WO2001098264A1 - Antagonistes du recepteur de piegeurs de macrophages - Google Patents

Antagonistes du recepteur de piegeurs de macrophages

Info

Publication number
WO2001098264A1
WO2001098264A1 PCT/US2001/019801 US0119801W WO0198264A1 WO 2001098264 A1 WO2001098264 A1 WO 2001098264A1 US 0119801 W US0119801 W US 0119801W WO 0198264 A1 WO0198264 A1 WO 0198264A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzamide
bromo
bromophenyl
chloro
fluorophenylsulfonamido
Prior art date
Application number
PCT/US2001/019801
Other languages
English (en)
Inventor
Joseph Weinstock
Robert G. Franz
Dimitri E. Gaitanopoulos
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 AU2001270029A priority Critical patent/AU2001270029A1/en
Publication of WO2001098264A1 publication Critical patent/WO2001098264A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • 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
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • 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
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
    • 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
    • C07C311/21—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 a carbon atom of a six-membered aromatic ring
    • 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
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • 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
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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.
  • LDL low density lipoprotein
  • HDL high cholesterol
  • diabetes mellitus diabetes mellitus
  • severe obesity severe obesity
  • cigarette smoking treatment of atherosclerosis has been narrowly focused on treating elevated cholesterol levels and modifying lipids has become the major focus of treatment and research.
  • recent studies have indicated that 40% of deaths due to coronary disease occurred in men with total cholesterol levels of below 220 mg/dl. It is thus obvious that too great an emphasis is being placed on lipid lowering. Indeed, only 30% of patients with atherosclerosis have elevated lipid levels, indicating that other pathogenic factors are involved.
  • a logical scenario for future therapies and preventive measures should therefore include a multidisciplinary approach consisting of diet modification, HMG-CoA reductase inhibition and novel therapies aimed directly at plaque growth and stability.
  • the initial lesion in atherosclerosis is the fatty streak, which arises from cholesteryl esters maintained as lipid droplets inside macrophage-derived foam cells. 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 rnacrophage scavenger receptor ("MSR"). If the rnacrophage is present in an environment that is continually generating modified LDL, it will accumulate lipid droplets of cholosteryl esters, continuing until the rnacrophage dies from its toxic lipid burden.
  • MSR rnacrophage scavenger receptor
  • the released lipid then forms the acellular necrotic core of the atherosclerotic lesion.
  • Subsequent recruitment of fibroblasts, vascular smooth muscle cells and circulating monocytes and T-lymphocytes complete the inflammatory response and formation of the mature atherosclerotic plaque.
  • 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 sulfonamidobenzanilide compounds represented by Formula (I) hereinbelow and their use as rnacrophage 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.
  • the present invention further provides methods for antagonizing the rnacrophage 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 ⁇ and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl, acyl, aroyl, haloalkyl, halo, carboxy, carboalkoxy, carbamyl, alkylcarbamyl, arylcarbamyl, cyano, alkoxy, hydroxy, phenylazo, amino, nitro, alkylamino, arylamino, arylalkylamino, acylamino, aroylamino, alkylthio, arylalkylthio, arylthio, alkysulfinyl, arylsulfinyl, arylalkylsulfinyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfamyl, arylsulfonamido, and alkylsulfonamido
  • R3 is independently selected from the group consisting of alkyl, haloalkyl, Ri aryl and R aralkyl, and R substituted heterocycles selected from the group consisting of thiophene, furan, pyridine, pyrimidine, pyrazine, imidazole, and thiazole, and benzo analogs thereof; or R3 and the ring it substitutes represents a Rj substituted heterocycle selected from the group consisting of thiophene, furan, pyridine, pyrimidine, and pyrazine, and benzo analogs thereof.
  • 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, hete ocyclic 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. AH of these compounds and diastereomers are contemplated to be within the scope of the present invention.
  • Preferred compounds of the present invention are selected from the group consisting of :
  • N-(3-Chloro-4-methoxyphenyl)-2-(4-methoxy phenylsulfonamido)benzamide N-Phenyl-2-(2-fluorophenylsulfonamido)benzamide, N-(4-Chlorophenyl-2-(3-trifluoromethylphenylsulfonamido)benzamide, N-Phenyl-2-(4-methoxyphenylsulfonamido)benzamide, N-(4-Chlorophenyl-2-(3-trifluoromethylphenylsulfonamido)-4-methoxy- benzamide, N-(3-Chloro-4-methoxyphenyl-2-(3-trifluoromethylphenylsulfonamido)-4- methoxybenzamide, N-(3,4-DicMorophenyl)-2-(2-fluorophenylsulfonamido)-5-methoxy
  • Most preferred compounds of the present invention are selected from the group consisting of: 5-Bromo-N-(4-Bromophenyl)-2-(4-chlorophenylsulfonamido)benzamide;
  • 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, j ⁇ -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, -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, -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 examples which follow illustrate 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.
  • Example 4 N-(3-Chloro-4-methoxyphenyl)-2-(4-methylphenylsulfonylamino)benzamide
  • a solution of 3.45 g (25 mmol) of sodium carbonate and 1.0 g (7.3 mmol) of anthranilic acid in 50 ml of water at 60° was treated with 2.09 g (10.95 mmol) of p- toluenesulfonyl chloride and held at 70° for 30 min.
  • the reaction mixture was cooled to ambient temperature and acidified with 10% HCl.
  • This procedure could be used to give a variety of N-substituted benzamides starting from a common N-sulfonylanthranilic acid and a variety of amines.
  • 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 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.
  • 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]-monoiodotyrosine the degradation product of 125[I]-AcLDL
  • 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-ATI 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.

Abstract

Cette invention se rapporte à des antagonistes du récepteur de piégeurs de macrophages, à des procédés pour traiter les maladies cardio-vasculaires, consistant à administrer de tels composés, lesquels inhibent l'accumulation de lipides dans les cellules mousses dérivées des macrophages.
PCT/US2001/019801 2000-06-21 2001-06-21 Antagonistes du recepteur de piegeurs de macrophages WO2001098264A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001270029A AU2001270029A1 (en) 2000-06-21 2001-06-21 Macrophage scavenger receptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US21307500P 2000-06-21 2000-06-21
US60/213,075 2000-06-21

Publications (1)

Publication Number Publication Date
WO2001098264A1 true WO2001098264A1 (fr) 2001-12-27

Family

ID=22793648

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/019801 WO2001098264A1 (fr) 2000-06-21 2001-06-21 Antagonistes du recepteur de piegeurs de macrophages

Country Status (2)

Country Link
AU (1) AU2001270029A1 (fr)
WO (1) WO2001098264A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1602931A1 (fr) * 2004-06-03 2005-12-07 Universiteit Leiden Antagoniste du SR-A
JP2006514945A (ja) * 2002-12-06 2006-05-18 ジーイー・ヘルスケア・リミテッド 循環器疾患造影用の標識マクロファージスカベンジャー受容体拮抗薬
US8357711B2 (en) 2007-03-23 2013-01-22 Pfizer Limited Heterocyclic sulfonamides as inhibitors of ion channels
WO2019232384A1 (fr) * 2018-06-01 2019-12-05 Promega Corporation Inhibiteurs de complexes bioluminescents dérivés de la luciférase oplophorus

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH373029A (de) * 1960-08-29 1963-11-15 Geigy Ag J R Verfahren zur Herstellung neuer Aminobenzoesäurederivate
US3162684A (en) * 1957-12-24 1964-12-22 Geigy Ag J R New aminobenzoic acid deriatives and compositions containing same
DE19830431A1 (de) * 1998-07-08 2000-01-13 Hoechst Marion Roussel De Gmbh Sulfonylamino-carbonsäure-N-arylamide als Guanylatcyclase-Aktivatoren

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3162684A (en) * 1957-12-24 1964-12-22 Geigy Ag J R New aminobenzoic acid deriatives and compositions containing same
CH373029A (de) * 1960-08-29 1963-11-15 Geigy Ag J R Verfahren zur Herstellung neuer Aminobenzoesäurederivate
DE19830431A1 (de) * 1998-07-08 2000-01-13 Hoechst Marion Roussel De Gmbh Sulfonylamino-carbonsäure-N-arylamide als Guanylatcyclase-Aktivatoren

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006514945A (ja) * 2002-12-06 2006-05-18 ジーイー・ヘルスケア・リミテッド 循環器疾患造影用の標識マクロファージスカベンジャー受容体拮抗薬
AU2003292384B2 (en) * 2002-12-06 2007-04-19 Ge Healthcare Limited Labeled macrophage scavenger receptor antagonists for imaging cardiovascular diseases
EP1602931A1 (fr) * 2004-06-03 2005-12-07 Universiteit Leiden Antagoniste du SR-A
WO2005119266A1 (fr) * 2004-06-03 2005-12-15 Universiteit Leiden Antagonistes du sr-a
US8357711B2 (en) 2007-03-23 2013-01-22 Pfizer Limited Heterocyclic sulfonamides as inhibitors of ion channels
US8741934B2 (en) 2007-03-23 2014-06-03 Pfizer Limited Inhibitors of ion channels
WO2019232384A1 (fr) * 2018-06-01 2019-12-05 Promega Corporation Inhibiteurs de complexes bioluminescents dérivés de la luciférase oplophorus
US11390599B2 (en) 2018-06-01 2022-07-19 Promega Corporation Inhibitors of oplophorus luciferase-derived bioluminescent complexes

Also Published As

Publication number Publication date
AU2001270029A1 (en) 2002-01-02

Similar Documents

Publication Publication Date Title
US6458845B1 (en) Macrophage scavenger receptor antagonists
EP1378247B1 (fr) Agents pour le traitement de maladies de la function visuelle
JP2003504403A (ja) リン酸輸送阻害物質
SK281184B6 (sk) Substituovaný sulfónamid, farmaceutická kompozícia na jeho báze a spôsob jeho prípravy
RU2247719C2 (ru) Аминобензофеноны как ингибиторы il-1 бета и tnf-альфа, фармацевтическая композиция и способ лечения и/или профилактики воспалительных заболеваний
WO2001087294A1 (fr) Inhibiteurs du transport de phosphate
JP2003518057A (ja) ウロテンシン−ｉｉ受容体アンタゴニスト
US6255298B1 (en) Macrophage scavenger receptor antagonists for use in the treatment of cardiovascular diseases
CA3010615C (fr) Modulateurs de mastocytes et leurs utilisations
WO2000003704A1 (fr) Antagonistes des recepteurs des monocytes macrophages
WO2001098264A1 (fr) Antagonistes du recepteur de piegeurs de macrophages
US20030216449A1 (en) Phosphate transport inhibitors
WO2000006147A1 (fr) Antagonistes des recepteurs accepteurs de macrophages
IE64515B1 (en) Tetrahydronaphthalene derivatives and preparation thereof
EP1568697A1 (fr) Derives de 1,3-benzothiazinone, leur procede de production et leur utilisation
JP2003524000A (ja) オルト−スルホンアミドアリールヒドロキサム酸、それらの製造方法およびマトリックスメタロプロテイナーゼ阻害薬としてのそれらの使用
CA2426521A1 (fr) Traitement des dysfonctionnement sexuels par l'antagoniste de la bombesine
JPH05262736A (ja) フェノキシ酢酸誘導体
JPH0812659A (ja) チアゾール誘導体及びこれを含有する医薬製剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP