5-ASA derivatives having anti-inflammatory and antibiotic...

Details 5-ASA derivatives having anti-inflammatory and antibiotic... 5-ASA derivatives having anti-inflammatory and antibiotic...

2001-08-29

2002-10-01

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Acyclic nitrogen double bonded to acyclic nitrogen, acyclic...

C534S660000

Reexamination Certificate

active

06458776

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to 5-ASA derivatives and methods of treating diseases therewith.
BACKGROUND OF THE INVENTION
Many people suffer from inflammatory bowel disease (IBD). TRD is a generic term used to refer to two inflammatory diseases, ulcerative colitis and Crohn's disease. Ulcerative colitis is a chronic inflammatory disease of unknown etiology that affects various portions of the gastrointestinal (GI) tract, particularly the lower GI tract, and more particularly the colon and/or rectum. Crohn's disease is a serious inflammatory disease of the GI tract. It predominates in the intestine (ileum) and the large intestine (colon). Various medications are being used to treat inflammatory bowel disease.
It is known to use mesalamine, 5-aminosalicylic acid (5-ASA) to treat ulcerative colitis. While mesalamine may be active in treating ulcerative colitis, it may be absorbed as it passes through the GI tract. This absorption may adversely affect the amount of mesalamine that reaches the lower GI tract, particularly the colon and rectum.
Various mesalamine formulations have been introduced in an attempt to protect mesalamine as it passes through the gut and the upper GI tract. One such formulation is a delayed-release formulation that relies on a pH-sensitive coating surrounding the mesalamine. The coating allows the mesalamine to pass through the gut and upper GI tract without being absorbed so that the mesalamine reaches the target (i.e. the lower GI tract, particularly the colon and/or rectum) intact. In another formulation, mesalamine microspheres surround a mesalamine core. This formulation releases mesalamine throughout the GI tract, rather than targeting the colon specifically. It may be difficult to predict the bioavailability of the various mesalamine formulations when administered to a wide variety of individuals. As a result, it may be difficult to determine the proper dosage for a given individual.
It is also known to use sulfasalazine having the following formula to treat ulcerative colitis.
However, sulfasalazine is metabolized in the body to form mesalamine (5-aminosalicylic acid (5-ASA)) and sulfapyridine. Several adverse side affects have been noted from the use of sulfasalazine including nausea, vomiting, abdominal discomfort, and headache to name just a few. These adverse side effects are usually attributed to the activity of sulfapyridine in the GI tract, as well as that absorbed into the system.
U.S. Pat. No. 4,412,992 to Chan proposes mesalamine derivatives. Unlike sulfasalazine, the breakdown of these compounds in the intestinal tract may not give rise to undesirable metabolic products. In fact, the non-mesalamine metabolic products may be innocuous.
It is also known to use olsalazine having the following formula to treat ulcerative colitis.
In addition to being relatively expensive to make, olsalazine may have adverse side effects including diarrhea.
It is also known to use azathioprine (6-(1-methyl-4-nitoimidazol-5-ylthio)purine) in the treatment of inflammatory bowel disease. Azathioprine has the following chemical structure:
It is also known to use 6-mercaptopurine, a metabolite of azathioprine, to treat inflammatory bowel disease. 6-mercaptopurine has the following chemical structure:
Methotrexate (L4amino-N
10
-methylpteroyl-glutamic acid) has also been used to treat inflammatory bowel disease. Methotrexate has the following chemical structure:
The polypeptide cyclosporine, which has traditionally been given to transplant patients to prevent organ rejection, has also been used to treat inflammatory bowel disease. The use of cyclosporine to treat IBD may be limited, however, by the various side effects associated with this medication. These side effects include high blood pressure, kidney damage, tremors, headaches, seizures, excessive hair growth, excessive gum growth, confusion, coma, and gout.
It is also known to use the absorbable antibiotics metronidazole and ciprofloxacin to treat inflammatory bowel disease.
SUMMARY OF THE INVENTION
According to embodiments of the present invention, compounds are provided having the structure of Formula I:
where R
1
is a substituted or unsubstituted phenyl group, and where Z is selected such that a compound, Z-R
1
-NH
2
, formed by cleavage of the azo bond is a non-absorbable antibiotic. Preferably, the compound, Z-R
1
-NH
2
, is a metabolite formed by in vivo cleavage of the azo bond. R
1
is preferably an unsubstituted phenyl group. When R
1
is a substituted phenyl, it is preferably substituted with lower alkyl.
According to other embodiments of the present invention, compounds are provided having the structure of Formula II:
where X is —SO
2
— or —CO— and Y is:
or the esters or pharmaceutically acceptable salts thereof.
Pharmaceutical compositions including compounds according to the present invention in admixture with a pharmaceutical diluent or carrier are also provided, as are methods of utilizing such compounds in the treatment or prophylaxis of various diseases including, but not limited to, inflammatory bowel disease.


REFERENCES:
patent: 2270676 (1942-01-01), Behnisch et al.
patent: 4412992 (1983-11-01), Chan
patent: 6197341 (2001-03-01), Friess et al.
Jain et al., “Studies in Sulphanilamides. Part XIII. Reaction with Dicarboxylic Acids. Some New N1- and N4-Acyl and Heterocyclic Derivatives,”J. Indian Chem. Soc., 24: 173-176 (1947).
Kimura et al., “Determination of the Active Moiety of BX661A, a New Therapeutic Agent for Ulcerative Colitis, by Studying Its Therapeutic Effects on Ulcerative Colitis Induced by Dextran Sulfate Sodium in Rats,”Drug Res., 48(II)(11): 1091-1096 (1998).
E. Hackmann & P.C. Ferreira, “Nuovi Azoderivati Solfammidici,”Boll. Chim. Farm., 114(9): 501-508 (1975).
Osman et al., “Synthesis of Sulfanilamido-Naphthoquinones as Potential Antituberculous Agents,”Journal of Pharmaceutical Sciences, 72(1): 68-71 (1983).
Frommel et al., “La Paraminobenzolsulfonesuccinylimide, Sulfamide Soluble Neutre et Injectable,”Helv. Physiol. Acta., 3: 261-268 (1945).
International Search Report corresponding to PCT/US 01/41910; date of mailing: Dec. 27, 2001.

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