ES2251316A1 - New pyrazole compounds are sigma receptor inhibitors, useful to treat or prevent e.g. learning, memory and attention deficits, diarrhea, lipoprotein disorders, migraine, obesity, arthritis, hypertension, arrhythmia and ulcers - Google Patents
New pyrazole compounds are sigma receptor inhibitors, useful to treat or prevent e.g. learning, memory and attention deficits, diarrhea, lipoprotein disorders, migraine, obesity, arthritis, hypertension, arrhythmia and ulcersInfo
- Publication number
- ES2251316A1 ES2251316A1 ES200402441A ES200402441A ES2251316A1 ES 2251316 A1 ES2251316 A1 ES 2251316A1 ES 200402441 A ES200402441 A ES 200402441A ES 200402441 A ES200402441 A ES 200402441A ES 2251316 A1 ES2251316 A1 ES 2251316A1
- Authority
- ES
- Spain
- Prior art keywords
- substituted
- unsubstituted
- alkyl
- compound
- heterocyclyl
- 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.)
- Granted
Links
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- 229940116362 tragacanth Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
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Abstract
Description
Inhibidores del receptor sigma.Sigma receptor inhibitors.
La presente invención se refiere a compuestos que tienen actividad farmacológica frente al receptor sigma (\sigma) y, más particularmente, a algunos derivados de pirazol, a los procedimientos de preparación de tales compuestos, a las composiciones farmacéuticas que los comprenden y a su uso en tratamiento y prevención, en particular para el tratamiento de la psicosis.The present invention relates to compounds that have pharmacological activity against the sigma receptor (?) and, more particularly, to some pyrazole derivatives, to procedures for preparing such compounds, at pharmaceutical compositions that comprise them and their use in treatment and prevention, in particular for the treatment of psychosis.
La mejor comprensión de la estructura de las proteínas y otras biomoléculas asociadas con enfermedades de interés ha contribuido enormemente a la búsqueda de nuevos agentes terapéuticos. Una clase importante de estas proteínas es el receptor sigma (\sigma), un receptor de la superficie celular del sistema nervioso central (SNC) que puede estar relacionado con los efectos estimulantes cardiacos, alucinógenos y disfóricos de los opioides. A partir de estudios de la biología y de la función de los receptores sigma, hay pruebas de que los ligandos del receptor sigma pueden ser útiles en el tratamiento de la psicosis y los trastornos del movimiento tales como la distonía y la discinesia tardía, y las alteraciones motoras asociadas con la corea de Huntington o el síndrome de Tourette y en la enfermedad de Parkinson (Walker, J.M. et al, Pharmacological Reviews, 1990, 42, 355). Se ha publicado que el ligando conocido del receptor sigma, rimcazol, muestra clínicamente efectos en el tratamiento de la psicosis (Snyder, S.H., Largent, B.L. J. Neuropsychiatry 1989, 1, 7). Los sitios de unión sigma tienen afinidad preferente por los isómeros dextrógiros de ciertos opioides benzomorfanos, tales como (+)SKF 10047, (+)ciclazocina y (+)pentazocina y también por algunos narcolépticos, tales como el haloperidol.The better understanding of the structure of proteins and other biomolecules associated with diseases of interest has greatly contributed to the search for new therapeutic agents. An important class of these proteins is the sigma receptor (sig), a central nervous system (CNS) cell surface receptor that may be related to the cardiac, hallucinogenic and dysphoric stimulating effects of opioids. From studies of the biology and function of sigma receptors, there is evidence that sigma receptor ligands may be useful in the treatment of psychosis and movement disorders such as dystonia and tardive dyskinesia, and motor alterations associated with Huntington's chorea or Tourette's syndrome and Parkinson's disease (Walker, JM et al , Pharmacological Reviews , 1990, 42, 355). It has been published that the known sigma receptor ligand, rimcazol, shows clinically effects in the treatment of psychosis (Snyder, SH, Largent, BLJ Neuropsychiatry 1989, 1, 7). Sigma binding sites have preferential affinity for the dextrogyric isomers of certain benzomorphan opioids, such as (+) SKF 10047, (+) cyclazocine and (+) pentazocine, and also for some narcoleptics, such as haloperidol.
El receptor sigma tiene al menos dos subtipos, que pueden distinguirse por los isómeros estereoselectivos de estos fármacos activos farmacológicamente. SKF 10047 tiene afinidad nanomolar por el sitio sigma 1 (\sigma-1) y tiene afinidad micromolar por el sitio sigma (\sigma-2). El haloperidol tiene afinidades similares por ambos subtipos. No se conocen los ligandos endógenos de sigma, aunque se ha sugerido que la progesterona es uno de ellos. Los posibles efectos farmacológicos mediados por el sitio sigma incluyen la modulación de la función del receptor del glutamato, la respuesta de los neurotransmisores, la neuroprotección, el comportamiento y la cognición (Quirion, R. et al. Trends Pharmacol. Sci., 1992, 13:85-86). La mayoría de los estudios han dado a entender que los sitios de unión sigma (receptores) son elementos del plasmalema (membrana celular) de la cascada de transducción de señal. Los fármacos conocidos que son ligandos selectivos de sigma se han evaluado como antipsicóticos (Hanner, M. et al. Proc. Natl. Acad. Sci., 1996, 93:8072-8077). La existencia de receptores sigma en el SNC, los sistemas inmunológico y endocrino, ha sugerido una posibilidad de que pueda servir como un nexo entre los tres sistemas.The sigma receptor has at least two subtypes, which can be distinguished by the stereoselective isomers of these pharmacologically active drugs. SKF 10047 has nanomolar affinity for the sigma 1 site (sig-1) and has micromolar affinity for the sigma site (sig-2). Haloperidol has similar affinities for both subtypes. Endogenous sigma ligands are not known, although it has been suggested that progesterone is one of them. Possible pharmacological effects mediated by the sigma site include modulation of glutamate receptor function, neurotransmitter response, neuroprotection, behavior and cognition (Quirion, R. et al . Trends Pharmacol. Sci ., 1992, 13: 85-86). Most studies have suggested that sigma binding sites (receptors) are elements of the plasmalema (cell membrane) of the signal transduction cascade. Known drugs that are selective sigma ligands have been evaluated as antipsychotics (Hanner, M. et al . Proc. Natl. Acad. Sci ., 1996, 93: 8072-8077). The existence of sigma receptors in the CNS, the immune and endocrine systems, has suggested a possibility that it can serve as a link between the three systems.
En vista de las potenciales aplicaciones terapéuticas de los agonistas o antagonistas del receptor sigma, ha habido un gran esfuerzo para encontrar ligandos selectivos. Varios documentos del estado de la técnica describen diferentes ligandos del receptor sigma.In view of the potential applications Therapeutics of sigma receptor agonists or antagonists, has There has been a great effort to find selective ligands. Various State of the art documents describe different ligands of the sigma receiver.
La solicitud de patente internacional número WO
91/09594 describe genéricamente una amplia clase de ligandos del
receptor sigma, algunos de los cuales son compuestos de
4-fenilpiperidina,
tetrahidro-piridina o piperazina que tienen un
sustituyente arilo o heteroarilo, alquilo, alquenilo, alquinilo,
alcoxilo o alcoxialquilo, opcionalmente sustituido, en el átomo de
N del anillo. Los términos arilo y heteroarilo se definen
refiriéndose al número de tales sustitu-
yentes.International patent application number WO 91/09594 generically describes a broad class of sigma receptor ligands, some of which are 4-phenylpiperidine, tetrahydro-pyridine or piperazine compounds having an aryl or heteroaryl, alkyl, alkenyl, alkynyl substituent , optionally substituted alkoxy or alkoxyalkyl, in the N atom of the ring. The terms aryl and heteroaryl are defined by referring to the number of such substituents.
go.
La publicación de patente europea número EP 0 414 289 A1 describe genéricamente una clase de derivados de 1,2,3,4-tetrahidro-espiro[naftaleno-1,4'-piperidina] y 1,4-dihidro-espiro[naftaleno-1,4'-piperidina] sustituidos en el átomo de N de la piperidina con un grupo hidrocarbonado, se afirma que tienen actividad antagonista selectiva del receptor sigma. El término hidrocarbonado, tal como se define en dicha patente, cubre todos los posibles grupos de cadena lineal, cíclicos, heterocíclicos, etc. Sin embargo, sólo se describen específicamente los compuestos que tienen bencilo, fenetilo, cicloalquilmetilo, furil o tienilmetilo o alquenilo o alquilo inferior como el sustituyente hidrocarbonado en el átomo de nitrógeno de la piperidina. Se indica que los compuestos desplazan la di-tolilguanidina (DTG) tritiada de los sitios sigma con concentraciones superiores a 200 nM. Como compuesto particularmente preferido se menciona la 1'-bencil-1,2,3,4-tetrahidro-espiro[naftaleno-1,4'-piperidina].European Patent Publication Number EP 0 414 289 A1 generically describes a class of derivatives of 1,2,3,4-tetrahydro-spiro [naphthalene-1,4'-piperidine] Y 1,4-dihydro-spiro [naphthalene-1,4'-piperidine] substituted on the N atom of piperidine with a group hydrocarbon, it is claimed that they have antagonistic activity selective sigma receptor. The term hydrocarbon, as defined in said patent, covers all possible chain groups linear, cyclic, heterocyclic, etc. However, I only know specifically describe the compounds that have benzyl, phenethyl, cycloalkylmethyl, furyl or thienylmethyl or alkenyl or lower alkyl as the hydrocarbon substituent on the atom of Piperidine nitrogen. It is indicated that the compounds displace tritiated di-tolylguanidine (DTG) sites Sigma with concentrations greater than 200 nM. As compound particularly preferred the 1'-benzyl-1,2,3,4-tetrahydro-spiro [naphthalene-1,4'-piperidine].
La publicación de patente europea número EP 0 445 974 A2 describe genéricamente los correspondientes derivados de espiro[indano-1,4'-piperidina] y espiro[benzociclohepteno-5,4'-piperidina]. De nuevo, sólo se indica que los compuestos desplazan la di-tolilguanidina (DTG) tritiada de los sitios sigma con concentraciones superiores a 200 nM.European Patent Publication Number EP 0 445 974 A2 generically describes the corresponding derivatives of spiro [indane-1,4'-piperidine] Y spiro [benzocycloheptene-5,4'-piperidine]. Again, it is only indicated that the compounds displace the tritiated di-tolylguanidine (DTG) from sigma sites with concentrations greater than 200 nM.
La solicitud de patente europea número EP-A-0 431 943 se refiere a otra clase extremadamente amplia de compuestos de espiropiperidina sustituidos en el átomo de N de la piperidina y se reivindica que son útiles como antiarrítmicos y para la función alterada del bombeo cardiaco. Dicha solicitud pone como ejemplo varios compuestos, la mayoría de los cuales contienen un sustituyente oxo y/o sulfonilamino en el sistema de anillo espirocíclico. De los compuestos restantes, la mayor parte tiene otro sustituyente polar unido al núcleo espiro y/o tienen algunos sustituyentes polares en el sustituyente en el átomo de N de la piperidina. No se dan sugerencias ni indicaciones del efecto de los compuestos sobre el receptor sigma.European patent application number EP-A-0 431 943 refers to another extremely broad class of spiropiperidine compounds substituted on the N atom of piperidine and it is claimed that they are useful as antiarrhythmics and for altered function of cardiac pumping This request gives as an example several compounds, most of which contain an oxo substituent and / or sulfonylamino in the spirocyclic ring system. Of the remaining compounds, most have another polar substituent attached to the spiro nucleus and / or have some polar substituents in the substituent on the N atom of piperidine. They do not occur suggestions or indications of the effect of the compounds on the sigma receiver
Con respecto a la estructura química de los compuestos descritos en la presente solicitud de patente, hay algunos documentos en la técnica anterior que describen derivados de pirazol caracterizados, entre otras cosas, por estar sustituidos por grupos amino-alcoxilo en diferentes posiciones del grupo pirazol.With respect to the chemical structure of Compounds described in the present patent application, there are some documents in the prior art describing derivatives of pyrazole characterized, among other things, by being substituted by amino-alkoxy groups in different positions from the pyrazole group.
La patente estadounidense US 4.337.263 describe 1-aril-4-arilsulfonil-3-aminopropoxi-1H-pirazoles, en los que el grupo amino puede estar constituido por un grupo cíclico con N como un grupo morfolino, piperidino o pirrolidino. Se utilizan como agentes hipolipemiantes o hipocolesterolémicos.US Patent 4,337,263 describes 1-aryl-4-arylsulfonyl-3-aminopropoxy-1H-pyrazoles, in which the amino group may be constituted by a group cyclic with N as a morpholino, piperidino or pyrrolidino group. Be used as lipid lowering agents or hypocholesterolemic agents.
En este sentido, la patente francesa FR 2301250 describe compuestos similares a los mencionados anteriormente, tales como 1,4-diaril-3-aminoalcoxipirazoles, en los que el grupo amino comprende derivados de pirrolidina, piperidina, hidroxipiperidina, morfolina o piperazina. Sin embargo, no se menciona la actividad de estos compuestos.In this regard, French patent FR 2301250 describes compounds similar to those mentioned above, such as 1,4-diaryl-3-aminoalkoxypyrazoles, in which the amino group comprises pyrrolidine derivatives, piperidine, hydroxypiperidine, morpholine or piperazine. But nevertheless, The activity of these compounds is not mentioned.
La solicitud de patente estadounidense US2003/0144309 se refiere a pirazoles con su posición 3 sustituida por un grupo dimetilaminoetoxilo y presentan en su posición 4 un grupo de pirimidina. Se utilizan como inhibidores de la actividad de la quinasa de JNK3, Lck o Src.The US patent application US2003 / 0144309 refers to pyrazoles with their position 3 replaced by a dimethylaminoethoxy group and present in position 4 a pyrimidine group. They are used as activity inhibitors of the kinase of JNK3, Lck or Src.
La solicitud de patente internacional WO 04017961 describe compuestos de pirazol en los que la posición 3 está sustituida por un grupo alcoxilo unido directamente a una amida cíclica, que se utilizan para tratar y/o prevenir terapéuticamente un estado relacionado con hormonas sexuales en un paciente.International patent application WO 04017961 describes pyrazole compounds in which position 3 is substituted by an alkoxy group directly attached to an amide cyclic, which are used to treat and / or prevent therapeutically a state related to sex hormones in a patient.
La solicitud de patente internacional WO 04/016592 describe derivados de pirazol que se utilizan para el tratamiento de enfermedades inflamatorias. Estos compuestos presentan en la posición 5 un grupo morfolin-etoxilo.WO international patent application 04/016592 describes pyrazole derivatives that are used for Treatment of inflammatory diseases. These compounds they present in group 5 a group morpholin-ethoxy.
La solicitud de patente internacional WO 04/016592 se refiere a compuestos de pirazol para inhibir la prenilación de proteínas que comprende, en la posición 5, un grupo alcoxilo unido directamente a una amida cíclica.WO international patent application 04/016592 refers to pyrazole compounds to inhibit protein compilation comprising, in position 5, a group alkoxy directly attached to a cyclic amide.
Sin embargo, ninguno de estos documentos indica el efecto de estos compuestos sobre el receptor sigma.However, none of these documents indicates The effect of these compounds on the sigma receptor.
Aún es necesario encontrar compuestos que tengan actividad farmacológica frente al receptor sigma, que sean tanto eficaces como selectivos, y que tengan buenas propiedades como fármaco, es decir, buenas propiedades farmacéuticas relacionadas con la administración, la distribución, el metabolismo y la excreción.It is still necessary to find compounds that have pharmacological activity against the sigma receptor, which are both effective as selective, and having good properties such as drug, that is, good related pharmaceutical properties with administration, distribution, metabolism and excretion.
Se ha encontrado una familia de derivados de pirazol estructuralmente distintos que son inhibidores particularmente selectivos del receptor sigma. Los compuestos presentan un grupo pirazol que está caracterizado por la sustitución en la posición 3 por un grupo alcoxilo unido directamente a un nitrógeno.A family of derivatives of structurally different pyrazoles that are inhibitors particularly selective sigma receptor. The compounds they have a pyrazole group that is characterized by substitution in position 3 by an alkoxy group directly attached to a nitrogen.
En un aspecto, la invención se refiere a un compuesto de fórmula I:In one aspect, the invention relates to a compound of formula I:
en la quein the that
- R_{1} y R_{2} se seleccionan independientemente del grupo formado por hidrógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, arilalquilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, heterociclilalquilo sustituido o no sustituido, -COR_{8}, -C(O)OR_{8}, -C(O)NR_{8}R_{9} -C=NR_{8}, -CN, -OR_{8}, -OC(O)R_{8}, -S(O)_{t}-R_{8}, -NR_{8}R_{9}, -NR_{8}C(O)R_{9}, -NO_{2}, -N=CR_{8}R_{9} o halógeno;R_ {1} and R2 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, cycloalkyl substituted or unsubstituted, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl substituted, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR 8, -C (O) OR_ {8}, -C (O) NR_ {8} R_ {9} -C = NR 8, -CN, -OR 8, -OC (O) R 8, -S (O) t -R 8, -NR_ {8} R_9, -NR_ {8} C (O) R_ {9}, -NO_ {2}, -N = CR 8 R 9 or halogen;
- R_{3} y R_{4} se seleccionan independientemente del grupo formado por alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, arilalquilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, heterociclilalquilo sustituido o no sustituido, COR_{8}, -C(O)OR_{8}, -C(O)NR_{8}R_{9} -C=NR_{8}, -CN, -OR_{8}, -OC(O)R_{8}, -S(O)_{t}-R_{8} , -NR_{8}R_{9}, -NR_{8}C(O)R_{9}, -NO_{2}, -N=CR_{8}R_{9} o halógeno, en los queR 3 and R4 are independently selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl substituted, substituted or unsubstituted alkenyl, substituted aryl or unsubstituted, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, heterocyclylalkyl substituted or unsubstituted, COR 8, -C (O) OR 8, -C (O) NR_R8 {9} -C = NR_ {8}, -CN, -OR_ {8}, -OC (O) R 8, -S (O) t -R 8, -NR_ {8} R_9, -NR_ {8} C (O) R_ {9}, -NO_ {2}, -N = CR 8 R 9 or halogen, in which
- t es 1, 2 ó 3;t is 1, 2 or 3;
- R_{8} y R_{9} se seleccionan cada uno independientemente de hidrógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, alcoxilo sustituido o no sustituido, ariloxilo sustituido o no sustituido, halógeno;R_ {8} and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl substituted, substituted or unsubstituted alkenyl, substituted aryl or unsubstituted, substituted or unsubstituted heterocyclyl, alkoxy substituted or unsubstituted, substituted or unsubstituted aryloxy, halogen;
- R_{5} y R_{6}, forman juntos, con el átomo de nitrógeno al que están unidos, un grupo heterociclilo sustituido o no sustituido;R 5 and R 6 form together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group;
- n se selecciona de 1, 2, 3, 4, 5, 6, 7, 8;n is selected of 1, 2, 3, 4, 5, 6, 7, 8;
o una sal farmacéuticamente aceptable, un isómero, un profármaco o un solvato del mismo.or a pharmaceutically salt acceptable, an isomer, a prodrug or a solvate of same.
En un segundo aspecto, la invención se refiere a un compuesto de fórmula IB:In a second aspect, the invention relates to a compound of formula IB:
en la quein the that
- R_{1} se selecciona del grupo formado por alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilalquilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, heterociclilalquilo sustituido o no sustituido, -COR_{8}, -C(O)OR_{8}, -C(O)NR_{8}R_{9} -C=NR_{8}, -CN, -OR_{8}, -OC(O)R_{8}, -NR_{8}R_{9}, -NR_{8}C(O)R_{9}, -NO_{2}, -N=CR_{8}R_{9} o halógeno,R_ {1} se select from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or non-substituted alkenyl substituted, substituted or unsubstituted arylalkyl, heterocyclyl substituted or unsubstituted, heterocyclylalkyl substituted or unsubstituted substituted, -COR_ {8}, -C (O) OR_ {8}, -C (O) NR 8 R 9 -C = NR 8, -CN, -OR_ {8}, -OC (O) R 8, -NR_ {8} R 9, -NR_ {8} C (O) R_ {9}, -NO_ {2}, -N = CR_ {R} {8} or halogen,
- R_{2}, R_{3} y R_{4} se seleccionan independientemente del grupo formado por hidrógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, arilalquilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, heterociclilalquilo sustituido o no sustituido, -COR_{8}, -C(O)OR_{8}, -C(O)NR_{8}R_{9} -C=NR_{8}, -CN, -OR_{8}, -OC(O)R_{8}, -S(O)_{t}-R_{8}, -NR_{8}R_{9}, -NR_{8}C(O)R_{9}, -NO_{2}, -N=CR_{8}R_{9} o halógeno;R 2, R 3 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, cycloalkyl substituted or unsubstituted, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl substituted, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR 8, -C (O) OR_ {8}, -C (O) NR_ {8} R_ {9} -C = NR 8, -CN, -OR 8, -OC (O) R 8, -S (O) t -R 8, -NR 8 R 9, -NR_ {8} C (O) R_ {9}, -NO_ {2}, -N = CR_ {R} {8} or halogen;
- en los quein the that
- t es 1, 2 ó 3;t is 1, 2 or 3;
- R_{8} y R_{9} se seleccionan cada uno independientemente de hidrógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, alcoxilo sustituido o no sustituido, ariloxilo sustituido o no sustituido, o halógeno;R_ {8} and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl substituted, substituted or unsubstituted alkenyl, substituted aryl or unsubstituted, substituted or unsubstituted heterocyclyl, alkoxy substituted or unsubstituted, substituted or unsubstituted aryloxy, or halogen;
- R_{5} y R_{6}, forman juntos, con el átomo de nitrógeno al que están unidos, un grupo heterociclilo sustituido o no sustituido;R 5 and R 6 form together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group;
- n se selecciona de 1, 2, 3, 4, 5, 6, 7, 8;n is selected of 1, 2, 3, 4, 5, 6, 7, 8;
o una sal farmacéuticamente aceptable, un isómero, un profármaco o un solvato del mismo.or a pharmaceutically salt acceptable, an isomer, a prodrug or a solvate of same.
En ambos casos (I) y (IB), puede aplicarse lo siguiente:In both cases (I) and (IB), the following may apply next:
En una realización, R_{1} es preferiblemente alquilo sustituido o no sustituido.In one embodiment, R1 is preferably substituted or unsubstituted alkyl.
En otra realización, cuando el compuesto es de fórmula (I), R_{1} es hidrógeno.In another embodiment, when the compound is of formula (I), R1 is hydrogen.
En otra realización, R_{2} es preferiblemente alquilo, más preferiblemente metilo.In another embodiment, R2 is preferably alkyl, more preferably methyl.
En una realización R_{3} y R_{4} son halógeno o alquilo. En una realización más preferida, son halógeno o haloalquilo.In one embodiment R 3 and R 4 are halogen or alkyl. In a more preferred embodiment, they are halogen or haloalkyl
Se prefiere que los sustituyentes de arilo R_{3} y R_{4} se sitúen en las posiciones meta y/o para del grupo fenilo.It is preferred that aryl substituents R_ {3} and R_ {4} are placed in the target and / or para positions of the phenyl group.
Además, en una realización preferida, n es preferiblemente 2, 3, 4, 5, ó 6, más preferiblemente n es 2.In addition, in a preferred embodiment, n is preferably 2, 3, 4, 5, or 6, more preferably n is 2.
En otra realización preferida, R_{5} y R_{6}, juntos, forman un grupo morfolin-4-ilo.In another preferred embodiment, R 5 and R 6, together, they form a group morpholin-4-yl.
En otro aspecto, la invención se refiere a un procedimiento para la preparación de un compuesto de fórmula (I) o (IB) o a una sal, isómero o solvato del mismo.In another aspect, the invention relates to a process for the preparation of a compound of formula (I) or (IB) or a salt, isomer or solvate thereof.
En otro aspecto, la invención se refiere a una composición farmacéutica que comprende un compuesto tal como se definió anteriormente o una sal farmacéuticamente aceptable, un enantiómero, un profármaco o un solvato del mismo, y un portador, adyuvante o vehículo farmacéuticamente aceptable.In another aspect, the invention relates to a pharmaceutical composition comprising a compound as it is defined above or a pharmaceutically acceptable salt, a enantiomer, a prodrug or solvate thereof, and a carrier, pharmaceutically acceptable adjuvant or vehicle.
En un aspecto adicional, la invención se refiere al uso de un compuesto de fórmula IV:In a further aspect, the invention relates to to the use of a compound of formula IV:
en la quein the that
- R_{1}, R_{2}, R_{3}, R_{4}, R_{5} y R_{6} se seleccionan independientemente del grupo formado por hidrógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, arilalquilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, heterociclilalquilo sustituido o no sustituido, -COR_{8}, -C(O)OR_{3}, -C(O)NR_{8}R_{9}, -C=NR_{8}, -CN, -OR_{8}, -OC(O)R_{8}, -S(O)_{t}-R_{8}, -NR_{8}R_{9}, -NR_{8}C(O)R_{9}, -NO_{2}, -N=CR_{8}R_{9} o halógeno, en los que dos de ellos pueden formar juntos un anillo, opcionalmente condensado,R_ {1}, R 2, R 3, R 4, R 5 and R 6 are selected regardless of the group consisting of hydrogen, alkyl substituted or unsubstituted, substituted or unsubstituted cycloalkyl substituted, substituted or unsubstituted alkenyl, substituted aryl or unsubstituted, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, heterocyclylalkyl substituted or unsubstituted, -COR 8, -C (O) OR 3, -C (O) NR_R8 {9}, -C = NR_ {8}, -CN, -OR_ {8}, -OC (O) R 8, -S (O) t -R 8, -NR_ {8} R_9, -NR_ {8} C (O) R_ {9}, -NO_ {2}, -N = CR 8 R 9 or halogen, in which two of them can together form a ring, optionally condensed,
- t es 1, 2 ó 3;t is 1, 2 or 3;
- R_{8} y R_{9} se seleccionan cada uno independientemente de hidrógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, alcoxilo sustituido o no sustituido, ariloxilo sustituido o no sustituido, o halógeno;R_ {8} and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl substituted, substituted or unsubstituted alkenyl, substituted aryl or unsubstituted, substituted or unsubstituted heterocyclyl, alkoxy substituted or unsubstituted, substituted or unsubstituted aryloxy, or halogen;
- n se selecciona de 1, 2, 3, 4, 5, 6, 7 u 8;n is selected of 1, 2, 3, 4, 5, 6, 7 or 8;
en la fabricación de un medicamento para el tratamiento o la prevención de una enfermedad o estado mediados por el receptor sigma.in the manufacture of a medicine for the treatment or prevention of a disease or condition mediated by the receiver sigma.
En una realización preferida, en el compuesto de fórmula IV n es 2, 3, 4, 5 ó 6, más preferiblemente 2, 3 ó 4, lo más preferiblemente 2.In a preferred embodiment, in the compound of formula IV n is 2, 3, 4, 5 or 6, more preferably 2, 3 or 4, so more preferably 2.
En otra realización preferida, el compuesto de fórmula IV se usa en la fabricación de un medicamento para el tratamiento de la diarrea, trastornos lipoproteicos, migraña, obesidad, artritis, hipertensión, arritmia, úlcera, trastornos cognitivos, dependencia a la cocaína, discinesia tardía, accidente cerebrovascular isquémico, epilepsia, accidente cerebrovascular, depresión, estrés, dolor, dolor especialmente neuropático o alodinia, o estado psicótico, esquizofrenia, tratamiento de adicción o cáncer; o al uso como herramienta farmacológica, como ansiolítico o como inmunosupresor.In another preferred embodiment, the compound of Formula IV is used in the manufacture of a medicament for treatment of diarrhea, lipoprotein disorders, migraine, obesity, arthritis, hypertension, arrhythmia, ulcer, disorders Cognitive, cocaine dependence, tardive dyskinesia, accident ischemic stroke, epilepsy, stroke, depression, stress, pain, especially neuropathic pain or allodynia, or psychotic state, schizophrenia, treatment of addiction or cancer; or to use as a pharmacological tool, such as anxiolytic or as an immunosuppressant.
En una realización más preferida, el medicamento es para el tratamiento del dolor, más preferiblemente del dolor neuropático o alodinia.In a more preferred embodiment, the medicament It is for the treatment of pain, more preferably pain neuropathic or allodynia
Las preferencias y realizaciones anteriormente mencionadas pueden combinarse para dar compuestos o usos preferidos adicionales.Preferences and achievements above mentioned can be combined to give preferred compounds or uses additional.
La figura 1 se refiere al ejemplo 3 y muestra el protocolo de prueba para todas las pruebas con filamentos de von Frey.Figure 1 refers to example 3 and shows the test protocol for all tests with von filaments Frey.
Las figuras 2 y 3 se refieren al ejemplo 3 y muestran el efecto del compuesto VII en un modelo de dolor neuropático, especialmente alodinia mecánica.Figures 2 and 3 refer to example 3 and show the effect of compound VII on a pain model Neuropathic, especially mechanical allodynia.
La figura 2 prueba la dependencia de la dosis del tratamiento con el compuesto VII para mostrar analgesia en el dolor neuropático inducido por capsaicina.Figure 2 proves the dose dependence of the treatment with compound VII to show pain analgesia Capsaicin-induced neuropathic.
La figura 3 demuestra que el tratamiento con el compuesto VII es eficaz específicamente en el dolor neuropático o la alodinia mecánica, tal como se muestra por la eficacia que depende de la fuerza de los filamentos de von-Frey, estando 0,5 g normalmente en el intervalo del dolor neuropáptico / alodinia.Figure 3 demonstrates that treatment with the compound VII is specifically effective in neuropathic pain or mechanical allodynia, as shown by the effectiveness that depends on the strength of von-Frey's filaments, 0.5 g being normally in the range of neuropathic pain / allodynia
Los compuestos típicos de esta invención inhiben eficaz y selectivamente al receptor sigma.Typical compounds of this invention inhibit effectively and selectively to the sigma receptor.
En la presente descripción, los siguientes términos tienen el significado indicado:In the present description, the following terms have the indicated meaning:
"Alquilo" se refiere a un radical de cadena hidrocarbonada, lineal o ramificada, que consiste en átomos de carbono e hidrógeno, sin contener insaturación, que tiene de uno a ocho átomos de carbono, y que está unido al resto de la molécula mediante un enlace sencillo, por ejemplo, metilo, etilo, n-propilo, i-propilo, n-butilo, t-butilo, n-pentilo, etc. Los radicales alquilo pueden estar sustituidos opcionalmente por uno o más sustituyentes tales como arilo, halógeno, hidroxilo, alcoxilo, carboxilo, ciano, carbonilo, acilo, alcoxicarbonilo, amino, nitro, mercapto, alquiltio, etc. Si se sustituye por arilo se obtiene un radical "Aralquilo", tal como bencilo y fenetilo."Alkyl" refers to a chain radical hydrocarbon, linear or branched, consisting of atoms of carbon and hydrogen, without containing unsaturation, which has from one to eight carbon atoms, and that is attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc. The alkyl radicals may be optionally substituted by one or more substituents such as aryl, halogen, hydroxyl, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto, alkylthio, etc. Yes it is replaced by aryl a radical "Aralkyl" is obtained, such like benzyl and phenethyl.
"Alquenilo" se refiere a un radical alquilo que tiene al menos 2 átomos de C y que tiene uno o más enlaces insaturados."Alkenyl" refers to an alkyl radical that has at least 2 C atoms and that has one or more bonds unsaturated
"Cicloalquilo" se refiere a un radical estable, monocíclico o bicíclico, de 3 a 10 miembros, que está saturado o parcialmente saturado, y que consiste únicamente en átomos de carbono e y hidrógeno, tal como ciclohexilo o adamantilo. A menos que se establezca específicamente lo contrario en la memoria descriptiva, el término "cicloalquilo" se refiere a que incluye radicales cicloalquilo que están opcionalmente sustituidos por uno o más sustituyentes tales como alquilo, halógeno, hidroxilo, amino, ciano, nitro, alcoxilo, carboxilo, alcoxicarbonilo, etc."Cycloalkyl" refers to a radical stable, monocyclic or bicyclic, 3 to 10 members, which is saturated or partially saturated, and consisting solely of carbon atoms and hydrogen, such as cyclohexyl or adamantyl. Unless specifically stated otherwise in memory descriptively, the term "cycloalkyl" refers to that includes cycloalkyl radicals that are optionally substituted by one or more substituents such as alkyl, halogen, hydroxyl, amino, cyano, nitro, alkoxy, carboxyl, alkoxycarbonyl, etc.
"Arilo" se refiere a radicales de anillo único y múltiples anillos, que incluyen radicales de múltiples anillos que contienen grupos arilo separados y/o condensados. Los grupos arilo típicos contienen desde 1 hasta 3 anillos separados o condensados y desde 6 hasta aproximadamente 18 átomos de carbono de anillo, tales como un radical fenilo, naftilo, indenilo, fenantrilo o antracilo. El radical arilo puede estar opcionalmente sustituido por uno o más sustituyentes, tal como hidroxilo, mercapto, halógeno, alquilo, fenilo, alcoxilo, haloalquilo, nitro, ciano, dialquilamino, aminoalquilo, acilo, alcoxicarbonilo, etc."Aryl" refers to ring radicals single and multiple rings, which include multiple radicals rings containing separate and / or condensed aryl groups. The Typical aryl groups contain from 1 to 3 separate rings or condensed and from 6 to about 18 carbon atoms of ring, such as a phenyl, naphthyl, indenyl, phenanthryl radical or anthracil. The aryl radical may be optionally substituted. by one or more substituents, such as hydroxyl, mercapto, halogen, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl, alkoxycarbonyl, etc.
"Heterociclilo" se refiere a un radical estable de anillo de 3 a 15 miembros que consiste en átomos de carbono y desde uno hasta cinco heteroátomos seleccionados del grupo que consiste en nitrógeno, oxígeno y azufre, preferiblemente un anillo de 4 a 8 miembros con uno o más heteroátomos, más preferiblemente un anillo de 5 ó 6 miembros con uno o más heteroátomos. Puede ser aromático o no. Para el objeto de esta invención, el heterociclo puede ser un sistema de anillo monocíclico, bicíclico o tricíclico, que puede incluir sistemas de anillos condensados; y los átomos de nitrógeno, carbono o azufre en el radical heterociclilo puede estar opcionalmente oxidados; el átomo de nitrógeno puede estar opcionalmente cuaternizado; y el radical heterociclilo puede estar parcial o completamente saturado o ser aromático. Ejemplos de tales heterociclos incluyen, pero no se limitan a, azepinas, bencimidazol, benzotiazol, furano, isotiazol, imidazol, indol, piperidina, piperazina, purina, quinolina, tiadiazol, tetrahidrofurano, cumarina, morfolina; pinol, pirazol, oxazol, isoxazol, triazol, imidazol, etc."Heterocyclyl" refers to a radical stable of ring of 3 to 15 members consisting of atoms of carbon and from one to five heteroatoms selected from group consisting of nitrogen, oxygen and sulfur, preferably a ring of 4 to 8 members with one or more heteroatoms, more preferably a 5 or 6 member ring with one or more heteroatoms It can be aromatic or not. For the purpose of this invention, the heterocycle can be a ring system monocyclic, bicyclic or tricyclic, which may include systems of condensed rings; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; he nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or completely saturated or be aromatic Examples of such heterocycles include, but not are limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, coumarin, morpholine; pinol, pyrazole, oxazole, isoxazole, triazole, imidazole, etc.
"Alcoxilo" se refiere a un radical de fórmula -ORa, donde Ra es un radical alquilo según se definió anteriormente, por ejemplo, metoxilo, etoxilo, propoxilo, etc."Alkoxy" refers to a radical of formula -ORa, where Ra is an alkyl radical as defined above, for example, methoxy, ethoxy, propoxy, etc.
"Amino" se refiere a un radical de fórmula -NH2, -NHRa o —NRaRb, opcionalmente cuaternizado."Amino" refers to a radical of formula -NH2, -NHRa or —NRaRb, optionally quaternized.
"Halógeno" o "halo" se refieren a bromo, cloro, yodo o flúor."Halogen" or "halo" refer to bromine, chlorine, iodine or fluorine.
Las referencias en el presente documento a grupos sustituidos en los compuestos de la presente invención se refieren al resto especificado que puede estar sustituido en una o más posiciones disponibles por uno o más grupos adecuados, por ejemplo, halógeno tal como flúor, cloro, bromo y yodo; ciano; hidroxilo; nitro; azido; alcanoílo tal como un grupo alcanoílo C1-6 tal como acilo y similares; carboxamido; grupos alquilo incluyendo aquellos grupos que tienen de 1 a aproximadamente 12 átomos de carbono o desde 1 hasta aproximadamente 6 átomos de carbono y, más preferiblemente, 1-3 átomos de carbono; grupos alquenilo y alquinilo incluyendo grupos que tienen uno o más enlaces insaturados y desde 2 hasta aproximadamente 12 átomos de carbono o desde 2 hasta aproximadamente 6 átomos de carbono; grupos alcoxilo que tienen uno o más enlaces a oxígeno y desde 1 hasta aproximadamente 12 átomos de carbono o desde 1 hasta aproximadamente 6 átomos de carbono; ariloxilo tal como fenoxilo; grupos alquiltio que incluyen aquellos restos que tienen uno o más enlaces tioéter y desde 1 hasta aproximadamente 12 átomos de carbono o desde 1 hasta aproximadamente 6 átomos de carbono; grupos alquilsulfinilo incluyendo aquellos restos que tienen uno o más enlaces sulfinilo y desde 1 hasta aproximadamente 12 átomos de carbono o desde 1 hasta aproximadamente 6 átomos de carbono; grupos alquilsulfonilo incluyendo aquellos restos que tienen uno o más enlaces sulfonilo y desde 1 hasta aproximadamente 12 átomos de carbono o desde 1 hasta aproximadamente 6 átomos de carbono; grupos aminoalquilo tales como grupos que tienen uno o más átomos de N y desde 1 hasta aproximadamente 12 átomos de carbono o desde 1 hasta aproximadamente 6 átomos de carbono; arilo carbocíclico que tiene 6 o más átomos de carbono, particularmente fenilo o naftilo y aralquilo tal como bencilo. A menos que se indique lo contrario, un grupo opcionalmente sustituido puede tener un sustituyente en cada posición sustituible del grupo y cada sustitución es independiente de la otra.References in this document to groups substituted in the compounds of the present invention refer to the specified remainder that may be substituted in one or more positions available by one or more suitable groups, for example, halogen such as fluorine, chlorine, bromine and iodine; cyano; hydroxyl; nitro; azido; alkanoyl such as an alkanoyl group C1-6 such as acyl and the like; carboxamide; alkyl groups including those groups that have 1 to approximately 12 carbon atoms or from 1 to about 6 carbon atoms and, more preferably, 1-3 carbon atoms; alkenyl and alkynyl groups including groups that have one or more unsaturated links and from 2 to about 12 carbon atoms or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen bonds and from 1 to about 12 atoms carbon or from 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups that include those remains that have one or more thioether bonds and from 1 to approximately 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those residues that have one or more sulfinyl bonds and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those residues that have one or more sulfonyl bonds and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups that have one or more atoms of N and from 1 to approximately 12 carbon atoms or from 1 to about 6 carbon atoms; carbocyclic aryl that has 6 or more carbon atoms, particularly phenyl or naphthyl and aralkyl such as benzyl. Unless otherwise indicated, a optionally substituted group may have a substituent in each replaceable position of the group and each substitution is independent of the other.
Un compuesto individual particular de la invención que cae bajo la fórmula (I) y que se prefiere es 4-{2-(1-(3,4-diclorofenil)-5-metil-1H-pirazol-3-iloxi)etil}morfolina (VII), sus sales, solvatos o profármacos.A particular individual compound of the invention that falls under formula (I) and which is preferred is 4- {2- (1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy) ethyl} morpholine (VII), its salts, solvates or prodrugs.
A menos que se indique lo contrario, los compuestos de la invención también se refiere a que incluyen compuestos que difieren sólo en la presencia de uno o más átomos isotópicamente enriquecidos. Por ejemplo, los compuestos que tienen las presentes estructuras, a excepción de la sustitución de un hidrógeno por un deuterio o un tritio, o la sustitución de un carbono por un carbono enriquecido en ^{13}C o ^{14}C o un nitrógeno enriquecido en ^{15}N están dentro del alcance de esta invención.Unless otherwise indicated, the Compounds of the invention also refers to which include compounds that differ only in the presence of one or more atoms Isotopically enriched. For example, the compounds that have the present structures, except for the replacement of a hydrogen by a deuterium or a tritium, or the replacement of a carbon by a carbon enriched in 13 C or 14 C or a nitrogen enriched in 15 N are within the scope of this invention.
El término "sales farmacéuticamente aceptables, solvatos, profármacos" se refiere a cualquier sal farmacéuticamente aceptable, éster, solvato o cualquier otro compuesto que, cuando se administra al receptor puede proporcionar (directa o indirectamente) un compuesto tal como se describe en el presente documento. Sin embargo, se apreciará que las sales farmacéuticamente no aceptables también caen dentro del alcance de la invención, puesto que pueden ser útiles en la preparación de sales farmacéuticamente aceptables. La preparación de sales, profármacos y derivados puede llevarse a cabo mediante métodos conocidos en la técnica.The term "pharmaceutically acceptable salts, solvates, prodrugs "refers to any salt pharmaceutically acceptable, ester, solvate or any other compound that, when administered to the recipient can provide (directly or indirectly) a compound as described in the present document However, it will be appreciated that the salts Pharmaceutically unacceptable also fall within the scope of the invention, since they can be useful in the preparation of pharmaceutically acceptable salts. Salt preparation, prodrugs and derivatives can be carried out by methods known in the art.
Por ejemplo, las sales farmacéuticamente aceptables de los compuestos previstos en el presente documento se sintetizan a partir del compuesto original que contiene un resto básico o ácido mediante métodos químicos convencionales. En general, tales sales se preparan, por ejemplo, haciendo reaccionar las formas de base o ácido libre de estos compuestos con una cantidad estequiométrica de la base o el ácido apropiados en agua o en un disolvente orgánico o en una mezcla de los dos. En general, se prefieren medios no acuosos como éter, acetato de etilo, etanol, isopropanol o acetonitrilo. Ejemplos de las sales de adición de ácidos incluyen sales de adición de ácido mineral tales como, por ejemplo, clorhidrato, bromhidrato, yodhidrato, sulfato, nitrato, fosfato, y sales de adición de ácido orgánico tales como, por ejemplo, acetato, maleato, fumarato, citrato, oxalato, succinato, tartrato, malato, mandelato, metanosulfonato y p-toluenosulfonato. Ejemplos de sales de adición de bases incluyen sales inorgánicas tales como, por ejemplo, sales de sodio, potasio, calcio, amonio, magnesio, aluminio y litio, y sales básicas orgánicas tales como, por ejemplo, etilendiamina, etanolamina, N,N-dialquilenetanolamina, trietanolamina, glucamina y sales de aminoácidos básicos.For example, pharmaceutically salts Acceptable of the compounds provided herein are synthesized from the original compound that contains a residue basic or acid by conventional chemical methods. In In general, such salts are prepared, for example, by reacting the base or free acid forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Examples of the addition salts of acids include mineral acid addition salts such as, by example, hydrochloride, hydrobromide, iodhydrate, sulfate, nitrate, phosphate, and organic acid addition salts such as, by example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. Examples of addition salts of bases include inorganic salts such as, for example, salts of sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium, and salts organic bases such as, for example, ethylenediamine, ethanolamine, N, N-dialkylene ethanolamine, triethanolamine, glucamine and basic amino acid salts.
Los derivados o profármacos particularmente favoritos son aquellos que aumentan la biodisponibilidad de los compuestos de esta invención cuando tales compuestos se administran a un paciente (por ejemplo, permitiendo que se administre un compuesto por vía oral para que se absorba más fácilmente en la sangre) o que potencian la administración del compuesto original a un compartimento biológico (por ejemplo, el cerebro o el sistema linfático) en relación con la especie original.Derivatives or prodrugs particularly favorites are those that increase the bioavailability of compounds of this invention when such compounds are administered to a patient (for example, allowing a composed orally so that it is more easily absorbed in the blood) or that enhance the administration of the original compound to a biological compartment (for example, the brain or the system lymphatic) in relation to the original species.
Cualquier compuesto que sea un profármaco de un compuesto de fórmula (I), (IB) o (IV) está dentro del alcance de la invención. El término "profármaco" se usa en su sentido más amplio y engloba aquellos derivados que se convierten in vivo en los compuestos de la invención. Tales derivados serán evidentes para aquellos expertos en la técnica, e incluyen, dependiendo de los grupos funcionales presentes en la molécula y sin limitación, los siguientes derivados de los compuestos presentes: ésteres, ésteres de aminoácido, ésteres de fosfato, ésteres de sulfonato de sales metálicas, carbamatos y amidas.Any compound that is a prodrug of a compound of formula (I), (IB) or (IV) is within the scope of the invention. The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo into the compounds of the invention. Such derivatives will be apparent to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the compounds present: esters, amino acid esters, phosphate esters, salt sulphonate esters metallic, carbamates and amides.
Los compuestos de la invención pueden estar en forma cristalina como compuestos libres o como solvatos y se pretende que ambas formas estén dentro del alcance de la presente invención. Los métodos de solvatación se conocen generalmente dentro de la técnica. Los solvatos adecuados son los solvatos farmacéuticamente aceptables. En una realización particular, el solvato es un hidrato.The compounds of the invention may be in crystalline form as free compounds or as solvates and it intends that both forms are within the scope of this invention. Solvation methods are generally known. within the technique Suitable solvates are solvates pharmaceutically acceptable. In a particular embodiment, the Solvate is a hydrate.
Los compuestos de fórmula (I) (IB) o (IV) o sus sales o solvatos están preferiblemente en forma farmacéuticamente aceptable o sustancialmente pura. Por forma farmacéuticamente aceptable se entiende, entre otros, que tienen un nivel de pureza farmacéuticamente aceptable, excluyendo aditivos farmacéuticos normales, tales como diluyentes y portadores, y no incluyendo material considerado tóxico a niveles de dosificación normales. Los niveles de pureza para el principio activo son preferiblemente superiores al 50%, más preferiblemente superiores al 70%, lo más preferiblemente superiores al 90%. En una realización preferida es superior al 95% del compuesto de fórmula (I) (IB) o (IV), o de sus sales, solvatos o profármacos.The compounds of formula (I) (IB) or (IV) or their salts or solvates are preferably in pharmaceutical form acceptable or substantially pure. By pharmaceutically acceptable means, among others, that they have a level of purity pharmaceutically acceptable, 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%, most preferably greater than 90%. In a preferred embodiment it is greater than 95% of the compound of formula (I) (IB) or (IV), or of its salts, solvates or prodrugs.
Los compuestos de la presente invención representados por la fórmula (I) (IB) o (IV) anteriormente descritas pueden incluir enantiómeros, dependiendo de la presencia de centros quirales o isómeros, dependiendo de la presencia de enlaces múltiples (por ejemplo, Z, E). Los isómeros, enantiómeros o diastereoisómeros individuales y las mezclas de los mismos caen dentro del alcance de la presente invención.The compounds of the present invention represented by formula (I) (IB) or (IV) above described may include enantiomers, depending on the presence of chiral centers or isomers, depending on the presence of multiple links (for example, Z, E). Isomers, enantiomers or individual diastereoisomers and mixtures thereof fall within the scope of the present invention.
Los compuestos de fórmula (I), (IB) o (IV) definidos anteriormente pueden obtenerse mediante procedimientos sintéticos disponibles similares a los descritos en la patente US 4.337.263 o el documento FR 2 472 564. Por ejemplo, pueden prepararse condensando un compuesto de fórmula (II):The compounds of formula (I), (IB) or (IV) defined above can be obtained by procedures available synthetics similar to those described in US Pat. 4,337,263 or FR 2 472 564. For example, they can Prepare by condensing a compound of formula (II):
en la que R_{1}-R_{4} son tal como se definieron anteriormente en las fórmulas (I) o (IV), con un compuesto de fórmula (III):in which R_ {1} -R_ {4} are as defined previously in formulas (I) or (IV), with a compound of formula (III):
en la que R_{5}, R_{6} y n son tal como se definieron anteriormente en la fórmula (I) o (IV), en este último caso no forman necesariamente un anillo.where R_ {5}, R_ {6} and n are as defined above in formula (I) or (IV), in the latter case does not necessarily form a ring.
La reacción de los compuestos de las fórmulas (II) y (III) se lleva a cabo preferiblemente a una temperatura en el intervalo de 60 a 120°C en un disolvente aprótico, pero sin limitarse a él, tal como dimetilformamida (DMF) en presencia de una base inorgánica, tal como K_{2}CO_{3}. Los compuestos de fórmula (III) están comercialmente disponibles o pueden prepararse mediante métodos convencionales. Los compuestos de fórmula (II) también pueden prepararse mediante métodos convencionales, tal como puede observarse en los ejemplos sintéticos de la presente solicitud de patente.The reaction of the compounds of the formulas (II) and (III) is preferably carried out at a temperature in the range of 60 to 120 ° C in an aprotic solvent, but without be limited to it, such as dimethylformamide (DMF) in the presence of a inorganic base, such as K 2 CO 3. The compounds of formula (III) are commercially available or can be prepared by conventional methods The compounds of formula (II) also they can be prepared by conventional methods, as you can be observed in the synthetic examples of the present application of patent.
Los productos de reacción obtenidos pueden purificarse, si se desea, mediante métodos convencionales, tales como cristalización, cromatografía y trituración. Cuando los procedimientos descritos anteriormente para la preparación de los compuestos de la invención dan lugar a mezclas de esteroisómeros, estos isómeros pueden separarse mediante técnicas convencionales tales como cromatografía preparativa. Si hay centros quirales, los compuestos pueden prepararse en forma racémica, o los enantiómeros individuales pueden prepararse mediante síntesis enantioespecífica o por resolución.The reaction products obtained can purified, if desired, by conventional methods, such as crystallization, chromatography and crushing. When the procedures described above for the preparation of Compounds of the invention give rise to mixtures of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. If there are chiral centers, the compounds can be prepared in racemic form, or enantiomers Individuals can be prepared by enantiospecific synthesis or by resolution.
Una forma farmacéuticamente aceptable preferida es la forma cristalina, incluyéndose tal forma en la composición farmacéutica. En el caso de las sales y los solvatos, los restos de disolventes y compuestos iónicos adicionales también deben ser no tóxicos. Los compuestos de la invención pueden presentar diferentes formas polimórficas; se pretende que la invención englobe todas esas formas.A preferred pharmaceutically acceptable form. it is the crystalline form, including such form in the composition Pharmaceutical In the case of salts and solvates, the remains of additional solvents and ionic compounds must also be non Toxic The compounds of the invention may have different polymorphic forms; it is intended that the invention encompasses all of those shapes.
Otro aspecto de esta invención se refiere a un método para tratar o prevenir una enfermedad mediada por el receptor sigma, método que comprende administrar a un paciente que necesita tal tratamiento una cantidad terapéuticamente eficaz de un compuesto de fórmula (IV) o una composición farmacéutica del mismo. Entre las enfermedades mediadas por sigma que pueden tratarse están la diarrea, trastornos lipoproteicos, migraña, obesidad, artritis, hipertensión, arritmia, úlcera, trastornos cognitivos, adicción a sustancias químicas tal como la dependencia a la cocaína, discinesia tardía, accidente cerebrovascular isquémico, epilepsia, accidente cerebrovascular, depresión, estrés, dolor, especialmente dolor neuropático o alodinia, estado psicótico o cáncer. Los compuestos de la invención también pueden emplearse como herramienta farmacológica o como ansiolítico o inmunosupresor.Another aspect of this invention relates to a method to treat or prevent a disease mediated by sigma receptor, a method that involves administering to a patient who such treatment needs a therapeutically effective amount of a compound of formula (IV) or a pharmaceutical composition thereof. Among the sigma-mediated diseases that can be treated are diarrhea, lipoprotein disorders, migraine, obesity, arthritis, hypertension, arrhythmia, ulcer, cognitive disorders, addiction to chemical substances such as cocaine dependence, tardive dyskinesia, ischemic stroke, epilepsy, stroke, depression, stress, pain, especially neuropathic pain or allodynia, psychotic state or cancer. The Compounds of the invention can also be used as Pharmacological tool or as an anxiolytic or immunosuppressant.
La presente invención proporciona además composiciones farmacéuticas que comprenden un compuesto de esta invención, o una sal, derivado, profármaco o esteroisómero farmacéuticamente aceptable del mismo, junto con un portador, adyuvante o vehículo farmacéuticamente aceptables, para su administración a un paciente.The present invention further provides pharmaceutical compositions comprising a compound of this invention, or a salt, derivative, prodrug or steroisomer pharmaceutically acceptable thereof, together with a carrier, pharmaceutically acceptable adjuvant or vehicle, for your administration to a patient
Ejemplos de composiciones farmacéuticas incluyen cualquier composición sólida (comprimidos, píldoras, cápsulas, gránulos, etc.) o líquida (soluciones, suspensiones o emulsiones) para la administración oral, tópica o parenteral.Examples of pharmaceutical compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) for oral, topical or parenteral administration.
En una realización preferida, las composiciones farmacéuticas están en forma oral, ya sea sólida o líquida. Las formas farmacéuticas adecuadas para la administración oral pueden ser comprimidos, cápsulas, jarabes o soluciones y pueden contender excipientes convencionales conocidos en la técnica tales como agentes aglutinantes, por ejemplo jarabe, goma arábiga, gelatina, sorbitol, tragacanto o polivinilpirrolidona; agentes de relleno, por ejemplo lactosa, azúcar, almidón de maíz, fosfato de calcio, sorbitol o glicina; lubricantes de preparación de comprimidos, por ejemplo estearato de magnesio; disgregantes, por ejemplo almidón, polivinilpirrolidona, glicolato sódico de almidón o celulosa microcristalina; o agentes humectantes farmacéuticamente aceptables tales como laurilsulfato sódico.In a preferred embodiment, the compositions Pharmaceuticals are in oral form, either solid or liquid. The Pharmaceutical forms suitable for oral administration may be tablets, capsules, syrups or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, gum arabic, jelly, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tablet preparation lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate or cellulose microcrystalline; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.
Las composiciones orales sólidas pueden prepararse mediante métodos convencionales de mezclado, relleno o preparación de comprimidos. Las operaciones de mezclado repetidas pueden usarse para distribuir el principio activo en aquellas composiciones que emplean grandes cantidades de agentes de relleno. Tales operaciones son convencionales en la técnica. Por ejemplo, los comprimidos pueden prepararse mediante granulación en húmedo o en seco y recubrirse de forma opcional según métodos bien conocidos en la práctica farmacéutica normal, en particular con un recubrimiento entérico.Solid oral compositions can be prepared by conventional methods of mixing, filling or tablet preparation Repeated mixing operations can be used to distribute the active substance in those compositions that employ large amounts of fillers. Such operations are conventional in the art. For example, the tablets can be prepared by wet granulation or in dry and optionally coated according to methods well known in normal pharmaceutical practice, particularly with a coating enteric.
Las composiciones farmacéuticas también pueden adaptarse para la administración parenteral, tal como soluciones, suspensiones o productos liofilizados estériles en la forma farmacéutica unitaria apropiada. Pueden usarse excipientes adecuados, tales como agentes de carga ("bulking agents"), agentes tamponantes o tensioactivos.Pharmaceutical compositions can also adapt for parenteral administration, such as solutions, suspensions or sterile lyophilized products in the form Appropriate unit pharmaceutical. Excipients can be used suitable, such as bulking agents, buffering agents or surfactants.
Las formulaciones mencionadas se prepararán usando métodos habituales tales como los descritos en las Farmacopeas Española y de los Estados Unidos y en textos de referencia similares.The mentioned formulations will be prepared using usual methods such as those described in Spanish and United States Pharmacopoeias and in texts of similar reference.
La administración de los compuestos o las composiciones de la presente invención puede realizarse mediante cualquier método adecuado, tal como infusión intravenosa, preparaciones orales, y administración intraperitoneal e intravenosa. Se prefiere la administración oral debido a la comodidad para el paciente y al carácter crónico de las enfermedades que se van a tratar.The administration of the compounds or Compositions of the present invention can be made by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal administration and intravenous Oral administration is preferred because of the comfort for the patient and the chronic nature of the diseases to be treated.
Generalmente, una cantidad eficaz administrada de un compuesto de la invención dependerá de la eficacia relativa del compuesto elegido, de la gravedad del trastorno que se está tratando y del peso del paciente. Sin embargo, los compuestos activos se administrarán normalmente una o más veces al día, por ejemplo 1, 2, 3 ó 4 veces al día, estando las dosis diarias totales habituales en el intervalo de entre 0,1 hasta 1000 mg/kg/día.Generally, an effective administered amount of A compound of the invention will depend on the relative efficacy of the compound chosen, of the severity of the disorder being trying and the patient's weight. However, the compounds assets will normally be administered one or more times a day, for example 1, 2, 3 or 4 times a day, the total daily doses being usual in the range of 0.1 to 1000 mg / kg / day.
Los compuestos y las composiciones de esta invención pueden usarse con otros fármacos para proporcionar una terapia de combinación. Los otros fármacos pueden formar parte de la misma composición, o administrarse como una composición separada para su administración al mismo tiempo o en un momento diferente.The compounds and compositions of this invention can be used with other drugs to provide a combination therapy The other drugs can be part of the same composition, or be administered as a separate composition for administration at the same time or at a time different.
Los siguientes ejemplos se facilitan únicamente como ilustración adicional de la invención, no deben tomarse como una definición de los límites de la invención.The following examples are provided only As an additional illustration of the invention, they should not be taken as a definition of the limits of the invention.
Etapa 1Stage one
Se liberó N'-(3,4-diclorofenil)hidrazina a partir de su clorhidrato (10,0 g, 46,8 mmoles) mediante el reparto del sólido entre una disolución de Na_{2}CO_{3} diluida (10 ml de disolución saturada y 40 ml de agua) y AcOEt (acetato de etilo). La fase acuosa se extrajo dos veces más con AcOEt, los extractos orgánicos se secaron (Na_{2}SO_{4}), el disolvente se eliminó a vacío, y el residuo se recogió en tolueno anhidro (100 ml). A esta disolución se añadió lentamente anhídrido acético (4,78 g, 46,8 mmoles), y la mezcla de reacción se agitó a temperatura ambiente durante 15 min. Se añadió éter de petróleo (50 ml), la mezcla se enfrió en la nevera (-20ºC), y los cristales resultantes se recogieron en un embudo de vidrio sinterizado y se lavaron con éter de petróleo frío. La recristalización en MeOH dio (V) (8,30 g, 81%) como cristales blancos brillantes, pf 179-182°C (bibl. 168-171°C^{101}). CCF CHCl_{3}/MeOH 9:1.He was released N '- (3,4-dichlorophenyl) hydrazine from its hydrochloride (10.0 g, 46.8 mmol) by solid distribution between a solution of dilute Na2CO3 (10 ml of saturated solution and 40 ml of water) and AcOEt (ethyl acetate). The aqueous phase was extracted twice more with AcOEt, the extracts Organic were dried (Na2SO4), the solvent was removed at vacuum, and the residue was taken up in anhydrous toluene (100 ml). This solution was added slowly acetic anhydride (4.78 g, 46.8 mmol), and the reaction mixture was stirred at room temperature for 15 min. Petroleum ether (50 ml) was added, the mixture was cooled in the refrigerator (-20 ° C), and the resulting crystals were collected in a sintered glass funnel and washed with ether of cold oil. Recrystallization from MeOH gave (V) (8.30 g, 81%) as bright white crystals, mp 179-182 ° C (bibl. 168-171 ° C 101). TLC CHCl 3 / MeOH 9: 1.
EM m/z (%): 222/220/218 (W, 3/22/34), 178 (64), 176 (100), 160 (20), 43 (94).MS m / z (%): 222/220/218 (W, 3/22/34), 178 (64), 176 (100), 160 (20), 43 (94).
Sólo se facilitan las señales de RMN del isómero dominante (ratio aproximadamente 9:1):Only the NMR signals of the isomer are provided dominant (approximately 9: 1 ratio):
^{1}H-RMN (DMSO-d_{6}): (ppm) 9,69 (d, 11-1, NH-CO, ^{3}J = 2,0 Hz), 8,09 (d, 1H, Ph-NH, ^{3}J = 2,0 Hz), 7,32 (d, 1H, Ph 1-1-5, ^{3}J(H5,1-16) = 8,8 Hz), 6,83 (d, 1H, H-2 Ph, ^{4}J(H2,H6) = 2,5 Hz), 6,66 (dd, 1H, H-6 Ph, ^{4}3(H2,146) 2,5 Hz, ^{3}J(H5,H6) = 8,8 Hz), 1,90 (s, 31-1, Me).1 H-NMR (DMSO-d6): (ppm) 9.69 (d, 11-1, NH-CO, 3 J = 2.0 Hz), 8.09 (d, 1H, Ph-NH, 3 J = 2.0 Hz), 7.32 (d, 1H, Ph 1-1-5, 3 J (H5.1-16) = 8.8 Hz), 6.83 (d, 1H, H-2 Ph, 4 J (H2, H6) = 2.5 Hz), 6.66 (dd, 1H, H-6 Ph, 4 3 (H2.146) 2.5 Hz, 3 J (H5, H6) = 8.8 Hz), 1.90 (s, 31-1, I).
^{13}C-RMN (DMSO-d_{6}): S (ppm) 169,2 (C=O), 149,6 (C-1 Ph), 131,2 (C-3 Ph), 130,5 (C-5 Ph), 119,1 (C-4 Ph), 112,9 (C-2 Ph*), 112,4 (C-6 Ph*), 20,6 (Me).13 C-NMR (DMSO-d6): S (ppm) 169.2 (C = O), 149.6 (C-1 Ph), 131.2 (C-3 Ph), 130.5 (C-5 Ph), 119.1 (C-4 Ph), 112.9 (C-2 Ph *), 112.4 (C-6 Ph *), 20.6 (I).
Etapa 2Stage 2
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A una mezcla de (V) (5,0 g, 22,8 mmoles) y acetoacetato de etilo (2,97 g, 22,8 mmoles) se añadió lentamente PCl_{3} (3,13 g, 22,8 mmoles). La mezcla se calentó hasta 50°C durante 1,5 h, se vertió en agua con hielo (150 ml), y el precipitado resultante se recogió en un embudo de vidrio sinterizado y se recristalizó en EtOH (etanol) dando (VI) (2,29 g, 41%) como cristales blancos, pf 208-211°C (bibl. 208-209°C 10I), CCF CHCl_{3}/MeOH 9:1.To a mixture of (V) (5.0 g, 22.8 mmol) and ethyl acetoacetate (2.97 g, 22.8 mmol) was added slowly PCl 3 (3.13 g, 22.8 mmol). The mixture was heated to 50 ° C for 1.5 h, it was poured into ice water (150 ml), and the resulting precipitate was collected in a sintered glass funnel and recrystallized from EtOH (ethanol) giving (VI) (2.29 g, 41%) as white crystals, mp 208-211 ° C (bibl. 208-209 ° C 10I), CCF CHCl 3 / MeOH 9: 1.
EM m/z (%): 246/244/242 (M+, 11/59/100), 207 (32), 147 (20), 145 (34), 111 (20), 109 (23), 75 (20).MS m / z (%): 246/244/242 (M +, 11/59/100), 207 (32), 147 (20), 145 (34), 111 (20), 109 (23), 75 (20).
^{1}H-RMN (CDCl_{3}): S (ppm) 11,72 (s ancho, 1H, OH), 7,54 (d, 1H, H-5 Ph, 3J(H5,H6) = 8,5 Hz), 7,48 (d, I H, Ph 11-2, 4J(H2,H6) - 2,5 Hz), 7,26 (dd, 1H, H-6 Ph, 4J(H2,H6) = 2,5 Hz, 3J(H5,H6) = 83 Hz), 5,63 (s, 1H, 4-H), 2,28 (s, 3H, 5-Me).1 H-NMR (CDCl 3): S (ppm) 11.72 (broad s, 1H, OH), 7.54 (d, 1H, H-5 Ph, 3J (H5, H6) = 8.5 Hz), 7.48 (d, I H, Ph 11-2, 4J (H2, H6) - 2.5 Hz), 7.26 (dd, 1H, H-6 Ph, 4J (H2, H6) = 2.5 Hz, 3J (H5, H6) = 83 Hz), 5.63 (s, 1H, 4-H), 2.28 (s, 3H, 5-Me).
^{13}C-RMN (CDCl_{3}): 6 (ppm) 163,1 (C-3 Pz), 141,2 (C-5 Pz), 137,9 (C-1 Ph), 133,1 (C-3 Ph), 131,4 (C-4 Ph), 131,0 (C-5 Ph), 126,1 (C-2 Ph), 123,6 (C-6 Ph), 94,5 (C-4 Pz), 12,7 (5-Me).13 C-NMR (CDCl 3): 6 (ppm) 163.1 (C-3 Pz), 141.2 (C-5 Pz), 137.9 (C-1 Ph), 133.1 (C-3 Ph), 131.4 (C-4 Ph), 131.0 (C-5 Ph), 126.1 (C-2 Ph), 123.6 (C-6 Ph), 94.5 (C-4 Pz), 12.7 (5-Me).
Etapa 3Stage 3
Una mezcla de (VI) (300 mg, 1,23 mmoles), clorhidrato de N-(2-cloroetil)morfolina (230 mg, 123 mmoles), K_{2}CO_{3} (341 mg, 2,47 mmoles), y NaI (185 mg, 1,23 mmol) en dimetilformamida anhidra (5 ml) se agitó durante la noche a 70ºC. La mezcla se vertió en agua (20 ml), se extrajo cuatro veces con Et_{2}O, y los extractos orgánicos se lavaron con disolución saturada de NaCl, se secaron (Na_{2}SO_{4}), y se concentraron a vacío. El residuo se purificó mediante MPLC (cromatografía líquida de media resolución) (éter de petróleo/AcOEt 4:1) dando (VI) (303 mg, 69%) como un aceite incoloro. CCF CHCl_{3}/MeOH 9:1.A mixture of (VI) (300 mg, 1.23 mmol), N- (2-Chloroethyl) morpholine hydrochloride (230 mg, 123 mmol), K2CO3 (341 mg, 2.47 mmol), and NaI (185 mg, 1.23 mmol) in anhydrous dimethylformamide (5 ml) was stirred for the night at 70 ° C. The mixture was poured into water (20 ml), extracted four times with Et2O, and the organic extracts were washed with saturated NaCl solution, dried (Na2SO4), and dried concentrated in vacuo. The residue was purified by MPLC (medium resolution liquid chromatography) (petroleum ether / AcOEt 4: 1) giving (VI) (303 mg, 69%) as a colorless oil. CCF CHCl3 / MeOH 9: 1.
EM m/z (%): 357/355 (Mt, 0,03/0,05), 114 (19), 113 (100), 100 (92), 98 (16), 56 (21).MS m / z (%): 357/355 (Mt, 0.03 / 0.05), 114 (19), 113 (100), 100 (92), 98 (16), 56 (21).
^{1}H-RMN (CDCl_{3}): S (ppm) 7,57 (d, 1H, H-2 Ph, 4J(H2,H6) = 2,5 Hz), 7,47 (d, 1H, H-5 Ph, 3J(H5,H6) = 8,6 Hz), 726 (dd, 1H, H-6 Ph, 4,1(H2,H6) = 2,5 Hz, 3J(H5,H6) = 8,6 Hz), 5,68 (s, 1H, 4-H), 4,31 (t, 2H, O-CHz, 3J = 5,6 Hz), 3,72 (m, 4H, H-2,6 Morf), 2,77 (t, 2H, CH -Morf, 3J = 5,6 Hz), 2,55 (m, 411, H-3,5 Morf), 2,30 (s, 3H, 5-Me).1 H-NMR (CDCl 3): S (ppm) 7.57 (d, 1H, H-2 Ph, 4J (H2, H6) = 2.5 Hz), 7.47 (d, 1H, H-5 Ph, 3J (H5, H6) = 8.6 Hz), 726 (dd, 1H, H-6 Ph, 4.1 (H2, H6) = 2.5 Hz, 3J (H5, H6) = 8.6 Hz), 5.68 (s, 1H, 4-H), 4.31 (t, 2H, O-CHz, 3J = 5.6 Hz), 3.72 (m, 4H, H-2.6 Morf), 2.77 (t, 2H, CH-Morph, 3J = 5.6 Hz), 2.55 (m, 411, H-3.5 Morf), 2.30 (s, 3H, 5-Me).
^{13}C-RMN (CDCl_{3}): S (ppm) 163,4 (C-3 Pz), 140,5 (C-5 Pz), 139,1 (C-1 Ph), 132,9 (C-3 Ph), 130,5 (C-5 Ph), 130,3 (C-4 Ph), 125,7 (C-2 Ph), 122,7 (C-6 Ph), 94,5 (C-4 Pz), 66,8 (C-2,6 Morf), 65,9 (O-CH2), 57,6 (CH2-Morf), 53,9 (C-3,5 Morf), 13,1 (5-Me).13 C-NMR (CDCl 3): S (ppm) 163.4 (C-3 Pz), 140.5 (C-5 Pz), 139.1 (C-1 Ph), 132.9 (C-3 Ph), 130.5 (C-5 Ph), 130.3 (C-4 Ph), 125.7 (C-2 Ph), 122.7 (C-6 Ph), 94.5 (C-4 Pz), 66.8 (C-2.6 Morf), 65.9 (O-CH2), 57.6 (CH2-Morf), 53.9 (C-3.5 Morf), 13.1 (5-Me).
Anal. Calc. para C16H19C12N302: C, 53,94; H, 5,38; N, 11,79, Hallado: C, 53,85; H, 5,13;N, 11,57.Anal. Calcd. For C16H19C12N302: C, 53.94; H 5.38; N, 11.79. Found: C, 53.85; H, 5.13; N, 11.57.
El compuesto VII obtenido en el ejemplo 1 se probó in vitro en una prueba de screening del receptor sigma-1 y sigma-2.Compound VII obtained in Example 1 was tested in vitro in a screening test for the sigma-1 and sigma-2 receptor.
La preparación de la membrana cerebral y los ensayos de unión para el receptor \sigma1 se realizaron tal como se ha descrito (DeHaven-Hudkins et al., 1992) con algunas modificaciones. En resumen, se homogeneizaron cerebros de cobaya en 10 vols. (p/v) de Tris-HCl 50 mM, sacarosa 0,32 M, pH 7,4, con un homogeneizador Kinematica Polytron PT 3000 a 15000 r.p.m. durante 30 s. El homogeneizado se centrifugó a 1000 g durante 10 min a 4°C y los sobrenadantes se recogieron y se centrifugaron de nuevo a 48000 g durante 15 min a 4°C. El sedimento se resuspendió en 10 volúmenes de tampón Tris-HCl (50 mM, pH 7,4), se incubó a 37°C durante 30 min, y se centrífugo a 48000 g durante 20 min a 4°C. Tras esto, el sedimento se resuspendió en tampón Tris-HCl nuevo (50 mM, pH 7,4) y se almacenó en hielo hasta su uso.Brain membrane preparation and binding assays for the para1 receptor were performed as described (DeHaven-Hudkins et al ., 1992) with some modifications. In summary, guinea pig brains were homogenized in 10 vols. (w / v) of 50 mM Tris-HCl, 0.32 M sucrose, pH 7.4, with a Kinematica Polytron PT 3000 homogenizer at 15,000 rpm for 30 s. The homogenate was centrifuged at 1000 g for 10 min at 4 ° C and the supernatants were collected and centrifuged again at 48000 g for 15 min at 4 ° C. The pellet was resuspended in 10 volumes of Tris-HCl buffer (50 mM, pH 7.4), incubated at 37 ° C for 30 min, and centrifuged at 48000 g for 20 min at 4 ° C. After this, the sediment was resuspended in fresh Tris-HCl buffer (50 mM, pH 7.4) and stored on ice until use.
Cada tubo de ensayo contenía 10 \muL de [^{3}H](+)-pentazocina (concentración final de 0,5 nM), 900 \muL de suspensión tisular hasta un volumen de ensayo final de 1 mL y una concentración tisular final de aproximadamente 30 mg de peso neto de tejido/mL. La unión no específica se definió mediante la adición de una concentración final de 1 \muM de haloperidol. Todos los tubos se incubaron a 37°C durante 150 min antes de la finalización de la reacción mediante filtración rápida sobre filtros de fibra de vidrio de Schleicher & Schuell GF 3362 [previamente sumergidos en una disolución de polietilenimina al 0,5% durante al menos 1 h]. Los filtros se lavaron entonces cuatro veces con 4 mL de tampón Tris-HCl (50 mM, pH 7,4) frío. Tras la adición de un cóctel de centelleo, se permitió que las muestras se equilibraran durante la noche. La cantidad de radiactividad unida se determinó mediante espectrometría de centelleo líquido usando un contador de centelleo líquido Wallac Winspectral 1414. Las concentraciones de proteínas se determinaron mediante el método de Lowry et al. (1951).Each test tube contained 10 µL of [3 H] (+) -pentazocine (final concentration of 0.5 nM), 900 µL of tissue suspension to a final test volume of 1 mL and a tissue concentration final of approximately 30 mg of net weight of tissue / mL. Non-specific binding was defined by the addition of a final concentration of 1 µM haloperidol. All tubes were incubated at 37 ° C for 150 min before the end of the reaction by rapid filtration on Schleicher & Schuell GF 3362 glass fiber filters [previously immersed in a 0.5% polyethyleneimine solution for at least 1 hour]. The filters were then washed four times with 4 mL of cold Tris-HCl buffer (50 mM, pH 7.4). After the addition of a scintillation cocktail, the samples were allowed to equilibrate overnight. The amount of bound radioactivity was determined by liquid scintillation spectrometry using a Wallac Winspectral 1414 liquid scintillation counter. Protein concentrations were determined by the method of Lowry et al . (1951).
DeHaven-Hudkins, D. L., L.C. Fleissner, y F. Y. Ford-Rice, 1992, "Characterization of the binding of [^{3}H](+) pentazocine to \sigma recognition sites in guinea pig brain", Eur. J Pharmacol. 227, 371-378. DeHaven-Hudkins , DL, LC Fleissner , and FY Ford-Rice , 1992 , "Characterization of the binding of [3 H] (+) pentazocine to \ sigma recognition sites in guinea pig brain", Eur. J Pharmacol. 227, 371-378 .
Lowry, O.H., N.J. Rosebrough, A.L. Farr y R.J. Randall, 1951, Protein measurement with the Folin phenol reagent, J. Biol. Chem, 193, 265. Lowry , OH, NJ Rosebrough , AL Farr and RJ Randall , 1951 , Protein measurement with the Folin phenol reagent, J. Biol. Chem , 193, 265.
Los estudios de unión para el receptor \sigma2 se llevaron a cabo tal como se ha descrito (Radesca et al., 1991) con algunas modificaciones. En resumen, se homogeneizaron cerebros de ratón deficiente ("knockout") en el receptor sigma tipo I (\sigma1) en un volumen de 10 mL/g de peso neto de tejido de Tris-HCl 10 mM enfriado en hielo, pH 7,4, que contenía sacarosa 320 mM (tampón Tris-sacarosa) con un homogeneizador Potter-Elvehjem (10 ciclos a 500 r.p.m.). Los homogeneizados se centrifugaron entonces a 1000 g durante 10 min a 4°C, y se guardaron los sobrenadantes. Los sedimentos se resuspendieron mediante agitación con vórtex en 2 mL/g de tampón Tris-sacarosa enfriado en hielo y se centrifugaron de nuevo a 1000 gdurante 10 min. Los sobrenadantes a 1000 g combinados se centrifugaron a 31000 gdurante 15 min a 4°C. Los sedimentos se resuspendieron mediante agitación con vórtex en 3 mL/g de Tris-HCl 10 mM, pH 7,4, y la suspensión se mantuvo a 25°C durante 15 min. Tras la centrifugación a 31000 gdurante 15 min, los sedimentos se resuspendieron mediante homogenización suave en Potter Elvehjem hasta obtener un volumen de 1,53 mL/g en Tris-HCl 10 mM, pH 7,4.Binding studies for the σ2 receptor were carried out as described (Radesca et al ., 1991) with some modifications. In summary, deficient mouse brains ("knockout") were homogenized in the sigma type I receptor (11) in a volume of 10 mL / g net weight of 10 mM Tris-HCl tissue cooled in ice, pH 7, 4, containing 320 mM sucrose (Tris-sucrose buffer) with a Potter-Elvehjem homogenizer (10 cycles at 500 rpm). The homogenates were then centrifuged at 1000 g for 10 min at 4 ° C, and the supernatants were stored. The sediments were resuspended by vortexing in 2 mL / g of ice-cold Tris-sucrose buffer and centrifuged again at 1000 for 10 min. The combined 1000 g supernatants were centrifuged at 31000 g for 15 min at 4 ° C. The sediments were resuspended by vortexing in 3 mL / g of 10 mM Tris-HCl, pH 7.4, and the suspension was maintained at 25 ° C for 15 min. After centrifugation at 31000 for 15 min, the sediments were resuspended by gentle homogenization in Potter Elvehjem until a volume of 1.53 mL / g was obtained in 10 mM Tris-HCl, pH 7.4.
Los tubos de ensayo contenían 10 \muL de [^{3}H]-DTG (concentración final de 3 nM), 400 \muL de suspensión tisular (5,3 mL/g en Tris-HCl 50 mM, pH 8,0) hasta un volumen de ensayo final de 0,5 mL. La unión no específica se definió mediante la adición de una concentración final de 1 \muM de haloperidol. Todos los tubos se incubaron a 25°C durante 120 min antes de la finalización de la reacción mediante filtración rápida sobre filtros de fibra de vidrio de Schleicher & Schuell GF 3362 [previamente sumergidos en una disolución de polietilenimina al 0,5% durante al menos 1 h]. Los filtros se lavaron entonces tres veces con volúmenes de 5 mL de tampón Tris-HCl frío (10 mM, pH 8,0). Tras la adición de un cóctel de centelleo, se permitió que las muestras se equilibraran durante la noche. La cantidad de radiactividad unida se determinó mediante espectrometría de centelleo líquido usando un contador de centelleo líquido Wallac Winspectral 1414. Las concentraciones de proteínas se determinaron mediante el método de Lowry et al. (1951).The test tubes contained 10 µL of [3 H] -DTG (final concentration of 3 nM), 400 µL of tissue suspension (5.3 mL / g in 50 mM Tris-HCl, pH 8.0 ) to a final test volume of 0.5 mL. Non-specific binding was defined by the addition of a final concentration of 1 µM haloperidol. All tubes were incubated at 25 ° C for 120 min before the end of the reaction by rapid filtration on Schleicher & Schuell GF 3362 fiberglass filters [previously immersed in a 0.5% polyethyleneimine solution for at least 1 hour]. The filters were then washed three times with volumes of 5 mL of cold Tris-HCl buffer (10 mM, pH 8.0). After the addition of a scintillation cocktail, the samples were allowed to equilibrate overnight. The amount of bound radioactivity was determined by liquid scintillation spectrometry using a Wallac Winspectral 1414 liquid scintillation counter. Protein concentrations were determined by the method of Lowry et al . (1951).
Radesca, L., W.D. Bowen, y L. Di Paolo, B.R. de Costa, 1991, Synthesis and Receptor Binding of Enantiomeric N-Substituted cis-N-[2-(3,4-Dichlorophenyl)etilo]-2-(1-pyrrolidinyl)ciclohexylamines as High-Affinity \sigma Receptor Ligands, J. Med. Chem. 34, 3065-3074. Radesca , L., WD Bowen , and L. Di Paolo , BR de Costa , 1991 , Synthesis and Receptor Binding of Enantiomeric N-Substituted cis-N- [2- (3,4-Dichlorophenyl) ethyl] -2- (1 -pyrrolidinyl) cyclohexylamines as High-Affinity \ sigma Receptor Ligands, J. Med. Chem . 34, 3065-3074.
Langa, F., Codony X., Tovar V., Lavado A., Giménez E., Cozar P., Cantero M., Dordal A., Hernández E., Pérez R., Monroy X., Zamanillo D., Guitart X., Montoliu Ll., 2003, Generation and phenotypic análisis of sigma receptor type I (Sigma1) knockout mice, European Journal of Neuroscience, Vol. 18, 2188-2196. Langa , F., Codony X., Tovar V., Wash A., Giménez E., Cozar P., Cantero M., Dordal A., Hernández E., Pérez R., Monroy X., Zamanillo D., Guitart X., Montoliu Ll., 2003 , Generation and phenotypic analysis of sigma receptor type I (Sigma1) knockout mice, European Journal of Neuroscience , Vol. 18, 2188-2196.
Lowry, O.H., N.J. Rosebrough, A.L. Farr, y R.J. Randall, 1951, Protein measurement with the Folin phenol reagent, J. Biol. Chem, 193, 265. Lowry , OH, NJ Rosebrough , AL Farr , and RJ Randall , 1951 , Protein measurement with the Folin phenol reagent, J. Biol. Chem , 193, 265.
El modelo de von Frey es un modelo para el dolor neuropático, especialmente hiperalgesia/alodinia, estimulado mecánicamente.Von Frey's model is a model for pain neuropathic, especially hyperalgesia / allodynia, stimulated mechanically.
Interés del modelo:Interest of the model:
- \bullet?
- La inyección de capsaicina a animales de experimentación produce dolor agudo seguido por hiperalgesia /alodiniaCapsaicin injection to experimental animals produce acute pain followed by hyperalgesia / allodynia
- \bullet?
- Los mecanismos que participan en el dolor agudo y la hiperalgesia inducidos por capsaicina son relativamente bien conocidos (principalmente la activación de los nociceptores periféricos y la sensibilización de las neuronas de la médula espinal, respectivamente)The mechanisms involved in acute pain and hyperalgesia induced by capsaicin are relatively well known (mainly the activation of peripheral nociceptors and sensitization of neurons in the spinal cord, respectively)
La figura 1 muestra el protocolo de prueba para todas las pruebas con filamentos de von Frey. Tras la habituación, según la figura 1, los ratones se trataron primero con el compuesto de prueba (o sin él en los controles). Después se inyectó capsaicina (al 1% en DMSO) en la pata, dando como resultado el desarrollo de dolor en la pata afectada. La pata afectada se trató entonces con un estímulo mecánico y se midió el tiempo de latencia antes de que retiraran la pata.Figure 1 shows the test protocol for All tests with von Frey filaments. After habituation, according to figure 1, the mice were first treated with the compound test (or without it at the controls). Then injected Capsaicin (1% in DMSO) in the leg, resulting in development of pain in the affected leg. The affected leg was treated then with a mechanical stimulus and the latency time was measured before they removed the leg.
Esta prueba farmacológica demostró el efecto del compuesto VI en el modelo de von-Frey descrito, un modelo de dolor neuropático.This pharmacological test demonstrated the effect of compound VI in the von-Frey model described, a Neuropathic pain model.
Tal como se muestra en la figura 2, hay una dependencia de la dosis en el tratamiento con el compuesto VII que muestra analgesia en el dolor neuropático inducido por capsaicina.As shown in Figure 2, there is a dose dependence in the treatment with compound VII which shows analgesia in neuropathic pain induced by Capsaicin
Tal como se demuestra en la figura 3, el tratamiento con el compuesto VII es eficaz específicamente en el dolor neuropático o en la alodinia mecánica mostrados por la fuerza de los filamentos de von-Frey, estando normalmente 0,5 g en el intervalo de dolor neuropático/alodinia.As shown in Figure 3, the treatment with compound VII is effective specifically in the neuropathic pain or mechanical allodynia shown by force of the von-Frey filaments, being normally 0.5 g in the range of neuropathic pain / allodynia.
Además, se encontró analgesia en otra prueba in vivo.In addition, analgesia was found in another in vivo test.
Claims (18)
- R_{1} y R_{2} se seleccionan independientemente del grupo formado por hidrógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, arilalquilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, heterociclilalquilo sustituido o no sustituido, -COR_{8}, -C(O)OR_{8}, -C(O)NR_{8}R_{9} -C=NR_{8}, -CN, -OR_{8}, -OC(O)R_{8}, -S(O)_{t}-R_{8}, -NR_{8}R_{9}, -NR_{8}C(O)R_{9}, -NO_{2}, -N=CR_{8}R_{9} o halógeno; R_ {1} and R2 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, cycloalkyl substituted or unsubstituted, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl substituted, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR 8, -C (O) OR_ {8}, -C (O) NR_ {8} R_ {9} -C = NR_ {8}, -CN, -OR_ {8}, -OC (O) R 8, -S (O) t -R 8, -NR 8 R 9, -NR_ {8} C (O) R_ {9}, -NO_ {2}, -N = CR_ {R} {8} or halogen;
- R_{3} y R_{4} se seleccionan independientemente del grupo formado por alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, arilalquilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, heterociclilalquilo sustituido o no sustituido, -COR_{8}, -C(O)OR_{8}, -C(O)NR_{8}R_{9} -C=NR_{8}, -CN, -OR_{8}, -OC(O)R_{8}, -S(O)_{t}-R_{8}, -NR_{8}R_{9}, -NR_{8}C(O)R_{9}, -NO_{2}, -N=CR_{8}R_{9} o halógeno, en los queR 3 and R4 are independently selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl substituted, substituted or unsubstituted alkenyl, substituted aryl or unsubstituted, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, heterocyclylalkyl substituted or unsubstituted, -COR_ {8}, -C (O) OR_ {8}, -C (O) NR_ {8} R_ {9} -C = NR 8, -CN, -OR 8, -OC (O) R 8, -S (O) t -R 8, -NR 8 R 9, -NR_ {8} C (O) R_ {9}, -NO_ {2}, -N = CR_ {R} {8} or halogen, in which
- t es 1, 2 ó 3;t is 1, 2 or 3;
- R_{8} y R_{9} se seleccionan cada uno independientemente de hidrógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, alcoxilo sustituido o no sustituido, ariloxilo sustituido o no sustituido, o halógeno;R_ {8} and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl substituted, substituted or unsubstituted alkenyl, substituted aryl or unsubstituted, substituted or unsubstituted heterocyclyl, alkoxy substituted or unsubstituted, substituted or unsubstituted aryloxy, or halogen;
- R_{5} y R_{6}, forman juntos, con el átomo de nitrógeno al que están unidos, un grupo heterociclilo sustituido o no sustituido;R 5 and R 6 form together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group;
- n se selecciona de 1, 2, 3, 4, 5, 6, 7 u 8;n is selected of 1, 2, 3, 4, 5, 6, 7 or 8;
- R_{1} se selecciona del grupo formado por alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilalquilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, heterociclilalquilo sustituido o no sustituido, -COR_{8}, -C(O)OR_{8}, -C(O)NR_{8}R_{9} -C=NR_{8}, -CN, -OR_{8}, -OC(O)R_{8}, -NR_{8}R_{9}, -NR_{8}C(O)R_{9}, -NO_{2}, -N=CR_{8}R_{9} o halógeno,R_ {1} se select from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or non-substituted alkenyl substituted, substituted or unsubstituted arylalkyl, heterocyclyl substituted or unsubstituted, heterocyclylalkyl substituted or unsubstituted substituted, -COR_ {8}, -C (O) OR_ {8}, -C (O) NR 8 R 9 -C = NR 8, -CN, -OR_ {8}, -OC (O) R 8, -NR_ {8} R 9, -NR_ {8} C (O) R_ {9}, -NO_ {2}, -N = CR_ {R} {8} or halogen,
- R_{2}, R_{3} y R_{4} se seleccionan independientemente del grupo formado por hidrógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, arilalquilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, heterociclilalquilo sustituido o no sustituido, -COR_{8}, -C(O)OR_{8}, -C(O)NR_{8}R_{9} -C=NR_{8}, -CN, -OR_{8}, -OC(O)R_{8}, -S(O)_{t}-R_{8}, -NR_{8}R_{9}, -NR_{8}C(O)R_{9}, -NO_{2}, -N=CR_{8}R_{9} o halógeno; en los que dos de ellos pueden formar juntos un anillo, opcionalmente condensado;R 2, R 3 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, cycloalkyl substituted or unsubstituted, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl substituted, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR 8, -C (O) OR_ {8}, -C (O) NR_ {8} R_ {9} -C = NR 8, -CN, -OR 8, -OC (O) R 8, -S (O) t -R 8, -NR_ {8} R_9, -NR_ {8} C (O) R_ {9}, -NO_ {2}, -N = CR 8 R 9 or halogen; in which two of them can form together a ring, optionally condensed;
- en los quein the that
- t es 1, 2 ó 3;t is 1, 2 or 3;
- R_{8} y R_{9} se seleccionan cada uno independientemente de hidrógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, alcoxilo sustituido o no sustituido, ariloxilo sustituido o no sustituido, o halógeno;R_ {8} and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl substituted, substituted or unsubstituted alkenyl, substituted aryl or unsubstituted, substituted or unsubstituted heterocyclyl, alkoxy substituted or unsubstituted, substituted or unsubstituted aryloxy, or halogen;
- R_{5} y R_{6}, forman juntos, con el átomo de nitrógeno al que están unidos, un grupo heterociclilo sustituido o no sustituido;R 5 and R 6 form together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group;
- n se selecciona de 1,2,3,4,5,6,7 u 8;n is selected of 1,2,3,4,5,6,7 or 8;
\newpage\ newpage
- R_{1} R_{2}, R_{3}, R_{4}, R_{5} y R_{6} se seleccionan independientemente del grupo formado por hidrógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, arilalquilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, heterociclilalquilo sustituido o no sustituido, -COR_{8}, -C(O)OR_{8}, -C(O)NR_{8}R_{9}, -C=NR_{8}, -CN, -OR_{8}, -OC(O)R_{8}, -S(O)_{t}-R_{8}, -NR_{8}R_{9}, -NR_{8}C(O)R_{9}, -NO_{2}, -N=CR_{8}R_{9} o halógeno, en los que dos de ellos pueden formar juntos un anillo, opcionalmente condensado,R 1 R 2, R 3, R 4, R 5 and R 6 are selected regardless of the group consisting of hydrogen, alkyl substituted or unsubstituted, substituted or unsubstituted cycloalkyl substituted, substituted or unsubstituted alkenyl, substituted aryl or unsubstituted, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, heterocyclylalkyl substituted or unsubstituted, -COR 8, -C (O) OR 8, -C (O) NR_R8 {9}, -C = NR_ {8}, -CN, -OR_ {8}, -OC (O) R 8, -S (O) t -R 8, -NR_ {8} R_9, -NR_ {8} C (O) R_ {9}, -NO_ {2}, -N = CR 8 R 9 or halogen, in which two of them can together form a ring, optionally condensed,
- t es 1, 2 ó 3;t is 1, 2 or 3;
- R_{8} y R_{9} se seleccionan cada uno independientemente de hidrógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, heterociclilo sustituido o no sustituido, alcoxilo sustituido o no sustituido, ariloxilo sustituido o no sustituido, o halógeno;R_ {8} and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl substituted, substituted or unsubstituted alkenyl, substituted aryl or unsubstituted, substituted or unsubstituted heterocyclyl, alkoxy substituted or unsubstituted, substituted or unsubstituted aryloxy, or halogen;
- n se selecciona de 1, 2, 3, 4, 5, 6, 7 u 8;n is selected of 1, 2, 3, 4, 5, 6, 7 or 8;
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US9782483B2 (en) | 2010-05-21 | 2017-10-10 | Laboratories Del Dr. Esteve, S.A. | Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy |
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US9789115B2 (en) | 2010-08-03 | 2017-10-17 | Laboratorios Del Dr. Esteve, S.A. | Use of sigma ligands in opioid-induced hyperalgesia |
US9844516B2 (en) | 2010-02-04 | 2017-12-19 | Laboratorios De Dr. Esteve | Sigma ligands for use in the prevention and/or treatment of post-operative pain |
US9914705B2 (en) | 2008-04-25 | 2018-03-13 | Laboratorios Del Dr. Esteve, S.A. | 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof |
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US9789115B2 (en) | 2010-08-03 | 2017-10-17 | Laboratorios Del Dr. Esteve, S.A. | Use of sigma ligands in opioid-induced hyperalgesia |
US9789117B2 (en) | 2011-05-18 | 2017-10-17 | Laboratorios Del Dr. Esteve, S.A. | Use of sigma ligands in diabetes type-2 associated pain |
US9931346B2 (en) | 2013-12-17 | 2018-04-03 | Laboratorios Del Dr. Esteve S.A. | Serotonin-norepinephrine reuptake inhibitors (SNRIs) and Sigma receptor ligands combinations |
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