4,5-dihydro-lH-imidazol-2-amine derivatives for use in the treatment of respiratory, cardiovascular, neurological or gastrointestinal disorders

Field of the Invention

The present invention relates to compounds of formula (I), to pharmaceutical compositions containing said compounds and to the use of said compounds in therapy. The present invention further relates to processes for the preparation of compounds of formula (I) and to new intermediates used in the preparation thereof.

Background of the Invention

Adrenergics constitute a group of drugs with very varied clinical use. The field of application is broad, from lifethreatening conditions as asthma and hypertension to use for minor ailments such as the common cold.

Adrenergic receptors or adrenoceptors are defined as the sites at wich the neurotransmitters adrenaline and noradrenaline produce their physiologic effect in the cell. They are cell membrane receptors belonging to the transmembrane G-protein-coupled family of receptors. These receptors are broadly classified into CCi-, OC ₂ - and β-receptors. The groups are further subdivided into six α-adrenoceptors, GC ₁ A, OC ₁ B, OC ₁ D, OC ₂ A, OC ₂ B, oc ₂ c and three β-adrenoceptors βi, β2, β ₃ (see e.g., Docherty J. R, European Journal of Pharmacology 361 (1998) 1-15). cc-receptors are widely studied because of the major physiological importance of these receptors in control of blood pressure and blood flow, neural modulation, digestion, micturition, airways, reproduction, pupil diameter, endocrine and metabolic processes and in behaviour.

CCi -adrenoceptors are implicated in processes such as vasoconstriction, glycogeno lysis, cardiac inotrophy and chronotrophy. cc ₂ -adrenoceptors are associated with platelet aggregation, neorotransmitter release, vasoconstriction, regulation of ion secretion and inhibition of insulin secretion, chronic pain, neuropathic pain, glaucoma and IBS, (see e.g. Abraham D. J., Burger's Medicinal Chemistry and Drug Discovery, 6 ^th edition, vol. 6, chapter one) and (Exp. Opin. Ther. Patents 10(11): 1741-1748).

Adrenergic agonists showing activity on both α and β receptor families have limited clinical application since the compounds would then stimulate the entire adrenergic system. There is therefore a further need for subtype-selective CC agonists.

WO 2006/125748 discloses the compounds N-[l-(3-chlorophenyl)-2-phenylethyl]-4,5- dihydro- lH-imidazol-2-amine, N-[I -(3-chlorophenyl)-2-phenylethyl]-4,5-dihydro- IH- imidazol-2-amine hydroiodide, N-[I -(4-chlorophenyl)-2-phenylethyl]-4,5-dihydro- IH- imidazol-2-amine hydroiodide, N-[I -(2-chloro-4-fluorophenyl)-2-phenylethyl]-4,5-dihydro- lH-imidazol-2-amine and N-[I -(3-fluorophenyl)-2-phenylethyl]-4,5-dihydro- lH-imidazol-2- amine.

The object of the present invention was to provide novel α-receptor agonists useful in therapy.

Outline of the Invention

The present invention provides a compound of formula (I)

(I)

wherein

Ar ¹ is

R ¹ is independently selected from halogen, hydroxy, cyano, Q-C5 alkoxy, Q-C3 alkyl, Q-

C3 alkylsulfonate or Q-C3 alkoxy substituted by Q-C3 alkoxy; wherein the alkyl group, alkoxy group or alkylsulfonate group may be substituted by one or more fluoro atom(s); m is 0, 1, 2, 3, 4 or 5; Ar ² is

R ² is independently selected from halogen, hydroxy or Q-C3 alkyl; wherein the alkyl group may be substituted by one or more fluoro atom(s);

n is O, 1, 2, 3 or 4;

or

Ar ¹ and Ar ² may be attached to each other and thus form an optionally substituted biphenyl group; or

Ar ¹ or Ar ² may be fused with a six-membered aromatic ring wherein the ring atoms are selected from C or N and at least three ring atoms are C;

X is carbon or nitrogen; Y is carbon or nitrogen; Z is carbon or nitrogen;

with the proviso that R is covalently attached to a carbon atom;

as well as pharmaceutically and pharmacologically acceptable salts thereof and enantiomers of the compound of formula (I) and salts thereof.

In one embodiment of the present invention R ¹ is chloro, hydroxy, fluoro, bromo, trifluoromethyl, methoxy, butoxy, methylsulfonate or cyano.

In one embodiment of the present invention R ² is chloro, hydroxy or trifluoromethyl.

In one embodiment of the present invention, m is 0, 1 or 2.

In one embodiment of the present invention, n is 0, 1 or 2.

In one embodiment X is carbon, Y is carbon and Z is carbon.

The present invention relates to compounds of formula (I) as defined above as well as to salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I).

The compounds of the present invention are capable of forming salts with various inorganic and organic acids and such salts are also within the scope of this invention. Examples of such acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclohexyl sulfamate, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nitrate, oxalate, palmoate, persulfate, phenylacetate, phosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), and undecanoate.

Pharmaceutically acceptable salts may be prepared from the corresponding acid in conventional manner. Non-pharmaceutically-acceptable salts may be useful as intermediates and as such are another aspect of the present invention.

Acid addition salts may also be in the form of polymeric salts such as polymeric sulfonates.

The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalent of the appropriate acid in a solvent or a medium in which the salt is hardly soluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.

Compounds of formula (I) have at least one chiral center, and it is to be understood that the invention encompasses all enantiomers and diastereomers. The compounds according to formula (I) can be in the form of the single stereoisomers, i.e. the single enantiomer (the R- enantiomer or the S-enantiomer) and/or diastereomer. The compounds according to formula (I) can also be in the form of a racemic mixture, i.e. an equimolar mixture of enantiomers.

It is to be understood that the present invention also relates to any and all tautomeric forms of the compounds of formula (I).

Some compounds can exist as a mixture of conformational isomers. The compounds of this invention comprise both mixtures of, and individual, conformational isomers.

Unless stated otherwise, the term "C1-C3 alkyl" includes straight as well as branched chain hydrocarbon groups having 1 to 3 carbon atoms, for example methyl, ethyl, n-propyl or i- propyl. The alkyl group may be substituted by one or more fluoro atoms, such as in difluoromethyl or trifluoromethyl.

Unless stated otherwise, the term "C1-C5 alkoxy" includes straight as well as branched alkyl groups having 1 to 5 carbon atoms attached via an oxygen atom, for example methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, 1 -methyl-prop oxy, 2-methyl-propoxy, t-butoxy, n- pentoxy, 1-methylbutoxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1 ,2-dimethylpropoxy, 2,2- dimethyl-propoxy and 1-ethylpropoxy. The alkyl group may be substituted by one or more fluoro atoms, such as in difluoromethoxy or trifluoromethoxy.

Unless stated otherwise, the term "halogen" includes fluorine, chlorine, bromine or iodine.

Unless stated otherwise, the term "C1-C3 alkylsulfonate" includes straight as well as branched alkyl groups having 1 to 3 carbon atoms attached via a sulfonate group, for example methanesulfonate, ethanesulfonate, propanesulfonate or iso-propanesulfonate.

Chemical names are generated by ACD/Labs ^® from Advanced Chemistry Development, Inc.

Pharmaceutical Formulations

According to one aspect of the present invention there is provided a pharmaceutical formulation comprising a compound of formula (I), as a single enantiomer, a racemate or a mixture thereof as a free base or pharmaceutically acceptable salt thereof, for use in

prevention and/or treatment of respiratory, cardiovascular, neurological, pain, oncology, imflammatory and/or gastrointestinal disorders.

The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation or insufflation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, pellets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.

In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.

The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.01 to 25 mg/kg body weight (and preferably of 0.1 to 5 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.

Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. For example a tablet or capsule for oral administration may conveniently contain up to 250 mg (and typically 5 to 100 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. In another example, for administration by inhalation, a compound of the formula (I) or a pharmaceutically acceptable salt thereof may be administered in a daily dosage range of 5 to 100 mg, in a single dose or divided into two to four daily doses. In a further example, for administration by intravenous or intramuscular injection or infusion, a sterile solution or suspension containing up to 10% w/w (and typically

5% w/w) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof may be used.

Medical and Pharmaceutical Use

The present invention provides a method of treating or preventing a disease condition wherein activation of CC adrenergic receptors is beneficial which comprises administering to a subject an effective amount of a compound of the formula (I) or a pharmaceutically-acceptable salt thereof. The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in a disease condition wherein agonism of CC adrenergic receptors is beneficial.

The compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof may be used in the manufacture of a medicament for use in the prevention or treatment of respiratory, cardiovascular, neurological, pain and/or gastrointestinal disorders.

Examples of such disorders are asthma, pulmonary disease, cough, cold, inflammation, chronic obstructive pulmonary disease, airway reactivity, urticaria, hypertension, edema, angiogenesis, chronic pain, neuropathic pain, allodynia, migraine, tension headache, psychoses, depression, anxiety, Alzheimer's disease, schizophrenia, Huntington's disease, bladder hypermotility, urinary incontinence, eating disorder, manic depression, substance dependence, movement disorder, cognitive disorder, obesity, stress disorders, micturition disorders, mania, hypomania and aggression, bipolar disorder, carcinoma, fibromyalgia, non cardiac chest pain, gastrointestinal hypermotility, gastric asthma, Crohn's disease, gastric emptying disorders, ulcerative colitis, irritable bowel syndrome, inflammatory bowel disease, emesis, diabetes or functional dyspepsia.

One aspect of the present invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment of any of the disorders defined hereinbefore.

A further aspect of the present invention is a method for the treatment or prevention of a disorder defined hereinbefore, comprising administering to a person in need thererof, a

therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Pharmacology

Three functional CC ₂ adrenoceptor subtypes are described, CC ₂ A, OC ₂ B and cc ₂ c and they all belonging to the GPCR superfamily. All three CC ₂ receptor subtypes are predominantly coupled to Ga ₁ and as a consequence of their activation, the level of intracellular cAMP is decreased. Clones of HEK293SG _qi 5 cells expressing each of human CC _2AB receptors were used for functional screening of compounds. Expression of engineered G _qi 5 (the last 5 amino acids of GcCq are replaced with the last 5 amino acids Of Ga ₁ ) allows to diverge signal from Ga ₁ coupled receptor to Ga _q signaling. Therefore the degree of receptor activation correlates to the release of intracellular Ca ²⁺ measured with a Fluorescence Imaging Plate Reader (FLIPR). This approach provided a robust and sensitive method to estimate both potency and efficacy of screened molecules. The potency and efficacy are expressed as EC50 (μM) and % of maximal response achieved by noradrenalin (NA) respectively. Transfection and culturing of cells used in FLIPR

Human embryonic kidney (HEK) 293SGqis cells were stably transfected with human α ₂ A or human α ₂ β receptors cDNA cloned into pIRESneo2 expression vector. Transfection was performed using cationic lipid reagent Lipofectamine plus and selection with 1 mg/ml Geneticin and 0.3 mg/ml hygromycin B. Individual clones were selected by flow cytometry for human α ₂ A receptor and by manually adding drops containing one cell to 96 well plates for human α ₂ β receptor. The HEK293SGqis cells stably expressing human α ₂ A and α ₂ β receptors were cultured in a humified incubator at 37°C under 5% CO ₂ , in DMEM, 10% FBS supplemented with withl mg/ml Geneticin and 0.3 mg/ml hygromycin B. Cells were grown in T- 175 flasks and routinely passaged 1:10 when they were 70-90% confluent.

Assessing the Potency of Selected test Compounds to Activate Human α ₂ A and α ₂ β receptors

The potency of a compound of the invention to activate CC ₂ A and CC ₂ B receptors was assessed by the following procedure:

HEK293Gqi5 cells stably transfected with human CC ₂ A and CC ₂ B receptors were detached from the flask by hitting it on the side and plated in Falcon Poly-D-Lysine coated black-walled, clear-bottomed 384-well plates at a density of 2 x 10 ⁵ cells/ml and 25 μl (5000 cells) in each well using a Multidrop 384 and grown for approximately 24h in normal growth media in a 37°C, CO ₂ incubator. The cells were then washed three times with wash buffer, Hanks balanced salt solution (HBSS) and 20 mM Hepes, using 100 μl /well in a BioTek EL _x 405 washer leaving 20 μl in each well after the last wash. Before the FLIPR assay the cells of each 384-well plate were loaded with fluorescent Ca ⁺ chelator. Fluo 4 at 2 μM in a loading buffer containing HBSS, 20 mM Hepes and 0.02% Pluronic F-127, 20 μl/well, using a Biomek NX ^P (Beckman coulter) and incubated at 37°C for 45-60 min.

Test compounds were diluted in serial dilutions with ten concentrations in steps of three in DMSO using a ROSYS with the highest concentration at 3.3 mM. A predilution plate of the compounds was made using a Biomek NX ^P (Beckman coulter) where 1 μl compound was diluted with 40 μl assay buffer (wash buffer and 0.1% (w/v) BSA) in quadruplicates in a 384 well plate. The cells were washed once again as before and placed in the 384 FLIPR together with the compound predilution plate where 20 μl of compound in assay buffer was added to each well automatically pipetted by FLIPR (pipettor height 40 μl, pipettor speed 20 μl/s). The fluorescence intensity was recorded (excitation 488 nm and emission 510-570 nm) by the FLIPR CCD camera for 3 min and results were calculated from RFU max-min values exported from FLIPR, samples 12-70 included. The baseline was exported as a separate statistic file set as the average of samples 1-5 to allow calculation of Fluo-4 loading level. The EC50 value was calculated from a ten-point concentration-response curve for each compound in an excel-based program. Intrinsic activity of compounds were expressed as a fraction of the maximum response relative to 0.1 μM of NA.

Results

In general, the compounds of the invention, which were tested, demonstrated statistically significant agonistic activity at CC _2B receptors at low levels. The EC50 value was generally less than 200 nM. Also, a number of the compounds of the invention, which were tested,

demonstrated statistically significant agonistic activity at CC ₂ A receptors at low levels (NT=not tested).

Biological evaluation

An in vivo gastric distension model is used as a model for functional gastrointestinal disorders, in particular for functional dyspepsia (FD), (Bayati A, Astin M, Ekman C, Mattsson H, Gastroenterology 2003; 124 (4, suppl 1): W1471 (abstract)) and

(Astin Nielsen M, Bayati A, Mattson H, Scandinavian Journal of Gastroenterology, 2006; 41: 773-781).

The gastric distension model enables detailed analysis of the physico -mechanical properties of the stomach, e.g. basal gastric tone, threshold for accommodation, accommodation rate, accommodation volume, and maximal gastric volume. By using the same model in both rats and humans it has been found that the gastric volume responses is very similar in the rat glandular stomach to that in human proximal stomach. Furthermore, it has been shown that patients with Functional Dyspepsia as well as Wistar Kyoto (WKY) rats have an impaired gastric adaptive response and also a lower total gastric volume as compared to healthy subjects and Sprague Dawley (SD) rats, respectively. In addition, the method has shown to be reproducible and reliable. Moreover, the advantage of the presently used barostat technique compared to other barostat techniques normally used in experimental clinical studies is that it is possible to discriminate between if a compound exerts its effect directly on gastric smooth muscles or if the effect involves the vagal reflex mechanism.

The rats are equipped with fistulas chronically implanted into the stomach. During gastric experiments, a small inflatable plastic bag with a spherical shape is inserted through fistula into the glandular part of the stomach (middle to distal part in the rat). The experiments are performed in conscious rats. For detailed analysis of the physico-mechanical properties of the

stomach, a combination of ramp and tonic distension paradigm is used. Pressure and volume data collected during experiments are saved for and further analysis.

In order to determine an animal's maximum gastric accommodation capacity, a balloon is inserted into the stomach of the animal and a four phase protocol which includes a start phase, a ramp phase, a tonic phase and an end phase is performed. The pressure applied to the balloon and the corresponding changes to the volume of the balloon are monitored throughout, e.g., using any barostat system known in the art (e.g., see Toma et al, Neurogastroenterol Mot., 8, 19-28, 1996).

During the start phase a minimum distension pressure, e.g., 1 mm Hg, is applied to the balloon until base line values are obtained. This is followed by a Ramp Phase. During this phase the pressure applied to the balloon is increased linearly with a constant increase in pressure. The pressure delivered to the balloon can be between 2-20 mm Hg. This phase is then followed by the Tonic Phase. During the tonic phase the pressure is kept constant at the maximum pressure. Finally the pressure is dropped to the starting minimum distension pressure and this period is known as the End Phase.

To determine if an agent, e.g., a compound is useful in the treatment of FD, the maximum gastric accommodation capacity in the animal following administration of the compound is calculated. A compound of interest will be a compound that alters the maximum gastric accommodation capacity in the animal and this is calculated by determining a difference in the maximum gastric accommodation capacity before and after administration of the compound.

The Wistar Kyoto rats (WKY; M&B Denmark) are starved about 8 or 18 hours before each experiment depending on if the experiments are performed in the morning or in the afternoon. A small, inflatable balloon is inserted through the central hole of the fistula into the distal part of stomach under isoflurane anaesthesia (Forene ^® , Abbott Scandinavia AB) and fixed in its position through the tightening of the fistula. The balloon has a spherical shape with a wall thickness of about 15 μm, a non-distensible max diameter of 25 mm and a max volume of about 7 ml. The balloon is connected to a double-lumen polyethylene catheter with an outer diameter of 1.40 mm and a length of about 20 cm. The inner lumen diameter of the catheter was about 0.58 mm. The animals are placed in a specially designed Bollmann cage, with an

inner diameter of 60 mm for females and 70 mm for males. The catheter is then, via a pressure transducer, connected to a barostat system.

A barostat system maintains the pressure by pumping air into and out of the balloon. After the experiment the balloon and the connecting cable are removed under isofiurane anaesthesia and the animals are returned to their normal cages.

A combination of ramp and tonic distension is used in all the experiments. The protocol starts with a minimum distension pressure of 1 mm Hg and continues for 20 min in order to collect base line values. The pressure is then increased by a velocity of 1-4 mm Hg/min for 10 min to a maximum pressure of 10-20 mm Hg (ramp phase). The barostat then keeps the pressure at the maximum pressure for 10 more min (tonic phase). After the tonic phase the pressure drops to the minimum distension pressure of 1 mm Hg in about Is. The pressure is then kept at this level for another 20-minute period.

Methods of Preparation

In another aspect the present invention provides a process for preparing a compound of the formula (I) or salts thereof which process comprises:

a) reacting a compound of the formula (II) with a compound of the formula (III):

(H)

(HI)

wherein Ar ¹ and Ar ² are as hereinbefore defined; L is a suitable leaving group such as methylthio or sulfo and R is a hydrogen atom or a protective group such as tert- butyloxycarbonyl; and wherein any other functional group before then has been protected, if necessary; and the conditions are such that an N-C bond is formed between the nitrogen atom of the amino group of the compounds of formula (II) and the 2-carbon atom of the imidazoline ring of the compounds of formula (III), and thereafter any optionally protective group is being removed by as for instance utilizing an acid or base catalysed hydrolytic reaction, and then by way of conclusion optionally forming a pharmaceutically acceptable salt.

The coupling reaction is typically performed at an elevated temperature, for example 30 - 130 ⁰ C, optionally by using microwave single node heating, preferably in a polar solvent for example methanol.

The compounds of the formulae (II) may be prepared, for example, by reacting a compound of formulae (IV) with ammonia under conditions of reductive amination.

(IV)

The reductive amination reaction is typically performed at a non-extreme temperature, for example 0-130 ⁰ C, in a substantially inert solvent for example dichloromethane. Typical reducing agents include borohydrides such as sodium cyanoborohydride.

The compounds of formula (II) may also be prepared by reacting a compound of formula (IV) with hydroxylamine followed by a reduction of the formed oxime using as for instance reductive hydrogenation conditions.

The compounds of formula (III) are known or may be prepared as for instance by the procedures described in Tetrahedron Lett; 41 (2000) 6563-6566.

The compounds of formula (IV) are known or may be prepared by standard techniques for obtaining aryl arylmethyl ketones. Examples of such methods are for instance Grignard reaction (see e.g. J. Am. Chem. Soc; 55 (1933) 703-704), Horner-Emmons condensation (see e.g. Tetrahedron Lett.; 39 (1998) 1717-1720), or Friedel-Craft acylation (see e.g. J. Med. Chem.; 46 (2003) 1870-1877).

Examples

The following abbreviations are used in the experimental description: DIPEA (N, N- diisopropylethylamine), DMF (7V,λ/-dimethylformamide), EDC (l-ethyl-3-[3- dimethylaminopropyl]carbodiimide), HOBt (N-hydroxybenzotriazole), THF (tetrahydrofuran) and RT (room temperature).

The following abbreviations are used in the chemical structures: Ms (methanesulfonyl) and Bu (n-butyl).

The following abbreviations are used in the presentation of the NMR data of the compounds: s-singlet; d-doublet; t-triplet; qt-quartet; qn-quintet; m-multiplet; b-broad.

The following examples will describe, but not limit, the invention.

Example 1 (Method A)

(+)-4-[ 1 -(4,5-dihvdro- lH-imidazol-2-ylamino)-2-phenylethvHphenol acetate

(+)-4-[l-Amino-2-phenylethyl]phenol (see Intermediate 1 b; 0.21 g, 0.97 mmol), tert-butyl 2- (methylthio)-4,5-dihydro-lH-imidazole-l-carboxylate (0.30 g, 1.4 mmol), acetic acid (0.5 mL) and methanol (4.5 mL) were mixed. The reaction mixture was heated at 100°C for one hour and then at 140°C for 10 min, each time using microwave single node heating. The solvent was removed by evaporation. The product was purified by means of reversed phase

chromatography (Kromasil ®, C8) using a mixture of acetonitrile and aqueous 0.2% acetic acid as eluent. The proper fraction were combined and the solvent was removed by freeze- drying. There was obtained 0.24 g (71%) of the title compound. ¹ H NMR (500 MHz, CD ₃ OD): 1.9 (s, 3H), 3.0-3.1 (m, 2H), 3.5-3.6 (s, 4H), 4.6 (t, IH), 6.8 (d, 2H), 7.1 (d, 2H), 7.2 (m, 3H), 7.3 (t, 2H); LC MS: m/z 282 (M+l) ⁺ ; [α] = +6.75 (c. 0.4 g/mL in chloroform, RT and 589 nm).

Example 2 (Method B)

(+)-4-[ 1 -(4,5-Dihvdro- lH-imidazol-2-ylamino)-2-phenylethvHphenol hydrochloride

(+)-4-[l -(4,5-Dihydro- lH-imidazol-2-ylamino)-2-phenylethyl]phenol acetate (0.17 g, 0.49 mmol) was dissolved in water (100 mL) and to the resultant solution was added hydrochloric acid (2M, 1 mL). The volatiles were removed by freeze-drying and there was obtained 0.14 g (90%) of the title compound. ¹ U NMR (500 MHz, CD ₃ OD): 3.0-3.1 (m, 2H), 3.5-3.6 (m, 4H), 4.6 (dd, IH), 6.8 (d, 2H), 7.1 (d, 2H), 7.2 (m, 3H), 7.3 (t, 2H); LC MS m/z 282 (M+l) ⁺ .

Example 3 (Method C)

N-(9, 10-Dihvdrophenanthren-9-yl)-4,5-dihydro- lH-imidazol-2-amine acetate

9,10-Dihydrophenanthren-9-amine (see J. Org. Chem.; 52; (1987) 753-759; 0.31 g, 1.6 mmol) and 4,5-dihydro-lH-imidazole-2-sulfonic acid (0.24 g, 1.6 mmol were mixed together with isobutanol (5 mL). The reaction mixture was heated at 140°C for 10 min using microwave single node heating. The solvent was removed by evaporation. The product was purified by means of reversed phase chromatography (Kromasil ®, C8) using a mixture of acetonitrile and aqueous 0.2 M ammonium acetate as eluent. The solvent was removed by freeze-drying. There was obtained 0.26 g (52%) of the title compound. ¹ H NMR (500 MHz, CDCl ₃ ): 1.7 (s,

3H), 2.8-3.0 (m, 2H), 3.4 (b, 4H), 3.7 (s, IH), 4.6 (dd, IH), 7.1 (d, IH), 7.2-7.4 (m, 5H), 7.6- 7.8 (m, 2H); LC MS: m/z 264 (M+l) ⁺ .

Example 4 (Method D) λ/-r2-(3,5-Difluorophenyl)-l-phenylethyll-4,5-dihvdro-lH-im idazol-2-amine formate

2-(3,5-Difluorophenyl)-l-phenylethanamine hydrochloride (see Intermediate 2; 0.27 g, 1.0 mmol) and 4,5-dihydro-lH-imidazole-2-sulfonic acid (0.18 g, 1.1 mmol) were mixed together with triethylamine (0.11 g, 1.1 mmol) and isopropanol (5 mL). The reaction mixture was heated at 140°C for 10 min. The solvent was removed by evaporation. The product was purified by means of reversed phase chromatography (SunFire™ Prep C 18) using a mixture of acetonitrile and aqueous formic acid (0.1 M) as eluent. The solvent was removed by vacuum-centrifugation. There was obtained 43 mg (14%) of the title compound. ¹ H NMR (600 MHz, DMSOd ₆ ): 3.0 (d, 2H), 3.4-3.5 (s, 4H), 4.7-4.8 (t, IH), 7.0 (d, 2H), 7.0-7.1 (t, IH), 7.2-7.3 (t, IH), 7.3-7.4 (m, 4H), 8.4-8.5 (s, IH); LC MS: m/z 302 (M+ 1) ⁺ .

Example 5

N- (2-phenyl- 1 -r3-(trifluoromethyl)phenvHethvU -4,5-dihydro- lH-imidazol-2-amine hydrobromide

N- (2-(4-Bromophenyl)- 1 -[3-(trifluoromethyl)phenyl]ethyl} -4,5-dihydro- lH-imidazol-2- amine (see Example 6; 48 mg, 0.12 mmol) and Pd/C (5%, 17 mg) were mixed together with a small amount of ethanol. The mixture was hydrogenated at RT for 2 h. The catalyst was filtered off and the solvent was removed by evaporation. The product was dissolved in water and the volatiles were removed by freeze-drying. There was obtained 43 mg (88%) of the title compound. ¹ R NMR (500 MHz, CD ₃ OD): 3.0-3.2 (m, 2H), 3.6 (s, 4H), 4.9 (dd, IH), 7.2-7.3 (m, 5H), 7.5-7.7 (m, 4H); LC MS: m/z 334 (M+l) ⁺ .

Examples 6-36 The following compounds, which are tabulated below, were synthesised in an analogous way to one or other of the examples above (Method A, Method B, Method C or Method D) using an appropriate intermediate amino compound (see below): 7V-{2-(4-bromophenyl)-l-[3- (trifluoromethyl)phenyl] ethyl} -4,5-dihydro- lH-imidazol-2-amine (Example 6), N-[2-(3- fluorophenyl)-l-phenylethyl]-4,5-dihydro-l//-imidazol-2-amin e formate (Example 7), 3-[2- (4,5-dihydro- l//-imidazol-2-ylamino)-2-(4-hydroxyphenyl)ethyl]benzonitril e acetate (Example 8), 3-[2-(4,5-dihydro- l//-imidazol-2-ylamino)-2-phenylethyl]phenyl methanesulfonate formate (Example 9), 4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)-2-(3- hydroxyphenyl)ethyl]benzonitrile (Example 10), 7V-[l-(3-chlorophenyl)-2-phenylethyl]-4,5- dihydro-lH-imidazol-2-amine acetate (Example 11), 7V-[2-(3-chlorophenyl)-l-phenylethyl]- 4,5-dihydro- lH-imidazol-2-amine hydrochloride (Example 12), 4-[2-(4,5-dihydro-lH- imidazol-2-ylamino)-2-phenylethyl]phenol acetate (Example 13), 4-[2-(4,5-dihydro-lH- imidazol-2-ylamino)-2-(4-hydroxyphenyl)ethyl]benzonitrile (Example 14), N-[2-(4- chlorophenyl)-l-phenylethyl]-4,5-dihydro-l//-imidazol-2-amin e acetate (Example 15), 4,4'- [ 1 -(4,5-dihydro- l//-imidazol-2-ylamino)ethane- 1 ,2-diyl]diphenol hydrochloride (Example 16), 3-[l -(4,5-dihydro- l//-imidazol-2-ylamino)-2-phenylethyl]phenol acetate (Example 17),

4-[l-(4,5-dihydro-lH-imidazol-2-ylamino)-2-phenylethyl]ph enol acetate (Example 18), (+)-3- [l-(4,5-dihydro-lH-imidazol-2-ylamino)-2-phenylethyl]phenol (Example 19), 7V-(1,2- diphenylethyl)-4,5-dihydro-lH-imidazol-2-amine acetate (Example 20), 7V-[2-(2,3- dimethoxyphenyl)-l-phenylethyl]-4,5-dihydro-lH-imidazol-2-am ine formate (Example 21), λ/-[2-(2-fiuorophenyl)-l-phenylethyl]-4,5-dihydro-lH-imidaz ol-2-amine acetate (Example 22), λ/-[2-(l-naphthyl)-l-phenylethyl]-4,5-dihydro-lH-imidazol-2 -amine formate (Example 23), 7V-[2-(2-chlorophenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine hydrochloride (Example 24), 7V-[2-(4-butoxyphenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine acetate (Example 25), 4-[2-(2,3-dichlorophenyl)-2-(4,5-dihydro-lH-imidazol-2- ylamino)ethyl]phenol acetate (Example 26), 3-[2-(4,5-dihydro-lH-imidazol-2-ylamino)-2- phenylethyljphenol formate (Example 27), λ/-{l-phenyl-2-[2-(trifluoromethyl)phenyl]ethyl}- 4,5-dihydro-lH-imidazol-2-amine formate (Example 28), 7V-[2-(3-butoxyphenyl)-l- phenylethyl]-4,5-dihydro-lH-imidazol-2-amine formate (Example 29), 7V-[2-(2,5- dimethoxyphenyl)-l-phenylethyl]-4,5-dihydro-lH-imidazol-2-am ine formate (Example 30), λ/-[2-(2-methoxyphenyl)-l-phenylethyl]-4,5-dihydro-lH-imida zol-2-amine formate (Example 31), 7V-[2-(2,3-difluorophenyl)-l-phenylethyl]-4,5-dihydro-lH-imi dazol-2-amine formate (Example 32), 7V-[2-(2-chloro-6-fluorophenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2- amine acetate (Example 33), 4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)-2- phenylethyljphenyl methanesulfonate acetate (Example 34), 7V-(2-phenyl-l-pyridin-3- ylethyl)-4,5-dihydro-lH-imidazol-2-amine (Example 35) and N-(2 -phenyl- 1 -pyridin-4- ylethyl)-4,5-dihydro-lH-imidazol-2-amine (Example 36).

The amino compounds, used as key intermediates in the syntheses of Examples 6-36, are either known compounds or the preparation thereof being described in the literature cited below, or the preparation thereof being described in the Intermediate examples below: Ex 6 (see Intermediate 3), Ex 7 (see Intermediate 4), Ex 8 (see Intermediate 5), Ex 9 (see Intermediate 6), Ex 10 (see Intermediate 7), Ex 11 (see US 4536599), Ex 12 (see Arzneimittel-Forschung; 28 (1978) 1561-1564), Ex 13 (see Arch. Pharm.; 274 (1936) 153- 173), Ex 14 (see Intermediate 8), Ex 15 (see Bull. Chem. Soc. Jap.; 59 (1986) 3581-3587), Ex 16 (see J. Am. Chem. Soc; 71 (1986) 3219-3221), Ex 17 (see Tetrahedron; 33 (1977) 489-

495), Ex 18 (see EP 356035), Ex 19 (see Intermediate 9), Ex 20 (commercially available), Ex 21 (see Intermediate 10), Ex 22 (see Intermediate 11), Ex 23 (see EP 659737), Ex 24 (see Intermediate 12), Ex 25 (see Angew. Chem.; 63 (1951) 421-430), Ex 26 (see Intermediate 13), Ex 27 (see J. of Med. Chem.; 21 (1978) 1265-1269), Ex 28 (see Intermediate 14), Ex 29

(see Intermediate 15), Ex 30 (see Intermediate 16), Ex 31 (see J. of Med. Chem.; 21 (1978) 1265-1269), Ex 32 (see Intermediate 17), Ex 33 (see Intermediate 18), Ex 34 (see Intermediate 19), Ex 35 and Ex 36 (see J. Med. Chem.; 38 (1995) 1600-1607).

Preparation of Starting Materials

The starting materials for the examples above are either commercially available or, they are readily prepared by standard methods from known materials. For example, the following reactions are an illustration, but not a limitation, of some of the starting materials.

Intermediate 1

(+) and (-)-enantiomers of 4-ri-amino-2-phenylethvHphenol

The enantiomers of 4-[l-amino-2-phenylethyl]phenol (for racemate, see Obshch. Khim.; 21 (1951) 867-875; 0.35 g, 1.6 mmol) were separated by means of chiral HPLC using a Chiralcel® OJ column (250x20 mm). Approximately 45 mg were loaded on the column and then successively eluted with a mixture of heptane, ethanol and triethylamine (90/10/0.1). In total, there was obtained 0.14 g (99.9 % ee.) of the (-)-enantiomer and 0.12 g (98.9% ee.) of the (+)-enantiomer. The (-)-isomer eluted first from the column.

(a) (-)-4-[ 1 -Amino-2-phenylethyl]phenol

¹ R NMR (500 MHz, CD ₃ OD): 2.9 (d, 2H), 4.0 (t, IH), 6.7 (d, 2H), 7.1 (m, 4H), 7.1-7.2 (t, IH), 7.2 (t, 2H); LC MS: m/z 214 (M+l) ⁺ ; [α] = -56.2° (0.5 g/100 mL in acetonitrile, RT and 589 mn)

(b) (+)-4-[ 1 -Amino-2-phenylethyl]phenol

¹ U NMR (500 MHz, CD ₃ OD): 2.9 (d, 2H), 4.0 (t, IH), 6.7 (d, 2H), 7.1 (m, 4H), 7.1-7.2 (t, IH), 7.2 (t, 2H); LC MS: m/z 214 (M+l) ⁺ ; [α] = +56.6° (0.5 g/100 mL in acetonitrile, RT and 589 nm).

Intermediate 2

2-(3 ,5-DifluorophenvD- 1 -phenylethanamine hydrochloride

(a) 2-(S, 5-Difluorophenyl)-l-phenylethanone

To a solution of 3,5-difluorophenylacetic acid (10.0 g, 0.058 mol) in dichloromethane (100 mL) was added thionyl chloride (8 mL, 0.11 mol) followed by a drop of DMF. The reaction mixture was stirred at RT for 2 h. The solvent was removed by evaporation and then the residue was dissolved in benzene (150 mL). The solution was cooled and aluminium chloride (16.7 g, 0.13 mol) was added portionwise. The reaction mixture was stirred at RT for 10 h and then quenched with ice water. The mixture was extracted with diethyl ether. The organic layer was washed with aqueous 15% NaHCO ₃ and then with brine. The solution was dried over Na ₂ SO ₄ and the solvent was removed by evaporation. The product was purified by chromatography on silica gel using a mixture of ethyl acetate and petroleum ether. There was obtained 8.0 g (60%) of 2-(3,5-difluorophenyl)-l-phenylethanone as a yellow oil.

(b) 2-(3,5-Difluorophenyl)-l -phenylethanamine hydrochloride

A mixture of 2-(3,5-difluorophenyl)-l-phenylethanone (4.0 g, 17 mmol), sodium acetate (3.5 g, 43 mmol), hydroxylamine hydrochloride (2.6 g, 34 mmol) and methanol (50 mL) was

heated to reflux for one hour. The solvent was removed by evaporation and the residue was partitioned between dichloromethane and water. The organic solution was washed with brine and dried over Na ₂ SO ₄ . The solvent was removed by evaporation and the residue (3.4 g) was dissolved in ethanol (50 mL). To the solution was added Pd/C (10%, 0.5 g) and the mixture was hydrogenated at RT overnight. The catalyst was filtered off using Celite® and the solvent was removed by evaporation. The residue was dissolved in diethyl ether (15 mL) and the solution was then treated with a saturated solution of HCl in diethylether (15 mL) for 30 min. The product was isolated by filtration and there was obtained 2.8 g (60%) of the title compound as a white solid. ¹ U NMR (400 MHz, DMSOd ₆ ): 3.1-3.2 (m, IH), 3.4 (m, IH), 4.6 (m, IH), 6.9 (d, 2H), 7.0 (m, IH), 7.3-7.4 (m, 3H), 7.5 (d, 2H), 8.7 (b, 3H); LCMS: m/z 234 (M+ 1) ⁺ .

Intermediate 3

2-(4-BromophenvD- 1 -r3-(trifluoromethyl)phenyllethanamine

To a solution of 2-(4-bromophenyl)-l-[3-(trifluoromethyl)phenyl]ethanone (0.71 g, 2.1 mmol) and ammonium acetate (1.5 g, 19 mmol) in methanol (50 mL) was added sodium cyano borohydride (1.5 g, 23.4 mmol). The reaction mixture was stirred at 60°C overnight. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO ₃ . The organic layer was washed with water and then extracted several times with HCl (aq, 2M). The combined aqueous solutions were neutralised with NaHCO ₃ and extracted three times with ethyl acetate. The organinc solutions were dried over MgSO ₄ and the solvent was removed by evaporation. The product was purified by reversed phase chromatography (Kromasil ®, C8) using a mixture of acetonitrile and aqueous 0.2% acetic acid as eluent. The proper fractions were combined and concentrated. The remaining concentrated aqueous solution was neutralised with NaHCO ₃ and then extracted three times with ethyl acetate. The organic solution was dried over MgSO ₄ and the solvent was removed by evaporation. There was obtained 0.32 g (45%) of the title compound as colorless oil. ¹ U NMR (500 MHz, CDCl ₃ ): 2.8 (dd, IH), 2.9-3.0 (dd, IH), 4.2 (dd, IH), 7.0 (d, 2H), 7.4 (m, 3H), 7.5 (m, 2H), 7.6 (s, IH); LC MS: m/z 345 (M+ 1) ⁺ .

Intermediate 4

2-(3 -Fluorophenyl)- 1 -phenylethanamine hydrochloride

The title compound was prepared according to the protocol described in Intermediate 2 b using 2-(3-fluorophenyl)-l-phenylethanone as the ketone starting material (yield 49%). ¹ H NMR (400 MHz, DMSOd ₆ ): 3.1-3.2 (m, IH), 3.4 (m, IH), 4.5-4.6 (m, IH), 6.9-7.0 (m, 2H), 7.2-7.3 (m, IH), 7.3-7.4 (m, 3H), 7.4-7.5 (m, 2H), 8.6-8.7 (b, 3H); LCMS: m/z 216 (M+l) ⁺ .

Intermediate 5

3-r2-Amino-2-(4-hvdroxyphenyl)ethvHbenzonitrile

The title compound was prepared according to the protocol described in Intermediate 2 a but using (3-cyanophenyl)acetyl chloride (see Pharmazie 31 (1976), 432-436) and phenol as starting materials, followed by an reductive amination procedure as described in inter-mediate 3 (yield 8%). ¹ U NMR (500 MHz, CD ₃ OD): 2.9 (dd, IH), 3.0 (dd, IH), 4.0 (t, IH), 6.7 (d, 2H), 7.0-7.1 (d, IH), 7.3-7.4 (m, 3H), 7.4-7.5 (m, IH); LCMS: m/z 239 (M+l) ⁺ .

Intermediate 6 3-(2-Amino-2-phenylethyl)phenyl methanesulfonate hydrochloride

(a) tert-Butyl [2-(3-hydroxyphenyl)-l-phenylethyl] carbamate

To a cooled mixture of 3-(2-amino-2-phenylethyl)phenol (see J. Med. Chem. 21 (1978),

1265; 4.0 g, 19 mmol) in THF (50 mL) and an aqueous solution of saturated NaHCO ₃ (50

mL) was added BOC-anhydride (4.5 g, 21 mmol) drop wise. The reaction mixture was stirred at RT for 2 h. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and with brine and then dried over Na ₂ SO ₄ . The solvent was removed by evaporation and there was obtained 6 g ( 100%) of tert-butyl [2-(3 -hydroxyphenyl)- 1 -phenylethyl] carbamate .

(b) 3-{2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}phenyl methanesulfonate

To an ice-cooled solution of tert-butyl [2-(3 -hydroxyphenyl)- 1 -phenylethyl] carbamate (3.0 g, 10 mmol) and triethylamine (2 mL, 14 mmol) in dichloromethane (30 mL) was added mesyl chloride (1.2 g, 10.5 mmol) dropwise. The reaction mixture was stirred at RT for one hour and then cooled water was added. The phases were separated and the aqueous solution was extracted with dichloromethane. The combined organic layers were washed with water and with brine and then dried over Na ₂ SO ₄ . The solvent was removed by evaporation and there was obtained 2.8 g (74%) of 3-{2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}phenyl methanesulfonate as a yellow gum.

(c) 3-(2-Amino-2-phenylethyl)phenyl methanesulfonate hydrochloride

To a solution of 3-{2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}phenyl methanesulfonate (2.8 g, 7.1 mmol) in ethanol (30 mL) was added concentrated hydrochloric acid (10 mL). The reaction mixture was stirred at RT for 2 h and then cooled water was added. The solvent was removed by evaporation and to the residue was added diethyl ether. The hydrochloride was isolated by filtration. There was obtained 1.5 g (64%) of the title compound as a white solid. ¹ U NMR (400 MHz, DMSO-de): 3.2 (dd, IH), 3.2-3.3 (s, 3H), 3.4 (m, IH), 4.5 (m, IH), 7.1- 7.2 (m, 3H), 7.4 (m, 4H), 7.4-7.5 (m, 2H), 8.7 (b, 3H); LC MS: m/z 292 (M+l) ⁺ .

Intermediate 7

4-r2-Amino-2-(3-hvdroxyphenyl)ethvHbenzonitrile

(a) 4- [2-Amino-2-(3-methoxyphenyl)ethyl] benzonitrile The compound was synthesised according to the reductive animation procedure described in Intermediate 3 but using 4-[2-(3-methoxyphenyl)-2-oxoethyl]benzonitrile as the ketone starting material (yield 47%).

(b) 4-[2-Am.ino-2-(3-hydroxyphenyl)ethyl]benzonitrile A solution of 4-[2-amino-2-(3-methoxyphenyl)ethyl]benzonitrile (0.16 g, 0.63 mmol) in dichloromethane (7 mL) under nitrogen was cooled to -78°C and then boron tribromide (2 mL, IM in dichloromethane, 2 mmol) was added dropwise. The reaction mixture was stirred at -78°C for one hour and then at RT for 30 min. Methanol (10 mL) was added with caution and the formed precipitation was dissolved gradually. The solvent was removed by evaporation and the residue was purified by reversed phase chromatography (Kromasil ®, C8) using a mixture of acetonitrile and aqueous 0.1 M ammonium acetate as eluent. The volatiles were removed by freeze-drying and there was obtained 0.12 g (40%) of the title compound as a white powder. ¹ R NMR (500 MHz, CD ₃ OD): 3.3 (m, IH), 3.4-3.5 (dd, IH), 4.5 (m, IH), 6.8-6.9 (m, 3H), 7.2-7.3 (t, IH), 7.3-7.4 (d, 2H), 7.6 (d, 2H); LC MS: m/z 239 (M+l) ⁺ .

Intermediate 8 4-r2-Amino-2-(4-hvdroxyphenyl)ethvHbenzonitrile acetate

The compound was synthesised according to the reductive amination procedure described in Intermediate 3 with the exception that the last neutralisation step was excluded and buy way of using 4-[2-(4-hydroxyphenyl)-2-oxoethyl]benzonitrile (see Pharmazie; 31 (1976) 432-436) as the ketone starting material (yield 5%). ¹ R NMR (500 MHz, CD ₃ OD): 1.9 (s, 3H), 3.2 (dd,

IH), 3.3-3.4 (dd, IH), 4.4 (dd, IH), 6.8 (d, 2H), 7.1-7.2 (d, 2H), 7.2-7.3 (d, 2H), 7.6 (d, 2H); LC MS: m/z 239 (M+l) ⁺ .

Intermediate 9 (+)-3-(l-amino-2-phenylethyl)phenol

The (+)-isomer was isolated by analogy with the procedure described in Intermediate 1 using racemic 3-(l-amino-2-phenylethyl)phenol (see Tetrahedron; 33 (1977) 489-495) as the ketone starting material (99.8% ee). ¹ R NMR (500 MHz, CD ₃ OD): 2.8-3.0 (m, 2H), 4.0 (t, IH), 6.6 (d, IH), 6.7 (s, IH), 6.7-6.8 (d, IH), 7.0-7.3 (m, 6H); LC MS: m/z 214 (M+l) ⁺ .

Intermediate 10

2-(2,3-DimethoxyphenvD- 1 -phenylethanamine hydrochloride

(a) 2-(2,3Diimethoxyphenyl)-N-methoxy-N-methylacetamide

To an ice-cooled solution of 2,3-dimethoxyphenyl acetic acid (5.0 g, 25 mmol), N, O-dimethyl hydroxylamine hydrochloride (2.7 g, 28 mmol), EDC hydrochloride (5.4 g, 28 mmol) and HOBt (0.58 g, 3 mmol) in dichloromethane (50 mL) triethylamine (11 mL, 76 mmol) was added under nitrogen. The mixture was stirred at RT over night and then diluted with water. The organic layer was washed with water and brine and then dried over Na ₂ SO ₄ . The solvent was removed by evaporation and there was obtained 5.8 g (96%) of 2-(2,3-dimethoxyphenyl)- 7V-methoxy-7V-methylacetamide as a brown oil.

(b) 2-(2, S -Dimethoxy phenyl) -1-phenylethanone Butyllithium (18.8 mL, 1.6 M in hexane, 30 mmol) was added to a solution of bromobenzene (3.0 mL, 27 mmol) in THF (50 mL) at -78°C under nitrogen. The mixture was stirred at -78°C

for 4 h and then 2-(2,3-dimethoxyphenyl)-λ/-methoxy-λ/-methylacetamide (5.8 g, 24 mmol) in THF (50 mL) was added dropwise. The mixture was stirred at -78°C for 5 h and then saturated aqueous ammonium chloride was added with caution and the mixture was concentrated. The residue was partitioned between dichloromethane and water. The organic layer was washed with water, dried over Na ₂ SO ₄ and then the solvent was removed by evaporation. The product was purified by chromatography on silica gel using a mixture of ethyl acetate and heptane. There was obtained 2.3 g (36%) of 2-(2,3-dimethoxyphenyl)-l- phenylethanone as an oil.

(c) 2-(2,3-Dimethoxyphenyl)-l-phenylethanamine hydrochloride

The compound was synthesised according to the procedure described in Intermediate 2b using 2-(2,3-dimethoxyphenyl)-l-phenylethanone (yield 61%). ¹ R NMR (400 MHz, DMSOd ₆ ): 3.1-3.2 (dd, IH), 3.3 (dd, IH), 3.6 (s, 3H), 3.7-3.8 (s, 3H), 4.5 (m, IH), 6.6 (t, IH), 6.8-6.9 (d, 2H), 7.3 (m, 3H), 7.4 (d, 2H), 8.7 (b, 3H); LC MS: m/z 358 (M+l) ⁺ .

Intermediate 11

2-(2-Fluorophenyl)- 1 -phenylethanamine

The compound was synthesised according to the reductive amination procedure described in Intermediate 3 but using 2-(2-fluorophenyl)-l-phenylethanone as the ketone starting material (yield 69%). ¹ U NMR (500 MHz, CDCl ₃ ): 2.9 (dd, IH), 3.1 (dd, IH), 4.3 (dd, IH), 7.0-7.4 (m, 9H); LC MS: m/z 216 (M+l) ⁺ . Intermediate 12 2-(2-Chlorophenyl)- 1 -phenylethanamine

The compound was synthesised according to the reductive amination procedure described in

Intermediate 3 but using 2-(2-chlorophenyl)-l-phenylethanone as the ketone starting material

(yield 73%). ¹ R NMR (500 MHz, CDCl ₃ ): 3.0 (dd, IH), 3.2 (dd, IH), 4.3 (dd, IH), 7.1-7.4 (m, 9H); LC MS: m/z 232 (M+l) ⁺ .

Intermediate 13 4-r2-Amino-2-(2,3-dichlorophenyl)ethvHphenol

(a) l-(2, 3-Dichlorophenyl)-2-(4-methoxyphenyl)ethanone

Bis(dibenzylideneacetone)palladium (0.24 g, 0.42 mmol), l,l '-bis(diphenylphosphmo)- ferrocene (0.25 g, 0.45 mmol) and potassium hexamethyldisilazide (2.3 g, 11.5 mmol) were mixed in a two necked flask under nitrogen. THF (10 mL) was added followed by 4- bromoanisole (0.99 g, 5.3 mmol). The mixture was stirred at RT for 30 min and then 2',3'- dichloroacetophenone was added. The reaction mixture was refluxed for 3 h, cooled to RT and then partitioned between ether and water. The organic layer was washed twice with water, dried over MgSO ₄ and then the solvent was removed by evaporation. The product was purified by chromatography on silica gel using a mixture of ethyl acetate and heptane. There was obtained 0.28 g (18%) of l-(2,3-dichlorophenyl)-2-(4-methoxyphenyl)ethanone as a solid.

(b) l-(2, 3-Dichlorophenyl)-2-(4-methoxyphenyl)ethanamine

The compound was synthesised according to the reductive amination procedure described in Intermediate 3 but using l-(2,3-dichlorophenyl)-2-(4-methoxyphenyl)ethanone as the ketone (yield 4%). ¹ R NMR (500 MHz, CD ₃ OD): 2.9 (dd, IH), 3.0-3.1 (dd, IH), 3.8-3.9 (s, 3H), 4.7 (t, IH), 6.8 (d, 2H), 7.0 (d, 2H), 7.3 (t, IH), 7.4-7.5 (m, 2H); LC MS: m/z 296 (M+l) ⁺ .

(c) 4-[2-Amino-2-(2, 3-dichlorophenyl)ethyl] phenol An aqueous solution of HBr (48%) was added to l-(2,3-dichlorophenyl)-2-(4- methoxyphenyl)ethanamine and the mixture was heated to reflux for 5 h and then left at RT over night. The mixture was extracted three times with ethyl acetate and the combined organic solutions were dried over MgSO ₄ and then the solvent was removed by evaporation. The residue was partitionated between dichloro methane and an aqueous solution OfNaHCO ₃ . The organic solution was dried using a phase separator and then the solvent was removed by

evaporation. There was obtained 7 mg (73%) of the title product. ¹ H NMR (500 MHz, CD ₃ OD): 2.7 (dd, IH), 2.9-3.0 (dd, IH), 4.6 (t, IH), 6.7 (d, 2H), 6.9 (d, 2H), 7.3 (m, IH), 7.4- 7.5 (m, 2H); LC MS: m/z 283 (M+l) ⁺ .

Intermediate 14

2-(2-TrifluoromethylphenvD- 1 -phenylethanamine

The compound was synthesised according to the procedures described in Intermediate 10 using 2-trifluoromethylphenyl acetic acid as the starting material (yield 6%). ¹ H NMR (400 MHz, DMSOd ₆ ): 3.3 (dd, IH), 3.4-3.5 (dd, IH), 4.5-4.6 (dd, IH), 7.2 (d, IH), 7.3-7.6 (m, 7H), 7.6-7.7 (d, IH); LC MS: m/z 266 (M+l) ⁺ .

Intermediate 15

2-(3-ButoxyphenvD- 1 -phenylethanamine hydrochloride

(a) tert-Butyl [2-(3-butoxyphenyl)-l-phenylethyl] carbamate To an ice-cooled mixture of tøt-butyl [2-(3-hydroxyphenyl)-l-phenylethyl] carbamate (see Intermediate 6a; 3.0 g, 10 mmol) and cesium carbonate (3.4 g, 10.5 mmol) in dichloromethane (30 mL) was added n-butyl iodide (1.9 g, 10.5 mmol) dropwise. The reaction mixture was stirred at RT for one hour and then cooled water was added. The phases were separated and the aqueous solution was extracted with dichloromethane. The combined organic layers were washed with water and with brine and then dried over Na ₂ SO ₄ . The solvent was removed by evaporation and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate and heptane. There was obtained 3.2 g (90%) of tert-hvXy\ [2-(3-butoxyphenyl)-l-phenylethyl] carbamate as a yellow gum.

(b) 2-(3-Butoxyphenyl)-l -phenylethanamine hydrochloride

Concentrated aqueous HCl (10 mL) was added dropwise to a solution of tert-bvXy\ [2-(3- butoxyphenyl)-l-phenylethyl] carbamate in ethanol (30 mL). The reaction mixture was stirred at RT for 2 h. The solvent was removed by evaporation and to the residue was added diethyl ether. The formed precipitate was isolated by filtration and there was obtained 1.5 g (57%) of 2-(3-butoxyphenyl)-l -phenylethanamine hydrochloride as a white solid. ¹ H NMR (400 MHz, DMSOd ₆ ): 0.9 (t, 3H), 1.4 (m, 2H), 1.6 (m, 2H), 3.1 (dd, IH), 3.2 (dd, IH), 3.8 (m, 2H), 4.5- 4.6 (dd, IH), 6.6 (m, 2H), 6.7 (d, IH), 7.1 (t, IH), 7.3-7.4 (m, 5H); LC MS: m/z 270 (M+l) ⁺ .

Intermediate 16

2-(2,5-Dimethoxyphenyl)- 1 -phenylethanamine

The compound was synthesised according to the procedures described in Intermediate 10 using 2,5-dimethoxyphenyl acetic acid as the starting material (yield 13%). ¹ H NMR (400 MHz, DMSOd ₆ ): 3.1-3.2 (dd, IH), 3.3 (dd, IH), 3.6 (s, 3H), 3.7 (s, 3H), 4.5 (m, IH), 6.6 (d, IH), 6.7 (dd, 2H), 6.8 (d, IH), 7.3 (m, 3H), 7.4 (d, 2H), 8.6-8.7 (b, 3H); LC MS: m/z 358 (M+ 1) ⁺ .

Intermediate 17

2-(2,3-DifluorophenvD- 1 -phenylethanamine

The compound was synthesised according to the procedures described in Intermediate 2 using 2,3-difluorophenyl acetic acid as the starting material (yield 35%). ¹ H NMR (400 MHz, DMSOd ₆ ): 3.2-3.3 (dd, IH), 3.3-3.4 (dd, IH), 3.6 (s, 3H), 4.5 (dd, IH), 6.9 (t, IH), 7.0 (m, IH), 7.2-7.3 (m, IH), 7.3-7.5 (m, 5H), 8.7 (b, 3H); LC MS: m/z 234 (M+l) ⁺ .

Intermediate 18

2-(2-Chloro-6-fluorophenyl)- 1 -phenylethanamine

The compound was synthesised according to the procedures described in Intermediate 2 using

2-chloro-6-fluorophenyl acetic acid as the starting material (yield 8%). ¹ H NMR (400 MHz,

DMSOd ₆ ): 3.4-3.5 (d, 2H), 4.7 (m, IH), 7.0-7.1 (m, IH), 7.2-7.4 (m, 7H), 9.0 (b, 3H); LC MS: m/z 234 (M+ 1) ⁺ .

Intermediate 19 4-(2-amino-2-phenylethyl)phenyl methanesulfonate

The compound was synthesised according to the procedures described in Intermediate 6 using 4-(2-amino-2-phenylethyl)phenol (see J. of Med. Chem.; 21 (1978) 1265-1269) as the starting material (yield 60%). ¹ U NMR (400 MHz, DMSOd ₆ ): 3.3 (s, 3H), 3.3-3.4 (m, 2H), 4.6-4.7 (m, IH), 7.2 (s, 4H), 7.4 (m, 2H), 7.4 (m, 3H); LC MS: m/z 292 (M+ 1) ⁺ .