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(12) United States Patent (10) Patent No.: US 9,375.433 B2 Dilly Et Al

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(12) United States Patent (10) Patent No.: US 9,375.433 B2 Dilly Et Al 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.
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