WO1999064389A1 - Inhibiteurs de vehicule d'anandamide comme agents analgesiques - Google Patents

Inhibiteurs de vehicule d'anandamide comme agents analgesiques Download PDF

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Publication number
WO1999064389A1
WO1999064389A1 PCT/US1999/012900 US9912900W WO9964389A1 WO 1999064389 A1 WO1999064389 A1 WO 1999064389A1 US 9912900 W US9912900 W US 9912900W WO 9964389 A1 WO9964389 A1 WO 9964389A1
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group
aryl
anandamide
substituted
biphenyl
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PCT/US1999/012900
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English (en)
Inventor
Alexandros Makriyannis
Sonyuan Lin
Daniele Piomelli
Andreas Goutopoulos
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Alexandros Makriyannis
Sonyuan Lin
Daniele Piomelli
Andreas Goutopoulos
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Application filed by Alexandros Makriyannis, Sonyuan Lin, Daniele Piomelli, Andreas Goutopoulos filed Critical Alexandros Makriyannis
Priority to EP99930176A priority Critical patent/EP1084098A4/fr
Priority to CA002337822A priority patent/CA2337822A1/fr
Priority to JP2000553399A priority patent/JP2002517479A/ja
Publication of WO1999064389A1 publication Critical patent/WO1999064389A1/fr
Priority to US10/899,191 priority patent/US7589220B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/27—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton

Definitions

  • ⁇ 9 THC is known to bind to CB1 receptors in the brain and CB2 receptors in the spleen.
  • Compounds which stimulate those receptors have been shown to induce analgesia and sedation, to cause mood elevation including euphoria and dream states, to control nausea and appetite and to lower intraocular pressure.
  • Cannabinoids have also been shown to suppress the immune system.
  • compounds which stimulate the receptors, directly or indirectly, are potentially useful in treating glaucoma, preventing tissue rejection in organ transplant patients, controlling nausea in patients undergoing chemotherapy, controlling pain and enhancing the appetite and controlling pain in individuals with AIDS Wasting Syndrome.
  • cannabinoids In addition to acting at the receptors, cannabinoids also affect cellular membranes, thereby producing undesirable side effects such as drowsiness, impairment of monoamine oxidase function and impairment of non-receptor mediated brain function. The addictive and psychotropic properties of cannabinoids also limit their therapeutic value.
  • Arachidonyl ethanolamide is an endogenous lipid that binds to and activates cannabinoid receptors and mimics the pharmacological activity of ⁇ 9 THC.
  • anandamide has been found to be somewhat less potent than ⁇ 9 THC.
  • the magnitude and duration of action of anandamide is relatively short, presumably because of a rapid inactivation process consisting of carrier-mediated transport into cells followed by intra- cellular hydrolysis by a membrane-bound amidohydrolase, anandamide amidase.
  • inhibitors of anandamide amidase have the effect of indirectly stimulating the receptors by increasing in vivo levels of anandamide.
  • attention is directed to Makriyannis et al U.S. Patents 5,688,825 and 5,874,459, the disclosures of which are incorporated herein by reference.
  • Anandamide released by depolarized neurons is believed to be subject to rapid cellular uptake followed by enzymatic degradation.
  • rat brain neurons and astrocytes in primary culture avidly take up radioactively labeled anandamide through a mechanism that meets four key criteria of a carrier-mediated transport; temperature dependence, high affinity, substrate selectivity, and saturation.
  • PGE 2 prostaglandin E 2
  • anandamide uses a similar mechanism. This accumulation may result from the activity of a transmembrane carrier or transporter, which may thus participate in termination of the biological actions of anandamide.
  • This carrier or anandamide transporter is believed to be involved in the inactivation of anandamide.
  • anandamide released from neurons on depolarization may be rapidly transported back into the cells and subsequently hydrolyzed by an amidase thereby terminating its biological actions. Consequently, the anandamide transporter is a potential therapeutic target for the development of useful medications.
  • Anandamide transport inhibitors may be used as experimental tools to reveal the possible physiological functions of this biologically active lipid. Many of these functions are still elusive despite a growing body of evidence suggesting that the endocannabinoid system is intrinsically active not only in brain and spinal cord, but also in peripheral tissue.
  • anandamide transport inhibitors may offer a rational therapeutic approach to a variety of disease states, including pain, psychomotor disorders, and multiple sclerosis, in which elevation of native anandamide levels may bring about a more favorable response and fewer side effects than direct activation of CB1 receptors by agonist drugs.
  • anandamide are potent inhibitors of transport of anandamide across cell membranes.
  • the transport inhibitor does not activate the cannabinoid receptors or inhibit anandamide hydrolysis per se but instead prevents anandamide reuptake thereby prolonging the level of the undegraded anandamide.
  • cannabinoid drugs were targeted toward cannabiniod receptors and amidase enzymes.
  • the anandamide transport inhibitor of the present invention targets activity of the anandamide transporter.
  • the inhibitors are analogs of anandamide and exhibit the tail, central and head pharmacophore portions represented by Structural
  • tail portion X is a fatty acid chain remnant or a biphenyl group with an akyl chain
  • central portion Y is a member selected from the group consisting of -NA-C(O)-, -NH-, -NH-C(O)-NH-, -NH-C(O)-O-, -C(O)- NH, -O-C(O)-, -S- and -H
  • head portion Z is selected form the group consisting of hydrogen, aryl, alkyl aryl, halogen substituted alkyl aryl, cyclic glycerols and substituted cyclic glycerols.
  • novel inhibitors of the present invention when tested in vitro, inhibit accumulation of anandamide in rat cortical neurons and astrocytes and enhance various effects of anandamide administration both in vitro and in vivo.
  • the vasodepressor responses are significantly potentiated and prolonged by the transport inhibitors.
  • the inhibitors are believed to be effective drugs for the treatment of cardivascular diseases and blood pressure disorders.
  • the novel biochemical pathway involving the anandamide transporter system and composition disclosed herein have other therapeutic uses.
  • the compounds and methods of the present invention like cannabinoids, can be effective in the relief of the pain caused by cancer and the nausea resulting from cancer chemotherapy as well as for the relief of peripheral pain. Beneficially, they would not be expected to have the undesirable membrane-related side-effects associated with cannabinoids.
  • the methods and compounds disclosed herein may be immunosuppressive and can therefore be used to prevent organ rejection in an individual undergoing an organ transplant. Because the compounds and methods of the present invention enhance the appetite of an individual, they can be used to treat patients with AIDS Wasting Syndrome, who are often suffering from malnourishment as a result of appetite loss.
  • the compounds could also be used in psychomotor disorders and multiple sclerosis and peripheral hypertension.
  • evaluation of anandamide levels may bring about a more favorable response and fewer side effects than direct activation of CB-1 and CB-2 receptors by agonist drugs.
  • novel inhibitors of anandamide transport disclosed herein also have research uses. For example, they can be used to maintain the level of anandamide in vivo to study the effect of anandamide on individuals and animals.
  • the anandamide transport inhibitors disclosed herein can also be used as an aid in drug design, for example as a control in assays for testing other compounds for their ability to inhibit anandamide transport and to determine the structural and activity requirements of such inhibitors.
  • Anandamide uptake in neurons and astrocytes has been found to be mediated by a high-affinity, Na + -independent transporter that is selectively inhibited by the inhibitors of the present invention.
  • the structural determinants governing recognition and translocation of substrates by the anandamide transporter have been determined.
  • the secondary amido group interacts favorably with the transporter, but may be replaced with other radicals, suggesting that it may serve as hydrogen acceptor.
  • Putative endogenous cannabinoid esters also serve as a substrate for the transporter.
  • Substrate recognition and translocation require the presence of at least one cis double bond situated at the middle region of the fatty acid hydrocarbon chain or a biphenyl group with an aliphatic chain, indicating a preference for ligands whose hydrophobic tail can adopt a bent U-shaped or hair-pin configuration.
  • Uptake experiments with radioactively labeled substrates favor two or more and preferably four cis nonconjugated double bonds for optimal translocation across the cell membrane, suggesting that substrates are transported in a folded hairpin conformation.
  • Fig. 1 is a graph showing the translocation of substrate inhibitors of the present invention at different concentration levels.
  • Fig. 2 is a graph similar to Fig. 1 for two different substrate inhibitors.
  • One embodiment of the present invention is directed to the discovery of a putative anandamide transporter system which has been characterized biochemically and pharmacologically and which can be used as a target for the discovery of novel medications. These would include all compounds that can inhibit the function of this transporter.
  • the invention further includes the pharmacological formula containing an effective amount of the inhibitor while another embodiment is directed to a method of inhibiting anandamide transport in an individual or animal by administering a therapeutically effective amount of the inhibitor and/or physiologically acceptable salts thereof.
  • the inhibition results in increased levels of anandamide in the individual or animal, thereby causing prolonged stimulation of cannabinoid receptors in the individual or animal, e.g., the CB1 receptor in the brain and the CB2 receptor in the spleen.
  • the present invention involves not only the inhibitor itself but also a method of reducing anandamide transporter activity in an individual or animal. It is to be understood that the present invention may also be used to reduce the activity of transporters not yet discovered for which anandamide and/or a cannabinoid act as an agonist.
  • the anandamide transport inhibitors of the present invention are amide, reverse amide or carbonyl amine, urea, carbamate and ester analogs of anandamide having the three pharmacophores of the
  • tail portion X is a fatty acid hydrophobic carbon chain having one or more nonconjugated cis double bonds in the middle portion of the aliphatic hydrocarbon chain or a biphenyl group having an alkyl or branched alkyl distal moiety of about 1 to about 1 0 carbon atoms.
  • the biphenyl group is substituted with 1 -
  • the fatty acid chain may contain four to thirty carbon atoms but preferably the chain length is about 1 0 to 28 carbon atoms and more preferably contains from about 1 7 to about 22 carbon atoms.
  • the aliphatic hydrocarbon chain may terminate with an aryl or alkyl aryl group.
  • analogs with fully saturated chains or with a trans or terminal double bond fail to compete successfully with [ 3 H]anandamide for transport and thus are ineffective as inhibitors.
  • the central pharmacophore Y is selected from the group set forth hereinbefore. However, compounds containing a free carboxylic acid, carboxyethyl and carboxymethyl groups, or a primary alcohol are inactive.
  • the head portion Z is selected from the group set forth hereinbefore.
  • aliphatic hydrocarbon includes, unless otherwise stated, one or more polyalkylene groups connected by one or more c/s-alkenyl linkages such that the total number of methylene carbon atoms is within the ranges set forth herein.
  • the structure of preferred tail portions have the formula II
  • R is selected from the groups consisting of hydrogen and lower alkyl groups, however the chain's terminal R may include phenyl and biphenyl groups that are unsubstituted or substituted with a member selected form the group consiting of hydroxyl, halogen, -NO 2 , -NH 2 , - SCH 3 , -CH 3 and -OCH 3 and a and c are integers 0 and 1 through 10 and b is an integer from 1 through 6.
  • a lower alkyl group is a straight or branched chain alkyl group having 1 to 5 carbon atoms, unless otherwise stated.
  • an "aryl” group is a carbocyclic aromatic ring system such as phenyl, biphenyl 1 -naphthyl or 2-naphthyl.
  • cyclic glycerols include members selected from the group consisting of
  • R' is a member selected form the group consisting of hydrogen, lower alkyl, aryl and substituted aryl radicals.
  • Arachidonyl azide To a magnetically stirred solution of 50 mg (0.1 7 mmol) of arachidonyl alcohol in 1 mL of pyridine 29.2 mg. (0.255 mmol) of mesyl chloride was added at 0°C. After stirring for 5 h, the reaction mixture was poured into 2 mL of iced water and extracted with Et 2 O (2 x 4 mL) . The ethereal layers were combined and washed with 1 N
  • Arachidonylamine To a magnetically stirred solution of 1 32 mg (0.43 mmol) of arachidonyl azide in 3 mL of Et 2 O, 4 mL of a 1 .0 M LAH solution in THF (4.0 mmol) was added dropwise at room temperature. The reaction mixture was refluxed for 3 h and then it was cooled to ambient temperature. 21 0 mg (5mmol) of NaF was added and the reaction was quenched with wet Et 2 O. The white mixture was filtered and the solvent was evaporated to dryness.
  • Arachidonyl-amine-trifluoroacetate To a magnetically stirred solution of 69 mg (0.6 mmol) of trifluoro acetic acid, in 2ml of dry methylene chloride, at 0°C, 0.046 ml (0.6 mmol) of dry DMF was added and then 0.3 ml (0.6 mmol) of 2.0 M solution of oxalyl chloride in methylene chloride, dropwise. The reaction mixture was stirred for 20 mins and then a solution of 1 72 mg (0.6 mmol) of arachidonyl amine in 2 ml of methylene chloride was added and the reaction was stirred for 2 hrs at ambient temperature.
  • the product was purified with silica gel column chromatography (eluents: petroleum ether/ethyl acetate, up to 50% ethyl acetate). Evaporation of the solvent, followed by millipore filtration of a CH 2 CI 2 solution of the product gave 1 53 mg (0.4 mmol, 67% yield) of arachidonyl-amine-trifluoroacetate as a colorless oil.
  • a primary criterion for defining carrier-mediated transport is pharmacological inhibition.
  • bromcresol green interfered with inanimate transport, albeit with limited potency and partial efficacy, bromcresol green inhibited [ 3 H]anandamide accumulation with an IC 50 (concentration needed to produce half- maximal inhibition) of 4 ⁇ M in neurons and 1 2 ⁇ M in astrocytes and acted noncompetitively.
  • bromcresol green had no significant effect on the binding of [ 3 H]WIN-5521 2-2 to rat cerebral membranes, on FAAH activity in brain microsomes and on uptake of [ 3 H]arachidonate or [ 3 H]ethanolamine in astrocytes.
  • PGE 2 carrier that this is not the case was shown by the lack of [ 3 H]PGE 2 accumulation in neurons or astrocytes and by the inability of PGE 2 to interfere with [ 3 H]anandamide accumulation. Previous results indicating that expression of PGE 2 transporter mRNA in brain tissue is not detectable further support this conclusion.
  • HBSS Hanks Balanced Salt Solution
  • a silanized 96 well plate was prepared as a mother plate for treating the cells.
  • a dilution sheet was generated to encompass a range of concentrations around a predicted
  • Reactions were stopped by removing the incubation media and rinsing the cells three times with 0.1 ml of ice-cold HBSS containing
  • inhibitors Some of the inhibitors have been identified as competitive since they are recognized as substrates by the transporter and will undergo membrane translocation.
  • the IC 50 data in Table I provide the affinity data for ligand recognition by the anandamide transporter, but do not provide information on whether the ligands also may serve as substrates for the transporter.
  • substrate translocation we used a representative set of radioactively labeled compounds.
  • AM404 [ 3 H]/V-(4- hydroxyphenyDarachidonamide
  • AM1 1 72, AM 1 1 77 and AM 1 1 91 arachidonylglycerol As shown in Figsl and 2, all of the analogs are transported as rapidly and effectively as [ 3 H]anandamide at levels of 50 mM and 500 mM.
  • Modifications of the hydrophobic fatty acid tail reveal unexpectedly distinct requirements for recognition and translocation of substrates by the anandamide transporter.
  • Substrate recognition requires the presence of at least one cis double bond situated at the middle of the fatty acid chain, pointing to a preference for ligands in which the hydrophobic tail can fold in the middle and adopt a bent U- shaped conformation.
  • analogs with fully saturated chains or those incorporating trans double bonds do not interact significantly with the transporter.
  • substrate translocation requires a minimum of four cis nonconjugated double bonds, as ligands containing one, two, or three olefins are transported either very slowly or not at all. This finding suggests that for transmembrane transport to occur substrates must be capable of adopting a tightly folded conformation, one that is not energetically favorable for ligands containing an insufficient number of cis double bonds.
  • one of the low-energy conformers of anandamide displays a folded hairpin shape with the two halves of the molecule facing each other.
  • the cis- triene analog may adopt an analogous conformation, though one that is wider than that of anandamide.
  • the width of the turn increases considerably in the cis-dienes and the two monoalkenes due to the marked increase in distance between the head group and tail of the molecule.
  • the distance between the head and tail is much greater.
  • anandamide like arachidonic acid may adopt either a closed-hairpin or a U-shaped conformation depending on the properties of the surrounding milieu
  • the hairpin conformation may be thermodynamically unfavorable to fatty acid ethanolamides containing only one or two double bonds.
  • recognition and translocation of substrates by the anandamide transporter are governed by distinct conformational preferences.
  • the initial recognition step may require that substrates assume a bent U-shaped conformation of variable width, the subsequent step of translocation across the cell membrane may impose a more tightly folded hairpin conformation.
  • a “therapeutically effective amount” of a compound, as used herein, is the quantity of a compound which, when administered to an individual or animal, results in a sufficiently high level of anandamide in the individual or animal to cause a discernabie increase or decrease in a cellular activity affected or controlled by cannabinoid receptors.
  • anandamide can stimulate receptor-mediated signal transduction that leads to the inhibition of forskolin-stimulated adenylate cyclase (Vogel et al., J. Neurochem. 60:352 (1993)).
  • Anandamide also causes partial inhibition of N-type calcium currents via a pertussis toxin- sensitive G protein pathway, independently of cAMP metabolism
  • a “therapeutically effective amount" of an anandamide inhibitor can also be an amount which results in a sufficiently high level of anandamide in an individual or animal to cause a physiological effect resulting from stimulation of cannabinoid receptors.
  • Physiological effects which result from cannabinoid receptor stimulation include analgesia, decreased nausea resulting from chemotherapy, sedation and increased appetite.
  • Other physiological functions include relieving intraocular pressure in glaucoma patients and suppression of the immune system.
  • a “therapeutically effective amount” of the compound ranges from about 10 mg/day to about 1 ,000 mg/day.
  • an "individual” refers to a human.
  • An “animal” refers to veterinary animals, such as dogs, cats, horses, and the like, and farm animals, such as cows, pigs, guinea pigs and the like.
  • the compounds of the present invention can be administered by a variety of known methods, including orally, rectally, or by parenteral routes (e.g., intramuscular, intravenous, subcutaneous, nasal or topical). The form in which the compounds are administered will be determined by the route of administration.
  • Such forms include, but are not limited to, capsular and tablet formulations (for oral and rectal administration), liquid formulations (for oral, intravenous, intramuscular or subcutaneous administration and slow releasing microcarriers (for rectal, intramuscular or intravenous administration) .
  • the formulations can also contain a physiologically acceptable vehicle and optional adjuvants, flavorings, colorants and preservatives.
  • Suitable physiologically acceptable vehicles may include saline, sterile water, Ringer's solution, and isotonic sodium chloride solutions.
  • the specific dosage level of active ingredient will depend upon a number of factors, including, for example, biological activity of the particular preparation, age, body weight, sex and general health of the individual being treated.

Abstract

La présente invention concerne des inhibiteurs de véhicule d'anandamide et leur utilisation comme analgésiques.
PCT/US1999/012900 1998-06-09 1999-06-09 Inhibiteurs de vehicule d'anandamide comme agents analgesiques WO1999064389A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP99930176A EP1084098A4 (fr) 1998-06-09 1999-06-09 Inhibiteurs de vehicule d'anandamide comme agents analgesiques
CA002337822A CA2337822A1 (fr) 1998-06-09 1999-06-09 Inhibiteurs de vehicule d'anandamide comme agents analgesiques
JP2000553399A JP2002517479A (ja) 1998-06-09 1999-06-09 鎮痛薬としてのアナンダミド輸送体阻害剤
US10/899,191 US7589220B2 (en) 1998-06-09 2004-07-26 Inhibitors of the anandamide transporter

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US8856898P 1998-06-09 1998-06-09
US60/088,568 1998-06-09

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US09701989 A-371-Of-International 1999-06-09
US10/899,191 Continuation-In-Part US7589220B2 (en) 1998-06-09 2004-07-26 Inhibitors of the anandamide transporter

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WO2000038671A1 (fr) * 1998-12-23 2000-07-06 Jaervinen Tomi Procede de preparation d'une composition pharmaceutique
WO2001064212A1 (fr) * 2000-03-01 2001-09-07 University College London Modulateurs de l'absorption d'endocannabinoide et des recepteurs de vallinoide
WO2002012167A1 (fr) * 2000-07-28 2002-02-14 Universidad Complutense De Madrid Derives d'acide arachidonique presentant une affinite pour le transporteur d'anandamide
ES2174716A1 (es) * 2000-07-28 2002-11-01 Univ Madrid Complutense Nuevos derivados de acido araquidonico con afinidad por el transportador de anandamida.
ES2181601A1 (es) * 2001-07-27 2003-02-16 Univ Madrid Complutense Derivados de acido araquidonico con afinidad por el transportador de anandamida
EP1509489A1 (fr) * 2002-05-16 2005-03-02 Sepracor, Inc. Amines inhibant un transporteur d'anandamide de type mammalien, et procedes d'utilisation
US6900236B1 (en) 1999-10-18 2005-05-31 University Of Connecticut Cannabimimetic indole derivatives
US6939977B2 (en) 1998-05-04 2005-09-06 The University Of Connecticut Analgesic and immunomodulatory cannabinoids
US6943266B1 (en) 1999-10-18 2005-09-13 University Of Connecticut Bicyclic cannabinoid agonists for the cannabinoid receptor
US6974568B2 (en) 2000-05-23 2005-12-13 The Regents Of The University Of California Treatment for cough
JP2005538151A (ja) * 2002-09-05 2005-12-15 ディービーエル・オーストラリア・プロプライアタリー・リミテッド 尿素−、グリセラート−及びヒドロキシアミド−頭部形成した炭化水素鎖のリオトロピック相形成性界面活性剤
US6995187B1 (en) 1999-10-18 2006-02-07 University Of Connecticut Peripheral cannabinoid receptor (CB2) selective ligands
EP1632236A1 (fr) * 2004-07-26 2006-03-08 University of Connecticut Inhibiteurs du transporteur d'Anandamide
US7057076B2 (en) 2001-07-13 2006-06-06 University Of Connecticut Bicyclic and tricyclic cannabinoids
US7161016B1 (en) 1998-11-24 2007-01-09 University Of Connecticut Cannabimimetic lipid amides as useful medications
US7173027B2 (en) 2001-01-29 2007-02-06 University Of Connecticut Receptor selective cannabimimetic aminoalkylindoles
US7183313B2 (en) 2002-08-23 2007-02-27 University Of Connecticut Keto cannabinoids with therapeutic indications
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US8114903B2 (en) 2005-03-02 2012-02-14 Btg International Limited Cytokine modulators using cyclic glycerides of essential polyunsaturated fatty acids

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US6939977B2 (en) 1998-05-04 2005-09-06 The University Of Connecticut Analgesic and immunomodulatory cannabinoids
US7161016B1 (en) 1998-11-24 2007-01-09 University Of Connecticut Cannabimimetic lipid amides as useful medications
WO2000038671A1 (fr) * 1998-12-23 2000-07-06 Jaervinen Tomi Procede de preparation d'une composition pharmaceutique
US6995187B1 (en) 1999-10-18 2006-02-07 University Of Connecticut Peripheral cannabinoid receptor (CB2) selective ligands
US6943266B1 (en) 1999-10-18 2005-09-13 University Of Connecticut Bicyclic cannabinoid agonists for the cannabinoid receptor
US6900236B1 (en) 1999-10-18 2005-05-31 University Of Connecticut Cannabimimetic indole derivatives
WO2001064212A1 (fr) * 2000-03-01 2001-09-07 University College London Modulateurs de l'absorption d'endocannabinoide et des recepteurs de vallinoide
US6974568B2 (en) 2000-05-23 2005-12-13 The Regents Of The University Of California Treatment for cough
ES2174716A1 (es) * 2000-07-28 2002-11-01 Univ Madrid Complutense Nuevos derivados de acido araquidonico con afinidad por el transportador de anandamida.
WO2002012167A1 (fr) * 2000-07-28 2002-02-14 Universidad Complutense De Madrid Derives d'acide arachidonique presentant une affinite pour le transporteur d'anandamide
US7173027B2 (en) 2001-01-29 2007-02-06 University Of Connecticut Receptor selective cannabimimetic aminoalkylindoles
US7057076B2 (en) 2001-07-13 2006-06-06 University Of Connecticut Bicyclic and tricyclic cannabinoids
ES2181601A1 (es) * 2001-07-27 2003-02-16 Univ Madrid Complutense Derivados de acido araquidonico con afinidad por el transportador de anandamida
AU2003219250B2 (en) * 2002-02-01 2008-02-28 Diagnostica Stago Sas Device for automatic analysis of a liquid sample
EP1509489A1 (fr) * 2002-05-16 2005-03-02 Sepracor, Inc. Amines inhibant un transporteur d'anandamide de type mammalien, et procedes d'utilisation
EP1509489B1 (fr) * 2002-05-16 2011-07-13 Sunovion Pharmaceuticals Inc. Amines inhibant un transporteur d'anandamide de type mammalien, et procedes d'utilisation
US7183313B2 (en) 2002-08-23 2007-02-27 University Of Connecticut Keto cannabinoids with therapeutic indications
JP2005538151A (ja) * 2002-09-05 2005-12-15 ディービーエル・オーストラリア・プロプライアタリー・リミテッド 尿素−、グリセラート−及びヒドロキシアミド−頭部形成した炭化水素鎖のリオトロピック相形成性界面活性剤
EP1632236A1 (fr) * 2004-07-26 2006-03-08 University of Connecticut Inhibiteurs du transporteur d'Anandamide
US8114903B2 (en) 2005-03-02 2012-02-14 Btg International Limited Cytokine modulators using cyclic glycerides of essential polyunsaturated fatty acids

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EP1084098A1 (fr) 2001-03-21
CA2337822A1 (fr) 1999-12-16
JP2002517479A (ja) 2002-06-18
EP1084098A4 (fr) 2004-12-22

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