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WO2007028849A1 - Derives de pirazolcarboxamide, procede d'obtention et applications comme antagonistes/agonistes inverses du recepteur cannabinoide cb1 et opioide mu - Google Patents

Derives de pirazolcarboxamide, procede d'obtention et applications comme antagonistes/agonistes inverses du recepteur cannabinoide cb1 et opioide mu Download PDF

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WO2007028849A1
WO2007028849A1 PCT/ES2006/070132 ES2006070132W WO2007028849A1 WO 2007028849 A1 WO2007028849 A1 WO 2007028849A1 ES 2006070132 W ES2006070132 W ES 2006070132W WO 2007028849 A1 WO2007028849 A1 WO 2007028849A1
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methyl
chlorophenyl
pyrazol
dichlorophenyl
phenethyl
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Spanish (es)
Inventor
Nadine Jagerovic
Cristina FERNÁNDEZ FERNÁNDEZ
Maria Pilar Goya Laza
Luis Felipe Callado Hernando
Jose Javier Meana Martinez
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Euskal Herriko Unibertsitatea
Consejo Superior de Investigaciones Cientificas CSIC
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Euskal Herriko Unibertsitatea
Consejo Superior de Investigaciones Cientificas CSIC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the present invention relates to new pyrazole-3-carboxamide derivatives as cannabinoid inverse agonists and their use as pharmacological tools and as drugs for the treatment of diseases in which cannabinoid and opioid receptors are involved.
  • CBi and CB 2 cannabinoid receptors
  • CBi cannabinoid receptors are found in the central nervous system while CB 2 cannabinoid receptors reach significant densities in different types of immune cells.
  • CBi cannabinoid receptors transmit their signal through the activation of pertussis toxin-sensitive G proteins to inhibit the adenylate cyclase system leading to a decrease in intracellular cyclic adenosyl monophosphate levels.
  • Compounds that interact with cannabinoid receptors may have therapeutic applications in various diseases such as appetite stimulants, anti- emetics, analgesics, antiglaucoma agents, in the treatment of neurodegenerative disorders such as multiple sclerosis.
  • Antagonists and inverse agonists of CBi cannabinoid receptors in particular, will be useful for the treatment of obesity, for tobacco addiction, for dependency treatments (cannabis, opiates or alcohol), to treat cerebral ischemia and trauma.
  • the pyrazole-3- carboxamide derivatives of Formula A act as a potent inverse agonist on CBi cannabinoid receptors.
  • CBi cannabinoid receptor antagonists are inverse agonists (Makriyannis A. et al., Neuropharmacology 2005, 48, 1068-1071) (Pertwee RG, Life Sci., 2005, 76, 1307-1324) ( Lange JHM et al., Drug Discovery Today, 2005, 10, 693-702).
  • the compounds described to date show an inverse agonist effect in itself less important than the antagonistic effect they produce on CBi receptor agonists either in vitro or in vivo.
  • An object of the present invention is a pyrazolecarboxamide derivative with cannabinoid properties, hereinafter compound of the invention, based on the following formula (A):
  • Another object of the invention is a process for the preparation of the compound of the invention, hereinafter the method of the invention, according to what is described in the reaction scheme represented in Figure 1.
  • the invention in another aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (A) for the treatment of and / or prevention of disorders or diseases in which cannabinoid receptors are involved, and more specifically the CBi subtype, and for the prevention and / or treatment of disorders in which opioid receptors are involved, specifically the mu subtype, and more specifically in the treatment of opioid drug dependence, together with, optionally, one or more pharmaceutically acceptable excipients.
  • said pharmaceutical composition is a composition comprising a compound of formula (A), by way of illustration and without limiting the scope of the invention, belonging to Table I, and mixtures thereof, together with, optionally, one or more pharmaceutically acceptable excipients.
  • the invention also relates to the use of a compound of formula (A), preferably a compound of Table I, in a method for the prevention and / or treatment of disorders or diseases in which cannabinoid receptors are involved, and more specifically the CBi subtype, and for the prevention and / or treatment of disorders or diseases in which opioid receptors are involved, and, more specifically, the mu subtype.
  • a particular embodiment of the invention relates to the use of a compound of formula (A) for the prevention and / or treatment of disorders or diseases in which the CB x cannabinoid receptor is involved, and more specifically to a disorder or disease belonging, by way of illustration and without limiting the scope of the invention, to the following group: appetite suppression, reduction of dyskinesia caused by
  • Alzheimer's disease obesity treatment, tobacco addiction treatment, dependency treatment
  • a particular embodiment of the invention relates to the use of a compound of formula (A) for the prevention and / or treatment of disorders or diseases in which the opioid receptor mu is involved, and more specifically, with the treatment and prevention from drug addiction to opiates.
  • the present invention relates to pyrazolecarboxamide derivatives with cannabinoid properties and more specifically with a strong inverse agonist activity by CBi receptors and by mu opioid receptors.
  • an object of the present invention is a pyrazolecarboxamide derivative with cannabinoid properties, hereinafter the compound of the invention, based on the following formula A:
  • - X represents an alkyl, dicyclohexyl, aryl or xylene group, or an isomer, derivative or solvate thereof.
  • the compounds of the present invention represented by the formula (A) described above may include isomers, depending on the presence of multiple bonds (eg, Z, E), including optical or enantiomeric isomers, depending on the presence of chiral centers.
  • the individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.
  • the individual enantiomers or diastereoisomers, as well as mixtures thereof, can be separated by conventional techniques.
  • the term "derivative” includes both pharmaceutically acceptable compounds, that is, derivatives of the compound of formula (A) that can be used in the manufacture of a medicament, as pharmaceutically unacceptable derivatives since these may be useful. in the preparation of pharmaceutically acceptable derivatives.
  • the nature of the pharmaceutically acceptable derivative is not critical as long as it is pharmaceutically acceptable. Also, within the scope of this invention are the prodrugs of the compounds of formula (A).
  • prodrug includes any compound derived from a compound of formula (A), for example, esters, including carboxylic acid esters, amino acid esters, phosphate esters, metal salt sulphonate esters, etc., carbamates, amides, etc., which, when administered to an individual, is capable of providing, directly or indirectly, said compound of formula (A) in said individual.
  • said derivative is a compound that increases the bioavailability of the compound of formula (A) when administered to an individual or that enhances the release of the compound of formula (A) in a biological compartment.
  • the nature of said derivative is not critical as long as it can be administered to an individual and provides the compound of formula (A) in a biological compartment of an individual.
  • the preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.
  • solvate includes both pharmaceutically acceptable solvates, that is, solvates of the compound of formula (A) that can be used in the manufacture of a medicament, as pharmaceutically acceptable solvates, which may be useful in the preparation of pharmaceutically acceptable solvates or salts.
  • pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable.
  • the solvate is a hydrate. Solvates can Obtained by conventional methods of solvation well known to those skilled in the art.
  • the compounds of formula (A), their isomers, salts, prodrugs or solvates will preferably be found in a pharmaceutically acceptable or substantially pure form, that is, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and not including material considered toxic at normal dosage levels.
  • the purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, and more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (A), or of its salts, solvates or prodrugs.
  • the compounds of the invention also include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having said structure, except for the replacement of a hydrogen with a deuterium or tritium, or the replacement of a carbon with a carbon enriched in 13 C or 14 C or a nitrogen enriched in 15 N are within of the scope of this invention.
  • said compound of formula (A) belongs, by way of illustration and without limiting the scope of the invention, to the following table I: Table I
  • Another object of the invention is a process for the preparation of the compound of the invention, hereinafter the method of the invention, according to what is described in the reaction scheme represented in Figure 1 and comprising the following steps: a) synthesis of 5- (4-chlorophenyl) -1- (2, 4- dichlorophenyl) -4-methyl-lH-pyrazol-3-carboxylic acid according to the synthetic procedures described in the literature and, in particular with the published experimental part by Krishnamurthy et al., Bioorg. Med.
  • the cannabinoid activity of the compounds of the general formula (A) was assessed by carrying out in vitro radioligand displacement assays in brain membranes (fraction P 2 ) of human cortex, and guanosine-5'-binding assays 0- (3- [ 35 S] uncle) triphosphate) ([ 35 S] GTP ⁇ S) in brain membranes (fraction P 2 ) of human cortex.
  • guanosine-5'-binding assays 0- (3- [ 35 S] uncle) triphosphate) [ 35 S] GTP ⁇ S
  • radioligand displacement assays [ 3 H] -DAMGO, a mu- opioid receptor agonist, were performed in vitro on brain membranes (fraction P 2 ) of human cortex.
  • the new compounds showed a moderate to good affinity for the mu-opioid receptor.
  • mice allow us to affirm that the compounds of the invention have a dual cannabinoid and opioid action whose efficacy in vivo is a consequence of the synergy that develops when the opioid and cannabinoid activity coincide in the same molecule, behaving in vivo as cannabinoid antagonists and opioid antagonists (Example 14 and 15; Figure 3, 4 and 5 ); although in the latter case contrary to what is planned taking into account the fentanyl part (opioid agonist) that is incorporated into the structure of the new compounds.
  • These new compounds of the present invention could be useful as antagonists of the effect of both natural (synthetic THC) and synthetic (WIN 55212-2 or CP 55940) agonists.
  • the compounds according to the invention can be used as a drug for the manufacture of a medicament for the treatment and / or prevention of disorders in which cannabinoid receptors are involved, and, more specifically, the subtype CBi.
  • the fact that the compounds of the present invention bind to both opioid and cannabinoid receptors as antagonists widens their therapeutic applications to the treatment of opioid drug dependence.
  • the compounds of the present invention whose opioid agonist functionality could be confirmed in vivo, could be used for the treatment of pain and in particular for the treatment of chronic pain (see Example 13).
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (A) for the treatment of and / or prevention of disorders or diseases in which cannabinoid receptors are involved, and more specifically the CBi subtype , and for the prevention and / or treatment of disorders in which opioid receptors are involved, specifically the mu subtype, and more specifically in the treatment of opioid drug dependence, together with, optionally, one or more pharmaceutically acceptable excipients.
  • disorders or diseases in which cannabinoid receptors are involved refers to a disorder or disease, by way of illustration and without limiting the scope of the invention.
  • appetite suppression reduction of dyskinesia caused by L-dopa in Parkinson's patients, treatment of acute schizophrenia, treatment of cognitive and memory dysfunctions associated with Alzheimer's disease, treatment of obesity, treatment of tobacco addiction, dependency treatments (cannabis, opiates or alcohol), to treat cerebral ischemia and head trauma.
  • the term "pharmaceutically acceptable excipient” refers to those substances, or combination of substances, known in the pharmaceutical sector, used in the preparation of pharmaceutical forms of administration and includes adjuvants, solids or liquids, solvents , surfactants, etc.
  • said pharmaceutical composition is a composition comprising a compound of formula (A), by way of illustration and without limiting the scope of the invention, belonging to Table I, and mixtures thereof, together with, optionally, one or more pharmaceutically acceptable excipients.
  • said pharmaceutical composition may contain, in addition, one or more natural, recombinant or synthetic therapeutic agents - which, eventually, enhance the therapeutic action of said compound of formula (A), for example, of the compounds of Table I or that increase their spectrum of action.
  • the compound of formula (A) will be present in the pharmaceutical composition in a therapeutically effective amount, that is, in an amount appropriate to exert its therapeutic effect.
  • the pharmaceutical composition provided by this invention contains between 0.01% and 99.99% by weight of a compound of formula (A), such as a compound selected from the compounds of Table I and mixtures thereof.
  • a compound of formula (A) such as a compound selected from the compounds of Table I and mixtures thereof.
  • a compound of formula (A) such as a compound selected from the compounds of Table I and mixtures thereof.
  • Said pharmaceutical composition can be used to prevent and / or treat diseases in which cannabinoid receptors are involved, and more specifically the CBi subtype, and for the prevention and / or treatment of disorders in which opioid receptors are involved, and more specifically the mu subtype, as opioid antagonists.
  • the invention also relates to the use of a compound of formula (A), preferably a compound of Table I, in a method for prevention and / or the treatment of disorders or diseases in which cannabinoid receptors are involved, and more specifically the CBi subtype, and for the prevention and / or treatment of disorders or diseases in which opioid receptors are involved, and, more specifically, e 1 subtype mu.
  • a compound of formula (A) preferably a compound of Table I
  • a particular embodiment of the invention relates to the use of a compound of formula (A) for the prevention and / or treatment of disorders or diseases in which the CBI cannabinoid receptor is involved, and more specifically to a disorder or disease belonging to , by way of illustration and without limiting the scope of the invention, to the following group: appetite suppression, reduction of dyskinesia caused by L-dopa in Parkinson's patients, treatment of acute schizophrenia, treatment of dysfunctions Cognitive and memory associated with Alzheimer's disease, the treatment of obesity, the treatment of tobacco addiction, the dependence treatments (cannabis, opiates or alcohol), to treat cerebral ischemia and traumatic brain injury.
  • a particular embodiment of the invention relates to the use of a compound of formula (A) for the prevention and / or treatment of disorders or diseases in which the opioid receptor mu is involved, and more specifically, with the treatment and prevention from drug addiction to opiates.
  • Figure 1 represents the synthetic scheme of the preparation of the compounds of the present invention of Formula A.
  • Figure 2 illustrates the effects of the compound of Example 4 (5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (6- ⁇ N- (1- (2- phenethyl) piperidin-4-yl) propionamido) hexyl) -4-methyl-lH-pyrazol-3-carboxamide) and Example 5 (5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (7- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) heptyl) -4-methyl-l-pyrazol-3-carboxamide) in the [ 35 S] GTP ⁇ S (0 fixation assays) , 5 nM) in brain membranes (fraction P 2 ) of human cortex.
  • FIG. 3 illustrates the effects of the compound of Example 5 (5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (7- (N- (1- (2- phenethyl) piperidin-4- il) propionamido) heptyl) -4-methyl-IH-pyrazol-3-carboxamide).
  • Figure 4 illustrates the effect of the compounds of Example 4 (5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (6- ⁇ N- (1- (2- phenethyl) piperidin-4 -yl) propionamido) hexyl) -4-methyl-IH-pyrazol-3-carboxamide) and Example 5 (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (7- (N - (1- (2-Phenethyl) piperidin-4- yl) propionamido) heptyl) -4-methyl-lH-pyrazol-3-carboxamide) in the hot plate test.
  • the bars represent the maximum possible effect% (mean ⁇ SEM, n ⁇ 10) produced by morphine at 10 mg / kg, compound of Example 4 at 10 mg / kg, compound of Example 5 at 10 mg / kg, morphine 10 mg / kg after a treatment with the compound of Example 4 at 10 mg / kg, morphine 10 mg / kg after a treatment with the compound of Example 5 at 10 mg / kg, or morphine 10 mg / kg after a treatment with naloxone at 1 mg / kg. (##) p ⁇ 0.01.
  • Figure 5 shows the intake control after administration of the compound of Example 5 (5- (4- chlorophenyl) -1- (2,4-dichlorophenyl) -N- (7- (N- (1- (2 - phenethyl) piperidin-4-yl) propionamido) heptyl) -4-methyl- IH- pyrazol-3-carboxamide) at 0.1, 1 and 2 mg / kg of animal and at times of 30, 60, 120 and 240 minutes.
  • Example 1 Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (3- ((N- (1- (2-phenethyl) piperidin-4- yl) propionamido ) methyl) benzyl) -4-methyl-lJ ⁇ -pyrazol-3- carboxamide
  • the desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1,3-diaminopropane.
  • the desired compound is prepared according to the embodiment described in step G of Example 1, from 60 mg of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-lH- pyrazol-3-carboxylic acid and 30 mg of N- (3- aminopropyl) -N- (1- (2-phenethyl) piperidin-4-yl) propionamide.
  • the desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1,4-diaminobutane.
  • the desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1,6-diaminohexane
  • Example 5 Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (7- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) heptyl) -4-methyl-lJ ⁇ -pyrazol-3-carboxamide.
  • the desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1, 7-diaminoheptane.
  • Example 6 Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (8- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) octyl) -4-methyl-lJ ⁇ -pyrazol-3-carboxamide A) N- (8-Aminooctyl) -N- (1- (2-phenethyl) piperidin-4- yl) propionamide
  • the desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1,8-diaminooctane.
  • Example 7 Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (9- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) nonyl) -4-methyl-lJ ⁇ -pyrazol-3-carboxamide A) N- (9-Aminononyl) -N- (1- (2-phenethyl) piperidin-4- yl) propionamide
  • the desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1, 9-diaminononan.
  • the desired compound is prepared according to the embodiment described in step G of Example 1, from 60 mg of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-lH- pyrazol-3-carboxylic acid and 30 mg of N- (9-aminononyl) -
  • Example 8.- Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (12- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) dodecyl) -4-methyl-lJ ⁇ -pyrazol-3-carboxamide.
  • the desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1,112-diaminododecane.
  • the desired compound is prepared according to the embodiment described in step G of Example 1, from 60 mg of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-lH- pyrazol-3-carboxylic acid and 30 mg of N- (12-aminododecyl) -N- (1- (2-phenethyl) piperidin-4-yl) propionamide.
  • Example 10 Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (4- ((4- (N- (l-phenethylpiperidin-4- yl) propionamido) cyclohexyl ) methyl) cyclohexyl) -4-methyl-IH- pyrazol-3-carboxamide
  • the desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 4,4'-methylenebis (cyclohexylamine).
  • the desired compound is prepared according to the embodiment described in step G of Example 1, from 49 mg of 5- (4-chlorophenyl) -4-methyl-1H-pyrazole-3-carboxylic acid and 70 mg of N -(4-(((-)
  • Example 11 Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (5- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) pentyl) -4-methyl-lJ ⁇ -pyrazol-3-carboxamide A) N- (5-Aminopentyl) -N- (1- (2-phenethyl) piperidin-4- yl) propionamide
  • the desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1,5-diaminopentane.
  • the desired compound is prepared according to the embodiment described in step G of Example 1, from 49 mg of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-lH- acid pyrazol-3-carboxylic acid and 81 mg of N- (5- aminopentyl) -N- (1- (2-phenethyl) piperidin-4-yl) propionamide.
  • the cannabinoid activity of the compounds of general formula (A) was assessed by carrying out in vitro radioligand displacement assays in brain membranes (fraction P 2 ) of human cortex.
  • the radioligand displacement [ 3 H] -CP55940, a CBi receptor agonist was evaluated by the new derivatives described in the present invention.
  • the values of the inhibition constants (K 1 ) obtained from the joint analysis of different competition experiments for each compound were determined.
  • the new derivatives showed a significant affinity for the CBi receptor.
  • octyl (Example 6) and methyldicyclohexyl (Example 10) exhibited greater affinity with K 1 values of 1925 + 705, 569 + 201, 2289 + 1857, 701 + 567, 3991 + 1366 and 2059 + 605 nM respectively.
  • the reference compound SR141716 showed an affinity for CBi cannabinoid receptors with a K 1 value of 3.73 + 2.5 nM.
  • Cannabinoid receptors are part of the family of G protein-coupled receptors.
  • the agonist, antagonist or inverse agonist efficacy of the new derivatives of the present invention can be studied by guanosine-5'-0- binding assays. (3- [ 35 S] uncle) triphosphate) ([ 35 S] GTPYS) in brain membranes
  • the compound of Example 4 showed an EC 50 of 5.11 + 0.35 ⁇ M and the compound of Example 5 an EC 50 of 0.26 + 0.03 ⁇ M.
  • the potency and efficacy of the new compounds were evaluated by comparing with the inverse reference agonist SR141716. In the fixation tests of
  • Example 13 Opioid activity assays of the compounds of the invention
  • the opioid activity of the compounds of the general formula (A) was assessed by carrying out radioligand displacement assays [ 3 H] -DAMGO, a mu-opioid receptor agonist, In vitro in brain membranes (fraction P 2 ) of human cortex.
  • the values of the inhibition constants (K 1 ) obtained from the joint analysis of different competition experiments for each compound of the invention were determined.
  • the new compounds showed a moderate to good affinity for the mu-opioid receptor.
  • X represents a propyl group (Example 2), butyl (Example
  • the compounds of the present invention can be used for the treatment of pain and in particular for the treatment of chronic pain.
  • the fact that the compounds of the present invention bind to both opioid and cannabinoid receptors extend their therapeutic applications to the treatment of opioid drug dependence.
  • Example 14 Cannabinoid activity of the compounds of the invention in mice
  • a set of four assays were performed in vivo in mice to analyze cannabinoid activity: rectal temperature, catalepsy, acute hot plate analgesia and spontaneous activity.
  • After intraperitoneal administration at a dose up to 10 mg / kg of the compound of Example 5 (5 - (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (7- (N- (1- (2-Phenethyl) piperidin-4-yl) propionamido) heptyl) -4-methyl-l-pyrazol-3-carboxamide), no significant differences are observed with respect to the control, which rules out a possible intrinsic cannabinoid agonist activity in vivo.
  • Example 5 reverses the effects produced by the cannabinoid agonist WIN55212-2 (1.5 mg / kg) ( Figure 3) so it can be affirmed that the compounds object of this patent are antagonists CBL cannabinoid in vivo.
  • In vivo titration of the opioid activity of the compounds of the invention was carried out using the hot plate test at a temperature of 55 ° C in mice.
  • the compound of Example 4 (10 mg / kg) and Example 5 (10 mg / kg) antagonize the antinociceptive effect of morphine ( Figure 4). From these results it can be concluded that the compounds object of the present patent are opioid antagonists.
  • Example 4 and Example 5 have a dual cannabinoid and opioid action whose efficacy in vivo is a consequence of the synergy that develops when the opioid activity coincides in the same molecule and cannabinoid In vivo they behave as cannabinoid antagonists and opioid antagonists.
  • the anorexic effect (intake suppressant) of cannabinoid antagonists mediated by CBl receptors is known.
  • the anorexigenic effect of the compounds object of the invention was evaluated by testing intake measures in male rats.
  • Each of the compounds of Example 4 and Example 5 were injected intraperitoneally at different doses (0.10 mg / kg; 1 mg / kg and 10 mg / kg) to male rats previously deprived of food for 24 hours.
  • the food intake was counted during the first 4 hours, observing that the compounds of Example 4 and Example 5 produce a decrease in food intake (Figure 5). Therefore, the compounds object of the present invention significantly reduce the intake of food in rats.

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Abstract

L'invention concerne un dérivé de pirazolcarboxamide avec des propriétés antagonistes cannabinoïdes et opioïdes. L'invention concerne également des compositions présentant lesdites propriétés, ainsi que leur utilisation dans les troubles ou les maladies associés aux récepteurs cannabinoïdes, et plus concrètement le sous-type Cbi, et dans la prévention et/ou le traitement des troubles ou maladies associés aux récepteurs opioïdes et plus concrètement le sous-type mu, en particulier le traitement de l'obésité et de la dépendance aux opioïdes.
PCT/ES2006/070132 2005-09-08 2006-09-07 Derives de pirazolcarboxamide, procede d'obtention et applications comme antagonistes/agonistes inverses du recepteur cannabinoide cb1 et opioide mu Ceased WO2007028849A1 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008017381A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
ES2291147A1 (es) * 2007-10-15 2008-02-16 Fundacion Instituto Mediterraneo Para La Biotecnologia Y La Investigacion Sanitaria (Imabis) Derivados pirazolicos de amidas de acidos grasos como activadores especificos de receptores ppar-alfa, procedimiento de preparacion y utilizacion.
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2010003624A2 (fr) 2008-07-09 2010-01-14 Sanofi-Aventis Composés hétérocycliques, leurs procédés de préparation, médicaments comprenant lesdits composés et leur utilisation
WO2010068601A1 (fr) 2008-12-08 2010-06-17 Sanofi-Aventis Hydrate de fluoroglycoside hétéroaromatique cristallin, ses procédés de fabrication, ses procédés d'utilisation et compositions pharmaceutiques le contenant
WO2011023754A1 (fr) 2009-08-26 2011-03-03 Sanofi-Aventis Nouveaux hydrates de fluoroglycoside hétéroaromatiques cristallins, substances pharmaceutiques comprenant ces composés et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
US10617681B2 (en) 2014-08-22 2020-04-14 Arizona Board Of Regents On Behalf Of The University Of Arizona 1-arylalkyl-4-acylaminopiperidine compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3164600A (en) * 1961-10-10 1965-01-05 Res Lab Dr C Janssen N V 1-aralkyl-4-(n-aryl-carbonyl amino)-piperidines and related compounds
WO2003051367A1 (fr) * 2001-12-18 2003-06-26 Alexza Molecular Delivery Corporation Formulations analgesiques parenterales contenant du fentanyl et un agoniste de recepteur cannabinoide
WO2003088968A1 (fr) * 2002-04-15 2003-10-30 Research Triangle Institute Composes presentant une selectivite de liaison au recepteur cb1 unique et procedes de production et d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3164600A (en) * 1961-10-10 1965-01-05 Res Lab Dr C Janssen N V 1-aralkyl-4-(n-aryl-carbonyl amino)-piperidines and related compounds
WO2003051367A1 (fr) * 2001-12-18 2003-06-26 Alexza Molecular Delivery Corporation Formulations analgesiques parenterales contenant du fentanyl et un agoniste de recepteur cannabinoide
WO2003088968A1 (fr) * 2002-04-15 2003-10-30 Research Triangle Institute Composes presentant une selectivite de liaison au recepteur cb1 unique et procedes de production et d'utilisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DYCK B. ET AL.: "Potent imidazole and triazole CB1 receptor antagonists related to SR141716", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, 2004, pages 1151 - 1154, XP002359079 *
WILEY J.L. ET AL.: "Novel pyrazole cannabinoids: insights into CB1 receptor recognition and activation", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 296, no. 3, 2001, pages 1013 - 1022, XP002968556 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008017381A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
ES2291147A1 (es) * 2007-10-15 2008-02-16 Fundacion Instituto Mediterraneo Para La Biotecnologia Y La Investigacion Sanitaria (Imabis) Derivados pirazolicos de amidas de acidos grasos como activadores especificos de receptores ppar-alfa, procedimiento de preparacion y utilizacion.
ES2291147B1 (es) * 2007-10-15 2008-11-01 Fundacion Instituto Mediterraneo Para La Biotecnologia Y La Investigacion Sanitaria (Imabis) Derivados pirazolicos de amidas de acidos grasos como activadores especificos de receptores ppar-alfa, procedimiento de preparacion y utilizacion.
WO2009050318A1 (fr) * 2007-10-15 2009-04-23 Fundación Instituto Mediterráneo Para El Avance De La Biotecnología Y La Investigación Sanitaria (Imabis) Dérivés pyrazoliques d'amides d'acides gras utilisés comme activateurs spécifiques de récepteurs ppar-alpha, procédé de préparation et utilisation
WO2010003624A2 (fr) 2008-07-09 2010-01-14 Sanofi-Aventis Composés hétérocycliques, leurs procédés de préparation, médicaments comprenant lesdits composés et leur utilisation
WO2010068601A1 (fr) 2008-12-08 2010-06-17 Sanofi-Aventis Hydrate de fluoroglycoside hétéroaromatique cristallin, ses procédés de fabrication, ses procédés d'utilisation et compositions pharmaceutiques le contenant
WO2011023754A1 (fr) 2009-08-26 2011-03-03 Sanofi-Aventis Nouveaux hydrates de fluoroglycoside hétéroaromatiques cristallins, substances pharmaceutiques comprenant ces composés et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
US10617681B2 (en) 2014-08-22 2020-04-14 Arizona Board Of Regents On Behalf Of The University Of Arizona 1-arylalkyl-4-acylaminopiperidine compounds

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