ES2345592A1 - Cromenopyrazole derivatives as cannabinoid receptor ligands - Google Patents
Cromenopyrazole derivatives as cannabinoid receptor ligands Download PDFInfo
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- ES2345592A1 ES2345592A1 ES200900802A ES200900802A ES2345592A1 ES 2345592 A1 ES2345592 A1 ES 2345592A1 ES 200900802 A ES200900802 A ES 200900802A ES 200900802 A ES200900802 A ES 200900802A ES 2345592 A1 ES2345592 A1 ES 2345592A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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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
- A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
Description
Derivados de cromenopirazoles como ligandos de receptores de cannabinoides.Chromenopyrazole derivatives as ligands of cannabinoid receptors
La presente invención se engloba en el campo de la farmacología. Específicamente, la presente invención se refiere compuestos derivados de 2,4-dihidrocroman[4,3-c]pirazol-9-oles y 1,4-dihidrocromeno[3,4-d]pirazol-9-oles, su uso para la fabricación de un medicamento, el uso de este medicamento para el tratamiento y/o la prevención de un trastorno asociado a los receptores de cannabinoides y el uso de estos compuestos como reactivos para ensayos relacionados con receptores de cannabinoides.The present invention is encompassed in the field of Pharmacology Specifically, the present invention relates to compounds derived from 2,4-dihydrochroman [4,3-c] pyrazol-9-oles Y 1,4-dihydrochromen [3,4-d] pyrazol-9-oles, its use for the manufacture of a medicine, the use of this medication for the treatment and / or prevention of a disorder associated with cannabinoid receptors and the use of these compounds as reagents for receptor-related assays of cannabinoids.
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Tras la identificación de los receptores cannabinoides y la clonación de dos tipos, CB_{1} y CB_{2} (Howlett A. C. y col., Pharmacol. Rev., 2002, 54, 161-202), la investigación en el campo del sistema endocannabinoide ha conocido un desarrollo exponencial (Di Marzo V, Nat. Rev. Drug Discov., 2008, 7, 438-455). Los receptores cannabinoides CB1 se encuentran principalmente en las neuronas del cerebro, la médula espinal y el sistema nervioso periférico. Los receptores CB2 se encuentran mayoritariamente en las células inmunitarias. Se han identificado diversos endocannabinoides y sintetizado compuestos capaces de actuar sobre este sistema y que muestran distinto grado de afinidad por los receptores CB1 y CB2. Así pues, se han desarrollado cannabinoides sintéticos que actúan como agonistas o antagonistas selectivos de uno u otro receptor (Jagerovic y col., Curr. Top. Med. Chem., 2008, 8, 205-230; Marrito KS y col., Curr. Top. Med. Chem., 2008, 8, 187-204).Following the identification of cannabinoid receptors and the cloning of two types, CB1 and CB2 (Howlett AC et al ., Pharmacol. Rev., 2002, 54 , 161-202), research in the field of endocannabinoid system has known an exponential development (Di Marzo V, Nat. Rev. Drug Discov., 2008, 7 , 438-455). CB1 cannabinoid receptors are found mainly in neurons of the brain, spinal cord and peripheral nervous system. CB2 receptors are found mostly in immune cells. Various endocannabinoids have been identified and synthesized compounds capable of acting on this system and showing different degrees of affinity for the CB1 and CB2 receptors. Thus, synthetic cannabinoids have been developed that act as selective agonists or antagonists of one or the other receptor (Jagerovic et al ., Curr. Top. Med. Chem., 2008, 8 , 205-230; Marrito KS et al ., Curr . Top. Med. Chem., 2008, 8, 187-204).
El fitocannabinoide mas conocido, el \Delta^{9}-tetrahidrocannabinol (\Delta^{9}-THC), es el cannabinoide farmacológicamente más activo de la planta de cannabis. La mayoría de sus efectos están mediados por sus acciones como agonista sobre los receptores cannabinoides tanto en humanos como en animales. Tiene aproximadamente igual afinidad tanto para el receptor CB1 como para el receptor CB2. En la actualidad, el \Delta^{9}-THC sintético llamado dronabinol (Marinol), la nabilona (Cesamet) y Sativex, un extracto de cannabis que contiene \Delta^{9}-THC y cannabidiol, son los únicos moduladores de receptores cannabinoides cuya prescripción esta permitida en algunos países como estimulante del apetito e inhibición de la nausea y del vómito en pacientes de sida o de quimioterapia. Varios estudios clínicos están poniendo de manifiesto otros usos clínicos de los cannabinoides (Pertwee RG, Br. J. Pharmacol., 2009, 156, 397-411). Entre los más avanzados, destacan los tratamientos del dolor oncológico y neuropático asociado a la esclerosis múltiple (Karst M y col., Expert Opin. Invest. Drugs, 2009, 18, 125-133), Baker D y col., Curr. Pharm. Des., 2008, 14, 2370), de los trastornos del movimiento asociados a enfermedades neurodegenerativas (Bisogno T y col., Curr. Pharm. Des. 2008, 14. 2299-3305; Fernández-Ruiz J, Br J Pharmacol., 2009, in press), de gliomas (Velasco y col., Mol. Neurobiol., 2007, 36, 60-67), de los traumatismos craneoencefálicos (Pellegrini-Giampietro DE y col., FEBS J, 2009, 276, 2-12), de perdida de la masa ósea (Idrid Al, Drugs News Perspect. 2008, 21, 533-540) y del glaucoma (Nucci y col., Prog. Brain Res., 2008, 173. 451-464). En la bibliografía se han descritos varios derivados de \Delta^{9}-THC con actividad cannabinoide (Makriyannis A. y col., Life Sci., 2005, 78, 454-466; Stern E y col., Chem. Biodivers., 2007, 4, 1707-1728).The best known phytocannabinoid, Δ9 -tetrahydrocannabinol (Δ9 -THC), is the most pharmacologically active cannabinoid in the cannabis plant. Most of its effects are mediated by its actions as an agonist on cannabinoid receptors in both humans and animals. It has approximately equal affinity for both the CB1 receptor and the CB2 receptor. Currently, synthetic Δ 9 -THC called dronabinol (Marinol), nabilone (Cesamet) and Sativex, a cannabis extract containing Δ 9 -THC and cannabidiol, are the only modulators of cannabinoid receptors whose prescription is allowed in some countries as an appetite stimulant and inhibition of nausea and vomiting in patients with AIDS or chemotherapy. Several clinical studies are showing other clinical uses of cannabinoids (Pertwee RG, Br. J. Pharmacol., 2009, 156 , 397-411). Among the most advanced, treatments for cancer and neuropathic pain associated with multiple sclerosis (Karst M et al ., Expert Opin. Invest. Drugs, 2009, 18 , 125-133), Baker D et al ., Curr. Pharm Des., 2008, 14 , 2370), of movement disorders associated with neurodegenerative diseases (Bisogno T et al ., Curr. Pharm. Des. 2008, 14. 2299-3305; Fernández-Ruiz J, Br J Pharmacol., 2009, in press), of gliomas (Velasco et al ., Mol. Neurobiol., 2007, 36 , 60-67), of head injuries (Pellegrini-Giampietro DE et al ., FEBS J, 2009, 276 , 2- 12), loss of bone mass (Idrid Al, Drugs News Perspect. 2008, 21, 533-540) and glaucoma (Nucci et al., Prog. Brain res., 2008, 173. 451-464). Several Δ9 -THC derivatives with cannabinoid activity have been described in the literature (Makriyannis A. et al ., Life Sci., 2005, 78 , 454-466; Stern E et al ., Chem. Biodivers. , 2007, 4 , 1707-1728).
Las variaciones estructurales sobre el
tetrahidrocannabinol han conducido en varias ocasiones a compuestos
muy potentes y selectivos para los dos tipos de receptores
cannabinoides CB1 y CB2. Los agonistas cannabinoides prometen un
gran potencial para el control del apetito y de las nauseas, el
tratamiento de enfermedades neurodegenerativas como la esclerosis
múltiple o la enfermedad de Alzheimer, el dolor oncológico y
neuropático y el tratamiento de
gliomas.Structural variations on tetrahydrocannabinol have repeatedly led to very potent and selective compounds for the two types of CB1 and CB2 cannabinoid receptors. Cannabinoid agonists promise great potential for the control of appetite and nausea, the treatment of neurodegenerative diseases such as multiple sclerosis or Alzheimer's disease, cancer and neuropathic pain and the treatment of
gliomas
En vista a la potencialidad de los agonistas cannabinoides, se hace necesario seguir buscando nuevos compuestos con potencial terapéutico que no presenten los problemas de efectos adversos, sobre todo los relacionados con el efecto psicotrópico y neurolépticos, y que presenten buenas propiedades farmacéuticas relacionadas con la administración, la distribución, el metabolismo y la excreción.In view of the potential of agonists cannabinoids, it is necessary to continue looking for new compounds with therapeutic potential that do not present the problems of effects adverse, especially those related to the psychotropic effect and neuroleptics, and have good pharmaceutical properties related to administration, distribution, metabolism and excretion.
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Los autores de la presente invención han encontrado sorprendentemente que los compuestos de fórmula (I) actúan como ligandos de receptores de cannabinoides y por tanto son útiles para modular procesos en los que están implicados dichos receptores.The authors of the present invention have surprisingly found that the compounds of formula (I) they act as ligands for cannabinoid receptors and therefore are useful for modulating processes in which these are involved receivers
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En un primer aspecto, la presente invención se refiere a un compuesto de fórmula general (I)In a first aspect, the present invention is refers to a compound of general formula (I)
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o un tautómero, una sal farmacéuticamente aceptable, prodroga o solvato del mismo;or a tautomer, a salt Pharmaceutically acceptable, prodrug or solvate of same;
donde:where:
- \bullet?
- R^{1} se selecciona entre hidrógeno o alquilo C_{6}-C_{18}R1 is selected from hydrogen or C 6 -C 18 alkyl
- \bullet?
- R^{2} se selecciona entre hidrógeno o alquilo o arilo.R2 is selected from hydrogen or alkyl or aryl.
- \bullet?
- R^{3} se selecciona entre hidrógeno o alquilo.R3 is selected from hydrogen or alkyl.
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De acuerdo con una realización preferida, la presente invención se refiere a un compuesto de fórmula general (II)According to a preferred embodiment, the The present invention relates to a compound of the general formula (II)
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o un tautómero, una sal farmacéuticamente aceptable, prodroga o solvato del mismo;or a tautomer, a salt Pharmaceutically acceptable, prodrug or solvate of same;
donde R^{1}, R^{2} y R^{3} se definen como anteriormente.where R 1, R 2 and R 3 are defined as previously.
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En otra realización preferida, la presente invención se refiere a un compuesto de fórmula general (III)In another preferred embodiment, the present invention refers to a compound of general formula (III)
o un tautómero, una sal farmacéuticamente aceptable, prodroga o solvato del mismo;or a tautomer, a salt Pharmaceutically acceptable, prodrug or solvate of same;
donde R^{1}, R^{2} y R^{3} se definen como anteriormente.where R 1, R 2 and R 3 are defined as previously.
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De acuerdo con una realización preferida, la presente invención se refiere a un compuesto de fórmula (I) donde R^{1} y R^{3} son hidrógeno.According to a preferred embodiment, the The present invention relates to a compound of formula (I) wherein R1 and R3 are hydrogen.
De acuerdo con una realización preferida, el compuesto de fórmula (I) se selecciona entre el grupo que consiste en:According to a preferred embodiment, the compound of formula (I) is selected from the group consisting in:
- --
- 4,4-dimetil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol4,4-dimethyl-1,4-dihydrochromen [3,4- d ] pyrazol-9-ol
- --
- 2,4,4-trimetil-2,4-dihidrocromeno[4,3-c]pirazol-9-ol2,4,4-trimethyl-2,4-dihydrochromen [4,3- c ] pyrazol-9-ol
- --
- 1,4,4-trimetil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol1,4,4-trimethyl-1,4-dihydrochromen [3,4- d ] pyrazol-9-ol
- --
- 4,4-dimetil-2-etil-2,4-dihidrocromeno[4,3-c]pirazol-9-ol4,4-dimethyl-2-ethyl-2,4-dihydrochromen [4,3- c ] pyrazol-9-ol
- --
- 4,4-dimetil-1-etil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol4,4-dimethyl-1-ethyl-1,4-dihydrochromen [3,4- d ] pyrazol-9-ol
- --
- 1-(3,4-diclorofenil)-4,4-dimetil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol1- (3,4-dichlorophenyl) -4,4-dimethyl-1,4-dihydrochromen [3,4- d ] pyrazol-9-ol
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De acuerdo con una realización preferida, la presente invención se refiere a un compuesto de fórmula (I) donde R^{1} es 1,1-dimetilheptilo y R^{3} es hidrógeno.According to a preferred embodiment, the The present invention relates to a compound of formula (I) wherein R 1 is 1,1-dimethylheptyl and R 3 is hydrogen.
De acuerdo con una realización preferida, el compuesto de fórmula (I) se selecciona entre el grupo que consiste en:According to a preferred embodiment, the compound of formula (I) is selected from the group consisting in:
- --
- 4,4-dimetil-7-(1,1-dimetilheptil)-1,4-dihidrocromeno[3,4-d]pirazol-9-ol4,4-dimethyl-7- (1,1-dimethylheptyl) -1,4-dihydrochromen [3,4- d ] pyrazol-9-ol
- --
- 7-(1,1-dimetilheptil)-2,4,4-trimetil-2,4-dihidrocromeno[4,3-c]pirazol-9-ol7- (1,1-dimethylheptyl) -2,4,4-trimethyl-2,4-dihydrochromen [4,3- c ] pyrazol-9-ol
- --
- 4,4-dimetil-7-(1,1-dimetilheptil)-1-etil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol4,4-dimethyl-7- (1,1-dimethylheptyl) -1-ethyl-1,4-dihydrochromen [3,4- d ] pyrazol-9-ol
- --
- 4,4-dimetil-7-(1,1-dimetilheptil)-2-etil-2,4-dihidrocromeno[4,3-c]pirazol-9-ol4,4-dimethyl-7- (1,1-dimethylheptyl) -2-ethyl-2,4-dihydrochromen [4,3- c ] pyrazol-9-ol
- --
- 1-(3,4-diclorofenil)-4,4-dimetil -7-(1,1-dimetilheptil)-1,4-dihidrocromeno[3,4-d]pirazol-9-ol1- (3,4-Dichlorophenyl) -4,4-dimethyl -7- (1,1-dimethylheptyl) -1,4-dihydrochromen [3,4- d ] pyrazol-9-ol
- --
- 1-(2,4-diclorofenil)-4,4-dimetil-7-(1,1-dimetilheptil)-1,4-dihidrocromeno[3,4-d]pirazol-9-ol.1- (2,4-Dichlorophenyl) -4,4-dimethyl-7- (1,1-dimethylheptyl) -1,4-dihydrochromen [3,4- d ] pyrazol-9-ol.
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El término "alquilo" se refiere, en la presente invención, a cadenas alifáticas, lineales o ramificadas, saturadas o insaturadas, que tienen de 1 a 18 átomos de carbono, preferiblemente entre 6 y 15 átomos de carbono. Por ejemplo, pero sin limitarse a, metilo, etilo, n-propilo, i-propilo, n-butilo, terc-butilo, sec-butilo, n-pentilo, n-hexilo, n-heptilo etc. Los grupos alquilo pueden estar opcionalmente sustituidos por uno o más sustituyentes tales como halógeno, hidroxilo o ácido carboxílico.The term "alkyl" refers, in the present invention, to aliphatic, linear or branched, saturated or unsaturated chains, having 1 to 18 carbon atoms, preferably between 6 and 15 carbon atoms. For example, but not limited to, methyl, ethyl, n -propyl, i -propyl, n -butyl, tert-butyl , sec -butyl, n-pentyl, n-hexyl, n-heptyl etc. The alkyl groups may be optionally substituted by one or more substituents such as halogen, hydroxyl or carboxylic acid.
El término "arilo" se refiere, en la presente invención, a anillos aromáticos sencillos o múltiples, que tienen de entre 5 a 18 eslabones en los que se ha eliminado un protón del anillo. Los grupos arilo son por ejemplo, pero sin limitarse a, fenilo, naftilo, difenilo, indenilo, fenantrilo o antracilo. Preferiblemente el grupo arilo tiene de 5 a 7 átomos de carbono y más preferiblemente el grupo arilo es un fenilo. Los radicales arilo pueden estar opcionalmente sustituidos por uno o más sustituyentes tales como alquilo (C_{1}-C_{6}), halógeno, hidroxilo o ácido carboxílico.The term "aryl" refers, in the present invention, to single or multiple aromatic rings, which they have between 5 to 18 links in which a proton of the ring. The aryl groups are for example, but without be limited to, phenyl, naphthyl, diphenyl, indenyl, phenanthryl or anthracil Preferably the aryl group has 5 to 7 atoms of carbon and more preferably the aryl group is a phenyl. The aryl radicals may be optionally substituted by one or more substituents such as (C 1 -C 6) alkyl, halogen, hydroxyl or carboxylic acid.
El término "halógeno" se refiere, en la presente invención, a bromo, cloro, yodo o flúor. Preferentemente a cloro.The term "halogen" refers, in the present invention, to bromine, chlorine, iodine or fluorine. Preferably to chlorine.
A menos que se indique lo contrario, los compuestos de la invención también se refieren 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 deuteno o por 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 refer 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 deutene or by 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 "tautómero" o "forma tautomérica", tal y como se usa en la presente invención, se refiere a isómeros estructurales de diferentes energías que son interconvertibles vía una barrera de baja energía. Por ejemplo, tautómeros protónicos (también conocidos como tautómeros prototrópicos) que incluyen interconversiones mediante la migración de un protón, como por ejemplo isomerizaciones ceto-enólicas o imina-enamina. Los tautómeros de valencia incluyen interconversiones por reorganización de algunos electrones de enlace.The term "tautomer" or "form tautomeric ", as used in the present invention, is refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, protonic tautomers (also known as tautomers prototropic) that include interconversions through migration of a proton, such as isomerizations keto-enol or imine-enamine. The Valencia tautomers include reorganization interconversions of some bond electrons.
El término "sales, solvatos, prodroga farmacéuticamente aceptables" se refiere a cualquier sal, éster, solvato farmacéuticamente aceptable, o cualquier otro compuesto que, cuando se administra a un receptor es capaz de proporcionar (directamente o indirectamente) un compuesto según se describe en el presente documento. Sin embargo, se apreciará que las sales farmacéuticamente no aceptables también están dentro del alcance de la invención ya que éstas pueden ser útiles en la preparación de sales farmacéuticamente aceptables. La preparación de sales, prodrogas y derivados puede llevarse a cabo mediante métodos conocidos en la técnica.The term "salts, solvates, prodrugs pharmaceutically acceptable "refers to any salt, ester, pharmaceutically acceptable solvate, or any other compound that, when administered to a recipient is able to provide (directly or indirectly) a compound as described in the present document However, it will be appreciated that the salts Pharmaceutically unacceptable are also within the scope of the invention since these may be useful in the preparation of pharmaceutically acceptable salts. Salt preparation, Drugs and derivatives can be carried out by methods known in the art.
Por ejemplo, sales farmacéuticamente aceptables de compuestos previstos en el presente documento, se sintetizan mediante métodos químicos convencionales a partir de un compuesto original que contiene un resto básico ó ácido. Generalmente, tales sales se preparan, por ejemplo, haciendo reaccionar las formas de ácido o base libre de los compuestos con una cantidad estequiométrica de la base o ácido apropiado en agua o en un disolvente orgánico o en una mezcla de los dos. Generalmente, se prefieren medios no acuosos como éter, acetato de etilo, etanol, isopropanol o acetonitrilo. Ejemplos de 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 de bases orgánicas tales como, por ejemplo, etilenodiamina, etanolamina, N,N-dialquilenetanolamina, tietanolamia, glucamina y sales de aminoácidos básicos.For example, pharmaceutically acceptable salts of compounds provided herein, are synthesized by conventional chemical methods from a compound original that contains a basic or acidic residue. Generally such salts are prepared, for example, by reacting the forms of free acid or base of the compounds with an amount stoichiometric base or appropriate acid in water or in a organic solvent or in a mixture of both. Generally they prefer non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Examples of acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, iohydrate, sulfate, nitrate, phosphate and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. Examples of base addition salts include inorganic salts. such as, for example, sodium, potassium, calcium, ammonium salts, magnesium, aluminum and lithium, and salts of organic bases such as, for example, ethylenediamine, ethanolamine, N, N-dialkylene ethanolamine, tietanolamia, glucamine and salts of basic amino acids.
Los derivados o prodrogas particularmente favoritos son aquellos que aumentan las biodisponibilidad de los compuestos de esta invención cuando se administran tales compuestos a un paciente (por ejemplo, haciendo que un compuesto administrado por vía oral se absorba mas fácilmente por la sangre), o que potencia la liberación del compuesto original en un compartimento biológico (por ejemplo, el cerebro o el sistema linfático) con relación a 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, by having a compound administered orally absorbed more easily by blood), or that enhances the release of the original compound in a compartment biological (for example, the brain or lymphatic system) with relation to the original species.
Cualquier compuesto que es un prodroga de un compuesto de fórmula (I) esta dentro del alcance de la invención. El termino "prodroga" se usa en su sentido más amplio y abarca aquellos derivados que se convierten en 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 esteres, esteres de aminoácido, esteres de fosfato, esteres de sulfonato de sales metálicas, carbamatos, y amidas.Any compound that is a prodrug of a Compound of formula (I) is within the scope of the invention. He term "prodrug" is used in its broadest sense and encompasses those derivatives that become live in the compounds of the invention. Such derivatives will be apparent to those experts in the technique, 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, esters phosphate, sulphonate esters of metal salts, carbamates, and Amides
Los compuestos de fórmula (I) pueden estar en forma cristalina como compuestos libres o como solvatos y se pretende que ambas formas están dentro del alcance de la presente invención. Los métodos de solvatación se conocen generalmente dentro de la técnica. Los solvatos adecuados son solvatos farmacéuticamente aceptables. En una realización particular, el solvato es un hidrato.The compounds of formula (I) may be in crystalline form as free compounds or as solvates and it It is intended that both forms are within the scope of this invention. Solvation methods are generally known within of technique Suitable solvates are pharmaceutically solvates acceptable. In a particular embodiment, the solvate is a hydrate.
Los compuestos de fórmula (I) o sus sales o solvatos están preferiblemente en una forma farmacéuticamente aceptable o sustancialmente pura. Por forma farmacéuticamente aceptable se entiende, entre otros, que tienen un nivel de pureza farmacéuticamente aceptable excluyendo los 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%, mas preferiblemente, superiores al 70%, más preferiblemente, superiores al 90%. En una realización preferida, son superiores al 95% del compuesto de fórmula (I), o de sus sales, solvatos o prodrogas.The compounds of formula (I) or their salts or solvates are preferably in a 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%, more preferably, greater than 90%. In a preferred embodiment, are greater than 95% of the compound of formula (I), or its salts, solvates or prodrugs.
Los compuestos de fórmula (I) definidos anteriormente pueden obtenerse mediante una combinación de reacciones sintéticas conocidas en el estado del arte tales como las mencionadas en el artículo Press J.B., J. Heterocyclic Chem., 1985, 22, 561-564.The compounds of formula (I) defined above can be obtained by a combination of synthetic reactions known in the state of the art such as those mentioned in Press JB, J. Heterocyclic Chem., 1985, 22 , 561-564.
En otro aspecto, la presente invención se refiere al uso de un compuesto de fórmula (I) para la fabricación de un medicamento.In another aspect, the present invention is refers to the use of a compound of formula (I) for the manufacture of a medicine
En otro aspecto, la presente invención se refiere al uso del medicamento mencionado anteriormente para el tratamiento y/o la prevención de un trastorno asociado a los receptores de cannabinoides.In another aspect, the present invention is refers to the use of the medication mentioned above for the treatment and / or prevention of a disorder associated with cannabinoid receptors
De acuerdo con una realización preferida, el trastorno asociado a receptores de cannabinoides se selecciona entre pérdida del apetito, reducción de disquinesia provocada por L-dopa en enfermos de Parkinson, esquizofrenia aguda o pérdida de las disfunciones cognitivas y de memoria asociadas a la enfermedad de Alzheimer.According to a preferred embodiment, the disorder associated with cannabinoid receptors is selected from loss of appetite, reduction of dyskinesia caused by L-dopa in Parkinson's patients, acute schizophrenia or loss of cognitive and memory dysfunctions associated with Alzheimer disease.
El término "trastorno" tal y como se usa en la presente invención, se refiere a la presencia de un comportamiento o de un grupo de síntomas identificables en la práctica clínica, que en la mayoría de los casos se acompañan de malestar o interfieren con la actividad habitual del individuo.The term "disorder" as used in The present invention refers to the presence of a behavior or a group of identifiable symptoms in the clinical practice, which in most cases are accompanied by discomfort or interfere with the habitual activity of the individual.
Los compuestos de fórmula (I), sus sales farmacéuticamente aceptables, prodrogas o solvatos del mismo, pueden ser utilizados, por tanto, en la prevención y/o el tratamiento de un trastorno que requiera modulación de los receptores de cannabinoides. Las composiciones farmacéuticas que contienen una cantidad terapéuticamente eficaz de un compuesto de fórmula (I), sus sales farmacéuticamente aceptables, prodrogas o solvatos del mismo, junto con los excipientes farmacéuticamente aceptables, constituyen un aspecto adicional de la presente invención.The compounds of formula (I), their salts pharmaceutically acceptable, prodrugs or solvates thereof, may be used, therefore, in the prevention and / or treatment of a disorder that requires modulation of the receptors of cannabinoids Pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I), its pharmaceutically acceptable salts, prodrugs or solvates thereof, together with pharmaceutically acceptable excipients, they constitute an additional aspect of the present invention.
La cantidad de compuesto de fórmula (I), sus sales farmacéuticamente aceptables, prodrogas o solvatos del mismo, terapéuticamente eficaz que debe administrarse así como su dosificación para tratar un estado patológico con dichos compuestos dependerá de numerosos factores, entre los que se encuentra la edad, el estado del paciente, la severidad de la enfermedad, la ruta y frecuencia de administración, el compuesto modulador a utilizar, etc.The amount of compound of formula (I), its pharmaceutically acceptable salts, prodrugs or solvates thereof, therapeutically effective to be administered as well as its dosage to treat a pathological state with said compounds It will depend on numerous factors, including age, the patient's condition, the severity of the disease, the route and administration frequency, the modulator compound to be used, etc.
Los compuestos y composiciones de esta invención pueden ser empleados solos o junto con otros fármacos para proporcionar una terapia combinada. Los otros fármacos pueden formar parte de la misma composición, o ser proporcionados como una composición separada, para su administración al mismo tiempo o en un momento diferente.The compounds and compositions of this invention they can be used alone or together with other drugs to Provide a combination therapy. The other drugs can form part of the same composition, or be provided as a separate composition, for administration at the same time or in a different time
Una terapia combinada puede ser especialmente interesante por el tipo de patologías a ser tratadas con estos compuestos tal y como se definen en la presente invención, estas patologías son especialmente complejas, ya que los pacientes en general presentan una combinación de síntomas así como una variedad de daños o alteraciones. Por lo tanto, puede ser interesante combinar varios fármacos, cada uno dirigido a prevenir, aliviar o curar específicamente un síntoma, daño o alteración concretos, o también a varios de ellos, resultando en una terapia combinada dirigida a la enfermedad o condición de una forma global, teniendo en cuenta muchos, la mayoría, o todos los aspectos implicados en la misma.A combination therapy can be especially interesting for the type of pathologies to be treated with these Compounds as defined in the present invention, these pathologies are especially complex, since patients in generally present a combination of symptoms as well as a variety of damages or alterations. Therefore, it can be interesting combine several drugs, each aimed at preventing, alleviating or specifically cure a specific symptom, damage or alteration, or also to several of them, resulting in a combination therapy directed to the disease or condition in a global way, taking account for many, most, or all aspects involved in the same.
Los fármacos a ser combinados con los compuestos de la presente invención pueden ser fármacos aprobados para el tratamiento de alguna de las enfermedades, o ser de nuevo desarrollo.The drugs to be combined with the compounds of the present invention may be drugs approved for treatment of any of the diseases, or be again developing.
En otro aspecto, la presente invención se refiere al uso de un compuesto de fórmula (I) para la fabricación de un reactivo en ensayos biológicos relacionados con receptores de cannabinoides.In another aspect, the present invention is refers to the use of a compound of formula (I) for the manufacture of a reagent in biological assays related to receptors of cannabinoids
En una realización preferida, los receptores de cannabinoides son del tipo CB_{1} y CB_{2}.In a preferred embodiment, the receptors of Cannabinoids are of the type CB1 and CB2.
En la presente invención, el término "reactivo" se refiere a una sustancia de prueba que se añade a un sistema para dar lugar a una reacción o comprobar si una reacción ocurre.In the present invention, the term "reagent" refers to a test substance that is added to a system to give rise to a reaction or check if a reaction it happens.
En la presente invención, el término "ensayo biológico" se refiere a un procedimiento para medir una sustancia, ya sea cuantitativa o cualitativamente, en un organismo vivo. Los ensayos cualitativos se usan para determinar los efectos físicos de una sustancia en dicho organismo. Los ensayos cuantitativos se usan para la estimación de la concentración o potencia de una sustancia mediante medición de la respuesta biológica que produce dicha sustancia.In the present invention, the term "test biological "refers to a procedure to measure a substance, either quantitatively or qualitatively, in an organism alive. Qualitative tests are used to determine the effects physicists of a substance in that organism. The essays Quantitative are used to estimate the concentration or potency of a substance by measuring the response biological produced by said substance.
Los siguientes ejemplos y dibujos se proporcionan a modo de ilustración, y no se pretende que sean limitativos de la presente invención.The following examples and drawings are provided by way of illustration, and are not intended to be Limitations of the present invention.
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Para la síntesis de los derivados de 2,4-dihidrocromeno[4,3-c]pirazol-9-oles y 1,4-dihidrocromeno[3,4-d]pirazol-9-oles de la presente invención se ha utilizado como producto de partida el benceno-1,3-diol. Cuando este producto de partida no es comercial se puede preparar a partir del dimetoxifenol correspondiente por reacción con el tribromuro de boro en exceso en diclorometano. Una acilación de Friedel-Crafts entre el ácido-3,3-dimetilacrílico y el difenol correspondiente usando como ácido y disolvente a la vez el ácido metanosulfónico bajo corriente de N_{2} y a 70ºC da lugar a una 7-alkyl-5-hidroxi-2,2-dimetil-2,3-dihidrocroman-4-ona. Un procedimiento alternativo consiste en realizar la síntesis de acilación de Friedel-Crafts asistida por la técnica de microondas. A continuación, la cromona formada se somete a una reacción aldólica usando como base hidruro de sodio y como electrófilo el formiato de etilo dando lugar a la formación de una 7-alkyl-5-hidroxi-3-hidroximetilen-2,2-dimetil-2,3-dihidrocroman-4-ona. Esta reacción puede ser asistida por microondas. La etapa siguiente consiste en la formación del pirazol, usando como reactivo distintas hidracinas obteniéndose los cromenopirazoles deseados. En caso de utilizar hidracinas alquiladas esta síntesis puede dar lugar a la formación de dos isómeros correspondientes a la sustitución en N1 o en N2 del anillo de pirazol que se separan por cromatografía sobre silica gel. El grupo hidroxilo de los cromenopirazoles se alquila utilizando el reactivo alquilante correspondiente.For the synthesis of the 2,4-dihydrochromen [4,3- c ] pyrazol-9-oles and 1,4-dihydrochromen [3,4- d ] pyrazol-9-oles derivatives of the present invention has been used as starting product benzene-1,3-diol. When this starting product is not commercial, it can be prepared from the corresponding dimethoxyphenol by reaction with the excess boron tribromide in dichloromethane. A Friedel-Crafts acylation between 3,3-dimethylacrylic acid and the corresponding diphenol using methanesulfonic acid as the acid and solvent at the same time under N2 current and at 70 ° C results in a 7-alkyl-5-hydroxy -2,2-dimethyl-2,3-dihydrochroman-4-one. An alternative procedure is to perform Friedel-Crafts acylation synthesis assisted by the microwave technique. The chromone formed is then subjected to an aldol reaction using sodium hydride as the base and as an electrophile the ethyl formate resulting in the formation of a 7-alkyl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl- 2,3-dihydrochroman-4-one. This reaction can be assisted by microwave. The next step consists in the formation of pyrazole, using different hydrazines as a reagent, obtaining the desired chromenopyrazoles. If alkylated hydrazines are used, this synthesis can lead to the formation of two isomers corresponding to the N1 or N2 substitution of the pyrazole ring that are separated by chromatography on silica gel. The hydroxyl group of the chromenopyrazoles is alkylated using the corresponding alkylating reagent.
Este procedimiento se resume en el siguiente esquema (I):This procedure is summarized in the following scheme (I):
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Esquema (I)Scheme (I)
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A una disolución de ácido metanosulfónico (22,6 mmol) saturado con dipentóxido de fósforo (10 mmol) se añade, bajo nitrógeno, resorcinol (8 mmol) y ácido 1,3-dimetilacrilico. La mezcla de reacción se calienta a 70ºC y se deja bajo agitación durante 3 horas. Transcurrido este tiempo se vierte la mezcla sobre hielo. El precipitado formado se extrae con éter etílico, la fase orgánica se seca sobre MgSO_{4}, y el disolvente se evapora. El producto bruto resultante se purifica por cromatografía sobre sílica gel usando como eluyente Hex/AcOEt en proporción 3:1, proporcionando la 5-hidroxi-2,2-dimetilcroman-4-ona. Rto.83% Aceite amarillo. ^{1}H RMN DMSO 300 MHz (\delta ppm): 7,56 (d, J = 8,6 Hz, 1H); 6,42 (dd, J = 8,7 Hz, J = 2,2 Hz, 1H); 6,23 (d, J = 8,7 Hz, 1H); 2,63 (s, 2H); 1,34 (s, 6H). ^{13}C RMN DMSO 300 MHz (\delta ppm): 190,40; 165,07; 161,78; 130,00; 116,01; 113,13; 110,15; 79,62; 48,15; 27,15. EM (ES^{+}) m/z = 192 ([MH]^{+}, 100%).To a solution of methanesulfonic acid (22.6 mmol) saturated with phosphorus dipentoxide (10 mmol) is added, under nitrogen, resorcinol (8 mmol) and acid 1,3-dimethylacrylic. The reaction mixture is Heat at 70 ° C and leave under stirring for 3 hours. After this time the mixture is poured onto ice. He formed precipitate is extracted with ethyl ether, the organic phase is Dry over MgSO4, and the solvent is evaporated. Gross product resulting is purified by chromatography on silica gel using as eluent Hex / AcOEt in 3: 1 ratio, providing the 5-hydroxy-2,2-dimethylchroman-4-one. Rto. 83% Yellow oil. 1 H NMR DMSO 300 MHz (δ ppm): 7.56 (d, J = 8.6 Hz, 1H); 6.42 (dd, J = 8.7 Hz, J = 2.2 Hz, 1H); 6.23 (d, J = 8.7 Hz, 1H); 2.63 (s, 2 H); 1.34 (s, 6H). 13 C NMR DMSO 300 MHz (δ ppm): 190.40; 165.07; 161.78; 130.00; 116.01; 113.13; 110.15; 79.62; 48.15; 27.15. MS (ES +) m / z = 192 ([MH] +, 100%).
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En un matraz bajo una corriente de nitrógeno se disuelve 5-hidroxi-2,2-dimetilcroman-4-ona (0,1 mmol) con THF anhidro. Se añade hidruro sódico seco al 95% (9 mmol). Se deja la reacción bajo agitación a temperatura ambiente durante 16 horas. Se añade hidróxido sódico (0,003 mol) a la mezcla de reacción. Después de 40 horas se añade formato de etilo lentamente a temperatura ambiente bajo atmósfera inerte. Pasadas 16 horas de reacción se evapora el disolvente, y se realiza la extracción del bruto de reacción con CH_{2}Cl_{2}. La fase acuosa se neutraliza con una solución de HCl y se vuelve a extraer con CH_{2}Cl_{2}. Las dos fases orgánicas se juntan en una y se seca sobre MgS04, se evapora y purifica por cromatografía sobre gel de sílice usando como eluyente Hex/AcOEt en proporción 1:1 aislándose 5-hidroxi-3-(hidrometilen)2,2-dimetilcroman-4-ona. Rto. 27% Sólido amarillo. ^{1}H RMN CDCl_{3} 300 MHz (\delta ppm): 14,95 (sa, 1H); 7,78 (s, 1H); 7,79 (m, 1H); 6,50 (d, J = 8,4 Hz, 1H); 6,32 (sa, 1H); 6,02 (sa, 1H ); 1,58 (s, 6H). ^{13}C RMN CDCl_{3} 300 MHz (\delta ppm): 182,6; 168,51; 163, 25; 161,46; 129,19; 114,25; 113,93; 110, 73; 104,38; 79,32; 28,78. EM (ES^{+}) m/z = 221 ([MH]^{+}, 100%).In a flask under a stream of nitrogen it dissolve 5-hydroxy-2,2-dimethylchroman-4-one (0.1 mmol) with anhydrous THF. 95% dry sodium hydride is added (9 mmol). The reaction is left under stirring at room temperature. for 16 hours Sodium hydroxide (0.003 mol) is added to the mixture of reaction. After 40 hours ethyl format is added slowly at room temperature under inert atmosphere. Past 16 hours of reaction the solvent is evaporated, and the extraction of the reaction crude with CH 2 Cl 2. The phase aqueous is neutralized with a solution of HCl and reextracted with CH 2 Cl 2. The two organic phases come together in one and dried over MgSO4, evaporated and purified by gel chromatography of silica using as eluent Hex / AcOEt in a 1: 1 ratio isolating 5-hydroxy-3- (hydrometylene) 2,2-dimethylchroman-4-one. Rto. 27% yellow solid. 1 H NMR CDCl 3 300 MHz (δ ppm): 14.95 (sa, 1 H); 7.78 (s, 1 H); 7.79 (m, 1 H); 6.50 (d, J = 8.4 Hz, 1H); 6.32 (sa, 1 H); 6.02 (sa, 1 H); 1.58 (s, 6H). 13 C NMR CDCl 3 300 MHz (δ ppm): 182.6; 168.51; 163, 25; 161.46; 129.19; 114.25; 113.93; 110, 73; 104.38; 79.32; 28.78. MS (ES +) m / z = 221 ([MH] +, 100%).
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A una disolución de 5-hidroxi-3-(hidrometilen)2,2-dimetilcroman-4-ona en EtOH se añade hidrazina monohidratada. La mezcla de reacción se agita a temperatura ambiente durante 16 horas. A continuación, se evapora el disolvente y el aceite resultante se purifica por cromatografía sobre gel de sílice usando como eluyente Hex/AcOEt en proporción 2:1 para dar el 4,4-dimetil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol (Ejemplo 1 de la presente invención). Rto. 90% Aceite amarillo. ^{1}H RMN MeOD 300 MHz (\delta ppm): 7,60 (sa, 2H); 6,41 (dd, J = 2,3 Hz, J = 8,6 Hz, 1H); 6,35 (s, 1H); 1,56 (s, 6H). ^{13}C RMN MeOD 300 MHz (\delta ppm): 159,07; 154,69; 122,75; 108,65; 104,43; 28,28. HPLC/EM: t_{R} = 9,13 min. (80%); MeCN + 0,08% Ac. Fórmico/H_{2}O + 0,1% Ac.Fórmico 20/80. Flujo = 0,25 mm/min; \lambda = 190-400 nm; ESI (m/z) = 217 (100%).To a solution of 5-hydroxy-3- (hydrometylene) 2,2-dimethylchroman-4-one in EtOH is added hydrazine monohydrate. The reaction mixture is stirred at room temperature for 16 hours. The solvent is then evaporated and the resulting oil is purified by chromatography on silica gel using as eluent Hex / AcOEt in a 2: 1 ratio to give 4,4-dimethyl-1,4-dihydrochromen [3,4-d ] pyrazol-9-ol (Example 1 of the present invention). Rto. 90% yellow oil. 1 H NMR MeOD 300 MHz (δ ppm): 7.60 (sa, 2H); 6.41 (dd, J = 2.3 Hz, J = 8.6 Hz, 1H); 6.35 (s, 1 H); 1.56 (s, 6H). 13 C NMR MeOD 300 MHz (δ ppm): 159.07; 154.69; 122.75; 108.65; 104.43; 28.28. HPLC / MS: t R = 9.13 min. (80%); MeCN + 0.08% Ac. Formic / H2O + 0.1% Formic Ac 20/80. Flow = 0.25 mm / min; λ = 190-400 nm; ESI (m / z) = 217 (100%).
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Ejemplo 2 y Ejemplo 3Example 2 and Example 3
yY
Se preparan los compuestos deseados según el modo de realización descrito en la etapa C del Ejemplo 1, utilizando metilhidrazina. Se obtiene una mezcla de 2,4,4-trimetil-2,4-dihidrocroman[4,3-c]pirazol-9-ol (Ejemplo 2) y de 1,4,4-trimetil-1,4-dihidrocroman[3,4-d]pirazol-9-ol (Ejemplo 3). Se separaron los 2 isómeros por cromatografía sobre silica gel.The desired compounds are prepared according to the embodiment described in step C of Example 1, using methylhydrazine. A mixture of 2,4,4-trimethyl-2,4-dihydrochroman [4,3- c ] pyrazol-9-ol (Example 2) and 1,4,4-trimethyl-1,4-dihydrochroman [ 3,4- d ] pyrazol-9-ol (Example 3). The 2 isomers were separated by chromatography on silica gel.
2,4,4-Trimetil-2,4-dihidrocroman[4,3-c]pirazol-9-ol (Ejemplo 2): Rto. 51% Sólido amarillo. P.f.: 240-242ºC. ^{1}H RMN CDCl_{3} 300 MHz (\delta ppm): 7,41 (d, J = 8 Hz, 1H); 7,25 (s, 1H); 6,53 (m, 2H); 4,10 (s, 3H); 1,58 (s, 6H). ^{13}C RMN CDCl_{3} 300 MHz (\delta ppm): 157,21; 154,90; 143,15; 132,21; 124,86; 120,93; 109,18; 106,09; 105,23; 76,88; 39,28; 28,62. EM (ES^{+}) m/z = 231 ([MH]^{+}, 100%). Anal.: 3[C_{13}H_{14}N_{2}O_{2}].H_{2}O; Teórico: C:65,23%; H: 6,68%; N: 11,10%; Hallado: C: 65,68%; H: 6,21%; N: 10,70%. 2,4,4-Trimethyl-2,4-dihydrochroman [4,3-c] pyrazol-9-ol (Example 2): Rto. 51% yellow solid. Mp: 240-242 ° C. 1 H NMR CDCl 3 300 MHz (δ ppm): 7.41 (d, J = 8 Hz, 1H); 7.25 (s, 1 H); 6.53 (m, 2H); 4.10 (s, 3 H); 1.58 (s, 6H). 13 C NMR CDCl 3 300 MHz (δ ppm): 157.21; 154.90; 143.15; 132.21; 124.86; 120.93; 109.18; 106.09; 105.23; 76.88; 39.28; 28.62. MS (ES +) m / z = 231 ([MH] +, 100%). Anal .: 3 [C 13 H 14 N 2 O 2] H 2 O; Theoretical: C: 65.23%; H: 6.68%; N: 11.10%; Found: C: 65.68%; H: 6.21%; N: 10.70%.
1,4,4-Trimetil-1,4-dihidrocroman[3,4-d]pirazol-9-ol (Ejemplo 3). Rto. 20% Sólido amarillo. P.f.: 213-216ºC. ^{1}H RMN CDCl_{3} 300 MHz (\delta ppm): 7,57 (m, 1H); 7,12 (m, 2H); 3,90 (s, 3H); 1,58 (s, 6H). ^{13}C RMN CDCl_{3} 300 MHz (\delta ppm): 156,12; 153,47; 130,74; 121,83; 109,11; 108,49; 105,69; 103,82; 77,20; 38,93; 28,48. EM (ES^{+}) m/z = 231 ([MH]^{+}, 100%). Anal.: 3[C_{13}H_{14}N_{2}O_{2}].H_{2}O; Teórico: C: 65,23%; H: 6,68%; N: 11,10%; Hallado: C: 65,16%; H: 5,97%; N: 10,81%. 1,4,4-Trimethyl-1,4-dihydrochroman [3,4-d] pyrazol-9-ol (Example 3). Rto. 20% yellow solid. Mp: 213-216 ° C. 1 H NMR CDCl 3 300 MHz (δ ppm): 7.57 (m, 1H); 7.12 (m, 2H); 3.90 (s, 3 H); 1.58 (s, 6H). 13 C NMR CDCl 3 300 MHz (δ ppm): 156.12; 153.47; 130.74; 121.83; 109.11; 108.49; 105.69; 103.82; 77.20; 38.93; 28.48. MS (ES +) m / z = 231 ([MH] +, 100%). Anal .: 3 [C 13 H 14 N 2 O 2] H 2 O; Theoretical: C: 65.23%; H: 6.68%; N: 11.10%; Found: C: 65.16%; H: 5.97%; N: 10.81%.
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Ejemplo 4 y Ejemplo 5Example 4 and Example 5
yY
Se preparan los compuestos deseados según el modo de realización descrito para los Ejemplos 2 y 3, utilizando etilhidrazina.The desired compounds are prepared according to embodiment described for Examples 2 and 3, using ethylhydrazine
2-Etil-4,4-dimetil-2,4-dihidrocromeno[4,3-c]pirazol-9-ol (Ejemplo 4): Rto. 22% Sólido amarillento. P.f.: 185-189ºC. ^{1}H RMN CDCl_{3} 300 MHz (\delta ppm): 7,58 (m, 1H); 7,12 (s, 1H); 6,45 (m, 2H); 4,17 (c, J = 7,3 Hz, 2H); 1,58 (s, 6H); 1,50 (t, J = 7,3 Hz). ^{13}C RMN CDCl_{3} 300 MHz (\delta ppm): 157,28; 154,89; 142,85; 123,51; 123,02; 121,00; 111,46; 109,19; 105,23; 76,98; 47,46; 29,64; 16,16. EM (ES^{+}) m/z = 244 ([MH]^{+}, 100%). Anal.: 5[C_{14}H_{16}N_{2}O_{2}].4[H_{2}O]; Teórico: C: 64,60%; H: 6,88%; N: 10,76%. Hallado: C: 64,84%; H: 6,88; N: 10,56. 2-Ethyl-4,4-dimethyl-2,4-dihydrochromen [4,3-c] pyrazol-9-ol (Example 4): Rto. 22% yellowish solid. Mp: 185-189 ° C. 1 H NMR CDCl 3 300 MHz (δ ppm): 7.58 (m, 1H); 7.12 (s, 1 H); 6.45 (m, 2H); 4.17 (c, J = 7.3 Hz, 2H); 1.58 (s, 6H); 1.50 (t, J = 7.3 Hz). 13 C NMR CDCl 3 300 MHz (δ ppm): 157.28; 154.89; 142.85; 123.51; 123.02; 121.00; 111.46; 109.19; 105.23; 76.98; 47.46; 29.64; 16.16. MS (ES +) m / z = 244 ([MH] +, 100%). Anal .: 5 [C 14 H 16 N 2 O 2] 4 [H 2 O]; Theoretical: C: 64.60%; H: 6.88%; N: 10.76%. Found: C: 64.84%; H: 6.88; N: 10.56.
1-Etil-4,4-dimetil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol (Ejemplo 5). Rto. 28% Sólido amarillento. P.f.: 188-193ºC. ^{1}H RMN CDCl_{3} 300 MHz (\delta ppm): 7,30 (m, 1H); 7,29 (s, 1H); 7,14 (sa, 1H); 6,53 (m, 2H); 4,42 (c, J = 7,2 Hz, 2H); 1,59 (s, 6H); 1,51 (t, J = 7,2 Hz, 3H). ^{13}C RMN CDCl_{3} 300 MHz (\delta ppm): 157,65; 154,56; 131,90; 122,16; 120,96; 108,78; 108,63; 105,83; 77,12; 46,20; 28,42; 15,30. EM (ES^{+}) m/z = 244 ([MH]^{+}, 100%). Anal.: C_{14}H_{16}N_{2}O_{2}; Teórico: C: 68,83%; H: 6,60%; N: 11,47%. Hallado: C: 68,60%; H: 6,37; N: 11,21. 1-Ethyl-4,4-dimethyl-1,4-dihydrochromen [3,4-d] pyrazol-9-ol (Example 5). Rto. 28% yellowish solid. Mp: 188-193 ° C. 1 H NMR CDCl 3 300 MHz (δ ppm): 7.30 (m, 1H); 7.29 (s, 1 H); 7.14 (sa, 1 H); 6.53 (m, 2H); 4.42 (c, J = 7.2 Hz, 2H); 1.59 (s, 6H); 1.51 (t, J = 7.2 Hz, 3H). 13 C NMR CDCl 3 300 MHz (δ ppm): 157.65; 154.56; 131.90; 122.16; 120.96; 108.78; 108.63; 105.83; 77.12; 46.20; 28.42; 15.30. MS (ES +) m / z = 244 ([MH] +, 100%). Anal .: C 14 H 16 N 2 O 2; Theoretical: C: 68.83%; H: 6.60%; N: 11.47%. Found: C: 68.60%; H: 6.37; N: 11.21.
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Se irradia con microondas (potencia constante de 100W) a presión atmosférica durante 10 minutos una disolución de 4,4-dimetil-1,4-dihidrocroman[4,3-c]pirazol-9-ol en EtOH (8 ml). Después se evapora el disolvente y se purifica por cromatografía sobre gel de sílice usando como eluyente Hex/AcOEt en proporción 1:1 para dar 2-(3,4-diclorofenil)-4,4-dimetil-2,4-dihidrocroman[4,3-c]pirazol-9-ol. Rto. 76% Sólido amarillo. P.f.: 262-267ºC. ^{1}H RMN DMSO 300 MHz (\delta ppm): 9,78 (sa, 1H); 7,84 (d, J = 2,4 Hz, 1H); 7,80 (d, J = 8,6 Hz, 1H); 7,65 (s, 1H); 7,49 (dd, J = 2,2 Hz, J = 8,6 Hz, 1H); 6,66 (d, J = 8,5 Hz, 1H); 6,38 (d, J = 2,3 Hz, 1H); 6,24 (dd, J = 2,4 Hz, J = 8,6 Hz, 1H); 1,54 (s, 6H). ^{13}C RMN DMSO 300 MHz (\delta ppm): 159,13; 153,82; 139,77; 135,30; 132,46; 131,78; 131,28; 131,20; 127,64; 125,96; 122,96; 121,69; 108,74; 106,20; 105,01; 76,91; 28,01. Anal.: C_{18}H_{14}Cl_{2}N_{2}O_{2}. H_{2}O; Teórico: C: 57,00%; H: 4,25%; N: 7,39%. Hallado: C: 56,63%; H: 4,20%; N: 7,08%. HPLC/EM: t_{R} = 14,47 min. (84%); MeCN + 0,08% Ac. Fórmico/H_{2}O + 0,1% Ac.Fórmico 20/80. Flujo = 0,25 mm/min; \lambda = 190-400 nm; ESI (m/z) = 361 (100%).A solution of 4,4-dimethyl-1,4-dihydrochroman [4,3-c] pyrazol-9-ol in EtOH (8 ml) is irradiated with microwave (constant power of 100W) at atmospheric pressure for 10 minutes. The solvent is then evaporated and purified by chromatography on silica gel using as eluent Hex / AcOEt in a 1: 1 ratio to give 2- (3,4-dichlorophenyl) -4,4-dimethyl-2,4-dihydrochroman [4 , 3-c] pyrazol-9-ol. Rto. 76% yellow solid. Mp: 262-267 ° C. 1 H NMR DMSO 300 MHz (δ ppm): 9.78 (sa, 1H); 7.84 (d, J = 2.4 Hz, 1H); 7.80 (d, J = 8.6 Hz, 1H); 7.65 (s, 1 H); 7.49 (dd, J = 2.2 Hz, J = 8.6 Hz, 1H); 6.66 (d, J = 8.5 Hz, 1H); 6.38 (d, J = 2.3 Hz, 1H); 6.24 (dd, J = 2.4 Hz, J = 8.6 Hz, 1H); 1.54 (s, 6H). 13 C NMR DMSO 300 MHz (δ ppm): 159.13; 153.82; 139.77; 135.30; 132.46; 131.78; 131.28; 131.20; 127.64; 125.96; 122.96; 121.69; 108.74; 106.20; 105.01; 76.91; 28.01. Anal .: C 18 H 14 Cl 2 N 2 O 2. H2O; Theoretical: C: 57.00%; H: 4.25%; N: 7.39%. Found: C: 56.63%; H: 4.20%; N: 7.08%. HPLC / MS: t R = 14.47 min. (84%); MeCN + 0.08% Ac. Formic / H2O + 0.1% Formic Ac 20/80. Flow = 0.25 mm / min; λ = 190-400 nm; ESI (m / z) = 361 (100%).
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Bajo nitrógeno se disuelve 5-(1,1-dimetilheptil)-1,3 dimetoxibenceno (0,7 mmol) en CH_{2}Cl_{2} seco a -16ºC. Después de 5 minutos se añade tribromuro de boro lentamente (1,8 mmol) a la misma temperatura. Posteriomente, se deja que la mezcla protegida de la luz y agitada alcance la temperatura ambiente. Después de 20 horas se vuelve a añadir tribromuro de boro (1,8 mmol), y ésta operación se repite durante 4 días más. Después se añade MeOH lentamente a 0ºC hasta alcanzar un pH neutro. El bruto de reacción se purifica mediante cromatografía sobre gel de sílice, obteniéndose el compuesto 5-(1,1-dimetilheptil)-benceno-1,3-diol. Rto. 73% Aceite amarillo. ^{1}H RMN CDCl_{3} 300 MHz (\delta ppm): 6,38 (m, 2H); 6,16 (m, 1H); 4,65 (sa, 2H); 1,51 (m, 2H); 1,22 (s, 6H); 1,19 (m, 6H); 1,03 (sa, 2H); 0,84 (t, J = 6,5 Hz, 3H). ^{13}C RMN CDCl_{3}300 MHz (\delta ppm): 111,23; 101,30; 45,03; 35,26; 31,13; 29,83; 25,07; 23,97; 14,82. HPLC/EM: t_{R} = 13,98 min. (90%); MeCN + 0,08% Ac. Fórmico/H_{2}O + 0,1% Ac.Fórmico 20/80. Flujo = 0,25 mm/min; \lambda = 190-400 nm; ESI (m/z) = 237 (100%).Under nitrogen, 5- (1,1-dimethylheptyl) -1,3 dimethoxybenzene (0.7 mmol) is dissolved in dry CH 2 Cl 2 at -16 ° C. After 5 minutes boron tribromide is added slowly (1.8 mmol) at the same temperature. Subsequently, the mixture protected from light and agitated is allowed to reach room temperature. After 20 hours boron tribromide (1.8 mmol) is added again, and this operation is repeated for another 4 days. Then MeOH is added slowly at 0 ° C until a neutral pH is reached. The reaction crude is purified by chromatography on silica gel, obtaining the compound 5- (1,1-dimethylheptyl) -benzene-1,3-diol. Rto. 73% Yellow oil 1 H NMR CDCl 3 300 MHz (δ ppm): 6.38 (m, 2H); 6.16 (m, 1 H); 4.65 (sa, 2H); 1.51 (m, 2 H); 1.22 (s, 6H); 1.19 (m, 6H); 1.03 (sa, 2H); 0.84 (t, J = 6.5 Hz, 3H). 13 C NMR CDCl 3 300 MHz (δ ppm): 111.23; 101.30; 45.03; 35.26; 31.13; 29.83; 25.07; 23.97; 14.82. HPLC / MS: t R = 13.98 min. (90%); MeCN + 0.08% Ac. Formic / H2O + 0.1% Formic Ac 20/80. Flow = 0.25 mm / min; λ = 190-400 nm; ESI (m / z) = 237 (100%).
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Se sintetizó siguiendo el procedimiento descrito en A del Ejemplo 1 utilizando como reactivo el 5-(1,1-dimetilheptil)-benceno-1,3-diol. Rto. 88% Aceite amarillo. ^{1}H RMN CDCl_{3} 300 MHz (\delta ppm): 6,45 (d, J = 1,62 Hz, 1H); 6,37 (d, J = 1,62 Hz, 1H); 2,71 (s, 2H); 1,55 (m, 2H); 1,46 (s, 6H); 1,22 (s, 6H); 1,19 (sa, 6H); 1,05 (sa, 2H), 0,87 (m, 3H). ^{13}C RMN CDCl_{3} 300 MHz (\delta ppm): 197,88; 163,01; 161,69; 159,96; 107,03; 106,17; 105,69; 79,12; 48,50; 40,99; 39,16; 32,12; 30,32; 28,83; 27,13; 24,98; 23, 03; 14,48. EM (ES^{+}) m/z = 318 ([MH]^{+}, 100%).It was synthesized following the procedure described in A of Example 1 using as reagent the 5- (1,1-dimethylheptyl) -benzene-1,3-diol. Rto. 88% Yellow Oil 1 H NMR CDCl 3 300 MHz (δ ppm): 6.45 (d, J = 1.62 Hz, 1H); 6.37 (d, J = 1.62 Hz, 1H); 2.71 (s, 2H); 1.55 (m, 2 H); 1.46 (s, 6H); 1.22 (s, 6H); 1.19 (sa, 6H); 1.05 (sa, 2H), 0.87 (m, 3H). 13 C NMR CDCl 3 300 MHz (δ ppm): 197.88; 163.01; 161.69; 159.96; 107.03; 106.17; 105.69; 79.12; 48.50; 40.99; 39.16; 32.12; 30.32; 28.83; 27.13; 24.98; 23, 03; 14.48. MS (ES +) m / z = 318 ([MH] +, 100%).
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Se sintetizó siguiendo el procedimiento descrito en B del Ejemplo 1 utilizando como reactivo la 7-(1,1-dimetilheptil)-5-hidroxi-2,2-dimetil-2,3-dihidrocroman-4-ona. Rto. 76% Aceite amarillo. ^{1}H RMN CDCl_{3} 300 MHz (\delta ppm): 13,48 (d, J = 11,6 Hz, 1H); 11,28 (s, 1H); 7,34 (d, J = 1,62 Hz, 1H); 6,46 (d, J = 1,62 Hz, 1H); 6,35 (d, J = 1,62 Hz, 1H); 1,58 (sa, 6H); 1,22 (sa, 6H); 1,18 (m, 6H); 1,03 (m, 2H); 0,83 (t, J = 6,7 Hz, 3H). ^{13}C RMN CDCl_{3} 300 MHz (\delta ppm): 189,84; 163,10; 162,01; 161,88; 159,09; 114,77; 107,80; 106,61; 105,25; 78,68; 44,45; 39,17; 32,1; 30,31; 28,82; 28,64; 24,98; 23,03; 14,47. HPLC/EM: t_{R} = 22,73 min. (100%); MeCN + 0,08% Ac. Fórmico/H_{2}O + 0,1% Ac.Fórmico 5/95. Flujo = 0,25 mm/min; \lambda = 190-400 nm; ESI (m/z) = 347 (100%).It was synthesized following the procedure described in B of Example 1 using as a reagent 7- (1,1-dimethylheptyl) -5-hydroxy-2,2-dimethyl-2,3-dihydrochroman-4-one. Rto. 76% Yellow Oil 1 H NMR CDCl 3 300 MHz (δ ppm): 13.48 (d, J = 11.6 Hz, 1H); 11.28 (s, 1 H); 7.34 (d, J = 1.62 Hz, 1H); 6.46 (d, J = 1.62 Hz, 1H); 6.35 (d, J = 1.62 Hz, 1H); 1.58 (sa, 6H); 1.22 (sa, 6H); 1.18 (m, 6H); 1.03 (m, 2H); 0.83 (t, J = 6.7 Hz, 3H). 13 C NMR CDCl 3 300 MHz (δ ppm): 189.84; 163.10; 162.01; 161.88; 159.09; 114.77; 107.80; 106.61; 105.25; 78.68; 44.45; 39.17; 32.1; 30.31; 28.82; 28.64; 24.98; 23.03; 14.47. HPLC / MS: t R = 22.73 min. (100%); MeCN + 0.08% Ac. Formic / H2O + 0.1% Formic Ac 5/95. Flow = 0.25 mm / min; λ = 190-400 nm; ESI (m / z) = 347 (100%).
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Se sintetizó siguiendo el procedimiento descrito en C del Ejemplo 1 utilizando como reactivo la 7-(1,1-dimetilheptil)-5-hidroxi-3-(hidroximetilen)-2,2-dimetil-2,3-dihidrocroman-4-ona. Rto. 41% Aceite naranja. ^{1}H RMN CDCl_{3} 300 MHz (\delta ppm): 7,32 (sa, 1H); 6,58 (d, J = 1,5 Hz, 1H); 6,51 (d, J = 1,5 Hz); 6,48 (s, 1H); 1,63 (sa, 6H); 1,53 (m, 2H); 1,25 (s, 6H); 1,18 (sa, 6H); 1,08 (m, 2H); 0,83 (t, J = 6,7 Hz, 3H). ^{13}C RMN CDCl_{3} 300 MHz (\delta ppm): 153,68; 153,54; 153,46; 144.12; 129,08; 123,43; 106,80; 106,53; 101,67; 77,02; 44,89; 38,45; 32,17; 30,40; 29,97; 29,26; 25,04; 23,06; 14,48. HPLC/EM: t_{R} = 18,93 min. (70%); MeCN + 0,08% Ac. Fórmico/H_{2}O + 0,1% Ac.Fórmico 20/80. Flujo = 0,25 mm/min; \lambda = 190-400 nm; ESI (m/z) = 343 (100%).It was synthesized following the procedure described in C of Example 1 using as a reagent 7- (1,1-dimethylheptyl) -5-hydroxy-3- (hydroxymethylene) -2,2-dimethyl-2,3-dihydrochroman-4-one . Rto. 41% Orange oil 1 H NMR CDCl 3 300 MHz (δ ppm): 7.32 (sa, 1H); 6.58 (d, J = 1.5 Hz, 1H); 6.51 (d, J = 1.5 Hz); 6.48 (s, 1 H); 1.63 (sa, 6H); 1.53 (m, 2 H); 1.25 (s, 6H); 1.18 (sa, 6H); 1.08 (m, 2H); 0.83 (t, J = 6.7 Hz, 3H). 13 C NMR CDCl 3 300 MHz (δ ppm): 153.68; 153.54; 153.46; 144.12; 129.08; 123.43; 106.80; 106.53; 101.67; 77.02; 44.89; 38.45; 32.17; 30.40; 29.97; 29.26; 25.04; 23.06; 14.48. HPLC / MS: t R = 18.93 min. (70%); MeCN + 0.08% Ac. Formic / H2O + 0.1% Formic Ac 20/80. Flow = 0.25 mm / min; λ = 190-400 nm; ESI (m / z) = 343 (100%).
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Se preparan el compuesto deseado según el modo de realización descrito en la etapa C del Ejemplo 1, utilizando metilhidrazina. Rto. 42%. Sólido amarillo. P.f.: superior a 310ºC ^{1}H RMN CDCl_{3} 300 MHz (\delta ppm): 8,23 (s, 1H); 7,09 (s, 1H); 6,57 (d, J = 1,6 Hz, 1H); 6,48 (d, J = 1,6 Hz, 1H); 3,90 (s, 3H); 1,63 (s, 6H); 1,59 (m, 2H); 1,24 (s, 6H); 1,18 (m, 6H); 1,06 (m, 2H); 0,83 (t, J = 6,7 Hz, 3H). ^{13}C RMN CDCl_{3} 300 MHz (\delta ppm): 152,17; 151,78; 151,56; 141,52; 122,95; 119,33; 105,52; 105,31; 100,20; 76,41; 43,50; 38,86; 38,01; 31,77; 30,00; 29,68; 28,87; 24,64; 22,65; 14,07. HPLC/EM: t_{R} = 19,73 min. (80%); MeCN + 0,08% Ac. Fórmico/H_{2}O + 0,1% Ac.Fórmico 20/80. Flujo = 0,25 mm/min; \lambda = 190-400 nm; ESI (m/z) = 343 (100%).The desired compound is prepared according to the embodiment described in step C of Example 1, using methylhydrazine. Rto. 42% Solid yellow. Mp: greater than 310 ° C 1 H NMR CDCl 3 300 MHz (δ ppm): 8.23 (s, 1H); 7.09 (s, 1 H); 6.57 (d, J = 1.6 Hz, 1H); 6.48 (d, J = 1.6 Hz, 1H); 3.90 (s, 3 H); 1.63 (s, 6H); 1.59 (m, 2 H); 1.24 (s, 6H); 1.18 (m, 6H); 1.06 (m, 2H); 0.83 (t, J = 6.7 Hz, 3H). 13 C NMR CDCl 3 300 MHz (δ ppm): 152.17; 151.78; 151.56; 141.52; 122.95; 119.33; 105.52; 105.31; 100.20; 76.41; 43.50; 38.86; 38.01; 31.77; 30.00; 29.68; 28.87; 24.64; 22.65; 14.07. HPLC / MS: t R = 19.73 min. (80%); MeCN + 0.08% Ac. Formic / H2O + 0.1% Formic Ac 20/80. Flow = 0.25 mm / min; λ = 190-400 nm; ESI (m / z) = 343 (100%).
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Ejemplo 9 y Ejemplo 10Example 9 and Example 10
yY
Se preparan los compuestos deseados según el modo de realización descrito en la etapa C del Ejemplo 1, utilizando etilhidrazina. Dos isómeros se forman y se separan por cromatografía sobre silica gel.The desired compounds are prepared according to embodiment described in step C of Example 1, using ethylhydrazine Two isomers are formed and separated by chromatography on silica gel.
4,4-Dimetil-7-(1,1-dimetilheptil)-1-etil-1,4-dihidrocroman[3,4-d]pirazol-9-ol (Ejemplo 9). Rto. 18% Aceite amarillo. ^{1}H RMN CDCl_{3} 300 MHz (\delta ppm): 8,77 (sa, 1H); 7,37 (s, 1H); 6,58 (dd, J = 1,6 Hz, J = 7,1 Hz, 2H); 4,67 (q, J = 7,1 Hz, 2H); 1,57 (s, 6H); 1,52 (m, 2H); 1,44 (t, J = 7,1 Hz, 3H); 1,23 (s, 6H); 1,17 (sa, 6H); 1.07 (sa, 2H); 0,818 (m, 3H). ^{13}C RMN CDCl_{3} 300 MHz (\delta ppm): 154,65; 153,10; 151,67; 133,11; 132,24; 123,42; 108,83; 107,96; 103,23; 76,66; 48,38; 44,80; 38,15; 32,14; 30,36; 29,05; 27,67; 25,01; 23,01; 16,35; 14,45. HPLC/EM: t_{R} = 20,46 min. (90%); MeCN + 0,08% Ac. Fórmico/H_{2}O + 0,1% Ac.Fórmico 5/95. Flujo = 0,25 mm/min; \lambda = 190-400 nm; ESI (m/z) = 371 (100%). 4,4-Dimethyl-7- (1,1-dimethylheptyl) -1-ethyl-1,4-dihydrochroman [3,4-d] pyrazol-9-ol (Example 9). Rto. 18% yellow oil. 1 H NMR CDCl 3 300 MHz (δ ppm): 8.77 (sa, 1H); 7.37 (s, 1 H); 6.58 (dd, J = 1.6 Hz, J = 7.1 Hz, 2H); 4.67 (q, J = 7.1 Hz, 2H); 1.57 (s, 6H); 1.52 (m, 2 H); 1.44 (t, J = 7.1 Hz, 3H); 1.23 (s, 6H); 1.17 (sa, 6H); 1.07 (sa, 2H); 0.818 (m, 3H). 13 C NMR CDCl 3 300 MHz (δ ppm): 154.65; 153.10; 151.67; 133.11; 132.24; 123.42; 108.83; 107.96; 103.23; 76.66; 48.38; 44.80; 38.15; 32.14; 30.36; 29.05; 27.67; 25.01; 23.01; 16.35; 14.45. HPLC / MS: t R = 20.46 min. (90%); MeCN + 0.08% Ac. Formic / H2O + 0.1% Formic Ac 5/95. Flow = 0.25 mm / min; λ = 190-400 nm; ESI (m / z) = 371 (100%).
4,4-Dimetil-7-(1,1-dimetilheptil)-2-etil-2,4-dihidrocroman[4,3-c]pirazol-9-ol (Ejemplo 10). Rto. 61% Sólido blanco. P.f.: 160-164ºC. ^{1}H RMN CDCl_{3} 300 MHz (\delta ppm): 8,32 (s, 1H); 7,13 (s, 1H); 6,57 (d, J = 1,5 Hz, 1H); 6,48 (s, 1H, J = 1,5 Hz); 4,16 (c, 2H, J = 7,2 Hz); 1,60 (s, 6H); 1,56 (sa, 2H); 1,50 (t, J = 7,3 Hz, 2H); 1,24 (s, 6H); 1,17 (sa, 6H); 0,97 (m, 2H); 0,82 (m, 3H). ^{13}C RMN CDCl_{3} 300 MHz (\delta ppm): 153,58; 153,20; 152,88; 142,72; 122,78; 120,32; 106,94; 106,70; 101,73; 76,40; 47,40; 44,94; 32,18; 30,41; 30,08; 29,30; 25,02; 23,06; 15,90; 14,48. HPLC/EM: t_{R} = 20,14 min. (100%); MeCN + 0,08% Ac. Fórmico/H_{2}O + 0,1% Ac.Fórmico 5/95. Flujo = 0,25 mm/min; \lambda = 190-400 nm; ESI (m/z) = 371 (100%). 4,4-Dimethyl-7- (1,1-dimethylheptyl) -2-ethyl-2,4-dihydrochroman [4,3-c] pyrazol-9-ol (Example 10). Rto. 61% White solid. Mp: 160-164 ° C. 1 H NMR CDCl 3 300 MHz (δ ppm): 8.32 (s, 1H); 7.13 (s, 1 H); 6.57 (d, J = 1.5 Hz, 1H); 6.48 (s, 1H, J = 1.5 Hz); 4.16 (c, 2H, J = 7.2 Hz); 1.60 (s, 6H); 1.56 (sa, 2 H); 1.50 (t, J = 7.3 Hz, 2H); 1.24 (s, 6H); 1.17 (sa, 6H); 0.97 (m, 2H); 0.82 (m, 3H). 13 C NMR CDCl 3 300 MHz (δ ppm): 153.58; 153.20; 152.88; 142.72; 122.78; 120.32; 106.94; 106.70; 101.73; 76.40; 47.40; 44.94; 32.18; 30.41; 30.08; 29.30; 25.02; 23.06; 15.90; 14.48. HPLC / MS: t R = 20.14 min. (100%); MeCN + 0.08% Ac. Formic / H2O + 0.1% Formic Ac 5/95. Flow = 0.25 mm / min; λ = 190-400 nm; ESI (m / z) = 371 (100%).
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Se preparan el compuesto deseado según el modo de realización descrito en la etapa C del Ejemplo 1, utilizando 3,4-diclorofenilhidrazina. Rto. 40% Sólido naranja. ^{1}H RMN CDCl_{3} 300 MHz (\delta ppm): 7,65 (d, J = 2,2 Hz); 7,50 (s, 1H); 7,43 (d, J = 8,5 Hz, 1H); 7,25 (dd, J = 2,3 Hz, J = 8,5 Hz, 1H); 6,66 (d, J = 1,6 Hz, 1H); 6,24 (d, J = 1,68 Hz, 1H); 1,68 (s, 6H); 1,56 (m, 2H); 1,22 (s, 6H); 1,20 (m, 6H); 1,04 (m, 2H); 0,84 (t, J = 6,5 Hz, 3H). ^{13}C RMN CDCl_{3} 300 MHz (\delta ppm): 154,58; 153,96; 150,02; 142,34; 135,29; 133,16; 132,66; 130,36; 126,46; 125,41; 123,91; 109,61; 108,04; 102,43; 76,25; 44,72; 38,27; 32,12; 30,28; 28,83; 27,67; 24,97; 22,99; 14,47. HPLC/EM: t_{R} = 21,17 min. (96%); MeCN + 0,08% Ac. Fórmico/H_{2}O + 0,1% Ac.Fórmico 20/80. Flujo = 0,25 mm/min; \lambda = 190-400 nm; ESI (m/z) = 487 (100%).The desired compound is prepared according to the embodiment described in step C of Example 1, using 3,4-dichlorophenylhydrazine. Rto. 40% orange solid. 1 H NMR CDCl 3 300 MHz (δ ppm): 7.65 (d, J = 2.2 Hz); 7.50 (s, 1 H); 7.43 (d, J = 8.5 Hz, 1H); 7.25 (dd, J = 2.3 Hz, J = 8.5 Hz, 1H); 6.66 (d, J = 1.6 Hz, 1H); 6.24 (d, J = 1.68 Hz, 1H); 1.68 (s, 6H); 1.56 (m, 2 H); 1.22 (s, 6H); 1.20 (m, 6H); 1.04 (m, 2H); 0.84 (t, J = 6.5 Hz, 3H). 13 C NMR CDCl 3 300 MHz (δ ppm): 154.58; 153.96; 150.02; 142.34; 135.29; 133.16; 132.66; 130.36; 126.46; 125.41; 123.91; 109.61; 108.04; 102.43; 76.25; 44.72; 38.27; 32.12; 30.28; 28.83; 27.67; 24.97; 22.99; 14.47. HPLC / MS: t R = 21.17 min. (96%); MeCN + 0.08% Ac. Formic / H2O + 0.1% Formic Ac 20/80. Flow = 0.25 mm / min; λ = 190-400 nm; ESI (m / z) = 487 (100%).
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Se preparan el compuesto deseado según el modo de realización descrito en la etapa C del Ejemplo 1, utilizando 2,4-diclorofenilhidrazina. Rto. 75% Aceite naranja. ^{1}H RMN CDCl_{3} 300 MHz (\delta ppm): 7,43 (s, 1H); 7,39 (d, J = 2,1 Hz, 1H); 7,27 (dd, J = 2,2 Hz, J = 8,7 Hz, 1H); 7,21 (d, J = 8,7 Hz, 1H); 6,56 (d, J = 1,7 Hz, 1H); 6,12 (d, J = 1,6 Hz, 1H); 1,64 (s, 3H); 1,44 (m, 2H); 1,16 (m, 6H); 1,14 (s, 3H); 1,02 (m, 2H); 0,82 (t, J = 6,9 Hz, 3H). ^{13}C RMN CDCl_{3} 300 MHz (\delta ppm): 154, 27; 153,56; 151,29; 140,29; 135,28; 135,00; 134,41; 132,97; 129,76; 129,60; 127,29; 123,42; 108,77; 107,56; 102,62. HPLC/EM: t_{R} = 18,99 min. (100%); MeCN + 0,08% Ac. Fórmico/H_{2}O + 0,1% Ac. Fórmico 5/95. Flujo = 0,25 mm/min; \lambda = 190-400 nm; ESI (m/z) = 487 (100%).The desired compound is prepared according to the embodiment described in step C of Example 1, using 2,4-dichlorophenylhydrazine. Rto. 75% Orange oil 1 H NMR CDCl 3 300 MHz (δ ppm): 7.43 (s, 1H); 7.39 (d, J = 2.1 Hz, 1H); 7.27 (dd, J = 2.2 Hz, J = 8.7 Hz, 1H); 7.21 (d, J = 8.7 Hz, 1H); 6.56 (d, J = 1.7 Hz, 1H); 6.12 (d, J = 1.6 Hz, 1H); 1.64 (s, 3 H); 1.44 (m, 2 H); 1.16 (m, 6H); 1.14 (s, 3 H); 1.02 (m, 2H); 0.82 (t, J = 6.9 Hz, 3H). 13 C NMR CDCl 3 300 MHz (δ ppm): 154, 27; 153.56; 151.29; 140.29; 135.28; 135.00; 134.41; 132.97; 129.76; 129.60; 127.29; 123.42; 108.77; 107.56; 102.62. HPLC / MS: t R = 18.99 min. (100%); MeCN + 0.08% Ac. Formic / H2O + 0.1% Ac. Formic 5/95. Flow = 0.25 mm / min; λ = 190-400 nm; ESI (m / z) = 487 (100%).
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En la presente invención se valoró la actividad cannabinoide de los compuestos de fórmula (I) llevando a cabo ensayos in vitro de desplazamiento del radioligando cannabinoide [^{3}H]-CP55940 (10 \muM) y [^{3}H]-WIN 55,212-2 (50 \muM) en células transfectadas por los receptores humanos CB1 o CB2. A continuación se proporcionan porcentajes de desplazamientos de [3H]-WIN 55,212-2 a modo de ilustración de los receptores CB1 y CB2:In the present invention, the cannabinoid activity of the compounds of formula (I) was evaluated by carrying out in vitro assays of cannabinoid radioligand displacement [3 H] -CP55940 (10 µM) and [3 H] -WIN 55,212-2 (50 µM) in cells transfected by human CB1 or CB2 receptors. The following are percentages of displacements of [3H] -WIN 55,212-2 by way of illustration of the CB1 and CB2 receptors:
- --
- 4,4-dimetil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol (Ejemplo 1) 27% (CB1), 21% (CB2);4,4-dimethyl-1,4-dihydrochromen [3,4- d ] pyrazol-9-ol (Example 1) 27% (CB1), 21% (CB2);
- --
- 2,4,4-trimetil-2,4-dihidrocroman[4,3-c]pirazol-9-ol (Ejemplo 2) 25% (CB1), 61% (CB2);2,4,4-trimethyl-2,4-dihydrochroman [4,3- c ] pyrazol-9-ol (Example 2) 25% (CB1), 61% (CB2);
- --
- 1,4,4-trimetil-1,4-dihidrocroman[3,4-d]pirazol-9-ol (Ejemplo 3) 23% (CB1), 50% (CB2);1,4,4-trimethyl-1,4-dihydrochroman [3,4- d ] pyrazol-9-ol (Example 3) 23% (CB1), 50% (CB2);
- --
- 2-etil-4,4-dimetil-2,4-dihidrocromeno[4,3-c]pirazol-9-ol (Ejemplo 4) 23% (CB1), 48% (CB2);2-ethyl-4,4-dimethyl-2,4-dihydrochromen [4,3- c ] pyrazol-9-ol (Example 4) 23% (CB1), 48% (CB2);
- --
- 1-etil-4,4-dimetil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol (Ejemplo 5) 57% (CB1), 38% (CB2);1-ethyl-4,4-dimethyl-1,4-dihydrochromen [3,4- d ] pyrazol-9-ol (Example 5) 57% (CB1), 38% (CB2);
- --
- 1-(3,4-diclorofenil)-4,4-dimetil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol (Ejemplo 6) 14% (CB1), 36%(CB2);1- (3,4-Dichlorophenyl) -4,4-dimethyl-1,4-dihydrochromen [3,4- d ] pyrazol-9-ol (Example 6) 14% (CB1), 36% (CB2);
- --
- 4,4-dimetil-7-(1,1-dimetilheptil)-1,4-dihidrocromeno[3,4-d]pirazol-9-ol (Ejemplo 7) 100% (CB1), 30% (CB2);4,4-dimethyl-7- (1,1-dimethylheptyl) -1,4-dihydrochromen [3,4- d ] pyrazol-9-ol (Example 7) 100% (CB1), 30% (CB2);
- --
- 7-(1,1-dimetilheptil)-2,414-trimetil-2,4-dihidrocromeno[4,3-c]pirazol-9-ol (Ejemplo 8) 98% (CB1), 11% (CB2);7- (1,1-dimethylheptyl) -2,414-trimethyl-2,4-dihydrochromen [4,3- c ] pyrazol-9-ol (Example 8) 98% (CB1), 11% (CB2);
- --
- 4,4-dimetil-7-(1,1 -dimetilheptil)-1-etil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol (Ejemplo 9) 96% (CB1), 56% (CB2);4,4-dimethyl-7- (1,1-dimethylheptyl) -1-ethyl-1,4-dihydrochromen [3,4- d ] pyrazol-9-ol (Example 9) 96% (CB1), 56% ( CB2);
- --
- 4,4-dimetil-7-(1,1-dimetilheptil)-2-etil-2,4-dihidrocromeno[4,3-c]pirazol-9-ol (Ejemplo 10) 99% (CB1), 44% (CB2);4,4-dimethyl-7- (1,1-dimethylheptyl) -2-ethyl-2,4-dihydrochromen [4,3- c ] pyrazol-9-ol (Example 10) 99% (CB1), 44% ( CB2);
- --
- 1-(3,4-diclorofenil)-4,4-dimetil-7-(1,1-dimetilheptil)-1,4-dihidrocromeno[3,4-d]pirazol-9-ol (Ejemplo 11) 89% (CB1), 65% (CB2);1- (3,4-Dichlorophenyl) -4,4-dimethyl-7- (1,1-dimethylheptyl) -1,4-dihydrochromen [3,4- d ] pyrazol-9-ol (Example 11) 89% ( CB1), 65% (CB2);
- --
- 1-(2,4-diclorofenil)-4,4-dimetil-7-(1,1-dimetilheptil)-1,4-dihidrocromeno[3,4-d]pirazol-9-ol (Ejemplo 12) 98% (CB1), 5% (CB2);1- (2,4-Dichlorophenyl) -4,4-dimethyl-7- (1,1-dimethylheptyl) -1,4-dihydrochromen [3,4- d ] pyrazol-9-ol (Example 12) 98% ( CB1), 5% (CB2);
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Los compuestos ejemplos de la presente invención con un desplazamiento superior a 90% exhiben una afinidad por el receptor CB1 con valores de K_{i} nanomolares (K_{i} = 5-100 nM).The compound examples of the present invention with a displacement greater than 90% exhibit an affinity for CB1 receptor with nanomolar Ki values (Ki = 5-100 nM).
Claims (13)
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- \bullet?
- R^{1} se selecciona entre hidrógeno o alquilo C_{6}-C_{18}R1 is selected from hydrogen or C 6 -C 18 alkyl
- \bullet?
- R^{2} se selecciona entre hidrógeno o alquilo o arilo sustituido o sin sustituir.R2 is selected from hydrogen or substituted or unsubstituted alkyl or aryl.
- \bullet?
- R^{3} se selecciona entre hidrógeno o alquilo.R3 is selected from hydrogen or alkyl.
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- --
- 4,4-dimetil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol4,4-dimethyl-1,4-dihydrochromen [3,4- d ] pyrazol-9-ol
- --
- 2,4,4-trimetil-2,4-dihidrocromeno[4,3-c]pirazol-9-ol2,4,4-trimethyl-2,4-dihydrochromen [4,3- c ] pyrazol-9-ol
- --
- 1,4,4-trimetil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol1,4,4-trimethyl-1,4-dihydrochromen [3,4- d ] pyrazol-9-ol
- --
- 4,4-dimetil-2-etil-2,4-dihidrocromeno[4,3-c]pirazol-9-ol4,4-dimethyl-2-ethyl-2,4-dihydrochromen [4,3- c ] pyrazol-9-ol
- --
- 4,4-dimetil-1-etil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol4,4-dimethyl-1-ethyl-1,4-dihydrochromen [3,4- d ] pyrazol-9-ol
- --
- 1-(3,4-diclorofenil)-4,4-dimetil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol1- (3,4-dichlorophenyl) -4,4-dimethyl-1,4-dihydrochromen [3,4- d ] pyrazol-9-ol
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- --
- 4,4-dimetil -7-(1,1-dimetilheptil)-1,4-dihidrocromeno[3,4-d]pirazol-9-ol4,4-dimethyl -7- (1,1-dimethylheptyl) -1,4-dihydrochromen [3,4- d ] pyrazol-9-ol
- --
- 7-(1,1-dimetilheptil)-2,4,4-trimetil-2,4-dihidrocromeno[4,3-c]pirazol-9-ol7- (1,1-dimethylheptyl) -2,4,4-trimethyl-2,4-dihydrochromen [4,3- c ] pyrazol-9-ol
- --
- 4,4-dimetil -7-(1,1-dimetilheptil)-1-etil-1,4-dihidrocromeno[3,4-d]pirazol-9-ol4,4-dimethyl -7- (1,1-dimethylheptyl) -1-ethyl-1,4-dihydrochromen [3,4- d ] pyrazol-9-ol
- --
- 4,4-dimetil-7-(1,1-dimetilheptil)-2-etil-2,4-dihidrocromeno[4,3-c]pirazol-9-ol4,4-dimethyl-7- (1,1-dimethylheptyl) -2-ethyl-2,4-dihydrochromen [4,3- c ] pyrazol-9-ol
- --
- 1-(3,4-diclorofenil)-4,4-dimetil -7-(1,1-dimetilheptil)-1,4-dihidrocromeno[3,4-d]pirazol-9-ol1- (3,4-Dichlorophenyl) -4,4-dimethyl -7- (1,1-dimethylheptyl) -1,4-dihydrochromen [3,4- d ] pyrazol-9-ol
- --
- 1-(2,4-diclorofenil)-4,4-dimetil-7-(1,1-dimetilheptil)-1,4-dihidrocromeno[3,4-d]pirazol-9-ol.1- (2,4-Dichlorophenyl) -4,4-dimethyl-7- (1,1-dimethylheptyl) -1,4-dihydrochromen [3,4- d ] pyrazol-9-ol.
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- a)to)
- reacción aldólica entre una 7-alquil-5-hidroxi-2,2-dimetil-2,3-dihidrocroman-4-ona y formiato de etilo dando lugar a la formación de una 7-alquil-5-hidroxi-3-hidroximetilen-2,2-dimetil-2,3-dihidrocroman-4-ona; yaldol reaction between a 7-alkyl-5-hydroxy-2,2-dimethyl-2,3-dihydrochroman-4-one and ethyl formate resulting in the formation of a 7-alkyl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-2,3-dihydrochroman-4-one; Y
- b)b)
- reacción de 7-alquil-5-hidroxi-3-hidroximetilen-2,2-dimetil-2,3-dihidrocroman-4-ona con una hidracina para formar el ciclo pirazólico.reaction of 7-alkyl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-2,3-dihydrochroman-4-one with a hydrazine to form the pyrazolic cycle.
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| ES2345592B1 (en) | 2011-07-21 |
| WO2010109050A1 (en) | 2010-09-30 |
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