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(11) EP 2 266 568 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 29.12.2010 Bulletin 2010/52 A61K 31/4985 (2006.01) A61K 31/519 (2006.01) A61K 38/09 (2006.01) A61P 13/08 (2006.01) (2006.01) (21) Application number: 09161076.6 A61P 15/00

(22) Date of filing: 26.05.2009

(84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • Engel, Jürgen HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL 63755, Alzenau (DE) PT RO SE SI SK TR • Günther, Eckard Designated Extension States: 63477 Maintal (DE) AL BA RS • Müller, Markus 60594 Frankfurt am Main (DE) (71) Applicant: Æterna Zentaris GmbH 60314 Frankfurt am Main (DE)

(54) Use of LHRH antagonists in combination with PDE V inhibitors for the treatment of sex hormone dependent disorders

(57) The present invention relates to methods of urinary tract symptoms (LUTS). treatment of sex hormone dependent disorders, includ- It further relates to pharmaceutical compositions ing genitourinary disorders, infertility and sexual dysfunc- comprising LHRH antagonists in combination with PDE tions, in which LHRH antagonists are used in combina- V inhibitors for use in the treatment of sex hormone de- tion with PDE V inhibitors. It particulary refers to the treat- pendent disorders. ment of benign prostatic hypertrophy (BPH) and lower EP 2 266 568 A1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 266 568 A1 2

Description of endometrial tissue frequently forms cysts containing altered blood. The condition results in debilitating pain FIELD OF THE INVENTION for millions of women worldwide and particularly occurs in conjunction with the monthly proliferation of endome- [0001] The present invention relates to methods of 5 trial tissue. is frequently a lifelong condi- treatment of sex hormone dependent disorders, includ- tion. ing genitourinary disorders, infertility and sexual dysfunc- [0008] Ovarian cancer is often called the silent killer tions, in which LHRH antagonists are used in combina- because many times there are no symptoms until the tion with PDE V inhibitors. disease has progressed to an advanced stage. One-third [0002] It further relates to pharmaceutical composi- 10 of American women will get some form of cancer in their tions comprising LHRH antagonists in combination with lifetime and approximately 1.4% of those cases will be PDE V inhibitors for use in the treatment of sex hormone cancer involving one or both ovaries. dependent disorders. [0009] Dysfunctional (or abnormal) uterine bleeding (DUB) is a problem that often affects women as they start BACKGROUND OF THE INVENTION 15 to get periods and as they get closer to menopause, al- though any woman who menstruates can experience [0003] Sex hormone dependent disorders, including DUB. The main symptoms are prolonged and/or irregular genitourinary disorders, infertility and sexual dysfunc- menstrual bleeding. The bleeding may be irregular spot- tions present one of the most serious threats to men’s ting during the cycle, but sometimes the bleeding is so and women’s health today. 20 heavy that a woman can’t participate in her normal day- [0004] Benign prostatic hypertrophy (BPH) is a dis- to-day activities, such as work and exercise. ease conditioned by age and affects approximately 60% [0010] The discovery and characterization of LHRH of all men older than 60. Pathogenetically, an elevated (-releasing hormone, also referred to accumulation of dihydrotestosterone in the prostate tis- as GnRH) as the first mediator in the hypothalamic- pitu- sue is assumed to cause enlargement of the prostate. 25 itary-gonadal axis has opened up new possibilities for The accumulation of dihydrotestosterone is thought to the treatment of sex hormone-dependent conditions be the result of elevated intracellular bonding based on such as , breast cancer, endometriosis, receptor increase.The increasein receptors is stimulated uterine leiomyoma (fibroids), ovarian cancer, prostatic by the elevation of the levels relative to andro- hyperplasia, sexual dysfunction, assisted reproductive gen levels which decrease with age. The urological30 therapy, and precocious puberty (The Lancet 358: symptoms consist in an elevated frequency of miction 1793-1803, 2001; Mol. Cell. Endo. 166:9-14, 2000). due to elevated residual urine, which bothers the patients [0011] LHRH plays a key role in the control of mam- especially during the night hours. This is accompanied malian reproduction. LHRH is secreted in a pulsatile by a weak flow of urine, a time-delayed start of miction, manner from hypothalamic neurons and regulates the and repeated infections of the bladder and kidneys. 35 synthesis and secretion of the (follicle [0005] Lower urinary tract symptoms (LUTS) are a stimulating hormone (FSH) and luteinizing hormone common problem affecting older men. Symptoms can be (LH)) from the anterior pituitary gonadotropes. This ac- categorised into filling symptoms (previously called irri- tion of LHRH is achieved by binding to and activation of tative) and voiding symptoms (previously called obstruc- its high affinity receptors located on the plasma mem- tive). Symptoms are non-specific and large studies of 40 brane of the gonadotropes. LHRH or LHRH-like immu- patients have failed to show any correlation between low- noreactivity and LHRH mRNA have been reported in hu- er urinary tract symptoms and a specific diagnosis. LUTS man ovary,breast, testes, pituitary,as well as in a number are common and not necessarily a reason for suspecting of human tumors and tumor cell lines. The existence of prostate cancer. high affinity LHRH receptor and its mRNA has been [0006] Prostate cancer is a serious condition that af- 45 shown using LHRH superagonists in radioreceptor as- fects increasing numbers of men worldwide. About one- says and reverse transcriptase-polymerase chain reac- third of all men have at least some cancerous prostatic tion techniques in human ovary, breast, prostate, testes, cells at age 50, with the incidence increasing to as many and in a number of hormone-related tumors including as 90 percent of men at age 90. In the United States breast tumor, prostate tumor, endometrial tumor, ovarian alone, about 40,000 men die each year from prostate 50 tumor, kidney tumor, pancreas tumor, and tumor cell cancer. lines. Nucleotide sequences of LHRH receptors isolated [0007] Endometriosis is one of the most frequently en- from a breast tumor cell line (MCF- 7) and from an ovarian countered pathologies diagnosed amongst gynecologi- tumor showed 100% homology with the human pituitary cal patients. For example, between 10% and 25% of receptor. women presenting with gynecological symptoms in UK 55 [0012] The cloning and sequencing of the LHRH re- and in the USA are affected. Endometriosis is the ectopic ceptor from human pituitary has made it possible to in- presence of endometrial type glands and stroma in sites vestigate the expression of LHRH and LHRH receptor which are outside of the uterus. This ectopic occurrence genes in human non-reproductive tissues. In human,

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LHRH receptor mRNA is also expressed in liver, heart, relates to combination treatment methods using GnRH skeletal muscle, and kidney (Cancer Letters 98 (1995) and/or GnRH analog and prostaglandin synthesis inhib- 57-62). itor and/or prostaglandin receptor antagonist for the treat- [0013] Because desensitization of the LHRH receptor ment of sex-hormone dependent diseases. Torrisi et al. is very effective in blocking LH/FSH release, several ana- 5 (British Journal of Cancer (2007), 97(6), 802-808) de- logs of LHRH have been approved for the treatment of scribe letrozole and GnRH analogue as primary therapy sex hormone dependent disorders in humans. in premenopausal women with ER and PgR positive lo- [0014] Several studies have shown that treatments cally advanced operable breast cancer. with the combination of a LHRH analog and a further [0016] An alternative approach to treat sex hormone active compound are more effective than treatments with 10 dependent disorders is the use of PDE5 inhibitors. a LHRH analog alone. [0017] DE19825591 refers to Pharmaceutical combi- [0015] WO9014839 describes the use of nations which compensate an abs. or relative testoster- releasing hormone analogues in combination with gona- one deficit with simultaneous prophylaxis against forma- dotropins and growth hormone for infertility treatment. tion of benign prostatic hyperplasia or prostate carcino- WO92/16233 describes the combined use of an inhibitor 15 ma. The combinations of the invention contain a natural of 5-alpha-reductase and an anti- for the treat- or synthetic androgen in combination with a phosphodi- ment of prostate cancer. The combination of Finasteride esterase inhibitor. WO2003028730 discloses combina- with an anti- androgen, e.g. , is also taught. The tions containing a phosphodiesterase inhibitor and i) an use of a composition of various LHRH agonists and of anti-diabetic agent; (ii) HMG-Co-A reductase inhibitors; an anti-androgen for treating BPH is also suggested in 20 (iii) an antihypertensive agent; or (iv) a serotonin re- the US patent US 4,472,382. DE 19604231 discloses the uptake inhibitor (SSRI) for the treatment of sexual dys- use of combinations of LH-RH analogs and function, hyperglycemia, hyperinsulinemia, hyperlipi- for the treatment of gynecological disorders.demia, hypertriglyceridemia, diabetes, insulin resist- DE19825591 refers to pharmaceutical combinations ance, impaired glucose metabolism, conditions of im- which compensate an abs. or relative testosterone deficit 25 paired glucose tolerance (IGT), conditions of impaired with simultaneous prophylaxis against formation of be- fasting plasma glucose, obesity, diabetic retinopathy, di- nign prostatic hyperplasia or prostate carcinoma. The abetic nephropathy, glomerulosclerosis, diabetic neu- combinations of the invention contain a natural or syn- ropathy, syndrome X, erectile dysfunction, coronary thetic androgen in combination with a gonadotropin-re- heart disease, hypertension, esp. ISH, angina pectoris, leasing hormone analog. WO9917767 describes meth- 30 myocardial infarction, stroke, vascular restenosis, en- ods of treating and preventing endometriosis with phy- dothelial dysfunction, impaired vascular compliance or toestrogens in combination with GnRH analogs, andro- congestive heart failure. WO2004087211 relates to gens, progestins, estrogens or any combination thereof. methods for the treatment of infertility with inhibitors of WO2001060365 discloses methods of Treatment or pre- phosphodiesterases (PDE) in conjunction with gonado- vention of prostate cancer with a COX- 2 selective inhib- 35 tropins. US2005222014 relates to Phosphodiesterase V iting drug in combination with LHRH analogs. Palomba inhibitor combination with melanocortin 3 and/or 4 recep- et al. (Human Reproduction (2002), 17(12), 3213-3219) tor agonist for treatment of sexual dysfunction. describe a combined administration of GnRH analogue WO2007039075 describes the use of PDE-5 inhibitors and raloxifene in the treatment of uterine leiomyomas. in combination with PDE-4 inhibitors for the treatment of WO2002056903 refers to methods for treating hormone 40 urological disorders benign prostate hyperplasia (BPH), associated conditions using a combination of LHRH an- lower urinary tract symptoms (LUTS) and in particular tagonists and specific estrogen receptor modulators. irritative symptoms caused by BPH- induced bladder out- WO2002036144 relates to GnRH analogues for treat- let obstruction (BOO). WO2007072156 refers to a Phar- ment of urinary incontinence and other side effects as- maceutical combination of a PDE5 inhibitor and a 5 alpha sociated with ovariectomy or reproductive senescence 45 reductase inhibitor for the treatment of lower urinary tract in humans and dogs in combination with an additional symptoms (LUTS), such as urgency, frequency, nocturia active ingredient such as: an estrogenic agent, a partial and urge incontinence. WO2007072169 relates to the estrogenic agent, a progestational agent, an a-adrener- combined use of a phosphodiesterase 5 inhibitor and a gic agonist, a b-adrenergic receptor blocking agent, a muscarinic antagonist in the treatment of lower urinary cholinergic receptor blocking compd., a cholinergic re- 50 tract symptoms (LUTS). WO2008054215 discloses the ceptor stimulating drug, a smooth muscle relaxant, a ni- use of 3-alpha- androstanediol in combination with a 5- tric oxide synthase substrate or a nitric oxide donor. HT1A agonist and a type 5 phosphodiesterase (PDE5) WO2004087190 discloses a method for the treatment of inhibitor for the treatment of male and/or female sexual advanced prostate cancer by administering an andro- dysfunction. WO2008138483 describes combinations of gen-suppressing LH releasing hormone agonist analog 55 a soluble guanylate cyclase stimulator or activator with and calcitriol. WO2005046691 describes a combination a PDE5 inhibitor for the treatment of urological disorders of a farnesyl transferase inhibitor with an antihormonal comprising benign prostate syndrome (BPS), benign agentfor the treatment of breast cancer. WO2006106311 prostate hyperplasia (BPH), benign prostate enlarge-

3 5 EP 2 266 568 A1 6 ment (BPE), bladder outlet obstruction (BOO), lower uri- decapeptide pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro- nary tract symptoms (LUTS), genitourinary disorders Gly- NH2 in which the pGlu is pyroglutamate. Peptidic comprising neurogenic bladder syndrome, such as over- LHRH antagonists have amino acid substitutions usually active bladder (OAB) and interstitial cystitis (IC) urinary at positions one, two, three, six and ten. Non- incontinence (UI), like mixed-, urge-, stress-, or overflow 5 LHRH antagonists have been described in PCT applica- incontinence (MUI, UUI, SUI, OUI) and pelvic pain. tion 2008/107446. Non-peptide LHRH antagonists offer [0018] Thus, it is well established in the prior art that the possible advantage of oral administration. The most sex hormone dependent disorders can be treated with preferred LHRH antagonist is Ozarelix. Other suitable LHRH analogs or PDE5 inhibitors in combination with LHRH antagonists include Teverelix, , Ganire- further active compounds. However, none of these10 lix, , Antarelix, Detirelix, Ramorelix, Antide, Aza- means is considered entirely satisfactory at the present line B, A-75998, 84861, A- RS-68439, Org30850, time. While significant strides have been made in this Org30276, ORF18260, Acycline, TAK-013, TAK-810, field, there remains a need for methods of treating sex NBI-42902, NBI-56418, T-98475, AG-045572, CAS- hormone related conditions, in which the therapeutic ef- 874112-24-0, CAS-874112-16-0, CAS-1056021-27-2, fect is improved and negative hormone withdrawal symp- 15 CAS-1056021-26-1, CAS-1056021-45-4 and CAS- toms are prevented. The present invention fulfills this 1056022-61-7. need, and provides other related advantages. [0026] The term "PDE V inhibitor" as used in the present invention means a compound that inhibits cGMP DESCRIPTION OF THE INVENTION hydrolysis by phosphodiesterase-5. PDE V inhibitors 20 preferably reduce PDE V enzymatic activity by at least [0019] The problem of the present invention is to pro- 5%. Methods for assaying the activity of a PDE V inhibitor vide novel methods of treatment of sex hormone depend- are known in the art. The most preferred PDE V inhibitors ent disorders, in particular BPH and LUTS, in which the are Sildenafil and Tadalafil. Other suitable PDE V inhib- therapeutic effect is improved and negative hormone itors are Vardenafil, Mirodenafil, Thioquinapiperifil, Zap- withdrawal symptoms are prevented. 25 rinast, Udenafil, Avanafil, Dasantafil, BMS 341400, BMS [0020] The problem of the present invention has sur- 281384, BMS 263504, LAS 34179, LAS 30904, LAS prisingly been solved inone aspectby providinga method 34837, AWD 12-250, FR 189318, FR 229934, FR of treating or preventing a sex hormone dependent dis- 226807, EMD 82639, UK 369003, UK 114502, UK order in a mammal, comprising administering to the 114542, EMR 62-203, QAD 171A, SR 265579 and SLx mammal at least one LHRH antagonist and at least one 30 2101. PDE V inhibitor. [0027] The LHRH antagonist may be administered at [0021] None of the documents of the prior art discloses the same time as the PDE V inhibitor or it may be admin- or suggests the combination of a LHRH antagonist and istered before or after. It will be appreciated that the in- a PDE V inhibitor for the treatment or prevention of a sex vention includes the administration to the mammal of one hormone dependent disorder in a mammal. 35 or more LHRH antagonists and one or more PDE V in- [0022] The mammal to be treated may be any mammal hibitors. such as cats, dogs, cows, sheep, horses and the like. It [0028] In a most preferred embodiment, the at least is particularly preferred if the mammal is a human. The one LHRH antagonist is Ozarelix and the at least one mammal may be female or male. PDE V inhibitor is Sildenafil or Tadalafil. [0023] The term "sex hormone dependent disorder" as 40 [0029] The present invention further relates to the use used in the present invention refers to BPH, LUTS, breast of a combination of at least one LHRH antagonist with at cancer, prostate cancer, ovarian cancer, uterine cancer least one PDE V inhibitor in the manufacture of a medi- endometriosis, premenstrual syndrome, polycystic ovary cament for treating or preventing a sex hormone depend- disease, postmenopausal syndrome, uterus myoma, in- ent disorder in a mammal. fertility, erectile dysfunction or female sexual dysfunction. 45 [0030] Finally, the present invention refers to a phar- In a preferred embodiment of the present invention, it maceutical composition comprising a therapeutically ef- refers to BPH or LUTS. fective amount of at least one LHRH antagonist, a ther- [0024] The term "LHRH antagonist" as used in the apeutically effective amount of at least one PDE V inhib- present invention means any LHRH analogue, whether itor, customary pharmaceutical carriers, excipients peptide or non-peptide, except for , which in- 50 and/or diluents, for use in the treatment or prevention of hibits, reduces or prevents signaling of the GnRH recep- a sex hormone dependent disorder in a mammal. tor. Inhibition, reduction or prevention of LHRH-R sign- [0031] The amounts of the therapeutic agents, i.e. the aling can readily be determined by a person of skill in the at least one LHRH antagonist and the at least one PDE art. V inhibitor which are administered are amounts which [0025] Current LHRH antagonists are LHRH-like de- 55 are effective to ameliorate the disorder condition of the capeptides which are generally administered by nasal mammal to a useful extent or are amounts which provide sprays, intravenously or subcutaneously presumably be- the desired clinical effect according to the use to which cause of negligible oral activity. By LHRH we mean the the therapeutic agents are put. This may be determined

4 7 EP 2 266 568 A1 8 by the clinician. The amount of therapeutic agents ad- 68439, Org30850, Org30276, ORF18260, Acycline, ministered to the mammal may be different according to TAK-013, TAK-810, NBI-42902, NBI-56418, T- the clinical application in question, and this may be de- 98475, AG-045572, CAS-874112-24-0, CAS- termined by the clinician. Similarly, the treatment regime 874112-16-0, CAS-1056021-27-2, CAS- (e.g. doses, timings of administration and so forth) may 5 1056021-26-1, CAS-1056021-45-4 and CAS- be determined by the clinician. 1056022-61-7. [0032] The therapeutic agents used in the methods of the invention may be administered using any suitable 5. The method according to any one of claims 1 to 4, means or route of administration. Conveniently, the wherein the at least one PDE V inhibitor is selected known means and routes of administration are used for 10 from the group consisting of: Sildenafil, Vardenafil, each of the different therapeutic agents. Tadalafil, Mirodenafil, Thioquinapiperifil, Zaprinast, [0033] It will be appreciated that the at least one LHRH Udenafil, Avanafil, Dasantafil, BMS 341400, BMS antagonist may be administered by one route and the at 281384, BMS 263504, LAS 34179, LAS 30904, LAS leastone PDE V inhibitor may be administered by another 34837, AWD 12-250, FR 189318, FR 229934, FR route; alternatively, they may both be administered by 15 226807, EMD 82639, UK 369003, UK 114502, UK the same route. 114542, EMR 62-203, QAD 171A, SR 265579 and SLx2101. EXAMPLE 6. The method according to any one of claims 1 to 5, Ozarelix + sildenafil 20 wherein the at least one LHRH antagonist is Ozare- lix. [0034] Treatment course with oxarelix will include one IM injection of 15mg ozarelix at the beginning of the treat- 7. The method according to any one of claims 1 to 6, ment course and one additional IM injection of 15mg oza- wherein the at least one PDE V inhibitor is selected relix 14 days later. This treatment course with oxarelix 25 from the group consisting of: Sildenafil and Tadalafil. will be repeated each six months. 8. The method according to any one of claims 1 to 7, COMBINED WITH wherein the at least one LHRH antagonist is Ozarelix and the at least one PDE V inhibitor is Sildenafil or [0035] 50 mg sildenafil per os once daily. Dosing of 30 Tadalafil. sildenafil may be escalated to 100mg once daily two weeks after the beginning of the treatment. 9. Use of a combination of at least one LHRH antago- nist except for Cetrorelix with at least one PDE V inhibitor in the manufacture of a medicament for Claims 35 treating or preventing a sex hormone dependent dis- order in a mammal. 1. A method of treating or preventing a sex hormone dependent disorderin a mammal, comprising admin- 10. Use according to claim 9, wherein the sex hormone istering to the mammal at least one LHRH antagonist dependent disorder is BPH, LUTS, breast cancer, except for Cetrorelix and at least one PDE V inhibitor. 40 prostate cancer, ovarian cancer, uterine cancer, en- dometriosis, uterus myoma, polycystic ovary dis- 2. The method according to claim 1, wherein the sex ease, premenstrual syndrome, postmenopausal hormone dependent disorder is BPH, LUTS, breast syndrome, infertility, erectile dysfunction or female cancer, prostate cancer, ovarian cancer, uterine sexual dysfunction. cancer, endometriosis, uterus myoma, polycystic 45 ovary disease, premenstrual syndrome, postmeno- 11. Use according to any one of claim 9 or 10, wherein pausal syndrome, infertility, erectile dysfunction or the sex hormone dependent disorder is BPH or female sexual dysfunction. LUTS.

3. The method according to any one of claim 1 or 2, 50 12. Use according to any one of claims 9 to 11, wherein wherein the sex hormone dependent disorder is BPH the at least one LHRH antagonist is selected from or LUTS. the group consisting of: Ozarelix, Teverelix, Degare- lix, , Abarelix, Antarelix, Detirelix, Ramore- 4. The method according to any one of claims 1 to 3, lix, Antide, Azaline B, A- 75998, A-84861, RS-68439, wherein the at least one LHRH antagonist is selected 55 Org30850, Org30276, ORF18260, Acycline, TAK- from the group consisting of: Ozarelix, Teverelix, De- 013, TAK-810, NBI-42902, NBI-56418, T-98475, garelix, Ganirelix, Abarelix, Antarelix, Detirelix, Ram- AG-045572, CAS-874112-24-0, CAS-874112-16-0, orelix, Antide, Azaline B, A-75998, A-84861, RS- CAS-1056021-27-2, CAS-1056021-26-1, CAS-

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1056021-45-4 and CAS-1056022-61-7. Sildenafil, Vardenafil, Tadalafil, Mirodenafil, Thio- quinapiperifil, Zaprinast, Udenafil, Avanafil, Dasan- 13. Use according to any one of claims 9 to 12, wherein tafil, BMS 341400, BMS 281384, BMS 263504, LAS the at least one PDE V inhibitor is selected from the 34179, LAS 30904, LAS 34837, AWD 12-250, FR group consisting of: Sildenafil, Vardenafil, Tadalafil, 5 189318, FR 229934, FR 226807, EMD 82639, UK Mirodenafil, Thioquinapiperifil, Zaprinast, Udenafil, 369003, UK 114502, UK 114542, EMR 62-203, QAD Avanafil, Dasantafil, BMS 341400, BMS 281384, 171A, SR 265579 and SLx 2101. BMS 263504, LAS 34179, LAS 30904, LAS 34837, AWD 12-250, FR 189318, FR 229934, FR 226807, 22. The pharmaceutical composition according to any EMD 82639, UK 369003, UK 114502, UK 114542, 10 one of claims 17 to 21, wherein the at least one LHRH EMR 62-203, QAD 171A, SR 265579 and SLx2101. antagonist is Ozarelix.

14. Use according to any one of claims 9 to 13, wherein 23. The pharmaceutical composition according to any the at least one LHRH antagonist is Ozarelix. one of claims 17 to 22, wherein the at least one PDE 15 V inhibitor is selected from the group consisting of: 15. Use according to any one of claims 9 to 14, wherein Sildenafil and Tadalafil. the at least one PDE V inhibitor is selected from the group consisting of: Sildenafil and Tadalafil. 24. The pharmaceutical composition according to any one of claims 17 to 23, wherein the at least one LHRH 16. Use according to any one of claims 9 to 15, wherein 20 antagonist is Ozarelix and the at least one PDE V the at least one LHRH antagonist is Ozarelix and the inhibitor is Sildenafil or Tadalafil. at least one PDE V inhibitor is Sildenafil or Tadalafil.

17. A pharmaceutical composition comprising a thera- peutically effective amount of at least one LHRH an- 25 tagonist except for Cetrorelix, a therapeutically ef- fective amount of at least one PDE V inhibitor, cus- tomary pharmaceutical carriers, excipients and/or diluents, for use in the treatment or prevention of a sex hormone dependent disorder in a mammal. 30

18. The pharmaceutical composition according to claim 17, wherein the sex hormone dependent disorder is BPH, LUTS, breast cancer, prostate cancer, ovarian cancer, uterine cancer, endometriosis, uterus myo- 35 ma, polycystic ovary disease, premenstrual syn- drome, postmenopausal syndrome, infertility, erec- tile dysfunction or female sexual dysfunction.

19. The pharmaceutical composition according to any 40 one of claim 17 or 18, wherein the sex hormone de- pendent disorder is BPH or LUTS.

20. The pharmaceutical composition according to any one of claims 17 to 19, wherein the at least one LHRH 45 antagonist is selected from the group consisting of: Ozarelix, Teverelix, Degarelix, Ganirelix, Abarelix, Antarelix, Detirelix, Ramorelix, Antide, Azaline B, A- 75998, A-84861, RS-68439, Org30850, Org30276, ORF18260, Acycline, TAK-013, TAK-810, NBI- 50 42902, NBI-56418, T-98475, AG-045572, CAS- 874112-24-0, 874112-16-0, CAS- CAS- 1056021-27-2, CAS-1056021-26-1, CAS- 1056021-45-4 and CAS-1056022-61-7. 55 21. The pharmaceutical composition according to any one of claims 17 to 20, wherein the at least one PDE V inhibitor is selected from the group consisting of:

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• WO 9014839 A [0015] • WO 2005046691 A [0015] • WO 9216233 A [0015] • WO 2006106311 A [0015] • US 4472382 A [0015] • WO 2003028730 A [0017] • DE 19604231 [0015] • WO 2004087211 A [0017] • DE 19825591 [0015] [0017] • US 2005222014 A [0017] • WO 9917767 A [0015] • WO 2007039075 A [0017] • WO 2001060365 A [0015] • WO 2007072156 A [0017] • WO 2002056903 A [0015] • WO 2007072169 A [0017] • WO 2002036144 A [0015] • WO 2008054215 A [0017] • WO 2004087190 A [0015] • WO 2008138483 A [0017]

Non-patent literature cited in the description

• The Lancet, 2001, vol. 358, 1793-1803 [0010] • Palomba et al. Human Reproduction, 2002, vol. 17 • Mol. Cell. Endo., 2000, vol. 166, 9-14 [0010] (12), 3213-3219 [0015] • Cancer Letters, 1995, vol. 98, 57-62 [0012] • Torrisi et al. British Journal of Cancer, 2007, vol. 97 (6), 802-808 [0015]

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