Biaryl- or Heterocyclic Biaryl-Substituted Cyclohexene Derivative Compounds as CETP Inhibitors

Abstract

The present invention provides biaryl- or heterocyclic biaryl-substituted cyclohexene derivative compounds, isomers thereof, or pharmaceutically acceptable salts. The compounds of the invention show a CETP inhibitory effect that increases HDL-cholesterol levels and reduces LDL-cholesterol levels. Pharmaceutical compositions comprising the compounds are useful for the prevention or treatment of dyslipidemia or dyslipidemia-related diseases.

Description

TECHNICAL FIELD[0001]The present invention relates to novel biaryl- or heterocyclic biaryl-substituted cyclohexene derivative compounds, and more particularly to novel biaryl- or heterocyclic biaryl-substituted cyclohexene derivatives having CETP inhibitory activity, isomers thereof, pharmaceutically acceptable salts thereof, the use for preparing pharmaceutical compositions, pharmaceutical compositions comprising the same, methods of treating diseases using these compositions, and methods for preparing novel biaryl- or heterocyclic biaryl-substituted cyclohexene derivatives.BACKGROUND ART[0002]Dyslipidemia generally refers to high blood cholesterol levels and is asymptomatic. However, dyslipidemia is a very serious condition, because it causes angina pectoris, myocardial infarction and arteriosclerosis. Statins, drugs that are commonly used to treat hyperlipidemia, exhibit therapeutic effects mainly by lowering LDL-C, but their effects on the prevention of cardiovascular diseases a...

AI Technical Summary

Benefits of technology

[0125]Novel biaryl- or heterocyclic biaryl-substituted cyclohexene derivative compounds according to the present invention, isomers thereof, or pharmaceutically acceptable salts thereof, have less side effects and exhibit the effect of effectively inhibiting CETP.

[0126]Novel biaryl- or heterocyclic biaryl-substituted cyclohexene derivative compounds according to the present invention, isomers thereof, or pharmaceutically acceptable salts thereof, can be used for the prevention or treatment of dyslipidemia or dyslipidemia-related diseases.MODE FOR THE INVENTION

[0127]Hereinafter, the present invention will be described in further detail with reference to Examples, preparation Examples and experimental Examples. It is to be understood, however, that these Examples are for illustrative purposes only and are not intended to limit the scope of the present invention.Preparation of Novel Compounds According to Reaction Scheme 3Intermediate Compound 3b: 2-(5-chloro-2-methoxyphenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde

[0128]Starting material 1 (3.5 g, 20.3 mmol), compound 2 (4.2 g, 22.3 mmol), sodium carbonate (6.4 g, 60.8 mmol) and Pd(dbpf)Cl2 (0.7 g, 1.0 mmol) were dissolved in dimethoxyethane (3 mL) / water (1 mL) at room temperature, and the reaction mixture was stirred at 100° C. for 18 hours. Then, water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to remove the solvent. The residue was purified by MPLC (Sift, EtOAc / hexane=0%˜5%) to obtain compound 3b (3.2 g, 56.6%) as yellow oil.Intermediate compound 5b: (1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((2-(5-chloro-2-methoxyphenyl)-5,5-dimethylcyclohex-1-enyl)methylamino)propan-1-ol

[0129]Starting material 3b (3.1 g, 11.1 mmol), compound 4 (3.5 g, 12.2 mmol) and acetic acid (0.7 mL, 12.2 mmol) were dissolved in methylene chloride (20 mL), and the reaction mixture was stirred at the same temperature for 1 hour, and then sodium cyanoborohydride (NaBH3CN) (0.8 g, 12.2 mmol) was added thereto at room temperature, followed by stiffing at the same temperature for 3 hours. Then, aqueous solution of saturated sodium bicarbonate was poured into the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate to remove water, and then concentrated under reduced pressure to remove the solvent. The residue was purified by MPLC (SiO2, EtOAc / hexane=0%˜20%) to obtain compound 5b (3.5 g, 57.2%) as yellow oil.Intermediate compound 6a: (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(5-chloro-2-methoxyphenyl)cyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one

[0130]Starting material 5a (0.8 g, 1.65 mmol) and 5-chloro-2-methoxyphenylboronic acid (0.37 g, 2.0 mmol) were dissolved in dimethoxyethane / water (v / v=3:1, 1 mL), and then degassed. Then, Pd(dbpf)Cl2 (54 mg, 0.08 mmol) and sodium carbonate (0.35 g, 3.3 mmol) were added to the reaction mixture, which was then stirred with microwave irradiation at 120° C. for 30 minutes. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and then washed with water and brine. The organic layer was dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to remove the solvent. The residue was purified by MPLC (SiO2 40 g, hexane / EtOAc=10%˜20%) to obtain compound 6a (0.68 g, 75%) as brown oil.Intermediate compound 6b: (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(5-chloro-2-methoxyphenyl)-5,5-dim ethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one

Problems solved by technology

However, dyslipidemia is a very serious condition, because it causes angina pectoris, myocardial infarction and arteriosclerosis.

Statins, drugs that are commonly used to treat hyperlipidemia, exhibit therapeutic effects mainly by lowering LDL-C, but their effects on the prevention of cardiovascular diseases are still very insufficient.

However, this drug needs to be taken in relatively large doses and causes side effects such as facial flushing (Taylor et al., Circulation, 2004, 110, 3512-3517).

However, among these CETP inhibitors, Torcetrapib (Pfizer) causes an increase in blood pressure and an increase in mortality rate, and thus was stopped phase III clinical trial.

It was reported that such side effects occur because Torcetrapib increases the levels of hormones, such as aldosterone and corticosterone, associated with an elevation in blood pressure, and increases the thickness of the vascular wall to cause inflammation, thus increasing mortality rate (Forrest et al, British Journal of Pharmacology, 2008, 1-9).

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