaminobutyrate, histidine, isoleucine, leucine, methionine, phenylalanine, serine, threonine and tyrosine. L-amino acids are preferred. Amino acid radicals are derived from the corresponding amino acids.
The following amino acid radicals are preferred:
Gly, Ala, Ser, Thr, Val, &bgr;-Ala, &ggr;-aminobutyrate, Asp, Glu, Asn, Gln, N&egr;-acetyllysine, N&dgr;-acetylornithine, N&ggr;-acetyldiaminobutyrate, N&agr;-acetyldiaminobutyrate.
The amino acids are abbreviated as is generally customary. The di- or tripeptide radicals are acid amides by their chemical nature and disintegrate into two or three amino acids upon hydrolysis. The amino acids in the di- or tripeptide radical are linked to each other by amide linkage.
Examples of suitably physiologically acceptable salts of the compound of the formula Ia or Ib are, for example, alkali metal salts, alkaline earth metal salts or ammonium salts, such as the sodium salt, potassium salt, magnesium salt, calcium salt, triethylamine salt or tris(2-hydroxy-ethyl)amine salt. Other physiologically acceptable salts of the compound of the formula Ia or Ib result from reaction with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid or with organic carboxylic or sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid. Compounds of the formula Ia or Ib in which the same number of basic and acidic groups, such as carboxyl or amino groups, exist, form internal salts.
The invention furthermore relates to a process for the preparation of di- or tripeptides or the salts thereof, which comprises
a) reacting a segment with a C-terminal free carboxylic group or an activated derivative thereof with a suitable segment with an N-terminal free amino group, or
b) synthesizing the di- or tripeptide stepwise, and, if appropriate, eliminating one or more protective groups in the compound obtained by a) or b) which have been introduced temporarily for protecting other functions and, if appropriate, converting the resulting compounds to a physiologically acceptable salt thereof.
The di- or tripeptides are prepared stepwise starting from the C-terminal end or by coupling segments, following the general methods of peptide chemistry (Houben-Weyl, Methoden der Organischen Chemie [Methods in Organic Chemistry], Volume 15/1,2). The peptide coupling steps can be effected for example by the mixed anhydride method, by active radicals or azides or by the carbodiimide method, in particular with the addition of substances which accelerate the reaction and prevent racemisization, such as 1-hydroxybenzotriazole, N-hydroxysuccinimide, 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine, N-hydroxy-5-norbornene-2,3-dicarboximide, furthermore using active derivatives of 1-hydroxybenzotriazole or anhydrides of phosphoric acids, phosphonic acids and phosphinic acids, at a reaction temperature of −10° C. to the boiling point of the solvent, preferably from −5° C. to 40° C.
Suitable solvents are dimethylformamide, dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide. Solvents such as methylene chloride, chloroform or tetrahydrofuran may also be employed if the reactants are sufficiently soluble.
If it is required to prevent secondary reactions or if required for the synthesis of specific peptides, the functional groups in the side chain of amino acids are additionally protected by suitable protecting groups, the following being employed in the main: Arg(Tos), Arg(Mts), Arg(Mtr), Arg(PMV), Asp(OBzl), Asp(OBut), Cys(4-MeBzl), Cys(Asm), Cys(SBut), Glu(Obzl), Glu(Obut), His(Tos), His(Fmoc), His(Dnp), His(Trt), Lys(Cl-Z), Lys(Boc), Met(O), Ser(Bzl), Ser(But), Thr(Bzl), Thr(But), Trp(Mts), Trp(CHO), Tyr(Br-Z), Tyr(Bzl) or Tyr(But).
Amino protecting groups which are preferably use

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