ES2324849A1 - Indane compounds - Google Patents

Abstract

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

Description

Indane compounds

Technical field

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

State of the art

Insomnia is the most common sleep disorder, affecting 20-40% of adults, with a increasing incidence with age. Insomnia has many causes. One of them is the interruption of the normal cycle of wakefulness This asynchrony can result in pathological changes A potential therapeutic treatment that allow to correct this effect consists in the resynchronization of the wake-sleep cycle by modulating the melatoninergic system (Li-Qiang Sun, Bioorganic & Medicinal Chemistry Letters 2005, 15, 1345-49).

Melatonin is a hormone secreted in the pineal gland responsible for photoperiodic information, the control of the circadian cycle in mammals and the modulation of the physiology of the retina. The synthesis of melatonin and its secretion during the night are controlled by the suprachiasmatic nucleus and synchronized by ambient light (Osamu Uchikawa et al ., J. Med. Chem. 2002, 45, 4222-39; Pandi-Perumal et al . , Nature Clinical Practice 2007, 3 (4), 221-228).

Segregation of melatonin in humans occurs simultaneously to nighttime sleep, and the increase in Melatonin levels correlates with the increase in propensity to sleep during nightfall.

In humans, the clinical applications of melatonin range from the treatment of delay syndrome in the I dream of treating the jet lag, going through the treatment applied to night work and as a hypnotic Properly said.

Melatonin receptors have been classified such as MT1, MT2 and MT3, based on pharmacological profiles. He MT1 receptor is located in the Central Nervous System hypothalamic, while the MT2 receptor is distributed in the Central Nervous System and in the retina. The presence of MT1 and MT2 receptors at the peripheral level. Receivers MT1 and MT2 are involved in a large number of pathologies, being the most representative depression, stress, alterations of sleep, anxiety, seasonal affective disorders, cardiovascular pathology, digestive system pathology, the insomnia or fatigue due to jet lag, schizophrenia, panic attacks, melancholy, appetite disturbances, obesity, insomnia, psychotic diseases, epilepsy, diabetes, Parkinson's disease, senile dementia, alterations associated with normal or pathological aging, migraine, memory loss, Alzheimer's disease and alterations of cerebral circulation. The MT3 receiver has been recently characterized as the quinone enzyme homolog reductase-2 (QR2). MT1 and MT2 are receptors G-protein coupled (GPCR) whose stimulation by an agonist leads to a decrease in adenylate cyclase activity and a consequent decrease in intracellular cAMP.

US 4600723 and US 4665086 patents advocate the use of melatonin to minimize alterations of circadian rhythms that are produced by changing schedules day-to-night work or rapid passage through several time zones by plane ("jet lag"). Diverse families of compounds with melatoninergic activity have been described in the 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.

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

one

where the substituents R, X, X_ {1} and Y have the meanings there described.

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Patent application WO 9608466 describes indane compounds as ligands of the receptors of the Melatonin belonging to the formula:

2

where the R 1 substituents, R2, R3 and R4 and the variables A, m and n have the meanings there described.

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

Ramelteon is a nonselective compound versus to MT1 and MT2, and selective against other receptors at the central level and peripheral. The Ki is 0.014 nM for MT1 and 0.045 nM for MT2. It has a good absorption but experiences a metabolic effect First important step. It is biotransformed into four metabolites, being one of them, the M-II, active and with a important distribution volume. Ramelteon removal is of 88%.

The investigation of new agonists of the Melatonin useful in the treatment of insomnia responds to a fundamental health need, being justified by consequently continue with the investigation of compounds with improved properties

Thus, the present invention is directed to new 6- (alkoxy or phenylalkoxy) -indan-1-alkyl  acylated amines active against melatonin receptors, in particular the MT1 and MT2 receptors. Consequently, the Compounds of the present invention are useful in the treatment and prevention of all diseases mediated by MT1 and MT2 receptors. They are non-limiting examples of melatoninergic disorders depression, stress, sleep disturbances, anxiety, affective disorders seasonal, cardiovascular pathology, system pathology digestive, insomnia or fatigue due to "jet lag", the schizophrenia, panic attacks, melancholy, changes in appetite, obesity, insomnia, psychotic diseases, epilepsy, diabetes, disease Parkinson's, senile dementia, alterations associated with the normal or pathological aging, migraine, loss of memory, Alzheimer's disease and alterations of the cerebral circulation

Detailed description of the invention

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

3

where:

R_ {1} is a radical selected from the group consisting of linear or branched alkyl (C 1 -C 6), NHR 7, cycloalkyl (C 3 -C 6) and OR 8;

R2 is hydrogen or a linear alkyl radical or branched (C 1 -C 6);

R_ {3} is a radical selected from the group consisting of hydrogen, linear or branched alkyl (C_ {1} -C_ {6}) and (CH 2) n -R 9;

R 4 is hydrogen or a linear alkyl radical or branched (C 1 -C 6);

R_ {5} is a radical selected from the group consisting of hydrogen, halogen, optionally substituted phenyl by one or two same or different groups selected from linear or branched alkyl (C 1 -C 6), OR 10 and halogen or heteroaryl selected from the group consisting of isoxazolyl, pyridyl and furyl, optionally replaced by one or two same or different groups selected between linear or branched alkyl (C 1 -C 6), OR 11 and halogen;

R_ {6} is a radical selected from the group consisting of linear or branched alkyl (C_ {1} -C_ {6}) and (CH 2) m -R 12;

R 7 is a linear or branched alkyl radical (C 1 -C 6);

R 8 is a linear or branched alkyl radical (C 1 -C 6);

R 9 is an optionally phenyl radical replaced by one or two same or different groups selected between linear or branched alkyl (C 1 -C 6), OR 13 and halogen;

R 10 is a linear alkyl radical or branched (C 1 -C 6);

R 11 is a linear alkyl radical or branched (C 1 -C 6);

R 12 is an optionally phenyl radical replaced by one or two same or different groups selected between linear or branched alkyl (C 1 -C 6), OR 14 and halogen;

R 13 is a linear alkyl radical or branched (C 1 -C 6);

R 14 is a linear alkyl radical or branched (C 1 -C 6);

n is an integer from 0 to 3; Y

m is an integer from 1 to 6; and its salts and hydrates pharmaceutically acceptable.

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Pharmaceutically acceptable salts are those salts that can be administered to a patient, such as a mammal (for example, salts that have acceptable safety in mammals for a given dosage schedule). Such salts can be obtained of pharmaceutically acceptable inorganic and organic bases and of Pharmaceutically acceptable inorganic and organic acids. The salts obtained from pharmaceutically acceptable inorganic bases include ammonium, calcium, copper, ferric, ferrous, salts of lithium, magnesium, manganic, manganous, potassium, sodium, zinc and Similar. Particularly preferred are ammonium, calcium salts, magnesium, potassium and sodium. The salts obtained from organic bases Pharmaceutically acceptable include primary amine salts, secondary and tertiary, including substituted amines, amines cyclic, natural amines and the like, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, resins of polyamine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. You go out obtained from pharmaceutically acceptable acids include acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, canphosulfonic, citric, ethanesulfonic, edisyl, fumaric, Gentysic, gluconic, glucuronic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic, methanesulfonic, mucus, naphthalene sulfonic, naphthalene-1,5-disulfonic, naphthalene-2,6-disulfonic acid, nicotinic, nitric, orotic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic,  xinafoic and similar. Acids are particularly preferred citric, hydrobromic, hydrochloric, isethionic, maleic, naphthalene-1,5-disulfonic, phosphoric, sulfuric and tartaric.

The specific compounds of formula I are select from the group consisting of:

one) 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) -ethyl] -2,2-dimethyl-propionamide;

eleven) [2- (6-Methoxy-3-methyl-indan-1-yl) -ethyl] -cyclopropancarboxamide;

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-yl) -ethyl] -propionamide;

fifteen) 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-Phenyloxy-indan-1-yl) -ethyl] -propionamide;

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

twenty-one) 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; Y

2. 3) {2- [6- (4-Phenyl-butoxy) -indan-1-yl] -ethyl} -carbamate of methyl

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

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TABLE 1

4

5

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

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

Another aspect of the present invention is to provide the use of said pharmaceutical compositions in the preparation of a medicine for the treatment or prevention of melatoninergic alterations. These melatoninergic alterations are selected from depression, stress, alterations of sleep, anxiety, seasonal affective disorders, cardiovascular pathology, digestive system pathology, the insomnia or fatigue due to jet lag, schizophrenia, panic attacks, melancholy, appetite disturbances, obesity, insomnia, psychotic diseases, epilepsy, diabetes, Parkinson's disease, dementia senile, the alterations associated with normal aging or pathological, migraine, memory loss, disease Alzheimer's and brain circulation disorders.

Obtaining compounds of general formula I It is described in the following schemes, where the substituents R1, R2, R3, R4, R5 and R6 have been described above.

When R2 is not hydrogen, obtaining Compounds of general structure I are described in Scheme 1, illustrated for R_ {1} = R_ {2} = R_ {6} = Me and R_ {3} = R 4 = R 5 = H.

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Scheme one

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6

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Starting from indanone commercially Affordable II, by Horner-Emmons reaction is possible to obtain intermediates III using NaH as base and tetrahydrofuran (THF) as solvent. These nitriles unsaturated can be reduced to IV amines at atmospheric pressure using hydrogen in Pd / C in acetic acid. Finally said IV amines are converted to amides I under usual conditions of coupling with acid chlorides. Similarly, when final products I are ureas or carbamates, the reagents of coupling are the appropriate isocyanates or chloroformates respectively.

To insert a substituent in position 2 of the indane ring to finally obtain compounds of formula I, There are two alternative synthetic methods. The first of them (Scheme 2) consists in converting said position into a position Malonic capable of nucleophilic substitutions. To do this it is it is necessary to carboxylate said position by reaction of indanone II with dimethyl carbonate to yield V. Following a synthesis malonic, the substituent R 3 is inserted and finally the resulting compounds VI are decarboxylated in basic medium. TO From this point, the chemistry to follow is similar to that described in Scheme 1 above. The commented nucleophilic strategy is described in the following Scheme 2, illustrated for R2 = R 4 = R 5 = H and R 6 = Me.

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(Scheme turns to page next)

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Scheme 2

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7

8

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On the other hand, if the insertion of a R3 substituent is performed by nucleophilic substitution on the carbon 2 of the indane ring, it is necessary to convert said carbon in an electrophilic point. To do this, said position is brominated following typical bromination bromination conditions, it is that is, copper bromide in ethyl acetate at reflux, to yield compounds of structure X. At this point the carbonyl group is protects with ethylene glycol to yield the corresponding acetal XI. It is at this time when the previous acetal suffers an attack nucleophile with phenylmagnesium bromide, which after deprotection Acidic acid yields compound XII. These compounds as well obtained follow the chemistry already described in Scheme 1. The Scheme 3 picks up this second electrophilic strategy, illustrating itself for R1 = Et, R2 = R4 = R5 = H, R3 = Ph and R_ {6} = Me.

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Scheme 3

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9

10

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To enter substitution at position 3 of the indane ring is necessary to synthesize the corresponding starting indanones XIX since these are not commercial. With this objective, and for the particular case in which the group R_ {4} is methyl, starting from phenyl XV and carrying out a reaction of Horner-Emmons is possible to obtain esters unsaturated XVI. These esters after saponification lead to unsaturated acids XVII. The double link can be reduced selectively under hydrogenation in Pd / C. The resulting acids XVIII are cycled intramolecularly by reaction of Friedel-Craft, to render substituted indanones XIX which follow the chemistry already described previously in the Scheme 1. Scheme 4 collects all this last strategy synthetic that leads to compounds substituted in R4, illustrated for R_ {2} = R_ {3} = R_ {5} = H and R_ {4} = R_ {6} = Me.

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Scheme 4

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eleven

12

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The indano ring position 5 can be easily replaced by Suzuki couplings. Starting off of type I compounds where R 5 is hydrogen, by reaction With bromine in acetic acid it is possible to obtain type I compounds where R 5 is bromine. At this point the links are made of Suzuki using the corresponding aryl boronic acid or heteroaryl. Scheme 5 shows the synthesis route, illustrated for R_ {1} = Et, R2_ = R_ {3} = R_ {4} = H and R_ {6} = Me.

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Scheme 5

13

Finally it remains to address the replacement in the position R_ {6}. Starting from the 6-hydroxyindanone XXII, the corresponding ethers XXIII are obtained by alkylation of Williamson. From this point the chemistry described in Scheme 1 is applied, so yield the substituted compounds I in R 6. Scheme 6 shows said strategy, illustrating itself for R_ {2} = R_ {3} = R 4 = R 5 = H.

Scheme 6

14

The pharmaceutical compositions comprising The compounds of the present invention include those that are suitable for oral, rectal and parenteral administration (including subcutaneous, intramuscular and intravenous), if well the most appropriate route will depend on the nature and severity of the pathology that is being treated. Often the way of preferred administration for the compounds herein Invention is the oral route.

The active ingredients can be mixed with one or more pharmaceutical excipients following the techniques conventional pharmaceutical formulation. They can be used various excipients depending on the pharmaceutical form a prepare. In liquid oral compositions (such as, for example, suspensions, solutions, emulsions, aerosols and elixirs) for example, water, glycols, oils, alcohols, flavorings, preservatives, dyes and the like. In the case of solid oral compositions are used, for example, starches, sugars (such as, for example, lactose, sucrose and sorbitol), celluloses (such as, for example, hydroxypropyl cellulose, carboxymethyl cellulose, ethyl cellulose and cellulose microcrystalline), talc, stearic acid, magnesium stearate, dicalcium phosphate, gums, copovidone, surfactants such as sorbitan monooleate and polyethylene glycol, metal oxides (such as, for example, titanium dioxide and ferric oxide) and other pharmaceutical diluents such as water. They form like this homogeneous preforms that contain the compounds of the present invention

In the case of preforms the compositions are homogeneous, so that the active substance is uniformly dispersed in the composition, so that it can be divide into equal unit doses such as tablets, the dragees, powders and capsules.

Due to their ease of administration, tablets and capsules represent the most oral forms advantageous If desired, the tablets may be coated. using conventional aqueous or non-aqueous techniques. It can use a wide variety of materials to form the coatings Such materials include large number of acids. polymeric and their mixtures with other components such as example, shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the compounds of the present invention can be incorporated for administration oral or injectable include aqueous solutions, capsules filled with liquid or gel, flavored syrups, aqueous suspensions or in oil and emulsions flavored with edible oils such as example, cotton oil, sesame oil, coconut oil or peanut oil, as well as elixirs and pharmaceutical vehicles Similar. Dispersing or suspending agents suitable for Prepare aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginates, dextrans, sodium carboxymethyl cellulose, methyl cellulose, polyethylene glycol, polyvinylpirrodidone or gelatin.

A suitable dosage range to use is a total daily dose of approximately 0.1 to 500 mg, plus preferably from 1 mg to 100 mg, either in one administration single or in divided doses if necessary.

Embodiments of the invention

The present invention is further illustrated. through the following examples, which are not intended to be limiting of its reach.

Example of pharmacological evaluation one

Determination of agonist activity on receptors MT1

For screening compounds on the receptor MT1 uses a cell line that is characterized by stably overexpress the human MT1 recombinant receptor in a cell line that in turn co-expresses mitochondrial apoaequorin and the Gα16 subunit.

The Gα16 subunit belongs to the family of G proteins, constituted by GPCR in which the transduction of Intracellular signal is produced through phospholipase (PLC). The PLC activation produces an increase in the levels of inositol triphosphate leading to an increase in intracellular calcium Overexpression of Gα16 allows therefore, an increase in intracellular calcium levels independently and compatible with the transduction path of own signal of the receiver in study.

Apoaequorin is the inactive form of aequorina, a phosphoprotein that requires a prosthetic group hydrophobic, coelenterazine, to give the active form. Behind the calcium binding, aequorin oxidizes coelenterazine to coelenteramide, reaction that releases CO2 and light.

The test protocol for the screening of possible agonists is to collect the cells and keep them in suspension overnight in the presence of coelenterazine to reconstitute the aequorin. The next day the cells are injected onto a plate where the compounds to be screened are diluted and the emitted luminescence is read immediately. In the case of wanting to analyze the possible antagonism of the same compounds, after 15-30 min of the first injection, the reference agonist compound is added in the same well, and the luminescence is evaluated
issued.

The activity of the agonists is calculated as percentage of activity with respect to the agonist of reference to the concentration corresponding to your EC100. The activity of the antagonists are expressed as percent inhibition on agonist activity of reference to concentration corresponding to your EC80.

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Example of pharmacological evaluation 2

Determination of agonist activity on receptors MT2

To study agonism against receptors MT2 uses a recombinant cell line that expresses such receptors and co-express mitochondrial apoaequorin and the Gα16 subunit as well as the model used for the screened on MT1.

According to the described methodologies, it has been proven that the compounds of the present invention have turned out to be potent agonists of the MT1 and MT2 receptors. In addition, advantageously the compounds of the present invention provide relevant pharmacokinetic improvements. In this sense, the compounds of the present invention surprisingly have better metabolic stability and better brain / plasma ratios than structurally close compounds.

Thus, studies of metabolic stability determined by disappearance of the compounds to be tested by incubation in human microsomes for 120 min at 1 µM, and studies of determination of levels in plasma (ng / mL) of rat at 15 min of administration po of 1 mg / kg of the compounds to be tested have shown that the compound of Example 1 has a medium metabolic stability (between 31% and 70%) and that the compound of Example 5 has a brain / plasma ratio equal to 1.5, while comparatively the (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 a low metabolic stability (less than 30%), plasma levels of 10.1 ng / mL and a brain / plasma ratio close to zero. Therefore, the compounds exemplified as 1 and 5, despite certain structural similarities with the reference compound have unexpectedly superior properties
Pharmacokinetics

In short, the present invention provides new compounds that, despite having a certain similarity structural with state of the art compounds, surprisingly they show less biotransformation, providing in this way a more sustained dream.

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Preparation example of intermediate one

General procedure for obtaining nitriles III

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Scheme 7

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fifteen

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4.61 mL (26.2 mmol) of Diethyl 1-cyanoethyl phosphonate in 30 mL of THF dry and slowly add 1.046 g (26.2 mmol) of 60% NaH. Be stir for 1 h at room temperature. It is added in one 3.86 g (23.78 mmol) of 6-methoxy-1-indanone in 30 mL of dry THF. Stir at room temperature for 2 h plus. 50 mL of water are added and stirred for 15 min at room temperature. THF is evaporated under reduced pressure and at resulting aqueous solution is added 100 mL of acetate ethyl. The phases are separated and the organic phase is dried over anhydrous magnesium sulfate. The organic phase is evaporated and obtained 7 g of an oil that solidifies. It is recrystallized from methanol, it Filter the solid formed and wash with cold methanol. Dries on anhydrous calcium chloride. 2.5 g of a yellow solid are obtained (Yield = 53%).

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

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Preparation example of intermediate 2

General procedure for obtaining IV amines

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Scheme 8

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16

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2.5 g (12.55 mmol) of nitrile III are dissolved in 50 mL of glacial acetic acid. 0.5 g of Pd / C are added to the 10% and hydrogen atmosphere is introduced. Stir for 30 min. The catalyst is filtered and the solvent of the filtrate is evaporated under reduced pressure. 2.7 g of an oil are obtained which is suspended in 120 mL of 1M HCl and 70 mL of dichloromethane are added (DCM) Stir for 20 min and the phases are separated. The phase Aqueous is basified with 3N NaOH and extracted with DCM again. Be Take the organic phase and dry over anhydrous magnesium sulfate. Be filter and remove the solvent under reduced pressure, to yield 1.2 g of IV (Yield = 47%) in the form of yellowish oil.

HPLC-MS: 99.5% purity, M + 1 = 206

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Preparation example of intermediate 3

General procedure for obtaining indanones carboxylated V

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Scheme 9

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17

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6.05 mL (71.8 mmol) of carbonate are added dimethyl at a solution of 10 g (59.8 mmol) indanone II in 200 mL of anhydrous dimethyl formamide (DMF). They are added slowly at 0 ° C 3.59 g (90 mmol) of 60% NaH. Stir at 0 ° C for 30 min and at room temperature for 3 h. 50 mL of MeOH and the Raw is taken to dryness. 100 mL of acetonitrile are added and stir at room temperature for 12 h. The solid is filtered obtained and washed with cold acetonitrile. It is dried over CaCl2 anhydrous and 13.72 g of V are obtained as a white solid (Yield = 94%).

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

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Preparation example of intermediate 4

General procedure for obtaining rented indanones SAW

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Scheme 10

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18

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3 g (13.62 mmol) of indanone V are suspended and 2.82 g (20.43 mmol) of potassium carbonate in 150 mL of acetonitrile The halogenated derivative is slowly added corresponding (20.43 mmol) and the suspension is stirred at 40 ° C for 12 h. Allow to cool and filter the reaction crude. obtained. It is evaporated to dryness and the residue VI thus obtained is used directly in the next stage of synthesis.

Example when R 3 = Et: 3.25 g are obtained (Yield = 39%).

HPLC-MS: 95% Purity, M + 1 = 249

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Preparation example of intermediate 5

General procedure for obtaining indanones decarboxylated VII

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Scheme eleven

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19

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13.09 mmol of indanone VI are suspended in 150 mL of MeOH / H2O (1: 1) and 26.2 mmol of KOH are added. It heats up at reflux for 2 h. Allow to cool and evaporate to dryness on reaction crude. 100 mL of water are added, and stirred at room temperature for 2 h. Solid VII is filtered like this obtained, and washed with water. It is dried over calcium chloride in vacuum stove.

Example when R 3 = Et: 1.63 g are obtained (Yield: 58%).

HPLC-MS: Purity 89%, M + 1 = 191

Type VII compounds continue from here the reactions described in Scheme 1, that is, the Horner-Emmons reaction with the corresponding phosphonate, reduction to amine and coupling with corresponding acid chlorides, isocyanates or chloroformates.

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Preparation example of intermediate 6

General procedure for obtaining 2-Bromoindanones X

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Scheme 12

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twenty

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20 g (123 mmol) of indanone II are dissolved in 250 mL of ethyl acetate. 33.1 g are added at once (148 mmol) of copper bromide and under strong stirring is heated at reflux for 4 h. During the agitation a change of crude color from black to green, indicative of the reduction of copper. After the reaction is allowed to cool and filtered over Celite® The filtrate is evaporated to dryness under reduced pressure. Be they obtain 27 g of a residue that is purified by chromatography of column, using DCM as eluent. 16.6 g are thus obtained (Yield = 44%) of a yellow solid X.

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

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Preparation example of intermediate 7

General procedure for obtaining Protected 2-Bromoindanones XI

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Scheme 13

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twenty-one

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16 g (66.4 mmol) of the Bromoindanone X in 150 mL of toluene and 16.48 g (265 are added mmol) of ethylene glycol. A device is placed Dean-Stark and boil for 15 h, until the distillation of 5 mL of water. Let it cool. The oil is wash twice with 150 mL of a saturated bicarbonate solution sodium The organic phase is evaporated and a residue is obtained that is use directly in the next reaction step.

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Preparation example of intermediate 8

General procedure for obtaining indanones XII (R 3 = Ph)

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Scheme 14

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22

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2.36 g (97) are introduced into a 500 mL flask mmol) of magnesium and 100 mL of dry THF. A tip of spatula of iodine and the addition of a solution of 10.73 begins mL (102 mmol) of bromobenzene in 50 mL of dry THF. Added the first drops of said solution it is observed that the reaction is start. The rest of the solution is added slowly. Be heat at reflux for 15 min. It cools in a bathroom water-ice and once reached 0ºC is added very slowly a solution of XI (13.84 g, 48.5 mmol) in 50 mL of dry THF. After the addition is heated at reflux for 12 h. Allow to cool and pour the crude over a suspension of 100 g of ice in 100 mL of water and 30 mL of 12M HCl. It shakes strongly and THF is evaporated under reduced pressure. Dissolution Aqueous is extracted with 100 mL of DCM. It is dried over magnesium sulfate anhydrous and evaporates to dryness. 16.8 g of a residue are obtained which is purified by column chromatography using as eluent DCM / hexane. 200 mg (Yield = 2%) of the 2-phenylindanone XII.

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

Type XII compounds continue from here the reactions described in Scheme 1, that is, the Horner-Emmons reaction with the corresponding phosphonate, reduction to amine and coupling with corresponding acid chlorides, isocyanates or chloroformates.

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Preparation example of intermediate 9

General procedure for obtaining compounds XVI

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Scheme fifteen

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2. 3

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8.2 g (36.6 mmol) of phosphonoacetate are dissolved of triethyl in 50 mL of dry THF. 1.46 g (36.6 mmol) of 60% NaH. The mixture is stirred at room temperature for 30 min. After stirring the mixture obtained is added drop by drop on a solution of 5 g (33.3 mmol) of XV in 10 mL of THF dry. It is stirred for a further 8 h and the solvent is evaporated under pressure. reduced 100 mL of water and 50 mL of DCM are added. The organic phase and dried over anhydrous magnesium sulfate. Evaporates the solvent under reduced pressure and the residue obtained is purified by column chromatography using as eluent hexane / ethyl acetate 9: 1. 2.48 g are obtained (Yield = 39%) of the ester XVI.

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

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Preparation example of intermediate 10

General procedure for obtaining compounds XVII

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Scheme 16

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24

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2.5 g (11.35 mmol) of XVI are dissolved in 30 mL of ethanol It is cooled with an ice-water bath and is slowly add 100 mL of an aqueous solution of KOH (0.636 g, 11.36 mmol). It is heated at 90 ° C for 1 h. It is allowed to cool and the mixture is poured onto a solution of 5N HCl. It is extracted with ethyl acetate and the solvent is evaporated under reduced pressure. He residue obtained is recrystallized from ethyl acetate / hexane to yield 1.2 g (Yield = 55%) of acid XVII.

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

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Preparation example of intermediate eleven

General procedure for obtaining compounds XVII

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Scheme 17

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25

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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 are added (10%, 50% water). It is stirred at room temperature and under pressure. atmospheric The catalyst is filtered. The filtrate is concentrated to yield 1.1 g (Yield = 91%) of acid XVIII.

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

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Preparation example of intermediate 12

General procedure for obtaining indanones XIX

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Scheme 18

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26

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0.68 g (3.5 mmol) of acid XVIII dissolve in 50 mL of DCM. 0.3 mL (3.5 mmol) of thionyl chloride are added. It is boiled for 1 h. It is allowed to cool and evaporates the solvent under reduced pressure. The residue obtained is dissolved in 1.2 mL of dichloroethane. A third of said solution is added on a solution cooled to 0 ° C aluminum trichloride anhydrous (0.23 g, 1.7 mmol) in 15 mL of dichloroethane. After stir for 15 min at 0 ° C the remaining solution of the acid chloride and 0.35 g (2.6 mmol) of anhydrous AlCl3. It shakes again for 15 min, at room temperature. The reaction oil on ice water. Stir during 30 min until the total destruction of the excess reagent. Is removed with ethyl acetate and the organic phase is washed with 1N HCl and with 1N NaOH Dry over anhydrous sodium sulfate, filter, and dry. evaporate the solvent under reduced pressure. The residue is purified obtained by column chromatography using as eluent hexane / ethyl acetate. 0.6 g (Yield = 97%) of a  yellowish liquid XIX.

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

Compounds of type XIX continue from here the reactions described in Scheme 1, that is, the Horner-Emmons reaction with the corresponding phosphonate, reduction to amine and coupling with corresponding acid chlorides, isocyanates or chloroformates.

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Preparation example of intermediate 13

General procedure for obtaining compounds O-rented XXIII

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Scheme 19

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27

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6-hydroxyindanone dissolves XXII (2 g, 13.09 mmol) in 50 mL of acetonitrile. 3.62 g are added (26.2 mmol) of potassium carbonate and 14.4 mmol of the derivative corresponding halogenated. It is boiled for 5 h. Be Let cool and filter the reaction crude. Evaporates to dryness under reduced pressure and dissolved in DCM. Wash with 1N NaOH. The Organic phase is separated, filtered and evaporated. They are obtained from this manner the derivatives XXIII in the form of solids.

Example when R 6 = PhCH 2 CH 2: Se they obtain 3.09 g (Yield: 80%).

HPLC-MS: Purity 85%, M + 1 = 253

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

100 mg of the amine IV (0.487 mmol) are dissolved in 5 mL of anhydrous DCM. 0.339 mL of triethylamine (2,436 mmol) are added slowly and subsequently 0.069 mL (0.974 mmol) of acetyl chloride are added slowly. Stir at room temperature for 2 h 30 min. 5 mL of 1N HCl is added and stirred for 10 min. The organic phase is separated and dried. It is evaporated to dryness and 100 mg of a white solid I is obtained (Yield =
99%)

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

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

Starting from intermediate VII (R 3 = Bn) and following the reactions described in Scheme 1, that is the Horner-Emmons reaction with the corresponding phosphonate, reduction to amine and coupling with the corresponding acid chloride, the N- [2- (2-Benzyl-6-methoxy-indan-1-yl) -ethyl] -acetamide.

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

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

Similarly to example 2 and starting from the appropriate intermediates, you get the N- [2- (2-Ethyl-6-methoxy-indan-1-yl) -ethyl] -propionamide.

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

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

Similarly to example 2 and starting from the appropriate intermediates, you get the N- [2- (6-Methoxy-2-propyl-indan-1-yl) -ethyl] -propionamide.

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

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

Starting from intermediate XII and following the reactions described in Scheme 1, ie the reaction of Horner-Emmons with the corresponding phosphonate, the reduction to amine and coupling with the corresponding chloride of acid, you get the N- [2- (6-Methoxy-2-phenyl-indan-1-yl) -ethyl] -propionamide.

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

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

Starting from intermediate XIX and following the reactions described in Scheme 1, ie the reaction of Horner-Emmons with the corresponding phosphonate, the reduction to amine and coupling with the corresponding chloride of acid, you get the N- [2- (6-Methoxy-3-methyl-indan-1-yl) -ethyl] -butyramide.

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

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

Similarly to example 6 and starting from the appropriate intermediates, you get the N- [2- (6-Methoxy-3-methyl-indan-1-yl) -ethyl] -propionamide.

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

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

Similarly to example 6 and starting from the appropriate intermediates, you get the N- [2- (6-Methoxy-3-methyl-indan-1-yl) -ethyl] -acetamide.

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

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

Similarly to example 6 and starting from the appropriate intermediates, you get the 1-Ethyl-3- [2- (6-methoxy-3-methyl-indan-1-yl) -ethyl] -urea.

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

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

Similarly to example 6 and starting from the appropriate intermediates, you get the N- [2- (6-Methoxy-3-methyl-indan-1-yl) -ethyl] -2,2-dimethyl-propionamide.

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

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Example 11 [2- (6-Methoxy-3-methyl-indan-1-yl) -ethyl] -cyclopropancarboxamide

Similarly to example 6 and starting from the appropriate intermediates, you get the [2- (6-Methoxy-3-methyl-indan-1-yl) -ethyl] -cyclopropancarboxamide.

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

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

0.38 g (1.63 mmol) of the compound are dissolved initial I (R5 = H) in 50 mL of acetic acid and 0.147 are added g (1.79 mmol) of sodium acetate. It is stirred at room temperature and a solution of bromine (0.26 g, 1.63 mmol) is slowly added in 10 mL acetic acid. Stir for 1 h at temperature ambient. The crude is evaporated to dryness and dissolved in acetate ethyl. It is extracted with 5% sodium bisulfite, with solution saturated with sodium bicarbonate and with water. The organic phase dries on anhydrous magnesium sulfate, filtered and evaporated under pressure reduced 0.447 g (Yield = 88%) of an oil are obtained yellow corresponding to the N- [2- (5-Bromo-6-methoxy-indan-1-yl) -ethyl] -propionamide.

HPLC-MS: 100% Purity, M + 1 = 327

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

0.05 g (0.16 mmol) of N- [2- (5-Bromo-6-methoxy-indan-1-yl) -ethyl] -propionamide  in 20 mL of dimethoxyethane and purged with an inert atmosphere of argon. A spatula tip of palladium-tetrakis (triphenylphosphine) and se 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 75 ° C for 3 h. Allow to cool and add 100 mL of water It is extracted with 50 mL of DCM. The organic phase is dried, filter and evaporate. The residue thus obtained is purified by preparative reverse phase chromatography, using acetonitrile / water as eluents. You get this way a yellow oil that corresponds to the N- [2- (6-Methoxy-5-phenyl-indan-1-yl) -ethyl] -propionamide.

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

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

Similarly to example 13 and starting from the appropriate intermediates, a yellow oil is obtained which corresponds to the N- [2- (6-Methoxy-5-p-tolyl-indan-1-yl) -ethyl] -propionamide.

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

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

Similarly to example 13 and starting from the appropriate intermediates, a yellow oil is obtained which corresponds to the N- {2- [6-Methoxy-5- (4-methoxy-phenyl) -indan-1-yl] -ethyl} -propionamide.

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

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

Similarly to example 13 and starting from the appropriate intermediates, a yellow oil is obtained which corresponds to the N- {2- [5- (3,5-Dimethyl-isoxazol-4-yl) -6-methoxy-indan-1-yl] -ethyl} -propionamide.

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

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

Similarly to example 13 and starting from the appropriate intermediates, a yellow oil is obtained which corresponds to the N- [2- (6-Methoxy-5-pyridin-4-yl-indan-1-yl) -ethyl] -propionamide.

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

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

Similarly to example 13 and starting from the appropriate intermediates, a yellow oil is obtained which corresponds to the N- [2- (5-Furan-2-yl-6-methoxy-indan-1-yl) -ethyl] -propionamide.

HPLC-MS: Purity 98%, M + 1 = 314

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Example 19 N- [2- (6-Phenyloxy-indan-1-yl) -ethyl] -propionamide

Starting from the 6-Phenethyloxy-indanone and following the reactions described in Scheme 1, that is the reaction of Horner-Emmons with the corresponding phosphonate, the reduction to amine and coupling with the corresponding chloride of acid, you get the N- [2- (6-Phenyloxy-indan-1-yl) -ethyl] -propionamide.

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

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

Similarly to example 19 and starting from the appropriate intermediates, you get the N- {2- [6- (4-Phenyl-butoxy) -indan-1-yl] -ethyl} -propionamide.

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

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

Similarly to example 19 and starting from the appropriate intermediates, you get the N- {2- [6- (4-Phenyl-butoxy) -indan-1-yl] -ethyl} -acetamide.

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

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

Similarly to example 19 and starting from the appropriate intermediates, you get the 1-Ethyl-3- {2- [6- (4-phenyl-butoxy) -indan-1-yl] -ethyl} -urea.

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

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Example 23 {2- [6- (4-Phenyl-butoxy) -indan-1-yl] -ethyl} -carbamate of methyl

Similarly to example 19 and starting from the appropriate intermediates, you get the {2- [6- (4-Phenyl-butoxy) -indan-1-yl] -ethyl} -carbamate of methyl

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

Claims (6)

1. Indane compounds selected from the group consisting of: one) 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) -ethyl] -2,2-dimethyl-propionamide; eleven) [2- (6-Methoxy-3-methyl-indan-1-yl) -ethyl] -cyclopropancarboxamide; 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-yl) -ethyl] -propionamide; fifteen) 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-Phenyloxy-indan-1-yl) -ethyl] -propionamide; twenty) N- {2- [6- (4-Phenyl-butoxy) -indan-1-yl] -ethyl} -propionamide; twenty-one) 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; Y 2. 3) {2- [6- (4-Phenyl-butoxy) -indan-1-yl] -ethyl} -carbamate of methyl; and its salts and hydrates pharmaceutically acceptable.

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2. The use of a compound of claim 1 for the preparation of a medication for the treatment or the prevention of melatoninergic disorders. 3. The use of claim 2 wherein the melatoninergic alterations are selected from depression, the stress, sleep disturbances, anxiety, disorders Seasonal affectives, cardiovascular pathology, pathology of the digestive system, insomnia or fatigue due to the "jet lag ", schizophrenia, panic attacks, melancholy, appetite disturbances, obesity, insomnia, psychotic diseases, epilepsy, diabetes, disease of Parkinson's, senile dementia, the alterations associated with the normal or pathological aging, migraine, loss of memory, Alzheimer's disease and alterations of the cerebral circulation 4. A pharmaceutical composition comprising a compound of claim 1 and one or more excipients pharmaceutically acceptable.

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5. The use of the pharmaceutical composition of the claim 4 for the preparation of a medicament for the treatment or prevention of alterations melatoninergic 6. The use of claim 5 wherein melatoninergic alterations are selected from depression, the stress, sleep disturbances, anxiety, disorders Seasonal affectives, cardiovascular pathology, pathology of the digestive system, insomnia or fatigue due to the "jet lag ", schizophrenia, panic attacks, melancholy, appetite disturbances, obesity, insomnia, psychotic diseases, epilepsy, diabetes, disease of Parkinson's, senile dementia, the alterations associated with the normal or pathological aging, migraine, loss of memory, Alzheimer's disease and alterations of the cerebral circulation