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WO2000004003A1 - Antagonistes du recepteur ccr-3 - Google Patents

Antagonistes du recepteur ccr-3 Download PDF

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Publication number
WO2000004003A1
WO2000004003A1 PCT/US1999/015865 US9915865W WO0004003A1 WO 2000004003 A1 WO2000004003 A1 WO 2000004003A1 US 9915865 W US9915865 W US 9915865W WO 0004003 A1 WO0004003 A1 WO 0004003A1
Authority
WO
WIPO (PCT)
Prior art keywords
ccr
nitrophenyl
pharmaceutically acceptable
receptor
ethyl
Prior art date
Application number
PCT/US1999/015865
Other languages
English (en)
Inventor
Dashyant Dhanak
Original Assignee
Smithkline Beecham Corporation
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 Corporation filed Critical Smithkline Beecham Corporation
Publication of WO2000004003A1 publication Critical patent/WO2000004003A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to the use of (S)-N-(l-(4,5-Dihydro-oxazol-2-yl)-2- (4-nitrophenyl)ethyl)-l-naphtharnide as a CKJ36/CCR-3 receptor antagonist.
  • Chemokines are a superfamily of small secreted proteins. There are approximately
  • chemokines known with many others being characterized. See Oppenheim et al., Properties of the Novel Proinflammatory Supergene "Intercrine” Cytokine Family, Ann. Rev. Immun. , 9, 617-648 (1991); and Baggiolini, et al, Interleukin-8 and Related Chemotactic Cytokines-CXC and CC Chemokines, Adv. Immun., 55, 97-179 (1994).
  • the properties of the chemokines suggest that they are essential for leukocyte trafficking and inflammatory processes, and are thus important components in a number of disease states.
  • Chemokines mediate their effects via interactions with 7TM-G-protein coupled receptors on the surface of immune and inflammatory cells.
  • Eosinophils are proinflammatory granulocytes that play a major role in allergic diseases, such as bronchial asthma, allergic rhinitis, pruritis and atopic dermatitis. Upon activation, eosinophils release lipid mediators, cytotoxic proteins, oxygen metabolites and cytokines, all of which have the potential to produce pathophysiology. Numerous studies have demonstrated the presence of eosinophils or eosinophil-specific products in inflamed tissues in human diseases.
  • Eotaxin A Potent Eosinophil Chemoattractant Cytokine Detected in Guinea Pig Model of Allergic Airways Inflammation, J. Exp.
  • Eotaxin Cloning of an Eosinophil Chemoattractant Cytokine and Increased mRNA Expression in Allergen-challenged Guinea-pig Lungs, Biochem.
  • Chemoattractant, Eotaxin Expression, Receptor Binding, and Functional Properties Suggest a Mechanism for Selective Recruitment of Eosinophils, J. Clin. Invest., 97, 604- 612 (1996).
  • Eotaxin and, to a lesser extent, RANTES and MCP-3 activate this receptor.
  • the CCR-3 receptor is expressed at high levels on eosinophils, typically 40,000- 400,000 receptors per cell are present. This is 10-100 fold more than the other chemokine receptor (CCR-1) expressed in eosinophils.
  • CCR-1 chemokine receptor
  • CCR-3 chemokine receptor
  • CCR-4 chemokine receptor
  • CCR-3 receptor antagonists thus offer a unique approach toward decreasing the pathophysiology associated with allergic diseases.
  • Antagonism of this receptor may be useful in the treatment of allergic disorders, including but not limited to bronchial asthma, allergic rhinitis, nasal polyposis, atopic dermatitis and pruritis.
  • the present invention involves the CCR-3 receptor antagonist (S)-N-(l-(4,5-
  • the present compound is useful in the treatment of a variety of diseases associated with allergic disorders, including but not limited to bronchial asthma, allergic rhinitis, nasal polyposis, atopic dermatitis and pruritis.
  • present compound signifies (S)-N-(l-(4,5-Dihydro- oxazol-2-yl)-2-(4-nitrophenyl)ethyl)- 1 -naphthamide.
  • present method signifies the use of the present compound as a CCR-3 receptor antagonist.
  • present composition signifies a composition comprising the present compound and a pharmaceutically acceptable carrier.
  • compositions of the present compound are also included in the present invention.
  • pharmaceutically acceptable salt complexes of the present compound are the ethylene diamine, sodium, potassium, calcium and ethanolamine salts.
  • the present compound was prepared as follows: a) (S)-2- ⁇ -Naphthoylamino)-3-(4-nitrophenyl)propionic acid
  • L-4-Nitrophenylalanine (5.33 g, 23.4 mmol) was dissolved in 2.0M NaOH (12.9 mL) and cooled to 5 °C.
  • 1-Naphthoyl chloride (4.90 g, 25.7 mmol) and 2.0M NaOH (14.2 mL) were added in several portions over 15 minutes. The mixture was warmed to room temperature over 30 minutes and washed with Et2 ⁇ . The aqueous portion was acidified using 6N HC1 and the precipitated off-white solid was filtered and dried (7.47 g, 88%).
  • Methoxy-carbonylsulfamoyl- triethylammonium hydroxide (0.32 g, 1.4 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes and heated to 70 °C for one hour. The mixture was cooled to room temperature and the solvent was removed in vacuo. Water was added to the residue and the pH adjusted to 5-6 using saturated aqueous NH4CI. Upon stirring, the crude product precipitated as a yellow solid. The product was filtered and purified by flash chromatography on silica gel ( 100% EtOAc as eluant) to furnish the title compound (0.18 g, 38%).
  • 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 bronchial asthma, allergic rhinitis, nasal polyposis, eczema, conjunctivitis, atopic dermatitis, pruritis and inflammatory bowel disease.
  • 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.
  • compositions and their 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, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame 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.
  • 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 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg/Kg, of the present compound or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person.
  • 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 present 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.
  • eosinophils Human eosinophils were purified by standard CD 16 cell depletion using a Miltenyi cell separation column and a magnetic Super Macs magnet. Eosinophils which were >95% pure as assessed by DiffQuick staining and light microscopy were washed in PBS and resuspended in binding buffer (RPMI- 1640 + 25mM Hepes + 0.1% Gelatin + 0.1% sodium azide + 0.008% CHAPS). Into a 96 well plate (Dynatek) 200,000 eosinophils, 0.25 nM 1251-Eotaxin (Amersham Pic), and compound of interest (1 nM to 100 uM) was added.
  • Bound from free 1251-eotaxin was separated using a Packard Filtermate 196, 96- well plate harvester. To determine total and non-specific binding (NSB) three wells for each condition were set aside. For total binding and NSB, wells received all additions except compound. In addition NSB wells received 200 nM cold eotaxin (PeproTech, Rocky Hill, NJ). Radioactivity associated with the filter was assessed in a Packard Top-count Microplate Scintillation Counter model number 49872V. Percent control binding was assessed by first subtracting the NSB from each well and then expressing the number of counts (CPM) associated with the compound treated sample as a percent of the control binding in the absence of compound addition.
  • CPM number of counts
  • RBL-2H3 cells expressing the human CCR-3 receptor were grown in cell medium
  • EMEM medium with Earl's salts containing 2mM L-Glutamine, 0.4 mg/ml G418 Sulfate from GIBCO BRL and 10% heat inactivated fetal calf serum from Hyclone Laboratories.
  • the cells were seeded 30,000 cells,/well into 96-well black clear bottom sterile plates from Costar.
  • the seeded plate was incubated overnight at 37 ⁇ C in 5% CO2* On the day of the assay the cell medium was aspirated before addition of calcium dye loading solution consisting of; 1 mg/mL bovine serum albumin (BSA), 1.5 mM sulfinpyrazone from SIGMA and 4uM Fluo-3 AM dye from Molecular Probes in cell medium, thereafter the 96- well plate was incubated for 1 hour at 37 ⁇ C. The loading solution containing dye was then aspirated and replaced with fresh solution without dye after which the plate was incubated for a further 10 mins at 37°C.
  • BSA bovine serum albumin
  • 4uM Fluo-3 AM dye from Molecular Probes
  • IC50 is the concentration of compound needed to inhibit 50% of the Eotaxin response.
  • Animal model for the in vivo evaluation of CCR-3 antagonists (Gonzalo, J.A. et al, Immunity, 1996, 4, 1.) BALs were obtained from Guinea Pigs (+ compound) 24 h after ovalbumin (OA) exposure to eotaxin administered via inhalation.
  • the animals were euthanized by cervical dislocation and exsanguinated.
  • the lungs were lavaged with 50 ml of DulBecco's PBS (5x1 Occ), which was aspirated after a gentle chest massage.
  • the BAL fluid was spun down and the pellet was resuspended in 0.25% NaCl to lyse residual erythrocytes. After centrifugation, the pellet was resuspended again in 0.9% NaCl. After a total cell count, slides were prepared and stained. The cells were differentiated into eosinophils, neutrophils and monocytes by counting a minimum of 200 cells and expressing the results as a percentage of total cells.
  • OA sensitized Guinea Pigs (+ compound) were exposed to OA via inhalation 24 h after OA exposure and lungs were obtained as described above and assessed for eosinophil infiltration.
  • the present compound (1 mg to 100 mg) 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. All publications, including but not limited to patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference as though fully set forth.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un antagoniste du récepteur CCR-3, ainsi que des méthodes d'utilisation dudit antagoniste.
PCT/US1999/015865 1998-07-14 1999-07-13 Antagonistes du recepteur ccr-3 WO2000004003A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US9281998P 1998-07-14 1998-07-14
US9282098P 1998-07-14 1998-07-14
US60/092,819 1998-07-14
US60/092,820 1998-07-14

Publications (1)

Publication Number Publication Date
WO2000004003A1 true WO2000004003A1 (fr) 2000-01-27

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WO (1) WO2000004003A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7101882B2 (en) 2000-09-29 2006-09-05 Glaxo Group Limited Morpholin-acetamide derivatives for the treatment of inflammatory diseases
WO2006129679A1 (fr) 2005-05-31 2006-12-07 Ono Pharmaceutical Co., Ltd. Compose de spiropiperidine et son utilisation medicinale
WO2007049771A1 (fr) 2005-10-28 2007-05-03 Ono Pharmaceutical Co., Ltd. Compose contenant un groupe basique et son utilisation
WO2007058322A1 (fr) 2005-11-18 2007-05-24 Ono Pharmaceutical Co., Ltd. Composé contenant un groupe basique et son utilisation
WO2007105637A1 (fr) 2006-03-10 2007-09-20 Ono Pharmaceutical Co., Ltd. Derive heterocyclique azote et agent pharmaceutique comprenant le derive en tant que principe actif
WO2007132846A1 (fr) 2006-05-16 2007-11-22 Ono Pharmaceutical Co., Ltd. Composé ayant un groupe acide qui peut être protégé et utilisation dudit composé
WO2008016006A1 (fr) 2006-07-31 2008-02-07 Ono Pharmaceutical Co., Ltd. Composé auquel un groupe cyclique est lié par une liaison spiro et son utilisation
EP2364982A1 (fr) 2003-04-18 2011-09-14 ONO Pharmaceutical Co., Ltd. Dérivés de spiropipéridine comme antgonistes du recepteur chémokine et leur usage médical
EP2385040A1 (fr) 2003-03-14 2011-11-09 ONO Pharmaceutical Co., Ltd. Dérivés hétérocycliques renfermant de l'azote et médicaments contenant ces dérivés comme principe actif
US10117931B2 (en) 2009-04-28 2018-11-06 Kameran Lashkari Methods for treatment of age-related macular degeneration

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5494926A (en) * 1992-05-27 1996-02-27 Merck Sharp & Dohme Ltd. 2/3-(heterocyclic alkyl amino)-1-(subst.-phenyl-methoxy)-ethanes/propanes as tachykinin-receptor antagonists
US5846993A (en) * 1992-12-22 1998-12-08 Agouron Pharmaceuticals, Inc. HIV protease inhibitors
US5919776A (en) * 1996-12-20 1999-07-06 Merck & Co., Inc. Substituted aminoquinolines as modulators of chemokine receptor activity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5494926A (en) * 1992-05-27 1996-02-27 Merck Sharp & Dohme Ltd. 2/3-(heterocyclic alkyl amino)-1-(subst.-phenyl-methoxy)-ethanes/propanes as tachykinin-receptor antagonists
US5846993A (en) * 1992-12-22 1998-12-08 Agouron Pharmaceuticals, Inc. HIV protease inhibitors
US5919776A (en) * 1996-12-20 1999-07-06 Merck & Co., Inc. Substituted aminoquinolines as modulators of chemokine receptor activity

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7101882B2 (en) 2000-09-29 2006-09-05 Glaxo Group Limited Morpholin-acetamide derivatives for the treatment of inflammatory diseases
US7560548B2 (en) 2000-09-29 2009-07-14 Glaxo Group Limited Morpholin-acetamide derivatives for the treatment of inflammatory diseases
EP2385040A1 (fr) 2003-03-14 2011-11-09 ONO Pharmaceutical Co., Ltd. Dérivés hétérocycliques renfermant de l'azote et médicaments contenant ces dérivés comme principe actif
EP2364982A1 (fr) 2003-04-18 2011-09-14 ONO Pharmaceutical Co., Ltd. Dérivés de spiropipéridine comme antgonistes du recepteur chémokine et leur usage médical
WO2006129679A1 (fr) 2005-05-31 2006-12-07 Ono Pharmaceutical Co., Ltd. Compose de spiropiperidine et son utilisation medicinale
WO2007049771A1 (fr) 2005-10-28 2007-05-03 Ono Pharmaceutical Co., Ltd. Compose contenant un groupe basique et son utilisation
EP2657235A1 (fr) 2005-10-28 2013-10-30 Ono Pharmaceutical Co., Ltd. Composé contenant un groupe basique et son utilisation
WO2007058322A1 (fr) 2005-11-18 2007-05-24 Ono Pharmaceutical Co., Ltd. Composé contenant un groupe basique et son utilisation
WO2007105637A1 (fr) 2006-03-10 2007-09-20 Ono Pharmaceutical Co., Ltd. Derive heterocyclique azote et agent pharmaceutique comprenant le derive en tant que principe actif
WO2007132846A1 (fr) 2006-05-16 2007-11-22 Ono Pharmaceutical Co., Ltd. Composé ayant un groupe acide qui peut être protégé et utilisation dudit composé
WO2008016006A1 (fr) 2006-07-31 2008-02-07 Ono Pharmaceutical Co., Ltd. Composé auquel un groupe cyclique est lié par une liaison spiro et son utilisation
US10117931B2 (en) 2009-04-28 2018-11-06 Kameran Lashkari Methods for treatment of age-related macular degeneration

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