WO2000032200A1 - Amides lipidiques cannabimimetiques s'utilisant comme medicaments - Google Patents

Amides lipidiques cannabimimetiques s'utilisant comme medicaments Download PDF

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WO2000032200A1
WO2000032200A1 PCT/US1999/028136 US9928136W WO0032200A1 WO 2000032200 A1 WO2000032200 A1 WO 2000032200A1 US 9928136 W US9928136 W US 9928136W WO 0032200 A1 WO0032200 A1 WO 0032200A1
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group
anandamide
alkyl
mmol
analogs
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PCT/US1999/028136
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English (en)
Inventor
Alexandros Makriyannis
Atmaram Khanolkar
Andreas Goutopoulos
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Alexandros Makriyannis
Atmaram Khanolkar
Andreas Goutopoulos
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Application filed by Alexandros Makriyannis, Atmaram Khanolkar, Andreas Goutopoulos filed Critical Alexandros Makriyannis
Priority to US09/600,786 priority Critical patent/US7161016B1/en
Priority to EP99961838A priority patent/EP1049474A4/fr
Priority to AU18336/00A priority patent/AU1833600A/en
Publication of WO2000032200A1 publication Critical patent/WO2000032200A1/fr
Priority to US10/110,862 priority patent/US7276613B1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • C07C233/02—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
    • C07C233/09—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 carbon atoms of an acyclic unsaturated carbon skeleton
    • 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
    • C07C233/12—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 halogen atoms or by nitro or nitroso groups
    • C07C233/13—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 halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • 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
    • C07C233/17—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 an acyclic carbon atom
    • C07C233/20—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 an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • 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
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated 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
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated

Definitions

  • Classical cannabinoids such as the marijuana derived cannabinoid ⁇ 9 -tetrahydrocannabinol, ( ⁇ 9 -THC) produce their pharmacological effects through interaction with specific cannabinoid receptors in the body. So far, two cannabinoid receptors have been characterized: CB1 found in the mammalian brain and peripheral tissues and CB2 found only in the peripheral tissues. 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 and affect the reproductive system.
  • compounds which stimulate the CB1 and CB2 receptors, directly or indirectly, are potentially useful as oral and topical contraceptive preparations, in treating glaucoma, preventing tissue rejection in organ transplant patients, controlling nausea in patients undergoing chemotherapy, controlling pain and enhancing the appetite in individuals with AIDS Wasting Syndrome.
  • cannabinoids such as ⁇ 9 -THC 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.
  • Arachidonylethanolamide is an endogenous lipid that binds to and activates the CB1 cannabinoid receptor with approximately equal affinity to that of ⁇ 9 -THC.
  • Anandamide also exhibits biochemical and pharmacological properties similar to that of ⁇ 9 - THC, albeit with a longer onset time and shorter duration of action.
  • anandamide amidase hydrolyzes anandamide. It is presumed that the magnitude of action and relatively short duration of action of anandamide is due to a rapid inactivation process consisting of carrier-mediated transport into cells followed by intra-cellular hydrolysis by anandamide amidase. There is considerable interest in developing analogs of anandamide possessing high CB1 receptor affinity and/or metabolic stability.
  • Such analogs may offer a rational therapeutic approach to a variety of disease states, including pain, psychomotor disorders, and multiple sclerosis, in which elevation of anandamide analog levels may bring about a more favorable response with fewer side effects and greater metabolic stability than direct activation of CB1 receptors by anandamide.
  • metabolic stability refers to the resistance to hydrolysis of the subject anandamide analog by anandamide amidase.
  • the analogs were prepared by structural modification of anandamide. The modifications were primarily made in the ethanolamido head group and comprised the substitution or addition of alkyl, substituted alkyl, alkenyl and alkynyl groups. Additionally, a number of retro-anandamides, in which the positions of the NH and CO groups are reversed, were prepared. The retro-anandamides comprised the substitution or addition of alkylacetoxy groups.
  • the analogs prepared are summarized in Table 1 .
  • anandamide and retro-anandamide would provide similar physiological results.
  • additional analogs comprise the headgroup substitution or addition of alkyl, substituted alkyl, alkenyl, alkynyl and alkylacetoxy groups, as well as cycloalkyl, polycyclic and heterocyclic groups.
  • structural modification may be made to the tail of the anandamide and retro-anandamide analogs, comprising substitution or addition of alkyl, substituted alkyl, O-alkyl, aryl, alkylaryl, O-alkylaryl, cyclic and heterocyclic groups.
  • the compounds of the present invention 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.
  • the 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 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 to treat psychomotor disorders, multiple sclerosis, peripheral hypertension and as oral and topical contraceptives.
  • novel lipid materials may also interact with the specific cannabinoid receptors.
  • novel lipid materials can be more resistant to hydrolysis by anandamide amidase than is anandamide, providing a greater magnitude of action and longer duration of action than anandamide.
  • novel lipid materials can have higher affinities for specific cannabinoid receptors than anandamide.
  • reaction mixture was stirred at ice-bath temperature for 2 hours and then transferred to a separatory funnel with more chloroform and washed successively with 1 0% hydrochloric acid, 1 0% sodium bicarbonate and water and dried (MgSO 4 ). Solvent was removed and the residue was purified by column chromatography on silica gel to afford 2.20 g (84%) of viscous colorless oil.
  • Arachidonic acid chloride was prepared from 50 mg (0J 65 mmol) of arachidonic acid as described under analog 5 and treated with 0.061 mL (0.83 mmol, 5 equiv) of allylamine.
  • Arachidonic acid chloride was prepared from 50 mg (0.1 65 mmol) of arachidonic acid as described under analog 5 and reacted with a solution of 1 1 1 .8 mg (0.825 mmol, 5 equiv) of 2,2,2-trifluoroethylamine hydrochloride in 0.5 mL of pyridine.
  • Arachidonyl alcohol To a magnetically stirred solution of 0.5 ml (0.5 mmol) of LiAIH 4 in Et 2 O, 1 00 mg (0.31 4 mmol) of arachidonic acid methyl ester in 2 mL of Et 2 O was added dropwise at 0°C. The reaction mixture was stirred for 1 h and then quenched by addition of 1 mL of EtOAC. 2 mL of saturated NH 4 CI solution was added and the organic layer was separated, dried with MgSO 4 , filtered and evaporated. Chromatography on silica gel (eluents: CH 2 CI 2 /petroleum ether up to
  • Arachidonylamine To a magnetically stirred solution of 50 mg (0J 7 mmol) of arachidonyl alcohol in 1 mL of pyridine was added 29.2 mg (0.225 mmol) of mesyl chloride at 0 °C. After stirring for 5 hours, the reaction mixture was poured into 2 mL of cold water and extracted with diethyl ether (2 x 4 mL) . The combined ether extracts were washed with 1 N sulfuric acid and saturated sodium bicarbonate solution and evaporated in vacuo.
  • the crude mesylate was dissolved in 2 mL of anhydrous DMF, and then a solution of 6.5 mg (0.85 mmol) of sodium azide in 4 mL of anhydrous DMF was added at room temperature.
  • the reaction mixture was heated to 90 °C for 24 hours behind a safety shield.
  • the mixture was cooled to room temperature, inorganic material was filtered off, and the filtrate was poured into 1 mL of cold water.
  • the crude azide was reduced to the title amine as follows: To a magnetically stirred solution of 1 32 mg (0.43 mmol) of arachidonyl azide in 3 mL of dry diethyl ether was added 4 mL of 1 .0 M solution of lithium aluminum hydride (4.0 mmol) in THF dropwise at room temperature. The reaction mixture was refluxed for 3 hours and then quenched with wet diethyl ether. The white suspension was filtered, and the filtrate was evaporated to dryness.
  • Analog 10, /V-(3-Hydroxypropionyl)arachidonylamine To a magnetically stirred solution of 48 mg (0J 7 mmol) of arachidonylamine in 2 mL of anhydrous dichloromethane was added 58 ⁇ L of a 2.0 M solution of trimethylaluminum (0J 7 mmol) in hexane at room temperature. The mixture was stirred for 20 min, and then 1 2.24 mg (0J 7 mmol) of ⁇ -propiolactone was added. The reaction mixture was refluxed for 6 hours, quenched with 1 N HCI, and extracted with dichloromethane.
  • Analog 1 1 ⁇ /-(2-Acetoxyacetyl)arachidonylamine.
  • AA refers to a portion of the anandamide molecule having the structure:
  • EXAMPLE 1 It is known that the enzymatic action of anandamide amidase can be moderated or prevented in vitro by the inclusion of phenylmethanesulfonyl fluoride (PMSF) . PMSF functions as a non- selective protease inhibitor. Thus the ligand binding determinations for the CB1 receptor were carried out in the presence and absence of PMSF, to obtain both CB1 receptor binding affinity and a relative measure of the analog's metabolic stability. The binding affinities (K i ) are expressed in nanomoles (nM) .
  • nM nanomoles
  • Membranes previously frozen at -80°C, were thawed on ice. To the stirred suspension was added three volumes of 25mM Tris-HCI buffer, 5 mM MgCI 2 and 1 mM EDTA, pH 7.4 (TME) containing 1 50 ⁇ M PMSF (made fresh in 2-propanol as a 1 00 mM stock) . The suspension was incubated at 4°C, and after 1 5 min a second addition of PMSF stock brought the concentration to 300 ⁇ M PMSF; then the mixture was incubated for another 1 5 min. At the end of the second 1 5-min incubation, the membranes were pelleted and washed three times with TME to remove un-reacted PMSF.
  • TME Tris-HCI buffer
  • PMSF pH 7.4
  • the treated membranes were subsequently used in the binding assay described below. Approximately 30 ⁇ g of PMSF-treated membranes were incubated in silanized 96-well microtiter plate with TME containing OJ % essentially fatty acid-free bovine serum albumin (BSA), 0.8 nM [ 3 H] CP-55,940, and various concentrations of anandamide analogues in a final volume of 200 °C for 1 hour. The samples were filtered using Packard Filtermate 1 96 and Whatman GF/C filterplates and washed with wash buffer (TME) containing 0.5 % BSA.
  • BSA bovine serum albumin
  • Radioactivity was detected using MicroScint 20 scintillation cocktail added directly to the dried filterplates, and the filterplates were counted using a Packard Instruments Top-Count. Nonspecific binding was assessed using 1 00 nM CP-55,940. Data collected from three independent experiments performed with duplicate determinations was normalized between 1 00% and 0% specific binding for [ 3 H] CP-55,940, determined using buffer and 100 nM CP-55,940. The normalized data was analyzed using a 4-parameter nonlinear logistic equation to yield IC 50 values.
  • Retro-anandamides are defined as anandamide analogs in which the position of the NH and CO groups have been reversed. Analogs 1 0, 1 1 and 1 2 are examples of some retro-anandamides. It should be noted that the retro-anandamides as a group show excellent affinity to, and selectivity for, the CB1 receptor. Further, the retro-anandamides show virtually no difference in CB1 affinities when tested with and without PMSF. Thus the retro-anandamides exhibit excellent metabolic stability. The results demonstrate that the retro-anandamides are not substrates for anandamide amidase and therefore are not susceptible to its hydrolytic actions.
  • PROPHETIC EXAMPLE 2 Based on the above testing and results, it is believed that lipid compounds based on structural formulas 1 and 2, illustrated in Table 2, would exhibit increased cannabinoid receptor affinities and/or selectivities as well as increased metabolic stability. In fact, structural formulas 1 and 2 include analogs 1 - 1 2 discussed above. TABLE 2
  • R T is selected from the group consisting of H and alkyl groups.
  • R is selected from the group consisting of H, CH 3 and (CH 3 ) 2 .
  • R 2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl and alkynyl groups. More specifically, R 2 is selected from the group consisting of CH(R)CH 2 Z, CH 2 CH(R)Z and CH(R)(CH 2 )nCH 2 Z, R being selected from the group consisting of H, CH, CH 3 CHCH, CH 2 CF 3 and (CH 3 ) 2 Z being selected from the group consisting of H, halogens, N 3 , NCS and OH and n being selected from the group consisting of 0, 1 and 2.
  • R 3 is selected from the group consisting of alkyl, substituted alkyl, aryl, alkylaryl, O-alkyl, O-alkylaryl, cyclic and heterocyclic groups.
  • O-alkyl and O-alkylaryl refer to groups in which an oxygen atom is interposed between carbon atoms on the anandamide portion and substituent group.
  • Non-limiting examples of such R 3 groups include cyclohexyl, cyclopentyl, alkylcyclohexyl, alkylcyclopentyl, piperidinyl, morpholinyi and pyridinyl.
  • R 3 is selected from the group consisting of n-C 5 H 10 Z', n-C 6 H 12 Z', n-C 7 H 14 Z' and 1 ', 1 '- C(CH 3 ) 2 (CH 2 ) 5 CH 2 Z', Z' being selected from the group consisting of H, halogens, CN, N 3 , NCS and OH .
  • R 1 is selected from the group consisting of H and alkyl groups. More specifically, R, is selected from the group consisting of H, CH 3 and (CH 3 ) 2 .
  • R 2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, O-alkyl, cyclic, polycyciic and heterocyclic groups. More specifically, R 2 is selected from the group consisting of
  • R 3 is selected from the group consisting of alkyl, substituted alkyl, aryl, alkylaryl, O-alkyl, O-alkyiaryl, cyclic and heterocyclic groups.
  • R 3 groups include cyclohexyl, cyclopentyl, alkylcyclohexyl, alkylcyclopentyl, piperidinyl, morpholinyi and pyridinyl.
  • R 3 may be selected from the group consisting of n- C 5 H 10 Z', n-C 6 H 12 Z', n-C 7 H 14 Z' and 1 ', 1 '-C(CH 3 ) 2 (CH 2 ) 5 CH 2 Z', Z' being selected from the group consisting of H, halogens, CN, N 3 , NCS and OH.

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Abstract

L'invention concerne de nouveaux analogues d'arachidonyléthanolamide possédant une grande affinité avec les sites récepteurs de cannabinoïdes CB1 et/ou CB2. En outre, la plupart des analogues possèdent une meilleure stabilité métabolique que l'arachidonyléthanolamide. Leur affinité élevée avec les récepteurs, leur sélectivité et/ou leur meilleure stabilité métabolique font de ces analogues des médicaments utiles contre la douleur causée par un cancer, les nausées provoquées par la chimiothérapie et les douleurs périphériques. On peut également utiliser les composés selon la présente invention comme contraceptifs oraux et topiques, lors d'une dépression du système immunitaire, pour augmenter l'appétit et pour le traitement de troubles psychomoteurs, de la sclérose en plaques et de l'hypertension.
PCT/US1999/028136 1998-11-24 1999-11-24 Amides lipidiques cannabimimetiques s'utilisant comme medicaments WO2000032200A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US09/600,786 US7161016B1 (en) 1998-11-24 1999-11-24 Cannabimimetic lipid amides as useful medications
EP99961838A EP1049474A4 (fr) 1998-11-24 1999-11-24 Amides lipidiques cannabimimetiques s'utilisant comme medicaments
AU18336/00A AU1833600A (en) 1998-11-24 1999-11-24 Cannabimimetic lipid amides as useful medications
US10/110,862 US7276613B1 (en) 1998-11-24 2000-10-18 Retro-anandamides, high affinity and stability cannabinoid receptor ligands

Applications Claiming Priority (2)

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US10961598P 1998-11-24 1998-11-24
US60/109,615 1998-11-24

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US10/110,862 Continuation-In-Part US7276613B1 (en) 1998-11-24 2000-10-18 Retro-anandamides, high affinity and stability cannabinoid receptor ligands

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Cited By (21)

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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
US6900236B1 (en) 1999-10-18 2005-05-31 University Of Connecticut Cannabimimetic indole derivatives
WO2005079771A1 (fr) * 2004-02-19 2005-09-01 Imperial Innovations Limited Procedes pour soulager la douleur
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
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
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
US7351729B2 (en) 2002-03-08 2008-04-01 Signal Pharmaceuticals, Llc JNK inhibitors for use in combination therapy for treating or managing proliferative disorders and cancers
US7897598B2 (en) 1998-06-09 2011-03-01 Alexandros Makriyannis Inhibitors of the anandamide transporter
WO2011079188A3 (fr) * 2009-12-23 2011-11-17 Life Technologies Corporation Modification de protéine pour l'oxydation d'analogues d'acides gras polyinsaturés aptes à la chimie clic
US8293786B2 (en) 2007-07-30 2012-10-23 Alltranz Inc. Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same
JP2013512255A (ja) * 2009-11-25 2013-04-11 サイトメティックス、インコーポレイテッド アラキドン酸類縁体、及びそれによる鎮痛治療
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KR20150030756A (ko) * 2012-07-10 2015-03-20 바제클리크 게엠베하 아난다미드-변형된 핵산 분자
US10588974B2 (en) 2016-04-22 2020-03-17 Receptor Holdings, Inc. Fast-acting plant-based medicinal compounds and nutritional supplements
US11246852B2 (en) 2016-12-02 2022-02-15 Receptor Holdings, Inc. Fast-acting plant-based medicinal compounds and nutritional supplements

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6939977B2 (en) 1998-05-04 2005-09-06 The University Of Connecticut Analgesic and immunomodulatory cannabinoids
US7897598B2 (en) 1998-06-09 2011-03-01 Alexandros Makriyannis Inhibitors of the anandamide transporter
US6995187B1 (en) 1999-10-18 2006-02-07 University Of Connecticut Peripheral cannabinoid receptor (CB2) selective ligands
US6900236B1 (en) 1999-10-18 2005-05-31 University Of Connecticut Cannabimimetic indole derivatives
US6943266B1 (en) 1999-10-18 2005-09-13 University Of Connecticut Bicyclic cannabinoid agonists for the cannabinoid receptor
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
US8449908B2 (en) 2000-12-22 2013-05-28 Alltranz, Llc Transdermal delivery of cannabidiol
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
US7351729B2 (en) 2002-03-08 2008-04-01 Signal Pharmaceuticals, Llc JNK inhibitors for use in combination therapy for treating or managing proliferative disorders and cancers
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