KR20070017970A - Polymorphic forms of a known antihyperlipemic agent - Google Patents

Abstract

In particular, in the preparation of pharmaceutical compositions useful for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis, ( E ) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl Two new polymorphisms of (methylsulfonyl) amino] pyrimidin-5-yl] (3 R , 5 S ) -3,5-dihydroxyhept-6-enoic acid tris (hydroxymethyl) methylammonium salt (1) Forms, methods for their preparation, and their use are disclosed.

Description

POLYMORPHIC FORMS OF A KNOWN ANTIHYPERLIPEMIC AGENT}

The present invention is particularly useful for the preparation of pharmaceutical compositions useful for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis, ( E ) -7- [4- (4-fluorophenyl) -6-isopropyl-2 - [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3 R, 5 S) -3,5- dihydroxy-hept-6-enoic acid tris (hydroxymethyl) methyl ammonium salt to (1) ( New polymorphic forms).

Formula 1

( E ) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3 R , 5 S ) -3, Sodium and calcium salts of 5-dihydroxyhept-6-enoic acid (hereinafter referred to as compound (2)) are disclosed in European Patent 0521471. This patent also describes a method for the synthesis of calcium salts via sodium salts.

Applicant's international patent application WO 00/42024 discloses the crystalline form of the calcium salt of (2), and a process for preparing the same.

Applicant's international patent application WO 01/60804 discloses an alternative crystalline salt of (2). One of these salts is tris (hydroxymethyl) methylammonium salt (1). In this application, the method illustrating the formation of tris (hydroxymethyl) methylammonium salt is: oxidation of the methylamine salt solution of (2) in acetonitrile and water, followed by addition of tris (hydroxymethyl) aminomethane at room temperature. Separation and drying of the organic layer, collection of the crystalline product at room temperature and then drying of the crystals at 30 ° C. under vacuum. The method is a single polymorphic needle crystal of salt (1) having an X-ray powder diffraction pattern with peaks at 2-θ = 7.9, 8.5, 10.2, 16.7, 18.4, 19.3, 19.8, 20.2, 21.5 and 24.9 °. Create

Applicant has found two additional polymorphic crystalline forms of the tris (hydroxymethyl) methylammonium salt (1) herein called Forms 2 and 3. Such polymorphic forms are formed with different solubility and / or stability and / or bioavailability and / or other impurity profiles (for example, few impurities resulting from manufacturing and / or isolation methods) and / or handling, micronization and / or purification. It may have a crystalline form that is easy to do.

According to one aspect of the invention, (E) -7- [4- (4-fluorophenyl) -6-isopropyl- having an X-ray powder diffraction pattern at 2-θ = 3.2, 6.3, 9.5 and 11.0 Provided by Crystalline Tris (hydroxymethyl) methylammonium Salt of 2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S) -3,5-dihydroxyhept-6-enoic acid do. This crystalline form is referred to as Form 2 below.

According to another aspect of the present invention, Form 2 is provided having an X-ray powder diffraction pattern at 2-θ = 3.2, 6.3, 9.5, 11.0, 12.0, 12.4, 13.9 and 21.5.

According to another aspect of the present invention, Form 2 having an X-ray powder diffraction pattern is provided at 2-θ = 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.

According to another aspect of the present invention, Form 2 is provided having an X-ray powder diffraction pattern substantially as shown in FIG. 1.

It is understood that the 2-θ values listed in the embodiments of the present invention in the following Embodiments 2 and 3 do not necessarily have the strongest peaks, but are selected because most of them can be clearly distinguished from each other.

Form 2 polymorphic salts of this aspect of the invention may be prepared by the following method: A sample of amorphous tris (hydroxymethyl) methylammonium salt (1) (which may be prepared by freeze drying an aqueous solution of salt (1)) Is slurried in a suitable organic solvent at a temperature below room temperature, the resulting mixture is filtered and the resulting product is dried as necessary.

Suitable organic solvents can be determined experimentally by one skilled in the art. Suitably the organic solvent is acetonitrile, ethyl acetate or MTBE (methyl t-butylether).

Suitably the mixture is suspended for a long time, for example 24 hours. Suitably the mixture is suspended at a temperature below room temperature, for example from about 0 ° C to 10 ° C, such as about 0 ° C and 5 ° C, and preferably about 0 ° C.

The product is suitably dried by delayed filtration under vacuum, preferably by avoiding use above room temperature to avoid the risk of conversion of the polymorphic form.

Form 2 may be prepared by alternative methodology, for example by crystallization from a solution in a suitable organic solvent at low temperature.

According to a further aspect of the invention, (E) -7- [4- (4-fluorophenyl) -6-isopropyl- having an X-ray powder diffraction pattern having peaks at 2-θ = 6.9 and 13.1. Provided by Crystalline Tris (hydroxymethyl) methylammonium Salt of 2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S) -3,5-dihydroxyhept-6-enoic acid do. This crystalline form is referred to as form 3 below.

According to a further aspect of the invention, Form 3 is provided having an X-ray powder diffraction pattern having peaks at 2-θ = 6.9, 13.1, 14.9 and 20.6.

According to a further aspect of the invention, Form 3 having an X-ray powder diffraction pattern with peaks at 2-θ = 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 This is provided.

According to another aspect of the present invention, Form 3 is provided having an X-ray powder diffraction pattern substantially the same as shown in FIG. 2.

Form 3 polymorphic salts of the above aspects of the invention can be prepared by the following method: A sample of amorphous tris (hydroxymethyl) methylammonium salt (1) (which can be prepared by freeze drying an aqueous solution of salt (1)) The isopropanol is slurried at a temperature below room temperature, the resulting mixture is filtered and the resulting product is dried.

Suitably the mixture is suspended for a long time, for example 24 hours. Suitably the mixture is suspended at a temperature below room temperature, for example from about 0 ° C to 10 ° C, such as about 0 ° C and 5 ° C, and preferably about 0 ° C.

The product is suitably dried by delayed filtration under vacuum, preferably by avoiding use above room temperature to avoid the risk of conversion of the polymorphic form.

Thermogravimetric analysis of the sample of Form 3 indicates that the polymorphic form is solvated, which results from the process of preparation and will be water and / or isopropanol.

Form 2 and Form 3 may also be characterized by any suitable method known in the art.

X-ray powder diffraction spectra can be measured by mounting a sample in crystalline form on a Siemans single silicon crystal (SSC) wafer mount and unfolding in thin layers using a microscope slide. The sample is rotated at 30 revolutions per minute (to improve coefficient statistics) and with X-rays generated by a copper long-fine focus tube operated at 40 kV and 40 mA with a wavelength of 1.5406 Hz. Is investigated. The aimed X-ray source passes through an automatic variable divergence slit set at V20 (20 mm passage length) and the reflected light with 2 mm antiscatter slit and 0.2 mm detector slit. Pass directly Samples are exposed for 4 seconds per 0.02 ° 2-θ increments (continuous scan mode) over the 2 ° to 40 ° 2-θ range in θ-θ mode. The run times were 2 hours 6 minutes and 40 seconds. The instrument was equipped with a scintillation counter as a detector. Control and data collection was done using a DECpc LPv 433sx personal computer running Diffrac AT (Socabim) software.

The 2-θ value of the X-ray powder diffraction pattern may vary slightly depending on the machine or sample, so the stated values should not be interpreted as absolute. Also, the relative intensities of the peaks may vary depending on the location of the sample under test so that the intensities of the XRD traces included herein are exemplary and are not intended to be used for absolute comparison.

Forms 2 and 3 obtained according to the invention are (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl ]-(3R, 5S) -3,5-dihydroxyhept-6-enoic acid is substantially free of other crystalline and amorphous forms of the tris (hydroxymethyl) methylammonium salt. The term "substantially free of other crystalline and amorphous forms" means that the desired crystalline form (form 2 or form 3) is (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- Any other form of the tris (hydroxymethyl) methylammonium salt of [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S) -3,5-dihydroxyhept-6-enoic acid It is understood to mean less than 50%, preferably less than 10%, more preferably less than 5%.

The usefulness of the present invention can be demonstrated by standard trials and clinical studies, including those described in EPA 521471.

According to a further feature of the invention, the invention provides a method for the treatment of a disease state in which inhibition of HMG CoA reductase is beneficial, comprising administering an effective amount of Form 2 or Form 3 to a constant temperature mammal. The invention also relates to the use of Form 2 or Form 3 in the manufacture of a medicament for use in a disease state.

The compounds of the present invention can be administered to incubated animals, especially humans, in need of treatment of diseases associated with HMG CoA reductase in the form of conventional pharmaceutical compositions. Thus, in another aspect of the invention, there is provided a pharmaceutical composition comprising Form 2 or Form 2 in admixture with a pharmaceutically acceptable carrier.

Such compositions may be administered in standard manner, for example by oral, topical, parenteral, oral, intranasal, intravaginal or rectal administration or inhalation for the treatment of disease states. For this purpose Form 2 or Form 3 may be prepared by methods known in the art, for example, in tablets, capsules, aqueous or oil solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or Inhalation aerosols and parenteral (including intravenous, intramuscular or injection) may be formulated in the form of sterile aqueous solutions or oil solutions or suspensions or sterile emulsions. Preferred routes of administration are oral. Form 2 or Form 3 will be administered to humans in daily dosages, for example, in the range set in EPA 521471. The daily dose may be given in divided doses as needed and the exact amount and route of administration taken depends on the weight, age and sex of the patient to be treated and the specific disease state to be treated according to principles known in the art. .

According to a further feature of the invention there is provided a process for the preparation of a pharmaceutical composition comprising form 2 or form 3 as the active ingredient, comprising mixing form 2 or form 3 with a pharmaceutically acceptable carrier.

Form 2 and Form 3 are (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidine-5, such as sodium or calcium salt -Yl]-(3R, 5S) -3,5-dihydroxyhept-6-enoic acid, which can then be converted, for example, as described below for Form 2 or Form 3. As can be seen, HMG CoA reductase can be used in the treatment of diseases in which the pharmaceutical composition is involved.

Thus, in a further aspect of the invention, (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] The use of Form 2 or Form 3 for use as an intermediate in the preparation of-(3R, 5S) -3,5-dihydroxyhept-6-acetate calcium salt is provided.

Isolation of crystalline salts such as Form 2 or Form 3 allows purification by recrystallization, if necessary. This may be advantageous if, for example, alternative forms of amorphous salts are needed. Thus, the form of the crystalline salt may be used as a processing aid in the preparation of the form of the amorphous salt, or in the form of the crystalline salt whose properties are not simple to purify by recrystallization. In particular, (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S) -3 It is known that calcium salts of, 5-dihydroxyhept-6-enoic acid are generally amorphous unless crystallized under certain conditions.

In a further aspect of the invention, (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-( Use of Form 2 or Form 3 as a processing aid in the preparation of 3R, 5S) -3,5-dihydroxyhept-6-acetate calcium salt is provided.

The invention is further illustrated, but not limited to the following examples.

Example  One

Aqueous tris (hydroxymethyl) methylammonium salt (1) (1 g), prepared by lyophilizing an aqueous solution of salt (which may be prepared according to the method described in WO 01/60804), is acetonitrile (10 ml) and stirred at 0 ° C. for 24 h. The slurry was filtered under vacuum and dried to give Tris (hydroxymethyl) methylammonium salt (1) Form 2.

¹ H NMR (d6-DMSO) δ: 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)

Example  2

Amorphous tris (hydroxymethyl) methylammonium salt (1) (1 g), prepared by lyophilizing an aqueous solution of salt, was added to ethyl acetate (10 ml) at 0 ° C. and stirred at 0 ° C. for 24 h. The slurry was filtered under vacuum and dried to give Tris (hydroxymethyl) methylammonium salt (1) Form 2.

Example  3

Amorphous tris (hydroxymethyl) methylammonium salt (1) (1 g), prepared by lyophilizing an aqueous solution of salt, was added to MTBE (10 ml) at 0 ° C. and stirred at 0 ° C. for 24 h. The slurry was filtered under vacuum and dried to give Tris (hydroxymethyl) methylammonium salt (1) Form 2.

Example  4

Amorphous tris (hydroxymethyl) methylammonium salt (1) (1 g), prepared by lyophilizing an aqueous solution of salt, was added to isopropyl alcohol (10 ml) at 0 ° C. and stirred at 0 ° C. for 24 h. The slurry was filtered under vacuum and dried to give Tris (hydroxymethyl) methylammonium salt (1) Form 3.

¹ H NMR (d6-DMSO) δ: 1.04 (d, isopropyl alcohol), 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, isopropyl alcohol), 4.21 (q, 1H), 5.54 ( dd, 1H), 6.51 (dd, 1H), 7.28 (t, 2H), 7.72 (m, 2H).

Confirmation of the sample was confirmed by ¹ H NMR. ¹ H NMR was analyzed using Bruker DPX400 operating at a field strength of 400 MHz and d6-dimethylsulfoxide as solvent. Chemical shifts were measured in parts per million relative to tetramethylsilane. Peak multiplicity is expressed as follows: s = singlet, d = doublet, q = quadruple, t = triplet, m = multiplet.

(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S)- Crystalline Tris (hydroxymethyl) methylammonium Salt Form 2 of 3,5-Dihydroxyhept-6-enoic Acid

(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S)- Crystalline Tris (hydroxymethyl) methylammonium Salt Form 3 of 3,5-Dihydroxyhept-6-enoic Acid

Claims (14)

(E) -7- [4- (4-fluorophenyl) -6-isopropyl- of formula (I) having an X-ray powder diffraction pattern with specific peaks at 2-θ = 3.2, 6.3, 9.5 and 11.0 Crystallinity of the Tris (hydroxymethyl) methylammonium Salt Compound of 2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S) -3,5-dihydroxyhept-6-enoic acid shape. Formula I

The crystalline form of claim 1, having an X-ray powder diffraction pattern with specific peaks at 2-θ = 3.2, 6.3, 9.5, 11.0, 12.0, 12.4, 13.9, and 21.5. The crystalline form of claim 1 having an X-ray powder diffraction pattern having specific peaks at 2-θ = 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. shape. (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) with an X-ray powder diffraction pattern with specific peaks at 2-θ = 6.9 and 13.1 Crystalline form of the tris (hydroxymethyl) methylammonium salt compound of) amino] pyrimidin-5-yl]-(3R, 5S) -3,5-dihydroxyhept-6-enoic acid. 5. The crystalline form of claim 4, having an X-ray powder diffraction pattern having specific peaks at 2-θ = 6.9, 13.1, 14.9, and 20.6. 5. The crystalline form of claim 4 having an X-ray powder diffraction pattern having specific peaks at 2-θ = 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. shape. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 6 together with a pharmaceutically acceptable carrier. A process for preparing the pharmaceutical composition according to claim 7 which comprises mixing the crystalline form according to claim 1 with a pharmaceutically acceptable carrier. Use in the manufacture of a medicament in the crystalline form according to claim 1. A method for treating a disease state in which inhibition of HMG CoA reductase is beneficial, comprising administering to a mammal a constant temperature an effective amount of the crystalline form of claim 1. a) slurrying a sample of amorphous tris (hydroxymethyl) methylammonium salt (1) in an organic solvent at a temperature below room temperature; b) filtering the resulting mixture; And c) drying the resulting product as needed The method for producing the crystalline form according to claim 1, which includes forming a crystal by using the compound. The process of claim 11 wherein the organic solvent is acetonitrile, ethyl acetate or MTBE (methyl t-butylether). 12. The process of claim 11 wherein the organic solvent is isopropanol. The method of claim 11, wherein the temperature is about 0 ° C. 15.