The present invention relates to the use 'of substituted dihydrobenzofuran derivatives which act as 5-HT ₄ receptor agonists in the treatment of gastrointestinal disorders and CNS disorders, to certain novel compounds having 5-HT ₄ receptor agonist activity, to a process for their preparation and to pharmaceutical compositions containing them. A non classical 5-hydroxytriptamine receptor has been designed (Trends Pharmacol. Sci. (1992) 13, 141-5) as the 5-HT ₄ receptor.

The prokinetic action of the substituted benzamide metoclopramide, which has long been in clinical use as a stimulant of gastrointestinal motility, is believed to be on the basis of its agonist effect on the 5-HT ₄ receptor

(Drug Design & Delivery (1988) 3, 273-295) .

Some 5-HT ₄ receptor agonists resulted active in appropriate animal behavioural tests for memory dysfunctions (Ghelardini et al. 19 ^th C.I.N.P. Congress, hashington, June 1994 ; Ghelardini et al . 10 ^th European Society for Neurochemistry, Jerusalem, August 1994) . International patent application WO 93/16072 describes 5-

HT ₄ receptor antagonists derived from the benzopyran, benzothiopyran or benzofuran nucleus.

International patent application WO 94/08995 relates to novel carboxylate or carboxamides of benzofuran or dibenzofuran having 5-HT ₄ antagonist activity.

We have identified a class of substituted dihydrobenzofuran carboxylic acid derivatives which possess 5-HT ₄ receptor agonist properties, despite their structural analogies with the closest prior art compounds such as, e.g., those disclosed in WO 93/16072 and WO 94/08995 having 5-HT ₄ antagonist activity.

By virtue of their 5-HT ₄ agonist activity, the compounds of the invention can be useful in all the pathologies wherein a stimulation of the 5-HT ₄ receptors is needed and therefore, the compounds of the invention can be useful, for example, as therapeutic prokinetic agents in the treatment of gastrointestinal disorders such as, e.g., dyspepsia, gastro-oesophageal reflux disease (GORD) and gastroparesis, and/or also in the treatment of CNS disorders characterized by learning and/or memory dysfunctions.

Accordingly, the present invention relates to dihyrobenzofuran derivatives of formula (I)

(I)

wherein

R _lf R ₂ and R ₃ are, each independently, hydrogen, C^Cg alkyl, halogen, hydroxy, C _j -^ alkoxy, amino, C ₁ -C ₄ alkylamino or C^^ di-alkylamino; X is 0, NH or CH ₂ ; Z is a group (a) , (b) , (c) or (d)

(CH.)„— (CH,

V_/ (a)

wherein n is 1, 2, 3 or 4; m is zero or 1; q is zero, 1 or 2;

R ₄ is hydrogen , C^Cg alkyl, benzyl, cyclohexylmethyl or

- CH ₂ -C-_ ₂ -S0 ₂ N__-R ₆ in which R ₆ is C^ Cg alkyl or benzyl ;

R ₅ is Ci-Cg alkyl ; and

T is halogen ; provided that, when Z is defined under (c) , then X is O or CH ₂ , and their pharmaceutically acceptable salts, for use as 5-HT ₄ agonists. The compounds of formula (I) can therefore be useful in the treatment of all the pathologies wherein a stimulation of the 5-HT ₄ receptor is needed. As an example, the compounds of formula (I) may be useful as therapeutic prokinetic agents in the treatment of gastrointestinal disorders such as, for example, dyspepsia, gastro-oesophageal reflux disease (GORD) or gastroparesis.

The compounds of formula (I) may also be useful, by virtue of their 5-HT ₄ agonist properties, as cognition activators, in the treatment of CNS disorders characterized by learning and/or memory dysfunctions.

The alkyl, alkoxy and alkylamino groups may be branched or straight groups.

Representative examples of alkyl groups include methyl, ethyl, n- and iso-propyl, n - , iso- , sec- and tert- butyl.

Representative examples of C -C. alkoxy groups include methoxy and ethoxy.

A C _x -C ₄ alkylamino group is, in particular, methylamino or ethylamino.

A C ₁ -C ₄ di-alkylamino group is, in particular, dimethylamino or diethylamino.

Halogen includes fluorine, bromine, chlorine or iodine, in particular, chlorine or bromine. The pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with inorganic, e.g. hydrochloric, hydrobromic, sulphuric, and phosphoric acids, or organic, e.g. acetic, propionic, lactic, oxalic, malic, maieic, tartaric, citric, benzoic, mandelic, salicylic and fumaric acids.

Examples of pharmaceutically acceptable salts of the compounds of formula (I) wherein Z is a group (a) or (b) include quaternary derivatives such as, e.g., the compounds quaternised by compounds of formula R _* -W wherein R- is C _x - C ₆ alkyl or phenyl-Ci-Cgalkyl and W is a radical corresponding to an anion of an acid.

Preferably, R _x is C--C ₄ alkyl or phenyl-C ₁ -C ₄ alkyl, in particular it is methyl, ethyl, n-propyl, ι_-butyl, benzyl or phenylethyl . Preferably, W is a halide such as, e.g., chloride, bromide or iodide.

Examples of pharmaceutically acceptable salts of the compounds of formula (I) wherein Z is a group (a) , (b) or (c) also include internal salts, such as, e.g. N-oxides. The compounds of formula (I) , their pharmaceutically

acceptable salts, (including quaternary derivatives and N- oxides) may also form pharmaceutically acceptable solvates, such as hydrates, which are also object of the present invention. Compounds of formula (I) wherein Z is a group (c) contain an asymmetric carbon atom and, for this reason, they can exist either as a mixture of optical isomers (racemic mixture) or as a single optical isomers (enantiomers) . The enantiomers can be separately synthesised from optically pure starting material or separated from the racemic mixture in a conventional manner.

The present invention also include within its scope both the metabolites and the pharmaceutically acceptable bio- precursors (otherwise known as pro-drugs) of the compounds of formula (I) .

This invention also refers to a preferred class of compounds within formula (I), as novel compounds. These compounds, which form a further object of the invention, are compounds of formula (I)

wherein

R _x is hydrogen;

R ₂ is chlorine or bromine;

R ₃ is amino; X is 0 or NH; Z is a group (a) , (b) , (c) or (d) :

"(CH,).— .(CHJ.

(a)

wherein n is 2 or 3; m is zero or 1; q is 1 or 2;

R ₄ is C ₃ -C ₅ alkyl or -CH ₂ -CH ₂ -S0 ₂ NH-CH ₃ ;

R ₅ is C ₃ -C ₃ alkyl;and T is chlorine or bromine; provided that, when Z is defined under (c) , then X is O; and their pharmaceutically acceptable salts. Examples of preferred compounds according to the invention are the following:

N- tl-butyl-1-azabicyclo [2, 2,2] oct-3-yl] -4-amino-5-chloro- 2 , 3 -dihydrobenzo [b] furan-7-carboxamide bromide; (1-azabicyclo [2,2,2] oct-3-yl) -4-amino-5-chloro-2, 3 -dihydro¬ benzo [b] furan- 7 -carboxylate; (i-butyl-piperid-4-yl)methyl-4-amino-5-chloro-2, 3-dihydro- benzo [b] furan-7-carboxylate;

(1-piperidyl) propyl-4-amino-5-chloro-2 , 3 -dihydrobenzo [b] furan- 7 -carboxylate;

(1-piperidyl) ethyl-4-amino-5-chloro-2 , 3 -dihydrobenzo [b] furan- 7 -carboxylate ;

N- [ ( 1 -butyl -piper id- 4 -yl) methyl] -4 -amino-5-chloro-2 , 3- dihydrobenzo [b] furan-7-carboxamide;

N- t (1 -piper idyl )propyl] -4-amino-5-chloro-2, 3 -dihydrobenzo [b] furan-7-carboxamide; and N- [ (1-piperidyl) ethyl] -4-amino-5-chloro-2 , 3 -dihydrobenzo [b] furan-7-carboxamide; if the case either as a single isomer or as a mixture of isomers thereof, and the pharmaceutically acceptable salts thereof . The compounds of formula (I) can be obtained by a process comprising : A) reacting a compound of formula (II)

^R 3 (II)

wherein

E is OH, Cl, Br or 1-imidazolyl, and

R _x , R ₂ and R ₃ are, each independently, hydrogen, C^Cg alkyl, halogen, hydroxy, ^■ C- _. -C ₄ alkoxy, amino, C- _. -^ alkylamino or C- _. -C ₄ di-alkylamino, with an amine or an alcohol of formula (III) , (IV) or (V)

^Q —(CH.). .(CH-)„

(III)

HO

(V) wherein ^{■ N} —N

Q is OH or NH ₂ ; n is 1,2,3 or 4; m is 0 or 1; q is 0,1 or 2; and

R ₄ is hydrogen, Ci-Cg alkyl, benzyl, cyclohexylmethyl or

-CH ₂ -CH ₂ -S0 ₂ -NH-R ₆ in which R ₆ is C^Cg alkyl or benzyl so obtaining a compound of formula (I) wherein R _{l t} R ₂ , R ₃ and R ₆ are as defined above, X is NH or O and Z is a group

(a) , (b) or (c) ; or

B) reacting a compound of formula (VI)

(VI)

wherein

Y is OH, Cl, Br or CH ₃ -NH-OCH ₃ , and R-, R ₂ and R ₃ are are as defined above, with an organometallic derivative of formula (VII) , (VIII) or (IX)

M—(CH,).—N (CH,) _m

(VII)

wherein

M is MgBr, MgCl or Li, and n, m, q, R ₄ and R ₅ are as defined above, so obtaining a compound of formula (I) wherein R _x , R ₂ and R ₃ are as defined above, X is CH ₂ and Z is a group (a) , (b) or (c) ; or C) reacting a compound of formula (X)

wherein R _x , R ₂ , R ₃ and X are as defined above, and X is NH, 0 or CH ₂ ,

with an alkyl halide of formula R ₅ T wherein R ₅ is alkyl and T is halogen, so obtaining a compound of formula

(I) wherein R^ R ₂ , R ₃ are as defined above, X is 0, NH, or

CH ₂ and Z is a group (d) ; and, if desired, when a compound of formula (I) contains an asymmetric carbon atom,

D) resolving the racemic mixture of a compound of formula

(I) into the single isomers; and/or, if desired,

E) converting a compound of formula (I) into a pharmaceutically acceptable salt thereof. The reaction of a compound of formula (II) with a compound of formula (III) , (IV) or (V) under step A) is an analogy process and can be carried out according to well known methods in the art. For instance, an acyl halide of formula

(II) can be reacted with an alcohol or an amine of formula (III) , (IV) or (V) in a suitable organic solvent such as, for instance, dichloromethane, tetrahydrofurane or acetonitrile, at a temperature ranging from about 0°C to about the reflux temperature of the mixture, in the presence of a proton scavenger such as, for instance, t-riethylamine, sodium hydrogen carbonate or potassium carbonate.

The reaction of a compound of formula (VI) with a compound of formula (VII) , (VIII) or (IX) under step B) can also be carried out according to well known methods in the art. For instance, an acyl halide of formula (VI) can be reacted

with a Grignard reactive of formula (VII) , (VIII) or (IX) in a suitable organic solvent such as, e.g., tetrahydrofuran or diethyl ether in the presence of, e.g., Fe (acetylacetonate) ₃ or Cul, at a temperature ranging from about -78°C to about 30°C.

The reaction of a compound of formula (X) with an alkyl halide R ₅ T under step C) can be carried out according to standard methodologies. For instance, a compound of formula (X) can be reacted with a compound R ₅ T as defined above, in the presence of a suitable organic solvent such as, e.g., methanol or ethanol, at a temperature ranging from about 30°C to about the reflux temperature of the mixture. The carboxylic acids of formulae (II) and (VI) wherein E and Y are OH are either commercially available or known products.

The acid derivatives (II) and (VI) are either known products (EP 0 234 872 Al Adria Laboratories Inc. ) or may be prepared from the corresponding acids by methods well known in the art. The alcohols and amines of formulae (III) , (IV) and (V) are either commercially available or known products. The organometallic derivatives of formulae (VII) , (VIII) and (IX) can be prepared by standard methodologies from the corresponding alkyl halides which are either commercially available products or can be easily prepared from the

corresponding alcohols of formulae (III), (IV) and (V) . The compounds of formula (X) wherein X is NH are known compounds (EP 0 234 872 Al Adria Laboratories Inc.). The alkyl halides of formula R _S T are commercially available products.

The separation of a mixture of isomers of a compound of the invention into single isomers and the conversion of a compound of formula (I) into a pharmaceutically acceptable salt thereof can be carried out according to well known methods in the art.

As already said, the compounds of the present invention are potent agonists of 5-HT (serotonin) on 5-HT ₄ receptors and can therefore be used in the treatment of the pathologies wherein a stimulation of the 5-HT ₄ receptor is needed. In particular, as 5-HT ₄ agonists are known being stimulant of gastrointestinal motility, the compounds of the present invention can be useful as therapeutic prokinetic agents, for example, in the treatment of gastrointestinal disease such as, for instance, dyspepsia, gastro-oesophageal reflux disease (GORD) or gastroparesis. In addition, in view of the fact that 5-HT ₄ receptors are believed to be involved in synaptic plasticity events and in memory processes (CNS Drugs (1994) 1, 6-15) , and that it has been demonstrated that 5-HT ₄ receptor stimulation facilitates in vivo acetylcholine release in rat frontal cortex (NeuroReport

(1994) 5, 1230-2) , another application of the compounds of the invention may also be as cognition activators in the treatment of CNS disorders characterized by learning and/or memory dysfunctions. 5-HT ₄ receptor affinity of the compounds of the present invention was determined by the inhibition of the binding of the 5-HT ₄ receptor radioligand [ ³ H] -GR-113808 in rat striatum, according to the method of Grossman et al . (Br.J.Pharmacol. , 1993, 109,618-624) . The activity of the compounds of the present invention as 5-HT ₄ agonists was evaluated "in vitro" by the receptor- mediated relaxation responses of rat, carbachol precontracted oesophageal muscolaris mucosae, following the method of Baxter et al. , (Naunhyn Schmiedeberg' s Arch. Pharmacol., 1991, 343, 439-446) .

As an example, a representative group of compounds according to this invention, namely

(S) - (+) -N- [l-butyl-l-azabicyclo[2,2,2]oct-3-yl] -4-amino- 5-chloro-2, 3-dihydrobenzo [b] furan-7-carboxamide bromide monohydrate (internal code FCE 28773A) ;

(1-butyl-piperid-4-yl)methyl-4-amino-5-chloro-2, 3- dihydrobenzo[b] furan-7-carboxylate hydrochloride (internal code FCE 29029A) ; N- [ (1-butyl-piperid-4-yl)methyl] -4-amino-5-chloro-2, 3- dihydrobenzo [b] furan-7-carboxamide hydrochloride

(internal code FCE 29030A) ;

(1-piperidyl) ethyl-4-amino-5-chloro-2, 3-dihydrobenzo[b] furan-7-carboxylate hydrochloride hemihydrate (internal code FCE 29032A) ; N- [ (1-piperidyl)ethyl] -4-amino-5-chloro-2, 3-dihydrobenzo

[b] furan-7-carboxamide hydrochloride hydrate (internal code FCE 29033A) ;

(1-piperidyl)propyl-4-amino-5-chloro-2,3- dihydrobenzo [b] furan-7-carboxylate hydrochloride hemihydrate (internal code FCE 29031A) ;

N- [ (1-piperidyl)propyl] -4-amino-5-chloro-2, 3- dihydrobenzo [b] furan-7-carboxamide hydrochloride hydrate

(internal code FCE 29034A) and

(S) - (+) - (l-azabicyclo[2,2,2]oct-3-yl) -4-amino-5-chloro- 2,3-dihydrobenzo[b] furan- -carboxylate hydrochloride (internal code FCE 28797A) ; were tested according to the methods described above and the obtained results are reported on Table 1. Table 1

IC.

K, = l + ΓLI

Kd where

IC ₅₀ = concentration of the tested compound which forces the displacements of 50% of the bound radioligand concentration, obtained in the absence of inhibitor. [L] = radioligand concentration Kd = dissociation constant of the radioligand-receptor complex.

EC ₅₀ = efficacy concentration: concentration of the tested compound which induces 50% of the max. response (in this case 50% of the max. relaxation) . i.a. = intrinsic activity: max. response/max response of the natural agonist (in this case max. relaxation/5-HT max.relaxation) .

The tabulated results clearly show that the compounds of the invention exhibit high affinity for the 5-HT ₄ receptor sites and, in the same time, are particularly effective in

promoting 5-HT ₄ receptor activity.

The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g. intramuscolarly, or by intravenous injection or infusion.

The dosage depends on the age, weight,, conditions of the patient and on the administration route; for example, the dosage adopted for oral administration to adult humans e.g. for the representative compound of the invention FCE 29034A may range from about 1 to about 500 mg pro dose, from 1 to 5 times daily.

The invention includes pharmaceutical compositions comprising a compound of the invention as an active principle in association with a pharmaceutically acceptable excipient (which can be a carrier or a diluent) . The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.

For example, the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, destrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or

calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.

The liquid dispersion for oral administration may be e.g. syrups, emulsions and suspension. The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

The suspensions or solutions for intramuscolar injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol,

and, if desidered, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, acqueous, isotonic saline solutions.

The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. The following examples illustrate but do not limit the invention.

Example 1

A mixture of 4-amino-5-chloro-2, 3-dihydrobenzo [b] furan-7- carboxylic acid (0.700g , 3.28 mmol) and carbonyldiimidazol (0.580g , 3.60 mmol) in 10 ml of anhydrous tetrahydrofuran was heated at 40°C for 1.5h. Afterward (1- piperidyDethylamine (0.427ml , 4.92mmol) in 5ml of tetrahydrofuran was added, the mixture was heated for additional 2h and stirred at 22°C for 16h. Volatilies were evaporated under reduced pressure and the residue was taken up with water and ethyl acetate; the layers were separated, the organic layer was dried over anhydrous sodium sulphate and evaporated to give 1.0 of raw material, which was partially purified by column chromatography over silica gel

(eluant chloroform/methyl alcohol/ammonia solution 30% 46:4:0.1) . The carboxamide was conveniently isolated as its hydrochloride by adding to the free base in aceton/isopropyl alcohol 1 equivalent of hydrochloric acid in isopropyl alcohol. Precipitated solid was filtered, washed with c.:.-._hy_ ether and dried, yielding 746mg (60%) of N- [ (1-piperidyl) ethyl] -4-amino-5-chloro-2 , 3 - dihydrobenzo [b] furan-7-carboxamide hydrochloride hydrate as a colorless solid (m.p. = 237-239°C) . Analogously, the following compounds were prepared :

N- t (l-piperidyl)propyl] -4-amino-5-chloro-2 , 3- dihydrobenzo [b] furan-7-carboxamide hydrochloride hydrate (m.p. 192-194°C) ; and N- [ (l-butyl-piperid-4-yl) methyl] -4-amino-5-chloro-2 , 3- dihydrobenzo [b] furan-7-carboxamide hydrochloride (m.p.260- 262°C) . Example 2

A mixture of 4-amino-5-chloro-2, 3-dihydrobenzo [b] furan-7- carboxylic acid (1.61g , 7.56 mmol) and carbonyldiimidazol (1.35g , 8.32 mmol) in 15 ml of anhydrous tetrahydrofuran was heated at 40°C for 1.5h. Afterward a solution of N- (1- butyl-piperid-4-yl)methyl alcohol (2.59g , 15.1mmol) and 1, 8-diazabicyclo [5,4 _> 0]undec-7-en (DBU) (1.13ml , 7.56 mmol) in 10ml of tetrahydrofuran was added and the mixture was heated for additional 2.5h. Volatilies were evaporated

under reduced pressure and the residue was taken up with water and diethyl ether; the layers were separated, the organic layer was dried over anhydrous sodium sulphate and evaporated to give 3.5g of raw material, which was purified by column chromatography over silica gel (eluant chloroform/methyl alcohol 46:4) yielding 1.5g (54%) of (1- butyl-piperid-4-yl) ethyl-4-amino-5-chloro-2, 3-dihydrobenzo [b] furan-7-carboxylate (m.p. = 124-126°C) as a colorless solid. Analogously, the following compounds can be prepared :

(1-piperidyl ) ethyl-4-amino-5-chloro-2 , 3 -dihydrobenzo [b] furan-7-carboxylate (m.p. = 152-154°C) ; (1-piperidyl ) propyl-4-amino-5-chloro-2 , 3-dihydrobenzo [b] furan-7-carboxylate; and (S) - (+) - (l-azabicyclo[2,2,2]oct-3-yl) -4-amino-5-chloro- 2, 3-dihydrobenzo [b] furan-7-carboxylate. Example 3

1 equivalent of hydrochloric acid in isopropyl alcohol was added at 5°C to a stirred solution of (1-piperidyl)propyl 4-amino-5-chloro-2, 3-dihydrobenzo [b] f ran-7-carboxylate (337mg , 0.996mmol) in aceton . Precipitated solid was was filtered, washed with diethyl ether and dried, yielding 342mg (89%) of (1-piperidyl)propyl 4-amino-5-chloro-2, 3- dihydrobenzo [b] furan-7-carboxylate hydrochloride hemihydrate as a colorless solid (m.p. = 226-228°C) .

Analogously, the following compounds were prepared : (1-piperidyl) ethyl-4-amino-5-chloro-2, 3- dihydrobenzo [b] furan-7-carboxylate hydrochloride hemihydrate (m.p. 255-257°C) ; (l-butyl-piperid-4-yl)methyl-4-amino-5-chloro-2, 3- dihydrobenzo [b] furan-7-carboxylate hydrochloride (m.p. = 238-240°C) ; and

(S) - (+) - (1-azabicyclo [2,2,2] oct-3-yl) -4-amino-5-chloro- 2, 3-dihydrobenzo [b] furan-7-carboxylate hydrochloride (m.p. 283.5-284.5); [a] _D " = +82 (c = 0.94 , D F) .

Example 4

A mixture of (S) - (+) - [1-azabicyclo [2, 2,2] oct-3-yl] -4- amino-5-chloro-2, 3-dihydrobenzo[b] furan-7-carboxamide (0.508g , 1.58mmol) and n-butylbromide (0.169ml , 1.58mmol) in ethyl alcohol was heated under reflux for

16h. The solvent was removed under reduced pressure, the residue was purified by column chromatography over silica gel (eluent chloroform/ methyl alcohol 4:1) and crystallized by water giving 0.43g (60%) of (S) - (+) -N- [1- butyl-1-azabicyclo [2,2,2] oct-3-yl] -4-amino-5-chloro-2, 3- dihydrobenzo [b] furan-7-carboxamide bromide monohydrate as an amorphous colorless solid ; [α] _D ²³ = +36 (c = 0.94 , DMF) .

Example 5

With the usual methods of pharmaceutical technique, preparation can be made of capsules having the following composition: N- (1-piperidyl)ethyl-4-amino-5-chloro-2, 3- dihydrobenzo [b] furan-7-carboxamide hydrochloride ' hydrate 50mg talc 2mg starch 2mg microcristalline cellulose 6mg magnesium stearate lmg