NZ753702B2 - Compositions and methods for the treatment of gastrointestinal polyps - Google Patents

Abstract

The disclosures herein provide compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, enantiomers, stereoisomers, solvates, and hydrates thereof. These salts may be formulated as pharmaceutical compositions. The pharmaceutical compositions may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, lozenge, spray, intravenous, oral solution, buccal mucosal layer tablet, parenteral administration, syrup, or injection. Such compositions may be used to treatment of gastrointestinal polyps or its associated complications. uccal, rectal, topical, transdermal, transmucosal, lozenge, spray, intravenous, oral solution, buccal mucosal layer tablet, parenteral administration, syrup, or injection. Such compositions may be used to treatment of gastrointestinal polyps or its associated complications.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF GASTROINTESTINAL POLYPS The present application claims the benefit of Indian Provisional Patent Application No. 201641038684 filed on 11-November-2016, the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference.

FIELD OF THE INVENTION This disclosure generally relates to compounds and compositions for the treatment of gastrointestinal . More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, solvates, enantiomer, stereoisomer, esters, salts, hydrates, prodrugs, or mixtures thereof.

OUND OF THE INVENTION Familial adenomatous polyposis (FAP) ts for approximately 1% of all large intestinal tumour diagnoses. The e occurs de novo with the ncy of somewhere between 1 in 8000 to 1 in 10000 births and the age of disease ance varies quite considerably even between siblings.

FAP symptoms occur earlier than in the most common hereditary predisposition to colorectal cancer, Lynch syndrome and generally start to appear in the second decade of life.

Patients have, however been reported to be as young as 5 years of age and in the group of our youngest patients, one was only 3 years old when polyps were diagnosed. The APC gene is a tumour suppressor gene that is involved in the control of β-catenin.Loss of APC function s in the constitutive activation of β-catenin, which culminates in cellular proliferation.

At the present time ts at risk of disease are screened by sigmoidoscopy every 12 months beginning at puberty. This makes it possible to discover symptoms long before the pment of an invasive neoplasm. Once polyps appear, the only effective measure to prevent the occurrence of the malignant disease is to remove surgically the entire colon and rectum. Prophylactic colectomy performed at an appropriate age prolongs the life expectancy of FAP patients, on average, from 45 to over 60 years of age.

Chemoprevention using NSAIDs has been proposed in FAP patients. The first drug that was shown to be effective in FAP was sulindac. Long-term use of this drug reduced the number of colorectal adenomas by >50% in the colon as well as in the rectum of patients after colectomy, but not in duodenal polyposis. However, sulindac does not prevent the development of as in FAP. Selective COX-2 inhibitor (cyclooxygenase-2) xib, associated with fewer gastrointestinal side effects than sulindac, was found to reduce the number of ctal adenomas by 28%, and also reduced the number of duodenal as. However, cardiovascular effects (myocardial infarction or stroke) have been bed in long-term users of another selective COX-2 inhibitor (rofecoxib), and therefore the role of these drugs remain controversial, and should be considered only in selected patients t cardiovascular risk There is currently a need in the art for new compositions to treatment or delay of the onset of gastrointestinal polyps and its associated complications progression.

SUMMARY OF INVENTION The present invention provides compounds, compositions containing these compounds and methods for using the same to treat, prevent and/or ameliorate the s of the conditions such as intestinal polyps.

The invention herein provides compositions comprising of formula I or pharmaceutical acceptable salts f. The invention also provides pharmaceutical itions comprising one or more compounds of formula I or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of gastrointestinal polyps and its associated complications.

Formula I In certain embodiments, the present invention relates to the compounds and compositions of formula I, or ceutically acceptable salts thereof, Formula I and pharmaceutically acceptable salts, hydrates, es, prodrugs, enantiomers, and stereoisomers thereof; Wherein, R1, R3, R5 each independently represents OD, OCH3, OCOCH3, NULL, , , , , , , , , , , , , , , , , , , , , , , , , , or R2 , R4 , R6 each ndently represents , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; n is independently 1, 2, 3, 4 or 5; a is independently 2,3 or 7; each b is independently 3, 5 or 6; e is independently 1, 2 or 6; c and d are each independently H, D, -OH, -OD, alkyl, -NH2 or -COCH3.

In certain embodiments, compounds of formula II are described: Formula II and pharmaceutically acceptable salts, es, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, R1 independently represents OD, OCH3, OCOCH3, NULL, , , , , , , , , , , , , , , , , , , , , , , , , , or R2 ndently represents , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; n is ndently 1, 2, 3, 4 or 5; a is independently 2,3 or 7; each b is independently 3, 5 or 6; e is independently 1, 2 or 6; c and d are each independently H, D, -OH, -OD, C1-C6-alkyl, -NH2 or -COCH3.

In certain embodiments, compounds of formula III are described: Formula III and ceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, R1 independently represents OD, OCH3, OCOCH3, NULL, , , , , , , , , , , , , , , , , , , , , , , , , , or R2 ndently represents , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; n is ndently 1, 2, 3, 4 or 5; a is ndently 2,3 or 7; each b is independently 3, 5 or 6; e is independently 1, 2 or 6; c and d are each independently H, D, -OH, -OD, C1-C6-alkyl, -NH2 or -COCH3.

In certain embodiments, compounds of formula IV are described: Formula IV and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, R1 independently represents OD, OCH3, OCOCH3, NULL, , , , , , , , , , , , , , , , , , , , , , , , , , or R2 ndently represents , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; n is independently 1, 2, 3, 4 or 5; a is independently 2,3 or 7; each b is independently 3, 5 or 6; e is independently 1, 2 or 6; c and d are each independently H, D, -OH, -OD, C1-C6-alkyl, -NH2 or -COCH3.

In certain embodiments, nds of formula V are described: Formula V and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, R1 ndently represents OD, OCH3, OCOCH3, NULL, , , , , , , , , , , , , , , , , , , , , , , , , , or R2 ndently represents , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; n is independently 1, 2, 3, 4 or 5; a is independently 2,3 or 7; each b is independently 3, 5 or 6; e is ndently 1, 2 or 6; c and d are each independently H, D, -OH, -OD, C1-C6-alkyl, -NH2 or -COCH3.

In certain embodiments, compounds of formula VI are described: Formula VI and pharmaceutically acceptable salts, hydrates, es, prodrugs, enantiomers, and stereoisomers thereof; Wherein, R1, R3 independently represents OD, OCH3, OCOCH3, NULL, , , , , , , , , , , , , , , , , , , , , , , , , , or R2 , R4 ndently represents , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; n is independently 1, 2, 3, 4 or 5; a is independently 2,3 or 7; each b is independently 3, 5 or 6; e is independently 1, 2 or 6; c and d are each independently H, D, -OH, -OD, alkyl, -NH2 or .

Herein the application also provides a kit sing any of the pharmaceutical compositions sed herein. The kit may comprise instructions for use in the treatment of gastrointestinal polyps or its d complications.

The application also discloses a pharmaceutical composition sing a pharmaceutically acceptable carrier and any of the compositions herein. In some aspects, the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, parenteral administration, injection, subdermal administration, or transdermal administration.

Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the treatment of gastrointestinal polyps or its related complications.

The compositions described herein have several uses. The present application provides, for example, methods of treating a patient ing from gastrointestinal polyps or its related cations manifested from metabolic or genetic conditions or disorders, gastrointestinal polyps , chronic diseases or disorders; neurodegenerative disorders, Hepatology, Cancer, Respiratory, Hematological, edic, Cardiovascular, Renal, Skin, ar or Ocular cations. [0025A] A further use of a compound and/or composition as described herein is in the manufacture of a ment for the treatment of one or more disease, disorders, and/or conditions as described herein. In some embodiments, the present disclosure relates to use of a compound and/or composition in the manufacture of a ment for the treatment of a gastrointestinal polyp, an intestinal polyp, and/or mation. [0025B] The present disclosure also describes a compound and/or composition as described herein for use in the treatment one or more disease, disorders, and/or conditions as described herein. In some embodiments, the present disclosure relates to a compound and/or composition for use in the treatment of a gastrointestinal polyp, an intestinal polyp, and/or inflammation.

BRIEF PTION OF FIGURES Figure 1: NMR spectra of Example 1 compound CLX-SYN-G157-C01.

Figure 2: NMR spectra of Example 1 nd N-G157-C01.

Figure 3: NMR spectra of Example 2 compound CLX-SYN-G157-CO3.

Figure 4: NMR spectra of Example 2 compound CLX-SYN-G157-CO3.

Figure 5: NMR a of Example 3 compound CLX-SYN-G157-CO5.

Figure 6: NMR spectra of Example 3 compound CLX-SYN-G157-CO5.

Figure 7: NMR spectra of Example 4 compound CLX-SYN-G157-CO6.

Figure 8: NMR spectra of Example 4 compound CLX-SYN-G157-CO6.

Figure 9: NMR spectra of Example 5 compound CLX-SYN-G157-CO7.

DETAILED DESCRIPTION OF THE INVENTION Definitions As used herein, the following terms and s shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ry skill in the art.

The compounds of the present invention can be present in the form of pharmaceutically acceptable salts. The compounds of the present invention can also be present in the form of pharmaceutically acceptable esters (i.e., the methyl and ethyl esters of the acids of formula I, formula II, formula III, formula IV, formula V or formula VI to be used as prodrugs). The compounds of the present invention can also be solvated, i.e. hydrated. The solvation can be affected in the course of the manufacturing process or can take place i.e. as a uence of hygroscopic ties of an initially anhydrous compound of formula I, a II, formula III, formula IV, formula V or formula VI (hydration).

Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Diastereomers are stereoisomers with te configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are non- superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric , for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn, lngold and Prelog, or by the manner in which the molecule s the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers tively). A chiral compound can exist as either individual enantiomer or as a mixture f. A mixture containing equal proportions of the enantiomers is called a ic mixture".

As used herein, the term "metabolic condition" refers to an Inborn errors of lism (or genetic metabolic conditions) are genetic disorders that result from a defect in one or more metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent.

The term "polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound.

The phrases "parenteral stration" and "administered parenterally" as used herein refer to modes of administration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, ennal, eritoneal, transtracheal, subcutaneous, subcuticular, articular, subcapsular, subarachnoid, pinal and intrastemal injection and infusion.

A "patient," "subject," or "host" to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.

The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the s of mammals, human beings and animals t excessive toxicity, irritation, allergic response, or other problem or cation, commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically acceptable carrier" is art-recognized, and includes, for example, ceutically acceptable materials, compositions or vehicles, such as a liquid or solid , diluent, t or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials which may serve as pharmaceutically acceptable rs e: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) ose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic ; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

The term "prodrug" is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention. A common method for making a prodrug is to include ed moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host .

The term "prophylactic or therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject itions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the ent is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side s thereof).

The term "predicting" as used herein refers to assessing the probability related es t will suffer from abnormalities or complication and/or terminal bowel disease or failure and/or death (i.e. mortality) within a defined time window (predictive window) in the future.

The ity may be caused by the l nervous system or complication. The predictive window is an interval in which the subject will develop one or more of the said complications ing to the predicted probability. The predictive window may be the entire remaining lifespan of the subject upon analysis by the method of the t invention.

The term "treating" is art -recognized and es preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; ting the e, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. ng the disease or condition es ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the metabolic me and diabetes related disorders includes such as gastrointestinal polyps includes such as fundic gland polyps, hyperplastic polyps, gastric adenomas (raised intraepithelial neoplasia), gastrointestinal stromal tumors, inflammatory fibroid polyps, gastric neuroendocrine tumors (carcinoids), bannayan-riley-ruvalcaba syndrome, cowden syndrome, al adenomatous polyposis, juvenile polyposis syndrome, coeliac disease, se malabsorption, mild infections, tic infections like giardiasis, l inflammatory bowel diseases, bile acid malabsorption, functional chronic constipation, small intestinal bacterial overgrowth, and chronic functional abdominal pain and other related diseases or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. of a subject by administration of an agent even though such agent does not treat the cause of the ion. The term "treating", "treat" or "treatment" as used herein includes curative, preventative (e.g., prophylactic), adjunct and palliative treatment.

The phrase "therapeutically effective amount" is an art-recognized term. In certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some d effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or ient to eliminate or reduce l ms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation.

In certain embodiments, the pharmaceutical compositions described herein are formulated in a manner such that said compositions will be delivered to a patient in a eutically effective amount, as part of a prophylactic or therapeutic treatment. The desired amount of the composition to be administered to a patient will depend on absorption, vation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severity of the ion to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the stration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art. onally, the optimal concentration and/or quantities or amounts of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters.

Such treatment parameters include the clinical use to which the ation is put, e.g., the site d, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or ion.

In n embodiments, the dosage of the subject compositions provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to ty may be used.

When used with respect to a pharmaceutical composition or other material, the term "sustained release" is art-recognized. For example, a subject composition which releases a substance over time may exhibit sustained release characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time. For example, in particular embodiments, upon contact with body fluids including blood, spinal fluid, mucus ions, lymph or the like, one or more of the pharmaceutically acceptable excipients may undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic and/or biologically active salt and/or composition, for a sustained or extended period (as compared to the release from a bolus). This release may result in prolonged ry of therapeutically ive amounts of any of the therapeutic agents disclosed herein.

The phrases "systemic stration," "administered systemically," "peripheral administration" and "administered peripherally" are art-recognized, and include the administration of a subject composition, therapeutic or other material at a site remote from the disease being treated. Administration of an agent for the disease being treated, even if the agent is subsequently distributed systemically, may be termed "local" or "topical" or "regional" administration, other than directly into the central nervous system, e.g., by subcutaneous stration, such that it enters the t’s system and, thus, is subject to metabolism and other like ses.

The phrase "therapeutically effective amount" is an cognized term. In certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation.

The present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said gs.

This application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula I, formula II, formula III, formula IV, formula V or formula VI may be formulated for systemic or topical or oral administration. The pharmaceutical composition may be also formulated for oral administration, oral solution, injection, subdermal administration, or transdermal administration. The pharmaceutical ition may further se at least one of a pharmaceutically acceptable stabilizer, t, tant, filler, binder, and lubricant.

In many embodiments, the ceutical compositions described herein will incorporate the disclosed nds and compositions la I and Formula II) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formula I, a II, formula III, formula IV, formula V or formula VIor composition as part of a prophylactic or therapeutic treatment. The desired concentration of formula I, formula II, formula III, a IV, formula V or formula VI or its pharmaceutical acceptable salts will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values may also vary with the ty of the condition to be ated. It is to be r understood that for any ular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or ising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts of any particular compound of formula I, a II, formula III, formula IV, formula V or formula VI may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which the preparation is put, e.g., the site d, the type of patient, e.g., human or man, adult or child, and the nature of the disease or condition.

The concentration and/or amount of any compound of formula I, formula II, formula III, formula IV, formula V or formula VImay be readily identified by e screening in animals, e.g., rats, by screening a range of concentration and/or amounts of the al in question using appropriate assays. Known methods are also available to assay local tissue concentrations, diffusion rates of the salts or compositions, and local blood flow before and after administration of eutic formulations disclosed herein. One such method is microdialysis, as reviewed by T. E. Robinson et al., 1991, microdialysis in the neurosciences, Techniques, volume 7, Chapter 1. The methods reviewed by Robinson may be applied, in brief, as follows. A microdialysis loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop. When compounds with a I, formula II, formula III, formula IV, formula V or formula VIsuch as those disclosed herein are injected adjacent to the loop, released drugs are collected in the ate in proportion to their local tissue trations.

The ss of diffusion of the salts or itions may be determined thereby with suitable calibration procedures using known concentrations of salts or compositions.

In certain embodiments, the dosage of the subject compounds of formula I, formula II, formula III, formula IV, formula V or formula VI provided herein may be determined by nce to the plasma concentrations of the therapeutic composition or other ulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.

Generally, in carrying out the methods detailed in this ation, an effective dosage for the compounds of Formulas I is in the range of about 0.01 mg/kg/day to about 100 mg/kg/day in single or divided doses, for instance 0.01 mg/kg/day to about 50 mg/kg/day in single or divided doses. The compounds of Formulas I may be administered at a dose of, for example, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, mg/kg/day, 30 day, or 40 mg/kg/day. Compounds of Formula I, formula II, formula III, formula IV, formula V or formula VI may also be administered to a human patient at a dose of, for example, between 0.1 mg and 1000 mg, between 5 mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000, 2000, 5000 mg per day. In certain embodiments, the compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the nd of formula I, formula II, formula III, formula IV, formula V or formula VIrequired for the same therapeutic benefit.

An effective amount of the compounds of a I, formula II, a III, a IV, formula V or a VIdescribed herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease.

An effective amount may be sufficient to prohibit, treat, alleviate, ameliorate, halt, restrain, slow or reverse the progression, or reduce the severity of a complication resulting from nerve damage or demyelization and/or elevated reactive oxidative-nitrosative species and/or abnormalities in neurotransmitter homeostasis’s, in ts who are at riskfor such complications. As such, these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriate. The amount and timing of compositions administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician. Thus, because of patient-to-patient variability, the dosages given above are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the patient. In considering the degree of ent desired, the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as ce of other diseases.

The compositions provided by this application may be administered to a subject in need of treatment by a variety of conventional routes of administration, ing , topically, parenterally, e.g., intravenously, subcutaneously or intramedullary. Further, the compositions may be administered intranasally, as a rectal itory, or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth t the need to use water. Furthermore, the compositions may be administered to a subject in need of treatment by controlled release dosage forms, site specific drug delivery, transdermal drug delivery, patch (active/passive) mediated drug delivery, by tactic injection, or in nanoparticles.

The compositions may be administered alone or in combination with ceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various c solvents. The pharmaceutical compositions formed by combining the compositions and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These ceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets ning various excipients such as L-arginine, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrates such as starch, alginic acid and n complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Appropriate als for this e lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring , coloring matter or dyes and, if desired, emulsifying or suspending agents, together with ts such as water, ethanol, propylene glycol, glycerin and ations f. The compounds of formula I, formula II, formula III, formula IV, formula V or formula VI may also comprise enterically coated comprising of various excipients, as is well known in the pharmaceutical art.

For eral administration, solutions of the compositions may be prepared in (for e) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be ed. Such aqueous solutions should be ly buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and eritoneal administration. In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those d in the art.

The formulations, for instance tablets, may contain e.g. 10 to 100, 50 to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700, 800 mg of the compounds of formula I, formula II, formula III, formula IV, formula V or formula VI disclosed herein, for instance, compounds of formula I, formula II, formula III, formula IV, formula V or formula VI or pharmaceutical acceptable salts of a compounds of formula I, formula II, formula III, formula IV, formula V or formula VI .

Generally, a composition as described herein may be administered , or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for e, where the patient is suffering from intestinal disorder that prevent oral administration, or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician. Localized administration may also be indicated, for example, when a high dose is desired at the target tissue or organ. For buccal administration the active composition may take the form of tablets or lozenges formulated in a conventional .

The dosage administered will be dependent upon the identity of the neurological disease; the type of host involved, including its age, health and weight; the kind of concurrent treatment, if any; the frequency of treatment and therapeutic ratio.

Illustratively, dosage levels of the administered active ingredients are: intravenous, 0.1 to about 200 mg/kg; intramuscular, 1 to about 500 mg/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of host body weight.

Expressed in terms of concentration, an active ingredient can be present in the itions of the t invention for localized use about the cutis, asally, pharyngolaryngeally, bronchially, intravaginally, ly, or ocularly in a concentration of from about 0.01 to about 50% w/w of the composition; preferably about 1 to about 20% w/w of the composition; and for parenteral use in a concentration of from about 0.05 to about 50% w/v of the composition and preferably from about 5 to about 20% w/v.

The compositions of the present invention are preferably ted for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, es, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral ons of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient. For oral administration either solid or fluid unit dosage forms can be prepared.

As discussed above, the tablet core contains one or more hydrophilic polymers. le hydrophilic polymers include, but are not d to, water swellable cellulose derivatives, polyalkylene glycols, thermoplastic kylene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof.

Examples of suitable water swellable cellulose derivatives include, but are not d to, sodium carboxymethylcellulose, cross-linked ypropylcellulose, ypropyl cellulose (HPC), ypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, and mixtures thereof. Examples of suitable kylene glycols include, but are not limited to, polyethylene glycol. Examples of suitable thermoplastic polyalkylene oxides include, but are not limited to, poly(ethylene oxide). Examples of suitable acrylic polymers include, but are not limited to, potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, high-molecular weight crosslinked acrylic acid homopolymers and copolymers such as those commercially available from Noveon Chemicals under the tradename CARBOPOLTM. Examples of suitable hydrocolloid s include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum , inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, , cyclodextrin, chitosan, and mixtures thereof. Examples of suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and laponite; magnesium trisilicate; magnesium aluminum silicate; and mixtures thereof. Examples of suitable gelling starches include, but are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch glycolate and derivatives f, and mixtures thereof.

Examples of le swelling cross-linked polymers include, but are not limited to, crosslinked polyvinyl pyrrolidone, cross-linked agar, and linked carboxymethylcellulose , and mixtures thereof.

The r may contain one or more le excipients for the formulation of tablets.

Examples of suitable excipients include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, ts, release-modifying excipients, superdisintegrants, antioxidants, and mixtures thereof.

Suitable binders include, but are not limited to, dry s such as polyvinyl idone and hydroxypropylmethylcellulose; wet binders such as soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, n, gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, , cyclodextrin, an, polyvinyl pyrrolidone, cellulosics, sucrose, and starches; and mixtures thereof. Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches, rystalline cellulose, and mixtures thereof.

Suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof.

Suitable glidants include, but are not limited to, colloidal silicon dioxide. le releasemodifying excipients include, but are not limited to, insoluble edible materials, pH-dependent polymers, and mixtures thereof.

Suitable ble edible materials for use as release-modifying excipients e, but are not limited to, water-insoluble polymers and low-melting hydrophobic als, copolymers thereof, and mixtures thereof. Examples of suitable water-insoluble polymers include, but are not limited to, ethylcellulose, polyvinyl ls, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof, and es thereof. Suitable low-melting hydrophobic materials include, but are not limited to, fats, fatty acid esters, olipids, waxes, and mixtures thereof. Examples of suitable fats include, but are not limited to, hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof. Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, yl behenate, yl palmitostearate, glyceryl monostearate, glyceryl tristearate, yl rylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides, and mixtures thereof. Examples of suitable phospholipids e otidyl choline, phosphotidyl serene, otidyl enositol, phosphotidic acid, and mixtures thereof. Examples of suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof. es of super disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and cross-linked povidone (crospovidone). In one embodiment the tablet core contains up to about 5 percent by weight of such super disintegrant.

Examples of antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, and mixtures thereof. Examples of preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof.

In one embodiment, the immediate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns; e.g., from about 250 microns to about 1000 microns. In embodiment, the immediate release coating is typically compressed at a density of more than about 0.9 g/cc, as measured by the weight and volume of that specific layer.

In one embodiment, the ate release coating contains a first portion and a second portion, wherein at least one of the portions contains the second pharmaceutically active agent. In one ment, the ns contact each other at a center axis of the tablet.

In one ment, the first portion es the first pharmaceutically active agent and the second portion includes the second pharmaceutically active agent.

In one embodiment, the first portion contains the first pharmaceutically active agent and the second portion contains the second pharmaceutically active agent. In one embodiment, one of the portions ns a third pharmaceutically active agent. In one embodiment one of the portions contains a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet core.

In one embodiment, the outer coating portion is prepared as a dry blend of materials prior to on to the coated tablet core. In another embodiment the outer g portion is included of a dried granulation including the ceutically active agent.

Formulations with different drug release mechanisms described above could be combined in a final dosage form containing single or multiple units. Examples of multiple units include multilayer tablets, capsules ning tablets, beads, or granules in a solid or liquid form. l, ate release formulations include compressed tablets, gels, films, coatings, liquids and particles that can be encapsulated, for example, in a n capsule. Many methods for preparing coatings, ng or incorporating drugs, are known in the art.

The immediate release dosage, unit of the dosage form, i.e., a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form, contains a therapeutically effective quantity of the active agent with tional pharmaceutical excipients. The immediate e dosage unit may or may not be coated, and may or may not be admixed with the delayed release dosage unit or units (as in an encapsulated mixture of ate release drug-containing granules, particles or beads and delayed release drug-containing granules or .

Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington—The Science and ce of Pharmacy", 20th. Ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000). A diffusion system typically consists of one of two types of devices, reservoir and matrix, which are own and described in die art. The matrix devices are lly prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.

An immediate release portion can be added to the extended release system by means of either applying an ate release layer on top of the extended release core; using coating or compression processes or in a multiple unit system such as a capsule ning extended and immediate release beads.

Delayed release dosage formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, but soluble in the neutral environment of small intestines. The d release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. The drug-containing composition may be a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.

A pulsed e dosage form is one that mimics a multiple dosing e without repeated dosing and typically allows at least a twofold reduction in dosing ncy as compared to the drug presented as a conventional dosage form (e.g., as a solution or prompt drug-releasing, conventional solid dosage form). A pulsed release profile is characterized by a time period of no release (lag time) or reduced release followed by rapid drug release.

Each dosage form contains a therapeutically effective amount of active agent. In one embodiment of dosage forms that mimic a twice daily dosing profile, approximately 30 wt. % to 70 wt. %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt. % to 3.0 wt. %, preferably 60 wt. % to 40 wt. %, of the total amount of active agent in the dosage form is ed in the second pulse. For dosage forms mimicking the twice daily dosing profile, the second pulse is preferably released imately 3 hours to less than 14 hours, and more preferably approximately 5 hours to 12 hours, following administration.

Another dosage form contains a compressed tablet or a capsule having a drugcontaining ate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit. In this dosage form, the immediate e dosage unit contains a plurality of beads, granules particles that release drug substantially immediately ing oral administration to provide an initial dose. The delayed release dosage unit contains a plurality of coated beads or granules, which release drug approximately 3 hours to 14 hours following oral administration to e a second dose.

For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, may be prepared.

Methods of preparing various pharmaceutical itions with a certain amount of one or more compounds of formula I, formula II, formula III, formula IV, formula V or formula VI or other active agents are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical es, Mack Publishing Company, Easton, Pa., 19th Edition (1995).

In addition, in certain ments, subject compositions of the present ation maybe lyophilized or ted to another appropriate drying technique such as spray drying.

The subject compositions may be administered once, or may be divided into a number of smaller doses to be administered at varying als of time, depending in part on the release rate of the compositions and the desired dosage.

Formulations useful in the methods ed herein include those le for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The formulations may iently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of a subject composition which may be combined with a carrier material to e a single dose may vary depending upon the subject being treated, and the particular mode of administration.

Methods of preparing these formulations or compositions include the step of bringing into association subject compositions with the carrier and, optionally, one or more accessory ingredients. In l, the formulations are prepared by uniformly and intimately bringing into association a subject composition with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

The compounds of formula I, formula II, formula III, formula IV, formula V or formula VI described herein may be administered in inhalant or aerosol formulations. The inhalant or aerosol formulations may comprise one or more agents, such as adjuvants, diagnostic , imaging agents, or eutic agents useful in tion therapy. The final aerosol formulation may for example contain 0.005-90% w/w, for ce 50%, 0.005- % w/w, or 0.01-1.0% w/w, of medicament relative to the total weight of the formulation.

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for e, carboxymethylcellulose, alginates, gelatin, polyvinyl idone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or a starch, alginic acid, certain silicates, and sodium carbonate; (5) solution ing agents, such as paraffin; (6) tion accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl e, and mixtures f; and (10) ng agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

Liquid dosage forms for oral administration include pharmaceutically able emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject compositions, the liquid dosage forms may contain inert diluents ly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl te, propylene , 1,3-butylene glycol, oils (in particular, cottonseed, corn, , sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the subject compositions, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable nonirritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, or a late, and which is solid at room temperature, but liquid at body temperature and, ore, will melt in the appropriate body cavity and release the encapsulated nd(s) and composition(s). Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for transdermal administration include powders, sprays, nts, pastes, , lotions, gels, solutions, s, and inhalants. A subject composition may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. For transdermal administration, the complexes may include lipophilic and hydrophilic groups to achieve the desired water lity and transport properties.

The ointments, pastes, creams and gels may contain, in addition to subject compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a t composition, excipients such as lactose, talc, c acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of such substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Methods of delivering a composition or compositions via a transdermal patch are known in the art. Exemplary s and methods of patch delivery are described in US Patent Nos. 6,974,588, 6,564,093, 6,312,716, 6,440,454, 6,267,983, 6,239,180, and 6,103,275.

In another embodiment, a transdermal patch may comprise: a substrate sheet comprising a ite film formed of a resin composition comprising 100 parts by weight of a polyvinyl chloride-polyurethane ite and 2-10 parts by weight of a styrene-ethylenebutylene-styrene mer, a first ve layer on the one side of the composite film, and a polyalkylene terephthalate film adhered to the one side of the composite film by means of the first adhesive layer, a primer layer which comprises a saturated polyester resin and is formed on the surface of the polyalkylene terephthalate film; and a second ve layer comprising a styrene-diene-styrene block copolymer containing a pharmaceutical agent d on the primer layer. A method for the manufacture of the above-mentioned substrate sheet comprises preparing the above resin composition molding the resin composition into a composite film by a calendar process, and then ng a polyalkylene terephthalate film on one side of the composite film by means of an adhesive layer thereby forming the substrate sheet, and forming a primer layer comprising a saturated polyester resin on the outer surface of the polyalkylene thalate film.

Another type of patch comprises incorporating the drug ly in a ceutically acceptable adhesive and laminating the drug-containing adhesive onto a suitable backing member, e.g. a polyester backing membrane. The drug should be t at a concentration which will not affect the adhesive properties, and at the same time deliver the required clinical dose.

Transdermal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver small-molecule drugs. Many of the newly ped proteins and peptide drugs are too large to be delivered through passive transdermal patches and may be delivered using technology such as electrical assist (iontophoresis) for large-molecule drugs.

Iontophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current. One example of an iontophoretic membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by which iontophoresis es molecular transport across the skin are (a) repelling a charged ion from an electrode of the same charge, (b) electroosmosis, the convective movement of solvent that occurs through a charged pore in response the preferential passage of counter-ions when an electric field is applied or (c) se skin permeability due to application of electrical current.

In some cases, it may be desirable to administer in the form of a kit, it may comprise a ner for containing the separate itions such as a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage als, or when titration of the individual components of the combination is desired by the ibing physician.

An e of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a plastic material that may be arent. s and compositions for the treatment of gastrointestinal polyps. Among other things, herein is provided a method of treating gastrointestinal polyps, comprising administering to a patient in need thereof a eutically effective amount of compound of Formula I: Formula I and pharmaceutically able salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, R1, R3, R5 each independently represents OD, OCH3, OCOCH3, NULL, , , , , , , , , , , , , , , , , , , , , , , , , , or R2 , R4 , R6 each ndently represents , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; n is independently 1, 2, 3, 4 or 5; a is independently 2,3 or 7; each b is independently 3, 5 or 6; e is independently 1, 2 or 6; c and d are each independently H, D, -OH, -OD, C1-C6-alkyl, -NH2 or -COCH3.

METHODS OF MAKING Examples of synthetic ys useful for making compounds of formula I are set forth in example below and generalized in scheme 1, scheme 2, scheme 3, scheme 4 and scheme 5: Scheme 1: Preparation of 2-amino((tert-butoxycarbonyl)amino)(difluoromethyl)pentanoic acid (Step-1): To a stirred on of Eflornithine.HCl (30 g, 137.26 mmol) in THF/H2O (480 mL, 1:1 v/v) was added NaHCO3 (40.3 g, 480.32 mmol) followed by (Boc)2O (3.89 g, 178.34 mmol) and stirred the reaction mixture at RT for 48 h. The progress of the reaction was monitored by TLC. THF was removed under reduced pressure; the aqueous layer was neutralized with 1 N HCl and concentrated under reduced pressure. The e was triturated with % MeOH/CH2Cl2 and the insoluble material was ed. The filtrate was concentrated under reduced pressure to afford 2-amino((tertbutoxycarbonyl )amino)(difluoromethyl)pentanoic acid (28 g, 73% yield) as white solid.

Preparation of (2,2-dimethyl-1,3-dioxolanyl)methyl 2-amino((tertbutoxycarbonyl )amino)(difluoromethyl)pentanoate (Step-2): To a stirred solution of o((tert-butoxycarbonyl)amino)(difluoromethyl) pentanoic acid (12 g, 42.55 mmol) in DMF (100 mL) was added DIPEA (27.44 g, 212.75 mmol), al (5.62 g, 42.55 mmol) followed by HATU (19.40 g, 51.06 mmol) and stirred the reaction mixture at RT for 4 h. The progress of the reaction was monitored by TLC. The reaction mixture was poured into ice-cold water (500 mL), extracted with ethyl acetate (2x300 mL). The combined organic layer was washed with water (3x200 mL), dried over anhydrous sodium sulphate and trated under d pressure. The crude compound was purified by column chromatography a gel 100- 200 mesh, eluted with 15-40% EtOAc in Hexane) to afford (2,2-dimethyl- 1,3-dioxolanyl)methyl 2-amino ((tert-butoxycarbonyl)amino) (difluoromethyl) pentanoate (5.5 g, 32% yield) as colorless liquid. ation of 2,3-dihydroxypropyl 2-amino((tert-butoxycarbonyl)amino) (difluoromethyl)pentanoate (Step-3): To a stirred solution of (2,2-dimethyl-1,3-dioxolanyl)methyl 2-amino((tertbutoxycarbonyl )amino)(difluoromethyl) pentanoate (5.5 g, 13.88 mmol) in MeOH (60 mL) was added PTSA (2.63 g, 13.88 mmol) and stirred the reaction mixture at RT for 20 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced re, the residue was diluted with H2O (50 mL), ed with saturated NaHCO3 solution, extracted with 10% MeOH/CH2Cl2 (4x200mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 100-200 mesh, eluted with 2-5% MeOH in CH2Cl2) to afford 2,3 -dihydroxypropyl 2-amino((tertbutoxycarbonyl )amino)(difluoromethyl)pentanoate (3.7 g, 75% yield) as colorless liquid.

Preparation of (5Z,5'Z,8Z,8'Z,11Z,11'Z,14Z,14'Z,17Z,17'Z)((2-amino((tertbutoxycarbonyl )(difluoromethyl)pentanoyl)oxy)propane-1,2-diyl bis(icosa- ,8,11,14,17-pentaenoate) (Step-4): To a stirred solution of 2,3-dihydroxypropyl o((tert-butoxycarbonyl)amino) (difluoromethyl) pentanoate (3.7 g, 10.38 mmol) in DMF (32 mL) was added EPA (6.90 g, 22.89 mmol), EDC.HCl (4.78 g, 24.91 mmol) followed by DMAP (506 mg, 4.15 mmol) and stirred the reaction mixture at RT for 20 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with EtOAc (500 mL), washed with H2O (3x200 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 100-200 mesh, eluted with 15-20% EtOAc in Hexane) to afford (5Z,5'Z,8Z,8'Z,11Z,11'Z,14Z,14'Z,17Z,17'Z)((2-amino((tert-butoxycarbonyl)amino) oromethyl)pentanoyl)oxy)propane-1,2-diyl bis(icosa-5,8,11,14,17-pentaenoate) (3 g, 31% yield) as yellow .

Preparation of (5Z,5'Z,8Z,8'Z,11Z,11'Z,14Z,14'Z,17Z,17'Z)((2,5-diamino (difluoromethyl) pentanoyl)oxy) propane-1,2-diyl bis(icosa-5,8,11,14,17-pentaenoate) hydrochloride 5): To a stirred solution of (5Z,5'Z,8Z,8'Z,11Z,11'Z,14Z, 14'Z,17Z,17'Z)((2-amino((tertbutoxycarbonyl )amino)(difluoromethyl) pentanoyl)oxy)propane-1,2-diyl bis(icosa- ,8,11,14,17-pentaenoate) (7 g, 7.56 mmol) in 1,4-dioxane (50 mL) was added HCl in 1,4-dioxane (4M, 60 mL) and stirred the reaction mixture at RT for 2 h. The progress of the on was monitored by TLC. The reaction mixture was concentrated, co-distilled with CH2Cl2 to afford (5Z,5'Z,8Z,8'Z,11Z,11'Z,14Z,14'Z,17Z,17'Z)((2,5-diamino (difluoromethyl)pentanoyl)oxy)propane-1,2-diyl bis(icosa-5,8,11,14,17-pentaenoate) hydrochloride (6.5 g) as brown gummy solid with 99.08% of HPLC purity.

Scheme 2: Preparation of (2,2-dimethyl-1,3-dioxolanyl)methyl 2-((3-chloro methylphenyl)amino)benzoate (Step-1): To a stirred solution of Solketal (6 g, 45.93 mmol), Tolfenamic acid (13.04 g, 49.97 mmol) in CH2Cl2 (120 mL) was added DCC (11 g, 54 mmol) followed by DMAP (549 mg, 4.50 mmol) and stirred the reaction mixture at RT for 3 h.

The progress of the reaction was monitored by TLC. The reaction mixture was d with CH2Cl2 (50 mL), filtered through a pad of celite, washed with CH2Cl2 (30 mL). The filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 0 mesh, eluted with 1% EtOAc in Hexane) to afford (2,2- dimethyl-1,3-dioxolanyl)methyl 2-((3-chloromethyl phenyl) amino) te (11 g, 64% yield) as pale yellow liquid.

Preparation of 2,3-dihydroxypropyl 2-(3-chloro methylphenylamino)benzoate (Step-2): A mixture of (2,2-dimethyl-1,3-dioxolanyl)methyl((3-chloro methylphenyl) amino)benzoate (8 g, 21.33 mmol) and 80% Acetic acid/H2O (80 mL) were stirred at 80 °C for 3 h. The progress of the reaction was monitored by TLC. The reaction e was poured into ice-cold water (800 mL); the solid formed was filtered and dried under vacuum to afford 2, 3-dihydroxypropyl((3-chloro methylphenylamino)benzoate (5.4 g, 75% yield) as off white solid.

Preparation of Z,8Z,8'Z,11Z,11'Z,14Z,14'Z,17Z,17'Z)((2-((3-chloromethylphenyl) amino) l) oxy) propane-1,2-diyl bis(icosa-5,8,11,14,17- pentaenoate) (Step-3): To a stirred solution of hydroxypropyl 2-((3-chloro methylphenyl)amino)benzoate (3 g, 8.95 mmol) in CH2Cl2 (60 mL) was added EPA (5.95 g, 19.70 mmol), DCC (4.06 g, 19.70 mmol) followed by DMAP (0.109 g, 0.89 mmol) and stirred the reaction mixture at RT for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with CH2Cl2 (25 mL), filtered through a pad of celite, washed with CH2Cl2 (25 mL). The filtrate was concentrated under reduced pressure at 30 °C to obtain crude compound.

Note: 4 x 3g Batches were combined and the resultant crude compound was ed by column chromatography (multiple times, silica gel 100-200 mesh, eluted with 2% EtOAc in ) to afford (5Z,5'Z,8Z,8'Z,11Z,11'Z,14Z,14'Z,17Z,17'Z)((2-((3-chloro methylphenyl) amino)benzoyl)- opane-1,2-diyl bis(icosa- ,8,11,14,17-pentaenoate) (3.3 g, 10% yield) as pale yellow liquid with 98.11% of HPLC purity.

Scheme 3: ation of (Z)-(2,2-dimethyl-1,3-dioxolanyl)methyl 2-(5-fluoromethyl(4- (methylsulfinyl) idene)-1H-indenyl)acetate (Step-1): To a stirred solution of Solketal (12 g, 90.90 mmol) in CH2Cl2 (300 mL) was added DCC (18.7 g, 90.90 mmol), DMAP (1.1 g, 9.09 mmol) followed by Sulindac (32.3 g, 90.90 mmol) and stirred the reaction mixture at RT for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with CH2Cl2 (100 mL), filtered through a pad of celite, washed with CH2Cl2 (100 mL). The filtrate was washed with water (2x100 mL). The combined organic layer was dried over anhydrous sodium sulphate concentrated under d pressure. The crude compound was purified by column tography (silica gel 60-120 mesh, eluted with 1% MeOH in CH2Cl2) to afford ( Z)-(2,2-dimethyl-1,3-dioxolanyl)methyl 2-(5-fluoromethyl (4-(methylsulfinyl) benzyli dene)-1H-indenyl)acetate (22 g, 52% yield) as yellow semi-solid.

Preparation of (Z)-2,3-dihydroxypropyl luoromethyl(4- (methylsulfinyl)benzylidene)-1H-indenyl)acetate (Step-2): A mixture of (Z)-(2,2-dimethyl-1,3-dioxolanyl)methyl(5-fluoromethyl(4- (methylsulfinyl) benzylidene)-1H- indenyl)acetate (15 g, 31.91 mmol) and 80% Acetic acid (150 mL) were stirred at 50 °C for 2 h. The progress of the reaction was monitored by TLC.

The reaction mixture was poured into ice-cold water (1000 mL), extracted with ethyl acetate (2x300 mL). The combined organic layer was washed with saturated NaHCO3 solution (3x200 mL), water (100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude compound was diluted with ethyl acetate (100 mL), d at RT 30 min, filtered and dried under vacuum to afford 3-dihydroxypropyl 2-(5-fluoromethyl(4- (methylsulfinyl)benzylidene)-1H-indenyl)acetate (9 g, 65% yield) as yellow solid.

Preparation of (5Z,5'Z,8Z,8'Z,11Z,11'Z,14Z,14'Z,17Z,17'Z) (2-((Z)fluoromethyl(4-(methylsulfinyl) benzylidene)- 1H-indenyl)acetoxy)propane-1,2-diyl bis(icosa-5,8,11,14,17- pentaenoate) (Step-3): To a stirred solution of (Z)-2,3-dihydroxypropyl 2-(5-fluoro methyl(4-(methylsulfinyl)benzylidene)-1H-indenyl)acetate (12 g, 27.90 mmol)in DMF (240 mL) was added EPA (18.6 g, 62.39 mmol), EDC.HCl (11.8 g, 62.39 mmol) followed by DMAP (681 mg, 5.58 mmol) and stirred the reaction mixture at RT for 16 h. The ss of the reaction was monitored by TLC. The reaction mixture was ed through a pad of celite, washed with ethyl acetate (100 mL). The filtrate was d with ethyl acetate (600 mL), washed with ice-cold water (3x250 mL), brine (150 mL), dried over anhydrous sodium sulphate and concentrated under reduced re at below 30 °C. The crude compound was purified by column chromatography (multiple times, silica gel 60-120 mesh, eluted with 4% EtOAc in CH2Cl2) followed by preparative HPLC (5% THF in Acetonitrile) to afford (5Z,5'Z,8Z,8'Z,11Z,11'Z,14Z,14'Z,17Z,17'Z)(2-((Z) fluoromethyl(4-(methylsulfinyl) benzylidene)-1H-indenyl)acetoxy)propane-1,2-diyl osa-5,8,11,14,17-pentaenoate) (4.8 g, 17% yield) as yellow liquid with 98.77% of HPLC purity.

Scheme 4: To a stirred on of (5Z,8Z,11Z,14Z,17Z)-2,3-dihydroxypropyl eicosa-5,8,11,14,17- pentaenoate (5 g, 14 mmol, Int-B) and 2-((3-chloromethyl phenyl)amino)benzoic acid (10.41 g, 30.8 mmol, ac) in dry CH2Cl2 (100 mL), was added DCC (9.58 g, 49 mmol) ed by DMAP (649 mg, 5.6 mmol) at 0-5 °C. The reaction mixture was allowed to RT and stirred for 16 h under Argon atmosphere. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through a pad of celite, washed with CH2Cl2 (30 mL). The filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 230-400 mesh, eluted with EtOAc). The obtained compound was again purified by preparative HPLC (eluted with HPLC grade Acetonitrile) to get 2.2 g of desired compound CLX-SYN-G157-C06, confirmed by 1H NMR.

Scheme 5: To a stirred solution of 4-((3-ethynylphenyl)amino)quinazoline-6,7-diol (1 g, 4 mmol, Compound-5) in dry CH2Cl2 (20 mL) and DMF (5 mL) was added EPA (3.27 g, 12 mmol), the reaction mixture was cooled to 0-5 °C, added EDC HCl (1.73 g, 10 mmol). The reaction mixture was allowed to RT and stirred for 4 h under Argon atmosphere. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with cold water (30 mL) stirred for 15 minutes. The reaction mass was filtered through a pad of celite; separated the organic layer, dried over Na2SO4 and t was ated under d pressure at 30 °C. The crude compound was purified by flash column chromatography (eluted with 13% EtOAc in pet ether). The obtained compound (850 mg) was again purified by preparative HPLC (eluted with HPLC grade Acetonitrile) to get 200 mg of desired compound CLX-SYN-G157-C07, confirmed by 1H EQUIVALENTS The present disclosure provides among other things compositions and methods for treating gastrointestinal polyps and their complications. While specific ments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the systems and methods herein will become apparent to those skilled in the art upon review of this specification. The full scope of the d systems and methods should be determined by reference to the claims, along with their full scope of lents, and the specification, along with such variations.

INCORPORATION BY REFERENCE ] All ations and patents mentioned herein, including those items listed above, are hereby incorporated by reference in their entirety as if each dual publication or patent was specifically and individually indicated to be orated by reference. In case of conflict, the present application, including any definitions herein, will control.

Claims (7)

1. A compound of Formula I: Formula I and pharmaceutically acceptable salts, hydrates, solvates, enantiomers, and stereoisomers thereof; wherein, R1, R3, and R5 each independently ents NULL; R2, and R4 each independently represents , , , , , , , , , , , , , , , , , , , , , , , , , , a is independently 2,3 or 7; each b is ndently 3, 5 or 6; e is independently 1, 2 or 6; c and d are each independently H, D, -OH, -OD, C1-C6-alkyl, -NH2 or -COCH3; and wherein R6 is represented by

2. A compound of claim 1 selected from the group consisting of

3. A pharmaceutical composition comprising a compound of claim 1 or claim 2, and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition of claim 3, which is formulated for oral administration, delayed release, sustained release, transmucosal administration, syrup, topical administration, parenteral administration, injection, subdermal administration, oral solution, rectal administration, buccal administration, or transdermal administration.

5. The pharmaceutical composition of claim 3 or claim 4 formulated for the treatment of a gastrointestinal polyp, an intestinal polyp, and/or inflammation.

6. A compound of claim 1 or claim 2, for use in the treatment of a gastrointestinal polyp, an intestinal polyp, and /or inflammation.

7. Use of a nd of any one of claims 1,2 or 6 or a ceutical composition of any one of claims 3-6 in the manufacture of ment for the treatment of a intestinal polyp, an inal polyp, and/or inflammation. [Stamp] lkasoju pboard 6.000 5.211 1.233 9.999 4.254 18.051 2.740 1.363 20.949 0.901 7 8 2.890 CBLLAL-RD001-173 9 2.009 1H DMSO-D6 012017(A4) Bruker NMR 400MHz