EP1100486A1 - Antagonistes des recepteurs accepteurs de macrophages - Google Patents

Antagonistes des recepteurs accepteurs de macrophages

Info

Publication number
EP1100486A1
EP1100486A1 EP99937612A EP99937612A EP1100486A1 EP 1100486 A1 EP1100486 A1 EP 1100486A1 EP 99937612 A EP99937612 A EP 99937612A EP 99937612 A EP99937612 A EP 99937612A EP 1100486 A1 EP1100486 A1 EP 1100486A1
Authority
EP
European Patent Office
Prior art keywords
bis
dicarboxamide
bromo
group
compound according
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Withdrawn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
EP99937612A
Other languages
German (de)
English (en)
Other versions
EP1100486A4 (fr
Inventor
Robert G. Franz
Dimitri E. Gaitanopoulos
Gerald R. Girard
Joseph P. Weinstock
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 EP1100486A1 publication Critical patent/EP1100486A1/fr
Publication of EP1100486A4 publication Critical patent/EP1100486A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Cardiovascular diseases are the leading cause of death in the U.S., accounting annually for more than one million deaths.
  • Atherosclerosis is the major contributor to coronary heart disease and a primary cause of non-accidental death in Western societies. Since the prevention of atherosclerosis is an enormous unmet medical need, considerable effort has been made in defining the etiology and potential treatment of atherosclerosis and its consequences, including myocardial infarction, angina, organ failure and stroke. Despite this effort, there are many unanswered questions including how and when atherosclerotic lesions become life-threatening, the best point of intervention, and how to detect and monitor the progression of lesions.
  • Atherosclerosis There is widespread agreement that multiple risk factors contribute to atherosclerosis including hypertension, elevated total serum cholesterol, high levels of low density lipoprotein (“LDL”) cholesterol, low levels of high density lipoprotein (“HDL”) cholesterol, diabetes mellitus, severe obesity, and cigarette smoking.
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • Macrophages down-regulate their LDL receptors and instead express mRNA and undergo new protein synthesis for a novel receptor for modified LDL.
  • This receptor recognizes all modified forms of low-density lipoprotein and has come to be known as the macrophage scavenger receptor ("MSR"). If the macrophage is present in an environment that is continually generating modified LDL, it will accumulate lipid droplets of cholosteryl esters, continuing until the macrophage dies from its toxic lipid burden. The released lipid then forms the acellular necrotic core of the atherosclerotic lesion.
  • Macrophage- derived foam cells are concentrated in the shoulders of plaques, where their secreted proteases and collagenases may contribute to plaque rupture which may lead to a fatal thrombotic event.
  • Plaque regression a function of the dynamic balance among initiation, progression, stabilization and removal of plaque constituents, has been unequivocally demonstrated in humans as well as in numerous animal models. Multiple regression studies in non-human primates have shown that even relatively advanced lesions regress over time when atherogenic dietary stimuli are discontinued or pharmacological regimens are initiated.
  • MSR antagonists provide a unique approach towards the pharmacotherapy of cardiovascular diseases such as atherosclerosis, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure, and hypercholesterolemia.
  • the present invention involves compounds represented by Formula (I) hereinbelow and their use as macrophage scavenger receptor (“MSR”) antagonists which are useful in the treatment of a variety of cardiovascular diseases including but not limited to atherosclerosis, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure and hypercholesterolemia.
  • MSR macrophage scavenger receptor
  • the present invention further provides methods for antagonizing the macrophage scavenger receptor in animals, including humans, comprising administering to an animal in need of treatment an effective amount of a compound of Formula (I), indicated hereinbelow.
  • the present invention further provides methods of inhibiting lipid accumulation within macrophage-derived foam cells.
  • R ! is independently selected from the group consisting of hydrogen, fluoroalkyl, halo, haloaryl, aryl, and alkoxy; or R1 represents a fused ring forming a naphthalene moiety with the six membered aryl ring it substitutes; R is independently selected from the group consisting of hydrogen, R ⁇ -benzamido, R'- benzyl ether, R ⁇ -benzylamino, amino, halo, hydroxy, alkoxy, alkyl, fluoroalkyl, cyano, nitro, aryloxy, nitroalkyl, aryl, and 1,2-benzo; or the R ⁇ moiety represents a fused ring forming a napthalene ring with the six membered aryl ring it substitutes; m is an integer from 1 to 4; and n is an integer from 1 to 3.
  • R* is selected from the group consisting of hydrogen, 5-trifluoromethyl, 5-chloro, 5-bromo, 4-bromo, 5-bromo-4-phenyl, 5-iodo, 5-iodo-4-phenyl, 4-phenyl, 5- phenyl and 5-methoxy.
  • R ⁇ is hydrogen, 5-trifluoromethyl or 5-bromo.
  • any R ⁇ aryl substituents are selected from the group consisting of hydroxy, halo, aryl, alkyl, cyano, nitro, R l" benzamidyl, alkoxy and aryloxy.
  • R ⁇ is selected from the group consisting of 2-chloro, 3,4-dichloro, 2,3-dichloro, 3-methoxy, 2-isopropyl, 3-cyano, 4-butyl, 2-nitro, 2-phenoxy, 2-nitro-4-methyl, 2-phenyl, 4-phenyl, 2-benzamidyl, 1,2-benzo.
  • R ⁇ is 3,4-dichloro, 4-bromo, 4- phenyl or 4-butyl.
  • alkyl refers to an optionally substituted hydrocarbon group joined together by single carbon-carbon bonds. Preferred alkyl substituents are as indicated throughout.
  • the alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated.
  • 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 substituents are as indicated throughout.
  • 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.
  • Particularly preferred compounds useful in the present invention include: bis-N-(4-biphenyl)-5-bromo-2-hydroxyisophthalic dicarboxamide, bis-N-(4-biphenyl)-5-trifluoromethyl-2-hydroxyisophthalic dicarboxamide, and bis-N-(4- biphenyl)- 2-hydroxyisophthalic dicarboxamide, bis-N-(3,4-dichlorophenyl)-2-hydroxyisophthalic dicarboxamide, bis-N-(3,4-dichlorophenyl)-5-bromo-2-hydroxyisophthalic dicarboxamide, bis-N-(3,4-dichlorophenyl-2-hydroxy-5-trifluoromethylisophthalic dicarboxamide, bis-N-(4-bromopheny l)-5-bromo-2-hydroxy isophthalic dicarboxamide, bis-N-(4-bromophenyl)-2-hydroxyisophthalic dicarboxamide, and bis-
  • 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.
  • salts for use when basic groups are present 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, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic 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 preparing preferred compounds described herein can be carried out as described in this section. The example which follows illustrates the synthesis of specific compounds. Using the protocols described herein as a model, one of ordinary skill in the art can readily produce other compounds of the present invention.
  • Compound 1 is commercially available (Aldrich).
  • the carboxylic acids can be activated towards condensation with amines by a variety of means.
  • One of the most convenient is conversion to the bis-acid chlorides such as 2 by oxalyl chloride.
  • Many other methods of making acid halides are well known as are procedures for preparing esters and especially activated esters.
  • Many procedures are well known for the cleavage of aromatic methyl ethers including hydrohalic acids and nucleophiles such as sulfur and selenium compounds.
  • An especially effective reagent is boron tribromide or an equivalent such as boron trichloride-sodium iodide.
  • 4-bromo-2-methoxy-isophthalic acid in place of 1 gives 4-bromo-bis-N,N'-(3,4-dichlorophenyl)-2-hydroxyisophthalic dicarboxamide, mp 292-295° C, 4-bromo-bis-N,N'-(4-bromophenyl)-2-hydroxyisophthalic dicarboxamide soften 169-170° C, mp 230-240° and 4-bromo-bis-N,N'-(4-biphenyl)-2-hydroxyisophthalic dicarboxamide mp 216-219° C.
  • 4-trifluoromethyl-2-methoxy-isophthalic acid in place of 1 gives 4-trifluoromethyl-bis-N,N'-(3,4-dichlorophenyl)-2-hydroxyisophthalic dicarboxamide, 4-trifluoromethyl-bis-N,N'-(4-bromophenyl)-2-hydroxyisophthalic dicarboxamide, and 4-trifluoromethyl-bis-N,N'-(4-biphenyl)-2-hydroxyisophthalic dicarboxamide.
  • Other 2-methoxyisophthalic acids and anilines may also be used to give the corresponding anticipated products.
  • Unsymmetrical 2-hydroxyisophthalanilides may be made by stepwise reaction of 2- methoxyisophthalic diacid chloride to give a monoanilide, hydrolyzing the unreacted acid chloride, and then reacting the resulting acid with an aniline using standard amide forming reagents. Finally the methoxy group is cleaved to give the required 2-hydroxy derivative.
  • 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 compounds 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 re- dissolved 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 barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • 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 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 bioavailability. For example, for compounds with low oral bioavailability, 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 100 mg/Kg, of a compound of Formula (I).
  • a topical formulation contains suitably 0.01 to
  • 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.
  • the MSR receptors described in the present application belong to a recently classified group designated the SR-A group and exist in two forms, type A-I and type A-II, which arise through differential exon splicing of a single gene.
  • the terms "MSR” and "SR- A” are used interchangeably in the present application.
  • Diseases and disorders which might be treated or prevented, based upon the affected cells include atherosclerosis, coronary artery disease, renal disease, thrombosis, transient ischemia during clotting, stroke, organ transplant, organ failure, myocardial infarction and hypercholesterolemia.
  • Composition 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.
  • 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 (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.
  • the medium is replaced with 500 ⁇ l fresh serum-free medium containing 2 mg/ml BSA and 125[I]-AcLDL (iodinated acetylated low density lipoprotein) at 5 ⁇ g/ml, and cells are incubated at 37C for 5 hours. After this suitable period for ligand degradation, cells are removed to a 4C cold room. Supernatant is removed into trichloroacetic acid, and the mixture is centrifuged. The supernatant is chloroform- extracted in order to isolate 125[I]-monoiodotyrosine, the degradation product of 125[I]- AcLDL, and portions are counted to determine degradative activity.
  • 125[I]-AcLDL iodinated acetylated low density lipoprotein
  • cell monolayers are washed and incubated at 4C with ice-cold buffer "A" containing 150 mM NaCl, 50 mM Tris-HCl, and 2 mg/ml BSA, pH 7.4, to eliminate nonspecifically bound counts.
  • Cells are washed three times rapidly with 1 ml, incubated twice for 10 min each on a rotary shaker in 1 ml buffer A, then washed twice rapidly in 1 ml buffer A without BSA. After aspiration of all wash buffer, cells are lysed in 0.1N NaOH and removed to counting vials for determination of binding/uptake and subsequent protein determination (Pierce BCA protein assay).
  • the present actives yield IC50 values of ⁇ 50 um in degradation assays and ⁇ 100um in binding/uptake assays.
  • the fluorescent compound Dil- AcLDL (l,l'-dioctadecyl-3,3,3',3'- tetramethylindocarbocyanine perchlorate-labeled LDL) has also been shown to be a useful tool in assessing activity of the macrophage scavenger receptor (Freeman et al., Proc. Natl. Acad. ScL, USA, 88:4931-4935 (1991); Penman et al., J. Biol. Chem., 266:23985-23993 (1991)).
  • HEK 293 cells transfected with SR-AI were used, although both SR-AI and SR-AII appeared to have equivalent activity in all studies performed.
  • HEK 293 cells were seeded at 2 x 10 ⁇ cells/ well in a 96-well plate in EMEM with 2mM glutamine, 10%FBS and 0.4mg/ml geneticin.
  • the assay was standardized and optimized, and testing was performed in serum-free EMEM containing 2mg/ml bovine serum albumin.
  • Confluent cells were incubated with Dil-AcLDL (final concentration 2ug/ml) in the absence and presence of inhibitors (quadruplicate wells) for 4 hours at 37C. Following aspiration of solution and a Locke's buffer wash, results were quantified with a fluorescence plate reader at 530nm exc/590nm em.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Transplantation (AREA)
  • Obesity (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'Invention concerne des antagonistes des récepteurs accepteurs de macrophages. L'invention concerne également des méthodes permettant de traiter les maladies cardio-vasculaires, consistant à administrer les composés de l'invention qui inhibent l'accumulation des lipides dans les cellules spumeuses dérivées des macrophages.
EP99937612A 1998-07-30 1999-07-30 Antagonistes des recepteurs accepteurs de macrophages Withdrawn EP1100486A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US9463598P 1998-07-30 1998-07-30
US94635P 1998-07-30
US9505998P 1998-08-03 1998-08-03
US95059P 1998-08-03
PCT/US1999/017166 WO2000006147A1 (fr) 1998-07-30 1999-07-30 Antagonistes des recepteurs accepteurs de macrophages

Publications (2)

Publication Number Publication Date
EP1100486A1 true EP1100486A1 (fr) 2001-05-23
EP1100486A4 EP1100486A4 (fr) 2003-01-15

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Family Applications (1)

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EP99937612A Withdrawn EP1100486A4 (fr) 1998-07-30 1999-07-30 Antagonistes des recepteurs accepteurs de macrophages

Country Status (4)

Country Link
EP (1) EP1100486A4 (fr)
JP (1) JP2002521437A (fr)
CA (1) CA2339094A1 (fr)
WO (1) WO2000006147A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1297848A4 (fr) * 2000-06-16 2004-05-19 Chugai Pharmaceutical Co Ltd Medicaments preventifs et therapeutiques destines au granulome
JP2004530654A (ja) 2001-02-23 2004-10-07 ブリストル−マイヤーズ・スクイブ・ファーマ・カンパニー アテローム硬化症および脆弱性プラークを画像診断するための標識マクロファージスカベンジャー受容体拮抗薬
CN105669487A (zh) * 2016-03-01 2016-06-15 重庆大学 一种温和条件下脱除酚羟基甲基保护基的方法
JP7072213B2 (ja) 2017-12-21 2022-05-20 国立研究開発法人理化学研究所 Ｂ型肝炎抗原タンパク質を標的としたイメージング用ｐｅｔプローブ
WO2020255425A1 (fr) * 2019-06-21 2020-12-24 国立研究開発法人理化学研究所 Agent anti-vhb

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH459172A (de) * 1961-09-11 1968-07-15 Wander Ag Dr A Verfahren zur Herstellung mehrbasischer Verbindungen

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *
See also references of WO0006147A1 *

Also Published As

Publication number Publication date
WO2000006147A1 (fr) 2000-02-10
EP1100486A4 (fr) 2003-01-15
CA2339094A1 (fr) 2000-02-10
JP2002521437A (ja) 2002-07-16

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