BG106854A - 4-carboxyamino-2-ethyl-1,2,3,4-tetrahydroquinoline crystal as cetp inhibitor - Google Patents

Abstract

Crystalline forms of a CEPT inhibitor of formula methods of making the crystals, methods of using the crystals and pharmaceutical compositions containing the crystals are disclosed. 21 claims, 2 figures

Description

CRYSTAL FORM OF 4-CARBOXIAMINO-2-ETHYL-1,2,3,4-TETRAHYDROCHINOLINE AS A SETTER INHIBITOR

2153/02 PC

Prior art)

The present invention relates to inhibitors of protein carrying cholesterol ester (CETP), pharmaceutical preparations containing such inhibitors and the use of such inhibitors to increase certain levels of plasma lipids, including high density lipoprotein (HO1) cholesterol and to reduce some levels plasma lipids, such as low-density lipoprotein (1_O1 _) - cholesterol and triglycerides, respectively, and treat diseases that are affected by low levels of HDL cholesterol and / or high levels of LDL-cholesterol and triglycerides, such as eroskleroza and cardiovascular diseases in certain mammals (i.e., those which have CETP in their plasma), including humans.

In particular, the present invention relates to CETP inhibitor crystals, pharmaceutical preparations containing these crystals, a process for preparing these crystals, and methods for treating atherosclerosis, obesity, and related diseases and / or conditions therein.

Atherosclerosis and associated coronary artery disease (CAD) is the leading cause of mortality in the industrialized world. Despite efforts to change secondary risk factors (smoking, obesity, immobilization) and treatment of dyslipidemia with dietary changes and drug therapy, coronary heart disease (CHD) remains the most common cause of death in the United States, heart disease they account for 44% of all deaths, with 53% associated with atherosclerotic coronary heart disease.

The risk of developing this condition has been shown to be highly dependent on some plasma lipid levels. While elevated LDL cholesterol may be the most recognized form of dyslipidemia, it is by no means the only significant lipid-related involvement in CHD. Low HDL-cholesterol is also a known risk factor for CHD (Gordon, D.J., et al., "High-density Lipoprotein Cholesterol and Cardiovascular Disease", Circulation, (1989), 79: 8-15).

Q High levels of LDL-cholesterol and triglycerides are positively correlated, while high levels of HDL-cholesterol are negatively correlated with the risk of developing cardiovascular disease. Thus, dyslipidemia is not an integral risk profile for CHD, but may be included in one or more lipid abnormalities.

Among the many factors controlling plasma levels of these disease-dependent principles, the activity of protein cholesterol ester (CETP) affects all three. The role of this 70,000 daltons of plasma glycoprotein, found in a number of animal species, including humans, is to transfer cholesterol ester and triglyceride between lipoprotein particles, including high density lipoprotein (HDL), low density lipoprotein (LDL), lipoprotein, and lipoprotein low density (VLDL) and chylomicrons. The net result of CETP activity is a decrease in HDL cholesterol and an increase in LDL cholesterol. This effect on the lipoprotein profile is considered to be pro-atherogenic, in particular in individuals whose lipid profile poses an increased risk of CHD.

There are no fully satisfactory HDL-enhancing therapies.

Niacin can significantly increase HDL, but there are major differences in tolerability, which diminishes consent by

9

9 99 relation its application. Fibrates and HMG CoA reductase inhibitors increased HDL-C only moderately (-10-12%). As a result, there is a significant mismatch in the medical needs of a well-tolerated agent that can significantly increase plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis.

Commonly defined U.S. application ser.No. No. 09 / 391,152 submitted on September 7, 1999, entitled 4-CARBOXIAMINO-

2-substituted-1,2,3,4-tetrahydroquinolines, the representation of which is hereby incorporated by reference, is directed to compounds of the following general formula:

In particular, the compound [2R, 4S] ethyl ester is described

4 - [(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid.

Thus, although there are various anti-sclerotic medications, there is a continuing need and ongoing research in this area for alternative therapies.

SUMMARY OF THE INVENTION

The present invention is directed to a crystal of

Formula I.

Alternatively, a crystal of the above Formula I is designated as [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro ethyl ester -2Hquinoline-1-carboxylic acid.

Another aspect of the present invention is directed to an anhydrous Formula I crystal.

Another aspect of the present invention is directed to a corresponding anhydrous crystal having the characteristic of X-ray powder analysis as shown in Figure 1.

Another aspect of the present invention is directed to an ethanolate crystal of Formula I.

Another aspect of the present invention is directed to a corresponding ethanolate crystal having the characteristic of X-ray powder analysis as shown in Figure 2.

• · · · · · · · · · · · · · · · · ·:: ·: ::: ·:: $ · · · · · · · · · · · ·

Another aspect of the present invention is directed to a method of treating atherosclerosis in a mammal (including humans) by administering to a mammal in need of such treatment for atherosclerosis a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method for treating a peripheral vascular disease in a mammal (including a human) by administering to a mammal in need of such treatment for a peripheral vascular disease a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating dyslipidemia in a mammal (including humans) by administering to a mammal in need of such treatment for dyslipidemia a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating hyperbeta-lipoproteinemia in a mammal (including a human) by administering to a mammal in need of such treatment for hyperbeta-lipoproteinemia a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating hypoalphalipoproteinemia in a mammal (including a human) by administering to a mammal in need of treatment for hypoalphalipoproteinemia a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating hypercholesterolemia in a mammal (including humans) by administering to a mammal in need of such treatment for hypercholesterolemia a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating hypertriglyceridemia in a mammal (including a human) by administration to a mammal in need thereof. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Another aspect of the present invention is directed to a method of treating familial hypercholesterolemia in a mammal (including a human) by administering to a mammal in need of such treatment for familial hypercholesterolemia a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating cardiovascular disorders in a mammal (including humans) by administering to a mammal in need of such treatment for cardiovascular disorders a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating angina in a mammal (including a human) by administering to a mammal in need of such treatment for angina a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating ischemia in a mammal (including a human) by administering to a mammal in need of such treatment for a ischemic disease a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating cardiac ischemia in a mammal (including a human) by administering to a mammal in need of such treatment for cardiac ischemia a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating a stroke in a mammal (including a human) by administering to a mammal in need of such stroke treatment a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating a myocardial infarction in a mammal (including a human) by administering to a mammal in need of such treatment for myocardial infarction a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating reperfusion injury in a mammal (including a human) by administering to a mammal in need of such treatment for reperfusion injury a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method © for treating angioplastic restenosis in a mammal (including a human) by administering to a mammal in need of such treatment for angioplastic restenosis a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating hypertension in a mammal (including a human) by administering to a mammal in need of such treatment for hypertension a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating vascular complications in diabetes in a mammal 0 (including humans) by administering to a mammal in need of such treatment for vascular complications in diabetes a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating obesity in a mammal (including a human) by administering to a mammal in need of such obesity treatment a therapeutic amount of a Formula I crystal.

Another aspect of the present invention is directed to a method of treating endotoxemia in a mammal (including a human) by administering to a mammal in need of such treatment for endotoxemia a therapeutic amount of a Formula I crystal.

. :.: :::: ». · · · · · · · · · · · · · · ·

The present invention is directed to pharmaceutical preparations which comprise a therapeutically effective amount of a Formula I crystal and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is directed to pharmaceutical preparations for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetaliproteinemia, hypoalphaloproteinemia, hypercholesterolemia, hypertriglyceridemia, auspicious hypersensitivity, heart attack, heart attack , angioplasty restenosis, hypertension, vascular complications in diabetes, obesity or endotoxemia in a mammal (including humans) containing a therapeutic effect an amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is directed to pharmaceutical preparations for the treatment of atherosclerosis in a mammal (including humans) containing an atherosclerosis therapeutic amount of a Formula I crystal and a pharmaceutically acceptable carrier, vehicle F or diluent.

The present invention is directed to pharmaceutical preparations for the treatment of peripheral vascular disease in a mammal (including humans) comprising a therapeutic amount for a crystal of peripheral vascular disease of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is directed to pharmaceutical preparations for the treatment of non-dyslipidemia in a mammal (including humans) comprising a therapeutic amount of a Formula I crystal and a pharmaceutically acceptable carrier, vehicle or diluent.

• · • ·. :.: ::: ·:: ια · · · · · · · · · · · · · · ·

The present invention is directed to pharmaceutical preparations for the treatment of hyperbeta-lipoproteinemia in a mammal (including humans) comprising a curative amount of a Formula I crystal and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is also directed to pharmaceutical preparations for the treatment of hypoalphalipoproteinemia in a mammal (including humans) comprising a therapeutic amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent for hypoalphalipoproteinemia.

The present invention is also directed to pharmaceutical preparations for the treatment of mammalian hypercholesterolemia (including humans) containing a hypercholesterolemic amount of a Formula I crystal and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is also directed to pharmaceutical preparations for the treatment of hypertriglyceridemia in a mammal (including humans) comprising a therapeutic amount of a crystal of Formula I and F a pharmaceutically acceptable carrier, vehicle or diluent for hypertriglyceridemia.

The present invention is also directed to pharmaceutical preparations for the treatment of familial hypercholesterolemia in a mammal (including humans) comprising a therapeutic amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is also directed to pharmaceutical preparations for the treatment of angina in a mammal (including man) which contain an amount of angina for treating angina. · · · · · · · · · · · · V is a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is also directed to pharmaceutical preparations for treating ischemia in a mammal (including humans) comprising a therapeutic amount of a crystalline Formula I crystal and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is also directed to pharmaceutical preparations for the treatment of cardiac ischemia in a mammal (including humans) comprising a therapeutic amount of a crystal of Formula I for the treatment of cardiac ischemia for the treatment of and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is also directed to pharmaceutical compositions for the treatment of stroke in a mammal (including humans) comprising a stroke-treating amount of a Formula I crystal and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is also directed to pharmaceutical preparations for treating myocardial infarction in a mammal (including humans) comprising a myocardial infarction therapeutic amount of a Formula I crystal and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is also directed to pharmaceutical preparations for the treatment of cardiac reperfusion injury in a mammal (including humans), which comprise an amount of Formula I crystalline cardiac reperfusion injury and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is also directed to pharmaceutical preparations for treating angioplasty restenosis in a " mm mammal (including human) comprising an amount of Formula I crystal and an pharmaceutically acceptable carrier, vehicle or diluent for treatment of angioplasty restenosis.

The present invention is also directed to pharmaceutical preparations for the treatment of hypertension in a mammal (including humans) comprising a hypertensive amount of a Formula I crystal and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is also directed to pharmaceutical preparations for the treatment of vascular complications in diabetes in a mammal (including humans), which contain for the treatment of diabetes mellitus a quantity of a Formula I crystal and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is also directed to pharmaceutical compositions for the treatment of obesity in a mammal (including humans) containing a curative amount of Formula I crystals and a pharmaceutically acceptable

carrier, vehicle or diluent.

The present invention is also directed to pharmaceutical preparations for the treatment of endotoxemia in a mammal (including humans) containing an endotoxemic amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention is also directed to a combination of a pharmaceutical composition comprising: a therapeutically effective amount of a preparation comprising a first compound, said first compound being a crystal of Formula I;

second compound, said second compound is an HMGCOA reductase inhibitor, a microsomal triglyceride carrying · · · · · · · · · · · · · · · · · · · · · ·· ···· · · 11 ···· ·· ·· ·· ···· Protein (MTP) / Apo Inhibitor, PPAR Activator, Bile Acid Reverse Inhibitor, Cholesterol Absorption Inhibitor , an inhibitor of the synthesis of cholesterol, fibrate, niacin, ion exchange resin, antioxidant, ACAT inhibitor or bile acid sequestrant; and / or optionally a pharmaceutical carrier, vehicle or diluent.

Preferred among the second compounds are the HMG-CoA reductase inhibitor and the MTP / Apo secretion inhibitor.

A particularly preferred inhibitor of HMG-CoA reductase is Q lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.

Another aspect of the present invention is a method of treating atherosclerosis in a mammal, characterized in that one first compound is administered to a mammal suffering from atherosclerosis, said first compound being a crystal of Formula I; and a second compound, said second compound is an HMG-CoA reductase inhibitor, an MTP / Apo B secretion inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, an ion exchange resin, a 0 or antioxidant secoxide an acid where the amounts of the first and second compounds give rise to a therapeutic effect.

A preferred aspect of the above method is when the second compound is an HMG-CoA reductase inhibitor or MTP / Apo B secretion inhibitor.

A particularly preferred aspect of the above method is when the HMGCoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.

Another aspect of the present invention is a kit comprising:

a. first compound, said first compound is a crystal of Formula I and a pharmaceutically acceptable carrier in one first unit dosage form;

b. second compound, said second compound is HMG-CoA reductase inhibitor, MTP / Apo B inhibitor, cholesterol absorption inhibitor, cholesterol synthesis inhibitor, fibrate, niacin, ion exchange resin, antioxidant acid, antioxidant

C and a pharmaceutically acceptable carrier in a second unit dosage form; and

c. ways of including said first and second dosage forms, wherein the amounts of the first and second compounds give rise to a therapeutic effect.

A preferred second compound is an HMG-CoA reductase inhibitor or MTP / Apo B secretion inhibitor.

A particularly preferred HMG-CoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.

The present invention is also directed to processes for the preparation of crystalline anhydrous ethyl ester of [2R, 4S] 4 - ((3,5bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6trifluoromethyl-3,4-dihydro -2H-quinoline-1-carboxylic acid by dissolving or mixing ethyl ester of [2R, 4S] 4 - [(3,5-bistrifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3, 4-Dihydro-2H-quinoline-1-carboxylic acid in the presence of a suitable organic solvent, preferably hexanes.

Another aspect of the present invention is directed to a process for the preparation of crystalline ethanolate of [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] ethyl ester] -

2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyl ········ 9 9 9 9 9 99

9 9 9 9 999 9 99 • · · · · · 99 1 «· '• 999 ·· 99 ·· · 4 * -> ···· Acid by dissolving or mixing ethyl ester of [2R.4S] 4 [ (3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid in ethanol / water at room temperature for about 0.5 to about 18 o'clock. Preferably, ethanol is used without water.

The present invention is also directed to a process for the preparation of crystalline anhydrous ethyl ester of [2R.4S] 4 - [(3,5bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid, characterized in that dissolved or mixed ethyl ester of [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -

2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid in ethanol at room temperature for about 2 to about 24 hours.

It is noted that since anhydrous and ethanolate crystals have different energy levels, nucleation with anhydrous or ethanol will determine the resulting isolated crystalline form. As is well known in the art, the presence of germ crystals in the air of a laboratory may be sufficiently "germ-forming". In one embodiment anhydrous crystals can be prepared using hexanes and the resulting anhydrous crystals can be used to nucleate further anhydrous crystals of ethanol.

As used herein, the term mammals is understood to refer to all mammals containing CETP in their plasma, for example, rabbits and primates, such as monkeys and humans. Some other mammals, such as dogs, cats, cattle, goats, sheep and horses, do not contain CETP in their plasma and are not included here.

The term ethanolate refers to solvated ethanol.

· · · · · · · · ·

• · · • · · · • · · f · ·· • · · · 16 ····

The term "treating", "treating" or "treating" as used herein includes preventive (for example, prophylactic) and palliative treatment.

"Pharmaceutically acceptable" means that the carrier, vehicle, diluent, excipients and / or salt must be compatible with the other ingredients of the combination and not be detrimental to the recipient.

As used herein, the terms " reaction-inert solvent " and " inert solvent " refer to a solvent or mixture of solvents which do not interact with the starting materials, reagents, intermediates or products in such a way as to adversely affect the desired yield. product.

It will be appreciated that the compound of the present invention may exist in an isotope-labeled form, i.e. said compound may include one or more atoms having an atomic mass or mass other than the atomic mass or mass number normally found in nature. Radioisotopes of hydrogen, carbon, phosphorus, fluorine and chlorine include ³ H, ¹⁴ C, ³² P, ³⁵ S, ¹⁸ F and Cl, respectively. The compound of the present Q invention, which includes these isotopes and / or other radioisotopes of other atoms, is within the scope of the present invention. Tritium, i.e. ³ H and carbon-14, i.e., ¹⁴ C, radioisotopes are particularly preferred because of their ease of preparation and detectability. A radiolabelled compound of the present invention can generally be prepared by well known methods by one of ordinary skill in the art. Typically, such radiolabelled compounds can be prepared by following the procedures presented in the Examples below, with one available radiolabelled reagent replacing a non-radioactive reagent.

Other features and advantages will be apparent from the specification and claims described in the invention.

Short description of the Figures

Figure 1 is a typical X-ray powder pattern showing that [2R.4S] 4 - [(3,5-bistrifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl anhydrous ethyl ester -3,4-Dihydro-2H-quinoline-1-carboxylic acid is crystalline. (Vertical axis: Intensity (CPS); Horizontal axis: Two theta ® (degrees))

Figure 2 is a typical X-ray diffraction pattern of [2R.4S] 4 - [(3,5-bistrifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-ethanol ethanol powder; 3,4-dihydro-2H-quinoline-1-carboxylic acid as crystal Vertical axis: Intensity (CPS); Horizontal axis: Two theta (degrees)

Detailed description of the invention

In general, the compound of the present invention can be prepared by processes that include processes analogous to those known in the chemical art, in particular in light of the description contained herein. Some processes for the manufacture of a compound of the invention are provided as further features of the invention and are described below, including in the Examples.

The amorphous form of the compound of the present invention, [2R.4S] 4 - [(3,5-bis-trifluoromethylbenzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- ethyl ester quinoline-1-carboxylic acid was prepared as presented below (see Example 1).

• * • 18

The anhydrous crystalline form of the above compound may be obtained from an amorphous compound by recrystallization from hexanes (solvent comprising hexane isomers (e.g., hexane, cyclohexane, methyl pentane, etc.)) at a temperature of about 40 ° C to about 80 ° C, preferably 60 ° C, usually followed by granulation, for about 2 to about 24 hours, then filtering the material and then drying it with air.

Alternatively, the anhydrous crystal may be obtained from the ethanolate crystalline form (described below) using analogous procedures to the immediately preceding procedure. In addition, the yield of this procedure can be enhanced by azeotroping ethanol from hexanes.

An ethanolate crystalline form of the above compound may be obtained from the amorphous compound by recrystallization from ethanol / water at a temperature of from about 20 ° C to about 25 ° C, preferably room temperature for about 0.5 hours to about 18 hours. Typically, the range is about 3% to about 10% ethanol and about 90% to about 97% water. Preferably, the ratio is about 10% to about 90% ethanol / water.

© Alternatively, the ethanolate crystalline form may be obtained using procedures analogous to those described above, but using ethanol alone. The filtered materials are typically granulated for about 2 hours to about 24 hours, followed by air drying.

The following Table 1 specifies important properties for the three forms of [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro- 2Hquinoline-1-carboxylic acid: amorphous (A); both crystalline forms ethanolate (B) and crystalline anhydrous (C).

TABLE 1

Thermal Stability Crystallinity Solubility Stability Amorphous A M.R. 21 ° C non-crystalline most soluble in water hygroscopic 'Ethanolate B (Figure 2) Melting point 45 ° C crystalline greater solubility in aqueous than anhydrous (C) non-hygroscopic @ 90% relative humidity for 24 hours Anhydrous C. (Figure 1) M.R. 89-90 ° C crystalline slightly soluble in water non-hygroscopic at 80% & 100% relative humidity for 3 days.

¹ Loses some ethanol in a closed vial at room conditions but remains crystalline

The compound of the present invention can be administered orally and accordingly used in combination with a pharmaceutically acceptable vehicle, carrier or diluent suitable for oral dosage forms. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical combinations in amounts sufficient to provide the desired amount of dosage within the range described below. Thus, for oral administration, the compound may be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical preparations may, if desired, contain additional components such as flavors, sweeteners, excipients and the like.

Tablets, pills, capsules and the like may also contain a binder such as tragacanth gum, arabic gum, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrating agent such as corn starch, potato starch, alginic acid, lubricant such as magnesium

·· • · • • • • · • • • · • • •

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

stearate; a sweetener such as sucrose, lactose or saccharin. When the unit dosage form is a capsule, such as a gel capsule, it may contain, in addition to / or instead, materials of the above type, a liquid carrier such as fatty glyceride, or mixtures of fatty glycerides such as olive oil or Miglyol ™ or Capmul ™ glycerides . Dosage forms may also include suspensions for oral administration.

Various other materials may be involved such as coatings or to change the physical form of the unit © dosage. For example, the tablets may be coated with shellac, sugar or both. Syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl or propylparaben as a preservative, colorant and flavoring such as cherry or orange flavor.

The compound of the present invention may also be administered parenterally. For parenteral administration, the compound may be combined with sterile aqueous or organic media to form injection solutions or suspensions. Injectable solutions thus prepared may then be administered intravenously, intraperitoneally, subcutaneously or intramuscularly.

Pharmaceutical forms suitable for injectable use include sterile solutions or dispersions and sterile powders for ex tempore preparation of sterile injectable solutions or dispersions. In all cases, the formulation must be sterile and must be liquid enough to be easily injectable. It must be stable under conditions of production and storage and must be protected against the contagious action of micro-organisms such as bacteria and molds. They can be sterilized, for example by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the preparations, or by irradiation or heating of the preparations, where such irradiation or heating is appropriate and compatible with the combination of the drug.

Additional pharmaceutical combinations may include, inter alia, suppositories, sublingual tablets, dosage forms for topical administration, and the like, and these may be prepared according to methods commonly accepted in the art.

Controlled-release, sustained-release and sustained-release oral or parenteral preparations may be used.

The dosage of the compound of the present invention administered may generally vary according to the principles known in the art, taking into account the severity of the condition being treated and the route of administration. In general, the compound may be administered to warm-blooded animals (such as humans, livestock, or pets) such that an effective dose, usually a daily dose, administered in a single dose or in divided portions, for example, in the range of about 0.01 to about 100mg / kg is administered. body weight, preferably about 0.1 to about 10 mg / kg / day body weight. The above dosages are exemplary of the average case; of course, there may be individual cases where higher or lower dosages are warranted and such deviations are within the scope of the present invention.

EXAMPLES

Melting points were determined with a Thomas Hoover melting point apparatus or DSC apparatus. Unless otherwise stated, CD3Cl3 was used for NMR spectra. A microanalysis was conducted by Schwarzkopf Microanalytical Laboratory. All reagents and solvents were obtained commercially and were used without purification.

Example 1

Cis-4-N (3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester:

N7C-4- (3,5-Bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester solution (2.0g, 3.7 mmol) and pyridine (0.58 g, 7.4 mmol) in 100 ml of dichloromethane was cooled in an ice water bath while methyl hpoformate (0.87 g, 9.2 mmol) was slowly added. After stirring overnight at room temperature, the reaction mixture was washed twice with 2N hydrochloric acid, dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product which was purified by silica gel chromatography using 510% ethyl acetate / hexanes as eluent to afford 1.8 g of the title product. MS m / z 601 (M ⁺ +1); ¹ H NMR (coalescing mixture of conformers, CDCI ₃ ) δ 0.6-0.8 (bm, 3H), 1.2-1.3 (bm, 3H), 1.3-1.5 (bm, 2H), 1.6-1.75 (bm, 1H), 2.1 -2.3 (bm, 1H), 3.7-3.9 (bs, 3H), 4.0-4.4 (bm, 4H), 5.0-5.6 (bm, 2H), 7.1 (s, 1H), 7.4-7.6 (bm, 2H) , 7.6-7.8 (bm, 3H).

[2P, 48] 4 - [(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester was obtained in an optically enriched form by digestion of the corresponding racemate, or an intermediate of its synthesis, using standard methods.

Example 2 (1-Benzotriazol-1-yl-propyl) - (4-trifluoromethyl-phenyl) -amine

One two-liter, four-necked flask was filled in a nitrogen atmosphere with benosotriazole (36.96 g, 310 mmol, 1.0 equiv-

• a

strips) and dry toluene (400 ml). A solution of 4- (trifluoromethyl) aniline (39.1 ml, 310 mmol, 1.0 equiv) and 50 ml toluene was added at room temperature within one minute. A solution of propionaldehyde (24.6 ml, 341 mmol, 1.0 equiv) and 50 ml toluene were then added at room temperature for 20 minutes. There is an exothermic reaction from 23 ° C to 30 ° C during this addition. After stirring for 24 hours, n-heptane (500 ml) was added and the slurry was stirred for an additional 1 hour. The suspension was filtered, the solids were washed with n-heptane (1 x 100ml, then 1 x 200 ml) and dried. (1-Benzotriazol-1-yl-propyl) - (4-trifluoromethyl-phenyl) -amine was isolated as shiny white needles (81.3 g, 82%). After 24 hours, a second crop of the filtrate (8.7 g, 9%), mp (melting point) 130-132 ° C was isolated; ¹ H NMR (DMSO-d 6, 400 MHz) δ 0.82 (t, 3H, J = 7.5 Hz), 2.25 (m, 2H), 6.49 (m, 1H), 6.80 (d, 2H, J = 8.7 Hz). 7.35 (m, 3H), 7.50 (m, 1H), 7.88 (d, 1H, J = 8.3 Hz), 7.99 (m, 1H), 8.09 (d, 1H, J = 8.5 Hz); ¹³ C NMR (DMSO-d6, 100 MHz) δ 149.19, 146.19, 131.46, 127.73, 126.8, 125.33 (q, J = 270 Hz), 124.44, 119.88, 118.27 (q, J = 31.7 Hz), 112.91, 111.56. 71.03, 28.08, 10.29; DEPT spectrum: quaternary carbon atoms δ 149.32, 146.19, 131.46, C 125.33, 118.27; CH carbon atoms δ 127.73, 126.8, 124.44, 119.88,

112.91, 111.56, 71.03; CH ₂ carbon δ 28.08; CH ₃ carbon δ 10.29; IR (infrared) (deviations) 3292 (s), 3038 (m), 2975 (m), 1621 (s), 1331 (s), 1320 (s), 1114 (vs); theory. calculated for this formula Ci6Hi ₅ N ₄ F _3: C, 59.99; H, 4.72; N, 17.49. Found (first yield): C, 60.16; H, 4.74; N, 17.86. Found (second yield): C, 59.97; H, 4.66; N, 17.63.

Example 3

Cis- (2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinolin-4-yl) -carbamic acid benzyl ester

N-vinyl-carbamic acid benzyl ester (27.66 g, 156 mmol, 1.0 equiv) and dry toluene (500 ml) were placed in a one-liter, four-necked flask under nitrogen atmosphere. (1-Benzotriazol-1-ylpropyl) - (4-trifluoromethyl-phenyl) -amine (50.0 g, 156 mmol, 1.0 equiv) and p-toluenesulfonic acid monohydrate (297 mg, 1.56 mmol, 0.01 equiv) were added and the mixture was heated to 70 ° C. After 2 hours, the mixture was cooled to room temperature and transferred to a separatory funnel. Ethyl acetate (500 ml) was added. The mixture was washed with 1 x 200 ml of 1N NaOH, 1 x 200 ml of H ₂ 0.1 x 200 ml of saturated sodium chloride solution and dried (MgSO ₄ ). The mixture was filtered and the solid was washed with 1 x 50 ml with ethyl acetate. The filtrate was concentrated to about 250 ml. 500 ml of toluene were added and the mixture was concentrated to about 500 ml. 500 ml of n-heptane was added, the slurry was stirred for 1 hour, filtered through a VisIPE funnel and dried. Cis- (2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid benzyl ester was isolated as a white powder (45.04 g, 76%): mp 155-157 ° C; ¹ H NMR (DMSO-d 6, 400 MHz) δ 0.92 (t, 3H, J = 7.5

Hz), 1.5 (m, 3H), 2.00 (m, 1H), 3.35 (m, 1H), 4.77 (m, 1H), 5.07 (d, 1H, J = 12.5 Hz), 5.15 (d, 1H, J = 12.5 Hz), 6.35 (s, 1H), 6.61 (d, 1H, J = 8.5 Hz), φ 7.12 (s, 1H), 7.18 (dd, 1H, J = 1.9, 8.5 Hz), 7.4 (m. 5H), 7.70 (d, 1H, J = 9.1

Hz); ¹³ C NMR (DMSO-66, 100 MHz) δ 157.03, 149.02, 137.79, 128.82, 128.23, 128.03, 125.9 (q, J = 270 Hz), 125.06, 123.50, 121.73, 115.2 (q, J = 31.7 Hz). 113.33, 65.85, 52.09, 47.83, 34.02, 28.68, 9.93; DEPT spectrum: quaternary carbon atoms δ 157.03, 149.02, 137.79, 125.9, 121.73, 115.2; CH carbon atoms δ 128.82, 128.23, 128.03, 125.06, 123.50, 113.33, 52.09, 47.83; CH ₂ carbon atoms δ 65.85, 34.02, 28.68; CH ₃ carbon δ 9.93; IR (deviations) 3430 (m), 3303 (s), 2951 (m), 1686 (vs), 1542 (vs), 1088 (vs); MS (APCI +) m / z (relative intensity) 379 (M + H ⁺ , 53), 228 (100); theoretically calculated for this

The formula C20H21N2O2F3: C, 63.48; H, 5.59; N, 7.40; Found: C, 63.69; H, 6.06; N, 7.36.

Example 4

Cis-4-Benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester

Cis- (2-ethyl-6-trifluoromethyl-1,2,3,4tetrahydro-quinolin-4-yl) -carbamic acid benzyl ester (96.0 g, 254 mmol, 1.0) was placed in a three-liter four-necked flask under a nitrogen atmosphere. equiv.), dry dichloromethane (720 ml) and dry pyridine (103 ml, 1.27 mol, 5.0 equiv). A solution of ethyl chloroformate (121 ml, 1.27 mol, 5.0 equivalents) in dry dichloromethane (240 ml) was added over four hours. Addition is exothermic and requires reflux. After completion of the chloroformate supplement, the reaction mixture was cooled in an ice bath and 1350 ml of 1N NaOH were added. The mixture was stirred for 15 minutes, then transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with 1 x 1L dichloromethane. The combined dichloromethane layers were washed 1 x 1350 ml of 1N HCl, 1 x 1L saturated aqueous NaHCO ₃ , 1 x 1L saturated sodium chloride and dried (Na ₂ SO ₄ ). The mixture was filtered and the filtrate was concentrated to give an orange oil. 570 ml of brine were added. ethanol and the solution is concentrated. The solid was dissolved in 1370 ml of brine. ethanol. 570 ml of H ₂ O was added dropwise over 45 minutes. The resulting thick broth was stirred for 18 hours and filtered. The solid was washed with cold 7: 3 absolute ethanol / water (1 x 250 ml, then 1 x 100 ml) and dried (vacuum oven, 45 ° C) to give cis-4benzyloxycarbonylamino-2-ethyl- 6-Trifluoromethyl-3,4-dihydro-2Hquinoline-1-carboxylic acid as a white, crystalline solid (94.54 g, 83%): mp 92-96 ° C; ¹ H NMR (CDCI ₃ , 400 MHz) δ 0.84 (t, 3H, · · · · · · · · · · · · · · · · · · · · · · · · · · · .......... * · 2 & · * ·

J = 7.4 Hz), 1.28 (t, 3H, J = 7.0 Hz), 1.4 (m, 2H), 1.62 (m, 1H), 2.53 (m, 1H), 4.23 (m, 2H), 4.47 (m. 1H), 4.79 (m, 1H), 5.01 (d, 1H, J = 9.2 Hz), 5.18 (m, 2H), 7.4 (m, 5H), 7.5 (m, 2H), 7.57 (m, 1H); ¹³ C NMR (CDCI ₃ , 100 MHz) δ 155.97, 154.43, 139.44, 136.21, 134.33, 128.61, 128.33, 128.22, 126.32 (q, J = 31.7 Hz), 126.18, 124.22, 124.19, 124.12 (q, J = 273 Hz), 120.74, 120.70, 67.22, 62.24, 53.47, 46.79, 37.75, 28.25, 14.38, 9.78; DEPT spectrum: quaternary carbon atoms δ 155.97, 154.43, 139.44,

136.21, 134.33, 126.32, 124.12; CH carbon atoms δ 128.61, 128.33,

128.22, 126.18, 124.22, 124.19, 120.74, 120.70, 53.47, 46.79; CH ₂ © carbon atoms δ 67.22, 62.24, 37.75, 28.25; CH ₃ carbon atoms δ 14.38, 9.78; IR (deviations) 3304 (s), 3067 (m), 3033 (m), 2982 (m), 2932 (m), 1723 (s), 1693 (s), 1545 (s); MS (APCI +) m / z (relative intensity) 451 (M + H ⁺ , 2), 300 (100); theoretically calculated for the formula C ₂₃ H ₂₅ N ₂ O ₄ F ₃ ; C, 61.33; Η, 5.60; 6.2, 6.22. Found: C, 61.07; Η, 5.69; 6.2, 6.22.

Example 5

Cis-4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro2H-quinoline-1-carboxylic acid ethyl ester

Cis-4-Benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (40.1 g, 89 mmol,) was placed in a one-liter, four-necked flask under nitrogen atmosphere. 1.0 equiv), methanol (400 ml) and ammonium formate (14.0 g, 223 mmol, 2.5 equiv). 10% Pd / C, 50% moisture content (4.0 g) was added and the broth was heated at 40 ° C for one hour. After 1.5 hours the mixture was cooled to room temperature and filtered through Celite®. The solidified mass was washed with 2 x 100 ml of methanol. The filtrate was concentrated to approximately 75 ml, transferred to a separatory funnel and diluted with 400 ml ethyl acetate. The mixture was washed 1 x 125 ml of saturated aqueous NaHCO ₃ , 1x 100 ml of saturated sodium chloride and dried (Na ₂ SO ₄ ). The mixture was filtered and the filtrate was

• Concentrated to a clear oil. The oil was crystallized from 100 ml of n-heptane to give cis-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as a white crystalline solid (26.05g, 93 %): mp 61.5-63.5 ° C; ¹ H NMR (CDCl 3, 400 MHz) δ 0.79 (t, 3H, J = 7.5 Hz), 1.24 (m, 4H), 1.42 (m, 1H), 1.51 (br s, 2H), 1.62 (m, 1H) , 2.46 (m, 1H), 3.73 (m, 1H), 4.17 (m, 2H), 4.36 (m, 1H), 7.44 (m, 2H), 7.66 (m, 1H); ¹³ C NMR (CDCl 3, 100 MHz) δ 154.6, 139.3, 138.9, 126.3 (q, J = 32 Hz), 125.7, 124.3 (q, J = 271 Hz), 123.5, 119.8, 61.96, 54.16, 46.91, 41.50. 28.85, 14.38, 9.60; DEPT spectrum: quaternary carbon atoms δ 154.6, 139.3, 138.9, 126.3, 124.3; CH carbon atoms δ 125.7, 123.5, 119.8, 54.16, 46.91; CH ₂ carbon atoms δ 61.96, 41.50, 28.85; CH ₃ carbon atoms δ 14.38, 9.60; IR (pivots) 3350 (s), 3293 (m), 2972 (s), 1697 (vs); MS (ES +) m / z (oth. Intensity) 358 (M + H + CH ₃ CN ⁺ , 55), 317 (M + H ⁺ , 7), 300 (100); calculated for C ₅ H ₁₉ N ₂ O ₂ F ₃ : C, 56.96; Η, 6.06; Ν, 8.86, Found: C, 56.86; 6.2, 6.28; Ν, 8.82.

Example 6

Hemi - (-) - dibenzoyl -! - tartrate salt of the ethyl ester of (2R, 4S) -4amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxy ^w hunting acid

Cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (24.0 g, 75.9 mmol, 1.0 equiv) was placed in a one-liter flask under nitrogen atmosphere. and (-) dibenzoyl-1-tartaric acid (anhydrous) (27.19 g, 75.9 mmol, 1.0 equiv). 300 ml of approximately 97% ethanol (obtained by adding 10.5 ml of H ₂ O to 500 ml of absolute ethanol, mixing and measuring 300 ml) were added. The mixture was stirred at room temperature for 18 hours and then filtered. The solid was washed with 1 x 48 ml of approximately 97% ethanol and dried to give the (2R, 48) -4-amino-2-ethyl-6- hemi - (-) - dibenzoyl-1-tartrate salt of ethyl ester. trifluoromethyl-3,4-dihydro-2Hquinoline-1-carboxylic acid as a white crystalline solid (14.77 g, 39%): mp 189.5-191.5 ° C (dec); ¹ H NMR (DMSO-d 6, 400 MHz) δ

0.62 (t, 3H, J = 7.3 Hz), 1.16 (t, 3H, J = 7.1 Hz), 1.3 (m, 3H), 2.5 (m, 1H), 4.1 (m, 4H), 5.63 (s, 1H) , methic proton in DBTA), 7.47 (m, 2H, DBTA aromatic H's), 7.6 (m, 3H, DBTA aromatic H's), 7.68 (s, 1H), 7.95 (m, 2H), 8.2 (br s, NH ₃ ⁺ , does not integrate); ¹³ C NMR (DMSO-d6, 100 MHz) δ 169.85, 165.53, 154.10, 140.14, 134.59, 133.51, 130.74, 129.69, 128.98,

126.74, 124.82 (q, J = 31.7 Hz), 124.69 (q, J = 271 Hz), 124.50, 120.90, © 74.49, 62.14, 53.51, 45.94, 38.81, 28.23, 14.63, 9.58; DEPT spectrum:

quaternary carbon atoms δ 169.85, 165.53, 154.10, 140.14,

134.59, 130.74, 124.82, 124.69; CH carbon atoms δ 133.51, 129.69,

128.98, 126.74, 124.50, 120.90, 74.49, 53.51, 45.94; CH ₂ carbon atoms δ 62.14, 38.81, 28.23; CH ₃ carbon atoms δ 14.63, 9.58; IR (deviation) 3278 (m), 2400-3100 (broad), 1703 (vs); MS (ES +) m / z (relative intensity) 358 (M + H + CH ₃ CN ⁺ , 55), 317 (M + H ⁺ , 7), 300 (100); theoretically calculated for the formula CisHw ^ C ^ Fs.CgHyCU: C, 58.18; H, 5.29; N, 5.65. Found: C, 57.99; H, 5.15; N, 5.64; Chiral HPLC: mobile phase 950: 50: 2 n-hexane: 2-propanol: HOAc, φ flow rate 1.50 µl / min, column temperature 40 ° C, chiralpak ™ AD

4.6 x 250 mm, sample concentration approximately 0.5 mg / ml in approximately 1: 1 n-hexane: 2-propanol. Authentic racemate shows retention times of 7.5 min and 10.0 min of the (2R, 48I-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline) hemi - (-) - dibenzoyl-tartrate salt of ethyl ester -1-carboxylic acid:

10.0 min, 88.9%, 7.5 min «1%, 2.0 min (solvent front)

11.1%; [α] _D = -153 (c = 1.07, CH ₃ OH).

··

Example 7

(-) - (2K48) -4- (3,5-Bis-trifluoromethyl-benzyl-amino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tosylate salt force acid

(2R, 4S) -4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (-) - dibenzoyl-1-tartarate salt of ethyl ester (13.0g, 26.2 mmol, 1.0 equiv) was suspended in 1,2 dichloroethane (260 ml) in a 500 ml separating funnel. The mixture was washed 1 x 65 ml of 1N NaOH, 2 x 65 ml of saturated sodium chloride solution and dried (MgSO ₄ ). The mixture was filtered, concentrated to approximately 80 ml and transferred to 250 ml three-necked flasks. 3,5-Bis (trifluoromethyl) benzaldehyde (4.53 ml, 27.5 mmol, 1.05 equiv) was added and the mixture was stirred for 1 hour at room temperature under nitrogen. Sodium triacetoxyborohydride (11.1 g, 52.4 mmol, 2.0 equiv.) Was added in one portion and the white butterfly was stirred for 18 hours. 50 ml of 1,2-dichloroethane and 50 ml of 2N NaOH were added and the aqueous layer was extracted with 2 x 50 ml of 1,2-dichloroethane. The combined organic extracts were washed 1 x 31 ml 1N HCl, 1 x 50 ml saturated aqueous NaHCO ₃ , 1 x 50 ml saturated sodium chloride and dried (Na ₂ SO ₄ ). The mixture was filtered and concentrated to a clear oil. The oil was dissolved in methanol (71 ml). P-Toluenesulfonic acid monohydrate (5.23 gm 27.5 mmol, 1.05 equiv) was added. After 5 minutes, 284 ml of isopropyl ether were added. The solution was concentrated to approximately 35 ml, transferred to 500 ml three-necked flasks (bubble stirrer) and diluted with 284 ml of isopropyl ether. A dense white whisk forms for 10 minutes. After stirring for 3 hours, the slurry was filtered and the solidified mass was washed with 2 x 70 ml isopropyl ether. After drying, the (-) - (2R, 4S) -4- (3,5-bistrifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- tosylate ethyl ester salt carboxylic acid was isolated as a white powder (16.18 g, 86% total): mp 191 -192 ° C; ¹ H NMR (DMSO-d 6, 400 MHz) δ 0.78 (t, 3H, J = 7.5 Hz), 1.21 (t, 3H, J = 7.0 Hz), 1.5 (m, 3H), 2.24 (s, 3H). 3.08 (m, 1H), 4.17 (m, 2H), 4.41 (m, 1H), 4.50 (m, 2H), 4.79 (m, 1H), 7.04 (d, 2H, J = 7.9 Hz), 7.42 (d , 2H, J = 7.9 Hz), 7.7 (m, 2H), 7.81 (s, 1H), 8.21 (s, 1H), 8.35 (s, 2H), 9.58 (br s, 1H), 9.83 (br s. 1H); ¹³ C NMR (DMSO-d6, 100 MHz) δ 154.00, 145.46, 140.21, 138.39, 135.33, 132.51, 131.62, 130.79 (q, J = 33.2 Hz), 128.49, 127.40, 125.82, 125.36, 124.99 (q, J = 31.7 Hz), 124.59 (q, J = 271 Hz), 123.69 (q, J = 273 Hz), 123.44, 120.33, 62.32, • 53.99, 53.79, 47.98, 33.30, 28.61, 21.13, 14.63, 9.58; DEPT spectrum: quaternary carbon atoms δ154.00, 145.46, 140.21, 138.39, 135.33, 130.79, 124.99, 124.59, 123.69; CH carbon atoms δ 132.51, 131.62, 128.49, 127.40, 125.82, 125.36, 123.44, 120.33, 53.99, 53.79;

CH ₂ carbon atoms δ 62.32, 47.98, 33.30, 28.61; CH ₃ carbon atoms δ 21.13, 14.63, 9.58: IR (deviation) 2300-3100 (broad), 2974 (t), 2731 (t), 2620 (t), 2455 (t), 1714 (s), 1621 (t ), 1283 (vs), 1169 (vs), 1126 (vs); MS (ES +) m / z (relative intensity) 584 (M + H + CH ₃ CN ⁺ , 100), 543 (M + H ⁺ , 80); theory. also calculated for formula C ₂ 4H ₂₃ N ₂ O ₂ F9.C ₇ H ₈ O ₃ S: C, 52.11; H, 4.37; N, 3.92. Found: C, 52.15; H, 4.22; N, 3.69; [α] ^D = - • 77.9 (0 = 1.05, CH 3 OH).

Example 8

(-H2R, 4S) -4 - [(3,5-Entrifluoromethyl-benzyl) -methoxycarbonyl-amino-2-ethyl-6-trisfluoromethyl-3,4-dihydro-2H-quinoline mono ethanolate 1-carboxylic acid

Na ₂ CO ₃ (s) (6.75 g, 63.7 mmol, 3.5 eq.) Was added at room temperature to a solution of the tosylate salt of (-) - (2R, 4S) -4- (3,5-bis) ethyl ester. -trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (13.0 g, 18.2 mmol, 1.0 equiv) in dry THF (130 ml). Pure methyl chloroformate (3.51 ml, 45.5 mmol, 2.5 equiv.) Was added dropwise in 51%.

for 2 minutes. After 24 hours, the mixture was concentrated to 65 ml, diluted with 260 ml ethyl acetate and transferred to a separatory funnel. The mixture was washed with 1 x 90 ml of 1N HCl (CO ₂ separation), 1 x 90 ml of saturated aqueous NaHCO ₃ , 1 x 90 ml of saturated sodium chloride solution and dried (MgSO ₄ ). Filtration and concentration of the filtrate yielded a clear oil which was treated with 3 x 33 ml of 2B ethanol. The oil was dissolved in 33 ml of 2B ethanol and nucleation was formed with several milligrams of (-) - (2R, 48) -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxy-carbonyl-carbonyl- amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid. After stirring for 18 hours at room temperature, the slurry was filtered and dried to give (-) - (2R, 4S) -4 - [(3,5-6mtrifluoromethyl-benzyl) -methoxycarbonyl-amino] - ethyl ester mono ethanolate - 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid as crystalline white powder (8.66 g, 74%): mp 54-58 ° C; ¹ H NMR (CDCl 3, 400 MHz, 55 ° C) δ 0.73 (t, 3H, J = 7.0 Hz), 1.20 (t, EtOH), 1.27 (t, 3H, J = 7.1 Hz), 1.42 (m, 2H ), 1.66 (m, 1H), 2.25 (brs, 1H), 3.67 (q, EtOH), 3.79 (s, 3H), 4.2 (m, 3H), 4.33 (m, 1H), 5.2 (brs, 2H) , 7.12 (s, 1H), 7.49 (d, 1H, J = 8.3 Hz), δ 7.57 (d, 1H, J = 8.5 Hz), 7.73 (s, 2H), 7.78 (s, 1H); ¹³ C NMR (CDCl 3, 400

MHz) δ 157.74, 154.37, 141.73, 140.05, 133.83, 132.14 (q, J = 33 Hz), 126.94, 124.49, 123.96 (q, J = 273 Hz), 123.13 (q, J = 273 Hz), 121.31, 119.17 , 62.29, 58.28, 54.42, 53.71, 53.08, 46.67, 37.01, 29.02, 18.29, 14.32, 9.22, (note: the fourth four appears to be covered below 126.94 peak, with J approximately 32 Hz); DEPT spectrum: quaternary carbon atoms δ 157.74, 154.37, 141.73, 140.05, 133.83, 132.14, 123.96, 123.13; CH carbon atoms δ 126.94, 124.49, 121.31, 119.17, 54.42, 53.08; CH ₂ carbon atoms δ 62.29, 58.28, 46.67, 37.01, 29.02;

CH ₃ carbon atoms δ 53.71, 18.29, 14.32, 9.22; IR (deviations) 3489 (s), 2974 (s), 2884 (m), 1701 (vs), 1280 (vs), 1131 (vs); MS (ES +) δ · 9 ···· m / z (relative intensity) 601 (M + H ⁺ , 100); calculated for the formula C26H25N2O4F9.C2H6O: C, 52.01; H, 4.83; N, 4.33. Found: C, 51.84; H, 4.54; N, 4.33; chiral HPLC: mobile phase 950: 50: 2 n-hexane: 2 propanol: HOAc, flow rate 1.0 ml / min, 254 nm, chiralpak AD 4.6 x 250 mm column temperature 40 ° C, sample concentration approximately 0.5 mg / ml at 90:10 n-hexane: 2-propanol, authentic racemate retention time 3.6 and 4.6 min. (-) - (2R, 4S) -4 - (((3,5-Bis-trifluoromethylbenzyl) ethyl ester mono ethanolate) ) -methoxy-carbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4® dihydro-2H-quinoline-1-carboxylic acid shows 4.6 min, 99.1% and 3.6 min, not found; [a] ^D = -93.3 (c = 1.08, CH3OH).

Example 9

(-H2R, 48) -4-N (3,5-Bis-trifluoromethylbenzyl) -methoxycarbonyl-amino-2-ethyl-6-trifluoromethyl-3,4-di anhydrous ethyl ester | hydro-2H-quinoline-1-carboxylic acid.

Portion of 2.6 g of 4 (S) - [(3,5-bis-trifluoromethylbenzyl) -methoxycarbonyl-amino] -2 (R) -ethyl-6-trifluoromethyl-3,4I dihydro-2H-quinoline ethyl ester- 1-carboxylic acid (a mixture of predominantly amorphous material with traces of ethanolate in crystalline form;

| The main compound was also prepared in an analogous manner, starting from pure amorphous or pure ethanolate material) was placed on 13 ml of hexanes and heated to obtain a solution at about 60 ° C. Heating was interrupted and the reaction was allowed to cool to room temperature for about one hour. The reaction mixture was seeded with anhydrous ethyl ester of (-) - (2P, 48) -4 - ((3,5-bis-trifluoromethyl-benzyl) methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2Hquinoline-1-carboxylic acid and was granulated for 18 hours at room temperature Alternatively, anhydrous crystals can be obtained from hexanes without germination The product is collected!

ΐ!

·· by filtration and air-dried. The X-ray diffraction characteristics of the isolated product corresponds to the calculated powder characteristics.

Density: 1,406

Crystal system: Trigonal

Microscopy: Well-formed rods and isometric (cracked rods) crystals exhibiting high double-beam values when observed perpendicular to the C axis. Being in the Trigonal Crystal System, non-F crystals exhibit a double refraction when observed parallel to the C axis. The crystals exhibit cleavage perpendicular to the C axis.

Fusion microscopy: In type A oil ------ dissolved at 50 ° C.

Dry ------------------- Clear melt at 86 ° C.

NMR: No trace of ethanolate

Degree of crystallinity: Highly crystalline

Hygroscopicity: Non-hygroscopic at 100% relative humidity for 48 hours.

Appearance: Freely rising white powder.

u The X-ray diffractometrically determined d-plane distance is presented in Table 2.

WMUnUHIH'iTl

• · • · «· • · • · • • • · • · ··· • • · • · · • ♦ · • • · • · • · • · · · • · ·· • *

• · · • · · · · · · ·

TABLE 2

Anode: CU - Wavelength 1: 1.54056 Wavelength 2: 1.54439 (relative intensity 0.500

Range # 1 - Combined: 3,000 to 40,000 Step Size: 0.040 Step Duration: 1.00 Smoothing Width: 0.300 Threshold: 1.0

d (A) 1 (rel) d (A) l (rel) d (A) l (rel) 11.21659 34.8 5.52958 60.0 4.04469 36.6 10.50618 12.0 5.39152 75.7 3.89345 39.6 9.66890 11.0 5.24818 80.5 3.72038 80.7 8.88669 4.1 4.84992 13.2 3.64330 15.0 7.31083 3.7 4.44170 100.0 3.49463 5.9 6.34185 56.4 4.32558 16.8 3.44831 7.2 6.09484 5.9 4.25150 31.0 3.33631 14.7 5.92806 38.4 4.08413 42.7 3.22157 6.7

d (A) Krel) d (A) l (rel) 3.16983 8.3 2.57207 8.5 3.11970 14.0 2.49503 3.6 2.96985 16.3 2.44562 2; 87051 8.7 2.42250 2.81002 6.8 2.38844 2.75539 6.8 2.36135 2.70226 3.6 2.32612 2.64524 8.9

Example 10

(-H2R, 4S) -44 (3, 5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-2-ethyl-6-trifluoromethyl-ethyl mono ethanolate

3,4-Dihydro-2H-quinoline-1-carboxylic acid

4.0 g of (-) - (2R, 43) ~ 4 - [(3,4-bis-trifluoromethyl-benzyl) methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro- 2Hquinoline-1-carboxylic acid was dissolved in 3.5 ml of ethanol and sonicated for two minutes until complete dissolution. A white solid was formed to which 10 ml of ethanol was added and stirred at room temperature overnight. White dust

···· filtered and collected on 0.22 µm LS filter paper, then washed with about 15 ml of ethanol. The X-ray picture of the isolated product coincides with the calculated powder picture. Density: 1.042

Crystal system: orthorhombic

Microscopy: crystalline needles with moderate double radiation. Fusion Microscopy: For Type A oil - melting and dissolving at 43 ° C with loss of water

Dry ------------- Clear melt at 43 ° C. NMR: shows ethanol on solvation

Degree of crystallinity: high crystalline

Hygroscopicity: non-hygroscopic Appearance: free-rising white powder X-ray diffraction determination of the d-interplanar space is presented in Table 3.

TABLE 3

Anode: CU-Wavelength 1: 1.54056 Wavelength 2: 1.54439 (Relative Intensity: 0.500)

Range # 1- combined: 3,000 to 40,000 Step size: 0.040 Step length: 1.00

Smoothing width: 0.300 Threshold: 1.0

d (A) 1 (rel) d (A) Krel) d (A) Krel) 22.15759 37.6 5.69284 6.9 4.18443 23.3 8.61222 15.1 5.45839 5.8 4.03073 30.9 8.15185 9.5 5.19975 19.0 3.96396 33.9 7.83462 47.0 4.90695 53.6 3.83314 35.0 7.47295 100.0 4.68527 42.1 3.77447 40.8 7.00403 9.6 4.80453 18.9 3.72125 33.1 6.46476 17.2 4.38780 16.3 3.62106 26.6 6.23035 14.8 4.30354 19.7 3.52462 17.1 5.90921 7.9

d (A) Krel) d (A) Krel) 3.44170 12.6 2.77147 5.0 3.35282 6.7 2.70399 7.5 3.25110 11.7 2.63859 4.6 3.12884 5.7 2.53872 6.4 3.03164 4.4 2.49493 5.3 2.94892 5.8 2.47186 5.0 2.86853 4.2 2.34837 4.7 2.79318 4.3 2.26951 4.1

Example 11 (-H2R, 48) -4-N (3,5-Bis-trifluoromethylbenzyl) -methoxycarbonyl-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 anhydrous ethyl ester - carboxylic acid.

A crude solution of about 42 g of (-) - (2R, 4S) -4 - [(3,5bis-trifluoromethylbenzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro ethyl ester -2H-quinoline-1-carboxylic acid in · 99 · 99

9 9 9 9 9 9 • 9 9 9 9 999 • · 9 9 9 9 9 • 9 9 9 9 9 ···· 99 99 99

500 ml of ethyl acetate (obtained by the process described in Example 8) was concentrated in vacuo to a volume of 100-135 ml. The remaining ethyl acetate was displaced with 3 x 220ml 2B EtOH to a final volume of 100-135 ml. In this solution, a single crystal crystal formation of anhydrous (-) - (2I, 4B) -4 - [(3,5-bis-tri-fluoromethylbenzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoro was formed -methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid. After stirring for 18 hours at room temperature, the slurry was filtered and dried in vacuo to give 19.81 g of anhydrous (-) - (2P, 45) -4 - [(3,5-bis-trifluoro-) ethyl ester. methylbenzyl) methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2Hquinoline-1-carboxylic acid. The behavior at the melting point is the same as the material obtained in the manner of Example 9, which confirms the anhydrous nature of the material.

Claims (21)

Patent Claims A crystalline form of the compound of formula I 2. Crystal which is anhydrous ethyl ester of [2R, 4S] 4 - [(3,5-bistrifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid. 3. A crystal that is ethanolate of [2R.4S] 4 - [(3,5-bistrifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- ethyl ester. quinoline-1-carboxylic acid. A crystal according to claim 1, which is an anhydrous crystal having a powder X-ray diffractometric analysis at the d-interplanar distance. • 9 9999 ·· 9 99 • · · · • · · Anode: CU - Wavelength 1: 1.54056 Wavelength 2: 1.54439 (relative intensity 0.500 Range # 1 - Combined: 3,000 to 40,000 Step Size: 0.040 Step Length: 1.00 Smoothing Width: 0.300 Threshold: 1.0 d (A) 1W. d (A) l (rel) d (A) l (rel) 11.21659 34.8 5.52958 60.0 4.04469 36.6 10.50618 12.0 5.39152 75.7 3.89345 39.6 9.66890 11.0 5.24818 80.5 3.72038 80.7 8.88669 4.1 4.84992 13.2 3.64330 15.0 7.31083 3.7 4.44170 100.0 3.49463 5.9 6.34185 56.4 4.32558 16.8 3.44831 7.2 6.09484 5.9 4.25150 31.0 3.33631 14.7 5.92806 38.4 4.08413 42.7 3.22157 6.7 d (A) Krel) d (A) Krel) 3.16983 8.3 2.57207 8.5 3.11970 14.0 2.49503 3.6 2.96985 16.3 2.44562 2.87051 8.7 2.42250 2.81002 6.8 2.38844 2.75539 6.8 2.36135 2.70226 3.6 2.32612 2.64524 8.9 f. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 40 · · · · · · · · «* I» »» 5. The crystal of claim 1, which is an ethanolate crystal having a powder X-ray diffraction analysis at the d-interplanar distance Anode: CU-Wavelength Τ. 1.54056 Wavelength 2: 1.54439 (Relation Intensity: 0.500) Range # 1- combined: 3,000 to 40,000 Step size: 0.040 Step duration: 1.00 Smoothing width: 0.300 Threshold: 1.0 d (A) 1 (rel) d (A) l (rel) d (A) Krel) 22.15759 37.6 5.69284 6.9 4.18443 23.3 8.61222 15.1 5.45839 5.8 4.03073 30.9 8.15185 9.5 5.19975 19.0 3.96396 33.9 7.83462 47.0 4.90695 53.6 3.83314 35.0 7.47295 100.0 4.68527 42.1 3.77447 40.8 7.00403 9.6 4.80453 18.9 3.72125 33.1 6.46476 17.2 4.38780 16.3 3.62106 26.6 6.23035 14.8 4.30354 19.7 3.52462 17.1 5.90921 7.9 d (A) . Krel) d (A) l (rel) 3.44170 12.6 2.77147 5.0 3.35282 6.7 2.70399 ^z 7.5 3.25110 11.7 2.63859 4.6 3.12884 5.7 2.53872 6.4 3.03164 4.4 2.49493 5.3 2.94892 5.8 2.47186 5.0 2.86853 4.2 2.34837 4.7 2.79318 4.3 2.26951 4.1 A pharmaceutical composition comprising a therapeutically effective amount of the crystal of claim 1 and a pharmaceutically acceptable carrier, vehicle or diluent. • · · · 7. The pharmaceutical composition as claimed in claim 6, wherein the pharmaceutical preparation for the treatment of atherosclerosis, peripheral vascular disease, dyslipemia, hyperbeta-lipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hyperhistemia, familial-hyperhistomia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular disorders in diabetes, obesity or endotoxemia, includes a therapeutic amount of a crystal with to Claim 1 and a pharmaceutically acceptable carrier, vehicle or diluent. A pharmaceutical composition as claimed in claim 6 for the treatment of atherosclerosis comprising a therapeutic amount for an atherosclerosis crystal of Formula 1 and a pharmaceutically acceptable carrier, vehicle or diluent. A pharmaceutical preparation as claimed in claim 8, wherein the therapeutic amount for an atherosclerosis crystal of Formula I is about 0.1 to 10 mg / kg / day and the pharmaceutical preparation is obtained by dissolving the crystal according to claim 1 in oil. The pharmaceutical composition of claim 8, wherein the crystal of Formula I is anhydrous. The pharmaceutical composition of claim 8, wherein the crystal of Formula I is an ethanolate crystal. A method for inhibiting CERT in a mammal in need thereof, characterized in that a CERT inhibitory amount of the crystal of Formula I is introduced, as presented in claim 1. 13. The method of claim 12, wherein the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterochemia, anemia, hypercholesterolemia, infarction, reperfusion injury, angioplasty restenosis, hypertension, vascular disorders in diabetes, obesity or endotoxemia by administration to a mammal in need of such treatment for therapeutic effective amount of a crystal of Formula I. The method of claim 13, wherein atherosclerosis is treated with a therapeutic amount for atherosclerosis from a crystal of Formula I. The method of claim 14, wherein the therapeutic amount for atherosclerosis of the crystal of Formula I is about 0.1 to 10 mg / kg / day and the crystal of Formula I is dissolved in oil. The method of claim 15, wherein the crystal of Formula I is anhydrous. The method of claim 15, wherein the salt of Formula I is ethanolate. • ·· · · · · ··· ···· ·· ·· ·· ·· 4? Y ·· 18. Process for the preparation of crystalline anhydrous ethyl ester of [2R.4S] 4 - [(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid, characterized in that it is dissolved or blends [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro2H-quinoline-1-carboxylic acid ethyl ester in hexanes at room temperature for about 2 to about 24 hours, wherein said precursor is not anhydrous crystalline form. 19. Process for the preparation of crystalline ethanolate of [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid by dissolving or mixing ethyl ester of [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3 , 4-dihydro-2H-quinoline-1-carboxylic acid in ethanol / water at room temperature for about 0.5 to about 18 hours, where said precursor is not a crystalline ethanolate form. The process of claim 19, wherein the ethanol is used without water. 21. Process for the preparation of crystalline anhydrous ethyl ester of [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid, characterized in that dissolved or mixed ethyl ester of [2R.4S] 4 - [(3,5-bis-trifluoromethylbenzyl) -methoxycarbonyl-amino] -2-ethyl-6 -trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid in ethanol at room temperature · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 44 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ENIC is not the anhydrous crystalline form.