WO2002012167A1 - Derives d'acide arachidonique presentant une affinite pour le transporteur d'anandamide - Google Patents

Derives d'acide arachidonique presentant une affinite pour le transporteur d'anandamide Download PDF

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WO2002012167A1
WO2002012167A1 PCT/ES2001/000305 ES0100305W WO0212167A1 WO 2002012167 A1 WO2002012167 A1 WO 2002012167A1 ES 0100305 W ES0100305 W ES 0100305W WO 0212167 A1 WO0212167 A1 WO 0212167A1
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provision
subunit
heteroatoms
furan
alkylaryl
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PCT/ES2001/000305
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English (en)
Spanish (es)
Inventor
Maria Luz Lopez Rodriguez
Alma Viso Beronda
Silvia Ortega Gutierrez
Isabel Lastres Becker
Sara Gonzalez Rodriguez De Castro
Javier J. Fernandez Ruiz
Jose Antonio Ramos Atance
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Universidad Complutense De Madrid
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Priority claimed from ES200001920A external-priority patent/ES2174716B1/es
Application filed by Universidad Complutense De Madrid filed Critical Universidad Complutense De Madrid
Priority to AU2001284061A priority Critical patent/AU2001284061A1/en
Priority claimed from ES200101769A external-priority patent/ES2181601B2/es
Publication of WO2002012167A1 publication Critical patent/WO2002012167A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Definitions

  • the present invention relates to products derived from arachidonic acid with affinity for the anandamide transporter.
  • Cannabis is among the most widespread drug abuse in the world. However, its active ingredients and synthetic analogues are now being considered for their therapeutic potential, due to the recent description in the animal organism of an endogenous cannabinoid system (Pertwee, RG Pharmacol. Ther. 1997, 74, 129).
  • This system is made up of at least two types of protein-coupled receptors that bind GTP, called CB-i (present mainly in the central nervous system) and CB 2 (present mainly in the immune system) (Howlett, A. O Annu. Rev. Pharmacol. Toxico !. 1995, 35, 607; Pertwee, RG Pharmacol. Ther.
  • the endocannabinoid system seems to play a modulating role in different physiological processes, mainly in the brain (Di Marzo, V .; Melck, D .; Bisogno, T .; De Petrocellis, L. Trends Neurosci. 1998, 21, 521; Fernández- Ruiz, J .; Berrendero, F .; Hernández, M. L; Ramos, - A. Trends Neurosci. 2000, 23, 14), although also in the immune systems (Parolaro, D. Life Sci. 1999, 65, 637) and cardiovascular (Wagner, JA; Varga, K .; Kunos, GJ Mol. Med. 1998, 76, 824).
  • endocannabinoids participate in the regulation of motor activity, nociception, neuronal communication, appetite as well as learning and memory processes (Di Marzo, V .; Melck, D .; Bisogno, T .; De Petrocellis, L Trends Neurosci. 1998, 21, 521; Sa ⁇ udo-Pe ⁇ a, M. C; Tsou, K .; Walker, JM Life Sci.
  • the AEA is synthesized from the hydrolysis caused by the phospholipase D of a membrane precursor (N-arachidonylphosphatidylethanolamine), and is released to the extracellular medium and recaptured by a transport system present in neurons and in sexual cells (Di Marzo, V .; Melck, D .; Bisogno, T .; De Petrocellis, L. Trends Neurosci. 1998, 21, 521). Once inside the cell, it is degraded by the action of a specific hydrolase for fatty acid amides [FAAH (Di Marzo, V .; Melck, D .; Bisogno, T .; De Petrocellis, L. Trends Neurosci. 1998, 21, 52)].
  • FAAH Di Marzo, V .; Melck, D .; Bisogno, T .; De Petrocellis, L. Trends Neurosci. 1998, 21, 52
  • cannabinoid receptor agonists have developed: (i) that have greater metabolic stability than the SAA, such as f? -Methanedamide (Khanolkar, AD; Makriyannis, A. Life Sci. 1999, 65, 607 ), (ii) with selective affinity for the different receptor subtypes, such as HU-308 (first selective CB 2 receptor agonist) (Hanus, L .; Breuer, A .; Tchilibon, S .; Shiloah, S. ; Golde ⁇ berg, D .; Horowitz, M .; Pertwee, RG; Ross, RA; Mechoulam, R .; Fride, EP Nati. Acad. Sci.
  • SAA such as f? -Methanedamide
  • HU-308 first selective CB 2 receptor agonist
  • FAAH inhibitors such as AM374, have been developed that can therefore prolong endocannabinoid activity (Gifford, AN; Bruneus, M .; Lin, SY; Goutopoulos, A .; Makriyannis, A .; Volkow, ND; Gatley, SJ Eur. J. Pharmacol. 1999, 383, 9).
  • the first endocannabinoid transporter inhibitors that act by enhancing their action in those processes whose completion involves a reuptake system (Beltramo, M .; Stella, N .; Calignano, A .; Un, SY; Makriyannis, have also been developed A .; Piomelli, D. Science 1997, 277, 1094).
  • the promising therapeutic applications for these inhibitors in the treatment of Huntington's chorea or multiple sclerosis have been described (Baker, D .; Pryce, G .; Croxford, J.
  • AM404 does not selectively act on the endocannabinoid transporter but may bind to other pharmacological targets such as vanilloid receptors (Zygmunt, PM; Chuang, H .; Movahed, P .; Julius D. ; Hógestátt, ED Eur. J. Pharmacol. 2000, 396, 39).
  • vanilloid receptors Zygmunt, PM; Chuang, H .; Movahed, P .; Julius D. ; Hógestátt, ED Eur. J. Pharmacol. 2000, 396, 39.
  • the metabolic fate of these inhibitors is another point to consider, as it has been described (Klaasen, CD Casarett &Doull's Toxicology The Basic Science of Poisons, 5th ed .; Me Graw-Hill Companies, Inc. USA, 1996; p.
  • X represents CO, CS or CH 2
  • Y represents CH 2 , O, S, NH or NR (R represents alkyl, alkylaryl or aryl)
  • Z represents H or an alkyl, alkylaryl or aryl group.
  • Heterocycle represents an aromatic monocyclic subunit or an aliphatic monocyclic subunit or its benzofused derivatives.
  • aromatic monocyclic subunit refers to an aromatic ring with one or two optionally substituted heteroatoms (with the provision that is not pyridine), e.g., thiophene, pyrrole, furan, isoxazole, substituted furan and the like.
  • aliphatic monocyclic subunit refers to an aliphatic ring containing one or two heteroatoms (with the provision that is not a 1,3-dioxolane system) and optionally substituted methylene units (with the provision that the substituent is not a hydroxyl group ).
  • the compounds described herein are capable of inhibiting the endocannabinoid transporter with greater potency than Structurally closer compounds known in the art. In addition, unlike these, they have a potential evolution to non-toxic metabolites, also exhibiting selectivity by the transporter against the CBi and CE ⁇ cannabinoid receptors and VR-
  • Noncommercial II and III derivatives are prepared following synthetic routes described in the literature (Hudiicky, M. Reductions in Organic Chemistry, 2 ⁇ d ed .; American Chemical Society: Washington DC, 1996; pp 187-190; Nahm, S .; Weinreb, SM Tetrahedron Lett. 1981, 22, 3815).
  • the final products have been structurally characterized by IR, NMR and quantitative elemental analysis techniques. For greater ease of handling when the final product is not crystalline it is transformed into a pharmaceutically acceptable salt, derived from an inorganic or organic acid.
  • reaction mixture was stirred at room temperature for "one hour” and then the solvent was removed using a vacuum pump, obtaining a solid residue that was redissolved in anhydrous methylene chloride (15 mL / mmol arachidonic acid), always under argon atmosphere. On the residue formed 10 equivalents of the corresponding derivative II dissolved in anhydrous methylene chloride (1 ml Jmmol) were added. The reaction was followed by thin layer chromatography (ccf) until the disappearance of the starting product using as eluent chloroform methanol, 95: 5. Finally, the reaction was hydrolyzed with distilled water (15 mL / mmol arachidonic acid).
  • Method B In a two-mouth flask, under an argon atmosphere, at 1 equivalent of arachidonic acid, (0.33 mmol, 111, 1 mg) (Sigma, 90% pure) in anhydrous methylene chloride (1.5 mL / mmol) and 1.5 equivalents of the corresponding derivative II dissolved in anhydrous methylene chloride (1 mL / mmol), cooled in an ice bath, a mixture of 1 equivalent (0.33 mmol, 68.1 mg) was added ) of dicyclohexylcarbodiimide (DCC) and 0.068 equivalents (0.022 mmol, 2.7 mg) of 4-dimethylaminopyridine (DMAP) in anhydrous methylene chloride (3 mL Jmmol DCC).
  • DCC dicyclohexylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • EXAMPLE 2 Determination of the inhibitory capacity of the endocannabinoid transporter
  • the determination of the ability of the different synthesized compounds to inhibit the reuptake of endocannabinoids has been carried out in cultures of the U937 human lymphoma cell line, using [ 3 H] -anandamide as a tracer in the presence or absence of different concentrations of each compound under study.
  • the anandamide reuptake assay was performed with intact cells in complete medium at a concentration of 10 6 cells / mL.
  • the cell suspensions (1 mL) were pre-incubated at 37 ° C for 10 minutes in the presence or absence of a concentration range (5x10 "5 -10 " 7 M) of the compound under study.
  • the inhibition of [ 3 H] -anandamide reuptake by the different compounds tested was determined by calculating the percentage of specific reuptake with respect to total reuptake in the absence of inhibitor. Specific reuptake was obtained after subtraction of quantified nonspecific reuptake in control experiments performed at 4 ° C. The IC 5 or for each compound was determined from the adjustment of the specific reuptake percentages found for each of the tested concentrations of the different compounds.
  • IC50 2.2 ⁇ 0.2 ⁇ M (Piomelli, D .; Beltramo, M .; Glasnapp, S .; Lin, SY; Goutopoulos, A .; Xie, X.-Q .; Makriyannis, AP Nati. Acad. Sci. USA. 1999, 96, 5802).
  • IC50 value 4 ⁇ 2 ⁇ M was obtained, which is in excellent agreement with the data previously described for this compound and confirmed the reliability of the assay.
  • Table 1 shows the data on the ability to inhibit the reuptake of anandamide expressed as IC50 ( ⁇ M) shown by the synthesized compounds, including that of AM404 as a reference value.
  • the determination of the binding capacity of the different compounds synthesized to the CB-] subtype of the cannabinoid receptor has been performed by in vitro radioligand displacement assays using rat cerebellum membranes and [ 3 H] -WIN55,212- 2 as a radioactive ligand.
  • incubation buffer 50 mM Tris-HCI, 1 mM EDTA, 3 mM MgCI 2 and 5 mg / mL free fatty acid BSA
  • the specific binding of the compounds was calculated as the difference between total binding and non-specific binding.
  • Table 1 shows the receptor affinity data expressed as (nM) shown by the synthesized compounds, including as reference the affinity value of the WIN55,212-2 ligand.
  • Determining the binding capacity of the different compounds synthesized to subtype CB 2 cannabinoid receptor was performed using displacement assays vitro in radioligand using as membranes tissue cells HEK293 transfected with the receptor CB 2 human (commercial kit) and [ 3 H] -CP55,940 as a radioactive ligand.
  • the binding assay was performed in borosilicate tubes previously siliconized with Sigmacote.
  • the cell membranes were incubated in a final volume of 0.2 mL of 50 mM Tris-HCI buffer, 2.5 mM EGTA,
  • the specific binding of the compounds was calculated as the difference between total binding and non-specific binding.
  • the calculation of IC 50 has been performed as detailed in example 3.
  • Table 1 shows the receptor affinity data expressed as ⁇ (nM) shown by the synthesized compounds, including as reference the affinity value of the WIN55.212-2 ligand.
  • the determination of the binding capacity of the different synthesized compounds to the VR ⁇ subtype of the vanilloid receptor has been performed by in vitro radioligand displacement assays using rat spinal cord membranes and [ 3 H] -RTX as radioactive ligand as tissue.
  • the specific binding of the compounds was calculated as the difference between total binding and non-specific binding.
  • the calculation of IC 50 has been performed as detailed in example 3.
  • Table 1 shows the receptor affinity data expressed as K ⁇ (nM) shown by the synthesized compounds, including as reference the affinity value of the RTX ligand.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des composés dérivés d'acide arachidonique représentés par la formule générale (I), ainsi que leurs stéréoisomères et leurs mélanges, et leurs sels et solvates acceptables d'un point de vue pharmaceutique. L'invention concerne également un procédé de préparation de ces composés, leur caractérisation pharmacologique et leurs applications thérapeutiques. Hétérocycle Dans ladite formule, X représente CO, CS ou CH2, Y représente CH2, O, S, NH, ou NR (R représente alkyle, alkylaryle ou aryle), Z représente H ou un groupe alkyle, alkylaryle ou aryle, et hétérocycle représente une sous-unité monocyclique aromatique ou une sous-unité monocyclique aliphatique constituée d'un ou de deux hétéroatomes et des unités méthyléniques ou les dérivés benzocondensés des deux sous-unités.
PCT/ES2001/000305 2000-07-28 2001-07-27 Derives d'acide arachidonique presentant une affinite pour le transporteur d'anandamide WO2002012167A1 (fr)

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AU2001284061A AU2001284061A1 (en) 2000-07-28 2001-07-27 Novel araquidonic acid derivatives with affinity toward the anandamide transporter

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Application Number Priority Date Filing Date Title
ES200001920A ES2174716B1 (es) 2000-07-28 2000-07-28 Nuevos derivados de acido araquidonico con afinidad por el transportador de anandamida.
ESP200001920 2000-07-28
ESP200101769 2001-07-27
ES200101769A ES2181601B2 (es) 2001-07-27 2001-07-27 Derivados de acido araquidonico con afinidad por el transportador de anandamida

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003004484A1 (fr) * 2001-07-02 2003-01-16 Maruha Corporation Nouveaux composes aliphatiques, procede de synthese et leur procede d'utilisation
EP1632236A1 (fr) * 2004-07-26 2006-03-08 University of Connecticut Inhibiteurs du transporteur d'Anandamide

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045407A1 (fr) * 1996-05-31 1997-12-04 University Of Connecticut Nouveaux inhibiteurs d'anandamide amidase utiles en tant qu'agents analgesiques
WO1999064389A1 (fr) * 1998-06-09 1999-12-16 Alexandros Makriyannis Inhibiteurs de vehicule d'anandamide comme agents analgesiques
WO2000032200A1 (fr) * 1998-11-24 2000-06-08 Alexandros Makriyannis Amides lipidiques cannabimimetiques s'utilisant comme medicaments
WO2001028498A2 (fr) * 1999-10-18 2001-04-26 University Of Connecticut Retro-anandamides, ligands des recepteurs des cannabinoides presentant une affinite et une stabilite elevees

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045407A1 (fr) * 1996-05-31 1997-12-04 University Of Connecticut Nouveaux inhibiteurs d'anandamide amidase utiles en tant qu'agents analgesiques
WO1999064389A1 (fr) * 1998-06-09 1999-12-16 Alexandros Makriyannis Inhibiteurs de vehicule d'anandamide comme agents analgesiques
WO2000032200A1 (fr) * 1998-11-24 2000-06-08 Alexandros Makriyannis Amides lipidiques cannabimimetiques s'utilisant comme medicaments
WO2001028498A2 (fr) * 1999-10-18 2001-04-26 University Of Connecticut Retro-anandamides, ligands des recepteurs des cannabinoides presentant une affinite et une stabilite elevees

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] D. PIONELLI ET AL.: "Structural determinants for recognition and translocation by the anandamide transporter", accession no. STN Database accession no. 1999:314488 *
PROC. NATL. ACAD. SCI. USA, vol. 96, 1999, pages 5802 - 5807 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003004484A1 (fr) * 2001-07-02 2003-01-16 Maruha Corporation Nouveaux composes aliphatiques, procede de synthese et leur procede d'utilisation
EP1632236A1 (fr) * 2004-07-26 2006-03-08 University of Connecticut Inhibiteurs du transporteur d'Anandamide

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