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    • 专利摘要:
    Compounds derived from 2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -1-alkyl/aryl-6, 7, 7a, 8-tetrahydro- 3H-pyrrolo (2,1-j) quinoline-3,9 (5H) -dione as antioxidant agents, Nrf2 inducers and nicotinic modulators for the treatment of neurodegenerative diseases. The present invention relates to compounds derived from 2-iodo-7 - (((2- (5-methoxy-1H-indol3-yl) ethyl) amino) methyl) -1-alkyl/aryl-6,7,7a, 8-tetrahydro-3H-pyrrolo (2,1-j) quinoline-3,9 (5H) -dione with modulating capacity of nicotinic receptors, inducing capacity of the transcription factor Nrf2, antioxidant and neuroprotective capacity. The present invention considers the use of the derivatives object of the same, for the treatment of diseases in whose pathogenesis oxidative stress intervenes, as well as in diseases that occur with dysregulation of the activity of phase II genes activated by the Nrf2 factor, such as neurodegenerative diseases. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2781377A1
    申请号:ES201930190
    申请日:2019-03-01
    公开日:2020-09-01
    发明作者:Martínez Rafael León；Comesaña Sheila Abril；Patrycja Michalska；Abaitua Izaskun Buendia；Sánchez Mercedes Salaices；Ramos José Carlos Menéndez；López Manuela García
    申请人:Universidad Complutense de Madrid；Universidad Autonoma de Madrid；Fundacion para la Investigacion Biomedica del Hospital Universitario de la Princesa；
    IPC主号:
    专利说明:

    [0003] 2-IODO-7 - (((2- (5-METHOXY-1 H-INDOL-3-IL) ETHYL) AMINO) METHYL) -1 -ALKYL / ARYL-6,7,7A, 8-
    [0004] NICOTINICS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
    [0006] FIELD OF THE INVENTION
    [0008] The present invention is mainly framed in the pharmaceutical sector with applications aimed at the prevention and / or treatment of diseases and any type of condition or damage that involves abnormal activity of nicotinic receptors or that occurs with high levels of oxidative stress and, specifically , in the identification of chemical compounds useful in the preventive and / or therapeutic treatment of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), multiple sclerosis (MS) or stroke.
    [0010] BACKGROUND OF THE INVENTION
    [0012] In the last century, scientific and technological advances, access to health care and improvements in the quality of life have contributed to a significant increase in the average life expectancy of the population. However, aging has led to the manifestation of diseases that were rare a century ago such as cardiovascular diseases, cancer and neurodegenerative diseases.
    [0014] According to data from the World Health Organization in 2016, it is estimated that there are some 47.5 million people in the world who suffer from dementia, with 7.7 million new cases being diagnosed each year, a number that will triple in the year 2050, with Alzheimer's disease (AD), the most common cause of dementia, accounting for between 60 and 70% of cases (Organization 2012). This disease not only generates disability and dependency in people who suffer from it, but also has a physical, psychological, social and economic impact on family members, caregivers and society in general. Considering that there is still no treatment to stop the progression of the disease, it is a public health priority, so the development of effective therapies for this type of pathologies is one of the great challenges for society and a priority for public health.
    [0016] AD is a biologically complex neurodegenerative disease. This neurological condition related to aging is fundamentally characterized by loss of memory and cognitive functions, mainly due to the death of cholinergic neurons in regions of the brain associated with attentional, spatial and episodic memory, such as the neocortex, temporal lobes and the hippocampus (Mesulam 2013). In addition to this synaptic loss, other pathophysiological features are the appearance of intracellular neurofibrillary tangles, which contain the hyperphosphorylated tau protein; senile extracellular plaques, composed mainly of p-amyloid peptide aggregates; mitochondrial dysfunction; deregulation of Ca2 + homeostasis; oxidative stress (Sanabria-Castro, Alvarado-Echeverría et al. 2017) and chronic inflammation (Glass, Saijo et al. 2010).
    [0018] Oxidative stress describes a condition where there is an imbalance between the systemic manifestation of free radicals and the ability of cells to eliminate them and avoid damaging effects on lipids, proteins, and DNA (Ahmadinejad, Geir Moller et al. 2017). Oxygen and nitrogen free radicals are biologically necessary since they perform various functions as intermediaries in enzymatic and non-enzymatic reactions (mitochondrial electron transport chain), defense against pathogens and infections, secondary messengers in intracellular signaling pathways, and low concentrations, as signaling molecules promoting cell proliferation, differentiation and migration. Therefore, maintaining a correct redox balance is key to avoiding cell damage and death. That is why the study of free radical scavenging compounds and antioxidants, and their beneficial effects in situations where there is a redox imbalance can provide new knowledge to develop new therapeutic strategies for diseases that occur with oxidative stress.
    [0020] In relation to the above, another way to reduce oxidative stress is by acting on the main cellular defense pathway against damage derived from oxidative stress, the Nrf2-ARE pathway. Under these conditions (or in the presence of electrophilic compounds), the transcription factor Nrf2 dissociates from its repressor protein Keap1, located in the cytosol, and rapidly translocates to the nucleus. Once there, it binds to DNA electrophilic response element (ARE) sequences, promoting the constitutive and inducible expression of antioxidant and anti-inflammatory enzymes (Buendia, Michalska et al. 2016). However, despite the increased oxidative stress, in neurodegenerative diseases (ENDs) this pathway defense is deregulated, which contributes to greater oxidative damage and consequent neuronal death (Ramsey, Glass et al. 2007).
    [0022] As already mentioned, one of the main characteristics of AD and the one responsible for its most notable symptoms is the decrease in cholinergic activity. In this sense, it is widely demonstrated that the modulation of nicotinic receptors (nAChR), particularly the nAChR-a7, in macrophages mediates anti-inflammatory responses in what is known as the “cholinergic anti-inflammatory pathway” (Wang, Yu et al. 2003) . Recently, a cerebral cholinergic pathway has been described that regulates the activation of microglia through the nAChR-a7 that mediates anti-inflammatory and neuroprotective responses (Egea, Buendia et al. 2015). The activation of these receptors triggers an intracellular signaling cascade that not only inhibits the production of pro-inflammatory cytokines and reactive oxygen species, but also promotes the translocation of Nrf2 to the nucleus, leading to the induction of antioxidant enzymes. Therefore, the modulation of these receptors would protect cholinergic neurons in situations of oxidative stress and inflammation.
    [0024] Patent documents WO2008 / 058096, WO2014 / 160783, WO2010 / 126605, WO2010 / 046710, WO2012 / 149478, WO2013 / 067036, WO2013 / 132124, WO2018 / 102885 propose different treatment options for neurodegenerative diseases based on one or more chemical compounds and / or natural products whose therapeutic target is the induction and / or modulation of the Nrf2-ARE pathway as a neuroprotective and immunomodulatory strategy or the modulating activity of nicotinic receptors in the same sense.
    [0025] DETAILED DESCRIPTION OF THE INVENTION
    [0027] The invention relates to the use of compounds with the structure 2-iodo-7 - (((2- (5-methoxy-1 H-indol-3-yl) ethyl) amino) methyl) -1-alkyl / aryl-6, 7,7a, 8-tetrahydro-3H-pyrrolo [2,1 - /] quinoline-3,9 (5H) -dione with modulating capacity of nicotinic receptors and inducing capacity of the Nrf2-ARE pathway with antioxidant, anti- inflammatory and neuroprotective that this entails. The present invention describes, for the first time, the inclusion in a single molecule of the modulating capacity of nicotinic receptors in addition to including the inducing capacity of the transcription factor Nrf2 thanks to the structural modifications made. The compounds object of the present invention possess Nrf2 inducing capacity. Furthermore, the compounds object of the present invention possess free radical scavenging capacity and neuroprotective capacity, therefore they can be potentially useful in the prevention and / or treatment of neurodegenerative diseases. More specifically, the object of the present invention is to provide new compounds useful as active ingredients of a medicine, which allow the prevention and / or treatment of neurodegenerative diseases.
    [0029] Therefore, in one aspect, the invention relates to a compound of formula (I) (defined below), its salts, prodrugs or solvates. Said compound of formula (I) can be used in the treatment of neurodegenerative diseases and / or diseases that are related to a dysregulation of the activity of nicotinic receptors in relation to the neuroprotection associated with the modulation of these in different neurodegenerative diseases or in diseases cerebrovascular.
    [0031] In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I), or a salt, a prodrug or a solvate thereof, and a pharmaceutically acceptable carrier.
    [0033] In another aspect, the invention protects the use of said compound of formula (I), or its pharmaceutically acceptable salts, prodrugs or solvates, in the preparation of a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases, or in cerebrovascular diseases. .
    [0035] In the context of the present invention, the following terms have the meaning detailed below:
    [0037] When the term "independently selected" is used, the substituents to which it refers (eg R groups, such as R1, R2, R3, R4, R5, R 6 or X or Y or Z groups or variables such as "n") the groups can be identical or different, or where appropriate when specified.
    [0039] The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms that do not contain unsaturations, having from one to eight carbon atoms, and which is linked to the rest of the molecule by a single bond. . Preferably, it refers to a straight or branched aliphatic chain radical having between 1 and 6, preferably between 1 and 3 ("C 1-3 alkyl") carbon atoms, and which is attached to the rest of the molecule by a single bond. . This term includes, for example and in a non-limiting sense, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc. Alkyl radicals can be optionally substituted by one or more substituents independently selected from the group consisting of halogens, hydroxyl, alkoxides, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto, and alkylthio.
    [0040] The term "alkoxy" refers to a group -O-alkyl, where alkyl is as previously defined. Preferably alkoxy is methoxy.
    [0042] The term "halogen" refers to bromine, chlorine, iodine, or fluorine. Preferably halogen is fluorine or chlorine or bromine.
    [0044] The term "haloalkyl" refers to an alkyl radical, as previously defined, that is substituted by one or more halogens, as also previously defined, including, for example, and in a non-limiting sense, trifluoromethyl, trichloromethyl, 2,2,2, -trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc.
    [0045] The term "alkoxycarbonyl" refers to a radical of formula -C (O) OR where R is an alkyl radical as previously described. Alkoxycarbonyl radicals can include, for example, and in a non-limiting sense, methoxy, ethoxy, propoxy, etc.
    [0047] The term "cycloalkyl" refers to a saturated or partially saturated mono or polycyclic aliphatic group, having between 3 and 10, preferably between 3 and 6 carbon atoms that is attached to the rest of the molecule through a single bond, including , for example, and in a non-limiting sense, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, etc.
    [0049] The term "amino" refers to a radical of formula -NH2.
    [0051] The term "aryl" refers to an aromatic group having between 6 and 18, preferably between 6 and 10 carbon atoms, comprising 1,2 or 3 aromatic nuclei, linked via a carbon-carbon bond or condensed, including for example and in a non-limiting sense phenyl, naphthyl, diphenyl, indenyl, phenanthryl, etc.
    [0053] The term "heterocycle" refers to a stable 3- to 10-membered ring radical, preferably a 5- or 6-membered ring, consisting of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. , and which may be partially or fully saturated, or may be aromatic ("heteroaryl"). For the purposes of this invention, the heterocycle can be a monocyclic, bicyclic, or tricyclic ring system, which can include fused ring systems. Examples of such heterocycles include, but are not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, benzimidazole, benzothiazole, furan, pyrrole, pyridine, pyrimidine, isothiazole, imidazole, indole, purine, quinoline, thiadizole.
    [0054] As understood in this technical area, there may be a certain degree of substitution on the radicals defined above. References herein to substituted groups indicate that the specified radical may be substituted at one or more available positions with one or more substituents. Such substituents include, for example, and in a non-limiting sense, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, aryl, heterocycle, halogen, CN, NO2, CF3, -N (Ra) ( Rb), -ORc, -SRd, -C (O) Re, -C (O) ORf, -C (O) N (Rg) (Rh), -OC (O) R i; wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, and Ri are independently selected from hydrogen, alkyl, C 1 -C6, aryl, heterocycle, and trifluoromethyl.
    [0056] The term "pharmaceutically acceptable" preferably refers to compositions and molecular entities that are physiologically tolerable and do not normally produce an allergic reaction or similar unfavorable reaction, such as gastric disorders, dizziness, and the like, when administered to a patient. be human or animal. The term "pharmaceutically acceptable" means that it is approved by a regulatory agency such as the European Medicines Agency or the US regulatory agency, or that it is listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and, accordingly more particularly, in humans.
    [0058] The term "salts" as used herein refers to any salt of the compound of formula (I) which, when administered to a subject, is capable of providing (directly or indirectly) said compound of formula (I). The term "subject" includes any animal, eg, a mammal, including humans. The preparation of said salts can be carried out by conventional methods known to those skilled in the art.
    [0060] The term "prodrug" is used, in this description, in the broadest sense, and includes any compound derived from a compound of formula (I) which, when administered to a subject, is capable of providing, directly or indirectly, a compound of formula (I), or a pharmaceutically acceptable salt thereof, in said subject. Advantageously, said derivative is a compound that increases the bioavailability of the compound of formula (I) when administered to a subject (for example, by making a compound of formula (I) administered orally more easily absorbed by the blood), or that enhances the release of a compound of formula (I) into a biological compartment (eg, the brain or lymphatic system) relative to the parent compound (without derivatization). The nature of said derivative is not critical, as long as it can be administered to a subject and provides a compound of formula (I) in a biological compartment of said subject. Such derivatives will be apparent to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the compounds present: esters, amino acid esters, phosphate esters, sulfonate esters of salts metals, carbamates and amides.
    [0062] The term "solvate" as used herein includes any compound formed by combining molecules of a solvent with molecules or ions of a compound of formula (I) or a salt thereof; said solvent can be an organic solvent, for example an alcohol, or an aqueous solvent, for example water, in which case the solvate is called a "hydrate".
    [0064] The term "pharmaceutically acceptable excipient" means one or more solids, or compatible liquids, diluents or encapsulating substances that are capable of being administered to a subject.
    [0066] The first aspect of the present invention refers to a compound of formula (I):
    [0071] where
    [0072] R is selected from the group consisting of:
    [0073] - Alkyl optionally substituted by one, two, or three halogen atoms selected from fluorine, chlorine and bromine; (C 3 -C 6 ) cycloalkyl; alkoxy (Cr C 6 ); cycloalkoxy (C3-C6); cyano and nitro; me
    [0074] - phenyl optionally substituted by one, two or three groups independently selected from fluorine; chlorine; bromine; alkyl optionally substituted by one, two, or three halogen atoms selected from fluorine, chlorine and bromine; (C3-C6) cycloalkyl; (C1-C6) alkoxy; cycloalkoxy (C3-C6); cyano and nitro; or two groups may together form a group -O (CH 2) oO-, - (CH2) p-, or -CH = CH-CH = CH-; or
    [0075] - a heteroaryl group optionally substituted by one, two or three groups independently selected from fluorine, chlorine, bromine, alkyl, cycloalkyl (C 3 -C 6 ), alkoxy (Cr C 6 ), cycloalkoxy (C 3 -C 6 ), cyano and nitro;
    [0076] R 1 and R2 are selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl, optionally substituted by one, two, or three groups independently selected from fluorine, chlorine, bromine, alkyl, alkoxy, (C3-C6) cycloalkyl, cycloalkoxy (C3-C6), cyano, nitro and carboxylate or both groups can together form a group -O (CH 2) qO-, - (CH2) r-, or -CH = CH-CH = CH-;
    [0077] R3 and R4 are selected from the group consisting of hydrogen, alkyl, cycloalkyl (C 3 -C 6 ), acetyl, phenyl, or heteroaryl, optionally substituted by one, two, or three groups independently selected from fluorine, chlorine, bromine, alkyl (C i -C 6 ), (C i -C 6 ) alkoxy, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) cycloalkoxy, cyano and nitro;
    [0078] X is selected from a carbon atom or a nitrogen atom;
    [0079] n is an integer selected from 0, 1 or 2;
    [0080] m is an integer selected from 0, 1,2, 3, 4, 5 or 6;
    [0081] 7 *, 7a * and 11a * indicate the presence of a chiral center whose configuration can be R or S;
    [0082] or their stereoisomers, salts, preferably pharmaceutically acceptable salts, prodrugs or solvates.
    [0084] In a particular embodiment, said salts of the compound of formula (I) are pharmaceutically acceptable salts, that is, salts that can be administered to a subject and provide a compound of formula (I) in a biological compartment of said individual.
    [0086] In another particular embodiment, said salts of the compound of formula (I) are pharmaceutically unacceptable salts, which may be useful in the preparation of pharmaceutically acceptable salts of the compound of formula (I), or of its prodrugs or solvates.
    [0088] The compounds of formula (I), or their salts, may be in crystalline form either as free compounds or as solvates, both forms being included within the scope of the present invention.
    [0089] In a particular embodiment, said solvate is a pharmaceutically acceptable solvate, that is, it can be administered to a subject and provide (directly or indirectly) a compound of formula (I) or a salt thereof.
    [0091] In another particular embodiment, said solvate is not pharmaceutically acceptable, but can be used in the preparation of pharmaceutically acceptable solvates of the compound of formula (I) or its salts.
    [0093] The preparation of said solvates can be carried out by conventional methods known to those skilled in the art, by contacting the compound of formula (I) or a salt thereof with the appropriate solvent.
    [0095] The compounds of the present invention represented by the formula (I) described above can include enantiomers by the presence of chiral centers or geometric isomers, depending on the presence of multiple bonds (for example R, S). Geometric isomers, enantiomers or diastereoisomers of the compounds of formula (I) and mixtures thereof are within the scope of the present invention.
    [0097] In another particular embodiment, the compounds subject to this invention give pharmaceutically acceptable compositions that comprise the compounds of formula (I) with a pharmaceutically acceptable carrier, for example, pharmaceutical composition that includes one or more compounds of formula (I), alone or in combination with one or more additional therapeutic agents as a mixture with pharmaceutically acceptable excipients.
    [0099] In a particular preferred embodiment, the invention relates to compounds of formula (I) in which:
    [0100] - R is selected from the group comprising a phenyl aromatic ring optionally substituted by one, two or three groups independently selected from fluorine, chlorine, alkyl (Cr C 6 ), optionally substituted by one, two, or three halogen atoms selected from fluorine , chlorine and bromine;
    [0101] - Alkyl optionally substituted by one, two, or three halogen atoms selected from fluorine, chlorine and bromine; (C 3 -C 6 ) cycloalkyl; alkoxy (Cr C 6 ); cycloalkoxy (C3-C6); cyano and nitro; me
    [0102] - a heteroaryl group optionally substituted by one, two or three groups independently selected from fluorine, chlorine, bromine, alkyl, cycloalkyl (C 3 -C 6 ), alkoxy (Cr C 6 ), cycloalkoxy (C 3 -C 6 ), cyano and nitro
    [0103] - Ri is selected from the group comprising an alkyl optionally substituted by one or two groups independently selected from fluorine, chlorine, and bromine; alkoxy (Ci-Ce), nitro and amino; preferably R 1 is -OCH 3 ;
    [0104] - R 2 is hydrogen;
    [0105] - R 3 is hydrogen;
    [0106] - R 4 is hydrogen;
    [0107] - n is an integer selected from 0, 1 and 2, preferably n = 1;
    [0108] - X is carbon;
    [0109] 7 *, 7a *, 11a * are carbons with R or S configuration in any of their possible combinations
    [0110] - or their stereoisomers, salts, preferably pharmaceutically acceptable salts, prodrugs or solvates.
    [0112] Particularly preferred compounds of formula (I) of the present invention are the following:
    [0113] • Iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -1-phenyl-6,7,7a, 8-tetrahydro-3H-pyrrolo [2 , 1 - /] quinoline-3.9 (5H) -dione.
    [0114] • (7S, 7afi, 11afi) -2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -1-phenyl-6,7,7a, 8-tetrahydro-3H-pyrrolo [2,1 - /] quinoline-3.9 (5H) -dione.
    [0115] • (7R, 7aS, 11 aS) -2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -1-phenyl-6.7, 7a, 8-tetrahydro-3H-pyrrolo [2,1 - /] quinoline-3.9 (5H) -dione.
    [0116] • 1- (3-fluorophenyl) -2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -6,7,7a, 8-tetrahydro- 3H-pyrrolo [2.1 - /] quinoline-3.9 (5H) -dione.
    [0117] • (7S, 7aR, 11aR) -1- (3-fluorophenyl) -2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -6 , 7.7a, 8-tetrahydro-3H-pyrrolo [2,1-j] quinoline-3.9 (5H) -dione.
    [0118] • (7R, 7aS, 11aS) -1- (3-fluorophenyl) -2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -6 , 7.7a, 8-tetrahydro-3H-pyrrolo [2.1 - /] quinoline-3.9 (5H) -dione.
    [0119] • 2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -1-propyl-6,7,7a, 8-tetrahydro-3H-pyrrolo [2.1 - /] quinoline-3.9 (5H) -dione.
    [0120] • (7S, 7aR, 11aR) -2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -1-propyl-6,7,7a, 8-tetrahydro-3H-pyrrolo [2,1 -_ /] quinoline-3.9 (5H) -dione.
    [0121] • (7R, 7aS, 11aSJ-2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -1-propyl-6,7,7a, 8-tetrahydro-3H-pyrrolo [2,1 -_ /] quinoline-3.9 (5H) -dione.
    [0122] • 1-cyclopropyl-2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -6,7,7a, 8-tetrahydro-3H-pyrrolo [2.1 - /] quinoline-3.9 (5H) -dione.
    [0123] (7S, 7afi, 11afi) -1-cyclopropyl-2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -6,7,7a, 8 -tetrahydro-3H-pyrrolo [2.1 - /] quinoline-3.9 (5H) -dione.
    [0124] (7fi, 7aS, 11aS) -1-cyclopropyl-2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -6,7,7a, 8-tetrahydro-3H-pyrrolo [2,1 - /] quinoline-3.9 (5H) -dione.
    [0125] 1-cyclohexyl-2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -6,7,7a, 8-tetrahydro-3H-pyrrolo [ 2.1 - /] quinoline-3.9 (5H) -dione.
    [0126] (7S, 7afi, 11afi) -1-cyclohexyl-2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -6,7,7a, 8-tetrahydro-3H-pyrrolo [2,1-j] quinoline-3.9 (5H) -dione.
    [0127] (7fi, 7aS, 11aS) -1-cyclohexyl-2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -6,7,7a, 8-tetrahydro-3H-pyrrolo [2,1 - /] quinoline-3.9 (5H) -dione.
    [0129] The compounds of formula (I) of the present invention can be obtained by a process that involves reacting a polycyclic aldehyde of formula (II).
    [0133] with a primary or secondary amine of formula (III):
    [0137] where R, R 1 , R 2 , R 3 , R 4 , X, m and n have the meaning already indicated.
    [0139] Therefore, in another aspect, the present invention describes a process for obtaining a compound of formula (I) which comprises reacting said compound of formula (II) with a compound of formula (III).
    [0140] Said reaction is carried out in an appropriate inert solvent, at the appropriate temperature in the presence of a suitable reducing compound. In a particular embodiment, the reaction is carried out initially by mixing the corresponding amine and the desired aldehyde at room temperature, keeping them under stirring for the necessary time. Subsequently, Na (AcO) 3BH is added. In another particular embodiment, the reaction is carried out in the presence of NaBH 4 . In another particular embodiment, the reaction is carried out in an inert solvent medium, such as that constituted by a halogenated aliphatic hydrocarbon such as: dichloromethane, 1,2-dichloroethane, chloroform, etc., or their mixtures, dichloromethane being especially suitable. .
    [0142] Therefore, the reaction between the compound of formula (II) and the compound of formula (III) is carried out in the presence of a reducing agent selected from NaBH4 or Na (AcO) 3BH, in a solvent selected from dichloromethane, 1,2 -dichloroethane, chloroform and their mixtures. If desired, the compound of formula (I) can be converted into a salt, prodrug or solvate thereof by conventional methods.
    [0144] The compounds of formula (II) are known compounds and can be obtained commercially or can be prepared by conventional methods.
    [0146] Another object of the invention is a process for obtaining the compound of formula (II) by enantioselective cyclization catalyzed by an organocatalyst.
    [0148] In another particular embodiment, the organocatalyst is [(R-2- (diphenyl ((trimethylsilyl) oxy) methyl) pyrrolidine]. In another particular embodiment, the catalyst is [(S-2- (diphenyl ((trimethylsilyl) oxy) methyl) pyrrolidine] In another particular embodiment, the organocatalyst is an equimolar mixture of both.
    [0150] The compounds of formula (III) are also known and can be obtained commercially or can be prepared by conventional methods.
    [0152] The compounds of formula (I) obtained by the above procedure, if desired, can be purified by conventional methods, such as crystallization or chromatography.
    [0153] The compounds of formula (I) of the present invention exhibit nicotinic receptor modulating activity, as well as free radical scavenging activity and factor Nrf2 inducing activity.
    [0155] In a particular embodiment, the invention comprises a compound of formula (I) for use in the treatment of diseases that improve with the administration of an inducer of Nrf2 and / or a free radical scavenger agent and / or a neuroprotective agent and / or or a nicotinic receptor modulator.
    [0157] Thus, in other aspects, the invention includes a compound of formula (I) for use in the prevention or treatment of a central and / or peripheral neurodegenerative disease or ischemic-cerebral disease (stroke).
    [0159] Therefore, the invention comprises a compound of formula (I) for use in the treatment of neurodegenerative diseases, eg, AD, PD, ALS, HD, MS and / or in the treatment of other neurodegenerative diseases in which loss of neurons occurs, as is the case with cerebrovascular accident (stroke).
    [0161] For their administration to a subject in need of treatment, the compounds of formula (I) of the present invention are conveniently formulated with the excipients suitable for administration by any appropriate route, for example, orally, parenterally, subcutaneously, intramuscularly. , intravascular or rectal, preferably orally.
    [0163] In a particular embodiment, the pharmaceutical composition of the invention is presented in a pharmaceutical form for oral administration, either in solid or liquid form. Illustrative examples of pharmaceutical forms for oral administration include tablets, capsules, granules, solutions, suspensions, etc., for which they will include the appropriate pharmaceutically acceptable excipients, such as binders, diluents, disintegrants, lubricants, humectants, etc., and they can be prepared by conventional methods. The pharmaceutical composition of the invention can also be adapted for parenteral administration (eg, intramuscularly, intravenously, etc.), in the form of, for example, sterile solutions, suspensions or lyophilized products, in the appropriate dosage form; in this case, said pharmaceutical compositions will include suitable excipients, such as buffers, surfactants, etc. The pharmaceutical composition of the invention can also be adapted for subcutaneous administration in the form of, for example, sterile solutions or suspensions, in the dosage form appropriate; in this case, said pharmaceutical compositions will include suitable excipients, such as buffers, surfactants, etc. The formulations can be prepared according to conventional methods such as those described in the Spanish, European or United States of America pharmacopoeias.
    [0165] The compound of formula (I) of the invention will be administered in a therapeutically effective amount that will generally depend on the efficacy of the compound of formula (I) chosen, on the severity of the pathology to be treated, etc. However, it will typically be administered at daily doses between 0.1 and 500 mg of compound of formula (I) per kg of body weight, more preferably the daily doses will be between 25 and 250 mg / kg body weight.
    [0167] The administration of the compounds of formula (I) of the invention, their pharmaceutically acceptable salts, prodrugs or solvates, can be carried out alone or in combination with additional drugs, such as drugs useful for the treatment of a neurodegenerative disease or of an ischemic-cerebral disease, to provide a combination therapy; said additional drugs may be part of the same pharmaceutical composition of the invention that comprises the compound of formula (I) and / or its pharmaceutically acceptable salts, prodrugs or solvates, or not, in which case, they will be administered simultaneously or sequentially to the administration of the pharmaceutical composition of the invention. Illustrative, non-limiting examples of such additional drugs that may be employed to provide combination therapy include agents such as memantine (an NMDA-type glutamate receptor blocker approved for use in the advanced stages of Alzheimer's disease), vitamins , anti-inflammatories or antidepressants.
    [0169] MODE OF EMBODIMENT OF THE INVENTION
    [0171] The present invention is further illustrated by the following examples, which are not intended to be limiting of its scope.
    [0173] 1. OBTAINING THE COMPOUNDS OF THE INVENTION
    [0175] The compounds whose biological activity is the object of the present invention were synthesized following the following procedures in organic synthesis (Leon, Jawalekar et al. 2011).
    [0176] General procedure of reductive amination
    [0178] To a solution of the aldehyde (1eq) in CH2Cl2 (43 mL / mmol) is added 5-methoxy-tryptamine (1 eq). The mixture is stirred at room temperature for one hour or overnight depending on the derivative. Subsequently, Na (AcO) 3BH (1.3 eq) is carefully added at 0 ° C. The solution is stirred and allowed to reach room temperature overnight, a saturated NaHCO 3 solution is added and extracted with CH2Cl2 (3x). The organic phase is dried over Na 2 SO 4 , concentrated in vacuo and purified by flash chromatography on silica gel.
    [0180] Example 1: Iodo-7 - (((2- (5-methoxy-1rtLindol-3-yl) ethyl) amino) methyl) -1-phenyl-6,7,7a, 8-tetrahydro-3H-pyrrolo [2, 1-j] quinoline-3.9 (5H) -dione (Compound 1).
    [0184] Following the procedure described for reductive amination, the reaction between 2-iodo-3,9-dioxo-1-phenyl-5,6,7,7a, 8,9-hexahydro-3H-pyrrolo [2,1-j] quinoline-7-carbaldehyde (100 mg, 0.23 mmol), 5-methoxytryptamine (43.91 mg, 0.23 mmol) and Na (AcO) 3BH (61.25 mg, 0.29 mmol) in CH2Cl2 (10 mL), over 20 h, produced, after flash chromatography on silica gel (CH2Ch / MeOH; 0-6%), 98 mg, (71%) of compound 1 as an ivory solid. Rf 0.22 (CH2Cl2 / MeOH 95: 5). mp 124-126 ° C. 1 H NMR (250 MHz, CDCls) 57.95 (s, 1H, H5 '), 7.51 -7.34 (m, 3H, H14, H15), 7.25 (d, J = 8.3 Hz, 1H, H11'), 7.22 - 7.13 (m, 2H, H13), 7.00 (d, J = 3.0 Hz, 1H, H6 '), 6.98 (d, J = 3.1 Hz, 1H, H8'), 6.85 (dd, J = 8.8, 2.4 Hz, 1H , H10 '), 6.35 (dd, J = 10.1, 1.8 Hz, 1H, H11), 6.29 (d, J = 10.1 Hz, 1H, H10), 4.40 (dt, J = 13.7, 3.1, 1.3 Hz, 1H, H5b), 3.84 (d, J = 3.6 Hz, 3H, OCH3), 2.84 (d, J = 4.2 Hz, 5H, H5a, 2xH3 ', 2xH4'), 2.69 (dd, J = 12.3, 3.1 Hz, 1H, H1 '), 2.52 - 2.28 (m, 2H, H8b, H1'), 2.01 (d, J = 10.2 Hz, 1H, H7a), 1.81 (dd, J = 17.5, 5.0 Hz, 1H, H8a), 1.73 - 1.43 (m, 3H, H6b, H7, H2 '), 1.33-1.12 (m, 1H, H6a) ppm. 13 C NMR (63 MHz, CDCls) 5 196.5, 165.1, 162.7, 154.0, 145.1, 134.8, 133.8, 131.6, 129.8, 129.2, 127.8, 127.8, 123.0, 113.4, 112.4, 112.1, 100.7, 99.6, 70.2, 56.1, 51.7, 50.1, 43.5, 38.6, 37.6, 36.7, 30.0, 25.7 ppm. IR (film) u / cm -1 3330, 3312, 2908, 2359, 1673, 1581, 1483, 1439, 1398, 1296, 1212, 1171, 1028, 920, 792, 759, 702. Purity was determined 100% by reverse phase HPLC Cia with UV detector at 254 nm, in gradient regime ACN / H2O, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1% formic acid.
    [0186] Example 2: (7S, 7aR, 11afí) -2-Iodo-7 - (((2- (5-methoxy-1rtLindol-3-yl) ethyl) amino) methyl) -1-phenyl-6,7,7a, 8-tetrahydro-3rtLpyrrolo [2,1-j] quinoline-3.9 (5H) -dione (Compound 2).
    [0191] Following the general procedure for reductive amination, the reaction between (7S, 7aR, 11afi) -2-iodo-3,9-dioxo-1-phenyl-5,6,7,7a, a, 9-hexahydro-3H- pyrrolo [2,1 - /] quinoline-7-carbaldehyde (100 mg, 0.23 mmol), 5-methoxy-tryptamine (44 mg, 0.23 mmol) and Na (AcO) 3BH (64 mg, 0.30 mmol) in CH2Ch (10 mL) for 20 h produced, after purification by flash chromatography on silica gel (CH2Ch / MeOH; 0-5%), 93 mg (66%) of compound 2 as an ivory solid. [a] 14 = -90.53 ° (c. 0.95 mg / ml, MeOH). ee 89%. The enantiomers were separated by HPLC (ULTRON ES OVM Analytical Chiral Reverse Phase, 5gm, 4.6 mm x 150 L, H2PO4-pH 4.3 / MeOH 70:30 buffer, flow 1.0 mL / min, retention time 3.167 min (minor) and 3.787 (majority). The purity was determined 100% by C18 reverse phase HPLC with UV detector at 254 nm, in ACN / H2O gradient regime, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1% acid formic.
    [0193] Example 3: (7ff, 7aS, 11aS) -2-iodo-7 - (((2- (5-methoxy-1fl-indol-3-yl) ethyl) amino) methyl) -1-phenyl-6.7, 7a, 8-tetrahydro-3H-pyrrolo [2,1- / jquinoline-3.9 (5H) -dione (Compound 3).
    [0194] Following the general procedure for reductive amination, the reaction between (7R, 7aS, 11aS) -2-iodo-3,9-dioxo-1-phenyl-5,6,7,7a, 8,9-hexahydro-3H- pyrrolo [2,1 - /] quinoline-7-carbaldehyde (83 mg, 0.19 mmol), 5-methoxy-tryptamine (36 mg, 0.19 mmol) and Na (AcO) 3BH (55 mg, 0.25 mmol) in CH2Ch (8 mL) for 20 h produced, after purification by silica gel flash chromatography (CH2Ch / MeOH; 0-5%), 83 mg (72%) of compound 3 as an ivory solid. [a] 14 = + 124.62o (c.0.65 mg / mL, MeOH) ee 87%. The enantiomers were separated by HPLC (ULTRON ES OVM Analytical Chiral Reverse Phase, 5gm, 4.6 mm x 150 L, H2PO4- pH 4.3 / MeOH 70:30 buffer, flow 1.0 mL / min, retention time 2.977 min (majority) and 3.607 (minority). The purity was determined 100% by C18 reverse phase HPLC with UV detector at 254 nm, in ACN / H2O gradient regime, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1% acid formic.
    [0196] Example 4: 1- (3-fluorophenyl) -2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -6,7,7a, 8 -tetrahydro-3HLpyrrolo [2,1- / quinoline-3.9 (5H) -dione (Compound 4).
    [0201] Following the general procedure for reductive amination, the reaction between 1- (3-fluorophenyl) -2-iodo-3,9-dioxo-5,6,7,7a, 8,9-hexahydro-3H-pyrrolo [2, 1 - /] quinoline-7-carbaldehyde (45mg, 0.10 mmol), 5-methoxy-tryptamine (19 mg, 0.10 mmol) and Na (AcO) 3 BH (28 mg, 0.13 mmol) in CH 2 Cl 2 (4 mL ) for 20 h produced, after purification by flash chromatography on silica gel (CH 2 Ch / MeOH, 1-4%), 33 mg (52%) of compound 4 as an ivory solid. Rf 0.17 (CH 2 Cl 2 / MeOH 95: 5) p . F. 122 - 124 ° C 1H NMR (500 MHz, CDCls) 5 7.99 (s, 1H, H5 '), 7.40 (td, J = 8.0, 5.7 Hz, 1H, H16), 7.25 (d, J = 8.2 Hz, 1H , H11 '), 7.15 (td, J = 8.5, 2.4 Hz, 1H, H15), 7.01 (d, J = 2.3 Hz, 2H, H6', H8 '), 6.96 (d, J = 7.7 Hz, 1H, H17), 6.90 (d, J = 8.6 Hz, 1H, H13), 6.86 (dd, J = 8.8, 2.4 Hz, 1H, H10 '), 6.32 (d, J = 1.4 Hz, 2H, H10, H11), 4.38 (dd, J = 13.4, 4.4 Hz, 1H, H5b), 3.85 (s, 3H, OCH3), 2.89 (dd, J = 10.5, 7.1 Hz, 4H, H3 ', H4'), 2.81 (td, J = 13.3, 2.8 Hz, 1H, H5a), 2.71 (dd, J = 12.5, 3.1 Hz, 1H, H1 '), 2.46 (dd, J = 12.5, 6.8 Hz, 1H, H1'), 2.40 (dd, J = 17.3, 2.1 Hz, 1H, H8b), 2.04 (d, J = 8.2 Hz, 1H, H7a), 1.84 (dd, J = 17.3, 4.9 Hz, 1H, H8a), 1.71 (t, J = 13.4 Hz, 2H, H6b, H7), 1.28-1.15 (m, 1H, H6a) ppm 13C NMR (126 MHz, CDCis) 5196.1, 164.8, 162.8 (d, J = 249.5 Hz), 161.2 (d, J = 2.3 Hz), 154.1, 144.8, 136.7 (d, J = 8.1 Hz), 134.0, 131.7, 131.2 ( d, J = 8.6 Hz), 127.8, 123.7 (d, J = 3.3 Hz), 123.1, 117.0 (d, J = 20.9 Hz), 115.3 (d, J = 22.6 Hz), 113.2, 112.5, 112.1, 100.8, 100.5, 70.2, 56.1, 51.5, 50.0, 43.4, 38.6, 37.7, 36.6, 29.9, 25.4 ppm 19 F NMR (235 MHz, CDCh) 5 -110.69 (td, J = 8.7, 5.8 Hz) ppm IR (film) u / cm -1 3314, 2916, 1673, 1579, 1481, 1437, 1399, 1284, 1211, 1171, 1065, 1027, 962, 827, 791, 766, 745, 712. Purity was determined 99% by reverse phase HPLC C18 with UV detector at 254 nm, in ACN / H2O gradient regime, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1% formic acid.
    [0203] Example 5: (7S, 7aR, 11aR) -1 - (3-Fluorophenyl) -2-iodo-7 - (((2- (5-methoxy-1 fl-indole-3-yl) ethyl) amino) methyl) -6,7,7a, 8-tetrahydro-3HLpyrrolo [2,1- / jquinoline-3.9 (5H) -dione (Compound 5).
    [0208] Following the general procedure for reductive amination, the reaction between (7S, 7afi, 11afi) -1- (3-fluorophenyl) -2-iodo-3,9-dioxo-5,6,7,7a, 8,9- hexahydro-3H-pyrrolo [2,1-y] quinoline-7-carbaldehyde (70 mg, 0.16 mmol), 5-methoxy-tryptamine (30 mg, 0.16 mmol) and Na (AcO) 3BH (45.9 mg, 0.21 mmol) in CH2Ch (8 mL) for 21 h produced, after purification by silica gel flash chromatography (CH2Ch / MeOH, 2-5%), 71 mg (70%) of compound 5 as an ivory solid. [a] 11 = -100.00 ° (c. 1.30 mg / ml, MeOH) ee 91%. The enantiomers were separated by HPLC (ULTRON ES OVM Analytical Chiral Reverse Phase, 5gm, 4.6 mm x 150 L, H2PO4- pH 4.3 / MeOH 70:30 buffer, flow 1.0 mL / min, retention time 3.180 min (minor) and 3.487 (majority). The purity was determined 100% by C18 reverse phase HPLC with UV detector at 254 nm, in ACN / H2O gradient regime, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1% acid formic.
    [0210] Example 6: (7fl, 7aS, 11aS) -1- (3-Fluorophenyl) -2-iodo-7 - (((2- (5-methoxy-1fl-indol-3-yl) ethyl) amino) methyl) - 6,7,7a, 8-tetrahydro-3H-pyrrolo [2,1- / jquinoline-3,9 (5H) -dione (Compound 6).
    [0212] Following the general procedure for reductive amination, the reaction between (7H, 7aS, 11aS) -1- (3-fluorophenyl) -2-iodo-3,9-dioxo-5,6,7,7a, 8,9- hexahydro-3H-pyrrolo [2,1-y] quinoline-7-carbaldehyde (40 mg, 0.09 mmol), 5-methoxy-tryptamine (17 mg, 0.09 mmol) and Na (AcO) 3BH (39 mg, 0.18 mmol) in CH2Ch (4 mL) for 23 h produced, after purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 2-5%), 29 mg (52%) of compound 6 as an ivory solid. [a] 14 = + 50.00o (c.0.75 mg / mL, MeOH) ee 89%. The enantiomers were separated by HPLC (ULTRON ES OVM Analytical Chiral Reverse Phase, 5gm, 4.6 mm x 150 L, H2PO4- pH 4.3 / MeOH 70:30 buffer, flow 1.0 mL / min, retention time 3.203 (majority) and 3.637 min (minority). Purity was determined 93% by C18 reverse phase HPLC with UV detector at 254 nm, in ACN / H2O gradient regime, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1% acid formic.
    [0214] Example 7: 2-Iodo-7 - (((2- (5-methoxy-1 rtLindol-3-yl) ethyl) amino) methyl) -1-propyl-6,7,7a, 8-tetrahydro-3H-pyrrolo [2,1 -y] quinoline-3.9 (5H) -dione (Compound 7).
    [0218] Following the general procedure for reductive amination, the reaction of 2-iodo-3,9-dioxo-1-propyl-5,6,7,7a, 8,9-hexahydro-3H-pyrrolo [2,1-y] quinoline-7-carbaldehyde (100 mg, 0.25 mmol), 5-methoxy-tryptamine (48 mg, 0.25 mmol) and Na (AcO) 3 BH (71 mg, 0.33 mmol) in CH 2 Ch (11 mL) for 24 h produced, after purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 0-5%), 108 mg (75%) of compound 7 as an ivory solid. Rf 0.17 (CH2Cl2 / MeOH 95: 5) p . F. 86-88 ° C 1 H NMR (250 MHz, CDCl 3) 57.92 (s, 1H, CHO), 7.26 (d, J = 8.8 Hz, 1H, H11), 7.02 (s, 2H, H6 ', H8' ), 6.86 (dd, J = 8.8, 2.4 Hz, 1H, H10 '), 6.28 (d, J = 10.2 Hz, 1H, H10), 6.10 (dd, J = 10.0, 1.9 Hz, 1H, H11), 4.32 (dd, J = 13.3, 4.0 Hz, 1H, H5b), 3.86 (d, J = 0.6 Hz, 3H, OCH3), 2.88 (d, J = 8.5 Hz, 5H, 2xH3 ', 2xH4', H8b), 2.81 - 2.68 (m, 3H, H5a, H8a, H1 '), 2.50 (dd, J = 12.4, 6.5 Hz, 1H, H1'), 2.39 (dd, J = 11.1,5.8 Hz, 1H, H12), 2.35 - 2.23 (m, 1H, H12), 2.07-1.91 (m, 1H, H7a), 1.87-1.58 (m, 4H, H6b, H7, H2 ', H13), 1.47 (d, J = 6.6 Hz, 1H, H13 ), 1.30 - 1.08 (m, 1H, H6a), 1.01 (t, J = 7.2 Hz, 3H, H14) ppm 13 C NMR (75 MHz, CDCls) 5196.6, 165.4, 163.6, 154.1, 147.4, 132.9, 131.7, 127.9, 122.9, 113.7, 112.4, 112.0, 100.9, 98.2, 69.7, 56.1,52.0, 50.3, 43.2, 38.4, 38.3, 37.3, 33.4, 30.16, 25.8, 21.8, 14.7 ppm IR (film) u / cm -1 3313 , 2923, 2871, 1728, 1706, 1670, 1483, 1451, 1401, 1379, 1294, 1211, 1170, 1100, 1066, 1028, 920, 792, 747, 684. Purity was determined from 9 9% by C18 reverse phase HPLC with UV detector at 254 nm, in ACN / H2O gradient regime, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1% formic acid.
    [0220] Example 8: (7S, 7aff, 11afí) -2-Iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -1-propyl-6,7, 7a, 8-tetrahydro-3rtLpyrrolo [2,1-j] quinoline-3.9 (5H) -dione (Compound 8).
    [0225] Following the general procedure for reductive amination, the reaction of (7S, 7aR, 11aR) -2-iodo-3,9-dioxo-1-propyl-5,6,7,7a, 8,9-hexahydro-3H- pyrrolo [2,1 - /] quinoline-7-carbaldehyde (80 mg, 0.20 mmol), 5-methoxy-tryptamine (38 mg, 0.20 mmol) and Na (AcO) 3BH (87 mg, 0.4 mmol) in CH2Ch (9 mL) for 22 h yielded, after purification by silica gel flash chromatography (CH2Ch / MeOH, 2-5%), 90 mg (79%) of compound 8 as a white solid. [a] 14 = -113.75 ° (c. 0.80 mg / ml, MeOH) ee 85%. The enantiomers were separated by HPLC (ULTRON ES OVM Analytical Chiral Reverse Phase, 5gm, 4.6 mm x 150 L, buffer H2PO4- pH 4.3 / MeOH 70:30, flow 1.0 mL / min, retention time 3.040 min (minor) and 4.300 (majority). The purity was determined 100% by HPLC in C18 reverse phase with UV detector at 254 nm, in ACN / H2O gradient regime, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1% formic acid.
    [0227] Example 9: (7R, 7aS, 11 aS> 2-Iodo-7 - (((2- (5-methoxy-1 rtLindol-3-yl) ethyl) amino) methyl) -1-propyl-6,7,7a , 8-tetrahydro-3HLpyrrolo [2,1- / quinoline-3.9 (5H) -dione (Compound 9).
    [0232] Following the general procedure for reductive amination, the reaction of ( 7R, 7aS, 11aS) -2-iodo-3,9-dioxo-1-propyl-5,6,7,7a, 8,9-hexahydro-3H- pyrrolo [2,1 -_ /] quinoline-7-carbaldehyde (72 mg, 0.18 mmol), 5-methoxy-tryptamine (34 mg, 0.18 mmol) and Na (AcO) 3BH (51 mg, 0.23 mmol) in CH2Ch ( 8 mL) over 18 h yielded, after purification by silica gel flash chromatography (CH2Ch / MeOH, 0-5%), 72 mg (70%) of compound 9 as a white solid. [a] 14 = + 145.45o (c.0.55 mg / mL, MeOH). ee 88%. The enantiomers were separated by HPLC (ULTRON ES OVM Analytical Chiral Reverse Phase, 5 gm, 4.6 mm x 150 L, H2PO4- pH 4.3 / MeOH 70:30 buffer, flow 1.0 mL / min, retention time 2,960 min (majority) and 4,613 min (minority). The purity was determined 93% by C18 reverse phase HPLC with UV detector at 254 nm, in ACN / H2O gradient regime, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1 % formic acid.
    [0234] Example 10: 1-Cyclopropyl-2-iodo-7 - (((2- (5-methoxy-1fl-indole-3-yl) ethyl) amino) methyl) -6,7,7a, 8-tetrahydro-3H- pyrrolo [2,1- / jquinoline-3.9 (5H) -dione (Compound 10).
    [0237] Following the general procedure for reductive amination, the reaction between 1-cyclopropyl-2-iodo-3,9-dioxo-5,6,7,7a, 8,9-hexahydro-3H-pyrrolo [2,1- /] quinoline-7-carbaldehyde (60 mg, 0.15 mmol), 5-methoxy-tryptamine (29 mg, 0.15 mmol) and Na (AcO) 3BH (49 mg, 0.23 mmol) in CH2Cl2 (7 mL) for 16 h produced, then Purification by silica gel flash chromatography (CH2Ch / MeOH, 2-5%), 44 mg (51%) of compound 10 as an ivory solid. Rf 0.16 (CH2Cl2 / MeOH 95: 5) mp 145-147 ° C 1 H NMR (250 MHz, CDCH) 57.96 (s, 1H, H5 '), 7.26 (d, J = 8.0 Hz, 1H, H11'), 7.09 - 7.00 (m, 2H, H6 ', H8'), 6.86 (dd, J = 8.8, 2.5 Hz, 1H, H10 '), 6.29 (d, J = 10.2 Hz, 1H, H10), 6.24 - 6.13 ( m, 1H, H11), 4.32 (dd, J = 13.7, 3.9 Hz, 1H, H5b), 3.87 (d, J = 1.8 Hz, 3H, OCH3), 3.30 (dd, J = 17.8, 5.1 Hz, 1H, H8b), 2.89 (d, J = 2.4 Hz, 4H, 2xH3 ', 2xH4'), 2.77 (ddd, J = 10.3, 8.2, 5.3 Hz, 3H, H5a, H8a, H1 '), 2.52 (dd, J = 12.3, 6.4 Hz, 1H, H1 '), 2.03 (d, J = 6.2 Hz, 1H, H7a), 1.81 - 1.55 (m, 4H, H6b, H7, H13, H2'), 1.57 -1.38 (m, 1H , H13), 1.30 - 1.16 (m, 1H, H13), 1.15 - 1.01 (m, 2H, H6a, H13), 0.92 (dt, J = 8.1, 5.5 Hz, 1H, H12) ppm 13 C NMR (63 MHz , CDCh) 5 197.1, 165.8, 161.6, 154.1, 147.7, 133.1, 131.6, 127.8, 123.0, 113.4, 112.4, 112.1, 100.7, 92.4, 70.5, 56.1,51.8, 50.1,43.7, 38.4, 38.2, 37.3, 30.0, 25.7, 12.7, 9.0, 7.7 ppm HRMS (ES +) m / z theoretical calculated C27H30IN3O3571.1332; found [(M + H) +], 572.1423 IR (film) v / cm -1 3313, 2902, 2827, 1670, 1597, 1483, 1441, 1406, 1298, 1211, 1171, 1106, 1065, 1027, 919, 794, 747. Purity was determined to be 99% by C18 reverse phase HPLC with UV detector at 254 nm, in ACN / H2O gradient regime, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1% acid formic.
    [0239] Example 11: (7S, 7aR, 11aR) -1-Cyclopropyl-2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -6,7 , 7a, 8-tetrahydro-3HLpyrrolo [2,1- / jquinoline-3.9 (5H) -dione (Compound 11).
    [0243] Following the general procedure for reductive amination, the reaction between (7S, 7aR, 11aR) -1-cyclopropyl-2-iodo-3,9-dioxo-5,6,7,7a, 8,9-hexahydro-3H- pyrrolo [2,1 - /] quinoline-7-carbaldehyde (147 mg, 0.37 mmol), 5-methoxy-tryptamine (70 mg, 0.37 mmol) and Na (AcO) 3BH (105 mg, 0.48 mmol) in CH2Ch (16 mL) for 21 h produced, after purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 0-5%), 134 mg (64%) of compound 11 as white solid. [a] B4 = -106.67 ° (c. 0.75 mg / ml, MeOH) ee 92%. The enantiomers were separated by HPLC (ULTRON ES OVM Analytical Chiral Reverse Phase, 5gm, 4.6 mm x 150 L, H2PO4- pH 4.3 / MeOH 70:30 buffer, flow 1.0 mL / min, retention time 3,247 min (minor) and 7,102 min (majority). Purity was determined to be 99% by C18 reverse phase HPLC with UV detector at 254 nm, in ACN / H2O gradient regime, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1% formic acid.
    [0245] Example 12: (7ff, 7aS, 11aS) -1-Cyclopropyl-2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -6,7, 7a, 8-tetrahydro-3HLpyrrolo [2,1- / jquinoline-3.9 (5H) -dione (Compound 12).
    [0250] Following the general procedure for reductive amination, the reaction between (7fi, 7aS, 11aS) -1-cyclopropyl-2-iodo-3,9-dioxo-5,6,7,7a, 8,9-hexahydro-3H- pyrrolo [2,1-y] quinoline-7-carbaldehyde (110 mg, 0.28 mmol), 5-methoxy-tryptamine (53 mg, 0.28 mmol) and Na (AcO) 3BH (80 mg, 0.36 mmol) in CH2Ch (12 mL) for 21 h yielded, after purification by silica gel flash chromatography (CH2Cb / MeOH, 0-5%), 115 mg (72%) of compound 12 as an ivory solid. [a] 14 = + 107.14 ° (c.0.70 mg / mL, MeOH) ee 86%. The enantiomers were separated by HPLC (ULTRON ES OVM Analytical Chiral Reverse Phase, 5gm, 4.6 mm x 150 L, H2PO4- pH 4.3 / MeOH 70:30 buffer, flow 1.0 mL / min, retention time 3.133 min (majority) and 7.157 min (minority). The purity was determined 99% by C18 reverse phase HPLC with UV detector at 254 nm, in ACN / H2O gradient regime, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1% formic acid.
    [0252] Example 13: 1-Cyclohexyl-2-iodo-7 - (((2- (5-methoxy-1fl-indol-3-yl) ethyl) amino) methyl) -6,7,7a, 8-tetrahydro-3H- pyrrolo [2,1- / jquinoline-3.9 (5H) -dione (Compound 13).
    [0255] Following the general procedure for reductive amination, the reaction between 1-cyclohexyl-2-iodo-3,9-dioxo-5,6,7,7a, 8,9-hexahydro-3H-pyrrolo [2,1- /] quinoline-7-carbaldehyde (65.0 mg, 0.15 mmol), 5-methoxy-tryptamine (28.5 mg, 0.15 mmol) and Na (AcO) 3BH (98.3 mg, 0.45 mmol) in CH2Cl2 (6.5 mL) for 23 h produced, then Purification by silica gel flash chromatography (CH2Ch / MeOH, 2-5%), 54.0 mg (59%) of compound 13 as white solid. Rf: 0.20 (95: 5 CH2Ch / MeOH) mp 128-130 ° C. 1H NMR (500 MHz, CDCls) 57.95 (s, IH, H5 '), 7.26 (d, J = 8.4 Hz, 1H, H11'), 7.02 (d, J = 2.8Hz 1H, H8 '), 7.01 (d , J = 2.8Hz 1H, H6 '), 6.85 (dd, J = 8.8, 2.5 Hz, 1H, H10'), 6.33 (d, J = 10.1 Hz, 1H, H10), 6.19 (dd, J = 10.2 , 2.0 Hz, 1H, H11), 4.31 (dd, J = 13.2, 4.2 Hz, 1H, H5b), 3.86 (s, 3H, OCH3), 2.96-2.82 (m, 5H, 2xH3 ', 2xH4', H8b) , 2.80-2.69 (m, 3H, H1 ', H5a, H8a), 2.49 (dd, J = 12.4, 6.6 Hz, 1H, H1'), 2.32 (dd, J = 18.8, 9.9 Hz, 2H, H12, H17 ), 2.25 (q, J = 11.4, 10.7 Hz, 1H, H13), 1.96 (dd, J = II. 1.5.3 Hz, 1H, H7a), 1.88 (d, J = 13.0 Hz, 1H, H16), 1.80 (d, J = 13.1 Hz, 1H, H14), 1.74-1.61 (m, 4H, H6b, H7, H15, H17), 1.36-1.23 (m, 2H, H13, H15), 1.23-1.10 (m, 3H, H6a, H14, H16) ppm 13C NMR (126 MHz, CDCls) 5196.6, 166.1, 165.9, 154.1, 146.3, 133.4, 131.7, 127.9, 123.0, 113.5, 112.5, 112.1, 100.8, 93.1,70.7, 56.1, 52.0 , 50.1,44.1, 39.1, 38.6, 38.2, 37.6, 30.1,28.8, 28.6, 26.5, 26.4, 25.7, 25.5 ppm IR film v / cm-13312, 2920, 2850, 1670, 1581, 1483, 1444, 1405, 1297 , 1213, 1171, 1065, 1029, 968, 921, 792, 745, 705 The purity was determined 100% by HPLC in reverse phase C18 with UV detector at 254 nm, under ACN / H2O gradient regime, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1% formic acid
    [0257] Example 14: (7S, 7aff, 11afí) -1-Cyclohexyl-2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -6,7 , 7a, 8-tetrahydro-3H-pyrrolo [2,1-j] quinoline-3.9 (5H) -dione (Compound 14).
    [0259] Following the general procedure for reductive amination, the reaction between (7S, 7aH, 11aH) -1-cyclohexyl-2-iodo-3,9-dioxo-5,6,7,7a, 8,9-hexahydro-3H- pyrrolo [2,1-y] quinoline-7-carbaldehyde (80 mg, 0.18 mmol), 5-methoxy-tryptamine (34 mg, 0.18 mmol) and Na (AcO) 3BH (79 mg, 0.36 mmol) in CH2Ch (8 mL) for 24 h produced, after purification by silica gel flash chromatography (CH2Ch / MeOH, 2-5%), 48 mg (43%) of compound 14 as an ivory solid. a¿4 = - 103.33 ° (C = 0.90 mg / mL, MeOH) ee 84% The enantiomers were separated by HPLC (ULTRON ES OVM Analytical Chiral Reverse Phase, 5gm, 4.6 mm x 150 L, buffer H2PO4- pH 4.3 / MeOH 70:30, flow 1.0 mL / min, retention time 4,300 min (minority) and 5,313 min (majority). The purity was determined to be 97% by C18 reverse phase HPLC with UV detector at 254 nm, in ACN gradient regime / H2O, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1% formic acid.
    [0261] Example 15: (7R, 7aS, 1 one aS) -1 -Cyclohexyl-2-iodo-7 - (((2- (5-methoxy-1 fl-indol-3-yl) ethyl) amino) methyl) -6,7,7a, 8-tetrahydro-3HLpyrrolo [2,1- / jquinoline-3.9 (5H) -dione (Compound 15).
    [0266] Following the general procedure for reductive amination, the reaction between (7R, 7aS, 11aS) -1-cyclohexyl-2-iodo-3,9-dioxo-5,6,7,7a, 8,9-hexahydro-3H- pyrrolo [2,1-y] quinoline-7-carbaldehyde 34 (62.0 mg, 0.14 mmol), 5-methoxy-tryptamine (26.6 mg, 0.14 mmol) and Na (AcO) 3BH (61.2 mg, 0.28 mmol) in CH2CI2 (6 mL) for 20 h produced, after purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 2-5%), 46.3 mg (54%) of compound 49 as an ivory solid. a¿4 = 65.45 ° (C = 1.10 mg / mL, MeOH) ee 81%. The enantiomers were separated by HPLC (ULTRON ES OVM Analytical Chiral Reverse Phase, 5pm, 4.6 mm x 150 L, H2PO4- pH 4.3 / MeOH 70:30 buffer, flow 1.0 mL / min, retention time 4.147 min (majority) 5.693 min (minority). The purity was determined 100% by C18 reverse phase HPLC with UV detector at 254 nm, in ACN / H2O gradient regime, 5:95 0.1% formic acid to ACN / H2O, 95: 5 0.1% acid formic.
    [0268] 2. BIOLOGICAL ACTIVITIES STUDIED IN THE COMPOUNDS OF THE INVENTION.
    [0270] Example 16
    [0271] Study of the modulating capacity of nicotinic receptors by the compounds object of the invention measured as modulation of the variation of the intracytosolic calcium concentration (fCa2 + µc induced by the stimulation of acetylcholine.
    [0273] SH-SY5Y neuroblastoma cell culture
    [0275] SH-SY5Y cells [ECACC 94030304], from passages between 5 and 16 after thawing, were kept in Dulbecco's modified Eagle medium (DMEM) containing 15 non-essential amino acids and supplemented with 10% fetal bovine serum, 1 mM glutamine, 50 units / mL penicillin and 50 pg / mL streptomycin (GIBCO reagents, Madrid, Spain). The cells were seeded in containers containing supplemented medium and kept in an incubator at 37 ° C in a humid atmosphere with 5% CO2, passing 1: 4 twice a week. For the experiments, cells were grown in 48-well plates at a density of 2x10 5 cells / well, or in 96-well plates at a density of 8x10 4 cells / well.
    [0277] Measurement of the cellular response to the stimulation of nicotinic receptors with acetylcholine.
    [0279] SH-SY5Y neuroblastoma cells were grown to confluence in 96-well black plates. The cells were loaded with the fluorescent probe fluo-4 / AM at the concentration of 5 pM for 1 hr at 37 ° C in DMEM, adding half the volume of 20% pluronic acid in DMSO, to permeabilize the cell membrane. They were then washed twice with a Krebs-HEPES solution and kept at room temperature for 30 min before starting the experiment.
    [0281] Fluorescence was measured in a fluorescence plate reader (FLUOstar Optima, BMG, Germany), the excitation and emission wavelengths being 485 and 520 nm respectively. Table 1 shows the effect of the different compounds of the invention at a concentration of 10 pM on the increase in cytosolic calcium concentration ([Ca2 +] c) induced by the stimulation of nicotinic receptors with acetylcholine at a concentration of 100 pM in cells. of human neuroblastoma of the SH-SY5Y line as a percentage of inhibition with respect to a control without any compound. Data are expressed as percentages of relative response to the total response obtained by stimulation with acetylcholine. A reduction in the relative response indicates the action of the compounds of the patent on the receptors stimulated by acetylcholine. The results are shown in Table 1 as a percentage of response relative to acetylcholine which is considered 100% ± SEM.
    [0283] Table 1
    [0284] Response percentages relative to acetylcholine agonist as mean of nine experiments ± SEM.
    [0288] Student's t test dependent data *, p <0.05, **, p <0.005, ***, p <0.0005.
    [0290] The results indicate that the compounds object of the invention are capable of blocking the response of the nicotinic receptors induced by their natural agonist, acetylcholine. The modulation of the nicotinic signal is related to neuroprotective effects and compared to the control compound, melatonin, all of them showed better blocking capacity than the control compound. Therefore, this experiment demonstrates that the compounds object of the invention exhibit nicotinic receptor antagonist activity, the best of which is compound 40 .
    [0292] Example 17
    [0293] Measurement of oxygen free radical scavenging capacity
    [0295] To study the oxygen free radical scavenging capacity of the compounds object of the invention, the ORAC-FL test (absorbance capacity of oxygen radicals) developed by Ou et al. (Ou, Hampsch-Woodill et al. 2001). The compounds were studied at six concentrations (0.03, 0.1, 0.3, 1, 3 and 5 pM). The different solutions of Trolox (1.2, 4, 6, 8 pM) and the compounds, as well as melatonin as a positive control at the same concentrations as the compounds, were made using the PBS buffer (10 mM, pH 7, as solvent). 4) at 37 ° C.
    [0297] Table 2
    [0298] Oxygen radical scavenging capacity in Trolox equivalents by the compounds of the invention, as well as melatonin as a positive control
    [0302] One-way ANOVA, Newman-Keuls post test. *, p <0.1 **, p <0.01; with respect to melatonin.
    [0304] Measurements were carried out at 37 ° C. First, a fluorescence measurement was performed using the FluoStar Optima multi-well reader (BMG Labtech) (Ex. 485 nm, Em.
    [0305] 520 nm) to determine the baseline signal. Then, 25 gl of AAPH (12 mM) were added with a multichannel pipet. Fluorescence was measured for 90 min at 37 ° C. From the area under the curve and the concentrations of the compounds, the slopes of the linear regressions were obtained, which are divided by the slope of the Trolox line, thus obtaining the results of each compound as Trolox equivalents (E.T.). The data are shown in Table 2 as the mean ± SEM of at least three duplicate experiments at six different concentrations.
    [0306] The free radical scavenging capacity of the compounds object of the invention has improved with respect to the reference compound Trolox, a known antioxidant, in the same magnitude as the positive control melatonin. In this study, compounds 42 and 46 stand out .
    [0307] Example 18
    [0309] Measurement of the induction of the Nrf2-ARE pathway by measuring Luciferase activity in AREc32 cells.
    [0311] The AREc32 cell line was used to study the induction of the transcription factor Nrf2. In the presence of electrophiles or oxidative stress, the Nrf2 factor translocates to the nucleus and binds to the ARE sequences, activating the expression of luciferase, forming a proportional amount of it. AREc32 cells were cultured in DMEM medium with glutamax, supplemented with 10% fetal bovine serum (FBS), 1% penicillin-streptomycin and 1.6% geneticin (G418). The cells were cultured in 75 cm2 flasks with 11 mL of the medium. Specific, they were incubated at 37 ° C and 5% CO2 and 1: 4 passages were made every 4-6 days when the cells reached 80% confluence. For the experiments, the cells were cultured in 96-well white plates, at a density of 20x10 4 cells / well in 100 pL / well. After 24 h of culture, the cells were treated with the compounds object of the invention at the desired concentrations (1, 5, 10, 15 pM) for 24 h. After 24 h of incubation with the compounds under study, luciferase activity was measured by a bioluminescence assay, for which the "Luciferase assay system" kit (Promega E1500) was used. After the incubation period, the treatments were removed and the cells were washed with 100 pL of 0.1 M PBS. After the wash was removed, 20 pL of the lysis buffer reagent was added to each of the wells. After 10 min, the plate was placed in a multiwell luminescence reader, Orion II microplate luminometer (Berthold, Germany).
    [0313] Table 3
    [0314] Induction of the transcription factor Nrf2 by the compounds of the invention. The CD values are included, which is the concentration that doubles the activity of the luciferase enzyme.
    [0316]
    [0317]
    [0319] Dependent samples t test; *, p <0.01; **, p <0.001; ***, p <0.0001. # Not calculable.
    [0321] The data is shown in Table 3 as the mean ± SEM of at least three duplicate experiments at four different concentrations. Measurements were made in duplicate and the values were normalized with respect to the luminescence of the baseline, taking its luciferase expression value as 1.
    [0323] The activity of the transcription factor Nrf2 is deregulated in neurodegenerative diseases, therefore, the activation of this antioxidant and anti-inflammatory pathway is considered beneficial in this type of disease. Nine of the compounds object of the invention induced the activation of this pathway, of which compounds 35 to 37 turned out to be as potent as the reference compound te / t-butylhydroquinone (TBHQ). Derivatives 41 to 46 have higher CD values, indicating the moderate induction of this transcription factor. In this case, compounds 41 and 42 are the best candidates, since it is intended to obtain a moderate induction of Nrf2, since a massive activation of this factor is considered deleterious for the cell.
    [0325] Example 19
    [0326] Study of the neuroprotective capacity of the compounds object of the invention against a model of hyperphosphorylation of tau
    [0328] Measurement of cell viability: 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazole, MTT
    [0330] The parameter used to measure cell viability was the metabolic reduction of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazole (MTT) bromide. The number of living cells is proportional to the amount of formazan formed (Mosmann 1983). To determine cell viability in human neuroblastoma cells, SH-SY5Y, 10 μl / well of MTT (5 mg / mL) are added and, after 2 h, the medium is removed without losing the formazan crystals, which dissolve in 100 pL of DMSO. Subsequently, the absorbance of the samples is measured at 570 nm with the FluoStar Optima reader (BMG Labtech). The absorbance values obtained with the toxin alone and with each compound in the presence of the toxin were subtracted from the absorbance value obtained in basal conditions, without treatment. The value obtained from the subtraction of the less toxic basal absorbance values only, was considered 100% death and the values obtained with the compounds in the presence of toxic were normalized as percentages of that value. To calculate percent survival, these values were subtracted from 100.
    [0332] Neuroprotection against tau hyperphosphorylation induced by okadaic acid (20 nM), pre-incubation and co-incubation protocol:
    [0334] We study the neuroprotective capacity of the compounds object of this patent in an in vitro model of tau hyperphosphorylation. The neuroprotective effect of the compounds was evaluated in human neuroblastoma cells, against the hyperphosphorylation of tau produced by okadaic acid (OA), a marine toxin that inhibits serine / threonine phosphatases PP1 and PP2A, which prevents dephosphorylation of tau (Kamat, Rai et al. 2014), performing the following protocol:
    [0336] Table 4
    [0338] Percentage of neuroprotection produced by the compounds of the invention and melatonin, at a concentration of 1 pM. Data are expressed as the mean ± SEM of six experiments in triplicate.
    [0342] One-way ANOVA, Newman-Keuls post test. **, p <0.001; ***, p <0.0001
    [0343] In this protocol, cells were pre-incubated with each of the derivatives studied at a concentration of 1 pM for 24 h. After the pre-incubation period, the medium was removed and was replaced by culture medium with the compounds and okadaic acid, at a concentration of 20 nM. After 18 h, cell viability was evaluated by the MTT reduction method. A positive control was used in all pharmacological tests for comparative purposes and to evaluate the goodness of the method used. For this, melatonin (1 pM) was used, which has shown neuroprotective capacity in various models of oxidative stress.
    [0345] The results obtained for the compounds described as compounds 35 to 49 are shown in Table 4, and are expressed as a percentage of cell survival and as a percentage of neuroprotective activity.
    [0347] In this protocol, all the compounds object of the invention, with the exception of 47 to 49 , are capable of showing their ability to induce factor Nrf2, thus favoring cell survival, and therefore neuroprotection, highlighting 36 and 43. Therefore, the combination The pharmacological activities of the compounds object of the invention translate into a neuroprotective effect.
    权利要求:
    Claims (14)
    [1]
    1. A compound of formula (I):

    [2]
    2. A compound according to claim 1 wherein
    R is selected from the group comprising a phenyl aromatic ring optionally substituted by one, two or three groups independently selected from fluorine, chlorine, (C1-C6) alkyl, optionally substituted by one, two, or three halogen atoms selected from fluorine, chlorine and bromine;
    Alkyl optionally substituted by one, two, or three halogen atoms selected from fluorine, chlorine and bromine; (C3-C6) cycloalkyl; (C1-C6) alkoxy; cycloalkoxy (C 3 -C 6 ); cyano and nitro; me
    a heteroaryl group optionally substituted by one, two, or three groups independently selected from fluorine, chlorine, bromine, alkyl, (C3-C 6 ) cycloalkyl, (C1-C6) alkoxy, (C 3 -C 6 ) cyanoalkoxy, cyano and nitro
    R1 is selected from the group comprising an alkyl optionally substituted by one or two groups independently selected from fluorine, chlorine, and bromine; (C1-C6) alkoxy, nitro and amino; preferably R1 is -OCH3;
    R2 is hydrogen;
    R3 is hydrogen;
    R4 is hydrogen;
    n is an integer selected from 0, 1 and 2, preferably n = 1;
    X is carbon;
    7 *, 7a *, 11a * are carbons with R or S configuration in any of their possible combinations
    or their stereoisomers, salts, preferably pharmaceutically acceptable salts, prodrugs or solvates.
    [3]
    3. A compound according to claims 1 or 2 characterized in that it consists of:
    • Iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -1-phenyl-6,7,7a, 8-tetrahydro-3H-pyrrolo [2 , 1 - /] quinoline-3.9 (5H) -dione;
    • (7S, 7aR, 11aR) -2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -1-phenyl-6,7,7a , 8-tetrahydro-3H-pyrrolo [2,1-y] quinoline-3.9 (5H) -dione;
    • (7R, 7aS, 11aS) -2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -1-phenyl-6,7,7a , 8-tetrahydro-3H-pyrrolo [2,1-y] quinoline-3.9 (5H) -dione;
    • 1 - (3-fluorophenyl) -2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -6,7,7a, 8-tetrahydro -3H-pyrrolo [2,1-y] quinoline-3.9 (5H) -dione;
    • (7S, 7afi, 11afi) -1- (3-fluorophenyl) -2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -6 , 7,7a, 8-tetrahydro-3H-pyrrolo [2,1-y] quinoline-3,9 (5H) -dione;
    • (7R, 7aS, 11aS) -1- (3-fluorophenyl) -2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -6 , 7,7a, 8-tetrahydro-3H-pyrrolo [2,1-y] quinoline-3,9 (5H) -dione;
    • 2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -1-propyl-6,7,7a, 8-tetrahydro-3H-pyrrolo [2,1- y] quinoline-3.9 (5H) -dione;
    • (7S, 7afi, 11afi) -2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -1-propyl-6,7,7a, 8-tetrahydro-3H-pyrrolo [2,1-y] quinoline-3.9 (5H) -dione;
    • (7R, 7aS, 11aSJ-2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -1-propyl-6,7,7a, 8-tetrahydro-3H-pyrrolo [2,1-y] quinoline-3.9 (5H) -dione;
    • 1 -cyclopropyl-2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -6,7,7a, 8-tetrahydro-3H-pyrrolo [2,1- y] quinoline-3.9 (5H) -dione;
    • (7S, 7aR, 11aR) -1-cyclopropyl-2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -6,7,7a , 8-tetrahydro-3H-pyrrolo [2,1-y] quinoline-3.9 (5H) -dione;
    • (7R, 7aS, 11aS) -1-cyclopropyl-2-iodo-7 - (((2- (5-methoxy-1H-indole-3-yl) ethyl) amino) methyl) -6,7,7a , 8-tetrahydro-3H-pyrrolo [2,1-y] quinoline-3.9 (5H) -dione;
    • 1-cyclohexyl-2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -6,7,7a, 8-tetrahydro-3H-pyrrolo [2,1- y] quinoline-3.9 (5H) -dione;
    • (7S, 7aR, 11aR) -1-cyclohexyl-2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -6,7,7a , 8-tetrahydro-3H-pyrrolo [2,1-y] quinoline-3.9 (5H) -dione.
    • (7R, 7aS, 11aS) -1-cyclohexyl-2-iodo-7 - (((2- (5-methoxy-1H-indol-3-yl) ethyl) amino) methyl) -6,7,7a , 8-tetrahydro-3H-pyrrolo [2,1-y] quinoline-3.9 (5H) -dione.
    [4]
    4. A process for the preparation of a compound of formula (I) according to claim 1 characterized by reacting a polycyclic aldehyde of formula (II)

    [5]
    5. Process according to claim 4, in which the compound of formula (II) is obtained by enantioselective cyclization catalyzed by an organocatalyst.
    [6]
    6. Process according to claim 4, wherein the reaction between the compound of formula (II) and the compound of formula (III) is carried out in the presence of a reducing agent selected from NaBH 4 or Na (AcO) 3BH, in a solvent selected from dichloromethane, 1,2-dichloroethane, chloroform and their mixtures.
    [7]
    7. Pharmaceutical composition comprising at least one compound of formula (I) according to any of claims 1 to 3 and a suitable excipient.
    [8]
    8. Compound of formula (I) according to any of claims 1 to 3 for use in medicine.
    [9]
    9. Compound of formula (I) according to claim 8 for use in the treatment or prevention of diseases that improve with the administration of an inducer of Nrf2 and / or a free radical scavenger agent and / or a neuroprotective agent and / or a nicotinic receptor modulator.
    [10]
    10. Compound of formula (I) according to claim 9 for use in the treatment or prevention of neurodegenerative diseases.
    [11]
    11. Compound of formula (I) according to claim 10 for use in the treatment or prevention of a central and / or peripheral neurodegenerative disease or of an ischemic-cerebral disease (stroke).
    [12]
    12. Compound of formula (I) according to claim 11 for use in the treatment or prevention of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and cerebral stroke.
    [13]
    13. Compound of formula (I) according to any of claims 7-11 characterized in that it is administered in daily doses between 0.1 and 500 mg.
    [14]
    14. Compound of formula (I) according to claim 13, characterized in that it is administered in daily doses between 25 and 250 mg.
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