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WO2001040190A1 - Cristaux de 4-carboxyamino-2-ethyl-1,2,3,4-tetrahydroquinoleine utilises en tant qu'inhibiteurs de cetp - Google Patents

Cristaux de 4-carboxyamino-2-ethyl-1,2,3,4-tetrahydroquinoleine utilises en tant qu'inhibiteurs de cetp Download PDF

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Publication number
WO2001040190A1
WO2001040190A1 PCT/IB2000/001650 IB0001650W WO0140190A1 WO 2001040190 A1 WO2001040190 A1 WO 2001040190A1 IB 0001650 W IB0001650 W IB 0001650W WO 0140190 A1 WO0140190 A1 WO 0140190A1
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WO
WIPO (PCT)
Prior art keywords
crystal
formula
trιfluoromethyl
recited
dιhydro
Prior art date
Application number
PCT/IB2000/001650
Other languages
English (en)
Inventor
Douglas John Meldrum Allen
Troy Anthony Appleton
Lyle Robinson Brostrom
Derek Lawrence Tickner
Original Assignee
Pfizer Products Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to MXPA02005354A priority Critical patent/MXPA02005354A/es
Priority to EA200200510A priority patent/EA200200510A1/ru
Priority to PL00355892A priority patent/PL355892A1/xx
Priority to HU0203521A priority patent/HUP0203521A2/hu
Priority to EEP200200277A priority patent/EE200200277A/xx
Priority to EP00971662A priority patent/EP1246804A1/fr
Priority to JP2001541875A priority patent/JP2003515592A/ja
Priority to APAP/P/2002/002531A priority patent/AP2002002531A0/en
Priority to IL14909700A priority patent/IL149097A0/xx
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Priority to BR0015836-4A priority patent/BR0015836A/pt
Priority to CA002392979A priority patent/CA2392979A1/fr
Priority to AU10488/01A priority patent/AU1048801A/en
Priority to KR1020027006914A priority patent/KR20020058057A/ko
Publication of WO2001040190A1 publication Critical patent/WO2001040190A1/fr
Priority to IS6338A priority patent/IS6338A/is
Priority to NO20022558A priority patent/NO20022558D0/no
Priority to BG106854A priority patent/BG106854A/bg

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms

Definitions

  • This invention relates to cholesteryl ester transfer protein (CETP) inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to elevate certain plasma lipid levels, including high density lipoprotein (HDL)- cholesterol and to lower certain other plasma lipid levels, such as low density lipoprotein (LDL)-cholesterol and triglycendes and accordingly to treat diseases which are affected by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycendes, such as atherosclerosis and cardiovascular diseases in certain mammals (i.e., those which have CETP in their plasma), including humans.
  • CETP cholesteryl ester transfer protein
  • this invention relates to CETP inhibitor crystals, pharmaceutical compositions comprising these crystals, a process for preparing these crystals and to methods of treating atherosclerosis, obesity, and related diseases and/or conditions with the crystals.
  • Atherosclerosis and its associated coronary artery disease is the leading cause of mortality in the industrialized world.
  • CAD coronary artery disease
  • CHD coronary heart disease
  • LDL-cholesterol may be the most recognized form of dyslipidemia, it is by no means the only significant lipid associated contributor to 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)
  • dyslipidemia is not a unitary risk profile for CHD but may be comprised of one or more lipid aberrations
  • cholesteryl ester transfer protein activity affects all three.
  • the net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol This effect on lipoprotein profile is believed to be pro-atherogenic, especially in subjects whose lipid profile constitutes an increased risk for CHD.
  • Another aspect of this invention is directed to an anhydrous crystal of Formula
  • Another aspect of this invention is directed to the corresponding anhydrous crystal having the X-ray powder diffraction pattern as shown in Figure 1
  • Another aspect of this invention is directed to an ethanolate crystal of Formula I
  • Another aspect of this invention is directed to the corresponding ethanolate crystal having the X-ray powder diffraction pattern as shown in Figure 2
  • a preferred dosage is about 0 01 to 100 mg/kg/day of a Formula I crystal
  • An especially preferred dosage is about 0 1 to 10 mg/kg/day of a Formula I crystal
  • compositions, combinations and kits reference is made to a crystal of Formula I While it is understood that if the crystal is in solution, the crystal form is not present (in contrast to e g , a dry tablet formulation), the following methods pharmaceutical compositions combinations and kits are intended to include a method or formulation resulting from a use of such crystal (e.g., administering a gelatin capsule including an oil formulation solution of the crystal).
  • Yet another aspect of this invention is directed to methods for treating atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypert ⁇ glyce ⁇ demia, fami al- hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human being either male or female) by administering to a mammal in need of such treatment an atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypert ⁇ glyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications
  • Yet another aspect of this invention is directed to a method for treating atherosclerosis in a mammal (including a human being) by administering to a mammal in need of such treatment an atherosclerosis treating amount of a Formula I crystal
  • Yet another aspect of this invention is directed to a method for treating peripheral vascular disease in a mammal (including a human being) by administering to a mammal in need of such treatment a peripheral vascular disease treating amount of a Formula I crystal.
  • Yet another aspect of this invention is directed to a method for treating dyslipidemia in a mammal (including a human being) by administering to a mammal in 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 treating hyperbetalipoproteinemia in a mammal (including a human being) by administering to a mammal in need of such treatment a hyperbetalipoproteinemia treating amount of a Formula I crystal.
  • Yet another aspect of this invention is directed to a method for treating hypoalphalipoproteinemia in a mammal (including a human being) by administering to a mammal in need of such treatment a hypoalphalipoproteinemia treating amount of a Formula I crystal
  • Yet another aspect of this invention is directed to a method for treating hypercholesterolemia in a mammal (including a human being) by administering to a mammal in need of such treatment a hypercholesterolemia treating amount of a Formula I crystal
  • Yet another aspect of this invention is directed to a method for treating hypertriglyce ⁇ demia in a mammal (including a human being) by administering to a mammal in need of such treatment a hypert ⁇ glyceridemia treating amount of a Formula I crystal
  • Yet another aspect of this invention is directed to a method for treating fami al-hypercholesterolemia in a mammal (including a human being) by administering to a mammal in need of such treatment a fami al- hypercholesterolemia treating amount of a Formula I crystal
  • Yet another aspect of this invention is directed to a method for treating cardiovascular disorders in a mammal (including a human being) by administering to a mammal in need of such treatment a cardiovascular disorder treating amount of a Formula I crystal
  • Yet another aspect of this invention is directed to a method for treating angina in a mammal (including a human being) by administering to a mammal in need of such treatment an angina treating amount of a Formula I crystal
  • Yet another aspect of this invention is directed to a method for treating ischemia in a mammal (including a human being) by administering to a mammal in need of such treatment an ischemic disease treating amount of a Formula I crystal
  • Yet another aspect of this invention is directed to a method for treating cardiac ischemia in a mammal (including a human being) by administering to a mammal in need of such treatment a cardiac ischemic treating amount of a Formula I crystal
  • Yet another aspect of this invention is directed to a method for treating stroke in a mammal (including a human being) by administering to a mammal in need of such treatment a stroke treating amount of a Formula I crystal
  • Yet another aspect of this invention is directed to a method for treating a myocardial infarction in a mammal (including a human being) by administering to a mammal in need of such treatment a myocardial infarction treating amount of a Formula I crystal
  • Yet another aspect of this invention is directed to a method for treating reperfusion injury in a mammal (including a human being) by administering to a mammal in need of such treatment a reperfusion injury treating amount of a Formula I crystal.
  • Yet another aspect of this invention is directed to a method for treating angioplastic restenosis in a mammal (including a human being) by administering to a mammal in need of such treatment an angioplastic restenosis treating amount of a Formula I crystal.
  • Yet another aspect of this invention is directed to a method for treating hypertension in a mammal (including a human being) by administering to a mammal in 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 the vascular complications of diabetes in a mammal (including a human being) by administering to a mammal in need of such treatment a vascular complications of diabetes treating amount of a Formula I crystal.
  • Yet another aspect of this invention is directed to a method for treating obesity in a mammal (including a human being) by administering to a mammal in need of such treatment an obesity treating amount of a Formula I crystal.
  • Yet another aspect of this invention is directed to a method for treating endotoxemia in a mammal (including a human being) by administering to a mammal in need of such treatment an endotoxemia treating amount of a Formula I crystal.
  • This invention is also directed to pharmaceutical compositions which comprise a therapeutically effective amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
  • This invention is also directed to pharmaceutical compositions for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyce ⁇ demia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human being) which comprise a therapeutically effective amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
  • This invention is also directed to pharmaceutical compositions for the treatment of atherosclerosis in a mammal (including a human being) which comprise an atherosclerosis treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • compositions for the treatment of dyslipidemia in a mammal which comprise a dyslipidemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • compositions for the treatment of hyperbetalipoproteinemia in a mammal which comprise a hyperbetalipoproteinemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • compositions for the treatment of hypoalphalipoproteinemia in a mammal which comprise a hypoalphalipoproteinemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • This invention is also directed to pharmaceutical compositions for the treatment of hypercholesterolemia in a mammal (including a human being) which comprise a hypercholesterolemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • This invention is also directed to pharmaceutical compositions for the treatment of hypert ⁇ glyceridemia in a mammal (including a human being) which comprise a hypertriglyce ⁇ demia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • compositions for the treatment of familial-hypercholesterolemia in a mammal which comprise a familial-hypercholesterolemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • compositions for the treatment of angina in a mammal which comprise an angma treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • compositions for the treatment of ischemia in a mammal which comprise an ischemic treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • compositions for the treatment of cardiac ischemia in a mammal which comprise a cardiac ischemic treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • This invention is also directed to pharmaceutical compositions for the treatment of stroke in a mammal (including a human being) which comprise a stroke treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • pharmaceutical compositions for the treatment of a myocardial infarction in a mammal (including a human being) which comprise a myocardial infarction treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • compositions for the treatment of reperfusion injury in a mammal which comprise a reperfusion injury treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • compositions for the treatment of angioplastic restenosis in a mammal which comprise an angioplastic restenosis treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • compositions for the treatment of hypertension in a mammal which comprise a hypertension treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • This invention is also directed to pharmaceutical compositions for the treatment of the vascular complications of diabetes in a mammal (including a human being) which comprise a vascular complications of diabetes treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • pharmaceutical compositions for the treatment of obesity in a mammal (including a human being) which comprise an obesity treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent
  • This invention is also directed to a pharmaceutical combination composition
  • a pharmaceutical combination composition comprising 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 t ⁇ giyceride transfer protein (MTP)/Apo B secretion inhibitor, a PPAR activator, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacm, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant, and/or optionally a pharmaceutical carrier, vehicle or diluent
  • HMG-CoA reductase inhibitor Preferred among the second compounds are an HMG-CoA reductase inhibitor and a MTP/Apo B secretion inhibitor
  • a particularly preferred HMG-CoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or ⁇ vastatin
  • Another aspect of this invention is a method for treating atherosclerosis in a mammal comprising administering to a mammal suffering from atherosclerosis a first compound, said first compound being a Formula I crystal, and a second compound, said second compound being an HMG-CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacm, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant wherein the amounts of the first and second compounds result in a therapeutic effect
  • the second compound is an HMG-CoA reductase inhibitor or an MTP/Apo B secretion inhibitor
  • kits comprising a a first compound, said first compound being a Formula I crystal, and a pharmaceutically acceptable carrier in a first in a unit dosage form, b a second compound, said second compound being an HMG CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacm, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant and a pharmaceutically acceptable carrier in a second unit dosage form, and c means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect
  • a preferred second compound is an HMG-CoA reductase inhibitor or an MTP/Apo B secretion inhibitor
  • a particularly preferred HMG-CoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or nvastatin
  • the present invention is also directed to processes for preparing crystalline anhydrous [2R.4S] 4-[(3,5-b ⁇ s-tr ⁇ fluoromethyl-benzyl)-methoxycarbonyl-am ⁇ no]-2- ethyl-6-tr ⁇ fluoromethyl-3,4-d ⁇ hydro-2H-qu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl ester by dissolving or mixing [2R,4S] 4-[(3,5-b ⁇ s-t ⁇ fluoromethyl-benzyl)-methoxycarbonyl- am ⁇ no]-2-ethyl-6-tr ⁇ fluoromethyl-3,4-d ⁇ hydro-2H-qu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl este
  • Another aspect of this invention is directed to a process for preparing crystalline ethanolate [2R.4S] 4-[(3,5-b ⁇ s-tr ⁇ fluoromethyl-benzyl)-methoxycarbonyl- am ⁇ no]-2-ethyl-6-tr ⁇ fluoromethyl-3,4-d ⁇ hydro-2H-qu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl ester by dissolving or mixing [2R,4S] 4-[(3,5-b ⁇ s-tr ⁇ fluoromethyl-benzyl)-methoxycarbonyl- am ⁇ no]-2-ethyl-6-tr ⁇ fluoromethyl-3,4-d ⁇ hydro-2H-qu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl ester in ethanol/water at ambient temperature for about 0 5 to about 18 hours
  • ethanol is used without water
  • This invention is also directed to a process for preparing crystalline anhydrous [2R,4S] 4-[(3,5-b ⁇ s-t ⁇ fluoromethyl-benzyl)-methoxycarbonyl-am ⁇ no]-2-ethyl-6- t ⁇ fluoromethyl-3,4-d ⁇ hydro-2H-qu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl ester comprising dissolving or mixing [2R,4S] 4-[3,5-b ⁇ s-tr ⁇ fluoromethyl-benzyl)-methoxycarbonyl- am ⁇ no]-2-ethyl-6-tr ⁇ fluoromethyl-3,4-d ⁇ hydro-2H-qu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl ester in ethanol at ambient temperature for about 2 to about 24 hours It is noted that as the anhydrous and ethanolate crystals are of different energy levels seeding with either anhydrous or ethanolate may determine the resulting isolated
  • mammals is meant to refer to all mammals which contain CETP in their plasma, for example, rabbits and primates such as monkeys and humans. Certain other mammals e.g., dogs, cats, cattle, goats, sheep and horses do not contain CETP in their plasma and so are not included herein.
  • ethanolate refers to an ethanol of solvation
  • treating includes preventative (e.g., prophylactic) and palliative treatment.
  • pharmaceutically acceptable it is meant the carrier, vehicle, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
  • reaction-inert solvent and “inert solvent” refers to a solvent or mixture of solvents which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
  • the compound of this invention can exist in radiolabelled form, i.e., said compound may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Radioisotopes of hydrogen, carbon, phosphorous, fluorine and chlorine include 3 H, 1 C, 32 P, 35 S, 8 F and 36 CI, respectively.
  • the compound of this invention which contains those radioisotopes and/or other radioisotopes of other atoms is within the scope of this invention.
  • radiolabelled compound of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabelled compounds can be prepared by carrying out the procedures disclosed in the Examples below by substituting a readily available radiolabelled reagent for a non-radiolabelled reagent
  • FIG. 1 is a characteristic x-ray powder diffraction pattern showing that anhydrous [2R,4S] 4-[(3,5-b ⁇ s-tr ⁇ fluoromethyl-benzyl)-methoxycarbonyl-am ⁇ no]-2- ethyl-6-tr ⁇ fluoromethyl-3,4-d ⁇ hydro-2H-qu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl ester is crystalline.
  • Vertical Axis Intensity (CPS); Horizontal Axis. Two theta (degrees)
  • FIG. 2 is the characteristic x-ray powder diffraction pattern of the ethanolate [2R.4S] 4-[(3,5-b ⁇ s-tr ⁇ fluoromethyl-benzyl)-methoxycarbonyl-am ⁇ no]-2-ethyl-6- tr ⁇ fluoromethyl-3,4-d ⁇ hydro-2H-qu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl ester as crystalline Vertical Axis: Intensity (CPS); Horizontal Axis: Two theta (degrees)) Detailed Description Of The Invention
  • the compound of this invention can be made by processes which include analogous processes known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compound of this invention are provided as further features of the invention and are described below including in the Examples.
  • An anhydrous crystalline form of the above compound may be prepared from the amorphous compound by recrystallization from hexanes (solvent comprised of hexane isomers (e.g., n-hexane, cyclohexane, methyl pentane, etc )) at a temperature of about 40°C to about 80°C, preferably 60° followed typically by granulating, for about 2 to about 24 hours, then filtering the material and subsequent air drying.
  • hexanes solvent comprised of hexane isomers (e.g., n-hexane, cyclohexane, methyl pentane, etc )
  • the anhydrous crystal may be prepared from the ethanolate crystalline form (described below) utilizing analogous procedures to the immediately preceding procedure.
  • the yield in this procedure may be enhanced by azeotroping the ethanol from the hexanes.
  • An ethanolate crystalline form of the above compound may be prepared from the amorphous compound by recrystallization from ethanol/water at a temperature of about 20°C to about 25°C, preferably ambient temperature for about 0 5 hour 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.
  • the ethanolate crystalline form may be prepared utilizing 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 compound of the instant invention is orally admmistrable and is accordingly used in combination with a pharmaceutically acceptable vehicle, carrier or diluent suitable to 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 compositions in amounts sufficient to provide the desired dosage amount in the range described below.
  • 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 compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin, excipients such as dicalcium phosphate, a disintegrating agent such as corn starch, potato starch, alginic acid, a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin
  • a dosage unit form is a capsule, for example a gel capsule, it may contain, in addition to or instead of materials of the above type, a liquid carrier such as a fatty glyce ⁇ de or mixtures of fatty glyce ⁇ des, such as olive oil, or MiglyolTM or CapmulTM glyce ⁇ des
  • Dosage forms may also include orral suspensions.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor
  • the compound of the instant invention may also be administered parenterally.
  • parenteral administration the compound may be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • injectable solutions prepared in this manner can then be administered intravenously, intrape ⁇ toneally, subcutaneously, or intramuscularly.
  • the pharmaceutical forms suitable for injectable use include sterile solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy sy ⁇ ngability exists It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, or by irradiating or heating the compositions where such irradiating or heating is both appropriate and compatible with the drug formulation.
  • Additional pharmaceutical formulations may include, inter alia, suppositories, subhngual tablets, topical dosage forms and the like and these may be prepared according to methods which are commonly accepted in the art. Controlled release, sustained release, and delayed release oral or parenteral compositions may be used.
  • the dosage of the compound of the instant invention which is administered will generally be varied according to principles well known in the art taking into account the severity of the condition being treated and the route of administration.
  • 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 unitary or divided portions, is received, for example a dose in the range of about 0.01 to about 100 mg/kg/day body weight, preferably about 0.1 to about 10 mg/kg/day body weight.
  • the above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such deviations are within the scope of this invention
  • [2R,4S]4-[(3,5-b ⁇ s-tr ⁇ fluoromethyl-benzyl)-methoxycarbonyl-am ⁇ no]-2-ethyl-6- t ⁇ fluoromethyl-3,4-d ⁇ hydro-2H-qu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl ester was prepared in optically enriched form by resolution of the corresponding racemate, or an intermediate in its synthesis, using standard methods.
  • Example 2 (1 -Benzotr ⁇ azol-1 -yl-propyl)-(4-t ⁇ fluoromethyl-phenyl)-am ⁇ ne
  • benzot ⁇ azole 36.96 g, 310 mmol, 1.0 equiv
  • dry toluene 400 mL
  • 4-(tr ⁇ fluoromethyl)an ⁇ l ⁇ ne 39.1 mL, 310 mmol, 1.0 equiv
  • 50 mL toluene was added over one minute.
  • Example 3 c ⁇ s-(2-Ethyl-6-tr ⁇ fluoromethyl-1 ,2,3,4-tetrahvdro-qu ⁇ nol ⁇ n-4-yl)-carbam ⁇ c acid benzyl ester
  • N-vinyl- carbamic acid benzyl ester 27.66 g, 156 mmol, 1.0 equiv
  • dry toluene 500 mL
  • the mixture was filtered and the solids washed 1 x 50 mL ethyl acetate.
  • the filtrate was concentrated to approximately 250 mL. 500 mL toluene were added, and the mixture concentrated to approximately 500 mL. 500 mL n-heptane were added, the slurry was stirred 1 h, filtered through a Buchner funnel, and dried.
  • Example 4 c ⁇ s-4-Benzyloxycarbonylam ⁇ no-2-ethyl-6-tr ⁇ fluoromethyl-3,4-d ⁇ hydro-2H-qu ⁇ nol ⁇ ne-1 - carboxylic acid ethyl ester
  • c ⁇ s-(2- ethyl-6-tr ⁇ fluoromethyl-1 ,2,3,4-tetrahydro-qu ⁇ nol ⁇ n-4-yl)-carbam ⁇ c acid benzyl ester (96.0 g, 254 mmol, 1.0 equiv), dry dichloromethane (720 mL), and dry pyndine (103 mL, 1.27 mol, 5.0 equiv).
  • Example 5 cis-4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester
  • a one liter, four neck flask under nitrogen atmosphere was charged with cis-4- benzyloxycarbonylamino-2-ethyl-6-thfluoromethyl-3,4-dihydro-2H-quinoline-1 - carboxylic acid ethyl ester (40.1 g, 89 mmol, 1.0 equiv), methanol (400 mL), and ammonium formate (14.0 g, 223 mmol, 2.5 equiv).
  • Example 7 (-H2R, 4S)-4-(3,5-B ⁇ s-tr ⁇ fluoromethyl-benzylam ⁇ no)-2-ethyl-6-t ⁇ fluoromethyl-3,4- d ⁇ hydro-2H-gu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl ester tosylate salt (-) (2R, 4S)-4-Am ⁇ no-2-ethyl-6-tr ⁇ fluoromethyl-3,4-d ⁇ hydro-2H-qu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl ester hem ⁇ -(-)-d ⁇ benzoyl-L-tartrate salt (13 0 g, 26 2 mmol, 1 0 equiv) was suspended in 1 ,2-d ⁇ chloroethane (260 mL) in a 500 mL separatory funnel.
  • the mixture was washed 1 x 65 mL 1 N NaOH, 1 x 65 mL brine, and dried (MgS0 4 ).
  • the mixture was filtered, concentrated to approximately approximately 80 mL, and transferred to a 250 mL three neck flask.
  • 3,5-B ⁇ s(tr ⁇ fluoromethyl)benzaldehyde (4.53 mL, 27.5 mmol, 1.05 equiv) was added, and the mixture stirred 1 h at room temperature under nitrogen atmosphere.
  • Sodium triacetoxyborohyd ⁇ de (11.1 g, 52.4 mmol, 2.0 equiv) was added in one portion, and the white slurry was stirred 18 h.
  • Example 8 (-H2R, 4S)-4-[(3,5-B ⁇ s-t ⁇ fluoromethyl-benzyl)-methoxycarbonyl-am ⁇ no1-2-ethyl-6- tr ⁇ fluoromethyl-3,4-d ⁇ hydro-2H-qu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl ester mono ethanolate Na 2 CO 3 (s) (6.75 g, 63.7 mmol, 3.5 equiv) was added to a room temperature solution of (-)-(2R, 4S)-4-(3,5-b ⁇ s-tr ⁇ fluoromethyl-benzylam ⁇ no)-2-ethyl-6-tr ⁇ fluoromethyl-3,4- d ⁇ hydro-2H-qu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl ester tosylate salt (13.0 g, 18.2 mmol, 1.0 equiv) in dry THF (130 m
  • Methyl chloroformate (3.51 mL, 45.5 mmol, 2.5 equiv) was added neat, dropwise over 2 mm. After 24 h, the mixture was concentrated to 65 mL, diluted with 260 mL ethyl acetate, and transferred to a separately funnel. The mixture was washed 1 x 90 mL 1 N HCI (C0 2 evolution), 1 x 90 mL saturated aq. NaHCO 3 , 1 x 90 mL brine, and dried (MgSO 4 ). Filtration and concentration of filtrate afforded a clear oil, which was cost ⁇ pped 3 x 33 mL 2B ethanol.
  • Example 9 Anhydrous, (-)-(2R,4S)-4-[(3,5-B ⁇ s-tr ⁇ fluoromethyl-benzyl)-methoxycarbonyl-am ⁇ nol-2- ethyl-6-tr ⁇ fluoromethyl-3,4-d ⁇ hydro-2H-qu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl ester.
  • Microscopy Well formed rods and equant (fractured rods) crystals demonstrating high birefringence when viewed across the C axis. Being in the Trigonal crystal system the crystals do not demonstrate birefringence when viewed down the C axis. The crystals demonstrate a cleavage plane perpendicular to the C axis Fusion Microsocopy In Type A oil dissolution at 50°C.
  • Microscopy crystalline needles with moderate birefringence.
  • Dry clear melt at 43°C NMR shows ethanol of solvation Degree of crystal nity: highly crystalline
  • Hygroscopicity non-hygroscopic
  • Example 11 Anhydrous (-)-(2R,4S)-4-[(3,5-b ⁇ s-tr ⁇ fluromethylbenzyl)-methoxycarbonyl-am ⁇ nol-2- ethyl-6-tr ⁇ fluoromethyl-3,4-d ⁇ hvdro-2H-gu ⁇ nol ⁇ ne-1 -carboxylic acid ethyl ester.

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Abstract

L'invention concerne des formes cristallines d'un inhibiteur de CETP de formule (I), des procédés de fabrication desdits cristaux, des procédés d'utilisation desdits cristaux ainsi que des compositions pharmaceutiques contenant lesdits cristaux.
PCT/IB2000/001650 1999-11-30 2000-11-14 Cristaux de 4-carboxyamino-2-ethyl-1,2,3,4-tetrahydroquinoleine utilises en tant qu'inhibiteurs de cetp WO2001040190A1 (fr)

Priority Applications (16)

Application Number Priority Date Filing Date Title
IL14909700A IL149097A0 (en) 1999-11-30 2000-11-14 4-carboxyamino-2-ethyl-1,2,3,4-thetrahydroquinoline crystal as cetp inhibitor
PL00355892A PL355892A1 (en) 1999-11-30 2000-11-14 4-carboxyamino-2-ethyl-1,2,3,4-tetrahydroquinoline crystal as cetp inhibitor
HU0203521A HUP0203521A2 (hu) 1999-11-30 2000-11-14 Kristályos 4-karboxi-amino-2-etil-1,2,3,4-tetrahidro-kinolin CEPT inhibitor, eljárás az előállítására, ezt tartalmazó gyógyszerkészítmény és alkalmazása
EEP200200277A EE200200277A (et) 1999-11-30 2000-11-14 4-karboksüamino-2-etüül-1,2,3,4-tetrahüdrokinoliini kristall kui CETP inhibiitor
EP00971662A EP1246804A1 (fr) 1999-11-30 2000-11-14 Cristaux de 4-carboxyamino-2-ethyl-1,2,3,4-tetrahydroquinoleine utilises en tant qu'inhibiteurs de cetp
JP2001541875A JP2003515592A (ja) 1999-11-30 2000-11-14 Ｃｅｔｐ阻害剤としての４−カルボキシアミノ−２−エチル−１，２，３，４−テトラヒドロキノリン結晶
APAP/P/2002/002531A AP2002002531A0 (en) 1999-11-30 2000-11-14 4-Carboboxyamino-2-ethyl-1,2,3,4-tetrahydroquinoline crystal as cetp inihibitor.
MXPA02005354A MXPA02005354A (es) 1999-11-30 2000-11-14 Cristal de 4-carboxamino-1,2,3,4-tetrahidroquinolina 2-sustituida.
BR0015836-4A BR0015836A (pt) 1999-11-30 2000-11-14 Cristal de 4-carboxiamino-2-etil-1,2,3,4-tetra-hidroquinolina como inibidor de cetp
EA200200510A EA200200510A1 (ru) 1999-11-30 2000-11-14 4-карбоксиамино-2-этил-1,2,3,4-тетрагидрохинолин в кристаллической форме как ингибитор сетр
CA002392979A CA2392979A1 (fr) 1999-11-30 2000-11-14 Cristaux de 4-carboxyamino-2-ethyl-1,2,3,4-tetrahydroquinoleine
AU10488/01A AU1048801A (en) 1999-11-30 2000-11-14 4-carboxyamino-2-ethyl-1,2,3,4-tetrahydroquinoline crystal as cetp inhibitor
KR1020027006914A KR20020058057A (ko) 1999-11-30 2000-11-14 콜레스테릴 에스테르 전달 단백질 저해제로서의4-카복시아미노-2-에틸-1,2,3,4-테트라하이드로퀴놀린 결정
IS6338A IS6338A (is) 1999-11-30 2002-04-12 4-karboxýamínó-2-etýl-1,2,3,4-tetrahýdrókínólín kristall sem CETP lati
NO20022558A NO20022558D0 (no) 1999-11-30 2002-05-29 4-karboksyamino-2-etyl-1,2,3,4-tetrahydrokinolinkrystall som CETP inhibitor
BG106854A BG106854A (bg) 1999-11-30 2002-06-20 Кристална форма на 4-карбоксиамино-2-етил-1,2,3,4-тетрахидрохинолин като сетр инхибитор

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US60/168,051 1999-11-30

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Cited By (24)

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WO2003000295A2 (fr) * 2001-06-21 2003-01-03 Pfizer Products Inc. Formulations auto-emulsifiantes d'inhibiteurs de la proteine de transfert du cholesterol esterifie (cetp)
WO2003029220A2 (fr) * 2001-09-28 2003-04-10 Pfizer Products Inc. Preparation d'un inhibiteur cetp anhydre a base de quinoline par cristallisation
WO2004056396A1 (fr) * 2002-12-20 2004-07-08 Pfizer Products Inc. Formes posologiques d'inhibiteurs de la proteine de transfert du cholesterol esterifie et d'inhibiteurs de la hmg-coa reductase presentant une efficacite amelioree
WO2004085401A1 (fr) * 2003-03-28 2004-10-07 Pfizer Products Inc. Derives de 1,2,3,4-tetrahydro- et 1,2 dihydro-quinoleine et 1,2,3,4-tetrahydro-quinoxaline 1,2,4-substitues, utiles comme inhibiteurs de cetp pour le traitement de l'atherosclerose et de l'obesite
JP2005517689A (ja) * 2002-02-01 2005-06-16 ファイザー・プロダクツ・インク 改良された噴霧乾燥装置を使用する均質な噴霧乾燥された固体の非晶質薬物分散物を製造する方法
WO2006033001A1 (fr) * 2004-09-23 2006-03-30 Pfizer Products Inc. Composes de quinoline
WO2006033004A1 (fr) * 2004-09-23 2006-03-30 Pfizer Products Inc. Composes de quinoline en tant qu'inhibiteurs de cetp
US7115279B2 (en) 2000-08-03 2006-10-03 Curatolo William J Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US7211672B2 (en) 2002-10-04 2007-05-01 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
US7276536B2 (en) 2003-03-17 2007-10-02 Japan Tobacco Inc. Method for increasing the bioavailability of the active form of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino) phenyl] 2-methylpropanethioate
US7332514B2 (en) 2002-08-30 2008-02-19 Japan Tobacco Inc. Dibenzylamine compound and medicinal use thereof
WO2008060476A2 (fr) 2006-11-15 2008-05-22 Schering Corporation Composés hétérocycliques contenant de l'azote et leurs procédés d'utilisation
EP1961419A1 (fr) 2002-12-20 2008-08-27 Pfizer Products Inc. Formes posologiques comprenant un inhibiteur de CETP et un inhibiteur de HMG-CoA reductase
WO2008112166A2 (fr) 2007-03-09 2008-09-18 Indigene Pharmaceuticals Inc. Combinaison de metformine r-(+) lipoate et d'agents antihyperlipidémiques pour le traitement de l'hyperglycémie diabétique et de complications diabétiques
US7504508B2 (en) 2002-10-04 2009-03-17 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
WO2010075069A1 (fr) 2008-12-16 2010-07-01 Schering Corporation Dérivés de pyranone bicycliques en tant qu'agonistes des récepteurs nicotiniques
WO2010075068A1 (fr) 2008-12-16 2010-07-01 Schering Corporation Dérivés de pyridopyrimidine et leurs procédés d'utilisation
US7749992B2 (en) 2003-10-08 2010-07-06 Eli Lilly And Company Compounds and methods for treating dislipidemia
US7951950B2 (en) 2005-02-24 2011-05-31 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
EP1920766A3 (fr) * 2002-02-01 2011-09-14 Pfizer Products Inc. Compositions pharmaceutiques de dispersions amorphes de médicaments et matériaux formant des microphases lipophiles
US8299060B2 (en) 2009-06-30 2012-10-30 Eli Lilly And Company Trans-4-[[(5S)-5-[[[3,5-bis(trifluoromethyl)phenyl]methyl] (2-methyl-2H-tetrazol-5-yl)amino]-2,3,4,5-tetrahydro-7,9-dimethyl-1H-1-benzazepin-1-yl]methyl]-cyclohexanecarboxylic acid
US9023393B2 (en) 2003-08-04 2015-05-05 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
US9486410B2 (en) 2002-02-01 2016-11-08 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
EP3795695A1 (fr) 2014-07-30 2021-03-24 F. Hoffmann-La Roche AG Marqueurs génétiques permettant de prédire la réponse à une thérapie

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WO2006098394A1 (fr) * 2005-03-14 2006-09-21 Japan Tobacco Inc. Méthode pour inhiber l’absorption de lipides et l’inhibiteur de l'absorption de lipides

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WO2000017164A1 (fr) * 1998-09-17 2000-03-30 Pfizer Products Inc. 4-carboxyamino-2-substitue-1,2,3,4-tetrahydroquinolines utilisees comme inhibiteurs de cetp

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WO1998033775A1 (fr) * 1997-02-03 1998-08-06 American Home Products Corporation Derives de l'-1-acyl-1,2-dihydroquinoline substituee en 2 augmentant la concentration en cholesterol hdl
WO2000017164A1 (fr) * 1998-09-17 2000-03-30 Pfizer Products Inc. 4-carboxyamino-2-substitue-1,2,3,4-tetrahydroquinolines utilisees comme inhibiteurs de cetp

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US8389011B2 (en) 2000-08-03 2013-03-05 Bend Research, Inc. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US8048452B2 (en) 2000-08-03 2011-11-01 Bend Research, Inc. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitor
US7115279B2 (en) 2000-08-03 2006-10-03 Curatolo William J Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
WO2003000295A2 (fr) * 2001-06-21 2003-01-03 Pfizer Products Inc. Formulations auto-emulsifiantes d'inhibiteurs de la proteine de transfert du cholesterol esterifie (cetp)
WO2003000295A3 (fr) * 2001-06-21 2004-05-27 Pfizer Prod Inc Formulations auto-emulsifiantes d'inhibiteurs de la proteine de transfert du cholesterol esterifie (cetp)
US6962931B2 (en) 2001-06-21 2005-11-08 Pfizer Inc. Self-emulsifying formulations of cholesteryl ester transfer protein inhibitors
WO2003029220A3 (fr) * 2001-09-28 2004-11-11 Pfizer Prod Inc Preparation d'un inhibiteur cetp anhydre a base de quinoline par cristallisation
WO2003029220A2 (fr) * 2001-09-28 2003-04-10 Pfizer Products Inc. Preparation d'un inhibiteur cetp anhydre a base de quinoline par cristallisation
US6573383B2 (en) 2001-09-28 2003-06-03 Pfizer Inc Preparation of anhydrous CETP inhibitor
JP2005517689A (ja) * 2002-02-01 2005-06-16 ファイザー・プロダクツ・インク 改良された噴霧乾燥装置を使用する均質な噴霧乾燥された固体の非晶質薬物分散物を製造する方法
EP1920766A3 (fr) * 2002-02-01 2011-09-14 Pfizer Products Inc. Compositions pharmaceutiques de dispersions amorphes de médicaments et matériaux formant des microphases lipophiles
US9486410B2 (en) 2002-02-01 2016-11-08 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
US10357455B2 (en) 2002-02-01 2019-07-23 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
US7807701B2 (en) 2002-08-30 2010-10-05 Japan Tobacco Inc. Dibenzylamine compounds and pharmaceutical use thereof
US7332514B2 (en) 2002-08-30 2008-02-19 Japan Tobacco Inc. Dibenzylamine compound and medicinal use thereof
US7211672B2 (en) 2002-10-04 2007-05-01 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
US7504508B2 (en) 2002-10-04 2009-03-17 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
EP1961419A1 (fr) 2002-12-20 2008-08-27 Pfizer Products Inc. Formes posologiques comprenant un inhibiteur de CETP et un inhibiteur de HMG-CoA reductase
WO2004056396A1 (fr) * 2002-12-20 2004-07-08 Pfizer Products Inc. Formes posologiques d'inhibiteurs de la proteine de transfert du cholesterol esterifie et d'inhibiteurs de la hmg-coa reductase presentant une efficacite amelioree
US7276536B2 (en) 2003-03-17 2007-10-02 Japan Tobacco Inc. Method for increasing the bioavailability of the active form of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino) phenyl] 2-methylpropanethioate
NL1025839C2 (nl) * 2003-03-28 2006-09-06 Pfizer Prod Inc Chinoline- en chinoxalineverbindingen.
WO2004085401A1 (fr) * 2003-03-28 2004-10-07 Pfizer Products Inc. Derives de 1,2,3,4-tetrahydro- et 1,2 dihydro-quinoleine et 1,2,3,4-tetrahydro-quinoxaline 1,2,4-substitues, utiles comme inhibiteurs de cetp pour le traitement de l'atherosclerose et de l'obesite
USRE47033E1 (en) 2003-08-04 2018-09-11 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
US9023393B2 (en) 2003-08-04 2015-05-05 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
US7749992B2 (en) 2003-10-08 2010-07-06 Eli Lilly And Company Compounds and methods for treating dislipidemia
WO2006033004A1 (fr) * 2004-09-23 2006-03-30 Pfizer Products Inc. Composes de quinoline en tant qu'inhibiteurs de cetp
WO2006033001A1 (fr) * 2004-09-23 2006-03-30 Pfizer Products Inc. Composes de quinoline
US7951950B2 (en) 2005-02-24 2011-05-31 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
WO2008060476A2 (fr) 2006-11-15 2008-05-22 Schering Corporation Composés hétérocycliques contenant de l'azote et leurs procédés d'utilisation
WO2008112166A2 (fr) 2007-03-09 2008-09-18 Indigene Pharmaceuticals Inc. Combinaison de metformine r-(+) lipoate et d'agents antihyperlipidémiques pour le traitement de l'hyperglycémie diabétique et de complications diabétiques
WO2010075068A1 (fr) 2008-12-16 2010-07-01 Schering Corporation Dérivés de pyridopyrimidine et leurs procédés d'utilisation
WO2010075069A1 (fr) 2008-12-16 2010-07-01 Schering Corporation Dérivés de pyranone bicycliques en tant qu'agonistes des récepteurs nicotiniques
US8329688B2 (en) 2009-06-30 2012-12-11 Eli Lilly And Company Trans-4-[[(5S)-5-[[[3,5-bis(trifluoromethyl)phenyl]methyl](2-methyl-2H-tetrazol-5-yl)amino]-2,3,4,5-tetrahydro-7,9-dimethyl-1H-1-benzazepin-1-yl]methyl]-cyclohexanecarboxylic acid
US8299060B2 (en) 2009-06-30 2012-10-30 Eli Lilly And Company Trans-4-[[(5S)-5-[[[3,5-bis(trifluoromethyl)phenyl]methyl] (2-methyl-2H-tetrazol-5-yl)amino]-2,3,4,5-tetrahydro-7,9-dimethyl-1H-1-benzazepin-1-yl]methyl]-cyclohexanecarboxylic acid
EP3795695A1 (fr) 2014-07-30 2021-03-24 F. Hoffmann-La Roche AG Marqueurs génétiques permettant de prédire la réponse à une thérapie

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EA200200510A1 (ru) 2002-10-31
EE200200277A (et) 2003-10-15
IS6338A (is) 2002-04-12
EP1246804A1 (fr) 2002-10-09
MA26845A1 (fr) 2004-12-20
TNSN00231A1 (fr) 2002-05-30
NO20022558L (no) 2002-05-29
AU1048801A (en) 2001-06-12
GT200000199A (es) 2002-05-23
NO20022558D0 (no) 2002-05-29
CA2392979A1 (fr) 2001-06-07
IL149097A0 (en) 2002-11-10
ECSP003792A (es) 2002-04-23
AP2002002531A0 (en) 2002-06-30
BR0015836A (pt) 2002-08-06
PE20010904A1 (es) 2001-09-10
HUP0203521A2 (hu) 2003-02-28

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