The present invention relates to a class of dopamine agonists, more particularly a class of agonists that are selective for D3 over D2. These compounds are useful for the treatment and/or prevention of sexual dysfunction, for example female sexual dysfunction (FSD), in particular female sexual arousal disorder

(FSAD), hypoactive sexual desire disorder (HSDD; lack of interest in sex), female orgasmic disorder

(FOD; inability to achieve orgasm); and male sexual dysfunction, in particular male erectile dysfunction

(MED). Male sexual dysfunction as referred to herein is meant to include ejaculatory disorders such as premature ejaculation, anorgasmia (inability to achieve orgasm) or desire disorders such as hypoactive sexual desire disorder (HSDD; lack of interest in sex). These compounds are also useful in treating neuropsychiatric disorders and neurodegenerative disorders.

The present invention provides for compounds of formula (I),

wherein: R ¹ is selected from: H and (C _r C ₆ )alkyl;

R ² is selected from: H, halo and C(O)NH ₂ ;

R ³ is selected from: H, C(O)OH, C(O)NH ₂ , C(O)O(C _r C ₆ )alkyl, OH and halo;

R ⁴ is selected from: NH ₂ , O(C _r C ₆ )alkyl, OCH ₂ Ph, C(O)OH, C(O)NH ₂ , C(O)(C _r C ₆ )alkyl, C(O)O(C ₁ - C ₆ )alkyl, OH, halo and (C _r C ₆ )alkyl, said alky! optionally substituted by OH;

R ⁵ is selected from: H, CN and C(O)NH ₂

and pharmaceutically acceptable salts, solvate, polymorphs and prodrugs thereof; with the provisos that when R ⁴ is NH ₂ and R ¹ , R ² and R ⁵ are all H, then R ³ cannot be OH or Cl; and when R ⁴ is Cl, R ¹ is H or CH ₃ , and R ² and R ⁵ are H, then R ³ cannot be Cl.

Unless otherwise indicated, (C _r C ₆ )alkyl may be straight chain or branched.

Unless otherwise indicated, the term halo means fluoro, chloro, bromo or iodo.

Unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternatives groups, the selected groups may be the same or different.

The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.

A pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties. Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods:

(i) by reacting the compound of formula (I) with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, for example; a lactone or lactam, using the desired acid or base; or

(iii) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').

The compounds of the invention may also exist in unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non- stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -COO ^' Na ⁺ , -COO ^" K ⁺ , or -SO ₃ -Na ⁺ ) or non-ionic (such as -N ^' N ⁺ (CH ₃ ) ₃ ) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4 ^th Edition (Edward Arnold, 1970).

Hereinafter all references to compounds of formula (I) include references to salts, solvates, multi- component complexes and liquid crystals thereof and to solvates, multi-component complexes and liquid crystals of salts thereof.

The compounds of the invention include compounds of formula (I) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (I).

As indicated, so-called 'prodrugs' of the compounds of formula (I) are also within the scope of the invention. Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro- drugs as Novel Delivery Systems. Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design. Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include

(i) where the compound of formula (I) contains a carboxylic acid functionality

(-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (I) is replaced by (Ci-C ₈ )alkyl;

(ii) where the compound of formula (I) contains an alcohol functionality (-OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula (I) is replaced by (C _r C ₆ )alkanoyloxymethyl; and

(iii) where the compound of formula (I) contains a primary or secondary amino functionality (-NH ₂ or - NHR where R ≠ H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (I) is/are replaced by (C ₁ - C ₁₀ )alkanoyl.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

Moreover, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include

(i) where the compound of formula (I) contains a methyl group, an hydroxymethyl derivative thereof (-CH ₃ -> -CH ₂ OH):

(ii) where the compound of formula (I) contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH);

(iii) where the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NR ¹ R ² -> -NHR ¹ or -NHR ² );

(iv) where the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHR ¹ -> -NH ₂ );

(v) where the compound of formula (I) contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and

(vi) where the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CONH ₂ -> COOH).

The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ² H and ³ H, carbon, such as ¹¹ C ₁ ¹³ C and ¹⁴ C, chlorine, such as ³⁶ CI, fluorine, such as

¹⁸ F, iodine, such as ¹²³ I and ¹²⁵ I, nitrogen, such as ¹³ N and ¹⁵ N, oxygen, such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorus, such as ³² P, and sulphur, such as ³⁵ S.

Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ² H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D ₂ O, d ₆ -acetone, d ₆ -DMSO.

The following alternative embodiments are also encompassed by the present invention:

In a first alternative embodiment R ¹ is selected from: H and (CrC^alkyl. In a second alternative embodiment R ¹ is H or propyl. In a third alternative embodiment R1 is n-propyl.

In a first alternative embodiment R ² is selected from H and halo. In a second alternative embodiment R ² is selected from H and Br. In a third alternative embodiment R ² is H.

In a first alternative embodiment R ³ is selected from: H, C(O)OH, C(O)NH ₂ , C(O)OCH ₃ , OH and I. In a second alternative embodiment R ³ is selected from H, I and OH. In a third alternative embodiment R ³ is selected from H and OH. In a fourth alternative embodiment R ³ is H. In a fifth alternative embodiment R ³ is OH.

In a first alternative embodiment R ⁴ is selected from: NH ₂ , OCH ₃ , OCH ₂ Ph, C(O)OH, C(O)NH ₂ , C(O)CH ₃ , C(O)OCH ₃ , OH, halo and CH ₂ OH.

In a second alternative embodiment R ⁴ is selected from: NH ₂ , OCH ₃ , OCH ₂ Ph, C(O)OH, C(O)NH ₂ ,

C(O)CH ₃ , C(O)OCH ₃ , OH, Br and CH ₂ OH.

In a third alternative embodiment R ⁴ is OH or Br.

In a fourth alternative embodiment R ⁴ is OH. In a fifth alternative embodiment R ⁴ is Br.

In a first alternative embodiment R is H or CN.

In a second alternative embodiment R ⁵ is H.

In an alternative embodiment of the present invention at least one of R ³ and R ⁴ is OH.

Representative compounds of the invention include: 3-Azetidin-3-ylphenol hydrochloride; 3-(1-Propylazetidin-3-yl)phenol trifluoroacetate; 2-lodo-5-(1 -propylazetidin-3-yl)phenol;

2,6-Dibromo-4-(1-propylazetidin-3-yl)phenol; and 2-Bromo-4-(1-propylazetidin-3-yl)phenol.

Compounds of the invention may be prepared, in known manner, in a variety of ways. The routes below illustrate methods of synthesising compounds of formula (I).

Compounds of formula (I) wherein R ¹ is H, R ² is H and R ³ , R ⁴ and R ⁵ are H or OH, wherein one of R ³ , R ⁴ and R ⁵ is OH, may be prepared according to reaction scheme 1.

(I) Scheme 1

PG is a protecting group suitable for protection of amines such as Cbz or Boc.

PG' is a protecting group suitable for the protection of hydroxy groups such as benzyl or acyl

When PG=f-Boc, compound (II) is commercially available

Compounds of general formula (III) can be prepared from compounds of formula (II) by process step i - Conversion of alcohol to a suitable leaving group (LG) such as triflate, mesylate or tosylate by reaction with a suitable anhydride or sulfonyl chloride such as trifluoromethanesulfonic anhydride/chloride, mesyl anhydride/chloride or tosyl chloride, in the presence of a suitable base such as 2,6-lutidine, pyridine or triethylamine, in a suitable solvent such as ethyl acetate, diethyl ether or dichloromethane, optionally at low temperature for 30-60 minutes. Typical conditions comprise of 1.0 equivalent of compound (II), 2.0 equivalents of 2,6-lutidine and 1.0-1.1 equivalents of trifluoromethanesulfonic anhydride, in dichloromethane, at -30 ⁰ C for 30 minutes.

Compounds of general formula (IV) can be prepared from compounds of general formula (III) by process step ii - substitution by reaction with a suitable iodide source such as potassium iodide, sodium iodide or tetra-n-butylammonium iodide, in a suitable solvent such as N,N-dimethylformamide, water or acetone, at a temperature between 0-100 ⁰ C, for up to 18 hours. Typical conditions comprise of 1.0 equivalent of compound (III) and 5.0 equivalents of potassium iodide in N,N-dimethylformamide, at a temperature between 0-25 ⁰ C for 18 hours.

Compounds of formula (V) can be prepared from compounds of formula (IV) by process step iii- cross coupling of compound (IV) with a suitably protected iodophenol (X) using a method analogous to that of S. Billotte (Synlett, 4, 379, 1998). Typical conditions comprise of 0.08 equivalents of 1 ,2-dibromoethane and an excess of zinc dust in N,N-dimethylformamide, at 7O ⁰ C for 10 minutes followed by sequential addition of 0.08 equivalents of chlorotrimethyl silane, (stirring at room temperature for 1 hour), 1.0 equivalent of compound (IV) (stirring at 4O ⁰ C for 1 hour) and 1.0-1.1 equivalents of iodophenol, a suitable palladium catalyst such as fr/s(dibenzylideneacetone) dipalladium(O) (cat) and tri(2-furyl)phosphine, at 7O ⁰ C for 4 hours.

Compounds of formula (Vl) can be prepared from compounds of formula (V) by process step (iv) - Removal of hydroxyl protection group (PG') using standard methodology as described in "Protecting Groups in Organic Synthesis" by T.W. Greene and P. Wutz. When PG' is benzyl, typical conditions comprise of 1.0 equivalent of compound (V), 5.0 equivalents of ammonium formate and 10% Pd/C (cat.) heated under reflux in ethanol, for 1-4 hours.

Compounds of formula (I) can be prepared from compounds of formula (Vl) by process step (v) - Removal of amino protection group (PG) using standard methodology as described in "Protecting Groups in Organic Synthesis" by T.W. Greene and P. Wutz. When PG is BOC, typical conditions comprise of 1.0 equivalent of compound (Vl) and excess hydrogen chloride gas in dichloromethane, at 0- 25 ⁰ C for 1-18 hours.

Alternatively, when R ¹ is (C _r C ₆ )alkyl, R ² is H and R ³ , R ⁴ and R ⁵ are H or OH, wherein one of R ³ , R ⁴ and R ^s is OH, may be prepared as described in Scheme 2.

iv

Scheme 2

Compounds of formula (V) can be prepared as described in scheme 1.

Compounds of formula (VII) can be prepared from compounds of formula (V) by process step v - Removal of amino protection group (PG) using standard methodology as described in "Protecting Groups in Organic Synthesis" by T.W. Greene and P. Wutz. When PG is BOC, typical conditions comprise of 1.0 equivalent of compound (Vl) and excess of trifluoroacetic acid in dichloromethane, at O- 25 ⁰ C for 1-6 hours.

Compounds of general formula (VIII) are commercially available.

Compounds of general formula (IX) can be prepared from compounds of formula (VII) and (VIII) by process step vii- reductive amination, in the presence of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, in a suitable solvent such as tetrahydrofuran, dichloromethane or dioxan, under ambient conditions for 1-48 hours. Typical conditions comprise of 1.0 equivalent of compound (VII), 1.5 equivalent of compound (VIII) and 1.5 equivalents of sodium triacetoxyborohydride, in dichloromethane for 18 hours.

Compounds of formula (I) may be prepared from compounds of formula (IX) by process step iv, as described in scheme 1.

It will be further appreciated that compounds of formula (I) can be converted into alternative compounds of formula (I) by a series of halogenation reactions.

For example, when one of groups R ³ , R ⁴ and R ⁵ is H, one of groups R ³ , R ⁴ and R ⁵ is OH and one of groups R ³ , R ⁴ and R ⁵ is I ₁ compounds of formula (I)' can be prepared by iodination of compound (I). Typical conditions comprise of 1.0 equivalent of compound (I) and 1.0-1.1 equivalents of iodine in dichloromethane, at 0-25 ⁰ C for 24 hours.

When one of groups R ³ , R ⁴ and R ⁵ is OH ₁ one of groups R ³ , R ⁴ and R ⁵ is Br and one of groups R ³ , R ⁴ and R ⁵ is selected from Br and H, compounds of formula (I)' can be prepared by bromination of compound (I). Typical conditions comprise of 1.0 equivalent of compound (I) and 1.0-1.1 equivalents of bromine in glacial acetic acid, at 10-25 ⁰ C for 18 hours.

All of the above reactions and the preparations of novel starting materials using in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the Examples and Preparations hereto.

The compounds of the present invention have utility as selective D3 agonists in the treatment of disease states. There are a number of compounds with activity as both D2 and D3 agonists; however the use of such compounds is associated with a large number of side effects including nausea, emesis, syncope, hypotension and bradycardia, some of which are a cause for serious concern.

It was previously held that the efficacy of the prior art compounds stemmed from their ability to agonise D2; however D2 agonism is implicated as a cause of the side effects detailed above.

The present invention provides a class of selective D3 agonists. Serendipitously, these have been found to be efficacious, whilst reducing the side effects associated with unselective prior art compounds.

Accordingly, a further aspect of the invention provides a compound of formula (I) for use as a pharmaceutical.

Compounds of the present invention are particularly useful in treating sexual dysfunction, female sexual dysfunction, including hypoactive sexual desire disorder, female sexual arousal disorder, female orgasmic disorder and sexual pain disorder; male erectile dysfunction, hypertension, neurodegeneration, depression, pain and psychiatric disorders.

Accordingly, the present invention provides for the use of a compound of formula (I) in the preparation of a medicament for the treatment or prevention of a disease or condition mediated by the dopamine D3 receptor.

Furthermore, the present invention provides for the use of a compound of formula (I), without proviso, in the preparation of a medicament for the treatment or prevention of sexual dysfunction.

The compounds of the present invention are useful in male sexual dysfunction, particularly male erectile dysfunction. Male erectile dysfunction (MED), otherwise known as male erectile disorder, is defined as:

"the inability to achieve and/or maintain a penile erection for satisfactory sexual performance" (NIH Consensus Development Panel on Impotence, 1993)"

It has been estimated that the prevalence of erectile dysfunction (ED) of all degrees (minimal, moderate and complete impotence) is 52% in men 40 to 70 years old, with higher rates in those older than 70 (Melman et a/ 1999, J. Urology, 161 , p5-11). The condition has a significant negative impact on the quality of life of the individual and their partner, often resulting in increased anxiety and tension which leads to depression and low self-esteem. Whereas two decades ago, MED was primarily considered to be a psychological disorder (Benet et a/ 1994 Comp. Ther., 20: 669-673), it is now known that for the majority of individuals there is an underlying organic cause. As a result, much progress has been made in identifying the mechanism of normal penile erection and the pathophysiologies of MED.

Penile erection is a haemodynamic event which is dependent upon the balance of contraction and relaxation of the corpus cavernosal smooth muscle and vasculature of the penis (Lerner ef a/ 1993, J. Urology, 149, 1256-1255). Corpus cavernosa! smooth muscle is also referred to herein as corporal smooth muscle or in the plural sense corpus , cavernosa. Relaxation of the corpus cavernosal smooth muscle leads to an increased blood flow into the trabecular spaces of the corpus cavernosa, causing them to expand against the surrounding tunica and compress the draining veins. This produces a vast elevation in blood pressure which results in an erection (Naylor, 1998, Br. J. Urology, 81 , 424-431).

The changes that occur during the erectile process are complex and require a high degree of co- ordinated control involving the peripheral and central nervous systems, and the endocrine system (Naylor, 1998, Br. J. Urology, 81, 424-431). Corporal smooth muscle contraction is modulated by sympathetic noradrenergic innervation via activation of postsynaptic Gt ₁ adrenoceptors. MED may be associated with an increase in the endogenous smooth muscle tone of the corpus cavernosum. However, the process of corporal smooth muscle relaxation is mediated partly by non-adrenergic, non- cholinergic (NANC) neurotransmission. There are a number of other NANC neurotransmitters found in the penis, other than NO, such as calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP). The main relaxing factor responsible for mediating this relaxation is nitric oxide (NO), which is synthesised from L-arginine by nitric oxide synthase (NOS) (Taub ef a/ 1993 Urology, 42, 698- 704). It is thought that reducing corporal smooth muscle tone may aid NO to induce relaxation of the corpus cavernosum. During sexual arousal in the male, NO is released from neurones and the endothelium and binds to and activates soluble guanylate cyclase (sGC) located in the smooth muscle cells and endothelium, leading to an elevation in intracellular cyclic guanosine 3',5'-monophosphate (cGMP) levels. This rise in cGMP leads to a relaxation of the corpus cavernosum due to a reduction in the intracellular calcium concentration ([Ca ²⁺ Ji), via unknown mechanisms thought to involve protein kinase G activation (possibly due to activation of Ca ²⁺ pumps and Ca ²⁺ -activated K ⁺ channels).

Multiple potential sites have been identified within the central nervous system for the modulation of sexual behaviour. The key neurotransmitters are thought to be serotonin, norepinephrine, oxytocin, nitric oxide and dopamine. By mimicking the actions of one of these key neurotransmitters sexual function may be adjusted. Dopamine D3 receptors are expressed almost exclusively in the limbic area of the brain, regions involved in the reward, emotional and cognitive processes.

Without being bound by any theory, it appears that "due to its role in the control of locomotor activity, the integrity of the nigrostriatal dopaminergic pathway is also essential for the display of copulatory behaviour. Somehow, more specific to sexual function, it is likely that dopamine can trigger penile erection by acting on oxytocinergic neurons located in the paraventricular nucleus of the hypothalamus, and perhaps on the pro-erectile sacral parasympathetic nucleus within the spinal cord". It now appears that the significant site is D3 and not as previously thought, D2.

In essence, D3 is an initiator of sexual behaviour.

Accordingly, the present invention provides for the use of a compound of formula (I), without proviso, in the preparation of a medicament for the treatment or prevention of male sexual dysfunction, particularly, but not limited to, male erectile dysfunction.

Patients with mild to moderate MED should benefit from treatment with the compounds according to the present invention, and patients with severe MED may also respond. However, early investigations suggest that the responder rate of patients with mild, moderate and severe MED may be greater with a selective D3 agonist/PDE5 inhibitor combination. Mild, moderate and severe MED will be terms known to the man skilled in the art, but guidance can be found in The Journal of Urology, vol. 151 , 54-61 (Jan 1994).

Early investigations suggest the below mentioned MED patient groups should benefit from treatment with a selective D3 agonist and a PDEδi (or other combination set out hereinafter). These patient groups, which are described in more detail in Clinical Andrology vol. 23, no.4, p773-782 and chapter 3 of the book by I. Eardley and K. Sethia "Erectile Dysfunction-Current Investigation and Management, published by Mosby-Wolfe, are as follows: psychogenic, organic, vascular, endocrinologic, neurogenic, arteriogenic, drug-induced sexual dysfunction (lactogenic) and sexual dysfunction related to cavernosal factors, particularly venogenic causes.

Accordingly the present invention provides for the use of a compound of formula (I), without proviso, in the preparation of a medicament in combination with a PDE5 inhibitor for the treatment of erectile dysfunction.

Suitable PDE5 inhibitors are described herein.

The compounds of the present invention are useful in the treatment or prevention of female sexual dysfunction (FSD) ₁ particularly female sexual arousal disorder (FSAD), hypoactive sexual desire disorder (HSDD; lack of interest in sex), FSAD with concomitant HSDD, and female orgasmic disorder (FOD; inability to achieve orgasm).

In accordance with the invention, FSD can be defined as the difficulty or inability of a woman to find satisfaction in sexual expression. FSD is a collective term for several diverse female sexual disorders (Leiblum, S. R. (1998) - Definition and classification of female sexual disorders. Int. J. Impotence Res., 10, S104-S106; Berman, J. R., Berman, L. & Goldstein, I. (1999) - Female sexual dysfunction: Incidence, pathophysiology, evaluations and treatment options. Urology, 54, 385-391.). The woman may have lack of desire, difficulty with arousal or orgasm, pain with intercourse or a combination of these problems. Several types of disease, medications, injuries or psychological problems can cause FSD. Treatments in development are targeted to treat specific subtypes of FSD, predominantly desire and arousal disorders.

The categories of FSD are best defined by contrasting them to the phases of normal female sexual response: desire, arousal and orgasm (Leiblum, S. R. (1998) - Definition and classification of female sexual disorders. Int. J. Impotence Res., 10, S104-S106). Desire or libido is the drive for sexual expression. Its manifestations often include sexual thoughts either when in the company of an interested partner or when exposed to other erotic stimuli. Arousal is the vascular response to sexual stimulation, an important component of which is genital engorgement and includes increased vaginal lubrication, elongation of the vagina and increased genital sensation/sensitivity. Orgasm is the release of sexual tension that has culminated during arousal.

Hence, FSD occurs when a woman has an inadequate or unsatisfactory response in any of these phases, usually desire, arousal or orgasm. FSD categories include hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorders and sexual pain disorders. Although the compounds of the invention will improve the genital response to sexual stimulation (as in female sexual arousal disorder), in doing so it may also improve the associated pain, distress and discomfort associated with intercourse and so treat other female sexual disorders.

Hypoactive sexual desire disorder is present if a woman has no or little desire to be sexual, and has no or few sexual thoughts or fantasies. This type of FSD can be caused by low testosterone levels, due either to natural menopause or to surgical menopause. Other causes include illness, medications, fatigue, depression and anxiety.

Female sexual arousal disorder (FSAD) is characterised by inadequate genital response to sexual stimulation. The genitalia do not undergo the engorgement that characterises normal sexual arousal. The vaginal walls are poorly lubricated, so that intercourse is painful. Orgasms may be impeded. Arousal disorder can be caused by reduced oestrogen at menopause or after childbirth and during lactation, as well as by illnesses, with vascular components such as diabetes and atherosclerosis. Other

causes result from treatment with diuretics, antihistamines, antidepressants e.g. selective serotonin reuptake inhibitors (SSRIs) or antihypertensive agents.

Sexual pain disorders (includes dyspareunia and vaginismus) is characterised by pain resulting from penetration and may be caused by medications which reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems.

As previously discussed, D3 is thought to be an initiator of sexual behaviour. The clitoris is considered to be a homologue of the penis (Levin, R.J. (1991), Exp. CHn. Endocrinol., 98, 61-69); the same mechanism that provides provides an erectile response in the male produces an increase in genital blood flow in the female with an associated effect upon FSD. In addition there are changes in proceptivity and receptivity.

Thus, in accordance with one aspect of the invention, there is provided use of a compound of formula (I), without proviso, in the preparation of a medicament for the treatment or prophylaxis of female sexual dysfunction, including hypoactive sexual desire disorder, female sexual arousal disorder, female orgasmic disorder and sexual pain disorder.

In one embodiment the compounds of formula (I) are useful in the treatment or prophylaxis of sexual arousal disorder, orgasmic disorder, and hypoactive sexual desire disorder, and in a further embodiment, in the treatment or prophylaxis of sexual arousal disorder.

In a further embodiment the compounds of formula (I), are useful in the treatment of a subject with female sexual arousal disorder and concomitant hypoactive sexual desire disorder.

The Diagnostic and Statistical Manual (DSM) IV of the American Psychiatric Association defines Female Sexual Arousal Disorder (FSAD) as being:

"... a persistent or recurrent inability to attain or to maintain until completion of the sexual activity adequate lubrication-swelling response of sexual excitement. The disturbance must cause marked distress or interpersonal difficulty. ...".

The arousal response consists of vasocongestion in the pelvis, vaginal lubrication and expansion and swelling of the external genitalia. The disturbance causes marked distress and/or interpersonal difficulty.

FSAD is a highly prevalent sexual disorder affecting pre-, peri- and post-menopausal (± hormone replacement therapy (HRT)) women. It is associated with concomitant disorders such as depression, cardiovascular diseases, diabetes and urogenital (UG) disorders.

The primary consequences of FSAD are lack of engorgement/swelling, lack of lubrication and lack of pleasurable genital sensation. The secondary consequences of FSAD are reduced sexual desire, pain during intercourse and difficulty in achieving an orgasm.

It has recently been hypothesised that there is a vascular basis for at least a proportion of patients with symptoms of FSAD (Goldstein ef a/., Int. J. Impot. Res., 10, S84-S90.1998) with animal data supporting this view (Park ef a/., Int. J. Impot. Res., 9, 27-37, 1997).

R.J. Levin teaches us that because "... male and female genitalia develop embryologically from the common tissue anlagen, [that] male and female genital structures are argued to be homologues of one another. Thus the clitoris is the penile homologue and the labia homologues of the scrotal sac. ..." (Levin, R.J. (1991), Exp. Clin. Endocrinol., 98, 61-69).

Drug candidates for treating FSAD, which are under investigation for efficacy, are primarily erectile dysfunction therapies that promote circulation to male genitalia.

The compounds of the present invention are advantageous by providing a means for restoring a normal sexual arousal response - namely increased genital blood flow leading to vaginal, clitoral and labial engorgement. This will result in increased vaginal lubrication via plasma transudation, increased vaginal compliance and increased genital sensitivity. Hence, the present invention provides a means to restore, or potentiate, the normal sexual arousal response.

Thus, in one embodiment of the invention, there is provided use of a compound of formula (I), without proviso, in the preparation of a medicament for the treatment or prophylaxis of female sexual arousal disorder.

By female genitalia herein we mean: "The genital organs consist of an internal and external group. The internal organs are situated within the pelvis and consist of ovaries, the uterine tubes, uterus and the vagina. The external organs are superficial to the urogenital diaphragm and below the pelvic arch. They comprise the mons pubis, the labia majora and minora pudendi, the clitoris, the vestibule, the bulb of the vestibule, and the greater vestibular glands" (Gray's Anatomy, CD. Clemente, 13 ^th American Edition).

The compounds of the invention find application in the following sub-populations of patients with FSD: the young, the elderly, pre-menopausal, peri-menopausal, post-menopausal women with or without hormone replacement therapy.

The compounds of the invention find application in patients with FSD arising from:-

i) Vasculogenic etiologies e.g. cardiovascular or atherosclerotic diseases, hypercholesterolemia, cigarette smoking, diabetes, hypertension, radiation and perineal trauma, traumatic injury to the iliohypogastric pudendal vascular system.

ii) Neurogenic etiologies such as spinal cord injuries or diseases of the central nervous system including multiple sclerosis, diabetes, Parkinsonism, cerebrovascular accidents, peripheral neuropathies, trauma or radical pelvic surgery. iii) Hormonal/endocrine etiologies such as dysfunction of the hypothalamic/pituitary/gonadal axis, or dysfunction of the ovaries, dysfunction of the pancreas, surgical or medical castration, androgen deficiency, high circulating levels of prolactin e.g. hyperprolactinemia, natural menopause, premature ovarian failure, hyper and hypothyroidism. iv) Psychogenic etiologies such as depression, obsessive compulsive disorder, anxiety disorder, postnatal depression/"Baby Blues", emotional and relational issues, performance anxiety, marital discord, dysfunctional attitudes, sexual phobias, religious inhibition or traumatic past experiences. v) Drug-induced sexual dysfunction resulting from therapy with selective serotonin reuptake inhibitors (SSRis) and other antidepressant therapies (tricyclics and major tranquillizers), antihypertensive therapies, sympatholytic drugs, chronic oral contraceptive pill therapy.

The Compounds of the present invention are also useful in the treatment of depression.

Dopamine D3 receptors are expressed almost exclusively in the limbic area of the brain, regions involved in reward, emotional and cognitive processes. Chronic treatment with several classes of antidepressants are known to increase the expression of D3 in the limbic area, and antidepressant effects of desipramine can be blocked by sulpride (D2/D3 antagonist) when injected to nucleus accumbens (area rich in D3) but not caudate-putamen (area rich in dopamine D2 receptors). In addition, antidepressant effects were observed preclinical models of depression and in patients treated with pramipexole, a D3-preferring D2/D3 agonist. The available information suggests that D3 receptors mediate the anti-depressant activity and that selective D3 receptor agonists represent a new class of antidepressant drugs. Since antidepressants are known to be effective in other psychiatric, disorders, D3 agonists would have the potential to treat psychiatric diseases.

Suitable conditions include depression (e.g. depression in cancer patients,' depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, major depression, child abuse induced depression, post partum depression and grumpy old man syndrome), single episodic or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early morning waking or psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and pediatric depression; bipolar disorders or manic depression, for example, bipolar I disorder, bipolar Il disorder and cyclothymic disorder; conduct disorder; disruptive behavior disorder; trichotillomania, kleptomania, attention deficit hyperactivity disorder (ADHD); behavioral disturbances associated with mental retardation, autistic disorder; borderline personality disorder; avoidant personality disorder; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social anxiety, social

phobia, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorders; emotional lability, pathological crying; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania and depression associated with bipolar disorder; mood disorders associated with schizophrenia; eating disorders (e.g. anorexia nervosa and bulimia nervosa), obesity; movement disorders such as akinesias, dyskinesias, including familial paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication- induced postural tremour; chemical dependencies and addictions (e.g., dependencies on, or addictions to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or phenobarbitol) and behavioral addictions such as an addiction to gambling; ocular disorders such as glaucoma and ischemic retinopathy; sleeping disorder (cataplexy) and shock.

In a further embodiment, the present invention provides for the use of a compound of formula (I) in the preparation of a medicament for the treatment of depression or psychiatric disorders.

Suitable depressive conditions and psychiatric disorders are described above.

The compounds of the present invention also have utility in the treatment of neurodegeneration; sources of neurodegeneration include neurotoxin poisoning; vision loss caused by neurodegeneration of the visual pathway, such as by a stroke in the visual pathway eg in retina, optic nerve and/or occipital lobe; epileptic seizures; and from impairment of glucose and/or oxygen supply to the brain.

Conditions related to neurodegeneration include Restless Leg Syndrome, Huntington's disease, Multiple Sclerosis, mild cognitive impairment, Down's syndrome, stroke, Hereditary Cerebral Hemorrhage with

Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, delirium, dementia, age-related cognitive decline (ARCD), and amnestic and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, dementia of the

Alzheimer's type, memory disorders, loss of executive function, vascular dementia, dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease, Pick's disease, Creutzfeldt-

Jakob disease, HIV or AIDS-related dementia, diffuse Lewy body type of Alzheimer's disease, frontotemporal dementias with parkinsonism (FTDP), head trauma, spinal cord injury, demyelinating diseases of the nervous system, peripheral neuropathy, pain, cerebral amyloid angiopathy, amyotrophic

lateral sclerosis, multiple sclerosis, dyskinesia associated with dopamine agonist therapy, mental retardation, learning disorders, including reading disorder, mathematics disorder, or a disorder of written expression; age-related cognitive decline, amnesic disorders, neuroleptic-induced parkinsonism, tardive dyskinesias, and acute and chronic neurodegenerative disorders.

Accordingly the present invention provides for the use of a compound of formula (I) in the preparation of a medicament for the treatment of neurodegeneration.

The compounds of the present invention also have utility in the treatment of pain, particularly, but not limited to, chronic nociceptive pain.

Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment. The system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral.transducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a review). These sensory fibres are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus. The nociceptors are found on nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated). The activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.

Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually in twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.

When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation are altered and there is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate. These effects lead to a hightened sensation of pain. In acute pain these mechanisms can be useful, in promoting protective behaviours which may better enable repair processes to take place. The normal expectation would be that sensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is often due to nervous system injury. This injury often leads to abnormalities in sensory nerve fibres associated with maladaptation and aberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768).

Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms.

Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia - Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.

Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain. Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain. Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy. Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.

Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patient's quality of life (Woolf and Mannion, 1999, Lancet, 353, 1959-1964). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and

paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).

The inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most common inflammatory pain. Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407). It has been estimated that almost 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom are over 60 years of age, and this is expected to increase to 40 million as the age of the population increases, making this a public health problem of enormous magnitude (Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook of Pain, 387-395). Most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies from intermittent episodes of back pain that occur throughout life to a severe chronic disease that attacks the spine, peripheral joints and other body organs.

Another type of inflammatory pain is visceral pain which includes pain associated with inflammatory bowel disease (IBD). Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered gastrointestinal (Gl) disorders that cause pain include functional bowel disorder (FBD) and inflammatory bowel disease (IBD). These Gl disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastroesophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain. Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.

It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. back pain and cancer pain have both nociceptive and neuropathic components.

Other types of pain include:

pain resulting from musculoskeletal disorders, including myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenosis, polymyositis and pyomyositis;

heart and vascular pain, including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia;

• head pain, such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; and orofacial pain, including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.

Accordingly the present invention provides for the use of a compound of formula (I), without proviso, in the preparation of a medicament for the treatment or prevention of pain. In a further embodiment the present invention provides for the use of a compound of formula (I), without proviso, in the preparation of a medicament for the treatment or prevention of chronic nociceptive pain.

In addition to their role in treating sexual dysfunction, depression, neurodegeneration, pain and psychiatric disorders, the compounds of the present invention are likely to be efficacious in a number of additional indications. Accordingly, the present invention provides for the use of compounds of formula (I) in the preparation of a medicament for the treatment of hypertension, premature ejaculation, obesity, cluster headache, migraine, pain, endocrine disorders (e.g. hyperprolactinaemia), vasospasm

(particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), premenstrual syndrome, fibromyalgia syndrome, stress incontinence, chronic paroxysmal hemicrania, and headache (associated with vascular disorders).

In another embodiment, the present invention provides a method for treating or preventing the conditions, diseases or disorders mentioned herein above,- which comprises administering to a mammalian subject, including a human, in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.

It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.

D3/D2 AGONIST BIND ASSAY

Gonazalez ef a/ (Eup. J Pharmacology 272 (1995) R1-R3) discloses an assay for determining the binding capability of a compound at D3 and/or D2 dopamine receptors and thus the binding selectivity of such compounds. This assay is, thus, herein referred to as a binding assay.

D3/D2 AGONIST FUNCTIONAL ASSAY

A suitable assay is disclosed in WO2004/052372.

Using the assays described above, the compounds of the present invention all exhibit a binding Ki at the D3 receptor of <2μM and/ or a functional potency at D3 receptor expressed as an EC50, lower than 20OnM. None of the compounds gave a detectable EC50 in the D2 functional assay.

As an illustration, the compound of example 2 has a functional potency at the D3 receptor, expressed as an EC50, of 61 nM, with an Emax (maximal response value) of 77% (relative to the maximal effect of standard agent pramipexole). In the D2 receptor functional assay described above, this compound gave only a 24% response (relative to the maximal effect of pramipexole) at 1000OnM.

PAIN ASSAYS

Suitable assays for determining the utility of the compounds of the invention in various pain conditions are described below.

Neuropathic pain

The activity of a compound in the treatment of neuropathic pain may be measured according to the following test protocol.

Animals: Male Sprague Dawley rats are housed in groups. All animals are kept under a 12h light/dark cycle (lights on at 07h OOmin) with food and water ad libitum. All experiments were carried out by an observer blind to the treatments and in accordance with the Home Office Animals (Scientific Procedures) Act 1986.

Chronic constriction injury (CCI) rat model of neuropathic pain

The CCI of sciatic nerve was performed as previously described by Bennett and Xie (Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain:33:87-107, 1988). Animals were anaesthetised with a 2% isofluorane/02 mixture. The right hind thigh was shaved and swabbed with 1% iodine. Animals were then transferred to a homeothermic blanket for the duration of the procedure and anaesthesia maintained during surgery via a nose cone, The skin was cut along the line of the thighbone. The common sciatic nerve was exposed at the middle of the thigh by blunt dissection through biceps femoris. About 7mm of nerve was freed proximal to the sciatic trifurcation, by inserting forceps under the nerve and the nerve gently lifted out of the thigh. Suture was pulled under the nerve using forceps and tied in a simple knot until slight resistance was felt and then double knotted. The procedure was repeated until 4 ligatures (4-0 silk) were tied loosely around the nerve with approx 1mm spacing. The incision was closed in layers and the wound treated with topical antibiotics.

Streptozocin (STZ)-induced diabetes neuropathy in the rat Diabetes was induced by a single intraperitoneal injection of streptozotocin (50mg/kg) freshly dissolved in 0.9% sterile saline. Streptozotocin injection induces a reproducible mechanical allodynia within 3

weeks, lasting for at least 7 weeks (Chen and Pan, (Chen SR and Pan HL. Hypersensitivity of Spinothalamic Tract Neurons Associated With Diabetic Neuropathic Pain in Rats. J Neurophysiol 87: 2726-2733, 2002).

Assessment of static and dynamic allodvnia Static allodvnia.

Animals were habituated to wire bottom test cages prior to the assessment of allodynia. Static allodynia was evaluated by application of von Frey hairs (Stoelting, Wood Dale, Illinois, USA.) in ascending order of force (0.6, 1 , 1.4, 2, 4, 6, 8, 10, 15 and 26 grams) to the plantar surface of hind paws. Each von Frey hair was applied to the paw for a maximum of 6 sec, or until a withdrawal response occurred. Once a withdrawal response to a von Frey hair was established, the paw was re-tested, starting with the filament below the one that produced a withdrawal, and subsequently with the remaining filaments in descending force sequence until no withdrawal occurred. The highest force of 26g lifted the paw as well as eliciting a response, thus represented the cut off point. Each animal had both hind paws tested in this manner. The lowest amount of force required to elicit a response was recorded as paw withdrawal threshold (PWT) in grams. Static allodynia was defined as present if animals responded to a stimulus of, or less than, 4g, which is innocuous in naive rats (Field MJ, Bramwell S, Hughes J, Singh L. Detection of static and dynamic components of mechanical allodynia in rat models of neuropathic pain: are they signalled by distinct primary sensory neurones? Pain,1999;83:303-11).

Dynamic allodvnia

Dynamic allodynia was assessed by lightly stroking the plantar surface of the hind 'paw with a cotton bud. To avoid recording general motor activity, care was taken to perform this procedure in fully habituated rats that were not active. At least two measurements were taken at each time point, the mean of which represented the paw withdrawal latency (PWL). If no reaction was exhibited within 15 sec the procedure was terminated and animals were assigned this withdrawal time. A pain withdrawal response was often accompanied with repeated flinching or licking of the paw. Dynamic allodynia was considered to be present if animals responded to the cotton stimulus within 8 sec of commencing stroking (Field et al, 1999).

Nociceptive pain

The activity of a compound in the treatment of nociceptive pain may be measured according to the following test protocols.

Hotplate

Experimental Procedure: Male Sprague Dawley rats are placed on a hot plate (Ugo Basile, Italy) maintained at 55 ± 5 ⁰ C. The time between placement of the animal on the hot plate and occurrence of either licking of fore or hind paw, shaking or jumping off the surface is measured. Baseline

measurements will be made and animals reassessed following drug administration. The cut off time for hot plate latencies is set at 20 seconds to prevent tissue damage.

Ovariohysterectomy (OVX)

Experimental Procedure: Female Sprague Dawley rats are placed into an anaesthetic chamber and anaesthetised with a 2% isofiuorane / O ₂ mixture. During surgery, anaesthesia is maintained via a nose cone. OVX is performed via a midline incision (2cm in length) in the linea alba, whilst the animal is on a heat blanket. The ovarian ligaments and cervix are ligated with 5-0 silk, using a single clamp technique. The ovaries and uterus are then removed. The abdominal wall is closed using 4 simple interrupted sutures and the skin closed using 4 wound clips. Immediately after surgery animals are placed in individual plexiglass chambers. Once the animal has recovered from the anaesthetic the abdominal body postures are recorded in 30 min bins at various time points. Postures scored are humpback position, contraction of the muscle of the abdomen associated with inward movements of the hind limb, stretching of the body and squashing of the lower abdomen against the floor. Each of these behaviours is scored as one posture.

Brennan

Experimental Procedure: Male Sprague Dawley rats are placed into an anaesthetic chamber and anaesthetised with a 2% isofiuorane / O ₂ mixture. During surgery, anaesthesia is maintained via a nose cone. The plantar aspect of the right hind paw is cleaned with 50% ethanol. A 1cm long longitudinal incision is made with a number 11 blade through the skin and fascia of the plantar aspect of the foot, starting 0.5cm from the proximal edge of the heel and extending toward the toes. The plantaris muscle is elevated using forceps and incised longitudinally, the muscle origin and insertion remain intact. After haemostasis with gentle pressure, the skin is closed with two simple sutures of braided silk.

Mono-lodoacetate (MIA)-induced OA model

Male 6 weeks-old Sprague-Dawley (SD, Japan SLC or Charles River Japan) rats are anesthetized with pentobarbital. Injection site is shaved and cleaned with 70% ethanol. 25 μl of MIA solution or saline is injected in the right knee joint using a 29G needle. 7, 14, 19 and 20 days after the MIA injection, train rats to measure the weight bearing (WB) without their stress. 21 days after the MIA injection, the WB on two of each hind paw is measured and the WB deficit is calculated as in 10.2. Define the WB deficit value as "pre value". Arrange for experimental group evenly in consideration of pre value and prepre value. After the administration of test compounds or vehicle, the WB on two of each hind paw was measured.

Cancer pain model

These experiments used adult male C3H/HeN mice (Ninon SLC, Shizuoka, Japan). The mice were housed in accordance with National Institutes of Health guidelines in a vivarium maintained at 22 °C with a 12-hour alternating light-dark cycle, and were given food and water ad libitum. The sarcoma injection protocol used has been described. After induction of general anesthesia with an inhalation of isofluran (2%), a superficial incision was made in the skin overlying the patella, using Mora scissors. The patellar ligament was then cut, exposing the condyles of the distal femur. A 30-gauge needle was inserted at the level of the intercondylar notch and into the medullary canal to create an initial core pathway. After the initial core was made, a 29-gauge needle was used to make the final pathway into the bone. A 0.5-mm depression was then made using a half-round bur in a pneumatic dental high speed handpiece, to serve as mechanical retention for the dental resin plug. Then, 20 μl α-minimum essential media (Sigma; sham injection) or 20 μl media containing 1 XiO ⁵ 2472 osteolytic sarcoma cells (American Type Culture Collection, Rockville, Maryland; sarcoma injection) was injected using a 29-gauge needle and a .25 cc syringe. To prevent leakage of cells outside the bone, the injection site was closed with dental resin, followed by copious irrigation with filtered water. Wound closure was achieved using auto wound clips (Becton Dickinson, San Jose, California). Wound clips were removed at day 5 to prevent interference with behavioral testing.

Assessment of static and dynamic allodvnia

Static allodvnia.

Procedure as described above for neuropathic pain.

Dynamic allodvnia

Procedure as described above for neuropathic pain.

Radiant heat paw withdrawal

Experimental procedure: Thermal paw withdrawal is assessed using the rat plantar test (Ugo Basile, Italy) following a modified method of Hargreaves et al., 1988. Rats are habituated to the apparatus that consists of three individual perspex boxes on an elevated glass table. A mobile radiant heat source is located under the table and focused onto the hind paw and paw withdrawal latencies (PWL) are recorded. There is an automatic cut off point of 22.5 s to prevent tissue damage. PWL are taken 2-3 times for both hind paws of each animal, the mean of which represents baselines for right and left hind paws. The apparatus is calibrated to give a PWL of approximately 10 s.

Weight bearing

Experimental procedure: Animals are examined for hypersensitivity in the weight-bearing test, using an "incapacitance tester" (Linton Instruments, Diss, Norfolk, U.K.). Rats were positioned with their fore

limbs up on a perspex slope and hind limb weight distribution was measured via force transducers under each of the hind paws. Each animal is placed in the apparatus and the weight load exerted by the hind paws is noted. The difference in weight bearing is calculated by subtracting the ipsilateral (injured) paw from the contralateral paw (normal) and this constitutes the raw data.

Inflammatory pain

The activity of compound in the treatment of inflammatory pain may be measured according to the following test protocol.

CFA-induced weight bearing deficits in rats

Male 7-week-old SD rats are fasted overnight. CFA (300 μg of Mycobacterium Tuberculosis H37 RA (Difco Laboratories) in 100 μL of liquid paraffin (Wako)) is injected into the rat's right hind footpad. Two days after the administration of CFA, the changes in hind paw weight distribution between the left (ipsilateral) and the right (contralateral) limbs are measured as an index of pain by using Linton lncapacitance tester (Linton Instrumentation, UK). The test compound suspended in 0.1% MC (Wako) is administered orally in a volume of 1 mL per 100 g body weight. Each animal is placed in the apparatus and the weight load exerted by the hind paws is measured before, 1 , 2 and 4 hours after drug administration.

Carrageenin-induced mechanical hyperalgesia in rats

Male 4-week-old SD rats are fasted overnight. Hyperalgesia is induced by intraplantar injection of Lambda-carrageenin (0.1 ml of 1% w/v solution in saline, Zushikagaku). The test compound (1ml of 0.1% methylcellulose/100g body weight) is given orally at 5.5 hours after the carrageenin injection. The paw withdrawal threshold (gram) is measured by analgesimeter (Ugo Basile) at 3.5, 4.5, 6.5 and 7.5 hours after the carrageenin injection. (Randall LO. & Selitto I.J., Arch. int. Pharmacodyn. 111, 409-419, 1957)

Carraαeenan-lnduced Thermal Hyperalgesia (CITH) in the Rat

Thermal hyperalgesia was assessed using the rat plantar test (Ugo Basile, Comerio, Italy), according to a method modified by Hargreaves et al. (1988). Briefly, rats were habituated to the apparatus that consisted of three individual Perspex boxes on a glass table. A mobile radiant heat source was located under the table and focused onto the desired paw. Paw withdrawal latencies (PWLs) were recorded three times for both hind paws of each animal, the mean of which represented baseline for left and right hind paws. The apparatus was calibrated to give a PWL of approximately 10 s in naϊve rats. To prevent tissue damage of the plantar zone, a 22.5 sec cut-off was observed. Lambda carrageenan was injected intraplantarly (100 μl, 20 mg/ml) the right hind paw and baseline recordings of PWT were taken 2 hr post administration.

Visceral pain

The activity of a compound in the treatment of visceral pain may be measured according to the following test protocols.

Several models are available to determine if a compound is effective in treating disorders of the viscera. These models include a LPS model (Eutamene H et a/, J Pharmacol Exp Ther2000 295 (1):162-7), a TNBS model (Diop L. et al, Gastroenterology 1999, 116, 4(2): A986), a IBD model (Clemett D, Markham A, Drugs 2000 Apr;59(4):929-56), a pancreatic pain model (IsIa AM, Hosp Med 2000 Jun;61 (6):386-9) and a visceral non digestive pain model (Boucher M et al, J Urol 2000 Jul;164(1):203-8).

TNBS-induced chronic visceral allodvnia in rats

In this experimental model of colonic distension in awake rats, previous injection of trinitrobenzenesulfonic acid (TNBS) into the proximal colon lowered the visceral pain threshold.

Materials and methods: Male Sprague-Dawley rats are used. The animals are housed 3 per cage in a regulated environment (20 ± 1 °C, 50 ± 5 % humidity, with light 8:00 am to 8:00 pm). At day 0, under anesthesia (ketamine 80 mg/kg /.p.; acepromazine 12 mg/kg Lp.), the injection of TNBS (50 mg/kg in ethanol 30 %), or saline (1.5 ml/kg) for control rats, is performed into the proximal colon wall (1 cm from the cecum). After the surgery, animals are individually housed in polypropylene cages and kept in a regulated environment (20 ± 1°C, 50 ± 5 % humidity, with light 8:00 a.m. to 8:00 p.m.) during 7 days. At day 7 after TNBS administration, a balloon (5-6 cm length) is inserted by anus, and kept in position (tip of balloon 5 cm from the anus) by taping the catheter to the base of the tail. Oral administration of the test compound is performed 1 h before the colonic distension cycle: the balloon is progressively inflated by steps of 5 mm Hg (0.667 kPa), from 0 to 75 mm Hg, each step of inflation lasting 30 s. Each cycle of colonic distension is controlled by a standard barostat. The threshold (mm Hg) corresponds to the pressure which produced the first abdominal contraction, and the cycle of distension is then discontinued. The colonic threshold is determined after performance of four cycles of distension on the same animal.

LPS-induced rectal hypersensitivity in rats

Intraperitoneal injection of bacterial lipo-polysaccharide (LPS) has been shown to induce rectal hyperalgesia in awake rats.

Materials and methods: Animals are surgically prepared for electromyography: rats are anaesthetized by intraperitoneal injection of acepromazine (0.6 mg/kg) and ketamine (120 mg/kg). Three groups of three electrodes are implanted in the abdominal external oblique musculature, just superior to the inguinal ligament. Electrodes are exteriorized on the back of the neck and protected by a glass tube attached to

the skin. Animals are individually housed in polypropylene cages and kept in a temperature-controlled room (21 ⁰ C). Food (UAR pellets, Epinay, France) and water are provided ad libitum.

Electromyographic recordings begin five days after surgery. The electrical activity of abdominal striated muscles is recorded with an electroencephalograph machine (Mini VIII Alvar, Paris, France) using a short time constant (0.03 s) to remove low-frequency signals (< 3 Hz) and a paper speed of 3.6 cm/min. Spike bursts are recorded as an index of abdominal contractions.

Distension procedure: Rats are placed in plastic tunnels (6 cm diameter x 25 cm long), where they cannot move, escape, or turn around, in order to prevent damage to the balloon. Animals are accustomed to this procedure for four days before rectal distension in order to minimize stress reactions during experiments. The balloon used for distension is an arterial embolectomy catheter (Fogarty, Edwards Laboratories Inc.). Rectal distension is performed by insertion of the balloon (2 mm diameter x 2 cm long) into the rectum, at 1 cm from the anus, and catheter is fixed at the base of the tail. It is inflated progressively with tepid water by steps of 0.4 ml, from 0 to 1.2 ml, each step of inflation lasting 5 min. To detect possible leakage, the volume of water introduced in the balloon is checked by complete removal with a syringe at the end of the distension period.

Suitable auxiliary active agents for use in the combinations of the present invention include:

1) Naturally occurring or synthetic prostaglandins or esters thereof. Suitable prostaglandins for use herein include compounds such as alprostadil, prostaglandin E^prostaglandin E ₀ , 13, 14 - dihydroprosta glandin E ₁ , prostaglandin E ₂ , eprostinol, natural synthetic and semi-synthetic prostaglandins and derivatives thereof including those described in WO-00033825 and/or US

6,037,346 issued on 14th March 2000 all incorporated herein by reference, PGE ₀ , PGE ₁ , PGAi, PGB-i, PGF ₁ α, 19-hydroxy PGA ₁ , 19-hydroxy - PGB ₁ , PGE ₂ , PGB ₂ , 19-hydroxy-PGA ₂ , 19- hydroxy-PGB ₂ , PGE ₃ α, carboprost tromethamine dinoprost, tromethamine, dinoprostone, lipo prost, gemeprost, metenoprost, sulprostune, tiaprost and moxisylate;

2) α - adrenergic receptor antagonist compounds also known as α - adrenoceptors or α-receptors or α-blockers. Suitable compounds for use herein include: the α-adrenergic receptor blockers as described in PCT application WO99/30697 published on 14th June 1998, the disclosures of which relating to α-adrenergic receptors are incorporated herein by reference and include, selective ^-adrenoceptor or α ₂ -adrenoceptor blockers and non-selective adrenoceptor blockers, suitable α _r adrenoceptor blockers include: phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramin, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaraxan, yohimbine, rauwolfa alkaloids, Recordati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591, doxazosin, terazosin, abanoquil and prazosin; α ₂ -blocker blockers from US 6,037,346 [14th March 2000] dibenarnine, tolazoline, trimazosin and dibenarnine; α-adrenergic

receptors as described in US patents: 4,188,390; 4,026,894; 3,511,836; 4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381 ,009; 4,252,721 and 2,599,000 each of which is incorporated herein by reference; α ₂ -Adrenoceptor blockers include: clonidine, papaverine, papaverine hydrochloride, optionally in the presence of a cariotonic agent such as pirxamine;

3) NO-donor (NO-agonist) compounds. Suitable NO-donor compounds for use herein include organic nitrates, such as mono- di or tri-nitrates or organic nitrate esters including glyceryl trinitrate (also known as nitroglycerin), isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside (SNP), 3- morpholinosydnonimine molsidomine, S-nitroso- N-acetyl penicilliamine (SNAP) S-nitroso-N- glutathione (SNO-GLU), N-hydroxy - L-arginine, amylnitrate, linsidomine, linsidomine chlorohydrate, (SIN-1) S-nitroso - N-cysteine, diazenium diolates.(NONOates), 1 ,5- pentanedinitrate, L-arginene, ginseng, zizphi fructus, molsidomine, Re - 2047, nitrosylated maxisylyte derivatives such as NMI-678-11 and NMI-937 as described in published PCT application WO 0012075;

4) Potassium channel openers or modulators. Suitable potassium channel openers/modulators for use herein include nicorandil, cromokalim, levcromakalim, lemakalim, pinacidil, cliazoxide, minoxidil, charybdotoxin, glyburide, 4-amini pyridine, BaCI ₂ ;

5) Vasodilator agents. Suitable vasodilator agents for use herein include nimodepine, pinacidil, cyclandelate, isoxsuprine, chloroprumazine, , Rec 15/2739, trazodone;

6) Thromboxane A2 agonists;

7) CNS active agents;

8) Ergot alkoloids; Suitable ergot alkaloids are described in US patent 6,037,346 issued on 14th March 2000 and include acetergamine, brazergoline, bromerguride, cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride and terguride;

9) Compounds which modulate the action of natruretic factors in particular atrial naturetic factor (also known as atrial naturetic peptide), B type and C type naturetic factors such as inhibitors or neutral endopeptidase;

10) Compounds which inhibit angiotensin-converting enzyme such as enapril, and combined inhibitors of angiotensin-converting enzyme and neutral endopeptidase such as omapatrilat.

11 ) Angiotensin receptor antagonists such as losartan;

12) Substrates for NO-synthase, such as L-arginine;

13) Calcium channel blockers such as amlodipine;

14) Antagonists of endothelin receptors and inhibitors or endothelin-converting enzyme;

15) Cholesterol lowering agents such as statins (e.g. atorvastatin/ Lipitor- trade mark) and fibrates;

16) Antiplatelet and antithrombotic agents, e.g. tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin activating factor inhibitors;

17) Insulin sensitising agents such as rezulin and hypoglycaemic agents such as glipizide;

18) Acetylcholinesterase inhibitors such as donezipil;

19) Steroidal or non-steroidal anti-inflammatory agents;

20) Estrogen receptor modulators and/or estrogen agonists and/or estrogen antagonists, preferably raloxifene or lasofoxifene, (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5, 6,7,8- tetrahydronaphthalene-2-ol and pharmaceutically acceptable salts thereof the preparation of which is detailed in WO 96/21656;

21) A PDE inhibitor, more particularly a PDE 2, 3, 4, 5, 7 or 8 inhibitor, preferably PDE2 or PDE5 inhibitor and most preferably a PDE5 inhibitor (see hereinafter), said inhibitors preferably having an IC50 against the respective enzyme of less than 10OnM (with the proviso that PDE 3 and 4 inhibitors are only administered topically or by injection to the penis);

22) Vasoactive intestinal protein (VIP), VIP mimetic, VIP analogue, more particularly mediated by one or more of the VIP receptor subtypes VPAC1.VPAC or PACAP (pituitary adenylate cyclase activating peptide), one or more of a VIP receptor agonist or a VIP analogue (e.g. Ro-125-1553) or a VIP fragment, one or more of a α-adrenoceptor antagonist with VIP combination (e.g. Invicorp, Aviptadil);

23) A melanocortin receptor (particularly of the MC3 or MC4 subtype) agonist or modulator or melanocortin enhance, such as melanotan II, PT-14, PT-141 or compounds claimed in WO- 09964002, WO-00074679, WO-09955679, WO-00105401 , WO-00058361 , WO-00114879, WO- 00113112, WO-09954358;

24) A serotonin receptor agonist, antagonist or modulator, more particularly agonists, antagonists or modulators for 5HT1A (including VML 670), 5HT2A, 5HT2C, 5HT3 and/or 5HT6 receptors, including those described in WO-09902159, WO-00002550 and/or WO-00028993;

25) A testosterone replacement agent (including dehydroandrostendione), testosternone (Tostrelle), dihydrotestosterone or a testosterone implant;

26) Estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (i.e. as a combination), or estrogen and methyl testosterone hormone replacement therapy agent (e.g. HRT especially Premarin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, Elleste Solo,

Estring, Eastraderm TTS, Eastraderm Matrix, Dermestril, Premphase, Preempro, Prempak, Premique, Estratest, Estratest HS, Tibolone);

27) A modulator of transporters for noradrenaline, dopamine and/or serotonin, such as bupropion, GW-320659;

28) A purinergic receptor agonist and/or modulator;

29) A neurokinin (NK) receptor antagonist, including those described in WO-09964008;

30) An opioid receptor agonist, antagonist or modulator, preferably agonists for the ORL-1 receptor;

31) An agonist, antagonist or modulator for oxytocin receptors, preferably a selective oxytocin agonist or modulator;

32) Modulators of cannabinoid receptors;

33) A SEP inhibitor (SEPi), for instance a SEPi having an IC ₅₀ at less than 100 nanomolar, more preferably, at less than 50 nanomolar.

Preferably, the SEP inhibitors according to the present invention have greater than 30-fold, more preferably greater than 50-fold selectivity for SEP over neutral endopeptidase NEP EC 3.4.24.11 and angiotensin converting enzyme (ACE). Preferably the SEPi also has a greater than 100-fold selectivity over endothelin converting enzyme (ECE).

34) An antagonist or modulator for the NPY (particularly Y1 and Y5 subtype) receptor.

35) A Sex Hormone Binding Globulin antagonist or modulator that inhibits estrogens and/or androgens from being bound.

36) An arginase Il inhibitor,

37) An agonist, antagonist or modulator for vassopressin receptors, preferably selective for the Via receptor

38) A PDE5 Inhibitor. Suitable PDE5 inhibitors include:

5-[2-ethoxy-5-(4-methyl-1 -piperazinylsulphonyl)phenyl]-1 -methyl-3-n-propyl-1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), particularly sildenafil citrate; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylene dioxyphenyl) pyrazino[2',1':6,1]pyrido[3,4-b]indole-1 ,4-dione (IC-351 or tadalafil); 2-[2-ethoxy-5-(4-ethyl-piperazin-1 -yl-1 -sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5, 1 - f][1,2,4]triazin-4-one (vardenafil); 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azeti dinyl)- 2,6-dihydro-7H-pyrazolo[4,3-c/]pyrimidin-7-one; 5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1- isopropyl-3-azetidinyl)-2,6-dihydro-7/-/-pyrazolo[4,3-d]pyri midin-7-one ; 5-[2-ethoxy-5-(4- ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-meth oxyethyl]-2,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one; 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl )pyrrolidin-1-yl]-

N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide (TA-1790); 3-(1-methyl-7-oxo-3-propyl-6,7- dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrr olidin-2-yl)ethyl]-4- propoxybenzenesulfonamide (DA 8159) and pharmaceutically acceptable salts thereof.

39) A selective dopamine D4 receptor agonist such as 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1 H- benzimidazole (ABT724).

40) One or more selective serotonin reuptake inhibitors (SSRIs) such as dapoxetine, paroxetine, 3- [(dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzene sulfonamide (Example 28, WO 0172687), 3-[(dimethylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phen oxy] benzenesulfonamide (Example 12, WO 0218333), Λ/-methyl-Λ/-({3-[3-methyl-4- (methylsulfanyl)phenoxy]-4-pyridinyl}methyl)amine (Example 38, PCT Application no PCT/IB02/01032).

41) one or more NEP inhibitors, preferably wherein said NEP is EC 3.4.24.11 and more preferably wherein said NEP inhibitor is a selective inhibitor for EC ^' 3.4.24.11 , more preferably a selective NEP inhibitor is a selective inhibitor for EC 3.4.24.11 , which has an IC ₅₀ of less than 10OnM (e.g. ompatrilat, sampatrilat) suitable NEP inhibitor compounds are described in EP-A-1097719; IC50 values against NEP and ACE may be determined using methods described in published patent application EP1097719-A1 , paragraphs [0368] to [0376];

42) Melanocortin receptor agonists (e.g. Melanotan Il and PT141) and selective MC3 and MC4 agonists (e.g.THIQ).

43) Mono amine transport inhibitors, particularly Noradrenaline Re-uptake Inhibitors (NRIs) (e.g. Reboxetine).

By cross reference herein to compounds contained in patents and patent applications which can be used in accordance with invention, we mean the therapeutically active compounds as defined in the claims (in particular of claim 1) and the specific examples (all of which is incorporated herein by reference).

If a combination of active agents is administered, then they may be administered simultaneously, separately or sequentially.

The compounds of the formula (I) can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

Accordingly the present invention provides for a pharmaceutical composition comprising a compound of formula (I), and a pharmaceutically acceptable diluent or carrier.

For example, the compounds of the formula (I) can be administered orally, buccally or sublingual^ in the form of tablets; soft or hard capsules containing multi- or nano-particulates, liquids-, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.

Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of the formula (I), may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).

Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.

The compound of formula (I) may be water-soluble or insoluble. A water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes. Alternatively, the compound of formula (I) may be in the form of multiparticulate beads.

The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.

Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.

Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.

The compounds of the formula (I), can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecal^, intraventricular^, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. For such parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.

The compounds of formula (I), can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using

electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the active compound comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. ^'

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as I- leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1μg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 μl to 100μl. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

They may also be administered by the ocular route. For ophthalmic use, the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

For application topically to the skin, the compounds of the formula (I) can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds of the formula (I) may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug- cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma- cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A- 94/02518 and WO-A-98/55148.

Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions.

Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula I in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used:

CID optical rotation at 587nm.

Ac ₂ O acetic anhydride

APCI atmospheric pressure chemical ionisation

Arbacel® filter agent br broad

Boc te/f-butoxycarbonyl

Bu butyl

CDCI ₃ chloroform-d1

CD ₃ OD methanol-d4 δ chemical shift d doublet dd double doublet

DCM dichloromethane

DMF Λ/,Λ/-dimethylformamide

DMSO dimethylsulfoxide eq (molar) equivalents

ESI electrospray ionisation

Et ethyl

EtOAc ethyl acetate h hours

HCI hydrogen chloride

HPLC high performance liquid chromatography

HR M/S high resolution mass spectrum

IPA isopropylalcohol

KOAc potassium acetate m multiplet

Me methyl

MeCN acetonitrile

M/S mass spectrum min minutes

NMR nuclear magnetic resonance q quartet r.t. room temperature

S singlet sat saturated

t triplet td triplet of doublets

Tf trifluoromethanesulfonyl

TFA trifluoroacetic acid

THF tetrahydrofuran

TIPS triisopropylsilyl

TLC thin layer chromatography

¹ H Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million H downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCI ₃ , deuterochloroform; DMSO, dimethylsulfoxide. The abbreviation psi means pounds per square inch and LRMS means low resolution mass spectrometry. Where thin layer chromatography (TLC) has been used it refers to silica gel TLC using silica gel 60 F ₂₅₄ plates, R _f is the distance travelled by a compound divided by the distance travelled by the solvent front on a TLC plate.

Example 1

3-Azetidin-3-ylphenol hydrochloride H

Hydrogen chloride gas was bubbled through an ice-cold solution of the product of preparation 5 (88mg, 0.35mmol) in dichloromethane (5mL) for 15 minutes. The mixture was then warmed to room temperature and was stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue was triturated with diethyl ether to afford the title compound as a white solid in 82% yield, 54.1mg. ¹ H NMR (400MHz, CD ₃ OD) δ: 4.20(m, 3H), 4.35(m, 2H), 6.75(m, 2H), 6.85(d, 1 H), 7.20(t, 1H). MS APCI m/z 150 [MH] ⁺ Microanalysis: C ₉ H ₁₁ NO requires (%): C 56.42; H 6.66; N 7.31 ; found (%) C 56.21 ; H 6.38, N 7.30

Example 2

3-(1-Propylazetidin-3-vπphenol trifluoroacetate

The title compound was prepared from the product of preparation 8, using a similar method to that of preparation 5. The crude compound was purified by column chromatography on silica gel, eluting with dichloromethane: methanol, 100:0 to 95:5, to afford the desired product as a pale yellow oil in 80% yield. ¹ H NMR (400MHz, CDCI ₃ ) δ: 1.00(t, 3H), 1.65(m, 2H), 3.05(t, 2H), 3.35(bm, 2H), 4.00(m, 3H), 6.60(m, 2H), 6.80(d, 1H), 7.15(t, 1 H). MS APCI m/z 192 [MH] ⁺ Microanalysis: C ₁₂ H ₁₇ NOOF ₃ CO ₂ H 0.2 CH ₃ OH requires (%): C 54.72; H 6.08; N 4.49; found (%) C 54.50; H 6.25, N 4.52

Example 3

2-lodo-5-(1-propylazetidin-3-yl)phenol

The product of example 2 was dissolved in dichloromethane and washed with potassium carbonate solution. The organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the free amine. A sample of the amine (1.5g, 7.85mmol) was dissolved in dichloromethane (4OmL) and the solution was cooled to O ⁰ C. A solution of iodine (2.09g, 8.25mmol) in dichloromethane (5OmL) was then added dropwise over a period of 1 hour. The mixture was warmed to room temperature and stirring continued for 24 hours. The reaction was then washed with potassium carbonate solution (5OmL) and 10% aqueous sodium thiosulfate solution (8OmL), and the organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate:methanol:0.88 ammonia, 90:10:0 to 90:10:1 , followed by further purification by HPLC using a Phenomenex Luna C18 system, eluting with 1OmM ammonium acetate (aqueous): 1OmM ammonium acetate (methanolic), 50:50 to 26:74, to afford the title compound as a gum. ¹ H NMR (400MHz, CDCI ₃ ) δ: 0.98(t, 3H), 1.45(m, 2H), 2.55(t, 2H), 3.22(dd, 2H), 3.72(m, 1 H), 3.80(dd, 2H), 6.55(d, 1 H), 6.82(s, 1 H), 7.60(d, 1 H). MS APCI m/z 318 [MH] ⁺

Examples 4 and 5

A solution of the product of preparation 10 (1.98g, 10.34mmol) in glacial acetic acid (3OmL) was cooled to 1O ⁰ C. A solution of bromine (558μL, 10.85mmol) in glacial acetic acid (3OmL) was added dropwise and the mixture was stirred for 18 hours at room temperature. A few drops of 10% sodium thiosulfate solution were added and the mixture was then concentrated in vacuo. The residue was partitioned between dichloromethane and sodium hydrogen carbonate solution and the aqueous layer was extracted with dichloromethane (x2). The combined organic solution was then dried over magnesium sulfate and concentrated in vacuo to give a pale brown foam. The foam was purified by column chromatography on silica gel, eluting with dichloromethane: methanol, 100:0 to 90:10 to afford firstly the product of example 4 followed by the product of example 5.

Example 4

2,6-Dibromo-4-(1-propylazetidin-3-yl)phenol

¹ H NMR (400MHz, DMSO-Cf ₆ ) δ: 0.91 (t, 3H) ₁ 1.30(m, 2H), 2.38(m, 2H), 3.01(m, 2H), 3.75(m, 1 H), 3.82(m, 2H), 7.44(s, 2H) MS APCI m/z 348/350 [MH] ⁺ ; Microanalysis: C ₁₂ H ₁₅ NOBr ₂ requires (%): C 41.29; H 4.33; N 4.01; found (%) C 41.13; H 4.61 , N 3.71 ; yield: 70mg (3%)

Example 5

2-Bromo-4-(1-propylazetidin-3-vQphenol

¹ H NMR (400MHz, CDCI ₃ ) δ: 0.95(t, 3H), 1.45(m, 2H), 2.55(m, 2H), 3.22(m, 2H), 3.70(m, 1 H), 3.88(m, 2H), 6.90(d, 1H), 7.10(d, 1H), 7.39(s, 1H) MS APCI m/z 272 [MH] ⁺ ; Microanalysis: C ₁₂ H ₁₆ NOBr 0.4 DCM requires (%): C 48.99; H 5.57; N 4.61 ; found (%) C 48.94; H 5.60, N 4.59; yield: 450mg (16%)

Preparation 1 terf-Butyl S-ir^rifluoromethvDsulfonvnoxylazetidine-i-carboxylate

2,6-Lutidine (13.4mL, 115.61 mmol) was added to a solution of 1-boc-3-(hydroxy)azetidine (10g, 57.8mmol) in dichloromethane (10OmL) and the solution was cooled to - 3O ⁰ C. Trifluoromethane sulfonic anhydride (12.7mL, 60.69mmol) was then added dropwise and the mixture was stirred at -3O ⁰ C for 30 minutes. The mixture was then warmed to room temperature, diluted with dichloromethane (5OmL) and washed with 1M hydrochloric acid (10OmL) and water (10OmL). The organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a red oil in quantitative yield.

¹ H NMR (400MHz, CDCI ₃ ) δ: 1.45(s, 9H), 4.15(m, 2H), 4.32(m, 2H), 5.40(m, 1 H)

Preparation 2 ferf-Butyl 3-iodoazetidine-1 -carboxylate

Potassium iodide (55.11g, 332.04mmol) was added to an ice-cold solution of the product of preparation 1 (57.8mmol) in N,N-dimethylformamide (15OmL) and the mixture was stirred at room temperature for 18 hours. The mixture was then diluted with water (3OmL) and extracted with diethyl ether (2x200mL). The combined organic solution was washed with water (2x200mL), dried over magnesium sulfate and concentrated in vacuo to give an orange oil. The oil was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 95:5, to afford the title compound, 12.2g. ¹ H NMR (400MHz, CDCI ₃ ) δ: 1.43(s, 9H), 4.25(m, 2H), 4.45(m, 1 H), 4.65(m, 2H)

Preparation 3 terf-Butyl 3-r4-(benzyloxy)phenvllazetidine-1 -carboxvlate

Zinc dust (1.39g, 21.2mmol) was dried in a vacuum oven at 100 ⁰ C for 18 hours, purged with nitrogen and suspended with 1,2-dibromoethane (0.12mL, 1.41 mmol) in anhydrous N,N-dimethylformamide (25mL). The reaction mixture was heated at 7O ⁰ C for 10 minutes and then cooled to room temperature. Chlorotrimethyl silane (0.18mL, 1.41 mmol) was added dropwise and stirring continued for 1 hour. A solution of the product of preparation 2 (5g, 17.66mmol) in N,N-dimethylformamide (2OmL) was then added and the mixture was heated at 4O ⁰ C for 1 hour before a mixture of 1-(benzyloxy)-3-iodobenzene (5.75g, 18.55mmol), frys(dibenzylideneacetone) dipalladium(O) (324mg, 0.35mmol) and tri(2- furyl)phosphine (164mg, 0.71 mmol) in N,N-dimethylformamide (5OmL) was added. The reaction mixture was warmed to 7O ⁰ C and stirred for 4 hours. The mixture was then cooled to room temperature and partitioned between diethyl ether and saturated ammonium chloride solution. The aqueous layer was separated and extracted with further diethyl ether. The combined organic solution was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate, 95:5 to 90:10, then afforded the title compound as a yellow oil in 60% yield, 3.6g. ¹ H NMR (400MHz, CDCI ₃ ) δ: 1.45(s, 9H), 3.70(m, 1 H), 3.95(m, 2H), 4.30(dd, 2H), 5.05(s, 2H), 6.90(brm, 3H), 7.27(m, 1 H), 7.35(m, 1 H) 7.40(brm, 4H).

Preparation 4 te/f-Butvl 3-r4-(benzvloxvtohβnvllazetidine-1 -carboxvlate

The title compound was prepared from the product of preparation 2 and 1-(benzyloxy)-4-iodobenzene, using a method similar to that of preparation 3, as a white solid in 57% yield.

¹ H NMR (400MHz, CDCI ₃ ) δ: 1.45(s, 9H), 3.65(m, 1 H), 3.90(m, 2H), 4.30(m, 2H), 5.05(s, 2H), 6.95(d, 2H) ₁ 7.22(d, 2H), 7.29-7.45(m, 5H)

Preparation 5 te/f-Butyl 3-(3-hvdroχyphenyl)azetidine-1 -carboxylate

10% Pd/C (10mg) and ammonium formate (93mg, 1.48mmol) were added to a solution of the product of preparation 3 (100mg, 0.29mmol) in ethanol (5mL) and the mixture was heated under reflux for 4 hours. The reaction mixture was then cooled to room temperature and filtered through Arbocel®, washing through with ethanol. Concentration in vacuo of the filtrate afforded the title compound as a clear oil in quantitative yield, 88mg.

¹ H NMR (400MHz, CDCI ₃ ) δ: 1.47(s, 9H), 3.59(m, 1H), 4.00(dd, 2H), 4.35(dd, 2H), 6.75(m, 2H), 6.95(s,

1 H), 7.15(m, 1 H)

Preparation 6 3-[3-(Benzyloxv)phenvllazetidine trifluoroacetate

Trifluoroacetic acid (5OmL, 627mmol) was added dropwise to an ice-cold solution of the product of preparation 3 (10.63g, 31.35mmol) in dichloromethane (5OmL) and the mixture was stirred at O ⁰ C for 45 minutes. The mixture was allowed to warm to room temperature and stirring continued for a further 4

hours. The reaction mixture was then concentrated in vacuo to afford the title compound as a soiid in quantitative yield, 1Og.

¹ H NMR (400MHz, CDCI ₃ ) δ: 4.20-4.65(brm, 5H), 5.05(s, 2H), 6.95(m, 3H), 7.30-7.50(m, 6H) MS ES m/z 240 [MH] ⁺

Preparation 7 3-r4-(Benzvloxv)phenvπazetidine trifluoroacetate

The title compound was prepared from the product of preparation 4 and trifluoroacetic acid, using a similar method to that of preparation 6, as a white solid in quantitative yield.

¹ H NMR (400MHz, CDCI ₃ ) δ: 4.10-4.30(brm, 3H), 4.35-4.40(brm, 2H), 5.00(s, 2H), 7.00(d, 2H), 7.25(m, 2H), 7.30-7.40(brm, 5H) MS APCI m/z 240 [MH] ⁺

Preparation 8 3-r3-(Benzyloxy)phenvπ-1 -propylazetidine trifluoroacetate

Propionaldehyde (3.4mL, 47.01 mmol) was added to a solution of the product of preparation 6 (7.94g, 31.34mmol) in dichloromethane (5OmL) and the mixture was stirred for 5 minutes. The reaction mixture was cooled to O ⁰ C and sodium triacetoxyborohydride (9.96g, 47.01 mmol) was then added portionwise. The mixture was stirred for 18 hours as the temperature warmed to 25 ⁰ C. The reaction was quenched with water (5mL) and partitioned between dichloromethane and potassium carbonate solution. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give a brown oil. Purification of the oil by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 96:4, afforded the title compound as a yellow oil in 96% yield, 8.43g. ¹ H NMR (400MHz, CDCi ₃ ) δ: 1.00(t, 3H), 1.65(m, 2H), 3.00(m, 2H), 3,80(brm, 2H), 4.22(m, 1 H), 4.50(brm, 2H), 5.05(s, 2H), 6.80-6.95(brm, 3H), 7.25-7.45(m, 6H) MS ES m/z 282 [MH] ⁺

Preparation 9

3-f4-(Benzyloxy)phenyl1-1-propylazetidine

The title compound was prepared from the product of preparation 7 and propionaldehyde, using a method similar to that of preparation 8, as a yellow oil in 66% yield.

¹ H NMR (400MHz, CDCI ₃ ) δ: 0.90(t, 3H), 1.40(m, 2H), 2.45(t, 2H), 3.05(m, 2H) 3.65-3.80(brm, 3H), 5.05(s, 2H), 6.95(d, 2H), 7.20(d, 2H), 7.30-7.45(brm, 5H) MS APCI m/z 282 [MH] ⁺

Preparation 10

4-(1-Propylazetidin-3-yl)phenol

The title compound was prepared from the product of preparation 9, using a method similar to that of preparation 5. The crude compound was triturated with diethyl ether to afford the desired product as a cream solid in 95% yield. ¹ H NMR (400MHz, CDCI3) δ: 0.95(t, 3H), 1.42(m, 2H), 2.51(t, 2H), 3.09(m, 2H), 3.75(m, 1 H), 3.82(m, 2H), 6.78(d, 2H), 7.11(d, 2H) MS APCI m/z 192 [MH] ⁺ Microanalysis: C ₁₂ H ₁₇ NO 0.1H ₂ O requires (%): C 74.65; H 8.98; N 7.25; found (%) C 74.58; H 9.02, N 7.02