4, 5-dihydro-l,3-thiazol-2-amine derivatives and their use in the treatment of respiratory, cardiovascular, neurological or gastrointestinal disorders

Field of the Invention

The present invention relates to compounds of formula (I), (XI) or (CI), 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), (XI) or (CI) 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 life-threatening 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 which 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 αi-, α ₂ - and β-receptors. The groups are further subdivided into six α-adrenoceptors, αiA, am, am, a ₂ A, (X ₂ B, ^{a2C anc} ^ three β-adrenoceptors βi, β ₂ , β ₃ (see e.g., Docherty J. R, European Journal of Pharmacology 361 (1998) 1-15). α-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. αi -adrenoceptors are implicated in processes such as vasoconstriction, glycogeno lysis, cardiac inotrophy and chronotrophy. α ₂ -adrenoceptors are associated with platelet aggregation, neurotransmitter 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 α agonists.

WO 2005/063724 describes certain l-(azolin-2-yl)amino-l,2-diphenylethane compounds.

Brown D. G. et al., "Design and synthesis of amino imidazoline derived analogs as selective α ₂ c-adrenoceptor agonists" describes 2-amino-indan analogues, poster presented at 219th American Chemical Society National Meeting, San Francisco, CA, March 26-30, 2000.

US 3636219 describes anticholinergic compositions containing certain thiazo lines or imidazolines.

Goro H. et al., Nippon Yakurigaku Zasshi (1965), 61(6), 479-89 describes the pharmacological effects of 2-( 1 ,2,3 ,4-tetrahydro- 1 -naphtyl-amino)-2-imidazoline hydrochloride.

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)

N

(I) wherein

Ar ¹ is

R ¹ is independently selected from halogen, hydroxy, cyano, C1-C5 alkoxy, C1-C3 alkyl, C1-C3 alkylsulfonate or C1-C3 alkoxy substituted by C1-C3 alkoxy; wherein the alkyl group, alkoxy group or alkylsulfonate group may be substituted by one or more fiuoro atom(s); m is O, 1, 2, 3, 4 or 5; Ar ² is

R ² is independently selected from halogen, hydroxy or C1-C3 alkyl; wherein the alkyl group may be substituted by one or more fiuoro atom(s); n is 0, 1, 2, 3, 4 or 5; 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 ² 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; with the exception of compounds wherein X and Y and Z are carbon; and R ¹ is methyl; and m is 0 or 1 or 2; and

R ² is halogen, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy or CF ₃ ; and n is 0 or 1 or 2 or 3; with the further exception of compounds wherein

X and Y and Z are carbon; R ¹ is methoxy or CF _{3 ;} and m is 1 or 2; and n is 0; with the further exception of compounds wherein

X and Y and Z are carbon; R ¹ is halogen;

and m is 1 or 2 or 3 or 4 or 5; and n is 0; with the further exception of compounds wherein

X and Y and Z are carbon; R ¹ is halogen or methoxy; and m is 1; and

R is halogen or methoxy; and n is 1. In one embodiment of the present invention R ¹ of formula (I) is chloro, fluoro, bromo, hydroxy, trifiuoromethyl, methoxy, butoxy, methylsulfonate or cyano.

In one embodiment of the present invention R ² of formula (I) is chloro, hydroxy or trifiuoromethyl.

In one embodiment of the present invention R ¹ of formula (I) is hydroxy. In one embodiment of the present invention R ² of formula (I) is hydroxy. In one embodiment of the present invention, m of formula (I) is 0, 1 or 2. In one embodiment of the present invention, n of formula (I) is 0, 1 or 2.

In one embodiment X or Y or Z of formula (I) is nitrogen. In one embodiment Y of formula (I) is nitrogen. The present invention also provides a compound of the general formula (XI)

(XI) wherein

R ¹ is hydrogen, phenyl or allyl;

wherein the phenyl may be substituted by carbamoyl, methylcarbamoyl or dimethylcarbamoyl in the para position or by one or two halogen atom(s) in any position;

R ² is hydrogen, Ci -C ₃ alkyl or hydroxy; n is 1 or 2; wherein the alkyl group or allyl group may be substituted by one or more fluoro atom(s); as well as pharmaceutically and pharmacologically acceptable salts thereof and stereoisomers of the compound of formula (XI) and salts thereof; with the exception of compounds wherein both R ¹ and R ² are H.

In one embodiment of the present invention R ¹ of Formula (XI) is phenyl.

In one embodiment of the present invention R ² of Formula (XI) is methyl or hydroxy.

In one embodiment of the present invention, n of Formula (XI) is 1.

The present invention further provides a compound of the general formula (CI)

(CI) wherein

R ¹ is hydrogen or Ci -C ₅ alkyl;

R is selected from hydrogen, halogen, Ci-C ₃ alkyl, Ci-C ₃ alkoxy, hydroxy, 4- carbamoyl, 4-methylcarbamoyl or 4-dimethylcarbamoyl;

R ³ is selected from hydrogen, halogen, Ci-C ₃ alkyl, Ci-C ₃ alkoxy or hydroxy;

X is O, S or NH; wherein the alkyl or alkoxy group may be substituted by one or more fluoro atom(s);

as well as pharmaceutically and pharmacologically acceptable salts thereof, and stereoisomers of the compound of formula (CI).

In one embodiment of the present invention R ¹ of Formula (CI) is hydrogen or C ₁ -C ₃ alkyl. In one embodiment of the present invention X of Formula (CI) is NH. In one further embodiment of the present invention X of Formula (CI) is S.

The present invention relates to compounds of formula (I), (XI) and (CI) 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), (XI) and (CI). 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), (XI) and (CI) 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), (XI) and (CI) 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), (XI) and (CI) 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), (XI) and (CI). 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 "Ci -C ₃ 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 "C ₁ -C ₅ 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-propoxy, 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 difiuoromethoxy or trifiuoromethoxy.

Unless stated otherwise, the term "C1-C5 alkyl" includes straight as well as branched alkyl groups having 1 to 5 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, 1-methyl-propyl, 2-methyl-propyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 1,1- dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethyl-propyl and 1-ethylpropyl.

Unless stated otherwise, the term "Ci-C ₃ alkoxy" includes straight as well as branched alkyl groups having 1 to 3 carbon atoms attached via an oxygen atom, for example methoxy, ethoxy, propoxy and iso-propoxy. The alkyl group may be substituted by one or more fluoro atoms, such as in difiuoromethoxy or trifiuoromethoxy. Unless stated otherwise, the term "halogen" includes fluorine, chlorine, bromine or iodine.

Unless stated otherwise, the term "Ci-C ₃ 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.

Unless stated otherwise, the term "allyl" is equvalent with prop-2-en-l-yl.

In one embodiment of the present invention, the compounds of formula (XI) are selective α ₂ B agonists. A selective α ₂ β agonist is defined herein as a compound having a ratio of EC50 for ot2A/ot2B >1 and ⁽ X ₁ AAx ₂ B ^> ^ -

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), (XI) or (CI), 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, inflammatory 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), (XI) or (CI) or a pharmaceutically acceptable salt thereof. In another example, for administration by inhalation, a compound of the formula (I), (XI) or (CI) 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), (XI) or (CI) 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 α adrenergic receptors is beneficial which comprises administering to a subject an effective amount of a compound of the formula (I), (XI) or (CI) or a pharmaceutically- acceptable salt thereof. The present invention also provides the use of a compound of formula (I), (XI) or (CI) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in a disease condition wherein agonism of α adrenergic receptors is beneficial. The compounds of formula (I), (XI) or (CI) 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), (XI) or (CI) 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 thereof, a therapeutically effective amount of a compound of formula (I), (XI) or (CI) or a pharmaceutically acceptable salt thereof.

Pharmacology Three functional α ₂ adrenoceptor subtypes are described, α ₂ A, CX _2B and α ₂ c and they all belonging to the GPCR superfamily. All three α 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 OI _2AB receptors were used for functional screening of compounds. Expression of engineered G _qi 5 (the last 5 amino acids of Gα _q 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 CC _2A or human CC _2B 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 CC _2A receptor and by manually adding drops containing one cell to 96 well plates for human CC ₂ B receptor. The HEK293SGqis cells stably expressing human CC ₂ A and CC ₂ B 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 CC _∑A and Cc ₂ B 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 _2B 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 ²⁺ 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. Apredilution 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 the CC ₂ A and/or CC ₂ B receptors at low levels. The EC50 (0C _2B ) value was generally less than 260 nM.

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 isofiurane 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 for formula (I)

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):

(Ill) wherein Ar ¹ and Ar ² are as hereinbefore defined for formula (I); L is a suitable leaving group such as bromo or chloro and; 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 carbon atom of the isothiocyanate group of the compounds of formula (III) and an S-C bond is formed between the sulfur atom of the compounds of formula (III) and the carbon atom adjacent to the leaving group L, 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 a non-extreme temperature, for example at room temperature (RT), preferably in a non-polar solvent as for instance THF (tetr ahydr o fur an) .

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 formulae (IV) with hydroxylamine followed by a reduction of the formed oxime using as for instance reductive hydrogenation conditions.

The compounds of formulae (III) are commercially available or may be prepared by standard techniques.

The compounds of formulae (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].

Methods of preparation for formula (XI)

In yet another aspect the present invention provides a process for preparing a compound of the formula (XI) or salts thereof which process comprises: a) reacting a compound of the formula (XII) with a compound of the formula

(XIII):

(XII)

(XIII) wherein n, R ¹ and R ² are as hereinbefore defined for formula (XI); L is a suitable leaving group such as methylthio or sulfo and R ³ is a hydrogen atom or a protective group such as tøt-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 (XII) and the 2-carbon atom of the imidazoline ring of the compounds of formula (XIII), and thereafter any optionally protective group is being removed by as for instance utilizing an acid or base catalysed

hydro lytic 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 2-propanol.

The compounds of the formulae (XII) are known or may be prepared, for example, by a reductive amination reaction utilizing ammonia, a reducing agent and a compound of formulae (XIV):

(XIV) wherein n, R ¹ and R ² are as hereinbefore defined for formula (XI). The reductive amination reaction were typically performed using microwave single node heating at 100 ⁰ C, preferably in a polar solvent for example methanol.

Typical reducing agents include borohydrides such as sodium cyanoborohydride. The compounds of formula (XII) may also be prepared by reacting a compound of formulae (XIV) with hydroxy lamine followed by a reduction of the formed oxime using as for instance reductive hydrogenation conditions.

The compounds of formulae (XIII) are known or may be prepared as for instance by the procedures described in Tetrahedron Lett.; 41 (2000) 6563-6566. The compounds of formulae (XIV) are known or may be prepared by standard techniques for obtaining indan-1-ones and 1-tetralones as for instance by the procedures described in Chemistry Lett.; 5 (1988) 901-904.

Methods of preparation for formula (CI)

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

When X is NH; a) reacting a compound of the formula (CII) with a compound of the formula

(CIII):

(CII)

(CIII) wherein

R ¹ , R ² and R ³ are as hereinbefore defined for formula (CI); X is NH; L ¹ is a suitable leaving group such as methylthio or sulfo and R ⁴ is a hydrogen atom or a protective group such as tøt-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 (CII) and the 2-carbon atom of the imidazoline ring of the compounds of formula (CIII), and thereafter any optionally protective group is being removed by as for instance utilizing an acid or base catalysed hydro lytic 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.

When X is O or S; b) reacting a compound of the formula (CII) with a compound of the formula

(CIV):

(CIV) wherein

R ¹ , R ² and R ³ are as hereinbefore defined for formula (CI); X is O or S; L ² is a suitable leaving group such as bromo or chloro and; 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 (CII) and the carbon atom of the isothiocyanate or isocyanate group of the compounds of formula (CIV) and an S-C or O-C bond is formed between the sulfur or oxygen atom of the compounds of formula (CIV) and the carbon atom adjacent to the leaving group L , and thereafter any optionally protective group is being removed by as for instance utilizing an acid or base catalysed hydro lytic reaction, and then by way of conclusion optionally forming a pharmaceutically acceptable salt.

The coupling reaction is typically performed at a non-extreme temperature, for example at room temperature (RT), preferably in a non-polar solvent as for instance THF (tetr ahydr o fur an) .

The compounds of the formula (CII) are known or may be prepared, for example, by the procedures described in Bulletin de Ia Societe Chim. De France (1969), 1227-1233.

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

The compounds of formulae (CIV) are commercially available or may be prepared by standard techniques.

Examples

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

The following examples will describe, but not limit, the invention. Example 1 λ/-(l,2-Diphenylethyl)-4,5-dihydro-l,3-thiazol-2-amine acetate

1 ,2-Diphenylethanamine (0.24 g, 0.1.2 mmol) was dissolved in dry THF (2.5 mL) under nitrogen and to the resultant solution was added 2-Chloroethyl isothiocyanate (50 mg, 0.41 mmol) drop-wise. The reaction mixture was stirred for 25 min at RT. The formed precipitate was filtered off and the residue was diluted with ethyl acetate. The solution was washed with water and brine and then dried over Na ₂ SO ₄ . The solvent was removed by evaporation. The product was purified by means of reversed phase chromatography using a mixture of acetonitrile and aqueous 0.2 M ammonium acetate as eluent. The proper fractions were combined and the solvent was removed by freeze- drying. There was obtained 36 mg (31%) of the title compound. ¹ U NMR (400 MHz, CD ₃ OD): 1.9 (s, 3H), 3.0-3.1 (m, 2H), 3.2-3.3 (t, 2H), 3.7-3.8 (m, 2H), 4.8 (t, IH), 7.1-7.4 (m, 10H); LC MS: m/z 283 (M+l) ⁺ .

Example 2 4-fl -(4,5-Dihvdro- 1 ,3-thiazol-2-ylamino)-2-phenylethvHphenol acetate

4-(l-Amino-2-phenylethyl)phenol (see EP 356035; 0.29 g, 1.1 mmol) was dissolved in methylenechloride (10 mL) together with triethylamine (0.22 g, 2.2 mmol). To the resultant

solution was then slowly added 2-chloroethyl isothiocyanate (0.14 g, 1.2 mmol) during 10 minutes. The solution was washed with aqueous K2CO3 and then dried using a phase separator column. The solvent was removed by evaporation. The product was purified by crystallisation from a mixture of ethyl acetate and then further purified by means of reversed phase chromatography using a mixture of acetonitrile and aqueous 0.2 M ammonium acetate as eluent. The proper fractions were combined and the solvent was removed by freeze-drying. There was obtained 42 mg (11%) of the title compound. ¹ H NMR (400 MHz, CDCl ₃ ): 2.2 (s, 3H), 3.0-3.2 (m, 2H), 3.2-3.3 (t, 2H), 3.8-3.9 (t, 2H), 4.5-4.6 (t, IH), 6.6 (d, 2H), 7.0 (d, 2H), 7.1 (d, 2H), 7.2-7.3 (m, 3H); LC MS: m/z 299 (M+l) ⁺ . Example 3

4.4'-fl -(4,5-Dihvdro- 1 ,3-thiazol-2-ylamino)ethane- 1 ,2-diylidiphenol acetate

4,4'-(l-Aminoethane-l,2-diyl)diphenol (see J. Am. Chem. Soc; 71 (1986) 3219-3221; 0.13 g, 0.57 mmol) was dissolved in a mixture of methylenechloride (25 mL) and THF (5 mL) together with triethylamine (0.20 g, 1.4 mmol). To the resultant solution was then slowly added 2-chloroethyl isothiocyanate (35 mg, 0.28 mmol). The solvent was removed by evaporation and the product was purified by means of reversed phase chromatography using a mixture of acetonitrile and aqueous 0.2% acetic acid as eluent. The proper fractions were combined and the solvent was removed by freeze-drying. There was obtained 28 mg (26%) of the title compound. ¹ U NMR (500 MHz, CD ₃ OD): 1.9 (s, 3H), 2.9-3.0 (d, 2H), 3.2-3.4 (m,

2H), 3.7-3.9 (m, 2H), 4.7 (t, IH), 6.6-6.7 (d, 2H), 6.7-6.8 (d, 2H), 7.0 (d, 2H), 7.1 (d, 2H); LC MS: m/z 315 (M+l) ⁺ .

Example 4 4-r2-(4,5-Dihvdro-l,3-thiazol-2-ylamino)-2-pyridin-3-ylethyl lphenol

4-(2-Amino-2-pyridin-3-ylethyl)phenol (see Intermediate 1; 98 mg, 0.46 mmol) was dissolved in dioxane (3 mL). To the resultant solution was then slowly added 2-chloroethyl isothiocyanate (56 mg, 0.46 mmol). The mixture was stirred at 80°C for one h. The solvent was removed by evaporation and the product was purified by chromatography on silica gel using a mixture of methanol and methylenechloride. There was obtained 19 mg (12%) of of the title compound. ¹ !! NMR (500 MHz, CD ₃ OD): 3.0 (dd, IH), 3.1 (dd, IH), 3.3-3.4 (m, 2H), 3.8 (m, 2H), 4.9 (t, IH), 6.7 (d, 2H), 7.0 (d, 2H), 7.4 (m, IH), 7.8 (d, IH), 8.4 (s, IH), 8.4-8.5 (d, IH); LC MS: m/z 300 (M+l) ⁺ .

Example 5

λ/-(2-phenyl-2,3-dihydro- lH-inden- 1 -yl)-4,5-dihydro- lH-imidazol-2-amine acetate

2-Phenylindan-l -amine (see Yakugaku Zasshi 82 (1962) 1597-1603; 0.16 g, 0.76 mmol) was mixed with 2-propanol (5 mL) together with 4,5-dihydro-lH-imidazole-2-sulfonic acid (0.12 g, 0.79 mmol). The reaction mixture was heated at 130°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 using a mixture of acetonitrile and aqueous 0.2 M ammonium acetate as eluent. The proper fractions were combined and the solvent was removed by freeze-drying. There was obtained 55 mg (21%) of the title compound as a white powder. The product was a mixture of the cis and trans isomer. ¹ H NMR (500 MHz, CDCl ₃ ): 1.9 (s, 3H), 3.0-3.9 (m, 7H), 4.9 and 5.1 (two doublets, IH), 7.2-7.5 (m, 9H); LC MS: m/z 278 (M+ 1) ⁺ .

Example 6

λ/-(4-methyl-2,3-dihydro- lH-inden- 1 -yl)-4,5-dihydro- lH-imidazol-2-amine

4-Methylindan-l -amine (70 mg, 0.38 mmol) was mixed with isobutanol (5 mL) together with 4,5-dihydro-lH-imidazole-2-sulfonic acid (58 mg, 0.39 mmol). The reaction mixture was heated at 140°C for 10 min using microwave single node heating. The mixture was filtered and the product was purified by means of reversed phase chromatography using a mixture of acetonitrile and aqueous 0.2 M ammonium acetate as eluent. The proper fractions were combined and the solvent was removed by freeze- drying. There was obtained 10 mg (9%) of the title compound. ¹ R NMR (500 MHz, CDCl ₃ ): 1.8 (s, 3H), 1.9-2.0 (m, IH), 2.2 (d, 3H), 2.4-3.0 (m, 3H), 4.9 (d, IH), 7.0-7.2 (m, 3H); LC MS: m/z 216 (M+l) ⁺ .

Example 7 cz ^' s- A/-(4-methyl-2-phenyl-2,3-dihvdro- lH-inden- 1 -yl)-4,5-dihydro- lH-imidazol-2-amine acetate

4-Methyl-2-phenylindan-l -amine (see Intermediate 2; 0.25 g, 1.1 mmol) was mixed with 2- propanol (5 mL) together with 4,5-dihydro-lH-imidazole-2-sulfonic acid (0.17 g, 1.1 mmol). The reaction mixture was heated at 140°C for 10 min using microwave single node heating. The solvent was removed by evaporation and the residue was partitioned between methylenechloride and an aqueous alkaline solution. The organic solution was dried using a phase separator column and the solvent was removed by evaporation. The product was purified by means of reversed phase chromatography using a mixture of acetonitrile and aqueous 0.2 M ammonium acetate as eluent (gradient, 0-40% acetonitrile during 30 minutes). The two stereoisomers separated as the cis isomer came out first from the column. These

fractions were combined and the solvent was removed by freeze-drying. There was obtained 51 mg (26%) of the title compound as a white powder. The product was contaminated with approximately 20% of the trans isomer. ¹ H NMR (500 MHz, DMSO-d6): 1.6 (s, 3H), 2.3 (s, 3H), 3.0-3.7 (m, 9H), 3.8 (qt, IH), 5.1-5.2 (d, IH), 7.0-7.4 (m, 8H); LC MS: m/z 292 (M+l) ⁴

Example 8 trαn5-λ/-(4-methyl-2-phenyl-2,3-dihvdro- lH-inden- 1 -yl)-4,5-dihydro- lH-imidazol-2-amine acetate

This isomer - the trans isomer - was separated from the cis isomer according to the procedure described in Example 7. The late fractions were combined and the solvent was removed by freeze-drying. There was obtained 47 mg (24%) of the title compound as a white powder. ¹ H NMR (500 MHz, DMSO-d6): 1.6 (s, 3H), 2.2-2.3 (s, 3H), 2.9 (dd, IH), 3.0-3.7 (m, 9H), 5.1 (d, IH), 7.0-7.4 (m, 8H); LC MS: m/z 292 (M+l) ⁺ .

Example 9 λ/-(2-allyl-4-methyl-2,3-dihydro- lH-inden- 1 -yl)-4,5-dihydro- lH-imidazol-2-amine acetate

In a similar manner to the description in Example 5, /V-(2-allyl-4-methyl-2,3-dihydro-lH- inden-l-yl)-4,5-dihydro-l//-imidazol-2-amine acetate was prepared starting from 2-allyl-4- methylindan-1 -amine (0.11 g, 0.61 mmol). There was obtained 21 mg (11%) of the title compound as a white powder. ¹ U NMR (500 MHz, D ₂ O): 1.8 (s, 3H), 2.2 (s, 3H), 2.3 (m, 3H), 2.4-2.5 (dd, IH), 3.0 (dd, IH), 3.6 (s, 4H), 4.5 (d, IH), 5.0 (m, IH), 5.1 (d, IH), 6.8-6.9 (m, IH), 7.0 (d, IH), 7.1-7.2 (m, 2H); LC MS: m/z 256 (M+l) ⁺ .

Example 10

5-(4,5-Dihvdro-lH-imidazol-2-ylamino)-5,6,7,8-tetrahvdron aphthalen-l-ol acetate

In a similar manner to the description in Example 5, the title compound was prepared starting from 5-amino-5,6,7,8-tetrahydronaphthalen-l-ol (see Zhurnal Obshchei Khimii; 34 (1964) 1581-1586; 0.23 g, 1.4 mmol). There was obtained 21 mg (5%) as a white powder. ¹ H NMR (500 MHz, CD ₃ OD): 1.8-2.1 (m, 7H), 2.6-2.8 (m, 2H), 3.7 (s, 4H), 4.6 (t, IH), 6.7 (d, IH), 6.8 (d, IH), 7.0 (t, IH); LC MS: m/z 232 (M+l) ⁺ .

Example 11

λ/-(4,5-Dihydro- lH-imidazol-2-yl)-2-phenyl- lH-indol-3-amine acetate

2-Phenyl-lH-indol-3-amine (0.26 g, 1.2 mmol) and 4,5-dihydro-lH-imidazole-2-sulfonic acid (0.20 g, 1.3 mmol) were mixed together with acetic acid (0.60 g, 10 mmol) and isopropanol (5 mL). The reaction mixture was heated at 120°C for 10 min using microwave single node heating. The solvent was removed by evaporation. The product crystallised on treatment with water (5 mL). The product was washed with ethyl acetate and methylenechloride. There was obtained 0.11 g (27%) of the title compound. ¹ R NMR (400 MHz, CDCl ₃ ): 1.9 (s, 3H), 3.4 (b, 2H), 3.7 (b, 2H), 7.0 (t, IH), 7.1 (t, IH), 7.2 (m, IH), 7.3 (m, 3H), 7.4 (d, IH), 7.6 (d, 2H); LC MS: m/z 277 (M+ 1) ⁺ .

Example 12 λ/-(4,5-dihydro- lH-imidazol-2-yl)- 1 -methyl-2-phenyl- lH-indol-3-amine acetate

l-Methyl-2-phenyl-lH-indol-3-amine (see Journal fuer Praktische Chemie 28 (1965), 169-77; 0.18 g, 0.86 mmol) and 4,5-dihydro-lH-imidazole-2-sulfonic acid (0.15 g, 1.0 mmol) were mixed together with acetic acid (0.60 g, 10 mmol) and isopropanol (5 mL). The reaction mixture was heated at 140°C for 5 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 proper fractions were concentrated on a rotavapor and the remaining solvent was removed by freeze-drying. There was obtained 0.11 g (27%) of the title compound. ¹ R NMR (400 MHz, CDCl ₃ ): 2.0 (s, 3H), 3.4 (m, 2H), 3.6-3.8 (m, 5H), 7.2 (t, IH), 7.3 (t, IH), 7.4 (d, IH), 7.5 (m, IH), 7.5-7.6 (m, 3H), 7.6 (d, IH); LC MS: m/z 291 (M+ 1) ⁺ .

Example 13

λ/-(4,5-Dihydro- 1 ,3-thiazol-2-yl)-2-phenyl- lH-indol-3-amine hydrochloride

2-Phenyl-lH-indol-3-amine (0.26 g, 1.2 mmol) and 2-chloroethyl isothiocyanate (0.13 g, 1.1 mmol) were mixed together with methylenechloride (5 mL). The reaction mixture was heated at 140°C for 30 min using microwave single node heating. The solvent was removed by evaporation. The product crystallised on treatment with ether and the crystals were washed with ether. There was obtained 0.11 g (77%) of the title compound. ¹ H NMR (400 MHz,

CDCl ₃ ): 3.3 (t, 2H), 3.9 (t, H), 7.1 (t, IH), 7.2 (m, IH), 7.3 (m, IH), 7.4 (m, 3H), 7.5 (d, IH), 7.7 (d, 2H); LC MS: m/z 294 (M+l) ⁺ .

Example 14

λ/-(4,5-dihydro- 1 ,3-thiazol-2-yl)- 1 -methyl-2-phenyl- IH- indo 1-3-amine

1 -Methyl-2-phenyl- IH- indo 1-3 -amine (see Journal fuer Praktische Chemie 28 (1965), 169-77; 0.22 g, 0.96 mmol) and 2-chloroethyl isothiocyanate (0.14 g, 1.5 mmol) were mixed together with methylenechloride (5 mL). The reaction mixture was heated at 140°C for 30 min using microwave single node heating. The solvent was removed by evaporation. The product crystallised on treatment with a mixture of methylenechloride and ether (1:5) and the crystals were washed with ether. There was obtained 0.24 g (71%) of the title compound. ¹ H NMR (400 MHz, CDCl ₃ ): 3.2-3.3 (t, 2H), 3.7 (s, IH), 3.9 (t, H), 7.2 (t, IH), 7.3 (t, IH), 7.4 (d, IH), 7.4-7.6 (m, 4H), 7.6 (d, 2H); LC MS: m/z 308 (M+l) ⁺ .

Example 15

λ/-(4,5-Dihydro- lH-imidazol-2-yl)-2-phenyl- 1 -propyl- IH- indo 1-3-amine acetate

In a similar manner to the description in Example 12, 7V-(4,5-dihydro-lH-imidazol-2-yl)-2- phenyl- 1 -propyl- IH- indo 1-3-amine acetate was prepared starting from 2-phenyl- 1 -propyl- IH- indol-3-amine (see Intermediate 1; 0.11 g, 0.46 mmol). There was obtained 34 mg (19%) of the title compound. ¹ R NMR (400 MHz, CDCl ₃ ): 0.8 (t, 3H), 1.5 (m, 2H), 1.9 (s, IH), 3.3 (t, 2H), 3.6 (t, 2H), 4.0 (t, 2H), 7.1 (t, IH), 7.2 (t, IH), 7.3 (d, IH), 7.3-7.4 (m, 5H), 7.5 (d, IH); LC MS: m/z 319 (M+l) ⁺ .

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

4-(2-Amino-2-pyridin-3-ylethyl)phenol

(a) tert-Butyl 4-(2-oxo-2-pyridin-3-ylethyl)phenyl carbonate Diphenyl [anilino(pyridin-3-yl)methyl]phosphonate (see Tetrahedron Lett.; 39 (1993) 1717- 1720; 1.0 g, 2.4 mmol) and tert-butyl 4-formylphenyl carbonate (0.59 g, 2.6 mmol) were dissolved in a mixture of 2-propanol (2 mL) and THF (9 mL) under nitrogen. Anhydrous cesium carbonate (1.3 g, 3.8 mmol) was added and the solution was stirred at RT over night. HCl aq (2M, 3.6 mL) was added dropwise and the mixture was stirred for 6 h. The solution was neutralized to pH 7-8 with aqueous NaOH (2M) and then extracted several times with ethyl acetate. The combined organic solutions were dried over Na ₂ SO ₄ and the was removed by evaporation. Theere was obtained 0.59 g (71%) of tert-butyl 4-(2-oxo-2-pyridin-3- ylethyl)phenyl carbonate partly contaminated with 2-(4-hydroxyphenyl)-l-pyridin-3- ylethanone, which is the target in the next step. LCMS: m/z 314 (M+l) ⁺ .

(b) 2-(4-Hydroxyphenyl)-l-pyridin-3-ylethanone tert-Butyl 4-(2-oxo-2-pyridin-3-ylethyl)phenyl carbonate (0.59 g, 1.9 mmol) was dissolved in a mixture of HCl and dioxane (4M, 6 mL). The solution was stirred at 80°C for 2 h and then cooled to RT. The acid was quenched by adding K ₂ CO ₃ . The solution was filtered and the filtrate was removed by evaporation. The residue was dissolved in a mixture of acetonitrile and water (1:1) and the solution was filtered through a reversed phase column eluting with acetonitrile and water. There was obtained 0.24 g (59%) of 2-(4-hydroxyphenyl)-l-pyridin-3-

ylethanone. ¹ R NMR (500 MHz, DMSO-J ₆ ): 4.4 (s, 2H), 6.7-6.8 (d, 2H), 7.1 (d, 2H), 7.9 (m, IH), 8.7 (d, IH), 9.0 (d, IH), 9.4 (s, IH); LCMS: m/z 214 (M+l) ⁺ .

(c) 4-(2-Amino-2-pyridin-3-ylethyl)phenol

2-(4-Hydroxyphenyl)-l-pyridin-3 -ylethanone (0.24 g, 1.1 mmol) was dissolved in methanol and to the resultant solution was added sodium cyano borohydride (0.10 g, 1.6 mmol), sodium acetate (0.85 g, 11 mmol) and molecular sieves (4A). The mixture was stirred at 100°C for 20 min using microwave single node heating. The solvent was removed by evaporation and the residue was dissolved in methanol. The organic solution was filtered through a strong cation exchange column eluting first with THF, then with methanol and finally with ammonia saturated methanol. The solvent was removed by evaporation and the residue was chromatographed on a reversed phase chromatography column using a mixture of acetonitrile and aqueous 0.2 M ammonium acetate as eluent. Theere was obtained 0.16 g (68%) of partly pure 4-(2-amino-2-pyridin-3-ylethyl)phenol which was used without additional purification. ¹ U NMR (500 MHz, CD ₃ OD): 2.7-2.8 (dd, IH), 2.8-2.9 (dd, IH), 4.0 (t, IH), 6.6 (d, 2H), 6.8 (d, 2H), 7.3 (m, IH), 7.7 (d, IH), 8.2 (s, IH), 8.3 (d, IH); LCMS: m/z 215 (M+l) ⁺ .

Intermediate 2

4-Methyl-2-phenylindan- 1 -amine

4-Methyl-2-phenylindan-l-one (see Chemistry Lett; 5 (1988) 901-904; 0.25 g, 1.1 mol), ammonium acetate (0.85 g, 11.1 mmol), sodium cyano borohydride (0.10 g, 1.7 mmol) and molecular sieves (4A). The reaction mixture was stirred at 100°C for 10 min and then at 140°C for 10 min each time using microwave single node heating. The solvent was removed by evaporation and then the residue was partitioned between methylenechloride and an aqueous alkaline solution. The organic layer was dried using a phase separator and the solvent was removed by evaporation. There was obtained 0.25 g (100%) of crude title compound which according to LC MS consisted of two stereoisomers (cis and trans). LC MS: m/z 224 (M+ 1) ⁺ .

Intermediate 3

2-Allyl-4-methylindan- 1 -amine

(a) 2-Allyl-4-methylindan-l-one

4-Methylindan-l-one (0.50 g, 3.4 mmol) and allylbromide (0.54 g, 4.4 mmol) were dissolved in THF (17 mL) under nitrogen. To the resultant solution, which was cooled externally with dry ice and ethanol, was then added lithium diisopropylamide (2M in THF, 2 mL, 4 mmol) in small portions during 40 minutes. The mixture was stirred at -72°C for 2 h and then at room temperature over night. The product was chromatographed on silica gel using a mixture of ethyl acetate and heptane as eluent (0-30% ethyl acetate and then 100% ethyl acetate). There was obtained 66 mg (10%) of 2-allyl-4-methylindan- 1 -one. ¹ R NMR (500 MHz, CDCl ₃ ): 2.1- 2.2 (m, IH), 2.3 (s, 3H), 2.6-2.8 (m, 3H), 3.0-3.2 (m, IH), 4.9 (dd, IH), 5.0 (dd, IH), 6.7-6.8 (m, IH), 7.2 (t, IH), 7.3 (d, IH), 7.5 (d, IH).

(b) 2-Allyl-4-methylindan-l -amine

In a similar manner to the description in Intermediate 2, 2-allyl-4-methylindan-l -amine was prepared starting from 2-allyl-4-methylindan-l-one (0.11 g, 0.61 mmol). There was obtained 0.11 g (100%) of the title compound. LC MS: m/z 188 (M+l) ⁺ .

Intermediate 4

2-Phenyl- 1 -propyl- lH-indol-3-amine

(a) l-Allyl-2-phenyl-3-phenyld.iazenyl-lH-ind.ole

2-Phenyl-3-phenyldiazenyl- IH- indole (see Indian Journal of Chem., Section B: 27B (1988), 454-457; 0.50 g, 1.7 mol), allylbromide (0.50 g, 4.1 mmol), potassium carbonate (0.30 g, 2.2 mmol) and potassium iodide (0.10 g, 0.60 mmol) were mixed with 7V,7V-dimethyl formamide (5 mL). The mixture was stirred at room temperature for 20 h. Water (20 mL) was added and the mixture was extracted with ether (50 mL). The organic solution was washed with brine

and then dried over Na ₂ SO ₄ . The solvent was removed by evaporation and there was obtained 0.54 g (95%) of l-allyl^-phenyl-S-phenyldiazenyl-lH-indole. ¹ U NMR (400 MHz, CDCl ₃ ): 4.8 (d, 2H), 5.1 (d, IH), 5.3 (d, IH), 6.0-6.1 (m, IH), 7.2-7.4 (m, 6H), 7.5 (m, 3H), 7.7 (m, 2H), 7.8 (d, 2H), 8.7 (m, IH); LCMS: m/z 338 (M+l) ⁺ . (b) 2-Phenyl-l-propyl-lH-indol-3-amine l-Allyl-2-phenyl-3-phenyldiazenyl- IH- indole (0.16 g, 0.47 mmol) and formic acid (0.20 g,

4.4 mmol) were dissolved in ethyl acetate (20 mL). To the solution was added Pd/C (10%, 0.1 g) and the mixture was stirred at room temperature for 30 min. The catalyst was filtered off using Celite® and the filter cake was washed with ethyl acetate and then with methylene chloride. The filtrate was washed with aqueous NaHCO ₃ and brine. The solution was dried over Na ₂ SO ₄ and the solvent was removed by evaporation. There was obtained 0.12 g (97%) of the title compound. ¹ U NMR (400 MHz, CDCl ₃ ): 0.6 (t, 3H), 1.5 (m, 2H), 3.9 (t, 2H), 6.6-

7.5 (m, 9H); LCMS: m/z 251 (M+l) ⁺ .