Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
2000-02-11
2001-10-30
Geist, Gary (Department: 1623)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
C540S492000, C544S316000, C544S318000, C548S313700, C548S322500
Reexamination Certificate
active
06310178
ABSTRACT:
The present invention relates to new ureins derived from &agr;, &ohgr;-diamino acids and to a new process for the preparation of such compounds.
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 &agr;,&ohgr;-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
&ohgr;
-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, &agr;,&ohgr;-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
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
1
-C
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 &agr;,&ohgr;-diamino acids, of especially 2,3-diaminopropanoic acid, 2,4-diaminobutanoic acid, ornithine, lysine, homolysine, 5-hydroxylysine, 6-methyl-lysine and 2,6-diaminopimelic acid.
Diamino acid derivative containing an N
&ohgr;
-aryloxycarbonyl group, also subsequently known as N
&ohgr;
-(aryloxycarbonyl)diamino acid, is understood to denote any &agr;,&ohgr;-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 &ohgr;-amino group of the diamino acid.
In the process according to the invention, the use of a diamino acid derivative containing an N
&ohgr;
-aryl-oxycarbonyl group is critical. In fact, it is apparent, surprisingly, that the aryloxycarbonyl group bonded to the &ohgr;-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.
The N
&ohgr;
-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, diethyl-phenyloxycarbonyl, propylphenyloxycarbonyl, isopropyl-phenyloxycarbonyl, naphthyloxycarbonyl and nitrophenyl-oxycarbonyl 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
&ohgr;
-phenyloxycarbonyl derivative of the diamino acid.
An N
&ohgr;
-aryloxycarbonyl derivative of any &agr;,&ohgr;-diamino acid can be used in the process according to the invention.
The N
&ohgr;
- (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
&egr;
-benzyloxycarbonyl-L-lysine. As the &agr;-amino functional group is complexed by the copper ion, the aryloxycarbonyl group can be selectively attached to the &ohgr;-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
&ohgr;
-(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
&ohgr;
-(aryloxycarbonyl)diamino acid is a derivative of an &agr;,&ohgr;-diamino acid in which the carbon chain of the group A consists of 1 to 3 carbon atoms, the N
&ohgr;
-(aryloxycarbonyl)diamino acid acts, in the process according to the invention, both as N&ohgr;-aryloxycarbonyl derivative and, via its &agr;-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
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
&bgr;
-aryloxycarbonyl-2,3-diaminopropanoic acid forms 2-oxoimidazolidinyl-4-carboxylic acid, N
&ggr;
-aryloxycarbonyl-
-2,4
-diaminobutyric acid forms 2-oxohexahydropyrimidinyl-4-carboxylic acid and N
67
- (aryloxycarbonyl)ornithine forms 2-oxohexahydro-1,3-diazepinyl-4-carboxylic acid.
When the N
&ohgr;
-(aryloxycarbonyl)diamino acid is a derivative of an &agr;,&ohgr;-diamino acid in which the carbon chain of the group A consists of at least 4 carbon atoms, the N
&ohgr;
- (aryloxycarbonyl)diamino acid is converted, in the process according to the invention, into a non-cyclic urein of general formula
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
&egr;
-(phenyloxycarbonyl)lysine and ammonia. When the compound comprising a free amino group is an amino acid, an N
&ohgr;
-(carboxyalkylcarbamoyl)-&agr;,&ohgr;-diamino acid is obtained by the process according to the invention.
An N
&ohgr;
-(aryloxycarbonyl)diamino acid incorporated in a peptide chain can, without disadvantage, be used in the process according to the invention.
Anteunis Marc
Becu Frank
Blondeel Georges
Callens Roland
Geist Gary
Maier Leigh C.
Schneller Martin V.
Solvay S.A.
Venable
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