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WO2000053172A1 - Antagonistes du récepteur ccr-3 - Google Patents

Antagonistes du récepteur ccr-3 Download PDF

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Publication number
WO2000053172A1
WO2000053172A1 PCT/US2000/005911 US0005911W WO0053172A1 WO 2000053172 A1 WO2000053172 A1 WO 2000053172A1 US 0005911 W US0005911 W US 0005911W WO 0053172 A1 WO0053172 A1 WO 0053172A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
nitrophenyl
naphthoylamino
propionamide
amino
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/US2000/005911
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English (en)
Inventor
Dashyant Dhanak
Steven D. Knight
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SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of WO2000053172A1 publication Critical patent/WO2000053172A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/76—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/42—Y being a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the use of ketone and amide 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.
  • 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. Biophys. Res. Comm., 205, 788- 794 (1994).
  • the human homologue of Guinea-pig eotaxin has been expressed and has been shown to induce eosinophil infiltration when injected into the skin of the rhesus monkey.
  • 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.
  • CCR-3 is potently activated by eotaxin 1, eotaxin and MCP-4.
  • eotaxin 1 eotaxin 1
  • MCP-4 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 ketone derivatives represented by Formulas (I) and (II) 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) or (II) as indicated hereinbelow.
  • R ⁇ and R2 are, independently, selected from the group consisting of hydrogen
  • X represents optionally substituted aryl or heteroaryl;
  • Y represents optionally substituted aryl or heteroaryl
  • C represents NR1 R2
  • B represents hydrogen, methyl, aryl, alkylaryl or arylalkyl
  • F represents hydrogen, C ⁇ .galkyl or aryl.
  • A is selected from the group consisting of O-phenyl, NH-phenyl,
  • C is selected from the group consisting of NH-phenyl, N(CH3)- phenyl and NH-(3-pyridinyl).
  • F is selected from hydrogen or CH3.
  • 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 ⁇ .A 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 trisubstituted.
  • Preferred heteroaryl moieties are selected from the group consisting of unsubstituted, monosubstituted, disubstituted or trisubstituted thienyl, quinolinyl, indolyl and pyridinyl.
  • Preferred compounds of formula (I) useful in the present invention are selected from the group consisting of: l-Phenoxy-3-(S)-(N-(l-naphthoyl)amino)-4-(4-nitrophenyl)-2-butanone; l-Mercaptophenyl-3-(S)-(N-(l-naphthoyl)amino)-4-(4-nitrophenyl)-2-butanone; l-Sulfonylphenyl-3-(S)-(N-(l-naphthoyl)amino)-4-(4-nitrophenyl)-2-butanone; and l-Phenylamino-3-(S)-(N-(l-naphthoyl)amino)-4-(4-chlorophenyl)-2-butanone.
  • Preferred compounds of formula (II) useful in the present invention are selected from the group consisting of:
  • a particularly preferred compound is (S)-2-[2-(l-naphthoylamino)-3-(4- nitrophenyl)propionylamino]-(N-phenyl)acetamide.
  • compositions of the present invention are pharmaceutically acceptable salt complexes.
  • Preferred are the ethylene diamine, sodium, potassium, calcium ethanolamine, hydrochloride, hydrobromide and trifluoroacetate salts.
  • 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.
  • Compounds of the present claim of formula (I) are readily prepared by conventional alkylation methods well known to those skilled in the art and are exemplified by Scheme 1 below:
  • 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 (II) 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 (II) 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.
  • 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 a compound of Formula
  • 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 (II) 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) or (II).
  • 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 (II) 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 (II) 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.
  • the following examples are illustrative but noflimiting of the embodiments of the present invention.
  • Example 1 l-Phenoxy-3-(S)-(N-(l-naphthoyl)amino)-4-(4-nitrophenyl)-2-butanone a) l-Bromo-3-(S)-(N- ?
  • Methylmorpholine (l.lg, 10.6 mmol) was added followed by isobutyl chloroformate (1.44g, 10.6 mmol) at a rate such that the temperature did not exceed -25°C.
  • dry ether 25 mL was added while cooling the reaction to -70°C.
  • the mixture was filtered under argon and the filtrate treated with an ethereal solution of diazomethane (40 mmol). The mixture was allowed to warm to room temperature over lh and stirred for an additional 2 hours. Excess diazomethane was purged with nitrogen, the solution evaporated and the residue taken up in ethyl acetate (50 mL).
  • the solid (0.2g, 0.48mmol) was treated with 0.5ml 4N HCI in dioxane and stirred at room temperature for 30 min. The solution was evaporated in vacuo, and the resulting solid was washed with diethyl ether to furnish the title product (0.15g, 89%) as a white solid.
  • Example 3 l-Sulfonylphenyl-3-(S)-(N-(l-naphthoyl)amino)-4-(4-nitrophenyl)-2-butanone 1 -Mercaptophenyl-3-(S)-(N-( 1 -naphthoyl)amino)-4-(4-nitrophenyl)-2-butanone (60mg, 0.13mmol) was dissolved in THF and treated with peracetic acid (0.07ml, 0.29mmol). The reaction mixture was stirred at room temperature for 16hrs.
  • N-BOC-Gly-OH 500mg, 2.9mmol was dissolved in THF (lOmL) and the solution cooled to -25°C before the addition of N-methylmorpholine (0.58g, 5.8mmol) and isobutylchloroformate (0.43g, 3. lmmol). After stirring for 10 min, aniline (0.29g, 2.9mmol) was added and the reaction mixture was warmed to room temperature over 1 hr. Solids were removed, the filtrate was evaporated to dryness and the residue was dissolved in ethyl acetate (20mL). The solution was washed with water, dried (MgSO4) and evaporated to yield a white solid (0.5g, 70%).
  • Example 9 (S),(S)-2-[2-(l-Naphthoylamino)-3-(4-chlorophenyl)propionylamino]-N-(3- pyridyl)propionamide a) (S)-2-Amino-N-(3-pyridyl)propionamide dihydrochloride Using the procedure of Example 1(a) above, N-BOC-L-Ala-OH was converted into the title compound in 68% yield. MS (ES+) m/e 166 [M+H]+, 207 [M+H+CH 3 CN]+.
  • 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) or (II), (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • Active ingredient 40 mg (Cpd of Form. I or II)
  • 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 a compound of Formula (I) or (II) 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des antagonistes du récepteur CCR-3 ainsi que leurs nouvelles méthodes d'utilisation.
PCT/US2000/005911 1999-03-08 2000-03-08 Antagonistes du récepteur ccr-3 Ceased WO2000053172A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US12323299P 1999-03-08 1999-03-08
US12324599P 1999-03-08 1999-03-08
US60/123,245 1999-03-08
US60/123,232 1999-03-08

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002059081A3 (fr) * 2001-01-26 2003-01-09 Janak Padia Derives d'uree en tant qu'inhibiteurs du recepteur ccr-3
US6875884B1 (en) 1999-07-28 2005-04-05 Kirin Beer Kabushiki Kaisha Urea derivatives as inhibitors for CCR-3 receptor
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
CN105461662A (zh) * 2014-08-31 2016-04-06 复旦大学 一种抗hiv药物中间体的手性环氧化合物的合成方法
US10117931B2 (en) 2009-04-28 2018-11-06 Kameran Lashkari Methods for treatment of age-related macular degeneration
WO2018209132A1 (fr) * 2017-05-10 2018-11-15 Cortexyme, Inc. Composés aminopyridine et procédés pour leur préparation et leur utilisation

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US4636522A (en) * 1985-03-22 1987-01-13 E. R. Squibb & Sons, Inc. Acylaminoalkanoyl urethanes or thiourethanes

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
US4514391A (en) * 1983-07-21 1985-04-30 E. R. Squibb & Sons, Inc. Hydroxy substituted peptide compounds
US4636522A (en) * 1985-03-22 1987-01-13 E. R. Squibb & Sons, Inc. Acylaminoalkanoyl urethanes or thiourethanes

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6875884B1 (en) 1999-07-28 2005-04-05 Kirin Beer Kabushiki Kaisha Urea derivatives as inhibitors for CCR-3 receptor
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
WO2002059081A3 (fr) * 2001-01-26 2003-01-09 Janak Padia Derives d'uree en tant qu'inhibiteurs du recepteur ccr-3
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
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