WO2007048643A1 - Novel compound - Google Patents

Abstract

The present invention relates to a novel benzofuran carboxamide derivative having pharmacological activity, to processes for its preparation, to compositions containing it and to its use in the treatment of diseases treatable by 5-HT4 agonism.

Description

BENZOFURAN-7-CARBOXAMIDE DERIVATE AS 5-HT4 AGONIST

The present invention relates to a novel benzofuran carboxamide derivative having pharmacological activity, to processes for its preparation, to compositions containing it and to its use in the treatment of diseases treatable by 5-HT4 agonism.

WO05/092882 (Pfizer Inc.) describes a series of 4-amino-5-halogeno-benzamide derivatives as 5-HT4 receptor agonists for the treatment of gastrointestinal, CNS, neurological and cardiovascular disorders. WO94/08995 (SmithKline Beecham pic) describes a series of heterocyclic condensed benzoic acid derivatives as 5- HT4 receptor antagonists. WO99/02156 (Janssen Pharmaceutica N.V.) describes a series of bicyclic benzamides of 3- or 4-substituted 4-(aminomethyl)- piperidine derivatives and EP 0389037 (Janssen Pharmaceutica N.V.) describes a series of N-(3-hydroxy-4-piperidinyl)(dihydrobenzofuran, dihydro-2H- benzopyran or dihydrobenzodioxin)carboxamide derivatives for gastrointestinal stimulating activity.

Alzheimer's disease is a chronic neurological disorder characterised by progressive cognitive decline, behavioural impairment and ultimately death. In the US alone, it is estimated that as many as 4.5 million people suffer from the disease, including nearly half of all people over 85 years of age. With an ageing world population, there is a clear need for effective therapies for Alzheimer's disease.

Although Alzheimer's disease is classically associated with loss of cholinergic neurons, deficits in a number of other neurotransmitter systems have also been reported, including that of the serotonergic system. With regard to 5-HT4 receptors, there is a wealth of pre-clinical data to support the use of 5-HT4 agonists as cognitive enhancers, both from in vivo and in vitro functional studies, such as rodent cognition models and electrophysiology (e.g. Moser P.C. et al., JPET 302(2):731-41 , Matsumoto M., JPET 296(3):676-82, Lucas G. et al., Biol. Psychiatry 57(8):918-25). The expression profile of the 5-HT4 receptor in the central nervous system also supports this, with high levels of expression in the hippocampus, striatum, prefrontal cortex and other limbic regions. There is also evidence that 5-HT4 receptor expression may be reduced in the course of Alzheimer's disease. These data suggest that 5-HT4 agonists such as the compound of the present invention could be useful for the treatment of cognitive impairments in neurological diseases such as Alzheimer's disease and related neurological disorders.

In addition, recent reports (e.g. Maillet M. et al., Curr. Alzheimer Res. 1 (2):79-85) suggest that activation of the 5-HT4 receptor can increase the release of soluble APP-alpha, which has potent neuroprotective and memory-enhancing actions, and in addition enhance the production of neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Thus 5-HT4 agonism could also provide a disease-modifying treatment for Alzheimer's disease.

5-HT4 agonists also have utility in the treatment of gastrointestinal disorders and tegaserod maleate is marketed by Novartis for the treatment of irritable bowel syndrome.

In a first aspect, the present invention provides a compound which is 4-amino-5- chloro-Λ/-{[1-(tetrahydro-2/-/-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran- 7-carboxamide (A),

(A) and/or a pharmaceutically acceptable salt or solvate thereof. When used herein "compound of the invention" means 4-amino-5-chloro-Λ/-{[1-(tetrahydro-2/-/- pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran-7-carboxamide and/or pharmaceutically acceptable salts and solvates thereof.

4-amino-5-chloro-Λ/-{[1-(tetrahydro-2/-/-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1- benzofuran-7-carboxamide may form acid addition salts. Such salts can be formed by reaction of the free base molecule (A) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, mandelic, benzoic, salicylic, glutamic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2- naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.

In one embodiment of the invention there is provided 4-amino-5-chloro-A/-{[1- (tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran-7- carboxamide, 4-amino-5-chloro-Λ/-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4- piperidinyl]methyl}-1 -benzofuran-7-carboxamide hydrochloride or 4-amino-5- chloro-Λ/-{[1-(tetrahydro-2/-/-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran- 7-carboxamide tosylate. In another embodiment of the invention there is provided 4-amino-5-chloro-Λ/-{[1-(tetrahydro-2/-/-pyran-4-ylmethyl)-4- piperidinyl]methyl}-1 -benzofuran-7-carboxamide. In still another embodiment of the invention there is provided 4-amino-5-chloro-Λ/-{[1-(tetrahydro-2H-pyran-4- ylmethyl)-4-piperidinyl]methyl}-1 -benzofuran-7-carboxamide hydrochloride. In a further embodiment of the invention there is provided 4-amino-5-chloro-Λ/-{[1- (tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran-7- carboxamide tosylate. When the compound of the invention is allowed to crystallise or is recrystallised from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, the compound of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lypohilisation. In addition, different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products. This invention includes within its scope all polymorphic forms of the compound of the invention.

Thus, the invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the compound of the invention including anhydrates, hydrates, solvates and polymorphs thereof.

In one embodiment of the invention there is provided 4-amino-5-chloro-Λ/-{[1- (tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran-7- carboxamide tosylate anhydrate. In one embodiment of the invention there is provided 4-amino-5-chloro-Λ/-{[1 -(tetrahydro-2/-/-pyran-4-ylmethyl)-4- piperidinyl]methyl}-1 -benzofuran-7-carboxamide tosylate monohydrate.

Figure 1 is a differential scanning calorimetry (DSC)/thermogravimetric analysis (TGA) plot for 4-amino-5-chloro-Λ/-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4- piperidinyl]methyl}-1 -benzofuran-7-carboxamide tosylate anhydrate. In one embodiment of the invention there is provided 4-amino-5-chloro-Λ/-{[1- (tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran-7- carboxamide tosylate anhydrate characterised in that it provides a DSCVTGA plot consistent with Figure 1.

Figure 2 is an X-ray powder diffraction (XRPD) pattern for 4-amino-5-chloro-Λ/- {[1-(tetrahydro-2/-/-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran-7-

- A - carboxamide tosylate anhydrate. A summary of the XRPD angles and calculated lattice spacings characteristic of this crystalline form is given in Table 1.

In one embodiment of the invention there is provided 4-amino-5-chloro-Λ/-{[1- (tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran-7- carboxamide tosylate anhydrate characterised in that it provides an XRPD pattern consistent with the data in Table I. In another embodiment of the invention there is provided 4-amino-5-chloro-Λ/-{[1-(tetrahydro-2H-pyran-4- ylmethyl)-4-piperidinyl]methyl}-1 -benzofuran-7-carboxamide tosylate anhydrate characterised in that it provides an XRPD pattern consistent with Figure 2.

Figure 3 is an XRPD pattern of 4-amino-5-chloro-Λ/-{[1-(tetrahydro-2/-/-pyran-4- ylmethyl)-4-piperidinyl]methyl}-1 -benzofuran-7-carboxamide tosylate monohydrate. A summary of the XRPD angles and calculated lattice spacings characteristic of this crystalline form is given in Table 2.

In one embodiment of the invention there is provided 4-amino-5-chloro-Λ/-{[1- (tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran-7- carboxamide tosylate monohydrate characterised in that it provides an XRPD pattern consistent with the data in Table 2. In another embodiment of the invention there is provided 4-amino-5-chloro-Λ/-{[1-(tetrahydro-2H-pyran-4- ylmethyl)-4-piperidinyl]methyl}-1 -benzofuran-7-carboxamide tosylate monohydrate characterised in that it provides an XRPD pattern consistent with Figure 3.

Figure 4 is a DSC/TGA plot for 4-amino-5-chloro-Λ/-{[1-(tetrahydro-2/-/-pyran-4- ylmethyl)-4-piperidinyl]methyl}-1 -benzofuran-7-carboxamide tosylate monohydrate. In one embodiment of the invention there is provided 4-amino-5- chloro-Λ/-{[1-(tetrahydro-2/-/-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran- 7-carboxamide tosylate anhydrate characterised in that it provides a DSC/TGA plot consistent with Figure 4. Since the compound of the invention is intended for use in pharmaceutical compositions, it will be understood that it is ideally used in substantially pure form, for example at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compound of the invention may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compound of the invention. Whenever possible, the compound of the invention is obtained in crystalline form

The present invention also includes within its scope isotopically-labelled forms of the compound of the invention. Such compounds are identical to the compound of the invention except that one or more atoms therein are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compound of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen and chlorine, such as 2H, 3H, 11C, 13C₁ 14C, 15N, 170, 180 and 36Cl.

Isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 11C isotopes are particularly useful in PET (positron emission tomography), and are useful in brain imaging. Further substitution with heavier isotopes such as deuterium, i.e., 2H₁ can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, lsotopically labelled forms of the compound of the invention may be prepared by carrying out the synthetic procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent. The present invention also provides processes for the preparation of the compound of the invention. One such process comprises reacting 4-amino-5- chloro-Λ/-(4-piperidinylmethyl)-1 -benzofuran-7-carboxamide or a salt or protected derivative thereof, with tetrahydro-2H-pyran-4-carbaldehyde or a protected derivative thereof; and optionally thereafter (i) deprotecting a protected compound and/or (ii) forming a pharmaceutically acceptable salt of the compound so formed. This process typically comprises the use of reductive conditions (such as treatment with a borohydride eg. sodium triacetoxyborohydride), in an appropriate solvent such as 1 ,2-dichloroethane at a suitable temperature such as reflux.

An alternative process for the preparation of the compound of the invention comprises reacting 4-amino-5-chloro-1-benzofuran-7-carboxylic acid or a salt or protected derivative thereof, with {[1-(tetrahydro-2H-pyranylmethyl)-4- piperidinyl]methyl}amine or a salt or protected derivative thereof; and optionally thereafter (i) deprotecting a protected compound and/or (ii) forming a pharmaceutically acceptable salt of the compound so formed. This process typically comprises the use of amide formation conditions. For example, the reaction may involve the use of a coupling agent such as N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride) in a suitable solvent such as dichloromethane. Alternatively, the reaction may involve the use of 2- chloro-4,6-dimethoxytriazine and N-ethylmorpholine in a suitable solvent such as acetonitrile.

Examples of protecting groups and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, Third Edition, 1999). Suitable amine protecting groups include sulfonyl (e.g. tosyl), acyl (e.g. acetyl, 2^I,2',2^I-trichloroethoxycarbonyl, benzyloxycarbonyl or t- butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g. using an acid such as hydrochloric acid in dioxan or trifluoroacetic acid in dichloromethane) or reductively (e.g. hydrogenolysis of a benzyl group or reductive removal of a 2',2',2'-trichloroethoxycarbonyl group using zinc in acetic acid) as appropriate. Other suitable amine protecting groups include trifluoroacetyl (-COCF₃) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6- dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with thfluoroacetic acid.

^Amino-δ-chloro-i-benzofuran-Z-carboxylic acid (II) and 4-amino-5-chloro-Λ/-(4- piperidinylmethyl)-1-benzofuran-7-carboxamide (V) may be prepared in accordance with Scheme 1 :

Scheme 1

wherein P¹ represents a suitable protecting group such as an alkyl group (e.g. methyl or ethyl) or aralkyl (e.g. benzyl), wherein P² represents a suitable amine protecting group such as acetyl and wherein P³ represents a suitable amine protecting group such as t-butoxycarbonyl. Step (i) comprises a deprotection reaction to provide 4-amino-5-chloro-1- benzofuran-7-carboxylic acid (II). Where P¹ and P² cannot be removed under the same conditions, this step comprises two sequential reactions (one reaction removing P¹ and the other removing P²). However, when P¹ and P² may be removed under the same conditions (e.g. when P¹ represents methyl and P² represents acetyl), this step may consist of a single reaction. The deprotection reactions may be performed in accordance with methods known in the art, for example those described in Greene vida ante. Where P¹ represents methyl and P² represents acetyl, both protecting groups may be removed by hydrolysis under basic conditions, for example using NaOH (aq) / ethanol.

Step (ii) typically comprises the use of amide formation conditions, such as treatment with a coupling agent (e.g. N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide or a salt thereof, for example, hydrochloride), in an appropriate solvent such as dichloromethane.

Step (iii) comprises a deprotection reaction to provide 4-amino-5-chloro-Λ/-(4- piperidinylmethyl)-1-benzofuran-7-carboxamide (V), or a salt thereof, and can be performed in accordance with methods known in the art, for example those described in Greene vida ante. Where P³ represents t-butoxycarbonyl, this may be removed by hydrolysis under acidic conditions, for example using 4M HCI in dioxan.

{[1-(Tetrahydro-2H-pyranylmethyl)-4-piperidinyl]methyl}amine may be prepared in accordance with Scheme 2: Scheme 2

(VII)

wherein P⁴ represents a suitable amine protecting group such as t- butoxycarbonyl.

Step (i) typically comprises the use of reductive conditions (such as treatment with a borohydride eg. sodium triacetoxyborohydride), in an appropriate solvent such as 1 ,2-dichloroethane or dichloromethane at a suitable temperature such as room temperature.

Step (ii) comprises a deprotection reaction to provide {[1-(tetrahydro-2H- pyranylmethyl)-4-piperidinyl]methyl}amine (IX), or a salt thereof, and can be performed in accordance with methods known in the art, for example those described in Greene vida ante. Where P⁴ represents t-butoxycarbonyl, this may be removed by hydrolysis under acidic conditions, for example using 4M HCI in dioxan.

Compounds of formula (I), such as methyl 4-(acetylamino)-5-chloro-1- benzofuran-7-carboxylate, may be prepared as described in Synlett (1993, 4: 269) and by analogous methods to those described therein in which certain reaction conditions and reagents are varied using conventional methods and techniques known in the art. Compounds of formula (III), (Vl) and (VII) are either commercially available or may be prepared from commercially available materials by standard methods. Tetrahydro-2H-pyran-4-carbaldehyde is commercially available, for example from PharmaCore Inc.

Scheme 3 provides a representative process for the preparation of 4-amino-5- chloro-Λ/-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran- 7-carboxamide and pharmaceutically acceptable salts thereof, via 4-amino-5- chloro-1-benzofuran-7-carboxylic acid:

Scheme 3

1 ) DCM, aq NaHCO,

wherein, MeOH = methanol, AC₂O = acetic anhydride, DCM = dichloromethane, EtOAc = ethyl acetate, DMF = dimethylformamide, Chloramine-T-trihydrate = N- chloro-p-toluenesulphonamide (sodium salt), TMSA = trimethylsilylacetylene, DIPEA = diisopropylethylamine, AcOH = acetic acid, ACN = acetonitrile and pTSA = para-toluenesulphonic acid.

The compound of the present invention is a partial agonist of the 5-HT4 receptor. Hence, it is believed to be of potential use in the treatment of diseases treatable by 5-HT4 agonism. Diseases treatable by 5-HT4 agonism include diseases of the central nervous system such as Alzheimer's disease and related neurological disorders, such as other dementias, cognitive disorder (especially mild cognitive impairment), generalised anxiety disorder, migraine, Parkinson's disease, multiple sclerosis, depression and schizophrenia. Diseases which may benefit from the application of a 5-HT4 receptor agonist also include functional gastrointestinal (Gl) diseases such as gastroesophageal reflux disease, gastric motility disorders such as gastroparesis, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, emesis, inflammatory bowel disease, post- operative ileus and visceral hypersensitivity as well as pain, urinary dysfunction, urinary incontinence, overactive bladder, diabetes and apnea syndrome, (especially caused by opioid administration), and cardiovascular disorders such as cardiac failure and heart arrhythmia (hereafter 'the disorders of the invention').

Thus the invention also provides the compound of the invention for use as a therapeutic substance in the treatment of the disorders of the invention, in particular Alzheimer's disease and related neurological disorders, and also functional Gl diseases.

The invention further provides a method of treatment of the disorders of the invention, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of the compound of the invention.

In another aspect, the invention provides the use of the compound of the invention in the manufacture of a medicament for use in the treatment of the disorders of the invention.

It is to be understood that reference to treatment includes both treatment of established symptoms and prophylactic treatment.

When used in therapy, the compound of the invention is usually formulated in a standard pharmaceutical composition. Such a composition can be prepared using standard procedures. Thus, the present invention further provides a pharmaceutical composition which comprises the compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical composition for use in the treatment of the disorders of the invention which comprises a compound of the invention and a pharmaceutically acceptable carrier.

The compound of the invention may be used in combination with other therapeutic agents.

When the compound of the invention is intended for use in the treatment of Alzheimer's disease, it may be used in combination with medicaments claimed to be useful as either disease modifying or symptomatic treatments of Alzheimer's disease. Suitable examples of such other therapeutic agents may be agents known to modify cholinergic transmission such as M1 muscarinic receptor agonists or allosteric modulators, nicotinic receptor agonists or allosteric modulators, symptomatic agents such as 5-HT6 receptor antagonists or H3 receptor antagonists, also NMDA receptor antagonists (such as memantine hydrochloride) or modulators or acetylcholinesterase inhibitors (such as donepezil hydrochloride), and disease modifying agents such as β or γ-secretase inhibitors.

When the compound of the invention is intended for use in the treatment of gastrointestinal disease, it may be used in combination with medicaments which induce symptoms treated by 5-HT4 receptor agonists and/or medicaments claimed to be useful as treatments of the same or different aspects of such disease. Suitable examples of therapeutic agents which evoke symptoms treated by 5-HT4 receptor agonists include those which evoke constipation, such as morphine or other opiate receptor ligands. Suitable examples of other therapeutic agents used to treat gastrointestinal disease include those known to modify gastric acid secretion, such as ranitidine or lansoprazole, gastrointestinal motility, such as almivopan, or visceral pain, such as codeine, as well as the use of these compounds to aid the therapeutic use of agents designed as laxatives.

When the compound of the invention is used in combination with other therapeutic agents, the compound and agent may be administered either sequentially or simultaneously by any convenient route.

The invention thus provides, in a further aspect, a combination comprising the compound of the invention together with a further therapeutic agent or agents.

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

When the compound of the invention is used in combination with a second therapeutic agent active the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.

For parenteral administration, fluid unit dosage forms may be prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions may be prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1 % to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 0.1 to

200 mg and even more suitably 1.0 to 200 mg. In one aspect, a suitable unit dose would be 0.1-50 mg. Such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.

The following Descriptions and Examples illustrate the preparation of the compound of the invention. Analytical methods for the Descriptions and Examples (E1-E4) and salts and solvates thereof were undertaken as set forth herein.

Where indicated, chromatography was carried out on silica gel cartridges on a Flashmaster Il automated chromatography system (Argonaut) and eluting with mixtures of methanol/dichloromethane or ethyl acetate/pentane.

¹H NMR spectra were recorded on a Bruker AVANCE 400 NMR spectrometer or a Bruker DPX250 NMR spectrometer. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants (J) are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m (multiplet), br (broad).

LC/Mass spectra were obtained using an Agilent 1100 series HPLC system coupled with a Waters ZQ Mass Spectrometer. LC analysis was performed on a Waters Atlantis™ dC-ι₈ column (50 x 4.6 mm, 3μm) (mobile phase: 97% [water +0.05% HCO₂H]/ 3% [CH₃CN +0.05% HCO₂H] for 0.1 min, then a gradient to 3% [water +0.05% HCO₂H]/97% [CH₃CN +0.05% HCO₂H] over 3.9 min, and then held under these conditions for 0.8 min); temperature = 30 ⁰C; flow rate = 3 mL/min; Mass spectra were collected using electrospray and/or APCI. In the mass spectra only one peak in the molecular ion cluster is reported. The UV detection range is from 220 to 330nm. All reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualised with UV light, 5% ethanolic phosphomolybdic acid, p-anisaldehyde solution, aqueous potassium permanganate or potassium iodide / platinum chloride solution in water.

A PANalytical X'Pert Pro X-ray powder diffractometer with X'Celerator Detector was used to generate the XRPD diffractograms using the following acquisition conditions:

Tube anode: Cu

Generator tension: 4OkV

Generator current: 45mA

Start angle: 2.0 °2Θ

End angle: 40.0 °2Θ Step size: 0.0167

Time per step: 31.75

The XRPD samples were mounted on silicon wafers.

Description 1

4-Amino-5-chloro-1-benzofuran-7-carboxylic acid (D1)

Methyl 4-(acetylamino)-5-chloro-1-benzofuran-7-carboxylate (1.247g, 4.67mmol) [prepared using an analogous method to that described in Synlett (1993, 4: 269)] was weighed into a 250 ml round-bottomed flask, to which ethanol (20ml) and 5N sodium hydroxide (20ml) was added. After stirring for ~60h under argon the mixture was a cream colour with a white precipitate. LCMS showed the reaction to be incomplete. The mixture was then heated at reflux (80⁰C) for 3h - reaction complete by LC/MS. The ethanol was removed in vacuo. The residue was dissolved in water (~10ml). 50 ml ethyl acetate was added and the aqueous layer was separated and acidified to pH4 with 5M HCI. The resulting precipitate was filtered and dried in a vacuum oven to afford the title compound (D1 ). The waste ethyl acetate was also filtered to afford the title compound as a pale brown solid

(D1 ) (1.122g, 100%). δH (DMSO-d6, 400MHz) 6.66 (2H, br s), 7.23 (1 H, s), 7.65 (1 H, s), 7.90 (1 H, s), 12.50 (1 H, br s). Mass Spectrum: C₉H₆CINO₃ requires 211/213; found 212/214 (MH⁺).

Description 2 1 ,1 -Dimethylethyl 4-({[(4-amino-5-chloro-1 -benzofuran-7- yl)carbonyl]amino}methyl)-1 -piperidinecarboxylate (D2)

To a solution of 4-amino-5-chloro-1-benzofuran-7-carboxylic acid (0.2g, 0.95mmol) in dichloromethane (20ml) was added 1 ,1 -dimethylethyl 4- (aminomethyl)-i -piperidinecarboxylate (0.304g, 1.42mmol), 1-ethyl-3(3- dimethylaminopropyl)carbodiimide hydrochloride (0.362g, 1.89mmol) and 4-(N₁N- dimethylamino)pyridine (23mg, 0.19mmol). The reaction mixture was stirred under argon at room temperature for 2h. LC/MS showed -50% starting material remaining. Stirring was continued for ~17h after which time the reaction was shown to be complete by LC/MS. The reaction mixture was transferred to a separating funnel. 20 ml dichloromethane and 20 ml sodium bicarbonate were added. The dichloromethane layer was separated using a phase separation cartridge. The DCM from was removed in vacuo and the resulting layer was purified by chromatography over silica eluting with a 0-95% gradient of ethyl acetate/pentane. The product containing fractions were identified and combined. The solvent was removed in vacuo to yield the title compound (D2) (0.269g, 69%). δH (CDCI₃, 400MHz) 1.15-1.35 (2H, m), 1.45 (9H, s), 1.70-1.90 (3H₁ m), 2.65-2.77 (2H, m), 3.40-3.47 (2H, m), 4.05-4.20 (2H, m), 4.67 (2H, br s), 6.80 (1 H, d, J = 2.4Hz), 7.33 (1 H, br s), 7.64 (1 H, d, J = 2.4Hz), 8.05 (1 H, s). Mass Spectrum: C₂oH₂₆CIN₃O₄ requires 407/409; found 406/408 (M-H)^".

Description 3

4-Amino-5-chloro-Λ/-(4-piperidinylmethyl)-1-benzofuran-7-carboxamide hydrochloride (D3)

4M HCI/1 ,4-dioxan (10ml) was added to 1 ,1 -dimethylethyl 4-({[(4-amino-5-chloro- 1 -benzofuran-7-yl)carbonyl]amino}methyl)-1 -piperidinecarboxylate (0.269g,

0.66mmol) and the resulting mixture left to stand for 0.5h. The solvent was then removed in vacuo to afford the title compound (D3) (0.246g, 100%). δH (MeOD, 400MHz) 1.46-1.59 (2H, m), 1.95-2.10 (3H, m), 2.90-3.05 (2H, m), 3.35-3.50 (4H, m), 7.11 (1 H, d, J = 2.4Hz), 7.76 (1 H, s), 7.79 (1 H, d, J = 2Hz). Mass Spectrum: Ci₅H₁₈CIN₃O₂ requires 307/309; found 308/310 (MH⁺).

4-Amino-5-chloro-Λ/-(4-piperidinylmethyl)-1-benzofuran-7-carboxamide hydrochloride was also prepared in accordance with Descriptions D1a - D3a.

Description 1a 4-Amino-5-chloro-1-benzofuran-7-carboxylic acid (D1a)

Methyl 4-(acetylamino)-5-chloro-1-benzofuran-7-carboxylate (4.14g, 15.5mmol) [prepared using an analogous method to that described in Synlett (1993, 4: 269)] was suspended in 5M sodium hydroxide solution (50ml) and ethanol (50ml) and then heated at reflux (80⁰C) for 6h. LC/MS showed the reaction to be complete. The resulting solution was allowed to cool and ethanol was removed in vacuo. The aqueous layer was acidified using 5M hydrochloric acid to pH 2 and the resulting precipitate was filtered, dried in vacuo at 4O⁰C to give the title compound (D1a) as a beige solid (3g, 92%) δH (DMSO-d6, 250MHz) 6.65 (2H, br s), 7.22 (1 H₁ d, J = 2.3Hz), 7.65 (1 H, s), 7.90 (1 H, d, J = 2.3Hz) Mass Spectrum: C₉H₆ CINO₃ requires 211/213; found 212/214 (MH⁺).

Description 1 b

4-Amino-5-chloro-1-benzofuran-7-carboxylic acid (D1b)

To a solution of methyl 4-(acetylamino)-5-chloro-1-benzofuran-7-carboxylate

(0.281 g, 1.05mmol) [prepared using an analogous method to that described in Synlett (1993, 4: 269)] in ethanol (15ml) was added 5M sodium hydroxide (10ml) and the solution stirred at reflux (8O⁰C) for 3h. The reaction was then shown to be complete by LC/MS and the organic solvent removed by evaporation. The mixture was then diluted with water (50ml) and acidified using concentrated hydrochloric acid. The resulting precipitate was filtered and dried to afford the title compound as an off-white solid (D1 b) (0.2g, 90%). δH (DMSO-d6, 250MHz) 6.67 (2H, br s), 7.23 (1 H, s), 7.65 (1 H, s), 7.90 (1 H, s), 12.50 (1 H, br s). Mass Spectrum: C₉H₆CINO₃ requires 211/213; found 212/214 (MH⁺). Description 2a

1 ,1 -Dimethylethyl 4-({[(4-amino-5-chloro-1 -benzofuran-7- yl)carbonyl]amino}methyl)-1-piperidinecarboxylate (D2a)

To a solution of 4-amino-5-chloro-1-benzofuran-7-carboxylic acid (0.2g, 0.94mmol) in dichloromethane (25ml) was added 1 ,1 -dimethylethyl 4- (aminomethyl)-i-piperidinecarboxylate (0.242g, 1.13mmol), 1-ethyl-3(3- dimethylaminopropyl)carbodiimide hydrochloride (0.362g, 1.89mmol) and 4-(N₁N- dimethylamino)pyridine (23mg, 0.19mmol). The reaction mixture was then stirred at room temperature for 2h, after which the reaction was shown to be complete by LC/MS. The organic solution was then washed with sodium bicarbonate solution (50ml), brine (50ml) before being dried using a phase separation cartridge. Organic solvents were then removed by evaporation to afford crude material. The crude material was purified on silica (eluting with a 0-100% gradient of ethyl acetate/pentane). Appropriate fractions were combined and solvent removed to afford the title compound as a brown residue (D2) (0.315g, 83%). δH (CDCI₃, 250MHz) 1.15-1.35 (2H, m), 1.45 (9H, s), 1.70-1.90 (3H, m), 2.63-2.77 (2H, m), 3.40-3.47 (2H, m), 4.05-4.20 (2H, m), 4.79 (2H, br s), 6.83 (1 H, d, J = 2.4Hz), 7.35 (1 H, br s), 7.62 (1 H, d, J = 2.4Hz), 8.03 (1 H, s). Mass Spectrum: C₂₀H₂₆CIN₃O₄ requires 407/409; found 406/408 (M-H)^".

Description 3a

4-Amino-5-chloro-Λ/-(4-piperidinylmethyl)-1-benzofuran-7-carboxamide hydrochloride (D3a)

To a solution of 1 ,1 -dimethylethyl 4-({[(4-amino-5-chloro-1-benzofuran-7- yl)carbonyl]amino}methyl)-1-pipehdinecarboxylate (0.315g, 0.77mmol) in methanol (10ml) was added 4M HCI/1 ,4-dioxan (20ml) and the reaction mixture stirred at room temperature for 1 h. The reaction was shown to be complete and volatiles were then removed to afford the title compound as an off-white solid

(D3) (0.267g, 100%). δH (MeOD, 250MHz) 1.40-1.60 (2H, m), 1.90-2.10 (3H, m), 2.90-3.05 (2H, m), 3.35-3.50 (4H, m), 7.11 (1 H, d, J = 2.4Hz), 7.76 (1 H, s), 7.79 (1 H, d, J = 2Hz). Mass Spectrum: Ci₅H₁₈CIN₃O₂ requires 307/309; found 308/310 (MH⁺).

Description 4 1,1-Dimethylethyl {[1-(tetrahydro-2H-pyran-4-ylmethyl)-4- piperidinyl]methyl}carbamate (D4)

A solution of tetrahydro-2H-pyran-4-carbaldehyde (0.267g, 2.3mmol) (PharmaCore Inc) in 1 ,2-dichloroethane (2mL) was added in one portion to a stirred (slight) suspension of 1 ,1-dimethylethyl (4-piperidinylmethyl)carbamate (0.5g, 2.3mmol) in 1 ,2-dichloroethane (5ml_) at room temperature under argon. After stirring for 15 minutes at room temperature under argon, sodium triacetoxyborohydride (0.974g, 4.6mmol) was added portionwise over 10 minutes and mixture then stirred for 1 h at room temperature under argon. Acetic acid (131uL) was added to the reaction mixture and the mixture left to stir for 18h at room temperature under argon (to ensure the reaction was complete). The reaction mixture was filtered under suction to remove inorganics, washed with 1 ,2-dichloroethane (2 x 5 ml_) and the filtrate was washed with water (1OmL). The water layer was then re-extracted with 1 ,2-dichloroethane (2x1 OmL). Combined organics were dried (MgSO₄) and concentrated to afford a scum. The aqueous extract was concentrated on a rotary evaporator (60⁰C, 5 mm Hg) and residue dissolved in 1 :1 methanol/dichloromethane (15mL). This solution was applied to a SCX cartridge (Varian, 1Og), eluting with dichloromethane (3 column volumes), methanol (3 column volumes) and 2M ammonia in methanol (3 column volumes). The 2M ammonia in methanol washings were collected and concentrated to a colourless oil which solidified upon standing at room temperature to yield the title compound (D4) (0.574g, 80%). δH (CDCI₃, 400MHz) 1.15-1.35 (4H, m), 1.44 (10H₁ s), 1.50-1.80 (m, 5H), 1.83-1.90 (2H, m), 2.15 (2H, d, J = 7Hz), 2.83-2.88 (2H, m), 2.90-3.05 (2H, m), 3.34-3.41 (2H₁ m), 3.93-3.97 (2H₁ m), 4.60 (1 H, br s).

Description 5 {[1-(Tetrahydro-2H-pyranylmethyl)-4-piperidinyl]methyl}amine (D5) 4M Hydrogen chloride in dioxan (1OmL) was added in one portion to a stirred solution of 1 ,1-dimethylethyl {[1-(tetrahydro-2H-pyran-4-ylmethyl)-4- piperidinyl]methyl}carbamate (0.54g, UOmmol) in water (1 mL) at room temperature (admixture of the reactants led to an increase in the temperature of the reaction mixture to ~40°C). The reaction flask was then stoppered and mixture stirred at room temperature for 18h. The reaction mixture was concentrated and then re-concentrated with toluene (2 x 5OmL). The residue was dissolved in 1 :1 methanol/dichloromethane (2OmL) and applied to an SCX (10g, Varian) cartridge, eluting with dichloromethane (3 column volumes), methanol (3 column volumes) and then 2M ammonia in methanol (3 column volumes). The latter eluent fractions were combined and concentrated to yield the title compound as a colourless oil which was dried in vacuo at room temperature for 2 hours (D5) (0.371 g, 100%). δH (DMSO-d6, 400MHz) 1.00-1.20 (5H, m), 1.55-1.65 (5H, m), 1.65-1.85 (4H, m), 2.07 (2H, d, J = 7Hz), 2.37 (2H, d, J = 6Hz), 2.77-2.80 (2H, m), 3.23-3.29 (2H, m), 3.78-3.82 (2H, m).

Example 1

4-Amino-5-chloro-Λ/-{[1-(tetrahydro-2/y-pyran-4-ylmethyl)-4- piperidinyl]methyl}-1 -benzofuran-7-carboxamide hydrochloride (E1 )

Method A

To a stirred solution of 4-amino-5-chloro-Λ/-(4-piperidinylmethyl)-1-benzofuran-7- carboxamide hydrochloride (0.1g, 0.29mmol) in 1 ,2-dichlorethane (10ml) was added tetrahydro-2H-pyran-4-carbaldehyde (50mg, 1.5 eq) and sodium triacetoxyborohydride (0.153g, 2.5 eq). The reaction mixture was stirred at room temperature for 18h and then heated at reflux (85°C) for 30 minutes. The reaction was shown to be complete by LC/MS analysis and methanol (5mL) was added to quench the reaction. Solvents were then removed by evaporation to afford crude material which was then purified on silica (eluting with a gradient of 0-20% methanol in dichloromethane) to give a colourless paste. This was treated with 1 M hydrogen chloride in diethyl ether to yield the title compound (E1 ) as a solid (68mg, 53%). δH (CD₃OD, 250MHz) 1.28-1.44 (2H₁ m), 1.55-1.71 (4H,m), 1.96-2.19 (4H, m), 2.92-3.02 (4H, m), 3.37-3.48 (4H, m), 3.53-3.54 (2H, m), 3.95 (2H, dd, J = 11 Hz, J = 2.8Hz), 7.11 (1 H, d, J = 2.3Hz), 7.76 (1 H, s), 7.79 (1 H, d, J = 2.3Hz). Mass Spectrum: C_2IH₂₈CIN₃O₃ requires 405/407; found 406/408 (MH⁺).

Method B

To a suspension of 4-amino-5-chloro-1-benzofuran-7-carboxylic acid (0.36g, 1.7mmol) and {[1-(tetrahydro-2H-pyranylmethyl)-4-piperidinyl]methyl}amine (0.36g, 1 Jmmol) in dry dichloromethane (2OmL) was successively added 4-(N₁N- dimethylamino)pyridine (21 mg, 0.17mmol) and 1-ethyl-3(3- dimethylaminopropyl)carbodiimide hydrochloride (0.49g, 2.6mmol) at room temperature and under argon. The flask was stoppered and vigorously stirred for 18h. The reaction mixture was washed with water (2OmL) and the latter washed with dichloromethane (15mL). The combined organics were washed with water (2OmL), saturated sodium hydrogen carbonate solution (20ml), dried (magnesium sulphate) and concentrated to a foam (0.46g). This was purified on silica gel (eluting with a gradient of 0-20% methanol/dichloromethane) and evaporated to dryness to give a pale yellow oil (0.35g). This material was treated with excess 1 M hydrogen chloride in diethyl ether and evaporated to dryness and then triturated with diethyl ether to afford a white solid. This solid was dissolved in warm methanol and precipitated with addition diethyl ether. The mixture was allowed to cool to room temperature and the resulting white precipitate filtered off and dried. This produced a white solid as the title compound (E1 ) (223mg, 32%). δH (CD₃OD, 400MHz) 1.30-1.45 (2H, m), 1.55-1.75 (4H,m), 1.95-2.09 (3H, m), 2.10-2.20 (1 H₁ m), 2.90-3.05 (4H, m), 3.40-3.50 (4H, m), 3.60-3.70 (2H, m), 3.90- 4.00 (2H₁ m), 7.11 (1 H, d, J = 2.4Hz), 7.76 (1 H, s), 7.79 (1 H, d, J = 2.4Hz). Mass Spectrum: C₂₁H₂₈CIN₃O₃ requires 405/407; found 406/408 (MH⁺). Example 2

4-Amino-5-chloro-Λ/-{[1-(tetrahydro-2W-pyran-4-ylmethyl)-4- piperidinyl]methyl}-1 -benzofuran-7-carboxamide (E2)

4-Amino-5-chloro-Λ/-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1- benzofuran-7-carboxamide hydrochloride (3.Og, 6.8mmol) was dissolved in methanol/water (4:1 ) (50ml) and applied to a column cartridge containing 7Og of Megabond Elut Flash SCX stationary phase material. The solution was allowed to run through the column under gravity until all of the material had been absorbed onto the column. The column was then successively eluted with the following solvent mixtures: methanol/water (4:1 ) (3 column volumes) [flow rate of ~30ml/min using vacuum]; methanol (2 column volumes) [flow rate of ~30ml/min using vacuum]; 2M ammonia in methanol solution (3 column volumes) [flow rate of ~30ml/min using vacuum]. Only fractions from the 2M ammonia/methanol elution phase were collected. These were pooled and evaporated under reduced pressure to afford the title compound as a colourless foam which was dried under vacuum at ambient temperature for 24h (2.8g, 6.9mmol, 100%). δH (CDCI₃, 400MHz) 1.20-1.40 (4H, m), 1.60-1.80 (6H, m, partially masked by water), 1.85-1.96 (2H, m), 2.15-2.17 (2H, m), 2.86-2.89 (2H, m), 3.34-3.44 (4H, m), 3.94-3.97 (2H, m), 4.66 (2H, br s), 6.79 (1 H, d, J = 2Hz), 7.32 (1 H, br s), 7.63 (1 H₁ Cl₁ J = 2Hz), 8.06 (1 H, s). Mass Spectrum: C_2IH₂₈CIN₃O₃ requires 405/407; found 406/408 (MH⁺). Example 3

4-Amino-5-chloro-/V-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4- piperidinyl]methyl}-1-benzofuran-7-carboxamide tosylate anhydrate (E3)

250.26mg of 4-Amino-5-chloro-Λ/-{[1 -(tetrahydro-2H-pyran-4-ylmethyl)-4- piperidinyl]methyl}-1-benzofuran-7-carboxamide was dispensed, the majority of which was dissolved up in 10ml tetrahydrofuran. 118mg of toluenesulfonic acid was dissolved in 2ml THF, and ~0.5ml of the resulting acid solution was added dropwise to the thin slurry containing the compound of the invention. This encouraged small quantities of solid to precipitate from solution, so the remaining acid solution was added to the thickening slurry, which was then left to stir at ambient temperature for ~1 hour. During this period the precipitant gummed, so the gum was taken up into the solvent using a hot air gun 3 times. During these heat/cool cycles, solid began precipitating from solution so the experiment was transferred to temperature cycle from 0-40⁰C overnight. Samples of this solid were analysed by polarised light microscopy before being isolated by filtration and dried overnight in vacuo at 40⁰C, and for an additional 2 hours the following morning at 60⁰C. 322.1 mg was recovered after drying (87.5 % yield).

Example 4a

4-Amino-5-chloro-Λ/-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4- piperidinyl]methyl}-1 -benzofuran-7-carboxamide hydrochloride (E4a)

The compound of the invention was also prepared according to Scheme 3 as follows: Stage 1

Methyl 4-aminosalicylate

4-Amino-2-hydroxybenzoic acid (1.0 eq.) was suspended in 10 vol MeOH (pale brown suspension) at T_out=20^oC. The suspension was cooled over 60 min to Ti=1°C. To the suspension was added 2.5 eq. borontrifluoride etherate over 65 min. at Ti=1 to 4°C giving a pale brown solution. The solution was heated to reflux over 3.5 h and kept refluxing for further 19.5 h at Ti=55°C. The reaction mixture was cooled over 2 h to Ti=20°C and stored in an inliner barrel (high density polyethylene coated drum).

The work-up procedure was done in two portions as outlined for one portion.

To the 160 L reactor was added 10 vol sat. NaHCO₃-solution at T_out=20^oC. Half of the reaction mixture was charged to the feeding tank from where the solution was added over 50 min. to a sat. NaHCO₃-solution to afford a pale brown suspension. The pH was determined via pH-electrode (pH=8.0). The suspension was cooled over 66 min. to Ti=14°C and filtered over a 50 L glass sinter funnel. The mother liquor was collected. The filter cake was washed in two portions with 1.5 vol water and in three portions with 1.5 vol heptane. The filter cake was dried for 18 h under an N₂-stream. The filter cake was further dried on the rotary evaporator at T_out=40°C and 16 mbar to afford the title compound in 3.885 kg (42% uncorr. yield; 99.4% a/a HPLC).

The second batch was worked-up in the same manner to give the title compound in 4.239 kg (46% uncorr. yield; 100% a/a HPLC). The overall yield was 88% (uncorrected).

Stage 2

Methyl 4-(acetylamino)-2-hydroxybenzoate Methyl 4-aminosalicylate (1.0 eq.) was dissolved in 9 vol dichloromethane at

T_Out=20°C to give a pale brown solution. The solution was cooled over 33 min. to

Ti=1°C. To the solution was added 1.2 eq. acetic acid anhydride in 2 vol dichloromethane over 52 min. at Ti=2 to 2.1⁰C. The solution was further stirred at Ti=2.1°C for 30 min., warmed to Ti=20°C over 32 min. and kept stirring at Ti=20°C for 3 h to give a pale brown suspension. After further stirring at Ti=20°C for 18 h the reaction was sampled to reveal 99% conversion according to HPLC. To the suspension was added 3 vol heptane at Ti=20°C. The suspension was cooled over 49 min. to Ti=IO⁰C and kept stirring for 32 min. at Ti=IO⁰C. The suspension was filtered over a glass sinter funnel; the mother liquor was collected and washed in two portions with 2 vol water and 2 vol heptane. The filter cake was dried on the sinter funnel under N₂-stream for 2.5 h. The filter cake was further dried on the rotary evaporator at T_out ⁼40^oC and 17 mbar to afford the title compound in 3.463 kg (36% uncorr. yield; 100% a/a HPLC). The second portion was dried on the rotary evaporator at T_out=40^oC and 16 mbar to afford the title compound in 4.225 kg (43% uncorr. yield; 100% a/a HPLC). The overall yield was 79% (uncorrected).

Stage 3

Methyl 4-(acetylamino)-5-chloro-2-hydroxybenzoate

Methyl 4-(acetylamino)-2-hydroxybenzoate (1.0 eq.) was suspended in 12 vol ethyl acetate at T_out=20^oC to give a pale brown suspension. The suspension was cooled to Ti=O.5⁰C over 41 min. To the suspension was added 1.05 eq. sulphuryl chloride in 2 vol ethyl acetate over 82 min. at Ti=O.5°C. The suspension was stirred at Ti=O.5°C for 38 min. and heated to Ti=20°C over 90 min. then stirred for 18.5 h (91.2% conversion according to HPLC).

The suspension was cooled to Ti=10°C over 63 min. and kept stirring for 33 min. at Ti=10°C. The suspension was filtered over a glass sinter funnel; the mother liquor was collected and washed in two portions with 2 vol ethyl acetate / heptane 1 :1. The filter cake was dried on the sinter funnel under N₂-stream for 16 h. The filter cake was further dried on the rotary evaporator at T_out=40^oC and 17 mbar to afford the title compound in 3.163 kg (36% uncorr. yield; 90.6% a/a HPLC). The second portion was dried on the rotary evaporator at T_out=40^oC and 15 mbar to afford the title compound in 2.496 kg (29% uncorr. yield; 90.4% a/a HPLC). The overall yield was 65% (uncorrected).

Stage 4

Methyl 4-(acetylamino)-5-chloro-2-hydroxy-3-iodobenzoate

Methyl 4-(acetylamino)-5-chloro-2-hydroxybenzoate (1.0 eq.) and 1.2 eq. sodium iodide were dissolved in 10 vol dimethylformamide at T_out=20°C. The pale brown solution was cooled over 35 min. to Ti=IO⁰C. 1.2 eq. chloroamine-T trihydrate was dissolved in 8 vol water at T_out=20^oC to give a slightly turbid solution. The chloroamine-T trihydrate solution was added over 1.5 h at Ti=10°C to the pale brown solution. The solution was stirred at Ti=10°C for 50 min. and heated to Ti=20°C over 50 min. The reaction mixture was stirred at Ti=20°C for 16.5 h (99.9% conversion by HPLC). To the pale brown solution was added 1 vol 5N HCI at Ti=20°C over 25 min. (pH=2.80 determined by pH-electrode). The suspension was cooled over 35 min. to Ti=IO⁰C and kept stirring for 35 min more. The suspension was filtered over a glass sinter funnel, the mother liquor was collected and the wet cake washed with 3 vol water, two portions of 3 vol ethyl acetate and one portion of 3 vol heptane. The filter cake was dried on the sinter funnel under N₂-stream and the wet cake was analyzed by HPLC (88.5% a/a HPLC) to give 28.03 kg of wet cake material. The wet cake material was suspended in 10 vol ethyl acetate (with respect to the starting material) to give a white-yellowish suspension. The suspension was heated to Ti=50°C over 61 min. and kept stirring for 61 min. at Ti=50°C. The suspension was cooled to Ti=10°C over 45 min. and kept stirring for 30 min. at Ti=10°C. The suspension was filtered through a glass sinter funnel and the wet cake washed with 1 vol ethyl acetate and two portions with 2 vol heptane. The filter cake was dried on the sinter funnel under N₂-stream for 1 h. The filter cake was further dried on the rotary evaporator at T_out=40^oC and 18 mbar to afford the title compound in 4.293 kg (63% uncorr. yield; 91.8% a/a HPLC). The overall yield was 63% (uncorrected). Stage 5

Methyl 4-(acetylamino)-5-chloro-2-(trimethylsilyl)-7-benzofurancarboxylate

Methyl 4-(acetylamino)-5-chloro-2-hydroxy-3-iodobenzoate (1.0 eq.), 0.02 eq. copper(l)iodide and 0.05 eq. Pd(PPh₃J₂CI₂ were suspended in 10 vol acetonitrile at T_ou_t ⁼20°C (yellow-brown suspension). To the suspension was added 5 vol diisopropylethylamine (Hϋnigs base) via a feeding tank over 5 min. at T_out=20^oC. The suspension was stirred for 10 min. at Ti=20°C and 1.2 eq. trimethylsilylacetylene was added over 5 min. at Ti=20°C via a feeding tank. The suspension was heated to Ti=50°C over 49 min. and the reaction mixture was stirred further for 20 h at Ti=50°C. The solution was cooled over 20 min. to

Ti=20°C and 10 vol half sat. NaCI-solution was added to the solution over 4 min. at Ti=20°C. In addition to that 10 vol dichloromethane was added and the dark- red solution was stirred for 5 min. (phase separation). The aqueous layer was separated (AL1 ) and the organic layer (OL1 ) transferred back to the vessel. To the OL1 layer was added 10 vol half sat. NaCI-solution and a second aqueous layer (AL2) was separated. To the remaining organic layer (OL2) was added further 10 vol half saturated NaCI-solution and a third aqueous layer (AL3) was separated. To the remaining organic layer (OL3) was added 5 vol water in the vessel at Ti=20°C and a final organic layer (OL4) was separated in an inliner- barrel.

The reactor was pre-dried with 15 vol acetone and 1 wf celite and 0.2 wt charcoal (Norit CA1 ) were charged to the vessel. OL4 was transferred to the vessel and stirred for 95 min. at Ti=20°C to give organic layer (OL5). For chromatography the glass sinter funnel was packed with 5 wt celite and washed with 4 vol dichloromethane. The suspension of OL5 was filtered onto the sinter funnel and purified by column using two portions of 4 vol dichloromethane. The filtrate of OL5 was collected and the volume was determined via feeding tank to give 123 L of OL5. 80% of the solvent (dichloromethane) was distilled off at T_out=50°C (Ti=40°C, 800-750 mbar) and the residue (OL6) was collected in an inliner-barrel. OL6 was finally concentrated on the rotary evaporator at T_0ut ⁼45^oC (<25 mbar) to give 2.543 kg of crude product (79.2% a/a HPLC). The crude product was dissolved in 2 wt dichloromethane for further purification by chromatography. The glass sinter funnel was prepared with 6 wt silica gel and washed with dichloromethane / ethyl acetate 19:1 (60 L). The dissolved crude product in dichloromethane was loaded onto the silica gel and purified via column chromatography. The volume was determined via feeding tank to afford 105 L. 50 to 60% of the solvent were distilled off at T_out=50^oC (Ti=35°) to give a residue volume of 42 L. The residue was concentrated on the rotary evaporator at T_ou_t=40°C (<16 mbar) to furnish 1.988 kg of the title product in 52% (uncorrected yield) 97.8% a/a HPLC).

Stage 5a

Methyl 4-(acetylamino)-5-chloro-2-(trimethylsilyl)-7-benzofurancarboxylate

Methyl 4-(acetylamino)-5-chloro-2-(trimethylsilyl)-7-benzofurancarboxylate (1.0 eq.), 7 vol fert-butyl methyl ether, 3.5 vol acetone and 3.5 vol acetonitrile were mixed in the reactor at T_out=20^oC to give a slightly turbid solution. Cysteine (0.5 eq.) was dissolved in 5 vol water at T_out=20^oC and the 10% cysteine-solution was added over 5 min. to the turbid solution of methyl 4-(acetylamino)-5-chloro-2- (trimethylsilyl)-7-benzofurancarboxylate. The clear brown solution was stirred at Ti=25°C for 1 h and cooled to Ti=20°C over 25 min.

Phase separation gave an organic layer (OL1 ) and an aqueous layer (AL1 ). To the OL1 layer was added sat. NaHCO₃-solution (5 vol) at Ti=20°C over 3 min., stirred for 5 min. and again separated to give an organic layer (OL2) and an aqueous layer (AL2). To OL2 were added 5 vol water at Ti=20°C over 2 min., stirred for 5 min. and separated to afford an organic layer (OL3) and an aqueous layer (AL3). The vessel was cleaned with 15 vol acetone, dried and loaded with 0.2 wt charcoal (Norit CA1 ). The OL3 layer was charged into the reactor and stirred at Ti=45°C for 1 h. The fine suspension was filtered through a 50 L glass sinter funnel containing 3 wt celite and washed with 5 vol dichloromethane to give an organic layer (OL4) filtrate. The reactor and the sinter funnel were washed in two portions with 3 vol dichloromethane and combined with OL4. The volume of OL4 was determined in the feeding tank (40 L). OL4 was concentrated on the rotary evaporator at T_out=40°C at <20 mbar to give the title compound as an off-white solid (1.631 kg, 86% recovery; 97.7% a/a HPLC).

Stage 6

4-Amino-5-chloro-7-benzofurancarboxylic acid

Methyl 4-(acetylamino)-5-chloro-2-(trimethylsilyl)-7-benzofurancarboxylate (1.0 eq.) was suspended in 5 vol water and 5 vol dioxane at T_out=20^oC. To the pale brown suspension was added 5 vol of a 10% KOH-solution at Ti=20°C over 16 min. to give a pale brown thin suspension. The reaction mixture was heated to Ti=70°C over 45 min. and kept stirring at Ti=70°C for 19.5 h. The pale brown solution was cooled to Ti=20°C over 1 h and 1.7 vol 5N HCI solution were added at Ti=20°C over 25 min. (pH determined by pH-electrode to give 5.3). The suspension was cooled to Ti=10°C over 35 min. and kept stirring for 52 min. at Ti=10°C. The suspension was filtered over a glass sinter funnel, the mother liquor was collected and washed in one portion with 2 vol water and two portions with 2 vol ethyl acetate / heptane 1 :3. The filter cake was dried on the sinter funnel under N₂-stream for 1 h. The filter cake was further dried on the rotary evaporator at T_out=40^oC and 18 mbar to afford the title compound in 0.860 kg (90% uncorr. yield; 99.9% a/a HPLC). The overall yield was 90% (uncorrected).

Stage 7

1-[(Tetrahydro-2h-pyran-4-yl)methyl]-4-piperidinemethanamine dihydrochloride (Boc-4-Aminomethylpiperidine (1.0 eq.) and NaBH(OAc)₃ (2.0 eq.) were suspended in 12 vol dichloromethane at T_out=20⁰C. To the suspension was added 1.0 eq. tetrahydro-2h-pyran-4-carboxaldehyde dissolved in 2 vol dichloromethane at Ti=21 to 24°C over 12 min. The suspension was stirred for 130 min. at Ti=25°C and analysis of a sample by gas chromatography (GC) revealed 100% conversion. The suspension was cooled to Ti=20°C and 1.0 eq. glacial acetic acid was added over 15 min. (to quench excess NaBH(OAc)₃). The suspension was further stirred for 30 min. and 2.9 vol 5N NaOH solution were added over 20 min. at Ti=20 to 22°C (pH determined by pH-electrode to give 5.8). To the turbid solution was added 6 vol water at Ti=25°C and 10 vol of dichloromethane / MeOH 9:1 for extraction. The organic layer (OL1 ) was separated and the aq. layer (AL1 ) was re-extracted with 10 vol dichloromethane / MeOH 9:1 to give an organic layer (OL2) and an aqueous layer (AL2). AL2 was further re-extracted with 10 vol dichloromethane / MeOH 9:1 to give an organic layer (OL3) and an aqueous layer (AL3). The combined organic layers were determined to afford 40 L. 80% of the solvent was distilled off at T_out=50^oC (Ti=38°C, 800 to 750 mbar) and to the remainder 8 L were given 5 vol dioxane at Ti=38°C over 2 min. (OL4). 25% of OL4 was distilled off at T_out=50^oC (Ti=38 to 44°C, 520 to 500 mbar) to afford 10.5 L of OL5. To OL5 was given 5 vol dioxane at Ti=43°C over 2 min. (OL6). The organic layer OL6 was cooled to Ti=10°C over 65 min. and 13 vol of 4M HCI in dioxane were added at Ti=9.9 to 7.2 over 39 min. to give a white suspension. The white suspension was further stirred at

Ti=9°C and warmed to Ti=20°C over 30 min. kept stirring for 16.5 h at Ti=20°C. A sample was withdrawn, concentrated to dryness to run a ¹H NMR for determination of complete Boc deprotection. The suspension was filtered over the 50 L glass sinter funnel and the mother liquor was collected. The filter cake was washed in two portions with 2 vol heptane and dried on the sinter funnel via N₂-stream for 2.5 h. The filter cake was further dried on the rotary evaporator at T_Ou_t=45°C and 18 mbar to afford the title compound in 1.301 kg. The overall yield was 87% (uncorrected).

Stage 8

4-Amino-5-chloro-W-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4- piperidinyl]methyl}-1 -benzofuran-7-carboxamide hydrochloride (E4a)

4-Amino-5-chloro-7-benzofurancarboxylic acid (1.0 eq.), 1.3 eq. 2-Chloro-4,6- dimethoxy-1 ,3,5-triazine and 1.15 eq. 1-[(Tetrahydro-2H-pyran-4-yl)methyl]-4- piperidinemethanamine were suspended in 20 vol acetonitrile at T_ou_t ⁼20°C to give a pale brown suspension. To the suspension were added 5 eq. of N- ethylmorpholine at Ti=25-30°C (slightly exothermic) over 12 min. and the suspension was stirred at Ti=25°C 20 h. The suspension was cooled to Ti=20°C and filtered over a 5OL glass sinter funnel to give the mother liquor. The vessel and the filter cake was washed in three portions with 3 vol acetonitrile. The filter cake was dried on the sinter funnel for 135 min. and on the rotary evaporator at Tout=45°C at <16 mbar to afford the title compound as a beige solid (1.461 kg, 109% uncorr. yield; HPLC: 96.8% a/a along with 1.9% a/a s.m.). 1.400 kg of the crude product (1.0 eq.) were suspended in 9.5 vol acetonitrile and 0.5 vol water at T_out=20^oC. The suspension was heated to Ti=50°C over 65 min. and kept stirring for 60 min. at Ti=50°C. The suspension was cooled to Ti=20°C over 60 min., filtered over the 50 L glass sinter funnel, washed with 2 vol acetonitrile and dried on the sinter funnel for 20 h. The filter cake was dried on the rotary evaporator at T_0ut=45^oC at <16 mbar to afford the title compound as a beige powder (1.188 kg, 85% recovery; HPLC: 98.2% a/a along with 0.85% a/a s.m.). The overall yield was 93% (uncorrected). δH (d6-DMSO, 400MHz) d 1.20

(2H,m), 1.65 (2H, d), 1.70 (2H₁ d), 1.82 (3H, d), 2.05 (1 H, m), 2.88 (4H, m), 3.30 (4H, m), 3.48 (2H₁ d), 3.82 (2H,q), 6.45 (2H,s), 7.28 (1 H, s), 7.60 (1 H, s), 7.91 (2H₁ m), 9.68 (1 H, s).

Example 4b

4-Amino-5-chloro-W-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4- piperidinyl]methyl}-1 -benzofuran-7-carboxamide (E4b)

4-Amino-5-chloro-Λ/-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1- benzofuran-7-carboxamide (1.0 eq.) hydrochloride was dissolved in 5 vol water and 1 vol acetonitrile at T_out=20°C (pH determined via pH-electrode 5.1 ). 1.0 eq. of sat. NaHCO₃-solution was added at T_out=20°C over 2 min. and the pH raised to 8.0. The clear brown solution was stirred for 60 min. at Ti=25°C (free-basing procedure) and 10 vol dichloromethane was added at Ti=25°C over 7 min. Stirring for 5 min. and phase separation afforded an organic layer (OL1 ) and an aqueous layer (AL1 ). AL1 was re-extracted using 10 vol dichloromethane, stirred for 5 min. at Ti=25°C, separated and combined with OL1. AL1 was again re- extracted with 10 vol dichloromethane, stirred for 5 min. at Ti=25°C, separated and combined with OL1. The volume was determined via feeding tank to give 30 L organic layer as a yellowish solution. 50% of the solvent were distilled off at T_out=50°C (Ti=34°C, 800-750 mbar) to furnish OL2. OL2 was concentrated on the rotary evaporator at T_0ut=35^oC (<20 mbar) and a sample was withdrawn (0.724 kg, 73% uncorr. yield; 99.1 % a/a HPLC) which corresponded to the free- base.

Example 4c 4-Amino-5-chloro-Λ/-{[1 -(tetrahydro-2H-pyran-4-ylmethyl)-4- piperidinyl]methyl}-1 -benzofuran-7-carboxamide tosylate monohydrate (E4c)

The free-base was dissolved in 10 vol dichloromethane at T_out=20^oC (salt- formation procedure). To the yellowish solution were added 1.05 eq. p- toluenesulphonic acid monohydrate dissolved in 2 vol THF at Ti=25°C over 16 min. An off-white suspension was obtained and the suspension was stirred for 110 min. at Ti=25°C. The suspension was cooled to Ti=10°C over 45 min. and kept stirring for 105 min. at Ti=10°C. The suspension was filtered through a 30 L glass sinter funnel, washed with two portions 2 vol dichloromethane and dried on the sinter funnel for 2 h. The filter cake was dried on the rotary evaporator at T_ou_t=35°C at <16 mbar to afford the title compound as a white to off-white powder (0.847 kg, 80% uncorr. yield; HPLC: 99.7% a/a along with 0.18% a/a unknown impurity). The overall yield was 60% (uncorrected). δH (d6-DMSO, 400MHz) d 1.20 (2H,m), 1.50 (2H, q), 1.60 (2H, d), 1.83 (3H,d), 2.03 (1 H, m), 2.27 (3H, s), 2.88 (4H, m), 3.25 (4H, s), 3.50 (2H, d), 3.82 (2H,q), 6.45 (2H,s), 7.13 (2H₁ d), 7.28 (1 H, s), 7.46 (2H,d), 7.60 (1 H, s), 7.91 (2H, m), 8.65 (1 H, s).

In stages 1 - 8 and Examples 4a, b and c, "Ti" means internal temperature (of the reaction vessel), "T_out" means outer temperature (of the heating vessel, e.g. mantle) and "a/a" means area over area. Biological Data

The compound of the invention may be tested for in vitro biological activity in accordance with the following assays:

Yeast functional 5-HT4a agonist assay

Yeast (Saccharomyces cerevisiae) cells expressing the human 5-HT4a receptor were generated by integration of an expression cassette into the ura3 chromosomal locus of yeast strain MMY23. This cassette consisted of DNA sequence encoding the human 5-HT4a receptor flanked by the yeast GPD promoter to the 5¹ end of 5-HT4a and a yeast transcriptional terminator sequence to the 3' end of 5-HT4a. MMY23 expresses a yeast/mammalian chimeric G- protein alpha subunit in which the C-terminal 5 amino acids of Gpa1 are replaced with the C-terminal 5 amino acids of human Gi1 (as described in Brown et al. (2000), Yeast 16:11-22). Cells were grown at 30⁰C in liquid Synthetic Complete (SC) yeast media (Guthrie and Fink (1991 ), Methods in Enzymology, Vol. 194) lacking uracil, tryptophan, adenine and leucine to late logarithmic phase (approximately 6 OD600/ml).

Agonists were prepared as 10 mM stocks in DMSO. EC50 values (the concentration required to produce 50% maximal response) were estimated using serial dilutions of between 3- and 5-fold (BiomekFX, Beckman) into DMSO. pEC50 corresponds to negative Iog10 of molar EC50. Agonist solutions in DMSO were transferred into black microtitre plates (96- or 384-well). Cells were suspended at a density of 0.2 OD600/ml in SC media lacking histidine, uracil, tryptophan, adenine and leucine and supplemented with 1 mM 3-aminotriazole, 0.1 M sodium phosphate pH 7.0, and 10^~5 M fluorescein di-β-D-glucopyranoside (FDGIu, Molecular Probes). This mixture (5OuI per well for 384-well plates, 20OuI per well for 96-well plates) was added to agonist in the assay plates, to give final assay concentration 1 % DMSO. After incubation at 30⁰C for 24 hours, fluorescence resulting from degradation of FDGIu to fluorescein due to exoglucanase, an endogenous yeast enzyme produced during agonist- stimulated cell growth, was determined (excitation wavelength: 485nm; emission wavelength: 535nm) using a Spectrofluor (Tecan) or similar microtitre plate reader. Fluorescence was plotted against compound concentration and iteratively curve fitted using a four parameter fit to generate a concentration effect value. Efficacy (Emax) was calculated from the equation:

Emax = Max[compound X] - Minfcompound X] / Max[5-HT] - Min[5-HT] x

100%

Where Max[compound X] and Minfcompound X] are the fitted maximum and minimum respectively from the concentration effect curve for compound X, and Max[5-HT] and Min[5-HT] are the fitted maximum and minimum respectively from the concentration effect curve for 5-hydroxytryptamine [5-HT]. Equieffective molar ratio (EMR) values were calculated from the equation:

EMR = EC50 [compound X] / EC50 [5-HT]

Where EC50 [compound X] is the EC50 of compound X and EC50 [5-HT] is the EC50 of 5-HT.

Mammalian functional 5-HT4a agonist assay

Human embryonic kidney cells stably expressing the human macrophage scavenger receptor type Il (HEK-293-MSR-II cells) were established in-house (Lysko PG et al., J Pharmacol Exp Ther. 289(3): 1277-85). These cells were grown in humidified conditions in Minimum Essential Medium containing 10% FCS, 1x non-essential amino acids, 2mM L-glutamine and 0.4 mg/ml geneticin at 37°C/5% CO₂.

BacMam plasmid constructs for the production of viruses for expression in mammalian cells were generated as described (Condreay JP et al., Proc. Natl. Acad. Sci. 96:127-132, Ames R et al., Receptors Channels 10(3-4): 117-24). A Kpnl-EcoRV fragment encoding the human 5-HT4a receptor cDNA (Genbank accession number Y08756) or a Kpnl-EcoRV fragment encoding the human G protein Gα16 (Genbank accession number M63904), both including an upstream Kozak sequence and start codon (GCCACCATG), were inserted separately into the BacMam shuttle vector multiple cloning site (Condreay JP et al., Proc. Natl. Acad. Sci. 96:127-132). Viruses containing these inserts were then generated using the Bac-to-Bac system (Invitrogen) according to manufacturer's instructions, and further propagated in Sf9 cells to generate high-titre virus stocks.

At 90% confluence, HEK-293-MSR-II cells were harvested in PBS by centrifugation and resuspended in the same media except that dialysed FCS was substituted for normal FCS. BacMam viruses encoding the 5HT4a cDNA and the Gα16 cDNA (see above) were both added to the cells at a multiplicity of infection of 5 and 10 respectively. The cells were then plated out in 96-well clear- bottomed, black-walled plates at 35,000 cells/well (in 100μl) and incubated for 24 hours.

The next day 50μl Fluo4am dye (at 6μM in Tyrodes buffer) was added to each well and incubated at 37°C/5% CO₂ for one hour. Cells were then washed five times in Tyrodes buffer, with the final wash leaving 150μl buffer in each well. Compounds to be tested for 5-HT4 agonism were prepared in 96-well plates as half-log dilution series from 4μM to 4OpM in Tyrodes buffer. A Fluorimetric

Imaging Plate Reader (FLIPR) was used to add the compounds (50μl per well) and to determine peak fluorescence emitted per well over the whole assay period. These data were analysed in Microsoft Excel using an in-house macro and iteratively curve fitted using a four parameter logistic fit (as described by Bowen and Jerman TiPS, 16, 413-417) to generate a concentration effect value and thus a pEC50 (negative Iog10 of molar EC50) and efficacy (maximal effect of compound expressed as a percentage of the maximal effect of 5-HT).

Results The compound of example E1 was tested in the yeast functional 5-HT4a agonist assay. The results are given below:

pEC50 = 9.39 ± 0.21 EMR = 0.31 ± 0.23 Efficacy = 90 ± 4.3%

Data are quoted as mean ± standard deviation from 20 test events over 10 independent test occasions, using two significant figures.

The compound of example E1 was also tested in the mammalian functional 5HT4a agonist assay. It exhibited agonism at the human recombinant 5-HT4a receptor with a pEC50 of 9.3 (s.e.m. = 0.09, range = 8.9-9.7, n = 8) and an efficacy of 85% (s.e.m. = 2, range = 76-97, n = 8).

Subsequent testing of the compound of Example E1 in the assays described herein afforded comparable results to those provided herein.

Claims

Claims

1. A compound which is 4-amino-5-chloro-Λ/-{[1-(tetrahydro-2H-pyran-4- ylmethyl)-4-piperidinyl]methyl}-1 -benzofuran-7-carboxamide (A),

(A)

or a pharmaceutically acceptable salt thereof.

2. A compound as defined in claim 1 , which is 4-amino-5-chloro-Λ/-{[1- (tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran-7- carboxamide hydrochloride.

3. A compound as defined in claim 1 , which is 4-amino-5-chloro-Λ/-{[1- (tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran-7- carboxamide tosylate.

4. A compound as defined in claim 1 , which is 4-amino-5-chloro-Λ/-{[1- (tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran-7- carboxamide tosylate monohydrate.

5. A compound as defined in claim 1 , which is 4-amino-5-chloro-Λ/-{[1- (tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran-7- carboxamide tosylate anhydrate.

6. A pharmaceutical composition which comprises a compound as defined in claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient.

7. A compound as defined in claim 1 or a pharmaceutically acceptable salt or solvate thereof for use in therapy.

8. A compound as defined in claim 1 or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of diseases treatable by 5-HT4 agonism.

9. Use of a compound as defined in claim 1 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of diseases treatable by 5-HT4 agonism.

10. A method of treatment of diseases treatable by 5-HT4 agonism which comprises administering to a host in need thereof an effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt or solvate thereof.

11. A pharmaceutical composition for use in the treatment of diseases treatable by 5-HT4 agonism which comprises a compound as defined in claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

12. A process for the preparation of 4-amino-5-chloro-Λ/-{[1 -(tetrahydro-2H- pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran-7-carboxamide or a salt or solvate thereof, which process comprises reacting 4-amino-5-chloro-Λ/-(4- piperidinylmethyl)-1-benzofuran-7-carboxamide or a salt or protected derivative thereof with tetrahydro-2H-pyran-4-carbaldehyde; and optionally thereafter (i) deprotecting a protected compound and/or (ii) forming a pharmaceutically acceptable salt of the compound so formed.

13. A process for the preparation of 4-amino-5-chloro-Λ/-{[1 -(tetrahydro-2/-/- pyran-4-ylmethyl)-4-piperidinyl]methyl}-1-benzofuran-7-carboxamide or a salt or solvate thereof, which process comprises reacting 4-amino-5-chloro-1- benzofuran-7-carboxylic acid or a salt or protected derivative thereof with {[1- (tetrahydro-2H-pyranylmethyl)-4-piperidinyl]methyl}amine or a salt or protected derivative thereof; and optionally thereafter (i) deprotecting a protected compound and/or (ii) forming a pharmaceutically acceptable salt of the compound so formed.