SI22674A - Procedure for preparation of telmisartan - Google Patents

Abstract

New procedures are described for preparation of a telmisartan nitrile intermediate, i.e.(4'-((2-n-propyl-4-methyl-6-(1-methyl- benzimidazol-2-yl)-benzimidazol-1-yl)-methyl)-biphenyl-2-nitrile), and further for its transformation into telmisartan and/or its salts.

Description

PROCEDURE FOR THE PREPARATION OF TELMISARTAN

FIELD OF THE INVENTION

The present invention relates to processes for the preparation of an telmisartan nitrile intermediate, (4 '- [[(2-n-propyl-4-methyl-6- (1-methyl-benzimidazol-2-yl) -benzimidazol-1-yl) - methyl] biphenyl-2-nitrile), and further for its conversion to telmisartan and / or its salts, which are cost effective and time efficient and give telmisartan in high yield and quality.

BACKGROUND OF THE INVENTION

Telmisartan, with its chemical name 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid and formula

is a nonpeptide antagonist of the angiotensin II receptor type AT _1; used to treat hypertension. It can be used alone or in combination with an active compound, e.g. hydrochlorothiazide.

It is described in EP 502314, as well as in J. Med. Chem. 36 (25), 4040-4051 (1993). Its polymorphs are known from EP 1144386 and J. Pharm. Sci, 89 (11), 1465-1479 (2000).

EP 502314A and J. Med. Chem., 36 (25), 4040 ^ 1051 (1993) describe a process for the preparation of telmisartan using a tert-butyl substituted intermediate (Scheme 1). The end product of this process was difficult to filter, wash and isolate. These qualities are a barrier to large-scale production.

Scheme 1:

Synthesis of telmisartan from a compound of formula 3 and the chemical name 4 '- [[(2-n-propyl-4methyl-6- (1-methyl-benzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl- 2-nitrile (hereinafter referred to as telmisartan nitrile)

is described in EP 502314A, WO 2004087676, CN 1412183 and US 2006/264491.

In WO 2004087676 and CN 1412183, telmisartan is prepared by hydrolysis of a compound of formula 3 (Scheme 2).

Scheme 2:

The process described can be used in the production of telmisartan on a large scale, giving an easily purified substance.

There is a need for an improved synthesis pathway to telmisartan nitrile.

Therefore, it is an object of the present invention to provide novel processes for the production of telmisartan nitrile that are suitable for an industrial scale, will be cost-effective, time-efficient and cost-effective and can be converted to high-quality telmisartan and / or its salts and in high yield.

Summary of the Invention

In one aspect, the present invention provides three different processes for the preparation of a key intermediate in the synthesis of telmisartan, namely telmisartan nitrile.

In another aspect, the present invention provides novel intermediates in the synthesis of telmisartan nitrile, optionally in isolated and / or purified form, and for use as intermediates in the preparation of telmisartan and / or its salts.

In another aspect, the present invention provides a pharmaceutical composition for administering an effective amount of telmisartan or its salts prepared by the methods of the present invention, in unit dosage form, alone or in combination with another active ingredient.

DETAILED DESCRIPTION OF THE INVENTION

It is an object of the present invention to provide a process for the preparation of telmisartan nitrile comprising:

a) acylation of alkyl substituted diamino benzene with starting compound 8 to form compound 7,

c) reduction to compound 5,

e) condensation to prepare 3

where:

R 1 is C 1 -C ₆ alkyl,

R _{2 is} C 1 -C 6 alkyl,

R ₃ C _r C ₆ alkyl,

With a group that can be converted into a tetrazoyl or carboxyl group,

X Cl, Br, J.

More specifically, it is an object of the present invention to provide a process for the preparation of telmisartan nitrile (Scheme 3) comprising:

a) acylation of 7V-methylbenzene-1,2-diamine with compound 8, 4- (butyramido) -3-methyl-5nitrobenzoic acid to form compound 7, 2V- (2-aminophenyl) -4- (butyramido) N, 3 -dimethyl-5-nitrobenzamide;

b) condensation of compound 7, 2V- (2-aminophenyl) -4- (butyramido-V, 3-dimethyl-5nitrobenzamide, to form compound 6, N- (2-methyl-4- (1-methyl-177benzo [d ] imidazol-2-yl) -6-nitrophenyl) butyramide;

c) reduction of compound 6, N- (2-methyl-4- (1-methyl-1 H -benzo [d] imidazol-2-yl) -6nitrophenyl) butyramide, to compound 5, 2V- (2-amino- 6-methyl-4- (1-methyl-1H-benzo [d] imidazol-2-yl) phenyl) butyramide;

d) alkylation of compound 5, N- (2-amino-6-methyl-4- (1-methyl-1 H -benzo [d] imidazol-2yl) phenyl) butyramide with 4 '- (bromomethyl) biphenyl-2-nitrile, to form compound 4, N ((2-nitrile-biphenyl-4'-methyl) amino-6-methyl-4- (1-methyl-1H-benzo [d] imidazol-2yl) phenyl) butyramide;

e) condensation of compound 4, V - ((2-nitrile-biphenyl-4'-methyl) amino-6-methyl-4- (1-methyl-1H-benzo [d] imidazol-2-yl) phenyl) butyramide to prepare compound 3, 4 '- [(2-n-propyl4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-nitrile.

Scheme 3:

Step a) involves the acylation of N-methylbenzene-1,2-diamine with compound 8 in the presence of a suitable solvent and catalyst to form compound 7, N- (2-aminophenyl) -4 (butyramido) -N, 3-dimethyl-5- nitrobenzamide.

Suitable catalysts that may be used include, but are not limited to, pyridine, triethylamine and the like.

Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, dimethylformamide and the like; and mixtures thereof.

The temperature for guiding the acylation may range from about 0 to about 100 ° C, in particular from about 20 to about 60 ° C, especially at the reflux temperature of the solvent used.

Step b) involves condensation of compound 7 in the presence of a suitable solvent and catalyst to form compound 6, N- (2-methyl-4- (1-methyl-1H-benzo [d] imidazol-2-yl) 6-nitrophenyl) butyramide .

Suitable catalysts that may be used include, but are not limited to, pyridine, p-toluene sulfonic acid, acetic acid and the like.

Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, dioxane, pyridine, acetic acid, toluene and the like, and any mixtures thereof.

The temperature for conducting the condensation may range from about 0 to about 130 ° C, in particular from about 20 to about 60 ° C, especially at the reflux temperature of the solvent used.

Step c) involves the reduction of N- (2-methyl-4- (1-methyl-1H-benzo [d] imidazol-2-yl) -6nitrophenyl) butyramide of formula 6 by hydrogenation in the presence of a suitable solvent and catalyst to give N - (2-Amino-6-methyl-4- (1-methyl-1H-benzo [d] imidazol-2yl) phenyl) butyramide of formula 5.

Suitable catalysts that can be used include, but are not limited to, palladium on charcoal, Raney-Ni and the like.

Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, methanol, ethanol, propanol and the like; water; and any mixtures thereof.

The temperature to guide the reduction can range from about 0 to about 100 ° C, in particular from about 20 to about 50 ° C, especially at the reflux temperature of the solvent used.

Step d) involves the alkylation of compound 5 with 4 '- (bromomethyl) biphenyl-2-nitrile in the presence of a suitable solvent and catalyst to form N - ((2-nitrile-biphenyl-4'methyl) amino-6-methyl-4- (1-Methyl-1H-benzo [d] imidazol-2-yl) phenyl) butyramide of formula 4.

Suitable catalysts may be inorganic basic catalysts including, but not limited to, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as e.g. sodium carbonate, potassium carbonate and the like; and alkali metal bicarbonates such as e.g. sodium bicarbonate, potassium bicarbonate and the like.

Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, acenitrile, toluene, Ν, Ν-dimethylformamide and the like; and any mixtures thereof.

The temperature for performing the alkylation may range from about 0 to about 100 ° C, in particular from about 20 to about 50 ° C, especially at the reflux temperature of the solvent used.

Step e) involves condensation of compound 4 in the presence of a suitable solvent and catalyst to form 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl) -methyl ] -biphenyl-2-nitrile of formula 3.

Suitable catalysts that may be used include, but are not limited to, pyridine, p-toluene sulfonic acid, acetic acid and the like.

Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, dioxane, pyridine, acetic acid, toluene and the like; and any mixtures thereof.

The temperature for conducting the condensation may range from about 0 to about 130 ° C, in particular from about 20 to about 60 ° C, especially at the reflux temperature of the solvent used.

The starting compound 8, 4- (butyramido) -3-methyl-5-nitrobenzoic acid can be prepared as described in J. Med. Chem. 36, 4040 (1993), or by acylation of 4-amino-5-methyl-3-nitrobenzoic acid described in U.S. Pat. No. 3691166, U.S. Pat. , such as activation with chlorides, mixed anhydrides and coupling reagents.

It is another object of the present invention to provide a process for the preparation of telmisartan nitrile comprising:

a) esterifying the starting compound 12 to form compound 11

b) alkylation to form compound 10

d) condensation to form compound 3

R is C _r C ₆ alkyl,

R ₂ is C 1 -C ₆ alkyl,

R ₃ is C _r C ₆ alkyl,

R is C 1 -C ₆ alkyl,

Z is a group which can be converted into a tetrazoyl or carboxyl group,

X is Cl, Br, J.

More specifically, it is an object of the present invention to provide a process for the preparation of telmisartan nitrile (Scheme 4) comprising:

a) esterification of the carboxylic group of compound 12, 7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid to form compound 11, methyl 7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid;

b) alkylation of compound 11, methyl 7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid with 4 '- (bromomethyl) biphenyl-2-nitrile to form compound 10, ((7-methyl -2propyl-3H-benzo [d] imidazol-5-methoxycarbonyl-3-yl) -methyl) -biphenyl-2-nitrile;

c) hydrolysis of compound 10, ((7-methyl-2-propyl-3H-benzo [d] imidazol-5-methoxycarbonyl3-yl) -methyl) -biphenyl-2-nitrile to form compound 9, ((7-methyl -2-propyl-3H-benzo [d] imidazole-5-carboxyl-3-yl) -methyl) -biphenyl-2-nitrile;

d) condensation of compound 9, ((7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxyl-3yl) -methyl) -biphenyl-2-nitrile, with N-methylbenzene-1,2-diamine to form compound 3,

4 '- [[(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] biphenyl-2-nitrile.

Scheme 4:

Step a) involves the esterification of the carboxylic group of compound 12 in the presence of a suitable solvent and catalyst to form compound 11, methyl 7-methyl-2-propyl-3Hbenzo [d] imidazole-5-carboxylic acid.

Suitable catalysts may be inorganic acid catalysts including, but not limited to, hydrochloric acid, sulfuric acid and the like.

Suitable solvents that may be used include, but are not limited to, methanol, tetrahydrofuran, acenitrile, toluene and the like; and any mixtures thereof.

The esterification temperature can range from about 0 to about 100 ° C, in particular from about 20 to about 50 ° C, especially at the reflux temperature of the solvent used.

Step b) involves the alkylation of methyl 7-methyl-2-propyl-3H-benzo [d] imidazole-5carboxylic acid with 4 '- (bromomethyl) biphenyl-2-nitrile in the presence of a suitable solvent and catalyst to form compound 10, (( 7-methyl-2-propyl-3H-benzo [d] imidazole-5methoxycarbonyl-3-yl) -methyl) -biphenyl-2-nitrile.

Suitable catalysts may be inorganic basic catalysts including, but not limited to, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; and alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like.

Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, acenitrile, toluene, Ν, Ν-dimethylformamide and the like; and any mixtures thereof.

The alkylation temperature can range from about 0 to about 100 ° C, in particular from about 20 to about 50 ° C, especially at the reflux temperature of the solvent used.

Step c) involves hydrolysis of ((7-methyl-2-propyl-3H-benzo [d] imidazole-5methoxycarbonyl-3-yl) -methyl) -biphenyl-2-nitrile in the presence of a suitable solvent and catalyst to form compound 9, ((7-Methyl-2-propyl-3H-benzo [d] imidazole-5carboxyl-3-yl) -methyl-biphenyl-2-nitrile.

Suitable catalysts may be inorganic basic catalysts including, but not limited to, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like.

Suitable solvents that may be used include, but are not limited to, methanol, ethanol, propanol and the like, and water; and any mixtures thereof.

The hydrolysis guidance temperature may range from about 0 to about 80 ° C, in particular from about 20 to about 50 ° C, especially at the reflux temperature of the solvents used.

Step d) involves the condensation of ((7-methyl-2-propyl-3H-benzo [d] imidazole5-carboxyl-3-yl) -methyl) -biphenyl-2-nitrile of formula 9 with N-methylbenzene-1,2- diamine in the presence of a catalyst and a suitable solvent to form compound 3, 4 '- [(2-n-propyl-4methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl- 2-nitrile.

Suitable catalysts that can be used include, but are not limited to, SOC1 ₂ and the like.

Suitable solvents which may be used include, but are not limited to, pyridine, toluene and the like; and mixtures thereof.

The temperature for conducting the condensation can range from about 0 to about 130 ° C, in particular from about 20 to about 100 ° C, especially at the reflux temperature of the solvents used.

The starting compound 12, 7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid can be prepared by any method known in the art, such as described in Journal of Medicinal Chemistry (1993), 36 (25), 4040-51, WO 9719911, CN 1623992, Youji Huaxue (2006), 26 (3), 318-323, WO 2006044754.

It is another object of the present invention to provide a process for the preparation of telmisartan nitrile comprising:

a) acylation of the alkyldiaminobenzene of compound 12 to form compound 15,

c) reduction to form compound 13,

d) condensation to form compound 3,

R is C _r C ₆ alkyl,

R ₂ is a C _r C ₆ alkyl,

R ₃ is C _r C ₆ alkyl,

Z is a group which can be converted to a tetrazoyl or carboxyl group, X is Cl, Br, J.

More specifically (In particular), it is an object of the present invention to provide a process for the preparation of telmisartan nitrile (Scheme 5) comprising:

a) acylation of N-methyl-2-nitrobenzenamine with compound 12, 7-methyl-2-propyl-3Hbenzo [d] imidazole-5-carboxylic acid to form compound 15, N, 7-dimethyl-N (2-nitrophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide,

b) alkylation of compound 15, benzo [d] imidazole-5-carboxamide, forms compound 14,

N, 7-dimethyl-N- (2-nitrophenyl) -2-propyl-3Hs 4 '- (bromomethyl) biphenyl-2-nitrile to ((N, 7-dimethyl-N- (2-nitrophenyl) -2- propyl-3H-benzo [d] imidazole-5-carboxamid-3-yl) -methyl) -biphenyl-2-nitrile,

c) reduction of compound 14, ((N, 7-dimethyl-N- (2-nitrophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide-3-yl) -methyl) -biphenyl-2-nitrile, to form compound 13, ((N, 7-dimethyl-2V- (2-aminophenyl) -2-propyl-3H-benzo [d] imidazole-5carboxamid-3-yl) -methyl) -biphenyl-2-nitrile,

d) condensation of compound 13, ((N, 7-dimethyl-N- (2-aminophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide-3-yl) -methyl) -biphenyl-2-nitrile to form compound 3, 4 '- [[(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-nitrile.

Scheme 5:

Step a) involves treating compound 12 with thionyl chloride or oxalyl chloride and 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-nitrophenyl) -2 -propyl-3Hbenzo [d] imidazole-5-carboxamide.

Suitable catalysts that may be used include, but are not limited to, pyridine, triethylamine and the like.

Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, dimethylformamide and the like; and any mixtures thereof.

The temperature for guiding the acylation may range from about 0 to about 100 ° C, in particular from about 20 to about 60 ° C, especially at the reflux temperature of the solvent used.

Step b) involves the alkylation of N, 7-dimethyl- N- (2-nitrophenyl) -2-propyl-3Hbenzo [d] imidazole-5-carboxamide with 4 '- (bromomethyl) biphenyl-2-nitrile in the presence of a suitable solvent, and catalyst to form compound 14, (((N, 7-dimethyl-N- (2-nitrophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide-3-yl) -methyl) -biphenyl-2-nitrile .

Suitable catalysts may be inorganic basic catalysts including, but not limited to, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; and alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like.

Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, acetonitrile, toluene, Ν, Ν-dimethylformamide and the like; and any mixtures thereof.

The alkylation guide temperature may range from about 0 to about 100 ° C, in particular from about 20 to about 50 ° C, especially at the reflux temperature of the solvent used.

Step c) involves the reduction of ((N, 7-dimethyl-N- (2-nitrophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide-3-yl) -methyl) -biphenyl-2-nitrile in the presence of suitable solvent and catalyst to form compound 13, (((N, 7-dimethyl-N- (2aminophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamid-3-yl) -methyl-biphenyl-2 -nitrile.

Suitable catalysts that can be used include, but are not limited to, palladium on charcoal, Raney-Ni and the like.

Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, methanol, ethanol, propanol and the like; water and any mixtures thereof.

The temperature to guide the reduction can range from about 0 to about 100 ° C, in particular from about 20 to about 50 ° C, especially at the reflux temperature of the solvent used.

Step d) involves the condensation of ((N, 7-dimethyl-N- (2-arinophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide-3-yl) -methyl) -biphenyl-2-nitrile in the presence of a suitable solvent and catalyst to form compound 3, 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2- nitrile.

Suitable catalysts that may be used include, but are not limited to, pyridine, p-toluene sulfonic acid, acetic acid and the like.

Suitable solvents that may be used include, but are not limited to, tetrahydro furan, dioxane, pyridine, acetic acid, toluene and the like; and any mixtures thereof.

The temperature for conducting the condensation can range from about 0 to about 130 ° C, in particular from about 20 to about 60 ° C, especially at the reflux temperature of the solvents used.

The starting compound 12, 7-methyl-2-propyl-3 H -benzo [d] imidazole-5-carboxylic acid can be prepared by any method known in the art, such as described in the Journal of Medicinal Chemistry (1993), 36 (25), 4040-51, WO 9719911, CN 1623992, Youji Huaxue (2006), 26 (3), 318-323, WO 2006044754.

Telmisartan nitrile of formula 3 and the chemical name 4 '- [(2-n-propyl-4-methyl-6- (1-methyl-benzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2- nitrile prepared according to the methods of the present invention is converted to telmisartan by the hydrolysis process (Scheme 6) according to methods known in the art, such as those described, for example, in EP 502314, CN 1412183, WO 2004087676 and the application which is at the same time in the proceedings, PCT / EP2007 / 056251.

Scheme 6

The resulting telmisartan is preferably converted to a pharmaceutically acceptable salt, such as sodium, potassium, meglumine, erbumine or any other salt known in the art, such as, for example, from a concurrent application PCT / EP2007 / 056251.

In another aspect, the present invention provides novel intermediates in the synthesis of telmisartan nitrile, optionally in isolated and / or purified form, selected from the group consisting of:

compound 4 with the chemical name N - ((2-cyano-biphenyl-4'-methyl) amino-6-methyl-4- (1-methyl-1 H -benzo [d] imidazol-2yl) phenyl) butyramide

compound 5 with the chemical name N- (2-amino-6-methyl-4- (1-methyl-177-benzo [d] imidazol-2-yl) phenyl-butyramide

compound 6 with the chemical name

N - (2-methyl-4- (1-methyl-1 H -benzo [d] imidazol-2-yl) -6-nitrophenyl) butyramide

compound 7 with a chemical name

Y- (2-aminophenyl) -4- (butyramido) -N, 3-dimethyl-5-nitrobenzamide

compound 8 with the chemical name

4- (butyramido) -3-methyl-5-nitrobenzoic acid

compound 9 with the chemical name ((7-methyl-2-propyl-3 H -benzo [d] imidazole-5-carboxyl-3-yl) -methyl) -biphenyl-2-nitrile

compound 10 with the chemical name ((7-methyl-2-propyl-377-benzo- [d] imidazol-5-methoxycarbonyl-3-yl) -methyl) -biphenyl-2-

compound 13 with the chemical name ((N, 7-dimethyl-N- (2-aminophenyl) -2-propyl-377-benzo [d] imidazole-5-carboxamide-3-yl)

compound 14 with the chemical name ((N, 7-dimethyl-A- (2-nitrophenyl) -2-propyl-3/7-benzo [d] imidazole-5-carboxamide-3-yl) -

compound 15 with the chemical name

N, 7-Dimethyl- N- (2-nitrophenyl) 2-propyl-3/7-benzo [d] imidazole-5-carboxamide

Me

M

I

N

Oh

NO ₂

In another aspect, the present invention provides the use of novel intermediates in the preparation of telmisartan and / or its salts.

The process of the present invention avoids a key intermediate in known syntheses of telmisartan by the chemical name l, 7'-dimethyl-2'-propyl-1H, 3'H-2,5'bibenzo [d] imidazole, which is difficult to prepare (processes described in the prior art use polyphosphomic acid at 150 ° C for 20 hours).

Another aspect of the present invention is a pharmaceutical composition for administering an effective amount of telmisartan and / or its salt prepared according to the present invention in a unit dosage form, alone or in combination with another active ingredient such as hydrochlorothiazide, and pharmaceutically acceptable carriers comprising inactive ingredients such as fillers (diluents), binders, disintegrants, gliders, lubricants and other excipients. Any manufacturing process for the solid oral dosage form may be used, including the wet granulation process (with water or any suitable and pharmaceutically acceptable organic solvent), the dry granulation process and the direct compression process, or any other method known in the art. Such pharmaceutical compositions may be administered to the patient in any dosage form, such as tablets, pills, lozenges, suction tablets, capsules, powder, liquids, suppositories, bags, elixirs, solutions, syrups, suspensions, etc. The dosage forms may be adapted for administration. for example, the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes.

The telmisartan salt prepared according to the present invention may be incorporated into the pharmaceutical composition or may be formed in situ during the preparation of the pharmaceutical composition. In the latter case, telmisartan is added to the solvent together with the appropriate basic agent and mixed together. Telmisartan is obtained in the form of dissolved salt. Telmisartan salt can be used directly either in the spray drying process or in the fluidized bed process.

Finally, the present invention provides a method of treating a disease condition prevented, improved or eliminated by administering telmisartan and / or its salts prepared according to the present invention to a patient in need of such treatment.

The following examples are given to illustrate certain aspects of the invention in more detail and should not be construed as limiting the invention in any way.

Example 1

Preparation of N- (2-aminophenyl) -4- (butyramido) - N, 3-dimethyl-5-nitrobenzylamide 7:

To a mixture of 3.9 g (20 mmol) / V-methylbenzene-1,2-diamine dihydrochloride and 10 ml of CH ₂ Cl ₂ , 1.6 ml of pyridine (20 mmol) was added, stirred at room temperature to give a solution of free / V-methylbenzene-1,2-diamine. The resulting solution was added to the mixture

2.66 g (10 mmol) of 8, 3.24 g (20 mmol) of CDI and 60 ml of THF were stirred for 3 hours and filtered. The wet cake was dried in an oven to give 2.26 g of solid 7 (61% yield).

Ή NMR (300 MHz, DMSO-d ₆ ): δ 8.33 (s, 1H), 8.19 (s, 1H), 7.11 (d, 2H, J = 6.9 Hz), 6.63 (d, 2H, J = 7.8 Hz), 2.70 (s, 3H), 2.30-2.36 (m, 5H), 1.60 (m, 2H), 0.93 (t, 3H, J = 7.5 Hz);

ESI-MS: 369 [M-1] '.

Example 2

Preparation of N- (2-methyl-4- (1-methyl-1-7-benzo [d] imidazol-2-yl) -6nitrophenyl) butyramide 6:

A mixture of 370 mg (1 mmol) of 7 and 5 ml of pyridine was heated to reflux and stirred for 5 hours. The mixture was diluted with ethyl acetate, washed with water, dried over Na ₂ SO ₄ , filtered and the solvent removed in vacuo to give 0.3 g of compound 6 (85% yield).

ESI-MS: 353 [M + 1] ⁺ .

Example 3

Preparation of N- (2-amino-6-methyl-4- (1-methyl-1Z7-benzo [d] imidazol-2yl) phenyl) butyramide 5:

A mixture of 0.21 g (0.6 mmol) of 6 and 8 ml of methanol, 3.5 mg (0.06 mmol) of Raney-Ni was stirred for 2 hours under H ₂ at room temperature. A white solid is formed, methanol is added to dissolve the white solid. The resulting mixture was filtered, the filtrate was evaporated in vacuo to give a solid, 0.183 g (94.8% yield).

^! H NMR (300 MHz, DMSO-d ₆ ); δ 7.61 (d, 1H, J = 4.5 Hz), 7.57 (d, 1H, J = 7.2 Hz), 7.24 (m, 2H), 7.05 (s, 1H) , 6.90 (s, 1H), 3.86 (s, 3H), 2.34 (t, 2H,> 7.2 Hz), 1.65 (m, 2H), 0.97 (t, 3H) ,> 4.5 Hz); ESI-MS: 323 [M + 1 +]

Example 4

Preparation of N - ((2-nitrile-biphenyl-4'-methyl) amino-6-methyl-4- (1-methyl-1Z7benzo [d] imidazol-2-yl) phenyl) butyramide 4:

To a mixture of 0.13 g (0.4 mmol) 5, 0.11 g K ₂ CO ₃ (0.8 mmol) and 5 ml DMF, 0.115 g (0.42 mmol) of 4'-bromomethyl-biphenyl-2 is added -carbonitrile, stirred for 22 hours at room temperature. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over Na ₂ SO ₄ , filtered and the solvent removed under reduced pressure to give a solid. Methanol was used to wash the solid to give 81 mg 4 (40% yield).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.93 (d, 1H,> 8.1 Hz), 7.79 (m, 1H), 7.45-7.62 (m, 8H. > 7.2 Hz), 7.21 (m, 2H), 6.90 (s, 1H), 6.62 (s, 1H), 4.52 (s, 2H), 3.49 (s, 3H) ), 2.42 (t, 2H,> 7.2 Hz), 1.69 (m, 2H), 0.96 (t, 3H,> 4.5 Hz); ESI-MS: 514 [M + 1] ⁺

Example 5

Preparation of 4 '- [(2-n-propyl-4-methyl-6 (1-methylbenzimidazol-2-yl) -benzimidazol-lyl) methyl] -biphenyl-2-nitrile 3 from 4:

To a mixture of 45 mg (0.08 mmol) 4 and 5 ml of toluene was added 15 mg (0.42 mmol) /? - TsOH, stirring to reflux for 5 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over Na ₂ SO ₄ , filtered and the solvent removed in vacuo to give 37 mg of compound 3 (86% yield).

NMR (300 MHz, CDC1 _3): δ 7.75 (m, 2H), 7.62 (m, IH), 7.16 to 7.51 (m, 1 IH), 5.48 (s, 2H) , 3.80 (s, 3H), 2.94 (t, 2H, J = 7.2 Hz), 2.77 (s, 3H), 1.85 (m, 2H), 1.06 (t. 3H, J = 4.5 Hz);

EI-MS: 495 [M] < ^{+ &} gt ; ^.

Example 6

Preparation of methyl 7-methyl-2-propyl-3ZZ-benzo [d] imidazole-5-carboxylic acid 11:

g (23 mmol) of 7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid was added to 100 ml of methanol, stirred, 3 ml of concentrated hydrochloric acid (37%) was added, heated to 70 ° C. 20 hours 3 ml of concentrated hydrochloric acid were added, heated to reflux for 4 hours. Add 4 ml of concentrated hydrochloric acid, reflux for 3 hours. The solvent was removed in vacuo to give 6.6 g of crude 11.

Example 7

Preparation of ((7-methyl-2-propyl-3ZZ-benzo [d] imidazol-5-methoxycarbonyl-3-yl) -methyl) biphenyl-2-nitrile 10:

6.6 g of crude 11 and 5.48 g (20 mmol) of 4'-bromomethyl-biphenyl-2-carbonitrile were dissolved in 100 ml of DMF, 13.8 g (100 mmol) of K ₂ CO _{3 was added} , stirred for 18 hours at room temperature. temperature. 150 ml of water was added to the mixture to form a white solid which was filtered to give a cake which was dried to give 8 g of crude 10, a yield of 82.5% in two harvests.

'H NMR (300 MHz, DMSO-d _6): δ 7.97 (m, 2H), 7.74 (t, IH, J = 6.3 Hz), 7.53 to 7.67 (m, 5H ), 7.19 (d, 2H, J = 8, 1 Hz), 5.68 (s, 2H), 3.83 (s, 3H), 2.88 (t, 2H, J = 7.2 Hz). ), 2.58 (s, 3H), 1.76 (m, 2H), 0.94 (t, 3H, J = 4.5 Hz).

Example 8

Preparation of ((7-methyl-2-propyl-3 H -benzo [d] imidazole-5-carboxyl-3-yl) -methyl) -biphenyl 2-nitrile 9:

To the mixture of 7.2 g of 10 and 180 ml of methanol was added 30 ml of 10% NaOH, heated to reflux for 5 hours. The solvent was removed in vacuo, 50 ml of water was added to the mixture and 1 M HCl was used to adjust the pH to 5 ~ 6. The mixture was filtered to give a wet cake, washed with water, dried to give 4.5 g of 9, yield 65%.

1 H NMR (300 MHz, DMSO-d ₆ ): δ 7.94 (m, 2H), 7.75 (t, 1H,> 6.3 Hz), 7.54-7.65 (m, 5H) , 7.20 (d, 2H, J = 8, 1 Hz), 5.68 (s, 2H), 2.88 (t, 2H, J = 7.5 Hz), 2.58 (s, 3H) , 1.77 (m, 2H), 0.96 (t, 3H, J = 4.5 Hz).

Example 9

Preparation of 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) methyl] -biphenyl-2-nitrile 3 from 9:

200 mg 9 was added to 1 ml of SOCl ₂ . The mixture was heated to reflux. After 2 hours, evaporate SOC1 ₂ at 45 ° C under reduced pressure to give a light yellow foam residue. The residue was dissolved in 2 ml of dry pyridine and 100 mg / V-methylbenzene-1,2diamine was added. The mixture was heated to reflux for 24 hours.

The pyridine was evaporated in vacuo. The residue was extracted with ethyl acetate, washed with aqueous NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ . It was then filtered and concentrated to give 188 mg (78% yield) of crude 3.

EI-MS: 496 [M + 1] < ^{+ &gt};.

Example 10

Preparation of A, 7-dimethyl-N - (2-nitrophenyl) -2-propyl-3 H -benzo [d] imidazole-5carboxamide 15:

To a mixture of 1.09 g (5 mmol) of 2-propyl-3Z-benzo [d] imidazole-5-carboxylic acid and 50 ml of CH ₂ Cl ₂ , 7.26 ml (100 mmol) of SOCl _{2 was added} . The mixture was stirred for 18 hours. The mixture was evaporated under reduced pressure.

The residue was dissolved in 30 ml of DMF and 1.6 g (10.5 mmol) of N-methyl-2-nitroaniline was added. The mixture was stirred at room temperature for 48 hours. Saturated NaHCO ₃ was added to adjust the pH to 8. The resulting mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ . It was then filtered and concentrated to give a residue, the residue was purified by silica gel chromatography to give 0.69 g (39% yield) 15.

NMR (300 MHz, DMSO-d ₆ ): δ 7.70-7.83 (m, 3H), 7.44 (m, 1H), 6.84-7.07 (m, 2H), 3.47 (s, 3H), 3.37 (s, 3H), 2.29 (m, 2H), 1.775 (m, 2H), 0.93 (t, 3H,> 4.5 Hz);

ESI-MS: 353 [M + 1] ⁺ ; 351 [Ml] '.

Example 11

Preparation of ((A, 7-dimethyl-N- (2-nitrophenyl) -2-propyl-3 H -benzo [d] imidazole-5carboxamide-3-yl) -methyl) -biphenyl-2-nitrile 14:

0.7 g of 15 (2 mmol) and 0.82 g (3 mmol) of 4'-bromomethyl-biphenyl-2-carbonitrile were dissolved in 30 ml of acetonitrile, 0.55 g (4 mmol) of K ₂ CO _{3 was added} and stirred 22 hours at room temperature. Methanol was added to dilute the reaction mixture, filtered, and the filtrate was concentrated in vacuo to give a residue. Ethylene acetate was used to dissolve the residue, washed with water, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a residue of 0.84 g of crude 14, yield 77%.

1 H NMR (300 MHz, DMSO-d ₆ ): δ 7.95 (d, 1H,> 4.8 Hz), 7.52-7.81 (m, 8H), 7.32 (m, 1H) , 6.88-6.99 (m, 4H), 5.38 (s, 3H), 3.37 (s, 3H), 2.71 (m, 2H), 2.39 (s, 3H). 1.66 (m, 2H), 0.91 (t, 3H, > 4.5 Hz); EI-MS: 543 [M] < ^{+ &gt};.

Example 12

Preparation of ((A, 7-dimethyl-Y- (2-aminophenyl) -2-propyl-3 H -benzo [d] imidazole-5carboxamide-3-yl) -methyl) -biphenyl-2-nitrile 13:

A mixture of 100 mg (0.2 mmol) 14 was dissolved in 35 ml of methanol, 40 mg Pd / C (10%) was added, stirred for 2 hours under H ₂ at room temperature. The reaction mixture was filtered to remove Pd / C, the filtrate was evaporated under vacuum to give a white solid 13.63 mg (67% yield).

The ESI-MS spectrum is: ESI-MS: 514 [M + 1] ⁺ .

Example 13

Preparation of 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) methyl] -biphenyl-2-nitrile 3 from 13:

A mixture of 100 mg (0.2 mmol) of 13 and 5 ml of pyridine was heated to reflux for 22 hours (TLC reaction monitoring), cooled to room temperature, ethyl acetate was added to dilute the reaction mixture. The organic phase was washed successively with water, saturated NH ₄ Cl solution and brine, dried over Na ₂ SO ₄ , filtered, concentrated to give 74 mg of residue. The residue was purified by silica gel chromatography to give 45 mg of compound 3, yield 47%.

1 H NMR (300 MHz, CDCl 3): δ 7.77 (m, 2H), 7.59 (m, 1H), 7.51-7.26 (m, 9H), 5.47 (s, 3H) , 3.78 (s, 3H), 2.94 (t, 2H, J = 7.8 Hz), 2.77 (s, 3H), 1.88 (m, 2H), 1.06 (t. 3H, J = 4.5 Hz);

EI-MS: 495 [M] < ^{+ &} gt ; ^.

Example 14

Preparation of 4 '- [(2 - [- propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid 1:

A mixture of 2.5 g 3 (5 mmol), 1.0 g sodium hydroxide (25 mmol), 0.18 g water (10 mmol) and 30 ml ethylene glycol was refluxed for 8 hours. The reaction ends. The reaction mixture was cooled to room temperature, H ₂ O (250 ml) was added. After adjusting the pH of the solution to 4 with HOAc (12 ml), the product was then precipitated and extracted three times with CH ₂ Cl ₂ , the combined organic layers were washed with brine, dried over NaSO ₄ , filtered, the filtrate was concentrated to give crude 1 2 , 55 g, 98% yield.

Example 15

Preparation of telmisartan and / or its pharmaceutically acceptable salts

Mixture of 1.0 g (2.0 mmol) 4 '- ((1,7'-dimethyl-2'-propyl-1H, 3'H-2,5'-bibenzo [d] imidazol-3'yl) methyl ) of biphenyl-2-carbonitrile, 5 ml of isopropanol, 5 ml of water and 1.03 g (18.4 mmol) of KOH was heated to 120 ° C for approximately 48 hours. The solution was then cooled to room temperature and 10 ml of water were added. The mixture was neutralized by the addition of 3 M HCl to a pH of about 7. The telmisartan product was filtered, washed and dried.

The resulting telmisartan is converted into its salts by the addition of a suitable acid or base and by isolation.

Example 16

Pharmaceutical formulations comprising telmisartan or its salts prepared by the methods of the present invention

mg mg mg mg mg mg Meglumine salt of telmisartan 54 54 54 54 54 54 Meglumine 10 10 KOH 4 4 NaOH 3 3 Poloxamer 188 8 8 8 Sorbitol 120 120 120 120 120 120 Microcrystalline cellulose 53,6 45,6 59.6 51.6 60.6 52,6 Magnesium stearate 2.4 2.4 2.4 2.4 2.4 2.4

mg mg mg mg mg mg Telmisartan 40,0 40,0 40,0 40,0 40,0 40,0 Meglumine 20,0 20,0 20,0 20,0 20,0 20,0 Povidon K30 12,0 12,0 12,0 12,0 12,0 12,0 Sorbitol 225,0 168.75 112.5 Lactose, agglomerated 225,0 56.25 112.5 Mannitol 225,0 Maltose 225,0 Magnesium stearate 3.0 3.0 3.0 3.0 3.0 3.0

The above-mentioned compositions containing telmisartan can be prepared by various procedures. Two of the suitable methods are spray drying and whirling granulation. If telmisartan is prepared by spray drying, telmisartan is dissolved together with a basic agent and optionally a crystallization retarder in a suitable solvent (water or organic solvent) and spray dried. The spray dried granulate is further mixed with other excipients to form the final composition ready for tableting. In the case of granulation in the vortex layer, telmisartan is dissolved together with a basic agent and optionally a crystallization retardant, in a suitable solvent (water or organic solvent) to form a granulation liquid. The other excipients are placed in a pelletizing machine in a fluidized bed and sprayed with the granulation fluid. When the granulation is complete, the granulate is dried and optionally mixed with additional excipients, such as a liquid control agent and / or lubricant, to form the final composition ready for tabletting.

Claims (15)

A process for the preparation of compound 3 comprising the steps of: a) acylating the diamino compound with compound 8 to form compound 7, b) condensation to form compound 6, c) reduction to compound 5, e) the condensation to form 3, where R1, R-2, R3 is C1-C8 alkyl, Z is a group which can be converted to a tetrazoyl or carboxyl group is X Cl, Br, J. The method of claim 1, wherein the compound is 3 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl2-nitrile. 3. A process for the preparation of 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl) -methyl] -biphenyl-2-nitrile, comprising the steps : a) acylation of N-methylbenzene-1,2-diamine with 4- (butyramido) -3-methyl-5-nitrobenzoic acid to form 7V- (2-aminophenyl) -4- (butyramido) - N, 3- dimethyl-5nitrobenzamide, b) condensation of A- (2-aminophenyl) -4- (butyramido- N, 3-dimethyl-5-nitrobenzamide to form N- (2-methyl-4- (1-methyl-1 H -benzo [ d] imidazol-2-yl) -6-nitrophenyl) butyramide, c) reduction of N- (2-methyl-4- (1-methyl-1H-benzo [d] imidazol-2-yl) -6nitrophenyl) butyramide in N- (2-amino-6-methyl-4- ( 1-methyl-1H-benzo [d] imidazol-2yl) phenyl) butyramide, d) alkylation of N- (2-amino-6-methyl-4- (1-methyl-1H-benzo [d] imidazol-2yl) phenyl) butyramide with 4 '- (bromomethyl) biphenyl-2-nitrile, to form N - ((2-nitrile 33 biphenyl-4'-methyl) amino-6-methyl-4- (1-methyl-1H-benzo [d] imidazol-2yl) phenyl) butyramide, e) condensation of N - ((2-nitrile-biphenyl-4'-methyl) amino-6-methyl-4- (1-methyl-1H-benzo [d] imidazol-2-yl) phenyl) butyramide to give 4 ' - [(2-n-propyl-4-methyl-6 (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-nitrile. The method of claims 1 to 3, wherein 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl 2-nitrile is further converted to telmisartan and / or its salts. 5. A process for the preparation of compound 3 comprising the steps of: a) esterifying the starting compound 12 to form compound 11, b) alkylation to form compound 10, o \ / = ^ \ o d) the condensation to form compound 3 are R 1, R ₂ , R 3, R 4 is C 1 -C 8 alkyl, Z is a group which can be converted to a tetrazoyl or carboxyl group is X Cl, Br, J. The method of claim 5, wherein the compound is 3 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl2-nitrile. 7. A process for the preparation of 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl) -methyl] -biphenyl-2-nitrile, comprising the steps : a) esterification of the 7-methyl-2-propyl-3 H -benzo [d] imidazole-5carboxylic acid carboxyl group to form methyl 7-methyl-2-propyl-3 H -benzo [d] imidazole-5 carboxylic acid, b) alkylation of methyl 7-methyl-2-propyl-3 H -benzo [d] imidazole-5-carboxylic acid with 4 '(bromomethyl) biphenyl-2-nitrile to form ((7-methyl-2-propyl- 3 // benzo [d] imidazol-5-methoxycarbonyl-3-yl) -methyl-biphenyl-2-nitrile, c) hydrolysis of ((7-methyl-2-propyl-3/7-benzo [d] imidazole-5-methoxycarbonyl-3- and 1) methyl) -biphenyl-2-nitrile to form ((7-methyl-2 -propyl-377-benzo [d] imidazole-5carboxyl-3-yl) -methyl) -biphenyl-2-nitrile, d) condensation of ((7-methyl-2-propyl-3 H -benzo [d] imidazole-5-carboxyl-3-yl) -methyl 1) biphenyl-2-nitrile, with N-methylbenzene-1,2 -diamine to form 4 '- [[(2-n-propyl-4methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-nitrile. The method of claims 4 to 7, wherein 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl 2-nitrile is further converted to telmisartan and / or its salts. 9. A process for the preparation of compound 3 comprising the steps of: a) acylation of an alkyldiaminobenzene compound 12 to form compound 15, b) alkylation to form compound 14, c) reduction to form compound 13, d) the condensation to form compound 3 wherein R 1, R ₂ , R _{3 is} C 1 -C ₆ alkyl, Z is a group which can be converted to a tetrazoyl or carboxyl group is X Cl, Br, J. The method of claim 9, wherein the compound is 3 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl · 2-nitrile. 11. A process for the preparation of 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl) -methyl] -biphenyl-2-nitrile, comprising the steps : a) acylation of N-methyl-2-nitrobenzenamide with 7-methyl-2-propyl-3 H -benzo [d] imidazole-5 carboxylic acid to form N, 7-dimethyl-N- (2-nitrophenyl) - 2-propyl-3H-benzo [d] imidazole-5-carboxamide, b) alkylation of N, 7-dimethyl- N- (2-nitrophenyl) -2-propyl-3H-benzo [d] imidazole-5carboxamide with 4 '- (bromomethyl) biphenyl-2-nitrile to form ((N, 7-dimethyl-N (2-nitrophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide-3-yl) methyl-biphenyl-2nitrile, c) reduction of ((N, 7-dimethyl-N- (2-nitrophenyl) -2-propyl-3H-benzo [d] imidazole-5 carboxamide-3-yl) -methyl) -biphenyl-2-nitrile, to form ((N, 7-dimethyl-N- (2aminophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide-3-yl) -methyl) -biphenyl-2 · nitrile, d) condensation of ((N, 7-dimethyl-N- (2-aminophenyl) -2-propyl-3H-benzo [d] imidazole-5carboxamid-3-yl) -methyl) -biphenyl-2-nitrile to give 4 '- [[(2-n-propyl-4-methyl-6 (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-nitrile. The method of claims 9 to 11, wherein 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl 2-nitrile is further converted to telmisartan and / or its salts . A pharmaceutical composition comprising telmisartan and / or its salts prepared according to any preceding claim and one or more pharmaceutically acceptable excipients. 14. A compound selected from the group consisting of N - ((2-cyano-biphenyl-4'-methyl) amino-6-methyl-4- (1-methyl-1 H -benzo [d] imidazol-2yl) N- (2-amino-6-methyl-4- (1-methyl-1H-benzo [d] imidazol-2-yl) phenyl) butyramide) N - (2-methyl-4- (1-methyl-1 H -benzo [d] imidazol-2-yl) -6-nitrophenyl) butyramide N- (2-aminophenyl) -4- (butyramido) - / V , 3-dimethyl-5-nitrobenzamide 4- (Butyramido) -3-methyl-5-nitrobenzoic acid ((7-methyl-2-propyl-3 H -benzo [d] imidazole-5-carboxyl-3-yl) -methyl 1-biphenyl 1 -2-nitr and 1 ((7-methyl-2-propyl-3H-benzo [d] imidazol-5-methoxycarbonyl-3-yl) -methyl-biphenyl-2-nitrile ((7V, 7-dimethyl) -7V- (2-aminophenyl) -2-propyl-3 H -benzo [d] imidazole-5-carboxamide-3-yl) methyl-biphenyl-2-nitrile ((N, 7-dimethyl-N- ( 2-nitrophenyl) -2-propyl-3 H -benzo [d] imidazole-5-carboxamid-3-yl) methyl) -biphenyl-2-nitrile / N, 7-dimethyl- N - (2-nitrophenyl) -2-propyl-3 H -benzo [d] imidazole-5-carboxamide. Use of the compounds of claim 14 in the preparation of telmisartan and / or its salts.