WO2000076990A1

WO2000076990A1 - New compounds

Info

Publication number: WO2000076990A1
Application number: PCT/SE2000/001250
Authority: WO
Inventors: Yevgeni Besidski; Britt-Marie Swahn
Original assignee: Astrazeneca Ab
Priority date: 1999-06-16
Filing date: 2000-06-15
Publication date: 2000-12-21
Also published as: SE9902267D0; AU6032100A

Abstract

The present invention relates to certain aminoalkyl substituted heterocyclic compounds of formula (I), and pharmaceutically acceptable salts thereof, which exhibit good analgesic properties and are particularly effective in the treatment of chronic pain.

Description

NEW COMPOUNDS

TECHNICAL FIELD

The present invention relates to novel heterocyclic compounds, and pharmaceutically acceptable salts thereof, with an analgesic effect. The compounds of the invention can thus be used in the prevention and treatment of pain. The compounds of the invention are I₂ receptor ligands and/or sodium channel blockers and these compounds are useful in the treatment of disorders known to be responsive to the I₂ receptor and to blockade of sodium channels, especially in the treatment of disorders such as chronic pain. In further aspects, the invention relates to compounds for use in therapy; to processes for preparation of such new compounds; to pharmaceutical compositions containing at least one compound of the invention, or a pharmaceutically acceptable salt thereof, as active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use indicated above. The invention also relates to new intermediates for use in the preparation of the novel compounds.

BACKGROUND ART

Certain 2-(aminoalkyl)coumarans are known as antidepressants from U.S. Patent No. 3,513,239 and some 2-(aminomethyl)coumarans are known as analgesic agents from Hirose et al. in Chem. Pharm. Bull. 1976, 24, 2661-2667 and 2912-2917.

However, there remains a need for new therapeutic agents to cure chronic pain. Chronic pain can be caused by injury to nerves or by a variety of lesions. As of today there is no clear understanding why they elicit pain. Medical doctors often find even strong analgesics, such as opioids, distressfully inefficacious when the pain state is involving the nervous system itself, peripheral as well as central. These pain states are often referred to as neuropathic pain. As a final resort clinicians often prescribe drugs which are not considered true analgesics but which by trial and error have been found partly useful. Such agents include tricyclic antidepressants, for example amitriptylin, anticonvulsants like carbamazepine and gabapentin, and some local anesthetics and an ti arrhythmic s, especially mexiletine.

It has surprisingly been found that certain aminoalkyl substituted heterocyclic compounds exhibit good analgesic properties and are particularly effective in the treatment of chronic pain.

DISCLOSURE OF THE INVENTION

It has surprisingly been found that compounds of the Formula I, which are aminoalkyl substituted heterocyclic compounds are particularly effective analgesic compounds and thereby suitable in the treatment of pain.

In one aspect, the invention thus relates to compounds of the general Formula I

or a pharmaceutically acceptable salt thereof, wherein R - R is independently selected from a group consisting of a) H, b) C]-C₆ alkyl, c) aiyl Ci-C_fs alkyl, d) Cj -Cg alkenyl, and

e) halogenated Ci -Cβ alkyl,

fs i

R - R is independently selected from a group consisting of a) H b) C]-C₆ alkyl,

c) aryl Cj -Cό alkyl,

d) amino C] -C6 alkyl,

e) Cj-C6 alkylamino C_rC₆ alkyl,

f) C]-C₆ alkoxy C_rC₆ alkyl,

g) C]-C₆ alkenyl,

h) halogenated C1-C6 alkyl, and

i) cycloalkyl Cj -C2 alkyl

(R , R ), (R , R ) and (R , R ) may, together with the carbon or nitrogen atoms to which they are bonded, form a saturated or unsaturated 4, 5, 6, 7, or 8 membered ring, optionally containing one or more heteroatoms.

8 1 1 R - R is independently selected from a group consisting of

a) H, b) C_rC₆ alkyl,

c) aryl - alkyl, d) OH, e) Cj-C6 alkoxy,

f) aryl Cj -Cό alkoxy, g) halogenated alkoxy, h) Cj-Cg alkylcarbonyloxy,

i) NO₂, j) NH₂, k) C]-C6 alkylamino,

1) Cj-Cg alkylcarbonylamino,

m)Cι-C6 alkoxycarbonylamino, n) halogen, o) cyano p) substituted or unsubstituted carbamoyl, q) Cj-C6 alkylcarbonyl, r) arylcarbonyl, s) aryl Cj-C6 alkylcarbonyl, t) Cj-C6 alkoxycarbonyl, and u) Cι -C6 alkylthio,

(R , R ), (R , R ) and (R , R ) may, together with the carbon atoms to which they are attached, form a further saturated or unsaturated 5, 6, 7 or 8-membered ring, optionally containing one or more further heteroatoms, and/or substituted with one or more substituents selected from halogen, C_j-Cg alkyl, Cj-Cg alkoxy, CF₃, OH, amino, C_j-Cg alkyl-NH- or (C,-C₆ alkyl)₂-N-;

m is zero or 1 n is zero or 1 ,

N inside the aryl moiety means that one of the carbon atoms in the aryl group optionally may be replaced with a nitrogen atom, provided that when the aryl group is benzene then at least one of the substituents R - R has to be other than hydrogen, and

excluding the racemic compounds l-(2,3-dihydro-l-benzofuran-2-yl)ethylamine, N-[ l-(2,3- dihydro- 1 -benzofuran-2-yl)ethyl]-N-methylamine, N-[ 1 -(2,3-dihydro- 1 -benzofuran-2- yl)ethyl]-N,N-dimethylamine, l-(7-methyl-2,3-dihydro-l-benzofuran-2-yl)ethylamine, N- methyl-N-[ 1 -(7-methyl-2,3-dihydro- 1 -benzofuran-2-yl)ethyl]amine, N,N-dimethyl-N-[ 1 -(7- methyl-2,3-dihydro-l-benzofuran-2-yl)ethyl]amine.

The pure enantiomers, racemic mixtures, except as specified above, and unequal mixtures of the enantiomers are within the scope of the invention. It should be understood that also all the diastereomeric forms possible are within the scope of the invention.

It will also be appreciated by those skilled in the art, although derivatives of compounds of formula I may not possess pharmacological activity as such, they may be administered parenterally or orally and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All prodrugs of compounds of formula I are included within the scope of the invention.

Depending on the process conditions the final products of the Formula I are obtained either in neutral or salt form. Both the free base and the salts of these end products are within the scope of the invention.

Acid addition salts of the new compounds may in a manner known per se be transformed into the free base using basic agents, such as alkali or by ion exchange. The free base obtained may also form salts with organic or inorganic acids.

In the preparation of acid addition salts, preferably such acids are used which form pharmaceutically acceptable salts. Examples of such acids are hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic carboxylic or sulfonic acids, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid.

Preferred compounds of the invention are those of Formula I wherein R - R is independently selected from a group consisting of

a) H, b) C]-C6 alkyl, and

c) halogenated Cj-C6 alkyl,

R is independently selected from a group consisting of

a) H b) Cι-C₆ alkyl,

c) aryl Cj-Cg alkyl,

d) amino Ci -C alkyl, and

e) Cj-Cό alkylamino C_j-C₆ alkyl,

(R , R ), (R , R ) and (R , R ) may, together with the carbon or nitrogen atoms to which they are bonded form a saturated or unsaturated 4, 5, 6, 7, or 8 membered ring, optionally containing one or more heteroatoms.

8 1 1 R - R is independently selected from a group consisting of

a) H, b) C]-C₆ alkyl, c) OH, d) C]-C6 alkoxy, e) halogenated alkoxy, 5 0 NO₂,

g) NH₂,

h) C]-C6 alkylamino,

i) C]-C6 alkylcarbonylamino, j) halogen, 0 k) cyano

1) substituted or unsubstituted carbamoyl, m)C]-C6 alkylcarbonyl, n) arylcarbonyl, o) aryl Cj -Cg alkylcarbonyl, and

s p) Cj-Cg alkyl thio,

(R , R ), (R , R ) and (R , R ) may, together with the carbon atoms to which they are attached, form a further saturated or unsaturated 5, 6, 7 or 8-membered ring, optionally containing one or more further heteroatoms, and/or substituted with one or more o substituents selected from halogen, Cj-Cg alkyl, C_]-Cg alkoxy, CF₃, OH, amino, C_]-C₆ alkyl-NH-, or (C_j-C₆ alkyl)₂-N-;

m is zero or 1 n is zero or 1 , 5

N inside the benzene moiety means that one of the carbon atoms in the aryl group optionally may be replaced with a nitrogen atom, provided that when the aryl group is benzene then at least one of the substituents R - R has to be other than hydrogen, and excluding the racemic compounds l-(2,3-dihydro-l-benzofuran-2-yl)ethylamine, N-[ l-(2,3- dihydro- 1 -benzofuran-2-yl)ethyl]-N-methylamine, N-f 1 -(2,3-dihydro- 1 -benzofuran-2- yl)ethyl]-N,N-dimethylamine, 1 -(7-methyl-2,3-dihydro- 1 -benzofuran-2-yl)ethylamine, N- methyl-N-[ l-(7-methyl-2,3-dihydro-l-benzofuran-2-yl)ethyl]amine, N,N-dimethyl-N-[ l-(7- methyl-2,3-dihydro-l-benzofuran-2-yl)ethyl]amine.

More preferred compounds of the invention are those of Formula I wherein R - R is independently selected from a group consisting of

a) H, and b) C]-C₆ alkyl,

R is independently selected from a group consisting of a) H b) Cι-C^"6 alkyl,

c) aryl C]-C₆ alkyl,

d) amino C\-C(, alkyl, and

e) Cj -Cό alkylamino C_rC₆ alkyl,

8 1 1 R - R is independently selected from a group consisting of a) H, b) Cι-C₆ alkyl, c) Ci-Cg alkoxy, d) ΝO₂, e) NH₂, and f) halogen m is zero or 1 n is zero or 1

N inside the benzene moiety means that one of the carbon atoms in the aryl group optionally may be replaced with a nitrogen atom, provided that when the aryl group is benzene then at least one of the substituents R - R has to be other than hydrogen, and

excluding the racemic compounds l-(2,3-dihydro-l-benzofuran-2-yl)ethylamine, N-[l-(2,3- dihydro- 1 -benzofuran-2-yl)ethyl]-N-methylamine, N-[ 1 -(2,3-dihydro- 1 -benzofuran-2- yl)ethyl]-N,N-dimethylamine, l-(7-methyl-2,3-dihydro-l-benzofuran-2-yl)ethylamine, N- methyl-N-[l-(7-methyl-2,3-dihydro-l-benzofuran-2-yl)ethyl]amine, N,N-dimethyl-N-[l-(7- methyl-2,3-dihydro-l-benzofuran-2-yl)ethyl]amine.

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

The term "C_j-Cg alkyl" denotes a straight or branched, substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms. Examples of said alkyl include, but is not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.

The term "Cι-C₆ alkoxy" denotes a group O-alkyl, wherein alkyl is as defined above.

The term "halogen" includes fluoro, chloro, bromo and iodo groups.

The term "aryl" denotes a substituted or unsubstituted C..-C14 aromatic hydrocarbon and includes, but is not limited to, benzene, naphtalene, indene, antracene, fenantrene, and fluorene The term "substituted" denotes an Cj-C₆ alkyl, C|-C₆ alkylaryl or aryl group as defined above which is substituted by one or more alkyl, alkoxy, halogen, amino, thiol, nitro, hydroxy, acyl or cyano groups.

The term "heteroatoms" denotes a nitrogen, oxygen, sulfur, phosphorous atom.

It has furthermore surprisingly been found that certain enantiomers of the compounds of the invention possess a higher analgesic activity than other enantiomers and are thus preferred for therapeutic use before the latter and the racemic mixtures.

Another aspect of the present invention is therefore the enantiomers of the compounds of the general Formula I.

PREPARATION

The compounds of the present invention can be prepared by methods known in the art using commercially available or readily prepared starting materials. The heterocyclic part of the compounds of the invention can be synthesized using several different synthetic routes. Some general procedures for the synthesis of the heterocyclic nucleus are described below.

The furan derivative (II) can be synthesized by a condensation reaction between a suitably substituted aromatic rtb -hydroxyaldehyde or ortbø-hydroxyarylalkylketone and chloroacetone, chloroacetaldehyde or ethyl chloroacetate as described by Elliot E. D. in J. Am. Chem. Soc. 1951, 73, 754.

The furan derivative (HI) can be synthesized using a palladium catalyzed reaction between a suitably substituted rtbo-iodophenol or ørtbo-iodopyridinol and an alkyne as described by Arcardi A. et al. in Synthesis 1986, 749.

The coumarin derivatives can be prepared by standard procedures as described by Gilchrist T.L, in Heterocyclic Chemistry, Pitman, 1985. Subsequent hydrogenation of the double bond and reduction of the lactone with diisobutyl aluminium hydride afforded the desired chroman-2-ol derivatives (IN).

The present invention also provides the following processes A, B and C for the preparation of compounds of the general Formula I.

Process A

Process A for the preparation of compounds of the general Formula I comprises the following steps:

a) Compounds of the general Formula II

can be reacted with amino compounds of the general Formula V,

■ 6

R^L

I (V)

.7/ NH

wherein R and R are as defined in Formula I, to give the amine of the Formula VI. The reaction can be carried out under standard conditions in an inert solvent.

b) Compounds of the general Formula VI can be reduced e.g. by using hydrogen and a catalyst such as Pd/C to give compounds of the Formula I. The reactions can be carried out in an inert solvent under standard conditions.

Process B

Process B for the preparation of compounds of the general Formula I comprises the following steps:

a) Compounds of the general Formula HI

can be reacted with an azide, like diphenylphosphoryl azide or sodium azide, to give the azide derivative of the general Formula NIL These reactions can be carried out under standard conditions in an inert solvent.

b) Using hydrogen and a catalyst such as Pd/C the compounds of the general Formula VII can be reduced to give compounds of the general Formula VHI. The reactions can be carried out in an inert solvent under standard conditions.

c) Compounds of the general Formula VHI can be alkylated using a) an alkyl halide, b) reductive alkylation using an alkylaldehyde and sodium cyanoborohydride, c) acylation with an acid chloride, to form an amide, which is subsequently reduced with lithium aluminium hydride or sodium bis(2-methoxyethoxy)aluminium hydride or borane-methyl sulfide complex to give compounds of the general Formula I. These reactions can all be carried out under standard conditions in an inert solvent.

Process C

Process C for the preparation of compounds of the general Formula I comprises the following steps:

a) Compounds of the general Formula IV can be reacted with an alkyl nitro compound under basic conditions in an inert solvent to yield compounds of the general Formula LX

b) Compounds of the general Formula LX can be reduced with Raney nickel in an inert solvent under standard conditions to yield compounds of the general Formula X.

c) Compounds of the general Formula X can be alkylated using a) an alkyl halide, b) reductive alkylation using an alkylaldehyde and sodium cyanoborohydride, c) acylation with an acid chloride, to form an amide, which is subsequently reduced with lithium aluminium hydride or sodium bis(2-methoxyethoxy)aluminium hydride or borane-methyl sulfide complex to give compounds of the general Formula I. These reactions can all be carried out under standard conditions in an inert solvent. The compounds of the invention can then be separated into pure stereoisomers by chromatography or via fractional crystallizations, or after derivatisation to yield a diastereomeric mixture that can be separated by chromatography or via fractional crystallizations.

MEDICAL USE

In a further aspect, the present invention relates to compounds of the formula I, or a pharmaceutically acceptable salt thereof for use in therapy, in particular for use in the treatment and/or prophylactics of pain, anxiety, mania, depression, panic disorders and/or aggression. The invention also provides the use of a compound of the formula I in the manufacture of a medicament for the treatment of pain, anxiety, mania, depression, panic disorders and/or aggression.

The compounds of the invention are useful in therapy, especially for the treatment of pain of widely different origins and causes and include acute as well as chronic pain states. Examples are pain caused by chemical, mechanical, radiation, thermal, infectious or inflammatory tissue trauma or cancer, postoperative pain, headache and migraine, various arthritic and inflammatory conditions such as osteo- and rheumatoid arthritis, myofascial and low back pain.

Also neuropathic conditions of central or peripheral origin can be treated with the compounds of the invention. Examples of these pain conditions are trigeminal neuralgia, postherpetic neuralgia (PHN), diabetic mono/poly neuropathy, nerve trauma, spinal cord injury, central post stroke, multiple sclerosis and Parkinson's disease.

Other pain states of visceral origin such as caused by ulcer, dysmenorrhea, endometriosis, IBS, dyspepsia etc. can also be treated with the compounds of the invention. The compounds of the invention are useful in disease states with inappropriate neuronal activity or in neuroprotection for example as anticonvulsants in epilepsy, in the treatment of itch, tinnitus, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), Alzheimer, stroke, traumatic bram injury, Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including arcadian rhythm disorders, insomnia & narcolepsy), tics (e g Tourette's syndrome), and muscular rigidity (spasticity)

The compounds of the invention are also useful for treatment of effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines

PHARMACEUTICAL FORMULATIONS

In yet a further aspect, the invention relates to pharmaceutical compositions containing at least one compound of the present invention, or a pharmaceutically acceptable salt thereof, as active ingredient

For clinical use, the compounds of the invention are formulated into pharmaceutical formulations for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other mode of administration The pharmaceutical formulation contains a compound of the invention in combination with one or more pharmaceutically acceptable ingredients The carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule These pharmaceutical preparations are a further object of the invention Usually the amount of active compounds is between 0 1-95% by weight of the preparation

In the preparation of pharmaceutical formulations containing a compound of the present invention the compound selected may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or pressed into tablets.

Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives or gelatine.

Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.

Liquid preparations may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing the active ingredient and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation to by reconstituted with a suitable solvent before use. The typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 0.1 to 1000 mg, per day, of active substance.

The compounds according to the present invention can also be used in formulations, together or in combination for simultaneous, separate or sequential use, with other active ingredients, e.g. opioids, like morphine and fentanyl; NMDA antagonists, like ketamine and remacemide; lighter analgesic, like acetylsalicylic acid and paracetamol; and β- blockers, like propranolol.

INTERMEDIATES

A further aspect of the invention is new intermediate compounds which are useful in the preparation of compounds according to the invention.

Thus, the invention includes compounds of the general formula XI

wherein R - -R , m, and n are as defined for Formula I and Y is N3 or NO₂, and compounds of the general formula XIa

wherein R - -R , m, and n are as defined for Formula I and Y is N3, NH₂ or NO₂.

EXAMPLES

The invention will now be described in more detail with the following examples that are not to be construed as limiting the invention.

All chemicals and reagents were used as received from suppliers. C nuclear magnetic resonance (NMR) spectra were recorded on a Varian Unity 400 (400 MHz) spectrometer. Silica gel and flash column chromatography were carried out on silica gel 60 (230-400 mesh).

Example 1: l-(2,3-Dihvdro-l-benzofuran-2-yl)-ethylamine.

A solution of benzofuran-2-yl methyl ketone (2.0 g, 12.5 mmol) in methanol (40 ml) was stirred with 4 A molecular sieves (1.0 g) as ammonium acetate (10.0 g, 125 mmol) was added. After the addition of sodium cyanoborohydride (0.78 g, 12.5 mmol), the reaction mixture was stirred 48 h at room temperature under a nitrogen atmosphere. The reaction mixture was filtered, concentrated on a rotary evaporator thereafter diluted with 10% NaOH solution and extracted twice with dichloromethane. The combined organic layers were dried (MgSO₄), filtered, and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel with ethyl acetate as eluent to give 1.0 g of 1 - (benzofuran-2-yl)ethylamine.

A mixture of the obtained l-(benzofuran-2-yl)ethylamine (0.7 g, 4.3 mmol) and Pd/C 10% (OJg) in acetic acid (20 ml) was hydrogenated at 50 psi in a Parr apparatus for 18 h. The mixture was filtered and the solvent was evaporated in vacuo to yield a residue which was diluted with 25% NaOH solution and dichloro methane. The organic layer was discarded and dried (MgSO₄), filtered and then concentrated on a rotary evaporator to yield 0.60 g of l-(2,3-dihydro-l-benzofuran-2-yl)ethylamine as a 1 : 1 mixture of diastereomers. C NMR (CDC1₃, 400MHz): δ 18.1, 18.8, 29.9, 32.4, 49.2, 50.9, 86.9, 88.0, 108.8, 109.0, 120.0, 120.1 , 124.6, 124.7, 126.5, 127.6, 127.7, 159.2, 159.5.

Isolation of individual stereoisomers of l-(2.3-dihydro-benzofuran-2-yl)-ethylamine. l-((R)-2,3-dihydro-benzofuran-2-yl)-(R)-ethylamine, l-((S)-2,3-dihvdro-benzofuran-2-yl)- (S)-ethylamine, l-((S)-2,3-dihvdro-benzofuran-2-yl)-(R)-ethylamine and l-((R)-2,3- dihydro-benzofuran-2-yl)-(S)-ethylamine:

l-(2,3-Dihydro-benzofuran-2-yl)-ethylamine was separated into the corresponding diastereoisomers by passing the substance (5 g, 30.6 mmol) through a column packed with silica gel (200 g) using 30 to 50% acetone in heptane as an eluent. A complete separation was achieved after a second elution to yield a racemic (R,S and S,R) [l-(2,3-dihydro- benzofuran-2-yl)-ethyl]-isopropylidene-amine, the faster fraction, 2.65 g (84%) and a racemic (R,R and S,S) [l-(2,3-dihydro-benzofuran-2-yl)-ethyl]-isopropylidene-amine, the slower fraction, 2.24 g (72%). Racemate (R,S and S,R) [l-(2,3-dihydro-benzofuran-2-yl)- ethyl] -isopropylidene-amine was treated with 10% HCl at 40°C for 0.5 h; the solution was neutralised with sodium carbonate and extracted with chloroform (3x50 ml). The extract was dried over sodium sulfate and concentrated in vacuum to leave a racemic (R,S and S,R) l-(2,3-dihydro-benzofuran-2-yl)-ethylamine (1.87 g, 88%). A similar treatment of racemate (R,R and S,S) [l-(2,3-dihydro-benzofuran-2-yl)-ethyl]-isopropylidene-amine yielded (R,R and S,S) l-(2,3-dihydro-benzofuran-2-yl)-ethylamine (1.62 g, 90%). Racemate (R,R and S,S) l-(2,3-dihydro-benzofuran-2-yl)-ethylamine was dissolved in dichloromethane (40 ml); to that solution R-methoxymandelic acid (1.73 g, 10.5 mmol) was added followed by dicyclohexylcarbodiimide (2.9 g, 14 mmol). The mixture was stirred for 4 h at room temperature before it was quenched with methanol. The volatiles were removed in vacuo. The residue was chromatographed twice on a column packed with silica gel (100 g) using 20 to 30% ethyl acetate in heptane as eluent leading to (R)-N-[l- (R)-(2,3-dihydro-benzofuran-2-yl)-ethyl]-(R)-2-methoxy-2-phenylacetamide, the faster fraction, 1.13 g (73%) and (S)-N-[ l-(S)-(2,3-dihydro-benzofuran-2-yl)-ethyl]-(R)-2- methoxy-2-phenylacetamide, the slower fraction, 1.02 g (66%). A similar treatment of racemate (R,S and S,R) l-(2,3-dihydro-benzofuran-2-yl)-ethylamine yielded (R)-N-[l-(S)-(2,3-dihydro-benzofuran-2-yl)-ethyl]-(R)-2-methoxy-2- phenylacetamide, the faster fraction, 1.34 g (75%) and (S)-N-[l-(R)-(2,3-dihydro- benzofuran-2-yl)-ethyl]-(R)-2-methoxy-2-phenylacetamide, the slower fraction, 1.36 g (76%).

Compound (R)-N-[l-(R)-(2,3-dihydro-benzofuran-2-yl)-ethyl]-(R)-2-methoxy-2- phenylacetamide was refluxed in 20% hydrochloric acid (30 ml) for 6 h. The volatiles were removed in vacuo. The residue was dissolved in water and extracted with chloroform (2x30 ml). The organic phase was discarded. The water phase was made alkaline with potassium carbonate, and the product was extracted with chloroform (3x40 ml). The extract was dried over sodium sulfate and concentrated in vacuo to leave l-((R)-2,3-dihydro-benzofuran-2- yl)-(R)-ethylamine (0.53 g, 90%). A similar treatment of compounds (S)-N-[l-(S)-(2,3- dihydro-benzofuran-2-yl)-ethyl]-(R)-2-methoxy-2-phenylacetamide, (R)-N-[l-(S)-(2,3- dihydro-benzofuran-2-yl)-ethyl]-(R)-2-methoxy-2-phenylacetamide, and (S)-N-[l-(R)-(2,3- dihydro-benzofuran-2-yl)-ethyl]-(R)-2-methoxy-2-phenylacetamide gave rise to respectively l-((S)-2,3-dihydro-benzofuran-2-yl)-(S)-ethylamine (0.40 g, 75%), l-((S)-2,3- dihydro-benzofuran-2-yl)-(R)-ethylamine (0.57 g, 81%) and l-((R)-2,3-dihydro- benzofuran-2-yl)-(S)-ethylamine (0.47 g, 66%).

Example 2: l-(2,3-Dihydro-l-benzofuran-2-yl)-N-ethyl-l-ethanamine was synthesized as described for l-(2,3-dihydro-l-benzofuran-2-yl)-ethylamine by using ethylamine in the reductive amination. ¹³C ΝMR (CDC1₃, 400MHz): δ 1 1.3 1 1.5, 121.6,

32.5, 32.8, 39.9, 40.8, 56.2, 56.3, 80.7, 81.9, 109.4, 109.9, 120.9, 121.1, 124.8, 125.0, 125.1, 128.2, 128.3, 158.3, 159.1.

Example 3: l-ri-(2,3-Dihvdro-l-benzofuran-2-yl)ethyl]pyrrolidine was synthesized as described for l-(2,3-dihydro-l-benzofuran-2-yl)-ethylamine by using pyrrolidine in the reductive amination. ¹³C ΝMR (CDC1₃, 400MHz): δ 12.7, 23.5, 33.4,

49.5, 51.4, 80.7, 109.1, 120.8, 125.8, 127.7, 128.2, 159.1.

Example 4:

1 -(2,3-Dihydro- 1 -benzofuran-2-yl)propylamine To l-(l-benzofuran-2-yl)-l-propanone (0.11 g, 0.65 mmol) in ethanol hydroxylamine (0.068 g, 0.97 mmol) and triethylamine (0.134 ml, 0.97 mmol) were added at room temperature. After heating to 80 °C for 30 minutes the mixture was stirred over night at room temperature. Then the solvent was evaporated in vacuo to yield a residue which was partitioned between ethyl acetate and saturated sodium hydrogencarbonate. The organic layer was discarded and dried (MgSO₄), filtered and then concentrated on a rotary evaporator to yield 0.121 g of 1 -( 1 -benzofuran-2-yl)- 1 -propanone oxime. A mixture of the obtained l-(benzofuran-2-yl)-l -propanone oxime (0.12 g, 0.63 mmol) and Pd/C 10% (O.lg) in methanol (10 ml) was hydrogenated at 50 psi in a Parr apparatus for 48 h. The mixture was filtered and the solvent was evaporated in vacuo to yield 0.1 g of 1- (2,3-dihydro-l-benzofuran-2-yl)propylamine. ¹³C ΝMR (CDC1₃, 400MHz): δ 18.7, 33.6,

35.6, 52.9, 94.9, 109.3, 120.9, 121.1, 125.8, 127.2,163.9.

Example 5:

1 -(2,3-Dihydro-5-nitro- 1 -benzofuran-2-yl)ethylamine A solution of l-(2,3-dihydro-5-nitro-l-benzofuran-2-yl)-l-ethanone (0.17 g, 0.82 mmol) in methanol (4 ml) was stirred with 4A molecular sieves (0.5 g) as ammonium acetate ( 0.63 g, 8.2 mmol) was added. After the addition of sodium cyanoborohydride (0.05 g, 0.82 mmol), the reaction mixture was stirred 48 h at room temperature under a nitrogen atmosphere. The reaction mixture was filtered, concentrated on a rotary evaporator thereafter diluted with 10% NaOH solution and extracted twice with dichloromethane. The combined organic layers were dried (MgSO₄), filtered, and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel with ethyl acetate as eluent to yield 0.090 g of l-(2,3-dihydro-5-nitro-l-benzofuran-2-yl)ethylamine as a 1 : 1 mixture of diastereomers. ¹³C NMR (CDC1₃, 400MHz): δ 18.2, 19.2, 29.2, 31.6, 49.0, 50.9, 89.6, 90.5, 108.7, 109.0, 121.1, 121.2, 125.6, 125.7, 128.4, 128.5, 141.7, 164.9, 165.2.

Example 6:

1 -(5-Amino-2,3-dihydro- 1 -benzofuran-2-yl)ethylamine A mixture of l-(2,3-dihydro-5-nitro-l-benzofuran-2-yl)ethylamine (0.03 g, 0.14 mmol) and Pd/C 10% (O.lg) in methanol (5 ml) was hydrogenated at atmosphere pressure for 48 h. The mixture was filtered and the solvent was evaporated in vacuo to yield 0.03 g of l-(5- amino-2,3-dihydro-l-benzofuran-2-yl)ethylamine. ¹³C NMR of the hydrochloride in D₂O: δ 10.8, 13.7, 30.3, 31.8, 50.1, 50.6, 82.3, 83.7, 109.8, 110.2, 1 19.9, 120.0, 122.8, 122.9, 122.9, 128.0, 128.1, 158.0, 158.9.

Example 7:

1 -(2,3-Dihydro-7-methoxy- 1 -benzofuran-2-yl)ethylamine was synthesized from l-(7-methoxy-l-benzofuran-2-yl)-l-ethanone according to the procedure described for the synthesis of l-(2,3-dihydro-l-benzofuran-2-yl)-ethylamine. ¹³C NMR (CDC1₃, 400MHz): δ 18.2, 18.8, 29.7, 32.6, 48.6, 50.7, 55.5, 55.6, 87.8, 88.9, 110.6, 110.9, 116.8, 116.9, 120.5,120.6, 127.7, 127.7, 143.8, 143.9, 147.5, 147.7.

Example 8: l-(2,3-Dihydro-5-methoxy-l-benzofuran-2-yl)ethylamine was synthesized from l-(5-methoxy-l-benzofuran-2-yl)-l-ethanone according to the

1 ^ procedure described for the synthesis of l-(2,3-dihydro-l-benzofuran-2-yl)-ethylamine. C

NMR (CDC1₃, 400MHz): δ 18.8, 19.2, 29.8, 32.8, 48.8, 50.9, 55.5, 55.6, 87.8, 89.0, 107.9,

108.1, 1 10.5, 1 10.9, 112.3, 112.4, 126.8, 153.8, 154.0.

Example 9: l-(5-Bromo-2,3-dihvdro-l-benzofuran-2-yl)ethylamine

To a stirred solution of l-(2,3-dihydro-l-benzofuran-2-yl)-ethylamine (1.6 g, 10 mmol) in acetic acid (15 ml) Br₂ (1.6 g, 10 mmol) in acetic acid (5 ml) was added dropwise at room temperature. The solution was stirred over night. The precipitated HBr-salt was filtered off.

Recrystallisation from acetic acid yielded 2.3 g of the HBr-salt of l-(5-bromo-2,3-dihydro- l-benzofuran-2-yl)ethylamine. ¹³C NMR (CDC1₃, 400MHz): δ 18.4, 33.9, 45.2, 88.5,

108.5, 109.5, 126.8, 127.9, 130.3,158.8.

Example 10:

N-r2-(Diethylamino)ethvIl-N-[l-(7-methoxy-2,3-dihydro-l-benzofuran-2-yl)ethvnamine was synthesized from l-(7-methoxy-l-benzofuran-2-yl)-l-ethanone by using 2- diethylaminoethylamine in the reductive amination according to the procedure described for the synthesis of l-(2,3-dihydro-l-benzofuran-2-yl)-ethylamine. ¹³C ΝMR (CDC1₃, 400MHz): δ 1 1.6, 15.2, 31.1, 44.9, 46.8, 48.6, 52.7, 55.8, 86.8, 111.4, 1 16.9, 120.4, 128.1, 144.1, 147.7.

Example 1 1 :

N-ri-(2,3-Dihydro-l-benzofuran-2-yl)ethyll-N-(3-phenylpropyl)amine was synthesized from l-(l-benzofuran-2-yl)-l-ethanone by using 3-phenyl-l-propylamine in the reductive amination according to the procedure described for the synthesis of l-(2,3- dihydro-l-benzofuran-2-yl)-ethylamine. ¹³C ΝMR (CDC1₃, 400MHz): δ 15.5, 31.2, 32.2,

33.9, 46.1, 56.2, 86.2, 108.2, 120.1, 120.3, 126.1, 127.2, 127.3, 127.7, 127.8, 127.9, 128.5, 142.0, 159.7. Example 12:

N-ri-(2,3-Dihvdro-l-benzofuran-2-yl)ethyll-N-[3-(l-pyrrolidinyl)propyl]amine was synthesized from l-(l-benzofuran-2-yl)- 1-ethanone by using Ν-(3- aminopropyl)pyrrolidine in the reductive amination according to the procedure described for the synthesis of l-(2,3-dihydro-l-benzofuran-2-yl)-ethylamine. ¹³C NMR (CDC1₃,

400MHz): δ 15.8, 22.7, 28.3, 30.3, 32.0, 45.8, 54.2, 55.8, 86.2, 108.2, 120.0, 124.3, 126.2, 126.8, 159.5.

Example 13: N-ri-(2,3-Dihydro-l-benzofuran-2-yl)ethyl1-N-[4-(dimethylamino)butyl]amine was synthesized from l-(l-benzofuran-2-yl)- 1-ethanone by using 4- dimethylaminobuthylamine in the reductive amination according to the procedure described for the synthesis of l-(2,3-dihydro-l-benzofuran-2-yl)-ethylamine. 1 ^ C ΝMR (CDC1₃, 400MHz): δ 15.6, 25.3, 28.0, 31.6, 32.1, 45.5, 47.1, 56.2, 59.9, 86.2, 108.5, 120.1, 125.0, 127.1 , 127.9, 159.5.

Example 14:

1 -(2,3-Dihydro- 1 -benzofuran-2-yl)- 1 -methylethylamine

Methyl lithium (1.6 M in THF, 6.25 ml) was added to a solution of l-(l-benzofuran-2-yl)- 1-ethanone (1.0 g, 6.24 mmol) in THF (20 ml) at -70 °C. After stirring for 0.5 h at -70 °C water was added and the mixture was allowed to reach room temperature. The solvent was evaporated in vavuo and the residue was dissolved in ethyl acetate and extracted. The organic layer was dried (MgSO₄), filtered, and then concentrated in vacuo to yield a slightly yellow oil of 2-(l-benzofuran-2-yl)-2-propanol. Trifluoroacetic acid (3.71 ml, 48.2 mmol) was slowly added to a stirred and cooled (0 °C) mixture of sodium azide (1.25 g, 19.2 mmol) in chloroform (15 ml). The mixture was stirred for 1 h and then 2-(l-benzofuran-2-yl)-2-propanol (1.7 g, 9.6 mmol) dissolved in chloroform (10 ml) was added slowly. The mixture was stirred for 0.5 h and then ammonium hydroxide was added. The mixture was extracted with chloroform and the organic layer was dried (MgSO₄), filtered, and then concentrated in vacuo. The residue was purified by silica gel chromatography with heptane/1 % ethyl acetate as eluent to yield 1.0 g of 2-( 1 -azido- 1 -methylethyl)- 1 -benzofuran.

A mixture of the obtained 2-(l -azido- 1 -methylethyl)- 1 -benzofuran (0.9 g, 4.47 mmol) and Pd/C 10% (0.9g) in acetic acid (20 ml) was hydrogenated at 50 psi in a Parr apparatus for 8 h. The reaction mixture was filtered, concentrated on a rotary evaporator thereafter diluted with 10% NaOH solution and extracted twice with dichloromethane. The combined organic layers were dried (MgSO₄), filtered, and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel with ethyl acetate/5 % methanol as eluent to yield 0.53 g of l-(2,3-dihydro-l-benzofuran-2-yl)-l-methylethylamine. ¹³C NMR (CDC1₃, 400MHz): δ 25.9, 32.4, 60.1, 88.1, 108.5, 121.1, 123.0, 125.1, 128.1, 159.5.

Example 15:

N-f 1 -(2,3-Dihydro- 1 -benzofuran-2-yl)- 1 -methylethyl] -N-ethyl amine

To a stirred and cooled (0 °C) mixture of l-(2,3-dihydro-l-benzofuran-2-yl)-l- methylethylamine (0.53 g, 2.99 mmol) and triethyl amine (0.63 ml, 4.48 mmol) in dichloromethane (10 ml) acetyl chloride (0.32 ml, 4.48 mmol) dissolved in dichloromethane (10 ml) was added. The mixture was allowed to reach room temperature and was stirred over night. Saturated sodium hydrogencarbonate solution was added and the mixture was extracted with dichloromethane. The organic layer was discarded and dried (MgSO₄), filtered, and then concentrated in vacuo to yield 0.4 g of crude N-[l-(l- benzofuran-2-yl)-l-methylethyl]acetamide which was dissolved in THF (10 ml) and treated with borane-methyl sulfide complex (2 M in THF, 2.0 ml). The mixture was refluxed for 1 h and then concentrated in vacuo. The residue was dissolved in ethanol (10 ml) then HCl in ethanol was added and the mixture was refluxed for 0.5 h. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and saturated sodium hydrogencarbonate solution. The organic layer was discarded dried (MgSO₄), filtered, and then concentrated in vacuo to yield 0.3 g of N-[l-(2,3-dihydro-l-benzofuran-2-yl)-l- methylethyl]-N-ethylamine. ¹³C ΝMR (CDC1₃, 400MHz): δ 18.2, 21.8, 22.1, 30.9, 38.2, 57.2, 88.5, 109.0, 120.1, 125.8, 127.8, 127.9, 159.8. Example 16:

N-l^" 1 -(2,3-Dihydro- 1 -benzofuran-2-yl)- 1 -methylethyl 1-NN-diethylamine was synthesized from N-[l-(2,3-dihydro-l-benzofuran-2-yl)-l-methylethyl]-N-ethylamine and acetyl chloride according to the procedure described for the synthesis of N-[l-(2,3- dihydro-l-benzofuran-2-yl)-l-methylethyl]-N-ethylamine. ¹³C ΝMR (CDC1₃, 400MHz): δ 18.1, 21.9, 23.9, 30.9, 38.2, 57.2, 89.5, 108.0, 121.1, 125.7, 126.8, 127.9, 158.8.

Example 17: N-Methyl-N-r(3-methyl-2,3-dihydro-l-benzofuran-2-yl)methyl]amine To a stirred mixture of 3-methylbenzofuran-2-carboxylic acid (1.0 g, 5.67 mmol) in toluene (20 ml) thionyl chloride (1.3 ml, 17 mmol) and 2 drops of DMF were added. The reaction mixture was heated to 70 °C for 1 h. The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (10 ml). Then a solution of methylamine (40 % in water, 1.4 ml, 17 mmol) was added at 0 °C and the mixture was stirred over night at room temperature. The solution was diluted with dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was dried (MgSO ), filtered, and then concentrated in vacuo to yield 1.0 g of N,3-dimethyl-l-benzofuran-2- carboxamide.

To a solution of N,3-dimethyl-l-benzofuran-2-carboxamide (1.0 g, 5.28 mmol) in toluene (20 ml) sodium bis(2-methoxyethoxy)aluminium hydride (3.5 M in toluene, 5 ml) was added at room temperature. Then the reaction mixture was heated to 50 °C for 2 h. The mixture was then allowed to cool to room temperature and water was added carefully. The organic layer was discarded and the water layer was washed with dichloromethane. The combined organic layers were dried (MgSO₄), filtered, and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel and dichloromethane/methanol 5: 1 as eluent to yield 0.8 g of N-methyl-N-[(3-methyl-l-benzofuran-2-yl)methyl]amine. A mixture of the obtained N-methyl-N-[(3-methyl-l-benzofuran-2-yl)methyl]amine (0.35 g, 2.0 mmol) and Pd/C 10% (0.4 g) in acetic acid (15 ml) was hydrogenated at 50 psi in a Parr apparatus for 65 h. The reaction mixture was filtered, concentrated on a rotary evaporator thereafter diluted with 10% ΝaOH solution and extracted twice with dichloromethane. The combined organic layers were dried (MgSO₄), filtered, and then concentrated in vacuo to yield 0.3 g of N-methyl-N-[(3-methyl-2,3-dihydro-l-benzofuran- 2-yl)methyl]amine. ¹³C ΝMR (CDC1₃, 400MHz): δ 14.1, 36.8, 38.2, 51.9, 85.1, 109.5, 120.5, 123.9, 128.2, 132.5, 158.5.

Example 18:

(3-Methyl-2,3-dihydro- 1 -benzofuran-2-yl)methylamine

To a stirred mixture of 3-methylbenzofuran-2-carboxylic acid (1.0 g, 5.67 mmol) in toluene

(20 ml) thionyl chloride (1.3 ml, 17 mmol) and 2 drops of DMF were added. The reaction mixture was heated to 70 °C for 1 h. The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (10 ml). Then a solution of methylamine (40 % in water, 1.4 ml, 17 mmol) was added at 0 °C and the mixture was stirred over night at room temperature. The solution was diluted with dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was dried (MgSO₄), filtered, and then concentrated in vacuo to yield 0.9 g of 3-methyl-l-benzofuran-2- carboxamide.

To a solution of 3-methyl-l-benzofuran-2-carboxamide (0.9 g, 5 mmol) in THF (5 ml) borane-methylsulfide complex (2 M in THF, 10 ml) was added. The mixture was heated to reflux for 2 h then 6 M HCl was added dropwise. The reaction mixture was concentrated in vacuo and the residue was diluted with dichloromethane and 10% ΝaOH solution. The mixture was extracted twice with dichloromethane and the combined organic layers were dried (MgSO ), filtered, and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel with ethyl acetate/methanol 4: 1 as eluent to yield 0.3 g of (3- methyl- 1 -benzofuran-2-yl)methylamine . A mixture of the obtained (3-methyl-l-benzofuran-2-yl)methylamine (0.22 g, 1.4 mmol) and Pd/C 10% (0.22 g) in acetic acid (10 ml) was hydrogenated at 50 psi in a Pan- apparatus for 65 h. The reaction mixture was filtered, concentrated on a rotary evaporator thereafter diluted with 10% ΝaOH solution and extracted twice with dichloromethane. The combined organic layers were dried (MgSO₄), filtered, and then concentrated in vacuo to yield 0.17 g of (3-methyl-2,3-dihydro-l-benzofuran-2-yl)methylamine. ¹³C NMR (CDC1₃, 400MHz): δ 14.2, 36.6, 52.9, 86.1, 109.7, 121.5, 124.9, 128.7, 132.7, 158.8.

Example 19: N,N-Diethyl-N-r(3-methyl-2,3-dihvdro-l-benzofuran-2-yl)methyl1amine was synthesized according to the procedure described for N-Methyl-N-[(3-methyl-2,3- dihydro-l-benzofuran-2-yl)methyl]amine by using diethylamine instead of methylamine as starting material.

¹³C ΝMR (CDC1₃, 400MHz): δ 11.4, 14.1, 38.2, 42.2, 51.9, 85.2, 109.4, 120.7, 123.9, 128.5, 132.6, 158.8.

Example 20:

(2-Methyl-2,3-dihydro- 1 -benzofuran-2-yl)methylamine

A solution of 2-(bromomethyl)-2-methyl-2,3-dihydro-l -benzofuran (0.5 g, 2.2 mmol) in benzylamine (3 ml, 22 mmol) was stirred at 200 °C under nitrogen atmosphere for 16 h. To the cooled mixture saturated sodium hydrogencarbonate solution and ethyl acetate were added. The organic layer was discarded and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography to yield N-benzyl-N-[(2-methyl-2,3- dihydro- 1 -benzofuran-2-yl)methyl] amine. Palladium black (0.25 g) was added to a solution of N-benzyl-N-[(2-methyl-2,3-dihydro-l- benzofuran-2-yl)methyl] amine (0.25 g, 1.0 mmol) in methanol (5 ml) containing 4.4% formic acid. The mixture was stirred over night under nitrogen atmosphere. The catalyst was filtered off and the solvent was evaporated. The residue was dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was dried (MgSO₄) and the solvent was evaporated in vacuo to yield 0.17 g of (2-methyl-2,3-dihydro-l-benzofuran-2-yl)methylamine. ¹³C ΝMR (CDC1₃, 400MHz): δ 24.4, 39.5, 51.2, 84.4, 1 10.1, 120.9, 125.2, 125.3, 128.2, 157.4.

Example 21 : (2-Ethyl-2,3-dihydro-l-benzofuran-2-yl)methylamine To a solution of 2-ethyl-2,3-dihydro-l-benzofuran-2-carboxylic acid (1.0 g, 5.2 mmol) in toluene (20 ml) thionyl chloride (1.15 ml, 16 mmol) and three drops of DMF were added, then the solution was heated to 70 °C for 1 h. The solvent was evaporated in vacuo and the residue was dissolved in dichloromethane then ammonia 25 % in water (1.3 ml, 17 mmol) was added at 0 °C. The mixture was stirred over night at room temperature. The organic layer was discarded and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography to give 0.7 g of 2-ethyl-2,3-dihydro-l-benzofuran-2- carboxamide.

To a solution of 2-ethyl-2,3-dihydro-l-benzofuran-2-carboxamide (0.4 g, 1.98 mmol) in toluene (10 ml) sodium bis(2-methoxyethoxy)aluminium hydride (1.2 ml, 3.97 mmol) was added at 0 °C. After stirring for 1.5 h at room temperature the mixture was cooled to 0 °C and water was carefully added. The resulting mixture was extracted with dichloromethane and the combined organic layers was dried (MgSO₄) and the solvent was evaporated in vacuo to yield 0.3 g of (2-ethyl-2,3-dihydro-l-benzofuran-2-yl)methylamine. ¹³C NMR (CDC1₃, 400MHz): δ 7.9, 31.2, 38.9, 52.3, 91.1, 109.3, 121.1, 124.9, 125.5, 127.9, 157.8.

Example 22:

2-(2,3-Dihydro- 1 -benzofuran-2-yl)piperidine

To a solution of 2-hydroxybenzaldehyde (1.28 ml, 12.2 mmol) in ethanol (20 ml) potassium hydroxide (0.7 g, 12.5 mmol) was added and the mixture was warmed until a clear solution had formed. Thereafter 2-picolyl chloride (1.0 g, 6.1 mmol) and finally more potassium hydroxide (0.7 g, 12.5 mmol) was added. The mixture was heated to 90 °C for 15 h and then water was added. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with saturated sodium hydrogencarbonate solution. The organic layer was dried (MgSO₄), filtered, and then concentrated in vacuo to yield 1.8 g of crude 2-(2-pyridinylmethoxy)benzaldehyde which was directly treated with refluxing acetic anhydride (30 ml) for 12 h. The reaction mixture was then concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with 10% NaOH solution. The organic layer was then washed with 2 M HCl and the water layer was alkalized with 10% NaOH solution and extracted twice with dichloromethane. The combined organic layers were dried (MgSO₄), filtered, and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel with toluene/ethyl acetate 15: 1 as eluent to yield 0.45 g of 2-( 1 -benzofuran-2-yl)pyridine.

A mixture of the obtained 2-( 1 -benzofuran-2-yl)pyridine (0.3 g, 1.5 mmol) and Pd/C 10% (0.10 g) in acetic acid (10 ml) was hydrogenated at 50 psi in a Parr apparatus for 24 h. The reaction mixture was filtered, concentrated on a rotary evaporator thereafter diluted with 10% NaOH solution and extracted twice with dichloromethane. The combined organic layers were dried (MgSO₄), filtered, and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel and ethyl acetate as eluent to yield 0.11 g of 2-(2,3-dihydro-l-benzofuran-2-yl)piperidine. ¹³C NMR (CDC1₃, 400MHz): δ 24.3, 26.1, 27.9, 32.3, 46.3, 60.8, 86.6, 109.2, 120.2, 124.8, 126.9, 127.8, 159.5.

Example 23: l-(2,3-Dihydro-l-benzofuran-2-yl)-2-propanamine Sodium hydride (0.36 g, 15.1 mmol) was added to a solution of benzofuran-2-carbaldehyde (2 g, 13.7 mmol) and nitroethane (1.47 ml, 20.5 mmol) in dimethylformamide (40 ml) at 0°C. The mixture was stirred at room temperature for 0.5 h before it was quenched with water (100 ml). The pH of the solution was adjusted to 5-6 with acetic acid and then extracted with chloroform (3x60 ml). The extract was washed with water and concentrated in vacuum to leave a crude l-benzofuran-2-yl-2-nitropropanol-l-ol (3.0 g).

The l-benzofuran-2-yl-2-nitropropanol-l-ol (3.0 g) was dissolved in trifluoroacetic acid (30 ml) and triethylsilane (11 ml, 68.5 mmol) was added. The mixture was stirred overnight at room temperature. The volatiles were removed in vacuo. The residue was chromatographed on a column packed with silica gel using 10-20% ethyl acetate in heptane as an eluent, and the fastest fraction was collected, yielding pure 2-(2-nitropropyl)- benzofuran (1.5 g, 7.53 mmol, 55%).

The 2-(2-nitropropyl)-benzofuran (1.5 g, 7.53 mmol) was subjected to hydrogenation under 60 psi H₂ in methanol, first over Raney nickel for 3 h then over Pd/C (10%) for 72 h. The catalysts were removed by filtration and the solvent was evaporated in vacuo. The residue was chromatographed on a column packed with silica gel using 50-100% ethyl acetate in methanol to elute 2-benzofuran-2-yl- 1 -methylethylamine (0.42 g, 2.4 mmol, 32%) and then - 0-10% water in methanol to elute the title compound (0.47g, 2.6 mmol, 35%). ¹³C NMR of the hydrochloride (in D₂O): δ 17.7, 17.9, 34.7, 35.0, 39.0, 39.8, 45.4, 46.4, 79.6, 81.0, 109.3, 121.1, 125.4, 126.7, 126.8, 128.1, 157.7, 157.9.

Example 24: l-(2,3-Dihvdro-furor3,2-blpyridin-2-yl)-ethylamine

To 2-iodo-pyridin-3-ol (2 g, 9.05 mmol) dissolved in dimethylformamide (25 ml) the following reagents were added sequentially at room temperature: piperidine (0.99 ml, 10 mmol), but-3-yn-2-ol (0J6 ml, 10 mmol), triphenylphosphine (0.131 g, 0.5 mmol), palladium acetate (0.052 g, 0.23 mmol), and copper iodide (88 mg, 0.46 mmol). The mixture was stirred at room temperature overnight. Water (100 ml) was added at 5-10°C, and the mixture was extracted with chloroform (3x70 ml). The extract was dried over sodium sulfate and concentrated in vacuum. The residue was purified on a column packed with silica gel using ethyl acetate as an eluent to give l-furo[3,2-b]pyridin-2-yl-ethanol ( 1.29 g, 7.9 mmol, 87%).

The product l-furo[3,2-b]pyridin-2-yl-ethanol ( 1.29 g, 7.9 mmol) was dissolved in toluene (30 ml), and treated with diphenylphosphoryl azide (2.55 ml, 1 1.9 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (1.78 ml, 11.9 mmol) at 0°C. After stirring for 15 h at room temperature the mixture was washed with water (50 ml), and the water phase was extracted with ethyl acetate (2x50 ml). The combined organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified on a column packed with silica gel using 40-60% ethyl acetate in heptane as an eluent to give l-furo[3,2-b]pyridin-2-yl-ethyl azide (1.13 g, 6.0 mmol, 76%).

The product l-furo[3,2-b]pyridin-2-yl-ethyl azide (1.13 g, 6.0 mmol) was hydrogenated over 10% Pd/C in methanol under 60 psi H₂ for 15 h. The catalyst and the methanol were removed by filtration and concentrated in vacuo. The residue was purified on a column packed with silica gel using 10-20% methanol in ethyl acetate in heptane as an eluent to give the title product (0.72 g, 4.4 mmol, 73%). ¹³C NMR (CDC1₃, 400MHz): δ 18.2, 19.0, 31.4, 33.9, 49.3, 51.1, 86.7, 87.7, 1 15.1, 1 15.3, 122.2, 122.3, 141.3, 141.4, 150.6, 150.7, 153.2, 153.5.

Example 25: l-(5-Methyl-2,3-dihvdro-furor3,2-b]pyridin-2-yl)-ethylamine was synthesized from 2-iodo-6-methyl-pyridin-3-ol instead of 2-iodo-pyridin-3-ol according to the procedure described for the synthesis of l-(2,3-dihydro-furo[3,2-b]pyridin- 2-yl)-ethylamine. ¹³C NMR (CDC1₃, 400MHz): δ 18.0, 18.8, 23.2, 31.6, 34.0, 49.4, 51.0, 86.5, 87.5, 115.6, 115.8, 121.4, 121.5, 149.5, 149.6, 149.7, 149.8, 151.1, 151.4.

Example 26: ri-(2,3-Dihvdro-furor3,2-blpyridin-2-yl)-ethyll-ethylamine l-Furo[3,2-b]pyridin-2-yl-ethanol (0.5 g, 3.1 mmol), synthesized according to to the procedure described above, was treated with methanesulfonyl chloride (0.48 ml, 6.1 mmol) and triethylamine (0.85 ml, 6.1 mmol) in dichloromethane at -20°C for 2 h. The mixture was washed with water, dried over sodium sulfate and concentrated in vacuum. The residue was treated with ethyl amine (0.27 g, 6 mmol) in dichloromethane (15 ml) for 20 h at room temperature. After removal of the volatiles the crude product was purified on a column packed with silica gel using 10-50% methanol in ethyl acetate as an eluent to give the title compound (0.21 g, 1.1 mmol, 35%). ¹³C NMR (CDC1₃, 400MHz): δ 13.0, 14.0, 14.1, 14.4, 32.9, 33.8, 40.8, 40.9, 55.8, 56.7, 83.5, 84.7, 115.4, 115.7, 122.4, 122.5, 141.4, 141.5, 150.1, 153.0, 153.6.

Example 27:

Ethyl-ri-(5-Methyl-2,3-dihvdro-furo|^"3,2-blpyridin-2-yl)-ethyl]-amine 2-Iodo-6-methyl-pyridin-3-ol was converted to 5-methyl-l-furo[3,2-b]pyridin-2-yl-ethanol according to the procedure described for the synthesis of l-furo[3,2-b]pyridin-2-yl-ethanol under the synthesis of l-(2,3-dihydro-furo[3,2-b]pyridin-2-yl)-ethylamine. 5-Methyl-l- furo[3,2-b]pyridin-2-yl-ethanol was converted to the title compound using the procedure described for l-furo[3,2-b]pyridin-2-yl-ethanol under the synthesis of [l-(2,3-dihydro- furo[3,2-b]pyridin-2-yl)-ethyl]-ethylamine. The diastereomers were separated on a column packed with silica gel using 10-50% methanol in ethyl acetate as an eluent. ¹³C NMR (CDC1₃, 400MHz): δ 15.0, 15.1, 23.2, 34.0, 41.0, 57.0, 85.6, 115.9, 121.5, 149.5, 149.9, 151.8. ¹³C NMR (CDCI₃, 400MHz): δ 14.0, 14.7, 23.0, 32.7, 41.2, 55.7, 84.2, 116.0, 121.7, 149.4, 149.8, 151. 7.

Example 28:

5-Methyl-2-pyrrolidin-l-ylmethyl-2,3-dihydro-furor3,2-b1pyridine

To 2-iodo-6-methyl-pyridin-3-ol (2.13 g, 9.05 mmol) dissolved in dimethylformamide (25 ml) the following reagents were added sequentially: piperidine (0.99 ml, 10 mmol), 3,3- diethoxy-propyne (1.28 g, 10 mmol), triphenylphosphine (0.131 g, 0.5 mmol), palladium acetate (0.052 g, 0.23 mmol), and copper iodide (88 mg, 0.46 mmol). The mixture was stirred at room temperature 3 h. Water (100 ml) was added at 5-10°C, and the mixture was extracted with chloroform (3x70 ml). The extract was concentrated in vacuum and the residue was purified on a column packed with silica gel using 40% ethyl acetate in methanol as eluent to give 2-diethoxymethyl- 5-methyl-furo[3,2-b]pyridine.

The synthesized 2-diethoxymethyl- 5-methyl-furo[3,2-b]pyridine was hydrolyzed with 5% HCl (30 ml) at room temperature overnight. The solvents were removed in vacuo. The residue was neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate (3x50 ml). The extract was dried with sodium sulfate and concentrated in vacuo to leave 5- methyl-furo[3,2-b]pyridine-2-carbaldehyde (1.34 g, 8.3 mmol, 92%).

To 5-methyl-furo[3,2-b]pyridine-2-carbaldehyde (1.34 g, 8.3 mmol) dissolved in methanol sodium cyanoborohydride (1.05 g, 16.6 mmol) and pyrrolidine (1.39 ml, 16.6 mmol) were added. The mixture was stirred at room temperature for 24 h. The methanol was evaporated in vacuo. The residue was treated with water and extracted with ethyl acetate (3x50 ml). The extract was dried with sodium sulfate and concentrated in vacuo. The crude 5-methyl- 2-pyrrolidin-l-ylmethyl-furo[3,2-b]pyridine in the residue was taken up in acetic acid (20 ml) and hydrogenated over 10% Pd/C under 50 psi H₂ for 48 h. The catalyst and the methanol were removed. The residue was purified on a column packed with silica gel using 50-100% methanol in ethyl acetate as an eluent to yield the title product (0.5 g, 2.3 mmol, 28%). ¹³C NMR (CDC1₃, 400MHz): δ 23.3, 23.4, 35.4, 54.7, 61.1, 81.2, 1 16.1, 121.4, 149.5, 149.6, 151.1.

Example 29: l-(2,3-Dihvdro-furor3,2-c]pyridin-2-yl)-ethylamine

The protocol for the synthesis of l-(2,3-dihydro-furo[3,2-b]pyridin-2-yl)-ethylamine was followed while 3-iodo-pyridin-4-ol was used instead of 2-iodo-pyridin-3-ol. ¹³C NMR of the dihydrochloride in CD₃OD: δ 10.6, 13.7, 27.9, 29.1, 49.6, 50.3, 86.7, 87.7, 107.8, 108.0, 127.4, 127.6, 137.8, 137.9, 143.4, 143.5, 171.3, 171.9.

Example 30: l-(5-Methyl-2,3-dihydro-furor2,3-b1pyridin-2-yl)-ethylamine

The protocol for the synthesis of l-(2,3-dihydro-furo[3,2-b]pyridin-2-yl)-ethylamine was followed while 3-iodo-5-methyl-pyridin-2-ol was used instead of 2-iodo-pyridin-3-ol. ¹³C NMR (CDCI₃, 400MHz): δ 17.5, 18.1, 18.8, 28.4, 30.8, 49.0, 51.0, 85.0, 86.1, 119.4, 119.5, 125.3, 125.4, 134.5, 145.5, 145.6, 166.0, 166.2.

Example 31 : 5-Methyl-2-pyrrolidin-l-ylmethyl-2.3-dihydro-furor2,3-blpyridine

The protocol for the synthesis of 5-methyl-2-pyrrolidin-l-ylmethyl-2,3-dihydro-furo[3,2- b]pyridine was followed while 3-iodo-5-methyl-pyridin-2-ol was used instead of 2-iodo-6- methyl-pyridin-3-ol. ^I3C NMR (CDC1₃, 400MHz): δ 17.7, 23.5, 32.3, 54.8, 60.4, 80.2, 119.2, 125.4, 134.6, 145.8, 166.2.

Example 32: l-(3,4-Dihydro-2H-chromen-2-yl)ethylamine

A solution of l-(3,4-dihydro-2H-chromen-2-yl)- 1-ethanone (0.18 g, 1.0 mmol) in methanol (5 ml) was stirred with 4A molecular sieves (0.18 g) as ammonium acetate ( 0.77 g, 10 mmol) was added. After the addition of sodium cyanoborohydride (0.063 g, 1.0 mmol), the reaction mixture was stirred 48 h at room temperature under a nitrogen atmosphere. The reaction mixture was filtered, concentrated on a rotary evaporator thereafter diluted with 10% NaOH solution and extracted twice with dichloromethane. The combined organic layers were dried (MgSO₄), filtered, and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel with ethyl acetate as eluent to give 0.11 g of l-(3,4-dihydro-2H-chromen-2-yl)ethylamine. ¹³C NMR (CDC1₃, 400MΗz): δ 18.5, 19.2,

22.0, 23.9, 24.5, 24.8, 49.6, 50.2, 80.2, 80.9, 1 16.4, 116.5, 119.8, 1 19.9, 121.8, 121.9, 127.0, 129.2, 129.3, 154.5,154.9.

Example 33: l-(3,4-Dihydro-6-methyl-2H-chromen-2-yl)-ethylamine

6-Methyl-2-chromanol (1 g, 6.1 mmol) was stirred with an excess of nitroethane and potassium carbonate at 90°C for 3 h. The potassium carbonate was filtered off and the nitroethane was evaporated in vacuum. The residue was purified on a column packed with silica gel using 10-20% ethyl acetate in heptane as an eluent to yield 6-methyl-2-(l- nitroethyl)-chromane (0.9 g, 4.1 mmol, 67%) which was hydrogenated in methanol over Raney nickel under 50 psi Η₂ overnight. The catalyst was filtered off and the methanol was evaporated. The residue was chromatographed on a column packed with silica gel using 10 to 50% methanol in ethyl acetate as an eluent to give the title product (0.45 g, 2.4 mmol, 58%). ¹³C NMR (CDC1₃, 400MHz): δ 18.7, 19.3, 20.4, 22.3, 24.2, 24.7, 24.9, 49.8, 50.3, 80.3, 81.1, 1 16.3, 116.4, 121.6, 121.7, 127.7, 129.1, 129.2, 129.7, 129.8, 152.5, 152.9.

Example 34: l-(3,4-Dihydro-6,7-dimethyl-2H-chromen-2-yl)-ethylamine

6,7-Dimethyl-chromen-2-one (2 g, 11.5 mmol) was hydrogenated over 10% Pd/C in ethyl acetate under 50 psi Η₂ for 48 h. The catalyst was filtered off and the solvent was evaporated. The residue was dissolved in toluene and diisobutyl aluminium hydride (13.8 ml, 1M, 13.8 mmol) was added at -78°C. The mixture was stirred at this temperature for 2 h before it was quenched with 10% solution of ammonium chloride. The organic solvent was removed in vacuum, and the product was extracted with ethyl acetate (2x70 ml). The solution was dried over sodium sulfate and concentrated in vacuum. Final purification on a column packed with silica gel using 20% ethyl acetate in heptane as an eluent yielded 6,7- dimethyl-2-chromanol (0.68 g, 3.8 mmol, 33%). This intermediate was employed in synthesis of the title compound according to the protocol used for the synthesis of l-(6- methyl-chroman-2-yl)-ethylamine. ¹³C NMR (CDC1₃, 400MHz): δ 13.9, 18.7, 19.4, 23.6, 24.2, 75.7, 84.8, 117.6, 118.2, 129.0, 130.2, 135.9, 151.5. ¹³C NMR in CD₃OD: δ 12.4, 18.5, 19.2, 23.1, 24.1, 50.3, 74.9, 1 17.2, 118.4, 128.9, 130.1, 135.6, 151.6.

Example 35: l-(6-Bromo-3,4-dihydro-2H-chromen-2-yl)-ethylamine The protocol for the synthesis of l-(6-methyl-chroman-2-yl)-ethylamine was followed while 6-bromo-chroman-2-ol was used instead of 6-methyl-2-chromanol. ¹³C NMR (CDC1₃, 400MΗz): δ 17.9, 18.5, 21.9, 23.6, 24.4, 24.7, 49.7, 50.5, 79.8, 80.3, 1 12.0, 112,1, 118.4, 1 18.5, 124.0, 124.1, 129.9, 130.0, 131.8, 131.9, 153.6, 154.0.

Example 36: l-(3,4-Dihydro-7-methoxy-2H-chromen-2-yl)-ethylamine

The protocol for the synthesis of l-(6-methyl-chroman-2-yl)-ethylamine was followed while 7-methoxy-chroman-2-ol was used instead of 6-methyl-2-chromanol. ¹³C NMR (CDCI₃, 400MΗz): δ 18.7, 19.3, 22.3, 23.9, 24.2, 24.3, 49.7, 50.2, 55.2, 80.6, 81.2, 101.3, 101.4, 106.9, 107.0, 114.1, 114.2, 129.7, 155.4, 155.7, 158.9.

Example 37:

Procedure for the isolation of individual stereoisomers of some of the compounds of the invention as example l-(2,3-dihydro-benzofuran-2-yl)ethylamine into l-((R)-2,3-dihydro-benzofuran-2-yl)-(R)-ethylamine, l-((S)-2,3-dihydro-benzofuran-2-yl)- (S)-ethylamine, l-((S)-2,3-dihydro-benzofuran-2-yl)-(R)-ethylamine and l-((R)-2,3- dihydro-benzofuran-2-yl)-(S)-ethylamine

l-(2,3-Dihydro-benzofuran-2-yl)-ethylamine was separated into the corresponding diastereoisomers by passing the substance (5 g, 30.6 mmol) through a column packed with silica gel (200 g) using 30 to 50% acetone in heptane as an eluent. A complete separation was achieved after a second elution to yield a racemic (R,S and S,R) [l-(2,3-dihydro- benzofuran-2-yl)-ethyl]-isopropylidene-amine, the faster fraction, 2.65 g (84%) and a racemic (R,R and S,S) [l-(2,3-dihydro-benzofuran-2-yl)-ethyl]-isopropylidene-amine, the slower fraction, 2.24 g (72%). Racemate (R,S and S,R) [l-(2,3-dihydro-benzofuran-2-yl)- ethyl] -isopropylidene-amine was treated with 10% HCl at 40°C for 0.5 h; the solution was neutralised with sodium carbonate and extracted with chloroform (3x50 ml). The extract was dried over sodium sulfate and concentrated in vacuum to leave a racemic (R,S and S,R) l-(2,3-dihydro-benzofuran-2-yl)-ethylamine (1.87 g, 88%). A similar treatment of racemate (R,R and S,S) [l-(2,3-dihydro-benzofuran-2-yl)-ethyl]-isopropylidene-amine yielded (R,R and S,S) l-(2,3-dihydro-benzofuran-2-yl)-ethylamine (1.62 g, 90%).

Racemate (R,R and S,S) l-(2,3-dihydro-benzofuran-2-yl)-ethylamine was dissolved in dichloromethane (40 ml); to that solution R-methoxymandelic acid (1.73 g, 10.5 mmol) was added followed by dicyclohexylcarbodiimide (2.9 g, 14 mmol). The mixture was stirred for 4 h at room temperature before it was quenched with methanol. The volatiles were removed in vacuo. The residue was chromatographed twice on a column packed with silica gel (100 g) using 20 to 30% ethyl acetate in heptane as eluent leading to (R)-N-[l- (R)-(2,3-dihydro-benzofuran-2-yl)-ethyl]-(R)-2-methoxy-2-phenylacetamide, the faster fraction, 1.13 g (73%) and (S)-N-[l-(S)-(2,3-dihydro-benzofuran-2-yl)-ethyl]-(R)-2- methoxy-2-phenylacetamide, the slower fraction, 1.02 g (66%).

A similar treatment of racemate (R,S and S,R) l-(2,3-dihydro-benzofuran-2-yl)-ethylamine yielded (R)-N-[ 1 -(S)-(2,3-dihydro-benzofuran-2-yl)-ethyl]-(R)-2-methoxy-2- phenylacetamide, the faster fraction, 1.34 g (75%) and (S)-N-[l-(R)-(2,3-dihydro- benzofuran-2-yl)-ethyl]-(R)-2-methoxy-2-phenylacetamide, the slower fraction, 1.36 g (76%).

Compound (R)-N-[l -(R)-(2,3-dihydro-benzofuran-2-yl)-ethyl]-(R)-2-methoxy-2- phenylacetamide was refluxed in 20% hydrochloric acid (30 ml) for 6 h. The volatiles were removed in vacuo. The residue was dissolved in water and extracted with chloroform (2x30 ml). The organic phase was discarded. The water phase was made alkaline with potassium carbonate, and the product was extracted with chloroform (3x40 ml). The extract was dried over sodium sulfate and concentrated in vacuo to leave l-((R)-2,3-dihydro-benzofuran-2- yl)-(R)-ethylamine (0.53 g, 90%). A similar treatment of compounds (S)-N-[l-(S)-(2,3- dihydro-benzofuran-2-yl)-ethyl]-(R)-2-methoxy-2-phenylacetamide, (R)-N-[l-(S)-(2,3- dihydro-benzofuran-2-yl)-ethyl]-(R)-2-methoxy-2-phenylacetamide, and (S)-N-[l-(R)-(2,3- dihydro-benzofuran-2-yl)-ethyl]-(R)-2-methoxy-2-phenylacetamide gave rise to respectively l-((S)-2,3-dihydro-benzofuran-2-yl)-(S)-ethylamine (0.40 g, 75%), l-((S)-2,3- dihydro-benzofuran-2-yl)-(R)-ethylamine (0.57 g, 81%) and l-((R)-2,3-dihydro- benzofuran-2-yl)-(S)-ethylamine (0.47 g, 66%). The absolute configuration was determined by X-ray crystallography. The absolute configuration could also be determined by NMR experiments after derivatization with (S)-O-methylmandelic acid as described by Trost B. M. et al. in J. Org. Chem. 1994, 59, 4202.

BIOLOGICAL TESTS

1. In vivo experiments

The analgesic effects of the compounds of the invention were evaluated in the mouse formalin test as described by Tjoelsen A. et al. in Pain, 1992, 51, 5. The mouse formalin test employs a tonic painful stimulus with both a first phase of direct chemical activation (acute pain) and a second phase involving central sensitization and peripheral inflammation. The analgesic activities were estimated as ED₅₀ values and were for the compounds of the invention between 5 and 200 μmol/kg.

Some of the compounds of the invention were also found to be active in the rat Chung model which is indicative of activity in neuropathic pain (Kim and Chung. Pain 1992, 50, 355). Antiinflammatory activity was evaluated in the rat carrageenan model essentially as described by Tonussi, C. and Ferreira, S., Pain 1992, 48, 421 and Coderre, T.J. and Wall, P.D., Pain 1987, 28, 379.

Claims

1. A compound of the formula I

or a pharmaceutically acceptable salt thereof, wherein R - R is independently selected from a group consisting of a) H, b) Cι-C₆ alkyl,

c) aryl - alkyl,

d) Cj-Cβ alkenyl, and

e) halogenated C]-C6 alkyl,

R is independently selected from a group consisting of a) H b) Cι -C₆ alkyl,

c) aryl C]-C₆ alkyl,

d) amino Cj -Cg alkyl,

e) C]-C6 alkylamino C_rC₆ alkyl, f) Cι -C₆ alkoxy C_rC₆ alkyl,

g) Cι-C₆ alkenyl,

h) halogenated Cj-Cg alkyl, and

i) cycloalkyl Cj-C₂ alkyl

(R , R ), (R , R ) and (R , R ) may, together with the carbon or nitrogen atoms to which they are bonded, form a saturated or unsaturated 4, 5, 6, 7, or 8 membered ring, optionally containing one or more heteroatoms,

8 1 1 R - R is independently selected from a group consisting of

a) H, b) C] -C₆ alkyl,

c) aryl C]-C₆ alkyl, d) OH, e) C]-C6 alkoxy,

f) aryl -Cό alkoxy, g) halogenated alkoxy, h) Ci-Cή alkylcarbonyloxy,

i) NO₂,

j) NH₂,

k) Cj-Cg alkylamino,

1) Ci-C alkylcarbonylamino,

m) C]-C6 alkoxycarbonylamino, n) halogen, o) cyano p) substituted or unsubstituted carbamoyl, q) -Cg alkylcarbonyl, r) arylcarbonyl, s) aryl -Cg alkylcarbonyl,

t) C]-C6 alkoxycarbonyl, and u) Ci-Cg alkyl thio,

(R , R ), (R , R ) and (R , R ) may, together with the carbon atoms to which they are attached, form a further saturated or unsaturated 5, 6, 7 or 8-membered ring, optionally containing one or more further heteroatoms, and/or substituted with one or more substituents selected from halogen, Cj-Cg alkyl, C]-C alkoxy, CF₃, OH, amino, C_j-Cg alkyl-NH- or ( - alkyl)₂-N~;

m is zero or 1 n is zero or 1,

2. A compound according to claim 1, wherein R - R is independently selected from a group consisting of a) H, b) C]-C₆ alkyl, and

c) halogenated Ci -Cg alkyl,

R is independently selected from a group consisting of

a) H b) C]-C₆ alkyl,

c) aryl Cj-Cβ alkyl,

d) amino C] -C6 alkyl, and

e) C_] -C6 alkylamino C_rC₆ alkyl,

(R , R ), (R , R ) and (R , R ) may, together with the carbon or nitrogen atoms to which they are bonded form a saturated or unsaturated 4, 5, 6, 7, or 8 membered ring, optionally containing one or more heteroatoms,

8 1 1 R - R is independently selected from a group consisting of

a) H, b) C]-C₆ alkyl, c) OH, d) C]-C6 alkoxy, e) halogenated alkoxy, f) NO₂,

g) NH₂,

h) C]-C6 alkylamino,

i) C_j-Cβ alkylcarbonylamino, j) halogen, k) cyano

1) substituted or unsubstituted carbamoyl, m) Cj-C alkylcarbonyl, n) arylcarbonyl, o) aryl C]-Cg alkylcarbonyl, and p) C_]-C₆ alkylthio,

(R , R ), (R , R ) and (R , R ) may, together with the carbon atoms to which they are attached, form a further saturated or unsaturated 5, 6, 7 or 8-membered ring, optionally containing one or more further heteroatoms, and/or substituted with one or more substituents selected from halogen, C_j-C₆ alkyl, C_j-C_β alkoxy, CF₃, OH, amino, C_j-C₆ alkyl-NH- or (C_j-C₆ alkyl)₂-N-;

m is zero or 1 n is zero or 1,

excluding the racemic compounds l-(2,3-dihydro-l-benzofuran-2-yl)ethylamine, N-[l-(2,3- dihydro-l-benzofuran-2-yl)ethyl]-N-methylamine, N-[l-(2,3-dihydro-l-benzofuran-2- yl)ethyl]-N,N-dimethylamine, 1 -(7-methyl-2,3-dihydro- 1 -benzofuran-2-yl)ethylamine, N- methyl-N-[l-(7-methyl-2,3-dihydro-l-benzofuran-2-yl)ethyl]amine, N,N-dimethyl-N-[l-(7- methyl-2,3-dihydro-l-benzofuran-2-yl)ethyl]amine.

3. A compound according to claim 1, wherein R - R is independently selected from a group consisting of

a) H, and b) C]-C₆ alkyl,

R - R is independently selected from a group consisting of a) H b) C_rC₆ alkyl, c) aryl C_rC₆ alkyl,

d) amino Cj-C6 alkyl, and e) C]-C6 alkylamino C_rC₆ alkyl,

8 1 1 R - R is independently selected from a group consisting of a) H, b) C,-C₆ alkyl, c) Cj-Cg alkoxy, d) NO₂, e) NH₂, and f) halogen

m is zero or 1 n is zero or 1

excluding the racemic compounds l-(2,3-dihydro-l-benzofuran-2-yl)ethylamine, N-[l-(2,3- dihydro-l-benzofuran-2-yl)ethyl]-N-methylamine, N-[l-(2,3-dihydro-l-benzofuran-2- yl)ethyl]-N,N-dimethylamine, l-(7-methyl-2,3-dihydro-l-benzofuran-2-yl)ethylamine, N- methyl-N-[l-(7-methyl-2,3-dihydro-l-benzofuran-2-yl)ethyl]amine, N,N-dimethyl-N-[l-(7- methyl-2,3-dihydro-l-benzofuran-2-yl)ethyl]amine.

4. A process for the preparation of a compound according to any one of claims 1 to 3 comprising the step of a) reducing a compound of the Formula VI

using hydrogen and a catalyst, such as Pd/C, in an inert solvent under standard conditions, or

b)alkylating a compound of the general formula VHJ,

using either a) an alkyl halide, b) reductive alkylation using an alkylaldehyde and sodium cyanoborohydride, or c) acylation with an acid chloride, to form an amide, which is subsequently reduced with lithium aluminium hydride or sodium bis(2- methoxyethoxy)aluminium hydride or borane-methyl sulfide complex in an inert solvent under standard conditions, or

c) alkylating a compound of the general formula X,

using either a) an alkyl halide, b) reductive alkylation using an alkylaldehyde and sodium cyanoborohydride, or c) acylation with an acid chloride, to form an amide, which is subsequently reduced with lithium aluminium hydride or sodium bis(2- methoxyethoxy)aluminium hydride or borane-methyl sulfide complex in an inert solvent under standard conditions, to give compounds of the general Formula I.

0

5. A pharmaceutical formulation containing a compound according to any one of claims 1 to 3 as active ingredient in combination with a pharmaceutically acceptable diluent or carrier.

s 6. Use of a compound according to any one of claims 1 to 3 in therapy.

7. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of pain.

o 8. A method for treatment or prophylaxis of pain or discomfort, comprising administering to a mammal, including man, in need of such treatment an effective amount of a compound of the formula I.

9. A pharmaceutical formulation for use in the treatment or prophylaxis of pain or 5 discomfort, comprising a compound of the formula I, in combination with a pharmaceutically acceptable carrier or diluent.