US 201001 12041A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/01 12041 A1 Ahmad et al. (43) Pub. Date: May 6, 2010 (54) ENDOXIFEN COMPOSITIONS AND Publication Classification METHODS (51) Int. Cl. (75) Inventors: Ateeq Ahmad, Wadsworth, IL st 4: :08: (US); Shoukath M. Ali, Vernon A69/10 (2006.015 Hills, IL (US); Moghis U. Ahmad, CD7C 2.3/10 (2006.015 Wadsworth, IL (US); Saifuddin A6IP35/00 (2006.015 Sheikh, Waukegan, IL (US): Imran C07C 215/08 (2006.015 Ahmad, Libertyville, IL (US) A69/48 (2006.01) A6IR 9/28 (2006.01) C d Address: E.S."9 Ave w- e. (52) U.S. Cl. ......... 424/450; 514/648; 424/484:564/324; 2275 DEMINGWAY, SUITE 310 424/463; 424/474 MIDDLETON, WI 53562 (US) (57) ABSTRACT (73) Assignee: UNA PHARMACEUTICALS The present invention provides compositions containing INC., Libertyville, IL (US) 9 endoxifen, formulations and liposomes of endoxifen, meth s s ods of preparation of such agents and formulations, and use of 21) Appl. No.: 12/S15.261 Such agents and formulations for the treatment of breast can (21) Appl. No 9 cer and other breast diseases and diseases Susceptible to (22) PCT Filed: Nov. 21, 2007 endoxifen. In particular, the compositions of the present e af-l invention include liposomes, complexes, Vesicles, emulsions, micelles and mixed micelles of endoxifen in which the com (86). PCT No.: PCT/US07/8.5443 positions further contain any of a variety of neutral or charged S371 (c)(1) lipids and desirably, cholesterol and cholesterol derivatives, (2), (4) Date: Jan. 8, 2010 sterols, Z- and E-guggulsterones, phospholipids, fatty acids, s a V8 vitamin D, and vitamin E.The present invention also provides O O methods of preparing endoxifen. The present invention pro Related U.S. Application Data vides methods for treating and preventing breast cancer and (60) Provisional application No. 60/860,420, filed on Nov. other breast related diseases by administrating novel formu 21, 2006, provisional application No. 60/860,788, lations or compositions comprising a therapeutically effec filed on Nov. 22, 2006. tive amount of endoxifen. 1. Mg, THF 2O s 2. THF, Reflux (C) Patent Application Publication May 6, 2010 Sheet 1 of 3 US 2010/01 12041 A1 Figure 1 Patent Application Publication May 6, 2010 Sheet 2 of 3 US 2010/01 12041 A1 Figure 2 Br ... O so. OH O OO C-RT r 1. 2 3 r C O as 1. Mg, THF 2C -- 2. THF, Reflux O. O O O 8-) 3 4 5 y HCHN '. () level. (C) -gC OH Patent Application Publication May 6, 2010 Sheet 3 of 3 US 2010/01 12041 A1 Figure 3 N. / C.e.g. C CYP2D6 - C, O SULT1A1 O) CYP2C19,(CYP2b6, CYP2C9, CYP3A) O) OH Tamoxifen (TAM) 4-hydroxyTAM CYP3A45 (CYP2C9 + other CYP isoforms) N. / ON/ H oU/N C o CYP2D6 C o C e O C SULT1A1 OH N-desmethylTAM Endoxifen US 2010/01 12041 A1 May 6, 2010 ENDOXFEN COMPOSITIONS AND is present in higher concentration (12.4 ng/mL) than 4-OH METHODS tamoxifen (1 ng/mL) in the human plasma. The majority of genes affected by endoxifen are estrogen-regulated genes (8-9). Use of endoxifen e.g., in place of Tamoxifen, avoids 0001. This application claims priority to U.S. Provisional several metabolic steps that rely on CYP2D6. Application Ser. No. 60/860,420, filed Nov. 21, 2006, and 0007. A strong need exists for methods to treat and to 60/860,788, filed Nov. 22, 2006, both of which are incorpo prevent breast diseases without significant adverse systemic rated herein by reference. side effects, particularly in the premenoposal population. In particular, there is a need for breast cancer treatments and FIELD OF THE INVENTION preventatives that having reduced interactive effect with other medications. 0002. The invention relates to the use of endoxifen in the treatment of mammalian diseases. The invention also relates to liposomes and other formulations such as complexes, SUMMARY OF THE INVENTION vesicles, emulsions, micelles and mixed micelles of endox 0008. The present invention provides methods and com ifen, methods of preparation, and uses, e.g., in the treatment positions for the syntheses and use of active agents such as of human and animal breast diseases. The invention in par anticancer agents. The present invention relates to methods ticular relates to compositions comprising endoxifen-lipid and compositions related to the formulations and uses of complexes, methods of preparation, and their use for the endoxifen, particularly in applications related to the treat treatment of breast diseases, in particular benign and malig ment or prevention of cancer. nant breast disease, enhancing disease regression and reduc 0009. In some embodiments, the present invention pro ing risk of patients developing breast cancer. The invention vides a method of treating a disease, comprising, preparing a further relates to methods of preparing endoxifen and use of composition comprising a therapeutically active amount of endoxifen prepared by inventive method in the treatment of endoxifen and administering the composition. In some human and animal diseases. embodiments, the endoxifen is a free base, or is in the form of a salt. In some preferred embodiments, the endoxifen is in the BACKGROUND OF THE INVENTION form of a salt selected from the group of salts consisting of citrate, acetate, formate, oxalate, tartarate, trifluoroacetane, 0003. Every year more than 210,000 women in the United methane Sulfonate, phosphate, Sulfate, chloride, bromide, States develop breast cancer. One in eight women in the US iodide, lactate, and formate. In some embodiments, the will develop breast cancer during their lives. Approximately endoxifen is predominantly in a form selected from the group 70 percent of breast cancers are fueled by estrogen, and many consisting of E-isomer, Z-isomer, and a mixture of E- and are treated with Tamoxifen, a drug designed to block the Z-isomer. effects of estrogen in breast tissue. 0004 Tamoxifen is an anti-estrogenic drug prescribed for 0010. In some embodiments, method comprises preparing long-term, low dose therapy of breast cancer. It has been a complex comprising an anticancer drug and at least one widely used for more than 30 years for the endocrine treat lipid. In some embodiments, the anticancer drug is endoxifen. ment of all stages of hormone receptor-positive breast cancer In some embodiments, the compounds of the invention are (1-2). Tamoxifen has also been approved for the prevention of not complexed with a lipid. In some embodiments, the com breast cancer (3). In women, one of the adverse events asso pound is in the form of a free base or is in the form of a salt. ciated with Tamoxifen is hot flashes. The risk of hot flashes is 0011. In some embodiments, the present invention pro two to three-folds higher among women who take Tamoxifen vides methods of preparing endoxifen, comprising reacting a than it is for those who do not (4). Selective serotonin-re compound of Formula 5 with acid, wherein the compound of uptake inhibitor (SSRI) antidepressants are prescribed to treat formula 5 has the structure: hot flashes. However, some SSRIs, such as paroxetine and fluoxetine, are known to inhibit cytochrome P450(CYP) 2D6 (5), an enzyme that is important for the metabolism of many C drugs, including Tamoxifen. Our understanding of Tamox ifen metabolism and effect has changed clinical practice through the wide spread recognition that the co-prescription of drugs that inhibit CYP2D6 may compromise Tamoxifen efficacy. It is known that co-administration of paroxetine decreases the plasma concentration of an active metabolite of Tamoxifen, 4-hydroxy-N-desmethyl-Tamoxifen (endox OH ifen). 0005 Endoxifen is generated via CYP3A4-mediated N-demethylation and CYP2D6 mediated hydroxylation of Tamoxifen (see, e.g., FIG. 3). Any drug that can be substrate of CYP3A4 or CYP2D6, especially CYP2D6 e.g., SSRIs, can O decrease the level of endoxifen (6) and thus reduce the thera peutic benefits of Tamoxifen. Therefore, to avoid such drug drug interactions, one should not give them together. 0006 Recently, endoxifen has been shown to be anti-es trogenic in breast cancer cells and to be more potent than Tamoxifen (7). In patients treated with Tamoxifen, endoxifen US 2010/01 12041 A1 May 6, 2010 0012 and, after the reaction of the compound of Formula least one lipid. In preferred embodiments, the at least one 5 with acid, reacting the compound with methylamine. In lipid is selected from the group consisting of egg phosphati Some embodiments, the compound of Formula 5 is prepared dylcholine (EPC), egg phosphatidylglycerol (EPG), soy by reacting compound of formula 4 phosphatidylcholine (SPC), hydrogenated soy phosphatidyl choline (HSPC), dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), dipalmi toylphosohatidylcholine (DPPC), disteroylphosphatidylg lycerol (DSPG), dipalmitoylphosphatidylglycerol (DMPG), cholesterol (Chol), cholesterol sulfate and its salts (CS), cho lesterol hemisuccinate and its salts (Chems), cholesterol phosphate and its salts (CP), cholesterylphosphocholine and other hydroxycholesterol or amino cholesterol derivatives, cholesteryl Succinate, cholesteryl oleate, polyethylene glycol derivatives of cholesterol (cholesterol-PEG), coprostanol, cholestanol, cholestane, cholic acid, cortisol, corticosterone, hydrocortisone, and calciferol, E-guggulsterone, Z-guggul ac sterone, mixture of E- and Z-guggulsterone, monoglycerides, with a compound of Formula 3. diglycerides, triglycerides, carbohydrate-based lipids selected from a group consisting of galactolipid, mannolipid, galactolecithin, B-sitosterol, Stigmasterol, Stigmastanol, lanosterol, C.-spinasterol, lathosterol, campesterol, phos Br phatidylcholine, phosphatidylglycerol, phosphatidylethano lamine, phosphatidylserine, phosphatdylinositol, phospha tidic acid, and pegylated derivatives of distearoylphosphatidylglycerol, dipalmitoylphosphatidylg lycerol, dimyristoylphosphatidylglycerol, and dioleoylphos phatidylglycerol. O O 0016. In some embodiments, a composition according to the present invention comprises endoxifen, cholesterol and/or cholesterol derivatives, and one or more phospholipids. In Some preferred embodiments, the composition comprises a cholesterol derivative, and the cholesterol derivative is cho 0013.