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WO2008018843A1 - Procédé de production de formes de sel utiles de composés de biphényl-tétrazole - Google Patents

Procédé de production de formes de sel utiles de composés de biphényl-tétrazole Download PDF

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Publication number
WO2008018843A1
WO2008018843A1 PCT/TR2006/000036 TR2006000036W WO2008018843A1 WO 2008018843 A1 WO2008018843 A1 WO 2008018843A1 TR 2006000036 W TR2006000036 W TR 2006000036W WO 2008018843 A1 WO2008018843 A1 WO 2008018843A1
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WO
WIPO (PCT)
Prior art keywords
irbesartan
alkali metal
alcohol
ray diffraction
salt
Prior art date
Application number
PCT/TR2006/000036
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English (en)
Inventor
Tuncer Aslan
Tuba Bicer
Yildiz Gulkok
Selda Turhan
Melek Koroglu
Serdar Soylemez
Original Assignee
Ulkar Kimya Sanayi Ve Ticaret As
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ulkar Kimya Sanayi Ve Ticaret As filed Critical Ulkar Kimya Sanayi Ve Ticaret As
Priority to PCT/TR2006/000036 priority Critical patent/WO2008018843A1/fr
Publication of WO2008018843A1 publication Critical patent/WO2008018843A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to a method for producing useful salt forms of biphenyl- tetrazole compounds of the general formula
  • M is a monovalent or divalent cation selected from group consisting OfNa + , K + , Ca ++ or Mg + * and n is an integer having the value of 1 or 2
  • R 1 being a straight chain or branched Q-C ⁇ -alkyl group; and R 2 and R 3 being the same or different and being selected from
  • Ci-C 20 -alkyl groups which can - optionally be substituted with halogen atoms;
  • -straight-chain or branched, saturated or unsaturated C 1 -C 2 o-heteroalkyl groups which can optionally be substituted with halogen atoms
  • -aromatic or aliphatic C 3 -C 18 -hydrocarbon rings which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms
  • -aromatic or aliphatic C 3 -C 18 -heterocycles which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further
  • R is the same as in Formula (I) and R 4 is a hydrogen or a monovalent cation like sodium or potasium with an alkali or earth alkali metal hydroxide or halogenide selected from the group consisting of NaOH, KOH, Mg(OH) 2 , Ca(OH) 2 , MgCl 2 or CaCl 2 or their hydrates or alkoxides without use of additional water.
  • R 4 is a hydrogen or a monovalent cation like sodium or potasium with an alkali or earth alkali metal hydroxide or halogenide selected from the group consisting of NaOH, KOH, Mg(OH) 2 , Ca(OH) 2 , MgCl 2 or CaCl 2 or their hydrates or alkoxides without use of additional water.
  • the reaction is carried out in an organic solvent or their mixtures.
  • the organic solvents are; Q-C ⁇ -alcohol, C 3 -C 6 - ketone, C 3 -C 6 .ester, C 3 -C 7 eter or C 5 -C 8 -hydrocarbon.
  • protic solvents more preferably a C 1 -C 6 alcohols and especially an alcohol selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol and a mixture of C 1 -C 6 alcohols with an aprotic solvent selected from the group of ethyl acetate, diethyl ether, tert-butyl methyl ether, pentane hexans or heptane.
  • an alcohol selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol and a mixture of C 1 -C 6 alcohols with an aprotic solvent selected from the group of ethyl acetate, diethyl ether, tert-butyl methyl ether, pentane hexans or heptane.
  • biphenyl-tetrazole compounds of Formula (I) form among others the backbone of a number of known antihypertensive agents, in which R is for example
  • Antihypertensive agents comprising such a biphenyl-tetrazole backbone belong to a group of angiotensin II-receptor antagonists which are generally referred to as "sartans".
  • Sartans which show such a biphenyl-tetrazole backbone include Candesartan (R is III), Irbesartan (R is IV), Tasosartan (R is V), Losartan (R is VI), Olmesartan (R is VII) and Valsartan (R is VIII).
  • Angiotensin II mediates among others smooth muscle contraction especially in blood vessels.
  • Angiotensin II receptor antagonists therefore act as powerful vasodilators.
  • the new salt forms of the active pharmaceuticals provide possibilities for the formulation studies and can increase the stability and solubility of the active ingredients in vivo.
  • Another object of the present invention is to provide alkali metal and earth alkali metal salts of Irbesartan and also a process for producing thereof.
  • Another object of the present invention is to provide new polymorphic forms of different salts of saltans
  • Fig 1 shows a representative X-ray diffraction pattern of Irbesartan Sodium in amorphous form
  • Fig 2 shows a representative X-ray diffraction pattern of Irbesartan Potassium in amorphous form
  • Fig 3 shows a representative X-ray diffraction pattern of Irbesartan Potassium in crystalline form
  • Fig 4 shows a representative X-ray diffraction pattern of Irbesartan Magnesium in amorphous form
  • Fig 5 shows a representative X-ray diffraction pattern of Irbesartan Calcium in amorphous form
  • Fig 6 shows a representative X-ray diffraction pattern of Losartan Magnesium in crystalline form
  • Fig 7 shows a representative X-ray diffraction pattern of Losartan Calcium in crystalline form
  • Fig 8 shows a representative X-ray diffraction pattern of Valsartan Calcium in crystalline form
  • the compounds of Formula (II) include precursors to the above sartans that are generally protected by a triphenylmethyl-protecting group and can be obtained deprotection of the protecting group on the tetrazole ring by using an acidic agent.
  • Irbesartan, its salts with acid or bases, methods of making and using them, is first described in EP0454511B1.
  • EP0708103B1 discloses form A and form B of Irbesartan and a process for the preparation thereof.
  • the product obtained according to EP0454511 is referred as form A.
  • WO9967236 discloses a new crystalline habit of form A of Irbesartan and a process for the preparation thereof.
  • WO04089938 discloses form C Irbesartan and a process for the preparation thereof.
  • WO03050110 discloses the amorph form of Irbesartan. None of these publications claims the polymorphic forms of different salts of Irbesartan.
  • WO06046043A1 discloses a process for the preparation of Irbesartan HCl in crystalline hydrated or anhydrous form or in amorphous form. No specific alkali or earth alkali metal salts of Irbesartan were described in the prior art.
  • Losartan is first described in EP0324377B1 in its no salt form. Lately, a process for the preparation of Losartan potassium with potassium hydroxide was described in EP324377B1. Potassium salt of Losartan is known to be the most convenient salt for the formulation.
  • WO 04066997 A2 comprises the earth alkali metal salts of Losartan.
  • the publication describes preparing suitable salt forms of Losartan by using a metal- alkoxide or hydroxide in isopropanol/water. Generally, the mixture is evaporated under reduced pressure to remove the water. Further n-heptane is used as an aprotic solvent to precipitate the Losartan salt. This procedure is almost the same with the patent EP0324377B1.
  • the main problem with these patents is that the given process is complicated due to pH adjustment and removal of the water, which is a time consuming process. Further during the removing of water, side product can be formed.
  • Valsartan is first described in EP443983B1. Salts of Valsartan was mentioned in EP443983B1 but special properties of specific salts were not mentioned. US 23207930 describes different Valsartan salts as well as salt mixtures thereof.
  • the process described herein comprises the reaction of Valsartan and the appropriate base such as KOH, Mg(OH) 2 and Ca(OH) 2 in a water containing organic solvent. In some cases water had to be removed by adding a co-solvent like toluene and acetonitrile to precipitate the formed salts, which is a time consuming process. At the end step acetonitrile is used which is not a preferable solvent due to the toxicity reasons. Additionally, some cases longer reaction time is necessary to crystallize the salt product.
  • Another object of this invention is the preparation of Ca and Mg salts of saltans, starting from their potassium and sodium salts.
  • the advantage of this process is the elimination of the use of Ca(OH) 2 and Mg(OH) 2 which shows solubility problems.
  • the present invention is a process for the preparation of alkali metal salts of Irbesartan by using a process comprising following steps: dissolving Irbesartan in an alcohol; dissolving alkali hydroxide in the same alcohol and mixing the solutions together; stirring the mixture at 20-85 0 C for 1-4.5 hours; reducing the volume; and in some cases adding the alcohol to an aprotic solvent or directly precipitating; isolating the formed salt by filtration.
  • the present invention is a process preparing earth alkali metal salts of Irbesartan from alkali metal salts of Irbesartan by replacement of sodium or potassium with magnesium or calcium using a process comprising the following steps: dissolving Irbesartan sodium or potassium in an alcohol; dissolving earth alkali metal chloride such as MgCl 2 or CaCl 2 or their hydrates or alkoxides in the same alcohol and mixing the solutions together; stirring the mixture at 20-85 0 C for 1-4.5 hours; reducing the volume; in some cases participitating the product between an organic solvent and aqueous solvent; reducing volume of organic solvent containing desired product and some cases adding the polar solvent into an aprotic solvent or directly precipitating; isolating the formed salt by filtration.
  • the present invention is a process for the preparation of earth alkali metal salts of Losartan from alkali metal salts of Losartan by replacement of sodium or potassium with magnesium or calcium using a process comprising following steps: dissolving Losartan sodium or potassium in an alcohol; dissolving earth alkali metal chloride such as MgCl 2 or CaCl 2 or their hydrates or alkoxides in the same alcohol and mixing the solutions together; stirring the mixture at 20-85 0 C for 1-4.5 hours; reducing the volume; in some cases participitating the product between an organic solvent and aqueous solvent; reducing volume of organic solvent containing desired product and directly precipitating; isolating the formed salt by filtration.
  • the present invention is a process for the preparation of earth alkali metal salts of Valsartan from alkali metal salts of Valsartan by replacement of sodium or potassium with magnesium or calcium using a process comprising following steps: dissolving Valsartan sodium or potassium in an alcohol; dissolving earth alkali metal chloride such as MgCl 2 or CaCl 2 or their hydrates or alkoxides in the same alcohol and mixing the solutions together; stirring the mixture at 20-85 0 C for 1-4.5 hours; reducing the volume; in some cases participitating the product between an organic solvent and aqueous solvent; reducing volume of organic solvent containing desired product and directly precipitating; isolating the formed salt by filtration.
  • a Rigaku Miniflex X-ray diffractometer is used for the measurements of X-ray diffractograms.
  • the scanning range was 2-40 degrees two-theta.
  • the samples were grounded before analysis.
  • the present invention is a process for preparing Irbesartan Sodium in amorphous form, characterized by X-ray powder diffraction pattern and depicted in Figure 1.
  • the present invention is a process for preparing Irbesartan potassium in amorphous form, characterized by X-ray powder diffraction pattern and depicted in Figure 2.
  • the present invention relates to Irbesartan Potassium in crystalline form Ul characterized by X-ray diffraction peaks (reflections) at about 5.2, 5.7, 6.6,
  • the present invention is a process for preparing Irbesartan
  • Magnesium in amorphous form characterized by X-ray powder diffraction pattern and depicted in Figure 4.
  • the present invention relates to Irbesartan Magnesium in Figure 4 having the water content between about 0.1 % to 10 %, particularly, between about 3
  • the present invention is a process for preparing Irbesartan Calcium in amorphous form, characterized by X-ray powder diffraction pattern and depicted in Figure 5.
  • the present invention relates to Irbesartan calcium in Figure 5 having the water content between about 0.1 % to 10 %, particularly, between about 4 % to 8 % determined by Karl Fischer analysis.
  • the present invention relates to Losartan Magnesium in crystalline form Ul characterized by X-ray diffraction peaks (reflections) at about 6.8, 7.2, 8.3, 11.2, 12.3, 12.9, 13.3, 14.4,14.9, 15.2, 16.5, 17.6, 18.7, 19.2, 20.0, 20.3, 20.9, 21.7, 22.2, 23.3, 23.9, 24.4, 24.9, 25.3, 25.8, 25.9, 27.0, 27.6, 28.4, 28.9, 29.2, 29.8, 30.8, 31.2, 31.8, 32.5, 33.2, 34.0, 35.0, 35.6, 36.2, and 37.2 + 2 degrees two theta as depicted in Figure 6. It is also an aspect, the present invention relates to Losartan Magnesium in form Ul having the water content between about 0.1 % to 10 %, particularly, between about 4 % to 8 % determined by Karl Fischer analysis.
  • the present invention relates to Losartan Calcium in crystalline form Ul characterized by X-ray diffraction peaks (reflections) at about 6.1, 9.36, 10.0, 11.6, 12.5, 13.9, 14.6, 15.5, 16.2, 16.7, 17.1, 18.9, 19.6, 20.4, 21.8, 22.9, 24.0, 25.8, 26.9, 28.7, 30.9, 31.8, and 36.5 ⁇ 2 degrees two theta as depicted in Figure 7. It is also an aspect, the present invention relates to Losartan Calcium in form Ul having the water content between about 0.1 % to 10 %, particularly, between about 4 % to 8 % determined by Karl Fischer analysis.
  • the present invention relates to Valsartan Calcium in crystalline form Ul characterized by X-ray diffraction peaks (reflections) at about 6.0, 9.4, 10.0, 11.6,
  • the present invention relates to Valsartan Calcium in form Ul having the water content between about 0.1 % to 10 %, particularly, between about 4 % to 8 % determined by Karl Fischer analysis.
  • the present invention is a process for preparing earth-alkali metal salts of Irbesartan starting from Irbesartan sodium by using a process comprising following steps: dissolving Irbesartan sodium in an alcohol; dissolving MgCl 2 or
  • the present invention is a process preparing earth-alkali metal salts of losartan starting from Losartan potassium by using a process comprising following steps: dissolving Losartan potassium in an alcohol; dissolving MgCl 2 or CaCl 2 hydrates in the same alcohol and mixing the solutions together; stirring the mixture at 50-70 0 C for 1-4.5 hours; reducing the volume; participitating the product between an organic solvent and water; concentrating organic solvent under reduced pressure; stirring for 1-2 hours and isolating the formed salt via filtration.
  • the compound of Formula (I) is a compound that shows angiotensin II -receptor antagonistic activity.
  • it is selected from the group consisting of Candesartan, Irbesartan, Losartan, Olmesartan, Tasosartan and Valsartan, whereby Irbesartan, Losartan and Valsartan are particularly preferred.
  • Such compounds are powerful vasodilators and antihypertensive agents and therefore are of high commercial interest.
  • the reaction is carried in an alcohol, more preferably a C 1 -C 6 alcohol especially an alcohol selected from the group consisting of methanol, ethanol and isopropanol by using 0.5 to 1 equivalent of the metal hydroxide or chloride.
  • the method further comprises isolating formed salt of biphenyl tetrazole compounds from the solvent preferably by precipitation.
  • an aprotic solvent like hexane, heptane, ether or ethyl acetate to precipitate the salts.
  • an aqueous extraction is necessary to remove formed sodium or potassium chloride then following concentration of organic phase result in precipitation of the desired salts.
  • Precipitation is a particularly preferred method for isolating the formed salts since it can be affected by simply stirring the mixture at room temperature without the need for more complex purification technique such as column chromatography.
  • the solvent is a protic solvent, preferably an alcohol, more preferably a C 1 -C 6 alcohol and especially an alcohol selected from the group consisting of methanol, ethanol and isopropanol.
  • protic solvents particularly alcohols, especially C 1 -C 6 alcohols
  • Methanol, ethanol, and isopropanol have thereby been shown to be the most suitable solvents.
  • the compound of formula (II) is reacted with the any metal hydroxide or earth alkali hydroxide or chloride, such as of NaOH,
  • the compound of formula (II) is reacted with the metal hydroxide or earth alkali hydroxides for 1.0 to 4.5 hours, preferably for 1.0 to 3.5 hours.
  • a biphenyl-tetrazole compound of the formula (II) is dissolved in an alcohol.
  • 0.5 to 1 equivalents of metal hydroxides or chlorides or their hydrates is dissolved in the same alcohol and both solutions are mixed together at 20-80 0 C.
  • the stirring is stopped.
  • the mixture is concentrated to precipitate the formed salt or evaporated to dryness under reduced pressure or participated between aqueous and organic phases and then precipitated by reducing volume of the organic phase.
  • the salt is dissolved in a polar solvent and added drop wise into an apolar solvent and isolated by filtration.
  • the aqueous phase was washed with another 50 mL ethyl acetate.
  • the ethyl acetate phase was filtered over celite and concentrated under reduced pressure and added to 100 mL of heptane dropwise while stirring.
  • the solid was isolated by filtration and after drying Irbesartan Mg was obtained (1.5g) as a white solid (77 % yield).
  • Valsartan Na was dissolved in 30 niL IPA at room temperature.
  • 1 ImL IPA 1.83 g (1 eq) CaCl2.2H 2 O was dissolved in 1 ImL IPA. This solution was added to the Valsartan Na solution. The mixture was stirred for 30 min. 6 rnL water and 250 mL ethyl acetate was added to the mixture. The aqueous phase was washed two times with ethyl acetate.
  • Valsartan Ca precipitated in ethyl acetate phase, filtered and after drying, Valsartan Ca (Form Ul) (4.0) was obtained as a white solid ( 68 % yield).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des procédés permettant de produire une forme de sel pharmaceutiquement utile de composés de biphényl-tétrazole répondant à la formule suivante par le remplacement du proton tétrazole acide par un métal alcalin ou le remplacement du métal alcalin des composés de tétrazole avec un métal alcalino-terreux. Le procédé selon l'invention permet d'obtenir de nouvelles formes polymorphes de sels de sartane.
PCT/TR2006/000036 2006-08-08 2006-08-08 Procédé de production de formes de sel utiles de composés de biphényl-tétrazole WO2008018843A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/TR2006/000036 WO2008018843A1 (fr) 2006-08-08 2006-08-08 Procédé de production de formes de sel utiles de composés de biphényl-tétrazole

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2006/000036 WO2008018843A1 (fr) 2006-08-08 2006-08-08 Procédé de production de formes de sel utiles de composés de biphényl-tétrazole

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018040065A1 (fr) * 2016-09-02 2018-03-08 诺瑞特国际药业股份有限公司 Formes cristallines de sel disodique de valsartan

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5541209A (en) * 1994-08-22 1996-07-30 Bristol-Myers Squibb Company Method of treating or preventing cardiac arrhythmia employing an N-substituted heterocyclic derivative
WO2002006253A1 (fr) * 2000-07-19 2002-01-24 Novartis Ag Sels de valsartan
WO2003066606A1 (fr) * 2002-02-04 2003-08-14 Novartis Ag Sels de valsartan
WO2004066997A2 (fr) * 2003-01-30 2004-08-12 Lek Pharmaceuticals D.D. Preparation de nouveaux sels pharmaceutiquement acceptables du losartan et des variantes correspondantes, et nouveaux procedes permettant de purifier et d'isoler ces sels
WO2005021535A2 (fr) * 2003-08-27 2005-03-10 Zentiva, A.S. Procede d'extraction du groupe protecteur de triphenylmethane
WO2005049587A1 (fr) * 2003-11-21 2005-06-02 Ranbaxy Laboratories Limited Procede de preparation de tetrazole de biphenyle
WO2006050923A1 (fr) * 2004-11-11 2006-05-18 Lek Pharmaceuticals D.D. Forme polymorphe d'irbesartan
WO2006084757A2 (fr) * 2005-02-14 2006-08-17 Novartis Ag Combinaison de sel ca/mg de valsartan avec un agent antidiabetique
WO2006131632A1 (fr) * 2005-06-06 2006-12-14 Sanofi Aventis Hydrates de sels alcalino-terreux d'irbesartan et leur preparation

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5541209A (en) * 1994-08-22 1996-07-30 Bristol-Myers Squibb Company Method of treating or preventing cardiac arrhythmia employing an N-substituted heterocyclic derivative
WO2002006253A1 (fr) * 2000-07-19 2002-01-24 Novartis Ag Sels de valsartan
WO2003066606A1 (fr) * 2002-02-04 2003-08-14 Novartis Ag Sels de valsartan
WO2004066997A2 (fr) * 2003-01-30 2004-08-12 Lek Pharmaceuticals D.D. Preparation de nouveaux sels pharmaceutiquement acceptables du losartan et des variantes correspondantes, et nouveaux procedes permettant de purifier et d'isoler ces sels
WO2005021535A2 (fr) * 2003-08-27 2005-03-10 Zentiva, A.S. Procede d'extraction du groupe protecteur de triphenylmethane
WO2005049587A1 (fr) * 2003-11-21 2005-06-02 Ranbaxy Laboratories Limited Procede de preparation de tetrazole de biphenyle
WO2006050923A1 (fr) * 2004-11-11 2006-05-18 Lek Pharmaceuticals D.D. Forme polymorphe d'irbesartan
WO2006084757A2 (fr) * 2005-02-14 2006-08-17 Novartis Ag Combinaison de sel ca/mg de valsartan avec un agent antidiabetique
WO2006131632A1 (fr) * 2005-06-06 2006-12-14 Sanofi Aventis Hydrates de sels alcalino-terreux d'irbesartan et leur preparation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018040065A1 (fr) * 2016-09-02 2018-03-08 诺瑞特国际药业股份有限公司 Formes cristallines de sel disodique de valsartan
CN109641856A (zh) * 2016-09-02 2019-04-16 诺瑞特国际药业股份有限公司 缬沙坦二钠盐的晶型
US10745363B2 (en) 2016-09-02 2020-08-18 Nanjing Noratech Pharmaceuticals Co., Ltd Crystal forms of valsartan disodium salt
CN109641856B (zh) * 2016-09-02 2022-09-30 南京诺瑞特医药科技有限公司 缬沙坦二钠盐的晶型

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