sign in sign up
<<
Home , Abanoquil, Acetergamine, Efaroxan

US 20060094704A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0094704 A1 B00lell (43) Pub. Date: May 4, 2006

(54) TREATMENT OF PREMATURE (60) Provisional application No. 60/260.564, filed on Jan. EUACULATION 9, 2001. (75) Inventor: Mitradev Boolell, Sandwich (GB) (30) Foreign Application Priority Data Correspondence Address: Nov. 20, 2000 (GB)...... OO28245.9 PFIZER INC O O 1SO EAST 42ND STREET Publication Classification STH FLOOR - STOP 49 (51) Int. Cl. NEW YORK, NY 10017-5612 (US) A6II 3/53 (2006.01) A 6LX 3/59 (2006.01) (73) Assignee: Pfizer Inc (52) U.S. Cl...... 514/210.21; 514/246; 514/248: 514/252.16 (21) Appl. No.: 11/292,713 (57) ABSTRACT (22) Filed: Dec. 1, 2005 This invention relates to the use of cyclic guanosine 3',5'- Related U.S. Application Data monophosphate phosphodiesterase type five inhibitors, including in particular the compound sildenafil. for the (63) Continuation of application No. 09/990,955, filed on treatment of premature ejaculation in patients with normal Nov. 16, 2001, now abandoned. erectile function. US 2006/0094704 A1 May 4, 2006

TREATMENT OF PREMATURE EACULATION 0011 Urologists currently form the bulk (59%) of phy sicians treating PE; GPs form 33% of doctors treating the CROSS-REFERENCE TO RELATED condition. Sex therapists, behavioural therapists and coun APPLICATIONS sellors also treat patients with PE. Experts estimate that 50% of presenters do so because of the impact the condition has 0001. The present application is a U.S. non-provisional on the relationship with the partner. Stress, relationship application. This application claims the benefit of U.S. difficulties and/or effect on quality of life are the key triggers 60/260,564, filed on Jan. 9, 2001, under 35 USC 119(e). for sufferers to seek treatment for PE. FIELD OF THE INVENTION 0012 Ejaculation is dependent on the sympathetic and parasympathetic nervous systems. Efferent impulses via the 0002 This invention relates to the use of cyclic gua sympathetic nervous system to the vas deferens and the nosine 3',5'-monophosphate phosphodiesterase type five epididymis produce Smooth muscle contraction, moving inhibitors (hereinafter PDE5 inhibitors) for the treatment of sperm into the posterior urethra. Similar contractions of the premature ejaculation (PE). Particular PDE5 inhibitors are seminal vesicles, prostatic glands and the bulbourethral sildenafil. IC-351, Vardenafil, 5-2-ethoxy-5-(4-ethylpiper glands increase the Volume and fluid content of semen. azin-1-ylsulphonyl)pyridin-3-yl)-3-ethyl-2-2-methoxy Expulsion of semen is mediated by efferent impulses origi ethyl-2,6-dihydro-7H-pyrazolo 4,3-dipyrimidin-7-one and nating from the nucleus of Onuf in the spinal cord, which 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-aze pass via the parasympathetic nervous system and cause tidinyl)-2,6-dihydro-7H-pyrazolo 4.3-dpyrimidin-7-one. rhythmic contractions of the bulbocavernous, ischiocavern ous and pelvic floor muscles. Cortical control of ejaculation BACKGROUND OF THE INVENTION is still under debate in humans. In the rat the medial 0003 PE is a relatively common sexual dysfunction in pre-optic area and the paraventricular nucleus of the hypo men. It has been defined in several different ways but the thalamus seem to be involved in ejaculation. most widely accepted is the Diagnostic and Statistical 0013 International patent application WO94/28902 dis Manual of Mental Disorders IV one which states: “PE is a closes compounds which are inhibitors of the coMP PDE5 lifelong persistent or recurrent ejaculation with minimal enzyme are potent and effective compounds for the treat sexual stimulation before, upon or shortly after penetration ment of male erectile dysfunction (MED, impotence) and for and before the patient wishes it. The clinician must take into female sexual disorders. This discovery led to the develop account factors that affect duration of the excitement phase, ment of the compound sildenafil (5-2-ethoxy-5-(4-methyl Such as age, novelty of the sexual partner or stimulation, and 1-piperazinylsulphonyl)phenyl-1-methyl-3-n-propyl-1,6- frequency of sexual activity. The disturbance causes marked dihydro-7H-pyrazolo 4,3-dipyrimidin-7-one) (VIAGRATM) distress or interpersonal difficulty.” which has proved to be outstandingly successful as the first 0004 The International Classification of Diseases 10 orally effective treatment for MED. definition states: “There is an inability to delay ejaculation 0014. There are at present no approved drugs available Sufficiently to enjoy lovemaking, manifest as either of the for treating PE. The most commonly off-label prescribed following: (1) occurrence of ejaculation before or very soon are the anti-depressants (for example clomi after the beginning of intercourse (if a time limit is required: pramine) and the selective seretonin re-uptake inhibitors (for before or within 15 seconds of the beginning of intercourse): example paroxetine and Sertraline). These drugs are often (2) ejaculation occurs in the absence of Sufficient erection to not well accepted by patients because they are regarded as make intercourse possible. The problem is not the result of anti-depressants. They are used off-label, and though prolonged abstinence from sexual activity.” effective when used as required (i.e. prin), due to their long 0005. Other definitions that have been used include clas pharmacokinetic T (time to maximum drug concentration sification on the following criteria: in plasma following oral administration of the drug) they are likely to have a slow onset of action. Side-effects common 0006 Related to the partner's orgasm to this class of drugs can be seen when used chronically. 0007. Duration between penetration and ejaculation Behavioural therapy has been the other management tool but 0008 Number of thrusts and capacity for voluntary con has not been very efficacious and has a high drop-out and trol relapse rate. New, more effective therapies, are required. 0009 Psychological factors may be involved in PE, with BRIEF SUMMARY OF THE INVENTION relationship problems, anxiety, depression, prior sexual fail ure all playing a role. 00.15 According to a first aspect, the invention provides the use of a PDE5 inhibitor in the manufacture of a medi 0010) The estimated prevalence of PE is about 22-38% of cament for treating premature ejaculation in patients with the male population; unlike MED it has no definite corre normal erectile function lation with age. Taking an average prevalence of 30%, that would make an estimated 24 million sufferers in the US DETAILED DESCRIPTION OF THE (males aged 18-65 was 80 million in 1995). There is little INVENTION data on prevalence by severity. It is estimated that the operational definition of PE may apply to 5-10% of men, 0016. According to a first aspect, the invention provides however, less than 0.2% present for treatment. The avail the use of a PDE5 inhibitor in the manufacture of a medi ability of an orally effective therapy is very likely to alter cament for treating premature ejaculation in patients with this situation. normal erectile function. US 2006/0094704 A1 May 4, 2006

0017. By PDE5 inhibitors it is meant a compound which 0029. Examples of PDE5 inhibitors for use with the is a potent and selective inhibitor of the coMP PDE5 invention are: isoenzyme. 0030 The pyrazolo 4.3-dpyrimidin-7-ones disclosed in 0018. The term “therapeutically effective amount’ as EP-A-0463756; the pyrazolo 4,3-dipyrimidin-7-ones dis used herein means that amount of active compound or closed in EP-A-0526004; the pyrazolo 4,3-dipyrimidin-7- pharmaceutical agent that elicits the biological or medicinal ones disclosed in published international patent application response in a tissue, System, animal or human that is being WO 93/06104; the isomeric pyrazolo 3,4-dpyrimidin-4- sought by a researcher, veterinarian, medical doctor or other ones disclosed in published international patent application clinician, which includes alleviation of the symptoms of the WO 93/07149; the quinazolin-4-ones disclosed in published disease being treated. international patent application WO 93/12095; the pyrido 3.2-dpyrimidin-4-ones disclosed in published international 0019. In accordance with the invention, patients with patent application WO94/05661; the purin-6-ones disclosed normal erectile function are those who are capable of in published international patent application WO94/00453; achieving an erection (without any medicament or medical the pyrazolo 4,3-dipyrimidin-7-ones disclosed in published device such as a vacuum pump) sufficient for vaginal international patent application WO 98/49166; the pyrazolo penetration and are able to maintain the erection until 4,3-dipyrimidin-7-ones disclosed in published international ejaculation. PE in these patients is typically primary PE. patent application WO 99/54333; the pyrazolo 4,3-dipyri 0020. In accordance with the invention, patients suffering midin-4-ones disclosed in EP-A-0995751; the pyrazolo 4.3- from PE but with normal erectile function experience per dpyrimidin-7-ones disclosed in published international sistent or recurrent ejaculation with minimal sexual stimu patent application WO 00/24745; the pyrazolo 4,3-dipyri lation shortly after penetration and before the person wishes midin-4-ones disclosed in EP-A-0995750; the compounds it. In addition, the PE in these patients is not situational or disclosed in published international application WO95/ secondary to a known organic cause. Typically PE in these 19978; the compounds disclosed in published international patients has been present since their first sexual experience. application WO99/24433 and the compounds disclosed in published international application WO 93/07124. 0021. In a preferred embodiment of the invention, 0031. The pyrazolo 4.3-dpyrimidin-7-ones disclosed in patients with normal erectile function are those who attain a published international application WO 01/27112; the pyra score of more than 22 (preferably more than 25) on the Zolo 4,3-dipyrimidin-7-ones disclosed in published inter Erectile Function Domain Questionnaire (see hereinafter). national application WO 01/27113; the compounds dis 0022 Hereinafter the term “the PDE5 inhibitor” means closed in EP-A-1092718 and the compounds disclosed in the PDE5 inhibitors for use with the invention. The term EPA-1092719. includes pharmaceutically acceptable salts, Solvates and 0032) Preferred PDE5 inhibitors for use with the inven polymorphs of the PDE5 inhibitors for use with the inven tion: tion. 0033 5-2-ethoxy-5-(4-methyl-1-piperazinylsulpho 0023 The suitability of the PDE5 inhibitor can be readily nyl)phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyra determined by evaluation of its potency and selectivity using Zolo4.3-dpyrimidin-7-one (sildenafil) also known as literature methods followed by evaluation of its toxicity, 1-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyra absorption, metabolism, pharmacokinetics etc., in accor Zolo4.3-dpyrimidin-5-yl)-4-ethoxyphenylsulphony14 dance with standard pharmaceutical practice. methylpiperazine (see EP-A-0463756); 0024 Preferably, the PDE5 inhibitors have an IC50 0034 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl against the PDE5 enzyme of less than 100 nanomolar, more 3-n-propyl-1,6-dihydro-7H-pyrazolo 4,3-dipyrimidin-7- preferably, at less than 50 nanomolar. one (see EP-A-0526004); 0025 IC50 values for the PDE5 inhibitors may be deter 0035) 3-ethyl-5-5-(4-ethylpiperazin-1-ylsulphonyl)-2-n- mined using the PDE5 assay in the Test Methods Section propoxyphenyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H hereinafter. pyrazolo 4,3-dipyrimidin-7-one (see WO98/49166); 0026. Preferably the PDE5 inhibitors are selective for the 0036 3-ethyl-5-5-(4-ethylpiperazin-1-ylsulphonyl)-2- PDE5 enzyme. Preferably they have a selectivity for PDE5 (2-methoxyethoxy)pyridin-3-yl)-2-(pyridin-2-yl)methyl over PDE3 of greater than 100 fold, more preferably greater 2,6-dihydro-7H-pyrazolo 4.3-dipyrimidin-7-one (see than 300 fold. More preferably the PDE5 inhibitors have a WO99/54333): selectivity over both PDE3 and PDE4 of greater than 100 0037 (+)-3-ethyl-5-5-(4-ethylpiperazin-1-ylsulphonyl)- fold, more preferably greater than 300 fold. 2-(2-methoxy-1 (R)-methylethoxy)pyridin-3-yl)-2-me 0027 Selectivity ratios may readily be determined by the thyl-2,6-dihydro-7H-pyrazolo 4,3-dipyrimidin-7-one, skilled person, by ratio of corresponding IC50 values for the also known as 3-ethyl-5-5-4-ethylpiperazin-1-ylsulpho particular enzymes concerned. IC50 values for the PDE3 nyl-2-((1R)-2-methoxy-1-methylethyloxy)pyridin-3- and PDE4 enzyme may be determined using established yl)-2-methyl-2,6-dihydro-7H-pyrazolo 4.3-dpyrimidin literature methodology, see S A Ballard et al. Journal of 7-one (see WO99/54333): Urology, 1998, vol. 159, pages 2164-2171. 0038 5-2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)py 0028 Preferably the PDE5 inhibitors have an IC50 ridin-3-yl)-3-ethyl-2-2-methoxyethyl-2,6-dihydro-7H against PDE5 of less than 100 nM and a selectivity over pyrazolo 4.3-dipyrimidin-7-one, also known as 1-6- PDE3 of greater than 100 fold. ethoxy-5-3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7- US 2006/0094704 A1 May 4, 2006

oxo-2H-pyrazolo 4,3-dipyrimidin-5-yl)-3- 0049. The contents of the published patent applications pyridylsulphonyl-4-ethylpiperazine (see WO 01/27113, and journal articles and in particular the general formulae of Example 8): the therapeutically active compounds of the claims and exemplified compounds therein are incorporated herein in 0.039 5-2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsulpho nyl)pyridin-3-yl)-3-ethyl-2-(1-methylpiperidin-4-yl)-2,6- their entirety by reference thereto. dihydro-7H-pyrazolo 4,3-dipyrimidin-7-one (see WO 0050 More preferred PDE5 inhibitors for use with the 01/27113, Example 15): invention are selected from the group: 0040 5-2-Ethoxy-5-(4-ethylpiperazin-1-ylsulpho 0051 5-2-ethoxy-5-(4-methyl-1-piperazinylsulpho nyl)pyridin-3-yl)-3-ethyl-2-phenyl-2,6-dihydro-7H-pyra nyl)phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyra Zolo 4,3-dipyrimidin-7-one (see WO 01/27113, Example Zolo4.3-dpyrimidin-7-one (sildenafil); 66); 0052 (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6- 0041 5-(5-Acetyl-2-propoxy-3-pyrid inyl)-3-ethyl-2-(1- (3.4-methylenedioxyphenyl)-pyrazino 2', 1:6,1pyrido3. isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo 4,3-d 4-bindole-1,4-dione (IC-351); pyrimidin-7-one (see WO 01/27112, Example 124); 0053 2-2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulpho nyl)-phenyl-5-methyl-7-propyl-3H-imidazo[5.1-f1.2, 0.042 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1- ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo 4.3-dpyri 4triazin-4-one (vardenafil); 0054 5-2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)py midin-7-one (see WO 01/27112, Example 132): ridin-3-yl)-3-ethyl-2-2-methoxyethyl-2,6-dihydro-7H 0.043 (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6- pyrazolo 4.3-dpyrimidin-7-one; and (3.4-methylenedioxyphenyl)-pyrazino 2', 1:6,1pyrido3. 4-bindole-1,4-dione (IC-351), i.e. the compound of 0055 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1- examples 78 and 95 of published international application ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo 4,3-dipyri WO95/19978, as well as the compound of examples 1, 3, midin-7-one and pharmaceutically acceptable salts 7 and 8: thereof. 0056. A particularly preferred PDE5 inhibitor is 5-2- 0044) 2-2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulpho ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl-1-me nyl)-phenyl-5-methyl-7-propyl-3H-imidazo[5.1-f1.2, thyl-3-n-propyl-1,6-dihydro-7H-pyrazolo 4,3-dipyrimidin 4triazin-4-one (vardenafil) also known as 1-3-(3,4- 7-one (sildenafil) (also known as 1-3-(6,7-dihydro-1- dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f-as methyl-7-oxo-3-propyl-1H-pyrazolo 4,3-dipyrimidin-5-yl)- triazin-2-yl)-4-ethoxyphenylsulphonyl-4- 4-ethoxyphenylsulphonyl-4-methylpiperazine) and ethylpiperazine, i.e. the compound of examples 20, 19. pharmaceutically acceptable salts thereof. Sildenafil citrate 337 and 336 of published international application WO99/ is a preferred salt. 24433; and 0057 Oral bioavailablity refers to the proportion of an 0045 the compound of example 11 of published interna orally administered drug that reaches the systemic circula tional application WO93/07124 (EISAI); and tion. The factors that determine oral bioavailability of a drug 0046) compounds 3 and 14 from Rotella D P. J. Med. are dissolution, membrane permeability and metabolic sta Chem., 2000, 43, 1257. bility. Typically, a screening cascade of firstly in vitro and then in vivo techniques is used to determine oral bioavail 0047 Still further PDE5 inhibitors for use with the inven ablity. tion include: 4-bromo-5-(pyridylmethylamino)-6-3-(4- chlorophenyl)-propoxy-3 (2H)pyridazinone; 1-4-(1,3- 0058 Dissolution, the solubilisation of the drug by the benzodioxol-5-ylmethyl)amiono-6-chloro-2-quinozolinyl aqueous contents of the gastro-intestinal tract (GIT), can be 4-piperidine-carboxylic acid, monosodium salt; (+)-cis-5,6a, predicted from in vitro solubility experiments conducted at 7.9,9.9a-hexahydro-2-4-(trifluoromethyl)-phenylmethyl-5- appropriate pH to mimic the GIT. Preferably the PDE5 methyl-cyclopent-4.5imidazo[2.1-bpurin-4(3H)one: inhibitors have a minimum solubility of 50 mcg/ml. Solu furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-oc bility can be determined by standard procedures known in tahydrocyclopent4.5-imidazo2.1-bpurin-4-one: 3-acetyl the art such as described in Adv. Drug Deliv. Rev. 23, 3-25, 1-(2-chlorobenzyl)-2-propylindole-6-carboxylate: 3-acetyl 1997. 1-(2-chlorobenzyl)-2-propylindole-6-carboxylate: 4-bromo 0059 Membrane permeability refers to the passage of a 5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl) propoxy)- compound through the cells of the GIT. Lipophilicity is a 3-(2H)pyridazinone: 1-methyl-5(5-morpholinoacetyl-2-n- key property in predicting this and is defined by in vitro Log propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4.3- D, measurements using organic solvents and buffer. Pref d)pyrimidin-7-one; 1-4-(1,3-benzodioxol-5- erably the PDE5 inhibitors have a Log D, of -2 to +4, more ylmethyl)amino-6-chloro-2-quinazolinyl-4- preferably -1 to +3. The log D can be determined by piperidinecarboxylic acid, monosodium salt; standard procedures known in the art such as described in J. Pharmaprojects No. 4516 (Glaxo Wellcome); Phar Pharm. Pharmacol. 1990, 42:144. maprojects No. 5051 (Bayer); Pharmaprojects No. 5064 0060 Cell monolayer assays such as CaCO add substan (Kyowa Hakko: see WO 96/26940); tially to prediction of favourable membrane permeability in 0048 Pharmaprojects No. 5069 (Schering Plough): the presence of efflux transporters such as p-glycoprotein, GF-196960 (GlaxoWellcome); E-8010 and E-4010 (Eisai): so-called caco-2 flux. Preferably, the PDE5 inhibitors have Bay-38-3045 & 38-9456 (Bayer) and Sch-51866. a caco-2 flux of greater than 2x10 cms, more preferably US 2006/0094704 A1 May 4, 2006

greater than 5x10 cms'. The caco flux value can be Formulation 2: determined by standard procedures known in the art such as 0069. An intravenous formulation may be prepared by described in J. Pharm. Sci, 1990, 79, 595-600. combining active ingredient (100 mg) with isotonic saline 0061 Metabolic stability addresses the ability of the GIT (1000 ml). or the liver to metabolise compounds during the absorption process: the first pass effect. Assay systems such as 0070 The tablets are manufactured by a standard pro microsomes, hepatocytes etc are predictive of metabolic cess, for example, direct compression or a wet or dry liability. Preferably the PDE5 inhibitors show metabolic granulation process. The tablet cores may be coated with stability in the assay system that is commensurate with a appropriate overcoats. hepatic extraction of less then 0.5. Examples of assay 0071 Solid compositions of a similar type may also be systems and data manipulation are described in Curr. Opin. employed as fillers in gelatin or HPMC capsules. Preferred Drug Disc. Devel., 201, 4, 3644, Drug Met. Disp., 2000, 28. excipients in this regard include lactose, starch, a cellulose, 1518-1523. milk Sugar or high molecular weight polyethylene glycols. 0062 Because of the interplay of the above processes For aqueous suspensions and/or elixirs, the PDE5 inhibitors further support that a drug will be orally bioavailable in may be combined with various Sweetening or flavouring humans can be gained by in vivo experiments in animals. agents, colouring matter or dyes, with emulsifying and/or Absolute bioavailability is determined in these studies by Suspending agents and with diluents such as water, ethanol, administering the compound separately or in mixtures by the propylene glycol and glycerin, and combinations thereof. oral route. For absolute determinations (% absorbed) the 0072 Modified release and pulsatile release dosage intravenous route is also employed. Examples of the assess forms may contain excipients such as those detailed for ment of oral bioavailability in animals can be found in Drug immediate release dosage forms together with additional Met. Disp., 2001, 29, 82-87; J. Med Chem, 1997, 40, excipients that act as release rate modifiers, these being 827-829, Drug Met. Disp., 1999, 27, 221-226. coated on and/or included in the body of the device. Release 0063) The PDE5 inhibitors can be administered alone but rate modifiers include, but are not exclusively limited to, will generally be administered in admixture with a suitable hydroxypropylmethyl cellulose, methyl cellulose, sodium pharmaceutical excipient, diluent or carrier selected with carboxymethylcellulose, ethyl cellulose, cellulose acetate, regard to the intended route of administration and standard polyethylene oxide, Xanthan gum, Carbomer, ammonio pharmaceutical practice. methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypro 0064. For example, the PDE5 inhibitors can be adminis pylmethyl cellulose phthalate, methacrylic acid copolymer tered orally, buccally or sublingually in the form of tablets, and mixtures thereof. Modified release and pulsatile release capsules, multi-particulates, gels, films, ovules, elixirs, Solu dosage forms may contain one or a combination of release tions or Suspensions, which may contain flavouring or rate modifying excipients. Release rate modifying excipients colouring agents, for immediate-, delayed-, modified-, Sus may be present both within the dosage form i.e. within the tained-, pulsed- or controlled-release applications. The matrix, and/or on the dosage form, i.e. upon the Surface or PDE5 inhibitors may also be administered as fast-dispersing coating. or fast-dissolving dosage forms or in the form of a high energy dispersion or as coated particles. Suitable formula 0073 Fast dispersing or dissolving dosage formulations tions may be in coated or uncoated form, as desired. (FDDFs) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croScarmellose Sodium, 0065. Such solid pharmaceutical compositions, for crospovidone, diascorbic acid, ethyl acrylate, ethyl cellu example, tablets, may contain excipients such as microcrys lose, gelatin, hydroxypropylmethyl cellulose, magnesium talline cellulose, lactose, Sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably Stearate, mannitol, methyl methacrylate, mint flavouring, corn, potato or tapioca Starch), disintegrants such as sodium polyethylene glycol, fumed silica, silicon dioxide, Sodium starch glycollate, croScarmellose sodium and certain com starch glycolate, sodium Stearyl fumarate, Sorbitol. Xylitol. plex silicates, and granulation binders such as polyvinylpyr The terms dispersing or dissolving as used herein to describe rolidone, hydroxypropylmethylcellulose (HPMC), hydrox FDDFs are dependent upon the solubility of the drug sub stance used i.e. where the drug Substance is insoluble a fast ypropylcellulose (HPC). Sucrose, gelatin and acacia. dispersing dosage form can be prepared and where the drug Additionally, lubricating agents such as magnesium Stearate, Substance is soluble a fast dissolving dosage form can be Stearic acid, glyceryl behenate and talc may be included. prepared. EXAMPLES 0074 The PDE5 inhibitors can also be administered parenterally, for example, intracavernousily, intravenously, 0.066 The following formulation examples are illustra intra-arterially, intraperitoneally, intrathecally, intraventricu tive only and are not intended to limit the scope of the larly, intraurethrally, intrasternally, intracranially, intramus invention. Active ingredient means a PDE5 inhibitor. cularly or Subcutaneously, or they may be administered by Formulation 1: infusion or needleless injection techniques. For Such parenteral administration they are best used in the form of a 0067. A tablet is prepared using the following ingredi sterile aqueous Solution which may contain other Sub ents: stances, for example, enough salts or glucose to make the 0068 Active ingredient (50mg) is blended with cellulose Solution isotonic with blood. The aqueous solutions should (microcrystalline), silicon dioxide, Stearic acid (fumed) and be suitably buffered (preferably to a pH of from 3 to 9), if the mixture is compressed to form tablets. necessary. The preparation of Suitable parenteral formula US 2006/0094704 A1 May 4, 2006

tions under sterile conditions is readily accomplished by The overall daily dose with an aerosol will be in the range standard pharmaceutical techniques well-known to those of from 1 Jug to 50 mg which may be administered in a single skilled in the art. dose or, more usually, in divided doses throughout the day. 0075. The following dosage levels and other dosage 0081 Alternatively, the PDE5 inhibitors can be admin levels herein are for the average human Subject having a istered in the form of a Suppository or pessary, or they may weight range of about 65 to 70 kg. The skilled person will be applied topically in the form of a gel, hydrogel, lotion, readily be able to determine the dosage levels required for a solution, cream, ointment or dusting powder. The PDE5 Subject whose weight falls outside this range. Such as inhibitors may also be dermally or transdermally adminis children and the elderly. tered, for example, by the use of a skin patch. They may also 0076) The dosage of the PDE5 inhibitor in such formu be administered by the pulmonary or rectal routes. lations will depend on its potency, but can be expected to be 0082) For application topically to the skin, the PDE5 in the range of from 1 to 500 mg for administration up to inhibitors can be formulated as a suitable ointment contain three times a day. In the case of sildenafil, a preferred dose ing the active compound Suspended or dissolved in, for is in the range 10 to 100 mg (e.g. 10, 25, 50 and 100 mg) example, a mixture with one or more of the following: which can be administered once, twice or three times a day mineral oil, liquid petrolatum, white petrolatum, propylene (preferably once). However the precise dose will be as glycol, polyoxyethylene polyoxypropylene compound, determined by the prescribing physician and will depend on emulsifying wax and water. Alternatively, they can be for the age and weight of the patient and severity of the mulated as a Suitable lotion or cream, Suspended or dis symptoms. Solved in, for example, a mixture of one or more of the 0.077 For oral and parenteral administration to human following: mineral oil, Sorbitan monostearate, a polyethyl patients, the daily dosage level of the PDE5 inhibitors will ene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, usually be from to 5 to 500 mg/kg (in single or divided cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and doses). Water. 0078 Thus tablets or capsules of the PDE5 inhibitors 0083) The PDE5 inhibitors may also be used in combi may contain from 5 mg to 250 mg (preferably 10 to 100 mg) nation with a cyclodextrin. Cyclodextrins are known to form of active compound for administration singly or two or more inclusion and non-inclusion complexes with drug molecules. at a time, as appropriate. The physician in any event will Formation of a drug-cyclodextrin complex may modify the determine the actual dosage which will be most suitable for solubility, dissolution rate, bioavailability and/or stability any individual patient and it will vary with the age, weight property of a drug molecule. Drug-cyclodextrin complexes and response of the particular patient. The above dosages are are generally useful for most dosage forms and administra exemplary of the average case. There can, of course, be tion routes. As an alternative to direct complexation with the individual instances where higher or lower dosage ranges drug the cyclodextrin may be used as an auxiliary additive, are merited and Such are within the scope of this invention. e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and The skilled person will appreciate that the PDE5 inhibitors gamma-cyclodextrins are most commonly used and Suitable may be taken as a single dose as needed or desired (i.e. prin). examples are described in WO-A-91/11172, WO-A-94/ It is to be appreciated that all references herein to treatment O2518 and WO-A-98/55148. include acute treatment (taken as required) and chronic 0084 Generally, in humans, oral administration of the treatment (longer term continuous treatment). PDE5 inhibitors is the preferred route, being the most 0079. The PDE5 inhibitors can also be administered convenient. In circumstances where the recipient Suffers intranasally or by inhalation and are conveniently delivered from a Swallowing disorder or from impairment of drug in the form of a dry powder inhaler or an aerosol spray absorption after oral administration, the drug may be admin presentation from a pressurised container, pump, spray, istered parenterally, Sublingually or buccally. atomiser or nebuliser, with or without the use of a suitable 0085. A further preferred route is topically via the skin, propellant, e.g. dichlorodifluoromethane, trichlorofluo preferably locally to the male genitalia. romethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A trade mark) 0086). In an embodiment of the invention, the PDE5 or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA trade inhibitors may also be combined with one or more additional mark), carbon dioxide or other suitable gas. In the case of active agents for treating PE in patients with normal erectile a pressurised aerosol, the dosage unit may be determined by function, the active agent being selected from the following providing a valve to deliver a metered amount. The pres list: Surised container, pump, spray, atomiser or nebuliser may 0087 1) one or more naturally occurring or synthetic contain a solution or Suspension of the active compound, e.g. or esters thereof. Suitable prostaglandins using a mixture of ethanol and the propellant as the solvent, for use herein include compounds Such as alprostadil, which may additionally contain a lubricant, e.g. Sorbitan E, prostaglandin Eo 13, 14-dihydroprosta trioleate. Capsules and cartridges (made, for example, from glandin E1, prostaglandin E, eprostinol, natural synthetic gelatin) for use in an inhaler or insufflator may be formulated and semi-synthetic prostaglandins and derivatives thereof to contain a powder mix of the PDE5 inhibitor and a suitable including those described in WO-00033825 and/or U.S. powder base Such as lactose or starch. Pat. No. 6,037,346 issued on 14 Mar. 2000 all incorpo 0080 Aerosol or dry powder formulations are preferably rated herein by reference, PGEO, PGE, PGA, PGB, arranged so that each metered dose or "puff contains from PGF.C., 19-hydroxy PGA, 19-hydroxy-PGB, PGE, 1 ug to 50 mg of a PDE5 inhibitor for delivery to the patient. PGB, 19-hydroxy-PGA 19-hydroxy-PGB, PGEC, US 2006/0094704 A1 May 4, 2006

tromethamine dinoprost, tromethamine, dino identifying NPY inhibitors is presented in WO-A-98/ prostone, lipo prost, , metenoprost, Sulprostune, 52890 (see page 96, lines 2 to 28); tiaprost and moxisylate; 0099. 13) one or more of vasoactive intestinal protein 0088. 2) one or more C.- receptor antagonists (VIP), VIP mimetic, VIP analogue, more particularly (also known as C.-adrenoceptor blockers, C.-receptor mediated by one or more of the VIP receptor subtypes blockers or C-blockers); suitable C.- VPAC1,VPAC or PACAP (pituitory adenylate cyclase antagonists include: , , phentola activating peptide), one or more of a VIP receptor agonist mine mesylate, , , , naftopi or a VIP analogue (eg Ro-125-1553) or a VIP fragment, dil, , , rauwolfa , one or more of a C.-adrenoceptor antagonist with VIP Recordati 15/2739, SNAP 1069, SNAP 5089, RS17053, combination (eg invicorp, aviptadil); SL 89.0591, , and ; suitable C2-adrenergic receptor antagonists include dibenamine, 0.100 14) one or more of a melanocortin receptor agonist , , , , or modulator or melanocortin enhancer, Such as melano and dibenamine; Suitable non-selective O-adr tan 11, PT-14, PT-141 or compounds claimed in energic receptor antagonists include ; further WO-09964.002, WO-00074679, WO-09955679, C.-adrenergic receptor antagonists are described in PCT WO-00105401, WO-00058361, WO-00114879, application WO99/30697 published on 14 Jun. 1998 and WO-00113112, WO-099.54358: US patents: U.S. Pat. Nos. 4,188,390; 4,026,894; 3,511, 0101) 15) one or more 5-HT, antagonist (preferably 836; 4,315,007; 3,527,761; 3,997,666: 2,503,059; 4,703, batanopride, granisetron, ondansetron, tropistron or 063; 3,381,009; 4,252,721 and 2,599,000 each of which is MDL-73147EF): incorporated herein by reference: 0102 16) one or more 5-HT agonist (preferably 0089 3) one or more vasodilator agents; suitable vasodi cisapride and D- diethylamide); lator agents for use herein include nimodepine, pinacidil, cyclandelate, , chloroprumazine, halo peridol, 0.103 17) one or more of testosterone, a testosterone replacement agent (inc dehydroandrostendione), test Rec 15/2739 and trazodone; osternone (Tostrelle), dihydrotestosterone or a testoster 0090 4) one or more alkoloids; suitable ergot one implant; alkaloids are described in U.S. Pat. No. 6,037.346 issued on 14 Mar. 2000 and include , brazergoline, 0104. 18) one or more of estradiol, estrogen, estrogen and bromerguride, cianergoline, delorgotrile, disulergine, medroxyprogesterone or medroxyprogesterone acetate ergonovine maleate, tartrate, etisulergine, ler (MPA) (i.e. as a combination), or estrogen and methyl gotrile, lysergide, , , metergota testosterone hormone replacement therapy agent (e.g. mine, , , propisergide, proterguride, HRT especially Premarin, Cenestin, Oestrofeminal, ; Equin, Estrace, Estrofem, Elleste Solo, Estring, Eastrad erm TTS, Eastraderm Matrix, Dermestril, Premphase, 0.091 5) one or more angiotensin receptor antagonists Preempro, Prempak, Premique, Estratest, Estratest HS, Such as losartan; Tibolone); 0092 6) one or more calcium channel blockers such as 0105. 19) one or more of a modulator of transporters for amlodipine; noradrenaline, and/or serotonin, Such as bupro 0093. 7) one or more antagonists of endothelin receptors pion and GW-320659; and inhibitors or endothelin-converting enzyme; 0106. 20) one or more of a purinergic receptor agonist 0094) 8) one or more cholesterol lowering agents such as and/or modulator, statins (e.g. atorvastatin/Lipitor-trade mark) and fibrates; 0.107 21) one or more of a neurokinin (NK) receptor 0.095 9) one or more acetylcholinesterase inhibitors such antagonist, including those described in WO-09964008; as donezipil; 0108) 22) one or more of an opioid receptor agonist, 0096. 10) one or more estrogen receptor modulators antagonist or modulator, and/or estrogen agonists and/or estrogen antagonists, preferably raloxifene or lasofoxifene, (-)-cis-6-phenyl-5- 0.109. 23) one or more of a modulator of cannabinoid 4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahy receptors; dronaphthalene-2-ol and pharmaceutically acceptable 0110 24) gabapentene; salts thereof the preparation of which is detailed in WO 0111 25) one or more angiotensin-converting9. 9. enzyme 96/21656; (ACE) inhibitors, e.g. quinapril; and 0097. 11) one or more further PDE inhibitors, particularly 0112 26) one or more anti-depressants; for example a PDE 2, 7 or 8 inhibitor, preferably a PDE2 inhibitor, said selective serotonin re-uptake inhibitors (sertraline, fluox inhibitors preferably having an IC50 against the respec etine, fluvoxamine, paroxetine, citalopram, Venlafaxine, tive enzyme of less than 100 nM; , , traZodone); tricyclic antidepres 0098 12) one or more of a NPY (neuropeptide Y) inhibi sants (TCA, associated with cardiovascular side effects) tor, more particularly NPY1 or NPY5 inhibitor, preferably , , , , NPY1 inhibitor, preferably said NPY inhibitors (including , , , , protrip NPY Y1 and NPY Y5) having an IC50 of less than 100 tyline, , bupropion); and monoamine oxidase nM, more preferably less than 50 nM; an assay for inhibitors phenelzine, tranylcypromine. US 2006/0094704 A1 May 4, 2006

0113 Preferred additional active agents for combination 0.126 iii) the use of a pharmaceutical combination for the with the PDE5 inhibitors (preferably sildenafil. Vardenafil. manufacture of a medicament for the treatment of pre IC-351, 5-2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)py mature ejaculation in patients with normal erectile func ridin-3-yl)-3-ethyl-2-2-methoxyethyl-2,6-dihydro-7H tion comprising a PDE5 inhibitor and an additional active pyrazolo 4,3-dipyrimidin-7-one and 5-(5-acetyl-2-butoxy agent as hereinabove defined; 3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro 7H-pyrazolo 4,3-dipyrimidin-7-one) for use with the 0.127 iv) a kit for treating premature ejaculation in invention are selected from the list: patients with normal erectile function, the kit comprising: a) a first pharmaceutical composition comprising a PDE5 0114) a) one or more C.-adrenergic receptor antagonists inhibitor; b) a second composition comprising an addi (preferably praZosin, traZodone, alfuzosin, indoramin, tional active agent as hereinabove defined; and c) a tamsulosin, phenoxybenzamine, yohimbine, doxazosin, container for the first and second compositions; terazosin, clonidine, Recordati 15/2739, SNAP 1069, 0.128 v) the use of a kit in the manufacture of a medi SNAP 5089 and RS17053); cament for treating premature ejaculation in patients with 0115 b) one or more 5-HT, antagonist (preferably normal erectile function, the kit comprising: a) a first batanopride, granisetron, ondansetron, tropistron or pharmaceutical composition comprising a PDE5 inhibi MDL-73147EF): tor; b) a second composition comprising an additional active agent as hereinabove defined; and c) a container for 0116 c) one or more of a modulator of transporters for the first and second compositions; noradrenaline, dopamine and/or serotonin, Such as bupro pion and GW-320659; and 0.129 vi) a method of treating a patient suffering from premature ejaculation with normal erectile function com 0117 d) an anti-depressant (preferably sertraline, fluox prising treating said patient with an effective amount of a etine, fluvoxamine, paroxetine, citalopram, Venlafaxine, clomipramine). PDE5 inhibitor; and 0.130 vii) a method of treating a patient suffering from 0118 Particularly preferred additional active agents for premature ejaculation with normal erectile function com combination with sildenafil for use with the invention are prising treating said patient with pharmaceutical combi selected from the list: sertraline, fluoxetine, paroxetine, nation comprising a PDE5 inhibitor and an additional clomipramine, ondansetron, phenoxybenzamine, alfuzosin active agent as hereinabove defined. and teraZosin. 0119 Particularly preferred additional active agents for 0131 The following study was conducted to investigate combination with 5-2-ethoxy-5-(4-ethylpiperazin-1-ylsul the use of PDE5 inhibitors for the treatment of PE in patients phonyl)pyridin-3-yl)-3-ethyl-2-2-methoxyethyl-2,6-dihy with normal erectile function. dro-7H-pyrazolo 4,3-dipyrimidin-7-one for use with the 0.132. The study was conducted using sildenafil (Via invention are selected from the list: sertraline, fluoxetine, graR), however it will be appreciated that the study may be paroxetine, clomipramine, ondansetron, phenoxyben conducted with other PDE5 inhibitors, for example one or Zamine, alfuZosin and teraZosin. more of the preferred PDE5 inhibitors listed hereinabove. 0120 Particularly preferred additional active agents for 0.133 The study comprised a phase 11, placebo-con combination with 5-(5-acetyl-2-butoxy-3-pyridinyl)-3- trolled study to assess the efficacy of oral sildenafil (Via ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo 4, graTM) one hour prior to sexual intercourse in patients with 3-dipyrimidin-7-one for use with the invention are selected premature ejaculation but with normal erectile function (i.e. from the list: Sertraline, fluoxetine, paroxetine, clomi patients scoring greater than 22 on the Erectile Function pramine, ondansetron, phenoxybenzamine, alfuZosin and Domain Questionnaire (see hereinafter)) teraZosin. 0.134. The following efficacy variables (end points) were 0121. It is to be appreciated that all references herein to used to evaluate the study. treatment include curative, palliative and prophylactic treat ment. 0.135 i) The Intra-vaginal Ejaculatory Latency Time (IELT). This formed the primary efficacy variable. The 0122) If a combination of active agents are administered, change in IELT from baseline of the Viagra group was then they may be administered simultaneously, separately or compared to that of the placebo group. IELT was deter sequentially. mined by stopwatch and was recorded by the patient via 0123. It will be appreciated that the invention provides a diary. The patient recorded the IELT for each sexual basis for the following further aspects and that the embodi event. Patients were asked to collect data on IELT for the ments specified hereinabove for the first aspect extend to first intra-vaginal penetration during any single event. In these aspects: addition, the diary captured information on dosing and corresponding sexual intercourse attempts, and was com 0124 i) a PDE5 inhibitor for treating premature ejacula pleted when the patient had taken study and/or tion in patients with normal erectile function; engaged in sexual activity. 0125 ii) a pharmaceutical combination for treating pre 0.136) ii) Index of Premature Ejaculation (IPE). This mature ejaculation in patients with normal erectile func index recorded the effects of the patient’s sexual problems tion comprising a PDE5 inhibitor and an additional active on his sex life. This formed a secondary efficacy endpoint agent as hereinabove defined; of the study. US 2006/0094704 A1 May 4, 2006

0137 iii) Sexual Quality of Life (Male) questionnaire skeletal muscle and bovine retina, essentially by the method (SQoI-M)—This questionnaire assesses the quality of of W. J. Thompson and M. M. Appleman (Biochem., 1971, sex life prior to and after treatment. This formed a 10, 311). In particular, the coMP-specific PDE (PDE5) and secondary efficacy endpoint of the study. the coMP-inhibited cAMP PDE (PDE3) can be obtained from human corpus cavernosum tissue, human platelets or 0138 iv) Global Efficacy Question. This question rabbit platelets; the coMP-stimulated PDE (PDE2) was recorded the improvement in the overall level of satisfac obtained from human corpus cavernoSum; the calcium/ tion during sexual intercourse with the treatment. This calmodulin (Ca/CAM)-dependent PDE (PDE1) from human formed a secondary efficacy endpoint of the study. cardiac ventricle: the cAMP-specific PDE (PDE4) from 0139 v) Time to ejaculation using penile vibratory stimu human skeletal muscle; and the photoreceptor PDE (PDE6) lation—A number of patients were asked to record their from bovine retina. Phosphodiesterases 7-11 can be gener time to ejaculation using penile vibratory stimulation. ated from full length human recombinant clones transfected This technique is a reliable method for measuring ejacu into SF9 cells. lation latency. Penile vibrators are available commer 0144 Assays can be performed either using a modifica cially, for example “FERTICARE(R) personal” (see www tion of the “batch' method of W. J. Thompson et al. multicept.com/ferticare.html, Multicept A/S, Lyngse Alle (Biochem., 1979, 18, 5228) or using a scintillation proximity 3, 2970Horsholm, Denmark). assay for the direct detection of AMP/GMP using a modi fication of the protocol described by Amersham pic under 0140 Components of the Erectile Function Domain product code TRKQ7090/7100. In summary, the effect of Questionnaire. PDE inhibitors was investigated by assaying a fixed amount of enzyme in the presence of varying inhibitor concentra tions and low substrate, (cGMP or cAMP in a 3:1 ratio QUESTION RESPONSE OPTIONS unlabelled to H-labeled at a conc ~% K) such that ICs-K. The final assay volume was made up to 100 ul with Q1: In the past 4 weeks, how often 0 = No sexual activity assay buffer 20 mM Tris-HCl pH 7.4, 5 mM MgCl, 1 were you able to get an erection = Almost never never during sexual activity? 2 = A few times (much less than mg/ml bovine serum albumin). Reactions were initiated with Q2: In the past 4 weeks, when you half the time) enzyme, incubated for 30-60 min at 30° C. to give <30% had erections with sexual 3 = Sometimes (about half the time) substrate turnover and terminated with 50 ul yttrium silicate stimulation, how often were your 4 = Most times (much more than half SPA beads (containing 3 mM of the respective unlabelled erections hard enough for he time) penetration? 5 = Almost always always cyclic nucleotide for PDEs 9 and 11). Plates were re-sealed Q3: In the past 4 weeks, when O = Did not attempt intercourse and shaken for 20 min, after which the beads were allowed you attempted sexual intercourse, = Almost never never to settle for 30 min in the dark and then counted on a how often were you able to 2 = A few times (much less than half penetrate (enter) your partner? he time) TopCount plate reader (Packard, Meriden, Conn.) Radioac Q4: In the past 4 weeks, during 3 = Sometimes (about half the time) tivity units were converted to % activity of an uninhibited sexual intercourse, how often 4 = Most times (much more than half control (100%), plotted against inhibitor concentration and were you able to maintain your he time) inhibitor ICs values obtained using the Fit Curve erection after you had penetrated 5 = Almost always always Microsoft Excel extension. (entered) your partner? Q5: In the past 4 weeks, during O = Did not attempt intercourse 0145 Although the foregoing invention has been sexual intercourse, how difficult = Extremely difficult was it to maintain your erection 2 = Very difficult described in some detail for purposes of illustration, it will to completion of intercourse? 3 = difficult be readily apparent to one skilled in the art that changes and 4 = Slightly difficult modifications may be made without departing from the 5 = Not difficult scope of the invention described herein. Q15: In the past 4 weeks, how do 1 = Very low you rate your confidence that you 2 = Low could get and keep an erection? 3 = Moderate 4 = High 1. (canceled) 5 = Very high 2. (canceled) 3. The method according to either claim 12 wherein the PDE5 inhibitor has an IC50 against the PDE5 enzyme of less Assay than 100 nanomolar. 4. The method according to claim 3 wherein the PDE5 0141 PDE potency values referred to herein are deter inhibitor has a selectivity over PDE3 of greater than 100 mined by the following assays. fold. 0142 Preferred PDE compounds suitable for use in 5. The method according to claim 4 wherein the PDE5 accordance with the present invention are potent and selec inhibitor has a selectivity over both PDE3 and PDE4 of tive PDE5 inhibitors. In vitro PDE inhibitory activities greater than 100 fold. against cyclic guanosine 3',5'-monophosphate (cGMP) and 6. The method according to claim 5 wherein the PDE5 cyclic adenosine 3',5'-monophosphate (cAMP) phosphodi inhibitor has an IC50 against PDE5 of less than 100 nMand esterases can be determined by measurement of their ICso a selectivity over PDE3 of greater than 100 fold. values (the concentration of compound required for 50% 7. The method according to claim 12 wherein the PDE5 inhibition of enzyme activity). inhibitor is selected from the group: 0143. The required PDE enzymes can be isolated from a (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4- variety of Sources, including human corpus cavernosum, methylenedioxyphenyl)-pyrazino 2', 1': 6,1pyrido 3,4- human and rabbit platelets, human cardiac ventricle, human bindole-1,4-dione (IC-351); US 2006/0094704 A1 May 4, 2006

2-2-ethoxy-5-(4-ethyl-piperazin-1-yl-l-Sulphonyl)-phe 10. The method according to claim 9 wherein the daily nyl-5-methyl-7-propyl-3H-imidazo[5.1-f1.2.4 tri dosage is 10 to 100 mg. azin-4-one (vardenafil); 11. (canceled) 12. A method for treating premature ejaculation in 5-2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin patients with normal erectile function comprising orally 3-yl)-3-ethyl-2-2-methoxyethyl-2,6-dihydro-7H administering an effective amount of a PDE5 inhibitor in pyrazolo 4.3-dpyrimidin-7-one; and combination with one or more O.-adrenergic receptor antago 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3- nists, NPY inhibitors, melanocortin enhancers, 5-HT or azetidinyl)-2,6-dihydro-7H-pyrazolo 4,3-dipyrimidin 5-HT, antagonists, modulator of transporters for noradrena 7-one and pharmaceutically acceptable salts thereof. line, dopamine and/or serotonin or anti-depressants. 8. (canceled) 13. The method according to claim 12 wherein the anti 9. The method according to claim 7 wherein the daily depressant is a selective serotonin re-uptake inhibitor. dosage is 5 to 500 mg. k k k k k