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Peroxisome proliferator activated receptor alpha agonists

a technology of activated receptor and proliferator, which is applied in the field of peroxisome proliferator activated receptor alpha agonists, can solve the problems of liver toxicity, significant weight gain, tzds and ises typically have little effect, etc., and achieves fewer side effects, lowering fibrinogen, and increasing hdl levels.

Inactive Publication Date: 2009-03-05
CANO IVAN COLLADO +15
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0096]The compounds of the present invention and pharmaceutically acceptable salts, solvates and hydrates thereof are believed to be effective in treating and preventing Syndrome X, Type II diabetes, hyperglycemia, hyperlipidemia, obesity, coagaulopathy, hypertension, atherosclerosis, and other disorders related to Syndrome X and cardiovascular diseases. In addition, the compounds exhibit fewer side effects than compounds currently used to treat these conditions. Further, compounds of this invention can be useful for lowering fibrinogen, increasing HDL levels, treating renal disease, controlling desirable weight, treating demyelinating diseases, treating certain viral infections, and treating liver disease.

Problems solved by technology

However, TZDs and ISEs typically have little effect in preventing the cardiovascular part of Syndrome X in that their administration usually dose not result in the lowering of triglycerides and LDL-cholesterol while raising HDL-cholesterol.
Furthermore, side effects commonly associated with treatment with TZDs include significant weight gain, and, for troglitazone, liver toxicity.

Method used

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  • Peroxisome proliferator activated receptor alpha agonists
  • Peroxisome proliferator activated receptor alpha agonists
  • Peroxisome proliferator activated receptor alpha agonists

Examples

Experimental program
Comparison scheme
Effect test

example 1

Compound 1(1)

[0206]Compound 1, shown below, was prepared according to the Steps outlined below:

Step A: Preparation of

[0207]

[0208]To a suspension of 4-(4-hydroxyphenyl)butyrylhydrazide (0.5 g, 2.58 mmol) in isopropanol (5 mL) was added 3-chloro-benzaldehyde (Aldrich, 420 mg, 3 mmol), followed by p-toluenesulphonic acid (25 mg). The reaction mixture was stirred at room temperature for 20 h. A solid separated, which was filtered, washed with isopropanol (0.25 mL), and dried to give the product as a solid. MS: m / z (M++1): 317 Additional compounds, shown below, were prepared by substituting the appropriate benzaldehyde for 3-chloro-benzaldehyde.

RMS: m / z (M+ + 1)3-Methylphenyl297Phenyl2832,4-Difluorophenyl3192-Methylphenyl2973-Methoxyphenyl313

Step B: Preparation of

[0209]

[0210]To a solution of the Step A product (650 mg, 2.05 mmol, Example 1) in a mixture of 5 mL of isopropanol, tetrahydrofuran, and acetic acid (1:1:0.3) was added sodium cyanoborohydride (1.25 g, 20 mmol). The reaction mix...

example 2

Compound 2(1)

[0223]The compound shown below was prepared as follows:

Step A: Preparation of:

[0224]

[0225]To a cooled (0° C.) solution of boron tribromide (50 g, 200 mmol) in CH2Cl2 (50 mL) was added a solution of methyl 4-(4-methoxyphenyl)butyrate (15.5 g, 74.4 mmol) in CH2Cl2 (100 mL) dropwise over one hour. After stirring for an additional hour at 0° C., the reaction mixture was treated with 1:1 CH3OH:CH2Cl2 (120 mL) with cooling and stirred overnight at ambient temperature. Concentration of the mixture gave an oil which was partitioned between ethyl acetate (150 mL) and water (150 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL), and the combined organic extracts washed with water (50 mL), brine (50 mL), dried (Na2SO4), then concentrated to give the desired phenol as an oil. C11H14O3 (MW=194.23); MS: m / z (M++1)=195

Step B: Preparation of:

[0226]

[0227]The phenol from Step A (18.6 g, 96 mmol) was dissolved in DMF (300 mL) and treated with t-butyl 2-bromoisobutyrate (50...

example 3

[0239]

Step A: Preparation of:

[0240]

[0241]To a solution of the methyl ester, specifically Compound 2(1) (100 mg, 0.29 mmol) in DMF (2 mL), was added 3,4,5-trimethoxybenzyl chloride (129 mg, 0.6 mmol) and powdered potassium carbonate (350 mg, 2.53 mmol) and the resulting mixture heated at 45° C. for 24 hours. After cooling to ambient temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×3 mL). The combined organic extracts were concentrated to an oil which was purified by flash chromatography (gradient elution, 1:4 ethyl acetate:hexanes to 4:1 ethyl acetate:hexanes) to give the desired product as an oil. C27H35N3O7 (MW=513.60); MS: m / z (M++1)=514

[0242]The compounds listed below were also prepared by alkylation of N-methyltriazolinone using appropriate alkylhalides in the place of 3,4,5-trimethoxybenzyl chloride.

RMS: m / z (M+ + 1)3,5-Dimethoxyphenyl4844-Biphenyl5003-Chlorophenyl4583-Chloro-4-methylphenyl472Bis-trifluoromethylphenyl5603,4-Di...

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Abstract

The present invention is directed to compounds represented by the following structural formula, and pharmaceutically acceptable salts, solvates and hydrates thereof,R1 is a substituted or unsubstituted group selected from C1-C8 alkyl, aryl-C0-2-alkyl, heteroaryl-C0-2-alkyl, C3-C6 cycloalkylaryl-C0-2-alkyl or phenyl. W is O or S. R2 is H or a substituted or unsubstituted group selected from C1-C6 alkyl, C3-C6 cycloalkyl and heteroaryl. X is a C2-C5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S. Y is C, O, S, NH or a single bond. Furthermore, E is (CH2)nCOOH, wherein n is 0, 1, 2 or 3, or C(R3)(R4)A, wherein A is an acidic functional group such as carboxyl, carboxamide substituted or unsubstituted sulfonamide, or substituted or unsubstituted tetrazole. R3 is H, saturated or unsaturated C1-C5 alkyl, C1-C5 alkoxy. Additionally, R4 is H, halo, a substituted or unsubstituted group selected from C1-C5 alkyl, C1-C5 alkoxy, C3-C6 cycloalkyl, arylC0-C4alkyl and phenyl, or R3 and R4 are combined to form a C3-C4 cycloalkyl.

Description

BACKGROUND OF THE INVENTION[0001]Peroxisome Proliferator Activated Receptors (PPARS) are members of the nuclear hormone receptor super family, which are ligand-activated transcription factors regulating gene expression. Various subtypes of PPARs have been discovered. These include PPARα, NUC1, PPARγ and PPARδ.[0002]The PPARα receptor subtypes are reported to be activated by medium and long-chain fatty acids. They are involved in stimulating beta-oxidation of fatty acids and with the activity of fibrates which reportedly produce a substantial reduction in plasma triglycerides and moderate reduction in low density lipoprotein (LDL) cholesterol.[0003]PPARα, PPARγ and PPARδ receptors have been implicated in diabetes mellitus, cardiovascular disease, obesity, Syndrome X and gastrointestinal disease, such as, inflammatory bowel disease. Syndrome X is the combination of symptoms which include hyperinsulemia combined with hypertension, elevated body weight, elevated triglycerides and elevat...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4196C07D249/12C07D405/02A61K31/42A61K31/4245A61K31/4439A61K31/4709A61K31/5377A61P3/00A61P3/04A61P3/06A61P3/10A61P9/00A61P43/00C07C257/22C07C281/04C07C281/06C07D401/06C07D403/12C07D405/06C07D405/12C07D407/06C07D409/06C07D409/12C07D413/06C07D417/12
CPCC07C257/22C07C281/04C07C281/06C07D249/12C07D401/06C07D405/06C07D409/06C07D409/12C07D413/06C07D417/12A61P3/00A61P3/04A61P3/06A61P43/00A61P9/00A61P9/10A61P9/12A61P3/10
Inventor CANO, IVAN COLLADODOMINIANNI, SAMUEL JAMESETGEN, JR., GARRET JAYGARCIA-PAREDES, CRISTINAJOHNSTON, RICHARD DUANELETOURNEAU, MICHAEL EDWARDMANTLO, NATHAN BRYANMARTINELLI, MICHAEL JOHNMAYHUGH, DANIEL RAYSAEED, ASHRAFTHOMPSON, RICHARD CRAIGWANG, XIAODONGCOFFEY, DAVID SCOTTSCHMID, CHRISTOPHER RANDALLVICENZI, JEFFREY THOMASXU, YANPING
Owner CANO IVAN COLLADO
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