MXPA98008960A - Benzofuaranos and benzopiranos as agents cronobiologi - Google Patents

Abstract

A compound of formula (I), wherein R 1 and R 2 -which could be the same or different- represent H, C 1-6 alkyl, C 3-7 cycloalkyl, R 3 and R 4 could be the same or different, and represent H, C 1-6 alkyl, or substituted aryl, R 5 represents Haloalkyl C 1-6 is an integer 0, 1 and 2 and m is an integer 1, 2, 3 or 4. The dotted line indicates the presence or absence of an additional link, and the pharmaceutically acceptable solvates of the same

Description

BENZOFURANS AND BENZOPIRANS AS CHRONOBIOLOGICAL AGENTS This invention relates to bicyclic compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their medical use.

The invention in this manner provides the compounds of Formula (I) wherein R1 and R2 which could be the same or different, represent H, C1-6 alkyl or substituted alkyl or C3-7 cycloalkyl; or aryl; R3 and R4, which could be the same or different, represent H, halogen, C1-s alkyl or aryl itsuide; REF .: 028682 Rs is H or C1-6 alkyl; n is an integer O or l and m is an integer 1, 2, 3 or 4; the dotted line indicates the presence or absence of an additional link; pharmaceutically acceptable solvates (eg hydrates) thereof.

It will be appreciated that in the above formula (I) the substituents R3 and R4 could be attached at any available position in the phenyl portion of the bicyclic system. Preferably when n is 0, R3 and R4 are substituted at positions 5 and / or 7 on the phenyl ring.

As used herein, an alkyl group could be a straight chain or branched chain alkyl group. Examples of suitable alkyl groups include C1-4 alkyl groups, for example methyl, ethyl, n-propyl and isopropyl groups. When optionally substituted, the substituent is one or more fluorine atoms.

A halogen substituent could be fluorine, chlorine, bromine or iodine.

As used herein, the term "aryl" as a group means phenyl, optionally substituted by one or more (eg 1-3) atoms or groups selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, halogen, nitro and trifluoromethyl.

The cycloalkyl groups could be cycloalkyl groups connected by bridges, e.g. ex. Norbornyl cycloalkyl groups or not bridged, p. ex. cyclopropyl.

Examples of the groups R3 and R4 include hydrogen, halogen (eg chlorine and / or fluorine) and C1-3 alkyl (eg methyl) m represents preferentially 2. n preferably represents 0.

R 2 could particularly represent hydrogen or C 1-3 alkenyl (eg methyl).

Rj. it could particularly represent hydrogen, C1-3 alkyl (eg methyl, ethyl, n-propyl or i-propyl) or cycloalkyl C3-s (eg cyclopropyl or cyclobutyl).

A particular group of compounds of the invention are compounds of the formula (la). and pharmaceutically acceptable solvates (eg hydrates) thereof, wherein R1, R3 and R4 are as defined above especially halogen, more especially R3 and R4 are chloro and / or fluorine, especially where R1 is methyl or cyclopropyl.

Another particular group of compounds of the invention are the compounds of the formula I (b) CHjíCHj -CO i (1b) wherein R 1 and R 2 which could be the same or different represent H, C 1-6 alkyl or substituted aryl, C 3-7 cycloalkyl or aryl; R3 and R4 which could be the same or different represent H, halogen, C1-6 alkyl or substituted aryl; n is an integer O or l and m is an integer 1, 2, 3 or 4; the dotted line indicates the presence or absence of an additional link; pharmaceutically acceptable solvates (eg hydrates) thereof.

A further particular group of compounds are the compounds of the formula I (c) wherein R1 and R2 which could be the same or different represent H, C1-6 alkyl or C3-7 cycloalkyl; R3 and R4 which could be the same or different represent H, halogen, or C1-s alkyl; R5 is H or C1-s alkyl; n is an integer O or l and m is an integer 1, 2, 3 or 4; the dotted line indicates the presence or absence of an additional link; pharmaceutically acceptable solvates (eg hydrates) thereof.

Particular compounds according to the present invention include N- [3- (2,3-dihydro-benzofuran-4-yl) -propyl] acetamide, [3- (2,3-dihydro-benzofuran-4-yl) propyl] ] -cyclopropanecarboxylic acid amide, [3- (5-chloro-2,3-dihydro-benzofuran-4-yl) propyl] -amide of cyclopropanecarboxylic acid[3- (5-chloro-7-fluoro-2, 3-dihydro-benzofuran-4-yl) -propyl] -amide of cyclopropanecarboxylic acid, [3- (5-chloro-7-f-luoro-benzofuran-4- il) ropil] -amide of cyclopropanecarboxylic acid, [3-bezofur an-4-i 1) pr op i 1] - amide of cyclopropanecarboxylic acid, (3-chroman-5-yl-propyl) -amide of cyclopropanecarboxylic acid , N- [3- (2, 3-dihydro-5-fluorobenzofuran-4-yl) propyl] acetamide, [3- (2,3-dihydro-5-fluoro-benzofuran-4-yl) propyl] -amide of the cyclopropanecarboxylic acid.

It is to be understood that the present invention covers all combinations of the particular and preferred groups above.

Subsequent references to a compound of the formula (I) includes the compound and its pharmaceutically acceptable solvates.

The compounds of formula (I) could contain at least one asymmetric carbon atom and could exist as stereoisomers. The compounds of the formula (I) thus include the R- and S- isomers and mixtures, for example racemic mixtures, thereof.

The compounds of formula (I) have a high affinity and selectivity for binding to melatonin receptors and have either agonist or melatonin antagonist activity as demonstrated in human ML1 receptors cloned in Chinese hamster ovary cells. Therefore, the compounds are of use as scientific tools to study the role of melatonin within biological systems.

The compounds of the formula (I) are also of use in the treatment of disorders that arise from a disturbed functioning of the systems that are regulated by melatonin. In particular the compounds of the formula (I) could be used in the treatment of cronobi.olo.gi.cos disorders, especially in the elderly population, glaucoma, cancer, psychiatric disorders, neurodegenerative diseases or neuroendocrine disorders that arise as a result of or influenced by systems that are regulated by melatonin Chronobiological disorders include temporary affective disorders (SAD), primary and secondary insomnia disorders, primary and secondary hypersomnia disorders, sleep-wake state disorders (including advanced phase type, delayed phase type, disorganized type and type of change frequently) and other disinsomnios, especially those caused by aging, dementia, blindness, work shift and by the route of the rapid time zone, commonly known as rapid delay.

Cancers that could be treated with a compound of formula (I) include solid tumors, e.g. ex. melanomas and breast carcinomas.

Psychiatric disorders that could be related to melatonin function altered or influenced by melatonin and circadian rhythms include mood disorders (which include bipolar disorders of all types, major depression, dysthymia, and other depressive disorders), dependence and abuse of psychoactive substance, anxiety disorders (which include panic disorder, agoraphobia, social phobia, simple phobia, obsessive compulsive disorder, disorder of post-traumatic stress and generalized anxiety disorder), schizophrenia, epilepsy and epileptic seizures (including great malignancy, small malignancy, myoclonic epilepsy and partial conversion seizures), involuntary movement disorders (including those due to Parkinson's disease, and involuntary movements induced by drugs) and dementias (which include primary degenerative dementia of the Alzheimer's type).

Neurodegenerative diseases that could be related to the function of melatonin altered or influenced by melatonin and biological rhythms include multiple sclerosis and attack.

Neuroendocrine disorders that could be related to the function of melatonin altered or influenced by melatonin and biological rhythms include peptic ulceration, emesis, psoriasis, benign prostatic hyperplasia, hair condition and body weight. Particular neuroendocrine disorders that could be treated include those that are related to the regulation of maturation and reproductive function include idiopathic delayed puberty, sudden infant death, premature birth, infertility, antifertility, premenstrual syndrome, (which includes dysphoric disorder of the last phase luteal) and sexual dysfunction (which includes disorders of sexual desire, male erectile disorder, post-menopausal disorders and orgasm disorders). The compounds could also be used to manipulate reproduction cycles, body weight, skin color and oviposition of susceptible hosts, including birds, insects and mammals. The compounds of formula (I) could also have analgesic and sedative effects, effects on microcirculation and immunomodulatory effects and could be useful for the treatment of hypertension, migraine, headache, appetite regulation and in the treatment of eating disorders. such as obesity, anorexia nervosa and bulimia nervosa.

Thus, a compound of the formula (I) for use in therapy, in particular in human medicine, is provided in a further aspect of the invention. It will be appreciated that use in therapy encompasses, but is not necessarily limited to, the use of a compound of the formula (I) as an active therapeutic substance.

Also provided as another aspect of the invention is a compound of the formula (I) for use in the preparation of a medicament for use in the treatment of conditions associated with a disturbed functioning of the melatonin system.

In an alternative or additional aspect of the invention there is provided a method for the treatment of a mammal, including man, comprising the administration of an effective amount of a compound of the formula (I), in particular for the treatment of the conditions associated with a disturbed functioning of the melatonin system.

It will be appreciated by those skilled in the art that the reference here to therapy and treatment extends to prophylaxis in addition to the treatment of established symptoms.

While it is possible that, for use in therapy, a compound of formula (I) could be administered as the crude chemical it is preferable that it present the active ingredient as a pharmaceutical formulation.

The invention in this manner further provides a pharmaceutical formulation comprising a compound of the formula (I) together with one or more pharmaceutically acceptable carriers thereof. The vehicle (s) may be acceptable in the sense that they are compatible with the other ingredients of the formulation and do not damage the container thereof.

Pharmaceutical formulations include those suitable for oral, rectal, vaginal, nasal, topical or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The formulations could, where appropriate, be conveniently presented in discrete dosage units and could be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with liquid carriers or finely divided solid carriers and then, if necessary, forming the product in the desired formulation.

For oral administration, the pharmaceutical compositions could take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (eg pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethyl cellulose); fillers (eg lactose, microcrystalline cellulose or calcium phosphate); lubricants (eg magnesium stearate, talc or silica); disintegrants (eg, potato starch or sodium starch glycolate); or humidifying agents (eg, sodium lauryl sulfate). The tablets could be coated by methods well known in the art. Liquid preparations for oral administration could take the form of, for example, solutions, syrups or suspensions, or they could be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations could be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (eg, sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsification agents (eg, lecithin or acacia); non-aqueous vehicles (eg almond oil, oily esters or ethyl alcohol); and preservatives (eg, methyl or propyl-p-hydroxybenzoates or sorbic acid).

For topical administration in the mouth, the compositions may take the form of buccal or sublingual tablets, drops or lozenges formulated in conventional manner.

For topical administration to the epidermis the compounds could be formulated as creams, gels, ointments or lotions or as a transdermal patch. Such compositions could, for example, be formulated with an oily or aqueous base with the addition of thickening agents, gelatinization, emulsification, stabilization, dispersion, suspension and / or coloring agents.

The compounds of the invention could be formulated for parenteral administration by means of injection, intravenous, intramuscular or subcutaneous injection conveniently, for example by bolus injection, continuous intravenous infusion. The formulations for injection could be presented in unit dosage form p. ex. in ampules or in multi-dose containers, with a condom added. The compositions could take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and could contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient could be in the form of powder for constitution with an appropriate vehicle, e.g. ex. sterilized pyrogen-free water, before use.

The compounds of the invention could also be formulated in rectal compositions, such as suppositories or retention enemas, e.g. ex. containing conventional suppository bases such as cocoa butter or other glyceride.

Pessaries for vaginal administration could be formulated in a similar manner.

For intranasal administration, the compounds of the invention could be used, for example, as a sprayable liquid, as a powder or in the form of drops.

For administration by inhalation, the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation of pressurized packings or a nebulizer, with the use of an appropriate propellant, e.g. ex. 1, 1, 1, 2-trifluoroethane (HFA 134A) and 1, 1, 1, 2, 3, 3, 3-heptafluropropane (HFA 227), carbon dioxide or other appropriate gas. In the case of a pressurized aerosol the dosing unit could be determined by providing a valve to release a measured quantity. Capsules and cartridges from p. ex. gelatin for use in an inhaler or insufflator could be formulated containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

Any of the pharmaceutical compositions described above could be presented in a conventional manner associated with the controlled release forms.

The active ingredient could conveniently be presented in a unit dosage form. A convenient unit dosage formulation contains the active ingredient in an amount of about 0.1 mg to about 200 mg.

It will be appreciated that the precise dose administered will depend on the age and condition of the patient, the particular compound used and the frequency and route of administration and will ultimately be at the discretion of the physician's attention. The compound could be administered in single or divided dosages and could be administered one or more times, for example 1 to 4 times per day.

A proposed dosage of the compounds of the invention for oral, rectal, vaginal, intranasal, topical or parenteral administration to humans (of approximately 70 kg body weight) for the treatment of conditions associated with disturbed functioning of the regulated systems by melatonin is 0.01 to 200 mg of the active ingredient per unit dose that could be administered, for example, 1 to 4 times per day.

For oral administration a unit dosage will preferably contain 0.1 to 200 mg of the active ingredient. A unit dosage for parenteral administration will preferably contain 0.1 to 5 mg of the active ingredient.

The aerosol formulations are preferably arranged so that each measured or "blown" dose released from a pressurized aerosol contains 0.2 mg to 2 mg of a compound of the invention, and the capsules or cartridges released from an insufflator or inhaler, contain 0.2 mg a 20 mg of a compound of the invention. The global daily dosage by inhalation with an aerosol will be within the range of 0.2 mg to 100 mg. The administration could be once or several times daily, for example 1 to 8 times, giving for example 1, 2 or 3 doses each time.

The dosages of the compounds of the invention for rectal, vaginal, intranasal or topical administration are similar to those for oral administration.

The compounds of the invention could, if desired, be administered in combination with one or more therapeutic agents such as an antidepressant or hypnotic agent, or an anticancer agent such as tamoxifen, or in combination with radiation therapy to treat cancer.

The combinations referred to above could conveniently be presented for use in the form of a pharmaceutical formulation and thus the pharmaceutical formulations comprise a compound of the formula (I) together with at least one other therapeutic agent and one or more pharmaceutically acceptable carriers which therefore comprise a additional aspect of the invention.

When the compounds of formula (I) are used in combination with other therapeutic agents, the compounds could be administered either sequentially or simultaneously by any convenient route.

When such combinations are employed, the dosage of each component of the combination will generally be that used for each component when used alone.

The compounds of the formula (I) and the pharmaceutically acceptable solvates (eg hydrates) thereof, could be prepared by methods known in the art for the preparation of analogous compounds. In particular, the compounds of the formula (I) could be prepared by methods described below and which form a further aspect of the invention. In the following processes, R1, R2, R3, R4, R5, n and m unless stated otherwise, are as defined above for formula (I).

According to a general process (A) a compound of formula (I) could be prepared by acylation of a compound of formula (II).

Suitable acylating agents that could be conveniently used in the above process include acid anhydrides and acid halides. The reaction is conveniently carried out in a suitable solvent such as an ether (eg diethyl ether, tetrahydrofuran or dioxane), a hydrocarbon such as toluene or a halogenated hydrocarbon. (eg dichloromethane), esters (eg ethyl acetate) preferably in the presence of a base such as pyridine or a tertiary amine (eg triethyl amine), at a temperature in the range of 0 to 100. ° C, preferably 0 to 200 ° C.

The compounds of formula (I) produced in this manner wherein the dotted line represents an additional bond could be converted into the corresponding compound wherein the dotted line does not represent an additional bond by hydrogenation, for example hydrogenation of the compound in ethanol via a catalyst of transition metal p. ex. rhodium which is then removed p. ex. by filtration and the compound is then subjected to additional purification techniques.

The compounds of the formula (I) in which R2 is hydrogen and the dotted line represents a bond, could conveniently be prepared by reduction of the compounds of the formula (III).

The reduction could be conveniently carried out using a reducing agent such as borane in an ether solvent (eg tetrahydrofuran) optionally in the presence of an appropriate acid (eg trifluoroacetic acid, hydrochloric acid or the like), and heating the mixture of reaction at reflux for about 3 to 5 hours. Alternatively, the reduction could employ catalytic hydrogenation in the presence of a noble metal catalyst such as platinum, palladium or the like, in an appropriate organic solvent, such as an alcohol solvent, e.g. ex. ethanol, conveniently at a temperature in the range of 0 ° C to 100 ° C, aptly at room temperature.

Alternatively, the compounds of the formula (Illa) and (Illb) in which p = 0, 1 they could be converted to the compound of the formula (II) in which R2 is hydrogen and m is 2, 3 or 4 by hydrogenation preferably in a suitable solvent such as acetic acid in the presence of for example, palladium or charcoal with platinum and / or rhodium on charcoal. This process is carried out at a pressure of 50-180 psi, preferably 50-110 psi and more preferably 70-100 psi, a temperature in the range of 30-100 ° C, preferably 30-80 ° C, more preferably 50 ° C for a sufficient period of time usually 24 hours.

Conveniently the compounds (Illb) could be converted directly into the compounds (I) by carrying out this hydrogenation in the presence of an acid anhydride. The temperature and pressure could be adjusted to determine the degree of halogenation and unsaturation in the final product.

The compounds of the formula (II) in which R2 is C1-S alkyl could be prepared by N-alkylation of the compounds of the formula (II) in which R2 is hydrogen using standard procedures.

The compounds of the formula (III) could be prepared from the following compounds of the formula (IV) where Hal represents one of the halide groups p. ex. chloride, bromide or iodide. The preparation involves the reaction with an alkali metal cyanide such as potassium cyanide and the like, suitably in the presence of an alcohol solvent.

The compounds of the formula (Illa) and (Illb) could be prepared from compounds of the formula (V) where Rs = H or C1-s alkyl. The preparation could be conveniently carried out using a Wittig or Horner-Emmons reagent, chemical type p. ex. using a cyanoalkyl dialkyl phosphonate p. ex. cyanomethyl diethyl phosphonate in the presence of a strong base p. ex. Sodium hydride in an appropriate solvent p. ex. THF In a particularly preferred embodiment of the Route A of the Compounds of the formula (II) wherein m is 2, n is zero, R5 is H, and the dotted line does not represent a link, (eg the ring of 5). members is saturated) could be prepared alternatively from the compounds of the formula (VI) by, for example, reflux heating treatment with borane in tetrahydrofuran.

The compounds of the formula (VI) could be prepared from a compound of the formula (VII) wherein J represents an appropriate leaving group, for example a mesylate group, a tosyl group or halogen by treatment with an organic cyanide, for example sodium cyanide.

The compounds of the formula (VII) could be prepared from the compounds of the formula (VIII) by reaction with appropriate activating reagents, for example, sulfonyl methane chloride, tosyl chloride or a halogenation agent.

The compounds of the formula (VIII) could be prepared from the compounds of the formula (IX) by reaction with appropriate acids, e.g. ex. hydrochloric acid. If required, substituents R3 and / or R4 (where R3 and / or R4 are both halogens) can be introduced into structure (VIII) with the appropriate reagents (eg N-bromosuccinimide if R3 and / or R4 is bromine or N-chlorosuccinimide if R3 and / or R4 is chlorine).

The compounds of the formula (IX) could be prepared from the compound of the formula (X) through ozonolysis. The compound of the formula (X) is commercially available, or it could be prepared by Birch reduction from the corresponding naphthol. At any stage in this process, the compounds in which R3 and / or R4 are H or halogen could be modified in the compounds in which R3 and / or R4 represent halogen, C1-6 alkyl or substituted aryl using reactions that would be apparent to an expert person.

According to an additional process (B), a compound of the formula (I) wherein n = 1 could be prepared by cyclization of a compound of the formula (XI) The cyclization is conveniently carried out by heating in a suitable high-boiling solvent (eg bromobenzene, N, N-diethylamine). The compounds of the formula (XI) could be prepared by the alkylation of a compound of the formula (XII) (XII) using a propargyl halide (eg propargyl bromide) in the presence of a base such as potassium carbonate in an appropriate solvent (eg DMF). The compounds of the formula (XII) could be prepared by acylation of a compound of the formula (XIII) Suitable acylating agents and conditions that could be conveniently used in this process include those previously described for the acylation of compounds of the formula (II).

It will be appreciated that the compounds of the formulas (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (XI), (XII) and (XIV) - (XVIII) are new intermediaries and represent aspects additional individual embodiments of the present invention.

According to an additional Process (C), the compounds of the formula (I) in which R2 = H and in which m = 2, 3 or 4 could be prepared from the compounds of the formula by treatment with a primary amine such as methylamine or hydrazine followed by acylation following the procedures described in Process (A).

The compounds of the formula (XIV) could be prepared from alcohols of the formula (XV) by reaction with phthalimide under Mitsunobu conditions using for example triphenyl phosphine and diethyl azodicarboxylate in an appropriate solvent such as tetrahydrofuran.

The alcohols of the formula (XV) could be prepared by a number of methods apparent to a skilled person such as by reduction of acids or esters of the formulas (XVI) or (XVII) using for example lithium aluminum hydride in an appropriate solvent such as tetrahydrofuran.

Such esters (XVI) and (XVII) are easily obtained using standard reactions. For example (XVI) could be prepared from aldehydes or ketones (V) via ittig type reactions, or (XVII) could be made from halides (XVIII) using standard malonate of chemical type.

There is further provided by the present invention a general interconversion process (D) wherein the compounds of the formula (I) can be converted to the corresponding compounds of the formula (I) using appropriate reaction techniques. For example, the compounds of the formula (I) wherein R3 represents a halogen atom, such as chlorine, could be converted into the corresponding compound of the formula (I) wherein R3 represents hydrogen, by appropriate reduction reactions. The compounds in which R3 and / or R4 represent hydrogen can be converted to compounds in which R3 and / or R4 represents a halogen by the addition of an appropriate halogen compound to the compound in the presence of glacial acetic acid.

According to another general process (E), a compound of the formula (I) could be prepared by subjecting a protected derivative of a compound of the formula (I) to reaction to remove the protecting group or groups.

Thus, at a closer stage in the preparation of a compound of the formula (I) it could have been necessary and / or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions.

The protecting groups used in the preparation of the compounds of the formula (I) could be used in a conventional manner. See for example "Protective Groups in Organic Chemistry" Ed. J.F.W. McOmie (Plenum Press 1973) or "Protective Groups in Organic Synthesis" by Theodora Greene (John Wiley and Sons 1991).

As will be appreciated, in the general process (A) described above it may be desirable or even necessary to protect any sensitive group in the molecule as described. Thus, a reaction step involving the deprotection of a protected derivative of the general formula (I) or a salt thereof could be carried out subsequent to the process described above (A).

The compounds of the invention could be isolated in association with the solvent molecules by crystallization or evaporation of an appropriate solvent.

Individual enantiomers of the compounds of the invention could be prepared from racemates by resolution using methods known in the art for the separation of racemic mixtures into their constituent enantiomers, for example using chiral HPLC.

In addition to being employed as the last major step in the preparation sequence, the general methods indicated above for the preparation of the compounds of the invention could also be used for the introduction of the desired groups in an intermediate step in the preparation of the required compound. It should therefore be appreciated that in such multi-step processes, the sequence of reactions should be chosen so that the reaction conditions do not affect the groups present in the molecule that are desired in the final product.

The invention is further illustrated by the following Examples which should not be construed as constituting a limitation thereof.

Intermediary 1 4-bromomethyl-7-chloro-benzofuran A mixture of 7-chloro-4-methyl-benzofuran (CAS-number 79444-97-6; 51.9 g), N-bromosuccinimide (61.4 g), benzoyl peroxide (0.52 g) and carbon tetrachloride (1200 ml) were heated to reflux under the lighting of an 800W projector for 20 h. The mixture was cooled, and filtered and the filtrate was evaporated to dryness. The residue was absorbed onto silica and purified by chromatography on silica using ethyl acetate and hexane (1:20) to give the titled compound (39.50 g) as a yellow solid.

Tic Si02 (cyclohexane) Rf 0.30 Intermediary 2 7-Chloro-benzofuran-4-carbaldehyde A solution of N-methylmorpholine-N-oxide (37.64 g) in acetonitrile (370 ml) containing 3A molecular sieves (36.6 g) was stirred at room temperature overnight and cooled on ice. A solution of 4-bromomethyl-7-chloro-benzofuran (39.44 g) in acetonitrile (90 ml) was added and the mixture was stirred at 0 ° C for 4 h. The mixture was filtered and the filtrate was evaporated to dryness. Water and ethyl acetate were added to the residue and the organic phase was separated, dried (Na2SO4) and evaporated to give the titled compound (21.3 g) as a pale yellow solid.

Tic Si02 (ethyl acetate / cyclohexane 1: 6) Rf 0.40 Intermediary 3 (E) -3- (7-chloro-benzofuran-4-yl) -acetonitrile and (Z) -3- (7-chloro-benzofuran-4-yl) -acetonitrile A solution of diethyl cyanomethylphosphonate (7.34 g) in dry tetrahydrofuran (20 ml) was added to a suspension of sodium hydrate (60% oily dispersion, 1.65 g) in THF (40 ml) for 5 min with ice cooling. After 15 min, a solution of 7-chloro-benzofuran-4-carbaldehyde in THF (20 ml) was added and after 5 min the solution was heated and stirred at room temperature for 2 h. Brine (40 ml) and ethyl acetate (40 ml) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 20 ml). The extracts were dried (MgSO4) and evaporated and the residue was crystallized from ethylene to give crystals in the form of almost white fluffy needles (2.95 g) of (E) -3- (7-chloro-benzofuran-4-yl. ) -acetonitrile.

Mass Spectrum Found MNH = 221 The mother liquors were evaporated and the residue (6 g) was chromatographed on silica using ethyl acetate: hexane (1: 5 changing to 1: 4) to give more of the E-isomer (1.19 g) and a sample of the Z-isomer (0.62 g). g).

Mass Spectrum Found MNH4 + = 221 Tic SiO 2 (ethyl acetate / hexane 1: 5) isomer E Rf 0.55, isomer Z Rf 0.35.

Intermediary 4 3- (2,3-dihydro-benzofuran-4-yl) -propylamine hydrochloride A solution of (E) -3- (7-chloro-benzofuran-4-yl) -acetonitrile (intermediate 3) (1.0 g) in acetic acid (30 ml) containing 10% palladium on charcoal (50 mg, 50% wet mass) and 5% platinum on charcoal (50 mg) was hydrogenated at 100 psi and 50 ° for 3 days. The solution was filtered through ice and evaporated to dryness and the residue was recrystallized from isopropanol to give the titled compound with white plates (583 mg).

Tic Si02 (dichloromethane / methanol / 0.880 ammonia 75: 8: 1) Rf 0.25 Mass spectrum MH + 178 Subjection of Z isomer to hydrogenation under similar conditions gave the same product.

Alternative Route A solution of 2- (2, 3-dihydrobenzofuran-4-yl) -propanonitrile (1.20 g) in tetrahydrofuran (12 ml) was treated with an im-borane solution in tetrahydrofuran (12 ml) and the solution was heated to reflux for 1 hour. The solution was cooled to 20 ° and quenched with methanol (0.5 ml) followed by 5M hydrochloric acid (8 ml). The solution was refluxed for 30 min then cooled to 20 ° and basified with 10 M sodium hydroxide (7 ml). The mixture was extracted with tert-butyl methyl ether (25 ml + 12 ml). The combined extracts were dried (K2C03) and the solvent was evaporated to give the free base of the title compound (1.43 g) as a yellow oil.

Mass spectrum MH * 178.

Intermediary 5 3- (5-bromo-2,3-dihydro-benzofuran-4-yl) -propylamine A solution of the free base (200 mg) released from 3- (2,3-dihydro-benzofuran-4-yl) -propylamine hydrochloride and N-bromosucciniraide (215 mg) in acetic acid (5 ml) was stirred at room temperature. atmosphere throughout the night. The solution was evaporated to dryness and the residue was placed in water, basified to pH 9-10 with 2N sodium hydroxide and extracted with ethyl acetate. The extracts were dried and evaporated to give the titled compound (256 mg) as a pale yellow oil.

Tic Si02 (dichloromethane / methanol / O .880 ammonia 75: 8: 1) Rf 0.53 Found mass spectrum MH4"256/258 The hydrochloride salt was prepared by dissolving the titrated compound in methanolic HCl and evaporating the solvent to give a colorless solid.

Intermediary 6 2- (7-chloro-benzofuran-4-ylmethyl) malonic acid diethyl ester Diethyl malonate (1.7 ml) was added dropwise to a suspension of sodium hydrate (60%, 0.3 g) in dry THF (40 ml) at 0 ° under nitrogen. The mixture was allowed to warm to room temperature for 15 min. Then a solution of 4-bromomethyl-7-chloro-benzofuran in dry THF (10 ml) was added in one portion and the mixture was stirred for 1 h, then it was divided between water (100 ml) and ethyl acetate (3 x). 50 ml). The combined organic extracts were washed with brine (50 ml), dried (MgSO 4) and evaporated to give the title compound as a pale yellow oil (2466).

Tic Si02 (Ether / cyclohexane 1: 5) Rf 0.33 Intermediary 7 methyl ester of 3- (7-chloro-benzofuran-4-yl) -acrylic acid Trimethylphosphonoacetate (363 mg) in dry DME (1 ml) was added dropwise to a suspension of sodium hydrate (60%, 329 mg) in dry DME (200 ml) at 0 ° under nitrogen. The resulting white precipitate was stirred for 40 min at room temperature, then a solution of 7-chloro-benzofuran-4-carbaldehyde (intermediate 2) (1238 g) in dry DME (15 ml) was added at room temperature for 1 min. The mixture was refluxed for 2 h, cooled to room temperature, then partitioned between water (150 ml) and ether (100 ml). The combined organic extracts were washed with brine (100 ml) and dried (MgSO) The solvent was evaporated to give the titled compound as a colorless solid (1.59 g) Tic Si02 (Dichloromethane / cyclohexane 1: 1) Rf 0.35 Intermediary 8 Ethyl 3- (7-chloro-benzofuran-4-yl) -propionic acid ester A mixture of 2- (7-chloro-benzofuran-4-ylmethyl) -malonic acid diethyl ester (2.47 g) and sodium chloride (0.656 g) in DMSO (12 ml) and water (0.5 ml) was heated to 200 ° for 4 h under nitrogen. The cooled mixture was partitioned between water (80 ml) and ether (3 x 50 ml) and the combined organic extracts were washed with brine (3 x 50 ml) and dried (MgSO 4). The solvent was evaporated to give the compound titled as a brown oil (1.28 g) Tic Si02 (Ether / cyclohexane 1: 5) Rf 0.4 Intermediary 9 3- (7-chloro-benzofuran-4-yl) -propan-1-ol Route A Lithium aluminum hydrate (1.0 M in ether, 0.24 ml) was added dropwise to a solution of methyl ester of 3- (7-chloro-benzofuran-4-yl) -acrylic acid (intermediate 7) (0.1 g) in Dry THF (5 ml) at 0 ° under nitrogen. The mixture was stirred at 0 ° for 5 min, then water (0.2 ml) in THF (2 ml) was added dropwise. The solvent was evaporated and the residue was partitioned between hydrochloric acid (2N, 10 ml) and ether (3 x 20 ml). The combined organic extracts were washed with brine (20 ml) and dried (MgSO4). The solvent was evaporated and the residue was purified by column chromatography, eluting with ether / cyclohexane 2: 1 gave the title compound as a colorless gum (29 mg) Tic Si02 (Ether / cyclohexane 2: 1) Rf 0.25 Route B Lithium aluminum hydrate (1.0 M in ether, 2.5 ml) was added dropwise to a solution of ethyl ester of 3- (7-chloro-benzofuran-4-yl) -propionic acid (intermediates) (0.588 g) in THF dry (intermediate 8) (5 ml) at 0 ° under nitrogen. The mixture was allowed to warm to room temperature and was stirred for 0.5 h, cooled to 0 ° and water was added dropwise (5 ml). Hydrochloric acid (2N, 2 ml) was added followed by water (10 ml) and the mixture was extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (20 ml) and dried (MgSO4). The solvent was evaporated and the residue was purified by column chromatography, eluting with ether / cyclohexane 3: 2 gave the title compound as a colorless gum (360 mg) Tic Si02 (Ether / cyclohexane 2: 1) Rf 0.25 Intermediary 10 2- f3- (7-chloro-benzofuran-4-yl) -propyl-isoindole-1,3-dione Diethylazodicarboxylate (0.35 ml) was added dropwise to a solution of triphenylphosphine (587 mg) and phthalimide (329 mg) in dry THF (10 ml) at 0 ° under nitrogen. A solution of 3- (7-chloro-benzofuran-4-yl) -propan-1-ol (364 mg) in THF (5 ml) was then added and the mixture was allowed to warm to room temperature and stirred for 2 h . The solvent was evaporated and the residue was purified by column chromatography, eluting with cyclohexane / ether 3: 1 gave the titled compound as a colorless solid (521 mg) Tic Si02 (Cyclohexane / ether 3: 1) Rf 0.24 Intermediary 11 l-chloro-4- (2,2-diethoxy-ethoxy) -2-methyl-benzene A mixture of 4-chloro-3-methylphenol (47 mg), bromoacetyldehyde diethyl acetal (45 ml) and potassium hydroxide (33.6 g) dimethyl sulfoxide (250 ml) was heated at 120 ° C for 2 h. The cooled mixture was partitioned between water (750 ml) and toluene (3 x 500 ml) and the combined organic extracts were washed with brine / water 1: 1 (3 x 300 ml) and dried (Na 2 SO 4). The solvent was evaporated to give the compound titled as a pale yellow oil (67.9 g) Tic Si02 (Hexane) Rf 0.2 Intermediary 12 mixture of 5-chloro-4-methyl-bezofuran with 5-chloro-6-methyl-benzofuran A solution of l-chloro-4- (2,2-diethoxy-ethoxy) -2-methyl-benzene (36.2 g) in toluene (150 ml) was added dropwise to a solution of polyphosphoric acid (72 g) in toluene (200 ml) at 100 ° under nitrogen. The mixture was heated at 100 ° for 1 h, cooled to room temperature and sodium hydroxide (2M, 400 ml) was added. The organic phase was separated and the aqueous phase was extracted with additional toluene (2 x 200 ml). The combined organic extracts were dried (Na2SO4) and evaporated. The residue was purified by column chromatography. Elution with cyclohexane gave the compound titled as a pale yellow oil (20.1 g) Tic Si02 (Ciciohexane) Rf 0.54 Intermediary 13 mixture of 4-bromomethyl-5-chloro-bezofuran with 6-bromomethyl-5-chloro-benzofuran A mixture of 5-chloro-4-methyl-benzofuran with 5-chloro-6-methyl-benzofuran (19.6 g), N-bromosuccinimide (23 g) and benzoyl peroxide (160 mg) in carbon tetrachloride (350 ml) it was heated to reflux under a 200W lamp for 36 h. The cooled mixture was filtered through ice and the filtrate was evaporated to give the titled compound as a dark oil (28.8 g) Tic Si02 (Ciciohexane) Rf 0.6 Intermediary 14 mixture of 5-chloro-bezofuran-4-carbaldehyde with 5-chloro-benzofuran-carbaldehyde A mixture of 4-bromomethyl-5-chloro-benzofuran with 6-bromomethyl-5-chloro-benzofuran (30.54 g) in dry acetonitrile (80 ml) was added dropwise to a mixture of N-methylmorpholine-- -oxide ( 29.14 g) and molecular sieves of 4A in dry ecetonitrile (100 ml) at 10 ° under nitrogen. The mixture was stirred at room temperature for 5 h, filtered through ice and the filtrate was evaporated. The residue was triturated in ether (100 ml) and filtered. The filtrate was evaporated and the residue was recrystallized from cyclohexane to give the title compound as a pale yellow solid (10.95 g) Tic Si02 (Dichloromethane / Hexane 1: 1) Rf 0.3 Intermediary 15 mixture of (E) -3- (5-chloro-benzofuran-4-yl) -arylonitrile with (E) -3- (5-chloro-benzofuran-6-yl) -acylonitrile A solution of diethyl cyanomethylphosphonate (11.5 ml) in dry ethylene glycol, dimethyl ether (DME, 10 ml) was added dropwise to a suspension of sodium hydrate (60%, 2.914 g) in DME (50 ml) at 0 ° C. ° under nitrogen. The mixture was stirred at 0 ° during 20 min. Then a solution of 5-chloro-benzofuran-4-carbaldehyde mixed with 5-chloro-benzofuran-6-carbaldehyde (10.95 g) in DME (50 ml) was added in one portion. The mixture was heated at 60 ° for 2 h. it was cooled to room temperature and partitioned between water (150 ml) and ether (3 x 100 ml). The combined organic extracts were washed with brine (2 x 100 ml) and dried (MgSO) The solvent was evaporated and the residue was purified by column chromatography Elution with cyclohexane / ethyl acetate 20: 1 gave the titled compound as a colorless solid (6.75 g) Tic Si02 (Cyclohexane / ethyl acetate 8: 1) Rf 0.31 Intermediary 16 mixture of 3- (5-chloro-benzofuran-4-yl) propylamine with 3- (5-chloro-benzofuran-6-yl) propylamine A solution of (E) -3- (5-chloro-benzofuran-4-yl) -acylonitrile mixed with (E) -3- (5-chloro-benzofuran-6-yl) -acrylonitrile (intermediate 15) (1 g ) in ethanolic ammonia (1.0 M, 50 ml) was hydrogenated with rhodium on alumina (130 mg) for 18 h. The catalyst was filtered and the filtrate was evaporated. The residue was purified by column chromatography, eluting with dichloromethane / ethanol / ammonia 100: 8: 1 gave the compound titled as a pale yellow gum (616 mg) Tic Si02 (Dichloromethane / ethanol / ammonia 100: 8: 1) Rf 0.15 Intermediary 17 2- (2, 2-dimethoxy-ethoxy) -1-fluoro-4-methyl-benzene Bromoacetaldehyde dimethyl acetal (42 ml) was added to a mixture of 2-fluoro-5-methyl phenol1 (22.05 g) and beads of potassium hydroxide (19.6 g) in methyl sulfoxide (160 ml) at room temperature under nitrogen. The mixture was heated at 100 ° for 16 h, cooled to room temperature and partitioned between water (500 ml) and ether (3 x 200 ml). The combined organic extracts were washed with brine / water 1: 1, (3 x 200 ml) and dried (MgSO) The solvent was evaporated to give the titled compound as an orange oil (48 g) Tic (Ciciohexane) Rf 0.4 Reference 1: Sing S. et al, J Amer. Chem Soc 1987. 109. (23), 7194-7196.

Intermediary 18 7-Fluoro-4-methyl-benzofuran A solution of 2- (2, 2-dimethoxy-ethoxy) -l-fluoro-4-methyl-benzene (48 g) in toluene (50 ml) was added dropwise to a refluxing solution of polyphosphoric acid (100 g). ) in toluene (350 ml) under nitrogen. The mixture was refluxed for 3 h, cooled to room temperature and sodium hydroxide (2N, 800 ml) was added. The mixture was extracted with ether (3 x 300 ml) and the combined organic extracts were washed with brine (2 x 300 ml) and dried (MgSO4). The solvent was evaporated and the residue was purified by column chromatography. The eluent with hexane gave the compound titled as a pale yellow oil (14.2 g) Tic Si02 (Hexane) Rf 0.4 Intermediary 19 4-bromomethyl-7-fluoro-benzofuran A mixture of 7-fluoro-4-methyl-benzofuran (14.2 g), N-bromosuccinimide (19.7 g), benzoyl peroxide (0.5 g) and carbon tetrachloride (600 ml) was heated to reflux under floodlighting of 80W during 20 h. The mixture was cooled, and the filtrate was evaporated to dryness to give the title compound as a pale orange oil (23.4 g) Tic (cyclohexane) Rf 0.18 Intermediary 20 7-fluoro-ben ofuran-4-carbaldehyde A solution of N-methylmorpholine-N-oxide (22.24 g) in acetonitrile (250 ml) containing 3A molecular sieves (8.71 g) was stirred at room temperature overnight, then cooled on ice. A solution of 4-bromomethyl-7-fluoro-benzofuran (23.45 g) in acetonitrile (50 ml) was added and the mixture was stirred for 4 h. The mixture was filtered and the filtrate was evaporated to dryness. Water and ether were added to the residue and the organic phase was separated, washed with brine (2 x 200 ml), dried (MgSO 4) and evaporated. The residue was triturated with ether (50 ml) and filtered to give the title compound as a pale yellow solid (5.45 g) Tic Si02 (Dichloromethane / hexane 1: 1) Rf 0.30 Intermediary 21 (E) -3- (7-Fluoro-benzofuran-4-yl) -acrylonitrile A solution of diethyl cyanomethylphosphonate (5.35 g) in ethylene glycol dimethyl ether (DME, 20 ml) was added to a suspension of sodium hydrate (60% oil dispersion; 1. 32 g) in DME (20 ml) at 0 ° under nitrogen for 5 min.

After 15 min, a solution of 7-fluoro-benzofuran-4-carbaldehyde (4.51 g) in DME (20 ml) was added and after min the solution was heated and stirred at room temperature for 2 h. Ammonium chloride solution was added (200 ml) and ethyl acetate (150 ml), the phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 150 ml). The extracts were dried (MgSO and evaporated and the residue was triturated with ether (20 ml) and filtered to give the E isomer as a beige solid (3.07 g) The mother liquors were evaporated to give a mixture of the E and Z isomers (4.25 g) Tic Si02 (Hexane / Dichloromethane 1: 1) Rf 0.40 Intermediary 22 3- (7-Fluoro-2,3-dihydro-benzofuran-4-yl) -propylamine A solution of (E) -3- (7-fluoro-benzofuran-4-yl) acrylonitrile (0.25 g) in ethanol (25 ml), ammonia (0.88; ml) containing 10% palladium on charcoal (50 mg, 50% wet mass and 5% rhodium on charcoal (50 mg) was hydrogenated at 70 psi and 70 ° for 18 h. The mixture was evaporated to dryness and the residue was purified by column chromatography The eluent with dichloromethane / ethanol / ammonia 100: 8: 1 gave the title compound (256 mg).

Tic Si02 (dichloromethane / methanol / O .880 ammonia 100: 8: 1) Rf 0.20 Mass spectrum found MH + 196 Intermediary 23 3- (5-chloro-2,3-dihydro-benzofuran-4-yl) propylamine hydrochloride A solution of 3- (2,3-dihydro-benzofuran-4-yl) -propylamine hydrochloride (150 mg) and N-chlorosuccinimide (199 mg) in acetic acid (50 ml) was stirred at room temperature all the night . The solution was evaporated to dryness and the residue was placed in water, basified with 2N hydroxide solution and extracted with dichloromethane. The extracts were dried and evaporated and the residue was dissolved in a solution of hydrogen chloride in methanol. Evaporation gave the titled compound (159 mg) as a slightly white powder after trituration with ether.

Mass spectrum Found MH + 212/214.

Intermediary 24 Í3- (3-hydroxy-phenyl-1) -propyl-amide of the cyclopropanecarboxylic acid Cyclopropanecarbonyl chloride (0.63 ml) was added dropwise to a suspension of 3- (3-amino-propyl) -phenol-1 (0.1 g) and N, N-diisopropylamine (0.23 ml) in dichloromethane (15 ml) in a bath of ice under nitrogen. The mixture was then stirred for 3 h at room temperature, then purified by passing it through a solid phase extraction cartridge. Elution with chloroform followed by ethyl acetate gave the title compound as a colorless gum (122 mg) Tic Si02 (Ether) Rf 0.34 1. T. Kametani et al J. Chem. Soc. Pekin Trans 1, 1974, 22., 2602-2604 Intermediary 25 Í3- (3-prop-2-ynyloxy-phenyl) -propyl-amide of cyclopropanecarboxylic acid Propargyl bromide (80% in toluene, 0.091 ml) was added dropwise to a mixture of [3- (3-hydroxy-phenyl) -propyl] -amide of cyclopropanecarboxylic acid (122 mg) and potassium carbonate (154 mg) ) in dry DMF (10 ml) in an ice bath under nitrogen. The mixture was allowed to warm to room temperature, then heated at 65 ° C for 18 h. The cooled mixture was partitioned between water (150 ml) and ethyl acetate (3 x 15 ml). The combined organic extracts were washed with brine / water 1: 1 (3 x 20 ml) and dried (MgSO4). The solvent was evaporated and the residue was purified by column chromatography on silica. Elution with hexane / ethyl acetate 2: 1 gave the titled compound as a colorless solid (79 mg) Tic Si02 (Hexane / ethyl acetate 2: 1) Rf 0.18 Intermediary 26 1- (2, 2-dimethoxyethoxy) -4-fluoro-3-methylbenzene A mixture of 4-fluoro-3-methylphenol (36.7 g), potassium hydroxide beads (19.5 g) and bromoacetaldehyde dimethyl acetal (34.6 ml) in dimethyl sulfoxide (240 ml) was heated at 110 ° for 24 h. The mixture was cooled, diluted with water (350 ml) and extracted with hexane. Evaporation of the extracts gave the compound titled as an oil (52.3 g).

Mass Spectrum Found MNH4 * 232 Intermediary 27 mixture of 5-fluoro-4-methylbenzofuran with 5-fluoro-6-methylbenzofuran Phosphoric acid (185 g) was heated to 100 ° and a solution of 1- (2,2-dimethoxyethoxy) -4-fluoro-3-methylbenzene (52.3 g) in toluene (520 ml) was added. The mixture was stirred at reflux for 5 h, cooled and the toluene decanted. The solution was concentrated and the residue was passed through silica (900 g) eluting with hexane. Evaporation gave the titled compound as a colorless liquid (14.95 g).

Tic (hexane) Rf 0.60 Intermediary 28 mixture of 4-bromomethyl-5-fluorobenzofuran with 6-bromomethyl-5-fluorobenzofuran A mixture of 5-fluoro-4-methylbenzofuran and 5-fluoro-6-methylbenzofuran (14.95 g), N-bromosuccinimide (16.57 g), benzoyl peroxide (0.32 g) and carbon tetrachloride (375 ml) was heated to reflux under the lighting of an 80W projector for 20 h. The mixture was cooled, and filtered and the filtrate was evaporated to dryness to give the crude product as an oil (24.0 g). This material was combined with a similar crude product (6.94 g) from an identical reaction run on a smaller scale and purified by chromatography on silica (900 g) using a mixture of ether hexane (1:30) as eluent to give the titled compound (13.5 g) as an oil.

Tic (hexane) Rf 0.38 Intermediary 29 mixture of 5-fluorobenzofuran-4-carbaldehyde (A) with 5-fluorobenzofuran-6-carbaldehyde (B) A solution of N-methylmorpholino-N-oxide (13.6 g) in acetonitrile (135 ml) containing 3A molecular sieves (13.2 g) was stirred at room temperature overnight and cooled on ice. A solution of 4-bromomethyl-5-fluorobenzofuran and 6-bromomethyl-5-fluorobenzofuran (13.33 g) in acetonitrile (35 ml) was added and the mixture was stirred at 5 ° for 4 h. The mixture was filtered and the filtrate was evaporated to dryness. Water and ethyl acetate were added to the residue and the organic phase was separated, dried and evaporated to give the aldehyde mixture. The mixture was separated by chromatography on silica (600 g) using a mixture of ethyl acetate and hexane (1: 9) as the eluent to give the titled compound (A) (2.19 g); Tic (Ethyl acetate / hexane 1: 9) Rf 0.47 Mass Spectrum Found MNH4 * 182 and the compound titled (B) (2.17 g) Tic (ethyl acetate / hexane 1: 9) Rf 0.35 Mass spectrum Found MNH4 + 182 Intermediary 30 (E) -3- ["5-Fluorobenzofuran-4-ip acrylonitrile and (Z) -3-y5-fluorobenzofuran-4-yl1 acrylonitrile.

A solution of diethyl cyanophosphonate (2.79 g) in dry tetrahydrofuran (10 ml) was added to a suspension of sodium hydrate (60% oil dispersion, 0.63 g) in THF (16 ml) for 5 min with cooling with ice. After 15 min, a solution of 5-fluorobenzofuran-4-carbaldehyde (2.15 g) in THF (10 ml) was added and after 5 min the solution was heated and stirred at room temperature for 3 h. Brine (20 ml) and ethyl acetate (20 ml) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 25 ml). The extracts were dried and evaporated and the residue was purified by chromatography (Biotage Flash 40; 90 g; ethyl acetate: hexane 1: 9) to give the compound titled as a solid cream (1.97 g) Tic (Ethyl acetate / hexane 1: 9) Rf 0.25 Mass spectrum MNH 205 Intermediary 31 hydrochloride - ie 3- (2,3-dihydro-5-fluorobenzofuran-4-yl) propylamine N- [3- [2,3-dihydro-5-fluorobenzofuran-4-yl] propyl] acetamide (0.55 g) was heated to reflux in 2M hydrochloric acid (10 ml) for 24 h. The mixture was cooled and washed with dichloromethane, basified with 2M sodium hydroxide and extracted with dichloromethane. Evaporation of the extracts gave an oil which was dissolved in 0.7M methanolic hydrogen chloride (8 ml). Evaporation gave the compound titled as a beige solid (0.28 g).

Mass spectrum MH + 196 Intermediary 32 2. 3-bis (2-hydroxyethyl) -phenol A solution of 5,8-dihydronaphth-1-ol (2.00 g) in methanol (40 ml) was cooled to 70 ° and ozone was bubbled in oxygen through the solution until the tic indicated that all the initiator material had been consumed The ozone was removed and nitrogen was bubbled through the solution for 5 min. Then sodium borohydrate (454 mg) was added and the solution allowed to slowly warm to 20 °. An additional portion of sodium borohydrate (227 mg) was added, followed by 10 min after acetic acid (1 ml) and then the solvent was evaporated. The residue was partitioned between 2M hydrochloric acid (50 ml) and ethyl acetate (2 x 50 ml). The combined ethyl acetate extracts were dried (Na2SO4) and the solvent was evaporated to a brown oil which was purified by chromatography on silica gel eluting with ethyl acetate to give the titled compound (1.49 g) as a brown oil. pale which crystallized in prolonged form.

Tic Si02 (ethyl acetate) Rf 0.46.

Intermediary 33 2- (2,3-dihydrobenzofuran-4-yl) -ethanol A mixture of 2,3-bis (2-hydroxyethyl) -phenol (1.2 g) and 36% aqueous hydrochloric acid (24 ml) was heated to reflux for 2 h. The mixture was cooled, diluted with water (24 ml) and extracted with ethyl acetate (2 x 24 ml). The combined extracts were dried (Na2SO4) and the solvent was evaporated to give the titled compound (1.2 g) as a brown oil.

Tic Si02 (ethyl acetate) Rf 0.67.

Intermediary 34 2- (2,3-dihydrobenzofuran-4-yl) methanesulfonic acid ethyl ester A solution of 2- (2,3-dihydrobenzofuran-4-yl) -ethanol (1.13 g) in dichloromethane (11 ml) was treated with triethylamine (1.25 ml), followed by methanesulfonyl chloride (0.64 ml). After 5 min the reaction mixture was poured into 2M hydrochloric acid (10 ml) and extracted with dichloromethane (2 x 100 ml). The combined extracts were washed with water (10 ml), dried (Na2SO4) and the solvent was evaporated to give the titled compound (1.76 g) as a yellow oil.

Tic SiO 2 (isohexane / ethyl acetate 1: 1) Rf 0.43.

Intermediary 35 3- (2,3-dihydrobenzofuran-4-yl) -propanonitrile A solution of 2- (2,3-dihydrobenzofuran-4-yl) methanesulfonic acid ethyl ester (1.71 g) in dimethyl sulfoxide (14 ml) was treated with sodium cyanide (381 mg) and heated at 80 ° C for 1 h. . The suspension was cooled to 20 °, diluted with water (14 ml) and extracted with ethyl acetate (2 x 17 ml). The combined extracts were washed with 5% aqueous sodium chloride (17 ml), dried (Na2SO4) and the solvent was evaporated to give the titled compound (1.22 g) as a brown oil which was permanently crystallized.

Tic SiO2 (isohexane / ethyl acetate 1: 1) Rf 0.62.

Example 1 N- T3- (5-bromo-2,3-dihydro-benzofuran-4-yl) -propyl-acetamide A solution of 3- (5-bromo-2,3-dihydro-benzofuran-4-yl) -propylamine (256 mg) in pyridine (3 ml) at 4 ° was treated with acetic anhydride (0.11 ml) and the solution stored all night at 4 °. The cold solution was acidified with 2N hydrochloric acid and the mixture was extracted with ethyl acetate.

The extracts were dried and evaporated and the residue chromatographed on silica (20 g) using dichloromethane: methanol: ammonia (100: 8: 1) to give the titled compound as a slowly solidifying oil (175 mg).

Tic Si02 (Dichloromethane / methanol / O .880 ammonia 75: 8: 1) Rf 0.67 Mass spectrum MH + Found 297/299.

Example 2 N- Í3- (7-chloro-benzofuran-4-yl) -propyl-acetamide A solution of 2- [3- (7-chloro-benzofuran-4-yl) -propyl] -isoindole-1,3-dione (0.5 g) in ethanolic methylamine (10 ml) was stirred at room temperature for 4 h. The solvent was evaporated and the residue was suspended in dry THF (15 ml) and cooled to 0 ° C. Pyridine (0.27 ml) and acetic anhydride (0.2 ml) were added and the mixture was allowed to warm to room temperature for 18 h. The solvent was evaporated and the residue was purified by column chromatography, the eluent with dichloromethane / methanol 100: 1 gave the title compound as a colorless solid (230 mg) mp 61-62 ° Tic SiO 2 (Dichloromethane / methanol 50: 1) Rf 0.16 A solution of E and Z-3- [7-chlorobenzofuran-4-yl] acrylonitrile (4.0 g) in acetic acid (100 ml) and acetic anhydride (3.7 ml) containing 10% palladium on charcoal (200 mg; 50% wet mass) and 5% platinum on charcoal (200 mg) was hydrogenated at 100 psi and 60 ° for 24 h. An aliquot (10 ml) was removed and methanol (1 ml) was added thereto. After 16 h the solution was filtered and evaporated and the residue was purified by chromatography (Biotage Flash 40; ethyl acetate) to give the titrated amide (99 mg) as an oil.

Tic (Ethyl acetate) Rf 0.30 Mass spectrum MH + 252/254 Example 3 N- T3- (7-chloro-2,3-dihydro-benzofuran-4-yl) -propyl-acetamide A solution of N- [3- (7-chloro-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide (48 mg) in ethanol (15 ml) was hydrogenated with rhodium catalyst (5% charcoal; 15 mg) for 7 h. The catalyst was filtered and the filtrate was evaporated. The residue was purified by column chromatography, the eluent with dichloromethane / methanol 50: 1 gave the titled compound as a colorless solid (37.6 mg) mp 76-78 ° Mass spectrum Found MH + 254/256 Tic Si02 (Dichloromethane / methanol 50: 1) Rf 0.16 Example 4 N- Í3- (2, 3-dihydro-benzofuran-4-yl) -propyl-acetamide A solution of N- [3- (7-chloro-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide, (78 mg) in ethanol (5 ml) was hydrogenated with palladium (10%; mg) for 64 h. The catalyst was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography, the eluent with dichloromethane / methanol 50: 1 gave the titled compound as a colorless solid (54 mg) mp 66-67 ° C Test Found: C, 71.0; H, 8.1; N, 6.6; C13H17N02 Required: C, 71.2; H, 7.8; N, 6.4% Tic Si02 (Dichloromethane / Methanol 50: 1) Rf 0.16 Alternative route A solution of E and Z-3- [7-chlorobenzofuran-4-yl] acrylonitrile (15 g) in acetic acid (330 ml), acetic anhydride (19.6 ml) and triethylamine (30.75 ml) containing 10% palladium on charcoal 80.76 g; 50% wet mass) and 5% platinum on charcoal (0.75 g) was hydrogenated at 150 psi and 75 ° for 4 days. More catalysts (as above) were added and the reaction was continued for an additional 24 h. The solution was filtered and evaporated and the residue was partitioned between dichloromethane (250 ml) and water (150 ml). The organic layer was washed successively with water (150 ml), 2M hydrochloric acid (2 x 100 ml), water (100 ml) and 2M sodium carbonate (100 ml) and then dried and evaporated to give the titled compound as a slightly white solid (15.4 g).

Tic (Dichloromethane / methanol 50: 1) Rf 0.16 Mass spectrum MH + 220 Example 5 N- Í3- (5-chloro-benzofuran-4-yl) -propyl-acetamide Acetic anhydride (1.95 ml) was added dropwise to a solution of 3- (5-chloro-benzofuran-4-yl) propylamine mixed with 3- (5-chloro-benzofuran-6-yl) propylamine (2.86 g) and pyridine (2.2 ml) in dry THF (70 ml) at 0 ° under nitrogen. The mixture was stirred at room temperature for 3 h, then evaporated to dryness in vacuo. The residue was purified by HPLC (column CN-PK5-10530). Eluting with 5% isopropanol / heptane gave the title compound as a colorless solid (1.37 g) mp 82-83 ° C.

Tic Si02 (Dichloromethane / ethanol / 0.880 ammonia 100: 8: 1) Rf 0.39 Example 6 N- T3- (5-chloro-2,3-dihydro-benzofuran-4-yl) -propyl-acetamide A solution of? - [3- (5-chloro-benzofuran-4-yl) -propyl] -acetamide (0.25 g) in ethanol (15 ml) was hydrogenated with 5% rhodium on carbon (80 mg) for 18 g . The catalyst was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica, eluting with dichloromethane / methanol 40: 1 gave the title compound as a colorless solid (131 mg) mp 91-92.

Mass Spectrum Found MH4"= 254.094828 C13H17C1N02 Required 254.094782 # Tic Si02 (Dichloromethane / Methanol 50: 1) Rf 0.22 Example 7 N- Í3- (5,7-dichloro-2,3-dihydro-benzofuran-4-yl) -propyl-acetamide N-chlorosuccinimide (173 mg) was added to a solution of N- [3- (5-chloro-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide (0.2 g) in glacial acetic acid (5 g). ml) at room temperature under nitrogen and the mixture was stirred for 64 h. The solution was adjusted to pH 9 with sodium carbonate (2N, 10 ml) and extracted with ethyl acetate (3 x 15 ml). The combined organic extracts were washed with brine (20 ml) and dried (MgSO4). The solvent was evaporated and the residue was purified by HPLC, eluting with 50% acetonitrile / water + 0.1% TFA gave the titled compound as a colorless solid (97 mg) Mass Spectrum Found MH + = 288. 055872 C13H1GC112N02 required 288. 055809 Tic Si02 (Dichloromethane / Methanol 50: 1) Rf 0. 22 Example 8 N- Í3- (7-fluoro-2,3-dihydro-benzsfuran-4-yl) -propyl acetamide Acetic anhydride (0.18 ml) was added dropwise to a solution of 3- (7-fluoro-2,3-dihydro-benzofuran-4-yl) -propylamine (256 mg) in dry THF (10 ml) containing pyridine. (0.21 ml) at 0 ° C under nitrogen and the solution was stirred overnight at room temperature. The solution was evaporated and the residue was purified by column chromatography. Eluting with dichloromethane: methanol (50: 1) gave the titled compound as a colorless oil (133 mg).

Tic (Dichloromethane / methanol 50: 1) Rf 0.18 Mass Spectrum Found MH + 238, MNH4 + 255 Example 9 N- Í3 - (5-Chloro-7-fluoro-2,3-dihydro-benzofuran-4-yl) -propyl acetamide N-chlorosuccinimide (47.7 mg) was added to a solution of N- [3- (7-fluoro-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide (77 mg) in glacial acetic acid (5 mg). ml) at room temperature under nitrogen and the mixture was stirred for 72 h. The solution was evaporated and the residue was partitioned between sodium carbonate (2N, 10 ml) and ethyl acetate (10 ml). The combined organic extracts were washed with brine (10 ml) and dried (MgSO4). The solvent was evaporated and the residue was purified by column chromatography. Eluting with dichloromethane / methanol 50: 1 gave the title compound as a colorless gum which was permanently crystallized (67 mg).

Mass Spectrum Found MH4"= 272/274 Tic Si02 (dichloromethane / methanol 50: 1) Rf 0.18 Example 10 N- Í3 - (5-bromo-7- fluoro-2,3-dihydro-benzofuran-4-yl) -propyl acetamide N-bromosuccinimide (569 mg) was added to a solution of N- [3- (7-fluoro-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide (690 mg) in glacial acetic acid (15 mg). ml) at room temperature under nitrogen and the mixture was stirred for 48 h. The solution was evaporated and the residue was partitioned between sodium carbonate (2? 20 ml) and ethyl acetate (20 ml). The combined organic extracts were washed with brine (25 ml) and dried (MgSO) The solvent was evaporated and the residue was purified by column chromatography Eluting with dichloromethane / methanol 50: 1 gave the title compound as a colorless solid (644 mg).

Mass Spectrum Found MH4"= 316/318 Tic Si02 (dichloromethane / methanol 50: 1) Rf 0.18 Example 11 Í3- (2, 3-dihydro-benzofuran-4-yl) -propyl-amide of cyclopropanecarboxylic acid 3- (2, 3-Dihydro-benzofuran-4-yl) -propylamine hydrochloride (200 mg) was partitioned between 2N sodium hydroxide (10 ml) and dichloromethane (10 ml) and the organic phase was separated, dried ( Na2SO4) and evaporated. The residual free base (160 mg) and triethylamine (110 mg) were dissolved in dichloromethane (2 ml), cooled on ice and carbonyl cyclopropane chloride (103 mg) was added. After 2 hours the solution was warmed to room temperature and 2N hydrochloric acid (10 ml) was added. The mixture was extracted with dichloromethane (3 x 20 ml), and the extracts were washed with 8% sodium bicarbonate, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica using a mixture of ethyl acetate and hexane (1: 1) as the eluent to give the titled compound as a white solid (95 mg).

Mass Spectrum Found MH4"246 Tic Si02 (Ethyl acetate / Hexane 1: 1) Rf 0.26 Example 12 f3- (5-Chloro-2,3-dihydro-benzofuran-4-yl) -propyl-amide of cyclopropanecarboxylic acid A mixture of 3- (5-chloro-2,3-dihydro-benzofuran-4-yl) -propylamine hydrochloride (142 mg), dimethylformamide (5 drops), triethylamine (0.64 ml) and dichloromethane (5 ml) was stirred on ice for 20 minutes. Cyclopropancarbonyl chloride (66 mg) was added and stirring was continued for 5 hours. The mixture was purified by chromatography on silica eluting with ethyl acetate / hexane (1: 1) to give the titled compound as a white solid (80 mg).

Tic Si02 (ethyl acetate / hexane 1: 1) Rf 0.17 Mass Spectrum Found MH4"= 280/282 Example 13 Í3- (5-bromo-2,3-dihydro-benzofuran-4-yl) -propyl-amide of cyclopropanecarboxylic acid A mixture of 3- (5-bromo-2,3-dihydro-benzofuran-4-yl) -propylamine hydrochloride (100 mg), dimethylformamide (3 drops), triethylamine (0.35 ml) and dichloromethane (3 ml) was stirred on ice for 15 minutes. Cyclopropanecarbonyl chloride (36 mg) was added and stirring was continued for 2 hours. The mixture was purified by chromatography on silica to give the titled compound as a white solid (86 mg).

Tic (ethyl acetate: hexane 1: 1) Rf 0.33 Mass Spectrum Found MH + = 324/326 Example 14 T3- (7-Fluoro-2, 3-dihydro-benzofuran-4-yl) -propyl-amide of cyclopropanecarboxylic acid A mixture of 3- (7-fluoro-2,3-dihydro-benzofuran-4-yl) -propylamine (114 mg), triethylamine (0.089 ml), dichloromethane (5 ml) and cyclopropanecarbonyl chloride (67 mg) was stirred on ice for 20 minutes and stirring was continued overnight. The mixture was partitioned between 2N hydrochloric acid and dichloromethane and the organic phase was washed with 8% sodium bicarbonate and evaporated. Purification of the residue by hplc gave the title compound as a white solid (16 mg).

Tic (ethyl acetate: hexane 1: 1) Rf 0.12 Mass Spectrum Found MH4"= 264 Example 15 F3- (5-chloro-7-fluoro-2, 3-dihydro-benzofuran-4-yl) -propyl-amide of cyclopropanecarboxylic acid A mixture of cyclopropanecarboxylic acid [3- (7-fluoro-2, 3-dihydro-benzofuran-4-yl) -propyl] -amide and N-chlorosuccinimide (248 mg) in glacial acetic acid (15 ml) was stirred at room temperature. environment for 72 h. The solvent was evaporated and the residual solid was triturated with water (10 ml) and filtered to give the titled compound as a colorless solid (236 mg).

Mass Spectrum Found MH4"298.1 / 300.1 Tic Si02 (hexane / ethyl acetate 1: 1) Rf 0.18 Example 16 Í3- (5-Chloro-7-fluoro-benzofuran-4-yl) -propyl] -amide of cyclopropanecarboxylic acid Lead tetraacetate (313 mg) was added to a solution of [3- (5-chloro-7-fluoro-2, 3-dihydro-benzofuran-4-yl) -propyl] -amide of cyclopropanecarboxylic acid (0.2 g) in glacial acetic acid (5 ml) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated and the residue was purified by preparative HPLC to give the titled compound as a colorless solid (20 mg).

Mass Spectrum Found MH4"296.1 / 298.1 Tic Si02 (hexane / ethyl acetate 1: 1) Rf 0.18 Example 17 N- T3- (benzofuran-4-yl) -propyl-acetamide Lead tetraacetate (210 mg) was added to a solution of N- [3- (2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide (100 mg) in acetic acid (1.5 ml) at 10 °. . The mixture was stirred at room temperature for 2 h and at 50 ° for 16 h. The solvent was evaporated and the residue was purified by chromatography to give the titled compound as an oil (41 mg).

Mass Spectrum Found MH + 218 Tic Si02 (ethyl acetate / hexane 2: 1) Rf 0.43 Example 18 1 * 3- (benzo furan-4-yl) -propyl-amide of cyclopropanecarboxylic acid Lead tetraacetate (194 mg) was added to a solution of [3- (2, 3-dihydro-benzofuran-4-yl) -propyl] -amide of cyclopropanecarboxylic acid (100 mg) in acetic acid (1.5 ml) to 10 mg. °. The mixture was stirred at room temperature for 2 h and at 50 ° for 24 h. The solvent was evaporated and the residue was purified by chromatography on silica. Elution with hexane / ethyl acetate gave the title compound as an oil (15 mg).

Mass Spectrum Found MH4"244 Tic SiO 2 (ethyl acetate / hexane 1: 1) Rf 0.13 Example 19 F3- (2,3-dihydro-benzofuran-4-yl) -propyl-amide of cyclobutanecarboxylic acid 3- (2,3-Dihydro-benzofuran-4-yl) -propylamine hydrochloride (100 mg) was suspended in dichloromethane (3 ml) containing triethylamine (0.33 ml) and cooled on ice. A solution of cyclobutanecarbonyl chloride (0.054 ml) in dichloromethane (1 ml) was added and the mixture was stirred on ice for 3 h. The mixture was purified by elution through a solid phase extraction cartridge to give the titled compound as a white solid (110 mg).

Tic Si02 (ethyl acetate: hexane 1: 1) Rf 0.33 Mass Spectrum MH4"260 13- (2,3-Dihydro-benzofuran-4-yl) -propyl-amide of cyclopentanecarboxylic acid The compound was prepared by the method described in Example 19 using cyclopentanecarbonyl chloride (0.058 ml) to give the titled compound as a white solid (90 mg).

Tic SiO2 (ethyl acetate: hexane 1: 1) Rf 0.43 Mass Spectrum MH4"274 Example 21 1 * 3- (2,3-dihydro-benzofuran-4-yl) -propyl-2-methylpropionic acid amide The compound was prepared by the method described in Example 19 using 2-methylpropionyl chloride (0.05 ml) to give the titled compound as a white solid (93 mg).

Tic Si02 (ethyl acetate: hexane 1: 1) Rf 0.35 Mass Spectrum MH4"248 Example 22 T3- (2,3-dihydro-benzofuran-4-yl) -propyl-propionic acid amide The compound was prepared by the method described in Example 19 using propionyl chloride (0.044 ml) to give the titled compound as a white solid (71 mg).

Tic Si02 (ethyl acetate: hexane 1: 1) Rf 0.22 Mass Spectrum MH4"234 Example 23 l "3- (2,3-dihydro-benzofuran-4-yl) -propyl-amide of butyric acid The compound was prepared by the method described in Example 19 using butyryl chloride (0.05 ml) to give the titled compound as a white solid (67 mg).

Tic Si02 (ethyl acetate: hexane 1: 1) Rf 0.27 Mass Spectrum MH4"248 24 r 3 - (2H-Chromen-7-yl) -propyl-amide of cyclopropanecarboxylic acid (A) and f3- (2H-chromen-5-yl) -propyl-cyclopropanecarboxylic acid amide (B) A solution of [3- (3-prop-2-ynyloxy-phenyl) -propyl] -amide of cyclopropanecarboxylic acid (415 mg) in N, N-diethylaniline (2 ml) was heated at 215 ° C for 24 h. The cooled mixture was purified by column chromatography on silica. Elution with hexane / ethyl acetate 3: 1 gave the titled compound as a colorless solid (16 mg).

Mass Spectrum Found MH4"258 Tic Si02 (hexane / ethyl acetate 2: 1) Rf 0.27 and the compound titled (B) as a colorless oil (79 mg) Mass Spectrum Found MH4"258 Tic SiO2 (hexane / ethyl acetate 2: 1) Rf 0.23 Example 25 (3-Chroman-5-yl-propyl) cyclopropanecarboxylic acid amide A solution of cyclopropanecarboxylic acid [3- (2H-chromen-5-yl) -propyl-amide (76 mg) in ethanol (5 ml) was hydrogenated over platinum (5% on carbon, 10 mg) for 16 h. The catalyst was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica. Elution with hexane / ethyl acetate 2: 1 gave the titled compound as a colorless solid (56 mg) Mass Spectrum Found MH4"260.2 TLC SiO2 (hexane / ethyl acetate 2: 1) Rf 0.23 Example 26 N- f3- 12 .3-dihydro-5-fluorobenzofuran-4-ill propyl acetamide A solution of E- and Z- 3- [5-fluorobenzofuran-4-yl] acrylonitriles (0.5 g) in acetic acid (20 ml) and acetic anhydride (1.25 ml) containing 10% palladium on charcoal (50 mg) 50% wet mass) and 5% platinum on charcoal (50 mg) was hydrogenated at 150 psi and 75 ° for 3 days. The solution was filtered through ice and evaporated to dryness and the residue purified by chromatography (Biotage Flash 40; 90 g; ethyl acetate: hexane 1: 1 then changed to ethyl acetate) to give an impure sample of the compound titrated with N- [3- [4-fluorobenzofuran-4-yl] propyl] acetamide. This material was combined with a similar product obtained from an identical reaction and subjected to another hydrogenation in acetic acid (25 ml) containing 10% palladium on charcoal (50 mg, 50% wet mass) and 5% of platinum on charcoal (50 mg) at 170 psi and 75 ° for 24 h. The solution was filtered and evaporated and the residue was dissolved in dichloromethane and washed with 4% sodium bicarbonate, dried and evaporated to give the titled compound (0.68 g) as an oil.

Tic (Ethyl acetate) Rf 0.27 Mass spectrum MH + 238 Example 27 l "3- (2,3-dihydro-5-fluorobenzofuran-4-yl) propip-amide 3- (2,3-Dihydro-5-fluorobenzofuran-4-yl) propylamine hydrochloride (0.27 g) in dichloromethane (5 ml) containing triethylamine (0.5 ml) was cooled in ice. Cyclopropancarbonyl chloride (0.12 ml) was added and stirring was continued at 5 ° for 2 h and at room temperature for 16 h. The mixture was washed with water and passed through a solid phase extraction cartridge using ethyl acetate / hexane (1: 1) to give the titled compound as a white solid (0.21 g).

Tic (Ethyl acetate / hexane 1: 1) Rf 0.25 Mass spectrum MH * 263 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (18)

1. A compound of formula (I) characterized in that R1 and R2 which could be the same or different represent H, C1-6 alkyl or alkyl substituted with fluorine, C3-7 cycloalkyl or aryl; R3 and R4 which could be the same or different represent H, halogen, or C1-6 alkyl; or aryl substituted by one or more groups selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, halogen, nitro and trifluoromethyl R 5 represents H or C 1-6 alkyl or; n is an integer 0, 1 or 2 and m is an integer 1, 2, 3 or 4; the dotted line indicates the presence or absence of an additional link; and the pharmaceutically acceptable solvates thereof.

2. A compound of formula (la) characterized in that R1 and R2 which could be the same or different represent H, C1-e alkyl or alkyl substituted with fluorine, C3-7 cycloalkyl or aryl; R3 and R4 which could be the same or different represent H, halogen, or C1-6 alkyl; n is an integer 0, 1 or 2 the dotted line indicates the presence or absence of an additional link; and the pharmaceutically acceptable solvates thereof.

3. A compound according to claim 1 or 2, characterized in that R3 and R4 are hydrogen, halogen and C1-3 alkyl.

4. A compound according to claim 3, characterized in that the halogen is chlorine and / or fluorine.

5. A compound according to claim 1 or 2, characterized in that R1 and R2 are hydrogen, C1-3 alkyl or C3-cycloalkyl.

6. A compound according to claim 5, characterized in that R1 is methyl or cyclopropyl.

7. A compound according to claim 6, characterized in that at least one of R1 and R2 are hydrogen.

8. A compound according. to any of the preceding claim, characterized in that n is zero.

9. A compound of formula l (b) (1 B) characterized in that R1 and R2 which could be the same or different represent H, C1-6 alkyl or alkyl substituted with fluorine, C3-7 cycloalkyl or aryl; R3 and R4 which could be the same or different represent H, halogen, or C1-6 alkyl; or aryl substituted by one or more groups selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, halogen, nitro and trifluoromethyl n is an integer O or l and m is an integer 2, 3, 4 or 5; the dotted line indicates the presence or absence of an additional link; and pharmaceutically acceptable solvates (eg, hydrates) thereof.

10. A compound of formula l (c) characterized in that R1 and R2 which could be the same or different represent H, C1-s alkyl or C3-7 cycloalkyl; R3 and R4 which could be the same or different represent H, halogen, or C1-s alkyl; R 5 represents H or C 1-6 alkyl; n is an integer 0, or 1 and m is an integer 1, 2, 3 or 4; the dotted line indicates the presence or absence of an additional link; and pharmaceutically acceptable solvates (eg, hydrates) thereof.

11. N- [3- (2, 3-dihydro-benzofuran-4-yl) -propyl] acetamide, [3- (2,3-dihydro-benzofuran-4-yl) propyl] -amide of cyclopropanecarboxylic acid, [3- Cyclopropanecarboxylic acid (5-chloro-2,3-dihydro-benzofuran-4-yl) propyl] -amide, [3- (5-chloro-7-fluoro-2,3-dihydro-benzofuran-4-yl) propyl) ] - cyclopropanecarboxylic acid amide, [3- (5-chloro-7-fluoro-benzofuran-4-yl) propyl] -amide of cyclopropanecarboxylic acid, [3-benzofuran-4-yl] propyl] -amide of cyclopropanecarboxylic acid, ( 3-Chromat-5-yl-propyl) -amide of cyclopropanecarboxylic acid, N- [3- (2, 3-dihydro-5-fluorobenzofuran-4-yl) propyl] acetamide, [3- (2,3-dihydro- 5-Fluoro-benzofuran-4-yl) propyl] -amide of cyclopropanecarboxylic acid.

12. A pharmaceutical formulation, characterized in that it comprises a compound of the formula (I) according to any of claims 1 to 11 together with one or more pharmaceutically acceptable carriers thereof.

13. A process for the preparation of a pharmaceutical formulation, characterized in that it comprises a compound of the formula (I) according to any of claims 1 to 11 together with one or more pharmaceutically acceptable vehicles thereof, this process comprises mixing the compound of the formula (I) together with one or more pharmaceutically acceptable vehicles thereof.

14. A compound of formula (I) according to any of claims 1 to 11, characterized in that it is used in therapy.

15. A compound of formula (I) according to any of claims 1 to 11, characterized in that it is used in the preparation of a medicament for use in the treatment of conditions associated with a disturbed function of the systems regulated by melatonin.

16. A method of treatment of a mammal, including man, characterized in that it comprises the administration of an effective amount of a compound of the formula (I) according to any of claims 1 to 11, for the treatment of the conditions associated with a disturbed function of the systems regulated by melatonin.

17. A process for the preparation of a compound of formula (I) according to any of claims 1-11, characterized in that the process comprises (A) Acylation of a compound of the formula (II). or (B) cyclization of a compound of the formula (XI)

18. The compounds of the formulas (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (XI), (XII), (XIII), ( XIV), (XV), (XVI), (XVII) and (XVIII). N