Ureins derived from alpha, omega-diamono acids and process for their preparation

Ureins are obtained by reaction, in basic medium, between an N.sup..omega. -(aryloxycarbonyl)diamino acid and a compound containing a free amino group. The chirality of the compounds is outstandingly well preserved.

FIELD OF THE INVENTION 
The present invention relates to new ureins derived from 
.alpha.,.omega.-diamino acids and to a new process for the preparation of 
such compounds. 
TECHNOLOGY REVIEW 
Ureins derived from diamino acids can conventionally be prepared by 
carbamoylation by means of a cyanate or of an isocyanate. This known 
procedure does not, however, appear entirely satisfactory, mainly due to 
insufficient specificity of these reactants for the amino functional group 
to be carbamoylated and due to the sometimes significant racemization 
which such a treatment can cause. 
The invention overcomes the disadvantages of the conventional processes by 
providing a new, particularly outstanding, process which makes it possible 
to obtain the desired product with an improved chemical yield while 
retaining outstandingly well the chiral purity of the compounds used. 
The invention consequently relates to a process for the preparation of 
ureins derived from an .alpha.,.omega.-diamino acid, according to which a 
compound containing a free amino group is reacted, in basic medium, with a 
diamino acid derivative containing an N.sup..omega. -aryloxycarbonyl 
group. 
Urein is understood to denote any compound whose molecular structure 
contains the structure --NH--CO--NH--. 
Amino acid is understood to denote, for the purposes of the present 
invention, any compound comprising at least one amino group and at least 
one carboxyl group. By extension, the term "amino acid" is also understood 
to encompass hereinbelow any amino acid in which certain other groups are 
optionally bonded to organic groups such as protective groups. In 
particular, .alpha.,.omega.-diamino acid is understood to denote any amino 
acid comprising at least one amino group and at least one carboxyl group 
bonded to the same carbon atom of the molecule and additionally comprising 
at least one other amino group bonded to another carbon atom. It most 
often concerns a compound of general formula 
##STR1## 
in which A represents a bivalent group consisting of a carbon chain 
containing 1 to 8 carbon atoms, which chain is optionally substituted by 
one or a number of groups chosen from C.sub.1 -C.sub.3 alkyl groups and 
functional groups comprising at least one oxygen or sulphur atom such as a 
carboxyl, acyl, hydroxyl, alkoxy or mercapto group, without the total 
number of carbon atoms in the group A being greater than 15. A is 
preferably a polymethylene group comprising from 2 to 5 carbon atoms. 
Mention may be made, as examples of .alpha.,.omega.-diamino acids, of 
especially 2,3-diaminopropanoic acid, 2,4-diaminobutanoic acid, ornithine, 
lysine, homolysine, 5-hydroxylysine, 6-methyllysine and 2,6-diaminopimelic 
acid. 
Diamino acid derivative containing an N.sup..omega. -aryloxycarbonyl group, 
also subsequently known as N.omega.-(aryloxycarbonyl)diamino acid, is 
understood to denote any .alpha.,.omega.-diamino acid derivative in which 
an aryloxycarbonyl group of formula R--O--CO--, R symbolizing an aryl 
group, is bonded to the nitrogen atom of the .omega.-amino group of the 
diamino acid. 
SUMMARY OF THE INVENTION 
In the process according to the invention, the use of a diamino acid 
derivative containing an N.sup..omega. -aryloxycarbonyl group is critical. 
In fact, it is apparent, surprisingly, that the aryloxycarbonyl group 
bonded to the .omega.-amino group of the amino acid leads, in the presence 
of a compound containing a free amino group, to the formation of a urein 
by substitution of the aryloxy fragment of the said aryloxycarbonyl group 
by the free amino group of the said compound. 
DETAILED DESCRIPTION OF THE INVENTION 
The N.sup..omega. -aryloxycarbonyl derivative of the diamino acid used 
generally contains, as aryloxycarbonyl group, a group comprising from 7 to 
15 carbon atoms. This aryloxycarbonyl group is most often a 
phenyloxycarbonyl or naphthyloxycarbonyl group optionally substituted by 
at least one group chosen from alkyl groups comprising from 1 to 4 carbon 
atoms and the nitro group. Mention may be made, as examples of 
aryloxycarbonyl groups which can be used in the process according to the 
invention, of the phenyloxycarbonyl, tolyloxycarbonyl, xylyloxycarbonyl, 
mesitylyloxycarbonyl, ethylphenyloxycarbonyl, diethylphenyloxycarbonyl, 
propylphenyloxycarbonyl, isopropylphenyloxycarbonyl, naphthyloxycarbonyl 
and nitrophenyloxycarbonyl groups. The aryloxycarbonyl group is preferably 
a phenyloxycarbonyl or p-tolyloxycarbonyl group. Good results have been 
obtained in the process according to the invention with the N.sup..omega. 
-phenyloxycarbonyl derivative of the diamino acid. 
An N.sup..omega. -aryloxycarbonyl derivative of any .alpha.,.omega.-diamino 
acid can be used in the process according to the invention. 
The N.sup..omega. -(aryloxycarbonyl)diamino acid is a product which is 
inexpensive and readily accessible. It can be prepared conventionally by 
resorting to well known selective acylation techniques, for example via 
the copper complex according to a procedure similar to that described in 
particular in "Methoden Der Organischen Chemie" (Houben-Weyl), 1974, 
Volume XV/1, p. 472, concerning N.sup..epsilon. 
-benzyloxycarbonyl-L-lysine. As the .alpha.-amino functional group is 
complexed by the copper ion, the aryloxycarbonyl group can be selectively 
attached to the .omega.-amino functional group of the diamino acid by 
reaction with an aryl chloroformate or an aryloxycarbonyloxysuccinimide. 
The compound comprising a free amino group which reacts with the 
N.sup..omega. -(aryloxycarbonyl)diamino acid in the process according to 
the invention is any compound of general formula R1R2NH in which R1 and R2 
represent, independently of one another, hydrogen atoms or alkyl, 
cycloalkyl or aralkyl radicals or in which R1 and R2 together form an 
alicyclic radical. In this compound, the alkyl, cycloalkyl, aralkyl or 
alicyclic radicals can be substituted by one or a number of functional 
groups comprising at least one oxygen, sulphur or nitrogen atom, for 
example by a carboxyl, hydroxyl, mercapto, indolyl or imidazolyl group. 
Compounds which can be used in the process according to the invention are 
in particular ammonia, primary or secondary amines and the amino acids as 
defined above. The process according to the invention is particularly 
advantageous when the compound comprising a free amino group is an amino 
acid. 
When the N.sup..omega. -(aryloxycarbonyl)diamino acid is a derivative of an 
.alpha.,.omega.-diamino acid in which the carbon chain of the group A 
consists of 1 to 3 carbon atoms, the N.sup..omega. 
-(aryloxycarbonyl)diamino acid acts, in the process according to the 
invention, both as N.sup..omega. -aryloxycarbonyl derivative and, via its 
.alpha.-amino group, as compound containing a free amino group. The result 
thereof, via an intramolecular reaction, is the formation of cyclic ureins 
of general formula 
##STR2## 
in which A represents a bivalent group consisting of an optionally 
substituted linear carbon chain formed from 1 to 3 carbon atoms. 
In the process of the invention, by way of illustration, N.sup..beta. 
-aryloxycarbonyl-2,3-diaminopropanoic acid forms 
2-oxoimidazolidinyl-4-carboxylic acid, N.sup..gamma. 
-aryloxycarbonyl-2,4-diaminobutyric acid forms 
2-oxohexahydropyrimidinyl-4-carboxylic acid and N.sup..delta. 
-(aryloxycarbonyl)ornithine forms 
2-oxohexahydro-1,3-diazepinyl-4-carboxylic acid. 
When the N.sup..omega. -(aryloxycarbonyl)diamino acid is a derivative of an 
.alpha.,.omega.-diamino acid in which the carbon chain of the group A 
consists of at least 4 carbon atoms, the N.sup..omega. 
-(aryloxycarbonyl)diamino acid is converted, in the process according to 
the invention, into a non-cyclic urein of general formula 
##STR3## 
in which R1 and R2 have the same meaning as above and in which A 
represents a bivalent group consisting of an optionally substituted linear 
carbon chain formed from at least 4 carbon atoms. In the process of the 
invention, by way of illustration, homocitrulline is obtained by reaction 
between N.sup..epsilon. -(phenyloxycarbonyl)lysine and ammonia. When the 
compound comprising a free amino group is an amino acid, an N.sup..omega. 
-(carboxyalkylcarbamoyl)-.alpha.,.omega.-diamino acid is obtained by the 
process according to the invention. 
An N.sup..omega. -(aryloxycarbonyl)diamino acid incorporated in a peptide 
chain can, without disadvantage, be used in the process according to the 
invention. In particular, when the N.sup..omega. -(aryloxycarbonyl)diamino 
acid is a derivative of an .alpha.,.omega.-diamino acid in which the 
carbon chain of the group A consists of 1 to 3 carbon atoms and when this 
compound constitutes the N-terminal residue of a peptide chain, the 
process according to the invention makes it possible easily to obtain 
peptides of general formula 
##STR4## 
in which A represents a bivalent group consisting of an optionally 
substituted linear carbon chain formed from 1 to 3 carbon atoms and in 
which NH--P represents any peptide chain bonded to the cyclic urein via an 
amide bond. 
The process according to the invention is carried out in a basic medium. 
The process according to the invention is generally carried out in a liquid 
medium in which the N.sup..omega. -(aryloxycarbonyl)diamino acid and the 
compound comprising a free amino group are at least partially soluble and 
preferably entirely soluble. Depending on the nature of the reactants, the 
medium can comprise water and/or an organic solvent. Organic solvents 
which are suitable in the process according to the invention are lower 
alcohols such as in particular methanol, ethanol and isopropanol, 
tetrahydrofuran and dimethoxyethane. Media consisting of water and of a 
water-miscible organic solvent are preferred. Good results have been 
obtained in particular in a water/ethanol medium. 
The basicity of the medium can be obtained by addition of a basic compound 
to the medium, for example by addition of an inorganic base such as LiOH, 
NaOH or KOH or by addition of an organic base which is inert under the 
reaction conditions, such as a tertiary amine. Good results have, in 
particular, been obtained in the presence of LiOH or of triethylamine. 
When the compound containing a free amino group is an amino acid 
containing free carboxyl functional groups, the basic compound must be 
used in an amount sufficient to neutralize the carboxyl functional groups. 
In order to obtain cyclic ureins, the intramolecular reactivity of the 
N.sup..omega. -(aryloxycarbonyl)diamino acid is such that it is possible, 
without problems, to add a compound containing a free amino group, such as 
ammonia, to achieve the desired basicity of the medium, without this 
appreciably affecting the yield of the reaction in cyclic urein. 
In order to obtain non-cyclic ureins, when the .alpha.-amino group of the 
N.sup..omega. -(aryloxycarbonyl)diamino acid is free, it is necessary, in 
order to avoid a condensation reaction of the N.sup..omega. 
-(aryloxycarbonyl)diamino acid concurrent with the desired reaction with 
the compound containing a free amino group, to operate with an excess, 
with respect to the stoichiometric amount necessary, of the compound 
containing a free amino group which it is desired to react with the 
N.sup..omega. -(aryloxycarbonyl)diamino acid. Good results are obtained 
when the reaction is carried out with a molar ratio of the compound 
containing a free amino group to the N.sup..omega. 
-(aryloxycarbonyl)diamino acid which is at least equal to 3. The reaction 
is preferably carried out with a ratio at least equal to 4. In principle, 
there is no upper limit to this ratio. In practice, however, it is 
generally pointless to carry out the reaction with a molar ratio of the 
compound containing a free amino group to the N.sup..omega. - 
(aryloxycarbonyl)diamino acid which is greater than 100. The molar ratio 
most often does not exceed 10. When the compound containing a free amino 
group is an amino acid or a peptide, the molar ratio preferably does not 
exceed 7. When the compound containing a free amino group has a 
sufficiently basic nature, it may prove to be pointless to add another 
basic compound to the medium. 
The process according to the invention can be implemented in a wide 
concentration range of the reactants in the liquid medium, in particular 
for obtaining cyclic ureins. The N.sup..omega. -(aryloxycarbonyl)diamino 
acid is generally used at a concentration of 0.05 to 5 mol/l, preferably 
of 0.1 to 1 mol/l. 
The reaction can be carried out from room temperature to the boiling 
temperature of the organic solvent. It is advantageously carried out from 
30 to 80.degree. C. A temperature of 40 to 60.degree. C. is very 
particularly preferred. 
Under these conditions, the reaction time is generally less than 10 hours. 
The reaction is most often complete after a time of 30 minutes to 4 hours. 
The process according to the invention appears particularly advantageous 
for preparing ureins derived from .alpha.,.omega.-diamino acids. The 
N.sup..omega. -aryloxycarbonyl derivative for the diamino acid used in the 
process according to the invention can be easily and cheaply prepared from 
the diamino acid. It can easily be isolated in the pure form. It is stable 
and can be stored for a long time without deteriorating. The process 
according to the invention is particularly outstanding. It makes it 
possible to obtain the desired ureins with a very high yield. It 
additionally has very little effect on the chirality of the compounds 
used. Moreover, the departure of the aryloxy fragment of the 
aryloxycarbonyl group only generates relatively inoffensive by-products in 
the medium which do not disturb the synthesis. For example, when it 
concerns the phenyloxycarbonyl group, only phenol is generated. 
Consequently, when the compounds used contain very labile groups, such as 
certain protective groups, the by-products generated in the medium do not 
cause any damage to these compounds. Purification of the desired products 
is markedly simpler than in the previous known processes. 
The invention also relates to N.sup..omega. 
-carboxyalkylcarbamoyl-.alpha.,.omega.-diamino acids, ureins derived from 
an .alpha.,.omega.-diamino acid, of general formula 
##STR5## 
in which A represents a bivalent group consisting of a linear carbon chain 
formed from 4 to 8 carbon atoms, which chain is optionally substituted by 
one or a number of groups chosen from C.sub.1 -C.sub.3 alkyl groups and 
functional groups comprising at least one oxygen or sulphur atom such as a 
carboxyl, acyl, hydroxyl, alkoxy or mercapto group, and in which R3--NH 
represents an amino acid or a peptide. A is preferably a polymethylene 
group containing 4 or 5 carbon atoms. R3--NH is preferably an amino acid 
and more preferentially an essential amino acid. 
These new compounds constitute compounds with a structure similar to that 
of dipeptides and can be used in particular in place of the corresponding 
dipeptides, in particular as a source of essential amino acids in 
parenteral human feeding or in animal feeding. 
The invention also relates to the cyclic ureins of general formula 
##STR6## 
in which A represents a bivalent group consisting of a linear carbon chain 
formed from 1 to 3 carbon atoms, which chain is optionally substituted by 
one or a number of groups chosen from C.sub.1 -C.sub.3 alkyl groups and 
functional groups comprising at least one oxygen or sulphur atom such as a 
carboxyl, acyl, hydroxyl, alkoxy or mercapto group, with the exception of 
2-oxoimidazolidinyl-4-carboxylic acid and 
(LD)-2-oxohexahydropyrimidinyl-4-carboxylic acid. A preferably represents 
a bivalent group consisting of an optionally substituted carbon chain 
consisting of 2 or 3 carbon atoms. In a particularly preferred way, A 
represents a trimethylene group --(CH.sub.2).sub.3 --. In this case, the 
urein formed is 2-oxohexahydro-1,3-diazepinyl-4-carboxylic acid, easily 
obtained by the process according to the invention from ornithine. 
Depending on whether the (D) or (L) enantiomer of the diamino acid is used 
in the process according to the invention, the (D) or (L) enantiomer of 
the corresponding cyclic urein is obtained in the chirally pure form. 
These cyclic ureins can be used in particular as the N-terminal residue of 
certain biologically active peptides, such as the hormone TRH (Thyrotropin 
Releasing Hormone), by replacing the N-terminal pyroglutamyl group of this 
peptide. 
Finally, the invention relates to peptides analogous to TRH, of general 
formula 
##STR7## 
in which A is a bivalent group consisting of a linear carbon chain formed 
from 2 or 3 carbon atoms, which chain is optionally substituted by one or 
a number of groups chosen from C.sub.1 -C.sub.3 alkyl groups and 
functional groups comprising at least one oxygen or sulphur atom such as a 
carboxyl, acyl, hydroxyl, alkoxy or mercapto group. A is preferably a 
polymethylene group. The peptide in which A is a trimethylene group is 
preferred. These peptides have an increased resistance to proteolytic 
digestion while retaining a high biological activity. 
The symbolic representations of the amino acids and of the peptides adopted 
in the description and examples follow the IU nomenclature 
recommendations generally adopted and described, for example, in 
"Nomenclature and Symbolism for Amino Acids and Peptides, Recommendations 
1983", Eur. J. Biochem. (1984), 138, p. 9-37. Except when otherwise 
stipulated, all the amino acids described are (L)-amino acids.