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WO2008123953A1 - Composé anti-hypercholestérolémique - Google Patents

Composé anti-hypercholestérolémique Download PDF

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Publication number
WO2008123953A1
WO2008123953A1 PCT/US2008/004140 US2008004140W WO2008123953A1 WO 2008123953 A1 WO2008123953 A1 WO 2008123953A1 US 2008004140 W US2008004140 W US 2008004140W WO 2008123953 A1 WO2008123953 A1 WO 2008123953A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
oxoazetidin
propyl
crystalline form
dihydroxy
Prior art date
Application number
PCT/US2008/004140
Other languages
English (en)
Inventor
Narayan Variankaval
Vicky K. Vydra
Robert M. Wenslow
Original Assignee
Merck & Co., 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
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Publication of WO2008123953A1 publication Critical patent/WO2008123953A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams

Definitions

  • the instant invention relates to a crystalline form of N-[3-(4- ⁇ (25',3i?)-2- ⁇ 4-[3,4- dihydroxy-3 -(hydroxymethyl)butyl]phenyl ⁇ -3 - [(35)-3 -(4-fluorophenyl)-3 -hydroxypropyl] -4- oxoazetidin-l-yl ⁇ phenyl)propyl]methanesulfonamide, and its use alone or in combination with other active agents to treat hypercholesterolemia and for preventing, halting or slowing the progression of atherosclerosis and related conditions and disease events.
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • this therapy is not easy to administer or tolerate and was therefore often unsuccessful except in specialist lipid clinics.
  • the fibrates produce a moderate reduction in LDL cholesterol accompanied by increased HDL cholesterol and a substantial reduction in triglycerides, and because they are well tolerated these drugs have been more widely used.
  • Probucol produces only a small reduction in LDL cholesterol and also reduces HDL cholesterol, which, because of the strong inverse relationship between HDL cholesterol level and CHD risk, is generally considered undesirable.
  • lovastatin the first inhibitor of HMG-CoA reductase to become available for prescription in 1987, for the first time physicians were able to obtain large reductions in plasma cholesterol with very few adverse effects.
  • lovastatin, simvastatin and pravastatin all members of the HMG-CoA reductase inhibitor class, slow the progression of atherosclerotic lesions in the coronary and carotid arteries.
  • Simvastatin and pravastatin have also been shown to reduce the risk of coronary heart disease events, and in the case of simvastatin a highly significant reduction in the risk of coronary death and total mortality has been shown by the Scandinavian Simvastatin Survival Study. This study also provided some evidence for a reduction in cerebrovascular events. Despite the substantial reduction in the risk of coronary morbidity and mortality achieved by simvastatin, the risk is still substantial in the treated patients.
  • Ezetimibe the first compound to receive regulatory approval in this class, is currently marketed in the U.S. under the tradename ZETIA®. Ezetimibe has the following chemical structure and is described in U.S. Patent No.'s Re. 37721 and 5,846,966:
  • WO2002/066464 Al discloses hypolipidemic compounds of general formula
  • R.2 is -CH2OH, -CH2 ⁇ C(O)-Ri, or -CO2R1;
  • R3 is -OH or -OC(O)Ri, and
  • R4 is -(CH2)kR5(CH2)i- where k and i are zero or integers of one or more, and k+i is an integer of 10 or less; and
  • LAG is a sugar residue, disugar residue, trisugar residue, tetrasugar residue; a sugar acid, or an amino sugar.
  • the instant invention provides a novel crystalline form of the cholesterol absorption inhibitor N- [3 -(4- ⁇ (2S,3R)-2- ⁇ 4- [3 ,4-dihydroxy-3 -(hydroxymethyl)butyl]phenyl ⁇ -3 - [(3S)-3-(4-fluorophenyl)-3 -hydroxypropyl] -4-oxoazetidin- 1 - yl ⁇ phenyl)propyl] methanesulfonamide .
  • FIG. 1 is a characteristic X-ray powder diffraction (XRPD) pattern of the crystalline Form I of N-[3-(4- ⁇ (25',3i?)-2- ⁇ 4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl ⁇ -3- [(35)-3 -(4-fluorophenyl)-3 -hydroxypropyl] -4-oxoazetidin- 1 - yl ⁇ phenyl)propyl] methanesulfonamide .
  • XRPD characteristic X-ray powder diffraction
  • FIG. 2 is a carbon- 13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum (13C-SSNMR) of crystalline Form I of N-[3-(4- ⁇ (2S,3R)- 2- ⁇ 4-[3 ,4-dihydroxy-3 -(hydroxymethyl)butyl]phenyl ⁇ -3 - [(3S)-3 -(4-fluorophenyl)-3 - hydroxypropyl] -4-oxoazetidin- 1 -yl ⁇ phenyl)propyl]methanesulfonamide.
  • CPMAS nuclear magnetic resonance
  • One object of the instant invention is to provide crystalline Form I of the cholesterol absorption inhibitor N-[3-(4- ⁇ (2S',37?)-2- ⁇ 4-[3,4-dihydroxy-3- (hydroxymethyl)butyl] phenyl ⁇ -3 -[(35)-3 -(4-fluorophenyl)-3 -hydroxypropyl] -4-oxoazetidin- 1 - yl ⁇ phenyl)propyl]methanesulfonamide which has the following chemical structural formula:
  • a second object of the instant invention is to provide a method for inhibiting cholesterol absorption comprising administering a therapeutically effective amount of Form I to a patient in need of such treatment. Another object is to provide a method for reducing plasma cholesterol levels, especially LDL-cholesterol, and treating hypercholesterolemia comprising administering a therapeutically effective amount of Form I.
  • methods for preventing or reducing the risk of developing atherosclerosis, as well as for halting or slowing the progression of atherosclerotic disease once it has become clinically evident, comprising the administration of a prophylactically or therapeutically effective amount, as appropriate, of Form I to a patient who is at risk of developing atherosclerosis or who already has atherosclerotic disease.
  • Another object of the present invention is the use of Form I for the manufacture of a medicament useful in treating, preventing or reducing the risk of developing these conditions.
  • Other objects of this invention are to provide processes for making Form I and to provide novel pharmaceutical compositions comprising Form I.
  • Crystalline Form I was characterized by X-Ray Powder Diffraction (XRPD) and
  • Major peaks from FIG. 1 that characterize Form I are (wavelength CuKa): °2-theta 18.7, 19.3, 17.1, 22, 22.6, 6.2, 11.8, 12.4 and 13.4.
  • Form I can be characterized by having an XRPD pattern obtained using CuKa radiation containing at least one °2-theta value selected from the group consisting of 18.7, 19.3, 17.1, 22, 22.6, 6.2, 11.8, 12.4, and 13.4.
  • Form I can be characterized by having an XRPD pattern obtained using CuKa radiation containing at least two °2-theta values selected from the group consisting of 18.7, 19.3, 17.1, 22, 22.6, 6.2, 11.8, 12.4, and 13.4. Even more particularly, Form I can be characterized by having an XRPD pattern obtained using CuKa radiation containing at least three °2-theta values selected from the group consisting of 18.7, 19.3, 17.1, 22, 22.6, 6.2, 11.8, 12.4, and 13.4.
  • Form I can be characterized by having an XRPD pattern obtained using CuKa radiation containing °2-theta values 18.7, 19.3 and l7.1; or 22, 22.6 and 6.2; or 11.8, 12.4 and 13.4; or a combination of two or three these groupings.
  • °2-theta values are accurate within ⁇ 0.1, based on the experiments described in the Examples provided. Additionally a listing of peaks below 28 degrees 2-theta are listed below in Table
  • Crystalline Form I of N-[3-(4- ⁇ (25,3i?)-2- ⁇ 4-[3,4-dihydroxy-3- (hydroxymethyl)butyl]phenyl ⁇ -3 - [(35)-3 -(4-fluorophenyl)-3 -hydroxypropyl] -4-oxoazetidin- 1 - yl ⁇ phenyl)propyl]methanesulfonamide can also be characterized by the X-ray powder diffraction pattern of Figure 1.
  • Form I can also be characterized by having an XRPD pattern obtained from ground Form I using CuKa radiation containing at least one °2-theta value selected from those listed in Table 2. More particularly, Form I can be characterized by having an XRPD pattern obtained from ground Form I using CuKa radiation containing at least two °2- theta values selected from those listed in Table 2. Even more particularly, Form I can be characterized by having an XRPD pattern obtained from ground Form I using CuKa radiation containing at least three °2-theta values selected from those listed in Table 2.
  • Form I can be characterized by having an XRPD pattern obtained from ground Form I using CuKa radiation containing °2-theta values 18.7, 19.3 and 17.1; or 22, 22.6 and 13.4; or 18.3, 19.0 and 20.4; or a combination of two or three of these groupings.
  • d-Spacings, distances between peaks and distances between d-spacings are also listed below in Table 3 for Form I. The peak at 18.7° 2-theta is taken as reference for these calculations.
  • Form I can also be characterized by having an XRPD pattern obtained using CuKa radiation having at least one distance between d-spacings listed in Table 3 using 18.7° 2-theta as reference. More particularly, Form I can be characterized by having an XRPD pattern obtained using CuKa radiation having at least two distances between d-spacings listed in Table 3 using 18.7° 2-theta as reference. Even more particularly, Form I can be characterized by having an XRPD pattern obtained using CuKa radiation having at least three distances between d-spacings listed in Table 3 using 18.7° 2-theta as reference.
  • Form I can alternatively be characterized by having an XRPD pattern obtained using CuKa radiation having the following distances between d-spacings using 18.7° 2-theta as reference: 0.000, -0.151 and 0.439; or -0.712, -0.808 and 1.883; or 0.101, -0.068 and -0.394; or a combination of two or three of these groupings.
  • Form I can also be characterized by having an XRPD pattern obtained using CuKa radiation having at least one distance between peaks listed in Table 3 using 18.7° 2-theta as reference. More particularly, Form I can be characterized by having an XRPD pattern obtained using CuKa radiation having at least two distances between peaks listed in Table 3 using 18.7° 2-theta as reference. Even more particularly, Form I can be characterized by having an XRPD pattern obtained using CuKa radiation having at least three distances between peaks listed in Table 3 using 18.7° 2-theta as reference.
  • Form I can alternatively be characterized by having an XRPD pattern obtained using CuKa radiation having the following distances between peaks using 18.7° 2-theta as reference: 0.0, 0.6 and -1.6; or 3.3, 3.9 and -5.3; or 0.3, 1.7 and -0.4; or a combination of two or three of these groupings.
  • XRPD pattern obtained using CuKa radiation having the following distances between peaks using 18.7° 2-theta as reference: 0.0, 0.6 and -1.6; or 3.3, 3.9 and -5.3; or 0.3, 1.7 and -0.4; or a combination of two or three of these groupings.
  • crystalline Form I was further characterized by solid-state carbon-13 nuclear magnetic resonance (13C- SSNMR) spectra.
  • the solid-state carbon-13 NMR spectra were obtained on a Bruker DSX 500WB NMR system using a Bruker 4 mm H/X/Y CPMAS probe.
  • the carbon-13 NMR spectra utilized proton/carbon- 13 cross-polarization magic-angle spinning with variable-amplitude cross polarization, total sideband suppression, and SPINAL decoupling at 10OkHz.
  • the samples were spun at 10.0 kHz, and a total of 4096 scans were collected with a recycle delay of 10 seconds. A line broadening of 10 Hz was applied to the spectra before FT was performed. Chemical shifts are reported on the TMS scale using the carbonyl carbon of glycine (176.03 p.p.m.) as a secondary reference.
  • Crystalline Form I exhibited characteristic signals by 1 3 C-SSNMR with chemical shift values of 28.8, 34.2, 43.4, 58.3, 74.8, 113.9, 129.9, 136.2, 146.5 and 168.3 parts per million (p.p.m. or ppm).
  • Form I can be characterized by having at least one chemical shift value obtained by 13C-SSNMR selected from the group consisting of 28.8, 34.2, 43.4, 58.3, 74.8, 113.9, 129.9, 136.2, 146.5 and 168.3 ppm.
  • Form I can be characterized by having at least two chemical shift values obtained by 13 C- S SNMR selected from the group consisting of 28.8, 34.2, 43.4, 58.3, 74.8, 113.9, 129.9, 136.2, 146.5 and 168.3 ppm. Even more particularly, Form I can be characterized by having at least three chemical shift values obtained by 13C-SSNMR selected from the group consisting of 28.8, 34.2, 43.4, 58.3, 74.8, 113.9, 129.9, 136.2, 146.5 and 168.3 ppm.
  • Form I can be characterized by 13C-SSNMR signals with chemical shift values of 28.8, 136.2, 43.4 and 74.8p.p.m.; or 129.9, 58.3, and 168.3 p.p.m.; or 34.2, 113.9 and 146.5 p.p.m.; or a combination of two or three of these groupings.
  • crystalline Form I can be characterized by 13C-SSNMR having chemical shift differences between the lowest ppm resonance and other resonances using 26.8 ppm as the lowest reference resonance.
  • Form I can be characterized by 13C- SSNMR having chemical shift differences between the lowest ppm resonance and other resonances as follows: 2.0, 7.4, 16.6, 31.5, 48.0, 87.1, 103.1, 109.4, 119.7, and 141.5.
  • Form I can be characterized by having at least one chemical shift difference between the lowest ppm resonance and other resonances, using 26.8 ppm as the lowest reference resonance, selected from the group consisting of 2.0, 7.4, 16.6, 31.5, 48.0, 87.1, 103.1, 109.4, 119.7 and 141.5.
  • Form I can be characterized by having at least two chemical shift differences between the lowest ppm resonance and other resonances, using 26.8 ppm as the lowest reference resonance, selected from the group consisting of 2.0, 7.4, 16.6, 31.5, 48.0, 87.1, 103.1, 109.4, 119.7 and 141.5. Even more particularly, Form I can be characterized by having at least three chemical shift differences between the lowest ppm resonance and other resonances, using 26.8 ppm as the lowest reference resonance, selected from the group consisting of 2.0, 7.4, 16.6, 31.5, 48.0, 87.1, 103.1, 109.4, 119.7 and 141.5.
  • Form I can be characterized by 13C-SSNMR having chemical shift differences between the lowest ppm resonance and other resonances as follows: 2.0, 109.4, 26.8 and 48.0; or 103.1, 31.5 and 141.5; or 7.4, 87.1 and 119.7; or a combination of two or three of these groupings.
  • the instant invention is further related to a process for preparing a crystal form of N-[3-(4- ⁇ (2,S,3i?)-2- ⁇ 4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl ⁇ -3-[(3 ⁇ )-3-(4- fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-l-yl ⁇ phenyl)propyl]methanesulfonamide comprising: a) adding a solvent to N-[3-(4- ⁇ (2S',3i?)-2- ⁇ 4-[3,4-dihydroxy-3- (hydroxymethyl)butyl]phenyl ⁇ -3-[(35)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-l- yl ⁇ phenyl)propyl]methanesulfonamide to create a slurry, and b) filtering the slurry to obtain a crystal form
  • the process further comprises: a) filtering the slurry to obtain solids, and b) drying the solids to obtain a crystal form of _V-[3-(4- ⁇ (2S,31?)-2- ⁇ 4-[3,4- dihydroxy-3 -(hydroxymethyl)butyl]phenyl ⁇ -3 -[(35)-3 -(4-fluorophenyl)-3 -hydroxypropyl] -4- oxoazetidin- 1 -yl ⁇ phenyl)propyl]methanesulfonamide.
  • the process for preparing a crystal form ofN-[3-(4- ⁇ (25,3i?)-2- ⁇ 4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl ⁇ -3-[(35)-3-(4- fluorophenyl)-3 -hydroxypropyl] -4-oxoazetidin- 1 -yl ⁇ phenyl)propyl]methanesulfonamide comprises: a) adding a solvent to N-[3-(4- ⁇ (25',3 ⁇ )-2- ⁇ 4-[3,4-dihydroxy-3- (hydroxymethyl)butyl]phenyl ⁇ -3 - [(3S)-3 -(4-fluorophenyl)-3 -hydroxypropyl] -4-oxoazetidin- 1 - yl ⁇ phenyl)propyl]methanesulfonamide, b) filtering to obtain filtrate solutions, and
  • the process comprises: a) adding a solvent to N-[3-(4- ⁇ (25',3i?)-2- ⁇ 4-[3,4-dihydroxy-3- (hydroxymethyl)butyl]phenyl ⁇ -3 - [(3S)-3 -(4-fluorophenyl)-3 -hydroxypropyl] -4-oxoazetidin- 1 - y 1 ⁇ pheny l)propy 1] methanesulfonamide, b) filtering to obtain filtrate solutions, c) cooling the filtrate solutions, c) drying the filtrate solutions to obtain a crystal form of N-[3-(4- ⁇ (25',3i?)-2- ⁇ 4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl ⁇ -3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl] -4-oxoazetidin- 1 -yl ⁇ phenyl
  • step c in a further embodiment of the fifth embodiment, after step c, supernatant is removed.
  • the instant invention is also directed to a process for for preparing a crystal form of7V-[3-(4- ⁇ (25,3i?)-2- ⁇ 4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl ⁇ -3-[(35)-3-(4- fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-l-yl ⁇ phenyl)propyl]methanesulfonamide comprising: a) adding a transesterification catalyst to a solution of 3- ⁇ 4-[(2S,3R)-3-[(3S)-3-
  • the alcohol is methanol or ethanol.
  • the solvent is IPA.
  • the transesterification catalyst is TMSOK.
  • the instant invention is also directed to a pharmaceutical composition
  • a pharmaceutical composition comprising about 5 mg to about 150 mg of crystal form of N-[3-(4- ⁇ (2S,3tf)-2- ⁇ 4-[3,4-dihydroxy-3-
  • the composition comprises about 10 mg to about 100 mg of crystal form of N- [3- (4- ⁇ (25,3/?)-2- ⁇ 4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl ⁇ -3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxoazetidin-l-yl ⁇ phenyl)propyl]methanesulfonamide, about 40 to about 140 mg of microcrystalline cellulose, about 40 mg to about 140 mg of lactose monohydrate, about 2 to about 15 mg of croscarmellose sodium, about 0.5 to about 5 mg of sodium laurgyl sulfate, about 0.5 to about 5 mg of magnesium stearate, and about 0.5 to about 5 mg of sodium stearyl fumarate
  • solvent refers to broad range of organic solvents known to those skilled in the art.
  • the solvent system is selected from the group consisting of alcohols, amines, arenes, and halogenated alkanes.
  • solvents that may be used in the process of the instant invention include, but are not limited to, 1 ,2- Dichloroethane, Acetonitrile, Nitromethane, iPrOAc in 1 ,2-dimethoxyethane, Cyclohexane in Ethyl Acetate, Cyclohexane in Ethanol, Cyclohexane in 2-Propanol, Ethyl Acetate: Heptanes, MIBK (methyl iso-butyl ketone), Water in 1 ,2- Dichloroethane, Cyclohexane in 1 ,2- Dimethoxyethane and the like.
  • the solvent may be selected from Water in 1 ,2- Dichloroethane, 1 ,2- Dichloroethane, Acetonitrile, Nitromethane, iPrO Ac in 1 ,2- dimethoxyethane, Cyclohexane in Ethyl Acetate, Cyclohexane in Ethanol, Cyclohexane in 2- Propanol, Ethyl Acetate: Heptanes, and Cyclohexane in 1 ,2- Dimethoxyethane.
  • the solvent may be selected from 100% 1,2-dichloroethane.
  • the antisolvent is selected from water or heptanes.
  • the solvent and antisolvent system may be selected from a) water in 1,2-dichloroethane and water, b) Water in Ethanol and water, c) THF in 1 -Propanol and heptanes, d) THF in Toluene and heptanes, e) THF in Ethanol and heptanes, f) iPrOAc in 2-Propanol and heptanes, g) Butyronitrile and heptanes, h) iPrOAc in Ethanol and heptanes, i) Cyclohexane in Ethyl Acetate and heptanes, j) Cyclohexane in Ethanol and heptanes, or k) Cyclohexane in 2-Propanol and
  • a transesterification catalyst is used.
  • Transesterification is the process of exchanging the alkoxy group of an ester compound by another alcohol. These reactions are often catalyzed by the addition of an acid or base.
  • the term "acid” refers to organic or inorganic acids. Examples of an organic acid include, but are not limited to, carboxylic acids such as stearic acid, acetic acid, formic acid, propionic acid, butyric acid, and the like. Examples of inorganic acid include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, and the like.
  • the term "base” refers to an organic base, an inorganic base, and the like.
  • a base include, but are n °t limited to, TMSOK, K2CO3, Cs 2 CC>3, Li 2 CO 3 , Na 2 CO 3 , KOH, LiOH, NaOH, CsOH, K 3 PO- ⁇ , KF, Et 3 N and other tertiary amines, diisopropylamine and other secondary amines, and butylamine and other primary amines.
  • the base is TMSOK.
  • the term "alcohol” is any organic compound in which a hydroxyl group (-OH) is bound to a carbon atom of an alkyl or substituted alkyl group.
  • the alcohol is selected from methanol, ethanol, propanol, isopropyl alcohol, and tert-butyl alcohol.
  • the alcohol is methanol or ethanol.
  • patient includes mammals, especially humans, who use the instant active agent for the prevention or treatment of a medical condition. Administering of the drug to the patient includes both self-administration and administration to the patient by another person. The patient may be in need of treatment for an existing disease or medical condition, or may desire prophylactic treatment to prevent or reduce the risk for diseases and medical conditions affected by inhibition of cholesterol absorption.
  • the term "therapeutically effective amount” is intended to mean that amount of a pharmaceutical drug that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the term “prophylactically effective amount” is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
  • the dosage a patient receives can be selected so as to achieve the amount of LDL cholesterol lowering desired; the dosage a patient receives may also be titrated over time in order to reach a target LDL level.
  • the dosage regimen utilizing the compound of the instant invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition.
  • the compound of the instant invention is a cholesterol absorption inhibitor and is useful for reducing plasma cholesterol levels, particularly reducing plasma LDL cholesterol levels, when used either alone or in combination with another active agent, such as an anti- atherosclerotic agent, and more particularly a cholesterol biosynthesis inhibitor, for example an HMG-CoA reductase inhibitor.
  • a cholesterol biosynthesis inhibitor for example an HMG-CoA reductase inhibitor.
  • hypercholesterolemia includes but is not limited to homozygous familial hypercholesterolemia (HoFH) and heterozygous familial hypercholesterolemia (HeFH) and therefore Form I can be used treat HoHF and HeHF patients.
  • Form I can also be used for the treatment of mixed hyperlipidemia which is characterized by an elevated LDL cholesterol level and elevated triglycerides level along with an undesirably low HDL cholesterol level.
  • Form I can also be used to treat or prevent sitosterolemia and/or to lower the concentration of one or more sterols other than cholesterol in the plasma or tissue of a patient.
  • methods for preventing or reducing the risk of developing atherosclerosis, as well as for halting or slowing the progression of atherosclerotic disease once it has become clinically evident comprising the administration of a prophylactically or therapeutically effective amount, as appropriate, of Form I to a patient who is at risk of developing atherosclerosis or who already has atherosclerotic disease.
  • Atherosclerosis encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine.
  • Atherosclerotic cardiovascular disease including restenosis following revascularization procedures, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease including multi-infarct dementia, and peripheral vessel disease including erectile dysfunction are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms "atherosclerosis” and "atherosclerotic disease.”
  • Form I may be administered to prevent or reduce the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication.
  • Coronary heart disease events are intended to include CHD death, myocardial infarction (i.e., a heart attack), and coronary revascularization procedures.
  • Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also known as cerebrovascular accidents) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vessel disease.
  • the term "atherosclerotic disease event" as used herein is intended to encompass coronary heart disease events, cerebrovascular events, and intermittent claudication. It is intended that persons who have previously experienced one or more non-fatal atherosclerotic disease events are those for whom the potential for recurrence of such an event exists.
  • the instant invention also provides a method for preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event comprising the administration of a prophylactically effective amount of Form I to a patient at risk for such an event.
  • the patient may or may not have atherosclerotic disease at the time of administration, or may be at risk for developing it.
  • Persons to be treated with the instant therapy include those at risk of developing atherosclerotic disease and of having an atherosclerotic disease event.
  • Standard atherosclerotic disease risk factors are known to the average physician practicing in the relevant fields of medicine. Such known risk factors include but are not limited to hypertension, smoking, diabetes, low levels of high density lipoprotein (HDL) cholesterol, and a family history of atherosclerotic cardiovascular disease.
  • HDL high density lipoprotein
  • the oral dosage amount of Form I is from about 0.1 to about 30 mg/kg of body weight per day, preferably about 0.1 to about 15 mg/kg of body weight per day.
  • the dosage level may be from about 1 mg to about 1000 mg of drug per day, and more particularly from about 1 mg to 250 mg per day.
  • dosage amounts will vary depending on factors as noted above.
  • the active drug of the present invention may be administered in divided doses, for example from two to four times daily, a single daily dose of the active drug is preferred.
  • the daily dosage amount may be selected from, but not limited to, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30mg, 35mg, 40 mg, 45mg, 50 mg, 55mg, 60mg, 65mg, 70mg, 75 mg, 80 mg, 85mg, 90mg, 95mg, 100 mg, 200 mg and 250 mg.
  • the active drug employed in the instant therapy can be administered in such oral forms as tablets, capsules, caplets, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Oral formulations are preferred, and particularly solid oral formulations such as tablets.
  • Administration of the active drug can be via any pharmaceutically acceptable route and in any pharmaceutically acceptable dosage form. This includes the use of oral conventional rapid-release, time controlled-release and delayed-release (such enteric coated) pharmaceutical dosage forms. Additional suitable pharmaceutical compositions for use with the present invention are known to those of ordinary skill in the pharmaceutical arts; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.
  • the active drug is typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
  • a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
  • suitable binders, lubricants, disintegrating agents and coloring and flavoring agents can also be incorporated into the mixture.
  • Stabilizing agents such as antioxidants, for example butylated hydroxyanisole (BHA), 2,6-di-tert-butyl-4-methylphenol (BHT), propyl gallate, sodium ascorbate, citric acid, calcium metabisulphite, hydroquinone, and 7-hydroxycoumarin, particularly BHA, propyl gallate and combinations thereof, can also be added to stabilize the dosage forms.
  • the use of at least one stabilizing agent is preferred in the composition, particularly BHA or a combination of BHA with propyl gallate.
  • suitable components include gelatin, sweeteners, natural and synthetic gums such as acacia, tragacanth or alginates, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • An example of a suitable pharmaceutical composition is one comprised of Form I, microcrystalline cellulose, lactose (particularly lactose monohydrate), croscarmellose sodium, and magnesium stearate, with or without the inclusion of sodium lauryl sulfate.
  • the drug load (% by weight of Form I based on total weight of the tablet without external surface coatings) in a single tablet can range for example from 1% to 35%. Examples of drug load include but are not limited to 1%, 10 %, 25% and 35%.
  • the instant invention also encompasses a process for preparing a pharmaceutical composition comprising combining Form I with a pharmaceutically acceptable carrier. Also encompassed is the pharmaceutical composition which is made by combining Form I with a pharmaceutically acceptable carrier.
  • One or more additional active agents may be administered in combination with Form I, and therefore an embodiment of the instant invention encompasses a drug combination.
  • the drug combination encompasses a single dosage formulation comprised of Form I and an additional active agent or agents, as well as administration of each of Form I and the additional active agent or agents in separate dosage formulations, which allows for concurrent or sequential administration of the active agents.
  • the additional active agent or agents can be lipid modifying agents, particularly a cholesterol biosynthesis inhibitor such as an HMG-CoA reductase inhibitor, or agents having other pharmaceutical activities, or agents that have both lipid-modifying effects and other pharmaceutical activities.
  • HMG-CoA reductase inhibitors useful for this purpose include statins in their lactonized or dihydroxy open acid forms and pharmaceutically acceptable salts and esters thereof, including but not limited to lovastatin (MEV ACOR®; see US Patent No. 4,342,767); simvastatin (ZOCOR®; see US Patent No. 4,444,784); dihydroxy open- acid simvastatin, particularly the ammonium or calcium salts thereof; pravastatin, particularly the sodium salt thereof (PRA V ACOL®; see US Patent No. 4,346,227); fluvastatin particularly the sodium salt thereof (LESCOL®; see US Patent No.
  • statins in their lactonized or dihydroxy open acid forms and pharmaceutically acceptable salts and esters thereof including but not limited to lovastatin (MEV ACOR®; see US Patent No. 4,342,767); simvastatin (ZOCOR®; see US Patent No. 4,444,784); dihydroxy open- acid simvastatin, particularly the
  • atorvastatin particularly the calcium salt thereof
  • CRESTOR® see US Patent No. 5,260,440
  • pitavastatin also referred to as NK- 104 (see PCT international publication number WO 97/23200).
  • additional active agents include but are not limited to one or more of FLAP inhibitors; 5-lipoxygenase inhibitors; additional cholesterol absorption inhibitors such as ezetimibe (ZETIA®), described in U.S. Patent No.'s Re.
  • cholesterol ester transfer protein (CETP) inhibitors for example JTT-705
  • HMG-CoA synthase inhibitors for example HMG-CoA synthase inhibitors
  • squalene epoxidase inhibitors squalene synthetase inhibitors (also known as squalene synthase inhibitors)
  • acyl-coenzyme A cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of ACAT-I or ACAT-2 as well as dual inhibitors of ACATl and -2
  • microsomal triglyceride transfer protein (MTP) inhibitors niacin; niacin receptor agonists such as acipimox and acifran, as well as niacin receptor partial agonists; niacin in combination with a DP receptor antagonist; LDL (low density lipoprotein) receptor inducers; platelet aggregation inhibitors, for example glycoprotein Ilb/IIIa fibrinogen receptor antagonists
  • Form I can be used in combination with PCSK9 antagonists; antisense; Apo-AI, Apo-AI variants such as Apo-AI milano, or Apo-AI mimetics such as D4F; an HDL selective delipidation process; anti-hypertensive agents such as renin inhibitors and angiotensin II antagonists; anti-diabetic agents such as DPP-IV inhibitors, including e.g., JANUVIA and JANUMET; anti-obesity agents such as CBl inverse agonists; and 1 l ⁇ HSDl inhibitors.
  • Form I can also be used in combination with a nucleic acid molecule inhibitor that targets NPClLl or other protein sequences involved in hyperlipidemia.
  • a polynucleotide-based gene expression inhibitor comprises any polynucleotide containing a sequence whose presence or expression in a cell causes the degradation of or inhibits the function, transcription, or translation of a gene in a sequence-specific manner.
  • Polynucleotide-based expression inhibitors may be selected from the group comprising: siRNA, microRNA, interfering RNA or RNAi, dsRNA, ribozymes, antisense polynucleotides, and DNA expression cassettes encoding siRNA, microRNA, dsRNA, ribozymes or antisense nucleic acids.
  • RNAi molecules are polynucleotides or polynucleotide analogs that, when delivered to a cell, inhibit RNA function through RNA interference.
  • Small RNAi molecules include RNA molecules less that about 50 nucleotides in length and include siRNA and miRNA.
  • SiRNA comprises a double stranded structure typically containing 15-50 base pairs and preferably 19-25 base pairs and having a nucleotide sequence identical or nearly identical to an expressed target gene or RNA within the cell.
  • An siRNA may be composed of two annealed polynucleotides or a single polynucleotide that forms a hairpin structure.
  • MicroRNAs are small noncoding polynucleotides, about 22 nucleotides long, that direct destruction or translational repression of their mRNA targets.
  • Antisense polynucleotides comprise sequence that is complimentary to a gene or mRNA.
  • Antisense polynucleotides include, but are not limited to: morpholinos, 2'-O-methyl polynucleotides, DNA, RNA and the like.
  • the polynucleotide-based expression inhibitor may be polymerized in vitro, recombinant, contain chimeric sequences, or derivatives of these groups.
  • the polynucleotide- based expression inhibitor may contain ribonucleotides, deoxyribonucleotides, synthetic nucleotides, or any suitable combination such that the target RNA and/or gene is inhibited.
  • a PCSK9-specific antagonist can be any binding molecule with specificity for PCSK9 protein including, but not limited to, antibody molecules as described below, any PCSK9-specific binding structure, any polypeptide or nucleic acid structure that specifically binds PCSK9, and any of the foregoing incorporated into various protein scaffolds; including but not limited to, various non-antibody-based scaffolds, and various structures capable of affording selective binding to PCSK9 including but not limited to small modular immunopharmaceuticals (or "SMIPs"; see, Haan & Maggos, 2004 Biocentury Jan 26); Immunity proteins (see, e.g., Chak et al., 1996 Proc.
  • SIPs small modular immunopharmaceuticals
  • Tetranectins see, Kastrup et al., 1998 Acta. Crystallogr. D. Biol. Crystallogr. 54:757-766
  • Adnectins Adnexus; see, Xu et al., 2002 Chem. Biol. 9:933-942
  • Anticalins Pieris; see Vogt & Skerra, 2004 Chemobiochem. 5:191-199; Beste et al., 1999 Proc. Natl. Acad. Sci. USA 96:1898-1903; Lamia & Erdmann, 2003 J. MoI. Biol. 329:381-388; and Lamia & Erdmann, 2004 Protein Expr. Purif.
  • CBM4-2 carbohydrate binding module 4-2
  • Tendamistat see McConnell & Hoess, 1995 J. MoI. Biol. 250:460-470, and Li et al., 2003 Protein Eng. 16:65-72
  • T cell receptor see Holler et al., 2000 Proc. Natl. Acad. Sci. USA 97:5387-5392; Shusta et al., 2000 Nat. Biotechnol. 18:754-759; and Li et al., 2005 Nat. Biotechnol.
  • Affibodies (Affibody; see Nord et al., 1995 Protein Eng. 8:601-608; Nord et al., 1997 Nat. Biotechnol. 15:772-777; Gunneriusson et al., 1999 Protein Eng. 12:873- 878); and other selective binding proteins or scaffolds recognized in the literature; see, e.g., Binz & Pluckthun, 2005 Curr. Opin. Biotech. 16:1-1 1; Gill & Damle, 2006 Curr. Opin. Biotechnol. 17:1-6; Hosse et al., 2006 Protein Science 15:14-27; Binz et al., 2005 Nat. Biotechnol.
  • non-antibody-based scaffolds or antagonist molecules with selectivity for PCSK9 that counteract PCSK9-dependent inhibition of cellular LDL-uptake form important embodiments of the present invention.
  • Aptamers nucleic acid or peptide molecules capable of selectively binding a target molecule
  • Peptide aptamers, nucleic acid aptamers (e.g., structured nucleic acid, including both DNA and RNA- based structures) and nucleic acid decoys can be effective for selectively binding and inhibiting proteins of interest; see, e.g., Hoppe-Seyler & Butz, 2000 J. MoI. Med.
  • a therapeutically or prophylactically effective amount, as appropriate, of Form I can be used for the preparation of a medicament useful for inhibiting cholesterol absorption, as well as for treating and/or reducing the risk for diseases and conditions affected by inhibition of cholesterol absorption, such as treating lipid disorders, preventing or reducing the risk of developing atherosclerotic disease, halting or slowing the progression of atherosclerotic disease once it has become clinically manifest, and preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event.
  • the medicament may be comprised of about 5 mg to about 1000 mg of Form I.
  • the medicament comprised of Form I may also be prepared with one or more additional active agents, such as those described supra.
  • iV-[3-(4- ⁇ (2.S,3i?)-2- ⁇ 4-[3,4-dihydroxy-3-(hydroxymethyl)buryl]phenyl ⁇ -3-[(35)- 3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-l-yl ⁇ phenyl)propyl]methanesulfonamide was determined to inhibit cholesterol absorption employing the Cholesterol Absorption Assay in Mice, below. This assay involves comparing a test compound to ezetimibe with respect to their ability to inhibit cholesterol absorption in mice. Both ezetimibe and the tested compound inhibited cholesterol absorption by >90% at the highest dose tested. The tested compound had an ID 50 ⁇ lmg/kg.
  • HPLC High Performance Liquid Chromatography
  • MPLC Medium Pressure Liquid Chromatography
  • pre TLC Prep TLC
  • GC Gas Chromatography
  • flash chromatography with silica gel or reversed-phase silica gel ion-exchange chromatography; and radial chromatography. All temperatures are degrees Celsius unless otherwise noted. Degrees Celsius may be noted in the examples as "C” without the degree symbol (e.g. 50C) or " 0 C” with a degree symbol (e.g. 50°C).
  • Methanesulfonylchloride (1.40 mL, 18.1 mmol) was added dropwise to a stirred solution of propargylamine (1.00 g, 18.1 mmol) and dimethylaminopyridine (44.0 mg, 0.36 mmol) in pyridine (10 mL) at 0°C. After aging for approximately 15 h, the reaction mixture was poured into IN HCl and extracted twice with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO 4 ), filtered and concentrated in vacuo, to afford the title compound i-1. Crude i-1 crystallized on standing and was used without further purification.
  • the organic layer was dried over Na 2 SO 4 , filtered and the solvent removed under vacuum to afford the crude intermediate.
  • the crude intermediate was dissolved in CH 2 Cl 2 (10OmL) under nitrogen atmosphere.
  • To the resulting solution was added simultaneously by syringe acetic anhydride (4.34mL, 46mmol) and TEA (6.4mL, 46mmol).
  • To the reaction mixture was added DMAP (0.56g, 4.6mmol).
  • the reaction mixture was stirred for 3hrs at room temperature at which time the reaction was quenched by the addition of IN aq. HCl (10OmL).
  • the reaction mixture was transferred to separately funnel and the organic layer was separated. The organic layer was was washed with aq.
  • Step A Preparation of 4- ⁇ (2S. 3R)-3- ⁇ (3S)-3 -(acetyloxyV 3 -(4-fluorophenyl)propyll - 1 -(A- (3-r(methylsulfonyl)aminolprop- 1 -yn- 1 -yl)phenyl)-4-oxoazetidin-2-yllphenyl acetate
  • Step B Preparation of 4-U2S. 3R)-3- ⁇ (3S >3-(acetyloxy>3-(4-fluorophenvnpropyll-l-(4- ⁇ 3 - l ⁇ methylsulfonvDaminoi propyl > phenyl)-4-oxoazetidin-2-yllphenyl acetate
  • Step C Preparation of (15)- 1 -(4-fluorophenyl)-3-IY3i?. 4 ⁇ -l-r4- ⁇ 3- [(methylsulfonyl)amino1propyUphenyl)-2-oxo-4-(4- ⁇ [( ' trifluoromethyl)- sulfonyl] oxy> phenyl)azetidin-3 -y 1] propyl acetate
  • Guanidine hydrochloride (1.34 g, 13.93 mmol) was added to a mixture of the intermediate from Step B, (8.5g, 13.93 mmol) and triethylamine (1.95 mL, 13.93 mmol) in methanol (150 mL). After 3 h, the solvent was removed under vacuum and the residue was dissolved in EtOAc (20OmL) / water (10OmL) and 2N aq. HCl. The mixture was transferred to a separatory funnel and the layers separated. The organic layer was washed with brine (10OmL), dried (MgSO 4 ), filtered and concentrated in vacuo to afford a clear oil.
  • the crude intermediate was dissolved in methylene chloride (100 mL) and to the solution was added (bis(trifluoromethylsulfonyl)amino pyridine (8.14g, 13.93 mmol), triethylamine (1.95 mL, 13.93mmol), DMAP (-100 mg, catalytic).
  • the resulting solution was stirred for 2 h at room temperature.
  • the reaction was quenched with IN aq. HCl and the organic layer was separated.
  • the organic extract was washed with brine, dried (MgSO 4 ) and concentrated in vacuo.
  • step E To a solution of the intermediate of step E (1.5 g, 2 mmol) in THF/water (16mL/4mL) was added TFA (1 mL). The reaction mixture was stirred at RT for 16hr. To the reaction mixture was added 10OmL toluene and the water was removed under vacuum with water bath temperature of 4O 0 C. The residue was treated twice with 10OmL toluene followed by azeotropic removal of water. The solvent was completely removed under vacuum. The crude product was purified by MPLC (silica column) with stepwise gradient elution (50 - 100% EtOAc/hexanes as eluent).
  • the starting material Compound A for these experiments was an amorphous solid which had been purified by chromatography over silica gel using mixtures of dichloromethane: Ethanol as eluent and was >99% pure by HPLC assay.
  • Compound A (amorphous solid) was dispensed into each well of a 96-well plate. A magnetic stir bar was added to each well. 900 ⁇ l of solvent was dispensed into each well. The 96-well plate was capped and the system was equilibrated at 65°C for 2 hours. The system was then filtered hot at 65°C. The remaining solids were dried and analyzed by XRPD.
  • Preferred solvent compositions to obtain the crystalline phase 0-20% (v/v) water in 1,2-dichloroethane (100 ⁇ l).
  • Antisolvent 200 ⁇ l of water. 20% (v/v) Water in Ethanol (100 ⁇ l).
  • Antisolvent 200 ⁇ l of water. 0-60% (v/v) THF in 1-Propanol (100 ⁇ l).
  • Antisolvent 200 ⁇ l of heptanes.
  • the vial was removed from the oven and 500 ⁇ l of the supernatant was added to 1 ml of room temperature heptanes (anti-solvent). A white precipitate formed. The solids were isolated by vacuum filtration over a glass frit and analyzed.
  • degrees Celsius may be represented as "C” or " 0 C” (for example 50C or 50 0 C).
  • Step G replacing the 1 eq of KCN at 50C, with a catalytic amount of potassium trimethylsilanolate (TMSOK), as the transesterification catalyst, at room temperature, produces Compound A.
  • Simple alcohols were chosen as solvents. Reaction rates are dependent on the size of the alcohol, and thus the use of smaller alcohols, which speed up the reaction, also allows for a reduction in the amount of the reagent. While other smaller alcohols such as EtOH may be used, the reaction is fastest in methanol (5 to 10 volumes) and requires only 10 mol% of TMSOK to drive the reaction to >99% completion in 1 hour at 2OC (2 hours at 10C).
  • PROCEDURE (DEPROTECTION AND CRUDE CRYSTALLIZATION FROM IP A/HEPTANE).
  • Step G a solution of diacetate in methanol was filtered through a 1 ⁇ m line filter into a 100 L round bottom flask.
  • the reaction was monitored by HPLC until ⁇ 1% of monoacetate was observed by HPLC (2 hours). Assay yield was 91% (305Og).
  • the temperature was kept constant throughout the reaction and the pH stayed also constant.
  • the solution was concentrated to 30 L and solvent switched to IPA by flushing a total of 110 L of IPA at constant volume.
  • a slurry was obtained after the solvent switch. The batch was heated up to 63C. The thin slurry obtained was line filtered while hot to remove KCl. After the filtration, temperature was brought back to 6OC to obtain a clear solution, cooled down to 58C and seeded at this point with 30g of Form I. The batch was then cooled down at 5C/hour until it reached room temperature and then aged overnight at 2OC. Concentration of Form I in the MLs was 18 mg/g. A total of 15 L of heptane were charged over 1 hour and the batched aged for two more hours.
  • Solids obtained 275Og; 90 wt%; 80.7% yield from the diacetate; 90.1 % yield for the crystallization.
  • PROCEDURE PROCEDURE (PURE CRYSTALLIZATION FROM CH3CN/IPAC).
  • Form I seed 150 mg were added. The mixture was cooled to 2OC over 3 hours and aged overnight at 2OC. Solids were filtered and washed with 150 mL of EtOH:H2O 1 :2 v/v. Obtained 25.Og of Form I of 98.7 wt%. Yield for the isolation was 87%.
  • the product as described in Example 8, was treated with Ecosorb (a kind of charcoal) or silica gel either before or after crude crystallization in order to remove impurities. It was then dissolved in MeCN (5 vol.) at 55-6O 0 C. The solution was cooled to 44-48 0 C, and seeded with 2.5 wt% media milled seed (typical size of seed is ⁇ 5 urn), charged as a slurry in 5/3 v/v toluene/MeCN. After aging the seed bed for 30-60 minutes, toluene (8.33 vol.) was charged over 10 hrs while maintaining the batch at 44-48°C.
  • Ecosorb a kind of charcoal
  • silica gel either before or after crude crystallization in order to remove impurities. It was then dissolved in MeCN (5 vol.) at 55-6O 0 C. The solution was cooled to 44-48 0 C, and seeded with 2.5 wt% media milled seed (typical size of seed is ⁇ 5 urn
  • the batch was cooled slowly to O 0 C over 6 hrs and aged at least 1 hr.
  • the crystallized batch was then filtered and washed with 5/3 v/v toluene/MeCN and toluene.
  • the washed cake was then dried under vacuum and nitrogen at 4O 0 C.
  • Form I is formulated as either dry filled capsules or compressed tablets in doses that generally will range from 1 mg to 250 mg of Form I. More generally, the doses will be in the range of 2-100 mg.
  • a typical capsule or tablet formulation contains Form I, microcrystalline cellulose (Avicel), lactose monohydrate, croscarmellose sodium, magnesium stearate and/or sodium stearyl fumarate, and may also contain sodium lauryl sulfate.
  • the capsule formulations are transferred to hard gelatin capsules. Tablet formulations may be coated with a film coat containing lactose, hypromellose, triacetin, titanium dioxide, and ferric oxide.
  • the formulations are manufactured by first blending Form I with the excipients, then compressing the mixture into ribbons by roller compaction, and then milling the ribbons into granules. The granules are then lubricated and either filled into capsules or compressed into tablets. If tablets are selected, a film coat may be applied to the compressed tablets.
  • compositions that provide lOmg and lOOmg dose of Form I are shown below.
  • the examples provide the composition for uncoated compressed tablets which contain sodium lauryl sulfate as well as both magnesium stearate and sodium stearyl fumarate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cette invention concerne une nouvelle forme cristalline de N-[3-(4-{(2S,3R)-2-{4-[3,4-dihydroxy-3-(hydroxyméthyl)butyl]phényl}-3-[(3S)-3-(4-fluorophényl)-3-hydroxypropyl]-4-oxoazétidin-1-yl}phényl)propyl]méthanesulfonamide. Le composé est utile pour diminuer les taux de cholestérol dans le plasma, en particulier le cholestérol LDL, et pour traiter une hyperlipidémie mixte.
PCT/US2008/004140 2007-04-02 2008-03-28 Composé anti-hypercholestérolémique WO2008123953A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010100255A1 (fr) 2009-03-06 2010-09-10 Lipideon Biotechnology Ag Compositions pharmaceutiques hypocholestérolémiques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5846966A (en) * 1993-09-21 1998-12-08 Schering Corporation Combinations of hydroxy-substituted azetidinone compounds and HMG CoA Reductase Inhibitors
US6605729B1 (en) * 2001-06-29 2003-08-12 Warner-Lambert Company Crystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5846966A (en) * 1993-09-21 1998-12-08 Schering Corporation Combinations of hydroxy-substituted azetidinone compounds and HMG CoA Reductase Inhibitors
US6605729B1 (en) * 2001-06-29 2003-08-12 Warner-Lambert Company Crystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010100255A1 (fr) 2009-03-06 2010-09-10 Lipideon Biotechnology Ag Compositions pharmaceutiques hypocholestérolémiques
US9212175B2 (en) 2009-03-06 2015-12-15 Lipideon Biotechnology Ag Pharmaceutical hypocholesterolemic compositions

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