US 20070078091A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0078091 A1 Hubler et al. (43) Pub. Date: Apr. 5, 2007 (54) PHARMACEUTICAL COMBINATIONS FOR (30) Foreign Application Priority Data COMPENSATING FORATESTOSTERONE DEFICIENCY IN MEN WHILE Sep. 6, 1998 (DE)..................................... 198 2.55918 SMULTANEOUSLY PROTECTING THE PROSTATE Publication Classification (76) Inventors: Doris Hubler, Schmieden (DE): (51) Int. Cl. Michael Oettel, Jena (DE); Lothar A6II 38/09 (2007.01) Sobek, Jena (DE); Walter Elger, Berlin A 6LX 3/57 (2007.01) (DE); Abdul-Abbas Al-Mudhaffar, A6II 3/56 (2006.01) Jena (DE) A 6LX 3/59 (2007.01) A 6LX 3/57 (2007.01) A61K 31/4709 (2007.01) Correspondence Address: A6II 3L/38 (2007.01) MILLEN, WHITE, ZELANO & BRANGAN, (52) U.S. Cl. ............................ 514/15: 514/171; 514/170; P.C. 514/651; 514/252.16; 514/252.17; 22OO CLARENDON BLVD. 514/3O8 SUTE 14OO ARLINGTON, VA 22201 (US) (57) ABSTRACT This invention relates to pharmaceutical combinations for (21) Appl. No.: 11/517,301 compensating for an absolute and relative testosterone defi ciency in men with simultaneous prophylaxis for the devel opment of a benign prostatic hyperplasia (BPH) or prostate (22) Filed: Sep. 8, 2006 cancer. The combinations according to the invention contain a natural or synthetic androgen in combination with a Related U.S. Application Data gestagen, an antigestagen, an antiestrogen, a GnRH analog. a testosterone-5C.-reductase inhibitor, an O-andreno-receptor (63) Continuation of application No. 09/719,221, filed on blocker or a phosphodiesterase inhibitor. In comparison to Feb. 16, 2001, filed as 371 of international application the combinations according to the invention, any active No. PCT/DE99/01652, filed on Jun. 7, 1999. ingredient by itself cannot achieve the desired goal. Patent Application Publication Apr. 5, 2007 US 2007/0078091A1 Cells/Well 10,000 : i i Figure 1. Inhibition of the Androgen-dependent cell proliferation in LNCaPProstate cells (# = 0.1 nM R1881, n = 4, V18) US 2007/0078091 A1 Apr. 5, 2007 PHARMACEUTICAL COMBINATIONS FOR gens by themselves—W94/26767 A1—or in combination COMPENSATING FORATESTOSTERONE with testolactone as an aromatase inhibitor DE 3121 152 DEFICIENCY IN MEN WHILE SIMULTANEOUSLY A1—, with testosterone-5C.-reductase inhibitor by itself PROTECTING THE PROSTATE EPO 547 691 A1: WO95/13077 A1 or in combination 0001. The invention relates to pharmaceutical combina with antiestrogens and/or aromatase inhibitors WO tions for compensating for an absolute and relative testoster 91/OO731 A1. one deficiency in men with simultaneous prophylaxis for the 0011 A testosterone replacement therapy without risk to development of a benign prostatic hyperplasia (BPH) or the prostate is not indicated. prostate cancer that contains a natural or synthetic androgen in combination with a gestagen, an antigestagen, an anties 0012. In the technical literature, it is shown that androgen trogen, a GnRH analog, a testosterone-5C.-reductase inhibi Substitution also improves physical and mental well-being as tor, an O-andreno-receptor blocker or a phosphodiesterase a person ages Bagatell et al. J. Clin. Endocrin. Metab. 79: inhibitor. 561-567 (1994); Tenover, J. S. Endocrinology and Metabo lism Clinics of North America 23: 878-892 (1994). 0002 Various endocrine functions vary during the course of the aging process. 0013 The androgen substitution in older men with reduced serum-testosterone levels is still a controversial 0003. The normal aging process in men is accompanied topic for a wide variety of reasons, however, and the by a reduction in the testicular function, especially a reduc increased risk of diseases of the prostate by overstimulation tion in the serum-testosterone level. is always emphasized. 0004 The serum-testosterone secretion is responsible for 0014. It is therefore inadvisable to undertake androgen the secondary sex characteristics, libido and potency and replacement therapy in the older or prematurely aged man also has an effect on the emotional and intellectual capa analogously to postmenopausal hormone Substitution of the bilities, on the erythropoiesis, bone metabolism, protein woman Rolf, C. and E. Nieschlag: Seneszenz Senescence anabolism and muscle mass, fat distribution and certain in E. Nieschlag and H. M. Behre (Editors): Andrologie— CNS functions. In lowering the serum-testosterone level, a Grundlagen und Klinik der reproduktiven Gesundheit des reduction of the libido and potency, as well as fatigue, Mannes Andrology Principles and Clinical Studies of the reduction of the muscle mass, osteoporosis, hot flashes, Reproductive Health of the Man). Springer 1996: Jackson, J. profuse Sweating and slight anemia can clinically occur. A. et al. Arch. Intern. Med. 149: 2365-2366 (1989): Jock 0005. An important role is ascribed to androgens for the enhbvel, F. Androgensubstitution des alteren Mannes An development and manifestations of both benign prostatic drogen Substitution of the Older Man). In: Allolio and Schulte (Editors). Praktische Endokirinologie Practical hyperplasia (BPH) and prostate cancer, however. Endocrinology). Urban & Schwarzenberg, Munich, pp. 416 0006. At older ages, diseases of the prostate occur in 419 (1996). clusters. In 50% of men over 50 years old, this leads to a non-malignant growth of the prostate (BPH). 0015. Also, e.g., after an 8-month therapy of 23 men at the ages of 40-65 years with testosterone undecanoate (160 0007 Hypogonadal males or castrated males never mg/day), Holmang, S. et al. Prostate 23, 99-106 (1996) develop a BPH. Geller, J.: Androgen Inhibition and BPH. in: could detect a 12% increase in size of the prostate. Bhasin et al. (Editors): Pharmacology, Biology and Clinical Applications of Androgens. John Wiley, New York (1996). 0016. In studies on male contraception with testosterone enanthate, an enlargement of the prostate was found in 0008. In men with and without BPH, however, no differ young men under exogenic testosterone administration by ences in androgen concentrations in the serum exist Lee, C. means of transrectal ultrasound studies Wu, C. W. et al. Prostate 6 Supple., 52-56 (1996), Levine, A. C. Trends Fertility and Sterility 65, 626-636 (1996); Wallace, E. M. et Endocrinol. Metab. 6, 128-132 (1995); Serio, M. and al. Int. J. Androl. 16: 35-40 (1993). Fiorelli, G. Mol. Cell. Endocrinol. 78, C77-C81 (1991), Cunningham, G. R.: Overview of Androgens on the Normal 0017 Patent DE 19610 645 A1 describes the use of and Abnormal Prostate. In: Bhasin et al. (Editors). Pharma dehydroepiandrosterone in combination with aromatase cology, Biology, and Clinical Applications of Androgens. inhibitors for treatment of a relative and absolute androgen John Wiley, New York (1996), so that obviously the cellular deficiency in men (hypoandrogenism). Aromatase inhibitors metabolism of testosterone into 5C.-dihydrotestosterone in terms of this patent are all those compounds that prevent (DHT) and estradiol in the prostate, together with local the formation of estrogens from their metabolic precursors growth factors, is of decisive importance for the develop (here DHEA) by inhibiting the enzyme aromatase (inhibi ment both of benign prostatic hyperplasia (BPH) and pros tion of the biosynthesis). tate Cancer. 0018 Androgen therapy with simultaneous protection of 0009 Both in men over 50 and in younger men with the prostate is not indicated, however. various chronic diseases and continuous stress, all indicated clinical symptoms in serum-testosterone levels demonstra 0.019 Patent WO 97/29735 claims androgens, antiandro bly occur in clusters even at the lower standard limits of 12.0 gens, estrogens or antiestrogens containing transdermal sys to 15 nmol/l. tems, individually or in combination, for androgen therapy in the case of a deficiency of the testosterone level in 0010. It is known from the literature or patent literature to hypogonadal men, for hormone substitution therapy in post treat androgen-dependent systemic diseases, such as, for menopausal women and for hormonal contraception in men example, the BHP and the prostate cancer, with antiandro and in women. US 2007/0078091 A1 Apr. 5, 2007 0020. Also, androgen therapy with simultaneous protec 0035) 113-(4-N,N-dimethylamino)-phenyl-17C.-hy tion of the prostate is not indicated here. droxy-17 B-(3-hydroxypropyl-13C.-methyl-gona-4,9-dien-3- one (ZK 98.299—onapristone); 0021. The object of this invention is to define suitable combination preparations for compensating for an absolute 0036) 113-(4-acetylphenyl)-17 B-hydroxy-17C.-propinyl and relative testosterone deficiency in men while simulta estra-4,9-dien-3-one (ZK 112993); neously protecting the prostate and in this case to avoid the 0037) 113-(4-N,N-dimethylamino)-phenyl-17 3-hy above-mentioned drawbacks and actions. droxy-17C.-(3-hydroxy-1-(Z)-propenyl)-estra-4,9-dien-3- 0022. The object is achieved by the use according to the one (ZK 98 734—lilopristone); invention of combination preparations according to claim 1 0038 113-(4-N,N-dimethylamino)-phenyl-17 3-hy for compensating for an absolute and relative testosterone droxy-17C.-(3-hydroxy-1-(Z)-propenyl)-estra-4-en-3-one deficiency with simultaneous therapy of the benign prostatic hyperplasia (BPH). (ZK 137 316): 0039) 113-(4-N,N-dimethylamino)-phenyl]-6B-methyl 0023 The use of the combination preparations according 4',5'dihydrospiro-estra-4,9-diene-17.2"(3'H)-furan-3-one to the invention is preferably characterized in that natural (ORG 31 710); androgen is one of the Substances testosterone, testosterone undecanoate, dehydroepiandrosterone, dehydroepiandros 0040 113-(4-N,N-dimethylamino)-phenyl-73-methyl terone Sulfate, testosterone propionate, testosterone enan 4',5'dihydrospiro-estra-4,9-diene-17.2"(3'H)-furan-3-one thate, testosterone buciclate, testosterone cypionate or (ORG 31 806); androstene dione, and the synthetic androgen is one of the 0041) 113-(4-acetylphenyl)-(3E)-ethylidene-4',5'dihy Substances 17-methyltestosterone, fluoxymesterone, dana drospiro-estra-4,9-diene-17.2"(3'H)-furan-3-one (ORG 33 Zol, mesterolone, nandrolone decanoate, nandrolone phenyl propionate, Oxandrolone, oxymetholone, or stanazolol.