ES2443538B1 - APAF1 inhibitor beta-lactam compounds - Google Patents
APAF1 inhibitor beta-lactam compounds Download PDFInfo
- Publication number
- ES2443538B1 ES2443538B1 ES201231137A ES201231137A ES2443538B1 ES 2443538 B1 ES2443538 B1 ES 2443538B1 ES 201231137 A ES201231137 A ES 201231137A ES 201231137 A ES201231137 A ES 201231137A ES 2443538 B1 ES2443538 B1 ES 2443538B1
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- carboxamide
- aryl
- pharmaceutically acceptable
- triazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn - After Issue
Links
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- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
Abstract
La presente invención se refiere a compuestos para la prevención y/o tratamiento de trastornos causados por muerte celular por apoptosis o para la prevención de procesos degenerativos causados por la muerte celular por apoptosis, a través de la inhibición del factor de activación de la peptidasa apoptótica 1 (APAF1, Apoptotic Peptidase Activating Factor 1).The present invention relates to compounds for the prevention and / or treatment of disorders caused by cell death by apoptosis or for the prevention of degenerative processes caused by cell death by apoptosis, through the inhibition of the apoptotic peptidase activation factor. 1 (APAF1, Apoptotic Peptidase Activating Factor 1).
Description
DESCRIPCIÓN DESCRIPTION
Compuestos beta-lactámicos inhibidores de APAF1. APAF1 inhibitor beta-lactam compounds.
La presente invención se refiere a compuestos para la prevención y/o tratamiento de trastornos causados por muerte 5 celular programada o apoptosis a través de la inhibición del factor de activación de la peptidasa apoptótica 1 (APAF1). The present invention relates to compounds for the prevention and / or treatment of disorders caused by programmed cell death or apoptosis through the inhibition of the apoptotic peptidase 1 activation factor (APAF1).
10 10
La apoptosis, o muerte celular programada, es un fenómeno fisiológico complejo implicado en el mantenimiento de la homeostasis celular. La apoptosis está regulada por múltiples mecanismos celulares de control y muchas patologías tienen su base en una disfunción de la apoptosis. Así, un exceso de apoptosis conduce a procesos de necrosis tisular (p.e. muerte de cardiomiocitos en los casos de infarto de miocardio), mientras que una apoptosis excesivamente inhibida conlleva la supervivencia celular ilimitada (p.e. procesos neoplásicos). Los componentes 15 celulares que regulan la apoptosis se encuentran en un constante equilibrio dinámico en una célula sana y su regulación depende tanto de estímulos celulares internos (por ejemplo, inducción de la replicación del DNA cuando la célula entra en división celular) como externos (por ejemplo, hormonas y factores de crecimiento). En algunas condiciones fisiopatológicas (por ejemplo, anoxia en células de órganos que deben ser transplantados, tratamiento con sustancias tóxicas) la apoptosis está incrementada y las células mueren en exceso, imposibilitando la 20 funcionalidad del tejido afectado y comprometiendo en algunos casos su supervivencia. Apoptosis, or programmed cell death, is a complex physiological phenomenon involved in the maintenance of cell homeostasis. Apoptosis is regulated by multiple cellular control mechanisms and many pathologies are based on apoptosis dysfunction. Thus, an excess of apoptosis leads to tissue necrosis processes (e.g. death of cardiomyocytes in cases of myocardial infarction), while an excessively inhibited apoptosis leads to unlimited cell survival (e.g. neoplastic processes). The cellular components that regulate apoptosis are in a constant dynamic equilibrium in a healthy cell and their regulation depends on both internal cellular stimuli (for example, induction of DNA replication when the cell enters cell division) and external (for example, hormones and growth factors). In some pathophysiological conditions (for example, anoxia in the cells of organs that must be transplanted, treatment with toxic substances), apoptosis is increased and the cells die excessively, making it impossible for the affected tissue to function and compromising survival in some cases.
Los mecanismos moleculares de inducción de la apoptosis inducen una cascada de señalización que activa una familia de cisteína aspartil proteasas denominadas caspasas, conocidas también como efectores de la apoptosis. Para que éstas puedan activarse es necesaria la formación de un complejo molecular denominado apoptosoma. El 25 apoptosoma es un complejo multiproteico holoenzimático formado por el factor de activación de la proteasa apoptótica 1 (APAF1, Apoptotic Peptidase Activating Factor 1) activado por citocromo-c, dATP y la procaspasa-9. Se ha demostrado que la inhibición de APAF1 inhibe la formación del complejo apoptosoma y que ello provoca una inhibición de la apoptosis (medida a través de la activación de caspasas). En ensayos celulares en los que se ha inducido apoptosis mediante compuestos químicos o por hipoxia, se ha observado un incremento de la 30 supervivencia de las células cuando éstas han sido previamente tratadas con inhibidores de apoptosis. The molecular mechanisms of induction of apoptosis induce a signaling cascade that activates a family of aspartyl cysteine proteases called caspases, also known as effectors of apoptosis. For them to be activated, the formation of a molecular complex called apoptosome is necessary. Apoptosome is a holoenzymatic multiproteic complex formed by the apoptotic protease 1 activation factor (APAF1, Apoptotic Peptidase Activating Factor 1) activated by cytochrome-c, dATP and procaspase-9. It has been shown that the inhibition of APAF1 inhibits the formation of the apoptosome complex and that this causes an inhibition of apoptosis (measured through the activation of caspases). In cellular assays in which apoptosis has been induced by chemical compounds or by hypoxia, an increase in cell survival has been observed when they have been previously treated with apoptosis inhibitors.
Se han descrito numerosos procesos patológicos en los que está implicada la apoptosis como pueden ser el daño cerebral producido tras una isquemia cerebral, traumatismos, daño en médula espinal, meningitis, enfermedad de Alzheimer, enfermedad de Parkinson, enfermedad de Huntington, enfermedad de Kennedy, esclerosis múltiple, 35 afecciones relacionadas con priones, infarto de miocardio, así como otras formas de enfermedades crónicas o agudas de corazón. También en el proceso de extracción y transplante de un órgano, sus células están sometidas a una situación de hipoxia que puede desembocar en la muerte celular comprometiendo la viabilidad y funcionalidad del órgano. En el mercado existen soluciones de transporte de órganos que exclusivamente aportan entornos tamponados y estériles, pero no contienen moléculas activas que impidan la muerte celular por apoptosis. Por otra 40 parte, una variedad de procesos inflamatorios tienen como consecuencia la mortalidad de células por vía apoptótica y entre el repertorio de soluciones terapéuticas para controlar esta pérdida de células no se encuentran compuestos específicos que actúen directamente como inhibidores de la apoptosis. También se ha constatado que numerosos procesos de neurodegeneración celular se producen con intervención decisiva de la vía apoptótica, sin que se hayan aplicado hasta el momento soluciones que tengan una acción protectora definida sobre esta vía de muerte celular 45 programada. También se ha relacionado con estados patológicos relacionados con hepatitis alcohólica y otras posibles aplicaciones se pueden relacionar con tratamientos de alopecia. Numerous pathological processes have been described in which apoptosis is involved, such as brain damage caused by cerebral ischemia, trauma, spinal cord damage, meningitis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Kennedy disease, Multiple sclerosis, 35 prion-related conditions, myocardial infarction, as well as other forms of chronic or acute heart disease. Also in the process of extracting and transplanting an organ, its cells are subjected to a situation of hypoxia that can lead to cell death compromising the viability and functionality of the organ. In the market there are organ transport solutions that exclusively provide buffered and sterile environments, but do not contain active molecules that prevent cell death by apoptosis. On the other hand, a variety of inflammatory processes result in apoptotic cell mortality and among the repertoire of therapeutic solutions to control this cell loss there are no specific compounds that act directly as apoptosis inhibitors. It has also been found that numerous processes of cellular neurodegeneration are produced with decisive intervention of the apoptotic pathway, without so far solutions having a defined protective action on this programmed cell death path have been applied. It has also been related to pathological conditions related to alcoholic hepatitis and other possible applications may be related to alopecia treatments.
La identificación de inhibidores del proceso de muerte celular por apoptosis puede ser de gran relevancia como alternativas terapéuticas en una amplia variedad de patologías y disfunciones de órganos. Así, se han diseñado 50 inhibidores que actúan a distintos niveles de la cascada apoptótica como son factores de transcripción, quinasas, reguladores de la permeabilización de la membrana mitocondrial e inhibidores de la familia de las caspasas. Sin embargo, dado que la formación del apoptosoma es una etapa clave en el inicio la cascada apoptótica y la consecuente activación de las caspasas, la inhibición de la activación de APAF1 puede tener un mayor impacto sobre la inhibición de la activación de las caspasas y por tanto de la apoptosis. 55 The identification of inhibitors of the process of cell death by apoptosis can be of great relevance as therapeutic alternatives in a wide variety of pathologies and organ dysfunctions. Thus, 50 inhibitors have been designed that act at different levels of the apoptotic cascade such as transcription factors, kinases, regulators of mitochondrial membrane permeabilization and inhibitors of the caspases family. However, since apoptosome formation is a key stage in the beginning of the apoptotic cascade and the consequent activation of caspases, inhibition of APAF1 activation may have a greater impact on inhibition of caspases activation and by both of apoptosis. 55
Por otra parte, investigaciones recientes destacan el papel que APAF-1 puede tener en otros procesos implicados con la mitocondria, con las rutas de inflamación o con la propia regulación de mecanismos celulares distintos de la apoptosis. On the other hand, recent research highlights the role that APAF-1 may have in other processes involved with the mitochondria, with the inflammation pathways or with the regulation of cellular mechanisms other than apoptosis.
60 60
Existen indicios en la literatura científica sobre las implicaciones terapéuticas de la inhibición de APAF1. Así, la transducción en un modelo animal de Parkinson de un dominante negativo de APAF1 mediante adenovirus, mostró ser más eficaz que los inhibidores de Caspasa-1 existentes en el mercado. Recientemente la sobreexpresión de la proteína específica inhibidora de APAF1 (specific APAF1 inhibitory protein – AIP) mostró actividad protectora frente daño cerebral inducido por isquemia (Gao et al Stroke 2010; 41) 65 There are indications in the scientific literature about the therapeutic implications of APAF1 inhibition. Thus, the transduction in a Parkinson's animal model of a dominant negative of APAF1 by adenovirus, proved to be more effective than the existing Caspasa-1 inhibitors in the market. Recently, overexpression of the specific APAF1 inhibitor protein (AIPA inhibitory protein - AIP) showed protective activity against ischemia-induced brain damage (Gao et al Stroke 2010; 41) 65
Por otra parte, el documento WO2007060524 describe compuestos derivados de [1,4]diazepan-2,5-diona que actúan como inhibidores de la apoptosis, así como a los procesos para su preparación, composiciones farmacéuticas que los contienen y su uso médico. Mientras que el documento WO2011012746 describe compuestos derivados de 2,5-piperazinediona, capaces de inhibir APAF1, también se describe su uso como principios activos farmacéuticos para la prevención y/o el tratamiento de una condición patológica y/o fisiológica asociada a un 5 incremento de la apoptosis. On the other hand, WO2007060524 describes compounds derived from [1,4] diazepan-2,5-dione that act as inhibitors of apoptosis, as well as the processes for their preparation, pharmaceutical compositions containing them and their medical use. While WO2011012746 describes compounds derived from 2,5-piperazinedione, capable of inhibiting APAF1, its use as pharmaceutical active ingredients for the prevention and / or treatment of a pathological and / or physiological condition associated with an increase is also described. of apoptosis.
Por tanto, actualmente existe la necesidad de obtener nuevos compuestos inhibidores de APAF1 más potentes, para su uso en la prevención y/o tratamiento de una condición patológica y/o fisiológica asociada a un incremento de la apoptosis. 10 Therefore, there is currently a need to obtain new, more potent APAF1 inhibitor compounds, for use in the prevention and / or treatment of a pathological and / or physiological condition associated with an increase in apoptosis. 10
BREVE DESCRIPCIÓN DE LA INVENCIÓN BRIEF DESCRIPTION OF THE INVENTION
La presente invención se refiere a una nueva familia de compuestos beta-lactámicos de fórmula general (I) y sales farmacéuticamente aceptables del mismo para uso en la prevención y/o tratamiento de una condición patológica y/o 15 fisiológica asociada a un incremento de la apoptosis, a través de la inhibición de APAF1. The present invention relates to a new family of beta-lactam compounds of general formula (I) and pharmaceutically acceptable salts thereof for use in the prevention and / or treatment of a pathological and / or physiological condition associated with an increase in the apoptosis, through the inhibition of APAF1.
DESCRIPCIÓN DETALLADA DE LA INVENCIÓN DETAILED DESCRIPTION OF THE INVENTION
La presente invención se refiere a una familia de compuestos de fórmula general (I) que poseen actividad como 20 inhibidores de APAF1. The present invention relates to a family of compounds of general formula (I) that possess activity as APAF1 inhibitors.
Así, un primer aspecto de la presente invención se refiere a un compuesto de fórmula (I) Thus, a first aspect of the present invention relates to a compound of formula (I)
25 NR3ONNNR1HNR2O 25 NR3ONNNR1HNR2O
(I) (I)
y cualquiera de sus sales farmacéuticamente aceptables, donde: and any of its pharmaceutically acceptable salts, where:
30 30
R1, R2 y R3 se seleccionan independientemente entre H, (C1-C10)alquilo, (C2-C10)alquenilo, (C0-C3)alquilo-arilo, (C0-C3)alquilo-heteroarilo, (C0-C3)alquilo-cicloalquilo y (C0-C3)alquilo-heterociclo no aromático, R1, R2 and R3 are independently selected from H, (C1-C10) alkyl, (C2-C10) alkenyl, (C0-C3) alkyl-aryl, (C0-C3) alkyl-heteroaryl, (C0-C3) alkyl- cycloalkyl and (C0-C3) non-aromatic alkyl heterocycle,
donde los grupos (C1-C10)alquilo, (C2-C10)alquenilo, (C0-C3)alquilo-arilo, (C0-C3)alquilo-heteroarilo, (C0-C3)alquilo-cicloalquilo y (C0-C3)alquilo-heterociclo no aromático pueden estar opcionalmente sustituidos por uno o 35 varios sustituyentes seleccionados independientemente entre halógeno, OH, OR4, OCF3, SH, SR4, N3, NH2, NR4R5, NHCOR4; COOH, COOR4, OCOR4, NO2, CN, COR4, CONR4R5, SO2NH2, NHSO2CH3, arilo, heteroarilo y heterociclo no aromático, donde R4 y R5 se seleccionan independientemente entre hidrogeno, (C1-C5)alquilo, (C2-C5)alquenilo, (C0-C3)alquilo-arilo, (C0-C3)alquilo-heteroarilo, (C0-C3)alquilo-cicloalquilo y (C0-C3)alquilo-heterociclo no aromático. 40 where the (C1-C10) alkyl, (C2-C10) alkenyl, (C0-C3) alkyl-aryl, (C0-C3) alkyl-heteroaryl, (C0-C3) alkyl-cycloalkyl and (C0-C3) alkyl groups Non-aromatic heterocycle may be optionally substituted by one or several substituents independently selected from halogen, OH, OR4, OCF3, SH, SR4, N3, NH2, NR4R5, NHCOR4; COOH, COOR4, OCOR4, NO2, CN, COR4, CONR4R5, SO2NH2, NHSO2CH3, aryl, heteroaryl and non-aromatic heterocycle, where R4 and R5 are independently selected from hydrogen, (C1-C5) alkyl, (C2-C5) alkenyl, (C0-C3) alkyl-aryl, (C0-C3) alkyl-heteroaryl, (C0-C3) alkyl-cycloalkyl and (C0-C3) non-aromatic alkyl-heterocycle. 40
Los términos “(C1-C10)alquilo, (C1-C5)alquilo y (C0-C3)alquilo” se refieren, en la presente invención, a radicales de cadenas hidrocarbonadas, lineales o ramificadas, que tienen de 1 a 10 átomos de carbono, de 1 a 5 o de 0 a 3, respectivamente, y que se unen al resto de la molécula mediante un enlace sencillo, por ejemplo, metilo, etilo, n-propilo, i-propilo, n- butilo, tercbutilo,sec-butilo, n-pentilo, n-hexilo, etc. 45 The terms "(C1-C10) alkyl, (C1-C5) alkyl and (C0-C3) alkyl" refer, in the present invention, to hydrocarbon radicals, linear or branched, having 1 to 10 atoms of carbon, from 1 to 5 or from 0 to 3, respectively, and which are attached to the rest of the molecule by a simple bond, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, sec -butyl, n-pentyl, n-hexyl, etc. Four. Five
El término “(C2-C10)alquenilo” se refiere a radicales de cadenas hidrocarbonadas no cíclicas, lineales o ramificadas, que tienen de 2 a 10 átomos de carbono y uno o más enlaces insaturados, y que están unidos al resto de la molécula por un enlace simple, por ejemplo, vinilo, 1-propenilo, alilo, isoprenilo, 2-butenilo o 1,3-butadienilo. The term "(C2-C10) alkenyl" refers to radicals of non-cyclic, linear or branched hydrocarbon chains, having 2 to 10 carbon atoms and one or more unsaturated bonds, and which are attached to the rest of the molecule by a single bond, for example, vinyl, 1-propenyl, allyl, isoprenyl, 2-butenyl or 1,3-butadienyl.
50 fifty
El término “cicloalquilo" se refiere, en la presente invención, a un radical estable monocíclico o bicíclico de 3 a 10 miembros, que está saturado o parcialmente saturado, y que solo consiste en átomos de carbono e hidrogeno. Son ejemplos de cicloalquilo los siguientes: ciclopropilo, ciclopentilo, ciclohexilo, 1-ciclohexenilo, cicloheptilo. The term "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. Examples of cycloalkyl are the following : cyclopropyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, cycloheptyl.
El término “arilo” se refiere en la presente invención a un sistema de anillo aromático mono o policíclico que contiene 55 átomos de anillo de carbono, que tienen de entre 5 a 10 eslabones. Los arilos preferidos son sistemas de anillo aromático monocíclicos o bicíclicos. Son ejemplos de arilo, pero sin limitarse, el fenilo, naftilo, indenilo, fenantrilo o The term "aryl" refers in the present invention to a mono or polycyclic aromatic ring system containing 55 carbon ring atoms, having between 5 to 10 links. Preferred aryls are monocyclic or bicyclic aromatic ring systems. Examples of aryl, but not limited to, are phenyl, naphthyl, indenyl, phenanthryl or
antracilo, preferiblemente fenilo. El término “(C0-C3)alquilo-arilo” se entiende que comprende: arilo, (C1-C3)alquilo-arilo, y aún más preferentemente (CH2)1-3-arilo y -(CH2)1-2-CH(arilo)2, donde el (C0-C3)alquilo-arilo está sustituido por un arilo en el grupo alquilo. anthracil, preferably phenyl. The term "(C0-C3) alkyl-aryl" is understood to comprise: aryl, (C1-C3) alkyl-aryl, and even more preferably (CH2) 1-3-aryl and - (CH2) 1-2-CH (aryl) 2, where (C0-C3) alkyl-aryl is substituted by an aryl in the alkyl group.
El término “heterociclo” se refiere, en la presente invención, a un radical estable monocíclico o bicíclico conteniendo 5 de 3 a 10 miembros que puede estar saturado o parcialmente insaturado (referido como “heterociclo no aromático” en el ámbito de esta memoria) o puede ser aromático (referido como “heteroarilo” en el ámbito de esta memoria), y que consiste en átomos de carbono y al menos un heteroátomo seleccionado del grupo que consiste en nitrógeno, oxigeno o azufre. Preferiblemente tiene de 4 a 8 miembros con uno o más heteroátomos y más preferiblemente de 5 a 6 miembros con uno o más heteroátomos. Para el propósito de esta invención el heterociclo puede ser un sistema 10 monocíclico o bicíclico, que puede incluir anillos fusionados. Los átomos de nitrógeno, carbono y azufre del radical heterocíclico opcionalmente pueden estar oxidados. Ejemplos de heterociclos pueden ser, no limitativamente: morfolinilo, piperazinilo, piperidinilo, pirrolidilo, azepinilo, indolilo, imidazolilo, isotiazolilo, tiadiazolilo, furanilo, tetrahidrofuranilo, benzimidazolilo, benzotiazolilo, quinolilo y similares. The term "heterocycle" refers, in the present invention, to a stable monocyclic or bicyclic radical containing 5 to 3 to 10 members that may be saturated or partially unsaturated (referred to as "non-aromatic heterocycle" within the scope of this specification) or it can be aromatic (referred to as "heteroaryl" within the scope of this specification), and consisting of carbon atoms and at least one heteroatom selected from the group consisting 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. For the purpose of this invention the heterocycle may be a monocyclic or bicyclic system, which may include fused rings. The nitrogen, carbon and sulfur atoms of the heterocyclic radical may optionally be oxidized. Examples of heterocycles may be, but are not limited to: morpholinyl, piperazinyl, piperidinyl, pyrrolidyl, azepinyl, indolyl, imidazolyl, isothiazolyl, thiadiazolyl, furanyl, tetrahydrofuranyl, benzimidazolyl, benzothiazolyl, quinolyl and the like.
15 fifteen
Algunos de los compuestos de formula (I) de la presente invención pueden tener uno o más centros estereogénicos. La presente invención abarca todos los posibles estereoisómeros no solo sus mezclas racémicas sino también sus isómeros óptimamente activos. La obtención de un único enantiómero puede conseguirse mediante alguno de los procedimientos comúnmente empleados, por ejemplo, por resolución de la mezcla racémica mediante técnicas de recristalización, síntesis quiral, resolución enzimática, biotransformación o resolución cromatográfica. 20 Some of the compounds of formula (I) of the present invention may have one or more stereogenic centers. The present invention encompasses all possible stereoisomers not only their racemic mixtures but also their optimally active isomers. Obtaining a single enantiomer can be achieved by one of the procedures commonly used, for example, by resolution of the racemic mixture by recrystallization techniques, chiral synthesis, enzymatic resolution, biotransformation or chromatographic resolution. twenty
El término “sales farmacéuticamente aceptables” significa aquellas sales que conservan la eficacia y las propiedades biológicas de las bases libres o de los ácidos libres y que no son molestas en sentido biológico ni en ningún otro. The term "pharmaceutically acceptable salts" means those salts that retain the efficacy and biological properties of free bases or free acids and that are not bothersome in the biological sense or in any other.
Las sales farmacéuticamente aceptables pueden incluir las sales de adición de ácidos, tales como mesilatos, 25 fumaratos, clorhidratos, citratos, maleatos o tartratos. También pueden formarse sales fisiológicamente aceptables con ácidos inorgánicos como son los ácidos sulfúrico o fosfórico. Asimismo, pueden formarse sales de tipo básico de un metal alcalino, como por ejemplo el sodio, o de un metal alcalinotérreo, por ejemplo calcio o magnesio. Puede haber más de un catión o anión dependiendo del número de funciones con carga y de la valencia de los cationes y aniones. 30 Pharmaceutically acceptable salts may include acid addition salts, such as mesylates, smokers, hydrochlorides, citrates, maleates or tartrates. Physiologically acceptable salts can also be formed with inorganic acids such as sulfuric or phosphoric acids. Likewise, basic type salts of an alkali metal, such as sodium, or an alkaline earth metal, for example calcium or magnesium, can be formed. There may be more than one cation or anion depending on the number of charged functions and the valence of the cations and anions. 30
En una realización particular de la invención, R1 es (C1-C3)alquilo-arilo. In a particular embodiment of the invention, R1 is (C1-C3) alkyl-aryl.
En otra realización particular de la invención, R2 es (C1-C6)alquilo o (C1-C3)alquilo-arilo. In another particular embodiment of the invention, R2 is (C1-C6) alkyl or (C1-C3) alkyl-aryl.
En otra realización particular de la invención, R3 es (C1-C3)alquilo-arilo, (C1-C3)alquilo-heteroarilo, CH2-CH(arilo)2 o CH2-CH2-CH(arilo)2. 35 In another particular embodiment of the invention, R3 is (C1-C3) alkyl-aryl, (C1-C3) alkyl-heteroaryl, CH2-CH (aryl) 2 or CH2-CH2-CH (aryl) 2. 35
De acuerdo con otro modo de realización preferente adicional, el compuesto de fórmula (I) tal como se ha definido anteriormente se selecciona de la lista que consiste en: In accordance with another additional preferred embodiment, the compound of formula (I) as defined above is selected from the list consisting of:
N-(2,4-Diclorofenetil)-2-(2-(2,4-diclorofenetil)-2H-1,2,3-triazol-4-il)-1-(3,3-difenilpropil)-4-oxoazetidina-2-carboxamida 40 N- (2,4-Dichlorofenetyl) -2- (2- (2,4-dichlorofenetil) -2H-1,2,3-triazol-4-yl) -1- (3,3-diphenylpropyl) -4- oxoazetidine-2-carboxamide 40
N-Bencil-2-(2-bencil-2H-1,2,3-triazo-4-il)-1-(4-fluorofenetil)-4-oxoazetidina-2-carboxamida N-Benzyl-2- (2-benzyl-2H-1,2,3-triazo-4-yl) -1- (4-fluorofenetyl) -4-oxoazetidine-2-carboxamide
2-(2-Bencil-2H-1,2,3-triazol-4-il)-N-(tert-butil)-1-(2,4-diclorofenetil)-4-oxoazetidina-2-carboxamida 2- (2-Benzyl-2H-1,2,3-triazol-4-yl) -N- (tert-butyl) -1- (2,4-dichlorophenethyl) -4-oxoazetidine-2-carboxamide
45 Four. Five
N-Bencil-2-(2-bencil-2H-1,2,3-triazol-4-il)-4-oxo-1-(2-tiofen-2-il)etil)azetidina-2-carboxamida N-Benzyl-2- (2-benzyl-2H-1,2,3-triazol-4-yl) -4-oxo-1- (2-thiophene-2-yl) ethyl) azetidine-2-carboxamide
N-Bencil-2-(2-(4-fluorofenetil)-2H-1,2,3-triazol-4-il)-1-(4-metoxifenetil)-4-oxoazetidina-2-carboxamida N-Benzyl-2- (2- (4-fluorofenetyl) -2H-1,2,3-triazol-4-yl) -1- (4-methoxyphenethyl) -4-oxoazetidine-2-carboxamide
N-(Tert-butil)-2-(2-(4-fluorofenetil)-2H-1,2,3-triazol-4-il)-1-(4-metoxifenetil)-4-oxoazetidina-2-carboxamida 50 N- (Tert-butyl) -2- (2- (4-fluorofenetyl) -2H-1,2,3-triazol-4-yl) -1- (4-methoxyphenethyl) -4-oxoazetidine-2-carboxamide 50
N-(Tert-butil)-2-(2-(4-fluorofenetil)-2H-1,2,3-triazol-4-il)-4-oxo-1-(4-trifluorometoxi)bencil)azetidina-2-carboxamida N- (Tert-butyl) -2- (2- (4-fluorofenetyl) -2H-1,2,3-triazol-4-yl) -4-oxo-1- (4-trifluoromethoxy) benzyl) azetidine-2 -carboxamide
N-Bencil-(2-(2,4-diclorofenetil)-2H-1,2,3-triazol-4-il)-1-(3,3-difenilpropil)-4-oxoazetidina-2-carboxamida N-Benzyl- (2- (2,4-dichlorophenethyl) -2H-1,2,3-triazol-4-yl) -1- (3,3-diphenylpropyl) -4-oxoazetidine-2-carboxamide
55 55
N-(Tert-butil)-1-(3,3-difenilpropil)-2-(2-(4-fluorofenetil)-2H-1,2,3-triazol-4-il)-4-oxoazetidina-2-carboxamida N- (Tert-butyl) -1- (3,3-diphenylpropyl) -2- (2- (4-fluorofenetyl) -2H-1,2,3-triazol-4-yl) -4-oxoazetidine-2- carboxamide
N-(Tert-butil)-2-(2-(2,4-diclorofenetil)-2H-1,2,3-triazol-4-il)-1-(3,3-difenilpropil)-4-oxoazetidina-2-carboxamida N- (Tert-butyl) -2- (2- (2,4-dichlorophenethyl) -2H-1,2,3-triazol-4-yl) -1- (3,3-diphenylpropyl) -4-oxoazetidine- 2-carboxamide
Otro aspecto de la presente invención se refiere a un compuesto de fórmula (I), o una sal farmacéuticamente 60 aceptable del mismo para uso como principio activo farmacéutico, en particular para uso en la prevención y/o tratamiento de una condición patológica y/o fisiológica asociada a un incremento de la apoptosis donde la condición patológica y/o fisiológica asociada a un incremento de la apoptosis se selecciona entre preservación de órganos o células, en particular transplante o conservación; prevención de citotoxicidad, en particular citotoxicidad mediada por sustancias químicas, por agentes físicos tales como radiación, trauma acústico, quemados, o por agentes biológicos 65 Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof for use as a pharmaceutical active ingredient, in particular for use in the prevention and / or treatment of a pathological condition and / or physiological associated with an increase in apoptosis where the pathological and / or physiological condition associated with an increase in apoptosis is selected from preservation of organs or cells, in particular transplantation or conservation; prevention of cytotoxicity, in particular cytotoxicity mediated by chemical substances, by physical agents such as radiation, acoustic trauma, burns, or by biological agents 65
tales como infección o hepatitis; patologías debidas a situaciones de hipoxia, tales como infarto cardíaco o infarto cerebral; patologías oculares, tales como lesiones ocasionadas por cirugía ocular, degeneración macular asociada a la edad, retinopatía diabética, retinitis pigmentosa o glaucoma; enfermedades neurodegenerativas, tales como Alzheimer, Huntington, Parkinson, enfermedad de Kennedy o esclerosis múltiple amiotrófica; diabetes, en particular preservación de islotes de Langerhans o citotoxicidad asociada a diabetes como, por ejemplo, nefrotoxicidad; 5 osteoartritis; artritis; inflamación o inmunodeficiencias. such as infection or hepatitis; pathologies due to hypoxia situations, such as heart attack or cerebral infarction; eye diseases, such as injuries caused by eye surgery, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa or glaucoma; neurodegenerative diseases, such as Alzheimer's, Huntington, Parkinson's, Kennedy's disease or amyotrophic multiple sclerosis; diabetes, in particular preservation of islets of Langerhans or cytotoxicity associated with diabetes, such as nephrotoxicity; 5 osteoarthritis; arthritis; inflammation or immunodeficiencies
Otro aspecto de la presente invención se refiere al uso de un compuesto de fórmula (I) o de una sal farmacéuticamente aceptable del mismo para la fabricación de un medicamento destinado a la prevención y/o tratamiento de una condición patológica y/o fisiológica asociada a un incremento de la apoptosis, en particular una 10 de las condiciones mencionadas anteriormente. Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament intended for the prevention and / or treatment of a pathological and / or physiological condition associated with an increase in apoptosis, in particular one of the conditions mentioned above.
Otro aspecto de la presente invención se refiere a un método de prevención y/o tratamiento de un individuo u órgano que padece o es susceptible de padecer una condición patológica y/o fisiológica asociada a un incremento de la apoptosis 15 Another aspect of the present invention relates to a method of prevention and / or treatment of an individual or organ that suffers or is susceptible to suffering from a pathological and / or physiological condition associated with an increase in apoptosis.
Los compuestos de la presente invención pueden usarse solos o en combinación con uno o más compuestos que sean útiles para la prevención y/o tratamiento de una condición patológica y/o fisiológica asociada a un incremento de la apoptosis, tal como preservación de órganos o células, en particular transplante o conservación; prevención de citotoxicidad, en particular citotoxicidad mediada por sustancias químicas, por agentes físicos tales como radiación, 20 trauma acústico, quemados, o por agentes biológicos tales como infección o hepatitis; patologías debidas a situaciones de hipoxia, tales como infarto cardíaco o infarto cerebral; patologías oculares, tales como lesiones ocasionadas por cirugía ocular, degeneración macular asociada a la edad, retinopatía diabética, retinitis pigmentosa o glaucoma; enfermedades neurodegenerativas, tales como Alzheimer, Huntington, Parkinson, enfermedad de Kennedy o esclerosis múltiple amiotrófica; diabetes, en particular preservación de islotes de Langerhans o 25 citotoxicidad asociada a diabetes como, por ejemplo, nefrotoxicidad; osteoartritis; artritis; inflamación o inmunodeficiencias. The compounds of the present invention can be used alone or in combination with one or more compounds that are useful for the prevention and / or treatment of a pathological and / or physiological condition associated with an increase in apoptosis, such as preservation of organs or cells. , in particular transplantation or conservation; prevention of cytotoxicity, in particular cytotoxicity mediated by chemical substances, by physical agents such as radiation, acoustic trauma, burns, or by biological agents such as infection or hepatitis; pathologies due to hypoxia situations, such as heart attack or cerebral infarction; eye diseases, such as injuries caused by eye surgery, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa or glaucoma; neurodegenerative diseases, such as Alzheimer's, Huntington, Parkinson's, Kennedy's disease or amyotrophic multiple sclerosis; diabetes, in particular preservation of islets of Langerhans or cytotoxicity associated with diabetes, such as nephrotoxicity; osteoarthritis; arthritis; inflammation or immunodeficiencies
Un segundo aspecto de la presente invención se refiere a una composición farmacéutica que comprende al menos una cantidad terapéuticamente aceptable de un compuesto de fórmula general (I) o sus sales farmacéuticamente 30 aceptables. Es asimismo objeto de la presente invención, el uso de un compuesto de fórmula general (I) para la preparación de una composición farmacéutica. A second aspect of the present invention relates to a pharmaceutical composition comprising at least a therapeutically acceptable amount of a compound of general formula (I) or its pharmaceutically acceptable salts. It is also the object of the present invention, the use of a compound of general formula (I) for the preparation of a pharmaceutical composition.
Según otra realización preferida, la composición farmacéutica se presenta en una forma adaptada a la administración parenteral, oral, sublingual, nasal, intratecal, bronquial, linfática, rectal, transdérmica o inhalada. 35 According to another preferred embodiment, the pharmaceutical composition is presented in a form adapted to parenteral, oral, sublingual, nasal, intrathecal, bronchial, lymphatic, rectal, transdermal or inhaled administration. 35
Según la invención, los compuestos de fórmula (I) y sus sales farmacéuticamente aceptables son útiles para la prevención y/o tratamiento de una condición patológica y/o fisiológica asociada a un incremento de la apoptosis mediante su actividad como inhibidores de APAF1. According to the invention, the compounds of formula (I) and their pharmaceutically acceptable salts are useful for the prevention and / or treatment of a pathological and / or physiological condition associated with an increase in apoptosis through their activity as APAF1 inhibitors.
40 40
A menos que se defina de otro modo, todos los términos técnicos y científicos aquí usados tienen el mismo significado a los comúnmente entendidos por una persona experta en el campo de la invención. Métodos y materiales similares o equivalentes a los aquí descritos pueden ser usados en la práctica de la presente invención. Unless defined otherwise, all the technical and scientific terms used here have the same meaning as those commonly understood by a person skilled in the field of the invention. Methods and materials similar or equivalent to those described herein may be used in the practice of the present invention.
Los compuestos de fórmula (I) pueden ser preparados siguiendo distintos métodos conocidos para cualquier 45 persona experta en el campo de la síntesis orgánica, en particular por los procedimientos generales que se presentan en los esquemas siguientes. Los materiales de partida para los métodos preparativos están disponibles comercialmente o bien se pueden preparar mediante métodos de la literatura. A menos que se indique lo contrario, los grupos R1, R2 y R3, tienen el significado descrito en la fórmula general (I). The compounds of formula (I) can be prepared following different methods known to any person skilled in the field of organic synthesis, in particular by the general procedures presented in the following schemes. The starting materials for the preparative methods are commercially available or can be prepared by methods of the literature. Unless otherwise indicated, groups R1, R2 and R3 have the meaning described in the general formula (I).
50 fifty
De manera general, los compuestos de fórmula (I) pueden obtenerse a partir de los métodos y esquemas descritos a continuación: In general, the compounds of formula (I) can be obtained from the methods and schemes described below:
R3NH2R2NCNNNOClCO2HNR1OOR3R2ClNOR3HNR2NNNR1NNNR1Obase++ R3NH2R2NCNNNOClCO2HNR1OOR3R2ClNOR3HNR2NNNR1NNNR1Obase ++
55 55
El método general para la obtención de los compuestos (I) comporta una reacción de tipo multicomponente de Ugi entre una amina primaria 2 (R3-NH2), un isonitrilo 3 (R2-NC), un aldehído triazólico 4 y el ácido cloroacético para dar lugar a un aducto intermedio 5 que contiene los tres puntos de diversidad incorporados y que por ciclación en medio The general method for obtaining compounds (I) involves a multi-component type Ugi reaction between a primary amine 2 (R3-NH2), an isonitrile 3 (R2-NC), a triazole aldehyde 4 and chloroacetic acid to give place to an intermediate adduct 5 that contains the three points of diversity incorporated and that by cyclization in between
básico genera la familia de compuestos deseados 1 (I). Basic generates the desired family of compounds 1 (I).
A Io largo de la descripción y las reivindicaciones la palabra "comprende" y sus variantes no pretenden excluir otras características técnicas, aditivos, componentes, pasos o estereoisómeros de los compuestos involucrados. Para los expertos en la materia, otros objetos, ventajas y características de la invención se desprenderán en parte de la 5 descripción y en parte de la práctica de la invención. Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components, steps or stereoisomers of the compounds involved. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention.
EJEMPLOS EXAMPLES
A continuación se ilustrará la invención mediante unos ensayos realizados por los investigadores que pone de 10 manifiesto la efectividad de los compuestos de fórmula general (I) de la presente invención. The invention will now be illustrated by tests carried out by the researchers that show the effectiveness of the compounds of the general formula (I) of the present invention.
Ejemplos de síntesis química Examples of chemical synthesis
EJEMPLO 1. Síntesis de los compuestos de formula I 15 EXAMPLE 1. Synthesis of the compounds of formula I 15
1. Síntesis de los aldehídos 4. 1. Synthesis of aldehydes 4.
i) Preparación del 4-hidroximetil-2H-1,2,3-triazol (7) i) Preparation of 4-hydroxymethyl-2H-1,2,3-triazole (7)
20 twenty
NNHNOH NNHNOH
(7) (7)
Una mezcla de formaldehido al 37% en agua (3.8 mL, 50 mmol), ácido acético glacial (428 L, 7.5 mmol), y 1,4-dioxano (3.8 mL) se agitó durante 15 min a 20 oC. La mezcla se trató con azida sódica (488 mg, 7.5 mmol), seguido 25 de la adición de alcohol propargílico (292 L, 5.0 mmol). En este punto el pH de la mezcla de reacción fue de 6.5. Tras agitar durante 10 min se añadió ascorbato sódico (176 mg, 1.0 mmol, 20mol %) y una solución de sulfato de cobre (II) (45 mg, 0.25 mmol, 5mol %) en 204 L de agua. La nueva mezcla de reacción se agitó durante 18 horas a 20 oC, se diluyó con agua (15 mL) y se lavó con diclorometano (3 x 10 mL). La fracción acuosa se concentró al vacío y el residuo se trató directamente con 20 mL de NaOH 2 M, agitando 20 horas a 20 oC. La mezcla de reacción se 30 neutralizó con HCl 2M y se concentró a presión reducida para obtener un sólido de color azul que se extrajo con metanol. El residuo obtenido tras la eliminación del disolvente correspondió con el alcohol triazólico deseado, que se utilizó sin ninguna purificación ulterior A mixture of 37% formaldehyde in water (3.8 mL, 50 mmol), glacial acetic acid (428 ,L, 7.5 mmol), and 1,4-dioxane (3.8 mL) was stirred for 15 min at 20 ° C. The mixture was treated with sodium azide (488 mg, 7.5 mmol), followed by the addition of propargyl alcohol (292 µL, 5.0 mmol). At this point the pH of the reaction mixture was 6.5. After stirring for 10 min, sodium ascorbate (176 mg, 1.0 mmol, 20mol%) and a solution of copper (II) sulfate (45 mg, 0.25 mmol, 5mol%) in 204 µL of water were added. The new reaction mixture was stirred for 18 hours at 20 ° C, diluted with water (15 mL) and washed with dichloromethane (3 x 10 mL). The aqueous fraction was concentrated in vacuo and the residue was treated directly with 20 mL of 2M NaOH, stirring for 20 hours at 20 ° C. The reaction mixture was neutralized with 2M HCl and concentrated under reduced pressure to obtain a blue solid that was extracted with methanol. The residue obtained after solvent removal corresponded with the desired triazole alcohol, which was used without further purification.
1H-RMN (MeOD, 500 MHz): (ppm) 7.74 (s, 1H, H1), 4.71 (s, 2H, H2). 1H-NMR (MeOD, 500 MHz): (ppm) 7.74 (s, 1H, H1), 4.71 (s, 2H, H2).
35 35
ii) Obtención de 2-(2,4-diclorofenetil)-4-hidroximetil-2H-1,2,3-triazol (8) ii) Obtaining 2- (2,4-dichlorophenethyl) -4-hydroxymethyl-2H-1,2,3-triazole (8)
ClClNNNHO ClClNNNHO
(8) (8)
40 40
El triazol 7 (2 mmol), disuelto en 10 ml de N,N-dimetilformamida (DMF), se calentó a 60 ºC y se trató con una solución de tosilato de O-(2,4-diclorofenetilo) (863 mg, 2.5 mmol) en acetonitrilo anhidro (10 mL) y carbonato sódico (212 mg, 2 mmol) y la mezcla se agitó durante 24 horas a 60 ºC. El crudo de reacción se diluyó con acetato de etilo (20 mL) y la solución se lava con agua (2 x 15 mL). Los extractos orgánicos se lavaron con una solución saturada de Triazole 7 (2 mmol), dissolved in 10 ml of N, N-dimethylformamide (DMF), was heated to 60 ° C and treated with a solution of O- (2,4-dichlorophenethyl) tosylate (863 mg, 2.5 mmol) in anhydrous acetonitrile (10 mL) and sodium carbonate (212 mg, 2 mmol) and the mixture was stirred for 24 hours at 60 ° C. The reaction crude was diluted with ethyl acetate (20 mL) and the solution was washed with water (2 x 15 mL). The organic extracts were washed with a saturated solution of
cloruro sódico (2 x 15 mL) y se secaron sobre sulfato de magnesio. El residuo obtenido tras la evaporación del disolvente orgánico rindió una mezcla de compuestos. Esta mezcla se purificó por cromatografía en columna sobre silicagel eluyendo con una mezcla hexano/acetato para obtener 112 mg (0.41 mmol, 21%) del producto 8. sodium chloride (2 x 15 mL) and dried over magnesium sulfate. The residue obtained after evaporation of the organic solvent yielded a mixture of compounds. This mixture was purified by column chromatography on silica gel eluting with a hexane / acetate mixture to obtain 112 mg (0.41 mmol, 21%) of product 8.
1H-RMN (CDCl3, 500 MHz): (ppm): 7.56 (s, 1H, H3), 7.40 (d, J = 2.0 Hz, 1H, H8), 7.12 (dd, J = 8.2, 2.0 Hz, 1H, 5 H10), 6.99 (d, J = 8.2 Hz, 1H, H11), 4.75 (s, 2H, H1), 4.65 (t, J = 7.3 Hz, 2H, H4), 3.36 (t, J = 7.3 Hz, 2H, H5), 2.2 (s, 1H, OH). HRMS para C11H11Cl2N3O: Calculado: 272.0357 (M+H)+; encontrado: 272.0350. 1H-NMR (CDCl3, 500 MHz): (ppm): 7.56 (s, 1H, H3), 7.40 (d, J = 2.0 Hz, 1H, H8), 7.12 (dd, J = 8.2, 2.0 Hz, 1H , 5 H10), 6.99 (d, J = 8.2 Hz, 1H, H11), 4.75 (s, 2H, H1), 4.65 (t, J = 7.3 Hz, 2H, H4), 3.36 (t, J = 7.3 Hz , 2H, H5), 2.2 (s, 1H, OH). HRMS for C11H11Cl2N3O: Calculated: 272.0357 (M + H) +; Found: 272.0350.
iii) Obtención de 2-(2,4-diclorofenetil)-4-formil-2H-1,2,3-triazol (4a) iii) Obtaining 2- (2,4-dichlorophenethyl) -4-formyl-2H-1,2,3-triazole (4a)
10 10
ClClNNNO ClClNNNO
4a 4th
Una solución del triazol 8 (112.4 mg, 0.4 mmol) y ácido 2-iodoxibenzoico (173.5 mg, 0.6 mmol) en acetato de etilo (4 mL) se agitó durante 4 horas a reflujo. El crudo de reacción se enfrió obteniendo un sólido que se filtró y se lavó con 15 acetato de etilo. El filtrado se lavó con bicarbonato sódico al 5% (2 x 10 mL) y con una solución saturada de cloruro sódico (2 x 10 mL). La fracción orgánica se secó sobre sulfato magnésico anhidro y se eliminó el disolvente a presión reducida para rendir el aldehído deseado 4a como un sólido de color amarillo pálido (94 mg, 0.35 mmol, 85%). A solution of triazole 8 (112.4 mg, 0.4 mmol) and 2-iodoxibenzoic acid (173.5 mg, 0.6 mmol) in ethyl acetate (4 mL) was stirred for 4 hours at reflux. The reaction crude was cooled to obtain a solid that was filtered and washed with ethyl acetate. The filtrate was washed with 5% sodium bicarbonate (2 x 10 mL) and with a saturated solution of sodium chloride (2 x 10 mL). The organic fraction was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to yield the desired aldehyde 4a as a pale yellow solid (94 mg, 0.35 mmol, 85%).
20 twenty
1H-RMN (CDCl3, 500 MHz): (ppm) 10.09 (s, 1H, H1), 8.07 (s, 1H, H3), 7.43 (d, J = 2.0 Hz, 1H, H8), 7.14 (dd, J = 8.2, 2.0 Hz, 1H, H10), 6.98 (d, J = 8.2 Hz, 1H, H11), 4.78 (t, J = 7.2 Hz, 2H, H4), 3.44 (t, J = 7.2 Hz, 2H, H5). HRMS para C11H9Cl2N3O: Calculada: 270.0201 (M+H)+; encontrada: 270.0203. 1H-NMR (CDCl3, 500 MHz): (ppm) 10.09 (s, 1H, H1), 8.07 (s, 1H, H3), 7.43 (d, J = 2.0 Hz, 1H, H8), 7.14 (dd, J = 8.2, 2.0 Hz, 1H, H10), 6.98 (d, J = 8.2 Hz, 1H, H11), 4.78 (t, J = 7.2 Hz, 2H, H4), 3.44 (t, J = 7.2 Hz, 2H , H5). HRMS for C11H9Cl2N3O: Calculated: 270.0201 (M + H) +; Found: 270.0203.
2. Obtención de los compuestos de fórmula I 25 2. Obtaining the compounds of formula I 25
Ejemplo 1.1. N-(2,4-Diclorofenetil)-2-(2-(2,4-diclorofenetil)-2H-1,2,3-triazol-4-il)-1-(3,3-difenilpropil)-4-oxoazetidina-2-carboxamida (I-1) Example 1.1 N- (2,4-Dichlorofenetyl) -2- (2- (2,4-dichlorofenetil) -2H-1,2,3-triazol-4-yl) -1- (3,3-diphenylpropyl) -4- oxoazetidine-2-carboxamide (I-1)
(I-1) NONNNHNOClClClCl(I-1) NONNNHNOClClClCl
Una solución del triazol aldehídico 4a (94 mg, 0.35 mmol) en metanol (0.1 mL) se trató con 3,3-difenilpropilamina (66 L, 0.14 mmol) y la mezcla se agitó 6 horas a 20 oC (control por 1H-RMN). A continuación se añadió una solución de isocianuro de 2,4-diclorofenetilo (69 mg, 0.35 mmol) en 0.1 mL de metanol y una solución de ácido cloroacético (33 mg, 0.35 mmol) en 0.1 mL de metanol, y la mezcla se agitó durante 48 horas a temperatura ambiente, bajo atmósfera de nitrógeno. El disolvente se eliminó a presión reducida y el residuo se trató, sin ninguna purificación 5 intermedia, con una solución de hidróxido potásico (20 mg, 0.35 mmol) en 2 mL de metanol, agitando la mezcla durante 12 horas a temperatura ambiente. Tras eliminar el disolvente, el residuo obtenido se purificó por cromatografía en columna de silicagel eluyendo con mezclas de hexano:acetato de etilo, para obtener el compuesto I-1 (48 mg, 0.07 mmol, 19%) en forma de sólido incoloro. A solution of the aldehyde triazole 4a (94 mg, 0.35 mmol) in methanol (0.1 mL) was treated with 3,3-diphenylpropylamine (66 L, 0.14 mmol) and the mixture was stirred 6 hours at 20 ° C (control for 1H- NMR). Then a solution of 2,4-dichlorophenethyl isocyanide (69 mg, 0.35 mmol) in 0.1 mL of methanol and a solution of chloroacetic acid (33 mg, 0.35 mmol) in 0.1 mL of methanol were added, and the mixture was stirred for 48 hours at room temperature, under nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was treated, without any intermediate purification, with a solution of potassium hydroxide (20 mg, 0.35 mmol) in 2 mL of methanol, stirring the mixture for 12 hours at room temperature. After removing the solvent, the residue obtained was purified by silica gel column chromatography eluting with mixtures of hexane: ethyl acetate, to obtain compound I-1 (48 mg, 0.07 mmol, 19%) as a colorless solid.
10 10
1H-RMN (CDCl3, 500 MHz): (ppm) 7.54 (s, 1H), 7.38 ( d, J = 2.1 Hz, 1H), 7.36 (d, J = 2.1 Hz, 1H), 7.29-7.26 (m, 4H), 7.20-7.16 (m, 6H), 7.13 (dd, J = 8.2, 2.1 Hz, 1H), 7.08 (dd, J = 8.2, 2.1 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H, 6.51 (t, J = 5.9 Hz, 1H, NH), 4.59 (t, J = 7.1 Hz, 2H), 3.90 (t, J = 7.7 Hz, 1H, H3), 3.54 (m, 2H), 3.34 (d, J = 14.4 Hz, 1H), 3.27 (t, J = 7.1 Hz, 2H), 3.27 (d, J = 14.4 Hz, 1H), 3.07 (m, 2H), 2.90 (m, 2H), 2.42 (m, 1H), 2.29 (m, 1H). HRMS para C37H34Cl4N5O2: Calculada: 720.1467 (M+H)+; encontrada: 720.1453. 15 1H-NMR (CDCl3, 500 MHz): (ppm) 7.54 (s, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.36 (d, J = 2.1 Hz, 1H), 7.29-7.26 (m , 4H), 7.20-7.16 (m, 6H), 7.13 (dd, J = 8.2, 2.1 Hz, 1H), 7.08 (dd, J = 8.2, 2.1 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H, 6.51 (t, J = 5.9 Hz, 1H, NH), 4.59 (t, J = 7.1 Hz, 2H), 3.90 (t, J = 7.7 Hz, 1H , H3), 3.54 (m, 2H), 3.34 (d, J = 14.4 Hz, 1H), 3.27 (t, J = 7.1 Hz, 2H), 3.27 (d, J = 14.4 Hz, 1H), 3.07 (m , 2H), 2.90 (m, 2H), 2.42 (m, 1H), 2.29 (m, 1H) HRMS for C37H34Cl4N5O2: Calculated: 720.1467 (M + H) +; found: 720.1453.
Aplicando el mismo procedimiento general, se pueden obtener los siguientes análogos sustituyendo las correspondientes aminas, isocianato y triazol. By applying the same general procedure, the following analogs can be obtained by substituting the corresponding amines, isocyanate and triazole.
Ejemplo 1.2. N-Bencil-2-(2-bencil-2H-1,2,3-triazol-4-il)-1-(4-fluorofenetil)-4-oxoazetidina-2-carboxamida (I-2) 20 Example 1.2. N-Benzyl-2- (2-benzyl-2H-1,2,3-triazol-4-yl) -1- (4-fluorofenetyl) -4-oxoazetidine-2-carboxamide (I-2) 20
NONNNHNOF NONNNHNOF
(I-2) (I-2)
1H-RMN (CDCl3, 500 MHz): (ppm) 7.59 (s, 1H), 7.33-7.28 (m, 8H), 7.17 (m, 2H), 7.02 (dd, J = 8.5, 5.4 Hz, 2H), 6.87 25 (t, J = 8.7 Hz, 2H), 6.61 (s, 1H, NH), 5.54 (s, 2H), 4.42 (dd, J = 14.8, 6.0 Hz, 1H), 4.30 (dd, J = 14.8, 6 Hz, 1H), 3.42 (m, 1H), 3.0 (m, 1H), 2.85 (m, 1H). HRMS para C28H27FN5O2: Calculada: 484.2149 (M+H)+; encontrada:484.2122. 1H-NMR (CDCl3, 500 MHz): (ppm) 7.59 (s, 1H), 7.33-7.28 (m, 8H), 7.17 (m, 2H), 7.02 (dd, J = 8.5, 5.4 Hz, 2H) , 6.87 25 (t, J = 8.7 Hz, 2H), 6.61 (s, 1H, NH), 5.54 (s, 2H), 4.42 (dd, J = 14.8, 6.0 Hz, 1H), 4.30 (dd, J = 14.8, 6 Hz, 1H), 3.42 (m, 1H), 3.0 (m, 1H), 2.85 (m, 1H). HRMS for C28H27FN5O2: Calculated: 484.2149 (M + H) +; Found: 484.2122.
Ejemplo 1.3. 2-(2-Bencil-2H-1,2,3-triazol-4-il)-N-(tert-butil)-1-(2,4-diclorofenetil)-4-oxoazetidina-2-carboxamida (I-3) Example 1.3. 2- (2-Benzyl-2H-1,2,3-triazol-4-yl) -N- (tert-butyl) -1- (2,4-dichlorophenethyl) -4-oxoazetidine-2-carboxamide (I- 3)
NONNNHNOClCl NONNNHNOClCl
(I-3) (I-3)
1H-RMN : (CDCl3, 500 MHz): (ppm) 7.55 (s, 1H), 7.33-7.31 (m, 5H), 7.12 (d, J = 1.2 Hz, 2H), 6.33 (s, 1H, NH), 5.55 5 (s, 1H), 3.42 (d, J = 14.2 Hz, 1H), 3.40 (m, 2H), 3.30 (d, J =14.2 Hz, 1H), 3.01 (m, 2H), 1.28 (s, 9H). HRMS para C25H28Cl2N5O2: Calculada: 500.162 (M+H)+; encontrada: 500.1600. 1H-NMR: (CDCl3, 500 MHz): (ppm) 7.55 (s, 1H), 7.33-7.31 (m, 5H), 7.12 (d, J = 1.2 Hz, 2H), 6.33 (s, 1H, NH ), 5.55 5 (s, 1H), 3.42 (d, J = 14.2 Hz, 1H), 3.40 (m, 2H), 3.30 (d, J = 14.2 Hz, 1H), 3.01 (m, 2H), 1.28 ( s, 9H). HRMS for C25H28Cl2N5O2: Calculated: 500.162 (M + H) +; Found: 500.1600.
Ejemplo 1.4. N-Bencil-6-(2-bencil-2H-1,2,3-triazol-4-il)-4-oxo-1-(2-tiofen-2-il)etil)azetidina-2-carboxamida (I-4) Example 1.4. N-Benzyl-6- (2-benzyl-2H-1,2,3-triazol-4-yl) -4-oxo-1- (2-thiophene-2-yl) ethyl) azetidine-2-carboxamide (I -4)
10 10
NONNNHNOS NONNNHNOS
(I-4) (I-4)
1H-RMN: (CDCl3, 500 MHz): (ppm) 7.60 (s, 1H), 7.32-7.30 (m, 4H), 7.28 (m, 3H), 7.18-7.15 (m, 3H), 7.08 (dd, J = 5, 1 Hz),, 6.8 (dd, J = 5, 3.4 Hz), 6.79 (dd, J = 3.4, 1 Hz, 1H), 6.75 (t, J = 6 Hz, 1H, NH), 5.54 (s, 1H), 4.44 (dd, J = 14.8, 15 6 Hz, 1H), 4.27 (dd, J = 14.8, 6 Hz, 1H), 3.52 (m, 1H), 3.37 (m, 2H), 3.32 (m, 1H), 3.27 (m, 1H), 3.11 (m, 1H). HRMS para C26H26N5O2S: Calculada: 472.1807 (M+H)+; encontrada: 472.1794. 1H-NMR: (CDCl3, 500 MHz): (ppm) 7.60 (s, 1H), 7.32-7.30 (m, 4H), 7.28 (m, 3H), 7.18-7.15 (m, 3H), 7.08 (dd , J = 5, 1 Hz) ,, 6.8 (dd, J = 5, 3.4 Hz), 6.79 (dd, J = 3.4, 1 Hz, 1H), 6.75 (t, J = 6 Hz, 1H, NH), 5.54 (s, 1H), 4.44 (dd, J = 14.8, 15 6 Hz, 1H), 4.27 (dd, J = 14.8, 6 Hz, 1H), 3.52 (m, 1H), 3.37 (m, 2H), 3.32 (m, 1H), 3.27 (m, 1H), 3.11 (m, 1H). HRMS for C26H26N5O2S: Calculated: 472.1807 (M + H) +; Found: 472.1794.
Ejemplo 1.5. N-Bencil-2-(2-(4-fluorofenetil)-2H-1,2,3-triazol-4-il)-1-(4-metoxifenetil)-4-oxoazetidina-2-carboxamida (I-5) Example 1.5. N-Benzyl-2- (2- (4-fluorofenetyl) -2H-1,2,3-triazol-4-yl) -1- (4-methoxyphenethyl) -4-oxoazetidine-2-carboxamide (I-5)
NONNNHNOCH3OF NONNNHNOCH3OF
(I-5) 5 (I-5) 5
1H-RMN (CDCl3, 500 MHz): (ppm): 7.62 (s, 1H, H8), 7.31 (m, 2H, H19), 7.29(m, 1H, H20), 7.14 (m, 2H, H18), 7.08 (d, J = 8.6 Hz, 2H, H10), 7.03 (m, 2H, H14), 6.9 (m, 2H, H15), 6.76 (d, J = 8.6 Hz, 2H, H11), 6.34 (m, 1H, NH), 4.61 (t, J = 7.3 Hz, 2H, H5), 4.36 (dd, J = 14.9, 6.4 Hz, 1H, H7), 4.13 (dd, J = 14.9, 5.7 Hz, 1H, H7), 3.71 (s, 3H, Me), 3.41 (m, 1H, H4), 3.32 (s, 2H, H2), 3.20 (t, 2H, H6), 3.06 (m, 1H, H4), 2.99 (m, 1H, H3), 2.79 (m, 1H, H3). HRMS para 10 C30H31FN5O3: Calculada: 528.2411 (M+H)+; encontrada: 528.2410. 1H-NMR (CDCl3, 500 MHz): (ppm): 7.62 (s, 1H, H8), 7.31 (m, 2H, H19), 7.29 (m, 1H, H20), 7.14 (m, 2H, H18) , 7.08 (d, J = 8.6 Hz, 2H, H10), 7.03 (m, 2H, H14), 6.9 (m, 2H, H15), 6.76 (d, J = 8.6 Hz, 2H, H11), 6.34 (m , 1H, NH), 4.61 (t, J = 7.3 Hz, 2H, H5), 4.36 (dd, J = 14.9, 6.4 Hz, 1H, H7), 4.13 (dd, J = 14.9, 5.7 Hz, 1H, H7 ), 3.71 (s, 3H, Me), 3.41 (m, 1H, H4), 3.32 (s, 2H, H2), 3.20 (t, 2H, H6), 3.06 (m, 1H, H4), 2.99 (m , 1H, H3), 2.79 (m, 1H, H3). HRMS for 10 C30H31FN5O3: Calculated: 528.2411 (M + H) +; Found: 528.2410.
Ejemplo 1.6. N-(Tert-butil)-2-(2-(4-fluorofenetil)-2H-1,2,3-triazol-4-il)-1-(4-metoxifenetil)-4-oxoazetidina-2-carboxamida (I-6) Example 1.6 N- (Tert-butyl) -2- (2- (4-fluorofenetyl) -2H-1,2,3-triazol-4-yl) -1- (4-methoxyphenethyl) -4-oxoazetidine-2-carboxamide ( I-6)
15 fifteen
NONNNHNOCH3OF NONNNHNOCH3OF
(I-6) (I-6)
1H-RMN: (CDCl3, 500 MHz): (ppm): 7.55 (s, 1H), 7.05 (m, 4H), 6.91 (t, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 6.29 (s, 1H, NH), 4.62 (t, J = 7.3 Hz, 2H), 3.77 (s, 3H), 3.38 (m, 1H), 3.34 (q, J = 14.5 Hz, 2H), 3.23 (m, 1H), 3.23 (t, J 20 = 7.3 Hz, 2H), 2.86 (m, 2H). HRMS para C27H33FN5O3: Calculada: 494.2567 (M+H)+; encontrada: 494.2561. 1H-NMR: (CDCl3, 500 MHz): (ppm): 7.55 (s, 1H), 7.05 (m, 4H), 6.91 (t, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz , 2H), 6.29 (s, 1H, NH), 4.62 (t, J = 7.3 Hz, 2H), 3.77 (s, 3H), 3.38 (m, 1H), 3.34 (q, J = 14.5 Hz, 2H) , 3.23 (m, 1H), 3.23 (t, J 20 = 7.3 Hz, 2H), 2.86 (m, 2H). HRMS for C27H33FN5O3: Calculated: 494.2567 (M + H) +; Found: 494.2561.
Ejemplo 1.7. N-(Tert-butil)-2-(2-(4-fluorofenetil)-2H-1,2,3-triazol-4-il)-4-oxo-1-(4-trifluorometoxi)bencil)azetidina-2-carboxamida (I-7) Example 1.7. N- (Tert-butyl) -2- (2- (4-fluorofenetyl) -2H-1,2,3-triazol-4-yl) -4-oxo-1- (4-trifluoromethoxy) benzyl) azetidine-2 -carboxamide (I-7)
NONNNHNOFOCF3 NONNNHNOFOCF3
(I-7) 5 (I-7) 5
1H-RMN: (CDCl3, 500 MHz): (ppm) 7.60 (s, 1H, H7), 7.27 (d, J = 8 Hz, 2H), 7.17 (d, J = 8 Hz, 2H), 7.08 (dd, J = 8.5, 5.4 Hz, 2H), 6.94 (t, J = 8.6 Hz, 2H), 5.8 (s, 1H, NH), 4.63 (t, J = 7.3 Hz, 2H), 4.58 (d, J = 15.5 Hz, 1H), 3.88 (d, J = 15.5 Hz, 1H), 3.43 (d, J = 14.8 Hz, 1H), 3.39 (d, J = 14.8 Hz, 1H), 3.23 (t, J = 7.3 Hz, 2H), 1.08 (s, 9H). HRMS para C26H28F4N5O3: Calculada: 534.2128 (M+H)+; encontrada: 534.2111. 10 1H-NMR: (CDCl3, 500 MHz): (ppm) 7.60 (s, 1H, H7), 7.27 (d, J = 8 Hz, 2H), 7.17 (d, J = 8 Hz, 2H), 7.08 ( dd, J = 8.5, 5.4 Hz, 2H), 6.94 (t, J = 8.6 Hz, 2H), 5.8 (s, 1H, NH), 4.63 (t, J = 7.3 Hz, 2H), 4.58 (d, J = 15.5 Hz, 1H), 3.88 (d, J = 15.5 Hz, 1H), 3.43 (d, J = 14.8 Hz, 1H), 3.39 (d, J = 14.8 Hz, 1H), 3.23 (t, J = 7.3 Hz, 2H), 1.08 (s, 9H). HRMS for C26H28F4N5O3: Calculated: 534.2128 (M + H) +; Found: 534.2111. 10
Ejemplo 1.8. N-Bencil-(2-(2,4-diclorofenetil)-2H-1,2,3-triazol-4-il)-1-(3,3-difenilpropil)-4-oxoazetidina-2-carboxamida (I-8) Example 1.8. N-Benzyl- (2- (2,4-dichlorophenethyl) -2H-1,2,3-triazol-4-yl) -1- (3,3-diphenylpropyl) -4-oxoazetidine-2-carboxamide (I- 8)
15 NONNNHNOClCl 15 NONNNHNOClCl
(I-8) (I-8)
1H-RMN: (CDCl3, 500 MHz): (ppm) 7.57 (s, 1H), 7.31 (d, J = 2.2 Hz, 1H,), 7.3 (m, 4H), 7.28-7.19 (m, 5H), 7.17-7.13 (m, 6H), 7.01 (dd, J = 8.2 Hz, 2.1 Hz, 1H,), 6.83 (d, J = 8.2 Hz, 1H), 6.78 (t, J =5.6 Hz, 1H, NH), 4.58 (t, J = 7.1 Hz, 2H), 4.44 (dd, J = 5.7, 2.3 Hz, 2H,), 3.86 (t, J = 7.8 Hz, 1H), 3.44 (d, J = 14.4 Hz, 1H), 3.30 (d, J =14.4 Hz, 1H), 3.24 20 (t, J = 7.1 Hz, 2H), 3.16 (m, 1H), 3.04 (m, 1H), 2.33 (m, 2H). HRMS para C36H34Cl2N5O2: Calculada: 638.209 (M+H)+; encontrada: 638.2071. 1H-NMR: (CDCl3, 500 MHz): (ppm) 7.57 (s, 1H), 7.31 (d, J = 2.2 Hz, 1H,), 7.3 (m, 4H), 7.28-7.19 (m, 5H) , 7.17-7.13 (m, 6H), 7.01 (dd, J = 8.2 Hz, 2.1 Hz, 1H,), 6.83 (d, J = 8.2 Hz, 1H), 6.78 (t, J = 5.6 Hz, 1H, NH ), 4.58 (t, J = 7.1 Hz, 2H), 4.44 (dd, J = 5.7, 2.3 Hz, 2H,), 3.86 (t, J = 7.8 Hz, 1H), 3.44 (d, J = 14.4 Hz, 1H), 3.30 (d, J = 14.4 Hz, 1H), 3.24 20 (t, J = 7.1 Hz, 2H), 3.16 (m, 1H), 3.04 (m, 1H), 2.33 (m, 2H). HRMS for C36H34Cl2N5O2: Calculated: 638.209 (M + H) +; Found: 638.2071.
Ejemplo 1.9. N-(Tert-butil)-1-(3,3-difenilpropil)-2-(2(4-fluorofenetil)-2H-1,2,3-triazol-4-il)-4-oxoazetidina-2-carboxamida (I-9) Example 1.9. N- (Tert-butyl) -1- (3,3-diphenylpropyl) -2- (2 (4-fluorofenetyl) -2H-1,2,3-triazol-4-yl) -4-oxoazetidine-2-carboxamide (I-9)
NONNNHNOF NONNNHNOF
(I-9) 5 (I-9) 5
1H-RMN: (CDCl3, 500 MHz): (ppm) 7.57 (s, 1H), 7.29-7.22 (m, 4H), 7.21-7.10 (m, 6H), 7.02 (dd, J = 8.5, 5.4 Hz, 2H), 6.92 (t, J = 8.5 Hz), 6.37 (s, 1H, NH), 4.55 (t, J = 7.4 Hz, 2H), 3.87 (t, J = 7.8 Hz, 1H), 3.38 (d, J = 14.4 Hz, 1H), 3.28 (d, J = 14.4 Hz, 1H), 3.19 (m, 1H), 3.16 (t, J = 7.4 Hz, 2H), 3.05 (m, 1H), 2.36 (m, 2H), 1.32 (s, 9H)..HRMS para C33H37FN5O2: Calculada: 554.2931 (M+H)+; encontrada: 554.2910. 10 1H-NMR: (CDCl3, 500 MHz): (ppm) 7.57 (s, 1H), 7.29-7.22 (m, 4H), 7.21-7.10 (m, 6H), 7.02 (dd, J = 8.5, 5.4 Hz , 2H), 6.92 (t, J = 8.5 Hz), 6.37 (s, 1H, NH), 4.55 (t, J = 7.4 Hz, 2H), 3.87 (t, J = 7.8 Hz, 1H), 3.38 (d , J = 14.4 Hz, 1H), 3.28 (d, J = 14.4 Hz, 1H), 3.19 (m, 1H), 3.16 (t, J = 7.4 Hz, 2H), 3.05 (m, 1H), 2.36 (m , 2H), 1.32 (s, 9H) .. HRMS for C33H37FN5O2: Calculated: 554.2931 (M + H) +; Found: 554.2910. 10
Ejemplo 1.10. N-(Tert-butil)-2-(2-(2,4-diclorofenetil)-2H-1,2,3-triazol-4-il)-1-(3,3-difenilpropil)-4-oxoazetidina-2-carboxamida (I-10) Example 1.10. N- (Tert-butyl) -2- (2- (2,4-dichlorophenethyl) -2H-1,2,3-triazol-4-yl) -1- (3,3-diphenylpropyl) -4-oxoazetidine- 2-carboxamide (I-10)
15 NONNNHNOClCl 15 NONNNHNOClCl
(I-10) (I-10)
1H-RMN: (CDCl3, 500 MHz): (ppm) 7.56 (s, 1H), 7.36 (d, J = 2.1 Hz, 1H), 7.29-7.22 (m, 4H), 7.21-7.10 (m, 6H), 7.06 (dd, J = 8.2, 2.1 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.43 (s, 1H, NH), 4.60 (t, J = 7.0 Hz, 2H), 3.88 (t, J = 7.8 Hz, 1H), 3.38 (d, J = 14.3 Hz, 1H), 3.28 (t, J = 7.0 Hz, 2H), 3.25 (d, J = 14.3 Hz, 1H), 3.17 (m, 1H), 3.05 (m, 1H), 2.36 (m, 2H), 20 1.32 (s, 9H). HRMS para C33H36Cl2N5O2: Calculada: 604.2246 (M+H)+; encontrada: 604.2298. 1H-NMR: (CDCl3, 500 MHz): (ppm) 7.56 (s, 1H), 7.36 (d, J = 2.1 Hz, 1H), 7.29-7.22 (m, 4H), 7.21-7.10 (m, 6H ), 7.06 (dd, J = 8.2, 2.1 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.43 (s, 1H, NH), 4.60 (t, J = 7.0 Hz, 2H), 3.88 (t, J = 7.8 Hz, 1H), 3.38 (d, J = 14.3 Hz, 1H), 3.28 (t, J = 7.0 Hz, 2H), 3.25 (d, J = 14.3 Hz, 1H), 3.17 (m , 1H), 3.05 (m, 1H), 2.36 (m, 2H), 20 1.32 (s, 9H). HRMS for C33H36Cl2N5O2: Calculated: 604.2246 (M + H) +; Found: 604.2298.
EJEMPLO 2. Ejemplos farmacológicos EXAMPLE 2. Pharmacological examples
Ejemplo 2.1. Ensayo in vitro de inhibición de la formación del apoptosoma: reconstitución del apoptosoma a partir de proteinas recombinantes. Example 2.1 In vitro assay of inhibition of apoptosome formation: reconstitution of apoptosome from recombinant proteins.
5 5
Se incubó Apaf-1 producido de forma recombinante en células de insecto (rApaf-1) en presencia (a una concentración 10µM) o ausencia (como control) de los compuestos a evaluar en el tampón de ensayo (20 mM Hepes-KOH pH 7,5, 10 mM KCl, 1,5 mM MgCl2, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 0,1 mM PMSF) durante 15 minutos a 30 ºC. La concentración final de rApaf-1 fue de 40 nM. A continuación se añadieron dATP/Mg (Sigma) y citocromo c purificado de caballo (Sigma) alcanzando concentraciones finales de 100 µM y 0,1 µM, respectivamente. 10 Se incubó durante 60 minutos a 30 ºC y a continuación se añadió procaspasa-9 recombinante producida en E. coli (rprocaspasa-9, concentración final 0,1 µM) y se incubó durante 10 minutos a 30 ºC antes de añadir el sustrato fluorogénico de caspasa-9 Ac-LEDH-afc (concentración final 50 µM). El volumen total de ensayo fueron 200 µL. La actividad caspasa se monitorizó de forma continua mediante la liberación de afc a 37 ºC en una Wallac 1420 Workstation (λexc = 390 nm; λem = 510 nm). 15 Apaf-1 produced recombinantly in insect cells (rApaf-1) was incubated in the presence (at a 10 µM concentration) or absence (as a control) of the compounds to be evaluated in the assay buffer (20 mM Hepes-KOH pH 7 , 5, 10 mM KCl, 1.5 mM MgCl2, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 0.1 mM PMSF) for 15 minutes at 30 ° C. The final concentration of rApaf-1 was 40 nM. Then dATP / Mg (Sigma) and purified horse cytochrome c (Sigma) were added reaching final concentrations of 100 µM and 0.1 µM, respectively. 10 It was incubated for 60 minutes at 30 ° C and then recombinant procaspase-9 produced in E. coli (rprocaspase-9, final concentration 0.1 µM) was added and incubated for 10 minutes at 30 ° C before adding the fluorogenic substrate of caspase-9 Ac-LEDH-afc (final concentration 50 µM). The total test volume was 200 µL. Caspase activity was monitored continuously by releasing afc at 37 ° C in a Wallac 1420 Workstation (λexc = 390 nm; λem = 510 nm). fifteen
En la tabla siguiente se indican los valores de actividad de algunos compuestos descritos en los ejemplos expresados como porcentaje de inhibición de APAF1 (Tabla I). The following table shows the activity values of some compounds described in the examples expressed as percent APAF1 inhibition (Table I).
Tabla I 20 Table I 20
- Ejemplo Example
- % Inhibición APAF1 Dsvt % APAF1 Dsvt inhibition
- I.1 I.1
- 43.4 9.0 43.4 9.0
- I.2 I.2
- 27.4 27.3 27.4 27.3
- I.3 I.3
- 18.3 11.4 18.3 11.4
- I.4 I.4
- 10.8 10.5 10.8 10.5
- I.5 I.5
- 10.7 10.3 10.7 10.3
- I.6 I.6
- 12.8 9.6 12.8 9.6
- I.7 I.7
- 9.8 8.6 9.8 8.6
- I.8 I.8
- 65.3 11.3 65.3 11.3
- I.9 I.9
- 19.5 12.9 19.5 12.9
- I.10 I.10
- 44.8 6.0 44.8 6.0
Ejemplo 2.2. Ensayo in vitro de inhibición de la formación del apoptosoma: reconstitución del apoptosoma en extractos celulares mediante adición de APAF1 recombinante Example 2.2 In vitro assay of inhibition of apoptosome formation: reconstitution of apoptosome in cell extracts by adding recombinant APAF1
25 25
La reconstitución del apoptosoma en extractos celulares de llevó a cabo utilizando extractos citosólicos (S100) de células HEK 293 a los que previamente se les había eliminado Apaf-1 endógeno. Para ello, extractos citosólicos de 2 x108 células fueron fraccionados mediante cromatografía de intercambio iónico en una columna Mono Q (Amersham Pharmacia Biotech). La fracción no retenida en la columna (FT) contiene caspasa-3, caspasa-9 y citocromo c, de manera que la adición exógena de Apaf-1 recombinante y dATP permite la reconstitución del apoptosoma. 30 Apoptosome reconstitution in cell extracts was carried out using cytosolic extracts (S100) of HEK 293 cells that had previously been removed endogenous Apaf-1. For this, cytosolic extracts of 2 x108 cells were fractionated by ion exchange chromatography on a Mono Q column (Amersham Pharmacia Biotech). The non-retained fraction in the column (FT) contains caspase-3, caspase-9 and cytochrome c, so that the exogenous addition of recombinant Apaf-1 and dATP allows reconstitution of the apoptosome. 30
Los compuestos (10M) se preincubaron en un volumen final de 100 μL durante 30 minutos a 30ºC en presencia de Apaf-1 recombinante (40 nM). Se adicionó el extracto citosólico de HEK 293 (10µg) y dATP (100nM) y tras 30 minutos de incubación a 37ºC se adicionó el substrato fluorogénico de caspasa-3 (afc-DEVD). La actividad caspasa se monitorizó de forma continua mediante el seguimiento de la liberación de afc a 37 ºC en una Wallac 1420 Workstation (λexc = 390 nm; λem = 510 nm) (Tabla 2). 35 The compounds (10M) were pre-incubated in a final volume of 100 µL for 30 minutes at 30 ° C in the presence of recombinant Apaf-1 (40 nM). The cytosolic extract of HEK 293 (10 µg) and dATP (100nM) was added and after 30 minutes of incubation at 37 ° C the fluorogenic substrate of caspase-3 (afc-DEVD) was added. Caspase activity was monitored continuously by monitoring the release of afc at 37 ° C in a Wallac 1420 Workstation (λexc = 390 nm; λem = 510 nm) (Table 2). 35
Tabla 2 Table 2
- Ejemplo Example
- % Inhibición APAF1 Dsvt % APAF1 Dsvt inhibition
- I.1 I.1
- 64.0 18.3 64.0 18.3
- I.2 I.2
- 35.5 28.0 35.5 28.0
- I.3 I.3
- 36.3 14.7 36.3 14.7
- I.4 I.4
- 15.4 14.5 15.4 14.5
- I.5 I.5
- 26.2 24.6 26.2 24.6
- I.6 I.6
- 3.3 0.9 3.3 0.9
- I.7 I.7
- 18.1 0.3 18.1 0.3
- I.8 I.8
- 21.9 10.2 21.9 10.2
- I.9 I.9
- 48.8 43.5 48.8 43.5
- I.10 I.10
- 62.8 15.5 62.8 15.5
Claims (13)
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