ES2326357A1 - Amorphous phase of a substituted pyrazoline, its preparation and use as medicament - Google Patents
Amorphous phase of a substituted pyrazoline, its preparation and use as medicament Download PDFInfo
- Publication number
- ES2326357A1 ES2326357A1 ES200850020A ES200850020A ES2326357A1 ES 2326357 A1 ES2326357 A1 ES 2326357A1 ES 200850020 A ES200850020 A ES 200850020A ES 200850020 A ES200850020 A ES 200850020A ES 2326357 A1 ES2326357 A1 ES 2326357A1
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- cancer
- disorders
- chlorophenyl
- dichlorophenyl
- Prior art date
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
-
- 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
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
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Fase amorfa de una pirazolina sustituida, su preparación y su uso como medicamento.Amorphous phase of a substituted pyrazoline, its Preparation and its use as a medicine.
La presente invención se refiere a una fase amorfa de una pirazolina sustituida, métodos para su preparación, medicamentos que comprenden el compuesto, así como su uso para la preparación de un medicamento para el tratamiento de seres humanos y animales.The present invention relates to a phase amorphous of a substituted pyrazoline, methods for its preparation, medicines comprising the compound, as well as its use for preparation of a medicament for the treatment of human beings And animals.
Los cannabinoides son compuestos que se derivan de la planta Cannabis sativa que se conoce comúnmente como marihuana. El compuesto químico más activo de los cannabinoides naturales es el tetrahidrocannabinol (THC), particularmente el \Delta^{9}-THC.Cannabinoids are compounds that are derived from the Cannabis sativa plant that is commonly known as marijuana. The most active chemical compound of natural cannabinoids is tetrahydrocannabinol (THC), particularly Δ9 -THC.
Estos cannabinoides naturales, además de sus análogos sintéticos, potencian sus efectos fisiológicos por medio de la unión a receptores acoplados a proteína G específicos, los denominados receptores de cannabinoides.These natural cannabinoids, in addition to their synthetic analogs, enhance their physiological effects through of binding to specific G-protein coupled receptors, the called cannabinoid receptors.
En la actualidad, se han identificado y clonado dos tipos diferenciados de receptores que se unen tanto a los cannabinoides naturales como a los sintéticos. Estos receptores, que se designan CB_{1} y CB_{2}, participan en una variedad de procesos fisiológicos o patofisiológicos en seres humanos y animales, por ejemplo, procesos relacionados con el sistema nervioso central, el sistema inmunitario, el sistema cardiovascular, el sistema endocrino, el sistema respiratorio, el tracto gastrointestinal o con la reproducción, tal como se describe por ejemplo, en Hollister, Pharm. Rev. 38, 1986, 1-20; Reny y Singha, Prog. Drug. Res., 36, 71-114, 1991; Consroe y Sandyk, en Marijuana/Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. y Barthe A. Eds., CRC Press, 1992.Currently, they have been identified and cloned two different types of receptors that bind both to natural cannabinoids as synthetic. These receivers, which are designated CB_ {1} and CB_ {2}, participate in a variety of physiological or pathophysiological processes in humans and animals, for example, system related processes central nervous, the immune system, the cardiovascular system, the endocrine system, the respiratory system, the tract gastrointestinal or with reproduction, as described by example, in Hollister, Pharm. Rev. 38, 1986, 1-20; Reny and Singha, Prog. Drug. Res., 36, 71-114, 1991; Consroe and Sandyk, in Marijuana / Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds., CRC Press, 1992.
Por tanto, los compuestos que tienen una alta afinidad de unión por estos receptores de cannabinoides y que son adecuados para modular estos receptores son útiles en la prevención y/o el tratamiento de trastornos relacionados con los receptores de cannabinoides.Therefore, compounds that have a high binding affinity for these cannabinoid receptors and that are suitable for modulating these receptors are useful in prevention and / or the treatment of disorders related to recipients of cannabinoids
En particular, el receptor CB_{1} participa en muchos trastornos diferentes relacionados con la ingestión de alimentos, tales como bulimia u obesidad, incluyendo obesidad asociada con la diabetes tipo II (diabetes no insulinodependiente) y por tanto, pueden utilizarse compuestos adecuados para regular este receptor en la profilaxis y/o el tratamiento de estos trastornos.In particular, the CB_ {1} receiver participates in many different disorders related to ingestion of foods, such as bulimia or obesity, including obesity associated with type II diabetes (non-insulin dependent diabetes) and therefore, suitable compounds can be used to regulate this receptor in the prophylaxis and / or treatment of these disorders.
Por tanto, un objeto de la presente invención fue proporcionar compuestos novedosos para su uso como principios activos en medicamentos. En particular, estos principios activos deben ser adecuados para la modulación de los receptores de cannabinoides, más particularmente para la modulación de los receptores de cannabinoides 1 (CB_{1}).Therefore, an object of the present invention was to provide novel compounds for use as principles Medication assets In particular, these active ingredients must be suitable for the modulation of the receptors of cannabinoids, more particularly for the modulation of cannabinoid 1 receptors (CB1).
Dicho objeto se consiguió proporcionando la fase amorfa del compuesto de piperidinil-pirazolina facilitado a continuación.Said object was achieved by providing the phase amorphous of the piperidinyl-pyrazoline compound provided below.
Se ha encontrado que estos compuestos tienen un alta afinidad por los receptores de cannabinoides, particularmente para el receptor CB_{1}, y que actúan como moduladores, por ejemplo, antagonistas, agonistas inversos o agonistas de estos receptores. Por tanto, son adecuados para la profilaxis y/o el tratamiento de diversos trastornos relacionados con el sistema nervioso central, el sistema inmunitario, el sistema cardiovascular, el sistema endocrino, el sistema respiratorio, el tracto gastrointestinal o con la reproducción en seres humanos y/o animales, preferiblemente en seres humanos incluyendo lactantes, niños y personas mayores.It has been found that these compounds have a high affinity for cannabinoid receptors, particularly for the CB1 receptor, and acting as modulators, by example, antagonists, inverse agonists or agonists of these receivers Therefore, they are suitable for prophylaxis and / or treatment of various system related disorders central nervous, immune system, system cardiovascular, endocrine system, respiratory system, gastrointestinal tract or with reproduction in humans and / or animals, preferably in humans including infants, Children and seniors.
Así, en uno de sus aspectos la presente invención se refiere a la fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida.Thus, in one of its aspects this invention refers to the amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxamide.
Un aspecto de la presente invención es la fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida, que muestra una transición vítrea en el análisis por DSC a 62 \pm 2ºC.An aspect of the present invention is the phase amorphous of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide, which shows a glass transition in the analysis by DSC to 62 ± 2 ° C.
Un aspecto de la presente invención es la fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida, que muestra en el espectro de FTIR picos a 1475 \pm 5 cm^{-1} y/o 1089 \pm 5 cm^{-1}, mientras que carece de un pico y/o picos a 1515 \pm 5 y/o 837 \pm 5 y/o 658 \pm 5 cm^{-1}. Preferiblemente, la fase amorfa muestra ambos picos o carece de los 3 picos, más preferiblemente, la fase amorfa muestra ambos picos y carece de los 3 picos.An aspect of the present invention is the phase amorphous of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide, showing in the spectrum of FTIR peaks at 1475 ± 5 cm -1 and / or 1089 ± 5 cm -1, while lacking a peak and / or peaks at 1515 ± 5 and / or 837 ± 5 and / or 658 ± 5 cm -1. Preferably, the amorphous phase shows both peaks or lacks the 3 peaks, more preferably, the amorphous phase shows both peaks and It lacks the 3 peaks.
La fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida, caracterizada porque muestra en el espectro de FTRaman bandas a 3067 \pm 5 cm^{-1} y/o 2940 \pm 5 cm^{-1} y/o 1667 \pm 5 cm^{-1} y/o 1589 \pm 5 cm^{-1} y/o 1392 \pm 5 cm^{-1} y/o 1242 \pm 5 cm^{-1} y/o 1090 \pm 5 cm^{-1} y/o 781 \pm 5 cm^{-1} y/o 662 \pm 5 cm^{-1}. Preferiblemente la fase amorfa muestra 2 de las bandas, más preferiblemente 4 de las bandas, de manera más preferida todas las bandas.The amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide, characterized in that it shows in the spectrum of FTRaman bands at 3067 ± 5 cm -1 and / or 2940 ± 5 cm -1 and / or 1667 ± 5 cm -1 and / or 1589 ± 5 cm -1 and / or 1392 ± 5 cm -1 and / or 1242 ± 5 cm -1 and / or 1090 ± 5 cm -1 and / or 781 ± 5 cm -1 and / or 662 ± 5 cm -1. Preferably the amorphous phase shows 2 of the bands, more preferably 4 of the bands, of most preferred way all bands.
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Es altamente preferido si la fase amorfa muestra la transición vítrea y los picos de FTIR, o bien, la transición vítrea y las bandas de FTRaman, o bien, los picos de FTIR y las bandas de FTRaman, más preferiblemente si muestra la transición vítrea, las bandas de FTRaman y los picos de FTIR.It is highly preferred if the amorphous phase shows the glass transition and the FTIR peaks, or the transition vitreous and the bands of FTRaman, or, the peaks of FTIR and the FTRaman bands, more preferably if it shows the transition vitreous, FTRaman bands and FTIR peaks.
En otro aspecto, la presente invención también proporciona un procedimiento para la preparación de la fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida, según el cual al menos un compuesto de benzaldehído de fórmula general IIIn another aspect, the present invention also provides a procedure for the preparation of the amorphous phase from (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide, according to which at least one benzaldehyde compound of formula general II
- \quadquad
- se hace reaccionar con un compuesto de piruvato de fórmula (III)it is reacted with a pyruvate compound of formula (III)
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- en la que G representa un grupo OR, siendo R un radical alquilo C_{1-6} ramificado o no ramificado, o G representa un grupo O^{-}K siendo K un catión, para dar un compuesto de fórmula (IV)in which G represents an OR group, where R is a C 1-6 alkyl radical branched or not branched, or G represents a group O - K with K being a cation, to give a compound of formula (IV)
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- que opcionalmente se aísla y/u opcionalmente se purifica, y que se hace reaccionar con una fenilhidrazina opcionalmente sustituida de fórmula (V)which is optionally isolated and / or optionally purifies, and that is reacted with a phenylhydrazine optionally substituted of formula (V)
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- o con una sal correspondiente de la misma, bajo atmósfera inerte, para dar un compuesto de fórmula (VI)or with a corresponding salt thereof, under inert atmosphere, to give a compound of formula (VI)
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- que opcionalmente se aísla y/u opcionalmente se purifica, y se transfiere opcionalmente bajo una atmósfera inerte a un compuesto de fórmula (VII) por medio de la reacción con un agente activantewhich is optionally isolated and / or optionally purifies, and is optionally transferred under an inert atmosphere to a compound of formula (VII) by reaction with a activating agent
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- en la que A representa un grupo saliente, aislándose opcionalmente y/o purificándose opcionalmente dicho compuesto, y al menos un compuesto de fórmula general (VII) se hace reaccionar con un compuesto de fórmulain which A represents a leaving group, isolating optionally and / or optionally purifying said compound, and at least one compound of general formula (VII) is reacted with a compound of formula
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- bajo atmósfera inerte para dar (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida, que opcionalmente se aísla y/u opcionalmente se purifica,under inert atmosphere to give (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide, which is optionally isolated and / or optionally purify,
- \quadquad
- seguido por una etapa de fusión en la que la (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida se funde y posteriormente una etapa de enfriamiento, en la que la masa fundida se enfría hasta temperatura ambiente (25ºC) o inferior, para dar la fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida.followed by a fusion stage in which the (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide a cooling stage is subsequently melted, in which the melt is cooled to room temperature (25 ° C) or lower, to give the amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxamide.
Se prefiere que la temperatura utilizada para la fusión en la etapa de fusión esté entre 185 y 205ºC, preferiblemente entre 190 y 200ºC.It is preferred that the temperature used for the melting in the melting stage is between 185 and 205 ° C, preferably between 190 and 200 ° C.
También se prefiere que la temperatura utilizada en la etapa de enfriamiento esté alrededor o por debajo de 0ºC.It is also preferred that the temperature used in the cooling stage it is around or below 0 ° C
La reacción del compuesto de benzaldehído de fórmula II con un compuesto de piruvato de fórmula III se lleva a cabo preferiblemente en presencia de al menos una base, más preferiblemente en presencia de un hidróxido de metal alcalino, tal como hidróxido de sodio o hidróxido de potasio o un metóxido de metal alcalino, tal como metóxido de sodio, como se describe, por ejemplo, en Synthetic communications, 26(11), 2229-33, (1996). La descripción respectiva se incorpora como referencia al presente documento y forma parte de la descripción. Preferiblemente, puede utilizarse piruvato de sodio como el compuesto de piruvato. Preferiblemente, dicha reacción se lleva a cabo en un medio de reacción prótico tal como un alcohol alquílico C_{1-4} o mezclas de estos. También pueden utilizarse mezclas de tales alcoholes con agua, por ejemplo, etanol/agua.The reaction of the benzaldehyde compound of formula II with a pyruvate compound of formula III is brought to preferably carried out in the presence of at least one base, plus preferably in the presence of an alkali metal hydroxide, such such as sodium hydroxide or potassium hydroxide or a methoxide of alkali metal, such as sodium methoxide, as described, by example, in Synthetic communications, 26 (11), 2229-33, (1996). The respective description is incorporates as reference to this document and is part of the description. Preferably, sodium pyruvate can be used as the pyruvate compound. Preferably, said reaction is carried out in a protic reaction medium such as an alcohol C 1-4 alkyl or mixtures thereof. Too mixtures of such alcohols with water can be used, for example, ethanol / water
La temperatura de reacción, así como la duración de la reacción, puede variar en un amplio intervalo. Las temperaturas de reacción preferidas oscilan desde -10ºC hasta el punto de ebullición del medio de reacción. Los tiempos de reacción adecuados pueden variar, por ejemplo, desde varios minutos hasta varias horas.The reaction temperature as well as the duration of the reaction, it can vary over a wide range. The Preferred reaction temperatures range from -10 ° C to boiling point of the reaction medium. Reaction times suitable may vary, for example, from several minutes to several hours.
También se prefiere llevar a cabo la reacción del compuesto de benzaldehído de fórmula II con un compuesto de piruvato de fórmula III en condiciones catalizadas por ácido, más preferiblemente llevando a reflujo la mezcla en diclorometano en presencia de trifluorometanosulfonato de cobre (II) tal como se describe, por ejemplo, en Synlett, (1), 147-149, 2001. La descripción respectiva se incorpora como referencia al presente documento y forma parte de la descripción.It is also preferred to carry out the reaction. of the benzaldehyde compound of formula II with a compound of pyruvate of formula III under acid catalyzed conditions, plus preferably refluxing the mixture in dichloromethane in presence of copper (II) trifluoromethanesulfonate as describes, for example, in Synlett, (1), 147-149, 2001. The respective description is incorporated as a reference to the present document and form part of the description.
La reacción del compuesto de fórmula (IV) con una fenilhidrazina sustituida de fórmula (V) se lleva a cabo preferiblemente en un medio de reacción adecuado, tal como alcoholes o éteres C_{1-4}, tales como dioxano o tetrahidrofurano o mezclas de al menos dos de estos compuestos anteriormente mencionados. También preferiblemente, dicha reacción puede llevarse a cabo en presencia de un ácido, mediante lo cual el ácido puede ser orgánico, tal como ácido acético y/o inorgánico, tal como ácido clorhídrico. Además, la reacción también puede llevarse a cabo en presencia de una base, tal como piperidina, piperazina, hidróxido de sodio, hidróxido de potasio, metóxido de sodio o etóxido de sodio, o también puede utilizarse una mezcla de al menos dos de estas bases.The reaction of the compound of formula (IV) with a substituted phenylhydrazine of formula (V) is carried out preferably in a suitable reaction medium, such as C 1-4 alcohols or ethers, such as dioxane or tetrahydrofuran or mixtures of at least two of these compounds previously mentioned. Also preferably, said reaction it can be carried out in the presence of an acid, whereby the acid can be organic, such as acetic and / or inorganic acid, such as hydrochloric acid. In addition, the reaction can also carried out in the presence of a base, such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, methoxide sodium or sodium ethoxide, or a mixture of At least two of these bases.
La temperatura de reacción, así como la duración de la reacción, puede variar en un amplio intervalo. Las temperaturas de reacción preferidas oscilan desde la temperatura ambiente, es decir, aproximadamente 25ºC, hasta el punto de ebullición del medio de reacción. Los tiempos de reacción adecuados pueden variar, por ejemplo, desde varios minutos hasta varias horas.The reaction temperature as well as the duration of the reaction, it can vary over a wide range. The Preferred reaction temperatures range from temperature ambient, that is, approximately 25 ° C, to the point of boiling of the reaction medium. Adequate reaction times they can vary, for example, from several minutes to several hours.
El grupo carboxílico del compuesto de fórmula (VI) puede activarse para reacciones posteriores mediante la introducción de un grupo saliente adecuado según métodos convencionales bien conocidos por los expertos en la técnica. Preferiblemente, los compuestos de fórmula (VI) se transfieren a un cloruro de ácido, un anhídrido de ácido, un anhídrido mixto, un éster alquílico C_{1-4}, un éster activado tal como éster p-nitrofenílico. Otros métodos bien conocidos para la activación de ácidos incluyen la activación con N,N-diciclohexilcarbodiimida o hexafluorofosfato de benzotriazol-N-oxotris(dimetilamino)fosfonio (BOP)).The carboxylic group of the compound of formula (VI) can be activated for subsequent reactions by introduction of a suitable leaving group according to methods Conventionals well known to those skilled in the art. Preferably, the compounds of formula (VI) are transferred to a acid chloride, an acid anhydride, a mixed anhydride, a C 1-4 alkyl ester, an activated ester such as p-nitrophenyl ester. Other methods well Known for acid activation include activation with N, N-dicyclohexylcarbodiimide or hexafluorophosphate benzotriazol-N-oxotris (dimethylamino) phosphonium (BOP)).
Si dicho compuesto activado de fórmula (VII) es un cloruro de ácido, se prepara preferiblemente mediante la reacción del ácido correspondiente de fórmula (VI) con cloruro de tionilo o cloruro de oxalilo, mediante lo cual dicho agente de cloración también se utiliza como disolvente. Preferiblemente, también puede utilizarse un disolvente adicional. Los disolventes adecuados incluyen hidrocarburos tales como benceno, tolueno o xileno, hidrocarburos halogenados tales como diclorometano, cloroformo o tetracloruro de carbono, éteres tales como dietil éter, dioxano, tetrahidrofurano o dimetoxietano. También pueden utilizarse mezclas de dos o más disolventes de una clase o dos o más disolventes de diferentes clases. La temperatura de reacción preferida oscila desde 0ºC hasta el punto de ebullición del disolvente y los tiempos de reacción desde varios minutos hasta varias horas.If said activated compound of formula (VII) is an acid chloride, is preferably prepared by reaction of the corresponding acid of formula (VI) with chloride thionyl or oxalyl chloride, whereby said Chlorination is also used as a solvent. Preferably, an additional solvent can also be used. Solvents Suitable include hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, dioxane, tetrahydrofuran or dimethoxyethane. They can also mixtures of two or more solvents of a class or two are used or more solvents of different kinds. Reaction temperature preferred ranges from 0 ° C to the boiling point of solvent and reaction times from several minutes to several hours.
Si dicho compuesto activado de fórmula (VII) es un anhídrido mixto, dicho anhídrido puede prepararse preferiblemente, por ejemplo, mediante la reacción del ácido correspondiente de fórmula (VI) con cloroformiato de etilo en presencia de una base, tal como trietilamina o piridina, en un disolvente adecuado.If said activated compound of formula (VII) is a mixed anhydride, said anhydride can be prepared preferably, for example, by the acid reaction corresponding of formula (VI) with ethyl chloroformate in presence of a base, such as triethylamine or pyridine, in a suitable solvent.
La reacción del compuesto de fórmula general (VII) conThe reaction of the compound of the general formula (VII) with
para dar (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida se lleva a cabo preferiblemente en presencia de una base tal como trietilamina en una medio de reacción tal como cloruro de metileno. La temperatura está preferiblemente en el intervalo de desde 0ºC hasta el punto de ebullición del medio de reacción. El tiempo de reacción puede variar a lo largo de un amplio intervalo, por ejemplo, desde varias horas hasta varios días.to give (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide it is preferably carried out in the presence of a base such as triethylamine in a reaction medium such as methylene chloride. The temperature is preferably in the range of from 0 ° C to the boiling point of the reaction medium. The time of reaction may vary over a wide range, by example, from several hours to several days.
Las reacciones anteriormente mencionadas que implican la síntesis del anillo de 4,5-dihidro-pirazol o la reacción de un compuesto que comprende dicho anillo se llevan a cabo bajo una atmósfera inerte, preferiblemente nitrógeno o argón, para evitar la oxidación del sistema cíclico.The aforementioned reactions that involve the synthesis of the ring of 4,5-dihydro-pyrazole or the reaction of a compound comprising said ring are carried out under an inert atmosphere, preferably nitrogen or argon, to avoid oxidation of the cyclic system.
Durante los procedimientos descritos anteriormente puede ser necesaria y/o deseable la protección de los grupos sensibles o de reactivos. La introducción de grupos protectores convencionales, además de su eliminación, puede realizarse mediante métodos bien conocidos por los expertos en la técnica.During the procedures described previously it may be necessary and / or desirable to protect sensitive groups or reagents. The introduction of groups Conventional protectors, in addition to their removal, can be carried out by methods well known to those skilled in the technique.
La purificación y el aislamiento de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida o cualquier producto intermedio de la misma puede llevarse a cabo, si es necesario, por métodos convencionales conocidos por los expertos en la técnica, por ejemplo, métodos cromatográficos o recristalización.The purification and isolation of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide or any intermediate product thereof can be carried out, if necessary, by conventional methods known to skilled in the art, for example, chromatographic methods or recrystallization
La fase amorfa según la invención es adecuada como principio activo farmacéutico para la preparación de medicamentos.The amorphous phase according to the invention is suitable as pharmaceutical active ingredient for the preparation of medicines.
Se ha encontrado que el compuesto (cuya fase amorfa se reivindica) tiene una alta afinidad por los receptores de cannabinoides, particularmente por los receptores de cannabinoides 1 (CB_{1}), es decir, son ligandos selectivos para el receptor CB_{1} y actúan como moduladores, por ejemplo, antagonistas, agonistas inversos o agonistas de estos receptores. En particular, el compuesto cuya fase amorfa se reivindica muestra poco o ningún desarrollo de tolerancia durante el tratamiento, particularmente con respecto a la ingestión de alimentos, es decir, si el tratamiento se interrumpe durante un periodo de tiempo dado y luego se continúa posteriormente, el compuesto utilizado según la invención mostrará de nuevo el efecto deseado. Tras finalizar el tratamiento con el compuesto se encuentra que continúa la influencia positiva sobre el peso corporal. Esto también se aplicará muy probablemente a su fase amorfa.It has been found that the compound (whose phase amorphous is claimed) has a high affinity for receptors of cannabinoids, particularly by the receptors of cannabinoids 1 (CB1), that is, they are selective ligands for the CB1 receptor and act as modulators, for example, antagonists, inverse agonists or agonists of these receptors. In particular, the compound whose amorphous phase is claimed shows little or no tolerance development during treatment, particularly with regard to food intake, that is, if the treatment is interrupted for a given period of time and then continue later, the compound used according to the invention will again show the desired effect. After finishing the treatment with the compound is found to continue the positive influence on body weight. This is also It will most likely apply to your amorphous phase.
Además, este compuesto muestra una afinidad por el canal Herg relativamente débil, por tanto, para estos compuestos se espera un bajo riesgo de prolongación del intervalo QT. Esto también se aplicará claramente a su fase amorfa.In addition, this compound shows an affinity for the relatively weak Herg channel, therefore, for these compounds a low risk of prolongation of the QT interval is expected. This It will also be clearly applied to your amorphous phase.
En resumen, el compuesto utilizado según la invención (en la fase amorfa) se distingue por un amplio espectro de efectos beneficiosos, mientras que al mismo tiempo muestra relativamente pocos efectos no deseados, es decir, efectos que no contribuyen de manera positiva a o que incluso interfieren con el bienestar del paciente.In summary, the compound used according to the invention (in the amorphous phase) is distinguished by a broad spectrum of beneficial effects, while at the same time showing relatively few unwanted effects, that is, effects that do not contribute positively to or even interfere with the patient well-being
Por tanto, otro aspecto de la presente invención se refiere a un medicamento que comprende la fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida según la invención, y opcionalmente uno o más excipientes farmacéuticamente aceptables.Therefore, another aspect of the present invention refers to a medicine that comprises the amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide according to the invention, and optionally one or more excipients pharmaceutically acceptable.
Otro aspecto de la presente invención es el uso de la fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida según la invención, y opcionalmente uno o más excipientes farmacéuticamente aceptables, para la preparación de un medicamento para la modulación de los receptores de cannabinoides, preferiblemente receptores de cannabinoides 1 (CB_{1}), para la profilaxis y/o el tratamiento de trastornos del sistema nervioso central, trastornos del sistema inmunitario, trastornos del sistema cardiovascular, trastornos del sistema endocrino, trastornos del sistema respiratorio, trastornos del tracto gastrointestinal o trastornos reproductores.Another aspect of the present invention is the use of the amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide according to the invention, and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the modulation of cannabinoid receptors, preferably cannabinoid 1 receptors (CB1), for prophylaxis and / or treatment of nervous system disorders central, immune system disorders, system disorders cardiovascular, endocrine system disorders, disorders of the respiratory system, gastrointestinal tract disorders or reproductive disorders
También se prefiere el uso de la fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida según la invención, y opcionalmente uno o más excipientes farmacéuticamente aceptables, para la profilaxis y/o el tratamiento de la psicosis.The use of the amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide according to the invention, and optionally one or more excipients Pharmaceutically acceptable, for prophylaxis and / or treatment of psychosis
También se prefiere particularmente el uso de la fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida según la invención, y opcionalmente uno o más excipientes farmacéuticamente aceptables, para la preparación de un medicamento para la profilaxis y/o el tratamiento de trastornos de la ingestión de alimentos, preferiblemente bulimia, anorexia, caquexia, obesidad y/o diabetes mellitus tipo II (diabetes mellitus no insulinodependiente), más preferiblemente obesidad.The use of the amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide according to the invention, and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the prophylaxis and / or treatment of ingestion disorders of food, preferably bulimia, anorexia, cachexia, obesity and / or type II diabetes mellitus (diabetes mellitus no insulin dependent), more preferably obesity.
También se prefiere el uso de la fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida según la invención, y opcionalmente uno o más excipientes farmacéuticamente aceptables, para la preparación de un medicamento para la profilaxis y/o el tratamiento del cáncer, preferiblemente para la profilaxis y/o el tratamiento de uno o más tipos de cánceres seleccionados del grupo que consiste en cáncer cerebral, cáncer óseo, cáncer de labio, cáncer de boca, cáncer de esófago, cáncer de estómago, cáncer de hígado, cáncer de vejiga, cáncer de páncreas, cáncer de ovarios, cáncer cervical, cáncer de pulmón, cáncer de mama, cáncer de piel, cáncer de colon, cáncer intestinal y cáncer de próstata, más preferiblemente para la profilaxis y/o el tratamiento de uno o más tipos de cánceres seleccionados del grupo que consiste en cáncer de colon, cáncer intestinal y cáncer de próstata.The use of the amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide according to the invention, and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the prophylaxis and / or treatment of cancer, preferably for the prophylaxis and / or treatment of one or more types of cancers selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, cancer pancreas, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, intestinal cancer and prostate cancer, more preferably for prophylaxis and / or treatment of one or more types of cancers selected from the group consisting of colon cancer, intestinal cancer and cancer of prostate.
También se prefiere el uso de la fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida según la invención, y opcionalmente uno o más excipientes farmacéuticamente aceptables, para la preparación de un medicamento para la profilaxis y/o el tratamiento del alcoholismo y/o la adicción al alcohol, abuso de nicotina y/o tabaquismo, abuso de drogas y/o drogadicción y/o abuso de fármacos y/o farmacodependencia, preferiblemente abuso de drogas y/o drogadicción y/o abuso de nicotina y/o tabaquismo.The use of the amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide according to the invention, and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the prophylaxis and / or treatment of alcoholism and / or the alcohol addiction, nicotine abuse and / or smoking, abuse of drugs and / or drug addiction and / or drug abuse and / or Drug dependence, preferably drug abuse and / or drug addiction and / or abuse of nicotine and / or smoking.
Medicamentos/drogas, que son frecuentemente objeto de abuso incluyen opioides, barbitúricos, cannabis, cocaína, anfetaminas, fenciclidina, alucinógenos y benzodiazepinas.Medications / drugs, which are frequently subject to abuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.
También se prefiere el uso de la fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida según la invención, y opcionalmente uno o más excipientes farmacéuticamente aceptables, para la preparación de un medicamento para la profilaxis y/o el tratamiento de uno o más trastornos seleccionados del grupo que consiste en trastornos óseos, preferiblemente osteoporosis (por ejemplo, osteoporosis asociada con una predisposición genética, déficit de hormonas sexuales o envejecimiento), enfermedad ósea asociada a cáncer o enfermedad ósea de Paget; esquizofrenia, ansiedad, depresión, epilepsia, trastornos neurodegenerativos, trastornos cerebelosos, trastornos espinocerebelosos, trastornos cognitivos, traumatismo craneal, traumatismo craneoencefálico, accidente cerebrovascular, ataques de pánico, neuropatía periférica, inflamación, glaucoma, migraña, enfermedad de Parkinson, enfermedad de Huntington, enfermedad de Alzheimer, enfermedad de Raynaud, temblores, trastornos compulsivos, demencia senil, trastornos tímicos, discinesia tardía, trastornos bipolares, trastornos de movimiento inducidos por medicamentos, distonía, choque endotoxémico, choque hemorrágico, hipotensión, insomnio, trastornos inmunológicos, placas escleróticas, vómitos, diarrea, asma, trastornos de la memoria, prurito, dolor, o para la potenciación del efecto analgésico de analgésicos narcóticos y no narcóticos, o para influir en el tránsito intestinal.The use of the amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide according to the invention, and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the prophylaxis and / or treatment of one or more disorders selected from the group consisting of bone disorders, preferably osteoporosis (for example, associated osteoporosis with a genetic predisposition, sex hormone deficit or aging), bone disease associated with cancer or disease Paget's bone; schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, disorders spinocerebellar, cognitive disorders, head trauma, head trauma, stroke, seizures panic, peripheral neuropathy, inflammation, glaucoma, migraine, Parkinson's disease, Huntington's disease, Alzheimer's disease, Raynaud's disease, tremors, disorders compulsive, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders, movement disorders induced by medications, dystonia, endotoxémic shock, hemorrhagic shock, hypotension, insomnia, immune disorders, plaques sclera, vomiting, diarrhea, asthma, memory disorders, pruritus, pain, or for the potentiation of the analgesic effect of narcotic and non-narcotic pain relievers, or to influence the intestinal transit.
También se prefiere el uso de la fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida según la invención, y opcionalmente uno o más excipientes farmacéuticamente aceptables, para la preparación de un medicamento para la profilaxis y/o el tratamiento del síndrome metabólico, especialmente independiente del peso, enfermedades cardiovasculares, factores de riesgo cardiovasculares, intolerancia a la glucosa y resistencia a la insulina; para la profilaxis y/o el tratamiento y/o la influencia en los parámetros sanguíneos, especialmente en los parámetros lipídicos, que parecen disminuir las partículas de LDL, mientras aumentan las partículas de HDL, incluyendo también el tratamiento de trastornos alimentarios (obesidad) en condiciones de diabetes desarrollada, especialmente de tipo II.The use of the amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide according to the invention, and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the prophylaxis and / or treatment of metabolic syndrome, especially independent of weight, diseases cardiovascular, cardiovascular risk factors, intolerance to glucose and insulin resistance; for prophylaxis and / or the treatment and / or influence on blood parameters, especially in lipid parameters, which seem to decrease LDL particles, while increasing HDL particles, also including the treatment of eating disorders (obesity) in conditions of developed diabetes, especially Type II
Otro aspecto preferido de la invención también es un método de tratamiento que engloba todos los usos anteriormente mencionados, en el que fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida según la invención, se aplica a una persona que lo necesita, para tratar el síndrome metabólico, especialmente independiente del peso, enfermedades cardiovasculares, especialmente para combatir factores de riesgo cardiovasculares, para influir los parámetros sanguíneos, especialmente los parámetros lipídicos, diabetes, especialmente de tipo II, intolerancia a la glucosa y resistencia a la insulina, trastornos óseos, preferiblemente osteoporosis (por ejemplo, osteoporosis asociada con una predisposición genética, déficit de hormonas sexuales o envejecimiento), enfermedad ósea asociada a cáncer o enfermedad ósea de Paget; esquizofrenia, ansiedad, depresión, epilepsia, trastornos neurodegenerativos, trastornos cerebelosos, trastornos espinocerebelosos, trastornos cognitivos, traumatismo craneal, traumatismo craneoencefálico, accidente cerebrovascular, ataques de pánico, neuropatía periférica, inflamación, glaucoma, migraña, enfermedad de Parkinson, enfermedad de Huntington, enfermedad de Alzheimer, enfermedad de Raynaud, temblores, trastornos compulsivos, demencia senil, trastornos tímicos, discinesia tardía, trastornos bipolares, trastornos de movimiento inducidos por medicamentos, distonía, choque endotoxémico, choque hemorrágico, hipotensión, insomnio, trastornos inmunológicos, placas escleróticas, vómitos, diarrea, asma, trastornos de la memoria, prurito, dolor, o para la potenciación del efecto analgésico de analgésicos narcóticos y no narcóticos, o para influir en el tránsito intestinal; alcoholismo y/o adicción al alcohol, abuso de nicotina y/o tabaquismo, abuso de drogas y/o drogadicción y/o abuso de fármacos y/o farmacodependencia, preferiblemente abuso de drogas y/o drogadicción y/o abuso de nicotina y/o tabaquismo; cáncer, preferiblemente para la profilaxis y/o el tratamiento de uno o más tipos de cánceres seleccionados del grupo que consiste en cáncer cerebral, cáncer óseo, cáncer de labio, cáncer de boca, cáncer de esófago, cáncer de estómago, cáncer de hígado, cáncer de vejiga, cáncer de páncreas, cáncer de ovarios, cáncer cervical, cáncer de pulmón, cáncer de mama, cáncer de piel, cáncer de colon, cáncer intestinal y cáncer de próstata, más preferiblemente para la profilaxis y/o el tratamiento de uno o más tipos de cánceres seleccionados del grupo que consiste en cáncer de colon, cáncer intestinal y cáncer de próstata; trastornos de la ingestión de alimentos, preferiblemente bulimia, anorexia, caquexia, obesidad y/o diabetes mellitus tipo II (diabetes no insulinodependiente), más preferiblemente de la obesidad; psicosis; de trastornos del sistema nervioso central, trastornos del sistema inmunitario, trastornos del sistema cardiovascular, trastornos del sistema endocrino, trastornos del sistema respiratorio, trastornos del tracto gastrointestinal o trastornos reproductores.Another preferred aspect of the invention also It is a treatment method that encompasses all uses previously mentioned, in which amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide according to the invention, it is applied to a person who needs it, to treat metabolic syndrome, especially independent of weight, cardiovascular diseases, especially to combat cardiovascular risk factors, to influence the parameters blood, especially lipid parameters, diabetes, especially type II, glucose intolerance and resistance to insulin, bone disorders, preferably osteoporosis (by example, osteoporosis associated with a genetic predisposition, deficit of sex hormones or aging), bone disease associated with cancer or bone disease of Paget; schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinocerebellar disorders, disorders Cognitive, cranial trauma, craniocerebral trauma, stroke, panic attacks, neuropathy peripheral, inflammation, glaucoma, migraine, Parkinson's disease, Huntington's disease, Alzheimer's disease, Raynaud, tremors, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders, medication-induced movement disorders, dystonia, endotoxemic shock, hemorrhagic shock, hypotension, insomnia, immunological disorders, sclera plaques, vomiting, diarrhea, asthma, memory disorders, pruritus, pain, or for potentiation of the analgesic effect of narcotic analgesics and not narcotics, or to influence intestinal transit; alcoholism and / or alcohol addiction, nicotine abuse and / or smoking, abuse of drugs and / or drug addiction and / or drug abuse and / or Drug dependence, preferably drug abuse and / or drug addiction and / or abuse of nicotine and / or smoking; Cancer, preferably for the prophylaxis and / or treatment of one or more types of cancers selected from the group consisting of cancer brain, bone cancer, lip cancer, mouth cancer, cancer esophagus, stomach cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, cancer lung, breast cancer, skin cancer, colon cancer, cancer intestinal and prostate cancer, more preferably for prophylaxis and / or treatment of one or more types of cancers selected from the group consisting of colon cancer, cancer intestinal and prostate cancer; ingestion disorders food, preferably bulimia, anorexia, cachexia, obesity and / or type II diabetes mellitus (non-insulin dependent diabetes), more preferably of obesity; psychosis; of disorders of central nervous system, immune system disorders, cardiovascular system disorders, system disorders endocrine, respiratory system disorders, disorders of the gastrointestinal tract or reproductive disorders.
El medicamento según la presente invención puede estar en cualquier forma adecuada para la aplicación a seres humanos y/o animales, preferiblemente a seres humanos que incluyen lactantes, niños y adultos, y pueden producirse mediante procedimientos habituales conocidos por los expertos en la técnica. La composición del medicamento puede variar dependiendo de la vía de administración.The medicament according to the present invention can be in any form suitable for application to beings humans and / or animals, preferably humans that include infants, children and adults, and can be produced by usual procedures known to those skilled in the art. The composition of the medication may vary depending on the route of administration.
El medicamento de la presente invención puede administrarse, por ejemplo, por vía parenteral en combinación con vehículos líquidos inyectables convencionales, tales como agua o alcoholes adecuados. Los excipientes farmacéuticos convencionales para inyección, tales como agentes estabilizantes, agentes solubilizantes y tampones, pueden incluirse en tales composiciones inyectables. Estos medicamentos pueden inyectarse, por ejemplo, por vía intramuscular, por vía intraperitoneal o por vía intravenosa.The medicament of the present invention can administered, for example, parenterally in combination with conventional injectable liquid vehicles, such as water or suitable alcohols. Conventional pharmaceutical excipients for injection, such as stabilizing agents, agents solubilizers and buffers, can be included in such compositions injectable These medications can be injected, for example, by intramuscularly, intraperitoneally or via intravenous
Los medicamentos según la presente invención también pueden formularse en composiciones que pueden administrarse por vía oral, que contienen uno o más vehículos o excipientes fisiológicamente compatibles, en forma sólida o líquida. Estas composiciones pueden contener componentes convencionales, tales como agentes aglutinantes, cargas, lubricantes y agentes humectantes aceptables. Las composiciones pueden tomar cualquier forma conveniente, tal como comprimidos, microgránulos, cápsulas, pastillas para chupar, disoluciones acuosas o aceitosas, suspensiones, emulsiones, o formas en polvo secas adecuadas para la reconstitución con agua u otro medio líquido adecuado antes de su uso, para la liberación inmediata o sostenida.Medications according to the present invention they can also be formulated in compositions that can administered orally, containing one or more vehicles or physiologically compatible excipients, in solid form or liquid These compositions may contain components. conventional, such as binding agents, fillers, acceptable lubricants and wetting agents. The compositions they can take any convenient form, such as tablets, microgranules, capsules, lozenges, solutions aqueous or oily, suspensions, emulsions, or powdered forms dried suitable for reconstitution with water or other medium suitable liquid before use, for immediate release or sustained.
Las formas orales líquidas para administración también pueden contener diversos aditivos tales como agentes edulcorantes, aromatizantes, conservantes y emulsionantes. También pueden formularse composiciones líquidas no acuosas para administración oral que contienen aceites comestibles. Tales composiciones líquidas pueden encapsularse convenientemente en, por ejemplo, cápsulas de gelatina en una cantidad de dosis unitaria.Liquid oral forms for administration they can also contain various additives such as agents sweeteners, flavorings, preservatives and emulsifiers. Too non-aqueous liquid compositions can be formulated for Oral administration containing edible oils. Such liquid compositions can be conveniently encapsulated in, by example, gelatin capsules in a dose amount unitary.
Las composiciones de la presente invención también pueden administrarse por vía tópica o por medio de un supositorio.The compositions of the present invention they can also be administered topically or through a suppository.
La dosificación diaria para seres humanos y animales puede variar dependiendo de factores que tienen su base en las especies respectivas u otros factores, tales como la edad, el sexo, el peso o el grado de enfermedad, etcétera. La dosificación diaria para seres humanos puede estar preferiblemente en el intervalo de desde 1 hasta 2000, preferiblemente de 1 a 1500, más preferiblemente de 1 a 1000 miligramos de principio activo que va a administrarse durante una o varias ingestas por día.The daily dosage for humans and Animals may vary depending on factors that are based on the respective species or other factors, such as age, sex, weight or degree of illness, etc. Dosage daily for humans can preferably be in the range from 1 to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active ingredient that is going to administered during one or several intakes per day.
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La determinación in vitro de la afinidad de los compuestos de pirazolina sustituidos de la invención por los receptores CB_{1}/CB_{2} se lleva a cabo tal como se describió en la publicación de Ruth A. Ross, Heather C. Brockie et al., "Agonist-inverse agonist characterization at CB_{1} and CB_{2} cannabinoid receptors of L-759633, L759656 y AM630", British Journal of Pharmacology, 126, 665-672, (1999), en la que se utilizan los receptores CB_{1} y CB_{2} humanos transfectados de Receptor Biology, Inc. El radioligando utilizado para ambos receptores es [^{3}H]-CP55940. Las partes respectivas se incorporan como referencia al presente documento y forman parte de la presente descripción. In vitro determination of the affinity of the substituted pyrazoline compounds of the invention for the CB1 / CB2 receptors is carried out as described in the publication of Ruth A. Ross, Heather C. Brockie et al ., "Agonist-inverse agonist characterization at CB_ {1} and CB_ {2} cannabinoid receptors of L-759633, L759656 and AM630", British Journal of Pharmacology, 126, 665-672, (1999), in which they use the transfected human CB1 and CB2 receptors of Receptor Biology, Inc. The radioligand used for both receptors is [3 H] -CP55940. The respective parts are incorporated by reference to this document and are part of this description.
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Se sabe que las sustancias con afinidad por los receptores de cannabinoides producen un amplio intervalo de efectos farmacológicos. También se sabe que la administración intravenosa de una sustancia con afinidad por los receptores de cannabinoides en ratones produce analgesia, hipotermia, sedación y catalepsia. Individualmente, ninguno de estos efectos puede considerarse como una prueba de que una sustancia probada tenga afinidad por los receptores de cannabinoides, ya que todos estos efectos son comunes para diversas clases de agentes activos en el sistema nervioso central. Sin embargo, las sustancias que muestran todos estos efectos, es decir, las sustancias que son activas en este modelo denominado de tétrada, se considera que tienen afinidad por los receptores de cannabinoides. Se ha mostrado además que los antagonistas del receptor de cannabinoides son sumamente eficaces en el bloqueo de los efectos de un agonista de cannabinoides en el modelo de tétrada de ratón.It is known that substances with affinity for cannabinoid receptors produce a wide range of effects Pharmacological It is also known that intravenous administration of a substance with affinity for cannabinoid receptors in mice it produces analgesia, hypothermia, sedation and catalepsy. Individually, none of these effects can be considered as proof that a tested substance has an affinity for cannabinoid receptors, since all these effects are common for various kinds of active agents in the nervous system central. However, the substances that show all these effects, that is, the substances that are active in this model called tetrad, they are considered to have affinity for cannabinoid receptors It has also been shown that cannabinoid receptor antagonists are extremely effective in blocking the effects of a cannabinoid agonist in the mouse tetrad model.
El modelo de tétrada se describe, por ejemplo, en la publicación de A. C. Howlett et al, International Union of Pharmacology XXVII. Classification of Cannabinoid Receptors, Pharmacol Rev 54, 161-202, 2002 y David R. Compton et al., "In-vivo Characterization of a Specific Cannabinoid Receptor Antagonist (SR141716A): Inhibition of Tetrahidrocannbinol- induced Responses and Apparent Agonist Activity", J. Pharmacol. Exp. Ther. 277, 2, 586-594, 1996. Las partes correspondientes de la descripción se incorporan como referencia al presente documento.The tetrad model is described, for example, in the publication of AC Howlett et al , International Union of Pharmacology XXVII. Classification of Cannabinoid Receptors, Pharmacol Rev 54, 161-202, 2002 and David R. Compton et al ., " In-vivo Characterization of a Specific Cannabinoid Receptor Antagonist (SR141716A): Inhibition of Tetrahydrocannbinol-induced Responses and Apparent Agonist Activity", J. Pharmacol. Exp. Ther. 277, 2, 586-594, 1996. The corresponding parts of the description are incorporated by reference to this document.
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En todos los experimentos siguientes se utilizan ratones NMRI macho con un peso de 20-30 g (Harlan, Barcelona, España).In all the following experiments they are used NMRI male mice weighing 20-30 g (Harlan, Barcelona, Spain).
Antes de las pruebas en los procedimientos conductuales facilitados a continuación, los ratones se aclimatan al entorno experimental. Los valores de control de previos al tratamiento se determinaron para medir la analgesia mediante latencia en placa caliente (en segundos), la temperatura rectal, la sedación y la catalepsia.Before the tests in the procedures behavioral behaviors then the mice acclimatize to the experimental environment. Control values prior to treatment were determined to measure analgesia using hot plate latency (in seconds), rectal temperature, sedation and catalepsy.
Con el fin de determinar la actividad agonista de la sustancia que va a probarse, se inyecta a los ratones por vía intravenosa la sustancia que va a probarse o el vehículo solo. 15 minutos después de la inyección, se mide la latencia de analgesia en placa caliente. 20 minutos después de la inyección se mide la temperatura rectal, la sedación y la catalepsia.In order to determine agonist activity of the substance to be tested, mice are injected via intravenous the substance to be tested or the vehicle alone. fifteen minutes after injection, analgesia latency is measured in hot plate. 20 minutes after the injection the rectal temperature, sedation and catalepsy.
Con el fin de determinar la actividad antagonista, se utiliza el procedimiento idéntico que para la determinación de los efectos agonistas, pero con la diferencia de que la sustancia que va a evaluarse para determinar su actividad antagonista se inyecta 5 minutos antes de la inyección intravenosa de 1,25 mg/kg de Win-55,212, un conocido agonista del receptor de cannabinoides.In order to determine the activity antagonist, the identical procedure is used as for determination of agonist effects, but with the difference of that the substance to be evaluated to determine its activity antagonist is injected 5 minutes before intravenous injection of 1.25 mg / kg of Win-55,212, a known agonist of the cannabinoid receptor.
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La analgesia en placa caliente se determina según el método descrito en Woolfe D. et al. "The evaluation of analgesic action of pethidine hydrochloride (Demerol)", J. Pharmacol. Exp. Ther. 80, 300-307,1944. La descripción respectiva se incorpora como referencia al presente documento y forma parte de la presente descripción.Hot plate analgesia is determined according to the method described in Woolfe D. et al . "The evaluation of analgesic action of pethidine hydrochloride (Demerol)", J. Pharmacol. Exp. Ther. 80, 300-307, 1944. The respective description is incorporated as a reference to this document and is part of this description.
Los ratones se sitúan sobre una placa caliente (analgesímetro Harvard) a 55 \pm 0,5ºC hasta que muestran una sensación dolorosa, lamiéndose sus patas o saltando, y se registra el tiempo para que se produzcan estas sensaciones. Esta lectura se considera como el valor basal (B). El límite de tiempo máximo que se permite que los ratones permanezcan sobre la placa caliente en ausencia de cualquier respuesta dolorosa es de 40 segundos con el fin de evitar lesiones cutáneas. Este periodo se denomina tiempo límite (PC).The mice are placed on a hot plate (Harvard analgesimeter) at 55 ± 0.5 ° C until they show a painful sensation, licking its legs or jumping, and registers the time for these sensations to occur. This reading is consider as the baseline value (B). The maximum time limit that mice are allowed to remain on the hot plate in absence of any painful response is 40 seconds with the In order to avoid skin lesions. This period is called time. limit (PC).
Quince minutos después de la administración de la sustancia que va a probarse, los ratones se sitúan de nuevo sobre la placa caliente y se repite el procedimiento anteriormente descrito. Este periodo se denomina lectura posterior al tratamiento (PT).Fifteen minutes after the administration of the substance to be tested, the mice are placed again on the hot plate and the procedure is repeated above described This period is called post-treatment reading. (PT).
El grado de analgesia se calcula a partir de la fórmula:The degree of analgesia is calculated from the formula:
%\ de\ MPE\ de\ analgesia = (PT- B)/(PC-B)\ x\ 100% \ of \ MPE \ of \ analgesia = (PT-B) / (PC-B) \ x \ 100
MPE = máximo efecto posible.MPE = maximum possible effect.
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La sedación y la ataxia se determinan según el método descrito en Desmet L. K. C. et al. "Anticonvulsive properties of Cinarizine and Flunarizine in Rats and Mice", Arzneim. -Forsch. (Frug Res) 25, 9, 1975. La descripción respectiva se incorpora como referencia al presente documento y forma parte de la presente descripción.Sedation and ataxia are determined according to the method described in Desmet LKC et al . "Anticonvulsive properties of Cinarizine and Flunarizine in Rats and Mice", Arzneim. -Forsch. (Frug Res) 25, 9, 1975. The respective description is incorporated by reference to this document and forms part of this description.
El sistema de puntuación elegido esThe scoring system chosen is
0: sin ataxia;0: no ataxia;
1: dudoso;1: doubtful;
2: tranquilidad y silencio obvios;2: obvious tranquility and silence;
3 ataxia pronunciada;3 pronounced ataxia;
antes de, además de después del tratamiento.before, in addition to after treatment.
El porcentaje de sedación se determina según la fórmula:The percentage of sedation is determined according to the formula:
%\ de\ sedación = media\ aritmética/3\ X\ 100%\ from\ sedation = mean \ arithmetic / 3 \ X \ 100
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La hipotermia se determina según el método descrito en David R. Compton et al. "In-vivo Characterization of a Specific Cannabinoid Receptor Antagonist (SR141716A) Inhibition of Tetrahidrocannbinol- induced Responses and Apparent Agonist Activity", J. Pharmacol Exp Ther. 277, 2, 586-594, 1996. La descripción respectiva se incorpora como referencia al presente documento y forma parte de la presente descripción.Hypothermia is determined according to the method described in David R. Compton et al . " In-vivo Characterization of a Specific Cannabinoid Antagonist Receptor (SR141716A) Inhibition of Tetrahydrocannbinol-induced Responses and Apparent Agonist Activity", J. Pharmacol Exp Ther. 277, 2, 586-594, 1996. The respective description is incorporated by reference to this document and forms part of this description.
Se determinan las temperaturas rectales iniciales con un termómetro (Yello Springs Instruments Co., Panlabs) y una sonda de termistor insertada a 25 mm antes de la administración de la sustancia que va a probarse. La temperatura rectal se mide de nuevo 20 minutos después de la administración de las sustancias que van a probarse. La diferencia de temperatura se calcula para cada animal, de modo que las diferencias \geq -2ºC se consideran que representan actividad.Rectal temperatures are determined initials with a thermometer (Yello Springs Instruments Co., Panlabs) and a thermistor probe inserted 25 mm before the administration of the substance to be tested. Temperature rectal is measured again 20 minutes after administration of the substances to be tested. The temperature difference is calculate for each animal, so that the differences ≥ -2 ° C They are considered to represent activity.
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La catalepsia se determina según el método descrito en Alpermann H. G. et al. "Pharmacological effects of Hoe 249: A new potential antidepressant", Drugs Dev. Res. 25, 267-282. 1992. La descripción respectiva se incorpora como referencia al presente documento y forma parte de la presente descripción.Catalepsy is determined according to the method described in Alpermann HG et al . "Pharmacological effects of Hoe 249: A new potential antidepressant", Drugs Dev. Res. 25, 267-282. 1992. The respective description is incorporated by reference to this document and forms part of this description.
El efecto cataléptico de la sustancia que va a probarse se evalúa según la duración de la catalepsia, poniéndose los animales cabeza abajo con sus patas sobre la parte superior del bloque de madera.The cataleptic effect of the substance that is going to be tested is evaluated according to the duration of the catalepsy, putting the animals head down with their legs on top of the wood block.
El sistema de puntuación elegido es:The scoring system chosen is:
Catalepsia durante:Catalepsy during:
más de 60 segundos = 6; 50 -60 segundos = 5, 40-50 segundos = 4, 30-40 segundos = 3, 20-30 segundos = 2, 5-10 segundos = 1, y menos de 5 segundos = 0.more than 60 seconds = 6; 50 -60 seconds = 5, 40-50 seconds = 4, 30-40 seconds = 3, 20-30 seconds = 2, 5-10 seconds = 1, and less than 5 seconds = 0.
El porcentaje de catalepsia se determina según la fórmula siguiente:The percentage of catalepsy is determined according to the following formula:
%\ de\ catalepsia = media\ aritmética/6\ X\ 100%\ from\ catalepsy = mean \ arithmetic / 6 \ X \ 100
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Las pruebas in vivo para determinar la actividad contra la obesidad de los compuestos de pirazolina de la invención se llevan a cabo tal como se describió en la publicación de G. Colombo et al., "Appetite Suppression and Weight Loss after the Cannabinoid Antagonist SR 141716"; Life Sciences, 63 (8), 113-117, (1998). La parte respectiva de la descripción se incorpora como referencia al presente documento y forma parte de la presente descripción. In vivo tests to determine the activity against obesity of the pyrazoline compounds of the invention are carried out as described in the publication of G. Colombo et al ., "Appetite Suppression and Weight Loss after the Cannabinoid Antagonist SR 141716 "; Life Sciences, 63 (8), 113-117, (1998). The respective part of the description is incorporated as a reference to this document and is part of this description.
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Las pruebas in vivo para determinar la actividad antidepresora de los compuestos de pirazolina de la invención en la prueba de natación forzada se llevan a cabo tal como se describió en la publicación de E.T. Tzavara et al., "The CB1 receptor antagonist SR141716A selectively increases monoaminargic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions"; Br. J. Pharmacol. 2003, 138(4):544:53. La parte respectiva de la descripción se incorpora como referencia al presente documento y forma parte de la presente descripción. In vivo tests to determine the antidepressant activity of the pyrazoline compounds of the invention in the forced swimming test are carried out as described in the publication of ET Tzavara et al ., "The CB1 receptor antagonist SR141716A selectively increases monoaminargic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions "; Br. J. Pharmacol. 2003, 138 (4): 544: 53. The respective part of the description is incorporated as a reference to this document and is part of this description.
La presente invención se ilustra a continuación con la ayuda de ejemplos. Estas ilustraciones se facilitan solamente a modo de ejemplo y no limitan el espíritu general de la presente invención.The present invention is illustrated below. With the help of examples. These illustrations are provided by way of example only and do not limit the general spirit of the present invention
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Ejemplo 1Example one
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En un matraz de tres bocas se disolvieron p-clorobenzaldehído (13,3 g, 95 mmol) y piruvato de etilo (10 g, 86 mmol) en 150 ml de etanol absoluto. La disolución se enfrió en hielo hasta 0ºC y se añadió gota a gota una disolución acuosa de NaOH (3,8 g en 45 mL de agua), manteniéndose la temperatura inferior o igual a 10ºC, mediante lo cual se formó un precipitado de color amarillo anaranjado. La mezcla de reacción se agitó durante 1 hora a 0ºC y adicionalmente durante 1,5 horas a temperatura ambiente (aproximadamente a 25ºC). Después, la mezcla de reacción se enfrió hasta aproximadamente 5ºC y se aisló la sal sódica insoluble del ácido 4-(4-clorofenil)-2-oxo-3-butenoico mediante filtración.In a three-mouth flask they dissolved p-chlorobenzaldehyde (13.3 g, 95 mmol) and pyruvate ethyl (10 g, 86 mmol) in 150 ml of absolute ethanol. Dissolution cooled on ice to 0 ° C and a solution was added dropwise aqueous NaOH (3.8 g in 45 mL of water), maintaining the temperature less than or equal to 10 ° C, whereby a orange yellow precipitate. The reaction mixture is stirred for 1 hour at 0 ° C and additionally for 1.5 hours at room temperature (approximately 25 ° C). Then the mixture The reaction was cooled to about 5 ° C and the salt was isolated acid insoluble sodium 4- (4-chlorophenyl) -2-oxo-3-butenoic by filtration
El filtrado se dejó en la nevera durante la noche, mediante lo cual se formó más precipitado, que se separó por filtración, se combinó con la primera fracción de la sal y se lavó con dietil éter. La sal sódica del ácido 4-(4-clorofenil)-2-oxo-3-butenoico se trató entonces con una disolución de HCl 2N, se agitó durante algunos minutos y se separó mediante filtración ácido 4-(4-clorofenil)-2-oxo-3-butenoico sólido y se secó para dar 12,7 g del producto deseado (70% del rendimiento teórico).The filtrate was left in the refrigerator during night, whereby more precipitate formed, which separated by filtration, it was combined with the first fraction of the salt and washed with diethyl ether. Sodium Salt of Acid 4- (4-chlorophenyl) -2-oxo-3-butenoic It was then treated with a 2N HCl solution, stirred for a few minutes and separated by acid filtration 4- (4-chlorophenyl) -2-oxo-3-butenoic solid and dried to give 12.7 g of the desired product (70% of theoretical performance).
IR (KBr, cm^{-1}): 3500-2500, 1719,3, 1686,5, 1603,4, 1587,8, 1081,9.IR (KBr, cm -1): 3500-2500, 1719.3, 1686.5, 1603.4, 1587.8, 1081.9.
^{1}H-RMN (CDCl_{3},
\delta) : 7,4 (d, J=8,4 Hz, 2H), 7,5 (d, J=16,1 Hz, 1H), 7,6 (d,
J=8,4 Hz, 2H), 8,1(d, J=16,1 Hz,
1H).1 H-NMR (CDCl 3, δ): 7.4 (d, J = 8.4 Hz, 2H), 7.5 (d, J = 16.1 Hz, 1H), 7 , 6 (d, J = 8.4 Hz, 2H), 8.1 (d, J = 16.1 Hz,
1 HOUR).
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Se mezclaron el ácido 4-(4-clorofenil)-2-oxo-3-butenoico obtenido según la etapa a) (12,6 g, 60 mmol), clorhidrato de 2,4-diclorofenilhidrazina (12,8 g, 60 mmol) y ácido acético glacial (200 mL) bajo una atmósfera de nitrógeno y se calentaron a reflujo durante 4 horas, se enfrió hasta la temperatura ambiente (aproximadamente 25ºC) y se añadió a agua con hielo, mediante lo cual se obtuvo una masa pegajosa que se extrajo con cloruro de metileno. Las fracciones de cloruro de metileno combinadas se lavaron con agua, se secaron con sulfato de sodio, se filtraron y se evaporaron hasta sequedad para dar un sólido amarillo pálido (12,7 g, 57% del rendimiento teórico).The acid was mixed 4- (4-chlorophenyl) -2-oxo-3-butenoic obtained according to step a) (12.6 g, 60 mmol), hydrochloride 2,4-dichlorophenylhydrazine (12.8 g, 60 mmol) and acid glacial acetic acid (200 mL) under a nitrogen atmosphere and it heated at reflux for 4 hours, cooled to room temperature (approximately 25 ° C) and added to water with ice, whereby a sticky dough was obtained that was extracted with methylene chloride. Methylene Chloride Fractions combined, washed with water, dried with sodium sulfate, dried filtered and evaporated to dryness to give a solid pale yellow (12.7 g, 57% of theoretical yield).
IR (KBr, cm^{-1}): 3200-2200, 1668,4, 1458, 1251,4, 1104,8.IR (KBr, cm -1): 3200-2200, 1668.4, 1458, 1251.4, 1104.8.
^{1}H-RMN (CDCl_{3}, \delta): 3,3 (dd, 1H), 3,7 (dd, 1H), 5,9 (dd, 1H), 7,09-7,25 (m, 7H).1 H-NMR (CDCl 3, δ): 3.3 (dd, 1H), 3.7 (dd, 1H), 5.9 (dd, 1H), 7.09-7.25 (m, 7H).
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Bajo atmósfera de nitrógeno, se disolvió el ácido 5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidropirazol-3-carboxílico (2,5 g, 6,8 mmol) obtenido según la etapa (b) en 4 mL de cloruro de tionilo y se calentó a reflujo durante 2,5 horas. El cloruro de tionilo en exceso se elimina de la mezcla de reacción a presión reducida y el residuo bruto resultante (2,6 g) se utiliza sin purificación adicional.Under nitrogen atmosphere, the acid 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxylic (2.5 g, 6.8 mmol) obtained according to step (b) in 4 mL of thionyl and heated at reflux for 2.5 hours. Chloride excess thionyl is removed from the pressure reaction mixture reduced and the resulting crude residue (2.6 g) is used without additional purification
IR (KBr, cm^{-1}) 1732,3, 1700, 1533,3, 1478,1, 1212,9, 826,6.IR (KBr, cm -1) 1732.3, 1700, 1533.3, 1478.1, 1212.9, 826.6.
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Bajo atmósfera de nitrógeno, se disolvieron
N-aminopiperidina (0,6 mL, 5,6 mmol) y trietilamina
(4 mL) en cloruro de metileno (25 mL). La mezcla resultante se
enfrió con hielo hasta 0ºC y se añadió gota a gota una disolución
del cloruro del ácido
5-(4-clorofenil)-1-(2,4-diclorofenil)-4,
5-dihidro-pirazol-3-carboxílico
obtenido en la etapa (c) en cloruro de metileno (15 mL). La mezcla
de reacción resultante se agitó a temperatura ambiente
(aproximadamente 25ºC) durante la noche. Después, la mezcla de
reacción se lavó con agua, seguido por una disolución acuosa
saturada de bicarbonato de sodio, entonces de nuevo con agua, se
secó sobre sulfato de sodio, se filtró y se evaporó hasta sequedad
en un rotavapor. El sólido crudo resultante se cristalizó en
etanol. El sólido cristalizado se separó mediante filtración y las
aguas madres se concentraron para dar una segunda fracción de
producto cristalizado. La dos fracciones se combinaron para dar una
cantidad total de 1,7 g (57% del rendimiento teórico) de
N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidropirazol-3-carboxamida
que tiene un punto de fusión de 183-
186ºC.Under nitrogen atmosphere, N-aminopiperidine (0.6 mL, 5.6 mmol) and triethylamine (4 mL) were dissolved in methylene chloride (25 mL). The resulting mixture was cooled with ice to 0 ° C and a solution of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic acid chloride was added dropwise. obtained in step (c) in methylene chloride (15 mL). The resulting reaction mixture was stirred at room temperature (approximately 25 ° C) overnight. Then, the reaction mixture was washed with water, followed by a saturated aqueous solution of sodium bicarbonate, then again with water, dried over sodium sulfate, filtered and evaporated to dryness on a rotary evaporator. The resulting crude solid was crystallized from ethanol. The crystallized solid was filtered off and the mother liquor was concentrated to give a second fraction of crystallized product. The two fractions were combined to give a total amount of 1.7 g (57% of theory) of N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazole -3-carboxamide having a melting point of 183-
186 ° C.
IR (KBr, cm^{-1}): 3222,9, 2934,9, 1647,4, 1474,7, 1268,3, 815,6.IR (KBr, cm -1): 3222.9, 2934.9, 1647.4, 1474.7, 1268.3, 815.6.
^{1}H-RMN (CDCl_{3}, \delta): 1,4 (m, 2H), 1,7 (m, 4H), 2,8 (m, 4H), 3,3 (dd, J=6,1 y 18,3 Hz, 1H), 3,7 (dd, J=12,5 y 18,3 Hz, 1H), 5,7 (dd, J=6,1 y 12,5 Hz, 1H), 7,0-7,2 (m, 6H), 7,4 (s, 1H).1 H-NMR (CDCl 3, δ): 1.4 (m, 2H), 1.7 (m, 4H), 2.8 (m, 4H), 3.3 (dd, J = 6.1 and 18.3 Hz, 1H), 3.7 (dd, J = 12.5 and 18.3 Hz, 1H), 5.7 (dd, J = 6.1 and 12.5 Hz, 1H), 7.0-7.2 (m, 6H), 7.4 (s, 1H).
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Ejemplo 2Example 2
La fase amorfa se preparó a partir de la masa fundida del compuesto según el ejemplo 1, (N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida) como racemato, a 190-200ºC bajo atmósfera inerte, mediante enfriamiento rápido en una baño de hielo.The amorphous phase was prepared from the dough melting of the compound according to example 1, (N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide) as a racemate, at 190-200 ° C under an inert atmosphere, by rapid cooling in an ice bath.
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Ejemplo 3Example 3
El análisis por DSC de la fase amorfa presenta una etapa de referencia con un punto medio a 62ºC que se corresponde con la transición vítrea (Tg) seguido por un fenómeno exotérmico que se corresponde con la transición a una fase cristalina y, finalmente, un pico de fusión agudo con un inicio a 183ºC y un máximo a 185ºC.DSC analysis of the amorphous phase presents a reference stage with a midpoint at 62 ° C that is corresponds to the glass transition (Tg) followed by a phenomenon exothermic that corresponds to the transition to a phase crystalline and, finally, an acute fusion peak with a beginning to 183 ° C and a maximum at 185 ° C.
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Ejemplo 4Example 4
En el análisis por TG de la fase amorfa se observa pérdida de peso a temperaturas superiores a 287ºC debido a la descomposición, y no se observa pérdida de peso a temperaturas inferiores.In the TG analysis of the amorphous phase, observes weight loss at temperatures above 287 ° C due to decomposition, and no weight loss is observed at temperatures lower.
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Ejemplo 5Example 5
El espectro de FTIR de la fase amorfa muestra los siguientes picos característicos: 1475 y 1089 cm^{-1}, mientras que no muestra ningún pico a 1515 \pm 5, 837 \pm 5 y 658 \pm 5 cm^{-1}.The FTIR spectrum of the amorphous phase shows the following characteristic peaks: 1475 and 1089 cm -1, while showing no peak at 1515 ± 5, 837 ± 5 and 658 ± 5 cm -1.
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Ejemplo 6Example 6
El espectro de FTRaman de la fase amorfa muestra bandas a 3067, 2940, 1667, 1589, 1392, 1242, 1090, 781 y 662 cm^{-1}.The FTRaman spectrum of the amorphous phase shows bands at 3067, 2940, 1667, 1589, 1392, 1242, 1090, 781 and 662 cm -1.
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Ejemplo 8Example 8
El patrón de difracción de rayos X en polvo convencional de la fase amorfa no muestra ningún pico estrecho o significativo.X-ray powder diffraction pattern Conventional amorphous phase shows no narrow peak or significant.
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Se determinó la afinidad de los compuestos de pirazolina sustituidos de la invención por los receptores CB_{1}/CB_{2}, tal como se describió anteriormente. Algunos de los valores obtenidos se facilitan en la siguiente tabla I:The affinity of the compounds of substituted pyrazoline of the invention by the receptors CB1 / CB2, as described above. Some of The values obtained are given in the following table I:
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Como puede observarse a partir de los valores facilitados en la tabla 1, los compuestos de pirazolina de la invención son particularmente adecuados para regular el receptor de CB_{1}.As can be seen from the values provided in table 1, the pyrazoline compounds of the invention are particularly suitable for regulating the receiver of CB_ {1}.
La determinación de la actividad cannabinoide se determinó tal como se describió anteriormente. Algunos de los valores obtenidos se facilitan en la siguiente tabla II:The determination of cannabinoid activity is determined as described above. Some of the values obtained are given in the following table II:
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Como puede observarse a partir de los valores facilitados en la tabla II, los compuestos de pirazolina de la invención muestran un efecto antagonista.As can be seen from the values provided in table II, the pyrazoline compounds of the invention show an antagonistic effect.
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Las pruebas in vivo para determinar la actividad contra la obesidad se llevaron a cabo tal como se describieron anteriormente, mediante lo cual se trataron cuatro grupos diferentes de 10 ratas cada uno como sigue: In vivo tests to determine activity against obesity were carried out as described above, whereby four different groups of 10 rats each were treated as follows:
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Grupo IGroup I
El grupo se trató con vehículo, concretamente goma arábiga (5% en peso) en agua.The group was treated with a vehicle, specifically gum arabic (5% by weight) in water.
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Grupo IIGroup II
Se trató el segundo grupo de ratas con el compuesto N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidropirazol-3-carboxamida de la invención según el ejemplo 1. Dicho compuesto se administró por vía intraperitoneal a las ratas durante un periodo de 14 días en una dosis diaria de (10 mg/kg de peso corporal).The second group of rats was treated with the compound N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydropyrazol-3-carboxamide of the invention according to example 1. Said compound was administered intraperitoneally to rats for a period of 14 days in a daily dose of (10 mg / kg body weight).
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Grupo IIIGroup III
El tercer grupo de ratas se trató con anfetamina, un principio activo conocido para reducir el apetito. Dicho compuesto se administró por vía intraperitoneal a las ratas durante un periodo de 14 días en una dosis diaria de (5 mg/kg de peso corporal).The third group of rats was treated with amphetamine, an active ingredient known to reduce appetite. Said compound was administered intraperitoneally to the rats. over a period of 14 days at a daily dose of (5 mg / kg of body weight).
Como puede observarse a partir de la figura 1, el peso corporal disminuye debido a la administración del compuesto de la invención según el ejemplo 1 y este efecto también se observa después de que haya finalizado el tratamiento.As can be seen from Figure 1, body weight decreases due to the administration of compound of the invention according to example 1 and this effect also It is observed after the treatment is finished.
La figura 2 muestra la reducción de la ingestión de alimentos debido a la administración del compuesto de la invención según el ejemplo 1.Figure 2 shows the reduction of ingestion of food due to the administration of the compound of the invention according to example 1.
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Las pruebas in vivo para determinar la actividad antidepresora de los compuestos de pirazolina de la invención en la prueba de natación forzada se llevaron a cabo tal como se describió anteriormente. En particular, el compuesto según el ejemplo 1 presentó efectos positivos con respecto al tiempo de inmovilización y tiempo de lucha. In vivo tests to determine the antidepressant activity of the pyrazoline compounds of the invention in the forced swimming test were carried out as described above. In particular, the compound according to example 1 had positive effects with respect to the immobilization time and fighting time.
Claims (14)
da.1. Amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxami-
gives.
cm^{-1}.4. Amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide, characterized in that it shows in the FTRaman spectrum bands at 3067 ± 5 cm -1 and / or 2940 ± 5 cm -1 and / or 1667 ± 5 cm -1 and / or 1589 ± 5 cm ^ {-1} and / or 1392 ± 5 cm -1 and / or 1242 ± 5 cm -1 and / or 1090 ± 5 cm -1 and / or 781 ± 5 cm -1 and / or 662 ± 5
cm -1.
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- \quadquad
- con un compuesto de piruvato de fórmula (III)with a pyruvate compound of the formula (III)
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- \quadquad
- en la que G representa un grupo OR, siendo R un radical alquilo C_{1-6} ramificado o no ramificado, o G representa un grupo O^{-}K siendo K un catión, para dar un compuesto de fórmula (IV)in which G represents an OR group, where R is a C 1-6 alkyl radical branched or not branched, or G represents a group O - K with K being a cation, to give a compound of formula (IV)
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- que opcionalmente se aísla y/u opcionalmente se purifica, y que se hace reaccionar con una fenilhidrazina opcionalmente sustituida de fórmula (V)which is optionally isolated and / or optionally purifies, and that is reacted with a phenylhydrazine optionally substituted of formula (V)
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- \quadquad
- o con una sal correspondiente de la misma, bajo atmósfera inerte, para dar un compuesto de fórmula (VI)or with a corresponding salt thereof, under inert atmosphere, to give a compound of formula (VI)
- \quadquad
- que opcionalmente se aísla y/u opcionalmente se purifica, y se transfiere opcionalmente bajo una atmósfera inerte a un compuesto de fórmula (VII) por medio de la reacción con un agente activantewhich is optionally isolated and / or optionally purifies, and is optionally transferred under an inert atmosphere to a compound of formula (VII) by reaction with a activating agent
- \quadquad
- en la que A representa un grupo saliente, aislándose opcionalmente y/o purificándose opcionalmente dicho compuesto, y al menos un compuesto de fórmula general (VII) se hace reaccionar con un compuesto de fórmulain which A represents a leaving group, isolating optionally and / or optionally purifying said compound, and at least one compound of general formula (VII) is reacted with a compound of formula
- \quadquad
- bajo atmósfera inerte para dar (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida, que opcionalmente se aísla y/u opcionalmente se purifica,under inert atmosphere to give (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide, which is optionally isolated and / or optionally purify,
- \quadquad
- seguido por una etapa de fusión en la que la (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida se funde y posteriormente una etapa de enfriamiento, en la que la masa fundida se enfría hasta temperatura ambiente (25ºC) o inferior, para dar la fase amorfa de (rac)-N-piperidinil-5-(4-clorofenil)-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida.followed by a fusion stage in which the (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide a cooling stage is subsequently melted, in which the melt is cooled to room temperature (25 ° C) or lower, to give the amorphous phase of (rac) -N-piperidinyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4,5-dihydro-1 H -pyrazol-3-carboxamide.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05384033 | 2005-07-29 | ||
EP05384033A EP1757589A1 (en) | 2005-07-29 | 2005-07-29 | Amorphous phase of a substituted pyrazoline, its preparation and use as medicament |
US70545405P | 2005-08-05 | 2005-08-05 | |
US60/705,454 | 2005-08-05 |
Publications (2)
Publication Number | Publication Date |
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ES2326357A1 true ES2326357A1 (en) | 2009-10-07 |
ES2326357B1 ES2326357B1 (en) | 2010-04-21 |
Family
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ES200850020A Expired - Fee Related ES2326357B1 (en) | 2005-07-29 | 2006-07-27 | AMORFA PHASE OF A REPLACED PIRAZOLINE, ITS PREPARATION AND ITS USE AS A MEDICINAL PRODUCT. |
Country Status (2)
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ES (1) | ES2326357B1 (en) |
WO (1) | WO2007017124A1 (en) |
Families Citing this family (11)
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EP2061767B1 (en) | 2006-08-08 | 2014-12-17 | Sanofi | Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use |
EP2025674A1 (en) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs |
TW201014822A (en) | 2008-07-09 | 2010-04-16 | Sanofi Aventis | Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof |
WO2010068601A1 (en) | 2008-12-08 | 2010-06-17 | Sanofi-Aventis | A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof |
DK2470552T3 (en) | 2009-08-26 | 2014-02-17 | Sanofi Sa | NOVEL, CRYSTALLINE, heteroaromatic FLUORGLYCOSIDHYDRATER, MEDICINES COVERING THESE COMPOUNDS AND THEIR USE |
US8933024B2 (en) | 2010-06-18 | 2015-01-13 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
US8828994B2 (en) | 2011-03-08 | 2014-09-09 | Sanofi | Di- and tri-substituted oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2012120053A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2012120056A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
WO2012120055A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
US8901114B2 (en) | 2011-03-08 | 2014-12-02 | Sanofi | Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005074920A1 (en) * | 2004-01-30 | 2005-08-18 | Solvay Pharmaceuticals B.V. | 1,3,5-trisubstituted 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity |
-
2006
- 2006-07-27 ES ES200850020A patent/ES2326357B1/en not_active Expired - Fee Related
- 2006-07-27 WO PCT/EP2006/007416 patent/WO2007017124A1/en active IP Right Grant
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005074920A1 (en) * | 2004-01-30 | 2005-08-18 | Solvay Pharmaceuticals B.V. | 1,3,5-trisubstituted 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity |
Non-Patent Citations (2)
Title |
---|
J. P. MESCHLER et al., "{}Inverse agonist properties of N- (piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide HCl (SR-141716A) and 1-(2- chlorophenyl)-4-cyano-5-(4-metoxyphenyl)-1H-pyrazole-3- carboxylic acid phenylamide (CP-272871) for the CB1 cannabinoid receptor"{}, Biochem. Pharmacol., 2000, vol. 60, páginas 1315-1323, ver figura 1, compuesto SR-141716A. * |
J. P. MESCHLER et al., "Inverse agonist properties of N- (piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide HCl (SR-141716A) and 1-(2- chlorophenyl)-4-cyano-5-(4-metoxyphenyl)-1H-pyrazole-3- carboxylic acid phenylamide (CP-272871) for the CB1 cannabinoid receptor", Biochem. Pharmacol., 2000, vol. 60, páginas 1315-1323, ver figura 1, compuesto SR-141716A. * |
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ES2326357B1 (en) | 2010-04-21 |
WO2007017124A1 (en) | 2007-02-15 |
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