Also provided is a barium salt of valsartan, and a pharmaceutical composition thereof.

Background of the Invention Chemically, valsartan is (S)-N-(l-carboxy-2-methylprop-1-yl) N-pentanoyl-N-[2'- (lH-tetrazol-5-yl)-biphenyl-4-ylmethyl] amine of Formula I,

FORMULA I and is Imown from U. S. Patent No. 5,399, 578. It has angiotensin II antagonist properties and is used for the prophylaxis and treatment of diseases or conditions which may be inhibited by blocking the ATl receptor, such as high blood pressure and cardiac insufficiency.

The synthesis of valsartan is disclosed in U. S. Patent No. 5,399, 578; CN 1317485; and U. S. Patent No. 6,271, 375.

U. S. Patent No. 5,399, 578 discloses recrystallization from diisopropyl ether to obtain valsartan after extracting reaction mixture with ethyl acetate.

The preparation of several salts of valsartan has been reported in PCT application Nos. WO 02/06253, WO 3/066606 and U. S. Patent Application No. US 2003/0171414.

PCT Application No. WO 02/06253 discloses valsartan salts including sodium, potassium, magnesium and calcium salts; ammonium salts; and salts of lysine and arginine in different solid state and hydrated forms. Mono and poly hydrate valsartan salts of magnesium and calcium are disclosed in U. S. Patent Application No. US 2003/0171414.

Summary of the Invention In one general aspect there is provided a process for preparation of pure valsartan.

The process includes dissolving crude valsartan in an inert solvent to form a mixture, adding an organic or inorganic base to the mixture to form a salt of valsartan, isolating the salt of valsartan in a solid state, and converting the salt of valsartan into pure valsartan.

Embodiments of the process may include one or more of the following features.

For example, the inert solvent may be one or more of water, alcohols, esters, nitriles, chlorinated hydrocarbons, cyclic ethers, dipolar aprotic solvents and mixtures thereof.

The alcohol may be one or more of methanol, ethanol, isopropanol, and mixtures thereof.

The organic base may be one or more of Cl-C4 alkyl ammonia; mono, di or tri C1- C4 alkyl amine; mono, di or tri hydroxy C1-C4 alkyl amine; morpholine ; thiomorpholine ; piperidine; and pyrrolidine.

The inorganic base may be one or more of metal carbonate, metal bicarbonate and metal hydroxide.

The metal carbonate may be one or more of lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate.

The metal bicarbonate may be one or more of sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate.

The metal hydroxide may be one or more of sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide.

The process may further include the step of adding an antisolvent to precipitate out the salt of valsartan.

The antisolvent may include one or more of lower alkyl ethers, hydrocarbons, ketones and mixtures thereof.

The ketone may be one or more of acetone, methyl isobutyl ketone and mixtures thereof.

The conversion of salts of valsartan to pure valsartan may be achieved by the addition of an acid. The acid may be one or more of hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid.

The pure valsartan obtained may have a chiral purity of greater than or equal to about 99%.

In another general aspect there is provided a barium salt of valsartan. The crystalline barium salt of valsartan may be characterized by X-ray peaks at about 5.40, 15.14, and 16.30 0.2 degrees two-theta. The crystalline barium salt of valsartan may also be characterized by X-ray diffraction pattern as shown in Figure I.

In another general aspect there is provided a process for the preparation of valsartan barium, the process comprising contacting valsartan with barium hydroxide in a suitable solvent and isolating valsartan barium.

Embodiments of the process may include one or more of the following features.

For example, the suitable solvent may include one or more of alcohols, esters, nitriles, chlorinated hydrocarbons, cyclic ethers, dipolar aprotic solvents and mixtures thereof.

The alcohol may be one or more of methanol, ethanol, isopropanol, and mixtures thereof. m another general aspect there is provided a method of producing angiotensin II antagonist activity in mammals. This method includes administering a pharmaceutical composition of valsartan barium.

In yet another general aspect there is provided a method of treating or preventing hypertension, congestive heart failure, renal failure, chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, hypothyroidism, post myocardial infarction (MI),

coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; endothelial dysfunction with or without hypertension, hyperlipidemia, hyperlipoproteinemia, and hypercholesterolemia, and glaucoma. The method includes administering a pharmaceutical composition comprising valsartan barium.

In another general aspect there is provided a pharmaceutical composition which includes valsartan barium and one or more pharmaceutically acceptable excipients.

Detailed Description of the Invention Crude valsartan may be prepared by methods known in the art including those described in U. S. Patent No. 5,399, 578; CN 1317485 ; and U. S. Patent No. 6,271, 375.

Crude valsartan may contain isomeric impurities or any other impurity. Valsartan barium may also be obtained as a solution, for example from a reaction mixture resulting directly from a reaction in which valsartan is formed.

Suitable inert solvents for carrying out the processes include one or more of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile ; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride ; dipolar aprotic solvents, such as dimethylsulfoxide and dimethylformamide ; esters, such as ethylacetate and isopropylacetate; cyclic ethers, such as dioxane and tetrahydrofuran ; and mixtures thereof.

The mixture of crude valsartan and an inert solvent can be obtained by dissolving, suspending, slurrying, stirring or a combination thereof.

Suitable salts of valsartan include salts with an organic or inorganic base.

Valsartan salts with an inorganic base may include salts with alkali metal, such as lithium, sodium or potassium and alkaline earth metals salts, such as magnesium, calcium and barium. Valsartan salts with an organic base may include salts with Cl-C4 alkyl ammonia; mono, di or tri Cl-C4 alkyl amine; mono, di or tri hydroxy Cl-C4 alkyl amine; morpholine; thiomorpholine; piperidine; and pyrrolidine.

The conversion of crude valsartan into salt of valsartan is achieved by adding the corresponding organic or inorganic base.

Suitable inorganic bases include one or more of alkali metal carbonate, bicarbonate, hydroxide and mixtures thereof.

Suitable alkali metal carbonates include one or more of lithium carbonate, sodium carbonate and potassium carbonate.

Suitable alkali metal bicarbonates include one or more of sodium bicarbonate and potassium bicarbonate.

Suitable alkali metal hydroxides include one or more of sodium hydroxide and potassium hydroxide.

Isolation of salt of valsartan may be accomplished by one or more of concentration, crystallization, precipitation, cooling, filtration, centrifugation or a combination thereof.

The precipitation of salt of valsartan may be spontaneous, depending upon the solvent used and the conditions. Precipitation may also occur with the addition of an antisolvent, i. e. , a solvent in which the salt of valsartan is insoluble or sparingly soluble, to the inert solvent in which the salt of valsartan is prepared. Alternatively, precipitation can be induced by concentrating and/or reducing the temperature of the inert solvent, particularly if the initial temperature is elevated.

The salts of valsartan may also be obtained from any of the methods described in PCT application Nos. WO 02/06253, WO 03/066606 and U. S. Patent Application No.

2003/0171414, the relevant portions of which are herein incorporated by reference.

The isolation of salts of valsartan in their solid states can be useful for the removal of impurities. Salts may be crystallized one or more times before conversion to valsartan to get a higher purity if desired. For example, the isolation of valsartan salt in crystalline form may result in obtaining very pure valsartan.

It has been observed that isolation of the valsartan obtain via valsartan salts can result in general purification as well as chiral purification. The chiral purity of valsartan may be greater than about 99%.

Suitable antisolvents that may be added to precipitate out a salt of valsartan include one or more of hydrocarbons, such as hexane, cyclohexane, toluene, heptane and octane; ketones, such as acetone and methyl isobutyl ketone; lower alkyl ethers, such as diethylether and diisopropylether; and mixtures thereof.

The amount of the solvent used varies depending on the type of solvent and lot size. Crystallization or precipitation may be conducted with or without stirring. The crystallization/precipitation time and temperature can vary. For example, the crystallization/precipitation may be performed at temperatures of from about 0°C to about 50°C for 30 minutes to 3 hours. The conversion of salts of valsartan to pure valsartan may be achieved by addition of an acid in a suitable solvent. Suitable acids include one or more of hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid.

The solvent used for the conversion of salts of valsartan to pure valsartan may be the same as those used for the preparation of valsartan salt as detailed above. The reaction time and temperature also varies. For example, the reaction may be performed at temperatures of from about 20°C to about 50°C for 30 minutes to 2 hours. Pure valsartan may be isolated in a manner similar to that detailed above for isolating a salt of valsartan.

Valsartan barium is a good crystalline solid. Crystalline valsartan barium may be characterized by a strong X-ray peak at about 5.40 0.2 degrees two-theta and peaks at 15.14 and 16.30 0.2 degrees two-theta. Crystalline valsartan barium may also be characterized by its IR spectra and DSC graph.

Brief Description of the Drawings FIG. I is a powder X-ray diffraction pattern of valsartan barium.

FIG. II is a table of the X-ray diffraction peak values FIG. III is an infrared absorption spectrum of valsartan barium.

FIG. IV is a DSC graph of valsartan barium The crude valsartan used in the preparation of valsartan barium may be prepared by any of the methods known in the art including those described U. S. Patent No.

5,399, 578; CN 1317485; and U. S. Patent No. 6,271, 375. The starting valsartan may also

be obtained as a solution directly from a reaction in which valsartan is formed and used as such without isolation.

The term"contacting"includes dissolving, slurrying, suspending, stirring or a combination thereof. Isolation may be accomplished by one or more of concentration, precipitation, cooling, filtration, centrifugation or a combination thereof, optionally followed by drying.

Solvents used for the preparation of valsartan barium, may be similar to those used for the preparation of salts of valsartan as defined above.

The isolation of valsartan barium may be similar to the isolation of salts of valsartan as defined above.

Valsartan barium is useful for the prophylaxis and treatment of diseases or conditions which may be inhibited by blocking the ATl receptor. The diseases or conditions include one or more of hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery, atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e. g. chronic renal failure, hypothyroidism, post myocardial infarction (MI), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension, endothelial dysfunction with or without hypertension, hyperlipidemia, hyperlipoproteinemia, and hypercholesterolemia, and glaucoma.

The salt is usually administered as part of a pharmaceutical composition. Also provided is a pharmaceutical composition that includes valsartan barium and one or more pharmaceutically acceptable excipients.

Suitable excipients include one or more of carriers, diluents, lubricants, distingrants and glidants.

The pharmaceutical composition may optionally include other therapeutic ingredients.

The pharmaceutical composition may be conventionally formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed, for example, peroral or parental.

In the following section embodiments are described by way of examples to illustrate the process of invention. However, these do not limit the scope of the present invention.

METHODS Powder XRD X-Ray Difractometer, Rigaku Coorperation, RU-H3R Goniometer CN2155A3 X-Ray tube with Cu target anode Divergence slits 1°, Receiving slit 0. 15mm, Scatter slit 1° Power: 40 KV, 100 mA Scanning speed: 2 deg/min step: 0.02 deg Wave length : 1.5406 A FT-IR Instrument: Perlcin Elmer, 16 PC SCAN: 16scans, 4.0 cm' according to the USP 25, general test methods page 1920, infrared absorption spectrum by potassium bromide pellet method.

DSC DSC821 e, Mettler Toledo Sample weight: 2-5 mg Temperature range: 50-300° C Heating rate: 20° C/min Nitrogen 50.0 mL/min Number of holes in the crucible: 1

Example 1: Preparation of N- [(2'-ceanobiphenyl-4-yl ! methel]-N-pentanoyl- (L !-valine benzyl ester A solution of N-[(2'-cyanobiphenyl-4-methyl]- (L) -valine benzyl ester hydrochloride (25 g, 57.5 mmol) in dichloromethane (250 ml) was treated with diisopropyl ethyl amine (23.8 g, 184.1 mmol) and valeryl chloride (13.86 g, 115 mmol) at 0 to 5°C for 4 hours. The reaction mixture was washed with water, 5% sodium bicarbonate solution and 0.5 N hydrochloric acid successively. The organic layer was then concentrated to obtain title compound as yellow-colored oil.

Preparation of (S)-N- (1-benzvloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-L' (lH- tetrazol-5-yllbiphenyl-4-vl-methyl] amine A mixture of the N- [ (2'-cyanobiphenyl-4-yl) methyl] -N-pentanoyl- (L)-valine benzyl ester as obtained above, tributyltin chloride (56.2 g, 172.6 mmol), sodium azide (11.2 g, 172.6 mmol) and tetra butyl ammonium bromide (2.5 g) in toluene (80 ml) was refluxed for 30 hours. It was cooled and stirred with solution of acetic acid (12 ml in 25ml water) for 1 hour. The organic layer was separated, concentrated and was stirred with the solution of potassium hydroxide (12.8 g in 250 ml water). The aqueous layer was washed with diisopropyl ether, acidified and extracted with ethylacetate. The ethyl acetate layer was concentrated at reduced pressure to obtain title compound as reddish thick syrupy mass. <BR> <BR> <P>Preparation of (S)-N- !-N-(1-carboxy-2-methyl-prop-1-yl !-N-pentanoyl-N-r2l (lH-tetrazol-5- yl) biphenyl-4-yl-methyl] amine barium salt (Valsartan Barium) Palladium carbon (3g, 10%) was added to the solution of (S)-N- (1- benzyloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N- [2' (lH-tetrazol-5-yl) biphenyl-4- yl-methyl] amine obtained above in methanol (l 00ml) and hydrogenated at room temperature. The reaction was monitored by TLC. After completion of the reaction, it was filtered, concentrated and treated with a solution of sodium carbonate (8.25 g in 100 ml water). The aqueous layer was washed with dichloromethane, acidified and extracted with ethyl acetate. The organic layer was concentrated (HPLC Purity: 93.5%). It was dissolved in a mixture of ethanol (150 ml) and water (150 ml). This solution was treated with barium hydroxide (18.1 g) and stirred for 1 hour. It was then filtered and concentrated to about 150 ml at 55 to 65°C under reduced pressure. It was treated with

acetone (150 ml) and stirred for 2 hours at 0 to 5°C. The solid obtained was filtered, washed with acetone (50 ml) and dried to obtain title salt as white crystalline solid.

Yield: 16.5 g; HPLC Purity: 99.3% ; XRD, IR spectra and DSC graph were identical to those shown in Fig. I, II and III respectively.

Example 2: Preparation ofN- [ (2'-cyanobiphenyl-4-yi) methyl]-N-pentanoyl- (D-valine methyl ester A solution of N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester hydrochloride (6 g, 16.7 mmol) in dichloromethane (50 ml), was treated with diisopropyl ethyl amine (7.6 g, 58.8 mmol) and valeryl chloride (4 g, 33.5 mmol) at 0 to 5°C for 1 hour. The reaction mixture was washed with water, 5% Sodium bicarbonate solution and 0. 5N hydrochloric acid successively. The organic layer was then concentrated to afford the title compound as yellow-colored oil.

Preparation of (S !-N-(l-methoxycarbonYl-2-methYl-prop-l-vl !-N-pentanoYl-N-[2v (1H- tetrazol-5-yl) biphenyl-4-yl-methyl] amine A mixture of the N- [ (2'-cyanobiphenyl-4-yl) methyl] -N-pentanoyl- (-valine methyl ester as obtained above, tributyltin chloride (16.34 g, 50.2 mmol), sodium azide (3.26 g, 50.2 mmol) and tetrabutyl ammonium bromide (0. 6 g) in toluene (30 ml) was refluxed for 30 hours. It was cooled and stirred with solution of acetic acid (3 ml in 6ml water) for 1 hour. The organic layer was separated and water (6 ml) was added to it.

Aqueous ammonia solution was then added to the mixture to adjust and pH to about 6.5.

The organic layer was separated and concentrated at reduced pressure to obtain title compound as reddish thick syrupy mass.

Preparation of (S)-N- (1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N- [2' (1H-tetrazol-5- yl) biphenyl-4-yl-methyl] amine barium salt (Valsartan Barium) Sodium hydroxide (1N, 92ml) was added to the mass of (S)-N- (1- methoxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'(1H-tet razol-5-yl) biphenyl-4-yl- methyl] amine as obtained above and was stirred for 12 hours at room temperature till the disappearance of the starting material. The reaction mixture was washed twice with dichloromethane (60 ml each). The aqueous layer was separated, acidified by concentrated hydrochloric acid to pH 2-2.1 and extracted with ethyl acetate (30ml). The organic layer was washed with water (6 ml) and concentrated to obtain crude valsartan (chiral purity:

96.07%, HPLC: purity 98.78%). It was then dissolved in ethanol (36ml) and water (36 ml) was added to it. Barium hydroxide octahydrate (5.28 g) was then added to the above mixture and stirred for 1 hour. The reaction mixture was filtered, concentrated to about 40ml at 50-55°C under reduced pressure, cooled and treated with acetone (36 ml). The reaction mixture was stirred for lhour, filtered and washed with acetone (12 ml). The solid obtained was dried to obtain valsas-tan barium.

Yield: 4.0 g; HPLC Purity: 99.7% ; Chiral purity: 99.75% ; XRD, IR spectra and DSC graph were similar to those shown in Fig. I, II and III respectively.

Example 3: Preparation of (S)-N- (l-carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N- [2' (lH- tetrazol-5-yl biphenvl-4-yl-methvl] amine barium salt (Valsartan Barium) Water (6 liters) was added to the solution of Valsartan (1 kg, HPLC Purity: 98.6%, Chiral purity: 96.5%) in ethanol (6 liters). It was then treated with barium hydroxide octahydrate (725 g) ) and stirred for 1 hour. The reaction mixture was filtered and concentrated to about 6 liters at 55-60°C under reduced pressure. The reaction mixture was then treated with acetone (6 litres) and stirred for 2 hours at 0-5°C. The obtained solid was filtered, washed with acetone (2 liters) and dried to obtain valsartan barium Yield: 1 kg ; HPLC Purity: 99.4% ; Chiral purity: 100%; XRD, IR spectra and DSC graph were similar to those shown in Fig. I, II and III respectively.

Example 4: Preparation of Pure (S)-N- (1-carboxy-2-metlml-ro-1-ylentanovl-N- [2' (, 1H-tetrazol-5-yl) biphenyl-4-yl-methyl] amine (Valsartan) A slurry of valsartan barium (0.95 kg) in ethyl acetate (9.5 liters) and water (3. 8 liters) was treated with hydrochloric acid to adjust pH to about 2-2.2. The organic layer was separated, washed with water thrice (0.33 liter each) and concentrated at about 45 to 50°C under reduced pressure. The residue was dissolved in ethyl acetate (3.61 liters) and stirred to get slurry. Pentane (21. 85 liters) was then added slowly and stirred for 1 hour at room temperature. The solid obtained was filtered, washed with pentane (2.37 liters) and dried under reduced pressure to obtain valsartan.

Yield: 0.57 kg ; Assay: 100.4% ; Chiral purity: 99.9%

Example 5: Preparation of Pure (S)-N- !-N-(l-carboxy-2-methyl-prop-l-yl !-N-pentanoyl-N [2' (1H-tetrazol-5-y) biphenyl-4-yl-methyl amine (Valsartan) A slurry of valsartan barium (10 g) in ethyl acetate (100 ml) and water (40 ml) was treated with hydrochloric acid to adjust pH to about 2-2.2. The organic layer was separated, washed with water and concentrated. The residue was dissolved in ethyl acetate (38 ml) and stirred to get slurry. Pentane (230 ml) was then added slowly and stirred for 1 hour at room temperature. The solid obtained was filtered, washed with pentane (25 ml) and dried under reduced pressure to obtain title compound as white solid.

Yield: 6 g.