Title:  Aryl nitrone therapeutics for the treatment of inflammatory bowel disease

United States Patent:   6,258,852

Assignee:  Centaur Pharmaceuticals, Inc. (Sunnyvale, CA)

Filed:  May 8, 2000

Disclosed are methods for treating or preventing inflammatory bowel disease (IBD) using aryl nitrone compounds. Pharmaceutical compositions containing aryl nitrone compounds which are useful for the treatment or prophylaxis of IBD are also disclosed.

SUMMARY OF THE INVENTION

It has now been found that certain aryl nitrone compounds are effective for the treatment and prophylaxis of IBD.

Accordingly, in one of its composition aspects, this invention provides a pharmaceutical composition for the treatment or prophylaxis of inflammatory bowel disease comprising a pharmaceutically acceptable carrier and an effective inflammatory bowel disease-treating amount of a compound selected from the group consisting of:

N-cyclohexyl-.alpha.-(2-ethoxyphenyl)nitrone,

N-tert-butyl-.alpha.-(3,5-di-tert-butyl-2-hydroxyphenyl)nitrone,

N-isobutyl-.alpha.-phenylnitrone,

N-tert-butyl-.alpha.-(4-benzyloxyphenyl)nitrone,

N-cyclobutyl-.alpha.-(2-ethoxyphenyl)nitrone,

N-benzyl-.alpha.-(4-acetamidophenyl)nitrone,

N-cyclopentyl-.alpha.-(2-ethoxyphenyl)nitrone,

N-tert-butyl-.alpha.-(1-methylindol-3-yl)nitrone,

N-tert-butyl-.alpha.-(3,5-di-tert-butyl-4-acetoxy)nitrone,

spiro[cyclohexane-1,3']-6-methoxy-3,4-dihydroisoquinoline-N-oxide,

N-tert-butyl-.alpha.-(4-aminosulfonylphenyl)nitrone,

and pharmaceutically acceptable salts thereof.

Another aspect of this invention is directed to methods for treating a patient suffering from or susceptible to an inflammatory bowel condition. Accordingly, this invention provides a method for treating a patient suffering from or susceptible to an inflammatory bowel condition comprising administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective inflammatory bowel condition-treating amount of a compound selected from the group consisting of:

N-cyclohexyl-.alpha.-(2-ethoxyphenyl)nitrone,

N-tert-butyl-.alpha.-(3,5-di-tert-butyl-2-hydroxyphenyl)nitrone,

N-isobutyl-.alpha.-phenylnitrone,

N-tert-butyl-.alpha.-(4-benzyloxyphenyl)nitrone,

N-cyclobutyl-.alpha.-(2-ethoxyphenyl)nitrone,

N-benzyl-.alpha.-(4-acetamidophenyl)nitrone,

N-cyclopentyl-.alpha.-(2-ethoxyphenyl)nitrone,

N-tert-butyl-.alpha.-(1-methylindol-3-yl)nitrone,

N-tert-butyl-.alpha.-(3,5-di-tert-butyl-4-acetoxy)nitrone,

spiro[cyclohexane-1,3']-6-methoxy-3,4-dihydroisoquinoline-N-oxide,

N-tert-butyl-.alpha.-(4-aminosulfonylphenyl)nitrone,

and pharmaceutically acceptable salts thereof.

In another of its method aspects, this invention provides a method for treating or preventing inflammatory bowel disease comprising:

(a) identifying a patient suffering from or susceptible to an inflammatory bowel condition; and

(b) administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective inflammatory bowel condition-treating amount of a compound selected from the group consisting of:

N-cyclohexyl-.alpha.-(2-ethoxyphenyl)nitrone,

N-tert-butyl-.alpha.-(3,5-di-tert-butyl -2-hydroxyphenyl)nitrone,

N-isobutyl-.alpha.-phenylnitrone,

N-tert-butyl-.alpha.-(4-benzyloxyphenyl)nitrone,

N-cyclobutyl-.alpha.-(2-ethoxyphenyl)nitrone,

N-benzyl-.alpha.-(4-acetamidophenyl)nitrone,

N-cyclopentyl-.alpha.-(2-ethoxyphenyl)nitrone,

N-tert-butyl-.alpha.-(1-methylindol-3-yl)nitrone,

N-tert-butyl-.alpha.-(3,5-di-tert-butyl-4-acetoxy)nitrone,

spiro[cyclohexane-1,3 ']-6-methoxy-3,4-dihydroisoquinoline-N-oxide,

N-tert-butyl-.alpha.-(4-aminosulfonylphenyl)nitrone,

and pharmaceutically acceptable salts thereof.

In the methods of this invention, the pharmaceutical compositions may be administered orally, parenterally, or rectally. The methods of this invention are be effective where the inflammatory bowel condition is ulcerative colitis or Crohn's disease.

In one embodiment of the above methods, the pharmaceutical composition is preferably administered as an oral dose in an amount of from 0.1 to about 150 mg/kg of patient weight.

In another embodiment of the above methods, the pharmaceutical composition is preferably administered intravenously in an amount of from about 0.01 mg/kg/hour to about 100 mg/kg/hour of patient weight for at least about 1 hour.

In still another embodiment of the above methods, the pharmaceutical composition is preferably administered rectally in an amount of from 1 to about 150 mg/kg of patient weight.

In one of its composition aspects, this invention is also directed to novel aryl nitrone compounds. Accordingly, this invention is directed to each of the following compounds:

N-isobutyl-.alpha.-phenylnitrone,

N-cyclobutyl-.alpha.-(2-ethoxyphenyl)nitrone,

N-benzyl-.alpha.-(4-acetamidophenyl)nitrone,

N-tert-butyl-.alpha.-(1-methylindol-3-yl) nitrone,

N-tert-butyl-.alpha.-(4-aminosulfonylphenyl)nitrone,

and pharmaceutically acceptable salts thereof.

Claim 1 of 5 Claims

What is claimed is:

1. A pharmaceutical composition for the treatment or prophylaxis of inflammatory bowel disease comprising a pharmaceutically acceptable carrier and an effective inflammatory bowel disease-treating amount of a compound selected from the group consisting of:

N-tert-butyl-.alpha.-(3,5-di-tert-butyl-2-hydroxyphenyl)nitrone,

N-isobutyl-.alpha.-phenylnitrone,

N-benzyl-.alpha.-(4-acetamidophenyl)nitrone,

N-tert-butyl-.alpha.-(1-methylindol-3-yl)nitrone,

N-tert-butyl-.alpha.-(3,5-di-tert-butyl-4-acetoxy)nitrone,

N-tert-butyl-.alpha.-(4-aminosulfonylphenyl)nitrone,

and pharmaceutically acceptable salts thereof.

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