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WO2000027800A1 - Antagonistes du recepteur ccr-3 - Google Patents

Antagonistes du recepteur ccr-3 Download PDF

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Publication number
WO2000027800A1
WO2000027800A1 PCT/US1999/026382 US9926382W WO0027800A1 WO 2000027800 A1 WO2000027800 A1 WO 2000027800A1 US 9926382 W US9926382 W US 9926382W WO 0027800 A1 WO0027800 A1 WO 0027800A1
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WO
WIPO (PCT)
Prior art keywords
propionamide
phenyl
propionylamino
νaphthoylamino
chlorophenyl
Prior art date
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Ceased
Application number
PCT/US1999/026382
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English (en)
Inventor
Dashyant Dhanak
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Filing date
Publication date
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Publication of WO2000027800A1 publication Critical patent/WO2000027800A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • 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
    • C07D295/04—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 substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—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 substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—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 substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/18—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 acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/66—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to the use of phenylalanine 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.
  • 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.
  • 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 phenylalanine amide 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 OR ] , wherein R ] is selected from the group consisting of hydrogen, C j .
  • R2 is selected from the group consisting of hydrogen, C ⁇ _6 alkyl, arylalkyl, alkylaryl and NH-(optionally substituted aryl); or R ] and
  • R2 together form a 5 or 6-membered ring
  • B represents hydrogen, methyl, optionally substituted aryl, alkylaryl or arylalkyl
  • F represents hydrogen, C j .galkyl, or aryl
  • X represents optionally substituted aryl or heteroaryl
  • Y represents optionally substituted aryl or heteroaryl
  • A is selected from the group consisting of O-tBu, OEt, NHNHPh,
  • NHEt NMe2 NH-aryl, N(CH3)-aryl and NH-(3-pyridinyl) and F is selected from hydrogen or CH3, NHCH2phenyl, piperidinyl and pyrrolidinyl.
  • 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 Cj.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 trisubstituted.
  • Preferred heteroaryl moieties are selected from the group consisting of unsubstituted, monosubstituted, disubstituted or trisubstituted thienyl, quinolinyl, indolyl and pyridinyl.
  • alkyl substituents are methyl or ethyl. More preferably, halo substituents are chloro or bromo.
  • Preferred compounds useful in the present invention are selected from the group consisting of:
  • 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.
  • 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.
  • 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.
  • 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 dichlorodifluoromefhane 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.
  • the biological activity of the compounds of Formula (I) are demonstrated by the following test: Human eosinophils were purified by standard CD 16 cell depletion using a Miltenyi cell separation column and a magnetic Super Macs magnet. Eosinophils which were >95% pure as assessed by DiffQuick staining and light microscopy were washed in PBS and resuspended in binding buffer (RPMI-1640 + 25mM Hepes + 0.1% Gelatin + 0.1% sodium azide + 0.008% CHAPS). Into a 96 well plate (Dynatek) 200,000 eosinophils, 0.25 nM 1251-Eotaxin (Amersham Pic), and compound of interest (1 nM to 100 uM) was added.
  • Bound from free 1251-eotaxin was separated using a Packard Filtermate 196, 96-well plate harvester. To determine total and non-specific binding (NSB) three wells for each condition were set aside. For total binding and NSB, wells received all additions except compound. In addition NSB wells received 200 nM cold eotaxin (PeproTech, Rocky Hill, NJ). Radioactivity associated with the filter was assessed in a Packard Top-count Microplate Scintillation Counter model number 49872V. Percent control binding was assessed by first subtracting the NSB from each well and then expressing the number of counts (CPM) associated with the compound treated sample as a percent of the control binding in the absence of compound addition.
  • CPM number of counts
  • BALs were obtained from Guinea Pigs (+ compound) 24 h after ovalbumin (OA) exposure to eotaxin administered via inhalation.
  • the animals were euthanized by cervical dislocation and exsanguinated.
  • the lungs were lavaged with 50 ml of DulBecco's PBS (5x1 Occ), which was aspirated after a gentle chest massage.
  • the BAL fluid was spun down and the pellet was resuspended in 0.25% NaCl to lyse residual erythrocytes. After centrifugation, the pellet was resuspended again in 0.9% NaCl. After a total cell count, slides were prepared and stained.
  • the cells were differentiated into eosinophils, neutrophils and monocytes by counting a minimum of 200 cells and expressing the results as a percentage of total cells.
  • OA sensitized Guinea Pigs (+ compound) were exposed to OA via inhalation 24 h after OA exposure and lungs were obtained as described above and assessed for eosinophil infltration.
  • Example 1 is illustrative but not limiting of the embodiments of the present invention.
  • Example 3(a) The compound of Example 3(a) (0.05 g, 0.11 mmol) was dissolved in dimethylformamide (1 mL). Phenylhydrazine (0.02 mL, 0.17 mmol) was added, followed by N-methylmorpholine (0.04 mL, 0.33 mmol), HOBT (0.02 g, 0.12 mmol), and EDCI (0.02 g, 0.12 mmol). The mixture was allowed to stir at room temperature for 3 d. Water ( 1 mL) was poured into the flask, and the resulting precipitate was filtered and washed with hexane.
  • 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, 3.1 mmol). 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 (MgS ⁇ 4) and evaporated to yield a white solid (0.5g, 70%).
  • the reaction mixture was diluted with brine and extracted into ethyl acetate.
  • the extracts were washed with brine, dried over sodium sulfate with decolorizing charcoal.
  • Example 14 (S),(S)-2-r2-(l-Naphthoylamino)-3-(4-chlorophenyl)propionylaminol-(N-(2- methoxy)phenyl)propionamide: MS (ES+) m e 530 [M+H] + .
  • Example 15 (S),(S)-2-f2-(l-Naphthoylamino)-3-(4-chlorophenyl)propionylaminol-(N-(4- acetyPphenvPpropionamide: MS (ES+) m/e 542[M+H]+.
  • Example 16
  • Example 3(a) The compound of Example 3(a) (0.11 g, 0.25 mmol) was dissolved in tetrahydrofuran (10 mL). N-methylmorpholine (0.06 mL, 0.50 mmol) was added, followed by isobutylchloroformate (0.04 g, 0.28 mmol). The mixture stirred at -20 °C for 5 min, at which point benzylamine (0.03 mL, 0.28 mmol) was added. The mixture was allowed to warm to room temperature, stirring for 40 min. The precipitate was filtered, and the filtrate was concentrated. The residue was dissolved in ethyl acetate (10 mL) and washed with water (10 mL).
  • 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 33
  • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des antagonistes du récepteur CCR-3 et leurs nouvelles techniques d'utilisation.
PCT/US1999/026382 1998-11-09 1999-11-09 Antagonistes du recepteur ccr-3 Ceased WO2000027800A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10771798P 1998-11-09 1998-11-09
US60/107,717 1998-11-09

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WO2000027800A1 true WO2000027800A1 (fr) 2000-05-18

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7101882B2 (en) 2000-09-29 2006-09-05 Glaxo Group Limited Morpholin-acetamide derivatives for the treatment of inflammatory diseases
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
US7230133B2 (en) * 2003-05-01 2007-06-12 Bristol-Myers Squibb Company Malonamides and malonamide derivatives as modulators of chemokine receptor activity
WO2007105637A1 (fr) 2006-03-10 2007-09-20 Ono Pharmaceutical Co., Ltd. Derive heterocyclique azote et agent pharmaceutique comprenant le derive en tant que principe actif
WO2007132846A1 (fr) 2006-05-16 2007-11-22 Ono Pharmaceutical Co., Ltd. Composé ayant un groupe acide qui peut être protégé et utilisation dudit composé
WO2008016006A1 (fr) 2006-07-31 2008-02-07 Ono Pharmaceutical Co., Ltd. Composé auquel un groupe cyclique est lié par une liaison spiro et son utilisation
EP2364982A1 (fr) 2003-04-18 2011-09-14 ONO Pharmaceutical Co., Ltd. Dérivés de spiropipéridine comme antgonistes du recepteur chémokine et leur usage médical
EP2385040A1 (fr) 2003-03-14 2011-11-09 ONO Pharmaceutical Co., Ltd. Dérivés hétérocycliques renfermant de l'azote et médicaments contenant ces dérivés comme principe actif
US10117931B2 (en) 2009-04-28 2018-11-06 Kameran Lashkari Methods for treatment of age-related macular degeneration
WO2019147182A1 (fr) * 2018-01-29 2019-08-01 Medscienta Ab Agents anti-athérosclérotiques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4025644A (en) * 1974-12-18 1977-05-24 Daiichi Seiyaku Co., Ltd. Tyrosine derivatives and use
US4339534A (en) * 1979-04-06 1982-07-13 De Forenede Bryggerier A/S Process for enzymatic production of peptides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4025644A (en) * 1974-12-18 1977-05-24 Daiichi Seiyaku Co., Ltd. Tyrosine derivatives and use
US4339534A (en) * 1979-04-06 1982-07-13 De Forenede Bryggerier A/S Process for enzymatic production of peptides

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7101882B2 (en) 2000-09-29 2006-09-05 Glaxo Group Limited Morpholin-acetamide derivatives for the treatment of inflammatory diseases
US7560548B2 (en) 2000-09-29 2009-07-14 Glaxo Group Limited Morpholin-acetamide derivatives for the treatment of inflammatory diseases
EP2385040A1 (fr) 2003-03-14 2011-11-09 ONO Pharmaceutical Co., Ltd. Dérivés hétérocycliques renfermant de l'azote et médicaments contenant ces dérivés comme principe actif
EP2364982A1 (fr) 2003-04-18 2011-09-14 ONO Pharmaceutical Co., Ltd. Dérivés de spiropipéridine comme antgonistes du recepteur chémokine et leur usage médical
US7468440B2 (en) 2003-05-01 2008-12-23 Bristol-Myers Squibb Company Malonamides and malonamide derivatives as modulators of chemokine receptor activity
US7230133B2 (en) * 2003-05-01 2007-06-12 Bristol-Myers Squibb Company Malonamides and malonamide derivatives as modulators of chemokine receptor activity
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
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