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WO 2019/077407 Al 25 April 2019 (25.04.2019) W 1P O PCT

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WO 2019/077407 Al 25 April 2019 (25.04.2019) W 1P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/077407 Al 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, A61K 36/886 (2006.01) A61K 36/739 (2006.01) EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, A61K 36/708 (2006.01) A6IK 36/82 (2006.01) MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, A61K 36/185 (2006.01) A6IK 36/59 (2006.01) TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, A61K 36/756 (2006.01) A61P 13/08 (2006.01) KM, ML, MR, NE, SN, TD, TG). A61K 36/47 (2006.01) A61P 15/00 (2006.01) A61K 36/28 (2006.01) A61P 35/00 (2006.01) Published: A61K 36/24 (2006.01) — with international search report (Art. 21(3)) — before the expiration of the time limit for amending the (21) International Application Number: claims and to be republished in the event of receipt of PCT/TB2018/001296 amendments (Rule 48.2(h)) (22) International Filing Date: 18 October 2018 (18. 10.2018) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/574,440 19 October 2017 (19. 10.2017) U S (71) Applicant: YALE UNIVERSITY [US/US]; Two Whitney Avenue, New Haven, CT 065 11 (US). (72) Inventors: CHENG, Yung-Chi; 961 Baldwin Road, Woodbridge, CT 06525 (US). LAM, Wing; 470 Prospect Street, Apt 38, New Haven, CT 065 11 (US). JIANG, Zaoli; 20 Cedar Rock Road, Woodbridge, CT 06525 (US). (74) Agent: COLEMAN, Henry, D.; Cosud Intellectual Prop¬ erty Solutions, P.C., 714 Colorado Avenue, Bridgeport, CT 06605-1601 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (54) Title: INHIBITION OF ANDROGEN RECEPTOR BY EXTRACTS OF MEDICINAL HERB S AND COMPOSITIONS THERE¬ o OF 1 - (57) Abstract: In one embodiment, the present invention is directed to a composition comprising an aqueous or ethanolic extract of at least one herb selected from the group consisting of Aloe barbadensis # , Rheum palmatum L . ( :Β 6) Stephania tetrandra (¾ © H:C4), Phellodendron chinense Schneid. (Hffi:D8), Euphorbia humifusa (¾#¾¾S6), Eclipta prostrata , A . venetum L . (H¾Jft:FI), Portulaca oleracea L . (¾¾T]¾:F5) and Sanguisorba officinalis L . (¾#s:E5 }, Camellia sinensis var.assamica (Mast) Kitamura (¾ :PE) and Punica granatum. (¾¾ :PG); and mixtures thereof. The composition is administered to a patient, in an effective o amount, in a method of treating, inhibiting, preventing, reducing the incidence of, ameliorating or resolving a disease state or condition caused in part or exacerbated by hyperactivity of the androgen receptor (AR), by inhibiting the androgen receptor protein. These compositions may also be used inhibit or stabilize hair loss or grow hair in a subject in need. INHIBITION . ANDROGEN RECEPTOR S EXTRACTS OF MEDICINAL HERBS AND COMPOSITIONS THEREOF Related Application Thi -application claims the benefit of priority of United States provisional application serial number US62 /574,440 of identical title filed October 19, 20 , the entire co te ts of which are incorporated by reference herein. Field of t e inve tio The presented invention relates to certain medicinal herbs and their extracts which have been found to inhibit the androge receptor and are useful i the treatment of disease states and conditions which result from hyperactivity of the androgen receptor. Pharmaceutical compositions base upo these herbs and/or extracts obtained therefrom represent an additional aspect of the invention. Methods of treating a variety of disease states which are a result of hyperactivity of the a droge receptor as otherwise disclosed herein represent an additional aspect of the invention. Background the invention The prostate is a gland i the ale reproductive system. Most prostate cancers grow slowly; however, some grow more rapidly. The cancer cells may sprea from the prostate to other parts of the body, particularly the bones and lymph nodes. Initially, prostate cancer may exhibit o symptoms. Symptoms arising at a later stage of development may include difficulty urinating, blood in the urine, o pain in the pelvis, bac or when urinating. Other !ate symptoms may include fatigue d e to low levels of red blood ceils. No single gene s believed to be responsible for prostate cancer; many different .genes have been implicated. Mutations in BRCAl and BRCA2, important risk factors for ovarian cancer and breast cancer in women, have also been implicated in prostate cancer. Other linked genes include the Hereditary Prostate cancer gene (HPC1), the androgen receptor, and the vitamin receptor. TMPRSS2-ETS gene family fusion, specifically TMPRSS2- ERG or TMPRSS2-ETV 4 promotes cancer ce l growth. The prostate glands require male hormones, known as androgens, to work properly. Androgens include testosterone, which is made in the testes; deiiydroepimidrosterone, made in the adrenal glands; an d hydrotestosterone, which is converted from testosterone within the prostate itself. Androgens are a so responsible for secondary se characteristics such as facial hair and increased muscle mass. The androgen receptor (A ), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), i a type of nuclear receptor that is activated by binding either of th androgenic hormones, testostero ne or dihydrotestosterone in the cytoplasm and the translocating into the nucleus. The main .function of the androgen receptor is as a DMA-binding transcription factor that regulates gene expression; however, the androgen receptor has other functions as well. The androgen receptor helps prostate cancer cells to survive and its inhibition is a target for many anti cancer research studies; so far, no: composition .has been found that is e fe iv in inhibiting the androgen receptor in humans. Prostate cancer, alopecia, hepatocellular carcinoma, and acne vulgaris are a few examples of the myriad of diseases linked to androgen receptor signaling. These diseases have a .significant impact on human health; for example. The American Cancer Society estimates that in 2009, prostate cancer will cause 27,360 deaths and 192.280 new cases wi l e diagnosed. n fact, one man in si will ge prostate cancer in his lifetime and one in thirty- five will die from this disease. Androgen receptor inhibitors are the primary treatment option for androgen-related diseases. Current inhibitors prevent ligand binding to the androgen receptor, but these treatments can result in acquired resistance and serious side effects. Due to the limitations of current treatment options, alternative antiandrogen therapies are urgently needed. Brief Descriptio the invention The present invention recognizes that certain herbs, which have a lon history of use by humans, may be able to inhibit the androgen receptor. Those herbs ca be used singly or in combination with others, or as a iead for isolation of active chemicals for inhibition of the androgen receptor. Those herbs may be useful for cancer prevention particularly prostate hyperplasia or prostate cancer and other diseases caused by hyperactivity of the androgen receptor. To address this potential, the inventors studied the effects of herbal water extracts from over 250 formulations, across 25 signaling pathways, using primary hiciferase reporter assay and other enzymatic reactions. Eleven ( ) herbs showe androgen receptor inhibition. The present invention therefore re tes to extracts obtained front the group of (eleven) herbs consisting of Aloe barbadensis (Aloe vbera) ' :F3 Rheum palmatum L. ( B6), Stephania tetrandra (St ¾ C4), Phellodendrem ch nense S hne d (H¾:DS), Euphorbia humifusa (¾I|¥:S6), Eclipta prostrate ¾ Apocyaum Sanguisorba officinalis L . (¾ i :E5), Camellia sinensis var.assamica (Mast.) itara ura Chaag (puer tea, ¾ :PE} Punica and mixtures thereof, including mixtures of two, three, four , five, six, seven, eight, nine, ten and eleven of the aforementioned herbs and/or their extracts). Such herbs are inhibitors of the androgen receptor an accordingly are effective in pharmaceutical compositions or nutritive supplements to treat, inhibit, prevent, reduce the incidence of, ameliorate and/or resolve any of a number of disease states or conditions resulting o androgen receptor hyperactivity. These diseases and/or conditions include for example, prostate hyperplasia, prostate cancer, including castration resistant prostate cancer, drug resistant prostate cancer, especially including drug resistant cancers associated with AR- Vs (androgen receptor splice variants), bicalutamide and/or enzalutamide resistant prostate cancer, hepatocellular cancer, hair loss and/or the growth of hair, especially in the scalp and i other regions of the body where
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