WO2013013060A1 - Agomelatine derivatives - Google Patents

Abstract

Derivatives of agomelatine having valuable properties are provided. The derivatives can be used for the preparation of medicaments.

Description

AGOMELATINE DERIVATIVES Related Application

[0001] This application claims priority from a U.S. Patent application serial no. 61/509,465, filed on July 19, 2011, which is incorporated herein by reference.

Background

[0002] Agomelatine, compound (A), is a melatonergic agonist (MT1 and MT2 receptors) and 5-HT2C antagonist.

(A)

Agomelatine has been marketed for the treatment of major depressive disorders and reported to have a reduced level of sexual side effects, as well as discontinuation effects, compared to other antidepressants. Agomelatine can also have positive effects on sleep associated with a number of disorders. Agomelatine is indicated for the treatment of major depressive episodes in adults.

[0003] Agomelatine was disclosed in U.S. Patent No. 5,194,614 and U.S. Patent No.

5,224,442. The patents disclose several compounds of naphthalene structure including agomelatine, their pharmaceutical composition and a method for treating a living animal afflicted with treatable disorder of the melatonergic system. Agomelatine is been reported to re- synchronize circadian rhythms, based on animal models of delayed sleep phase syndrome and other circadian rhythm disruptions. It has been reported to increase noradrenaline and dopamine release specifically in the frontal cortex and has no known influence on the extracellular levels of serotonin. Agomelatine has also been reported to provide an antidepressant-like effect in animal depression models (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm de-synchronization and in models related to stress and anxiety. In humans, agomelatine has been reported to provide positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset.

[0004] Published reports also indicate that agomelatine does not alter daytime vigilance and/or awakenings in healthy volunteers. In depressed patients, treatment with the drug increased slow wave sleep without very significant modification of Rapid Eye Movement (REM) sleep amount or REM latency. Agomelatine is also reported to induce an advance of the time of sleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients. Agomelatine has no abuse potential as measured in healthy volunteer studies.

[0005] Agomelatine is also reported to cause fewer sexual side effects and discontinuation effects than sertraline and paroxetine. Additionally, possibly because of its action on melatonin receptors, agomelatine is reported to improve sleep quality, with no reported daytime

drowsiness. Agomelatine has demonstrated anxiolytic properties in rodents. Its efficacy in generalized anxiety disorder has been assessed by Stein et al. (2008) who reported it

significantly more effective than placebo treatment.

[0006] Agomelatine is poorly soluble in water and has very poor bioavailability (less than 20%) when formulated as orally dispersible tablets. Currently there is an unmet need for Agomelatine derivatives and compositions that include agomelatine and its derivatives that have improved pharmacokinetic properties without comprising therapeutic efficacy. This invention provides novel melatonergic modulating compounds that meet these needs.

Summary

[0007] The present invention provides, in one aspect, compounds which are melatonergic agonists (MT1 and MT2 receptors) and 5-HT2C antagonists. Accordingly, there is provided compounds of Formula (I):

(I)

wherein R is -COR¹; -CO(CHR²)NH₂; -COO(CHR³)OCOR⁴; -S0₂R⁵; -S0₂NR⁶R⁷, or -CH₂NHCOPh;

R¹ is methyl, ethyl, n-propyl, z^'so-propyl, n-butyl, z^'so-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-chlorophenyl, 4-bromophenyl, 4-cyanophenyl, 4-nitrophenyl or 4-methylphenyl;

R² is hydrogen, methyl, z^'so-propyl, z^'so-butyl, benzyl, imidazole-4-methyl or

indole-3 -methyl;

R³ and R⁴ are independently methyl, ethyl, n-propyl, z^'so-propyl, n-butyl, z^'so-butyl, tert-butyl, cyclohexyl, cyclopentyl, cyclobutyl, or cyclopropyl;

R⁵ is methyl, ethyl, n-propyl, z^'so-propyl, n-butyl, z^'so-butyl, tert-butyl, trifluoromethyl, benzyl; phenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 4-aminophenyl, 4-fluoro- phenyl, 4-methylphenyl or 4-methoxyphenyl;

R⁶ and R⁷, which may be same or different, and are independently hydrogen, ethyl, tert-butyl, z^'so-butyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, benzyl or - CH(CH₃)Ph;

R⁸ is methyl, ethyl, n-propyl, or 1-methylethyl (isopropyl), and

R⁹ is methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, n-pentyl, t- butyl (1,1-dimethylethyl), or phenyl;

or a pharmaceutically acceptable salt thereof.

8] In another aspect the invention provides, compounds of formula (II)

(II)

wherein, R¹ is methyl, ethyl, n-propyl, z^'so-propyl, n-butyl, z^'so-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, phenyl, 4-chlorophenyl, 4-bromophenyl, 4- cyanophenyl, 4-nitrophenyl or 4-methylphenyl; or a pharmaceutically acceptable salt thereof.

[0009] In another aspect, the present invention provides compounds of formula (III):

(HI)

wherein, R is hydrogen, methyl, z^'so-propyl, z^'so-butyl, benzyl, imidazole-4-methyl or indole-3 -methyl; or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, the present invention provides compounds of formula (IV):

(IV)

wherein, R³ and R⁴ are independently methyl, ethyl, n-propyl, z^'so-propyl, n-butyl, iso- butyl, tert-butyl, cyclohexyl, cyclopentyl, cyclobutyl, or cyclopropyl; or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, the present invention provides compounds of the formula (V):

(V)

wherein, R⁵ is from methyl, ethyl, n-propyl, z^'so-propyl, n-butyl, z^'so-butyl, tert-butyl, trifluoromethyl, benzyl, phenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 4-amino- phenyl, 4-fluorophenyl, 4-methylphenyl or 4-methoxyphenyl; or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, the present invention provides compounds of the formula (VI):

(VI)

wherein, R⁶ and R⁷, which may be same or different, and are independently hydrogen, ethyl, tert-butyl, z^'so-butyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, benzyl or -CH(CH₃)Ph;

or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, the present invention provides compounds having formula (VII)

(VII)

or a pharmaceutically acceptable salt thereof. [0014] In another aspect, the disclosed compounds and methods are directed to melatonergic agonists (MT1 and MT2 receptors) and 5-HT₂c antagonists that have activity as selective inhibitors of the MT1 and MT2 receptors or have activity as 5-HT₂c antagonists.

[0015] In another aspect, the invention provides a compound of any of the Formulae, I, II, III, IV, V, VI, VII, or a pharmaceutically acceptable salt thereof, for use in medical treatment for example treatment of disorders such as, major depressive disorders, or re-synchronization of circadian rhythms in a mammalian species (for example, a human).

[0016] In another aspect, the invention provides pharmaceutical compositions including the disclosed compounds of Formulae, I, II, III, IV, V, VI, VII, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. More particularly, the disclosed compounds can be formulated as pharmaceutical compositions using standard pharmaceutically acceptable carriers, fillers, solubilizing agents and stabilizers known to those skilled in the art.

[0017] In another aspect, the present invention provides compositions comprising a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, VII, or a pharmaceutically equivalent salt thereof, for treating pain and pain related sleep disorders. The disclosed compositions can be formulated for any route of administration (e.g., the formulations described herein) and can be administered in a single dose or multiple doses to a subject in need thereof.

[0018] In another aspect, the present invention provides Methods for treating pain and pain related sleep disorders comprising a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, VII, or a pharmaceutically equivalent salt thereof, to a patient in need thereof. The disclosed method includes administration of compositions formulated for any route of administration (e.g., the formulations described herein) and can be administered in a single dose or multiple doses to a subject in need thereof.

[0019] The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. In several places throughout the application, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list. [0020] The details of one or more embodiments of the invention are set forth in the accompanying description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

[0021] In describing and claiming the invention, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any materials and methods similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred materials and methods are described herein. Each of the following terms has meaning associated with it in this section. Exemplary and preferred values listed below for radicals, substituents, and ranges are for illustrations only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.

[0022] The terms "a," "an," "the," "at least one," and "one or more" are used

interchangeably. Thus, for example, a composition that comprises "an" element means one element or more than one element.

[0023] The term "pharmaceutically-acceptable salt" refers to salts which retain the biological effectiveness and properties of the disclosed compounds and which are not biologically or otherwise undesirable. In many cases, the disclosed compounds are capable of forming acid or base salts by virtue of the presence of amino or carboxyl groups or groups similar thereto.

[0024] An "effective amount" means an amount sufficient to produce a selected effect.

[0025] The present invention also provides pharmaceutical compositions including a therapeutically acceptable amount of one of the disclosed compounds. More particularly, such compounds can be formulated as pharmaceutical compositions using standard pharmaceutically acceptable carriers, fillers, solubilizing agents and stabilizers known to those skilled in the art. For example, a pharmaceutical composition including a disclosed compound, analog, derivative, or modification thereof, as disclosed herein, is used to administer the appropriate compound to a subject.

[0026] The disclosed method includes a kit comprising a compound of Formulae, I, II, III, IV, V, VI, VII, or a pharmaceutically acceptable salt thereof and instructional material that describes administering the inhibitor compound or a composition comprising the inhibitor compound to a cell or a subject. This should be construed to include other embodiments of kits that are known to those skilled in the art, such as a kit comprising a (preferably sterile) solvent for dissolving or suspending the inhibitor compound or composition prior to administering the compound or composition to a cell or a subject. Preferably, the subject is a human.

[0027] The term "instructional material" includes a publication, a recording, a diagram, or any other medium of expression that can be used to communicate the usefulness of the disclosed compounds in the kit for effecting alleviation of the various diseases or disorders recited herein. Optionally, or alternately, the instructional material may describe one or more methods of alleviating the diseases or disorders in a cell or a tissue of a mammal. The instructional material of the kit may, for example, be affixed to a container which contains a disclosed compound or be shipped together with a container which contains the identified compound. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient.

[0028] The disclosed compounds can be in the form of pharmaceutically acceptable salts thereof, such as for example, acid addition salts or base addition salts. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutylate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate,

methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutylate, citrate, lactate, gamma- hydroxybutylate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1- sulfonate, napththalene-2-sulfonate, mandelate and the like. Acids commonly employed to form acid addition salts are inorganic acids, such as for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p- toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.

[0029] Base addition salts include those derived from inorganic bases, such as for example, ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.

General Methods

[0030] The compounds described herein may be prepared by techniques known in the art, such as, for example, by following the procedures disclosed in International Patent No.

WO2009/120999; WO2010/075520; U.S. Patent No. 6,825,350; Naik et al, ARKIVOC 2004 (i) 55-63; J. Org. Chem. 36(11), 1971, 829-832; Vogel's Practical Organic Chemistry: 5^th edition). The starting materials, e.g., Agomelatine (CAS number 138112-76-2) are either commercially available or can be prepared by the procedures known in the art. Further, in the schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which are known in the art, are also within the scope of the present invention. All the isomers of the compounds described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.

[0031] It will be appreciated by those skilled in the art that the disclosed compounds having chiral centers may exist in and be isolated in optically active, racemic or enantiomerically enriched forms. It is to be understood that the disclosed compounds encompass any racemic, optically active or stereoisomeric form, or mixtures thereof, of the disclosed compounds, which possess the useful properties disclosed herein, such as the S,R; S,S; R,R; or R,S diastereomers. It is well known in the art how to prepare such optically active forms (for example, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or by chromatographic separation using a chiral stationary phase. In addition, enantiomerically enriched compounds of the invention can also be obtained from enantiomerically enriched precursors. Scheme 1

f^ormula <^A> formula (II)

[0032] Scheme 1 depicts a general procedure for the preparation of compounds of formula (II). Compounds of formula (II), wherein R¹ is as defined above, can be prepared by a process known in the art of organic chemistry. For example, a compound of formula (A) reacts with an appropriate carboxylic acid anhydride or carboxylic acid chloride in the presence of a suitable solvent to afford compound of formula (II).

Scheme 2

formula (III)

[0033] A general procedure for the preparation of compounds of formula (III), wherein R² is as defined above in the description, is depicted in Scheme 2. A compound having formula (A) reacts with an activated form of N-protected (e.g., N-BOC) amino acid in presence of a suitable solvent, base and coupling agent to provide a compound of formula (B). De-protection of the compound of formula (B) with a suitable reagent, e.g., trifluoroacetic acid in a suitable solvent affords a compound of formula (III). Scheme 3

(C)

formula (IV)

[0034] A general procedure for the preparation of compounds of formula (IV), wherein R³ and R⁴ are as defined above, is depicted in Scheme 3. A compound having formula (A) reacts with a 1-chloroalkyl chloro formate (e.g., 1-chloroethyl chloro formate) in the presence of a base and suitable solvent to provide a compound of formula (C). The coupling of compound (C) with an appropriate carboxylic acid in the presence of a suitable solvent and base afford a compound of formula (IV).

Scheme 4

formula (V)

(D) formula (VI) [0035] Scheme 4 depicts the general procedure for the preparation of sulfonyl and sulfonamide derivatives. A compound having formula (A) upon reaction with an appropriately substituted sulfonyl halide or sulfonyl anhydride in the presence of a suitable organic base and suitable organic solvent provides a compound of formula (V) wherein R⁵ is as defined above.

[0036] Similarly, a compound of formula (VI), wherein R⁶ and R⁷ are as defined above, can be prepared by reacting compound having formula (A) with thionyl chloride, followed by reaction with an amine of the formula R⁶R⁷NH in a suitable organic solvent. Alternatively, a compound having formula (A) can react, e.g., with dimethylsulfamoyl chloride in the presence of a suitable base and in a suitable solvent to provide a compound of formula (VI) wherein both R⁶ and R⁷ are methyl.

Pharmaceutical Compositions

[0037] The active ingredient, for the disclosed compositions and methods, are compounds of formula I, II, III, IV, V, VI, or VII, and are preferably used in the free amphoteric form.

Pharmaceutically acceptable salts that retain the biological effectiveness and properties of the compounds of formula I, II, III, IV, V, VI, or VII, that are not biologically or otherwise undesirable, can also be used and can show superior bioavailability. As used herein, the term "compound of any of formulae I, II, III, IV, V, VI, or VII" is intended to include the agent, as well as their pharmaceutically acceptable salts.

[0038] The disclosed pharmaceutical compositions are intended for parenteral, intranasal, topical, oral, buccal, or local administration, such as by a transdermal means, for prophylactic and/or therapeutic treatment. Commonly, the pharmaceutical compositions are administered parenterally (e.g., by intravenous, intramuscular, or subcutaneous injection), or by oral ingestion, or by topical application at areas affected by pain and pain related sleep disorders.

[0039] In the preparation of pharmaceutical formulations either singly or with an additional therapeutic agent in the form of dosage units for oral administration the agent can optionally be mixed with solid, powdered inert ingredients, such as lactose, microcrystalline cellulose, maltodextrin, 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 is then processed into granules or pressed into tablets such as chewable and oral disintegrating tablets.

[0040] Soft gelatin capsules can be prepared by mixing the active agent with vegetable oil, fat, or other suitable vehicle. Hard gelatin capsules can contain granules of the active agent, alone or in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.

[0041] Liquid preparations for oral administration can be prepared in the form of syrups or suspensions, e.g., solutions or suspensions containing about 0.2-20 wt % of the active agent and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations can optionally contain coloring agents, flavoring agents, saccharin and carboxymethyl cellulose or other thickening agents. Liquid preparations for oral administration can also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

[0042] The disclosed compounds can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms adapted to the chosen route of administration, e.g. , orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.

[0043] Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least about 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

[0044] The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

[0045] Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0046] The invention is now described with reference to the following Examples and Embodiments. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the disclosed compounds. The following working examples therefore, are provided for the purpose of illustration only and specifically point out the preferred embodiments, and are not to be construed as limiting in any way the remainder of the disclosure. Therefore, the examples should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

Example 1: Formula IIA

[0047] Formula IIA: To a heterogeneous suspension of N-[2-(7-methoxy-l-naphthyl)ethyl]- acetamide (1 mmol) in water (5 mL), 6N HC1 (in the volume range of 240-400 μί) is added until the solution becomes homogeneous (pH ca.1.5). The resulting homogenous solution is cooled in an ice bath. Acetic anhydride (-1-1.5 mmol) is added, followed by addition of solid sodium bicarbonate (-185-300 mg) until there is no further effervescence, or the pH of the reaction mixture becomes approximately about 5.5. The precipitated product is filtered, washed with water (2 x 1 mL), and dried by pressing between folds of filter paper. Traces of water are removed in a vacuum desiccator to obtain N-acetyl-N-(2-(7-methoxynaphthalen-l-yl)ethyl)- acetamide, II-A. The yield was 31%. Molecular Formula = C18H19NO3 Formula Weight = 297.34836 and CHN Composition = C(72.71%) H(6.44%) N(4.71%) 0(16.14%).

[0048] 1H NMR (300 MHz, DMSO-d6) d 1.83 (s, 3H), 3.12 (t, J = 8.3 Hz, 2H), 3.33, (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 7.20 (dd, J = 9.0 and 2.4 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H) and 7.68 (d, J = 9.0 Hz, 1H). Mass Spectra- M+ = 297.135945 Da, M- = 297.137042 Da, [M+H] + = 298.14377 Da, [M+H]- = 298.144867 Da, [M- H]+ =296.12812 Da and [M-H]- = 296.129217 Da.

[0049] By using an appropriate acid anhydride or acid chloride and an analogous procedure as disclosed above, compound of formulae II-B to II-N are prepared.

II-B CH2CH3 N-acetyl-N-(2-(7-methoxynaphthalen- 1 - yl)ethyl)propionamide

II-C CH₂CH₂CH₃ N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)butyramide

II-D CH(CH₃)₂ N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)- isobutyramide

II-E C(CH₃)₃ N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)pivalamide

II-F cyclopropyl N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)- cyclopropane-carboxamide

II-G cyclobutyl N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)cyclobutane- carboxamide

II-H cyclohexyl N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)cyclohexane- carboxamide

II-I phenyl N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)benzamide

II-J 4-chlorophenyl N-acetyl-4-chloro-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)- benzamide

II-K 4-bromophenyl N-acetyl-4-bromo-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)- benzamide

II-L 4-cyanophenyl N-acetyl-4-cyano-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)- benzamide

II-M 4-nitrophenyl N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)-4-nitro- benzamide

II-N 4-methylphenyl N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)-4-methyl- benzamide

Example 2: Formula III-C

[0050] Formula III-C: Triethyl amine is added into a solution of N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide in dichloromethane. The mixture is cooled and an activated form of N-Boc-valine (e.g., O-t-butyloxycarbonyl valine) is added. The mixture is stirred for 10-12 hours and quenched the reaction by adding aqueous sodium bicarbonate. The mixture is washed with dilute HC1 (aqueous) and extracted with ethyl acetate. The organic extracts are combined and dried over a desiccant (e.g., magnesium sulfate anhydrous). The resulting reaction mixture is filtered to remove organic solvent which furnish the tert-butyl (l-(N-(2-(7-methoxy- naphthalen- 1 -yl)ethyl)acetamido)-3 -methyl- 1 -oxobutan-2-yl)carbamate .

[0051] tert-Butyl ( 1 -(N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)acetamido)-3 -methyl- 1 - oxobutan-2-yl)carbamate prepared above is dissolved in dichloromethane. The solution is cooled and trifluoroacetic acid is added. The mixture is stirred for 10-12 hours. The reaction is quenched by adding aqueous sodium bicarbonate. The mixture is extracted with ethyl acetate and the organic extracts are dried over anhydrous magnesium sulfate. The reaction mixture is filtered and the solvent removed provide the desired compound. The yield was 33%. Molecular Formula = C21H26N2O3, Formula Weight = 354.44274 and CHN Composition = C(71.16%) H(7.39%) N(7.90%) 0(13.54%. 1

[0052] 1H NMR (300 MHz, DMSO-d6) d 1.82 (s, 3H), 3.13 (t, J = 8.3 Hz, 2H), 3.32, (m, 2H), 3.94 (s, 3H), 4.2 (septet,lH), 1.6 (d, 6H), 7.21 (dd, J = 9.0 and 2.4 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H) and 7.67 (d, J = 9.0 Hz, 1H), M+ = 354.193794 Da, M- = 354.194891 Da, [M+H]+ = 355.201619 Da, [M+H]- = 355.202716 Da, [M-H]+ = 353.185969 Da and [M-H]- = 353.187066 Da.

[0053] By using an appropriate amino acid and an analogous procedure as disclosed above, compound of formulae IIIA to III-H are prepared.

III-G N-acetyl-2-amino-3-(lH-imidazol-4-yl)-N-(2-(7-

N H methoxynaphthalen- 1 -yl)ethyl)propanamide

III-H N-acetyl-2-amino-3-(lH-indol-3-yl)-N-(2-(7- methoxynaphthalen- 1 -yl)ethyl)propanamide

Example 3: Formula IV-A

[0054] Formula IV-A: N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (1 mmol) is mixed with chloroethylchloro formate (1.1 mmol) in toluene (5 ml). The flask is cooled in an ice-water bath and N-methylmoropholine (2 mmol) is added drop-wise over a period of 30 minutes. The reaction mixture is allowed to warm to room temperature, and stirred for 2 hours. Isobutyric acid (5 mmol) is added followed by drop-wise addition of premixed isobutyric acid (5 mmol) and N- methylmorpholine (5 mmol). The reaction mixture is cooled to room temperature, stirred for 16 hours, and diluted with hexane and water. The organic phase is separated and washed twice with water, twice with NaHC0₃, and brine. The organic phase is dried over anhydrous sodium sulfate and the solvent evaporated to provide the desired product. The yield was 45%. Molecular Formula = C₂₃H₂7N0₆, Formula Weight = 413.46358 and CHN Composition = C(66.81%) H(6.58%) N(3.39%) 0(23.22%).

[0055] 1H NMR (300 MHz, DMSO-d6) d 1.83 (s, 3H), 3.12 (t, J = 8.3 Hz, 2H), 3.33, (m, 2H), 3.94 (s, 3H), 7.20 (dd, J = 9.0 and 2.4 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H) and 7.68 (d, J = 9.0 Hz, 1H), 1.46 (d, 4.2 Hz, 3H), 1.15 (d, 6.9 Hz, 6H). Mass Spectra-M+ = 413.183289 Da, M- = 413.184386 Da, [M+H]+ = 414.191114 Da, [M+H]- = 414.192211 Da, [M-H]+ = 412.175464 Da, [M-H]- = 412.176561 Da.

[0056] By using an appropriate carboxylic acid and an analogous procedure as disclosed above, compounds of formulae IV-B to IV-M are prepared.

SN R³ R⁴ Product

IV-A CH₃ CH(CH₃)₂ 1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)- carbamoyl)oxy)ethyl isobutyrate

IV-B CH₃ CH₃ 1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)- carbamoyl)oxy)ethyl acetate

IV-C CH₃ CH₂CH₃ 1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)- carbamoyl)oxy)ethyl propionate

IV-D CH₃ CH₂CH₂CH₃ 1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)- carbamoyl)oxy)ethyl butyrate

IV-E CH₃ cyclobutyl 1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)- carbamoyl)oxy)ethyl cyclobutanecarboxylate

IV-F CH₃ cyclopentyl 1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)- carbamoyl)oxy)ethyl cyclopentanecarboxylate

IV-G CH₃ cyclohexyl 1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)- carbamoyl)oxy)ethyl cyclohexanecarboxylate

IV-H CH(CH₃)₂ CH(CH₃)₂ 1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)- carbamoyl)oxy)-2-methylpropyl isobutyrate

IV-I CH₂CH₃ CH(CH₃)₂ 1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)- carbamoyl)oxy)propyl isobutyrate

IV-J CH₂CH₂CH₃ CH(CH₃)₂ 1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)- carbamoyl)oxy)butyl isobutyrate

IV-K cyclobutyl CH(CH₃)₂ ((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)- carbamoyl)oxy)(cyclobutyl)methyl isobutyrate

IV-L cyclopentyl CH(CH₃)₂ ((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)- carbamoyl)oxy)(cyclopentyl)methyl isobutyrate

IV-M cyclohexyl CH(CH₃)₂ ((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)- carbamoyl)oxy)(cyclohexyl)methyl isobutyrate Example 4: Formula V-A

[0057] Formula V-A: Benzenesulfonyl chloride (3.5 mmol) was added drop-wise to a stirring solution of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (3.2 mmol), dichlormethane and pyridine. The reaction mixture was stirred at room temperature for four hours and concentrated under vacuum. The residue was purified by flash column chromatography, followed by recrystallization from an appropriate solvent to afford the desired product.

[0058] Formula V-B: Methanesulfonic anhydride (3.4 mmol) was added drop-wise to a stirring solution of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (3.2 mmol) and acetonitrile. A precipitate was formed within a minutes. The solvent was removed and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic fraction was separated dried over anhydrous magnesium sulfate. The crude was filtered, concentrated and recrystallized from appropriate solvent to get the desired product. The yield was 29%. Molecular Formula= Ci₇Hi₉N0₄S, Formula Weight= 333.40206, CHN Composition = C(61.24%) H(5.74%) N(4.20%) 0(19.20%) S(9.62%).

[0059] 1H NMR (300 MHz, DMSO-d6) d 1.83 (s, 3H), 3.12 (t, J = 8.3 Hz, 2H), 3.33, (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 7.20 (dd, J = 9.0 and 2.4 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H) and 7.68 (d, J = 9.0 Hz, 1H),. Mass Spectra-M+ = 333.102929 Da, M- = 333.104027 Da, [M+H]+ = 334.110755 Da, [M+H]-= 334.111852 Da, [M- H]+= 332.095104 Da and [M-H]- = 332.096202 Da.

[0060] By using an appropriate sulfonyl halide or appropriate sulfonyl anhydride and analogous procedure as described above, compound of formulae V-C to V-M are prepared.

v-c n-propyl N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)-N-(propyl- sulfonyl)acetamide

V-D n-butyl N-(butylsulfonyl)-N-(2-(7-methoxynaphthalen- 1 -yl)- ethyl)acetamide

V-E CF₃ N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)-N-((trifluoro- methyl)sulfonyl)acetamide

V-F CH₂Ph N-(benzylsulfonyl)-N-(2-(7-methoxynaphthalen- 1 -yl)- ethyl)acetamide

V-G 3-nitrophenyl N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)-N-((3 -nitrophenyl)- sulfonyl)acetamide

V-H 4-nitrophenyl N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)-N-((4-nitrophenyl)- sulfonyl)acetamide

V-I 3-aminophenyl N-((3-aminophenyl)sulfonyl)-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)acetamide

V-J 4-aminophenyl N-((4-aminophenyl)sulfonyl)-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)acetamide

V-K 4-fluorophenyl N-((4-fluorophenyl)sulfonyl)-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)acetamide

V-L 4-methylphenyl N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)-N-tosylacetamide

V-M 4-methoxyphenyl N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)-N-((4-methoxy- phenyl)sulfonyl)acetamide

[0061] Formula VI-A: The starting material, N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide in 2 dram (7.4 mL) was added to dichloromethane (2 mL) and diisopropylethylamine (1.2 eq.) in a vial. Dimethylsulfamoyl chloride (1.1 eq.) was added to the reaction mixture and the vial was placed on shaker for about 2-4 hours at ambient temperature. The reaction mixture was analyzed by LC/MS to confirm the formation of the desired product. The solvent was removed and the residue was purified by semi-preparative HPLC to furnish the desired product.

[0062] Formula VI -B: N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide was placed in a 2 dram (7.4 mL) vial and with 4-(dimethylamino) pyridine (1 eq.) and dichloromethane (800 μί). The vial was sealed and cooled to -78° C in a dry ice/acetone bath. Sulfuryl chloride (186 μί; 1 M in dichloromethane) was added and the vial was placed on shaker for about 30 minutes. The vial was cooled to -78° C. Separately, another vial with an appropriate amine (e.g., tert-butyl amine) (2 eq.), was mixed with triethyl amine (2.0 eq.) and dichloromethane (1 mL) and cooled to -78° C. The amine/triethyl amine solution was mixed gradually to the first vial and the vial was placed on a shaker at ambient temperature for about 1 hour. The reaction mixture was monitored by LC/MS to confirm the formation of the desired product. The solvent was removed and the residue was purified by semi preparative HPLC to get the desired product. The yield was 33%. Molecular Formula= C19H26N2O4S, Formula Weight= 378.48574, CHN Composition =

C(60.29%) H(6.92%) N(7.40%) 0(16.91%) S(8.47%).

Example 5-Formula VI:

[0063] 1H NMR (300 MHz, DMSO-d6) d 1.83 (s, 3H), 3.12 (t, J = 8.3 Hz, 2H), 3.33, (m, 2H), 3.94 (s, 3H), 7.22 (dd, J = 9.0 and 2.4 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 8.14 (br s, 1H). Mass Spectra- M+ = 378.160779 Da, M- = 378.161876 Da, [M+H]+ = 379.168604 Da, [M+H]-= 379.169701 Da, [M- H]+ = 377.152954 Da and [M-H]-= 377.154051 Da

[0064] By using an appropriate amine and an analogous procedure as described above, compound of formula VI-C to VI-H are prepared.

VI-F H phenyl N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)-N-(N-phenyl- sulfamoyl)acetamide

VI-G H CH(CH₃)Ph N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)-N-(N-( 1 - phenylethyl)sulfamoyl)acetamide

VI-H H CH₂Ph N-(N-benzylsulfamoyl)-N-(2-(7-methoxynaphthalen- 1 - yl)ethyl)acetamide

EXAMPLE 6: N-((N-(2-(7-methoxynaphthalen-l-yl)ethyl)acetamido)methyl)benzamide

[0065] N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (1 mmol) was mixed with 36 % formaldehyde (2.2 mmol) in a flask equipped with a magnetic stirrer and a condenser. The mixture was heated for 24 hours in a constant temperature bath, at 80°C, for 24 hours. The reaction mixture was decomposed over ice-cooled water and extracted three times with 15 ml of ethyl ether. The combined ether extracts was washed with water and then dry over anhydrous magnesium sulfate. The mixture was filtered to remove the organic solvent and the resulting N- (hydroxymethyl)-N-(2-(7-methoxynaphthalen-l-yl)ethyl)acetamide was purified. The purified N-(hydroxymethyl)-N-(2-(7-methoxynaphthalen-l-yl)ethyl)acetamide was dissolved in dichloromethane. Benzamide was added to the solution and the reaction mixture was refluxed for 2-10 hours. The solvent was removed and the crude product is passed through a column chromatograph using a suitable solvent (For Example Petroleum Ether or Chloroform or carbon Tetrachloride or a mixture thereof) to afford the desired product. The yield was 67%. Molecular Formula= C₂₃H24N₂0₃, Formula Weight= 376.44826 and CHN Composition = C(73.38%) H(6.43%) N(7.44%) 0(12.75%).

[0066] NMR Spectra- 1H NMR (300 MHz, DMSO-d6) d 1.83 (s, 3H), 3.12 (t, J = 8.3 Hz, 2H), 3.33, (m, 2H), 3.94 (s, 3H), 7.22 (dd, J = 9.0 and 2.4 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 8.14 (br s, 1H). Mass Spectra- M+ = 376.178144 Da, M- = 376.179241 Da, [M+H]+ = 377.185969 Da, [M+H]-= 377.187066 Da, [M-H]+ = 375.170319 Da and [M-H]- = 375.171416 Da.

EXAMPLE 7: Stability Studies in Simulated Gastric and Intestinal Fluids

[0067] The compounds of this invention are tested for stability under physiological conditions- Gastric and Intestinal Fluids over 2 hours at 37 'C and the resulting agomelatine bioprecursors are analyzed using high performance liquid chromatography. The results are shown in Table 1.

TABLE 1

EXAMPLE 8: Acute Toxicity Test

[0068] The compounds according to formula (I) were evaluated for their acute toxicity in mice. The animals weighing 16-27 grams were procured from Charles River Laboratories. They were housed in standard cages for six days for acclimatization. The animals were fed at regular intervals all six days and observed by a veterinarian. On day 7, the mice were administered with investigative compound and were observed at regular intervals during the first day and daily during the two weeks following treatment. The LD₅₀, killing 50% of the animals was evaluated and demonstrated the low toxicity of the compounds of the invention.

EXAMPLE 9: MT1 and MT2 Receptor Binding Studies

[0069] The disclosed compounds of Formula (I) were evaluated for their receptor binding at MT1 or MT2 receptors by using 2 - [¹²⁵I]-iodomelatonin as radio ligand reference. A liquid scintillation counter was used to measure the retained radioactivity. The protocol involved performing competitive binding experiments in triplicate, with various test compounds at a range of different concentrations was tested for each compound. The results are used to determine the binding affinities of the compounds tested (Ki). For example, the compound V-L, (N-(2-(7- methoxynaphthalen-l-yl)ethyl)-N-tosylacetamide ) prepared in Example 4 shows a Ki (MT1 ) of 6 nM and a Ki (MT2 ) of 0.5 nM.

EXAMPLE 10: Testing the forced swimming

[0070] The Forced Swimming Test with mice is a commonly used animal testing model for correlation of the effects of an antidepressant of drug candidates. The compounds of the formula (I) were tested in a Forced Swimming Test before and after oral administration of the test compound. The downtime of the animal was recorded in an apparatus consisting of a glass cylinder filled with water. Each animal was tested separately for 5-7 minutes by placing the animal at the center of the apparatus. Again the animal was tested 1 minute after the

administration of the test compound, before starting the test. The compounds of the formula (I) significantly reduce downtime attesting to their antidepressant activity.

EXAMPLE 11: Orcadian Rhythm activity in Rat Model

[0071] Circadian rhythms produce daily changes in critical elements of various disorders such as pain, depression and other CNS diseases. Thus, they are a reliable indicator of the activity of the endogenous circadian clock. The pharmacology of melatoninergic compounds are usually evaluated by studying circadian rhythms. The effects of compounds of formula (I) are tested on circadian rhythms of locomotor activity in Rat model. Wistar rats (weight 154=1=7 g) were procured from Charles River Laboratories and were housed in a temperature-, humidity- and light-controlled environment with free access to rodent chow and water. The animals were training in light-dark cycle was 12 hours: 12 hours with the light phase from 06:00 to 18:00 for an acclimatization period of 4 weeks. The animals were transferred to experimental cages. Each cage was placed on an Animex (MK-Animex, Muromachi Kikai, Tokyo) to detect locomotor activity. Drinking activity was measured by a drinkometer (O'Hara, Tokyo). The cage and the Animex were placed in a ventilated lightproof cabinet (71 x 46 x 35 cm) illuminated by a krypton bulb (KRlOO/110V40PS35WK, Toshiba Lightech, Tokyo) fixed on the inner wall of the cabinet, which was placed in a temperature-controlled (26 ± 2°C) experimental room.

Illumination, measured at the center of the cage, was -100 lux during the light (L)-period and 0 lux during the dark (D)-period. Although drinking and locomotor activity data behaved similarly throughout the experiment, we analyzed locomotor activity data because locomotor activity recorded by Animex was generally more distinct in the onset and offset of the activity period than was drinking activity. To determine whether locomotor activity of a rat had circadian rhythmicity, a chi-square periodogram periodogram (The chisquareperiodogram: Its utility for analysis of circadian rhythms, Phillip G. Sokolove and Wayne N. Bushell, J. of Theor. Biol., 1978, Vol. 72, No. 1, Pages 131-160.) was applied. When a significant peak was found in the circadian range, we classified the rat as having a circadian rhythm. The observations are made through visualization of the rhythms of activity such as training activity rhythms by the light rhythm, the disappearance of the rhythms in constant darkness, drive by daily administration of the molecule; effect transient or permanent. It was demonstrated that the test compounds of the formula (I) result in modulating circadian rhythm via the melatoninergic system.

EXAMPLE 12: Test of light / dark cage

[0072] Several experimental models have been developed to facilitate pre-clinical research on the behavioral pharmacology of anxiety (Belzung C, and Le Pape G, Physiol Behav. 1994, Vol. 56(3), pages 623-8; and Rodgers R.J., et al. 1997 Braz. J. Med. Biol. Res., 1997, Vol. 30(3) 289-304). One of those models, chosen for the present study, is the light/dark test (LD) are disclosed by Crawley, J.N., and Goodwin, F.K., Pharmacol. Biochem. Behav., 1980, Vol. 13(2), pages 167-70., and later further validated and modified by others (Costall, B., et al. Pharmacol. Biochem. Behav., 1989, vol. 32, pages 777 - 785), Onaivi, E.S., et al., Biol. Psychiatry, 1989, Vol. 13, pages 963 - 976, and Hascoet, M., et al., Pharmacol. Biochem. Behav., 1998, Vol. 60, pages 645 - 653).

[0073] The test compounds of formula (I) were tested in a behavioral model, the test, light / dark cage, allowing the anxiolytic activity of molecules. The light/dark box consisted of a Makrolon type III cage divided into two equally sized compartments: one light compartment painted white on three sides and the fourth side of transparent plastic (to allow video recording), and an open top and one dark compartment painted black on all four sides with a sliding lid on the top to allow for placement of the mouse. A clear Perspex tunnel connected the two compartments. The illumination in the black compartment was 50 lux, in the white area it was increased to 1000 lux, generated by an additional light source. Before each test the box was cleaned with 70% ethanol and wiped with a paper tissue. The mouse was placed in the middle of the dark compartment and was allowed to explore the test apparatus for 5 min. The time spent by mice in the illuminated box and the number of transitions through the tunnel are recorded after the first entry in the dark box. The test compounds were administered 30 minutes before the test. It was shown that the compounds of formula (I) increase of significantly the time spent in the illuminated cage and the number of transitions, which illustrates the anxiolytic activity of the disclosed compounds.

EXAMPLE 13: Injection vials

[0074] A solution of 100 g of a compound of Formula (I) and 5 g of disodium hydrogen phosphate in 3 L of double-distilled water is adjusted to pH 6.5 with 2N hydrochloric acid. The solution is sterile-filtered, filled into injection vials, lyophilized and sterile-sealed. Each injection vial contains about 5 mg of active ingredient.

EXAMPLE 14: Suppositories

[0075] A mixture of 20 mg of a compound of Formula (I) is melted with 100 g of soya lecithin and 1,400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains about 20 mg of the compound of Formula I.

EXAMPLE 15: Sterile Solution

[0076] A solution of 1 g of a compound of Formula (I), 9.38 g of NaH₂P0₄'2H₂0, 28.48 g of Na₂HP0₄ ^»2H₂0 and 0.1 g of benzalkonium chloride is prepared in 940 ml of double-distilled water. The pH is adjusted to 6.8, and the solution is made up with distilled water and sterilized by irradiation. This solution can be used, e.g., as eye drops.

EXAMPLE 16: Ointment

[0077] A compound of Formula (I), 500 mg, is mixed with 99.5 g of petroleum jelly under aseptic conditions. This provides an ointment with 0.5 % active agent.

EXAMPLE 17: Tablets

[0078] A mixture of 1 kg of a compound of Formula (I), 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in conventional manner such that each tablet contains about 10 mg of active ingredient.

EXAMPLE 18: Coated tablets

[0079] Tablets are prepared and formed by compression as described in Example 17 and covered in conventional manner with a coating prepared, e.g., with sucrose, potato starch, talc, tragacanth and colorant.

EXAMPLE 19: Capsules

[0080] The compound of Formula (I), 2 kg, is filled into hard gelatin capsules in

conventional manner so that each capsule contains about 20 mg of the active ingredient. The capsules can also use a composition having optional inactive ingredients, such as those used to from the tablets, etc.

EXAMPLE 20: Ampoules

[0081] A solution of 1 kg of a compound of a Formula (I) in 60 L of double-distilled water is filled into ampoules and lyophilized under aseptic conditions and the ampoules are sealed under sterile conditions. Each ampoule contains about 10 mg of active ingredient.

[0082] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The disclosures of each and every patent, patent application, and publication cited herein are expressly incorporated herein by reference in their entirety into this disclosure. In the case of any inconsistencies, the present disclosure, including any definitions therein will prevail. Illustrative embodiments of this disclosure are discussed and reference has been made to possible variations within the scope of this disclosure. The invention has been described with reference to various specific and preferred embodiments and techniques, these and other variations and modifications in the disclosure will be apparent to those skilled in the art without departing from the scope of the disclosure, and it should be understood that this disclosure and the claims shown below are not limited to the illustrative embodiments set forth herein.

Claims

A compound having formul

(I)

wherein R is -COR¹; -CO(CHR²)NH₂; -COO(CHR³)OCOR⁴; -S0₂R⁵; -S0₂NR⁶R⁷ or -CH₂NHCOPh;

R¹ is methyl, ethyl, n-propyl, z^'so-propyl, n-butyl, z^'so-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl, phenyl, 4-chlorophenyl, 4-bromophenyl, 4-cyanophenyl, 4- nitrophenyl or 4-methylphenyl;

R² is hydrogen, methyl, z^'so-propyl, z^'so-butyl, benzyl, imidazole-4-methyl or indole-3 - methyl;

R³ and R⁴ are independently methyl, ethyl, n-propyl, z^'so-propyl, n-butyl, z^'so-butyl, tert-butyl, cyclohexyl, cyclopentyl or cyclobutyl;

R⁵ is from methyl, ethyl, n-propyl, z^'so-propyl, n-butyl, z^'so-butyl, tert-butyl, trifluoromethyl, benzyl; phenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 4- aminophenyl, 4-fluorophenyl, 4-methylphenyl or 4-methoxyphenyl; and

R⁶ and R⁷, are independently hydrogen, ethyl, tert-butyl, z^'so-butyl, cyclohexyl, phenyl, benzyl or -CH(CH₃)Ph;

R⁸ is methyl, ethyl, n-propyl, or 1-methylethyl (isopropyl), and

R⁹ is methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, n-pentyl, t- butyl (1,1-dimethylethyl), or phenyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, having the formula:

cyclopropyl, cyclobutyl, cyclohexyl, phenyl, 4-chlorophenyl, 4-bromophenyl, 4- cyanophenyl, 4-nitrophenyl or 4-methylphenyl;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, which is;

N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)acetamide;

N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)propionamide;

N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)butyramide;

N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)-isobutyramide;

N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)pivalamide;

N-acetyl-N-(2-(7-methoxynaphthalen-l-yl)ethyl)-'cyclopropane-carboxamide;

N-acetyl-N-(2-(7-methoxynaphthalen-l-yl)ethyl)cyclobutane-carboxamide;

N-acetyl-N-(2-(7-methoxynaphthalen-l-yl)ethyl)cyclohexane-carboxamide;

N-acetyl-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)benzamide;

N-acetyl-4-chloro-N-(2-(7-methoxynaphthalen-l-yl)ethyl)-benzamide;

N-acetyl-4-bromo-N-(2-(7-methoxynaphthalen-l-yl)ethyl)-benzamide;

N-acetyl-4-cyano-N-(2-(7-methoxynaphthalen-l-yl)ethyl)-benzamide;

N-acetyl-N-(2-(7-methoxynaphthalen-l-yl)ethyl)-4-nitro-benzamide;

N-acetyl-N-(2-(7-methoxynaphthalen-l-yl)ethyl)-4-methyl-benzamide;

or a pharmaceutically acceptable salt thereof . The compound of claim 1, having the formula:

indole-3 -methyl;

or a pharmaceutically acceptable salt thereof.

The compound of claim 4, which is;

N-acetyl-2-amino-N-(2-(7-methoxynaphthalen-l-yl)-ethyl)acetamide;

N-acetyl-2-amino-N-(2-(7-methoxynaphthalen-l-yl)-ethyl)propanamide;

N-acetyl-2-amino-N-(2-(7-methoxynaphthalen- 1 -yl)-ethyl)-3 -methylbutanamide;

N-acetyl-2-amino-N-(2-(7-methoxynaphthalen-l-yl)-ethyl)-4-methylpentanamide;

N-acetyl-2-amino-N-(2-(7-methoxynaphthalen- 1 -yl)-ethyl)-3 -methylpentanamide;

N-acetyl-2-amino-N-(2-(7-methoxynaphthalen- 1 -yl)-ethyl)-3 -phenylpropanamide;

N-acetyl-2-amino-3-(lH-imidazol-4-yl)-N-(2-(7-methoxynaphthalen-l- yl)ethyl)propanamide;

N-acetyl-2-amino-3-(lH-indol-3-yl)-N-(2-(7-methoxynaphthalen-l- yl)ethyl)propanamide;

or a pharmaceutically acceptable salt thereof.

The compound of claim 1, having the formula:

(IV) wherein, R³ and R⁴ are independently methyl, ethyl, n-propyl, z^'so-propyl, n-butyl, iso- butyl, tert-butyl, cyclohexyl, cyclopentyl or cyclobutyl;

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, which is;

1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)-carbamoyl)oxy)ethyl isobutyrate; 1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)-carbamoyl)oxy)ethyl acetate;

1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)-carbamoyl)oxy)ethyl propionate; 1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)-carbamoyl)oxy)ethyl butyrate;

1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)-carbamoyl)oxy)ethyl cyclobutane- carboxylate;

1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)-carbamoyl)oxy)ethyl cyclopentane- carboxylate;

1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)-carbamoyl)oxy)ethyl cyclohexane- carboxylate;

1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)-carbamoyl)oxy)-2-methylpropyl isobutyrate;

1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)-carbamoyl)oxy)propyl isobutyrate; 1 -((acetyl(2-(7-methoxynaphthalen- 1 -yl)ethyl)-carbamoyl)oxy)butyl isobutyrate; ((acetyl(2-(7-methoxynaphthalen-l-yl)ethyl)-carbamoyl)oxy)(cyclobutyl)methyl isobutyrate;

((acetyl(2-(7-methoxynaphthalen-l-yl)ethyl)-carbamoyl)oxy)(cyclopentyl)methyl isobutyrate;

((acetyl(2-(7-methoxynaphthalen-l-yl)ethyl)-carbamoyl)oxy)(cyclohexyl)methyl isobutyrate;

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, having the formula:

trifluoromethyl, benzyl, phenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 4- aminophenyl, 4-fluorophenyl, 4-methylphenyl or 4-methoxyphenyl;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8, which is;

N-(2-(7-methoxynaphthalen-l-yl)ethyl)-N-(phenyl-sulfonyl)acetamide;

N-(2-(7-methoxynaphthalen-l-yl)ethyl)-N-(methyl-sulfonyl)acetamide;

N-(2-(7-methoxynaphthalen-l-yl)ethyl)-N-(propyl-sulfonyl)acetamide;

N-(butylsulfonyl)-N-(2-(7-methoxynaphthalen-l-yl)-ethyl)acetamide;

N-(2-(7-methoxynaphthalen-l-yl)ethyl)-N-((trifluoro-methyl)sulfonyl)acetamide;

N-(benzylsulfonyl)-N-(2-(7-methoxynaphthalen-l-yl)-ethyl)acetamide;

N-(2-(7-methoxynaphthalen-l-yl)ethyl)-N-((3-nitrophenyl)-sulfonyl)acetamide;

N-(2-(7-methoxynaphthalen-l-yl)ethyl)-N-((4-nitrophenyl)-sulfonyl)acetamide;

N-((3 -aminophenyl)sulfonyl)-N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)acetamide;

N-((4-aminophenyl)sulfonyl)-N-(2-(7-methoxynaphthalen-l-yl)ethyl)acetamide;

N-((4-fluorophenyl)sulfonyl)-N-(2-(7-methoxynaphthalen-l-yl)ethyl)acetamide;

N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)-N-tosylacetamide;

N-(2-(7-methoxynaphthalen-l-yl)ethyl)-N-((4-methoxy-phenyl)sulfonyl)acetamide; or a pharmaceutically acceptable salt thereof. The compound of claim 1 , having the formula

(VI)

wherein, R⁶ and R⁷, are independently hydrogen, ethyl, tert-butyl, z^'so-butyl, cyclohexyl, phenyl, benzyl or -CH(CH₃)Ph;

or a pharmaceutically acceptable salt thereof.

The compound of claim 10, which is;

N-(N,N-dimethylsulfamoyl)-N-(2-(7-methoxy-naphthalen-l-yl)ethyl)acetamide;

N-(N-(tert-butyl)sulfamoyl)-N-(2-(7-methoxy-naphthalen-l-yl)ethyl)acetamide;

N-(2-(7-methoxynaphthalen-l-yl)ethyl)-N-(N-methyl-sulfamoyl)acetamide;

N-(N-isobutylsulfamoyl)-N-(2-(7-methoxynaphthalen-l-yl)ethyl)acetamide;

N-(N-cyclohexylsulfamoyl)-N-(2-(7-methoxy-naphthalen-l-yl)ethyl)acetamide;

N-(2-(7-methoxynaphthalen-l-yl)ethyl)-N-(N-phenyl-sulfamoyl)acetamide;

N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)-N-(N-( 1 -phenylethyl)sulfamoyl)acetamide,

N-(N-benzylsulfamoyl)-N-(2-(7-methoxynaphthalen-l-yl)ethyl)acetamide, or a pharmaceutically acceptable salt thereof.

The compound of claim 1 , which is;

N-((N-(2-(7-methoxynaphthalen- 1 -yl)ethyl)acetamido)methyl)benzamide; or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising a compound of any of claims 1-10, and a pharmaceutically acceptable carrier.

A kit for administering a pharmaceutical composition to a subject to treat cancer or an angiogenesis-associated disease or disorder, said kit comprising a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 , an applicator, and an instructional material for the use thereof.

15. The composition of claim 64, wherein the composition is in the form of a kit.

16. A method for prevention or treatment of a pathological condition or disorder in a

mammal, wherein the condition or disorder is for treating pain and pain related sleep disorders, comprising administering to said mammal an effective amount of a compound of any of claims 1-10.

17. The method of claim 16, wherein the mammal is human.

18. A compound of any of claims 1-10 for use in medical therapy.

19. Use of a compound of any of claims 1-10 to prepare a medicament useful for prevention or treatment of a pathological condition or disorder in a mammal, wherein the condition or disorder is pain and pain related sleep disorders.

20. The use of claim 17, wherein the medicament comprises a liquid carrier.

21. The use of claim 17, wherein the medicament comprises a solid carrier.