JP2002521437A - Macrophage scavenger receptor antagonist - Google Patents

Abstract

  (57) [Summary] The present invention provides macrophage scavenger receptor antagonists. Also provided is a method of treating a cardiovascular disease comprising administering a compound of the present invention. The compounds of the present invention inhibit lipid accumulation in macrophage-derived foam cells.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION Cardiovascular disease is the leading cause of death in the United States, accounting for over one million deaths each year. Atherosclerosis is the leading cause of coronary heart disease and the leading cause of death in Western countries, except for accidents. Prevention of atherosclerosis is possible because of its poor medical needs, the etiology and treatment of atherosclerosis and consequent diseases, including myocardial infarction, angina, organ failure, thrombosis Extensive efforts have been made to limit gender. Despite these efforts, how and when the atherosclerotic lesion becomes life-threatening, the most appropriate stage of treatment, how to detect the progression of the lesion,
Many issues, such as whether to monitor, remain unsolved. Hypertension, high serum total cholesterol, high levels of low density lipoproteins ("L
There is widespread consensus that a number of risk factors contribute to atherosclerosis, including cholesterol, low levels of high density lipoprotein ("HDL") cholesterol, diabetes, severe obesity, and smoking. I do. To date, treatment of atherosclerosis has focused on treating high concentrations of cholesterol, and lipid modification has been the main focus of treatment and research. However, recent studies have shown that 40% of deaths from coronary artery disease occurred in people with total cholesterol levels lower than 220 mg / dl. Thus, it is clear that there is too much emphasis on lipid lowering. In fact, only 30% of patients with atherosclerosis have high lipid levels, indicating that another etiology is involved. Diet therapy, HMG-CoA reductase inhibition,
There are many multidisciplinary solutions consisting of novel therapies aimed directly at plaque formation and stability.

[0002] The early lesion of atherosclerosis is linear fat deposition, which is due to cholesterol esters which are incorporated as lipid droplets into macrophage-derived foam cells. Macrophages downregulate their LDL receptor,
Instead, it expresses the modified LDL m-RNA and synthesizes a novel receptor for it. This receptor recognizes all modified forms of low density lipoprotein and has become known as the macrophage scavenger receptor (MSR).
If the macrophages are in an environment that continuously produces modified LDL, the macrophages will accumulate cholesterol ester lipid droplets until the macrophages die of a toxic lipid storage load. The released lipid then forms the cell-free necrotic nucleus of the atherosclerotic lesion. Subsequent recruitment of fibroblasts, vascular smooth muscle cells and circulating monocytes and T lymphocytes terminates the inflammatory response and the formation of mature atherosclerotic plaques. Macrophage-derived foam cells collect at the shoulders of the plaques, where the proteolytic enzymes and collagenase secreted by the foam cells can cause plaque rupture, which can lead to fatal thrombotic events. The function of plaque regression, the dynamic equilibrium between initiation, progression, stabilization and elimination of plaque composition, has been defined in humans and numerous animal models. Regression studies in non-human primates have shown that, even with relatively advanced lesions, the lesions regress when the atherogenic dietary stimulus is stopped or drug administration is started. Using MSR antagonists to inhibit lipid accumulation in macrophage-derived foam cells inhibits the onset of plaque formation, slows plaque progression,
It is thought to initiate plaque regression via "reverse cholesterol transport" to the acceptor HDL. Because of this, MSR antagonists are used in cardiovascular diseases such as atherosclerosis, coronary artery disease, kidney disease, thrombosis, transient ischemia due to clots, heart attacks, myocardial infarction, organ transplantation, organ failure and hypercholesterolemia. It provides a unique solution to pharmacological treatment of disease.

DISCLOSURE OF THE INVENTION The present invention relates to a compound represented by formula (I) described below and atherosclerosis, coronary artery disease, kidney disease, thrombosis, transient ischemia due to clot, heart attack, myocardial infarction. Including, but not limited to, organ transplantation, organ failure and hypercholesterolemia,
Macrophage scavenger receptors ("M") useful in the treatment of various cardiovascular diseases
SR ") related to the use of said compounds as antagonists. Further, the present invention provides a method for antagonizing a macrophage scavenger receptor in an animal including a human, which comprises administering an effective amount of a compound represented by the following formula (I) to an animal in need of the treatment. To provide a method. The present invention also provides a method for inhibiting lipid accumulation in foam cells derived from macrophages.

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention has the following formula (I):

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[Wherein, R¹Is independently hydrogen, fluoroalkyl, halogen, haloaryl, ant
Or a group selected from the group consisting of¹Replace it
A fused ring which forms a naphthalene moiety together with the six-membered aryl ring;²Is independently hydrogen, R¹-Benzamide, R¹-Benzyl ether, R ¹ -Benzylamino, amino, halogen, hydroxyl, alkoxy, alkyl
, Fluoroalkyl, cyano, nitro, aryloxy, nitroalkyl, ant
Selected from the group consisting of²Is it put
And m is an integer of 1 to 4; n is an integer of 1 to 3]. You.

Preferably, R ¹ is hydrogen, 5-trifluoromethyl, 5-chloro, 5-bromo, 4-bromo, 5-bromo-4-phenyl, 5-iodo, 5-iodo-4-phenyl, Selected from the group consisting of -phenyl, 5-phenyl and 5-methoxy. More preferably, R ¹ is hydrogen, 5-trifluoromethyl, 5-bromo. Preferably, any R ² aryl substituent is selected from the group consisting of hydroxyl, halogen, aryl, alkyl, cyano, nitro, R ¹ -benzamidyl, alkoxy and aryloxy. More preferably, R ² is 2-chloro, 3
, 4-Dichloro, 2,3-dichloro, 3-methoxy, 2-isopropyl, 3-cyano, 4-butyl, 2-nitro, 2-phenoxy, 2-nitro-4-methyl,
-Phenyl, 4-phenyl, 2-benzamidyl, 1,2-benzo. Most preferably, ^{R 2} is 3,4-dichloro, 4-bromo, 4-phenyl, 4-butyl.

“Alkyl” as used herein refers to an optionally substituted hydrocarbon group linked by one carbon-carbon bond. Preferred alkyl substituents are as described throughout the specification. The term "aryl" as used herein refers to an optionally substituted aromatic group that has at least one ring with a conjugated pi-electron system containing up to two conjugated or fused ring systems. "Aryl" refers to carbocyclic aryl, heterocyclic aryl and diaryl groups, all of which may be optionally substituted. Preferred aryl substituents are as indicated throughout the specification. The compounds of the present invention may contain one or more asymmetric carbon atoms,
It can also exist as a racemate or an optically active form. The present invention contemplates all of these compounds and diastereomers as being within the scope of the present invention.

Particularly preferred compounds useful in the present invention are: bis-N- (4-biphenyl) -5-bromo-2-hydroxyisophthaldicarboxamide, bis-N- (4-biphenyl) -5-trifluoromethyl -2-hydroxyisophthaldicarboxamide, bis-N- (4-biphenyl) -2-hydroxyisophthaldicarboxamide, bis-N- (3,4-dichlorophenyl) -5-bromo-2-hydroxyisophthaldicarboxamide Bis-N- (3,4-dichlorophenyl) -2-hydroxy-5-trifluoromethylisophthaldicarboxamide, bis-N- (4-bromophenyl) -5-bromo-2-hydroxyisophthaldicarboxamide, Bis-N- (4-bromophenyl) -2-hydroxyisoph Distearate carboxamide, and bis -N- (4- bromophenyl) -2-hydroxy-5-trifluoromethyl isophthalic dicarboxamide.

[0009] These compounds can also be formulated as pharmaceutically acceptable salts or complexes thereof. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. Pharmaceutically acceptable salts used when there are basic groups are acid addition salts, for example,
Sulfate, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, Salts including p-toluenesulfonate, cyclohexylsulfamate, and quinate are included. Pharmaceutically acceptable salts include hydrochloric, maleic, sulfuric, phosphoric, sulfamic, acetic, citric, lactic, tartaric, malonic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, It can be obtained from acids such as cyclohexylsulfamic acid, fumaric acid and quinic acid.

In the presence of acidic functional groups such as carboxylic acids and phenols, pharmaceutically acceptable salts include benzacine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, Includes base addition salts such as those containing sodium, ammonium, alkylamine and zinc. The present invention provides compounds of formula (I) as described above, which can be prepared using standard techniques. The methods of preparing the preferred compounds described herein can be performed as described in this section. The following examples illustrate the synthesis of certain compounds. Using the protocols described herein, one of skill in the art can readily produce other compounds of the present invention.

[0011]

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[0012] Compound 1 is commercially available (Aldrich). The carboxylic acid can be activated to condense with the amine in various ways. One of the most convenient is to convert to a bis-acid chloride such as compound 2 with oxalyl chloride. Another method for producing acid halides is known as a method for preparing esters, especially activated esters. Many methods are well known for cleaving aromatic methyl ethers, including hydrohalic acids and nucleophiles such as sulfur and selenium compounds. Particularly effective reagents are boron tribromide or boron trichloride-sodium iodide equivalents.

Example 1 Bis-N, N ′-(3,4-dichlorophenyl) -2-hydroxyisodicarboxyphthalamide (5) 2-methoxyisophthalic acid (0.89 g, 4.61 mmol) in dichloromethane ( (25 ml) was reacted with oxalyl chloride (4.68 g, 36.8 mmol) and DMF (2, 3 drops). After 2.5 hours, the reaction mixture was filtered, concentrated in vacuo, toluene was added and again concentrated in vacuo to reduce volume. The residue was stirred with toluene (150 ml) and 3,4-dichloroaniline (2.2
7 g, 14 mmol) and a toluene solution (50 ml) containing triethylamine (3.2 ml, 23.05 mmol). After 18 hours, the reaction mixture was filtered and the collected solid was washed with fresh toluene. This solid was dissolved in EtOAc and the organic solution was washed with water, then with brine and dried over magnesium sulfate. Concentrate in vacuo to give a milky white powder of bis-N, N '-(3,4-dichlorophenyl) -2-methoxyisophthaldicarboxamide (mp 205-20).
(6 ° C.) (4) was obtained.

A suspension of the compound of 4 (250 mg, 0.52 mmol) in dichloromethane (25 ml) under argon was treated with a solution of 1 M boron tribromide (1.3 mmol) (
1.3 ml). After 4 hours, 15 ml of MeOH was added and after 20 minutes concentrated under vacuum to give a solid, which was recrystallized from toluene. Thus, straw-like yellow crystals of bis-N, N '-(3,4-dichlorophenyl) -2-hydroxyisophthaldicarboxamide (melting point: 232 to 235 ° C.) were obtained. The same operation is performed using 4-aminobiphenyl in place of the compound of No. 4 to obtain bis-N, N ′-(4-biphenyl) -2-hydroxyisophthaldicarboxamide (melting point: 200 to 202 ° C.). Similarly, bis-N, N '-(4-bromophenyl) -2-hydroxyisophthaldicarboxamide (mp 189-191 ° C) is obtained using 4-bromoaniline instead of compound 4. 4-bromo-bis-N, N ′-(3,4-dichlorophenyl) -2-hydroxyisophthaldicarboxamide (mp 292-substituted) using 4-bromo-2-methoxy-isophthalic acid in place of compound 1. 295 ° C), 4-bromo-bis-N, N '-(4-
Bromophenyl) -2-hydroxyisophthaldicarboxamide (softening point 16
9-170 ° C, melting point 230-240 ° C) and 4-bromo-bis-N, N '-(
4-biphenyl) -2-hydroxyisophthaldicarboxamide (mp 216
219 ° C). Using 4-trifluoromethyl-2-methoxyisophthalic acid in place of the compound of 1, 4-trifluoromethyl-bis-N, N ′-(3,
4-dichlorophenyl) -2-hydroxyisophthaldicarboxamide, 4-
Trifluoromethyl-bis-N, N '-(4-bromophenyl) -2-hydroxyisophthaldicarboxamide and 4-trifluoromethyl-bis-N, N
'-(4-Biphenyl) -2-hydroxyisophthaldicarboxamide is obtained. The corresponding expected products can also be obtained with other 2-methoxyisophthalic acids and anilines. Reflux the mixture of 2,4-dihydroxyisophthalic acid, PCl ₃ and 4-chloroaniline in chlorobenzene to give N, N′-bis- (4-chlorophenyl) -2,4-dihydroxyisophthalamide.

The 2-methoxyisophthal diacid chloride is stepwise reacted to give monoanilide, the unreacted acid chloride is hydrolyzed and reacted, and the resulting acid is converted to a conventional amide-forming reagent By reacting the compound with aniline, 2-hydroxyisophthalanilide which is symmetrical left and right can be prepared. Finally, cleavage of the methoxy group yields the desired 2-hydroxy derivative.

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Example 2 1- [N- (4-bromophenyl)]-2-hydroxy-3- [N′-4- (biphenyl)] isophthaldicarboxamide (9) 4-bromoaniline (0.44 g 2.6 mmol) and triethylamine (0
. A solution of 2-methoxyisophthal diacid chloride (0.59 g, 2.25 mmol) in toluene (40 g, 36 g, 2.5 mmol) in dry toluene (25 ml) was prepared.
ml). After stirring at 25 ° C. for 18 hours, the volatiles are removed in vacuo and the residue is dissolved in 30 ml of EtOAc. The solution is diluted with water, dilute hydrochloric acid, water and 1
It wash | cleaned in order of 0% sodium hydroxide aqueous solution. HCl was added to bring the pH of the alkaline extract to 1, and monoanilide 7 with the expected MS (mp 193-19-1).
6 ° C.). 9 (0.35 g, 1 mmol), HOBT (0.148 g, 1.1 mmol) EDC. Hydrochloric acid (0.211 g, 1.1 mmol) and DIEA (0.
38 g, 2.2 mmol) in 1-methyl-2-pyrrolidine at 25 ° C.
Stir for 0 min, then add 4-aminobiphenyl (0.22 g, 2.2 mmol) and DMAP (0.018 g, 0.15 mmol). After stirring at ambient temperature for 18 hours, the mixture was diluted with water, extracted with EtOAc, and the extract was extracted with water,
Washed with 0% aqueous hydrochloric acid, water, 5% sodium carbonate, water and brine. It was dried over magnesium sulfate, concentrated under vacuum, and the residue was recrystallized from methanol to give compound 8 (mp 205-208 ° C).

Compound 8 (0.31 g, 0.61 mmol) in dichloromethane (30 ml)
The solution in solution was 1.0 M boron tribromide in dichloromethane (1.52 ml, 1.
52 mmol) at 25 ° C. for 18 hours. MeOH was carefully added to destroy excess reagents and then the solution was concentrated in vacuo to give a yellow residue which was
Dissolved in OH, filtered, concentrated under vacuum, triturated with hexane,
A yellow solid was obtained. This was dissolved in dichloromethane, filtered and diluted with hexane to give a solid, dissolved in trichloromethane and filtered through a short silica column.
Concentration afforded 9 compounds (mp 214-218 ° C). This compound has C, H,
N and Br showed satisfactory elemental analysis results. In the same procedure, 3- [N- (4-bromophenyl)]-1- [N-3,4-dichlorophenyl]]-2-hydroxyisophthaldicarboxamide (melting point: 218)
２２０220 ° C.).

Example 3 N, N′-bis- (4-chlorophenyl) -2,4-dihydroxyisophthalamide 2,4-dihydroxyisophthalic acid (0.4529 g, 2.4 mmol), 4
- chloroaniline (0.62 g, 4.84 mmol) and _PCl 3 (0.22
(2.2 ml) in chlorobenzene (10 ml) was refluxed for 3 hours. The hot reaction mixture was filtered and subjected to cold filtration, followed by preparative HPLC (C18,
Purification with 20-95% acetonitrile-0.1% aqueous TFA), C, H and N
The desired product showing satisfactory elemental analysis for was obtained.

By appropriately devising and protecting any functional groups, other compounds of formula (I) can be synthesized in a manner analogous to that described above and analogously to those described in the experimental section. it can. For use of the compounds of Formula (I) or pharmaceutically acceptable salts for treating humans and other mammals, they will generally be formulated according to standard pharmaceutical methods, such as pharmaceutical compositions. The compounds of the present invention can be administered by a variety of routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical (transdermal) or transmucosal. In the case of systemic administration, oral administration is preferred. For example, for oral administration, the compounds can be formulated into common oral dosage forms such as capsules and tablets, and liquid preparations such as syrups, elixirs and concentrated drops. Alternatively, for example, intramuscular, intravenous, intraperitoneal and subcutaneous injections (parenteral administration) can be used. For injection, the compounds of the invention are formulated in liquids, preferably in physiologically compatible buffers or solutions, such as saline, Hank's solution, or Ringer's solution. In addition, the compound may be formulated as a solid and redissolved or suspended immediately before use. Lyophilized forms can also be produced.

[0020] Systemic administration may also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, a surfactant may be used to facilitate penetration. In the case of transmucosal administration, it may be through nasal sprays, rectal suppositories, vaginal suppositories. For topical administration, the compounds of the invention may be formulated into ointments, salves, gels, or creams as generally known in the art.

The amounts of the various compounds administered will take into account such factors as the compound's IC ₅₀ , EC ₅₀ , biological half-life of the compound, age, height and weight of the patient, type of disease or disorder. Can be determined according to standard procedures. The significance of these and other factors to consider is known to those skilled in the art. Dosage also depends on route of administration and oral physiological availability. For example, compounds with poor oral physiological availability require the administration of relatively large amounts of the compound. Preferably, the compositions are formulated in a unit dosage form. For example, it can be formulated into tablets or capsules for oral administration, a metered aerosol dose for nasal administration, a topical formulation or patch for transdermal administration, or a buccal patch for transmucosal administration. it can. In each case, the dose is the amount that the patient can take at one time.

For oral administration, the written dosage unit is suitably 0.01-500 mg / Kg, preferably 0-500 mg / Kg, calculated as the free base of the compound of formula (I) or a pharmaceutically acceptable salt thereof. 0.1 to 50 mg / Kg. The daily dose by parenteral, nasal, oral, transmucosal or transdermal route is suitably 0.01% of the compound of formula (I).
-100 mg / Kg. A topical formulation may suitably contain a compound of formula (I)
. It contains 0.1 to 5.0%. Administration of the active ingredient 1 to 6 times, preferably once a day, can be sufficient to administer the desired activity, which amounts will be apparent to the skilled person.

As used herein, “treatment” of a disease includes, but is not limited to, prevention, delay and prevention of the disease. The MSR receptors described in this application belong to a closely classified class called the SR-A group, and exist in two forms, type AI and type II. They arise by subjecting a single gene to a fractional exon splicing operation. "MSR" and "S
The term "RA" is used interchangeably herein.

Diseases or disorders to be treated or prevented based on the damaged cells include atherosclerosis, coronary artery disease, kidney disease, thrombosis, transient ischemia due to blood clots, heart attack, organ transplantation,
Includes organ failure, myocardial infarction and hypercholesterolemia.

The compounds of formula (I) and pharmaceutically acceptable salts thereof that are active when administered orally can be formulated into syrups, tablets, capsules and lozenges. In general, a syrup will consist of a liquid carrier of the compound or salt, for example, ethanol, peanut oil, olive oil, glycerin, or a suspension or solution in water with flavor or color. When the composition is a tablet, any of the conventionally used pharmaceutical carriers can be used to prepare a solid formulation. Examples of such media include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose, sucrose. Where the composition is in the form of a capsule, any conventional encapsulation operation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. When the composition is in the form of a soft gelatin capsule shell, the pharmaceutical carriers conventionally used to prepare dispersions or suspensions may be variously considered as, for example, aqueous gums, celluloses, silicates or oils. Formulated in capsule shells.

A typical parenteral composition may contain a parenterally acceptable oil of the compound or salt, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil, sterile or Consists of a solution or suspension in a non-sterile carrier. A typical composition for inhalation is in the form of a solution, suspension or emulsion. It can be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorofluoromethane or trichlorofluoromethane. A typical suppository formulation may contain a compound of formula (I) or a pharmaceutically acceptable salt which is active when administered in this manner, with a binding and lubricating agent such as a glycol polymer, gelatin, cocoa butter or other. Low-melting vegetable oils or synthetic analogs thereof.

Typical skin and transdermal formulations include the usual aqueous or non-aqueous vehicles, such as creams, ointments, lotions or pastes, or are in the form of medicated plasters, patches or films. Preferably, the compositions are in unit dosage form, such as a tablet, capsule, or metered aerosol dosage form so that the patient can take a single dose. No unacceptable toxic effects are expected when the compounds of the present invention are administered in accordance with the present invention. The biological activity of the compound of formula (I) is determined in the following test. For assays of both MSR activity, ie, degradation and binding / absorption, Goldstein et al., “Receptor-,” the entire contents of which are incorporated herein by reference.
mediated Endocytosis of Low-density Lipoprotein in cultured Cells ”, Met
hods Enzymol. 98: 241-260 (1983) is used. Simply put, M
The SRI or MSRII and 293 cells transfected, glutamine 2 mM, 10% FCS, geneticin (geneticin) 0.4mg / ml in Eagle's minimum essential medium containing 24-well dishes in ¹⁰⁵ cells / ml / well of the cell Sowed. Two days later, the medium was washed with BSA 2 mg / ml and iodine 125-AcLDL (
Replace with 500 μl of fresh serum-free medium containing 5 μg / ml of iodinated (acetylated low density lipoprotein) and incubate the cells at 37 ° C. for 5 hours. After an appropriate time required for the ligand degradation, the cells are transferred to a cold room at 4 ° C. The supernatant is placed in trichloroacetic acid and the mixture is centrifuged. Iodine 125-A
The supernatant is extracted with chloroform to isolate iodine-125 monoiodotyrosine, a degradation product of cLDL, and the extract is counted to determine the degradation activity. To determine the bound ligand of the cells, wash the monolayer of cells and
P containing 150 mM sodium chloride, 50 mM Tris-HCl, 2 mg / ml BSA
Incubate with H7.4 ice-cold buffer "A" to subtract the number of non-specific binding ligands. The cells are quickly washed three times with 1 ml of buffer solution A,
Incubate twice in 1 ml buffer solution A for 10 minutes each on a rotary shaker. Wash twice quickly with 1 ml of BSA-free buffer solution A. After sucking out all the buffer solution used for washing, the cells are lysed in 0.1 N sodium hydroxide, and to determine the binding / absorption, and then to determine the protein (Pierce BCA protein assay). Transfer to survey bin. The activator of the present invention can be used in degradation assays to
C50 values were < ₅₀ um and <100 um in the binding / absorption assay.

Fluorescent compound: DiI-AcLDL (1,1-dioctadecyl-3,3,3 ′,
3'-Tetramethylindocarboxyanine perchlorate-labeled LDL) has also been shown to be a useful tool in assaying macrophage scavenger receptor activity (Freeman et al., Proc. Natl. Acad. Sci., USA, 88:
4931-4935 (1991); Penman et al., J. Biol. Chem., 266: 2398.
5-23993 (1991)). We transfected HEK2.
Based on the absorption of DiI-AcLDL by 93 cells, it was also used for MSR antagonist assays. Clearly, SR-AI and SR-AII had similar activity in all of the experiments performed, and most experiments used HEK293 cells transfected with SR-AI. Briefly, HEK2
93 cells were treated with glutamine 2 mM, 10% FBS, Geneticin 0.4 mg / m
1 × 2 × 10 ⁴ cells / well in 96-well plates in EMEM medium supplemented. The assay was standardized and optimized, and the test was performed with bovine serum albumin 2m
Performed in serum-free EMEM containing g / ml. Confluent cells were incubated with DiI-AcLDL (final concentration 2 μg / ml) with or without inhibitor (quadruplicate wells) for 4 hours at 37 ° C. After aspirating the solution and the Loche buffer wash, a fluorescent plate reader 530 nm exc / 590 nm e
The result was measured in the range of m.

All publications, including but not limited to patents and patent applications, cited herein are tentatively well described, even if each individual publication is specifically and individually Even if the source is explicitly stated as a part of the present specification, the source is clearly indicated as a part of the present specification.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/10 A61P 9/10 101 101 13/12 13/12 37/06 37/06 43/00 105 43 / 00 105 111 111 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), CA, JP, US (72) Inventor Dimitri e Gaitanopoulos 1134, Bayles Place, Eagleville, Pennsylvania, United States 19403 (72) Inventor Gerald Earl Girard, Llanfair Place 4741, Bensalem, Pennsylvania, United States 19020 (72) Inventor Joseph P. Weinstock United States 19087 Pennsylvania Shuu Ein, Painter's Lane # 10 F-term (reference) 4C206 AA01 AA02 AA03 GA07 GA31 HA14 MA01 MA04 NA14 ZA36 ZA45 ZA54 ZA81 ZB08 ZB21 ZC02 ZC33 ZC42 4H006 AA01 AB20 AB23 BJ50 BM30 BM72 BM73 BN30 BV74

Claims (12)

[Claims] (1) Formula (I):[Wherein: R¹Is independently hydrogen, fluoroalkyl, halogen, haloaryl, ant
Or a group selected from the group consisting of¹Replace it
A fused ring which forms a naphthalene moiety together with the six-membered aryl ring;²Is independently hydrogen, R¹-Benzamide, R¹-Benzyl ether, R ¹ -Benzylamino, amino, halogen, hydroxyl, alkoxy, alkyl
, Fluoroalkyl, cyano, nitro, aryloxy, nitroalkyl, ant
Selected from the group consisting of²Is it put
A condensed ring which forms a naphthalene ring together with the substituted 6-membered aryl ring; m is an integer of 1 to 4; n is an integer of 1 to 3] . 2. R ¹ is selected from the group consisting of hydrogen, 5-trifluoromethyl, 5-chloro, 5-bromo, 4-bromo, 5-iodo, 4-phenyl, 5-phenyl and 5-methoxy; R ² is 2-chloro, 3,4-dichloro, 2,3-dichloro, 3-methoxy,
-Isopropyl, 3-cyano, 4-butyl, 2-nitro, 2-phenoxy, 2-
Nitro-4-methyl, 2-phenyl, 4-phenyl, 2-benzamidyl, 1,
The compound of claim 1, wherein the compound is selected from the group consisting of 2-benzo. 3. The compound of claim 2, wherein the R ² aryl substituent is selected from the group consisting of hydrogen, hydroxyl, halogen, aryl, alkyl, cyano, nitro, R ¹ -benzamidyl, alkoxy and aryloxy. 4. The compound according to claim 3, wherein R ² is selected from 3,4-dichloro, 2-benzamidyl, 4-bromo, 4-phenyl or 4-butyl. 5. R ¹ is hydrogen, 5-trifluoromethyl, 5-bromo.
A compound according to claim 5. 6. The compound comprising: bis-N- (4-biphenyl) -5-bromo-2-hydroxyisophthaldicarboxamide, bis-N- (4-biphenyl) -5-trifluoromethyl-2-
Hydroxyisophthaldicarboxamide, bis-N- (4-biphenyl) -2
-Hydroxyisophthaldicarboxamide, bis-N- (3,4-dichlorophenyl) -2-hydroxyisophthaldicarboxamide, bis-N- (3,4
-Dichlorophenyl) -5-bromo-2-hydroxyisophthaldicarboxamide, bis-N- (3,4-dichlorophenyl) -2-hydroxy-5-trifluoromethylisophthaldicarboxamide, bis-N- (4-bromo Phenyl) -5-bromo-2-hydroxyisophthaldicarboxamide, bis-N- (
4-bromophenyl) -2-hydroxyisophthaldicarboxamide, bis-
The compound according to claim 5, wherein the compound is selected from the group consisting of N- (4-bromophenyl) -2-hydroxy-5-trifluoromethylisophthaldicarboxamide. 7. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier. 8. A method for treating a cardiovascular disease or condition, comprising administering to a subject in need thereof an effective amount of the compound of claim 1. 9. The disease or disorder comprises atherosclerosis, coronary artery disease, kidney disease, thrombosis, transient ischemia due to blood clots, organ transplantation, organ failure, heart attack, myocardial infarction, and hypercholesterolemia. 9. The method of claim 8, wherein the method is selected from the group consisting of: 10. The disease or disorder to be treated is atherosclerosis.
The method according to claim 9. 11. A method of antagonizing a macrophage scavenger receptor, which comprises administering to a subject in need thereof an effective amount of the compound of claim 1. 12. A method for inhibiting the accumulation of lipids in foam cells derived from macrophages, which comprises administering the compound according to claim 1 to a subject in need of such treatment. Method.