WO2007049121A1 - Forme cristalline de sodium ; (3r,5r)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate - Google Patents

Forme cristalline de sodium ; (3r,5r)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate Download PDF

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WO2007049121A1
WO2007049121A1 PCT/IB2006/002967 IB2006002967W WO2007049121A1 WO 2007049121 A1 WO2007049121 A1 WO 2007049121A1 IB 2006002967 W IB2006002967 W IB 2006002967W WO 2007049121 A1 WO2007049121 A1 WO 2007049121A1
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sodium
imidazol
dihydroxy
heptanoate
isopropyl
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PCT/IB2006/002967
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English (en)
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Jonathan Mark Miller
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Pfizer Products Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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

Definitions

  • High levels of blood cholesterol and blood lipids are conditions involved in the onset of atherosclerosis.
  • the conversion of HMG-CoA to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase.
  • HMG-CoA reductase It is known that inhibitors of HMG-CoA reductase are effective in lowering the blood plasma level of low density lipoprotein cholesterol (LDL-C) 1 in man. (cf. M.S. Brown and J. L. Goldstein, New England Journal of Medicine, 305, No. 9, 515-517 (1981)). It has been established that lowering LDL-C levels affords protection from coronary heart disease (cf . Journal of the American Medical Association, 251 , No. 3, 351 - 374 (1984)).
  • LDL-C low density lipoprotein cholesterol
  • Statins are collectively lipid lowering agents.
  • Representative statins include atorvastatin, lovastatin, pravastatin, simvastatin and rosuvastatin.
  • Atorvastatin and pharmaceutically acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase.
  • a number of patents have issued disclosing atorvastatin. These include: United States Patent Numbers 4,681 ,893; 5,273,995 and 5,969,156, ⁇ vhich are incorporated herein by reference.
  • statins interfere, to varying degrees, with the conversion of HMG-CoA to the cholesterol precursor mevalonate by HMG-CoA reductase. These drugs share many features, but also exhibit differences in pharmacologic attributes that may contribute to differences in clinical utility and effectiveness in modifying lipid risk factors for coronary heart disease. (Clin. Cardiol. BoI. 26 (Suppl. Ill), I1I-32-III-38 (2003)).
  • statin therapy Some of the desirable pharmacologic features with statin therapy include potent reversible inhibition of HMG-CoA reductase, the ability to produce large reductions in LDL-C and non- high-density lipoprotein cholesterol (non-HDL-C), the ability to increase HDL cholesterol (HDL-C), tissue selectivity, optimal pharmacokinetics, availability of once a day dosing and a low potential for drug-drug interactions. Also desirable is the ability to lower circulating very-low-density- lipoprotein(VLDL) as well as the ability to lower triglyceride levels.
  • VLDL very-low-density- lipoprotein
  • the most potent statins display in vitro IC 50 values, using purified human HMG-CoA reductase catalytic domain preparations, of between about 5.4 and about 8.0 nM.
  • statin therapy Two important pharmacokinetic variables for statins are bioavailability and elimination half-life. It would be advantageous to have a statin with limited systemic availability so as to minimize any potential risk of systemic adverse effects, while at the same time having enough systemic availability so that any pleiotropic effects can be observed in the vasculature with statin treatment. These pleiotropic effects include improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, reduction in blood plasma levels of certain markers of inflammation such as C-reactive protein, decreasing oxidative stress and reducing vascular inflammation. (Arterioscler. Thromb. Vase. Biol. 2001; 21 :1712-1719; Heart Dis. 5(1 ):2-7, 2003). Further, it would be advantageous to have a statin with a long enough elimination half-life to maximize effectiveness for lowering LDL-C.
  • statin that is either not metabolized or minimally metabolized by the CYP 3A4 systems so as to minimize any potential risk of drug-drug interactions when statins are given in combination with other drugs.
  • statin having a combination of desirable properties including high potency in inhibiting HMG-CoA reductase, the ability to produce large reductions in LDL-C and non-high density lipoprotein cholesterol, the ability to increase HDL cholesterol, selectivity of effect or uptake in hepatic cells, optimal systemic bioavailability, prolonged elimination half-life, and absence or minimal metabolism via the CYP3A4 system.
  • compounds exhibiting optimal solubility and hygroscopicity properties are desirable for pharmaceutical applications. More specifically, compounds having high aqueous solubility and low hygroscopicity in combination with high physical and chemical stability would be most beneficial for use in pharmaceutical formulations.
  • the present invention provides a crystalline form, "form A", of sodium; (3R, 5R)-7-[4- benzylcarbamoyl-2-(4-f luorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate having an x-ray powder diffraction containing the following 2 ⁇ values measured using CuKoc radiation: 7.1 , 8.6, 9.8, 10.4, 14.1 , 15.0, and 19.5.
  • Crystalline form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluoropheynl)-5- isopropyI-imidazol-1-yl]-3,5-dihydroxy-heptanoate exhibits high water solubility, non-hygroscopicity, non- hydration, and high physical/chemical stability. Accordingly, crystalline form A of sodium; (3R, 5R)-7-[4- benzylcarbamoyl-2-(4-fluoropheynl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate is particularly useful for pharmaceutical formulation and application.
  • the novel crystalline form of sodium; (3R, 5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate described herein is a useful hypolipidemic and hypocholesterolemic agent as well as an agent in the treatment of osteoporosis and Alzheimer's disease.
  • a further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of crystalline Form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5- isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate in unit dosage form in the treatment methods mentioned above.
  • the present invention is directed to methods for the production of crystalline Form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyI-2-(4-fluorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy- heptanoate in unit dosage form in the treatment methods mentioned above.
  • FIG. 1 Powder x-ray diffractogram of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2- (4-fluorophenyl)-5 ⁇ isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate.
  • FIG. 2 Simulated powder x-ray diffractogram of crystal form A of sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dlhydroxy-heptanoate generated from single crystal structure.
  • FIG. 3 Solid-state 13 C nuclear magnetic resonance spectrum of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate with spinning side bands identified by an asterisk.
  • FIG. 4 Raman spectrum of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4- fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate.
  • FIG. 5 Solid-state 19 F nuclear magnetic resonance spectrum of crystal form A of sodium; (3R,5R)-7-t4-benzylcarbamoyl-2-(4-fluorophenyI)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate with spinning side bands identified by an asterisk.
  • Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fIuorophenyl)-5-isopropyl-imidazol- 1-yl]-3,5-dihydroxy-heptanoate was characterized by x-ray powder diffractometry.
  • the x-ray powder diffraction pattern was collected on a Rigaku Ultima-plus X-ray powder diffractometer using Cu Ka radiation (1.54 A).
  • the tube voltage and amperage were set to 4OkV and 40 mA, respectively.
  • the sample was scanned from 3° to 50° 2-theta at a step size of 0.04° 2-theta and at 2.4 seconds per step.
  • the diffractometer was calibrated for peak positions in 2-theta using a silicon standard.
  • the sample was analyzed in an ASC-6 silicon sample holder purchased from Gem Dugout [State College, PA]. The analysis was conducted at room temperature, which is generally 2O 0 C to 30 0 C. Data were collected and integrated using RigMeas software version 2.8. Diffractograms were evaluated using DiffracPlus software, release 2003, with Eva version 8.0.
  • the sample is typically placed into a cavity in the middle of the silicon sample holder.
  • the sample powder is pressed by a glass slide or equivalent to ensure a random surface and proper sample height.
  • the sample holder is then placed into the Rigaku Ultima-plus instrument and the powder x-ray diffraction pattern is collected using the instrumental parameters specified above.
  • Measurement differences associated with such X-ray powder diffraction analyses result from a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration errors, (d) operator errors (including those errors present when determining the peak locations), and (e) the nature of the material (e.g. preferred orientation errors). Calibration errors and sample height errors often result in a shift of all the peaks in the same direction. Small differences in sample height when using a flat holder will lead to large displacements in x-ray powder diffraction peak positions.
  • Figure 1 shows the x-ray powder diffraction pattern of crystal form A of sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-f luorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate.
  • Table 1 lists peak positions in degrees 2-theta and relative intensities (>14%) for the x-ray powder diffraction pattern of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5- dihydroxy-heptanoate.
  • the error for the peak positions in Table 1 is expected to be about +/- 0.1 degrees 2-theta.
  • the relative intensities are expected to vary from sample to sample depending on the experimental conditions and preferred orientation.
  • the determined structure was consistent with the intended structure.
  • the simulated x-ray powder diffraction pattern was generated from the crystal information file (cif) from the crystal structure solution using MS Modeling software suite provided by Accelrys Software (2004).
  • Figure 2 shows the simulated x-ray powder diffraction pattern of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyI)-5-isopropyi-imidazol-1-yl]-3,5-dihydroxy-heptanoate.
  • Table 2 lists peak positions in degrees 2-theta and relative intensities (>10%) for the simulated x-ray powder diffraction pattern of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5- isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate.
  • the error for the peak positions in Table 2 is expected to be about +/- 0.1 degrees 2-theta.
  • Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol- 1 -yl]-3,5-dihydroxy-heptanoate was characterized by 13 C solid-state nuclear magnetic resonance spectroscopy (SS-NMR). 13 C cross-polarization magic angle spinning (CP/MAS) NMR data were acquired at a frequency of 125.65 MHz on a 500 MHz Varian INOVA spectrometer, and externally referenced to the methyl resonance of hexamethylbenzene (17.35 ppm). The spectrometer was equipped with a 7.5 mm Chemagnetics Pencil probe.
  • Figure 3 shows the solid-state 13 C CP/MAS NMR spectra of crystal form A of sodium; (3R,5R)-7- [4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate. Resonances due to spinning sidebands are marked with asterisks (*).
  • Table 3 lists chemical shifts in ppm and relative intensities (>14%) for the 13 C CP/MAS NMR spectrum of crystal form A of sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate.
  • the error for the chemical shifts in Table 3 is expected to be about +/- 0.1 ppm.
  • the relative intensities are expected to vary from sample to sample depending on the experimental conditions.
  • Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyI-imidazol- 1-yl]-3,5-dihydroxy-heptanoate was characterized by Raman spectroscopy.
  • the Raman spectrum was collected on a Kaiser Optical Systems Raman microscope interfaced with a Raman spectrometer.
  • the laser source was a 300 mW diode laser operating at 785 nm, with an average power output of about 30 to
  • the sample was prepared for analysis by placing a small amount onto a microscope slide and placing it under the microscope.
  • Figure 4 shows the Raman spectrum of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl- 2-(4-fluorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate.
  • Table 4 lists Raman shifts in cm “1 and relative intensities (>13%) for the Raman spectrum of crystal form A of sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1 -yI]-3,5-dihydroxy-heptanoate.
  • the error for the chemical shifts in Table 4 is expected to be about +/- 2 cm '1 .
  • the relative intensities are expected to vary from sample to sample depending on the experimental conditions.
  • 1 -yl]-3,5-dihydroxy-heptanoate was characterized by 19 F solid-state nuclear magnetic resonance spectroscopy (SS-NMR). Approximately 80 mg of the sample were tightly packed into a 4 mm ZrO spinner. The spectra were collected at ambient conditions on a Bruker-Biospin 4 mm BL HFX CPMAS probe positioned into a wide-bore Bruker-Biospin Avance DSX 500 MHz NMR spectrometer. The sample was positioned at the magic angle and spun at 15.0 kHz. The fast spinning speed minimized the intensities of the spinning side bands. The number of scans was adjusted to obtain adequate S/N.
  • SS-NMR solid-state nuclear magnetic resonance spectroscopy
  • the 19 F solid state spectrum was collected using a proton decoupled magic angle spinning (MAS) experiment.
  • the proton decoupling field of approximately 80 kHz was applied and 8 scans were collected.
  • the recycle delay was set to 500 seconds to ensure acquisition of quantitative spectra.
  • Proton longitudinal relaxation times ( 1 H T 1 ) were calculated based on a fluorine detected proton inversion recovery relaxation experiment.
  • Fluorine longitudinal relaxation times ( 19 F T 1 ) were calculated based on a fluorine detected fluorine inversion recovery relaxation experiment.
  • the spectrum was referenced using an external sample of trifluoro-acetic acid (50% V/V in H 2 O), setting its resonance to -76.54 ppm.
  • Figure 5 shows the solid-state 19 F MAS NMR spectra of crystal form A of sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate. Resonances due to spinning sidebands are marked with asterisks (*).
  • Table 5 lists chemical shifts in ppm for the 19 F MAS NMR spectrum of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluoropheny!-5- isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate.
  • the error for the chemical shifts in Table 5 is expected to be about +/- 0.1 ppm.
  • Crystalline forms in general, can have advantageous properties.
  • a polymorph, hydrate, or solvate is defined by its crystal structure and properties.
  • the crystal structure can be obtained from X-ray data or approximated from other data. The properties are determined by testing.
  • the chemical formula and chemical structure does not describe or suggest the crystal structure of any particular polymorphic or crystalline hydrate form.
  • a chemical compound can exist in three states - solid, solution, and gas - crystalline solid forms exist only in the solid state. Once a chemical compound is dissolved or melted, the crystalline solid form is destroyed and no longer exists (Wells J.I., Aulton M. E.
  • Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyI)-5-isopropyl-imidazoI- 1-yl]-3,5-dihydroxy-heptanoate is highly water soluble. 200 mg of sodium; (3R,5R)-7-[4-benzy!carbamoyl- 2-(4-fluorophenyI)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate form A readily dissolves in 0.2 mL of water.
  • Crystal form A of sodium; (3R,5R)-7-[4-benzyIcarbamoyl-2-(4-fIuorophenyl)-5-isopropyI-imidazol- 1-yl]-3,5-dihydoxy-heptanoate is non-hygroscopic.
  • Sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4- fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate form A adsorbs less than 2 weight % water at 25 0 C and 90% RH as measured by dynamic water vapor sorption analysis.
  • Grystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fIuorophenyl)-5-isopropyl-imidazol- 1 -yl]-3,5-dihydroxy-heptanoate is anhydrous.
  • Anhydrous forms are generally preferred as they have a lower propensity to dehydrate/transform to another solid form during processing and storage.
  • Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol- 1-yl]-3,5-dihydroxy-heptanoate is thermodynamically and physically stable.
  • Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate does not transform to any more thermodynamically stable polymorphs or hydrates during storage at 23 0 C and 90% RH.
  • crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5- isopropyl-imidazoi-1 -yl]-3,5-dihydroxy-heptanoate does not transform to any more thermodynamically stable polymorphs or hydrates when suspended in organic solvents or aqueous-organic solvent mixtures.
  • crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol- 1 -yl]-3,5-dihydroxy-heptanoate does not transform to any more thermodynamically stable polymorphs or hydrates upon heating up to about 200 0 C
  • Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol- 1 -yl]-3,5-dihydroxy-heptanoate is chemically stable.
  • Crystal form A of sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate remains chemically stable during storage at 40 0 C and 75% RH.
  • crystal form A of sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate remains chemically stable during storage at 70 0 C.
  • the present invention provides a process for the preparation of crystalline Form A of sodium; (3R, 5R)-7-t4-benzylcarbamoyI-2-(4-fluorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate which comprises crystallizing sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1- yl]-3,5-dihydroxy-heptanoate from a solution in solvents under conditions which yield crystalline Form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yi]-3,5-dihydroxy- heptanoate.
  • the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneous ⁇ , subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds of the present invention can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either compounds or a corresponding pharmaceutically acceptable salt of a compound of the present invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from two or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, retention enemas, and emulsions, for example water or water propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.5 mg to 1000 mg, preferably 1.0 mg to 200 mg, 2.5 mg to 150 mg, 5.0 to 100 mg, and from 10 mg to 80 mg, according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents. '
  • the crystalline Forms A of sodium; (3R,5R) ⁇ 7-[4-benzylcarbamoyl- 2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.5 mg to about 1000 mg daily.
  • Daily dose ranges of about 1.0 mg to about 200 mg; about 2.5 mg to about 150 mg; about 5.0 to about 100 mg, and from about 10 mg to about 80 mg are preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • 3,5-dihydroxy-heptanoate as prepared above was combined with a mixture of 2-propanol/water (99:1) (75 ⁇ L) and heated for one hour at 60°C. The solution was then cooled to afford crystalline Form A of sodium; (3R,5R)-7-[4-Benzylcarbamoyl-2-(4-- ⁇ luorophenyl)-5-isopropyl-imidazol-1-y!]-3,5-dihydroxy- heptanoate.
  • Amorphous sodium; (3R,5R)-7-[4-Benzylcarbamoy!-2-(4-fluorophenyl)-5-isopropyl-imidazo!-1-yl]- 3,5-dihydroxy-heptanoate as prepared above was combined with a mixture of ethanol/water (99:1) (75 //L) and heated for one hour at 60 0 C.
  • Amorphous sodium; (3R,5R)-7-[4-Benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1 -yl]- 3,5-dihydroxy-heptanoate as prepared above was combined with a mixture of acetonitrile/water (99:1) (75 ⁇ L) and heated for one hour at 60 0 C.
  • 3,5-dihydroxy-heptanoate as prepared above was combined with a mixture of acetonitrile/water (95:5) (75 ⁇ L) and heated for one hour at 6O 0 C. The resulting solution was cooled and seeded with crystalline Form A of sodium; (3R,5R)-7-[4-Benzylcarbamoyl-2-(4-f luorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy- heptanoate obtained from Method A to afford crystalline Form A of sodium; (3R,5R)-7-[4- BenzylcarbamoyI-2-(4-fIuorophenyl)-5-isopropyl-imidazol-1-yI]-3,5-dihydroxy-heptanoate.
  • a 3-necked, 5 L round-bottomed flask was equipped with a mechanical stirrer, a J-KEM temperature probe, and a N 2 inlet adapter connected to a bubbler.
  • the round-bottomed flask was charged with glycine benzyl ester hydrochloride (505.2 g, 2.51 mol, 1.0 equiv.) and CH 2 CI 2 (3.0 L).
  • the milky, white reaction mixture was treated with benzophenone imine (471.1 g, 97%, 2.6 mol, 1.00 equiv.) and an exotherm (+ 4.5 0 C) was observed.
  • reaction mixture stirred at 20 0 C for 3h and TLC (50% ethyl acetate/heptane) showed a trace of starting material.
  • Additional benzophenone imine (25.0 g, 0.14 mol) was added to the reaction mixture and the mixture was stirred for 15h at 20 0 C. TLC confirmed reaction completion. This mixture was filtered through a short pad of Celite to remove ammonium chloride, and the filter cake was rinsed with CH 2 CI 2 (1.5 L).
  • a 3-necked, 3 L round-bottomed flask was equipped with a magnetic stir bar, a J-KEM temperature probe, an addition funnel, and a N 2 inlet adapter connected to a bubbler.
  • the flask was charged with potassium fert-butoxide (112.0 g, 998 mmol, 1.53 equiv) and THF (750 mL).
  • the white suspension was cooled to -70 0 C and was treated with (Benzhydrylideneamino)-acetic acid benzyl ester (215.0 g, 658 mmol, 1.00 equiv.) as a solution in THF (700 ml_).
  • the orange solution stirred for 30 min at -70 0 C and was then transferred via cannula into a solution of isobutyryl chloride (100.0 mL, 101 g, 947 mmol, 1.45 equiv.) in THF (200 mL) at -70 0 C.
  • the addition rate was such that the reaction temperature did not warm past -50 °C.
  • the reaction mixture was held at -50 "C for 1 h, and was then warmed to -30 0 C. At this temperature, the reaction was quenched with 3 M HCl (670 mL, 2.0 mol, 3.1 equiv.). The cold bath was removed, and the reaction mixture stirred at 20 0 C for 15 h.
  • the reaction mixture was concentrated in vacuo to produce a yellow residue that was re-dissolved in water (400 mL).
  • the benzophenone side-product was removed by extraction with diethyl ether (2 x 400 mL), and the aqueous layer was concentrated in vacuo to produce a light yellow residue that was concentrated twice on the rotary evaporator from methanol (2 x 500 mL) to azeotropically remove water.
  • the resulting residue was then re-dissolved in anhydrous methanol (500 mL) and potassium chloride (KCl, -82.0 g) was removed by vacuum filtration.
  • the light yellow filtrate was concentrated in vacuo to produce a light yellow residue (16, 143.1 g, 81%).
  • the resultant solution was cooled to 0 0 C and was treated with a solution of potassium carbonate (546 g, 3.95 mol, 2.51 equiv.) in deionized water (1.5 L) to produce a creamy reaction mixture.
  • the pot temperature was kept below 5 0 C during the potassium carbonate addition.
  • the mixture was treated with a solution of 4-fluorobenzoyl chloride (209 mL, 276 g, 1.74 mol, 1.11 equiv.) in CH 2 CI 2 (500 mL) at 0 0 C at a rate such that the pot temperature was kept below 5 0 C.
  • N-(1-Benzylcarbamoyl-3-methyl-2-oxo-butyl)-4-fluorobenzamide A 4-necked, 3 L round-bottomed flask was equipped with a J-KEM temperature probe, a magnetic stirrer, a condenser connected to a bubbler via a N 2 inlet adapter, and an addition funnel. The flask was charged with 2-(4-Fluorobenzoylamino)-4-methyl-3-oxo-pentanoic acid benzyl ester (200.0 g, 0.56 mol, 1.00 equiv.) and NMP (850 mL).
  • the resultant solution was heated to 160 °C and treated in one portion with neat benzylamine (65.0 mL, 31.48 g, 0.29 mol, 1.05 equiv.).
  • the reaction mixture was maintained at 160 0 C for 3 h, TLC and HPLC (50:50 ethyl acetate/hexanes) showed desired product and very little starting material.
  • the reaction mixture was cooled to 75 0 C and NMP (-600 mL) was removed by vacuum distillation.
  • the concentrated reaction mixture was poured portionwise onto a cold brine solution (1.5 L; approximately 1:2 in ice/water) and was diluted with ethyl acetate (1 L).
  • Step E r(4R,6RV6-(2-Amino-ethyl)-2,2-dimethyl- ⁇ ,31dioxan-4-yll-acetic acid tert-butyl ester
  • a 5-gallon stainless steel reactor was charged with 250 g of Ra-Ni, ((4R,6R)-6-Cyanomethyl-2,2- dimethyl-[1 ,3]dioxan-4-yl)-acetic acid tert-butyl ester (1.0 kg, 3.71 mol), toluene (6 L), methanol (675 mL), and with 6.5M NH 3 ZMeOH (800 mL).
  • the reactor was sealed, pressure tested to 3.5 bar with N 2 , and purged 3 times with 3.5 bar of N 2 .
  • the reactor was purged with H 2 to 3.5 bar three times without any agitation.
  • the reaction stirred for 2-6 h, and a small exotherm to 30 to 40 0 C was observed. Stirring was continued until H 2 uptake ceased, then the reaction mixture was stirred at 30 to 40 0 C for a further 30 min.
  • the mixture was cooled to 20 to 25 0 C, the H 2 source and the agitator were switched off, and the H 2 was vented from the reactor.
  • the agitator was switched on and the stainless steel reactor was purged with N 2 to 3.5 bar 3 times.
  • Spent Ni catalyst was filtered under a bed of nitrogen, and the stainless steel reactor and spent catalyst bed were washed with toluene (250 mL). The combined filtrates were concentrated to an approximate volume of 500 mL at a maximum temperature of 55 0 C under vacuum. [Note: the vacuum was broken with nitrogen]. A saturated sodium chloride solution was added and stirred for 10 minutes under nitrogen. The agitation was stopped and the phases were separated.
  • TBIA 5.0 g, 18.0 mmol, 0.06 equiv
  • the reactor was cooled to 30 0 C, and the contents were fully dissolved with ethyl acetate (600 mL), washed with saturated sodium bicarbonate solution (2 x 400 mL), washed with 10% aqueous sodium chloride, then concentrated in vacuo to provide 400.1 g of a very thick orange oily solid. This solid was taken up into MeOH (600 mL) while heating to 40 0 C (difficult to dissolve).
  • Fractions 3-6 (500 mL each) contained the purple impurity, and fractions 10-22 were combined and concentrated to afford 103.5 g of a dark grey oil that formed a tan foamy residue while drying under vacuum. NMR of this residue showed contamination with benzoic acid, so this crude product was re-dissolved in ethyl acetate (500 mL), washed with saturated sodium bicarbonate solution (2 x 200 mL), followed by washing with 100 mL water.

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Abstract

La présente invention concerne une forme crystalline de sodium A ; le (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophényl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate.
PCT/IB2006/002967 2005-10-28 2006-10-16 Forme cristalline de sodium ; (3r,5r)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate WO2007049121A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050239857A1 (en) * 2004-04-16 2005-10-27 Bolton Gary L Novel imidazoles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050239857A1 (en) * 2004-04-16 2005-10-27 Bolton Gary L Novel imidazoles

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