KR20000011021A - Benzofurans and benzopyrans as chronobiological agents - Google Patents

Abstract

PURPOSE: A benzofuran and a benzopyran are provided to treat a sudden death of infant, a premature birth, an antifertility, and diseases related to a system lowering function of melatonin. CONSTITUTION: A compound of formula (I), wherein R1 and R2 which may be the same or different represent H, C1-6 alkyl, C3-7 cycloalkyl or aryl; R3, and R4 which may be the same or different represent H, halogen, C1-6 alkyl; or substitutional; R5 represents H or C1-6 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 bond; and pharmaceutically acceptable solvates thereof.

Description

Benzofuran and Benzopyrane, Time Biological Agents

The present invention relates to bicyclic compounds, methods for their preparation, pharmaceutical compositions containing them and their medical uses.

Accordingly, the present invention provides a compound of formula I and pharmaceutically acceptable solvates thereof (eg hydrates).

Wherein R ¹ and R ² may be the same or different and represent H, C _1-6 alkyl or substituted alkyl or C _3-7 cycloalkyl, or aryl,

R ³ and R ⁴ may be the same or different and represent H, halogen, C _1-6 alkyl, or substituted aryl,

R ⁵ is H or C _1-6 alkyl,

n is an integer of 0 or 1,

m is an integer of 1, 2, 3 or 4,

The dashed line indicates the presence or absence of additional binding.

It will be appreciated that the substituents R ³ and R ⁴ in formula I above may be attached at any available position on the phenyl portion of the bicyclic system. Preferably when n is 0, R ³ and R ⁴ are substituted at the 5 and / or 7 positions on the phenyl ring.

As used herein, an alkyl group can be a straight or branched chain alkyl group. Examples of suitable alkyl groups are C _1-4 alkyl groups such as methyl, ethyl, n-propyl and isopropyl groups. When optionally substituted, the substituent is one or more fluorine atoms.

Halogen substituents may be fluorine, chlorine, bromine or iodine.

As used herein, the term "aryl" refers to phenyl, optionally one or more (eg 1 to 3) atoms or C _1-6 alkyl, C _1-6 alkoxy, hydroxy, halogen, nitro and By phenyl substituted by groups selected from trifluoromethyl.

The cycloalkyl group can be a crosslinked cycloalkyl group, such as norbornyl or uncrosslinked cycloalkyl group, such as cyclopropyl.

Examples of groups R ³ and R ⁴ are hydrogen, halogen (eg chlorine and / or fluorine) and C _1-3 alkyl (eg methyl).

m preferably represents 2.

n preferably represents 0.

R ² may in particular represent hydrogen or C _1-3 alkyl (eg methyl).

R ¹ especially represents hydrogen, C _1-3 alkyl (eg methyl, ethyl, n-propyl or i-propyl) or C _3-5 cycloalkyl (eg cyclopropyl or cyclobutyl).

Specific groups of the compounds of the present invention are the compounds of formula 1a and their pharmaceutically acceptable solvates (eg hydrates).

Wherein R ¹ , R ³ and R ⁴ are as defined above, in particular halogen, more particularly R ³ and R ⁴ are chlorine and / or fluorine, wherein R ¹ is especially methyl or cyclopropyl.

Another specific group of the compounds of the present invention are the compounds of formula 1b and their pharmaceutically acceptable solvates (eg hydrates).

Wherein R ¹ and R ² may be the same or different and represent H, C _1-6 alkyl or substituted alkyl, C _3-7 cycloalkyl or aryl,

R ³ and R ⁴ may be the same or different and represent H, halogen, C _1-6 alkyl or substituted aryl,

n is an integer of 0 or 1,

m is an integer of 1, 2, 3 or 4,

The dashed line indicates the presence or absence of additional binding.

Further specific groups of compounds are compounds of Formula 1c and pharmaceutically acceptable solvates (eg hydrates) thereof.

Wherein R ¹ and R ² may be the same or different and represent H, C _1-6 alkyl or C _3-7 cycloalkyl,

R ³ and R ⁴ may be the same or different and represent H, halogen or C _1-6 alkyl,

R ⁵ is H or C _1-6 alkyl,

n is an integer of 0 or 1,

m is an integer of 1, 2, 3 or 4,

The dashed line indicates the presence or absence of additional binding.

Specific compounds according to the invention include N- [3- (2,3-dihydro-benzofuran-4-yl) -propyl] acetamide, cyclopropanecarboxylic acid- [3- (2,3-dihydro -Benzofuran-4-yl) -propyl] amide, cyclopropanecarboxylic acid- [3- (5-chloro-2,3-dihydro-benzofuran-4-yl) propyl] amide, cyclopropanecarboxylic acid -[3- (5-Chloro-7-fluoro-2,3-dihydro-benzofuran-4-yl) propyl] amide, cyclopropanecarboxylic acid- [3- (5-chloro-7-fluoro -Benzofuran-4-yl) -propyl] -amide, cyclopropanecarboxylic acid- [3-benzofuran-4-yl) -propyl] -amide, cyclopropanecarboxylic acid (3-chroman-5-yl -Propyl) -amide, N- [3- (2,3-dihydro-5-fluorobenzofuran-4-yl) propyl] acetamide, cyclopropanecarboxylic acid [3- (2,3-dihydro -5-fluoro-benzofuran-4-yl) propyl] amide.

It should be understood that the present invention covers all combinations of the specific and preferred groups described above.

Those referred to below as compounds of formula (I) include the compound and its pharmaceutically acceptable solvates.

Compounds of formula (I) may contain one or more asymmetric carbon atoms and may exist as stereoisomers. Accordingly, the compounds of formula (I) include the R- and S-isomers and mixtures, for example racemic mixtures.

Compounds of formula (I) have high affinity and selectivity for binding to melatonin receptors and have melatonin agonist or antagonist activity as evidenced in human ML1 receptors cloned in Chinese hamster ovary cells. Thus, the compounds are used as scientific tools to study the role of melatonin in biological systems.

The compounds of formula (I) are also used in the treatment of disorders arising from the inhibited function of the system regulated by melatonin. In particular, the compounds of formula (I) may be useful for the treatment of temporal biological diseases (especially in older populations), glaucoma, cancer, psychotic diseases, neurodegenerative diseases or neuroendocrine diseases resulting from or influenced by a system regulated by melatonin. It can be used for treatment.

Time-biological disorders include seasonal emotional disorders (SAD), primary and secondary insomnias, primary and secondary hypersomnias, sleep-memory schedule disorders (early, delayed, disintegrating and frequent changes), and other sleep disorders. In particular, there are those caused by aging, dementia, ignorance, shift work and rapid time-band movements, often known as jet fatigue.

Cancers that can be treated with the compounds of formula (I) include solid tumors such as melanoma and breast cancer.

Psychological disorders associated with altered melatonin function or may be affected by melatonin and crossover include mood disorders (including all kinds of bipolar disorders, major depression, mood modulation and other depressive disorders), psychoactive substance dependence and abuse , Anxiety disorders (including panic disorder, agoraphobia, interphobia, simple polio, obsessive compulsive disorder, post-traumatic stress disorder and generalized anxiety disorder), schizophrenia, epilepsy and epileptic seizures (large seizures, small seizures, myoclones) Nick epilepsy and partial seizures), involuntary movement disorders (including those caused by Parkinson's disease and involuntary movements caused by drugs) and dementia (including Alzheimer's primary degenerative dementia).

Neurodegenerative diseases that are related to modified melatonin function or that may be affected by melatonin and biological rhythms include multiple sclerosis and stroke.

Neuroendocrine diseases that are related to altered melatonin function or that may be affected by melatonin and biological rhythms include peptic ulcer, vomiting, psoriasis, benign prostate hyperplasia, hair disease and weight change. Specific neuroendocrine diseases that can be treated are those related to the regulation of reproductive maturity and function, such as idiopathic delayed puberty, infant sudden death, premature birth, infertility, antifertility, premenstrual syndrome (luteal discomfort) And sexual dysfunction (including sexual desire disorders, male erectile dysfunction, postmenopausal disorders and orgasm disorders). The compounds can also be used to control the breeding cycle, body weight, skin color and spawning of sensitive hosts, including birds, insects and mammals. The compounds of formula (I) may also have sedative and analgesic effects, microcirculation and immunopurifying effects and may be useful in the treatment of hypertension, migraine, cluster headaches, appetite control, and regimen diseases such as obesity, anorexia nervosa and anorexia nervosa. have.

Thus, a further aspect of the present invention is to provide a compound of formula (I) for treatment, in particular for human medicine. Therapeutic use will be understood to mean, but not necessarily limited to, the use of a compound of formula (I) as an active therapeutic substance.

A further aspect of the present invention is also to provide a compound of formula (I) for the manufacture of a medicament for use in the treatment of diseases associated with melatonin system inhibiting function.

An alternative or additional aspect of the present invention is to provide a method for the treatment of a mammal, including a human, comprising the administration of an effective amount of a compound of formula (I), in particular for the treatment of diseases associated with melatonin system inhibitory function.

It will be appreciated by those skilled in the art that the treatments and treatments used herein mean extended to the treatment of prevented and advanced symptoms.

For therapeutic use, the compounds of formula (I) may be administered as raw chemicals, but it is preferred to provide the active ingredient as a pharmaceutical composition.

The present invention therefore further provides a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers thereof. The carrier (s) must be an "acceptable" ingredient meaning miscible with other ingredients of the composition and must not be toxic to its prescription.

Pharmaceutical compositions include those that are suitable for oral, rectal, intravaginal, intranasal, topical or parenteral (intramuscular, subcutaneous and intravenous) administration or for aspiration or inhalational administration. The formulations may, if appropriate, usually be presented in separate dosage units or prepared by any method known in the art of pharmacy. All methods include the step of combining the active compound with a liquid carrier or finely divided solid carrier or both and then molding the product into the desired formulation, if necessary.

For oral administration, the pharmaceutical composition may be prepared by conventional means such as binders (e.g. pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose), fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate). Tablets prepared with pharmaceutically acceptable excipients, such as lubricants (eg magnesium stearate, talc or silica), disintegrants (eg potato starch or sodium starch glycolate) or wetting agents (eg sodium lauryl sulfate) Or it may be shaped like a capsule. Tablets may be coated by methods known in the art. Liquid preparations for oral administration may be in the form of, for example, solutions, syrups or suspensions, or may be provided as a dry product consisting of water or other suitable vehicle before use. Such liquid preparations include suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol) and preservatives (e.g. , Methyl or propyl-p-hydroxybenzoate or sorbic acid) can be prepared by conventional means.

For oral topical administration, the compositions may be in the form of oral or sublingual tablets, drops or rosin preparations formulated in conventional manner.

For topical epidermal administration, the compounds may be formulated as creams, gels, ointments or lotions, or transdermal patches. The compositions can be formulated, for example, with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifying, stabilizing, dispersing, suspending and / or coloring agents.

The compounds of the invention may be formulated for parenteral administration, for example by bolus injection or continuous intravenous infusion, usually by injection such as intravenous, intramuscular or subcutaneous injection. Injectable formulations may be presented in unit dosage form in ampoules or in multiple dose containers with preservatives. The composition may be in the form of a suspension, liquid or emulsion in an oily or aqueous vehicle and may contain formulation agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form consisting of a suitable vehicle, such as water, free of sterile pyrogen prior to use.

The compounds of the invention may also be formulated in rectal compositions such as suppositories or delayed enema containing, for example, conventional suppository bases such as cocoa butter or other glycerides.

Pessaries for vaginal administration can also be formulated in a similar manner.

For intranasal administration, the compounds of the present invention can be used, for example, in the form of liquid sprays, powders and dropping agents.

For administration by inhalation, the compounds according to the invention are usually formulated with suitable propellants (eg, 1,1,1,2-trifluoroethane (HFA 134A) and 1,1,1,2,3,3,3- Delivered in the form of an aerosol spray presentation or nebulizer from a pressurized pack using heptafluoropropane (HFA 227), carbon dioxide and other suitable gases). In the case of a pressurized aerosol, the dosage unit can be determined by providing a value for delivering a metered amount. Capsules and cartridges, such as gelatin used in an inhaler or insufflator, containing a compound of the present invention and a powder mixture based on a suitable powder base such as lactose or starch can be formulated.

Any of the pharmaceutical compositions described above may be provided by conventional methods associated with controlled release forms.

The active ingredient may usually be presented in unit dosage form. Typical unit dosage formulations contain the active ingredient in an amount from about 0.1 mg to about 200 mg.

It will be understood that the precise dosage administered will depend on the age and condition of the patient, the specific compound used and the frequency and route of administration, and ultimately the decision of the attending physician. The compound may be administered once or in several divided doses and may be administered one or more times, for example 1 to 4 times daily.

For the treatment of diseases associated with the inhibited function of the melatonin-controlled system, the present invention is proposed for oral, rectal, vaginal, intranasal, topical or parenteral administration to a human (about 70 kg body weight). The dosage of the compound is 0.01 to 200 mg of the active ingredient per unit dosage that can be administered (eg 1 to 4 times daily).

For oral administration, unit dosages will preferably contain 0.1 to 200 mg of active ingredient. The unit dosage for parenteral administration will preferably contain 0.1 to 5 mg of active ingredient.

Preferably, the aerosol formulation is arranged such that the "puff" delivered from each metered dose or pressurized aerosol contains 0.2 mg to 2 mg of a compound of the invention, and the capsule delivered from an inhaler or inhaler, and The cartridge contains 0.2 mg to 20 mg of the compound of the present invention. The total daily dose by inhalation with aerosol is in the range of 0.2 mg to 100 mg. Administration can be once daily or several times daily (eg 1 to 8 times) to provide for example 1, 2 or 3 times the dose each time.

The dosage of the compounds of the invention for rectal, vaginal, intranasal or topical administration is similar to that for oral administration.

The compounds of the present invention can be administered, if desired, in combination with one or more other therapeutic agents, such as hypnotics or antidepressants, or in combination with anticancer agents, such as tamoxifen, or in combination with radiation therapy for the treatment of cancer.

Since the aforementioned combinations are usually intended for use in the form of pharmaceutical compositions, pharmaceutical compositions comprising a compound of formula (I) and at least one therapeutic agent and at least one pharmaceutically acceptable carrier constitute a further aspect of the present invention.

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

When using this combination, the dosage of each component in the formulation will generally be the same as the amount of each component when used alone.

Compounds of formula (I) and pharmaceutically acceptable solvates (eg hydrates) thereof may be prepared by methods known in the art for the preparation of cognate compounds. In particular, compounds of formula (I) may be prepared by the process outlined below to form further embodiments of the invention. In the methods below, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , n and m are as defined in formula (I) unless otherwise noted.

According to general process (A), compounds of formula (I) can be prepared by acylating compounds of formula (II).

Suitable acylating agents that may be conventionally used in the process are acid anhydrides and acid halides. This reaction is usually carried out in the presence of a base such as pyridine or tertiary amine (eg triethylamine), at a temperature in the range from 0 to 100 ° C., preferably 0 to 20 ° C., usually in an ether (eg diethyl ether). , Tetrahydrofuran or dioxane), hydrocarbons such as toluene or halogenated hydrocarbons (e.g. dichloromethane), esters (e.g. ethyl acetate).

The compounds of formula I thus produced, where the dashed lines represent additional bonds, are hydrogenated, for example hydrogenating a compound in ethanol over a transition metal catalyst such as rhodium, filtering off the catalyst and then further purifying the compound. By reaction, the dashed line can be converted to the corresponding compound, which does not mean further binding.

Compounds of formula II wherein R ² is hydrogen and the dotted line represents a bond can be prepared conventionally by reducing the compound of formula III.

This reduction can optionally be carried out using a reducing agent such as borane in an ether solvent (eg tetrahydrofuran) in the presence of a suitable acid (eg trifluoroacetic acid, hydrochloric acid, etc.) and heating the reaction mixture for about 3 to 5 hours. It can be carried out conventionally by refluxing. Alternatively, the reduction reaction is catalytic catalytic hydrogenation in the presence of a noble metal catalyst such as platinum, palladium, in a suitable organic solvent, such as an alcoholic solvent (e.g. ethanol), at a temperature in the range from 0 ° C to 100 ° C, suitably at room temperature. Can be used.

Alternatively, compounds of formulas IIIa and IIIb, wherein p is 0, preferably by hydrogenation in a suitable solvent, such as acetic acid, for example in the presence of palladium on charcoal and / or rhodium on charcoal with platinum. Or 1) can be converted to a compound of formula II wherein R ² is hydrogen and m is 2, 3 or 4. This process is generally carried out at a pressure of 50 to 180 psi, preferably 50 to 110 psi and more preferably 70 to 100 psi and at a temperature of 30 to 100 ° C, preferably 30 to 80 ° C, more preferably 50 ° C. For a sufficient time which is 24 hours.

Typically compound (IIIb) can be converted directly to compound (I) by carrying out the hydrogenation reaction in the presence of an acid anhydride. Temperature and pressure can be adjusted to determine the degree of halogenation and unsaturation in the final product.

Compounds of formula II wherein R ² is C _1-6 alkyl may be prepared by standard methods using N-alkylation of compounds of formula II wherein R ² is hydrogen.

Compounds of formula III can be prepared from compounds of formula IV below.

Wherein Hal is any one of halide groups such as chlorine, bromine and iodine. This preparation suitably involves reaction with alkali metal cyanide, such as potassium cyanide, in the presence of an alcoholic solvent.

Compounds of formula (IIIa) and (IIIb) may be prepared from compounds of formula (V).

Wherein R ⁵ is hydrogen or C _1-6 alkyl. This preparation uses a Wittich or Horner-Emmons type chemical, ie diethyl cyanomethyl phosphonate, in the presence of a strong base such as sodium hydride in a suitable solvent such as THF. This can be done using alkyl cyanoalkyl phosphonates.

In a particularly preferred embodiment of route A, the compound of formula II, wherein m is 2, n is 0, R ⁵ is hydrogen and the dashed line does not represent a bond; i.e. the 5-membered ring is saturated, alternatively It can be prepared from a compound of formula VI by heating under reflux with borane in tetrahydrofuran.

Compounds of formula VI can be prepared by treating compounds of formula VII with organic cyanide, such as sodium cyanide.

Wherein J is a suitable leaving group such as mesylate group, tosyl group or halogen.

Compounds of formula (VII) can be prepared by reacting a compound of formula (VIII) with a suitable activating reagent such as methane sulfonyl chloride, tosyl chloride or halogenating agent.

Compounds of formula (VIII) may be prepared by reacting a compound of formula (IX) with a suitable acid, such as hydrochloric acid.

If necessary, the substituents R ³ and / or R ⁴ , wherein R ³ and / or R ⁴ are both halogen, may be substituted with a suitable reagent (eg, N-bromo when R ³ and / or R ⁴ is bromine). Succinimide or N-chlorosuccinimide when R ³ and / or R ⁴ is chlorine).

Compounds of formula (IX) may be prepared by ozone decomposition of compounds of formula (X). The compound of formula (X) is commercially available or can be prepared by subjecting the naphthol to a odor reduction reaction. In any step of this process, compounds in which R ³ and / or R ⁴ is hydrogen or halogen may be reacted by reactions well known to those skilled in the art by R ³ and / or R ⁴ being halogen, C _1-6 alkyl Or a compound which is substituted aryl.

According to a further process (B), compounds of formula I, wherein n is 1, can be prepared by cyclizing compounds of formula XI.

Cyclization is usually carried out by heating in a suitable high boiling solvent (eg bromobenzene, N, N-diethylaniline).

Compounds of formula (XI) may be prepared by alkylating compounds of formula (XII) with propargyl halides (eg propargyl bromide) in the presence of a base such as potassium carbonate in a suitable solvent (eg DMF). Compounds of formula (XII) may be prepared by acylating compounds of formula (XIII).

Suitable acylating agents and conditions that may conventionally be used in this process are those described in Acylation of Compounds of Formula (II).

It will be appreciated that the compounds of formulas II, III, IV, V, VI, VII, VIII, IX, XI, XII and XIII and the following XIV-XVIII are novel intermediate products and each represent a further aspect of the invention.

According to a further process (C), the compound of formula (I) wherein R ² is hydrogen and m is 2, 3 or 4 is treated with a compound of formula XIV with a primary amine such as methylamine or hydrazine, followed by process (A It can be manufactured by acylating according to the method of description).

Compounds of formula (XIV) may be prepared by reacting an alcohol of formula (XV) with phthalimide using triphenyl phosphine and diethyl azodicarboxylate in a suitable solvent such as tetrahydrofuran under Mitsunobu conditions. .

Alcohols of formula (XV) can be prepared by many methods known to those skilled in the art, such as, for example, using a lithium aluminum hydride in a suitable solvent such as tetrahydrofuran to reduce the acid or ester of formula (XVI) or (XVII). .

The esters (XVI and XVII) can be readily produced using standard reactions. For example, compound XVI can be prepared by vitich-type reaction of aldehyde or ketone (V), or compound (XVII) can be prepared from halide (XVII) using standard malonate type chemistry.

<Formula V>

There is further provided by the present invention a general interconversion process (D) capable of converting compounds of formula (I) to the corresponding compounds of formula (I) using suitable reaction techniques. For example, compounds of formula (I) in which R ³ represents a halogen atom such as chlorine can be converted to the corresponding compound of formula (I) in which R ³ represents hydrogen by a suitable reduction reaction. R ³ and (or) R ⁴ is hydrogen The compound can be added to a suitable halogen compound in the presence of glacial acetic acid to said compound is R ³ and (or) R ⁴ converted to halogen.

According to another general process (E), compounds of formula (I) can be prepared by subjecting protected derivatives of compounds of formula (I) to a reaction which removes the protecting group (s).

Thus, in the earlier steps in the preparation of compounds of formula (I), it may be 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 formula (I) can be used in conventional manner. See, eg, 'Protective Groups in Organic Chemistry' Ed.J.F.W. McOmie (Plenum Press 1973); or 'Protective Groups in Organic Synthesis' by Theodora W Greene (John Wiley and Sons 1991).

As can be seen, it may be desirable or even necessary to protect any sensitive groups in the molecule as described immediately above in the general process (A) described above. Thus, a reaction step comprising deprotection of the protected derivative of formula (I) or salt thereof can be carried out following the above process (A).

Compounds of the present invention can be isolated in the context of solvent molecules by crystallization from a suitable solvent or evaporation thereof.

Each enantiomer of a compound of the invention can be prepared from racemates by redissolution into their constituent enantiomers (eg, using chiral HPLC) using methods known in the art for the separation of racemic mixtures. Can be.

In addition to being used as the last major step of the preparation sequence, the general method described above for the preparation of the compounds of the present invention may also be used for the introduction of the desired groups in an intermediate step in the preparation of the desired compounds. Therefore, it should be appreciated that in a multistage process the reaction sequence should be chosen such that the reaction conditions do not affect the groups present in the molecules required for the final product.

The invention is further illustrated by the following non-limiting examples.

Intermediate product 1

4-bromomethyl-7-chloro-benzofuran

7-chloro-4-methyl-benzofuran (CAS-No. 79444-97-6; 51.9 g), N-bromosuccinide (61.4 g), benzoyl peroxide (0.52 g) and carbon tetrachloride (1200 ml) The mixture of was heated under reflux while irradiating with 80 W flood lamp for 20 hours. The mixture was cooled down, filtered and the filtrate was evaporated to dryness. The residue was adsorbed on silica and purified by chromatography on silica using ethyl acetate and hexanes (1:20) to yield the title compound (39.50 g) as a yellow solid. Tlc SiO ₂ (cyclohexane) Rf 0.30

Intermediate 2

7-chloro-benzofuran-4-carbaldehyde

A solution of N-methylmorpholine-N-oxide (37.64 g) in acetonitrile (370 ml) containing 3x molecular sieves (36.6 g) was stirred overnight at room temperature and cooled with 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 hours. 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 (Na ₂ SO ₄ ) and evaporated to yield the title compound (21.3 g) as a pale yellow solid. Tlc SiO ₂ (ethyl acetate / cyclohexane 1: 6) Rf 0.40

Intermediate 3

(E) -3- (7-chloro-benzofuran-4-yl) -acrylonitrile and (Z) -3- (7-chloro-benzofuran-4-yl) -acrylonitrile

Sodium hydride (60% oil dispersion; 1.65 g) in THF (40 ml) cooling with ice over 5 minutes with a solution of diethyl cyanomethylphosphonate (7.34 g) in dry tetrahydrofuran (20 ml) To the resulting suspension. After 15 minutes, a solution of 7-chloro-benzofuran-4-carbaldehyde in THF (20 ml) was added and after 5 minutes the solution was warmed up and stirred at room temperature for 2 hours. Brine (40 ml) and ethyl acetate (40 ml) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2 × 20 ml). The extract was dried (MgSO ₄ ), evaporated and the residue was crystallized from ethanol to give (E) -3- (7-chloro-benzofuran-4-yl) -acrylic as a grayish white lint-free needle. Nitrile (2.95 g) was produced.

Mass spectrum found MNH ₄ ⁺ = 221

The mother liquor was evaporated and the residue (6 g) was chromatographed on silica using ethyl acetate: hexanes (changed from 1: 5 to 1: 4) to yield higher amounts of E-isomers (1.19 g) and Z-isomers. A sample (0.62 g) was produced.

Mass spectrum found MNH ₄ ⁺ = 221

Tlc SiO ₂ (ethyl acetate / hexane 1: 5) E-isomer Rf 0.55, Z-isomer Rf 0.35

Intermediate product 4

3- (2,3-Dihydro-benzofuran-4-yl) -propylamine hydrochloride

(E) -3- (7-chloro-benzofuran-4-yl in acetic acid (30 ml) containing 10% palladium on charcoal (50 mg; 50% wet paste) and 5% platinum on charcoal (50 mg) The solution of) -acrylonitrile (intermediate product 3; 1.0 g) was hydrogenated at 100 psi and 50 ° C. for 3 days. This solution was filtered through hyflo and evaporated to dryness and the residue was recrystallized from isopropanol to yield the title compound (583 mg) as a white paste.

Tlc SiO ₂ (dichloromethane / methanol / 0.880 ammonia 75: 8: 1) Rf 0.25

Mass Spectrum MH ⁺ 178

The Z-isomer was hydrogenated under similar conditions to give the same product.

Alternative Path

Treatment of a solution of 2- (2,3-dihydrobenzofuran-4-yl) -propanonitrile (1.20 g) in tetrahydrofuran (12 ml) with a 1M borane solution in tetrahydrofuran (12 ml) And this solution was heated at reflux for 1 hour. The solution was cooled to 20 ° C. and quenched with methanol (0.5 ml) followed by 5M hydrochloric acid (8 ml). The solution was heated at reflux for 30 minutes and then cooled to 20 ° C. and basified with 10 M sodium hydroxide (7 ml). This mixture was extracted with t-butyl methyl ether (25 ml + 12 ml). The combined extracts were dried (K ₂ CO ₃ ) and the solvent was evaporated to yield the free base of the title compound (1.43 g) as a yellow oil.

Mass Spectrum MH ⁺ 178

Intermediate 5

3- (5-Bromo-2,3-dihydro-benzofuran-4-yl) -propylamine

Free base (200 mg) from 3- (2,3-dihydro-benzofuran-4-yl) -propylamine hydrochloride and N-bromosuccinimide (215 mg) in acetic acid (5 ml) The prepared solution was stirred overnight at room temperature. The solution was evaporated to dryness and the residue taken up in water, basified to pH 9-10 with 2N sodium hydroxide and extracted with ethyl acetate. The extract was dried and evaporated to yield the title compound (256 mg) as a pale yellow oil.

Tlc SiO ₂ (dichloromethane / methanol / 0.880 ammonia 75: 8: 1) Rf 0.53

Mass spectrum found MH ⁺ 256/258

The title compound was dissolved in methanolic HCl to make hydrochloride, and the solvent was evaporated to yield a colorless solid.

Intermediate product 6

2- (7-Chloro-benzofuran-4-ylmethyl) -malonic acid diethyl ester

Diethyl malonate (1.7 ml) was added dropwise to a suspension of sodium hydride (60%; 0.3 g) in dry THF (40 ml) at 0 ° C. under nitrogen. The mixture was allowed to warm to room temperature over 15 minutes. Then a solution of 4-bromomethyl-7-chloro-benzofuran in dry THF (10 ml) was added all at once and the mixture was stirred for 1 hour, followed by water (100 ml) and ethyl acetate (3 × 50 ml). The combined organic extracts were washed with brine (50 ml), dried (MgSO ₄ ) and evaporated to yield the title compound (2.466 g) as a pale yellow oil.

Tlc SiO ₂ (ether / cyclohexane 1: 5) Rf 0.33

Intermediate product 7

3- (7-Chloro-benzofuran-4-yl) -acrylic acid methyl ester

Trimethylphosphonoacetate (363 mg) in dry DME (1 ml) was added dropwise to a suspension of sodium hydride (60%; 329 mg) in dry DME (20 ml) under nitrogen at 0 ° C. The resulting white precipitate was stirred for 40 minutes at room temperature, then a solution of 7-chloro-benzofuran-4-carbaldehyde (intermediate product 2; 1.238 g) in dry DME (15 ml) was added at room temperature for 1 minute. . The mixture was heated at reflux for 2 hours, cooled to room temperature and then separated between water (150 ml) and ether (100 ml). The combined organic extracts were washed with brine (100 ml) and dried (MgSO ₄ ). Evaporation of the solvent gave the title compound (1.59 g) as a colorless solid.

Tlc SiO ₂ (dichloromethane / cyclohexane 1: 1) Rf 0.35

Intermediate product 8

3- (7-Chloro-benzofuran-4-yl) -propionic acid ethyl 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 purged with 200 Heat at 4 ° C. The cooled mixture was partitioned between water (80 ml) and ether (3 × 50 ml) and the combined organic extracts were washed with brine (3 × 50 ml) and dried (MgSO ₄ ). The solvent was evaporated to yield the title compound (1.28 g) as a brown oil.

Tlc SiO ₂ (ether / cyclohexane 1: 5) Rf 0.4

Intermediate product 9

3- (7-chloro-benzofuran-4-yl) -propan-1-ol

Path A

Lithium aluminum hydride (1.0 M in ether; 0.24 ml) was dried under 0 ° C. nitrogen at 0 ° C. 3- (7-chloro-benzofuran-4-yl) -acrylic acid methyl ester (intermediate product 7; 0.1 g ) Was added dropwise to the solution. The mixture was stirred for 5 min at 0 ° C., then water (0.2 ml) in THF (2 ml) was added dropwise. This solvent was evaporated and the residue was partitioned between hydrochloric acid (2N; 10 ml) and ether (3 × 20 ml). The combined organic extracts were washed with brine (20 ml) and dried (MgSO ₄ ). The solvent was evaporated and the residue was purified by column chromatography, eluting with ether / cyclohexane 2: 1 to give the title compound (29 mg) as a colorless gum.

Tlc SiO ₂ (ether / cyclohexane 2: 1) Rf 0.25

Path B

Lithium aluminum hydride (1.0 M in ether, 2.5 ml) 3- (7-chloro-benzofuran-4-yl) -propionic acid ethyl ester (intermediate product) in dry THF (intermediate 8; 5 ml) under nitrogen at 0 ° C 8; 0.588 g) dropwise. The mixture was allowed to warm to room temperature and then stirred for 0.5 h, cooled to 0 ° C. and water (1 ml) in THF (5 ml) was added dropwise. Hydrochloric acid (2 N; 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 (MgSO ₄ ). The solvent was evaporated and the residue was purified by column chromatography eluting with ether / cyclohexane 3: 2 to give the title compound (360 mg) as a colorless gum.

Tlc SiO ₂ (ether / cyclohexane 2: 1) Rf 0.25

Intermediate product 10

2- [3- (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 ° C. under nitrogen. Then a solution of 3- (7-chloro-benzofuran-4-yl) -propan-1-ol (364 mg) in THF (5 ml) is added and the mixture is allowed to warm to room temperature for 2 hours Stirred. The solvent was evaporated and the residue was purified by column chromatography eluting with cyclohexane / ether 3: 1 to give the title compound (521 mg) as a colorless solid.

Tlc SiO ₂ (cyclohexane / ether 3: 1) Rf 0.24

Intermediate product 11

1-Chloro-4- (2,2-diethoxy-ethoxy) -2-methyl-benzene

A mixture of 4-chloro-3-methylphenol (47 g), bromoacetaldehyde diethyl acetal (45 ml) and potassium hydroxide (33.6 g) in dimethyl sulfoxide (250 ml) was heated at 120 ° C. for 2 hours. It was. The cooled mixture was partitioned between water (750 ml) and toluene (3 × 500 ml) and the combined organic extracts were washed with brine / water 1: 1 (3 × 300 ml) and dried (Na ₂ SO ₄ ). The solvent was evaporated to yield the title compound (67.9 g) as a pale yellow oil.

Tlc SiO ₂ (hexane) Rf 0.2

Intermediate 12

Mixture of 5-chloro-6-methyl-benzofuran and 5-chloro-4-methyl-benzofuran

A solution of 1-chloro-4- (2,2-diethoxy-ethoxy) -2-methyl-benzene (36.2 g) in toluene (150 ml) was added to polyphosphoric acid in toluene (200 ml) at 100 ° C. under nitrogen. (72 g) was added dropwise. This mixture was heated at 100 ° C. for 1 hour, cooled to room temperature and sodium hydroxide (2M, 400 ml) was added. The organic phase was separated and the aqueous phase further extracted with toluene (2 × 200 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by column chromatography. Elution with cyclohexane gave the title compound (20.1 g) as a pale yellow oil.

Tlc SiO ₂ (cyclohexane) Rf 0.54

Intermediate Product 13

Mixture of 6-bromomethyl-5-chlorobenzofuran and 4-bromomethyl-5-chloro-benzofuran

A mixture of 5-chloro-6-methyl-benzofuran and 5-chloro-4-methyl-benzofuran in carbon tetrachloride (350 ml) (19.6 g), N-bromosuccinimide (23 g) and benzoyl peroxide (160 mg) was heated at reflux under a 200 W lamp for 36 hours. The cooled mixture was filtered through hyflo and the filtrate was evaporated to yield the title compound (28.8 g) as a dark oil.

Tlc SiO ₂ (cyclohexane) Rf 0.6

Intermediate product 14

Mixture of 5-chloro-benzofuran-6-carbaldehyde and 5-chloro-benzofuran-4-carbaldehyde

A solution of a mixture of 6-bromomethyl-5-chloro-benzofuran and 4-bromomethyl-5-chloro-benzofuran (30.54 g) in dry acetonitrile (80 ml) was dried at 10 ° C. under nitrogen. To the mixture of N-methylmorpholine-N-oxide (29.14 g) and 4 ′ molecular sieve in nitrile (100 ml) was added dropwise. The mixture was stirred at rt for 5 h, filtered through hyflo and the filtrate was evaporated. The residue was triturated under ether (100 ml) and filtered. The filtrate was evaporated and the residue was recrystallized from cyclohexane to give the title compound (10.95 g) as a pale yellow solid.

Tlc SiO ₂ (dichloromethane / hexanes 1: 1) Rf 0.3

Intermediate 15

A mixture of (E) -3- (5-chloro-benzofuran-6-yl) -acrylonitrile and (E) -3- (5-chloro-benzofuran-4-yl) -acrylonitrile

A solution of diethyl cyanomethylphosphonate (11.5 ml) in dry ethylene glycol dimethyl ether (DME; 10 ml) was diluted with sodium hydride (60%; 2.914 g) in DME (50 ml) at 0 ° C. under nitrogen. Dropwise to the suspension. The mixture was stirred at 0 ° C. for 20 minutes. Then a solution of a mixture of 5-chloro-benzofuran-6-carbaldehyde and 5-chloro-benzofuran-4-carbaldehyde (10.95 g) in DME (50 ml) was added all at once. This mixture was heated at 60 ° C. for 2 hours, cooled to room temperature and partitioned between water (150 ml) and ether (3 × 100 ml). The combined organic extracts were washed with brine (2 × 100 ml) and dried (MgSO ₄ ). The solvent was evaporated and the residue was purified by column chromatography. Elution with cyclohexane / ethyl acetate 20: 1 gave the title compound (6.75 g) as a colorless solid.

Tlc SiO ₂ (cyclohexane / ethyl acetate 8: 1) Rf 0.31

Intermediate product 16

Mixture of 3- (5-chloro-benzofuran-6-yl) -propylamine with 3- (5-chloro-benzofuran-4-yl) -propylamine

(E) -3- (5-chloro-benzofuran-6-yl) -acrylonitrile and (E) -3- (5-chloro-benzofuran-4- in ethanol ammonia (1.0 M, 50 ml) A solution of a mixture of yl) -acrylonitrile (middle product 15; 1 g) was hydrogenated over rhodium on alumina (130 mg) for 18 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography eluting with dichloromethane / ethanol / ammonia 100: 8: 1 to give the title compound as pale yellow gum (616 mg).

Tlc SiO ₂ (dichloromethane / ethanol / ammonia 100: 8: 1) Rf 0.15

Intermediate product 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 phenyl ¹ (22.05 g) and potassium hydroxide pellets (19.6 g) in dimethyl sulfoxide (160 ml) at room temperature. This mixture was heated at 100 ° C. for 16 h, cooled to rt and partitioned between water (500 ml) and ether (3 × 200 ml). The combined organic extracts were washed with brine / water 1: 1 (3 × 200 ml) and dried (MgSO ₄ ). The solvent was evaporated to yield the title compound (48 g) as an orange oil.

Tlc (cyclohexane) Rf 0.4

Reference 1: Singh S et al, J Amer, Chem Soc 1987, 109, (23), 7194-7196

Intermediate product 18

7-fluoro-4-methyl-benzofuran

A solution of 2- (2,2-dimethoxy-ethoxy) -1-fluoro-4-methyl-benzene (48 g) in toluene (50 ml) was added to polyphosphoric acid (100 ml) in toluene (350 ml) under nitrogen. g) was added dropwise to the reflux solution. The mixture was heated at reflux for 3 hours, cooled to room temperature and sodium hydroxide (2 N; 800 ml) was added. The mixture was extracted with ether (3 × 300 ml) and the combined organic extracts were washed with brine (2 × 300 ml) and dried (MgSO ₄ ). The solvent was evaporated and the residue was purified by column chromatography. Elution with hexanes gave the title compound (14.2 g) as a pale yellow oil.

Tlc SiO ₂ (hexane) Rf 0.4

Intermediate 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 added to a 80 W flood lamp for 20 hours. Heated under reflux with irradiation. The mixture was cooled, filtered and the filtrate was evaporated to dryness to yield the title compound (23.4 g) as a pale orange oil.

Tlc (cyclohexane) Rf 0.18

Intermediate product 20

7-fluoro-benzofuran-4-carbaldehyde

A solution of N-methylmorpholine-N-oxide (22.24) in acetonitrile (250 ml) containing 3 cc molecular sieves (8.71 g) was stirred overnight at room temperature and then cooled with 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 hours. 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 × 200 ml), dried (MgSO ₄ ) and evaporated. The residue was triturated in ether (50 ml) and filtered to yield the title compound (5.45 g) as a pale yellow solid.

Tlc SiO ₂ (dichloromethane / hexanes 1: 1) Rf 0.30

Intermediate 21

(E) -3- (7-fluoro-benzofuran-4-yl) -acrylonitrile

A solution of diethyl cyanomethylphosphonate (5.35 g) in dry ethylene glycol dimethyl ether (DME; 20 ml) was added sodium hydride (60% oil dispersion) in DME (20 ml) over 5 minutes at 0 ° C. under nitrogen. To 1.32 g). After 15 minutes, a solution of 7-fluoro-benzofuran-4-carbaldehyde (4.51 g) in DME (20 ml) was added and after 5 minutes the solution was warmed up and stirred at room temperature for 2 hours. Ammonium chloride solution (200 ml) and ethyl acetate (150 ml) were added, the phases were separated and the aqueous phase was extracted using ethyl acetate (2 × 150 ml). The extract was dried (MgSO ₄ ) and evaporated and the residue triturated in ether (20 ml) and filtered to yield the E isomer (3.07 g) as a tan solid.

The mother liquor was evaporated to yield a mixture of E and Z isomers (4.25 g).

Tlc SiO ₂ (hexane / dichloromethane 1: 1) Rf 0.40

Intermediate 22

3- (7-Fluoro-2,3-dihydro-benzofuran-4-yl) -propylamine

(E) -3- (7-fluoro-benzofuran-4-yl) -acrylonitrile (0.25 g) in ethanol (25 ml), 10% palladium and charcoal on charcoal (50 mg; 50% wet paste) A solution of ammonia (0.88; 10 ml) containing 5% rhodium on (50 mg) was hydrogenated at 70 psi and 70 ° C. for 18 hours. The solution was filtered through hyflo, evaporated to dryness and the residue was purified by column chromatography. Elution with dichloromethane / ethanol / ammonia 100: 8: 1 gave the title compound (256 mg).

Tlc (dichloromethane / methanol / 0.880 ammonia 100: 8: 1) Rf 0.20

Mass spectrum found MH ⁺ 196

Intermediate product 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 (100 mg) in acetic acid (50 ml) overnight at room temperature Stirred. The solution was evaporated to dryness and the residue taken up in water, basified with 2N sodium hydroxide and extracted with dichloromethane. The extract was evaporated to dryness and the residue was dissolved in a solution of hydrogen chloride in methanol. Evaporation and trituration with ether gave the title compound (159 mg) as a grayish white powder.

Mass spectrum found MH ⁺ 212/214

Intermediate product 24

Cyclopropanecarboxylic acid [3- (3-hydroxy-phenyl) -propyl] -amide

3- (3-amino-propyl) -phenyl ¹ (0.1 g) and N, N-diisopropylamine (0.23) in dichloromethane (15 ml) in cyclopropanecarbonyl chloride (0.063 ml) in an ice bath under nitrogen ml) was added dropwise. The mixture was then stirred at room temperature for 3 hours and then purified by passing through a solid phase extraction cartridge. Elution with chloroform followed by ethyl acetate gave the title compound (122 mg) as a colorless gum.

Tlc SiO ₂ (ether) Rf 0.34

1. T. Kametani et al J. Chem Soc. Perkin Trans 1, 1974, 22, 2602-2604

Intermediate 25

Cyclopropanecarboxylic acid [3- (3-prop-2-ynyloxy-phenyl) -propyl] -amide

Cyclopropanecarboxylic acid [3- (3-hydroxy-phenyl) -propyl] -amide (122 in propagyl bromide (80% in toluene, 0.091 ml) in a dry DMF (10 ml) in an ice bath under nitrogen. mg) and sodium carbonate (154 mg) dropwise. The mixture was allowed to warm to room temperature and then heated at 65 ° C. for 18 hours. The cooled mixture was partitioned between water (50 ml) and ethyl acetate (3 × 15 ml). The combined organic extracts were washed with brine / water 1: 1 (3 × 20 ml) and dried (MgSO ₄ ). The solvent was evaporated and the residue was purified by column chromatography on silica. Elution with hexanes / ethyl acetate 2: 1 gave the title compound (79 mg) as a colorless solid.

Tlc SiO ₂ (hexane / ethyl acetate 2: 1) Rf 0.18

Intermediate 26

1- (2,2-dimethoxyethoxy) -4-fluoro-3-methylbenzene

A mixture of 4-fluoro-3-methylphenyl (36.7 g), potassium hydroxide pellets (19.5 g) and bromoacetaldehyde dimethyl acetal (34.6 ml) in dimethyl sulfoxide (240 ml) was heated at 110 ° C. for 24 hours. It was. The mixture was cooled, diluted with water (350 ml) and extracted with hexanes. The extract was evaporated to yield the title compound (52.3 g) as an oil.

Mass spectrum found MNH ₄ ⁺ 232

Intermediate 27

Mixture of 5-fluoro-6-methylbenzofuran and 5-fluoro-4-methylbenzofuran

Polyphosphoric acid (185 g) was heated to 100 ° C. 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 hours, cooled and decanted. This solution was concentrated and the residue passed through silica (900 g) eluting with hexane. Evaporation gave the title compound (14.95 g) as a colorless liquid.

Tlc (hexane) Rf 0.60

Intermediate 28

Mixture of 6-bromomethyl-5-fluorobenzofuran and 4-bromomethyl-5-fluorobenzofuran

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) The heated mixture was heated under reflux while being irradiated with an 80 W flood lamp for 20 hours. The mixture was cooled, filtered and the filtrate was evaporated to dryness to yield an crude oily product (24.0 g). This material was combined with similar crude product from the same reaction run on a smaller scale (6.94 g) and purified by chromatography on silica (900 g) using an ether hexane mixture (1:30) as eluent to give the title in oil form. Compound (13.5 g) was produced.

Tlc (hexane) Rf 0.38

Intermediate 29

Mixture of 5-fluorobenzofuran-6-carbaldehyde (B) and 5-fluorobenzofuran-4-carbaldehyde (A)

A solution of N-methylmorpholine-N-oxide (13.6 g) in acetonitrile (135 ml) containing 3 ′ molecular sieve (13.2 g) was stirred at room temperature overnight and cooled in ice. A solution of 4-bromomethyl-5-fluorobenzofuran and 6-bromomethyl-5-fluorobenzofuran in acetonitrile (35 ml) was added and the mixture was stirred at 5 ° C. for 4 hours. . This 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 yield an aldehyde hydrochloride mixture. The mixture was separated by chromatography on silica (600 g) using a mixture of ethyl acetate and hexanes (1: 9) as eluent to give the title compound (A) (2.19 g) and the title compound (B) (2.17 g). Produced.

Title compound A: Tlc (ethyl acetate / hexane 1: 9) Rf 0.47

Mass spectrum found MNH ₄ ⁺ 182

Title compound B: Tlc (ethyl acetate / hexane 1: 9) Rf 0.35

Mass spectrum found MNH ₄ ⁺ 182

Intermediate 30

(E) -3- [5-fluorobenzofuran-4-yl] acrylonitrile and (Z) -3- [5-fluorobenzofuran-4-yl] acrylonitrile

A solution of diethyl cyanophosphonate (2.79 g) in dry tetrahydrofuran (10 ml) was added to a suspension of sodium hydride (60% oil dispersion; 0.63 g) in THF (16 ml) with ice cooling for 5 minutes. It was. After 15 minutes, a solution of 5-fluorobenzofuran-4-carbaldehyde (2.15 g) in THF (10 ml) was added and after 5 minutes the solution was warmed up and stirred at room temperature for 3 hours. Brine (20 ml) and ethyl acetate (20 ml) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2 × 25 ml). The extracts were evaporated to dryness and the residue was purified by chromatography (Biotage Flash 40; 90 g; ethyl acetate: hexanes 1: 9) to give the title compound (1.97 g) as a cream solid.

Tlc (ethyl acetate / hexane 1: 9) Rf 0.25

Mass spectrum MNH ₄ ⁺ 205

Intermediate 31

3- (2,3-dihydro-5-fluorobenzofuran-4-yl) propylamine hydrochloride

N- [3- [2,3-dihydro-5-fluorobenzofuran-4-yl] propyl] acetamide (0.55 g) was heated at reflux in 2M hydrochloric acid (10 ml) for 24 hours. The mixture was cooled and washed with dichloromethane, basified with 2M sodium hydroxide and extracted with dichloromethane. The extract was evaporated to yield an oil dissolved in 0.7 M methanolic hydrogen chloride (8 ml). This was evaporated to yield the title compound (0.28 g) as a beige solid.

Mass Spectrum MH ⁺ 196

Intermediate 32

2,3-bis (2-hydroxyethyl) -phenol

The solution of 5,8-dihydronaphth-1-ol (2.00 g) in methanol (40 ml) was cooled to 70 ° C. and the solution was dissolved in ozone in oxygen until tlc indicated that all starting materials had been consumed. Caused bubbles. Ozone was shut off and bubbled through the solution for 5 minutes with nitrogen. Sodium borohydride (454 mg) was then added and the solution was allowed to slowly warm to 20 ° C. Additional sodium borohydride (227 mg) was added, after 10 minutes acetic acid (1 ml) was added and the solvent was evaporated. The residue was partitioned between 2M hydrochloric acid (50 ml) and ethyl acetate (2 × 50 ml). The combined ethyl acetate extracts were dried (Na ₂ SO ₄ ) and the solvent was evaporated to yield a brown oil which was purified by chromatography on silica gel eluting with ethyl acetate to leave the title compound as a pale brown oil which solidified if left alone. 1.49 g) was produced.

Tlc SiO ₂ (ethyl acetate) Rf 0.46

Intermediate 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 at reflux for 2 hours. The mixture was cooled down, diluted with water (24 ml) and extracted with ethyl acetate (2 × 24 ml). The combined extracts were dried (Na ₂ SO ₄ ) and the solvent was evaporated to yield the title compound (1.2 g) as a brown oil.

Tlc SiO ₂ (ethyl acetate) Rf 0.67

Intermediate product 34

Methanesulfonic acid 2- (2,3-dihydrobenzofuran-4-yl) -ethyl ester

A solution of 2- (2,3-dihydrobenzofuran-4-yl) ethanol (1.13 g) in dichloromethane (11 ml) was added to triethylamine (1.25 ml) followed by methanesulfonyl chloride (0.64 ml) Treated with. After 5 minutes, the reaction mixture was poured into 2M hydrochloric acid (10 ml) and extracted with dichloromethane (2 × 10 ml). The combined extracts were washed with water (10 ml), dried (Na ₂ SO ₄ ) and the solvent evaporated to yield the title compound (1.76 g) as a yellow oil.

Tlc SiO ₂ (iso-hexane / ethyl acetate 1: 1) Rf 0.43

Intermediate 35

3- (2,3-dihydrobenzofuran-4-yl) -propanenitrile

A solution of methanesulfonic acid 2- (2,3-dihydrobenzofuran-4-yl) ethyl ester (1.71 g) in dimethylsulfoxide (14 ml) was treated with sodium cyanide (381 mg) and 80 ° C. for 1 hour. Heated at. This suspension was cooled to 20 ° C., diluted with water (14 ml) and extracted with ethyl acetate (2 × 17 ml). The combined extracts were washed with 5% aqueous sodium chloride (17 ml), dried (Na ₂ SO ₄ ) and the solvent evaporated to yield the title compound (1.22 g) as a brown oil which solidified upon leaving.

Tlc SiO ₂ (iso-hexane / ethyl acetate 1: 1) Rf 0.62

<Example 1>

N- [3- (5-Bromo-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide

Treated solution with 3- (5-bromo-2,3-dihydro-benzofuran-4-yl) -propylamine (256 mg) in pyridine (3 ml) at 4 ° C. with acetic anhydride (0.11 ml) And stored at 4 ° C. overnight. The cold solution was acidified with 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was evaporated to dryness and chromatographed on silica (20 g) using dichloromethane: methanol: ammonia (100: 8: 1) to give the title compound (175 mg) in the form of an oil that slowly solidified.

Tlc SiO ₂ (dichloromethane / methanol / 0.880 ammonia 75: 8: 1) Rf 0.67

Mass spectrum MH ⁺ found 297/299

<Example 2>

N- [3- (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 ethanol methylamine (10 ml) was stirred for 4 hours at room temperature. Stirred at. 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 and stirred for 18 hours. The solvent was evaporated and the residue was purified by column chromatography eluting with dichloromethane / methanol 100: 1 to give the title compound (230 mg) as a colorless solid with a melting point of 61-62 ° C.

Tlc SiO ₂ (dichloromethane / methanol 50: 1) Rf 0.16

E- and Z-3- [7-] in acetic acid (100 ml) and acetic anhydride (3.7 ml) containing 10% palladium on charcoal (200 mg; 50% wet paste) and 5% platinum on charcoal (200 mg). The solution with chlorobenzofuran-4-yl] acrylonitrile (4.0 g) was hydrogenated at 100 psi and 60 ° C. for 24 hours. A portion (10 ml) was removed and methanol (1 ml) was added. After 16 h the solution was filtered and evaporated and the residue was purified by chromatography (Biotage Flash 40; ethyl acetate) to yield the title amide (99 mg) as an oil.

Tlc (ethyl acetate) Rf 0.30

Mass spectrum MH ⁺ 252/254

<Example 3>

N- [3- (7-Chloro-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide

A solution of N- [3- (7-chloro-benzofuran-4-yl) -propyl] -acetamide (48 mg) in ethanol (15 ml) was subjected to a rhodium catalyst (5% on carbon; 15 over 7 hours). mg)). The catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography eluting with dichloromethane / methanol 50: 1 to give the title compound (37.6 mg) as a colorless solid with a melting point of 76 to 78 ° C.

Mass spectrum found MH ⁺ 254/256

Tlc SiO ₂ (dichloromethane / methanol 50: 1) Rf 0.16

<Example 4>

N- [3- (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 treated with palladium (10 %; 20 mg) was hydrogenated. The catalyst was filtered off and the filtrate was concentrated in vacuo. This residue was purified by column chromatography, eluting with dichloromethane / methanol 50: 1 to give the title compound (54 mg) as a colorless solid with a melting point of 66 to 67 ° C.

Anal Found: C, 71.0; H, 8.1; N, 6.6;

C ₁₃ H ₁₇ NO ₂ requires: C, 71.2; H, 7.8; N, 6.4%

Tlc SiO ₂ (dichloromethane / methanol 50: 1) Rf 0.16

Alternative Path

E- in acetic acid (330 ml), acetic anhydride (19.6 ml) and triethylamine (30.75 ml) containing 10% palladium on charcoal (0.75 g; 50% wet paste) and 5% platinum on charcoal (0.75 g). And a solution of Z-3- [7-chlorobenzofuran-4-yl] acrylonitrile (15 g) were hydrogenated at 150 psi and 75 ° C. for 4 days. Additional catalysts (as used previously) were added and the reaction continued for an additional 24 hours. 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 × 100 ml), water (100 ml) and 2M sodium carbonate (100 ml) and then evaporated to dryness to give 15.4 g of the title compound as a grayish white solid. Produced.

Tlc (dichloromethane / methanol 50: 1) Rf 0.16

Mass spectrum MH ⁺ 220

Example 5

N- [3- (5-Chloro-benzofuran-4-yl) -propyl] -acetamide

Acetic anhydride (1.95 ml) was added 3- (5-chloro-benzofuran-6-yl) -propylamine and 3- (5-chloro-benzofuran-4-yl in dry THF (70 ml) under nitrogen at 0 ° C. To the solution in which a mixture of) -propylamine (2.86 g) and pyridine (2.2 ml) were dissolved was added dropwise. The mixture was stirred at rt for 3 h and then evaporated to dryness in vacuo. The residue was purified by HPLC (CN-PK5-10530 column). Elution with 5% isopropanol / heptane yielded 1.37 g of the title compound as a colorless solid with a melting point of 82-83 ° C.

Tlc SiO ₂ (dichloromethane / ethanol / 0.880 ammonia 100: 8: 1) Rf 0.39

<Example 6>

N- [3- (5-Chloro-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide

A solution of N- [3- (5-chloro-benzofuran-4-yl) -propyl] -acetamide (0.25 g) in ethanol (15 ml) was stirred for 18 hours on 5% rhodium on carbon (80 mg). Hydrogenation reaction was carried out. The catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane / methanol 40: 1 to yield 131 mg of the title compound as a colorless solid with a melting point of 91 to 92 ° C.

Mass spectrum found MH ⁺ = 254.094828

C ₁₃ H ₁₇ ClNO ₂ requires 254.094782

Tlc SiO ₂ (dichloromethane / methanol 50: 1) Rf 0.22

<Example 7>

N- [3- (5,7-Dichloro-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide

N-chlorosuccinimide in a solution of 0.2 g N- [3- (5-chloro-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide in 5 ml glacial acetic acid at room temperature under nitrogen 173 mg was added and the mixture was stirred for 64 hours. 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 (MgSO ₄ ). The solvent was evaporated and the residue was purified by HPLC eluting with 50% acetonitrile / water + 0.1% TFA to give 97 mg of the title compound as a colorless gum.

Mass spectrum found MH ⁺ = 288.055872

C ₁₃ H ₁₆ Cl ₂ NO ₂ requires 288.055809

Tlc SiO ₂ (dichloromethane / methanol 50: 1) Rf 0.22

<Example 8>

N- [3- (7-Fluoro-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide

0.18 ml of acetic anhydride was made up to 256 mg of 3- (7-fluoro-2,3-dihydro-benzofuran-4-yl) -propylamine in 10 ml of dry THF containing 0.21 ml of pyridine at 0 ° C. under nitrogen. To the solution was added dropwise and the solution was stirred overnight at room temperature. This solution was evaporated and the residue was purified by column chromatography. Elution with dichloromethane: methanol 50: 1 gave 133 mg of the title compound as a colorless oil.

Tlc (dichloromethane / methanol 50: 1) Rf 0.18

Mass spectrum found MH ⁺ 238, MNH ₄ ⁺ 255

Example 9

N- [3- (5-Chloro-7-fluoro-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide

47.7 mg of N-chlorosuccinimide is 77 mg of N- [3- (7-fluoro-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide in 5 ml of glacial acetic acid at room temperature under nitrogen. Was added to the resulting solution and the mixture was stirred for 72 h. This 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 10 ml brine and dried (MgSO ₄ ). The solvent was evaporated and the residue was purified by column chromatography. Elution with dichloromethane / methanol 50: 1 gave 67 mg of the title compound as a colorless gum that would otherwise crystallize.

Mass spectrum found MH ⁺ = 272/274

Tlc SiO ₂ (dichloromethane / methanol 50: 1) Rf 0.18

<Example 10>

N- [3- (5-Bromo-7-fluoro-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide

569 mg N-bromosuccinimide was added to N- [3- (7-fluoro-2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide 690 in 15 ml of glacial acetic acid at room temperature under nitrogen. To the solution in mg was added and the mixture was stirred for 48 hours. This solution was evaporated and the residue was partitioned between sodium carbonate (2N, 20 ml) and 20 ml of ethyl acetate. The combined organic extracts were washed with 25 ml brine and dried (MgSO ₄ ). The solvent was evaporated and the residue was purified by column chromatography. Elution with dichloromethane / methanol 50: 1 gave 644 mg of the title compound as a colorless solid.

Mass spectrum found MH ⁺ = 316/318

Tlc SiO ₂ (dichloromethane / methanol 50: 1) Rf 0.18

<Example 11>

Cyclopropanecarboxylic acid [3- (2,3-dihydro-benzofuran-4-yl) -propyl] -amide

200 mg of 3- (2,3-dihydro-benzofuran-4-yl) -propylamine hydrochloride are divided between 10 ml of 2N sodium hydroxide and 10 ml of dichloromethane, the organic phase is separated and dried (Na ₂ SO ₄ ) And evaporated. 160 mg of residual free base and 110 mg of triethylamine were dissolved in 2 ml of dichloromethane, cooled on ice and 103 mg of cyclopropane carbonyl chloride was added. After 2 hours, the solution was warmed to room temperature and 10 ml of 2N hydrochloric acid was added. This mixture was extracted with dichloromethane (3 × 20 ml) and the extract was washed with 8% bicarbonate, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by chromatography on silica using a mixture of ethyl acetate and hexanes (1: 1) as eluent to yield 95 mg of the title compound as a white solid.

Mass spectrum found MH ⁺ 246

Tlc SiO ₂ (ethyl acetate / hexane 1: 1) Rf 0.26

<Example 12>

Cyclopropane carboxylic acid [3- (5-chloro-2,3-dihydro-benzofuran-4-yl) -propyl] -amide

A mixture of 142 mg of 3- (5-chloro-2,3-dihydro-benzofuran-4-yl) -propylamine hydrochloride, 5 drops of dimethylformamide, 0.64 ml of triethylamine and 5 ml of dichloromethane was added. Stir on ice for min. 66 mg of cyclopropanecarbonyl chloride was added and stirring continued for 5 hours. This mixture was purified by chromatography on silica eluting with ethyl acetate / hexanes (1: 1) to yield 80 mg of the title compound as a white solid.

Tlc (ethyl acetate / hexane 1: 1) Rf 0.17

Mass spectrum found MH ⁺ 280/282

Example 13

Cyclopropanecarboxylic acid [3- (5-Bromo-2,3-dihydro-benzofuran-4-yl) -propyl] -amide

A mixture of 100 mg of 3- (5-bromo-2,3-dihydro-benzofuran-4-yl) -propylamine hydrochloride, 3 drops of dimethylformamide, 0.35 ml of triethylamine and 3 ml of dichloromethane Stir on ice for 15 minutes. 36 mg of cyclopropanecarbonyl chloride was added and stirring continued for 2 hours. The mixture was purified by chromatography on silica to yield 86 mg of the title compound as a white solid.

Tlc (ethyl acetate: hexane 1: 1) Rf 0.33

Mass spectrum found MH ⁺ 324/326

<Example 14>

Cyclopropanecarboxylic acid [3- (7-Fluoro-2,3-dihydro-benzofuran-4-yl) -propyl] -amide

A mixture of 114 mg of 3- (7-fluoro-2,3-dihydro-benzofuran-4-yl) -propylamine, 0.089 ml of triethylamine, 5 ml of dichloromethane and 67 mg of cyclopropanecarbonyl chloride was prepared. Stir for 20 minutes on ice and continue stirring at room temperature overnight. The mixture was partitioned between 2N hydrochloric acid and dichloromethane and the organic phase was washed with 8% sodium bicarbonate and evaporated. The residue was purified by preparative HPLC to yield 16 mg of the title compound as a white solid.

Tlc (ethyl acetate / hexane 1: 1) Rf 0.12

Mass spectrum found MH ⁺ 264

<Example 15>

Cyclopropanecarboxylic acid [3- (5-chloro-7-fluoro-2,3-dihydro-benzofuran-4-yl) -propyl] -amide

A mixture of 445 mg of cyclopropanecarboxylic acid [3- (7-fluoro-2,3-dihydro-benzofuran-4-yl) -propyl] -amide and 248 mg of N-chlorosuccinamide in 15 ml of glacial acetic acid Was stirred at rt for 72 h. The solvent was evaporated and the residual solid was triturated in water (10 ml) and filtered to yield the title compound (236 mg) as a colorless solid.

Mass spectrum found MH ⁺ 298.1 / 300.1

Tlc SiO ₂ (hexane / ethyl acetate 1: 1) Rf 0.18

<Example 16>

Cyclopropanecarboxylic acid [3- (5-chloro-7-fluoro-benzofuran-4-yl) -propyl] -amide

313 mg of lead tetraacetate is added to 0.2 g of cyclopropanecarboxylic acid [3- (5-chloro-7-fluoro-2,3-dihydro-benzofuran-4-yl) -propyl] -amide in 5 ml of glacial acetic acid. Solution was added and the mixture was stirred at rt for 18 h. The solvent was evaporated and the residue was purified by preparative HPLC to yield 20 mg of the title compound as a colorless solid.

Mass spectrum found MH ⁺ 296.1 / 298.1

Tlc SiO ₂ (hexane / ethyl acetate 1: 1) Rf 0.18

<Example 17>

N- [3- (benzofuran-4-yl) -propyl] -acetamide

210 mg of lead tetraacetate was added to a solution of N- [3- (2,3-dihydro-benzofuran-4-yl) -propyl] -acetamide (100 mg) in 1.5 ml of acetic acid at 10 ° C. The mixture was stirred at room temperature for 2 hours and at 50 ° C. for 16 hours. The solvent was evaporated and the residue was purified by chromatography to give 41 mg of the title compound as an oil.

Mass spectrum found MH ⁺ 218

Tlc SiO ₂ (ethyl acetate / hexane 2: 1) Rf 0.43

Example 18

Cyclopropanecarboxylic acid [3- (benzofuran-4-yl) -propyl] -amide

194 mg of lead tetraacetate was added to a solution of 100 mg of cyclopropanecarboxylic acid [3- (2,3-dihydro-benzofuran-4-yl) -propyl] -amide in 1.5 ml of acetic acid at 10 ° C. The mixture was stirred at room temperature for 4 hours and at 50 ° C. for 24 hours. The solvent was evaporated and the residue was purified by chromatography on silica. Elution with hexane / ethyl acetate gave 15 mg of the title compound as an oil.

Mass spectrum found MH ⁺ 244

Tlc SiO ₂ (ethyl acetate / hexane 1: 1) Rf 0.13

Example 19

Cyclobutanecarboxylic acid [3- (2,3-dihydro-benzofuran-4-yl) -propyl] -amide

100 mg of 3- (2,3-dihydro-benzofuran-4-yl) -propylamine hydrochloride were suspended in 3 ml of dichloromethane containing 0.33 ml of triethylamine and cooled with ice. A solution of 0.054 ml of cyclobutanecarbonyl chloride in 1 ml of dichloromethane was added and the mixture was stirred on ice for 3 hours. The mixture was purified by eluting through a solid phase extraction cartridge to yield 110 mg of the title compound as a white solid.

Tlc SiO ₂ (ethyl acetate / hexane 1: 1) Rf 0.33

Mass spectrum MH ⁺ 260

Example 20

Cyclopentanecarboxylic acid [3- (2,3-dihydro-benzofuran-4-yl) -propyl] -amide

0.058 ml of cyclopentanecarbonyl chloride was used to produce 90 mg of the title compound as a white solid according to the method described in Example 19.

Tlc SiO ₂ (ethyl acetate / hexane 1: 1) Rf 0.43

Mass Spectrum MH ⁺ 274

Example 21

2-Methylpropionic acid [3- (2,3-dihydro-benzofuran-4-yl) -propyl] -amide

0.05 mg of 2-methylpropionyl chloride was used to produce 93 mg of the title compound as a white solid following the method described in Example 19.

Tlc SiO ₂ (ethyl acetate / hexane 1: 1) Rf 0.35

Mass spectrum MH ⁺ 248

<Example 22>

Propionic acid [3- (2,3-dihydro-benzofuran-4-yl) -propyl] -amide

0.044 ml of propionyl chloride was used to produce 71 mg of the title compound as a white solid following the method described in Example 19.

Tlc SiO ₂ (ethyl acetate / hexane 1: 1) Rf 0.22

Mass spectrum MH ⁺ 234

<Example 23>

Butyric acid [3- (2,3-dihydro-benzofuran-4-yl) -propyl] -amide

0.05 ml of butyryl chloride was used to produce 67 mg of the title compound as a white solid according to the method described in Example 19.

Tlc SiO ₂ (ethyl acetate / hexane 1: 1) Rf 0.27

Mass spectrum MH ⁺ 248

<Example 24>

Cyclopropanecarboxylic acid [3- (2H-chromen-7-yl) -propyl] -amide (A) and cyclopropanecarboxylic acid [3- (2H-chromen-5-yl) -propyl] -amide (B)

A solution of 415 mg of cyclopropanecarboxylic acid [3- (3-prop-2-ynyloxy-phenyl) -propyl] -amide in 2 ml of N, N-diethylaniline was heated at 215 ° C. for 24 hours. . This cooled mixture was purified by column chromatography on silica. Elution with hexane / ethyl acetate 3: 1 gave 16 mg of the title compound (A) as a colorless solid and 79 mg of the title compound (B) as a colorless oil.

Title compound A: Mass spectrum found MH ⁺ 258

Tlc SiO ₂ (hexane / ethyl acetate 2: 1) Rf 0.27

Title compound B: Mass spectrum found MH ⁺ 258

Tlc SiO ₂ (hexane / ethyl acetate 2: 1) Rf 0.23

<Example 25>

Cyclopropanecarboxylic acid (3-chroman-5-yl-propyl) -amide

Hydrogenation of a solution of 76 mg of cyclopropanecarboxylic acid [3- (2H-chromen-5-yl) -propyl] -amide in 5 ml of ethanol over platinum (5% on carbon, 10 mg) for 16 hours I was. The catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography on silica. Elution with hexane / ethyl acetate 2: 1 gave 56 mg of the title compound as a colorless solid.

Mass spectrum found MH ⁺ 260.2

TLC SiO ₂ (hexane / ethyl acetate 2: 1) Rf 0.23

Example 26

N- [3- [2,3-Dihydro-5-fluorobenzofuran-4-yl] -propyl] -acetamide

E- and Z-3- [5- in acetic acid (20 ml) and acetic anhydride (1.25 ml) containing 10% palladium on charcoal (50 mg; 50% wet paste) and 5% platinum on charcoal (50 mg). A solution of fluorobenzofuran-4-yl] -acrylonitrile (0.5 g) was hydrogenated at 150 psi and 75 ° C. for 3 days. The solution was filtered through hyflo and evaporated to dryness and the residue was purified by chromatography (Biotage Flash 40; 90 g; ethyl acetate: hexanes 1: 1 to ethyl acetate), N- [3- [4- A sample of the title compound was obtained in a pure state with fluorobenzofuran-4-yl] -propyl] acetamide. This material was combined with similar products resulting from the same reaction and in 25 ml of acetic acid containing 10% palladium on charcoal (50 mg, 50% wet paste) and 5% platinum on charcoal (50 mg) at 170 psi and 75 ° C. Further hydrogenation was carried out for 24 hours. This solution was filtered and evaporated, the residue was dissolved in dichloromethane, washed with 4% sodium bicarbonate and dried evaporated to yield 0.68 g of the title compound as an oil.

Tlc (ethyl acetate) Rf 0.27

Mass spectrum MH ⁺ 238

Example 27

Cyclopropane carboxylic acid [3- (2,3-dihydro-5-fluorobenzofuran-4-yl) propyl] -amide

3- (2,3-dihydro-5-fluorobenzofuran-4-yl) -propylamine hydrochloride (0.27 g) in 5 ml of dichloromethane containing 0.5 ml of triethylamine was cooled in ice. Cyclopropanecarbonyl chloride (0.12 ml) was added and stirring continued for 2 hours at 5 ° C. and 16 hours at room temperature. The mixture was washed with water and passed through a solid phase extraction cartridge using ethyl acetate / hexanes (1: 1) to yield 0.21 g of the title compound as a white solid.

Tlc (ethyl acetate / hexane 1: 1) Rf 0.25

Mass spectrum MH ⁺ 263

Claims (18)

Compounds of formula (I) and pharmaceutically acceptable solvates thereof. <Formula I> Wherein R ¹ and R ² may be the same or different and represent H, C _1-6 alkyl, C _3-7 cycloalkyl or aryl, R ³ and R ⁴ may be the same or different and represent H, halogen, C _1-6 alkyl, or substituted aryl, R ⁵ represents H or C _1-6 alkyl, n is an integer of 0, 1 or 2, m is an integer of 1, 2, 3 or 4, The dashed line indicates the presence or absence of additional binding. Compounds of Formula 1a and pharmaceutically acceptable solvates thereof. <Formula 1a> Wherein R ¹ and R ² may be the same or different and represent H, C _1-6 alkyl or substituted alkyl, C _3-7 cycloalkyl or aryl, R ³ and R ⁴ may be the same or different and represent H, halogen or C _1-6 alkyl, n is an integer of 0, 1 or 2, The dashed line indicates the presence or absence of additional binding. The compound of claim 1 or 2 wherein R ³ and R ⁴ are hydrogen, halogen and C _1-3 alkyl. The compound of claim 3, wherein the halogen is chlorine and / or fluorine. The compound of claim 1 or 2, wherein R ¹ and R ² are hydrogen, C _1-3 alkyl or C _3-5 cycloalkyl. The compound of claim 5, wherein R ¹ is methyl or cyclopropyl. The compound of claim 6, wherein at least one of R ¹ and R ² is hydrogen. 8. A compound according to any one of claims 1 to 7, wherein n is zero. Compounds of Formula 1b and pharmaceutically acceptable solvates thereof (eg hydrides). <Formula 1b> Wherein R ¹ and R ² may be the same or different and represent H, C _1-6 alkyl or substituted alkyl, C _3-7 cycloalkyl or aryl, R ³ and R ⁴ may be the same or different and represent H, halogen, or C _1-6 alkyl or substituted aryl, n is an integer of 0 or 1, m is an integer of 2, 3, 4 or 5, The dashed line indicates the presence or absence of additional binding. Compounds of Formula 1c and pharmaceutically acceptable solvates thereof (eg hydrides). <Formula 1c> Wherein R ¹ and R ² may be the same or different and represent H, C _1-6 alkyl or C _3-7 cycloalkyl, R ³ and R ⁴ may be the same or different and represent H, halogen, or C _1-6 alkyl, R ⁵ represents H or C _1-6 alkyl, n is an integer of 0 or 1, m is an integer of 1, 2, 3 or 4, The dashed line indicates the presence or absence of additional binding. N- [3- (2,3-Dihydro-benzofuran-4-yl) -propyl] acetamide, cyclopropanecarboxylic acid- [3- (2,3-dihydro-benzofuran-4-yl) -Propyl] amide, cyclopropanecarboxylic acid- [3- (5-chloro-2,3-dihydro-benzofuran-4-yl) propyl] amide, cyclopropanecarboxylic acid- [3- (5-chloro -7-fluoro-2,3-dihydro-benzofuran-4-yl) propyl] amide, cyclopropanecarboxylic acid- [3- (5-chloro-7-fluoro-benzofuran-4-yl) -Propyl] -amide, cyclopropanecarboxylic acid-[(3-benzofuran-4-yl) -propyl] -amide, cyclopropanecarboxylic acid (3-chroman-5-yl-propyl) -amide, N -[3- (2,3-dihydro-5-fluorobenzofuran-4-yl) propyl] acetamide, cyclopropanecarboxylic acid [3- (2,3-dihydro-5-benzofuran-4 -Yl) propyl] amide. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 and at least one pharmaceutically acceptable carrier thereof. A compound according to any one of claims 1 to 11, comprising mixing a compound of formula (I) according to any one of the preceding claims with at least one pharmaceutically acceptable carrier thereof. A process for the preparation of a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable carrier thereof. 12. A compound of formula I according to any one of claims 1 to 11 for treatment. A compound of formula (I) according to any one of claims 1 to 11 for use in the manufacture of a medicament for the treatment of a disease associated with the inhibitory function of a system controlled by melatonin. 12. Treatment of mammals, including humans, comprising administering an effective amount of a compound of formula (I) according to any one of claims 1 to 11 for the treatment of diseases associated with the inhibitory function of a melatonin controlled system. Way. (A) acylating the compound of formula II, or (B) A process for preparing a compound of formula (I) according to any one of claims 1 to 11, which comprises cyclizing the compound of formula (XI). <Formula II> <Formula XI> Compounds of Formulas II, III, IV, V, VI, VII, VIII, IX, XI, XII, XIII, XIV, XV, XVI, XVII and XVIII.