WO2011051535A1 - Dérivés de bis(aralkyl)amine et système (hétéro)aromatiques à six membres et utilisation de ceux-ci pour le traitement de pathologies neurodégénératives, y compris la maladie d'alzheimer - Google Patents

Dérivés de bis(aralkyl)amine et système (hétéro)aromatiques à six membres et utilisation de ceux-ci pour le traitement de pathologies neurodégénératives, y compris la maladie d'alzheimer Download PDF

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WO2011051535A1
WO2011051535A1 PCT/ES2010/070702 ES2010070702W WO2011051535A1 WO 2011051535 A1 WO2011051535 A1 WO 2011051535A1 ES 2010070702 W ES2010070702 W ES 2010070702W WO 2011051535 A1 WO2011051535 A1 WO 2011051535A1
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methyl
amino
formula
compound according
benzamide
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Spanish (es)
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Mª Isabel RODRÍGUEZ FRANCO
Santiago Conde Ruzafa
Beatriz Lopez Iglesias
Concepción PEREZ MARTÍN
Mercedes Villarroya Sanchez
Manuela Garcia Lopez
Antonio Garcia Garcia
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Consejo Superior De Investigaciones Científicas (Csic)
Universidad Autónoma De Madrid (Uam)
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Definitions

  • the present invention which is included in the field of research and pharmaceutical industry, refers to chemical compounds derived from bis (aralkyl) amino and (hetero) aryl, to the processes for their preparation, to pharmaceutical compositions containing them and its use for the manufacture of a medication for the treatment of cognitive disorders.
  • it deals with compounds and compositions that protect neurons from mitochondrial oxidative stress, that increase the levels of the neurotransmitter acetylcholine and that stop neurodegeneration related to the dysfunction of the ⁇ -amyloid peptide.
  • These pharmacological properties are useful for the treatment of neurodegenerative pathologies, including Alzheimer's disease.
  • AD Alzheimer's disease
  • a complex neurodegenerative pathology of the central nervous system characterized by a progressive loss of intellectual abilities (memory, language and reasoning) and by psychiatric disorders (apathy , anxiety, depression, aggressiveness).
  • apathy anxiety, depression, aggressiveness
  • senile plaques deposits of ⁇ -amyloid derived from the abnormal metabolism of the amyloid precursor protein
  • neurofibrillary tangles compounds by protein abnormally hyperphosphorylated tau
  • oxidative damage in various cellular structures and low levels of the neurotransmitter acetylcholine oxidative damage in various cellular structures and low levels of the neurotransmitter acetylcholine.
  • the AChE enzyme has two important sites: the catalytic active center (CAS) where acetylcholine hydrolysis occurs and is located at the bottom of a narrow throat, and the peripheral anionic site (PAS) located at the throat entrance catalytic
  • CAS catalytic active center
  • PAS peripheral anionic site
  • AChE has other functions related to neuronal differentiation, cell adhesion and amyloid peptide aggregation.
  • Different biochemical studies have shown that AChE favors the formation of aggregates of ⁇ -amyloid ( ⁇ ), establishing AChE- ⁇ complexes that are more toxic than the isolated ⁇ itself.
  • dual AChE inhibitors capable of interacting simultaneously with the CAS and PAS sites, are of great interest in AD since they can alleviate cognitive deficits and stop neur ⁇ -related neurotoxicity (from Ferrari, GV et al., Biochemistry 2001, 40, 10447-10457).
  • dual AChE inhibitors have been described (for example, Fernández-Bachiller, MI et al., ChemMedChem 2009, 4, 828-841; Mu ⁇ oz-Torrero, D., Curr. Med. Chem. 2008, 15, 2433-2455).
  • oxidative damage is a fact that precedes the appearance of other lesions characteristic of the disease, such as senile plaques and neurofibrillar clews (Gu, F. et al., Neurosci. Lett. 2008, 440, 44-48; Moreira, PI et al., CNS Neurol. Disord. Drug Targets 2008, 7, 3-10; Goldsbury, C. et al., Aging Ce // 2008, 7, 771-775) .
  • the present invention relates to a compound of formula (I):
  • R a and R b are independently selected from hydrogen, alkyl (substituted or unsubstituted), cycloalkyl (substituted or unsubstituted), alkoxy (substituted or unsubstituted), alkenyl (substituted or unsubstituted), aryl (substituted or unsubstituted), heteroaryl (substituted or unsubstituted), or halogen, with the proviso that they are not halogen when bound to an N.
  • r is selected from 0, 1 or 2.
  • j and k are numbers that are independently selected between 1 and 8.
  • W, X, Y and Z are independently selected from CH or N; when W is N, then R 12 does not exist;
  • R15 does not exist; or an isomer, a pharmaceutically acceptable salt, a pro-drug or a solvate thereof.
  • the present invention also relates to the use of the previously defined compounds of general formula I in the manufacture of a medicament or a pharmaceutical composition with neuroprotective, antioxidant and cholinergic properties, preferably for the treatment of cognitive disorders such as senile dementia, dementia vascular, cognitive impairment, attention deficit disorder, and / or neurodegenerative diseases such as Alzheimer's disease, prion pathologies (eg Creutzfeld-Jacob disease), Parkinson's disease, systemic amyloidosis, amyotrophic lateral sclerosis and related ailments.
  • cognitive disorders such as senile dementia, dementia vascular, cognitive impairment, attention deficit disorder, and / or neurodegenerative diseases such as Alzheimer's disease, prion pathologies (eg Creutzfeld-Jacob disease), Parkinson's disease, systemic amyloidosis, amyotrophic lateral sclerosis and related ailments.
  • the authors of the present invention have designed new multifunctional products derived from bis (aralkyl) amino- (hetero) aryl that combine neuroprotective and cholinergic properties in a low molecular weight molecule. They are potent neuroprotectors against mitochondrial oxidative stress and increase the levels of the neurotransmitter acetylcholine through its union with the CAS of AChE. In addition, these products bind to the AChE PAS by inhibiting the aggregation of ⁇ mediated by AChE. In addition, they are not toxic and would cross the blood brain barrier to reach their therapeutic targets located in the CNS.
  • the compounds of the invention are characterized by two aromatic fragments derived respectively from 6-membered bis (aralkyl) amine and aromatic system, linked by a suitable linker. Their biological properties can be modulated by varying the nature of the aromatic and spacer fragments, as well as modifying the number and nature of the substituents of the aromatic rings and the spacer, as well as the length of the latter. As will be demonstrated with the examples, the compounds of the invention are not toxic, have interesting neuroprotective properties against mitochondrial oxidative stress, inhibit AChE by interacting simultaneously with the enzyme's CAS and PAS sites, inhibit ⁇ aggregation and penetrate the SNC
  • the present invention relates to a compound of formula (I)
  • R a and R are independently selected from hydrogen, alkyl (substituted or unsubstituted), cycloalkyl (substituted or unsubstituted), alkoxy (substituted or unsubstituted), alkenyl (substituted or unsubstituted), aryl (substituted or no- substituted), heteroaryl (substituted or unsubstituted), or halogen, with the proviso that they are not halogen when bound to an N.
  • r is selected from 0, 1 or 2.
  • j and k are numbers that are independently selected between 1 and 8.
  • W, X, Y and Z are independently selected from CH or N;
  • R15 does not exist; or an isomer, a pharmaceutically acceptable salt, a pro-drug or a solvate thereof.
  • alkyl refers, in the present invention, to radicals of hydrocarbon chains, linear or branched, having 1 to 10 carbon atoms, preferably 1 to 4, and which are attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, / -propyl, n-butyl, ferc-butyl, sec-butyl, n-pentyl, n-hexyl etc.
  • the alkyl groups may be optionally substituted by one or more substituents such as halogen, hydroxyl, alkoxy, carboxyl, carbonyl, cyano, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.
  • alkenyl refers to hydrocarbon chain radicals containing one or more double carbon-carbon bonds, for example, vinyl, 1- propenyl, allyl, isoprenyl, 2-butenyl, 1,3-butadienyl etc.
  • Alkenyl radicals may be optionally substituted by one or more substituents such as halo, hydroxy, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.
  • Cycloalkyl refers, in the present invention, to a stable monocyclic or bicyclic radical of 3 to 10 members, which is saturated or partially saturated, and which only consists of carbon and hydrogen atoms, such as cyclopentyl, cyclohexyl or adamantyl and which may be optionally substituted by one or more groups such as alkyl, halogen, hydroxyl, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.
  • aryl refers in the present invention to a phenyl, naphthyl, indenyl, phenanthryl or anthracil radical.
  • the aryl radical may be optionally substituted by one or more substituents such as alkyl, haloalkyl, aminoalkyl, dialkylamino, hydroxyl, alkoxy, phenyl, mercapto, halogen, nitro, cyano and alkoxycarbonyl.
  • heterocycle refers, in the present invention, to a stable monocyclic or bicyclic radical of 3 to 15 members, which is unsaturated, saturated or partially saturated, and consisting of carbon atoms and at least one heteroatom selected from the group which consists of nitrogen, oxygen or sulfur. Preferably it has 4 to 8 members with one or more heteroatoms and more preferably 5 to 6 members with one or more heteroatoms.
  • the heterocycle may be a monocyclic, bicyclic or tricyclic system, which may include fused rings.
  • the nitrogen, carbon and sulfur atoms of the heterocyclic radical may optionally be oxidized;
  • the nitrogen atoms may optionally be quaternized and the heterocyclic radical may be partially or fully saturated or aromatic.
  • heterocycles can be, not limited to: azepines, indols, imidazoles, isothiazoles, thiadiazoles, furan, tetrahydrofuran, benzimidazole, benzothiazole, piperidine, piperazine, purine, quinoline.
  • aryloxy refers to a radical of formula Ar-O-R, where Ar is an aryl group and R is an alkyl group as defined above.
  • alkoxy refers to a radical of formula O-R where R is an alkyl group as defined above.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • R3-R5 and R7-R10 are H.
  • R6 is C1-C4 alkyl. In a more preferred embodiment, R6 is CH 3 .
  • j and k are 1.
  • R1 and R2 are independently selected from hydrogen, halogen or alkoxy.
  • the present invention relates to a compound of formula (II)
  • R to R15 are independently selected from H, OH or alkoxy.
  • m + n + p + q is a value that is selected from 2, 3, 4, 5, 6, 7,
  • m + n + p + q is a value that is selected from 3, 4 or 5.
  • the spacer [A] m - [B] n - [D] p - [E] q is selected from the formulas (CH 2 ) r-CO-N Ra- (CH 2 ) s-, - (CH 2 ) r -NR to -CO- (CH 2 ) s -, (CH 2 ) r -CO-O- (CH 2 ) S -, - (CH 2 ) r -O-CO- (CH 2 ) s-, wherein R a is defined as in claim 1; rys are independently selected from 0 to 8.
  • the spacer has the formula - (CH 2 ) r -CO-N R a - (CH 2 ) s - more preferably, r is 0 and s is 2.
  • the spacer has the formula - (CH 2 ) r -NR to -CO- (CH 2 ) s-. More preferably, r is 1 and s is 2. More preferably, r is 1 and s is 0. More preferably, R a is H.
  • the spacer has the formula (CH 2 ) r-CO-0- (CH 2 ) s-. More preferably, r is 0 and s is 1.
  • the present invention relates to a compound of formula (IV):
  • Rn to Ri 4 are independently selected from hydrogen or OH.
  • m + n + p + q is a value that is selected from 2, 3, 4, 5, 6, 7, 8, 9, or 10. More preferably m + n + p + q is 2.
  • the spacer [A] m - [B] n - [D] p - [E] q is selected from the formulas (CH 2 ) r -CO-NR a - (CH 2 ) s -, - (CH 2 ) r -NR to -CO- (CH 2 ) s -, (CH 2 ) r -CO- O- (CH 2 ) s -, - (CH 2 ) r -O-CO- (CH 2 ) s-, wherein R a is defined as in claim 1; rys are independently selected from a value between 0 and 8.
  • the spacer has the formula - (CH 2 ) r -CO-NR a - (CH 2 ) s -.
  • rys are zero.
  • R a is H.
  • the present invention relates to a compound that is selected from the following group:
  • the compounds of the present invention represented by formula (I) may include isomers, depending on the presence of multiple bonds (eg, Z, E), including optical isomers or enantiomers, depending on the presence of chiral centers.
  • the individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention, that is, the term isomer also refers to any mixture of isomers, such as diastereomers, racemic, etc., even their optically isomers. assets or mixtures in different proportions thereof.
  • the individual enantiomers or diastereoisomers, as well as mixtures thereof, can be separated by conventional techniques.
  • prodrugs of the compounds of formula (I) include any compound derived from a compound of formula (I) - for example and not limited to: esters (including carboxylic acid esters, amino acid esters, phosphate esters, esters of sulphonate of metal salts, etc.), carbamates, amides, etc. - that when administered to an individual can be transformed directly or indirectly into said compound of formula (I) in said individual.
  • said derivative is a compound that increases the bioavailability of the compound of formula (I) when administered to an individual or that enhances the release of the compound of formula (I) in a biological compartment.
  • the nature of said derivative is not critical as long as it can be administered to an individual and provides the compound of formula (I) in a biological compartment of an individual.
  • the preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.
  • the compounds of the invention may be in crystalline form as free compounds or as solvates.
  • the term "solvate”, as used herein includes both pharmaceutically acceptable solvates, that is, solvates of the compound of formula (I) that can be used in the manufacture of a medicament, as pharmaceutically acceptable solvates, which may be useful in the preparation of pharmaceutically acceptable solvates or salts.
  • the nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable.
  • the solvate is a hydrate.
  • Solvates can be obtained by conventional solvation methods known to those skilled in the art.
  • the compounds of formula (I), their salts, prodrugs or solvates will preferably be found in a pharmaceutically acceptable or substantially pure form, that is, having a pharmaceutically acceptable level of purity excluding pharmaceutical additives. normal such as diluents and carriers, and not including material considered toxic at normal dosage levels.
  • the purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, and still more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (I), or of its salts, solvates or prodrugs.
  • the compounds of the present invention of formula (I) can be obtained or produced by a chemical synthetic route or obtained from a natural material of different origin.
  • compositions are the adjuvants and vehicles known to those skilled in the art and commonly used in the elaboration of therapeutic compositions.
  • therapeutically effective amount refers to the amount of the agent or compound capable of developing the therapeutic action determined by its pharmacological properties, calculated to produce the desired effect and, in general, will be determined, among other causes, due to the characteristics of the compounds, including the age, condition of the patient, the severity of the alteration or disorder, and the route and frequency of administration.
  • the compounds described in the present invention, their salts, prodrugs and / or solvates as well as the pharmaceutical compositions containing them can be used together with other drugs, or additional active ingredients, to provide a combination therapy.
  • Said additional drugs may be part of the same pharmaceutical composition or, alternatively, they may be provided in the form of a separate composition for simultaneous or non-simultaneous administration to the pharmaceutical composition comprising a compound of formula (I), or a salt, prodrug or solvate thereof.
  • said therapeutic composition is prepared in the form of a solid form or aqueous suspension, in a pharmaceutically acceptable diluent.
  • the therapeutic composition provided by this invention may be administered by any appropriate route of administration, for which said composition will be formulated in the pharmaceutical form appropriate to the route of administration chosen.
  • administration of the therapeutic composition provided by this invention is performed orally, topically, rectally or parenterally (including subcutaneously, intraperitoneally, intradermally, intramuscularly, intravenously, etc.).
  • the present invention relates to the process of obtaining a compound of formula (I) comprising the following steps:
  • step (b) Add triethylamine and benzotriazol-1-yl-oxytripyrrolidinphosphonium hexafluorophosphate (PyBOP) to the solution of step (a) under inert conditions.
  • PyBOP benzotriazol-1-yl-oxytripyrrolidinphosphonium hexafluorophosphate
  • step (b) React the solution obtained in step (b) with the solution obtained in step (c) at room temperature.
  • the present invention also relates to pharmaceutical compositions comprising at least one compound of the invention, or a tautomer, a pharmaceutically acceptable salt, a derivative or a prodrug thereof, together with a pharmaceutically acceptable carrier or carrier, an excipient or a vehicle, for administration to a patient.
  • the pharmaceutical composition further comprises another active ingredient.
  • compositions are solids (tablets, pills, capsules, granulated solid, etc.) or liquids (solutions, suspensions or emulsions) prepared for oral, nasal, topical or parenteral administration.
  • the pharmaceutical compositions are suitable for oral administration, in solid or liquid form.
  • Possible forms for oral administration are tablets, capsules, syrups or solutions and may contain conventional excipients known in the pharmaceutical field, as aggregating agents (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinyl pyrrolidone), fillers (eg lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), disintegrants (eg starch, polyvinyl pyrrolidone or microcrystalline cellulose) or a pharmaceutically acceptable surfactant such as sodium lauryl sulfate.
  • aggregating agents eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinyl pyrrolidone
  • fillers eg lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine
  • disintegrants eg starch, polyviny
  • compositions for oral administration can be prepared by conventional methods of Galenic Pharmacy, as mixing and dispersion.
  • the tablets can be coated following methods known in the pharmaceutical industry.
  • compositions can be adapted for parenteral administration, as sterile solutions, suspensions, or lyophilized products of the invention, using the appropriate dose.
  • Suitable excipients such as pH buffering agents or surfactants, can be used.
  • the aforementioned formulations can be prepared using conventional methods, such as those described in the Pharmacopoeias of different countries and in other reference texts.
  • the administration of the compounds or compositions of the present invention can be performed by any suitable method, such as intravenous infusion and oral, intraperitoneal or intravenous routes. Oral administration is preferred for the convenience of patients and for the chronic nature of the diseases to be treated.
  • the amount administered of a compound of the present invention will depend on the relative efficacy of the compound chosen, the severity of the disease to be treated and the weight of the patient. However, the compounds of this invention will be administered one or more times a day, for example 1, 2, 3 or 4 times daily, with a total dose between 0.1 and 1000 mg / kg / day. It is important to keep in mind that it may be necessary to introduce variations in the dose, depending on the age and condition of the patient, as well as modifications in the route of administration.
  • the compounds and compositions of the present invention can be used together with other medicaments in combination therapies.
  • the other drugs may be part of the same composition or of a different composition, for administration at the same time or at different times.
  • the present invention relates to the use of at least one compound of formula (I) for the manufacture of a medicament.
  • the present invention relates to the use of at least one compound of formula (I) for the manufacture of a medicament for the treatment of a cognitive disorder that is selected from senile dementia, cerebrovascular dementia, mild alteration of knowledge, disorders of the attention deficit, neurodegenerative dementia diseases associated with aberrant protein aggregations such as Alzheimer's disease, amyotrophic lateral sclerosis, prion diseases such as Creutzfeldt-Jakob disease or Gerstmann-Straussler-Scheinker disease, Parkinson's disease, polyglutamine disease, tauopathies such as Pick's disease, frontotemporal dementia, progressive supranuclear paralysis or systemic amyloidosis.
  • a cognitive disorder that is selected from senile dementia, cerebrovascular dementia, mild alteration of knowledge, disorders of the attention deficit, neurodegenerative dementia diseases associated with aberrant protein aggregations such as Alzheimer's disease, amyotrophic lateral sclerosis, prion diseases such as Creutzfeldt-Jakob disease or Gerstmann-
  • the cognitive disorder is Alzheimer's disease.
  • the present invention relates to the use of a compound of formula (I) as a reagent in biological assays.
  • Scheme 1 shows the process for the preparation of the compounds of the invention of general formula I, when the connector contains a group amide.
  • Other methods of synthesizing compounds with amine, ether or ester linkages are apparent to an experienced chemist.
  • reaction products can be purified by conventional methods, such as crystallization or chromatography.
  • crystallization or chromatography When the process described above leads to mixtures of isomers, these can be separated by conventional techniques such as preparative chromatography.
  • stereogenic centers In the case of stereogenic centers the compounds can be obtained in the form of racemic or pure enantiomers can be prepared by stereospecific synthesis or by resolution.
  • the cell viability of the compounds of the invention was measured in the human neuroblastoma cell line SH-SY5Y.
  • the cells used were between passages 3 and 16 after thawing and were maintained in DMEM medium (Dulbecco's modified Eagle's medium), containing 15 non-essential amino acids and supplemented with 10% fetal bovine serum, 1 mM glutamine, 50 U mL "1 of penicillin, and 50 ⁇ g mL " 1 of streptomycin (GIBCO, Madrid, Spain). Cultures were seeded in flasks containing medium supplemented and maintained at 37 0 C in humidified air with 5% carbon dioxide, passaging 1: 4 twice a week.
  • DMEM medium Dulbecco's modified Eagle's medium
  • SH-SY5Y cells were recultured in 48-well plates with a seeding density of 10 5 cells per well and were treated for 24 hours with the compounds of the invention at various concentrations.
  • the quantitative measurement of cell death was performed by measuring the percentage of the enzyme lactate dehydrogenase (LDH) released to the extracellular medium (cytotoxicity detection kit, Roche).
  • LDH lactate dehydrogenase
  • the amount of LDH was evaluated using a microplate reader (Labsystems MES Reader MF) at 492 nm (excitation wavelength) and 620 nm (emission wavelength). Controls with 100% cell viability were used. At 1 ⁇ all products have 100% cell viability, indicating that the compounds of the present invention are not toxic and have a wide range of therapeutic safety.
  • Example 3 Neuroprotective properties of the compounds of the invention against mitochondrial oxidative stress
  • the cytoprotective action of the compounds against cell death caused by mitochondrial free radicals was evaluated.
  • Mitochondrial oxidative stress conditions were simulated using a mixture of rotenone (30 ⁇ ) and oligomycin A (10 ⁇ ). The compounds were incubated with the cells for 24 hours, after which time, the medium was replaced by a new one containing the compound to be evaluated and the toxic agent, then incubated for an additional 24 hours. Cellular survival was determined by measuring LDH activity.
  • Extracellular and intracellular LDH activity was measured by UV-vis using a cytotoxicity kit (Roche-Boehringer. Mannheim, Germany), following the manufacturer's instructions.
  • Total LDH activity is defined as the sum of intra- and extracellular activity and LDH activity released as the percentage of extracellular activity compared to total activity. The activity of the released LDH was calculated for each experiment considering as 100% the extracellular LDH, released by the vehicle with respect to the total.
  • LDHe + LDHi compound + toxic
  • the results are expressed as the average of at least three independent cultures, each containing four repetitions of each compound evaluated.
  • Melatonin was used as a reference, which has recognized neuroprotective properties against oxidative stress (Rosales-Corral, S. et al. J. Pineal Res. 2003, 35, 80-84).
  • the results are shown in table 1 and are the average of three independent experiments.
  • the compounds of the invention are capable of capturing mitochondrial free radicals and protecting neurons from mitiocondrial oxidative damage.
  • the compounds of this invention are potential drugs for the treatment of pathologies or conditions related to oxidative stress or excessive mitochondrial free radical production.
  • Example 4 Evaluation of the compounds of the invention as inhibitors of the human acetylcholinesterase enzyme (h-AChE).
  • h-AChE human acetylcholinesterase
  • the compounds to be evaluated were pre-incubated with the enzyme for 5 minutes at 30 ° C, the substrate was added and the absorbance changes at 412 nm were measured every 5 minutes in a 96-well microplate UV-vis reader (Multiskan Spectrum, Thermo Electron Co.). The reaction rates were compared and the percentages of inhibition due to the presence of the compounds being analyzed were calculated. The value of IC 5 or is defined as the concentration of compound that reduces enzymatic activity by 50%. Tacrine, a known h-AChE inhibitor was used as control of the quality of the assay. The results are found in table 1, expressed as the average of three independent experiments.
  • the h-AChE inhibition results indicate that the compounds of the invention are capable of increasing neurotransmitter levels and, therefore, are capable of increasing cognitive abilities. As a consequence, the compounds of the invention are potential drugs for the symptomatic treatment of Alzheimer's disease and related pathologies.
  • Example 5 Test for displacement of propidium iodide from the peripheral anionic site of AChE by the compounds of the invention.
  • the results of the propidium displacement test indicate that the compounds of the invention bind to the peripheral anionic site of AChE and therefore, would be able to inhibit the aggregation of Abeta promoted by This enzyme
  • the compounds of this invention are potential drugs for the treatment of neurodegenerative diseases in which aberrant protein aggregates are produced, such as Alzheimer's disease.
  • NP neuroprotection (NP,%) against rotenone: oligomycin A (30:10 ⁇ ) using 1 ⁇ of compound, inhibition of human acetylcholinesterase (h- AChE) as IC50 ( ⁇ ), and displacement of propidium (%) from the peripheral anionic site (PAS) of AChE at three concentrations of the compounds evaluated.
  • h- AChE human acetylcholinesterase
  • PAS peripheral anionic site
  • Example 6 In vitro evaluation of the penetration into the central nervous system of the compounds of the invention.
  • pH 7.4 saline phosphate buffer (PBS) and dodecane were purchased from Sigma, Aldrich, Acros and Fluka.
  • Millex filters PVDF membrane, 25 mm diameter, pore size 0.45 ⁇
  • 96-well microplates were purchased from Millipore.
  • the pig brain lipid extract (PBL) was purchased from Avanti Polar Lipids.
  • PVDF filter pore size 0.45 ⁇
  • the wells of the acceptor plate are tear-shaped.
  • the receptor plate was filled with 170 ⁇ of PBS: ethanol (9: 1) and the donor plate filter surface was impregnated with 4 ⁇ of PBL in dodecane (20 mg mL "1 ).
  • the compounds to be evaluated were dissolved in PBS: ethanol (9: 1) at 1 mg mL "1 , filtered through a Millex filter and then added to the donor wells (170 ⁇ ).
  • the donor plate was carefully placed on the acceptor for 240 minutes at 25 ° C. After incubation, the donor plate was Withdrawal and concentration of each of the products on the acceptor plate was determined by UV-vis. Each sample was analyzed at five wavelengths in four wells and at least in three independent experiments. The results are expressed as mean ⁇ standard deviation.
  • An optimal penetration into the CNS is an essential property that drugs designed to treat pathologies or conditions that affect the brain must possess, such as Alzheimer's disease.
  • the results of the PAMPA-BBB test indicate that the compounds of the invention would be able to penetrate the CNS and therefore, would be able to reach their therapeutic targets located in the brain.

Abstract

La présente invention concerne le domaine de la recherche et de l'industrie pharmaceutique, plus précisément, l'invention concerne des composés chimiques dérivés de bis(aralkyl)amine et d'(hétéro)aryle, les procédés permettant de les préparer, les compositions pharmaceutiques les contenant et leur utilisation pour la fabrication d'un médicament destiné au traitement de troubles cognitifs. En particulier, l'invention concerne des composés et des compositions protégeant les neurones du stress oxydatif mitochondrial, augmentant les niveaux du neuroémetteur acétylcholine et empêchant la neurodégénérescence associée au dysfonctionnement du peptide β-amiloïde. Ces propriétés pharmacologiques sont utiles pour le traitement de pathologies neurodénératives, y compris la maladie d'alzheimer.
PCT/ES2010/070702 2009-10-29 2010-10-28 Dérivés de bis(aralkyl)amine et système (hétéro)aromatiques à six membres et utilisation de ceux-ci pour le traitement de pathologies neurodégénératives, y compris la maladie d'alzheimer WO2011051535A1 (fr)

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