JP7064527B2 - Sakubitril calcium salt - Google Patents

Description

The present disclosure is generally N- (3-carboxy-1-oxopropyl)-(4S)-.
It relates to the calcium salt of (p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377, also known as sacubitril). The present disclosure specifically relates to a polymorphic form of the calcium salt of AHU377. The present disclosure also generally comprises a pharmaceutical composition comprising the polymorphic form, a neutral endopeptidase (EC 3.4.24).
.. 11) It relates to a method of using the polymorphic form in the treatment of various conditions and disorders in response to inhibition, as well as a method of obtaining the polymorphic form.

A polymorphic phenomenon is the presence of different crystalline forms of a single compound in a solid state. Therefore, polymorphs have the same molecular formula but have unique physical characteristics. Thus, a single compound can have different polymorphic forms, each form having different unique physical characteristics such as solubility, melting point, and / or X-ray diffraction pattern.

Biaryl-substituted phosphonic acid derivatives are known in the art and are useful as neutral endopeptidase (NEP) inhibitors, eg, inhibitors of ANF-degrading enzymes in mammals, and thereby more. By inhibiting the degradation of ANF into less active metabolites, it prolongs and enhances the diuretic, sodium diuretic and vasodilatory properties of ANF in mammals. Therefore, the NEP inhibitor is a neutral endopeptidase (
It is particularly useful for the treatment of conditions and disorders in response to inhibition of EC3.4.24.11), particularly cardiovascular disorders such as renal failure including hypertension, edema and salt retention, pulmonary edema and congestive heart failure.

Several dicarboxylic acid dipeptide neutral endopeptidase (NEP) inhibitors are GM
Kasander et al., J. Med. Chem. 1995, 38, 1689-1700, "Dicarboxylic Acid Dipeptid"
e Neutral Endopeptidase (NEP) inhibitors ".
-Carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-
The sodium salt of 4-amino- (2R) -methylbutanoic acid ethyl ester is disclosed.
The compound is actually an actual NEP inhibitor, N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid. Although in prodrug form, also referred to below as a NEP inhibitor for convenience of reference, the term also includes any of the transformations of the calcium salt described herein.

US Pat. No. 5,217,996 also contains N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenyl-phenylmethyl) -4-amino- (2R) -methylbutanoic acid. The ethyl ester and its sodium salt form are disclosed.

International Publication No. 2008/031567 generally describes N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -ethyl methylbutanoate. The reaction scheme for obtaining the calcium salt of the ester is disclosed, but the method for preparing it is not disclosed in detail.

In the pamphlet of International Publication No. 2008/083967, the calcium salt is N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-.
It is disclosed as a preferred salt of amino- (2R) -methylbutanoic acid ethyl ester.

The prior art does not describe any specific physical form of the calcium salt of AHU377 or how to prepare such form. Therefore, it is necessary to develop a defined physical form of the calcium salt of AHU377. It is also therefore important to provide the calcium salt of AHU377, which is a physical form that can be reliably prepared and purified on a large or commercial scale. Its physical form should ideally be stable and should not decompose during storage. The selected physical form must also be stable while the drug substance is manufactured as a suitable formulation for the chosen route of administration. In that respect
It may be necessary to study the physical properties of the physical form that result in handling properties or higher bulk densities. In particular, non-hygroscopicity is particularly important for obtaining good flow properties.

The properties of the final product should also be predictable and reliably reproducible. For example, materials obtained in an inconsistent manner should be carefully monitored, for example if the water content varies from batch to batch. This leads to complications in the handling, manufacturing, analysis and formulation of APIs.

While one, for example, crystalline form may exhibit properties that are considered suitable, another form also has properties that, with proper measures, may lead to successful development of the drug. Can be. Therefore, the determination of whether a compound is suitable for commercialization depends on the discovery of a (eg, crystalline) form of the compound that has the proper balance of desired characteristics.

The pharmaceutical product is affected by the delivery rate or bioavailability of the pharmaceutically active substance in different (eg crystalline or amorphous) forms or polymorphs. This relationship between different forms or polymorphs and bioavailability is known in the pharmaceutical industry and across a wide range of pharmaceutical products.

The present inventors have focused on developing advantageous forms of calcium salts and methods for their preparation.

In one aspect, the invention particularly relates to formula (I).

を有する、Ｎ－（３－カルボキシル－１－オキソプロピル）－（４Ｓ）－（ｐ－フェニル
フェニルメチル）－４－アミノ－（２Ｒ）－メチルブタン酸エチルエステル（ＡＨＵ３７
７）のカルシウム塩の結晶性または非晶質形態を調製するための方法に関する。

N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU37)
7) The present invention relates to a method for preparing a crystalline or amorphous form of a calcium salt.

In a further aspect, among other things, formula (I)

を有する、Ｎ－（３－カルボキシル－１－オキソプロピル）－（４Ｓ）－（ｐ－フェニル
フェニルメチル）－４－アミノ－（２Ｒ）－メチルブタン酸エチルエステルのカルシウム
塩を調製するための方法であって、Ｎ－（３－カルボキシル－１－オキソプロピル）－（
４Ｓ）－（ｐ－フェニルフェニルメチル）－４－アミノ－（２Ｒ）－メチルブタン酸エチ
ルエステルのナトリウム塩の溶液を、カルシウム塩、とりわけハロゲン化カルシウム、好
ましくはＣａＣｌ_２と反応させることを含む、方法が提供される。

By the method for preparing the calcium salt of N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester having. There, N- (3-carboxy-1-oxopropyl)-(
4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester solution comprising reacting with a calcium salt, particularly calcium halide, preferably CaCl ₂ . Is provided.

In a further embodiment, N- (3-carboxy-1-oxopropyl)-(4S)-(p)
An aqueous solution of a sodium salt of -phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester is prepared with a calcium salt, especially calcium halide, preferably C.
Methods are provided that include reacting with an aqueous solution of aCl ₂ .

In one aspect, the invention particularly relates to formula (I).

を有する、Ｎ－（３－カルボキシル－１－オキソプロピル）－（４Ｓ）－（ｐ－フェニル
フェニルメチル）－４－アミノ－（２Ｒ）－メチルブタン酸エチルエステルのカルシウム
塩の結晶性形態を提供する。

Provides a crystalline form of the calcium salt of N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester having. ..

In another aspect of the invention, N- (3-carboxy-1-oxopropyl)-(4S)-
(P-Phenylphenylmethyl) -4-amino- (2R) -Methylbutanoic acid ethyl ester calcium salt and N- (3-carboxy-1-oxopropyl)-(4S)-(
For preparing a calcium salt of the above compound having a ratio of p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester to calcium of 2: 1, especially one having the formula (I) shown above. By the method, a solution of a sodium salt of N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester is aqueous. Methods are provided that include reacting with a solution of a solvent, such as a calcium salt in water, in particular calcium halide, preferably CaCl ₂ .

Embodiments of these crystalline forms of the AHU377 calcium salt include those characterized herein as Metamorphosis A, Metamorphosis _B (particularly preferred), Metamorphosis C and Metamorphosis BB (favorable).

In a further aspect, the present invention presents the N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester of formula (I). Provides an amorphous form of the calcium salt of.

Each crystalline or amorphous morphology can be characterized by one or more or all of the peaks in its corresponding X-ray diffraction pattern described in the figure below.

In another aspect of the invention, there is provided a pharmaceutical composition comprising the crystalline or amorphous form described herein and one or more pharmaceutically acceptable carriers or additives. .. The composition may contain at least 50, 60, 70, 80 or 90% by weight the crystalline form of the compound of formula (I) based on the weight of the compound of formula (I) in the composition. In another aspect of the invention, the pharmaceutical composition comprises an additional therapeutic agent.

The prevalence of one type of polymorphic crystalline form can be determined by X-ray powder diffraction (XRPD) and quantification of characteristic signals in the XRPD spectrum.

In a further aspect, the crystalline or amorphous form or pharmaceutical composition described above is provided for use in the treatment or prevention of conditions and disorders in response to inhibition of neutral endopeptidase (EC 3.4.24.11). Will be done. As one aspect of the invention, such a crystalline form or thereof for producing a pharmaceutical for treating or preventing a condition and disorder associated with inhibition of neutral endopeptidase (EC 3.4.24.11). The use of such pharmaceutical compositions is also provided.

The condition or disorder (or disease) is preferably hypertension, acute heart failure, chronic heart failure, congestive heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmia, atrial fibrillation. , Atrial turbulence, harmful vascular remodeling, cardiomyopathy and its sequelae, atherosclerosis, angina (unstable or stable), renal failure (diabetic and non-diabetic), heart failure, angina, diabetes , Secondary aldosteronism, primary and secondary pulmonary hypertension,
Diabetic nephropathy, glomeruloscleritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy, migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia , Cognitive dysfunction, glaucoma and stroke.

In a further aspect, methods for treating or preventing conditions and disorders associated with inhibition of neutral endopeptidase (EC 3.4.24.11), which are described herein in need thereof. A method is provided comprising administering a therapeutically effective amount of a crystalline or amorphous form or a therapeutically effective amount of a pharmaceutical composition.

In addition, a method for producing any one of the crystalline forms, preferably transformation B, is provided.

In addition, a method for producing any one of the crystalline forms, preferably a transformed _HB , is provided.

Further embodiments and embodiments of the present disclosure are set forth in the following description and claims (these are incorporated herein by reference).

It is a figure which shows the X-ray powder diffraction (XRPD) pattern of transformation A. It is a figure which shows the X-ray powder diffraction (XRPD) pattern of transformation B. It is a figure which shows the X-ray powder diffraction (XRPD) pattern of transformation C. It is a figure which shows the X _- ray powder diffraction (XRPD) pattern of transformation HB. It is a figure which shows the X-ray powder diffraction (XRPD) pattern of the amorphous calcium salt of AHU377. It is a figure which shows the thermogravimetric analysis (TGA) of the transformation A. It is a figure which shows the thermogravimetric analysis (TGA) of the transformation B. It is a figure which shows the thermogravimetric analysis (TGA) of the transformation C. It is a figure which shows the thermogravimetric analysis (TGA) of the transformation H _B. It is a figure which shows the thermogravimetric analysis (TGA) of the amorphous calcium salt of AHU377.

The disclosure of the present invention is described herein and characterized by N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (
2R) -with respect to the crystalline form of the calcium salt of methylbutanoic acid ethyl ester (AHU377).

Definitions of the various terms used herein are listed below. The following definitions, with more specific explanations of the more general terms, and the above definitions are intended to replace one, two, more, or all of the general terms in any embodiment of the invention. It can be used, which results in further preferred embodiments of the invention, all of which should be considered disclosed herein.

As used herein, "polymorph" refers to a crystalline form that has the same chemical composition but a different spatial arrangement of molecules, atoms, and / or ions that form the crystal.

The particular crystalline form of the compound of formula (I) may be referred to as "crystalline form X", "Crystalline form X", "Polymorphic form X", "Transformation X", or "H _X ". Yes, where "X" is the letter assigned to that particular crystalline form. Corresponding names in which the "X" is replaced with a specific symbol (letter or string) are used herein.

As used herein, the term "crystalline morphology" refers to anhydrous crystalline morphology, partially crystalline morphology, mixtures of crystalline morphology, hydrated crystalline morphology and solvated crystalline morphology. include.

As used herein, the term "hydrate" refers to a crystalline form containing one or more water molecules in a three-dimensional periodic sequence. It can include non-chemical hydrates or chemical hydrates such as hemihydrates, monohydrates, dihydrates and trihydrates.

As used herein, the term "solvate" refers to the crystalline form of a molecule, atom, and / or ion that further comprises a molecule of solvent incorporated into a crystalline lattice structure. Solvent molecules in the solvate can be present in ordered and / or disordered sequences. The solvate may contain either stoichiometric or non-stoichiometric solvent molecules. For example, a solvate with a non-stoichiometric amount of solvent molecule can result from a partial loss of solvent from the solvate. Solvation is
Two or more molecules within the crystalline lattice structure or N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester ( It can exist as a dimer or oligomer containing the calcium salt of AHU377).

A hydrate is a specific variant of a solvent, also a solvent with two or more solvents other than water or a solvent with one or more solvents other than water in combination with water. , Included in the definition of "solvent" herein.

As used herein, the term "amorphous" refers to the solid form of non-crystalline molecules, atoms, and / or ions. Amorphous solids do not show a clear X-ray diffraction pattern (see, eg, FIG. 5).

As used herein, "substantially pure", when used in terms of form, exceeds 50, 60, 70, 80 or 90% by weight of compound ABC, eg, based on the weight of the compound. 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight
Means a compound having a purity greater than, and more than, for example, equal to about 100% by weight. The remaining material contains other forms of the compound and / or reaction and / or processing impurities resulting from its preparation. For example, N- (3-carboxy-1-oxopropyl)-(
The crystalline form of the calcium salt of 4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is known at this time and is generally accepted in the art. Measured by the means used, it can be considered substantially pure in that it has a purity greater than 90% by weight, where the remaining less than 10% by weight material is the other of compound ABC. Includes morphology and / or reaction impurities and / or processing impurities. The prevalence of one type of polymorphic crystalline form can be determined by X-ray powder diffraction (XRPD) and quantification of characteristic signals in the XRPD spectrum.

The term "compound of the invention" refers to N- (3-carboxy-1-oxopropyl)-.
Solid form of (4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) (particularly represented as a compound of formula (I)).
, Preferably any one, plural or all metamorphosis described in the Examples. This includes anhydrous crystalline morphology, partially crystalline morphology, mixtures of crystalline morphology, hydrated crystalline morphology and solvated crystalline morphology.

The phrase "pharmaceutically acceptable" is in contact with human or animal tissue without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio. Compounds, materials, compositions, which are considered by those of skill in the art to be suitable for use.
And / or as used herein to refer to a dosage form.

When "substantially" is used, this means that the number or other feature is essentially the same as that described after "substantially", eg ± of that number. It means that it shows a variation of 5% or is preferably the same.

When "20-25 ° C" is used, this preferably refers to about 22 ° C, more preferably 22 ° C.

The present invention includes all crystalline and pharmaceutically acceptable isotope-labeled forms of the compound of formula (I). In the isotope-labeled form, one or more atoms are replaced by atoms having the same atomic number but having an atomic mass or mass number different from the atom mass or mass number that dominates in nature. Suitable isotopes are hydrogen isotopes, such as ² H and ³ H.
, Carbon isotopes such as ¹¹ C, ¹³ C and ¹⁴ C, nitrogen isotopes such as ¹³ N and ¹⁵ N, and oxygen isotopes such as ¹⁵ O, ¹⁷ O and ¹⁸ O. Certain isotope-labeled compounds, such as those incorporating radioisotopes, are useful in the study of tissue distribution of drugs and / or substrates. The radioisotopes tritium, i.e. ^3H , and carbon-14, i.e. ^14C , are particularly useful for this purpose given their ease of incorporation and quick detection. Substitution with heavier isotopes, such as deuterium, ie ^2H ,
Certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, can therefore be preferred in some situations. Substitution with positron emission isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N may be useful in positron emission tomography (PET) studies to determine substrate receptor occupancy. Isotope-labeled compounds are generally provided by conventional techniques known to those of skill in the art, or by using appropriate isotope-labeled reagents in place of previously used non-labeled reagents. It can be prepared by a method similar to that described in.

As used herein and in the claims, the term "treatment" is used.
Including all different forms or methods of treatment known to those of skill in the art, especially prevention, cure,
It includes treatments for delaying and alleviating progression, and also includes treatments that improve the patient's condition with respect to one or more symptoms of the disease.

Solid State Physical Properties Different crystalline or amorphous morphologies can exhibit different solid state physical properties such as hygroscopicity, compaction behavior, storage stability, and solid fluidity. These properties, in turn, affect the suitability of a particular solid state form as an active pharmaceutical product for commercial production. For example, fluidity affects the ease of handling a material during processing into a pharmaceutical product. When the particles of the powdered compound do not easily flow away from each other, the pharmaceutical expert may consider when developing a tablet or capsule formulation.
That fact must be taken into account, which may require the use of flow promoters such as colloidal silicon dioxide, talc, starch or tricalcium phosphate. Compressibility and / or stability under wet or dry granulation conditions are also important features.

Different crystalline or amorphous forms of the same drug can also have substantial differences in pharmaceutically important properties such as dissolution rate and bioavailability. Dissolution rate is not only a consideration in formulating syrups, elixirs and other liquid pharmaceuticals, but may also have therapeutic importance. For example, the rate of dissolution of the active ingredient in the patient's gastric juice may have therapeutic importance as it imposes an upper limit on the rate at which the orally administered active ingredient can reach the patient's blood flow.

These practical physical properties are influenced by the conformation and orientation of the molecules in the unit cell and / or the resulting crystalline form, which can define a particular polymorphic form of the substance. Polymorphic forms can also give rise to different thermal behavior than those of amorphous materials or other polymorphic forms. Thermal behavior is measured in the laboratory by techniques such as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and is used to distinguish some polymorphic forms from others. be able to. Certain polymorphic forms can also give rise to unique spectroscopic properties that can be detected by single crystal or powder X-ray crystal analysis, solid state ¹³ C-NMR and ¹⁹ F-NMR spectroscopy and infrared spectroscopy. .. The methods used to characterize crystal morphology also include infrared spectroscopy and melting point determination.

Crystalline Forms of Compounds of Formula (I) The present invention also comprises crystalline forms of the calcium salt of AHU377, preferably from the various transformations detailed herein, preferably transformations A, _B , C and BB. Provides the crystalline form of choice.

In one embodiment, the crystalline form is selected from transformations A, _B , C and HB. In another embodiment, the crystalline form is the anhydrous / hydrated form. In another embodiment, the crystalline form is
Metamorphosis _B or Metamorphosis HB.

Each transformation, among other things, is essentially the peak depicted in the figure or the same distance as shown in the figure (2θ).
Characterized by its X-ray diffraction pattern with peaks spaced apart from each other (expressed as distance). Therefore, preferably X substantially follows what is shown in the corresponding figure.
Provided are crystalline forms selected from the various transformations detailed herein, characterized by having a linear powder diffraction pattern.

As an example, N- (3-carboxy-1-oxopropyl)-(4S)-, which is a form of transformation B characterized by a powder X-ray diffraction pattern substantially following that shown in FIG.
A crystalline form of the calcium salt of (p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377), which preferably has formula I, is provided.

Alternatively, each transformation is characterized by an X-ray diffraction pattern with the characteristic peaks listed in its corresponding table. In a further embodiment, the invention has an angular variation of ± 0.3.
Provided are any of the crystalline forms of the compounds of formula (I) described herein, which are ° 2θ, or ± 0.2 ° 2θ, or ± 0.15 ° 2θ.

In a further embodiment, the invention is presented in each Example at a temperature of 20-25 ° C.7
Four, five or more or all 2θ values (± 0.1 °) selected from the group consisting of two 2θ values
) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å) of the crystalline form of the compound of formula (I) after or in the Examples below, characterized by a powder diffraction pattern. Provide either.

As an example, at a temperature of 20 to 25 ° C, 4.6, 6.0, 7.1, 9.3, 11.1, 1
2.0, 12.6, 14.0, 14.4, 14.7, 15.5, 16.6, 18.1, 1
2θ value (± 0.1) selected from the group consisting of 9.6, 20.7, 21.1, 21.6, 22.5, 24.6, 25.3, 25.5, and 31.5. °) (CuKα; 45kV, 4
N- (3-carboxy-1-oxopropyl)-(4S)-(4S)-(3-carboxyl-1-oxopropyl)-(4S)-(4S)-(3-carboxyl-1-oxopropyl)-(4S)-(3.
A crystalline form of the calcium salt of p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

As an example, at a temperature of 20-25 ° C, 4.6 (particularly preferred), 6.0 (particularly preferred), 12.6, 15.5, 16.6, 18.1, 19.6 and 22.5. 4, 5, 6 or more 2θ values (± 0.1 °) (CuKα; 45k) selected from the group consisting of
N- (3-carboxy-1-oxopropyl)-(4S), a form of transformation B characterized by a powder X-ray diffraction pattern containing V, 40 mA; λ = 1.540598 Å).
)-(P-Phenylphenylmethyl) -4-amino- (2R) -Methylbutanoic acid ethyl ester (AHU377) provides a crystalline form of the calcium salt.

As an example, at a temperature of 20 to 25 ° C, 4.6, 6.0, 12.6, 15.5, 16.6
, 18.1, 19.6 and 22.5 selected from the group consisting of 7 or more 2θ values (± 0).
.. N- (3-carboxy-1), a form of transformation B, characterized by a powder X-ray diffraction pattern containing 1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å).
-Oxopropyl)-(4S)-(p-Phenylphenylmethyl) -4-amino- (2R)
)-A crystalline form of the calcium salt of methylbutanoic acid ethyl ester (AHU377) is provided.

In a further embodiment, the invention is presented in each Example at a temperature of 20-25 ° C.7
Five or more 2θ values (± 0.1 °) (CuKα; 45) selected from the group consisting of two 2θ values.
Provided is one of the crystalline forms of the calcium salt of AHU377 described in the Examples, further characterized by a powder diffraction pattern comprising kV, 40 mA; λ = 1.540598 Å).

In a further embodiment, the invention has the following features:
(A) Seven 2θ values (± 0.1 °) presented for each transformation at a temperature of 20 to 25 ° C.
4 or more 2θ values (± 0.1 °) (CuKα; 45kV, 40) selected from the group consisting of
An X-ray powder diffraction pattern, substantially following those shown in the figure associated with XRPD or its particular transformations, comprising mA; λ = 1.540598 Å).
(B) Melting point presented for each transformation in the section of Examples,
(C) The calcium salt of AHU377 described in Example, which is a specific form of transformation, characterized by having at least one of the differential thermal analysis thermograms presented for each transformation in the section of Examples. Provides any of the crystalline forms of.

Therefore, as an example, the following features:
(A) At a temperature of 20 to 25 ° C., 4.6, 6.0, 12.6, 15.5, 16.6, 18
.. 4 or more 2θ values (± 0.1 °) selected from the group consisting of 1, 19.6 and 22.5
) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å) and an X-ray powder diffraction pattern substantially according to that shown in FIG.
(B) Melting point starting at 173 ° C (± 2.4 ° C),
(C) Differential thermal analysis thermogram with endothermic starting at 173 ° C (± 2.5 ° C),
(D) N- (3-carboxy-1-oxopropyl)-(3-carboxyl-1-oxopropyl)-(d), a form of transformation B, characterized by at least one of the thermogravimetric analysis (TGA) diagrams that are substantially the same as those shown in FIG. 4S)-(p-Phenylphenylmethyl) -4-amino-
A crystalline form of the calcium salt of (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

In a further aspect of the invention, there is provided a form consisting essentially of each transformation of the calcium salt of AHU377, or a substantially pure form of each transformation, in particular a form of transformation _B or transformation HB. As used herein, "being essentially from each transformation" or "substantially pure", when used with respect to crystalline form, is a compound of formula (I) based on the weight of the compound. More than 50, 60, 70, 80 or 90% by weight, eg 90, 91, 92, 93,
Means compounds having a purity greater than 94, 95, 96, 97, 98, and 99% by weight, further equal to, for example, about 100% by weight. The prevalence of one type of polymorphic crystalline form can be determined by X-ray powder diffraction (XRPD) and quantification of characteristic signals in the XRPD spectrum. The remaining material contains other forms of the compound and / or reaction and / or processing impurities resulting from its preparation. For example, the crystalline form of the compound of formula (I) is known at this time and is measured by means generally accepted in the art in that it has a purity greater than 90% by weight. Can be considered substantially pure in the above, where the remaining less than 10% by weight material comprises other forms of the compound of formula (I) and / or reaction impurities and / or processing impurities.

In other embodiments, the desired transformation is at least 80, 85, 90, 95 or 99% by weight.
A crystalline form containing is provided.

A crystalline form containing at least 95 or 99% by weight of the desired transformation is also provided. Thus, as an example, each of the preferred transformations, especially transformation B, is at least 95 or 9
A crystalline form containing 9% by weight is provided.

As an example, at a temperature of 20 to 25 ° C, 3.6, 6.1, 6.4, 7.6, 8.4, 10
.. 8, 11.3, 12.8, 14.6, 15.3, 16.8, 17.8, 19.7, 20
.. 2θ value selected from the group consisting of 6, 21.4, 22.5, 23.4 and 24.8 (
Powder X containing ± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å)
N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4 _- amino-, which is a form of metamorphic HB characterized by a linear diffraction pattern.
A crystalline form of the calcium salt of (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

As an example, at a temperature of 20 to 25 ° C, 3.6, 6.4, 8.4, 14.6, 15.3,
4, 5, 6 selected from the group consisting of 16.8, 17.8, 19.7 and 20.6
One or more 2θ values (± 0.1 °) (CuKα; 45kV, 40mA; λ = 1.5
N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino, which is a form of transformed HB characterized by a powder X-ray diffraction pattern containing ₄₀₅₉₈ Å). -(2R) -Methylbutanoic acid ethyl ester (AHU377)
A crystalline form of the calcium salt of is provided.

As an example, at a temperature of 20 to 25 ° C, 3.6, 6.4, 8.4, 14.6, 15.3,
7 or more 2θs selected from the group consisting of 16.8, 17.8, 19.7 and 20.6
N- (3-carboxy _- 1- A crystalline form of the calcium salt of oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

In a further embodiment, the invention is presented in each Example at a temperature of 20-25 ° C.7
Five or more 2θ values (± 0.1 °) (CuKα; 45) selected from the group consisting of two 2θ values.
Provided is one of the crystalline forms of the calcium salt of AHU377 described in the Examples, further characterized by a powder diffraction pattern comprising kV, 40 mA; λ = 1.540598 Å).

Therefore, as an example, the following features:
(A) At a temperature of 20 to 25 ° C., 3.6, 6.4, 8.4, 14.6, 15.3, 16.
4 or more 2θ values (±) selected from the group consisting of 8, 17.8, 19.7 and 20.6
X-ray powder diffraction pattern, comprising 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å) or substantially following that shown in FIG.
(B) Melting point starting at 180 ° C (± 2.4 ° C),
( _D ) N- (3-carboxyl-, a form of transformed HB, characterized by having at least one differential thermal analysis thermogram having endothermic starting at 180 ° C. (± 2.5 ° C.). A crystalline form of the calcium salt of 1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

As an example, at a temperature of 20 to 25 ° C, 3.6, 5.1, 10.7, 11.7, 12.2
, 13.1, 15.1, 15.8, 17.3, 17.8, 20.7, 21.7, 23.0
2θ value (± 0.1 °) selected from the group consisting of 2,5.0 and 26.8 (CuKα;
N- (3-carboxy-1-oxopropyl)-, a form of transformation A, characterized by a powder X-ray diffraction pattern containing 45 kV, 40 mA; λ = 1.540598 Å).
A crystalline form of the calcium salt of (4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

As an example, at a temperature of 20 to 25 ° C, 3.6, 5.1, 15.1, 15.8, 17.3
, 17.8, 20.7 and 21.7 selected from the group consisting of 4, 5, 6 or more 2θ values (± 0.1 °) (CuKα; 45kV, 40mA; λ = 1). .54059
N-, a form of transformation A, characterized by a powder X-ray diffraction pattern containing 8 Å).
The crystalline form of the calcium salt of (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) Provided.

As an example, at a temperature of 20 to 25 ° C, 3.6, 5.1, 15.1, 15.8, 17.3
, 17.8, 7 or more 2θ values (± 0) selected from the group consisting of 20.7 and 21.7.
.. N- (3-carboxy-1), a form of transformation A, characterized by a powder X-ray diffraction pattern containing 1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å).
-Oxopropyl)-(4S)-(p-Phenylphenylmethyl) -4-amino- (2R)
)-A crystalline form of the calcium salt of methylbutanoic acid ethyl ester (AHU377) is provided.

In a further embodiment, the invention is the seven two presented in each example at a temperature of about 22 ° C.
Five or more 2θ values (± 0.1 °) selected from the group consisting of θ values (CuKα; 45kV,
N- (3-carboxy-1-oxopropyl)-(4S)-described in the Examples, further characterized by a powder diffraction pattern comprising 40 mA; λ = 1.540598 Å).
(P-Phenylphenylmethyl) -4-amino- (2R) -Methylbutanoic acid ethyl ester (AHU377) provides any of the crystalline forms of the calcium salt.

As an example, the following features:
(A) At a temperature of about 22 ° C., 3.6, 5.1, 15.1, 15.8, 17.3, 17.8,
4 or more 2θ values (± 0.1 °) selected from the group consisting of 20.7 and 21.7 (C)
X-ray powder diffraction pattern, comprising uKα; 45 kV, 40 mA; λ = 1.540598 Å) or substantially following that shown in FIG.
(B) Melting point starting at 192 ° C (± 2.4 ° C),
(C) N- (3-carboxy-1-oxopropyl), a form of transformation A, characterized by at least one differential thermal analysis thermogram with endothermic starting at 192 ° C (± 2.5 ° C). )-(4S)-(p-Phenylphenylmethyl) -4-amino-
A crystalline form of the calcium salt of (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

As an example, at a temperature of 20 to 25 ° C, 4.6, 6.2, 14.5, 15.4, 20.4
, 2θ value (± 0.1 °) selected from the group consisting of 21.7 and 22.1 (CuKα;
N- (3-carboxy-1-oxopropyl)-, a form of transformation C, characterized by a powder X-ray diffraction pattern containing 45 kV, 40 mA; λ = 1.540598 Å).
A crystalline form of the calcium salt of (4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

As an example, at a temperature of 20 to 25 ° C, 4.6, 6.2, 14.5, 15.4, 20.4
, 2, 5, 6 or more 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å) selected from the group consisting of 21.7 and 22.1. N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R), a form of transformation C characterized by a powder X-ray diffraction pattern containing -A crystalline form of the crystalline form of the calcium salt of methylbutanoic acid ethyl ester (AHU377) is provided.

As an example, at a temperature of 20 to 25 ° C, 4.6, 6.2, 14.5, 15.4, 20.4
, 22.7 and 7 2θ values (± 0.1 °) selected from the group consisting of 22.1 (Cu)
N- (3-carboxy-1-oxopropyl)-(4S)-(p), a form of transformation C, characterized by a powder X-ray diffraction pattern containing Kα; 45 kV, 40 mA; λ = 1.540598 Å). A crystalline form of the calcium salt of −phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester is provided.

Therefore, as an example, the following features:
(A) 4.6, 6.2, 14.5, 15.4, 20.4, 21 at a temperature of 20 to 25 ° C.
.. 4 or more 2θ values (± 0.1 °) (CuK) selected from the group consisting of 7 and 22.1
An X-ray powder diffraction pattern, comprising (α; 45 kV, 40 mA; λ = 1.540598 Å) or substantially following that shown in FIG.
(B) Melting point starting at 180 ° C (± 2.4 ° C),
(C) N- (3-carboxy-1-oxopropyl), a form of metamorphic C, characterized by at least one differential thermal analysis thermogram with endothermic starting at 180 ° C (± 2.5 ° C). )-(4S)-(p-Phenylphenylmethyl) -4-amino-
A crystalline form of the calcium salt of (2R) -methylbutanoic acid ethyl ester is provided.

As an example, at a temperature of 20 to 25 ° C, a 2θ value (± 0.1 °) of 3.7 (CuKα; 45).
N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino, characterized by a powder X-ray diffraction pattern containing kV, 40 mA; λ = 1.540598 Å) An amorphous form of the calcium salt of-(2R) -methylbutanoic acid ethyl ester is provided.

Therefore, as an example, the following features:
(A) At a temperature of 20 to 25 ° C., a 2θ value (± 0.1 °) of 3.7 (CuKα; 45 kV,
A powder X-ray diffraction pattern containing 40 mA; λ = 1.540598 Å) or an X-ray powder diffraction pattern substantially following that shown in FIG. 5 without characteristic peaks.
(B) Melting point starting at 204 ° C (± 2.4 ° C),
(C) N- (3-carboxy-1-oxopropyl)-(4S) characterized by having at least one of the differential thermal analysis thermograms having endothermic starting at 204 ° C (± 2.5 ° C). )-(P-Phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester is provided in an amorphous form of the calcium salt.

Preparation of Crystalline Form of Calcium Salt of AHU377 In a further aspect, the invention provides a method of making a calcium salt transformation HB of _AHU377 starting from an AHU377 alkali metal salt, such as a sodium salt.

In a further aspect, the invention provides a method of starting with transformation HB to produce transformation _B , or the use of transformation HB to produce transformation _B.

The present invention provides a method for making a calcium salt transformation _B of AHU377, starting from the AHU377 transformation HB.

In a further aspect, the invention provides a method of producing transformation B from the calcium salt of AHU377.

In a further aspect, the invention starts with the amorphous calcium salt of AHU377 and transforms A.
Provided is a method for producing the above, or the use of an amorphous calcium salt of AHU377 for producing the transformation A.

In a further aspect, the invention starts with the amorphous calcium salt of AHU377 and transforms C.
Provided is a method for making the above, or the use of an amorphous calcium salt of AHU377 to generate the transformation C.

In a further aspect, the invention starts with the sodium salts of AHU377 and AHU377.
Provided is a method for making an amorphous calcium salt of AHU 377, or the use of a sodium salt of AHU 377 for producing an amorphous calcium salt of AHU 377.

In a further aspect, the invention provides the use of any of the crystalline forms described herein to produce another crystalline form. Preferably, the transformation HB is used to produce another crystalline form and more preferably to the transformation _B.

The present invention is also a method for preparing transformation B, which is a calcium salt of AHU377,
In particular, the compound of formula (I), for example in the form of transformation HB, is dispersed or slurryed in a solvent system, the resulting mixture is heated and refluxed, cooled, seed crystals of transformation _B are added, and a suspension is added. Provide a method of stirring, filtering the resulting solid, and drying the resulting residue after filtration.

Alternatively, the solvent system may be a single solvent system and the solvent comprises ethanol, preferably absolute ethanol, or even heptane or 2-propanol.

Transformation B also prepares Transformation B using crystallization of AHU377 from a clear solution.
Can be obtained using the method. This is a requirement imposed by some drug regulatory authorities in that clear filtration from a clear solution is performed in the API generation step itself to remove insoluble particles, eg, the suitability of the Food and Drug Administration. It has the major advantage of directly enabling compliance with Good Manufacturing Practice (GMP) requirements.

The same filtration can be performed prior to any other crystallization of the transformation of the AHU377 calcium salt described herein.

Therefore, the present invention is also a method for preparing transformation B using a recrystallization method.
(A) A step of dissolving the compound of the formula (I) in a solvent, preferably ethanol,
(B) A step of heating the reaction mixture to a temperature between 60 ° C. and the reflux temperature.
(C) A step of cooling the reaction mixture to 40-80 ° C, for example 50 ± 5 ° C.
(D) Optional step of adding the seed crystal of transformation B, and
(E) With the step of stirring the reaction mixture, optionally (or preferably), preferably for at least 12 hours.
(F) A step of filtering a solid from the mixture obtained at the end of steps (c), (d) or (e), and
(G) Provided is a method including, optionally, a step of drying the crystals.

The present invention is also a method for preparing a transformed _HB using crystallization and recrystallization methods.
(A) A step of concentrating a solution of the sodium salt of AHU377 in a solvent system by heating the reaction mixture under reduced pressure, wherein the solvent system is water.
(B) The step of diluting the reaction mixture with water and
(C) A step of heating the reaction mixture to 65 to 95 ° C, for example 83 ± 5 ° C.
(D) The step of adding the calcium chloride aqueous solution and
(E) A step of stirring the reaction mixture at 65 to 95 ° C., for example 83 ± 5 ° C. for at least 4.5 hours.
(F) A step of cooling the reaction mixture to 65 ± 5 ° C.
(G) A step of heating the reaction mixture to 65 to 95 ° C, preferably 83 ± 5 ° C.
(H) A step of repeating these cycles at least three times,
(I) A step of cooling the reaction mixture to at least 40-80 ° C, eg 50 ± 5 ° C.
(J) A step of filtering the mixture obtained at the end of step (h), and
(K) Provided is a method including, optionally, a step of drying the crystals.

Therefore, the present invention is also a method for preparing a transformed _HB using crystallization and recrystallization methods.
(A) A step of heating a solution of the sodium salt of AHU377 in a solvent system, wherein the solvent system is water.
(B) The step of adding isopropyl acetate to the reaction mixture and
(C) A step of heating the reaction mixture to 65 to 95 ° C, for example 83 ± 5 ° C.
(D) The step of adding the calcium chloride aqueous solution and
(E) A step of stirring the reaction mixture (eg, at least 15 hours) to 50 ± 5 ° C.
(F) The step of filtering the mixture obtained at the end of step (e), and
(G) The step of suspending the solid obtained in step (f) in a solvent system, wherein the solvent system is water and isopropyl acetate.
(H) The reaction mixture is stirred (eg at least 20 minutes) at 40-80 ° C, eg 50.
Steps to ± 5 ° C and
(I) The step of filtering the mixture obtained at the end of step (h), and
(J) The step of suspending the solid obtained in step (i) in a solvent system, wherein the solvent system is water.
(K) A step of stirring the reaction mixture for at least 20 minutes to 40-80 ° C, for example 50 ± 5 ° C.
(L) The step of filtering the mixture obtained at the end of step (k), and
(M) Provided is a method including, optionally, a step of drying the crystals.

Administration and Pharmaceutical Preparations The compounds of the invention are usually orally, intravenously, subcutaneously, buccal, transrectally, transdermally, nasally, transtracheally, transbronchially. Is administered orally or as a nasal spray or via inhalation by any parenteral route. Parenteral administration methods include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intra-articular injections and infusions. Suitable pharmaceutical compositions for the delivery of the compounds of the invention and methods for their preparation are, for example, Remington's Pharmaceut.
It can be found in ^ical Sciences, 19th Edition, Mack Publishing Company, 1995.

The compounds of the invention can be orally administered. Advantageously, the compounds of the invention are orally active and may have rapid onset of activity and low toxicity. Oral administration may be accompanied by swallowing so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used in which the compound enters the bloodstream directly through the mouth.

Examples of formulations suitable for oral administration include solid formulations such as tablets, microparticles, liquids, or capsules containing powders, troches (including filled with liquids), chewing agents, mulch and nanoparticles, gels, etc. Solid solutions, liposomes, films, ovules, sprays and liquid formulations.

Examples of liquid formulations include suspensions, liquids, syrups and elixirs. These may be used as fillers in soft or hard capsules, typically with carriers such as water.
Includes ethanol, polyethylene glycol, propylene glycol, methylcellulose, or suitable oils, as well as one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared, for example from sachets, by solid reconstitution.

The injectable composition is preferably an aqueous isotonic solution or suspension, and the suppository is advantageously prepared from a fatty emulsion or suspension. The composition may be sterile and / or contains an adjuvant such as a preservative, stabilizer, wetting or emulsifying agent, lysis accelerator, and salt and / or buffer for regulating osmotic pressure. You may. In addition, they may also contain other therapeutically beneficial substances. The compositions are prepared according to conventional mixing, granulation or coating methods, respectively, and contain about 0.1-75%, preferably about 1-50% of the active ingredient.

Suitable formulations for transdermal application contain therapeutically effective amounts of the compounds of the invention with the carrier. Advantageous carriers include absorbent, pharmacologically acceptable solvents that aid in the passage of the host's skin. Characteristically, the transdermal device comprises a lining member, a reservoir containing the compound optionally with a carrier, and optionally a rate control to deliver the compound to the skin of the host at a controlled and predetermined rate over a long period of time. It is a form of bandage that includes a barrier and a means of fixing the device to the skin.

The compound may be administered alone or as a composition in combination with a pharmaceutically acceptable excipient, additive or carrier. Accordingly, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention alone or in combination with one or more pharmaceutically acceptable carriers (additives). The combination partner is, for example, an angiotensin receptor blocker (A).
RB), preferably ARB selected from the group consisting of losartan, irbesartan, candesartan, eprosartan, thermisartan, olmesartan and balsartan, preferably balsartan, or pharmaceutically acceptable salts thereof.

Most preferably, the compound AHU377 (sakubitril) is a complex with valsartan,
In particular, hexakis (4-{[(1S, 3R) -1-([1,1'-biphenyl] -4-
Ilmethyl) -4-ethoxy-3-methyl-4-oxobutyl] amino} -4-oxobutanoic acid) Hexakis (N-pentanoyl-N-{[2'-(1H-tetrazole-1-id-5-yl)] [ 1,1'-biphenyl] -4-yl] methyl} -L-valine) 18 sodium-can be part of water (1/15), which is International Publication No. 20.
It can be synthesized according to the 07/056546 pamphlet and disclosed in the same document. The AHU377 calcium salt of the present invention can advantageously be used to prepare this complex.

The compounds of the invention, eg, any one of various transformations, eg, crystalline forms, may be used alone or in combination with one or more carriers or additives or other pharmaceutically active ingredients, or in combination thereof. It can be formulated to provide a suitable formulation for the treatment of the indications identified above.

Examples of such carriers or additives include, but are not limited to, any one or more of the following:
a) Excipients such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine,
b) Lubricants such as silica, talcum, stearic acid, magnesium or calcium salts thereof and / or polyethylene glycol,
c) Binders such as magnesium aluminum silicate, starch paste, gelatin,
Tragacanth, Methyl Cellulose, Sodium Carboxymethyl Cellulose and / or Polyvinylpyrrolidone,
d) Disintegrants such as starch, agar, alginic acid or sodium salts thereof, or effervescent mixtures, and e) absorbers, colorants, flavoring agents and / or sweeteners.

Additional examples of useful additives are in the Handbook of pharmaceuticals preferablys, 3rd edition,
edited by AH Kibbe, published by the American Pharmaceutical Association, Was
hington DC, ISBN: 0-917330-96-X, or Handbook of Pharmaceutical Excipients (4 ^t)
h edition), edited by Raymond C. Rowe, published by Science and Practice, which are incorporated herein by reference or provided solely as the basis for reference.

Depending on the disorder to be treated and the patient and route of administration, the composition may be administered at equal or variable doses. Generally, the daily dose range of the compounds of the invention, in single or divided doses, is from about 0.0001 mg / kg to about 100 mg / kg, preferably from about 0.001 mg / kg to about 50 mg / kg per body weight of the subject. It is within range. On the other hand, in some cases it may be necessary to use doses outside these limits.

When an oral composition is used, the preferred dosage range of the compounds of the invention is, for example, from about 0.001 mg / kg to about 100 mg / kg body weight of the subject in the composition per day, preferably about 0 mg / kg per day. It is from 01 mg to about 2000 mg. For oral administration, the composition
Preferably 0.01 mg to 2000 mg, for example 0.01, 0.05, 0.1, 0
.. 2,0.5,1.0,2.5,10,15,20,25,30,40,50,75
, 80 mg, provided in the form of tablets.

In one embodiment, the compounds of the invention are used / formulated at doses of 1 to 2000 mg, 1 to 1000 mg, 2 to 500 mg, 5 to 500 mg, 10 to 400 mg, or 20 to 300 mg. In another embodiment, the NEP inhibitor is 5, 10, 15, 20, 25,
Used in doses of 30 40, 50, 100 or 200 mg. In a preferred embodiment, the NEP inhibitor is 50, 100, or 200 mg, based on the amount of compound of formula (I).
Used in doses of.

It should be understood that the doses cited herein refer to free forms of NEP inhibitors (not as salts). If a pharmaceutically acceptable salt of the NEP inhibitor is used, the dose used should be adjusted accordingly.

The present invention further comprises the pharmaceutical compositions described herein, preferably tablets or gelatin capsules, comprising the second active ingredient (ie, combination partner) described in the "Combination Therapy" section below. offer.

Accordingly, the present invention provides the pharmaceutical compositions described herein for use as pharmaceuticals. For use in the treatment of disorders or conditions associated with NEP inhibitory activity,
The pharmaceutical compositions described herein are also provided. Also provided are pharmaceutical compositions described herein for producing a pharmaceutical for treating a disorder or condition associated with NEP inhibitory activity.

Also provided are methods of preventing or treating disorders or conditions associated with NEP inhibitory activity, comprising administering a therapeutically effective amount of the composition to a subject in need of such treatment.

Use As described above, the compounds of the invention may be useful in treating or preventing disorders or conditions mediated by NEP inhibitory activity in animals, especially humans.

Accordingly, the invention is also a method for treating or preventing a condition or disorder associated with NEP inhibitory activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention. , Provide a method.

Accordingly, the invention is the invention alone or in combination with another therapeutic agent (see below) for producing a pharmaceutical for treating or preventing a condition or disorder associated with NEP inhibitory activity in animals, especially humans. Provides the use of the compounds of. NEP in animals, especially humans
Also provided are compounds of the invention for use in the treatment or prevention of conditions or disorders associated with inhibitory activity, alone or in combination with another therapeutic agent (see below).

[Example]
The following examples illustrate the present invention without limitation.

The following abbreviations are used herein.

Other abbreviations used are those commonly used in the art.

Methods, equipment and criteria used (i) X-ray powder diffraction (XRPD)
The X-ray powder diffraction pattern was determined using a Bruker D8 discovery diffractometer device. The X-ray diffraction pattern is 2 using CuK radiation (45 kV, 40 mA).
Recorded between ° and 35 ° (2θ). The measurements are about 45 kV and 40 under the following conditions:
Conducted at mA:
Scanning speed: 0.5 ° (2θ) / min Chopper increment: 0.02 °
Slit (from left to right): 2, 3, 0.3, 0.2 mm

The spectrum was recorded in reflection mode.

The XRPD profile of each solid form is shown in the figure.

The characteristic peaks of the compounds of the invention are listed herein in the table below and are shown in the figures. The peaks listed herein are shown in degrees 2θ (± 0.2 °, preferably ± 0.1 °).

As will be appreciated by those skilled in the art, the relative intensities of the various peaks in the table shown below may be, for example, the effect of crystal orientation on an X-ray beam, or the purity of the material being analyzed, or the crystallinity of the sample. It can vary due to a number of factors. Peak positions can also shift with respect to sample height fluctuations, but peak positions remain substantially as defined in the given table. It will also be appreciated by those skilled in the art that measurements using different wavelengths will result in different shifts according to the Bragg equation −nλ = 2d sin θ. Such alternative XRPD patterns produced by the use of alternative wavelengths still represent the same material.

(Ii) Thermal weight / differential thermal analysis (TG / DTA)
The differential scanning calorimetry is performed by TA Instruments ™ model Q1000 (TA).
Instruments, New Castle, DE, USA) were used to perform each crystalline form. 100 mL / DSC cell / sample chamber for each analysis
Purged with ultra-high purity nitrogen gas. The instrument was calibrated with high purity indium. The heating rate is
In the temperature range between 25 and 300 ° C, it was 10 ° C per minute. The heat flow normalized by sample weight was plotted against the measured sample temperature. Data were reported in watts / gram (“W / g”) units. The plot was created with a downward endothermic peak. The endothermic melting peak (melting point) was evaluated for extrapolation manifestation temperature.

As used herein, "a concentrate of a given transformation in a given solvent (X), another solvent (
The term "adding Y)" means that a given transformation is carried out at a high concentration (> 75 mg /) in the former solvent (X).
It means that the solution obtained after dissolving in ml) and the latter solvent (Y) are added to initiate crystallization.

Calcium salt (AHU) of N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester
377 calcium salt)
To the mixture of AHU377 free acid (17.7 g) in isopropyl acetate (190 mL),
By adding solid sodium hydroxide (1.9 g), AHU377 sodium salts are obtained and used directly in the production of calcium salts. The mixture is stirred at 25 ° C. for 70 minutes to give a turbid mixture. Solid calcium chloride (2.4 g) is added, followed by seeding of AHU377 transformation B (eg, obtained as described in Example 2) at room temperature. The white suspension is stirred at 25 ° C. for 20 hours, then filtered, washed with isopropyl acetate and under reduced pressure 50.
After drying at ° C., a solid AHU377 calcium salt is obtained.

Hentai B
AHU377 calcium salt (2500 g) from Examples 3, 7 or 8 is suspended in absolute ethanol (60 L) at room temperature. The reaction mixture is heated (reflux) to 78 ° C. over 30 minutes, then further stirred at this temperature for 30 minutes and then cooled to 50 ° C. over 30 minutes. Hentai B
Seed crystals (2 g) are added and the suspension is stirred for 12-18 hours. The solid is filtered at 50 ° C and
Wash with absolute ethanol (9.5 L) and dry at 60 ° C. under reduced pressure to give AHU377 calcium salt, transformation B.

When characterized by X-ray powder diffraction, transformation B gives the pattern shown in FIG. The characteristic peaks (± 0.1 °) are shown in the table below.

X-ray diffraction changes depending on the hydration level of transformation B. The above X-ray pattern is obtained under ambient conditions, ie, at temperatures between 20 ° C and 25 ° C and relative humidity between 40% and 65%.

The data listed below show total solvent loss (LOD by thermogravimetric analysis (TG)).
Thermal transition (DTA signal) indicates the temperature at which the solvent is lost. Transformation B exhibits one endothermic at 173 ° C, suggesting this crystalline morphology.

Characteristics of Transformation B Transformation B is highly crystalline and very slightly hygroscopic under typical humidity levels (7).
Up to 5% RH <2%). Metamorphosis B is highly crystalline and very slightly hygroscopic at typical humidity levels (<2% up to 75% RH). Transformation B is thermally stable up to its melting point. The water uptake rate of metamorphosis B can reach up to 11%. Hydrate formation was observed by wet granulation with water or equilibration in water with ethanol / water 1: 1.

AHU377 Calcium Salt-Amorphous Synthetic A solution of AHU377 sodium salt (4.33 g) in water (40 mL) is treated with a solution of calcium chloride (0.74 g) in water (10 mL) at 25 ° C. 2 of the obtained suspension
Further agitate at 5 ° C. for 2 hours and then filter. The filtered cake is washed with water (10 mL) and then dried under reduced pressure at 50 ° C. to give the amorphous AHU377 calcium salt.

Amorphous AHU377 calcium salt gives the pattern shown in FIG. 5, when characterized by powder X-ray diffraction. The characteristic peaks (± 0.1 °) are shown in the table below.

The data listed below show total solvent loss (LOD by thermogravimetric analysis (TG)).
Thermal transition (DTA signal) indicates the temperature at which the solvent is lost. The amorphous AHU377 calcium salt exhibits one endothermic at 204 ° C, suggesting this morphology.

Characteristics of Amorphous AHU377 Calcium Salt Wet granulation of amorphous AHU377 calcium salt results in rapid hydrate formation. Upon exposure to high humidity (> 75% RH), the amorphous AHU377 calcium salt becomes a crystalline hydrate.

Amorphous AHU377 calcium salt exhibits a water uptake rate of 15.2% at 80% RH. 1
No change in amorphous morphology was observed by XRPD after compression or grinding at 0 t for 5 minutes. Wet granulation of the amorphous AHU377 calcium salt results in rapid hydrate formation. Upon exposure to high humidity (> 75% RH), the amorphous AHU377 calcium salt becomes a crystalline hydrate.

Synthesis of AHU377 Calcium Salt-Transformation A Amorphous AHU377 calcium salt is dissolved in absolute ethanol at 25 ° C. Stirring at 25 ° C. causes precipitation of the solid AHU377 calcium salt. The solid is filtered and dried under reduced pressure to give AHU377 calcium salt, transformation A.

When characterized by X-ray powder diffraction, transformation A gives the pattern shown in FIG. The characteristic peaks (± 0.1 °) are shown in the table below.

X-ray diffraction changes depending on the hydration level of transformation A. The above X-ray pattern is obtained under ambient conditions, ie, at temperatures between 20 ° C and 25 ° C and relative humidity between 40% and 65%.

The data listed below show total solvent loss (LOD by thermogravimetric analysis (TG)).
Thermal transition (DTA signal) indicates the temperature at which the solvent is lost. Transformation A exhibits one endothermic at 192 ° C, suggesting this crystalline morphology.

Characteristics of Metamorphosis A Metamorphosis A is hygroscopic.

Metamorphosis A exhibits a water uptake rate of 13.8% at 95% RH.

Synthesis of AHU377 Calcium Salt-Transformation C Amorphous AHU377 calcium salt is dissolved in acetonitrile at 50 ° C. Stirring at 50 ° C. causes precipitation of the solid AHU377 calcium salt. The solid is filtered and dried under reduced pressure to give AHU377 calcium salt, transformation C.

When characterized by X-ray powder diffraction, transformation C gives the pattern shown in FIG. The characteristic peaks (± 0.1 °) are shown in the table below.

X-ray diffraction changes depending on the level of hydration with the transformation C. The above X-ray pattern is obtained under ambient conditions, ie, at temperatures between 20 ° C and 25 ° C and relative humidity between 40% and 65%.

The data listed below show total solvent loss (LOD by thermogravimetric analysis (TG)).
Thermal transition (DTA signal) indicates the temperature at which the solvent is lost. Transformation C exhibits one endothermic at 180.0 ° C, suggesting this crystalline morphology.

AHU377 Calcium Salt-Synthesis of Metamorphic HB, Procedure 1
A solution of AHU377 sodium salts (20.37 g) in water (120 mL) (sodium salts prepared according to the procedure shown in Example 8) is concentrated under reduced pressure at 50 ° C. to remove all residual isopropyl acetate. .. After concentration, the solution is diluted with water to its original volume. AHU37
7 The aqueous sodium salt solution is heated to 83 ° C. over 30 minutes, then a solution of calcium chloride (2.61 g) in water (104 mL) is added over 1 hour. The resulting suspension is stirred at 83 ° C. for 4.5 hours. The temperature is lowered to 65 ° C. over 90 minutes and then raised again to 83 ° C. over 30 minutes. This cycle is repeated 3 more times. The reaction mixture is then cooled to 50 ° C. over 2 hours and further stirred at this temperature for 2 hours. The crystals are filtered off at 50 ° C. and the filtered cake is washed with water at 50 ° C. (2 x 65 mL). The solid is dried under reduced pressure at 60 ° C. to AH.
Obtain _U377 calcium salt, metamorphosis HB.

When characterized by X _- ray powder diffraction, the transformation HB gives the pattern shown in FIG. The characteristic peaks (± 0.1 °) are shown in the table below.

X _- ray diffraction varies with the hydration level of the transformed HB. The above X-ray pattern is obtained under ambient conditions, ie, at temperatures between 20 ° C and 25 ° C and relative humidity between 40% and 65%.

Metamorphosis HB is particularly suitable for industrial scale _- up. This is a crystalline form that remains dry at 25 ° C. and relative humidity in the range 0% to 80%.

The data listed below show total solvent loss (LOD by thermogravimetric analysis (TG)).
Thermal transition (DTA signal) indicates the temperature at which the solvent is lost. Metamorphosis H _B is 98 ° C, 134
It shows three endotherms at ° C and 180 ° C, suggesting this crystalline form.

Characteristics of Metamorphic H _B Metamorphic H _B is obtained at water levels in the range 1.4-4.1%. 97 ° C for complete dehydration
Super heating is required and melt decomposition begins above 180 ° C. Metamorphosis _HB exhibits good fluidity properties.

The water uptake rate of the metamorphic _HB at 95% RH is 2.0%. The metamorphic HB is retained during water uptake and release (eg, in adsorption _- desorption experiments).

AHU377 Calcium Salt-Synthesis of Metamorphic HB, Procedure 2
A solution of AHU377 sodium salt (20.37 g) in water (120 mL) (the sodium salt was prepared according to the procedure shown in Example 8) was heated to 50 ° C., followed by isopropyl acetate (12.9 mL). Added. Calcium chloride in water (104 mL) (2.6)
1 g) solution is added over 1 hour. The resulting suspension is stirred at 50 ° C. for 15 hours. The solid is isolated by filtration, then reintroduced into the reaction flask, suspended in water (240 mL) and isopropyl acetate (8 mL), and stirred at 50 ° C. for 20 minutes. The solid is isolated by filtration, then reintroduced into the reaction flask, suspended in water (240 mL) and stirred at 50 ° C. for 20 minutes. By filtering and drying at 60 ° C. under reduced pressure, AHU377 calcium salt, transformation H
Get _B.

AHU377 Sodium Salts For example, the sodium salts of AHU377 used in Example 3 are synthesized from AHU377 free acid by treatment with sodium hydroxide according to the general scheme below.

In most cases, an isopropyl acetate solution of AHU377 prepared according to the method described in Example 1 is used. The sodium salt of AHU377 is generally not isolated as a pure substance, but is used as an aqueous solution after treating an isopropyl acetate solution of AHU377 with an aqueous solution of sodium hydroxide.

Sodium hydroxide (8.62 g, 1.00) in water (270 ml) at room temperature in a solution of free acid (88.7 g, 1.00 eq) of AHU377 in isopropyl acetate (850 ml).
Equivalent) of the solution is added. The two-phase mixture is heated to 50 ° C. and then stirred at this temperature for 15 minutes. After phase separation at 50 ° C., the organic layer is extracted with water (105 ml). The combined aqueous phase is washed with isopropyl acetate (2 x 255 ml) to give an aqueous solution of the sodium salt of AHU377, which is used directly without further purification.

In the examples of the invention, the free acid of AHU377 was prepared as follows by acylation of the amine (according to the scheme presented in WO 2008/031567):

Ethyl (2R, 4S) -5-([1,1'-biphenyl] -4-yl) -4-amino-2-methylpentanoate hydrochloride in isopropyl acetate (800 ml) (100 g, 1.
Acetic acid at 0 ° C. in a suspension of (00 eq) (prepared as described in US Pat. No. 5,217,996) and succinic anhydride (33.1 g, 1.15 eq). A solution of triethylamine (51 ml, 1.28 eq) in isopropyl (100 ml) is added over 1 hour. The reaction mixture is further stirred at 0 ° C. for 1 hour and then warmed to room temperature over 1 hour. The reaction is quenched by adding a solution of citric acid (68.5 g, 1.24 eq) in water (300 ml). After phase separation, the organic layer is washed with water (2 x 200 ml) to obtain an isopropyl acetate solution of the free acid of AHU277, which is used directly in the next step without further purification (see Example 8). .. The free acid of AHU377 can be obtained as a pure substance by concentrating a solution of isopropyl acetate and used in the next step without further purification (see Example 1).

Capsules The following are examples of pharmaceutical dosage forms suitable for use in the present invention.

を有する、［１］に記載のカルシウム塩。
［３]
変態Ａ、ＢもしくはＣまたはその水和物形態、好ましくは変態Ｂまたは水和物形態Ｈ _Ｂ を含む結晶性形態である、［１］または［２］に記載のカルシウム塩。
［４]
非晶質形態である、［１］または［２］に記載のカルシウム塩。
［５]
２０から２５℃の温度で、４．６、６．０、７．１、９．３、１１．１、１２．０、１２．６、１４．０、１４．４、１４．７、１５．５、１６．６、１８．１、１９．６、２０．７、２１．１、２１．６、２２．５、２４．６、２５．３、２５．５、および３１．５からなる群から選択される２θ値（±０．１°）（ＣｕＫα；４５ｋＶ、４０ｍＡ；λ＝１．５４０５９８Å）を含む粉末Ｘ線回折パターンによって特徴付けられる、変態Ｂの形態である、［１］または［２］に記載のカルシウム塩の結晶性形態。
［６]
以下の特徴：
ｉ）２０から２５℃の温度で、４．６、６．０、１２．６、１５．５、１６．６、１９．６および２２．５°からなる群から選択される４つ、５つ、６つまたは７つの２θ値（±０．１°）（ＣｕＫα；４５ｋＶ、４０ｍＡ；λ＝１．５４０５９８Å）を含むＸ線粉末回折パターン、
ｉｉ）図２に示すＸ線粉末回折スペクトルに実質的に従うＸ線粉末回折パターン、
ｉｉｉ）１７３±２．４℃で開始する融点、
ｉｖ）１７３±２．５℃で開始する吸熱を有する示差熱分析（ＤＴＡ）サーモグラム、
ｖ）図７に示すものと実質的に同じ示差熱分析（ＤＴＡ）サーモグラム、
ｖｉ）図７に示すものと実質的に同じ熱重量分析（ＴＧＡ）ダイアグラム
の少なくとも１つ、２つ、３つ、４つ以上またはすべてを有することを特徴とする、変態Ｂの形態である、［３］に記載のカルシウム塩。
［７]
以下の特徴：
ｉ）２０から２５℃の温度で、３．６、６．４、８．４、１４．６、１５．３、１６．８、１７．８、１９．７および２０．６°からなる群から選択される４つ、５つまたはそれ以上の２θ値（±０．１°）（ＣｕＫα；４５ｋＶ、４０ｍＡ；λ＝１．５４０５９８Å）を含むＸ線粉末回折パターン、
ｉｉ）図４に示すＸ線粉末回折スペクトルに実質的に従うＸ線粉末回折パターン、
ｉｉｉ）１８０±２．４℃で開始する融点、
ｉｖ）１８０±２．５℃で開始する吸熱を有する示差熱分析（ＤＴＡ）サーモグラム、
ｖ）図９に示すものと実質的に同じ示差熱分析（ＤＴＡ）／ＴＧＡサーモグラム
の少なくとも１つ、２つ、３つ、４つ以上またはすべてを有することを特徴とする、変態Ｈ _Ｂ の形態である、［３］に記載のカルシウム塩。
［８]
以下の特徴：
ｉ）２０から２５℃の温度で、３．６、５．１、１５．１、１５．８、１７．３、１７．８、２０．７および２１．７°からなる群から選択される４つ、５つまたはそれ以上の２θ値（±０．１°）（ＣｕＫα；４５ｋＶ、４０ｍＡ；λ＝１．５４０５９８Å）を含むＸ線粉末回折パターン、
ｉｉ）図１に示すＸ線粉末回折スペクトルに実質的に従うＸ線粉末回折パターン、
ｉｉｉ）１９２±２．４℃で開始する融点、
ｉｖ）１９２±２．５℃で開始する吸熱を有する示差熱分析（ＤＴＡ）サーモグラム、
ｖ）図６に示すものと実質的に同じ示差熱分析（ＤＴＡ）またはＴＧＡサーモグラム
の少なくとも１つ、２つ、３つ、４つ以上またはすべてを有することを特徴とする、変態Ａの形態である、［３］に記載のカルシウム塩。
［９]
以下の特徴：
ｉ）２０から２５℃の温度で、４．６、６．２、１４．５、１５．４、２０．４、２１．７および２２．１°からなる群から選択される４つ、５つまたはそれ以上の２θ値（±０．１°）（ＣｕＫα；４５ｋＶ、４０ｍＡ；λ＝１．５４０５９８Å）を含むＸ線粉末回折パターン、
ｉｉ）図３に示すＸ線粉末回折スペクトルに実質的に従うＸ線粉末回折パターン、
ｉｉｉ）１８０±２．４℃で開始する融点、
ｉｖ）１８０±２．５℃で開始する吸熱を有する示差熱分析（ＤＴＡ）サーモグラム、
ｖ）図８に示すものと実質的に同じ示差熱分析（ＤＴＡ）サーモグラム、
ｖｉ）図８に示すものと実質的に同じ熱重量分析（ＴＧＡ）ダイアグラム
の少なくとも１つ、２つ、３つ、４つ以上またはすべてを有することを特徴とする、変態Ｃの形態である、［３］に記載のカルシウム塩。
［１０]
以下の特徴：
ｉ）図５に示すＸ線粉末回折スペクトルに実質的に従うＸ線粉末回折パターン、
ｉｉ）２０４±２．４℃で開始する融点、
ｉｉｉ）２０４±２．５℃で開始する吸熱を有する示差熱分析（ＤＴＡ）サーモグラム、
図１０に示すものと実質的に同じ示差熱分析（ＤＴＡ）またはＴＧＡサーモグラム
の少なくとも１つ、２つ、３つ、４つ以上またはすべてを有することを特徴とする、非晶質形態である、［１］、［２］または［４］に記載のカルシウム塩。
［１１]
［１］から１０のいずれか一項］に記載のカルシウム塩と、１種または複数の薬学的に許容される担体または添加剤とを含む、医薬組成物。
［１２]
前記結晶性形態が、変態Ｂ、変態Ｈ _Ｂ およびそれらの組合せからなる群から選択され、好ましくは変態Ｂ、より好ましくは実質的に純粋な形態のものである、［１１］に記載の医薬組成物。
［１３]
アンジオテンシン受容体遮断薬（ＡＲＢ）、好ましくはロサルタン、イルベサルタン、カンデサルタン、エプロサルタン、テルミサルタン、オルメサルタンおよびバルサルタンからなる群から選択されるＡＲＢ、好ましくはバルサルタン、または薬学的に許容されるその塩とそれぞれ組み合わせた、［１１］または［１２］のいずれかに記載の医薬組成物。
［１４]
高血圧、心不全（急性および慢性）、うっ血性心不全、左室機能障害、肥大型心筋症、糖尿病性心筋症、上室性および心室性不整脈、心房細動、心房粗動、有害な血管リモデリング、心筋梗塞およびその続発症、アテローム性動脈硬化症、アンギナ（不安定または安定）、腎不全（糖尿病性および非糖尿病性）、心不全、狭心症、糖尿病、続発性アルドステロン症、原発性および続発性肺高血圧、糖尿病性腎症、糸球体腎炎、強皮症、糸球体硬化症、原発性腎疾患のタンパク尿、腎血管性高血圧、糖尿病性網膜症、片頭痛、末梢血管疾患、レイノー病、管腔過形成、認知機能障害、緑内障ならびに脳卒中からなる群から選択される状態または障害の処置において使用するための、［１］から［１０］のいずれかに記載のカルシウム塩または［１１］、［１２］もしくは［１３］に記載の医薬組成物。
［１５]
［６］に記載の変態Ｂのカルシウム塩を作製するための方法であって、
ｉ）式（Ｉ）の化合物を溶媒、好ましくはエタノールに溶解するステップと、
ｉｉ）反応混合物を６０℃から還流の間の温度に加熱するステップと、
ｉｉｉ）反応混合物を４０から８０℃、好ましくは５０から８０℃、例えば５０±５℃に冷却するステップと、
ｉｖ）任意選択で、変態Ｂの種結晶を添加するステップと、
ｖ）反応混合物を好ましくは少なくとも１２時間撹拌するステップと、
ｖｉ）ステップ（ｃ）、（ｄ）または（ｅ）の終わりに得られた固体を濾過するステップと、
ｖｉｉ）任意選択で、得られた結晶を乾燥するステップと
を含む、方法。 Preparation of 1,000 capsules containing 50 mg of AHU377 calcium salt transformation B as the active ingredient, respectively. 50.00 g of active ingredient, 187.00 g of lactose, 80.00 g of modified starch and 3.00 g of magnesium stearate. , Each passed through a sieve with an opening of 0.6 mm. The drug substance is placed in a suitable mixer and mixed first with magnesium stearate, then with lactose and starch until homogeneous. No. 2 hard gelatin capsules are each filled with 300 mg of the mixture using a capsule filling machine.
The inventions described in the original claims of the present application are described below.
[1]
Calcium salt of N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester in crystalline or amorphous form or its Solvates, especially hydrates.
[2]
Equation (I)

The calcium salt according to [1].
[3]
The calcium salt according to [1] or [2], which is a crystalline form containing metamorphosis A, _B or C or a hydrated form thereof, preferably metamorphosis B or hydrated form HB .
[4]
The calcium salt according to [1] or [2], which is in an amorphous form.
[5]
At temperatures of 20 to 25 ° C, 4.6, 6.0, 7.1, 9.3, 11.1, 12.0, 12.6, 14.0, 14.4, 14.7, 15. From the group consisting of 5, 16.6, 18.1, 19.6, 20.7, 21.1, 21.6, 22.5, 24.6, 25.3, 25.5, and 31.5. A form of transformation B characterized by a powder X-ray diffraction pattern containing a selected 2θ value (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å), [1] or [2]. ] The crystalline form of the calcium salt according to.
[6]
The following features:
i) Four, five selected from the group consisting of 4.6, 6.0, 12.6, 15.5, 16.6, 19.6 and 22.5 ° at a temperature of 20 to 25 ° C. , X-ray powder diffraction pattern containing 6 or 7 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å),
ii) An X-ray powder diffraction pattern that substantially follows the X-ray powder diffraction spectrum shown in FIG.
iii) Melting point starting at 173 ± 2.4 ° C,
iv) Differential thermal analysis (DTA) thermogram with endothermic starting at 173 ± 2.5 ° C.,
v) A differential thermal analysis (DTA) thermogram, substantially the same as that shown in FIG.
vi) A thermogravimetric analysis (TGA) diagram that is substantially the same as that shown in FIG.
The calcium salt according to [3], which is a form of transformation B, characterized by having at least one, two, three, four or more, or all of the above.
[7]
The following features:
i) From the group consisting of 3.6, 6.4, 8.4, 14.6, 15.3, 16.8, 17.8, 19.7 and 20.6 ° at a temperature of 20 to 25 ° C. An X-ray powder diffraction pattern containing four or more selected 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å).
ii) An X-ray powder diffraction pattern that substantially follows the X-ray powder diffraction spectrum shown in FIG.
iii) Melting point starting at 180 ± 2.4 ° C,
iv) Differential thermal analysis (DTA) thermogram with endothermic starting at 180 ± 2.5 ° C.
v) Substantially the same differential thermal analysis (DTA) / TGA thermogram as shown in FIG.
The calcium salt according to [3], which is a form of metamorphic _HB , characterized by having at least one, two, three, four or more, or all of the above.
[8]
The following features:
i) Selected from the group consisting of 3.6, 5.1, 15.1, 15.8, 17.3, 17.8, 20.7 and 21.7 ° at a temperature of 20 to 25 ° C. 4 X-ray powder diffraction pattern containing one, five or more 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å),
ii) An X-ray powder diffraction pattern that substantially follows the X-ray powder diffraction spectrum shown in FIG.
iii) Melting point starting at 192 ± 2.4 ° C,
iv) A differential thermal analysis (DTA) thermogram with endothermic starting at 192 ± 2.5 ° C.,
v) Substantially the same differential thermal analysis (DTA) or TGA thermogram as shown in FIG.
The calcium salt according to [3], which is a form of transformation A, characterized by having at least one, two, three, four or more, or all of the above.
[9]
The following features:
i) Four or five selected from the group consisting of 4.6, 6.2, 14.5, 15.4, 20.4, 21.7 and 22.1 ° at a temperature of 20 to 25 ° C. An X-ray powder diffraction pattern containing a 2θ value (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å) of 2θ or more.
ii) An X-ray powder diffraction pattern that substantially follows the X-ray powder diffraction spectrum shown in FIG.
iii) Melting point starting at 180 ± 2.4 ° C,
iv) Differential thermal analysis (DTA) thermogram with endothermic starting at 180 ± 2.5 ° C.
v) A differential thermal analysis (DTA) thermogram, substantially the same as that shown in FIG.
vi) A thermogravimetric analysis (TGA) diagram that is substantially the same as that shown in FIG.
The calcium salt according to [3], which is a form of transformation C, characterized by having at least one, two, three, four or more, or all of the above.
[10]
The following features:
i) An X-ray powder diffraction pattern that substantially follows the X-ray powder diffraction spectrum shown in FIG.
ii) Melting point starting at 204 ± 2.4 ° C,
iii) Differential thermal analysis (DTA) thermogram with endothermic starting at 204 ± 2.5 ° C.
Substantially the same differential thermal analysis (DTA) or TGA thermogram as shown in FIG.
The calcium salt according to [1], [2] or [4], which is an amorphous form, characterized by having at least one, two, three, four or more, or all of the above.
[11]
A pharmaceutical composition comprising the calcium salt according to any one of [1] to 10] and one or more pharmaceutically acceptable carriers or additives.
[12]
The pharmaceutical composition according to [11], wherein the crystalline form is selected from the group consisting of transformation B, transformation HB and combinations thereof, preferably in transformation B, more preferably in substantially pure form _. thing.
[13]
Angiotensin receptor blocker (ARB), preferably an ARB selected from the group consisting of losartan, ilbesartan, candesartan, eprosartan, thermisartan, olmesartan and balsartan, preferably in combination with balsartan, or a pharmaceutically acceptable salt thereof, respectively. The pharmaceutical composition according to any one of [11] and [12].
[14]
Hypertension, heart failure (acute and chronic), congestive heart failure, left ventricular dysfunction, hypertrophic myocardium, diabetic myopathies, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, harmful vascular remodeling, Myocardial infarction and its sequelae, atherosclerosis, angina (unstable or stable), renal failure (diabetic and non-diabetic), heart failure, angina, diabetes, secondary aldosteronism, primary and secondary Pulmonary hypertension, diabetic nephropathy, glomerular nephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy, migraine, peripheral vascular disease, Raynaud's disease, tube The calcium salt according to any one of [1] to [10] or [11], [ 12] or the pharmaceutical composition according to [13].
[15]
[6] A method for producing the calcium salt of the metamorphosis B according to [6].
i) Dissolving the compound of formula (I) in a solvent, preferably ethanol,
ii) The step of heating the reaction mixture to a temperature between 60 ° C. and reflux,
iii) With the step of cooling the reaction mixture to 40-80 ° C, preferably 50-80 ° C, eg 50 ± 5 ° C.
iv) Optional step of adding the seed crystal of transformation B,
v) With the step of stirring the reaction mixture, preferably for at least 12 hours.
vi) The step of filtering the solid obtained at the end of step (c), (d) or (e), and
vii) Optionally, with the step of drying the obtained crystals
Including, how.

Claims (13)

Equation (I)

N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid It is a calcium salt of ethyl ester.
Transformation B is a 2θ value in the group consisting of 4.6, 6.0, 12.6, 15.5, 16.6, 19.6 and 22.5 ° at a temperature of 20 to 25 ° C. A calcium salt characterized by having an X-ray powder diffraction pattern comprising all of (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å). Equation (I)

N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid It is a calcium salt of ethyl ester.
Metamorphosis B is a calcium salt, characterized in that the form has a melting point starting at 173 ± 2.4 ° C. Equation (I)

N- (3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid It is a calcium salt of ethyl ester.
Metamorphosis B is a calcium salt, wherein the form has a differential thermal analysis (DTA) thermogram with endotherm starting at 173 ± 2.5 ° C. The transformation B has a form of 4.6, 6.0, 7.1, 9.3, 11.1, 12.0, 12.6, 14.0, 14 at a temperature of 20 to 25 ° C. 4.4, 14.7, 15.5, 16.6, 18.1, 19.6, 20.7, 21.1, 21.6, 22.5, 24.6, 25.3, 25.5 , And a powder X-ray diffraction pattern comprising all of the 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å) of the group consisting of 31.5. The calcium salt according to any one of 1 to 3. A pharmaceutical composition comprising the calcium salt according to any one of claims 1 to 4 and one or more pharmaceutically acceptable carriers or additives. The pharmaceutical composition according to claim 5, which is combined with an angiotensin receptor blocker (ARB). The pharmaceutical composition according to claim 6, wherein the ARB is selected from the group consisting of losartan, irbesartan, candesartan, eprosartan, thermisartan, olmesartan and balsartan, or pharmaceutically acceptable salts thereof. The pharmaceutical composition according to claim 6 or 7, wherein the ARB is selected from the group consisting of valsartan or a pharmaceutically acceptable salt thereof. Hypertension, heart failure (acute and chronic), congestive heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy, atrial fibrillation, atrial flutter, adverse vascular remodeling, myocardial infarction and its sequelae , and primary and secondary The calcium salt according to any one of claims 1 to 4 or any one of claims 5 to 8 for use in the treatment of a condition or disorder selected from the group consisting of pulmonary hypertension . The pharmaceutical composition according to description. The method for producing the calcium salt of the transformation B according to any one of claims 1 to 4.
a) The step of dissolving the compound of the formula (I) in ethanol,
b) The step of heating the reaction mixture to a temperature between 60 ° C. and reflux,
c) A step of cooling the reaction mixture to 40-80 ° C.
d) Arbitrarily, the step of adding the seed crystal of transformation B and
e) The step of stirring the reaction mixture and
f) The step of filtering the solid obtained at the end of step (c), (d) or (e), and
g) A method comprising, optionally, drying the resulting crystals. 10. The method of claim 10, wherein the cooling temperature in step c) is 50 to 80 ° C. The method according to claim 10 or 11, wherein the cooling temperature in step c) is 50 ± 5 ° C. The method according to any one of claims 10 to 12, wherein the reaction mixture is stirred for at least 12 hours in step e).

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