New family of 1-indazolyl carbonyl derivatives cannabinoid and/or colinergic containers and/or beta-

专利摘要:
New family of 1-indazolyl carbonyl derivatives with cannabinoid and/or cholinergic properties and/or regulators of beta-amyloid peptide. The present invention relates to substituted 1-indazolyl carbonyl derivatives of formula (I), which exhibit cannabinoid and/or cholinergic and/or regulatory properties of the beta-amyloid peptide, and its use for the treatment and prevention of diseases and diseases. Disorders regulated by the mentioned systems. Therefore, these compounds may be useful for the treatment of neurodegenerative diseases and dementias. (Machine-translation by Google Translate, not legally binding)
公开号:ES2625037A1
申请号:ES201531846
申请日:2015-12-18
公开日:2017-07-18
发明作者:Juan Antonio PÁEZ PROSPER；Nuria Eugenia Campillo Martín；Concepción Pérez Martín；Pedro José GONZÁLEZ NARANJO；Natalia PÉREZ MACIAS；María LÓPEZ DE CEBALLOS LAFARGA；Ángeles MARTÍN REQUERO；Carolina ALQUÉZAR BURILLO；M. Isabel MARTÍN FONTELLES；María Del Rocío GIRÓN MORENO；Eva María Sánchez Robles；Julián ROMERO PAREDES
申请人:Hospital Universitario Fundacion Alcorcon；Hospital Univ Fundacion Alcorcon；Consejo Superior de Investigaciones Cientificas CSIC；Universidad Rey Juan Carlos；
IPC主号:

专利说明:

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Currently, among the therapeutic applications of cannabinoid agonists its use can be cited for the reduction of nausea and vomiting in anticancer therapy and for the stimulation of appetite and in the treatment of pain.
In relation to Alzheimer's disease, the therapeutic interest of the cannabinoid system is evidenced by the pathophysiological alterations that occur during the evolution of the disease. On the one hand, it has been described that in the postmortem brains of Alzheimer's patients, the cannabinoid system is altered.
Thus, there is a decrease in the protein CB1R, an increase in CB2R, particularly in microglia, a lower degradation of endocannbinoids and anandamide levels in AD. On the other hand, it has been described that cannabinoid agonists, particularly selective CB2R, decrease the levels of Ap in TgAPP animals, counteract the existing neuroinflammation in addition to improving the deficit in learning and memory, after prolonged administration (Ramirez, BG, et al ., J. Neurosci. 2005, 25, 1904-13, Martin-Moreno, AM, et al., J Neuroinflammation 2012, 9, 8).
On the other hand, some cannabinoid agonists can inhibit cholinergic system enzymes (AChE / BuChE) (Gonzalez-Naranjo, P., et al., Curr Alzheimer Res 2013, 10, 22939).
In addition to all these studies that prove the alterations of the cannabinoid system in AD, and the beneficial effects of cannabinoids, these have also demonstrated a clear neuroprotective effect against acute hypoxia, excitotoxicity and against oxidative and traumatic damages both in vitro and in vivo (Campillo, NE, Paez, JA, Mini Rev. Med. Chem, 2009, 9, 539-59).
The cholinergic system is one of the most important modulatory systems of neuronal transmission, regulating cognitive functions such as memory, learning, development and neuronal differentiation. Its main neurotransmitter is acetylcholine that is degraded to choline and acetate by the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).
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It has been observed that the content of the BuChE enzyme in the brain increases with age, while that of the AChE enzyme decreases. The catalytic activity of the BuChE enzyme, therefore, may play a more prominent role in the hydrolysis of acetylcholine in the aged brain, suggesting that inhibition of this enzyme may have a greater impact on cholinergic neurotransmission in the disease of Alzheimer's It has also been shown that the BuChE enzyme is associated with p-amyloid plaques at the point of maturation, when they are transformed from the benign to the neurotoxic form (Lane, RMet al., Int J Neuropsychopharmacol 2006, 9 , 101-24).
Cholinergic drugs such as AChE inhibitors that include donepezil, rivastigmine or galantamine, are the reference medications and the most commonly used for the treatment of Alzheimer's disease. The only therapeutic alternative available corresponds to memantine (Ebixa®) that acts through a different mechanism, as an NMDA receptor antagonist.
Cholinergic drugs are used in the treatment of dementia, such as in dementia with Lewy bodies and in Parkinson's disease (the aforementioned cholinergic drug donepezil is also used for the treatment of dementia linked to the disease of Parkinson's), mainly for the treatment of dementia symptoms, such as memory and learning deficits, to attenuate psychotic symptoms (visual hallucinations) especially in Parkinson's disease and for the treatment of cognitive disorders in patients with schizophrenia.
In addition, AChE inhibitors are used in myasthenia gravis to increase neuromuscular transmission, in autism to prolong REM sleep and promote lucid dreaming and for cognitive impairment in multiple sclerosis.
On the other hand, the increase in the production of the toxic p-amyloid peptide (Ap) in the brain and / or the decrease in its elimination are the triggers of the series of pathogenic events that lead to Alzheimer's disease (AD ). Ap peptides are generated from the amyloid precursor protein (APP) by the consecutive action of two enzymes known as p- and y-secretase. The activity of p-secretase (BACE-1), an enzyme closely related to early dementia where an appreciable increase in BACE-1 levels is observed in the cerebral cortex, is attributed to a
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only protelna known as p site APP Cleavage Enzyme. Different studies with deficient modified mice (knockout) in the BACE-1 enzyme have allowed us to draw two important conclusions, the first is that the modified mice do not show significant phenotypic differences compared to the unmodified mice and the second is the complete loss of any form of the Ap peptide in primary neuronal cultures generated from knockout mice, this means that BACE-1 is the only enzyme responsible for the generation of the Ap peptide. Said enzyme is critical in the disease development process of Alzheimer, as it is responsible for the release of p-amyloid by proteolytically processing the precursor amyloid precursor (APP). Therefore, the inhibition of BACE-1 is a possible strategy for the reduction of p-amyloid production (Huang, W.H., et al., Curr Med Chem 2009, 16, 1806-20).
In the present invention, a series of chemical compounds capable of interacting with various molecular targets related to the cannabinoid receptor and / or the cholinergic deficit and / or the generation of the p-amyloid peptide are described. Such targets considered in the present invention patent are the CB1 / 2 receptors (cannabinoid system), AChE / BuChE (cholinergic system) and the enzyme BACE-1. These targets are being studied by the scientific community, individually, as possible pharmacological targets for the treatment of Alzheimer's disease, using the classic strategy to search for compounds of high selectivity and potency. However, the present invention describes chemical compounds that act on two or three of these targets simultaneously to obtain a more effective therapeutic tool in the treatment of neurodegenerative diseases and dementias.
Although the chemical structures already described in the state of the art of the compounds that interact with the cannabinoid receptors, with the AChE / BuChE or BACE-1 enzymes are very varied and include different heterocyclic compounds such as pyrazoles, triazoles, indoles, oxazoles , etc., to date no example of carbonyl derivative of 1-indazolyl has been described as a ligand of any of the three targets.
In WO2011039388, a broad family of 3-indazolyl ethers with cannabinoid activity and / or BuChE inhibitors is described, where no example of 3- indazolyl ether is shown characterized by the presence of a substituted carbonyl in position 1 of the indazolyl. In addition, it has not been described that the 3-indazolyl ethers described as examples
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of realization in WO2011039388 modulate the enzyme BACE-1 (Gonzalez-Naranjo, P., et al., Eur. J. Med. 2014, 73, 56-72).
SHORT DESCRIPTION
The authors of the present invention have found a family of compounds characterized by being modulators of the CB1 and / or CB2 cannabinoid receptors, the enzymes of the AChE and / or BuChE cholinergic system and / or the BACE-1 enzyme. Therefore, the compounds of the invention can be useful in the treatment or prophylaxis of diseases that are related to the regulation of said systems.
The present invention relates to the use of a compound of general formula (I)
its pharmaceutically acceptable salts, tautomers, prodrugs, solvates and hydrates where,
- n is selected between 1,2, 3 and 4;
- R1 and R2 are independently selected from hydrogen, halogen, -NO2 and -NH2;
- R3 is selected from cycloalkyl, heteroaryl, optionally substituted aryl and
optionally substituted aralkyl;
- R4 is selected from heterocycloalkyl and -NR5R6;
- R5 and R6 are independently selected from hydrogen and alkyl.
Likewise, the present invention also relates to the use of a compound of general formula (I)
OR
r (CH2) n-R4
image 1
^ R3
Formula (I)
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Rl
R.
■ 2
image2
^ R.
■ 3
Formula (I)
its pharmaceutically acceptable salts, tautomers, prodrugs, solvates and hydrates where,
- n is selected between 1,2, 3 and 4;
- R1 and R2 are independently selected from hydrogen, halogen, -NO2 and -NH2;
- R3 is selected from cycloalkyl, heteroaryl, optionally substituted aryl and
optionally substituted aralkyl;
- R4 is selected from heterocycloalkyl and -NR5R6.
- R5 and R6 are independently selected from hydrogen and alkyl,
for the preparation of a medicament for the treatment and / or prevention of a disease, disorder or prophylaxis mediated by CB1 and / or CB2 cannabinoid receptors, AChE and / or BuChE enzymes and / or BACE-1 enzyme.
The present invention also refers to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable isomer, prodrug, salt or solvate thereof, and at least one pharmaceutically acceptable adjuvant, vehicle or excipient.
In addition, the present invention refers to the use of a compound of formula (I) or a pharmaceutically acceptable isomer, prodrug, salt or solvate thereof, for the manufacture of a medicament.
DETAILED DESCRIPTION OF THE INVENTION
In a first aspect, the present invention relates to a compound of general formula (I)
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OR
Ri
R
■ 2
image3
N
^ R.
■ 3
Formula (I)
its pharmaceutically acceptable salts, tautomers, prodrugs, solvates and hydrates where,
- n is selected between 1,2, 3 and 4;
- R1 and R2 are independently selected from hydrogen, halogen, -NO2 and -NH2;
- R3 is selected from cycloalkyl, heteroaryl, optionally substituted aryl and optionally substituted aralkyl;
- R4 is selected from heterocycloalkyl and -NR5R6;
- R5 and R6 are independently selected from hydrogen and alkyl.
The term "alkyl" refers in the present invention to aliphatic, linear or branched chains, having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, ferc- butyl, sec-butyl, n-pentyl or n-hexyl.
The term "optionally substituted aryl" refers in the present invention to an aromatic carbocyclic chain, having from 6 to 18 carbon atoms, being able to be single or multiple ring; in the latter case, with separate and / or condensed rings that it is not substituted or which may be optionally substituted with one more substituents selected from alkyl, halogen, hydroxy, -Oalkyl, -NO2, -NH2, phenyl or benzyloxy.For the present invention, a phenyl substituted by five hydrogen groups is outside the definition of aryl, so that phenyl substituted by five hydrogen groups would not be considered as an aryl.A non-limiting example of aryl is a substituted phenyl, diphenyl, naphthyl, indenyl, phenanthryl or anthracil.For the present invention, a "substituted phenyl" is a phenyl comprising 1 or more substituents selected from the group consisting of alkyl, halogen, hydroxyl, -Oalkyl, -NO2, -NH2, phenyl or benzyloxy.
The term "heteroaryl" refers to a stable ring radical of 5 to 18 members consisting of carbon atoms and one to five heteroatoms selected from the group
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which consists of nitrogen, oxygen and sulfur, preferably a 5 or 6 member ring containing one or more heteroatoms. The heteroaryl, according to this invention, may be a monocyclic or bicyclic ring system that may include condensed ring systems and the nitrogen atom may be optionally quaternized. Examples of heteroaryl radicals include but are not limited to, imidazole, pyrrole, pyridine, pyridazine, piperidine, pyrazine, quinoline, indole, thiophene, furan, oxazole and pyrazole.
The term "optionally substituted aralkyl" refers in the present invention to a stable, linear or branched aliphatic chain radical of 1 to 6 carbon atoms, attached to a phenyl substituted by five hydrogens or to an aryl of 6 to 18 atoms. of carbon which is not substituted or which is optionally substituted with one or more substituents selected from halogen, hydroxyl or -alkyl. Non-limiting examples of aralkyl are benzyl, 4-chlorobenzyl, 4-methoxybenzyl and phenethyl.
The term "cycloalkyl" refers to a stable radical of 3 to 10 membered monocyclic or bicyclic carbon chains, which is saturated or partially saturated, and which only consists of carbon and hydrogen atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.
The term "heterocycloalkyl" refers, in the present invention, to a stable monocyclic or bicyclic radical of 3 to 10 members, which is unsaturated, saturated or partially saturated, and consisting of carbon atoms and at least one heteroatom selected from the group consisting of nitrogen, oxygen or sulfur. The nitrogen atom can be optionally quaternized. Examples of heterocycloalkyl can be but not limited to: piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl or tetrahydrofuryl.
The term "halogen" refers, in the present invention, to bromine, chlorine, iodine or fluorine.
The compounds of the present invention represented by formula (I) may include isomers, including optical isomers or enantiomers, depending on the presence of chiral centers. The individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.
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It should be understood that the present invention encompasses all isomers of the compounds of formula (I), that is, all geometric, tautometric and optical forms, and mixtures thereof (eg, racemic mixtures). When there are more chiral centers in the compounds of formula (I), the present invention includes within its scope all possible diastereomers, including mixtures thereof. The different isomeric forms can be separated or resolved from one another by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific, stereoselective or asymmetric synthesis. The present invention also includes compounds labeled with isotopes, which are identical to those cited in formula (I) except that one or more atoms have been replaced by an atom that has an atomic mass or mass number different from the atomic mass or number mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine, such as 3H, 11C, 14C, 18F, 123I and
1251
Within the scope of the present invention are compounds of the present invention and pharmaceutically acceptable salts of said compounds containing the aforementioned isotopes and / or other isotopes of other atoms. The isotope-labeled compounds of the present invention, for example those in which radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and / or tissue distribution assays. Particularly preferred are tritium isotopes, i.e. 3H, and carbon-14, i.e. 14C, for their ease of preparation and detectability. Isotopes 11C and 18F are particularly useful in PET (positron emission tomograph), and isotopes 125I are particularly useful in SPECT (single photon emission computerized tomograph), all useful in brain imaging. In addition, substitution with heavier isotopes such as deuterium, that is, 2H, may provide some therapeutic advantages that result from increased metabolic stability, for example, may in vivo half-life or lower dosage requirements, and therefore, in Some cases may be preferred. The isotopically labeled compounds of formula (I) can generally be prepared by performing the procedures described in the examples below, substituting an isotopically unlabeled reagent for an easily available isotopically labeled reagent.
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The term "tautomer" or "tautomeric form", as used herein, refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, protonic tautomers (also known as prototropic tautomers ) which include interconversions by migrating a proton, such as keto-enolic or imine-enamine isomerizations, Valencia tautomers include interconversions by reorganization of some binding electrons.
It will be appreciated that, for pharmaceutical use, the salts mentioned above will be physiologically acceptable salts, but other salts may find utility, for example in the preparation of compounds of formula (I) and their acceptable physiological salts. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. The term "pharmaceutically acceptable salts" refers to salts prepared from non-toxic pharmaceutically acceptable bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines, and basic ionic exchange resins, such as arginine, betama, cafema, choline, N, N '-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucaine, resins, pipeline of polyamine, procama, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, dtrico, ethanesulfonic, fumaric, gluconic, glutamic, bromhydric, hydrochloric, isethionic, lactic, maleic, malico, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, pantothenic, pantothenic , sucdnic, sulfuric, tartaric, ptoluenesulfonic and the like.
Preferred examples of pharmaceutically acceptable salts include ammonium, calcium, magnesium, potassium and sodium salts, and those formed from maleic, fumaric, benzoic, ascorbic, pamoic, sucdnic, chlorhydric, sulfuric, bismethylenesalidyl acids,
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methanesulfonic, ethanedisulfonic, propionic, tartaric, salicylic, chloric, gluconic, aspartic, stearic, palmetic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, phosphoric and nitric.
Particularly preferred derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (for example, by making a compound administered orally more easily absorbed by the blood), or that enhance the release of the original compound in a biological compartment (for example, a tumor) in relation to the original species.
Any compound that is a prodrug of a compound of formula (I) is within the scope of the invention. The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo into the compounds of the invention. 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, salt sulphonate esters metal, carbamates and amides.
The compounds of formula (I) 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. Solvation methods are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment, the solvate is a hydrate.
The compounds of formula (I) or their salts or solvates are preferably in a pharmaceutically acceptable or substantially pure form. Pharmaceutically acceptable means, among others, that they have 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 its salts, solvates or prodrugs.
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In a more preferred embodiment, the present invention relates to a compound of general formula (I) wherein R 3 is selected from 1-naphthyl, 2-naphthyl, 4-tolyl, 3,4,5-trimethylphenyl, 2-benzyloxyphenyl, 3 , 4,5-Trimethoxyphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,6-dichlorophenyl, 2,3,6-trifluorophenyl, 2-chlorophenyl, 3-fluorophenyl, 3-chloro-2-fluorophenyl, 4 - biphenyl, 4-chlorobenzyl, 4-methoxybenzyl and 1-adamantyl.
In a still more preferred embodiment, the present invention relates to a compound of general formula (I) wherein R 3 is selected from 1-naphthyl, 2-naphthyl, 2-benzyloxyphenyl, 2,3-dichlorophenyl and 4-methoxybenzyl.
In a preferred embodiment, the present invention relates to a compound of general formula (I) wherein R 4 is selected from heterocycloalkyl, diisopropylamino, dimethylamino and diethylamino.
In a more preferred embodiment, the present invention relates to a compound of general formula (I) wherein R 4 is a heterocycloalkyl.
In a still more preferred embodiment, the present invention relates to a compound of general formula (I) wherein R4 is selected from piperidinyl, morpholinyl and pyrrolidinyl.
In an even more preferred embodiment, the present invention relates to a compound of general formula (I) wherein R 4 is piperidinyl.
In a preferred embodiment, the present invention relates to a compound of general formula (I) where n is selected from 2 to 3.
In a preferred embodiment, the present invention relates to a compound of general formula (I) wherein R 4 is a heterocycloalkyl and R 3 is selected from 1-naphthyl, 2-naphthyl and substituted phenyl.
In another preferred embodiment, the present invention relates to a compound of general formula (I) wherein R4 is a heterocycloalkyl, R3 is selected from 1-naphthyl, 2- naphthyl or substituted phenyl and R1 and R2 are independently selected from hydrogen and halogen.
In a preferred embodiment, the present invention relates to a compound of general formula (I) wherein R4 is -NR5R6 and R3 is selected from heteroaryl, optionally substituted aryl and optionally substituted aralkyl.
In a more preferred embodiment, the present invention relates to a compound of general formula (I) wherein R4 is -NR5R6 and R3 is selected from 1-naphthyl, 2-naphthyl and substituted phenyl.
In a more preferred embodiment, the present invention relates to a compound of general formula (I) wherein R4 is -NR5R6, R3 is selected from 1-naphthyl, 2-naphthyl or substituted phenyl and R1 and R2 are independently selected from hydrogen and halogen.
In a preferred embodiment, the compound of general formula (I) is selected from the list comprising:
(1-Naphthyl) (3- (2-piperidinoethoxy) -5-nitro-1-indazolyl) ketone (NP40)
(2,3-dichlorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1-
indazolyl) ketone
(3- (2- (diisopropylamino) ethoxy5-nitro-1-indazolyl) (4-
tolyl) ketone
(2-Naphthyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone
(3- (2- (diethylamino) ethoxy) -1-indazolyl) (4-tolyl) ketone
(3- (2- (dimethylamino) ethoxy) -1-indazolyl) (1-naphthyl) ketone
(2,3-dichlorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -5-nitro-1-
indazolyl) ketone
(NP43)
(NP46)
(NP73)
(NP75)
(NP76)
(NP79)
(3- (2- (1-Pyrrolidinyl) ethoxy) -1-indazolyl) (2-thienyl) ketone
(4-biphenylyl) (3- (2- (diisopropylamino) ethoxy) -1-
indazolyl) ketone
(2,4,6-trimethylphenyl) (3- (2-piperidinoethoxy) -1-
indazolyl) ketone
(1-adamantyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone
(4-Chloro-3-pyridyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone
(3- (2-morpholinoethoxy) -1-indazolyl) (1-naphthyl) ketone
(2,3-dichlorophenyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone
(2-Chlorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1-indazolyl) ketone
(2,3-Difluorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1-
indazolyl) ketone
(3-fluorophenyl) (3- (2- (dimethylamino) ethoxy) -1-
indazolyl) ketone
(2,3,6-trifluorophenyl) (3- (2-piperidinoethoxy) -1-
indazolyl) ketone
(2,3-dichlorophenyl) (3- (2- (dimethylamino) ethoxy) -1-
indazolyl) ketone
(3,4,5-trimethoxyphenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1-
indazolyl) ketone
(3- (2- (diisopropylamino) ethoxy) -1-indazolyl) (4-
methoxyphenyl) ketone
(2,6-dichlorophenyl) (3- (3- (dimethylamino) propoxy) -1-
indazolyl) ketone
(2,6-Dichlorophenyl) 2- (2- (piperidinoethoxy) -1-indazolyl) ketone
(2,3-dichlorophenyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(2,3-dichlorophenyl) (3- (2-morpholinoethoxy) -1-
indazolyl) ketone
(4-biphenylyl) (3- (3- (dimethylamino) propoxy) -1-
indazolyl) ketone
(1-Naphthyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone
(3- (3- (dimethylamino) propoxy) -1-indazolyl) (4-
methoxyphenyl) ketone
(NP91)
(NP93)
(NP94)
(NP100)
(NP101)
(NP104)
(NP107)
(NP108)
(NP111)
(NP113)
(NP116)
(NP117)
(NP118)
(NP119)
(NP120)
(NP121)
(NP123)
(NP124)
(NP125)
(2-Chlorophenyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone
(2,4,6-trimethylphenyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(3-Chloro-2-fluorophenyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(4-Chlorobenzyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(4-methoxybenzyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(1-naphthyl) (3- (3-piperidinopropoxy) -6-chloro-1-
indazolyl) ketone
(2-benzyloxyphenyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(1-Naphthyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone
(2-Naphthyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone
(1-Naphthyl) (3- (3- (1-pyrrolidinyl) propoxy) -1-indazolyl) ketone
(4-biphenylyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone
(2-benzyloxyphenyl) (3- (2-piperidinoethoxy) -5-nitro-1-
indazolyl) ketone
(2,3-dichlorophenyl) (3- (3-piperidinopropoxy) -5-nitro-1-
indazolyl) ketone
(2-benzyloxyphenyl) (3- (2-piperidinopropoxy) -5-nitro-1-
indazolyl) ketone
(1-naphthyl) (3- (3-piperidinopropoxy) -5-nitro-1-
indazolyl) ketone
(2-benzyloxyphenyl) (3- (2-piperidinoethoxy) -5-amino-1-
indazolyl) ketone
(2,3-dichlorophenyl) (3- (3-piperidinopropoxy) -5-amino-1-
indazolyl) ketone
(2-benzyloxyphenyl) (3- (2-piperidinopropoxy) -5-amino-1-
indazolyl) ketone
(1-naphthyl) (3- (2-piperidinopropoxy) -5-amino-1-
indazolyl) ketone
(6-Chloro-3- (2-piperidinoethoxy) -1-indazolyl) (1-
(NP129)
(NP132)
(NP137)
(NP145)
(NP148)
(NP152)
(NP153)
(NP154)
(NP174)
(NP181)
(NP182)
(NP183)
(NP184)
(NP192)
(NP193)
(NP194)
(NP195)
(NP196)
naphthyl) (ketone)
(2-benzyloxyphenyl) (5-chloro-3- (3-piperidinopropoxy) -1- (NP197)
indazolyl) ketone
In a more preferred embodiment, the compound of general formula (I) is selected from the list comprising:
(2,3-dichlorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1- (NP43)
indazolyl) ketone
(2,3-dichlorophenyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP101) (2,3-dichlorophenyl) (3- (3-piperidinopropoxy) -1- (NP120)
indazolyl) ketone
(1-Naphthyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone (NP124)
(4-methoxybenzyl) (3- (3-piperidinopropoxy) -1- (NP137)
indazolyl) ketone
(1-naphthyl) (3- (3-piperidinopropoxy) -6-chloro-1- (NP145)
indazolyl) ketone
(2-benzyloxyphenyl) (3- (3-piperidinopropoxy) -1- (NP148)
indazolyl) ketone
(1-Naphthyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP152)
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According to the present specification, any of the compounds defined above, that is, those compounds that respond to the general formula (I), can also be referred to herein as "compound or compounds of the invention".
In a second aspect, the present invention relates to the use of a compound of general formula (I)
 Rk  . / VN O '
 Ip ^ l
 R2 '    N
Wn-R N
O '' R3
Formula (I) 17
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its pharmaceutically acceptable salts, tautomers, prodrugs, solvates and hydrates where,
- n is selected between 1,2, 3 and 4;
- R1 and R2 are independently selected from hydrogen, halogen, -NO2 and -NH2;
- R3 is selected from cycloalkyl, heteroaryl, optionally substituted aryl and
optionally substituted aralkyl;
- R4 is selected from heterocycloalkyl and -NR5R6;
- R5 and R6 are independently selected from hydrogen and alkyl, for
preparation of a medicament for the treatment and / or prevention of a disease, disorder or prophylaxis mediated by CB1 and / or CB2 cannabinoid receptors, AChE and / or BuChE cholinergic enzymes and / or BACE-1 enzyme.
In a preferred embodiment, the present invention relates to the use of a compound of general formula (I) wherein R 3 is selected from optionally substituted aryl, optionally substituted aralkyl, 2-thienyl and 4-chloro-3-pyridyl.
In a more preferred embodiment, the present invention relates to the use of a compound of general formula (I) wherein R 3 is selected from 1-naphthyl, 2-naphthyl, 4-tolyl, 3,4,5-trimethylphenyl, 2-benzyloxyphenyl , 3,4,5-trimethoxyphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,6-dichlorophenyl, 2,3,6-trifluorophenyl, 2-chlorophenyl, 3-fluorophenyl, 3-chloro-2-fluorophenyl , 4- biphenyl, 4-chlorobenzyl, 4-methoxybenzyl and 1-adamantyl.
In a still more preferred embodiment, the present invention relates to the use of a compound of general formula (I) wherein R 3 is selected from 1-naphthyl, 2-naphthyl, 2- benzyloxyphenyl, 2,3-dichlorophenyl and 4-methoxybenzyl.
In a preferred embodiment, the present invention relates to the use of a compound of general formula (I) wherein R4 is selected from heterocycloalkyl, diisopropylamino, dimethylamino and diethylamino.
In a more preferred embodiment, the present invention relates to the use of a compound of general formula (I) wherein R 4 is a heterocycloalkyl.
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In an even more preferred embodiment, the present invention relates to the use of a compound of general formula (I) where R 4 is piperidinyl.
In a preferred embodiment, the present invention relates to the use of a compound of general formula (I) where n is selected from 2 to 3.
In a preferred embodiment, the present invention relates to the use of a compound of
general formula (I) where R4 is a heterocycloalkyl and R3 is selected from 1-naphthyl, 2-
Naphthyl and substituted phenyl.
In a more preferred embodiment, the present invention relates to the use of a compound of general formula (I) wherein R4 is a heterocycloalkyl and R3 is selected from 1-naphthyl, 2- naphthyl, 2-benzyloxyphenyl, 2,3-dichlorophenyl and 4-methoxybenzyl.
In another preferred embodiment, the present invention relates to the use of a compound of general formula (I) wherein R4 is a heterocycloalkyl, R3 is selected from 1-naphthyl, 2- naphthyl or substituted phenyl and R1 and R2 are independently selected from hydrogen and halogen.
In a preferred embodiment, the present invention relates to the use of a compound of
general formula (I) where R4 is -NR5R6 and R3 is selected from heteroaryl, aryl
optionally substituted and optionally substituted aralkyl.
In a more preferred embodiment, the present invention relates to the use of a compound of general formula (I) wherein R4 is -NR5R6 and R3 is selected from 1-naphthyl, 2-naphthyl and substituted phenyl.
In a more preferred embodiment, the present invention relates to the use of a compound of general formula (I) wherein R4 is -NR5R6, R3 is selected from 1-naphthyl, 2-naphthyl or substituted phenyl and R1 and R2 are independently selected from hydrogen and halogen.
In a preferred embodiment, the compound of general formula (I) is selected from the list comprising:
(1-Naphthyl) (3- (2-piperidinoethoxy) -5-nitro-1-indazolyl) ketone (NP40) (2,3-dichlorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1- ( NP43)
indazolyl) ketone
(3- (2- (diisopropylamino) ethoxy5-nitro-1-indazolyl) (4- (NP46)
tolyl) ketone
(2-Naphthyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP73)
(3- (2- (diethylamino) ethoxy) -1-indazolyl) (4-tolyl) ketone (NP75)
(3- (2- (dimethylamino) ethoxy) -1-indazolyl) (1-naphthyl) ketone (NP76)
(2,3-dichlorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -5-nitro-1- (NP79)
indazolyl) ketone
(3- (2- (1-Pyrrolidinyl) ethoxy) -1-indazolyl) (2-thienyl) ketone (NP83)
(4-biphenylyl) (3- (2- (diisopropylamino) ethoxy) -1- (NP89)
indazolyl) ketone
(2,4,6-trimethylphenyl) (3- (2-piperidinoethoxy) -1- (NP91)
indazolyl) ketone
(1-adamantyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP93)
(4-Chloro-3-pyridyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP94)
(3- (2-morpholinoethoxy) -1-indazolyl) (1-naphthyl) ketone (NP100)
(2,3-dichlorophenyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP101)
(2-Chlorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1-indazolyl) ketone (NP104)
(2,3-Difluorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1- (NP107)
indazolyl) ketone
(3-fluorophenyl) (3- (2- (dimethylamino) ethoxy) -1- (NP108)
indazolyl) ketone
(2,3,6-trifluorophenyl) (3- (2-piperidinoethoxy) -1- (NP111)
indazolyl) ketone
(2,3-dichlorophenyl) (3- (2- (dimethylamino) ethoxy) -1- (NP113)
indazolyl) ketone
(3,4,5-trimethoxyphenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1- (NP116)
indazolyl) ketone
(3- (2- (diisopropylamino) ethoxy) -1-indazolyl) (4- (NP117)
methoxyphenyl) ketone
(2,6-dichlorophenyl) (3- (3- (dimethylamino) propoxy) -1-
indazolyl) ketone
(2,6-Dichlorophenyl) 2- (2- (piperidinoethoxy) -1-indazolyl) ketone
(2,3-dichlorophenyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(2,3-dichlorophenyl) (3- (2-morpholinoethoxy) -1-
indazolyl) ketone
(4-biphenylyl) (3- (3- (dimethylamino) propoxy) -1-
indazolyl) ketone
(1-Naphthyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone
(3- (3- (dimethylamino) propoxy) -1-indazolyl) (4-
methoxyphenyl) ketone
(2-Chlorophenyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone
(2,4,6-trimethylphenyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(3-Chloro-2-fluorophenyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(4-Chlorobenzyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(4-methoxybenzyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(1-naphthyl) (3- (3-piperidinopropoxy) -6-chloro-1-
indazolyl) ketone
(2-benzyloxyphenyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(1-Naphthyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone
(2-Naphthyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone
(1-Naphthyl) (3- (3- (1-pyrrolidinyl) propoxy) -1-indazolyl) ketone
(4-biphenylyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone
(2-benzyloxyphenyl) (3- (2-piperidinoethoxy) -5-nitro-1-
indazolyl) ketone
(2,3-dichlorophenyl) (3- (3-piperidinopropoxy) -5-nitro-1-
indazolyl) ketone
(NP118)
(NP119)
(NP120)
(NP121)
(NP123)
(NP124)
(NP125)
(NP127)
(NP128)
(NP129)
(NP132)
(NP137)
(NP145)
(NP148)
(NP152)
(NP153)
(NP154)
(NP174)
(NP181)
(NP182)
 (2-benzyloxyphenyl) (3- (2-piperidinopropoxy) -5-nitro-1- indazolyl) ketone  (NP183)
 (1-Naphthyl) (3- (3-piperidinopropoxy) -5-nitro-1- indazolyl) ketone  (NP184)
 (2-benzyloxyphenyl) (3- (2-piperidinoethoxy) -5-amino-1- indazolyl) ketone  (NP192)
 (2,3-dichlorophenyl) (3- (3-piperidinopropoxy) -5-amino-1- indazolyl) ketone  (NP193)
 (2-benzyloxyphenyl) (3- (2-piperidinopropoxy) -5-amino-1- indazolyl) ketone  (NP194)
 (1-Naphthyl) (3- (2-piperidinopropoxy) -5-amino-1- indazolyl) ketone  (NP195)
 (6-Chloro-3- (2-piperidinoethoxy) -1-indazolyl) (1- naphthyl) (ketone)  (NP196)
 (2-benzyloxyphenyl) (5-chloro-3- (3-piperidinopropoxy) -1-indazolyl) ketone  (NP197)
In a more preferred embodiment, the compound of general formula (I) is selected from the list comprising:
(2,3-dichlorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1- (NP43)
indazolyl) ketone
(2,3-dichlorophenyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP101) (2,3-dichlorophenyl) (3- (3-piperidinopropoxy) -1- (NP120)
indazolyl) ketone
(1-Naphthyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone (NP124)
(4-methoxybenzyl) (3- (3-piperidinopropoxy) -1- (NP137)
indazolyl) ketone
(1-naphthyl) (3- (3-piperidinopropoxy) -6-chloro-1- (NP145)
indazolyl) ketone
(2-benzyloxyphenyl) (3- (3-piperidinopropoxy) -1- (NP148)
indazolyl) ketone
(1-Naphthyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP152)
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In a third aspect, the invention relates to a pharmaceutical composition comprising the compound of formula (I), as described above and at least one excipient, adjuvant and / or a pharmaceutically acceptable carrier. In addition, it is contemplated that the pharmaceutical composition contains another active ingredient.
Pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I), its pharmaceutically acceptable isomers, prodrugs, salts or solvates thereof, together with pharmaceutically acceptable carriers, constitute a further aspect of the present invention. It refers to a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the invention. Hereinafter, said pharmaceutical composition may also be referred to as "pharmaceutical composition of the invention".
The term "vehicle" refers to a diluent, adjuvant or excipient with which the active substance is administered. Such pharmaceutical vehicles may be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solutions of saline solution and aqueous solutions of dextrose and glycerol, particularly for injectable solutions, are preferably used as vehicles. Suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences" by EW Martin, 1995. Preferably, the vehicles of the invention are approved by the regulatory agency of a state government or a federal government, or are listed in the United States Pharmacopoeia, in the European Pharmacopoeia or other pharmacopoeia generally recognized for use in animals, and more particularly in humans.
The amount of compound of the invention, its pharmaceutically acceptable isomers, prodrugs, salts or solvates thereof, therapeutically effective to be administered (also referred to herein as "therapeutically effective or effective amount"), as well! As its dosage to treat a pathological state with said compounds, it will depend on numerous factors, among which are the age, the patient's condition, the severity of the disease, the route and frequency of administration, the modulating compound to be used, etc. .
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The compounds and pharmaceutical compositions of this invention can be used alone or together with other drugs to provide a combination therapy. The other drugs may be part of the same pharmaceutical composition, or be provided as a separate pharmaceutical composition, for administration at the same time or at a different time. Examples of pharmaceutical compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) for oral, topical or parenteral administration.
The present invention also relates to the compounds of formula (I) as previously defined for the manufacture of a medicament.
Another aspect of the present invention relates to the use of the compounds of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above or a pharmaceutically tautomer, prodrug, salt or solvate acceptable for the preparation of a drug or pharmaceutical composition for the treatment and / or prevention of diseases, where CB1 and / or CB2 cannabinoid receptors, AChE and / or BuChE cholinergic enzymes, and / or BACE-1 enzyme Neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and dementias are implicated, for example, but not limited to, dementia with Lewy bodies.
The compounds of general formula (I) are modulators of the CB1 and / or CB2 cannabinoid receptors, the AChE and / or BuChE cholinergic enzymes, and / or the BACE-1 enzyme, therefore said compounds can be used for the treatment and / or prevention of diseases in which said receptors and enzymes are involved.
In a preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above, a tautomer, prodrug, salt or solvate pharmaceutically acceptable thereof, for the manufacture of a medicament for the treatment of a disease where CB1 and / or CB2 cannabinoid receptors are relevant.
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In a preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above, a tautomer, prodrug, salt or solvate pharmaceutically acceptable thereof, for the manufacture of a medicament for the treatment of a disease where the cholinergic enzymes AChE and / or BuChE are relevant.
In a preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above, a tautomer, prodrug, salt or solvate pharmaceutically acceptable thereof, for the manufacture of a medicament for the treatment of a disease the enzyme BACE-1 is relevant.
In a more preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above, a tautomer, prodrug, salt or pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of a disease where CB1 and / or CB2 cannabinoid receptors and to AChE and / or BuChE cholinergic enzymes are relevant.
In an even more preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above, a tautomer, prodrug, salt or pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of a disease where CB1 and / or CB2 cannabinoid receptors, AChE and / or BuChE cholinergic enzymes and BACE-1 enzyme are relevant.
In a preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above or a tautomer, prodrug, salt or solvate pharmaceutically acceptable thereof, for the manufacture of a medicament for the treatment of Alzheimer's diseases, amyotrophic lateral sclerosis and multiple sclerosis.
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In a preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above or a tautomer, prodrug, salt or solvate pharmaceutically acceptable thereof, for the manufacture of a medicament for the treatment of amyotrophic lateral sclerosis (ALS).
In a preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above or a tautomer, prodrug, salt or solvate pharmaceutically acceptable thereof, for the manufacture of a medicament for the treatment of multiple sclerosis (MS).
In a more preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above or a tautomer, prodrug, salt or pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of Alzheimer's disease (AD).
In a preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above or a tautomer, prodrug, salt or solvate pharmaceutically acceptable thereof, for the manufacture of a medicament for the treatment of dementia.
In a more preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above or a tautomer, prodrug, salt or pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of dementia with Lewy bodies.
According to the present description, the use of a compound of the invention or of a pharmaceutical composition for the manufacture of a medicament or alternatively its use as a medicament, for the treatment of a disorder or disease that can potentially be regulated by modulating the receptors CB1 and / or CB2 cannabinoids,
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Cholinergic enzymes AChE and / or BuChE and / or the enzyme BACE-1, can obviously be understood as a method of treatment of such disorder or disease, which comprises the administration to a subject of a therapeutically effective amount of said compound or pharmaceutical composition of the invention In other words, the present invention also relates to a method of treating a disorder or disease (preferably selected from Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and dementia with Lewy bodies, and more preferably Alzheimer's) that it comprises administering to a subject the compound of the invention in a therapeutically effective amount, or a pharmaceutical composition of the invention comprising the compound of the invention in a therapeutically effective amount.
Thanks to their cannabinoid and / or cholinergic and / or modulating properties of the p-amyloid peptide, the compounds according to the invention can be used as active ingredients of medicaments intended for prophylaxis or for the treatment of disorders in which cannabinoid receptors are involved and / or cholinergic receptors and / or BACE-1.
Another aspect of the invention relates to the use of the compounds of formula (I) of the present invention for use as pharmacological tools for the pharmacological characterization of the receptors involved.
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 invention relates to a process for obtaining the compounds of general formula (I) according to the following reaction scheme.
Scheme 1
 OH
 RlN    r-O R3-CO-Cl R1
 [N. ---------------- ►
 R2 ^    N] IV R2
 H
image4
OH N
OR
'(CH2) n-R4
W. X- (CH2) n-R4 Rl
OR

V
R3
R2
image5
N N
O ^ R3
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The synthetic route described in scheme 1 comprises different stages:
The first consists in the preparation of compounds of general formula (II) from the 1H-indazol-3-ol derivatives of general formula (III) where R1 and R2 have the aforementioned significance, by reaction with the corresponding chlorides of general formula (IV) acid where R3 has the aforementioned significance.
The second step consists in the preparation of the carbonyl derivatives of 1-indazolyl of the general formula (I) from the derivatives of the general formula (II), by reaction with the corresponding halides of the general formula (V), where R 4 has the aforementioned meaning
DESCRIPTION OF THE FIGURES
Figure 1. Agonist effect of carbonyl derivatives of 1-indazolyl. The agonist effect (expressed as% inhibition of electrically induced contraction in the mouse vas deferens) of the selected compounds is shown. They all show cannabinoid activity, in many cases similar or superior to that of the reference compound WIN 55, 212-2.
The compounds of the present invention shown in Figure 1 show a concentration-dependent inhibition of the contraction induced by electrical stimulation of the preparations, this effect being blocked by the addition of CB1 AM251 or CB2 AM630 antagonists (Figure 2), which demonstrates the cannabinoid agonist effect of carbonyl derivatives of 1-indazolyl.
Figure 2. Blocking the agonist effect of carbonyl derivatives of 1-indazolyl. Be
shows the blockade of the agonist effect of the selected 1-indazolyl carbonyl derivatives and of the reference compound WIN 55, 212-2, induced by CB1 or CB2 antagonists, AM251 (10-6 M) and AM630 (10-6 M) respectively. Statistical significance: * p <0.05, ** p <0.01, *** p <0.001: Inhibitory effect of the contraction of the selected compounds at the concentration of 8.1 x 10-6 M in the presence vs. absence of the AM251 or AM630 antagonists (2-vl ANOVA, Bonferroni).
Figure 3. Effects of NP137 and NP148 on cell viability and proliferative activity.
(A) For MTT assays 200,000 cells were seeded per well, in triplicates on a 96 plate, in the presence of increasing concentrations (0-20 pM) of NP137 and NP148, for 72 hours. (B) Lymphoblasts were cultured at a density of 1x106 cells x 5 mL-1 in the presence and absence of 5 pM of NP133 and NP148. 72 hours later, they were performed
counts of the number of cells in the TC10TM cell counter of Bio-Rad Laboratories S.A. The values represented reflect the mean ± SEM of several different experiments carried out in 9 control individuals and 11 AD patients. | p <0.01 significantly different from untreated AD lymphoblasts.
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In Fig. 3B it is shown that the proliferative rate of EA lymphoblasts was significantly higher than that of control cells according to previous results (Munoz, U., et al., Neurobiol Aging 2008, 29, 1474-84) and that the administration of NP137 and NP148 at a concentration of 5 DM effectively reduces the rate of cell proliferation in lymphoblasts
15 of control patients without significantly affecting the control lymphoblasts. The antiproliferative effect of CB2 agonists is accompanied by the blockage of overactivation of PI3K / Akt, and hyperphosphorylation of protelna pRb in EA lymphoblasts after 72 hours of serum stimulation (Fig. 3B)
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Figure 4. Effects of NP137 and NP148 on cell proliferation and phosphorylation status of Akt and pRb
Lymphoblasts from control and EA individuals were seeded at an initial density of 1x106 cells xml-1 in RPMI medium with 10% serum, in the presence of 5 pM NP137 or NP148 for three days. Proliferation was determined by cell count in an automatic counter and protein levels determined by Western blot. The values show the mean ± the standard error of four independent experiments taken from cell lines of different individuals. *** p <0.011 significantly different from the control cell values; |, |, p <0.05, p <0.01 significantly different from the values of EA lymphoblasts in the absence of CB2 agonists.
Ultimately, these results show that the CB2 agonists tested are capable of reversing the abnormal response to serum of lymphoblasts in patients with Alzheimer's disease. In order to validate these results obtained in patients' extraneural cells, we proceeded to assess the neuroprotective potential of these compounds in primary cultures of rat cortical neurons treated with the p-amyloid peptide. Figure 4 shows the results of these experiments. It can be seen that both compounds reverse p-family-induced cell death.
Figure 5 Effect of the addition of NP137 and NP148 on the survival of primary cultures of cortical neurons.
A total of 30,000 cells per well were incubated in 96-well plates with DMEM medium for 72 hours in the absence or presence of 5 pM PGN 137 and PGN 148 for 1 h before the administration of 5 pM p-amyloid. MTT reduction was measured. The columns represent the mean ± standard error of five experiments in triplicate. *** p> 0.001 significantly different from untreated cells. |; m p <0.05, 0.001 significantly different from cells treated only with p-amyloid.
Figure 6. Effect of the NP43 derivative on the expression of the iNOS and COX-2 enzymes, and the TNF-alpha and IL1b cytokines.
The results obtained indicate that the compound tested NP43 (PGN) has anti-inflammatory activity, according to the decreases observed in the expression of the enzymes iNOS and COX-2, as well as the cytokines TNF-alpha and IL1b.
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Figure 7. Effect of derivative NP137 in animal model of Alzheimer's disease (male mouse Tg APP).
WT means "wild type" and refers to the use of wild-type mice; veh means vehicle; APP means "amyloid precursor protein" or early amyloid precursor; Tg means "transgenic mice" or transgenic mouse. In the graphs, the ordinate axis indicates the time elapsed in days while the axis of the abscissa indicates latency in seconds or what is the same, the time elapsed from the moment of administration until the pharmacological effect begins.
EXAMPLES AND MODE OF EMBODIMENT OF THE INVENTION
The invention is illustrated below by tests carried out by the inventors, which show the effectiveness of the compounds of the invention.
EXAMPLE 1. General procedure for the synthesis of carbonyl derivatives of 1- indazolyl.
To a suspension of a carbonyl derivative of 1-indazolyl in K2CO3 and 2-butanone, the corresponding halide and KI in catalytic amounts are added. The mixture is refluxed and, once the reaction is finished, it is allowed to cool and the solvent is evaporated in vacuo. The reaction crude is dissolved in chloroform and extracted with water. The organic phase is taken to dryness and purified in each case. The reaction and purification conditions are described for each compound individually.
Preparation and obtaining (2,3-dichlorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1-
indazolyl) ketone (NP43).
It is made from 154 mg (0.50 mmol) of (2,3-dichlorophenyl) (3-hydroxy-1-indazolyl) ketone, 86 mg (0.51 mmol) of 1- (2-chloroethyl) hydrochloride pyrrolidine, 135.4 mg (0.98 mmol) of K2CO3, KI in catalytic amounts and 25 mL of 2-butanone The reaction crude is purified by column chromatography with the solvent mixture water: methanol (50: 1). Reaction time: 16 h. Yield: 173 mg (86%) Oil.
1H-NMR (CDCl3) □: 8.50 (d, 1H, 4-H); 7.71 (d, 1H, 7-H); 7.63 (t, 1H, 5-H); 7.57 (dd, 1H, Ar); 7.40 (m, 2H, Ar); 7.31 (t, 1H, 6-H); 4.38 (t, 2H, 1 ’- H); 2.88 (t, 2H, 2 ’- H); 2.56 (s, 4H, 4-H ’); 1.78 (m, 4H, 5-H ’‘). 13C-NMR (CDCl3) □: 165.3 (C-1 ’); 160.3 (C-3); 140.6 (C-7a); 137.5 (C, Ar); 133.3 (C, Ar); 131.4 (C, Ar); 130.6 (C-5); 127.2 (C-6); 127.0 (C, Ar); 125.0 (C, Ar); 120.1
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EXAMPLE 2. Preparation and obtaining (2,3-dichlorophenyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone (NP120)
Following the procedure of Example 1, it is made from 250 mg (0.81 mmol) of (2,3-dichlorophenyl) (3-hydroxy-1-indazolyl) ketone, 188 mg (0.98 mmol) of hydrochloride of 1- (3- chloropropyl) piperidine, 224 mg (1.62 mmol) of K2CO3, KI in catallotic amounts and 50 mL of 2-butanone. The reaction crude is dissolved in dichloromethane and, by adding a small amount of hexane, precipitates the pure final product that is recovered by filtration. Reaction time: 72 h. Yield: 184 mg (52%).
P.F. = 85-88 ° C. 1H-NMR (CDCh) □: 8.51 (d, 1H, 4-H); 7.70 (d, 1H, 7-H); 7.63 (d, 1H, 5-H); 7.58 (dd, 1H, Ar); 7.40 (m, 2H, Ar); 7.31 (t, 1H, 6-H); 4.27 (t, 2H, 1 ’- H); 2.42 (m, 6H, 3 ’- H, 5’ - H); 1.98 (m, 2H, 2 ’- H); 1.58 (m, 4H, 6 ’- H); 1.44 (m, 2H, 7 ’- H). 13C-NMR (CDCl3) □: 164.2 (C-1 ’); 159.4 (C-3); 139.6 (C-7a); 136.5 (C, Ar); 132.2 (C, Ar); 130.4 (C, Ar); 129.5 (C-5);
129.0 (C, Ar); 126.2 (C, Ar); 126.1 (C, Ar); 123.9 (C-6); 118.9 (C-7); 117.6 (C-3a); 115 (C-4); 67.3 (C-1 ’); 54.8 (C-2 ’); 53.51 (C-5 ’); 25.2 (C-3 ’); 24.8 (C-5 ’); 23.3 (C-6 ’). HPLC-MS (ES +): acetonitrile / water 15/85, tg: 7 min., Tr: 3.28, [M + H] + = 433.05.
EXAMPLE 3. Preparation and obtaining (1-naphthyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone (NP124)
Following the procedure of Example 1, it is made from 250 mg (0.87 mmol) of (3- hydroxy-1-indazolyl) (1-naphthyl) ketone, 213 mg (1.04 mmol) of 1- hydrochloride (3- chloropropyl) piperidine, 240 mg (1.74 mmol) of K2CO3, KI in catallotic amounts and 50 mL of 2-butanone. The reaction crude is purified by flash chromatography with the dichloromethane: methanol solvent mixture (96: 4). Reaction time: 72 h. Yield: 161 mg (47%).
P.F. = 83-86 ° C. 1H-NMR (CDCh) □: 8.55 (d, 1H, 4-H); 7.95 (m, 3H, Ar); 7.77 (dd, 1H, Ar); 7.69 (d, 1H, 7-H); 7.64 (t, 1H, 5-H); 7.57 (t, 1 H, Ar); 7.49 (m, 2H, Ar); 7.40 (t, 1H, 6-H); 4.16 (t, 2H, 1 ’- H); 2.35 (m, 6H, 3 ’- H, 5’ - H); 1.89 (t, 2H, 2 ’- H); 1.55 (m, 4H, 6 ’- H); 1.41 (m, 2H, 6 ’- H). 13C-NMR (CDCl3) □: 168.8 (C-1 ’); 160.2 (C-3); 141.6 (C-7a); 133.8 (C, Ar); 133.0 (C, Ar); 131.2 (C, Ar); 130.8 (C, Ar); 128.7 (C-5); 127.9 (C, Ar); 127.2 (C, Ar); 126.5 (C, Ar);
126.0 (C, Ar); 125.0 (C, Ar); 124.8 (C-6); 120.3 (C-7); 118.7 (C-3a); 116.6 (C-4); 68.4 (C-1 ’);
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EXAMPLE 4. Preparation and obtaining (4-methoxybenzyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone (NP137)
Following the procedure of Example 1, it is made from 972.0 mg (3.44 mmol) of (3- hydroxy-1-indazolyl) (4-methoxybenzyl) ketone, 818.5 (4.13 mmol) of hydrochloride 1- (3- chloropropyl) piperidine, 1420.4 mg (10.32 mmol) of K2CO3, KI in catallotic amounts and 60 mL of 2-butanone. The reaction crude is purified by flash chromatography with the dichloromethane: methanol solvent mixture (75:25). Reaction time: 24h. Yield: 148.0 mg (11%).
P.F. = 67-69 ° C. 1H-NMR (CDCh) □: 8.33 (d, 1H, 4-H); 7.62 (d, 1H, 7-H); 7.52 (td, 1H, 5-H); 7.30 (m, 2H, 6-H, Ar); 6.86 (d, 1 H, Ar); 4.54 (t, 2H, 1 ’- H); 4.30 (s, 2H, H-2 ’); 3.78 (OCH3); 2.58 (m, 6H, 3 ’- H, 5’ - H); 2.20 (m, 2H, 2 ’- H); 1.70 (m, 4H, H6 ’); 1.49 (m, 2H, 7 ’- H). 13C-NMR (CDCl3) □: 169.8 (C-1 ’); 158.2 (C-3); 157.6 (C, Ar); 139.7 (C-7a); 129.7 (C, Ar); 129.3 (C-5); 125.5 (C, Ar); 123.1 (C-6); 118.6 (C-7); 116.8 (C-3a); 114.9 (C-4); 113.0 (C, Ar); 66.8 (C-1 ’); 54.7 (C-3 ’); 54.3 (C-2 ’); 53.4 (C-5 ’); 39.8 (OCH3); 24.9 (C-2 ’); 24.3 (C-6 ’); 23.0 (C-7 ’). HPLC-MS (ES +): acetonitrile / water 15/85, tg: 8 min., Tr: 3.06, [M + H] = 409.
EXAMPLE 5. Preparation and obtaining of (1-naphthyl) (3- (3-piperidinopropoxy) -6-chloro-1- indazolyl) ketone (NP145)
Following the procedure of Example 1, it is made from 100 mg (0.31 mmol) of (6- chloro-3-hydroxy-1-indazolyl) (1-naphthyl) ketone, 76 mg (0.37 mmol) of 1- (3- Chloropropyl) piperidine hydrochloride, 128 mg (0.93 mmol) of K2CO3, KI in cataloge amounts and 40 mL of 2-butanone. The reaction crude is purified by flash chromatography with the dichloromethane: methanol solvent mixture (40:60). Reaction time: 20h. Yield: 59.1 mg (43%). Oil.
1H-NMR (CDCl3) □: 8.52 (s, 1H, 4-H); 7.84 (d, 2H, Ar); 7.75 (m, 1 H, Ar); 7.65 (d, 1 H, Ar); 7.40 (m, 4H, 7-H, Ar); 7.21 (dd, 1H, 5-H); 4.20 (t, 2H, 1 ’- H); 2.19 (m, 6H, 3 ’- H, 5’ - H); 1.73 (m, 2H, 2 ’- H); 1.40 (m, 4H, H6 ’); 1.27 (7 ’- H). 13C-NMR (CDCl3) □: 168.7 (C-1 ’); 159.7 (C-3); 141.9 (C-7a); 137.2 (C, Ar); 133.8 (C, Ar); 132.4 (C, Ar); 131.4 (C, Ar); 131.1 (C, Ar); 128.8 (C-5); 128.2 (C, Ar); 127.4 (C, Ar); 126.6 (C, Ar); 125.8 (C, Ar); 1224.8 (C-6); 121.1 (C-7);
117.2 (C-3a); 116.8 (C-4); 68.7 (C-1 ’); 56.1 (C-3 ’); 54.9 (C-5 ’); 26.6 (C-2 ’); 26.3 (C-6 ’);
24.8 (C-7 ’). HPLC-MS (ES +): acetonitrile / water 15/85, tg: 8 min., Tr: 3.51, [M + H] = 448.27.
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EXAMPLE 6. Preparation and obtaining of (2-benzyloxyphenyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone (NP148)
Following the procedure of Example 1, it is made from 200 mg (0.58 mmol) of (2- benzyloxyphenyl) (3-hydroxy-1-indazolyl) ketone, 285 mg (1.40 mmol) of 1- hydrochloride (3- chloropropyl) -piperidine, 241 mg (1.74 mmol) of K2CO3, KI in catallotic amounts and 60 mL of 2-butanone. The reaction crude is purified by flash chromatography with the dichloromethane: methanol solvent mixture (80:20). Reaction time: 48h. Yield: 34 mg (12%). Oil.
1H-NMR (CDCh) □: 8.45 (sa, 1H, 4-H); 7.67 (dd, 1H, 7-H); 7.59 (t, 1H, 5-H); 7.50 (dd, 1H, Ar); 7.42 (td, 1H; Ar); 7.36 (t, 1H, 6-H); 7.17 (m, 5H, Ar); 7.06 (t, 1 H, Ar); 7.00 (d, 1 H, Ar); 5.11 (s, 2H, CH2); 4.26 (t, 2H, 1 ’- H); 2.52 (m, 6H, 3 ’- H, 5’ - H); 2.06 (m, 2H, 2 ’- H); 1.68 (s, 4H, 6 ’- H); 1.47 (s, 2H, 7 ’- H). 13C-NMR (CDCl3) □: 170.4 (C-1 ’); 154.9 (C-3); 139.9 (C-7a);
135.8 (C, Ar); 130.5 (C, Ar); 129.2 (C, Ar); 128.2 (C, Ar); 127.3 (C, Ar); 126.5 (C, Ar); 125.3 (C, Ar); 124.9 (C, Ar); 123.3 (C-6); 119.6 (C, Ar); 118.6 (C-7); 114.9 (C-3a); 111.8 (C-4); 98.6 (C, Ar); 69.2 (CH2); 66.5 (C-1 ’); 54.6 (C-3 ’); 53.2 (C-5 ’). HPLC-MS (ES +): acetonitrile / water 15/85, tg: 9 min., Tr: 3.32, [M + H] = 470.29.
EXAMPLE 7. Preparation and obtaining (1-naphthyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP152)
Following the procedure of Example 1, it is made from 250 mg (0.87 mmol) of (3- hydroxy-1-indazolyl) (1-naphthyl) ketone, 195.5 mg (1.04 mmol) of hydrochloride of 1- (3- chloroethyl) piperidine, 361 mg (2.61 mmol) of K2CO3, KI in catallotic amounts and 60 mL of 2-butanone. The reaction crude is purified by flash chromatography with the dichloromethane: methanol solvent mixture (98: 2). Reaction time: 24h. Yield: 124 mg (36%). Oil.
1H-NMR (CDCh) □: 8.58 (sa, 1H, 4-H); 7.99 (d, 1 H, Ar); 7.90 (t, 2H, Ar); 7.70 (m, 3H, 5-H, 7- H, Ar); 7.50 (m, 4H, 6-H, Ar); 4.41 (t, 2H, 1 ’- H); 2.81 (m, 2H, 2’-H); 2.51 (s, 4H, 4 ’- H); 1.67 (s, 4H, 5 ’- H); 1.45 (s, 2H, 6 ’- H). 13C-NMR (CDCh) □: 167.4 (C-1 ’); 158.1 (C-3); 140.2 (C-7a); 132.2 (C, Ar); 131.7 (C, Ar); 129.5 (C, Ar); 127.3 (C-5); 126.3 (C-5); 125.8 (C, Ar); 125.1 (C, Ar); 124.5 (C, Ar); 123.8 (C, Ar); 123.6 (C, Ar); 118.9 (C-7); 116.8 (C-3a); 115.2 (C-4); 64.5 (C-1 ’); 55.0 (C-2 ’); 53.2 (C-4 ’); 23.4 (C-5 ’); 22.1 (C-6 ’). HPLC-MS (ES +): acetonitrile / water 15/85, tg: 9 min., Tr: 3.07, [M + H] = 400.31.
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EXAMPLE 8. Preparation and obtaining (2,3-dichlorobenzyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP101)
Following the procedure of Example 1, it is made from 150 mg (0.49 mmol) of (2,3-dichlorophenyl) (3-hydroxy-1-indazolyl) ketone, 91.75 mg (0.49 mmol) of 1- (2- Chloroethyl) piperidine hydrochloride, 135.4 mg (0.98 mmol) of K2CO3, KI in catalytic amounts and 50 mL of 2-butanone. The reaction crude is purified by flash chromatography with the solvent mixture water: methanol (30:70). Reaction time: 48 h. Yield: 36.2 mg (18%). P.F. = 118-121 ° C. 1H-NMR (CDCh) □: 8.51 (d, 1H, 4-H); 7.69 (d, 1H, 7-H); 7.63 (t, 1H, 5-H); 7.57 (dd, 1H, Ar); 7.40 (td, 2H, Ar); 7.31 (td, 1H, 6-H); 4.37 (t, 2H, 1 ’- H); 2.75 (t, 2H, 2 ’- H); 2.43 (m, 4H, 4 ’- H); 1.55 (m, 4H, 5 ’- H); 1.44 (m, 2H, 6 ’- H). 13C-NMR (CDCh) □: 164.3 (C-1 ’);
159.2 (C-3); 139.6 (C-7a); 136.5 (C, Ar); 132.2 (C, Ar); 130.4 (C, Ar); 129.5 (C, Ar); 129.0 (C, Ar); 126.0 (C-5); 124.0 (C-6); 139.6 (C-7a); 119.0 (C-7); 117.5 (C-3a); 114.9 (C-4); 66.2 (C-1 ’); 56.0 (C-2 ’); 53.8 (C-4 ’); 24.8 (C-5 ’); 23.1 (C-6 ’). HPLC-MS (ES +): acetonitrile / water 15/85, tg: 8 min., Tr: 3.10, [M + H] + = 418
EXAMPLE 9. Preparation and obtaining of (2-benzyloxyphenyl) (3- (2-piperidinopropoxy) -5-nitro-1-indazolyl) ketone (NP183)
Following the procedure of Example 1, it is made from 3.30 g (8.48 mmol) of (2,3-dichlorophenyl) (5-nitro-1-indazolyl) ketone, 60 ml of 2-butanone, 2, 10 g of ground K2CO3, 1.40 g (8.50 mmol) of KI and 1.90 g (9.50 mmol) of 1- (2-chloropropyl) piperidine. Reaction time: 72 h. Yield: 1.18 g (27%).
P.F. = 110.5 ° C. 1H-NMR: (300 MHz, CDCh) □: 8.44-8.22 (m, 3H, 4-H, 6-H, 7-H); 8.22-7.04 (m, 9H, Ar); 4.39 (t, 2H, 1'-H); 2.64 (t, 2H, 3'-H); 1.62 (m, 2H, 2'-H); 2.41-1.20 (m, 10H, Pip). HPLC-MS (ES +): MeCN / H2O 10:90, tr: 2.97, [M + H] + = 514.
EXAMPLE 10. General procedure for the synthesis of the carbonyl derivatives of 5-amino-1-indazolyl.
To a solution of the carbonyl derivative of 5-nitroindazole in ethanol, the excess SnCl2 is added. The mixture is heated to 90 ° C and, once the reaction is finished, it is allowed to cool and the reaction mixture is filtered in celite, the solvent is evaporated in vacuo and the reaction crude is purified by flash chromatography with the solvent mixture. water: methanol (40:60).
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Preparation and obtaining of (2-benzyloxyphenyl) (3- (2-piperidinoethoxy) -5-amino-1- indazolyl) ketone (NP192)
From 62.9 mg (0.13 mmol) of (2-benzyloxyphenyl) (3- (2-piperidinoethoxy) -5-nitro-1- indazolyl) ketone, 30 ml of ethanol and 380.0 mg (2, 0 mmol) of SnCl2. Reaction time: 7 h. Yield: 19.6 mg (31%). Oil.
1H-NMR: (300 MHz, CDCl3) □: 8.21 (d, 1H, 7-H); 8.09-7.06 (m, 9H, R1); 7.37 (dd, 1H, 6-H); 7.31 (d, 1H, 4-H); 5.16 (s, 2H, O-CH2); 4.73 (t, 2H, 1'-H); 4.73-3.41 (m, 2H, NH2); 3.41-2.16 (m, 2H, 2'-H); 2.50-1.25 (m, 10H, Pip). HPLC-MS (ES +): MeCN / H2O 10:90, tr: 2.77, [M + H] + = 471.
EXAMPLE 11. Preparation and obtaining of (2-benzyloxyphenyl) (3- (2-piperidinopropoxy) -5-amino-1-indazolyl) ketone (NP194)
Following the procedure of Example 10, from 920 mg (1.8 mmol) of (2- benzyloxyphenyl) (3- (2-piperidinopropoxy) -5-nitro-1-indazolyl) ketone, 70 ml of ethanol and 5, 17 g (26.5 mmol) of SnCl2. Reaction time: 7 h. Yield: 346 mg (40%). Oil. 1H-NMR: (300 MHz, CDCh) □: 8.29 (d, 1H, 7-H); 7.81-7.03 (m, 9H, R1); 6.98 (dd, 1H, 6-H); 6.82 (d, 1H, 4-H); 5.11 (s, 2H, O-CH2); 4.38 (t, 2H, 1'-H); 4.24 (m, 2H, NH2); 2.80 (dt, 2H, 3'-H); 1.82 (q, 2H, 2'-H); 2.50-1.43 (m, 10H, Pip). HPLC-MS (ES +): MeCN / H2O 10:90, tr: 2.83, [M + H] + = 485.
EXAMPLE 12. Preparation and obtaining of (1-naphthyl) (3- (2-piperidinopropoxy) -5-amino-1- indazolyl) ketone (NP195)
Following the procedure of Example 10, from 112.5 mg (0.25 mmol) of (1-naphthyl) (3- (2-piperidinopropoxy) -5-nitro-1-indazolyl) ketone, 20 ml of ethanol and 190 mg (1.00 mmol) of SnCl2. Reaction time: 28 h. Yield: 20.5 mg (20%). Oil.
1H-NMR: (300 MHz, CDCh) □: 8.36 (d, 1H, 7-H); 6.99 (dd, 1H, 6-H); 6.89 (d, 1H, 4-H); 7,987.46 (m, 7H, Ar); 4.11 (t, 2H, 1'-H); 3.83 (s, 2H, NH2); 2.29 (m, 2H, 3'-H); 1.84 (m, 2H, 2'-H); 2.29-1.41 (m, 10H, Pip). HPLC-MS (ES +): MeCN / H2O 10:90, tr: 3.15, [M + H] + = 429.
EXAMPLE 13. General procedure for the synthesis of 3- hydroxy-1-indazolyl carbonyl derivatives.
To a solution of 1H-indazol-3-ol in pyridine at 0 ° C the corresponding acid chloride is added little by little. The reaction is maintained with stirring and letting it temper slowly. Once finished, it is poured into water and acidified with acetic acid. Be
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Let it precipitate overnight and filter to recover the solid. This is washed with water and allowed to air dry.
Preparation and obtaining of (3-hydroxy-1-indazolyl) (2-benzyloxyphenyl) ketone
It is made from 1.00 g (7.45 mmol) of 1H-indazol-3-ol, 2.28 g (8.95 mmol) of 2-benzyloxybenzoyl chloride and 20 mL of pyridine. Once the reaction is complete, abundant water and acetic acid are added. The oil that forms is decanted and dissolved in methylene chloride. Small amounts of methanol are added, observing the precipitation of the pure product. Reaction time: 24 hours. Yield: 0.57 g (22%). P.F. = 82-87 ° C. 1H-NMR (CDCh) □: 10.60 (sa, 1H, OH); 8.15 (dd, 1H, 4-H); 7.08 (t, 1H, 6- H). 13C-NMR (CDCl3) □: 162.0 (C-1 ’); 158.2 (C-3); 140.5 (C-7a); 117.8 (C-3a); 112.8 (C-4). HPLC-MS (ES +): MeCN / H2O 15:85, tr: 5.27, [M + H] + = 345.22.
EXAMPLE 14. Preparation and obtaining (2,3-dichlorobenzyl) (3-hydroxy-1- indazolyl) ketone
Following the procedure of Example 13, it is made from 255 mg (1.90 mmol) of 1H-indazol-3-ol, 370 mg (1.77 mmol) of 2,3-dichlorobenzoyl chloride and 10 mL of pyridine . Reaction time: 16 h. Yield: 422 mg (78%).
P.F. = 112-115 ° C. 1H-NMR (300 MHz, DMSO-d6) □: 12.97 (s, 1H, OH); 8.38 (d, 1H, 4-H); 7.99 (d, 1H, 7-H); 7.63 (m, 3H, 7.45, 5-H, 6-H, Ar); 7.17 (t, 1H, Ar). 13C-NMR (300 MHz, DMSO-d6pD: 164.6 (N1-CO); 160.1 (C-3); 128.7 (C-5); 125.2 (C-6); 112.8 (C-3a); 110.9 (C-4); 141.3 (C, Ar); 134.5 (C, Ar); 131.8 (C, Ar) 130.2 (C, Ar); 127.1 (C, Ar); 119.0 (C, Ar). HPLC-MS (ES +): 10/90 acetonitrile / water, tg: 6 min., Tr: 4.78, [M + H] + = 307.2.
EXAMPLE 15. Preparation and obtaining of (1-naphthyl) (3-hydroxy-1-indazolyl) ketone
Following the procedure of Example 13, it is made from 301 mg (2.25 mmol) of 1H-indazol-3-ol, 428 mg (2.25 mmol) of 2-naphthoyl chloride and 15 mL of pyridine. Reaction time: 16 h. Yield: 395 mg (61%).
P.F. = 121-124 ° C. 1H-NMR (300 MHz, DMSO-d6) □: 12.16 (s, 1H, OH); 8.56 (s, 1 H, Ar); 8.43 (d, 1H, 4-H); 8.04 (m, 4H, Ar); 7.83 (d, 1H, 7-H); 7.65 (m, 3H, 5-H, Ar); 7.45 (t, 1H, 6-H). 13C-NMR (300 MHz, DMSO-d6) □: 166.8 (N1-CO); 158.8 (C-3); 140.6 (C-7a); 128.0 (C-5); 124.6 (C-6); 120.4 (C-7); 117.9 (C-3a); 115.6 (C-4); 134.0 (C, Ar); 131.7 (C, Ar); 131.3 (C, Ar)
130.8 (C, Ar); 130.4 (C, Ar); 129.0 (C, Ar); 127.6 (C, Ar); 127.2 (C, Ar); 126.8 (C, Ar); 126.3 (C, Ar). HPLC-MS (ES +): 10/90 acetonitrile / water, tg: 8 min., Tr: 5.08, [M + H] + = 289.2.
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EXAMPLE 16. Preparation and obtaining of (3-hydroxy-1-indazolyl) (4-methoxyphenyl) ketone
Following the procedure of Example 13, it is made from 1.00 g (7.45 mmol) of 1H-
indazol-3-ol, 1.57 g (8.94 mmol) of 4-methoxybenzoyl chloride and 20 mL of pyridine at a
temperature of -78 ° C. Reaction time: 5 hours. Yield: 1.96 g (98%).
P.F. = 134 - 138 ° C. 1H-NMR (CDCl3) □: 10.0 (sa, 1H, OH); 7.59 (d, 1H, 4-H); 7.40 (m, 1H, 7-H); 7.38 (m, 1H, 5-H), 7.16 (tt, 1H, 6-H). 13C-NMR (CDCl3) □: 164.3 (C-1 ’); 150.2 (C-3);
142.2 (C-7a); 128.1 (C-5); 121.7 (C-6); 120.2 (C-7); 114.8 (C-3a); 110.8 (C-4).
EXAMPLE 17. Preparation and obtaining of (6-chloro-3-hydroxy-1-indazolyl) (1- naphthyl) ketone
Following the procedure of Example 13, it is made from 200 mg (1.19 mmol) of 6-
Chloro-1H-indazol-3-ol, 460 mg (2.37 mmol) of 1-naphthoyl chloride and 10 mL of pyridine.
Reaction time: 24 hours. Yield: 210 mg (55%).
P.F. = 173-178 ° C. 1H-NMR (CDCh) □: 12.24 (s, 1H, OH); 8.60 (dd, 1H, 4-H); 8.13 (dd, 1H, 7-H); 7.68 (t, 1H, 5-H). 13C-NMR (CDCh) □: 164.2 (C-3); 142.0 (C-7a); 132.2 (C-5); 121.9 (C-6); 121.5 (C-7); 112.7 (C-3a); 110.8 (C-4).
EXAMPLE 18. Cannabinoid Effect
The characterization of the cannabinoid activity of the new compounds described in the present invention was carried out by analyzing their activity in isolated tissues classically used to evaluate cannabinoid agonists and antagonists. The mouse vas deferens (Gonzalez-Naranjo, P., et al., Eur J Med Chem 2014, 73, 56-72) was used for isolated tissue tests. Cannabinoid agonists, by stimulating these receptors, reduce the strength of contractions induced by electrical stimulation. Cannabinoid antagonists are able to selectively block this effect (the agonist effect of the new compounds has been evaluated by performing non-cumulative concentration-response curves of them (10-7-2x10-5 M)). The effect has been compared with that of the non-selective synthetic cannabinoid agonist CB1 / CB2 WIN 55,212-2.
For compounds that presented an interesting agonist profile, it has been tested whether their effect is blocked by selective CB1 (AM251) or CB2 (AM630) antagonists.
Figure 1 shows the agonist effect (expressed as% inhibition of electrically induced contraction in the mouse vas deferens) of the compounds
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more interesting All of them show cannabinoid activity, in many cases similar or superior to that of the reference compound WIN 55, 212-2.
EXAMPLE 19. Cholinergic Effect
For the determination of the action of the derivatives of the compounds as inhibitors of acetylcholinesterase (AChE) (Sigma Chemical Co., human recombinant), butyrylcholinesterase (BuChE) (Sigma Chemical Co., human serum) the Ellman method has been followed (Ellman, GL, et al., Biochem. Pharmacol. 1961, 7, 88-95). The test solution consists of 0.1 M sodium phosphate buffer, pH 8, 400 p, M 5.5 -diobis -2-nitrobenzoic acid (DTNB), 0.05 units / ml AChE or 0.024 U / ml BuChE, and 800 p, M acetylcholine iodide or 500 p, M butyrylcholine as AChE and BuChE substrates, respectively. The compounds to be tested are added to the test solution before the enzyme, once added the enzyme is pre-incubated for a period of 5 minutes at 30 ° C and finally the substrate is added. Absorbance changes at 412 nm are measured for 5 minutes in a UV / Vis spectrophotometer, Multiskan Spectrum. The enzymatic activity at each concentration of compound is expressed as a percentage of activity with respect to the control in the absence of compound. The IC50 is defined as the concentration of compound that inhibits 50% enzymatic activity with respect to the control of untreated enzyme.
Table 1 shows, as examples, the IC50 data of some of the derivatives of the carbonyl derivatives of 1-indazolyl. As the IC50 data shown in Table 1 demonstrate, derivatives of the present invention inhibit the enzymes acetylcholinesterase or butyrylcholinesterase. It should be noted that all derivatives inhibit butyrylcholinesterase, some of them in the nanomolar order with a clear selectivity against the other enzyme.
Table 1. IC50 data of indazolyl carbonyl derivatives.
OR
r (CH2) n-R4
image6
^ R3
 n R1 / R 2 R4 R3 IC50 hAChE (MM) IC50 hBuChE (MM)
 Donepezil or          (1.0 ± 0.2) 10-2 2.50 ± 0.07 a
 Rivastigmi na          00 54 b
 NP43  2 H pyrrolidinyl 2,3-dichlorophenyl> 10 0.23 ± 0.02
 NP79  2 5- NO2 pyrrolidinyl 2,3-dichlorophenyl> 10 (45%) c 6.1 ± 0.6
 NP83  2 H pyrrolidinyl 2-thienyl 12.1 ± 0.7 6.6 ± 0.6
 NP104  2 H pyrrolidinyl 2-chlorophenyl 9.7 ± 0.8 1.3 ± 0.5
 NP152  2 H piperidino 1-naphthyl> 10 (37%) c (0.26 ± 0.07) 10-3
 NP40  2 5- NO2 piperidino 1-naphthyl> 10 (37%) c 0.57 ± 0.05
 NP73  2 H piperidino 2-naphthyl> 10 (43%) c 4.0 ± 0.3
 NP94  2 H piperidino 4-chloro-3-pyridyl 13 ± 1 14.7 ± 0.9
 NP93  2 H adamantine piperidine 8 ± 1 2 ± 1
 NP91  2 H piperidino 2,4,6-trimethylphenyl 11.6 ± 0.7 0.29 ± 0.03
 NP101  2 H piperidino 2,3-dichlorophenyl 10.5 ± 0.5 0.6 ± 0.3
 NP111  2 H piperidino 2,3,6- trifluorophenyl 9.4 ± 0.6 9.4 ± 0.3
 NP119  2 H piperidino 2,6-dichlorophenyl> 10 (25%) c 0.010 ± 0.008
 NP76  2 H dimethylamino 1-naphthyl> 10 (39%) c 2.00 ± 0.2
 NP108  2 H dimethylamino 3-fluorophenyl> 10 (47%) c> 10 (44%) c
 NP117  2 H diisopropylamine 4-methoxyphenyl 8 ± 1 3.7 ± 0.4
 NP100  2 H morpholino 1-naphthyl 12 ± 1 5.1 ± 0.3
 NP123  3 H dimethylamino 4-biphenylyl> 10 8.7 ± 0.3
 NP154  3 H pyrrolidinyl 1-naphthyl> 10 (35%) c (0.15 ± 0.03) 10-3
 NP120  3 H piperidino 2,3-dichlorophenyl 17 ± 2 0.080 ± 0.003
 NP124  3 H piperidino 1-naphthyl> 10 (43%) c (0.07 ± 0.01) 10-3
 NP127  3 H piperidino 2-chlorophenyl 9.7 ± 0.3 0.07 ± 0.01
 NP128  3 H piperidino 2,4,6-trimethylphenyl> 10 0.58 ± 0.06
 NP129  3 H piperidino 3-chloro-2-fluorophenyl> 10 (48%) c 0.80 ± 0.04
 NP148  3 H piperidino 2-benzyloxyphenyl> 10 (31%) c (3 ± 1) 10-3
 NP153  3 H piperidino 2-naphthyl> 10 (33%) c 2.1 ± 0.3
 NP137  3 H piperidino 4-methoxybenzyl> 10 (43%) c> 10 (42%) c
 NP145  3 6-Cl piperidino 1-naphthyl> 10 (41%) c (6 ± 1) 10-3
 NP174  3 H piperidino 4-biphenylil> 10 (38%) c 2.5 ± 0.9
 NP196  2 6-Cl piperidino 1-naphthyl> 10 (33%) c 0.05 ± 0.008
 NP197  3 5-Cl piperidino 2-benzyloxyphenyl> 10 (34%) c 0.81 ± 0.06
 NP183  3 5- NO2 piperidino 2-benzyloxyphenyl> 10 0.3 ± 0.3
 NP192  2 NH2 piperidino 2-benzyloxyphenyl> 10 0.08 ± 0.01
 NP195  3 NH2 piperidino 1-naphthyl> 10 0.28 10-3 ± 0.03
to experimental IC50 in BuChE of equine serum; b Referenda Gonzalez-Naranjo, P.,
Campillo, N. E., Perez, C. and Paez, J. A. (2013). "Multitarget cannabinoids as novel strategy for Alzheimer disease." Curr Alzheimer Res 10 (3): 229-39; c Percent inhibition 5 to 10 pM;
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EXAMPLE 20. Enzymatic assay of BACE-1.
The inhibition capacity of the compounds studied in BACE-1 was carried out in accordance with the manufacturer's protocol available from Invitrogen ( http://tools.invitrogen.com/content/sfs/manuals/L0724.pdf).
Briefly, the in vitro test of BACE1 was performed using the Fluorescence Energy Resonant Transfer (FRET) procedure. A peptide substrate based on APP- (rhodamine-EVNLDAEFK-quencher, Km of 20 mM) was used which carries the Swedish mutation and contains a rhodamine as a fluorescence donor and an extinction acceptor at each end. The intact substrate is weakly fluorescent and becomes highly fluorescent after enzymatic disruption. The assays were carried out in 50 mM sodium acetate buffer, pH 4.5, in a final enzyme concentration (1 U / ml). Inhibitor is tested at a concentration of 10pM. The mixture was incubated for 60 min at 25 ° C under dark conditions and then stopped by adding 2.5 M sodium acetate. Fluorescence was measured with a FLUOstar Optima microplate reader (BMG Labtechnologies GmbH, Offenburg, Germany) at 545 nm excitation and 585 nm emission. The test has been validated by the manufacturer.
Table 2 shows the results obtained for some of the carbonylcos derivatives of 1-indazolyl which are collected in the present invention. As demonstrated from the IC50 data obtained, the compounds collected in Table 2 inhibit the enzyme BACE-1 in the micromolar order.
Table 2. Results of the BACE-1 inhibition test of the selected indazolyl carbonyl derivatives.
 R1s    OR'
 IT'S
 R /    N
• (CH2) n-R
N
O'R
3
4
 Bace
 n R1 / R2 R4 R3 (% at 10 MM)
 NP43  2 H pyrrolidinyl 2,3-dichlorophenyl 32.6 ± 0.1
 NP73  2 H piperidino 2-naphthyl 50 ± 5
 NP89  2 H diisopropylamino 4-biphenylyl 61.0 ± 0.9
 NP119  2 H piperidino 2,6-dichlorophenyl 34 ± 1
 NP120  3 H piperidino 2,3-dichlorophenyl 45.1 ± 0.9
 NP123  3 H dimethylamino 4-biphenylyl 57 ± 2
 NP124  3 H piperidino 1-naphthyl 42 ± 2
 NP128  3 H piperidino 2,4,6-trimethylphenyl 45 ± 4
 NP129  3 H piperidino 3-chloro-2- fluorophenyl 34 ± 1
 NP132  3 H piperidino 4-chlorobenzyl 50 ± 2
 NP137  3 H piperidino 4-methoxybenzyl 60 ± 8
 NP145  3 6-Cl piperidino 1-naphthyl 53 ± 3
 NP148  3 H piperidino 2-benzyloxyphenyl 38 ± 1
 NP153  3 H piperidino 2-naphthyl 38 ± 3
 NP174  3 H piperidino 4-biphenyl 93 ± 2
 NP196  2 6-Cl piperidino 1-naphthyl 46 ± 1
 NP197  3 5-Cl piperidino 2-benzyloxyphenyl 56 ± 1
 NP194  3 nh2 piperidino 2-benzyloxyphenyl 49 ± 2
Analyzing the results obtained in Figures 1 and 2, and Tables 1 and 2, it can be determined that there are 1-indazolyl carbonyl derivatives that behave as CB1 / CB2 cannabinoid agonists and / or BuChE and / or BACE-1 inhibitors.
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EXAMPLE 21. Study of the action of CB2 agonists in Alzheimer's cell models.
For these studies two compounds NP137 and NP148, CB2 agonists with inhibitory activity of BACE-1 the first and BACE-1 and BuChE the second were selected. First, the efficacy of these compounds in the proliferative activity of immortalized lymphocytes derived from sporadic Alzheimer's patients was assessed and, secondly, the possible neuroprotective effect of these compounds in primary cultures of rat cortical neurons treated with □ -amiloid was studied. .
The use of lymphoblastic lines of patients as an experimental model for the study of relevant pathogenetic events in neurodegenerative processes is widely accredited. The lymphoblasts of Alzheimer's patients present alterations in the control of the cell cycle as a result of failures in the processes of cellular signaling mediated by PI3K / Akt, which result in an increase in the phosphorylation of the retinoblastoma prothena (pRb), facilitating the transit between the S and G2 / M phases of the cell cycle. These alterations are considered systematic manifestations of the aberrant entry into the cell cycle of vulnerable neurons, one of the earliest pathogenic events of Alzheimer's disease (Munoz, et al. Neurobiol Aging 2008, 29, 1474-84).
Lymphocyte immortalization was performed by infection with the Esptein Barr virus as described. The determination of cell viability, proliferative activity and levels of the pRb, p27 and Akt proteins was carried out as previously described (Munoz, et al. Neurobiol Aging 2008, 29, 1474-84). Primary cultures of cortical neurons were prepared from rat embryos (E15-16) as described (Alquezar, C., Barrio, E., Esteras, N., de la Encarnacion, A., Bartolome, F., Molina, JA and Martin-Requero, A. (2015). "Targeting cyclin D3 / CDK6 activity for treatment of Parkinson's disease." J Neurochem 133 (6): 886).
Initially dose-response experiments were performed to analyze the influence of NP137 and NP148 on cell viability. The administration of increasing doses of these compounds reduces cell viability preferably in the lymphoblasts of Alzheimer's patients as seen in Figure 3A).
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EXAMPLE 23. Evaluation in an animal model of Alzheimer's disease (5xFAD mouse)
5xFAD transgenic animals (rodent Alzheimer's disease animal model), which contain five mutations that overexpress the human beta amyloid peptide (Oakley et al., Journal of Neuroscience 2006, 26, 10129-10140) and their corresponding mice with no phenotype 6-month-old mutated (wild type) were treated for twelve days with a dose of 3mg / kg NP43, or vehicle (DMSO-Cremophor-Salino [1: 1: 18]), administered intraperitoneally .
The mice were sacrificed by cervical dislocation and their brains rapidly extracted and frozen in liquid isopentane at -80 ° C. Subsequently, the cerebral cortex was dissected and the mRNA was extracted with the Tripure kit (Roche Diagnostics, Manheim, Germany). The determination of the expression of inflammatory parameters was carried out by quantitative PCR in real time, using LightCycler technology (Roche Diagnostics). The QuantiMix Easy Probes kit (Biotools, Madrid, Spain) was used for the amplification. For each PCR 2 microliters of the cDNA were used and the concentration of the primers and probes was 0.5 and 0.2 micromolar, respectively. The expression of the 18S gene was used as load control and a negative control without mold was included in each run. The genes studied included those of the enzymes inducible nitric oxide synthase (iNOS), cyclooxygenase type 2 (COX-2) and cytokine interleukin 1-beta (IL1 b) and tumor necrosis factor-alpha (TNFa). The analysis of the results was carried out using ANOVA, using the Graphpad Prism 5.0 program.
The results obtained indicate that the NP43 tested compound has a significant anti-inflammatory activity, which is reflected in the decreases observed in the expression of the iNOS and COX-2 enzymes, as well as the TNF-alpha and IL1b cytokines.
EXAMPLE 24. Evaluation in an animal model of Alzheimer's disease (male mouse TgAPP)
To test the possible beneficial effect of compound NP137 in a transgenic model of Alzheimer's disease, male TgAPP mice (line 2576), 10 months old at the beginning of treatment, were treated. Wild mice ("wild type" or wt) of the
same litters were used as controls. The compounds were administered in the drinking water at a dose of 1mg / kg / dla for 3 and a half months, and control mice (Tg APP or wt) received vehicle (DMSO, 0.25%).
5 Control wild animals learned a spatial task (Morris water maze) for 5 days, while vehicle-treated TgAPP mice showed a learning deficit. The compound NP137 in "wild type" mice did not alter the performance of the task the last day, although it delayed learning.It should be noted that this compound, NP137, completely normalized the spatial memory of TgAPP mice.
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1.- A compound of general formula (I)
 R1v    OR'
 IT'S
 R2 "    N
(CH2) n-R N
O '' 'R3
Formula (I)
its pharmaceutically acceptable salts, tautomers, solvates and hydrates where,
- n is selected between 1,2, 3 and 4;
- R1 and R2 are independently selected from hydrogen, halogen, -NO2 and -NH2;
- R3 is selected from cycloalkyl, heteroaryl, optionally substituted aryl and optionally substituted aralkyl;
- R4 is selected from heterocycloalkyl and -NR5R6;
- R5 and R6 are independently selected from hydrogen and alkyl.
2. - A compound of formula (I) according to claim 1, wherein R3 is selected from optionally substituted aryl, optionally substituted aralkyl, 2-thienyl and 4-chloro-3-pyridyl.
3. - A compound of formula (I) according to claim 1, wherein R3 is selected from 1- naphthyl, 2-naphthyl, 4-tolyl, 3,4,5-trimethylphenyl, 2-benzyloxyphenyl, 3,4,5- trimethoxyphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,6-dichlorophenyl, 2,3,6-trifluorophenyl, 2-chlorophenyl, 3- fluorophenyl, 3-chloro-2-fluorophenyl, 4-biphenylyl, 4- chlorobenzyl, 4-methoxybenzyl and 1-adamantyl.
4. - A compound of formula (I) according to claim 1, wherein R3 is selected from 1- naphthyl, 2-naphthyl, 2-benzyloxyphenyl, 2,3-dichlorophenyl and 4-methoxybenzyl.
5. - A compound of formula (I) according to claim 1, wherein R4 is selected from heterocycloalkyl, diisopropylamino, dimethylamino and diethylamino.

权利要求:
Claims (9)
[6]
6. A compound of formula (I) according to claim 1, wherein R4 is a heterocycloalkyl.
[7]
7. - A compound of formula (I) according to claim 1, wherein R4 is selected from piperidinyl, morpholinyl and pyrrolidinyl.
[8]
8. - A compound of formula (I) according to claim 1, wherein n is selected between 2 and 3.
9. A compound of formula (I) according to claim 1, which is selected from the list that
understands
(1-Naphthyl) (3- (2-piperidinoethoxy) -5-nitro-1-indazolyl) ketone (NP40)
(2,3-dichlorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1- (NP43)
indazolyl) ketone
(3- (2- (diisopropylamino) ethoxy5-nitro-1-indazolyl) (4- (NP46)
tolyl) ketone
(2-Naphthyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP73)
(3- (2- (diethylamino) ethoxy) -1-indazolyl) (4-tolyl) ketone (NP75)
(3- (2- (dimethylamino) ethoxy) -1-indazolyl) (1-naphthyl) ketone (NP76)
(2,3-dichlorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -5-nitro-1- (NP79)
indazolyl) ketone
(3- (2- (1-Pyrrolidinyl) ethoxy) -1-indazolyl) (2-thienyl) ketone (NP83)
(4-biphenylyl) (3- (2- (diisopropylamino) ethoxy) -1- (NP89)
indazolyl) ketone
(2,4,6-trimethylphenyl) (3- (2-piperidinoethoxy) -1- (NP91)
indazolyl) ketone
(1-adamantyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP93)
(4-Chloro-3-pyridyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP94)
(3- (2-morpholinoethoxy) -1-indazolyl) (1-naphthyl) ketone (NP100)
(2,3-dichlorophenyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP101)
(2-Chlorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1-indazolyl) ketone (NP104)
(2,3-Difluorophenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1- (NP107)
indazolyl) ketone
(3-fluorophenyl) (3- (2- (dimethylamino) ethoxy) -1- (NP108)
indazolyl) ketone
(2,3,6-trifluorophenyl) (3- (2-piperidinoethoxy) -1-
indazolyl) ketone
(2,3-dichlorophenyl) (3- (2- (dimethylamino) ethoxy) -1-
indazolyl) ketone
(3,4,5-trimethoxyphenyl) (3- (2- (1-pyrrolidinyl) ethoxy) -1-
indazolyl) ketone
(3- (2- (diisopropylamino) ethoxy) -1-indazolyl) (4-
methoxyphenyl) ketone
(2,6-dichlorophenyl) (3- (3- (dimethylamino) propoxy) -1-
indazolyl) ketone
(2,6-Dichlorophenyl) 2- (2- (piperidinoethoxy) -1-indazolyl) ketone
(2,3-dichlorophenyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(2,3-dichlorophenyl) (3- (2-morpholinoethoxy) -1-
indazolyl) ketone
(4-biphenylyl) (3- (3- (dimethylamino) propoxy) -1-
indazolyl) ketone
(1-Naphthyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone
(3- (3- (dimethylamino) propoxy) -1-indazolyl) (4-
methoxyphenyl) ketone
(2-Chlorophenyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone
(2,4,6-trimethylphenyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(3-Chloro-2-fluorophenyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(4-Chlorobenzyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(4-methoxybenzyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(1-naphthyl) (3- (3-piperidinopropoxy) -6-chloro-1-
indazolyl) ketone
(2-benzyloxyphenyl) (3- (3-piperidinopropoxy) -1-
indazolyl) ketone
(NP111)
(NP113)
(NP116)
(NP117)
(NP118)
(NP119)
(NP120)
(NP121)
(NP123)
(NP124)
(NP125)
(NP127)
(NP128)
(NP129)
(NP132)
(NP137)
(NP145)
(NP148)
(1-Naphthyl) (3- (2-piperidinoethoxy) -1-indazolyl) ketone (NP152)
(2-Naphthyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone (NP153)
(1-Naphthyl) (3- (3- (1-pyrrolidinyl) propoxy) -1-indazolyl) ketone (NP154)
(4-biphenylyl) (3- (3-piperidinopropoxy) -1-indazolyl) ketone (NP174)
(2-benzyloxyphenyl) (3- (2-piperidinoethoxy) -5-nitro-1- (NP181)
indazolyl) ketone
(2,3-dichlorophenyl) (3- (3-piperidinopropoxy) -5-nitro-1- (NP182)
indazolyl) ketone
(2-benzyloxyphenyl) (3- (2-piperidinopropoxy) -5-nitro-1- (NP183)
indazolyl) ketone
(1-naphthyl) (3- (3-piperidinopropoxy) -5-nitro-1- (NP184)
indazolyl) ketone
(2-benzyloxyphenyl) (3- (2-piperidinoethoxy) -5-amino-1- (NP192)
indazolyl) ketone
(2,3-dichlorophenyl) (3- (3-piperidinopropoxy) -5-amino-1- (NP193)
indazolyl) ketone
(2-benzyloxyphenyl) (3- (2-piperidinopropoxy) -5-amino-1- (NP194)
indazolyl) ketone
(1-naphthyl) (3- (2-piperidinopropoxy) -5-amino-1- (NP195)
indazolyl) ketone
(6-Chloro-3- (2-piperidinoethoxy) -1-indazolyl) (1- (NP196)
naphthyl) (ketone)
(2-benzyloxyphenyl) (5-chloro-3- (3-piperidinopropoxy) -1- (NP197)
indazolyl) ketone
[10]
10. A pharmaceutical composition comprising a compound as defined in any one of claims 1-9 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable adjuvant, vehicle or excipient.
5
[11]
11. - Use of a compound of formula (I) as defined in any one of claims 1-9, for the preparation of a medicament.
[12]
12. - Use of a compound of general formula (I)
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 R1v    OR'
 IT'S
 R2 "    N
(CH2) n-R N
O 'R3
its pharmaceutically acceptable salts, tautomers, solvates and hydrates where,
- n is selected between 1,2, 3 and 4;
- R1 and R2 are independently selected from hydrogen, halogen, -NO2 and -NH2;
- R3 is selected from cycloalkyl, heteroaryl, optionally substituted aryl and optionally substituted aralkyl;
- R4 is selected from heterocycloalkyl and -NR5R6;
- R5 and R6 are independently selected from hydrogen and alkyl;
for the preparation of a medicament for the treatment and / or prevention of a disease, disorder or prophylaxis mediated by CB1 and / or CB2 cannabinoid receptors, AChE and / or BuChE enzymes and / or BACE-1 enzyme.
[13]
13. - Use of a compound of formula (I) as defined in claim 12, wherein the disease mediated by CB1 and / or CB2 cannabinoid receptors, AChE and / or BuChE cholinergic enzymes, and / or BACE- enzyme 1 is selected from neurodegenerative diseases and dementias.
[14]
14. - Use of a compound of formula (I) as defined in the preceding claim, wherein the disease mediated by CB1 and / or CB2 cannabinoid receptors, AChE and / or BuChE cholinergic enzymes, and / or BACE- enzyme 1 is selected from Alzheimer's, amyotrophic lateral sclerosis and multiple sclerosis.
[15]
15. - Use of a compound of formula (I) as defined in claim 11, wherein the disease mediated by CB1 and / or CB2 cannabinoid receptors, AChE and / or BuChE cholinergic enzymes, and / or BACE- enzyme 1 is dementia with Lewy bodies.
% lnhibicion% lnhibicion
image 1
♦ Control —O — WIN - * - NP43 -O NP119 ■■■ * • ■ NP120 - • --NP127 - ■ - NP128 ••• * •• NP129 ^^ NP132 -A -NP152
image2
♦ Control -O - WIN —A— NP91 -O-NP101 NP104 - • --NP124 —0— NP137 ••• * ■ • NP148 —JK— NP154
[Ml
FIG. 1

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GB9824310D0|1998-11-05|1998-12-30|Univ London|Activators of soluble guanylate cyclase|

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ES2378139B1|2009-10-01|2013-07-01|Universidad Rey Juan Carlos|FAMILY OF 3-INDAZOLIL ETERES WITH CANNABINOID AND / OR COLINERGICAL PROPERTIES.|

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PCT/ES2016/070906| WO2017103319A1|2015-12-18|2016-12-16|Novel family of carbonyl derivatives of 1-indazolyl with cannabinoid and/or cholinergic and/or beta-amyloid-peptide-regulating properties|