MXPA06003052A - Polymorphic forms of a known antihyperlipemic agent - Google Patents

Abstract

Two new polymorphic forms of (E)-7 -[4-(4-fluorophenyl)- 6-isopropyl -2-[methyl (methylsulfonyl)amino]pyrimidin -5-yl](3R, 5S)-3, 5-dihydroxyhept -6-en oic acid tris(hydroxymethyl) methylammonium salt (1), processes for making them and their use in the production of a pharmaceutical useful in the treatment of, interalia, hypercholesterolemia, hyperlipoproteinemia and atherosclerosis are described.

Description

POLYMORPHIC FORMS OF AN ANTI-HYPERLIPEMIC AGENT KNOWN This invention relates to new polymorphic forms of the tris- (hydroxy-methyl) -methyl-ammonium salt of (E) -7- [4- (4-fluoro-phenyl) -6-isopropyl-2- [methyl] - (Methyl-sulfonyl) -amino] -pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxy-hept-6-enoic (1) (illustrated below), which is useful for the production of a pharmaceutical product useful in the treatment of, among others, hypercholesterolemia, hyper-lipoproteinemia, and atherosclerosis.

The sodium salt and the calcium salt of (E) -7- [4- (4-fluoro-phenyl) -6-isopropyl-2- [methyl- (methyl-sulfonyl) -amino] -pyrimidine- 5-yl] - (3R, 5S) -3,5-dihydroxy-hept-6-enoic (hereinafter referred to as the compound (2)), were disclosed in European Patent Number 0521471. This patent also describes a process for the synthesis of the calcium salt, by means of the sodium salt. Our International Patent Application Number WO 00/42024 discloses a crystalline form of the calcium salt of (2), and processes for making it. Our International Patent Application Number WO 01/60804 discloses alternative crystalline salts of (2). One of these salts is the tris- (hydroxy-methyl) -methyl-ammonium salt (1). In this application, the exemplified process for the formation of the tris- (hydroxy-methyl) -methyl-ammonium salt is: the acidification of a solution of the methyl-amine salt of (2) in acetonitrile and water, the separation and the drying of the organic layer, followed by the addition of tris- (hydroxy-methyl) -amino-methane at room temperature, the collection of the crystalline product at room temperature, and then the drying of the crystals at 30 ° C under vacuum . This process produces needle-shaped crystals of a single polymorph of salt (1) with an X-ray powder diffraction pattern with peaks at 2-teta = 7.9, 8.5, 10.2, 16.7, 18.4, 19.3, 19.8, 20.2, 21.5, and 24.9 °. We have discovered two additional polymorphic crystalline forms of the tris- (hydroxy-methyl) -methyl-ammonium salt (1) named as Forms 2 and 3. These polymorphic forms may have different solubilities and / or stabilities and / or bioavailabilities and / or different impurity profiles (minor impurities that occur, for example, due to the manufacturing and / or isolation process) and / or crystal forms that are easier to handle, micronize, and / or form into tablets. According to one aspect of the invention, a crystalline tris- (hydroxy-methyl) -methyl-ammonium salt of (E) -7- [4- (4-fluoro-phenyl) -6-isopropyl-2-acid is provided. - [Methyl- (methyl-sulfonyl) -amino] -pyrimidin-5-yl] - (3R, 5S) -3,5-d¡-hydroxy-hept-6-enoic, which has a powder diffraction pattern of X-rays with peaks in 2-teta = 3.2, 6.3, 9.5, and 11.0. This crystalline form is hereinafter referred to as Form 2. According to another aspect of the invention, Form 2 is provided having an X-ray powder diffraction pattern with peaks at 2-teta = 3.2, 6.3, 9.5, 11.0, 12.0, 12.4, 13.9, and 21.5. In accordance with another aspect of the invention, Form 2 having an X-ray powder diffraction pattern with peaks at 2-teta = 3.2, 6.3, 9.5, 11.0, 12.0, 12.4, 13.9, 15.8, 21.5 is provided. , 22.7, 23.6, and 24.9. In accordance with another aspect of the invention, Form 2 is provided having an X-ray powder diffraction pattern substantially as shown in Figure 1. It will be appreciated that the 2-teta values listed in the The present invention for Form 2, and later in the present for Form 3, is selected because it differentiates one Form more clearly from another, although they do not necessarily represent the most intense peaks. The polymorphic salt of Form 2 of this aspect of the invention can be produced by the following process: a sample of the amorphous salt of tris- (hydroxy-methyl) -methyl-ammonium (1) (which can be prepared by Freeze drying of an aqueous solution of salt (1)), it is formed into a paste in a suitable organic solvent at a temperature lower than room temperature, the resulting mixture is filtered, and the resulting product is dried as necessary. Suitable organic solvents can be determined experimentally by the skilled person. Conveniently, the organic solvent is acetonitrile, ethyl acetate, or MTBE (methyl-tert-butyl ether). Conveniently, the mixture is formed into a paste for a prolonged period, for example for 24 hours. Conveniently, the mixture is formed into a paste at a temperature lower than room temperature, which is, for example, between about 0 ° C and 10 ° C, such as between about 0 ° C and 5 ° C, and preference at approximately 0 ° C. The product is conveniently dried by prolonged vacuum filtration, preferably avoiding the use of temperatures higher than the ambient temperature in order to avoid any risk of conversion of the polymorphic form. It will be appreciated that Form 2 can be produced by alternative methods, for example crystallization from a solution in a suitable organic solvent at low temperature. In accordance with a further aspect of the invention, a crystalline salt of (E) -7- [4- (4-fluoro-phenyl) -6- (hydroxy-methyl) -methyl-ammonium acid is provided. iso-propyl-2- [methyl- (methyl-sulfonyl) -amino] -pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxy-hept-6-enoic, which has a diffraction pattern in X-ray powder with peaks in 2-teta = 6.9 and 13.1. This crystalline form is hereinafter referred to as Form 3. In accordance with a further aspect of the invention, Form 3 having an X-ray powder diffraction pattern with peaks at 2-teta = 6.9 is provided, 13.1, 14.9, and 20.6. According to a further aspect of the invention, Form 3 is provided having an X-ray powder diffraction pattern with peaks at 2-teta = 6.9, 8.5, 9.0, 13.1, 14.9, 17.2, 18.2, 18.6, 19.0, 19.4, 20.6, and 25.4. In accordance with another aspect of the invention, Form 3 is provided having an X-ray powder diffraction pattern substantially as shown in Figure 2. The polymorphic salt of Form 3 of the foregoing aspects of the invention is can produce by the following process: a sample of the amorphous salt of tri s- (hydroxy-methyl) -methyl-ammonium (1) (which can be prepared by freeze-drying an aqueous solution of the salt (1) ), is formed in a paste in isopropanol at a temperature lower than room temperature, the resulting mixture is filtered, and the resulting product is dried. Conveniently, the mixture is formed into a paste for a prolonged period, for example for 24 hours. Conveniently, the mixture is formed into a paste at a temperature lower than room temperature, which is, for example, between about 0 ° C and 10 ° C, such as between about 0 ° C and 5 ° C, and Preference of about 0 ° C. The product is conveniently dried by prolonged filtration under vacuum, preferably avoiding the use of temperatures higher than room temperature in order to avoid any risk of conversion of the polymorphic form. The Thermal Gravimetric Analysis of the samples of Form 3, indicates that the polymorphic form is solvated, which is presented of the manufacturing method, and it will be water and / or isopropanol.

Form 2 and Form 3 can also be characterized by any suitable method known in the art. X-ray powder diffraction spectra were determined by mounting a sample of the crystalline form on silicon single crystal wafer (SSC) assemblies from Siemans, and spreading the sample in a thin layer with the aid of a glass slide. microscope. The sample was centrifuged at 30 revolutions per minute (to improve the count statistics), and was irradiated with X-rays generated by a thin and long copper focus tube operated at 40 kV and at 40 mA with a wavelength of 1.5406 Angstroms. The collimated X-ray source was passed through an automatic variable divergence slot set to V20 (path length of 20 millimeters), and the reflected radiation directed through a 2 mm dispersion slot and a detector slot of 0.2 mm. The sample was exposed for 4 seconds by 2-theta increments of 0.02 degrees (continuous scan mode) over the range of 2 degrees to 40 degrees 2-theta in the teta-theta mode. The execution time was 2 hours 6 minutes and 40 seconds. The instrument was equipped with a scintillation counter as a detector. The control and the capture of data was by means of a personal computer DECpc LPv 433sx running with the software Diffrac AT (Socabim). It will be understood that the 2-teta values of an X-ray powder diffraction pattern may vary slightly from one machine to another, or from one sample to another, and thus, the values quoted should not be interpreted as absolute. It will also be understood that the relative intensities of the peaks may vary according to the orientation of the sample under test, such that the intensities in the XRD traces included herein are illustrative and are not intended to be used for an absolute comparison. Forms 2 and 3 obtained in accordance with the present invention are substantially free of other forms of crystal and not crystal of the tris- (hydroxy-methyl) -methyl ammonium salt of (E) -7- [ 4- (4-fluoro-phenyl) -6-iso-propyl-2- [methyl- (methyl-sulfonyl) -amino] -pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxy-hepty -6-enoic. It should be understood that the term "substantially free of other forms of glass and not glass" means that the desired crystal form (Form 2 or Form 3) contains less than 50 percent, preferably less than 10 percent, more preferably less than 5 percent of any other forms of the (E) -7- [4- (4-fluoro-phenyl) -6-iso-propyl-2-tris- (hydroxy-methyl) -methyl-ammonium salt - [Methyl- (methyl-sulfonyl) -amino] -pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxy-hept-6-enoic.

The utility of the compounds of the invention can be demonstrated by conventional tests and clinical studies, including those described in European Patent Number EPA 521471. In accordance with a further feature of the invention, a method for the treatment of a condition of disease wherein the inhibition of HMG CoA reductase, which comprises administering to a warm-blooded mammal, an effective amount of Form 2 or Form 3, is beneficial. The invention also relates to the use of Form 2 or Form 3, in the manufacture of a drug to be used in a disease condition. The compound of the invention can be administered to a warm-blooded animal, in particular to a human being, who needs it, for the treatment of a disease in which HMG CoA reductase is involved, in the form of a conventional pharmaceutical composition. Accordingly, in another aspect of the invention, there is provided a pharmaceutical composition comprising Form 2 or Form 3, in admixture with a pharmaceutically acceptable carrier. These compositions can be administered in a conventional manner for the disease condition to be treated, for example by oral administration, topical, parenteral, buccal, nasal, vaginal, or rectal, or by inhalation. For these purposes, Form 2 or Form 3 can be formulated by means known in the art, in the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays. , suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular, or infusion), sterile aqueous or oily solutions or suspensions, or sterile emulsions. A preferred route of administration is oral. Form 2 or Form 3 will be administered to humans in a daily dose, for example, at the intervals stipulated in European Patent Number EPA 521471. Daily doses may be given in divided doses as necessary, the precise amount depending on The form received and the route of administration, of the weight, age, and sex of the patient being treated, and of the particular disease condition being treated, in accordance with the principles known in this field. In accordance with a further feature of the invention, there is provided a process for the manufacture of a pharmaceutical composition containing Form 2 or Form 3 as an active ingredient, which comprises mixing Form 2 or Form 3 together with a pharmaceutically vehicle acceptable.

It will be appreciated that Form 2 and Form 3 can be converted to alternative salts of (E) -7- [4- (4-fluoro-phenyl) -6-iso-propyl-2- [methyl- (methyl-sulfonyl)] ) -aminoj- pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxy-hept-6-enoic, such as the sodium or calcium salt, and then the alternative salt can be used for the treatment of a disease wherein HMG CoA reductase is involved, for example as a pharmaceutical composition, as described hereinabove for Form 2 and Form 3. Accordingly, in a further aspect of the invention, the use of of Form 2 or Form 3, as an intermediate in the manufacture of the calcium salt of (E) -7- [4- (4-fluoro-phenyl) -6-iso-propyl-2- [methyl] acid - (Methyl-sulfonyl) -amino] -pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxy-hept-6-enoic. The isolation of a crystalline salt, such as Form 2 or Form 3, allows purification by recrystallization if necessary. This may be convenient, for example, when an alternative non-crystalline salt form is required. Accordingly, a crystalline salt form can be used as a processing aid in the manufacture of non-crystalline salt forms, or crystalline salt forms, whose properties are such that purification by recrystallization is not direct. In particular, it is known that the calcium salt of (E) -7- [4- (4-fluoro-phenyl) -6-iso-propyl-2- [methyl- (methyl-sulfonyl) -amino] -pyrimidine acid -5-yl] - (3R, 5S) -3,5-dihydroxy-hept-6-enoic is generally amorphous, unless it crystallizes under specific conditions. In a further aspect of the invention, the use of Form 2 or Form 3 is provided as a processing aid in the manufacture of the calcium salt of (E) -7- [4- (4-f -f-enyl) -6-iso-propyl-2- [methyl- (methyl-sulfonyl) -amino] -pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxy-hept-6-enoic . The invention is further illustrated, but not limited, by the following examples. Example 1 The amorphous tris- (hydroxymethyl) -methyl-ammonium salt (1) (1 gram), prepared by freeze-drying an aqueous solution of the salt (which can be prepared in accordance with method described in International Publication Number WO 01/60804), to acetonitrile (10 milliliters) at 0 ° C, and stirred at 0 ° C for 24 hours. The aqueous slurry was vacuum filtered to dryness to give Form 2 salt of t ri s- (hydroxymethyl) -methyl ammonium (1), 1 H-NMR (d6-DMSO) d: 1.22 (dd.6H), 1.36 (m, 1H), 1.52 (m, 1H), 2.07 (m, 1H), 2.19 (m, 1H), 3.37 (s, 6H), 3.45 (s, 3H), 3.55 (s, 3H), 3.76 (m, 1H), 4.21 (q, 1H), 5.54 (dd, 1H), 6.51 (dd, 1H), 7.28 (t, 2H), 7.72 (m, 2H).

Eiem pio 2 The amorphous tris- (hydroxy-methyl) -methyl-ammonium salt (1) (1 gram), prepared by freeze-drying an aqueous solution of the salt, was added to ethyl acetate (10 milliliters) at 0 ° C, and stirred at 0 ° C for 24 hours. The aqueous paste was vacuum filtered to dryness to give Form 2 of the tris- (hydroxy-methyl) -methyl-ammonium salt (1).

Example 3 Amorphous tris- (hydroxy-methyl) -methyl-ammonium salt (1) (1 gram), prepared by freeze-drying an aqueous solution of the salt, added to methyl tert-butyl ether (10 milliliters) at 0 ° C, and stirred at 0 ° C for 24 hours. The aqueous paste was vacuum filtered to dryness to give Form 2 of the tris- (hydroxy-methyl) -methyl-ammonium salt (1).

Eiem pio 4 The amorphous tris- (hydroxy-methyl) -methyl-ammonium salt (1) (1 gram), prepared by freeze-drying an aqueous solution of the salt, was added to isopropyl alcohol (10 milliliters) to 0 ° C, and stirred at 0 ° C for 24 hours. The aqueous paste was vacuum filtered to dryness, to give Form 3 of the tris- (hydroxy-methyl) -methyl-ammonium salt (D-1H-NMR (d6-DMSO) d: 1.04 (d, from alcohol-so-propyl), 1.22 (dd, 6H), 1.36 (m, 1H), 1.52 (m, 1H), 2.07 ( m, 1H), 2.19 (m, 1H), 3.37 (s, 6H), 3.45 (s, 3H), 3.55 (s, 3H), 3.76 (m, 1H), 3.78 (m, from alcohol sopropyl alcohol ), 4.21 (q, 1H), 5.54 (dd, 1H), 6.51 (dd, 1H), 7.28 (t, 2H), 7.72 (m, 2H).

The identity of the samples was confirmed by 1 H-NMR. The 1 H-NMR was analyzed using a Bruker DPX400 operating at a 400 MHz field strength, using d6-dimethyl sulfoxide as a solvent. Chemical changes were measured in parts per million in relation to tetra-methyl silane. Peak multiplicities are expressed as follows: s = singlet, d = doublet, q = quartet, t = triplet, m = m ultiplete.

Claims (14)

1. A crystalline form of the compound of tris- (hydroxy-methyl) -methyl-ammonium salt of (E) -7- [4- (4-fluoro-phenyl) -6-isopropyl-2- [methyl- (methyl- sulfonyl) -amino] -pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxy-hept-6-enoic of the formula (I), which has a powder diffraction pattern of X-rays with specific peaks in 2-teta = 3.2, 6.3, 9.5, and 11.0.

2. A crystalline form as claimed in claim 1, which has an X-ray powder diffraction pattern with specific peaks at 2-teta = 3.2, 6.3, 9.5, 11.0, 12.0, 12.4, 13.9, and 21.5.

3. A crystalline form as claimed in claim 1, which has an X-ray powder diffraction pattern with specific peaks at 2-teta = 3.2, 6.3, 9.5, 11.0, 12.0, 12.4, 13.9, 15.8, 21.5, 22.7, 23.6, and 24.9.

4. A crystalline form of the compound of (tris- (hydroxy-methyl) -methyl-ammonium salt of (E) -7- [4- (4-f luoro-phenyl) -6-isopropyl-2- [] methyl- (methyl-sulfonyl) -amino] -pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxy-hept-6-enoic, which has a powder diffraction pattern of X-rays with specific peaks in 2-teta = 6.9 and 13.1.

5. A crystalline form as claimed in claim 4, which has an X-ray powder diffraction pattern with specific peaks at 2-teta = 6.9, 13.1, 14.9, and 20.6.

6. A crystalline form as claimed in claim 4, which has an X-ray powder diffraction pattern with specific peaks at 2-teta = 6.9, 8.5, 9.0, 13.1, 14.9, 17.2, 18.2, 18.6, 19.0, 19.4, 20.6, and 25.4.

7. A pharmaceutical composition, which comprises a crystalline form as claimed in any of the preceding claims, together with a pharmaceutically acceptable carrier.

A process for the manufacture of a pharmaceutical composition as claimed in claim 5, which comprises mixing a crystalline form as claimed in claim 1 or claim 4, together with a pharmaceutically acceptable carrier.

9. The use of a crystalline form as claimed in claim 1 or claim 4, in the manufacture of a medicament.

10. A method for the treatment of a disease condition wherein the inhibition of HMG CoA reductase, which comprises administering to a warm-blooded mammal, an effective amount of a crystalline form as claimed in claim 1 or Claim 4

11. A process for the manufacture of a crystalline form as claimed in claim 1 or claim 4, which comprises forming crystals by: a) forming a paste of a sample of amorphous tris- (hydroxy-methyl) -methyl salt -amonium (1) in an organic solvent, at a temperature lower than room temperature; b) filter the resulting mixture; and c) drying the resulting product as necessary.

12. A process as claimed in claim 11, for the manufacture of Form 2, wherein the organic solvent is acetonitrile, ethyl acetate, or MTBE (methyl tertiary butyl ether).

13. A process for the manufacture of a crystalline form as claimed in claim 11, for the manufacture of Form 3, wherein the organic solvent is isopropanol.

14. A process as claimed in any of claims 11 to 13, wherein the temperature is about 0 ° C.