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EP1076557A1 - Ccr-3 receptor antagonists - Google Patents

Ccr-3 receptor antagonists

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Publication number
EP1076557A1
EP1076557A1 EP99920102A EP99920102A EP1076557A1 EP 1076557 A1 EP1076557 A1 EP 1076557A1 EP 99920102 A EP99920102 A EP 99920102A EP 99920102 A EP99920102 A EP 99920102A EP 1076557 A1 EP1076557 A1 EP 1076557A1
Authority
EP
European Patent Office
Prior art keywords
propionate
ethyl
hydroxyphenyl
sulfonylamino
group
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.)
Withdrawn
Application number
EP99920102A
Other languages
German (de)
French (fr)
Inventor
Dashyant Dhanak
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 EP1076557A1 publication Critical patent/EP1076557A1/en
Withdrawn legal-status Critical Current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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of phenylalanine sulfonamide derivatives, and pharmaceutical compositions containing these compounds as Chemok ⁇ ne/CCR-3 receptor antagonists
  • Chemokines are a superfamily of small secreted proteins There are approximately 30 distinct chemokines known with many others being characte ⁇ zed See Oppenheim et al , Properties of the Novel Promflammatory Supergene "Interc ⁇ ne” Cytokine Family. Ann Rev Immun , 9, 617- 648 (1991), and Baggiolini, et al , Interleuk ⁇ n-8 and Related Chemotactic Cytokmes-CXC and CC Chemokines, Ad ⁇ Immun .
  • Eosinophils are promflammatory granulocytes that play a major role in allergic diseases, such as bronchial asthma, allergic rhinitis, pru ⁇ tis and atopic dermatitis Upon activation, eosinophils release hpid 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 eosmophil-specific products in inflamed tissues in human diseases
  • Eotaxm a CC chemokine
  • T e human homologue of Guinea-pig eotaxm has been expressed and has been shown to induce eosmophil infiltration when injected into the skin of the rhesus monkey See Ponath, et al , Cloning of the Human Eosmophil Chemoattractant, Eotaxin Expression, Receptor Binding, and Functional Properties Suggest a Mechanism for Selective Recruitment of Eosinophils, J_ Chn Invest . 97, 604-612 (1996)
  • 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. Additionally, CCR-3 is potently activated by eotaxin 1, eotaxin and MCP-4.
  • chemokines appear to activate more than one chemokine receptor, e.g. RANTES binds to CCR- 1 , CCR-3, CCR-4 and CCR-5 receptors.
  • 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 pruritis.
  • the present invention involves phenylalanine sulfonamide 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.
  • 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.
  • R j represents substituted or unsubstituted alkyl, aryl or heteroaryl; and R2 is selected from the group consisting of 4-OH, 4-(2,5-Cl2-Ph)0, and 4-(2.4-F 2 -Ph)0.
  • Preferred alkyl moieties are C1.4 alkyl. most preferably methyl.
  • Preferred aryl moieties are phenyl or naphthyl, unsubstituted, monosubstituted, disubstituted or trisubstituted.
  • Preferred heteroaryl moieties are selected from the group consisting of unsubstituted. monosubstituted, disubstituted or trisubstituted thienyl, quinolinyl, and pyrazolyl.
  • alkyl substituents are methyl. More preferably, halo substituents are chloro or bromo.
  • Preferred compounds useful in the present invention are selected from the group consisting of:
  • More preferred compounds useful in the present invention include:
  • the most preferred compounds useful in the present invention include:
  • compositions of the present invention are pharmaceutically acceptable salt complexes.
  • Preferred are the ethylene diamine, sodium, potassium, calcium and ethanolamine salts.
  • the compounds of the present invention may contain one or more
  • compounds of the present invention are represented by the following structure:
  • the present compounds can be prepared by the using the overall strategies provided hereinbelow. Such strategies are readily found in the art. See e.g. Comprehensive Organic Transformations. R.C. Larock, VCH Publishers, 1989, 772 (and references therein); and Organic chemistry, Vol. 1 : 1. L. Finar, Longman Group, 1973, 406.
  • 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.
  • 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 mtranasal 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 mtranasal 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 pu ⁇ fied 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 m binding buffer (RPMI-1640 + 25mM Hepes + 0 1% Gelatin + 0 1% sodium azide + 00087c CHAPS) Into a 96 well plate (Dynatek) 200,000 eosinophils, 0.25 nM 1251-Eotax ⁇ n (Amersham Pic), and compound of interest ( 1 nM to 100 uM) was added.
  • RPMI-1640 + 25mM Hepes + 0 1% Gelatin + 0 1% sodium azide + 00087c CHAPS Into a 96 well plate (Dynatek) 200,000 eosinophils, 0.25 nM 1251
  • Bound from free 1251-eotaxm 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
  • 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
  • EXAMPLE 2 Inhalant Formulation 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.
  • 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.

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  • Ophthalmology & Optometry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

CCR-3 receptor antagonists and novel methods for their use are provided.

Description

CCR-3 RECEPTOR ANTAGONISTS FIELD OF THE INVENTION
The present invention relates to the use of phenylalanine sulfonamide derivatives, and pharmaceutical compositions containing these compounds as Chemokιne/CCR-3 receptor antagonists
Chemokines are a superfamily of small secreted proteins There are approximately 30 distinct chemokines known with many others being characteπzed See Oppenheim et al , Properties of the Novel Promflammatory Supergene "Intercπne" Cytokine Family. Ann Rev Immun , 9, 617- 648 (1991), and Baggiolini, et al , Interleukιn-8 and Related Chemotactic Cytokmes-CXC and CC Chemokines, Ad\ 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 See Kita et al , Chemokines Active on Eosinophils Potential Roles in Allergic Inflammation, J_ Exp_ ed . 183, 2421 -2426 ( 1996) , Stπeter et al "The Good, the Bad and the Ugly" The Role of Chemokines in Models of Human Diseases, J_ Immun . 157, 3583-3586 (1996), and Baggiolini, Eotaxm a VIC (Very Important Chemokine) of Allergic Inflammation, J_ Chn Invest . 97, 587 (1996)
Chemokines mediate their effects via interactions with 7TM-G-protem coupled receptors on the surface of immune and inflammatory cells Eosinophils are promflammatory granulocytes that play a major role in allergic diseases, such as bronchial asthma, allergic rhinitis, pruπtis and atopic dermatitis Upon activation, eosinophils release hpid 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 eosmophil-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 Recently, a CC chemokine, Eotaxm, was identified in guinea pigs and demonstrated to be present in a guinea pig model of allergic airway inflammation See Jose, et al , Eotaxm A Potent Eosmophil Chemoattractant Cytokine Detected in Guinea Pig Model of Allergic Airways Inflammation, J_ Exp Med , 179, 881-887 (1994), and Jose, et al , Eotaxm Cloning of an Eosmophil Chemoattractant Cytokine and Increased mRNA Expression in Allergen-challenged Guinea-pig Lungs. Biochem Biophys Res Comm . 205. 788-794 (1994) T e human homologue of Guinea-pig eotaxm has been expressed and has been shown to induce eosmophil infiltration when injected into the skin of the rhesus monkey See Ponath, et al , Cloning of the Human Eosmophil Chemoattractant, Eotaxin Expression, Receptor Binding, and Functional Properties Suggest a Mechanism for Selective Recruitment of Eosinophils, J_ Chn Invest . 97, 604-612 (1996)
- 1 - The cloning, expression and characterization of a novel C-C chemokine receptor, designated CCR-3 from peripheral blood eosinophils and from an eosinophil cDNA library have also been reported. See Kitaura, et al., Molecular Cloning of Human Eotaxin, an Eosinophil-selective CC Chemokine, and Identification of a Specific Eosinophil Eotaxin Receptor, CC Chemokine Receptor 3, J. Biol. Chem.. 271, 7725-7730 (1996); Ahuja, et al., Cloning and Functional Expression of a
Human Eosinophil CC Chemokine Receptor. J. Biol. Chem.. 270, 16491-16494 (1995); Daugherty, et al., Cloning, Expression and Characterization of the Human Eosinophil Eotaxin Receptor, L Exp. Med. 183. 2349-2354 (1996); and Ponath, et al., Molecular Cloning and Characterization of a Human Eotaxin Receptor Expressed Selectively on Eosinophils, J. Exp. Med.. 183, 2437-2448 (1996). Eotaxin. MCP-4 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. 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. Additionally, 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. Clin. Invest. 99 926-936 (1997). In contrast, other known chemokines appear to activate more than one chemokine receptor, e.g. RANTES binds to CCR- 1 , CCR-3, CCR-4 and CCR-5 receptors.
The foregoing research advances have provided the impetus to investigate the inhibition of eosinophil-specific chemokines in order to examine its role in blocking cellular infiltration in inflamed tissues. 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 pruritis.
SUMMARY OF THE INVENTION
The present invention involves phenylalanine sulfonamide 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.
2 - 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.
DETAILED DESCRIPTION OF THE INVENTION
The compounds useful in the present methods are selected from Formula (I) hereinbelow:
Formula (I) wherein Rj represents substituted or unsubstituted alkyl, aryl or heteroaryl; and R2 is selected from the group consisting of 4-OH, 4-(2,5-Cl2-Ph)0, and 4-(2.4-F2-Ph)0.
Preferred alkyl moieties are C1.4 alkyl. most preferably methyl.
Preferred aryl moieties are phenyl or naphthyl, unsubstituted, monosubstituted, disubstituted or trisubstituted. Preferred heteroaryl moieties are selected from the group consisting of unsubstituted. monosubstituted, disubstituted or trisubstituted thienyl, quinolinyl, and pyrazolyl. Preferred aryl and heteroaryl substituents are selected from the group consisting of Cj_4 alkyl, NCμ 4 alkyl, halo. OC1.4 alkyl, CH=CH, CF3, pyridine, phenyl, N02 and MeO.
More preferably, alkyl substituents are methyl. More preferably, halo substituents are chloro or bromo.
Preferred compounds useful in the present invention are selected from the group consisting of:
(S)-Ethyl-2-(4-methylbenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate; (S)-Ethyl-2-(5-dimethylaminonaphthalene- l-sulfonylamino)-3-(4-hydroxy-phenyl)propionate; (S)-Ethyl-2-(naphthalene-2-sulfonylamino)-3-(4-hydroxyphenyl)propionate; (S)-Ethyl-2-(thiophene-2-sulfonylamino)-3-(4-hydroxyphenyl)propionate; (S)-Ethyl-2-(quinoline-8-sulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-(2,4.6-trimethylbenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate; (S)-Ethyl-2-(4-bromobenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate; (S)-Ethyl-2-(4- chlorobenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-(4-methoxybenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate; (S)-Ethyl-2- methanesulfonylamino-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-[2-(E)-styrylsulfonylamino]-3-(4-hydroxyphenyl)propionate;
- 3 - (S)-Ethyl-2-(3-trifluoromethylbenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-(2,5-dichlorothiophene-3-sulfonylamino)-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-(2-bromobenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-[5-(2-pyridyl)thiophene-2-sulfonylamino]-3-(4-hydroxyphenyl) propionate; (S)-Ethyl-2-(l,3-dimethyl-5-chloro-2-pyrazolin-4-sulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-(4-biphenylsulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-(2-nitro-4-methoxybenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-(2,5-dichlorobenzenesulfonylamino)-3-[4-(2,5-dichlorobenzene- sulfonyloxy)phenyl]propionate; and (S)-Ethyl-2-(2,4-difluorobenzenesulfonylamino)-3-[4-(2,4-difluorobenzene- sulfonyloxyphenyl)]propionate.
More preferred compounds useful in the present invention include:
(S)-Ethy l-2-(5-dimethy laminonaphthalene- 1 -sulf ony lamino)-3-(4-hydroxy-pheny l)propionate ;
(S)-Ethyl-2-(thiophene-2-sulfonylamino)-3-(4-hydroxyphenyl)propionate; (S)-Ethy l-2-(2,4.6-trimethy lbenzenesulfony lamino)-3-(4-hydroxypheny 1) propionate ;
(S)-Ethyl-2-(4-bromobenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate; (S)-Ethyl-2-(4- chlorobenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-(4-methoxybenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-[2-(E)-styrylsulfonylamino]-3-(4-hydroxyphenyl)propionate; (S)-Ethyl-2-(3-trifluoromethylbenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-(2,5-dichlorothiophene-3-sulfonylamino)-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-(2-bromobenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-[5-(2-pyridyl)thiophene-2-sulfonylamino]-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-(2-nitro-4-methoxybenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate; and (S)-Ethyl-2-(2,5-dichlorobenzenesulfonylamino)-3-[4-(2,5-dichlorobenzene- sulfonyloxy)phenyl]propionate.
The most preferred compounds useful in the present invention include:
(S)-Ethyl-2-(2,5-dichlorothiophene-3-sulfonylamino)-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-(2-bromobenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate; and (S)-Ethyl-2-(2,5-dichlorobenzenesulfonylamino)-3-[4-(2,5-dichlorobenzene- sulfonyloxy)phenyl]propionate.
Also included in the present invention are pharmaceutically acceptable salt complexes. Preferred are the ethylene diamine, sodium, potassium, calcium and ethanolamine salts. The compounds of the present invention may contain one or more
- 4 - 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. Preferably, compounds of the present invention are represented by the following structure:
The present compounds can be prepared by the using the overall strategies provided hereinbelow. Such strategies are readily found in the art. See e.g. Comprehensive Organic Transformations. R.C. Larock, VCH Publishers, 1989, 772 (and references therein); and Organic chemistry, Vol. 1 : 1. L. Finar, Longman Group, 1973, 406.
Compounds of formula I are readily prepared by conventional sulfonylation methods well known to those skilled in the art and are exemplified in Scheme 1 below:
SCHEME 1
HO
A: 4-Me-Ph-S02Cl, Na2C03, CHC13, H20
With appropriate manipulation and protection of any chemical functionality, synthesis of the remaining compounds of Formula (I) is accomplished by methods analogous to those above and to those described in the Experimental section.
In order to use a compound of the Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
As used herein, "treatment" of a disease 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.
- 5 - 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.
Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the 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. Where the 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.
Typical 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.
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.
Preferably 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 mtranasal 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 mtranasal 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
No unacceptable toxicological effects are expected when compounds of the present invention are administered accordance with the present invention
The biological activity of the compounds of Formula (I) are demonstrated by the following test.
Human eosinophils were puπfied 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 m binding buffer (RPMI-1640 + 25mM Hepes + 0 1% Gelatin + 0 1% sodium azide + 00087c CHAPS) Into a 96 well plate (Dynatek) 200,000 eosinophils, 0.25 nM 1251-Eotaxιn (Amersham Pic), and compound of interest ( 1 nM to 100 uM) was added. This mixture of cells compound and ligand was allowed to incubate for 60 mm at room temperature before harvesting For harvesting, free ligand from bound ligand was separated over a Packard Umfιlter-96 GFC, (cat #6005174) which had been pre-blocked with 1% polyethylemmme (Sigma Cat # P3143) and 1% Bovine Serum Albumin (BSA) for 2 hours pπor to use. After drying, and sealing the plate with Topseal (Packard Topseal A Cat # 6005185) 50 ul of MicroScint (Packard Mιcroscιnt-20 Cat # 6013621) was added to each well. Bound from free 1251-eotaxm 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
- 7 - the number of counts (CPM) associated with the compound treated sample as a percent of the control binding in the absence of compound addition.
Animal model for the in vivo evaluation of CCR-3 antagonists Guinea pig bronchoalveolar lavage (BAL) model (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. Alternatively, 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.
The following examples are illustrative but not limiting of the embodiments of the present invention. EXAMPLE 1
(S)-Ethyl-2-(4-methylbenzenesulfonylamino)-3-(4-hvdroxyphenyl)propionate L-Tyrosine ethyl ester (0.30g, 1.42 mmol) was dissolved in CHCI3 (5 mL). A solution of Na2CC>3 (1 eq, 1.42 mmol, 0.15g) in 1 mL H20 was added and the mixture was allowed to stir vigorously, p- Toluenesulfonyl chloride ( 1 eq, 1.42 mmol, 0.27g) was then added and the mixture was allowed to stir vigorously for 3.5 hours. An additional 2 eq Na Cθ3 in 2 mL H20 was added over the next few hours and the mixture was allowed to stir for three days. The mixture was then partitioned between CH2C1 and H20. The organic portion was separated and the aqueous portion washed again with CH2C12. The combined organic portions were dried over MgSθ4, filtered, and concentrated to a pale yellow oil (0.44g, 85%). MS (ES+) m/e 363 [M]+, 385 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.
EXAMPLE 2 Inhalant Formulation 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 3
Tablet Formulation
Tablets/Ingredients Per Tablet
1. Active ingredient 40 mg
(Cpd of Form. I)
2. Corn Starch 20 mg
3. Alginic acid 20 mg
4. Sodium Alginate 20 mg
5. Mg stearate 1.3 mg
Procedure for tablet formulation:
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 4
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.
9 -

Claims

What is claimed is:
1. A method of antagonizing a CCR-3 receptor by administering a compound selected from
Formula (I) hereinbelow:
Formula (I)
wherein Rj is selected from the group consisting of substituted or unsubstituted alkyl, aryl and heteroaryl; and R2 is selected from the group consisting of 4-OH, 4-(2,5-Cl2-Ph)0, and 4-(2,4-F2-Ph)0.
2. A method according to claim 1 wherein the compound is selected from Formula (II) hereinbelow:
Formula (II); any aryl or heteroaryl moieties are selected from the group consisting of unsubstituted, monosubstituted. disubstituted or trisubstituted phenyl, naphthyl, thienyl, quinolinyl, and pyrazolyl; and any alkyl moieties are C1.4 alkyl.
3. A method according to claim 2 wherein any alkyl moieties are methyl.
4. A method according to claim 2 wherein any aryl or heteroaryl substituents are selected from the group consisting of Cj_4 alkyl, NC]_4 alkyl, halo, OC╬╣ _4 alkyl, CH=CH, CF3, pyridine, phenyl, N0 and MeO.
5. A method according to claim 1 wherein the compound is selected from the group consisting of:
(S)-Ethyl-2-(4-methylbenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate; (S)-Ethyl-2-(5-dimethylaminonaphthalene-l-sulfonylamino)-3-(4-hydroxy-phenyl)propionate; (S)-Ethyl-2-(naphthalene-2-sulfonylamino)-3-(4-hydroxyphenyl)propionate; (S)-Ethyl-2-(thiophene-2-sulfonylamino)-3-(4-hydroxyphenyl)propionate;
10 - (S)-Ethyl-2-(quinoline-8-sulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-(2,4,6-trimethylbenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-(4-bromobenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-(4-chlorobenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate; (S)-Ethyl-2-(4-methoxybenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-methanesulfonylamino-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-[2-(E)-styrylsulfonylamino]-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-(3-trifluoromethylbenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-(2,5-dichlorothiophene-3-sulfonylamino)-3-(4-hydroxyphenyl) propionate; (S)-Ethyl-2-(2-bromobenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-[5-(2-pyridyl)thiophene-2-sulfonylamino]-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-(l,3-dimethyl-5-chloro-2-pyrazolin-4-sulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-(4-biphenylsulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-(2-nitro-4-methoxybenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate; (S)-Ethyl-2-(2,5-dichlorobenzenesulfonylamino)-3-[4-(2,5-dichlorobenzene- sulfonyloxy)phenyl]propionate; and
(S)-Ethyl-2-(2,4-difluorobenzenesulfonylamino)-3-[4-(2,4-difluorobenzene- sulfonyloxyphenyl)]propionate.
6. A method according to claim 5 wherein the compound is selected from the group consisting of:
(S)-Ethyl-2-(5-dimethylaminonaphthalene-l-sulfonylamino)-3-(4-hydroxy-phenyl)propionate;
(S)-Ethyl-2-(thiophene-2-sulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-(2,4,6-trimethylbenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-(4-bromobenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate; (S)-Ethyl-2-(4-chlorobenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-(4-methoxybenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-[2-(E)-styrylsulfonylamino]-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-(3-trifluoromethylbenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-(2,5-dichlorothiophene-3-sulfonylamino)-3-(4-hydroxyphenyl) propionate; (S)-Ethyl-2-(2-bromobenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate;
(S)-Ethyl-2-[5-(2-pyridyl)thiophene-2-sulfonylamino]-3-(4-hydroxyphenyl) propionate;
(S)-Ethyl-2-(2-nitro-4-methoxybenzenesulfonylamino)-3-(4-hydroxyphenyl) propionate; and
(S)-Ethyl-2-(2,5-dichlorobenzenesulfonylamino)-3-[4-(2,5-dichlorobenzene- sulfonyloxy)phenyl]propionate.
- 11 -
7. A method according to claim 6 wherein the compound is selected from the group consisting of:
(S)-Ethyl-2-(2,5-dichlorothiophene-3-sulfonylamino)-3-(4-hydroxyphenyl) propionate; (S)-Ethyl-2-(2-bromobenzenesulfonylamino)-3-(4-hydroxyphenyl)propionate; and (S)-Ethyl-2-(2,5-dichlorobenzenesulfonylamino)-3-[4-(2,5-dichlorobenzene- sulfonyloxy)phenyl]propionate.
8. A method of treating an allergic disease comprising administering to a patient in need of treatment a safe and effective amount of a compound according to formula (I) below:
Formula (I) wherein R\ is selected from the group consisting of substituted or unsubstituted alkyl, aryl and heteroaryl; and
R2 is selected from the group consisting of 4-OH, 4-(2,5-cl2-ph)0 and 4-(2,4-F2-ph)0.
9. A method according to claim 8 wherein the disease is selected from the group consisting of bronchial asthma, eczema, conjunctivitis, allergic rhinitis, nasal polyposis, atopic dermatitis, pruritis and inflammatory bowel disease.
- 12
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Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000041685A1 (en) * 1999-01-19 2000-07-20 Smithkline Beecham Corporation Ccr-3 receptor antagonists
US7101882B2 (en) 2000-09-29 2006-09-05 Glaxo Group Limited Morpholin-acetamide derivatives for the treatment of inflammatory diseases
ATE517884T1 (en) 2001-04-27 2011-08-15 Mitsubishi Tanabe Pharma Corp 3,4-DIHALOBENSYLPIPERIDINE DERIVATIVES AND THEIR MEDICAL USE
JP2003081937A (en) * 2001-09-07 2003-03-19 Bayer Ag Benzenesulfonamide derivative
EP2161254B1 (en) 2002-03-05 2014-08-13 Sumitomo Chemical Company, Limited Intermediate for preparing a biaryl compound
SE0200843D0 (en) 2002-03-19 2002-03-19 Astrazeneca Ab Chemical compounds
EP2399903A1 (en) 2002-05-24 2011-12-28 Millennium Pharmaceuticals, Inc. Ccr9 inhibitors and methods of use thereof
US7420055B2 (en) 2002-11-18 2008-09-02 Chemocentryx, Inc. Aryl sulfonamides
PT1562940E (en) 2002-11-18 2007-07-23 Chemocentryx Inc Aryl sulfonamides
US7741519B2 (en) 2007-04-23 2010-06-22 Chemocentryx, Inc. Bis-aryl sulfonamides
US7227035B2 (en) 2002-11-18 2007-06-05 Chemocentryx Bis-aryl sulfonamides
CA2517888C (en) 2003-03-14 2012-05-01 Ono Pharmaceutical Co., Ltd. Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient
RU2380356C2 (en) 2003-03-24 2010-01-27 Актимис Фармасьютикалз, Инк. Derivatives of 2-phenoxy and 2-phenylsulphonamide with ccr3 antagonistic activity for treating asthma and other inflammatory or immunological diseases
SE0300957D0 (en) 2003-04-01 2003-04-01 Astrazeneca Ab Chemical compounds
JP4710606B2 (en) 2003-04-18 2011-06-29 小野薬品工業株式会社 Spiropiperidine compounds and pharmaceutical uses thereof
WO2006028284A1 (en) 2004-09-08 2006-03-16 Mitsubishi Pharma Corporation Morpholine compound
JP4894518B2 (en) 2004-09-13 2012-03-14 小野薬品工業株式会社 Nitrogen-containing heterocyclic derivatives and drugs containing them as active ingredients
JPWO2006129679A1 (en) 2005-05-31 2009-01-08 小野薬品工業株式会社 Spiropiperidine compounds and pharmaceutical uses thereof
WO2007011293A1 (en) 2005-07-21 2007-01-25 Astrazeneca Ab Novel piperidine derivatives
PT1942108E (en) 2005-10-28 2013-10-24 Ono Pharmaceutical Co Compound containing basic group and use thereof
PT1961744E (en) 2005-11-18 2013-05-15 Ono Pharmaceutical Co Basic group-containing compound and use thereof
WO2007105637A1 (en) 2006-03-10 2007-09-20 Ono Pharmaceutical Co., Ltd. Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient
US8618122B2 (en) 2006-05-16 2013-12-31 Ono Pharmaceutical Co., Ltd. Compound having acidic group which may be protected, and use thereof
WO2008016006A1 (en) 2006-07-31 2008-02-07 Ono Pharmaceutical Co., Ltd. Compound having cyclic group bound thereto through spiro binding and use thereof
WO2010129351A1 (en) 2009-04-28 2010-11-11 Schepens Eye Research Institute Method to identify and treat age-related macular degeneration
CN102892754A (en) 2010-03-17 2013-01-23 埃克希金医药品有限公司 Arylsulfonamide ccr3 antagonists

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09255572A (en) * 1996-03-26 1997-09-30 Takeda Chem Ind Ltd Medicine for antagonizing chemokine receptor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9955324A1 *

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