NZ623381B2 - Oral immediate release formulations for substituted quinazolinones - Google Patents

Abstract

Disclosed are oral immediate release solid pharmaceutical formulations comprising a quinazolinone as an active ingredient and (i) from about 10% w/w to about 85% w/w of microcrystalline cellulose; (ii) about 4% w/w of sodium starch glycolate as a disintegrant; (iii) about 0.5% w/w of magnesium stearate; and (iv) about 2.5% w/w of colloidal silicon dioxide as a glidant. The pharmaceutical formulations are useful for regulating the expression of apolipoprotein A-I (ApoA-I) and as BET inhibitors, for the treatment and prevention of cardiovascular disease, and cholesterol- or lipid-related disorders, including, for example, metabolic syndrome, inflammatory disease, Alzheimer's disease, atherosclerosis, diabetes, and cancer. The pharmaceutical active ingredient is selected from: 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5, 7 -dimethoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; ate; and (iv) about 2.5% w/w of colloidal silicon dioxide as a glidant. The pharmaceutical formulations are useful for regulating the expression of apolipoprotein A-I (ApoA-I) and as BET inhibitors, for the treatment and prevention of cardiovascular disease, and cholesterol- or lipid-related disorders, including, for example, metabolic syndrome, inflammatory disease, Alzheimer's disease, atherosclerosis, diabetes, and cancer. The pharmaceutical active ingredient is selected from: 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5, 7 -dimethoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

Description

Oral ate Release Formulations For Substituted Quinazolinones Epidemiologic data demonstrate an inverse onship n circulating levels of high density lipoprotein cholesterol (HDL-C) and the incidence of clinically significant atherosclerosis. Each 1 mg/dl increment in the HDL—C serum level is associated with a 2—3% decrement in cardiovascular risk; a 1% reduction in LDL—C reduces coronary heart disease (CHD) risk by 2% (Gordon et al. (1997) Am. J. Med. 62, 707—714). mental evidence further supports the protective effect of HDL—C against cardiovascular disease. For example, in subjects with low HDL—C, administration of gemfibrozil results in a 6% increase in the HDL-C level and a corresponding 22% reduction of the CHD risk (Rubins et al. (1999) N. Engl. J. Med. 341, 8). Observations in genetic disorders associated with low HDL-C due to reduced ApoA-l expression, also indicate the link between elevated risk of CHD and low HDL-C.

HDL-C appears to exert its anti-atherogenic effect by mediating reverse cholesterol transport (RCT), in which cholesterol is recruited from peripheral tissues and transported to the liver. In addition, HDL—C also exerts nflammatory and anti— oxidant effects and es fibrinolysis. HDL-C particles protect against oxidation of LDL, an important l step in promoting cholesterol uptake by arterial macrophages.

HDL-C exists in two main forms, one ning both apolipoprotein A—l (ApoA—l) and apolipoprotein A-ll (ApoA—ll), and the other containing ApoA—l without ApoA-ll (Schultz et al. (1993) Nature 365, 762-764). The cardioprotective effect of HDL—C is mostly, but not exclusively, attributable to ApoA-l.

Clinical and experimental data suggest that the production of ApoA—l is a critical determinant of circulating HDL—C. For e, persons with familial WO 64900 hyperaiphaiipepreteinemia (eievated Ape/{tut} appear to be ted from atheroscieresis, white these ent in ApeAnt (hypeaiphaiipcprcteinernia) show rated cardiavascuiar disease. in addition, varieus experimentai manipuiaticns in increase production at ApcA~i are asseciated with reduced athercgenicity. Fcr exarnpie, human ApoA-i is ’tive in transgenic animai rncdeis (Shah et at. (1998) Circniaticn 9?, 7805785; Rubin at ai. (1991) Nature 353, 265~26?), and treatment with Apart—imam ts athercscterctic iesicns and Heads to regression of athercscierctic piaques in human patients (Nissan et ai. {2603) JAMA ass, 2292—2300): Further tines of research trate that ApeA~i piays a rate in enhancing reverse cheiesterci ort, attenuating cxidative stress, increasing paracxcnase activity, enhancing anticaageiant activity, and increasing anti— inflammatory activity (Andersscn (199?) Curr. Opin, Lipidci. 8, 225—228).

Accerdingiy, ApcAmi is an attractive target for therapeutic interventicn i004} Currentiy avaiiapie therapeutic agents that increase the piasrna ocncentratien ct ApcA—i, fer exampie, recombinant ApcAmi er peptides that mimic ApcA—i, have pctentiai drawbacks with t tc, e.g., stabiiity during storage, detivery of active product, and in viva hait—iifeu Thus, smaii rnciecuie cornpcuncis that tip-reguiate the preducticn ct endegeneus ApcA—i, such as, for exempts, upn ters ct ApeA~i expression, wcuid be very attractive as new therapeutic agents for cardicvascuiar disease. {005} One ciass ct cempeunds that are thought tc contribute to the prevention at various diseases, ing cancer and cardicvascuiar disease, is pciyphencis. Peiyphenets are present in meat iced and beverages at piant origin and are the most abundant dietary anticxidants (Scaihert it Wiiiianiscn (2009) J.

Nutr: 13%, 2073320858). ever, the protective properties of poiypheneis have “2 a. 2012/002721 not been iuiiy reaiized due to poor bioavaiiabiiity (Mensch et ai. {2905) Am. J. Ciin.

Nutr. at, 2303—2423), tack of ciinicei significance in various reported studies ing them (Wiiiiamson 8: Manach (2005) Am. J. Ciin. Nutr. 81, 24382553), and deieterious effects at higher dose concentrations. For exampieg an nt and avaiiabie source of resveratroi, a weii known stiibene ooiyphenoi, is red wine (Wu et; a1. (2001} int. J. Moi. Med. 3, 347). However, red wine cannot be consumed in therapeuticeiiy efficacious quantities on a deity basis due to the numerous weii documented deieterious effects of ive aicohoi consumption. The effects of resveratroi may be better or safer in the absence of aioohoi. {006] Severai human ciinicai studies invoiving the antioxidant effect of various ooiyphenois in various foods or beverages? have faiied to demonstrate an unequivocai benefit with respect to primary ciinicai endpoints, such as ive stress, a, and inflammation (Wiiiiamson 81 Mensch (2005) Am. J. Ciin. Nutr. St, 2438—2558). For examoie, out ottweive recent intervention studies with differing poiyphenoi sources, six showed no effect on iipid ters and six showed an improvement in the iipid parameters (Mensch (ZGOS) Curr. Gain. Lipidoi, “id, 737—84).

Such inconciusive data has d the potentiai use of enois, despite their many beneficiai properties. {00?} The use of naturaiiy occurring enois as potentiai therapeutics has aiso been impeded by the inabiiity to achieve efficacious ieveis in the body, parity due to poor bioavaiiahiiity (Manach et el. (2005) Am. J. Ciin. Nutr. 81, 23iLiSw 2428). The bioavaiiabiiity of any given poiyphenoi varies wideiy (from t~26%) in different individueis. This variabiiity is aiso seen with administration of different poiyphenois to the same individuai due to differences in absorption, iism, and excretion rates. For exampie, poiyphenoi fiavonoids, such as ouercetin, have been 2012/002721 reported to have iess than 1% inai absorption toiiowing orai administration (Gugier at at. (19775) Eur. J. Ciirr Pharm. 9, 2294334). in addition, some poiyphenoi metahoiites are known to negativeiy intiuence the hioiogicai activity of the parent compounds h et at. (2065) Am. J. Ciin. Nurr. at; 428). Such metahciites otteh differ from the parent compound in terms of toxicity, efficacy, and iength of residence in the piasma. Another iimiting factor is the poor soiubiiity of many poiyphenois that iimits the potentiai routes of strationw These and other factors have made it difficuit to determine appropriate dosages of the naturaiiy occurring noiyphenois, naringenin or resveratroi, for use in humans {308} Thus, there exists a need for poiyohenoidike compounds to he deyeiooed as therapeutic agents for the treatment and prevention of cardiovascuiar disease and reiated diseases, oarticuiariy, choiesteroin or iipid~reiated disorders, such as, for examoie, atheroscierosis. it is therefore one of the s of the present disciosure to provide nds that up—reguiate the expression of ApoAdu in addition, the compounds may have more favorabie pharmaeoiogicai properties than naturaiiy occurring poiyohenois. {(3053} Cancer is a group of diseases caused by dysreguiated ceii oroiiteration. Therapeutic approaches aim to decrease the numbers of cancer ceiis by inhibiting ceii repiication or by inducing cancer ceii differentiation or death, but there is stiii significant unmet medioai need for more efficacious therapeutic agents.

Cancer ceiis iate genetic and epigenetic changes that aiter ceii growth and metaboiism in order to promote ceii proiiferation and increased resistance to programmed ceii death, or apoptosis. Some of these changes inciude inactivation of tumor suppressor genes, activation of oncogenes, as wait as modifications of the reguiation of chromatin structure. Watson, Cancer Discovery 80 (2911); Morin et at, Nature 476:293303 (201 t). [010} Many cations of histories in chromatin have been characterized, ing acetyiation at moitipie iysinee in hietones H3 and H4. Peserieo and Simone, J“ Biomed, Biotechnoi. 2911371832 {201i}. Histone acetyiation is oontrciied by acetyiaeee (HATS) ae weii as deacetyiaeee (HDACs), and smeii moiecuie HDAC inhibitors have been deveiooed with cancer as an tion” Hoehino and Mateuhara, Sure. Today/402809815 (2010). Hietone acetyiation controis gene expression by recruiting protein compiexee that hind directiy to acetyiateci iyeine via eromooomains. Sanchez and Zhoo, Curr. Opin. Drug Discov.

Bevel, 12(5):659~665 (2609). One such famiiy, the hrornoriornain and extra terminai domain (BET) proteins, comprises BrdZ, Brci3, Bret-4, and Brett" each of which contains two hrornociornaine in tandem that can independentiy bind to ateci iyeinee. Wu and , J. Bioi, Chem. 282(18):t3141~13145 (260?). BET ns exert some of their effects on transcription by recruiting the poeitive ription eiongation factor b (meEFh), which stimuiatee transcription eiongation by phosphoryiating the Caterminai domain of RNA noiymerase ii and reeuits in increased expression of growth ing genes, such ae, e.g., c~Myc and the wait estahiished cancer target Aurora 8. Fiiipnakooouioe et at, Nature 468:10674073 (2010). {011} Moiecoiee that bind to BEE" ns and prevent them from binding to chromatin, inhibit transcription and prevent ceti repiioation, which is usetoi in cancer therapy and other Settings. For exampie, it has been shown that BET proteins; can he dispiaced from the chromatin hy emaii moiecuie inhibitors, such as, e.g., JQt, i~ BET, and i—BET’SS’E, which icaiiy compete with the acetyi—iyeine binding pocket of the BET protein bromodomains y preventing transcription eiongation of their target genes. Fiiinpakopoutos et ai. (2016); Nicodeme et at, Nature 488:1119—1123 (2615); Bawson et at, Nature 478:529—533 (2011). [012} inhibition of BET bromodornainuprontoter ctions s in a subsequent reduction of myc ription and protein ieveist This resuits in Gt arrest and extensive apostosis in a variety of ieukernia and orna ceii tines Mart}: et at, PNAS ):16t-359~16674 ( 2911). The Mvc famiiy of proto~ oncogenes (cwmyc, i—myc, ) is activated in 25—35% of aii human cancers. Vita and Henrickson, Seminars in Cancer are. 15:318w33fi (2066). Mouse rnodeis of cancer driven by overexpression of c-rnyc demonstrate that entiy inhibiting cw myc expression can cause turner regression, ceii death, and in some cancers such as teukernia, compiete disease remission Scucek et at, Nature 4552679683 (2008). The absence of a ciear iiganciwbinciing domain of curriyc has matte the deveienn‘ient of an inhibitor a formidabie chaiienge, thus atternative strategies to targeting owrnyc transcription must be deveioced. Deirnore et ail, Ceii 146904—9317 (3201 t). A mouse rnodei of aggressive human meduiichiastoma, in which curriyc is everexpressedi suggests that BET inhibitors may be usefui for treating myc—arnoiifieo obiastoma. Kawauchi et ai., Cancer Ceiithtt38~18t3 (2012); Pei et at", Cancer Cat! 21 :155-«167 (2012)“ Simiiariy. inhibition of n~rnyc through RNA interference significantiy reduced tumor growth in neurohiastorna mouse mode-is.

Jiang et at, Biochem. Biopns. Res. Commun. 410:364«3?0 (2011)., A simiiar roie for i—rnyc was ted in srnaii ceii iung carcinoma ceii tines using antisense eiigonucieotides to inhibit i—myo amoiification. —Akita et at, Cancer Res. 552155394564 (19535). Therefore BET inhibitors have potentiai to be efficacious in treating rnuitipie types of cancer. [0i3i in tact, smaii ies that target the bromodomains of BET tarnity members have demonstrated potentiai therapeutic use in ng cancer. See, e.g., Dawson et at. (201 1), showing that a smaii moiecoie inhibitor of the BET tamiiy has a profound efficacy against human and murine mixed iineage ieukemia (MLLi—tusion ceii tines by eariy ceii cycie arrest and aooptosis. its mechanism of efficacy is the seiective abrogation of Brd3/4 recruitment to chromatin. BET inhibitor JQ’i has trated potent mor activity in murine aott modeis of NUT (nuciear protein in testis) midiine carcinoma (Nit/iii), a rare but ietnai term of cancer“ NMC tumor ceii growth is driven by a transiocation of the Brdit gene to the notiin 1 gene.

Fiiiopakopouics et at, (zero). JQt was aiso shown to he a potent antiproiiterator in moitipie a, associated with ceii cycie arrest and ceiiuiar senescence.

Deimore et at. (2911). [014} BET inhibitors are aiso expected to be potentiai therapeutics for other types of cancer For e, in acute myeioid ieuiremia (AML), Bide is required to n myc expression and continued disease progression. Zuoer et at, Nature 4?8:524~8 (2011)“ Moreover, vation of Brdéi resutts in a rapid and drastic downn reguiation of the transcription of the prom-oncogenes c—myc and nfimyc in ceii tines they are amoiitied. Dawson et at. (2011); Deimore et at. (26311); Zuber et at. {2011); Mertz et at. (2011) Conseotientiy, ent of tumors that have activation of c—rnyc with a BET inhibitor resuited in tumor regression through inactivation of ornyc transcription. BET inhibitors are aiso expected to have appiication in moitioie myeioma, as the mnitioie myeiorna SET domain {Mt/SET) which is impiicated in this disease aiso binds to BET proteins. Dawson et at. (2611). [015} in addition to cancer, BET inhibitors are aiso expected to have have antinintiammatory and immunomoduiatory properties. Lamotte et at, Bioorganic 8: Med. Chem. Letters (February 24, 2012); Prinjha et al., Trends Pharmacol. Sci. 146- 153 (2012). BET inhibitors l-BET and l—BET151 decrease lL-6 expression in vivo. I-BET was shown to confer protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis and l—BET151 was shown to suppress bacterial—induced inflammation and sepsis in a murine model. Nicodeme et al. (2010); Lamotte et al.(2012).

In addition, BET inhibitors may modulate responses to viral and bacterial infections, including HlV, herpes, and papilloma viruses. [015a] Definitions of the specific embodiments of the invention as claimed herein . [015b] According to a first embodiment of the invention, there is provided an oral ate release formulation sing an active ingredient selected from: 2-(4-(2—hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 2—(3—chloro-4—(2—hydroxyethoxy)pheny|)—5,7-dimethoxyquinazolin-4(3H)—one; 2-(4—(2—hydroxyethoxy)—3-methoxyphenyl)—5,7—dimethoxyquinazolin—4(3H)— one; 2-(4-hydroxy(2-hydroxyethyl)phenyl)-5,7—dimethoxyquinazolin-4(3H)-one; 2—(4-(2—hydroxyethoxy)-3,5—dimethylphenyl)—5,7-dimethquuinazolin—4(3H)—one; 2—(4-(2—hydroxyethoxy)—3,5—dimethylphenyl)methoxyquinazolin-4(3H)—one; 2-(4—(2—hydroxyethoxy)methylphenyl)—5,7-dimethoxyquinazolin—4(3H)—one; 2—(4-(2—hydroxyethoxy)-3,5—dimethylphenyI)—5,7-dimethoxyquinazolin—4(3H)— one; and pharmaceutically able salts, stereoisomers, hydrates, or tautomers thereof; wherein the ation r comprises: (i) from about 10% w/w to about 85% w/w of microcwstalline cellulose; (ii) about 4% w/w of sodium starch glycolate; (iii) about 0.5% w/w of magnesium stearate; and (iv) about 2.5% w/w of colloidal silicon dioxide; and wherein the sum of all components of the formulation is equal to 100% w/w. [015C] According to a second embodiment of the invention, there is provided use of a pharmaceutical formulation of the first embodiment in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease, metabolic syndrome, matory disease, Alzheimer’s disease, diabetes, or cancer, in a human in need thereof.

The invention es an immediate release formulation comprising, (i) a compound Formula l as an active ingredient (Re)p (R7)p (Reap N \ (Rap Formula | or a pharmaceutically acceptable salt, stereoisomer, e, or tautomer thereof, wherein: R1 and R3 are each independently selected from alkoxy, alkyl, and hydrogen; R6 and R8 are each independently selected from alkoxy, alkyl, halogen, and hydrogen; R7 is ed from alkoxy, alkyl, ether, hydrogen, and hydroxyl; or [TEXT CONTINUES ON PAGE 9] —8b- two adjacent substituents seiected from R4,, R3, R5, R7, R5, and are connected to form a group seiected from aryi, heteroaryi, cycioaikyi, and heterocyoiyi; provided that it R4, is hydrogen, then R3 is aikoxy; provided that it R3 is hydrogen then R4, is ; and provided that it R7 is seiected from aikyi, hydroxyi, and aikoxy, then at ieast one of R5 and R5 are independentiy seiected from aikyi or aikoxy; (ii) at ieast one giidant; and (iii) at ieast one disintegrant. i017} ant considerations during the manufacturing of a soiid ceuticai tormuiation inciude preservation of the cai and physicai properties of the active ingredient, enhancement of hioavaiiabiiity, ease of administration, and overaii stahiiity. in each case, the tormuiation rnost be based on the properties of the activeidrug substance, haianoing factors iike disintegration, dissoiution, ie size, size of unit, compatihiiity of ents, and stahiiity (see, erg”, The Pharmaceuticai Codex, Principies and Practice of ceutics. Ed: Waiter Land; 24308, s Pharmaceuticai Dosage Forms and Drug Beiivery Systems, Lippincott Wiiiiarns 8t Withins, 2010, Pharmaceuticai Dosage forms: s, Vci ’i, 2. Eds: Liberman, Lachman and Schwartz. Ed edition). {018] Disintegration and dissoiution are prerequisite steps for absorption, and the efficacy of these steps can affect the hioavaiiahiiity of an active/drug substance.

The soiuoiiity and thus the dissoiution rate for weak acids and bases are influenced by the pH of the gastrointestinai fluids“ For compounds that have reduced soiuhiiity in neutrai and basic environments, iike the srnaii intestine, and a higher sciuhiiity at gastric pH, rapid disintegration and dissoiution in the acidic gastric tiuids may be criticai for absorption in the srnaii intestine (Principies of Drug Absorption, iviiohaei “E3 " Mayersohn. in Modern Pharmaceutics; Drugs and the Pharmaceutical Sciences, Voi 7'2, edited by James Swarhriok). [019} Many active compounds, ing compounds of Formuia i, have poor s soiuoiiity, thus reducing their potentiai for absorption from the intestinai tract. A chaiienge to working with compounds having poor aqueous soiubiiity is that it can be ditticuit to improve soiuhiiity without decreasing ity of the compound, thus reducing sheit iiie to an unacceptabie ieveisu The hydrophobicity of compounds of Formuia i can be aitered when tuted with ionizabie basic substituents, such as amines and/or amides, providing an opportunity for sed soiubiiization and absorption from the acidic gastric environment when dosed oraiiy.

However, due to the increasing pH gradient (pi-t 3 to 7) in the gastrointestinai cavity, the opportunity for dissoiution and absorption is dependent on the rate of dissoiution.

As a resuit, it these compounds are not dissoived in the right gastric environment, absorption and bioavaiiahiiity in the smaii intestine is reduced or test, Thus, any improved bioiogicai activity gained from substituting compounds of Formuia i with ionizabie basic subsitutents is mised because of their diminished soiubiiity in the smaii intestine, which ieads to a decrease in the overaii efficacy and therapeutic effects of the active drug substance. [329} e compounds oi Formuia i have been shown to reguiate expression of AponA’i and given the cerreiation between increased expression of Apo~At and treating or preventing vascuiar and ohoiesteroi— or iipid—reiated disorders, there is a need to deveiop soiid ceuticai tormuiations comprising substituted ouinazoiinones, such as those described herein, where the pharmaceuticai tormuiations improve dissoiution of the duinazoiinone drug -13” substance, have favorahie hioavaiiabiiity, are convenient to administer, and which are stahie for an extended period of time. [021} The invention provides novei soiid pharmaceutioai formotations comprising compounds of the a i, as defined above, and processes for their oreparation. The tormoiations of the invention are stahie and have improved egration and dissoiution protiies for compounds of Formuia i and improved oioavaiiahiiity,i of the drug substance. The present invention aiso es, in part, methods of using the oharmaceoticai formuiations of the ion that are osetui for reguiating the expression of apoiipoprotein Ami {ApoAmifir and as BET tors, for the treatment and prevention of cardiovascuiar disease, and choiesteroi- or iioidureiated disorders, inciuding, for examoie, metaooiio syndrome, inflammatory disease, Aizheimeris disease, atheroscierosis, es, and cancer. Cancers that may he treated or ted with the methods of the invention inciude cancers that are sensitive to a compound that binds to bromodomains of BET tarniiv oroteins, inciuding NUT midiine carcinoma; cancers that exhibit o~rnvc overexoression, inciuding, out not iimited to, Burkitt’s ivrnohoma, acute myeiogenoos ia, moitipie myeioma, aggressive human medoiiobiastoma; cancers pressing n— myo; and s that reiy on the recruitment of o'i'iEEFh to reguiate activated oncogenes such as, so, NOTCH’i. {@223 As used in this specification, the term “active ingredient” refers to a compound of Formuia 3. These compounds may he prepared as described in US.

PatentAooiication No. ”it/579,238 (US. Patent 440), US. Patent Aopiication No, 121490,8?7 (US. Patent 8,114,995), and US. Provisionai Apoiioation No. 61/635,726, iiied Anni 1Q, 2012, incorporated herein by reference. {023] A dash (“~“) that is not between two ietters or s is used to indicate a point of attachment for a sobetitoent. For exampie, «CONHZ is attached through the carbon atom. [@224] The expression "unit dosage form” as used herein, refers to a physicaiiy discrete unit of a oharmaceoticai formoiation appropriate for the subject to he treated. The totai weight of a singie unit dosage form, is determined by adding aii the s of the components in the unit dosage form, and does not inciode the weight of any ooatingts) which may he apniied to the unit dosage form or capsuie that may he ioaded with the unit dosage form. The totai weight of a singie unit dosage form is used as the basis for caisuiating the weight percentage of each of the components that comprise the unit dosage form. {025} As used herein, ”w/w %” means by weight as a percentage of the totai weight. {023] The term ”about” is intended to mean aporoximateiy, in the region of, y, or around. When the term ” is used in ction with a numericai range, it modifies that range by extending the boundaries above and heiow the numerioai vaities set forth. in generai, the term “about" is intended to modify a nomericai vaine above and beiow the stated vaiue by a variance of s 10%. {627] Compounds of Formuia i may exist as ners. it is intended that a description of any active ingredient, i.e., a compound of Formiiia i encompasses aii tautomeric forms of the compound even it onty one tautomeric structure is depicted or one compound name is recited. For exampie, any description of active ingredient A beiow is tood to egnaiiy represent taotomerio structures i3 and C, and vice versa, individuaiiy or as mixtures.

(Re)p (R6)p (Re)p (R7)p (R7)p (R7)p (R3)pm (R3)p (R3)pN\ (Rs)p——> /N (Rs)p (R1)p O (R1)p0 (R1)p OH A B C As used herein, the term “hydrate” refers to a l form of a compound of Formula | with either a stoichiometric or non—stoichiometric amount of water incorporated.

The term “alkoxy” as used herein refers to an alkyl group attached to an oxygen (-O—alkyl-). “Alkoxy” groups also include an alkenyl group attached to an oxygen (“alkenyloxy”) or an alkynyl group attached to an oxygen (“alkynyloxy”) groups.

Exemplary alkoxy groups include, but are not limited to, groups with an alkyl, alkenyl or alkynyl group of 1—22, 1-8, or 1—6 carbon atoms, referred to herein as (Cl—C22)alkoxy, )alkoxy, and (C1—Ce)alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy and ethoxy.

The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-22, 1—8, or 1-6 carbon atoms, referred to herein as (C1-sz)alkyl, (C1-Cg)alkyl, and (C1—Ce)alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, , isopropyl, 2-methylpropyl, yIpropyl, 2—methylbutyl, 3—methyl butyl, 2—methyl-3—butyl, 2,2—dimethylpropyl, yl-1—pentyl, 3-methylpentyl, 4— methyl—1—pentyl, 2—methyl—2—pentyl, yl—2-pentyl, 4—methyl—2-pentyl, 2,2—dimethyl— 1-butyl, 3,3—dimethylbutyl, 2—ethyI—1—butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

{G31} The term “aryi” as used herein refers to a , bi—, er ether muiti—earboeyeiie, ic ring system. The aryi group can optionaiiy be fused te ene er mere rings seieeted from aryis, eyeieeikyis, and heterecyeiyis, The aryi greues of the eemeeunds used in the fermuiatiens er the invention can be substituted with grdups seieeted frern aikexy, aryiexy, aihyi, aikenyi, aikynyi, amide, amine, aryi, aryiaikyi, earhamate, earhexy, eyeno, eyeieaikyi, ester, ether, , haiegen, haieaikyi, heterearyt, hetereeyciyi, hydrexyi, ketene, nitre, phosphate, suifide, suitinyi, suitenyi, suitenie acid, sutfenamide, and thieketene. Exempiary aryi groups indiude, but are net ed te, phenyt, teiyi, anthreeenyi, tiuerenyi, i, yi, and naphthyi, as weti as henze-tused earheeyeiie meieties such as 5,63,8— tetrehydrenaphthyi. Exemeiary aryi groups aise ineiude, but are net iimited te a mendeyetic arernatie ring system, wherein the ring edmprises E3 carhen aten’rs, ed is herein as “(tigers/L” [632} The term “eyeieatkyi” as used herein refers ts a ted er unsaturated cystic, hieyeiie, er bridged hieyeiie hydroearhen group ef3~12 earhens, er 3—8 carhens, referred to herein as ”(Cg~€35}icycteaikyi,” derived frern a eyeioaikane.

Exempiary eyeieaikyi greups insiude, but are net iirnited ts, eyciehexanes, eysiehexenes, eysiepentenes, and eyeiepentenes. Cyeieatkyi groups may be substituted with etkexy, aryiexy, aikyi, aikenyi, aikynyi, amide, amine, aryi, aryiaikyi, earhamate, carhexy, eyene, cycteaihyi, ester, ether, , haiogen, heioeikyi, heterearyi, hetereeyeiyi, hydrexyt, ketene, nitre, phesphate, e, suitinyi, suifenyi, suifenic acid, suitenamide and thieketene. ikyi groups can be fused to ether eyeieaikyi saturated or unsaturated, aryi, er hetereeyeiyi groups.

E033} The term ” refers to the structure “Fifi—Rm” where RE and Rm can independentiy be aikyi, aikenyi, aikynyi, aryi, eycieaikyi, heteresyeiyi, and ether. _ 14 _ 2012/002721 The ether can be attached to the parent rneieeuier group through R; or Rm Exempiery ethere ineiude‘ but are net iirriited to, eikexyaikyi and eryi groups.

Ethere aiee ee peiyethere, e.g., where ene or both of R; and Rm are ethers. [034} The terms “hate” and “heiegen” ere interehengeehie and refer to F, CE, 8r, er 5. {035} The term oeryi” as used herein refers tr) e mane, hi~, er muiti— cystic, aremetie ring eyetem containing one or mere heteroeter‘ns, fer exempie t~3 hetereetome, such as nitrogen, exygen, end suifur. Heteroeryie can be eubetituted with one er mere substituente indenting eikexy, eryiexy, atkyi, eikenyi, eikynyi‘ amide, amino, eryi, eryieikyi, eerbemete, y, eyene, eycieaikyi, ester, ether, termyi, heiegen, heieeikyt, hetereeryi, hetereeyeiyi, hydroxyi, ketonea nitro, phosphate, e, suifihyt, suitenyi, sutfenic eoid, suitenernide end thieketene. Hetereeryie can eiee be fused t0 hen—aromatic rings. itiuetretive exempiee et heteroeryi greups ineiude, but are net d to, pyridinyi, pyridezinyi, pyrimidyi, pyrezyi, triezinyi, pyrreiyi, iyi, imidezeiyi, (1,2,3)— and (1,2,4iutriezeiyi, pyrezinyi, pyrirrtidiiyi, tetrezeiyi, furyi, thienyi, ieexezetyi, thiezoiyi, turyi, phenyi, ieexezeiyi, end exezeiyii Exempiary heteroeryi groups ineiude, but are not iimited tn: a eiie aromatic: ring, wherein the ring comprises 2~5 carbon eterne and 1—3 hetereateme, ed te herein as “(Cg—Cgh‘ietereeryif [036} The terms “hetereeyeie, 2! H hetereeyeiyi,” er ”heterecyciic" as used herein refer te a saturated or uneetureted 3—, 4—, 5~, 6—! or 7~mernbered ring eenteining one, twe, or three hetereetems independentiy eeieoteci from nitrogen, exygen, end eui‘tur.

Heterecycies can he aremetio (hetereeryie) er ometie. Hetereeyeies can be substituted with one er more substituents ineiuding eikexy, aryiexyg eikyi, eikenyi, WO 64900 aikynyi, arnide, amine, eryi, aryieikyi, carbarnate, y, cyene, eyeieeikyi, ester, ether, tennyi, beiegen, kyi, hetereeryi, betereeyeiyi, hydrexyi, ketene, nitre, phosphate, suifide, suitinyi, euitenyi, suitenie acid, euticnarnide, end thieketene.

Hetereeyeies eise inciude bieyeiie, tie, and tetracyciie greupe in which any of the above hetereeyaiic rings is fused te ene er twe rings independentiy seieeted from eryt, eycieeikyt, and hetereeyete, Exembtary heterecyeiee ineiude eeridinyt, benzimidezeiyi, benzet’uryi, benzetniezeiyi, benzethienyi, benzexazeiyi, bietinyi, cinnetinyi, dinydrefuryi, dinydreindeiyt, dihydrepyranyi, dihydrethienyi, zoiyi, furyi, hemepieeridinyi, imidezeiidinyi, irnidezeiinyi, irnidezeiyi, t, isequineiyt, isethiazeiidinyi, isethiazeiyi, ieexezeiidinyi, isexazeiyi, rnerpheiinyt, exeeiazeiyt, exezeiidinyi, exezeiyi, piperezinyt, piperidinyi, pyranyi, eyrazeiidinyi, pyrezinyi, iyi, iinyi, eyridazinyi, pyridyi, pyrimidinyi, pyrimidyi, eyrretidinyi, pyrreiidin~2—enyi, inyi, pyrreiyi, quineiinyi, duinexeieyi, tetrehydrefuryi, tetrehydreieequineiyi, tetrabydrepyrenyi, tetrabydrequineiyi, tetrazeiyt, thiadiazeiyi, thiazeiidinyi, tbiezeiyi, thienyi, thiemerphetinyi, tbiepyranyi, and triazetyi. {037} “Aikyt” greups can be substituted with er interrupted by er branched with at ieeet one group eeiected trern aikexy, aryiexy, eikyi, aikenyi, eikynyi, amide, amine, eryi, kyi, cerbar’nate, earbexy, eyene, eyeieaikyt, ester, ether, fermyi, heiegen, haieaikyi, ketene, hetereeryi, heterecyeiyi, hydrexyi, nitre, phosphate, suitide, suitinyi, suitenyi, suitenic ecid, eutfenemide, thieketene, ureide, and N. The tuente may be branched to term a tuted er unsubstituted beterecycie er ikyi. {038] “Aikexy” greups can be substituted with er interrupted by er branched with at ieaet ene group seieeted from aikexy, arytexy, aikyi, eikenyi, aikynyi, amide, amine, aryi, eryieikyi, cerbamete, eerbenyi, Gerbexy, cyene, eyeieaikyi, ester, ether, tormyi, haiogen, hetoaikyt, heteroaryi, cyoiyi, hydroxyi, ketone, nitro, phosphate, suitide, yi, suitonyi, suifonic acid, amide, thioketone, ureido, and N. The substituents may be branched to form a substituted or unsubstituted cycie or oycioaikyi. [039} The term ”pharmaceuticaiiy aooeptahie satt(s)“ refers to saits of acidic or basic groups that mat,i be present in nds of Formuia 5, Compounds of Formuia i that are basic in nature are caoahie of forming a wide y of saits with various inorganic and c acids. The acids that may he used to prepare pharmaceuticaiiy acceptahie acid addition saits of such basic compounds are those that form non—toxic acid addition satts, i.e., saits containing pharmacoiogicaiiy aooeptapie anions, inotuding but not iimited to suitate, citrate, , acetate, oxaiate, chioride, bromide, iodide, e, sutiate, hisuitate, phosphate, acid ate, isohiootinate, acetate, iactate, saticyiate, citrate, tartrate, oieate, tanhate, pantothenate, hitattrate, ascorbate, succinate, maieate, gentisinate, fumarate, giuconate, giucaronate, saccharate, formate, benzoate, giutamate, methanesuitohate, ethanesuitonate, benzenesuiionate, p—toiuenesuitonate and pamoate (i.e., t,t‘wmethyieneuhisu{2mhydroxym3~naphthoate)) saits. Compounds of Formuia i that inciude an amino moiety may form pharmaceuticaiiy acceptabie saits with various amino acids, in addition to the acids mentioned above, Compounds of Formuia i that are acidic in nature are capahie of forming base saits with various pharmacoiogioaiiy ahie cations. Exampies of such saits inciude aiitaii metai or aikaiine earth metai saits and, partiouiariy, catcium, magnesium, sodium, iithiurn, zinc, potassium, and iron saits. i040] Compounds of Formuia i may contain one or more chirai centers and/or doubie ponds and, therefore, exist as stereoisomers, such as geometric .47“ isomers, enantiomers or diastereomers. The term “stereoisorners” when used herein consist of aii geometric isomers, omers or diastereomere. These compounds may be designated by the symbois R or “3” depending on the configuration of substituents around the stereogenic carbon atom. Compounds of Formuia i encompass stereoisomers and mixtures thereof. Stereoisomers inciude enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “(a)” in nomenciaturey but the skiiied artisan wiii recognize that a structure may contain an impiioit ohirai center. {0413 duai isomers of compounds of Formuia i can be prepared tioaiiy from commerciaiiy avaiiabie ng materiais that contain asymmetric or stereogenio centers, or by preparation of o mixtures toiiowed by resoiution methods weii known to those of ordinary skiii in the art: These methods of resoiution inoiude, but are not d to (t) attachment of a mixture of enantiomers to a ohirai auxiiiary, separation of the resuiting mixture of diastereomers by reorystaiiization or chromatography and iiheration of the opticaiiy pure product from the auxiiiary, (2) sait formation empicying an ootioaiiy active ing agent or (3) direct separation of the mixture of ootioai enantiomers on chirai chromatographic coiumns.

Stereoisomeric mixtures can aiso be resoived into their component stereoisomers by weii known methods, ing, but not iimited to chirai—phase gas chromatography, chirainphase high performance iiduid chromatography, crystaiiizing the compound as a ohirai sait oompiex, andlor orystaiiizing the compound in a chirai soivent.

Stereoisomers can aieo be obtained from stereomericaiiyupure intermediates, reagents, and sts by weii known asymmetric synthetic methods [042i Compounds of a i may aiso exist as geometric isomers or mixtures thereof resutting from the arrangement of substituents around a carbon» —’i8~ 2012/002721 carbon dodhie bond or arrangement of srihstituents around a oarhoeyeiie ring.

Suhstituents around a earhonnoaroen deuhie trend are ated as being in the “”Z or ”E" configuration wherein the terms “”2 and “E" are used in accordance with EUPAC standards. Uniess otherwise specified, structures ing deuhie bonds encempass both the E and Z isorners. {943] tdents arennd a carbon—carbon dodhie bond aiterrrativehi can he ed to as "his” or “trans,” where “ois” ents snhstituents on the same side dt the doubts bond and “trans” represents suhstituents en opposite sides of the douhie bQi‘iCii The arrangements of substituents areund a carhooyeiie ring are designated as “sis“ or “trans.” The term “sis” represents substitnents en the same side of the piane ot the ring and the term “trans” represents suhstituehts an opposite sides of the piane of the ring, Mixtures of oompeunds et Formuia i wherein the snbstitnents are disposed on both the same and opposite sides of piane of the ring are designated “sis/trans.” {044} Cine exempiary embodiment of the invention is e pharmaceutieei tormdiation comprising, as an active ingredient, a compound er‘ Fermuia i wherein: R1 and R3 are each independentiy seieeted from aikoxy, sikyi, and hydrogen; R5 and R3 are each independentiy seieeted trorn aikyi, aihdxy. and hydrogen; R7 is seiected trorn eikyi, yi, and ; provided that it R1 is hydrdgen, then R3 is aikoxy; provided that it R3 is hydrogen then R! is aikoxy; and provided that it R7 is seieeted trorn eikyi, hydrexyi, and , then at ieast one of R5 and R8 ere independentiy seieoted from aihyi er eikoxy, [(3451 in one embodiment, termuiations of the inventidn eernprise, as an active ingredient a compound of Forrhdia i, wherein: - to w R1 and R3 are each eikexy; RE, and R8 are each eikyi; and R7 is seieeted trem eikexy substituted with e yi. {046] in certain embodiments, termuietiens of the inventien comprise, es an active ient, a nd of Fennnia i, wherein: R1 and R3 are each methexy; R5 and R3 are each methyi; and R7 is seieeted frern eikexy substituted with a yi. {347] in certain embediments, fermnietiens ef the invention eemprise an active ient wherein R7 is seiected trem hydrexyi and aikexy substituted with e hydrexyi. in ether embedirnents, R7 is hydrexyi substituted with eiitexy. in further embodiments, R7 is 2~hydrexyethexv [048} in some ments, the active ingredient is 2-(4~(2—hydrexyethexy)m 3,5~dimethyiphenyi)~5,7ndimethexyddinezeiin—4(3H)~ene er a phermeeeutieeiiy eeceetehie sait, stereeiserner, hydratei er tautemer thereet. {049} in ether embodiments, the active ingredient is the hydreehieride sait et 2—(4—(2-hydrexyethexyys,5~dimethyiphenyi)—5,7~dimethexyquinezeiin-4(3H)~ene, er 3 stereeisemer er tautemer thereef. [056} in ether embediments, fermuietiens of the inventien comprise an active ingredient seiected trern: 2—(4~(2—hydrexyethexy)-—3,5—dimethyiphenyi)euinazeiin-dtiitiimene; 2u(3uehiere-dniznhydrexyetitexy)pheiiyi)—5,7—dimethexyquinezeiin—éiiBi—t)nene; 2—(4m(2—hydrexyethexy)—3~methexyphenyi)u5,7—dimethexydninezeiin~4(3it)~ one; "29* 2012/002721 2—(4-bydroxy—EBi-(znydroxyetbytipbenyiifi,7’—dimetboxyouinazoiinn4(3H)--one; 2~(4—(2~nydroxyethoxy)u3,5dirnetnytonenyiiéjoimethyieuinazoiin«4{3H)—one; 2n(4~{2~nydroxyethoxy)~3,5~dimetnyibnenyii~5~metnoxyouinazoiin~4t3iti~one; 2—bydroxyetboxy)—3~methyipbenyi)u5,77—dimetboxyouinazoiin~4(3i~t)none, or a pberrneoeutioeiiy abte eait, stereoieomer, hydrate, or tautomer thereot {051} in certain ments, the pita of the corresponding eoid otthe active ingredient of a E is < 3. in some embodiments the peniote size of the active ingredient ranges from about t~250 microns, about tu’iOG microbe, or about ”MD microns. {052] in certain embodiments, formuiations of the invention are stebie over extended periods of time. For exempie, in some embodiments, the formuiatione are stebie for at ieeet two yeere. {053] in some embodimente‘ the at Eeaet one giident in the formuietions of the invention is present an amount of 140% WAN, or 24% w/w, or 2.5% wiw. in some embodiments, the giidant is ooiioidei siiioon dioxide such as, for exempie, Cot» OwSii. {(354} The at ieeet one dieintegrant in the formutations of the invention may be present in an amount of about O~25% wlw, about 445% WAN, about 040% WAN, about 08% WW, about t~8% wiw‘ about 2-5% w/w, about 2—4% wlw, or about 4% MW. in some embodiments, at ieeet one dieintegrant is present in an amount of about 4% wlw to about 25% w/w. Suitabie dieintegrents ineiude, for exempie, powdered oeiiutose, oaioium eiiieete, crosoovidone, eeioium eiginate, rnetnyi oeiiuioee, obitoean, y metbyi oeiiuioee, oroeoarmeiioee sodium, oarboxymethyi n21" starch, sodium aiginate, sodium starch giycoiate (egn Exoioiah), pregeiatinized starch, and mixtures thereof. See, e.g., The Pharmaceuticai Codex, Principies and Practice of Pharmaceutics. Ed: Waiter Lund; 20(38. {055] in certain embodiments, ations of the present disciosure comprise an active ingredient of the Formuia i, coiioidai siiicon dioxide and at ieast one disintegrant seiected from sodium starch giycoiate, croscarmeiiose sodium, and mixtures thereof. {056] in certain embodiments, coiioidai siiioon e is present in an amount of about 2.5% w/w and sodium starch giycoiate and croscarmeiiose sodium are each present in an amount of about 4% w/w to about 25% w/w rescectiveiy. in other embodiments, coiioidai n dioxide is present in an amount of about 2.5% wfw and sodium starch giycoiate is t in an amount of about 4% wiw. {058} in on to the active ingredient, at ieast one giidant, and at ieast one egrant, the formuiations may comprise one or more tiiiers or diiuents, in some embodiments, the 'iiiieridiiuent is present in an amount up to 85% War, or about 15in 65% w/w, or about 20—45% Wiw. Suitabie tiiiersfdiiuents inciude, for exampie, microcrystaiiine ceiiuiose, mannitoi, ethyi ceiiuiose, oi, starch, sucrose, caicium phosphate, powdered ceiiuiose, siiicitied rystaiiine ceiiuiose, and mixtures thereof, {C359} in some embodiments, the ’diiuent is rnicrocrystaiiine ceiiuiose. in certain embodiments, the microcrystaiiine ceiiuiose is Avicei PH~30t {08(3] The tormuiations may further comprise one or more iuhricants, in some embodiments, the iuhricant is present in an amount of about 9—294: w/W, about 04% vv/vv, or about 0.5% w/w. Suitabte iubrioants e, for examoie, ium stearate, stearic acid, sodium steaivi tumarate, giyoeryi behenate, hydrogenated vegetabie oii, zinc stearate, caieium stearate, sucrose stearate, ooiyvinyi aicohoi, magnesium iauryi suiiate, and mixtures thereof. in some embodiments, the iubricant is magnesium te. {061} The tormuiations of the invention mat,i r comprise a surfactant. in some embodiments, the surfactant is present in an amount of about 0—59?) wlw, about 053% wiw, or about 1% wivv. Suitabie surfactants inciude, tor exambie, sodium iauryi suifate, sodium dodeoyi e, poiysorbates (such as Tween 29 and Tween 86), ooioxamers (such as mer 188), giyceryi monooieate, and mixtures thereof. in some embodiments, the surfactant is Poioxamer i88, sodium iauryi suifate, and mixtures thereof. {(2362} in an ary embodiment of the invention, the oharmaceuticai formuiation comprises an active ingredient of Formuia i, 1G—85% miorocrystaiiine oeiiuiose, t—8% sodium starch giyooiate, {Ito—2% magnesium stearate, 149% coiioidai siiicon dioxide, 92% sodium iauryi suitate, and 025% orosoermeiiose sodium. [063} in other ments, the formuaition comprises an active ingredient of Formuia i, 106.5% microorystaiiine ceiiuiose, 4% sodium starch giyooiate, 0.5% magnesium stearate, and 2.5% coiioidai siiicon dioxide. [064} in certain embodiments, the tormuiation ses an active ingredient of Formuia i, 10w85% microcrystaiiine oeiiuiose, 4% sodium starch giycoiate, 25% crosoarmeiiose sodium, 0.5% magnesium stearate, and 2.5% coiioidai siiioon dioxide. {055} in an exempiary embodiment, the fermuietieh of the ihvehtEeh comprises: (E) about 19-12% wiw 2—(4—(2—hydrexyethexy)—3,5»dimethyiphenyt}—5,7n dimethexyquirtezeEEh—4(3H)—ene; (it) abeut 82n83% wlw Avieet PH 301; (iii) about 2.5% w/W ceiieidet eiiieen e; (iv) ebeut 4% wiw sodium starch giyeeiete; and (v) abeut 0.5% w/w magnesium steerete. [066} in an ettemete embodiment the hydrechieride seit of 2w(4—(2~ hydrexyethexy)—3,S—dimethyiphehyt)~5,?mdimethexyduihezetih—4(3H)uehe may be Substituted fer 2—(4~(2~hydrexyethexy)~3,5-dimethytphenyE)—5,ldimethexyeuinazeiie 4(SH)uehe in this termuEetien, {G677} in another exemptery embediment, the termuietieh of the éeh ses: (i) ebeut 20u22% wlw 2-—(4m{2~hydrexyethexy)~3,5-dimethyiphehyE)--5,7m dimethexyquinezetin~4<3H)~ene; (it) eheut “KG—72% wlw Avicei PH 391; (iii) about 2.5% w/w dat siiiceh diexide; (Ev) about 4% w/w sedium starch gtyeeflete; and (v) about (15% w/w magnesium eteerete. [(3638] in an eiternete embodiment the hydreehieride sait et 2-(4~(2— hydmxyethexy)—3,5~dimethyiphehyi)u5,7-—dimethexyquinezoiih-4(3HMme may be W0 2013/064900 substituted for 2~(4—(2—bydroxyethoxy)—3,S—oimethyipbenyii~5,7edimeihoxyquinazoiion 4(3H)~one in this formuiation. [069} in another exemoiary embodiment, the formuiaiion ofthe ioveniion ses: (i) about 31~33% wiw 2--(4-—(2~hydroxyeihoxyjfl,5~dimetbyibbenyi)~5,7- dimetboxyquinazoiin—4(3H)mone; (ii) about 606294: wlw Avioei PH 301; (iii) about 2.5% MW oai siiioon e; (iv) about 4% wiw sodium eiarob giyooieie; and (v) about 0.5% w/w magnesium etearate.

[G703 in an aitemate embodiment the bydroobioride suit of 24442— iiyoioxyeiboxy)-3,5-dimetbyipbenyE)—5,?»dimeiboxyouinazoiin~4{SH)—one may be substituted for 2~(4-—(2nbydroxyetboxyi—S,S—dimeihyioheoyi)—5,7—oimetboxyquinazoiinu 4(3H)~one in this formuiaiion. {071] in r exemoiary embodiment, the formuiaiiori of the invention comprises: (3) about 414396 w/w Zia-(241wroxyethoxy)—3,SedimeihyiohenyEySJ— dimeiboxyquinazoiiii—4(3iii—one; (ii) about 595196 Wlw Avioei PH 301; (iii) aboui 2.5% w/w ooiioidai eiiioon dioxide; (iv) about 4% wlw sodium starch giyooiate; and (v) about 0.5% w/w magnesium siearate. _25_ {(372} in an aitemate embodiment the hydtoohioride eaii: oi 2—(4—(2-~ bydroxyethoxy)~-3,5—dime‘thyibhenyi)«5i7—dimethoxyquinazoiin—4(3i—i}none may be substituted for 2«(4m(2~hydroxyethoxy)—3,5—dimethyiohenyi)n5,7—dimethoxyouinazoiin— 4(3H)~one in this formuiation. {073} in another exembiary embodiment, the formuiation ot’ the invention comprises: (i) about 10—12% W/W 2—(442—hydroxyethoxyy3,5~dimetbyibbebyi)w5,7~ dimeihoxyouinazoiin—4i3ii)uone or e hydrocbioride sait tbeteof; (ii) about 55-57% who Avioei PH 301; (iii) about 25% w/w ooiioidei eiiioon dioxide; (iv) about 4% w/w sodium staroh giyooiate; (v) about 05% wlw magnesium stearate; and (vi) about 25% wlw oroeoarmeiiose sodium. {0‘24} in an aitemate ment the hydrocbionde eait of 2~(4—(2~ yethoxy)u3,5--dime‘ihyibbenyi)—5,?—dimethoxyouinazoiinudHSE-i)«one may be substituted for 2“(4m{2~hydroxyetboxyyi5ndimetbyiobenyi)—5,7—dimethoxyouinazoiinu )—one in this tonnuietion. {075} in another exempiaty embodiment, the totmuiation of the invention ses: (i) about 42—43% w/w 2—(4~(2—hydtoxyethoxy)—3,5--dimethyibhenyi)—5,7— dimethoxyquinazoiinu4i3H)—one or e bydroobioride eait thereof; (ii) about 24—25% wiw Avioei PH 301; (iii) about 2.5% w/w ooiioidai n dioxide; w 25 - (iv) about 4% vvlw sodium starch giyoeiate; (v) about 0.5% vvlw magnesium stearate; (vi) about 25% wiw orosearmeiiose sodium; and (vii) about 1% wivv sodium iauryi suttate, [G7dj in an atternate embodiment the hydrochtoride sait of iii—(442m hydroxyethoxy)n3,5—dimethyiphenyi)—5,7»dimethoxyguinazoiin—4(3H)—one may be substituted for Zwte—(Z—hydroxyethoxyjnS,5ndimethyiphenyij—S,deimethoxyquinazoiin— 4(3H)~one in this iatien. {(3771 The physieai and chemieai ity of the tormuiation may be tested in a sonventionai manner, for exampie, the measurement of dissoiution or disintegration time, or moisture content, or assay for the active ingredient or degradation products after storage at different temperatures and reiative humidity for different s of time. [078} The nharmeeeutieai ations of the invention may be administered using any amount effective for treating the disease. The exact amount required Wiii vary from subject to subject, depending on the s, age, and generai condition of the subject, the severity of the e and/or disorder, the particutar active ient, its mode of administration, and the iiite. in one aspect, the pharmaceutieai tormuiations are tormuiated in an orai pharmaceuticei unit dosage form for ease of administration and uniformity of dosage. it wiii be understood, however, that the tetai daiiy usage of the pharmaceutieai formuiation of the present invention wiii be decided by the attending physician within the scope of sound medicai judgment. {079'} The specific: effective dose ievei for any partiouiar subject wiii depend on a variety of factors inoiuding, tor exampie, the e being treated and the severity of the disease; the activity of the specific compound empioyed; the specific composition emoioyed; the age, body weight, generai heaith, gender, and diet of the t; the time of administration, and rate of excretion of the specific compound emoioyed; the duration of the treatment; drugs used in combination or ooinoidentai with the soeoitio compound empioyed, and iiite factors weii known in the medioai arts. {6%} in some embodiments, the unit dosage form comprises between 25450 mg of the active pharmaceutieai ingredient. in some embodiments, the Linit dosage form comprises about 25, 50, 3’5, ”EGG or 150 mg of the active pharmaceutioai ient.

{Q81} in one embodiment, the present disoiosure es for pharmaceutioei tormuietions in soiid orai oharmaoeutioei dosage terms. Exampies of soiid orai oeutioai dosage forms ineiude, for examoie, tabiets, oepsuies, piiis, powders, and es. in certain embodiments, the pharmaceutioei tormuiation is in the form of a oepsuie. White iormuiations of the invention are described with reference to densities as the exemoiary dosage form, other dosage forms are aiso within the scope of this invention. {082'} in some ments, the oepsuies are titted with a totai weight between 100 and 500 mg per oapsuie. in some embodiments, the oaosuies are fitted with a totai weight of about 203—250 mg per e; and in some embodiments, the oapsoies are fitted with a totai weight of about 230 mg per oapsuie. -23" {083} As used herein, the term “cardiovascuiar disease” refers to diseases and disorders of the heart and circuiatory system. Exemciary cardiovascuiar diseases, inciuding teroi— or iipidwreiated disorders, inciude, but are not iirnited to acute coronary syndrome, angina, arterioscierosis, atheroscierosis, carotid atheroscierosis, cerebroyasciiiar disease, cerebrai infarction, congestive heart taiiure, congenitai heart disease, coronary heart disease, coronary artery disease, coronary piaqoe stahiiization, dysiipidemias, dysiipocroteinemias, endotheiium dysfunctions, famiiiai hyperchoieasteroiemia, tarniiiai combined hyperiioidemia, hypoaiphaiiooproteinemia, hypertrigiyceridemia, hyperoetaiioooroteinemia, hyperchoiesteroiemia, hypertension, ioidernia, intermittent cation, ischemia, nia receriosion injury, ischemio heart es, cardiac ia, metahoiic syndrome, muiti~intarct dementia, myocardiai infarction, obesity, oeripherai vascuiar disease, repertosion injury, restenosis, renai artery atheroscierosis, rheumatic heart disease, stroke, thrombotic disorder, tory ischemic attacks, and iiooorotein ahnormaiities associated with Aizheimer’s disease, obesity, diabetes meiiitds, syndrome X, impotence, rniiitipie scierosis, Parkinson’s diseases and atory diseases. i684} es and conditions associated with “diabetes meiiitus” as defined herein refer to chronic metahoiic disorderts) caused by absoiote or reiative insuiin ency inciuding, but not iirnited to hypergiycemia, hyperinsuiinemia, hyperiicidemia, insdiin resistance, imoaired giucose metahoiism, y, diabetic retinopathy, maooiar degeneration, cataracts, ic nephrocathy, giomeruioscierosis, diabetic neuropathy, erectiie ction, prernenstruai syndrome, ar restenosis, uicerative coiitis, skin and connective tissue m29_ WO 64900 disorders, toot oicerations, metaboiic acidosis, arthritis, osteoporosis and ed giticose tcierance. {085} in certain embodiments, the cancer to be treated is a midiine carcinoma. in some embodiments, the cancer is characterized by c—myc activation or overexpression. in other embodiments, the cancer is characterized by overexbressicn or activation of n--myc. in certain embodiments, the cancer is Borkitt’s iymphoma, acute myeiogenous ietikernia, rnnitipie myeicma, or aggressive human medniiobiastoma, in some embodiments, the cancer reiies on the recruitment of ba'FEFb to reguiate activated oncogenes such as, eg., NOTCHt. in some embodiments, the cancer to be treated or prevented by the methods of the invention is seiected from the group consisting of hematoiogicai, iiai incioding hing, breast and coion carcinomas, midiine carcinomas, mesenchymai, hepatic, renai and neuroiogicai tumours. rose} The certain embodiments, stration of a compound of Formuia i or Formnia ii or a taotomer, stereoisomer, pharmaceuticaiiy acceptabie sait or hydrate thereof, to a mammai suffering from a cancer s aboctosis in cancer ceiis by decreasing expression of the anti~apcntosis gene BciZ. Thus, some embodiments of the invention provide a method of ng or preventing a disease or disorder in a mammai that benefits from increased ceii death or entiation, or decreased ceii proiiteration, comprising administering a compound of Formuia i or Formnia it or a tautcmer, stereoisomer, oharmacenticaiiy acceptabie sait or hydrate thereof. [0877} The invention is r iiiustrated by the toiicwing non—iimiting examoies.

Exampies i088} 2~(4n(2~hydroxyethexy)—3,Sudirnethyinherryh—S,7—dimethoxyquinazoiinm 4(3H)—ene (Cempdund t) was prepared aeeerding to the synthetic: methods described in US. Patent Apbiieatien Nash ttlt370,238 and 12/490,871 incorparated herein by reference. {089} Capsuies containing tdrrnuiatiens at the inventidn may be produced using any ie apparatus or preeedure. Typicaiiy, the riate amount at the active pharmaceuticai ingredient and aptienaiiy, sodium starch gtyeeiate are weighed out and transferred to a V~biender er binmhiender and biended, fer exempts, for about 2 min at about 25 rpm. Cbiieidai siiieen oxide and appreximateiy 1/3 at the desired amount at a titter/diiuent, such as micreerystaiiine ceiiuiese are ed and added to the same V—biender, and the ingredients are biended for about 2 min at about 25 rpm. The remaining titierldiiuent, such as miereerystatiine ese is added to the same V~biender, and the ingredients are biended far about 4 min at abdut 25 ram. {(390} A iubrieant, such as magnesium stearate, is screened through a 30 mesh screen and transferred tn the V~biender containing the ether ingredients. The tinai termuiatien is biended for about :3 min at about 25 rpm. {091} {Disintegration ef es was menitered visuaiiy during the first 5 min White conducting disseiutien testing, as seen by bursting at the capsuie to retease and disperse the fermutatien biend tram the eapsuie sheii. Dissetutien testing was conducted in a USP Paddie type it apparatus at 50 andler 75 rpm in 0.1 N HCE at 37°C, The disseiution e at the terrnuiations were determined by sampiing the APE reieased from the termination in the utien media at frequent time points, such as 5, tit, 15, 30, 45, 60, and 90 min. Sampies were d for drug content “31, by HPLC and e dissoiution e was generated. For these experiments, the upper threshoid for dissoiution profiies inoinded these which exhibited >85% drug reieesed in 30 min er tees, at ":75 rent peddie speed. A tower paddie speed (50 rpm) wee used to differentiate diseoiutien performance of eiesety perferming termuietiens. {092] Ceneiderihg teeters such esw fer exemeie, number of exoipientsi density at hiendi stehiiity, end hiiity, the numerous: formuietiens were produced at various APE weight tages. The feiiewing fermuietions provided higher ieveis of drug iead end a higher density ieeding to increased menufecturebiiity, reducing the re of ve ingredients te subjects. in additien, the combination of two or more dieintegrents in conjunctien with high ieveie of giident (e.g., eiiicen diexide) improved disintegration and disseiution proiiiee. fermiiiatien D4 {25 mgieegsniei I mg I ients i % wt.lwt "scarier-rte........itttttttttttttttttttttttttttttttttttttttttt I Cempeiind 1 25.00 I 10.?3 I Miereoryeteiiine eeiiuiese (Avieei PH 3M) 191.69 I 82.2? Coiieidei eiiieen dioxide (Ceb—O—Sii MSP) 5 83 2 5 ‘ Herd sheii geietin oepeuie wiiiteiwhite Size 1 Capsueet £11313331§111E9.11.921.1:59.._.1:111§1511§1§1111§1 mg l ingredients 1 % wtjwt capsuie Compound 1 51) 21.46 Microcrystaiiine ceiiuiose (Avicei PH 301) ”166.69 71.54 Cciioidai siiiccn dioxide nSEE M5?) Sodium starch giycaiate (ExpioTab) ‘ \xxx..“V»VVVVVVVVVVV\\ Magnesium stearate (Vegetabie Source) 1.17 0.5 Hard sheii n capsuie white/white Size “E ~ w Cawgei_ T013! Wwwmgimmuw mg i ingredients “lo wtfwt capsuie3 Compound 1 75.013 32.19 Microcrystaiiine ceiiuiose (Avicei PH 301) 141.69 60.81 Sodium starch ate (ExpioTab) 9.32 4.0 1.17 0.5 Hard shei! geiatin capsuie white/White Size: 1 -» Gamma? ............. 233.01 190.0 xvvvmmfim momooo “\ “ooo“o“k\kooooouuuuuuuu...._...........................‘_"mum“.............“““.iw“““‘ E95513uia:§o:1.i§§.§i§9wmgfil§o§oiéu ients 0/0 wtlwt oapsuie Compound 1 100.00 42.9 Mioroorystaifline ceiiuidse {Avioei PH 361) 118.639 50.1 Coifloida! siiioon dioxide (Cab—O—SEE MSP) 5.83 2.5 Sodium starch giyooiate (ExpioTab) 9.32 4.0 l Magnooium to (Vegetabie Source) ”3.17 0.5 Hard sheii geiatin e white/white Size 1 a cu 839% $ ients l %w’z.iwt oapsuie EWM ‘M.

Compound 1 25.00 10,73 o‘ooooooooomofik..kk“A“.U..ww“w“w‘HH“oH"vv",____....__.................r.r.oh“\“w...............__________“Rod“...bfiufiuu__“uNu........~m»».»»».... .........................r.\\“\\\\\\\\::\ Micr‘oorys’taiiino oeiiuiose (Avioei PH 301) 197.0 56.29 Coiioida§ siiicon dioxide (Cab~Q~8iE MSP) 5.83 i 2.5 Sodium starch gflyooiate {Expio’i‘ab} 9.32 4.0 Magnesium stearate (vegetabio souroe) I 1.17 l 0.5 “34" ‘ ‘ Crescaimeiiese sodium 58.25 25 Hard sheii geiaiin eapeuie white/White Size 1 - « Capsueei Fermuiaiien F3” i100 iiji_g[§§i_g§ii_i§} _.,,Va.eewe‘d‘we\\\\‘\\._\keekkkk__\\\\\\\\\\\aaaaaaaa......................_]._................___________....““.........\‘,,,“““VV‘V mg i ingredients % wilwij Compound 1 100 42.9 Miereeryeiaiiine ceiiuiese (Avieei PH 301) 56.25 24.14 Ceiieidei eiiieon dioxide (Cab~0~8ii MfiP) 5.83 2.5 Sedium starch giyeeiaie Tab) 9.32 4.0 ee:e______________‘deeddddddddeeeeA.__AA_...........eeeeeeeeeee.‘VV.dV...ddddv».dd....V»..............................==\\\\\\~~\\““‘ Magnesium eieeraie (Vegetabie Seurce) 1.1? 0.5 deeded..‘ddddd....ee..AAAAAAAAAA_____...........““eeeeeeee......dddvvvvvvvvd»v..........................aaxxxxx\\\\\\\\\““xx“‘\‘\::_____,__ed..¥¥eeeeee~~~~~~..~~..______AA______......

Crescarrneiiese sodium 58.25 25 Sodium iaui'yi suifeie 2.33 1 Hard sheii geiaiin eeeeuie white/white Size 1 ............................................................................................................................................................................................................................................................ {093i Oiihe fermuietione above, D4 had the fewest inactive ients, and time, the highest ieveis of drug iced and density, thereby reducing ssary exposure id inactive ingredients. Dieeeiuiien ee of the fermuiaiiens above are provided in Tabie 1. _ 35 _ WO 64900 _i._:_“iiieeeietien__t§eeeii§ Compoundieisoived Capeuie Strength Ferrnuietieri Paddte Speed geofiiveeseij iee tin/31530 ....,,,,. ....,,,,,,““,,,,.., ..\....‘.i,,,,,,,,‘ii‘iiVVVV‘ii“‘VVV“VAN“‘NNN““‘ 45 tEtietieeez;_teei t3 50 W§§§£ 64105615 .\\\}\\ 230i LE Sjid 325399 “JLKu 20G£used2ceps§ e4 50 53.09 66.08 740; "VVVV““‘““‘““"VVVV““““““VV“VVVVVV“V "VV‘e“VVVVVVVVVVVV~~~~~~~~\\~~~~\‘__.:...."__________“eeeeeeee“eee““ee;“e“e~e““e““eeekkK\kkeekkKKKKkKexKkKKKK\\\\\\\\\\\\\\\\\\55“c\\ {094] Thus, the present disciosure provides in part, a teehnicai eeiutien to the existing probiern of deveioping termuietiene that increase the bieeveiiebiiity Of cernpeunde Qt Formuie i, white preserving commend stebiiity and eheifuiite.

Because etthe known y of cernpeunde ef Fennuie i to reguiate expression at ApeAmt and ee BET inhibitere, the aforementioned immediate reieeee fermuietione eieo provide en avenue fer the treatment and prevention Of cerdievaecuier disease, and cheieetereiu or iipid~reiated ers, ineiuding, for exempie, metebeiic me, infiernmetery disease, Aiznein'ier’e disease, ethereeeiernsis, diabetes; and cancer. ”35.

Claims (9)

WHAT IS CLAIMED IS

1. An oral immediate release formulation sing an active ingredient selected from: 2-(4-(2—hydroxyethoxy)—3,5—dimethylphenyl)quinazolin-4(3H)—one; 2-(3-chloro-4—(2-hydroxyethoxy)phenyI)—5,7-dimethoxyquinazolin—4(3H)—one; 2—(4-(2-hydroxyethoxy)methoxyphenyI)—5,7-dimethoxyquinazolin—4(3H)—one; 2-(4-hydroxy—3—(2-hydroxyethyl)phenyI)—5,7—dimethoxyquinazolin—4(3H)—one; 2—(4-(2—hydroxyethoxy)—3,5—dimethylphenyI)—5,7-dimethquuinazolin-4(3H)—one; 2-(4—(2-hydroxyethoxy)—3,5—dimethylphenyI)-5—methoxyquinazolin—4(3H)—one; 2—(4—(2-hydroxyethoxy)—3-methylphenyl)—5,7—dimethoxyquinazolin-4(3H)—one; 2—(4~(2—hydroxyethoxy)—3,5~dimethylphenyI)-5,7—dimethoxyquinazolin-4(3H)-one; and pharmaceutically acceptable salts, stereoisomers, hydrates, or tautomers thereof; wherein the formulation r comprises: (i) from about 10% w/w to about 85% w/w of microcrystalline cellulose; (ii) about 4% w/w of sodium starch ate; (iii) about 0.5% w/w of magnesium stearate; and (iv) about 2.5% w/w of colloidal silicon dioxide; and wherein the sum of all components of the formulation is equal to 100% WM.

2. The formulation of claim 1, wherein the active ingredient is present: (a) in an amount from about 10% w/w to about 12% w/w and the formulation further comprises: (i) from about 82% w/w to about 83% w/w of microcrystalline cellulose; (ii) about 2.5% w/w of colloidal silicon dioxide; (iii) about 4.0% w/w of sodium starch glycolate; and (iV) about 0.5% w/w of magnesium stearate; (b) in an amount from about 20% w/w to about 22% w/w and the formulation further comprises: from about 70% w/w to about 72% w/w of rystalline cellulose; (ii) about 2.5% w/w of colloidal silicon dioxide; (iii) about 4.0% w/w of sodium starch glycolate; and (W) about 0.5% w/w of magnesium stearate; (c) in an amount from about 31% w/w to about 33% w/w and the formulation further ses: from about 60% w/w to about 62% w/w of microcrystalline cellulose; about 2.5% w/w of colloidal silicon dioxide; about 4.0% w/w of sodium starch glycolate; and about 0.5% w/w of magnesium stearate. (d) in an amount from about 41% w/w to about 43% w/w and the formulation further comprises: (i) from about 50% w/w to about 51% w/w of microcrystalline cellulose; (ii) about 2.5% w/w of colloidal silicon dioxide; (iii) about 4.0% w/w of sodium starch glycolate; and (W) about 0.5% w/w of magnesium stearate; n the sum of all components of the formulation is equal to 100% w/w.

3. The formulation of claim 1 or claim 2, wherein the ation comprises from about 25 mg to about 150 mg of the active pharmaceutical ingredient. -38—

4. The formulation of any one of claims 1 to 3, wherein the active ingredient is present in the formulation in an amount selected from about 25 mg, about 50 mg, about 75 mg, about 100 mg, or about 150 mg.

5. The formulation of any one of claims 1 to 4, wherein the active ingredient is 2— hydroxyethoxy)—3,5—dimethylphenyl)—5,7—dimethoxyquinazolin—4(3H)—one.

6. The formulation of any one of claims 1 to 4, wherein the active ingredient is the hydrochloride salt of 2-(4-(2—hydroxyethoxy)—3,5-dimethylphenyl)—5,7—dimethoxyquinazolin- one.

7. The ation of any one of claims 1 to 6, wherein the particle size of the active ingredient ranges from about 1-250 microns, about 1—100 microns, or about 1-10 microns.

8. The formulation of any one of claims 1 to 7, n the formulation has a disintegration time of 120 seconds or less.

9. Use of a pharmaceutical formulation of any one of claims 1 to 8 in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease, metabolic syndrome, inflammatory disease, Alzheimer’s disease, diabetes, or cancer, in a human in need f. Resverlogix Corp. By the patent attorneys for the applicant CULLENS