ES2360150B1 - COMPOUNDS DERIVED FROM 1,8-NAFTIRIDINES AND THEIR USE IN THE TREATMENT OF NEURODEGENERATIVE DISEASES - Google Patents

Abstract

Compounds derived from 1,8-naphthyridines and their use in the treatment of neurodegenerative diseases # Compounds derived from 1,8-naphthyridines, their method of obtaining and their use as agents for the treatment of diseases of the central nervous system caused by a series of processes included in what is generically called neurodegeneration. These diseases can be selected from the list comprising Alzheimer's disease, Parkinson's disease and Huntington's disease.

Description

Compounds derived from 1,8-naphthyridines and their use in the treatment of neurodegenerative diseases.

The present invention relates to compounds of general formula (I). The invention also refers to its method of obtaining and its use as agents for the treatment of diseases of the central nervous system caused by a series of processes included in what is generically called neurodegeneration. The present invention can be framed in the field of the pharmaceutical industry.

Prior art

The progressive aging of the world population brings with it the unwanted consequence of an increase in neurodegenerative diseases and senile dementias. Among these, Alzheimer's disease, EA hereafter, is the most common neurodegenerative disease, responsible for approximately two-thirds of total dementia cases (varying between 42 and 81% according to different studies), with a prevalence closely related to age, which is close to 50% in the population over 85 years of age, and which affects women more than men.

There are several biochemical processes affected in the brains of AD patients: abnormal metabolism and aggregation of the amyloid protein, hyperphosphorylation of the tau protein, uncontrolled presence of oxidizing species, alterations of homeostasis of calcium ions (Ca2 + hereafter), neuronal loss, problems in cholinergic neurotransmission, etc., in the brains of AD patients. Undoubtedly, an improvement of any of these pathologies separately would be a correct, if incomplete, approach to the treatment of the disease. Currently, the drugs used for the treatment of AD are agents that improve cholinergic neurotransmission, capable of alleviating the cognitive and memory deficits associated with AD, although only temporarily (Arch. Gerontol. Geriatr. Suppl. 2004 , 9, 297-307).

Given this situation, it is obvious the convenience of having drugs capable of acting in the early stages of the disease or, better yet, producing a protective activity in the initial phase of the disease, in the ideal case of having a system of adequate early diagnosis (Ann. Neurol. 2007, 61, 120-129), and that they are capable of restoring or, at least, maintaining the physiological processes affected in neurodegenerative diseases at the levels closest to functional normality.

Studies carried out in both animal and human models show that the loss of balance between the oxidizing species generated by brain metabolism and antioxidant protective mechanisms produces so-called oxidative stress, when these defensive systems decrease their effectiveness and are overwhelmed. This oxidative stress increases with age and is among the first causes of the pathogenesis of AD (Neurobiol. Aging 2007, 28, 1009-1014) possibly associated with dysfunctions of neuronal mitochondria. Likewise, it is known that products with antioxidant properties are capable of preventing apoptosis induced by amyloid peptide, as well as alterations of Ca2 + homeostasis in cortical neuron cultures (Life Sci. 2000, 66, 1879-1892).

On the other hand, the hyperphosphorylation of the tau protein, associated with the stability of the cell microtubules, results in the formation of neuro fi brillary tangles inside the neurons that are reflective of the destruction of microtubules and neuro fi laments, which ultimately causes damage and neuronal death.

On the other hand, some 1,8-naphthyridine derivatives have been described with neuroprotective activity (José Marco-Contelles et al., Bioorqanic & Medicinal Chemistry 14 (2006) 8176-8185; Rafael León, et al., Bioorqanic & Medicinal Chemistry 16 (2008) 7759-7769).

Description of the invention

The present invention is related to the ability of cholinesterase enzyme inhibitors to exert symptomatic improvements in Alzheimer's patients, through a mechanism of action that would not only involve the inhibition of this type of enzymes, but would additionally be capable of carrying out other non-cholinergic activities,

globally showing a neuroprotective profile of neurons sensitive to stimuli triggered by the neurodegenerative process. These effects have been observed in the family of compounds described in the present invention.

More specifically, the present invention refers to a family of compounds with the structural characteristic of being derived from the 1,8-naphthyridine heterocyclic system, which have pharmacological properties potentially useful for the treatment of neurodegenerative diseases such as AD.

In the pharmacological studies to which they have been subjected, the compounds of the present invention have shown a series of potentially very useful activities in the treatment of neurodegenerative diseases, notwithstanding that in deeper studies, new biological properties of possible interest appear. The activities studied, and which have shown positive results, have been:

-

Inhibition of the enzyme acetylcholinesterase.

-

Inhibition of the enzyme butyrylcholinesterase.

-

Neuroprotective effect on a neuroblastoma line under oxidative stress.

-

Neuroprotective effect on a neuroblastoma line undergoing hyperphosphorylation of the tau protein.

As described is the prior art prior to the present invention, and there is an increasing number of experimental evidence, the presence of oxidizing species above physiologically acceptable levels, the so-called oxidative stress, is at the origin of EA, and is also strongly related to uncontrolled inputs of Ca2 + ions.

Therefore, a first aspect of the present invention refers to a compound of general formula (I) (hereafter compounds of the invention):

where:

R1 and R2 are the same or different groups and each is independently selected from a (C1-C10) alkyl group; Y

n is an integer between 0-5, and represents the number of additional carbon atoms to close the cycloalkane fused to the 1,8-naphthyridine heterocycle. Preferably n is 0, 1, 2 or 3.

By "compound of the invention" also refers herein to any of its derivatives, isomers, pharmaceutically acceptable salt and / or solvate thereof.

The term "alkyl" refers in the present invention to aliphatic, linear or branched chains, having 1 to 10 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert- butyl, sec-butyl, n-pentyl, n-hexyl, etc. Preferably the alkyl group has between 1 and 6 carbon atoms. The alkyl radicals (R1 and / or R2) may be optionally substituted by one or more substituents such as a cycloalkyl, aryl, heteroaryl, alkoxy, halogen, haloalkyl, nitro, amino, aminoalkyl, aminocycloalkyl, ammoniumalkyl, ammoniumcycloalkyl or, in general, any substituent located in any position.

In a preferred embodiment of the present invention, R1 is methyl or ethyl. In another preferred embodiment, R2 is methyl.

In another more preferred embodiment, the compound of the invention is selected from the list comprising:

• methyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo [b] [1,8] naphthyridine-3-carboxylate,

•

Ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo [b] [1,8] naphthyridine-3-carboxylate,

•

Methyl 5-amino-2-methyl-7,8-dihydro-6H-cyclopenta [b] [1,8] naphthyridine-3-carboxylate,

•

Ethyl 5-amino-2-methyl-7,8-dihydro-6H-cyclopenta [b] [1,8] naphthyridine-3-carboxylate,

•

Methyl 5-amino-2-methyl-7,8,9,10-tetrahydro-6H-cyclohepta [b] [1,8] naphthyridine-3-carboxylate,

•

Ethyl 5-amino-2-methyl-7,8,9,10-tetrahydro-6H-cyclohepta [b] [1,8] naphthyridine-3-carboxylate,

•

Methyl 5-amino-2-methyl-6,7,8,9,10,11-hexahydrocycloocta [b] [1,8] naphthyridine-3-carboxylate, and

•

Ethyl 5-amino-2-methyl-6,7,8,9,10,11-hexahydrocycloocta [b] [1,8] naphthyridine-3-carboxylate.

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. Another aspect of the present invention relates to a process for obtaining the compounds of the invention of formula (I), or an isomer, pharmaceutically acceptable salt and / or solvate thereof, characterized in that it comprises the following steps:

a) reaction of an alkyl acylacetate of formula (II),

wherein R1 and R2 represent the substituents indicated above when describing the general formula (I), under substitution conditions with a dimethylformamide diaalkylacetal. This reaction would result in a Michael acceptor substituted in beta position with a dimethylamino group, which, by reaction with cyanoacetamide under basic conditions with dimethylamine evolution and subsequent 6-exo-trig cyclization, yields the corresponding 2-pyridone (III) .

b) nucleophilic substitution on 2-pyridone (III) by an excess of phosphorus oxychloride to obtain pyridine (IV);

c) nucleophilic substitution on this pyridine (IV) to incorporate at the position of the Cl atom an amine, reaction that can be done by bubbling ammonia, or by treating with benzylamine in a polar solvent, obtaining protected pyridine (V).

d) these pyridines are subjected to deprotection conditions to leave the amino group released following common and known methods, such as treatment with tri-fluoromethanesulfonic acid in any organic solvent known to a person skilled in the art, or bubbling of hydrogen gas in the presence of amounts Palladium catalysts on an active carbon support, to obtain pyridine type (VI).

e) Friedländer condensation reaction of the basic heterocyclic system (VI) to achieve the final products object of the present invention, of general formula (I). These derivatives were obtained following particular methodologies according to the nature of the R1 and R2 groups.

A further aspect of the present invention relates to any of the compounds of general formula (I) for use as a medicament or pharmaceutical composition, and preferably a medicament or pharmaceutical composition that is used for the treatment of pathologies or diseases caused by oxidative processes. , by processes of formation of neuro fi brillary clews or, in general, of diseases susceptible of benefiting from the biological activities shown by the products described in the present invention, or of a pharmaceutically acceptable salt, derivative, prodrug or solvate thereof.

The compounds of the present invention represented by formula (I) may include isomers, depending on the presence of multiple bonds (eg, Z and E), including optical isomers or enantiomers, depending on the presence of chiral centers in the R1 chains. and R2. The individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention. The individual enantiomers or diastereoisomers, as well as mixtures thereof, can be separated by conventional techniques.

The compounds of the present invention represented by formula (I) present in position 4 of the naphthyridine heterocycle, a hydrogen atom, therefore lacking another type of substitution. This structural limitation could facilitate its binding to the catalytic site of the enzyme acetylcholinesterase, according to previously analyzed computational results.

As used herein, the term "derivative" includes both pharmaceutically acceptable compounds, that is, derivatives of the compound of formula (I) that can be used in the manufacture of a medicament, as pharmaceutically unacceptable derivatives since they can be useful in the preparation of pharmaceutically acceptable derivatives. The nature of the pharmaceutically acceptable derivative is not critical, as long as it is pharmaceutically acceptable.

Also, within the scope of this invention are the prodrugs of the compounds of formula (I). The term "prodrug" as used herein includes any compound derived from a compound of formula (I), for example, esters, including carboxylic acid esters, amino acid esters, phosphate esters, metal salt sulphonate esters, etc., carbamates, amides, etc., which, when administered to an individual, is capable of providing, directly or indirectly, 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) into a biological receptor. 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 receptor 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 and it is intended that both forms are within the scope of the present invention. In this sense, the term "solvate", as used herein, includes both pharmaceutically acceptable solvates, that is, solvates of the compound of formula

(I)

which can be used in the preparation of a medicament, such as pharmaceutically acceptable solvates, which may be useful in the preparation of solvates or pharmaceutically acceptable 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 well known to those skilled in the art. For their application in therapy, the compounds of formula (I), their isomers, salts, prodrugs or solvates, will preferably be in a pharmaceutically acceptable or substantially pure form, that is, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives 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%, 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.

Unless otherwise indicated, the compounds of the invention also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having such a structure, with the exception of replacing a hydrogen with a deuterium or tritium, or replacing a carbon with a carbon enriched in 13Co 14C or a nitrogen enriched in 15N, are within the scope of this invention.

The compounds described in the present invention, their pharmaceutically acceptable salts, prodrugs and / or solvates as well as the pharmaceutical compositions containing them can be used together with other additional drugs 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 prodrug, solvate, derivative or a pharmaceutically acceptable salt thereof.

Another preferred embodiment of the present invention refers to a pharmaceutical composition useful for the treatment of pathologies or diseases of the nervous system that can be caused by oxidative processes, by the development of neuro fi brillary clews or that at least such processes play a pathologically significant role or , in general, of diseases susceptible of benefiting from the biological activities shown by the products described in the present invention, hereinafter pharmaceutical composition of the invention, comprising a compound, in therapeutically effective amount, of formula (I), or mixtures of the same, a salt, prodrug, solvate

or pharmaceutically acceptable stereoisomer thereof together with a pharmaceutically acceptable carrier, adjuvant or vehicle, for administration to a patient.

Another preferred embodiment of the present invention refers to the pharmaceutical composition of the invention in the group of neurodegenerative nervous system diseases to which they belong, by way of illustration and without limiting the scope of the invention: EA, Creutzfeldt-Jakob, Parkinson or Huntington, dementia with Lewy bodies or, in general, diseases resulting from a deterioration of neurons caused by oxidation processes, formation of neuro fi brilar or other balls such as imbalances in the concentration of calcium ions, systems of neurotransmission, etc; that the nervous system of the affected patient is not able to control.

The scope of a neurodegenerative process in the present invention is characterized by neuronal loss, failures in neurotransmission processes or processes derived from failures in the control of the oxidizing species created in the brain that give rise to pathological oxidative stress or the development of sheep neuro fi brilar inside the neurons.

Another aspect of the present invention relates to a pharmaceutical composition comprising at least one compound of general formula (I) or mixture of compounds and a pharmaceutically acceptable carrier. Optionally said composition may comprise another active ingredient.

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

In another aspect, the present invention relates to a method for the treatment of patients affected by diseases of the central nervous system in which uncontrolled oxidative processes, deposition of neuro-fibrinous tangles or other processes take place where the products of the present invention produce a beneficial effect. This treatment consists in the administration to the individuals affected by these diseases of therapeutically effective amounts of a compound of formula (I), or a pharmaceutical composition that includes it. By way of example, diseases contemplated in this invention are AD, Creutzfeldt-Jakob, Parkinson or Huntington, dementia with Lewy bodies or, in general, diseases resulting from a deterioration of neurons caused by oxidative stress-like processes, destabilization of the microtubules due to the formation of neuro fi brilar clews, ionic imbalances or failures in some neurotransmission system that the nervous system of the affected patient is not able to control.

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.

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.). A review of the different pharmaceutical forms of drug administration and of the excipients necessary to obtain them can be found, for example, in the "Galician Pharmacy Treaty", C. Faulí i Trillo, 1993, Luzán 5, S.A. Ediciones, Madrid, or other habitual or similar ones of the Spanish and United States Pharmacopoeias.

The use of the compounds of the present 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.

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

The invention will now be illustrated by tests carried out by the inventors, which develop the process of selecting the compounds of the invention.

1. Obtaining the compounds of the invention

The compounds whose biological activity is the subject of the present invention were synthesized following a general procedure in organic synthesis. Said procedure is represented in the following Reaction Scheme:

Scheme 1

Synthesis of the compounds of formula (I)

This synthesis in several steps starts from acylacetate (II), commercial product or obtained by usual procedures in organic synthesis, easily executed by any expert in this field. This compound (II) was reacted with a dialkylacetal derivative of dimethylformamide, to form a reaction intermediate with Michael acceptor structure, which, by reaction with cyanoacetamide under basic conditions with dimethylamine evolution and subsequent 6-exo cyclization -trig, yields the corresponding 2-pyridone (III). In general, the resulting pyridone is obtained with sufficient purity so as not to require further purification, the generated compound is isolated from the reaction medium by precipitation in slightly acidic medium. From this starting product, it is necessary to replace the carbonyl in position 2 with an amine functional group. To carry out this transformation, it is necessary to transform the carbonyl into an easily leaving group, the formation of 2-chloropyridine (IV) was chosen for this. This intermediate in the synthesis route is formed in the presence of an excess of chlorinating electrophile, such as phosphorus pentachloride or phosphorus oxychloride, being able to act as a solvent in the reaction. The use of phosphorus oxychloride facilitates the process of product isolation since, once the reaction is finished (24h-2d), the 2-chloropyridine IV derivatives precipitate when ice is added. Thus, they are obtained by filtration and drying, without the need for further purification. The chlorinated intermediate (IV) is subjected to a nucleophilic substitution to incorporate at the position of the Cl atom an amine, a reaction that can be done in several ways, for example by ammonia bubbling, or by treatment with benzylamine in a polar solvent, obtaining protected pyridine (V). The use of benzylamine requires a subsequent step. However, it is the method of choice because it avoids the use of high pressure bottled gas ammonia, not without danger to the researcher. Thus, the type precursors (VI) are obtained through the elimination of the benzyl group in (V), under classical conditions of deprotection of this type of functionalities, such as hydrogen gas bubbling in the presence of catalytic amounts of Pd on a active carbon support. Alternatively and in order to avoid the use of hazardous gases, which sometimes require an increase in the pressure in the reactor, it is possible to undergo (V) a treatment with tri-fluoromethanesulfonic acid in organic solvent, which similarly yields pyridine of type (VI) . Alternatively, it is possible to reach pyridine VI from the alkyl ester of β-aminocrotonic acid and 2-ethoxymethylenemalonitrile in the presence of acetic acid, in a single reaction step, but with low yield. These pyridines are the necessary substrate for the Friedlander type condensation reaction with cyclic ketones in the presence of a Lewis acid, to achieve the final products object of the

present invention, of general formula (I). The products are obtained with good performance, and if all reaction steps are considered, the overall performance of the synthetic route from commercial products is around 18-26%. This performance can be increased in the last step of the condensation of Friedlánder with the use of a microwave apparatus. This method has been tested with the synthesis of compound 2, increasing the yield in the last step from 55 to 90%. This synthetic efficiency allows these compounds to be considered accessible for preparation in a pilot plant by the pharmaceutical industry.

In particular, and following the synthesis protocol represented in Scheme 1, the following compounds were obtained and characterized:

Compound 1

Methyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo [b] [1,8] naphthyridine-3-carboxylate. Solid yellow. Melting point> 200 ° C; IR (KBr) ν 3338, 3229, 2941, 2862, 1716, 1620, 1601, 1568, 1543, 1437, 1361, 1284, 1246, 1116,1070, 802, 779 cm − 1; 1H NMR (CDCl3, 200 MHz) δ (ppm) 8.82 (s, 1H, H4), 5.19 (bs, 2H, NH2), 3.94 (s, 3H, CH3O), 3.07 (m, 2H, H9), 2.95 [ s, 3H, CH3C (2)], 2.59 (m, 2H, H6), 1.93 (m, 4H, H7, H8); 13C NMR (CDCl3, 75.4 MHz) δ (ppm):

166.4 (C = O), 161.9 (C9a), 159.6 (C2), 154.1 (C10a), 150.9 (C5), 136.0 (C4), 119.7 (C3), 109.9 (C5a), 108.3 (C4a),

52.1 (CH3O), 33.4 (C9), 25.2 [CH3C (2)], 23.3 (C6), 22.1, 22.0 (C7, C8); MS (APIES +): m / z 272 [(M + 1) +, 100], 248 (12), 205 (13). Purity: Anal. Elem. Calc. For C15H17N3O2: C, 66.40; H, 6.32; N, 15.49. Found: C, 66.10; H, 6.61; N, 15.18.

Compound 2

Ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo [b] [1,8] naphthyridine-3-carboxylate. Solid yellow. Melting point> 200 ° C; IR (KBr) ν 3374, 3324, 3182, 2934, 1717, 1664, 1602, 1577, 1546, 1434, 1363, 1350, 1252, 1222, 1120, 1072, cm − 1; 1H NMR (CDCl3, 300 MHz) δ (ppm) 8.82 (s, 1H, H4), 5.33 (bs, 2H, NH2), 4.39 (q, J = 7.5 Hz, 2H, CO2CH2CH3), 3.05 (m, 2H, H9), 2.91 [s, 3H, CH3C (2)], 2.58 (m, 2H, H6), 1.92 (m, 4H, H7, H8), 1.41 (t, J = 7.5 Hz, 3H, CO2CH2CH3); 13C NMR (CDCl3, 75.4 MHz) δ (ppm) 166.7 (C = O), 163.9 (C9a), 162.0 (C2), 154.6 (C10a), 149.5 (C5), 135.0 (C4), 121.8 (C3), 111.5 (C5a), 109.0 (C4a), 61.8 (OCH2CH3), 34.2 (C9), 26.4 [CH3C (2)], 23.9 (C6), 22.8 (C7, C8), 14.7 (CH3CH2O); MS (APIES +): m / z 286 [(M + 1) +, 100], 593 [(2 × M + Na) +, 5], 308 [(M + Na) +, 4], 272 (10) , 258 (12). Purity: Anal. Elem. Calc. For C16H19N3O2: C, 67.35; H, 6.71; N, 14.73. Found: C, 67.12; H, 6.54; N,

14.55.

Compound 3

Methyl 5-amino-2-methyl-7,8-dihydro-6H-cyclopenta [b] [1,8] naphthyridine-3-carboxylate. Solid yellow. Melting point> 200 ° C; IR (KBr) ν 3317, 3188, 2951, 2844, 1724, 1645, 1601, 1549, 1431, 1358, 1259, 1114, 802, 777 cm − 1; 1H NMR (CDCl3, 200 MHz) δ (ppm) 8.74 (s, 1H, H4), 4.76 (bs, 2H, NH2), 3.97 (s, 3H, CH3O), 3.16 (t, J7.8 = 7.6 Hz, 2H, H8), 2.98 [s, 3H, CH3C (2)], 2.86 (t, J6.7 = 7.6 Hz, 2H, H6), 2.23 (quotate, 2H, J6.7.8 = 7.6 Hz, H7) ; 13C NMR (CDCl3, 75.4 MHz) δ (ppm) 171.8 (C = O), 166.5 (C8a), 158.9 (C2), 157.0 (C9a), 148.1 (C4), 135.8 (C5), 119.5 (C3),

114.1 (C5a), 109.0 (C4a), 52.1 (CH3O), 35.1 (C8), 27.5 [CH3C (2)], 25.3 (C6), 21.8 (C7); MS (APIES +): m / z 258 [(M + 1) +, 100], 245 (11), 205 (10), 157 (10). Purity: Anal. Elem. Calcd. For C14H15N3O2: C, 65.35; H, 5.88; N, 16.33. Found: C, 65.21; H, 5.78; N, 16.09.

Compound 4

Ethyl 5-amino-2-methyl-7,8-dihydro-6H-cyclopenta [b] [1,8] naphthyridine-3-carboxylate. Solid yellow. Melting point> 200 ° C; IR (KBr) ν 3329, 3176, 2964, 1716, 1657, 1604, 1550, 1433, 1400, 1358, 1252, 1217, 1117, 1086, 1051, 806, 779 cm − 1; 1H NMR (CDCl3, 200 MHz) δ (ppm) 8.74 (s, 1H, H4), 4.80 (bs, 2H, NH2), 4.44 (q, J = 7.2 Hz, 2H, CO2CH2CH3), 3.16 (t, J7, 8 = 7.6 Hz, 2H, H8), 2.98 [s, 3H, CH3C (2)], 2.88 (t, J6.7 = 7.6 Hz, 2H, H6), 2.23 (quit, 2H, J6.7.8 = 7.6 Hz, H7), 1.45 (t, J = 7.2 Hz, 3H, CO2CH2CH3); 13C NMR (CDCl3, 50.2 MHz) δ (ppm) 171.6 (C = O),

166.1 (C8a), 158.7 (C2), 156.9 (C9a), 148.0 (C4), 135.6 (C5), 120.0 (C3), 114.0 (C5a), 109.0 (C4a), 60.8 (OCH2CH3),

35.0 (C8), 27.5 (C6), 25.2 [CH3C (2)], 21.8 (C7), 14.1 (OCH2CH3); MS (APIES +): m / z 272 [(M + 1) +, 100], 258 (8), 245 (7). Purity: Anal. Elem. Calc. For C15H17N3O2: C, 66.40; H, 6.32; N, 15.49. Found: C, 66.41; H, 6.61; N,

15.22.

Compound 5

Methyl 5-amino-2-methyl-7,8,9,10-tetrahydro-6H-cyclohepta [b] [1,8] naphthyridine-3-carboxylate. Solid yellow. Melting point> 200 ° C; IR (KBr) ν 3330, 3199, 2918, 2850, 1720, 1651, 1601, 1579, 1543, 1429, 1361, 1346, 1257, 1105, 1082, 810, 779 cm − 1; 1H NMR (CDCl3, 200 MHz) δ (ppm) 8.77 (s, 1H, H4), 5.03 (bs, 2H, NH2), 3.96 (s, 3H, CH3O), 3.19 (m, 2H, H10), 2.96 [ s, 3H, CH3C (2)], 2.75 (m, 2H, H6), 1.98-1.46 (m, 6H, H7, H8, H9); 13C NMR (DMSOd6, 75.4 MHz) δ (ppm) 169.1 (C = O), 166.4 (C10a), 159.0 (C2), 154.5 (C11a), 149.2 (C5), 136.0 (C4), 120.1 (C3), 114.9 (C5a), 109.2 (C4a), 52.0 (OCH3), 39.2 (C10), 31.4 (C9), 27.3 (C8), 26.2 (C6), 25.0, 24.9 (C2, C7); MS (APIES +) m / z 286 [(M + 1) +, 100], 248 (12), 205 (15). Purity: Anal. Elem. Calc. For C16H19N3O2 · ¼H2O: C, 66.30; H, 6.78; N, 14.50. Found: C, 66.60; H, 6.80; N, 14.12.

Compound 6

Ethyl 5-amino-2-methyl-7,8,9,10-tetrahydro-6H-cyclohepta [b] [1,8] naphthyridine-3-carboxylate. Solid yellow. Melting point> 200 ° C; IR (KBr) ν 3381, 3327, 3153, 2923, 2850, 1714, 1670, 1603, 1576, 1543, 1344, 1288, 1254, 1223, 1111, 1082, 1049, 812, 781 cm − 1; 1H NMR (CDCl3, 200 MHz) δ (ppm) 8.75 (s, 1H, H4), 5.03 (bs, 2H, NH2), 4.44 (q, J = 7.0 Hz, 2H, CO2CH2CH3), 3.19 (m, 2H, H10), 2.96 [s, 3H, CH3C (2)], 2.75 (m, 2H, H6), 2.00

1.60 (m, 6H, H7, H8, H9), 1.44 (t, J = 7.0 Hz, 3H, CO2CH2CH3); 13C NMR (DMSOd6, 75.4 MHz) δ (ppm) 169.1 (C = O), 166.1 (C10a), 158.8 (C2), 154.6 (C11a), 149.1 (C5), 135.9 (C4), 120.5 (C3), 114.9 (C5a), 109.3 (C4a), 60.8 (OCH2CH3), 39.2 (C10), 31.5 (C9), 27.3 (C8), 26.2 (C6), 25.1, 25.0 (C2, C7), 14.1 (OCH2CH3); MS (APIES +) m / z 300 [(M + 1) +, 100], 205 (17), 157 (13). Purity: Anal. Elem. Calc. For C17H21N3O2: C, 68.20; H, 7.07; N, 14.04. Found: C, 68.12; H, 6.89; N, 13.92.

Compound 7

Methyl 5-amino-2-methyl-6,7,8,9,10,11-hexahydrocycloocta [b] [1,8] naphthyridine-3-carboxylate. Solid white. Melting point> 200 ° C; IR (KBr) ν 3349, 2923, 2851, 1725, 1713, 1620, 1600, 1571, 1541, 1432, 1361, 1351, 1291, 1260, 1249, 1109, 1093 cm − 1. 1H NMR (CDCl3, 200 MHz) δ (ppm) 8.80 (s, 1H, H4), 5.10 (bs, 2H, NH2), 3.97 (s, 3H, CH3O), 3.15 (m, 2H, H11), 2.98 [ s, 3H, CH3C (2)], 2.88 (m, 2H, H6), 1.90 (m, 2H, H10), 1.73 (m, 2H, H7), 1.43 (m, 4H, H8, H9); 13C NMR (CDCl3, 75.4 MHz) δ (ppm) 167.6 (C = O), 166.5 (C11a), 161.9 (C2), 148.2 (C12a), 146.2 (C5), 134.9 (C4), 121.4 (C3), 114.2 (C5a), 109.0 (C4a), 52.4 (OCH3), 36.2 (C11), 30.8 (C10), 27.8 (C7), 26.3, 26.2 (C8, C9), 25.9 (C2), 24.7 (C6). MS (APIES +) m / z 300 [(M + 1) +, 100], 322 [(M + Na) +, 13], Purity: Anal. Elem. Calc. For C17H21N3O2: C, 68.20; H, 7.07; N, 14.04. Found: C, 68.50; H, 7.31; N, 14.08.

Compound 8

Ethyl 5-amino-2-methyl-6,7,8,9,10,11-hexahydrocycloocta [b] [1,8] naphthyridine-3-carboxylate. Solid white. Melting point> 200 ° C; IR (KBr) ν 3345, 2920, 2846, 1716, 1618, 1599, 1570, 1541, 1431, 1356, 1350, 1290, 1259, 1242, 1167, 1107, 1090, 818, 779 cm − 1; 1H NMR (CDCl3, 200 MHz) δ (ppm) 8.75 (s, 1H, H4), 5.02 (bs, 2H, NH2), 4.43 (q, J = 7.0 Hz, 2H, CO2CH2CH3), 3.14 (m, 2H, H11), 2.97 [s, 3H, CH3C (2)], 2.87 (m, 2H, H6), 1.88 (m, 2H, H10),

1.72

(m, 2H, H7), 1.43 (t, J = 7.0 Hz, 3H, CO2CH2CH3), 1.38 (m, 4H, H8, H9); 13C NMR (CDCl3, 75.4 MHz) δ 166.6 (C11a), 166.1 (C = O), 159.3 (C2), 154.6 (C12a), 149.9 (C5), 136.0 (C4), 120.5 (C3), 112.5 (C5a) , 108.8 (C4a), 60.8 (OCH2CH3), 35.7 (C11), 30.7 (C10), 27.8 (C7), 26.0, 25.8 (C8, C9), 25.1 [CH3C (2)], 23.7 (C6), 14.1 ( OCH2CH3); MS (APIES +) m / z 314 [(M + 1) +, 100], 205 (12). Purity: Anal. Elem. Calc. For C18H23N3O2: C, 68.98; H, 7.40; N, 13.41. Found: C, 68.69; H, 7.68; N, 13.12.

2.

Biological activities studied in the compounds of the invention

2.1 Neuroprotective properties of the compounds of the invention

The cytoprotective effect of the compounds in human neuroblastoma cells was evaluated, specifically the neuroprotective potential of these compounds against (i) the oxidative stress produced by rotenone and oligomycin A, blockers of the mitochondria respiratory chain as described in J. Neurochem 1992, 59, 1609-1623 and in Toxicological Sciences 2004, 79, 137-146, respectively, and (ii) the hyperphosphorylation of the tau protein induced by okadaic acid which is an accepted model for neuronal death that occurs in AD and which is related to tau hyperphosphorylation (Neuroscience 2004, 126, 277-284; Neurosci Lett. 1997, 235, 149-153).

The viability parameter that was measured in the first case was the activity of the enzyme lactate dehydrogenase (LDH hereinafter), an enzyme that is released to the extracellular medium when the cell dies (J. Pharmacol. Exp. Ther. 2005, 315, 1346-1353). In experiments with okadaic acid, the assay based on the metabolic reduction of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazole (MTT) bromide conducted by the cell was used to measure cell survival mitochondrial enzyme succinate dehydrogenase in a blue compound (formazan), which allows to determine the mitochondrial functionality of the treated cells (J. Immunol. Meth. 1983, 65, 55-63). Okadaic acid produces mitochondrial changes in cells treated with this toxic, causing a decrease in mitochondrial membrane potential (Toxicology in Vitro 2001, 15, 199-208), thus initiating the process that will lead to cell death. Therefore, a method such as MTT that allows us to know the metabolic state of mitochondria in cells subjected to incubation with okadaic acid was considered more appropriate.

The experimental method used, following a previously described procedure (Neuropharmacology 2004, 46, 103-114) is as follows: SHSY5Y human neuroblastoma cells were seeded and cultured in a DMEM medium (Dulbecco's modi fi ed Eagle's medium) containing 15 non-essential amino acids and supplemented with 10% fetal calf serum, 1 millimolar glutamine, 50 units per milliliter of penicillin and 50 micrograms per milliliter of streptomycin, keeping them at 37 ° C in humidified air containing 5% carbon dioxide. In the assays, SH-SY5Y cells were subcultured in 48-well plates with a seeding density of 1x105 cells per well. In the cytotoxicity experiments, the cells thus prepared were treated with the compounds to be measured in serum-free DMEM.

To study the cytoprotective action of the different compounds against cell death induced by a combination of rotenone with 30 micromolar and 10 micromolar oligomycin A respectively or with 30 nanomolar okadaic acid, all compounds (1 to 8) were evaluated at the concentration of 1 micromolar For this, the cells were treated with the product to be evaluated for 24 hours. Then, the media were replaced by fresh media that still contained the compound plus cytotoxic agents, and were thus maintained for an additional period of 24 hours. The cell viability was checked in the case of incubation with the combination rotenone / oligomycin A by measuring the activity of the LDH enzyme by means of the "Cytotoxicity Cell Death" kit (Roche-Boehringer Mannheim) following the instructions of the manufacturer of said kit. The samples were analyzed spectrophotometrically in a plate reader (Labsystems iEMS Reader MF), using the appropriate fi lter (490 nm), obtaining the absorbance values using the DeltaSOFTII Version 3.71 EMS program. Total LDH activity was defined as the sum of intra and extracellular LDH activities. The LDH activity released by the cells at death was defined as the percentage of extracellular LDH activity versus total LDH activity.

When the cytotoxic used was okadaic acid, the viability assessment was made by measuring the reduction of a soluble tetrazolium salt (MTT), yellow, to an insoluble blue formazan. To do this, 50 microliters of the commercial MTT reagent (Sigma) was added to each well with 500 microliters of medium keeping the culture plates for 3 hours in the dark and at 37 ° C. After this time, the supernatant medium was gently removed, leaving a precipitate that was dissolved with 300 microliters of dimethylsulfoxide (DMSO). After stirring for 10 minutes, samples were taken from the wells and the absorbance was read on a plate reader (Labsystems iEMS Reader MF) at a wavelength of 540 nanometers. Absorbance values obtained with the toxic alone and with each compound in the presence of the toxic were subtracted from the absorbance value obtained under baseline conditions, without treatment. The value obtained from the subtraction of the basal absorbance values less toxic alone, 100% death was considered and the values obtained with the compounds in the presence of toxic were normalized as percentages of said value. To calculate the survival percentage, these values of 100 were subtracted.

In all pharmacological trials, a positive control was used as a comparison and to assess the goodness of the method used. In the case of rotenone / oligomycin A experiments, N-acetylcysteine (NAC), a well-known antioxidant, was used; When okadaic acid was used as a toxic agent, galantamine was used as a positive control, which had previously shown a protective effect (J. Pharmacol. Exp. Ther. 2005, 315, 13461353).

The results obtained for the compounds described as compounds 1 to 8 shown in Tables 1 and 2, are expressed as a percentage of the neuroprotective activity.

TABLE 1

Percentage of neuroprotection against the mixture of rotenone (30 μM) and oligomycin A (10 μM) of 1,8-naphthyridine derivatives at the concentration of 1 micromolar

The results are the average of 4 independent experiments (in triplicate). * p <0.05.

These results indicate that the compounds object of the present invention are able to moderately reduce the presence of root species with the consequent neuroprotective effect, which makes them potential drugs for the treatment of pathologies generated or favored by oxidative stress or presence of radical species in general.

TABLE 2

Percentage of neuroprotection against 30 nM okadaic acid of 1,8-naphthyridine derivatives at the concentration of 1 micromolar

The results are the average of 8 independent experiments (in triplicate). * p <0.05, ** p <0.01, *** p <0.001.

These results show that most of the compounds object of the present invention protect remarkably against death induced by the formation of neuro fi brial clews, with values close to 60% protection for some of them.

2.2 Properties of the compounds object of the invention as inhibitors of the enzymes acetyl and butyrylcholinesterase

The inhibitory activity of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of the compounds studied by the method of Ellman (Biochem. Pharmacol. 1961, 7, 88-95) was evaluated. The electric eel acetylcholinesterase enzyme (Electrophorus electricus), a great analogy to the human neuronal, was chosen as the neuronal model. To comparatively analyze the hypothetical peripheral inhibition, potentially associated with the adverse effects found in the administration of anticholinesterase agents, the AChE inhibitory activity extracted from human erythrocytes was evaluated. To evaluate the inhibition of BuChE, the one extracted from equine serum was chosen.

Inhibition of cholinesterase enzymes is the predominant therapeutic target in the clinic for the treatment of AD. This therapeutic approach is based on the so-called cholinergic hypothesis (Science 2006, 314, 777-781), which suggests that the selective loss of cholinergic neurons in AD causes a deficit of the acetylcholine neurotransmitter (ACh) in specific regions of the brain that control learning and memory (Lancet Neurol. 2003, 2, 539547). Thus, there are three drugs approved by international drug regulatory administrations (donepecyl, galantamine and rivastigmine) that improve the symptoms of AD through the inhibition of AChE, the enzyme responsible for hydrolyzing ACh, consequently raising the levels of this neurotransmitter in the synaptic cleft (Pharmacol. Res. 2004, 50, 441-451). Recently, a renewed interest in AChE inhibitors has been generated, stimulated by the potential role of AChE in accelerating the formation of amyloid fibrils in the brain and the generation of stable complexes with Aβ (Neuron 1996, 16, 881-891). This feature involves the AChE peripheral anionic junction site (PAS), as evidenced by the fact that propidium iodide, which binds to PAS, affects Aβ aggregation in vitro, while inhibitors that bind to the Catalytic site do not exhibit this effect.

The experimental method used, following the procedure previously described (Biochem. Pharmacol. 1961, 7, 88-95) is as follows: for the measurement of AChE inhibition (either extracted from electric eel or human serum) carry out the reaction in wells with a final volume of 3 ml of a PBS buffer solution at pH 8, containing 0.035 units / ml of AChE and 0.35 mM of 5,5'-dithiobis-2-nitrobenzoic acid (DTNB), Used to produce the yellow anion of 5-thio-2-nitrobenzoic acid. Inhibition curves with the different compounds were performed in quadruplicate by incubating with at least 9 concentrations of the compounds for 10 min. After this time, the 0.35 mM acetylthiocholine iodide substrate was added from a 10 mM stock solution. To measure the inhibition of BuChE extracted from equine serum, the reaction was carried out in wells with a final volume of 3 ml of a PBS buffer solution at pH 8, containing 0.05 units / ml of BuChE and 0.35 mM of 5,5'-dithiobis-2-nitrobenzoic acid (DTNB). Inhibition curves with the different compounds were performed in quadruplicate by incubating with at least 9 concentrations of the compounds for 10 min. After this time, the 0.5 mM butyrylthiocholine iodide substrate was added from a 10 mM stock solution. In both types of experiments (AChE and BuChE), a quadruplicate sample without compound was always present to yield 100% of the enzymatic activity. At 15 min, the color production at 412 nm was measured in a 96-well plate spectrophotometric reader as a signal of enzymatic activity.

The concentration of drug that produces 50% inhibition of enzyme activity (IC50) was calculated by sigmoidal regression of the logarithmic representation of the concentration. The results were expressed as mean ± standard error of at least three experiments. The results obtained for the compounds described as compounds 1-8 are shown in Table 3.

TABLE 3

Cholinesterase enzyme inhibitory activity by compounds derived from 1,8-naphthyridine

The results are the average of at least 3 independent experiments (in quadruplicate). Where S (BuChE / eeAChE) refers to the BuChE / eeAChE selectivity.

These results indicate that the compounds object of the present invention are capable of inhibiting cholinesterase enzymes in a moderate and dual manner, except 1 and 2, which show a potent and selective inhibitory activity for AChE. It is remarkable its greater activity on AChE of electric eel, isoform very similar to the human neuronal, than on AChE of human erythrocytes. This discovery is important in that it could mean a lower incidence of side effects associated with the inhibition of this peripheral enzyme. These results make them potential drugs for the treatment of Alzheimer's disease.

Claims (15)

1. Compound of general formula (I): where R1 and R2 are the same or different and are independently selected from a (C1-C10) alkyl group; and n is an integer with a value of between 0 to 5.

2.

Compound according to claim 1, wherein R1 and / or R2 are a (C1-C6) alkyl group.

3.

Compound according to claim 2, wherein R1 is methyl or ethyl.

Four.

Compound according to any of claims 2 or 3, wherein R2 is methyl.

5.

Compound according to any of claims 1-4, where n is 0, 1,2 or 3.

6.

Compound according to any of claims 1-5, selected from the list comprising:

•

Methyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo [b] [1,8] naphthyridine-3-carboxylate,

•

Ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo [b] [1,8] naphthyridine-3-carboxylate,

•

Methyl 5-amino-2-methyl-7,8-dihydro-6H-cyclopenta [b] [1,8] naphthyridine-3-carboxylate,

•

Ethyl 5-amino-2-methyl-7,8-dihydro-6H-cyclopenta [b] [1,8] naphthyridine-3-carboxylate,

•

Methyl 5-amino-2-methyl-7,8,9,10-tetrahydro-6H-cyclohepta [b] [1,8] naphthyridine-3-carboxylate,

•

Ethyl 5-amino-2-methyl-7,8,9,10-tetrahydro-6H-cyclohepta [b] [1,8] naphthyridine-3-carboxylate,

•

Methyl 5-amino-2-methyl-6,7,8,9,10,11-hexahydrocycloocta [b] [1,8] naphthyridine-3-carboxylate, and

•

Ethyl 5-amino-2-methyl-6,7,8,9,10,11-hexahydrocycloocta [b] [1,8] naphthyridine-3-carboxylate.

7. Method of obtaining the compounds of formula (I) according to any of claims 1 to 6, comprising the following steps: to. reacting an alkyl acylacetate of formula (II), wherein: R1 and R2 have been described in claim 1, with a dimethylformamide diaalkylacetal and subsequently with cyanoacetamide under basic conditions;

b.

Nucleophilic substitution on the 2-pyridone of formula (III) obtained in step (a) by an excess of phosphorus oxychloride:

C.

nucleophilic substitution on the pyridine of formula (IV), obtained in step (b), incorporating at the position of the Cl atom an amine:

d.

deprotection of the pyridines of formula (V), obtained in step (c), leaving the amino group free, and

and.

Friedlander condensation of the basic heterocyclic system of formula (VI), obtained in step (d):

8.

Process according to claim 7, wherein step (c) is carried out by ammonia bubbling or by treatment with benzylamine in a polar solvent.

9.

Process according to any of claims 7u8, in which step (d) is carried out by treatment with tri-fluoromethanesulfonic acid in organic solvent or by bubbling hydrogen gas in the presence of catalytic amounts of palladium on an active carbon support.

10. Use of the compound according to any of claims 1-6, for the preparation of a medicament.

eleven.

Use of the compound according to any of claims 1 to 6, for the preparation of a medicament for the treatment of neurodegenerative diseases.

12.

Use of the compound according to the preceding claim, wherein neurodegenerative diseases are selected from the list comprising Alzheimer's disease, Parkinson's disease and Huntington's disease.

13.

Pharmaceutical composition comprising at least one compound of general formula (I) together with one or more pharmaceutically acceptable excipients.

14.

Pharmaceutical composition according to the preceding claim, further comprising one or more active therapeutic agents.

SPANISH PATENTS AND BRANDS OFFICE Application no .: 200930903 SPAIN Date of submission of the application: 26.10.2009

REPORT ON THE STATE OF THE TECHNIQUE

Priority Date:    

51 Int. Cl.:

C07D 471/04 (2006.01)

A61K 31/4375 (2006.01)

 RELEVANT DOCUMENTS  

Category

56 Documents cited Claims Affected

TO

J L MARCO et al., Bioorganic Medicinal Chemistry 2001, vol 9, pp. 727-732. "Synthesis and acetylcholinesterase / inhibition activity of new tacrine-like analogues" the whole document, in particular page 728, scheme 3 compounds 5 and 6. 1-14

TO

J L MARCO et al., Bioorganic Medicinal Chemistry 2004, vol 12, pp. 2199-2218. "Synthesis, biological avaluation and molecular modeling of diversely functionalized heterocyclic derivatives as inhibitors of acetylcholinesterase / butirylcholinesterase" the whole document, in particular page 2200, compounds 2,15-29,63-67. 1-14

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 29.09.2010

Examiner P. Fernández Fernández Page 1/4

Application number: 200930903 REPORT ON THE STATE OF THE TECHNIQUE Minimum documentation sought (classification system followed by classification symbols) C07D, 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: 200930903 Date of Written Opinion: 29.09.2010

Statement

Novelty (Art. 6.1 LP 11/1986)

Claims 1-14 Claims _____________________________________ Yes NO

Inventive activity

Claims 1-14 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: 200930903 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

Bioorganic Medicinal Chemistry 2001, vol 9, pp 727-732 2001

D02

Bioorganic Medicinal Chemistry 2004, vol 12, pp 2199-2218 2004

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 1,8-naphthyridine derivatives of formula (I) (claim 1), the method for obtaining them (claims 7-9) and their use for the preparation of a medicament for the treatment of neurodegenerative diseases ( claims 10-14). Document D1 discloses compounds of formula C (see page 728 and scheme 3 compounds 5 and 6). Document D2 discloses compounds of formula B (see page 2200 and compounds 2,15-29 and 63-67) analogous to those described in D1 and their potential utility in the treatment of Alzheimer's disease. The compounds of formula (I) of the application differ from those disclosed in D1 and D2 in the substitution in position 4 of the naphthyridine heterocycle, the former are substituted in position 4 by hydrogen, while in the compounds disclosed in D1 and D2 this substituent is always a substituted or not substituted phenyl. On the other hand, there is no evidence nor can it be deduced a priori that changing the substituent in position 4 with hydrogen results in better results in terms of its pharmaceutical application. Therefore, claims 1-14 of the application are considered to meet the requirements of novelty and inventive activity according to Art. 6.1 and 8.1 of Patent Law 11/1986. Report on the State of the Art (Written Opinion) Page 4/4