Crystalline hydrated form of the calcium salt of bis[(e)-7-[4-(4-forfinal)-6-isopropyl-2- [methyl(methylsulphonyl)amino]-piri midin-5-yl]-(3r,5s)-3,5 - dihydroxide-6-ene acid], its preparation, pharmaceutical composition, its preparation and method of treatment
The invention relates to a new crystalline hydrated form of the calcium salt of bis[(E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]-pyrimidine-5-yl](3R,5S)-3,5-dihydroxide-6-ene acid] of the formula I:
having a powder x-rays with characteristic peaks at values of angle 2-theta (2)=4,92; 11,50; 6,93; 9,35; 23,12 and 18,76for the manufacture of a medicinal product having the properties of an inhibitor of HMG-COA reductase inhibitor. The method of obtaining the specified salt includes the formation of crystals from a mixture of the compounds of formula I, water and an organic solvent selected from acetonitrile, acetone or a mixture of methanol and methyl tert-butyl ether. The invention also relates to pharmaceutical compositions and method of reception and treatment of the disease condition for which it is useful in the inhibition of HMG-COA reductase inhibitor. 5 C. and 1 C.p. f-crystals, 1 Il., 1 PL.
The present invention relates to a new crystalline chemical compound and, more specifically, a new crystalline form of the calcium salt of bis[(E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrim the inhibitor of the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A-reductase (HMG-COA-reductase) (HMG CoA reductase) and is used as a pharmaceutical agent, for example, when hyperlipidemia, hypercholesterolemia and atherosclerosis, and other diseases or conditions that are associated with the action of HMG-COA reductase inhibitor. The invention also relates to methods of obtaining crystalline forms, pharmaceutical compositions containing the crystalline form, and application of crystalline forms of treatment.
In European patent application No. 521471 (here denoted by EPA 521471), which is incorporated in this description by reference, describes an amorphous (powdered) form of "agent" is obtained by dissolving the corresponding sodium salt in water, the addition of calcium chloride and isolation of the resulting precipitate by filtration.
The amorphous form of compound intended for pharmaceutical use may cause problems during its production and it is therefore necessary to identify the crystalline forms of such compounds, which have different physical characteristics compared to the amorphous form and which may be useful in obtaining compounds or in the preparation of compositions comprising the compound, to achieve purity and homogeneity, which are required for approval of a drug regulatory authority is R improved bioavailability.
In this work unexpectedly discovered that the "agent" can be obtained in crystalline form.
In accordance with the present invention the obtained crystalline form of the agent and its hydrates, having a powder x-rays with characteristic peaks at values of angle 2-theta equal to 4.92; 11,50; 6,93; 9,35; 23,12 and 18,76(crystalline form referred to herein as "form A").
X-ray powder diffraction pattern was obtained in the following way: put a sample of the crystalline form of the holder of the records of the silicon single crystal (SSC) Siemans and distributed the sample in the form of a thin layer using a glass cover. The sample was rotated at a speed of 30 revolutions per minute (to smooth out statistical fluctuations in the pulse count) and were irradiated by x-rays with a wavelength of 1,5406 Angstrom generated by a copper tube with slot focus at a voltage of 40 kV and current of 40 mA. A collimated x-ray beam from the source passes through the slit, which automatically adjusts the projection of the beam on the sample, V20 (path length 20 mm) and reflected from the sample, the radiation is directed through a slit width of 2 mm to eliminate the parasitic scattering and through the slit of the detector width of 0.2 mm Sample exonerate angles 2-theta from 2 degrees to 40 degrees in theta-theta. Time-taken x-rays was 2 hours 6 minutes 40 seconds. The instrument was equipped with a scintillation counter as a detector. Control and data acquisition was performed using a personal computer DECpc LPv 433 sx, working with software package Diffrac AT (Socabim).
Powder x-ray (diffraction) of a typical sample form As shown in the drawing. It should be understood that the value of the angle 2-theta, a powder x-ray can slightly change from one x-ray machine to another or from one form And another, and so the values should not be considered absolute.
In a typical case, the shape And received in hydrated form with a water content of, for example, about 7% wt./wt.
Another aspect of the present invention includes a method of obtaining a form And in which form And crystallized from a mixture of "agent, water and one or more organic solvents. The optimal ratio of organic solvent and water in the mixture to obtain forms And depends on the characteristics of the organic solvents and process conditions. The exact conditions can be determined empirically. For example, the form can be obtained as follows: suspend the ol and methyl tert-butyl ether (MTBE), heat the mixture until complete dissolution and then allow the solution to cool, then release form And, for example, by filtration. Suitable mixtures of water and co-solvent are, for example, a mixture of 1:1 water/acetonitrile, 1:1 water/acetone 1:1:1 water/methanol/MTBE, where the ratios are by volume. Amorphous form of "agent", which is used as starting substance to obtain forms And can be obtained, for example, as described in EPA 521471.
The usefulness of the compounds of this invention can be demonstrated using standard tests and clinical studies, including those described in EPA 521471.
According to further aspect this invention relates to a method for the treatment of painful conditions, which is useful in the inhibition of HMG-COA-reductase, which includes the introduction of warm-blooded mammal an effective amount of "agent". The invention also relates to the application form And to obtain a medicinal product for use in the treatment of painful conditions.
The compound of this invention it is possible to introduce a warm-blooded animal, in particular a man, if he needs treatment of the disease, which is associated with HMG-COA-reductase, in the form of a conventional pharmaceutical composition is citiesi acceptable carrier.
Such compositions can be entered in a standard way with a painful condition, which is desirable to treat, for example, by oral, local, parenteral, transbukkalno, nasal, vaginal or rectal injection or by inhalation. For these purposes, the agent can be prepared in dosage forms by methods known in the art, such as, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, sprays for insertion into the nose, suppositories, fine powders or aerosols for inhalation and used for parenteral injection (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions. The preferred method of administration is oral. "Agent" you can enter a man in a daily dose of, for example, within the limits specified in EPA 521471. Daily dose can be entered as separate doses, and the exact amount of "agent" and the route of administration depends on the weight, age and sex of the patient who is being treated and the particular painful condition that should be treated, in accordance with principles known the second composition, contains the form And as an active ingredient, which involves mixing forms And pharmaceutically acceptable carrier.
The invention is further illustrated by the following non-limiting his example.
Amorphous form of "agent" (the compounds of formula 1) (465 mg) was added to a mixture of water (5 ml) and acetonitrile (5 ml) under 15C. the Mixture was heated to 40For complete dissolution. The mixture is then slowly cooled to room temperature and stirred 16 hours
The crystalline product was separated by filtration at room temperature and dried at 50With the vacuum obtaining forms And (337 mg) as white crystals.
The water content of 7.1% wt./wt.
NMR1H (d6-DMSO): 7,7 (2H, t); and 7.3 (2H, t); and 6.5 (1H, d), and 5.5 (1H, DD); to 4.2 (1H, m); and 3.8 (1H, m); 3,5 (3H, s); 1,9-2,1 (2H, DD); 1,3-1,5 (2H, m); 1,2 (6N, e).
Mass spectrum: MN+482,3.
1. Crystalline hydrated form of the calcium salt of bis[(E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]-pyrimidine-5-yl]-(3R,5S)-3,5-dihydroxide-6-ene acid] of the formula I
">)=4,92; 11,50; 6,93; 9,35; 23,12 and 18,76.
2. Pharmaceutical composition for use as an inhibitor of HMG-COA reductase inhibitor containing crystalline form under item 1 together with a pharmaceutically acceptable carrier.
3. A method of obtaining a crystalline hydrated form under item 1, which includes the formation of crystals from a mixture of the compounds of formula 1, water and an organic solvent selected from acetonitrile, acetone or a mixture of methanol and methyl tertiary butyl ether.
4. A method of obtaining a pharmaceutical composition according to p. 2 for use as an inhibitor of HMG-COA reductase inhibitor, which comprises mixing a crystalline form under item 1 with a pharmaceutically acceptable carrier.
5. Crystalline hydrated form under item 1 for the manufacture of a medicinal product for use as an inhibitor of HMG-COA reductase inhibitor.
6. A method for the treatment of painful conditions, which is useful in the inhibition of HMG-COA-reductase, which includes the introduction of warm-blooded mammal an effective amount of crystalline hydrated form under item 1.
< / BR>where is phenyl, pyridyl or pyrimidyl; each R3- H, halogen, NO2, СООR, where R is H, C1-6alkyl, CN, CF3WITH1-6alkyl, -S - C1-6alkyl, -SO-Cl - C1-6alkyl, -SO2-Cl-C1-6alkyl, C1-6alkoxy and up to10aryloxy, n= 1, 2, or 3; R is a direct bond; And - piperazinil, X1and X2IS N; Y IS-SO2-; Z IS - N(OH)-CHO; Q - CH2-; R1- H, C1-6alkyl, C5-7cycloalkyl until10aryl, until10heteroaryl until1-2aralkyl or until12heteroallyl, R4- H, C1-6alkyl, and others; R2- H, C1-6alkyl, or together with R1- carbocyclic or heterocyclic Spiro 5-, 6 - or 7-membered ring containing at least one heteroatom selected from N, O or S, and the group Q can be associated either with R1or R2with the formation of 5,- 6 - or 7-membered alkyl or heteroalkyl ring that includes one or more O, S or N
< / BR>possibly in the form of R(+) or S(-) isomers, or salts of its accession acid
or its pharmaceutically acceptable salts, which have the properties of inhibitors of the enzyme Lp-PLA2and can be used to treat or prevent a painful condition associated with the activity of the specified enzyme