Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Acyclic nitrogen double bonded to acyclic nitrogen – acyclic...
Patent
1997-05-08
1998-05-05
Powers, Fiona T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Acyclic nitrogen double bonded to acyclic nitrogen, acyclic...
534664, A61K 31655, C07D47104
Patent
active
057474770
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP96/03921 filed Sep. 6, 1996.
FIELD OF THE INVENTION
The present invention relates to new azo derivatives of 5-aminosalicylic acid, to pharmaceutical compositions containing these compounds, to a process for their preparation and to their use in the treatment or prevention of inflammatory bowel disease.
DESCRIPTION OF THE PRIOR ART
Inflammatory bowel disease (IBD) is a general term for a group of chronic inflammatory disorders of unknown etiology involving the gastrointestinal tract. IBD may be divided into two major groups, ulcerative colitis and Crohn's disease. Both of them are of a recurrent nature, characterized by periodic outbreaks and remissions. Relapses occur even after surgery and therefore this option is reserved for specific complications or intractability of the disease.
Sulfasalazine, although originally developed in the 1940's for the treatment of rheumatoid arthritis, is now one of the most widely prescribed drugs for inflammatory bowel disease. Sulfasalazine consists of a salicylate (5-aminosalicylate) linked to sulfapyridine by an azo bond. It has been demonstrated that sulfasalazine is split by the colonic bacteria, releasing 5-aminosalicylic acid (5-ASA), and sulfapyridine. Sulfapyridine is almost completely absorbed from the colon, metabolised and excreted in the urine, while 5-ASA is poorly absorbed from the colon. Most of the side effects of sulfasalazine have been ascribed to the sulfapyridine moiety (Das et al., New Engl. J. Med. 1973; 289:491-495). In 1977 Azad Khan et al. demonstrated that in ulcerative colitis the active moiety is 5-ASA (Azad Khan, A.K. et al., Lancet 1977; 2: 892-5) and that sulfapyridine acts only as a carrier and favouring the liberation of 5-ASA in the colon. After this discovery, several new 5-ASA based drugs have been developed, such as slow- or delayed-release formulations of plain 5-ASA or other azo compounds (e. g. Olsalazine, Balsalazine, Ipsalazide). However, no drug is presently available which is able to produce a complete remission of the symptoms and prevent subsequent relapses.
Recently, it has been suggested that PAF could play a key role in the pathogenesis of ulcerative colitis, since elevated levels of this substance have been detected in samples of colonic tissue from patients with this disorder (Wengrower et al., Gastroenterology, 1987; 92) and it has been shown that intravenous administration of PAF induces colitis (Gonzalez-Crusi et al., Am. J. Pathol. 1983; 112:127-35 and Hseuh et al. Am. J. Pathol. 1986; 122:231-9) and gastritis (Rosam et al., Nature 1986; 319:54-6 and Wallace et al., Prostaglandins 1986; 31:989-98).
The present invention discloses a series of compounds containing the 4-hydroxy-3-carboxyphenylazo moiety which can be metabolised in the colon in a similar manner to sulfasalazine, delivering 5-ASA and an aromatic amine having PAF antagonist activity. With the compounds of the present invention not only it is possible to avoid the side effects of sulfapyridine, but also, by using. a PAF antagonist as the carrier of 5-ASA, they may be more effective in the therapy of inflammatory bowel disease than current treatments. Such an approach is totally new since never before compounds combining in the same molecule a PAF antagonist and 5-aminosalicylic acid have been described in the literature.
DESCRIPTION OF THE INVENTION
The present invention relates to new azo derivatives of 5-aminosalicylic acid of general formula I: ##STR2## wherein: the 4-hydroxy-3-carboxyphenylazo moiety can be at the 3- or 4-position of the benzene ring; represents hydrogen or C.sub.1-4 alkyl; ##STR3## wherein these groups are bound to the phenyl ring in formula I via B and Z, respectively; --SO.sub.2 --, B can also represent a group of formula (iv), (v), (vi) or (vii); ##STR4## n represents 0, 1, 2 or 3; p represents 0 or 1; C.sub.3-7 cycloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl or aryl; R.sup.6, and when A represents --CO-- or --SO.sub.2 --, then R.sup.4 can also represent --NR.sup.5 R.sup.6, --NR.sup.7 C(=O)OR
REFERENCES:
patent: 2396145 (1946-03-01), Anders et al.
patent: 4312806 (1982-01-01), Lambert et al.
patent: 5516783 (1996-05-01), Whittaker et al.
Almansa Carmen
Balsa Dolors
Bartroli Javier
Carceller Elena
Ferrando Rosa
J. Uriach & Cia S.A.
Powers Fiona T.
LandOfFree
Azo derivatives of 5-aminosalicylic acid does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Azo derivatives of 5-aminosalicylic acid, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Azo derivatives of 5-aminosalicylic acid will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-54755