HK1175465B - Pharmaceutical combinations of an angiotensin receptor antagonist and an nep inhibitor - Google Patents

Description

Pharmaceutical combination of angiotensin receptor antagonist and NEP inhibitor

The present application is a divisional application of PCT application PCT/US2006/043710 entitled "pharmaceutical combination of angiotensin receptor antagonist and NEP inhibitor" filed on 8/11/2006, with a date of entry into the national phase of china on 2/7/2007 and with application number 200680001733.0.

Technical Field

The present invention relates to dual-acting complexes (compounds) and combinations of angiotensin receptor blockers and neutral endopeptidase inhibitors, in particular dual-acting molecules, wherein the angiotensin receptor blockers and the neutral endopeptidase inhibitors are linked by non-covalent bonds or are supramolecular complexes (complexes) of angiotensin receptor blockers and neutral endopeptidase inhibitors, also known as linked prodrugs, such as mixed salts or co-crystals, pharmaceutical combinations comprising such dual-acting complexes or combinations, methods of preparing such dual-acting complexes and methods of treating patients using such dual-acting complexes or combinations. In particular, the invention relates to dual-acting complexes or supramolecular complexes of two active ingredients having the same or different mode of action in one molecule.

Background

Angiotensin II is a hormone that causes vasoconstriction, which in turn leads to hypertension and heart strain. Angiotensin II is known to interact with receptors on the surface of target cells. Two receptor subtypes of angiotensin II have been identified, known as AT 1and AT 2. In recent times, great efforts have been made to identify substances capable of binding to the AT1 receptor. It is now known that angiotensin receptor blockers (ARBs, angiotensin II antagonists) are able to cause a reduction in blood pressure by preventing angiotensin II from binding to its receptors on the blood vessel wall. By virtue of their ability to inhibit the AT1 receptor, such antagonists may be useful in the treatment of hypertension, or for the treatment of congestive heart failure, among other indications.

Neutral endopeptidases (EC3.4.24.11; enkephalinase; atriopeptidase; NEP) are zinc-containing metalloproteinases that are capable of cleaving peptide substrates on the amino terminus of various hydrophobic residues [ see PharmacolRev, Vol.45, p.87(1993) ]. Substrates for this enzyme include, but are not limited to, atrial natriuretic peptide (ANP, also known as ANF), Brain Natriuretic Peptide (BNP), methionine enkephalin and leucine enkephalin, bradykinin, neurokinin a, endothelin-1, and substance P. ANP is a potent vasodilator and natriuretic drug [ see jhapertens, vol.19, p.1923(2001) ]. Infusion of ANP into normal subjects resulted in a significant increase in the reproducibility of natriuresis and diuresis, including an increase in sodium excretion fraction, urine flow rate and glomerular filtration rate [ see JClinPharmacol, vol.27, p.927(1987) ]. However, ANP has a short circulating half-life and NEP in the kidney cortex membrane is an important enzyme capable of degrading this peptide [ see Peptides, vol.9, p.173(1988) ]. Therefore, NEP inhibitors (neutral endopeptidase inhibitors, NEPi) are able to lower plasma levels of ANP and thus can lead to natriuretic and diuretic effects.

Therefore, drugs (e.g., angiotensin receptor blockers and neutral endopeptidase inhibitors) can be used to control hypertension. Essential hypertension is a polygenic disease and cannot be completely controlled by single treatment. In 2000, approximately 33300 million adults and approximately 6500 million (one third of adults) in the united states suffered from Hypertension [ see Lancet, volume 365, page 217 (2005) and Hypertension, volume 44, page 398 (2004) ]. Chronic and uncontrolled hypertensive vascular disease will ultimately lead to pathological changes in target organs (e.g., heart and kidney). Persistent hypertension can also lead to increased incidence of stroke. Therefore, in addition to the effect of lowering blood pressure, there is an urgent need to evaluate the effect of antihypertensive therapy, additional cardiovascular endpoints (endpoints), in order to further judge the benefit of combination therapy.

The nature of hypertensive vascular disease is multifactorial. In some cases, drugs with different mechanisms of action may be used in combination. However, any combination of drugs that only considers different modes of action does not necessarily lead to a combination with good effect. Thus, there is a need for effective combination therapy without the production of harmful side effects.

Disclosure of Invention

In a first aspect, the invention relates to dual-acting complexes, such as supramolecular complexes, including

(a) An angiotensin receptor antagonist;

(b) neutral endopeptidase inhibitors (NEPi); and optionally

(c) A pharmaceutically acceptable cation.

The invention also relates to a dual-acting complex, such as a supramolecular complex, obtainable by:

(i) dissolving an angiotensin receptor antagonist and a neutral endopeptidase inhibitor (NEPi) in a suitable solvent;

(ii) dissolving a Cat basic compound in a suitable solvent, wherein Cat is a cation;

(iii) (iii) mixing the solutions obtained in steps (i) and (ii);

(iv) precipitating the solid and drying to obtain a dual-action compound; or

Obtaining a dual acting complex by the following steps and exchanging the solvents used in steps (i) and (ii):

(iva) evaporating the resulting solution to dryness;

(va) redissolving the solid in a suitable solvent;

(via) the solid is precipitated and dried to give a dual action complex.

The present invention also relates to linked prodrugs comprising:

(a) an angiotensin receptor antagonist or a pharmaceutically acceptable salt thereof; and

(b) the NEPi or the pharmaceutically acceptable salt thereof,

wherein the angiotensin receptor antagonist or a pharmaceutically acceptable salt thereof and the NEPi or a pharmaceutically acceptable salt thereof are linked through a linking group.

The invention also relates to the following combination product comprising:

(a) a pharmaceutically acceptable salt of an angiotensin receptor antagonist; and

(b) a pharmaceutically acceptable salt of a neutral endopeptidase inhibitor (NEPi);

wherein the angiotensin receptor antagonist and the pharmaceutically acceptable salt of the NEPi are the same and are selected from Na, K or NH₄And (3) salt.

In a preferred embodiment, the angiotensin receptor antagonist and the NEPi have an acidic group which contributes to the formation of a dual-acting complex, such as the supramolecular complex of the present invention.

Preferably, the angiotensin receptor antagonist is selected from the group consisting of valsartan, losartan, irbesartan, telmisartan, eprosartan, candesartan, olmesartan, saprolisartan (saprisartan), tasosartan, elisartan, and combinations thereof.

In a preferred embodiment, the NEPi is selected from the following: SQ28, 603; n- [1(S) -carboxy-3-phenylpropyl ] - (S) -phenylalanyl ] - (S) -isoserine; n- [ ((1S) -carboxy-2-phenyl) ethyl ] - (S) -phenylalanyl ] - β -alanine; n- [2(S) -mercaptomethyl-3- (2-methylphenyl) -propionyl ] methionine; (cis-4- [ [ [1- [ 2-carboxy-3- (2-methoxyethoxy) propyl ] -cyclopentyl ] carbonyl ] amino ] -cyclohexanecarboxylic acid); thiorphan; retro-thiorphan; a phosphoramidyl dipeptide; SQ 29072; ethyl N- (3-carboxy-1-oxopropyl) - (4S) -p-phenylphenylmethyl) -4-amino-2R-methylbutyrate; (S) -cis-4- [1- [2- (5-indanyloxycarbonyl) -3- (2-methoxyethoxy) propyl ] -1-cyclopentanecarboxamide ] -1-cyclohexanecarboxylic acid; 3- (1- [ 6-endo-hydroxymethylbicyclo [2, 2, 1] heptane-2-exo-carbamoyl ] cyclopentyl) -2- (2-methoxyethyl) propionic acid; n- (1- (3- (N-tert-butoxycarbonyl- (S) -prolylamino) -2(S) -tert-butoxy-carbonylpropyl) cyclopentanecarbonyl) -O-benzyl- (S) -serine methyl ester; 4- [ [2- (mercaptomethyl) -1-oxo-3-phenylpropyl ] amino ] benzoic acid; 3- [1- (cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-r-1-carbamoyl) cyclopentyl ] -2S- (2-methoxyethoxymethyl) propionic acid; n- ((2S) -2- (4-biphenylmethyl) -4-carboxy-5-phenoxyvaleryl) glycine; n- (1- (N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl) -L-phenylalanine; (S) - (2-biphenyl-4-yl) -1- (1H-tetrazol-5-yl) ethylamino) methylphosphonic acid; (S) -5- (N- (2- (phosphonomethyl) -amino) -3- (4-biphenyl) propanoyl) -2-aminoethyl) tetrazole; beta-alanine; 3- [1, 1' -biphenyl ] -4-yl-N- [ diphenylphosphinyloxyphosphinyl ] methyl ] -L-alanyl; n- (2-carboxy-4-thienyl) -3-mercapto-2-benzylpropionamide; 2- (2-mercaptomethyl-3-phenylpropionylamino) thiazol-4-yl carboxylic acid; (L) - (1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) -methoxy) carbonyl) -2-phenylethyl) -L-phenylalanyl) - β -alanine; n- [ (L) - [1- [ (2, 2-dimethyl-1, 3-dioxolan-4-yl) -methoxy ] carbonyl ] -2-phenylethyl ] -L-phenylalanyl ] - (R) -alanine; n- [ (L) -1-carboxy-2-phenylethyl ] -L-phenylalanyl ] - (R) -alanine; n- [ 2-acetylthiomethyl-3- (2-methyl-phenyl) propionyl ] -methionine ethyl ester; n- [ 2-mercaptomethyl-3- (2-methylphenyl) propionyl ] -methionine; n- [2(S) -mercaptomethyl-3- (2-methylphenyl) propanoyl ] - (S) -isoserine; n- (S) - [ 3-mercapto-2- (2-methylphenyl) propionyl ] - (S) -2-methoxy- (R) -alanine; n- [1- [ [1(S) -benzyloxycarbonyl-3-phenylpropyl ] amino ] cyclopentylcarbonyl ] - (S) -isoserine; n- [1- [ [1(S) -carbonyl-3-phenylpropyl ] amino ] -cyclopentylcarbonyl ] - (S) -isoserine; 1, 1' - [ dithiobis- [2(S) - (2-methylbenzyl) -1-oxo-3, 1-propanediyl ] ] -bis- (S) -isoserine; 1, 1' - [ dithiobis- [2(S) - (2-methylbenzyl) -1-oxo-3, 1-propanediyl ] ] -bis- (S) -methionine; n- (3-phenyl-2- (mercaptomethyl) -propionyl) - (S) -4- (methylmercapto) methionine; n- [ 2-acetylmethylsulfanyl-3-phenyl-propionyl ] -3-aminobenzoic acid; - Λ/- [ 2-mercaptomethyl-3-phenyl-propionyl ] -3-aminobenzoic acid; n- [1- (2-carboxy-4-phenylbutyl) -cyclopentane-carbonyl ] - (S) -isoserine; n- [1- (acetylthiomethyl) cyclopentane-carbonyl ] - (S) -methionine ethyl ester; 3(S) - [2- (acetylthiomethyl) -3-phenyl-propionyl ] amino-caprolactam; n- (2-acetylthiomethyl-3- (2-methylphenyl) propionyl) -methionine ethyl ester; or a combination thereof. Preferably, the dual acting complex or combination thereof (especially supramolecular complexes) is a mixed salt or cocrystal. It is also preferred that the linked prodrugs are mixed salts or co-crystals.

In a second aspect, the present invention relates to a pharmaceutical composition comprising the following components:

(a) the aforementioned dual-acting complexes or combinations thereof, such as the aforementioned complexes; and

(b) at least one pharmaceutically acceptable additive.

The invention also relates to pharmaceutical compositions containing linked prodrugs comprising the following components:

(a) an angiotensin receptor antagonist or a pharmaceutically acceptable salt thereof;

(b) NEPi or a pharmaceutically acceptable salt thereof;

wherein the angiotensin receptor antagonist or a pharmaceutically acceptable salt thereof and the NEPi or a pharmaceutically acceptable salt thereof are linked by a linking group; and

(c) at least one pharmaceutically acceptable additive.

In a third aspect, the present invention relates to a method for the preparation of a dual-acting complex, in particular a supramolecular complex, comprising

(a) An angiotensin receptor antagonist;

(b) neutral endopeptidase inhibitors (NEPi); and optionally

(c) Pharmaceutically acceptable from Na, K and NH₄A cation of (2).

The method comprises the following steps:

(i) dissolving an angiotensin receptor antagonist and a neutral endopeptidase inhibitor (NEPi) in a suitable solvent;

(ii) dissolving a Cat basic compound in a suitable solvent, wherein Cat represents a cation;

(iii) (iii) combining the solutions obtained in steps (i) and (ii);

(iv) precipitating the solid and drying to obtain a dual-action compound; or

Obtaining a dual acting complex by the following steps and exchanging the solvents used in steps (i) and (ii):

(iva) evaporating the resulting solution to dryness;

(va) redissolving the solid in a suitable solvent;

(via) the solid is precipitated and dried to give a dual action complex.

The invention also relates to methods of making linked prodrugs comprising

(a) An angiotensin receptor antagonist or a pharmaceutically acceptable salt thereof;

(b) NEPi or a pharmaceutically acceptable salt thereof, wherein the angiotensin receptor antagonist or a pharmaceutically acceptable salt thereof and the NEPi or a pharmaceutically acceptable salt thereof are linked by a linking group; the method comprises adding a linking group and a solvent to a mixture of an angiotensin receptor antagonist and a NEPi;

(d) isolating the linked prodrug.

In a fourth aspect, the invention relates to a method of treating or preventing diseases or disorders such as hypertension, heart failure (acute and chronic), congestive heart failure, left ventricular insufficiency and hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (unstable or stable), renal insufficiency (diabetic and non-diabetic), heart failure, angina, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure diseases (such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerulosclerosis, primary nephrotic proteinuria and renovascular hypertension), diabetic retinopathy, other vascular diseases such as migraine, peripheral vascular disease, raynaud's disease, luminelperplasia, cognitive disorders (e.g. cognitive disorders of Alzheimer's), glaucoma and stroke, comprising administering to a patient in need of such treatment the aforementioned dual acting complex or a composition thereof, in particular administering the supramolecular complex or the aforementioned linked prodrug, preferably administering the complex.

Drawings

FIG. 1 is a representation of a unit cell (cell) of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi pentahydrate supramolecular complex, which includes two asymmetric units. The following colors were used for marking: gray ═ carbon atoms; blue ═ nitrogen atoms; red ═ oxygen atom; purple ═ sodium atom.

Detailed description of the invention

The present invention relates to dual-acting complexes or combinations thereof, in particular supramolecular complexes or linked prodrugs, or in particular supramolecular complexes of two active ingredients with different mechanisms of action, angiotensin receptor antagonists and neutral endopeptidase inhibitors, which can form unique molecules useful for the treatment of patients suffering from various cardiovascular and/or renal diseases.

One embodiment of the present invention is directed to a physical combination product comprising:

(a) a pharmaceutically acceptable salt of an angiotensin receptor antagonist; and

(b) a pharmaceutically acceptable salt of a neutral endopeptidase inhibitor (NEPi);

wherein the pharmaceutically acceptable salts of the angiotensin receptor antagonist and the NEPi are the same and are selected from Na, K or NH₄And (3) salt.

In particular, it is preferred that the two active ingredients combine with each other to form a single dual-acting complex, in particular a supramolecular complex. In this way, new molecular or supramolecular bodies are formed, which have properties that are significantly different from the above-mentioned physical combinations.

The present invention therefore relates to a dual-acting complex, in particular a supramolecular complex, comprising:

(a) an angiotensin receptor antagonist;

(b) neutral endopeptidase inhibitors (NEPi); and

(c) a pharmaceutically acceptable cation, preferably selected from Na, K and NH₄。

The invention also relates to a dual-acting complex, in particular a supramolecular complex, obtainable by:

(i) dissolving an angiotensin receptor antagonist and a neutral endopeptidase inhibitor (NEPi) in a suitable solvent;

(ii) adding Cat basic compound such as (Cat) OH, (Cat)₂CO₃、(Cat)HCO₃Dissolved in a suitable solvent, where Cat represents a cation, preferably selected from Na, K and NH₄；

(iii) (iii) combining the solutions obtained in steps (i) and (ii);

(iv) precipitating the solid and drying to obtain a dual-action compound; or

Obtaining a dual acting complex by the following steps and exchanging the solvents used in steps (i) and (ii):

(iva) evaporating the resulting solution to dryness;

(va) redissolving the solid in a suitable solvent;

(via) the solid is precipitated and dried to give a dual action complex.

The present invention further relates to linked prodrugs comprising:

(a) an angiotensin receptor antagonist or a pharmaceutically acceptable salt thereof; and

(b) the NEPi or the pharmaceutically acceptable salt thereof,

wherein the angiotensin receptor antagonist or a pharmaceutically acceptable salt thereof and the NEPi or a pharmaceutically acceptable salt thereof are linked by a linking group.

Both components are attached to a linking group, thereby forming a linked prodrug. Preferably, the linked prodrug is substantially pure; as used herein, "substantially pure" means at least 90% pure, more preferably at least 95% pure, and most preferably at least 98% pure.

In a preferred embodiment of the invention, the linked prodrug has a structure such that the linking of the two components via the linking group enables the formation of a supramolecular complex.

In the present invention, the term "dual acting complexes" means that these complexes have two different modes of action in one complex, one being angiotensin receptor blockade resulting from the ARB molecular moiety and the other being neutral endopeptidase inhibition resulting from the NEPi molecular moiety.

In the present invention, the term "complex" refers to a chemical substance that comprises a covalent bond within two pharmaceutically active ingredients and that there is a non-covalent interaction between the two pharmaceutically active ingredients (ARB and NEPi molecular moieties). In general, hydrogen bonds can be observed between the two pharmaceutically active ingredients (ARB and NEPi molecular moieties). There may be an ionic bond between the cation and one or both of the two pharmaceutically active ingredients (ARB and NEPi molecular moieties). Other types of bonds, such as van der waals forces, may be present in the composite. For convenience of illustration, the dual action complex of the invention may be as follows:

(ARB)-(L)_m-(NEPi)

wherein L is a linking group, such as a cationic or non-covalent bond, and m is 1 or an integer greater than 1. Alternatively, the ARB and NEPi moieties may be linked by non-covalent bonds, for example by hydrogen bonds. Alternatively, they may be linked by a linking group, such as a cation.

In one embodiment, the dual-acting complex may be a linked prodrug, i.e., a prodrug that links two pharmaceutically active ingredients (ARB and NEPi) through a linking group, such as a cation, to form these ingredients, which can be released immediately when the linked prodrug is taken up and absorbed.

In a preferred embodiment, the dual-acting complex is a complex, in particular a supramolecular complex.

In the present invention, the term "supramolecular complex" refers to the interaction between two pharmaceutically active ingredients, a cation and any other substance (e.g. a solvent, especially water), which interact through non-covalent intermolecular bonds. These interactions result in the binding of the components present in the supramolecular complex to each other, which binding makes the complex different from the physical mixture of these components.

The bonds between non-covalent molecules may be any interaction known in the art capable of forming such supramolecular complexes, such as hydrogen bonding, van der waals forces, and pi-pi stacking. Ionic bonds may also be present. Preferably, ionic bonds and additional hydrogen bonds are present to form an interactive network in the complex. The supramolecular complex is preferably present in the solid state, but may also be present in the liquid state. In a preferred embodiment of the invention, the complex is crystalline, in which case mixed crystals or co-crystals are preferred.

In general, dual-acting complexes, and in particular supramolecular complexes, exhibit properties (e.g., melting point, IR spectrum, etc.) that are different from their physical mixture.

Preferably, the dual acting complex, in particular the supramolecular complex, has a network of non-covalent bonds, in particular hydrogen bonds, between the two pharmaceutically active ingredients and any solvent, if present, preferably water. And more preferably, the dual-acting complex, in particular the supramolecular complex, has a network of non-covalent bonds, in particular ionic and hydrogen bonds, between the two pharmaceutically active ingredients and any solvent, if present, preferably water. The cation preferably binds to a plurality of oxygen ligands, thereby forming a linkage between these oxygen ligands. The oxygen ligands originate from the carbonyl and carboxylate groups of the two pharmaceutically active ingredients, preferably also from any solvent, preferably water if present.

The dual acting complex contains the molecular moiety of an angiotensin receptor antagonist. This means that the part of the molecule derived from the angiotensin receptor antagonist is involved in the construction of a dual-acting complex. The angiotensin receptor antagonist is part of a complex and is linked directly or indirectly via a non-covalent bond to the NEP inhibitor. For convenience, in the present application, the term "angiotensin receptor antagonist" may be used when describing this part of the complex. Angiotensin receptor Antagonists (ARBs) suitable for use in the present invention include, but are not limited to valsartan, losartan, irbesartan, telmisartan, eprosartan, candesartan, olmesartan, sapprisartan, tasosartan, elisartan, compounds referred to as E-1477 having the formula:

a compound designated SC-52458 having the formula:

a compound referred to as ZD-8731 having the formula:

suitable angiotensin II receptor antagonists also include, but are not limited to, saralasin acetate, candesartan cilexetil, CGP-63170, EMD-66397, KT3-671, LR-B/081, valsartan, A-81282, BIBR-363, BIBS-222, BMS-184698, candesartan, CV-11194, EXP-3174, KW-3433, L-161177, L-162154, LR-B/057, LY-235656, PD-150304, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, losartan potassium, E-4177, EMD-73495, eprosartan, HN-65021, irbesartan, L-159282, ME-3221, SL-91.0102, tasosartan, telmisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-159689, L-162234, L-162441, L-163007, PD-123177, A-81988, BMS-180560, CGP-38560-A, CGP-48369, DA-2079, DE-3489, DuP-167, EXP-063, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, isoolivine, KRI-1177, L-158809, L-158978, L-159874, LRB087, LY-285434, LY-302289, LY-315995, RG-13647, RWJ 38970, RWJ8336, S-8307, Sal-8908, Saotan, Saeslin, WrK-13608, WZD-13608, WJX-D7155, ICI-D8731, ISeolide, L-1177, L-1587, L-158809, L-158978, L-315995, LtRWoT-68845, and W, ZD-7155, ZD-8731, BIBS39, CI-996, DMP-811, DuP-532, EXP-929, L-163017, LY-301875, XH-148, XR-510, zolasartan and PD-123319.

Combinations of the above ARBs are also included within the scope of the present invention.

The ARBs used to prepare the combination or complex of the present invention may be commercially available or may be prepared according to known methods. ARBs may be used in the present invention in their free form as well as in any suitable salt or ester form.

Preferred salt forms include acid addition salts. Complexes having at least one acidic group (for example, COOH or 5-tetrazolyl) can also form salts with bases. Suitable salts with bases are, for example, metal salts (for example alkali metal or alkaline earth metal salts, such as sodium, potassium, calcium or magnesium salts), or salts with ammonia or organic amines (for example morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-or tri-lower alkylamine (e.g. ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl-or dimethylpropylamine) or mono-, di-or trihydroxy lower alkylamine (e.g. mono-, di-or triethanolamine) may also form the corresponding inner salts The crystalline form of valsartan is selected from the group consisting of a mono-potassium salt of amorphous valsartan, a dipotassium salt of amorphous or crystalline valsartan, in particular in the form of a hydrate thereof, a calcium salt of crystalline valsartan, in particular in the form of a hydrate thereof, predominantly a tetrahydrate, a magnesium salt of crystalline valsartan, in particular in the form of a hydrate thereof, predominantly a hexahydrate, a calcium/magnesium mixed salt of crystalline valsartan, in particular in the form of a hydrate thereof, a bis-dipropylammonium salt of crystalline valsartan, in particular in the form of a hydrate thereof, predominantly a hemihydrate, a mono-L-arginine salt of amorphous valsartan, a bis-L-arginine salt of amorphous valsartan, a mono-L-lysine salt of amorphous valsartan, a bis-L-lysine salt of amorphous valsartan.

When preparing dual action complexes, particularly complexes of the invention, it is preferred to employ the free form of the ARB.

In a preferred embodiment of the invention, the angiotensin receptor blocker used in the combination and complex of the invention is valsartan, the molecular structure of which is shown below:

valsartan can be in the racemic form or one of two isomers shown below:

preference is given to

Valsartan ((S) -N-pentanoyl-N- { [ 2' - (1H-tetrazol-5-yl) -biphenyl-4-yl ] -methyl } -valine) for use in the present invention may be purchased commercially or may be prepared according to known methods. For example, the preparation of valsartan is described in U.S. Pat. No. 5,399,578 and EP0443983, the entire disclosures of which are incorporated herein by reference. Valsartan may be used in the present invention in its free acid form as well as in the form of any suitable salt. In addition, esters or other derivatives of the carboxyl group may be used in the synthesis of linked prodrugs, as may salts and derivatives of tetrazole. References to ARBs also include pharmaceutically acceptable salts thereof.

Preferably, the ARB is a diprotic acid. The charge of the angiotensin receptor blocker is therefore 0, 1 or 2, depending on the pH of the solution.

In the combination of the invention, the ARB is in the form of a pharmaceutically acceptable salt selected from Na, K or NH₄Salt, preferably Na salt. It includes mono-and di-salts, preferably di-salts, of these cations. Especially in the case of valsartan, this means that both the carboxylic acid moiety and the tetrazole moiety form salts.

In dual-acting complexes, in particular supramolecular complexes of the invention, the free form of ARB is generally employed in the preparation, and the cationic moiety in the complex can be introduced by employing a base such as (Cat) OH.

The dual acting complex comprises the molecular moiety of a neutral endopeptidase inhibitor. This means that the part of the molecule derived from the neutral endopeptidase inhibitor is involved in the construction of a dual acting complex. The neutral endopeptidase inhibitor is part of the complex and is linked directly to the ARB or indirectly via a non-covalent bond. For convenience, in the present application, when describing this portion of the complex, the term "neutral endopeptidase inhibitor" is used. Neutral endopeptidase inhibitors suitable for use in the present invention include those compounds of the following formula (I):

wherein:

R₂is alkyl of 1-7 carbons, trifluoromethyl, phenyl, substituted phenyl, - (CH)₂)_{1 -4}-phenyl or- (CH)₂)_1-4-a substituted phenyl group;

R₃is hydrogen, alkyl of 1-7 carbons, phenyl, substituted phenyl, - (CH)₂)_1-4-phenyl or- (CH)₂)_1-4-a substituted phenyl group;

R₁is hydroxy, alkoxy of 1-7 carbons or NH₂；

n is an integer of 1 to 15;

the term substituent in a substituted phenyl group is selected from: lower alkyl of 1-4 carbons, lower alkoxy of 1-4 carbons, lower alkylthio of 1-4 carbons, hydroxy, Cl, Br or F.

Preferred neutral endopeptidase inhibitors of formula (I) include compounds wherein the groups are defined as follows:

R₂is benzyl;

R₃is hydrogen;

n is an integer of 1 to 9; and is

R₁Is a hydroxyl group.

Another preferred neutral endopeptidase inhibitor is (3S, 2' R) -3- {1- [ 2' - (ethoxycarbonyl) -4' -phenyl-butyl]-cyclopent-1-carbonylamino-2,3, 4, 5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid or a pharmaceutically acceptable salt thereof.

Neutral endopeptidase inhibitors suitable for use in the present invention include, but are not limited to, the following: SQ28, 603; n- [1(S) -carboxy-3-phenylpropyl ] - (S) -phenylalanyl ] - (S) -isoserine; n- [ ((1S) -carboxy-2-phenyl) ethyl ] - (S) -phenylalanyl ] - β -alanine; n- [2(S) -mercaptomethyl-3- (2-methylphenyl) -propionyl ] methionine; (cis-4- [ [ [1- [ 2-carboxy-3- (2-methoxyethoxy) propyl ] -cyclopentyl ] carbonyl ] amino ] -cyclohexanecarboxylic acid); thiorphan; retro-thiorphan; a phosphoramidyl dipeptide; SQ 29072; (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester; n- (3-carboxy-1-oxopropyl) - (4S) -p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid; (S) -cis-4- [1- [2- (5-indanyloxycarbonyl) -3- (2-methoxyethoxy) propyl ] -1-cyclopentanecarboxamide ] -1-cyclohexanecarboxylic acid; 3- (1- [ 6-endo-hydroxymethylbicyclo [2, 2, 1] heptane-2-exo-carbamoyl ] cyclopentyl) -2- (2-methoxyethyl) propionic acid; n- (1- (3- (N-tert-butoxycarbonyl- (S) -prolylamino) -2(S) -tert-butoxy-carbonylpropyl) cyclopentanecarbonyl) -O-benzyl- (S) -serine methyl ester; 4- [ [2- (mercaptomethyl) -1-oxo-3-phenylpropyl ] amino ] benzoic acid; 3- [1- (cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-r-1-carbamoyl) cyclopentyl ] -2S- (2-methoxyethoxymethyl) propionic acid; n- ((2S) -2- (4-biphenylmethyl) -4-carboxy-5-phenoxyvaleryl) glycine; n- (1- (N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl) -L-phenylalanine; (S) - (2-biphenyl-4-yl) -1- (1H-tetrazol-5-yl) ethylamino) methylphosphonic acid; (S) -5- (N- (2- (phosphonomethyl) -amino) -3- (4-biphenyl) propanoyl) -2-aminoethyl) tetrazole; beta-alanine; 3- [1, 1' -biphenyl ] -4-yl-N- [ diphenoxyphosphinyl ] methyl ] -L-alanyl; n- (2-carboxy-4-thienyl) -3-mercapto-2-benzylpropionamide; 2- (2-mercaptomethyl-3-phenylpropionylamino) thiazol-4-yl carboxylic acid; (L) - (1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) -methoxy) carbonyl) -2-phenylethyl) -L-phenylalanyl) - β -alanine; n- [ (L) - [1- [ (2, 2-dimethyl-1, 3-dioxolan-4-yl) -methoxy ] carbonyl ] -2-phenylethyl ] -L-phenylalanyl ] - (R) -alanine; n- [ (L) -1-carboxy-2-phenylethyl ] -L-phenylalanyl ] - (R) -alanine; n- [ 2-acetylthiomethyl-3- (2-methyl-phenyl) propionyl ] -methionine ethyl ester; n- [ 2-mercaptomethyl-3- (2-methylphenyl) propionyl ] -methionine; n- [2(S) -mercaptomethyl-3- (2-methylphenyl) propanoyl ] - (S) -isoserine; n- (S) - [ 3-mercapto-2- (2-methylphenyl) propionyl ] - (S) -2-methoxy- (R) -alanine; n- [1- [ [1(S) -benzyloxycarbonyl-3-phenylpropyl ] amino ] cyclopentylcarbonyl ] - (S) -isoserine; n- [1- [ [1(S) -carbonyl-3-phenylpropyl ] amino ] -cyclopentylcarbonyl ] - (S) -isoserine; 1, 1' - [ dithiobis- [2(S) - (2-methylbenzyl) -1-oxo-3, 1-propanediyl ] ] -bis- (S) -isoserine; 1, 1' - [ dithiobis- [2(S) - (2-methylbenzyl) -1-oxo-3, 1-propanediyl ] ] -bis- (S) -methionine; n- (3-phenyl-2- (mercaptomethyl) -propionyl) - (S) -4- (methylmercapto) methionine; n- [ 2-acetylthiomethyl-3-phenyl-propionyl ] -3-aminobenzoic acid; - Λ/- [ 2-mercaptomethyl-3-phenyl-propionyl ] -3-aminobenzoic acid; n- [1- (2-carboxy-4-phenylbutyl) -cyclopentane-carbonyl ] - (S) -isoserine; n- [1- (acetylthiomethyl) cyclopentane-carbonyl ] - (S) -methionine ethyl ester; 3(S) - [2- (acetylthiomethyl) -3-phenyl-propionyl ] amino-caprolactam; n- (2-acetylthiomethyl-3- (2-methylphenyl) propionyl) -methionine ethyl ester; and combinations thereof.

Neutral endopeptidase inhibitors can be purchased commercially or can be prepared according to known methods, for example as described in the following references: U.S. patent No. 4,722,810, U.S. patent No. 5,223,516, U.S. patent No. 4,610,816, U.S. patent No. 4,929,641, south american patent application 84/0670, UK69578, U.S. patent No. 5,217,996, EP00342850, GB02218983, WO92/14706, EP00343911, JP06234754, EP00361365, WO90/09374, JP07157459, WO94/15908, U.S. patent No. 5,273,990, U.S. patent No. 5,294,632, U.S. patent No. 5,250,522, EP00636621, WO93/09101, EP 90005442, WO93/10773, U.S. patent No. 5,217,996, each of which disclosures are incorporated herein by reference. Neutral endopeptidase inhibitors may be used in the present invention in their free form or in the form of any suitable salt. References to neutral endopeptidase inhibitors also include pharmaceutically acceptable salts thereof.

In addition, esters or other derivatives of any carboxyl group, as well as salts and derivatives of any other acidic group, may also be used in the synthesis of linked prodrugs. In a preferred embodiment of the invention, NEPi is 5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester of formula (II) or hydrolyzed form of 5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid.

The compound of formula (II) may be in the form of the (2R, 4S), (2R, 4S) or (2R, 4S) isomer. Preferred are (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester shown below:

compounds of formula (II) are specific inhibitors of NEP and are disclosed in U.S. patent No. 5,217,996. It can be purchased commercially or prepared according to known methods. The compounds of formula (II) may be used in the present invention in their free form or in any suitable salt or ester form.

Preferably, NEPi is a simple molecular acid. Therefore, depending on the pH of the solution, the NEPi charge is 0 or 1.

In the combination of the invention, the NEPi is in the form of a pharmaceutically acceptable salt selected from Na, K or NH₄Salt, preferably Na salt.

In dual-acting complexes (in particular supramolecular complexes of the invention), the free form of NEPi is generally used in the preparation, and the cation in the complex can be introduced by using a base (Cat) OH.

The dual acting complex is preferably non-covalent between the ARB and NEPi. In addition, it optionally contains a linking group, such as a pharmaceutically acceptable cation.

Linking groups include, but are not limited to, compounds that are Generally Regarded As Safe (GRAS) or other pharmacologically acceptable compounds. The linking group may be an ionic or neutral molecule. In the case where the linking group is ionic, the linked prodrug is a salt, and when the linking group is a neutral molecule, the linked prodrug is co-crystalline. Without being bound by any particular theory, the acidic moieties of ARB and NEPi donate a proton to the basic linker, thereby allowing all three components to combine to form one molecule. When the linked prodrug is ingested by a host in need of treatment, the acidic digestive environment allows the linked prodrug to separate into individual components so that it is converted to the active ingredient upon ingestion and absorption, thereby providing its beneficial biological effects for the treatment of the corresponding disease.

In the case of a linked prodrug salt or a dual action complex, the linking moiety or cation, respectively, is preferably a mono-, di-or tri-valent cation, an organic base or an amino acid. Preferably the cation (Cat) of the prodrug and the dual action complex (especially the complex) used for the linkage is a basic cation, more preferably a metal cation. Preferred metal cations include, but are not limited to, Na, K, Ca, Mg, Zn, Fe or NH₄. Amine bases and salt-forming agents are also possible, for example N, N' -dibenzylethylenediamine (benzathine), hydrabamine, ethylenediamine, N-N-dibenzylethylenediamine, L-arginine, choline hydroxide, N-methyl-glucamine (meglumine), L-lysine, dimethylaminoethanol (Deanol), tert-butylamine, diethylamine, 2- (diethylamino) -ethanol, 4- (2-hydroxyethyl) -morpholine, Thromethane (TRIS), 4-acetaminophenol, 2-amino-2-methyl-1, 3-propanediol, 2-amino-2-methyl-propanol, benzylamine, cyclohexylamine, diethanolamine, ethanolamine, imidazole, piperazine and triethanolamine.

Most preferred cations are Na, K or NH₄Such as Na. In one embodiment, Ca is preferred.

When the linked prodrug is co-crystalline, the linking moiety may also be a neutral molecule capable of providing hydrogen bonding functionality.

In one embodiment, the linked prodrugs of the invention are shown below, wherein scheme (1) and (2) represent salts and scheme (3) represents co-crystals:

NEPi, Xa, ARB graphic representation (1)

NEPi, XaYb, ARB graphic representation (2)

NEPi, Zc, ARB scheme (3),

wherein

X is Ca, Mg, Zn or Fe;

y is Na, K or NH 4;

z is a neutral molecule; and is

A. b and c represent the valency of the linked prodrug, preferably a, b and c are 1⁺、2⁺Or 3⁺And (4) price.

In the linked prodrugs of schemes (1) and (2) above, it is preferred that NEPi is a monoprotic acid and ARB is a diprotic acid. The angiotensin receptor blocker is charged to 0, 1 or 2 and the NEPi is charged to 0 or 1 depending on the pH of the solution, so the whole molecule is neutral. The ratio of ARB to NEPi is 1: 1, 1: 2, 1: 3, 3: 1, 2: 1, 1: 1, preferably 1: 1, 1: 2 or 1: 3, most preferably 1: 1.

Multicomponent salts (in particular zinc and calcium salts) have been reported in the literature: for example, chemparmball, volume 53, page 654 (2005). These ions require coordination geometry to facilitate crystallization of the multicomponent system. The metal ions all have a coordination geometry determined by the atomic orbitals.

Valsartan contains two acidic groups: carboxylic acid and tetrazole. In one embodiment of this aspect of the invention, the linked prodrug of valsartan and NEPi comprises a linkage between a carboxylic acid and a linking group or a linkage between a tetrazole group and a linking group in the molecular structure. In another embodiment, the linked prodrug comprises a trivalent linking group linking the valsartan carboxylic acid group, the tetrazole group and the NEPi.

In one embodiment of this aspect of the invention, valsartan is ionically linked to (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester via the calcium salt.

In a preferred embodiment of the invention the molar ratio between the angiotensin receptor antagonist and the neutral endopeptidase inhibitor in the combination product and the supramolecular complex is 1: 1, 1: 2, 1: 3, 3: 1, 2: 1, more preferably 1: 1. The same is true for the linked prodrugs. Also, the molar ratio between the angiotensin receptor antagonist, the neutral endopeptidase inhibitor and the cation in the complex is 1: 1, 1: 2, 1: 3, more preferably 1: 3. The same applies to linked prodrugs.

The combination or dual action complex, particularly the complex of the invention, may contain a solvent. This is more particularly preferred in dual-acting complexes (in particular complexes) where the solvent may contribute to intramolecular structures such as supramolecular interactions. Preferred solvents include water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, methyl-tert-butyl ether, acetonitrile, toluene and dichloromethane, preferably water. If a solvent is present, one or more molecules per molecule of the active ingredient may also be present. To this end, that is to say when a stoichiometric amount of solvent is present, there are preferably 1, 2,3, 4 or 5 (more preferably 3) molecules of solvent (e.g. water) per molecule of active ingredient. Alternatively, the solvent may be present in a non-stoichiometric amount. This means that any stoichiometric amount of solvent may be preferred, for example, 0.25, 0.5, 0.75, 1.25, 1.5, 1.75, 2.25, 2.5, 2.75, 3.25, 3.5, 3.75, 4.25, 4.5 and 4.75 (preferably 2.5) molecules of solvent (e.g. water) may be present for each molecule of active ingredient. If the dual-acting complex (particularly the complex) is in a crystalline form, the solvent may be packed and trapped in the crystal lattice as part of the molecule.

In a preferred embodiment of the invention, therefore, the dual-acting complexes (in particular supramolecular complexes) are described by the general formula:

[ARB(NEPi)]Na_1-3·xH₂o, where x is 0, 1, 2 or 3, for example preferably 3,

[ARB(NEPi)]Na₃·xH₂o, wherein x is 0, 1, 2 or 3, for example more preferably 3,

[ Valsartan ((2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester]Na₃·xH₂O, wherein x is 0, 1, 2 or 3, e.g. 3.

In a preferred embodiment of the invention, therefore, the dual-acting complexes (in particular supramolecular complexes) are described by the general formula:

[ARB(NEPi)]Na_1-3·xH₂o, where x is from 0 to 3, for example preferably 2.5,

[ARB(NEPi)]Na₃·xH₂o, wherein x is 0 to 3, for example more preferably 2.5,

[ (N-pentanoyl-N- { [ 2' - (1H-tetrazol-5-yl) -biphenyl-4-yl)]-methyl } -valine) (5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester) Na₃·xH₂O, especially [ ((S) -N-pentanoyl-N- { [ 2' - (1H-tetrazol-5-yl) -biphenyl-4-yl]-methyl } -valine) ((2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester) Na₃·xH₂O, where x is 0 to 3, e.g., 2.5. In the most preferred embodiment, the complex is named [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid]Trisodium hemipentahydrate.

The simplified structure of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi pentahydrate used to formally calculate the relative molecular weight is shown below:

valsartan contains two acidic groups: carboxylic acid and tetrazole. In one embodiment of this aspect of the invention, the dual acting complex (particularly a complex) of valsartan and NEPi comprises in its molecular structure an interaction between a carboxylic acid and a cation (e.g. sodium) or a solvent (e.g. water), or a linking group between a tetrazole group and a cation (e.g. Na) or a solvent (e.g. water). In another embodiment, the dual acting complex (particularly a complex) comprises an interaction between a valsartan carboxylic acid group, a tetrazole group or a NEPi group and a cation (e.g. Na) or a solvent (e.g. water).

The combination or dual action complex (in particular complex) of the invention is preferably in solid form. In the solid state, it may be in crystalline, partially crystalline, amorphous or polymorphic form, preferably in crystalline form.

The combination or dual action complex (especially a complex) of the invention is distinct from a mixture of ARB and NEPi obtained by simple physical mixing of the two active ingredients. It therefore has different properties which make it particularly suitable for manufacturing and therapeutic applications. The difference between the dual acting complex (in particular the complex) and the mixture can be illustrated by the dual acting complex of (S) -N-pentanoyl-N- { [ 2' - (1H-tetrazol-5-yl) -biphenyl-4-yl ] -methyl } -valine and (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester, which is characterized by very distinct spectral peaks and shifts, which are not observed in physical mixtures.

In particular, such dual action composites are preferably characterized by an X-ray powder diffraction pattern obtained using a ScintagXDS2000 powder diffractometer using Cu-Ka irradiation (. lamda. about. 1.54056A) at room temperature (25 ℃) using a Peltier-cooled silicon detector. The scan range is from 1.5 deg. to 40 deg. in the 2 theta interval, and the scan speed is 3 deg./min. The most important reflections in the X-ray diffraction pattern include the following lattice plane spacings (interclaticeplaneintervalues):

preferred characteristics of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazole-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi pentahydrate are obtained from the determined lattice plane spacing d of the X-ray diffraction pattern, the following values being the average value of 2 θ in [ ° ] (error range ± 0.2):

4.5、5.5、5.6、9.9、12.8、15.7、17.0、17.1、17.2、18.3、18.5、19.8、21.5、21.7、23.2、23.3、24.9、25.3、27.4、27.9、28.0、30.2，

or an average error range of ± 0.1:

4.45、5.52、5.57、9.94、12.82、15.66、17.01、17.12、17.2、18.32、18.46、19.76、21.53、21.72、23.17、23.27、24.88、25.3、27.4、27.88、28.04、30.2，

the most intense reflections in the X-ray diffraction pattern show the following lattice plane spacing:

2 θ [ ° ]: 4.5, 5.6, 12.8, 17.0, 17.2, 19.8, 21.5, 27.4, in particular 4.45, 5.57, 17.01, 17.2, 19.76, 21, 27.4.

A preferred method of validating the average of the above lattice plane spacing and the experimentally determined intensity of X-ray diffraction for a given material involves calculating the plane spacing and its intensity from a single crystal structure. This structural determination yields the unit cell constants and atomic positions that enable the X-ray diffraction pattern corresponding to a solid to be calculated by computer-aided calculation methods. The program used is PowderPattern in the application software materials studio (Accelrys). The following table shows a comparison of the data obtained by measuring and calculating the single crystal data, i.e., the lattice plane spacing and intensity of the most important lines of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi pentahydrate:

watch (A)

The present invention relates to [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazole-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi pentahydrate, which is a crystalline solid characterized by data and parameters obtained by single crystal X-ray analysis and X-ray powder modeling. Further discussion of the theory of single crystal X-ray diffraction methods and the definition of the evaluation of crystallization data and parameters can be found in Stout & Jensen, X-ray structure determination; apractcalguide, macmillianco, new york, n.y. (1968), chapter 3.

Note that:

two sets of data for two appropriate single crystals were collected at different temperatures to ensure that no phase change occurred during cooling.

No hydrogen atom or amine nitrogen atom of water is observed in Fourier spectrum, so they are not included in refining (refining).

Computer program for structure resolution:

SHELXD(Sheldrick，)

in three dimensions, a unit cell is defined by three side lengths (a, b, and c) and three interaxial angles (α, β, and γ)_c. For a description of the differences between these crystallization parameters, reference is made to Stout&Jensen (see above) chapter 3. [3- ((1S,3R) -1-Biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid from single crystal measurements (in particular atomic co-ordinates, isotropic thermal parameter, hydrogen atomic co-ordinates and corresponding isotropic thermal parameter)]Details of trisodium hemipentahydrate indicate the presence of monoclinic unit cells, C₄₈H₅₅N₆O₈Na₃·2.5H₂The unit cell content of 12 structural units of O is present in two asymmetric units of two fold positions.

Noncentral space group P2 for single crystal X-ray texture measurement₁Is a spacer population of conventional enantiomerically pure molecules. There are two general positions (generation) in this spacer group, which means that for 12 structural units in a unit cell there must be 18 sodium ions and 15 water in the asymmetric unit.

A schematic representation of a unit cell of a supramolecular complex of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi pentahydrate containing two asymmetric units is shown in FIG. 1.

Based on the single crystal structure solution, the asymmetric units of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi pentahydrate supramolecules each contain 6 ARB and NEPi moieties, 18 sodium atoms, and 15 water molecules. The [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi pentahydrate may be referred to as a sodium supramolecular complex, which may be coordinated by an oxygen ligand. These oxygens are derived from 13 of the 12 carboxylate groups and 18 carbonyl groups and 15 water molecules of the above moiety. The crystals are an infinite three-dimensional network of these sodium complexes.

Such composites can also be characterized by infrared absorption spectroscopy using a Fourier transform attenuated Total reflectance Infrared Spectroscopy (ATR-FTIR) spectrometer (NicoletMagna-IR560) using the wavelength bands of interest (in reciprocal of wavelength data (cm) as described below)^-1) Representation) qualitative:

2956(w), 1711(st), 1637(st), 1597(st), 1488(w), 1459(m), 1401(st), 1357(w), 1295(m), 1266(m), 1176(w), 1085(m), 1010(w), 1942(w), 907(w), 862(w), 763(st), 742(m), 698(m), 533 (st). The complexes are characterized in particular by the following peaks: 1711(st), 1637(st), 1597(st) and 1401 (st). Error of all absorption bands of ATR-IR is + -2 cm^-1. The intensity of the absorption band is expressed as follows: (w) weak; (m) ═ medium; and (st) is strong.

Such complexes can also be characterized by raman chromatography using a raman chromatograph with a 785nm laser excitation source (kaiser optical systems, Inc.) the following important wavelength bands (in reciprocal of wavelength data (cm.)^-1) Represents:

3061(m), 2930(m, width), 1612(st), 1523(m), 1461(w), 1427(w), 1287(st), 1195(w), 1108(w), 11053(w), 1041(w), 1011(w), 997(m), 866(w), 850(w), 822(w), 808(w), 735(w), 715(w), 669(w), 643(w), 631(w), 618(w), 602(w), 557(w), 522(w), 453(w), 410(w), 328 (w).

Error of all Raman bands. + -. 2cm^-1. The intensity of the absorption band is expressed as follows: (w) weak; (m) ═ medium; and (st) is strong.

Such complexes may also be characterized by different melting properties as determined by differential scanning calorimetry. The melting onset temperature and maximum peak temperature for such complexes were 139 ℃ and 145 ℃ respectively, using a Q1000 (taiinstruments) apparatus. The heating rate was 10K/min.

A second embodiment of the present invention relates to a pharmaceutical composition comprising a combination, a linked prodrug or a dual action complex, in particular a complex as described herein, and at least one pharmaceutically acceptable additive. The details of the combination and complex comprising ARB and NEPi are as described above in the first embodiment of the invention.

The pharmaceutical compositions of the invention can be prepared according to well-known methods and are suitable for gastrointestinal (e.g. oral or rectal) and parenteral administration to mammals (warm-blooded animals), including man, by administering a therapeutically effective amount of a combination product or dual action complex (especially a complex) alone or in combination with at least one pharmaceutically acceptable carrier, especially one suitable for parenteral or parenteral use. Typical oral formulations include tablets, capsules, syrups, elixirs and suspensions. Typical injectable formulations include solutions and suspensions.

Pharmaceutically acceptable additives suitable for use in the present invention include, but are not limited to, diluents or fillers, disintegrants, glidants, lubricants, binders, colorants and combinations thereof, provided that they are chemically inert and thus do not adversely affect the combination product or dual action complex, and the amount of each additive in the solid formulation can vary within the ordinary skill in the art. Examples of typical pharmaceutically acceptable carriers suitable for use in the above formulations are: sugars such as lactose, sucrose, mannitol, and sorbitol; starches, such as corn starch, tapioca starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates, such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; a glycol polymer; beta-cyclodextrin; fatty alcohols; and grain hydrolyzed solids and other nontoxic compatible excipients commonly used in pharmaceutical formulations, such as fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, colorants, and the like.

Pharmaceutical preparations for parenteral or parenteral administration are, for example, unit dosage forms, such as coated tablets, capsules or suppositories, and furthermore ampoules. They may be prepared according to well-known methods, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes. Thus, pharmaceutical compositions for oral use can be obtained by mixing the linked prodrug, combination product or dual action complex (especially a complex) with a solid excipient, if desired granulating a mixture obtained as described above, and, if desired or necessary, after addition of suitable auxiliary materials, shaping the mixture or granules into tablets or cores of coated tablets.

The dosage of the active compounds in the combination or in the dual-action complex, in particular the complex, depends on various factors, for example on the mode of administration, the species of warm-blooded animal, the age and/or the individual condition. Oral dosing ranges from about 0.1 mg/kg/day to about 1000 mg/kg/day to set efficacy in animal disease models, and human treatment ranges from about 0.1 mg/day to about 2000 mg/day. Preferred dosages of the linked prodrug range from about 40 mg/day to about 960 mg/day, more preferably from about 80 mg/day to about 640 mg/day. The ARB component is administered at a dose of from about 40 mg/day to about 320 mg/day and the NEPi component is administered at a dose of from about 40 mg/day to about 320 mg/day. More preferably, the dosage of ARB/NEPi includes 40mg/40mg, 80mg/80mg, 160mg/160mg, 320mg/320mg, 40mg/80mg, 80mg/160mg, 160mg/320mg, 320mg/640mg, 80mg/40mg, 160mg/80mg and 320mg/160mg, respectively. These dosages are "therapeutically effective amounts". The preferred dosage of the linked prodrug, combination or dual action complex (especially the complex) of the pharmaceutical composition of the invention is a therapeutically effective dose.

The pharmaceutical composition may contain another therapeutic ingredient, for example, each in a therapeutically effective amount as reported in the art: including a) antidiabetic drugs such as insulin, insulin derivatives and mimetics; insulin secretagogues, for example sulfonylureas such as glipizide, glibenclamide and nimoramide; insulinotropic sulfonylurea receptor ligands, for example, meglitinides such as nateglinide and repaglinide; peroxisome proliferator-activated receptor (PPAR) ligands; protein tyrosine phosphatase-1B (PTP-1B) inhibitors, such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors, such as SB-517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands, such as GW-0791 and AGN-194204; sodium-dependent glucose co-transporter inhibitors, such as T-1095; glycogen phosphorylase a inhibitors, such as BAYR 3401; biguanides, such as metformin; alpha-glucosidase inhibitors, such as acarbose; GLP-1 (glucagon-like peptide-1), GLP-1 analogs such as Exendin-4 and GLP-1 mimetics; and DPPIV (dipeptidase IV) inhibitors, such as LAF 237;

b) hypolipidemic agents, such as 3-hydroxy-3-methyl-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitors, for example, lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin; a squalene synthase inhibitor; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; a fibrate; nicotinic acid and aspirin;

c) anti-obesity drugs such as orlistat; and

d) antihypertensive drugs, e.g. loop diureticsDrugs such as ethacrynic acid, furosemide and torasemide, Angiotensin Converting Enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril, Na-K-ATPase membrane pump inhibitors such as digoxin, ACE/NEP inhibitors such as omatra (omapatrilat), lapachol and fasidol, β -adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol, positive inotropic drugs such as digoxin, palmatine and milrinone, calcium channel blockers such as amlodipine, benpropendil, diltiazemFelodipine, nicardipine, nimodipine, nifedipine, nisoldipine, and verapamil; an aldosterone receptor antagonist; and an aldosterone synthase inhibitor. The most preferred combination is a diuretic (e.g. hydrochlorothiazide) and/or a calcium channel blocker (e.g. amlodipine or a salt thereof).

Other antidiabetic compounds are described by PatelMona in ExpertOpinInvestigDrugs, 2003, 12(4), 623-. The complexes of the invention may be administered simultaneously, before or after the other active ingredients, or separately by the same or different routes of administration, or together in the same formulation.

The structure of the therapeutic identified by code, generic or trade name can be obtained from a standard catalog of the current edition "MerckIndex" or from a database such as PatentsInternational (e.g., IMSWorldpublications). The corresponding content of which is hereby incorporated by reference.

Accordingly, the present invention provides a pharmaceutical composition further comprising a therapeutically effective amount of another therapeutic agent, preferably selected from an antidiabetic agent, a hypolipidemic agent, an antiobesity agent or an antihypertensive agent, most preferably selected from the antidiabetic agents, antihypertensive agents or hypolipidemic agents described above.

The person skilled in the art is fully enabled to select relevant experimental models to demonstrate the efficacy of the combination of the invention as described above and below in the treatment of said indications.

A representative study was conducted with the following complex: [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi pentahydrate, for example, was applied in the following methodological studies:

the antihypertensive and neutral endopeptidase24.11 (NEP) -inhibiting activity of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi pentahydrate was evaluated in conscious rats. The effect of blood pressure reduction was evaluated in double transgenic rats (dTGRs) overexpressing human renin and its substrate, human angiotensinogen (Bohlender et al, high humanization hypertension. hypertension; 29(1Pt 2): 428-34, 1997). In conclusion, these animals all have angiotensin II-dependent hypertension. NEP-inhibitory effects of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi pentahydrate were determined in conscious Sprague-Dawley rats infused with exogenous Atrial Natriuretic Peptide (ANP). The increase in plasma ANP levels was used as an indicator of NEP inhibition in vivo. In both models, [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi pentahydrate was administered orally as a powder filled into gelatin microcapsules. The results are summarized below.

● conscious dTGRs, a dose-dependent and long-lasting antihypertensive half-pentahydrate of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium after oral administration in a rat animal model with explosive hypertension.

● Rapid administration of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi pentahydrate, which is able to inhibit NEP in a dose-dependent manner and exert its effect over a longer period of time, is marked by its effect on increasing plasma ANP immunoreactivity (ANPir) in conscious Sprague-Dawle rats infused with exogenous ANP.

●

In vivo antihypertensive effect

dTGRs were fitted with radio telemetry sensors for continuous measurement of arterial blood pressure and heart rate. Animals were randomly assigned to vehicle (empty capsules) or treatment groups (dose 2, 6, 20 or 60mg/kg, oral). In all groups, the baseline for the 24 hour Mean Arterial Pressure (MAP) was approximately 170-180 mmHg. The semi-pentahydrate of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium dose-dependently reduced MAP. The values from the treatment groups were dose-dependent, with the results from the three highest dose groups being significantly different from the vehicle control group.

Inhibition of NEP in vivo

The extent and duration of in vivo inhibition of NEP by [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazole-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi-pentahydrate can be assessed according to the methods described previously (Trapani et al CGS35601and dinitroallellyactive pro-CGS 37808 aspergillolytic gene binding protein-converting enzyme-1, neutralendopeptidase24.11, and andiotensin-converting enzyme. JCardiovasccol; Supply 1: S211-5, 2004). RatANP (1-28) was intravenously infused at a rate of 450ng/kg/min into conscious, long-term intubated male Sprague-Dawley rats. 1 hour after infusion, rats were randomly assigned to one of six groups: untreated control, vehicle (empty capsule) control, or one of the four dose drug groups (2, 6, 20, or 60mg/kg, oral). ANP infusion was continued for an additional 8 hours. Blood samples for the determination of plasma ANPir were collected and determined by commercial enzyme immunoassay kits at the following times: -60 minutes (i.e. before starting ANP infusion), -30 minutes (30 minutes after starting ANP infusion), 0 minutes ("baseline"; 60 minutes after ANP infusion but before administration of the drug or its excipients), and 0.25, 0.5, 1, 2,3, 4,5, 6, 7 and 8 hours after administration.

Prior to ANP infusion, ANPir was lower (0.9-1.4ng/ml) and all 6 groups were similar. Rapid infusion of ANP (30 min) increased ANPir to-10 ng/ml. The untreated group and vehicle control group maintained this ANPir level throughout the experiment. In contrast, rapid (within 15 minutes) administration of [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi pentahydrate resulted in a dose-dependent increase in ANPir. In summary, oral rapid administration of LCZ696 dose-dependently increased NEP with a longer duration of action marked by an increase in plasma ANPir.

The results obtained demonstrate the unexpected therapeutic effect of the complexes of the invention.

In a third aspect, the present invention relates to a process for the preparation of a linked prodrug of ARB or a pharmaceutically acceptable salt thereof and NEPi or a pharmaceutically acceptable salt thereof, which process comprises the steps of:

(a) adding an inorganic salt forming reagent to the solvent to form a salt forming solution of the linked prodrug;

(b) adding a salt to the mixture of ARB and NEPi to form a solution such that ARB and NEPi form a linked prodrug; and

(c) isolating the linked prodrug.

Preferably, the ingredients are added in the same equivalent.

Inorganic salt-forming agents include, but are not limited to: calcium hydroxide, zinc hydroxide, calcium methoxide, calcium acetate, calcium hydrogen carbonate, calcium formate, magnesium hydroxide, magnesium acetate, magnesium formate and magnesium hydrogen carbonate, sodium hydroxide, sodium methoxide, sodium acetate, sodium formate. The inorganic salt forming reagent releases the linked moiety into the solvent such that the linked prodrug is formed when ARB and NEPi are present.

Solvents included within the scope of the present invention include, but are not limited to, solvents in which ARB, NEPi and inorganic salt forming agents have low solubility and which enable crystallization of the linked prodrug are preferred. Such solvents may include, but are not limited to, water, methanol, ethanol, 2-propanol, ethyl acetate, methyl-tert-butyl ether, acetonitrile, toluene, and dichloromethane, and mixtures of such solvents.

When the inorganic salt-forming reagent and solvent are mixed, they should have a pH that facilitates formation of the linked prodrug. The pH may be between about 2 and about 6, preferably between about 3 and about 5, most preferably between 3.9 and 4.7.

The linked prodrug can be isolated by crystallization and chromatography. Specific types of chromatography include, for example, ligand-specific resin chromatography, reverse phase resin chromatography, and ion exchange resin chromatography.

Specific examples include reacting a divalent salt of one component of the linked prodrug with a monovalent salt of another component. A special mixed salt of valsartan and a mono-basic NEPi is synthesized by reacting the calcium salt of valsartan with the sodium salt of the NEPi component. The separation of the desired mixed salts is carried out by selective crystallization or ligand-specific resin chromatography, reverse phase resin chromatography or ion exchange resin chromatography. Also, the process may be carried out using a monovalent salt of the two components, for example the sodium salt of the two components.

In another embodiment of this aspect of the invention, a co-crystal of the linked prodrug is obtained. In a method of preparing a co-crystal of a linked prodrug, the inorganic salt-forming reagent is replaced with a neutral molecule capable of providing hydrogen binding properties. The solvent may be part of the molecule, filling and being trapped in the crystal lattice.

In a preferred embodiment of the third aspect, the present invention relates to a method of preparing a dual action complex comprising:

(a) an angiotensin receptor antagonist;

(b) neutral endopeptidase inhibitors (NEPi); and optionally

(c) A pharmaceutically acceptable cation;

the method comprises the following steps:

(i) dissolving an angiotensin receptor antagonist and a neutral endopeptidase inhibitor (NEPi) in a suitable solvent;

(ii) dissolving a Cat basic compound in a suitable solvent, wherein Cat is a cation;

(iii) (iii) combining the solutions obtained in steps (i) and (ii);

(iv) precipitating and drying the solid to obtain a compound with dual functions; or

Obtaining a dual acting complex by the following steps and exchanging the solvents used in steps (i) and (ii):

(iva) evaporating the resulting solution to dryness;

(va) redissolving the solid in a suitable solvent;

(via) the solid is precipitated and dried to give a dual action complex.

Details regarding the complex (including ARB, NEPi and cation) are as described above in the first embodiment of the invention.

Preferably, in step (i), the amount of ARB and NEPi added is the same molar amount. Both ARB and NEPi are preferably in free form. The solvent used in step (i) may be any solvent capable of dissolving ARB and NEPi. Preferred solvents include those mentioned above, i.e. water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, isopropyl acetate, methyl-tert-butyl ether, acetonitrile, toluene, DMF, NMF and dichloromethane as well as mixtures of such solvents, e.g. ethanol-water, methanol-water, 2-propanol-water, acetonitrile-water, acetone-water, 2-propanol-toluene, ethyl acetate-heptane, isopropyl acetate-acetone, methyl-tert-butyl ether-heptane, methyl-tert-butyl ether-ethanol, ethanol-heptane, acetone-ethyl acetate, acetone-cyclohexane, toluene-heptane, more preferably acetone.

Preferably, the Cat basic compound in step (ii) is a compound capable of forming a salt with the acidic functional groups of ARB and NEPi. Examples include certain of the above compounds, such as calcium hydroxide, zinc hydroxide, calcium methoxide, calcium ethoxide, calcium acetate, calcium hydrogen carbonate, calcium formate, magnesium hydroxide, magnesium acetate, magnesium formate, magnesium hydrogen carbonate, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium methoxide, sodium ethoxide, sodium acetate, sodium formate, potassium hydroxide, potassium carbonate, potassium hydrogen carbonate, potassium methoxide, potassium ethoxide, potassium acetate, potassium formate, ammonium hydroxide, ammonium methoxide, ammonium ethoxide, and ammonium carbonate. Perchlorates may also be employed. Such amine base or salt forming agents as described above, in particular benzathine, L-arginine, cholin, ethylenediamine, L-lysine or piperazine, may also be used. Typically, an inorganic base is used with the specific Cat herein. Preferably, the basic compound is (Cat) OH, (Cat)₂CO₃、(Cat)HCO₃More preferably cat (oh), such as NaOH. The basic compound is used in an amount corresponding to at least 3 equivalents of ARB or NEPi, preferably it is used in stoichiometric amounts to obtain a dual action complex, in particular a complex with three cations. The solvent used in step (ii) may be any solvent or mixture of solvents capable of dissolving cat (oh). Preferred solvents include water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, isopropyl acetate, methyl-tert-butyl ether, acetonitrile, toluene and dichloromethane and mixtures of such solvents, more preferably water.

In step (iii), the solutions obtained in steps (i) and (ii) are combined. This can be replaced by the following steps: (iii) adding the solution obtained in step (i) to the solution obtained in step (ii) or vice versa, preferably, adding the solution obtained in step (ii) to the solution obtained in step (i).

According to a first alternative method, once combined and preferably mixed, the dual acting complex (in particular the complex) is precipitated in step (iv). The mixing and precipitation is typically facilitated by stirring the solution at room temperature for a suitable time, for example 20 minutes to 6 hours, preferably 30 minutes to 3 hours, more preferably 2 hours. It is advantageous to seed the dual action complex. This method aids in precipitate formation.

In a first alternative step (iv), a co-solvent is typically added. The co-solvent employed is one in which the complex forms ARB and NEPi have low solubility, which enables the complex to precipitate. The distillation (continuous or fractional) replaced by the co-solvent results in a preponderance of the amount of co-solvent in the solvent. Preferred solvents include ethanol, 2-propanol, acetone, ethyl acetate, isopropyl acetate, methyl-t-butyl ether, acetonitrile, toluene and dichloromethane and mixtures of such solvents, with isopropyl acetate being more preferred. Preferably, the minimum amount of solvent that will aid in precipitation is employed. The solid is collected, for example by filtration, and dried to give a dual action complex, in particular a complex of the invention. The drying step may be carried out at room temperature or at elevated temperature, for example 30-60 c, preferably 30-40 c. Reduced pressure may be employed to assist in the removal of the solvent, preferably, the drying is carried out at atmospheric pressure or reduced pressure, for example 10 to 30bar, such as 20 bar.

According to a second alternative, the dual action complex (particularly the complex mixture) preferably forms a clear solution once combined and preferably mixed. The mixing is usually carried out by stirring the solution at room temperature for a suitable time, for example 20 minutes to 6 hours, preferably 30 minutes to 3 hours, more preferably 1 hour. If desired, the temperature may be increased to ensure a clear solution is obtained.

The mixture obtained is then further treated by solvent exchange to obtain a dual-acting complex, in particular a complex.

In the second alternative process step (iva), the solution is preferably evaporated to dryness at elevated temperature, for example from above room temperature to 50 ℃, more preferably from 30 to 40 ℃.

Preferably, in step (va), the solvent or solvent mixture used is a solvent in which the ARB and NEPi in complex form have low solubility, which enables the dual action complex (particularly the complex) to form a precipitate. Preferred solvents include those in step (i) above, such as water, ethanol, 2-propanol, acetone, ethyl acetate, isopropyl acetate, methyl-tert-butyl ether, acetonitrile, toluene and dichloromethane and mixtures of such solvents, more preferably isopropyl acetate. Preferably, the minimum amount of solvent or solvent mixture that can contribute to the formation of a precipitate is employed.

In step (via), the precipitation may be carried out at room temperature. It can be carried out by leaving the mixture to stand or by stirring the mixture, preferably by stirring. This step is preferably carried out by stirring and/or sonication. After precipitation, the solid is collected, for example by filtration, and dried to give the complex of the invention. The drying step may be carried out at room temperature or at elevated temperature, for example 30-60 ℃, preferably room temperature. Reduced pressure may be employed to aid in the removal of the solvent, and preferably, drying is carried out at atmospheric pressure.

In a fourth aspect, the invention relates to a method of treating or preventing diseases or disorders such as hypertension, heart failure (acute and chronic), congestive heart failure, left ventricular insufficiency and hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (unstable or stable), renal insufficiency (diabetic and non-diabetic), heart failure, angina pectoris, diabetes, secondary hyperaldosteronism, primary and secondary pulmonary hypertension, renal failure diseases (such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerulosclerosis, primary nephrotic proteinuria and renovascular hypertension), diabetic retinopathy, other vascular diseases such as migraine, peripheral vascular disease, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (unstable or stable), renal insufficiency (diabetic and non-diabetic), heart failure, angina pectoris, diabetes mellitus, diabetic retinopathy, primary and secondary hyperaldosteronism, Raynaud's disease, luminelperplasia, cognitive disorders (e.g., Alzheimer's cognitive disorder), glaucoma, and stroke, comprising administering to a patient in need of such treatment the foregoing combination, linked prodrug, or dual action complex, particularly a complex.

The combination, linked prodrug or dual action complex (particularly a complex) of the first embodiment may be administered alone or in the form of a pharmaceutical composition of the second embodiment. The dosage (i.e., therapeutically effective amount) is the same regardless of the mode of administration of the combination, linked prodrug or dual action complex (particularly a complex).

In view of the convenience as first line therapy, formulation and ease of manufacture, the combination, linked prodrug or dual action complex (especially a complex) is advantageous over the use of either ARBs or neutral endopeptidase inhibitors alone or in combination with other ARB/NEPi.

Detailed Description

Specific embodiments of the present invention are illustrated with reference to the following examples. It will be understood that these examples are disclosed only for illustrating the present invention and are not to be construed as limiting the present invention in any way.

Example 1

[ Valsartan ((2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester]Na₃·2.5H₂O

By mixingThe dual acting complex of valsartan and ethyl (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoate was prepared by dissolving 0.42g of (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoate free acid (-95% purity) and 0.41g of valsartan free acid in 40ml of acetone. In addition, 0.111g of NaOH was dissolved in 7ml of H₂And (4) in O. The two solutions were combined and stirred at room temperature for 1 hour to give a clear solution. The solution was evaporated at 35 ℃ to give a glassy solid. The glassy solid residue was then placed in 40ml of acetone and the resulting mixture was stirred and sonicated until a precipitate formed (-5 minutes). The precipitate was filtered and the solid was air dried at room temperature for 2 days until a stable amount of crystalline solid was obtained.

A variety of qualitative methods are able to demonstrate the presence of valsartan and (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester and the formation of the complex relative to a simple physical mixture. Important spectral peaks of the complexes can be observed in e.g. XRPD, IR and raman spectra, which are not present in the physical mixture. See the qualitative section below for details.

Example 2

[ Valsartan ((2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester) Na₃·2.5H₂Alternative preparation of O

A dual acting complex of valsartan and (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester was prepared by dissolving 22.96mmol of (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester free acid (-95% purity) and valsartan (10.00 g; 22.96mmol) in acetone (300 mL). The suspension was stirred at room temperature for 15 minutes to give a clear solution. A solution of NaOH (2.76 g; 68.90mmol) in water (8mL) was then added to the above solution over a period of 10 minutes. A solid precipitate began to form within 10 minutes. Alternatively, precipitation may be induced by seeding. The suspension was stirred at 20-25 ℃ for 2 hours. The suspension was concentrated at 15-30 ℃ under reduced pressure (180-. Then, isopropyl acetate (150mL) was added to the batch and the suspension was again concentrated at 15-30 ℃ under reduced pressure (180-. This procedure (150mL of isopropyl acetate added to the batch and concentrated) was repeated once more. The suspension was stirred at 20-25 ℃ for 1 hour. The solid was collected by filtration through a Buchner funnel under nitrogen, washed with isopropyl acetate (20mL) and dried at 35 ℃ under reduced pressure (20mbar) to give the complex.

Qualitatively, the same is shown as for the product in example 1.

Example 3

[ Valsartan ((2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester) Na₃·2.5H₂Alternative preparation of O, using a seeding process

To the reactor was added 2.00kg (2,323mmol) of AHU377 calcium salt and 20L of isopropyl acetate. The suspension was stirred at 23. + -. 3 ℃ and 4.56L of 2N HCl was added. The mixture was stirred at 23 ± 3 ℃ for 15 minutes to give a clear two-phase solution. The organic layer was separated and washed with 3X 4.00L of water. The organic layer was concentrated at 30-100mbar and 22 + -5 deg.C to give-3.5L (3.47kg) of an AHU377 free acid isopropyl acetate solution as a colorless solution

To a reactor containing-3.5L (3.47kg) of AHU377 free acid isopropyl acetate solution was charged 1.984kg (4,556mmol) of valsartan and 40L of acetone. The reaction mixture was stirred at 23 ± 3 ℃ to give a clear solution which was filtered into one reactor. A1.0L aqueous solution of 547.6g (13,690mmol) of NaOH was added to the reaction mixture over 15-30 minutes at 23. + -. 3 ℃ while maintaining the internal temperature at 20-28 ℃ with on-line filtration (a slight exotherm occurs). The flask was rinsed with 190mL of water and added to the reaction mixture. The reaction mixture was stirred at 23. + -. 3 ℃ for 15 minutes, and 4.0g of [ valsartan ((2R, 4S) -5)-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester) Na₃·2.5H₂Heating the suspension to 40 + -3 ℃ within 20 minutes, adding 20L isopropyl acetate within 20 minutes while keeping the internal temperature at 40 + -3 ℃, stirring the suspension at this temperature for another 30 minutes, concentrating the mixture at an internal temperature of 35 + -5 ℃ (Tj45 + -5 ℃) under reduced pressure (200 + -350mbar) to obtain 35L white slurry (collecting solvent: -25L), adding 30L isopropyl acetate, concentrating the mixture at 35 + -5 ℃ (Tj45 + -5 ℃) under reduced pressure (100 minus 250mbar) to obtain 30L white slurry (collecting solvent: -40L), adding 40L isopropyl acetate again, concentrating the mixture at 35 + -5 ℃ (Tj45 + -5 ℃) under reduced pressure (100 minus 200mbar) to obtain 30L white slurry (collecting solvent: -40L), filtering the mixture at 35 + -5 ℃ (Tj45 + -5 ℃) under reduced pressure (100 minus 200mbar) to obtain 30L white slurry (collecting solvent ℃.: 355 ℃ under reduced pressure (355 mbar), filtering the mixture at 355 ℃ under reduced pressure to obtain 355 ℃ after cooling the product, filtering the product at 355 ℃ under reduced pressure to obtain 355 ℃ and drying the product of polypropylene under reduced pressure (2 × 5 ℃, and filtering the product of 3. + -. 3 ℃ to obtain the product, and drying the product.

Qualitative indication shows the same product obtained as in example 1.

Powder X-ray diffraction

An X-ray powder spectrum is obtained by using a ScintagXDS2000 powder diffractometer, and lattice plane spacing calculation is carried out on the most important lines of the sample, so as to obtain the following results:

21.2(s)，17.0(w)，7.1(s)，5.2(w)，4.7(w)，4.6(w)，4.2(w)，3.5(w)，3.3(w)

error of all lattice plane spacing ±. + -.)The peak intensities are shown below: (w) weak; (m) ═ medium; (st) is strong.

The average value of 2 theta [ deg. ] is expressed as (error range. + -. 0.2)

4.5，5.5，5.6，9.9，12.8，15.7，17.0，17.1，17.2，18.3，18.5，19.8，21.5，21.7，23.2，23.3，24.9，25.3，27.4，27.9，28.0，30.2。

Elemental analysis

Elemental analysis yielded the following measurements of the elements present in the sample. Within the error range, the results of the elemental analysis are compared with the general formula (C)₄₈H₅₅N₆O₈Na₃)·2.5H₂And O is consistent:

measured value: c: 60.05% H: 6.24% N: 8.80 percent

Calculated value^*：C：60.18％H：6.31％N：8.77％

Infrared spectroscopy

The infrared absorption spectrum of the sample was obtained using a Fourier transform attenuated Total reflectance Infrared Spectroscopy (ATR-FTIR) spectrometer (NicoletMagna-IR560), and the important bands are listed below, expressed in reciprocal of wavelength (cm)^-1)：

2956(w)，1711(st)，1637(st)，1597(st)，1488(w)，1459(m)，1401(st)，1357(w)，1295(m)，1266(m)，1176(w)，1085(m)，1010(w)，1942(w)，907(w)，862(w)，763(st)，742(m)，698(m)，533(st)。

Error of all absorption bands of ATR-IR is + -2 cm^-1。

The intensity of the absorption band is expressed as follows: (w) weak; (m) ═ medium; (st) is strong.

Raman spectroscopy

The raman spectrum of the sample measured by a diffusion raman spectrometer (kaiser optical systems, Inc.) with a 785nm laser excitation source had the following reciprocal wavelengths (cm)^-1) Band of light represented:

3061(m), 2930(m, width), 1612(st), 1523(m), 1461(w), 1427(w), 1287(st), 1195(w), 1108(w), 11053(w), 1041(w), 1011(w), 997(m), 866(w), 850(w), 822(w), 808(w), 735(w), 715(w), 669(w), 643(w), 631(w), 618(w), 602(w), 557(w), 522(w), 453(w), 410(w), 328 (w).

Error of all Raman bands is + -2 cm^-1.

The intensity of the absorption band is expressed as follows: (w) weak; (m) ═ medium; and (st) is strong.

High resolution CP-MAS¹³CNMR spectroscopy

Using Bruker-BioSpinaVANCE500NMR chromatograph, by high resolution CP-MAS (CrossPolarizationNagleping)¹³CNMR Spectroscopy of samples, the chromatograph equipped with 300 Watts high energy¹H. Two 500 watt high energy X-amplifiers (necessary high energy pre-amplifiers), one "MAS" controller and a 4mm biosolids high resolution Bruker probe.

Each sample was filled to 4mmZrO₂In the rotor. The key experimental parameter is 3msec¹³C contact time, magic Angle rotation speed of 12KHz, "ramped" contact time, using "SPINAL 64"¹H decoupling protocol, cycle delay time of 10 seconds, at 293degK 1024 scans. Chemical shifts were determined using the glycine carbonyl at 176.04ppm as external standard.

High resolution CP-MAS¹³CNMR shows the following important peaks (ppm):

179.0，177.9177.0，176.7，162.0，141.0，137.2，129.6，129.1，126.7，125.3，64.0，61.5，60.4，50.2，46.4，40.6，38.6，33.5，32.4，29.8，28.7，22.3，20.2，19.1，17.8，16.8，13.1，12.1，11.1。

the physical mixture of the individual sodium salts of valsartan and (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester shows a simple inert mixture of the two salts. However, the sample of the complex prepared in example 1 had a significantly different spectral signature compared to the 1: 1 mixture of sodium salts.

DSC and TGA

The melting onset temperature and the peak temperature of the sample were 139 ℃ and 145 ℃ respectively, as determined by Differential Scanning Calorimetry (DSC) using a Q1000 (taiinstruments) instrument.

DSC and thermogravimetric analysis (TGA) show that, when heated, the hydrated water is released through two steps: the first step occurs below 100 ℃ and the second step occurs above 120 ℃.

The heating rate of the DSC and TGA instruments was 10K/min.

Example 4

Preparation of the prodrugs linked in scheme (1)

Linked prodrugs of valsartan calcium salt and (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester are prepared as follows: 114mg of valsartan calcium salt and 86mg of (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester free acid are dissolved in 2mL of methanol at room temperature, and the methanol is evaporated. 3mL of acetonitrile was then added to the glassy solid residue and equilibrated for 10 minutes. Sonicate, then magnetically stir for 20 hours. About 120mg of white solid was collected by filtration. Liquid Chromatography (LC) and elemental analysis showed a 1: 1 ratio between (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester and valsartan. X-ray powder diffraction showed the sample to be amorphous.

Preparation of the prodrugs linked in scheme (2)

The linked prodrug of valsartan calcium salt and (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester and Tris was prepared as follows: 57mg of valsartan calcium salt, 43mg of (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester free acid and 12.6mg of Tris (hydroxymethyl) aminomethane (Tris) were dissolved in 2mL of methanol, and the methanol was evaporated. Subsequently, 3mL of acetonitrile was added to the glassy solid residue and equilibrated for 10 minutes. Sonicate, then magnetically stir for 20 hours. About 83mg of white solid was collected by filtration. LC and elemental analysis showed a 1: 1 ratio between (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester and valsartan. X-ray powder diffraction showed the sample to be amorphous.

The present invention has been described in terms of the specific embodiments above, but it is evident that many alternatives, modifications and variations can be employed without departing from the inventive concepts disclosed herein. Accordingly, it is intended to embrace all such changes, modifications and variations that fall within the spirit and broad scope of the appended claims. All patent applications, patents, and other publications cited herein are incorporated by reference in their entirety.

Claims (14)

1. A complex having the formula [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-yl) biphenyl-4 ' -ylmethyl } amino) butanoic acid]Na₃·xH₂O, wherein x is 0 to 3, the complex being in solid form and characterized by a Fourier transform attenuated Total reflectance Infrared Spectroscopy (ATR-FTIR) having the following absorption bands expressed in reciprocal of wavelength (cm)^-1)(±2cm^-1): 1711(st), 1637(st), 1597(st), and 1401 (st).

2. The complex of claim 1, wherein the complex is a supramolecular complex.

3. The complex of claim 1 or 2, in crystalline form.

4. The complex of claim 1 or 2, wherein the compound is in amorphous form.

5. A pharmaceutical composition comprising:

(a) the complex of any one of claims 1-4; and

(b) at least one pharmaceutically acceptable additive.

6. The pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable additive is selected from the group consisting of: diluents or fillers, disintegrants, glidants, lubricants, binders, colorants, and combinations thereof.

7. Use of a complex according to any one of claims 1-4 for the preparation of a medicament for the treatment or prevention of a disease or disorder selected from hypertension, heart failure, left ventricular insufficiency, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina, renal insufficiency, diabetes, secondary aldosteronism, glomerulonephritis, scleroderma, glomerulosclerosis, primary nephroproteinuria, diabetic retinopathy, migraine, peripheral vascular disease, raynaud's disease, luminal hyperplasia (luminal hyperplasia), cognitive disorders, glaucoma and stroke.

8. Use of a complex as claimed in claim 7, wherein the hypertension is selected from primary and secondary pulmonary hypertension, or renovascular hypertension.

9. Use of a complex according to claim 7, characterized in that the disease or condition is hypertension.

10. Use of a complex as claimed in claim 7, wherein the disease or condition is chronic heart failure.

11. Use of a complex according to any one of claims 1-4 for the preparation of a medicament for the treatment or prevention of a disease or condition selected from the group consisting of acute heart failure, chronic heart failure, congestive heart failure, unstable angina, stable angina, diabetic renal insufficiency, diabetic nephropathy and non-diabetic renal insufficiency.

12. A pharmaceutical composition comprising:

(a) the complex of any one of claims 1-4;

(b) a therapeutic agent selected from the group consisting of antidiabetics, hypolipidemic agents, antiobesity agents and antihypertensive agents; and

(c) at least one pharmaceutically acceptable additive.

13. The pharmaceutical composition of claim 12 wherein the therapeutic agent is amlodipine besylate.

14. The pharmaceutical composition of claim 12, wherein the therapeutic agent is hydrochlorothiazide.