ES2325569A1 - Cycloalkane-substituted pyrazoline compounds, their preparation and use as medicaments - Google Patents
Cycloalkane-substituted pyrazoline compounds, their preparation and use as medicaments Download PDFInfo
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- ES2325569A1 ES2325569A1 ES200850015A ES200850015A ES2325569A1 ES 2325569 A1 ES2325569 A1 ES 2325569A1 ES 200850015 A ES200850015 A ES 200850015A ES 200850015 A ES200850015 A ES 200850015A ES 2325569 A1 ES2325569 A1 ES 2325569A1
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- Prior art keywords
- alkyl
- substituted
- aryl
- heterocyclyl
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- 239000003814 drug Substances 0.000 title claims abstract description 53
- 150000003219 pyrazolines Chemical class 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
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- 238000011282 treatment Methods 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 99
- -1 trifluoromethylthio, trifluoromethoxy, methylsulfonyl Chemical group 0.000 claims description 79
- 239000000460 chlorine Substances 0.000 claims description 68
- 150000003839 salts Chemical class 0.000 claims description 68
- 229910052794 bromium Inorganic materials 0.000 claims description 67
- 229910052801 chlorine Inorganic materials 0.000 claims description 66
- 229910052740 iodine Inorganic materials 0.000 claims description 52
- 229910052731 fluorine Inorganic materials 0.000 claims description 49
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 43
- 239000002253 acid Substances 0.000 claims description 42
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 38
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- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 5
- NNVSXGVCXJHPAO-UHFFFAOYSA-N 3-(4-chlorophenyl)-n-cycloheptyl-2-(2,4-dichlorophenyl)-3,4-dihydropyrazole-5-carboxamide Chemical compound C1=CC(Cl)=CC=C1C1N(C=2C(=CC(Cl)=CC=2)Cl)N=C(C(=O)NC2CCCCCC2)C1 NNVSXGVCXJHPAO-UHFFFAOYSA-N 0.000 claims description 5
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
Description
Compuestos de pirazolina cicloalcanosustituidos, su preparación y su uso como medicamentos.Compounded cycloalkane pyrazoline compounds, its preparation and its use as medicines.
La presente invención se refiere a compuestos de pirazolina cicloalcanosustituidos, métodos para su preparación, medicamentos que comprenden estos compuestos, además de su uso para la preparación de un medicamento para el tratamiento de seres humanos y animales.The present invention relates to compounds of substituted cycloalkane pyrazoline, methods for its preparation, medicines comprising these compounds, in addition to their use for the preparation of a medicine for the treatment of beings humans and animals
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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 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 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 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.
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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}).An object of the present invention was 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).
Se consiguió dicho objeto proporcionando los compuestos de pirazolina cicloalcanosustituidos de fórmula I facilitados a continuación, sus estereoisómeros, sales correspondientes y solvatos correspondientes de los mismos.This object was achieved by providing the substituted cycloalkane pyrazoline compounds of formula I provided below, its stereoisomers, salts corresponding and corresponding solvates thereof.
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 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, the immune system, the cardiovascular system, the endocrine system, the respiratory system, the tract gastrointestinal or with reproduction in humans and / or animals, preferably in humans including infants, Children and seniors.
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Por tanto, en uno de sus aspectos la presente invención se refiere a compuestos de pirazolina cicloalcanosustituidos de fórmula general I,Therefore, in one of its aspects this invention relates to pyrazoline compounds substituted cycloalkanes of general formula I,
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en la quein the that
X e Y independientemente representan fenilo, tienilo, naftilo o piridilo, cuyos grupos puede estar sustituidos con 1, 2 ó 3 sustituyentes W, que pueden ser igual o diferentes, seleccionados del grupoX and Y independently represent phenyl, thienyl, naphthyl or pyridyl, whose groups may be substituted with 1, 2 or 3 substituents W, which may be the same or different, selected from the group
- \quadquad
- alquilo C_{1-3} ramificado o lineal o alcoxi C_{1-3} ramificado o lineal, fenilo, hidroxilo, cloro, bromo, fluoro, yodo, SH, trifluorometilo, CHF_{2}, CH_{2}F, OCHF_{2}, trifluorometiltio, trifluorometoxi, metilsulfonilo, carboxilo, trifluorometilsulfonilo, ciano, carbamoílo, sulfamoílo y acetilo; O-P, indicando P un grupo profármaco que consiste en arilo, alquilo C_{8-20}, heterociclilo, C(O)-arilo, C(O)-heterociclilo, C(O)- alquilo C_{1-20};C 1-3 branched alkyl or linear or branched or linear C 1-3 alkoxy, phenyl, hydroxyl, chlorine, bromine, fluoro, iodine, SH, trifluoromethyl, CHF 2, CH 2 F, OCHF 2, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl; O-P, indicating P a prodrug group consisting in aryl, C 8-20 alkyl, heterocyclyl, C (O) -aryl, C (O) -heterocyclyl, C (O) - alkyl C 1-20;
- R^{8} representa un cicloalquilo no sustituido o al menos monosustituido con 1, 2 ó 3 sustituyentes Z, que pueden ser igual o diferentes, seleccionados del grupo:- R 8 represents a cycloalkyl not substituted or at least monosubstituted with 1, 2 or 3 Z substituents, which may be the same or different, selected from the group:
- \quadquad
- H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2};H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2;
- n siendo 0 ó 1- n being 0 or 1
opcionalmente en forma de su racemato, estereoisómeros puros, especialmente enantiómeros o diastereómeros, o en forma de las mezclas de estereoisómeros, especialmente enantiómeros o diastereómeros, en cualquier razón de mezcla;optionally in the form of your racemate, pure stereoisomers, especially enantiomers or diastereomers, or in the form of stereoisomer mixtures, especially enantiomers or diastereomers, in any reason of mixing;
en la forma mostrada o en forma del ácido o la
base o en forma de una sal, especialmente una sal fisiológicamente
aceptable, o en forma de un solvato, especialmente un hidrato o en
forma del N-óxido correspondiente de los
mismos.in the form shown or in the form of the acid or base or in the form of a salt, especially a physiologically acceptable salt, or in the form of a solvate, especially a hydrate or in the form of the corresponding N-oxide of the
same.
En un aspecto preferido de este aspecto de la invención, R^{8} es cicloalquilo C_{7-8} no sustituido o al menos monosustituido con 1, 2 ó 3 sustituyentes Z, que pueden ser igual o diferentes, seleccionados del grupo:In a preferred aspect of this aspect of the invention, R 8 is C 7-8 cycloalkyl not substituted or at least monosubstituted with 1, 2 or 3 Z substituents, which may be the same or different, selected from the group:
- \quadquad
- H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2}.H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2.
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En otro aspecto muy preferido, la presente invención se refiere a compuestos de pirazolina cicloalcanosustituidos de fórmula general I,In another very preferred aspect, the present invention relates to pyrazoline compounds substituted cycloalkanes of general formula I,
en la quein the that
X e Y independientemente representan fenilo, tienilo, naftilo o piridilo, cuyos grupos puede estar sustituidos con 1, 2 ó 3 sustituyentes W, que pueden ser igual o diferentes, seleccionados del grupoX and Y independently represent phenyl, thienyl, naphthyl or pyridyl, whose groups may be substituted with 1, 2 or 3 substituents W, which may be the same or different, selected from the group
- \quadquad
- alquilo C_{1-3} ramificado o lineal o alcoxi C_{1-3} ramificado o lineal, fenilo, hidroxilo, cloro, bromo, fluoro, yodo, SH, trifluorometilo, CHF_{2}, CH_{2}F, OCHF_{2}, trifluorometiltio, trifluorometoxi, metilsulfonilo, - carboxilo, trifluorometilsulfonilo, ciano, carbamoílo, sulfamoílo y acetilo; O-P, indicando P un grupo profármaco que consiste en arilo, alquilo C_{8-20}, heterociclilo, C(O)-arilo, C(O)-heterociclilo, C(O)-alquilo C_{1-20};C 1-3 branched alkyl or linear or branched or linear C 1-3 alkoxy, phenyl, hydroxyl, chlorine, bromine, fluoro, iodine, SH, trifluoromethyl, CHF 2, CH 2 F, OCHF 2, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, - carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl; O-P, indicating P a prodrug group consisting in aryl, C 8-20 alkyl, heterocyclyl, C (O) -aryl, C (O) -heterocyclyl, C (O) -alkyl C 1-20;
- R^{8} representa un cicloalquilo C_{7-8} no sustituido o al menos monosustituido con 1, 2 ó 3 sustituyentes Z, que pueden ser igual o diferentes, seleccionados del grupo:- R 8 represents a cycloalkyl C_ {7-8} unsubstituted or at least monosubstituted with 1, 2 or 3 Z substituents, which may be the same or different, selected from the group:
- \quadquad
- H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2};H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2;
- n siendo 0 ó 1- n being 0 or 1
opcionalmente en forma de su racemato, estereoisómeros puros, especialmente enantiómeros o diastereómeros, o en forma de las mezclas de estereoisómeros, especialmente enantiómeros o diastereómeros, en cualquier razón de mezcla; en la forma mostrada o en forma del ácido o la base o en forma de una sal, especialmente una sal fisiológicamente aceptable, o en forma de un solvato, especialmente un hidrato o en forma del N-óxido correspondiente de los mismos.optionally in the form of your racemate, pure stereoisomers, especially enantiomers or diastereomers, or in the form of stereoisomer mixtures, especially enantiomers or diastereomers, in any reason of mixing; in the form shown or in the form of the acid or base or in the form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate or in the form of N-oxide corresponding thereof.
En el contexto de esta invención, se entiende que el radical o grupo alquilo significan hidrocarburos saturados e insaturados, lineales o ramificados, que pueden estar no sustituidos o monosustituidos o polisustituidos. Por tanto, por alquilo insaturado se entiende que comprende grupos alquenilo e alquinilo, como, por ejemplo, -CH=CH-CH_{3} o -C\equivC-CH_{3}, mientras que alquilo saturado comprende, por ejemplo, -CH_{3} y -CH_{2}-CH_{3}. En estos radicales, alquilo C_{1-2} representa alquilo C1- o C2-, alquilo C_{1-3} representa alquilo C1-, C2- o C3, alquilo C_{1-4} representa alquilo C1-, C2-, C3- o C4, alquilo C_{1-5} representa alquilo C1-, C2-, C3-, C4-, o C5, alquilo C_{1-6} representa alquilo C1-, C2-, C3-, C4-, C5- o C6, alquilo C_{1-7} representa alquilo C1-, C2-, C3-, C4-, C5-, C6- o C7, alquilo C_{1-8} representa alquilo C1-, C2-, C3-, C4-, C5-, C6-, C7- o C8-alquilo, alquilo C_{1-10} representa alquilo C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- o C10 y alquilo C_{1-18} representa alquilo C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- o C18. Los radicales alquilo son preferiblemente metilo, etilo, vinilo (etenilo), propilo, alilo (2-propenilo), 1-propinilo, metiletilo, butilo, 1-metilpropilo, 2-metilpropilo, 1,1-dimetiletilo, pentilo, 1,1-dimetilpropilo, 1,2-dimetilpropilo, 2,2-dimetilpropilo, hexilo, 1- metilpentilo, si está sustituido también CHF_{2}, CF_{3} o CH_{2}OH, etc.In the context of this invention, it is understood that the radical or alkyl group means saturated hydrocarbons and unsaturated, linear or branched, which may not be substituted or monosubstituted or polysubstituted. Therefore for unsaturated alkyl is understood to comprise alkenyl groups and alkynyl, such as -CH = CH-CH 3 or -C? -CH3, while saturated alkyl it comprises, for example, -CH 3 and -CH_ {2} -CH_ {3}. In these radicals, alkyl C 1-2 represents C1- or C2- alkyl, alkyl C 1-3 represents C1-, C2- or C3 alkyl, alkyl C 1-4 represents C1-, C2-, C3- or C4 alkyl, C 1-5 alkyl represents C1-, C2-, C3- alkyl, C4-, or C5, C1-6 alkyl represents C1- alkyl, C2-, C3-, C4-, C5- or C6, C 1-7 alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7 alkyl, alkyl C 1-8 represents C1-, C2-, C3-, C4- alkyl C5-, C6-, C7- or C8-alkyl, alkyl C 1-10 represents C1-, C2-, C3-, C4- alkyl, C5-, C6-, C7-, C8-, C9- or C10 and C 1-18 alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, alkyl C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18. The radicals alkyl are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1- methylpentyl, if it is also substituted CHF2, CF3 or CH2OH, etc.
En el contexto de la invención, se entiende que el radical o grupo cicloalquilo significan hidrocarburos cíclicos saturados e insaturados (pero no aromáticos) (sin heteroátomo en el anillo), que pueden estar no sustituidos o monosustituidos o polisustituidos. Además, cicloalquilo C_{3-4} representa cicloalquilo C3- o C4, cicloalquilo C_{3-5} representa cicloalquilo C3-, C4- o C5-cicloalquilo, cicloalquilo C_{3-6} representa cicloalquilo C3-, C4-, C5- o C6, cicloalquilo C_{3-7} representa cicloalquilo C3-, C4-, C5-, C6- o C7-, cicloalquilo C_{3-8} representa cicloalquilo C3-, C4-, C5-, C6-, C7- o C8, cicloalquilo C_{4-5} representa cicloalquilo C4- o C5, cicloalquilo C_{4-6} representa cicloalquilo C4-, C5- o C6, cicloalquilo C_{4-7} representa cicloalquilo C4-, C5-, C6- o C7, C_{4-8} representa cicloalquilo C4-, C5-, C6-, C7- o C8, cicloalquilo C_{5-6} representa cicloalquilo C5- o C6 y cicloalquilo C_{5-7} representa cicloalquilo C5-, C6- o C7-. Sin embargo, los cicloalquilos monoinsaturados o poliinsaturados, preferiblemente monoinsaturados, estarán dentro del término cicloalquilo siempre y cuando el cicloalquilo no sea un sistema aromático. Los radicales alquilo y cicloalquilo son preferiblemente metilo, etilo, vinilo (etenilo), propilo, alilo (2-propenilo), 1-propinilo, metiletilo, butilo, 1-metilpropilo, 2-metilpropilo, 1,1-dimetiletilo, pentilo, 1,1-dimetilpropilo, 1,2-dimetilpropilo, 2,2-dimetilpropilo, hexilo, 1-metilpentilo, ciclopropilo, 2-metilciclopropilo, ciclopropilmetilo, ciclobutilo, ciclopentilo, ciclopentilmetilo, ciclohexilo, cicloheptilo, ciclooctilo, y también adamantilo.In the context of the invention, it is understood that the radical or cycloalkyl group means cyclic hydrocarbons saturated and unsaturated (but not aromatic) (no heteroatom in the ring), which may be unsubstituted or monosubstituted or polysubstituted In addition, C 3-4 cycloalkyl represents C3- or C4 cycloalkyl, cycloalkyl C 3-5 represents C3-, C4- or cycloalkyl C5-cycloalkyl, cycloalkyl C 3-6 represents C3-, C4-, C5- or cycloalkyl C6, C 3-7 cycloalkyl represents cycloalkyl C3-, C4-, C5-, C6- or C7-, C 3-8 cycloalkyl represents C3-, C4-, C5-, C6-, C7- or C8 cycloalkyl, cycloalkyl C 4-5 represents C4- or C5 cycloalkyl, C 4-6 cycloalkyl represents C4- cycloalkyl, C5- or C6, C 4-7 cycloalkyl represents C4-, C5-, C6- or C7 cycloalkyl, C 4-8 represents C4-, C5-, C6-, C7- or C8 cycloalkyl, cycloalkyl C 5-6 represents C5- or C6 cycloalkyl and C 5-7 cycloalkyl represents C5- cycloalkyl, C6- or C7-. However, monounsaturated cycloalkyl or polyunsaturated, preferably monounsaturated, will be within the term cycloalkyl as long as the cycloalkyl is not a aromatic system The alkyl and cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl.
En relación con el grupo alquilo o alifático - a menos que se defina lo contrario - se entiende que el término sustituido en el contexto de esta invención significa sustitución de al menos un radical hidrógeno por F, Cl, Br, I, NH_{2}, SH o OH, se entiende que radicales "polisustituidos" significa que la sustitución tiene lugar tanto en átomos diferentes como varias veces en el mismo átomo con el mismo sustituyente o con sustituyentes diferentes, por ejemplo tres veces en el mismo átomo de C, como en el caso de CF_{3}, o en lugares diferentes, como en el caso de, por ejemplo, -CH(OH)-CH=CH-CHCl_{2}.In relation to the alkyl or aliphatic group - a unless otherwise defined - it is understood that the term substituted in the context of this invention means replacement of at least one hydrogen radical by F, Cl, Br, I, NH2, SH or OH, it is understood that "polysubstituted" radicals means that the substitution takes place in both different and several atoms times in the same atom with the same substituent or with different substituents, for example three times on the same atom of C, as in the case of CF_ {3}, or in different places, as in the case of, for example, -CH (OH) -CH = CH-CHCl2.
Se entiende que el término (CH_{2})_{3-6} significa -CH_{2}-CH_{2}-CH_{2}-, -CH_{2}-CH_{2}-CH_{2}-CH_{2}-, -CH_{2}-CH_{2}-CH_{2}-CH_{2}-CH_{2}- y -CH_{2}-CH_{2}-CH_{2}-CH_{2}-CH_{2}-CH_{2}-, se entiende que (CH_{2})_{1-4} significa -CH_{2}-, -CH_{2}-CH_{2}-, -CH_{2}-CH_{2}-CH_{2}- y -CH_{2}-CH_{2}-CH_{2}-CH_{2}-, se entiende que (CH_{2})_{4-5} Significa -CH_{2}-CH_{2}-CH_{2}-CH_{2}- y -CH_{2}-CH_{2}-CH_{2}-CH_{2}-CH_{2}-, etc.It is understood that the term (CH 2) 3-6 means -CH_ {2} -CH_ {2} -CH_ {2} -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} - Y -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {-} it is understood that (CH2) 1-4 means -CH_ {2} -, -CH_ {2} -CH_ {2} -, -CH_ {2} -CH_ {2} -CH_ {2} - and -CH 2 -CH 2 -CH 2 -CH 2 -, It is understood that (CH 2) 4-5 Means -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} - Y -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} -CH_ {2} -, etc.
Se entiende que un grupo o radical arilo significa un sistema en anillo con al menos un anillo aromático pero sin heteroátomos incluso en sólo uno de los anillos. Los ejemplos son fenilo, naftilo, fluorantenilo, fluorenilo, tetralinilo o indanilo, en particular radicales 9H-fluorenilo o antracenilo, que pueden estar no sustituidos, monosustituidos o polisustituidos.It is understood that an aryl group or radical means a ring system with at least one aromatic ring but without heteroatoms even in only one of the rings. The Examples are phenyl, naphthyl, fluorantenyl, fluorenyl, tetralinyl or indanyl, particularly radicals 9H-fluorenyl or anthracenyl, which may be not substituted, monosubstituted or polysubstituted.
En el contexto de esta invención, se entiende que alquil-arilo significa un grupo arilo (ver anteriormente) que está conectado a otro átomo a través de un grupo alquilo (ver anteriormente) (preferiblemente un alquilo C_{1-4}), mientras que el alquilo siempre está saturado y lineal o ramificado siempre se refiere al alquilo. Entre los ejemplos se incluye un grupo bencilo.In the context of this invention, it is understood what alkyl-aryl means an aryl group (see above) that is connected to another atom through a group alkyl (see above) (preferably an alkyl C_ {1-4}), while the alkyl is always saturated and linear or branched always refers to alkyl. Between Examples include a benzyl group.
Se entiende que un grupo o radical heterociclilo significa sistemas en anillo heterocíclicos, saturados o insaturados, que contienen uno o más heteroátomos en el anillo del grupo que consiste en nitrógeno, oxígeno y/o azufre y pueden también estar monosustituidos o polisustituidos. Se pueden mencionar ejemplos del grupo heterociclilo que son furano, benzofurano, tiofeno, benzotiofeno, pirrol, piridina, pirimidina, pirazina, quinolina, isoquinolina, ftalazina, benzo-1,2,5-tiadiazol, benzotiazol, indol, benzotriazol, benzodioxolano, benzodioxano, carbazol y quinazolina.It is understood that a heterocyclyl group or radical means heterocyclic ring systems, saturated or unsaturated, containing one or more heteroatoms in the ring of the group consisting of nitrogen, oxygen and / or sulfur and can also be monosubstituted or polysubstituted. Can be mention examples of the heterocyclyl group that are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole and quinazoline
En el contexto de esta invención, se entiende que alquil-heterociclilo significa un grupo heterociclilo (ver anteriormente) que está conectado a otro átomo a través de un grupo alquilo (ver anteriormente) (preferiblemente un alquilo C_{1-4}), mientras que el alquilo siempre está saturado y lineal o ramificado siempre se refiere al alquilo.In the context of this invention, it is understood what alkyl heterocyclyl means a group heterocyclyl (see above) that is connected to another atom at through an alkyl group (see above) (preferably a C 1-4 alkyl), while alkyl always is saturated and linear or branched always refers to the I rent.
En relación con arilo, alquil-arilo, cicloalquilo o alquil-cicloalquilo, heterociclilo o alquil-heterociclilo, sustituido se entiende - a menos que se defina lo contrario - la sustitución del sistema anular del arilo o alquil-arilo, cicloalquilo o alquil-cicloalquilo; heterociclilo o alquil-heterociclilo por OH, SH. =O, halcogeno (F, Cl, Br, I), CN, NO_{2}, COOH; NHR_{x}R_{y}, siendo R_{x}y R_{y}, independientemente, o H o alquilo C_{1-6} saturado o insaturado, lineal o ramificado, sustituido o no sustituido; alquilo C_{1-6} saturado o insaturado, lineal o ramificado, sustituido o no sustituido; -O-alquilo C_{1-6} (alcoxi) saturado o insaturado, lineal o ramificado, sustituido o no sustituido; -S-alquilo C_{1-6} saturado o insaturado, lineal o ramificado, sustituido o no sustituido; un grupo -C(O)-alquilo C_{1-6} saturado o insaturado, lineal o ramificado, sustituido o no sustituido; un grupo -C(O)-O-alquilo C_{1-6} saturado o insaturado, lineal o ramificado, sustituido o no sustituido; un arilo o alquil-arilo sustituido o no sustituido; un cicloalquilo o alquil-cicloalquilo sustituido o no sustituido; un heterociclilo o alquil-heterociclilo sustituido o no sustituido.In relation to aryl, alkyl-aryl, cycloalkyl or alkyl-cycloalkyl, heterocyclyl or alkyl-heterocyclyl, substituted is understood - a unless otherwise defined - system replacement annular aryl or alkyl-aryl, cycloalkyl or alkylcycloalkyl; heterocyclyl or alkyl heterocyclyl by OH, SH. = O, halogen (F, Cl, Br, I), CN, NO2, COOH; NHR_ {R} {y}, where R_ {y} is R y, independently, or H or C 1-6 alkyl saturated or unsaturated, linear or branched, substituted or not replaced; C 1-6 alkyl saturated or unsaturated, linear or branched, substituted or unsubstituted; -O-C 1-6 alkyl (alkoxy) saturated or unsaturated, linear or branched, substituted or not replaced; -S-C 1-6 alkyl saturated or unsaturated, linear or branched, substituted or not replaced; a group -C (O) -alkyl C_ {1-6} saturated or unsaturated, linear or branched, substituted or unsubstituted; a group -C (O) -O-alkyl C_ {1-6} saturated or unsaturated, linear or branched, substituted or unsubstituted; an aryl or substituted or unsubstituted alkyl aryl; a cycloalkyl or substituted or non-substituted alkyl cycloalkyl replaced; a heterocyclyl or alkyl-heterocyclyl substituted or unsubstituted.
Se entiende que el término "sal" significa cualquier forma de compuesto activo usado según la invención en la que se asume una forma iónica o está cargada y se acopla con un contraión (un catión o un anión) o está en disolución. También debe entenderse complejos de los compuestos activos con otras moléculas e iones, en particular complejos que se acomplejan a través de interacciones iónicas.It is understood that the term "salt" means any form of active compound used according to the invention in the that an ionic form is assumed or charged and coupled with a counterion (a cation or an anion) or is in solution. Must also understood as complexes of the active compounds with other molecules and ions, in particular complexes that are complexed through ionic interactions.
El término "sal fisiológicamente aceptable" significa en el contexto de esta invención cualquier sal que se tolera fisiológicamente (la mayor parte del tiempo significa que no es especialmente tóxico no causada por el contraión) si se usa apropiadamente para un tratamiento especialmente si se usa en, o se aplica, a seres humanos y/o mamíferos.The term "physiologically acceptable salt" means in the context of this invention any salt that is tolerates physiologically (most of the time means no it is especially toxic not caused by the counterion) if used appropriately for a treatment especially if used in, or It applies to humans and / or mammals.
Estas sales fisiológicamente aceptables pueden formarse con cationes o bases y se entiende que en el contexto de esta invención significan sales de al menos uno de los compuestos usados según la invención - normalmente un ácido (desprotonado)- como un anión con al menos un catión preferiblemente inorgánico, que se tolera fisiológicamente, especialmente si se usa en seres humanos y/o mamíferos. Se prefieren de forma particular las sales de metales alcalinos y alcalinotérreos, y también aquellas sales de NH4, pero en particular sales (mono)- o (di)sódicas, (mono)- o (di)potásicas, magnésicas o cálcicas.These physiologically acceptable salts can form with cations or bases and it is understood that in the context of this invention means salts of at least one of the compounds used according to the invention - normally an acid (deprotonated) - as an anion with at least one preferably inorganic cation, which is physiologically tolerated, especially if used in beings humans and / or mammals. Salts are particularly preferred of alkali and alkaline earth metals, and also those salts of NH4, but in particular (mono) - or (di) sodium salts, (mono) - or (di) potassium, magnesium or calcium.
Estas sales fisiológicamente aceptables pueden también formarse con aniones o ácidos se entiende que en el contexto de esta invención significan sales de al menos uno de los compuestos usados según la invención -normalmente protonados, por ejemplo en el nitrógeno- como el catión con al menos un anión que se toleran fisiológicamente - especialmente si se usan en seres humanos y/o mamíferos. Se entiende por esto, en particular, en el contexto de esta invención, la sal formada con un ácido tolerado fisiológicamente, es decir sales del compuesto activo particular con ácidos orgánicos e inorgánicos que se toleran fisiológicamente especialmente si se usan en seres humanos y/o mamíferos. Ejemplos de sales toleradas fisiológicamente de ácidos particulares son sales de ácido clorhídrico, ácido bromhídrico, ácido sulfúrico, ácido metanosulfónico, ácido fórmico, ácido acético, ácido oxálico, ácido succínico, ácido málico, ácido tartárico, ácido mandélico, ácido fumárico, ácido láctico o ácido cítrico.These physiologically acceptable salts can also be formed with anions or acids it is understood that in the context of this invention mean salts of at least one of the compounds used according to the invention - normally protonated, by example in nitrogen- like the cation with at least one anion that they are physiologically tolerated - especially if used on beings humans and / or mammals. It is understood by this, in particular, in the context of this invention, the salt formed with a tolerated acid physiologically, ie salts of the particular active compound with organic and inorganic acids that are physiologically tolerated especially if used in humans and / or mammals. Examples of physiologically tolerated salts of particular acids are salts of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
Los compuestos de la presente invención pueden estar en forma cristalina o como compuestos libres o como solvatos y se pretende que estas formas estén dentro del alcance de la presente invención. Los métodos de solvatación son generalmente conocidos en la técnica. Los solvatos adecuados son solvatos farmacéuticamente aceptables. Se entiende que el término "solvato" según esta invención significa cualquier forma de compuesto activo según la invención en la que el compuesto está unido a través de uniones no covalentes a otra molécula (más probablemente un disolvente polar) que incluye especialmente hidratos y alcoholatos, por ejemplo metanolato.The compounds of the present invention can be in crystalline form or as free compounds or as solvates and it is intended that these forms are within the scope of the present invention Solvation methods are generally known in the art. Suitable solvates are solvates pharmaceutically acceptable. It is understood that the term "solvate" according to this invention means any form of active compound according to the invention in which the compound is bound through non-covalent bonds to another molecule (more probably a polar solvent) that especially includes hydrates and alcoholates, for example methanolate.
A menos que se diga lo contrario, los compuestos de la invención incluyen compuestos que difieren sólo en la presencia de uno o más átomos enriquecidos de forma isotópica. Por ejemplo, compuestos que tienen las presentes estructuras excepto por la sustitución de un carbono por carbono enriquecido ^{13}C- o ^{14}C- o nitrógeno enriquecido ^{15}N están dentro del alcance de esta invención.Unless stated otherwise, the compounds of the invention include compounds that differ only in the presence of one or more atoms enriched in an isotopic manner. By example, compounds having the present structures except by the substitution of a carbon for enriched carbon 13 C- or 14 C- or enriched nitrogen 15 N are within the scope of this invention.
Los compuestos de fórmula (I) o sus sales o solvatos están preferiblemente en forma farmacéuticamente aceptable o sustancialmente pura. Por forma farmacéuticamente aceptable se entiende, entre otras cosas, que tiene un nivel de pureza farmacéuticamente aceptable excluyendo los aditivos farmacéuticos normales, tales como diluyentes y portadores, e incluyendo el material no considerado tóxico en niveles de dosificación normales. Los niveles de pureza para la sustancia fármaco están preferiblemente por encima del 50%, más preferiblemente por encima del 70%, aún más preferiblemente por encima del 90%. En una realización preferida, está por encima del 95% del compuesto de fórmula (I), o, de sus sales, solvatos o profármacos.The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable form or substantially pure. By pharmaceutically acceptable form it understand, among other things, that it has a level of purity pharmaceutically acceptable excluding pharmaceutical additives normal, such as diluents and carriers, and including the material not considered toxic at normal dosage levels. The purity levels for the drug substance are preferably above 50%, more preferably above 70%, even more preferably above 90%. In a preferred embodiment, is above 95% of the compound of formula (I), or, of its salts, solvates or prodrugs.
En una realización preferida de la invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención tienen las fórmulas generales Ia o IbIn a preferred embodiment of the invention, the cycloalkane pyrazoline compounds substituted according to the present invention have the general formulas Ia or Ib
en la quein the that
X e Y independientemente representan fenilo, tienilo, naftilo o piridilo, cuyos grupos puede estar sustituidos con 1, 2 ó 3 sustituyentes W, que pueden ser igual o diferentes, seleccionados del grupoX and Y independently represent phenyl, thienyl, naphthyl or pyridyl, whose groups may be substituted with 1, 2 or 3 substituents W, which may be the same or different, selected from the group
- \quadquad
- alquilo C_{1-3} ramificado o lineal o alcoxi C_{1-3} ramificado o lineal, fenilo, hidroxilo, cloro, bromo, fluoro, yodo, SH, trifluorometilo, CHF_{2}, CH_{2}F, OCHF_{2}, trifluorometiltio, trifluorometoxi, metilsulfonilo, carboxilo, trifluorometilsulfonilo, ciano, carbamoílo, sulfamoílo y acetilo; O-P, indicando P un grupo profármaco que consiste en alquilo C_{8-20} o C(O)-alquilo C_{1-20} sustituidos o no sustituidos, ramificados o lineales, saturados o insaturados; arilo, alquil-arilo, heterociclilo o alquil-heterociclilo sustituidos o no sustituidos; C(O)-arilo, C(O)-alquil-arilo, C(O)-heterociclilo o C(O)-alquil-heterociclilo sustituidos o no sustituidos;C 1-3 branched alkyl or linear or branched or linear C 1-3 alkoxy, phenyl, hydroxyl, chlorine, bromine, fluoro, iodine, SH, trifluoromethyl, CHF 2, CH 2 F, OCHF 2, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl; O-P, indicating P a prodrug group consisting in C 8-20 alkyl or C (O) -C 1-20 alkyl substituted or unsubstituted, branched or linear, saturated or unsaturated; aryl, alkyl-aryl, heterocyclyl or substituted or unsubstituted alkyl heterocyclyl; C (O) -aryl, C (O) -alkyl-aryl, C (O) -heterocyclyl or C (O) -alkyl-heterocyclyl substituted or unsubstituted;
- R^{8} representa un cicloalquilo C_{7-8} no sustituido o al menos monosustituido con 1, 2 ó 3 sustituyentes Z, que pueden ser igual o diferentes, seleccionados del grupo:- R 8 represents a cycloalkyl C_ {7-8} unsubstituted or at least monosubstituted with 1, 2 or 3 Z substituents, which may be the same or different, selected from the group:
- \quadquad
- H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2};H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2;
- n siendo 0 ó 1- n being 0 or 1
opcionalmente en la forma mostrada o en forma del ácido o la base o en forma de una sal, especialmente una sal fisiológicamente aceptable, o en forma de un solvato, especialmente un hidrato o en forma del N-óxido correspondiente de los mismos.optionally in the form shown or in form of the acid or base or in the form of a salt, especially a salt physiologically acceptable, or in the form of a solvate, especially a hydrate or in the form of the corresponding N-oxide of the same.
En una realización preferida de la presente invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención tienen la fórmula general IIIn a preferred embodiment of the present invention, the substituted cycloalkane pyrazoline compounds according to the present invention they have the general formula II
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en la quein the that
R^{11}, R^{12}, R^{13} y R^{14}, independientemente entre sí, representan: H; alquilo C_{1-3} ramificado o lineal o alcoxi C_{1-3} ramificado o lineal, fenilo, hidroxilo, cloro, bromo, fluoro, yodo, SH, trifluorometilo, CHF_{2}, CH_{2}F, OCHF_{2}, trifluorometiltio, trifluorometoxi, metilsulfonilo, carboxilo, trifluorometilsulfonilo, ciano, carbamoílo, sulfamoílo y acetilo; alquilo C_{8-20} o C(O)-alquilo C_{1-20} sustituidos o no sustituidos, ramificados o lineales, saturados o insaturados; arilo, alquil-arilo, heterociclilo o alquil-heterociclilo sustituidos o no sustituidos; C(O)-arilo, C(O)-alquil-arilo, C(O)-heterociclilo o C(O)-alquil-heterociclilo sustituidos o no sustituidos;R 11, R 12, R 13 and R 14, independently of each other, they represent: H; I rent C 1-3 branched or linear or alkoxy C 1-3 branched or linear, phenyl, hydroxyl, chlorine, bromine, fluoro, iodine, SH, trifluoromethyl, CHF2, CH 2 F, OCHF 2, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl; I rent C 8-20 or C (O) -alkyl C 1-20 substituted or unsubstituted, branched or linear, saturated or unsaturated; aryl, alkyl-aryl, heterocyclyl or substituted or unsubstituted alkyl heterocyclyl; C (O) -aryl, C (O) -alkyl-aryl, C (O) -heterocyclyl or C (O) -alkyl-heterocyclyl substituted or unsubstituted;
- R^{18} representa un cicloalquilo C_{7-8} no sustituido o al menos monosustituido con 1, 2 ó 3 sustituyentes Z, que pueden ser igual o diferentes, seleccionados del grupo:- R 18 represents a cycloalkyl C_ {7-8} unsubstituted or at least monosubstituted with 1, 2 or 3 Z substituents, which may be the same or different, selected from the group:
- \quadquad
- H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2};H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2;
- m siendo 0 ó 1- m being 0 or 1
opcionalmente en forma de su racemato, estereoisómeros puros, especialmente enantiómeros o diastereómeros, o en forma de las mezclas de estereoisómeros, especialmente enantiómeros o diastereómeros, en cualquier razón de mezcla;optionally in the form of your racemate, pure stereoisomers, especially enantiomers or diastereomers, or in the form of stereoisomer mixtures, especially enantiomers or diastereomers, in any reason of mixing;
en la forma mostrada o en forma del ácido o la
base o en forma de una sal, especialmente una sal fisiológicamente
aceptable, o en forma de un solvato, especialmente un hidrato o en
forma del N-óxido correspondiente de los
mismos.in the form shown or in the form of the acid or base or in the form of a salt, especially a physiologically acceptable salt, or in the form of a solvate, especially a hydrate or in the form of the corresponding N-oxide of the
same.
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En una realización preferida de la presente invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención tienen las fórmulas generales IIa o IIbIn a preferred embodiment of the present invention, the substituted cycloalkane pyrazoline compounds according to the present invention they have the general formulas IIa or IIb
en la quein the that
R^{11}, R^{12}, R^{13} y R^{14}, independientemente entre sí, representan: H; alquilo C_{1-3} ramificado o lineal o alcoxi C_{1-3} ramificado o lineal, fenilo, hidroxilo, cloro, bromo, fluoro, yodo, SH, trifluorometilo, trifluorometiltio, trifluorometoxi, CHF_{2}, CH_{2}F, OCHF_{2}, metilsulfonilo, carboxilo, trifluorometilsulfonilo, ciano, carbamoílo, sulfamoílo y acetilo; alquilo C_{8-20} o C(O)-alquilo C_{1-20} sustituidos o no sustituidos, ramificados o lineales, saturados o insaturados; arilo, alquil-arilo, heterociclilo o alquil-heterociclilo sustituidos o no sustituidos; C(O)-arilo, C(O)-alquil-arilo, C(O)-heterociclilo o C(O)-alquil-heterociclilo sustituidos o no sustituidos;R 11, R 12, R 13 and R 14, independently of each other, they represent: H; I rent C 1-3 branched or linear or alkoxy C 1-3 branched or linear, phenyl, hydroxyl, chlorine, bromine, fluoro, iodine, SH, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, CHF2, CH2F, OCHF2, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl; C 8-20 alkyl or C (O) -C 1-20 alkyl substituted or unsubstituted, branched or linear, saturated or unsaturated; aryl, alkyl-aryl, heterocyclyl or substituted or unsubstituted alkyl heterocyclyl; C (O) -aryl, C (O) -alkyl-aryl, C (O) -heterocyclyl or C (O) -alkyl-heterocyclyl substituted or unsubstituted;
- R^{18} representa un cicloalquilo C_{7-8} no sustituido o al menos monosustituido con 1, 2 ó 3 sustituyentes Z, que pueden ser igual o diferentes, seleccionados del grupo:- R 18 represents a cycloalkyl C_ {7-8} unsubstituted or at least monosubstituted with 1, 2 or 3 Z substituents, which may be the same or different, selected from the group:
- \quadquad
- H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2};H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2;
- m siendo 0 ó 1- m being 0 or 1
opcionalmente en la forma mostrada o en forma del ácido o la base o en forma de una sal, especialmente una sal fisiológicamente aceptable, o en forma de un solvato, especialmente un hidrato o en forma del N-óxido correspondiente de los mismos.optionally in the form shown or in form of the acid or base or in the form of a salt, especially a salt physiologically acceptable, or in the form of a solvate, especially a hydrate or in the form of the corresponding N-oxide of the same.
En una realización preferida de la invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención tienen las fórmulas generales II, IIa o IIb, en los queIn a preferred embodiment of the invention, the cycloalkane pyrazoline compounds substituted according to the present invention have the general formulas II, IIa or IIb, in those who
R^{11}, R^{12} R^{13} y R^{14}, independientemente entre sí, representan H, CH_{3}, C_{2}H_{5}, C_{3}H_{7}, OCH_{3}, OC_{2}H_{5}, OH, SH, F, Cl, Br, I, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, OCHF_{2};R 11, R 12 R 13 and R 14, independently of each other, they represent H, CH 3, C 2 H 5, C 3 H 7, OCH 3, OC 2 H 5, OH, SH, F, Cl, Br, I, CF 3, CHF 2, CH 2 F, OCF 3, OCHF2;
preferiblementepreferably
R^{11}, R^{12}, R^{13} y R^{14}, independientemente entre sí, representan H, OH, OCH_{3}, F Cl, Br, I, CF_{3}, CHF_{2} o OCF_{3}.R 11, R 12, R 13 and R 14, independently of each other, they represent H, OH, OCH 3, F Cl, Br, I, CF 3, CHF 2 or OCF 3.
En una realización preferida de la invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención tienen las fórmulas generales II, IIa o IIb, en los queIn a preferred embodiment of the invention, the cycloalkane pyrazoline compounds substituted according to the present invention have the general formulas II, IIa or IIb, in those who
los sustituyentes Z, que pueden ser igual o diferentes, se seleccionan del grupo:Z substituents, which may be the same or different, are selected from the group:
- \quadquad
- H, F, Cl, Br, I, OH, CH_{3}, C_{2}H_{5}, OCH_{3}, OCF_{3} o CF_{3}.H, F, Cl, Br, I, OH, CH 3, C 2 H 5, OCH_ {3}, OCF_ {3} or CF_ {3}.
En una realización preferida de la presente invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención tienen la fórmula general IIIIn a preferred embodiment of the present invention, the substituted cycloalkane pyrazoline compounds according to the present invention they have the general formula III
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en la quein the that
R^{21}, R^{22}, R^{23} y R^{24}, independientemente entre sí, representan H; alquilo C_{1-3} ramificado o lineal o alcoxi C_{1-3} ramificado o lineal, fenilo, hidroxilo, cloro, bromo, fluoro, yodo, SH, trifluorometilo, trifluorometiltio, trifluorometoxi, metilsulfonilo, carboxilo, trifluorometilsulfonilo, ciano, carbamoílo, sulfamoílo y acetilo; alquilo C_{8-20} o C(O)-alquilo C_{1-20} sustituidos o no sustituidos, ramificados o lineales, saturados o insaturados; arilo, alquil-arilo, heterociclilo o alquil-heterociclilo sustituidos o no sustituidos; C(O)-arilo, C(O)-alquil-arilo, C(O)-heterociclilo o C(O)-alquil-heterociclilo sustituidos o no sustituidos;R 21, R 22, R 23 and R 24, independently of each other, they represent H; I rent C 1-3 branched or linear or alkoxy C 1-3 branched or linear, phenyl, hydroxyl, chlorine, bromine, fluoro, iodine, SH, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl; C 8-20 alkyl or C (O) -C 1-20 alkyl substituted or unsubstituted, branched or linear, saturated or unsaturated; aryl, alkyl-aryl, heterocyclyl or substituted or unsubstituted alkyl heterocyclyl; C (O) -aryl, C (O) -alkyl-aryl, C (O) -heterocyclyl or C (O) -alkyl-heterocyclyl substituted or unsubstituted;
- R^{28} representa un cicloalquilo C_{7-8} no sustituido o al menos monosustituido con 1, 2 ó 3 sustituyentes Z, que pueden ser igual o diferentes, seleccionados del grupo:- R 28 represents a cycloalkyl C_ {7-8} unsubstituted or at least monosubstituted with 1, 2 or 3 Z substituents, which may be the same or different, selected from the group:
- \quadquad
- H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2};H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2;
- p siendo 0 ó 1- p being 0 or 1
opcionalmente en forma de su racemato, estereoisómeros puros, especialmente enantiómeros o diastereómeros, o en forma de las mezclas de estereoisómeros, especialmente enantiómeros o diastereómeros, en cualquier razón de mezcla;optionally in the form of your racemate, pure stereoisomers, especially enantiomers or diastereomers, or in the form of stereoisomer mixtures, especially enantiomers or diastereomers, in any reason of mixing;
en la forma mostrada o en forma del ácido o la
base o en forma de una sal, especialmente una sal fisiológicamente
aceptable, o en forma de un solvato, especialmente un hidrato o en
forma del N-óxido correspondiente de los
mismos.in the form shown or in the form of the acid or base or in the form of a salt, especially a physiologically acceptable salt, or in the form of a solvate, especially a hydrate or in the form of the corresponding N-oxide of the
same.
\newpage\ newpage
En una realización preferida de la invención, los compuestos de pirazolina cicloalcanosustituidos según la invención tienen las fórmulas generales III, IIIa o IIIb,In a preferred embodiment of the invention, the cycloalkane pyrazoline compounds substituted according to the invention have the general formulas III, IIIa or IIIb,
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\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
en las quein the that
R^{21}, R^{22}, R^{23} y R^{24}, independientemente entre sí, representan H; alquilo C_{1-3} ramificado o lineal o alcoxi C_{1-3} ramificado o lineal, fenilo, hidroxilo, cloro, bromo, fluoro, yodo, SH, trifluorometilo, trifluorometiltio, trifluorometoxi, metilsulfonilo, carboxilo, trifluorometilsulfonilo, ciano, carbamoílo, sulfamoílo y acetilo; alquilo C_{8-20} o C(O)-alquilo C_{1-20} sustituidos o no sustituidos, ramificados o lineales, saturados o insaturados; arilo, alquil-arilo, heterociclilo o alquil-i heterociclilo sustituidos o no sustituidos; C(O)-arilo, C(O)-alquil-arilo, C(O)-heterociclilo o C(O)-alquil-heterociclilo sustituidos o no sustituidos;R 21, R 22, R 23 and R 24, independently of each other, they represent H; I rent C 1-3 branched or linear or alkoxy C 1-3 branched or linear, phenyl, hydroxyl, chlorine, bromine, fluoro, iodine, SH, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl; C 8-20 alkyl or C (O) -C 1-20 alkyl substituted or unsubstituted, branched or linear, saturated or unsaturated; aryl, alkyl-aryl, heterocyclyl or substituted or unsubstituted alkyl-heterocyclyl; C (O) -aryl, C (O) -alkyl-aryl, C (O) -heterocyclyl or C (O) -alkyl-heterocyclyl substituted or unsubstituted;
- R^{28} representa un cicloalquilo C_{7-8} no sustituido o al menos monosustituido con 1, 2 ó 3 sustituyentes Z, que pueden ser igual o diferentes, seleccionados del grupo:- R 28 represents a cycloalkyl C_ {7-8} unsubstituted or at least monosubstituted with 1, 2 or 3 Z substituents, which may be the same or different, selected from the group:
- \quadquad
- H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2};H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2;
- p siendo 0 ó 1- p being 0 or 1
opcionalmente en la forma mostrada o en forma del ácido o la base o en forma de una sal, especialmente una sal fisiológicamente aceptable, o en forma de un solvato, especialmente un hidrato o en forma del N-óxido correspondiente de los mismos.optionally in the form shown or in form of the acid or base or in the form of a salt, especially a salt physiologically acceptable, or in the form of a solvate, especially a hydrate or in the form of the corresponding N-oxide of the same.
En una realización preferida de la invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención tienen las fórmulas generales III, IIIa o IIIb, en las queIn a preferred embodiment of the invention, the cycloalkane pyrazoline compounds substituted according to the present invention have the general formulas III, IIIa or IIIb, in which
R^{21} representa O-P, indicando P un grupo profármaco que consiste en arilo, alquilo C_{8-20}, heterociclilo, C(O)-arilo, C(O)-heterociclilo, C(O)-alquilo C_{1-20}, mientras queR 21 represents O-P, P indicating a prodrug group consisting of aryl, alkyl C 8-20, heterocyclyl, C (O) -aryl, C (O) -heterocyclyl, C (O) -C 1-20 alkyl, while
R^{22}, R^{23} y R^{24}, independientemente entre sí, representan H, CH_{3}, C_{2}H_{5}, C_{3}H_{7}, OCH_{3}, OC_{2}H_{5}, OH, SH, F, Cl, Br, I, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, OCHF_{2};R 22, R 23 and R 24, independently of each other, they represent H, CH 3, C 2 H 5, C 3 H 7, OCH 3, OC 2 H 5, OH, SH, F, Cl, Br, I, CF 3, CHF 2, CH 2 F, OCF 3, OCHF2;
\newpage\ newpage
preferiblementepreferably
R^{21} representa O-P, indicando P un grupo profármaco que consiste en arilo, alquilo C_{8-20}, heterociclilo, C(O)- arilo, C(O)-heterociclilo, C(O)-alquilo C_{1-20}, mientras queR 21 represents O-P, P indicating a prodrug group consisting of aryl, alkyl C 8-20, heterocyclyl, C (O) -aryl, C (O) -heterocyclyl, C (O) -C 1-20 alkyl, while
R^{22}, R^{23} y R^{24}, independientemente entre sí, representan H, OH, OCH_{3}, F, Cl, Br, I, CF_{3}, CHF_{2} u OCF_{3};R 22, R 23 and R 24, independently of each other, they represent H, OH, OCH 3, F, Cl, Br, I, CF 3, CHF 2 or OCF 3;
más preferiblementemore preferably
R^{21} representa O-P, indicando P un grupo profármaco que consiste en arilo, alquilo C_{8-20}, heteroarilo, C(O)-arilo, C(O)-heteroarilo, C(O)-alquilo C_{1-20}, mientras queR 21 represents O-P, P indicating a prodrug group consisting of aryl, alkyl C 8-20, heteroaryl, C (O) -aryl, C (O) -heteroaryl, C (O) -C 1-20 alkyl, while
R^{22}, R^{23} y R^{24}, independientemente entre sí, representan OH, OCH_{3}, F, Cl, Br, I, u OCF_{3}R 22, R 23 and R 24, independently of each other, they represent OH, OCH 3, F, Cl, Br, I, or OCF_ {3}
En una realización preferida de la invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención tienen las fórmulas generales III, IIIa o IIIb, en las queIn a preferred embodiment of the invention, the cycloalkane pyrazoline compounds substituted according to the present invention have the general formulas III, IIIa or IIIb, in which
R^{21}, R^{22}, R^{23} y R^{24}, independientemente entre sí, representan H, CH_{3}, C_{2}H_{5}, C_{3}H_{7}, OCH_{3}, OC_{2}H_{5}, OH, SH, F, Cl, Br, I, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, OCHF_{2};R 21, R 22, R 23 and R 24, independently of each other, they represent H, CH 3, C 2 H 5, C 3 H 7, OCH 3, OC 2 H 5, OH, SH, F, Cl, Br, I, CF 3, CHF 2, CH 2 F, OCF 3, OCHF2;
preferiblementepreferably
R^{21}, R^{22}, R^{23} y R^{24}, independientemente entre sí, representan H, OH, OCH_{3}, F, Cl, Br, I, CF_{3}, CHF_{2} u OCF_{3};R 21, R 22, R 23 and R 24, independently of each other, they represent H, OH, OCH 3, F, Cl, Br, I, CF 3, CHF 2 or OCF 3;
más preferiblementemore preferably
R^{21} representa H, mientras que R^{22}, R^{23} y R^{24}, independientemente entre sí, representan OH, OCH_{3}, F, Cl, Br, I, u OCF_{3}.R 21 represents H, while R 22, R 23 and R 24, independently of each other, represent OH, OCH_ {3}, F, Cl, Br, I, or OCF_ {3}.
En una realización preferida de la invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención tienen las fórmulas generales III, IIIa o IIIb, en las queIn a preferred embodiment of the invention, the cycloalkane pyrazoline compounds substituted according to the present invention have the general formulas III, IIIa or IIIb, in which
los sustituyentes Z, que pueden ser iguales o diferentes, se seleccionan del grupo:Z substituents, which may be the same or different, are selected from the group:
- \quadquad
- H, F, Cl, Br, I, OH, CH_{3}, C_{2}H_{5}, OCH_{3}, OCF_{3} o CF_{3}.H, F, Cl, Br, I, OH, CH 3, C 2 H 5, OCH_ {3}, OCF_ {3} or CF_ {3}.
En una realización preferida de la invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención tienen las fórmulas generales III y se seleccionan del grupo que consiste en:In a preferred embodiment of the invention, the cycloalkane pyrazoline compounds substituted according to the present invention have the general formulas III and it select from the group consisting of:
\bullet 5-(4-clorofenil)-N-cicloheptil-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida,? 5- (4-Chlorophenyl) -N-cycloheptyl-1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,
\bullet (R)- 5-(4-clorofenil)-N-cicloheptil-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida,? (R) - 5- (4-Chlorophenyl) -N-cycloheptyl-1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,
\bullet (S) 5-(4-clorofenil)-N-cicloheptil-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida,? (S) 5- (4-Chlorophenyl) -N-cycloheptyl-1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,
\bullet 5-(4-clorofenil)-N-(cicloheptilmetil)1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida,? 5- (4-chlorophenyl) -N- (cycloheptylmethyl) 1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,
\bullet 5-(4-clorofenil)-N-ciclooctil-1-(2,4-diclorofenil)-4, 5-dihidro-1H-pirazol-3-carboxamida,? 5- (4-chlorophenyl) -N-cyclooctyl-1- (2,4-dichlorophenyl) -4, 5-dihydro-1H-pyrazol-3-carboxamide,
\bullet 5-(4-bromofenil)-N-cicloheptil-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida,? 5- (4-bromophenyl) -N-cycloheptyl-1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,
\bullet 5-(4-fluorofenil)-N-cicloheptil-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida,? 5- (4-fluorophenyl) -N-cycloheptyl-1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,
\bullet 5-(4-metoxifenil)-N-cicloheptil-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida,? 5- (4-methoxyphenyl) -N-cycloheptyl-1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,
opcionalmente en forma de su racemato, estereoisómeros puros, especialmente enantiómeros o diastereómeros, o en forma de las mezclas de estereoisómeros, especialmente enantiómeros o diastereómeros, en cualquier razón de mezcla;optionally in the form of your racemate, pure stereoisomers, especially enantiomers or diastereomers, or in the form of stereoisomer mixtures, especially enantiomers or diastereomers, in any reason of mixing;
opcionalmente en la forma de un N-óxido correspondiente, una sal correspondiente o un solvato correspondiente.optionally in the form of an N-oxide corresponding, a corresponding salt or a solvate correspondent.
\newpage\ newpage
En una realización preferida de la invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención tienen las fórmulas generales IV, IVa o IVbIn a preferred embodiment of the invention, the cycloalkane pyrazoline compounds substituted according to the The present invention has the general formulas IV, IVa or IVb
en la quein the that
R^{31}, R^{32} R^{33} y R^{34}, independientemente entre sí, representan H; alquilo C_{1-3} ramificado o lineal o alcoxi C_{1-3} ramificado o lineal, fenilo, hidroxilo, cloro, bromo, fluoro, yodo, SH, trifluorometilo, trifluorometiltio, trifluorometoxi, metilsulfonilo, carboxilo, trifluorometilsulfonilo, ciano, carbamoílo, sulfamoílo y acetilo; alquilo C_{8-20} o C(O)-alquilo C_{1-20} sustituidos o no sustituidos, ramificados o lineales, saturados o insaturados; arilo, alquil-arilo, heterociclilo o alquil-heterociclilo sustituidos o no sustituidos; C(O)-arilo, C(O)-alquil-arilo, C(O)-heterociclilo o C(O)-alquil-heterociclilo sustituidos o no sustituidos;R 31, R 32 R 33 and R 34, independently of each other, they represent H; I rent C 1-3 branched or linear or alkoxy C 1-3 branched or linear, phenyl, hydroxyl, chlorine, bromine, fluoro, iodine, SH, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl; C 8-20 alkyl or C (O) -C 1-20 alkyl substituted or unsubstituted, branched or linear, saturated or unsaturated; aryl, alkyl-aryl, heterocyclyl or substituted or unsubstituted alkyl heterocyclyl; C (O) -aryl, C (O) -alkyl-aryl, C (O) -heterocyclyl or C (O) -alkyl-heterocyclyl substituted or unsubstituted;
R^{35}, R^{36} y R^{37} se seleccionan, independientemente entre sí, de H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2};R 35, R 36 and R 37 are selected, independently of each other, from H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2;
opcionalmente en la forma mostrada o en forma del ácido o la base o en forma de una sal, especialmente una sal fisiológicamente aceptable, o en forma de un solvato, especialmente un hidrato o en forma de un N-óxido correspondiente de los mismos.optionally in the form shown or in form of the acid or base or in the form of a salt, especially a salt physiologically acceptable, or in the form of a solvate, especially a hydrate or in the form of a corresponding N-oxide of the same.
En una realización preferida de la presente invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención tienen las fórmulas generales IV, IVa o IVb, en las queIn a preferred embodiment of the present invention, the substituted cycloalkane pyrazoline compounds according to the present invention they have the general formulas IV, IVa or IVb, in which
R^{31} representa O-P, indicando P un grupo profármaco que consiste en arilo, alquilo C_{8-20}, heterociclilo, C(O)-arilo, C(O)-heterociclilo, C(O)-alquilo C_{1-20}, mientras queR 31 represents O-P, P indicating a prodrug group consisting of aryl, alkyl C 8-20, heterocyclyl, C (O) -aryl, C (O) -heterocyclyl, C (O) -C 1-20 alkyl, while
R^{32}, R^{33} y R^{34}, independientemente entre sí, representan H, CH_{3}, C_{2}H_{5}, C_{3}H_{7}, OCH_{3}, OC_{2}H_{5}, OH, SH, F, Cl, Br, I, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, OCHF_{2};R 32, R 33 and R 34, independently of each other, they represent H, CH 3, C 2 H 5, C 3 H 7, OCH 3, OC 2 H 5, OH, SH, F, Cl, Br, I, CF 3, CHF 2, CH 2 F, OCF 3, OCHF2;
preferiblementepreferably
R^{31} representa O-P, indicando P un grupo profármaco que consiste en arilo, alquilo C_{8-20}, heterociclilo, C(O)-arilo, C(O)-heterociclilo, C(O)-alquilo C_{1-20}, mientras queR 31 represents O-P, P indicating a prodrug group consisting of aryl, alkyl C 8-20, heterocyclyl, C (O) -aryl, C (O) -heterocyclyl, C (O) -C 1-20 alkyl, while
R^{32}, R^{33} y R^{34}, independientemente entre si, representan H, OH, OCH_{3}, F, Cl, Br, I, CF_{3}, CHF_{2} u OCF_{3};R 32, R 33 and R 34, independently of each other, they represent H, OH, OCH 3, F, Cl, Br, I, CF 3, CHF 2 or OCF 3;
más preferiblementemore preferably
R^{31} representa O-P, indicando P un grupo profármaco que consiste en arilo, alquilo C_{8-20}, heterociclilo, C(O)-arilo, C(O)-heterociclilo, C(O)-alquilo C_{1-20}, mientras queR 31 represents O-P, P indicating a prodrug group consisting of aryl, alkyl C 8-20, heterocyclyl, C (O) -aryl, C (O) -heterocyclyl, C (O) -C 1-20 alkyl, while
R^{32}, R^{33} y R^{34}, independientemente entre sí, representan OH, OCH_{3}, F, Cl, Br, I, u OCF_{3}R 32, R 33 and R 34, independently of each other, they represent OH, OCH 3, F, Cl, Br, I, or OCF_ {3}
En una realización preferida de la invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención tienen las fórmulas generales IV, IVa, IVb, en las queIn a preferred embodiment of the invention, the cycloalkane pyrazoline compounds substituted according to the The present invention has the general formulas IV, IVa, IVb, in which
R^{31}, R^{32}, R^{33} y R^{34}, independientemente entre sí, representan H, CH_{3}, C_{2}H_{5}, C_{3}H_{7}, OCH_{3}, OC_{2}H_{5}, OH, SH, F, Cl, Br, I, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, OCHF_{2};R 31, R 32, R 33 and R 34, independently of each other, they represent H, CH 3, C 2 H 5, C 3 H 7, OCH 3, OC 2 H 5, OH, SH, F, Cl, Br, I, CF 3, CHF 2, CH 2 F, OCF 3, OCHF2;
preferiblementepreferably
R^{31}, R^{32}, R^{33} y R^{34}, independientemente entre si, representan H, OH, OCH_{3}, F, Cl, Br, I, CF_{3}, CHF_{2} u OCF_{3};R 31, R 32, R 33 and R 34, independently of each other, they represent H, OH, OCH 3, F, Cl, Br, I, CF 3, CHF 2 or OCF 3;
más preferiblementemore preferably
R^{31} representa H, mientras que R^{32}, R^{33} y R^{34}, independientemente entre sí, representan OH, OCH_{3}, F, Cl, Br, I, u OCF_{3}.R 31 represents H, while R 32, R 33 and R 34, independently of each other, represent OH, OCH_ {3}, F, Cl, Br, I, or OCF_ {3}.
En una realización preferida de la invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención tienen las fórmulas generales IV, IVa, o IVb, en las queIn a preferred embodiment of the invention, the cycloalkane pyrazoline compounds substituted according to the present invention have the general formulas IV, IVa, or IVb, in which
R^{35}, R^{36} y R^{37}, independientemente entre sí, se seleccionan de H, F, Cl, Br, I, OH, CH_{3}, C_{2}H_{5}, OCH_{3}, OCF_{3}, o CF_{3}.R 35, R 36 and R 37, independently of each other, they are selected from H, F, Cl, Br, I, OH, CH 3, C 2 H 5, OCH 3, OCF 3, or CF 3.
En una realización preferida de la invención, los compuestos de pirazolina cicloalcanosustituidos según la presente invención de fórmulas generales IV, IVa, IVb, IVc, IVd, IVe se seleccionan del grupo que consiste en:In a preferred embodiment of the invention, the cycloalkane pyrazoline compounds substituted according to the present invention of general formulas IV, IVa, IVb, IVc, IVd, IVe are selected from the group consisting of:
\bullet 5-(4-clorofenil)-N-cicloheptil-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida,? 5- (4-Chlorophenyl) -N-cycloheptyl-1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,
\bullet (R)- 5-(4-clorofenil)-N-cicloheptil-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida,? (R) - 5- (4-Chlorophenyl) -N-cycloheptyl-1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,
\bullet (S) 5-(4-clorofenil)-N-cicloheptil-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida,? (S) 5- (4-Chlorophenyl) -N-cycloheptyl-1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,
\bullet 5-(4-clorofenil)-N-(cicloheptilmetil)1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida,? 5- (4-chlorophenyl) -N- (cycloheptylmethyl) 1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,
\bullet 5-(4-bromofenil)-N-cicloheptil-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida,? 5- (4-bromophenyl) -N-cycloheptyl-1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,
\bullet 5-(4-fluorofenil)-N-cicloheptil-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida,? 5- (4-fluorophenyl) -N-cycloheptyl-1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,
\bullet 5-(4-metoxifenil)-N-cicloheptil-1-(2,4-diclorofenil)-4,5-dihidro-1H-pirazol-3-carboxamida,? 5- (4-methoxyphenyl) -N-cycloheptyl-1- (2,4-dichlorophenyl) -4,5-dihydro-1H-pyrazol-3-carboxamide,
opcionalmente en forma de su racemato, estereoisómeros puros, especialmente enantiómeros o diastereómeros, o en forma de las mezclas de estereoisómeros, especialmente enantiómeros o diastereómeros, en cualquier razón de mezcla;optionally in the form of your racemate, pure stereoisomers, especially enantiomers or diastereomers, or in the form of stereoisomer mixtures, especially enantiomers or diastereomers, in any reason of mixing;
opcionalmente en la forma de un N-óxido correspondiente, una sal correspondiente o un solvato correspondiente.optionally in the form of an N-oxide corresponding, a corresponding salt or a solvate correspondent.
En otro aspecto la presente invención proporciona también un procedimiento para la preparación de compuestos de pirazolina cicloalcanosustituidos de fórmula general I facilitada anteriormente, en el que al menos un compuesto de benzaldehído de fórmula general VIn another aspect the present invention it also provides a procedure for the preparation of substituted cycloalkane pyrazoline compounds of the general formula I provided above, in which at least one compound of benzaldehyde of general formula V
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en el que X tiene el significado mencionado anteriormente, se hace reaccionar con un compuesto de piruvato de fórmula general (VI)in which X has the meaning mentioned above, it is reacted with a compound of general formula pyruvate (SAW)
en el 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 general (VII)in which G represents an OR group R being a branched C 1-6 alkyl radical or unbranched or G represents a group O - K with K being a cation, to give a compound of general formula (VII)
en el que X tiene el significado mencionado anteriormente, que opcionalmente se aísla y/u opcionalmente se purifica, y que se hace reaccionar con una fenilhidrazina opcionalmente sustituida de fórmula general (VIII)in which X has the meaning mentioned above, which is optionally isolated and / or optionally it is purified, and that is reacted with a optionally substituted phenylhydrazine of the general formula (VIII)
o una sal correspondiente del mismo, en la que Y tiene el significado mencionado anteriormente, bajo atmósfera inerte, para dar un compuesto de fórmula general (IX)or a corresponding salt of same, in which Y has the meaning mentioned above, under inert atmosphere, to give a compound of general formula (IX)
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en el que X e Y tiene el significado mencionado anteriormente, que opcionalmente se aísla y/u opcionalmente se purifica, y opcionalmente se transfiere bajo atmósfera inerte a un compuesto de fórmula general (XI) a través de la reacción con un agente activantein which X and Y has the meaning mentioned above, which is optionally isolated and / or optionally purified, and optionally transferred under inert atmosphere to a compound of general formula (XI) through the reaction with an agent activating
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en el que los sustituyentes X e Y tiene el significado mencionado anteriormente y A representa un grupo saliente, siendo dicho compuesto opcionalmente aislado y/u opcionalmente purificado, y al menos un compuesto de fórmula general (XI) se hace reaccionar con un compuesto de fórmula general XIIin which the substituents X and Y It has the meaning mentioned above and A represents a leaving group, said compound being optionally isolated and / or optionally purified, and at least one compound of formula general (XI) is reacted with a compound of general formula XII
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en los que n y R^{8} son tal y como se han definido anteriormente; bajo atmósfera inerte para dar un compuesto de pirazolina sustituido de fórmula general I, que opcionalmente se aísla y/u opcionalmente se purifica.where n and R 8 are such and as defined above; under inert atmosphere to give a substituted pyrazoline compound of general formula I, which optionally it is isolated and / or optionally purify
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(Esquema pasa a página siguiente)(Scheme turns to page next)
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El procedimiento de la invención también se ilustra en el esquema I que se facilita a continuación:The process of the invention is also illustrated in scheme I, given below:
Esquema 1Scheme one
La reacción del compuesto de benzaldehído de fórmula general V con un compuesto de piruvato de fórmula general VI 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 incluye en este documento por referencia y forma parte de la descripción. Preferiblemente se utiliza piruvato sódico como el compuesto de piruvato. Dicha reacción se lleva a cabo preferiblemente en un medio de reacción prótico tal como un alcohol alquílico C_{1-4} o mezclas de éstos. También se pueden utilizar mezclas de dichos alcoholes con agua, por ejemplo, etanol/agua.The reaction of the benzaldehyde compound of general formula V with a pyruvate compound of general formula VI is preferably carried out in the presence of at least one base, more preferably in the presence of a metal hydroxide alkali such as sodium hydroxide or potassium hydroxide or a alkali metal methoxide such as sodium methoxide, as describes, for example, in Synthetic communications, 26 (11), 2229-33, (1996). The respective description is included in this document by reference and is part of the description. Preferably sodium pyruvate is used as the pyruvate compound This reaction is carried out. preferably in a protic reaction medium such as an alcohol C 1-4 alkyl or mixtures thereof. I also know they can use mixtures of said alcohols with water, 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 de manera preferida, la reacción del compuesto de benzaldehído de fórmula general V con un compuesto de piruvato de fórmula general VI se lleva a cabo en condiciones catalizadas por ácido, más preferiblemente llevando a reflujo la mezcla en diclorometano en presencia de trifluorometanosulfonato de cobre(II) como se describe, por ejemplo, en Synlett, (1), 147-149, 2001. La descripción respectiva se incluye en este documento como referencia y forma parte de la descripción.Also preferably, the reaction of benzaldehyde compound of general formula V with a compound of pyruvate of general formula VI is carried out under conditions acid catalyzed, more preferably refluxing the dichloromethane mixture in the presence of trifluoromethanesulfonate of copper (II) as described, for example, in Synlett, (1), 147-149, 2001. The respective description is included in this document as a reference and is part of the description.
La reacción del compuesto de fórmula general (VII) con una fenilhidrazina opcionalmente sustituido de fórmula general (VIII) 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 mencionados anteriormente. También de manera preferida, dicha reacción puede llevarse a cabo en presencia de un ácido, en el que el ácido puede ser orgánico, tal como ácido acético y/o inorgánico tal como ácido clorhídrico. Además, la reacción puede llevarse a cabo también en presencia de una base tal como piperidina, pierazina, hidróxido de sodio, hidróxido de potasio, metóxido de sodio o etóxido de sodio, o puede usarse también una mezcla de al menos dos de estas bases.The reaction of the compound of the general formula (VII) with an optionally substituted phenylhydrazine of the formula general (VIII) is preferably carried out in a medium of suitable reaction such as alcohols or ethers C 1-4 such as dioxane or tetrahydrofuran or mixtures of at least two of these mentioned compounds previously. Also preferably, said reaction can carried out in the presence of an acid, in which the acid can be organic, such as acetic and / or inorganic acid such as acid hydrochloric. In addition, the reaction can also be carried out in presence of a base such as piperidine, pierazine, hydroxide sodium, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these may also be used bases.
La temperatura de la reacción así como la duración de la reacción puede variar en un amplio intervalo. Las temperaturas de reacción adecuadas oscilan desde 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 Reaction duration may vary over a wide range. The suitable 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 general (VIII) puede activarse para reacciones adicionales mediante la introducción de un grupo saliente adecuado según métodos convencionales bien conocidos por los expertos en la técnica.The carboxylic group of the compound of formula general (VIII) can be activated for additional reactions by the introduction of a suitable leaving group according to methods Conventionals well known to those skilled in the art.
Preferiblemente, los compuestos de fórmula general (IX) se transfieren dentro de un cloruro de ácido, un anhídrido mezclado, un éster alquílico C_{1-4}, un éster activado tal como p-nitrofeniléster. 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).Preferably, the compounds of formula general (IX) are transferred into an acid chloride, a mixed anhydride, a C 1-4 alkyl ester, a activated ester such as p-nitrophenyl ester. Others Well known methods for acid activation include the activation with N, N-dicyclohexylcarbodiimide or hexafluorophosphate benzotriazol-N-oxotris (dimethylamino) phosphonium (BOP)
Si dicho compuesto activado de fórmula general (XI) es un cloruro de ácido, se prepara preferiblemente por reacción del ácido correspondiente de fórmula general (IX) con cloruro de tionilo o cloruro de oxalilo, en los que dicho agente de cloración se usa también como el disolvente. También puede usarse preferiblemente un disolvente adicional. 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. Pueden usarse también mezclas de dos o más disolventes de una clase o de dos o más disolventes de clases diferentes. La temperatura de reacción preferida tiene un intervalo desde 0ºC hasta el punto de ebullición del disolvente y tiempos de reacción desde varios minutos hasta varias horas.If said activated compound of general formula (XI) is an acid chloride, preferably prepared by reaction of the corresponding acid of general formula (IX) with thionyl chloride or oxalyl chloride, wherein said Chlorination is also used as the solvent. Can also be used preferably an additional solvent. Suitable solvents 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. Mixtures of two or more solvents of one class or two or more solvents of different classes The preferred reaction temperature has a range from 0 ° C to the boiling point of the solvent and reaction times from several minutes to several hours.
Si dicho compuesto activado de fórmula general (XI) es un anhídrido mixto, dicho anhídrido puede preparase preferiblemente, por ejemplo, por reacción del ácido de fórmula general (IX) correspondiente con cloroformiato de etilo en presencia de una base tal como trietilamina o piridina, en un disolvente adecuado.If said activated compound of general formula (XI) is a mixed anhydride, said anhydride can be prepared preferably, for example, by reaction of the acid of formula general (IX) corresponding with ethyl chloroformate in presence of a base such as triethylamine or pyridine, in a suitable solvent.
Las reacciones mencionadas anteriormente que implican la síntesis del anillo 4,5-dihidropirazol o la reacción de un compuesto que comprende dicho anillo se llevan a cabo en un atmósfera inerte, preferiblemente nitrógeno o argón, para evitar la oxidación del sistema anular.The reactions mentioned above that involve the synthesis of the 4,5-dihydropyrazole ring or the reaction of a compound comprising said ring are brought to conducted in an inert atmosphere, preferably nitrogen or argon, to prevent oxidation of the annular 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, así como su eliminación, se pueden llevar a cabo mediante métodos conocidos por los expertos en la materia.During the procedures described previously it may be necessary and / or desirable to protect sensitive groups or reagents. The introduction of groups conventional protectors, as well as their removal, can be carry out by methods known to experts in the matter.
Si los compuestos de pirazolina
cicloalcanosustituidos de fórmula general (I) se obtienen ellos
mismos en forma de una mezcla de estereoisómeros, en particular
enantiómeros o diastereómeros, dichas mezclas pueden separarse por
procedimientos habituales usados por los expertos en la técnica,
por ejemplo, métodos cromatográficos o cristalización con reactivos
quirales. También es posible obtener estereoisómeros puros a través
de la síntesis estereo-
selectiva.If the substituted cycloalkane pyrazoline compounds of the general formula (I) are themselves obtained in the form of a mixture of stereoisomers, in particular enantiomers or diastereomers, said mixtures can be separated by usual procedures used by those skilled in the art, for example, chromatographic methods. or crystallization with chiral reagents. It is also possible to obtain pure stereoisomers through stereo synthesis.
selective
En un aspecto adicional la presente invención proporciona también un procedimiento para la preparación de sales de compuestos de pirazolina cicloalcanosustituidos de fórmula general I y estereoisómeros de los mismos, en los que al menos un compuesto de fórmula general I que tiene al menos un grupo básico se hace reaccionar con al menos un ácido orgánico y/o inorgánico, preferiblemente en presencia de un medio de reacción adecuado. Medios de reacción adecuados incluyen, por ejemplo, cualquiera de los facilitados anteriormente. Ácidos inorgánicos adecuados incluyen ácido clorhídrico, ácido bromhídrico, ácido fosfórico, ácido sulfúrico, ácido nítrico, ácidos orgánicos adecuados son, por ejemplo, ácido cítrico, ácido maleico, ácido fumárico, ácido tartárico, o derivados de los mismos, ácido p-toluensulfónico, ácido metanosulfónico o ácido canforsulfónico.In a further aspect the present invention it also provides a process for the preparation of salts of substituted cycloalkane pyrazoline compounds of formula general I and stereoisomers thereof, in which at least one compound of general formula I having at least one basic group is reacted with at least one organic and / or inorganic acid, preferably in the presence of a suitable reaction medium. Suitable reaction media include, for example, any of those provided above. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, suitable organic acids are, for example, citric acid, maleic acid, fumaric acid, acid tartaric acid, or derivatives thereof, acid p-toluenesulfonic acid, methanesulfonic acid or acid camphorsulfonic.
En aún otro aspecto adicional la presente invención proporciona también un procedimiento para la preparación de sales de compuestos de pirazolina cicloalcanosustituidos de fórmula general I o estereoisómeros de los mismos, en los que al menos un compuesto de fórmula general I con al menos un grupo ácido se hace reaccionar con una o más bases adecuadas, preferiblemente en presencia de un medio de reacción adecuado. Las bases adecuadas son, por ejemplo, hidróxidos, carbonatos o alcóxidos, que incluyen cationes adecuados, derivados, por ejemplo, de metales alcalinos, metales alcalinotérreos o cationes orgánicos, por ejemplo [NH_{n}R_{4-n}]^{+}, en el que n es 0, 1, 2, 3 ó 4 y R representa un radical alquilo C_{1-4} ramificado o no ramificado. Los medios de reacción adecuados son, por ejemplo, cualquiera de los facilitados anteriormente.In yet another additional aspect the present invention also provides a process for the preparation of salts of substituted cycloalkane pyrazoline compounds of general formula I or stereoisomers thereof, in which at less a compound of general formula I with at least one acidic group it is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium. The right bases they are, for example, hydroxides, carbonates or alkoxides, which include suitable cations, derived, for example, from alkali metals, alkaline earth metals or organic cations, for example [NH_ {n} R_-4] +, where n is 0, 1, 2, 3 or 4 and R represents an alkyl radical C 1-4 branched or unbranched. The means of Suitable reactions are, for example, any of those provided previously.
También pueden obtenerse los solvatos, preferiblemente hidratos, de los compuestos de pirazolina cicloalcanosustituidos de fórmula general I, de los correspondientes estereoisómeros, de los correspondientes N-óxidos o de las correspondientes sales de los mismos mediante procedimientos habituales conocidos por los expertos en la técnica.You can also get solvates, preferably hydrates, of the pyrazoline compounds substituted cycloalkanes of general formula I, of the corresponding stereoisomers, of the corresponding N-oxides or of the corresponding salts thereof by usual procedures known to experts in the technique.
También pueden obtenerse compuestos de pirazolina de fórmula general I, que comprenden anillos, saturados, insaturados o aromáticos que contienen un átomo de nitrógeno en la forma de sus N-óxidos mediante métodos bien conocidos por los expertos en la técnica.Compounds of pyrazoline of general formula I, comprising rings, saturated, unsaturated or aromatic containing a nitrogen atom in the form of their N-oxides by methods well known to experts in the art.
Los expertos en la materia entienden que el término compuestos de pirazolina sustituidos tal y como se utiliza en la presente invención se entiende que comprende también derivados, tales como éteres, ésteres y complejos de estos compuestos. El término "derivados" tal y como se utiliza en la solicitud se define aquí que significa un compuesto químico que ha sufrido un proceso de derivación a partir de un compuesto activo para cambiar (mejorar para el uso farmacéutico) cualquiera de sus propiedades físico-químicas, especialmente un denominado profármaco, por ejemplo, sus ésteres y éteres. Ejemplos de métodos bien conocidos para producir un profármaco de un compuesto activo dado son conocidos a los expertos en la técnica y pueden encontrarse, por ejemplo, en Krogsgaard-Larsen et al., Textbook of Drugdesign and Discovery, Taylor & Francis (Abril 2002). La descripción respectiva se incorpora en la presente por referencia y forma parte de la descripción.Those skilled in the art understand that the term substituted pyrazoline compounds as used in the present invention is understood to also comprise derivatives, such as ethers, esters and complexes of these compounds. The term "derivatives" as used in the application is defined herein as meaning a chemical compound that has undergone a process of derivation from an active compound to change (improve for pharmaceutical use) any of its physicochemical properties. , especially a so-called prodrug, for example, its esters and ethers. Examples of well known methods for producing a prodrug of a given active compound are known to those skilled in the art and can be found, for example, in Krogsgaard-Larsen et al ., Textbook of Drugdesign and Discovery, Taylor & Francis (April 2002) . The respective description is incorporated herein by reference and is part of the description.
La purificación y el aislamiento de los compuestos de pirazolina sustituidos de fórmula general I de la invención, de un correspondiente estereoisómero, o sal, o N-óxido, o solvato o cualquier producto intermedio de los mismos puede llevarse a cabo, si se desea, mediante métodos convencionales conocidos por los expertos en la técnica, por ejemplo, métodos cromatográficos o recristalización.The purification and isolation of substituted pyrazoline compounds of general formula I of the invention of a corresponding stereoisomer, or salt, or N-oxide, or solvate or any intermediate thereof be carried out, if desired, by conventional methods known to those skilled in the art, for example, methods chromatographic or recrystallization.
Los compuestos de pirazolina cicloalcanosustituidos de fórmula general I facilitada anteriormente, sus estereoisómeros, los correspondientes N-óxidos, las correspondientes sales de los mismos y los correspondientes solvatos son toxicológicamente aceptables y, por tanto, adecuados como principios activos farmacéuticos para la preparación de medicamentos.Pyrazoline compounds substituted cycloalkanes of general formula I provided previously, its stereoisomers, the corresponding N-oxides, the corresponding salts thereof and the corresponding Solvates are toxicologically acceptable and therefore suitable as pharmaceutical active ingredients for the preparation of medicines.
Se ha encontrado que los compuestos de pirazolina cicloalcanosustituidos de fórmula general I facilitada anteriormente, estereoisómeros de los mismos, N-óxidos de los mismos, las correspondientes sales y correspondientes solvatos tienen una alta afinidad por los receptores de cannabinoides, particularmente 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, en estos receptores. En particular, estos compuestos de pirazolina sustituidos muestran 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 y luego se continúa posteriormente, los compuestos de pirazolina utilizados según la invención mostrarán de nuevo el efecto deseado. Tras finalizar el tratamiento con los compuestos de pirazolina, se encuentra que continúa la influencia positiva sobre el peso corporal.It has been found that the compounds of substituted cycloalkane pyrazoline of general formula I provided previously, stereoisomers thereof, N-oxides of the same, the corresponding salts and corresponding solvates they have a high affinity for cannabinoid receptors, particularly cannabinoid 1 receptors (CB1), is that is, they are selective ligands for the CB1 receptor and act as modulators, for example antagonists, inverse agonists or agonists, in these receptors. In particular, these compounds of substituted pyrazoline show little or no development of tolerance during treatment, particularly with respect to food intake, that is, if the treatment is interrupt for a period of time and then continue subsequently, the pyrazoline compounds used according to the invention will again show the desired effect. After finishing the treatment with pyrazoline compounds, it is found that The positive influence on body weight continues.
Además, estos compuestos de pirazolina cicloalcanosustituidos muestran una afinidad por el canal Herg relativamente débil, por tanto, para estos compuestos se espera un bajo riesgo de prolongación del intervalo QT.In addition, these pyrazoline compounds substituted cycloalkanes show an affinity for the Herg channel relatively weak, therefore, for these compounds an expected low risk of prolongation of the QT interval.
En resumen, los compuestos de pirazolina 4- sustituidos según la invención se distinguen por un amplio espectro de efectos beneficiosos, mientras que al mismo tiempo muestran 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, pyrazoline compounds 4- substituted according to the invention are distinguished by a broad spectrum of beneficial effects, while at the same time show 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 al menos un compuesto de pirazolina cicloalcanosustituido de fórmula general I, opcionalmente en forma de uno de sus estereoisómeros, preferiblemente enantiómeros o diastereómeros, un racemato o en forma de una mezcla de al menos dos de sus estereoisómeros, preferiblemente enantiómeros y/o diastereómeros, en cualquier razón de mezcla, o un N-óxido correspondiente de los mismos, o una sal fisiológicamente aceptable de los mismos, o un solvato correspondiente de los mismos, y opcionalmente al menos un agente auxiliar fisiológicamente aceptable.Therefore, another aspect of the present invention refers to a medicament comprising at least one compound of substituted cycloalkane pyrazoline of general formula I, optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and / or diastereomers, in any reason of mixture, or a corresponding N-oxide thereof, or a salt physiologically acceptable thereof, or a solvate corresponding thereof, and optionally at least one agent Physiologically acceptable auxiliary.
Preferiblemente dicho medicamento es adecuado para la modulación (regulación) de receptores de cannabinoides, preferiblemente de los 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.Preferably said medicament is suitable. for the modulation (regulation) of cannabinoid receptors, preferably of the cannabinoid 1 (CB1) receptors, for the prophylaxis and / or treatment of system disorders central nervous, immune system disorders, disorders of the cardiovascular system, disorders of the endocrine system, respiratory system disorders, tract disorders gastrointestinal or reproductive disorders.
Particularmente, preferiblemente dicho medicamento es adecuado para la profilaxis y/o el tratamiento de la psicosis.Particularly, preferably said medication is suitable for prophylaxis and / or treatment of psychosis.
Además, de manera particularmente preferida dicho medicamento es adecuado 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 no insulinodependiente). El medicamento de la invención también parece ser activo en la profilaxis y/o el tratamiento de trastornos del apetito, por ejemplo, los compuestos de pirazolinas de fórmula general I también reducen el deseo de comer dulces.In addition, particularly preferably said medication is suitable for prophylaxis and / or the treatment of eating disorders, preferably bulimia, anorexia, cachexia, obesity and / or diabetes Type II mellitus (non-insulin dependent diabetes). The medicine of the invention also appears to be active in prophylaxis and / or the treatment of appetite disorders, for example, the compounds of general formula I pyrazolines also reduce the desire to eat candies.
Además, de manera particularmente preferida dicho medicamento es adecuado 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.In addition, particularly preferably said medication is suitable for prophylaxis and / or the cancer treatment, preferably for prophylaxis and / or the treatment of one or more types of cancers selected from the group which consists of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, cancer liver, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, intestinal cancer and prostate cancer, more preferably for the prophylaxis and / or treatment of one or more types of cancers selected from the group consisting of cancer of colon, bowel cancer and prostate cancer.
De manera particularmente preferida dicho medicamento es adecuado 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.Particularly preferably said medication is suitable for prophylaxis and / or treatment of alcoholism and / or alcohol addiction, nicotine abuse and / or smoking, drug abuse 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.
El medicamento también es adecuado para la profilaxis y/o el tratamiento de uno o más de los 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 medicine is also suitable for prophylaxis and / or treatment of one or more of the 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.
Otro aspecto de la presente invención es el uso de al menos un compuesto de pirazolina cicloalcanosustituido de fórmula general I facilitada anteriormente como principios activos, opcionalmente en forma de uno de los estereoisómeros, preferiblemente enantiómeros o diastereómeros, un racemato o en forma de una mezcla de al menos dos de los estereoisómeros, preferiblemente enantiómeros y/o diastereómeros, en cualquier razón de mezcla, o un N-óxido correspondiente de los mismos, o una sal correspondiente de los mismos, o un solvato correspondiente de los mismos, 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 at least one cycloalkane pyrazoline compound substituted from general formula I previously provided as active ingredients, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and / or diastereomers, in any reason of mixture, or a corresponding N-oxide thereof, or a salt corresponding thereof, or a corresponding solvate of the themselves, and optionally one or more pharmaceutically excipients acceptable, for the preparation of a medicine for cannabinoid receptor modulation, preferably cannabinoid 1 (CB1) receptors, for prophylaxis and / or treatment of. central nervous system disorders, disorders of the immune system, disorders of the cardiovascular system, endocrine system disorders, system disorders respiratory, gastrointestinal tract disorders or disorders players.
Se prefiere particularmente el uso de al menos uno de los respectivos compuestos de pirazolina cicloalcanosustituidos, opcionalmente en forma de uno de los estereoisómeros, preferiblemente enantiómeros o diastereómeros, un racemato o en forma de una mezcla de al menos dos de los estereoisómeros, preferiblemente enantiómeros y/o diastereómeros, en cualquier razón de mezcla, o un N-óxido correspondiente de los mismos, o una sal correspondiente de los mismos, o un solvato correspondiente de los mismos, y opcionalmente uno o más excipientes farmacéuticamente aceptables, para la preparación de un medicamento para la profilaxis y/o el tratamiento de la psicosis.Particularly preferred is the use of at least one of the respective pyrazoline compounds substituted cycloalkanes, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding N-oxide of the themselves, or a corresponding salt thereof, or a solvate corresponding thereof, and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the prophylaxis and / or treatment of psychosis.
También se prefiere particularmente el uso de al menos uno de los respectivos compuestos de pirazolina cicloalcanosustituidos, opcionalmente en forma de uno de los estereoisómeros, preferiblemente enantiómeros o diastereómeros, un racemato o en forma de una mezcla de al menos dos de los estereoisómeros, preferiblemente enantiómeros y/o diastereómeros, en cualquier razón de mezcla, o un N-óxido correspondiente de los mismos, o una sal correspondiente de los mismos, o un solvato correspondiente de los mismos, 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 al is also particularly preferred. minus one of the respective pyrazoline compounds substituted cycloalkanes, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding N-oxide of the themselves, or a corresponding salt thereof, or a solvate corresponding thereof, 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 particularmente se prefiere el uso de la menos uno de los compuestos de pirazolina, tal y como se definene en la presente invención, y opcionalmente uno o más excipientes farmacéuticamente aceptables, para la preparación de un medicamento para el tratamiento del síndrome metabólico.Also particularly preferred is the use of the minus one of the pyrazoline compounds, as defined in the present invention, and optionally one or more excipients pharmaceutically acceptable, for the preparation of a medicine for the treatment of metabolic syndrome.
El síndrome metabólico y las definiciones del mismo, se describen en detalle por Eckel et al, The Lancet, Vol 365 (2005), 1415-1428, incluidos en el presente documento como referencia. Una de las definiciones respectivas se estableció por la OMS en 1998 (según se describe en Alberti et al., Diabet. Med. 1998, 15, páginas 539-53, las descripciones respectivas se incorporan como referencia al presente documento y forman parte de la descripción). La otra definición más ampliamente aceptada de síndrome metabólico se estableció por el Adult Treatment Panel (ATP III) del US National Cholesterol Education Program (NCEP) en 2001, según se describe en JAMA 2001; 285;2486-97, las descripciones respectivas se incorporan como referencia al presente documento y forman parte de la descripción.The metabolic syndrome and its definitions are described in detail by Eckel et al , The Lancet, Vol 365 (2005), 1415-1428, included herein as a reference. One of the respective definitions was established by WHO in 1998 (as described in Alberti et al ., Diabet. Med. 1998, 15, pages 539-53, the respective descriptions are incorporated by reference to this document and are part of the description). The other more widely accepted definition of metabolic syndrome was established by the Adult Treatment Panel (ATP III) of the US National Cholesterol Education Program (NCEP) in 2001, as described in JAMA 2001; 285; 2486-97, the respective descriptions are incorporated by reference to this document and are part of the description.
El síndrome metabólico se caracteriza por una interacción de varios parámetros fisiológicos tales como triglicéridos, lípidos, presión sanguínea, niveles de glucosa y niveles de insulina.The metabolic syndrome is characterized by a interaction of several physiological parameters such as triglycerides, lipids, blood pressure, glucose levels and insulin levels
Incluso aunque la obesidad juega un papel crítico en el desarrollo del síndrome metabólico, muchos de sus aspectos son independientes del peso, especialmente algunos parámetros lipídicos. Especialmente la influencia positiva en los aspectos independientes del peso del síndrome metabólico (véase por ejemplo, Pagotto and Pasquali, The Lancet, Vol. 365 (2005), 1363,1364, incluidos en el presente documento como referencia) como algunos parámetros sanguíneos, especialmente parámetros lipídicos es una de las principales y sorprendentes ventajas de los compuestos de piperazina sustituidos usados según la invención.Even though obesity plays a role critical in the development of metabolic syndrome, many of its aspects are independent of weight, especially some lipid parameters. Especially the positive influence on independent aspects of the weight of the metabolic syndrome (see for example, Pagotto and Pasquali, The Lancet, Vol. 365 (2005), 1363,1364, included herein as reference) as some blood parameters, especially lipid parameters It is one of the main and surprising advantages of substituted piperazine compounds used according to the invention.
Otro aspecto de la invención es el uso de uno o más compuestos de pirazolina, tal como se definen en el presente documento, para la fabricación de un medicamento para la mejora de factores de riesgo cardiovasculares y/o metabólicos, tales como uno o más de los siguientes factores:Another aspect of the invention is the use of one or more pyrazoline compounds, as defined herein document, for the manufacture of a medicine for the improvement of cardiovascular and / or metabolic risk factors, such as one or more of the following factors:
Triglicéridos elevados, en los que los niveles
elevados de triglicéridos se entiende preferiblemente que son >
150 mg/dl,High triglycerides, in which elevated triglyceride levels are preferably understood to be>
150 mg / dl,
Colesterol de las HDL bajo, en el que los niveles bajos de colesterol de las HDL se entiende preferiblemente que son < 40 mg/dl en hombres y < 50 mg/dl en mujeres,Low HDL cholesterol, in which the low cholesterol levels of HDL is preferably understood which are <40 mg / dl in men and <50 mg / dl in women,
Hipertensión, en la que hipertensión se entiende preferiblemente que es > 130/85 mmHg,Hypertension, in which hypertension is understood preferably that is> 130/85 mmHg,
Alteración de la glucosa en ayunas, en la que la alteración de la glucemia en ayunas se entiende preferiblemente que es > 110 mg/dl,Fasting impaired glucose, in which the fasting impaired glycemia is preferably understood which is> 110 mg / dl,
Resistencia a la insulinaInsulin resistance
Dislipidemia.Dyslipidemia
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Otro aspecto de la invención es el uso de uno o más compuestos de pirazolina, tal como se definen en el presente documento, para la fabricación de un medicamento para el tratamiento de los aspectos independientes del peso del síndrome metabólico.Another aspect of the invention is the use of one or more pyrazoline compounds, as defined herein document, for the manufacture of a medicine for the treatment of the independent aspects of the weight of the syndrome metabolic.
Otro aspecto de la invención es un método para mejorar los factores de riesgo cardiovasculares y/o metabólicos, tales como uno o más de los siguientes factores:Another aspect of the invention is a method for improve cardiovascular and / or metabolic risk factors, such as one or more of the following factors:
Triglicéridos elevados, en los que los niveles elevados de triglicéridos se entiende preferiblemente que son > 150 mg/dl,Elevated triglycerides, in which levels elevated triglycerides are preferably understood to be> 150 mg / dl,
Colesterol de las HDL bajo, en el que los niveles bajos de colesterol de las HDL se entiende preferiblemente que son < 40 mg/dl en hombres y < 50 mg/dl en mujeres,Low HDL cholesterol, in which the low cholesterol levels of HDL is preferably understood which are <40 mg / dl in men and <50 mg / dl in women,
Hipertensión, en la que hipertensión se entiende preferiblemente que es > 130/85 mmHg,Hypertension, in which hypertension is understood preferably that is> 130/85 mmHg,
Alteración de la glucosa en ayunas, en la que la alteración de la glucemia en ayunas se entiende preferiblemente que es > 110 mg/dl,Fasting impaired glucose, in which the fasting impaired glycemia is preferably understood which is> 110 mg / dl,
Resistencia a la insulinaInsulin resistance
Dislipidemia,Dyslipidemia,
en un sujeto, preferiblemente un ser humano.in a subject, preferably a human being.
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Otro aspecto de la invención es un método para tratar los aspectos independientes del peso del síndrome metabólico.Another aspect of the invention is a method for treat independent aspects of the weight of the syndrome metabolic.
También se prefiere particularmente el uso de al menos uno de los respectivos compuestos de pirazolina cicloalcanosustituidos, opcionalmente en forma de uno de los estereoisómeros, preferiblemente enantiómeros o diastereómeros, un racemato o en forma de una mezcla de al menos dos de los estereoisómeros, preferiblemente enantiómeros y/o diastereómeros, en cualquier razón de mezcla, o un N-óxido correspondiente de los mismos, o una sal correspondiente de los mismos, o un solvato correspondiente de los mismos, 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 al is also particularly preferred. minus one of the respective pyrazoline compounds substituted cycloalkanes, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding N-oxide of the themselves, or a corresponding salt thereof, or a solvate corresponding thereof, 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 particularmente el uso de al
menos uno de los respectivos compuestos de pirazolina
cicloalcanosustituidos, opcionalmente en forma de uno de los
estereoisómeros, preferiblemente enantiómeros o diastereómeros, un
racemato o en forma de una mezcla de al menos dos de los
estereoisómeros, preferiblemente enantiómeros y/o diastereómeros,
en cualquier razón de mezcla, o un N-óxido correspondiente de los
mismos, o una sal correspondiente de los mismos, o un solvato
correspondiente de los mismos, 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.Also particularly preferred is the use of at least one of the respective substituted cycloalkane pyrazoline compounds, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers and / or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a drug for the prophylaxis and / or treatment of alcoholism and / or alcohol addiction, nicotine and / or smoking abuse, drug and / or drug abuse and / or drug and / or drug dependence abuse, 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.
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También se prefiere el uso de al menos uno de los respectivos compuestos de pirazolina cicloalcanosustituidos, opcionalmente en forma de uno de los estereoisómeros, preferiblemente enantiómeros o diastereómeros, un racemato o en forma de una mezcla de al menos dos de los estereoisómeros, preferiblemente enantiómeros y/o diastereómeros, en cualquier razón de mezcla, o un N-óxido correspondiente de los mismos, o una sal correspondiente de los mismos, o un solvato correspondiente de los mismos, 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.Also preferred is the use of at least one of the respective substituted cycloalkane pyrazoline compounds, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and / or diastereomers, in any reason of mixture, or a corresponding N-oxide thereof, or a salt corresponding thereof, or a corresponding solvate of the themselves, and optionally one or more pharmaceutically excipients acceptable, for the preparation of a medicine for prophylaxis and / or treatment of one or more selected disorders from the group consisting of bone disorders, preferably osteoporosis (for example, osteoporosis associated 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.
El medicamento según la presente invención puede estar en cualquier forma adecuada para la aplicación a seres humanos y/o animales, preferiblemente seres humanos incluyendo lactantes, niños y adultos y puede producirse mediante procedimientos habituales conocidos por los expertos en la técnica. El medicamento puede producirse mediante procedimientos habituales conocidos por los expertos en la técnica, por ejemplo, a partir del índice de "Pharmaceutics: The Science of Dosage Forms", segunda edición, Aulton, M.E. (ED. Churchill Livingstone, Edimburgo (2002); "Encyclopedia of Pharmaceutical Technology", segunda edición, Swarbrick, J. y Boiloan J.C. (Eds.), Marcel Dekker, Inc. Nueva York (2002); "Modern Pharmaceutics", cuarta edición, Banker G.S. y Rhodes C.T. (Eds.) Marcel Dekker, Inc. Nueva York 2002 y "The Theory and Practice of Industrial Pharmacy", Lachman L., Lieberman H. Y Kanig J. (Eds.), Lea & Febiger, Filadelfia (1986). Las descripciones respectivas se incorporan como referencia al presente documento y forman parte de la descripción. 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 including infants, children and adults and can be produced by usual procedures known to those skilled in the art. The medicine can be produced by usual procedures known to those skilled in the art, for example, from "Pharmaceutics: The Science of Dosage Forms" index, second edition, Aulton, M.E. (ED. Churchill Livingstone, Edinburgh (2002); "Encyclopedia of Pharmaceutical Technology", second edition, Swarbrick, J. and Boiloan J.C. (Eds.), Marcel Dekker, Inc. New York (2002); "Modern Pharmaceutics", fourth edition, Banker G.S. and Rhodes C.T. (Eds.) Marcel Dekker, Inc. New York 2002 and "The Theory and Practice of Industrial Pharmacy", Lachman L., Lieberman H. and Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986). The respective descriptions are incorporated as reference to this document and are part of the description. The composition of the medication may vary depending on the route of administration.
El medicamento de la presente invención puede, por ejemplo, administrarse por vía parenteral en combinación con vehículos líquidos inyectables convencionales, tales como agua o alcoholes adecuados. Pueden incluirse excipientes farmacéuticos convencionales para inyección, tales como agentes estabilizantes, agentes solubilizantes y tampones, 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, for example, administered parenterally in combination with conventional injectable liquid vehicles, such as water or suitable alcohols. Pharmaceutical excipients may be included. conventional for injection, such as stabilizing agents, solubilizing agents and buffers, 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. Las formas multiparticuladas, tales como los microgránulos, pueden, por ejemplo, llenarse en una cápsula, comprimirse en comprimidos o suspenderse en un líquido adecuado.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. Multiparticulate forms, such as microgranules, can, for example, be filled in a capsule, compressed into tablets or suspended in a liquid suitable.
Se conocen de la técnica anterior formulaciones de liberación controlada adecuadas, materiales y métodos para su preparación, por ejemplo, a partir del índice de "Modified-Release Drug Delivery Technology", Rathbone, M.J. Hadgraft, J. y Roberts, M.S. (Eds.), Marcel Dekker, Inc., Nueva York (2002); "Handbook of Pharmaceutical Controlled Release Technology", Wise, D.L. (Ed.), Marcel Dekker, Inc. Nueva York, (2000); "Controlled Drug Delivery", Vol, I, Basic Concepts, Bruck, S.D. (Ed.), CRD Press Inc., Boca Raton (1983) y de Takada, K. y Yoshikawa, H., "Oral Drug Delivery", Encyclopedia of Controlled Drug Delivery, Matiowitz, E. (Ed.), John Wiley & Sons, Inc., Nueva York (1999), Vol. 2, 728-742; Fix, J., "Oral drug delivery, small intestine and colon", Encyclopedia of Controlled Drug Delivery, Matiowitz, E. (Ed.), John Wiley & Sons, Inc., Nueva York (1999), Vol. 2, 698-728. Las descripciones respectivas se incorporan como referencia al presente documento y forman parte de la descripción.Formulations are known from the prior art of suitable controlled release, materials and methods for its preparation, for example, from the index of "Modified-Release Drug Delivery Technology", Rathbone, M.J. Hadgraft, J. and Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); "Handbook of Pharmaceutical Controlled Release Technology ", Wise, D.L. (Ed.), Marcel Dekker, Inc. New York, (2000); "Controlled Drug Delivery", Vol, I, Basic Concepts, Bruck, S.D. (Ed.), CRD Press Inc., Boca Raton (1983) and of Takada, K. and Yoshikawa, H., "Oral Drug Delivery", Encyclopedia of Controlled Drug Delivery, Matiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 728-742; Fix, J., "Oral drug delivery, small intestine and colon", Encyclopedia of Controlled Drug Delivery, Matiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 698-728. The respective descriptions are incorporated as a reference to this document and are part of the description.
Los medicamentos según la presente invención también pueden comprender un recubrimiento entérico, de modo que si disolución depende del valor de pH. Debido a dicho recubrimiento, el medicamento puede pasar por el estómago sin disolverse y el respectivo compuesto de fenilpiperazina nitrosustituido se libera en el tracto intestinal. Preferiblemente, el recubrimiento entérico es soluble a un valor de pH de 5 a 7,5. Los materiales y métodos adecuados para la preparación son conocidos de la técnica anterior.Medications according to the present invention they can also comprise an enteric coating, so that if dissolution depends on the pH value. Because of said coating, the medicine can pass through the stomach without dissolve and the respective phenylpiperazine compound Nitrosubstituted is released in the intestinal tract. Preferably, The enteric coating is soluble at a pH value of 5 to 7.5. Suitable materials and methods for preparation are known from the prior art.
Normalmente, los medicamentos según la presente invención pueden contener un 1-60% en peso de uno o más compuestos de pirazolina cicloalcanosustituidos, tal como se definen en el presente documento y un 40-99% en peso de una o más sustancias auxiliares (aditivos).Normally, medications according to this invention may contain 1-60% by weight of one or more substituted cycloalkane pyrazoline compounds, as defined herein and 40-99% by weight of one or more auxiliary substances (additives).
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.
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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Los siguientes compuestos se prepararon según los procedimientos generales descritos anteriormente. Los expertos en la materia están familiarizados con los materiales de partida que son necesarios para obtener dichos compuestos.The following compounds were prepared according to the general procedures described above. The experts in the matter they are familiar with the starting materials which are necessary to obtain said compounds.
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(donde W tiene el significado facilitado anteriormente).(where W has the meaning facilitated previously).
En un matraz de tres bocas se disolvieron benzaldehído sustituido en para (95 mmoles) y piruvato de etilo (86 mmoles) 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-(fenil 4-sustituido)-2-oxo-3-butenoico mediante filtración.In a three-mouth flask they dissolved para-substituted benzaldehyde (95 mmol) and ethyl pyruvate (86 mmol) in 150 ml of absolute ethanol. The solution was cooled in ice to 0 ° C and an aqueous solution of NaOH (3.8 g in 45 mL of water), maintaining the temperature less than or equal to 10 ° C, whereby a precipitate formed Orange yellow color. The reaction mixture was 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 4- (phenyl acid insoluble sodium 4-substituted) -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-(fenil 4-sustituido)-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-(fenil 4-sustituido)-2-oxo-3-butenoico sólido y se secó para dar el producto deseado (intervalo de rendimiento: 20-70%).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 4- (phenyl acid 4-substituted) -2-oxo-3-butenoic It was then treated with a 2N HCl solution, stirred for a few minutes and 4- (phenyl acid filtered off 4-substituted) -2-oxo-3-butenoic solid and dried to give the desired product (range of yield: 20-70%).
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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 (400 MHz, 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 (400 MHz, 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, 1H).
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^{1}H-RMN (400 MHz, CDCl_{3}, \delta): 7,55 (2H, m, ArH), 7,61 5 (3H, m, Ar H), 8,09 (1H, d, J= 16,4 Hz)1 H-NMR (400 MHz, CDCl 3, δ): 7.55 (2H, m, ArH), 7.61 5 (3H, m, Ar H), 8.09 (1H, d, J = 16.4 Hz)
^{13}C RMN (100 MHz, CDCl_{3}, 5): 118,1 (CH), 127,2 (C), 130,7 (CH), 132,7 (CH), 149,7 (C + CH), 160,0 (CO), 182,2 (CO).13 C NMR (100 MHz, CDCl 3, 5): 118.1 (CH), 127.2 (C), 130.7 (CH), 132.7 (CH), 149.7 (C + CH), 160.0 (CO), 182.2 (CO).
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^{1}H-RMN (400 MHz, CDCl_{3}, \delta): 7,15 (2H, apt, J 8,4 Hz, ArH), 7,53 (1H, d, J 16,0 Hz, CH), 8,11 (1H, d, J=16,0 Hz)1 H-NMR (400 MHz, CDCl 3, δ): 7.15 (2H, apt, J 8.4 Hz, ArH), 7.53 (1H, d, J 16.0 Hz, CH), 8.11 (1H, d, J = 16.0 Hz)
^{13}C RMN (100 MHz, CDCl_{3}, \delta): 116,5 (CH, d, JF 24 Hz), 117,4 (CH, d, JF 8,7 Hz), 130,1 (C, d, JF 2,4 Hz), 131,7 (CH, d, JF 9,1 Hz), 149,9 (CH), 162,0 (C, d, JF 320 Hz), 166,7 (CO), 182,4 (CO).13 C NMR (100 MHz, CDCl 3, δ): 116.5 (CH, d, JF 24 Hz), 117.4 (CH, d, JF 8.7 Hz), 130.1 (C, d, JF 2.4 Hz), 131.7 (CH, d, JF 9.1 Hz), 149.9 (CH), 162.0 (C, d, JF 320 Hz), 166.7 (CO), 182.4 (CO).
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^{1}H-RMN (400 MHz, CDCl_{3}, \delta): 3,88 (3H, s, OCH_{3}), 6,95 (2H, d, J 6,8 Hz), 7,45 (2H, d, J 15,6 H), 7,65 (2H, d, J 6,8 Hz), 8,09 (2H, d, J 15,6 Hz).1 H-NMR (400 MHz, CDCl 3, δ): 3.88 (3H, s, OCH 3), 6.95 (2H, d, J 6.8 Hz), 7.45 (2H, d, J 15.6 H), 7.65 (2H, d, J 6.8 Hz), 8.09 (2H, d, J 15.6 Hz)
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(donde W tiene el significado facilitado anteriormente y X = Cl, H).(where W has the meaning given above and X = Cl, H).
Se mezclaron el ácido 4-(fenil 4-sustituido)-2-oxo-3-butenoico obtenido según la etapa a) (60 mmoles), clorhidrato de 2,4-diclorofenilhidrazina o 2-clorofenilhidrazina (60 mmoles) 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 o blanco (intervalo del rendimiento 10-90%). Los dos enantiómeros de este ácido se pueden separar mediante HPLC quiral o mediante cristalización de las sales diastereoisoméricas formadas con aminas quirales (se obtiene ee \geq 99%)4- (Phenyl acid) was mixed 4-substituted) -2-oxo-3-butenoic obtained according to step a) (60 mmol), hydrochloride 2,4-dichlorophenylhydrazine or 2-chlorophenylhydrazine (60 mmol) and acetic acid glacial (200 mL) under a nitrogen atmosphere and heated to reflux for 4 hours, cooled to room temperature (approximately 25 ° C) and added to ice water, by which obtained a sticky dough that was extracted with methylene The combined methylene chloride fractions are washed with water, dried with sodium sulfate, filtered and evaporated to dryness to give a pale yellow solid or white (yield range 10-90%). Both enantiomers of this acid can be separated by chiral HPLC or by crystallization of the diastereoisomeric salts formed with chiral amines (ee ≥ 99% is obtained)
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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 (400 MHz, CDCl_{3}, \delta): 3,3 (dd, 1H), 3,7 (dd, 1H), 5,9 (dd, 1H), 7,09-7,25 (m, 7H).1 H-NMR (400 MHz, 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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IR (KBr, cm^{-1}): 3200-2200, 1685, 1571, 1549, 1480, 1112.IR (KBr, cm -1): 3200-2200, 1685, 1571, 1549, 1480, 1112.
^{1}H-RMN (400 MHz, CDCl_{3}, \delta): 3,27 (1H, dd, J 18, 0, 6,4 Hz, ArH), 3,71 (1H, dd, J 18, 12,8 Hz, Ar H), 5,88 (1H, dd, J 12,8, 6,4 Hz, CH), 7,02 (2H, d, J 7,6 Hz, Ar H), 5 7,08 (1H, m, ArH), 7,19 (1H, d, J 8,4 Hz, ArH), 7,26 (1H, m ArH), 7,37 (2H, d, 7,6 Hz, ArH).1 H-NMR (400 MHz, CDCl 3, δ): 3.27 (1H, dd, J 18, 0, 6.4 Hz, ArH), 3.71 (1H, dd, J 18, 12.8 Hz, Ar H), 5.88 (1H, dd, J 12.8, 6.4 Hz, CH), 7.02 (2H, d, J 7.6 Hz, Ar H), 5 7.08 (1H, m, ArH), 7.19 (1H, d, J 8.4 Hz, ArH), 7.26 (1H, m ArH), 7.37 (2H, d, 7.6 Hz, ArH).
^{13}C RMN (100 MHz, CDCl_{3}, \delta): 40,4 (CH_{2}), 67,4 (CH), 122,7 (C), 126,0 (CH), 126,5 (C), 127,6 (CH), 128,3 (CH), 130,2 (CH), 131,2 (C), 132,2 (CH), 138,4 (C), 138,5 (C), 140,2, (C), 165,7 (C).13 C NMR (100 MHz, CDCl 3, δ): 40.4 (CH2), 67.4 (CH), 122.7 (C), 126.0 (CH), 126.5 (C), 127.6 (CH), 128.3 (CH), 130.2 (CH), 131.2 (C), 132.2 (CH), 138.4 (C), 138.5 (C), 140.2, (C), 165.7 (C).
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IR (KBr, cm^{-1}): 3200-2200, 1687,5, 1478, 1230, 1107.IR (KBr, cm -1): 3200-2200, 1687.5, 1478, 1230, 1107.
^{1}H-RMN (400 MHz, CDCl_{3}, \delta): 3,30 (1H, dd, J 18, 0, 6,4 Hz, ArH), 3,72 (1H, dd, J 18, 12,8 Hz, Ar H), 5,93 (1H, dd, J 12,8, 6,4 Hz, CH), 6,92 (2H, t, J 8,4 Hz, ArH), 7,09-7,12 (3H, m, ArH), 7,22 (1H, bs, ArH), 7,26 (1H, m ArH).1 H-NMR (400 MHz, CDCl 3, δ): 3.30 (1H, dd, J 18, 0, 6.4 Hz, ArH), 3.72 (1H, dd, J 18, 12.8 Hz, Ar H), 5.93 (1H, dd, J 12.8, 6.4 Hz, CH), 6.92 (2H, t, J 8.4 Hz, ArH), 7.09-7.12 (3H, m, ArH), 7.22 (1H, bs, ArH), 7.26 (1H, m ArH).
^{13}C RMN (100 MHz, CDCl_{3}, \delta): 40,7 (CH_{2}), 67,8 (CH), 115,9 (CH, d, JF 21 Hz), 126,1 (CH), 126,5 (C), 127,6 (CH), 128,3 (CH, d, JF 8,2 Hz), 130,1 (CH), 131,2 (C), 135,1 (C, d, JF 3 Hz), 138,6 (C), 140,1 (C), 160, 6, (C, d, JF 240 Hz), 166,3 (C).13 C NMR (100 MHz, CDCl 3, δ): 40.7 (CH2), 67.8 (CH), 115.9 (CH, d, JF 21 Hz), 126.1 (CH), 126.5 (C), 127.6 (CH), 128.3 (CH, d, JF 8.2 Hz), 130.1 (CH), 131.2 (C), 135.1 (C, d, JF 3 Hz), 138.6 (C), 140.1 (C), 160, 6, (C, d, JF 240 Hz), 166.3 (C).
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IR (NaCl película, cm^{-1}) v 2938, 2833, 1663, 1476.IR (NaCl film, cm -1) v 2938, 2833, 1663, 1476.
IR (KBr, cm^{-1}): v 3200-2200, 1685, 1513, 1478, 1248, 1105.IR (KBr, cm -1): v 3200-2200, 1685, 1513, 1478, 1248, 1105.
^{1}H-RMN (400 MHz, CDCl_{3}, \delta): 1,45 (2H, m, CH_{2}), 1,75 (4H, m), 2,84 (4H, m), 3,45 (1H, dd, J 4,8, 18 Hz), 3,61 (1H, dd J 11,2, 19,6 Hz), 5,93 (1H, dd, J 4,8 11,2 Hz), 6,57 (2H, ap, s), 7,13 (2H, m), 7,32 (1H, m), 7,40 (1H, m).1 H-NMR (400 MHz, CDCl3, δ): 1.45 (2H, m, CH2), 1.75 (4H, m), 2.84 (4H, m), 3.45 (1H, dd, J 4.8, 18 Hz), 3.61 (1H, dd J 11.2, 19.6 Hz), 5.93 (1H, dd, J 4.8 11.2 Hz), 6.57 (2H, ap, s), 7.13 (2H, m), 7.32 (1H, m), 7.40 (1H, m).
^{13}C RMN (100 MHz, CDCl_{3}, \delta): 23,4 (CH_{2}), 25,3 (CH_{2}), 40,5 (CH_{2}), 57,3 (CH_{2}), 63,7 (CH), 125,7 (CH), 125,8 (CH), 126,1 (CH), 127,1 (C), 127,8 (CH), 130,1 (CH), 131,1 (C), 139, 6, (C), 139,9 (C), 146,1 (C), 158,9 (CO).13 C NMR (100 MHz, CDCl 3, δ): 23.4 (CH2), 25.3 (CH2), 40.5 (CH2), 57.3 (CH2), 63.7 (CH), 125.7 (CH), 125.8 (CH), 126.1 (CH), 127.1 (C), 127.8 (CH), 130.1 (CH), 131.1 (C), 139, 6, (C), 139.9 (C), 146.1 (C), 158.9 (CO).
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(donde W y X tienen el significado facilitado anteriormente).(where W and X have the meaning facilitated previously).
Se disolvió el ácido 5-(fenil 4-sustituido)-1-(2,4-diclorofenil) o (2-clorofenil)-4,5-dihidropirazol-3-carboxílico (15 mmoles) obtenido según la etapa (b) en 120 mL de tolueno anhidro y cloruro de tionilo (18 mmoles). La mezcla se calentó hasta 80ºC durante 2,5 horas. El disolvente se elimina a presión reducida y el residuo i crudo resultante se utiliza sin purificación adicional.The acid 5- (phenyl) was dissolved 4-substituted) -1- (2,4-dichlorophenyl) or (2-Chlorophenyl) -4,5-dihydropyrazol-3-carboxylic (15 mmol) obtained according to step (b) in 120 mL of toluene anhydrous and thionyl chloride (18 mmol). The mixture was heated up to 80 ° C for 2.5 hours. The solvent is removed under pressure reduced and the resulting crude and residue is used without purification additional.
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IR (KBr, cm^{-1}): 1732, 1700, 1533, 1478, 1212, 826.IR (KBr, cm -1): 1732, 1700, 1533, 1478, 1212, 826.
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IR (KBr, cm^{-1}): 1737, 1534, 1477, 1212, 1127.IR (KBr, cm -1): 1737, 1534, 1477, 1212, 1127
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IR (KBr, cm^{-1}): 1733, 1548, 1511, 1478, 1212, 832.IR (KBr, cm -1): 1733, 1548, 1511, 1478, 1212, 832.
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IR (KBr, cm^{-1}): 1735, 1513, 1477, 1249, 1129.IR (KBr, cm -1): 1735, 1513, 1477, 1249, 1129
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(donde W, n, R^{28} y x tienen el significado facilitado anteriormente).(where W, n, R 28 and x have the meaning provided previously).
Bajo atmósfera de nitrógeno, se disolvieron una amina apropiada (5,6 mmoles) 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-(fenil 4-sustituido)-1-(2,4-diclorofenil)-4,5-dihidro-pirazol-3-carboxílico (4,6 mmoles) 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. Las dos fracciones se combinaron para dar el producto deseado (intervalo de rendimiento: 60-80%). Alternativamente, el compuesto se puede purificar mediante la cristalización de su forma clorhidratada, preparada con una solución de HCl 2N en éter o HCl 2,8 N en etanol.Under nitrogen atmosphere, a appropriate amine (5.6 mmol) and triethylamine (4 mL) in methylene (25 mL). The resulting mixture was cooled with ice until 0 ° C and a solution of the acid chloride was added dropwise 5- (phenyl 4-substituted) -1- (2,4-dichlorophenyl) -4,5-dihydro-pyrazol-3-carboxylic (4.6 mmol) obtained in step (c) in methylene chloride (15 mL) The resulting reaction mixture was stirred at temperature. ambient (approximately 25 ° C) overnight. Then the mixture reaction was washed with water, followed by an aqueous solution saturated sodium bicarbonate, then again with water, it dried over sodium sulfate, filtered and evaporated to dryness in a rotary evaporator. The resulting crude solid crystallized from ethanol. The crystallized solid was filtered off and the mother waters were concentrated to give a second fraction of crystallized product The two fractions were combined to give the desired product (performance range: 60-80%) Alternatively, the compound can be purify by crystallization of its hydrochloride form, prepared with a solution of 2N HCl in ether or 2.8 N HCl in ethanol.
Si el material de partida en la etapa c) es un ácido quiral.If the starting material in step c) is a chiral acid
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^{1}H-RMN (300 MHz, DMSO-d_{6}) \delta ppm: 1,53 (m, 10H), 1,79 (m, 2H), 3,05 (dd, J = 18,16, 5,71 Hz, 1H), 3,64 (dd, J = 18,16 11,94 Hz, 1H), 3,85 (m, 1H), 5,80 (dd, J = 11,94, 5,71 Hz, 1H), 7,13 (m, 2H), 7,27 (m, 2H), 7,43 (d, J = 2,34 Hz, 1H), 7,51 (d, J = 8,79 Hz, 1H), 8,10 (d = J = 8,35 Hz, 1H).1 H-NMR (300 MHz, DMSO-d6) δ ppm: 1.53 (m, 10H), 1.79 (m, 2H), 3.05 (dd, J = 18.16, 5.71 Hz, 1H), 3.64 (dd, J = 18.16 11.94 Hz, 1H), 3.85 (m, 1H), 5.80 (dd, J = 11.94, 5.71 Hz, 1H), 7.13 (m, 2H), 7.27 (m, 2H), 7.43 (d, J = 2.34 Hz, 1H), 7.51 (d, J = 8.79 Hz, 1H), 8.10 (d = J = 8.35 Hz, 1H).
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^{1}H-RMN (300 MHz, DMSO-d_{6}) \delta ppm 1,61 (m, 2 H) 2,14 (m, 4 H) 3,05 (cid, J=18,16, 5,57 Hz' 1 H) 3,63 (dd, J=18,16, 11,94 Hz, 1 H) 4,33 (m, 1 H) 5,81 (dd, J=11.94, 5,57 Hz, 1 H) 7,13 (m, 2 H) 7.27 (m, 3 H) 7,43 (d, J=2,34 Hz, 1 H) 7,52 (d, J=8,79 Hz, 1 H) 8,53 (d, J=8.06 Hz, 1 H).1 H-NMR (300 MHz, DMSO-d 6) δ ppm 1.61 (m, 2 H) 2.14 (m, 4 H) 3.05 (cid, J = 18.16, 5.57 Hz '1 H) 3.63 (dd, J = 18.16, 11.94 Hz, 1 H) 4.33 (m, 1 H) 5.81 (dd, J = 11.94, 5.57 Hz, 1 H) 7.13 (m, 2 H) 7.27 (m, 3 H) 7.43 (d, J = 2.34 Hz, 1 H) 7.52 (d, J = 8.79 Hz, 1 H) 8.53 (d, J = 8.06 Hz, 1 H).
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^{1}H-RMN (300 MHz, CLOROFORMO-d) \delta ppm 0,99 (m, 2 H) 1,21 (m, 4 H) 1,69 (m, 1 H) 1,76 (m, 4 H) 3,15 (dd, J=17,98, 6,06 Hz, 1 H) 3,32 (dt, J=12,60, 6,40 Hz, 2 H) 3,67 (dd, J=17,98, 12,11 Hz, 1 H) 5,73 (dd, J=12,11, 6,06 Hz, 1 H) 6,75 (t, J=6,06 Hz, 1 H) 7,06 (m, 3 H) 7,12 (m, 1 H) 7,17 (d, J=8,60 Hz, 2 H) 7,26 (m, 1 H).1 H-NMR (300 MHz, CHLOROFORM-d) δ ppm 0.99 (m, 2 H) 1.21 (m, 4 H) 1.69 (m, 1 H) 1.76 (m, 4 H) 3.15 (dd, J = 17.98, 6.06 Hz, 1 H) 3.32 (dt, J = 12.60, 6.40 Hz, 2 H) 3.67 (dd, J = 17.98, 12.11 Hz, 1 H) 5.73 (dd, J = 12.11, 6.06 Hz, 1 H) 6.75 (t, J = 6.06 Hz, 1 H) 7.06 (m, 3 H) 7.12 (m, 1 H) 7.17 (d, J = 8.60 Hz, 2 H) 7.26 (m, 1 H).
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^{1}H-RMN (400 MHz, CLOROFORMO-d) \delta ppm 1,59 (m, 12 H) 1,91 (m, 2 H) 3,32 (dd, J=18,37, 5,86 Hz, 1 H) 3,66 (dd, J=18,37, 12,11 Hz, 1 H) 4,10 (ddd, J=8,60, 4,01, 3,71 Hz, 1 H) 5,72 (dd, J=12.11, 5,86 Hz, 1 H) 6,65 (d, J=8,60 Hz, 1 H) 7,07 (m, 3 H) 7,15 (m, 3 H) 7.25 (m, 1 H).1 H-NMR (400 MHz, CHLOROFORM-d) δ ppm 1.59 (m, 12 H) 1.91 (m, 2 H) 3.32 (dd, J = 18.37, 5.86 Hz, 1 H) 3.66 (dd, J = 18.37, 12.11 Hz, 1 H) 4.10 (ddd, J = 8.60, 4.01, 3.71 Hz, 1 H) 5.72 (dd, J = 12.11, 5.86 Hz, 1 H) 6.65 (d, J = 8.60 Hz, 1 H) 7.07 (m, 3 H) 7.15 (m, 3 H) 7.25 (m, 1 H).
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^{1}H RMN (400 MHz, CLOROFORMO-d) \delta ppm 1,44 - 1,75 (m, 6 H) 2,06 (td, J=13,09, 5,86 Hz, 2 H) 3,32 (dd, J=18,37, 6,25 Hz, 1 H) 3,66 (dd, J=18,37, 12,11 Hz, 1 H) 4,31 (m, 1 H) 5,73 (dd, J=12,11, 6,25 Hz, 1 H) 6,62 (d, J=7,82 Hz_{1} 1 H) 7,06 (m, 3 H) 7,12 (s, 1 H) 7,17 (m, 2 H) 7,25 (m, 1 H).1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 - 1.75 (m, 6 H) 2.06 (td, J = 13.09, 5.86 Hz, 2 H) 3.32 (dd, J = 18.37, 6.25 Hz, 1 H) 3.66 (dd, J = 18.37, 12.11 Hz, 1 H) 4.31 (m, 1 H) 5.73 (dd, J = 12.11, 6.25 Hz, 1 H) 6.62 (d, J = 7.82 Hz 1 H) 7.06 (m, 3 H) 7.12 (s, 1 H) 7.17 (m, 2 H) 7.25 (m, 1 H).
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^{1}H RMN (300 MHz, DMSO-d_{6}) \delta ppm 1,29 (m, 20 H) 1,63 (m, 2 H) 3,06 (dd, J=18,09, 5,93 Hz, 1 H) 3,65 (dd, J=18,09, 11,86 Hz, 1 H) 4,04 (m, 1 H) 5,81 (dd, J=11,86, 5,93 Hz, 1 H) 7,14 (m, 2 H) 7,28 (m, 3 H) 7,43 (d, J=2,34 Hz, 1 H) 7,50 (d, J=8,79 Hz, 1 H) 8,00 (d, J=8,79 Hz, 1 H).1 H NMR (300 MHz, DMSO-d 6) δ ppm 1.29 (m, 20 H) 1.63 (m, 2 H) 3.06 (dd, J = 18.09, 5.93 Hz, 1 H) 3.65 (dd, J = 18.09, 11.86 Hz, 1 H) 4.04 (m, 1 H) 5.81 (dd, J = 11.86, 5.93 Hz, 1 H) 7.14 (m, 2 H) 7.28 (m, 3 H) 7.43 (d, J = 2.34 Hz, 1 H) 7.50 (d, J = 8.79 Hz, 1 H) 8.00 (d, J = 8.79 Hz, 1 H).
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^{1}H RMN (300 MHz, METHNOL-d_{4}) \delta ppm 1,49 - 1,78 (m, 10 H) 1,95 (br. s., 2 H) 3,21 (dd, J=18,09, 5,79 Hz, 1 H) 3,67 (dd, J=18,09, 12,08 Hz, 1 H) 3,99 (m, 1 H) 5,86 (dd, J=12,08, 5,79 Hz_{1} 1 H) 7,09 (d, J=8,50 Hz, 2 H) 7,15 (dd, J=8,79, 2,34 Hz, 1 H) 7,30 (d, J=2,34 Hz, 1 H) 7,33 - 7,44 (m, 3 H).1 H NMR (300 MHz, METHNOL-d4) δ ppm 1.49 - 1.78 (m, 10 H) 1.95 (br. S., 2 H) 3.21 (dd, J = 18.09, 5.79 Hz, 1 H) 3.67 (dd, J = 18.09, 12.08 Hz, 1 H) 3.99 (m, 1 H) 5.86 (dd, J = 12.08, 5.79 Hz_ {1} 1 H) 7.09 (d, J = 8.50 Hz, 2 H) 7.15 (dd, J = 8.79, 2.34 Hz, 1 H) 7.30 (d, J = 2.34 Hz, 1 H) 7.33-7.44 (m, 3 H).
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^{1}H RMN (300 MHz, DMSO-d_{6}) \delta ppm 1,36 - 1,67 (m, 10 H) 1,72 - 1,87 (m, 2 H) 3,05 (dd, J=18,02, 5,64 Hz, 1 H) 3,63 (dd, J=18,02, 11,79 Hz, 1 H) 3,79 - 3,92 (m, J=8,95, 1 H) 5,80 (dd, J=11,79, 5,64 Hz, 1 H) 7,04 (t, J=8,79 Hz, 2 H) 7,12 - 7,18 (m, 2 H) 7,26 (dd, J=8,79, 2,34 Hz, 1 H) 7,43 (d, J=2,34 Hz, 1 H) 7,50 (d, J=8,79 Hz, 1 H) 8,10 (d, J=8.20 Hz, 1 H).1 H NMR (300 MHz, DMSO-d 6) δ ppm 1.36-1.67 (m, 10 H) 1.72 - 1.87 (m, 2 H) 3.05 (dd, J = 18.02, 5.64 Hz, 1 H) 3.63 (dd, J = 18.02, 11.79 Hz, 1 H) 3.79-3.92 (m, J = 8.95, 1 H) 5.80 (dd, J = 11.79, 5.64 Hz, 1 H) 7.04 (t, J = 8.79 Hz, 2 H) 7.12 - 7.18 (m, 2 H) 7.26 (dd, J = 8.79, 2.34 Hz, 1 H) 7.43 (d, J = 2.34 Hz, 1 H) 7.50 (d, J = 8.79 Hz, 1 H) 8.10 (d, J = 8.20 Hz, 1 H).
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(Tabla pasa a página siguiente)(Table goes to page next)
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 by 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 Transfected human CB 1 and CB 2 receptors from Receptor Biology, Inc. are used. 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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La afinidad de los compuestos de pirazolina sustituidos de la invención por los receptores CB_{1}/CB_{2} se determinó tal y como se ha descrito anteriormente. Algunos de los valores EC50 obtenidos se proporcionan en la Tabla 1.The affinity of pyrazoline compounds substituted of the invention by the CB1 / CB2 receptors are determined as described above. Some of the EC50 values obtained are provided in Table 1.
Tal como se puede observar de los valores dados en la tabla 3, los compuestos de pirazolina de la invención son particularmente adecuados para regular el receptor CB_{1}.As can be seen from the given values in table 3, the pyrazoline compounds of the invention are particularly suitable for regulating the CB1 receptor.
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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 by intravenously the substance to be tested or the vehicle alone. 15 minutes after the injection, the latency of hot plate analgesia. 20 minutes after the injection It measures 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.
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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 100MPE% 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% sedation = arithmetic mean / 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 descripciónHypothermia 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.
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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% of catalepsy = arithmetic mean / 6 X 100
Se cultivaron células de ovario de hámster chino (CHO) que expresan de forma estable el receptor de cannabinoide humano 1 recombinante en una mezcla de nutrientes F12 de Ham suplementado con un 10% de suero bovino fetal inactivado con el calor, 2 mM de L-glutamina, 50 U/ml de penicilina, 50 U/ml de estreptomicina y 0,5 mg/ml de geneticina. Con el fin de obtener células, se lavaron los matraces de cultivo dos veces con solución salina tamponada con fosfato y se rascaron. A continuación, se recogieron las células mediante centrifugación (200 x g, 10 minutos) y se guardaron en seco a -80ºC. Las células se homogeneizaron en HEPES 20 mM enfriado con hielo, EDTA 10 mM (pH 7,5) y se centrifugaron a 40.000 x g durante 15 minutos a 4ºC. El pélet se resuspendió en HEPES 20 mM, EDTA 0,1 mM (pH 7,5) y se centrifugó durante 15 minutos a 4ºC. El pélet final se resuspendió en HEPES 20 mM, EDTA 0,1 mM (pH 7,5) y se dividió en partes alícuotas y se guardaron a -80ºC hasta su uso.Chinese hamster ovary cells were cultured (CHO) that stably express the cannabinoid receptor recombinant human 1 in a mixture of Ham F12 nutrients supplemented with 10% fetal bovine serum inactivated with the heat, 2 mM L-glutamine, 50 U / ml penicillin, 50 U / ml streptomycin and 0.5 mg / ml geneticin. With the purpose of to obtain cells, the culture flasks were washed twice with phosphate buffered saline and scratched. TO then the cells were collected by centrifugation (200 x g, 10 minutes) and stored dry at -80 ° C. The cells homogenized in ice cold 20 mM HEPES, 10 mM EDTA (pH 7.5) and centrifuged at 40,000 x g for 15 minutes at 4 ° C. He pellet was resuspended in 20 mM HEPES, 0.1 mM EDTA (pH 7.5) and centrifuged for 15 minutes at 4 ° C. The final pellet was resuspended in 20 mM HEPES, 0.1 mM EDTA (pH 7.5) and divided into parts aliquots and stored at -80 ° C until use.
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La reacción se realizó en placas de 96 pocillos. Las membranas se incubaron (15 \mug/pocillo) durante 60 minutos a 30ºC en tampón (HEPES 50 mM, KC1 100 mM, MgCl_{2} 5 mM, EDTA 1 mM, albúmina de suero bovino al 0,1% p/v, GDP 5 \muM, saponina (10 \mug/ml), [^{35}S]GTP\gammaS 0,5 nM, pH 7,4) con un compuesto a una concentración final de 1 \muM en ausencia o presencia de una curva dosis-respuesta de agonista WIN 55,212-2 entre 3 nM y 3 \muM. La incubación se terminó mediante filtración rápida a través de fibra de vidrio FB Millipore Multiscreen y se enjuagó dos veces con tampón de ensayo enfriado en hielo. Las placas de filtrado se secaron y se añadieron 30 \mul de líquido de centelleo. La radioactividad se determinó utilizando Wallac Microbeta Trilux. Cada experimento se realizó al menos por duplicado. Se realizó sistemáticamente una dosis-respuesta de WIN 55,212-2.The reaction was performed in 96-well plates. The membranes were incubated (15 µg / well) for 60 minutes at 30 ° C in buffer (50 mM HEPES, 100 mM KC1, 5 mM MgCl2, EDTA 1 mM, 0.1% w / v bovine serum albumin, 5 µM GDP, saponin (10 µg / ml), [35 S] 0.5 nM GTPγS, pH 7.4) with a compound at a final concentration of 1 µM in the absence or presence of an agonist dose-response curve WIN 55,212-2 between 3 nM and 3 µM. Incubation It was terminated by rapid filtration through fiberglass FB Millipore Multiscreen and rinsed twice with buffer ice cold test. The filtering plates were dried and dried. they added 30 µl of scintillation liquid. The radioactivity is determined using Wallac Microbeta Trilux. Each experiment is performed at least in duplicate. A systematically performed WIN dose response 55,212-2.
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El promedio de unión de [^{35}S]GTP\gammaS basal se sustrajo se todos los datos de unión. Con el fin de comparar los resultados de antagonismo de un grupo de cribado con respecto a otro, la diferencia entre el efecto agonista máximo de Win 55,212-2 solo y el efecto de antagonismo máximo debido a WIN 55,212-2 más Rimonabant (1 \muM) se definió como el 100%.The average union of [35 S] GTP? Baseline was subtracted from all data of Union. In order to compare the results of antagonism of one screening group with respect to another, the difference between the maximum agonist effect of Win 55,212-2 alone and the maximum antagonism effect due to WIN 55,212-2 more Rimonabant (1 µM) was defined as 100%.
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La determinación de la actividad cannabinoide in vivo se determinó tal y como se ha descrito anteriormente. El efecto antagonístico (contra Win 55212-2) se determinó para algunos de los compuestos tal y como se indica en la siguiente Tabla 3.The determination of cannabinoid activity in vivo was determined as described above. The antagonistic effect (against Win 55212-2) was determined for some of the compounds as indicated in the following Table 3.
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(Tabla pasa a página siguiente)(Table goes to page next)
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Los resultados de las pruebas de algunos de los ejemplos anteriores para la unión y el antagonismo se muestran juntos en la siguiente tabla 3:The test results of some of the previous examples for binding and antagonism are shown together in the following table 3:
Se habituaron ratas normalmente tratadas a un ciclo inverso 12/12 h, y el compuesto candidato, así como la solución salina, se administraron oralmente de forma aguda. Después de la administración, se midieron a las 6 h y 24 h la ingesta de alimentos acumulada (g). Después de esto, se midió la diferencia en el peso corporal entre los animales de control y los animales tratados con el compuesto.Normally treated rats were habituated to a reverse cycle 12/12 h, and the candidate compound, as well as the saline solution, were administered orally acutely. After after administration, the intake of accumulated food (g). After this, the difference in body weight between control animals and animals treated with the compound.
La figura 1 muestra los resultados para 10 mg/kg del compuesto según el ejemplo 2. El número de ratas utilizado fue de 11 para solución salina y 12 para el compuesto.Figure 1 shows the results for 10 mg / kg of the compound according to example 2. The number of rats used was of 11 for saline and 12 for the compound.
Además, el compuesto según el ejemplo 18 muestra una buena actividad en este modelo.In addition, the compound according to example 18 shows A good activity in this model.
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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.
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.
Claims (25)
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- \quadquad
- alquilo C_{1-3} ramificado o lineal o alcoxi C_{1-3} ramificado o lineal, fenilo, hidroxilo, cloro, bromo, fluoro, yodo, SH, trifluorometilo, CHF_{2}, CH_{2}F, OCHF_{2}, trifluorometiltio, trifluorometoxi, metilsulfonilo, carboxilo, trifluorometilsulfonilo, ciano, carbamoílo, sulfamoílo y acetilo; O-P, indicando P un grupo profármaco que consiste en arilo, alquilo C_{8-20}, heterociclilo, C(O)-arilo, C(O)-heterociclilo, C(O)-alquilo C_{1-20}; O-P, indicando P un grupo profármaco que consiste en alquilo C_{8-20} o C(O)-alquilo C_{1-20} sustituidos o no sustituidos, ramificados o lineales, saturados o insaturados; arilo, alquil-arilo, heterociclilo o alquil-heterociclilo sustituidos o no sustituidos; C(O)-arilo, C(O)-alquil-arilo, C(O)-heterociclilo o C(O)-alquil-heterociclilo sustituidos o no sustituidos;C 1-3 branched alkyl or linear or branched or linear C 1-3 alkoxy, phenyl, hydroxyl, chlorine, bromine, fluoro, iodine, SH, trifluoromethyl, CHF 2, CH 2 F, OCHF 2, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl; O-P, indicating P a prodrug group consisting in aryl, C 8-20 alkyl, heterocyclyl, C (O) -aryl, C (O) -heterocyclyl, C (O) -C 1-20 alkyl; O-P, indicating P a prodrug group consisting in C 8-20 alkyl or C (O) -C 1-20 alkyl substituted or unsubstituted, branched or linear, saturated or unsaturated; aryl, alkyl-aryl, heterocyclyl or substituted or unsubstituted alkyl heterocyclyl; C (O) -aryl, C (O) -alkyl-aryl, C (O) -heterocyclyl or C (O) -alkyl-heterocyclyl substituted or unsubstituted;
- \quadquad
- H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2};H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2;
mismos.in the form shown or in the form of the acid or base or in the form of a salt, especially a physiologically acceptable salt, or in the form of a solvate, especially a hydrate or in the form of the corresponding N-oxide of the
same.
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- \quadquad
- alquilo C_{1-3} ramificado o lineal o alcoxi C_{1-3} ramificado o lineal, fenilo, hidroxilo, cloro, bromo, fluoro, yodo, SH, trifluorometilo, CHF_{2}, CH_{2}F, OCHF_{2}, trifluorometiltio, trifluorometoxi, metilsulfonilo, carboxilo, trifluorometilsulfonilo, ciano, carbamoílo, sulfamoílo y acetilo; O-P, indicando P un grupo profármaco que consiste en alquilo C_{8-20} o C(O)-alquilo C_{1-20} sustituidos o no sustituidos, ramificados o lineales, saturados o insaturados; arilo, alquil-arilo, heterociclilo o alquil-heterociclilo sustituidos o no sustituidos; C(O)-arilo, C(O)-alquil-arilo, C(O)-heterociclilo o C(O)- alquil-heterociclilo sustituidos o no sustituidos;C 1-3 branched alkyl or linear or branched or linear C 1-3 alkoxy, phenyl, hydroxyl, chlorine, bromine, fluoro, iodine, SH, trifluoromethyl, CHF 2, CH 2 F, OCHF 2, trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl; O-P, indicating P a prodrug group consisting in C 8-20 alkyl or C (O) -C 1-20 alkyl substituted or unsubstituted, branched or linear, saturated or unsaturated; aryl, alkyl-aryl, heterocyclyl or substituted or unsubstituted alkyl heterocyclyl; C (O) -aryl, C (O) -alkyl-aryl, C (O) -heterocyclyl or C (O) - alkyl or heterocyclyl substituted or not substituted;
- \quadquad
- H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2};H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2;
\newpage\ newpage
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- \quadquad
- H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2};H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2;
mismos.in the form shown or in the form of the acid or base or in the form of a salt, especially a physiologically acceptable salt, or in the form of a solvate, especially a hydrate or in the form of the corresponding N-oxide of the
same.
\newpage\ newpage
- \quadquad
- H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2};H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2;
- \quadquad
- H, F, Cl, Br, I, OH, CH_{3}, C_{2}H_{5}, OCH_{3}, OCF_{3} o CF_{3}.H, F, Cl, Br, I, OH, CH 3, C 2 H 5, OCH_ {3}, OCF_ {3} or CF_ {3}.
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- \quadquad
- H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2};H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2;
mismos.in the form shown or in the form of the acid or base or in the form of a salt, especially a physiologically acceptable salt, or in the form of a solvate, especially a hydrate or in the form of the corresponding N-oxide of the
same.
\newpage\ newpage
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- \quadquad
- H, F, Cl, Br, I, OH, SH, alquilo C_{1-4}, alcoxi C_{1-4}, CF_{3}, CHF_{2}, CH_{2}F, OCF_{3}, un grupo ceto, NO_{2} o NH_{2};H, F, Cl, Br, I, OH, SH, alkyl C 1-4, C 1-4 alkoxy, CF 3, CHF 2, CH 2 F, OCF 3, a keto group, NO 2 or NH2;
- \quadquad
- H, F, Cl, Br, I, OH, CH_{3}, C_{2}H_{5}, OCH_{3}, OCF_{3} o CF_{3}.H, F, Cl, Br, I, OH, CH 3, C 2 H 5, OCH_ {3}, OCF_ {3} or CF_ {3}.
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EP05384018 | 2005-07-15 | ||
EP05384018A EP1743888A1 (en) | 2005-07-15 | 2005-07-15 | Carbonyl substituted pyrazoline compounds, their preparation and use as CB1 receptor modulators |
US70543305P | 2005-08-05 | 2005-08-05 | |
US60/705,433 | 2005-08-05 | ||
EP06008580 | 2006-04-26 | ||
EP06008580A EP1849775A1 (en) | 2006-04-26 | 2006-04-26 | Cycloalkane-substituted pyrazoline compounds, their preparation and use as medicaments |
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WO2005037199A2 (en) * | 2003-10-10 | 2005-04-28 | Bristol-Myers Squibb Company | Pyrazole derivatives as cannabinoid receptor modulators |
US20050261281A1 (en) * | 2004-05-24 | 2005-11-24 | Paolo Lazzari | Pharmaceutical compounds |
US20060030563A1 (en) * | 1999-10-18 | 2006-02-09 | Alexandros Makriyannis | Novel pyrazole analogs acting on cannabinoid receptors |
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US20060030563A1 (en) * | 1999-10-18 | 2006-02-09 | Alexandros Makriyannis | Novel pyrazole analogs acting on cannabinoid receptors |
WO2005037199A2 (en) * | 2003-10-10 | 2005-04-28 | Bristol-Myers Squibb Company | Pyrazole derivatives as cannabinoid receptor modulators |
US20050261281A1 (en) * | 2004-05-24 | 2005-11-24 | Paolo Lazzari | Pharmaceutical compounds |
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