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Tissue factor production inhibitor

A tissue factor and drug technology, applied in the direction of pill delivery, drug combination, medical preparations containing active ingredients, etc., can solve the problem of unknown role of LXR tissue factor

Inactive Publication Date: 2008-02-06
SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the effect on LXR tissue factor production is so far unknown

Method used

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  • Tissue factor production inhibitor
  • Tissue factor production inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1009] Compounds A to J in Table 7 of Example 1 and Table 8 of Example 2 represent the following compounds.

[1010] Compound A: N-(2,2,2-trifluoroethyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl }Benzenesulfonamide (compound 12 described on page 55 of WO2000 / 054759)

[1011] [chem 25]

[1012]

[1013] Compound B: 3-chloro-4-(3-(2-propyl-3-trifluoromethyl-6-benzene-[4,5]-isoxazolyloxy)propylthio)phenylacetic acid (WO1997 / 028137 The compound described in Example 20 on page 70; the effect on LXR is described in Endocrinology, 143, pp.2548-2558, 2002)

[1014] [chem 26]

[1015]

[1016] Compound C: 2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-phenyl)acetic acid (The compound described in Example 16 on page 46 of WO2002 / 24632)

[1017] [chem 27]

[1018]

[1019] Compound D: 2-benzyl-6,7-dimethoxy-3-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl] -4(3H)-quinazolinone (the compound described in...

Embodiment 2

[1067] (Example 2) LPS-administered mouse tissue factor mRNA analysis

[1068] The test compound was dissolved in a solution obtained by mixing propylene glycol (Wako Pure Chemical Industries, Ltd.) and Tween 80 (Kao) at a ratio of 4:1 (hereinafter referred to as "PG / Tween"). Male C57BL / 6T mice (Charles River ) for mandatory oral administration for 7 days, once a day in the evening, with a dose of 10 mg / kg. LPS 4 mg / kg was intraperitoneally administered at 9:00 am on the second day after the seventh administration, and 6 hours later, the abdomen was opened under ether anesthesia, and the kidney was removed. Kidney RNA was extracted with Trizolregent (Invitrogen). After performing reverse transcription reaction on the obtained RNA using First-Strand cDNA Synthesis Kit, the expression levels of tissue factor mRNA and cyclophilin mRNA were measured by quantitative RT-PCR in the same manner as in Test Example 1 above. Table 8 shows the tissue factor mRNA expression level when on...

reference example 1

[1098] (Reference Example 1) 6-Chloro-7-methoxy-3-{2-methyl-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl] Phenyl}-2-(3-ethynylmethyl)-4(3H)-quinazolinone (quinazolinone)

[1099] Operate in the same manner as the method described in the document (Example 1 on page 271 of WO2003 / 106435), and the 5-chloro-4-methoxy-ortho Aminobenzoic acid (201mg, 1.0mmol), phenylacetic acid (142mg, 1.0mmol), triphenyl phosphite (0.29ml, 1.1mmol) and the embodiment 147 (1 )] 2-(3-amino-4-methylphenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (273mg, 1.0mmol) synthesized by the method described, prepared The title compound (344 mg, yield 61%) was obtained as a colorless solid.

[1100] 1 H-NMR (500MHz, DMSO-d 6 ): δ8.89 (1H, br), 8.06 (1H, s), 7.78 (1H, s), 7.70 (1H, d, J = 8.0Hz), 7.42 (1H, d, J = 8.0Hz), 7.34 -7.41(2H, m), 6.70(1H, s), 6.59(1H, d, J=5.0Hz), 4.05(3H, s), 3.81(1H, d, J=15.0Hz), 3.76(1H, d,J=15.0Hz), 1.63(3H,s).

[1101] ESI(ES+)(m / z): 563([M+H] + ), ESI(ES-)(m / z): 561 ([...

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PUM

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Abstract

A pharmaceutical having the potency of inhibiting the production of tissue factors, which pharmaceutical comprises an LXR ligand as an active ingredient. There is provided a pharmaceutical for the treatment and / or prevention of vascular re-stenosis encountered after angioplasty, endarterectomy, percutaneous coronary angioplasty (PTCA) or stent placement, or for the treatment and / or prevention of blood coagulation disorder, diseases induced by platelet aggregation including stable or unstable angina, disorders of cardiovascular and cerebrovascular systems including thromboembolism induced by diabetes, re-thrombosis encountered after thrombolysis, brain ischaemia seizure, infarction, apoplexy, dementia resulting from ischemia, peripheral arterial disease, thromboembolism encountered during the use of aortocoronary bypass, glomerulosclerosis, kidney embolism, tumor or cancer metastasis, which pharmaceutical comprises an LXR ligand as an active ingredient.

Description

technical field [0001] The present invention relates to inhibitors of tissue factor production containing ligands for the liver X receptor. Background technique [0002] Atherosclerosis is increasing due to Westernization of diet and aging population. Atherosclerosis is a major cause of ischemic heart disease (myocardial infarction, unstable angina, etc.), ischemic encephalopathy (cerebral infarction, intracerebral hemorrhage, etc.), peripheral circulatory insufficiency, and the like. In addition, risk factors for atherosclerosis include, in addition to hyperlipidemia (especially hypercholesterolemia), hypertension and abnormal glucose metabolism due to insulin resistance. Hyperlipidemia not only acts as a vascular endothelial cell disorder, but is also related to the supply of cholesterol deposited on the blood vessel wall. In this sense, its control is also very important. [0003] It is known that in the case of ischemic heart disease, particularly acute coronary heart ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K9/10A61K31/18A61K31/404A61K31/423A61K31/517A61K31/5377A61P7/02A61P9/00A61P13/12A61P35/00A61P35/04A61P43/00C07D239/70C07D239/90C07D239/91C07D261/20C07D401/04C07D401/06C07D401/12C07D403/04C07D403/06C07D403/12C07D409/04C07D417/04C07J9/00
CPCA61K9/4858A61K31/18A61K31/381A61K9/2018A61K9/06C07D409/12C07D409/06A61K31/44A61K9/10C07D401/14A61K9/2054C07D239/90A61K31/192C07D333/24C07D209/12A61K9/4875A61K31/404A61K31/517A61P13/12A61P35/00A61P35/04A61P43/00A61P7/02A61P7/04A61P9/00A61P9/10A61K45/00A61K31/5377
Inventor 寺坂直生广岛綾乃
Owner SANKYO CO LTD
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