WO2008038098A1 - Crystalline form of 7 [5-cyclopropyl)-4-o-fluorobenzylcarbamoyl)-2-(4-fluorophenyl)-imidazol-1-yl]-3r,5r-dihydroxyheptanoic - Google Patents
Crystalline form of 7 [5-cyclopropyl)-4-o-fluorobenzylcarbamoyl)-2-(4-fluorophenyl)-imidazol-1-yl]-3r,5r-dihydroxyheptanoic Download PDFInfo
- Publication number
- WO2008038098A1 WO2008038098A1 PCT/IB2007/002769 IB2007002769W WO2008038098A1 WO 2008038098 A1 WO2008038098 A1 WO 2008038098A1 IB 2007002769 W IB2007002769 W IB 2007002769W WO 2008038098 A1 WO2008038098 A1 WO 2008038098A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fluoro
- imidazol
- cyclopropyl
- dihydroxy
- phenyl
- Prior art date
Links
Classifications
-
- 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
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), 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, which 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), III-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. ⁇ Am. J. Cardiol. 2001; 87(suppl): 28B-32B; Atheroscer Suppl.2002;2:33-37).
- the most potent LDL-C-lowering statins are also the most potent non-HDL-C-lowering statins.
- maximum inhibitory activity is desirable.
- the known statins generally produce only modest increases in HDL-C. Therefore, the ability to effect greater increases in HDL-C would be advantageous as well.
- 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.
- 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.
- the present invention provides novel imidazole, a crystalline form thereof, and a process for making same. More specifically, the present invention provides 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4- fluoro-phenyl)-imidazol-1 -yl]-3R,5-R-dihydroxy-heptanoic acid, pharmaceutically acceptable salts, esters, amids, lactone forms, and stereoisomers thereof, a crystalline form thereof, and a process for making same.
- Step 1 1 and 2 (See, e.g., WO 2005/105079 A2, schemes 7 and 1 1 , and 60/726092, schemes 1 and 4), are coupled by heating with benzoic acid in heptane to afford 3. Excess benzoic acid is removed by extraction with aqueous sodium carbonate.
- Step 2 3 is treated with methanolic hydrochloric acid, aqueous sodium hydroxide and acetic acid to form 4; 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy-heptanoic acid, which is extracted into ethyl acetate, concentrated by distillation, crystallized, and isolated by filtration.
- Step 3 To purify, 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1 ⁇ yl]-3R,5-R- dihydroxy-heptanoic acid; 4 is treated with aqueous sodium hydroxide in acetonitrile to form 7-[5- cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1 -yl]-3R,5-R-dihydroxy-heptanoic acid; sodium salt, 5, which is then crystallized and isolated by filtration.
- Step 4 5; 7-t5-cyclopropyl-4-(3-fluoro-bBnzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1-yl]-3R,5-R- dihydroxy-heptanoic acid; sodium salt is treated with aqueous acid to form 7-[5-cyclopropyl-4-(3-fluoro- benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1 -yl]-3R,5-R-dihydroxy-heptanoic acid; 4 which is extracted into ethyl acetate, crystallized, and isolated by filtration.
- 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)- imidazol-1-yl]-3R,5-R-dihydroxy-heptanoic acid, 4, can be re-crystallized from acetone and then further isolated by filtration.
- High-resolution positive electrospray ionization mass spectrometric data were acquired for 7-[5- cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy-heptanoic acid for using a Waters QTOF Micro mass spectrometer.
- a 5g/mL solution of the sample (1 part water to 1 part acetonitrile with 0.1% formic acid) was infused into the mass spectrometer at 10L/min.
- Positive electrospray ionization was performed at a cone voltage of 20 V.
- Figure 4 illustrates the numbering key used for assignments given based upon chemical shift, integration, coupling, and homo- and hetero-nuclear correlation experiments.
- the ultraviolet spectrum ( Figure 5) of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro- phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy-heptanoic acid was acquired by dissolving the material in phosphate buff er:acetonitrile 1 :1 and measuring absorptivity of the solution on a CARY UV spectrometer. Sample preparations were carried out using buffers with pH values of 5.5 and 7.4. The appearances of the spectra at these two pH values are essentially the same. An absorption maximum is observed at 252 nm.
- the initial crystalline phase (Form A) did not convert to a more stable anhydrous polymorphic or hydrate in any of the solvents, with the exception of acetonitrile, over 17 days, indicating that Form A is likely the thermodynamically most stable form of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2- (4-fluoro-phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy-heptanoic acid.
- the material did convert to a solvate in the acetonitrile slurry.
- thermal properties of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fiuoro-phenyl)- imidazol-1 -yl]-3R,5-R-dihydroxy-heptanoic acid were investigated using differential scanning calorimetry (DSC) and thermogravimetry (TGA). DSC and TGA thermograms are provided in Figure 8 and Figure 9, respectively.
- the TGA thermogram exhibited no weight loss until 140 0 C. There was no evidence of residual solvent present.
- the hygroscopicity of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1 - yl]-3R,5-R-dihydroxy-heptanoic acid was evaluated using an automated vapor sorption/desorption analyzer at 25 0 C. At the start of the run, the sample was dried at 40 0 C before exposure to increases in relative humidity. After drying, the sample was exposed to humidities from 10% RH up to 90%RH in increments of 10% RH to collect the adsorption curve.
- the sample wieght was assumed to be at equilibrium when the weight change was not more than 0.04% in 5 minutes, with a maximum time of 60 minutes at each step.
- the humidity was decreased back to 10% RH in increments of 10% RH using the same equilibration criteria.
- 90% RH the compound's weight change was 0.16%. Therefore, the compound is not considered hygroscopic.
- the vapor solution curve is illustrated in Figure 10.
Abstract
Provided is a crystalline form A of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-1-yl]-3R,5-R-dihydroxy-heptanoic acid and a process for making same.
Description
CRYSTALLINE FORM OF - [5-CYCLOPROPYL) -4- O-FLUOROBENZYLCARBAMOYL) -2- (4 -FLUOROPHENYL) -IMIDAZOL- 1-YL]R, 5R-DIHYDR0XYHEPTAN0IC
BACKGROUND QF THE INVENTION
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. It is known that inhibitors of HMG-CoA reductase are effective in lowering the blood plasma level of low density lipoprotein cholesterol (LDL-C), 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)).
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, which are incorporated herein by reference.
All 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), III-32-III-38 (2003)). 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.
At the present time, the most potent statins display in vitro IC50 values, using purified human HMG- CoA reductase catalytic domain preparations, of between about 5.4 and about 8.0 nM. {Am. J. Cardiol. 2001; 87(suppl): 28B-32B; Atheroscer Suppl.2002;2:33-37). Generally, the most potent LDL-C-lowering statins are also the most potent non-HDL-C-lowering statins. Thus, maximum inhibitory activity is desirable. With respect to HDL-C, the known statins generally produce only modest increases in HDL-C. Therefore, the ability to effect greater increases in HDL-C would be advantageous as well. With respect to tissue selectivity, differences among statins in relative lipophilicity or hydrophilicity may influence drug kinetics and tissue selectivity. Relatively hydrophilic drugs may exhibit reduced access to nonhepatic cells as a result of low passive diffusion and increased relative hepatic cell uptake through selective organic ion transport. In addition, the relative water solubility of a drug may reduce the need for extensive cytochrome P450 (CYP) enzyme metabolism. Many drugs, including the known statins, are metabolized by the CYP3A4 enzyme system. (Arch. Intern. Med. 2000; 160:2273-2280; J. Am. Pharm.
Assoc. 2000; 40:637-644). Thus, relative hydrophilicity is desirable with 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. Finally, it would be advantageous to have a 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.
Accordingly, it would be most beneficial to provide a 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.
WO 2005/105079 A2 and U.S. Provisional Application 60/726,920 (PC33098, filed October 14, 2005), each fully incorporated herein by reference, disclose and claim certain novel iiimidazolees.
SUMMARY OF THE INVENTION
The present invention provides novel imidazole, a crystalline form thereof, and a process for making same. More specifically, the present invention provides 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4- fluoro-phenyl)-imidazol-1 -yl]-3R,5-R-dihydroxy-heptanoic acid, pharmaceutically acceptable salts, esters, amids, lactone forms, and stereoisomers thereof, a crystalline form thereof, and a process for making same.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1
IR Spectrum of 7-[5-cyclopropyl-4-(3-f luoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1 -yl]- 3R,5-R-dihydroxy-heptanoic acid
Figure 2 Mass Spectrum for 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyiy-imidazol-1 -yl]-
3R,5-R-dihydroxy-heptanoic acid
Figure 3
1H NMR Spectrum of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)- imidazol-1- yl]-3R,5-R-dihydroxy-heptanoic acid
Figure 4
7-[5-cyclopropyl-4-(3-fluoro-benzylcarbannoyl)-2-(4-1luoro-phenyl)-imiclazol-1 -yl]-3R>5-R-dihydroxy- heptanoic acid Structure, Indicating Assignments
Figure 5
UV Spectrum for 7-[5-cyclopropyl-4-(3-f luoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-i -yl]- 3R,5-R-dihydroxy-heptanoic acid in Phosphate BufferAcetonitrile 1 :1 , pH 5.5
Figure 6 Single Crystal Structure of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)- imidazol-1 -yl]-3R,5-R-dihydroxy-heptanoic acid
Powder X-Ray Diffractogram of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-f luoro-phenyl)- imidazol-1 -yl]-3R,5-R-dihydroxy-heptanoic acid
Figure 8
DSC Thermogram of 7-[5-cyciopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-f luoro-phenyl)-imidazol-1 - yl]-3R,5-R-dihydroxy-heptanoic acid
Figure 9
TGA Thermogram of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1 - y!]-3R,5-R-dihydroxy-heptanoic acid, Lot R
Figure 10
Vapor Sorption/Desorption Graph for 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro- phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy-heptanoic acid, Lot R
DETAILED DESCRIPTION
The synthetic route used to prepare supplies of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4- f luoro-phenyl)-imidazol-1 -yl]-3R,5-R-dihydroxy-heptanoic acid is outlined below. The synthesis involves 4 steps, and an optional purification step, starting from materials shown.
Step 1 : 1 and 2 (See, e.g., WO 2005/105079 A2, schemes 7 and 1 1 , and 60/726092, schemes 1 and 4), are coupled by heating with benzoic acid in heptane to afford 3. Excess benzoic acid is removed by extraction with aqueous sodium carbonate.
alcohol (aq.)
Step 2: 3 is treated with methanolic hydrochloric acid, aqueous sodium hydroxide and acetic acid to form 4; 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy-heptanoic acid, which is extracted into ethyl acetate, concentrated by distillation, crystallized, and isolated by filtration.
Step 3: To purify, 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1 ~yl]-3R,5-R- dihydroxy-heptanoic acid; 4 is treated with aqueous sodium hydroxide in acetonitrile to form 7-[5- cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1 -yl]-3R,5-R-dihydroxy-heptanoic acid; sodium salt, 5, which is then crystallized and isolated by filtration.
Step 4: 5; 7-t5-cyclopropyl-4-(3-fluoro-bBnzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1-yl]-3R,5-R- dihydroxy-heptanoic acid; sodium salt is treated with aqueous acid to form 7-[5-cyclopropyl-4-(3-fluoro- benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1 -yl]-3R,5-R-dihydroxy-heptanoic acid; 4 which is extracted into ethyl acetate, crystallized, and isolated by filtration.
For additional purification, 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)- imidazol-1-yl]-3R,5-R-dihydroxy-heptanoic acid, 4, can be re-crystallized from acetone and then further isolated by filtration.
Control of Materials
Reagents, Solvents, and Catalysts
A list of the reagents, solvents, and catalysts used in the manufacture of the drug substance is given below in Table 1.
Characterization
Elucidation of Structure and Other Characteristics
Introduction
The established structure of 7-[5-cyclopropyI-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)- midazol-1-yl]-3R,5-R-dihydroxy-heptanoic acid is consistent with the method of synthesis and all micro analytical and spectroscopic data obtained from the analysis of the lot that is being certified as Analytical Reference Standard. Details of the analyses to elucidate the structure follow.
Elemental Analysis
Elemental analysis results are provided in Table 2. All measurements were within standard experimental error of the values calculated for the empirical formula 027!-!29N3F2O5 of 7-[5-cyclopropyl-4-(3- fluoro-benzylcarbamoyO^^^fluoro-phenyO-imidazol-i-yO-SR.δ-R-dihydroxy-heptanoic acid.
Table 2. Elemental Analysis of T-β-cyclopropyM-β-fluoro-benzylcarbamoyO^-^-fluoro-phenyl)- imidazol-1 -yl]-3R,5-R-dihydroxy-heptanoϊc acid
The KBr infrared absorption spectrum (Figure 1) exhibits absorption as presented in Table 3. The spectrum was obtained as KBr pellet. The spectrum is consistent with the assigned structure.
Table 3. Proposed IR Vibrational Band Assignments for 7-[5-cyclopropyl-4-(3-fluoro- benzylcarbamoyO^^-fluoro-phenylJ-imidazol-i-yll-SRjB-R-dihydroxy-heptanoic acid
Mass Spectrometry (MS)
High-resolution positive electrospray ionization mass spectrometric data were acquired for 7-[5- cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy-heptanoic acid for using a Waters QTOF Micro mass spectrometer. A 5g/mL solution of the sample (1 part water to 1 part acetonitrile with 0.1% formic acid) was infused into the mass spectrometer at 10L/min. Positive electrospray ionization was performed at a cone voltage of 20 V. External and internal calibrations were established for the analysis such that m/∑ measurements were accurate to + 0.0020 m/z for all ions observed. Molecular ions were generated from the sample in the form of the protonated ion (MH+) at m/z 514 and the sodium adduct (MNa+) at m/z 536. Accurate mass measurements showed the MH+ ion to have an m/z value of 514.2168, which correlates to an empirical formula of C2TH2QN3O5F2 for the neutral substance. The assignment of ions in the mass spectrum is presented in Table 4 and is consistent with the assigned structure.
Table 4. Ion Structure Assignments for the Mass Spectrum of 7-[5-cyc!opropyl-4-(3-fluoro- benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy-heptanoic acicl
Nuclear Magnetic Resonance Spectroscopy
Proton (Figure 3), gCOSY, multiplicity-edited gHSQC, gHMBC, and carbon nuclear magnetic resonance (NMR) spectra were acquired using a Varian INOVA 500 MHz NMR spectrometer equipped with a 5 mm gradient triple resonance Cold-probe, at a proton frequency of 500.03 MHz. A solution of about 30 mg of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy- heptanoic acid, dissolved in 0.75 ml_ dimethyl sulfoxide (d-6; 99.8% D>, was used to acquire the spectra, which were referenced to the solvent signal (2.50 ppm for proton and 39.51 ppm for carbon). The data were recorded at 25°C.
Figure 4 illustrates the numbering key used for assignments given based upon chemical shift, integration, coupling, and homo- and hetero-nuclear correlation experiments.
Table 5 1 H Chemical Shift Assignments for 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4- f luoro-pheny l)-imidazol-1 -yl]-3R,5-R-dihydroxy-heptanoic acid
Ultraviolet Spectrum
The ultraviolet spectrum (Figure 5) of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro- phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy-heptanoic acid was acquired by dissolving the material in
phosphate buff er:acetonitrile 1 :1 and measuring absorptivity of the solution on a CARY UV spectrometer. Sample preparations were carried out using buffers with pH values of 5.5 and 7.4. The appearances of the spectra at these two pH values are essentially the same. An absorption maximum is observed at 252 nm. The molar extinction coefficient of 7-[5-cyclopropyl-4-(3-fluoro-benzyIcarbamoyl)-2-(4-fluoro-phenyl)- imidazol-1 -y!]-3R,5-R-dihydroxy-heptanoic acid in phosphate buffeπacetonitrile 1 :1 at 290 nm is 1917 at pH 5.5 and 1883 at pH 7.4. No absorption maxima are observed at or above 290 nm.
Single Crystal X-Ray Crystallography
Single crystals of 7-[5-cyclopropyl-4-(3-f luoro-benzylcarbamoyl)-2-(4-f luoro-phenyl)-imidazol-1 -yl]- 3R,5-R-dihydroxy-heptanoic acid were grown by heat/cool in methyl alcohol resulting in single crystals appropriate for X-ray structure determination. A representative crystal was surveyed and data were collected at ambient temperature using an APEX (Bruker-AXS) diffractometer. All crystallographic calculations were facilitated by the SHELXTL software package. The crystal structure was solved and refined in the orthorhombic crystal system in the P212121 space group. This structure solution is proof of relative configuration; the stereocenters are known relative to each other, only R1R or S1S configuration are possible. The refined structure fits well to the data with a final R-index 4.76% and no missing or misplaced electron density observed in the final difference Fourier. The asymmetric unit from the crystal structure is plotted in Figure S.3.1-6 and confirms the molecular structure and chirality of 7-[5-cyclopropyl-4-(3-fluoro- benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy-heptanoic acid; atom numbering in the figure is arbitrary and does not reflect IUPAC numbering conventions.
Polymorphism
7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy- heptanoic acid, was subjected to a stable form screen to determine the most stable crystalline form. Suspensions of the test compound were prepared in various solvents with a wide range of polarities. After 17 days, the solubility was determined by gravimetry and the polymorphic identity of the slurried material was determined by powder x-ray diffraction (PXRD). The resulsts of the stable form screen are contained in Table S.3.1-5. The initial crystalline phase (Form A) did not convert to a more stable anhydrous polymorphic or hydrate in any of the solvents, with the exception of acetonitrile, over 17 days, indicating that Form A is likely the thermodynamically most stable form of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2- (4-fluoro-phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy-heptanoic acid. The material did convert to a solvate in the acetonitrile slurry.
Table 6. Stable Form Screen of 7-[5-cydopropyl-4-(3-fIuoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)- imidazol-1 -yl]-3R,5-R-dihydroxy-heptanoic acid
X-ray Diffraction
The powder x-ray diff ractogram (PXRD) for 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4- f luoro-phenyl)-imidazol-i -yl]-3R,5-R-dihydroxy-heptanoic acid (Form A) is provided in Figure 7.
Thermal Properties
The thermal properties of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fiuoro-phenyl)- imidazol-1 -yl]-3R,5-R-dihydroxy-heptanoic acid were investigated using differential scanning calorimetry (DSC) and thermogravimetry (TGA). DSC and TGA thermograms are provided in Figure 8 and Figure 9, respectively.
Differential scanning calorimetry was used to examine the melting point and heat of fusion of 7-[5- cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy-heptanoic acid. Lot R appears to melt at ~160°C. However, this apparent melting point coincides with degradation based on mass loss observed by TGA.
The TGA thermogram exhibited no weight loss until 1400C. There was no evidence of residual solvent present.
Isomerism
7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1-yl]-3R,5-R-dihydroxy- heptanoic acid has 2 assymmetric chiral centers. While the potential for interconversion of isomers is low, solid state samples are being monitored during stability testing. Vapor-Sorption Analysis
The hygroscopicity of 7-[5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-1 - yl]-3R,5-R-dihydroxy-heptanoic acid was evaluated using an automated vapor sorption/desorption analyzer at 250C. At the start of the run, the sample was dried at 400C before exposure to increases in relative humidity. After drying, the sample was exposed to humidities from 10% RH up to 90%RH in increments of 10% RH to collect the adsorption curve. The sample wieght was assumed to be at equilibrium when the weight change was not more than 0.04% in 5 minutes, with a maximum time of 60 minutes at each step. To collect the desorption curve, the humidity was decreased back to 10% RH in increments of 10% RH using
the same equilibration criteria. At 90% RH, the compound's weight change was 0.16%. Therefore, the compound is not considered hygroscopic. The vapor solution curve is illustrated in Figure 10.
Claims
1. A crystalline Form A of 7-f5-cyclopropyl-4-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-imidazol-
1 -yl]-3R,5-R-dihydroxy-heptanoic acid.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US84716206P | 2006-09-25 | 2006-09-25 | |
US600/847,162 | 2006-09-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2008038098A1 true WO2008038098A1 (en) | 2008-04-03 |
Family
ID=38884684
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2007/002769 WO2008038098A1 (en) | 2006-09-25 | 2007-09-17 | Crystalline form of 7 [5-cyclopropyl)-4-o-fluorobenzylcarbamoyl)-2-(4-fluorophenyl)-imidazol-1-yl]-3r,5r-dihydroxyheptanoic |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2008038098A1 (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005105079A2 (en) * | 2004-04-16 | 2005-11-10 | Warner-Lambert Company Llc | Novel imidazoles |
WO2007042910A1 (en) * | 2005-10-14 | 2007-04-19 | Pfizer Products Inc. | Imidazoles and their use as hmg-coa reductase inhibitors |
WO2007107843A1 (en) * | 2006-03-22 | 2007-09-27 | Pfizer Products Inc. | Methods of treatment with cetp inhibitors |
-
2007
- 2007-09-17 WO PCT/IB2007/002769 patent/WO2008038098A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005105079A2 (en) * | 2004-04-16 | 2005-11-10 | Warner-Lambert Company Llc | Novel imidazoles |
WO2007042910A1 (en) * | 2005-10-14 | 2007-04-19 | Pfizer Products Inc. | Imidazoles and their use as hmg-coa reductase inhibitors |
WO2007107843A1 (en) * | 2006-03-22 | 2007-09-27 | Pfizer Products Inc. | Methods of treatment with cetp inhibitors |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20190367458A1 (en) | Crystal form of quinoline compound and process for its production | |
EP2785702B1 (en) | Crystalline dapagliflozin hydrate | |
US20090023922A1 (en) | Process for preparing voriconazole, new polymorphic form of intermediate thereof, and uses thereof | |
JP2010523559A (en) | Crystal form of [3- (4- {2-butyl-1- [4- (4-chloro-phenoxy) -phenyl] -1H-imidazol-4-yl} -phenoxy) -propyl] -diethylamine | |
US7674923B2 (en) | Process for preparing forms of atorvastatin calcium substantially free of impurities | |
US20090247542A1 (en) | Syntheses and preparations of polymorphs of crystalline aripiprazole | |
WO2009147529A1 (en) | Substantially pure deferasirox and processes for the preparation thereof | |
WO2012106584A2 (en) | Pitavastatin salts | |
US7884212B2 (en) | Process for the preparation of candesartan cilexetil | |
WO2008038098A1 (en) | Crystalline form of 7 [5-cyclopropyl)-4-o-fluorobenzylcarbamoyl)-2-(4-fluorophenyl)-imidazol-1-yl]-3r,5r-dihydroxyheptanoic | |
JP2009538904A (en) | New crystal form | |
WO2002102382A9 (en) | A PROCESS FOR PREPARING PAROXETINE HCl WHICH LIMITS FORMATION OF PINK COLORED COMPOUNDS | |
CN102753534B (en) | For the preparation of the method for key intermediate of synthesis rosuvastatin or its pharmacologically acceptable salt | |
EP2189456A1 (en) | New compounds prepared from omeprazole | |
EP2373609B1 (en) | Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates | |
AU2002311322B2 (en) | Processing Method of Lactonization in the Preparation of Statins | |
WO2013084150A1 (en) | Novel crystal form of (2s)-2-amino-3-hydroxy-n-[2-methoxy-2-[(1z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl]propanamide and method of preparation thereof | |
AU2013204129C1 (en) | Crystal Form of Quinoline Compound and Process for its Production | |
EP2729460B1 (en) | Crystalline solvates of 6-(piperidin-4-yloxy)-2h-isoquinolin-1-one hydrochloride | |
EP3368506B1 (en) | Process for the preparation of enclomiphene citrate having needle shaped crystal habit. | |
WO2010131118A2 (en) | Polymorphs of etravirine and processes for preparation thereof | |
US20130012479A1 (en) | Polymorphs of 6-(piperidin-4-yloxy)-2h-isoquinolin-1-one hydrochloride | |
EP2327682A1 (en) | Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates | |
WO2008059372A2 (en) | Crystal form of (3r,5r)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-metyl-benzylcarbamoyl)-2h-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt | |
WO2007049121A1 (en) | Crystal form of sodium; (3r,5r)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 07804962 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 07804962 Country of ref document: EP Kind code of ref document: A1 |