5-aminosalicylic acid derivatives for the therapy of chronic inf

Details 5-aminosalicylic acid derivatives for the therapy of chronic inf 5-aminosalicylic acid derivatives for the therapy of chronic inf

1993-03-03

1995-06-13

Warden, Jill

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 18, 530331, 530330, C07K 510, C07K 508, C07K 506, A61K 3806

Patent

active

054242924

DESCRIPTION:

BRIEF SUMMARY
The invention refers to 5-aminosalicylic acid (5-ASA) derivatives of general formula 1 ##STR1## wherein R.sub.1 is hydrogen, glutamyl (Glu) or aspartyl (Asp) and R.sub.2 is OH or the residue leucyl-prolyl, with the proviso that R.sub.1 and R.sub.2 cannot be contemporaneously hydrogen and hydroxy, respectively.
The present invention also relates to a process for the preparation of compounds of formula 1.
The compounds of the invention of the general formula 1 have therefore the following formulae: ##STR2##
The invention refers also to the non-toxic salts of the above compounds, to pharmaceutical compositions containing them and to processes for the preparation thereof.
Said compounds are useful in chronic inflammatory bowel diseases, thanks to their topical antiinflammatory effect on intestinal mucosa portions affected by the lesions.
This activity involves interactions with specific peptidases present on the brush border of small intestine, which can hydrolize selectively the amino acidic residues, releasing in situ the active principle 5-ASA. It is in fact known that some chronic inflammatory diseases, such as Chron's disease and ulcerative rectocolitis, are since many years treated with drugs able to inhibit the arachidonic acid derivatives biosynthesis, such as PGE.sub.2, leucotrienes and thromboxane B.sub.2. Sulfasalazine, of formula 7, was one of the first drugs used; it is metabolized to 5-ASA and sulfapyridine by reductive cleavage of the azide bond by intestinal bacteria..sup.1,2. ##STR3##
The properties of sulfasalazine seem to be nontherapeutic against Crohn's disease and of ulcerative rectocolitis. Moreover, sulfasalazine is responsible in some patients of the following side-effects:
All the above effects are mainly due to sulfapyridine and in about 10% of the patients were so serious as to ask for the drop out of the treatment..sup.3
Moreover 5-ASA, the active part of the sulfasalazine molecule, is not stable at the gastric pH and it is rapidly absorbed in the small intestine. This prevents its use as such by the oral use, unless at high doses.
The compounds of general formula 1, having specific amino acidic residues bound to the 1-carboxy and/or 5-amino substituents of the corresponding 5-ASA, are hydrolized in vivo at the level of brush border of the ileum where specific aminopeptidases are present (Aminopeptidases A) .sup.5-7,8,12 which are able to hydrolize selectively an N-terminal amidic bond when a Glu or Asp residue is bound to that position. Moreover, dipeptides containing amino acids Glu or Asp as terminal residues are known to be resistant to pancreatic peptidases,.sup.5-7,8-10 important requisite for the non-occurrence of the fast 5-ASA release. Finally, always in the brush border, a second class of peptidases is present, namely the carboxypeptidases, which are able to selectively hydrolize a C-terminal amide bond between an amino acid and a penultimate Pro residue..sup.1--3,4-6
Thanks to these characteristics the compounds of the invention may then undergo a chemoselective enzymatic hydrolysis so as to release 5-ASA directly at the distal intestine.
The compounds of the invention are easily prepared in liquid phase by means of usual methods for the peptide synthesis, starting from 5-aminosalicylic acid which is suitably protected and then reacted with an N-protected glutamic or aspartic acid derivatives and/or with a suitably protected leucyl-prolyl derivative. The removal of the protecting groups yields the desired compounds.
A general synthesis scheme is hereinbelow reported and the experimental conditions used for the preparation of the compounds 2, 3, 4, 5, 6 are described. ##STR4##


5-(N-benzyloxycarbonyl)-aminosalicylic acid 8

5-aminosalicylic acid (30 g, 0.20 tool) was suspended into a saturated NaHCO.sub.3 solution (500 ml ). Solid NaHCO.sub.3 (10 g) was then added to the suspension at 0.degree. C. under stirring and then benzylchloroformate (36.7 g, 0.215 tool) was added dropwise.
An abundant precipitate of the desired product was formed when the reaction was over and it

REFERENCES:
patent: 4505898 (1985-03-01), Marks et al.
patent: 5120306 (1992-06-01), Gosselin

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