OA12099A

OA12099A - 4-Carboxyamino-2-ethyl-1,2,3,4-tetrahydroquinolinecrystal as CETP inhibitor.

Info

Publication number: OA12099A
Application number: OA1200200158A
Authority: OA
Inventors: Douglas John Meldrum Allen; Troy Anthony Appleton; Lyle Robinson Brostrom; Derek Lawrence Tickner
Original assignee: Prifzer Products Inc
Priority date: 1999-11-30
Filing date: 2000-11-14
Publication date: 2006-05-04
Also published as: AP2002002531A0; PE20010904A1; AU1048801A; HUP0203521A2; CA2392979A1; IS6338A; CO5271716A1; EA200200510A1; EE200200277A; BG106854A; MA26845A1; UY26454A1; ECSP003792A; MXPA02005354A; TNSN00231A1; GT200000199A; WO2001040190A1; EP1246804A1; NO20022558L; KR20020058057A

Abstract

Crystalline forms of a CETP inhibitor of formula (I), methods of making the crystals, methods of using the crystals and pharmaceutically compositions containing the crystals are disclosed.

Description

-1- 1 2 099

4-CARBOXYAMlNO-2-ETHYL-l,2.3,4-TETRAHYDROQUINOLÎNECRYSTAL AS CETP INHIBfTOR

Backqround Of The Invention

This invention relates to cholesteryl ester transfer protein (CETP) inhibitors,pharmaceutical compositions containing such inhibitors and the use of such inhibitorsto elevate certain plasma lipid levels, including high density lipoprotein (HDL)-cholesterol and to lower certain other plasma lipid levels, such as low densitylipoprotein (LDL)-cholesterol and triglycérides and accordingly to treat diseases whichare affected by low levels of HDL cholestérol and/or high levels of LDL-cholesteroland triglycérides, such as atherosclerosis and cardiovascular diseases in certainmammals (i.e., those which hâve CETP in their plasma), including humans.

More particularly, this invention relates to CETP inhibitor crystais,pharmaceutical compositions comprising these crystais, a process for preparingthese crystais and to methods of treating atherosclerosis, obesity, and relateddiseases and/or conditions with the crystais.

Atherosclerosis and its associated coronary artery disease (CAD) is the z t, leading cause of mortality in the industrialized world. Despite attempts to modifysecondary risk factors (smoking, obesity, lack of exercise) and treatment ofdyslipidemia with dietary modification and drug therapy, coronary heart disease(CHD) remains the most common cause of death in the U.S., where cardiovasculardisease accounts for 44% of ail deaths, with 53% of these associated withatherosclerotic coronary heart disease.

Risk for development of this condition has been shown to be stronglycorrelated with certain plasma lipid levels. While elevated LDL-cholesterol may bethe most recognized form of dyslipidemia, it is by no means the only significant lipidassociated contributor to CHD. Low HDL-cholesterol is also a known risk factor forCHD (Gordon, D.J., et al.,: “High-density Lipoprotein Cholestérol and CardiovascularDisease”, Circulation, (1989), 79: 8-15).

High LDL-cholesterol and triglycéride levels are positively correlated, whilehigh levels of HDL-cholesterol are negatively correlated with the risk for developingcardiovascular diseases. Thus, dyslipidemia is not a unitary risk profile for CHD butmay be comprised of one or more lipid aberrations.

Among the many factors controlling plasma levels of these diseasedépendent principles, cholesteryl ester transfer protein (CETP) activity affects ail -2- 1 2 09 9 three. The rôle of this 70,000 dalton plasma glycoprotein found in a number of animalspecies, including humans, is to transfer cholesteryl ester and triglycéride betweeniipoprotein particles, including high density iipoproteins (HDL), low density lipoproteins(LDL), very low density lipoproteins (VLDL), and chylomicrons. The net resuit of 5 CETP activity is a lowering of HDL cholestérol and an increase in LDL cholestérol.This effect on Iipoprotein profile is believed to be pro-atherogenic, especially insubjects whose lipid profile constitutes an increased risk for CHD.

No wholly satisfactory HDL-elevating thérapies exist. Niacin can significantlyincrease HDL, but has serious toleration issues which reduce compliance. Fibrates 10 and the HMG CoA reductase inhibitors raise HDL-C only modestiy (-10-12%). As a resuit, there is a significant unmet medical need for a well-tolerated agent which cansignificantly elevate plasma HDL levels, thereby reversing or slowing the progressionof atherosclerosis.

Commonly assigned U.S. application ser. No. 09/391,152 filed September 7, 15 1999 entitled 4-CARBOXYAMINO-2-SUBSTITUTED-1,2,3,4- TETRAHYDROQUINOLINES, the disclosure of which is hereby incorporated byreference, is directed to compounds of the following'general formula:

20

Specifically, the compound [2R.4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is described.

Thus, although there are a variety of anti-atherosclerosis thérapies, there is a25 continuing need and a continuing search in this field of art for alternative thérapies. -3-

jyy

Summary Of The InventionThis invention is directed to a Formula I crystai

Aiternatively, a crystai of the above Formula I is named as [2R.4S] 4-5 [(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyI-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester.

Another aspect of this invention is directed to an anhydrous crystai of Formula I.

Another aspect of this invention is directed to the corresponding anhydrous10 crystai having the X-ray powder diffraction pattern as shown in Figure 1.

Another aspect of this invention is directed to an ethanolate crystai of Formula

Another aspect of this invention is directed to the corresponding ethanolatecrystai having the X-ray powder diffraction pattern as shown in Figure 2. 15 A preferred dosage is about 0.01 to 100 mg/kg/day of a Formula I crystai. An especially preferred dosage is about 0.1 to 10 mg/kg/day of a Formula I crystai.

In the text herein including the following methods, pharmaceuticalcompositions, combinations.and kits reference is made to a crystai of Formula I.While it is understood that if the crystai is in solution, the crystai form is not présent 20 (in contrast to e.g., a dry tablet formulation), the following methods pharmaceuticalcompositions combinations and kits are intended to include a method or formulation 1 2 09 9 -4- resulting from a use of such crystal (e.g., administering a gelatin capsule including anoil formulation solution of the crystal).

Yet another aspect of this invention is directed to methods for treatingatherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia,stroke, myocardial infarction, reperfusion injury, angioplastie restenosis, hypertension,vascular complications of diabètes, obesity or endotoxemia in a mammal (including ahuman being either male or female) by administering to a mammal in need of suchtreatment an atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia,hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury,angioplastie restenosis, hypertension, vascular complications of diabètes, obesity orendotoxemia treating amount of a Formula I crystal.

Yet another aspect of this invention is directed to a method for treatingatherosclerosis in a mammal (including a human be'ing) by administering to amammal in need of such treatment an atherosclerosis treating amount of a Formula Icrystal.

Yet another aspect of this invention is directed to a method for treatingperipheral vascular disease in a mammal (including a human being) by administeringto a mammal in need of such treatment a peripheral vascular disease treatingamount of a Formula I crystal.

Yet another aspect of this invention is directed to a method for treatingdyslipidemia in a mammal (including a human being) by administering to a mammalin need of such treatment a dyslipidemia treating amount of a Formula I crystal.

Yet another aspect of this invention is directed to a method for treatinghyperbetalipoproteinemia in a mammâl (including a human being) by administering toa mammal in need of such treatment a hyperbetalipoproteinemia treating amount of aFormula I crystal.

Yet another aspect of this invention is directed to a method for treatinghypoalphalipoproteinemia in a mammal (including a human being) by administering toa mammal in need of such treatment a hypoalphalipoproteinemia treating amount ofa Formula I crystal. -5- 1 2099

Yet another aspect of this invention is directed to a method for treatinghypercholesterolemia in a mammal (including a human being) by administering to amammal in need of such treatment a hypercholesterolemia treating amount of aFormula I crystal.

Yet another aspect of this invention is directed to a method for treatinghypertriglyceridemia in a mammal (including a human being) by administering to amammal in need of such treatment a hypertriglyceridemia treating amount of aFormula I crystal.

Yet another aspect of this invention is directed to a method for treatingfamilial-hypercholesterolemia in a mammal (including a human being) byadministering to a mammal in need of such treatment a familial-hypercholesterolemia treating amount of a Formula I crystal.

Yet another aspect of this invention is directed to a method for treatingcardiovascular disorders in a mammal (including a human being) by administering toa mammal in need of such treatment a cardiovascular disorder treating amount of aFormula I crystal.

Yet another aspect of this invention is directed to a method for treating anginain a mammal (including a human being) by administering to a mammal in need ofsuch treatment an angina treating amount of a Formula I crystal.

Yet another aspect of this invention is directed to a method for treatingischemia in a mammal (including a human being) by administering to a mammal inneed of such treatment an ischémie disease treating amount of a Formula I crystal.

Yet another aspect of this invention is directed to a method for treatingcardiac ischemia in a mammal (including a human being) by administering to amammal in need of such treatment a cardiac ischémie treating amount of a Formula Icrystal.

Yet another aspect of this invention is directed to a method for treating strokein a mammal (including a human being) by administering to a mammal in need ofsuch treatment a stroke treating amount of a Formula I crystal.

Yet another aspect of this invention is directed to a method for treating amyocardial infarction in a mammal (including a human being) by administering to amammal in need of such treatment a myocardial infarction treating amount of aFormula I crystal. -6-

Yet another aspect of this invention is directed to a method for treatingreperfusion injury in a mammal (including a human being) by administering to amammal in need of such treatment a reperfusion injury treating amount of a FormulaI crystal.

Yet another aspect of this invention is directed to a method for treatingangioplastie restenosis in a mammal (including a human being) by administering to amammal in need of such treatment an angioplastie restenosis treating amount of aFormula I crystal.

Yet another aspect of this invention is directed to a method for treatinghypertension in a mammal (including a human being) by administering to a mammalin need of such treatment a hypertension treating amount of a Formula I crystal.

Yet another aspect of this invention is directed to a method for treating thevascular complications of diabètes in a mammal (including a human being) byadministering to a mammal in need of such treatment a vascular complications ofdiabètes treating amount of a Formula I crystal.

Yet another aspect of this invention is directed to a method for treating obesityin a mammal (including a human being) by administering to a mammal in need ofsuch treatment an obesity treating amount of a Formula I crystal.

Yet another aspect of this invention is directed to a method for treatingendotoxemia in a mammal (including a human being) by administering to a mammalin need of such treatment an endotoxemia treating amount of a Formula I crystal.

This invention is also directed to pharmaceutical compositions which comprisea therapeutically effective amount of a crystal of Formula I and a pharmaceuticaliyacceptable carrier, vehicle or diluent.

This invention is also directed to pharmaceutical compositions for thetreatment of atherosclerosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia,hypertriglyceridemia, familial-hyperch'olesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury,angioplastie restenosis, hypertension, vascular complications of diabètes, obesity orendotoxemia in a mammal (including a human being) which comprise atherapeutically effective amount of a crystal of Formula I and a pharmaceuticaliyacceptable carrier, vehicle or diluent. 1 2099 -7-

This invention is also directed to pharmaceutical compositions for thetreatment of atherosclerosis in a mammal (including a human being) which comprisean atherosclerosis treating amount of a crystal of Formula I and a pharmaceuticallyacceptable carrier, vehicle or diluent.

This invention is also directed to pharmaceutical compositions for thetreatment of peripheral vascular disease in a mammal (including a human being)which comprise a peripheral vascular disease treating amount of a crystal of FormulaI and a pharmaceutically acceptable carrier, vehicle or diluent

This invention is also directed to pharmaceutical compositions for thetreatment of dyslipidemia in a mammal (including a human being) which comprise adyslipidemia treating amount of a crystal of Formula I and a pharmaceuticallyacceptable carrier, vehicle or diluent.

This invention is also directed to pharmaceutical compositions for thetreatment of hyperbetalipoproteinemia in a mammal (including a human being) whichcomprise a hyperbetalipoproteinemia treating amount of a crystal of Formula I and apharmaceutically acceptable carrier, vehicle or diluent.

This invention is also directed to pharmâceutical compositions for thetreatment of hypoalphalipoproteinemia in a mammal (including a human being) whichcomprise a hypoalphalipoproteinemia treating amount of a crystal of Formula I and apharmaceutically acceptable carrier, vehicle or diluent.

This invention is also directed to pharmaceutical compositions for thetreatment of hypercholesterolemia in a mammal (including a human being) whichcomprise a hypercholesterolemia treating amount of a crystal of Formula I and apharmaceutically acceptable carrier, vehicle or diluent.

This invention is also directed to pharmaceutical compositions for thetreatment of hypertriglyceridemia in a mammal (including a human being) whichcomprise a hypertriglyceridemia treating amount of a crystal of Formula I and apharmaceutically acceptable carrier, vehicle or diluent.

This invention is also directed to pharmaceutical compositions for thetreatment of familial-hypercholesterolemia in a mammal (including a human being)which comprise a familial-hypercholesterolemia treating amount of a crystal ofFormula I and a pharmaceutically acceptable carrier, vehicle or diluent.

This invention is also directed to pharmaceutical compositions for thetreatment of angina in a mammal (including a human being) which comprise an -8- 1 2 099 angina treating amount of a crystal of Formula I and a pharmaceutically acceptablecarrier, vehicle or diluent.

This invention is aiso directed to pharmaceutical compositions for thetreatment of ischemia in a mammal (including a human being) which comprise anischémie treating amount of a crystal of Formula I and a pharmaceutically acceptablecarrier, vehicle or diluent.

This invention is also directed to pharmaceutical compositions for thetreatment of cardiac ischemia in a mammal (including a human being) whichcomprise a cardiac ischémie treating amount of a crystal of Formula I and apharmaceutically acceptable carrier, vehicle or diluent.

This invention is also directed to pharmaceutical compositions for thetreatment of stroke in a mammal (including a human being) which comprise a stroketreating amount of a crystal of Formula I and a pharmaceutically acceptable carrier,vehicle or diluent.

This invention is also directed to pharmaceutical compositions for thetreatment of a myocardial infarction in a mammal (including a human being) whichcomprise a myocardial infarction treating amount of.a crystal of Formula I and apharmaceutically acceptable carrier, vehicle or diluent.

This invention is also directed to pharmaceutical compositions for thetreatment of reperfusion injury in a mammal (including a human being) whichcomprise a reperfusion injury treating amount of a crystal of Formula I and apharmaceutically acceptable carrier, vehicle or diluent..

This invention is also directed to pharmaceutical compositions for thetreatment of angioplastie restenosis in a mammal (including a human being) whichcomprise an angioplastie restenosis treating amount of a crystal of Formula I and apharmaceutically acceptable carrier, vehicle or diluent.

This invention is also directed to pharmaceutical compositions for thetreatment of hypertension in a mammal (including a human being) which comprise ahypertension treating amount of a crystal of Formula I and a pharmaceuticallyacceptable carrier, vehicle or diluent.

This invention is also directed to pharmaceutical compositions for thetreatment of the vascular complications of diabètes in a mammal (including a humanbeing) which comprise a vascular complications of diabètes treating amount of acrystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent. -9- 1 2 099

This invention is also directed to pharmaceutical compositions for thetreatment of obesity in a mammal (inciuding a human being) which comprise anobesity treating amount of a crystal of Formula I and a pharmaceutically acceptablecarrier, vehicle or diluent.

This invention is also directed to pharmaceutical compositions for thetreatment of endotoxemia in a mammal (inciuding a human being) which comprise anendotoxemia treating amount of a crystal of Formula I and a pharmaceuticallyacceptable carrier, vehicle or diluent.

This invention is also directed to a pharmaceutical combination compositioncomprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a Formula I crystal;a second compound, said second compound being an HMG-CoA reductase inhibitor, an microsomal triglycéride transfer protein (MTP)/Apo B sécrétion inhibitor,a PPAR activator, a bile acid reuptake inhibitor, a cholestérol absorption inhibitor, acholestérol synthesis inhibitor, a fibrate, niacin, an ion-exchange resin, anantioxidant, an ACAT inhibitor or a bile acid séquestrant; and/or optionally a pharmaceutical carrier, vehicle or diluent. '

Preferred among the second compounds are an HMG-CoA reductaseinhibitor and a MTP/Apo B sécrétion inhibitor. A particularly preferred HMG-CoA reductase inhibitor is lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.

Another aspect of this invention is a method for treating atherosclerosis in amammal comprising administering to a mammal suffering from atherosclerosis a first compound, said first compound being a Formula I crystal; anda second compound, said second compound being an HMG-CoA reductase inhibitor, an MTP/Apo B sécrétion inhibitor, a cholestérol absorption inhibitor, acholestérol synthesis inhibitor, a fibrate, niacin, an ion-exchange resin, anantioxidant, an ACAT inhibitor or a bile acid séquestrant wherein the amounts of thefirst and second compounds resuit in a therapeutic effect. A preferred aspect Of the above method is wherein the second compound isan HMG-CoA reductase inhibitor or an MTP/Apo B sécrétion inhibitor. A particularly preferred aspect of the above method is wherein the HMG-CoAreductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin orrivastatin. 1 2099 -10-

Yet another aspect of this invention is a kit comprising: a. a first compound, said first compound being a Formula I crystal, and apharmaceutically acceptable carrier in a first in a unit dosage form; b. a second compound, said second compound being an HMG CoAreductase inhibitor, an MTP/Apo B sécrétion inhibitor, a cholestérol absorptioninhibitor, a cholestérol synthesis inhibitor, a fibrate, niacin, an ion-exchange resin, anantîoxidant, an ACAT inhibitor or a bile acid séquestrant and a pharmaceuticallyacceptable carrier in a second unit dosage form; and c. means for containing said first and second dosage forms wherein theamounts of the first and second compounds resuit in a therapeutic effect. A preferred second compound is an HMG-CoA reductase inhibitor or anMTP/Apo B sécrétion inhibitor. A particularly preferred HMG-CoA reductase inhibitor is lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.

The présent invention is also directed to processes for preparing crystallineanhydrous [2R.4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino}-2-ethyl-6-trifiuoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester bydissolving or mixing [2R,4S] 4-[(3,5-bis-trifluoromethyI-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl esterin the presence of a suitable organic solvent, preferably hexanes.

Another aspect of this invention is directed to a process for preparingcrystalline ethanolate [2R.4S] 4-((3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifiuoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl esterby dissolving or mixing [2R,4S] 4-((3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl esterin ethanol/water at ambient température for about 0.5 to about 18 hours.

Preferably éthanol is used without water.

This invention is also directed to a process for preparing crystalline anhydrous(2R,4S( 4-((3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyi-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester comprisingdissolving or mixing [2R,4S] 4-[3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl esterin éthanol at ambient température for about 2 to about 24 hours. -11- 1 2099

It is noted thaï as the anhydrous and ethanolate crystals are of differentenergy levels seeding with either anhydrous or ethanolate may détermine theresulting isolated crystalline form. As is known in the art the presence of seedcrystals in the air in a iab may be sufficient “seeding.” In one embodiment anhydrouscrystals may be obtained using hexanes and the resulting anhydrous crystals may beused to seed the production of further anhydrous crystals from éthanol.

As used herein the term mammals is meant to refer to ail mammals whichcontain CETP in their plasma, for example, rabbits and primates such as monkeysand humans. Certain other mammals e.g., dogs, cats, cattle, goats, sheep andhorses do not contain CETP in their plasma and so are not included herein.

The term ethanolate refers to an éthanol of solvation.

The term “treating", “treat" or “treatment" as used herein includes preventative(e.g., prophylactic) and palliative treatment.

By "pharmaceutically acceptable" it is meant the carrier, vehicie, diluent,excipients, and/or sait must be compatible with the other ingrédients of theformulation, and not deleterious to the récipient thereof.

As used herein, the expressions "reactiôn-inert solvent" and “inert solvent"refers to a solvent or mixture of solvents which does not interact with startingmatériels, reagents, intermediates or products in a manner which adversely affectsthe yield of the desired product.

It will be recognized that the compound of this invention can exist inradiolabelled form, i.e., said compound may contain one or more atoms containing anatomic mass or mass number different from the atomic mass or mass number usuallyfound in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine andchlorine include 3K, 14C, æP, 35S, 18F and ^Cl, respectively. The compound of thisinvention which contains those radioisotopes and/or other radioisotopes of otheratoms is within the scope of this invention. Tritiated, i.e., 3H, and carbon-14, i.e., 14C,radioisotopes are particularly preferred for their ease of préparation and detectability. A radiolabelled compound of this invention can generally be prepared by methodswell known to those skilled in the art. Conveniently, such radiolabelled compoundscan be prepared by carrying out the procedures disclosed in the Examples below bysubstituting a readily available radiolabelled reagent for a non-radiolabelled reagent.

Other features and advantages will be apparent from the spécification anddaims which describe the invention. 1 2 099 -12-

Brief Description of the Drawings FIG. 1 is a characteristic x-ray powder diffraction pattern showing thatanhydrous [2R.4SJ 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoiine-1-carboxylic acid ethyl ester iscrystalline. (Vertical Axis: Intensity (CPS); Horizontal Axis: Two thêta (degrees)) FIG. 2 is the characteristic x-ray powder diffraction pattern of the ethanolate[2R.4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as crystallineVertical Axis: Intensity (CPS); Horizontal Axis: Two thêta (degrees))

Detailed Description Of The Invention

In general the compound of this invention can be made by processes whichinclude analogous processes known in the Chemical arts, particularly in light of thedescription contained herein. Certain processes for the manufacture of the compoundof this invention are provided as further features of the invention and are describedbelow including in the Examples.

The amorphous form of the compound of this invention [2R,4S] 4-[(3,5-bis-trifluoromethy!-benzyl)-methoxycarbonyl-amino]~2-ethyl-6-trifluoromethyi-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester is prepared as disclosed below (seeExample 1 ).

An anhydrous crystalline form of the above compound may be prepared fromthe amorphous compound by recrystallization from hexanes (solvent comprised ofhexane isomers (e.g., n-hexane, cyclohexane, methyl pentane, etc.)) at atempérature of about 40°C to about 80°C, preferably 60° followed typically bygranulating, for about 2 to about 24 hours, then filtering the material and subséquentair drying.

Altematively, the anhydrous crystal may be prepared from the ethanolatecrystalline form (described below) utilizing analogous procedures to the immediatelypreceding procedure. In addition, the yield in this procedure may be enhanced byazeotroping the éthanol from the hexanes.

An ethanolate crystalline form of the above compound may be prepared fromthe amorphous compound by recrystallization from ethanol/water at a température ofabout 20°C to about 25°C, preferably ambient température for about 0.5 hour toabout 18 hours. Typically the range is about 3% to about 10% éthanol and about -13- 1 2 099 90% to about 97% water. Preferably the ratio is about 10% to about 90%ethanol/water.

Alternatively, the ethanolate crystalline form may be prepared utilizingprocedures analogous to those described above but using éthanol alone. The filtered 5 materials are typically granulated for about 2 hours to about 24 hours followed by airdrying.

The following Table 1 details important properties for three forms of [2R.4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifiuoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester: the amorphous (A); and the 10 two crystalline forms ethanolate (B) and crystalline anhydrous (C). -14- 1 2099 TABLE 1

Thermal

Amorphous

A 1Ethanolate

B (Fig. 2)

Anhydrous

C (Fig. 1)

Stability

Crystallinity Solubiiity Stability M.P. 21°C Non- crystalline Most solublein aqueous hygrocopic Melt onset 45°C Crystalline Highersolubiiity inaqueous thanAnhydrous(C) non-hygroscopic@ 90% relativehumidity over 24hours M.P. 89-90°C Crystalline Least solublein water non-hygroscopicat 80% & 100%relative humidityover 3 days.

Loses some éthanol at closed bottle ambient conditions but remains crystalline

The compound of the instant invention is orally administrable and is accordinglyused in combination with a pharmaceutically acceptable vehicle, carrier or diluentsuitable to oral dosage forms. Suitable pharmaceutically-acceptable carriers includeinert solid fillers or diluents and stérile aqueous. or organic solutions. The activecompound will be présent in such pharmaceutical compositions in amounts sufficientto provide the desired dosage amount in the range described below. Thus, for oraladministration the compound may be combined with a suitable solid or liquid carrieror diluent to form capsules, tablets, powders, syrups, solutions, suspensions and thelike. The pharmaceutical compositions may, if desired, contain additionalcomponents such as flavorants, sweeteners, excipients and the like.

The tablets, pills, capsules, and the like may also contain a binder such as gumtragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acid; a lubricant suchas magnésium stéarate; and a sweetening agent such as sucrose, lactose orsaccharin. When a dosage unit form, is a capsule, for example a gel capsule, it maycontain, in addition to or instead of materials of the above type, a liquid carrier suchas a fatty glyceride or mixtures of fatty glycerides, such as olive oil, or Miglyol™ orCapmul™ glycerides. Dosage forms may also include orrai suspensions.

Various other materials may be présent as coatings or to modify the physicalform of the dosage unit. For instance, tablets may be coated with shellac, sugar orboth. A syrup or élixir may contain, in addition to the active ingrédient, sucrose as a -15- i 2 09 9 sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoringsuch as cherry or orange flavor.

The compound of the instant invention may also be administered parenterally.For parentéral administration the compound may be combined with stérile aqueous ororganic media to form injectable solutions or suspensions. The injectable solutionsprepared in this manner can then be administered intravenously, intraperitoneally,subcutaneously, or intramuscularly.

The pharmaceutical forms suitable for injectable use include stérile solutions ordispersions and stérile powders for the extemporaneous préparation of stérileinjectable solutions or dispersions. In ail cases, the form must be stérile and must befiuid to the extent that easy syringability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against the contaminating actionof microorganisms such as bacteria and fungi. They may be sterilized, for example,by filtration through a bacteria-retaining fiiter, by incorporating sterilizing agents intothe compositions, or by irradiating or heating the compositions where such irradiatingor heating is both appropriate and compatible with the drug formulation.

Additional pharmaceutical formulations may inolude, inter alia, suppositories,sublingual tablets, topical dosage forms and the like and these may be preparedaccording to methods which are commonly accepted in the art.

Controlled release, sustained release, and delayed release oral or parentéralcompositions may be used.

The dosage of the compound of the instant invention which is administered willgenerally be varied according to principles well known in the art taking into accountthe severity of the condition being treated and the route of administration. In general,the compound will be administered to a warm blooded animal (such as a human,livestock or pet) so that an effective dose, usually a daily dose administered in unitaryor divided portions, is received, for example a dose in the range of about 0.01 toabout 100 mg/kg/day body weight, preferably about 0.1 to about 10 mg/kg/day bodyweight. The above dosages are exemplary of the average case; there can, ofcourse, be individual instances where higher or lower dosage ranges are merited,and such déviations are within the scope of this invention.

EXAMPLES

Melting points were determined with a Thomas Hoover melting pointapparatus or a DSC apparatus. Unless otherwise stated, CD3CI3 was used for NMR -16- 1 2Q99 spectra. Microanaiysis was performed by Scbwarzkopf Microanalytical Laboratory.

Ail reagents and solvents were obtained commercially and used without purification.Exampie 1 c/s-4-IY3,5-Bis-trifluoromethvl-benzyl)-methoxycarbonvl-amino1-2-ethyl-6- trifluoromethyl-3,4-dihvdro-2H-quinoline-1-carboxylic acid ethyl ester: A solution of c/s-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (2.0 g, 3.7 mmol) and pyridine(0.58 g, 7.4 mmol) in 100 mL of dichloromethane was cooled in an ice/water bath asmethyl chloroformate (0.87 g, 9.2 mmol) was added slowly. After stirring overnight atroom température, the reaction mixture was washed twice with a 2N hydrochloric acidsolution, dried over magnésium sulfate, filtered and concentrated in vacuo to affordthe crude product, which was purified by silica gel chromatography using 5-10% ethylacetate/hexanes as eluent to afford 1.8 g of the title product. MS m/z 601 (M+ + 1 ); 1H NMR (coalescing mixture of conformers, CDCI3) 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). f.

[2R,4S34-[(3,5-bis-trifluoromethyi-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dÎhydro-2H-quinoline-1-carboxylic acid ethyl ester was prepared inoptically enriched form by resolution of the corresponding racemate, or anintermediàte in its synthesis, using standard methods.

Example 2 ( 1 -Benzotriazol-1 -yl-propvl)-(4-trifluoromethyl-phenyl)-amine A two liter, four neck flask under nitrogen atmosphère was charged with benzotriazole (36.96 g, 310 mmol, 1.0 equiv) and dry toluene (400 mL). A roomtempérature solution of 4-(triftuoromethyl)aniline (39.1 mL, 310 mmol, 1.0 equiv) and50 mL toluene was added over one minute. A room température solution ofpropionaldéhyde (24.6 mL, 341 mmol, 1.1 equiv) and 50 mL toluene was then addedover 20 minutes. There was an exotherm from 23°C to 30°C during this addition.

After stirring 24 h, n-heptane (500 mL) was added, and the slurry stirred an additional1 h. The suspension was filtered, the solids were washed with n-heptane (1 x 100mL, then 1 x200 mL, and dried. (1 -Benzotriazol-1 -yl-propyI)-(4-trifluoromethyl-phenyl)-amine was isolated as shiny white needles (81.3 g, 82%). After 24 h, asecond crop was isolated from the filtrate (8.7 g, 9%). mp 130-132 °C; 1H NMR -17- 1 2099 (DMSO-d6, 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); 13C NMR (DMSO-d6, 100 MHz) δ 149.32, 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 carbons δ 149.32, 146.19, 131.46, 125.33, 118.27; CH carbons δ 127.73, 126.8, 124.44, 119.88, 112.91,111.56, 71.03;CH2 carbon δ 28.08; CH3 carbon δ 10.29; IR (drifts) 3292 (s), 3038 (m), 2975 (m),1621 (s), 1331 (s), 1320 (s), 1114 (vs); Anal. Calcd for C16H15N4F3: C, 59.99; H, 4.72;N, 17.49. Found (first crop): C, 60.16; H, 4.74; N, 17.86. Found (second crop): C,59.97; H, 4.66; N, 17.63.

Example 3 cis-(2-Ethvl-6-trifluoromethvl-1,2.3.4-tetrahvdro-quinolin-4-vl)-carbamÎc acid benzyl ester A one liter, four neck flask under nitrogen atmosphère was charged with N-vinyl-carbamic acid benzyl ester (27.66 g, 156 mmol, 1.0 equiv) and dry toiuene (500 mL).(1-Benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine (50.0 g, 156 mmol, 1.0equiv) and p-toluenesulfonic acid monohydrate (297 mg, 1.56 mmol, 0.01 equiv) wereadded, and the mixture heated to 70°C. After 2 h, the mixture was cooled to roomtempérature and transfered to a separatory funnel. Ethyl acetate (500 mL) wasadded. The mixture was washed 1 x 200 mL 1N NaOH, 1 x 200 mL H20,1 x 200 mLbrine, and dried (MgSO4). The mixture was filtered and the solids washed 1 x 50 mLethyl acetate. The filtrate was concentrated to approximately 250 mL. 500 mLtoiuene were added, and the mixture concentrated to approximately 500 mL. 500 mLn-heptane were added, the slurry was stirred 1 h, filtered through a Buchner funnel,and dried. cis-(2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamicacid benzyl ester was isolated as a white powder (45.04 g, 76%): mp 155-157 °C; 1HNMR (DMSO-d6, 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 (ε, 1H),6.61 (d, 1H, J=8.5 Hz), 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); 13C NMR (DMSO-d6, 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: quaternarycarbons δ 157.03, 149.02, 137.79, 125.9, 121.73, 115.2; CH carbons δ 128.82, -18- 1 2 099 128.23, 128.03, 125.06, 123.50, 113.33, 52.09, 47.83; CH2 carbons δ 65.85, 34.02,28.68; CH3 carbon δ 9.93; IR (drifts) 3430 (m), 3303 (s), 2951 (m), 1686 (vs), 1542(vs), 1088 (vs); MS (APCI+) m/z (rel. intensity) 379 (M+H+, 53), 228 (100); Anal.Calcd for C2qH21N2O2F3: C, 63.48; H, 5.59; N, 7.40; Found; C, 63.69; H, 6.06, N,7.36.

Example 4 cis-4-Benzvloxycarbonvlannino-2-ethvl-6-trifluoromethvl-3.4-dihydro-2H-quinoline-f- carboxylic acid ethyl ester A three liter, four neck flask under nitrogen atmosphère was charged with cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester(96.0 g, 254 mmol, 1.0 equiv), dry dichloromethane (720 mL), and dry pyridine (103mL, 1.27 mol, 5.0 equiv). A solution of ethyl chloroformate (121 mL, 1.27 mol, 5.0equiv), in dry dichloromethane (240 mL), was added slowly over 4 h. The additionwas exothermic and required a reflux condenser. Once the chloroformate additionwas complété, the reaction was cooled in an ice bath and 1350 mL 1N NaOH wereadded. The mixture was stirred 15 min, then transferred to a separatory funnel. Thelayers were separated and the aqueous extracted 1 ,x 1L dichloromethane. Thecombined dichloromethane layers were washed 1 x 1350 mL 1N HCl, 1 x 1Lsaturated aq. NaHCO3,1 x 1L brine, and dried (Na2SO4). The mixture was filtered,and the filtrate concentrated to an orange oii. 570 mL abs. éthanol were added, andthe solution was concentrated. The solids were dissolved in 1370 mL abs. éthanol.570 mL H2O were added dropwise over 45 min. The résultant thick slurry was stirred18 h and filtered. The solids were washed with cold 7:3 abs. ethanol/water (1 x 250mL, then 1 x 100 mL) and dried (vac oven, 45°C) to give cis-4- benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as a white, crystalline solid (94.54 g, 83%); mp 92-96°C;1H NMR (CDCI3, 400 MHz) δ 0.84 (t, 3H, 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); 13C NMR (CDCI3,100 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 carbonsδ 155.97,154.43,139.44,136.21, 134.33,126.32, 124.12; CH carbons δ 128.61, -19- 1 2099 128.33, 128.22, 126.18, 124.22, 124.19, 120.74, 120.70, 53.47, 46.79; CK2 carbons δ67.22, 62.24, 37.75, 28.25; CH3 carbons δ 14.38, 9.78; IR (drifts) 3304 (s), 3067 (m),3033 (m), 2982 (m), 2932 (m), 1723 (s), 1693 (s), 1545 (s); MS (APCI+) m/z (rel.intensity) 451 (M+H+, 2), 300 (100); Anal. Calcd for C23H25N2O4F3: C, 61.33; H, 5.60;N, 6.22. Found: C, 61.07; H, 5.69; N, 6.22.

Example 5 cis-4-Amino-2-ethvl-6-trifluoromethyl-3,4-dihvdro-2H-quinoline-t -carboxylic acid ethyl ester A one liter, four neck flask under nitrogen atmosphère was charged with cîs-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyI-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (40.1 g, 89 mmol, 1.0 equiv), methanol (400 mL), andammonium formate (14.0 g, 223 mmol, 2.5 equiv). 10% Pd/C, 50% water wet (4.0 g)was added, and the slurry heated to 40° C over 1 h. After 1.5 h, the mixture wascooled to room température and filtered through Celite®. The cake was washed 2 x100 mL methanol. The filtrate was concentrated to approximately 75 mL, transferredto a separatory funnel, and diiuted with 400 mL ethyl acetate. The mixture waswashed 1 x 125 mL saturated aq. NaHCO3,1 x 100 mL brine, and dried (Na2SO4).

The mixture was filtered and the filtrate concentrated to a clear oil. The oil wascrystallized from 100 mL 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 (26.05 g,93%); mp 61.5-63.5° C; 1H NMR (CDCI3,400 MHz) δ 0.79 (t, 3H, J=7.5 Hz), 1.24 (m,4H), 1.42 (m, 1H), 1.51 (brs, 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); 13C NMR (CDCI3,100 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: quatemary carbons δ154.6, 139.3, 138.9, 126.3, 124.3; CH carbons δ 125.7, 123.5, 119.8, 54.16, 46.91; CH2 carbons δ 61.96, 41.50,28.85; CH3 carbons δ 14.38, 9.60; IR (drifts) 3350 (s),3293 (m), 2972 (s), 1697 (vs); MS (ES+) m/z (rel. intensity) 358 (M+H+CH3CN+, 55),317 (M+H+, 7), 300 (100); Anal. Calcd for C,5H19N2O2F3: C, 56.96; H, 6.06; N, 8.86.Found: C, 56.86; H, 6.28; N, 8.82.

Example 6 (-) (2R, 4S)-4-Amino-2-ethvl-6-trifluoromethvl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester hemi-(-)-dibenzovl-L-tartrate sait 1 2 099 -20- A one liter fiask under nitrogen atmosphère was charged with 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) and (-) dibenzoyl-L-tartaricacid (anhydrous) (27.19 g, 75.9 mmol, 1.0 equiv). 300 mL of approximately 97%éthanol (prepared by adding 10.5 mL H2O to 500 mL absolute éthanol, mixing, andmeasuring out 300 mL) was added. The mixture was stirred at room température for18 h, then filtered. The solids were washed 1 x 48 mL approximately 97% éthanol,and dried to give (-) (2R, 4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester hemi-(-)-dibenzoyl-L-tartrate sait as a whitecrystalline solid (14.77 g, 39%): mp 189.5-191.5 °C (dec); 1H NMR (DMSO-d6, 400MHz) Ô 0.62 (t, 3H, J=7.3 Hz), 1.16 (t, 3H, J=7.1Hz), 1.3 (m, 3H), 2.5 (m, 1H), 4.1 (m,4H), 5.63 (s, 1 H, methine 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, NH3+, did notintegrate); 13C 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=271Hz), 124.50,120.90, 74.49, 62.14, 53.51,45.94, 38.81,28.23, 14.63, 9.58; DEPTspectrum: quaternary carbons δ 169.85,165-53,1E>4.10,140.14,134.59,130.74,124.82,124.69; CH carbons δ 133.51, 129.69,128.98, 126.74,124.50, 120.90, 74.49, 53.51,45.94; CH2 carbons δ 62.14, 38.81, 28.23; CH3 carbons δ 14.63, 9.58;IR (drifts) 3278 (m), 2400-3100 (broad), 1703 (vs); MS (ES+) m/z (rel. intensity) 358(M+H+CH3CN+, 55), 317 (M+H+, 7), 300 (100); Anal. Calcd for C15H19N2O2F3.C9H7O4: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-propanoI:HOAc, flow rate 1.50 mL/min, column temp40°C, chiralpak™ AD 4.6 x 250 mm, sample concentration approximately 0.5 mg/mLin approximately 1:1 n-hexane:2-propanol. Authentic racemate shows rétention timesof 7.5 min and 10.0 min. (-) (2R, 4S)-4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester hemi-(-)-dibenzoyl-L-tartrate sait: 10.0 min,88.9%, 7.5 min «1 %, 2.0 min (solvent front) 11.1%; [a]D = -153 (c=1.07, CH3OH).

Example 7 (-)-(2R, 4S)-4-(3,5-Bis-trifluoromethvl-benzvlamino)-2-ethvl-6-trifluoromethvl-3,4- dihydro-2H-quinoline-1 -carboxyiic acid ethyl ester tosylate sait (-) (2R, 4S)-4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxyiicacid ethyl ester hemi-(-)-dibenzoyI-L-tartrate sait (13.0 g, 26.2 mmol, 1.0 equiv) was -21- 1 2 099 suspended in 1,2-dichloroethane (260 mL) in a 500 mL separatory funnel. Themixture was washed 1 x 65 mL 1N NaOH, 1 x 65 mL brime, and dried (MgSO4). Themixture was filtered, concentrated to approximately approximateiy 80 mL, andtransferred to a 250 mL three neck flask. 3,5-Bis(trifIuoromethyl)benzaldehyde (4.53mL, 27.5 mmol, 1.05 equiv) was added, and the mixture stirred 1 h at roomtempérature under nitrogen atmosphère. Sodium triacetoxyborohydride (11.1 g, 52.4mmol, 2.0 equiv) was added in one portion, and the white slurry was stirred 18 h. 50mL 1,2-dichloroethane and 50 mL 2N NaOH were added, and the aqueous layerextracted 2 x 50 mL 1,2-dichloroethane. The combined organic extracts werewashed 1 x 31 mL 1N HCl, 1 x 50 mL saturated aq. NaHCO3, 1 x 50 mL brine, anddried (Na2SO4). The mixture was filtered and concentrated to a clear oil. The oil wasdissolved in methanol (71 mL). p-Toluenesulfonic acid monohydrate (5.23 g, 27.5mmol, 1.05 equiv) was added. After 5 min, 284 mL isopropyl ether was added. Thesolution was concentrtated to approximately 35mL, transferred to a 500 mL threeneck fiask (mech. stirrer), and diluted with 284 mL isopropyl ether. A thick whiteslurry formed in 10 minutes. After stirring 3 h, the slurry was filtered and the cakewashed 2 x 70 mL isopropyl ether. After drying, (-)-,(2R, 4S)-4-(3,5-bis- trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester tosylate sait was isolated as a white powder (16.18 g, 86%overall): mp 191-192°C; 1H NMR (DMSO-d6,400 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, 1 H); 13C 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 carbons δ154.00,145.46, 140.21, 138.39, 135.33,130.79,124.99, 124.59, 123.69; CH carbonsδ 132.51, 131.62, 128.49, 127.40, 125.82, 125.36, 123.44, 120.33, 53.99, 53.79; CH2carbons δ 62.32, 47.98, 33.30, 28.61 ; CH3 carbons δ 21.13, 14.63, 9.58: IR (drifts)2300-3100 (broad), 2974 (m), 2731 (m), 2620 (m), 2455 (m), 1714 (s), 1621 (m), 1283 (vs), 1169 (vs), 1126 (vs); MS (ES+) m/z (rel. intensity) 584 (M+H+CH3CN+, 100), 543 (M+H+, 80); Anal. Calcd for C^H^NsOaFg.CyHgOaS: C, 52.11 ; H, 4.37; N, 1 2099 -22- 3.92. Found: C, 52.15; H, 4.22; N, 3.69; [a]D = -77.9 (c = 1.05, CH3OH).

Example 8 (-H2R, 4S)-4-f(3,5-Bis-trifluoromethyl-benzvl)-methoxvcarbonvl-aminol-2-ethvl-6- trifluoromethvl-3,4-dihvdro-2H-quinoline-1-carboxylic acid ethyl ester mono ethanolate

Na2CO3 (s) (6.75 g, 63.7 mmol, 3.5 equiv) was added to a room température solutionof (-)-(2R, 4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester tosylate sait (13.0 g, 18.2 mmol, 1.0 equiv) in dry THF (130 mL). Methyl chloroformate (3.51 mL, 45.5 mmol, 2.5equiv) was added neat, dropwise over 2 min. After 24 h, the mixture wasconcentrated to 65 mL, diiuted with 260 mL ethyl acetate, and transferred to aseparatory tunnel. The mixture was washed 1 x 90 mL 1N HCl (CO2 évolution), 1 x90 mL saturated aq. NaHCO3, 1 x 90 mL brine, and dried (MgSO4). Filtration andconcentration of filtrate afforded a clear oil, which was costripped 3 x 33 mL 2Béthanol. The oil was dissolved in 33 mL 2B éthanol and seeded with a few miiligramsof (-)-(2R, 4S)-4-[(3,5-bis-trifluoromeihyl-benzyI)-methoxycarbonyl-amino]-2-ethyl-6-trifiuoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester monoethanolate. After stirring 18 h at room température, the slurry was filtered and driedto give (-)-(2R, 4S)-4-[(3,5-bis-trifiuoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoiine-1-carboxylic acid ethyl ester monoethanolate as a white crystalline powder (8.66 g, 74%); mp 54-58 °C; 1H NMR(CDCI3i 400 MHz, 55°C) δ 0.73 (t, 3H, J=7.0 Hz), 1.20 (t, EtOH), 1.27 (t, 3H, J=7.1Hz), 1.42 (m, 2H), 1.66 (m, 1 H), 2.25 (br s, 1 H), 3.67 (q, EtOH), 3.79 (s, 3H), 4.2 (m,3H), 4.33 (m, 1H), 5.2 (br s, 2H), 7.12 (s, 1H), 7.49 (d, 1H, J=8.3 Hz), 7.57 (d, 1H,J=8.5 Hz), 7.73 (s, 2H), 7.78 (s, 1H); 13C NMR (CDCI3, 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 quartet appears to be buried underthe δ 126.94 peak, with J approximately 32 Hz); DEPT spectrum: quaternary carbonsδ 157.74,154.37, 141.73, 140.05, 133.83, 132.14, 123.96, 123.13; CH carbons δ126.94, 124.49, 121.31,119.17, 54.42, 53.08; CH2 carbons δ 62.29, 58.28, 46.67,37.01,29.02; CH3 carbons δ 53.71,18.29, 14.32, 9.22; IR (drifts) 3489 (s), 2974 (s),2884 (m), 1701 (vs), 1280 (vs), 1131 (vs); MS (ES+) m/z (rel. intensity) 601 (M+H+,100); Anal. Calcd for C26H25N2O4F9.C2H6O; C, 52.01; H, 4.83; N, 4.33. Found; C, -23- rc 1 2 099 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, columntemp 40°C, sample concentration approximately 0.5 mg/mL in 90:10 n-hexane:2-propanol, authentic racemate rétention times 3.6 and 4.6 min. (-)-(2R, 4S)-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester mono ethanolate shows 4.6 min, 99.1 %and 3.6 min, not detected; [a]D = -93.3 (c = 1.08, CH3OH).

Example 9

Anhydrous, (-)-(2R.4S)-4-f(3,5-Bis-trifluoromethvl-benzvl)-methoxvcarbonyl-amino1-2- ethvl-6-trifluoromethyl-3,4-dihvdro-2H-quinoline-1 -carboxylic acid ethyl ester. A 2.6g portion of 4(S)-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(R)-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (amixture of predominantly amorphous material with traces of ethanolate crystallineform; the titie compound was also prepared in an analogous manner starting frompure amorphous or pure ethanolate material) was charged to 13 milliliters of hexanesand heated to effect a solution at about 60°C. The heat was removed and thereaction was allowed to cool to ambient over aone toour period. The reaction wasseeded with anhydrous (-)-(2R,4S)-4-[(3,5-bis-trifluoromethyI-benzyl)- methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and granulated for eighteen hours under ambientconditions. Altemately, the anhydrous crystals may be prepared from hexaneswithout seeding. The product was collected by filtration and air dried. The isoiatedproduct X-ray pattern matched the calculated powder pattern.

Density: 1.406

Crystal System: Trigonal

Microscopy: Well formed rods and equant (fractured rods) crystals demonstratinghigh biréfringence when viewed across the C axis. Being in the Trigonal crystalSystem the crystals do not demonstrate biréfringence when viewed down the C axis.

The crystals demonstrate a cleavage plane perpendicular to thé C axis.

Fusion Microsocopy: In Type A oil--------dissolution at 50°C.

Dry-------------------clear me|t at 86°C. NMR: No trace of ethanolateDegree of crystallinity: Highly crystalline -24- 1 2 099

Hygroscopicity: Non-hygroscopic at 100% relative humidity over 48 hours.Appearance: Free flowing white powder.

The X-Ray diffraction d-spacing is provided in Table 2. 1 2099 -25- TABLE 2

Anode: CU - Wavelenqth 1: 1.54056 Wavelenqth 2: 1.54439 (Rel Intensity: 0.500)

Range #1 - Coupled: 3.000 to 40.000 StepSize: 0.040 StepTime: 1.005 Smoothing Width: 0.300 Threshold: 1.0 ___ d(A) 1 (rel) d(A) Krel) d(A) •(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) •(rel) 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 z f

Example 10

Monoethanolate, (-)-(2R,4S)-4-i(3.5-Bis-trifluoromethyl-benzvl)-methoxvcarbonvl- 10 amino1-2-ethvl-6-trifluoromethvl-3.4-dihvdro-2H-quinoline-1 -carboxylic acid ethyl ester.

4.0 grams of (-)-(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester.weredissolved in 3.5 ml éthanol and sonicated for two minutes to complété dissolution. A 15 white solid formed to which 10 ml éthanol was added and stirred at ambient température ovemight. A white powder was filtered and collected on 0.22 pm LSfilter paper followed by washing with about 15 ml. éthanol. The isolated product X-raypattern matched the calculated powder pattern.

Density: 1.402 20 Crystal System: orthorhombic

Microscopy: crystalline needles with moderate biréfringence.

Fusion Microsocopy: In Type A oil-----melt and dissolution at 43°C with loss of water

Dry----------------

clear melt at 43°C

P -26- 1 2 09 9 NMR: shows éthanol of solvationDegree of crystallinity: highly crystallineHygroscopicity: non-hygroscopicAppearance: free-flowing white power 5 The X-Ray diffraction d-spacing is provided in Table 3. TABLE 3

Anode: CU - Wavelenqth 1:1.54056 Wavelenqth 2: 1.54439 (Rel Intensity: 0,500)

Range #1 - Coupled: 3.000 to 40.000 StepSize: 0.040 StepTime: 1.0010 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) l(rel) d(A) l(rel) 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 15 Anhvdrous (-)-(2R.4S)-4-f(3,5-bis-trifluromethvlbenzvO-methoxvcarbonyl-aminol-2- ethvl-6-trifluorornethvl-3.4-dihvdro-2H-quinoline-1-carboxylic acid ethyl ester. A crude solution of approximately 42 g of (-)-(2R,4S)-4-[(3,5-bis-trifluromethylbenzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in 500 ml of ethyl acetate (obtained via the process 20 described in Example 8) was concentrated under vacuum to a volume of 100-135 ml.The remaining ethyl acetate was displaced with 3 X 220 ml 2B EtOH to a final volume -27- of 100-135 ml. This solution was seeded with a crystal of anhydrous (-)-(2R,4S)-4-[(3,5-bis-trifluromethylbenzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifiuoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. After stirring 18 hr at roomtempérature the slurry was filtered and vacuum dried to give 19.81 g of anhydrous (-) 5 (2R,4S)-4-[(3,5-bis-trifluromethylbenzyl)-methoxycarbonyl-amino]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. The meltingpoint behaviour was the same as the material prepared via Example 9 confirming theanhydrous nature of the material.

Claims

-28- 1 2 099 CLAIMS

1. A crystalline form of the compound of formula I
2. A crystal which is anhydrous [2R.4S] 4-[(3,5-bis-trifluoromethyl-benzyI)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.
3. A crystal which is the ethanolate of [2R.4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-10 methoxycarbonyi-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 - carboxylic acid ethyl ester.
4. A crystal of ciaïm 1 which is the anhydrous crystal having the x-ray powderdiffraction d-spacing 15 -29- 1 2 099 Anode: CU - Wavelenqth 1: 1.54056 Wavelenqth 2: 1.54439 (Rel Intensity: 0.500) Range #1 - Coupied: 3.000 to 40.000 StepSize: 0.040 StepTime: 1.00Smoothing Width: 0.300 Threshold: 1.0 d(A) 1(rel) d(A) l(rel) d(A) l(ref) 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) l(rel) 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 1 2099 -30-
5. A crystal of ciaim 1 which is the ethanoiate crystal having the x-ray powderdiffraction d-spacing Anode: CU - Wavelenqth 1:1.54056 Wavelenqth 2: 1.54439 fRel Intensity: 0.500) Range #1 - Coupled: 3.000 to 40.000 StepSize: 0.040 StepTime: 1.00Smoothing 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) l(rel) d(A) l(rel) 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
6. A pharmaceutical composition which comprises a therapeutically effectiveamount of a crystal of daim 1 and a pharmaceutically acceptable carrier, vehicle ordiluent.
7. The pharmaceutical composition as recited in daim 6 wherein the pharmaceutical composition comprises an atherosclerosis, peripheral vasculardisease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia,cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial 20 infarction, reperfusion injury, angioplastie restenosis, hypertension, vascular -31- 1 2099 complications of diabètes, obesity or endotoxemia treating amount of the crystal ofclaim 1 and a pharmaceutically acceptable carrier, vehicle or diluent.
8. The pharmaceutical composition as recited in claim 6 for the treatment ofatherosclerosis which comprises an atherosclerosis treating amount of a crystal ofFormula I and a pharmaceutically acceptable carrier, vehicle or diluent.
9. The pharmaceutical composition as recited in claim 8 wherein theatherosclerosis treating amount of the Formula I crystal is about 0.1 to 10 mg/kg/day,and the pharmaceutical composition was prepared by dissolving the ciystal of claim 1in a fatty oil.
10. The pharmaceutical composition as recited in claim 8 wherein the Formula Icrystal is anhydrous.
11. The pharmaceutical composition as recited in claim 8 wherein the Formula Icrystal is the ethanolate crystal.
12. Use of the Formula I crystal as recited in claim 1, in the manufacture of amédicament for inhibiting CETP in a mammal in need thereof.
13. Use as recited in claim 12 comprising treating atherosclerosis,peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia,stroke, myocardial infarction, reperfusion injury, angioplastie restenosis, hypertension,vascular complications of diabètes, obesity or endotoxemia by administering to amammal, in need of such treatment a therapeutically effective amount of the FormulaI crystal. 14. ' Use as recited in claim 13 wherein atherosclerosis istreated with anatherosclerosis treating amount of the Formula I crystal.
15. Use as recited in claim 14 wherein the atherosclerosis treatingamount of the Formula I crystal is about 0.1 to 10 mg/kg/day and the Formula Icrystal was dissolved in a fatty oil.
16. Use i as recitèd in claim 15 wherein the Formula I crystal is anhydrous.
17. Use as recited in claim 15 wherein the Formula I sait is theethanolate.
18. A process for preparing crystalline anhydrous [2R,4S] 4-[(3,5-bis- trifluoromethyl-benzyl)-methoxycarbonyI-amino]-2-ethyl-6-trifiuoromethyl-3,4-dihydro- -32- 1 2099 2H-quinoline-1-carboxylic acid ethyl ester comprising dissolving or mixing [2R,4S] 4-[(315-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4dihydro-2H-quinoline-1-carboxylic acid ethyl ester in hexanes at ambient températurefor about 2 to about 24 hours wherein said precursor is not an anhydrous crystaliine 5 form.
19. A process for preparing crystalline ethanolate [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester by dissolving or mixing [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyI)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyI-3,4-dihydro- 10 2H-quinoline-1 -carboxylic acid ethyl ester in ethanol/water at ambient température forabout 0.5 to about 18 hours wherein said precursor is not a crystalline ethanolateform.
20. The process as recited in claim 19 wherein éthanol is used without water.
21. A process for preparing crystalline anhydrous [2R,4S] 4-[(3,5-bis- 15 trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester comprising dissolving or mixing [2R.4S] 4-[3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyi-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in éthanol at ambient températurefor about 2 to about 24 hours wherein said precursor is not an anhydrous crystalline 20 form.