ES2360435B1 - DERIVATIVES OF BISS (ARALQUIL) AMINO AND SYSTEMS (6 + 5) -HETEROAROMATICOS AND ITS USE IN THE TREATMENT OF NEURODEGENERATIVE PATHOLOGIES, INCLUDING ALZHEIMER'S DISEASE - Google Patents

Abstract

The present invention, which is included in the field of research and pharmaceutical industry, relates to chemical compounds derived from bis (aralkyl) amino and [6 + 5] heteroaryl, to the processes for their preparation, to the pharmaceutical compositions which They already contain their use for the manufacture of a medicament for the treatment of cognitive disorders. # In particular, it deals with compounds and compositions that protect neurons from mitochondrial oxidative stress, which capture radicálicas oxygen species (ROS), which increase the levels of Acetylcholine neurotransmitter and stop neurodegeneration related to the {be} -amiloid peptide dysfunction. These pharmacological properties are useful for the treatment of neurodegenerative pathologies, including Alzheimer's disease.

Description

Derivatives of bis (aralkyl) amino and [6 + 5] -heteroaromatic systems and their use in the treatment of neurodegenerative pathologies, including Alzheimer's disease.

The present invention, which is included in the field of research and pharmaceutical industry, refers to chemical compounds derived from bis (aralkyl) amino and [6 + 5] heteroaryl, to the processes for their preparation, to the pharmaceutical compositions which They already contain their use for the manufacture of a medicine for the treatment of cognitive disorders. In particular, it deals with compounds and compositions that protect neurons from mitochondrial oxidative stress, that capture radicálicas oxygen species (ROS), that increase the levels of the neurotransmitter acetylcholine and that stop neurodegeneration related to the dysfunction of the β-amyloid peptide. These pharmacological properties are useful for the treatment of neurodegenerative pathologies, including Alzheimer's disease.

Prior art

Alzheimer's disease (AD), the most common dementia in the elderly, is a complex neurodegenerative pathology of the central nervous system, characterized by a progressive loss of intellectual abilities (memory, language and reasoning) and by psychiatric disorders (apathy , anxiety, depression, aggressiveness). Although its etiology is not completely known, there are several characteristics of the disease that play an important role in this pathology, such as senile plaques (deposits of β-amyloid derived from the anomalous metabolism of the amyloid precursor protein), neurofilar tangles (compounds by abnormally hyperphosphorylated tau protein), oxidative damage in various cell structures and low levels of the neurotransmitter acetylcholine.

Current treatments are fundamentally symptomatic. In recent decades, the cholinergic approach has put four drugs on the market for the treatment of the disease: the inhibitors of the enzyme acetylcholinesterase (AChE) tacrine, donepezil, rivastigmine and galantamine, which increase neurotransmission in the cholinergic synapses of the brain, palliating cognitive deficits (Villarroya, M. et al., Expert Opin. Investig. Drugs 2007, 16, 1987-1998). So far, the only approved drug of a non-cholinergic nature is memantine, an N-methyl-D-aspartate receptor antagonist, which increases memory and intellectual abilities by modulating the glutamatergic system (Parsons, CG et al. , Neuropharmacology 2007, 53, 699-723). The drugs approved for the treatment of Alzheimer's disease are shown below:

The AChE enzyme has two important sites: the catalytic active center (CAS) where acetylcholine hydrolysis occurs and is located at the bottom of a narrow throat, and the peripheral anionic site (PAS) located at the throat entrance catalytic

In addition to its role in cholinergic transmission, AChE has other functions related to neuronal differentiation, cell adhesion and amyloid peptide aggregation. Different biochemical studies have shown that AChE favors the formation of aggregates of β-amyloid (Aβ), establishing AChE-Aβ complexes

which are more toxic than the isolated Aβ itself. Since the point of adhesion between the enzyme and the peptide is located in the PAS, dual AChE inhibitors, capable of interacting simultaneously with the CAS and PAS sites, are of great interest in AD since they can alleviate cognitive deficits and stop Aβ-related neurotoxicity (from Ferrari, GV et al., Biochemistry 2001, 40, 10447-10457). In recent years, different families of dual AChE inhibitors have been described (for example, Fernández-Bachiller, MI et al., ChemMedChem 2009, 4, 828-841; Muñoz-Torrero, D., Curr. Med. Chem. 2008, 15, 2433-2455).

On the other hand, the endogenous antioxidant system decreases with age and there is clear evidence of the implication of oxidative stress in the onset and progression of neurodegenerative diseases, including AD (Nunomura, A. et al., J. Neuropathol. Exp. Neurol 2006, 65, 631-641). Specifically, in the EA recent studies have shown that oxidative damage is a fact that precedes the appearance of other lesions characteristic of the disease, such as senile plaques and neuro fi brial clews (Gu, F. et al., Neurosci. Lett. 2008, 440, 44-48; Moreira, PI et al., CNS Neurol. Disord. Drug Targets 2008, 7, 3-10; Goldsbury, C. et al., Aging Cell 2008, 7, 771-775). Therefore, products capable of protecting neurons against oxidative stress are beneficial, both for the prevention and for the treatment of neurodegenerative diseases, among which is Alzheimer's disease EA (Zhang, HY et al., Drug Discov. Today 2006, 11, 749-754).

Melatonin is an endogenous substance, with a [6 + 5] -heteroaromatic structure, which is secreted by the pineal gland and whose levels decrease dramatically in patients affected by AD. Melatonin has a potent antioxidant action, capturing a wide variety of reactive oxygen species (ROS). It also stimulates the biosynthesis of other endogenous antioxidant enzymes, improves mitochondrial metabolism, reduces tau hyperphosphorylation and has neuroprotective actions against Aβ (Pandi-Perumal, SR et al., FEBS J. 2006, 273, 28132838; Reiter, RJ et al., Adv. Med. Sci. 2007, 52, 11-28; Tomás-Zapico, C. et al., J. Pineal Res. 2005, 39, 99-104).

Brief Description of the Invention

In a first aspect, the present invention relates to a compound of formula (I)

where

R1 to R15 are independently selected from hydrogen, alkyl (substituted or unsubstituted), cycloalkyl (substituted or unsubstituted), alkoxy (substituted or unsubstituted), alkenyl (substituted or unsubstituted), aryl (substituted

or unsubstituted), heteroaryl (substituted or unsubstituted), CORa, C (O) ORa, C (O) NRaRb, C = NRa, CN, ORa, OC (O) Ra, S (O) r-Ra , NRaRb, NRaC (O) Rb, NO2, N = CRaRb or halogen;

Ra and Rb are independently selected from hydrogen, alkyl (substituted or unsubstituted), cycloalkyl (substituted or unsubstituted), alkoxy (substituted or unsubstituted), alkenyl (substituted or unsubstituted), aryl (substituted or non-substituted) substituted), heteroaryl (substituted or unsubstituted), or halogen, with the proviso that they are not halogen when bound to an N.

r is selected from 0.1 or 2.

j and k are numbers that are independently selected between 1 and 8.

A, B, DyE are independently selected from CRaRb, CRa = CRb, CO, O, S, or NRa; where Ra and Rb are defined as before;

m, n, p, and q are numbers that are independently selected from a value between 0 and 10, with the proviso that their sum is at least four, m + n + p + q ≥ 4

XeY are independently selected from CH or N; Z is selected from CH, O, SoN, with the proviso that at least one of X, YoZ is a heteroatom;

when Z is C or N, then R11 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkoxy or substituted or unsubstituted aryloxy; when Z is O or S, then R11 does not exist.

the spacer [A] m- [B] n- [D] p- [E] q is suitable as a substituent in XoY when X or Y are C, which are C instead of CH.

or an isomer, a pharmaceutically acceptable salt, a pro-drug or a solvate thereof.

The present invention also refers to the use of the previously defined compounds of general formula I in the manufacture of a medicament or a pharmaceutical composition with neuroprotective, antioxidant and cholinergic properties, preferably for the treatment of cognitive disorders such as senile dementia, dementia vascular, cognitive impairment, attention deficit disorder, and / or neurodegenerative diseases such as Alzheimer's disease, prion pathologies (eg Creutzfeld-Jacob disease), Parkinson's disease, systemic amyloidosis, amyotrophic lateral sclerosis and related ailments.

Detailed description of the invention

The authors of the present invention have designed new multifunctional products derived from bis (aralkyl) amino- [6 + 5] heteroaryl that combine neuroprotective, antioxidant and cholinergic properties in a low molecular weight molecule. They are potent neuroprotectors against mitochondrial oxidative stress, they are capable of capturing reactive oxygen species (ROS) and increasing the levels of the neurotransmitter acetylcholine through their union with the CAS of AChE. In addition, these products bind to AChE PAS by inhibiting AChE-mediated Aβ aggregation. In addition, they are not toxic and would cross the blood brain barrier to reach their therapeutic targets located in the CNS.

The compounds of the invention are characterized by two aromatic fragments derived respectively from bis (aralkyl) amine and a heterocycle [6 + 5], linked by a suitable linker. Their biological properties can be modulated by varying the nature of the aromatic and spacer fragments, as well as modifying the number and nature of the substituents of the aromatic rings and the spacer, as well as the length of the latter. As will be demonstrated by the examples, the compounds of the invention are not toxic, have interesting neuroprotective properties against mitochondrial oxidative stress, are capable of capturing ROS free radicals, inhibit AChE by interacting simultaneously with the enzyme's CAS and PAS sites, would inhibit aggregation of the Aβ and would penetrate the CNS.

In a first aspect, the present invention relates to a compound of formula (I)

where

R1 to R15 are independently selected from hydrogen, alkyl (substituted or unsubstituted), cycloalkyl (substituted or unsubstituted), alkoxy (substituted or unsubstituted), alkenyl (substituted or unsubstituted), aryl (substituted

or unsubstituted), heteroaryl (substituted or unsubstituted), CORa, C (O) ORa, C (O) NRaRb, C = NRa, CN, ORa, OC (O) Ra, S (O) r-Ra , NRaRb, NRaC (O) Rb, NO2, N = CRaRb or halogen;

Ra and Rb are independently selected from hydrogen, alkyl (substituted or unsubstituted), cycloalkyl (substituted or unsubstituted), alkoxy (substituted or unsubstituted), alkenyl (substituted or unsubstituted), aryl (substituted or non-substituted) substituted), heteroaryl (substituted or unsubstituted), or halogen, with the proviso that they are not halogen when bound to an N.

r is selected from 0.1 or 2.

j and k are numbers that are independently selected between 1 and 8.

A, B, DyE are independently selected from CRaRb, CRa = CRb, CO, O, S, or NRa; where Ra and Rb are defined as before;

m, n, p, and q are numbers that are independently selected from a value between 0 and 10, with the proviso that their sum is at least four, m + n + p + q ≥ 4.

XeY are independently selected from CH or N; Z is selected from CH, O, SoN, with the proviso that at least one of X, YoZ is a heteroatom;

when Z is C or N, then R11 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkoxy or substituted or unsubstituted aryloxy; when Z is O or S, then R11 does not exist.

the spacer [A] m- [B] n- [D] p- [E] q is suitable as a substituent in XoY when X or Y are C, which are C instead of CH.

or an isomer, a pharmaceutically acceptable salt, a pro-drug or a solvate thereof.

The term "alkyl" refers, in the present invention, to radicals of hydrocarbon chains, linear or branched, having 1 to 10 carbon atoms, preferably 1 to 4, and which are attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, etc. The alkyl groups may be optionally substituted by one or more substituents such as halogen, hydroxyl, alkoxy, carboxyl, carbonyl, cyano, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.

The term "alkenyl" refers to hydrocarbon chain radicals containing one or more double carbon-carbon bonds, for example, vinyl, 1-propenyl, allyl, isoprenyl, 2-butenyl, 1,3-butadienyl, etc. Alkenyl radicals may be optionally substituted by one or more substituents such as halo, hydroxy, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.

"Cycloalkyl" refers, in the present invention, to a stable monocyclic or bicyclic radical of 3 to 10 members, which is saturated or partially saturated, and which only consists of carbon and hydrogen atoms, such as cyclopentyl, cyclohexyl or adamantyl and which may be optionally substituted by one or more groups such as alkyl, halogen, hydroxyl, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.

The term "aryl" refers in the present invention to a phenyl, naphthyl, indenyl, phenanthryl or anthracil radical. The aryl radical may be optionally substituted by one or more substituents such as alkyl, haloalkyl, aminoalkyl, dialkylamino, hydroxyl, alkoxy, phenyl, mercapto, halogen, nitro, cyano and alkoxycarbonyl.

The term "heterocycle" refers, in the present invention, to a stable monocyclic or bicyclic radical of 3 to 15 members, which is unsaturated, saturated or partially saturated, and consisting of carbon atoms and at least one heteroatom selected from the group consisting of nitrogen, oxygen or sulfur. Preferably it has 4 to 8 members with one or more heteroatoms and more preferably 5 to 6 members with one or more heteroatoms. For the purpose of this invention the heterocycle may be a monocyclic, bicyclic or tricyclic system, which may include fused rings. The nitrogen, carbon and sulfur atoms of the heterocyclic radical may optionally be oxidized; The nitrogen atoms may optionally be quaternized and the heterocyclic radical may be partially or fully saturated or aromatic. Examples of heterocycles may be, but are not limited to: azepines, �? Nols, imidazoles, isothiazoles, thiadiazoles, furan, tetrahydrofuran, benzimidazole, benzothiazole, piperidine, piperazine, purine, quinoline.

The term "aryloxy" refers to a radical of formula Ar-O-R, where Ar is an aryl group and R is an alkyl group as defined above.

The term "alkoxy" refers to a radical of formula O-R where R is an alkyl group as defined above.

Halogen refers to fluorine, chlorine, bromine or iodine.

In a preferred embodiment, R3-R5 and R7-R10 are H.

In a preferred embodiment, R6 is C1-C4 alkyl. In a more preferred embodiment, R6 is CH3.

In a preferred embodiment, j and k are 1.

In a preferred embodiment, R1 and R2 are independently selected from hydrogen, halogen or alkoxy.

In a preferred embodiment, the present invention relates to a compound of formula (II)

where R1, R2, R6, R11-R15 A, B, D, E, m, n, p, q, X, Y, Z, are defined as before.

Preferably, one of XYYesCyel the other CH. Preferably Z is N. Preferably, R11, R12 and R15 are H. In another preferred embodiment, the present invention relates to a compound of formula (III)

wherein R1, R2, R6, R13, R14, A, B, D, E, m, n, p, which are defined as in claim 1.

Preferably, R13 and R14 are independently selected from H, halogen, OH, or alkoxy.

Preferably, m + n + p + q is a value that is selected from 4, 5, 6, 7, 8, 9, or 10. More preferably m + n + p + q is 4.

In a preferred embodiment, the spacer [A] m- [B] n- [D] p- [E] q is selected from the formulas (CH2) rCO-NRa (CH2) s-, - (CH2) r-NRa -CO- (CH2) s-, (CH2) r-CO-O- (CH2) s-, - (CH2) rO-CO- (CH2) s-, where Ra is defined as in claim 1; rys are selected independently between 0 to 8.

Preferably spacer has the formula - (CH2) r-CO-NRa- (CH2) s-. More preferably, r is 0 and s is 2. More preferably, Ra is H.

In another preferred embodiment, the present invention relates to a compound that is selected from the following group:

•

N- (2- (1H-Indol-3-yl) ethyl) -4 - ((benzyl (methyl) amino) methyl) benzamide;

•

4 - ((Benzyl (methyl) amino) methyl) -N- (2- (5-hydroxy-1H-indol-3-yl) ethyl) benzamide;

•

4 - ((Benzyl (methyl) amino) methyl) -N- (2- (5-methoxy-1H-indole-3-yl) ethyl) benzamide;

•

4 - ((Benzyl (methyl) amino) methyl) -N- (2- (6-methoxy-1H-indol-3-yl) ethyl) benzamide;

•

4 - ((Benzyl (methyl) amino) methyl) -N- (2- (6- fl uoro-1H-indole-3-yl) ethyl) benzamide;

•

N- (2- (1H-Indol-3-yl) ethyl) -4 - (((2-chlorobenzyl) (methyl) amino) methyl) benzamide;

•

4 - (((2-Chlorobenzyl) (methyl) amino) methyl) -N- (2- (5-methoxy-1H-indol-3-yl) ethyl) benzamide;

•

N- (2- (1H-Indol-3-yl) ethyl) -4 - (((3-chlorobenzyl) (methyl) amino) methyl) benzamide;

•

4 - (((3-Chlorobenzyl) (methyl) amino) methyl) -N- (2- (5-methoxy-1H-indol-3-yl) ethyl) benzamide;

•

4 - (((3-Chlorobenzyl) (methyl) amino) methyl) -N- (2- (6-methoxy-1H-indol-3-yl) ethyl) benzamide;

•

N- (2- (1H-Indol-3-yl) ethyl) -4 - (((2-methoxybenzyl) (methyl) amino) methyl) benzamide;

•

N- (2- (5-Methoxy-1H-indol-3-yl) ethyl) -4 - (((2-methoxybenzyl) (methyl) amino) methyl) benzamide;

•

N- (2- (1H-Indol-3-yl) ethyl) -4 - (((3-methoxybenzyl) (methyl) amino) methyl) benzamide;

•

N- (2- (5-Methoxy-1H-indol-3-yl) ethyl) -4 - (((3-methoxybenzyl) methyl) amino) methyl) benzamide;

or an isomer, a pharmaceutically acceptable salt, a pro-drug or a solvate thereof.

The compounds of the present invention represented by formula (I) may include isomers, depending on the presence of multiple bonds (eg, Z, E), including optical isomers or enantiomers, depending on the presence of chiral centers. The individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention, that is, the term isomer also refers to any mixture of isomers, such as diastereomers, racemic, etc., even their optically isomers. assets or mixtures in different proportions thereof. The individual enantiomers or diastereoisomers, as well as mixtures thereof, can be separated by conventional techniques.

Also, within the scope of this invention are the prodrugs of the compounds of formula (I). The term "prodrug" or "prodrug" as used herein includes any compound derived from a compound of formula (I) - for example and not limited to: esters (including carboxylic acid esters, amino acid esters, phosphate esters, esters of sulphonate of metal salts, etc.), carbamates, amides, etc. - which when administered to an individual can be transformed directly or indirectly into said compound of formula (I) in said individual. Advantageously, said derivative is a compound that increases the bioavailability of the compound of formula (I) when administered to an individual or that enhances the release of the compound of formula (I) in a biological compartment. The nature of said derivative is not critical as long as it can be administered to an individual and provides the compound of formula (I) in a biological compartment of an individual. The preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.

The compounds of the invention may be in crystalline form as free compounds or as solvates. In this sense, the term "solvate", as used herein, includes both pharmaceutically acceptable solvates, that is, solvates of the compound of formula (I) that can be used in the manufacture of a medicament, as pharmaceutically acceptable solvates, which may be useful in the preparation of pharmaceutically acceptable solvates or salts. The nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable. In a particular embodiment, the solvate is a hydrate. Solvates can be obtained by conventional solvation methods known to those skilled in the art.

For application in therapy, the compounds of formula (I), their salts, prodrugs or solvates, will preferably be found in a pharmaceutically acceptable or substantially pure form, that is, having a pharmaceutically acceptable level of purity excluding pharmaceutical additives. normal such as diluents and carriers, and not including material considered toxic at normal dosage levels. The purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, and still more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (I), or of its salts, solvates or prodrugs.

The compounds of the present invention of formula (I) can be obtained or produced by a chemical synthetic route or obtained from a natural material of different origin.

In another aspect, the present invention relates to a process for obtaining a compound of formula (I) comprising:

a) Dissolve a compound of formula (IV):

wherein R1-R10, [A] m, j and k are defined as in claim 1, in anhydrous dimethylformamide. b) Add triethylamine and benzotriazol-1-yl-oxytripyrrolidinphosphonium hexa fluorophosphate (PyBOP) to the solution of step (a) under inert conditions. c) Dissolve a compound of formula (V)

in anhydrous dimethylformamide,

d) React the solution obtained in step (b) with the solution obtained in step (c) at room temperature.

In another aspect, the present invention also relates to pharmaceutical compositions comprising at least one compound of the invention, or a tautomer, a pharmaceutically acceptable salt, a derivative or a prodrug thereof, together with a pharmaceutically acceptable carrier or carrier, an excipient or a vehicle, for administration to a patient.

In a preferred embodiment, the pharmaceutical composition further comprises another active ingredient.

The pharmaceutically acceptable adjuvants and vehicles that can be used in said compositions are the adjuvants and vehicles known to those skilled in the art and commonly used in the elaboration of therapeutic compositions.

In the sense used in this description, the term "therapeutically effective amount" refers to the amount of the agent or compound capable of developing the therapeutic action determined by its pharmacological properties, calculated to produce the desired effect and, in general, will be determined, among other causes, due to the characteristics of the compounds, including the age, condition of the patient, the severity of the alteration or disorder, and the route and frequency of administration.

The compounds described in the present invention, their salts, prodrugs and / or solvates as well as the pharmaceutical compositions containing them can be used together with other drugs, or additional active ingredients, to provide a combination therapy. Said additional drugs may be part of the same pharmaceutical composition or, alternatively, they may be provided in the form of a separate composition for simultaneous or non-simultaneous administration to the pharmaceutical composition comprising a compound of formula (I), or a salt, prodrug or solvate thereof.

In another particular embodiment, said therapeutic composition is prepared in the form of a solid form or aqueous suspension, in a pharmaceutically acceptable diluent. The therapeutic composition provided by this invention may be administered by any appropriate route of administration, for which said composition will be formulated in the pharmaceutical form appropriate to the route of administration chosen. In a particular embodiment, administration of the therapeutic composition provided by this invention is performed orally, topically, rectally or parenterally (including subcutaneously, intraperitoneally, intradermally, intramuscularly, intravenously, etc.).

In a preferred embodiment of the present invention, the pharmaceutical compositions are suitable for oral administration, in solid or liquid form. Possible forms for oral administration are tablets, capsules, syrups or solutions and may contain conventional excipients known in the pharmaceutical field, such as additives (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinyl pyrrolidone), fillers (eg lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), disintegrants (eg starch, polyvinyl pyrrolidone or microcrystalline cellulose) or a pharmaceutically acceptable surfactant such as sodium lauryl sulfate.

Compositions for oral administration can be prepared by conventional methods of Galenic Pharmacy, as mixing and dispersion. The tablets can be coated following methods known in the pharmaceutical industry.

The pharmaceutical compositions can be adapted for parenteral administration, such as sterile solutions, suspensions, or lyophilized products of the invention, using the appropriate dose. Suitable excipients, such as pH buffering agents or surfactants, can be used.

The aforementioned formulations can be prepared using conventional methods, such as those described in the Pharmacopoeias of different countries and in other reference texts.

The administration of the compounds or compositions of the present invention can be performed by any suitable method, such as intravenous infusion and oral, intraperitoneal or intravenous routes. Oral administration is preferred for the convenience of patients and for the chronic nature of the diseases to be treated.

The amount administered of a compound of the present invention will depend on the relative efficacy of the compound chosen, the severity of the disease to be treated and the weight of the patient. However, the compounds of this invention will be administered one or more times a day, for example 1, 2.3 or 4 times a day, with a total dose between 0.1 and 1000 mg / kg / day. It is important to keep in mind that it may be necessary to introduce variations in the dose, depending on the age and condition of the patient, as well as modifications in the route of administration.

The compounds and compositions of the present invention can be used together with other medicaments in combination therapies. The other drugs may be part of the same composition or of a different composition, for administration at the same time or at different times.

In another aspect the present invention refers to the use of at least one compound of formula (I) for the manufacture of a medicament.

In another aspect the present invention relates to the use of at least one compound of formula (I) for the manufacture of a medicament for the treatment of a cognitive disorder that is selected from senile dementia, cerebrovascular dementia, mild alteration of knowledge, disorders of the attention deficit, neurodegenerative dementia diseases associated with aberrant protein aggregations such as Alzheimer's disease, amyotrophic lateral sclerosis, prion diseases such as Creutzfeldt-Jakob disease or Gerstmann-Straussler-Scheinker disease, Parkinson's disease, polyglutamine disease , tauopathies such as Pick's disease, frontotemporal dementia, progressive supranuclear palsy or systemic amyloidosis.

Preferably, the cognitive disorder is Alzheimer's disease.

The use of the compounds of the invention is compatible with their use in protocols in which the compounds of the formula (I), or mixtures thereof are used by themselves or in combinations with other treatments or any medical procedure.

In a final aspect, the present invention relates to the use of a compound of formula (I) as a reagent in biological assays.

Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.

Examples

Example 1

Synthesis of the compounds of the invention

Scheme 1 shows the process for the preparation of the compounds of the invention of general formula I, when the connector contains an amide group. Other methods of synthesizing compounds with amine, ether or ester type bonds are apparent to an experienced chemist.

Scheme 1

For example, to a solution of the corresponding bis (aralkyl) amine derivative (0.5 mmol) in anhydrous dimethylformamide (DMF, 8 mL), triethylamine (1.2 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium (PyBOP 0.6) was added mmol), and the corresponding amino derivative (0.5 mmol), under an inert atmosphere. The mixture was stirred at room temperature overnight and then the DMF was evaporated to dryness under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL) and washed consecutively with an aqueous solution of citric acid (10%, 3x10 mL), an aqueous solution of NaHCO3 (10% 3x10 mL) and water (3x10 mL). The organic phase was dried over Na2SO4, the solvent was completely removed under reduced pressure.

The reaction products can be purified by conventional methods, such as crystallization or chromatography. When the process described above leads to mixtures of isomers, they can be separated by conventional techniques such as preparative chromatography. In the case of stereogenic centers the compounds can be obtained in the form of racemic or pure enantiomers can be prepared by stereospecific synthesis or by resolution.

Example 1.1

N- (2- (1H-Indol-3-yl) ethyl) -4 - ((benzyl (methyl) amino) methyl) benzamide

Pale yellow solid. Yield: 46%. Mp .: 94-96 ° C. MS (HEI): m / e = 398 [M + H] +. 1H-NMR (400 MHz, CDCl3), δ (ppm): 8.20 (s, NH), 7.65 (s, 1H), 7.62 (d, 2H, J = 8.2), 7.37 (d, 2H, J = 8.2) , 7.33 (m, 5H), 7.25 (m, 1H),

7.21 (td, 1H, J = 7.1, J = 1.0), 7.12 (td, 1H, J = 7.9, J = 1.0), 7.05 (m, 1H), 6.22 (t, NH, J = 5.4), 3.79 ( q, 2H, J = 6.6), 3.53 (s, 2H), 3.51 (s, 2H), 3.09 (t, 2H, J = 6.6), 2.16 (s, 3H). 13C-NMR (400 MHz, CDCl3), δ (ppm): 167.4 (CONH), 142.9 (C), 138.8 (C), 136.4 (C), 133.4 (C), 128.9 (2CH), 128.9 (2CH), 128.3 (2CH), 127.3 (C), 127.1 (CH), 126.8 (2CH),

122.2 (CH), 122.1 (CH), 119.5 (CH), 118.7 (CH), 113.0 (C), 111.3 (CH), 61.8 (CH2), 61.3 (CH2), 42.2 (CH3), 40.2 (CH2), 25.3 (CH2). Analysis (%), calculated for C26H27N3O: C, 78.56, H, 6.85, N, 10.57; Found: C, 78.95, H, 7.20, N, 10.48.

Example 1.2

4 - ((Benzyl (methyl) amino) methyl) -N- (2- (5-hydroxy-1H-indole-3-yl) ethyl) benzamide

Solid white. Yield: 30%. Mp .: 75-77 ° C. MS (HEI): m / e = 414 [M + H] +. 1H-NMR (500 MHz, CD3OD), δ (ppm): 7.74 (d, 2H, J = 8.2), 7.41 (d, 2H, J = 8.2), 7.32 (m, 4H), 7.24 (t, 1H, J = 7.1), 7.15 (d, 1H, J = 8.5), 7.03 (s, 1H), 6.99 (d, 1H, J = 2.2), 6.66 (dd, 1H, J = 8.5, J = 2.2), 3.63 (d, 2H, J = 7.4), 3.54 (s, 2H), 3.51 (s, 2H), 2.98 (t, 2H, J = 7.4), 2.16 (s, 3H). 13C-NMR (500 MHz, CD3OD), δ (ppm): 170.6 (CONH), 151.7 (C), 144.2 (C), 140.1 (C), 135.3 (C), 133.6 (C), 130.8 (2CH), 130.7 (2CH), 130.0 (C), 129.8 (2CH), 128.8 (CH), 128.7 (2CH), 124.7 (CH), 113.2 (CH), 113.1 (C), 112.9 (CH), 104.1 (CH), 63.3 (CH2), 62.7 (CH2), 42.9 (CH3), 42.5 (CH2), 26.8 (CH2) Analysis (%), calculated for C26H27N3O2: C, 75.52, H, 6.58, N, 10.16; Found: C, 75.12, H, 6.37, N, 9.93.

Example 1.3

4 - ((Benzyl (methyl) amino) methyl) -N- (2- (5-methoxy-1H-indole-3-yl) ethyl) benzamide

Pale yellow solid. Yield: 72%. Mp .: 102-103 ° C. MS (HEI): m / e = 428 [M + H] +. 1H-NMR (400 MHz, CDCl3), δ (ppm): 8.68 (s, NH), 7.66 (d, 2H, J = 8.2), 7.36 (d, 2H, J = 8.2), 7.32 (m, 4H) , 7.20 (d, 1H, J = 8.8), 7.04 (d, 1H, J = 2.3), 6.95 (d, 1H, J = 2.3), 6.84 (dd, 1H, J = 8.8, J = 2.3), 6.52 (t, NH, J = 5.5), 3.75 (q, 2H, J = 6.7), 3.74 (s, 3H), 3.51 (s, 4H), 3.03 (t, 2H, J = 6.7), 2.16 (s, 3H). 13C-NMR (400 MHz, CDCl3), δ (ppm): 167.4 (CONH), 153.8 (C),

143.0 (C), 138.8 (C), 133.1 (C), 131.5 (C), 128.8 (2CH), 128.8 (2CH), 128.2 (2CH), 127.6 (C), 127.0 (CH), 126.8 (2CH), 123.0 (CH), 112.3 (C), 112.2 (CH), 112.1 (CH), 100.2 (CH), 61.7 (CH2), 61.1 (CH2), 55.6 (CH3), 42.1 (CH3),

40.4 (CH2), 25.2 (CH2). Analysis (%), calculated for C27H29N3O2: C, 75.85, H, 6.84, N, 9.83; Found: C, 76.13, H, 7.12, N, 10.15.

Example 1.4

4 - ((Benzyl (methyl) amino) methyl) -N- (2- (6-methoxy-1H-indole-3-yl) ethyl) benzamide

Pale yellow solid. Yield: 65%. Mp .: 119-121 ° C. MS (HEI): m / e = 428 [M + H] +. 1H-NMR (400 MHz, acetone-d6), δ (ppm): 7.87 (d, 2H, J = 8.2), 7.49 (d, 1H, J = 8.6), 7.44 (d, 2H, J = 8.2), 7.37 (m, 2H), 7.31 (m, 2H),

7.23 (m, 1H), 7.05 (s, 1H), 6.90 (d, 1H, J = 2.2), 6.68 (dd, 1H, J = 8.6, J = 2.2), 3.76 (s, 3H), 3.69 (t , 2H, J = 7.4), 3.54 (s, 2H), 3.51 (s, 2H), 3.02 (t, 2H, J = 7.4), 2.12 (s, 3H). 13C-NMR (400 MHz, acetone-d6), δ (ppm): 167.2 (CONH),

157.2 (C), 143.7 (C), 140.2 (C), 138.2 (C), 134.7 (C), 129.5 (2CH), 129.3 (2CH), 129.0 (2CH), 127.9 (2CH), 127.7 (CH), 122.9 (C), 121.7 (CH), 119.9 (CH), 113.4 (C), 109.6 (CH), 95.2 (CH), 62.3 (CH2), 61.9 (CH2), 55.6 (CH3), 42.3 (CH3), 41.2 (CH2), 26.3 (CH2). Analysis (%), calculated for C27H29N3O2: C, 75.85, H, 6.84, N, 9.83; Found: C, 75.77, H, 6.95, N, 9.78.

Example 1.5

4 - ((Benzyl (methyl) amino) methyl) -N- (2- (6- fl uoro-1H-indole-3-yl) ethyl) benzamide

Pale yellow solid. Yield: 65%. Mp .: 83-85 ° C. MS (HEI): m / e = 416 [M + H] +. 1H-NMR (400 MHz, CDCl3), δ (ppm): 8.63 (s, NH), 7.63 (d, 2H, J = 8.2), 7.49 (dd, 1H, J = 9.0, J = 5.2), 7.36 ( d, 2H, J = 8.2), 7.32 (m, 4H),

7.24 (m, 1H), 6.99 (dd, 1H, J = 9.7, J = 2.3), 6.96 (d, 1H, J = 2.3), 6.84 (td, 1H, J = 9.0, J = 2.3), 6.40 ( t, 1H, J = 5.7),

3.74 (q, 2H, J = 6.7), 3.24 (s, 2H), 3.51 (s, 2H), 3.02 (t, 2H, J = 6.7), 2.16 (s, 3H). 13C-NMR (400 MHz, CDCl3), δ (ppm): 167.5 (CONH), 161.1 (C), 158.8 (C), 143.0 (C), 138.7 (C), 136.3 (C, J = 12.2), 128.9 (2CH), 128.8 (2CH),

128.3 (2CH), 127.1 (CH), 126.8 (2CH), 123.9 (C), 122.4 (CH), 122.3 (CH), 119.4 (C), 119.3 (CH), 112.8 (CH), 108.0 (CH, J = 24.4), 97.6 (CH, J = 25.9), 61.8 (CH2), 61.2 (CH2), 42.1 (CH3), 40.2 (CH3), 25.2 (CH2). Analysis (%), calculated for C26H26FN3O: C, 75.16, H, 6.31, N, 10.11; Found: C, 74.83, H, 5.96, N, 9.86.

Example 1.6

N- (2- (1H-Indol-3-yl) ethyl) -4 - (((2-chlorobenzyl) (methyl) amino) methyl) benzamide

Solid white. Yield: 49%. Mp .: 97-99 ° C. MS (HEI): m / e = 432 [M + H] +. 1H-NMR (500 MHz, CDCl3), δ (ppm): 8.20 (s, NH), 7.65 (d, 1H, J = 8.1), 7.62 (d, 2H, J = 8.3), 7.52 (dd, 1H, J = 7.6, J = 1.2), 7.38 (d, 2H, J = 8.3),

7.37 (d, 1H, J = 8.1), 7.34 (dd, 1H, J = 7.8, J = 1.0) .7.21 (m, 4H), 7.13 (t, 1H, J = 7.2), 7.06 (d, J = 2.0), 6.23 (t, NH, J = 5.4), 3.80 (q, 2H, J = 6.6), 3.63 (s, 2H), 3.60 (s, 2H), 3.09 (t, 2H, J = 6.6), 2.19 (s, 3H). 13C-NMR (500 MHz, CDCl3), δ (ppm): 167.3 (CONH), 143.0 (C), 136.5 (C), 136.4 (C), 134.2 (C), 133.4 (C), 130.6 (CH), 129.4 (CH), 128.9 (2CH),

128.1 (CH), 127.2 (CH), 126.8 (2CH), 126.6 (CH), 122.2 (CH), 122.1 (CH), 119.5 (CH), 118.7 (CH), 113.0 (C),

111.3 (CH), 61.7 (CH2), 58.5 (CH2), 42.2 (CH3), 40.2 (CH2), 25.3 (CH2). Analysis (%), calculated for C26H26ClN3O: C, 72.29, H, 6.07, N, 9.73; Found: C, 72.42, H, 6.11, N, 9.77.

Example 1.7

4 - (((2-Chlorobenzyl) (methyl) amino) methyl) -N- (2- (5-methoxy-1H-indol-3-yl) ethyl) benzamide

Solid white. Yield: 57%. Mp .: 120-122 ° C. MS (HEI): m / e = 462 [M + H] +. 1H-NMR (500 MHz, CD3OD), δ (ppm): 7.73 (d, 2H, J = 8.3), 7.54 (d, 1H, J = 8.3), 7.46 (d, 1H, J = 8.3), 7.44 ( d, 2H, J = 8.6), 7.32 (d, 1H, J = 8.3), 7.36 (m; 1H), 7.21 (d, J = 8.8), 6.72 (dd, 1H, J = 8.8, J = 2.4) , 3.72 (s, 3H), 3.66 (s, 2H), 3.63 (s, 2H), 3.34 (t, 2H, J = 7.3),

3.03 (t, 2H, J = 7.3), 2.20 (s, 3H). 13C-NMR (500 MHz, CD3OD), δ (ppm): 170.1 (CONH), 154.9 (C), 137.5 (C), 135.5 (C), 134.8 (C), 133.3 (C), 132.3 (C), 132.3 (CH), 130.5 (CH), 130.4 (CH), 130.3 (C), 130.2 (2CH), 129.7 (CH), 129.2 (C), 128.3 (2CH), 113.3 (C), 112.9 (CH), 112.7 (CH), 101.2 (CH), 62.6 (CH2), 59.4 (CH2), 56.1 (CH3), 42.5 (CH2),

42.3 (CH3), 26.3 (CH2). Analysis (%), calculated for C27H28ClN3O2: C, 70.19, H, 6.11, N, 9.10; Found: C, 70.42, H, 6.31, N, 9.43.

Example 1.8

N- (2- (1H-Indol-3-yl) ethyl) -4 - (((3-chlorobenzyl) (methyl) amino) methyl) benzamide

Solid white. Yield: 55%. Mp .: 110-112 ° C. MS (HEI): m / e = 432 [M + H] +. 1H-NMR (400 MHz, CDCl3), δ (ppm): 8.21 (s, NH), 7.64 (d, 2H, J = 8.3), 7.64 (m, 1H), 7.37 (d, 2H, J = 8.3) , 7.37 (m, 2H), 7.23 (m, 4H), 7.13 (td, 1H, J = 7.5, J = 1.0), 7.06 (d, 1H, J = 2.5), 6.23 (t, NH, J = 5.5 ), 3.80 (q, 2H, J = 6.7), 3.52 (s, 2H), 3.46 (s, 2H), 3.09 (t, 2H, J = 6.7), 2.16 (s, 3H). 13C-NMR (400 MHz, CDCl3), δ (ppm): 167.4 (CONH), 142.8 (C), 141.3 (C), 136.4 (C),

134.2 (C), 133.5 (C), 129.5 (CH), 128.8 (2CH), 128.7 (2CH), 127.3 (C), 127.2 (CH), 126.9 (2CH), 122.2 (CH), 122.1 (CH), 119.5 (CH), 118.7 (CH), 113.0 (C), 111.3 (CH), 61.4 (CH2), 61.2 (CH2), 42.3 (CH3), 40.2 (CH2), 25.3 (CH2). Analysis (%), calculated for C26H26ClN3O: C, 72.29, H, 6.07, N, 9.73; Found: C, 72.31, H, 6.13, N, 9.81.

Example 1.9

4 - (((3-Chlorobenzyl) (methyl) amino) methyl) -N- (2- (5-methoxy-1H-indol-3-yl) ethyl) benzamide

Pale yellow solid. Yield: 82%. Mp .: 108-110 ° C. MS (HEI): m / e = 462 [M + H] +. 1H-NMR (400 MHz, CDCl3), δ (ppm): 8.15 (s, NH), 7.62 (d, 2H, J = 8.3), 7.35 (d, 2H, J = 8.3), 7.34 (s, 2H) , 7.25 (d, 1H, J = 8.6), 7.22 (m, 3H), 7.03 (s. 2H), 6.85 (dd, 1H, J = 8.6, J = 2.3), 6.27 (t, NH, J = 5.6 ), 3.77 (q, 2H, J = 6.5), 3.86 (s, 3H), 3.51 (s, 2H)

3.45 (s, 2H), 3.04 (t, 2H, J = 6.5), 2.14 (s, 3H). 13C-NMR (400 MHz, CDCl3), δ (ppm): 167.6 (CONH), 154.3 (C),

143.1 (C), 141.5 (C), 134.4 (C), 133.6 (C), 131.7 (C), 129.8 (CH), 129.1 (2CH), 129.0 (2CH), 127.9 (C), 127.5 (CH),

127.2 (2CH), 123.2 (CH), 113.0 (C), 112.8 (CH), 112.3 (CH), 100.5 (CH), 61.7 (CH2), 61.4 (CH2), 56.0 (CH3), 42.5 (CH3), 40.5 (CH2), 25.5 (CH2). Analysis (%), calculated for C27H28ClN3O2: C, 70.19, H, 6.11, N, 9.10; Found: C, 70.11, H, 6.09, N, 9.31.

Example 1.10

4 - (((3-Chlorobenzyl) (methyl) amino) methyl) -N- (2- (6-methoxy-1H-indol-3-yl) ethyl) benzamide

Pale yellow solid. Yield: 82%. Mp .: 58-60 ° C. MS (HEI): m / e = 462 [M + H] +. 1H-NMR (400 MHz, CDCl3), δ (ppm): 8.31 (s, NH), 7.65 (d, 2H, J = 8.4), 7.48 (d, 1H, J = 8.6), 7.36 (d, 2H, J = 8.4), 7.35 (s, 1H), 7.23 (m, 3H), 6.91 (d, 1H, J = 2.2), 6.84 (d, 1H, J = 2.2), 6.78 (dd, 1H, J = 8.6 , J = 2.2), 6.35 (t, NH, J = 5.6), 3.81 (s, 3H), 3.75 (q, 2H, J = 6.6), 3.52 (s, 2H) 3.46 (s, 2H), 3.03 ( t, 2H, J = 6.6), 2.15 (s, 3H). 13C-NMR (400 MHz, CDCl3), δ (ppm):

167.4 (CONH), 156.5 (C), 142.7 (C), 141.2 (C), 137.2 (C), 134.1 (C), 133.4 (C), 129.85 (CH), 128.8 (2CH), 128.7 (2CH), 127.2 (CH), 126.9 (2CH), 121.6 (C), 120.9 (CH), 119.3 (C), 112.7 (C), 109.4 (CH), 94.7 (CH), 61.4 (CH2),

61.2 (CH2), 55.6 (CH3), 42.2 (CH3), 40.2 (CH2), 25.3 (CH2). Analysis (%), calculated for C27H28ClN3O2: C, 70.19, H, 6.11, N, 9.10; Found: C, 70.06, H, 6.13, N, 9.23.

Example 1.11

N- (2- (1H-Indol-3-yl) ethyl) -4 - (((2-methoxybenzyl) (methyl) amino) methyl) benzamide

Solid white. Yield: 61%. Mp .: 80-82 ° C. MS (HEI): m / e = 428 [M + H] +. 1H-NMR (500 MHz, CD3OD), δ (ppm): 7.74 (d, 2H, J = 8.3), 7.60 (d, 1H, J = 8.1), 7.42 (d, 2H, J = 8.3), 7.31 ( m, 2H), 7.24 (td, 1H, J = 7.8, J = 1.7),

7.09 (s, 1H), 7.06 (m, 1H), 6.97 (td, 1H, J = 8.1, J = 1.0), 6.93 (m, 1H), 6.91 (td, 1H, J = 7.6, J = 1.0) , 3.78 (s, 3H), 3.66 (t, 2H, J = 7.4), 3.54 (s, 2H) 3.34 (s, 2H), 3.06 (t, 2H, J = 7.4), 2.18 (s, 3H). 13C-NMR (500 MHz, CD3OD), δ (ppm):

170.1 (CONH), 159.4 (C), 143.7 (C), 138.1 (C), 134.7 (C), 132.1 (CH), 130.4 (2CH), 129.7 (CH), 128.8 (C), 128.2 (2CH), 127.0 (C), 123.4 (CH), 122.3 (CH), 121.2 (CH), 119.6 (CH), 119.4 (CH), 113.4 (C), 112.2 (CH), 111.6 (CH),

62.5 (CH2), 56.0 (CH3), 55.7 (CH2), 42.6 (CH3), 42.2 (CH2), 26.3 (CH2). Analysis (%), calculated for C27H29N3O3: C, 75.85, H, 6.84, N, 9.83; Found: C, 75.77, H, 6.81, N, 9.91.

Example 1.12

N- (5-Methoxy-1H-indol-3-yl) ethyl) -4 - (((2-methoxybenzyl) (methyl) amino) methyl) benzamide

Pale yellow solid. Yield: 76%. Mp .: 58-60 ° C. MS (HEI): m / e = 458 [M + H] +. 1H-NMR (400 MHz, CDCl3), δ (ppm): 8.18 (s, NH), 7.62 (d, 2H, J = 8.6), 7.40 (m, 1H), 7.39 (d, 2H, J = 8.6) , 7.25 (d, 1H, J = 9.0), 7.22 (td, 1H, J = 7.7, J = 2.0), 7.03 (m, 2H), 6.94 (td, 1H, J = 7.7, J = 1.0), 6.85 (m, 2H), 6.27 (t, NH, J = 5.6), 3.79 (s, 3H), 3.77 (s, 3H), 3.75 (q, 2H, J = 6.6), 3.58 (s, 2H) 3.55 ( s, 2H), 3.05 (t, 2H, J = 6.6), 2.20 (s, 3H). 13C-NMR (400 MHz, CDCl3), δ (ppm): 167.4 (CONH), 157.7 (C), 154.0 (C), 143.3 (C), 133.2 (C), 131.5 (C), 130.3 (CH), 128.9 (2CH), 128.0 (CH),

127.7 (C), 126.8 (C), 126.7 (2CH), 122.9 (CH), 120.3 (CH), 112.8 (C), 112.5 (CH), 112.0 (CH), 110.3 (CH), 100.3 (CH), 61.7 (CH2), 55.8 (CH2), 55.3 (CH3), 55.2 (CH3), 42.4 (CH3), 40.3 (CH2), 25.3 (CH2). Analysis (%), calculated for C28H31N3O3: C, 75.50, H, 6.83, N, 9.18; Found: C, 75.61, H, 6.79, N, 9.12.

Example 1.13

N- (2- (1H-Indol-3-yl) ethyl) -4 - (((3-methoxybenzyl) (methyl) amino) methyl) benzamide

Pale yellow solid. Yield: 78%. Mp .: 81-83 ° C. MS (HEI): m / e = 428 [M + H] +. 1H-NMR (400 MHz, CD3OD), δ (ppm): 7.74 (d, 2H, J = 8.4), 7.60 (dd, 1H, J = 8.1, J = 1.0), 7.42 (d, 2H, J = 8.4 ), 7.32 (dd, 1H, J = 8.1, J = 1.0), 7.22 (t, 1H, J = 8.1), 7.09 (s, IH), 7.06 (td, 1H, J = 8.1, J = 1.0), 6.98 (td, 1H, J = 8.1, J = 1.0), 6.93 (d, 1H, J = 2.0),

6.91 (d, 1H, J = 8.1), 6.80 (dd, 1H, J = 8.1, J = 2.0), 3.77 (s, 3H), 3.66 (t, 2H, J = 7.4), 3.53 (s, 2H) 3.48 (s, 2H), 3.05 (t, 2H, J = 7.4), 2.16 (s, 3H). 13C-NMR (400 MHz, CD3OD), δ (ppm): 170.1 (CONH), 161.2 (C), 143.8 (C), 141.3 (C),

138.1 (C), 134.8 (C), 130.3 (CH), 130.3 (2CH), 128.8 (C), 128.3 (2CH), 123.4 (CH), 122.5 (CH), 122.3 (CH), 119.6 (CH), 119.4 (CH), 115.7 (CH), 113.7 (CH), 113.4 (C), 112.2 (CH), 62.7 (CH2), 62.1 (CH2), 55.6 (CH3), 42.5 (CH3),

42.2 (CH2), 26.3 (CH2). Analysis (%), calculated for C27H29N3O2: C, 75.85, H, 6.84, N, 9.83; Found: C, 75.66, H, 6.71, N, 9.81.

Example 1.14

N- (2- (5-Methoxy-1H-indol-3-yl) ethyl) -4 - (((3-methoxybenzyl) (methyl) amino) methyl) benzamide

Solid white. Yield: 63%. Mp .: 82-84 ° C. MS (HEI): m / e = 458 [M + H] +. 1H-NMR (500 MHz, CD3OD), δ (ppm): 7.71 (d, 2H, J = 8.3), 7.38 (d, 2H, J = 8.3), 7.21 (d, 1H, J = 8.7), 7.20 ( t, 1H, J = 7.6), 7.06 (d, 1H, J = 2.4), 7.05 (s, 1H), 6.90 (d, 1H, J = 1.2), 6.88 (d, 1H, J = 7.6), 6.78 (dd, 1H, J = 7.6, J = 1.2), 6.72 (dd, 1H, J = 8.7, J = 2.4), 3.75 (s, 3H), 3.70 (s, 3H), 3.63 (t, 2H, J = 7.3), 3.49 (s, 2H) 3.44 (s, 2H), 3.02 (t, 2H, J = 7.3), 2.13 (s, 3H). 13C-NMR (500 MHz, CD3OD), δ (ppm): 170.0 (CONH), 161.2 (C), 154.9 (C), 143.8 (C), 141.3 (C), 134.7 (C), 133.3 (C), 130.3 (CH),

130.2 (2CH), 129.2 (C), 128.3 (2CH), 124.2 (CH), 122.5 (CH), 115.6 (CH), 113.7 (CH), 113.3 (C), 112.9 (CH), 112.7 (CH), 101.2 (CH), 62.7 (CH2), 62.1 (CH2), 56.1 (CH3), 55.6 (CH3), 42.5 (CH2), 42.3 (CH3), 26.3 (CH2). Analysis (%), calculated for C28H31N3O3: C, 75.50, H, 6.83, N, 9.18; Found: C, 75.38, H, 6.78, N, 8.82.

Example 2

Cell viability of the compounds of the invention

The cell viability of the compounds of the invention was measured in the human neuroblastoma cell line SH-SY5Y. The cells used were between passages 3 and 16 after thawing and were maintained in DMEM medium (Dulbecco's modi fi ed Eagle's medium), containing 15 non-essential amino acids and supplemented with 10% fetal bovine serum, 1 mM glutamine, 50 U mL − 1 of penicillin, and 50 μgmL − 1 of streptomycin (GIBCO, Madrid, Spain). The cultures were seeded in jars containing supplemented medium and kept at 37 ° C in humidified air with 5% carbon dioxide, making 1: 4 passes twice a week. For assays, SH-SY5Y cells were recultured in 48-well plates with a seeding density of 105 cells per well and were treated for 24 hours with the compounds of the invention at various concentrations. The quantitative measurement of cell death was performed by measuring the percentage of the enzyme lactate dehydrogenase (LDH) released to the extracellular medium (cytotoxicity detection kit, Roche). The amount of LDH was evaluated using a microplate reader (Labsystems iMES Reader MF) at 492 nm (excitation wavelength) and 620 nm (emission wavelength). Controls with 100% cell viability were used. At 1 μM all products have 100% cell viability, which indicates that the compounds of the present invention are non-toxic and have a wide range of therapeutic safety.

Example 3

Neuroprotective properties of the compounds of the invention against mitochondrial oxidative stress

Using the human neuroblastoma cell line SH-SY5Y, the cytoprotective action of the compounds against cell death caused by mitochondrial free radicals was evaluated. Mitochondrial oxidative stress conditions were simulated using a mixture of rotenone (30 μM) and oligomycin A (10 μM). The compounds were incubated with the cells for 24 hours, after which time, the medium was replaced by a new one containing the compound to be evaluated and the toxic agent, then incubated for an additional 24 hours. Cellular survival was determined by measuring LDH activity.

Extracellular and intracellular LDH activity was measured by UV-vis using a cytotoxicity kit (Roche-Boehringer. Mannheim, Germany), following the manufacturer's instructions. Total LDH activity is defined as the sum of intra-and extracellular activity and LDH activity released as the percentage of extracellular activity compared to total activity. The activity of the released LDH was calculated for each experiment considering as 100% the extracellular LDH, released by the vehicle with respect to the total.

where subídices e, i refer to extracellular and intracellular, respectively.

The calculation of the% protection of each of the derivatives was carried out as follows: in each individual experiment, the LDH obtained in untreated cells (baseline) was subtracted from the LDH released after treatment with the toxic and normalized to 100%. This value was subtracted from 100.

The results are expressed as the average of at least three independent cultures, each containing four repetitions of each compound evaluated.

Melatonin was used as a reference, which has recognized neuroprotective properties against oxidative stress (Rosales-Corral, S. et al. J. Pineal Res. 2003, 35, 80-84). The results are shown in table 1 and are the average of three independent experiments.

Neuroprotection results indicate that the compounds of the invention are capable of capturing mitochondrial free radicals and protecting neurons from mitochondrial oxidative damage. As a consequence, the compounds of this invention are potential drugs for the treatment of pathologies or conditions related to oxidative stress or excessive mitochondrial free radical production.

Example 4

Evaluation of the compounds of the invention as inhibitors of the human acetylcholinesterase enzyme (h-AChE)

Inhibition of human acetylcholinesterase (h-AChE) was performed following the method of Ellman (Ellman, G.

L. et al. Biochem Pharmacol 1961, 7, 88-95). The test solution was formed by 0.1 M phosphate buffer at pH = 8, 400 μM 5,5'-dithiobisnitrobenzoic acid (DTNB, Ellman reagent), 0.05 units / mL of the recombinant h-AChE enzyme (Sigma Chemical Co.) and acetylthiocholine iodide (800 μM) as a substrate for the enzymatic reaction. The compounds to be evaluated were pre-incubated with the enzyme for 5 minutes at 30 ° C, the substrate was added and the absorbance changes were measured at 412 nm every 5 minutes in a 96-well microplate UV-vis reader (Multiskan Spectrum, Thermo Electron Co. ). The reaction rates were compared and the percentages of inhibition due to the presence of the compounds being analyzed were calculated. The IC50 value is defined as the concentration of compound that reduces enzymatic activity by 50%. Tacrine, a known h-AChE inhibitor was used as control of the quality of the assay. The results are found in table 1, expressed as the average of three independent experiments.

The h-AChE inhibition results indicate that the compounds of the invention are capable of increasing neurotransmitter levels and, therefore, are capable of increasing cognitive abilities. As a consequence, the compounds of the invention are potential drugs for the symptomatic treatment of Alzheimer's disease and related pathologies.

Example 5

Test of displacement of propidium iodide from the peripheral anionic site of AChE by the compounds of the invention

In order to determine whether the new compounds were capable of binding to the peripheral anionic site (PAS) of AChE, their experimental affinity for the PAS was studied by displacing propidium iodide. This salt is a specific ligand of PAS, which when it is bound to the enzyme has a 10-fold increase in its fluorescence signal, which makes it a very useful probe to evaluate if a certain compound binds to the PAS of The enzyme

A solution of bovine AChE was used at a concentration of 5 μM in Tris buffer (0.1 Mm, Ph 8.0). Aliquots of the products to be tested were added at concentrations of 0.3, 1.0 and 3.0 µM and the solutions were left at room temperature for 6 hours. The samples were then incubated for 15 minutes with propidium iodide at a final concentration of 20 μM and the fluorescence was measured in a 96-well microplate reader (Fluostar Optima, BMG, Germany). The excitation and emission wavelengths were 485 and 620 nm, respectively. The results are expressed as the average of three independent experiments and are found in table 1.

The results of the propidium displacement assay indicate that the compounds of the invention bind to the peripheral anionic site of AChE and therefore, would be able to inhibit the aggregation of Abeta promoted by this enzyme. As a consequence, the compounds of this invention are potential drugs for the treatment of neurodegenerative diseases in which aberrant protein aggregates are produced, such as Alzheimer's disease.

TABLE 1

Neuroprotection (NP,%) against rotenone: oligomycin A (30:10 μM) using 1 μM of compound, inhibition of human acetylcholinesterase (h-AChE) as IC50 (μM), and displacement of propidium (%) from the peripheral anionic site (PAS) of AChE at three concentrations of the compounds evaluated

Example 6

Test to evaluate the ability of the compounds of the invention to capture oxygen radicals (ORAC-FL method)

The antioxidant capacity of the compounds of the invention was determined by their competition with fl uorescein in the capture of oxygen radicals following the ORAC-FL method, widely established and used in the food industry (Ou, B. et al. J. Agric Food Chem. 2001, 49, 4619-4626; Dávalos, A. et al. J. Agric. Food Chem. 2004, 52, 48-54).

The ORAC-FL experiments were carried out on a Polarstar Galaxy fluorometer with 96-well plate reader (BMG Labtechnologies GMBH, Offenburg, Germany), with excitation and emission filters at 485-P and 520-P. The equipment was controlled by the Fluostar Galaxy software (version 4.11-0) for the measurement of fluorescence. Reagents 2,2'-azobis- (amidinopropane) dihydrochloride (AAPH), (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox), and fl uorescein (FL) were purchased from Sigma -Aldrich. The reaction was performed in phosphate buffer (75 nM, pH 7.4) and the final reaction volume was 200 μL. A mixture of the compound to be evaluated (20 μL) and fl uorescein (120 μL; 70 nM, final concentration) was placed in a black 96-well microplate (Nunc). The mixture was pre-incubated for 15 minutes at 37 ° C and then the AAPH solution (60 µL; 12 mM, final concentration) was added very quickly by a multichannel pipette. The microplate was quickly introduced into the reader and the fluorescence was measured every minute for a period of 80 minutes. Before each reading, the microplate was automatically shaken. The products were evaluated using eight different concentrations (0.1-1 μM). For the calibration of each test, eight solutions of trolox (1-8 μM) were measured, as well as a blank (FL + AAPH) in which phosphate buffer was used without any product. All reaction mixtures were prepared in duplicate, and at least three independent experiments were performed for each of the samples to be evaluated. Fluorescence curves as a function of time were normalized by subtracting the target curve corresponding to each test, then calculating the area under the curve (AUC). The net AUC of each sample was calculated by subtracting the blank AUC from the AUC obtained for each of the samples. The representation of the net AUC versus the concentration of compound provided straight lines, which were adjusted by linear regression. The ORAC-FL values are expressed as μmol of trolox / μmol of compound (trolox equivalents) on a dimensionless scale, in which trolox is assigned the ORAC-FL = 1 value. The results in Table 2 are the average ± SEM of three independent experiments.

TABLE 2

Oxygen radical absorption capacity by fluorescence (ORAC-FL)

The results of the ORAC experiments indicate that the compounds of the invention are between 1.5 and 4.3 times more potent than trolox (the active part of vitamin E) in the capture of oxygen radicals and, therefore, can reduce biological damage produced by these reactive species. Therefore, the compounds of the invention are potential drugs for the treatment of pathologies or conditions related to the excessive production of free radicals, such as Alzheimer's disease.

Example 7

In vitro evaluation of the penetration in the central nervous system of the compounds of the invention

The passage of the blood-brain barrier of the compounds of the invention was evaluated using a permeability test through an artificial membrane, PAMPA (Artificial Parallel Membrane Permeation Assay), following the procedure of Di et al (Eur. J. Med. Chem 2003, 38, 223-232) which has been optimized in our laboratory for molecules of reduced aqueous solubility (Rodríguez-Franco, MI et al., J. Med. Chem. 2006, 49, 459-462;

Reviriego, F. et al., J. Am. Chem. Soc. 2006, 128, 16458-16459; Pavón, F. J. et al., Neuropharmacology 2006, 51, 358366; Marco-Contelles, J. et al., J. Med. Chem. 2009, 52, 2724-2732; Camps, P. et al., J. Med. Chem. 2009, 52, 53655379).

Commercial standards, pH 7.4 saline phosphate buffer (PBS) and dodecane were purchased from Sigma, Aldrich, Acros and Fluka. Millex filters (PVDF membrane, 25 mm diameter, 0.45 μm pore size) and 96-well microplates were purchased from Millipore. The pig brain lipid extract (PBL) was purchased from Avanti Polar Lipids. At the bottom of each of the 96 wells of the donor microplate there is a PVDF filter (pore size 0.45 μm) and the wells of the acceptor plate are in the form of a tear.

The receptor plate was filled with 170 μL of PBS: ethanol (9: 1) and the fi lter surface of the donor plate was impregnated with 4 μL of PBL in dodecane (20 mg mL -1). The compounds to be evaluated were dissolved in PBS: ethanol (9: 1) a1mgmL-1, filtered through a Millex filter and then added to the donor wells (170 μL). The donor plate was carefully placed on the acceptor for 240 minutes at 25 ° C. After incubation, the donor plate was removed and the concentration of each of the products in the acceptor plate was determined by UVvis. Each sample was analyzed at five wavelengths in four wells and at least in three independent experiments. The results are expressed as mean ± standard deviation. In each experiment, 17 commercial drugs of which their degree of penetration into the CNS were known: testosterone, verapamil, imipramine, desipramine, astemizole, progesterone, promazine, chloropromazine, clonidine, corticosterone, piroxicam, hydrocortisone, caffeine, aldosterone, lome fl oxacino, enoxacin, or fl oxacino. According to the permeability described, the experimental values of Pe (106 cm s − 1) were between 11.1 ± 0.1 (testosterone) and 0.2 ± 0.01 (or fl oxacino). The results obtained for the compounds of the invention are in Table 3 and are the mean ± SD of three independent experiments.

TABLE 3

Permeability (Pe, 10−6 cm s − 1) of the compounds in the PAMPA-BBB test and the prediction of their penetration into the CNS

aCompounds with high blood brain barrier permeability (cns +): Pe> 210−6 cms − 1

An optimal penetration into the CNS is an essential property that drugs designed to treat pathologies or conditions that affect the brain must possess, such as Alzheimer's disease. The results of the PAMPA-BBB test indicate that the compounds of the invention would be able to penetrate the CNS and therefore, would be able to reach their therapeutic targets located in the brain.

Claims (28)

1. A compound of formula (I) where R1 to R15 are independently selected from hydrogen, alkyl (substituted or unsubstituted), cycloalkyl (substituted or unsubstituted), alkoxy (substituted or unsubstituted), alkenyl (substituted or unsubstituted), aryl (substituted or non-substituted) substituted), heteroaryl (substituted or unsubstituted), CORa, C (O) ORa, C (O) NRaRb, C = NRa, CN, ORa, OC (O) Ra, S (O) r-Ra, NRaRb, NRaC (O) Rb, NO2, N = CRaRb or halogen; Ra and Rb are independently selected from hydrogen, alkyl (substituted or unsubstituted), cycloalkyl (substituted or unsubstituted), alkoxy (substituted or unsubstituted), alkenyl (substituted or unsubstituted), aryl (substituted or non-substituted) substituted), heteroaryl (substituted or unsubstituted), or halogen, with the proviso that they are not halogen when bound to an N. r is selected from 0.1 or 2. j and k are numbers that are independently selected between 1 and 8. A, B, D and E are independently selected from CRaRb, CRa = CRb, CO, O, S, or NRa; where Ra and Rb are defined as before; m, n, p, and q are numbers that are independently selected from a value between 0 and 10, with the proviso that their sum is at least four, m + n + p + q ≥ 4 X and Y are independently selected from CH or N; Z is selected from CH, O, S or N, with the proviso that at least one of X, YoZ is a heteroatom; when Z is CoN, then R11 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkoxy or substituted aryloxy or not substituted; When Z is OoS, then R11 does not exist. the spacer [A] m- [B] n- [D] p- [E] q is suitable as a substituent in XoY when X or Y are C, which are C instead of CH. or an isomer, a pharmaceutically acceptable salt, a pro-drug or a solvate thereof.

2.

Compound according to claim 1 wherein R3-R5 and R7-R10 are H.

3.

Compound according to any of claims 1 or 2 wherein R 6 is C 1 -C 4 alkyl.

Four.

Compound according to claim 3 wherein R6 is CH3.

5.

Compound according to any of claims 1-4 where jykson 1.

6. A compound according to any one of claims 1 to 5 wherein R1 and R2 are independently selected from hydrogen, halogen or alkoxy. 7. Compound of formula (II) according to claim 1: wherein R1, R2, R6, R11-R15, A, B, D, E, m, n, p, q, W, X, Y and Z are defined as in claim 1.

8.

Compound according to claim 7 wherein one of XYYCyel the other is CH.

9.

Compound according to claim 8 wherein Z is N.

10.

Compound according to claim 9 wherein R11, R12 and R15 are H.

eleven.

Compound of formula (III) according to claim 1:

wherein R1, R2, R6, R13, R14, A, B, D, E, m, n, p, which are defined as in claim 1.

12.

Compound according to claim 11 wherein R13 and R14 are independently selected from H, halogen, OH, or alkoxy.

13.

Compound according to any of claims 1 to 12 wherein m + n + p + q is a value that is selected from 4, 5, 6, 7, 8, 9, or 10.

14. Compound according to claim 13 wherein m + n + p + q is 4. 15. Compound according to claim 13 wherein the spacer [A] m- [B] n- [D] p- [E] q is selected from the formulas (CH2) rCO-NRa- (CH2) s-, - (CH2 ) r-NRa-CO- (CH2) s-, (CH2) r-CO-O- (CH2) s-, - (CH2) rO-CO- (CH2) s-, where Ra is defined as in claim one; r and s are independently selected from a value between 0 and 8.

16.

Compound according to claim 15 wherein the spacer has the formula - (CH2) r-CO-NRa- (CH2) s-.

17.

Compound according to claim 16 wherein r es0yses2.

18.

Compound according to claim 17 wherein Ra is H.

19.

Compound that is selected from the group consisting of:

•

N- (2- (1H-Indol-3-yl) ethyl) -4 - ((benzyl (methyl) amino) methyl) benzamide;

•

4 - ((Benzyl (methyl) amino) methyl) -N- (2- (5-hydroxy-1H-indol-3-yl) ethyl) benzamide;

•

4 - ((Benzyl (methyl) amino) methyl) -N- (2- (5-methoxy-1H-indole-3-yl) ethyl) benzamide;

•

4 - ((Benzyl (methyl) amino) methyl) -N- (2- (6-methoxy-1H-indol-3-yl) ethyl) benzamide;

•

4 - ((Benzyl (methyl) amino) methyl) -N- (2- (6- fl uoro-1H-indole-3-yl) ethyl) benzamide;

•

N- (2- (1H-Indol-3-yl) ethyl) -4 - (((2-chlorobenzyl) (methyl) amino) methyl) benzamide;

•

4 - (((2-Chlorobenzyl) (methyl) amino) methyl) -N- (2- (5-methoxy-1H-indol-3-yl) ethyl) benzamide;

•

N- (2- (1H-Indol-3-yl) ethyl) -4 - (((3-chlorobenzyl) (methyl) amino) methyl) benzamide;

•

4 - (((3-Chlorobenzyl) (methyl) amino) methyl) -N- (2- (5-methoxy-1H-indol-3-yl) ethyl) benzamide;

•

4 - (((3-Chlorobenzyl) (methyl) amino) methyl) -N- (2- (6-methoxy-1H-indol-3-yl) ethyl) benzamide;

•

N- (2- (1H-Indol-3-yl) ethyl) -4 - (((2-methoxybenzyl) (methyl) amino) methyl) benzamide;

•

N- (2- (5-Methoxy-1H-indol-3-yl) ethyl) -4 - (((2-methoxybenzyl) (methyl) amino) methyl) benzamide;

•

N- (2- (1H-Indol-3-yl) ethyl) -4 - (((3-methoxybenzyl) (methyl) amino) methyl) benzamide;

•

N- (2- (5-Methoxy-1H-indol-3-yl) ethyl) -4 - (((3-methoxybenzyl) (methyl) amino) methyl) benzamide;

or an isomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof. 20. Method of obtaining a compound of formula (I) comprising: a) Dissolving a compound of formula (IV): wherein R1-R10, [A] m, j and k are defined as in claim 1, in anhydrous dimethylformamide. b) Add triethylamine and benzotriazol-1-yl-oxytripyrrolidinphosphonium hexa fluorophosphate (PyBOP) to the solution of step (a) under inert conditions. c) Dissolve a compound of formula (V) in anhydrous dimethylformamide, d) React the solution obtained in step (b) with the solution obtained in step (c) at room temperature.

twenty-one.

Pharmaceutical composition comprising a compound of formula (I) according to any of claims 1-19 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

22. Composition according to claim 21 further comprising another active ingredient.

2. 3.

Use of at least one compound of formula (I) according to any of claims 1-19 for the manufacture of a medicament.

24.

Use of at least one compound of formula (I) according to any of claims 1-19 for the manufacture of a medicament for the treatment of a cognitive disorder that is selected from senile dementia, cerebrovascular dementia, mild knowledge alteration, attention deficit disorders, neurodegenerative dementia diseases associated with aberrant protein aggregations such as Alzheimer's disease, amyotrophic lateral sclerosis, prion diseases such as Creutzfeldt-Jakob disease or Gerstmann-Straussler-Scheinker disease, Parkinson's disease, polyglutamine disease, tauopathies as disease Pick, frontotemporal dementia, progressive supranuclear palsy or systemic amyloidosis.

25.

Use according to claim 24 wherein the cognitive disorder is Alzheimer's disease.

26.

Use according to any of claims 24 or 25 for oral administration.

27.

Use of a compound according to any of claims 1-19 as a reagent in biological assays.

SPANISH PATENTS AND BRANDS OFFICE Application no .: 200930936 SPAIN Date of submission of the application: 30.10.2009

REPORT ON THE STATE OF THE TECHNIQUE

Priority Date:    

51 Int. Cl.:

See additional sheet

 RELEVANT DOCUMENTS  

Category

56 Documents cited Claims Affected

TO

F BELLUTI et al., European Journal of Medicinal Chemistry 2009, vol 44, pp. 1341-1348. "Design, synthesis and evaluation of benzophenone derivatives as novel acetylcholinesterase inhibitors", the whole document. 1-27

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of realization of the report 24.09.2010

Examiner P. Fernández Fernández Page 1/4

Application number: 200930936 REPORT ON THE STATE OF THE TECHNIQUE CLASSIFICATION OBJECT OF THE APPLICATION  C07D 209/12 (2006.01) C07D 209/14 (2006.01) C07C 211/27 (2006.01) A61K 31/404 (2006.01) Minimum documentation sought (classification system followed by classification symbols) C07D, C07C, A61K Electronic databases consulted during the search (name of the database and, if possible, search terms used) INVENTIONS, EPODOC, WPI, CAS, REGISTRY  WRITTEN OPINION Application number: 200930936 Date of Written Opinion: 24.09.2010

Statement

Novelty (Art. 6.1 LP 11/1986)

Claims 1-27 Claims _____________________________________ Yes NO

Inventive activity

Claims 1-27 Yes

(Art. 8.1 LP11 / 1986)

Claims _____________________________________ NO

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published.  WRITTEN OPINION Application number: 200930936 1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

European Journal Medicinal Chemistry 2009, vol 44, pp 13411348 03-2009

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The application refers to the bis (aralkyl) amino derivatives of formula I (claim 1) and more specifically to the derivatives of formulas II and III (claims 7 and 11), the process for obtaining them (claim 20) and their use as dual acetylcholinesterase inhibitors for the treatment of neurodegenerative diseases such as Alzheimer's disease. Document D1 is considered the closest in the state of the art, discloses analogs of donepezil acetylcholinesterase inhibitors based on dual inhibitors containing an aromatic moiety and a tertiary amine connected by a spacer, see page 1342 figure 1 formula 1; its synthesis and anticholinesterase activity. Although the compounds disclosed in D1 are the closest to those of the application, they differ in the structure of the spacer, since in the compounds disclosed in D1 it is a C = O group and in those of the application other spacers such as CH2 are used. -CO-NR-CH2, CH2-NR-CO-CH2, ...: see claims 15 and 16 of the application. Therefore, claims 1-27 of the application are considered to meet the requirements of novelty and inventive activity, as set forth in Art. 6.1 and 8.1 of Patent Law 11/1986. Report on the State of the Art (Written Opinion) Page 4/4