TWI316935B - Valsartan salts and process of preparing the same - Google Patents

Description

1316935 A7 _ B7 V. INSTRUCTION DESCRIPTION (1) The present invention relates to the following formula AT receptor antagonist (S)-N-(l-mono-2-yl-propyl-1-yl)-N-pentanyl Novel salts of --Ν-[2'·(1Η-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (Farsartan)

The active component of falsartan is a free acid, which is described in particular in ΕΡ0443983', particularly in Example 16; it has two acidic hydrogen atoms: (i) a hydrogen atom of a carboxyl group (a halogen atom), and (Π) The hydrogen atom of the tetrazole ring. Therefore, an acidic ruthenium atom (mainly carboxy η atom) or two acidic η atoms may be substituted by a monovalent or higher valence number, such as a divalent cation, or may form a mixed salt. ΕΡ443983 does not reveal any specific salts of Farsartan. Moreover, it does not mention the special nature of any salt. In the meantime, the active component of Farsattan was introduced into a series of countries under the name DIO VAN as an antihypertensive agent. The free acid frarsartan has a melting point of 80 to 95 ° C in a closed crucible, a melting point of 105 to 1 l ° ° C in an open crucible, and a melting enthalpy of 12 2 joules per paper scale for the Chinese country. Standard (CNS) A4 specification (210X 297 mm) 1316935 A7 _ ____B7 V. Invention description (2) ~~~ ' - Moer. The optical rotation at a concentration of ^% in methanol is [a] 2 〇 D = (_7 〇乜) 〇. The density of the falsartan crystals and the salt hydrate was measured by a helium pycnometer (Micromedtics, N〇rcross, GA, USA "Accupyc"). The density of the crystal of the free acid frarsartan is 〖2〇±〇 〇2. The X-ray diffraction pattern consists essentially of a very broad, diffuse X-ray reflection; therefore the free acid exhibits almost amorphous characteristics under χ-rays. The melting point of the melting enthalpy measured in combination with 12 Å joules/mole clearly confirms the existence of a residual arrangement of multiparticulate or domain morphology of the multi-free acid falsartan. There is a need for a jellyfish, such as a crystalline form of falsartan, because it is extremely easy to control during the drying or milling process after the final stage of the chemical preparation process and in the steps of preparing the pharmaceutical formulation. A number of ineffective attempts have been made to find a preferred form by salt formation, which is ideally as crystalline as possible and physically and chemically stable. Only the salts according to the invention, their solvates and their polymorphic forms exhibit the desired properties. The formation of Farsattan salts with superior properties proved to be difficult. In the main examples, for example, an amorphous salt having a small stability (e.g., a hard foam, a wax or an oil) is obtained. Extensive research has shown that it is particularly advantageous to use the fasartan salt according to the invention compared to the free acid of falsartan. The object of the present invention is a salt of falsartan selected from the group consisting of a monosodium salt, a monopotassium salt, a dipotassium salt, a magnesium salt, a calcium salt, a bis-diethylammonium salt, a bis-dipropyl salt, Bis-dibutylammonium salt, mono-L-arginine, bis-L-arginine, mono-L-isoamine and bis-L-isoamine and salt mixtures, or each thereof Amorphous forms, solvates, especially hydrates and polymorphic forms. This paper scale is applicable to China National Standard (CNS) A4 specification (21〇X297 公爱) 1316935

5. Description of the invention (3) Two manufacturing and use and pharmaceutical preparations containing the same. Potassium salt and dipotassium are salts of falsartan, which are selected from monosodium salt, single wind, magnesium a salt, a calcium salt, a bis-diethylammonium salt, a bis-ammonium salt, a bis-dibutyl group, a propyl group, a mono-L-isoamine acid serotonin, a bis-L arginine, ―, now and bis-L-isoamine, or each of its amorphous energy, solvate, especially Θu, > heart, 符 疋 hydrate and polymorphic form A "monomide" formed by a different cation selected from the group of the above-mentioned groups. "Second, for example, a salt of a single salt form which is present in a stacked form is preferably a mono-salt salt selected from amorphous forms; Amorphous or crystalline form of falsartan disodium salt, especially hydrated state. ° y amorphous form of falsaltan monopotassium salt; amorphous or crystalline form of falsaltan dipotassium Salt, special form. 疋,, hydrate crystalline form of falsartan calcium salt, especially its hydrate form, if its tetrahydrate; ~ 'main line crystallization a salt of falsartan, especially a hydrated form thereof, if it is a tetrahydrate; a calcium/magnesium mixed salt of falsartan in the main crystalline form, especially a hydrate/form; Bis-diethylammonium salt of the crystalline form of falsartan, special state; 疋水口形形-6- 1316935 5. Description of the invention (4 crystalline form of bis-dipropyl salt of falsartan, In particular, the water state; the bis-dibutylammonium salt of the crystalline form of Farsattan, especially the hydrate form, mainly its hemihydrate; the amorphous form of Farsanthan Amine; amorphous form of bismuth arginine of falsartan; amorphous form of fulsaltan monostearate; amorphous form of falsartan double The sulphate salt; in accordance with the present invention, the salt is preferably present in a purely morphologically pure form, for example, two or two percent > 98% > 99% purity. The salt (corresponding to the purity of the isomer is > 98%, preferably > 99%. = Compared with the acid, 'the salt or the amorphous form thereof, the solvent such as the salt according to the present invention Salt hydrates and corresponding polymorphic forms have unpredictable beneficial properties. In established strains T ^

‘' ‘,·· σ 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日 日According to this date, the salt is stable and has better quality than Farsattan, and 2 = points: the same is true in the process. Amorphous or partially amorphous salts have limited ampoules 'that are as solid' and they have a limited range of stability. To be stable, they need to be able to achieve a specific amount, for example, by herbal formula. Moreover, according to the present invention, the crystalline and amorphous salts have high solubility in water, so that the solubility in water can be substantially improved. These properties are advantageous because: the aspect dissolution procedure is faster. On the other hand, the solution required for these solutions is y. Moreover, 'under certain conditions, higher water solubility also makes the salt or salt hydrate have a higher organism in the case of solid formulation morphology 1316935 A7

Availability. It is beneficial to obtain improved properties, especially for patients. Furthermore, it has been demonstrated that some of the salts according to the invention have unpredictable physical stability: in particular alkaline earth metal salts. At room temperature and at a slightly higher temperature for the same relative degree of 'the same according to the invention, the salt hydrate does not show any moisture absorption or water knife loss in the broadness of ^ ^ and hours ' for 4 hours, for example, 4 hours. Moreover, for example, the melting points of the salts according to the invention will not be altered by storage at different relative humidities. The preferred physicochemical properties of particular salts or specific salt hydrates are extremely important when they are formulated into pharmaceutically active substances and when they are stored and applied. In this way, starting with the better stability of the physical parameters, it is sure to obtain a very high quality formulation. The high hydrate stability of this salt or salt can also provide the advantage of economic advantage by making simpler procedures in the formation process. The high crystallinity of the particular salt hydrate allows for the use of a selective analytical method, particularly a variety of χ-ray methods, which accomplish a clear and simple analysis of its release. This factor is also important for the quality of the active substance and its herbal form during manufacture, storage and administration to the patient. Moreover, complex regulations for the active constituents of the stable herbal formulation can be avoided. The invention therefore relates to crystals of falsartan, as well as to partially crystalline and amorphous salts. As well as solvates, such as hydrates, the invention also relates to polycrystalline forms of the salts according to the invention. The solvates and hydrates of the salts according to the present invention may be individually used, for example, in the form of semi-, mono-, di-, tri-, tetra-, penta-, hexa-solvate or hydrate. China National Standard (CNS) Α 4 Specifications (210X297 mm) ' --

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Line V. The invention (6) state exists. Solvents for crystallization, such as alcohols, especially methanol, ethanol, aldehydes, ketones, especially acetone, vinegars such as ethyl acetate can be embedded in the crystal lattice. The extent to which the solvent or water in the crystallization and subsequent procedure steps results in the granules or hydrates or the direct production of free acids is generally unpredictable and depends on the conditions of the various conditions and various valsartan and selected solvents. In particular, the combination of forces between the waters. The stability of each of the resulting salts, solvates and hydrates, as well as the crystalline or amorphous solids of the corresponding salt solvate or salt hydrate form, must be determined experimentally. It is therefore impossible to refer to the stoichiometric ratio of molecules in the chemical composition and the resulting solids, since different crystalline solids and different amorphous materials may be produced under these circumstances. When the water molecules of the crystal structure t are bound by force and thus represent the basic elements formed by the structures of these crystals, the preference is to select a salt mixture, such as a corresponding hydrate, in which some of the crystals are exceptionally stable. But hey, water molecules also exist in specific lattices that combine weakly intermolecular forces. Such molecules are more or less incorporated in the formation of crystal structures, but are less active. & and the water content of the giant, amorphous solids can be clearly determined as crystalline hydrates, but depending on the drying and surrounding conditions. Conversely, in the case of stabilized hydrates, there is a clear stoichiometric ratio between the pharmaceutically active substance and water. In many cases, these ratios do not fully comply with the stoichiometric enthalpy because some crystal defects are generally closer to lower than theoretical. For weakly bound water, the ratio of organic molecules to water species can vary to a considerable extent, for example to a di-, tri- or tetra-hydrate. On the other hand, in amorphous solids, the molecular structure of water is not stoichiometric; however, only occasionally this classification can be stoichiometric. -9- This paper scale applies to China National Standard (CNS) Α4 specification (210X297 public) 1316935 A7 B7 V. Invention description (7) In some cases, because of the layer structure, such as in alkali metal salts, especially In potassium salts, it is impossible to distinguish the exact stoichiometry of water molecules, so the embedded water molecules cannot be measured in a clear form. For crystalline solids of the same chemical composition, the term polymorph is used to summarize the different resulting lattices. As appropriate and convenient, any of the above and below references relating to salts according to the invention may be understood to also relate to corresponding solvates, such as hydrates and polymorphs, as well as amorphous forms. Particularly preferred are the tetrahydrate of the calcium salt of falsartan and the hexahydrate of the magnesium salt of falsartan. The X-ray diffraction patterns of the two salt hydrate powders have many different X-ray reflections and do not actually have any signal of amorphous or amorphous portions. Therefore, the degree of crystallization of these predetermined salt hydrates is surprisingly high. Similarly, a considerable amount of crystals are cultured from a specific salt hydrate, and in crystallographic sense, these are single crystals. This single crystal allows the solid structure to be measured. It is performed by computer-assisted evaluation of the reflected intensity measured by the X-ray dimmer. The procedure for determining the crystal structure can be carried out under normal conditions, such as the high physical, chemical and corresponding isomer purity of the crystals evaluated, so that the defined structure is determined at the molecular or atomic level, ie the symmetry and size of the basic crystal lattice, the atomic position. And the temperature factor, and from the confirmed lattice volume, the X-ray imaging density is based on the molecular weight. At the same time, the X-ray imaging structure provides its quality details. The superior properties of these two brine preparations are based on the Chinese National Standard (CNS) A4 specification (210X 297 mm) by each Farsartan -10- paper scale.

Line 1316935 A7 ____B7 V. Description of the invention (8~) ' :-- Sub-incorporation of four or six water molecules to form crystals of these salts. Therefore, in fact, it is possible to produce an excellent three-dimensional lattice. The solubility of the two salts in water is several times higher than that of the free acid of falsartan, which is particularly surprising at high melting points and melting enthalpy. Eight or five times larger than free acid. The extraordinary lattice of these two brine compounds is the basis for the chemical and physical stability of these two compounds. A particularly valuable salt hydrate is the tetrashydrate of the falsartan calcium salt. In the closed sample container, the heating rate for Tr = 1 〇 K / min has a melting point of 205 ± 1.5 ec and a melting enthalpy of 98 ± 4 仟 joule / mol-1. The salt sart salt + tetrahydrate is unstable in relation to hydrated water and molecular structure at relatively high temperatures. The melting point referred to is the melting point of the hydrate which can only be measured in a closed sample container. A gold container having a wall thickness of 〇·2 cm is used; after weighing a sample of 2 and 43⁄4 grams of the salt hydrate, it is cooled by cold welding. seal. These gold containers have an internal free volume of about 22 microliters. The sample volume and the volume of the pressurized vat must be properly adjusted so that the salt water does not dehydrate strongly during the measurement of the scent. The partial pressure of water at 205 ° C is about I 8 bar, so that it is converted into a water supply in a DSC (differential scanning calorimeter) having an open vessel during the measurement of the melting point. If data obtained from several heatings (Tr=i〇, 2〇, 40K/min·) is extrapolated to a continuous rapid heating rate, resulting in a melting point of 213 ± 2 C and 1 2 4 ± 5 shJo / Mo Ear 1 melting 焓. Both the high melting point and the high melting enthalpy of the hydrate are a representation of the excellent stability of the tetrahydrate lattice of the falsartan calcium salt. These two thermodynamic characteristics illustrate advantageous physical properties with two related data, namely 9 (the melting point in a closed system of rc and the free acid of a melting enthalpy of 12 仟 joules/mole-1). These thermodynamic data are combined with X. -The ray data proves the high stability of this crystal lattice. They are the standard of the Chinese standard (CNS) A4 specification for the standard of silver on the standard of the paper (210X297 public ^------_ A7 B7 1316935 five, invention description (9) The basis of the special physical and chemical resistance of the Satan calcium salt tetrahydrate. The infrared absorption spectrum of the tetrahydrate of Farsattan calcium salt in the potassium bromide compressed ingot is shown as the reciprocal of the wave number (cm·1 Important spectral bands indicated: 3750-3000 (st); 3400-2500 (st); 1800-1520 (st); 1500-1380 (st); 1380-1310 (m); 1290-1220 (w); 1220 -1190(w); 1190-1160(w); 1160-1120(w); 1120-1050(w); 1030-990(m); 989-960(w); 950-920(w); 780- 715(m) ; 710-470(m) The intensity of the 〇 absorption band is expressed as follows: (w) = weak; (m) = medium; and (st) = strong intensity. The measurement of the infrared spectrum is also by ATR-IR (Attenuated Total Reflection - Infrared The spectroscopic method was carried out using the instrument Spektrum BX available from Perkin-Elmer, Beaconsfield, Bucks, England. The salt of the falsartan salt has the following absorption bands expressed as the reciprocal of the wave number (cm-1): 3594(w); 3306(w); 3054(w); 2953(w); 2870(w); 1621(st); 1578(m); 1458(m); 1441(m); 1417(m); 1364(m); 1336(w); 1319(w); 1274(w); 1241(w); 1211(w); 1180(w); 1149(w); 1137(w); ll〇6(w 1099(w) ; 1012(m) ; 1002(w) ; 974(w); 966(w) ; 955(w) ; 941(w) ; 863(w) ; 855(w) ; 844(w 824(w); 791(w); 784(w); 758(m); 738(m); 696(m); 666(m). The intensity of the absorption band is expressed as follows: (w) = weak ; (m) = medium; and (st) = strong intensity. The strongest absorption band of ATR-IR spectroscopy is represented by the reciprocal of the following number of waves (cm_1): 3306(w); 1621(st); 1578(m); 1458(m); 1441( m); 1417(m); 1364(m); 1319(w); 1274(w); 1211(w); 1180(w); 1137(w); 1012(m); 1002(w); 758( m); 738(m); 696(m); 666(m). -12- This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1316935 A7 B7 V. Invention Description (ίο) All ATR-1 R absorption bands have an error range of ±2 cm-1. For the ferranac calcium salt tetrahydrate, the theoretical water content is 13.2%. Using a thermo-scale TGS-2 (Perkin-Elmer, Norwalk' CT USA), the measured water content was 12.9%. From then on (C24H27N503) 2_Ca2 + · (3.9 ± 0.1) H20 can be calculated as the total chemical formula. The weight loss, i.e., the weight loss of the tetrahydrate with temperature, was measured by a pyrolysis method in an anhydrous N2 atmosphere at a heating rate of 10 K/min. The results are shown in Table 1. Table 1 Temperature [°c] Weight loss or moisture loss % 25 0 50 0 75 0.5 100 3.5 125 10.2 150 12.4 175 12.8 200 12.9 225 12.9 250 13.0 275 13.2 For the salt of Valsartan calcium salt at 2 2 ° Water-ethanol mixed at the temperature of C-13 - The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1316935 A7 B7 V. Description of the invention (11) The solubility in the composition is shown in Table 2.

Table 2 Volume % of ethanol in water Farsantan #5 salt tetrahydrate solubility at 22 ° C, grams / liter of solution 0 9 (pH = 7.4) 10 9 30 14 50 46 loaded according to the invention two most important A comparison of the solubility of salts and free acids in distilled water is shown in Table 3. Table 3 Compound Solubility at 22 ° C, gram / liter solution Falsartan 0.17 Farsanta salt salt tetrahydrate 9 Farsaltan magnesium salt hexahydrate 59

Lines Other characteristics of the tetrashydrate of the salt of the falsartan are caused by the interplanar plane spacing measured by the X-ray powder pattern. Measurement of the X-ray powder pattern was performed at room temperature with a Guinier camera (FR552 from Enraf Nonius, Delft, NL) on a X-ray film using transmission geometry using Cu-Kai radiation. The film was evaluated by vision and using a line scanner (Johansson T5by, S) to calculate the interplanar plane spacing while measuring the reflection intensity. -14- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1316935 A7 B7 V. Description of invention (12) The better characteristics of the tetrahydrate of Farsartan calcium salt have been determined The interplanar spacing d between the X-ray diffraction patterns is obtained, and therefore, in the following data, the average 値 is indicated by an appropriate error bound. It is expressed as [Angstrom] (1:16.1±0_3, 9.9±0.2, 9.4±0.2, 8.03±0.1, 7.71±0.1, 7.03±0.1, 6.50±0.1, 6_33 soil 0.1, 6.20±0.05, 5.87±0.05, 5.74 ±0.05, 5.67±0.05, 5.20±0.05, 5.05±0.05, 4.95±0.05, 4.73±0.05, 4.55±0.05, 4.33±0.05, 4.15±0.05, 4.12±0.05, 3.95±0.05, 3.91±0.05, 3.87±0.05 , 3·35±0·05 ° 'The strongest reflection in the X-ray diffraction pattern shows the interplanar spacing between the following lattices: expressed in [Angstrom] (1:16.1 ± 0.3, 9.9 ± 0.2, 9.4 ± 0.2, 7.03 ± 0_1, 6.50±0.1, 5.87±0.05, 5.74±0.05, 4.95±0.05, 4.73±0.05, 4.33±0.05, 4.15±0.05, 4.12±0.05, 3.95±0.05. A kind of X to obtain a given substance by Guinier The best method for measuring the average tantalum and intensity of the interplanar plane spacing shown above by the experiment of the ray diffraction pattern consists of calculating the spacing and its intensity from the integrated single crystal structure measurement. Constant and atomic position, which allows X-ray diffraction diagrams of solids to be computed by computer-aided calculations (program CaRine Crystallography, Universiti de CompiSgne, France) Comparing these data, that is, the measurement by the Guinier camera and the inter-lattice plane spacing and the most important line strength of the tetrasal of the falsartan calcium salt obtained from the calculation of the single crystal data are shown in Table 4. Table 4 Measurements are calculated and calculated. Calculated -15- \Applicable Chinese National Standard (CNS) A4 Specification (210X 297 mm) 1316935 V. Invention Description (13) A7 ________Β7 d, [Angstrom] Strength d, [Angstrom] Intensity d, [Angstrom] Intensity d, [Angstrom] Intensity 16.10 Very strong 16.02 Very strong 5.67 Very weak 5.658 Very weak 9.89 Strong 9.88 Very strong 5.20 Very weak 5.199 Very weak 9.38 Average 9.37 Average 5.05 Very weak 5.040 Very weak 8.03 Weak 8.02 Average 4.95 Average 4.943 Weak 7.71 Weak 7.70 Weak 4.73 Weak 4.724 Weak 7.03 Average 7.01 Average 4.55 Weak 4.539 Weak 6.50 Average 6.49 Average 4.33 Weak 4.338 Weak 6.33 Weak 6.33 Weak 4.15 Strong 4.150 Strong 6.20 Very weak 6.19 Very weak 4.12 Weak 4.14 Weak 5.87 Average 5.862 Average 3.95 average 3.941 average 5.74 average 5.738 average 3.35 weak 3.349 weak - the present invention relates to (S)-N -(l-carboxyl_2_mercaptopropenyl)-N-pentyl-indole-[2,·(1Η-tetrazole-5(yl))biphenyl-4methyl-amine] Crystalline tetrahydrate, a crystalline solid characterized by data and parameters obtained from single crystal chirped ray analysis and X-ray powder pattern. The theory of single crystal 绕 line diffraction method and the evaluation of the crystallization data and parameters can be determined in Stout & jensen, X-ray structure; Millian Company, New York City, New York (1968), Chapter 3 White manual, Ma Farsattan calcium salt tetrahydrate single crystal χ · shot. And the parameters are included in Table 5. The number of measurements measured •16-

This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1316935 A7 B7 V. Description of invention (14) Table 5 Crystallization data and parameter crystallization data of Farsattan calcium salt tetrahydrate (C24H27N5 〇3) 2'Ca2+ +4H20 Molecular mass 545.65 Crystal color Colorless crystal shape Flat prismatic crystal system Dotted spacer group Ρ2ι Single crystal size 0.42·0.39·0.17 Cubic centimeter basic lattice size and angle a=10.127 ( 2) angb=8.596(2) angstrom c=32.214(6) angstrom α=90° β=95.34(3)° γ=90° basic lattice volume Vc=2792.1(10) angstroms 3 in the basic lattice Number of molecules 4 F(OOO) 1160 Measurement range of lattice parameters (Θ) 7.47-16.50° Calculated density 1.298 (g•cm·3) Linear absorption coefficient 0.274 cm -17 -17- This paper scale applies to Chinese National Standard (CNS) A4 size (210X 297 mm) 1316935 A7 B7 V. Invention description (15) X-ray measurement data diffractometer Enraf Nonius CAD4 X-ray (graphite monochromator) ΜοΚα Wavelength 0.71073 Temperature 295Κ Scanning range (Θ) 1.27 -31.99° scan mode ω / 2θ collected Reflection/Unique 19384/18562 Number of Important Reflections (1>2σ(Ι)) 10268 Change in Intensity 1.7% Absorption Correction Digital Structure Improvement Method Full Matrix, Least Squares, F2 Number of Parameters 893 Compliance Index (R) 6.2% Weighted Match Index (Rw) 14.4% S factor 1.085 The number of reflections used in 18562 molecules, including all differences in all hydrogen atoms in the water molecule - the processing of the Fourier operator, almost all isotropically modified extinction correction, a few Theoretically fixed (parked) No -18- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1316935 A7 B7 V. Invention description (16) Final difference - Fourier calculation 0.662/ -0.495(e·A·3) Maximum/minimum residual electron density absolute structural parameter 0.00(4) Computer program used SHEXLS 86 (Sheldrick, Gsttingen, 1990) SHELX 96 (Sheldrick, Gattingen, 1996) SCHAKAL 86 (Keller, Freiburg 1986,) PLATON (Spek, Acta Cryst, 1990) The basic lattice system is defined by six parameters, namely the lattice constants a, b and c and the axial angles, namely α, β and γ. In this way, the volume Vc of the basic crystal lattice can be measured. A description of the distinction between these crystallization parameters is given in Stout & Jensen (see above), Chapter 3. The details of the tetrahydrate of the falsartam calcium salt obtained from the single crystal measurement, especially the atomic coordinates, the isotropic thermal parameter, the coordinates of the hydrogen atom, and the corresponding isotropic thermal parameter 'the presence of the single crystal lattice The result of the two-crystal independent unit at the double position results in the lattice content of its four-form unit C a2 + Farsartan 2_·4Η20. The determined centerless spacer group Ρ 2 is determined from the single crystal X-ray structure measurement, except for the racemate. Therefore, it was proved that the S-configuration of (S)-Ν-(1-carboxy-2-methylprop-1-yl)-N-pentanyl-indole-[2'-(1Η-tetrazole-5- The corresponding isomer purity of the crystalline tetrahydrate of the biphenyl-4-phenylindenyl]-amine calcium salt. For physico-chemical procedures such as drying, sieving, grinding and herbal preparations completed with pharmaceutical excipients, ie in mixing procedures, granulation, spray drying

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Line-19- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1316935 A7 B7 V. Description of invention (17) In the ingot process, the essential feature of a pure active substance quality is moisture. The absorbance or the loss of moisture of the active substance depending on the temperature and the relative humidity of the environment in question, by means of a specific formulation, does not introduce free and bound water with the excipient and/or adds water to the relevant formulation procedure. In the program substance. In this way, depending on the temperature of the different activities (partial vapor pressure), the pharmaceutically active substance can be exposed to free water for a longer period of time. The isothermal measurement using dynamic vapor absorption (obtained from Surface Measurement Systems, Inc., Marlow, Buckinghamshire, UK DVS-1) at predetermined time intervals and predetermined relative humidity provides a characteristic that clearly demonstrates this property. Table 6 illustrates the change in mass, i.e., for a sample of 9.5 mg of fasaltan calcium salt tetrahydrate and water uptake or loss at 25 ° C with a relative humidity as a function of 4 hours. The following series indicate the cycle of relative humidity change: 40-90; 90-0; 0-90; 90-0% relative humidity: -20- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1316935 A7 B7 V. INSTRUCTIONS (18) Table 6 Relative Humidity, Moisture Absorption or Loss, Relative Humidity, Moisture Absorption or Loss, % % .^ % % 40 0.04 10 0.00 50 0.04 ____ 0 -0.01 60 0.03 _ 10 0.00 70 0.02 20 0.00 _8〇0.02 __ 30 0.00 —90 0.00 40 0.00 ___ 80 0.02 50 0.00 70 0.02 60 0.01 _ 60 0.02 70 0.00 —50 0.02 80 -0.01 40 0.02 90 -0.02 —30 0.01 0 -0.02 —20 0.01 (from値)) 0.00 The measurement error of the absorption method based on the pyrolysis method is about 〇.丨%. Therefore, the tetrahydrate of Farsartan calcium salt showed no measurable moisture absorption or loss under the conditions used, and the conditions used were practical from the pharmaceutical-herbal point of view. This is extremely surprising because the hydrates that have held about 13% bound water in the crystalline structure are inert to water redundancy, even at very high relative humidity. This property is important in the final stages of chemical manufacturing and in the process of performing all of the different dosage forms of the herb procedure. This -21 -

A7 B7 1316935 V. INSTRUCTIONS (19) The special stability is similar to that of the patient through the continued use of the active ingredient. The solubility rate of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt of the salt is higher than The specific stability of the salt of the falsartan calcium salt, especially its tetrahydrate, is also demonstrated in the stability test. In these tests, the water content of the Farsattan calcium salt tetrahydrate at 40 ° C and 75 % relative humidity remained fixed in the open container and the sealed ampoule. Due to the advantageous crystallinity of the calcium salt, especially its tetrahydrate, this salt is suitable for direct extrusion to form the corresponding tablet. Moreover, it is true that the tablet can achieve a better dissolution profile. In the study of the dissolution profile, the establishment of a calcium salt, in particular its tetrahydrate, was released from the film-coated tablet in 100 minutes in 15 minutes. It belongs to the group of novel crystalline solids, preferably falsartan magnesium salt hydrate, especially hexahydrate. The thermal behavior of this salt hydrate in the melting point range shows some chemical and physical instability. Therefore, the thermal data depends on the measurement conditions. The melting point of the salt of the ferrsartan magnesium salt is 1 3 in a closed gold sample container having an internal free volume of 22 ml, containing 2 to 4 mg of sample and heating at Tr = i 〇 K / min -1 2 ± 1 5 » C and the melting enthalpy is 5 6 ± 3 shJo / m · 1. The apparently higher melting point of the hexahydrate of the ferrsartan magnesium salt, which is about 5 times higher than the free acid of the falsartan, is a measure of the stability of the novel lattice at about room temperature. The optical rotation of a 1% solution of falsartan magnesium salt hexahydrate in methanol at 2 〇 C is [a] 2QD = _14. . -twenty two-

1316935 A7 ___B7___ V. Description of invention (2〇~~) " Measuring the infrared absorption spectrum of fasartan magnesium salt hexahydrate in brominated unloading ingot shows the following reciprocal of wave number (cm-1) Important spectral bands: 3800-3000 (3 〇; 3000-2500 (5 〇; 1800-1500 (5 玄); 1500-1440 (m); 1440-1300 (τη); 1280-1240 (w); 1240-1190 (w); 1190-1150(w); 1120-1070(w); 1050-990(w); 990-960(w); 960-9200); 920-700(m); 700-590(w) 590-550(w) The intensity of the absorption band is expressed as follows: (w) = weak; (m) = medium; and (st) = strong intensity. The infrared spectrum is measured by ATR-1R ( The attenuated total reflection-infrared spectroscopy method was performed using the instrument Spektrum BX from Perkin-Elmer, Beaconsfield, Bucks, UK. The salt of the salt of the salt of the salt of the falsartan has the following reciprocal of the wave number (cm·1) The indicated absorption bands are: 3378(m); 3274(m); 2956(m); 2871(w); 2357(w); 1684(w); 1619(st); 1557(m); 1464(m); 1419 (m); 1394 (st); 1374 (m); 1339 (w); 1319 (w); 1300 (w); 1288(w); 1271(w); 1255(w); 1223(w); 1210(w); 1175(m); 1140(w); 1106(w); 1047(w); 1024(w); 1015(w); 1005(w); 989(w); 975(w); 955(w); 941(w); 888(w); 856(w); 836(m); 820〇); 766 (st); 751(m); 741(st); 732(st). The intensity of the absorption band is expressed as follows: (w) = weak; (m) = medium; and (st) = strong intensity. The strongest absorption band of the ATR-1R spectroscopy is represented by the reciprocal of the following wavenumbers (cm-1): 3378(m); 3274(m); 2956(m); 1619(st); 1557 (m) ; 1464(m) ; 1419(m) ; 1394(st) ; 1271(w) 23·^ Paper scale applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) A ' 1316935 A7 B7 5 , invention description (21); 1175 (m); 1015 (w); 975 (w); 836 (m); 766 (st); 751 (m); 741 (st); 732 (st). All A T R -1R absorption bands have an error range of ±2 cm _1. The theoretical water content of the valsartan magnesium salt hexahydrate is 19.1%. Using a coupled instrument based on thermogravimetric-Fourier transform-infrared spectroscopy (available from Natzsch Geratebau GmbH, Selb, Bayern and Bruker Optik GmbH, Karlsruhe TG-FTIR, IFS 28), while using infrared spectroscopy The method measures the weight loss and identifies the substance component (water release) that was discarded. The water content is 18.5%, which is in line with the theoretical enthalpy. For hexahydrate, this corresponds to a molar ratio of 5.8 ± 0.2 mol H20 / Magnesium salt Mo. Table 7 shows that the weight loss measured by the heating rate of 10 K 7 min-1 in the N2 atmosphere of the pyrartan magnesium salt hexahydrate on the pyrolysis weight thermal analyzer indicates that the water loss varies with temperature. From the T G - FTIR measurement, the correction of the weight loss is ensured only by the release of water. -24- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1316935 A7 B7

V. INSTRUCTIONS (22) Table 7 Temperature [c] Weight loss 25 0 50 1.2 75 4.2 100 ~~ A 11.0 — 125 —1 — — — ---- ---- 16.7 150 17.7 175 18.3 — 200 18.5 225 18.7 250 18.9 — _ 275 _____ 19.3, Farsaltan magnesium salt hexahydrate at 22. The solution dissolved in the distilled water was 59 g per liter of p Η値 9 · 3 . The crystalline morphological characteristics of the valsartan magnesium salt hexahydrate can be clearly represented by the interplanar plane spacing calculated from the lines in the X-powder pattern. The measurement and analysis methods are the same as those of the fersartan calcium salt tetrahydrate. The preferred hexahydrate characteristic of the salt of the falsartan is obtained from the interplanar spacing d, whereby the average enthalpy is indicated by the appropriate margin of error: d: 19·7± expressed in [A] 0·3,10·1±〇2,9 8±〇2,7 28±〇”, 6.48±(U,,5 81±〇”, 5 68±〇”, 5 4_ 〇5, $ 2 rush 1316935 A7 B7 V. Description of invention (23) 0.05, 5.12±0.05, 5.03±0.05, 4.88±0.05, 4.33±0.05, 4.22±0.05, 4.18±0.05, 4.08±0.05, 3.95±0.05, 3.46±0.05, 3.42±0.05 ° The strongest reflection in the X-ray diffraction pattern shows the following interplanar spacing: 4:19.7±0.3, 10.11 soil 0.2, 9.8±0.2, 7.28±0.1, 5.81±0.05, 5.68±0.05, expressed in [A]. 5.03±0.05, 4.88±0 05, 4.18±0.05, 4.08±0.05, 3.46±0.05. An average of the interplanar plane spacing measured above by an experiment using a Guinier camera to obtain an X-ray diffraction pattern of a given substance. The preferred method of enthalpy and strength consists of calculating the spacing and its intensity from a comprehensive single crystal structure measurement. This structure determines the lattice constant and atomic position, which gives the X of the solid. The ray diffraction pattern can be calculated by computer-aided calculation method (Calcine Crystallography, U niversite de Compi6gne, France). Comparing these data, the measurement with the Guinier camera and the obtained Farsartan magnesium from the calculation of single crystal data. The interplanar spacing of the salt hexahydrate and the strength of the most important line are shown in Table 8. -26- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1316935 A7 B7 , invention description (24) measured to obtain ί d, [A] intensity d, [Ai 19.7 very strong 19.66 10.11 average 10.09 9.83 average 9.84 7.28 average 7.27 6.48 weak 6.46 6.00 weak 6.00 5.81 average 5.805 5.68 average 5.676 5.40 very weak 5.391 5.22 Weak 5.217 intensity is very strong average very strong average weak weak average strong very weak table 8 fast # get d, [Ai] 5·12 4.88 4.22 4.18 4.08 3.95 3.46 3.42 weak strength calculation d, [A] 124 intensity 5.032 strong very Weak average average weak average weak 4.878 4.341 4.215 4.181 4.079 3.946 3.463 3.428 Weak very strong very strong weak weak average average weak Average Weakness The present invention relates in particular to (S)-N-(1-carboxy-2-methylpropanyl)_N pentyl-indole-[2'-(1Η·tetras-5-yl)biphenyl- The crystalline hexahydrate of 4-methylmethamine, which is characterized by the data obtained by single crystal X-ray analysis and the crystal solids clearly indicated by the parameters. The in-depth discussion of the single crystal χ•ray diffraction method and the definition of the evaluated crystallization data and parameters can be

JenSen’X·Ray Structure MeasurementTM Internship Handbook, MaeMlllian, New York City, New York (1968), found in Chapter 3. Money-Farsartan-Tetrahydrate military product y series contains data and parameters in Table 9 仏 仏 ray analysis • 27-1316935 A7 B7 V. Invention description (25) Table 9 Farsartan magnesium salt Crystallization data and parameter crystallization data of hydrates General formula (C24H27N5 03)2-Mg2 + .6H2〇 Molecular mass 565.91 Crystal color Colorless crystal shape Flat prismatic crystal system Monoclinic spacer group C2 Single crystal size 0.013·0.50·0.108 Cubic centimeter basic lattice size and angle a = 40.075 (8) angstrom b = 7.400 (l) ang c = 12.25 (2) angstrom α = 90 ° β = 100 · 85 (3) 0 γ = 90 ° basic lattice Volume Vc=2992.6(9)A3 Number of molecules in the basic lattice 4 F(000) 1208 Measurement range of lattice parameters (Θ) 2.82-11.15° Calculated density 1.256 (g•cm·3) Linear absorption coefficient 0.114 Cm-28 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1316935 A7 B7 V. Invention description (26) X-ray measurement data diffractometer Enraf Nonius CAD4 X-ray (graphite monochrome Light) ΜοΚα Wavelength 0.71073 Temperature 295Κ Scanning range (Θ) 1.03-26.00° Scan mode ω / 2Θ Number of reflections/extra 5954/5868 important reflections (1>2σ(Ι)) 1341 Change in intensity <1% absorption correction Digital structure improvement method Full matrix, least squares, number of F2 parameters 243 Compliance index (R) 10.7% Weighted conformity index (Rw) 13.8% S factor 1.001 Number of reflections used in 5868 molecules, including all hydrogen atoms in water molecules, according to the "parking" pattern, nine water treatment molecules The atom isotropically improved by the difference-Fourier calculation to obtain the extinction correction 0.00098(10) -29- The paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇X 297 mm) 1316935 A7 B7 V. INSTRUCTIONS (27) Final difference - Fourier calculation 0.473/-0.614 (e·A·3) Absolute structural parameter of maximum/minimum residual electron density 0.0(10) Computer program used by SHEXLS 86 (Sheldrick, Gattingen, 1990) SHELX 96 (Sheldrick, Gfittingen, 1996) SCHAKAL 86 (Keller, Freiburg 1986,) PLATON (Spek, Acta Cryst, 1990) The basic lattice system consists of six parameters, namely the lattice constant a. b and c axis angle, i.e. defined by α, β and γ. In this way, the volume V c of the basic lattice can be measured. A description of the distinction between these crystallization parameters is given in Stout & Jensen (see above), Chapter 3. The details of the hexahydrate of the salt of the falsartan obtained from the single crystal measurement, especially the atomic coordinates, the isotropic thermal parameters, the coordinates of the hydrogen atom, and the corresponding isotropic thermal parameters. 5 Its lattice content is produced by four units of Mg2 + falsartan 6 Η 20. The determined centerless spacer group C 2 was measured from the single crystal X-ray structure measurement except for the racemate. Therefore, the corresponding isomer purity of the crystalline hexahydrate of the Farsaltan magnesium salt of the S-configuration was demonstrated. Table 10 illustrates the change in mass, i.e., for a sample of 9.5 mg of magnesium-farsaltan-hexahydrate and the moisture uptake or loss was varied with relative humidity at 25 °C over a period of 4 hours. The following series indicate the cycle of relative humidity change: 4 0 - 9 0 -30- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1316935 A7 B7 Five invention descriptions (28) 9〇·〇; 0- 90 ; 90·0% relative degree: Table 1 0 Relative humidity, moisture absorption or loss, relative humidity, moisture absorption or loss, -^% % % % --40 0.06 10 -0.12 ^_J〇0.14 0 -4.3 ^_6〇0.19 10 -0.79 ___70 0.25 , 20 0.14 __80 0.41 30 -0.05 _90 0.58 40 0.02 —_____80 0.32 50 0.09 ~~~~~~1〇_ 0.22 60 0.14 -_60 0.14 70 0.20 _5〇_ 0.08 80 0.28 __40 0.16 90 0.51 __ 30 -0.03 0 -3.68 20 -0.07 (starting 値) -0.01 The measurement error of the absorption method based on the thermogravimetric method is about %1%. Therefore, 'Farsaltan magnesium salt hexahydrate Displaying weak, reproducible moisture absorption or loss in the range of 2 〇 to 80% relative humidity under the conditions used. This is surprisingly a tooth' because the crystal structure has been filled with about 丨9 0/0 binding water. The hexahydrate reversibly absorbs or releases water, even at extremely high relative humidity, while -31 - the paper size is suitable China National Standard (CNS) Α4 Specifications (210 X 297 mm) 1316935 V. INSTRUCTIONS (μ and j are relatively insensitive to the average range of relative humidity. This property can develop a simple physical-chemical procedure and can choose the most Dosage state suitable for patients. The specific stability of Farsaltan magnesium salt, especially its hexahydrate, to water is also shown in the defooting test. In these tests, Farsatan magnesium; salt hexahydrate The water content of the material at 40 ° C and 7 5 % relative humidity for four weeks remains fixed in the open container and the sealed ampoule. This salt is suitable for use because of the favorable crystallinity of the salt salt, especially its hexahydrate. Direct extrusion to form the corresponding tablet. And 'determine the tablet to obtain a better dissolution profile. In the dissolution profile of the nine, the construction of magnesium salt, especially its hexahydrate can be coated from film within 15 minutes The tablet 1 〇〇〇/〇 is released. Moreover, the fersartan magnesium salt, especially its hexahydrate, exhibits a favorable calendar hardness profile. The calcium/magnesium mixed salt of Farsartan also has advantageous properties. For example, a uniform knot can be produced Crystal deposits. These systems are useful in herbal formulations. At pH 1, pH 4.5 and pH 6.8, the intrinsic dissolution rate of the fasartan dipotassium salt is superior to those of these falsartan. Another object of the invention is to prepare salts according to the invention. The preparation of salts according to the invention, including their amorphous or crystalline forms, is as follows: To form a salt, the procedure is carried out in a solvent system, wherein the two reactants, namely the acid falsartan and the respective bases, Fully dissolved. It is convenient to use a solvent or a solvent mixture in which the salt obtained is only slightly dissolved or completely -32-

1316935 V. Description of the invention (3〇2 to achieve the effect of crystallization or sedation. - a variation of the salt according to the invention

: Make: a solvent that is very soluble in this salt, and then add an anti-solvent to this.

1 anti-solvent is - the solubility of the resulting salt is extremely L = crystallization, the change method is by, for example, by heating, if necessary, at low pressure or by slowly adding the body to the seed, or ;: agent = to warm τ, or concentrated by the seeding crystals, etc.: the solvent that can be used to form the desired water activity is, for example, Ci.C5 marriage, preferably ethanol and decyl alcohol ' := The :cr-ketones are preferably C, and mixtures thereof with water. Factory: The two 'agents can be, for example, C3_C7·alkylnitrile, especially B C2_C7, acid 々C5_ phenous vinegar, such as ethyl or isopropyl vinegar, _(C1_C5•院基). Acid, For example, the third butyl methyl group is in addition to the 'tetrahydrofuran and c5_C8i class, especially the penta-burning, hex-burning or Gengyuan. For the production of hydrates, a dissolution and crystallization procedure, or a water equilibrium crystallization procedure, is used. The dissolution and crystallization procedures are characterized by: (1) reacting the dragon and the appropriate test in an organic solvent preferably containing water, (ii) by heating, for example, at low pressure and by seeding the crystal. Into the seed crystal or by slowly evaporating, such as at room temperature to concentrate the solvent system, then initiate crystallization or sedimentation and (iii) separate the salt obtained. In the dissolution and crystallization procedures, the aqueous organic dispensing system used is more suitable for this paper scale. The Chinese National Standard (CNS) A4 specification (210X 297 public) binding line -33- 1316935 A7

An alcohol mixture and water. 'Equivalent crystallization procedures such as ethanol and water, or calcination, especially acetonitrile in the manufacture of hydrates, are characterized by (i) adding falsartan and a suitable base to a water-containing, ν π depleting agent, = If the solvent is concentrated by heating 'if necessary under low pressure' or by slow evaporation, such as at ambient temperature, (111) balance the evaporation residue with the required amount of water by the following means: U) suspending the evaporation residue - a suitable solvent wherein the base hair is preferably still warm and which still contains some water, or (b) an excess of water in the equilibrium solvent; thus in a) and b), the water is present or added It is present in an amount such that water is dissolved in the organic solvent and does not form another phase; and, (iv) the salt obtained is isolated. The solvent system for use as the aqueous organic solvent preferably comprises a mixture of suitable alcohols, such as C!-C alcohol, especially a mixture of ethanol and water. A suitable solvent for equilibration is, for example, an ester such as an alkanecarboxylic acid-CrC:7-alkyl ester, especially ethyl acetate, or a ketone such as di-C 1 -C 5- Alkyl ketone, especially acetone. The equilibrium procedure is known, for example, for its high yield and excellent reproducibility. When producing monoalkali metal salts according to the invention, 'amorphous forms are mainly obtained. On the other hand, The second test metal salt and the soil test metal salt of the present invention are obtained from a suitable solvent conventionally used in the production process, wherein a suitable solvent such as a Ci-Cr alkanecarboxylic acid-CrC?-alkyl-34 is obtained. · This paper scale applies to China National Standard (CNS) A4 specification (210X 297 public) 1316935

5. Description of the invention (32) Esters 'especially ethyl acetate, ketones such as di-Ci_C5_alkyl ketones, especially acetone, C3-C7_anti- carbonitriles, especially acetonitrile or hydrazines, bis(Cl) a -c5_dry basis bond, such as a third butyl methyl acid, and a tetrahydroanthracene or solvent mixture: by means of a dissolution and crystallization procedure or a water equilibrium crystallization procedure, the reproducible mantle can be crystallized and polymorphic. a hydrate as defined. Further, the preparation of the bis-dialkyl group according to the present invention, which is not a hydrate, is preferably carried out in a step using a compounding agent which is mixed with an anti-dropping agent. In this way, crystalline salts can be obtained. In general, an amine salt of the present invention in an amorphous form can be obtained. The procedure for forming salts is likewise an object of the present invention. These salts and salt hydrates according to the invention are obtained, for example, from the test of each cation and the acid falsartan. This neutralization is suitably carried out in an aqueous medium, e.g., in water or a mixture of water and solvent, wherein the agent dissolves the falsartan more readily than water. Salts containing weaker tests can be converted to other salts by using a stronger treatment or by acid treatment and then neutralizing them by other tests. ' Crystallization, #别是土土金属盐 The salt is carried out in water or in an aqueous medium consisting of water and at least one solvent, wherein the solvent is water-soluble or partially soluble, ie the polarity is not too small For example, alkanols such as methanol, ethanol, propanol, isopropanol, butanol, acetone, methyl ethyl ketone, acetonitrile, read, DMSO. The sterol partial amount amounts to about 1G to 9. , or 2. To 7. Preferably, it is from 3 to 50% by volume. For materials with a higher carbon number, less polar solvents can also be present at lower concentrations. This procedure often occurs in suspension due to the limited water solubility of farattan, or if Farsattan (4) is dissolved in the second -35-1316935 A7 - B7 V. Inventions (33~) "" ---- Other ▲ ingredients. In one embodiment, for example, an aqueous solution of falsartan is neutralized with a calcium hydroxide solution at room temperature and the solution is allowed to stand to be crystallized to produce a crude salt of falsartan. In a preferred procedure, the crystallization is carried out in water/liposolvent solvent, and the total amount of ethanol is about 3 〇 to 5 〇 vol. In the "excellent form", the crystallization is carried out in a closed system in a volume of 3 vol% ethanol by a low temperature gradient (especially in the case of 4 〇. (1:1). In a variant, the crystallization can be adjusted, as can be accelerated by the addition of at least one seeding crystal. A salt according to the invention, for example in the form of a pharmaceutical preparation, can be used, which contains the active substance, such as a therapeutically effective amount of the active substance, as the case may be. In combination with a pharmaceutically acceptable carrier, for example, a pharmaceutically acceptable carrier with an inorganic or organic, solid, (4), or also optionally with a liquid, wherein the carrier is suitable for use in the intestine, such as orally or Parenteral administration. In particular, the invention relates to a pharmaceutical composition, particularly in the form of a solid dosage unit, preferably for oral administration, optionally in combination with a pharmaceutically acceptable substance. Such a pharmaceutical preparation can be used, for example, for example. Prevention and treatment can inhibit 4 diseases or conditions by blocking the receptor, for example, a condition or disease selected from the group consisting of the following symptoms or diseases> (a) hypertension, congestive heart Failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes Type-36-

1316935 A7 B7 V. Description of invention (34) 2. Obesity, kidney disease, renal failure, such as chronic renal failure, hypothyroidism, myocardial infarction after survival (ΜI), coronary heart disease, elderly hypertension, familial Lipid metabolism, increased formation of collagen, fibrosis, and remodeling of mixed hypertension (complex anti-proliferative effects), all of these related or unrelated hypertensive lipid diseases or conditions; (c) endothelial function with or without hypertension Disorders, (d) hyperlipidemia, hyperlipoproteinemia, atherosclerosis and hypercholesterolism in bile, and (e) glaucoma. The main dose is for the treatment of hypertension and congestive heart failure, as well as post-myocardial infarction. Appropriate and standard animal testing models can be selected in the appropriate technical field to demonstrate the indications and beneficial effects of the treatments described above and below. Pharmaceutical activity can be demonstrated by the use of a corresponding pharmacological model well known in the appropriate art to demonstrate that a composition of a representative salt of the invention or an active agent according to the invention can be used. Those skilled in the art of this technology can choose the relevant animal test model to demonstrate the indications and beneficial effects of the treatments mentioned above and below. These beneficial effects can be demonstrated, for example, in the experimental mode disclosed by G. Jeremic et al., J. Cardovasc. Pharmacol, 27: 347-3, 1996. For example, the potential of the salts or compositions of the present invention for preventing and treating the risk of myocardial infarction can be found using the following test patterns. Study Design-37- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1316935 A7 B7 V. Description of invention (35) In the study to be completed, permanent coronary artery closure in rats (CAO) It is used as an acute myocardial infarction pattern. This experiment was carried out with 5 treatment groups with the following characteristics: • Falsely manipulated animals • CAO + excipients • CAO + salts according to the invention, optionally selected • CA0 + salt + combination according to the invention. The following variables were measured during the study: • Infarct size • LV chamber volume • LV myocardial interstitial and perivascular collagen density • COL-I and COL-III protein content in LV myocardium isolated from Western blot • In LV Cross-sectional area and length of myocardial cells in myocardial sections • Plasma concentration of renin and aldosterone • Urine concentration of sodium, potassium and aldosterone • Blood pressure of conscious animals • LV and carotid blood pressure in anesthetized animals Methodic infarct size: tetrazolium Blue stained the horizontal section of the left ventricle of six micrometers thick and obtained it by B/W XC-77CE CCD camera (Xinli). The resulting images were processed on a KS300 image analysis system (Carl Zeiss TV pattern) using specially developed software (Porzio et al., 1995). Can't see -38- The paper size is applicable to China National Standard (CNS) A4 specification (210X297 public director)

Binding

Line 1316935 A7 B7 V. Description of the Invention (36) A single operator interactively defines the boundaries of the interventricular septum, and the infarcted area on each slice is semi-automatically defined as the area of unstained ventricular tissue. The software automatically calculates the components of each ventricular slice as defined by a set of geometric parameters (Porzio et al., 1995) such as chamber, septum, infarct area, infarct LV wall, and viable LV wall. Histology: Intermittent injection of sputum. After 5M KC1 terminates the diastolic phase, the heart is fixed in place by retrograde perfusion with buffered 4% furfural. After fixation, weigh the left ventricle (L V) and the free wall of the right ventricle separately; measure the longer diameter of L V with a caliper. L V tissue sections were stained with hematoxylin and eosin to qualitatively measure and quantify the myocardial cell cross-section by semi-automatic image analysis routine. Tissue collagen deposition in LV was assessed on sirius red-stained sections using a semi-automated image analysis routine (Masson et al., 1998). The collagen content in the myocardium separated by L V: The L V tissue was uniform in the separated myocardium, and PAGE-SDS electrophoresis and electro-contamination were performed on the nitrocellulose membrane. The stain is exposed to the primary antibody, i.e., rabbit anti-mouse collagen type I or type III immune serum (Chemicon). The primary antibody can be identified by a secondary antibody that binds to alkaline phosphatase (for collagen type I) or peroxidase (collagen type III). Left ventricular volume: The volume of the L V chamber was measured at the end of the diastolic phase (KCL) and fixed in the heart of the formalin at a hydrostatic pressure equal to the measured final V V of the L V . Insert the metric ruler into the L V to measure the internal length of the L V. The transverse diameter of the L V chamber was measured in two 1 cm thick transverse sections near the bottom and apex of the chamber (Jeremic et al., 1996). The volume of the chamber can be calculated from an equation that integrates the lateral straight diameter and the inner length. System and left ventricular hemodynamics: a recorder will be connected (Windograf, -39- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) A7 B7 1316935 V. Description of invention (37)

Gould Electronics' microtip pressure transducer (Millar SPC-320) was inserted into the right carotid artery to record systolic and diastolic blood pressure. The pressure transducer is pushed into the LV to measure LV contraction (LVSP) and final diastolic (LVEDP) pressure, a differential of the LV pressure versus time (+ d P / d t) and heart rate. Non-invasive blood pressure: systolic blood pressure and heart rate were measured in conscious rats by the tail-tail method (Letica LE 5002). Urine electrolytes, hormones: The rats were each placed in a metabolic cage and the urine was collected in 1 ml of HC1 6N. Measurement of absorbed water "Urine benzophenanthrene was extracted in a Bondelut C18 column (Varian) and separated by HPLC (Apex-II Cis, 3 μm, 50 x 4.5 variable analysis column, Jones chromatographic analysis) It was quantified by an electrochemical detector (Coulochem 11, ESA) (Goldstein et al., 198 1). Plasma and urinary steroids and plasma angiotensin 11 were measured by specific radioimmunoassay (Aldoctk-2, DiaS or in and angiotensin 11, Nichols diagnostic method). Urine sodium and potassium are measured by flame spectroscopy. Sample Size 10 analyzable animals in each treatment group were sufficient to detect biologically significant differences. Only mice with an infarct size of at least 10% LV sections were included in the final analysis. Endothelial dysfunction is considered a key factor in vascular disease. The endothelium plays a bimodal role as a source of various opposite hormones or by-products: vasodilation and vasoconstriction, inhibition or promotion of growth, fibrinolysis or thrombosis, manufacture of antioxidants or oxidants. Animals with a genetic predisposition to hypertension with endothelial dysfunction constitute an effective model for assessing the efficacy of cardiovascular therapy. -40- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1316935 A7 B7 V. Description of invention (38) Endothelial dysfunction is caused by, for example, higher oxidative stress, resulting in lower nitric oxide , coagulation or fibrinolysis contains more factors such as plasminogen activator inhibitor-1 (PAI-1), tissue factor (TF), tissue plasminogen activator (tPA), more adhesive molecules Such as ICAM and VCAM, more. Growth factors such as bFGF, TGFb, PDGF, VEGF, all factors that cause cell growth inflammation and fibrosis indicate its characteristics. Treatments such as endothelial dysfunction are described in the following pharmacological tests: Materials and Methods S HR, which is commercially available from RCC GmbH (Ftillingsdorf, Switzerland) and 20-24 weeks old, is retained in the free channel to the mouse. Food (Nafag 933 1, Gossau, Switzerland) and tap water temperature control - and light control - in the room. This experiment was carried out in accordance with the guidelines and was endorsed by Canton Veterinary (Bew 161, kantonales Veterin 3ramt, Liestal, Switzerland). All murine N O was treated with synthetic inhibitor l-NAME (Sigma Chemical Company) for 12 weeks via drinking water (50 mg/L). The average L-NAME dose was 2.5 mg/kg/曰 (range 2.1-2.7) from the water consumed. Dividing the mice into 2 or 3 groups: the first group, the control group (η = such as 40); the second group, a salt according to the invention; (η = such as 40); for the test combination of the third group, the combination partner; η = such as 3 0 ). The drug is administered as a drinking fluid. The pressure effect of Ang II obtained at 1 mg/kg in normal blood pressure control mice in the control group can be reduced after treatment with the salt according to the invention (Gervais et al., 1999). Body weight is measured daily. The systolic blood pressure and heart rate were recorded by tail-cylinder pressure plethysmography 3 and 2 weeks before the start of the study and after the drug administration. The week before the start of treatment and the 4th and 2nd week, the collection was kept at 24 hours. -41 - This paper size applies to the China National Standard (CNS) A4 specification (21〇X297 mm).

1316935 A7

The urine of each (metabolic) caged rat was measured for volume and protein, creatinine, sodium and potassium were measured using standard laboratory methods. At the same time point, a blood sample (up to 丨ml) is taken from the sputum reticular tissue for creatinine,

Na + and κ+. At the 4th week, 1 group of rats were sacrificed to collect kidney and heart for morphological analysis. The younger brother sacrificed the remaining rats in 2 weeks. Record the weight of the heart and kidneys. Final blood sampling was performed in 5% EDTA at Week 4 (morphological study) and 12 (end study) weeks to determine retention by radioimmunoassay using the DPC-membrane count aldosterone _RIA kit (Biihlmann, Switzerland) ketone. Statistical Draw: All data is expressed as the average SEM. Statistical analysis was performed using one-way AN0VA followed by Duncan's multi-range test and Newman-Keuls test 7 to compare the different groups. The probability that the probability is lower than 〇 〇 5 is considered statistically important. Improve the improvement of joint sclerosis without affecting the amount of serum lipids, for example, using animal models as disclosed by the 生物 Kano et al. at the Biochemistry and Biophysical Research Symposium 259 Ο4·4〗 9.9%). The salt or composition according to the present invention can be used for the degradation of joint hardening caused by the cholesterol diet, and can be illustrated by a test mode as described by C. Jiang et al., Br. J. Pharmacol (1991), '1033-1037. Salts or compositions according to the invention may be used for the treatment of renal failure, particularly chronic renal failure, which may utilize a test pattern as described by D. Cohen et al., J. C., Pharmacology 32: 87-95 (1998). Explain it. The pharmaceutical preparation of the present invention, if desired, may also comprise other pharmacologically active substances', and the preparation may be previously known, for example, conventionally mixed, granulated, coated, and coated with -42-book paper, gi^^NS) k^-QX 297 mm) 1316935 A7 B7 Five inventions description (

Prepared by a coating, dissolving or freeze-drying procedure, and which may comprise from about 0.1% to about 100% 'especially from about 1% to about 5% by weight, up to i 〇〇% of the active substance freeze-dried Things. 4 The present invention is identical to compositions containing salts according to the invention. The present invention is equally applicable to a formulation according to the present invention which is preferably used for the manufacture of a pharmaceutical preparation, particularly for the prevention and treatment of a disease or condition which can be inhibited by the AT1 recipient. The main use is in the treatment of hypertension and congestive heart failure, as well as post-myocardial infarction. The invention is equally applicable to the prevention and treatment of a disease or condition which inhibits the disease or condition by blocking an AT1 recipient, characterized in that a patient in need of such treatment, including a human patient, is administered a therapeutically effective amount of a salt according to the invention, optionally in combination with at least A composition for treating cardiovascular and related conditions and diseases listed above or below. The invention likewise relates to a composition, such as a pharmaceutical composition, comprising a salt of the invention, or a pharmaceutically acceptable salt thereof in each case in combination with at least one of a cardiovascular and related condition and a disease listed above or below. The composition, or each of its pharmaceutically acceptable h, contains the same combination of other compositions for treating heart, blood vessel and related conditions and the diseases listed above or below, or the pharmaceutically acceptable salts thereof in each case This is the object of the present invention. For example, it may be combined with a composition selected from the group consisting of: (i) an HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof, (ii) angiotensin converting enzyme (ACE). Inhibitor or its medicinal salt, -43- This paper scale is remote: using Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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Line 1316935 A7 B7 V. INSTRUCTION DESCRIPTION (41) (iii) a calcium channel blocker or a pharmaceutically acceptable salt thereof, (iv) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof, (v) An aldosterone antagonist or a pharmaceutically acceptable salt thereof, (vi) a dual angiotensin converting enzyme/neutral peptide endoenzyme (ACE/NEP) inhibitor or a pharmaceutically acceptable salt thereof, (vii) An endothelin antagonist or a pharmaceutically acceptable salt thereof, (viii) a renal enzyme inhibitor or a pharmaceutically acceptable salt thereof, and (ix) a diuretic or a pharmaceutically acceptable salt thereof. HMG-Co-A reductase inhibitors (also known as β-hydroxy-β-methylpentadienyl-coenzyme purine reductase inhibitors) are known to be useful in reducing the amount of lipids including cholesterol in the blood. . HMG-Co-A reductase inhibitors comprise 'compounds having different structural characteristics. For example, it may be mentioned that it is selected from the group consisting of atorvastatin, cerivastain, compactin, dalvaststin, dihydroconductin. (dihydrocompactin), fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, spectroscopy A compound of the group consisting of pravastatin, rivastatin, simvastatin, and velostatin, or a pharmaceutically acceptable salt thereof in each case. Preferred HMG-C 〇 - A reductase inhibitors are these commercially available agents, preferably fufenstatin, statastatin or a pharmaceutically acceptable salt thereof in each case. -44- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) binding

Line 1316935 A7 B7 V. INSTRUCTION DESCRIPTION (42) Saliva is called a ACE-inhibitor (also known as an angiotensin converting enzyme inhibitor). The degradation of the enzyme blocking the angiotensin I to angiotensin II is a successful variant for the regulation of blood pressure, thus making a medical treatment for congestive heart failure feasible. ACE-inhibitors contain compounds with different structural characteristics. For example, it may be mentioned that it is selected from the group consisting of aacepril, benazepril, benazeprilat, captopril, and colora. Ceronapril, cilazapril, deLapril, enalapril, enaprilat, Fusin Fosinopril, imidapril, lisinopril, moveltopril, perindopril, sapphire a compound of the group consisting of quinapril, ramipril, spirapril, temocapril, and trandolapril, or A pharmaceutically acceptable salt thereof in each case. Preferred ACE inhibitors are these sold agents, the best of which are Bunninger and Innapulil. The CCB class basically comprises dihydropyridine (DHP) and non-DHP such as (diltiazem) type and verapamil type CCB. The CCB which can be used in the composition is preferably a representative selected from the group consisting of alodipine, felodipine, ryosidine, isradipine, and lacy. Lacidipine, nicardipine, nifedipine -45- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 1316935 V. Description of invention (43 ), Niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine a representative of the group of DHP, and preferably selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil , a non-DHP representative of a group consisting of mibefradil, anipamil, tiapamil, and verapamil, and pharmaceutically acceptable in each case salt. All of these CCBs are used therapeutically, such as antihypertensive, anti-stenosis or anti-arrhythmia. Better CCBs include Arroyobin, diltiazem, Isla Dybin, Nika Dabbin, Nifi Dybin, Nemo Dybin, Nisso Dybin, Nie Dalbin and Verapamil Or, depending on the particular CCB, its pharmaceutically acceptable salt. A particularly good DHP is Arrodabin or a pharmaceutically acceptable salt, especially its besylate. A particularly good non-DHP representative is verapamil or a pharmaceutically acceptable salt, especially its hydrogenated hydrogen. An aldosterone synthase inhibitor is a method of converting corticosterone to aldehyde retention by hydroxylating cortocosterone to form 1 8 -0 Η -corticosterone and 1 8 -0H-corticosterone to aldosterone Ketone enzymes. It is known that aldosterone synthase inhibitors can be used in the treatment of hypertension, and the main aldosterone contains steroids and non-steroidal aldosterone synthase inhibitors, and the latter is the best. Preferred are aldosterone synthase inhibitors available from commercial companies or aldosterone synthase inhibitors approved by these health authorities. Aldosterone synthase inhibitors include compounds with different structural characteristics -46- The paper size is applicable to China National Standard (CNS) Α4 specification (210X297 mm) 1316935 A7 B7 V. Invention description (44). For example, it may be mentioned that it is selected from the non-steroidal aromatase inhibitors anastrozole, fadrozole (including its (+) counterpart isomer), and the steroid-alcohol aromatase inhibitor Axis A compound of the group consisting of exemestane, or a pharmaceutically acceptable salt thereof in each of the applicable examples. The best non-steroidal aldosterone synthase inhibitors are the (+) corresponding isomers of the following formula (U.S. Patents 46173 07 and 48 89861)

HCI's better steroid aldosterone antagonist is the following type of Epleenone (eplerenone)

Or spiral inside (spironolactone). A better dual angiotensin-converting enzyme/neutral peptide endoenzyme (ACE/NEP) inhibitor is, for example, omapatrilate (see-47- This paper scale applies to Chinese national standards (CNS) A4 size (210X 297 mm) 1316935 A7 B7 V. Description of invention (45) Test EP 629627), fasid〇tril or fasidotrilate, or if appropriate, A pharmaceutically acceptable salt. Preferred endothelin antagonists are, for example, bosentan (see EP 526708 A)' and tezosentan (cf. WO 96/19459), in each case, pharmaceutically acceptable salts thereof. A renal enzyme inhibitor is, for example, a compound of the following formula

Chemically defined as 2(S), 4(S), 5(S), 7(S)-N-(3-amino-2,2-dimercapto-3-ketopropyl)_2,7 Bis(1-mercaptoethyl)_4-hydroxy-5-amino-8-[4-methoxy-3-(3-methoxy-propoxy)phenyl]-butanamine. Its representative is specifically disclosed in EP 6*78503 A. It is especially good for its half horse rich acid ester. The diuretic is, for example, a thiazine derivative selected from the group consisting of chlorothiazide, hydrogen thiazide, sulfhydrazine, and chlorothalidon. The best hydrogen oxazine can be used simultaneously or in any order. In combination, a therapeutically effective amount of the active agent according to the composition of the present invention is administered separately or in a fixed combination. The structure of the agent according to the generic or trade name may be taken from the standard summary, the Mock Index " actual version or data Kuru International Patent (IMS# publication). Here is the paper size _ 'Reading (CNS) M specification (黯公公爱) 1316935 A7 _____B7 V. Invention description (46) For reference, based on these references, any skilled practitioner can identify the active agent and, in the same manner, can manufacture and test the in vitro and in vivo medical signs and properties of the standard test mode. Solvent forms such as water can also be used. a compound or a corresponding active ingredient or a pharmaceutically acceptable salt comprising other solvents for crystallization. The compound to be combined may be in the form of a pharmaceutically acceptable salt. There may be, for example, at least one azimuthal center which may form an acid adduct salt. If desired, a corresponding acid adduct salt having an additional basic center may also be formed. "A compound having an acid group (such as WC00H) is also Salts may be formed with a base. In the variants thereof, the invention is equally applicable to the "component kit", for example, according to the invention, the components to be combined may be used alone or by different amounts of different fixing compositions. The method of use, ie, at the same time or at different time points, then the ingredients of the kit, such as simultaneous or chronologically interleaved, in other words, the composition of any of the kits, at different points in time and at the same or different Time interval. It is preferred to select the time interval such that the use of the binding component has a greater effect on the treatment of the disease or condition than is achieved by using only one of the ingredients. Further, the invention relates to a composition comprising the composition according to the invention and simultaneously, Commercial packages for separate or sequential use instructions. Dosage depends on a number of factors, such as application pattern, species, age and/or For oral administration, the daily dose is between about 〇25 and 10 mg/kg, and for warm-blooded animals weighing about 7 〇 kg, preferably between about 20 mg and 50. 〇 between mg, especially 40 mg-49- A4^w2l〇x297^)- 1316935

DESCRIPTION OF THE INVENTION 80 grams, 160 milligrams and 32 () milligrams, based on free acid. The invention is particularly illustrated by way of example, and also with respect to the novel compounds named in the examples and their use and methods for their preparation. The following examples serve to illustrate the work of the present invention and are not intended to be limiting in any way. For example, 'the formation of the dipotassium salt of falsartan, especially its hydrate. Dipotassium. Salts are particularly noticeable in their remarkable solubility in water. A crystalline tetrahydrate having a melting point of 135.0 elsaltan dipotassium salt is specifically mentioned. According to the elemental analysis, a specific example of this hydrate has a water content of 3 72 mol water/mole dipotassium salt. At room temperature, for high relative humidity, tetrahydrate is formed, and for low relative humidity, an anhydrate of dipotassium salt is formed. The ferrsartan magnesium salt is prepared in the same manner, in this case as an amorphous solid containing 3.4% Η 20 t. The glass transition temperature, such as the specific heat is 焦85 joules • [the average enthalpy of the gram·β(:] period is 167. No melting point is observed. Two facts, namely the presence of glass transition and no melting point and the change in specific heat measured値 起 证实 证实 证实 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法 法3 0/〇. Example 1: Manufacture of (S)-N-(l-carboxy-2-mercaptopropane- ι·*)_ν-pentyl-N-[2'- (1H-four-to-5) An alkali salt of the biphenyl form of biphenyl _4_ decyl oxime, at room temperature, 21.775 g (S)-N-(l-carboxy-2-indolyl- 1-yl)-N-pentamethylene-^[.-(^-tetrazol-yl(tetra)phenyl-cardyl decylamine is dissolved in 300 ml of ethanol. By carefully adding 3 liters of water, Reduce the ethanol concentration to 50% by volume. Using a magnet stirrer, slowly add 3 89 g of Ca(〇H)2 •50· The paper scale is @金家料(CNS) A (21GX297 mm) A7 B7 1316935 V. INSTRUCTIONS (48) Add this clarified, slightly acidic (pH 4) solution in small portions, so p is short The ground does not exceed about 8. Since it absorbs c〇2 from the air, the Ca(OH)2 used contains a trace amount of CaC03; therefore, the amount added includes an excess of 5%. After adding the stoichiometric amount of Ca(0H)2, 'p Η It is about 6, and it is increased to 7. after the addition of this excess. The solution becomes cloudy by a small amount of finely dispersed CaC03, which is removed by a folding filter to allow the solution to stand at room temperature to remove the alcohol content. The product contained in the solution is continuously crystallized. This procedure can be accelerated by a flat treatment in a cyclone oven at 40 ° C. After concentration to about half, the alcohol content of the solution is reduced to about 10% by volume, and most of the product is crystallized. Filter it, wash it with 10% by volume of ethanol for a short time and dry at 4 Torr. Dry down until _ fixed weight. Obtain (S)-N-(l-carboxy_2_methylpropyl 4 • group a tetrahydrate of the calcium salt of _N_pentamyl-indole-[2'-(1Η-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine. Felsa according to Example 1. The tetracalcium tetracalcium salt has a melting point of 205 ° C and a melting enthalpy of 205 at a heating rate of 1 〇K /min·1 in a closed sample container having a small internal volume. Joule/Moole-丨. According to the example, the calcium-falsartan-tetrahydrate was measured by the pycnometer to have a crystal density of 1.297 g) cubic centimeter. This is confirmed to be 1 from the single crystal structure. The theoretical calculation of 298 g / cm 3 値. The optical rotation of the tetrahydrate according to the example of the law of the fasaltan calcium salt in the decyl alcohol was [a] 2 〇 D =: +1. The enantiomeric purity of the salt hydrate prepared was determined by the stereo-specific HPLc method. This stereo-specific separation is achieved by the palm of the hand (palm AGp). The enantiomeric purity was determined to be e e = 1 〇〇%. Calculate the batch method from the X-ray powder pattern taken by the Guinier camera -51 - 1316935 A7 B7 V. Inventive Note (49) The interplanar spacing of the most important lines of the sartan calcium salt tetrahydrate is as follows : d [A]: 16.27 ' 9.90 ' 9.39, 8.04, 7.71, 7.05, 6.49, 6.34, 6.2 '.5.87 ' 5.75, 5.66, 5.20, 5.05, 4.95, 4.73, 4.55 7 4.33 9 4.15 9 4.12 y 3.95 5 3.91 > 3.87 > 3.35 Elemental analysis provides the following measurements of elements and water present in the tetrahydrate of the salt of Valsaltan. The water quantity assessment is at 130. (: After dehydration. The discovery of elemental analysis is within the error limit, equivalent to the total formula (C24H27N503) 2Xa2 + .4H20. % found % calculated C 52.82 52.83 Η 6.42 "------ 6.47 Ν 12.91 12.83 0 20.20 20.53 Water 13.25 ~ ""-----13.21 Ca 7.03 ~--------- 7.35 Example 2 Manufacture (S)-N-(1-Rebel-2-methylpropane Base) _N_ 酿 基 _ ν · [2, · (1Η-tetram-5-yl)biphenyl-4-ylmethyl]-amine in the original Liushui human magnesium salt at room temperature, will be 43.55 Kefalstan [to >)_1^. , ^ ^ ; ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 600 ml of 50 ml. /〇Ethanol (from absolute alcohol - see Moben paper scale applicable to China National Standard (CNS) Α4 specification (210X 297 mm) *52. 1316935 A7 _____.__B7 V. Invention description (5〇) ~~~ ~ gram And quartz double distilled water). After adding 5 ml of 5 vol% ethanol, the slightly turbid solution became clear. Using a magnet stirrer, 4.03 g or 0.1 M Mg 〇 (mock p a ) was slowly added to the micro acid solution of the hopper. The pH is thus increased to about 6. This procedure was carried out in an excess of 1%, i.e., another 0.40 g of MgO was added. This excess is not completely dissolved, and the surface is raised to about 7.5. The small residue was filtered off from the solution through a pleated filter and washed with 5 liters of 50 vol% ethanol. The solution was carefully concentrated at 40 ° C and the clear solution was stirred while stirring in a large crystal dish with a magnet stirrer. This procedure ended with a tendency to harden into a smooth gel. Scratching in a glass rod in this phase initiates crystallization at the same place, which can be confirmed by the formation of a white crystalline solid. The product is dried in a 5 〇β (: under a whirlwind oven until a fixed weight is reached. The yield of magnesium _ falsartan-hexahydrate is 53.7 g or 95%, based on the Farsattan used as the free acid. The salt hydrate prepared according to Example 2, namely, magnesium·falsatan hexahydrate, was measured at a heating rate of 丨〇κ/min·! and a volume of 2.24 mg in a closed sample container having a small internal volume. The melting point was 132. (: and the enthalpy of fusion was 64 仟 joules/mole η. - μ The crystal density of the hexahydrate of the falsartan magnesium salt prepared according to Example 2 was measured by the pycnometer to be 1273 g/ Cubic centimeter β This confirms the theoretical calculation of 1.25 g/cm 3 calculated from the single crystal structure. Magnesium-falsatan hexahydrate prepared according to Example 2 was measured in decyl alcohol as a 1 〇/〇 solution. The optical rotation is [a ] 2 〇-D = _ i 4. The enantiomeric purity of the salt hydrate prepared according to Example 2 is based on the stereo _ paper scale of the acacia (CNS) M Specifications (21QX297 public)

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Line -53 1316935 V. Description of the invention h Measured by HPLC method. This stereo-specific separation is achieved by the palm of the hand (palm AGP). The enantiomeric purity was determined to be ee = 996%. From the X-ray powder pattern taken by the Guinier camera, the interplanar spacing between the most important lines of the lottery-Farsartan-hexahydrate was calculated as follows: d, [A]: 19.78, 10.13, 9.84, 7.28, 6.00, 5.81, 5 67, 5_21, 5.04, 4_88, 4.21, 4.18, 4.08, 3_95, 3.46, 3'42. Elemental analysis provides the following measurements of the elements and water present in the hexahydrate of the salt of the valsartan. The water quantity assessment was carried out after dehydration at 130 eC. The discovery of elemental analysis, within the error limit, is equivalent to the general formula (C24H2*7N5C)3;)2 · Mg2+ ·6Η20 0 %% found C 51.03 50.94 Η 7.00 6.95 — Ν 12.45 ——- 12.38 0 25.02 ——~ -— 25.44 Water 19.08 !9,0 Mg 4.35 4.29 ' *------ Example 3 Manufacture of (S)-N-(l-carboxy-2-methylpropan-1-yl)-oxime-pentamethylene · Hydrate of ν_[2,_(1Η-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine dipotassium salt (3.5±1.〇莫耳Η20) Capacitance 5g (S )-N-(l-Fusyl-2-methylpropan-1-yl)-indole-pentanyl-Bu•54- 1 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) PCT j -

_____I 1316935 _____I A7

[2,-(1H_tetracentric 5_yl)biphenyl-4-ylmethyl]-amine, while gently heating in 11.5 ml of 2N hydrogen hydroxide solution and mixing with 32 ml of B. The mixture was heated for 5 minutes to reflux (cloudy solution), allowed to stand at room temperature without stirring for 3 days (seeding), and then allowed to stand at π for 24 hours. Decant the mother liquor. The crystal was washed twice with acetonitrile and (4) dried in air for 3 M until a fixed weight was reached. Obtaining (S)-N-(1_carboxy·2_methylpropyl)_n_pentyl-N-[2,-(1H-tetrazol-5-yl)biphenylmethyl]-amine II A hydrate of a potassium salt (3. 7 moles of water per mole of potassium salt). In a closed sample container, the melting point is 1 35 °C.

Alizarin analysis: C24H27N503K2, 3.72Η20, molar mass 578 72. % found % calculated C 49.90 49.81 Η 5.92 6.00 Ν 12.14 12.10 0 18.55 18.58 Water 11.58 — -— 11.58 Κ 13.50 ——^ 13.51 Using X-ray diffraction diagram of CuKa radiation with a drier from Scintag, Inc., Cupertino, California, USA . Binding

Line The most important line of reflection and intensity of the fassartan-potassium salt hexahydrate is 2 Θ. Indicates the 値: \ -55- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1316935 A7 B7 V. Invention description (53 2Θ, °) Strength 4.6 Strong 8.8 Medium 9.2 Strong 11.1 Weak 12.5 Weak 14.8 Strong 15.3 Weak 16.4 Medium 17.8 Strong 18.2 Medium 18.4 Medium 18.9 Medium 20.4 Medium 21.1 Weak 21.3 Medium 22.3 Weak 22.5 Strong 23.1 Medium 23.9 Strong 25.6 Weak 26.6 Strong 26.9 Medium 28.1 Medium-56· This paper scale applies to China National Standard (CNS) A4 Specification (210 x 297 mm) 1316935 A7 B7 V. Description of the Invention (54) It is preferred to have a hydrate having a medium and strong intensity peak. Table 1 1 : Crystallization data and parameters of Farsattan dipotassium salt crystallization data General formula (C24H27N503) 2-2K+.xH20 (x=3.5 soil 1.0) Molecular mass 574.78 Crystal system orthorhombic spacer group Ρ2ι2ι2 a(Angstrom) 38.555(2) b(Angstrom) 7.577(1) c(Angstrom) 10.064(1) V(cubic angstrom) 2940.0(5) Z 4 F(000) 1212 Dcalc(g/cm3) 1.286 Lattice Number of reflections of the parameter 25 Θ range of the lattice parameter (°) 30-38 μ (cm 3.24 temperature (°c) 23 Crystal shape prismatic crystal size (Amy) 0.63x0.20x0.14 -57- This paper size applies China National Standard (CNS) A4 Specification (210X297 mm) 1316935 A7 B7 V. Description of Invention (55) Crystal Color Colorless Data Collection Diffraction Enraf Nonius CAD4 Radiation (Graphite Monochromator) CuKa Wavelength (Angstrom) 1.54178 Scan Mode ω / 2θ Scan range (Θ) 3-74 Absorption correction No number of reflections measured 3450 Number of reflections observed (1 > 2σ(Ι)) 2867 h Range -48 ~~ k range -9 - 1 range -1240 Standard reflection Number of 3 intensity changes per 120 minutes ± 5% Structural improvement improvement Improve F2, total matrix parameter number 341 R 0.069 Ry/ 0.182 S 1.57 Number of reflections used 2867 -58- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1316935 A7 B7 V. Description of invention (56) Hydrogen Atomic processing "parking", separating these water molecules 'the system is ignored Δ / 〇 max 0.24 extinction correction 0.0010 (5) final difference - Fourier (Fourier) 0.815 / -0_676 (e · ang · 3) Maximum/minimum residual electron density absolute structural parameter -0.02(4) Program used by SHEXLS86 (Sheldrick,

Gottingen) XHELXL93(Sheldrick, Gottingen) SCHAKAL92(Keller, Freiburg) Example 4 Manufacture of (S)-N-(l-carboxy-2-mercaptopropan-1-yl)-N-pentamethylene-N-[2' -(1H-tetrazol-5-yl)biphenyl-4-ylindenyl]-amine dipotassium salt 25 g (S)-N-(l-carboxy-2-methylpropyl-bu)- N-pentamethylene-N-[2,-(1Η-tetrazol-5-yl)biphenyl-4-ylindenyl]-amine was dissolved in 200 ml of ethanol. 50 ml of water was added, the solution was cooled to 〇 ° C, and then mixed with 5 7.4 ml of 2 N aqueous solution. The mixture was concentrated by evaporation in a rotary evaporator, evaporated with toluene and acetonitrile, and dried at high temperature at 50 ° C for 15 minutes. Dissolve the product in 290 ml of acetonitrile/water (95:5) hot mix -59- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1316935

Mix with another 110 ml of acetonitrile and let it cool at 3 Torr. Sowing under €. The mixture was allowed to stand at room temperature for 4 days and suction filtered. The residue was washed with acetonitrile/water (95 · 5) and dried at 8 (high vacancy in rc) to obtain (s)_N_(1-carboxy-2-methylpropan-1-yl)-1^ _Pentyl group_1^_[2,-(1^tetrazole-5-yl)biphenyl-4-ylmethyl]-amine dipotassium salt white powder. Melting point >3〇〇ι. : The obtained material is hygroscopic and equilibrated in air (C24H27N5O3K2 ' 3.96 mol η 20). % found % calculated C 49.15 49.44 Η 6.02 6.04 Ν 11,91 12.01 0 19.18 19.1 Water 12.23 12.24 Κ 13.4 13.41 Example 5 Binding

Manufacture of (S)-N-(l-carboxy-2-methylpropan-1-yl)_Ν_pentamethylene _ν_[2,_(1Η-tetrazol-5-yl)biphenyl-4-yl The disodium salt of methyl]-amine will be 1 g of (S)-N-(l-methyl-2-methylpropan-1·yl)·Ν_pentamyl·v_[2, -(1Η-four The oxazol-5-yl)biphenyl-4-ylmethyl]-amine is dissolved in 5 ml of ethanol, mixed with 2.3 ml of 2 Ν sodium hydroxide solution and concentrated by evaporation, and the residue is separately combined with ethanol and ethyl acetate. evaporation. The white residue was stirred in hot acetonitrile and filtered at room temperature. It was dried overnight at 80 ° C in high vacancy. -60·^ Paper strength ruler i is applicable @@家^柯卿 A4 specification (21GX297 公爱) ; -- 1316935

Produces (S)-N-(l-·^yl-2_methylpropan-i-yl)pentanyl_N_[2,_(1H-tetrazol-5-yl)biphenyl-4-yl a white powder of the base diamine salt. The melting point is from 260 ° C, brown fading at 295 ° C. Elemental analysis: The resulting material (hygroscopic) was equilibrated in air (C24H27N5O3Na2'5.36 mole H2O, molar mass 576 05). % found % calculated C 49.79 50.04 Η 6.51 6.60 Ν 12.00 12.16 0 23.44 23.22 Water 16.75 16.76 Na 8.09 7.98 Example 6: Manufacture of (S)-N-(1-carboxy-2-mercapto-propenyl-N-pentamethylene _n[2,_(1H-tetradent-5-yl)biphenyl-4-ylindenyl]-amine salt 5 g (S)-N-(1-carboxy-2-methylpropane Mercapto_n_[2,-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine was added to a suspension of 666 g of magnesium hydroxide in 20 ml of water. Add 40 ml. Methanol, then the mixture was stirred at room temperature for 2 hours and concentrated. The residue was taken in EtOAc EtOAc (EtOAc). The mixture was filtered off with air and dried overnight at 9 CTC to obtain (S)-N-(l-carboxy-2-methylpropan-bry)^.pentanyl•61 · A7 B7

1316935 V. INSTRUCTIONS (59) ^[2^(1H•tetrazole·5_yl)biphenyl-4-ylmethyl]-amine magnesium salt white^Valley: When heated, the sample turns brown and faces 30 ( TC becomes vitrified. π-element+analysis: C24H27N503Mg, 0.89 Moh H20, Moer temporary | 473.85 〇飞贞量·_ —---- ------ %% found C ---^. 61.26 60.83 Η 6.13 6 12 Ν 14.88 14 78 0 13.13 Water 3.39 3.38 Mg 4.74 5.13

实例 Example 7: _ order

Manufacture of (S)-N-(l-carboxy_2_mercaptopropyl)_N_pentyl _^_[2,_(1H-tetras-5-yl)biphenyl_4_ylindenyl] - amine feed salt will be 5 grams of (S)-N-(l-carboxy_2-mercaptopropyl)_N-pentyl-yl-v_[2,-(1Η-tetrazol-5-yl)biphenyl_ 4-Methylmethyl]-amine was added to a suspension of 0851 g of calcium hydroxide in 20 ml of water and then mixed with 2 ml of ethanol. The mixture was stirred at room temperature for a few hours and concentrated. The residue is dissolved in decyl alcohol, filtered through a hard filter, concentrated by evaporation to dryness (revaporation with acetonitrile), which is disturbed by heat (each with traces of ethanol and water) and pumped at room temperature. Gas is over; 0.95 g of salt is heated to reflux in 20 ml of acetonitrile/water (1: 丨), so the mixture is -62- This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1316935

The compound is almost dissolved. The mixture was allowed to cool to room temperature, mixed with 20 mL of acetonitrile, and was purged twice and washed twice with acetonitrile/water (1:1) at 80. (: The next high vacancy is dried overnight. Melting point: from 300. (: (decomposition). Alizarin analysis: C24H27N503Ca, 1.71 moles 2 〇, molar mass 5 〇 4.39 (water quantity evaluation is at 150. (3 after dehydration is carried out ^). -----1 ---- % found % calculated C 56.88 57.15 Η 6.13 6.08 Ν 13.89 13.88 0 14.94 Water 6.12 6.11 Ca 7.94 7.95 Example 8: Manufacturing (S)-N- (l-carboxyl_2-mercaptopropyl)_Ν_pentamyl _ν_[2,_(1Η_四峻_5_yl)biphenyl_4_yldecylamine monopotassium salt will be 2g (S)_N-(1-carboxy-2-methylpropan-1-yl)-indole-pentyl-(1Η-tetrazol-5-yl)biphenyl·4-ylmethylbumin is suspended in 2〇 In ml of water, and mixed with 2.296 ml of 2 Ν potassium hydroxide solution. Stir the mixture for 3 并 minutes and mix with 50 ml of ethanol' at this time to obtain a colorless solution. Evaporate and concentrate the solution and evaporate once with acetonitrile and from the third butanol. Liquefaction (with traces of water) Elemental analysis (after equilibration in air): CnHuNshK, 169 mole 40, molar mass 504.06 (water quantity evaluation is carried out after dehydration at 150 ° c. -63·

This paper ruler New Zealand @时料(CNS) M Specifications (21GX tear public love) - 1316935

% found % calculated C 57.30 57.19 Η 6.35 6.27 Ν -13.61 13.89 0 14.58 14 89 Water 6.04 6.04 Κ -7.72 7.76 t Example 9: Preparation of hexahydrate form of falsartan magnesium salt by water balance procedure ▲ in a mixing container A suspension of 16 g offalsartan and 682 g of isopropanol was stirred at room temperature and mixed with an 80 liter glass container. The mixing vessel was washed in portions with 3 919 g of isopropyl alcohol and the washing solution was added to the main mixture. After adding 3800 grams of deionized water, the mixture was transferred to a uniform drop with stirring. Then, 156 3 g of magnesium oxide suspended in 152 g of deionized water was added and the suspension was replenished with 1 00 g of deionized water. Magnesium oxide was dissolved in the solution by slow stirring at room temperature. The p H 所得 of the resulting solution was about 7 2 . The pH was increased to about 83 by adding another 2.5 grams of magnesium oxide. The resulting mixture became cloudy due to an unknown type of undissolved particles in the magnesium oxide. The mixture was transferred via a filter candle into a 35 liter enamel boiler and the glass vessel and pipette were rinsed with 805 grams of isopropanol and 1122 grams of deionized water. For a slight concentration, create a hollow in the boiler to the beginning of the theory of 89·1 〇〇 値 -64-

1316935

V. Description of the invention (62) With a heating medium temperature of 4 5 5 0 C and a boiling temperature of 3 7 _ 4 〇, the mixture is boiled at a temperature of 13.66 kg of aqueous isopropanol. By lowering the distillation pressure to w mbar値 and simultaneously increase the temperature of the heating medium to 65. 〇, the amount of distillate is increased to a total of 17.12 kg. 93 grams of ethyl acetate, followed by 14 9 grams as a seed crystal of the salt of the salt of fasartan With the addition of the contents of the cooler, finally, 668 grams of ethyl acetate was dispersed therein and cooled to room temperature with stirring. This stirring procedure was maintained for at least 24 hours. The suspension was then filtered through a Biichner filter. Therefore, a wet cake is obtained. The crucible is cleaned with 1 Π 1 g of ethyl acetate, and the cleaning mixture is used to clean the filter cake. The mash is placed in a hollow drying chamber at a pressure of 5 mbar and 4 Torr. The panels were dried for 6.5 hours until a fixed weight was produced to produce dry matter. Physical data, in particular the χ-ray powder pattern, corresponded to the magnesium hexahydrate salt of Example 2. Example 1 0: Falcontan in the form of k tetrahydrate Dancing salt in the mix 1600 g of falsartan and 7000 g of ethanol were stirred at room temperature to form a suspension, which was added to a 35 liter enamel boiling vessel with stirring. The mixing vessel was washed in 2000 g of ethanol and the washing solution was added to the main solution. In the mixture, after adding 9000 g of deionized water, the mixture was transferred to a homogeneous volume with stirring. Then, 272 g of calcium hydroxide suspended in 1500 g of deionized water was added and the suspension was replenished with 1300 g of deionized water. Calcium hydroxide was dissolved in the solution by stirring slowly at room temperature. The p Η値 of the resulting solution was about 6.9. By adding another 9.6 g of calcium hydroxide, the ρ Η値 system was increased to about 10.6. Calcium hydroxide in the undissolved particles (calcium carbonate) and mixed -65- This paper scale is suitable for gg standard (CNS) A4 specification tearing public love) 1316935 A7 -----------B7 Description of the invention (63) :--- Turbidity. The mixture was transferred via a filter candle into a 35 liter enamel boiler and the glass vessel was washed with a solution of alcohol and 1 00 g of deionized water and the g was removed. For a slight concentration, create a hollow in the boiler to the theory of 1〇〇 _ 120 mbar. A total of 1132 kg of aqueous ethanol was co-distilled at a heating medium temperature of about (10) and a maximum of 4 generations (boiled temperature of the mixture). The crystallization was automatically formed in the Xiaowang, and the suspension was cooled with stirring. To about 5T' and stirred for 16 hours in rc. The suspension was then filtered through a Buhner filter. The mixture was rinsed with a mixture of 36 liters of deionized and 4 liters of ethanol. The mixture was cooled to 5 〇c. This cleaning mixture was used to clean the filter cake. A wet cake was thus obtained. Part of the amount was dried on a metal plate at a pressure of 50 mbar in a hollow dry bath and at a temperature of 4 generations of oven for 24 hours until a fixed weight was produced to produce dry matter. The physical data, in particular the X-ray powder pattern, is equivalent to the calcium tetrahydrate salt of the example. Example 1 1 : hydrate of the valsartan disodium salt (2 4 ±1 . 〇莫耳 h20): 50 ml of 2N sodium hydroxide solution was added dropwise at 5 ° C to 2 丨 5 g of falsartan in a volume of 2003⁄4 liters of isopropanol. The clarified solution was concentrated at about 4 ° C in the sputum. (p Η about 7 _ 2 ). The amorphous residue of the disodium salt Suspended in 100 ml of isopropanol and concentrated and degased again in the air for about 4 〇 to remove water. The amorphous residue was suspended in 75 ml of acetone and 2 ml of water at about 4 °C. At about 25-30 Torr, 200 ml of tert-butyl methyl ether was added. Thus the initially oily composition was gradually transferred to the crystallization suspension. After stirring at about 25 ° C overnight, the suspension was cooled to 66- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1316935 A7 B7 V. Invention description (64) --- 10 °c and about 1 hour after pumping and filtering to remove the atmosphere The water was then washed with 20 ml of tert-butyl methyl ether. The wet cake was dried overnight at about 3 mbar and 3 Torr C. A colorless, slightly hygroscopic crystalline powder was obtained. Elemental analysis: C24H27N503Na2, 2.44 Mo Ear h2〇% found % calculated C 55.03 55.07 Η 6.16 6.14 Ν 13.38 13.38 0 16.63 Water 8.40 8.41 Na 8.67 8.78 Measure the crystal hydrate of falsartan disodium salt using CuKoc radiation with a drier from Scintag, Cupertino, California, USA X-shot Diffraction pattern (reflection line and intensity of the most important line): -67- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1316935 A7 B7 V. Description of invention (65) 2Θ Strength 4.7 Strong 9.1 Strong 13.3 Weak 13.7 Weak 15.6 Medium 16.4 Medium 17.2 Medium 17.9 Medium 18.7 Medium 19.6 Medium 21.3 Medium 21.9 Medium 22.8 Strong 24.0 Weak 24.8 Weak 25.5 Weak 26.5 Medium 26.8 Weak 27.3 Weak 27.8 Weak 28.6 Weak 29.4 Weak 29.9 Medium Paper Size Applicable to China National Standard (CNS) A4 Specification (210X297 mm) -68- 1316935 A7 B7

Example 1 2 Farsattan dipotassium salt hydrate (3.4 ± 1 〇 Mo Er h2 〇): At a temperature of about 25 ° C, 6 · 9 g of potassium sulphate was added to 21.7 g of falsartan in 〖5 〇 ml A solution of two ketones and 20 ml of water. After stirring for about 2 hours at about 25, a nearly clarified solution was obtained which was concentrated in the air at about 5 〇. 55 ml of acetone was added to the residue (29 g) containing residual moisture, and a total of 25 ml of tributyl methyl ether was dispersed therein at about 35 ° C for about 2 hours. At about 25. (After stirring, the easily stirred crystal suspension is cooled to 1 ° C, stirred for at least 1 hour, evacuated and washed with 20 ml of tert-butyl methyl ether. At about 3 mbar and The wet cake was dried overnight at 3 ° C. A colorless, slightly hygroscopic crystalline powder was obtained. Elemental analysis: C24H27N503K2, 3.42 mole 112%% found C 50.37 50.28 Η 5.87 5.95 Ν 12.24 12.22 0 17.92 Water 10.76 10.75 Κ 13.4 13.64 X-ray diffraction pattern measured by CuKa light shot with a diffraction device from Scintag, Cupertino, California, USA, USA. The most important line reflection line and intensity in Farsatan dipotassium salt hydrate. This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1316935 Α7 Β7 5. Invention description (67) is expressed as 2 θ°: 2Θ,° intensity 4.9 strong 9.4 strong 11.4 weak 12.8 weak 14.0 Weak 15.0 Weak 15.6 Weak 16.6 Medium 18.0 Weak 18.5 Weak 18.9 Weak 20.7 Weak 21.5 Weak 22.0 Weak 22.7 Medium 23.3 Weak 24.1 Medium 25.6 Weak 25.8 Weak 27.1 Medium 29.4 Weak -70- This paper scale applies to China National Standard (CNS) A4 Specification (210X 297 mm) 1316935 Description of the Invention (68 is preferably a hydrate containing medium and strong intensity peaks. f Example 1 3 Farsartan calcium/magnesium mixed salt: 21.5 g of False Stir in 2 ml of isopropanol and 1 ml of water at about 25 ° C with 1 _ 5 g of magnesium hydroxide and 1.9 g of calcium hydroxide for about 3 hours. Concentrate the actual clear solution at about 50 T in the sputum. A total of 24 ml of ethyl acetate was added to the still warm, semi-solid residue containing residual moisture with stirring. After stirring overnight at about 25 C, the initial viscous composition was transferred to a homogeneous suspension. The suspension was air-filtered and washed with 20 ml of ethyl acetate. The wet cake was dried in the air at 30-400 ° C to obtain a colorless crystalline powder. The X-ray diffraction pattern is equivalent to Example 1 and 2 an aggregate of about tetrahydrate and magnesium hexahydrate. Example 1 4 Farsatamine bis-diethylammonium salt: 1 · 5 g of diethylamine was added dropwise at 4 ° C at 4 ° C · 3 5 g of falsartan in a solution of 60 ml of acetonide. After a short time, the crystallization started slowly. After stirred overnight, at about 2 billion (: crystallization under suction filtration, washed with cold acetone and dried at the air Zhen about 50 ° C. A colorless crystalline powder was obtained. Elemental analysis: C32H51N703, 0. 1 Moh h20 -71 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm)

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1316935 A7 B7 V. INSTRUCTIONS (69) % found % calculated C 65.82 65.84 Η 8.90 8.84 Ν 16.84 16.80 0 8.52 Water 0.34 0.34 Crystalline bis-diethyl 1 salt X-ray diffraction pattern (most important line Reflection line and intensity) 2Θ Strength 4.7 Weak 8.5 Strong 9.3 Strong 10.8 Strong 11.3 Weak 13.4 Strong 14.0 Medium 14.3 Weak 14.9 Medium 17.1 Medium 17.4 Medium 17.6 Medium-72- This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1316935 A7 B7 V. INSTRUCTIONS (70) 18.3 Weak 19.0 Medium 20.0 Weak 21.2 Medium 21.6 Weak 22.4 Medium 22.7 Weak 24.9 Medium 25.2 Weak 27.0 _m Example 1 5 : Farsattan bis-dipropylammonium salt: at 25° 2.1 g of dipropylamine was added dropwise to a solution of 4.35 g of falsartan in 60 ml of acetone at C. At the beginning of the crystallization, the temperature was raised to 40 ° C in a short time and returned to room temperature in about 2 hours. After stirring overnight, the crystals were filtered off with suction, washed twice with 15 ml of acetone and dried at about 40 ° C in a hollow. A granular crystal was obtained. Elemental analysis: C36H69N703, 0.05 Mo H20%% found C 67.74 67.69 Η 9.32 9.33 Ν 15.36 15.35 0 7.64 Water 0.13 0.14 -73- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1316935 A7 B7 V. INSTRUCTIONS (71) X-ray diffraction pattern of crystalline bis-dipropylammonium salt (the most important line reflection line and intensity) 2Θ strength 8.5 strong 8.9 weak 9.4 strong 10.0 medium 11.2 weak 11.6 weak 12.5 Weak 13.2 Strong 13.9 Strong 14.3 Weak 14.7 Weak 15.1 Weak 15.6 Weak 16.0 Weak 17.0 Medium 17.9 Medium 18.7 Strong 19.9 Weak 20.4 Weak 20.6 Weak -74- This paper scale applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 1316935 A7 B7 V. INSTRUCTIONS (72) 21.0 Strong 21.7 Weak 22.3 Medium 23.1 Strong 24.5 Weak 25.5 Medium 25.8 Weak 26.7 Weak 28.6 Weak Example 1 6 : Felsaltan bis-dibutylammonium salt: at about 25 ° C The solution of 1.25 g of falsartan in 30 ml of acetone was mixed with 1.4 g of dibutylamine. The crystallization started after the lapse of time and the suspension was gradually diluted with 20 ml of isopropyl acetate over a period of about 1 hour. After stirring at about 25 ° C for 4 hours, the crystals were removed by suction, washed twice with 10 ml of isopropyl acetate and dried at 50 ° C in the air. A colorless, slightly hygroscopic crystalline powder was obtained. Elemental analysis: C4()H67N703, 0.5 Mo H20%% found C 68.25 68.30 Η 9.79 9.75 Ν 13.89 13.94 0 8.01 Water 1.33 1.33 -75- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 PCT) 1316935 A7 B7 V. INSTRUCTIONS (73) X-ray diffraction pattern of crystalline bis-dibutylammonium salt (reflection line and intensity of the most important line) 2Θ Strength 7.5 Very strong 8.5 Medium 9.7 Strong 12.7 Strong 13.3 Weak 14.1 Strong 15.1 16.4 Strong 17.7 Weak 18.2 Weak 19.5 Strong 19.9 Medium 20.5 Medium 21.4 Medium 21.9 Medium 22.2 Medium 22.6 Medium 23.0 Strong 23.7 Weak 24.2 Weak -76- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 1316935 A7 B7 V. Description of invention (74) 24.7 Medium 25.7 Medium 26.0 Weak 26.5 Weak 28.8 Weak blending Example 1: Direct compression of ingot: Number of components per batch of core per spindle [g] Servings [克] 1 Farsatan #5 salt tetrahydrate 134.24 80+) 2 Avicel PH102 60.408 36 3 Lactose (crystallization) 96.1494 57.3 4 Crospovidon 7.551 4.5 5 Love Aero sil 200 0.839 0.5 6 Magnesium stearate (vegetable) 2.8526 1.7 7 Magnesium stearate (vegetable) 3.356 2 』Based on free acid component number 1 through 0.5 cm hard sieve and in Turbula with composition Mix 1 - 6 for 2 hours. Use KORSCH/^^ printer 8 cm R gK (90 °) to mix example 2: Direct compression ingot: -77- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1316935 A7 B7 Five , description of the invention (75) number of parts per batch [g] part per core [g] 1 farsartan magnesium salt hexahydrate 400 80+) 2 Avicel PH102 270 54 3 Crospovidon 75 15 4 aero sil 200 7.5 1.5 5 magnesium stearate (vegetable) 15 3 6 magnesium stearate (vegetable) 7.5 1.5 + > ingot based on free acid It is extruded by a roller in a Freund extruder. -78-

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This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1316935

Application for the deadline No. 090116493 Category C(f[ P Abl/^ίώ. A

.98. d. 2S A4 C4 , /Λ

Patent Description I, S name Chinese English name Nationality -, invention; i a person living, residence name (name) nationality three, applicant f affairs 4 representative name Farsattan salt and its method Swiss Novartis NOVARTIS AG Switzerland

VALSARTAN SALTS AND PROCESS OF PREPARING THE SAME 1_ ERWIN MARRTI 2. Hansrudorf Oswald HANS RUDOLF OSWALD 3. Peter Bumyer PETER BUHLMAYER 4. Wavgen Martel WOLFGANG MARTERER 1. -3.Switzerland 4.Germany 1. 181 Emlangent Road, Basel, Switzerland 2. No. 25, Bumanlo Street, Starkkirch, Switzerland 3. No. 18, Hans Chong, Arihan, Switzerland 4 215 Schiphol Woodley Road, Basel, Switzerland, 29 Schiphol Street, Fort Worth, Germany

1. Hans Rudolf Haus HANS-RUDOLF HAUS 2. Henriette Bruno HENRIETTE BRUNNER binding line

Claims (1)

Patent application D 1 16493 Partially crystallization or non-Chinese patent application scope replacement (July 1998) ten Γί 1_ A kind of Farsantan mother salt. 2 · According to the salt of the first paragraph of the patent application, it is in crystalline crystal form. A puer according to item 1 of the scope of patent application. Satay #5 salt of tetrahydrate according to the patent application scope of the third hydrate, characterized by (i) a ini-ray powder pattern obtained with a Guinier camera, which contains the following interplanar plane spacing: [A] Indicated d: 16.1±0.3, 9.9 soil 〇.2,9 4±〇2, 7 〇3± 0.1 > 6.50±0.1 , 5.87+0.05 > 5.74±0.05 - 4.95±〇.〇5 · 4.73 + 〇 .05'4.33士〇.〇5'4.15±0.〇5'4_12±0.05,3.95±0.〇5; or (ii) an ATR-IR spectrum with the following reciprocal of the wavenumber (cm) : 1621(st) ; 1578(m) ; 1458(m) ; 1441(m) ; 1417(m); 1364(m) ; 1012(m) ; 758(m) ; 738(m) ; 696(m) 666(m) 5 The salt according to any one of claims 1 to 4 is in a form selected from the group consisting of (i) a crystalline form; (ii) a partially crystalline form; (iii) an amorphous form; and (iv) a polymorphic form. 6. A method for the manufacture of a salt according to claim 1 of the patent application 'characterized by 72257-980703.doc 1316935 (1) Will Farr Satan and suitable Adding to an aqueous organic solvent, (=Yes, under low house or by slow evaporation to concentrate the solvent, (iv) Evaporation of the residual material by the following procedure and the required water (a) Temporarily stop the evaporation heat of the residue in the appropriate solvent And it still contains - some water ' or # is still good 疋 i (b) by the excess water in the solvent to reach equilibrium; Thus, in a) and b), the water present or added is present in the solvent in an amount which does not form an additional phase; and is soluble in the organic (iv) salt obtained by separation. 72257-980703.doc