HK1172021B - 5-(3,4-dichloro-phenyl)-n-(2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide and salts thereof as hdl cholesterol raising agents - Google Patents

Description

5- (3, 4-dichloro-phenyl) -N- (2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide and salts thereof as HDL cholesterol raising agents

The invention relates to compounds of formula I

And isomeric forms thereof and pharmaceutically acceptable salts thereof, their manufacture, pharmaceutical compositions containing them and their use as medicaments. The compounds of formula I, their isomeric forms and pharmaceutically acceptable salts are particularly useful as HDL-cholesterol raising agents.

Atherosclerosis and its associated coronary heart disease are the leading causes of death in the industrialized world. The risk of developing coronary heart disease has been shown to be strongly correlated with certain plasma lipid levels. Lipids are transported in the blood by lipoproteins. The overall structure of lipoproteins is a core of neutral lipids (triglycerides and cholesterol esters) and a shell of polar lipids (phospholipids and non-esterified cholesterol). There are 3 different classes of plasma lipoproteins, which differ in their core lipid content: cholesterol Ester (CE) -rich low-density lipoproteins (LDL); high Density Lipoprotein (HDL) also rich in Cholesterol Esters (CE); and Very Low Density Lipoprotein (VLDL) rich in Triglycerides (TG). Different lipoproteins can be separated based on their different floating densities or sizes.

High LDL-cholesterol (LDL-C) and triglyceride levels are positively correlated with the risk of developing cardiovascular disease, while high levels of HDL-cholesterol (HDL-C) are negatively correlated with the risk of developing cardiovascular disease.

There is no entirely satisfactory HDL-raising therapy. Niacin can significantly increase HDL, but has serious tolerability issues that reduce compliance. Fibrates and HMG CoA reductase inhibitors only marginally (-10-12%) raise HDL-cholesterol. As a result, there is a significant unmet medical need for well-tolerated agents that can significantly elevate plasma HDL levels.

Thus, HDL-cholesterol raising agents are useful as medicaments for the treatment and/or prevention of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia.

In addition, the HDL-cholesterol raising agent may be used in combination with another compound which is an HMG-CoA reductase inhibitor, an microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor, a PPAR activator, a bile acid reuptake inhibitor, a Cholesteryl Ester Transfer Protein (CETP) inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, fibrate, nicotinic acid, a preparation containing nicotinic acid or other HM74a agonist, an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant.

Accordingly, it is an object of the present invention to provide compounds which are potent HDL-cholesterol raising agents. It has been found that the compounds of formula I according to the invention are very useful for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents, i.e. the compounds of formula I are particularly useful for the treatment and/or prophylaxis of dyslipidemia, atherosclerosis and cardiovascular diseases. It is also an object of the present invention to provide a compound that does not interact with the CB1 receptor at therapeutically active concentrations that raise HDL concentrations. This is because CB1 receptor ligands may compromise the therapeutic utility of HDL cholesterol raising agents because both agonists and antagonists of the CB1 receptor have the potential to cause side effects.

Compounds having a common structural element have been disclosed as CB1 receptor antagonists (WO2006/106054) and hybrid CB1 receptor antagonists/HDL cholesterol raising agents (WO 2008/040651).

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used herein to describe the invention.

"isomeric forms" are all forms of a compound characterized by the same molecular formula but differing in the nature or order of bonding of their atoms or in the arrangement of their atoms in space. Preferably, the isomeric forms differ in their arrangement in atom space and may also be referred to as "stereoisomers". Stereoisomers that are non-mirror images of each other are referred to as "diastereomers", while stereoisomers that are non-superimposable mirror images are referred to as "enantiomers", or sometimes optical isomers. Carbon atoms that bind 4 non-identical substituents are called "chiral centers".

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological efficacy and properties of the free base or free acid, which are not biologically or otherwise undesirable. The salts are formed using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. Thus, preferred "pharmaceutically acceptable salts" include the acetate, bromide, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate and tosylate salts of the compounds of formula I. In addition, pharmaceutically acceptable salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, the following salts: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethylamine, lysine, arginine, N-ethylpiperidine, piperidine, piperazine and the like. The compounds of formula I may also exist in zwitterionic form or in the form of hydrates. A particularly preferred pharmaceutically acceptable salt of a compound of formula I is the hydrochloride salt.

In a preferred aspect, the present invention relates to 5- (3, 4-dichloro-phenyl) -N- ((1R, 2R) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide, i.e. the compound of formula I in isomeric form Ia.

The invention also relates to 5- (3, 4-dichloro-phenyl) -N- ((1R, 2R) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide and pharmaceutically acceptable salts thereof.

In another preferred aspect, the present invention relates to 5- (3, 4-dichloro-phenyl) -N- ((1S, 2R) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide, i.e. the compound of formula I in isomeric form Ib.

The invention also relates to 5- (3, 4-dichloro-phenyl) -N- ((1S, 2R) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide and pharmaceutically acceptable salts thereof.

The compounds of formula I may be prepared by a process comprising:

reacting a compound of formula II

Wherein X is halogen, with an aryl metal species of formula III

Wherein M represents boric acid or boric acid ester, and is coupled under alkaline conditions in the presence of Pd catalyst,

and optionally separating the isomers on a chiral HPLC column,

and if desired, converting the resulting compound of formula I into a pharmaceutically acceptable salt thereof.

The aryl metal species is preferably an arylboronic acid or arylboronic ester. The palladium catalyst is preferably a palladium (II) acetate/triphenylphosphine mixture or a palladium (II) chloride-dppf complex, which is used in the presence of a base, preferably triethylamine or sodium carbonate. X is halogen, more preferably X is bromine or iodine.

The synthesis of compounds having the general structure I can be accomplished according to schemes 1 to 2 below.

Following the procedure according to scheme 1, compound AA (5-bromo-6-chloro-3-pyridinecarboxylic acid, CAS RN 29241-62-1) can be used as starting material. AA is commercially available or alternatively can be prepared from 6-hydroxy-3-pyridinecarboxylic acid by a multistep sequence, following literature procedures.

Compound AC can be prepared from AA by reaction with an appropriately substituted primary or secondary alcohol of formula AB in the presence of a base, such as potassium hydroxide, in an inert solvent, such as dimethylsulfoxide, at a temperature from room temperature to the reflux temperature of the solvent, preferably at room temperature.

Compound AE can be prepared by coupling AC and the corresponding amine of formula AD via a suitable amide bond formation reaction. These reactions are known in the art. For example, coupling agents such as N, N '-carbonyl-diimidazole (CDI), N, N' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1- [ bis (dimethylamino) -methylene ] -may be used]-1H-1, 2, 3-triazolo [4, 5-b]Pyridine compound-3-oxide Hexafluorophosphate (HATU), 1-hydroxy-1, 2, 3-benzotriazole (HOBT) and O-benzotriazol-1-yl-N, N, N ', N' -tetramethylureaTetrafluoroborate (TBTU) to perform such conversion. One convenient method is to use, for example, TBTU and a base, such as penniscidine (N-ethyldiisopropylamine), in an inert solvent such as dimethylformamide at room temperature.

In the following steps, the compound of formula I is obtained by: an appropriately substituted aryl metal species of formula AF, preferably an aryl boronic acid or aryl boronic ester, is coupled with AE in the presence of a suitable catalyst, preferably a palladium catalyst and more preferably a palladium (II) acetate/triphenylphosphine mixture or a palladium (II) -dppf (1, 1' -bis (diphenylphosphino) ferrocene) chloride complex and a base, preferably triethylamine or sodium carbonate, in an inert solvent such as dimethylformamide or toluene.

Scheme 1

Compounds of formula AE or compounds I prepared according to scheme 1 may contain one or more chiral centers, depending on the precise nature of the amine AD. The chiral compound AE-chirality or I-chirality can be obtained by various methods known in the art, such as synthesis from chiral precursors or chiral separation methods. For compounds with higher solubility in the mobile phase, chiral separation on a chiral HPLC column is advantageously performed. Compounds of formula AE are generally more soluble in heptane/alcohol mixtures than compounds of formula I. The separation of AE-chiral 1 and AE-chiral 2 from AE-racemate can be performed according to scheme 2 as follows: using a suitable chiral HPLC column such as ChiralPak ADOr a similar stationary phase, either batchwise or in the form of a moving bed process, and with a suitable mobile phase such as a heptane/isopropanol mixture.

Scheme 2

As mentioned above, the compounds of the formula I according to the invention can be used as medicaments for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents. Examples of such diseases are atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia. The use as a medicament for the treatment and/or prevention of dyslipidemia, atherosclerosis and cardiovascular diseases is preferred.

The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant, which are useful for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents.

Accordingly, the present invention relates to a pharmaceutical composition as defined above for use in the treatment and/or prevention of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia.

In another embodiment, the present invention relates to a method for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. Examples of such diseases are atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia. Methods for treating and/or preventing dyslipidemia, atherosclerosis, and cardiovascular disease are preferred.

Furthermore, the present invention relates to the use of compounds of the formula I as defined above for the preparation of medicaments for the treatment and/or prophylaxis of diseases which can be treated with HDL-raising agents. Examples of such diseases are atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia. The use of compounds of formula I as defined above for the preparation of medicaments for the treatment and/or prophylaxis of dyslipidemia, atherosclerosis and cardiovascular diseases is preferred.

In addition, the HDL-raising agent of formula I may be used in combination or association with another compound selected from: HMG-CoA reductase inhibitors, microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors, PPAR activators, Cholesteryl Ester Transfer Protein (CETP) inhibitors, bile acid reuptake inhibitors, cholesterol absorption inhibitors, cholesterol synthesis inhibitors, fibrates, nicotinic acid, formulations containing nicotinic acid or other HM74a agonists, ion exchange resins, antioxidants, ACAT inhibitors or bile acid sequestrants.

The invention therefore also relates to a pharmaceutical composition comprising a compound of formula I as defined above, in combination or association with a compound selected from: HMG-CoA reductase inhibitors, microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors, PPAR activators, Cholesteryl Ester Transfer Protein (CETP) inhibitors, bile acid reuptake inhibitors, cholesterol absorption inhibitors, cholesterol synthesis inhibitors, fibrates, nicotinic acid, formulations containing nicotinic acid or other HM74a agonists, ion exchange resins, antioxidants, ACAT inhibitors or bile acid sequestrants.

The invention also relates to the use of a compound of formula I as defined above, selected from HMG-CoA reductase inhibitors, microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors, PPAR activators, Cholesteryl Ester Transfer Protein (CETP) inhibitors, bile acid reuptake inhibitors, cholesterol absorption inhibitors, cholesterol synthesis inhibitors, fibrates, nicotinic acid, formulations containing nicotinic acid or other HM74a agonists, ion exchange resins, antioxidants, ACAT inhibitors or bile acid sequestrants, in combination or association with a compound for the preparation of a medicament for the treatment and/or prophylaxis of diseases such as atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia.

The present invention also relates to a method for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents, which method comprises administering a therapeutically effective amount of a compound according to formula I in combination or association with a therapeutically effective amount of a compound selected from the group consisting of: HMG-CoA reductase inhibitors, microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors, PPAR activators, Cholesteryl Ester Transfer Protein (CETP) inhibitors, bile acid reuptake inhibitors, cholesterol absorption inhibitors, cholesterol synthesis inhibitors, fibrates, nicotinic acid, formulations containing nicotinic acid or other HM74a agonists, ion exchange resins, antioxidants, ACAT inhibitors or bile acid sequestrants.

The compounds of formula I and/or their pharmaceutically acceptable salts can be used in the form of pharmaceutical compositions for enteral, parenteral or topical administration. They can be administered, for example, orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions; oral administration, for example in the oral form; rectal administration, for example in the form of suppositories; parenteral administration, for example in the form of injection or infusion solutions for intramuscular, intravenous or subcutaneous injection; or topically, e.g., in the form of an ointment, cream, or oil. Oral administration is preferred.

The production of pharmaceutical compositions can be carried out in any manner familiar to the person skilled in the art by bringing the compounds of the formula I and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, nontoxic, inert, therapeutically compatible solid or liquid carrier substances and, if desired, customary pharmaceutical auxiliaries.

Suitable carrier materials are not only inorganic carrier materials but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient, however, carriers may not be required in the case of soft gelatine capsules). Suitable carrier substances for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical formulations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Conventional stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavor-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants are contemplated as pharmaceutical adjuvants.

The therapeutically effective amount or dose of the compound of formula I may vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient, and the mode of administration, and will of course be fitted to the individual requirements in each particular case. For adult patients, a daily dose of about 1-100mg, especially about 1-50mg, is contemplated. Depending on the severity of the disease and the precise pharmacokinetic profile, the compounds may be administered in 1 or several daily dosage units, e.g. 1-3 dosage units.

The pharmaceutical composition conveniently contains from about 1 to 100mg, preferably 5 to 50mg, of a compound of formula I.

In the following examples, tests performed to determine the activity of the compounds of formula I, in particular their valuable pharmacological properties, are described.

Examples

MS ═ mass spectrum; EI-electron impact; ISP, ion spray, corresponds to ESI (electrospray); NMR data are expressed in parts per million (. delta.) relative to the internal tetramethylsilane and are referenced from the sample solvent (d)₆-DMSO unless otherwise indicated); coupling constant (J) in hertz, mp ═ melting point; bp is boiling point; HPLC ═ LC ═ HPLC, Rt ═ retention time, TLC ═ thin layer chromatography, Rt ═ room temperature, TBTU ═ O- (benzotriazol-1-yl) -N, N' -tetramethyl-urea-a tetrafluoroborate salt; DMF ═ dimethylformamide, DMSO ═ dimethyl sulfoxide, THF ═ tetrahydrofuran, CAN ═ CAS registry number.

Example 1

Effect on hamster plasma lipid levels

The efficacy of the compounds in modulating plasma lipid levels was determined in hamsters 5 days after administration of the compounds daily. Male hamsters 6-8 weeks old were used in the study. After one week of acclimation, blood samples were collected from 4 hour fasted animals for plasma lipid assay. Animals were then assigned to treatment groups based on HDL-cholesterol levels. The compounds were administered by gavage once a day for 5 days. Control animals received vehicle only. On day 5, blood was collected from 4-hour fasted hamsters 2 hours after the last treatment for plasma lipid analysis. Total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides were determined using a colorimetric enzyme assay (Roche diagnostic GmbH, Mannheim, Germany). HDL-cholesterol is also determined after selective precipitation of HDL from plasma by standard procedures.

Table 1: effect on hamster HDL Cholesterol level

Example 2

Affinity for CB1 and CB2 receptors

The affinity of the compounds of the present invention for cannabinoid receptors was determined using membrane preparations of Human Embryonic Kidney (HEK) cells transiently transfected with human cannabis CB1 receptor using the Semliki ForestVirus system in combination with [3H ] -CP-55,940 as a radioligand. After incubation of freshly prepared cell membrane preparations with [3H ] -ligand, separation of bound and free ligand was carried out by filtration on a glass fiber filter with or without addition of the compound according to the invention. Radioactivity on the filter was measured by scintillation counting.

The affinity of the compounds of the present invention for the cannabinoid CB2 receptor was determined using a membrane preparation of Human Embryonic Kidney (HEK) cells transiently transfected with the human cannabis CB2 receptor using the Semliki forest Virus system in combination with [3H ] -CP-55,940 as a radioligand. After incubation of freshly prepared cell membrane preparations with [3H ] -ligand, separation of bound and free ligand was carried out by filtration on a glass fiber filter with or without addition of the compound according to the invention. Radioactivity on the filter was measured by scintillation counting.

From IC using Cheng-Prusoff equation₅₀Calculating K_iThe value is obtained.

Table 2: affinity for CB1 and CB 2-receptors

Example 3

Preparation of 5- (3, 4-dichloro-phenyl) -N- ((1R, 2R) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide

a) 5-bromo-6- (2,2, 2-trifluoro-ethoxy) -nicotinic acid

5-bromo-6-chloro-3-pyridinecarboxylic acid (68.0g, 0.288mol, CAN 29241-62-1) was dissolved in DMSO (1000 mL). To this solution was added potassium hydroxide (48.25g, 0.86mol) with stirring, and after stirring for 10 minutes at room temperature was added 2,2, 2-trifluoroethanol (26.9mL, 0.374 mol). The mixture was stirred at room temperature for 24 h. Water (1000mL) and concentrated hydrochloric acid (107mL, 1280mmol, 37%) were added and the suspension was stirred vigorously for 4 hours. The precipitate was filtered, washed with water (4 × 100mL) and dried under vacuum overnight to give the title compound (80.4g) as an off-white solid; MS (EI)299, 301(M)⁺。

b) 5-bromo-N- ((1R, 2R) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide

5-bromo-6- (2,2, 2-trifluoro-ethoxy) -nicotinic acid (50.0g, 0.166mol) was dissolved in DMF (600 mL). To the solution was added TBTU (58.9g, 0.183mol), N, N-diisopropylethylamine (142.6mL, 0.83mol) and (1R, 2R) -2-amino-cyclohexanol (21.1g, 0.183 mol). The reaction mixture was stirred at rt for 3 h. The solvent was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate (1200mL) and THF (300 mL). The solution was washed twice with water (700mL) and the aqueous phase was extracted with ethyl acetate (600 mL). The organic phase was pooled, dried over MgSO4 and concentrated to about 900 mL. The product precipitated after stirring and cooling to 0 ℃. Filtration, washing with ethyl acetate/n-heptane (1: 1) and drying in vacuo gave the title compound (53.1g) as a white solid; MS (ISP)397, 399(M)⁺。

c)5- (3, 4-dichloro-phenyl) -N- ((1R, 2R) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide

5-bromo-N- ((1R, 2R) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide (59.8g, 151mmol) was dissolved in toluene (2500mL) and DMF (200 mL). To this solution was added [1, 1' -bis (diphenylphosphino) ferrocene ] with stirring]Palladium (II) dichloride CH₂Cl₂(6.15g, 7.5mmol), 3, 4-dichlorophenylboronic acid (30.2g, 158mmol) and sodium carbonate solution (2M, 150 mL). The mixture was heated to 90 ℃ for 2h, cooled to room temperature and filtered through celite. The filter cake was washed thoroughly with ethyl acetate (3000 mL). The filtrates were combined, washed twice with water (2x2000mL), and the aqueous phase was extracted with ethyl acetate (2x1500 mL). The organic phases were pooled, dried over MgSO4 and the volatiles were removed in vacuo. The residue was purified by filtration over silica (500g) with ethyl acetate. The solvent was removed and the residue triturated with diethyl ether to give, after drying in vacuo, the title compound (45.6g) as a grey solid; MS 463.079, 465.077(M + H)⁺。

Example 4

Preparation of 5- (3, 4-dichloro-phenyl) -N- ((1S, 2R) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide

a) 5-bromo-N- ((1SR, 2RS) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide

5-bromo-6- (2,2, 2-trifluoro-ethoxy) -nicotinic acid (75.0g, 0.25mol) was dissolved in DMF (850 mL). To the solution was added TBTU (91.0g, 0.275mol), N, N-diisopropylethylamine (214mL, 1.25mol) and (1SR, 2RS) -2-amino-cyclohexanol hydrochloride (41.7g, 0.275 mol). The reaction mixture was stirred at rt for 1.5 h. The solvent was evaporated in vacuo, the residue partitioned between ethyl acetate (2500mL) and 1N sodium hydroxide solution (2000mL), the aqueous phase was separated, extracted once more with ethyl acetate (1000mL) and washed with water (2 × 1500mL)The organic phase was run twice. The organic phase was pooled, dried over MgSO4 and concentrated to about 900 mL. The product precipitated after stirring and cooling to 0 ℃. Filtration, washing with ethyl acetate/n-heptane (1: 1) and drying in vacuo gave the title compound (81.1g) as a white solid; MS (ISP)397, 399(M)⁺。

b) 5-bromo-N- ((1S, 2R) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide

5-bromo-N- ((1SR, 2RS) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide (91.3g, 0.23mol) was placed in a ChiralPak ADPreparative HPLC was performed (250x110mm column) using n-heptane/isopropanol 85/15 as the mobile phase. A baseline separation was achieved and the title compound (43.6g) was isolated from the first peak as a colorless solid; ms (isp)395.2, 397.2 (M-H); ORD (589nM, 20 ℃, CHCl3) -21.6 °.

c)5- (3, 4-dichloro-phenyl) -N- ((1S, 2R) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide

5-bromo-N- ((1S, 2R) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide (42.0g, 106mmol) was dissolved in toluene (1900mL) and DMF (100 mL). To this solution was added [1, 1' -bis (diphenylphosphino) ferrocene ] with stirring]Palladium (II) dichloride CH₂Cl₂(0.9g, 1.06mmol), 3, 4-dichlorophenylboronic acid (20.2g, 106mmol) and sodium carbonate solution (2M, 106 mL). The mixture was heated to 90 ℃ for 2h, cooled to room temperature and partitioned between ethyl acetate (1000mL) and water (2000mL), the aqueous phase was separated, extracted twice with ethyl acetate (2 × 1000mL) and the organic phase was washed once with water and once with brine (1000mL each). The organic phases were pooled, dried over MgSO4 and the volatiles were removed in vacuo. The residue was dissolved in diethyl ether (500mL) and filtered through celite. The title compound precipitated when n-heptane (500mL) was added dropwise to the diethyl ether solution, filtered off and dried in vacuo to yield 33.3g of the titled compoundCompound as an off-white solid; MS 463.079(M + H)⁺。

Example 5

Film-coated tablets containing the following ingredients can be prepared in a conventional manner:

composition (I)	Each sheet is
			And (3) nucleus:
a compound of formula (I)	10.0mg	200.0mg
			Microcrystalline cellulose	23.5mg	43.5mg
Hydrous lactose	60.0mg	70.0mg
			Polyvinylpyrrolidone (Povidone) K30	12.5mg	15.0mg
Sodium starch glycolate	12.5mg	17.0mg
			Magnesium stearate	1.5mg	4.5mg
(core weight)	120.0mg	350.0mg
			Film coating:
hydroxypropyl methylcellulose	3.5mg	7.0mg
			Polyethylene glycol 6000	0.8mg	1.6mg
Talc	1.3mg	2.6mg

Iron oxide (yellow)	0.8mg	1.6mg
			Titanium dioxide	0.8mg	1.6mg

The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone. The granules were then mixed with sodium starch glycolate and magnesium stearate and compressed to give 120 or 350mg of cores, respectively. The cores were sprayed with the film-coated aqueous solution/suspension described above.

Example 6

Capsules containing the following ingredients can be prepared in a conventional manner:

composition (I)	Each capsule
		A compound of formula (I)	25.0mg
Lactose	150.0mg
		Corn starch	20.0mg
Talc	5.0mg

The components were sieved and mixed and filled into size 2 capsules.

Example 7

The injection solution may have the following composition:

a compound of formula (I)	3.0mg
		Polyethylene glycol 400	150.0mg
Acetic acid	Adding into pH 5.0
		Water for injection	Adding to 1.0ml

The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was adjusted to 5.0 by adding acetic acid. The volume was adjusted to 1.0ml by adding the remaining amount of water. The solution was filtered, filled into vials with the appropriate excess, and sterilized.

Claims (18)

1. A compound of formula I

And enantiomers and diastereomers and pharmaceutically acceptable salts thereof.

2. A compound of formula I according to claim 1, wherein the compound is

5- (3, 4-dichloro-phenyl) -N- ((1R, 2R) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide.

3. A compound of formula I according to claim 1, wherein the compound is

5- (3, 4-dichloro-phenyl) -N- ((1S, 2R) -2-hydroxy-cyclohexyl) -6- (2,2, 2-trifluoro-ethoxy) -nicotinamide.

4. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier and/or adjuvant.

5. The pharmaceutical composition according to claim 4, for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents.

6. A compound of formula I according to any one of claims 1 to 3 for use as a medicament.

7. A compound of formula I according to claim 6 for use as a medicament for the treatment and/or prophylaxis of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, cardiovascular diseases.

8. A compound of formula I according to claim 6 for use as a medicament for the treatment and/or prophylaxis of familial hypercholesterolemia, angina, ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia.

9. A compound of formula I according to claim 6 for use as a medicament for the treatment and/or prevention of cardiac ischemia.

10. A compound of formula I according to claim 6 for use as a medicament for the treatment and/or prevention of dyslipidemia.

11. A compound of formula I according to claim 6 for use as a medicament for the treatment and/or prevention of atherosclerosis.

12. A compound of formula I according to claim 6 for use as a medicament for the treatment and/or prevention of cardiovascular diseases.

13. The use of compounds of the formula I according to any one of claims 1 to 3 for the preparation of medicaments for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents.

14. Use according to claim 13 for the preparation of a medicament for the treatment and/or prevention of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, cardiovascular diseases.

15. Use according to claim 13 for the preparation of a medicament for the treatment and/or prevention of familial hypercholesterolemia, angina, ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia.

16. Use according to claim 13 for the preparation of a medicament for the treatment and/or prevention of cardiac ischemia.

17. Use according to claim 13 for the preparation of a medicament for the treatment and/or prevention of dyslipidemia, atherosclerosis and cardiovascular diseases.

18. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 3, which process comprises: coupling a compound of formula II with an aryl metal species of formula III in the presence of a Pd catalyst under basic conditions,

in the formula II, X is a halogen,

in the formula III, M represents boric acid or boric acid ester,

and optionally separating the isomers on a chiral HPLC column,

and if desired, converting the resulting compound of formula I into a pharmaceutically acceptable salt thereof.