AMIDE THERAPEUTICS FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASE

Abstract: Disclosed are methods for treating or preventing inflammatory bowel disease (IBD) using amide and related compounds. Pharmaceutical compositions containing amide compounds which are useful for the treatment or prophylaxis of IBD are also disclosed.

Description: AMIDE THERAPEUTICS FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASE CROSS-REFERENCE TO RELATED APPLICATIONS The application claims the benefit of U.S. Patent Application Serial No. 60/085,990, filed May 19, 1998, the disclosure of which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION Field of the Invention This invention relates to the treatment of inflammatory bowel disease (IBD). More specifically, this invention is directed to methods for treating or preventing IBD using amide compounds. This invention is also directed to pharmaceutical compositions containing amide compounds which are useful for the treatment or prophylaxis of IBD. State of the Art The term inflammatory bowel disease ("IBD") describes a group of chronic inflammatory disorders of unknown causes involving the gastrointestinal tract ("GI tract"). The prevalence of IBD in the US is estimated to be about 200 per 100,000 population or approximately 500,000 people. Patients with IBD can be divided into two major groups, those with ulcerative colitis ("UC") and those with Crohn's disease ("CD"). In patients with UC, there is an inflammatory reaction primarily involving the colonic mucosa. The inflammation is typically uniform and continuous with no intervening areas of normal mucosa. Surface mucosal cells as well as crypt epithelium and submucosa are involved in an inflammatory reaction with neutrophil infiltration. Ultimately, this situation typically progresses to epithelial damage with loss of epithelial cells resulting in multiple ulcerations, fibrosis, dysplasia and longitudinal retraction of the colon. CD differs from UC in that the inflammation extends through all layers of the intestinal wall and involves mesentery as well as lymph nodes. CD may affect any part of the alimentary canal from mouth to anus. The disease is often discontinuous, i.e., severely diseased segments of bowel are separated from apparently disease-free areas. In CD, the bowel wall also thickens which can lead to obstructions. In addition, fistulas and fissures are not uncommon. Clinically, IBD is characterized by diverse manifestations often resulting in a chronic, unpredictable course. Bloody diarrhea and abdominal pain are often accompanied by fever and weight loss. Anemia is not uncommon, as is severe fatigue. Joint manifestations ranging from arthralgia to acute arthritis as well as abnormalities in liver function are commonly associated with IBD. Patients with IBD also have an increased risk of colon carcinomas compared to the general population. During acute "attacks" of IBD, work and other normal activity are usually impossible, and often a patient is hospitalized. Although the cause of IBD remains unknown, several factors such as genetic, infectious and immunologic susceptibility have been implicated. IBD is much more common in Caucasians, especially those of Jewish descent. The chronic inflammatory nature of the condition has prompted an intense search for a possible infectious cause. Although agents have been found which stimulate acute inflammation, none has been found to cause the chronic inflammation associated with IBD. The hypothesis that IBD is an autoimmune disease is supported by the previously mentioned extraintestinal manifestation of IBD as joint arthritis, and the known positive response to IBD by treatment with therapeutic agents such as adrenal glucocorticoids, cyclosporine and azafhioprine, which are known to suppress immune response. In addition, the GI tract, more than any other organ of the body, is continuously exposed to potential antigenic substances such as proteins from food, bacterial byproducts (LPS), etc. Once the diagnosis has been made, typically by endoscopy, the goals of therapy are to induce and maintain a remission. The least toxic agents which patients are typically treated with are the aminosalicylates. Sulfasalazine (Azulfidine), typically administered four times a day, consists of an active molecule of aminosalicylate (5-ASA) which is linked by an azo bond to a sulfapyridine. Anaerobic bacteria in the colon split the azo bond to release active 5-ASA. However, at least 20% of patients cannot tolerate sulfapyridine because it is associated with significant side-effects such as reversible sperm abnormalities, dyspepsia or allergic reactions to the sulpha component. These side effects are reduced in patients taking olsalazine. However, neither sulfasalazine nor olsalazine are effective for the treatment of small bowel inflammation. Other formulations of 5-ASA have been developed which are released in the small intestine (e.g. mesalamine and asacol). Normally it takes 6- 8 weeks for 5-ASA therapy to show full efficacy. Patients who do not respond to 5-ASA therapy, or who have a more severe disease, are prescribed corticosteroids. However, this is a short term therapy and cannot be used as a maintenance therapy. Clinical remission is achieved with corticosteroids within 2-4 weeks, however the side effects are significant and include a Cushing goldface, facial hair, severe mood swings and sleeplessness. The response to sulfasalazine and 5-aminosalicylate preparations is poor in Crohn's disease, fair to mild in early ulcerative colitis and poor in severe ulcerative colitis. If these agents fail, powerful immunosuppressive agents such as cyclosporine, prednisone, 6-mercaptopurine or azathioprine (converted in the liver to 6-mercaptopurine) are typically tried. For Crohn's disease patients, the use of corticosteroids and other immunosuppressives must be carefully monitored because of the high risk of intra-abdominal sepsis originating in the fistulas and abscesses common in this disease. Approximately 25 % of IBD patients will require surgery (colectomy) during the course of the disease. Oxygen-derived free radicals such as HO» , the superoxide anion and other reactive oxygen species such as HOC1, have emerged as a common pathway of tissue injury in a wide variety of diseases whose underlying cause is an inappropriately vigorous and sustained immune response (failure to control or down regulate response to the initial, appropriate stimulus). Examples of other diseases, in addition to IBD and arthritis, where this mechanism appear to be the operative cause are ARDS, septic shock, asthma, diabetes, multiple sclerosis, uveitis, etc. Typically, both a cytokine-mediated immune response and a nonspecific inflammatory cascade are involved in the primary inappropriate response with both responses mediated through active oxygen species (oxidative stress). The inappropriate secondary response, also mediated through oxidative stress) may involve tissue damaging oxidation by neutrophils and tissue macrophages. Various approaches have been taken to suppress this inappropriate inflammatory response. Small molecule inhibitors of the various leukotriene, PAF and cyclooxygenase pathways have shown only limited efficacy, perhaps because blocking only one of many pathways does not provide a sufficiently large decrease in overall oxidative stress. Another approach has been the use of antibodies or cloned receptor molecules which target specific proteins in the inflammatory cascade such as IL-1, IL-6 or TNF- . However, this approach is practical only for acute conditions, like septic shock or ARDS, where IV administration and antibody formation against the therapeutic protein is less of a concern. For a chronic condition like IBD, an orally active small molecule that is fully active when dosed once-a-day would be the preferred method of treatment. Another approach to mitigating the oxidative stress resulting from an inflammatory response is to employ nitrone-related therapeutics (NRTs). The prototype NRT is α-phenyl-t-butyl nitrone (PBN) shown below. NRTs represent a new category of therapeutics with the inherent capacity to overcome the shortcomings of other previously studied compounds. Among other properties, NRTs such as PBN are believed to trap free radicals (R») by adding the radical to form a more unreactive nitroxyl free radical. Nitrones were first used as analytical tools capable of reacting with highly reactive radicals to yield free radical adducts that are much less reactive. In many cases, the free radical/nitrone adduct complex is stable enough to allow in vivo isolation and quantitation using electron spin resonance (ESR). The concept of using nitrones as therapeutics in, for example, neurodegenerative diseases resulted from the observations that nitrones, such as PBN, trap reactive oxygen species and/or secondary free radicals following ischemia. The therapeutic effects of nitrones may result because the nitrones convert highly reactive radicals into much less reactive products. Certain NRTs have been shown to protect experimental animals from ischemia/reperfusion injury (stroke). NRTs, administered chronically, reverse the age-associated increase in oxidatively damaged protein and the age-associated decrease in the activity of the oxidative- sensitive enzyme, glutamine synthetase, in the brain. Accompanying the NRT-mediated changes in oxidized protein and glutamine synthetase activity is a significant improvement in the performance of animals in behavioral tests measuring short-term spatial memory. For example, it has been shown that prototype NRTs mitigate the effects of this inflammatory cascade in a number of in vivo models. Of particular interest is the consistent and well documented protection shown by PBN against the lethality induced by LPS in various rodent models of septic shock. Remarkably, PBN has also been shown to increase the life span of senescence-accelerated mice by one third, perhaps by mitigating free radical damage. PBN has also been shown to block inducible nitric oxide synthetase ("iNOS"), the enzyme responsible for producing large amounts of the highly damaging NO* . Thus, PBN can both trap HO* and suppress formation of NO* , potentially neutralizing the effects of the two agents considered to be the most damaging to tissue. When evaluating the prospects of using an antioxidant to successfully treat IBD, it is perhaps also useful to consider that the anti-oxidant defense of the human colon is relatively deficient compared to human liver (mucosal levels of SOD, catalase and GSH representing 8% , 4% and 40% , respectively of liver levels), thus leaving the colon particularly sensitive to oxidative stress. A considerable number of chemical modifications have been made to increase NRTs suitability as therapeutic agents. The effects of intrinsic chemical reactivity and radical trapping ability have been examined by substituting the phenyl ring with electron donating or electron withdrawing substituents. More water soluble analogues have also been made which, for example, have a carboxylate or sodium sulfonate group on the phenyl ring. In addition, lipophilic analogues have been made with functional group substitutions on either the phenyl ring or the nitronyl nitrogen. The alkyl nitrogen substituent has also been varied through the standard straight chain and branched C 3 -C 5 substituents. Nitrone isosteres and related compounds have also targeted and examined for efficacy. This approach has led to various classes of compounds, such as substituted ureas, amides, thioamides, azoxy derivatives, sulphones, and hydroxamic acids. Among these, some benzamide compounds substantially similar in structure to some nitrones, such as PBN, have been shown to have activity in the treatment of Parkinson's disease, HIV dementia, and related conditions. As a final aspect of background, in evaluating the effectiveness of compounds in the treatment of IBD, an in vivo model based upon trinitrobenzene sulfonic acid ("TNBS") is used. References relating to the above-mentioned subjects include: Glickman. RM (1994) Inflammatory Bowel Disease in Harrison's Principles of Internal Medicine (McGraw Hill, New York, NY) Chapter 255: 1403-1416. Calkins, BM, Mendeloff, Al (1986) Epidemiology of Inflammatory Bowel Disease, Epidemiology Review 8: 60-90. Levin, B. (1992) Inflammatory Bowel Disease and Colon Cancer, Cancer (Supplement), 70: 1313-1316. Crotty, B. (1994) Ulcerative Colitis and Xenobiotic Metabolism, Lancet, 343: 35-38. Hanauer. SB, Baert, F. (1994) Medical Therapy of Inflammatory Bowel Disease, Med Clin North Am, 78: 1413-1426. MacDermott, RP (1994) Alterations in the Mucosal System in Ulcerative Colitis and Crohn's Disease, Med Clin North Am, 78: 1207-1231. Hanauer. B. (1993) Medical Therapy of Ulcerative Colitis, Lancet, 342: 412-417. Winrow. VR, Winyard, PG, Morris, CJ, Blake, DR (1993) Free radicals in Inflammation: Second Messengers and Mediators of Tissue Destruction, Br Med Bull 49 : 506-522. Floyd, RA and Carney, J., Nitrone Radical Traps (NRTs) Protect in Experimental Neurodegenerative Diseases, in Neuroprotective Approaches to the Treatment of Parkinson's Disease and Other Neurodegenerative Disorders (Olanow, CW, Jenner, P and Youssim E, Eds.) Academic Press, New York, New York, in press. Cao, X. and Phillis, JW (1994) a-Phenyl-N-tert-butyl-nitrone Reduces Cortical Infarct and Edema in Rats Subjected to Focal Ischemia. Brain Res. 644: 267-272. Zhao, Q., Pahlmark, K., Smith, M.-J., and Siesjo, B. (1994) Delayed Treatment with the Spin Trap a-phenyl-n-tert-butyl nitrone (PBN) Reduces Infarct Size Following Transient Middle Cerebral Artery Occlusion in Rats. Acta Physiol. Scad. 152: 349-350. Oliver, CN, Starke-Reed, PE, Stadtman, ER, Carney, JM and Floyd, RA (1990) Oxidative Damage to Brain Proteins, Los of Glutamine Synthetase Activity and Production of Free Radicals During Ischemia Induced Injury to Gerbil Brain. Proc. Natl. Acad. Sci. USA 87: 5144-5147. Carney. JM, Starke-Reed, PE Oliver, CN, Landrum, RW, Cheng, MS, Wu, JF and Floyd, RA (1991) Reversal or age-related increase in brain protein oxidation in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert- butyl-α-phenylnitrone. Proc. Natl. Acad. Sci., 88: 3633-3636. Novelli. GP (1992) Oxygen Radicals in Experimental Shock: Effects of Spin-Trapping Nitrones in Ameliorating Shock Pathophysiology, Critical Care Medicine, 20: 499-507. Hamburger, SA, McCay, PB (1989) Endotoxin-Induced Mortality in Rats is Reduced by Nitrones, Circulatory Shock, 29: 329-334. Progrebniak, HW, Merino, MJ, Hahn, SM, Mitchell, JB, Pass, HI (1992) Spin Trap Salvage from Endotoxemia: The Role of Cytokine Down-Regulation, Surgery, 112: 130-139. McKechnie, K., Furman, BL, Paratt JR (1986), Modification by Oxygen Free Radical Scavengers of the Metabolic and Cardiovascular Effects of Endotoxin Infusion in Conscious Rats, Circulatory Shock 19: 429-439. Edamatsu,R, Mori, A., Packer, L (1995) The Spin Trap N-tert-α-phenyl- butylnitrone Prolongs the Life Span of the Senescence Accelerated Mouse, Biochem Biophys Res Comm 211 : 847-849. Miyajima, T., Kotake, Y. (1995) Spin Trapping Agent, Phenyl N- Tert Butyl Nitrone, Inhibits Induction of Nitric Oxide Synthase in Endotoxin-Induced Shock in Mice, Biochem Biophys Res Commun, 215: 114-121. Boettner, GR (1987) ESR Parameters of Spin Adducts, Free Radical Biology, 3: 259-303. Harris, ML, Schiller, HJ, Reilly, PM, Donowitz, M, Grisham, MB, Bulkley (1992), Free Radicals and Other Reactive Oxygen Metabolites in Imflammatory Bowel Disease: Cause, Consequence or Epiphenomenom, Pharmacol. Ther., 53: 375-408. Grisham MB, MacDermott, RP, Deitch EA (1990), Oxidant Defence Mechanisms in the Human Colon, Inflammation, 14: 669-680. Elson, CO, Startor, RB, Tennyson, GS, Ridell, RH (1995), Experimental Models of Inflammatory Bowel Disease, Gastroenterology , 109: 1344- 1367. Yamada, T, Marshall, S, Specian, RD, Grisham, MB (1992) A Comparative Analysis of Two Models of Colitis in Rats, Gastroenterology, 102: 1524-1534. Wallace, JA, MacNaughton, WK, Morris, GP, Beck PL (1989) Inhibition of Leulotriene Synthesis Markedly Accelerates Healing in a Rat Model of Inflammatory Bowel Disease, Gastroenterology , 95: 29-35. Higa, A. McKnight, GW, Wallace, JL (1993) Attenuation of Epithelial Injury in Acute Experimental Colitis by Immunomodulators, Eur. J. Pharmacol. 239: 171-178. Castro, GA, Roy, SA, Stockstill, RD (1974) Trichinella Spiralis: Peroxidase Activity in Isolated Cells from the Rat Intestine, Exp. Parasitol., 36: 307-315. SUMMARY OF THE INVENTION It has now been found that certain amide compounds are effective for the treatment and prophylaxis of IBD. It has also been discovered that certain related 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 of formula I: wherein A is selected from the group consisting of alkylene and cycloalkylene; R 1 is naphthyl or a group having the formula: wherein each R a is independently selected from the group consisting of aminocarbonyl. hydroxy and trifluoromethyl; R b is hydrogen or acyl; R 2 is selected from the group consisting of hydrogen, alkyl, aralkyl and cycloalkyl; R 3 is selected from the group consisting of alkyl, aralkyl and cycloalkyl; m is an integer from 0 to 3; and n is 0 or 1; and pharmaceutically acceptable salts thereof; with the proviso that: when R 2 is hydrogen, R 3 is tert-butyl and n is 0, then R 1 is not a 4- hydroxyphenyl group or a 4-tert-butylaminocarbonyl group. When present, A is preferably alkylene having from about 2 to about 4 carbon atoms or cycloalkylene having from about 3 to about 5 carbon atoms. More preferably, A is ethylene, i.e., -CH 2 CH 2 -, or tr /w-cyclopropylene, i.e., Preferably, R 1 is phenyl, 4-trifluoromethylphenyl, 2-hydroxyphenyl, 2- naphthyl, indol-5-yl, l-acetylindol-5-yl, and the like. R 2 is preferably hydrogen or methyl, more preferably R 2 is hydrogen. Preferably, R 3 is alkyl or cycloalkyl having 3 to 6 carbon atoms. More preferably, R 3 is alkyl having 3 to 6 carbon atoms. Still more preferably, R 3 is n-butyl, tert-butyl or cyclohexyl. Preferably, m is 0 or 1. In another 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-n-butyl 3-phenylpropionamide, N-«-butyl trans-2-phenyl-l-cyclopropanecarboxamide, N-tert-butyl 4-trifluoromethy lbenzamide , N-tert-butyl 2-hydroxybenzamide, N-tert-butyl naphthylene-2-carboxamide , N-tert-butyl indole-5-carboxamide, N-tert-butyl l-acetylindole-5-carboxamide, and pharmaceutically acceptable salts thereof. It has also been discovered that certain structurally-related compounds are effective for the treatment and prophylaxis of IBD. Accordingly, in yet another 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: 4-(acetamido)benzoic acid, N-tert-butyl 4-[2-(4-(3-methoxyphenyl)piperazin-l-yl)acetamido)]- benzamide, 7-nitroindole, 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 of formula I: wherein A is selected from the group consisting of alkylene and cycloalkylene; R 1 is naphthyl or a group having the formula: wherein each R a is independently selected from the group consisting of aminocarbonyl, hydroxy and trifluoromethyl; R b is hydrogen or acyl; R 2 is selected from the group consisting of hydrogen, alkyl, aralkyl and cycloalkyl; R 3 is selected from the group consisting of alkyl, aralkyl and cycloalkyl; m is an integer from 0 to 3; and n is 0 or 1; and pharmaceutically acceptable salts thereof; with the proviso that: when R 2 is hydrogen, R 3 is tert-butyl and n is 0, then R 1 is not a 4- hydroxyphenyl group or a 4-tert-butylaminocarbonyl group. Preferably, A, R 1 , R 2 , R 3 , n and m are as described above. 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 of formula I above. In still another of its method aspects, 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-n-butyl 3-phenylpropionamide, N-/*ϊ-butyl trans- -phenyl- 1 -cyclopropanecarboxamide , N-tert-butyl 4-trifluoromethylbenzamide , N-tert-butyl 2-hydroxybenzamide, N-tert-butyl naphthylene-2-carboxamide , N-tert-butyl indole-5-carboxamide, N-tert-butyl 1 -acetylindole-5 -carboxamide , and pharmaceutically acceptable salts thereof. In yet another of its method aspects, 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: 4-(acetamido)benzoic acid, N-tert-butyl 4-[2-(4-(3-methoxyphenyl)piperazin-l-yl)acetamido)]- benzamide, 7-nitroindole, and pharmaceutically acceptable salts thereof. In still 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: 4-(acetamido)benzoic acid, N-tert-butyl 4-[2-(4-(3-methoxyphenyl)piperazin-l-yl)acetamido)]- benzamide, 7-nitroindole, 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 amide compounds. Accordingly, this invention is directed to each of the following compounds: N-n-butyl 3-phenylpropionamide, N-n-butyl trαns-2-phenyl-l-cyclopropanecarboxamide, N-tert-butyl 4-trifluoromethy lbenzamide , N-tert-butyl 2-hydroxybenzamide, N-tert-butyl naphthylene-2-carboxamide , N-tert-butyl indole-5-carboxamide, N-tert-butyl l-acetylindole-5-carboxamide, N-tert-butyl 4-[2-(4-(3-methoxyphenyl)piperazin-l-yl)acetamido)]- benzamide, and pharmaceutically acceptable salts thereof. DET AILED DESCRIPTION OF THE INVENTION The treatment methods and pharmaceutical compositions of this invention employ one or more amides or related compounds as the active agent. For the purposes of this invention, the amide compounds are named using conventional amide nomenclature, i.e., the substituents on the amide nitrogen atom are given the N- prefix. For example, N-tert-butyl 4-trifluoromethylbenzamide has the formula: In some cases, the amides of this invention may contain one or more chiral centers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) of the amide of formula I are included within the scope of this invention. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like. Additionally, all geometric isomers of the amide compounds of formula I are included within the scope of this invention including, for example, all cis and trans isomers of the amides of formula I wherein A is cycloalkylene. Definitions When describing the compounds, pharmaceutical compositions and methods of this invention, the following terms have the following meanings unless otherwise specified. "Acyl" refers to the group "-C(O)R" where R is alkyl or aryl. "Acylamino" refers to the group "-NRC(O)R" where each R is independently hydrogen, alkyl, aralkyl or cycloalkyl. "Acetamido" refers to the group "-NHC(O)CH 3 ". "Alkoxy" refers to the group "-OR" where R is alkyl. "Alkyl" refers to monovalent alkyl groups preferably having from 1 to about 12 carbon atoms, more preferably 1 to 8 carbon atoms and still more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propy , isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and the like. The term "lower alkyl" refers to alkyl groups having 1 to 6 carbon atoms. "Alkylene" refers to divalent alkylene groups preferably having from 1 to 12 carbon atoms and more preferably 1 to 6 carbon atoms which can be straight chain or branched. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like. "Aminocarbonyl" refers to the group "-C(O)NRR" where each R is independently hydrogen, alkyl, aralkyl or cycloalkyl. " Aralkyl" refers to "aryl-alkylene-" groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 14 carbon atoms in the aryl moiety. Such aralkyl groups are exemplified by benzyl, phenethyl, and the like. "Aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like. Unless otherwise indicated, such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkoxy, alkoxycarbonyl, carboxyl, cyano, halo, hydroxy, nitro. thioalkoxy and the like. "Carboxyl" refers to the group "-C(O)OH" and salts thereof. "Cyano" refers to the group "-CN". "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed rings which can be optionally substituted with from 1 to 3 alkyl groups. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like. "Cycloalkylene" refers to divalent cyclic alkyl groups of from 3 to 10 carbon atoms having a single cyclic ring which can be optionally substituted with from 1 to 3 alkyl groups. Such cycloalkyl groups include, by way of example, cyclopropylene. cyclobutylene, cyclopentylene and the like. "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo. "Hydroxy" refers to the group "-OH". "Nitro" refers to the group "-NO 2 ". "Sulfonate" or "sulfo" refers to the group "-SO 3 H" and salts thereof. "Thioalkoxy" or "alkylthioether" refers to "alkyl-S-" groups. Preferred thioalkoxy groups include, by way of example, thiomethoxy, thioethoxy, n- thiopropoxy, isothiopropoxy, «-thiobutoxy and the like. "Trifluoromethyl" refers to the group "-CF 3 ". "Pharmaceutically acceptable salt" refers to salts which are acceptable for administration to mammals including, by way of illustration, alkali and alkaline earth metal salts and addition salts of free acids and amines. Such pharmaceutically acceptable salts may be derived from a variety of organic and inorganic counter-ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to a pharmaceutically acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. General Synthetic Procedures The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protecting and deprotecting various functional groups are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. In a preferred method of synthesis, the amide compounds of this invention are prepared by coupling a carboxylic acid halide of formula II: wherein A, R 1 and n are as defined above, and X is halo, preferably chloro or bromo, with an amine of formula III: R 2 -NH-R 3 III wherein R 2 and R 3 are as defined above, under conventional reaction conditions. The coupling reaction is typically conducted by contacting the carboxylic acid halide II with an excess, preferably about 1.1 to about 3 equivalents per carbonyl halide group, of amine III. This reaction is typically conducted at a temperature of from about -10 °C to about 30 °C for about 1 to about 24 hours. Typically, the reaction is conducted in an inert diluent such as dichloromethane, chloroform, benzene, toluene, acetonitrile, tetrahydrofuran and the like. Preferably, the coupling reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, triethylamine, diisopropylethylamine, N- methylmorpholine and the like. Alternatively, an excess of amine III may be used to scavenge the acid generated during the reaction. Upon completion of the coupling reaction, the amide is recovered by conventional methods including precipitation, chromatography, filtration, distillation and the like. If a protecting group has been employed, the protecting group is then removed using conventional procedures. For example, when 2- acetoxybenzoyl chloride is coupled with an amine, the acetyl group of the resulting amide may be removed to re-generate a hydroxyl group by treating the amide with 5 % hydrochloric acid in an inert diluent. The carboxylic acid halides employed in the coupling reaction are either commercially available or can be prepared from commercially available starting materials and reagents using conventional procedures. For example, carboxylic acid halides can be readily prepared from the corresponding carboxylic acid by contacting the carboxylic acid with an inorganic acid halide, such as thionyl chloride, phosphorous trichloride, phosphorous tribromide or phosphorous pentachloride, or alternatively, with oxalyl chloride under conventional conditions. Generally, this reaction is conducted using about 1 to 5 molar equivalents of the inorganic acid halide or oxalyl chloride, either neat or in an inert solvent, such as carbon tetrachloride, at temperature in the range of about 0°C to about 80°C for about 1 to about 48 hours. A catalyst, such as N,N- dimethylformamide, may also be used in this reaction. Preferred carboxylic acid halides for use in this invention 3- phenylpropionyl chloride, trans-2-phenyl-l-cyclopropanecarbonyl chloride, 4- trifluoromethylbenzoyl chloride, 2-acetoxybenzoyl chloride, terephthaloyl chloride, 2-naphthoyl chloride and the like. The amines of formula III are also either known compounds or compounds that can be prepared from known starting material and reagents by conventional procedures. Examples of suitable amines for use in this reaction include, but are not limited to, methylamine, ethylamine, n-propy lamine, isopropylamine. «-buty lamine, isobutylamine, sec-buty lamine, tert-butylamine, n-penty lamine, cyclopentylamine, n-hexylamine, cyclohexylamine, n-octy lamine, tert-octylamine. dimethylamine, diethylamine, di-n-propy lamine, diisopropylamine, di-n-butylamine, diisobutylamine, di-sec-buty lamine, di-n- hexylamine, methylethylamine, methy 1-n-propy lamine, methylisopropylamine, methyl-n-butylamine, methy 1-tert-buty lamine, methyl-tert-octylamine, methy lcyclopenty lamine , methy lcyclohexy lamine , ethy 1-n-propy lamine , ethylisopropylamine, ethyl-n-buty lamine, ethy lcyclohexy lamine, benzylamine, pyrrolidine, piperidine and the like. Preferred amine include n-buty lamine and tert-butylamine. Alternatively, the amides of formula I can be prepared by coupling a carboxylic acid (i.e., a compound of formula II where X is OH) with an amine of formula III using conventional coupling reagent, such as dicyclohexyl- carbodiimide and the like, or N,N -carbonyldiimidazole. This reaction can be conducted with or without the use of well known additives such as N- hydroxy succinimide, 1-hydroxybenzotriazole, etc. which are known to facilitate the coupling of carboxylic acids and amines. The 4-acetamidobenzoic acid employed in the pharmaceutical compositions and methods of this invention is commercially available from, for example, Aldrich Chemical Company. Pharmaceutical Compositions When used as pharmaceuticals, the compounds employed in this invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one active compound. Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. The compound(s) is typically formulated into a pharmaceutical composition suitable for oral, parenteral (e.g. intravenous or intramuscular injection), or rectal (e.g. suppository) administration. The compositions for oral administration can take the form of liquid solutions or suspensions, powders, tablets, capsules or the like. In such compositions, the amide compound is usually a minor component (0.1 to about 50% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form. A liquid form may include a suitable aqueous or nonaqueous vehicle with buffers, suspending dispensing agents, colorants, flavors and the like. A solid form may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, sugar, methyl salicylate, or orange flavoring. Injectable compositions are commonly based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. Again, the active amide compound is typically a minor component, often being from about 0.05 to 10% by weight, with the remainder being the injectable carrier and the like. Rectal administration is usually by suppository. Suppositories are generally made with a base component of cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, or fatty acid esters of polyethylene glycol. The active amide compound is usually a minor component, often from about 0.05 to 20% by weight, with the remainder being the base component. The components for orally administrable, injectable compositions and suppositories are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences. 18th edition, 1990, Mack Publishing Company, Easton, Pennsylvania, 18042, which is incorporated herein by reference. One can also administer the compounds of the invention in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in the incorporated materials in Remington's Pharmaceutical Sciences. Conditions Treated and Treatment Regimens The conditions treated with the pharmaceutical compositions of this invention generally include IBD and the various symptoms which fall within a definition of IBD. The formulations are administered to achieve a therapeutic effect. For those compounds that exhibit a long residency in the body, a once-a- day regimen is possible. Alternatively, multiple doses, such as up to three doses per day, typically, may offer more effective therapy. Thus, a single dose or a multidose regimen may be used. In any event, the pharmaceutical composition is administered in such a manner so that compound is delivered into the patient's bloodstream. One excellent mode for accomplishing this is intravenous administration. Intravenous dose levels for treating IBD range from about 0.01 mg/kg/hour of active amide compound to about 100 mg/kg/hour, all for from about 1 to about 120 hours and especially 1 to 96 hours. A preloading bolus of from about 50 to about 5000 mg may also be administered to achieve adequate steady state levels. Other forms of parenteral administration, such as intramuscular injection can be used, as well. In this case, similar dose levels are employed. With oral dosing, one to three oral doses per day, each from about 0.1 to about 150 mg/kg of active compound are employed, with preferred doses being from about 0.15 to about 100 mg/kg. With rectal dosing, one to three rectal doses per day, each from about 1 to about 150 mg/kg of active compound are employed, with preferred doses being from about 1 to about 100 mg/kg. In any treatment regimen, the health care professional should assess the patient's condition and determine whether or not the patient would benefit from treatment. Some degree of routine dose optimization may be required to determine an optimal doing level and pattern. A positive dose-response relationship has been observed. As such and bearing in mind the severity of the side effects and the advantages of providing maximum possible amelioration of symptoms, it may be desired in some settings to administer large amounts of active compound, such as those described above. The following formulation examples illustrate representative pharmaceutical compositions of this invention. The present invention, however, is not limited to the following pharmaceutical compositions. Formulation 1 - Tablets A compound of formula I is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press. Formulation 2 - Capsules A compound of formula I is admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule). Formulation 3 - Liquid A compound of formula I (125 mg), sucrose (1.75 g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 mL. Formulation 4 - Injection The compound of formula I is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL. The following synthetic and biological examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention. EXAMPLES In the examples below, all temperatures are in degrees Celsius (unless otherwise indicated). Examples 1-8 describe the synthesis of various amides; and the Bioassay Examples describe the testing of such compounds. In the examples below, the following abbreviations have the following meanings. Abbreviations not defined below have their generally accepted meaning. bd = broad doublet bs = broad singlet d = doublet dd = doublet of doublets dec = decomposed dH 2 O = distilled water EtOAc = ethyl acetate EtOH = ethanol g = grams h = hours Hz = hertz L = liter m = multiplet min = minutes M = molar MeOH = methanol mg = milligram MHz = megahertz mL = milliliter mmol = millimole m.p. = melting point N = normal q = quartet quint. = quintet s = singlet t = triplet THF = tetrahydrofuran tic = thin layer chromatography μg = microgram μ = microliter UV = ultraviolet Example 1 Synthesis of N-tert-Buty\ 4-Trifluoromethylbenzamide To N-tert-butylamine (3.50 g, 0.0048 mol) in 75 mL of benzene was added 4-trifluoromethylbenzoyl chloride (5.00 g, 0.024 mol). The temperature was maintained below 15 °C during the addition and then the reaction mixture was allowed to warm to ambient temperature and stirred for 3 hours. The solvent was then stripped and the residue was dissolved in 75 mL of dichloromethane. This solution was washed with 5% hydrochloride acid (2 x 75 mL), water (2 x 75 mL), dried over MgSO 4 and then the solvent was removed in vacuo to provide 5.05 g (85.9% yield) of the title compound, m.p. 146-148°C. Example 2 Synthesis of N-«-ButyI 3-Phenylpropionamide Following the procedure of Example 1 above and using 3- phenylpropionyl chloride and n-butylamine (and ethyl acetate in place of benzene), the title compound was prepared as a white solid, m.p. 26.7-33.1 °C. Example 3 Synthesis of N-n-Butyl frøns-2-Phenyl-l-cyclopropanecarboxamide Following the procedure of Example 1 above and using tra/7s-2-phenyl-l- cyclopropanecarbonyl chloride and rc-butylamine (and ethyl acetate in place of benzene), the title compound was prepared as a waxy white solid. Example 4 Synthesis of iV-te/*-Butyl Naphthalene-2-carboxamide Following the procedure of Example 1 above and using 2-naphthoyl chloride and tert-butylamine (and ethyl acetate in place of benzene), the title compound was prepared as a white solid, m.p. 154.8-159.2°C. Example 5 Synthesis of N-tert- uty\ 2-Hydroxybenzamide Step A: Synthesis of N-tert-Butyl 2-Acetoxybenzamide Following the procedure of Example 1 above and using 2-acetoxybenzoyl chloride and tert-butylamine, the title compound was prepared. Step B: Synthesis of N-tgrt-Butyl 2-Hydroxybenzamide The product from Step A (2.35 g, 0.010 mol) was dissolved in THF wand 10 mL of water was added to form a clear suspension. Hydrochloric acid (5%) was added until the solution reached a pH ~ 1. The reaction mixture was then refluxed for 24 hours. TLC indicated that about half of the starting material remained, so an additonal 10 mL of 5% hydrochloric acid was added and the reaction mixture was refluxed for 24 hours. The THF was then removed by rotoevaporation and the remaining aqueous mixture was extracted with hexanes (2 x 20 mL). The combined hexane layers were washed with water (2 x 40 mL), dried over MgSO 4 and the hexane removed in vacuo to provide 1.56 g (80.8 % yield) of the title compound as a white crystalline solid, m.p. 78-79.5 °C. Example 6 Synthesis of N-tert-Buty\ Indole-5-carboxamide To a cooled to -30 °C solution of indole-5-carboxylic acid and triethylamine in DMF was added methyl sulfonyl chloride in portions to avoid temperature elevation. Following the addition, solution was warmed to room temperature and was stirred for 1 hour and 15 minutes. Reaction mixture was then cooled to -20 °C and Ν-tert-butyl-amine was added in two portions so the temperature remained at -10 °C. After 13 hours of stirring, the solution was diluted with water and saturated with sodium chloride. The solution was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated under vacuum to afford the title compound as a thick brown oil (NMR showed 34% DMF) (28% yield), melting point = 176.4°C. Spectroscopic data was as follows: Η NMR (CDCl j , 270 MHZ): δ= 10.48 ppm (IH, s), 8.11 ppm (IH, m) 7.65 ppm (IH, dd, J = 8.66; 1.73), 7.42 ppm (IH, dt, J=8.66; 0.74), 7.38 ppm (IH, dd, J=2.94), 6.98 ppm (IH, s), 6.53 ppm (IH, ddd, J=2.94; 2.10; 0.74) 1.48 ppm (9H, s). Example 7 Synthesis of N-tert-B tyl l-Acetylindole-5-carboxamide N-tert-Butyl indole-5-carboxamide was dissolved in dry THF and solution was cooled to -78 °C. Butyllithium was added dropwise with continuous stirring. The reaction mixture was stirred at -78 °C for 40 minutes followed by dropwise addition of acetyl chloride. After addition was complete, the reaction mixture was stirred at -78 °C for 30 minutes and then stirred for 1 hour at room temperature. The reaction mixture was diluted with water and organic phase separated. The aqueous phase was saturate with sodium chloride and was extracted with ethyl acetate. The extracts were combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatrography to afford the title compound as a white solid (14.1 % yield), melting point = 186.8°C. Spectroscopic data was as follows: Η ΝMR (CDCI 3 , 270 MHZ): δ= 8.38 ppm (IH, d, J-8.66), 8.09 ppm (IH, d, J= 1.49). 7.82 ppm (2H, dd, J=8.66; 1.49), 7.81 ppm (2H, d, J=3.71), 7.14 ppm (IH. s), 6.74 ppm (IH, d, J = 3.71), 2.69 ppm (3H, s), 1.48 ppm (9H, s). Example 8 Synthesis of N-tert-b tyl 4-[2-(4-(3-methoxyphenyl)piperazin-l-yl)acetamido)]benzamide To a cooled to -20 °C solution of tert-butyl 4-aminobenzamide and triethylamine (1.30 eq.) in ethyl acetate was added chloroacetyl chloride portion- wise with continuous stirring. The reaction mixture was stirred for a total of 4 hours at room temperature. The solution was then diluted with water and extracted with ethyl acetate and the organic phases were combined, washed with water and brine, and dried over magnesium sulfate. The organic phases were concentrated under vacuum to give N-tert-butyl 4-(2-chloroacetamido)benzamide as a grayish solid (74% yield). N-tert-Butyl 4-(2-chloroacetamido)benzamide, l-(3-methoxyphenyl)- piperazine dichloride (1.1 eq.) and sodium bicarbonate (4.0 eq) were all dissolved in DMF and stirred at 85 °C for 10 hours. The reaction mixture was diluted with methylene chloride/water and the organic phase was washed with water/brine and was dried over magnesium sulfate. Evaporation of the solvent gave gray-brownish solid which was purified by dry flash column chromatography (ethyl acetate; methylene chloride = 1:1) to give the title compound as a white solid (53.4% yield), melting point = 183.2°C. Spectroscopic data was as follows: Η NMR (CDC1 3 , 270 MHZ): δ= 9.28 ppm (IH, s), 7.71 ppm (2H, d, J = 8.91), 7.62 ppm (2H, d, J = 8.91), 7.19 ppm (IH, m), 6.56 ppm (IH, ddd, J = 8.23; 2.23: 0.74), 6.49 ppm (2H, m), 6.44 (IH, d, J=2.47), 5.99 ppm (IH, s), 3.79 ppm (3H, s), 3.27 ppm (4H, t, J=4.89), 3.20 ppm (2H, s), 2.77 ppm (4H, t, J=4.89), 1.47 ppm (9H, s). Bioassy Example 1 Evaluation of Compounds in TNBS Model for IBD In this experiment, the ability of compounds of this invention to reduce colonic inflammation is demonstrated using the trinitrobenzene sulphonic acid ("TNBS") model for IBD. The TNBS model is one of the standard IBD models used in IBD discovery research and it has been extensively evaluated in rodents. See. for example, C O. Elson et al. (1995), Experimental Models of Inflammatory Bowel Disease, Gastroenterology, 109: 1344-1367 and references cited therein. In this model, a single enema of TNBS induces a prolonged colonic inflammatory response (up to several weeks) that is transmural and is accompanied by oxidative damage as evidenced by an increase in myeloperoxidase ("MPO") activity. Additionally, the inflammation is characterized by discrete areas of acute necrosis, inflammation and muscle thickening. Agents with anti-inflammatory effects in patients with IBD show efficacy in this model. Although the mechanism by which TNBS induces an inflammatory response is unknown, it is thought to have an immunological basis. Induction of Colitis Male Sprague-Dawley rats (200-250 g) were housed in standard cages (2 per cage) and fed rat chow and tap water ad libitum. After an overnight fast, rats were brought into the laboratory and randomized into treatment groups. Colitis was induced by intrarectal administration of 0.5 ml of TNBS solution (50 mg/kg in 50% ethanol) using a 1 mL syringe attached to a 5 cm polyethylene catheter. Control animals received saline (0.9%) or a 1 % methyl cellulose suspension at identical time points. Tissue Analysis Three days after TNBS administration, the rats were sacrificed and the colons excised and opened longitudinally. In 5 cm segments of colon, gross morphology was determined using the following scale: The weights of each 5 cm colonic segment were also recorded to assess inflammatory induced edema. Dosing Regimen Each of the compounds from Examples 1-6 were tested in the TNBS model at 10 mg/kg p.o. (oral) dosing. Each of the test compounds was administered by oral gavage as a 1 % carboxy methyl cellulose ("CMC") suspension 1 hour prior to the administration of TNBS. Control rats were given CMC only. Results Each of the test compounds reduced TNBS-induced damage compared to the controls. The reduction in TNBS-induced damage ranged from about 25% to about 71 % (average scores). Surprisingly, N-tert-butyl 4-hydroxybenzamide, a positional isomer of N-tert-butyl 2-hydroxybenzamide, was found to exacerbated the TΝBS-induced damage compared to the controls. Bioassay Example 2 Mouse Dextran Sulfate IBD Model Another model used for screening candidate IBD-treating compounds is the Dextran Sulfate ("DSS") model. Similar to the TΝBS model, DSS induced colitis is widely used as a screening tool for IBD therapeutics. When administered orally, DSS induces IBD-like symptoms in Swiss-Webster mice. This model can be used to determine the effectiveness of compounds of this invention when such compounds are administered orally (p.o.). Individually housed 30-40 g male Swiss-Webster mice (B & K Universal, Fremont, CA) receive 3% DSS (Sigma Chemicals, St. Louis, MO) in their drinking water for 7 days. All animals receive food and water ad libitum. Two groups of mice are dosed orally with either the test compound in a dosing vehicle (1 % methyl cellulose, dose range of 10 mg/kg to 30 mg/kg) or dosing vehicle alone (control). Clinical signs of colitis are assessed by a disease activity index ("DAI") consisting of changes in stool characteristics, fecal occult bleeding and body weight loss. The DAI is very similar to the Crohn's Disease Activity Index used in clinical trials to evaluate new agents to prevent/treat IBD. The DAI data are analyzed using Proc Anova in SAS with a Bonferoni post-hoc analysis, and Model 108 in WinΝonlin™ (Professional Version 1.5, Scientific Consulting, Apex, ΝC) for the ED 50 and E max values. The wet weight and myeloperoxidase ("MPO") data (collected only on Day 7) are analyzed by Proc TTest in SAS. MPO is a marker for neutrophil infiltration. The following criteria are employed in this assay: DAI Scoring (Daily Stool Characteristic: 0 = normal, 2 = loose and 4 = diarrhea Fecal Occult Blood: 0 = negative, 2 = positive, 4 = gross bleeding Weight Change: 0 = 0-1 % , 1 = 1 to < 5% , 2 = 5% to < 10%, 3 = 10 to <20%, 4 = >20% MPO (Day 7 Only') Two strips of colonic tissue/mouse MPO activity by spectrophotometric assay Bioassay Example 3 Establishment of the Dose-response Characteristics in the Mouse Dextran Sulfate Model To determine the dose-response relationship of a test compound in the DSS Mouse Model, the following procedure is used. Experimental conditions and statistical analyses are the same as the Mouse Dextran Sulfate IBD Model, except four groups of mice (n = 8-10/group) are used. Animals are dosed orally with either test compound (3, 10 or 30 mg/kg) or vehicle alone. In addition, the following procedure is introduced to evaluate the histology in the animals: Histology Score 5-6 slices/segment with 15-18 total pieces/colon Score for extent of damage: 0 = 1-25% involvement, 1 = 26-50% involvement, 2 = 51-75% involvement, 3 = 76-100% involvement Score for grade: 0 = intact crypt, 1 = loss of 1/3 crypt, 2 = loss of 2/3 crypt, 3 = loss of entire crypt with surface epithelium intact, 4 = loss of entire crypt and erosion of surface epithelium Score for Severity: 0 = normal, 1 = focal inflammatory cell infiltrate including PMNs, 2 = inflammatory cell infiltration, gland dropout and crypt abscess, 3 = mucosal ulceration Single, evaluator (qualified pathologist) blinded to the treatment conditions. Bioassay Example 4 Effect of Test Compounds on Flux of Reactive Oxygen Species Induced by TNF-cc Oxidative stress agents (OSA) are thought to be involved in cell death in IBD and are key initiator in the cascade of events leading to apoptosis. The purpose of this study is to evaluate the effect of a test compound on cytokine- induced OSA flux. To visualize OSA, the dye dihydrodichlorofluorescein diacetate is used. This non-fluorescent dye is taken up by cells and deacetylated to its non- fluorescent congener dihydrodichlorofluorescein (H 2 DCF), which is trapped within cells. Reactive oxygen species ("ROS") react with H 2 DCF, converting it to the highly fluorescent DCF. DCF fluorescence can be measured spectrofluorometrically and can also be visualized in intact cells using fluorescent microscopy. SK-N-MC cells (American Type Culture Collection, Rockville, MD) are plated at 250,000 cells/well in 24-well Corning plates. Following plating, the cells are maintained in retinoic acid medium (5 μM) for five days and then treated with a test compound at 100μM for 1 hour prior to TNF-α (3.0 ng/mL) treatment. TNF-α and H 2 DCF are added simultaneously and cultures are incubated for an additional 4 hours. Following incubation, cultures are read in a cytofluorometer at 485-530 nm wavelength to detect increased DCF formation. Relative fluorescence units (RFU) values for the respective treatment conditions are compared. In this assay, higher fluorescence readings indicate ROS production. Thus, reductions in fluorescence indicates reduction in ROS production. Bioassay Example 5 Effect of Compound A on TNF-α Induced Apoptosis in a Human Cell Model This test is used to evaluate the potential of a test compound to prevent TNF-α induced apoptosis. A test compound is evaluated in an in vitro model of TNF-α induced toxicity (see Pulliam et al. J. Neurosci. Res. 21 :521-530 (1998)). In this model, human brain cell aggregates from fetal tissue are treated with TNF-α which caused an apoptotic cell death. Brain cell aggregates prepared from 1 brain were incubated for 10-12 days before experimentation. Aggregates are weighed out (100 mg/flask) and aliquoted into 10 mL flasks. TNF-α is used at a concentration of 1 ng. The test compound is added 1 hour prior to the TNF-α. Experiments include untreated brain aggregates, TNF-α-treated brain aggregates, TNF-α- + test compound treated aggregates and test compound treated aggregates. After TNF-α is added, aggregates are incubated for an additional 48 h. After this time, brain aggregates are centrifuged for 5 min at 500 rpm. The supernatant is removed and the pellet is lysed for determination of programmed cell death (Boeringer Mannheim Cell Death Kit ELISA). Bioassay Example 6 Effect of Test Compound on TNF-α Induced Reduction in bcl-2 Cytokine-mediated apoptosis or programmed cell death is believed to be involved in a number of diseases including IBD. Reductions in bcl-2 are a major signal in initiation of the apoptotic cascade (see Jourd'heuil et al., J. Clin Gastroenterol. 25(Suppl):S61-S72 (1997)). The purpose of this study is to investigate the effects of a test compound on bcl-2 protein levels in a cellular model of cytokine mediated apoptosis. SK-N-MC cells (American Type Culture Collection, Rockville, MD) are plated at 500,000 cells/plate and treated with retinoic acid ("RA") (5 μM) for 5 days. Following RA treatment, the cells are incubated with a test compound (100 μM) for 1 hour. Cells are then treated with increasing concentrations of TNF-α (0, 0.3 and 3 ng/mL) for 6 h. The cells are harvested and lysed and bcl- 2 is measured in the lysate using an ELISA assay (Boehringer Manheim). Quantification of bcl-2 is based on a standard curve and results are expressed as units/mL of bcl-2 in the sample.

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 of formula I: wherein A is selected from the group consisting of alkylene and cycloalkylene; R 1 is naphthyl or a group having the formula: R b wherein each R a is independently selected from the group consisting of aminocarbonyl. hydroxy and trifluoromethyl; R b is hydrogen or acyl; R 2 is selected from the group consisting of hydrogen, alkyl, aralkyl and cycloalkyl; R 3 is selected from the group consisting of alkyl, aralkyl and cycloalkyl; m is an integer from 0 to 3; and n is 0 or 1; and pharmaceutically acceptable salts thereof; with the proviso that: when R 2 is hydrogen, R 3 is tert-butyl and n is 0, then R 1 is not a 4- hydroxyphenyl group or a 4-tert-butylaminocarbonyl group. 2. The pharmaceutical composition of Claim 1 wherein A is alkylene having from about 2 to about 4 carbon atoms or cycloalkylene having from about 3 to about 5 carbon atoms. 3. The pharmaceutical composition of Claim 2 wherein A is ethylene or trαns-cyclopropylene. 4. The pharmaceutical composition of Claim 1 wherein R 1 is selected from the group consisting of phenyl, 4-trifluoromethylphenyl, 2-hydroxyphenyl, 2-naphthyl, indol-5-yl and l-acetylindol-5-yl. 5. The pharmaceutical composition of Claim 1 wherein R 2 is hydrogen or methyl. 6. The pharmaceutical composition of Claim 5 wherein R 3 is alkyl or cycloalkyl having 3 to 6 carbon atoms. 7. The pharmaceutical composition of Claim 6 wherein R 3 is « -butyl, tert-butyl or cycloalkyl. 8. The pharmaceutical composition of Claim 1 wherein m is 0 or 1. 9. 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-n-butyl 3-phenylpropionamide, N-λz-buty 1 trans-2 -phenyl- 1 -cyclopropanecarboxamide , N-tert-butyl 4-trifluoromethylbenzamide, N-tert-butyl 2-hydroxybenzamide, N-tert-butyl naphthy lene-2-carboxamide , N-tert-butyl indole-5-carboxamide, N-tert-butyl 1 -acetylindole-5-carboxamide , and pharmaceutically acceptable salts thereof. 10. 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: 4-(acetamido)benzoic acid, N-tert-butyl 4-[2-(4-(3-methoxyphenyl)piperazin-l-yl)acetamido)]- benzamide, 7-nitroindole, and pharmaceutically acceptable salts thereof. 11. 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 of formula I: wherein A is selected from the group consisting of alkylene and cycloalkylene; R 1 is naphthyl or a group having the formula: wherein each R a is independently selected from the group consisting of aminocarbonyl, hydroxy and trifluoromethyl; R b is hydrogen or acyl; R 2 is selected from the group consisting of hydrogen, alkyl, aralkyl and cycloalkyl; R 3 is selected from the group consisting of alkyl, aralkyl and cycloalkyl; m is an integer from 0 to 3; and n is 0 or 1; and pharmaceutically acceptable salts thereof; with the proviso that: when R 2 is hydrogen, R 3 is tert-butyl and n is 0, then R 1 is not a 4- hydroxyphenyl group or a 4-tert-butylaminocarbonyl group. 12. The method of Claim 11 wherein A is alkylene having from about 2 to about 4 carbon atoms or cycloalkylene having from about 3 to about 5 carbon atoms. 13. The method of Claim 12 wherein A is ethylene or trans- cyclopropylene. 14. The method of Claim 11 wherein R 1 is selected from the group consisting of phenyl, 4-trifluoromethylphenyl, 2-hydroxyphenyl, 2-naphthyl, indol-5-yl and l-acetylindol-5-yl. 15. The method of Claim 11 wherein R 2 is hydrogen or methyl. 16. The method of Claim 15 wherein R 3 is alkyl or cycloalkyl having 3 to 6 carbon atoms. 17. The method of Claim 16 wherein R 3 is n-butyl, tert-butyl or cyclohexyl. 18. The method of Claim 11 wherein m is 0 or 1. 19. The method of Claim 11 wherein said pharmaceutical composition is administered orally. 20. The method of Claim 11 wherein said pharmaceutical composition is administered parenterally. 21. The method of Claim 11 wherein said pharmaceutical composition is administered rectally. 22. The method of Claim 11 wherein said inflammatory bowel condition is ulcerative colitis. 23. The method of Claim 11 wherein said inflammatory bowel condition is Crohn's disease. 24. The method of Claim 11 wherein said pharmaceutical composition is administered as an oral dose in an amount of from 0.1 to about 150 mg/kg of patient weight. 25. The method of Claim 11 wherein said pharmaceutical composition is 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. 26. The method of Claim 11 wherein said pharmaceutical composition is administered rectally in an amount of from 1 to about 150 mg/kg of patient weight. 27. 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 of formula I: wherein A is selected from the group consisting of alkylene and cycloalkylene; R 1 is naphthyl or a group having the formula: wherein each R a is independently selected from the group consisting of aminocarbonyl, hydroxy and trifluoromethyl; R b is hydrogen or acyl; R 2 is selected from the group consisting of hydrogen, alkyl, aralkyl and cycloalkyl; R 3 is selected from the group consisting of alkyl, aralkyl and cycloalkyl; m is an integer from 0 to 3 ; and n is 0 or 1 ; and pharmaceutically acceptable salts thereof; with the proviso that: when R 2 is hydrogen, R 3 is tert-butyl and n is 0, then R 1 is not a 4- hydroxyphenyl group or a 4-tert-butylaminocarbonyl group. 28. 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-n-butyl 3-phenylpropionamide, N-n-buty 1 trαns-2-pheny 1- 1 -cy clopropanecarboxamide , N-tert-butyl 4-trifluoromefhylbenzamide , N-tert-butyl 2-hydroxybenzamide, N-tert-butyl naphthy lene-2-carboxamide , N-tert-butyl indole-5-carboxamide, N-tert-butyl l-acetylindole-5-carboxamide, and pharmaceutically acceptable salts thereof. 29. 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: 4-(acetamido)benzoic acid, N-tert-butyl 4-[2-(4-(3-methoxyphenyl)piperazin-l-yl)acetamido)]- benzamide, 7-nitroindole, and pharmaceutically acceptable salts thereof. 30. 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: 4-(acetamido)benzoic acid, N-tert-butyl 4-[2-(4-(3-methoxyphenyl)piperazin-l-yl)acetamido)]- benzamide, 7-nitroindole, and pharmaceutically acceptable salts thereof. 31. A compound selected from the group consisting of: N-π-butyl 3-phenylpropionamide, N-n-butyl trans -2-phenyl- 1 -cyclopropanecarboxamide , N-tert-butyl 4-tr ifluor omethy lbenzamide , N-tert-butyl 2-hydroxybenzamide, N-tert-butyl naphthylene-2-carboxamide, N-tert-buty 1 indole-5-carboxamide , N-tert-butyl l-acetylindole-5-carboxamide, N-tert-butyl 4-[2-(4-(3-methoxyphenyl)piperazin-l-yl)acetamido)]- benzamide, and pharmaceutically acceptable salts thereof.

Inventors: FLITTER WILLIAM D, GARLAND WILLIAM A, GREENWOOD-VAN MEERVELD BEVERLY, IRWIN IAN, FLITTER, WILLIAM, D., GARLAND, WILLIAM, A., GREENWOOD-VAN MEERVELD, BEVERLY, IRWIN, IAN
Applicants: CENTAUR PHARMACEUTICALS INC, FLITTER WILLIAM D, GARLAND WILLIAM A, GREENWOOD VAN MEERVELD BEVERLY, IRWIN IAN, CENTAUR PHARMACEUTICALS, INC., FLITTER, WILLIAM, D., GARLAND, WILLIAM, A., GREENWOOD-VAN MEERVELD, BEVERLY, IRWIN, IAN
Application year: 1999
Main classification: A61K31
IPC codes: A61K31