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EP1365753A2 - Combinaisons d'uroguanyline et d'inhibiteur de cyclooxygenase-2 pour l'inhibition du cancer de l'intestin - Google Patents

Combinaisons d'uroguanyline et d'inhibiteur de cyclooxygenase-2 pour l'inhibition du cancer de l'intestin

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Publication number
EP1365753A2
EP1365753A2 EP02702137A EP02702137A EP1365753A2 EP 1365753 A2 EP1365753 A2 EP 1365753A2 EP 02702137 A EP02702137 A EP 02702137A EP 02702137 A EP02702137 A EP 02702137A EP 1365753 A2 EP1365753 A2 EP 1365753A2
Authority
EP
European Patent Office
Prior art keywords
composition
amino acid
group
acid residues
glycine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP02702137A
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German (de)
English (en)
Inventor
Jaime L. Masferrer
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Pharmacia LLC
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Pharmacia LLC
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Publication date
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Publication of EP1365753A2 publication Critical patent/EP1365753A2/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of certain peptides, more particularly the use of uroguanylin and prouroguanylin in combination with any one of or combination of naturally occurring, extract of a naturally occurring, or a chemically synthesized cyclooxygenase-2 inhibitor, preferably a selective cyclooxygenase-2 inhibitor or inhibitors, to retard the development of polyps and prevent, inhibit or treat cancer in the intestine.
  • the pathogenesis of colorectal cancer is characterized as a multistep process that begins with increased proliferation and/or decreased apoptosis of colorectal epithelial cells resulting in generation of polyps, followed by adenoma formation and ultimately to adenocarcinoma.
  • Certain individuals develop multiple colorectal adenomas and subsequent carcinomas early in life because of a genetic defect in the APC gene responsible for causing a condition called familial adenomatous polyposis (FAP) .
  • FAP familial adenomatous polyposis
  • Dihlmann et al Dominant negative effect of the APC 1309 mutation : a possibl e explanation for genotype-phenotype correlations in familial adenomatous polyposis, Cancer Res. 1999 Apr.
  • GC-C guanylate cyclase
  • Krause W.J. et al, The guanylin and uroguanylin peptide hormones and their receptors, Acta. Anat. (Basel) 160:213-231 (1997) .
  • GC-C receptors are localized on the luminal surface of enterocytes throughout the GI tract. Swenson, E.S. et al, The guanylin/ STa receptor is expressed in crypts and apical epithelium throughout the mouse intestine, Biochem. Biophys. Res. Commun.
  • uroguanylin is a circulating peptide hormone with naturi ureti c activi ty, Am. J. Kidney Dis. 28:296-304 (1996) .
  • CFTR chloride channel proteins Activation of CFTR chloride channel proteins and the subsequent enhancement of transepithelial secretion of chloride leads to stimulation of sodium (Na + ) and water secretion into the intestinal lumen.
  • Na + sodium
  • water secretion into the intestinal lumen.
  • Guanylin regulatory peptides structures, biological activi ties mediated by cyclic GMP and pathobiology, Regul. Pept. 81:25-39 (1999) . Therefore, one of the major physiological functions of these hormones is the regulation of fluid and electrolyte transport in the gastrointestinal (GI) tract by serving as paracrine regulators of CFTR activity.
  • GI gastrointestinal
  • uroguanylin The precursor of uroguanylin is prouroguanylin, which is broken down by endogenous proteases in the intestinal tract to produce the active uroguanylin. Chymotrypsin activates prouroguanylin to cleave it into its active form of uroguanylin. Forte, et el, Salt and Water Homeostasis : Uroguanylin Is a Circulating Peptide Hormone Wi th Natriuretic Activi ty, Am. J. Kid. Dis. 1996, 28, No.2, 296-304.
  • Uroguanylin is an acid-stable and proteolysis-resistant peptide, which will remain in- tact to act on the intestinal lumen directly rather than being absorbed systemically. Uroguanylin and guanylin are produced throughout the intestinal mucosa and in the myocardium. Forte et al, Salt and water homeostasis : uroguanylin is a circulating peptide hormone wi th natriuretic activi ty Am. J. Kidney Dis. 28:296-304
  • Uroguanylin Binding of uroguanylin or guanylin to the guanylin cyclase receptor stimulates the intracellular production of the cGMP ultimately resulting in the stimulation of salt and water secretion into the intestinal lumen.
  • Uroguanylin and guanylin receptors are found on the luminal surface of epithelial cells lining the intestinal tract and renal proximal tubules as well as in other organs. Forte et al, Salt and Water Homeostasis : Uroguanylin Is a Circulating Peptide Hormone wi th Natriuretic Activi ty, Am. J. Kid. Dis.1996,- 28, No. 2, 296-304. Uroguanylin has been found to stimulate increases in cyclic GMP levels in a manner similar to another family of heat stable enterotoxins
  • STs secreted by pathogenic strains of E. coli and other enteric bacteria that activate intestinal guanylate cyclase and cause secretory diarrhea, which is a major cause of traveler's diarrhea and many deaths in developing countries.
  • Lymphoguanylin Cloning and Characterization of a Unique Member of the Guanylin Peptide Family, Endocrinology Vol. 140, No. 4, p.1800-1806.
  • These ST peptides act as molecular mimics of the endogenous mammalian peptides of uroguanylin and prouroguanylin.
  • the STs from enteric bacteria do not have a decrease in potency when the pH changes in the colon. STs are more potent than either uroguanylin or guanylin under both acidic and alkaline conditions.
  • Guanylin a peptide regulator of epi thelial transport , The FASEB Journal, vol. 9, 643- 650 (1995) .
  • Uroguanylin is believed to regulate fluid and electrolyte transport in a manner similar to guanylin and the STs in the GI tract. Therefore, as mentioned in previous publications the human uroguanylin may act as a laxative and be useful in patient suffering from constipation.
  • NSAID's common non-steroidal anti- inflammatory drugs
  • corticosteroids which also produce • severe adverse effects, especially when long term therapy is involved.
  • NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX) .
  • COX cyclooxygenase
  • cyclooxygenase-2 (COX-2) " or “prostaglandin G/H synthase II" provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
  • COX-2 COX-2
  • prostaglandin G/H synthase II prostaglandin G/H synthase II
  • [Pyrazol-l-yl]benzenesulfonamides have been described as inhibitors of cyclooxygenase-2 and have shown promise in the treatment of inflammation, arthritis, and pain, with minimal side effects in pre- clinical and clinical trials.
  • Their use for preventing colon cancer has been described in U.S. Patent No. 5,466,823.
  • their use for treating or preventing intestinal cancer, in combination with uraguanylin has not been described.
  • peptides particularly uroguanylin or prouroguanylin
  • a single or multiple natural occurring, extract of a natural occurring, or a chemically synthesized cyclooxygenase-2 inhibitor, preferably a selective cyclooxygenase-2 inhibitor or inhibitors may be useful in treating, preventing, inhibiting or retarding the development of polyps and cancer in the intestine.
  • the provision of a process for retarding the development of polyps and preventing, and a process for inhibiting and treating cancer or neoplasia in a subject Preferably the method is useful for treating the development of polyps and preventing, and a process for inhibiting and treating cancer in the intestine of a subject, more preferably the small intestine or the colon.
  • the present invention is directed to a process for retarding the development of polyps in a subject which comprises the administration of a peptide including the amino acid sequence:
  • each of Xi, X 2 , X 3 , X 4 , X5, X ⁇ , and X 7 is an amino acid residue
  • the polypeptide is cross-linked by a disulfide bond between the cystine residue immediately adjacent the amine group of Xi and the cystine residue immediately adjacent the amine group of X and by a disulfide bond between the cystine residue immediately adjacent the amine group of X 3 and the cystine residue immediately adjacent the carboxy group of X , in combination with any one of or combination of naturally occurring, or an extract of a natural occurring, or a chemically synthesized cyclooxygenase-2 inhibitor, preferably a selective cyclooxygenase-2 inhibitor or inhibitors .
  • the invention is further directed to a process for retarding the development of polyps and to a process for the prevention, inhibition or treatment of cancer in a subject by administration of a composition
  • a composition comprising any one of or combination of the following peptides: uroguanylin, human uroguanylin, pro-uroguanylin, and human pro-uroguanylin, guanylin, ly phoguanylin, prolymphoguanylin and heat stable enterotoxin in combination with any one of or combination of naturally occurring, or an extract of a natural occurring, or a chemically synthesized cyclooxygenase-2 inhibitor, preferably a selective cyclooxygenase-2 inhibitor or inhibitors .
  • the invention is directed to a process for retarding the development of polyps and a process for the prevention, inhibition or treatment of cancer by administration of a composition comprising any one of or a combination of agonist peptides and/or other agonist compounds to the guanylate cyclase receptor GC-C in combination with any one of or combination of naturally occurring, or an extract of a natural occurring, or a chemically synthesized cyclooxygenase-2 inhibitor, preferably a selective cyclooxygenase-2 inhibitor or inhibitors.
  • the cancer or neoplasia which can be treated with the present inventive method can be located anywhere in the body, for example, the head, neck, chest, lungs, skin, liver, blood, kidneys, heart, intestines, bladder, gall bladder, brain, throat, musculoskeletal system, lymphatic system, central nervous system, and others.
  • the methods of the present invention are used to treat cancer or neoplasia located in the intestine, for example, the small intestine or colon.
  • Other objects of this invention will be in part apparent and, in part, pointed out hereinafter.
  • treatment includes partial or total inhibition of the tumor growth, either benign or malignant, spreading or metastasis, as well as partial or total destruction of the neoplastic cells.
  • prevention includes either preventing the onset of clinically evident neoplasia altogether or preventing the onset of a preclinically evident stage of neoplasia in individuals at risk. Also intended to be encompassed by this definition is the prevention of initiation for malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing the neoplasia.
  • the phrase "therapeutically-effective" is intended to qualify the amount of each agent which will achieve the goal of improvement in disease severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.
  • subject for purposes of treatment includes any human or animal subject who has any one of the known neoplasia or tumor disorders, and preferably is a human subject.
  • the subject is any human or animal subject, and preferably is a human subject who is at risk for obtaining an intestinal cancer or neoplasia-related disorder, either benign or malignant, including metastasis.
  • the subject may be at risk due to exposure to carcinogenic agents, being genetically predisposed to have the neoplasia, and the like.
  • neoplasia includes both benign and cancerous tumors and growths .
  • the epithelial cell-derived neoplasia includes epithelial carcinomas such as basal cell carcinoma, adenocarcinoma, colon cancer, prostate cancer, renal cell carcinoma, and other known neoplasias that effect epithelial cells throughout the body.
  • the epithelial cell-derived neoplasia is selected from gastrointestinal cancer, liver cancer, prostate cancer, kidney cancer, brain cancer, bladder cancer, cervical cancer, lung cancer, breast cancer and skin cancer.
  • Inhibitors of the cyclooxygenase pathway in the metabolism of arachidonic acid used in the prevention and treatment of cancer or neoplasia may inhibit enzyme activity through a variety of mechanisms.
  • the use of cyclooxygenasse-2 selective inhibitors is highly advantageous in that it minimize the gastric side effects that can occur with non-selective NSAID's, especially where prolonged prophylactic treatment is expected.
  • cyclooxygenase-2 inhibitor denotes a compound able to inhibit cyclooxygenase-2 without significant inhibition of cyclooxygenase-1.
  • it includes compounds which have a cyclooxygenase-2 IC50 of less than about 0.2 uM, and also have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, and more preferably of at least 100.
  • the compounds have a cyclooxygenase-1 ' IC50 of greater than about 1 uM, and more preferably of greater than 10 M.
  • purified means partially purified and/or completely purified.
  • a “purified composition” may be either partially purified or completely purified.
  • An extract of a naturally occurring cyclooxygenase-2 inhibitor may be paritially purified or purified.
  • Uroguanylin is secreted naturally by the goblet cells of the intestinal mucosal lining as prouroguanylin, a functionally inactive form, which is then converted to the functionally active uroguanylin in the intestine by endogenous proteases.
  • Uroguanylin is an acid-stable, proteolysis-resistant peptide. Therefore, orally delivered prouroguanylin and uroguanylin will act on the lu enal intestinal surface and not be absorbed systemically.
  • Oral administration of uroguanylin, prouroguanylin and other like peptides, containing the amino acid sequences similar to the active domain, are expected to induce apoptosis, cell death, in the intestinal mucosal cell lining.
  • the induced apoptosis in the intestinal mucosal cell lining is expected to retard the incidence of polyp formation and subsequent intestinal cancer.
  • the peptides of the invention exert their effects by increasing the rate of apoptosis, cell death, in the intestinal mucosal cell lining promoting the perfect balance between the cell proliferation and the programmed cell death thereby retarding the growth of polyps and preventing, inhibiting, and treating cancer in the intestine and other epithelial-derived cancer possessing receptors for guanylin, uroguanylin, lymphoguanylin and STa family of peptides.
  • the rate of cell proliferation and cell death in the intestinal mucosa is very rapid.
  • the cells of the intestinal mucosa are in a steady state of turnover to insure a perfect balance between cell proliferation and cell death.
  • the constant rapid renewal of the GI tract epithelium fulfills the functions of maintaining the integrity of normal mucosa, repairing and replenishing differentiated epithelial cells that have specialized functions.
  • the prevention of apoptosis in the intestinal mucosal cells creating an imbalance in the renewal process results in an increased incidence of polyp formation and subsequent intestinal cancer. See Eastwood et al, A review of gastrointestinal epi thelial renewal and i ts relevance to the development of adenocarcinomas of the gastrointestinal tract, J. Clin. Gastroenterol.
  • guanylin has been shown to be completely diminished in colon cancer cells and evenly expressed in normal intestinal mucosal cells. This finding suggest that guanylin is involved > in the maintenance of colonic differentiation or functions as a tumor modifier gene. Mitchell et al., Guanylin mRNA Expression in Human Intestine and Colorectal Adenocarcinoma, Lab. Invest. 1998, Vol. 78, No. 1, 101- 108. Recent data demonstrates that the guanylin cyclase receptor known as GC-C receptor is expressed in all primary and metastatic colorectal cancers and it may serve as a specific marker for these tumors. Carrithers, S.L.
  • Guanylin cyclase C is a selective marker for metastatic colorectal tumors in human extraintestinal tissues, Proc. Natl. Acad. Sci. USA. 93:14827-14832.
  • the expression of guanylin has been shown to be down-regulated in colorectal cancer tissues and cell lines. Cohen, M.B. et al, Guanylin mRNA expression in human intestine and colorectal adenocarcinoma, Lab. Invest. 78:101-108.
  • uroguanylin was shown to be completely diminished in colon cancer cells and evenly distributed in normal intestinal mucosal cells. Additionally, the expression of uroguanylin and guanylin in human colon cancer and the adjacent normal tissues was reportedly completely diminished in all human colon cancer specimens examined. That study suggested that either the reduced expression of uroguanylin and/or guanylin leads to or is a result of adenocarcinoma formation.
  • a polypeptide which contains the active domain of human uroguanylin or which binds to the guanylate cyclase receptor GC-C in the intestine of the subject is administered to a subject. While the polypeptide may be administered prophylactically, it will typically be administered to a subject who has been determined to have intestinal cancer, intestinal polyps, or a genetic predisposition for the growth of polyps in the intestine.
  • polypeptide is a polypeptide having the sequence as identified in SEQ. ID. 1:
  • each of Xi, X 2 , X 3 , X 4 , X5, X 6 , and X 7 is an amino acid residue
  • X 8 and X 9 are independently hydrogen or at least one amino acid residue
  • the polypeptide is cross-linked by a disulfide bond between the cystine residue immediately adjacent the amine group of Xi and the cystine residue immediately adjacent the amine group of X ⁇ and by a disulfide bond between the cystine residue immediately adjacent the amine group of X 3 and the cystine residue immediately adjacent the carboxy group of X .
  • the polypeptide is guanylan, uroguanylin, pro-uroguanylin, or another polypeptide which contains the active domain of uroguanylin.
  • amino acids in a peptide or protein can be substituted for other amino acids having a similar hydropathic index or score and produce a resultant peptide or protein having similar biological activity, i.e., which still retains biological functionality.
  • amino acids having hydropathic indices within .2 are substituted for one another. More preferred substitutions are those wherein the amino acids have hydropathic indices within .1. Most preferred substitutions are those wherein the amino acids have hydropathic indices within .0.5.
  • Like amino acids can also be substituted on the basis of hydrophilicity.
  • 4,554,101 discloses that the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with a biological property of the protein.
  • the following hydrophilicity values have been assigned to amino acids, (according to the Hopp-Woods values): arginine/lysine (+3.0); aspartate/glutamate (+3.0 ⁇ 1); serine (+0.3); asparagine/glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5 ⁇ 1); alanine/histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine/isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5); and tryptophan (-3.4).
  • amino acids having hydropathic indices within +2 are preferably substituted for one another, those within ⁇ 1 are more preferred, and those within ⁇ 0.5 are most preferred.
  • amino acid substitutions in the peptides of the present invention can be based on the relative similarity of the amino acid side-chain substituents in the non-active domain of the peptide to create a protein with the same biological activity as the human uroguanylin peptide.
  • Xi may be selected from the group of all amino acid residues, but preferably is selected from the group of amino acid residues consisting of aspartic acid, glutamic acid, glycine, lysine, asparagine, proline, glutamine, arginine, serine and threonine .
  • the more preferred amino acid residues that may be substituted for Xi are glutamic acid, aspartic acid, arginine, and lysine.
  • the most preferred amino acid residue that may be used for Xi is glutamic acid.
  • X 2 may be selected from all amino acid residues, however the preferred amino acid residues for substitution are leucine, isoleucine, tyrosine, phenylalanine, tryptophan, valine, methionine, cysteine, alanine, histidine, proline, threonine, glycine, asparagine, and glutamine.
  • the more preferred amino acid residues that may be substituted for X 2 are cysteine, phenylalanine, glycine, isoleucine, leucine, methionine, valine, and tyrosine.
  • the even more preferred amino acid residues for substitution for X 2 are leucine, isoleucine, tyrosine, valine, and methionine.
  • the most preferred amino acid residue for substitution for X 2 is leucine.
  • X 3 and X 4 may be selected from all amino acid residues, but the preferred amino acid residues are valine, isoleucine, tyrosine, phenylalanine, tryptophan, methionine, cysteine, alanine, histidine, proline, threonine, glycine, glutamine, asparagine, and serine.
  • the more preferred amino acid residues that may be substituted for X 3 and X 4 are valine, isoleucine, leucine,- tyrosine, phenylalanine, methionine, cysteine, alanine, histidine, and proline.
  • the even more preferred amino acid residues that may be substituted for X 3 and X 4 are valine, isoleucine, leucine-, methionine, and cysteine. Even more preferable for substitution for X 3 and X 4 are isoleucine and valine. The most preferred amino acid residue for substitution for X 3 and X 4 is valine.
  • X5 may be selected from all amino acid residues, but the preferred amino acid residues are alanine, histidine, cysteine, methionine, valine, leucine, isoleucine, tyrosine, phenylalanine, proline, threonine, glycine, glutamine, asparagine, and serine.
  • the more preferred amino acid residues that may be substituted for X 5 are alanine, histidine, cysteine, methionine, valine, proline, threonine, glycine, glutamine, asparagine, and serine.
  • amino acid residues for substitution for X5 are alanine, histidine, cysteine, proline, threonine, glycine, glutamine, asparagine, and serine.
  • the most preferred amino acid residue for substitution for X 5 is alanine.
  • X s may be selected .from all amino acid residues, but the preferred amino acid residues for substitution are threonine, proline, alanine, histidine, cysteine, methionine, valine, leucine, isoleucine, tyrosine, glycine, glutamine, asparagine, and serine.
  • the more preferred amino acid residues for substitution for X 6 are threonine, proline, alanine, histidine, cysteine, methionine, glycine, glutamine, asparagine, and serine. Even more preferred amino acid residues for substitution threonine, proline, alanine, histidine, and glycine.
  • the most preferred amino acid residue for substitution for X ⁇ is threonine.
  • X may be selected from all amino acid residues, but the preferred amino acid residues are glycine, threonine, proline, alanine, histidine, cysteine, methionine, valine, leucine, isoleucine, glutamine, asparagine, serine, glutamic acid, and aspartic acid.
  • the more preferred amino acid residues for substitution for X are glycine, threonine, proline, alanine, histidine, cysteine, glutamine, asparagine, and serine.
  • amino acid residues for substitution for X 7 are glycine, threonine, proline, alanine, histidine, glutamine, asparagine, and serine.
  • the most preferred amino acid residue for substitution for X is glycine.
  • polypeptides and compounds of the present invention can be combined with various excipient vehicles and/or adjuvants well known in this art which serve as pharmaceutically acceptable carriers to permit drug administration in the form of, e.g., injections, suspensions, emulsions, tablets, capsules, and ointments.
  • These pharmaceutical compositions may be administered by any acceptable means.
  • administration can be oral, parenteral,- subcutaneous, intravenous, intramuscular and/or intraperitoneal .
  • the specific dose administered will be dependent upon such factors as the general health and physical condition of the subject as well as the subject's age and weight, the stage of the subject's disease condition, the existence of any concurrent treatments, and the frequency of administration; typically, the dose will be in the range of about 0.5 to about 2.0 g/kg for human subjects.
  • the composition will contain one or more of the polypeptide (s) of the present invention in a concentration of at least about 0.0001% by weight, more typically at least about 0.001% by weight, still more typically at least about 0.01%, still more typically at least about 0.1% and, in some embodiments, in a concentration of at least about 1% by weight of the composition.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
  • the compound may be combined with a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
  • a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
  • Such formulations may be prepared by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride, glycine, and the like, and having a buffered pH compatible with physiological conditions to produce an aqueous solution, and rendering said solution sterile.
  • the formulations may be present in unit or multi-dose containers such as sealed ampoules or vials.
  • the compound may be formulated with acid-stable, base- labile coatings known in the art which begin to dissolve in the high pH small intestine. Formulation to enhance local pharmacologic effects and reduce systemic uptake are preferred.
  • Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably made isotonic. Preparations for injections may also be formulated by suspending or emulsifying the compounds in non-aqueous solvent, such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol.
  • non-aqueous solvent such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol.
  • Formulations for topical use include known gels, creams, oils, and the like.
  • the compounds may be formulated with known aerosol exipients, such as saline, and administered using commercially available nebulizers.
  • Formulation in a fatty acid source may be used to enhance biocompatibility.
  • Aerosol delivery is the preferred method of delivery for epithelial neoplasias of the lung for prevention application.
  • the active ingredient may be formulated into suppositories using bases which are solid at room temperature and melt or dissolve at body temperature. Commonly used bases include coca butter, glycerinated gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty esters of polyethylene stearate.
  • the dosage form and amount can be readily established by reference to known treatment or prophylactic regiments.
  • the amount of therapeutically active compound that is administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, the location of the neoplasia, as well as the pharmacokinetic properties of the individual treated, and thus may vary widely.
  • the dosage will generally be lower if the compounds are administered locally rather than systemically, and for prevention rather than for treatment. Such treatments may be administered as often as necessary and for the period of time judged necessary by the treating physician.
  • the pharmaceutical compositions may contain active ingredient in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg and most preferably between about 1 and 200 mg.
  • the daily dose can be administered in one to four doses per day.
  • Human uroguanylin cDNA has been cloned in bacteria, and chemically synthesized by solid phase peptide synthesis.
  • Uroguanylin peptide can be chemically synthesized by using the procedure as described in U.S. patent number 5,489,670 Human Uroguanylin and in U.S. patent number 5,140,102 Pentadecapeptide, guanylin, which stimulates intestinal guanylate cyclase.
  • Peptides similar to uroguanylin peptides have been identified in mouse, rat, porcine, and bovine species. The functionally active domain in most of these peptides are highly conserved.
  • these peptides may be similar, and these peptides may be used as intestinal cancer preventative agents as well.
  • these peptides may be used as intestinal cancer preventative agents as well.
  • substitutions in the non-active domains may be achieved with no change in the activity of the peptides.
  • the cyclooxygenase inhibitor can be, by way of example, a COX-2 nonselective inhibitor or a COX-2 selective inhibitor.
  • COX-2 nonselective inhibitors include the well-known compounds ' aspirin, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, tolmetin, ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, oxaprozin, flurbiprofen, piroxicam, tenoxicam, phenylbutazone, apazone, or nimesulide or a pharmaceutically acceptable salt or derivative or prodrug thereof.
  • the COX-2 nonselective inhibitor is selected from the- group comprising aspirin, acetaminophen, indomethacin, ibuprofen, or naproxen.
  • the cyclooxygenase-2 inhibitor is selected from compounds of Formula I
  • A is a substituent selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings; wherein R 1 is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R- 1 - is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; wherein R ⁇ is methyl or amino; and wherein R3 is a radical selected from hydrido, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl
  • a preferred class of compounds which inhibit cyclooxygenase-2 consists of compounds of Formula I wherein A is selected from 5- or 6-member partially unsaturated heterocyclyl, 5- or 6-member unsaturated heterocyclyl, 9- or 10-member unsaturated condensed heterocyclyl, lower cycloalkenyl and phenyl; wherein R- 1 - is selected from 5- and 6-membered heterocyclyl, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R ⁇ is optionally substituted at a substitutable position with one or more radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower
  • a more preferred class of compounds which inhibit cyclooxygenase-2 consists of compounds of Formula I wherein A is selected from oxazolyl, isoxazolyl, furyl, thienyl, dihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazolyl, benzofuryl, cyclopentenyl, cyclopentadienyl, phenyl, and pyridyl; wherein R ⁇ is selected from pyridyl optionally substituted at a substitutable position with one or more methyl radicals, and phenyl optionally substituted at a substitutable position with one or more radicals selected from methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbon
  • a family of specific compounds of particular interest within Formula I consists of compounds and pharmaceutically-acceptable salts thereof as follows :
  • a family of specific compounds of more particular interest within Formula I consists of compounds and pharmaceutically-acceptable salts thereof as follows: 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -IH- pyrazol-1-yl] benzenesulfonamide;
  • a subclass of cyclooxygenase-2 inhibitors is selected from compounds of Formula II
  • R ⁇ is selected from hydrido, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, carboxyalkylaminocarbonyl, carboxyalkyl, aralkoxycarbonylalkylaminocarbonyl, aminocarbonylalkyl, alkoxycarbonylcyanoalkenyl and hydroxyalkyl; wherein R ⁇ is selected from hydrido, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halo; and wherein R ⁇ is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic; wherein R ⁇ is optionally substituted at a substitutable position with one or more radicals selected from halo,
  • a class of compounds of particular interest consists of those compounds of Formula I wherein R 4 is selected from hydrido, lower alkyl, lower haloalkyl, lower alkoxycarbonyl, cyano, lower cyanoalkyl, carboxyl, aminocarbonyl, lower alkylaminocarbonyl, lower cycloalkylaminocarbonyl, arylaminocarbonyl, lower carboxyalkylaminocarbonyl, lower aminocarbonylalkyl, lower aralkoxycarbonylalkyla inocarbonyl, lower carboxyalkyl, lower alkoxycarbonylcyanoalkenyl and lower hydroxyalkyl; wherein R ⁇ is selected from hydrido, lower alkyl, cyano, lower hydroxyalkyl, lower cycloalkyl, lower alkylsulfonyl and halo; and wherein R ⁇ is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl
  • a family of specific compounds of particular interest within Formula I consists of compounds, derivatives and pharmaceutically-acceptable salts thereof as follows: 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -lH-pyrazol-1- yl] benzenesulfonamide; 4- [5-phenyl-3- (trifluoromethyl) -lH-pyrazol-1- yl] benzenesulfonamide;
  • a family of specific compounds of more particular interest within Formula I consists of compounds and pharmaceutically-acceptable salts or derivatives thereof as follows:
  • Derivatives are intended to encompass any compounds which are structurally related to the cyclooxygenase-2 inhibitors or which possess the substantially equivalent biologic activity.
  • inhibitors may include, but are not limited to, prodrugs thereof.
  • hydro denotes a single hydrogen atom (H) .
  • This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH2-) radical.
  • haloalkyl alkylsulfonyl
  • alkoxyalkyl alkoxyalkyl
  • hydroxyalkyl the term “alkyl” embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms .
  • alkyl radicals are "lower alkyl” radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, pentyl, iso-amyl, hexyl and the like.
  • alkenyl embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms.
  • alkyl radicals are "lower alkenyl” radicals having two to about six carbon atoms.
  • alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4- methylbutenyl .
  • alkynyl denotes linear or branched radicals having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms.
  • More preferred alkynyl radicals are "lower alkynyl” radicals • having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.
  • alkenyl "lower alkenyl” embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations.
  • cycloalkyl embraces saturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkenyl embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms.
  • More preferred cycloalkenyl radicals are "lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl .
  • halo means halogens such as fluorine, chlorine, bromine or iodine.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • “Lower haloalkyl” embraces radicals having 1-6 carbon atoms.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl .
  • hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals.
  • More preferred hydroxyalkyl radicals are "lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl .
  • the terms "alkoxy” and “alkyloxy” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
  • alkoxyalkyl embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
  • the "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals.
  • More preferred haloalkoxy radicals are "lower haloalkoxy" radicals having one to six carbon atoms and one or more halo radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl .
  • Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl .
  • the term "heterocyclyl” embraces saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.).
  • saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.
  • saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g.
  • heteroaryl embraces unsaturated heterocyclyl radicals.
  • unsaturated heterocyclyl radicals also termed “heteroaryl” radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, 1H-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, etc.) tetrazolyl (e.g.
  • unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo [1, 5- b] pyridazinyl, etc.), etc.
  • unsaturated 3 to 6- membered heteromonocyclic group containing an oxygen atom for example, pyranyl, furyl, etc.
  • unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom for example, thienyl, etc.
  • benzoxazolyl, benzoxadiazolyl, etc. unsaturated 3 to 6- membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4- thiadiazolyl, 1, 3, 4-thiadiazolyl, 1,2,5- thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like.
  • the term also embraces radicals where heterocyclyl radicals are fused with aryl radicals.
  • fused bicyclic radicals examples include benzofuran, benzothiophene, and the like.
  • Said "heterocyclyl group” may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having alkyl radicals of one to six carbon atoms.
  • alkylthioalkyl embraces radicals containing an alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred alkylthioalkyl radicals are "lower alkylthioalkyl” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkyl radicals include methylthiomethyl .
  • alkylsulfonyl denotes respectively divalent radicals -S ⁇ 2 ⁇ .
  • alkylsulfonyl embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl .
  • alkylsulfonyl radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals.
  • halo atoms such as fluoro, chloro or bromo
  • sulfamyl denote NH2O2S-.
  • acyl denotes a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals.
  • lower alkanoyl radicals examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl .
  • aroyl embraces aryl radicals with a carbonyl radical as defined above. Examples of aroyl include benzoyl, naphthoyl, and the like and the aryl in said aroyl may be additionally substituted.
  • carbboxy or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes -CO2H.
  • Carboxyalkyl embraces alkyl radicals substituted with a carboxy radical. More preferred are “lower carboxyalkyl” which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl .
  • alkoxycarbonyl means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are "lower alkoxycarbonyl” radicals with alkyl porions having 1 to 6 carbons.
  • alkoxycarbonyl (ester) radicals examples include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl .
  • alkylcarbonyl examples include radicals having alkyl, aryl and aralkyl radicals, as defined above, attached to a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl and benzylcarbonyl .
  • aralkyl embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl .
  • the aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • benzyl and phenylmethyl are interchangeable.
  • heterocyclylalkyl embraces saturated and partially unsaturated heterocyclyl-substituted alkyl radicals, such as pyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals, such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl .
  • the heteroaryl in said heteroaralkyl may be additionally " substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • aralkoxy embraces aralkyl radicals attached through an oxygen atom to other radicals.
  • aralkoxyalkyl embraces aralkoxy radicals attached through an oxygen atom to an alkyl radical .
  • aralkylthio embraces aralkyl radicals attached to a sulfur atom.
  • aralkylthioalkyl embraces aralkylthio radicals attached through a sulfur atom to an alkyl radical.
  • aminoalkyl embraces alkyl radicals substituted with one or more amino radicals. More preferred are “lower aminoalkyl” radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like.
  • alkylamino denotes amino groups which have been substituted with one or two alkyl radicals.
  • lower N- alkylamino radicals having alkyl portions having 1 to 6 carbon atoms.
  • Suitable lower alkylamino may be mono or dialkylamino such as N- methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.
  • arylamino denotes amino groups which have been substituted with one or two aryl radicals, such as N-phenylamino .
  • the "arylamino" radicals may be further substituted on the aryl ring portion of the radical.
  • aralkylamino embraces aralkyl radicals attached through an amino nitrogen atom to other radicals.
  • N- arylaminoalkyl and N-aryl-N-alkyl-aminoalkyl denote amino groups which have been substituted with one aryl radical or one aryl and one alkyl radical, respectively, and having the amino group attached to an alkyl radical. Examples of such radicals include N-phenylaminomethyl and N- phenyl-N-methylaminomethyl.
  • alkylaminocarbonyl denotes an aminocarbonyl group which has been substituted with one or two alkyl radicals on the amino nitrogen atom.
  • N- alkylaminocarbonyl N,N-dialkylaminocarbonyl radicals.
  • More preferred are “lower N- alkylaminocarbonyl” "lower N,N- dialkyla inocarbonyl” radicals with lower alkyl portions as defined above.
  • alkylaminoalkyl embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical.
  • aryloxyalkyl embraces radicals having an aryl radical attached to an alkyl radical through a divalent oxygen atom.
  • arylthioalkyl embraces radicals having an aryl radical attached to an alkyl radical through a divalent sulfur atom.
  • the compounds utilized in the methods of the present invention may be present in the form of free bases or pharmaceutically acceptable acid addition salts thereof.
  • pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic) , methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, D-3-hydroxybutyric, salicylic, galactaric and
  • Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I.
  • the cyclooxygenase inhibitor can be a cyclooxygenase-2 selective inhibitor, for example, the COX-2 selective inhibitor meloxicam, Formula B-l (CAS registry number 71125-38-7) or a pharmaceutically acceptable salt or derivative or prodrug thereof.
  • the cyclooxygenase-2 selective inhibitor is the COX-2 selective inhibitor RS 57067, 6- [ [5- (4-chlorobenzoyl) - 1, 4-dimethyl-lH-pyrrol-2-yl]methyl] -3 (2H) -pyridazinone, Formula B-2 (CAS registry number 179382-91-3) or a pharmaceutically acceptable salt or derivative or prodrug thereof.
  • the cyclooxygenase-2 selective inhibitor is a COX-2 selective inhibitor of the chromene structural class that is a substituted benzopyran or a substituted benzopyran analog selected from the group consisting of substituted benzothiopyrans, dihydroquinolines, or dihydronaphthalenes having the general Formula II shown below and possessing, by way of example and not limitation, the structures disclosed in Table 1, including the diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrugs thereof.
  • the cycloxygenase-2 selective inhibitor is the substituted benzopyran (S) -6, 8-dichloro-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid, Formula B-8, or a pharmaceutically acceptable salt or derivative or prodrug thereof.
  • the cyclooxygenase inhibitor is selected from the class of tricyclic cyclooxygenase-2 selective inhibitors represented by the general structure of Formula III
  • A is a substituent selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings; wherein R ⁇ is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R!
  • R ⁇ is methyl or amino; and wherein R ⁇ is a radical selected from hydrido, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioal
  • the cyclooxygenase-2 selective inhibitor represented by the above Formula III is selected from the group of compounds, illustrated in Table 2, consisting of celecoxib (B-18), valdecoxib (B-19) , deracoxib (B-20) , rofecoxib (B-21) , etoricoxib (MK-663; B-22) , JTE-522 (B-23) , or a pharmaceutically acceptable salt or derivative or prodrug thereof.
  • the COX-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib and etoricoxib.
  • parecoxib, B-24 which is a therapeutically effective prodrug of the tricyclic cyclooxygenase-2 selective inhibitor valdecoxib, B-19, may be advantageously employed as a source of a cyclooxygenase inhibitor (US 5,932,598, herein incorporated by reference) .
  • the compound ABT-963 having the formula B-25 that has been previously described in International Publication number WO 00/24719 is another tricyclic cyclooxygenase-2 selective inhibitor which may be advantageously employed.
  • the cyclooxygenase inhibitor can be selected from the class of phenylacetic acid derivative cyclooxygenase-2 selective inhibitors represented by the general structure of Formula V:
  • R .16 is methyl or ethyl; R 17 is chloro or fluoro; R 18 is hydrogen or fluoro
  • R 19 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy
  • R 20 is hydrogen or fluoro
  • R > 21 -L is chloro, fluoro, trifluoromethyl or methyl, provided that R 17 , R 18 , R 19 and R 20 are not all fluoro when R 16 is ethyl and R 19 is H.
  • a particularly preferred phenylacetic acid derivative cyclooxygenase-2 selective inhibitor that is described in WO 99/11605 is a compound that has the designation of COX189 (CAS RN 346670-74-4), and that has the structure shown in Formula V, wherein R 16 is ethyl;
  • R 17 and R 19 are chloro
  • R 18 and R 20 are hydrogen; and and R 21 is methyl.
  • cyclooxygenase-2 selective inhibitors that can be used in the present invention have the general structure shown in formula VI, where the J group is a carbocycle or a heterocycle. Particularly preferred embodiments have the structure:
  • X is 0; J is 1 -phenyl; R ⁇ is 2-NHS0 2 CH 3 ; R 22 is 4-N0 2 ; and there is no R2 3 group, (nimesulide) , and X is 0; J is l-oxo-inden-5-yl; R 21 is 2-F; R 2 is 4-F; and R 23 is 6-NHS0 2 CH 3 , (flosulide) ; and X is 0; J is cyclohexyl; R 2 ⁇ is 2-NHS0 2 CH 3 ; R 22 is 5-N0 2 ; and there is no R 23 group, (NS-398) ; and X is S; J is l-oxo-inden-5-yl; R 2 ⁇ is 2-F; R 2 ⁇ is 4-F; and R 23 is 6-N ⁇ S0 2 CH 3 • Na + , (L-745337) ; and X is S; J is thiophen-2-yl; R 2 ⁇ is 4-F;
  • R 23 is 4- (p-S0 2 CH 3 ) C 6 H 4 , (L-784512) .
  • N- (2- cyclohexyloxynitrophenyl) methane sulfonamide (NS-398, CAS RN 123653-11-2), having a structure as shown in formula B-26, have been described by, for example, Yoshimi, N. et al . , in
  • diarylmethylidenefuran derivatives such as those described in U.S. Patent No. 6,180,651.
  • Such diarylmethylidenefuran derivatives have the general formula shown below in formula VII:
  • the rings T and M independently are: a phenyl radical, a naphthyl radical, a radical derived from a heterocycle comprising 5 to 6 members and possessing from 1 to 4 heteroatoms, or a radical derived from a saturated hydrocarbon ring having from 3 to 7 carbon atoms; at least one of the substituents Qi, Q 2 , Li or L 2 is: an —S(0) n —R group, in which n is an integer equal to 0, 1 or 2 and R is a lower alkyl radical having 1 to 6 carbon atoms or a lower haloalkyl radical having 1 to 6 carbon atoms, or an -S0 2 NH 2 group; and is located in the para position, the others independently being: a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a trifluoromethyl radical, or a lower 0-alkyl radical having 1 to 6 carbon atoms, or
  • Qi and Q 2 or Li and L 2 are a methylenedioxy group
  • R 2 , 25, R26 and R 27 independently are: a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl; or, R24, R25 or R 2 6, R27 are an oxygen atom, or R 2 4, R25 or R6, R27, together with the carbon atom to which they are attached, form a saturated hydrocarbon ring having from 3 to 7 carbon atoms; or an isomer or prodrug thereof.
  • Particular materials that are included in this family of compounds, and which can serve as the cyclooxygenase-2 selective inhibitor in the present invention include N- (2-cyclohexyloxynitrophenyl) ethane sulfonamide, and (E) -4- [ (4-methylphenyl) (tetrahydro-2- oxo-3-furanylidene) methyl] benzenesulfonamide.
  • Preferred cyclooxygenase-2 selective inhibitors that are useful in the present invention include the following individual compounds; darbufelone (Pfizer),
  • CS-502 (Sankyo), LAS 34475 (Al irall Profesfarma) , LAS 34555 (Almirall Profesfarma), S-33516 (Servier) , SD 8381 (Pharmacia, described in U.S. Patent No. 6,034,256), BMS-347070 (Bristol Myers Squibb, described in U.S. Patent No.
  • Another preferred embodiment of the invention is the compound BMS-347070, having the formula:

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Abstract

L'invention concerne une méthode destinée à retarder le développement de polypes et de prévention, d'inhibition et de traitement du cancer dans l'intestin d'un sujet consistant en l'administration d'une composition contenant un peptide présentant le domaine actif de l'uroguanyline ou de n'importe quel peptide ou composé agoniste se fixant au récepteur guanylate cyclase GC-C dans l'intestin, en combinaison avec un inhibiteur de cyclooxygénase-2 naturel, dérivé d'un inhibiteur de cyclooxygénase-2 naturel ou un inhibiteur de cyclooxygénase-2 synthétisé par voie chimique, de préférence un inhibiteur de cyclooxygénase-2 sélectif.
EP02702137A 2001-02-02 2002-02-04 Combinaisons d'uroguanyline et d'inhibiteur de cyclooxygenase-2 pour l'inhibition du cancer de l'intestin Withdrawn EP1365753A2 (fr)

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