US 2005.0054688A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0054688A1 May et al. (43) Pub. Date: Mar. 10, 2005 (54) SELECTIVE SEROTONN REUPTAKE Related U.S. Application Data INHIBITORS IN THE TREATMENT OF DISEASE (60) Provisional application No. 60/528,136, filed on Dec. 9, 2003. (75) Inventors: Kathryn Elizabeth May, County of Kent (GB); Paul Quinn, County of (30) Foreign Application Priority Data Kent (GB) Aug. 8, 2003 (GB)......................................... O3187O6.9 Correspondence Address: PFIZER INC. Publication Classification PATENT DEPARTMENT, MS8260-1611 EASTERN POINT ROAD (51) Int. Cl." ......................... A61K 31/44; A61K 31/18; GROTON, CT 06340 (US) A61K 31/137 (52) U.S. Cl. ........................... 514/345; 514/602; 514/649 (73) Assignee: Pfizer Inc (57) ABSTRACT (21) Appl. No.: 10/911,806 The present invention provides the use of Selective Serotonin reuptake inhibitors (SSRIs) to treat premature female (22) Filed: Aug. 5, 2004 Orgasm. US 2005/0054688A1 Mar. 10, 2005 SELECTIVE SEROTONIN REUPTAKE 0009 b) Interpersonal difficulties arise from female INHIBITORS IN THE TREATMENT OF DISEASE lack of motivation for/discomfort with continued Sexual Stimulation. 0001. This application claims priority from United King dom Application Number 0318706.9, filed on Aug. 8, 2003 0010 c) The disturbance gives rise to negative psy and the benefit of U.S. Provisional Application No. 60/528, chosocial consequences where arousal occurs in 136, filed on Dec. 9, 2003. inappropriate situations 0002 This invention relates to the use of compounds 0011 d) The disturbance itself causes marked dis which exhibit activity as Selective Serotonin re-uptake treSS or interpersonal difficulty inhibitors (SSRIs) to treat premature female orgasm, and to 0012. According to a first aspect, the invention provides pharmaceutical formulations containing Such compounds. for a Selective Serotonin reuptake inhibitor in the preparation 0003) Whilst anorgasmia and difficulties with orgasm are of a medicament for the treatment or prevention of prema well-represented in the female Sexual dysfunction literature, ture female orgasm. rapid orgasm-a female problem, Sharing components with 0013 By SSRI it is meant a compound with a serotonin premature ejaculation (PE) in men—is notable by its re-uptake inhibition (SRI) ICso value of less than or equal to absence. DSMIVR (2000) includes no mention of it, 100 nM. Preferred compounds have a serotonin re-uptake although it has an otherwise comprehensive Section on inhibition (SRI) ICso value of less than or equal to 50 nM. orgasmic disorders. Particularly preferred compounds have a Serotonin re-uptake inhibition (SRI) ICso value of less than or equal to 10 nM. 0004. It has been suggested that the distribution curve for female orgasm is likely to be very similar to that used to 0014. In a preferred embodiment the compounds are describe male experience (Cole and Dryden, 1988). How more than 10-fold as potent in the inhibition of serotonin ever, both clinically and in the research and its literature, the re-uptake than in the inhibition of dopamine re-uptake, retarded as opposed to the premature end of this is very preferred compounds are more than 100-fold as potent, much the focus of interest. This weighting is also Strongly particularly preferred compounds are more than a 1000-fold reflected in cases Seen, with cases of rapid orgasm in women as potent. presenting rarely and representing a far Smaller percentage 0015. In a preferred embodiment the compounds are of the female caseload than the 30% or more of male more than 10-fold as potent in the inhibition of serotonin caseload taken by PE. This is partly because male partners re-uptake than in the inhibition of noradrenaline re-uptake, often choose to take rapid orgasm as positive feedback on preferred compounds are more than 100-fold as potent, their skill as a lover and partly because, generally Speaking, particularly preferred compounds are more than a 1000-fold it presents fewer problems in terms of continuing with as potent. intercourse than PE. This is particularly So where the female partner is multi-orgasmic and therefore potentially well 0016 Particularly suitable SSRIs for use in treating pre motivated to continue. mature female orgasm may be characterised by having a rapid onset and a short duration of action. 0005. Unfortunately, a proportion of women with rapid orgasm find continued post-orgasmic Stimulation uncom 0017 Suitable SSRIs for use in the present invention include: Sertraline, fluoxetine, fluvoxamine, paroxetine, cit fortable, if not painful. This group has no wish to continue allopram, dapoxetine, 3-(dimethylamino)methyl-4-4-(me with intercourse, having reached orgasm, and indeed may thylsulfanyl)phenoxybenzenesulfonamide (Example 28, feel unable to do so. This tends to give rise to interpersonal WO 0172687), 3-(dimethylamino)methyl-4-3-methyl-4- distress, which is difficult to resolve and these tend to be the (methylsulfanyl)phenoxybenzenesulfonamide (Example couples referred to Sex Therapy Clinics and gynaecology. 12, WO 0218333), N-methyl-N-({3-3-methyl-4-(methyl The problem of disengagement of the female partner is also Sulfanyl)phenoxy-4-pyridinyl)methyl)amine (Example 38, reported, with males feeling incidental or rejected, in the PCT Application no PCT/IB02/01032), methyl-3-(4-meth same way as female partners of men with PE. ylsulfanyl-phenoxy)-pyridin-4-ylmethylamine (Example 0006 Cognitive/behavioural treatments are more difficult 35 WO02/083643), Escitalopram, Litoxetine, 403U76, to describe and implement than in PE, the arousal element VN-2222, Roxindle, Milnacipran, RS-1439, R-fluoxetine, of the Human Sexual Response curve being So attenuated WF-32, DOV-216303, LY-393558, LY-433221, Cer that women find it immensely difficult to assert any kind of iclamine, UP-23761, Indalpine, YM-992/Lubazodone, control. Whilst men with PE are educated to recognise the A-80426, Nefazodone, DuP-631, Biciifadine, Duloxetine, point of ejaculatory inevitability, a corresponding point of LY-214821, LY-393558, LU-10134-C, Sibutramine, SPD orgasmic inevitability is not identified and intervention to 473, Tramadol, CI-275838, McN-5652, L792239, Vilaz disrupt it would anyway presumably prove to be problem odone, NS-2359, NS-2381, ORG-6582, Femoxetine, atic. The adoption of other treatment Strategies used in PE RS-1259, R-DDMS, S-Sibutramine, S-fluoxetine, Dexen (SS cream, local anaesthetics, SSRIs) is not reported in the furamine, S-34324, Du-125530, SLV-210, SLV-313, SLV Small available literature on rapid orgasm in Women. 314 and Venlafaxine. 0018 Preferred SSRIs are sertraline, fluoxetine, fluvox 0007 Premature female orgasm may be defined as: amine, paroxetine, citalopram, dapoxetine, 3-(dimethy 0008 a) Persistent or recurrent orgasm with mini lamino)methyl-4-4-(methylsulfanyl)phenoxybenzene mal Sexual Stimulation, occurring before, upon or Sulfonamide (Example 28, WO 0172687), Shortly after penetration and generally before the 3-(dimethylamino)methyl-4-3-methyl-4-(methylsulfa perSon/couple wishes it. nyl)phenoxybenzenesulfonamide (Example 12, WO US 2005/0054688A1 Mar. 10, 2005 0218333), methyl-3-(4-methylsulfanyl-phenoxy)-pyridin H-Dopamine substrates. All reactions were carried out at 4-ylmethylamine (Example 35 WO02/083643), N-methyl room temperature in a shaking incubator. Incubation times N-(3-3-methyl-4-(methylsulfanyl)phenoxy-4- were 5 minutes for the hSERT and hDAT assays and 15 pyridinyl)methyl)amine (Example 38, PCT Application no minutes for the hNET assay. Reactions were terminated by PCT/IB02/01032). removal of the reaction mixture using a vacuum manifold 0019 More preferred SSRIs are 3-(dimethylamino)m- followed by rapid washing with ice cold assay buffer. The ethyl-4-4-(methylsulfanyl)phenoxybenzenesulfonamide quantity of H-substrate incorporated into the cells was then (Example 28, WO 0172687), 3-(dimethylamino)methyl-4- quantified. 3-methyl-4-(methylsulfanyl)phenoxybenzenesulfonamide 0030 Assay plates were dried in a microwave oven, (Example 12, WO 0218333), methyl-3-(4-methylsulfanyl Scintillation fluid added, and radioactivity measured. phenoxy)-pyridin-4-ylmethylamine (Example 35 WO02/ Potency of test compounds was quantified as ICso values 083643), N-methyl-N-(3-3-methyl-4-(methylsulfa (concentration of test compound required to inhibit the nyl)phenoxy-4-pyridinyl)methyl)amine (Example 38, PCT specific uptake of radiolabelled substrate into the cells by Application no PCT/IB02/01032), paroxetine and dapoxet 50%). C. 0031 (iii) Standard Assay Buffer Composition: 0020 Yet more preferred are 3-(dimethylamino)m- ethyl-4-4-(methylsulfanyl)phenoxybenzenesulfonamide 0.032 Trizma hydrochloride (26 mM) (Example 28, WO 0172687), 3-(dimethylamino)methyl-4- 0033 NaCl (124 mM) 3-methyl-4-(methylsulfanyl)phenoxybenzenesulfonamide (Example 12, WO 0218333), methyl-3-(4-methylsulfanyl 0034). KCl (4.5 mM) phenoxy)-pyridin-4-ylmethylamine (Example 35 WO02/ 0035). KHPO (1.2 mM) 083643), N-methyl-N-(3-3-methyl-4-(methylsulfa nyl)phenoxy-4-pyridinyl)methyl)amine (Example 38, PCT 0036) MgCl,.6HO (1.3 mM) Application no PCT/IB02/01032). 0037 Ascorbic acid (1.136 mM) 0021. The text of the aforementioned patents and all other 0038 Glucose (5.55 mM) references cited in this Specification are hereby incorporated by reference in their entirety. 0039 pH 7.40 0022. It should be understood that compounds suitable 0040 CaCl (2.8 mM) for use in the present invention, as exemplified above or as 0041 Pargyline (100 uM) identified by the assays described herein, may encompass pharmaceutically acceptable Salts, Solvates and prodrugs 0042. Note: The pH of the buffer was adjusted to 7.40 thereof. with 1M NaOH before addition of CaCl and pargyline. 0023 Compounds suitable for use as an SSRI may be 0043 (iv) Summary of Assay Parameters identified by the use of the following assay: 0024 Biological Activity hSERT hDAT hNET 0.025 Compounds may be tested for their ability to Assay Assay Assay inhibit the uptake of Serotonin by human Serotonin trans Cell concentration per 75,000 75,000 75,000 porters, dopamine by human dopamine transporters or assay well.