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WO1999026612A1 - Nouveaux modulateurs de recepteurs de cannabinoïdes - Google Patents

Nouveaux modulateurs de recepteurs de cannabinoïdes Download PDF

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Publication number
WO1999026612A1
WO1999026612A1 PCT/US1998/024803 US9824803W WO9926612A1 WO 1999026612 A1 WO1999026612 A1 WO 1999026612A1 US 9824803 W US9824803 W US 9824803W WO 9926612 A1 WO9926612 A1 WO 9926612A1
Authority
WO
WIPO (PCT)
Prior art keywords
receptor
pharmaceutically acceptable
subject
effective amount
phenol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1998/024803
Other languages
English (en)
Inventor
Paul E. Bender
Siegfried Benjamin Christensen, Iv
Jonathan A. Lee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of WO1999026612A1 publication Critical patent/WO1999026612A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol

Definitions

  • the present invention relates to the use of dialkyl phenol derivatives, and pharmaceutical compositions containing these compounds as cannabinoid peripheral receptor agonists.
  • Cannabinoids are a specific class of psychoactive compounds present in Indian cannabis (Cannabis sativa), including about sixty different molecules, the most representative being cannabinol, cannabidiol and several isomers of tetrahydrocannabinol. Knowledge of the therapeutic activity of cannabis dates back to the ancient dynasties of
  • Cannabinoids are known to cause different effects on various systems and/or organs, the most important being on the central nervous system and on the cardiovascular system. These effects include alterations in memory and cognition, euphoria, and sedation. Cannabinoids also increase heart rate and vary systemic arterial pressure. Peripheral effects related to bronchial constriction, immunomodulation, and inflammation have also been observed.
  • cannabinoids to reduce intraocular pressure and to affect respiratory and endocrine systems. See e.g. L.E. Hollister, Health Aspects of Cannabis. Pharmacological Reviews. Vol. 38, pp. 1-20, (1986). More recently, it was found that cannabinoids suppress the cellular and humoral immune response and have antiinflammatory properties. Wirth et al., Antiinflammatory Properties of Cannabichrome, Life Science. Vol. 26, pp. 1991-1995, (1980). The initial demonstration of the existence of a cannabinoid receptor by radioreceptor binding occurred in 1988 followed by the cloning and characterization of the central acting receptor and peripheral receptor in 1990 and 1993 respectively.
  • CB 1 Central Receptor
  • delta-9-THC is capable of influencing the function of macrophage Exposure to delta-9- THC lowers the cytolytic action of activated macrophages, measured as synthesis, release and cytotoxicity of TNF-alpha. Because the macrophages release various molecules having a cytolytic potential, other than TNF-alpha, it is considered that they can represent a target for delta-9-THC. See Fischer-Stenger et el.. "Delta9-tetrahydrocannabinol Inhibition of Tumor Necrosis Factor-alpha: Suppression of Post-translational Events," PeL. Vol. 267, Pp. 1558- 1565 ( 1993).
  • cannabinoids as analgesics, antiemetics, anticonvulsives, antispastics, antiglaucoma and, more recently, antiinflammatory agents, is limited by the undesirable side effects and by the possibility of addiction and pharmacological tolerance.
  • the foregoing research advances have provided the impetus to investigate the role of the cannabinoid receptors in immunomodulation, inflammation, osteoporosis, cardiovascular, neurological, renal and other disease conditions.
  • Cannabinoid receptor modulators thus offer a unique approach toward the pharmacotherapy of immunosuppression, neurological inflammation, arthritis, osteoporosis, renal ischemia, hematopoiesis, analgesia, neuropathic pain, pathologies related to improper small blood vessel vasodilation and other pathophysiological conditions.
  • cannabinoid receptor agonists may find therapeutic uses as analgesics, antiemetics, anticonvulsives, antispastics, antiglaucoma, immunomodulators and antiinflammatory agents and not be limited by the undesirable side effects and by the possibility of addiction.
  • the present invention involves 2,4-bis-( l-adamantyl)phenol and its use as a cannabinoid receptor agonist, useful in the treatment of a variety of diseases associated with cardiovascular, renal, neurological and immune disorders, including but not limited to immunologically-mediated inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple schlerosis, diabetis and thyroiditis; bone conditions including but not limited to ankylosing spondylitis, gout, arthritis associated with gout, osteoarthritis and osteoporosis.
  • immunologically-mediated inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple schlerosis, diabetis and thyroiditis
  • bone conditions including but not limited to ankylosing spondylitis, gout, arthritis associated with gout, osteoarthritis and osteoporosis.
  • the present invention further provides methods for agonizing cannabinoid receptors in an animal, including humans, which comprises administering to a subject in need of treatment an effective amount of the present compound.
  • the compound useful in the present methods is 2,4-bis-( l-adamantyl)phenoI:
  • compositions are also included in the present invention.
  • pharmaceutically acceptable salt complexes Preferred are the ethylene diamine, sodium, potassium and calcium salts.
  • the present compound can be prepared by the using the strategies provided hereinbelow as well as the specific example cited.
  • A-X represents 1-adamantyl halide, wherein the halide is chloride, iodide or preferably bromide.
  • Formula I compounds are prepared by the process of Scheme 1 which comprises: heating a 1-adamantyl halide of Formula 2 with a phenol of formula 1 at 50 to 150 °C in a dry suitable solvent such as carbon tetrachloride, or dichloroethane for 10 to 48 h in the presence of a Lewis acid catalyst such as silica (activated by heating between 100 and 250 °C under vacuum for 1 to 24 h.).
  • a Lewis acid catalyst such as silica
  • treatment includes, but is not limited to prevention, retardation and prophylaxis of the disease.
  • the present compound is useful for the treatment of diseases including but not limited to immunologically- mediated inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple schlerosis, diabetis and thyroiditis.
  • the present compound modulates bone formation/resorption and is useful in the treatment of conditions including but not limited to ankylosing spondylitis, gout, arthritis associated with gout, osteoarthritis and osteoporosis.
  • the present compound and its pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, dermally, transdermally, rectally, via inhalation or via buccal administration.
  • composition of the present compound and its pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent.
  • a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • composition is in the form of a capsule
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil.
  • a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises the present compound or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • a conventional aqueous or non-aqueous vehicle for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
  • Each dosage unit for oral administration contains suitably from 0.1 mg to
  • each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg/Kg, of a compound of Formula(I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • Each dosage unit for intranasal administration contains suitably 1-
  • a topical formulation contains suitably 0.01 to 5.0% of the present compound.
  • the daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of the present compound or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of the compound or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person.
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
  • Rat CB l membranes are made from homogenized cerebellum, recombinant human CB l membranes (hCB l) are obtained from Receptor Biology Inc. (Baltimore, MD), and human CB2 membranes (hCB2) are made from a polyclonal HEK 293 cell line stably expressing the human CB2 receptor.
  • the assay buffer comprises 50 mM Tris(pH7.4), 5mM MgC12, 2.5 mM EDTA and 5 mg/ml Bovine Seriu Albumin Fraction V fatty acid- free(Cal Biochem). Unless otherwise noted, all chemicals are from Sigma. Tritiated 5-(l,l- dimethylheptyl)-2-(5-hydroxypropyl)cyclohexyl)-l alpha, 2beta, 5 alpha)-phenol([ ⁇ H]-
  • CP55.940, 103.4 Ci/mmol, lmCi/ml) is purchased from DuPont NEN. Test compounds are made by Medicinal Chemistry SmithKline Beecham Pharmacuticals and are dissolved in DMSO.
  • the ligand binding mixture contains 1.3-1.8nM [ ⁇ H]-CP55,940, 5 ul of each test compound in a total reaction volume of 150 ul of assay buffer and either 50 ug/ml of rCB 1, 25 ug/ml hCB 1, or 20 ug/ml hCB2 membranes.
  • the final concentrations of compounds range from 1.00E-4 to 1.00E-10M; and the final DMSO concentration is 3.3%.
  • the ligand binding mixtures are incubated in 96 deep well polypropylene microtiter plates for one hour at 30° C and terminated by rapid filtration (Brandel 96-well cell harvester) over GF/B filters treated with wash buffer(50 mM Tris, 0.5 mg/ml fatty acid-free BSA, pH7.4), and followed by five washes with 3 ml ice-cold buffer.
  • the filters are air-dried and [->H]- CP55.940 bound radioactivity is determined by liquid scintillation counting. Non-specific binding is determined in the presence of 1 uM CP55.940.
  • the binding data is analyzed with the program GraphPad Prism. Kj values ranging from 1 nM to 10 uM are obtained for the compounds of the present invention.
  • EMEM media supplemented with Earl's salts, L-glutamine, 10% FBS, and 0.5mg/ml G418 sulfate.
  • 200 uL of cell suspension (25,000-50,000 cells/well) are added to a 96 well plate pre-treated with dilute Matrigel (Collaborative Biomedical Products: diluted 1/50 with PBS and treated for 1 hr at room temperature) and incubated at 37 °C for three days in a 5% CO,
  • cAMP assay buffer EMEM media supplemented with Earl's salts, L-glutamine, 20mM Hepes, pH 7.4, 0.1 mM MgCl, and 2mg/ml BSA Fraction V
  • 50 uL of assay buffer are added to each well, followed by 100 uL of 250 uM Zardaverine (a PDE 3-4
  • c AMP determinations 200 uL of cell lysate is transferred to a 96 well round- bottom plate and 40 uL of 0.1N NaOH and O. lmM CaC12 is added to neutralize the lysate. Following centrifugation at 2400 rpm for 5 minutes, 20-50 ⁇ L of supernatant is assayed for
  • Activated silica was prepared by heating Silica Gel 60 (EM Industries) in a flask under high vacuum at 180 °C for 12 h. and was stored under an argon atmosphere. A stirred suspension of activated silica ( 1.5g) 1-adamantyl bromide (2.6 g. 12 mmol) and anhydrous phenol (188 mg, 2 mmol), in dry carbon tetrachloride was heated at reflux under an argon atmosphere for 18 h. Another portion of activated silica (0.43 g) was added and the mixture refluxed another 18 h. The resulting mixture was filtered on a Buchner funnel, the solid rinsed with methylene chloride, and the chilled filtrate neutralized with chilled sodium carbonate solution.
  • Silica Gel 60 EM Industries
  • Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
  • the present compound is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • Ingredients 1, 2, 3 and 4 are blended in a suitable mixer/blender. Sufficient water is added portion-wise to the blend with careful mixing after each addition until the mass is of a consistency to permit its conversion to wet granules.
  • the wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
  • the wet granules are then dried in an oven at 140°F (60°C) until dry.
  • the dry granules are lubricated with ingredient No. 5, and the lubricated granules are compressed on a suitable tablet press.
  • a pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of the present compound in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cette invention se rapporte à des modulateurs de récepteurs de cannabinoïdes et à des procédés d'utilisation de ces modulateurs.
PCT/US1998/024803 1997-11-21 1998-11-20 Nouveaux modulateurs de recepteurs de cannabinoïdes Ceased WO1999026612A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US6635397P 1997-11-21 1997-11-21
US60/066,353 1997-11-21
US6808597P 1997-12-19 1997-12-19
US60/068,085 1997-12-19

Publications (1)

Publication Number Publication Date
WO1999026612A1 true WO1999026612A1 (fr) 1999-06-03

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Application Number Title Priority Date Filing Date
PCT/US1998/024803 Ceased WO1999026612A1 (fr) 1997-11-21 1998-11-20 Nouveaux modulateurs de recepteurs de cannabinoïdes

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001028588A1 (fr) * 1999-10-15 2001-04-26 Universite De Montreal Cannabinoides utilises en tant que vasodilatateurs et cardioprotecteurs contre l'ischemie
WO2004078261A1 (fr) * 2003-03-07 2004-09-16 The University Court Of The University Of Aberdeen Agonistes inverses de recepteurs de cannabinoides et antagonistes neutres agissant en tant qu'agents therapeutiques destines au traitement de troubles osseux
WO2004103410A1 (fr) * 2002-06-06 2004-12-02 Yissum Research Development Company Of The Hebrew University Of Jerusalem Compositions de procedes et articles de fabrication destines a moduler la croissance osseuse
US7067539B2 (en) 2001-02-08 2006-06-27 Schering Corporation Cannabinoid receptor ligands
US7071213B2 (en) 2001-11-14 2006-07-04 Schering Corporation Cannabinoid receptor ligands
US7217732B2 (en) 2002-06-19 2007-05-15 Schering Corporation Cannabinoid receptor agonists
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
WO2008065939A1 (fr) * 2006-11-29 2008-06-05 Idemitsu Kosan Co., Ltd. Dérivé d'adamantane, son procédé de fabrication, et composition de résine contenant un dérivé d'adamantane
US7507767B2 (en) 2001-02-08 2009-03-24 Schering Corporation Cannabinoid receptor ligands
US7642272B2 (en) 2003-03-20 2010-01-05 Schering Corporation Cannabinoid receptor ligands

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OONG S. H.: "ADAMANTYL-SUBSTITUTED PHENOLS.", JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL COMMUNICATIONS., CHEMICAL SOCIETY. LETCHWORTH., GB, vol. 18., 1 January 1970 (1970-01-01), GB, pages 1180., XP002916566, ISSN: 0022-4936 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001028588A1 (fr) * 1999-10-15 2001-04-26 Universite De Montreal Cannabinoides utilises en tant que vasodilatateurs et cardioprotecteurs contre l'ischemie
US7718702B2 (en) 2001-02-08 2010-05-18 Schering Corporation Cannabinoid receptor ligands
US7507767B2 (en) 2001-02-08 2009-03-24 Schering Corporation Cannabinoid receptor ligands
US7067539B2 (en) 2001-02-08 2006-06-27 Schering Corporation Cannabinoid receptor ligands
US7071213B2 (en) 2001-11-14 2006-07-04 Schering Corporation Cannabinoid receptor ligands
US7645774B2 (en) 2001-11-14 2010-01-12 Schering Corporation Cannabinoid receptor ligands
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
WO2004103410A1 (fr) * 2002-06-06 2004-12-02 Yissum Research Development Company Of The Hebrew University Of Jerusalem Compositions de procedes et articles de fabrication destines a moduler la croissance osseuse
US7749953B2 (en) 2002-06-06 2010-07-06 Yissum Research Development Company Of The Hebrew University Of Jerusalem Methods compositions and articles of manufacture for modulating bone growth
US7217732B2 (en) 2002-06-19 2007-05-15 Schering Corporation Cannabinoid receptor agonists
WO2004078261A1 (fr) * 2003-03-07 2004-09-16 The University Court Of The University Of Aberdeen Agonistes inverses de recepteurs de cannabinoides et antagonistes neutres agissant en tant qu'agents therapeutiques destines au traitement de troubles osseux
US7642272B2 (en) 2003-03-20 2010-01-05 Schering Corporation Cannabinoid receptor ligands
WO2008065939A1 (fr) * 2006-11-29 2008-06-05 Idemitsu Kosan Co., Ltd. Dérivé d'adamantane, son procédé de fabrication, et composition de résine contenant un dérivé d'adamantane
JP2008133246A (ja) * 2006-11-29 2008-06-12 Idemitsu Kosan Co Ltd アダマンタン誘導体、その製造方法及びアダマンタン誘導体を含む樹脂組成物
US8110614B2 (en) 2006-11-29 2012-02-07 Idemitsu Kosan Co., Ltd. Adamantane derivative, method for producing the same, and resin composition containing adamantane derivative
KR101440769B1 (ko) * 2006-11-29 2014-09-23 오사카 유키가가쿠고교 가부시키가이샤 아다만탄 유도체, 그 제조 방법 및 아다만탄 유도체를 함유하는 수지 조성물

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