Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
• • 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
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
  • C07D235/08—Radicals containing only hydrogen and carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2

Definitions

• the present invention is directed to processes for preparing a telmisartan intermediate substituted on position 2 of the biphenyl group of (4'-[(2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-biphenyI) and further converting such an intermediate to telmisartan and/or salts thereof.
• the processes according to the invention are cost and time effective and produce telmisartan with high yield and quality.
• ATj -antagonist angiotensin II receptor
• telmisartan From a compound with the chemical name 4'-[(2-n-propy!-4- methyl-6-(l-methylbenzimidazo]-2-yl)-benzimidazol-l -yl)-methyl]-biphenyl-2-nitrile (further named as telmisartan nitriie) and represented by formula 3
• the disclosed method can be used in the large-scale production of telmisartan and allows for a relatively easy purification thereof.
• US 2006/0264491 discloses reacting 4'((l,4 " -dimethyl-2'-propyl(2,6'-bi-lH- benzimidazol)-r-yl)-methyl)-( l ,r-biphenyl)-2-carboxamide via hydrolysis into telmisartan, isolating crude telmisartan and optionally purifying the crude telmisartan via crystallization.
• telmisartan is disclosed in US 2006/1 11417 and WO 2006/050921, while crystalline forms of telmisartan are disclosed in WO 00/43370, IN 2005MU00164 and US 2006/0276525.
• telmisartan Various salts of telmisartan are known, for example from CN 1548421, WO 03/037876, WO 2006/044754, WO 2006/050509, WO 2006/050921, EP 1 719 766, WO 2006/136916, WO 2007/01055k and WO 20C7/ 14788 ⁇ >
• the object of the present invention is to provide new methods for the production of telmisartan intermediates substituted on position 2 of the biphenyl group of (4'-[(2-n- pro ⁇ yl-4-methy]-6-( l-methylbenzimidazol-2-yl)-benzimidazol-l-yI)-methyl]-biphenyl) which methods are suitable for use on an industrial scale and which are economical, i.e. both cost and time effective and allow for the production of intermediates that can be converted into telmisartan and/or salts thereof with high quality and high yield.
• Another object of the present invention is to provide novel intermediates of telmisartan and derivatives thereof that enable new, cost and time effective synthetic routes to such compounds.
• the present invention provides processes for the preparation of the key intermediate of the synthesis of telmisartan, namely a telmisartan intermediate substituted on position 2 of the biphenyl group of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazoi- 2-yl)-benzimidazol-l-yl)-methyl]-biphenyl.
• the present invention provides novel intermediates useful for the synthesis of telmisartan intermediates substituted on position 2 of the biphenyl group of 4 " - [(2-n-propyl-4-methy ] ⁇ 6-(l -methylbenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]- biphenyl optionally in isolated and/or purified form and their use as intermediates in the preparation of telmisartan and/or its salts.
• the present invention provides telmisartan intermediates substituted on position 2 of the biphenyl group of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2- yl)-benzimidazol-l-yl)-methyl]-biphenyl prepared by the processes according to the oresenr invention having a purity of greater than 989r preferablv greater than 99 ⁇ 7r , wherein the amount of each individual impurity is less than 0.15%.
• the present invention provides a pharmaceutical composition for administering an effective amount of telmisartan or salts thereof prepared by the processes according to the present invention in a unit dosage form, either alone or in combination with another active ingredient.
• the object of the present invention is to provide novel time- and cost-effective processes for the preparation of intermediates of telmisartan derivatives substituted on position 2 of the biphenyl group of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yI)- benzimidazol- 1 -yl)-methyl]-biphenyl.
• These derivatives are represented by formula 3"
• Ri is Cj-C 6 alkyl
• R 2 is C 1 -C 6 alky I
• R 3 is Ci-C 6 alkyl
• Z is a group which can be converted to a tetrazolyl or a carboxyl group and can be selected from the group consisting of CN and COR O , wherein Rc can be N(R) 2 or ORi, wherein R is
• Z is -CN, -COOMe, -COOEt, -CONH 2 or -CONMe 2 .
• the first of the inventive processes comprises the steps of: a) acylation of an N-alkyl-substituted diamino benzene with the starting compound to form compound 7", b) condensation to form compound 6", c) reduction to give compound 5", d) aralkylation to give compound 4" and e) condensation to prepare compound 3"
• R] is Ci-C 6 alkyl
• R 2 is C 1 -C 6 alkyl
• R 3 is CrC 6 alkyl
• Z is a group which can be converted to a tetrazolyl or a carboxyl group and can be selected from the group consisting of CN and CORc, wherein Re can be N(R) 2 or ORi, wherein R is
• X is Cl, Br or I.
• the object of the present invention is to provide a process for the preparation of telmisartan intermediates represented by formula 3' (Scheme 3. wherein Z is as defined above):
• the object of the present invention is to provide a process for the preparation of telmisartan nitrile (Scheme 3, wherein Z is CN) comprising the following steps:
• Step a) Acylation of N-raethylbenzene- 1 ,2-diamine with compound 8 in the presence of a suitable solvent and a suitable catalyst, to form compound 7 (N-(2- aminophenyl)-4 ⁇ (butyramido) ⁇ N,3-dimethyl-5-mtrobenzamide).
• Suitable catalysts that can be used include, but are not limited to, pyridine, lriethylamine and similar.
• Suitable solvents that can be used include, but are not limited (o, tetrahydrofuran, dioxane, dichloro methane, chloroform, toluene, dimethylformamide and similar, ana anv mixtures tucreoi .
• the temperature for conducting the acylation can be in the range from about 0 to about 100 0 C. particularly from aboui 20 to about 60 0 C and more particularly at the reflux temperature of the solvent(s) used.
• the above preferred reaction conditions, catalysts and solvents are also the preferred embodiments to carry out the acylation step (a) according to the broader aspects of this invention. The same applies in the following mutatis mutandis.
• Step b) Condensation of compound 7 in the presence of a suitable solvent and a suitable catalyst, to form compound 6 (N-(2-methyl-4-(l-methyl-lH-benzo[d]imidazol- 2-yI)-6- nitrophenyl)butyramide).
• Suitable catalysts include, but are not limited to, pyridine, p-toluene sulphonic acid, acetic acid and similar organic and inorganic compounds that assist intramolecular condensation.
• Suitable solvents that can be used in step b) include, but are not limited to, tetrahydrofuran, dioxane, pyridine, acetic acid, toluene and similar solvents; and any mixtures thereof.
• the temperature for conducting the condensation can be in the range from about 0 to about 130 0 C, particularly from about 20 to about 60 0 C and more particularly at the reflux temperature of the solvent(s) used.
• Step c) Reduction of compound 6 by hydrogenation in the presence of a suitable solvent and a suitable catalyst to give compound 5 (N-(2-amino-6-methyl-4-( I -methyl- IH- benzo[d]imidazol-2-yI)phenyl)butyramide).
• Suitable catalysts that can be used in step c) include, but are not limited to, palladium on charcoal, Raney-Ni and similar hydrogenation catalysts.
• Suitable solvents that can be used include, but are not limited to, tetrahydrofuran, methanol, ethanol, propanol and other lower alcohols and ethers having Jess than 6 carbon atoms; water: and anv mixtures thereof.
• the temperature for conducting the reduction can be in the range from about 0 about 100 0 C. particularly from about 20 to about 50 0 C and more particularly at the reflux temperature of the solvent(s) used.
• Step d) Alkylation of compound 5 with 4'-(bromomefhyl) biphenyl-2- ⁇ itriIe in the presence of a suitable solvent and a suitable catalyst to form compound 4 (N-((2-nitrile- biphenyl-4'-methyl)amino-6-methyl-4-(l-methyl-lH-benzo fd] imidazol -2-yl) phenyl) butyramide).
• Suitable catalysts for step d) can be inorganic basic catalysts including, but not limited to, hydroxides of alkaline metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and other alkaline hydroxides; carbonates of alkaline metals such as for example sodium carbonate, potassium carbonate and other basic carbonates; and bicarbonates of alkaline metals such as for example sodium bicarbonate, potassium bicarbonate and similar hydrogen carbonates. Mixtures of these compounds may also be used as may be alkaline phosphates such as trisodium phosphate.
• Suitable solvents that can be used in step d) include, but are not limited to, tetrahydrofuran, acetonitrilc. toluene, N,N ⁇ dimethylforrnamide and similar; and any mixtures thereof.
• the temperature for conducting the alkylation can be in the range from about 0 to about 100 0 C, particularly from about 20 to about 50 0 C and more particularly at the reflux temperature of the solvent(s) used.
• Step e Condensation of compound 4 in the presence of a suitable solvent and a suitable catalyst to form compound 3 (4'-[(2-n-propy]-4-methyl-6 ⁇ (l-methylbenzimidazol-2-yl)- benzimidazol-l-yl)-methyl]-biphenyl-2-nitrile).
• Suitable catalysts that can be used in this step include, but not limited to, pyridine, p- toluene sulphonic acid, acetic acid and similar.
• Suitable solvents include, but are not limited to, tetrahydrofuran, dioxane, pyridine, acetic acid, toluene and similar; and any mixtures thereof.
• the temperature for conducting the condensation can be in the range from about 0 to about 130 0 C. particularly from about 20 to about 60 0 C and more particularly at the reflux temperature of the sumble(s) used.
• the starting compound 8" or 8 (4-(butyramido)-3-methyl-5-nitrobenzoic acid) can be prepared as disclosed in J. Med. Chem., 36(25), 4040-4051 (1993), or by acylation of 4- amino-5-methyl-3-nitrobenzoic acid, which is disclosed in US 3691166, US 7220862, WO 2005/065779 and WO 2007/056155.
• acylation reaction processes those known in the art for the acylation of amino groups such as activation with chlorides, mixed anhydrides and coupling reagents can be employed.
• Process B Another aspect of the present invention is Process B.
• This process is again directed at the preparation of intermediate telmisartan derivatives substituted on position 2 of the biphenyl group of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2 ⁇ yl)-benzimidazoi-l-yl)- methyl] -biphenyl as represented by formula 3". and comprises the steps of:
• R is Ci-C 6 alkyl
• R 2 is C,-C 6 alkyl
• R 3 is Ci-C 6 alkyl
• R 4 is CONR 5 , wherein R 5 is H or Ci-C 3 alkyl, Z is a group which can be converted to a tetrazoly] or a carboxyl group and can be selected from the group consisting of CN and COR 6 , wherein R 6 can be N(R) 2 or OR 1 , wherein R is
• X is Cl, Br or I.
• a preferred aspect of the present invention is a shortened process for the preparation of telmisarlan intermediates with formula ?" (Scheme 4. wherein Z is defined above!' Scheme 4
• telmisartan nitrile Scheme 4, wherein Z is CN
• Step a) involves the esterification of carboxyl group of compound 12 in the presence of a suitable solvent and a suitable catalyst, to form compound 11 (methyl 7-methyl-2-propyl- 3H ⁇ benzo[d]imidazole-5-carboxylate).
• Suitable catalysts can be inorganic acid catalysts including, but not limited to, hydrochloric acid, sulfuric acid and similar strong inorganic acids.
• Suitable solvents that can be used include, but are not limited to, methanol, tetrahydrofuran, acetomtrile, toluene and similar organic solvents; and any mixtures thereof.
• the temperature for conducting the esterification can be in the range from about 0 to about 100 0 C, particularly from about 20 to about 50 0 C and more particularly at the reflux temperature of the solvent(s) used.
• Step b) involves the alkylation of compound 11 with 4'-(bromomethyl)biphenyJ-2-nitril ⁇ , in the presence of a suitable solvent and a suitable catalyst to form compound 10 (4'-((7- methyl-2-piOpyl-3H-benzo[d]imidazole-5-methoxycarbonyl-3-yl)-methy ] )-biphenyl-2- nitrile).
• Suitable catalysts can be inorganic basic catalysts including, but not limited to, hydroxides of alkaline metals such as for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar alkaline oxides and hydroxides; carbonates of alkaline metals such as for example sodium carbonate, potassium carbonate and similar carbonates such as ammonium carbonate; and bicarbonates of alkaline metals such as for example sodium bicarbonate, potassium bicarbonate and similar bicarbonates such as ammonium hydrogen carbonate.
• hydroxides of alkaline metals such as for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar alkaline oxides and hydroxides
• carbonates of alkaline metals such as for example sodium carbonate, potassium carbonate and similar carbonates such as ammonium carbonate
• bicarbonates of alkaline metals such as for example sodium bicarbonate, potassium bicarbonate and similar bicarbonates such as ammonium hydrogen carbonate.
• Suitable solvents include, but are not limited to, acetone, tetrahydrofuran. acetonitrile, toluene. N,N-dimethylformamide and similar organic solvents: and anv mixrures thereof.
• the temperature for conducting the aikylation can be in the range from about 0 to about 100 0 C, particularly from about 20 to about 50 0 C and more particularly at the reflux temperature of the solvent(s) used.
• Step c) involves the hydrolysis of compound 10 in the presence of a suitable solvent and a suitable catalyst, to form compound 9 (4 > -((7-methyJ-2-propyl-3H-benzo[d]imidazole- 5- carboxyl-3-yl)-methyl)-biphenyl-2-nitrile).
• Suitable catalysts can be inorganic basic catalysts including, but not limited to, hydroxides of alkaline metals such as for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar; carbonates of alkaline metals such as for example sodium carbonate, potassium carbonate and similar carbonates such as ammonium carbonate.
• hydroxides of alkaline metals such as for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar
• carbonates of alkaline metals such as for example sodium carbonate, potassium carbonate and similar carbonates such as ammonium carbonate.
• S uj table solvents that can be used include, but are not limited to, methanol, ethanol, propanol and similar, water; and any mixtures thereof.
• the temperature for conducting the hydrolysis can be in the range from about 0 to about 80 0 C, particularly from about 20 to about 50 0 C and more particularly at the reflux temperature of the solvents used.
• Step d ⁇ involves the condensation of compound 9 with, N-methylbenzene-1.2-diamine in the presence of a suitable solvent and a suitable catalyst, to form compound 3 (4' ⁇ f(2-n- propyl-4 ⁇ methyl-6-(l-methylbenzimidazol-2-yl)-benzimidazol-l -yI)-methyl]-biphenyl-2- nitrile).
• Suitable catalysts that can be used include, but are not limited to, SOCl ? and similar compounds that assist the removal of water.
• Suitable solvents that can be used include, but are not limited to, methylene chloride, toluene, chlorobenzene and the like: and their mixtures.
• the temperature for conducting the condensation can be in the range from about 0 about 130 0 C particularly from about 20 to about 100 0 C and more particularly at the reflux temperature of the solvents used. As mentioned above, these preferred conditions apply to process B in general and are not limited to the particular embodiment of preparing telrnisartan nitrile by process B.
• the starting compound 12' ' or 12 (7 ⁇ methyl-2- ⁇ ropyl-3H-benzo[d] imidazole-5-carboxyiic acid), can be prepared by any method known from the prior art as for example from J. Med. Chern., 36(25), 4040-4051 (1993), WO 97/19911, CN 1623992, Youji Huaxue 26(3), 318-323 (2006) and WO 2006/044754.
• Yet a further preferred aspect of the present invention is the following process for the preparation of intermediates of telmisartan derivatives substituted on position 2 of the biphenyl group of 4'-[(2-n-propyl-4-methyl-6-(l -methyIbenzimidazol-2-yl)-benzimidazol- l -yl)-methyl]-biphenyl) with formula 3".
• This process comprises the steps of:
• R 1 is C 1 -Q, alkyl
• R2 is Ci-Cf 1 alkyl
• R 3 is C 1 -C 6 alkyl
• R 4 is CONR 5 , wherein R 5 is H or C 1 -C 3 alkyl,
• Z is a group which can be converted to a tetrazolyl or a carboxyl group and can be selected from the group consisting of CN and CORc.
• R ⁇ can be N(R) 2 or OR t , wherein R is H, Ci-C f1 alkyl or benzyl and X is Cl, Br or I.
• Step a) involves the alkylation of compound 11 " in the presence of a suitable solvent and a suitable catalyst to form compound 10" and optionally the hydrolysis of compound 10" in the presence of a suitable solvent and a suitable catalyst to form compound 9".
• Suitable catalysts can be inorganic basic catalysts including, but not limited to, hydroxides of alkaline metals such as for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar alkaline oxides and hydroxides; carbonates of alkaline metals such as for example sodium carbonate, potassium carbonate and similar carbonates such as ammonium carbonate; and bicarbonates of alkaline metals such as for example sodium bicarbonate, potassium bicarbonate and similar bicarbonates such as ammonium hydrogen carbonate.
• hydroxides of alkaline metals such as for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar alkaline oxides and hydroxides
• carbonates of alkaline metals such as for example sodium carbonate, potassium carbonate and similar carbonates such as ammonium carbonate
• bicarbonates of alkaline metals such as for example sodium bicarbonate, potassium bicarbonate and similar bicarbonates such as ammonium hydrogen carbonate.
• Suitable solvents that can be used include, but are not limited to, tetrahydrofuran, acetonitrile, toluene, N,N-dimethylformamide and similar; and any mixtures thereof.
• the temperature for conducting the alkylation can be in the range from about 0 to about 100 0 C, particularly from about 20 to about 50 0 C and more particularly at the reflux temperature of the solvent(s) used.
• Step b) involves the condensation of compound 9" or compound 10" with N- methylbenzene- 1 ,2-diamine in the presence in the presence of a suitable solvent and a suitable catalyst, to form compound 3" .
• the object of the present invention is to provide a process for the preparation of the telmisartan intermediates with formula 3' (Scheme 5, wherein Z if- as defined above), comprising: Scheme 5
• Z is a group which can be converted Io a tetrazolyl or a carboxyl group and can be selected from the group consisting of CN and COR 6 , wherein R 6 can be N(R) 2 or OR], wherein R is H. C]-C O alkyl or benzyl and Ri is C]-Q 1 alkyl.
• the object of the present invention is to provide a process for the preparation of telmisartan nitrile (Scheme 5, wherein Z is CN) comprising the steps of:
• Step a) involves the alkylation of compound 11 (methyl 7-methyl-2-propyl-3H- benzo[d]imidazole-5-carboxylat) with 4 " -(bromomethyl)biphenyl-2-nitrile in the presence of a suitable solvent and a suitable catalyst to form after hydrolysis compound 9 (4'-((7- methyl-2-propyl-3H-benzo[d]imidazoIe-5-methoxycarbonyl-3-yl)-methy])-biphenyl-2- nitrile) without the isolation of the ester.
• Suitable catalysts can be inorganic basic catalysts including, but not limited to. hydroxides of alkaline metals such as for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar alkaline oxides and hydroxides; carbonates of alkaline metals such as for example sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate and similar strongly alkaline salts; and bicarbonates of alkaline metals such as for example sodium bicarbonate, potassium bicarbonate and similar bicarbonates such as ammonium hydrogen carbonate.
• hydroxides of alkaline metals such as for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar alkaline oxides and hydroxides
• carbonates of alkaline metals such as for example sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate and similar strongly alkaline salts
• bicarbonates of alkaline metals such as for example sodium bicarbonate, potassium bicarbonate and similar bicarbonates such as ammonium hydrogen carbonate.
• Additional catalysts can be used such as iodides, including sodium iodide, potassium iodide and lithium iodide.
• iodides including sodium iodide, potassium iodide and lithium iodide.
• potassium iodide is used.
• Suitable solvents include, but are not limited to, tetrahydrofuran, 1,4- dioxane, 1 ,2-dimethoxyethane, acetonitrile, toluene, N,N-dimethylfor ⁇ iamide, N.N- dimethylacelamide, DMSO, acetone, 2-butanone, 3- ⁇ entanone and similar; and any mixtures thereof.
• the temperature for conducting the alkylation can be in the range from about 0 to about
• Suitable solvents that can be used include, but are not limited to. methanol, ethanol. propanol and similar alcohols; water, and any mixtures thereof.
• Suitable catalysts can be inorganic basic catalysts including, but not limited to, hydroxides of alkaline metals such as for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar alkaline oxides and hydroxides; and carbonates of alkaline metals such as for example sodium carbonate, potassium carbonate and similar carbonates such as ammonium carbonate.
• the temperature for conducting the hydrolysis can be in the range from about 0 to about 80 0 C, particularly from about 20 to about 50 °C and more particularly at the reflux temperature of the solvents used.
• the mixture is cooled and the pH of the mixture is adjusted to a value of 2-7, preferably to 5-6. by adding an acid such as a mineral acid, for example aqueous HCl, H 2 SO 4 or HiPO 4 ; preferably aqueous HCl is added.
• an acid such as a mineral acid, for example aqueous HCl, H 2 SO 4 or HiPO 4 ; preferably aqueous HCl is added.
• Step b) involves the condensation of compound 9 with N-methylbenzene- l,2-diamine in the presence of a suitable solvent and a suitable reagent to form compound 9a (1 ⁇ (( ' 2'- cyanobiphenyI-4-yl)methyl)-4-methy4-N-(2-(raethylamino)phenyl)-2- ⁇ ropyl-lH- benzofd]imidazole-6-carboxamide).
• N-methylbenzene-l,2-diamine can be used in form of a salt with an inorganic acid such as HCl. H 1 PO 4 and H 2 SO 4 .
• Suitable reagents for amide bond formation mat can be used include, but are not limited to, SOCI 2 and similar.
• the amount of the catalyst(s) is from 1 to 7 equivalents, preferably 3 to 5 equivalents.
• Suitable solvents that can be used include, but are not limited Io pyridine. K- methylpyrrolidone, toluene, dichloromethane. chloroform, 1 ,2-dimethoxyethane, THP. 2- methyl -THF, 1.4-dioxane, pentane and similar polar aprotic organic solvents: and their mixtures,
• the temperature for conducting the condensation can be in the range from about 0 about 13O 0 C, particularly from about 20 to about 100 0 C and more particularly at the reflux temperature of the solvent used.
• the product (compound 9a) is precipitated by adding an organic solvent such as a nonpolar solvent, preferably hexane, heptane, petroleum ether, cyclohexane, ethers (diethyl ether, diisopropyl ether, tert-butyl methyl ether), benzene, toluene, xylenes and similar.
• organic solvent such as a nonpolar solvent, preferably hexane, heptane, petroleum ether, cyclohexane, ethers (diethyl ether, diisopropyl ether, tert-butyl methyl ether), benzene, toluene, xylenes and similar.
• Step c) involves the cyclization of compound 9a to form compound 3 (4'-[(2-n-propyl-4- methyl-6-(l-mcthylbenzimidazol-2-yl ⁇ -benzimidazol-l -yl)-methyl]-biphenyI-2- nitrilej.
• organic solvent the following solvents can be used: toluene, ' xylenes, benzene, cyclohexane, 1,4-dioxane, THF, 2-mefnyl-THF, 1,2- dimethoxyethane, diisopropyl ether, tert-butyl methyl ether and similar.
• an acid catalyst is added to this mixture.
• a Lewis acid preferably H 3 BO 1 is used.
• the acidic catalyst is present in an amount from 1 to 50 mol%, preferably from 1 to 10 mol7r.
• the temperature for conducting the cyclization can be in the range from about 0 about 140 0 C and particularly at the reflux temperature of the solvents used. Water formed during the reaction can be separated and removed.
• the reaction mixture can optionally be worked up with activated charcoal.
• the product solution is cooled to a temperature between -10 and 30 0 C, preferably between 15 and 25 0 C, and the product is separated and dried.
• the starting compound 11 " or 11 (methyl 7-methyl-2-propyl- 3H-benzo[d] imidazole-5- carboxylate) can be prepared by any method known from the prior art as for example from J. Med. Chem.. 36(25), 4040-4051 (1993), WO 97/19911, CN 1623992, Youji Huaxue 26(3), 318-323 (2006) and WO 2006/044754.
• Another aspect of the presenl invention is Process C tor the preparation of intermediate lelmisartan derivatives substituted on position 2 of the biphenyl group of 4'-f(2-n-pro ⁇ yI- 4-methyl-6-(l -methylbenzimidazol-2-y] )-benzimidazol- ] -yl)-methyl]-biphenyl represented by formula 3 " .
• This process comprises the steps of: a) acyla ⁇ on of alkyldiaminobenzene of compound 12" to form compound 15"
• Ri is C 1 -C 6 alkyl
• R 2 is CrQ, alkyl.
• R 3 is C 5 -C 6 alkyl
• Z is a group which can be converted to a tetrazolyl or a carboxyl group and can be selected from the group consisting of CN and CORe, wherein R ⁇ can be N(R) 2 or ORj, wherein R is
• X is Cl, Br or I.
• a particular aspect of the present invention is a process for the preparation of the telmisartan intermediates with formula 3' (Scheme 6, wherein Z is as defined above):
• R . is C-G, alkyl
• R 2 is Ci-Q, alkyl.
• R 3 is Ci-C 0 alkyl.
• Z is a group which can be converted to a tetrazolyl or a carboxyl group and can be selected from the group consisting of CN and COR 6 , wherein R 6 can be N(R) 2 or ORi, wherein R is H, Ci-C 6 alkyl or benzyl.
• a preferred aspect of the present invention is a process for the preparation of telmisartan nitrile (Scheme 6, wherein Z is CN) comprising the steps of:
• Step a) involves the treatment of compound 12 with thionyl chloride or oxalyl chloride and the subsequent acylation of N-methyl-2-nitrobenzenamine in the presence of a suitable solvent and catalyst to form compound 15 (N,7 ⁇ dimethyl ⁇ N-(2-ni ⁇ rophenyl) ⁇ 2-propyl-3H ⁇ benzo[d]imidazoIe-5- carboxamide).
• Suitable catalysts include, but are not limited to, pyridine, triethyiarnine and similar basic catalysts.
• Suitable solvents include, but are not limited to. letrahydrofuran. dioxane, dichloromethane, chloroform, loiuene. dimetnvlformamide and similar; and any mixtures thereof.
• the temperature for conducting the acylation can be in the range from about 0 about 100 °C, particularly from about 20 to about 60 0 C and more particularly at the reflux temperature of the solvent(s) used.
• Step b) involves the alkylation of compound 15 with 4 ' -(bromomethy ⁇ bipheuyl-2-nitrile, in the presence of a suitable solvent and a suitable catalyst, to form compound 14 (4'- ((N,7-dimethyl-N-(2-nitrophenyl)-2-propyl-3H-benzo[d]imidazole-5-carboxamide-3-yl)- methyl)-biphenyl-2-nitriJe).
• Suitable catalysts can be inorganic basic catalysts including, but not limited to, hydroxides of alkali metals such as for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar; carbonates of alkaline metals such as for example sodium carbonate, potassium carbonate and similar; and bicarbonates of alkaline metals such as for example sodium bicarbonate, potassium bicarbonate and similar.
• hydroxides of alkali metals such as for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar
• carbonates of alkaline metals such as for example sodium carbonate, potassium carbonate and similar
• bicarbonates of alkaline metals such as for example sodium bicarbonate, potassium bicarbonate and similar.
• the expression “and similar” may particularly include the corresponding ammonium hydroxide, carbonate and hydrogen carbonate: the same applies throughout this application.
• Suitable solvents that can be used include, but are not limited to, tetrahydrofuran, acetonitrile, toluene, N.N-dimethylformarmde and similar polar aprotic solvents: and any mixtures thereof.
• the temperature for conducting the alkylation can be in the range from about 0 to about 100 0 C, particularly from about 20 to about 50 0 C and more particularly at the reflux temperature of the solvent(s) used.
• Step c) involves the reduction of compound 14 in the presence of a suitable solvent and a suitable catalyst to form compound 13 (4'-((N,7-dimethyI-N-(2-aminophenyl) -2-pro ⁇ yl-
• Suitable catalysts that can be used include, but are not limited to, palladium on charcoal,
• Suitable solvents that can be used include, but are not limited to, letrahydrofuran. methanol, ethanol. propanol and similar protic solvents; water; and any mixtures thereof.
• the temperature for conducting the reduction can be in the range from about 0 to about
• Step d) involves the condensation of compound 13 in the presence of a suitable solvent and a suitable catalyst to form compound 3 (4'-[(2-n- propyl -4-methy]-6-(l- methylbenziniidazol-2-yl)-benzimidazol-l-yl)-methyl] -biphenyl-2-nitrile).
• Suitable catalysts that can be used include, but are not limited to, pyridine, p-toluene sulphonic acid, acetic acid and similar compounds (see above).
• Suitable solvents that can be used include, but are not limited to, tetrahydrofuran, dioxane, pyridine, acetic acid, toluene and similar compounds (see above); and any mixtures thereof.
• the temperature for conducting the condensation can be in the range from about 0 to about 130 0 C, particularly from about 20 to about 60 0 C and more particularly at the reflux temperature of the solvent(s) used.
• the stalling compound 12" or 12 (7 ⁇ methyl-2-propyl- 3H-benzo[d]imidazole-5-carboxylic acid) can be prepared according to any method known from the prior art as for example from J. Med. Chem., 36(25), 4040-4051 (1993). WO 97/1991 1, CN 1623992, Youji Huaxue 26(3), 318-323 (2006) and WO 2006/044754.
• Another embodiment of the present invention are the telmisartan intermediate substituted on position 2 of the biphenyl group of 4'-[(2 ⁇ n-propyl-4-methyI-6-(l-methylbenzimidazoI- 2 ⁇ yl)-benzimidazol-l -y])-methyl]-biphenyl with formula 3 as well as the derivatives thereof represented by formulae 3' and 3" prepared by the processes according to the present invention having a purity of greater than 98%, preferably greater than 99%, wherein the amount of each individual impurity is less than 0.15%.
• the chemical purity of the compound with formula 3 or 3' or 3 plays an important role in the manufacturing process of telmisartan or telmisartan derivatives and/or salts thereof. If. for example, the chemical purity of the compound with formula 3 is less than 98%, the telmisartan substance further prepared from the compound with formula 3 does not comply with the pharmacopoeia requirements.
• telmisartan and of the telmisartan derivatives substituted on position 2 of the biphenyl group of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)- benzimidazol-l-yl)-methyl]-biphenyl with formulae 3' and 3" prepared by the processes according to the present invention are converted to telmisaitan and the telmisartan derivatives with formulae 1 and 1 ", respectively, by a hydrolysis process (Scheme 7a and Scheme 7b).
• Suitable hydrolysis processes are known from the prior art and are for example disclosed in EP 0 502 314, CN 1412183.
• Ri Ci-C 6 alkyl
• h. 2 is C
• R ⁇ is Ci-C 6 alkyl
• Z is a group which can be converted to a letrazolyl or a carboxyl group and can be selected from the group consisting of CN and COR G , wherein R 6 can be N(R) 2 or ORj, wherein R is H. C J -C 6 alkyl or benzyl.
• the obtained telmisartan is preferably converted to a pharmaceutically acceptable salt, such as the sodium, potassium, meglumine, erbumine or any other salt known from the prior art as for example from the co-pending application WO 2007/147889.
• the present invention provides novel intermediates of the synthesis of telmisartan nitriie, optionally in isolated and/or purified form selected from the group consisting of:
• the present invention provides the use of the novel intermediates in the preparation of telmisartan and/or its salts.
• Another aspect of the present invention is a pharmaceutical composition for administering an effective amount of telmisartan and/or its salts prepared by one of the processes according to the present invention, alone or in combination with another active ingredient and at least one pharmaceutically acceptable excipient selected from the group consisting of, but not limited to. basic agents, diluents, binders, disintegrants. surfactants, crystallization retarders, lubricants and glidants.
• pharmaceutically acceptable excipient denotes the additives used to convert pharmacologically active compounds into pharmaceutical dosage forms suitable for administration to patients.
• the solid pharmaceutical composition according to the present invention is preferably formulated in a unit dosage form, each dosage containing from about 10 to 160 mg, preferab ⁇ v from about 20 to 80 mg of telmisartan and/or its salts
• said other active ingredient can be present in an amount of 6.25 to 50 mg. preferably in an amount of 12.5 to 25 mg.
• the term ,umt dosage form refers to physically discrete units suitable as unitary dosages for human objects and other mammals. each unit containing a predetermined quantity of telmisartan and/or its salts calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical acceptable excipient.
• the term basic agent denotes such agents that maintain the pH of the pharmaceutical composition at a value of least 7, preferably at least 8.
• the pH of the pharmaceutical composition is measured by dissolving an appropriate amount thereof in neutral water and preparing a 20% [w/wj solution. Any standard pH meter can be used for the pH measurement.
• the basic agents used in the pharmaceutical composition according to the present invention may be selected from, but not restricted to, the group consisting of ammonia, choline, tert-butylamine, ethanolamme, NaOH, KOH, Ca(OH) 2 , Na- and K- carbonates, hydrogen carbonates and phosphates, meglumine, piperazine, diethylamine, L- arginine and any mixtures thereof. Preferred are ammonia, NaOH, KOH and meglumine.
• the diluent used in the pharmaceutical composition according to the present invention may be selected from, but not restricted to, the group consisting of mjcrocrystaliine cellulose, powdered cellulose, lactose (anhydrous and monohydrate), compressible sugar, fructose, dextrates, sugar alcohols such as mannitol, sorbitol, raaltitol, xylitol, lactitol, or other sugars such as saccharose, raffinose, trehalose, fructose or any mixtures thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate and any mixtures thereof.
• Preferred are water-soluble fillers like mannitol, sorbitol, xylitol and lactose other sugars.
• the binder used in the pharmaceutical composition according to the present invention may be selected from, but not restricted to, the group consisting of polyvinylpyrrolidone, microcrystalline cellulose, hydroxyethylceliulose, hydroxypropylcellulose, hydroxypropylmethylcellulose or other cellulose ethers, starch, pregelatinized starch, or polymethacrylate and any mixtures thereof.
• the disintegrant used in the pharmaceutical composition according to the present invention may be selected from, but not restricted to, the group consisting of crospovidone, starch, pregelatinized starch. sodium starch glycolate, microcrystalline cellulose. carboxymethylcellulose sodium (CMC-Na) or calcium (CMC-Ca), cross-linked CMC-Na, polacrilin potassium, low-substituted hydroxypropylcellulose and any mixtures thereof, Preferably, at least one disintegrant is selected from cross-linked CMC-Na, starch and low- substituted hydroxypropylcellulose.
• the surfactant used in the pharmaceutical composition according to the present invention may be selected from, but not restricted to, the group consisting of anionic, cationic, ampholytic and nonionic surfactants.
• Anionic surfactants are those where the hydrophilic group carries a negative charge are such as for example carbony] (RCOO " ), sulphonate (RSOV) or sulphate (ROSCV); examples include potassium laurate and sodium lauryl sulphate (GHb(CH 2 ) I iSO ⁇ a + ).
• Cationic surfactants are those where the hydrophilic group carries a positive charge (e.g., quaternary ammonium haiides, RiN + CF); examples include cetrimide, a mixture mainly consisting of tetradecyl (ca. 68%), dodecyl (ca. 22%), and hexadecyltrimethylammonium bromides (ca. 7%), as well as benzalkonium chloride, a mixture of alkylbenzyldimethylammonium chlorides of the general formula [C 6 HsCH 2 N + (CH 3 )OR]Cr, where R represents a mixture of the alkyls from C R H I7 to Ci 8 Hr 5 .
• quaternary ammonium haiides RiN + CF
• examples include cetrimide, a mixture mainly consisting of tetradecyl (ca. 68%), dodecyl (ca. 22%), and hexadecyltrimethylammoni
• Ampholytic surfactants are those where the molecule contains, or can potentially contain, both a negative and a positive charge (e.g., the sulfobetaines: RN + (CH 3 )OCH 2 CH 2 SOr 1 " ); examples include N-Dodecyl -NjNf- Dimethylbetaine (Ci 2 H 2S N + (CHs) 2 CHaCOO " ).
• Nonionic surfactants are a group of surfactants where the hydrophilic group carries no charge but derives its water solubility from highly polar groups such as hydroxyl or polyoxyethylene groups ((-CH?CH 2 O-) n ); examples include polyoxyethylated glycol monoethers (e.g. cetomacrogol), sorbitan esters (Spans”) and polysorbates (Tweens ® ), polyoxyethylene-polyoxypropylene copolymers and any mixtures thereof. Preferred are nonionic surfactants.
• the crystallization retarder used in the pharmaceutical composition according to the present invention may be selected from, but not restricted to the group consisting of povidone. copovidone, crospovidone. carboxymethylcellulose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose and any mixtures thereof. Preferred are povidone and copovidone.
• the lubricant and the glidant used in the pharmaceutical composition according to the present invention may be selected from, but not restricted to, the group consisting of stearic acid or stearic acid salts, such as for example magnesium stearate, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil. hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols, silicon dioxide and any mixtures thereof.
• at least one lubricant is selected from the group consisting of stearic acid, magnesium slearate and hydrogehated vegetable oil.
• the pharmaceutical composition according to the present invention may comprise one or more excipients selected from the group consisting of meglumine, Poloxarner 388, Povidone K30, KOH, NaOH, sorbitol, microcrystalline cellulose, lactose, mannitol, maltose and magnesium stearate.
• the pharmaceutical composition according to the present invention comprises meglumine, Povidone K30, NaOH, sorbitol, lactose and magnesium stearate as excipients.
• the pharmaceutical composition according to the present invention is characterized in that it is composed of telmisartan or a pharmaceutically acceptable sail thereof, meglumine, Povidone K30, NaOH, sorbitol, lactose, magnesium stearate.
• meglumine may be present in an amount of 1 to 30mg
• Povidone K30 may be present in an amount of 5 to 30mg
• NaOH and magnesium stearate may each be present in an amount of 2 to 1 Omg
• sorbitol and lactose may each be present in an amount of 50 to 300mg.
• the pharmaceutical composition according to the present invention can be prepared by any method known from the state of the art such as for example spray-drymg, fluid-bed granulation and lyophilization. If the pharmaceutical composition is prepared by a spray- drying method, telmisartan and/or its salts optionally together with a basic agent and/or optionally a crystallization retarder is dissolved in an appropriate solvent such as for example water or an organic solvent and spray-dried. The spray-dried granulate is further mixed with other pharmaceutically acceptable excipients to form the final composition.
• telmisartan and/or its salts optionally together with a basic agent and/or a crystallization retarder is dissolved in an appropriate solvent such as for example water or an organic solvent to form a granulation liquid.
• an appropriate solvent such as for example water or an organic solvent
• Other pharmaceutically acceptable excipients are placed in the fluid-bed granulating machine and sprayed with the granulation liquid.
• the obtained granulate is dried and optionally mixed with additional pharmaceutically acceptable excipients to form the final composition.
• the pharmaceutical composition according to the present invention can further contain at least one other active pharmaceutical ingredient. Any combinations of therapeutic doses of telmisartan and/or its salts and at least one other active pharmaceutical ingredient can be used in the pharmaceutical composition according to the present invention.
• the other active pharmaceutical ingredient can be selected from the group consisting of, but not limited to, diuretics such as for example hydrochlorothiazide or indapamide; antihypertensives such as for example angiotensin converting enzyme (ACE) inhibitors such as for example captopril, enalapril, lisinopril, trandolapril, cilazapril, ramipril, fosinopril, perindopril or any pharmaceutically acceptable salt thereof; angiotensin receptor blockers (ARBs); ATi -receptor antagonists such as for example candesaitan, irbesartan, iosartan, olmesartan, valsartan or any pharmaceutically acceptable
• fluvastatin. cerivastatin. rosuvastatin or any pharmaceutically acceptable salts thereof and antidiabetics such as for example sulfonyl urea, meglitinides (such as nateglinide and repaglmide) or an ⁇ ' pharmaceutically acceptable salts thereof, thiazolidinediones (such as pioglitazone and rosiglitazone) or any pharmaceutically acceptable salts thereof, alpha glucosidase inhibitors, incretin mimetics or bigua ⁇ ides such as for example metformin or the like and the pharmaceutically acceptable salts thereof.
• Diuretics such as hydrochlorothiazide or indapamide can be present exclusively within the granulate or they can be added exclusively as extragranular phase after granulation or they can be divided between the granulate and the extragranular phase.
• the amount of the diuretic can be between 5 and 50 mg, preferably between 10 and 30 mg, per dosage unit.
• telmisartan and/or its salts with a diuretic of any of these amounts are possible; for example, the ratio of telmisartan and/or its salts to hydrochlorothiazide
• [mg:mg] may be 40: 12.5, 80: 12.5 and 80:25.
• indapamide used as diuretic
• 0.5 to 3 mg, preferably 1.25 mg of indapamide is combined with 20, 40. or 80 mg of felmisartan
• telmisartan and/or its salts and at least one other active pharmaceutical ingredient such as for example hydrochlorothiazide
• telmisartan and/or its salts can be granulated by spray-drying or by a fluid-bed method to form a telmisartan-containing granulate.
• the granulate is then mixed with at least one other active pharmaceutical ingredient and compressed into tablets.
• telmisartan and/or its salts can be granulated and the other active pharmaceutical ingredient can be granulated as well. Two separate granulates are then mixed together to form a final composition.
• At least one other active pharmaceutical ingredient can be granulated and the obtained granulate is then mixed with telmisartan and/or its salts and then formed into a final composition.
• telmisartan and/or its salts are granulated and the obtained granulate is then coated with any particle-separating agent. The coated granulate is then mixed with the other active agent and then the final composition is formed.
• at least one other active pharmaceutical ingredient can be granulated and coated by any particle-separating agent. This coated granulate is then mixed with a telmisartan and/or its salts containing granulate and then the final composition is formed.
• a bilayer tablet can be prepared.
• telmisartan and/or its salts contains at least one other active pharmaceutical ingredient.
• a bilayer tablet can be prepared according to the previous method, where the two layers are additionally separated by a third layer that assures separation of particles.
• a bilayer tablet having a central core and an outer layer surrounding the core can be prepared.
• the two layers can be separated by an additional particle separating layer. Either telmisartan and/or its salts can be present in the core layer and the other active pharmaceutical ingredient is present in the outer layer or vice-versa.
• composition according to the present invention may be administered to a patient in any dosage form, such as for example tablet, pill, troche, lozenge, capsule, powder, liquid, suppository, sachet, elixir, solution, syrup, suspension etc., preferably in form of tablets or capsules.
• dosage forms may be adapted for administration to the patient by for example oral, buccal, parenteral, ophthalmic, rectal as well as transdermal route and preferably for oral route.
• a telmisartan salt prepared according to the present invention can be included in the pharmaceutical composition or it can be formed in-situ during the preparation of the pharmaceutical composition according to the present invention.
• telmisartan is placed in a solvent together with a corresponding basic agent and mixed together. Thereby, a dissolved salt form of telmisartan is obtained.
• the telmisartan salt can be used directly either m a spray-drying or in a fluid-bed process.
• the present invention provides a method of treating a disease state, which is prevented, ameliorated or eliminated by the administration of telmisartan and/or its salts prepared by the processes according to the present invention to a patient in need of such treatment.
• the present invention also provides the use of telmisartan and/or its salts prepared by the processes according to lhe present invention for the oreparation of a medicament comprising a pharmaceutical composition as described heremabove for treating a disease state, which is prevented, ameliorated or eliminated by the administration of lelmisartan and/or its salts.
• the present invention furthermore provides the use of telmisartan and/or its salts prepared by the processes according to the present invention for treating a disease state, which is prevented, ameliorated or eliminated by the administration of telmisartan and/or its salts.
• Example 10 Preparation of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yf)-benzimidazoI- l-yI)-methyl]-biphenyJ-2-nitrile (compound 3) from compound 9: 200 mg of compound 9 was added in ImI SOCIi. The mixture was heated to reflux. After 2 hours, SOCl 2 was evaporated at 45 0 C under reduced pressure to obtain a light-yellow foamy residue. The residue was dissolved in 2 ml dry pyridine and 100 mg N- methylbenzene-l,2-diamine was added. The mixture was heated to reflux for 24 h.
• telmisartan A mixture of 3 g of telmisartan and 20 ml of N,N-dimethylforrnamide was heated to a temperature of about 100 0 C until telmisartan was dissolved. Then the solution was filtered and cooled to room temperature. The solution was stirred at this temperature for 3h and then 2h at 0 0 C. The product was filtered, washed with DMF and dried under reduced pressure at 70-90 0 C to give 2.7 g of telmisartan (HPLC purity: 99.5%).
• telmisartan A mixture of 21.4 g of telmisartan, 107 ml of ethanol and 1.3 g of charcoal was stirred at room temperature for 15 min. Then 4.7 ml of 25% NH-, was added and the mixture was stirred for another 1.5h. The mixture was then filtered and the filtrate was heated to 80 0 C. At this temperature. 4.76 ml of acetic acid was slowly added and the mixture was cooled to room temperature. The mixture was stirred at this temperature for Ih, then the product was filtered, washed with water and ethanol and dried under reduced pressure at 70-90 0 C to give 19.7 g of telmisartan (HPLC purity: 99.6%)
• telmisartan was converted to its salts by adding a corresponding acid or base and subsequent isolation.
• telmisartan or salts thereof prepared by the processes according to the present invention or by any known processes
• compositions containing telmisartan can be prepared by various methods. Two appropriate methods are spray-drying and fluid-bed granulation. If telmisartan and/or its salts are prepared by a spray-drying method, telmisartan and/ov its salts together with a basic agent and optionally a crystallization retarder are dissolved in an appropriate (water or organic) solvent and spray-dried. The spray-dried granulate is mixed further with other excipients to form a final composition ready for tabletting. In case of
• I O fluid-bed granulation, telmisartan and/or its salts together with a basic agent and optionally a crystallization retarder are dissolved in an appropriate (water or organic) sumble to iorm a granulation liquid.
• Other excipients are placed in the fluid-bed granulating machine and sprayed with the granulation liquid.
• the granulate is d ⁇ ed and optionally mixed with additional excipients like flow control agents and/or lubricants5 to form a final composition ready for tabletting.
• compositions comprising a combination product containing telmisartan and/or its salts prepared by the processes according to the present invention or by any known processes and hydrochlorothiazide
• the telmisartan-containing granulate can, for instance, be prepared according to example 21.
• the hydrochlorothiazide-containing granulate can be prepared by any known method, for instance by wet or dry granulation, spray-drying etc.
• the final composition is then prepared bv mixing the two granulates together.
• Another possibilit y ' is that telmisartan and/or its salts are granulated and the obtained granulate is then coated with any particle- separating agent.
• the coated granulate is then mixed with the hydrochlorothiazide- containing granulate in order to prepare the final composition.
• Another possibility is thai the hydrochlorothiazide-containing granulate is coated by any particle-separating agent.
• telmisartan and/or its salts are then mixed with the telmisattan and/or its salts containing granulate and then the final composition is formed.
• a bilayer tablet can be prepared. One layer contains a granulate of telmisartan and/or its salts and the other layer contains a hydrochlorothiazide-containing granulate.
• a bilayer tablet can be prepared according to the previous method, where the two layers are additionally separated by a third layer that assures separation of particles.
• a bilayer tablet having a central core and an outer layer surrounding the core can be prepared. Optionally, the two layers can be separated by an additional particle separating layer. Either telmisartan and/or its salts can be present in the core layer and hydrochlorothiazide is present in the outer layer or vice- versa.

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