NZ616076B2 - Derivatives of sulindac, use thereof and preparation thereof - Google Patents

Abstract

The disclosure relates to a family of compounds that are derivatives of sulindac (abstract figure). The disclosure also relates to the method of manufacture of these compounds for treatment of cancer, chronic inflammatory disease or neurodegenerative disease and a method of preparing the compounds. Example compounds include: (Z)-2-(5-fluoro-2-methyl-1-4-(methylthio)benzylidene)-1H-inden-3-yl)-N-(2-(piperidin-1-yl)ethyl)ethanamine (Z)-N-benzyl-2-(5-fluoro-2-methyl-1-(pyridine-4-ylmethylene)-1H-inden-3-yl)ethanamine (Z)-1-(5-Fluoro-2-methyl-1-(4-(methylthlo)benzylidene)-1H-inden-3-yl)-N,N-bis(pyridin-4-ylmethy)methanamine Example compounds include: (Z)-2-(5-fluoro-2-methyl-1-4-(methylthio)benzylidene)-1H-inden-3-yl)-N-(2-(piperidin-1-yl)ethyl)ethanamine (Z)-N-benzyl-2-(5-fluoro-2-methyl-1-(pyridine-4-ylmethylene)-1H-inden-3-yl)ethanamine (Z)-1-(5-Fluoro-2-methyl-1-(4-(methylthlo)benzylidene)-1H-inden-3-yl)-N,N-bis(pyridin-4-ylmethy)methanamine

Description

DERIVATIVES OF SULINDAC USE THEREOF AND PREPARATION THEREOF DESCRIPTION Technical Field The present sure relates to certain derivatives of sulindac and especially amino derivatives of sulindac. The t sure also relates to pharmaceutical compositions comprising the disclosed derivatives of sulindac, as well as methods of using the disclosed derivatives of sulindac for the treatment and prevention of precancerous conditions and cancer in a mammal. The disclosed tives of sulindac are also suitable for treating chronic inflammatory conditions. The present sure also relates to methods for producing the disclosed compounds.

BACKGROUND Even though significant es have occurred in the treatment of cancer, it still remains a major health n. Cancer has been reported as the leading cause of death in the United States with one of every four Americans likely to be diagnosed with the disease. By way of example, colorectal cancer is the third most commonly sed cancer in the world that accounts for approximately 600,000 deaths per year. While a colonoscopy allows for the early detection of the disease and the identification of individuals who are at high risk of disease progression, the mortality rate from colorectal cancer has sed only marginally in the last two decades (1 ). Additionally, certain lesions such as flat adenomas cannot be readily detected by a colonoscopy (2) and surgical management of adenomas in high risk individuals, such as with familial adenomatous polyposis (F AP) often requires complete or segmental l of the colon (3). Given the slow progression of carcinogenesis and the limitations of colonoscopy, much research has focused on cancer chemoprevention to reduce the development and progression of colorectal cancer. 184L-NZ 2J381-00IOI-WO Included among the known chemotherapeutic drugs are carmusline, bicin, methotrexate, paclitaxel, cyclophosphamide, procarbazine, and vinblastine, to name only a few. However, many herapeutic drugs also e undesirable side effects in the patient.

Certain nonsteroidal anti-innammalory drugs (NSAlDs) have been nx:ognized to have broad anticancer activity in animal models alone and in combination with chemotherapy or radiation. Representative examples include: Hial et al., "Alteralion oftumar growth by aspirin and indomethacin: studies with two transplantable tumors in mouse" EliI'. J. Pharm. 37: 367-316, 1976; Lynch et aI., "Mechanism af inhibition aftumor growth by aspirin and indomethacin" Br. J. Cancer 38: 503-512, 1978; Bennett et al., ased survival ofcancerbearing mice treated with inhibitors of prostaglandin synthesis alone or with herapy" Sr. J. Cancer 45; 762- 768, 1982; PallaI'd and Luckert "Prolonged antitumor effect of indomethacin on autochthonous intestinaltumars in rats" J. Natl. Cancer Inst. 70: 1103-1105, 1983; Fulton, "Inhibition ofexperimental asis with indomethacin: role ofmacro phages and natural killer cells" Prostaglandins: 35: 413-425, 1988; Moorghen el aI., "The effect of sulindac all colonic tumor formation in dimethylhydrazine-treated mice" Acta bistochemica 29: 195-199, 1990; and Moorghen et al., "A protective effect ofsulindac against chemicallyinduced primary colonic tumours in mice" J. ofPath. 156: 341-347.

Epidemiological studies have shown that long-tenn use ofNSAIDs can significantly reduce the incidence and risk ofdeath from colorectal cancer (4). In addition, certain prescription strength NSAIDs, such as sulindac can cause the regression and prevent recurrence ofadenomas in individuals with FAP (5). The antineoplastic activity ofNSA1Ds is widely attributed to their cyclooxygenase (COX) inhibitory activity because prostaglandins are elevated in colon tumors (6) and a icant tage ofcolon tumors express high levels of the inducible COX-2 isozyme (1). r, there is evidence that alternative mechanisms either contribute to or fully account for the ctal cancer chemopreventive activity ofNSAIDs (8-10). For example, the non-COX inhibitory e metabolite of sulindac has been reported to inhibit the growth and induce apoptosis ofcolon tumor cell 111 vitro (II, 12) and suppress colon fumorigenesis in animal models (13-15). Sulindac sulfone (exisulind) was also shown to ss a formation in duals with FAP or sporadic adenomas (16, 17), but did not receive FDA approval due to hepatotoxicity. The use ofNSAIDs is ated with gastrointestinal, renal and cardiovascular toxicities from suppressing prostaglandin synthesis (18,19).

Sl84L-NZ 21J81WO Previous studies have shown that n NSAIDs can se nuclear levels of~ catenin by inducing proteosomal degradation to inhibit the transcription of genes (e.g. cyclin D, survivin) that provide a survival advantage 10 allow for clonal expansion of neoplastic cells (20-22). Several groups have reported that ac sulfone can also induce the degradation of oncogenic p-calenin, which suggests that the underlying biochemical mechanism by which NSAIDs suppress p-catcnin signaling may not require COX inhibition (22-24).

As mentioned above, Sulindac (Clinorir'Tlol) is a NSAID that has demonstrated ncer activity. 11 has been ized as having benefils for treating precancerous conditions as evidenced by a numbel'of clinical trials in familial adenomatOllS polyposis patients which have shown the ability ofsulindac to cause the regression ofexisting as (size and number) and to inhibit new a (polyp) fonnalion. For example, see Waddell et ai, "Sulindac for polyposis oftile colon". J. . 157: 175-179, 1989; Labayle et al., "Sulindac causes regression of rectal polyps in familial adenomatous sis" Gastroenterology 101: 635-639, 1991; Nugent et al., "Randomized controlled trial ofthe effect ofsulindac on duodenal and rectal polyposis and cell proliferation in patienlS with familial adenomatous polyposis" Br. J. Surg. 80: 1618-1619, 1993; Giardiello, et aI., "Treatment of colonic and rectal adenomas with ac in familial adenomatous polyposis" N. Eng. J. Med 328: ]313-6,1993; and Winde et al., "Complete reversion and prevention of reclal adenomas in coleclomized patients with familial adenomatous polyposis by rectal low· dose sulindac maintenance ent" Dis. Colon Rectum 38: 813-830, 1995.

The mechanism responsible for the anti·inflammalory efficacy and the toxicity of NSAlDs and COX-2 selective inhibitors ointestinal, renal, hematological, cardiovascular) has been shown 10 involve cycloox.ygenase COX-] or COX-2 inhibition.

Sulindac and certain other NSAIDs also have hepatic ty. For instance, see Vane, "Mode ofaCliOn ofaspirin and similar compounds" In Prostaglandin Synthetase Inhibitors, Eds Robinson, Raven Press, New York. NY, 1914; Eaker ointestinal injury related to the use ofnonsleroidal anti-inflammatory drugs" Gastrointestinal Disease Today 6: 1·8, 1997; Wolfe et al., "Gastrointestinal toxicity of nonsteroidal anti·inf1arnmatol'ydrugs" N. Eng. J.

Med 340: 1888·99. 1999; Palmer "Renal complications associated with use of roidal anti-inflammatory agents" J. Invest. Medicine 43: 516-533, 1995; Tarazj et aJ., "Sulindac· associated hepatic injury: analysis of91 cases reported to the Food and Drug Administration" 21381-00101·WD Gastroenterology 104: 569-574, 1993; and Mukherjee et at "Risk iovascular events ated with selective CDX-2 inhibitors" lAMA 286: 954-959, 2001.

Most investigators attribute the mechanism for the anticancer activity ofNSAIDs to anti-inflammatory activity involving COX inhibition, although there is some evidence for a COX-independent mechanism as mentioned below. For example. the activity ofthe sulfone metabolite ndac has been described which retains anticancer activity in prcclinical and clinical trials but does not t cyclooxygenase and displays less 01 toxicity. See for example, Piazza el aI., "Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoplosis" Cancer Res. 55: 3110-3116, 1995; Pill2Z8 et aI., "Sulindac sulfone inhibits 8zoxymethane·induced colon carcinogenesis in rats without reducing prostaglandin levels" Cancer Res. 57: 915, 1997; Piazza et aI., "Apoptosis ily accounts for the growth inhibitory properties ofsulindac lites and involves a mechanism that is independent ofcyclooxygcnasc inhibition, cell cycle , and p53 induction" Cancer Res. 57: 2452·2459, 1997; Piazza et ai, "Exisulind a novel proapoptotic drug inhibits rat urinary r tumorigenesis" Cancer Res., 61: 3961-3968. 200 I; and Chan "Nonsteroidal antiinflammatory drugs, apoptosis, and colon-cancer chemoprevention" The Lancet Oncology 3: 166-174, 2002.

The mechanism responsible for the antineoplastic activity ofsulindac sulfone has been previously reported to involve cyclic guanosine monophosphate (cOMP) phosphodiesterase (PDE) inhibition (23, 25). More recently, it has been reported that the COX inhibitory sulfide metabolite ofsulindac and n other NSAIDs also inhibit cOMP PDE, and that this activity is closely associated with their tumor cell growth tory and apoptosis·inducing properties (26-28). Cyclic nucleotide roes are a large amily of s responsible for regulating second messengcr signaling by hydrolyzing the 3',5'- phosphodiester bond in cOMP and/or cAMP. There are at least eleven POE isozyme family members having different substrate specificities, regulatory properties, tissue localization, and inhibitor sensitivity (29). POE 1,2.3, 10 and 11 are dual substrate·degrading es, while PDES. 6. and 9 are selective for cOMP and PDE4. 7. and 8 are cAMP selcctive. In addilion, each isozyme family contains multiple isofonns or splice ts. Depending on the PDE isozyme content ofthc target cell population and tor selectivity, POE inhibitors can increase the magnitude and/or the dural ion ofthe cAMP and/or cGMP intracellular signal(s). Increasing cyclic nucleotide levels can induce specific signaling 5184L·NZ 213SI·00l01·WO pathways, which, in the case ofcGMP, can activate protein kinase G (PKG) 10 regulate cellular activity (30).

There are publications suggesting that certain chemical modifications 10 the carboxylic acid moiety ofNSAIDs will result in ed safety (Le., as prodrugs or by localized release of nitric oxide). For example, see Mahmud ct aI., "A unifying hypothesis for the mechanism D d gastrointestinal toxicity". Ann, tic Diseases 55: 211-213, 1996; Venuti el al., "Synthesis and biological evaluation of(N,N,N,· ylammonium) alkyl esters and Ihioesters ofcarboxylic acid nonsteroidal antiinflammatory drugs" Pharmaceutical Research 6: 867-873,1989; eni el al., "New esters ofN-arylanthranilic acids" Farmaco 30: 276·86, 1975; and Elliot et a!. "A nitric oxidereleasing nonsteroidal anii-inflammatory drug accelerates gastric ulcer healing in rats" Gastroenterology 109: 524-530,1995.

In addilion, US s 5,401,TI4, 6,166,053 and 6,200.771 suggesl certain modifications to sulindac sulfone which is not a NSAID.

As another example, a series ofamide and ester tives of indomethacin and meclofenamic acid involving cations to the carboxylic acid moiety wel'~ described by Marnen et al. These compounds were described as having safety advantages over the parent NSAIDs based on selectivity for the cyclooxygenase-2 isozyme. However, anticancer activity was not described and modifications to improve anticancer efficacy (potency) were not described. For example, see Kalgutkar et aI., "Biochemical based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion ofnonsteroidal anti-inflammatory drugs to potent and highly selective COX-2 inhibitors" Prot. Nat!. Acad. Sci. 97: 0, 2000; Kalgutkar et 81. "Amide derivatives ofmeclofenamic acid as selective xygenase- 2 inhibitors" Bioorganic and Medicinal Chemistry Leiters 12: 521-524,2002; Kalgutkarct al., "Ester and amide derivatives of the nonsteroidal anti-inflammatory drug, indomethacin, as selective cyclooxygenase-2 tors" J. Moo. Chern. 43: 2860-2870, 2000; US Patent 19110 Marnell and Kalgutkar tive inhibitors of prostaglandin endoperoxide synthetase-2"; and US Patent 5,475,021 to Marnell and Kalgutkar unds and compositions for inhibition of cyclooxygenasc activity".

More recently, various !l.1nide derivatives ofsulindac have been disclose<! in US patent applications serial numbers 6on55,S47 filed January 4, 2006 and 11/649,373 filed January 4, 2007, now US PatentS,044,048 to Piazza et a!. and assigned to rn Research Institute, the assignee of the present application, However, during animal testing, modest metabolism 5184l·NZ of the amide e from at least one of the amide derivatives of sulindac was noted, producing sulindac sulfide a known COX 1 and COX 2 inhibitor. tion ofthis product is likely a result of non—specific enzymes known as amidases that can regenerate the carboxylic acid and can cause side effects resulting from COX inhibition. The metabolism of the amide to the carboxylic acid has been previously reported by Piazza et al, "A novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits tumor cell growth and induces apoptosis with antitumor activity" Cancer Prev. Res. 2: 0, 2009.

Notwithstanding the advances in treatments for cancer and other diseases there still remains an unmet medical need for improved drugs that are effective for the prevention and treatment of , while at the same time exhibiting reduced adverse side effects.

SUMMARY According to a first aspect of the invention there is provided a compound selected from the group of compounds represented by the following formulae: 5184L-NZ 0‘ CH3 pharmaceutically able salts thereof, solvates thereof and prodrugs f wherein the prodrugs are formed at hydroxyl or amino functionalities.

According to a second aspect of the invention there is provided use of of a compound selected from the group of compounds represented by the following formulae: 5184L-NZ 0‘ CH3 pharmaceutically acceptable salts thereof, es thereof and prodrugs thereof wherein the prodrugs are formed at hydroxyl or amino functionalities; in the manufacture of a medicament for treating a ous or precancerous condition. pharmaceutically acceptable salts thereof, es thereof and mixtures thereof.

According to a third aspect of the invention there is provided the use of a compound selected from the group of compounds represented by the following formulae: 5184L-NZ pharmaceutically acceptable salts thereof, solvates thereof and prodrugs thereof wherein the prodrugs are formed at hydroxyl or amino functionalities; in the manufacture of a medicament for treating a chronic atory disease.

According to a fourth aspect of the invention there is provided the use of a nd selected from the group of compounds represented by the following formulae: 5184L-NZ 0‘ CH3 F 0‘ /o I pharmaceutically acceptable salts thereof, solvates thereof and prodrugs f wherein the prodrugs are formed at hydroxyl or amino functionalities; in the cture of a medicament for treating a neurodegenerative disease.

Certain compounds according to preferred embodiments of the present ion can be prepared by converting an ester of sulindac or a derivative therefore represented by the following formula: 5184L-NZ 21381·00101-WQ Ar is a substituted or unsubstituted 5 or 6 member ring. Non-limiting examples ofAr include R, R, , __0 wherein each RI. R2 and R1 is individually selected from the group consisting of H, Salkyl. alkyl and alkoxy; An aldehyde represented by the ing formula is obtained according to the above process step; The aldehyde is the reacted with a or an amine represented by R..RsNH. Each ~ and Rs is individually selectedfrom the group consisting ofH, alkyl. a substituted or unsllhstituted 5 or 6 member ring; and when both ~ and Rs are a substituted or unsubstitutcd or 6 member ring, both of~ and RsaTe a substituted or unsubstituted pyridyl ring. Non- ng examples of~ and R, include 5184L-NZ 21381·OQIOI·WO ()~)~NCY" • • , and A compound represented by the fOlTllula is ed by the above process step: x ""'"' Other compounds according to the present disclosure can be prepared by the following : o 1. borane, THF, OOC F F 2. TBAI, PyrIdine, . TI,o 3. NaN" CH,CN 4. PPh, -s -s Still other objeclS and advantages orthe prescnt disclosure will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described only the preferred embodiments, simply by way ofilJustration of the best mode, As will be realized, the disclosure is capable of other and different ments. and its several details are capable of modifications in various obvious respects, without ing from the disclosure. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.

Brief Description ofFigures Figurel rates the cyclooxygenase (COX). I and·2 inhibitory activity ofthe NSAID, sulindac e (55), and Ihc lack of this effect from (Z)-N-benzyl·2·(S·f1uoro melhyI-I-(4·(methylsulfinyl) benzylidene)-I H-indenyl)ethanamine und 6 disclosed herein below), an amino derivative ofsulindac.

Figure 2 illustrates tumor cell growth inhibitory activity ofa trimethoxy amino derivative ofsulindac und 6) and sulindac sulfide (55) against Ihe human - 231 breast tumor cell line.

Best and Various Modes TIle present disclosure is concerned with novel derivatives ofsulindac represented by the a: wherein each of~ and Rj is selected from the group consisting of H. alkyl. a substituted or unsubstiluted 5 or 6 member ring provided thai 81lcast one of~ and R.s is other than H; and when both ~ and Rs are a substituted or unsubstituted 5 or 6 member ring, both of~ and Rsare a substituted or unsubstituted pyridyl ring; Rt. is a tuted or unsubstituted 5 or 6 member ring; and X is a halogen; and phannaceutically acceptable salts thereof, prodrugs thereof, solvates thereofand mixtures thereof.

The substituted or unsubstituted 5 or 6 member ring group for ~, Rs and Ruean be a saturated or unsaturated ring and includes carbon, and optionally a heteroatom such as N or 0; substitutions e at least one alkyl group, halo group, alkoxy group, amino group or aminoalkyl group; The alkyl group typically contains 1-12 carbon atoms. The alkyl group more typically contains 1-4 carbon atoms. Examples ofsuitable alkyl groups include methyl, ethyl and propyl. Examples ed alkyl groups include isopropyl and I-bulyl. Examples of alkyl substituted aromatic groups (aralkyl) are phenyl CI.) alkyl and benzyl. 5184L-NZ 21381wa Typical alkyl substituted aromatic groups containing 7 to 10 carbon atorns in the aromatic ring. When substituted the alkyl group typically contains 1~6 carbon atoms.

Examples ofhalo groups are el, F, Sr and I.

The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl, and diphenyl groups, each of which may be substituted such as with a halo or alkyl group.

Examples of5 and 6 member ring groups are ; N-heterocyclo groups such as pyridyl, pyrrolidinyl, dinyl, piperazinyl, nyl, pyrrolyl, pyrazolyl, pyrazinyl pyrimidinyl, pyridazinyl, imidazoyl and imidazofidinyl; a-heterocyclo groups such as furanyl and pyranyl; heterocyclo groups containing both N and a such as morpholinyl. When substituted these groups are IYpically substituted with at least one alkyl group, halo, alkoxy group, amino group or aminoalkyl group. The rings can be substituted with more than one substituent, for instance, trimethoxy.

It is ofcourse understood that the compounds of the present disclosure relate to all optical isomers and stereo-isomers at the various possible atoms ofthe molecule, unless ied otherwise.

The compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc. groups as the prodrug fonning moieties. For instance, the hydroxymethyl position may fonn mono-, di- or triphosphales and again these phosphates can fonn prodrugs. ations ofsuch prodrug derivatives are sed in various literature sources (examples are: Alexander et al., J. Med. Chem. 1988,31,318; -Martin et aI., PCT WO ppl41531, p.JO). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms ofa nd of the disclosure.

"Pharmaceutically able salls" refer to derivatives of the disclosed compounds wherein the parent nd is modified by making aeid or base salts thereof. Tl1e nds of this disclosure form acid addition salts with a wide y oforganic and nic acids and includes the logically acceptable salts which are often used in pharmaceutical chemistry. Such salls are also part ofthis disclosure. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic., nitric, sulfuric, phosphoric. hypophosphoric and the like.

Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkonic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic 5184l-NZ 21381WO sulfonic acids, may also be used. Such phannaceutically acceptable salts thus include acetate, phenylacetate, lrifluoroacetate. acrylate, ate, benzoate, chlorobenzoate, dinitrobenzoatc. hydroxybcnzoate, mcthoxybenzoatc, mcthylbenzoate. o-aceloxybenzoate, naphthalene·2·benzoatc, bromide, isobutyrate, phenylbutyrate, p·hydl'Oxybutyratc,butyne·1,4.Jioatc, hexyne- oate, caprate, caprylate. chloride.. dnnamate, citrate, fonnale. fumarate, glycollate. heptanoate, hippurate, e, malate., maleate, hydroxy maleate, malonate. mandelate, mesylate. nicotinate. isonicotinatc, e, oxalate. phthalate, leraphthalate, phosphate, monohydrogen phosphate, dihydrogenphosphate, melaphosphalc, pyrophosphate, propiolate, propionate, phenylpl'Opionate, salicylate, sebacate, succinate. suberate, sulfate, bisulfate. pyrosulfate. sulfite. bisulfite, sulfonate, benzene-sulfonate,?" bromobenzenesulfonate, chlorobenzcnesulfonate, ethanesulfon3te, 2-hydroxyethanesulfonate. mcthanesulfonate. naphthalene-I-sui fonate, alene-2·sulfonatc,p-toleunesuIfonate, xylcncsulfonate, tartarate, and the like.

"Solvates" refers to the compound formed by the interaction ofa solvent and a solute and includes hydrates. Solvates are y crystalline solid adducts containing solvent les within the crystal structure, in either stoichiometric or ichiometric proportions.

Thc lenn "comprising" (and its grammatical variations) as used herein is used in the ive sense ing" or "including" and not in the exclusive sense sisting only of." The teons "a" and "the" as used herein are tood to encompass the plural as well as the singular.

The term "precancerous condition" refers to patients having a propensity for being afflicted with cancer.

Compounds according to the present disclosure can, for example, be prepared by the following methods. 5184l-NZ 21381·0010\·WO -4'uf"- '"'. 'Cf" N N Ar' ,!O'"0' _;0' ::q 0- o 0,0 Some exemplary compounds were ed by the following scheme.

F o F F 1, Oolyl cIl!orkte, DMF, CH:C~, 11 CHO, N'{OAehBH~ 2.ltlmeIhyls/lylalkle. ~ ~ l,2-DlchJc>rollCh.".

R, . """"""11·~"C R, 12·13 Compounds R,R1,R2& Rl IC" (~M) HT29 PC3 MDA- R1& R3 '" H, R2=SCHl 15.99 33.60 19.33 II RI, R2& R3 "" ocr!) 14.64 29.73 15.35 12 Rl & R3 := H, R2 '" SCH3, R = methyl 10.76 12.73 9.50 4-pyridyl 13 RI. R2 & RJ = OCH3, R=melhyI4- 9.83 9.09 8.21 5184L·NZ 21381WQ pyridyl Also s compounds according to the present disclosure can be prepared as follows: OH NH, 1. borane, THF. 0 "C F F 2. TBAl, Pyrldine, CHz(:I:, TfP • 3, NaN3' CH3CN 4. PPh3 -s -s PPh) refers to triphenylphosphine and TflO refers trifluoromethanesulfonic acid Method A To a solution ofester (1 equivalent) in dry toluene at -7ifC under argon atmosphere was slowly added diisobutyl aluminium hydride (I M) in toluene (1.2 equivalent) and the resulting mixture stirred at ·7ffc for 1-2 hours. ol (10 mL) was added slowly at ·70°C and allowed to wann to room temperature. TIle reaction mixture was washed with IN s HCI and extracted with CI-hCh (2 x 20 mL). The combined organic fractions were dried over anhydrous Na2S04 and evaporated in VacUIiO. The crude aldehyde was used for the next step without further purification.

Method B Aldehyde (1 equivalent) and amine (1.5 equivalent) were mixed in dry MeOH al room temperature under argon atmosphere. The reaction mixture was d at room temperature and progress of the reaction was monitored by TLC. Afier the complete fonnation of aldimine (3-5 h), NaBH 4 (I ,5 equivalent) was added slowly at room temperature, The on mixture was stirred for 15 minutes and quenched with IN NaOH. The product was extraded wilh CH1Ch (3 x 20 mL) and dried over ous Na2S04. The solvent was evaporated in vaCUlIO and purified by column chromatography 10 afTord sulindac amine as yellow s liquid.

Method C S184l-NZ 21381-00101·WO Aldehyde (1 equivalent) and amine ('.5equivalent) were mixed in dry 1.2- dichloroelhane under argon here and then trealed wilh sodium triacctoxyborohydride (1.5 equivalent). The reaction e was stirred at room temperature until the complete disappearance of aldehyde (3-5 h). The reaction e was quenched with aqueous saturated NaHCO} and the product was extracted with CH,CI, (3 x 20 mL). The combined organic rractions were dried over anhydrous Na2S0~ and evaporated in vacuuo. The t was purified by column chromatography to afford ac amine as yellow viscous liquid. l yields of the reactions in MeUm B &C is range from 50 to 90%.

Method n Oxalyl de was added 10 a on ofsulindac (1.0 equivalent) in CH2Ch (50 rnL) followed by 2 drops of DMF. The resulted reaction mixture was stirred at room temperature for I h. Solvent was removed in vacuuo and the crude acid chloride was used in the next step without any further purification. Crude acid chloride was ded in CCI4 (25 mL) and was added trimelhylsilyl azide (1.5 equivalent) at room temperature. The reaction mixture was d at room temperature 15 min. and slowly heated while stirring until the evolution of nitrogen ceased. Solvent was removed under reduced pressure to give isocyanate as viscous yellow liquid. To the crude isocyanate in acetic acid (80 mL) was added Cone.

HCl (20 mL). The on mixture was heated on a steam bath at 50°C for 30 min. Diluted Ihe reaction mixture with cold H20 (100 mL) and filtered. The solid filtered was washed with water and then ether to fonn suJindac methaneamine as hydrochloride salt.

Method E Aldehyde (2.0 equivalent) and amine (1.0 equivalent) were mixed in dry 1.2- dichloroethane under argon atmosphere and then treated with sodium triacetoxyborohydride (1.5 equivalent). The reaction mixture was stirred at room temperature until the complete disappearance or amine (3-5 h). The reaction mixture was quenched with aqueous ted NaHCO} and the product was extracted with CH,CI, (3 x 20 mL). The combined organie fractions were dried over anhydrous N82S04 and evaporated in vacuuo. The product was purified by using lsec Teledyne chromatographic machine to afford sulindac amine as yellow viscous liquid. 5184L-NZ 00101-WO Method F To a solution ofsulindac sulfide (I equivalent) in THF at 0 °c under nitrogen atmosphere, was added a solution ofborane in THF (1.2 lent) and the reaction e stirred in the cold for 30 minutes, then at room temperature for 2 h. Water was slowly added to the reaction mixture and extracted with CH2Cl, (3 x 20 roll. The crude alcohol was purified by column chromatography. To a solution ofabove alcohol and fctrabutylammonium iodide (2 equivalent) in pyridine (2.2 equivalent) and CH2Ch was slowly added lrifluoromethane sulfonic anhydride (1.8 equivalent) at _78°C for 15 minutes. then at room temperature for I h. It was then diluted with CH2CI2 (50 mL) and washed successively with % aqueous sodium lfate, IN aqueous Hel, ted NaHCOJ• and brine. TIle crude residue from the evaporation ofthe organic phase was ehromatgraphed to obtain sulindae iodide. The above iodide compound was refluxed with sodium azide (1.5 equivalent) in CH~CN for 10 h. Triphenyl phosphine (PPhJ) (I equivalent) was added to above solution st room temperature and the reaction mixture was stirred under nitrogen Iltmosphcre for 3 hours.

CH~CI~ (50 mL) was added to the reaction mixture and washed with saturated NaHCOJ.

Solvent was removed under reduced pressure and the product was purified by silica gel column chromatography to provide ae amine as yellow viscous liquid.

Example I (Z)-N-benzy1(S-flu ororn ethyl-t-{4-(methylsulfinyl)benzylidene)-1H -Indcn-J- yl)elhanAmine (1): By following methods A & C. the title compound 1 was ed as a yellow viscous liquid.

'H NMR (CDCI, 300 MHz): 7.63 (4H, In, 2'-H, 3'-H, 5'-H, 6'-H),7.32-7.22 (5H, In, Ph-H), 7.15 (1 H, dd. J= 5,4 Hz., 8.4 Hz, 7.H), 7.08 (1 H, s, 8-H), 6.85 (I H, dd, J= 2.7 Hz, 9.3 Hz, 4-H), 6.57 (I H, ddd, J= 2.4 Hz, 9.3 Hz, 11.1 Hz, 6-H), 3.84 (2H, s, -CH,-Ph), 2.9Q.2.75 (4H, m, H~-NH), 2.80 (3H, s, -SOCHJ), 2.17 (3H, s, 2-CHJ). HRMS calcd for [CnH~FNOS+Hr: 432.17919, Found: 432.17990. Anal. calcd for [CnH26FNOS+o.5 H20]: C. 73.61; H. 6.18; N. 3.18. Found: C, 73.74; H, 5.95; N. 3.08.

(Z)(S-fl uoromethy1(4-(met hylsuIfinyl)benzylidene)-1 H -iodenyJ)-N-{fu ran ylmethyl)ethanamine (2) 5184L-NZ 21381WO By following methods A & B,the title compound 2 was obtained as a yellow viscous ESI-MS mlz: 422 [M+Hr,IH NMR (CDCh. 300 MHz): ~7.72-7.64 (4H, m. 2'-H, )'-H,5'· H, 6'·H),7.35 (I H, dd, J~ 0.6 Hz, 1.8 Hz, 5"·H), 7.14 (I H, dd,J- 5.1 Hz, 8.1 Hz, HI), 7.08 (I H, S, g-H), 6.85 (I H, dd, J- 2.4 Hz, 9.0 Hz, 4·B), 6.57 (I H, ddd, J= 2.4 Hz, 9.0 Hz, .8 Hz, 6·H). 6.31 (I H, ddt J"" 2.1 Hz. 3.3 Hz.. 4"1), 6.17 (I H, ddt Jc 0.6 Hz, 3.0 Hz, 3"- H), 3.83 (21-1, s, -CH1-Furan), 2.84-2.16 (4H, m, -CHrCHrNH), 2.80 (3H, s, -SOCH), 2,16 (3H, s, 2-CH}). Anal. calcd fol' (C2SH1~FN01S+0.4 H20]: C. 70.04; H, 5.83; N. 3.27. Found: C, 70.05; H, 5.95; N, 3.26.

Example 3 (Z)-N-benzyl(S-fluoromethyl-t-(4-(nlelhyllhio)bcnzylldcne)·!H-lnden yl)ethanamlne (3) By ing methods A & B. the title nd 3 was obtained as a yellow viscous liquid.

ESJ-MS m/z: 416 [M+Ht.'H NMR (CDCh, 300 MHz): 6 7.44 (2H, d, J: 8,' Hz, 3'·H,5'· H), 7.35-7.21 (8H, In, 2'·H,6'-H, 7·H, Ph·H), 7.06 (I H, s, 8-H), 6.84 (I H, dd, J~ 2.4 Hz, 9.0 Hz, 4-H), 6.59 (I H, ddd, J: 2.4 Hz, 9.3 Hz, 10,g Hz, 6·H), 3.83 (2H, 5, ·CHrPh), 2.89-2,75 (4H, m, ·CH2~CHrNH), 2,54 (3H, 50 . 2,16 (3H, 5, 2-CHJ), HRMS calcd for [CnH26FNS+Hf: 416.18428, Found: 416.18452. Anal. calcd for [CnH16FNS+O,2 H20]: C, 77.36; H, 6.35; N, 3.34. Found: C, 77,40; H, 6,48; N. 3.21.

(Z)-2.-(s-n uoro·2-methyl·l-(4-(melhylthio)benzylidene)-IH·lnden·3-yl)-N-(Curan-2· ylmethyl)ethanamine (4) By following method~ A & B, the title compound 4 was obtained as a yellow viscous liquid.

ESI·MS mk: 406 [M+Ht:H NMR (CDCh, 300 MHz): tS7A4 (2H, d, J:=: 8,4 Hz, 3'-H,5'- H), 7.36-7.26 (4H, In, 2'·H,6'-H, 7·H, 5"·H),7.06 (I H, s, 8-H), 6.84 (I H, dd, J~ 2.4 Hz, 9.0 Hz, 4-H), 6.59 (1 H, ddd, J:=: 2.4 Hz, 9.3 Hz, 10.8 Hz, 6-H), 6.31 (I H, dd, J- 1.8 Hz, 3.3 Hz, 4"-H), 6.16 (I H, dd, J~ 0.6 Hz, 3.0 Hz, 3"-H), 3.82 (2H, s, ·CH,·Funm),2.86-2.73 (4H, In, -CHrCHrNH), 2.54 (3H, 5, ·SCHJ),2.16 (3H. S, 2-CHJ). HRMS calcd for FNOSHI)': 406.16354, Found: 406.16388. Anal. calcd for [C2~H24F'NOS+O.2 H10]: C, 73.39; H, 6.01; N, 3,42. Found: C, 73.25; H, 5,97; N, 3,20. 5184L·NZ 21J81-ooI01-wa Example 5 (Z)·z-{s-nuoro-2.meth)'I-]-(4-{mcth)'ltblo)ben7.ylldene}-lH-inden-J-yl}-N-(2-(piperidinl-yl )cthyl)etbanllmine (S) By following methods A & B, the title compound 5 was obtained as a yellow viscous liquid.

ESI-MS m/z: 437 [M+Ht.IH NMR (CDCh, 300 MHz): 15'7.43 (2H, d,J= 8.4 Hz, J'-H, 5'- H), 7.36 (IH, dd, J; 5.4 Hz, 8.4 Hz, 7-H), 7.29 (2H, d, J= 8.4 Hz, 2'-H, 6'-H), 7.09 (I H, 5, 8-H), 6.87 (I H, dd, J= 2.4 Hz, 9.0 Hz, 4-H), 6.60 (I H, ddd, J= 2.4 Hz, 9.0 Hz, 11.7 Hz, 6- H), 2.88-2.77 (6H. m, -CH1-CHrNH-eHz-), 2.5-4 (3H. s, , 2.51 (2H, I, J= 6.0 Hz, CH,-NO, 2.38 (4H, I. J= 5.1 Hz, 2"-H, 6"-H), 2.19 (3H, S, 2-CH,), 1.51- 1.48 (4H, m, 3"-H, "-H), 1.41-1.35 (2H. m, 4"·H). Anal. caled for [C27H33FN2S+o.8 H20): C, 71.90; H, 7.73; N, 6.21. Found: C, 72.04; H, 8.08; N, 5.81.

Example 6 (Z)-Nl-(2-{S-nuoromethyl-l-(4-(metbylthio)benzyJldenc}-lH-indcnyl)etbyl).

N2,N2-dlmethylethane-l.l-dillmlne (6) By ing methods A & B, the title compound 6 was obtained as a yellow s liquid.

ESI-MS //lIz: 397 .1 HNMR (CDCll, 300 MHz): 0 7.44 (2H, d, J - 8.1 Hz, 3'-H, 5'- H), 7.35 (IH, dd,J- 5.1 Hz, 8.4 Hz, 7-H), 7.29 (2H, d, J= 8.4 Hz, 2'.H,6'-H), 7.07 (IH, S, 8-H), 6.88 (I H, dd, J. 2.4 Hz, 9.3 Hz, 4-H), 6.59 (I H, ddd, J = 2.4 Hz, 9.3 Hz, 11.1 Hz, 6- H), 2.86-2.72 (6H, ro, -CH,-CH,-NH-CH,-), 2.54 (3H, ~ -SCH,), 2.45 (2H, t, J=6.3 Hz, CH,·NO, 2.22 (6H, s, -N(CHJh), 2.17 (3H, s, 2-CHJ). HRMS calcd for [C,~HNFN,S+Hr: 397.21082, Found: 066.

Example 7 (Z)·N·benzyI·2-(5- nu oro·2-methyl·t-(4·(methylsu IfonyI)benzyIidene)-1 H-juden-)· yl)ethanamlne (7) By following s A & C, the tille compound 7 was obtained as a yellow viscous liquid.

'H NMR(CaCI" 300 MHz): 0 8.00 (2H, d,J= 8.4 Hz, 3'-H,5'-H), 7.69 (2H, d, J= 8.4 Hz, 2'-H,6'-H), 7.)2-7.22 (5H, m, Ph-H), 7.09 (I H, dd,J= 5.2 Hz, 8.4 Hz, 7-H), 7.04 (I H, S, 8- H), 6.84 (I H, dd, J= 2.4 Hz, 8.8 Hz, 4-H), 6.57 (I H, ddd, J= 2.4 Hz, 8.8 Hz, 11.2 Hz, 6.H), 3.84 (2H, S, -CH,-Ph), 3.13 (3H, S, -Sa,CH,), 2.89 (2H, I, J= 6.8 Hz, -CHd~lli-NH), 2.79 5184l·NZ 21J81WO (2H, I,J= 6.4 Hz, -Q:U-CH,-NH), 2.16 (3H, 5, 2-CH,). HRMS caled fo, rC27H:NiFN~S+Hr: 448.17410, Found: 448.17467. Anal. calcd for [C21H26FN02S+O.S H20); C, 71.03; H. 5.96; N, 3.07. Found: C. 70.82; H, 5.71; N, 2.93.

Example 8 (Z)-N-benzyl(5-fluoromethyl-I-(J,4,5-trimelhoxybenzylidene)-lH-inden yl)ethanllmine (8) By following methods A & C, the title compound 8 was obtained as a yellow viscous liquid (LCMS purity: 100%).

'H NMR (CDCh, 300 MHz): d 7.41 (tH. dd, J= 5.2 Hz, 8.4 Hz, 7-H), 7.32-7.22 (SH. m. Ph- H), 7.07 (IH, 5, 8-H), 6.86 (IH, dd,J- 2.4 Hz, 9.2 Hz, HI), 6.73 (2H, 5, 2'-H,6'-H),6.60 (11-1, ddd, J= 2.4 Hz, 9.2 Hz, 11.6 Hz, 6-H), 3.92 (3H, S, 4'-OCH1). 3.87 (2H, S, -CH2-Ph). 3.84 (6H, S, " 5'·OCH,),2.89 (2H, I, J= 6.8 Hz, ·CI1,·Q:U·NH),2.80 (2H, I, J= 6.8 Hz, H2·NH),2.16 (3H. S, 2-CH). HRMS calcd for rC29H30FNOJ+H)": 460.22825.

Found: 460.22836.

Example 9 (Z)-N-ben zyl-2·(5-nuoro methyl-l-(pyridinylmet )-1 H-indenyl)el II ana mine By following s A & B. the title compound 9 was obtained as a yellow viscous liquid.

ESI-MS mlz: 37 J IH NMR (CDCI" 300 MHz): 0 8.68 (2H, d, J= 5.7 Hz, 3'-H. 5'· H), 7.38 (2H, d, J~ 5.4 Hz, 2'·H,6'·H),7.))-7.21 (5H, m, Ph·H), 7.11 (I H, dd, J: 5.1 Hz, 8.4 Hz, 7·H), 6.95 (I H, s, 8-H), 6.85 (I H, dd,J' 2.4 Hz, 9.0 Hz, 4-H), 6.57 (I H, ddd,J= 2.4 Hz, 9.0 Hz, 11,4 Hz, 6·H). 3.87 (2H, s, -CH2·Ph). 2.89-2.79 (4H, m. -CHr CH2-NH), 2.15 (3H, 50 2-CH). Anal. calcd for [C2,H1JFN2+O.5 H20): C, 75.89; H. 6.57; N. 7.08. Found: C, 75.87; H, 5.87; N, 6.25.

Example 10 {ZH5-Pluorom ethyl-t-(4-(methy Itb 10)benzylidene)-1 H·lnden-3·yl)methana mine (10) By following method D. the title compound 10 was obtained as a yellow viscous liquid in 70% (HPLC purity: 98.7%) yield.

'H NMR (DMSO, 400 MHz): S 7.48 (2H, d, J = 8.4 Hz, 2'-H, 6'-H), 7.35 (2H, d, J = 8.4 Hz, 3'-H,5'-H), 7.32 (IH, dd, J = 5.6 Hz, 8.4 Hz, 7·H), 7.24 (IH, 5, 10-H), 7.20 (IH, dd, J = 2.0 S184L·NZ 21181·ooI01·WO Hz, 9.2 Hz, 4-H), 6.71 (1 H. td, J = 2.0 Hz, 9.2 Hz, 6-H), 3.65 (2H. S, CH1·NH2), 2.53 (3H. S,· SCH,), 2.15 (lH, S, 2·CH,), 1.64 (2H, S, NH,).

Example 11 (Z)-(5-Fluonr2-methyl-l-(3,4.5-trimethoxybenzylidene}-lH-indenyl)metblnamine (12) By following metnod 0, the title compound 11 was ed as a yellow solid in 88% (HPLC purity: 90.5%) yield.

M. P. 108.8 (le.

IH NMR (CDCh. 400 MHz): 6 7.45 (IH, ddt J = 4.8 Hz, 8.0 Hz., 7·H). 7.14 (IH, S, IO-H), 6.96 (I H, dd, J • 2.4 Hz, 8.4 Hz, 4·H), 6.74 (2H, S, 2'·H,6'·H),6.61 (IH, Id, J ~ 2.8 Hz, 9.6 Hz, 6-H), 3.93 (31-1,5, 4'·OCH3). 3.84 (6H, S, )'-QCH), 5'-OCH), 3.82 (2H, 5, CH1-NH1), 2.73 (2H, S, NH2). 2.21 (3H, s. 2-CH J).

Example 12 (Z)-l-{S-Fluoromethyl-l-{4-(methyllhlo)benzyJidene)-lH-indenyl}-N.N- bls(pyridinylmethyl)methanamlne (12) By following methods D and E, the title compound 11 was ed as 8 yellow viscous liquid in 84% (HPLC purity: 95.9%) yield.

I H NMR (CDCh, 400 MHz): S 8.56 (4H, dd, J =: 1.6 Hz, 4.8 Hz, 2"-H. 6"-H), 7.41 (2H, d, J - 8.4 Hz, 2'·H,6'·H),7.12 (IH, dd, J - 5.2 Hz, 8.4 Hz, 7·H), 7.28·7.26 (6H, m, l'·H,S'·H, 3"·H, S"·H), 7.09 (I H, S, Ill-H), 6.98 (I H, dd, J • 2.4 Hz, 9.6 Hz, 4·H), 6.58 (I H, Id, J • 2.4 Hz, 9.2 Hz, 6·H), 3.55 (4H, S, CH,·Ar), 1.51 (2H, S, l·CH,), 2.53 (lH, s, ·SCH,), 2.18 (lH, s, 2-CH3). HRMS calcd for [C3IHnFNlS+Ht: 607, Found: 494.20636.

Example 13 (Z)-t-(5-Flu methyl-I-(3,4,5-1 rimcthoxybenzylldene)~ 1H·lndelly1)-N,N· bis(pyrid inyl melhyl)m etba namin e (13) By following melhods D and E, the title compound 13 was obtained as a yellow solid in 75% (HPLC : 100%) yield.

M. P. 66.4 °C I H NMR (CDCh, 400 MHz): S 8.56 (4H, ddt J= 1.6 Hz, 4.4 Hz, 2"-H, 6"-H), 7.39 (IH, dd, J ~ 5.2 Hz, 8.4 Hz. 7·H), 7.28 (4H, dd, J ~ 1.6 Hz, 4.8 Hz, l"·H, S"·H), 7.09 (IH, s, Ill-H), 7.00 (I H, dd, J • 2.0 Hz, 9.2 Hz, HI), 6.71 (2H", 2'.H,6'.H),6.60 (I H, Id, J ~ 2.4 Hz, 9.2 21381·00101·WO Hz, 6-H), 3.92 (3H. S, 4'·OCH,).3.83 (6H. s. 3··OCH" 5'.QCH,).3.56 (4H, s. CH,Ar), 3.51 (2H, s, , 2.19 (31-1, S, 2-CHJ). HRMS calcd for [CJJHnFNJOJ+Ht: 538.25005, Found: 538.25017.

Example 14 (Z)-Z.(S-Fluoromethy1(4-(methylthio)benzylldene)-1 H-In denyl)ethaoa mine By following method F, the title compound 14 was obtained as a yellow viscous .

ESI-MS m/z: 326.18 [M+Hf.IH NMR (CDeh, 300 MHz): 8 7.43 (2H, d, J - 8.1 Hz, )'1, '·H),7.34 (I H. dd. J = 5.4 Hz, 8.4 Hz, 7·H), 7.28 (2H, d, J • 8.1 Hz, '·H),7.08 (IH. s, 10-H), 6.84 (IH, dd, J = 2.4 Hz, 9.0 Hz, 4-H), 6.56 (IH, td, J =2.4 Hz, 9.0 Hz, 6-H), 2.94 (2H, t, J "" 6.3 Hz, Cth-NH2), 2.71 (2H, I, J = 6.9 Hz, 3-CH2), 2.54 (3H, S, -SCHJ), 2.18 (3H, s, 2-CHJ). HRMS calcd for (C20H2oFNS+Hf: 326.13732, found: 326.13805.

It has been found according to the present disclosure that compounds sed arc surprisingly and advantageously useful in ng mammalian cancer.

The following tables demonstrate improved properties achievable by Ihe present invention.

Table I. Colon tumor cell growth inhibilory activity ofsulindac amine derivatives and reductive amination products. Results from three human colon tumor cell lines are shown in the Tables shown below.

Compound Structure Colon tumor tell growth inllibitory designation lldiYily (IC~ JiM) "1'2' SW480 HCT'116 I j Y 2.7 J.J 4.' 2 { 4.6 5.2 7.' 5184l-NZ 00101-WQ 3 ~r-o 3.0 5.4 3.8 4 i 4.1 4.1 4.' S ''10 2.7 · · 6 'yO 6.1 7.07 6.72 ''0} :ii" 7 '1")) 2.3 · · 8 1U 1.3 · · , 0 :7 1.8 · · ''O;}- . - Not tested 5184L·NZ 00101-WO No Structure Tumor cell growth inhibitory actlyity (IC", .M) HT29 PC3 MDA- MB-231 (breast) ~NH, 15.99 33.60 19.33 -s.D Chemioll Formula: C, ....,.FNS 12 rC' 10.76 12.73 9.50 F r''-O lJ-}- N ctIItr*:IIf~C,IH~HsS II rNH, 14.64 29.73 15.35 1'1' '}- /:j:{ Chemlcal Formula: C1,H"HIO] 13 r'QS 9.83 9.09 8.21 I X"- ' ~f{j ChO!ll1'lk:al l'ClfMlla: ~l'N~~ 5184l-NZ 21381WQ Compound Stnlcture l tumor cell growth designation inhibitory activity (IC:lOI ,..M) MCF-7 MDA-MB- SKBRJ 1 ~? 6.8 5.8 3.4 v.., _.r:; 2 ,~? 15.2 10.2 6.4 v.., _.r:; 3 "(y,..r"O 6.4 '.3 4.8 4 'jf~ '.9 ,., 3.9 , -, :ro - - - ~}-- 6 , 'yO 12.2 14.7 7.1 V,or :-q~ 7 jft> - 3.7 - 2IJ81·00101-WO 8 1° . 6.9 5.9 - = Not teSled As mentioned herein above, 8 unique characteristic ofthe disclosed compounds is lhat they lack inhibitory effects on cyclooxygenase, types I and 2, enzymes, that otherwise would result in the depletion of physiologically important prostaglandins, which can result in gastrointestinal, renal and cardiovascular tOlticity. This property is illustrated in Figure I by comparing the ability ofa NSAID, such as sulindac sulfide to inhibillhe enzymatic activity ofcyclooxygenases, types I and 2. while a lrimelhoxy benzyl amino derivative ofsulindac ed 10 as Compound 6 herein with the entioned properties lacks this activity.

Figure I demonstrates the cyclooxygenase COX-I and -2 inhibilOry activity of the NSAID, sulindac sulfide (88). and the lack of this effect from Compound 6, an £Imino derivative of sulindac. The enzyme activity was measured using a colorimetric assay using recombinant COX s. ICso values (50010 inhibitory concentration) are listed for each COX isozyme.

Figure 2 shows tumor cell growth inhibitory activity ofa trimethoxy amino derivative of sulindac (Compound 6) and sulindac sulfide (88) against the human MDA-MB-2J I breast hlmor cell line. The growth inhibitory activity was determined following 72 hours of treatment using a standard cell viability assay (Cell Titer Glo, Prolllega Corp).

The cted improvement in potency ofCompound 6 to inhibit tumor cell growth compared with sulindac e is another advantage ofsuch compounds as shown in Figure 2 and Tables 2 and J. Another aspect is that the sed compounds were found to y potent tumor cell growth inhibitory activity against a variety of tumor cells types d from solid tumors and logical ancies as illustrated in Table 2 by the sensitivity ofhuman tumor cell lines from the "NCI·60" panel to Compound 6. The sensitivity ofhuman colon tumor cell lines derived from adenomas (precancerous lesions) or adenocarcinomas (malignant lesions) to various amino derivatives ofsulindac is shown in Table J.

Table 2. Broad speclrum tumor cell growth tory activity ofCompound 6 in human tumor cell lines from the "NCI-60 panel" 5184l·NZ 21381-00101 Origin Cell Line Compound 6 Origin Cell line nd 6 IC50 (~M) ICy (.M) HematopoietIc CCFR-CEM 1.70 Renal ACHN 2.67 SR 0.96 UO-31 2.79 HL-60(TB) 1.47 CAKI·l 3.51 K562 1.27 A498 2.85 RPMI-8226 1.45 RXF·393 2.65 MOLT-4 1.29 SN12C 2.90 786-0 2.44 Colon HCT-15 1.80 TK-l0 2.57 HCT-116 2.90 98 2.14 Breast T-470 1.44 KM12 2.31 MOA-MB-231 2.10 SW-620 2.62 MDA-MB-468 2.62 COL0205 2.47 8T-549 2.89 HT29 1.91 Hs578T 1.96 MCF-7 2.40 Lung NCI-H522 1.79 NCI-H460 1.86 NCI-H322M 3.51 Ovarian OVCAR-5 1.91 NCI·H23 3.03 OVCAR-8 2.13 NCI-H226 2.44 OVCAR-4 3.39 A549 2.50 OVCAR-3 2.00 EKVX 3.77 IGROV-l 2.31 HOP-62 2.71 SK-OV-3 3.21 HOP-92 2.52 Prostate OU-145 5.56 Renal ACHN 2.67 PC-3 2.74 UO-31 2.79 CAKI-l 3.51 Melanoma UACC-62 2.01 A498 2.85 UACC-257 2.16 RXF·393 2.65 LOX lMVl 2.82 SN12C 2.90 M14 1.31 786-0 2.44 MAlME-3M 2.88 TK-l0 2.57 -435 1.02 SK-MEL-2 3.55 Broast T-470 1.44 SK-MEL-5 1.83 MDA-MB-231 2.10 SK·MEl·28 2.04 MOA-MB-468 2.62 BT-549 2.89 CNS SNB-75 2.65 Hs578T 1.96 U251 1.99 MCF-7 2.40 SF-268 2.86 SNB·19 2.72 Other NCI-AOR/RES 2.17 SF-539 1.67 SF-295 , .36 5184L-NZ 21381·00101-WO Cells were seeded into 96-well tissue culture treated microtiter plates at 8 density of 5000- 2ססoo cells/well (depending on cell line) in a total volume of 50 j.ll. RPMI-1640 containing % fetal bovine serum was used as assay media for all the cell lines. After overnight incubation. the cells were treated with SRI 21882 for 72 h by adding 50 j.ll of 2X stock solutions to riate wells already containing 50 j.ll ofcells and medium to expose cells to the final concentrations ofcompounds required. Cell viability was measured by the Cell Titer Glo Assay (Promega).

Table 3. Tumor cell growth inhibitory RClivity ora series ofamino derivatives ndac.

The y to inhibit tumor cell growth was determined by calculating ICsovalues using a standard cell viability assay (Cell Titer 010, PlUmega Corp,) following n hours oftrealmenl. The human colon lumorceillincs, HT.29, SW480, HCT116, and Colo 741 were derived from colon ndenocarcinom.s, while LT97 is derived from an adenoma. Fellli human cytes (FHC) are l'epresentative of nonnal cyres. 1lle lack ofeffect inhibiting cyclooxygenases I and 2 (CDX-1 and ·2) is also soown. Sulindac sulfide is shown for comparison.

No. Struclure Hn9 SW480 HCTI16 LT97 FHC Colo74I Cox-l/·2 (lC~) (IC",) (IC3Ul (IC",) (IC,,)) (IC",) Inhibition,e Sulindac ~: sulfide 73.6 8S.2 733 37.8 >200 149.9 3.3S1 9.68 I -0 2.67 3.2. 4.93 6.82 7.83 8.8S >2001 >200 • 1° 3.14 10.70 12.47 3S.2 17.42 12.8S >2001 >200 ....

Sl84l-NZ . ,}? ><" S.J6 6.«4 US 11.11 S." >1001 >'00 ;jb_\'If , S.21 2.90 ).16 ';)0 3,11 S.JS ~IOO >100 1100 0".

It has also been noted according to the present disclosure that amino derivatives ing to the present disclosure have the ability to activate cGMP signaling in tumor cells and suppress oncogenic ~-catenin transcriptional activity and have shown desirable pharmacokinelic properties in mice.

In keeping with the present disclosure, the derivatives ofsulindac can be used alone or in appropriate association, and also may be used in combination with pharmaceutically acceptable carriers and other pharmaceutically active compounds such as s cancer treatment drugs including NSAIDs and/or along with radiation. The active agent may be present in the pharmaceutical composition in any suitable quantity.

The pharmaceutically acceptable carriers described , for example, vehicles, adjuvants, ents, or diluents, are nown to those who are skilled in the art.

Typically, the pharmaceutically acceptable carrier is chemically inert to the active compounds and has no ental side effects or toxicity under the conditions ofuse. The pharmaceutically acceptable rs can include polymers and polymer matrices.

The choice ofcarrier will be determined in part by the particular method used to ster the composition. Accordingly, there is a wide y ofsuitable formulations ofthe pharmaceutical composition ofpreferred embodiments ofthe present invention. The following fonnulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, rectal, and vaginal administration are merely exemplary and are in no way limiting.

Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount ofthe compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, s, lozenges, and troches, each containing a predetennined 5184l-NZ 00JOJ-WO amount of the active ient, as solids or granule; (c) powders; (d) suspensions in an appropriate liquid; and (c) le emulsions. Liquid formulations may include diluenlS, such as water, cyclodextrin. dimethyl sulfoxide and alcohols, for ex.ample, ethanol, benzyl l, propylene glycol, glycerin, and the polyethylene ls including polyethylene glycol, either with or without the addition ora pharmaceUlicaily acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be oflhe ordinary hard~or soft· shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and com . Tablet forms can include one or more ofthe following: lactose, sucrose, mannitol, com starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc. magnesium stearate, calcium stearate, zinc stearate, c acid, and other excipients, colorants, diluents, buffering agents, disintegrating agems, moistening , preselvatives, flavoring agents, and pharmacologically ible carriers. Lozenge forms can comprise the active ingredient in a , usually sucrose and acacia or tragacanth, as well as les comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acadia, emulsions, and gels containing, the addition to the active ingredient in an inert base, such as gelatin and glycerin, or e and acadia, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.

The tives ofsulindac alone or in combination wilh other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized accepTable propellants, such as rodifluoromethane, e, and nitrogen. They also may be fonnulated as pharmaceuticals for non-pressured preparations, such as in II nebulizer or an atomizer.

Formulations suitable for parenteral administration include aqueous and non~aql1eous, iSOIonic sterile injection solutions, which can contain 8nti~oxidants, buffers, bacteriostats, aoo solutes that render the fommlalion isotonic with the blood of the intended ent, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents. stabilizers, and vatives. The compound can be administered in II physiologically acceptable t in a pharmaceutical carrier, such as a sterile liquid or mixture of s, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol such as poly(ethyleneglycol) 400, glycerol ketals, such as 2,2- dimethyl-I, 3-dioxolanemethanol, ethers, an oil, a fatty acid, a fany acid ester or glyceride, 21381WQ or an acetylated fatty acid glyceride with or without the on ofa pharmaceutically acceptable surfactant, such as a soap or 8 detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcelluslose, or emulsifying agents and other pharmaceutical adjuvants.

Oils, which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, com, olive, petrolatum, and mineral. Suitable fll.tty acids for usc in parenteral fomlulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristale are examples ofsuitable fatty acid . Suitable soaps for use in parenteral formulations include fany alkali metal, ammonium, and triethanolamine salts, and le detergents include (a) ic detergents such 8.<;, for example. dimethyldialkylammonium halides, and alkylpyridinium halides, (b) anionic detergents such as, for e, alkyl, aryl, and olefin sulfonates, alkY,1 olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) non ionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene opylene copolymers, (d) amphoteric ents such as, for examplc, alkyl B-aminopropionates, and limidazoline quaternary ammonium salls, and (e) mixtures thereof.

The parenteral formulations typically contain from about 0.5% to about 25% by weight ofthe active ingredient in on. Suitable preservatives and buffers can be used in such fonnulations. In order to ze or ate irritation at the site of injection, such compositions may contain one or more nonionic sunactants having a hile-lipophile balance (HLB) offrom about 12 to about 17. The quantity ofsurfactant in such formulations ranges from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters. such as sorbitan monooleate and the high molecular weight Il.dducts ofethylene oxide with a hydrophobic base, fonned by the condensation of propylene oxide with propylene glycol.

Pharmaceutically acceptable excipicnts are also well-known to those who are skilled in the an. The choice ofexcipient wilt be ined in part by the particular compound, as well as by the pal1icular method used to administer the composition. ingly, there is a wide variety ofsuitable formulations of the ceutical composition of the present disclosure. The following methods and excipients are merely exemplary and are in no way limiting. The phannaceutically acceptable excipients preferably do not ere with the action of lhe active ingredients and do not cause adverse side-effects. Suitable carriers and 21381·00101-WO excipients include solvents such as water, alcohol, and propylene glycol, solid absorbants and diluents, surface active agents, suspending agent, tableting binders, lubricants, flavors, and coloring agents.

The formulations can be ted in unit-does or multi-dose sealed containers, such as s and vials, and can be stored in a freeze..dried (lyophilized) condition requiring only the addition ofthe e liquid excipient, for example, water, for injections. immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, es, and s. The requirements for effective pharmaceutical carriers for injectable compositions arc well known to those of ordinary skill in the an. See Pharmaceulics and Pharmacy Practice, J.B. Lippincon Co., Philadelphia, PA, Banker and Chalmers, Eds., 238-250 (1982) and ASHP Handbook on Injec/able Drugs, Toissel, 4lb ed., 622-630 (1986).

Formulations suitable for topical administration include lozenges comprising the active ingredient in a flavor, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes sing the active ingredient in a suitable liquid carrier; as wel1 as creams, emulsions, and gels containing, in addition to the active ingredient, such rs as are known in the art. onally, formulations suitable for rectal administration may be presented as suppositories by mixing with a variety of bases such as emulsifying bases or water·soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray as containing, in addition to the aclive ingredient, such rs as are known in the an 10 be appropriate.

One skilled in the art will appreciate lhat suitable methods of exogenously stering a compound oflhe present disclosure to an animal are available, and, although more Ihan one roule can be used to ster a particular compound, a particular route can provide a more immediate and more effective reaction than aoother route.

The present disclosure further provides a method oftreating precancerous conditions or dysplosia (i.e. - intraepithelial neoplasia) as well as cancer in a mammal, especially humans. The melhod ses administering an ive ent wnount ofa derivative ofsulindac disclosed above to the mammal.

As regards Illest: applicalions, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, ofa eutically effective 5184L-NZ 2J381WO amount ofthe compound effective in the inhibition lasia and tumor growth and treating malignant disease including metastases, especially colorectal cancer. The method also includes the administration ofa therapeutically effect amount ofthe compound for the treatment ofand precancerous lesions such as adenomatous polyps ofthe colon and other dysplastic lesions ofthe skin (actinic keratosis), r, cervix, esophagus, oral . lung, prostate and breast sometimes referred to a::; intracpithclial neoplasia.

The disclosed compounds and compositions can be administered to treat a number of s, including leukemias and lymphomas such as acute lymphocytic leukemia, acute nonlymphocytic leukemias, c cytic leukemia, chronic myelogenous leukemia, Hodgkin's e. non-Hodgkin's lymphomas. and multiple myeloma, childhood solid tumors such as brain tumors, lastoma, retinoblastoma, Wilms Tumor, bone tumors, and soft-tissue sarcomas, common solid tumors ofadults such as lung cancer. breast cancer, prostate cancer. urinary cancers, uterine cancers, oral cancers, pancreatic cancer, melanoma and other skin s, stomach cancer, ovarian cancer, brain , liver cancer, laryngeal cancer, thyroid cancer, esophageal cancer, and testicular cancer.

The present disclosure also s to treating cenain chronic matory conditions which NSAIDs have shown benefit, but may be contraindicated due to cyclooxygenase inhibition (i.e. - inflammatory bowel disease) or do not appear (0 require cyclooxygenase inhibition for efficacy such as certain neurodegenerative diseases. including Alzheimer's e. Still there are additional disease indications that benefit from treatment with NSAIDs, which can also be treated or prevented with compounds described in the present sure.

The dose administered to an animal, particularly a human, in the context of the present ion should be sufficient to affect a therapeutic response in the animal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety oHactors including the condition ofthe animal. the body weight of the animal, as well as the severity and stage oflhe cancer.

A suitable dose is thai which will result in a concentration ofthe active agent in tumor tissue which is known to affect the desired response. The preferred dosage is the amount which results in maximum inhibition ofcancer, without unmanageable side effects.

TIle (otal amount of the compound ofthe present disclosure administered in a typical treatment is ably between about 10 mglkg and about 1000 mglkg of body weight for mice. and between about 100 mglkg and about 500 mglkg of body weight, and more 5184l-NZ 21381-00101·WO preferably between 200 mglkg and about 400 mglkg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series ler doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.

The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent orany adverse side effects thai might accompany Ihe administration ofthe compound and the desired logical effect. It will be appreciated by one ofskill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.

The method disclosed comprises r administering ofchemotherapeutic agent other than the derivatives of the present invention. Any suitable chemotherapeutic agent can be employed for this purpose. The chemotherapeutic agent is lly selected from the group consisting ofalkylBting agents, anti metabolites, l products, anti-inflammatory , hormonal agents, molecular targeted drugs, anti-angiogenic drugs, and miscellaneous agents.

Examples ofalkylating chemothcrapeutic agents include carmustine, chlorambucil, cisplatin, ine, cyclophosphamide, melphalan, mechlorethamine, bazine, thiotepa, uracil mustard, triethylenemelamine, busulfan, pipobroman, streptozocin, ifosfamide, azine, carboptatin, and hexamethylmelamine. es ofchemotherapeutic agents that are antimetaboJites include cytosine arabinoside fluorouracil, gcmcitsbinc, mercaptopurine, methotrexate, thioguanine, floxuridine, fludarabine, and c1adribine.

Examples of chemotherapeutic agents that are natural ts include actinomycin D, bleomycin, camptothecins, daunomycin, doxorubicin, etoposide, mitomycin C, paclitsxcl. redocctaxel, tenisposide, stine, vinblastine, lbine, idarubicin, mitoxantrone, mycin and deoxycoformycin.

Examples of hormonal agents include estrogen receptor antagonists such as tamoxlfen and fluvestrant, aromatase inhibitors such as anastrozole, androgen receptor antagonists such as cyproterone and flutamine, as well as gonadotropin release hormone agonists such as leuprolide. Examples ofanti-inflammatory drugs include corticoids such as prednisone, and nonsteroidal anti·inflammatory drugs such as sulindac or celecoxib.

Examples of molecular targeted drugs include monoclonal antibodies such as rituximab, 5184l-NZ 21381-00101~WO cetuximab, lrastuzumab and small molecules such as imatinib, erlotinib. ortizumib.

Examples ofanti-angiogenic drugs include thalidomide and bevacizimab. Examples of the aforesaid miscellaneous chemotherapeutic agents include mitotane, arsenic trioxide, oin, thalidomide, levamisolc, raginase and hydroxyurea.

Exemplary embodiments ofthe present disclosure include: Embodiment A: Compound represented by the formula: wherein each of Rot and ~ is selected from the group consisting ofH, alkyl. a substituted or unsubstituted 5 or 6 member ring, provided that at least one ofR.. and Rj is other than H; and when both R~ and Rj are a substituted or unsubstituted 5 or 6 member ring. both of~ and R$ are a substituted or unsubstituted pyridyl ring; ~is a tuted or unsubstituted 5 or 6 member ring; X is a halogen; and phannaceutically acceptable salts f. prodrugs thereof, solvates thereof and mixtures thereof.

Embodiment B: The compound ofEmbodiment A being represented by the following fonnula: , pharmaceutically acceptable salts thereof, gs thereof, solvatcs thereof and mixtures Ihereof. 5184l·NZ 21381WO Embodiment C: The compound ofEmbodimenl A being represented by the following fannula; pharmaceutically acceptable salts thereof, prodrugs thereof, solvales thereof and mixlUres Embodiment 0: The compound of Embodiment A being represented by the following formula: NY • pharmaceutically acceptable salls thereof, prodrugs thereof, solvates thereof and es thereof.

Embodiment E: The compound ofEmbodiment A being represented by the ing formula: 21381WO NH~O phannaceuticalty able salts thereof, prodmgs thereof, solvates thereofand mixtures thereof.

Embodiment F: The compound ofEmbodiment A represented by the following CHJ V phannaceutically acceptable salls thereof, prodrugs thereof, solvales thereofand mixtures thereof.

Sl84l-NZ 21381·00101·WO Embodiment G: TIle compound of Embodiment A being represc!lted by the following formula: pharmaceutically acceptable salts thereof, prodrugs thereof, solvates thereofand mixtures Embodiment H: The nd of Embodiment A being represented by the following formula: pharmaceufically acceptable salls f, prodrugs thereof, solvates thereofand mixtures thereof. 5184l-NZ 21381·00101·WO Embodiment I: The compound of Embodiment A being represented by the following fannula: ",co "' OC", pharmaceutically acceptable salls thereof, gs thereof, solvates thcrcofand mixtures thereof.

Embodiment J: The compound of ment A being represented by the following formula: 5184L-NZ 21J81WO pharmaceulically acceptable salts thereof, prodrugs thereof, solvates thereofand mixtures then:of. ment K: The compound of Embodiment A being represented by the following formula: pharmaceutically acceptable salls thereof, gs thereof, solvates thereof and mixtures Ihereof. 5184L·NZ 2IJ81·00101·WO Embodiment L: A compound being represented by the following fannula: phannaceutically acceptable salts thereof, prodrugs thereof, solvates Ihereofand mixtures thereof.

Embodiment M: The compound dimenl A being represented by the following (onnull,: phannaceutically acceptable salts thereof. prodrugs thereof, solvates thereofand mixtures 5184l-NZ 21381WO Embodiment N: A ceulical composition comprising a nd represented by the formula: wherein each of R... and Rs is selected from the group consisting ofH, alkyl, a substituted or unsubstituted 5 or 6 member ring, provided that at least one of ~ and Rs is other than H; and when both R~ and Rs are a substituted or unsubstitutcd 5 or 6 member ring, both of R... and Rs are a substituted or unsubstituled pyridyl ring; Rt. is a substituted or unsubstituted 5 or 6 member ring; and X is a halogen; and/or a nd according to anyone of Embodiments A-M, pharmaccutically acceptable salls thereof. prodrugs thereof, solvates thereof and mixtures thereof; and a pharmaceutically acceptable carrier.

Embodiment 0:. A method of treating a precancerous condition or cancer in a mammal comprising adminislering 10 the mammal an effective treatment amount ofa compound ented by the a: wherein each of~and R$ is selected from the group consisling ofH, alkyl, a substituted or unsubstituted 5 or 6 member ring, provided that at least one ofR... and R$ is other than H; and when both Rot and R$ are a substituted or unsubstitutcd 5 or 6 member ring, both of~ and R, are a substituted or unsubstituted pyridyl ring; R6 is a tuted or unsubstituted 5 or 6 member ring; and X is a n; and/or a compound aecording to anyone ofEmbodiments A-M. phannaceulically acceptable salts thereof. prodrugs thereof, solvates thereof and mixtures thereof. 21381·00101·WO Embodiment P: A method for treating a patient with a chronic inflammatory disease, which comprises administering to the t an effective treatment amount ofa compound represented by the formula: wherein each of~ and Rs is selected from the group consisting ofH, alkyl. a substituted or unsubstituted 5 or 6 member ring, provided that at least one of~ and Rs is other than H; and when both ~ and Rj 8re a substituted or unsubstituted 5 or 6 member ring, both of~ and R, are a substituted or unsubstituted pyridyl ring; ~is a substituted or unsubstituted 5 or 6 member ring; and X is a halogen; and/or a compound according to anyone ofEmbodiments A·M, pharmaceutically acceptable sails thereof, gs f, solvales thereof and es thereof.

Embodiment Q: The method according to Embodiment P, wherein the chronic inflammatory disease is inflammatory bowel disease.

Embodiment R: A method for treating a patient having a neurodegenerative disease, which ses administering to the patient an effective treatment amount ofa compound represented by the fonnula: n each of ft4and Rs is selected from Ihe group consisting of H, alkyl, a tuted or ullsubstituted 5 or 6 member ring, provided that alleast one of~ and R~ is other than H; and when both ~ and Rs are a substituted or unsubslituted 5 or 6 member ring, both ofR.. and Rs are a substituted or unsubstillJled pyridyl ring; ~ isa substituted or unsubstituted 5 or 6 member ring; and 5184L-NZ 21J81WO X is a halogen; andlor a compound according to anyone of Embodiments A-M, pharmaceutically acceptable salts thereof, prodrugs thereof, es thereof and mixtures thereof.

Embodiment S: TIle method ing 10 Embodiment R, wherein the neurodegenerative disease is Alzheimer'sdisease.

Embodiment T: A method for preparing a compound according to anyone of Embodiments A-K and M which comprise converting an ester ndac or a derivative therefore represented by the following formula: , 0- wherein Ar is a substituted or unsubstiluted 5 or 6 member ring compound to obtain an aldehyde represented by the following fonnula; , " reacting the de with ammonia or an amine represented by R.R}NH, wherein each R.. and R} is at least one member selected from the group consisting ofH, alkyl. a substituted or unsubstiluted 5 or 6 member ring; and when both R. and R$ are a substituted or unsubstituted or 6 member ring, both of R.t and R} are a substituted or unsubstitUied pyridyl ring.

The term "comprising" (and its grammatical ions) as used herein is used in the inclusive sense of"having" or "including" and not in the exclusive sense of"consisting only of." The terms "a", "an" and "the" as used herein are understood to encompass the plural as welt as the singular, unless indicated otherwise.

The foregoing description rates and describes the disclosure. Additionally, the disclosure shows and bes only the preferred ments but, as mentioned above. it is 5184l-NZ 21J81·1lO10\·WO to be understood thaI it is capable to use in various other combinations, cations, and environments and is capable orchanges or modifications within the scope orlhe invention concepts as expressed herein, commensurate with the above teachings and/or the skill or knowledge orlhe nt art. The embodiments described herein above are further intended explain best modes known by ant and 10 enable others skilled in the arllc utilize the disclosure in such, or other, embodiments and with the various modifications required by the ular applications or uses thereof. Accordingly, the description is not intended to limit the ion to the fonn disclosed herein. Also, it is intended to the appended claims be construed 10 include altemative ments.

All publications and patent ations cited in this specification are herein orated by reference, and for any and all purposes, as ifeach individual publication or patent application were specifically and dually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls.

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Treatment ofcolonic and rectal as with sulindac in familial adenomatous polyposis. N EnglJ Mcd 1993;328; 1313-6. 6. Rigas B, Goldman IS, Levine L. Altered eicosanoid levels in human colon cancer. J LabClin Med 1993; 122; 518-23. 5184L-NZ 21381-00IOI-WO 7. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, bach S, DuBois RN. Upregulation ofcyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. enterology 1994: 107: 1183-8. 8. Hwang DH, Fung V, Dannenberg AJ. National Cancer Institute workshop on chemopreventive properties of nonsteroidal anti-inflammatory drugs: role ofCOX- dependent and -independent mechanisms. Neoplasia 2002; 4: 91-7. 9. Rigas B, Kashfi K. Cancer prevention: a new era beyond cyclooxygenase-2. J Pharmacol Exp Ther 2005; 314: J-8.

. Albel1s OS, Hixson L, Ahnen D, Bogert C, Einspahr J, Paranka N, et a!. Do NSAIDs exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin tase? J Cell m Suppl 1995; 22: 18-23.

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Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by ng apoptosis. Cancer Res 1995; 55: 3110-6. 12. Piazza GA, Rahm AK, Finn TS, Fryer BH, Li H, Stoumen AL, et a!. Apoplosis primarily accounts for the growth-inhibitory properties ofsulindac metabolites and involves a ism that is independent ofcyclooxygenase inhibition, cell cycle arrest, and p53 induction. Cancer Res 1997; 57: 2452-9. 13. Piaz:t.8 GA, Alberts DS, Hixson U, Paranka NS, Li H, Finn T, et al. Sulindac sulfone inhibits azoxymethanc-induced colon ogenesis in rats without ng prostaglandin levels. Cancer Res 1997; 57: 5. 14. Charalambous 0, O'Brien PE. Inhibition ofcolon cancer precursors in the rat by sulindac sulphone is not dependem on inhibition of prostaglandin synthesis. J Gastroenterol Hepatol 1996; 11: 307-10.

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Chemopreventive efficacy ofsulindac sulfone against colon cancer depends on time ofadministration during carcinogenic process. Cancer Res 1999; 59: 3387-91. 16. Stoner GO, Budd GT, Ganapathi R, g B, Kresty LA. Niten M, et at. Sulindac sulfone induced regression of rectal polyps in patients with familial adenomatous polyposis. Adv Exp Moo Bioi 1999; 470: 45-53. 17. Arbcr N, Kuwada S, Leshno M, l R, Hultcrantz R, Rex D. Sporadic adenomatous polyp regression with ex.isulind is effective but toxic: a randomised, double blind, placebo controlled, dose-response study. Ou12006; 55: 367-73. 5184l-NZ 21381WO 18, Huang ES, Strate LL, Ho WW, Lee SS, Chan AT. Long-tenn use of aspirin and the risk ofgastrointestinal bleeding. Am J Me<! 2011; 124: 426-33. 19. Mukherjee 0, Nissen SE, Topol EJ. Risk ofcardiovascular events associated with selective COX-2 inhibitors. Jama 2001; 286: 954-9.

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Sulindac inhibits beta--catenin expression in -appearing colon ofhercditary nonpolyposis colorectal cancer and familial atous polyposis patients. Cancer Epidemiol Biomarkers Prev 2005; 14: 1608-12. 21. Boon EM, Keller JJ, Wormhoudt TA, Oiardiel1o FM, OfTerhaus OJ, van def Neut R- et a!. Sulindac largets nuclear beta~catenin accumulation and Wnt ling in adenomas of patients with familial adenomatous polyposis and in human ctal cancer cclliines. Sr J Cancer 2004; 90: 224-9. 22. Rice PL. Kelloff J. Sullivan H. Driggers LJ. Beard KS, Kuwada S, et a1. Sulindac lites induce caspase- and proteasome-dependent degradation ofbeta-caten in protein ill human colon cancer cells. Mol Cancer Ther 2003; 2: . 23. Thompson WJ, Piazza GA, Li H, Liu L, Fetter J, Zhu a, et ai, Exisulind induction of apoptosis involves guanosine 3',5'-cyc1icmonophosphate odiesterase inhibition, protein kinase G activation, and attenuated beta-catenin. Cancer Res 2000; 60: 3338-42. 24. Clapper ML, Coudl'y J, Chang we. beta-catenin-mediated signaling: a molecular target for early chemopreventive intervention. Mutat Res 2004; 555: 97-105.

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Claims (9)

Claims 1.

1. A compound ed from the group ofcompounds represented by the following formulae: 5184L-NZ -8'\\ .---0 pharmaceutically acceptable salts thereof, solvates thereof and prodrugs f wherein the prodrugs are formed at hydroxyl or amino functionalities.

2. A ceutical composition comprising a compound according to claim 1, pharmaceutically acceptable salts thereof, solvates thereof and gs thereof wherein the prodrugs are formed at hydroxyl or amino functionalities; and a pharmaceutically acceptable carrier.

3. Use ofa compound selected from the group ofcompounds represented by the following formulae: 5184L-NZ NH~O pharmaceutically acceptable salts thereof, solvates thereof and prodrugs thereof wherein the prodrugs are formed at hydroxyl or amino functionalities; in the manufacture ofa medicament for treating a cancerous or precancerous condition. pharmaceutically acceptable salts thereof, solvates f and mixtures thereof.

4. The use m 3 wherein the medicament is administered orally, intravenously or intraperitoneally.

5. Use ofa compound selected from the group of compounds represented by the following formulae: 5184L-NZ NH51 NH~O ___0 pharmaceutically acceptable salts thereof, es thereofand prodrugs thereofwherein the prodrugs are formed at hydroxyl or amino functionalities; in the manufacture of a medicament for treating a chronic inflammatory disease.

6. The use ing to claim 5, wherein the chronic inflammatory disease is matory bowel disease.

7. Use ofa compound selected from the group ofcompounds represented by the following formulae: 5184L-NZ ___0 pharmaceutically acceptable salts thereof, solvates thereof and gs thereof wherein the prodrugs are formed at yl or amino functionalities; in the manufacture of a medicament for treating a neurodegenerative disease.

8. The use according to claim 9, wherein the neurodegenerative disease is Alzheimer's disease.

9. A method for preparing a compound ofclaim I which comprise ting an ester ofsulindac or a derivative therefore represented by the following formula: 5184L-NZ wherein Ar is a substituted or tituted 5 or 6 member ring compound to obtain an aldehyde represented by the following formula; Ar Ar reacting the aldehyde with ammonia or an amine represented by ~RsNH, wherein each R4 and Rsis at least one member selected from the group consisting ofH, alkyl, a substituted or unsubstituted 5 or 6 member ring; and when both ~ and Rsare a substituted or unsubstituted 5 or 6 member ring, both ofRt and Rsare a substituted or unsubstituted pyridyl ring. Dated this 27th day ofAugust 2015 SOUTHERN RESEARCH INSTITUTE FRASER OLD & SOHN Patent eys for the Applicant 5184l-NZ WO 20121135650 peTIUS