AZABICYCLOβ^.ilOCTANE DERIVATIVES

The present invention relates to novel compounds, processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as serotonin (5-HT), dopamine (DA) and norepinephrine (NE), reuptake inhibitors.

Brain tissue is constituted of neuronal cells which are able to communicate with each other via specific cellular structures named synapses. The exchange of signals between neurons in the synapses happens through neurochemical messengers named neurotransmitters, acting on specific target protein molecules, both post and pre-synaptic, referred to as receptors. Monoamines represent a family of small neurotransmitter molecules sharing common chemical features, and include serotonin (5-HT), dopamine (DA) and norepinephrine (NE).

Monoamine neurotransmitters are released into the synaptic cleft between neurons and interact with receptors present on the membrane of the target cells. The switch of the neurochemical signal occurs mainly by removal of the neurotransmitter molecules through other protein molecules referred to as monoamine transporters (SERT for 5-HT, DAT for DA and NET for NE). Transporters are able to bind neurotransmitter molecules and move them into the presynaptic terminals, this cellular mechanism referred to as re-uptake. Pharmacological inhibition of the re-uptake process can cause an increase of monoamine at synaptic level and as a consequence an enhancement of the physiological activity of neurotransmitters.

Serotonergic neurotransmission in the brain is mediated by a large family of receptors comprising both the G-protein coupled receptors and ligand-gated ion channels including 14 subtypes, and is involved in a vast variety of physiologic functions. Compounds endowed of inhibitory properties at the SERT are predicted to have the ability to treat in mammals, including humans, a variety of disorders associated with this neural system, for example eating disorders, major depression and mood disorders, obsessive compulsive disorders, panic disorders, alcoholism, pain, memory deficits and anxiety. Included among these disorders are disorders related to depression, such as pseudodementia or Ganser's syndrome, migraine pain, bulimia, obesity, pre-menstrual syndrome or late luteal phase syndrome, tobacco abuse, panic disorder, post-traumatic

syndrome, memory loss, dementia of ageing, acquired immunodeficiency syndrome dementia complex, memory dysfunction in ageing, social phobia, attention deficit hyperactivity disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism or trichotillomania.

Major depression is an affective disorder, or disorder of mood, characterized by several symptoms including feeling of profound sadness, worthlessness, despair and loss of interest in all pleasures (anhedonia), recurrent thoughts of death, mental slowing, loss of energy, an inability to take decision, often associated with anxiety and agitation. These symptoms are persistent and can range from mild to severe.

The pathophysiology of major depression is poorly understood being a multifactorial syndrome and, due to this, several neurotransmitter systems have been implicated. However, it is generally believed that the disorder stems from a decrease in the synaptic concentration of monoamine neurotransmitters, mainly NE and 5-HT, in critical brain areas, leading to the "monoamine theory" of depression.

Several lines of preclinical and clinical evidence indicate that an enhancement of serotonin-mediated neurotransmission might be effective in the treatment of major depression and actually the selective serotonin re-uptake inhibitors (SSRIs ) have come to dominate the therapy of depression over the last two decades. Fluoxetine, the first SSRI to be introduced, is the prototype of this group. Other members include Paroxetine, Sertraline, Fluvoxamine, Citalopram.

However, it is not clear exactly how these agents act to relieve depression. As with other classes of antidepressant, there is a lag of several weeks before the onset of the mood- elevating effect, despite the rapid blockade of the serotonin re-uptake. It is presumed that secondary adaptive changes must occur at serotonergic synapses after chronic administration of SSRIs i.e. down-regulation of release-regulating autoreceptors and increased neurotransmitter release. The delayed onset of anti-depressant effect is considered to be a serious drawback to currently used SSRIs. Moreover, although there is generally good tolerability of SSRIs, the elevation of 5-HT levels at central and peripheral synapses leads to stimulation of receptor subtypes like 5-HT _2C and 5-HT ₃ , which contributes to agitation and restless, along with gastrointestinal and sexual side-effects.

The success of the SSRIs rekindled interest in the development of selective norepinephrine re-uptake inhibitors (SNRIs) as potential antidepressants. A number of such compounds have been synthesized, e.g. Nisoxetine, Maprotiline, Tomoxetine and

Reboxetine. Furthermore, many compounds, including old tricyclic antidepressants, have a mixed NET and SERT inhibition profile, like lmipramine and Amitriptyline (with SERT potency > NET) and Desipramine, Nortriptyline, and Protriptyline (NET potency > SERT).

The pharmacological manipulation of the DAT can in principle have the ability to elevate DA levels in the mesolimbic system, reversing the anhedonia that is a core symptom of major depression. A DAT inhibition component, in combination with a blockade of SERT and NET, can also have the ability to improve the lack of motivation and attention and enhance cognitive deficits seen in depressed patients. On the other hand, blockade of DAT has to be carefully managed in order to avoid potential reinforcing effects and abuse liability. However compounds with DAT inhibition in their pharmacology, such as Dexmethylphenidate, Methylphenidate and Bupropion, have been successfully marketed. Clinical studies indicate that patients with poor response to SSRIs benefit from combination therapy with agents that enhance dopaminergic tone. As a result, compounds with a strong SERT inhibiting activity combined with a well balanced NET blockade and moderate DAT inhibiting activity may therefore provide a replacement for current combination therapies for treating unresponsive patients, providing greater efficacy and therapeutic flexibility with a more rapid onset of anti-depressant effect.

Due to their valuable DAT inhibition, the compounds of the present invention are considered useful for the treatment of Parkinsonism, depression, obesity, narcolepsy, drug addiction or misuse, including cocaine abuse, attention-deficit hyperactivity disorders, Gilles de Ia Tourettes disease and senile dementia. Dopamine re-uptake inhibitors enhance indirectly via the dopamine neurones the release of acetylcholine and are therefore also useful for the treatment of memory deficits, e.g. in Alzheimers disease, presenile dementia, memory dysfunction in ageing, and chronic fatigue syndrome. Noradrenaline re-uptake inhibitors are considered useful for enhancing attention, alertness, arousal, vigilance and for treating depression.

The object of the present invention is to provide novel compounds which are serotonin (5- HT), dopamine (DA) and norepinephrine (NE) re-uptake inhibitors.

In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof:

wherein

R ₁ is hydrogen or C _1-4 alkyl;

R ₂ is a group A or W, wherein

A is:

wherein p is 0, 1 , 2, 3, 4 or 5 and R ₅ is halogen, cyano or C _1-4 alkyl, each of them being the same or different; and

W is an α or β naphthyl group, optionally substituted by 1 or 2 groups R ₅ , each of them being the same or different; R ₃ is a group P:

,O>

>K^ R _c

wherein R ₆ is selected from the group consisting of hydrogen, C _1-4 alkyl, haloC _1-4 alkyl, C ₃ - ₆ cycloalkyl and C ₃ - ₆ cycloalkylCi _-3 alkyl, and n is 1 or 2; R ₄ is hydrogen, linear or branched C _1-4 alkyl, hydroxyl or C _1-2 alkoxy.

The term 'C _1-4 alkyl' refers to an alkyl group having from one to four carbon atoms, in all isomeric forms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert- butyl.

The term 'C ₃ -C ₆ cycloalkyl' as used herein means a non aromatic monocyclic hydrocarbon ring of 3 to 6 carbon atom such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, or

cyclohexyl; while unsaturated cycloalkyls include cyclopentenyl and cyclohexenyl, and the like.

The term 'C ₃ - ₆ cycloalkylCi _-3 alkyr as used herein means an alkyl having from one to three carbon atoms wherein one hydrogen atom is replaced with a C ₃ -C ₆ cycloalkyl group as above defined, for example methylcyclopropane.

The term 'halo Ci _-4 alkyl' as used herein means an alkyl group having one or more carbon atoms and wherein at least one hydrogen atom is replaced with halogen, preferably fluorine, such as for example a trifluoromethyl group and the like.

The term "halogen" and its abbreviation "halo" refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Where the term "halo" is used before another group, it indicates that the group is substituted by one or more halogen atoms.

The term "Ci _-2 alkoxy" refers to a linear chain or branched chain alkoxy (or "alkyloxy") group having from one or two carbon atoms, such as methoxy or ethoxy.

Any of these groups may be attached to the rest of the molecule at any suitable position.

In one embodiment, R ₁ is hydrogen or C _1-4 alkyl (for example methyl). In another embodiment, R ₁ is hydrogen.

In one embodiment, R ₂ is a group A or W. In another embodiment, R ₂ is a group A. In a further embodiment, R ₂ is a group W.

In one embodiment, the group W is a β naphthyl group.

In one embodiment, R ₄ is hydrogen, linear or branched C _1-4 alkyl, hydroxyl or C _1-2 alkoxy. In another embodiment, R ₄ is hydrogen. In a further embodiment, R ₄ is linear or branched C _{1- 4} alkyl or C _1-2 alkoxy.

In one embodiment, n is 1 or 2. In another embodiment, n is 1.

In one embodiment, R ₆ is hydrogen , C _1-4 alkyl, C ₃ - ₆ cycloalkyl or Cs-ecycloalkyld-salkyl. In another embodiment, R ₆ is hydrogen or In a further embodiment, R ₆ is hydrogen. In a still further embodiment, R ₆ is C _1-4 alkyl (for example methyl or ethyl).

Certain groups/substituents included in the present invention may be present as isomers. The present invention includes within its scope all such isomers, including racemates, enantiomers, tautomers and mixtures thereof.

Certain groups in compounds of formula (I) or in intermediates used to prepare them, may exist in one or more tautomeric forms. The present invention includes within its scope all such tautomeric forms, including mixtures.

As used herein, the term "salt" refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts and also includes pharmaceutically acceptable salts. Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a physiologically acceptable anion or cation.

Salts of compounds of formula (I) may be prepared through conventional methods and are included within the scope of the present invention.

Certain of the compounds of the invention may form acid or base addition salts with one or more equivalents of the acid or of the base. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compound of formula (I) using conventional methods.

Suitably pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, naphtoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic,

stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and p-toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and internally formed salts. Salts having a non-pharmaceutically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates of the compounds of the invention are within the scope of the invention. The compounds of formula (I) may readily be isolated in association with solvent molecules by crystallisation or evaporation of an appropriate solvent to give the corresponding solvates.

In addition, prodrugs are also included within the context of this invention. As used herein, the term "prodrug" means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130.

Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol, sulfhydryl and amine functional groups of the compounds of structure (I). Further, in the case of a carboxylic acid (-COOH), esters may be employed, such as methyl esters, ethyl esters, and the like. Esters may be active in their own right and /or be hydrolysable

under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.

Hereinafter, compounds of formula (I) and their pharmaceutically acceptable salts, solvates and prodrugs defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".

Furthermore, some of the crystalline forms of the compounds of the present invention, may exist as polymorphs, which are included in the present invention.

Those skilled in the art will appreciate that in the preparation of the compounds of the invention, it may be necessary and/or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions. Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, "Protective groups in organic synthesis" by T.W. Greene and P. G. M. Wuts (John Wiley & sons 1991 ) or "Protecting Groups" by PJ. Kocienski (Georg Thieme Verlag 1994). Examples of suitable amino protecting groups include acyl type protecting groups (e.g. formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (e.g. benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane protecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t- butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl). Examples of suitable oxygen protecting groups may include for example alky silyl groups, such as trimethylsilyl or tert- butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such as acetate.

The present invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ ^ C _l l, 123ι I and _| 125ι I.

Compounds of the present invention and non-pharmaceutically acceptable salts thereof that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ³ H, ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ H, and carbon-14, i.e., ¹⁴ C, isotopes are particularly preferred for their ease of

11 1 ft preparation and detectability. C and F isotopes are particularly useful in PET (positron emission tomography), and ¹²⁵ I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ² H, can 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, lsotopically labelled compounds of the present invention and non-pharmaceutically acceptable salts thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

In one embodiment, the compounds of the invention are selected from the list consisting of: (1 S,4S,5R/1 R,4R,5S)-5-(3,4-dichlorophenyl)-4-(methyloxy)-4-[(methyloxy) methyl]-2- azabicyclo[3.2.1]octane;

(1S,4R,5R/1 R,4S,5S)-5-(3,4-dichlorophenyl)-4-methyl-4-[(methyloxy)methy l]-2- azabicyclo[3.2.1]octane;

(1S,4R,5S/1 R,4S,5R)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2- azabicyclo[3.2.1]octane;

(1S,4R,5S)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2 -azabicyclo[3.2.1]octane;

(1 R,4S,5R)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2-azab icyclo[3.2.1]octane;

(1S,4S,5S/1 R,4R,5R)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2- azabicyclo[3.2.1]octane; (1S,4S,5S)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2-az abicyclo[3.2.1]octane;

(1 R,4R,5R)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2-azab icyclo[3.2.1]octane; and pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides a process for preparing a compound of formula (I) or a salt thereof as defined above.

Compounds of the invention may be prepared in a variety of ways. In the following reaction schemes and hereafter, unless otherwise stated, R-| to Rg, A, W P and n are as defined for compounds of formula (I).

Throughout the specification, general formulae are designated by Roman numerals (I), (II), (III), (IV) etc. Subsets of these general formulae are defined as (Ia), (Ib), (Ic) etc .... (IVa), (IVb), (IVc) etc.

Compounds of formula (Ia), i.e. compounds of formula (I) wherein R ₁ , is hydrogen, R ₃ is a group P wherein n is 1 and R ₄ is C _1-4 alkyl, compounds of formula (Ib), i.e. compounds of formula (I) wherein R ₁ is hydrogen, R ₃ is a group P wherein n is 1 and R ₄ is C _1-2 alkoxy, and compounds of formula (Ic), i.e. compounds of formula (I) wherein R ₁ and R ₄ are hydrogen and R ₃ is a group P wherein n is 1 ,may be prepared according to the following synthetic Scheme 1.

In Scheme 1 , for compounds of formula (Ilia) , (Na) and (lib), R4 is C _1-4 alkyl.

Scheme 1

Step a) means formation of compounds of formula (Vl) starting from compounds of formula VII by means of double bond formation through reaction with diethyl malonate. Step a) may be performed in an appropriate solvent, such as THF, in the presence of TiCI ₄ and CCI ₄ , at a temperature ranging from 0 ⁰ C to room temperature.

Step b) means formation of compound (V) starting from compounds of formula (Vl) by means of a Grignard reagent conjugate addition. Step b) may be performed in an appropriate solvent, such as THF, in presence of CuI at a temperature ranging from 0 ⁰ C to room temperature.

Step c) means formation of compound (IV) starting from compounds of formula (V) by deprotection of the amine and basic cyclisation. Deprotection may be performed in an appropriate solvent, such as DCM, in presence of an acid , such as Trifluoroacetic Acid,

at room temperature and cyclisation may be obtained by treatment with a base, such as triethylamine, at a temperature over 50 ⁰ C.

Step d) means formation of compound (lie) starting from compounds of formula (IV) by means of reduction and protection of the resulting amine. Reduction maybe performed by an appropriate reducing agent, such as borane, in an appropriate solvent, such as THF, at a temperature over 50 ⁰ C. Protection of the resulting amine may be perfomed with ditertbutylcarbonate in an appropriate mixture of solvents , such as THF/water.

Step e) means formation of compound (Ic) starting from compounds of formula (lie) by means of a treatment with an alkylating agent, such as methyl iodide, in presence of an appropriate base, such as NaH, in a opportune solvent, such as THF. Deprotection my be obtained with appropriate acid, such as trifluoroacetic acid..

Step f) means formation of compounds (Ilia) and (NIb) starting from compounds of formula (IV) by means of a treatment with an alkylating agent, such as methyl iodide, in presence of an appropriate base, such as NaH, in a solvent, such as THF.

Step g) means formation of compounds (Na) and (lib) starting from compounds of formula (Ilia) and (NIb) by reduction, dealkylation of the resulting amine and final protection.

Reduction may be performed by an appropriate reducing agent, such as borane , in a solvent , such as THF, at a temperature over 50 ⁰ C. Dealkylation may be obtained by the use of an appropriate dealkylating agent, such as ACE-CI, followed by treatment with methanol at a temperature over 90°C. Protection may be obtained by treatment with ditertbutylcarbonate.

Step h) means formation of compounds (Ia) and (Ib) starting from compounds of formula (Na) and (lib) by means of a treatment with an alkylating agent, such as methyl iodide, in presence of an appropriate base, such as NaH, in a solvent, such as THF. Deprotection may be obtained with appropriate acid, such as trifluoroacetic acid..

Compounds of formula (Ig), i.e. compounds of formula (I) wherein R ₁ and R ₄ are hydrogen and R ₃ is a group P wherein n is 2, may be prepared according to the following synthetic Scheme 2.

Scheme 2

Step n) means formation of compound (XIII) starting from compounds of formula (IV) by means of reduction and protection of the resulting amine. Reduction may be performed by an appropriate reducing agent, such as borane, in an appropriate solvent, such as THF, at a temperature over 50 ⁰ C. Protection of the resulting amine may be perfomed with ditertbutylcarbonate in an appropriate mixture of solvents , such as THF/water.

Step o) means formation of compound (XII) starting from compounds of formula (XIII) by means of oxidation of the alcholic moiety. Step o) may be performed by the use of an appropriate oxidant agent such as Dess-Martin periodinane, in an appropriate solvent, such as dichloromethane.

Step p) means formation of compound (Xl) starting from compounds of formula (XII) by means a double bond formation through reaction with (methoxymethyl)triphenylphosphonium chloride in presence of a base , such as potassium tertbutoxide, in an opportune solvent, such as THF.

Step q) means formation of compound (X) starting from compounds of formula (Xl) by means reduction of the double bond. Step q) may be performed with hydrogen at appropriate pressure, such as 1 bar, in presence of a catalyst, such as Pd/C.

Step r) means formation of compound (Ig) starting from compounds of formula (X) by treatment with an appropriate acid, such as trifluoroacetic acid, in an opportune solvent such as dichloromethane.

Compounds of formula (Ih), i.e. compounds of formula (I) wherein R ₁ is hydrogen, R ₄ is is and R3 is a group P wherein n is 2, may be prepared according to the following synthetic Scheme 3.

Scheme 3

J

€^=

(Ih)

Step s) means formation of compound (XIX) starting from compounds of formula (IX) by means of double bond formation through reaction with trimethylsilylchloride. Step s) may be performed in an appropriate solvent, such as THF, in the presence of a base, such as LiHMDS at a temperature below 0 ⁰ C.

Step t) means formation of compound (XVIII) starting from compounds of formula (XIX) by means of epoxide formation through reaction with metachloroperbenzoic acid. Step t) may be performed in an appropriate solvent, such as DCM.

Step u) means formation of compound (XVII) starting from compounds of formula (XVIII) by means of epoxide opening through reaction with sodium hydroxide. Step u) may be performed in an appropriate solvent, such as THF.

Step v) means formation of compound (XVI) starting from compounds of formula (XVII) by means a double bond formation through reaction with an appropriate agent, such as (methoxymethyl)triphenylphosphonium chloride, in presence of a base , such as potassium tertbutoxide, in an opportune solvent, such as THF.

Step z) means formation of compounds (XV) starting from compounds of formula (XVI) by means of a treatment with an alkylating agent, such as methyl iodide, in presence of an appropriate base, such as NaH, in a opportune solvent, such as THF.

Step j) means formation of compound (XIV) starting from compounds of formula (XV) by means reduction of the double bond. Step j) may be performed with hydrogen at appropriate pressure, such as 1 bar, in presence of a catalyst, such as Pd/C.

Step k) means formation of compound (Ih) starting from compounds of formula (XIV) by treatment with an appropriate acid, such as trifluoroacetic acid, in an opportune solvent such as dichloromethane.

Compounds of formula (Im), i.e. compounds of formula (I) wherein R ₁ is hydrogen, R ₄ is is linear or branched and R3 is a group P wherein n is 2, may be prepared according to the following synthetic Scheme 4.

Scheme 4

Step x) means formation of compounds (XXII) starting from compounds of formula (IX) by means of a treatment with an alkylating agent, such as methyl iodide, in presence of an appropriate base, such as NaH, in a opportune solvent, such as THF

Step y) means formation of compound (XXI) starting from compounds of formula (XXIII) by means a double bond formation through reaction with an appropriate reagent, such as (methoxymethyl)triphenylphosphonium chloride, in presence of a base , such as potassium tertbutoxide, in an opportune solvent, such as THF.

Step i) means formation of compound (XX) starting from compounds of formula (XXI) by means reduction of the double bond. Step i) may be performed with hydrogen at appropriate pressure, such as 1 bar, in presence of a catalyst, such as Pd/C.

Step ii) means formation of compound (Im) starting from compounds of formula (XX) by treatment with an appropriate acid, such as trifluoroacetic acid, in an opportune solvent such as dichloromethane.

Compounds of formula (Id), i.e. compounds of formula (I) or subsets thereof wherein R ₁ is ma be prepared according to Scheme 5 starting from compounds of formula (Ie), i.e. compounds of formula (I) or subsets thereof wherein R ₁ is hydrogen, by means of nitrogen alkylation with the appropriate alkylating agent through procedures well known in the art.

Scheme 5

When a specific enantiomer or diastereoisomer of a compound of formula (I) or salts thereof, is required, this may be obtained for example by resolution of a corresponding enantiomeric or diastereoisomeric mixture using conventional methods.

Thus, for example, specific enantiomers or diastereoisomers of the compounds may be obtained from the corresponding enantiomeric or diastereoisomeric mixture using chiral chromatographic methods such as for example chiral HPLC.

Alternatively, specific enantiomers or diastereoisomers of the compounds may be obtained from the corresponding enantiomeric or diastereoisomeric mixture using chiral crystallization methods such as precipitation with chiral acids.

Furthermore a specific enantiomer or diastereoisomer of a compound of the invention may be synthesised from the appropriate optically active intermediate using any of the general processes described herein. Alternatively, a specific enantiomer or diastereoisomer of a compound the invention may be synthesised from the appropriate stereochemical^ enriched intermediate using any of

the general processes described herein and by combining it with any of the conventional resolution methods above described.

Optically active intermediates or stereochemical^ enriched intermediates, may be generated by resolution of a corresponding enantiomeric or diastereosiomeric mixtures using conventional methods, or by performance of stereoselective reactions or by combining different resolution techniques.

Also specific enantiomers or diastereoisomers of the compounds may be obtained by combining conventional methods above described.

The compounds of the present invention may be useful in the treatment of disorders or diseases responsive to the monoamine neurotransmitter re-uptake inhibiting activity of the compounds. This activity of the compounds of the invention can make them useful in the treatment of Parkinsonism, depression, eating disorders, sleep disorders, substance related disorders, attention-deficit hyperactivity disorders, anxiety disorders, cognition impairment, sexual dysfunctions, obsessive compulsive spectrum disorders, Gilles de Ia Tourettes disease and senile dementia, as well as other disorders sensitive to the monoamine neurotransmitter re-uptake-inhibiting activity of the compounds.

Within the context of the present invention, the terms describing some indications used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.

The term "depression" includes:

Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (31 1 ); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major

Depressive-like Episode, With Manic Features and With Mixed Features), Substance-

Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90): Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80);

The term "anxiety disorders" includes:

Anxiety disorders including Panic Attack; Panic Disorder including Panic Disorder without Agoraphobia (300.01 ) and Panic Disorder with Agoraphobia (300.21 ); Agoraphobia; Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29, formerly Simple Phobia) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type), Social Phobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81 ), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder, Separation Anxiety Disorder (309.21 ), Adjustment Disorders with Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified (300.00):

The term "substance related disorder" includes:

Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced Sexual Dysfunction, Substance- Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol- Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9); Amphetamine (or Amphetamine-I_ike)-Related Disorders such as Amphetamine

Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89),

Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine- Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine- Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9); Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine- Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis-Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis-Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine- Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9); Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9); Inhalant-Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant- Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9); Nicotine-Related Disorders such as Nicotine Dependence (305.1 ), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9); Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-lnduced Psychotic Disorder, Opioid-lnduced Mood Disorder, Opioid-lnduced Sexual Dysfunction, Opioid-lnduced Sleep Disorder and Opioid- Related Disorder Not Otherwise Specified (292.9); Phencyclidine (or Phencyclidine-Like)- Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine-lnduced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine-lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not

Otherwise Specified (292.9); Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such

as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified (292.9); Polysubstance- Related Disorder such as Polysubstance Dependence (304.80); and Other (or Unknown) Substance-Related Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide;

The term "Sleep disorder" includes:

Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type;

The term "eating disorder" include:

Eating disorders such as Anorexia Nervosa (307.1 ) including the subtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; Binge Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50):

The term "Attention-Deficit/Hyperactivity Disorder" includes:

Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81 ), Adolescent- Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23);

The term "Cognition impairment" includes:

Cognition impairment including cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease;

The term "Sexual dysfunctions" includes:

Sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and Sexual Aversion Disorder (302.79); sexual arousal disorders such as Female Sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder

(302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia

(302.76) and Vaginismus (306.51 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89),

Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84), Transvestic

Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and

Gender Identity Disorder in Adolescents or Adults (302.85); and Sexual Disorder Not Otherwise Specified (302.9);

The term "Obsessive compulsive spectrum disorder" includes:

Obsessive compulsive spectrum disorder including Obsessive compulsive disorders (300.3), somatoform disorders including body dysmorphic disorder (300.7) and hyperchondriasis (300.7), bulimia nervosa (307.51 ), anorexia nervosa (307.1 ), eating

disorders not elsewhere classified (307.50) such as binge eating, impulse control disorders not elsewhere classified (including intermitted explosive disorder (312.34), compulsive buying or shopping, repetitive self-mutilation, onychophagia, psychogenic excoriation, kleptomania (312.32), pathological gambling (312.31 ), trichotillomania (312.39) and internet addiction), paraphilia (302.70) and nonparaphilic sexual addictions, Sydeham's chorea, torticollis, autistic disorders (299.0), compulsive hoarding, and movement disorders, including Tourette's syndrome (307.23).

All of the various forms and sub-forms of the disorders mentioned herein are contemplated as part of the present invention.

In an embodiment, compounds of the invention may be useful as analgesics. For example they may be useful in the treatment of chronic inflammatory pain (e.g. pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis); musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.

Compounds of the invention may be useful in the treatment of neuropathic pain. Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. These conditions are difficult to treat and although several drugs are known to have limited efficacy, complete pain control is rarely achieved. The symptoms of neuropathic pain are incredibly heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and

dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).

Compounds of the invention may also be useful in the amelioration of inflammatory disorders, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD); gastrointestinal tract disorders (e.g. aphthous ulcer, Crohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, inflammatory bowel disease, gastroesophageal reflux disease); other conditions with an inflammatory component such as migraine, multiple sclerosis, myocardial ischemia.

In one embodiment, compounds of the invention are useful in the treatment of depression and anxiety disorders.

In another embodiment, compounds of the invention are useful in the treatment of depression.

"Treatment" includes prophylaxis, where this is appropriate for the relevant condition(s).

In an alternative or further aspect there is provided a method for the treatment of a mammal, including man, in particular in the treatment of disorders or diseases responsive to the monoamine neurotransmitter re-uptake inhibiting activity of the compounds, comprising administration of an effective amount of a compound of the invention.

In one embodiment, the invention provides a method of treating a condition for which inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE), is beneficial, which comprises administering to a mammal (e.g. human) in need thereof an effective amount of a compound of the invention.

In another aspect, the invention provides a compound of the invention for use in therapy.

In a further embodiment, the invention provides a compound of the invention for use in the treatment of a condition in a mammal for which inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) is beneficial.

In one aspect, the invention provides the use of compounds of the invention, for the manufacture of a medicament for the treatment of disorders or diseases responsive to monoamine neurotransmitter re-uptake inhibiting activity.

In one embodiment, the invention provides the use of a compound of a compound of the invention in the manufacture of a medicament for the treatment of a condition in a mammal for which inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) is beneficial.

The compounds of the invention may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of the invention together with a further therapeutic agent.

The compounds of the invention may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).

The compounds of the invention may be used in combination with antidepressants to treat or prevent depression and mood disorders.

The compounds of the invention may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilisers; ii) antipsychotics; and iii) antidepressants.

The compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.

The compounds of the invention may be used in combination with the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; and ii) bupropion.

The compounds of the invention may be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; and iii) Opioid receptor antagonists for example naltrexone.

The compounds of the invention may be used in combination with the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; and iii) vasodilatory antihypertensives for example lofexidine.

The compounds of the invention may be used in combination with the following agents to treat or prevent sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita and phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate and chlormethiazole.

The compounds of the invention may be used in combination with the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; and v) premenstral agents for example pyridoxine and progesterones.

The compounds of the invention may be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; and vii) premenstral agents.

The compounds of the invention may be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulants for example methylphenidate, amphetamine formulations and pemoline.

The compounds of the invention may be used in combination with the following agents to treat or prevent ADHD: i) stimulants for example methylphenidate, amphetamine formulations and pemoline; and ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).

The compounds of the invention may be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; and iv) anxiolytics.

The compounds of the invention may be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil and sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine and vii) 5-HT1A agonists, for example flibanserine.

The compounds of the invention may be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and in addition an estrogen agonist such as estradiol.

Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone and amisulpride).

Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and

tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).

Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.

Anxiolytics include benzodiazepines such as alprazolam and lorazepam.

For use in medicine, the compounds of the present invention are usually administered as a standard pharmaceutical composition. The present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of the invention and a pharmaceutically (i.e physiologically) acceptable carrier. The pharmaceutical composition can be for use in the treatment of any of the conditions described herein.

The compounds of the invention may be administered by any convenient method, for example by oral, parenteral (e.g. intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.

The compounds of the invention which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example

aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluoro- chlorohydrocarbon. The aerosol dosage forms can also take the form of a pump- atomiser.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

Compositions suitable for transdermal administration include ointments, gels and patches.

In one embodiment, the composition is in unit dose form such as a tablet, capsule or ampoule.

Each dosage unit for oral administration contains for example from 0.5 to 250 mg (and for parenteral administration contains for example from 0.05 to 25 mg) of a compound of the invention calculated as the free base.

The pharmaceutically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 500 mg, for example between 1 mg and 400 mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, for example between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a salt thereof calculated as the free base, the compound being administered 1 to 4 times per day, for example 1 to 2 time a day. In one embodiment, the compound of the invention may be administered once a day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

For oral administration a typical dose may be in the range of 1 to 200 mg per day, for example 60 to 200 mg per day.

When a compound of the invention or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone.

Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.

The invention is also directed to a novel kit-of-parts that is suitable for use in the treatment of disorders as above defined comprising a first dosage form comprising a

compound of the invention and a second dosage form comprising another therapeutic agent, for simultaneous, separate or sequential administration.

When administration is sequential, either the compound of the invention or the second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

Biological Assays

Cell biology a) Generation of stable LLCPK cell lines expressing hSERT, hNET, and hDAT

Stable cell line expressing human serotonin transporter (hSERT) may be created by transfecting Lewis Lung Carcinoma Porcine tubule Kidney (LLC-PK1 or LLCPK) cells with hSERT cloned into the mammalian expression vector pCDNA3.1 Hygro(+).

Stable cell line expressing human norepinephrine transporter (hNET) may be created by transfecting LLCPK cells with hNET cloned into the mammalian expression vector pRC/CMV. Stable cell line expressing human dopamine transporter (hDAT) may be created by transfecting LLCPK cells with hDAT cloned into the mammalian expression vector pDESTCDNA3.1.

One example of reference procedure for transfecting LLCPK cells with hDAT, hSERT and hNET may be found in H. Gu, S. C. Wall and G. Rudnick, J. Biol. Chem. (1994) 269 : 7124-7130.

Each cell line is cultured independently in Dulbecco's modified Eagle's medium (DMEM) containing 10% of Foetal Bovine Serum (FBS) supplemented with 400 μg/ml hygromicin

(hSERT) or geneticin at 500 μg/ml (hNET) or at 1000 μg/ml (hDAT). Cells are maintained at 37°C in a humidified environment containing 5% CO2 in air.

b) Generation of BacMam viruses for the expression of hSERT, hNET, and hDAT in mammalian cells

Membranes for the SPA-binding assays are produced by HEK-293F cell infection with BacMam viruses generated for each single human SERT, NET, and DAT transporter. hSERT and hDAT are cloned into pFBMRfA vector whereas hNET is cloned into pFASTBacMami vector. The generation and use of BacMam viruses is described in Condreay JP et al, Proc. Natl. Acad. Sci. USA, 1999, 96:127-132 and Hassan NJ et al, Protein Expression and Purification, 47(2): 591-598, 2006.

Affinity to the human transporters SERT, NET and DAT

The affinities of the compounds of the invention for the human serotonin transporter (SERT), human norepinephrine transporter (NET) and for the human dopamine transporter (DAT) may be determined by one of the assays described below. Such affinity is typically calculated from the IC ₅₀ obtained in competition experiments as the concentration of a compound necessary to displace 50% of the radiolabeled ligand from the transporter, and is reported as a "K," value calculated by the following equation: κ _ IC ₅₀

¹ 1 + L / K _D where L = radioligand and K ₀ = affinity of radioligand for transporter (Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973). In the context of the present invention pKi values (corresponding to the antilogarithm of Ki) are used instead of Ki; pKi results are only estimated to be accurate to about 0.3-0.5.

a) Filtration binding assay on membranes form hSERT, hNET, and hDAT LLCPK cell lines

• Membrane preparation hSERT-LLCPK or hDAT-LLCPK or hNET-LLCPK cell lines are used for the membrane preparations for radioligand binding assays. Each cell line is cultured independently in Dulbecco's modified Eagle's medium (DMEM) containing 10% of Foetal Bovine Serum (FBS) supplemented with 400 μg/ml hygromicin (hSERT) or geneticin at 500 μg/ml (hNET) or at 1000 μg/ml (hDAT).When cells are at 70-80% of confluence, the culture medium is removed and the cells harvested with phosphate buffered saline (PBS) containing 5 mM EDTA. Cell suspension is centrifuged at 90Og for 5 minutes at 4 ⁰ C. The resultant pellets are re-suspended in 30-50 volumes of Assay Buffer (5OmM Tris pH 7.7

containing 12OmM NaCI, 5mM KCI, 10μM pargyline and 0.1% ascorbic acid) and homogenized using a glass-teflon Potter homogeniser and centrifuged at 4800Og for 20 minutes at 4 ⁰ C. The resultant membrane pellets are re-suspended in the same volume of Assay Buffer, incubated for 20 minutes at 37 ⁰ C and centrifuged as before at 4800Og. The final protein concentration for each preparation is adjusted to give approximately 480μg protein/ml for hSERT-LLCPK, hDAT-LLCPK and hNET-LLCPK, as determined by the Bio- Rad Protein Assay kit. Membranes are stored at -80 ⁰ C as 1 ml aliquots until required.

• Filtration assay protocol for hSERT, hNET, and hDAT General references for monoamine transporters filtration binding assay may be: Michael J. Owens, et al, Neurotrasmitter receptor and transporter binding profile of antidepressants and their metabolites, JPET, 283:1305-1322, 1997; Per Allard, Jan O. Marcusson, Svate B. Ross, [3H]WIN-35,428 binding in the human brain, Brain Res., 706. -347-350, 1996. The affinity of the compounds of the invention to bind the re-uptake site of SERT may be assessed using [3|H]citalopram filtration binding assay performed on hSERT-LLCPK cell membranes. In details, competition binding assay is conducted in deep-well 96 well plate (1 ml, NUNC, cod.260252) in a total volume of 400μl, with each concentration in duplicate. 4μl of test compound (100X solution in neat DMSO as 7 point curve ranging from 10 ^"6 to 10 ^"12 M, final concentration) or DMSO (to define total binding) or a final concentration of 10μM fluoxetine in DMSO (to define non-specific binding, NSB) are added to wells; after this, 200μl of [N-Methyl- ³ H]citalopram (Amersham Biosciences, 80 Ci/mmol) at the final concentration of 0.25nM in Assay Buffer, is added to all wells and finally the reaction is started by adding 200μl/well of membranes diluted 1 :80 in Assay Buffer at concentration of about 2.5μg/well of protein. The reaction is carried out at room temperature for 2 hours and then stopped by rapid filtration through GF/B Unifilter 96-filterplate (Perkin-Elmer) pre-soaked in 0.5% polyethylenimmine (PEI) using a Perkin-Elmer FilterMat-196 harvester. Filterplate is washed 3 times with 1 ml/well ice-cold 0.9% NaCI solution. The plate is dried in an oven for 60 min at 50 ⁰ C then opaque bottom-seal is placed on the underside of the plate and 50μl of Microscint 20 (Perkin-Elmer) added to each well. Plate is sealed with a TopSeal and the radioactivity in the samples is counted for 4 min using TopCount liquid scintillation counter (Packard-Perkin-Elmer) and recorded as counts per minute (CPM). Competition binding assay for hNET may be conducted essentially as previously reported for hSERT in 96 well format and in a final assay volume of 400μl, except for the use of

hNET-LLCPK cell membranes (1 :40 dilution i.e. 4.8μg of protein/well) and [ ³ H]nisoxetine as radioligand (1.5nM [N-methyl- ³ H]nisoxetine, Amersham Biosciences, 84 Ci/mmol). 10μM desipramine is used for NSB.

Competition binding assay for hDAT may be conducted essentially as previously reported for hSERT and hNET in 96 well format and in a final assay volume of 400μl, except for the use of hDAT-LLCPK cell membranes (1 :20 i.e. 9.6μg of protein/well) and [ ³ H]WIN- 35,428 as radioligand (1OnM [N-Methyl- ³ H]WIN-35,428, Perkin Elmer, 85.6 Ci/mmol). Furthermore, 10μM GBR-12909 is used for NSB and the incubation time of the binding reaction is 1 hour at room temperature.

b) Scintillation Proximity Assay (SPA) for human DAT, NET and SERT binding

• Transduction of HEK-293F cells with hSERT/hDAT/hNET BacMam viruses

The HEK-293F suspension cell line (Invitrogen) is routinely grown in 293_Freestyle Expression media (Invitrogen) in shake flask suspension culture. The culture is transduced with the appropriate transporter BacMam at a MOI (multiplicity of infection) of 100 virus particles per cell and incubated for 48hrs at 37 ⁰ C, 5% CO ₂ in air, shaken at 90rpm in a humidified shaker incubator. The culture is then harvested by centrifugation at 100Og, 4 ⁰ C, for 10 minutes and the cell pellet stored at -8O ⁰ C until required.

• Preparation of BacMam hSERT/hDAT/hNET-HEL293F cell membranes

Transduced cell pellets are re-suspended to 10x volume with buffer-A (5OmM HEPES, 1 mM EDTA, 1 mM leupeptin, 25ug/ml_ bacitracin, 1 mM phenylmethylsulfonylfluoride, PMSF, 2μM pepstatin A, pH 7.7) and homogenised with 2x 15 second bursts in a glass Waring blender. The homogenate is then centrifuged for 20 minutes at 50Og. Following this, the supernatant is pooled and centrifuged at 13,00Og for 30 minutes. Pellets are then re-suspended to 4x original pellet volume with buffer-B (5OmM TRIS pH 7.4, 13OmM NaCI) and forced through a 0.8mm needle to give a homogeneous suspension. Membrane aliquots are stored at -8O ⁰ C until required. The protein concentration is quantified by Bradford assay.

• SPA-binding assay protocol for hSERT, hNET, and hDAT

The affinity of the compounds of the invention to the hSERT, hNET or hDAT can be also assessed by using the [ ³ H]citalopram, [ ³ H]nisoxetine or [ ³ H]WI N-35, 428 binding assays with the SPA technology on BacMam-recombinant human SERT, NET and DAT membranes produced as described before. With the SPA technology (GE Healthcare,

Amersham) only transporter-bound radioactivity can elicit bead excitation thus no separation of the bound/ unbound radioligand is required.

The protocol for hSERT binding SPA is based on Trilux beta-counter (Wallac, Perkin- Elmer). Briefly, 0.5μl_ of test compound in neat DMSO (or 1 μM fluoxetine as positive control) is added by 50μl_ of the SPA mixture, containing 2mg/ml_ SPA beads (Amersham RPNQ0001 ), 4μg/ml_ hSERT Bacmam membranes, 0.01 % pluronic F-127, 2.5nM [ ³ H]citalopram in the assay buffer (2OmM HEPES, 145mM NaCI, 5mM KCI, pH 7.3). Incubation are performed at room temperature for at least 2 hours. Counts are stable and could be read up to 3 days. Alternatively, hDAT hNET and hSERT SPA-binding assays are performed by using a Viewlux beta-counter (Wallac, Perkin-Elmer) with imaging PS-WGA beads (Amersham RPNQ0260) in a final assay volume of 30μl_ and in a 384-well plate format (Greiner 781075). Briefly, 0.3μl_ of test compound in neat DMSO and 0% and 100% effect controls (DMSO for total binding and 10 or 1 μM indatraline as positive control) are added to the wells by using a Hummingbird (Genomic Solutions), followed by the addition of 30μl_ of the SPA mixture, containing 1 mg/ml_ SPA beads (hSERT) or 2mg/ml SPA beads (hDAT and hNET), 40μg/ml or 20μg/ml or 6 μg/ml of hDAT or hNET or hSERT BacMam membranes, 0.02% pluronic F-127, 1OnM [ ³ H]WI N-35,428 or 1 OnM [ ³ H]nisoxetine or 3nM [ ³ H]citalopram for hDAT or hNET or hSERT binding SPA in the assay buffer (2OmM HEPES, 145mM NaCI, 5mM KCI, pH 7.3-7.4). Incubation is performed at room temperature for at least 2 hours, best overnight in the dark. Bound radioactivity is recorded by using a 600s 6x binning and 613nm emission filter with the Viewlux instrument.

Compound affinity range for human transporters SERT, NET, and DAT

The compounds of formula (I)' typically show pKi greater than 4.5 towards each of the three transporters SERT, NET and DAT. In one embodiment, the compounds of formula(l) typically show pKi greater than 5.5 for each of the three transporters. In another embodiment, the compounds of formula (I)' typically show pKi greater than 6.5 for each of the three transporters. In a further embodiment, the compounds of formula (I)' typically show pKi greater than 7.5 for each of the three transporters.

Examples

The invention is further illustrated by the following non-limiting examples.

In the procedures that follow, after each starting material, reference to a Preparation or Example by number is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to.

Where reference is made to the use of a "similar" or "analogous" procedure, as will be appreciated by those skilled in the art, such a procedure may involve minor variation, for example reaction temperature, reagent/solvent amount, reaction time, work-up conditions or chromatographic purification conditions.

In the procedures that follow, the use of dotted or thick bond in the graphical representation of molecules is not intended to provide any indication on the absolute configuration of stereogenic centers but to provide the relative disposition in the space of substituents attached to the 6-membered aza ring.

For example, in Intermediates 4 shown below the carboxylic group and the C2-carbon bridge are intended to be on opposite faces of 6-membered aza ring, while in Intermediate 5 shown below they are intended to be on the same face of 6-membered aza ring.

Absolute stereochemistry, if available, is provided by absolute configuration of stereogenic centers indicated in names of compounds.

Wherein the compounds' name only refers to absolute configuration of stereogenic centers by quoting opposite configurations divided by a slash sign, these are to be intended as 1 :1 mixtures of the corresponding diastereoisomers, actually being a racemic

mixture [for example, (1 S,4S,5S/1 R,4R,5R) represents a mixture of (1S,4S,5S) and (1 R,4R,5R) diastereoisomers)].

Compounds are named using ACD/Name PRO 6.02 chemical naming software (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).

All temperatures refer to ⁰ C.

Proton Magnetic Resonance (NMR) spectra are typically recorded either on Varian instruments at 300, 400 or 500 MHz, or on a Bruker instrument at 300 and 400 MHz.

Chemical shifts are reported in ppm (d) using the residual solvent line as internal standard. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad. The NMR spectra were recorded at a temperature ranging from 25 to

9O ⁰ C. When more than one conformer was detected the chemical shifts for the most abundant one is reported.

Mass spectra (MS) are typically taken on a 4 Il triple quadrupole Mass Spectrometer (Micromass UK) or on a Agilent MSD 1100 Mass Spectrometer, operating in ES (+) and ES (-) ionization mode or on an Agilent LC/MSD 1100 Mass Spectrometer, operating in ES (+) and ES (-) ionization mode coupled with HPLC instrument Agilent 1 100 Series. In the mass spectra only one peak in the molecular ion cluster is reported.

LCMS may be recorded under the following conditions:

DAD chromatographic traces, mass chromatograms and mass spectrums may be taken on a UPLC/MS AcquityTM system coupled with a Micromass ZQTM mass spectrometer operating in ESI positive. The phases used are: A) H2O + 0.1 % HCOOH ; B) ACN +

0,06% HCOOH. Gradient: t=0 min 3% (B), to 6%(B) in 0.1 min, to 70% (B) in 0.5 min, to 99%(B) in 0.5min , 99% to 3% (B) in 0.35 min.

Column: Acquity BEH C18 2.1x50mm 1.7um 35 ⁰ C Flow: 600 uL/min. Mass tune: Capillary 3.25 kV, cone 20V, source temperature 1 15°C desolvation T 350 ⁰ C.

Preparative HPLC purifications (FractionLynx) may be performed under the following conditions:

MDAP FractionLynx Autopurification System™ Waters Column: SUPELCOSIL ABZ +Plus, 100 x 21 ,2 mm, 5 μm ps Mobile phase: A: H2O + 0.1% HCOOH; B: CH ₃ CN + 0.1 % HCOOH

Gradient: t=0 min 5% (B) in 1 min, 5% to 95% (B) in 9 min, 95% to 100% (B) in 3 min, 100% to 5% (B) in 0.50min Flow rate: 20 ml/min UV range: 210-400 nm Ionization: ES+/ES- Mass range: 150-900 da

Flash silica gel chromatography was carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or over Varian Mega Be-Si pre-packed cartridges or over pre-packed Biotage silica cartridges.

In a number of preparations, purification was performed using either Biotage manual flash chromatography (Flash+) or automatic flash chromatography (Horizon or SP1 ) systems. All these instruments work with Biotage Silica cartridges.

The following abbreviations are used in the text: DCE= dichloroethane, TIc refers to thin layer chromatography on silica plates, and dried refers to a solution dried over anhydrous sodium sulphate, r.t. (RT) refers to room temperature, Rt = retention time, DMSO = dimethyl sulfoxide; DCM = dichloromethane; DMF = N,N'-dimethylformamide; MeOH = methanol; TEA or Et ₃ N= triethylamine; THF = tetrahydrofurane; EA, AcOEt or EtOAc = ethyl acetate; cy = cyclohexane; EtOH = ethyl alcohol; TFA = trifluoroacetic acid; Et ₂ O = diethyl ether; SPE Cartridge = Solid Phase Extraction Cartridge; SCX Cartridge = Strong Cation Exchange Cartridge.

Intermediate 1 : 1 ,1-dimethylethyl (3-oxocyclopentyl)carbamate (11)

The title compound was prepared following an analogous procedures to that described in U.S. 2005/0054658 A1. 1H NMR (500 MHz, CDCI ₃ ): δ 4.58 (br s, 1 H); 4.23 (d, 1 H); 2.63 (dd, 1 H); 2.36 (m, 2H); 2.25 (m, 1 H); 2.1 1 (dd, 1 H); 1.85 (m, 1 H); 1.45 (9H).

Intermediate 2: diethyl [3-({[(1 ,1- dimethylethyljoxylcarbony^aminojcyclopentylidenelpropanedioa te (I2)

A mixture of dry THF (4ml) and dry CCI ₄ (0.5ml) was cooled at 0 ⁰ C and treated with TiCI ₄ (0.18ml, Aldrich). The resulting yellow - orange suspension was stirred at 0 ⁰ C for 10min and treated sequentially with Intermediate 1 (0.15g, 0.754mmol) and diethylmalonate

(0.12ml; 0.79mmol, Aldrich) then stirred at 0 ⁰ C for 1 hour. The reaction mixture was treated with dry Pyridine (0.2ml), stirred at 0 ⁰ C for 1 hour and at room temperature for 4 hours. The reaction was quenched with water and extracted with EtOAc. The organic phases were dried on Na ₂ SO4, concentrated under vacuum and the residue purified by

Flash Chromatography (90:1 O=Cy: EtOAc) to afford Intermediate 2 as a colorless oil

(0.1 g).

¹ H NMR (400 MHz, CDCI ₃ ): δ 4.53 (br. s., 1 H), 4.18 - 4.33 (m, 4 H), 4.1 1 (br. s., 1 H), 3.08 (dd, 1 H), 2.51 - 2.93 (m, 3 H), 2.00 - 2.15 (m, 1 H), 1.62 - 1.75 (m, 1 H), 1.46 (br. s., 9 H), 1.25 - 1.36 (m, 6 H).

Intermediate 4 and Intermediate 5: ethyl (1S,4S,5S/1R,4R,5R)-5-(3,4-dichlorophenyl)- 3-oxo-2-azabicyclo[3.2.1]octane-4-carboxylate (I4) and ethyl (1S,4R,5S/1R,4S,5R)-5- (3,4-dichlorophenyl)-3-oxo-2-azabicyclo[3.2.1]octane-4-carbo xylate (I5)

4 5

CuI (160 mg; O.δmmol, Aldrich) was charged in a 2-necked flask under vacuum for 30 minutes. Dry THF (50ml) was charged under N ₂ and diethyl [3-({[(1 ,1- dimethylethyl)oxy]carbonyl}amino)cyclopentylidene]propanedio ate (I2, 1.1 g; 3.22 mmol) was added. The suspension was cooled at O ⁰ C by an ice bath and a 0.5M Grignard solution (16ml, 8mmol) was added dropwise. The yellow solution was left to stir for 1 hour at 0 ⁰ C and finally the bath was removed. NH ₄ CI saturated aqueous solution was added and extracted with EtOAc. The organic phase was dried on Na ₂ SO ₄ and finally the solvent evaporated under vacuum to obtain a crude material (1.5g) that was dissolved in dry DCM (15ml) and treated with Trifluoroacetic acid (3ml, Aldrich). The solution was left to stir 30 min at rt. The solution was evaporated to dryness to obtain a brown solid (2g) used in the next step without any purification.

This material was suspended in EtOH (20ml) and Et ₃ N (2ml, Aldrich) was added. The solution was heated at 120 ⁰ C for 35min by MW.

The brown solution was completely evaporated. NH ₄ CI saturated aqueous solution was added to the residue and extracted 3 times with EtOAc. The organic phase was evaporated and the crude purified by Flash Chromatography (6:4=Cy:EtOAc to 6:3:1 =Cy:EtOAc:MeOH) gave a pale brown solid (420mg).

Trituration by Et ₂ O-Eptane mixture (1 :1 , 10vol) gave a white solid (280mg, Intermediate 4) and the mother liquor evaporated led to a brown solid (140mg) that was purified by a preparative HPLC to obtain 35mg of white solid (Intermediate 5). Intermediate 4: 1H NMR (500 MHz, CDCI ₃ ): δ 7.40 (d, 1 H), 7.32 (d, 1 H), 7.09 (dd, 1 H), 7.08 (br. s., 1 H), 3.90 - 3.98 (m, 1 H), 3.82 (q, 2 H), 3.52 (s, 1 H), 2.99 (d, 1 H), 2.21 - 2.31 (m, 1 H), 2.02 - 2.15 (m, 2 H), 1.92 - 2.03 (m, 1 H), 1.84 (dd, 1 H), 0.86 (t, 3 H)

Intermediate 5: 1H NMR (500 MHz, CDCI ₃ ): δ 7.40 (d, 1 H), 7.32 (d, 1 H), 7.09 (dd, 1 H), 6.81 (br. s., 1 H), 4.01 - 4.13 (m, 2 H), 3.85 - 3.90 (m, 1 H), 3.53 (s, 1 H), 3.17 - 3.26 (m, 1 H), 2.40 (d, 1 H), 2.12 - 2.21 (m, 1 H), 1.93 - 2.04 (m, 3 H), 1.06 (t, 3 H)

Intermediate 6: 1,1 -dimethylethyl (1S,4S,5S/1R,4R,5R)-5-(3,4-dichlorophenyl)-4- (hydroxymethyl)-2-azabicyclo[3.2.1]octane-2-carboxylate (I6)

ethyl (1 S,4S,5S/1 R,4R,5R)-5-(3,4-dichlorophenyl)-3-oxo-2-azabicyclo[3.2.1]oct ane-4- carboxylate_(l4, 585mg; 1.72mmol) was dissolved in dry THF (10ml) under N ₂ atmosphere. BH3 1 M solution in THF (9ml; 9mmol, Aldrich) was added at room temperature and heated to a gentle reflux for 3hours. The reaction was quenched by adding dropwise 6N HCI with gas evolution. After stirring 30min at rt the suspension was cooled with an ice bath and NaOH 2N was added to reach pH>8. To this solution Ditertbutyl dicarbonate (41 1 mg, Aldrich) was added and after 1 hour the reaction was partitioned between brine and DCM. The organic phase was dried on

Na ₂ SO ₄ and evaporated. The crude material was purified by Flash Chromatography (9:1 to 7:3=Cy:EtOAc) to afford the title compound (450mg) as a white foam.

Intermediate 7: 1,1 -dimethylethyl (1S,4R,5S/1 R,4S,5R)-5-(3,4-dichlorophenyl)-4- (hydroxymethyl)-2-azabicyclo[3.2.1]octane-2-carboxylate (I7)

1 ,1-dimethylethyl (1 S,4R _! 5S/1 R _! 4S _! 5R)-5-(3,4-dichlorophenyl)-4-(hydroxymethyl)-2- azabicyclo[3.2.1]octane-2-carboxylate (I7, 0.7g) was prepared in a similar manner to that described in the procedure reported above for Intermediate 6, starting from ethyl (1S,4R,5S/1 R,4S,5R)-5-(3,4-dichlorophenyl)-3-oxo-2-azabicyclo[3.2.1]oct ane-4- carboxylate (I5, 0.48g).

Intermediate 8 and Intermediate 9: ethyl (1S,4R,5R/1R,4S,5S)-5-(3,4-dichlorophenyl)- 2,4-dimethyl-3-oxo-2-azabicyclo[3.2.1]octane-4-carboxylate (I8) and ethyl (1S,4S,5R/1S,4S,5R)-5-(3,4-dichlorophenyl)-4-hydroxy-2-methy l-3-oxo-2- azabicyclo[3.2.1]octane-4-carboxylate (I9)

ethyl (1 S,4S,5S/1 R,4R,5R)-5-(3,4-dichlorophenyl)-3-oxo-2-azabicyclo[3.2.1]oct ane-4^ carboxylate (I4, 300mg, 0.9mmol) was dissolved in dry THF (10ml). NaH (60% in mineral oil, 105mg, 2.63mmol, Aldrich) and MeI (0.14ml, 2.2 mmol, Aldrich) were added at room temperature and stirred for 3 hours. The reaction was quenched with NH ₄ CI saturated aqueous solution and extracted with Et ₂ O, dried on Na ₂ SO ₄ and finally evaporated in vacuo to obtain a mixture of ethyl (1S,4R,5R/1 R,4S,5S)-5-(3,4-dichlorophenyl)-2,4-dimethyl-3-oxo-2- azabicyclo[3.2.1]octane-4-carboxylate (I8) and ethyl (1S,4S,5R/1 S,4S,5R)-5-(3,4- dichlorophenyl)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.2.1] octane-4-carboxylate (I9) in a 90:10 ratio.

A small portion of this mixture was purified by a preparative HPLC (Fraction Lynx) in order to characterise the pure products.

Intermediate 8:

¹ H NMR (500 MHz, CDCI ₃ ): δ 7.35 (d, 1 H), 7.15 (d, 1 H), 6.92 (dd, 1 H), 4.22 - 4.31 (m, 1 H), 4.12 - 4.20 (m, 1 H), 3.66 - 3.73 (m, 1 H), 3.06 - 3.14 (m, 1 H), 3.00 (s, 3 H), 2.59 (d, 1 H), 2.05 - 2.18 (m, 1 H), 1.93 - 2.03 (m, 1 H), 1.75 - 1.90 (m, 2 H), 1.25 (s, 3 H), 1.27 (t, 3 H)

Intermediate 9: 1H NMR (500 MHz, CDCI ₃ ): δ 7.36 (d, 1 H), 7.26 (d, 1 H), 7.02 (dd, 1 H), 4.34 - 4.42 (m, 1 H), 4.26 - 4.32 (m, 1 H), 3.83 - 3.86 (m, 1 H), 3.72 - 3.79 (m, 1 H), 3.14 - 3.24 (m, 1 H), 3.02 (s, 3 H), 2.99 (d, 1 H), 1.97 - 2.08 (m, 2 H), 1.88 - 1.97 (m, 1 H), 1.74 (dd, 1 H), 1.35 (t, 3 H)

Intermediate 10 and Intermediate 11 :

[(1S,4R,5R/1 R,4S,5S)-5-(3,4-dichlorophenyl)-2,4-dimethyl-2-azabicyclo[3. 2.1]oct-4- yl]methanol (110) and (1S,4S,5R/1 R,4R,5S)-5-(3,4-dichlorophenyl)-4-

(hydroxymethyl)-2-methyl-2-azabicyclo[3.2.1]octan-4-ol (111)

The mixture of ethyl (1S _! 4R _! 5R/1 R _! 4S _! 5S)-5-(3 _! 4-dichlorophenyl)-2,4-dimethyl-3-oxo-2- azabicyclo[3.2.1]octane-4-carboxylate (I8) and ethyl (1S,4S _! 5R/1 S _! 4S _! 5R)-5-(3,4- dichlorophenyl)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.2.1] octane-4-carboxylate (I9)

(prepared as above described for I8 and I9, 200mg) was dissolved in dry THF (5ml) and

BH ₃ 1 M in THF solution (3ml) were added at room temperature.

The mixture was heated to reflux for 5hours.

HCI 3N aqueous solution (2ml) was added and the mixture heated for 30 min at 60 ⁰ C.

The mixture was evaporated in vacuo and purified by a SCX cartridge to obtain 170mg of a white foam as a mixture of title compounds.

LC/MS: Intermediate 10 [M+1 =314] : Intermediate 11 [M+1 =316], ratio 90:10

Intermediate 12 and Intermediate 13:

1,1-dimethylethyl (1S,4R,5R/1 R,4S,5S)-5-(3,4-dichlorophenyl)-4-(hydroxymethyl)-4- methyl-2-azabicyclo[3.2.1]octane-2-carboxylate (112) 1,1-dimethylethyl

(1S,4S,5R/1 R,4R,5S)-5-(3,4-dichlorophenyl)-4-hydroxy-4-(hydroxymethyl)- 2- azabicyclo[3.2.1]octane-2-carboxylate (113)

A mixture of [(1S,4R,5R/1 R,4S,5S)-5-(3,4-dichlorophenyl)-2,4-dimethyl-2- azabicyclo[3.2.1]oct-4-yl]methanol (110) and (1 S,4S,5R/1 R,4R,5S)-5-(3,4-dichlorophenyl)- 4-(hydroxymethyl)-2-methyl-2-azabicyclo[3.2.1]octan-4-ol (11 1 )

(prepared as above described for 110 and 11 1 , 170mg) was dissolved in dry DCE (5ml). 1- Chloroethyl Chloroformate (0.3ml, 2.7mmol, Aldrich) was added and the mixture was heated by MW irradiation at 140 ⁰ C for 40min. The suspension was evaporated to dryness and recovered with dry MeOH (2ml). The mixture was heated at 100 ⁰ C for 30 min by MW. The mixture was evaporated to dryness and recovered in a mixture of THF (2ml) and of NaOH 1 N aqueous solution (2ml). Diterbutyldicarbonate (190mg, Aldrich) was added and the mixture left to stir for 1 hour. The reaction was diluted in water and extracted 3 times with EtOAc. The organic solvent was dried on Na ₂ SO ₄ and evaporated in vacuo. The crude material was purified by Flash Chromatography (9:1 to 6:4=Cy:EOAc) to obtain a mixture of Intermediate 12 and Intermediate 13 (35mg) as a colorless oil.

Intermediate 14 and Intermediate 15 : 1 ,1-dimethylethyl (1S,4R,5R/1 R,4S,5S)-5-(3,4- dichlorophenyl)-4-methyl-4-[(methyloxy)methyl]-2-azabicyclo[ 3.2.1]octane-2- carboxylate (114) and 1,1 -dimethylethyl (1S,4S,5R/1 R,4R,5S)-5-(3,4-dichlorophenyl)- 4-(methyloxy)-4-[(methyloxy)methyl]-2-azabicyclo[3.2.1]octan e-2-carboxylate (115)

A mixture of 1 ,1-dimethylethyl (1 S,4R,5R/1 R,4S,5S)-5-(3,4-dichlorophenyl)-4- (hydroxymethyl)-4-methyl-2-azabicyclo[3.2.1]octane-2-carboxy late (112) and 1 ,1- dimethylethyl (1 S,4S,5R/1 R,4R,5S)-5-(3,4-dichlorophenyl)-4-hydroxy-4-(hydroxymethyl)- 2-azabicyclo[3.2.1]octane-2-carboxylate (I13)_(prepared as above described for 112 and 113, 35mg) was dissolved in dry THF (4ml) and chilled at 0°C. NaH (60% in mineral oil;

11 mg, Aldrich) was added followed by MeI (20μl). The mixture was left to stir at room temperature for 4.5h. NH ₄ CI saturated aqueous solution was added and the mixture extracted 3 times with Et ₂ O. The organic phase was dried on Na ₂ SO ₄ and finally evaporated. The mixture was purified by preparative HPLC (Fraction Lynx) to obtain pure title compound 114 (30mg) and title compound 115 (5mg). LC/MS: Intermediate 14 [M+1 =414] : Intermediate 15 [M+1 =430] = 90:10

Example 1 : (1S,4S,5S/1 R,4R,5R)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2- azabicyclo[3.2.1]octane hydrochloride (E1)

CIH

1 ,1-dimethylethyl (1 S,4S _! 5S/1 R _! 4R _! 5R)-5-(3,4-dichlorophenyl)-4-(hydroxymethyl)-2- azabicyclo[3.2.1]octane-2-carboxylate (I6, 110mg; 0.282mmol) was dissolved in dry THF (4ml) and chilled at 0 ⁰ C. NaH (60% in mineral oil; 14mg; 0.343mmol, Aldrich) was added followed by MeI (21 μl, 0.343mmol, Aldrich). The mixture was left to stir at room temperature for 4.5h. NH ₄ CI saturated aqueous solution was added and the mixture extracted 3 times with Et ₂ O. The organic phase was dried on Na ₂ SO ₄ and finally evaporated. The crude material was purified by flash chromatography to obtain a crude material that was dissolved in dry DCM (2ml). Trifluoro Acetic Acid (0.4ml, Aldrich) was added dropwise and stirred at rt. After 10min the reaction was completely evaporated in vacuo and partitioned in EtOAc\NaHCθ3 aqueous solution. The organic phase was dried on Na ₂ SO ₄ and evaporated to give an oily material that was dissolved in Et ₂ O (2ml) and the HCI (1 M Et20 solution; 0.3ml) was added dropwise with the formation of a white precipitate. After stirring for 10min the organic phase was removed by filtration and the precipitate was triturated 2 times with Et ₂ O and 2 times with pentane. The resulting material was left under vacuum overnight to obtain the title compound (35mg) as a white solid.

¹ H NMR (500MHz, d ⁶ DMSO): δ 9.06 (br. s., 1 H), 8.99 (br. s., 1 H), 7.60 (d, 1 H), 7.50 (d, 1 H), 7.24 (dd, 1 H), 3.87 - 3.96 (m, 1 H), 3.47 (t, 1 H), 3.19 (s, 2 H), 3.10 (s, 3 H), 2.73 (dd, 1 H), 2.32 - 2.42 (m, 1 H), 2.23 (d, 1 H), 2.14 - 2.20 (m, 1 H), 1.88 - 2.04 (m, 2 H), 1.78 (dd, 1 H), 1.59 - 1.68 (m, 1 H)

Example EI ₁ and Example EI ₂ : (1S,4S,5S or 1R,4R,5R)-5-(3,4-dichlorophenyl)-4- [(methyloxy)methyl]-2-azabicyclo[3.2.1]octane hydrochloride (EI ₁ ) and (1R,4R,5R or 1S,4S,5S)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2-aza bicyclo[3.2.1]octane hydrochloride (EI ₂ )

(1S,4S,5S/1 R,4R,5R)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2- azabicyclo[3.2.1]octane hydrochloride (E1 , 40mg) was resolved by using a preparative HPLC separation (Chiralcel OD, n-Hexane/lsopropanol +0.1 % isopropylamine 90/10, Flow 14ml/min) to obtain (1 S,4S,5S or 1 R,4R,5R)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]- 2-azabicyclo[3.2.1]octane (Enantiomer 1 , free base of compound EI ₁ , 15mg, Rt = 8.983min) and (1 R,4R,5R or 1S,4S,5S)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2- azabicyclo[3.2.1]octane (Enantiomer 2, free base of compound EI _2, 13mg, Rt =11.1 12min) based on the order of elution. These 2 compounds were dissolved in dry Et ₂ O (1.5ml) and treated with HCI 1 M solution in Et ₂ O (0.75ml) . The mixtures were shaked for 1 hour, all the volatiles evaporated and finally triturated with Et ₂ O. Title compound EI ₁ (8 mg) and title compound EI ₂ (7 mg) were thus recovered.

Example 2: (1 S,4R,5S/1 R,4S,5R)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2- azabicyclo[3.2.1]octane hydrochloride (E2)

(1S,4R,5S/1 R,4S,5R)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2- azabicyclo[3.2.1]octane hydrochloride (480mg) was prepared in a similar manner to that described in the procedure reported above for Example 1 , starting from 1 ,1- dimethylethyl (1 S,4R,5S/1 R,4S,5R)-5-(3,4-dichlorophenyl)-4-(hydroxymethyl)-2- azabicyclo[3.2.1]octane-2-carboxylate (I7, 300mg).

¹ H NMR (500MHz, d ⁶ DMSO): δ 8.87 (br. s., 2 H), 7.61 (d, 1 H), 7.43 (d, 1 H), 7.22 (dd, 1 H), 3.91 - 3.99 (m, 1 H), 3.20 - 3.27 (m, 1 H), 3.05 (s, 3 H), 3.07 (dd, 1 H), 2.87 - 2.98 (m, 1 H), 2.81 (dd, 1 H), 2.33 - 2.41 (m, 2 H), 2.09 - 2.18 (m, 1 H), 1.97 - 2.09 (m, 1 H), 1.89 - 1.96 (m, 1 H), 1.80 - 1.89 (m, 1 H), 1.74 (dd, 1 H)

Example E2i and Example E2 ₂ : (1S,4R,5S or 1 R,4S,5R)-5-(3,4-dichlorophenyl)-4- [(methyloxy)methyl]-2-azabicyclo[3.2.1]octane hydrochloride (E2 _! ) and (1R,4S,5R or 1S,4R,5S)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2-aza bicyclo[3.2.1]octane hydrochloride (E2 ₂ )

(1S,4R,5S/1 R,4S,5R)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2- azabicyclo[3.2.1]octane hydrochloride (E2, 10 mg) was resolved by using using a Preparative Chiral HPLC System (Chiralcel OD-H , n-Hexane/lsopropanol +0.1% IPA 97/3, Flow: 15ml/min) to obtain after evaporation of volatiles and salt formation performed in a similar manner to that described above for Examples EI ₁ and EI ₂ , (1S,4R,5S or 1 R,4S,5R)-5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2-azab icyclo[3.2.1]octane hydrochloride (E2-,) (Enantiomer 1 , 4 mg) and (1 R,4S,5R or 1 S,4R,5S)-5-(3,4- dichlorophenyl)-4-[(methyloxy)methyl]-2-azabicyclo[3.2.1]oct ane hydrochloride (E2 ₂ ) (Enantiomer 2, 4 mg) based on the order of elution.

Example 3: (1S,4R,5R/1R,4S,5S)-5-(3,4-dichlorophenyl)-4-methyl-4-

[(methyloxy)methyl]-2-azabicyclo[3.2.1]octane hydrochloride (E3)

1 ,1-dimethylethyl (1S,4R,5R/1 R,4S,5S)-5-(3,4-dichlorophenyl)-4-methyl-4-

[(methyloxy)methyl]-2-azabicyclo[3.2.1]octane-2-carboxylate (114, 30mg) was dissolved in HCI 1.25M in methanol (5ml) and stirred for 2hours. TFA (0.8ml, Aldrich) was added and the mixture stirred overnight. All the volatiles were distilled off and the crude partitioned between DCM and NaHCO3 saturated aqueous solution. The organic phase was evaporated and the colorless oil obtained recovered in Et ₂ O (1 ml) . HCI 1 M solution in Et ₂ O (0.8ml) was added and after 30min stirring at room temperature the mixture completely evaporated. The white solid obtained was triturated with Et ₂ O and finally dried under vacuum at 40 ⁰ C for 1 hour to obtain the title compound (4mg). 1 H NMR (500MHz, d ⁶ DMSO): δ 8.54 - 9.00 (br.s., 2 H), 7.59 (dd, 1 H), 7.35 - 7.44 (m, 1 H), 7.18 (dd, 1 H), 3.84 - 3.97 (m, 1 H), 3.50 (d,1 H), 3.47 (d,1 H), 3.27 - 3.30 (m, 3 H), 3.17 - 3.23 (m, 3 H), 3.05 - 3.13 (m, 1 H), 2.86 - 2.97 (m, 1 H), 2.75 (d, 1 H), 2.59 - 2.69 (m, 1 H), 1.78 - 2.07 (m, 2 H), 1.60 - 1.77 (m, 1 H), 1.54 (dd, 1 H)

Example 4: (1 S,4S,5R/1 R,4R,5S)-5-(3,4-dichlorophenyl)-4-(methyloxy)-4-

[(methyloxy)methyl]-2-azabicyclo[3.2.1]octane hydrochloride (E4)

(1S,4S,5R/1 R,4R,5S)-5-(3,4-dichlorophenyl)-4-(methyloxy)-4-[(methyloxy) methyl]-2- azabicyclo[3.2.1]octane hydrochloride (1.5mg) was obtained according to a similar

procedure to that described above for Example 3, starting from 1 ,1-dimethylethyl (1S,4S,5R/1 R,4R,5S)-5-(3,4-dichlorophenyl)-4-(methyloxy)-4-[(methyloxy) methyl]-2- azabicyclo[3.2.1]octane-2-carboxylate (115, 4mg)

1H NMR (500MHz, d ^G DMSO): δ ppm 8.80 (br. s., 2 H), 7.56 (d, 1 H), 7.41 (d, 1 H), 7.22 (dd, 1 H), 3.81 - 3.87 (m, 1 H), 3.50 (d, 1 H), 3.47 (d, 1 H), 3.21 (s, 3 H), 3.16 (s, 3 H), 2.96 (d, 1 H), 2.83 - 2.92 (m, 2 H), 2.43 - 2.54 (m, 1 H), 1.92 - 2.05 (m, 2 H), 1.81 - 1.92 (m, 1 H), 1.44 (dd, 1 H)

It is to be understood that the present invention covers all combinations of particular groups described herein above.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims.