WO2009053443A2

WO2009053443A2 - Indane compounds

Info

Publication number: WO2009053443A2
Application number: PCT/EP2008/064392
Authority: WO
Inventors: José L. FALCÓ; Albert Palomer; Antonio Guglietta
Original assignee: Ferrer Internacional S.A.
Priority date: 2007-10-25
Filing date: 2008-10-23
Publication date: 2009-04-30
Also published as: AR070951A1; TW200934477A; WO2009053443A3; ES2324849A1; CL2008003138A1; UY31422A1

Abstract

This invention provides new indane compounds, their use for the treatment or prevention of melatoninergic disorders and its compositions.

Description

INDANE COMPOUNDS

Field of the art

The present invention belongs to the field of compounds with activity on melatonin receptors, especially indanes, and more specifically acylated 6- (alkoxy or phenylalkoxy)-indan-1-alkyl amines.

State of the art

Insomnia is the most common sleep disorder and affects 20-40% of adults, with a frequency that increases with age. Insomnia has many causes. One of these is the interruption of the normal wakefulness-sleep cycle. This dyssynchrony may result in pathological changes. A potential therapeutic treatment that allows correcting said effect consists in re-synchronising the wakefulness-sleep cycle by modulating the melatoninergic system (Li-Qiang Sun, Bioorganic & Medicinal Chemistry Letters 2005, 15, 1345-49).

Melatonin is a hormone segregated by the pineal gland that is responsible for information on the light-dark cycles, for controlling the circadian rhythm in mammals and for modulating retinal physiology. Melatonin synthesis and its nightly secretion are controlled by the suprachiasmatic nucleus and synchronised by environmental light (Osamu Uchikawa et al., J. Med. Chem. 2002, 45, 4222-39; Pandi-Perumal et al., Nature Clinical Practice 2007, 3 (4), 221 -228).

Melatonin secretion in humans occurs simultaneously to sleep at night, and the increase in melatonin levels is correlated with the increase in the desire to sleep during the evening.

In humans, the clinical applications of melatonin range from treatment of the delayed sleep phase syndrome to jet lag treatment, including treatment applied to night shift workers and as a hypnotic treatment. Melatonin receptors have been classified as MT1 , MT2 and MT3 based on pharmacological profiles. The MT1 receptor is located in the hypothalamus central nervous system, whereas the MT2 receptor is distributed throughout the central nervous system and the retina. The presence of MT1 and MT2 receptors has been described at the peripheral level. The MT1 and MT2 receptors are involved in a large amount of pathologies, the most representative of these being depression, stress, sleep disorders, anxiety, seasonal affective disorders, cardiovascular pathologies, digestive system pathologies, insomnia or fatigue due to jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic diseases, epilepsy, diabetes, Parkinson's disease, senile dementia, disorders associated to normal or pathological aging, migraine, memory loss, Alzheimer's disease and brain circulation disorders. The MT3 receptor has been recently characterised as the homologue of the quinone reductase-2 (QR2) enzyme. MT1 and MT2 are G protein-coupled receptors (GPCR), the stimulation of which by an agonist leads to a reduction in adenylate cyclase activity and the resulting reduction in intracellular cAMP.

Patents US 4600723 and US 4665086 advocate the use of melatonin to minimise alterations of the circadian rhythms that occur due to changes in work shifts from days to nights or from passing quickly through several time zones in an airplane (jet lag). Several families of compounds with melatoninergic activity had been described in patent documents EP 848699B1 , US 5276051 , US

5308866, US 5633276, US 5708005, US 6034239 (ramelteon, examples 19 and 20), US 6143789, US 6310074, US 6583319, US 6737431 , US 6908931 ,

US 7235550, WO 8901472 and WO 2005062992.

Patent US 5661186 describes indane compounds as melatoninergic agents belonging to formula:

wherein the substituents R, X, Xi and Y have the meanings described therein.

Patent application WO 9608466 describes indane compounds as ligands to melatonin receptors belonging to formula:

wherein substituents Ri, R2, R3 and R₄ and variables A, m and n have the meanings described therein.

Ramelteon, N-[2-[(8S)-1 ,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8- yl)ethyl]propionamide, is the first melatonin agonist introduced in therapy. It is indicated in insomnia and its mechanism of action is based on the agonism of the MT1 and MT2 receptors.

Ramelteon is a non-selective compound against MT1 and MT2, and selective against other receptors at the central and peripheral level. Its Ki is 0.014 nM for MT1 and 0.045 nM for MT2. It has resorption, but experiences an important first-pass metabolic effect. It is biotransformed into four metabolites, one of these being M-Il, active and with an important distribution volume. Ramelteon clearance is 88%. The research of new melatonin agonists that may be useful in the treatment of insomnia responds to a fundamental health need, and therefore justifies continued research for compounds with improved properties.

Therefore, the present invention is aimed at new acylated 6-(alkoxy or phenylalkoxy)-indan-1 -alkyl amines that are active against melatonin receptors, especially MT1 and MT2 receptors. As a result, the compounds of the present invention are useful in the treatment and prevention of all those diseases that are mediated by MT1 and MT2 receptors. Some non-limiting examples of melatoninergic disorders are depression, stress, sleep disorders, anxiety, seasonal affective disorders, cardiovascular pathologies, digestive system pathologies, insomnia or fatigue due to jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic diseases, epilepsy, diabetes, Parkinson's disease, senile dementia, disorders associated to normal or pathological aging, migraine, memory loss, Alzheimer's disease and brain circulation disorders.

Detailed description of the invention

The present invention relates to indane compounds of general formula I:

wherein:

Ri is a radical chosen from the group consisting of a linear or branched (Ci-C₆) alkyl, NHR₇, (C₃-C₆) cycloalkyl and OR₈;

R₂ is hydrogen or a linear or branched (CrC₆) alkyl radical; R3 is a radical chosen from the group consisting of hydrogen, linear or branched

(CrC₆) alkyl and (CH₂)n-R₉;

R₄ is hydrogen or a linear or branched (CrC₆) alkyl radical;

R₅ is a radical chosen from the group consisting of hydrogen, a halogen , a phenyl group optionally substituted by one or two equal or different groups chosen from a linear or branched (CrC₆) alkyl, OR10 and a halogen or heteroaryl chosen from the group consisting of isoxazolyl, pyridyl and furyl, optionally substituted by one or two equal or different groups chosen from a linear or branched (CrC₆) alkyl, ORn and a halogen ; Re is a radical chosen from the group consisting of a linear or branched (CrC₆) alkyl and (CH₂)_m-Ri₂;

R₇ is a linear or branched (CrC₆) alkyl radical;

Rs is a linear or branched (CrC₆) alkyl radical;

Rg is a phenyl radical optionally substituted by one or two equal or different groups chosen from linear or branched (CrC₆) alkyl, ORi₃ and a halogen ;

Rio is a linear or branched (CrC₆) alkyl radical;

Rn is a linear or branched (CrC₆) alkyl radical;

Ri2 is a phenyl radical optionally substituted by one or two equal or different groups chosen from a linear or branched (CrC₆) alkyl, ORi₄ and a halogen ; Ri3 is a linear or branched (CrC₆) alkyl radical;

Ri₄ is a linear or branched (CrC₆) alkyl radical; is an integer from 0 to 3; and m is an integer from 1 to 6; and pharmaceutically acceptable salts and hydrates thereof.

Pharmaceutically acceptable salts are those that may be administered to a patient, such as a mammal (e.g. salts with acceptable safety in mammals for a given dosing regimen). Such salts may be obtained from pharmaceutically acceptable inorganic and organic bases and from pharmaceutically acceptable inorganic and organic acids. The salts obtained from pharmaceutically acceptable inorganic bases include ammonium, calcium, copper, ferric and ferrous salts, lithium, magnesium, manganic and manganous salts, potassium, sodium, zinc salts and the like. Especially preferred are the ammonium, calcium, magnesium, potassium and sodium salts. The salts obtained from pharmaceutically acceptable organic bases include primary, secondary and tertiary amine salts, including substituted amines, cyclic amines, natural amines and the like, such as arginine, betaine, caffeine, choline, N,N'-2- dibenzylethylendiamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpipehdine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, thethylamine, trimethylamine, tripropylamine, tromethamine and the like. The salts obtained from pharmaceutically acceptable acids include acetic, ascorbic, benzene sulphonic, benzoic, camphosulphonic, citric, ethanesulphonic, edisylic, fumaric, gentisic, gluconic, glucuronic, glutamic, hippuhc, hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic, methanesulphonic, mucic, naphthalenesulphonic, naphthalene-1 ,5-disulphonic, naphthalene-2,6- disulphonic, nicotinic, nitric, orotic, pamoic, pantothenic, phosphoric, succinic, sulphuric, tartaric, p-toluenesulphonic, xinafoic and the like. Particularly preferred are citric, hydrobromic, hydrochloric, isethionic, maleic, naphthalene- 1 ,5-disulphonic, phosphoric, sulphuric and tartaric acids.

The specific compounds of Formula I are chosen from the group consisting of:

1 ) N-[2-(6-Methoxy-indan-1 -yl)-propyl]-acetamide;

2) N-[2-(2-Benzyl-6-methoxy-indan-1 -yl)-ethyl]-acetamide;

3) N-[2-(2-Ethyl-6-methoxy-indan-1 -yl)-ethyl]-propionamide; 4) N-[2-(6-Methoxy-2-propyl-indan-1 -yl)-ethyl]-propionamide;

5) N-[2-(6-Methoxy-2-phenyl-indan-1 -yl)-ethyl]-propionamide;

6) N-[2-(6-Methoxy-3-methyl-indan-1 -yl)-ethyl]-butyramide;

7) N-[2-(6-Methoxy-3-methyl-indan-1 -yl)-ethyl]-propionamide;

8) N-[2-(6-Methoxy-3-methyl-indan-1 -yl)-ethyl]-acetamide; 9) 1 -Ethyl-3-[2-(6-methoxy-3-methyl-indan-1 -yl)-ethyl]-urea;

10) N-[2-(6-Methoxy-3-methyl-indan-1 -yl)-2,2-dimethyl-propionamide;

11 ) [2-(6-Methoxy-3-methyl-indan-1 -yl)-ethyl]-cyclopropanecarboxamide;

12) N-[2-(5-Bromine-6-methoxy-indan-1 -yl)-ethyl]-propionamide;

13) N-[2-(6-Methoxy-5-phenyl-indan-1 -yl)-ethyl]-propionamide; 14) N-[2-(6-Methoxy-5-p-tolyl-indan-1 -il)-ethyl]-propionamide;

15) N-{2-[6-Methoxy-5-(4-methoxy-phenyl)-indan-1 -yl]-ethyl}-propionamide;

16) N-{2-[5-(3,5-Dimethyl-isoxazol-4-yl)-6-methoxy-indan-1 -yl]-ethyl}- propionamide;

17) N-[2-(6-Methoxy-5-pyridin-4-yl-indan-1 -yl)-ethyl]-propionamide;

18) N-[2-(5-Furan-2-yl-6-methoxy-indan-1 -yl)-ethyl]-propionamide;

19) N-[2-(6-Phenethyloxy-indan-1 -yl)-ethyl]-propionamide;

20) N-{2-[6-(4-Phenyl-butoxy)-indan-1 -yl]-ethyl}-propionamide;

21 ) N-{2-[6-(4-Phenyl-butoxy)-indan-1 -yl]-ethyl}-acetamide;

22) 1 -Ethyl-3-{2-[6-(4-phenyl-butoxy)-indan-1 -yl]-ethyl}-urea; and

23) Methyl {2-[6-(4-Phenyl-butoxy)-indan-1 -yl]-ethyl}-carbamate.

Table 1 shows the meaning of the substituents for each compound:

Table 1

Another aspect of the present invention is to provide the use of a specific compound from Table 1 to prepare a medicinal product for the treatment or prevention of melatoninergic disorders. Said melatoninergic disorders are chosen from depression, stress, sleep disorders, anxiety, seasonal affective disorders, cardiovascular pathologies, digestive system pathologies, insomnia or fatigue due to jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic diseases, epilepsy, diabetes, Parkinson's disease, senile dementia, disorders associated to normal or pathological aging, migraine, memory loss, Alzheimer's disease and brain circulation disorders.

Another aspect of the present invention is to provide pharmaceutical compositions comprising a specific compound from Table 1 and one or more pharmaceutically acceptable excipients.

Another aspect of the present invention is to provide the use of said pharmaceutical compositions in the preparation of a medicinal product for the treatment or prevention of melatoninergic disorders. Said melatoninergic disorders are chosen from depression, stress, sleep disorders, anxiety, seasonal affective disorders, cardiovascular pathologies, digestive system pathologies, insomnia or fatigue due to jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic diseases, epilepsy, diabetes, Parkinson's disease, senile dementia, disorders associated to normal or pathological aging, migraine, memory loss, Alzheimer's disease and brain circulation disorders. How to obtain compounds of general formula I is described in the following diagrams, wherein the substituents Ri, R2, R3, R₄, R5 and Re are as described above.

When R₂ is not hydrogen, the compounds of general structure I are obtained as described in Diagram 1 , shown for Ri = R₂ = R₆ = Me and R3 = R₄ = R₅ = H.

IV

Diagram 1

Starting from commercially available indanone II, by means of a Horner-

Emmons reaction we can obtain the intermediate products III using NaH as a base and tetrahydrofurane (THF) as a solvent. These unsaturated nitriles can be reduced to amines IV at atmospheric pressure using hydrogen in Pd/C in acetic acid. Finally, said amines IV are transformed into amides I in usual conditions for coupling with acid chlorides. Similarly, when the final products I are ureas or carbamates, the coupling reagents are the appropriate isocyanates or chloroform iates, respectively.

There are two alternative synthetic methods to insert a substituent at position 2 of the indane ring to finally obtain compounds of formula I. The first of these (Diagram 2) consists in transforming said positioning into a malonic acid position capable of performing nucleophilic substitutions. To do this it is necessary to carboxylate said position by the reaction of indanone Il with dimethyl carbonate to produce V. The substituent R₃ is inserted by malonic synthesis and finally the resulting compounds Vl are decarboxylated in a basic medium. Starting at this point, the chemistry to be performed is similar to that described in Diagram 1 above. The nucleophilic strategy is described in Diagram 2 below, shown for R₂ = R₄ = Rs = H and Re = Me.

VII

Vl

VIII IX

Diagram 2

On the other hand, if the insertion of a substituent R₃ is performed by nucleophilic substitution on carbon 2 of the indane ring, it is necessary to convert said carbon into an electrophilic site. To do this, said position is brominated following typical bromation conditions for phenones, i.e. copper bromide in ethyl acetate under reflux, to provide compounds of structure X. At this point the carbonyl group is protected with ethylene glycol to provide the corresponding acetal Xl. It is at this time when the previous acetal undergoes a nucleophilic attack with phenylmagnesium bromide, which yields compound XII after deprotection in an acid medium. The compounds thus obtained follow the chemistry described above in Diagram 1. Diagram 3 shows this second electrophilic strategy, illustrated for Ri = Et, R₂ = R₄ = Rs = H, R₃ = Ph and Re = Me.

Xl XII

XIII

XIV

Diagram 3

In order to introduce substitutions at position 3 of the indane ring it is necessary to synthesise the corresponding starting indanones XIX, since these are not commercially available. To this end, and for the particular case in which the R₄ group is methyl, starting from the phenone XV and performing a Horner- Emmons reaction, it is possible to obtain the unsaturated esters XVI. After saponification these esters lead to unsaturated acids XVII. The double bond can be selectively reduced under hydrogenation to Pd/C. The resulting acids XVIII are cyclized intramolecularly by a Friedel-Craft reaction in order to yield substituted indanones XIX that follow the chemistry described above in Diagram 1. Diagram 4 shows this entire synthetic strategy that yields compounds substituted at R₄, illustrated for R₂ = R3 = R5 = H and R₄ = Re = Me.

XIX XX

XXI

Diagram 4

Position 5 of the indane ring can be easily substituted by Suzuki couplings. Starting from type I compounds wherein R₅ is hydrogen, by reaction with bromine in acetic acid it is possible to obtain type I compounds wherein R₅ is bromine. The Suzuki couplings are performed at this point using the corresponding aryl or heteroaryl boronic acid. Diagram 5 shows the synthetic pathway, illustrated for Ri = Et, R₂ = R3 = R₄ = H and Re Me.

I (R₅=H) I (R₅=Br)

Diagram 5

Finally, we must approach the substitution at position R₆. Starting from 6- hydroxyindanone XXII, the corresponding ethers are obtained by Williamson alkylation. From this point we apply the chemistry described in Diagram 1 , in order to yield compounds I substituted at R₆. Diagram 6 shows said strategy, illustrated for R₂ = R3 = R₄ = R₅ = H.

XXlIl XXIV

XXV

Diagram 6

Pharmaceutical compositions comprising compounds of the present invention include those that are adequate for oral, rectal and parenteral administration (including the subcutaneous, intramuscular and intravenous routes), although the most suitable route will depend on the nature and seriousness of the pathology being treated. The preferred administration route for the compounds of the present invention is frequently the oral route.

The active ingredients can be mixed with one or more pharmaceutical excipients following conventional pharmaceutical techniques for formulation. Several excipients can be used according to the pharmaceutical form to be prepared. Liquid oral compositions (such as, for example, suspensions, solutions, emulsions, aerosols and mouthwashes) may use, for example, water, glycols, oils, alcohols, flavour enhancers, preservatives, colorants and the like. Solid oral compositions use, for example, starches, sugars (such as, for example, lactose, sucrose and sorbitol)celluloses (such as, for example, hydroxypropyl cellulose, carboxymethyl cellulose, ethyl cellulose and microcrystalline cellulose), talc, stearic acid, magnesium stearate, dicalcium phosphate, rubbers, copovidone, surfactants such as sorbitan monooleate and polyethyleneglycol, metallic oxides (such as, for example, titanium dioxide and ferric oxide) and other pharmaceutical diluents such as water. Homogeneous preformulations are thus formed containing the compounds of the present invention.

In the case of the preformulations the compositions are homogeneous, such that the active ingredient is dispersed uniformly in the composition, which can therefore be divided in equal unit doses such as tablets, coated tablets, powders and capsules.

Tablets and capsules are most advantageous oral forms due to their ease of administration. Tablets can be coated using aqueous or nonaqueous conventional techniques if so desired. A large variety of materials can be used to form the coating. Such materials include a large number of polymeric acids and their mixtures with other components such as, for example, shellac, cetyl alcohol and cellulose acetate.

Liquid forms in which the compounds of the present invention can be incorporated for oral or injectable administration include aqueous solutions, capsules filled with fluid or gel, syrups with flavour enhancers, aqueous suspensions in oil and emulsions flavoured with edible oils such as, for example, cottonseed oil, sesame oil, coconut oil or peanut oil, as well as mouthwashes and similar pharmaceutical carriers. Suitable dispersing or suspension agents for the preparation of aqueous suspensions include synthetic and natural gums such as tragacanth, Acacia, alginates, dextranes, sodium carboxymethylcellulose, methylcellulose, polyethyleneglycol, polyvinylpyrrodidone or gelatin.

A suitable dosage range to be used is a total daily dose from 0.1 to 500 mg approximately, more preferably from 1 mg to 100 mg, either in a single administration or in separate doses if necessary.

Embodiments of the invention

The present invention is additionally illustrated by means of the following examples, which do not intent to limit the scope thereof.

Example of pharmacological assessment 1

Determination of the agonist activity on MT1 receptors

In order to screen compounds for the MT1 receptor a cell line is used that is characterised by stable overexpression of the recombinant human MT1 receptor in a cell line that in turn co-expresses mitochondrial apoaequorin and the Gα16 subunit.

The Ga16 subunit belongs to the G protein family, formed by GPCR, wherein the transduction of intracellular signals occurs via phospholipase (PLC). PLC activation produces an increase in inositol-triphosphate levels that leads to an increase in intracellular calcium. Ga16 overexpression thus allows an increase in intracellular calcium levels that is independent and compatible with the study receptor's own signal transduction pathway. Apoaequorin is the inactive form of aequorin, a phosphoprotein that requires a hydrophobic prosthetic group, coelenterazine, to produce the active form. Following its binding to calcium, the aequorin oxidises coelenterazine to coelenteramide, a reaction that releases CO2 and light.

The trial protocol for the screening of possible agonists consists in collecting the cells and keeping them in suspension overnight in the presence of coelenterazine in order to reconstitute aequorin. On the following day the cells are injected on a plate where the compounds to be screened are diluted, and the luminescence released is read immediately. When wishing to study the possible antagonism of the same compounds, the reference agonist compound is added in the same well after 15-30 min from the first injection and the luminescence released is assessed.

Agonist activity is calculated as percentage activity with respect to the reference agonist at the concentration corresponding to its EC100. Antagonist activity is expressed as percentage inhibition over the reference agonist activity at the concentration corresponding to its EC80.

Example of pharmacological assessment 2

Determination of agonist activity on MT2 receptors

In order to study agonism against MT2 receptors we use a recombinant cell line that expresses these receptors and coexpresses mitochondrial apoaequorin and the Ga16 subunit, as in the model used for MT1 screening.

According to the methodologies described, the compounds of the present invention were verified to be powerful agonists of MT1 and MT2 receptors. Moreover, the compounds of the present invention advantageously provide relevant pharmacokinetic improvements. In this sense, the compounds of the present invention remarkably have better metabolic stability and better brain/plasma ratios than structurally similar compounds. Therefore, studies of metabolic stability determined by the disappearance of the compounds to be tested by incubation in human microsomes for 120 min at 1 μM, and studies for the determination of levels in rat plasma (ng/mL) at 15 min after po administration of 1 mg/Kg of the compounds to be tested have shown that the compound from Example 1 has average metabolic stability (comprised between 31 % and 70%) and that the compound from Example 5 has a brain/plasma ratio of 1.5, whereas comparatively (1 S)-N-[2-(6-methoxy- indan-1-yl)-ethyl]-propionamide (WO 9608466 and O. Uchikawa et al., J. Med. Chem., 2002, 45, 4222-4239; compound 60) shows low metabolic stability (less than 30%). plasma levels of 10.1 ng/mL and a brain/plasma ratio close to zero. Consequently, the compounds of examples 1 and 5, despite certain structural similarities with the reference compound, show unexpectedly higher pharmacokinetic properties.

In short, the present invention provides new compounds that, despite having certain structural similarity with compounds of the state of the art, surprisingly show lower biotransformation, thus providing more sustained sleep.

Example of the preparation of intermediate products 1

General procedure for obtaining nitriles III

Diagram 7

4.61 ml_ (26.2 mmol) of diethyl 1-cyanoethylphosphonate are dissolved in 30 ml_ of dry THF and 1.046 g (26.2 mmol) of 60% NaH are slowly added. It is stirred for 1 h at room temperature. 3.86 g (23.78 mmol) of 6-methoxy-1 - indanone are added at once to 30 ml_ of dry THF. It is stirred at room temperature for 2 h more. 50 ml_ of water are added and it is stirred for 15 min at room temperature. The THF is evaporated at low pressure reduce and 100 ml_ of ethyl acetate are added to the resulting aqueous solution. The phases are separated and the organic phase is dried on anhydrous magnesium sulphate. The organic phase is evaporated and 7 g are obtained of an oil that solidifies. It is recrystallised from methanol, the solid formed is filtered and it is washed with cold methanol. It is dried over anhydrous calcium chloride. 2.5 g of a yellow solid are obtained (Yield = 53%).

HPLC-MS: Purity 99.7%, M+1 = 200

Example of the preparation of intermediate products 2

General procedure for obtaining amines IV

I" IV

Diagram 8

2.5 g (12.55 mmol) of nitrile III are dissolved in 50 ml_ of glacial acetic acid. 0.5 g of 10% Pd/C are added and it is introduced in a hydrogen atmosphere. It is stirred for 30 min. The catalyst is filtered and the solvent is evaporated from the filtrate under low pressure. 2.7 g of an oil are obtained that is suspended in 120 ml_ of 1 M HCI and 70 ml_ of dichloromethane (DCM) are added. It is stirred for 20 min and the phases are separated. The aqueous phase is basified with 3N NaOH and extracted again with DCM. The organic phase is taken and dried over anhydrous magnesium sulphate. The solvent is filtered and eliminated at low pressure to produce 1.2 g of IV (Yield = 47%) as a yellowish oil.

HPLC-MS: Purity 99.5%, M+1 = 206 Example of the preparation of intermediate products 3

General procedure for obtaining carboxylated indanones V

Diagram 9

6.05 ml_ (71.8 mmol) of dimethyl carbonate are added to a solution of 10 g (59.8 mmol) of indanone Il in 200 ml_ of anhydrous dimethylformamide (DMF). 3.59 g (90 mmol) of 60% NaH are slowly added at O⁰C. It is stirred at O⁰C for 30 min and at room temperature for 3 h. 50 ml_ of MeOH are added and the crude product is evaporated to dryness. 100 ml_ of acetonitrile are added and it is stirred at room temperature for 12 h. The solid obtained is filtered and washed with cold acetonitrile. It is dried over anhydrous CaCI₂ and 13.72 g of V are obtained as a white solid (Yield = 94%).

HPLC-MS: Purity 94%, M+1 = 221

Example of the preparation of intermediate products 4

General procedure for obtaining alkylated indanones Vl

V Vl

Diagram 10

3g (13.62 mmol) of indanone V and 2.82 g (20.43 mmol) of potassium carbonate are suspended in 150 ml_ of acetonitrile. The corresponding halogenated derivative (20.43 mmol) is slowly added and the suspension is stirred at 4O⁰C for 12 h. It is allowed to cool and the reaction crude obtained is filtered. It is evaporated to dryness and the residue Vl thus obtained is used directly in the following step of the synthesis.

Example when R₃ = Et: 3.25 g are obtained (Yield = 39%). HPLC-MS: Purity 95%, M+1 = 249

Example of the preparation of intermediate products 5

General procedure for obtaining decarboxylated indanones VII

Vl VII

Diagram 11

13.09 mmol of the indanone Vl are suspended in 150 ml_ of MeOH/H₂O (1 :1 ) and 26.2 mmol of KOH are added. It is heated under reflux for 2 h. It is allowed to cool and the reaction crude is evaporated to dryness. 100 ml_ of water are added and it is stirred at room temperature for 2 h. The solid VII thus obtained is filtered and washed with water. It is dried over calcium chloride in a vacuum drying oven.

Example when R₃ = Et: 1.63 g are obtained (Yield: 58%). HPLC-MS: Purity 89%, M+1= 191

From this point the type VII compounds follow the reactions described in Diagram 1 , i.e. the Horner-Emmons reaction with the corresponding phosphonate, the reduction to amine and the coupling with the corresponding acid chlorides, isocyanates or chloroformiates.

Example of the preparation of intermediate products 6

General procedure to obtain 2-bromoindanones X

Diagram 12

20 g (123 mmol) of indanone Il are dissolved in 250 ml_ of ethyl acetate. 33.1 g (148 mmol) of copper bromide are added at once and it is heated under reflux for 4 h with strong stirring. During the stirring a change in colour is observed in the crude from black to green, indicating the copper reduction. Once the reaction has finished it is allowed to cool and filtered over Celite®. The filtrate is evaporated to dryness under low pressure. 27 g are obtained of a residue that is purified by column chromatography, using DCM as an eluant. 16.6 g (Yield = 44%) are thus obtained of a yellow solid X.

HPLC-MS: Purity 93.7%, M+1 =242

Example of the preparation of intermediate products 7

General procedure to obtain protected 2-bromoindanones Xl

Xl

Diagram 13

16 g (66.4 mmol) of bromoindanone X are dissolved in 150 ml_ of toluene and 16.48 g (265 mmol) of ethylene glycol are added. A Dean-Stark apparatus is placed and it is brought to boil for 15 h, until the distillation of 5 ml_ of water. It is allowed to cool. The crude is washed twice with 150 ml_ of a saturated sodium bicarbonate solution. The organic phase is evaporated and a residue is obtained that is used directly in the following step of the reaction. Example of the preparation of intermediate products 8

General procedure to obtain indanones XII (R3 = Ph)

Diagram 14

2.36 g (97 mmol) of magnesium and 100 ml_ of dry THF are placed in a 500 ml_ flask. A spatula tip of iodine is added and then slowly add a solution of

10.73 ml_ (102 mmol) of bromobenzene in 50 ml_ of dry THF. The reaction can be seen to start after adding the first drops of said solution. The rest of the solution is slowly added. Heat under reflux for 15 min. It is cooled in a water-ice bath and when it reaches O⁰C add very slowly a solution of Xl (13.84 g, 48.5 mmol) in 50 ml_ of dry THF. Having finished the addition it is heated under reflux for 12 h. It is allowed to cool and then the crude product is poured over a suspension of 100 g of ice in 100 ml_ of water and 30 ml_ of 12 M HCI. It is stirred strongly and the THF is evaporated under low pressure. The aqueous solution is extracted with 100 ml_ of DCM. It is dried over anhydrous magnesium sulphate and evaporated to dryness. 16.8 g are obtained of a residue that is purified by column chromatography using DCM/hexane as an eluant. 200 mg

(Yield = 2%) are obtained of 2-phenylindanone XII.

HPLC-MS: Purity 97.6%, M+1 = 239

From this point the type XII compounds follow the reactions described in

Diagram 1 , i.e. the Horner-Emmons reaction with the corresponding phosphonate, the reduction to amine and the coupling with the corresponding acid chlorides, isocyanates or chloroformiates. Example of the preparation of intermediate products 9

General procedure for obtaining compounds XVI

XV XVI

Diagram 15

8.2 g (36.6 mmol) of triethyl phosphonoacetate are dissolved in 50 ml_ of dry THF. 1.46 g (36.6 mmol) of 60% NaH are added. The mix is stirred at room temperature for 30 min. Having finished the stirring the mix obtained is added dropwise to a solution of 5 g (33.3 mmol) of XV in 10 ml_ of dry THF. It is stirred for 8 h more and the solvent is evaporated under low pressure. 100 ml_ of water and 50 ml_ of DCM are added. The organic phase is separated and dried over anhydrous magnesium sulphate. The solvent is evaporated under low pressure and the residue obtained is purified by column chromatography using 9:1 hexane/ethyl acetate as an eluant. 2.48 g (Yield = 39%) of ester XVI are obtained.

HPLC-MS: Purity 100%, M+1 =221

Example of the preparation of intermediate products 10

General procedure for obtaining compounds XVII

XVI XVII

Diagram 16

2.5 g (11.35 mmol) of XVI are dissolved in 30 ml_ of ethanol. It is cooled in an ice-water bath and 100 ml_ of an aqueous solution of KOH (0.636 g, 11.36 mmol) are slowly added. It is heated at 9O⁰C for 1 h. It is allowed to cool and the mixture is poured over a 5 N HCI solution. The ethyl acetate is extracted and the solvent is evaporated under low pressure. The residue obtained is recrystallised from ethyl acetate/hexane to produce 1.2 g (Yield = 55%) of acid XVII.

HPLC-MS: Purity 100%, M+1 =193

Example of the preparation of intermediate products 11

General procedure for obtaining compounds XVIII

Diagram 17

A solution of 1.2 g (6.24 mmol) of XVII in 150 ml_ of ethanol is placed in a hydrogenator and 0.2 g of Pd/C (10%, 50% water) are added. It is stirred at room temperature at atmospheric pressure. The catalyst is filtered. The filtrate is concentrated to produce 1.1 g (Yield = 91 %) of acid XVIII.

HPLC-MS: Purity 100%, M+1 =195

Example of the preparation of intermediate products 12

General procedure for obtaining indanones XIX

Diagram 18 0.68 g (3.5 mmol) of acid XVIII are dissolved in 50 ml_ of DCM. 0.3 ml_ (3.5 mmol) of thionyl chloride are added. Boil for 1 h. Allow to cool and evaporate the solvent under low pressure. Dissolve the residue obtained in 1.2 ml_ of dichloroethane. Add a third of said solution over a solution of anhydrous aluminium trichloride (0.23 g, 1.7 mmol) in 15 ml_ of dichloroethane cooled to O⁰C. After stirring for 15 min at O⁰C add the rest of the acid chloride solution and 0.35 g (2.6 mmol) of anhydrous AICI3. Stir again for 15 min at room temperature. Pour the reaction crude over ice-water. Stir for 30 min until the complete destruction of excess reagent. Extract with ethyl acetate and wash the organic phase with 1 N HCI and 1 N NaOH. Dry over anhydrous sodium sulphate, filter, and evaporate the solvent under low pressure. The residue obtained is purified by column chromatography using hexane/ethyl acetate as an eluant. 0.6 g (Yield = 97%) of a yellowish liquid XIX are obtained.

HPLC-MS: Purity 100%, M+1 = 177

From this point the type XIX compounds follow the reactions described in Diagram 1 , i.e. the Horner-Emmons reaction with the corresponding phosphonate, the reduction to amine and the coupling with the corresponding acid chlorides, isocyanates or chloroform iates.

Example of the preparation of intermediate products 13

General procedure for obtaining O-alkylated compounds XXIII

XXII XXIII

Diagram 19

6-hydroxyindanone XXII (2 g, 13.09 mmol) is dissolved in 50 ml_ of acetonitrile. 3.62 g (26.2 mmol) of potassium carbonate and 14.4 mmol of the corresponding halogenated derivative are added. Boil for 5 h. Allow to cool and filter the reaction crude. Evaporate to dryness under low pressure and dissolve in DCM. Wash with 1 N NaOH. Separate the organic phase, filter and evaporate. The XXIII derivatives are thus obtained in solid form.

Example when R₆ = PhCh₂CH₂: 3.09 g are obtained (Yield: 80%). HPLC-MS: Purity 85%, M+1 = 253

Example 1

N-[2-(6-Methoxy-indan-1-yl)-propyl]-acetamide

100 mg of amine IV (0.487 mmol) are dissolved in 5 ml_ of anhydrous DCM. 0.339 ml_ of triethylamine (2.436 mmol) are slowly added and subsequently 0.069 ml_ (0.974 mmol) of acetyl chloride are slowly added. Stir at room temperature for 2 h and 30 min. 5 ml_ of 1 N HCI area added and it is stirred for 10 min. Separate the organic phase and dry. Evaporate to dryness and 100 mg are obtained of a white solid I (Yield = 99%).

HPLC-MS: Purity 99.5%, M+1 = 248

Example 2

N-[2-(2-Benzyl-6-methoxy-indan-1-yl)-ethyl]-acetamide

N-[2-(2-Benzyl-6-methoxy-indan-1 -yl)-ethyl]-acetamide is obtained starting from intermediate product VII (R₃ = Bn) and following the reactions described in Diagram 1 , i.e. the Horner-Emmons reaction with the corresponding phosphonate, the reduction to amine and coupling with the corresponding acid chloride.

HPLC-MS: Purity 99%, M+1 = 324 Example 3

N-[2-(2-Ethyl-6-methoxy-indan-1-yl)-ethyl]-propionamide

N-[2-(2-Ethyl-6-nnethoxy-indan-1-yl)-ethyl]-propionannide is obtained similarly to example 2 and starting from the appropriate intermediate products.

HPLC-MS: Purity 100%, M+1 = 276

Example 4

N-[2-(6-Methoxy-2-propyl-indan-1-yl)-ethyl]-propionamide

N-[2-(6-Methoxy-2-propyl-indan-1 -yl)-ethyl]-propionamide is obtained similarly to example 2 and starting from the appropriate intermediate products.

HPLC-MS: Purity 98%, M+1 = 290

Example 5

N-[2-(6-Methoxy-2-phenyl-indan-1-yl)-ethyl]-propionamide

N-[2-(6-Methoxy-2-phenyl-indan-1 -yl)-ethyl]-propionamide is obtained starting from intermediate product XII and following the reactions described in Diagram 1 , i.e. the Horner-Emmons reaction with the corresponding phosphonate, the reduction to amine and coupling with the corresponding acid chloride.

HPLC-MS: Purity 99.2%, M+1 = 324

Example 6

N-[2-(6-Methoxy-3-methyl-indan-1-yl)-ethyl]-butyramide N-[2-(6-Methoxy-3-methyl-indan-1 -yl)-ethyl]-butyramide is obtained starting from intermediate product XIX and following the reactions described in

Diagram 1 , i.e. the Horner-Emmons reaction with the corresponding phosphonate, the reduction to amine and coupling with the corresponding acid chloride.

HPLC-MS: Purity 99%, M+1 = 276

Example 7

N-[2-(6-Methoxy-3-methyl-indan-1-yl)-ethyl]-propionamide

N-[2-(6-Methoxy-3-methyl-indan-1 -yl)-ethyl]-propionamide is obtained similarly to example 6 and starting from the appropriate intermediate products.

HPLC-MS: Purity 95%, M+1 = 262

Example 8

N-[2-(6-Methoxy-3-methyl-indan-1-yl)-ethyl]-acetamide

N-[2-(6-Methoxy-3-methyl-indan-1 -yl)-ethyl]-acetamide is obtained similarly to example 6 and starting from the appropriate intermediate products.

HPLC-MS: Purity 82%, M+1 = 248

Example 9

1-Ethyl-3-[2-(6-methoxy-3-methyl-indan-1-yl)-ethyl]-urea

1 -Ethyl-3-[2-(6-methoxy-3-methyl-indan-1 -yl)-ethyl]-urea is obtained similarly to example 6 and starting from the appropriate intermediate products.

HPLC-MS: Purity 96%, M+1 = 277 Example 10

N-[2-(6-Methoxy-3-methyl-indan-1-yl)-ethyl]-2,2-dimethyl-propionamide

N-[2-(6-Methoxy-3-methyl-indan-1 -yl)-ethyl]-2,2-dimethyl-propionamide is obtained similarly to example 6 and starting from the appropriate intermediate products.

HPLC-MS: Purity 90%, M+1 = 290

Example 11

P-fβ-Methoxy-S-methyl-indan-i-ylj-ethylJ-cyclopropanecarboxamide

^-(θ-Methoxy-S-methyl-indan-i -ylJ-ethyll-cyclopropanecarboxamide is obtained similarly to example 6 and starting from the appropriate intermediate products.

HPLC-MS: Purity 91 %, M+1 = 274

Example 12

N-[2-(5-Bromo-6-methoxy-indan-1-yl)-ethyl]-propionamide

0.38 g (1.63 mmol) of initial compound I (R₅ = H) are dissolved in 50 mL of acetic acid and 0.147 g (1.79 mmol) of sodium acetate are added. Stir at room temperature and slowly add a bromine solution (0.26 g, 1.63 mmol) in 10 mL of acetic acid. Stir for 1 h at room temperature. Evaporate the crude product to dryness and dissolve in ethyl acetate. Extract with 5% sodium bisulphite, a saturated solution of sodium bicarbonate and water. The organic phase is dried over anhydrous magnesium sulphate, filtered and evaporated under low pressure. 0.447 g (Yield = 88%) of a yellow oil are obtained corresponding to N- [2-(5-Bromine-6-methoxy-indan-1 -yl)-ethyl]-propionamide. HPLC-MS: Purity 100%, M+1 =327

Example 13

N-[2-(6-Methoxy-5-phenyl-indan-1-yl)-ethyl]-propionamide

0.05 g (0.16 mmol) of N-[2-(5-Bromine-6-methoxy-indan-1 -yl)-ethyl]- propionamide are dissolved in 20 ml_ of dimethoxyethane and purged in an inert argon atmosphere. Add the tip of a spatula of palladium tetrakis(triphenylphosphine) and add 0.29 mmol of phenyl-boronic acid and a solution of 0.057 g (0.53 mmol) of sodium carbonate in 1 ml_ of water. Stir at 75⁰C for 3 h. Allow to cool and add 100 ml_ of water. Extract with 50 ml_ of DCM. Dry, filter and evaporate the organic phase. The residue thus obtained is purified by reverse-phase preparative chromatography, using acetonithle/water as an eluant. This produces a yellow oil corresponding to N-[2-(6-Methoxy-5- phenyl-indan-1-yl)-ethyl]-propionamide.

HPLC-MS: Purity 96%, M+1 =324

Example 14

N-[2-(6-Methoxy-5-p-tolyl-indan-1-yl)-ethyl]-propionamide

A yellow oil corresponding to N-[2-(6-Methoxy-5-p-tolyl-indan-1 -yl)-ethyl]- propionamide is obtained similarly to example 13 and starting from appropriate intermediate products.

HPLC-MS: Purity 95%, M+1 =338

Example 15

N-{2-[6-Methoxy-5-(4-methoxy-phenyl)-indan-1-yl]-ethyl}-propionamide A yellow oil corresponding to N-{2-[6-Methoxy-5-(4-methoxy-phenyl)- indan-1-yl]-ethyl}-propionamide is obtained similarly to example 13 and starting from appropriate intermediate products.

HPLC-MS: Purity 99%, M+1 =354

Example 16

N-{2-[5-(3,5-Dimethyl-isoxazol-4-yl)-6-methoxy-indan-1-yl]-ethyl}- propionamide

A yellow oil corresponding to N-{2-[5-(3,5-Dimethyl-isoxazol-4-yl)-6- methoxy-indan-1 -yl]-ethyl}-propionamide is obtained similarly to example 13 and starting from appropriate intermediate products.

HPLC-MS: Purity 99%, M+1 =343

Example 17

N-[2-(6-Methoxy-5-pyridine-4-yl-indan-1-yl)-ethyl]-propionamide

A yellow oil corresponding to N-[2-(6-Methoxy-5-pyhdine-4-yl-indan-1-yl)- ethyl]-propionamide is obtained similarly to example 13 and starting from appropriate intermediate products.

HPLC-MS: Purity 99%, M+1 =325

Example 18

N-[2-(5-Furan-2-yl-6-methoxy-indan-1-yl)-ethyl]-propionamide

A yellow oil corresponding to N-[2-(5-Furan-2-yl-6-methoxy-indan-1-yl)- ethyl]-propionamide is obtained similarly to example 13 and starting from appropriate intermediate products. HPLC-MS: Purity 98%, M+1 =314

Example 19

N-[2-(6-Phenethyloxy-indan-1-yl)-ethyl]-propionamide

N-[2-(6-Phenethyloxy-indan-1-yl)-ethyl]-propionamide is obtained starting from 6-and following the reactions described in Diagram 1 , i.e. the Horner- Emmons reaction with the corresponding phosphonate, the reduction to amine and coupling with the corresponding acid chloride.

HPLC-MS: Purity 91 %, M+1 = 338

Example 20

N-{2-[6-(4-Phenyl-butoxy)-indan-1-yl]-ethyl}-propionamide

N-{2-[6-(4-Phenyl-butoxy)-indan-1 -yl]-ethyl}-propionamide is obtained similarly to example 19 and starting from the appropriate intermediate products.

HPLC-MS: Purity 96%, M+1 = 367

Example 21

N-{2-[6-(4-Phenyl-butoxy)-indan-1-yl]-ethyl}-acetamide

N-{2-[6-(4-Phenyl-butoxy)-indan-1 -yl]-ethyl}-acetamide is obtained similarly to example 19 and starting from the appropriate intermediate products.

HPLC-MS: Purity 100%, M+1 = 352 Example 22

1-Ethyl-3-{2-[6-(4-phenyl-butoxy)-indan-1-yl]-ethyl}-urea

1 -Ethyl-3-{2-[6-(4-phenyl-butoxy)-indan-1-yl]-ethyl}-urea is obtained similarly to example 19 and starting from the appropriate intermediate products.

HPLC-MS: Purity 100%, M+1 = 382

Example 23

Methyl {2-[6-(4-Phenyl-butoxy)-indan-1-yl]-ethyl}-carbamate

Methyl {2-[6-(4-Phenyl-butoxy)-indan-1-yl]-ethyl}-carbamate is obtained similarly to example 19 and starting from the appropriate intermediate products.

HPLC-MS: Purity 99%, M+1 = 368

Claims

1. lndane compounds chosen from the group consisting of:

I ) N-[2-(6-Methoxy-indan-1 -yl)-propyl]-acetamide; 2) N-[2-(2-Benzyl-6-methoxy-indan-1 -yl)-ethyl]-acetamide;

3) N-[2-(2-Ethyl-6-methoxy-indan-1 -yl)-ethyl]-propionamide;

4) N-[2-(6-Methoxy-2-propyl-indan-1 -yl)-ethyl]-propionamide;

5) N-[2-(6-Methoxy-2-phenyl-indan-1 -yl)-ethyl]-propionamide;

6) N-[2-(6-Methoxy-3-methyl-indan-1 -yl)-ethyl]-butyramide; 7) N-[2-(6-Methoxy-3-methyl-indan-1 -yl)-ethyl]-propionamide;

8) N-[2-(6-Methoxy-3-methyl-indan-1 -yl)-ethyl]-acetamide;

9) 1 -Ethyl-3-[2-(6-methoxy-3-methyl-indan-1 -yl)-ethyl]-urea;

10) N-[2-(6-Methoxy-3-methyl-indan-1 -yl)-2,2-dimethyl-propionamide;

I 1 ) [2-(6-Methoxy-3-methyl-indan-1 -yl)-ethyl]-cyclopropanecarboxamide; 12) N-[2-(5-Bromo-6-methoxy-indan-1 -yl)-ethyl]-propionamide;

13) N-[2-(6-Methoxy-5-phenyl-indan-1 -yl)-ethyl]-propionamide;

14) N-[2-(6-Methoxy-5-p-tolyl-indan-1 -il)-ethyl]-propionamide;

15) N-{2-[6-Methoxy-5-(4-methoxy-phenyl)-indan-1 -yl]-ethyl}-propionamide;

17) N-[2-(6-Methoxy-5-pyridin-4-yl-indan-1 -yl)-ethyl]-propionamide;

18) N-[2-(5-Furan-2-yl-6-methoxy-indan-1 -yl)-ethyl]-propionamide;

19) N-[2-(6-Phenethyloxy-indan-1 -yl)-ethyl]-propionamide;

20) N-{2-[6-(4-Phenyl-butoxy)-indan-1 -yl]-ethyl}-propionamide; 21 ) N-{2-[6-(4-Phenyl-butoxy)-indan-1 -yl]-ethyl}-acetamide;

22) 1 -Ethyl-3-{2-[6-(4-phenyl-butoxy)-indan-1 -yl]-ethyl}-urea; and

23) Methyl {2-[6-(4-Phenyl-butoxy)-indan-1 -yl]-ethyl}-carbamate; and pharmaceutically acceptable salts and hydrates thereof.

2. The use of a compound of claim 1 to prepare a medicinal product for the treatment or prevention of melatoninergic disorders.

3. The use of claim 2 wherein said melatoninergic disorders are chosen from depression, stress, sleep disorders, anxiety, seasonal affective disorders, cardiovascular pathologies, digestive system pathologies, insomnia or fatigue due to jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic diseases, epilepsy, diabetes, Parkinson's disease, senile dementia, disorders associated to normal or pathological aging, migraine, memory loss, Alzheimer's disease and brain circulation disorders.

4. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable excipients.

5. The use of the pharmaceutical composition of claim 4 to prepare a medicinal product for the treatment or prevention of melatoninergic disorders.

6. The use of claim 5 wherein said melatoninergic disorders are chosen from depression, stress, sleep disorders, anxiety, seasonal affective disorders, cardiovascular pathologies, digestive system pathologies, insomnia or fatigue due to jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic diseases, epilepsy, diabetes, Parkinson's disease, senile dementia, disorders associated to normal or pathological aging, migraine, memory loss, Alzheimer's disease and brain circulation disorders.

7. A method of treating or preventing melatoninergic diseases that comprises administering an effective amount of one or more compounds of claim 1 to a patient.