WO2005080390A1

WO2005080390A1 - Imidazopyridine derivatives as bsr-3 antagonists

Info

Publication number: WO2005080390A1
Application number: PCT/GB2005/000547
Authority: WO
Inventors: Terence James Ward; Roger Crossley; Martin John Slater
Original assignee: Biofocus Discovery Ltd
Priority date: 2004-02-18
Filing date: 2005-02-16
Publication date: 2005-09-01
Also published as: GB0403578D0

Abstract

Compounds of the general formula (I): wherein X, Y, R and R’ are as described in the specification. Further included are pharmaceutical compositions comprising the compounds, processes for their preparation, as well as the use of the compounds for the preparation of a medicament against BRS-3 receptor-related disorders.

Description

IMIDAZOPYRIDINE DERIVATIVES AS BSR-3 ANTAGONISTS

TECHNICAL FIELD

The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds for the preparation of a medicament against BRS-3 receptor-related disorders.

BACKGROUND OF THE INVENTION

The orphan receptor human bombesin receptor subtype 3 (BRS-3) was assigned to the G-protein coupled bombesin receptor family because of its high sequence homology with neuromedin B receptor (NMB-R) (BBl) and gastrin-releasing peptide receptor (GRP-R) (BB2). Studies of the distribution of this orphan receptor show that the BRS-3 receptor is present in the central nervous system and gastrointestinal tract.

The roie of BRS-3 in physiological or pathological processes remains unknown due to the lack of selective ligands or identification of its endogenous ligand. Data obtained from the knock-out mouse model suggest that the BRS-3 receptor may be required for the regulation of glucose metabolism, energy balance and maintenance of blood pressure (Okhi-Hamazaki, H.; Watase, K. Yamamoto, K.; Ogura, H.; Yamano, M,; Yamada, K.; aeno, H.; Imaki, J. Kikuyama, S.; Wada, E.; Wada, K., Nature, 390, 165 (1997); Yamada, K. Wada, E.; Imaki, J.; Okhi-Hamazaki, H.; Wada, K., Physiol. Behav., 66, 863 (1999)). Mice lacking functional BRS-3 developed mild obesity, diabetes and hypertension.

Bombesin like peptides are involved in the growth regulation of various cancers (Toi-Scott, M.; Jones, C.L.; Kane, M.A., Lung Cancer, 15, 3, 341 (1996)). Expression of BRS-3 in human tumor was found preferentially in the neuroendocrine tumors of the lung (bronchial carcinoids, small-cell lung cancer cell lines and large cell neuroendocrine carcinoma), which may indicate that BRS-3 could serve as a potential therapeutic target for human lung carcinoma (Fathi, Z.; Corjay, M.H.; Shapira, H.; Wada, E.; Benya, R.; Jensen, R.; Viallet, . J.; Sausville, E.A.; Battey, J.F., J. Biol. Chem., 268, 8, 5979 (1993); Reubi, J.C.; Wenger, S.; Schmuckli-Maurer, J.; Schaer, J.C.; Gugger, M., Clin. Cancer. Res., 8, 4, 1139 (2002)). BRS-3 antagonists may therefore be useful in the treatment of such cancers.

Recently BRS-3 was connected to the treatment of neurological disorders such as stroke, ischaemia, head injury, Alzheimer's disease, and also learning, memory and attention disorders (Smart, D.; Strijbos, P., Bombesin receptor subtype 3 polynucleotides, polypeptides and ligands for use in treating neurological disorders. PTC Int. Appl. WO 0168120 (2001)).

BRS-3 antagonists may also be useful in the treatment of anxiety and panic disorders and in the oncology area, in particular for the treatment of small cell lung cancer, ovarian cancer and prostate cancer.

However, despite indications that BRS-3 antagonists may be useful in the treatment of a variety of diseases, no non-peptide BRS-3 antagonists are known. The development of non-peptide BRS-3 antagonists with good activity, selectivity and pharmacokinetic profiles is therefore needed to fully exploit the clinical potential of this target receptor.

Remarkably, the present invention provides a class of compounds which interact with the BRS-3 receptor.

DISCLOSURE OF THE INVENTION

In a first aspect the invention provides a compound of the Formula (I)

Formula (I) wherein R is selected from aryl optionally independently substituted with one or more of Cι_₆- alkyl, Cι_-6-alkoxy, methylenedioxy, aryl, halogen and halo-Cι_-6-alkyl; or heteroaryl optionally independently substituted with one or more of Cι_-6-alkyl, Cι_-6-alkoxy, methylenedioxy, aryl, halogen and halo-C_1-5-alkyl;

R ' is selected from - aryl and heteroaryl optionally independently substituted with one or more of Cι_-6-alkyl, Cι_-6-alkoxy, methylenedioxy, aryl, halogen, halo-Cι_-6-alkyl, cyano and nitro; or aryl-Cι_-6-alkyl optionally independently substituted with one or more of

Cι-₆-alkyl, Cι_-6-alkoxy, methylenedioxy, aryl, halogen, halo-Cι-₆-alkyl, cyano and nitro; or heteroaryl-Cι-₆-alkyl optionally independently substituted with one or more of Cι_-6-alkyl, Cι_-6-alkoxy, methylenedioxy, aryl, halogen, halo-Cι_-6-alkyl, cyano and nitro;

X is selected from carbon and nitrogen;

Y is selected from hydrogen, Cι_-6-alkyl, Cι_-6-alkoxy or halogen;

and pharmaceutically acceptable salts, hydrates, solvates, geometrical isomers, tautomers, optical isomers, and prodrug forms thereof.

In a preferred embodiment R is selected from phenyl independently substituted with one or more of methyl, methoxy, and ethoxy; It is especially preferred that R is selected from phenyl, 2-methoxyphenyl and 3-methoxyphenyl.

In a preferred embodiment R ' is selected from - phenyl independently substituted with one or more methyl; or benzyl independently substituted with one or more methyl.

It is especially preferred that R' is selected from 2,6-dimethyl phenyl, 2,4,6- trimethyl phenyl, 2-methyl phenyl and α-methyl benzyl.

Preferred compounds are given in Examples 1-5.

In a second aspect the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable diluent or carrier.

In a third aspect the invention provides a process for the preparation of a compound as mentioned above, which process comprises the following steps: a) reaction of a compound of Formula (II)

Formula (II)

X is selected from carbon and nitrogen;

Y is selected from hydrogen, Cι-₆-alkyl, Ci-₆-alkoxy or halogen;

with a Grignard reagent of Formula R-MgBr and then reduction with a reducing agent such as sodium borohydride wherein R is selected from aryl optionally independently substituted with one or more of Cι_-6- alkyl, Cι-₆-alkoxy, methylenedioxy, aryl, halogen and halo-Cι_-6-alkyl; or - heteroaryl optionally independently substituted with one or more of

Ci-e-alkyl, Cι_-6-alkoxy, methylenedioxy, aryl, halogen and halo-Cι-₆-alkyl; to give a compound of Formula (III) wherein X, Y and R are as defined above

Formula (III)

b) reaction with proline in the presence of CDI to give the pyrrolidine of formula (IV)

Formula (IV) wherein X, Y and R are as defined above

c) Cyclisation using phosphorous oxychloride to give the compound of formula (V)

Formula (V) wherein X, Y and R are as defined above,

d) reaction of a compound of formula (V) to give a compound of formula (I)

Formula (I) with an isocyanate of formula R'NCO wherein R ' is selected from aryl and heteroaryl optionally independently substituted with one or more of Cι_-6-alkyl, Cι-₆-alkoxy, methylenedioxy, aryl, halogen, halo-Cι_-6-alkyl, cyano and nitro; or - aryl-Cι-₆-alkyl optionally independently substituted with one or more of

Ci-β-alkyI, Cι-₆-alkoxy, methylenedioxy, aryl, halogen, halo-Cι.₆-alkyl, cyano and nitro; or heteroaryl-Cι-₆-alkyl optionally independently substituted with one or more of Cι_-6-alkyl, Cι_-6-alkoxy, methylenedioxy, aryl, halogen, halo-Cι_-6-alkyl, cyano and nitro;

and X, Y and R are as defined above.

In a fourth aspect the invention provides a method for the prophylaxis or treatment of a BRS-3 receptor-related disorder, which comprises administering to a subject in need of such treatment an effective amount of a compound as mentioned above.

In a fifth aspect the present invention provides a method for modulating BRS- 3 receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a compound or a pharmaceutical formulation as mentioned above. In a sixth aspect the present invention provides a compound as mentioned above for use in therapy, especially for use in the prophylaxis or treatment of a BRS-3 receptor-related disorder.

In another aspect the present invention provides the use of a compound as mentioned above for the manufacture of a medicament for use in the prophylaxis or treatment of a BRS-3 receptor-related disorder.

The compounds as mentioned above may be agonists, partial agonists or antagonists for the BRS-3 receptor.

Examples of putative BRS-3 receptor-related disorders are obesity, diabetes and hypertension. Expression of BRS-3 in human tumor was found preferentially in the neuroendocrine tumors of the lung (bronchial carcinoids, small-cell lung cancer cell lines and large cell neuroendocrine carcinoma), which may indicate that BRS-3 could serve as a potential therapeutic target for human lung carcinoma. Recently BRS-3 was connected to the treatment of neurological disorders such as stroke, ischaemia, head injury, Alzheimer's disease, and also learning, memory and attention disorders.

Definitions

The following definitions shall apply throughout the specification and the appended claims.

Unless otherwise stated or indicated, the term ^λCι_-6-alkyl" denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said lower alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, t-butyl and straight- and branched-chain pentyl and hexyl. For parts of the range ^wCι_-6-alkyl" all subgroups thereof are contemplated such as Cι_-5- alkyl, Cι_-4-alkyl, C_1-3-alkyl, Cι_-2-alkyl, C_2-6-alkyl, C_2-5-alkyl, C₂.₄-alkyl, C_2-3-alkyl, C₃.₆-alkyl, C_4-5-alkyl, etc. ^λΗalo-Cι_-6-alkyl" means a Cι-₆-alkyl group substituted with one or more halogen atoms. Likewise, "aryl-Cι_-6-alkyl" means a Cι_-6-alkyl group substituted with one or more aryl groups. Unless otherwise stated or indicated, the term "C₃-₈-cycloalkyl" denotes a cyclic alkyl group having a ring size from 3 to 8 carbon atoms. Examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, and cyclooctyl. For parts of the range "C₃.₈- cycloalkyl" all subgroups thereof are contemplated such as C_3- -cycloalkyl, C₃- ₆-cycloalkyl, C₃-₅-cycloalkyl, C_3-4-cycloalkyl, C_4-8-cycloalkyl, C _-7-cycloalkyl, C _-6- cycloalkyl, C₄.₅-cycloalkyl, C_5-7-cycloalkyl, C_6-7-cycloalkyl, etc.

Unless otherwise stated or indicated, the term "Cι_-6 alkoxy" denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms. Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso- butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy. For parts of the range "Cι-₆-alkoxy" all subgroups thereof are contemplated such as C_._-5-alkoxy, Cι_-4-alkoxy, C_1-3-alkoxy, Cι_-2-alkoxy, C_2-6- alkoxy, C_2-5-alkoxy, C_2- -alkoxy, C_2-3-alkoxy, C₃-₆-alkoxy, C_4-5-alkoxy, etc.

Unless otherwise stated or indicated, the term "halogen" shall mean fluorine, chlorine, bromine or iodine.

Unless otherwise stated or indicated, the term "aryl" refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryls are phenyl, pentalenyl, indenyl, indanyl, isoindolinyl, chromanyl, naphthyl, fluorenyl, anthryl, phenanthryl and pyrenyl. The aryl rings may optionally be substituted with Cι-₆-alkyl. Examples of substituted aryl groups are benzyl and 2- methylphenyl. Likewise, aryloxy refers to an aryl group bonded to an oxygen atom.

The term "heteroaryl" refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S. Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, indolyl, pyrazolyl, pyridazinyl, quinolinyl, benzofuranyl, dihydrobenzofuranyl, benzodioxolyl, benzodioxinyl, benzothiazolyl, benzothiadiazolyl, and benzotriazolyl groups.

The term "leaving group" refers to a group to be displaced from a molecule during a nucleophilic displacement reaction. Examples of leaving groups are bromide, chloride and methanesulfonate, especially bromide and methanesulfonate.

"Pharmaceutically acceptable" means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.

"Treatment" as used herein includes prophylaxis of the named disorder or condition, or amelioration or elimination of the disorder once it has been established.

"An effective amount" refers to an amount of a compound that confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).

The term "prodrug forms" means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug. Reference is made to Goodman and Gilman 's, The

Pharmacological basis of Therapeutics, 8^th ed., Mc-Graw-Hill, Int. Ed. 1992,

"Biotransformation of Drugs", p. 13-15.

The following abbreviations have been used:

ACN means acetonitrile, DEA means diethylamine,

DEPT means distortion enhancement polarisation transfer,

DMSO means dimethyl sulfoxide,

ELS means electron light scattering,

HPLC means high performance liquid chromatography, Rt means retention time,

TFA means trifluoroacetic acid,

THF means tetrahydrofuran,

TLC means thin layer chromatography.

All diastereomeric forms possible (pure enantiomers, tautomers, racemic mixtures and unequal mixtures of two or more enantiomers) are within the scope of the invention. Such compounds can also occur as cis- or trans-, E- or Z- double bond isomer forms. All isomeric forms and mixtures thereof are contemplated.

The compounds of the formula (I) may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof. The pharmacologically acceptable addition salts mentioned above are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds are able to form. Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid. Exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like. Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and amino acids, such as, e.g. arginine and lysine. The term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates and the like.

For clinical use, the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients. Examples of excipients are water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. Such formulations may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like.

The formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc. The formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections. Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.

In a further aspect the invention relates to methods of making compounds of any of the formulae herein comprising reacting any one or more of the compounds of the formulae delineated herein, including any processes delineated herein. The compounds of the formula (I) above may be prepared by, or in analogy with, conventional methods.

The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. A pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Examples of addition salt forming acids are mentioned above.

The compounds of formula (I) may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers. The separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns.

The necessary starting materials for preparing the compounds of formula (I) are either known or may be prepared in analogy with the preparation of known compounds. The dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy. The daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body_weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.

The invention will now be further illustrated by the following non-limiting Examples.

EXAMPLES

Experimental methods

All reagents were commercial grade and were used as received without further purification, unless otherwise specified. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified. Column chromatography was performed on Matrex® silica gel 60 (35-70 micron). TLC was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). H NMR spectra were recorded on a Bruker Avance250 at 250 MHz. Chemical shifts for ^XH NMR spectra are given in part per million and either tetramethylsilane (0.00 ppm) or residual solvent peaks were used as internal reference. Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; m, multiplet; br, broad. Coupling constants are given in Hertz (Hz). Only selected data are reported. The ¹³C NMR spectra were recorded at 62.5 MHz. DEPT experiments were used to help assign ¹³C NMR resonances where necessary. Chemical shifts for ¹³C NMR spectra are expressed in parts per million and residual solvent peaks were used as internal reference. HPLC analyses were performed using a Waters Xterra MS C18 column (100 x 4.6 mm, 5μ) eluting with a gradient of 5% ACN in 95% water to 95% ACN in 5% water (0.2% TFA buffer) over 3.5 mins, then 95% ACN in 5% water (0.2% TFA buffer) for a further 2.5 mins at a flow rate of 3 ml/min on a Waters 600E or Gilson system with monitoring at 254 nm. Reverse phase preparative HPLC was carried out using a Xterra MS C18 column (100 x 19 mm, 5μm) eluting with a gradient of 5% ACN in 95% water to 95% ACN in 5% water (0.05% DEA) over 12.0 mins, then 95% ACN in 5% water (0.05% DEA) for a further 5.0 mins at a flow rate of 25 ml/min with monitoring at 254 nm. The fractions that contained the desired product were concentrated under reduced pressure and the resultant residue was lyophilised from a mixture of dioxane and water. Electrospray MS spectra were obtained on a Micromass platform LCMS spectrometer. Compounds were named using AutoNom 2000.

EXAMPLE 1 (General Procedure A)

2-[l-(2-Methoxy-phenyl)-imidazo[l_f5]pyridϊn-3-yl]-pyrroIidin2-l- carboxylϊc acid (1-phenyl ethyl)- amide. S isomer

Step 1; C-(2-methoxy-phenyl)-C-pyridin-2-yl-methylamine

2-Cyanopyridine (7g, 0.068mol) was dissolved in anhydrous toluene (225mL) and cooled to 0-5°C and 2-methoxyphenylmagnesium bromide (1.0M sol in THF, 75mmol, 75mL) was added dropwise over 30 minutes. The suspension was stirred for a further 30 minutes at this temperature then /so-butanol (90mL) was added keeping the temperature below 15 °C. The suspension was cooled to 0°C and sodium borohydride (3.6g, 95mmol) added portion wise and the solution was stirred for a further 18 hours. The reaction was quenched with aqueous methanol, evaporated, extracted with dichloromethane and the organic layer concentrated under reduced pressure to afford a green oil (13.8g, 95%) as the crude compound. HPLC 88%, Rt = 1.44 min. MS (AP) m/z 215 (M⁺+H).

Step 2; 2-{[(2-Methoxy-phenyI)-pyridin-2-yl-methyl]-carbamoyl}- pyrrolidine-1-carboxylic acid tert-butyl ester

A solution of 1,1-carbonyldiimidazole (4.5g, 28mmol) in dichloromethane (30mL) was added to a solution of boc-L-proline (6g, 28mmol) in anhydrous dichloromethane (60mL). The suspension was stirred at room temperature for 30 minutes. A solution of C-(2-methoxy-phenyl)-C-pyridin-2-γl-methylamine (6g, 28mmol) in dichloromethane (30mL) was added and the reaction was stirred at room temperature for further 18 hours. The solution was washed with water, dried over magnesium sulfate and concentrated in vacuo to give a green oil (6.7g, 60%) which was used without further purification. HPLC 73%, Rt = 1.86 min. MS (AP) m/z 412 (M⁺+H).

Step 3; 2-[l-(2-Methoxyl-phenyl)-ϊmidazo[l,5]pyridin-3-yl]- pyrrolidine-1-carboxylic acid tert-butyl ester

2-{[(2-Methoxy-phenyl)-pyridin-2-yl-methyl]-carbamoyl}-pyrrolidine-l- carboxylic acid tert-butyl ester (6.7g, 16mmol) was dissolved in anhydrous dichloromethane (80 ml) and pyridine (7.6g, 96 mmol). The reaction was cooled in ice and a solution of phosphorous oxychloride (3.0g, 19.2mmol) in dichloromethane ( 20 ml) was added under stirring. After addition the reaction was warmed to room temperature and stirred for a further 17 hours. The reaction was washed with water (3 x 100 ml), brine (100 ml), dried (MgSO₄) and concentrated under reduced pressure to give a crude compound as a green oil (5.77g, 92%). HPLC 86%, Rt = 2.02 min. MS (AP) m/z 412 (M⁺+H), 312 [M + l-(BOC)] (100).

Step 4; l-(2-Methoxyl-phenyl)-3-pyrrolidin-2-yl-imidazo[l,5]pyridine

To 2-[l-(2-Methoxyl-phenyl)-imidazo[l,5]pyridin-3-yl]-pyrrolidine-l- carboxylic acid tert-butyl ester (3.0g, 7.62mmol) was added dropwise HCI in dioxane (4 M, 12.0 ml, 45.7mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure to give the required product as a brown solid (3.55g, 100%). HPLC 93%, Rt = 1.73 min. MS (AP) m/z 294 (M⁺+H).

Step 5; 2-[l-(2-Methoxy-phenyl)-imidazo[l,5]pyridin-3-yl]- pyrrolidin2-l-carboxylic acid (1-phenyl ethyl)- amide. S isomer l-(2-Methoxyl-phenyl)-3-pyrrolidin-2-yl-imidazo[l,5]pyridine (lOOmg, 0.34 mmol) was dissolved in acetonitrile (1 ml). Triethylamine (142μ, 1.02mmol) and a solution of S-(-)-α-methylbenzyl isocyanate (lOOmg, 0.63mmol) in acetonitrile (0.5 ml) were added to the solution. The reaction was stirred at room temperature for 20 hours. The mixture was washed with IN HCI, brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography eluting with a mixture of ethyl acetate: hexane, 1 :1 gave the required product as a yellow solid (54mg, 36%). HPLC 93%, Rt =- 2.06 min. MS (AP) m/z 442 (M⁺+H).

EXAMPLE 2

2-[l-(2-Methoxy-phenyl)-imidazo[l_f5]pyridin-3-yl]-pyrrolidin2-l- carboxylic acid (1-phenyl ethyl)- amide. R isomer l-(2-Methoxyl-phenyl)-3-pyrrolidin-2-yl-imidazo[l,5]pyridine (lOOmg, 0.34 mmol) was dissolved in acetonitrile (1 ml). Triethylamine (142μ, 1.02mmol) and R-(-)-α-methylbenzyl isocyanate (lOOmg, 0.63mmol) in acetonitrile (0.5 ml) were added to the solution. The reaction was stirred at room temperature for 20 hours. The mixture was washed with IN HCI, brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography eluting with a mixture of ethyl acetate: hexane, 1: 1 gave the required product as a yellow solid (16mg, 11%). HPLC 97%, Rt =- 2.08 min. MS (AP) m/z 442 (M⁺+H).

EXAMPLE 3 2-[l-(2-Methoxy-phenyl)-imidazo[l,5]pyridin-3-yl]-pyrrolidin2-l- car boxy lie acid (2,6-dimethylphenyl)- amide l-(2-Methoxyl-phenyl)-3-pyrroIidin-2-yl-imidazo[l,5]pyridine (lOOmg, 0.34 mmol) was dissolved in acetonitrile (1 ml). Triethylamine (142μ, 1.02mmol) and 2,6-dimethylphenyl isocyanate (lOOmg, 0.63mmol) in acetonitrile (0.5 ml) were added to the solution. The reaction was stirred at room temperature for 20 hours. The mixture was washed with IN HCI, brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography eluting with diethyl ether (100%) gave the required product as a yellow solid (20.4mg, 14%). HPLC 95%, Rt =- 2.04 min. MS (AP) m/z 442 (M⁺+H).

EXAMPLE 4

2-[l-(3-Methoxy-phenyl)-imidazo[l,5-a]pyridin-3-yl]-pyrrolidine-l- carboxylic acid O-tolylamide

Triethylamine (0.1ml) was added drop-wise to a mixture of l-(3-methoxy- phenyl)-3-pyrrolidin-2-yl-imidazol[l,5-a]pyridine hydrochloride* (O.lg, 0.3mmol) in dry acetonitrile (3ml) at room temperature under a nitrogen atmosphere. The mixture was stirred for 5 minutes and a solution of o-tolyl isocyanate (48.4mg, 0.36mmol) in dry acetonitrile (2ml) was added. The reaction mixture was stirred for 1 hour and the solvent was removed under reduced pressure. The solid residue was dissolved in ethyl acetate. The solution was washed with 1M hydrochloric acid, dried over magnesium sulfate, and evaporated in vacuo. The resulting residue was purified by flash chromatography eluting with ethyl acetate-hexane 3:2 v/v to afford the product (115mg, 89%) as yellow solid.

^XH-NMR (250MHz, CDCI₃) δ 1.96 (s, 3H), 2.19 (m, IH), 2.41-2.65 (m, 3H), 3.81-3.92 (m, 5H), 5.57 (t, IH, J 6.6 Hz), 6.23 (brs, IH, NH), 6.63 (t, IH, J 7.3 Hz), 6.77-6.95 (m, 3H), 7.03 (d, IH, J 6.7 Hz), 7.11 (t, IH, J 7.3 Hz), 7.32-7.44 (m, 3H), 7.69 (d, IH, J 7.9 Hz), 7.79 (d, IH, J 9.3 Hz), 8.24 (d, IH, J 7.2 Hz); HPLC 100%, Rt = 2.07 min. MS (AP) m/z 427 (M⁺+H). *Was synthesised according to general procedure A, steps 1-4.

EXAMPLE 5

2-[l-Phenyl-imidazo[l,5-a]pyridin-3-yl]-pyrroIidine-l-carboxylϊc acid (l-phenyl-ethyl)-amide

Triethylamine (0.22ml) was added drop-wise to a mixture of l-phenyl-3- pyrrolidin-2-yl-imidazol[l,5-a]pyridine hydrochloride* (190mg, 0.634mmol) in dry acetonitrile (8ml) at room temperature. The mixture was stirred for 5 minutes and a solution of (S)-(-)-α-methylbenzyl isocyanate (102.6mg, 0.697mmol) in dry acetonitrile (2ml) was added. The reaction mixture was stirred for 30 minutes and the solvent was removed in vacuo. The resulting solid was purified by flash chromatography (ethyl acetate-hexane 3:2) to afford the product (124.7mg, 48%) as a pale green solid.

^XH-NMR (250MHz, CDCI₃) δ 1.18-1.32 (d, 3H, J 6.76 Hz, CH₃), 2.09 (m, IH), 2.32-2.55 (m, 3H), 3.56-3.81 (m, 2H), 4.73 (m, IH), 4.85 (q, IH, J 7.08 Hz), 5.43 (t, IH, J 6.65 Hz), 6.56 (m, IH), 6.77 (m, IH), 6.83 (m, IH), 7.06-7.08 (m, 2H), 7.17-7.32 (m, 3H), 7.44 (t, 2H, J 7.50 Hz), 7.75-7.86 (m, 3H), 8.14 (m, IH); HPLC 98%, Rt =- 2.10 min. MS (AP) m/z 411 (M⁺+H). *Was synthesised according to general procedure A, steps 1-4.

EXAMPLE 6

2-[l-(2-Methoxy-phenyl)-imidazo[l_/5]pyridin-3-yl]-pyrrolidin2-l- carboxylic acid (2,4,6-trimethylphenyl)- amide l-(2-Methoxyl-phenyl)-3-pyrrolidin-2-yl-imidazo[l,5]pyridine* (130mg, 0.34 mmol) was dissolved in acetonitrile (1 ml). Triethylamine (0.4mL, 1.02mmol) and 2,4,6-dimethylphenyl isocyanate (107mg, 0.66mmol) in acetonitrile (0.5 ml) were added to the solution. The reaction was stirred at room temperature for 20 hours. The mixture was washed with IN HCI, brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography eluting with a gradient of dichloromethane/methanol (97:7 to 94:6)) gave the required product as a yellow solid (83.4mg, 60%). HPLC 100%, Rt = 2.69 min. MS (AP) m/z 455 (M⁺+H).

^XH-NMR (250MHz, CDCI₃) δ 1.88 (brs, 6H, -Me), 2.18 (s, 3H, -Me), 2.48-2.61 (m, 3H, -CH-), 2.22-2.33 (m, IH, -CH), 2.43-2.64 (m, 3H, -CH-), 3.70 (s, 2H, -CH₂), 3.78 (s, 3H, -OMe), 3.85-4.02 (m, IH, -CH), 5.58 (t, IH, J 6.7 Hz, -CH- N), 5.74 (brs, IH, -NH), 6.57 (t, IH, J 6.1Hz, Harom), 6.60-6.76 (m, 3H, Harom), 6.97-7.07 (m, 2H, Harom), 7.27-7.34 (m, IH, Harom), 7.50-7.67 (m, 2H, Harom), 8.19 (d, IH, J 7.2 Hz, Harom). *Was synthesised according to general procedure A, steps 1-4. PREPARATION OF A PHARMACEUTICAL COMPOSITION

EXAMPLE 6: Preparation of tablets Ingredients mg/tablet

1. Active compound of formula (I) 10.0

2. Cellulose, microcrystalline 57.0

3. Calcium hydrogen phosphate 15.0

4. Sodium starch glycolate 5.0 5. Silicon dioxide, colloidal 0.25

6. Magnesium stearate 0.75

The active ingredient 1 is mixed with ingredients 2, 3, 4 and 5 for about 10 minutes. The magnesium stearate is then added, and the resultant mixture is mixed for about 5 minutes and compressed into tablet form with or without film-coating.

BIOLOGICAL METHODS

Experimental methods

Primary screening and IC₅₀ determination

HEK293EBNA cells stably expressing the BRS-3 seeded in 96 well plates are pre-loaded with Fluo-4AM fluorescent dye at a concentration of 4 μM for one hour. Subsequently, test compounds at a final concentration of 5 μM for primary screen are added automatically. Fluorescent intensity is recorded using a Fluorometric imaging plate reader (FLIPR-98, 96-well format, Molecular Devices) and inhibition of the peak response evoked by dY-bombesin (EC₇₀ concentration) is calculated.

IC₅₀ determinations are performed utilizing the same functional assay as described for primary screening, applying the compounds in the concentration range of 0.34 nM to 20 μM. Biological summary

The calculation of the Kj values for the inhibitors was performed by use of Activity Base. The K, value is calculated from IC50 using the Cheng Prushoff equation (with reversible inhibition that follows the Michaelis-Menten equation): K, = IC50 (1+[S]/K_m) [Cheng, Y.C.; Prushoff, W.H. Biochem. Pharmacol. 1973, 22, 3099-3108]. The compounds of Formula (I) exhibit IC50 values for the BRS-3 in the range from 35 nM to 1.5 μM.

BRS-3 antagonist lead compounds were identified in FLIPR-based functional screening of the BRS-3. One of these compounds was tested in equilibrium displacement binding measurements at the BRS-3. The results set out below in Table 1 show that Example 6 is a high affinity ligand for the BRS-3 receptor subtype, with a K| value of 444.

Table 1

The table shows the affinity of Example 6 for the BRS-3 compared to the inhibition constant from functional studies.

It will be appreciated by those skilled in the art that the foregoing description is exemplary and explanatory in nature, and is intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognise apparent modifications and variations that may be made without departing from the spirit as scope of the invention as defined in the appended claims.

Claims

Claims 1. A compound of the Formula (I)

wherein R is selected from - aryl optionally independently substituted with one or more of C_halky!, Cι_-6-alkoxy, methylenedioxy, aryl, halogen and halo-Cι_-6-alkyl; or - heteroaryl optionally independently substituted with one or more of Cι-₆-alkyl, C_1-6-alkoxy, methylenedioxy, aryl, halogen and halo-Cι_-6- alkyl; R' is selected from - aryl and heteroaryl optionally independently substituted with one or more of Cι-₆-alkyl, Cι_-6-alkoxy, methylenedioxy, aryl, halogen, halo-C_1-6- alkyl, cyano and nitro; or - aryl-Cι_-6-alkyl optionally independently substituted with one or more of Ci-β-alkyI, Cι_-6-alkoxy, methylenedioxy, aryl, halogen, halo-Cι_-6-alkyl, cyano and nitro; or - heteroaryl-Cι-₆-alkyl optionally independently substituted with one or more of Cι-₆-alkyl, Cι_-6-alkoxy, methylenedioxy, aryl, halogen, halo-Cι_-6- alkyl, cyano and nitro;

X is selected from carbon and nitrogen; Y is selected from hydrogen, Cι_-6-alkyl, Cι-₅-alkoxy or halogen; and pharmaceutically acceptable salts, hydrates, solvates, geometrical isomers, tautomers, optical isomers, and prodrug forms thereof.

2. A compound according to claim 1, wherein R is selected from - phenyl independently substituted with one or more of methyl, methoxy, and ethoxy;

3. A compound according to claim 1 or 2, wherein R is selected from phenyl, 2-methoxyphenyl and 3-methoxyphenyl.

4. A compound according to any one of claims 1 to 3, wherein R' is selected from - phenyl independently substituted with one or more methyl; or - benzyl independently substituted with one or more methyl.

5. A compound according to any one of claims 1 to 4, wherein R' is selected from 2,6-dimethyl phenyl, 2,4,6-tri methyl phenyl, 2-methyl phenyl and α- methyl benzyl.

6. A compound according to any one of claims 1 to 5, wherein X is selected from carbon and nitrogen;

7. A compound according to any one of claims 1 to 6, wherein Y is selected from hydrogen, C_1-6-alkyl, Cι_-6-alkoxy or halogen;

8. A compound according to any one of claims 1 to 7, which is selected from: 2-[l-(2-Methoxy-phenyl)-imidazo[l,5]pyridin-3-yl]-pyrrolidin2-l-carboxylic acid (1-phenyl ethyl)- amide. S isomer 2-[l-(2-Methoxy-phenyl)-imidazo[l,5]pyridin-3-yl]-pyrrolidin2-l-carboxylic acid (1-phenyl ethyl)- amide. R isomer

2-[l-(2-Methoxy-phenyl)-imidazo[l,5]pyridin-3-yl]-pyrrolidin2-l-carboxylic acid (2,6-dimethylphenyl)- amide

2-[l-(3-Methoxy-phenyl)-imidazo[l,5-a]pyridin~3-yl]-pyrrolidine-l-carboxylic acid O-tolylamide 2-[l-Phenyl-imidazo[l,5-a]pyridin-3-yl]-pyrrolidine-l-carboxylic acid (1- phenyl-ethyl)-amide

2-[l-(2-Methoxy-phenyl)-imidazo[l,5]pyridin-3-yl]-pyrrolidin2-l-carboxylic acid (2,4,6-trimethylphenyl)- amide.

9. A pharmaceutical formulation comprising a compound according to any preceding claim and a pharmaceutically acceptable diluent or carrier.

10. A process for the preparation of a compound according to any one of claims 1 to 8, which process comprises at least one of the steps of: a) reaction of a compound of Formula (II)

Formula (II)

X is selected from carbon and nitrogen; Y is selected from hydrogen, Cι_-6-aIkyl, C_1-6-alkoxy or halogen;

with a Grignard reagent of Formula R-MgBr and then reduction with a reducing agent such as sodium borohydride wherein R is selected from - aryl optionally independently substituted with one or more of C^- alkyl, Cι_-6-alkoxy, methylenedioxy, aryl, halogen and halo-Cι_-6-alkyl; or - heteroaryl optionally independently substituted with one or more of Cι-₆-alkyl, C_1-6-alkoxy, methylenedioxy, aryl, halogen and halo-C_1-6- alkyl;

to give a compound of Formula (III) wherein X, Y and R are as defined above

Formula (III)

Formula (IV) wherein X, Y and R are as defined above

Formula (V) wherein X, Y and R are as defined above,

d) reaction of a compound of formula (V) to give a compound of formula (I)

Formula (I) with an isocyanate of formula R'NCO wherein R' is selected from - aryl and heteroaryl optionally independently substituted with one or more of Cι-₆-alkyl, C__.-₆-alkoxy, methylenedioxy, aryl, halogen, halo-Cι_₆- alkyl, cyano and nitro; or - aryl-Cι_-6-alkyl optionally independently substituted with one or more of Cι-₆-alkyl, Cι_-6-alkoxy, methylenedioxy, aryl, halogen, halo-Cι-₆-alkyl, cyano and nitro; or - heteroaryl-Cι-₆-alkyl optionally independently substituted with one or more of C_1-6-alkyl, C_1-6-alkoxy, methylenedioxy, aryl, halogen, halo-Cι-₆- alkyl, cyano and nitro;

and X, Y and R are as defined above.

11. A method according to claim 10 which comprises all of steps a) to d).

12. A method for the prophylaxis or treatment of a BRS-3 receptor-related disorder, which comprises administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutical formulation according to claim 9.

13. The method according to claim 12, wherein the disorder is selected from obesity, diabetes, hypertension, oncology, in particular for the treatment of small cell lung cancer, ovarian cancer and prostate cancer, neurological disorders such as stroke, ischaemia, head injury, Alzheimer's disease, and also learning, anxiety and panic disorders, memory and attention disorders.

14. A method for modulating BRS-3 receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutical formulation according to claim 9.

15. A compound according to any one of claims 1 to 8 for use in therapy.

16. A compound according to claim 15 for use in the prophylaxis or treatment of a BRS-3 receptor-related disorder.

17. A compound according to claim 15 or 16, wherein the disorder is selected from obesity, diabetes, hypertension, oncology, in particular for the treatment of small cell lung cancer, ovarian cancer and prostate cancer, neurological disorders such as stroke, ischaemia, head injury, Alzheimer's disease, and also learning, anxiety and panic disorders, memory and attention disorders.

18. Use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament for use in the prophylaxis or treatment of a BRS-3 receptor-related disorder.

19. The use according to claim 18, wherein the disorder is selected from obesity, diabetes, hypertension, oncology, in particular for the treatment of small cell lung cancer, ovarian cancer and prostate cancer, neurological disorders such as stroke, ischaemia, head injury, Alzheimer's disease, and also learning, anxiety and panic disorders, memory and attention disorders.