WO2011051527A1 - 1,8-naphthyridine-derived compounds and the use thereof in the treatment of neurodegenerative diseases - Google Patents

1,8-naphthyridine-derived compounds and the use thereof in the treatment of neurodegenerative diseases Download PDF

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Publication number
WO2011051527A1
WO2011051527A1 PCT/ES2010/070687 ES2010070687W WO2011051527A1 WO 2011051527 A1 WO2011051527 A1 WO 2011051527A1 ES 2010070687 W ES2010070687 W ES 2010070687W WO 2011051527 A1 WO2011051527 A1 WO 2011051527A1
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methyl
naphthyridine
amino
carboxylate
formula
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PCT/ES2010/070687
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Spanish (es)
French (fr)
Inventor
Cristobal De Los Rios Salgado
Alejandro ROMERO MARTÍNEZ
Javier Egea Maiquez
Rafael LEÓN MARTÍNEZ
Mercedes VILLARROYA SÁNCHEZ
Manuela GARCÍA LÓPEZ
Antonio GARCÍA GARCÍA
José Luís MARCO CONTELLES
Elena SORIANO SANTAMARÍA
Abdelouahid Samadi
Mourad Chioua
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Consejo Superior De Investigaciones Científicas (Csic)
Universidad Autónoma De Madrid (Uam)
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Publication of WO2011051527A1 publication Critical patent/WO2011051527A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds of general formula (I).
  • the invention also relates 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.
  • Alzheimer's disease 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.
  • AD Alzheimer's disease
  • abnormal metabolism and aggregation of the amyloid protein hyperphosphorylation of the tau protein, uncontrolled presence of oxidizing species, alterations of calcium ion homeostasis (Ca 2+ hereafter ), neuronal loss, cholinergic neurotransmission problems, etc.
  • Ca 2+ calcium ion homeostasis
  • neuronal loss cholinergic neurotransmission problems, etc.
  • an improvement of any of these pathologies separately would be a correct, if incomplete, approach to the treatment of the disease.
  • the drugs used for the treatment of AD are agents that improve cholinergic neurotransmission, capable of relieving cognitive and memory deficits associated with AD, although only temporarily (Arch. Gerontol. Geriatr. Suppl. 2004 , 9, 297-307).
  • 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, showing globally 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 relates to a family of compounds with the structural characteristic of being derived from the 1, 8-naphthyridine heterocyclic system, which have potentially useful pharmacological properties for the treatment of neurodegenerative diseases such as AD.
  • a first aspect of the present invention relates to a compound of general formula (I) (hereafter compounds of the invention):
  • R1 and R2 are the same or different groups and each is independently selected from an alkyl group (C1-C10); Y
  • n 0, 1, 2 or 3.
  • 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.
  • the alkyl group has between 1 and 6 carbon atoms.
  • the alkyl radicals 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.
  • 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.
  • R 1 is methyl or ethyl. In another preferred embodiment, R 2 is methyl.
  • the compound of the invention is selected from the list comprising:
  • 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),
  • these pyridines are subjected to deprotection conditions to leave the amino group released following common and known methods, such as treatment with trifluoromethanesulfonic 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).
  • 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 neurofibrillar clews or, in general, of diseases susceptible to benefit 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 Ri chains. and F3 ⁇ 4.
  • 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.
  • 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 these 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.
  • the prodrugs of the compounds of formula (I) are also included in the scope of this invention.
  • prodrug 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.
  • 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 an individual's biological receptor.
  • the preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.
  • solvate 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.
  • pharmaceutically acceptable solvate is not critical, as long as it is pharmaceutically acceptable.
  • the solvate is a hydrate. Solvates can be obtained by conventional solvation methods well known to those skilled in the art.
  • 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.
  • the compounds of the invention also include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having said structure except for the replacement of a hydrogen with a deuterium or tritium, or the replacement of a carbon with a carbon enriched in 13 C or 14 C or a nitrogen enriched in 15 N, are within of 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.
  • composition of the invention which comprises a compound, in therapeutically effective amount, of formula (I), or mixtures thereof, a pharmaceutically acceptable salt, prodrug, solvate or stereoisomer thereof together with a pharmaceutically acceptable carrier, adjuvant or vehicle, for administration.
  • Another preferred embodiment of the present invention relates 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 neurofibrillar or other balls such as imbalances in calcium ion concentration, systems of neurotransmission, etc; that the nervous system of the affected patient is not able to control.
  • 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 neurofibrillar or other balls such as imbalances in calcium ion concentration, systems of neurotransmission, etc; that the nervous system of the affected patient is not able to control.
  • 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 neurofibrilar inside the neurons.
  • compositions comprising at least one compound of general formula (I) or mixture of compounds and a pharmaceutically acceptable carrier.
  • said composition may comprise another active ingredient.
  • 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 neurofibrillar clews or other processes in which 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.
  • 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 microtubules due to the formation of neurofibrillary tangles, ionic imbalances or failures in some neurotransmission system that the nervous system of the affected patient is not able to control.
  • 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.
  • 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.
  • administration of the therapeutic composition provided by this invention is performed orally, topically, rectally or parenterally (including subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous, etc.).
  • parenterally including subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous, etc.
  • the chlorinated intermediate (IV) is subjected to a nucleophilic substitution to incorporate at the position of the Cl atom an amine, 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.
  • 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.
  • 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).
  • LDH lactate dehydrogenase
  • 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, 103-1 14) is as follows: SHSY5Y human neuroblastoma cells were seeded and cultured in a DMEM (Dulbecco's modified Eagle's medium) 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.
  • SH-SY5Y cells were subcultured in 48-well plates with a seeding density of 1 x 10 5 cells per well. In the cytotoxicity experiments, the cells thus prepared were treated with the compounds to be measured in serum-free DMEM.
  • the samples were analyzed spectrophotometrically in a plate reader (Labsystems iEMS Reader MF), using the appropriate filter (490 nm), obtaining the absorbance values by means of the DeltaSOFTI l 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.
  • the viability assessment was made by measuring the reduction of a soluble tetrazolium salt (MTT), yellow, to an insoluble blue formazan.
  • MTT soluble tetrazolium salt
  • N-acetylcysteine N-acetylcysteine (NAC)
  • 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, 1346-1353).
  • Table 1 Percentage of neuroprotection against the mixture of rotenone (30 ⁇ ) and oligomycin A (10 ⁇ ) of the derivatives of 1,8-naphthyridine at the concentration of 1 micromolar Compound% protection at 1 uM
  • PAS peripheral binding site
  • the 0.35 mM acetylthiocholine iodide substrate was added from a 10 mM stock solution.
  • 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.
  • the concentration of drug that produces 50% inhibition of enzyme activity 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 to 8 are shown in Table 3. Table 3.- Cholinesterase enzyme inhibitory activity by compounds derived from 1,8-naphthyridine.

Abstract

1,8-Naphthyridine-derived compounds, the method for the production thereof and the use thereof as agents in the treatment of diseases of the central nervous system caused by a series of processes included in that which is generically known as neurodegeneration. Said diseases may be selected from the list that includes Alzheimer's disease, Parkinson's disease and Huntington's disease.

Description

COMPUESTOS DERIVADOS DE 1 ,8-NAFTIRIDINAS Y SU USO EN EL TRATAMIENTO DE ENFERMEDADES NEURODEGENERATIVAS  COMPOUNDS DERIVED FROM 1, 8-NAFTIRIDINES AND THEIR USE IN THE TREATMENT OF NEURODEGENERATIVE DISEASES
La presente invención se refiere a compuestos de fórmula general (I). La invención también se refiere a su procedimiento de obtención y su uso como agentes para el tratamiento de enfermedades del sistema nervioso central provocadas por una serie de procesos incluidos en lo que genéricamente se denomina neurodegeneración. La presente invención se puede enmarca en el campo de la industria farmacéutica. The present invention relates to compounds of general formula (I). The invention also relates 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.
Figure imgf000002_0001
Figure imgf000002_0001
(I)  (I)
ESTADO DE LA TÉCNICA ANTERIOR STATE OF THE PREVIOUS TECHNIQUE
El progresivo envejecimiento de la población mundial trae consigo la indeseada consecuencia de un aumento de las enfermedades neurodegenerativas y demencias seniles. Entre éstas, la enfermedad de Alzheimer, EA en lo sucesivo, es la enfermedad neurodegenerativa más común, responsable de aproximadamente dos tercios del total de casos de demencia (variando entre 42 y 81 % según distintos estudios), con una prevalencia muy relacionada con la edad, que se aproxima al 50% en la población mayor de 85 años, y que afecta más a las mujeres que a los hombres. Varios son los procesos bioquímicos afectados en los cerebros de pacientes de EA: metabolismo anómalo y agregación de la proteína amiloide, hiperfosforilación de la proteína tau, presencia incontrolada de especies oxidantes, alteraciones de la homeostasis de los iones calcio (Ca2+ en lo sucesivo), pérdida neuronal, problemas en la neurotransmisión colinérgica, etc., en los cerebros de pacientes de EA. Sin duda, una mejora de cualquiera de estas patologías por separado sería una aproximación correcta, si bien incompleta, al tratamiento de la enfermedad. En la actualidad, los fármacos empleados para el tratamiento de la EA son agentes que mejoran la neurotransmisión colinérgica, capaces de aliviar los déficits cognitivos y de memoria asociados a la EA, aunque sólo de manera temporal (Arch. Gerontol. Geriatr. Suppl. 2004, 9, 297-307). 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 calcium ion homeostasis (Ca 2+ hereafter ), neuronal loss, cholinergic neurotransmission problems, 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 relieving cognitive and memory deficits associated with AD, although only temporarily (Arch. Gerontol. Geriatr. Suppl. 2004 , 9, 297-307).
Ante esta situación, resulta obvia la conveniencia de disponer de fármacos capaces de actuar en los primeros estadios de la enfermedad o, mejor aún, que produzcan una actividad protectora en la fase inicial de la enfermedad, en el caso ideal de disponer de un sistema de diagnóstico precoz adecuado {Ann. Neurol. 2007, 61, 120-129), y que sean capaces de restablecer o, al menos, mantener los procesos fisiológicos afectados en las enfermedades neurodegenerativas en los niveles más próximos posibles a la normalidad funcional. 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.
Estudios llevados a cabo tanto en modelos animales como en humanos demuestran que la pérdida del equilibrio entre las especies oxidantes generadas por el metabolismo cerebral y los mecanismos protectores antioxidantes produce el llamado estrés oxidativo, cuando dichos sistemas defensivos disminuyen su eficacia y son desbordados. Este estrés oxidativo aumenta con la edad y se encuentra entre las primeras causas de la patogénesis de la EA (Neurobiol. Aging 2007, 28, 1009-1014) posiblemente asociado a disfunciones de las mitocondrias neuronales. Asimismo, se conoce que los productos con propiedades antioxidantes son capaces de prevenir la apoptosis inducida por el péptido amiloide, así como las alteraciones de la homeostasis de Ca2+ en cultivos de neuronas corticales {Life Sci. 2000, 66, 1879-1892). 66, 1879-1892). 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 homeostasis of Ca 2+ in cortical neuron cultures {Life Sci. 2000, 66, 1879-1892) . 66, 1879-1892).
Por otra parte, la hiperfosforilación de la proteína tau, asociada a la estabilidad de los microtúbulos celulares, da lugar a la formación de ovillos neurofibrilares en el interior de las neuronas que son reflejo de la destrucción de microtúbulos y neurofilamentos, lo que finalmente ocasiona daño y muerte neuronal. On the other hand, hyperphosphorylation of the tau protein, associated with the stability of cell microtubules, leads to the formation of neurofibrillary tangles. inside the neurons that reflect the destruction of microtubules and neurofilaments, which ultimately causes damage and neuronal death.
Por otro lado, algunos derivados de 1 ,8-naftiridina se han descrito con actividad neuroprotectora (José Marco-Contelles et al., Bioorqanic & Medicinal Chemistrv 14 (2006) 8176-8185; Rafael León, et al., Bioorqanic & Medicinal Chemistrv 16 (2008) 7759-7769). On the other hand, some derivatives of 1,8-naphthyridine have been described with neuroprotective activity (José Marco-Contelles et al., Bioorqanic & Medicinal Chemistrv 14 (2006) 8176-8185; Rafael León, et al., Bioorqanic & Medicinal Chemistrv 16 (2008) 7759-7769).
DESCRIPCIÓN DE LA INVENCIÓN DESCRIPTION OF THE INVENTION
La presente invención está relacionada con la capacidad de inhibidores de enzimas colinesterasas de ejercer mejoras sintomáticas en pacientes de Alzheimer, a través de un mecanismo de acción que no sólo implicaría la inhibición de este tipo de enzimas, sino que adicionalmente serían capaces de llevar a cabo otras actividades no colinérgicas, mostrando globalmente un perfil neuroprotector de las neuronas sensibles a los estímulos disparados por el proceso neurodegenerativo. Estos efectos se han observado en la familia de compuestos descritos en la presente invención. Más concretamente, la presente invención se refiere a una familia de compuestos con la característica estructural de ser derivados del sistema heterocíclico 1 ,8-naftiridina, que presentan propiedades farmacológicas potencialmente útiles para el tratamiento de enfermedades neurodegenerativas como, por ejemplo, la EA. 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, showing globally 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 relates to a family of compounds with the structural characteristic of being derived from the 1, 8-naphthyridine heterocyclic system, which have potentially useful pharmacological properties for the treatment of neurodegenerative diseases such as AD.
En los estudios farmacológicos a que han sido sometidos, los compuestos de la presente invención han mostrado una serie de actividades potencialmente muy útiles en el tratamiento de enfermedades neurodegenerativas, sin perjuicio de que en estudios mas profundos, vayan apareciendo nuevas propiedades biológicas de posible interés. Las actividades estudiadas, y que han mostrado resultados positivos, han sido: 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:
- Inhibición de la enzima acetilcolinesterasa. - Inhibición de la enzima butirilcolinesterasa. - Inhibition of the enzyme acetylcholinesterase. - Inhibition of the enzyme butyrylcholinesterase.
- Efecto neuroprotector sobre una línea de neuroblastoma sometida a estrés oxidativo.  - Neuroprotective effect on a neuroblastoma line subjected to oxidative stress.
- Efecto neuroprotector sobre una línea de neuroblastoma sometida a hiperfosforilación de la proteína tau.  - Neuroprotective effect on a neuroblastoma line undergoing hyperphosphorylation of the tau protein.
Como se ha descrito es el estado de la técnica anterior a la presente invención, y cada vez existe un mayor número de evidencias experimentales, la presencia de especies oxidantes por encima de niveles fisiológicamente aceptables, el llamado estrés oxidativo, se encuentra en el origen de la EA, y a su vez está fuertemente relacionado con entradas incontroladas de iones Ca2+. 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, in turn, is strongly related to uncontrolled inputs of Ca 2+ ions.
Por lo tanto, un primer aspecto de la presente invención se refiere a un compuesto de fórmula general (I) (a partir de ahora compuestos de la invención): Therefore, a first aspect of the present invention relates to a compound of general formula (I) (hereafter compounds of the invention):
Figure imgf000005_0001
Figure imgf000005_0001
donde: R1 y R2 son grupos iguales o distintos y se seleccionan cada uno de forma independiente de un grupo alquilo (C1-C10); y where: R1 and R2 are the same or different groups and each is independently selected from an alkyl group (C1-C10); Y
es un número entero de entre 0 a 5, y representa el número de átomos de carbono adicionales para cerrar el cicloalcano fusionado al heterociclo de 1 ,8-naftiridina. Preferiblemente n es 0, 1 , 2 ó 3.  it is an integer from 0 to 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.
Por "compuesto de la invención" también se refiere en la presente invención a cualquiera de sus derivados, isómeros, sal farmacéuticamente aceptable y/o solvato del mismo. El término "alquilo" se refiere en la presente invención a cadenas alifáticas, lineales o ramificadas, que tienen de 1 a 10 átomos de carbono, por ejemplo, metilo, etilo, n-propilo, i-propilo, n-butilo, tert-butilo, sec-butilo, n-pentilo, n- hexilo, etc. Preferiblemente el grupo alquilo tiene entre 1 y 6 átomos de carbono. Los radicales alquilo (Ri y/o R2) pueden estar opcionalmente sustituidos por uno o más sustituyentes tales como un cicloalquilo, arilo, heteroarilo, alcoxilo, halógeno, haloalquilo, nitro, amino, aminoalquilo, aminocicloalquilo, amonioalquilo, amoniocicloalquilo o, en general, cualquier sustituyente situado en cualquier posición. 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 (Ri and / or R 2 ) 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.
En una realización preferida de la presente invención, R1 es metilo o etilo. En otra realización preferida, R2 es metilo. In a preferred embodiment of the present invention, R 1 is methyl or ethyl. In another preferred embodiment, R 2 is methyl.
En otra realización más preferida, el compuesto de la invención se selecciona de la lista que comprende: In another more preferred embodiment, the compound of the invention is selected from the list comprising:
• 5-amino-2-metil-6,7,8,9-tetrahidrobenzo[ib][1 ,8]naftiridina-3-carboxilato de metilo,  • methyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo [ib] [1,8] naphthyridine-3-carboxylate,
• 5-amino-2-metil-6,7,8,9-tetrahidrobenzo[ib][1 ,8]naftiridina-3-carboxilato de etilo,  • ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo [ib] [1,8] naphthyridine-3-carboxylate,
• 5-amino-2-metil-7,8-dihidro-6/-/-ciclopenta[ib][1 ,8]naftiridina-3-carboxilato de metilo,  • methyl 5-amino-2-methyl-7,8-dihydro-6 / - / - cyclopenta [ib] [1,8] naphthyridine-3-carboxylate,
• 5-amino-2 metil-7,8-dihidro-6/-/-ciclopenta[ib][1 ,8]naftiridina-3-carboxilato de etilo,  • ethyl 5-amino-2-methyl-7,8-dihydro-6 / - / - cyclopenta [ib] [1,8] naphthyridine-3-carboxylate,
• 5-amino-2 metil-7,8,9,10-tetrahidro-6/-/-ciclohepta[ib][1 ,8]naftiridina-3- carboxilato de metilo,  • 5-amino-2 methyl-7,8,9,10-tetrahydro-6 / - / - cyclohepta [ib] [1,8] naphthyridine-3-methyl carboxylate,
• 5-amino-2-metil-7,8,9,10-tetrahidro-6/-/-ciclohepta[ib][1 ,8]naftiridina-3- carboxilato de etilo,  • ethyl 5-amino-2-methyl-7,8,9,10-tetrahydro-6 / - / - cyclohepta [ib] [1,8] naphthyridine-3-carboxylate,
• 5-amino-2-metil-6,7,8,9, 10,1 1 -hexahidrocicloocta[ib][1 ,8]naftiridina-3- carboxilato de metilo, y  • methyl 5-amino-2-methyl-6,7,8,9, 10,1-1-hexahydrocycloocta [ib] [1,8] naphthyridine-3-carboxylate, and
• 5-amino-2-metil-6,7,8,9, 10,1 1 -hexahidrocicloocta[ib][1 ,8]naftiridina-3- carboxilato de etilo. Los compuestos de la presente invención de fórmula (I) pueden ser obtenidos o producidos mediante una vía sintética química u obtenidos a partir de una materia natural de distinto origen. Otro aspecto de la presente invención se refiere a un procedimiento de obtención de los compuestos de la invención de fórmula (I), o un isómero, sal farmacéuticamente aceptable y/o solvato del mismo, caracterizado porque comprende las siguientes etapas: a) reacción de un acilacetato alquilo de fórmula (II), • 5-Amino-2-methyl-6,7,8,9, 10,1 1 -hexahydrocycloocta [ib] [1,8] naphthyridine-3-carboxylate ethyl. 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),
Figure imgf000007_0001
en que Ri y R2 representan los sustituyentes indicados más arriba al describir la fórmula general (I), en condiciones de sustitución con un diaalquilacetal de dimetilformamida. Esta reacción daría lugar a un aceptor Michael sustituido en posición beta con un grupo dimetilamino, el cual, por reacción con cianoacetamida en condiciones básicas con evolución de dimetilamina y la posterior ciclación 6-exo-trig, rinde la correspondiente 2-piridona (III).
Figure imgf000007_0001
in which Ri and R 2 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) .
Figure imgf000007_0002
Figure imgf000007_0002
(III)  (III)
b) sustitución nucleófila sobre la 2-piridona (III) mediante un exceso de oxicloruro de fósforo para obtener la piridina (IV);
Figure imgf000007_0003
(IV) c) sustitución nucleófila sobre esta piridina (IV) para incorporar en la posición del átomo de Cl una amina, reacción que se puede hacer mediante burbujeo de amoniaco, o mediante tratamiento con benzilamina en un disolvente polar, obteniendo la piridina protegida (V). b) nucleophilic substitution on 2-pyridone (III) by an excess of phosphorus oxychloride to obtain pyridine (IV);
Figure imgf000007_0003
(IV) c) nucleophilic substitution on this pyridine (IV) to incorporate in 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).
Figure imgf000008_0001
Figure imgf000008_0001
d) estas piridinas se someten a condiciones de desprotección para dejar el grupo amino liberado siguiendo métodos comunes y conocidos, como el tratamiento con ácido trifluorometanosulfónico en cualquier disolvente orgánico conocido por un experto en la materia, o el burbujeo de gas hidrógeno en presencia de cantidades catalíticas de paladio sobre un soporte de carbón activo, para obtener las piridina del tipo (VI).
Figure imgf000008_0002
d) these pyridines are subjected to deprotection conditions to leave the amino group released following common and known methods, such as treatment with trifluoromethanesulfonic 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).
Figure imgf000008_0002
(VI)  (SAW)
e) reacción de condensación tipo Friedlánder del sistema heterocíclico básico (VI) para conseguir los productos finales objeto de la presente invención, de fórmula general (I). Estos derivados se obtuvieron siguiendo metodologías particulares según la naturaleza de los grupos Ri y F½. e) Friedlander type 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 Ri and F½ groups.
Figure imgf000008_0003
Figure imgf000008_0003
(I) Otro aspecto más de la presente invención se refiere a cualquiera de los compuestos de fórmula general (I) para su uso como medicamento o composición farmacéutica, y preferiblemente un medicamento o composición farmacéutica que se utilice para el tratamiento de patologías o enfermedades provocadas por procesos oxidativos, por procesos de formación de ovillos neurofibrilares o, en general, de enfermedades susceptibles de beneficiarse de las actividades biológicas mostradas por los productos descritos en la presente invención, o bien de una sal, derivado, profármaco o solvato farmacéuticamente aceptables del mismo. (I) 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 neurofibrillar clews or, in general, of diseases susceptible to benefit from the biological activities shown by the products described in the present invention, or of a pharmaceutically acceptable salt, derivative, prodrug or solvate thereof.
Los compuestos de la presente invención representados por la fórmula (I) pueden incluir isómeros, dependiendo de la presencia de enlaces múltiples (por ejemplo, Z y E), incluyendo isómeros ópticos o enantiómeros, dependiendo de la presencia de centros quirales en las cadenas Ri y F¾. Los isómeros, enantiómeros o diastereoisómeros individuales y las mezclas de los mismos caen dentro del alcance de la presente invención. Los enantiómeros o diastereoisómeros individuales, así como sus mezclas, pueden separarse mediante técnicas convencionales. Los compuestos de la presente invención representados por la fórmula (I) presentan en posición 4 del heterociclo de naftiridina, un átomo de hidrógeno, careciendo por lo tanto de otro tipo de sustitución. Esta limitación estructural podría facilitar su unión al sitio catalítico de la enzima acetilcolinesterasa, según resultados computacionales previamente analizados. 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 Ri chains. and F¾. 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.
Tal como aquí se utiliza, el término "derivado" incluye tanto a compuestos farmacéuticamente aceptables, es decir, derivados del compuesto de fórmula (I) que pueden ser utilizados en la elaboración de un medicamento, como derivados farmacéuticamente no aceptables ya que éstos pueden ser útiles en la preparación de derivados farmacéuticamente aceptables. La naturaleza del derivado farmacéuticamente aceptable no es crítica, siempre y cuando sea farmacéuticamente aceptable. Asimismo, dentro del alcance de esta invención se encuentran los profármacos de los compuestos de fórmula (I). El término "profármaco" tal como aquí se utiliza incluye a cualquier compuesto derivado de un compuesto de fórmula (I), por ejemplo, ásteres, incluyendo ásteres de ácidos carboxílicos, ásteres de aminoácidos, ásteres de fosfato, ásteres de sulfonato de sales metálicas, etc., carbamatos, amidas, etc., que, cuando se administra a un individuo es capaz de proporcionar, directa o indirectamente, dicho compuesto de fórmula (I) en dicho individuo. Ventajosamente, dicho derivado es un compuesto que aumenta la biodisponibilidad del compuesto de fórmula (I) cuando se administra a un individuo o que potencia la liberación del compuesto de fórmula (I) en un receptor biológico. La naturaleza de dicho derivado no es crítica siempre y cuando pueda ser administrado a un individuo y proporcione el compuesto de fórmula (I) en un receptor biológico de un individuo. La preparación de dicho profármaco puede llevarse a cabo mediante métodos convencionales conocidos por los expertos en la materia. 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 these 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 an individual's biological receptor. The preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.
Los compuestos de la invención pueden estar en forma cristalina como compuestos libres o como solvatos y se pretende que ambas formas están dentro del alcance de la presente invención. En este sentido, el término "solvato", tal como aquí se utiliza, incluye tanto solvatos farmacéuticamente aceptables, es decir, solvatos del compuesto de fórmula (I) que pueden ser utilizados en la elaboración de un medicamento, como solvatos farmacéuticamente no aceptables, los cuales pueden ser útiles en la preparación de solvatos o sales farmacéuticamente aceptables. La naturaleza del solvato farmacéuticamente aceptable no es crítica, siempre y cuando sea farmacéuticamente aceptable. En una realización particular, el solvato es un hidrato. Los solvatos pueden obtenerse por métodos convencionales de solvatación bien conocidos por los técnicos en la materia. Para su aplicación en terapia, los compuestos de fórmula (I), sus isómeros, sales, profármacos o solvatos, se encontrarán, preferentemente, en una forma farmacéuticamente aceptable o sustancialmente pura, es decir, que tenga un nivel de pureza farmacéuticamente aceptable excluyendo los aditivos farmacéuticos normales tales como diluyentes y portadores, y no incluyendo material considerado tóxico a niveles de dosificación normales. Los niveles de pureza para el principio activo son preferiblemente superiores al 50%, más preferiblemente superiores al 70%, más preferiblemente superiores al 90%. En una realización preferida, son superiores al 95% del compuesto de fórmula (I), o de sus sales, solvatos o profármacos. 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) 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 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.
A menos que se indique lo contrario, los compuestos de la invención también incluyen compuestos que difieren sólo en la presencia de uno o más átomos isotópicamente enriquecidos. Por ejemplo, compuestos que tienen dicha estructura, a excepción de la sustitución de un hidrógeno por un deuterio o por tritio, o la sustitución de un carbono por un carbono enriquecido en 13C o 14C o un nitrógeno enriquecido en 15N, están dentro del alcance de esta invención. Los compuestos descritos en la presente invención, sus sales farmacéuticamente aceptables, profármacos y/o solvatos así como las composiciones farmacéuticas que los contienen pueden ser utilizados junto con otros fármacos adicionales para proporcionar una terapia de combinación. Dichos fármacos adicionales pueden formar parte de la misma composición farmacéutica o, alternativamente, pueden ser proporcionados en forma de una composición separada para su administración simultánea o no a la de la composición farmacéutica que comprende un compuesto de fórmula (I), o un profármaco, solvato, derivado o una sal farmacéuticamente aceptable de los mismos. 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 said structure, except for the replacement of a hydrogen with a deuterium or tritium, or the replacement of a carbon with a carbon enriched in 13 C or 14 C or a nitrogen enriched in 15 N, are within of 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.
Otra realización preferida de la presente invención se refiere a una composición farmacéutica útil para el tratamiento de patologías o enfermedades del sistema nervioso que puedan ser provocadas por procesos oxidativos, por el desarrollo de ovillos neurofibrilares o que al menos dichos procesos jueguen un papel patológicamente significativo o, en general, de enfermedades susceptibles de beneficiarse de las actividades biológicas mostradas por los productos descritos en la presente invención, en adelante composición farmacéutica de la invención, que comprende un compuesto, en cantidad terapéuticamente efectiva, de fórmula (I), o mezclas de los mismos, una sal, profármaco, solvato o estereoisómero farmacéuticamente aceptable del mismo junto con un portador, adyuvante o vehículo farmacéuticamente aceptable, para la administración a un paciente. Another preferred embodiment of the present invention relates to a pharmaceutical composition useful for the treatment of diseases or diseases of the nervous system that can be caused by oxidative processes, by the development of neurofibrillar clews or at least such processes play a pathologically significant role or , in general, of diseases susceptible to benefit from the biological activities shown by the products described in the present invention, hereinafter pharmaceutical composition of the invention, which comprises a compound, in therapeutically effective amount, of formula (I), or mixtures thereof, a pharmaceutically acceptable salt, prodrug, solvate or stereoisomer thereof together with a pharmaceutically acceptable carrier, adjuvant or vehicle, for administration. to a patient
Otra realización preferida de la presente invención se refiere a la composición farmacéutica de la invención en el grupo de enfermedades del sistema nervioso de carácter neurodegenerativo a que pertenecen, a título ilustrativo y sin que limite el alcance de la invención: EA, Creutzfeldt- Jakob, Parkinson o Huntington, la demencia con cuerpos de Lewy o, en general, las enfermedades resultado de un deterioro de las neuronas causado por procesos de oxidación, de formación de ovillos neurofibrilares o de otro tipo tales como desequilibrios en la concentración de iones calcio, sistemas de neurotransmisión, etc; que el sistema nervioso del paciente afectado no es capaz de controlar. Another preferred embodiment of the present invention relates 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 neurofibrillar or other balls such as imbalances in calcium ion concentration, systems of neurotransmission, etc; that the nervous system of the affected patient is not able to control.
El alcance de un proceso neurodegenerativo en la presente invención se caracteriza por pérdida neuronal, fallos en los procesos de neurotransmisión o procesos derivados de fallos en el control de las especies oxidantes creadas en el cerebro que dan lugar a estrés oxidativo patológico o del desarrollo de ovillos neurofibrilares en el interior de las neuronas. 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 neurofibrilar inside the neurons.
Otro aspecto de la presente invención se refiere a una composición farmacéutica que comprende al menos un compuesto de fórmula general (I) o mezcla de compuestos y un vehículo farmacéuticamente aceptable. Opcionalmente dicha composición puede comprende otro principio activo. 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.
Los "vehículos farmacéuticamente aceptables" que pueden ser utilizados en dichas composiciones son los vehículos conocidos por los técnicos en la materia y utilizados habitualmente en la elaboración de composiciones terapéuticas. En otro aspecto, la presente invención se refiere a un método para el tratamiento de pacientes afectados por enfermedades del sistema nervioso central en las que tengan lugar procesos oxidativos incontrolados, depósito de ovillos neurofibrilares u otros procesos en los que los productos de la presente invención produzcan un efecto benéfico. Este tratamiento consiste en la administración a los individuos afectados por estas enfermedades de cantidades terapéuticamente efectivas de un compuesto de fórmula (I), o una composición farmacéutica que lo incluya. A título de ejemplo, enfermedades contempladas en esta invención son la EA, Creutzfeldt-Jakob, Parkinson o Huntington, la demencia con cuerpos de Lewy o, en general, las enfermedades resultado de un deterioro de las neuronas causado por procesos de tipo estrés oxidativo, desestabilización de los microtúbulos por formación de ovillos neurofibrilares, desequilibrios iónicos o fallos en algún sistema de neurotransmisión que el sistema nervioso del paciente afectado no es capaz de controlar. 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 neurofibrillar clews or other processes in which 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 microtubules due to the formation of neurofibrillary tangles, ionic imbalances or failures in some neurotransmission system that the nervous system of the affected patient is not able to control.
En el sentido utilizado en esta descripción, la expresión "cantidad terapéuticamente efectiva" se refiere a la cantidad del agente o compuesto capaz de desarrollar la acción terapéutica determinada por sus propiedades farmacológicas, calculada para producir el efecto deseado y, en general, vendrá determinada, entre otras causas, por las características propias de los compuestos, incluyendo la edad, estado del paciente, la severidad de la alteración o trastorno, y de la ruta y frecuencia de administración. En otra realización particular, dicha composición terapéutica se prepara en forma de una forma sólida o suspensión acuosa, en un diluyente farmacéuticamente aceptable. La composición terapéutica proporcionada por esta invención puede ser administrada por cualquier vía de administración apropiada, para lo cual dicha composición se formulará en la forma farmacéutica adecuada a la vía de administración elegida. En una realización particular, la administración de la composición terapéutica proporcionada por esta invención se efectúa por vía oral, tópica, rectal o parenteral (incluyendo subcutánea, intraperitoneal, intradérmica, intramuscular, intravenosa, etc.). Una revisión de las distintas formas farmacéuticas de administración de medicamentos y de los excipientes necesarios para la obtención de las mismas puede encontrarse, por ejemplo, en el "Tratado de Farmacia Galénica", C. Faulí i Trillo, 1993, Luzán 5, S.A. Ediciones, Madrid, o en otros habituales o similares de las Farmacopeas Española y de Estados Unidos. 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 subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous, 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, SA Ediciones , Madrid, or in other or similar ones of the Spanish and United States Pharmacopoeias.
El uso de los compuestos de la presente invención es compatible con su uso en protocolos en que los compuestos de la fórmula (I), o sus mezclas se usan por sí mismos o en combinaciones con otros tratamientos o cualquier procedimiento médico. 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.
A lo largo de la descripción y las reivindicaciones la palabra "comprende" y sus variantes no pretenden excluir otras características técnicas, aditivos, componentes o pasos. Para los expertos en la materia, otros objetos, ventajas y características de la invención se desprenderán en parte de la descripción y en parte de la práctica de la invención. Los siguientes ejemplos se proporcionan a modo de ilustración, y no se pretende que sean limitativos de la presente invención. 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.
EJEMPLOS EXAMPLES
A continuación se ilustrará la invención mediante unos ensayos realizados por los inventores, que desarrollan el proceso de selección de los compuestos de la invención. 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. OBTENCIÓN DE LOS COMPUESTOS DE LA INVENCIÓN 1. OBTAINING THE COMPOUNDS OF THE INVENTION
Los compuestos cuya actividad biológica es objeto de la presente invención se sintetizaron siguiendo un procedimiento general en síntesis orgánica. Dicho procedimiento está representado en el siguiente Esquema de reacciones: 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:
Figure imgf000015_0001
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0002
I  I
Esquema 1 . Síntesis de los compuestos de fórmula (I)  Scheme 1. Synthesis of the compounds of formula (I)
Esta síntesis en varios pasos parte del acilacetato (II), producto comercial u obtenido por procedimientos habituales en síntesis orgánica, de fácil ejecución por parte de cualquier experto en este campo. Este compuesto (II) se sometió a reacción con un derivado dialquilacetal de la dimetilformamida, para formar un intermedio de reacción con estructura de aceptor Michael, el cual, por reacción con cianoacetamida en condiciones básicas con evolución de dimetilamina y la posterior delación 6-exo-trig, rinde la correspondiente 2-piridona (III). En general, la piridona resultante se obtiene con pureza suficiente como para no ser necesaria una posterior purificación, el compuesto generado se aisla del medio de reacción por precipitación en medio ligeramente ácido. A partir de este producto de partida, se necesita sustituir el carbonilo en posición 2 por un grupo funcional amina. Para llevar a cabo esta transformación, se necesita transformar el carbonilo en un grupo fácilmente saliente, se eligió para ello la formación de 2-cloropiridina (IV). Este intermedio en la ruta de síntesis se forma en presencia de un exceso de electrófilo clorante, como el pentacloruro de fósforo o el oxicloruro de fósforo, pudiendo actuar como disolvente en la reacción. El uso de oxicloruro de fósforo facilita el proceso de aislamiento del producto ya que, una vez terminada la reacción (24h-2d), los derivados de 2- cloropiridina IV precipitan al añadir hielo. Así, se obtienen por filtración y secado, sin necesidad de mayor purificación. El intermedio clorado (IV) se somete a una sustitución nucleófila para incorporar en la posición del átomo de Cl una amina, reacción que se puede hacer de varias maneras, por ejemplo mediante burbujeo de amoniaco, o mediante tratamiento con bencilamina en un disolvente polar, obteniéndose la piridina protegida (V). El uso de bencilamina exige de un paso posterior. Sin embargo, es el método de elección porque evita el uso de amoniaco gas embotellado a alta presión, no exento de peligrosidad para el investigador. Así, se obtienen los precursores tipo (VI) a través de la eliminación del grupo bencilo en (V), en condiciones clásicas de desprotección de este tipo de funcionalidades, como es el burbujeo de gas hidrógeno en presencia de cantidades catalíticas de Pd sobre un soporte de carbón activo. Alternativamente y para evitar el uso de gases peligrosos, que necesitan a veces de un aumento de la presión en el reactor, se puede someter (V) a un tratamiento con ácido trifluorometanosulfónico en disolvente orgánico, que rinde análogamente las piridina del tipo (VI). Alternativamente, es posible llegar a la piridina VI a partir del éster alquílico del ácido β-aminocrotónico y el 2- etoximetilenmalononitrilo en presencia de ácido acético, en un solo paso de reacción, pero con bajo rendimiento. Estas piridinas son el sustrato necesario para la reacción de condensación tipo Friedlánder con cetonas cíclicas en presencia de un ácido de Lewis, para conseguir los productos finales objeto de la presente invención, de fórmula general (I). Los productos se obtienen con buen rendimiento, y si se considera todos los pasos de reacción, el rendimiento global de la ruta sintética desde productos comerciales está entorno al 18-26%. Este rendimiento se puede aumentar en el último paso de la condensación de Friedlánder con la utilización de un aparato de microondas. Se ha probado este método con la síntesis del compuesto 2, aumentando el rendimiento en el último paso de un 55 al 90%. Esta eficacia sintética permite considerar a estos compuestos accesibles para su preparación en planta piloto por la industria farmacéutica. En particular, y siguiendo el protocolo de síntesis representado en el Esquema 1 , se obtuvieron y caracterizado los siguientes compuestos: 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-exolation -trig, yields the corresponding 2-pyridone (III). In general, the resulting pyridone is obtained with sufficient purity that subsequent purification is not necessary, 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. In order to carry out this transformation, it is necessary to transform the carbonyl into an easily leaving group, the 2-chloropyridine (IV) formation. 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, 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 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 trifluoromethanesulfonic acid in organic solvent, which similarly yields pyridine 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 efficacy 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:
Compuesto 1 : Compound 1:
5-amino-2-metil-6,7,8,9-tetrahidrobenzo[í)][1 ,8]naftiridina-3-carboxilato de metilo. Sólido amarillo. Punto de fusión > 200 °C; IR (KBr) v 3338, 3229, 2941 , 2862, 1716, 1620, 1601 , 1568, 1543, 1437, 1361 , 1284, 1246, 1 1 16, 1070, 802, 779 cm"1; 1 H NMR (CDCI3, 200 MHz) δ (ppm) 8.82 (s, 1 H, H4), 5.19 (bs, 2H, NH2), 3.94 (s, 3H, CH30), 3.07 (m, 2H, H9), 2.95 [s, 3H, CH3C(2)], 2.59 (m, 2H, H6), 1 .93 (m, 4H, H7, H8); 13C NMR (CDCI3, 75.4 MHz) δ (ppm): 166.4 (C=0), 161 .9 (C9a), 159.6 (C2), 154.1 (C10a), 150.9 (C5), 136.0 (C4), 1 19.7 (C3), 109.9 (C5a), 108.3 (C4a), 52.1 (CH30), 33.4 (C9), 25.2 [CH3C(2)], 23.3 (C6), 22.1 , 22.0 (C7, C8); EM (APIES+): m/z 272 [(M+1 )+, 100], 248 (12), 205 (13). Pureza: Anal. Elem. Cale, para Ci5Hi7N302: C, 66.40; H, 6.32; N, 15.49. Encontrado: C, 66.10; H, 6.61 ; N, 15.18. Methyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo [í)] [1,8] naphthyridine-3-carboxylate. Solid yellow. Melting point> 200 ° C; IR (KBr) v 3338, 3229, 2941, 2862, 1716, 1620, 1601, 1568, 1543, 1437, 1361, 1284, 1246, 1 1 16, 1070, 802, 779 cm "1 ; 1 H NMR (CDCI 3 , 200 MHz) δ (ppm) 8.82 (s, 1 H, H4), 5.19 (bs, 2H, NH 2 ), 3.94 (s, 3H, CH 3 0), 3.07 (m, 2H, H9), 2.95 [ s, 3H, CH 3 C (2)], 2.59 (m, 2H, H6), 1.93 (m, 4H, H7, H8); 13 C NMR (CDCI 3 , 75.4 MHz) δ (ppm): 166.4 (C = 0), 161 .9 (C9a), 159.6 (C2), 154.1 (C10a), 150.9 (C5), 136.0 (C4), 1 19.7 (C3), 109.9 (C5a), 108.3 (C4a), 52.1 (CH 3 0), 33.4 (C9), 25.2 [CH 3 C (2)], 23.3 (C6), 22.1, 22.0 (C7, C8); MS (APIES +): m / z 272 [(M + 1) + , 100], 248 (12), 205 (13) Purity: Anal. Cale Element, for Ci 5 Hi 7 N 3 0 2 : C, 66.40; H, 6.32; N, 15.49. Found: C, 66.10 ; H, 6.61; N, 15.18.
Compuesto 2: Compound 2:
5-amino-2-metil-6,7,8,9-tetrahidrobenzo[í)][1 ,8]naftiridina-3-carboxilato de etilo. Sólido amarillo. Punto de fusión > 200 °C; IR (KBr) v 3374, 3324, 3182, 2934, 1717, 1664, 1602, 1577, 1546, 1434, 1363, 1350, 1252, 1222, 1 120, 1072, cm"1; 1 H NMR (CDCI3, 300 MHz) δ (ppm) 8.82 (s, 1 H, H4), 5.33 (bs, 2H, NH2), 4.39 (q, J = 7.5 Hz, 2H, C02CH2CH3), 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, C02CH2CH3); 13C NMR (CDCI3, 75.4 MHz) δ (ppm) 166.7 (C=0), 163.9 (C9a), 162.0 (C2), 154.6 (C10a), 149.5 (C5), 135.0 (C4), 121 .8 (C3), 1 1 1 .5 (C5a), 109.0 (C4a), 61 .8 (OCH2CH3), 34.2 (C9), 26.4 [CH3C(2)], 23.9 (C6), 22.8 (C7, C8), 14.7 (CH3CH20); EM (APIES+): m/z 286 [(M+1 )+, 100], 593 [(2xM+Na)+, 5], 308 [(M+Na)+, 4], 272 (10), 258 (12). Pureza: Anal. Elem. Cale, para C16H19N3O2: C, 67.35; H, 6.71 ; N, 14.73. Encontrado: C, 67.12; H, 6.54; N, 14.55. Ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo [í)] [1,8] naphthyridine-3-carboxylate. Solid yellow. Melting point> 200 ° C; IR (KBr) v 3374, 3324, 3182, 2934, 1717, 1664, 1602, 1577, 1546, 1434, 1363, 1350, 1252, 1222, 1 120, 1072, cm "1 ; 1 H NMR (CDCI 3 , 300 MHz) δ (ppm) 8.82 (s, 1 H, H4), 5.33 (bs, 2H, NH 2 ), 4.39 (q, J = 7.5 Hz, 2H, C0 2 CH 2 CH 3 ), 3.05 (m, 2H , H9), 2.91 [s, 3H, CH 3 C (2)], 2.58 (m, 2H, H6), 1.92 (m, 4H, H7, H8), 1.41 (t, J = 7.5 Hz, 3H , C0 2 CH 2 CH 3 ); 13 C NMR (CDCI 3 , 75.4 MHz) δ (ppm) 166.7 (C = 0), 163.9 (C9a), 162.0 (C2), 154.6 (C10a), 149.5 (C5), 135.0 (C4), 121 .8 (C3), 1 1 1 .5 (C5a), 109.0 (C4a), 61 .8 (OCH 2 CH 3 ), 34.2 (C9), 26.4 [CH 3 C (2)] , 23.9 (C6), 22.8 (C7, C8), 14.7 (CH 3 CH 2 0); MS (APIES +): m / z 286 [(M + 1) + , 100], 593 [(2xM + Na) + , 5], 308 [(M + Na) + , 4], 272 (10), 258 (12). Purity: Anal. Cale Elem., For C16H19N3O2: C, 67.35; H, 6.71; N, 14.73. Found: C, 67.12; H, 6.54; N, 14.55.
Compuesto 3: Compound 3:
5-amino-2-metil-7,8-dihidro-6H-ciclopenta[ 3][1 ,8]naftiridina-3-carboxilato de metilo. Sólido amarillo. Punto de fusión > 200 °C; IR (KBr) v 3317, 3188, 2951 , 2844, 1724, 1645, 1601 , 1549, 1431 , 1358, 1259, 11 14, 802, 777 cm"1 ; 1H NMR (CDCI3, 200 MHz) δ (ppm) 8.74 (s, 1 H, 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, J6J = 7.6 Hz, 2H, H6), 2.23 (quíntete, 2H, J6 ,8 = 7.6 Hz, H7); 13C NMR (CDCI3,Methyl 5-amino-2-methyl-7,8-dihydro-6H-cyclopenta [3] [1,8] naphthyridine-3-carboxylate. Solid yellow. Melting point> 200 ° C; IR (KBr) v 3317, 3188, 2951, 2844, 1724, 1645, 1601, 1549, 1431, 1358, 1259, 11 14, 802, 777 cm "1 ; 1 H NMR (CDCI3, 200 MHz) δ (ppm) 8.74 (s, 1 H, H4), 4.76 (bs, 2H, NH 2 ), 3.97 (s, 3H, CH3O), 3.16 (t, J 7 , 8 = 7.6 Hz, 2H, H8), 2.98 [s, 3H, CH 3 C (2)], 2.86 (t, J 6J = 7.6 Hz, 2H, H6), 2.23 (quit, 2H, J 6 , 8 = 7.6 Hz, H7); 13 C NMR (CDCI 3 ,
75.4 MHz) δ (ppm) 171 .8 (C=0), 166.5 (C8a), 158.9 (C2), 157.0 (C9a), 148.1 (C4), 135.8 (C5), 1 19.5 (C3), 1 14.1 (C5a), 109.0 (C4a), 52.1 (CH30), 35.1 (C8),75.4 MHz) δ (ppm) 171 .8 (C = 0), 166.5 (C8a), 158.9 (C2), 157.0 (C9a), 148.1 (C4), 135.8 (C5), 1 19.5 (C3), 1 14.1 ( C5a), 109.0 (C4a), 52.1 (CH 3 0), 35.1 (C8),
27.5 [CH3C(2)], 25.3 (C6), 21 .8 (C7); EM (APIES+): m/z 258 [(M+1 )+, 100], 245 (1 1 ), 205 (10), 157 (10). Pureza: Anal. Elem. Cale, para Ci4Hi5N302: C, 65.35; H, 5.88; N, 16.33. Encontrado: C, 65.21 ; H, 5.78; N, 16.09. 27.5 [CH 3 C (2)], 25.3 (C6), 21 .8 (C7); MS (APIES +): m / z 258 [(M + 1) + , 100], 245 (1 1), 205 (10), 157 (10). Purity: Anal. Elem. Cale, for Ci 4 Hi 5 N 3 0 2 : C, 65.35; H, 5.88; N, 16.33. Found: C, 65.21; H, 5.78; N, 16.09.
Compuesto 4: Compound 4:
5-amino-2-metil-7,8-dihidro-6H-ciclopenta[í)][1 ,8]naftiridina-3-carboxilato de etilo. Sólido amarillo. Punto de fusión > 200 °C; IR (KBr) v 3329, 3176, 2964, 1716, 1657, 1604, 1550, 1433, 1400, 1358, 1252, 1217, 1 117, 1086, 1051 , 806, 779 cm"1; 1 H NMR (CDCI3, 200 MHz) δ (ppm) 8.74 (s, 1 H, H4), 4.80 (bs, 2H, NH2), 4.44 (q, J = 7.2 Hz, 2H, C02CH2CH3), 3.16 (t, J7¡8 = 7.6 Hz, 2H, H8), 2.98 [s, 3H, CH3C(2)], 2.88 (t, J6 = 7.6 Hz, 2H, H6), 2.23 (quíntete, 2H, J6,7,8 = 7.6 Hz, H7), 1 .45 (t, J = 7.2 Hz, 3H, C02CH2CH3); 13C NMR (CDCI3, 50.2 MHz) δ (ppm) 171 .6 (C=0), 166.1 (C8a), 158.7 (C2), 156.9 (C9a), 148.0 (C4), 135.6 (C5), 120.0 (C3), 1 14.0 (C5a), 109.0 (C4a), 60.8 (OCH2CH3), 35.0 (C8), 27.5 (C6), 25.2 [CH3C(2)], 21 .8 (C7), 14.1 (OCH2CH3); EM (APIES+): m/z 272 [(M+1 )+, 100], 258 (8), 245 (7). Pureza: Anal. Elem. Cale, para Ci5Hi7N302: C, 66.40; H, 6.32; N, 15.49. Encontrado: C, 66.41 ; H, 6.61 ; N, 15.22. Compuesto 5: Ethyl 5-amino-2-methyl-7,8-dihydro-6H-cyclopenta [í)] [1,8] naphthyridine-3-carboxylate. Solid yellow. Melting point> 200 ° C; IR (KBr) v 3329, 3176, 2964, 1716, 1657, 1604, 1550, 1433, 1400, 1358, 1252, 1217, 1 117, 1086, 1051, 806, 779 cm "1 ; 1 H NMR (CDCI 3 , 200 MHz) δ (ppm) 8.74 (s, 1 H, H4), 4.80 (bs, 2H, NH 2 ), 4.44 (q, J = 7.2 Hz, 2H, C0 2 CH 2 CH 3 ), 3.16 (t, J 7¡8 = 7.6 Hz, 2H, H8), 2.98 [s, 3H, CH 3 C (2)], 2.88 (t, J 6 = 7.6 Hz, 2H, H6), 2.23 (quit, 2H, J 6 , 7 , 8 = 7.6 Hz, H7), 1.45 (t, J = 7.2 Hz, 3H, C0 2 CH 2 CH 3 ); 13 C NMR (CDCI 3 , 50.2 MHz) δ (ppm) 171 .6 ( C = 0), 166.1 (C8a), 158.7 (C2), 156.9 (C9a), 148.0 (C4), 135.6 (C5), 120.0 (C3), 1 14.0 (C5a), 109.0 (C4a), 60.8 (OCH 2 CH 3 ), 35.0 (C8), 27.5 (C6), 25.2 [CH 3 C (2)], 21 .8 (C7), 14.1 (OCH 2 CH 3 ); MS (APIES +): m / z 272 [( M + 1) + , 100], 258 (8), 245 (7) Purity: Anal. Cale Element, for Ci 5 Hi 7 N 3 0 2 : C, 66.40; H, 6.32; N, 15.49. Found : C, 66.41; H, 6.61; N, 15.22. Compound 5:
5-amino-2-metil-7 ,9,10-tetrahidro-6H-ciclohepta[£)][1 ,8]naftiridina-3- carboxilato de metilo. Sólido amarillo. Punto de fusión > 200 °C; IR (KBr) v 3330, 3199, 2918, 2850, 1720, 1651 , 1601 , 1579, 1543, 1429, 1361 , 1346, 1257, 1 105, 1082, 810, 779 cm"1 ; 1H NMR (CDCI3, 200 MHz) δ (ppm) 8.77 (s, 1 H, 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 (C1 1 a), 149.2 (C5), 136.0 (C4), 120.1 (C3), 1 14.9 (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); EM (APIES+) m/z 286 [(M+1 )+, 100], 248 (12), 205 (15). Pureza: Anal. Elem. Cale, para Ci6Hi9N3O2 ¼H2O: C, 66.30; H, 6.78; N, 14.50. Encontrado: C, 66.60; H, 6.80; N, 14.12. Compuesto 6: Methyl 5-amino-2-methyl-7, 9,10-tetrahydro-6H-cyclohepta [£]] [1,8] naphthyridine-3-carboxylate. Solid yellow. Melting point> 200 ° C; IR (KBr) v 3330, 3199, 2918, 2850, 1720, 1651, 1601, 1579, 1543, 1429, 1361, 1346, 1257, 1 105, 1082, 810, 779 cm "1 ; 1 H NMR (CDCI 3 , 200 MHz) δ (ppm) 8.77 (s, 1 H, H4), 5.03 (bs, 2H, NH 2 ), 3.96 (s, 3H, CH 3 O), 3.19 (m, 2H, H10), 2.96 [s , 3H, CH 3 C (2)], 2.75 (m, 2H, H6), 1 .98-1 .46 (m, 6H, H7, H8, H9); 13 C NMR (DMSOd 6 , 75.4 MHz) δ (ppm) 169.1 (C = O), 166.4 (C10a), 159.0 (C2), 154.5 (C1 1 a), 149.2 (C5), 136.0 (C4), 120.1 (C3), 1 14.9 (C5a), 109.2 ( C4a), 52.0 (OCH 3 ), 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. Cale Element, for Ci 6 Hi 9 N 3 O 2 ¼H 2 O: C, 66.30; H, 6.78; N, 14.50 Found: C, 66.60; H, 6.80; N, 14.12 Compound 6:
5-amino-2-metil-7,8,9,10-tetrahidro-6H-ciclohepta[£)][1 ,8]naftiridina-3- carboxilato de etilo. Sólido amarillo. Punto de fusión >200 °C; IR (KBr) v 3381 , 3327, 3153, 2923, 2850, 1714, 1670, 1603, 1576, 1543, 1344, 1288, 1254, 1223, 1 1 1 1 , 1082, 1049, 812, 781 cm"1 ; 1H NMR (CDCI3, 200 MHz) δ (ppm) 8.75 (s, 1 H, 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 (C11 a), 149.1 (C5), 135.9 (C4), 120.5 (C3), 1 14.9 (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); EM (APIES+) m/z 300 [(M+1 )+, 100], 205 (17), 157 (13). Pureza: Anal. Elem. Cale, para Ci7H2i N3O2: C, 68.20; H, 7.07; N, 14.04. Encontrado: C, 68.12; H, 6.89; N, 13.92. Compuesto 7: Ethyl 5-amino-2-methyl-7,8,9,10-tetrahydro-6H-cyclohepta [£]] [1,8] naphthyridine-3-carboxylate. Solid yellow. Melting point> 200 ° C; IR (KBr) v 3381, 3327, 3153, 2923, 2850, 1714, 1670, 1603, 1576, 1543, 1344, 1288, 1254, 1223, 1 1 1 1, 1082, 1049, 812, 781 cm "1 ; 1 H NMR (CDCI 3 , 200 MHz) δ (ppm) 8.75 (s, 1 H, H4), 5.03 (bs, 2H, NH 2 ), 4.44 (q, J = 7.0 Hz, 2H, CO 2 CH 2 CH 3 ), 3.19 (m, 2H, H10), 2.96 [s, 3H, CH 3 C (2)], 2.75 (m, 2H, H6), 2.00-1 .60 (m, 6H, H7, H8, H9) , 1.44 (t, J = 7.0 Hz, 3H, CO 2 CH 2 CH 3 ); 13 C NMR (DMSOd 6 , 75.4 MHz) δ (ppm) 169.1 (C = O), 166.1 (C10a), 158.8 ( C2), 154.6 (C11 a), 149.1 (C5), 135.9 (C4), 120.5 (C3), 1 14.9 (C5a), 109.3 (C4a), 60.8 (OCH 2 CH 3 ), 39.2 (C10), 31. 5 (C9), 27.3 (C8), 26.2 (C6), 25.1, 25.0 (C2, C7), 14.1 (OCH 2 CH 3 ); MS (APIES +) m / z 300 [(M + 1) + , 100] , 205 (17), 157 (13). Purity: Anal. Cale element, for Ci 7 H 2 and N 3 O 2 : C, 68.20; H, 7.07; N, 14.04. Found: C, 68.12; H, 6.89; N, 13.92. Compound 7:
5-amino-2-metil-6,7,8,9,10,11-hexahidrocicloocta[í)][1,8]naftiridina-3- carboxilato de metilo. Sólido blanco. Punto de fusión > 200 °C; IR (KBr) v 3349, 2923, 2851, 1725, 1713, 1620, 1600, 1571, 1541, 1432, 1361, 1351, 1291, 1260, 1249, 1109, 1093 cm"1.1H NMR (CDCI3, 200 MHz) δ (ppm) 8.80 (s, 1H, H4), 5.10 (bs, 2H, NH2), 3.97 (s, 3H, CH30), 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 (CDCI3, 75.4 MHz) δ (ppm) 167.6 (C=0), 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). EM (APIES+) m/z 300 [(M+1)+, 100], 322 [(M+Na)+, 13]. Pureza: Anal. Elem. Cale, para Ci7H2iN302: C, 68.20; H, 7.07; N, 14.04. Encontrado: C, 68.50; H, 7.31; N, 14.08. Compuesto 8: Methyl 5-amino-2-methyl-6,7,8,9,10,11-hexahydrocycloocta [í)] [1,8] naphthyridine-3- carboxylate. Solid white. Melting point> 200 ° C; IR (KBr) v 3349, 2923, 2851, 1725, 1713, 1620, 1600, 1571, 1541, 1432, 1361, 1351, 1291, 1260, 1249, 1109, 1093 cm "1. 1 H NMR (CDCI 3 , 200 MHz) δ (ppm) 8.80 (s, 1H, H4), 5.10 (bs, 2H, NH 2 ), 3.97 (s, 3H, CH 3 0), 3.15 (m, 2H, H11), 2.98 [s, 3H , CH 3 C (2)], 2.88 (m, 2H, H6), 1.90 (m, 2H, H10), 1.73 (m, 2H, H7), 1.43 (m, 4H, H8, H9); 13 C NMR (CDCI 3 , 75.4 MHz) δ (ppm) 167.6 (C = 0), 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 (OCH 3 ), 36.2 (C11), 30.8 (C10), 27.8 (C7), 26.3, 26.2 (C8, C9), 25.9 (C2), 24.7 (C6). APIES +) m / z 300 [(M + 1) +, 100], 322 [(M + Na) +, 13]. Purity: Anal. Elem. Cale, for Ci 7 H 2 iN 3 0 2 : C, 68.20 ; H, 7.07; N, 14.04. Found: C, 68.50; H, 7.31; N, 14.08. Compound 8:
5-amino-2-metil-6,7,8,9,10,11-hexahidrocicloocta[í)][1,8]naftiridina-3- carboxilato de etilo. Sólido blanco. Punto de fusión > 200 °C; IR (KBr) v 3345, 2920, 2846, 1716, 1618, 1599, 1570, 1541, 1431, 1356, 1350, 1290, 1259, 1242, 1167, 1107, 1090, 818, 779 cm"1; 1H NMR (CDCI3, 200 MHz) δ (ppm) 8.75 (s, 1 H, H4), 5.02 (bs, 2H, NH2), 4.43 (q, J = 7.0 Hz, 2H, C02CH2CH3), 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, C02CH2CH3), 1.38 (m, 4H, H8, H9); 13C NMR (CDCI3, 75.4 MHz) δ 166.6 (C11a), 166.1 (C=0), 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). Pureza: Anal. Elem. Cale, para Ci8H23N302: C, 68.98; H, 7.40; N, 13.41. Encontrado: C, 68.69; H, 7.68; N, 13.12. 2. ACTIVIDADES BIOLÓGICAS ESTUDIADAS EN LOS COMPUESTOS DE LA INVENCIÓN Ethyl 5-amino-2-methyl-6,7,8,9,10,11-hexahydrocycloocta [í)] [1,8] naphthyridine-3- carboxylate. Solid white. Melting point> 200 ° C; IR (KBr) v 3345, 2920, 2846, 1716, 1618, 1599, 1570, 1541, 1431, 1356, 1350, 1290, 1259, 1242, 1167, 1107, 1090, 818, 779 cm "1 ; 1 H NMR ( CDCI 3 , 200 MHz) δ (ppm) 8.75 (s, 1 H, H4), 5.02 (bs, 2H, NH 2 ), 4.43 (q, J = 7.0 Hz, 2H, C0 2 CH 2 CH 3 ), 3.14 (m, 2H, H11), 2.97 [s, 3H, CH 3 C (2)], 2.87 (m, 2H, H6), 1.88 (m, 2H, H10), 1.72 (m, 2H, H7), 1.43 (t, J = 7.0 Hz, 3H, C0 2 CH 2 CH 3 ), 1.38 (m, 4H, H8, H9); 13 C NMR (CDCI 3 , 75.4 MHz) δ 166.6 (C11a), 166.1 (C = 0 ), 159.3 (C2), 154.6 (C12a), 149.9 (C5), 136.0 (C4), 120.5 (C3), 112.5 (C5a), 108.8 (C4a), 60.8 (OCH 2 CH 3 ), 35.7 (C11), 30.7 (C10), 27.8 (C7), 26.0, 25.8 (C8, C9), 25.1 [CH 3 C (2)], 23.7 (C6), 14.1 (OCH 2 CH 3 ); MS (APIES +) m / z 314 [(M + 1) + , 100], 205 (12) Purity: Anal. Cale Element, for Ci 8 H 23 N 3 0 2 : 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 Propiedades neuroprotectoras de los compuestos de la invención 2.1 Neuroprotective properties of the compounds of the invention
Se evaluó el efecto citoprotector de los compuestos en células de neuroblastoma humano, concretamente el potencial neuroprotector de estos compuestos frente a (i) el estrés oxidativo producido por rotenona y oligomicina A, bloqueantes de la cadena respiratoria de la mitocondria según se describe en J. Neurochem. 1992, 59, 1609-1623 y en Toxicological Sciences 2004, 79, 137-146, respectivamente, y (ii) la hiperfosforilación de la proteína tau inducida por ácido okadaico que es un modelo aceptado para la muerte neuronal que ocurre en la EA y que está relacionada con la hiperfosforilación de tau (Neuroscience 2004, 126, 277-284; Neurosci Lett. 1997, 235, 149-153). 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).
El parámetro de viabilidad que se midió en el primer caso era la actividad de la enzima lactatodeshidrogenasa (LDH en lo sucesivo), una enzima que se libera al medio extracelular cuando muere la célula (J. Pharmacol. Exp. Ther. 2005, 315, 1346-1353). En los experimentos con ácido okadaico se utilizó para medir la supervivencia celular el ensayo que se basa en la reducción metabólica del bromuro de 3-(4,5-dimetiltiazol-2-ilo)-2,5-difeniltetrazol (MTT) realizada por la enzima mitocondrial succinato-deshidrogenasa en un compuesto de color azul (formazan), lo que permite determinar la funcionalidad mitocondrial de las células tratadas (J. Immunol.Meth. 1983, 65, 55-63). El ácido okadaico produce cambios mitocondriales en las células tratadas con dicho tóxico, originando disminución del potencial de membrana mitocondrial ( Toxicology in Vitro 2001 , 15, 199-208), iniciándose así el proceso que llevará a la muerte celular. Por ello, se consideró más adecuado un método como el de MTT que nos permite conocer el estado metabólico de la mitocondria en las células sometidas a incubación con ácido okadaico. El método experimental utilizado, siguiendo un procedimiento previamente descrito (Neuropharmacology 2004, 46, 103-1 14) es el siguiente: las células SHSY5Y de neuroblastoma humano fueron sembradas y cultivadas en un medio DMEM (Dulbecco's modified Eagle's médium) conteniendo 15 aminoácidos no esenciales y suplementada con un 10% de suero fetal de ternera, glutamina 1 milimolar, 50 unidades por mililitro de penicilina y 50 microgramos por mililitro de estreptomicina, manteniéndolas a 37°C en aire humidificado conteniendo 5% de dióxido de carbono. En los ensayos, las células SH-SY5Y fueron subcultivadas en placas de 48 pocilios con una densidad de sembrado de 1 x105 células por pocilio. En los experimentos de citotoxicidad, las células así preparadas fueron tratadas con los compuestos a medir en DMEM libre de suero. 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. Met. 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, 103-1 14) is as follows: SHSY5Y human neuroblastoma cells were seeded and cultured in a DMEM (Dulbecco's modified Eagle's medium) 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 1 x 10 5 cells per well. In the cytotoxicity experiments, the cells thus prepared were treated with the compounds to be measured in serum-free DMEM.
Para estudiar la acción citoprotectora de los diferentes compuestos contra la muerte celular inducida por una combinación de rotenona con oligomicina A 30 micromolar y 10 micromolar respectivamente o con ácido okadaico 30 nanomolar, todos los compuestos (1 a 8) fueron evaluados a la concentración de 1 micromolar. Para ello, las células fueron tratadas con el producto a evaluar durante 24 horas. Después, los medios fueron reemplazados por medios frescos que aún contenían el compuesto más los agentes citotóxicos, y fueron así mantenidos por un período adicional de 24 horas. La viabilidad celular fue comprobada en el caso de la incubación con la combinación rotenona/oligomicina A midiendo la actividad de la enzima LDH mediante el kit "Cytotoxicity Cell Death" (Roche-Boehringer Mannheim) siguiendo las instrucciones del fabricante de dicho kit. Las muestras se analizaron espectrofotométricamente en un lector de placas (Labsystems iEMS Reader MF), empleando el filtro adecuado (490 nm), obteniendo los valores de absorbancia mediante el programa DeltaSOFTI l Versión 3,71 EMS. La actividad LDH total fue definida como la suma de las actividades LDH intra y extracelular. La actividad LDH liberada por las células al morir fue definida como el porcentaje de la actividad LDH extracelular frente a la actividad LDH total. Cuando el citotóxico empleado fue el ácido okadaico la evaluación de la viabilidad se hizo midiendo la reducción de una sal de tetrazolio (MTT) soluble, de color amarillo, a un formazán insoluble de color azul. Para ello, se añadió 50 microlitros del reactivo de MTT comercial (Sigma) a cada pocilio con 500 microlitros de medio manteniendo las placas de cultivo durante 3 horas en oscuridad y a 37 °C. Transcurrido este tiempo se retiró suavemente el medio sobrenadante, quedando depositado un precipitado que se disolvió con 300 microlitros de dimetilsulfóxido (DMSO). Tras 10 minutos agitando se tomaron muestras de los pocilios y se leyó la absorbancia en un lector de placas (Labsystems iEMS Reader MF) a una longitud de onda de 540 nanómetros. Los valores de absorbancia obtenidos con el tóxico solo y con cada compuesto en presencia del tóxico se restaron del valor de absorbancia obtenido en condiciones básales, sin tratamiento. El valor obtenido de la resta de los valores de absorbancia basal menos tóxico solo, se consideró el 100 % de muerte y los valores obtenidos con los compuestos en presencia de tóxico se normalizaron como porcentajes de dicho valor. Para calcular el porcentaje de supervivencia, se restaron estos valores de 100. 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 filter (490 nm), obtaining the absorbance values by means of the DeltaSOFTI l 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. For 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 basic 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.
En todos los ensayos farmacológicos se utilizó un control positivo como comparación y para evaluar la bondad del método empleado. En el caso de los experimentos con rotenona/oligomicina A se utilizó N-acetilcisteina (NAC), un bien conocido antioxidante; cuando se empleó ácido okadaico como tóxico se utilizó como control positivo galantamina, que en trabajos previos había demostrado un efecto protector (J. Pharmacol. Exp. Ther. 2005, 315, 1346- 1353). 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, 1346-1353).
Los resultados obtenidos para los compuestos descritos como compuestos 1 a 8 que se muestran en las Tablas 1 y 2, vienen expresados en porcentaje de la actividad neuroprotectora. 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.
Tabla 1 .- Porcentaje de neuroprotección frente a la mezcla de rotenona (30 μΜ) y oligomicina A (10 μΜ) de los derivados de 1 ,8-naftiridina a la concentración de 1 micromolar Compuesto % protección a 1 uMTable 1 .- Percentage of neuroprotection against the mixture of rotenone (30 μΜ) and oligomycin A (10 μΜ) of the derivatives of 1,8-naphthyridine at the concentration of 1 micromolar Compound% protection at 1 uM
1 25.8* 1 25.8 *
2 41 .5* 2 41 .5 *
3 29.1 * 3 29.1 *
4 28.7* 4 28.7 *
5 27.5* 5 27.5 *
6 21 .9* 6 21 .9 *
7 34.6* 7 34.6 *
8 32.6* 8 32.6 *
NAC 24.4* NAC 24.4 *
Los resultados son la media de 4 experimentos independientes (por triplicado). *p< 0.05. The results are the average of 4 independent experiments (in triplicate). * p <0.05.
Estos resultados indican que los compuestos objeto de la presente invención son capaces de reducir de manera moderada la presencia de especies radicálicas con el consiguiente efecto neuroprotector, lo que los convierte en potenciales fármacos para el tratamiento de patologías generadas o favorecidas por estrés oxidativo o presencia de especies radicálicas en general. 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.
Tabla 2.- Porcentaje de neuroprotección frente a ácido okadaico 30 nM de los derivados de 1 ,8-naftiridina a la concentración de 1 micromolar Compuesto % protección a 1 μΜ Table 2.- Percentage of neuroprotection against 30 nM okadaic acid of 1, 8-naphthyridine derivatives at the concentration of 1 micromolar Compound% protection at 1 μΜ
1 47.2*** 1 47.2 ***
2 58.6*** 2 58.6 ***
3 59.4** 3 59.4 **
4 52.3*** 4 52.3 ***
5 50.8*** 5 50.8 ***
6 16.8*** 6 16.8 ***
7 56.1 ** 8 47.6 *** 7 56.1 ** 8 47.6 ***
Galantamina 46.9*  Galantamine 46.9 *
Los resultados son la media de 8 experimentos independientes (por triplicado). *p< 0.05, **p< 0.01 , ***p< 0.001 . The results are the average of 8 independent experiments (in triplicate). * p <0.05, ** p <0.01, *** p <0.001.
Estos resultados muestran que la mayor parte de los compuestos objeto de la presente invención protegen de manera notable frente a la muerte inducida por la formación de ovillos neurofibrilares, con valores cercanos al 60% de protección para algunos de ellos. These results show that most of the compounds object of the present invention protect remarkably against death induced by the formation of neurofibrillar clews, with values close to 60% protection for some of them.
2.2 Propiedades de los compuestos objeto de la invención como inhibidores de las enzimas acetil y butirilcolinesterasa Se evaluó la actividad inhibidora de las enzimas acetilcolinesterasa (AChE) y butirilcolinesterasa (BuChE) de los compuestos estudiados por el método de Ellman (Biochem. Pharmacol. 1961 , 7, 88-95). Se eligió como modelo neuronal la enzima acetilcolinesterasa de anguila eléctrica (Electrophorus electricus), de gran analogía a la neuronal humana. Para analizar comparativamente la hipotética inhibición periférica, potencialmente asociada a los efectos adversos encontrados en la administración de anticolinesterásicos, se evaluó la actividad inhibidora de la AChE extraída de eritrocitos humanos. Para evaluar la inhibición de BuChE, se eligió la extraída de suero equino. La inhibición de las enzimas colinesterasas es la diana terapéutica predominante en la clínica para el tratamiento de la EA. Este abordaje terapéutico se basa en la denominada hipótesis colinérgica (Science 2006, 314, 777-781 ), la cual sugiere que la pérdida selectiva de neuronas colinérgicas en la EA provoca un déficit del neurotransmisor acetilcolina (ACh) en regiones específicas del cerebro que controlan el aprendizaje y la memoria (Lancet Neurol. 2003, 2, 539-547). Así, existen tres fármacos aprobados por las administraciones reguladoras del medicamento internacionales (donepecilo, galantamina y rivastigmina) que mejoran los síntomas de la EA a través de la inhibición de AChE, la enzima responsable de hidrolizar ACh, elevando consecuentemente los niveles de este neurotransmisor en la hendidura sináptica (Pharmacol. Res. 2004, 50, 441 -451 ). Recientemente se ha generado un renovado interés por los inhibidores de AChE, estimulado por el potencial papel de la AChE en acelerar la formación de fibrilas amiloides en el cerebro y la generación de complejos estables con Αβ (Neuron 1996, 16, 881 -891 ). Esta característica implica al sitio de unión periférico aniónico (PAS) de la AChE, como lo demuestra el hecho de que yoduro de propidio, que se une al PAS, afecta a la agregación de Αβ in vitro, mientras que los inhibidores que se unen al sitio catalítico no presentan este efecto. 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,) was evaluated. 7, 88-95). 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 neurotransmitter acetylcholine (ACh) in specific regions of the brain that control learning and memory (Lancet Neurol. 2003, 2, 539-547). Thus, there are three drugs approved by international drug regulatory administrations (donepezil, 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 Αβ (Neuron 1996, 16, 881-891). This characteristic involves the anionic peripheral binding site (PAS) of AChE, as evidenced by the fact that propidium iodide, which binds to PAS, affects the aggregation of Αβ in vitro, while inhibitors that bind to the Catalytic site do not exhibit this effect.
El método experimental utilizado, siguiendo el procedimiento previamente descrito (Biochem. Pharmacol. 1961 , 7, 88-95) es el siguiente: para la medida de la inhibición de AChE (ya sea extraída de anguila eléctrica o de suero humano) se llevó a cabo la reacción en pocilios con un volumen final de 3 mi de una solución tampón de PBS a pH 8, conteniendo 0,035 unidades/ml de AChE y 0,35 mM de ácido 5,5'-ditiobis-2-nitrobenzoico (DTNB), utilizado para producir el anión de color amarillo ácido 5-tio-2-nitrobenzoico. Las curvas de inhibición con los diferentes compuestos se realizaron por cuadruplicado incubando con al menos 9 concentraciones de los compuestos durante 10 min. Pasado este tiempo, se añadió el sustrato de yoduro acetiltiocolina a 0,35 mM, desde una solución madre 10 mM. Para la medida de la inhibición de BuChE extraída de suero equino se llevó a cabo la reacción en pocilios con un volumen final de 3 mi de una solución tampón de PBS a pH 8, conteniendo 0,05 unidades/ml de BuChE y 0,35 mM de ácido 5,5'-ditiobis-2-nitrobenzoico (DTNB). Las curvas de inhibición con los diferentes compuestos se realizaron por cuadruplicado incubando con al menos 9 concentraciones de los compuestos durante 10 min. Pasado este tiempo, se añadió el sustrato de yoduro butiriltiocolina a 0,5 mM, desde una solución madre 10 mM. En los dos tipos de experimentos (AChE y BuChE), una muestra por cuadruplicado sin compuesto estuvo siempre presente para rendir el 100% de la actividad enzimática. A los 15 min se midió la producción de color a 412 nm en un lector espectrofotométrico de placas de 96 pocilios como señal de la actividad enzimática. 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) The reaction was carried out 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 it was measured 412 nm color production in a 96-well plate spectrophotometric reader as a signal of enzymatic activity.
La concentración de fármaco que produce la inhibición del 50 % de la actividad enzimática (CI50) se calculó por regresión sigmoidal de la representación logarítmica de la concentración. Los resultados se expresaron como media ± error estándar de al menos tres experimentos. Los resultados obtenidos para los compuestos descritos como compuestos 1 a 8 se muestran en la Tabla 3. Tabla 3.- Actividad inhibidora de enzimas colinesterasas por parte de los compuestos derivados de 1 ,8-naftiridina.
Figure imgf000027_0001
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 to 8 are shown in Table 3. Table 3.- Cholinesterase enzyme inhibitory activity by compounds derived from 1,8-naphthyridine.
Figure imgf000027_0001
Compuesto eeAChE hAChE eaBuChE SÍBuChE/eeAChE)  Compound eeAChE hAChE eaBuChE SÍBuChE / eeAChE)
1 93 ± 5 1000 ± 141 3400 ± 315 37  1 93 ± 5 1000 ± 141 3400 ± 315 37
2 60 ± 6 780 ± 84 12000 ± 1000 200  2 60 ± 6 780 ± 84 12000 ± 1000 200
3 120 ± 12 1900 ± 202 5000 ± 1075 42  3 120 ± 12 1900 ± 202 5000 ± 1075 42
4 350 ± 43 2100 ± 240 39000 ± 7387 1 1 1  4 350 ± 43 2100 ± 240 39000 ± 7387 1 1 1
5 360 ± 74 2000 ± 290 490 ± 32 1 ,4  5 360 ± 74 2000 ± 290 490 ± 32 1, 4
6 310 ± 16 2000 ± 282 2100 ± 209 6,8  6 310 ± 16 2000 ± 282 2100 ± 209 6.8
7 250 ± 34 1800 ± 163 4070 ± 74 16  7 250 ± 34 1800 ± 163 4070 ± 74 16
8 400 ± 18 1800 ± 284 5300 ± 307 13  8 400 ± 18 1800 ± 284 5300 ± 307 13
Galantamina 560 ± 64 600 ± 43 12000 ± 1325 21  Galantamine 560 ± 64 600 ± 43 12000 ± 1325 21
Tacrina 27 ± 2 100 ± 13 5,2 ± 0,2 0, 19  Tacrine 27 ± 2 100 ± 13 5.2 ± 0.2 0.19
Donepecilo 13,4 ± 0,9 8,2 ± 0,4 840 ± 47 63  Donepezil 13.4 ± 0.9 8.2 ± 0.4 840 ± 47 63
Los resultados son la media de al menos 3 experimentos independientes (por cuadruplicado). Donde S(BuChE/eeAChE) se refiere a la selectividad BuChE/eeAChE.  The results are the average of at least 3 independent experiments (in quadruplicate). Where S (BuChE / eeAChE) refers to the BuChE / eeAChE selectivity.
Estos resultados indican que los compuestos objeto de la presente invención son capaces de inhibir las enzimas colinesterasas de manera moderada y dual, exceptuando 1 y 2, que muestran una potente actividad inhibidora y selectiva para AChE. Es destacable su mayor actividad sobre AChE de anguila eléctrica, isoforma muy parecida a la humana neuronal, que sobre la AChE de eritrocitos humanos. Este descubrimiento es importante en cuanto que podría significar una menor incidencia de efectos secundarios asociados a la inhibición de esta enzima periférica. Estos resultados los convierten en potenciales fármacos para el tratamiento de la enfermedad de Alzheimer. 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

REIVINDICACIONES
1. Compuesto de fórmula general (I): 1. Compound of general formula (I):
Figure imgf000029_0001
Figure imgf000029_0001
(i) donde: Ri y R2 son iguales o distintos y se seleccionan de forma independiente de un grupo alquilo (C1-C10); y (i) where: Ri and R2 are identical or different and are selected independently from an alkyl group (C1-C10); Y
n es un número entero con un valor de entre 0 a 5.  n is an integer with a value between 0 to 5.
2. Compuesto según la reivindicación 1 , donde R1 y/o R2 son un grupo alquilo (Ci-C6). 2. A compound according to claim 1, wherein R1 and / or R 2 are an alkyl group (Ci-C 6).
3. Compuesto según la reivindicación 2, donde R1 es metilo o etilo. 3. Compound according to claim 2, wherein R1 is methyl or ethyl.
4. Compuesto según cualquiera de las reivindicaciones 2 ó 3, donde R2 es metilo. 4. Compound according to any of claims 2 or 3, wherein R 2 is methyl.
5. Compuesto según cualquiera de las reivindicaciones 1 a 4, donde n es 0, 1 , 5. Compound according to any of claims 1 to 4, wherein n is 0, 1,
Compuesto según cualquiera de las reivindicaciones 1 a 5, seleccionado de la lista que comprende: Compound according to any one of claims 1 to 5, selected from the list comprising:
• 5-amino-2-metil-6,7,8,9-tetrahidrobenzo[ib][1 ,8]naftiridina-3-carboxilato de metilo,  • methyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo [ib] [1,8] naphthyridine-3-carboxylate,
• 5-amino-2-metil-6,7,8,9-tetrahidrobenzo[ib][1 ,8]naftiridina-3-carboxilato de etilo, 5-amino-2-metil-7,8-dihidro-6H-ciclopenta[ib][1 ,8]naftiridina-3-carbox^ de metilo, • ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo [ib] [1,8] naphthyridine-3-carboxylate, Methyl 5-amino-2-methyl-7,8-dihydro-6H-cyclopenta [ib] [1,8] naphthyridine-3-carbox ^,
5-amino-2-metil-7,8-dihidro-6H-ciclopenta[ib][1 ,8]naftiridina-3-carboxilato de etilo,  Ethyl 5-amino-2-methyl-7,8-dihydro-6H-cyclopenta [ib] [1,8] naphthyridine-3-carboxylate,
5-amino-2-metil-7,8,9,10-tetrahidro-6/-/-ciclohepta[ib][1 ,8]naftiridina-3- carboxilato de metilo,  Methyl 5-amino-2-methyl-7,8,9,10-tetrahydro-6 / - / - cyclohepta [ib] [1,8] naphthyridine-3-carboxylate,
5-amino-2-metil-7,8,9,10-tetrahidro-6/-/-ciclohepta[ib][1 ,8]naftiridina-3- carboxilato de etilo,  Ethyl 5-amino-2-methyl-7,8,9,10-tetrahydro-6 / - / - cyclohepta [ib] [1,8] naphthyridine-3-carboxylate,
5-amino-2-metil-6,7,8,9, 10,1 1 -hexahidrocicloocta[ib][1 ,8]naftiridina-3- carboxilato de metilo, y  Methyl 5-amino-2-methyl-6,7,8,9, 10,1 1 -hexahydrocycloocta [ib] [1,8] naphthyridine-3-carboxylate, and
5-amino-2-metil-6, 5-amino-2-methyl-6,
7,8,9, 10,1 1 -hexahidrocicloocta[ib][1 ,8]naftiridina-3- carboxilato de etilo. 7,8,9, 10,1 1 -hexahydrocycloocta [ib] [1,8] ethyl naphthyridine-3-carboxylate.
Procedimiento de obtención de los compuestos de fórmula (I) según cualquiera de las reivindicaciones 1 a 6, que comprende los siguientes pasos: Process for obtaining the compounds of formula (I) according to any of claims 1 to 6, comprising the following steps:
a. hacer reaccionar un acilacetato alquilo de fórmula (I I),  to. reacting an alkyl acylacetate of formula (I I),
Figure imgf000030_0001
donde: Ri y R2 se ha descrito en la reivindicación 1 ,
Figure imgf000030_0001
where: Ri and R 2 described in claim 1,
con un diaalquilacetal de dimetilformamida y posteriormente con cianoacetamida en condiciones básicas; b. sustitución nucleófila sobre la 2-piridona de fórmula (I II) obtenida en el paso (a) mediante un exceso de oxicloruro de fósforo:  with a dimethylformamide diaalkylacetal and subsequently with cyanoacetamide under basic conditions; b. Nucleophilic substitution on the 2-pyridone of formula (I II) obtained in step (a) by an excess of phosphorus oxychloride:
Figure imgf000030_0002
(III)
Figure imgf000030_0002
(III)
c. sustitución nucleófila sobre la piridina de fórmula (IV), obtenida en el paso (b), incorporando en la posición del átomo de Cl una amina:  C. nucleophilic substitution on the pyridine of formula (IV), obtained in step (b), incorporating at the position of the Cl atom an amine:
Figure imgf000031_0001
Figure imgf000031_0001
(IV)  (IV)
d. desprotección de las piridinas de fórmula (V), obtenidas en el paso (c), dejando libre el grupo amino, y  d. deprotection of the pyridines of formula (V), obtained in step (c), leaving the amino group free, and
Figure imgf000031_0002
Figure imgf000031_0002
(V) e. condensación tipo Friedlánder del sistema heterocíclico básico de fórmula (VI), obtenido en el paso (d):  (Go. Friedlander condensation of the basic heterocyclic system of formula (VI), obtained in step (d):
Figure imgf000031_0003
Figure imgf000031_0003
(VI) (SAW)
8. Procedimiento según la reivindicación 7, en el que el paso (c) se lleva a cabo mediante burbujeo de amoniaco o mediante tratamiento con benzilamina en un disolvente polar. 8. The method according to claim 7, wherein step (c) is carried out by ammonia bubbling or by treatment with benzylamine in a polar solvent.
9. Procedimiento según cualquier de las reivindicaciones 7 u 8, en el que el paso (d) se lleva a cabo por tratamiento con ácido trifluorometanosulfónico en disolvente orgánico o por burbujeo de gas hidrógeno en presencia de cantidades catalíticas de paladio sobre un soporte de carbón activo. 9. The method according to any of claims 7 or 8, wherein step (d) is carried out by treatment with trifluoromethanesulfonic acid in organic solvent or by bubbling hydrogen gas in the presence of catalytic amounts of palladium on an active carbon support.
10. Uso del compuesto según cualquiera de las reivindicaciones 1 a 6, para la elaboración de un medicamento. 10. Use of the compound according to any of claims 1 to 6, for the preparation of a medicament.
11 . Uso del compuesto según cualquiera de las reivindicaciones 1 a 6, para la elaboración de un medicamento para el tratamiento de enfermedades neurodegenerativas. 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. Uso del compuesto según la reivindicación anterior, donde las enfermedades neurodegenerativas se seleccionan de la lista que comprende enfermedad de Alzheimer, enfermedad de Parkinson y enfermedad de Huntington. 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. Composición farmacéutica que comprende al menos un compuesto de fórmula general (I) junto con uno o más excipientes farmacéuticamente aceptable. 13. Pharmaceutical composition comprising at least one compound of general formula (I) together with one or more pharmaceutically acceptable excipients.
14. Composición farmacéutica según la reivindicación anterior, que además comprende uno o más agentes terapéuticos activo. 14. Pharmaceutical composition according to the preceding claim, further comprising one or more active therapeutic agents.
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