US009375433B2

(12) United States Patent (10) Patent No.: US 9,375.433 B2 Dilly et al. (45) Date of Patent: *Jun. 28, 2016

(54) MODULATORS OF ANDROGENSYNTHESIS (52) U.S. Cl. CPC ...... A6 IK3I/519 (2013.01); A61 K3I/201 (71) Applicant: Tangent Reprofiling Limited, London (2013.01); A61 K3I/202 (2013.01); A61 K (GB) 31/454 (2013.01); A61K 45/06 (2013.01) (72) Inventors: Suzanne Dilly, Oxfordshire (GB); (58) Field of Classification Search Gregory Stoloff, London (GB); Paul USPC ...... 514/258,378,379, 560 Taylor, London (GB) See application file for complete search history. (73) Assignee: Tangent Reprofiling Limited, London (56) References Cited (GB) U.S. PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this 5,364,866 A * 1 1/1994 Strupczewski...... CO7C 45/45 patent is extended or adjusted under 35 514,254.04 U.S.C. 154(b) by 0 days. 5,494.908 A * 2/1996 O’Malley ...... CO7D 261/20 514,228.2 This patent is Subject to a terminal dis 5,776,963 A * 7/1998 Strupczewski...... CO7C 45/45 claimer. 514,217 6,977.271 B1* 12/2005 Ip ...... A61K 31, 20 (21) Appl. No.: 14/708,052 514,560 OTHER PUBLICATIONS (22) Filed: May 8, 2015 Calabresi and Chabner (Goodman & Gilman's The Pharmacological (65) Prior Publication Data Basis of Therapeutics, 10th ed., 2001).* US 2015/O238491 A1 Aug. 27, 2015 (Cecil's Textbook of Medicine pp. 1060-1074 published 2000).* Stedman's Medical Dictionary (21st Edition, Published 2000).* Okamoto et al (Journal of Pain and Symptom Management vol. 34. Related U.S. Application Data pp. 217-222 published 2007).* (63) Continuation-in-part of application No. 14/037,481, filed on Sep. 26, 2013, now Pat. No. 9,072,743. * cited by examiner (60) Provisional application No. 61/990,800, filed on May 9, 2014, provisional application No. 61/871,662, filed Primary Examiner — Paul Zarek on Aug. 29, 2013, provisional application No. Assistant Examiner — George W. Kosturko 61/705,790, filed on Sep. 26, 2012. (74) Attorney, Agent, or Firm — One3 IP Management, P.C.; Dean G. Stathakis; Peter D. Weinstein (51) Int. Cl. A 6LX3L/505 (2006.01) (57) ABSTRACT A6 IK3I/20 (2006.01) The present specification discloses compositions comprising A6 IK3I/42 (2006.01) at least one therapeutic compound capable of modulating A 6LX3/59 (2006.01) androgen production and methods and uses for treating a A6 IK3I/20 (2006.01) disorder associated with androgen production using Such A6 IK 45/06 (2006.01) compositions and/or compounds. A6 IK3I/202 (2006.01) A6 IK3 L/454 (2006.01) 24 Claims, 2 Drawing Sheets

U.S. Patent Jun. 28, 2016 Sheet 2 of 2 US 9,375.433 B2

120 Survival 100 NN 3 --Wehicle E 80 -O-Risperidone g N \ -A-Rumenic Acid F 60 S \ Low dose Combo 3. -(e-High dose Combo 40 -HDOCetoxel S di 20 O 10 20 30 40 50 Doys FIG. 2

20

16 --Wehicle 12 -O-Risperidone -A-Rumenic Acid -Low dose Combo -(e-High dose combo --DOCetoxel

Study Day FIG. 3 US 9,375,433 B2 1. 2 MODULATORS OF ANDROGEN SYNTHESIS sition disclosed herein may reduce an unwanted side and/or reduce a symptom of a disorder associated with androgen This application is a continuation-in-part and claims the production. benefit of priority pursuant to 35 U.S.C. S 120 to U.S. patent Aspects of the present specification also disclose methods application Ser. No. 14/037,481, filed on Sep. 26, 2013, a U.S. 5 of treating an individual with a disorder associated with Non-Provisional patent application that claims priority pur androgen production. The disclosed methods comprising the suant to 35 U.S.C. S 119(e) to U.S. Provisional application step of administering to an individual in need thereof a phar 61/705,790, filed on Sep. 26, 2012 and U.S. Provisional maceutical composition disclosed herein, wherein adminis Patent Application 61/871,662, filed on Aug. 29, 2013, and tration reduces a symptom of a disorder associated with also claims the benefit of priority pursuant to 35 U.S.C. S 119 10 androgen production. A disorder associated with androgen (e) to U.S. Patent Application 61/990,800, filed on May 9, production may be a disorder associated with steroid 2014, each of which is hereby incorporated by reference in its hydroxy-dehydrogenase activity, a disorder associated with entirety. HSD17B activity, a disorder associated with HSD17B10 activity, or any combination thereof. A disorder associated BACKGROUND 15 with androgen production may be a hormone-dependent dis order like a hormone-dependent proliferative disorder or a Androgen is a generic term for any natural or synthetic hormone-dependent non-proliferative disorder. A disorder compound (often a steroid hormone). Androgens stimulate or associated with androgen production may be a cancer, a hor control the development and maintenance of male character mone-refractory cancer, benign prostatic hyperplasia (BPH), istics in vertebrates by binding to androgen receptors. This polycystic ovary syndrome, acne Vulgaris, seborrhea, female includes the activity of the accessory male sex organs and hirsutism, or androgenic alopecia. Administration of a phar development of male secondary sex characteristics. Andro maceutical composition may reduce the frequency of a symp gens are also the original anabolic steroids and the precursor tom, the number of symptoms, the severity of a symptom, or of estrogens, the female sex hormones. The androgens any combination thereof. Administration of a pharmaceutical include dihydrotestosterone testosterone, androstenedione, 25 composition may also reduce an unwanted side in the indi androstenediol, and dehydroepiandrosterone. vidual. Certain disorders or disease conditions are exacerbated by Aspects of the present specification disclose uses of the the presence of androgens. One Such example is a hormone disclosed compositions and/or therapeutic compounds in the sensitive or hormone-dependent cancer. A hormone-sensitive manufacture of a medicament for the treatment of a disorder or hormone-dependent cancer is one where the proliferation 30 associated with androgen production. of tumor cells depends on the presence of a hormone or its Aspects of the present specification disclose uses of the activity. Non-limiting examples of hormone-dependent can disclosed compositions and/or therapeutic compounds in the cers include cancers of the breast, endometrium, prostate, treatment of a disorder associated with androgen production. ovary, testis, thyroid and bone. Other examples of a hormone sensitive or hormone-dependent disorder include, without 35 BRIEF DESCRIPTION OF THE DRAWINGS limitation, a non-cancerous cell proliferation disorder like a uterine fibroid, a fibrocystic breast disease, an ovarian cyst, FIG. 1 shows the steroidogenesis pathway for sex hor and prostate enlargement; abnormal uterine bleeding, amen mones, including the enzymes involved in the pathway. orrhoea, premenstrual syndrome (PMS), endometriosis, FIG.2 shows the survival rate of animal groups treated with adenomyosis, and alopecia. 40 different drug and drug combinations. Hormone depletion therapy is the current treatment option FIG. 3 shows the tumor growth inhibition rate of animal available to people diagnosed with certain hormone-sensitive groups treated with different drug and drug combinations. or hormone-dependent disorders, such as, e.g. a hormone dependent cancer. The basic of this therapy is that growth of DETAILED DESCRIPTION a cancer can be reduced or halted by starving tumor cells of a 45 hormone inducing cell proliferation. Typically, this is Many patients treated with a hormone depletion therapy achieved by reducing the overall systemic levels of a hor become resistant to this therapy. The present specification mone, by preventing the endogenous hormone from interact discloses that one possible mechanism for why certain hor ing with its cognate receptor, or both. Although effective at mone-sensitive or hormone-dependent disorders become first, most hormone dependent cancers become refractory 50 refractory is the presence of a secondary pathway that pro after one to three years and resume growth despite continued duces the hormone or hormonal activity targeted for deple hormone depletion therapy. Once a hormone-sensitive or hor tion. For example, prostate cancer is a hormone-dependent mone-dependent disorder becomes hormone refractory, the cancer and patients diagnosed with this cancer are typically treatment options available to a patient are limited. treated using an androgen depletion therapy. However, many Thus, there is a still exists a need for the development of 55 such patients become refractory to this treatment after one to pharmaceutical compositions and/or therapeutic compounds three years. One possible explanation for this treatment resis effective at treating a disorder associated with androgen pro tance is the presence of an additional pathway that becomes duction. responsible for generating testosterone (or dihydrotestoster one) in a manner useful to support proliferation of prostate SUMMARY 60 tumor cells. The present specification discloses compounds and phar Aspects of the present specification disclose compositions maceutical compositions comprising compounds that pro comprising a therapeutic compound capable of modulating duce therapeutic effects in reducing a symptom of a disorder androgen production. Therapeutic compounds include, with associated with androgen production. In aspects of this out limitation, a benzo(iso)oxazolepiperidine, a fatty acid, a 65 embodiment, the therapeutic effect is achieved by reducing or 5C. reductase inhibitor, a chemotherapeutic agent, an anti inhibiting the activity facilitated by an alternative or second proliferative agent, or any combination thereof. The compo ary pathway responsible for androgen production. In aspects US 9,375,433 B2 3 4 of this embodiment, the therapeutic effect is achieved by peutic compound disclosed herein may comprise a R-enanti reducing or inhibiting the activity facilitated by the primary omer only, a S-enantiomer only, or a combination of both a pathway responsible for androgen production in addition to R-enantiomer and a S-enantiomer of a therapeutic com reducing or inhibiting the activity facilitated by an alternative pound. A therapeutic compound disclosed herein may also be or secondary pathway responsible for androgen production. 5 provided as prodrug or active metabolite. Aspects of the present specification disclose, in part, a A therapeutic compound disclosed herein may reduce a pharmaceutical composition. As used herein, the term “phar symptom of a disorder associated with androgen production maceutical composition' is synonymous with “pharmaceuti by, e.g., reducing a steroid hydroxy-dehydrogenase activity, cally acceptable composition' and refers to a therapeutically reducing a 113-hydroxysteroid dehydrogenase activity, effective concentration of an active ingredient, such as, e.g., 10 reducing a symptom of a disorder associated with a 3.3-hy any of the therapeutic compounds disclosed herein. As used droxysteroid dehydrogenase activity, reducing a 17B-hydrox herein, the term “pharmaceutically acceptable” refers to any ysteroid dehydrogenase activity, reducing a 203-hydroxys molecular entity or composition that does not produce an teroid dehydrogenase activity, or any combination thereof. A adverse, allergic or other untoward or unwanted reaction therapeutic compound disclosed herein may reduce a symp when administered to an individual. A pharmaceutical com- 15 tom of a disorder associated with androgen production by, position disclosed herein is useful for medical and veterinary e.g., reducing a level or an activity of a dihydrotestosterone, applications. A pharmaceutical composition may be admin reducing a level or an activity of a testosterone, reducing a istered to an individual alone, or in combination with other level or an activity of an androstenedione, reducing a level or Supplementary active ingredients, agents, drugs or hormones. an activity of an androstenediol, reducing a level oran activity A pharmaceutical composition disclosed herein may com- 20 of a dehydroepiandrosterone, or any combination thereof. prise one or more therapeutic compounds disclosed herein. In In one embodiment, a therapeutic compound disclosed one embodiment, pharmaceutical composition disclosed herein reduces a symptom of a disorder associated with herein may comprise only a single a therapeutic disclosed androgen production. In aspects of this embodiment, a thera herein. In another embodiment, pharmaceutical composition peutic compound disclosed herein reduces a symptom of a disclosed herein may comprise a plurality of therapeutic com- 25 disorder associated with androgen production by, e.g., at least pounds disclosed herein. In aspects of this embodiment, a 10%, at least 15%, at least 20%, at least 25%, at least 30%, at pharmaceutical composition disclosed herein comprises at least 35%, at least 40%, at least 45%, at least 50%, at least least one therapeutic compound, at least two therapeutic com 55%, at least 60%, at least 65%, at least 70%, at least 75%, at pounds, at least three therapeutic compounds, or at least four least 80%, at least 85%, at least 90% or at least 95%. In other therapeutic compounds. In other aspects of this embodiment, 30 aspects of this embodiment, a therapeutic compound dis a pharmaceutical composition disclosed herein comprises at closed herein reduces a symptom of a disorder associated most two therapeutic compounds, at most three therapeutic with androgen productionby, e.g., about 10% to about 100%, compounds, or at most four therapeutic compounds. In yet about 20% to about 100%, about 30% to about 100%, about other aspects of this embodiment, a pharmaceutical compo 40% to about 100%, about 50% to about 100%, about 60% to sition disclosed herein comprises one to three therapeutic 35 about 100%, about 70% to about 100%, about 80% to about compounds, two to fourtherapeutic compounds, two to five 100%, about 10% to about 90%, about 20% to about 90%, therapeutic compounds, three to five therapeutic compounds, about 30% to about 90%, about 40% to about 90%, about 50% or two to three therapeutic compounds. to about 90%, about 60% to about 90%, about 70% to about A pharmaceutical composition disclosed herein may 90%, about 10% to about 80%, about 20% to about 80%, reduce the occurrence of an unwanted side effect elicited by 40 about 30% to about 80%, about 40% to about 80%, about 50% administration of one or more of the therapeutic compounds to about 80%, or about 60% to about 80%, about 10% to about contained in the pharmaceutical composition. Examples of an 70%, about 20% to about 70%, about 30% to about 70%, unwanted side effect, include, without limitation, feminiza about 40% to about 70%, or about 50% to about 70%. tion in males and defeminisation of females. Examples of In another embodiment, atherapeutic compound disclosed male feminization include, without limitation, chemical cas- 45 herein reduces the frequency of a symptom of a disorder tration, decreased erections, reduced sexual desire, bone pain, associated with androgen production incurred over a given breast tenderness, gynaecomastia, hot flushes, weight gain, time period. In aspects of this embodiment, a therapeutic gastrointestinal disorders, fatigue, headache, depression, compound disclosed herein reduces the frequency of a symp nausea, hepatic changes including elevated levels of tran tom of a disorder associated with androgen production saminases and jaundice. Examples of female defeminisation 50 incurred overagiven time periodby, e.g., at least 10%, at least include, without limitation, unwanted hair growth, increased 15%, at least 20%, at least 25%, at least 30%, at least 35%, at risk for developing osteoporosis and joint disorders such as least 40%, at least 45%, at least 50%, at least 55%, at least arthritis, arthrosis and arthralgia, infertility, aggressive 60%, at least 65%, at least 70%, at least 75%, at least 80%, at behaviour, adrenal insufficiency, kidney failure, and liver dys least 85%, at least 90% or at least 95%. In other aspects of this function. 55 embodiment, a therapeutic compound disclosed herein Aspects of the present specification disclose, in part, a reduces the frequency of a symptom of a disorder associated therapeutic compound. A therapeutic compound is a com with androgen production incurred over a given time period pound that provides pharmacological activity or other direct by, e.g., about 10% to about 100%, about 20% to about 100%, effect in the diagnosis, cure, mitigation, treatment, or preven about 30% to about 100%, about 40% to about 100%, about tion of disease, or to affect the structure or any function of the 60 50% to about 100%, about 60% to about 100%, about 70% to body of man or animals. Any Suitable form of a therapeutic about 100%, about 80% to about 100%, about 10% to about compound may be chosen. A therapeutic compound dis 90%, about 20% to about 90%, about 30% to about 90%, closed herein may be used in the form of a pharmaceutically about 40% to about 90%, about 50% to about 90%, about 60% acceptable salt, Solvate, or Solvate of a salt, e.g. the hydro to about 90%, about 70% to about 90%, about 10% to about chloride. Additionally, therapeutic compound disclosed 65 80%, about 20% to about 80%, about 30% to about 80%, herein may be provided as racemates, or as individual enan about 40% to about 80%, about 50% to about 80%, or about tiomers, including the R- or S-enantiomer. Thus, the thera 60% to about 80%, about 10% to about 70%, about 20% to US 9,375,433 B2 5 6 about 70%, about 30% to about 70%, about 40% to about 60% to about 100%, about 70% to about 100%, about 80% to 70%, or about 50% to about 70%. about 100%, about 10% to about 90%, about 20% to about In another embodiment, atherapeutic compound disclosed 90%, about 30% to about 90%, about 40% to about 90%, herein reduces the number of symptoms of a disorder associ about 50% to about 90%, about 60% to about 90%, about 70% ated with androgen production incurred over a given time to about 90%, about 10% to about 80%, about 20% to about period. In aspects of this embodiment, a therapeutic com 80%, about 30% to about 80%, about 40% to about 80%, pound disclosed herein reduces the number of symptoms of a about 50% to about 80%, or about 60% to about 80%, about disorder associated with androgen production incurred overa 10% to about 70%, about 20% to about 70%, about 30% to given time period by, e.g., at least 10%, at least 15%, at least about 70%, about 40% to about 70%, or about 50% to about 20%, at least 25%, at least 30%, at least 35%, at least 40%, at 10 70%. least 45%, at least 50%, at least 55%, at least 60%, at least In another embodiment, atherapeutic compound disclosed 65%, at least 70%, at least 75%, at least 80%, at least 85%, at herein reduces the frequency of a symptom of a disorder least 90% or at least 95%. In other aspects of this embodi associated with steroid hydroxy-dehydrogenase activity ment, a therapeutic compound disclosed herein reduces the incurred over a given time period. In aspects of this embodi number of symptoms of a disorder associated with androgen 15 ment, a therapeutic compound disclosed herein reduces the production incurred over a given time period by, e.g., about frequency of a symptom of a disorder associated with steroid 10% to about 100%, about 20% to about 100%, about 30% to hydroxy-dehydrogenase activity incurred over a given time about 100%, about 40% to about 100%, about 50% to about periodby, e.g., at least 10%, at least 15%, at least 20%, at least 100%, about 60% to about 100%, about 70% to about 100%, 25%, at least 30%, at least 35%, at least 40%, at least 45%, at about 80% to about 100%, about 10% to about 90%, about least 50%, at least 55%, at least 60%, at least 65%, at least 20% to about 90%, about 30% to about 90%, about 40% to 70%, at least 75%, at least 80%, at least 85%, at least 90% or about 90%, about 50% to about 90%, about 60% to about at least 95%. In other aspects of this embodiment, a therapeu 90%, about 70% to about 90%, about 10% to about 80%, tic compound disclosed herein reduces the frequency of a about 20% to about 80%, about 30% to about 80%, about 40% symptom of a disorder associated with steroid hydroxy-de to about 80%, about 50% to about 80%, or about 60% to about 25 hydrogenase activity incurred over a given time period by, 80%, about 10% to about 70%, about 20% to about 70%, e.g., about 10% to about 100%, about 20% to about 100%, about 30% to about 70%, about 40% to about 70%, or about about 30% to about 100%, about 40% to about 100%, about 50% to about 70%. 50% to about 100%, about 60% to about 100%, about 70% to In another embodiment, atherapeutic compound disclosed about 100%, about 80% to about 100%, about 10% to about herein reduces the severity of a symptom of a disorder asso 30 90%, about 20% to about 90%, about 30% to about 90%, ciated with androgen production. In aspects of this embodi about 40% to about 90%, about 50% to about 90%, about 60% ment, a therapeutic compound disclosed herein reduces the to about 90%, about 70% to about 90%, about 10% to about severity of a symptom of a disorder associated with androgen 80%, about 20% to about 80%, about 30% to about 80%, production by, e.g., at least 10%, at least 15%, at least 20%, at about 40% to about 80%, about 50% to about 80%, or about least 25%, at least 30%, at least 35%, at least 40%, at least 35 60% to about 80%, about 10% to about 70%, about 20% to 45%, at least 50%, at least 55%, at least 60%, at least 65%, at about 70%, about 30% to about 70%, about 40% to about least 70%, at least 75%, at least 80%, at least 85%, at least 70%, or about 50% to about 70%. 90% or at least 95%. In other aspects of this embodiment, a In another embodiment, atherapeutic compound disclosed therapeutic compound disclosed herein reduces the severity herein reduces the number of symptoms of a disorder associ of a symptom of a disorder associated with androgen produc 40 ated with Steroid hydroxy-dehydrogenase activity incurred tion by, e.g., about 10% to about 100%, about 20% to about over a given time period. In aspects of this embodiment, a 100%, about 30% to about 100%, about 40% to about 100%, therapeutic compound disclosed herein reduces the number about 50% to about 100%, about 60% to about 100%, about of symptoms of a disorder associated with steroid hydroxy 70% to about 100%, about 80% to about 100%, about 10% to dehydrogenase activity incurred over a given time period by, about 90%, about 20% to about 90%, about 30% to about 45 e.g., at least 10%, at least 15%, at least 20%, at least 25%, at 90%, about 40% to about 90%, about 50% to about 90%, least 30%, at least 35%, at least 40%, at least 45%, at least about 60% to about 90%, about 70% to about 90%, about 10% 50%, at least 55%, at least 60%, at least 65%, at least 70%, at to about 80%, about 20% to about 80%, about 30% to about least 75%, at least 80%, at least 85%, at least 90% or at least 80%, about 40% to about 80%, about 50% to about 80%, or 95%. In other aspects of this embodiment, a therapeutic com about 60% to about 80%, about 10% to about 70%, about 20% 50 pound disclosed herein reduces the number of symptoms of a to about 70%, about 30% to about 70%, about 40% to about disorder associated with Steroid hydroxy-dehydrogenase 70%, or about 50% to about 70%. activity incurred over a given time period by, e.g., about 10% In one embodiment, a therapeutic compound disclosed to about 100%, about 20% to about 100%, about 30% to about herein reduces a symptom of a disorder associated with Ste 100%, about 40% to about 100%, about 50% to about 100%, roid hydroxy-dehydrogenase activity. In aspects of this 55 about 60% to about 100%, about 70% to about 100%, about embodiment, a therapeutic compound disclosed herein 80% to about 100%, about 10% to about 90%, about 20% to reduces a symptom of a disorder associated with steroid about 90%, about 30% to about 90%, about 40% to about hydroxy-dehydrogenase activity by, e.g., at least 10%, at least 90%, about 50% to about 90%, about 60% to about 90%, 15%, at least 20%, at least 25%, at least 30%, at least 35%, at about 70% to about 90%, about 10% to about 80%, about 20% least 40%, at least 45%, at least 50%, at least 55%, at least 60 to about 80%, about 30% to about 80%, about 40% to about 60%, at least 65%, at least 70%, at least 75%, at least 80%, at 80%, about 50% to about 80%, or about 60% to about 80%, least 85%, at least 90% or at least 95%. In other aspects of this about 10% to about 70%, about 20% to about 70%, about 30% embodiment, a therapeutic compound disclosed herein to about 70%, about 40% to about 70%, or about 50% to about reduces a symptom of a disorder associated with steroid 70%. hydroxy-dehydrogenase activity by, e.g., about 10% to about 65 In another embodiment, atherapeutic compound disclosed 100%, about 20% to about 100%, about 30% to about 100%, herein reduces the severity of a symptom of a disorder asso about 40% to about 100%, about 50% to about 100%, about ciated with steroid hydroxy-dehydrogenase activity. In US 9,375,433 B2 7 8 aspects of this embodiment, a therapeutic compound dis HSD17B subtype 14 (HSD17B14) activity or a therapeutic closed herein reduces the severity of a symptom of a disorder compound capable of modulating HSD17B subtype 15 associated with steroid hydroxy-dehydrogenase activity by, (HSD17B15) activity. e.g., at least 10%, at least 15%, at least 20%, at least 25%, at In one embodiment, a therapeutic compound disclosed least 30%, at least 35%, at least 40%, at least 45%, at least herein reduces a symptom of a disorder associated with 50%, at least 55%, at least 60%, at least 65%, at least 70%, at HSD17B activity. In aspects of this embodiment, a therapeu least 75%, at least 80%, at least 85%, at least 90% or at least tic compound disclosed herein reduces a symptom of a dis 95%. In other aspects of this embodiment, a therapeutic com order associated with HSD17B activity by, e.g., at least 10%, pound disclosed herein reduces the severity of a symptom of at least 15%, at least 20%, at least 25%, at least 30%, at least 10 35%, at least 40%, at least 45%, at least 50%, at least 55%, at a disorder associated with steroid hydroxy-dehydrogenase least 60%, at least 65%, at least 70%, at least 75%, at least activity by, e.g., about 10% to about 100%, about 20% to 80%, at least 85%, at least 90% or at least 95%. In other about 100%, about 30% to about 100%, about 40% to about aspects of this embodiment, a therapeutic compound dis 100%, about 50% to about 100%, about 60% to about 100%, closed herein reduces a symptom of a disorder associated about 70% to about 100%, about 80% to about 100%, about 15 with HSD17B activity by, e.g., about 10% to about 100%, 10% to about 90%, about 20% to about 90%, about 30% to about 20% to about 100%, about 30% to about 100%, about about 90%, about 40% to about 90%, about 50% to about 40% to about 100%, about 50% to about 100%, about 60% to 90%, about 60% to about 90%, about 70% to about 90%, about 100%, about 70% to about 100%, about 80% to about about 10% to about 80%, about 20% to about 80%, about 30% 100%, about 10% to about 90%, about 20% to about 90%, to about 80%, about 40% to about 80%, about 50% to about about 30% to about 90%, about 40% to about 90%, about 50% 80%, or about 60% to about 80%, about 10% to about 70%, to about 90%, about 60% to about 90%, about 70% to about about 20% to about 70%, about 30% to about 70%, about 40% 90%, about 10% to about 80%, about 20% to about 80%, to about 70%, or about 50% to about 70%. about 30% to about 80%, about 40% to about 80%, about 50% A therapeutic compound disclosed herein may be capable to about 80%, or about 60% to about 80%, about 10% to about of modulating 17 B-Hydroxysteroid dehydrogenase 25 70%, about 20% to about 70%, about 30% to about 70%, (HSD17B) activity. As used herein, the term “capable of about 40% to about 70%, or about 50% to about 70%. modulating HSD17B activity” refers to the ability of the In another embodiment, atherapeutic compound disclosed therapeutic compound disclosed herein to directly or indi herein reduces the frequency of a symptom of a disorder rectly alter the oxidative activity of a HSD17B, directly or associated with HSD17B activity incurred over a given time 30 period. In aspects of this embodiment, a therapeutic com indirectly alter the reductive activity of a HSD17B, directly or pound disclosed herein reduces the frequency of a symptom indirectly decrease the level of a progesterone in an indi of a disorder associated with HSD17B activity incurred over vidual, directly or indirectly decrease the level of an androgen a given time periodby, e.g., at least 10%, at least 15%, at least in an individual, directly or indirectly decrease the level of an 20%, at least 25%, at least 30%, at least 35%, at least 40%, at estrogen in an individual, or any combination thereof. Steroid 35 least 45%, at least 50%, at least 55%, at least 60%, at least hydroxy-dehydrogenases are a class of enzyme involved in 65%, at least 70%, at least 75%, at least 80%, at least 85%, at androgen production. 17 B-hydroxysteroid dehydrogenases least 90% or at least 95%. In other aspects of this embodi (17B HSDs or HSD17Bs) are responsible for oxidation and ment, a therapeutic compound disclosed herein reduces the reduction of androgens via this bio-synthetic pathway. Most frequency of a symptom of a disorder associated with of these enzymes are capable of working in both redox direc 40 HSD17B activity incurred over a given time period by, e.g., tions, but predominantly carry out one reaction in vivo. about 10% to about 100%, about 20% to about 100%, about HSD17B10 (HSD17B10 or HSD10) is known to be up-regu 30% to about 100%, about 40% to about 100%, about 50% to lated in certain cancers as well as cancer that have become about 100%, about 60% to about 100%, about 70% to about hormone refractory. 100%, about 80% to about 100%, about 10% to about 90%, In aspects of this embodiment, a therapeutic compound 45 about 20% to about 90%, about 30% to about 90%, about 40% capable of modulating HSD17B activity includes, without to about 90%, about 50% to about 90%, about 60% to about limitation, a therapeutic compound capable of modulating 90%, about 70% to about 90%, about 10% to about 80%, HSD17B subtype 1 (HSD17B1) activity a therapeutic com about 20% to about 80%, about 30% to about 80%, about 40% pound capable of modulating HSD17B subtype 2 to about 80%, about 50% to about 80%, or about 60% to about (HSD17B2) activity a therapeutic compound capable of 50 80%, about 10% to about 70%, about 20% to about 70%, modulating HSD17B subtype 3 (HSD17B3) activity athera about 30% to about 70%, about 40% to about 70%, or about peutic compound capable of modulating HSD17B subtype 4 50% to about 70%. (HSD17B4) activity a therapeutic compound capable of In another embodiment, atherapeutic compound disclosed modulating HSD17B subtype 5 (HSD17B5) activity athera herein reduces the number of symptoms of a disorder associ peutic compound capable of modulating HSD17B subtype 6 55 ated with HSD17B activity incurred over a given time period. (HSD17B6) activity a therapeutic compound capable of In aspects of this embodiment, a therapeutic compound dis modulating HSD17B subtype 7 (HSD17B7) activity athera closed herein reduces the number of symptoms of a disorder peutic compound capable of modulating HSD17B subtype 8 associated with HSD17B activity incurred over a given time (HSD17B8) activity a therapeutic compound capable of periodby, e.g., at least 10%, at least 15%, at least 20%, at least modulating HSD17B subtype 9 (HSD17B9) activity athera 60 25%, at least 30%, at least 35%, at least 40%, at least 45%, at peutic compound capable of modulating HSD17B subtype 10 least 50%, at least 55%, at least 60%, at least 65%, at least (HSD17B10) activity a therapeutic compound capable of 70%, at least 75%, at least 80%, at least 85%, at least 90% or modulating HSD17B subtype 11 (HSD17B11) activity a at least 95%. In other aspects of this embodiment, a therapeu therapeutic compound capable of modulating HSD17B sub tic compound disclosed herein reduces the number of symp type 12 (HSD17B12) activity a therapeutic compound 65 toms of a disorder associated with HSD17B activity incurred capable of modulating HSD17B subtype 13 (HSD17B13) over a given time period by, e.g., about 10% to about 100%, activity a therapeutic compound capable of modulating about 20% to about 100%, about 30% to about 100%, about US 9,375,433 B2 9 10 40% to about 100%, about 50% to about 100%, about 60% to embodiment, a therapeutic compound disclosed herein about 100%, about 70% to about 100%, about 80% to about modulates androgen production by, e.g., about 10% to about 100%, about 10% to about 90%, about 20% to about 90%, 100%, about 20% to about 100%, about 30% to about 100%, about 30% to about 90%, about 40% to about 90%, about 50% about 40% to about 100%, about 50% to about 100%, about to about 90%, about 60% to about 90%, about 70% to about 60% to about 100%, about 70% to about 100%, about 80% to 90%, about 10% to about 80%, about 20% to about 80%, about 100%, about 10% to about 90%, about 20% to about about 30% to about 80%, about 40% to about 80%, about 50% 90%, about 30% to about 90%, about 40% to about 90%, to about 80%, or about 60% to about 80%, about 10% to about about 50% to about 90%, about 60% to about 90%, about 70% 70%, about 20% to about 70%, about 30% to about 70%, to about 90%, about 10% to about 80%, about 20% to about about 40% to about 70%, or about 50% to about 70%. 10 80%, about 30% to about 80%, about 40% to about 80%, In another embodiment, atherapeutic compound disclosed about 50% to about 80%, or about 60% to about 80%, about herein reduces the severity of a symptom of a disorder asso 10% to about 70%, about 20% to about 70%, about 30% to ciated with HSD17B activity. In aspects of this embodiment, about 70%, about 40% to about 70%, or about 50% to about atherapeutic compound disclosed herein reduces the severity 70%. In yet other aspects of this embodiment, modulation of of a symptom of a disorder associated with HSD17B activity 15 androgen production may include modulation of a steroid by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, hydroxy-dehydrogenase activity. In still other aspects of this at least 30%, at least 35%, at least 40%, at least 45%, at least embodiment, modulation of androgen production may 50%, at least 55%, at least 60%, at least 65%, at least 70%, at include a 113-hydroxysteroid dehydrogenase activity, a least 75%, at least 80%, at least 85%, at least 90% or at least 3f3-hydroxysteroid dehydrogenase activity, a 17f8-hydroxys 95%. In other aspects of this embodiment, a therapeutic com teroid dehydrogenase activity, a 203-hydroxysteroid dehy pound disclosed herein reduces the severity of a symptom of drogenase activity, or any combination thereof. a disorder associated with HSD17B activity by, e.g., about In another embodiment, atherapeutic compound disclosed 10% to about 100%, about 20% to about 100%, about 30% to herein reduces a level of a dihydrotestosterone. In aspects of about 100%, about 40% to about 100%, about 50% to about this embodiment, a therapeutic compound disclosed herein 100%, about 60% to about 100%, about 70% to about 100%, 25 reduces a level of a dihydrotestosterone by, e.g., at least 10%, about 80% to about 100%, about 10% to about 90%, about at least 15%, at least 20%, at least 25%, at least 30%, at least 20% to about 90%, about 30% to about 90%, about 40% to 35%, at least 40%, at least 45%, at least 50%, at least 55%, at about 90%, about 50% to about 90%, about 60% to about least 60%, at least 65%, at least 70%, at least 75%, at least 90%, about 70% to about 90%, about 10% to about 80%, 80%, at least 85%, at least 90% or at least 95%. In other about 20% to about 80%, about 30% to about 80%, about 40% 30 aspects of this embodiment, a therapeutic compound dis to about 80%, about 50% to about 80%, or about 60% to about closed herein reduces a level of a dihydrotestosterone by, e.g., 80%, about 10% to about 70%, about 20% to about 70%, about 10% to about 100%, about 20% to about 100%, about about 30% to about 70%, about 40% to about 70%, or about 30% to about 100%, about 40% to about 100%, about 50% to 50% to about 70%. about 100%, about 60% to about 100%, about 70% to about In another embodiment, atherapeutic compound disclosed 35 100%, about 80% to about 100%, about 10% to about 90%, herein reduces the severity of a symptom of a disorder asso about 20% to about 90%, about 30% to about 90%, about 40% ciated with HSD17B10 (or HSD10) enzymatic activity. In to about 90%, about 50% to about 90%, about 60% to about aspects of this embodiment, a therapeutic compound dis 90%, about 70% to about 90%, about 10% to about 80%, closed herein reduces the severity of a symptom of a disorder about 20% to about 80%, about 30% to about 80%, about 40% associated with HSD17B10 enzymatic activity by, e.g., at 40 to about 80%, about 50% to about 80%, or about 60% to about least 10%, at least 15%, at least 20%, at least 25%, at least 80%, about 10% to about 70%, about 20% to about 70%, 30%, at least 35%, at least 40%, at least 45%, at least 50%, at about 30% to about 70%, about 40% to about 70%, or about least 55%, at least 60%, at least 65%, at least 70%, at least 50% to about 70%. 75%, at least 80%, at least 85%, at least 90% or at least 95%. In another embodiment, atherapeutic compound disclosed In other aspects of this embodiment, a therapeutic compound 45 herein reduces a level of a testosterone. In aspects of this disclosed herein reduces the severity of a symptom of a dis embodiment, a therapeutic compound disclosed herein order associated with HSD17B10 enzymatic activity by, e.g., reduces a level of a testosterone by, e.g., at least 10%, at least about 10% to about 100%, about 20% to about 100%, about 15%, at least 20%, at least 25%, at least 30%, at least 35%, at 30% to about 100%, about 40% to about 100%, about 50% to least 40%, at least 45%, at least 50%, at least 55%, at least about 100%, about 60% to about 100%, about 70% to about 50 60%, at least 65%, at least 70%, at least 75%, at least 80%, at 100%, about 80% to about 100%, about 10% to about 90%, least 85%, at least 90% or at least 95%. In other aspects of this about 20% to about 90%, about 30% to about 90%, about 40% embodiment, a therapeutic compound disclosed herein to about 90%, about 50% to about 90%, about 60% to about reduces a level of a testosterone by, e.g., about 10% to about 90%, about 70% to about 90%, about 10% to about 80%, 100%, about 20% to about 100%, about 30% to about 100%, about 20% to about 80%, about 30% to about 80%, about 40% 55 about 40% to about 100%, about 50% to about 100%, about to about 80%, about 50% to about 80%, or about 60% to about 60% to about 100%, about 70% to about 100%, about 80% to 80%, about 10% to about 70%, about 20% to about 70%, about 100%, about 10% to about 90%, about 20% to about about 30% to about 70%, about 40% to about 70%, or about 90%, about 30% to about 90%, about 40% to about 90%, 50% to about 70%. about 50% to about 90%, about 60% to about 90%, about 70% In another embodiment, atherapeutic compound disclosed 60 to about 90%, about 10% to about 80%, about 20% to about herein modulates androgen production. In aspects of this 80%, about 30% to about 80%, about 40% to about 80%, embodiment, a therapeutic compound disclosed herein about 50% to about 80%, or about 60% to about 80%, about modulates androgen production by, e.g., at least 10%, at least 10% to about 70%, about 20% to about 70%, about 30% to 15%, at least 20%, at least 25%, at least 30%, at least 35%, at about 70%, about 40% to about 70%, or about 50% to about least 40%, at least 45%, at least 50%, at least 55%, at least 65 70%. 60%, at least 65%, at least 70%, at least 75%, at least 80%, at In another embodiment, atherapeutic compound disclosed least 85%, at least 90% or at least 95%. In other aspects of this herein reduces a levelofanandrostenedione. In aspects of this US 9,375,433 B2 11 12 embodiment, a therapeutic compound disclosed herein reduces a level of an estrogen by, e.g., at least 10%, at least reduces a level of an androstenedione by, e.g., at least 10%, at 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 15%, at least 20%, at least 25%, at least 30%, at least least 40%, at least 45%, at least 50%, at least 55%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 60%, at least 65%, at least 70%, at least 75%, at least least 85%, at least 90% or at least 95%. In other aspects of this 80%, at least 85%, at least 90% or at least 95%. In other embodiment, a therapeutic compound disclosed herein aspects of this embodiment, a therapeutic compound dis reduces a level of an estrogen by, e.g., about 10% to about closed herein reduces a level of an androstenedione by, e.g., 100%, about 20% to about 100%, about 30% to about 100%, about 10% to about 100%, about 20% to about 100%, about about 40% to about 100%, about 50% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to 10 about 100%, about 60% to about 100%, about 70% to about 60% to about 100%, about 70% to about 100%, about 80% to 100%, about 80% to about 100%, about 10% to about 90%, about 100%, about 10% to about 90%, about 20% to about about 20% to about 90%, about 30% to about 90%, about 40% 90%, about 30% to about 90%, about 40% to about 90%, to about 90%, about 50% to about 90%, about 60% to about about 50% to about 90%, about 60% to about 90%, about 70% 90%, about 70% to about 90%, about 10% to about 80%, 15 to about 90%, about 10% to about 80%, about 20% to about about 20% to about 80%, about 30% to about 80%, about 40% 80%, about 30% to about 80%, about 40% to about 80%, to about 80%, about 50% to about 80%, or about 60% to about about 50% to about 80%, or about 60% to about 80%, about 80%, about 10% to about 70%, about 20% to about 70%, 10% to about 70%, about 20% to about 70%, about 30% to about 30% to about 70%, about 40% to about 70%, or about about 70%, about 40% to about 70%, or about 50% to about 50% to about 70%. 70%. In another embodiment, atherapeutic compound disclosed herein reduces a level of an androstenediol. In aspects of this In an embodiment, a therapeutic compound disclosed embodiment, a therapeutic compound disclosed herein herein is a benzo(iso)oxazolepiperidine. BenZO(iso)oxazol reduces a level of an androstenediolby, e.g., at least 10%, at epiperidines are a family of antipsychotic drugs. In aspects of least 15%, at least 20%, at least 25%, at least 30%, at least 25 this embodiment, a benzo(iso)oxazolepiperidine may be Ilo 35%, at least 40%, at least 45%, at least 50%, at least 55%, at peridone { 1-4-3-4-(6-fluoro-1,2-benzoxazol-3-yl)piperi least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In other din-1-yl)propoxy-3-methoxyphenylethanone, Ocaperi aspects of this embodiment, a therapeutic compound dis done 3-4-4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl) closed herein reduces a level of an androstenediol by, e.g., 30 ethyl-2,9-dimethylpyrido 1,2-alpyrimidin-4-one, about 10% to about 100%, about 20% to about 100%, about paliperidone or 9-hydroxyrisperidone {3-2-4-(6-fluo 30% to about 100%, about 40% to about 100%, about 50% to robenzodisoxazol-3-yl)-1-piperidylethyl-7-hydroxy-4- about 100%, about 60% to about 100%, about 70% to about methyl-1,5-diazabicyclo[4.4.0deca-3,5-dien-2-one}, and 100%, about 80% to about 100%, about 10% to about 90%, risperidone {3-2-4-(6-fluoro-1,2-benzoxazol-3-yl)piperi about 20% to about 90%, about 30% to about 90%, about 40% 35 din-1-yl)ethyl-2-methyl-6,7,8,9-tetrahydropyrido 1,2-apy to about 90%, about 50% to about 90%, about 60% to about rimidin-4-one. 90%, about 70% to about 90%, about 10% to about 80%, In an embodiment, a therapeutic compound disclosed about 20% to about 80%, about 30% to about 80%, about 40% herein is compound I or an optionally Substituted compound to about 80%, about 50% to about 80%, or about 60% to about I. 80%, about 10% to about 70%, about 20% to about 70%, 40 about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%. In another embodiment, atherapeutic compound disclosed herein reduces a level of a dehydroepiandrosterone (DHEA). In aspects of this embodiment, a therapeutic compound dis 45 closed herein reduces a level of a DHEAby, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In other 50 aspects of this embodiment, a therapeutic compound dis closed herein reduces a level of a DHEAby, e.g., about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 55 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 60 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%. In another embodiment, atherapeutic compound disclosed 65 In some embodiment, a therapeutic compound disclosed herein reduces a level of an estrogen. In aspects of this herein is compound II or an optionally Substituted compound embodiment, a therapeutic compound disclosed herein II. US 9,375,433 B2 13 14 includes one C, N, O, S, Si, F, Cl, Br, or I atom. Examples of Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, het eroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcar 5 boxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-car bamyl. N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-Sulfonamido, N-sulfonamido, isocy anato, thiocyanato, isothiocyanato, nitro, silyl, Sulfenyl, Sulfi CC 2 nyl, Sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesulfo 10 nyl, trihalomethanesulfonamido, amino, etc. For convenience, the term “molecular weight’ is used with respect to a moiety or part of a molecule to indicate the Sum of the atomic masses of the atoms in the moiety or part of a In some embodiment, a therapeutic compound disclosed 15 molecule, even though it may not be a complete molecule. herein is compound III oran optionally Substituted compound As used herein, the term “alkyl has the broadest meaning III. generally understood in the art, and may include a moiety composed of carbon and hydrogen containing no double or triple bonds. Alkyl may be linear alkyl, branched alkyl, III cycloalkyl, or a combination thereof, and in Some embodi ments, may contain from one to thirty-five carbon atoms. In Some embodiments, alkyl may include Colinear alkyl. Such as methyl (—CH), ethyl (—CHCH), n-propyl (—CH2CHCH), n-butyl ( CHCHCHCH), n-pentyl 25 (—CH2CH2CHCHCH), n-hexyl (—CH2CH2CH2CH2CH2CH), etc.; Co. branched alkyl, Such as C.H., (e.g. iso-propyl), C.H. (e.g. branched butyl lo) isomers), C.H. (e.g. branched pentyl isomers), C.H. (e.g. branched hexyl isomers), CHs (e.g. heptyl isomers), etc.; Co cycloalkyl. Such as CHs (e.g. cyclopropyl), CH, (e.g. cyclobutyl isomers such as cyclobutyl, methylcyclopropyl. etc.), C5Ho (e.g. cyclopentyl isomers such as cyclopentyl, In some embodiment, a therapeutic compound disclosed methylcyclobutyl, dimethylcyclopropyl, etc.) C.H. (e.g. herein is compound IV or an optionally Substituted com cyclohexyl isomers), C.H. (e.g. cycloheptyl isomers), etc.; pound IV 35 and the like. In an embodiment, a therapeutic compound disclosed herein is a pharmaceutically-acceptable fatty acid. A fatty acid comprises a carboxylic acid with a long unbranched hydrocarbon chain which may be either saturated or unsatur 40 ated. This arrangement confers a fatty acid with a polar, hydrophilic end, and a nonpolar, hydrophobic end that is insoluble in water. Most naturally occurring fatty acids have a hydrocarbon chain of an even number of carbon atoms, -CO typically between 4 and 24 carbons, and may be attached to 45 functional groups containing oxygen, halogens, nitrogen, and Sulfur. Synthetic or non-natural fatty acids may have a hydro carbon chain of any number of carbon atoms from between 3 and 40 carbons. Where a double bond exists, there is the possibility of either a cis or a trans geometric isomerism, Unless otherwise indicated, when a compound or chemical 50 which significantly affects the molecule's molecular configu structural feature disclosed herein is referred to as being ration. Cis-double bonds cause the fatty acid chain to bend, an “optionally substituted, it includes a feature that has no sub effect that is more pronounced the more double bonds there stituents (i.e. unsubstituted), or a feature that is “substituted.” are in a chain. Most naturally occurring fatty acids are of the meaning that the feature has one or more Substituents. The cis configuration, although the trans form does exist in some term “substituent has the broadest meaning known to one of 55 natural and partially hydrogenated fats and oils. Examples of ordinary skill in the art, and includes a moiety that replaces fatty acids include, without limitation, Capryllic acid, pelar one or more hydrogen atoms attached to a parent compound gonic acid, Capric acid. Undecylic acid, Lauric acid, Tride or structural feature. In some embodiments, a Substituent may cylic acid, Myristic acid, Myristoleic acid, Pentadecyclic be an ordinary organic moiety known in the art, which may acid, Palmitic acid, Palmitoleic acid, Sapienic acid, Margaric have a molecular weight (e.g. the Sum of the atomic masses of 60 acid, Stearic acid, Oleic acid, Elaidic acid, Vaccenic acid, the atoms of the substituent) of 15 g/mol to 50 g/mol, 15 g/mol Linoleic acid, Linoelaidic acid, C-Linolenic acid, Y-Linolenic to 100 g/mol, 15 g/mol to 150 g/mol, 15 g/mol to 200 g/mol. acid, Stearidonic acid. Nonadecylic acid, Arachidic acid, 15 g/mol to 300 g/mol, or 15 g/mol to 500 g/mol. In some Eicosenoic acid, Dihomo-y-linolenic acid, Mead acid, embodiments, a Substituent comprises, or consists of 0-30, Arachidonic acid, Eicosapentaenoic acid, Heneicosylic acid, 0-20, 0-10, or 0-5 carbon atoms; and 0-30,0-20, 0-10, or 0-5 65 Behenic acid, Erucic acid, Docosahexaenoic acid, Tricosylic heteroatoms, wherein each heteroatom may independently acid, Lignoceric acid, Nervonic acid, Pentacosylic acid, be: N, O, S, Si, F, Cl, Br, or I; provided that the substituent Cerotic acid, Heptacosylic acid, Montanic acid, Nonacosylic US 9,375,433 B2 15 16 acid, Melissic acid, Henatriacontylic acid, Lacceroic acid, limitation, 5-Dodecenoic acid (12:1), 7-Tetradecenoic acid Psyllic acid, Geddic acid, Ceroplastic acid, and Hexatriacon (14:1), 9-Hexadecenoic acid (Palmitoleic acid) (16:1), tylic acid. 11-Decenoic acid (Vaccenic acid) (18:1), 9Z,11E conjugated In aspects of this embodiment, a saturated or unsaturated Linoleic acid (Rumenic acid)(18:2), 13-Eicosenoic acid fatty acid comprises, e.g., at least 8, at least 10, at least 12, at 5 (Paullinic acid) (20:1), 15-Docosenoic acid (22:1), and least 14, at least 16, at least 18, at least 20, at least 22, at least 17-Tetracosenoic acid (24:1). 24, at least 26, at least 28, or at least 30 carbonatoms, In other Omega-9 fatty acids (also known as n-9 fatty acids or ()-9 aspects of this embodiment, a saturated or unsaturated fatty fatty acids) area family of unsaturated fatty acids that have in acid comprises, e.g., between 4 and 24 carbonatoms, between common a final carbon-carbon double bond in the n-9 posi 6 and 24 carbon atoms, between 8 and 24 carbon atoms, 10 tion, that is, the ninth bond, counting from the methyl end of between 10 and 24 carbon atoms, between 12 and 24 carbon the fatty acid. An omega-9 fatty acid includes, without limi atoms, between 14 and 24 carbon atoms, or between 16 and tation, Oleic acid (18:1), Elaidic acid (18:1), Eicosenoic acid 24 carbonatoms, between 4 and 22 carbonatoms, between 6 (20:1). Mead acid (20:3), Erucic acid (22:1), Nervonic acid and 22 carbon atoms, between 8 and 22 carbon atoms, (24:1), and Ricinoleic acid. between 10 and 22 carbon atoms, between 12 and 22 carbon 15 A pharmaceutically-acceptable fatty acid useful in the atoms, between 14 and 22 carbon atoms, or between 16 and pharmaceutical compositions disclosed herein may be a phar 22 carbonatoms, between 4 and 20 carbonatoms, between 6 maceutically-acceptable conjugated fatty acid. Conjugated and 20 carbon atoms, between 8 and 20 carbon atoms, fatty acids are positional and geometric isomers of polyun between 10 and 20 carbon atoms, between 12 and 20 carbon saturated fatty acids in which at least one pair of double bonds atoms, between 14 and 20 carbon atoms, or between 16 and are separated by only one single bond. In one aspect of this 20 carbonatoms. If unsaturated, the fatty acid may have, e.g., embodiment, a pharmaceutically-acceptable conjugated fatty 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, or 6 or acid is, e.g., a C16 conjugated fatty acid, a C18 conjugated more double bonds. fatty acid, a C20 conjugated fatty acid, a C22 conjugated fatty In another embodiment, an adjuvant may comprise one acid, a C24 conjugated fatty acid, a C26 conjugated fatty acid, kind of pharmaceutically-acceptable fatty acid. In another 25 a C28 conjugated fatty acid or a C30 conjugated fatty acid. In embodiment, an adjuvant may comprise a plurality of differ one aspect of this embodiment, pharmaceutically-acceptable ent pharmaceutically-acceptable fatty acids. In aspects of this conjugated fatty acid is, e.g., a C16-C18 conjugated fatty embodiment, an adjuvant may comprise, e.g., two or more acid, a C16-C20 conjugated fatty acid, a C16-C22 conjugated different fatty acids, three or more different fatty acids, four or fatty acid, a C16-C24 conjugated fatty acid, a C16-C26 con more different fatty acids, five or more different fatty acids, or 30 jugated fatty acid, a C16-C28 conjugated fatty acid, a C16 six or more different fatty acids. C30 conjugated fatty acid, a C18-C20 conjugated fatty acid, A pharmaceutically-acceptable fatty acid useful in the a C18-C22 conjugated fatty acid, a C18-C24 conjugated fatty pharmaceutical compositions disclosed herein may be a phar acid, a C18-C26 conjugated fatty acid, a C18-C28 conjugated maceutically-acceptable omega fatty acid. Non-limiting fatty acid, a C18-C30 conjugated fatty acid, a C20-C22 con examples of an omega fatty acid include an omega-3 fatty 35 jugated fatty acid, a C20-C24 conjugated fatty acid, a C20 acid, an omega-6 fatty acid, an omega-7 fatty acid, an C26 conjugated fatty acid, a C20-C28 conjugated fatty acid, omega-9 fatty acid. Omega-3 fatty acids (also known as n-3 a C20-C30 conjugated fatty acid, a C22-C24 conjugated fatty fatty acids or c)-3 fatty acids) are a family of essential unsat acid, a C22-C26 conjugated fatty acid, a C22-C28 conjugated urated fatty acids that have in common a final carbon-carbon fatty acid, a C22-C30 conjugated fatty acid, a C24-C26 con double bond in the n-3 position, that is, the third bond, count 40 jugated fatty acid, a C24-C28 conjugated fatty acid, a C24 ing from the methyl end of the fatty acid. The omega-3 fatty C30 conjugated fatty acid, a C26-C28 conjugated fatty acid, acids are “essential fatty acids because they are vital for a C26-C30 conjugated fatty acid, or C28-C30 conjugated normal metabolism and cannot be synthesized by the human fatty acid. body. An omega-3 fatty acid includes, without limitation, In another aspect of this embodiment, a pharmaceutically Hexadecatrienoic acid (16:3), C-Linolenic acid (18:3), 45 acceptable conjugated fatty acid includes, e.g., a conjugated Stearidonic acid (18:4). Eicosatrienoic acid (20:3), Eicosatet Linoleic acid, a conjugated Linoelaidic acid, a conjugated raenoic acid (20:4). Eicosapentaenoic acid (20:5), Hene C-Linolenic acid, a conjugated Y-Linolenic acid, a conjugated icosapentaenoic acid (21:5), Docosapentaenoic acid (Clu Calendic acid, a conjugated Eicosadienoic acid, a conjugated panodonic acid) (22:5), Docosahexaenoic acid (22:6), Stearidonic acid, a conjugated Nonadecylic acid, a conju Tetracosapentaenoic acid (24:5), Tetracosahexaenoic acid 50 gated Arachidic acid, a conjugated Dihomo-y-linolenic acid, (Nisinic acid) (24:6). a conjugated DocoSadienoic, a conjugated Mead acid, a con Omega-6 fatty acids (also known as n-6 fatty acids or (O-6 jugated Arachidonic acid, a conjugated Eicosapentaenoic fatty acids) are a family of unsaturated fatty acids that have in acid, a conjugated Adrenic acid, a conjugated Docosapen common a final carbon-carbon double bond in the n-6 posi taenoic acid, a conjugated Heneicosylic acid, a conjugated tion, that is, the sixth bond, counting from the methyl end of 55 Tetracosatetraenoic acid, a conjugated Tetracosapentaenoic the fatty acid. An omega-6 fatty acid includes, without limi acid, a conjugated Behenic acid, a conjugated Docosa tation, Linoleic acid (18:2), Y-linolenic acid (18:3), Calendic hexaenoic acid, a conjugated Tricosylic acid, a conjugated acid (18:3), Eicosadienoic acid (20:2), Dihomo-y-linolenic Lignoceric acid, a conjugated Pentacosylic acid, a conjugated acid (20:3), Arachidonic acid (20:4), Docosadienoic acid (22: Cerotic acid, a conjugated Heptacosylic acid, a conjugated 2), Adrenic acid (22:4). Docosapentaenoic acid (22:5), Tet 60 Montanic acid, a conjugated Nonacosylic acid, a conjugated racosatetraenoic acid (24:4), and Tetracosapentaenoic acid Melissic acid, a conjugated Henatriacontylic acid, a conju (24:5). gated Lacceroic acid, a conjugated Psyllic acid, a conjugated Omega-7 fatty acids (also known as n-7 fatty acids or (O-7 Geddic acid, a conjugated Ceroplastic acid, a conjugated fatty acids) are a family of unsaturated fatty acids that have in Hexatriacontylic acid, or any combination thereof. common a final carbon-carbon double bond in the n-7 posi 65 A pharmaceutically-acceptable fatty acid useful in the tion, that is, the seventh bond, counting from the methyl end pharmaceutical compositions disclosed herein may be a phar of the fatty acid. An omega-7 fatty acid includes, without maceutically-acceptable conjugated linoleic acid (CLA). US 9,375,433 B2 17 18 Conjugated linoleic acid (CLA) refers to a group of at least 28 mycin, Sulfate (blenoxane), therarubicin, bleomycinic acid, positional and geometric isomers of linoleic acid (cis-9, cis idarubicin, bleomycin A, rubidazone, bleomycin B, plicamy 12, octadecadienoic acid). The double bonds of CLAS are cin, mitomycin C, porfiromycin, MEN-10755 (Menarini), conjugated, with only one single bond between them. Virtu cyanomorpholinodoxorubicin, GPX-100 (Gem Pharmaceu ally all cis- and trans-isomeric combinations of CLA have ticals), or mitoxantrone (novantrone), antimitotic agents, been identified. A CLA includes, without limitation, cis-9, such as, for example, paclitaxel, SB 408075 (GlaxoSmith trans-11, conjugated linoleic acid (c-9, t-1 1 CLA), cis-9, cis Kline), docetaxel, E7010 (Abbott), colchicines, PG-TXL 11, conjugated linoleic acid (c-9, c-1 1 CLA), trans-9, trans (Cell Therapeutics), vinblastine, IDN 5109 (Bayer), Vincris 11, conjugated linoleic acid (t-9, t-1 1 CLA), and trans-9, tine A, 105972 (Abbott), vinorelbine. A 204197 (Abbott), cis-11, conjugatedlinoleic acid (t-9, c-1 1 CLA), cis-10, trans 10 vindesine, LU 223651 (BASF), dolastatin 10 (NCI), D24851 12, conjugated linoleic acid (c-10, t-12 CLA), cis-10, cis-12, (ASTAMedica), rhizoxin (Fujisawa), ER-86526 (Eisai), conjugated linoleic acid (c-10, c-12 CLA), trans-10, trans-12, mivobulin (Warner-Lambert), combretastatin A4 (BMS), conjugated linoleic acid (t-10, t-12 CLA), and trans-10, cis cemadotin (BASF), isohomohalichondrin-B (PharmaMar), 12, conjugated linoleic acid (t-10, c-12 CLA), or any combi RPR 109881A (Aventis), ZD 6126 (AstraZeneca), TXD 258 nation thereof. 15 (Aventis), PEG-paclitaxel (Enzon.) epothilone B (Novartis), In an embodiment, a therapeutic compound disclosed AZ10992 (Asahi), T900607 (Tularik), IDN-5109 (Indena), T herein is a 5C. reductase inhibitor. The enzyme 5C.-reductase 138067 (Tularik), AVLB (Prescient NeuroPharma), crypto is involved in the conversion of testosterone to the active form phycin 52 (Eli Lilly), azaepothilone B (BMS), vinflunine dihydrotestosterone (DHT) by reducing the A4.5 double (Fabre), BNP-7787 (BioNumerik), auristatin PE (Teikoku bond. In benign prostatic hyperplasia, dihydrotestosterone Hormone), CA-4 prodrug (OXiGENE), BMS 247550 acts as a potent cellular androgen and promotes prostate (BMS), dolastatin-10 (NIH), BMS 184476 (BMS), CA-4 growth; therefore, inhibiting the enzyme reduces the exces (OXiGENE), BMS 188797 (BMS), or taxoprexin (Protarga); sive prostate growth. In alopecia, male-pattern baldness is aromatase inhibitors, such as, for example, aminoglutethim one of the effects of androgenic receptor activation. Thus, ide, exemestane, letrozole, atamestane (BioMedicines), anas reducing the levels of dihydrotestosterone reduces alopecia. 25 trazole, YM-511 (Yamanouchi), or formestane; thymidylate These inhibitors decrease the levels of available 5C.-reductase synthase inhibitors, such as, for example, pemetrexed (Eli prior to testosterone's binding with the enzyme, thus reducing Lilly), nolatrexed (Eximias), ZD-9331 (BTG), or CoFactorTM levels of dihydrotestosterone that derives from such a bond. A (Biokeys); DNA antagonists, such as, for example, trabect 5C. reductase inhibitor include, without limitation, Alfatra edin (PharmaMar), mafosfamide (Baxter International), glu diol, Bexlosteride, Dutasteride, Epristeride, Finasteride, 30 fosfamide (Baxter International), apaziquone (Spectrum Isotretinoin, Lapisteride, Turosteride Pharmaceuticals), albumin-i-...sup.32P (Isotope Solutions), 06 In an embodiment, a therapeutic compound disclosed benzyl guanine (Paligent), thymectacin (NewBiotics), or herein is a chemotherapeutic agent or an anti-proliferative edotreotide (Novartis); farnesyltransferase inhibitors, such agent. A chemotherapeutic agent or other anti-proliferative as, for example, arglabin (NuOncology Labs), tipifarnib agent include, without limitation, alkylating agents, such as, 35 (Johnson & Johnson), lonafarnib (Schering-Plough), perillyl for example, cyclophosphamide, lomustine, buSulfan procar alcohol (DOR BioPharma), or BAY-43-9006 (Bayer); Pump bazine, ifosfamide, altretamine, melphalan, estramustine inhibitors, such as, for example, CBT-1 (CBA Pharma), Zosu phosphate, hexamethylmelamine, mechlorethamine, quidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biri thiotepa, Streptozocin, chlorambucil, temozolomide, dacar codar dicitrate (Vertex), or MS-209 (Schering AG); Histone bazine, Semustine, or carmustine; platinum agents, such as, 40 acetyltransferase inhibitors, such as, for example, tacedina for example, cisplatin, carboplatinum, oxaliplatin, ZD-0473 line (Pfizer), pivaloyloxymethyl butyrate (Titan), SAHA (AnorMED), spiroplatinum, lobaplatin (Aeterna), carbox (Aton Pharma), depsipeptide (Fujisawa), or MS-275 (Scher yphthalatoplatinum, satraplatin (Johnson Matthey), tetrapl ing AG); Metalloproteinase inhibitors, such as, for example, atin BBR-3464, (Hoffmann-La Roche), ormiplatin, Neovastat (Aeterna Laboratories), CMT-3 (CollaGenex), SM-11355 (Sumitomo), iproplatin, or AP-5280 (Access); 45 marimastat (British Biotech), or BMS-275291 (Celltech): antimetabolites. Such as, for example, azacytidine, tomudex, ribonucleoside reductase inhibitors, such as, for example, gemcitabine, trimetrexate, capecitabine, deoxycoformycin, gallium maltolate (Titan), tezacitabine (Aventis), triapine 5-fluorouracil, fludarabine, floxuridine, pentostatin, 2-chlo (Vion), or didox (Molecules for Health); TNFalpha agonists/ rodeoxyadenosine, raltitrexed, 6-mercaptopurine, hydrox antagonists, such as, for example, virulizin (Lorus Therapeu yurea, 6-thioguanine, decitabine (SuperGen), cytarabin, clo 50 tics), revimid (Celgene), CDC-394 (Celgene), entanercept farabine (Bioenvision), 2-fluorodeoxy cytidine, irofulven (Immunex Corp.), infliximab (Centocor, Inc.), or adali (MGI Pharma), methotrexate, DMDC (Hoffmann-La mumab (Abbott Laboratories); endothelin A receptor antago Roche), idatrexate, or ethynylcytidine (Taiho); topoi nists, such as, for example, atrasentan (Abbott)YM-598 (Ya Somerase inhibitors, such as, for example, amsacrine, rubite manouchi) or ZD-4054 (AstraZeneca); retinoic acid receptor can (SuperGen), epirubicin, exatecan mesylate (Daiichi), eto 55 agonists, such as, for example, fenretinide (Johnson & poside, quinamed (ChemGenex), teniposide, mitoxantrone, Johnson) alitretinoin (Ligand) or LGD-1550 (Ligand); gimatecan (Sigma-Tau), irinotecan (CPT-11), diflomotecan immuno-modulators, such as, for example, interferon deXo (Beaufour-Ipsen), 7-ethyl-10-hydroxy-camptothecin, Some therapy (Anosys), oncophage (Antigenics), pentrix TAS-103 (Taiho), topotecan, elsamitrucin (Spectrum), dexra (Australian Cancer Technology), GMK (Progenics), ISF-154 Zoxanet (TopoTarget), J-107088 (Merck & Co), pixantrone 60 (Tragen), adenocarcinoma vaccine (Biomira), cancer vaccine (Novuspharma), BNP-1350 (BioNumerik), rebeccamycin (Intercell), CTP-37 (AVI BioPharma), norelin (Biostar), analogue (Exelixis), CKD-602 (Chong Kun Dang), BBR IRX-2 (Immuno-RX), BLP-25 (Biomira), PEP-005 (Peplin 3576 (Novuspharma), or KW-2170 (Kyowa Hakko); antitu Biotech), MGV (Progenics), synchroVax vaccines (CTL morantibiotics, such as, for example, dactinomycin (actino Immuno), beta-alethine (Dovetail), melanoma vaccine (CTL mycin D), amonafide, doxorubicin (adriamycin), azonafide, 65 Immuno), CLL, therapy (Vasogen), or p21 RAS vaccine deoxyrubicin, anthrapyrazole, valrubicin, oxantrazole, (GemVax); hormonal and antihormonal agents, such as, for daunorubicin (daunomycin), losoxantrone, epirubicin, bleo example, estrogens, prednisone, conjugated estrogens, meth US 9,375,433 B2 19 20 ylprednisolone, ethinyl estradiol, prednisolone, chlortria ZO(iso)oxazolepiperidine and an Omega-9 fatty acid where nisen, aminoglutethimide, idenestrol, leuprolide, hydrox there is a synergistic effect between the benzo(iso)oxazolepi yprogesterone caproate, goserelin, medroxyprogesterone, peridine and the Omega-9 fatty acid. In other aspects, a phar leuporelin, testosterone, bicalutamide, testosterone propi maceutical composition comprises Risperidone and an onate, fluoxymesterone, flutamide, methyltestosterone, oct Omega-3 fatty acid, an Omega-6 fatty acid, an Omega-7 fatty reotide, diethylstilbestrol, nilutamide, megestrol, mitotane, acid, an Omega-9 fatty acid, or any combination thereof tamoxifen, P-04 (Novogen), toremofine, 2-methoxyestradiol where there is a synergistic effect between the benzo(iso) (EntreMed), dexamethasone, or arzoxifene (Eli Lilly); pho oxazolepiperidine and the Omega-3 fatty acid, the Omega-6 todynamic agents, such as, for example, talaporfin (Light fatty acid, the Omega-7 fatty acid, the Omega-9 fatty acid, or Sciences), Pd-bacteriopheophorbide (Yeda). Theralux (Ther 10 any combination thereof. In yet other aspects, a pharmaceu atechnologies), lutetium texaphyrin (Pharmacyclics), tical composition comprises Risperidone and C-Linolenic motexafin gadolinium (Pharmacyclics), or hypericin; and acid, Arachidonic acid, Docosahexaenoic acid, Rumenic tyrosine kinase inhibitors. Such as, for example, imatinib acid, or any combination thereof. (Novartis), kahalide F (PharmaMar), leflunomide (Sugen/ In an embodiment, a pharmaceutical composition com Pharmacia), CEP-701 (Cephalon), ZD1839 (AstraZeneca), 15 prises a benzo(iso)oxazolepiperidine in an amount of about CEP-751 (Cephalon), erlotinib (Oncogene Science), 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 MLN518 (Millenium), canertinib (Pfizer), PKC412 (Novar mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, tis), squalamine (Genaera), phenoxodiol, SU5416 (Pharma about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg. cia), trastuzumab (Genentech), SU6668 (Pharmacia), C225 about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg. (ImClone), ZD4190 (AstraZeneca), rhu-Mab (Genentech), about 11 mg, about 12 mg, about 13 mg, about 14 mg, about ZD6474 (AstraZeneca), MDX-H210 (Medarex), vatalanib 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, (Novartis), 2C4 (Genentech), PK1166 (Novartis), MDX-447 or about 20 mg and a fatty acid like an Omega-3 fatty acid, an (Medarex), GW2016 (GlaxoSmithKline), ABX-EGF (Ab Omega-6 fatty acid, an Omega-7 fatty acid, an Omega-9 fatty genix), EKB-509 (Wyeth), IMC-1C11 (ImClone), or EKB acid, or any combination thereof in an amount of about 0.1 569 (Wyeth). 25 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg. Depending upon the particular condition, or disease, to be about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, treated, additional therapeutic agents that are normally about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg. administered to treat that condition may also be present in the about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg. compositions disclosed herein. As used herein, additional about 11 mg, about 12 mg, about 13 mg, about 14 mg, about therapeutic agents that are normally administered to treat a 30 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, particular disease, or condition, are known as “appropriate for or about 20 mg. the disease, or condition, being treated’. In an embodiment, a pharmaceutical composition com In an embodiment, a pharmaceutical composition com prises a benzo(iso)oxazolepiperidine in an amount of at least prises a benzo(iso)oxazolepiperidine and a fatty acid. In an 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least aspect of this embodiment, a pharmaceutical composition 35 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least comprises a benzo(iso)oxazolepiperidine and an Omega-3 0.9 mg, at least 1 mg, at least 2 mg, at least 3 mg, at least 4 mg. fatty acid. In another aspect of this embodiment, a pharma at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least ceutical composition comprises a benzo(iso)oxazolepiperi 9 mg, at least 10 mg, at least 11 mg, at least 12 mg, at least 13 dine and an Omega-6 fatty acid. In yet another aspect of this mg, at least 14 mg, at least 15 mg, at least 16 mg, at least 17 embodiment, a pharmaceutical composition comprises a ben 40 mg, at least 18 mg, at least 19 mg, or at least 20 mg and a fatty ZO(iso)oxazolepiperidine and an Omega-7 fatty acid. In still acid like an Omega-3 fatty acid, an Omega-6 fatty acid, an another aspect of this embodiment, a pharmaceutical compo Omega-7 fatty acid, an Omega-9 fatty acid, or any combina sition comprises a benzo(iso)oxazolepiperidine and an tion thereof in an amount of at least 0.1 mg, at least 0.2 mg, at Omega-9 fatty acid. In other aspects, a pharmaceutical com least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, position comprises Risperidone and an Omega-3 fatty acid, 45 at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1 mg, an Omega-6 fatty acid, an Omega-7 fatty acid, an Omega-9 at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least fatty acid, or any combination thereof. In yet other aspects, a 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, at least 10 mg. pharmaceutical composition comprises Risperidone and at least 11 mg, at least 12 mg, at least 13 mg, at least 14 mg. C-Linolenic acid, Arachidonic acid, Docosahexaenoic acid, at least 15 mg, at least 16 mg, at least 17 mg, at least 18 mg, Rumenic acid, or any combination thereof. 50 at least 19 mg, or at least 20 mg. In an embodiment, a pharmaceutical composition com In an embodiment, a pharmaceutical composition com prises a benzo(iso)oxazolepiperidine and a fatty acid where prises a benzo(iso)oxazolepiperidine in an amount of at most there is a synergistic effect between the benzo(iso)oxazolepi 0.1 mg, at most 0.2 mg, at most 0.3 mg, at most 0.4 mg, at peridine and the fatty acid. In an aspect of this embodiment, a most 0.5 mg, at most 0.6 mg, at most 0.7 mg, at most 0.8 mg, pharmaceutical composition comprises a benzo(iso)oxazol 55 at most 0.9 mg, at most 1 mg, at most 2 mg, at most 3 mg, at epiperidine and an Omega-3 fatty acid where there is a syn most 4 mg, at most 5 mg, at most 6 mg, at most 7 mg, at most ergistic effect between the benzo(iso)oxazolepiperidine and 8 mg, at most 9 mg, at most 10 mg, at most 11 mg, at most 12 the Omega-3 fatty acid. In another aspect of this embodiment, mg, at most 13 mg, at most 14 mg, at most 15 mg, at most 16 a pharmaceutical composition comprises a benzo(iso)oxazol mg, at most 17 mg, at most 18 mg, at most 19 mg, or at most epiperidine and an Omega-6 fatty acid where there is a syn 60 20 mg and a fatty acid like an Omega-3 fatty acid, an Omega-6 ergistic effect between the benzo(iso)oxazolepiperidine and fatty acid, an Omega-7 fatty acid, an Omega-9 fatty acid, or the Omega-6 fatty acid. In yet another aspect of this embodi any combination thereof in an amount of at most 0.1 mg, at ment, a pharmaceutical composition comprises a benzo(iso) most 0.2 mg, at most 0.3 mg, at most 0.4 mg, at most 0.5 mg. oxazolepiperidine and an Omega-7 fatty acid where there is a at most 0.6 mg, at most 0.7 mg, at most 0.8 mg, at most 0.9 synergistic effect between the benzo(iso)oxazolepiperidine 65 mg, at most 1 mg, at most 2 mg, at most 3 mg, at most 4 mg. and the Omega-7 fatty acid. In still another aspect of this at most 5 mg, at most 6 mg, at most 7 mg, at most 8 mg, at most embodiment, a pharmaceutical composition comprises a ben 9 mg, at most 10 mg, at most 11 mg, at most 12 mg, at most US 9,375,433 B2 21 22 13 mg, at most 14 mg, at most 15 mg, at most 16 mg, at most A pharmaceutical composition disclosed herein can 17 mg, at most 18 mg, at most 19 mg, or at most 20 mg. optionally include, without limitation, other pharmaceuti In an embodiment, a pharmaceutical composition com cally acceptable components (or pharmaceutical compo prises a benzo(iso)oxazolepiperidine in an amount of about nents), including, without limitation, buffers, preservatives, 0.1 mg to about 1 mg, about 0.1 mg to about 5 mg, about 0.1 tonicity adjusters, salts, antioxidants, osmolality adjusting mg to about 10 mg, about 0.1 mg to about 15 mg, about 0.1 mg agents, physiological Substances, pharmacological Sub to about 20 mg, about 0.5 mg to about 1 mg, about 0.5 mg to stances, bulking agents, emulsifying agents, wetting agents, about 5 mg, about 0.5 mg to about 10 mg, about 0.5 mg to flavoring agents, coloring agents, and the like. Various buffers about 15 mg, about 0.5 mg to about 20 mg, about 1 mg to and means for adjusting pH can be used to prepare a pharma 10 ceutical composition disclosed herein, provided that the about 5 mg, about 1 mg to about 10 mg, about 1 mg to about resulting preparation is pharmaceutically acceptable. Such 15 mg, about 1 mg to about 20 mg, about 5 mg to about 10 mg. buffers include, without limitation, acetate buffers, citrate about 5 mg to about 15 mg, about 5 mg to about 20 mg, about buffers, phosphate buffers, neutral buffered saline, phosphate 10 mg to about 15 mg, about 10 mg to about 20 mg, or about buffered saline and borate buffers. It is understood that acids 15 mg to about 20 mg, and a fatty acid like an Omega-3 fatty 15 or bases can be used to adjust the pH of a composition as acid, an Omega-6 fatty acid, an Omega-7 fatty acid, an needed. Pharmaceutically acceptable antioxidants include, Omega-9 fatty acid, or any combination thereof in an amount without limitation, sodium metabisulfite, sodium thiosulfate, of about 0.1 mg to about 1 mg, about 0.1 mg to about 5 mg. acetylcysteine, butylated hydroxyanisole and butylated about 0.1 mg to about 10 mg, about 0.1 mg to about 15 mg. hydroxytoluene. Useful preservatives include, without limi about 0.1 mg to about 20 mg, about 0.5 mg to about 1 mg, tation, benzalkonium chloride, chlorobutanol, thimerosal, about 0.5 mg to about 5 mg, about 0.5 mg to about 10 mg. phenylmercuric acetate, phenylmercuric nitrate, a stabilized about 0.5 mg to about 15 mg, about 0.5 mg to about 20 mg. oxychloro composition and chelants, such as, e.g., DTPA or about 1 mg to about 5 mg, about 1 mg to about 10 mg, about DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. 1 mg to about 15 mg, about 1 mg to about 20 mg, about 5 mg Tonicity adjustors useful in a pharmaceutical composition to about 10 mg, about 5 mg to about 15 mg, about 5 mg to 25 include, without limitation, salts such as, e.g., Sodium chlo about 20 mg, about 10 mg to about 15 mg, about 10 mg to ride, potassium chloride, mannitol or glycerin and other phar about 20 mg, or about 15 mg to about 20 mg. maceutically acceptable tonicity adjustor. The pharmaceuti A pharmaceutical composition disclosed herein may cal composition may be provided as a salt and can be formed optionally include a pharmaceutically-acceptable carrier that with many acids, including but not limited to, hydrochloric, facilitates processing of an active ingredient into pharmaceu 30 Sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend tically-acceptable compositions. As used herein, the term to be more soluble in aqueous or other protonic solvents than “pharmacologically-acceptable carrier' is synonymous with are the corresponding free base forms. It is understood that “pharmacological carrier and means any carrier that has these and other Substances known in the art of pharmacology Substantially no long term or permanent detrimental effect can be included in a pharmaceutical composition. when administered and encompasses terms such as “pharma 35 A therapeutic compound disclosed herein, or a composi cologically acceptable vehicle, stabilizer, diluent, additive, tion comprising such a therapeutic compound, may be for auxiliary or excipient. Such a carrier generally is mixed with mulated for either local or systemic delivery using topical, an active compound or permitted to dilute or enclose the enteral or parenteral routes of administration. Additionally, a active compound and can be a solid, semi-solid, or liquid therapeutic compound disclosed herein may beformulated by agent. It is understood that the active ingredients can be 40 itself in a pharmaceutical composition, or may be formulated soluble or can be delivered as a suspension in the desired together with one or more other therapeutic compounds dis carrier or diluent. Any of a variety of pharmaceutically closed herein in a single pharmaceutical composition. acceptable carriers can be used including, without limitation, A therapeutic compound disclosed herein, or a composi aqueous media Such as, e.g., water, Saline, glycine, hyaluronic tion comprising Such a therapeutic compound, may be made acid and the like; Solid carriers such as, e.g., mannitol, lactose, 45 into an inhaled formulation. Inhaled formulations suitable for starch, magnesium Stearate, sodium saccharin, talcum, cellu enteral or parenteral administration include, without limita lose, glucose, Sucrose, magnesium carbonate, and the like; tion, aerosols, dry powders. A therapeutic compound or com Solvents; dispersion media; coatings; antibacterial and anti position disclosed herein intended for Such administration fungal agents; isotonic and absorption delaying agents; or any may be prepared according to any method known to the art for other inactive ingredient. Selection of a pharmacologically 50 the manufacture of pharmaceutical compositions. acceptable carrier can depend on the mode of administration. In Such inhaled dosage forms, the therapeutic compound Except insofar as any pharmacologically acceptable carrier is may be prepared for delivery as an aerosol in a liquid propel incompatible with the active ingredient, its use in pharmaceu lant for use in a pressurised (PDI) or other metered dose tically acceptable compositions is contemplated. Non-limit inhaler (MDI). Propellants suitable for use in a PDI or MDI ing examples of specific uses of such pharmaceutical carriers 55 include, without limitation, CFC-12, HFA-134a, HFA-227, can be found in Pharmaceutical Dosage Forms and Drug HCFC-22 (difluorochloromethane), HFA-152 (difluoroet Delivery Systems (Howard C. Ansel et al., eds., Lippincott hane and isobutane). A therapeutic compound may also be Williams & Wilkins Publishers, 7th ed. 1999); REMING delivered using a nebulisers or other aerosol delivery system. TON: THE SCIENCE AND PRACTICE OF PHARMACY A therapeutic compound may be prepared for delivery as a (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 60 dry powder for use in a dry powder inhaler (DPI). A dry 20th ed. 2000); Goodman & Gilman's The Pharmacological powderfor use in the inhalers will usually have a mass median Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw aerodynamic diameterofless than 30 pm, preferably less than Hill Professional, 10th ed. 2001); and Handbook of Pharma 20 pm and more preferably less than 10 pm. Microparticles ceutical Excipients (Raymond C. Rowe et al., APhA Publi having aerodynamic diameters in the range of about 5 pm to cations, 4th edition 2003). These protocols are routine 65 about 0.5 pm will generally be deposited in the respiratory procedures and any modifications are well within the Scope of bronchioles, whereas Smaller particles, having aerodynamic one skilled in the art and from the teaching herein. diameters in the range of about 2 pm to about 0.05 pm, are US 9,375,433 B2 23 24 likely to be deposited in the alveoli. A DPI may be a passive disclosed herein typically may also be between about delivery mechanism, which relies on the individuals inspi 0.0001% (w/w) to about 60% (w/w), about 0.001% (w/w) to ration to introduce the particles into the lungs, or an active about 40.0% (w/w), or about 0.01% (w/w) to about 20.0% delivery mechanism, requiring a mechanism for delivering (w/w). the powder to the individual. In inhalatory formulations, a A therapeutic compound disclosed herein, or a composi therapeutically effective amount of a therapeutic compound tion comprising Such a therapeutic compound, may be made disclosed herein for an inhaled formulation may be between into a liquid formulation. Liquid formulations suitable for about 0.0001% (w/v) to about 60% (w/v), about 0.001% enteral or parenteral administration include, without limita (w/v) to about 40.0% (w/v), or about 0.01% (w/v) to about tion, Solutions, syrups, elixirs, dispersions, emulsions, and 20.0% (w/v). In inhalatory formulations, a therapeutically 10 Suspensions. A therapeutic compound or composition dis effective amount of a therapeutic compound disclosed herein closed herein intended for Such administration may be pre for an inhaled formulation may also be between about pared according to any method known to the art for the 0.0001% (w/w) to about 60% (w/w), about 0.001% (w/w) to manufacture of pharmaceutical compositions. In Such liquid about 40.0% (w/w), or about 0.01% (w/w) to about 20.0% dosage forms, a therapeutic compound or composition dis (w/w). 15 closed herein may be admixed with (a) Suitable aqueous and A therapeutic compound disclosed herein, or a composi nonaqueous carriers, (b) diluents, (c) solvents, such as, e.g., tion comprising Such a therapeutic compound, may be made water, ethanol, propylene glycol, polyethyleneglycol, glyc into a solid formulation. Solid formulations suitable for erol, vegetable oils, such as, e.g., rapeseed oil and olive oil, enteral or parenteral administration include, without limita and injectable organic esters such as ethyl oleate; and/or tion, capsules, tablets, pills, troches, lozenges, powders and fluidity agents, such as, e.g., Surfactants or coating agents like granules Suitable for inhalation or for reconstitution into ster lecithin. In the case of dispersions and Suspensions, fluidity ile injectable solutions or dispersions. A therapeutic com can also be controlled by maintaining a particular particle pound or composition disclosed herein intended for Such size. In liquid formulations, a therapeutically effective administration may be prepared according to any method amount of a therapeutic compound disclosed herein typically known to the art for the manufacture of pharmaceutical com 25 may be between about 0.0001% (w/v) to about 60% (w/v), positions. In Such solid dosage forms, the therapeutic com about 0.001% (w/v) to about 40.0% (w/v), or about 0.01% pound may be admixed with (a) at least one inert customary (w/v) to about 20.0% (w/v). excipient (or carrier). Such as, e.g., Sodium citrate or dical Syrups and elixirs may be formulated with Sweetening cium phosphate or (b) fillers or extenders, as for example, agents, for example glycerol, propylene glycol, Sorbitol or starch, lactose, Sucrose, glucose, mannitol, isomalt, and 30 Sucrose. Such formulations may also contain a demulcent, a silicic acid, (c) binders, such as, e.g., carboxymethylcellu preservative, flavoring agents, and coloring agents. lose, alignates, gelatin, polyvinylpyrrolidone, sucrose and Liduid suspensions may be formulated by suspending a acacia, (d) humectants, such as, e.g., glycerol, (e) disintegrat therapeutic compound disclosed herein in admixture with ing agents, such as, e.g., agar-agar, calcium carbonate, corn excipients suitable for the manufacture of aqueous Suspen starch, potato starch, tapioca starch, alginic acid, certain com 35 sions. Such excipients are suspending agents, for example plex silicates and sodium carbonate, (f) solution retarders, sodium carboxymethylcellulose, methylcellulose, hydrox Such as, e.g., paraffin, (g) absorption accelerators, such as, ypropylmethylcellulose, Sodium alginate, pectin, polyvinyl e.g., quaternary ammonium compounds, (h) Wetting agents, pyrrolidone, polyvinyl alcohol, natural gum, agar, gum traga Such as, e.g., cetyl alcohol and glycerol monostearate, (i) canth and gum acacia; dispersing or wetting agents may be a adsorbents, such as, e.g., kaolin and bentonite, () lubricants, 40 naturally occurring phosphatide, for example lecithin, or con Such as, e.g., talc, Stearic acid, calcium Stearate, magnesium densation products of an alkylene oxide with fatty acids, for Stearate, Solid polyethylene glycols, sodium lauryl Sulfate or example polyoxyethylene Stearate, or condensation products mixtures thereof, and (k) buffering agents. The tablets may be of ethylene oxide with long-chain aliphatic alcohols, for uncoated or they may be coated by known techniques to delay example heptadecaethyleneoxycetanol, or condensation disintegration and absorption in the gastrointestinal tract and 45 products of ethylene oxide with partial esters derived from thereby provide a Sustained action over a longer period. For fatty acids, for example polyoxyethylene Sorbitan example, a time delay material Such as glyceryl monostearate monooleate. or glyceryl distearate may be employed. In solid formula Oily Suspensions may be formulated by Suspending a tions, atherapeutically effective amount ofatherapeutic com therapeutic compound disclosed herein in admixture with (a) pound disclosed herein typically may be between about 50 Vegetable oils, such as, e.g., almond oil, arachis oil, avocado 0.0001% (w/w) to about 60% (w/w), about 0.001% (w/w) to oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, about 40.0% (w/w), or about 0.01% (w/w) to about 20.0% grape seed oil, hazelnut oil, hemp oil, linseed oil, olive oil, (w/w). palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, A therapeutic compound disclosed herein, or a composi sesame oil, Soybean oil, Soya oil, Sunflower oil, walnut oil, tion comprising Such a therapeutic compound, may be made 55 wheat germ oil, or a combination thereof, (b) a saturated fatty into a semi-solid formulation. Semi-solid formulations Suit acid, an unsaturated fatty acid, or a combination thereof. Such able for topical administration include, without limitation, as, e.g., palmitic acid, Stearic acid, oleic acid, linoleic acid, ointments, creams, salves, and gels. A therapeutic compound linolenic acid, or a combination thereof, (c) mineral oil Such or composition disclosed herein intended for Such adminis as, e.g., liquid paraffin, (d) Surfactants or detergents. The oily tration may be prepared according to any method known to 60 Suspensions may contain a thickening agent, for example the art for the manufacture of pharmaceutical compositions. beeswax, hard paraffin or cetyl alcohol. Sweetening agents, In semi-solid formulations, a therapeutically effective Such as those set forth above, and flavoring agents may be amount of a therapeutic compound disclosed herein typically added to provide a palatable oral preparation. These compo may be between about 0.0001% (w/v) to about 60% (w/v), sitions may be preserved by the addition of an antioxidant about 0.001% (w/v) to about 40.0% (w/v), or about 0.01% 65 Such as ascorbic acid. (w/v) to about 20.0% (w/v). In semi-solid formulations, a Dispersible powders and granules Suitable for preparation therapeutically effective amount of a therapeutic compound of an aqueous Suspension by the addition of water provide the US 9,375,433 B2 25 26 combined therapeutic compounds in admixture with a dis D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, persing or wetting agent, Suspending agent and one or more caprolactone, and combinations thereof. preservatives. One of ordinary skill in the art appreciates that the selection A therapeutic compound disclosed herein may be in the of a Suitable polymer for forming a Suitable disclosed drug form of oil-in-water emulsions. The oily phase may be a delivery platform depends on several factors. The more rel Vegetable oil as disclosed herein or a mineral oil as disclosed evant factors in the selection of the appropriate polymer(s), herein or mixtures thereof. Suitable emulsifying agents may include, without limitation, compatibility of polymer with be naturally occurring gums, such as, e.g., gum acacia or gum drug, desired release kinetics of drug, desired biodegradation tragacanth, naturally occurring phosphatides, for example kinetics of platformat implantation site, desired bioerodible Soya bean, lecithin, and esters or partial esters derived from 10 kinetics of platform at implantation site, desired bioresorb fatty acids and hexitol anhydrides, for example sorbitan able kinetics of platform at implantation site, in vivo monooleate and condensation products of the said partial mechanical performance of platform, processing tempera esters with ethylene oxide, for example polyoxyethylene sor tures, biocompatibility of platform, and patient tolerance. bitan monooleate. Other relevant factors that, to some extent, dictate the in vitro A therapeutic compound disclosed herein, or a composi 15 and in vivo behavior of the polymer include the chemical tion comprising Such a therapeutic compound, may also be composition, spatial distribution of the constituents, the incorporated into a drug delivery platform in order to achieve molecular weight of the polymer and the degree of crystal a controlled release profile over time. Such a drug delivery linity. platform comprises a therapeutic compound disclosed herein A drug delivery platform includes both a sustained release dispersed within a polymer matrix, typically a biodegradable, drug delivery platform and an extended release drug delivery bioerodible, and/or bioresorbable polymer matrix. As used platform. As used herein, the term “sustained release' refers herein, the term “polymer refers to synthetic homo- or to the release of a therapeutic compound disclosed herein copolymers, naturally occurring homo- or copolymers, as over a period of about seven days or more. As used herein, the well as synthetic modifications or derivatives thereof having term “extended release' refers to the release of a therapeutic a linear, branched or star structure. Copolymers can be 25 compound disclosed herein over a period of time of less than arranged in any form, such as, e.g., random, block, seg about seven days. mented, tapered blocks, graft, or triblock. Polymers are gen In aspects of this embodiment, a Sustained release drug erally condensation polymers. Polymers can be further modi delivery platform releases a therapeutic compound disclosed fied to enhance their mechanical or degradation properties by herein with substantially Zero order release kinetics over a introducing cross-linking agents or changing the hydropho 30 period of, e.g., about 7 days after administration, about 15 bicity of the side residues. If crosslinked, polymers are usu days after administration, about 30 days after administration, ally less than 5% crosslinked, usually less than 1% about 45 days after administration, about 60 days after admin crosslinked. istration, about 75 days after administration, or about 90 days Suitable polymers include, without limitation, alginates, after administration. In other aspects of this embodiment, a aliphatic polyesters, polyalkylene oxalates, polyamides, 35 Sustained release drug delivery platform releases a therapeu polyamidoesters, polyanhydrides, polycarbonates, polyes tic compound disclosed herein with substantially Zero order ters, polyethylene glycol, polyhydroxyaliphatic carboxylic release kinetics over a period of, e.g., at least 7 days after acids, polyorthoesters, polyoxaesters, polypeptides, poly administration, at least 15 days after administration, at least phosphaZenes, polysaccharides, and polyurethanes. The 30 days after administration, at least 45 days after adminis polymer usually comprises at least about 10% (w/w), at least 40 tration, at least 60 days after administration, at least 75 days about 20% (w/w), at least about 30% (w/w), at least about after administration, or at least 90 days after administration. 40% (w/w), at least about 50% (w/w), at least about 60% In aspects of this embodiment, a Sustained release drug (w/w), at least about 70% (w/w), at least about 80% (w/w), or delivery platform releases a therapeutic compound disclosed at least about 90% (w/w) of the drug delivery platform. herein with substantially first order release kinetics over a Examples of biodegradable, bioerodible, and/or bioresorb 45 period of, e.g., about 7 days after administration, about 15 able polymers and methods useful to make a drug delivery days after administration, about 30 days after administration, platform are described in, e.g., Drost, et. al., Controlled about 45 days after administration, about 60 days after admin Release Formulation, U.S. Pat. No. 4,756,911; Smith, et. al., istration, about 75 days after administration, or about 90 days Sustained Release Drug Delivery Devices, U.S. Pat. No. after administration. In other aspects of this embodiment, a 5,378.475; Wong and Kochinke. Formulation for Controlled 50 Sustained release drug delivery platform releases a therapeu Release of Drugs by Combining Hyrophilic and Hydrophobic tic compound disclosed herein with substantially first order Agents, U.S. Pat. No. 7,048,946; Hughes, et. al., Composi release kinetics over a period of, e.g., at least 7 days after tions and Methods for Localized Therapy of the Eye, U.S. administration, at least 15 days after administration, at least Patent Publication 2005/0181017: Hughes, Hypotensive 30 days after administration, at least 45 days after adminis Lipid-Containing Biodegradable Intraocular Implants and 55 tration, at least 60 days after administration, at least 75 days Related Methods, U.S. Patent Publication 2005/0244464; after administration, or at least 90 days after administration. Altman, et al., Silk Fibroin Hydrogels and Uses Thereof, U.S. In aspects of this embodiment, a drug delivery platform Patent Publication 2011/0008437; each of which is incorpo releases a therapeutic compound disclosed herein with Sub rated by reference in its entirety. stantially Zero order release kinetics over a period of, e.g., In aspects of this embodiment, a polymer composing the 60 about 1 day after administration, about 2 days after adminis matrix is a polypeptide Such as, e.g., silk fibroin, keratin, or tration, about 3 days after administration, about 4 days after collagen. In other aspects of this embodiment, a polymer administration, about 5 days after administration, or about 6 composing the matrix is a polysaccharide Such as, e.g., cel days after administration. In other aspects of this embodi lulose, agarose, elastin, chitosan, chitin, or a glycosaminogly ment, a drug delivery platform releases a therapeutic com can like chondroitin Sulfate, dermatan Sulfate, keratan Sulfate, 65 pound disclosed herein with substantially Zero order release or hyaluronic acid. In yet other aspects of this embodiment, a kinetics over a period of, e.g., at most 1 day after administra polymer composing the matrix is a polyester Such as, e.g., tion, at most 2 days after administration, at most 3 days after US 9,375,433 B2 27 28 administration, at most 4 days after administration, at most 5 pendent cancer include, without limitation, a prostate cancer, days after administration, or at most 6 days after administra a testicular cancer, a breast cancer, an endometrial cancer, an tion. ovarian cancer, a lung cancer, a thyroid cancer, a pancreatic In aspects of this embodiment, a drug delivery platform cancer, an adenocarcinoma, a neuroendocrine cancer, and a releases a therapeutic compound disclosed herein with Sub bone cancer. Examples of a hormone-sensitive or hormone stantially first order release kinetics over a period of, e.g., dependent non-cancerous cell proliferation disorder include, about 1 day after administration, about 2 days after adminis without limitation, a uterine fibroid, a fibrocystic breast dis tration, about 3 days after administration, about 4 days after ease, an ovarian cyst, a polycystic ovary syndrome, and pros administration, about 5 days after administration, or about 6 tate enlargement like benign prostatic hyperplasia (BPH). days after administration. In other aspects of this embodi 10 Examples of a hormone-sensitive or hormone-dependent ment, a drug delivery platform releases a therapeutic com non-cell proliferation disorder include, without limitation, an pound disclosed herein with substantially first order release acne Vulgaris, a seborrhea, a femalehirsutism, abnormal uter kinetics over a period of, e.g., at most 1 day after administra ine bleeding, amenorrhoea, premenstrual syndrome (PMS), tion, at most 2 days after administration, at most 3 days after endometriosis, adenomyosis, and an alopecia. administration, at most 4 days after administration, at most 5 15 An adenocarcinoma is a tumor of epithelial tissue that has days after administration, or at most 6 days after administra glandular origin, glandular characteristics, or both. Examples tion. of an adenocarcinoma include, without limitation, an esoph Aspects of the present specification disclose, in part, a ageal cancer, a pancreatic cancer, a prostate cancer, a cervical method of treating an individual with a disorder associated cancer, a stomach cancer, a throat cancer, a non-Small cell with androgen production. In one embodiment, the method lung cancer, a ductal carcinoma of the breast including inva comprises the step of administering to an individual in need sive ductal carcinoma and ductal carcinoma in situ, a lobular thereofa benzo(iso)oxazolepiperidine disclosed herein and a carcinoma of the breast including an invasive lobular carci pharmaceutically-acceptable conjugated fatty acid disclosed noma, a colorectal cancer, adenocarcinoma of the lung herein, wherein administration reduces a symptom of a dis including large cell lung cancer, squamous cell lung cancer, order associated with androgen production, thereby treating 25 Small-cell lung cancer, bronchioloalveolar lung cancer, non the individual. The benzo(iso)oxazolepiperidine disclosed Small cell lung cancer, cholangiocarcinoma and vaginal can herein and a pharmaceutically-acceptable conjugated fatty C. acid disclosed herein may be administered sequentially or Aspects of the present specification disclose, in part, treat simultaneously. When administered simultaneously, the ben ing an individual Suffering from a disorder associated with ZO(iso)oxazolepiperidine disclosed herein and a pharmaceu 30 androgen production. As used herein, the term “treating.” tically-acceptable conjugated fatty acid disclosed herein may refers to reducing or eliminating in an individual a clinical be formulated as separate compositions or as a single com symptom of a disorder associated with androgen production; position. In one embodiment, the method comprises the step or delaying or preventing in an individual the onset of a of administering to an individual in need thereof a pharma clinical symptom of a disorder associated with androgen pro ceutical composition disclosed herein, wherein administra 35 duction. For example, the term “treating can mean reducing tion reduces a symptom of a disorder associated with andro a symptom of a disorder associated with androgen production gen production, thereby treating the individual. In aspects of by, e.g., at least 20%, at least 25%, at least 30%, at least 35%, this embodiment, a disorder associated with androgen pro at least 40%, at least 45%, at least 50%, at least 55%, at least duction includes, without limitation, a disorder associated 60%, at least 65%, at least 70%, at least 75%, at least 80%, at with steroid hydroxy-dehydrogenase activity, a disorder asso 40 least 85%, at least 90% at least 95%, or at least 100%. As ciated with HSD17B activity, and a disorder associated with another example, the term “treating can mean controlling a HSD17B10 activity. symptom of a disorder associated with androgen production Aspects of the present specification disclose, in part, a Such as, e.g., reducing the number of symptoms per given method of treating an individual with a cancer. In one embodi time period and/or the severity of a symptom. The actual ment, the method comprises the step of administering to an 45 symptoms associated with a disorder associated with andro individual in need thereofa benzo(iso)oxazolepiperidine dis gen production are well known and can be determined by a closed herein and a pharmaceutically-acceptable conjugated person of ordinary skill in the art by taking into account fatty acid disclosed herein, wherein administration reduces a factors, including, without limitation, the location of the dis symptom of a cancer, thereby treating the individual. The order associated with androgen production, the cause of the benzo(iso)oxazolepiperidine disclosed herein and a pharma 50 disorder associated with androgen production, the severity of ceutically-acceptable conjugated fatty acid disclosed herein the disorder associated with androgen production, and/or the may be administered sequentially or simultaneously. When cells, tissue or organ affected by the disorder associated with administered simultaneously, the benzo(iso)oxazolepiperi androgen production. Those of skill in the art will know the dine disclosed hereinanda pharmaceutically-acceptable con appropriate symptoms or indicators associated with a specific jugated fatty acid disclosed herein may be formulated as 55 type of a disorder associated with androgen production and separate compositions or as a single composition. In one will know how to determine if an individual is a candidate for embodiment, the method comprises the step of administering treatment as disclosed herein. to an individual in need thereofa pharmaceutical composition The actual symptoms of a disorder associated with andro disclosed herein, wherein administration reduces a symptom gen production are well known and can be determined by a of a cancer, thereby treating the individual. 60 person of ordinary skill in the art by taking into account In one embodiment, a disorder associated with androgen factors, including, without limitation, the location of the dis production may be a hormone-sensitive or hormone-depen order associated with androgen production, the cause of the dent disorder. Such as, e.g., a hormone-sensitive or hormone disorder associated with androgen production, the severity of dependent cancer, a hormone-sensitive or hormone-depen the disorder associated with androgen production, the cell, dent non-cancerous cell proliferation disorder, or a hormone 65 tissue and/or organ affected by the disorder associated with sensitive or hormone-dependent non-cell proliferation androgen production. For example, a disorder associated with disorder. Examples of a hormone-sensitive or hormone-de androgen production may cause one or more of the following US 9,375,433 B2 29 30 symptoms: urinary hesitancy, frequent urination, dysuria into account factors, including, without limitation, the type of (painful urination), increased risk of urinary tract infections, the disorder associated with androgen production, the loca and urinary retention, abnormal bleeding, inflammation, tion of the disorder associated with androgen production, the abnormal hair growth, pain, sexual dysfunction. cause of the disorder associated with androgen production, Aspects of the present invention provide, in part, reducing the severity of the disorder associated with androgen produc a symptom associated with a hormone-sensitive or hormone tion, the degree of relief desired, the duration of relief desired, dependent cancer. A treatment using the disclosed therapeutic the particular therapeutic compound used, the rate of excre compounds and compositions disclosed herein may decrease tion of the therapeutic compound used, the pharmacodynam the growth rate of tumor cells, decrease the cell division rate ics of the therapeutic compound used, the nature of the other of tumor cells, decrease the extent of invasion of tumor cells 10 compounds to be included in the composition, the particular into adjacent tissue or organs, decrease the extent of metasta formulation desired, the particular route of administration, sis, decrease angiogenesis, increase apoptosis, increase the particular characteristics, history and risk factors of the tumor cell death, increase tumor cell necrosis, or any combi patient, such as, e.g., age, weight, general health and the like, nation thereof. or any combination thereof. Additionally, where repeated Aspects of the present invention provide, in part, reducing 15 administration of a therapeutic compound is used, an effec a symptom associated with a hormone-sensitive or hormone tive amount of a therapeutic compound will further depend dependent non-cancerous cell proliferation disorder. A treat upon factors, including, without limitation, the frequency of ment using the disclosed therapeutic compounds and compo administration, the half-life of the therapeutic compound, or sitions disclosed herein may decrease hyperplasia, decrease any combination thereof. In is known by a person of ordinary the growth rate of hyperproliferating cells, decrease the cell skill in the art that an effective amount of a therapeutic com division rate of hyperproliferating cells, decrease the extent to pound disclosed herein can be extrapolated from in vitro which hyperproliferating cells becomes cancerous, decrease assays and in Vivo administration studies using animal mod angiogenesis, decrease nodule formation, decrease cyst for els prior to administration to humans. mation, increase apoptosis, increase tumor cell death and/or Wide variations in the necessary effective amount are to be increase tumor cell necrosis, or any combination thereof. 25 expected in view of the differing efficiencies of the various Aspects of the present invention provide, in part, reducing routes of administration. For instance, oral administration of a symptom associated with a hormone-sensitive or hormone a therapeutic compound disclosed herein generally would be dependent non-cancerous cell proliferation disorder. A treat expected to require higher dosage levels than administration ment using the disclosed therapeutic compounds and compo by inhalation. Similarly, systemic administration of a thera sitions disclosed herein may improve at least one hair 30 peutic compound disclosed herein would be expected to attribute including, without limitation, increase hair length, require higher dosage levels than a local administration. increase hair thickness, increase new hair growth, increase Variations in these dosage levels can be adjusted using stan hair growth rate, increase hair number, increase conversion of dard empirical routines of optimization, which are well intermediate hair into terminal hair, increase hair density, known to a person of ordinary skill in the art. The precise increase number of hairs per follicle, and/or increase hair 35 therapeutically effective dosage levels and patterns are pref pigmentation, increase hair melanization, or any combination erably determined by the attending physician in consideration thereof. of the above-identified factors. One skilled in the art will A composition or compound is administered to an indi recognize that the condition of the individual can be moni vidual. An individual is typically a human being. Typically, tored throughout the course of therapy and that the effective any individual who is a candidate for a conventional treatment 40 amount of a therapeutic compound disclosed herein that is is a candidate for a disorder associated with androgen pro administered can be adjusted accordingly. duction treatment disclosed herein. Pre-operative evaluation In aspects of this embodiment, a therapeutically effective typically includes routine history and physical examination in amount ofatherapeutic compound disclosed herein reduces a addition to thorough informed consent disclosing all relevant symptom associated with a disorder associated with androgen risks and benefits of the procedure. 45 production by, e.g., at least 10%, at least 15%, at least 20%, at A pharmaceutical composition disclosed herein may com least 25%, at least 30%, at least 35%, at least 40%, at least prise a therapeutic compound in a therapeutically effective 45%, at least 50%, at least 55%, at least 60%, at least 65%, at amount. As used herein, the term “effective amount' is syn least 70%, at least 75%, at least 80%, at least 85%, at least onymous with “therapeutically effective amount”, “effective 90%, at least 95% or at least 100%. In other aspects of this dose”, or “therapeutically effective dose” and when used in 50 embodiment, a therapeutically effective amount of a thera reference to treating a disorder associated with androgen peutic compound disclosed herein reduces a symptom asso production refers to the minimum dose of a therapeutic com ciated with a disorder associated with androgen production pound disclosed herein necessary to achieve the desired by, e.g., at most 10%, at most 15%, at most 20%, at most 25%, therapeutic effect and includes a dose sufficient to reduce a at most 30%, at most 35%, at most 40%, at most 45%, at most symptom associated with a disorder associated with androgen 55 50%, at most 55%, at most 60%, at most 65%, at most 70%, production. The effectiveness of a therapeutic compound dis at most 75%, at most 80%, at most 85%, at most 90%, at most closed herein in treating a disorder associated with androgen 95% or at most 100%. In yet other aspects of this embodi production can be determined by observing an improvement ment, a therapeutically effective amount of a therapeutic in an individual based upon one or more clinical symptoms, compound disclosed herein reduces a symptom associated and/or physiological indicators associated with the disorder 60 with a disorder associated with androgen production by, e.g., associated with androgen production. An improvement in a about 10% to about 100%, about 10% to about 90%, about disorder associated with androgen production also can be 10% to about 80%, about 10% to about 70%, about 10% to indicated by a reduced need for a concurrent therapy. about 60%, about 10% to about 50%, about 10% to about The appropriate effective amount of a therapeutic com 40%, about 20% to about 100%, about 20% to about 90%, pound disclosed herein to be administered to an individual for 65 about 20% to about 80%, about 20% to about 20%, about 20% a particular disorder associated with androgen production can to about 60%, about 20% to about 50%, about 20% to about be determined by a person of ordinary skill in the art by taking 40%, about 30% to about 100%, about 30% to about 90%, US 9,375,433 B2 31 32 about 30% to about 80%, about 30% to about 70%, about 30% M/day, at least 700 uM/day, at least 800 uM/day, at least 900 to about 60%, or about 30% to about 50%. :M/day, or at least 1,000 uM/day. In yet other aspects of this In aspects of this embodiment, a therapeutically effective e mbodiment, an effective amount of a therapeutic compound amount ofatherapeutic compound disclosed herein generally isclosed herein may be, e.g., about 1 uM/day to about 100 is in the range of about 0.01 mg/kg/day to about 50 mg/kg/ M/day, about 1 uM/day to about 200 uM/day, about 1 day. In other aspects of this embodiment, an effective amount M/day to about 400 uM/day, about 1 uM/day to about 600 of a therapeutic compound disclosed herein may be, e.g., at M/day, about 1 uM/day to about 800 uM/day, about 1 least 0.01 mg/kg/day, at least 0.025 mg/kg/day, at least 0.05 M/day to about 1,000 uM/day, about 10M/day to about 100 mg/kg/day, at least 0.075 mg/kg/day, at least 0.1 mg/kg/day, M/day, about 10 uM/day to about 200 uM/day, about 10 at least 0.25 mg/kg/day, at least 0.5 mg/kg/day, at least 0.75 10 M/day to about 400 uM/day, about 10 uM/day to about 600 mg/kg/day, at least 1.0 mg/kg/day, at least 2.5 mg/kg/day, at M/day, about 10 uM/day to about 800 uM/day, about 10 least 5.0 mg/kg/day, at least 7.5 mg/kg/day, at least 10 mg/kg/ M/day to about 1,000 uM/day, about 25uM/day to about 100 day, at least 25 mg/kg/day, or at least 50 mg/kg/day. In yet M/day, about 25 M/day to about 200 uM/day, about 25 other aspects of this embodiment, an effective amount of a M/day to about 400 uM/day, about 25uM/day to about 600 therapeutic compound disclosed herein may be, e.g., at least 15 M/day, about 25uM/day to about 800 uM/day, or about 25 0.1 mg/kg/day, at least 0.2 mg/kg/day, at least 0.3 mg/kg/day, M/day to about 1,000 uM/day. at least 0.4 mg/kg/day, at least 0.5 mg/kg/day, at least 0.6 In aspects of this embodiment, a therapeutically effective mg/kg/day, at least 0.7 mg/kg/day, at least 0.8 mg/kg/day, at amount of a benzo(iso)oxazolepiperidine disclosed herein least 0.9 mg/kg/day, at least 1.0 mg/kg/day, at least 1.25 generally is in the range of about 0.01 mg/kg/day to about 10 mg/kg/day, at least 1.5 mg/kg/day, at least 1.75 mg/kg/day, at mg/kg/day. In other aspects of this embodiment, an effective least 2.0 mg/kg/day, at least 2.25 mg/kg/day, at least 2.5 amount of a benzo(iso)oxazolepiperidine disclosed herein mg/kg/day, at least 2.75 mg/kg/day, at least 3.0 mg/kg/day, at may be, e.g., at least 0.01 mg/kg/day, at least 0.025 mg/kg/ least 3.25 mg/kg/day, at least 3.5 mg/kg/day, at least 3.75 day, at least 0.05 mg/kg/day, at least 0.075 mg/kg/day, at least mg/kg/day, at least 4.0 mg/kg/day, at least 4.25 mg/kg/day, at 0.1 mg/kg/day, at least 0.25 mg/kg/day, at least 0.5 mg/kg/ least 4.5 mg/kg/day, at least 4.75 mg/kg/day, or at least 5.0 25 day, at least 0.75 mg/kg/day, at least 1.0 mg/kg/day, at least mg/kg/day. In yet other aspects of this embodiment, an effec 2.5 mg/kg/day, at least 5.0 mg/kg/day, at least 7.5 mg/kg/day, tive amount of a therapeutic compound disclosed herein may or at least 10 mg/kg/day. In yet other aspects of this embodi be, e.g., about 0.01 mg/kg/day to about 0.1 mg/kg/day, about ment, an effective amount of a benzo(iso)oxazolepiperidine 0.01 mg/kg/day to about 0.5 mg/kg/day, about 0.01 mg/kg/ disclosed herein may be, e.g., about 0.01 mg/kg/day to about day to about 1 mg/kg/day, about 0.01 mg/kg/day to about 5 30 0.1 mg/kg/day, about 0.01 mg/kg/day to about 0.25 mg/kg/ mg/kg/day, about 0.01 mg/kg/day to about 10 mg/kg/day, day, about 0.01 mg/kg/day to about 0.5 mg/kg/day, about 0.01 about 0.1 mg/kg/day to about 0.1 mg/kg/day, about 0.1 mg/kg/day to about 0.75 mg/kg/day, about 0.01 mg/kg/day to mg/kg/day to about 0.5 mg/kg/day, about 0.1 mg/kg/day to about 1 mg/kg/day, about 0.01 mg/kg/day to about 1 mg/kg/ about 1 mg/kg/day, about 0.1 mg/kg/day to about 5 mg/kg/ day, about 0.01 mg/kg/day to about 2.5 mg/kg/day, about 0.01 day, or about 0.1 mg/kg/day to about 10 mg/kg/day. 35 mg/kg/day to about 5 mg/kg/day, about 0.01 mg/kg/day to In aspects of this embodiment, a therapeutically effective about 10 mg/kg/day, about 0.05 mg/kg/day to about 0.1 amount ofatherapeutic compound disclosed herein generally mg/kg/day, about 0.05 mg/kg/day to about 0.25 mg/kg/day, is in the range of about 1 mg/day to about 500 mg/day. In other about 0.05 mg/kg/day to about 0.5 mg/kg/day, about 0.05 aspects of this embodiment, an effective amount of a thera mg/kg/day to about 0.75 mg/kg/day, about 0.05 mg/kg/day to peutic compound disclosed herein may be, e.g., at least 1 40 about 1 mg/kg/day, about 0.05 mg/kg/day to about 1 mg/kg/ mg/day, at least 5 mg/day, at least 10 mg/day, at least 25 day, about 0.05 mg/kg/day to about 2.5 mg/kg/day, about 0.05 mg/day, at least 50 mg/day, at least 75 mg/day, at least 100 mg/kg/day to about 5 mg/kg/day, about 0.05 mg/kg/day to mg/day, at least 150 mg/day, at least 200 mg/day, at least 250 about 10 mg/kg/day, about 0.1 mg/kg/day to about 0.25 mg/day, at least 300 mg/day, at least 350 mg/day, at least 400 mg/kg/day, about 0.1 mg/kg/day to about 0.5 mg/kg/day, mg/day, at least 450 mg/day, or at least 500 mg/day. In yet 45 about 0.1 mg/kg/day to about 0.75 mg/kg/day, about 0.1 other aspects of this embodiment, an effective amount of a mg/kg/day to about 1 mg/kg/day, about 0.1 mg/kg/day to therapeutic compound disclosed herein may be, e.g., about 1 about 2.5 mg/kg/day, about 0.1 mg/kg/day to about 5 mg/kg/ mg/day to about 100 mg/day, about 1 mg/day to about 150 day, about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.5 mg/day, about 1 mg/day to about 200 mg/day, about 1 mg/day mg/kg/day to about 0.75 mg/kg/day, about 0.5 mg/kg/day to to about 250 mg/day, about 1 mg/day to about 300 mg/day, 50 about 1 mg/kg/day, about 0.5 mg/kg/day to about 2.5 mg/kg/ about 1 mg/day to about 350 mg/day, about 1 mg/day to about day, about 0.5 mg/kg/day to about 5 mg/kg/day, or about 0.5 400 mg/day, about 1 mg/day to about 450 mg/day, about 1 mg/kg/day to about 10 mg/kg/day. mg/day to about 500 mg/day, about 10 mg/day to about 100 In aspects of this embodiment, a therapeutically effective mg/day, about 10 mg/day to about 150 mg/day, about 10 amount of a benzo(iso)oxazolepiperidine disclosed herein mg/day to about 200 mg/day, about 10 mg/day to about 250 55 generally is in the range of about 0.1 mg/day to about 100 mg/day, about 10 mg/day to about 300 mg/day, about 10 mg/day. In other aspects of this embodiment, an effective mg/day to about 350 mg/day, about 10 mg/day to about 400 amount of a benzo(iso)oxazolepiperidine disclosed herein mg/day, about 10 mg/day to about 450 mg/day, or about 10 may be, e.g., at least 0.1 mg/day, at least 0.5 mg/day, at least mg/day to about 500 mg/day. 1 mg/day, at least 2.5 mg/day, at least 5 mg/day, at least 7.5 In aspects of this embodiment, a therapeutically effective 60 mg/day, at least 10 mg/day, at least 20 mg/day, at least 30 amount ofatherapeutic compound disclosed herein generally mg/day, at least 40 mg/day, at least 50 mg/day, at least 60 is in the range of about 1 uM/day to about 1,000 uM/day. In mg/day, at least 70 mg/day, at least 80 mg/day, at least 90 other aspects of this embodiment, an effective amount of a mg/day, or at least 100 mg/day. In yet other aspects of this therapeutic compound disclosed herein may be, e.g., at least embodiment, an effective amount of a benzo(iso)oxazolepi 1 uM/day, at least 5 uM/day, at least 10 uM/day, at least 50 65 peridine disclosed herein may be, e.g., about 0.1 mg/day to uM/day, at least 100 uM/day, at least 200 uM/day, at least 300 about 10 mg/day, about 0.1 mg/day to about 12.5 mg/day, uM/day, at least 400 uM/day, at least 500 uM/day, at least 600 about 0.1 mg/day to about 15 mg/day, about 0.1 mg/day to US 9,375,433 B2 33 34 about 17.5 mg/day, about 0.1 mg/day to about 20 mg/day, about 2.5 mg/kg/day, about 0.01 mg/kg/day to about 5 mg/kg/ about 0.1 mg/day to about 30 mg/day, about 0.1 mg/day to day, about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.05 about 40 mg/day, about 0.1 mg/day to about 60 mg/day, about mg/kg/day to about 0.1 mg/kg/day, about 0.05 mg/kg/day to 0.1 mg/day to about 80 mg/day, about 0.1 mg/day to about about 0.25 mg/kg/day, about 0.05 mg/kg/day to about 0.5 100 mg/day, about 0.5 mg/day to about 10 mg/day, about 0.5 mg/kg/day, about 0.05 mg/kg/day to about 0.75 mg/kg/day, mg/day to about 12.5 mg/day, about 0.5 mg/day to about 15 about 0.05 mg/kg/day to about 1 mg/kg/day, about 0.05 mg/day, about 0.5 mg/day to about 17.5 mg/day, about 0.5 mg/kg/day to about 1 mg/kg/day, about 0.05 mg/kg/day to mg/day to about 20 mg/day, about 0.5 mg/day to about 30 about 2.5 mg/kg/day, about 0.05 mg/kg/day to about 5 mg/kg/ mg/day, about 0.5 mg/day to about 40 mg/day, about 0.5 day, about 0.05 mg/kg/day to about 10 mg/kg/day, about 0.1 mg/day to about 60 mg/day, about 0.5 mg/day to about 80 10 mg/kg/day to about 0.25 mg/kg/day, about 0.1 mg/kg/day to mg/day, about 0.5 mg/day to about 100 mg/day, about 1 about 0.5 mg/kg/day, about 0.1 mg/kg/day to about 0.75 mg/day to about 10 mg/day, about 1 mg/day to about 12.5 mg/kg/day, about 0.1 mg/kg/day to about 1 mg/kg/day, about mg/day, about 1 mg/day to about 15 mg/day, about 1 mg/day 0.1 mg/kg/day to about 2.5 mg/kg/day, about 0.1 mg/kg/day to about 17.5 mg/day, about 1 mg/day to about 20 mg/day, to about 5 mg/kg/day, about 0.1 mg/kg/day to about 10 about 1 mg/day to about 30 mg/day, about 1 mg/day to about 15 mg/kg/day, about 0.5 mg/kg/day to about 0.75 mg/kg/day, 40 mg/day, about 1 mg/day to about 60 mg/day, about 1 about 0.5 mg/kg/day to about 1 mg/kg/day, about 0.5 mg/kg/ mg/day to about 80 mg/day, about 1 mg/day to about 100 day to about 2.5 mg/kg/day, about 0.5 mg/kg/day to about 5 mg/day, about 2.5 mg/day to about 10 mg/day, about 2.5 mg/kg/day, or about 0.5 mg/kg/day to about 10 mg/kg/day. mg/day to about 20 mg/day, about 2.5 mg/day to about 40 In aspects of this embodiment, in conjunction with a benzo mg/day, about 2.5 mg/day to about 60 mg/day, about 2.5 (iso)oxazolepiperidine disclosed herein, a therapeutically mg/day to about 80 mg/day, or about 2.5 mg/day to about 100 effective amount of a fatty acid disclosed herein generally is mg/day. in the range of about 0.1 mg/day to about 100 mg/day. In other In aspects of this embodiment, a therapeutically effective aspects of this embodiment, an effective amount of a fatty amount of a benzo(iso)oxazolepiperidine disclosed herein acid disclosed herein may be, e.g., at least 0.1 mg/day, at least generally is in the range of about 1 uM/day to about 1,000 25 0.5 mg/day, at least 1 mg/day, at least 5 mg/day, at least 10 uM/day. In other aspects of this embodiment, an effective mg/day, at least 20 mg/day, at least 30 mg/day, at least 40 amount of a benzo(iso)oxazolepiperidine disclosed herein mg/day, at least 50 mg/day, at least 60 mg/day, at least 70 may be, e.g., at least 1 uM/day, at least 5 uM/day, at least 10 mg/day, at least 80 mg/day, at least 90 mg/day, or at least 100 uM/day, at least 50 uM/day, at least 100 uM/day, at least 200 mg/day. In yet other aspects of this embodiment, in conjunc uM/day, at least 300 uM/day, at least 400 uM/day, at least 500 30 tion with a benzo(iso)oxazolepiperidine disclosed herein, an uM/day, at least 600 uM/day, at least 700 uM/day, at least 800 effective amount of a fatty acid disclosed herein may be, e.g., uM/day, at least 900 uM/day, or at least 1,000 uM/day. In yet about 0.1 mg/day to about 10 mg/day, about 0.1 mg/day to other aspects of this embodiment, an effective amount of a about 12.5 mg/day, about 0.1 mg/day to about 15 mg/day, benzo(iso)oxazolepiperidine disclosed herein may be, e.g., about 0.1 mg/day to about 17.5 mg/day, about 0.1 mg/day to about 1 uM/day to about 100 uM/day, about 1 uM/day to 35 about 20 mg/day, about 0.1 mg/day to about 30 mg/day, about about 200 uM/day, about 1 uM/day to about 400 uM/day, 0.1 mg/day to about 40 mg/day, about 0.1 mg/day to about 60 about 1 uM/day to about 600 uM/day, about 1 uM/day to mg/day, about 0.1 mg/day to about 80 mg/day, about 0.1 about 800 uM/day, about 1 uM/day to about 1,000 uM/day, mg/day to about 100 mg/day, about 0.5 mg/day to about 10 about 10 uM/day to about 100 uM/day, about 10 uM/day to mg/day, about 0.5 mg/day to about 12.5 mg/day, about 0.5 about 200 uM/day, about 10 uM/day to about 400 uM/day, 40 mg/day to about 15 mg/day, about 0.5 mg/day to about 17.5 about 10 uM/day to about 600 uM/day, about 10 uM/day to mg/day, about 0.5 mg/day to about 20 mg/day, about 0.5 about 800 uM/day, about 10 uM/day to about 1,000 uM/day, mg/day to about 30 mg/day, about 0.5 mg/day to about 40 about 25 uM/day to about 100 uM/day, about 25 uM/day to mg/day, about 0.5 mg/day to about 60 mg/day, about 0.5 about 200 uM/day, about 25 M/day to about 400 uM/day, mg/day to about 80 mg/day, about 0.5 mg/day to about 100 about 25 uM/day to about 600 uM/day, about 25 uM/day to 45 mg/day, about 1 mg/day to about 10 mg/day, about 1 mg/day about 800 uM/day, or about 25 uM/day to about 1,000 to about 12.5 mg/day, about 1 mg/day to about 15 mg/day, uM/day. about 1 mg/day to about 17.5 mg/day, about 1 mg/day to In aspects of this embodiment, in conjunction with a benzo about 20 mg/day, about 1 mg/day to about 30 mg/day, about (iso)oxazolepiperidine disclosed herein, a therapeutically 1 mg/day to about 40 mg/day, about 1 mg/day to about 60 effective amount of a fatty acid disclosed herein generally is 50 mg/day, about 1 mg/day to about 80 mg/day, about 1 mg/day in the range of about 0.01 mg/kg/day to about 10 mg/kg/day. to about 100 mg/day, about 2.5 mg/day to about 10 mg/day, In other aspects of this embodiment, in conjunction with a about 2.5 mg/day to about 20 mg/day, about 2.5 mg/day to benzo(iso)oxazolepiperidine disclosed herein, an effective about 40 mg/day, about 2.5 mg/day to about 60 mg/day, about amount of a fatty acid disclosed herein may be, e.g., at least 2.5 mg/day to about 80 mg/day, or about 2.5 mg/day to about 0.01 mg/kg/day, at least 0.025 mg/kg/day, at least 0.05 mg/kg/ 55 100 mg/day. day, at least 0.075 mg/kg/day, at least 0.1 mg/kg/day, at least In aspects of this embodiment, in conjunction with a benzo 0.25 mg/kg/day, at least 0.5 mg/kg/day, at least 0.75 mg/kg/ (iso)oxazolepiperidine disclosed herein, a therapeutically day, at least 1.0 mg/kg/day, at least 2.5 mg/kg/day, at least 5.0 effective amount of a fatty acid disclosed herein generally is mg/kg/day, at least 7.5 mg/kg/day, or at least 10 mg/kg/day. In in the range of about 1 uM/day to about 1,000 uM/day. In yet other aspects of this embodiment, in conjunction with a 60 other aspects of this embodiment, an effective amount of a benzo(iso)oxazolepiperidine disclosed herein, an effective fatty acid disclosed herein may be, e.g., at least 1 uM/day, at amount of a fatty acid disclosed herein may be, e.g., about least 5uM/day, at least 10M/day, at least 50 uM/day, at least 0.01 mg/kg/day to about 0.1 mg/kg/day, about 0.01 mg/kg/ 100 uM/day, at least 200 uM/day, at least 300 uM/day, at least day to about 0.25 mg/kg/day, about 0.01 mg/kg/day to about 400 uM/day, at least 500 uM/day, at least 600 uM/day, at least 0.5 mg/kg/day, about 0.01 mg/kg/day to about 0.75 mg/kg/ 65 700 LM/day, at least 800 uM/day, at least 900 uM/day, or at day, about 0.01 mg/kg/day to about 1 mg/kg/day, about 0.01 least 1,000 uM/day. In yet other aspects of this embodiment, mg/kg/day to about 1 mg/kg/day, about 0.01 mg/kg/day to in conjunction with a benzo(iso)oxazolepiperidine disclosed US 9,375,433 B2 35 36 herein, an effective amount of a fatty acid disclosed herein 5C. reductase inhibitor disclosed herein may be, e.g., about 0.1 may be, e.g., about 1 uM/day to about 100 uM/day, about 1 mg/day to about 10 mg/day, about 0.1 mg/day to about 12.5 uM/day to about 200 uM/day, about 1 uM/day to about 400 mg/day, about 0.1 mg/day to about 15 mg/day, about 0.1 uM/day, about 1 uM/day to about 600 uM/day, about 1 mg/day to about 17.5 mg/day, about 0.1 mg/day to about 20 uM/day to about 800 uM/day, about 1 uM/day to about 1,000 mg/day, about 0.1 mg/day to about 30 mg/day, about 0.1 uM/day, about 10 uM/day to about 100 uM/day, about 10 mg/day to about 40 mg/day, about 0.1 mg/day to about 60 uM/day to about 200 uM/day, about 10 uM/day to about 400 mg/day, about 0.1 mg/day to about 80 mg/day, about 0.1 uM/day, about 10 uM/day to about 600 uM/day, about 10 mg/day to about 100 mg/day, about 0.5 mg/day to about 10 uM/day to about 800M/day, about 10 uM/day to about 1,000 mg/day, about 0.5 mg/day to about 12.5 mg/day, about 0.5 uM/day, about 25 uM/day to about 100 uM/day, about 25 10 mg/day to about 15 mg/day, about 0.5 mg/day to about 17.5 uM/day to about 200 uM/day, about 25 uM/day to about 400 mg/day, about 0.5 mg/day to about 20 mg/day, about 0.5 uM/day, about 25 uM/day to about 600 uM/day, about 25 mg/day to about 30 mg/day, about 0.5 mg/day to about 40 uM/day to about 800 uM/day, or about 25 M/day to about mg/day, about 0.5 mg/day to about 60 mg/day, about 0.5 1,000 uM/day. mg/day to about 80 mg/day, about 0.5 mg/day to about 100 In aspects of this embodiment, in conjunction with a benzo 15 mg/day, about 1 mg/day to about 10 mg/day, about 1 mg/day (iso)oxazolepiperidine disclosed herein, a therapeutically to about 12.5 mg/day, about 1 mg/day to about 15 mg/day, effective amount of a 5C. reductase inhibitor disclosed herein about 1 mg/day to about 17.5 mg/day, about 1 mg/day to generally is in the range of about 0.01 mg/kg/day to about 10 about 20 mg/day, about 1 mg/day to about 30 mg/day, about mg/kg/day. In other aspects of this embodiment, in conjunc 1 mg/day to about 40 mg/day, about 1 mg/day to about 60 tion with a benzo(iso)oxazolepiperidine disclosed herein, an mg/day, about 1 mg/day to about 80 mg/day, about 1 mg/day effective amount of a 5C. reductase inhibitor disclosed herein to about 100 mg/day, about 2.5 mg/day to about 10 mg/day, may be, e.g., at least 0.01 mg/kg/day, at least 0.025 mg/kg/ about 2.5 mg/day to about 20 mg/day, about 2.5 mg/day to day, at least 0.05 mg/kg/day, at least 0.075 mg/kg/day, at least about 40 mg/day, about 2.5 mg/day to about 60 mg/day, about 0.1 mg/kg/day, at least 0.25 mg/kg/day, at least 0.5 mg/kg/ 2.5 mg/day to about 80 mg/day, or about 2.5 mg/day to about day, at least 0.75 mg/kg/day, at least 1.0 mg/kg/day, at least 25 100 mg/day. 2.5 mg/kg/day, at least 5.0 mg/kg/day, at least 7.5 mg/kg/day, In aspects of this embodiment, in conjunction with a benzo or at least 10 mg/kg/day. In yet other aspects of this embodi (iso)oxazolepiperidine disclosed herein, a therapeutically ment, in conjunction with a benzo(iso)oxazolepiperidine dis effective amount of a 5C. reductase inhibitor disclosed herein closed herein, an effective amount of a 5C. reductase inhibitor generally is in the range of about 1 uM/day to about 1,000 disclosed herein may be, e.g., about 0.01 mg/kg/day to about 30 uM/day. In other aspects of this embodiment, in conjunction 0.1 mg/kg/day, about 0.01 mg/kg/day to about 0.25 mg/kg/ with a benzo(iso)oxazolepiperidine disclosed herein, an day, about 0.01 mg/kg/day to about 0.5 mg/kg/day, about 0.01 effective amount of a 5C. reductase inhibitor disclosed herein mg/kg/day to about 0.75 mg/kg/day, about 0.01 mg/kg/day to may be, e.g., at least 1 uM/day, at least 5 uM/day, at least 10 about 1 mg/kg/day, about 0.01 mg/kg/day to about 1 mg/kg/ uM/day, at least 50 uM/day, at least 100 uM/day, at least 200 day, about 0.01 mg/kg/day to about 2.5 mg/kg/day, about 0.01 35 uM/day, at least 300 uM/day, at least 400 uM/day, at least 500 mg/kg/day to about 5 mg/kg/day, about 0.01 mg/kg/day to uM/day, at least 600 uM/day, at least 700 uM/day, at least 800 about 10 mg/kg/day, about 0.05 mg/kg/day to about 0.1 uM/day, at least 900 uM/day, or at least 1,000 uM/day. In yet mg/kg/day, about 0.05 mg/kg/day to about 0.25 mg/kg/day, other aspects of this embodiment, in conjunction with a benzo about 0.05 mg/kg/day to about 0.5 mg/kg/day, about 0.05 (iso)oxazolepiperidine disclosed herein, an effective amount mg/kg/day to about 0.75 mg/kg/day, about 0.05 mg/kg/day to 40 of a 5C. reductase inhibitor disclosed herein may be, e.g., about 1 mg/kg/day, about 0.05 mg/kg/day to about 1 mg/kg/ about 1 uM/day to about 100 uM/day, about 1 uM/day to day, about 0.05 mg/kg/day to about 2.5 mg/kg/day, about 0.05 about 200 uM/day, about 1 uM/day to about 400 uM/day, mg/kg/day to about 5 mg/kg/day, about 0.05 mg/kg/day to about 1 uM/day to about 600 uM/day, about 1 uM/day to about 10 mg/kg/day, about 0.1 mg/kg/day to about 0.25 about 800 uM/day, about 1 uM/day to about 1,000 uM/day, mg/kg/day, about 0.1 mg/kg/day to about 0.5 mg/kg/day, 45 about 10 uM/day to about 100 uM/day, about 10 uM/day to about 0.1 mg/kg/day to about 0.75 mg/kg/day, about 0.1 about 200 uM/day, about 10 uM/day to about 400 uM/day, mg/kg/day to about 1 mg/kg/day, about 0.1 mg/kg/day to about 10 uM/day to about 600 uM/day, about 10 uM/day to about 2.5 mg/kg/day, about 0.1 mg/kg/day to about 5 mg/kg/ about 800 uM/day, about 10 uM/day to about 1,000 uM/day, day, about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.5 about 25 uM/day to about 100 uM/day, about 25 uM/day to mg/kg/day to about 0.75 mg/kg/day, about 0.5 mg/kg/day to 50 about 200 uM/day, about 25 uM/day to about 400 uM/day, about 1 mg/kg/day, about 0.5 mg/kg/day to about 2.5 mg/kg/ about 25 uM/day to about 600 uM/day, about 25 uM/day to day, about 0.5 mg/kg/day to about 5 mg/kg/day, or about 0.5 about 800 uM/day, or about 25 uM/day to about 1,000 mg/kg/day to about 10 mg/kg/day. uM/day. In aspects of this embodiment, in conjunction with a benzo Dosing can be single dosage or cumulative (serial dosing), (iso)oxazolepiperidine disclosed herein, a therapeutically 55 and can be readily determined by one skilled in the art. For effective amount of a 5C. reductase inhibitor disclosed herein instance, treatment of a disorder associated with androgen generally is in the range of about 0.1 mg/day to about 100 production may comprise a one-time administration of an mg/day. In other aspects of this embodiment, in conjunction effective dose of a pharmaceutical composition disclosed with a benzo(iso)oxazolepiperidine disclosed herein, an herein. Alternatively, treatment of a disorder associated with effective amount of a 5C. reductase inhibitor disclosed herein 60 androgen production may comprise multiple administrations may be, e.g., at least 0.1 mg/day, at least 0.5 mg/day, at least of an effective dose of a pharmaceutical composition carried 1 mg/day, at least 5 mg/day, at least 10 mg/day, at least 20 out over a range of time periods, such as, e.g., once daily, mg/day, at least 30 mg/day, at least 40 mg/day, at least 50 twice daily, trice daily, once every few days, or once weekly. mg/day, at least 60 mg/day, at least 70 mg/day, at least 80 The timing of administration can vary from individual to mg/day, at least 90 mg/day, or at least 100 mg/day. In yet other 65 individual, depending upon Such factors as the severity of an aspects of this embodiment, in conjunction with a benzo(iso) individual’s symptoms. For example, an effective dose of a oxazolepiperidine disclosed herein, an effective amount of a pharmaceutical composition disclosed herein can be admin US 9,375,433 B2 37 38 istered to an individual once daily for an indefinite period of 3. The composition according to embodiments 1 or 2, wherein time, or until the individual no longer requires therapy. A the therapeutic compound reduces a symptom of a disorder person of ordinary skill in the art will recognize that the associated with androgen production by at least 10%. condition of the individual can be monitored throughout the 4. The composition according to any one of embodiments 1-3, course of treatment and that the effective amount of a phar wherein the therapeutic compound reduces the frequency maceutical composition disclosed herein that is administered of a symptom of a disorder associated with androgen pro can be adjusted accordingly. duction incurred over a given time period. Various routes of administration can be useful for admin 5. The composition according to any one of embodiments 1-4. istering a therapeutic compound disclosed herein, according wherein the therapeutic compound reduces the frequency to a method of treating a disorder associated with androgen 10 of a symptom of a disorder associated with androgen pro production disclosed herein. A pharmaceutical composition duction incurred over a given time period by at least 10%. may be administered to an individual by any of a variety of 6. The composition according to any one of embodiments 1-5, means depending, e.g., on the type of the disorder associated wherein the therapeutic compound reduces the number of with androgen production to be treated, the location of the 15 symptoms of a disorder associated with androgen produc disorder associated with androgen production to be treated, tion incurred over a given time period. the specific therapeutic compound or composition used, or 7. The composition according to any one of embodiments 1-6. other compound to be included in the composition, and the wherein the therapeutic compound reduces the number of history, risk factors and symptoms of the individual. As such, symptoms of a disorder associated with androgen produc topical, enteral or parenteral routes of administration may be tion incurred over a given time period by at least 10%. Suitable for of treating a disorder associated with androgen 8. The composition according to any one of embodiments 1-7. production disclosed herein and such routes include both wherein the therapeutic compound reduces the severity of local and systemic delivery of a therapeutic compound or a symptom of a disorder associated with androgen produc composition disclosed herein. Compositions comprising tion. either a single therapeutic compound disclosed herein, or two 25 9. The composition according to any one of embodiments 1-8, or more therapeutic compounds disclosed herein are intended wherein the therapeutic compound reduces the severity of for inhaled, topical, intranasal, Sublingual, injection, infu a symptom of a disorder associated with androgen produc Sion, instillation, rectal and/or vaginal use may be prepared tion by at least 10%. according to any method known to the art for the manufacture 10. The composition according to any one of embodiments of pharmaceutical compositions. 30 1-9, wherein the disorder associated with androgen pro duction is a disorder associated with a steroid hydroxy A pharmaceutical composition disclosed herein can be dehydrogenase activity. administered to an individual in a single formulation or in 11. The composition according to any one of embodiments separate formulations, for combined, simultaneous or 1-9, wherein the disorder associated with androgen pro sequential administration. In one embodiment, an individual 35 duction is a disorder associated with a 113-hydroxysteroid is administered a first composition comprising a benzo(iso) dehydrogenase activity, a 33-hydroxysteroid dehydroge oxazolepiperidine and a second composition comprising nase activity, a 17B-hydroxysteroid dehydrogenase activ another therapeutic compound like a fatty acid, a 5C-reduc ity, a 20B-hydroxysteroid dehydrogenase activity, or any tase inhibitor, a chemotherapeutic agent, or an anti-prolifera combination thereof. tive agent. In aspects of this embodiment, an individual is 40 12. The composition according to embodiment 11, wherein administered a first composition comprising at least one ben the disorder associated with a 17 B-hydroxysteroid dehy ZO(iso)oxazolepiperidine and a second composition compris drogenase activity is a 17B-hydroxysteroid dehydrogenase ing at least one other therapeutic compound like a fatty acid, subtype 10 activity. a 5C.-reductase inhibitor, a chemotherapeutic agent, or an 13. The composition according to any one of embodiments anti-proliferative agent. 45 1-12, wherein the therapeutic compound reduces a level of In another embodiment, an individual is administered a a dihydrotestosterone. composition comprising a benzo(iso)oxazolepiperidine and 14. The composition according to any one of embodiments another therapeutic compound like a fatty acid, a 5C-reduc 1-13, wherein the therapeutic compound reduces a level of tase inhibitor, a chemotherapeutic agent, or an anti-prolifera a dihydrotestosterone by at least 10%. tive agent. In aspects of this embodiment, an individual is 50 15. The composition according to any one of embodiments administered a composition comprising at least one benzo 1-14, wherein the therapeutic compound reduces a level of (iso)oxazolepiperidine and at least one other therapeutic a testosterone, a level of an androstenedione, a level of an compound like a fatty acid, a 5C-reductase inhibitor, a che androstenediol, a level of a dehydroepiandrosterone, or any motherapeutic agent, or an anti-proliferative agent. combination thereof. A pharmaceutical composition disclosed hereincan also be 55 16. The composition according to any one of embodiments administered to an individual in combination with other 1-15, wherein the therapeutic compound reduces a level of therapeutic compounds to increase the overall therapeutic a level of a testosterone, a level of an androstenedione, a effect of the treatment. The use of multiple compounds to level of an androstenediol, a level of a dehydroepiandros treat an indication can increase the beneficial effects while terone, or any combination thereof by at least 10%. reducing the presence of side effects. 60 17. The composition according to any one of embodiments Aspects of the present specification may also be described 1-16, wherein the therapeutic compound reduces a level of as follows: an estrogen. 1. A composition comprising a therapeutic compound 18. The composition according to any one of embodiments capable of modulating androgen production. 1-17, wherein the therapeutic compound reduces a level of 2. The composition according to embodiment 1, wherein the 65 an estrogen by at least 10%. therapeutic compound reduces a symptom of a disorder 19. The composition according to any one of embodiments associated with androgen production. 1-18, wherein the therapeutic compound includes a benzo US 9,375,433 B2 39 40 (iso)oxazolepiperidine, a fatty acid, a 5C, reductase inhibi cenoic acid, 9-Hexadecenoic acid (Palmitoleic acid), tor, a chemotherapeutic agent, an anti-proliferative agent, 11-Decenoic acid (Vaccenic acid), 13-Eicosenoic acid or any combination thereof. (Paullinic acid), 15-Docosenoic acid, 17-Tetracosenoic 20. The composition according to embodiment 19, wherein acid, and 9Z,11E conjugated Linoleic acid (Rumenic acid), the benzo(iso)oxazolepiperidine is an optionally Substi or any combination thereof. tuted Iloperidone, an optionally substituted ocaperidone, 29. The composition according to embodiment 25, wherein an optionally Substituted paliperidone, an optionally Sub the omega-9 fatty acid Oleic acid, Elaidic acid, Eicosenoic stituted risperidone, or any combination thereof. acid, Meadacid, Erucic acid, Nervonic acid, and Ricinoleic 21. The composition according to embodiment 19, wherein acid, or any combination thereof. the fatty acid comprises a conjugated fatty acid. 10 30. The composition according to embodiment 19, wherein 22. The composition according to embodiment 21, wherein the 5C. reductase inhibitor is Alfatradiol, Bexlosteride, the conjugated fatty acid comprises a C16-C30 conjugated Dutasteride, Epristeride, Finasteride, Isotretinoin, Lapis fatty acid. teride, Turosteride, or any combination thereof. 23. The composition according to embodiment 21, wherein 31. The composition according to embodiment 19, wherein the conjugated fatty acid comprises a conjugated Linoleic 15 the chemotherapeutic agent oranti-proliferative agent is an acid, a conjugated Linoelaidic acid, a conjugated C-Lino alkylating agent, a platinum agent, an antimetabolite, a lenic acid, a conjugated Y-Linolenic acid, a conjugated topoisomerase inhibitor, an antitumor antibiotic, an aro Calendic acid, a conjugated Eicosadienoic acid, a conju matase inhibitor, a thymidylate synthase inhibitor, a DNA gated Stearidonic acid, a conjugated Nonadecylic acid, a antagonist, farnesyltransferase inhibitor, a pump inhibitor, conjugated Arachidic acid, a conjugated Dihomo-Y-lino a histone acetyltransferase inhibitor, a metalloproteinase lenic acid, a conjugated Docosadienoic, a conjugated inhibitor, a ribonucleoside reductase inhibitor, a TNFC. Mead acid, a conjugated Arachidonic acid, a conjugated agonist, a TNFC. antagonist, an endothelin A receptor Eicosapentaenoic acid, a conjugated Adrenic acid, a con antagonist, a retinoic acid receptor agonist, an immuno jugated Docosapentaenoic acid, a conjugated Heneicosylic modulator, a hormonal and antihormonal agent, a photo acid, a conjugated Tetracosatetraenoic acid, a conjugated 25 dynamic agent, a tyrosine kinase inhibitor, or any combi Tetracosapentaenoic acid, a conjugated Behenic acid, a nation thereof. conjugated Docosahexaenoic acid, a conjugated Tricosylic 32. The composition according to any one of embodiments acid, a conjugated Lignoceric acid, a conjugated Pentaco 1-31, wherein the pharmaceutical composition reduces an sylic acid, a conjugated Cerotic acid, a conjugated Hepta unwanted side. cosylic acid, a conjugated Montanic acid, a conjugated 30 33. The composition according to embodiment 32, wherein Nonacosylic acid, a conjugated Melissic acid, a conjugated the unwanted side includes feminization in males or Henatriacontylic acid, a conjugated Lacceroic acid, a con defeminisation of females. jugated Psyllic acid, a conjugated Geddic acid, a conju 34. The composition according to any one of embodiments gated Ceroplastic acid, a conjugated Hexatriacontylic acid, 1-29, wherein the modulating activity of the therapeutic or a combination thereof. 35 compound reduces a symptom of a disorder associated 24. The composition according to embodiment 23, wherein with androgen production. the conjugated linoleic acid comprises a cis-9, trans-11, 35. The composition according to embodiment 34, wherein conjugated linoleic acid, cis-9, cis-11, conjugated linoleic the modulating activity of the therapeutic compound acid, trans-9, trans-11, conjugated linoleic acid, and trans reduces a symptom of a disorder associated with androgen 9, cis-11, conjugated linoleic acid, cis-10, trans-12, conju 40 production by at least 10%, at least 15%, at least 20%, at gated linoleic acid, cis-10, cis-12, conjugated linoleic acid, least 25%, at least 30%, at least 35%, at least 40%, at least trans-10, trans-12, conjugated linoleic acid, and trans-10. 45%, at least 50%, at least 55%, at least 60%, at least 65%, cis-12, conjugated linoleic acid, or any combination at least 70%, at least 75%, at least 80%, at least 85%, at thereof. least 90%, or at least 95%. 25. The composition according to embodiment 19, wherein 45 36. The composition according to embodiment 35, wherein the fatty acid is an omega-3 fatty acid, an omega-6 fatty the symptom includes the frequency of a symptom, the acid, an omega-7 fatty acid, an omega-9 fatty acid, or any number of symptoms, the severity of a symptom, or any combination thereof. combination thereof. 26. The composition according to embodiment 25, wherein 37. The composition according to any one of embodiments the omega-3 fatty acid is Hexadecatrienoic acid (16:3). 50 1-36, wherein the disorder associated with androgen pro C-Linolenic acid (18:3), Stearidonic acid (18:4). Eicosa duction is a hormone-dependent disorder. trienoic acid (20:3), Eicosatetraenoic acid (20:4), Eicosa 38. The composition according to embodiment 37, wherein pentaenoic acid (20:5), Heneicosapentaenoic acid (21:5), the hormone-dependent disorder is a hormone-dependent Docosapentaenoic acid (Clupanodonic acid) (22:5), proliferative disorder. Docosahexaenoic acid (22:6), Tetracosapentaenoic acid 55 39. The composition according to embodiments 37, wherein (24:5), Tetracosahexaenoic acid (Nisinic acid) (24:6), or the hormone-dependent disorder is a hormone-dependent any combination thereof. non-proliferative disorder. 27. The composition according to embodiment 25, wherein 40. The composition according to embodiments 37, wherein the omega-6 fatty acid is Linoleic acid (18:2), Y-linolenic the hormone-dependent disorder is a cancer. acid (18:3), Calendic acid (18:3), Eicosadienoic acid (20: 60 41. The composition according to embodiment 40, wherein 2), Dihomo-y-linolenic acid (20:3), Arachidonic acid (20: the cancer is a prostate cancer, a lung cancer, a breast 4), Docosadienoic acid (22:2), Adrenic acid (22:4). cancer, an ovarian cancer, testicular cancer, an adenocar Docosapentaenoic acid (22:5), Tetracosatetraenoic acid cinoma, neuroendocrine cancer, or a pancreatic cancer. (24:4), and Tetracosapentaenoic acid (24:5), or any com 42. The composition according to embodiment 40, wherein bination thereof. 65 the cancer is an adenocarcinoma. 28. The composition according to embodiment 25, wherein 43. The composition according to embodiment 42, wherein the omega-7 fatty acid is 5-Dodecenoic acid, 7-Tetrade the adenocarcinoma is an esophageal cancer, a pancreatic US 9,375,433 B2 41 42 cancer, a prostate cancer, a cervical cancer, a stomach 55. The composition according to embodiment 49 or 50, cancer, a throat cancer, a non-Small cell lung cancer, a wherein the fatty acid is an omega-3 fatty acid, an omega-6 ductal carcinoma of the breast including invasive ductal fatty acid, an omega-7 fatty acid, an omega-9 fatty acid, or carcinoma and ductal carcinoma in situ, a lobular carci any combination thereof. noma of the breast including an invasive lobular carci 5 56. The composition according to embodiment 55, wherein noma, a colorectal cancer, an adenocarcinoma of the lung the omega-3 fatty acid is Hexadecatrienoic acid (16:3), including large cell lung cancer, squamous cell lung can C-Linolenic acid (18:3), Stearidonic acid (18:4), Eicosa cer, Small-cell lung cancer, bronchioloalveolar lung can trienoic acid (20:3), Eicosatetraenoic acid (20:4), Eicosa cer, and non-Small cell lung cancer, a cholangiocarcinoma pentaenoic acid (20:5), Heneicosapentaenoic acid (21:5), or a vaginal cancer. 10 Docosapentaenoic acid (Clupanodonic acid) (22:5), 44. The composition according to embodiment 43, wherein Docosahexaenoic acid (22:6), Tetracosapentaenoic acid the lung cancer is a non-Small cell lung cancer. (24:5), Tetracosahexaenoic acid (Nisinic acid) (24:6), or 45. The composition according to embodiment 40, wherein any combination thereof. the cancer is a hormone-refractory cancer. 15 57. The composition according to embodiment 55 or 56, 46. The composition according to embodiments 39, wherein wherein the omega-6 fatty acid is Linoleic acid (18:2), the hormone-dependent disorder is benign prostatic hyper Y-linolenic acid (18:3), Calendic acid (18:3), Eicosadi plasia (BPH) or polycystic ovary syndrome. enoic acid (20:2), Dihomo-y-linolenic acid (20:3), Arachi 47. The composition according to embodiments 39, wherein donic acid (20:4), Docosadienoic acid (22:2), Adrenic acid the hormone-dependent disorder is acne Vulgaris, sebor (22:4), Docosapentaenoic acid (22:5), Tetracosatetraenoic rhea, or female hirsutism. acid (24:4), and Tetracosapentaenoic acid (24:5), or any 48. The composition according to embodiments 39, wherein combination thereof. the hormone-dependent disorder is androgenic alopecia. 58. The composition according to any one of embodiments 49. The composition according to any one of embodiments 55-57, wherein the omega-7 fatty acid is 5-Dodecenoic 1-48, wherein the composition includes a benzo(iso)OX 25 acid, 7-Tetradecenoic acid, 9-Hexadecenoic acid (Palmi aZolepiperidine and a fatty acid. toleic acid), 11-Decenoic acid (Vaccenic acid), 13-Eicose 50. The composition according to embodiment 49, wherein noic acid (Paullinic acid), 15-Docosenoic acid, 17-Tetra the benzo(iso)oxazolepiperidine is an optionally Substi coSenoic acid, and 9Z,11E conjugated Linoleic acid tuted Iloperidone, an optionally substituted ocaperidone, (Rumenic acid), or any combination thereof. an optionally Substituted paliperidone, an optionally Sub 30 59. The composition according to any one of embodiments stituted risperidone, or any combination thereof. 55-58, wherein the omega-9 fatty acid Oleic acid, Elaidic 51. The composition according to embodiment 49 or 50, acid, Eicosenoic acid, Mead acid, Erucic acid, Nervonic wherein the fatty acid comprises a conjugated fatty acid. acid, and Ricinoleic acid, or any combination thereof. 52. The composition according to embodiment 51, wherein 60. The composition according to any one of embodiments the conjugated fatty acid comprises a C16-C30 conjugated 35 1-48, wherein the composition includes a benzo(iso)OX fatty acid. azolepiperidine and a 5C. reductase inhibitor. 53. The composition according to embodiment 51, wherein 61. The composition according to embodiment 60, wherein the conjugated fatty acid comprises a conjugated Linoleic the benzo(iso)oxazolepiperidine is an optionally Substi acid, a conjugated Linoelaidic acid, a conjugated C-Lino tuted Iloperidone, an optionally substituted ocaperidone, lenic acid, a conjugated Y-Linolenic acid, a conjugated 40 an optionally Substituted paliperidone, an optionally Sub Calendic acid, a conjugated Eicosadienoic acid, a conju stituted risperidone, or any combination thereof. gated Stearidonic acid, a conjugated Nonadecylic acid, a 62. The composition according to embodiment 60 or 61, conjugated Arachidic acid, a conjugated Dihomo-Y-lino wherein the 5C, reductase inhibitor is Alfatradiol, Bexlos lenic acid, a conjugated Docosadienoic, a conjugated teride, Dutasteride, Epristeride, Finasteride, Isotretinoin, Mead acid, a conjugated Arachidonic acid, a conjugated 45 Lapisteride, Turosteride, or any combination thereof. Eicosapentaenoic acid, a conjugated Adrenic acid, a con 63. The composition according to any one of embodiments jugated Docosapentaenoic acid, a conjugated Heneicosylic 1-48, wherein the composition includes a benzo(iso)OX acid, a conjugated Tetracosatetraenoic acid, a conjugated azolepiperidine and a chemotherapeutic agent or an anti Tetracosapentaenoic acid, a conjugated Behenic acid, a proliferative agent. conjugated Docosahexaenoic acid, a conjugated Tricosylic 50 64. The composition according to embodiment 63, wherein acid, a conjugated Lignoceric acid, a conjugated Pentaco the benzo(iso)oxazolepiperidine is an optionally Substi sylic acid, a conjugated Cerotic acid, a conjugated Hepta tuted Iloperidone, an optionally substituted ocaperidone, cosylic acid, a conjugated Montanic acid, a conjugated an optionally Substituted paliperidone, an optionally Sub Nonacosylic acid, a conjugated Melissic acid, a conjugated stituted risperidone, or any combination thereof. Henatriacontylic acid, a conjugated Lacceroic acid, a con 55 65. The composition according to embodiment 63 or 64. jugated Psyllic acid, a conjugated Geddic acid, a conju wherein the chemotherapeutic agent or anti-proliferative gated Ceroplastic acid, a conjugated Hexatriacontylic acid, agent is an alkylating agent, a platinum agent, an antime or a combination thereof. tabolite, a topoisomerase inhibitor, an antitumorantibiotic, 54. The composition according to embodiment 53, wherein an aromatase inhibitor, a thymidylate synthase inhibitor, a the conjugated Linoleic acid comprises a cis-9, trans-11, 60 DNA antagonist, farnesyltransferase inhibitor, a pump conjugated linoleic acid, cis-9, cis-11, conjugated linoleic inhibitor, a histone acetyltransferase inhibitor, a metallo acid, trans-9, trans-11, conjugated linoleic acid, and trans proteinase inhibitor, a ribonucleoside reductase inhibitor, a 9, cis-11, conjugated linoleic acid, cis-10, trans-12, conju TNFC agonist, a TNFC. antagonist, an endothelin A recep gated linoleic acid, cis-10, cis-12, conjugated linoleic acid, torantagonist, a retinoic acid receptoragonist, an immuno trans-10, trans-12, conjugated linoleic acid, and trans-10. 65 modulator, a hormonal and antihormonal agent, a photo cis-12, conjugated linoleic acid, or any combination dynamic agent, a tyrosine kinase inhibitor, or any thereof. combination thereof. US 9,375,433 B2 43 44 66. A method of treating an individual with a disorder asso orectal cancer, an adenocarcinoma of the lung including ciated with androgen production, the method comprises large cell lung cancer, squamous cell lung cancer, Small the step of administering to an individual in need thereof a cell lung cancer, bronchioloalveolar lung cancer, and non pharmaceutical composition as defined in embodiments Small cell lung cancer, a cholangiocarcinoma or a vaginal 1-65, wherein administration reduces a symptom of a dis CaCC. order associated with androgen production, thereby treat 83. The method according to embodiment 82, wherein the ing the individual. lung cancer is a non-Small cell lung cancer. 84. The method according to embodiment 79, wherein the 67. The method according to embodiment 66, wherein cancer is a hormone-refractory cancer. administration of the pharmaceutical composition reduces 85. The method according to embodiments 76, wherein the the occurrence of an unwanted side. 10 hormone-dependent disorder is benign prostatic hyperpla 68. The method according to embodiment 67, wherein the sia (BPH) or polycystic ovary syndrome. unwanted side includes feminization in males or defemi 86. The method according to embodiments 76, wherein the nisation of females. hormone-dependent disorder is acne Vulgaris, seborrhea, 69. The method according to any one of embodiments 66-68, or female hirsutism. wherein the symptom is reduced by at least 10%, at least 15 87. The method according to embodiments 76, wherein the 15%, at least 20%, at least 25%, at least 30%, at least 35%, hormone-dependent disorder is androgenic alopecia. at least 40%, at least 45%, at least 50%, at least 55%, at 88. Use of a pharmaceutical composition as defined in least 60%, at least 65%, at least 70%, at least 75%, at least embodiments 1-65 for the manufacture of a medicament 80%, at least 85%, at least 90%, or at least 95%. for the treatment of a disorder associated with androgen 70. The method according to any one of embodiments 66-69, production. wherein the symptom includes the frequency of a symp 89. Use of a pharmaceutical composition as defined in tom, the number of symptoms, the severity of a symptom, embodiments 1-65 for treating a disorder associated with or any combination thereof. androgen production. 71. The method according to any one of embodiments 66-70, 90. The use according to embodiment 88 or 89, wherein wherein the therapeutically effective amount of the thera 25 administration of the pharmaceutical composition reduces peutic compound is in the range of about 0.01 mg/kg/day to the occurrence of an unwanted side. 91. The use according to embodiment 90, wherein the about 50 mg/kg/day. unwanted side includes feminization in males or defemi 72. The method according to any one of embodiments 66-71, nisation of females. wherein the therapeutically effective amount of the thera 92. The use according to any one of embodiments 88-91, peutic compound is in the range of about 1 mg/day to about 30 wherein the symptom is reduced by at least 10%, at least 500 mg/day. 15%, at least 20%, at least 25%, at least 30%, at least 35%, 73. The method according to any one of embodiments 66-72, at least 40%, at least 45%, at least 50%, at least 55%, at wherein the therapeutically effective amount of the thera least 60%, at least 65%, at least 70%, at least 75%, at least peutic compound is in the range of about 1 uM/day to about 80%, at least 85%, at least 90%, or at least 95%. 1,000 uM/day. 35 93. The use according to any one of embodiments 88-92. 74. The method according to any one of embodiments 66-73, wherein the symptom includes the frequency of a symp wherein the disorder associated with androgen production. tom, the number of symptoms, the severity of a symptom, 75. The method according to embodiment 74, wherein the or any combination thereof. disorder associated with androgen production is a disorder 94. The use according to any one of embodiments 88-93, associated with Steroid hydroxy-dehydrogenase activity, a 40 wherein the amount of the therapeutic compound admin disorder associated with HSD17B activity, a disorder asso istered is in the range of about 0.01 mg/kg/day to about 50 ciated with HSD17B10 activity, or any combination mg/kg/day. thereof. 95. The use according to any one of embodiments 88-93, 76. The method according to embodiment 74, wherein the wherein the amount of the therapeutic compound admin disorder associated with androgen production is a hor 45 istered is in the range of about 1 mg/day to about 500 mone-dependent disorder. mg/day. 96. The use according to any one of embodiments 88-93, 77. The method according to embodiment 76, wherein the wherein the amount of the therapeutic compound admin hormone-dependent disorder is a hormone-dependent pro istered is in the range of about 1 uM/day to about 1,000 liferative disorder. uM/day. 78. The method according to embodiments 76, wherein the 50 hormone-dependent disorder is a hormone-dependent non EXAMPLES proliferative disorder. 79. The method according to embodiments 76, wherein the The following non-limiting examples are provided for hormone-dependent disorder is a cancer. illustrative purposes only in order to facilitate a more com 80. The method according to embodiment 68, wherein the 55 plete understanding of representative embodiments now con cancer is a prostate cancer, a lung cancer, a breast cancer, an templated. These examples should not be construed to limit ovarian cancer, testicular cancer, an adenocarcinoma, a any of the embodiments described in the present specifica neuroendocrine cancer, or a pancreatic cancer. tion, including those pertaining to the compounds, pharma 81. The method according to embodiment 79, wherein the ceutical compositions, or methods or uses of treating a disor cancer is an adenocarcinoma. 60 der disclosed herein. 82. The method according to embodiment 81, wherein the adenocarcinoma is an esophageal cancer, a pancreatic can Example 1 cer, a prostate cancer, a cervical cancer, a stomach cancer, a throat cancer, a non-small cell lung cancer, a ductal HSD10 Enzyme Inhibition Assay carcinoma of the breast including invasive ductal carci 65 noma and ductal carcinoma in situ, a lobular carcinoma of An HSD10 inhibition assay was performed to determine the breast including an invasive lobular carcinoma, a col the effect of several anti-psychotics on enzyme activity. US 9,375,433 B2 45 46 PC3 cells are from a cell line derived from a hormone TABLE 1-continued refractory prostate cancer and are known to overexpress HSD10. PC3 cells were seeded at a density of 4,000 cells per HSD10 Enzymatic Activity in Presence of Different Drugs well in a 96 well plate, and incubated at 37°C., 5% CO, for 48 Oxidative Activity Reductive Activity hours in standard growth media (F12K nutrient media, 7% Fetal Calf Serum, 2 mM L-Glutamine, 45 mg/L ascorbic Rate Drug Rate acid). The media was then removed by pipette and replaced Drug (i.M/min) Inhibition (i.M/min) Drug Inhibition with the appropriate drug treatment as follows: 50 uMChlo Risperidone 1.O 88% 3.3 63% rpromazine (a typical anti-psychotic) in PC3 treatment media Diphenhydramine 8.0 59 8.3 6% (F12K nutrient media, 125 uM fatty acid free BSA, 2 mM 10 L-Glutamine, 45 mg/L ascorbic acid); 50 uM Clozapine (an A cell metabolism inhibition assay was performed to deter atypical anti-psychotic) in PC3 treatment media: 50 uM Clo mine the effect of different fatty acids on cellular metabolic mipramine (a tricyclic anti-depressant) in PC3 treatment rate. The fatty acids tested were C-Linolenic acid, omega 3 media: 50 M Risperidone (an atypical anti-psychotic) in fatty acid (ALA), Arachidonic acid, omega 6 fatty acid (AA), PC3 treatment media: 50 uM Diphenhydramine (a sedative) 15 9Z, 11E conjugated Linoleic acid, omega 7 fatty acid (CLA), in PC3 treatment media. Cells line tests were carried out in Docosahexaenoic acid, omega 3 fatty acid (DHA), Eicosap presence and absence of testosterone for comparison. After entaenoic acid, omega 3 fatty acid (EPA), Oleic acid, omega incubation in the drug treatment for 96 hours at 37° C., 5% 9 fatty acid (OA), Ricinoleic acid, omega 9 hydroxylated fatty CO, the supernatant was removed from all wells of cells, and acid (RA). cells washed with 200 uL PBS. PC3 cells are from a cell line derived from a hormone After removal of the PBS, cell number was determined refractory prostate cancer and are known to overexpress using a lysed cell LDH assay (CytoTox 96 Non-radioactive HSD10. PC3 cells were seeded at a density of 4,000 cells per cytotoxicity assay (LDH Assay); Promega, Co., Madison wellina 96 well plate, and incubated at 37°C., 5% CO, for 48 Wis.). Cells were lysed with 0.9%Triton-XinPBS for 2 hours hours in standard growth media (F12K nutrient media, 7% 25 Fetal Calf Serum, 2 mM L-Glutamine, 45 mg/L ascorbic at 37°C., 5% CO and 50L of this cell lysate was transferred acid). The media was then removed by pipette and replaced to a fresh 96 well plate. About 50 uL of CytoTox 96 assay with the appropriate drug treatment as follows: 20 uM, or 40 reagent was added to the transferred cell lysate and this mix uM, or 60 uM, or 80 uM, or 100 uMALA in PC3 treatment ture was incubated at room temperature in the dark for 20 media (F12K nutrient media, 125 uM fatty acid free BSA, 2 minutes. After the addition of 50 uL stop reagent, the optical mML-Glutamine, 45 mg/L ascorbic acid); 20 LM, or 40 uM, absorbance was determined for each incubated mixture at 492 30 or 60 uM, or 80 uM, or 100 uMAA in PC3 treatment media: nm. The percentage cell number was calculated by normal 20 uM, or 40 uM, or 60 uM, or 80 uM, or 100 uMCLA in PC3 izing the experimental counts, where 100% is set to cells treatment media; 20 uM, or 40 uM, or 60 uM, or 80 uM, or 100 receiving no drug treatment, and 0% is set to readings from uM DHA in PC3 treatment media; 20 uM, or 40 uM, or 60 wells containing no cells. The mean and standard error was uM, or 80 uM, or 100 M EPA in PC3 treatment media: 20 calculated from at least 3 wells. 35 uM, or 40 uM, or 60 uM, or 80 uM, or 100 uMOA in PC3 As seen in Table 1, Risperidone showed an inhibitory effect treatment media; and 20 uM, or 40 uM, or 60 uM, or 80 uM, on both oxidative (88% inhibition) and reductive (63% inhi or 100 uMRA in PC3 treatment media. After incubation in bition) performance of HSD10. No other drug tested the drug treatment for 72 hours at 37°C., 5% CO., 50 uL Cell appeared to have effectively inhibited both oxidative and titre Blue Assay Reagent was added to each well and the plate reductive performance of HSD10. 40 return to incubation at 37°C., 5% CO, for a further 24 hours, at which time the absorbance at 620 nm was recorded. The reduction of absorbance at 620 nm represents a higher meta TABLE 1. bolic rate, and the data below has been normalized such that HSD10 Enzymatic Activity in Presence of Different Drugs 100% represents cells that have been grown in the presence of 45 undrugged media, and 0% represents wells containing no Oxidative Activity Reductive Activity cells. Rate Drug Rate As seen in Table 2, AA, CLA, DHA, and EPA showed a Drug (i.M/min) Inhibition (i.M/min) Drug Inhibition significant inhibitory effect on cellular metabolic activity. AA No Drug 8.4 O% 8.8 O% showed about 35-40% metabolic inhibition in the 80-100 uM Chlorpromazine 7.7 8% 7.2 18% 50 range. CLA showed at least about 35-40% metabolic inhibi Clozapine 4.8 43% 7.5 15% tion in the 60-100 uM range. DHA showed about 40-65% Clomipramine 2.3 7396 7.5 15% metabolic inhibition in the 60-100 uM range. EPA showed about 50-65% metabolic inhibition in the 80-100 uM range. TABLE 2 Cellular Metabolic Activity in Presence of Different Fatty Acids Fatty Acid 20 M 40 M 60 M 80 M 100 M

ALA 118 - O.S 1180.9 1180.2 1170.9 114 - 1.2 AA 1073.9 90 - 5.6 78 6.4 66 7.2 605.9 CLA 86 2.4 71 - 3.8 592.8 63 - 4.0 67 S.O DHA 90 - 8.2 74 - 7.6 S85.9 49, 7.7 34 7.O EPA 94.94 71 - 8.2 67 7.4 49, 7.4 375.9 OA 1092.7 108 - O.9 1112.2 1102.2 1112.0 RA 91 6.O 94 - 4.7 90 - 6.2 90 - 6.O 94 3.1 US 9,375,433 B2 47 48 Example 2 To determine the optimal concentration of Risperidone and CLA necessary to inhibit cell growth, alysed cell LDHassay Cell Growth Inhibition Assay was conducted using various concentration of Risperidone and CLA. PC3 cells were cultured and alysed cell LDHassay To determine whether Risperidone could be effective in 5 was conducted as described above, except that the various inhibiting growth of cancer cells overexpressing HSD10, a drug treatments evaluated contained either OuM, 12.5uM, 25 lysed cell LDH assay was conducted using cells from a PC3 uM, or 50 LM Risperidone in combination with OuM, 6.25 cell line. uM, 12.5uM, 25uM, 50 uM, or 100 uMCLA (see Table 3). PC3 cells are from a cell line derived from a hormone The data demonstrated that combination treatments com refractory prostate cancer and are known to overexpress 10 prising 50 uM Risperidone and either 50 or 100 uM CLA HSD10. PC3 cells were seeded at a density of 4,000 cells per exhibited about 65% growth inhibition of PC3 cells (Table 4). well in a 96 well plate, and incubated at 37°C., 5% CO, for 48 In addition, 50 LM Risperidone and 25 uMCLA or 25 uM hours in standard growth media (F12K nutrient media, 7% Risperidone and 50 uM CLA both exhibited about 50% Fetal Calf Serum, 2 mM L-Glutamine, 45 mg/L ascorbic growth inhibition of PC3 cells (Table 4). These inhibitory 15 effects were all Synergistic in nature since treatment contain acid). The media was then removed by pipette and replaced ing either 25uM or 50 uM Risperidone alone only inhibited with the appropriate drug treatment as follows: 12.5 LM, 25 cell growth by about 20-30%. uM, or 50 uM Risperidone in PC3 treatment media (F12K nutrient media, 125 uM fatty acid free BSA, 2 mM TABLE 4 L-Glutamine, 45 mg/L ascorbic acid); 12.5uM, 25uM, or 50 Anti-Cancer Activity of uMCLA in PC3 treatment media; 12.5uM,25uM, or 50 uM Risperidone and CLA Combinations in PC3 Cells DHA in PC3 treatment media; 12.5uM Risperidone and 12.5 uM CLA, DHA, or both CLA and DHA in PC3 treatment Percentage of Lysed Cells (%) media; 25uM Risperidone and 25 uMCLA, DHA, or both Risperidone CLA Concentration 25 CLA and DHA in PC3 treatment media; and 50 uM Risperi Concen- 6.25 12.5 1OO done and 50 uMCLA, DHA, or both CLA and DHA in PC3 tration OM IM M 25 M 50 M M treatment media. Cells line tests were carried out in presence OM 1OO 96 - 90 - 1129.5 103 66 0.7 2.7 9.3 11.8 and absence of testosterone for comparison. After incubation 12.5 M 813.6 114 - 112 95 2.5 in the drug treatment for 96 hours at 37° C., 5% CO, the 30 22 7.1 supernatant was removed from all wells of cells, and cells 25 M 73 - 22 - 94 89 6.8 542.8 1.8 washed with 200 uL PBS. 50 M 79 0.7 - 552.6 36 34 After removal of the PBS, cell number was determined O.81 1.2 using a lysed cell LDH assay (CytoTox 96 Non-radioactive cytotoxicity assay (LDH Assay); Promega, Co., Madison 35 Wis.). Cells were lysed with 0.9%Triton-XinPBS for 2 hours Example 3 at 37°C.5% CO, and 50 uL of this cell lysate was transferred to a fresh 96 well plate. About 50 uL of CytoTox 96 assay Cell Growth Inhibition Assay reagent was added to the transferred cell lysate and this mix 40 ture was incubated at room temperature in the dark for 20 To determine whether Risperidone could be effective in minutes. After the addition of 50 uL stop reagent, the optical inhibiting growth of cancer cells overexpressing HSD10, a absorbance was determined for each incubated mixture at 492 lysed cell LDH assay was conducted using cells taken from a nm. The percentage cell number was calculated by normal prostate cancer cell line, a lung cancer cell line, a breast 45 cancer cell line, an ovarian cancer cell line, each of which was izing the experimental counts, where 100% is set to cells known to overexpress HSD10, and a non-cancerous cell line. receiving no drug treatment, and 0% is set to readings from To determine whether Risperidone alone, or in combina wells containing no cells. The mean and standard error was tion with CLA could inhibit cell growth of cells taken from a calculated from at least 3 wells. prostate cancer cell line overexpressing HSD10, a lysed cell The results show that 50 LM Risperidone exhibited about 50 LDH assay was conducted on PC3 cells as described in 50% growth inhibition of PC3 cells (Table 3). In addition, Example 2, except that the various drug treatments evaluated although having no effect alone, CLA in combination Ris contained: 50 uM Risperidone in PC3 treatment media: 50 peridone had a synergistic effect, inhibiting PC3 cell growth uMCLA in PC3 treatment media: 50 uM Risperidone and 50 by over 60%. uMCLA in PC3 treatment media: 50 uM Risperidone and 1 TABLE 3 Anti-Cancer Activity of Risperidone in PC3 Cells Percentage of Lysed Cells (90 Risperidone Risperidone Risperidone plus Concentration Risperidone plus CLA plus DHA DHA/CLA CLA DHA 12.5 M 1025.4 104 - 3.2 1145.5 113 - 1.6 1090.56 109 11 25 M 93 - 0.51 851.7 102. O.12 88 1.9 1121.1 1023.5 50 M 52 0.22 38 - 18 66 3.4 36 - O.47 107 24 953.8 US 9,375,433 B2 49 50 uMTestosterone (T) in PC3 treatment media: 50 uM Risperi hours at 37°C., 5% CO, the supernatant was removed from done, 50 uMCLA, and 1 uM Testosterone in PC3 treatment all wells of cells, and cells washed with 200 uL PBS. media. To determine whether Risperidone alone, or in combina To determine whether Risperidone alone, or in combina tion with CLA could inhibit cell growth of cells taken from a tion with CLA could inhibit cell growth of cells taken from a lung cancer cell line overexpressing HSD10, A549 cells were non-cancerous cell line, VERO cells, derived from kidney seeded at a density of 2,000 cells per well in a 96 well plate, cells) were seeded at a density of 2,000 cells per well in a 96 well plate, and incubated at 37°C., 5% CO for 48 hours in and incubated at 37° C., 5% CO for 48 hours in standard standard growth media (EMEM nutrient media, 10% Fetal growth media (DMEM nutrient media, 10% Fetal Calf 10 Calf Serum, 2 mM L-Glutamine, 1 mM sodium pyruvate). Serum, 2 mML-Glutamine). The media was then removed by The media was then removed by pipette and replaced with the pipette and replaced with the appropriate drug treatment as appropriate drug treatment as follows: 50 LM Risperidone in follows: 50 uM Risperidone in A459 treatment media VERO treatment media (EMEMinutrient media, 125uMfatty (DMEM nutrient media, 125 uM fatty acid free BSA, 2 mM 15 acid free BSA, 2 mML-Glutamine, 1 mM sodium pyruvate); L-Glutamine); 50 uMCLA in A459 treatment media: 50 LM 50 uMCLA in VERO treatment media: 50 uM Risperidone Risperidone and 50 uMCLA in A459 treatment media: 50LM and 50 uMCLA in VERO treatment media: 50 uM Risperi Risperidone and 1 uMTestosterone in A459 treatment media; done and 1 uM Testosterone in VERO treatment media: 50 50 uM Risperidone, 50 uMCLA, and 1 M Testosterone in uM Risperidone, 50 uM CLA, and 1 uM Testosterone in A459 treatment media. After incubation in the drug treatment VERO treatment media. After incubation in the drug treat for 96 hours at 37°C., 5% CO, the Supernatant was removed ment for 96 hours at 37° C., 5% CO, the supernatant was from all wells of cells, and cells washed with 200 uL PBS. removed from all wells of cells, and cells washed with 200 uL To determine whether Risperidone alone, or in combina PBS. 25 tion with CLA could inhibit cell growth of cells taken from a After removal of the PBS from the cell cultures described breast cancer cell line overexpressing HSD10, MCF7 cells above, cell number was determined using a lysed cell LDH were seeded at a density of 4,000 cells per well in a 96 well assay. Cells were lysed with 0.9%Triton-X in PBS for 2 hours plate, and incubated at 37°C., 5% CO, for 48 hours in stan 30 at 37°C., 5% CO and 50L of this cell lysate was transferred dard growth media (EMEM nutrient media, 10% Fetal Calf to a fresh 96 well plate. About 50 uL of CytoTox 96 assay Serum, 2 mM L-Glutamine, 0.1 mM non-essential amino reagent was added to the transferred cell lysate and this mix acids). The media was then removed by pipette and replaced ture was incubated at room temperature in the dark for 20 with the appropriate drug treatment as follows: 50 uM Ris 35 minutes. After the addition of 50 uL stop reagent, the optical peridone in MCF7 treatment media (EMEM nutrient media, absorbance was determined for each incubated mixture at 492 125 uM fatty acid free BSA, 2 mM L-Glutamine, 0.1 mM nm. The percentage cell number was calculated by normal non-essential amino acids); 50 MCLA in MCF7 treatment media: 50 uM Risperidone and 50 uMCLA in MCF7 treat izing the experimental counts, where 100% is set to cells receiving no drug treatment, and 0% is set to readings from ment media: 50 uM Risperidone and 1 uM Testosterone in 40 MCF7 treatment media: 50 uM Risperidone, 50 uM CLA, wells containing no cells. The mean and standard error was and 1 uMTestosterone in MCF7 treatment media. After incu calculated from at least 3 wells. bation in the drug treatment for 96 hours at 37°C., 5% CO, The results show that 50 uM Risperidone exhibited about the supernatant was removed from all wells of cells, and cells 45 50% growth inhibition of PC3 cells, over 60% growth inhi washed with 200 uL PBS. bition of A549 cells, about 65% growth inhibition of MCF7 To determine whether Risperidone alone, or in combina cells, and about 35% growth inhibition of OVCAR-3 cells tion with CLA could inhibit cell growth of cells taken from an (Table 3). In addition, CLA in combination Risperidone dem ovarian cancer cell line overexpressing HSD10, OVCAR-3 onstrated a synergistic growth inhibition effect on most can cells were seeded at a density of 8,000 cells per well in a 96 50 cer cell lines tested. Thus, 50 M Risperidone in combination well plate, and incubated at 37°C., 5% CO, for 48 hours in with CLA exhibited over 60% growth inhibition of PC3 cells, standard growth media (RPMI-1640 nutrient media, 20% almost 100% growth inhibition of A549 cells, and over 70% Fetal Calf Serum, 2 mM L-Glutamine, 0.01 mg/mL insulin, growth inhibition of MCF7 cells (Table 3). Importantly, nei 4.5 g/L glucose, 10 mM HEPES, 1 mM sodium pyruvate). 55 ther Risperidone nor CLA had any measurable effect on The media was then removed by pipette and replaced with the growth on cell from the non-cancerous cell line VERO. appropriate drug treatment as follows: 50 LM Risperidone in The results also show that the mechanism of action of OVCAR-3 treatment media (RPMI-1640 nutrient media, Resperidone is related to Testosterone in that adding an exter 0.5% Fetal Calf Serum, 125 uM fatty acid free BSA, 2 mM nal source of Testosterone to Risperidone-treated cells par L-Glutamine, 0.01 mg/mL insulin, 4.5 g/L glucose, 10 mM 60 tially negated the effect of the Risperidone alone. However, in HEPES, 1 mM sodium pyruvate); 50 uMCLA in OVCAR-3 the presence of CLA, Testosterone failed to negate the effect treatment media: 50 LM Risperidone and 50 uM CLA in of the Risperidone. This suggests the CLA is acting on one OVCAR-3 treatment media: 50 uM Risperidone and 1 uM Testosterone pathway and Risperidone on another Testoster Testosterone in OVCAR-3 treatment media: 50 LM Risperi 65 one pathway. None of the cells from the cell lines tested done, 50 uM CLA, and 1 uM Testosterone in OVCAR-3 responded to a 1 uM Testosterone treatment without drug treatment media. After incubation in the drug treatment for 96 present. US 9,375,433 B2 51 52 TABLE 5 Anti-Cancer Activity of Risperidone in Various Cancer Cells Percentage of Lysed Cells (% Risperidone Risperidone Risperidone Cell Line Risperidone CLA plus CLA plus T plus CLAT PC3 S21.7 107 24 38 - 18 67 2.8 41 + 4.3 A549 38 1.9 4.50.3 10.1 48 + 4.1 10.1 MCF7 35 2.4 562.6 28 0.6 543.6 26 - 1.1 OVCAR-3 640.4 87 6.0 692.1 84 - 4.0 701.8 VERO 94 - 1.7 98 - 2.7 94 3.5 96.O.9 98 1.8

Example 4 15 TABLE 6 Anti-Cancer Activity of Risperidone in Pancreatic Cancer Cells Cell Growth Inhibition Assay Drug Treatment O.1 M 2 uM SOM Risperidone 94% 85% 40% To determine whether Risperidone alone, or in combina CLA 1.03% 71.9% 11.9% tion with CLA could inhibit cell growth of cells taken from a Risperidone: CLA 83% SO% 16% pancreatic cancer cell line overexpressing HSD10, a resa Zurin-based cell viability assay was conducted on Bx-PC3 The results show that Risperidone alone inhibited cancer cells. cell growth, exhibited about 60% growth inhibition of Bx BXPC-3 cells are from a cell line derived from a human 25 PC3 cells at 50 uM (Table 6). Surprisingly, although having pancreatic adenocarcinoma and are known to overexpress no effect cytostatic or cytotoxic alone, CLA, in combination HSD10. BXPC-3 cells were seeded at a density of 4,000 cells Risperidone, had a synergistic effect, with equimolar combi per well in a 384 well plate, and incubated at 37°C., 5% CO, nations inhibiting Bx-PC3 cell growth by about 50% at 2 uM and about 84% at 50 uM. for 24 hours in standard growth media (RPMI nutrient media, 30 5% heat-inactivated Fetal Calf Serum, 2 mM L-Glutamine). Example 5 The media was then removed by pipette and replaced with 50 uL BXPC-3 treatment media comprising 125 uM fatty acid In Vivo Animal Model Studies on Prostate Cancer free BSA, 2 mML-Glutamine and one of the following drug treatments: 0.1 uM, 2 uM, or 50 uM Risperidone; 0.1 uM, 2 35 In vivo studies were performed to determine the effect of uM, or 50 uMCLA; or 0.1 uM,2uM, or 50 uMofRisperidone Risperidone in combination with Rumenic acid on orthotopic and CLA (in equimolar amounts). After incubation in the prostate tumor growth in a mouse Xenograft model utilizing drug treatment for 72 hours at 37° C., 5% CO, viable cell novel luciferase labelled BXPC-3 cells. Immunodeficeint male mice (athymic nude mice) were acclimated to the labo number was determined using a resaZurin-based cell viability ratory for at least one week prior to implantation of tumor. assay (PRESTOBLUER: Invitrogen, Carlsbad, Calif.). To 40 PC-3M-luc cells obtained directly from in vitro culture were each well, 7 ul of PRESTOBLUE(R) reagent was added and then injected into the prostate on Day 0. Animals were divided the plates incubated for 60 minutes at 37° C., 5% CO. After into six groups of 12 mice each. Primary tumor size and incubation, the fluorescence intensity of each well was deter metastases were assessed by bioluminescence measurements mined using a microplate readerby excitation and 570 nm and on day 6, 13, 20, 27, 34, and 40. On day 7 a five week recording emission at 600 nm. The percentage of viable cell 45 treatment regime was initiated. Both individual drug and high number was calculated by normalizing the experimental fluo and low dose combination were examined by administering rescence intensity, where 100% is set to cells receiving no the drugs twice daily on an individual body weight basis using drug treatment (cells metabolizing at optimal rate), and 0% is a dose escalation protocol (Table 7). If tumors grew above a set to readings from cells treated with Paclitaxel (cells not pre-determined level, or mice lost more than 10% of body metabolizing at all due to their destruction by anti-cancer 50 weight, they were culled. The primary tumor was excised, drug). A value under 50% could be considered a useful indi weighed and measured. Individual organs were imaged to cation of potential efficacy. assess metastatic burden. TABLE 7 Dosing Regime of Animal Groups Animal Group

4 5 1 2 3 Low Dose High Dose 6 Day Vehicle Risperidone Rumenic Acid Combination Combination* Docetaxel 7 0.25 mg/kg 0.18 mg/kg 0.25 mg/kg 1:1 0.25 mg/kg 1:1 5 mg/kg i.v. oral BID oral BID combination combination twice weekly, oral BID oral BID plus BID oral vehicle (as Group 1) US 9,375,433 B2 53 54 TABLE 7-continued Dosing Regime of Animal Groups Animal Group

4 5 1 2 3 Low Dose High Dose 6 Day Vehicle Risperidone Rumenic Acid Combination* Combination* Docetaxel 11 0.5 mg/kg oral 0.35 mg/kg 0.5 mg/kg1:1 0.5 mg/kg1:1 5 mg/kg i.v. BID oral BID combination combination twice weekly, oral BID oral BID plus BID oral vehicle (as Group 1) 15 1.0 mg/kg oral 0.70 mg/kg 0.5 mg/kg1:1 1.0 mg/kg1:1 5 mg/kg i.v. BID oral BID combination combination twice weekly, oral BID oral BID plus BID oral vehicle (as Group 1) combination doses were calculated according to the dosage of Risperidone; rumenic acid was added to an equimolar level.

One parameter of increased efficacy measured was animal 1 animals (negative control). For example, animals from survival in each group, both in terms of overall survival at the Group 2 (Risperidone) showed anonset delay of tumorlethal end of the study as well as survival rate. Group 1 animals were ity as a decrease in Survivorship rate was pushed back to day dosed on a vehicle and served as the negative control and 34 with only about 10% animal loss. However, a rapid exhibited an overall survivorship of 45% (Table 8). Group 6 25 decrease of survive rate was then observed resulting in only animals were dosed on Docetaxel and served as the positive 33% animal survivorship by day 40 (FIG. 2). Similarly, ani control; this group showed 100% survival at day 40 (Table 8). mals from Group 3 (Rumenic Acid) showed a decline in the Looking at the groups where only a single drug was admin survival rate by day 27. Although survival remained high with istered, Group 2 (Risperidone) showed an overall survivor only about 10% animal loss by day 34, there was a sharp ship of 33% while Group 3 (Rumenic Acid) showed an overall 30 decline in survival rates until only 45% of the mice were alive survivorship of 45% (Table 8). These results indicate that by day 40 (FIG. 2). In contrast, both the onset of tumor administration of a single drug alone was ineffective in treat lethality and the survival rate improved in animals treated ing prostate cancer. On the other hand, groups where a drug with the combination therapy. For example, a decline in Sur combination was administered revealed increased overall vival rate was not observed until day 34 with about 10% 35 (Group 5) or 34% (Group 4) loss of animals (FIG. 2). By day survivorship of animals. Animals from Group 4 and 5 were 40, 70% of the animals in Group 4 were alive whereas 64% of dosed low and high Risperidone and Rumenic Acid combi the animals in Group 5 were also alive (FIG. 2). These results nations. Group 4 animals showed an overall Survivorship of demonstrate that both the low and high dose drug combina 70% while Group 5 animals showed an overall survivorship tions showed increase efficacy by increasing Survival rates of 64% (Table 8). These results demonstrate a synergistic 40 both in terms of delaying the onset of tumor lethality and well interaction between Risperidone and Rumenic Acid as nei as improving the Survival rate in the treated animals. ther drug alone was effective, yet in combination these drugs Another parameter of increased efficacy measured was increased overall survival by at least 1.4-fold and as much as growth inhibition of the prostate tumor. Group 1 (Vehicle) 2.1-fold. Thus, both the low and high dose drug combinations animals severing as the negative control showed no inhibition exhibited increase efficacy by improving overall survivorship 45 of tumor growth, whereas Group 6 (Docetaxel) animals sev in the treated animals. ering as the positive control showed a 94% inhibition of tumor growth (Table 8). Animal groups treated with a single drug TABLE 8 regime showed little effect on tumor growth inhibition. Ani Dosing Regime of Animal Groups mals from Group 2 (Risperidone) showed only a 16% inhi 50 bition of tumor growth (Table 8). Similarly, Group 3 (Ru Group Animal Survival Tumor Growth Inhibition* menic Acid) animals showed only a 21% inhibition of tumor 1 45% O% growth (Table 8). In contrast, animal groups treated with both 2 33% 16% low and high dose drug combinations exhibited significant 3 45% 21% tumor growth inhibition. For example, animals from Group 4 4 70% 70% 55 (Low Dose) showed 70% inhibition of tumor growth whereas 5 64% 65% animals from Group 5 (High Dose) showed 65% inhibition of 6 100% 94% tumor growth (Table 8). Analysis of tumor growth inhibition *Tumor growth inhibition data is as calculated on Day 34, except for Group 5 which had throughout the course of the study indicated that the rate of sufficient mice alive to calculate on Day 40. tumor growth inhibition was consistent (FIG. 3). These With regards to survival rate, a decline in the survival of 60 results demonstrate that both the low and high dose drug Group 1 (Vehicle) animals was observed by day 27 with an combinations showed increase efficacy by dramatically almost 20% animal loss and continued to drop steadily inhibiting tumor growth. throughout the course of the study (FIG. 2). Group 6 (Doc Lastly, the general health and overall condition of the ani etaxel) animals showed 100% survival throughout the course mals in each group was assessed by monitoring body weight of the study (FIG. 2). Similar to overall survivorship, animals 65 throughout the study. Groups 1 (Vehicle) and Group 6 (Doc belonging to the groups where only a single drug was admin etaxel) animals were on a trend of losing weight by Day 40, istered showed no real differences when compared to Group whereas Group 4 animals gained weight and Groups 2, 3, 5 US 9,375,433 B2 55 56 animals maintained a constant weight. These results showed nescence imaging parameters (area, average radiation and that both the low and high dose drug combinations did not total flux) on Day 34 (Table 9). adversely affect the general health and overall condition of With respect to Group 3 and 4, treatment VAL401 at either the animals. In contrast, although demonstrating efficacy, dose did not have any effect on animal body weight gain Docetaxel administration had adverse consequences on the 5 compared to vehicle treatment (Table 9). Animals treated general health and overall condition of the animals. with VAL401 did exhibited a statistically significant decrease in pancreatic tumor Volume in both studied doses and the Example 6 same trend was seen in pancreatic tumor weight when com pared to vehicle group (Table 9). In addition, VAL401-treated In Vivo Animal Model Studies on Pancreatic Cancer 10 animals showed a statistically significant decrease in biolu minescence imaging parameter evaluating area compared to In vivo studies were performed to determine the effect of vehicle group on Day 34 and the same trend was seen in in Risperidone in combination with Rumenic acid on orthotopic other bioluminescence imaging parameters (average radia pancreatic tumor growth in amouse Xenograft model utilizing tion and total flux) (Table 9). novel luciferase labelled BXPC-3 cells. Immunodeficeint 15 male mice (athymic nude mice) were acclimated to the labo TABLE 9 ratory for at least one week prior to implantation of tumor. BxPC-3 cells obtained directly from in vitro culture were then Summary of Data injected into the pancreas on Day 0. Animals were divided 20 VAL401 VAL4O1 into four groups of 10 mice each which underwent the fol PARAMETER Gemcitabine dose 1 mg/kg dose 2 mg/kg lowing treatment regime: Group 1, daily oral administration Body weight of vehicle comprising 1% (v/v) ethanol, 20% (v/v) PEG 400, 79% (v/v) acid solution and 0.4% (w/v) TWEENTM 80 at a Body weight curves NS NS NS Body weight at sacrifice NS NS NS final pH of 3.1-3.3 (Control); Group 2, intraperitoneal admin- 25 relative to Day -1 istration of 60 mg/kg of Reference Compound gemcitabine body weight every third day for four rounds followed by one week rest Tumor volume before repeating the dosing: Group 3. daily oral administra Pancreatic tumor weight NS NS NS tion of 1 mg/kg of Test Compound VAL401; and Group 4, Pancreatic tumor volume ** * ** daily administration of 2 mg/kg Test Compound VAL401. 30 Bioluminescence Administration of Test and Reference Compounds began on imaging Day 1 and continued until Day 33. Body weights of the Area NS NS NS animals were measured two times a week throughout the Average radiation NS NS NS in-life phase and blood samples for PK analyses were col Total flux NS NS NS lected from saphenous vein from all animals 2 hours after 35 Area (day 34) NS * * compound administration at study Day 24. Primary tumor Average radiation NS NS NS size and metastases were assessed by bioluminescence mea (day 34) surements on Day 6, 13, 20, 27, and 34 using fluorescent Total flux (day 34) NS NS NS imaging system. The animals were sacrificed at Day 34. At Notation: the termination, brain tissues were collected and frozen. 40 ***= statistically significant difference with p-value < 0.001, Tumors were weighed, measured in three dimensions fol **= p-value < 0.01, lowed by fixation and embedding in paraffin for possible *= p-value <0.05, a = p-value < 0.1, and NS = Non-Significant. histopathological assessment. Also spleen, liver and lungs were collected for possible analysis. Example 7 Statistical analysis was performed with statistical software 45 R (version 3.1.2). The parameters with multiple measure In Vivo Animal Model Studies on Non-Small Cell ments in different time points per animal were analyzed using Lung Cancer mixed-effects models and model contrasts. The models had fixed effects for treatment, time point, and their interaction. In vivo studies were performed to determine the effect of The obtained p-values values were adjusted for multiple com- 50 Risperidone in combination with Rumenic acid on a Subcu parisons if necessary. The continuous valued end-point taneous non-Small cell lung cancer tumor growth in a mouse parameters were analyzed using parametric or non-paramet xenograft model. MF1 female mice were acclimated to the ric test. If the groups were normally distributed with equal laboratory for at least one week prior to implantation of variance, parametric one-way ANOVA followed by Tukey's tumor. H2228 cells obtained directly from in vitro culture HSD post hoc test was used. If the assumptions were not 55 were then injected subcutaneously on Day 0. Animals were fulfilled as Such or after data transform (e.g. logarithmic), divided into five groups of 15 mice each which underwent the nonparametric Kruskal-Wallis test followed by Mann-Whit following treatment regime: Group 1, daily oral administra ney U test was used. tion of vehicle; Group 2, daily oral administration of 50 The summary of the results obtained are provided in Table mg/kg of Reference Compound Crizotinib. Group 3, daily 9. With respect to Group 2, treatment with gemcitabine did 60 oral administration of 0.1 mg/kg of Test Compound VAL401; not have any effect on animal body weight gain compared to and Group 4, daily administration of 0.5 mg/kg Test Com vehicle treatment (Table 9). Animals treated with Gemcitab pound VAL401; Group 5, daily oral administration of 2 ine did exhibit a statistically significantly decreased pancre mg/kg of Test Compound VAL401. Administration of Test atic tumor volume when compared to vehicle group (Table 9). and Reference Compounds began on Day 22 and continued Although not statistically different when compared to vehicle 65 until Day 64. Body weights of the animals were measured group, Gemcitabine-treated animals also showed a trend in daily throughout the in-life phase and primary tumor size decreased pancreatic tumor weight as well as in the biolumi measured with calipers in two dimensions three times a week US 9,375,433 B2 57 58 with volumes calculated using the formula 0.5(LxWXW). disclosed herein. The patients condition is monitored and The animals were sacrificed at Day 65. At the termination, after about one month after treatment, the physician deter tumors were weighed, measured in three dimensions. mines that the size of the prostate has not increased in size. At No significant differences were observed in bodyweight three and six month check-ups, the physician determines that during the experiment. No adverse events were recorded, and 5 there is a decrease in the size of the tumor and that serum PSA no mice were terminated early. Data was assessed such that levels are within the normal range. This reduction in tumor the treatment groups were pooled and treated mice were size and/or reduces serum PSA levels indicates successful observed to be split into responder and non-responder treatment with the composition disclosed herein. In a similar categories. 40% of treated mice responded, and the tumour manner, a pharmaceutical composition any of the other benzo growth for the groups is seen below in Table 10. The tumour 10 (iso)oxazolepiperidines disclosed herein and/or any of the growth of the treatment non-responders is seen to be compa other fatty acids disclosed herein, such as, e.g., an omega-3 rable to the untreated animals, validating the non-response fatty acid, an omega-6 fatty acid, an omega-7 fatty acid, an criteria (Table 10). Responders are seen to have significantly omega-9 fatty acid, or any combination thereof, may be for lower tumour growth than untreated animals (Table 10). 15 mulated into a pharmaceutical composition and administered to the patient as described above. Additionally, administra TABLE 10 tion of other therapeutic compounds disclosed herein, Such Summary of Data as, e.g., a 5C. reductase inhibitor, a chemotherapeutic agent, an anti-proliferative agent, or any combination thereof may Percent Tumour growth (Mean t Standard Error be used in the treatment of this cancer. Day 50 Day 52 Day 55 Day 57 A 61 year old woman complains of a solid mass in her left breast. After routine history and physical examination, a phy Untreated 31% 4.2%. 33% 4.3%. 37% 4.4% 40% 4.5% Treatment 31% 2.7%. 34% 2.9% 41% 3.0% 46% 3.1% sician diagnosis the woman with breast cancer. The woman is Non treated systemically by oral administration a pharmaceutical Responders 25 composition comprising Risperidone and Rumenic acid as Treatment 17% 2.8%. 18% - 2.5%. 19% 2.3%. 19% - 2.0% disclosed herein. The patients condition is monitored and Responders after about one month after treatment, the physician notes that the growth of the mass has slowed down. At three and six month check-ups, the physician determines that there is a Example 8 30 decrease in the size of the tumor. The reduction in tumor size indicates successful treatment with the composition dis Treatment of a Disorder Associated with Androgen closed herein. In a similar manner, a pharmaceutical compo Production sition any of the other benzo(iso)oxazolepiperidines dis closed herein and/or any of the other fatty acids disclosed A 58 year old man complains of difficulty in urinating. 35 herein, such as, e.g., an omega-3 fatty acid, an omega-6 fatty After routine history and physical examination, a physician acid, an omega-7 fatty acid, an omega-9 fatty acid, or any diagnosis the man with prostate cancer. The man is treated combination thereof, may be formulated into a pharmaceuti systemically by intravenous administration a pharmaceutical cal composition and administered to the patient as described composition comprising Risperidone and Rumenic acid as above. Additionally, administration of other therapeutic com disclosed herein. The patient’s condition is monitored and 40 pounds disclosed herein, such as, e.g., a 5C, reductase inhibi after about one month after treatment, the physician deter tor, a chemotherapeutic agent, an anti-proliferative agent, or mines that the size of the prostate has become smaller. At any combination thereof may be used in the treatment of this three and six month check-ups, the physician determines that CaCC. there is a further decrease in the size of the tumor and that A 53 year old woman complains of pelvic pain. After serum PSA levels are within the normal range. This reduction 45 routine history and physical examination, a physician diag in tumor size and/or reduces serum PSA levels indicates nosis the woman with ovarian cancer. The woman is treated Successful treatment with the composition disclosed herein. systemically by oral administration a pharmaceutical compo In a similar manner, a pharmaceutical composition any of the sition comprising Risperidone and Rumenic acid as disclosed other benzo(iso)oxazolepiperidines disclosed herein and/or herein. The patient’s condition is monitored and after about any of the other fatty acids disclosed herein, such as, e.g., an 50 one month after treatment, the physician notes that the growth omega-3 fatty acid, an omega-6 fatty acid, an omega-7 fatty of the malignant tumor has slowed down. At three and six acid, an omega-9 fatty acid, or any combination thereof, may month check-ups, the woman indicates that the pelvic pain is be formulated into a pharmaceutical composition and admin much reduced and the physician determines that there is a istered to the patient as described above. Additionally, admin decrease in the size of the tumor. The reduction in pain and/or istration of other therapeutic compounds disclosed herein, 55 tumor size indicates Successful treatment with the composi Such as, e.g., a 5C. reductase inhibitor, a chemotherapeutic tion disclosed herein. In a similar manner, a pharmaceutical agent, an anti-proliferative agent, or any combination thereof composition any of the other benzo(iso)oxazolepiperidines may be used in the treatment of this cancer. disclosed herein and/or any of the other fatty acids disclosed A 67 year old man previously treated for prostate cancer herein, such as, e.g., an omega-3 fatty acid, an omega-6 fatty with a hormone depletion therapy complains of a return of 60 acid, an omega-7 fatty acid, an omega-9 fatty acid, or any symptoms such as difficulty in urination. After routine history combination thereof, may be formulated into a pharmaceuti and physical examination, a physician determines that the cal composition and administered to the patient as described cancer in the prostate has increase in mass and has metasta above. Additionally, administration of other therapeutic com sized into the bones. The physician diagnosis the man with a pounds disclosed herein, such as, e.g., a 5C, reductase inhibi hormone refractory prostate cancer. The man is treated sys 65 tor, a chemotherapeutic agent, an anti-proliferative agent, or temically by intravenous administration a pharmaceutical any combination thereof may be used in the treatment of this composition comprising Risperidone and Rumenic acid as CaCC. US 9,375,433 B2 59 60 A 69 year old man complains of chest pain and that it is pharmaceutical composition and administered to the patient difficult to breath and wheezing. After routine history and as described above. Additionally, administration of other physical examination, a physician diagnosis the man with therapeutic compounds disclosed herein, Such as, e.g., a 5C. lung cancer. The man is treated Systemically by intravenous reductase inhibitor, may be used in the treatment of this hair administration a pharmaceutical composition comprising loss. Risperidone and Rumenic acid as disclosed herein. The In closing, it is to be understood that although aspects of the patient’s condition is monitored and after about one month present specification are highlighted by referring to specific after treatment, the physician notes that the growth of the embodiments, one skilled in the art will readily appreciate malignant tumor has slowed down. At three and six month that these disclosed embodiments are only illustrative of the check-ups, the man indicates that the chest pain is reduced, 10 principles of the subject matter disclosed herein. Therefore, it normal breathing has returned, and the physician determines should be understood that the disclosed subject matter is in no that there is a decrease in the size of the tumor. The reduction way limited to a particular methodology, protocol, and/or in pain and/or tumor size indicates Successful treatment with reagent, etc., described herein. As such, various modifications the composition disclosed herein. In a similar manner, a phar or changes to or alternative configurations of the disclosed maceutical composition any of the other benzo(iso)oxazol 15 Subject matter can be made in accordance with the teachings epiperidines disclosed herein and/or any of the other fatty herein without departing from the spirit of the present speci acids disclosed herein, Such as, e.g., an omega-3 fatty acid, an fication. Lastly, the terminology used herein is for the purpose omega-6 fatty acid, an omega-7 fatty acid, an omega-9 fatty of describing particular embodiments only, and is not acid, or any combination thereof, may be formulated into a intended to limit the scope of the present invention, which is pharmaceutical composition and administered to the patient defined solely by the claims. Accordingly, the present inven as described above. Additionally, administration of other tion is not limited to that precisely as shown and described. therapeutic compounds disclosed herein, Such as, e.g., a 5C. Certain embodiments of the present invention are reductase inhibitor, a chemotherapeutic agent, an anti-prolif described herein, including the best mode knownto the inven erative agent, or any combination thereof may be used in the tors for carrying out the invention. Of course, variations on treatment of this cancer. 25 these described embodiments will become apparent to those A 61 year old man complains of abdominal pain. After ofordinary skill in the art upon reading the foregoing descrip routine history and physical examination, a physician diag tion. The inventor expects skilled artisans to employ Such nosis the man with pancreatic cancer. The man is treated variations as appropriate, and the inventors intend for the systemically by oral administration a pharmaceutical compo present invention to be practiced otherwise than specifically sition comprising Risperidone and Rumenic acid as disclosed 30 described herein. Accordingly, this invention includes all herein. The patient’s condition is monitored and after about modifications and equivalents of the Subject matter recited in one month after treatment, the physician notes that the growth the claims appended hereto as permitted by applicable law. of the malignant tumor has slowed down. At three and six Moreover, any combination of the above-described embodi month check-ups, the man indicates that the abdominal pain ments in all possible variations thereof is encompassed by the is much reduced and the physician determines that there is a 35 invention unless otherwise indicated herein or otherwise decrease in the size of the tumor. The reduction in pain and/or clearly contradicted by context. tumor size indicates Successful treatment with the composi Groupings of alternative embodiments, elements, or steps tion disclosed herein. In a similar manner, a pharmaceutical of the present invention are not to be construed as limitations. composition any of the other benzo(iso)oxazolepiperidines Each group member may be referred to and claimed individu disclosed herein and/or any of the other fatty acids disclosed 40 ally or in any combination with other group members dis herein, such as, e.g., an omega-3 fatty acid, an omega-6 fatty closed herein. It is anticipated that one or more members of a acid, an omega-7 fatty acid, an omega-9 fatty acid, or any group may be included in, or deleted from, a group for reasons combination thereof, may be formulated into a pharmaceuti of convenience and/or patentability. When any such inclusion cal composition and administered to the patient as described or deletion occurs, the specification is deemed to contain the above. Additionally, administration of other therapeutic com 45 group as modified thus fulfilling the written description of all pounds disclosed herein, such as, e.g., a 5C, reductase inhibi Markush groups used in the appended claims. tor, a chemotherapeutic agent, an anti-proliferative agent, or Unless otherwise indicated, all numbers expressing a char any combination thereof may be used in the treatment of this acteristic, item, quantity, parameter, property, term, and so CaCC. forth used in the present specification and claims are to be A 20 year old man begins losing hair on his scalp. After 50 understood as being modified in all instances by the term routine history and physical examination, a physician diag “about.” As used herein, the term “about” means that the nosis the man with androgenic alopecia. The man is treated characteristic, item, quantity, parameter, property, or term so locally by topical administration a pharmaceutical composi qualified encompasses a range of plus or minus ten percent tion comprising Risperidone and Rumenic acid as disclosed above and below the value of the stated characteristic, item, herein. The patient’s condition is monitored and after about 55 quantity, parameter, property, or term. Accordingly, unless one month after treatment, the physician notes that further indicated to the contrary, the numerical parameters set forthin loss of hair has slowed. At three and six month check-ups, the the specification and attached claims are approximations that man indicates that he has noticed regrowth in the areas where may vary. For instance, as mass spectrometry instruments can hair loss occurred on his scalp and physician determines that vary slightly in determining the mass of a given analyte, the there is a further decrease in hair loss. This reduction in hair 60 term “about in the context of the mass of an ion or the loss and/or new hair growth indicates successful treatment mass/charge ratio of an ion refers to +/-0.50 atomic mass with the composition disclosed herein. In a similar manner, a unit. pharmaceutical composition any of the other benzo(iso)OX At the very least, and not as an attempt to limit the appli azolepiperidines disclosed herein and/or any of the other fatty cation of the doctrine of equivalents to the scope of the claims, acids disclosed herein, Such as, e.g., an omega-3 fatty acid, an 65 each numerical indication should at least be construed in light omega-6 fatty acid, an omega-7 fatty acid, an omega-9 fatty of the number of reported significant digits and by applying acid, or any combination thereof, may be formulated into a ordinary rounding techniques. US 9,375,433 B2 61 62 Use of the terms “may' or "can' in reference to an embodi these documents is based on the information available to the ment or aspect of an embodiment also carries with it the applicants and does not constitute any admission as to the alternative meaning of “may not or “cannot.” As such, if the correctness of the dates or contents of these documents. present specification discloses that an embodiment or an The invention claimed is: aspect of an embodiment may be or can be included as part of 5 1. A method of treating an individual with an adenocarci the inventive Subject matter, then the negative limitation or noma, the method comprising the step of administering to an exclusionary proviso is also explicitly meant, meaning that an individual in need thereofa benzo(iso)oxazolepiperidine and embodiment or an aspect of an embodiment may not be or about 0.01 mg/kg/day to about 0.5 mg/kg/day of a 9Z,11E cannot be included as part of the inventive subject matter. In conjugated Linoleic Acid, wherein administration reduces a a similar manner, use of the term “optionally in reference to 10 symptom associated with the adenocarcinoma, thereby treat an embodiment or aspect of an embodiment means that Such ing the individual, embodiment or aspect of the embodiment may be included as wherein the benzo(iso)oxazolepiperidine comprises an part of the inventive subject matter or may not be included as optionally Substituted Iloperidone, an optionally Substi part of the inventive subject matter. Whether such a negative tuted Ocaperidone, an optionally Substituted paliperi limitation or exclusionary proviso applies will be based on 15 done, an optionally Substituted risperidone, or any com whether the negative limitation or exclusionary proviso is bination thereof, and recited in the claimed subject matter. wherein there is a synergistic effect between the benzo(iso) Notwithstanding that the numerical ranges and values set oxazolepiperidine and the 9Z,11E conjugated Linoleic ting forth the broad scope of the invention are approxima Acid. tions, the numerical ranges and values set forth in the specific 2. The method according to claim 1, wherein the benzo(iso) examples are reported as precisely as possible. Any numerical oxazolepiperidine is in an about from 0.1 mg/day to about 20 range or value, however, inherently contains certain errors mg/day. necessarily resulting from the standard deviation found in 3. The method according to claim 1, wherein the benzo(iso) their respective testing measurements. Recitation of numeri oxazolepiperidine is in an amount from about 0.01 mg/kg/day cal ranges of values herein is merely intended to serve as a 25 to about 0.5 mg/kg/day. shorthand method of referring individually to each separate 4. The method according to claim 1, wherein the 9Z,11E numerical value falling within the range. Unless otherwise conjugated Linoleic Acid is in an amount from about 1 indicated herein, each individual value of a numerical range is mg/day to about 20 mg/day. incorporated into the present specification as if it were indi 5. The method according to claim 1, wherein the benzo(iso) vidually recited herein. 30 oxazolepiperidine is risperidone. The terms “a,” “an,” “the' and similar referents used in the 6. The method according to claim 5, the risperidone is in an context of describing the present invention (especially in the about from 0.1 mg/day to about 20 mg/day. context of the following claims) are to be construed to cover 7. The method according to claim 5, wherein the risperi both the singular and the plural, unless otherwise indicated done is in an amount from about 0.01 mg/kg/day to about 0.5 herein or clearly contradicted by context. All methods 35 mg/kg/day. described herein can be performed in any suitable order 8. The method according to claim 1, wherein the benzo(iso) unless otherwise indicated herein or otherwise clearly con oxazolepiperidine and the 9Z,11E conjugated Linoleic Acid tradicted by context. The use of any and all examples, or are administered sequentially or simultaneously. exemplary language (e.g., “such as') provided herein is 9. The method according to claim 1, wherein the benzo(iso) intended merely to better illuminate the present invention and 40 oxazolepiperidine and the 9Z,11E conjugated Linoleic Acid does not pose a limitation on the Scope of the invention are administered to the individual as a single composition. otherwise claimed. No language in the present specification 10. The method according to claim 1, wherein the reduced should be construed as indicating any non-claimed element symptom includes a reduction in the frequency of a symptom essential to the practice of the invention. of an adenocarcinoma, a reduction in the number of symp Specific embodiments disclosed herein may be further lim 45 toms of an adenocarcinoma, or any combination thereof. ited in the claims using consisting of or consisting essentially 11. The method according to claim 1, wherein the adeno of language. When used in the claims, whether as filed or carcinoma includes an esophageal cancer, a pancreatic can added per amendment, the transition term "consisting of cer, a prostate cancer, a cervical cancer, a stomach cancer, a excludes any element, step, or ingredient not specified in the throat cancer, a non-Small cell lung cancer, a ductal carci claims. The transition term “consisting essentially of limits 50 noma of the breast, a lobular carcinoma of the breast, a col the scope of a claim to the specified materials or steps and orectal cancer, adenocarcinoma of the lung, cholangiocarci those that do not materially affect the basic and novel char noma or vaginal cancer. acteristic(s). Embodiments of the present invention so 12. The method according to claim 2, wherein the benzo claimed are inherently or expressly described and enabled (iso)oxazolepiperidine is in an about from 0.5 mg/day to herein. 55 about 17.5 mg/day. All patents, patent publications, and other publications 13. The method according to claim 4, wherein the 9Z,11E referenced and identified in the present specification are indi conjugated Linoleic Acid is in an about from 0.5 mg/day to vidually and expressly incorporated herein by reference in about 17.5 mg/day. their entirety for the purpose of describing and disclosing, for 14. The method according to claim 6, wherein the risperi example, the compositions and methodologies described in 60 done is in an about from 0.5 mg/day to about 17.5 mg/day. Such publications that might be used in connection with the 15. A method of treating an individual with an adenocar present invention. These publications are provided solely for cinoma, the method comprising the step of administering to their disclosure prior to the filing date of the present applica an individual in need thereof about 0.01 mg/kg/day to about tion. Nothing in this regard should be construed as an admis 0.5 mg/kg/day of a risperidone and about 0.01 mg/kg/day to sion that the inventors are not entitled to antedate such dis 65 about 0.5 mg/kg/day of a 9Z,11E conjugated Linoleic Acid, closure by virtue of prior invention or for any other reason. All wherein administration reduces a symptom associated with statements as to the date or representation as to the contents of the adenocarcinoma, thereby treating the individual, US 9,375,433 B2 63 64 wherein there is a synergistic effect between the risperi wherein there is a synergistic effect between the risperi done and the 9Z,11E conjugated Linoleic Acid. done and the 9Z,11E conjugated Linoleic Acid. 16. The method according to claim 15, wherein the risperi 20. The method according to claim 19, wherein the risperi done and the 9Z,11E conjugated Linoleic Acid are adminis done is in an about from 0.5 mg/day to about 17.5 mg/day. tered sequentially or simultaneously. 21. The method according to claim 19, wherein the 9Z,11E 17. The method according to claim 15, wherein the risperi conjugated Linoleic Acid is in an about from 0.5 mg/day to done and the 9Z,11E conjugated Linoleic Acid are adminis about 17.5 mg/day. tered to the individual as a single composition. 22. The method according to claim 19, wherein the risperi 18. The method according to claim 15, wherein the adeno done and the 9Z,11E conjugated Linoleic Acid are adminis carcinoma includes an esophageal cancer, a pancreatic can 10 cer, a prostate cancer, a cervical cancer, a stomach cancer, a tered sequentially or simultaneously. throat cancer, a non-small cell lung cancer, a ductal carci 23. The method according to claim 19, wherein the risperi noma of the breast, a lobular carcinoma of the breast, a col done and the 9Z,11E conjugated Linoleic Acid are adminis orectal cancer, adenocarcinoma of the lung, cholangiocarci tered to the individual as a single composition. noma or vaginal cancer. 15 24. The method according to claim 19, wherein the adeno 19. A method of treating an individual with an adenocar carcinoma includes an esophageal cancer, a pancreatic can cinoma, the method comprising the step of administering to cer, a prostate cancer, a cervical cancer, a stomach cancer, a an individual in need thereof about from 0.1 mg/day to about throat cancer, a non-Small cell lung cancer, a ductal carci 20 mg/day of a risperidone and about 1 mg/day to about 20 noma of the breast, a lobular carcinoma of the breast, a col mg/day of a 9Z,11E conjugated Linoleic Acid, wherein 20 orectal cancer, adenocarcinoma of the lung, cholangiocarci administration reduces a symptom associated with the adeno noma or vaginal cancer. carcinoma, thereby treating the individual, k k k k k