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WO2000027843A1 - Antagonistes du recepteur ccr3-3 - Google Patents

Antagonistes du recepteur ccr3-3 Download PDF

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Publication number
WO2000027843A1
WO2000027843A1 PCT/US1999/026411 US9926411W WO0027843A1 WO 2000027843 A1 WO2000027843 A1 WO 2000027843A1 US 9926411 W US9926411 W US 9926411W WO 0027843 A1 WO0027843 A1 WO 0027843A1
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WO
WIPO (PCT)
Prior art keywords
nitrophenyl
hydrazinocarbonyl
ethyl
benzamide
dimethylphenyl
Prior art date
Application number
PCT/US1999/026411
Other languages
English (en)
Inventor
Dashyant Dhanak
Michael G. Darcy
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 WO2000027843A1 publication Critical patent/WO2000027843A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/34—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a carbon skeleton further substituted by nitrogen atoms

Definitions

  • the present invention relates to the use of acyl hydrazine derivatives, and pharmaceutical compositions containing these compounds as Chemokine/CCR-3 receptor antagonists.
  • Chemokines are a superfamily of small secreted proteins. There are approximately 30 distinct 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.
  • 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. The mechanisms responsible for the selective infiltration of eosinophils in allergic diseases have yet to be clarified.
  • Eotaxin a CC chemokine
  • Eotaxin A Potent Eosinophil Chemoattractant Cytokine Detected in Guinea Pig Model of Allergic Airways Inflammation, J. Exp. Med., 179, 881- 887 (1994); and Jose, et al., Eotaxin: Cloning of an Eosinophil Chemoattractant Cytokine and Increased mRNA Expression in Allergen-challenged Guinea-pig Lungs, Biochem. Biophys. Res. Comm..
  • 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
  • Monoclonal antibodies raised to the CCR-3 receptor demonstrate that the receptor is primarily restricted to eosinophils and a subset of Th2 T- cells This restricted expression on eosinophils and T-cells may be responsible for the selective recruitment of eosinophils and Th2 T-cells in allergic inflammation
  • CCR-3 is potently activated by eotaxin 1 , eotaxin and MCP-4 See Stellato et al , Production of the Novel CC Chemokine MCP-4 by Airway Cells and Comparison of Its Biological Activity to other CC-Chemokines J Chn Invest 99 926-936 ( 1997) In
  • 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, eczema, nasal polyposis, conjunctivitis, atopic dermatitis, inflammatory bowel disorder and pru ⁇ tis SUMMARY OF THE INVENTION
  • the present invention involves acyl hydrazine derivatives represented by Formula (I) hereinbelow and their use as CCR-3 receptor antagonists which is useful in the treatment of a variety of diseases associated with allergic disorders, including but not limited to bronchial asthma, eczema, allergic rhinitis, conjunctivitis, nasal polyposis, atopic dermatitis, pruritis and inflammatory bowel disease.
  • diseases associated with allergic disorders including but not limited to bronchial asthma, eczema, allergic rhinitis, conjunctivitis, nasal polyposis, atopic dermatitis, pruritis and inflammatory bowel disease.
  • the present invention further provides methods for antagonizing CCR-3 receptors in an animal, including humans, which comprises administering to a subject in need of treatment an effective amount of a compound of Formula (I) as indicated hereinbelow.
  • A represents hydrogen, C j _ alkyl, alkylaryl, arylalkyl, aryl, or heteroaryl;
  • B represents hydrogen, or C j_g alkyl; or A and B together form a 5 or 6-membered carbocyclic ring;
  • X represents aryl or heteroaryl;
  • Y represents aryl or heteroaryl.
  • alkyl refers to an optionally substituted hydrocarbon group joined together by single carbon-carbon bonds.
  • the alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated.
  • the group is linear.
  • the group is unsubstituted.
  • the group is saturated.
  • Preferred alkyl moieties are C j _4 alkyl, most preferably methyl.
  • aryl refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems.
  • Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. Preferred aryl moieties are phenyl or naphthyl, unsubstituted, monosubstituted, disubstituted or tri substituted.
  • Preferred heteroaryl moieties are selected from the group consisting of unsubstituted, monosubstituted, disubstituted or trisubstituted thienyl, quinolinyl, and pyridinyl and indolyl.
  • Preferred compounds useful in the present invention are selected from the group consisting of:
  • the most preferred compounds useful in the present invention include: (S)-N- [ 1 -(N'-Pheny 1-hydrazinocarbony l)-2-(4-nitropheny l)ethy 1 ]- 1 -naphthamide; and
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated to be within the scope of the present invention.
  • Suitable N-protecting groups include but are not limited to tert-butyloxycarbonyl (t-BOC) and benzyloxycarbonyl (CBZ).
  • t-BOC tert-butyloxycarbonyl
  • CBZ benzyloxycarbonyl
  • treatment includes, but is not limited to prevention, retardation and prophylaxis of the disease.
  • the present compounds are useful for the treatment of diseases including but not limited to bronchial asthma, eczema, allergic rhinitis, conjunctivitis, nasal polyposis, atopic dermatitis, pruritis and inflammatory bowel disease.
  • Compounds of Formula (I) and their 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 Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules, creams 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. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used.
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • 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 a compound of Formula (I) 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 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- 400 mg and preferably 10 to 200 mg per person.
  • a topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I).
  • the daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula(I) 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 a compound of Formula (I) 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.
  • 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 (5xl0cc), 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 infltration.
  • 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.
  • a compound of Formula I (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • Example 14 A compound of Formula I, (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.
  • Example 15 Parenteral Formulation A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of Formula I 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

Antagonistes du récepteur CCR-3 et nouvelles méthodes d'utilisation desdits antagonistes.
PCT/US1999/026411 1998-11-09 1999-11-09 Antagonistes du recepteur ccr3-3 WO2000027843A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10771698P 1998-11-09 1998-11-09
US60/107,716 1998-11-09

Publications (1)

Publication Number Publication Date
WO2000027843A1 true WO2000027843A1 (fr) 2000-05-18

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1010691A2 (fr) * 1998-12-17 2000-06-21 Adir Et Compagnie Dérives de l'hydrazide, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
ES2187334A1 (es) * 2001-01-17 2003-06-01 Servier Lab Nuevos derivados de la hidrazida, su procedimiento de preparacion y las composiciones farmaceuticas que los contienen.
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
EP2546234A1 (fr) 2004-09-13 2013-01-16 Ono Pharmaceutical Co., Ltd. Dérivés hétérocycliques azotés et médicament le contenant comme ingrédient actif
US10117931B2 (en) 2009-04-28 2018-11-06 Kameran Lashkari Methods for treatment of age-related macular degeneration

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS MUZAROV ET AL.: "New Analogs of Thyrotropin-Releasing Factor" *
KHIM. FARM. ZH., vol. 21, no. 11, December 1987 (1987-12-01), pages 1310 - 1313 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1010691A3 (fr) * 1998-12-17 2002-06-19 Les Laboratoires Servier Dérives de l'hydrazide, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
EP1010691A2 (fr) * 1998-12-17 2000-06-21 Adir Et Compagnie Dérives de l'hydrazide, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
US7560548B2 (en) 2000-09-29 2009-07-14 Glaxo Group Limited Morpholin-acetamide derivatives for the treatment of inflammatory diseases
US7101882B2 (en) 2000-09-29 2006-09-05 Glaxo Group Limited Morpholin-acetamide derivatives for the treatment of inflammatory diseases
ES2187334A1 (es) * 2001-01-17 2003-06-01 Servier Lab Nuevos derivados de la hidrazida, su procedimiento de preparacion y las composiciones farmaceuticas que los contienen.
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
EP2546234A1 (fr) 2004-09-13 2013-01-16 Ono Pharmaceutical Co., Ltd. Dérivés hétérocycliques azotés et médicament le contenant comme ingrédient actif
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
US10117931B2 (en) 2009-04-28 2018-11-06 Kameran Lashkari Methods for treatment of age-related macular degeneration

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