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WO1999015490A1 - Ligands pour recepteurs de c3a - Google Patents

Ligands pour recepteurs de c3a Download PDF

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Publication number
WO1999015490A1
WO1999015490A1 PCT/US1998/020051 US9820051W WO9915490A1 WO 1999015490 A1 WO1999015490 A1 WO 1999015490A1 US 9820051 W US9820051 W US 9820051W WO 9915490 A1 WO9915490 A1 WO 9915490A1
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WO
WIPO (PCT)
Prior art keywords
acetylarginine
dichlorobenzylamino
optionally substituted
acetylargιnιne
dιchlorobenzylamιno
Prior art date
Application number
PCT/US1998/020051
Other languages
English (en)
Inventor
Dennis Lee
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to JP2000512802A priority Critical patent/JP2001517648A/ja
Priority to EP98950673A priority patent/EP1017664A1/fr
Priority to CA002303883A priority patent/CA2303883A1/fr
Publication of WO1999015490A1 publication Critical patent/WO1999015490A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups

Definitions

  • the present invention relates to novel C3A receptor hgands, pharmaceutical compositions containing these compounds and methods of using the present compounds to treat inflammation
  • Anaphylatoxins are 74-77 amino acid bioactive fragments of C5, C3 and C4 that are generated in vivo during complement activation Binding of the anaphylatoxins to specific cell surface receptors initiates and maintains the inflammatory process The fragments are believed to elicit mast cell and basophil degranulation with release of histamine, cytokines and other inflammatory mediators and induce smooth muscle cell contraction They are potent inflammatory mediators, inducing cellular degranulation, smooth muscle contraction arachidomc acid metabolism, cytoktne release, cellular chemotaxis See Gerard, C .
  • C3A hgands offer a unique approach towards the pharmacotherapy of immune
  • ⁇ and inflammatory diseases such as rheumatoid arthritis, Alzheimer's disease, psoriasis, gout, multiple sclerosis, systemic lupus erythe atosus, glomeruloneph ⁇ tis and adult respiratory distress syndrome
  • C3A receptor hgands which are useful in the treatment of a variety of diseases associated with complement activation and/or increased levels of anaphylatoxins, including but not limited to rheumatoid arthritis, Alzheimer's disease, pso ⁇ asis, gout, multiple sclerosis, systemic lupus erythematosus, glomeruloneph ⁇ tis and adult respiratory distress syndrome
  • the present invention further provides methods for antagonizing C3A receptors in an
  • A represents Cj.4 alkylene, optionally substituted by C ] _4 alkyl or aryl; or A forms a 5-8 membered fused aliphatic ring with the adjacent phenyl ring;
  • m is an integer from 1 to 3 ;
  • each R] is independently selected form the group consisting of halo, C ⁇ _4 alkyl, methanesulfonyl, alkoxy, nitrile, dimethylamine, methylenedioxy and CF3;
  • R2 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted alkylsulfonyl, heteroarylsufonyl, optionally substituted phenylalkylaminocarbonyl, phenylaminocarbonyl, optionally substituted phenylalkyl, optionally substituted phenylsulfonyl, optionally substituted phenylalkylsulfonyl, optionally substituted naphthylalkylsulfonyl, heteroaryl carbonyl, heteroarylalkanoyl, optionally substituted alkylcarbonyl, optionally substituted phenylcarbonyl, and optionally substituted phenylalkylcarbonyl; wherein any substituents are selected from the group consisting of acyl, amide, C j .4 alkyl, halo, methylenedioxy, phenoxy and al
  • R4 represents hydrogen or methyl.
  • A represents unsubstituted methylene.
  • n is 2.
  • m represents a 3,5 substitution on the aryl ring.
  • R1 represents chloro.
  • R2 represents phenylpropionyl.
  • R3 represents hydrogen
  • R4 represents methyl
  • R2 represents 3,5 dichlorophenylsulfonyl.
  • 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. 5
  • cycloalkyl refers to 3-7 membered carbocyclic rings.
  • heterocycloalkyl refers to 4-7 membered heterocyclic rings containing 1 to 2 heteroatoms selected from N, O and S.
  • 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 0 fused ring systems.
  • Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
  • a preferred aryl group is phenyl.
  • acyl refers to alkylcarbonyl.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All 15 of these compounds and diastereomers are contemplated to be within the scope of the present invention.
  • Preferred compounds in the present invention include:
  • More preferred compounds useful in the present invention include
  • An especially preferred compound in the present invention is [3,5-D ⁇ chlorobenzylam ⁇ no-N-(3,5-d ⁇ chlorophenylsulfonyl)]acetylarg ⁇ n ⁇ ne
  • the present compounds can also be formulated as pharmaceutically acceptable salts and complexes thereof
  • Pharmaceutically acceptable salts are non-toxic salts in the amounts and concentrations at which they are administered
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfu ⁇ c acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tarta ⁇ c acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fuma ⁇ c acid, and quinic acid
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, chohne, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxyhc acid or phenol are present
  • the present invention provides compounds of Formula (I) above which can be prepared using standard techniques An overall strategy for prepa ⁇ ng preferred compounds described herein can be earned out as described in this section
  • the examples which follow illustrate the synthesis of specific compounds Using the protocols desc ⁇ bed herein as a model, one of ordinary skill in the art can readily produce other compounds of the present invention
  • a compound of 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.
  • the present ligands can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or transmucosal administration.
  • oral administration is preferred.
  • the compounds can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.
  • injection parenteral administration
  • the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Systemic administration can also be by transmucosal or transdermal means
  • penetrants appropriate to the bar ⁇ er to be permeated are used in the formulation
  • penetrants are generally known m the art, and include, for example, for transmucosal administration, bile salts and fusidic acid de ⁇ vatives
  • detergents may be used to facilitate permeation
  • Transmucosal administration for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories
  • the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art
  • the amounts of various calcilytic compounds to be administered can be determined by standard procedures taking into account factors such as the compound IC50, EC50, the biological half-life of the compound, the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art
  • Amounts administered also depend on the routes of administration and the degree of oral bioavailabihty For example, for compounds with low oral bioavailabihty, relatively higher doses will have to be administered
  • the composition is in unit dosage form
  • a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered
  • dosing is such that the patient may administer a single dose
  • Each dosage unit for oral administration contains suitably from 0 01 to 500 mg/Kg, and preferably from 0 1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base
  • the daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0 01 mg to
  • a topical formulation contains suitably 0 01 to 5 0% of a compound of Formula (I)
  • the active ingredient may be administered from 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art
  • treatment includes, but is not limited to prevention, retardation and prophylaxis of the disease
  • compositions of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent. 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. No unacceptable toxological effects are expected when compounds of the present invention are administered in accordance with the present invention.
  • RBL-2H3 cells expressing the human C3A receptor (hC3AR) were cultured to confluency at 37° C in a humidified incubator with 5% C02/95% air, in Earls MEM supplemented with non-essential amino acids, 10% fetal calf serum and 400 ⁇ g/ml G418 Although this cell line is normally adherent, nonadherent cells are always present in cultures The nonadherent cells were adapted to grow in suspension Nonadherent cells from three T-150 flasks were cent ⁇ fuged at 1,000 x g for 10 min and resuspended in 50-ml of the above medium in a 250 ml shake flask and over 7-10 days the cells were expanded to 2 5 1 in a spinner flask Cells were harvested by cent ⁇ fugation, 1 ,000 x g for 10 min at 4° C, and membranes were isolated using a modification of the procedure of Ross et al , (1977) Briefly, the cell pellet was washed
  • the membranes were prebound to SPA beads for 30 minutes on ice while shaking The mixture of membranes and beads were cent ⁇ fuged for three minutes at 2000 rpm The supernatant was removed and the pellet was resuspended to original volume in binding buffer with 50 ug/mL BSA Samples of interest were dissolved in neat DMSO to yield a 20X solution followed by a 1 1 mixture with H2O to yield a 10X, 50% DMSO working solution The order of addition was 10 uLs sample, 45 uLs membrane bound SPA beads followed by 45 uLs of radiolabled ligand in binding buffer containing 0 06% CHAPS The plates were covered with plate sealers from Dynex Technologies, Inc, and shaken for 20 minutes and incubated an additional 40 minutes at room temperature The plates were then cent ⁇ fuged for three minutes at 2000 rpm followed by counting on the Wallac 1450 Micro Beta Plus Liquid Scintillation counter
  • RBL-2H3-C3a Cell Culture Conditions RBL-2H3-C3a cells were cultured to near confluence in T-150 flasks at 37° C in a humidified incubator with 5% C ⁇ 2/95% air in Earls MEM with Earls salts (Gibco) supplemented with non-essential am o acids and L-glutamate, with 10% fetal calf serum (Gibco) and 400 ug/ml G418 (Gibco) Fluorescent Measurements-Calcium Mobilization: The functional assay used to assess antagonist activity of compounds was C3a- mduced calcium mobilization in intact RBL-2H3-C3a cells Cells were washed with 50 mM T ⁇ s, pH 7 4 containing 1 mM EDTA The [Ca ⁇ +j, was estimated with the calcium fluorescent probe fura 2 (Grynkiewicz, et al , J Biol Chem , 1985, 260, 3440-3450) The media was aspir
  • the calcium assay described above was converted to a high-throughput-screen (HTS) with the use of a 96 well Fluorescent Imaging Plate Reader (FLIPR) from Biomolecular Devices. This technology allows the measurement of the intracellular calcium mobilization in cells attached to the bottom of a 96 well plate.
  • HTS high-throughput-screen
  • FLIPR Fluorescent Imaging Plate Reader
  • Fluo-3 was generally used. Typically 4 uM Fluo-3 was loaded into the cells for 1 hr at 37 °C in cell media without fetal calf serum and with 1.5 mM sulfinpyrazone to inhibit dye release from the cells. The media is aspirated from the cells and fresh media was added for 10 min at 37 °C to allow hydrolysis of the dye and remove extracellular dye. The media was aspirated and replaced with KRH buffer (buffer A above). After 10 min at 37 °C the cells were placed in FLIPR apparatus for analysis.
  • FLIPR has 3-96 well plates. In addition to the plate with dye loaded cells, there is a plate containing varying concentrations of compound or vehicle and the third plate has the agonist at varying concentrations to establish agonist potency or a single concentration, e.g., 1 nM of C3a for antagonist activity.
  • FLIPR obtains a baseline fluorescence for -30 sec, then it adds the compounds to all 96 wells simultaneously and begins to monitor changes in intracellular Ca2+. After 2 min, the contents or the agonist plate is added to the cells. The maximal Ca2+ response (in optical units) for 1 nM C3a in the presence of vehicle ( 100%) or the various concentrations of compound is determined. Inhibition curves were generated essentially as described for the single cuvette Fura-2 assay described above.
  • Example 1 is illustrative of the present invention but not intended to be limiting in any way.
  • Example 1 is illustrative of the present invention but not intended to be limiting in any way.
  • Example 2a To the title compound of Example 2a) ( 100 mg) in py ⁇ dine (5 mL) was added phenylsulfonyl chloride (124 uL), and the mixture was agitated for 4 h The liquid phase was drained and the resin was washed with CH2CI2 (6X) b) r3,5-D ⁇ chlorobenzylam ⁇ no-N-( phenylsulfonvDlacetylarginine Prepared according to the procedure of Example Id) except substituting
  • Example 5 2-1(3.5-D ⁇ chlorobenzylam ⁇ no-N-(3,5-d ⁇ chlorophenylsulfonyl)]prop ⁇ onylarg ⁇ n ⁇ ne a) Fmocarg ⁇ n ⁇ ne(Boc) ⁇ Wang To Fmocarginine(Boc) 2 (1.8 g, 3 mmol) and Wang resin (2 g, 2 mmol) in CH2CI2 (40 mL) was added EDC (573 mg, 3mmol) and DMAP (244 mg, 2mmol). The mixture was shaken overnight and washed with DMF (2X)/CH 2 C1 (6X).
  • N ⁇ -methylarginine(Mtr)OMe TFA salt (0.48g, 0.91mmol) in 4.5 mL of DMF was added DIEA (0.24 g, 1.8 mmol). Then a premixed solution of [3,5- dichlorobenzylarnino-N-(3,5-dichlorophenylsulfonyl)]acetic acid (0.429g, 1.0 mmol), PyBOP (0.95 g, 1.8 mmol) and DIEA (0.47 g, 3.6 mmol) dissolved in 2 mL of DMF was added. The solution was stirred at RT overnight.
  • Example 10 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
  • a compound of Formula (I), (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • 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 12 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 (to 100 mL) The solution is then rendered ste ⁇ le by filtration through a 0 22 micron membrane filter and sealed in sterile containers

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Transplantation (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Psychiatry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Quinoline Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)

Abstract

L'invention concerne des nouveaux ligands pour C3A ainsi que leurs procédés d'utilisation pour le traitement de maladies auto-immunes et inflammatoires.
PCT/US1998/020051 1997-09-23 1998-09-23 Ligands pour recepteurs de c3a WO1999015490A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2000512802A JP2001517648A (ja) 1997-09-23 1998-09-23 Ｃ３ａレセプターリガンド
EP98950673A EP1017664A1 (fr) 1997-09-23 1998-09-23 Ligands pour recepteurs de c3a
CA002303883A CA2303883A1 (fr) 1997-09-23 1998-09-23 Ligands pour recepteurs de c3a

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US5975097P 1997-09-23 1997-09-23
US6994997P 1997-12-17 1997-12-17
US60/069,949 1997-12-17
US60/059,750 1997-12-17

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US09509238 A-371-Of-International 2000-03-23
US09/803,311 Continuation US20010056185A1 (en) 1997-09-23 2001-03-12 C3A receptor ligands

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JP (1) JP2001517648A (fr)
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WO (1) WO1999015490A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002044737A3 (fr) * 2000-11-29 2003-05-15 Lifespan Biosciences Inc Compositions pour applications diagnostiques et therapeutiques et methodes associees au recepteur couple aux proteines g (gpcr) le recepteur anaphylatoxine c3a
WO2005101013A3 (fr) * 2004-04-15 2006-03-02 Reglia Ab Substances et procedes pour le criblage de modulateurs de la regeneration neuronale
WO2006102760A1 (fr) * 2005-04-01 2006-10-05 Methylgene Inc. Inhibiteurs de l'histone desacetylase
WO2007034282A3 (fr) * 2005-09-19 2007-05-18 Pfizer Prod Inc Composes de biphenylimidazole utilises comme antagonistes du recepteur du c3a
WO2008079371A1 (fr) * 2006-12-22 2008-07-03 Encysive Pharmaceuticals, Inc. Modulateurs du récepteur du c3a et leurs procédés d'utilisation
WO2012174591A1 (fr) * 2011-06-20 2012-12-27 The University Of Queensland Prévention et traitement de conditions inflammatoires aiguës

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994007815A2 (fr) * 1992-09-25 1994-04-14 Abbott Laboratories Ligands du recepteur du petit peptide anaphylatoxine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994007815A2 (fr) * 1992-09-25 1994-04-14 Abbott Laboratories Ligands du recepteur du petit peptide anaphylatoxine

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002044737A3 (fr) * 2000-11-29 2003-05-15 Lifespan Biosciences Inc Compositions pour applications diagnostiques et therapeutiques et methodes associees au recepteur couple aux proteines g (gpcr) le recepteur anaphylatoxine c3a
WO2005101013A3 (fr) * 2004-04-15 2006-03-02 Reglia Ab Substances et procedes pour le criblage de modulateurs de la regeneration neuronale
WO2006102760A1 (fr) * 2005-04-01 2006-10-05 Methylgene Inc. Inhibiteurs de l'histone desacetylase
WO2007034282A3 (fr) * 2005-09-19 2007-05-18 Pfizer Prod Inc Composes de biphenylimidazole utilises comme antagonistes du recepteur du c3a
WO2008079371A1 (fr) * 2006-12-22 2008-07-03 Encysive Pharmaceuticals, Inc. Modulateurs du récepteur du c3a et leurs procédés d'utilisation
WO2012174591A1 (fr) * 2011-06-20 2012-12-27 The University Of Queensland Prévention et traitement de conditions inflammatoires aiguës
AU2012272550B2 (en) * 2011-06-20 2017-06-01 The University Of Queensland Prevention and treatment of acute inflammatory conditions

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Publication number Publication date
EP1017664A1 (fr) 2000-07-12
CA2303883A1 (fr) 1999-04-01
JP2001517648A (ja) 2001-10-09

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