IE910686A1 - New benzimidazole derivatives, process for their production¹and their pharmaceutical use - Google Patents
New benzimidazole derivatives, process for their production¹and their pharmaceutical useInfo
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- IE910686A1 IE910686A1 IE068691A IE68691A IE910686A1 IE 910686 A1 IE910686 A1 IE 910686A1 IE 068691 A IE068691 A IE 068691A IE 68691 A IE68691 A IE 68691A IE 910686 A1 IE910686 A1 IE 910686A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- 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
Abstract
The invention relates to benzimidazole derivatives of formula (I), where R<1> stands for H, C1-C3 alkyl, Br or OH, R<2> stands for H, COOH, CH2OH or OH, where R<1> and R<2> cannot stand for hydrogen simultaneously and R<1> cannot be CH3 if R<2> and R<3> both stand for hydrogen simultaneously, or R<2> stands for CH2OH, R<3> stands for hydrogen or fluorine and R<4> stands for COOH or 2-tetrazolyl, as well as their acid or base addition salts, a method for preparing them and their pharmaceutical use.
Description
New benzimidazole derivatives, process for their production and their pharmaceutical use
Patent Application by
SCHERING AKTIENGESELLSCHAFT, a German Company of Berlin and Bergkamen, Federal Republic of Germany.
3a
New benzimidazole derivatives, process for their production and their pharmaceutical use
This invention relates to new benzimidazole derivatives, process for their production and their pharmaceutical use.
Angiotensin II is a hormone produced within the body, which has strongly vasoconstrictive properties. Angiotensin II plays an important role in causing high blood pressure and atherosclerotic processes. Competitive angiotensin II --. antagonists should be well suited for therapy of these diseases. But the angiotensin II antagonists known so far are peptides, which, besides their insufficient bioavailability, have also partial agonist properties, which limits their use as antihypertensives. Thus, e.g., saralasin as the best known representative of this class of compounds can be administered only intravenously.
Imidazole derivatives of general formula A are known from EP 2563 310 and EP 324 377 as nonpeptidergic, orally effective angiotensin II antagonists
R3 Rj
4,5,6,7-Tetrahydroimidazole[4,5-c]pyridine derivatives of general formula B with antihypertensive activity are described in EP 245,637.
It has now been found that the benzimidazole derivatives of formula I are competitive angiotensin II antagonists, which bind on the angiotensin II receptors with great affinity and inhibit angiotensin II effects in vitro and in vivo. Thus they represent effective antihypertensive agents.
The invention thus relates to benzimidazole derivatives of formula I
in which
R1 means H, C.,-C3 alkyl, Br or OH,
R2 means H, COOH, CH2OH or OH,and R1 and R2 cannot be hydrogen at the same time and R1 cannot be CH3, if R2 and R3 at the same time mean hydrogen or R2 means CH2OH,
R3 means hydrogen or fluorine and
R4 means COOH or 2-tetrazolyl as well as their acid or base addition salts.
The alkyl group can be methyl, ethyl, propyl, isopropyl, and methyl is preferred.
For the salt formation with free acids inorganic and organic bases are suitable, as they are known to one skilled in the art for formation of physiologically compatible salts. There can be mentioned, for example: alkali hydroxides, such as sodium and potassium hydroxide, alkaline-earth hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethandlamine, triethanolamine, N-methylglucamine, morpholine, tris(hydroxymethyl)-methylamine, etc.
For the salt formation physiologically compatible acid radicals are suitable as acid radicals. Preferred acids are organic carboxylic acids and sulfonic acids with 1-15 carbon atoms, which belong to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic and heterocyclic series. These acids can be saturated, unsaturated and/or polybasic and/or substituted in the usual way. As examples for the substituents there can be mentioned C,-C4 alkyl, hydroxy, alkoxy, oxo or amino groups or halogen atoms (F, Cl, Br)
For example, the following carboxylic acids can be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic, acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopropylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acid substituted with halogen groups, trifluoromethyl groups, hydroxy groups, or carboxy groups, nicotinic acid, isonicotinic acid, 2furancarboxylic acid, cyclopentylpropionic acid. Considered as especially preferred acyl radicals are those with up to 10 carbon atoms. As sulfonic acids there are suitable, for example, methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic acid, beta-chloroethanesulfonic acid, butanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, pchlorobenzenesulfonic acid, N,N-dimethylaminosulfonic acid, N,Ndiethylaminosulfonic acid, N,N-bis(beta-chloroethylaminosulfonic acid, Ν,Ν-diisobutylaminosulfonic acid, N,N-dibutylaminosulfonic acid, pyrrolidino, piperidino, piperazino, N-methylpiperazino and morpholino sulfonic acid.
Further, the invention relates to a process for the production of benzimidazole derivatives of formula I, characterized in that in a way known in the art
a) a benzimidazole derivative of formula II
in which R1 and R2 have the above-indicated meanings, is reacted with an alkylation reagent of formula III
in which R3 and R4 have the above-indicated meanings and R5 means Cl, Br, OSO2CH3, OSO2C6H4CH3(p) , or b) a phenylenediamine derivative of formula IV
R,
in which R1, R2, R3 and R4 have the above-indicated meanings, is reacted with an orthocarboxylic acid ester of formula V (R6O)3C-C3H7 (V), in which R6 means C1-C4 alkyl, and optionally then protecting groups are cleaved off.
The reaction of benzimidazole derivatives II with alkylation agents III is preferably performed in polar solvents, such as lower alcohols, dimethylformamide or dimethyl sulfoxide with addition of bases, such as sodium hydride, sodium methanolate or potassium carbonate. For example, a compound of formula II is dissolved in dimethylformamide and reacted with addition of sodium hydride with 4'-bromomethyl-biphenyl-2-carboxylic acid methyl ester at temperatures of 0-50°C. The subsequent cleavage of the protecting groups takes place optionally by acid or alkaline hydrolysis.
Starting from the nitroaniline derivatives VI
with R1 and R2 having the above-indicated meanings there are obtained by reaction with the alkylation reagents of formula III
N-substituted nitroaniline derivatives of formula VII
•7 with R1, R2, R3, and R4 having the above-indicated meanings, which are hydrogenated with Raney nickel or palladium/carbon to the starting compounds of formula IV.
The reaction of nitroaniline derivatives VI with alkylation agents III is preferably performed in polar solvents, such as lower alcohols, dimethylformamide or dimethyl sulfoxide with addition of bases, such as sodium hydride, sodium methanolate or potassium carbonate. For example, a compound of formula VI is dissolved in dimethylformamide and reacted with addition of potassium carbonate with 4'-bromomethyl-biphenyl-2-carboxylic acid methyl ester at temperatures of 0-50°C. The subsequent reduction of the nitro group preferably takes place by a hydrogenation in polar solvents such as acetic acid or lower alcohols with addition of hydrogenation catalysts such as Raney nickel or palladium on carbon. The ring closure to benzimidazole derivatives I is preferably performed with orthocarboxylic acid esters V at increased temperature. The subsequent cleavage of the protecting groups optionally takes place by acid or^alkaline hydrolysis.
The compounds of formula I, thus obtained, can subsequently be converted with mineral acids such as hydrochloric acid, hydrobromic acid or sulfuric acid or with organic acids such as, acetic acid, fumaric acid or maleic acid, or else with bases such as sodium hydroxide solution, potassium hydroxide solution or triethylamine into salts suitable for therapeutic use.
The compounds according to the invention of formula. I are suitable for treatment of diseases of the cardiovascular system, which are affected by angiotensin II antagonists, such as, for example, hypertonia, cardiac insufficiency, angina pectoris'and arteriosclerosis. The compounds according to the invention are effective in doses between 0.01 and 100 mg/kg.
The invention thus relates to the use of the compounds of formula I as pharmaceutical agents. For the preparation of pharmaceutical agents, which contain one or more of the compounds comprised by formula I, the auxiliary agents and vehicles usual in galenicals are used.
PREPARATION OF THE STARTING COMPOUNDS
A 4z-Bromomethyl-biphenyl-2-carboxvlic acid methyl ester
a) 78.6 g of 2-iodobenzoic acid methyl ester is dissolved in 400 ml of toluene and mixed with 300 ml of a two-molar sodium carbonate solution. A solution of 43.4 g of 4methylphenylboronic acid in 150 ml of methanol is added. The reaction vessel is flushed with nitrogen and 3.0 g of tetrakis(triphenylphosphine)-palladium (0) is added. The reaction mixture is heated for five hours to 100°C with vigorous stirring. After cooling, the reaction mixture is poured on a mixture of one liter of two-molar sodium carbonate solution and 50 ml of ammonia solution and extracted several times with dichloromethane. The combined organic phases are dried on sodium sulfate, filtered off and concentrated by evaporation. The residue is distilled at 0.03 mbar and 110-120°C and the recrystallized from hexane. 66.0 g of 4·-methyl-biphenyl-2-carboxylic acid methyl ester with a melting point of 56-58°C is obtained.
b) 23.0 g of the compounds obtained under a) is dissolved in 250 ml of carbon tetrachloride and mixed with 18.0 g of Nbromosuccinimide and 1.0 g of dibenzoyl peroxide. The reaction mixture is refluxed for four hours. After cooling, the resulting succinimide is filtered off and the filtrate is concentrated by evaporation. The residue is distilled in a high vacuum. 28.0 g of 4z—bromomethyl-biphenyl-2—carboxylic acid methyl ester is obtained as viscous oil.
B 4z—Bromomethvl—biphenyl—2—carboxylic acid tert-butvl ester
a) 15 g of 4'—methyl—biphenyl—2—carboxylic acid methyl ester and 6.6 g of sodium hydroxide are boiled in 200 ml of 90% ethanol for 3 hours. It is acidified with 1 n hydrochloric acid and the precipitated 4'-methyl-biphenyl-2-carboxylic acid is filtered off and dried. 10 g of this compound is boiled with 17 ml of thionyl chloride for 4 hours, then is concentrated by evaporation. The residue was stirred with 21 g of potassium tert-butylate in 15 ml of tert-butanol for 16 hours at room temperature. It was concentrated by evaporation, mixed with water and the compound taken up with diethyl ether. After washing, drying and concentration by evaporation, 4z-methylbiphenyl-2- carboxylic acid-tert-butyl ester was obtained, which was further used as crude product.
b) 4'-Bromo-methyl-biphenyl-2-carboxylic acid tert-butyl ester is obtained analogously to A) from the above tert-butyl ester.
Example 1
2-[4-(4-Bromo-2-propyl-l-benz imidazolylmethy1)-phenyl]-benzoic acid
a) 1.01 g of 2-bromo-6-nitroaniline is dissolved in 100 ml of ethyl acetate, mixed with 0.1 g of Raney nickel and hydrogenated under standard pressure. When absorption of the hydrogen is completed, it is filtered from the catalyst,, dried and concentrated by evaporation. 0.83 g of 3-bromo-ophenylenediamine is obtained as bright yellow oil.
b) 0.56 g of the compound obtained under a) is dissolved in 10 ml of methanol, mixed with 12 ml of 0.8 molar ethereal hydrochloric acid, stirred for 15 minutes and concentrated by evaporation. The crystalline residue is taken up in 50 ml of methanol, mixed with 1.6 ml of orthobutyric acid trimethyl ester and refluxed for 3 hours. Then the residue it taken up with ethyl acetate and saturated sodium bicarbonate solution, the organic phase is washed with water, dried and concentrated by evaporation. 0.77 g of 4-bromo-2-propyl-lH-benzimidazole in crystalline form is obtained.
c) 0.1 g of 80% sodium hydride is suspended in 40 ml of dimethylformamide and mixed with a solution of 0.77 of 4-bromo2-propyl-lH-benzimidazole in 5 ml of dimethylformamide. After completion of the generation of hydrogen, a solution of^l.l g of 4'—bromomethyl—biphenyl—2—carboxylic acid methyl ester in 5 ml of dimethylformamide is instilled at room temperature. After 18 hours the reaction mixture is poured onto water and is extracted with ethyl acetate. The organic phase is dried, concentrated by evaporation, and the residue is chromatographed on silica gel with an ethyl acetate-cyclohexane mixture 1:1. 0.96 g of 2-[4(4-bromo-2-propyl-l-benzimidazolylmethyl)-phenyl]-benzoic acid methyl ester in crystalline form is obtained.
d) 0.83 g of the compound obtained under c) is refluxed in 80 ml of 0.1 normal ethanolic sodium hydroxide solution for 4 hours. Then the mixture is concentrated by evaporation,'taken up with water and washed with ether. The pH of the aqueous solution is adjusted to pH = 5.5 with 1 normal hydrochloric acid and the resulting precipitate is suctioned off and dried on phosphorus pentoxide. 0.74 g of 2-[4-(4-bromo-2-propyl-lbenzimidazolylmethyl)-phenyl-benzoic acid with a melting point 282=285°C is obtained.
Example 2
2-[4-(4-Hydroxy-2-propyl-l-benzimidazolylmethyl)-phenyl]-benzoic acid, hydrobromide
a) 5 g of 3-methoxy-2-nitroaniline and 9.1 g of 4'bromomethyl-biphenyl-2-carboxylic acid methyl ester is dissolved in 50 ml of dimethylformamide and mixed with 3 g of potassium carbonate. The reaction mixture is stirred for 3 days at room temperature, poured onto water and extracted with ethyl acetate. The ethyl acetate extract is dried and concentrated by evaporation. The residue is chromatographed on silica gel with a cyclohexane-ethyl acetate mixture (4:1). For final purification it is distilled on a bulb tube (melting point 120°C at 10'4 inbars). 0.8 g of N-(3-methoxy-2-nitrophenyl)-4'-aminomethylbiphenyl-2-carboxylic acid methyl ester is obtained.
b) 0.8 g of the compound obtained under a) is dissolved in 45 ml of ethanol, mixed with 0.1 g of Raney nickel and hydrogenated under standard pressure. When the hydrogen absorption is completed, the catalyst is filtered off and the filtrate is acidified with cone, hydrochloric acid. Then it is evaporated several times with ethanol. The remaining Ν-ρίπε thoxy-2 -aminophenyl) -4 z-aminomethyl-biphenyl—2-carboxylic acid methyl ester dihydrochloride is further reacted as crude product
c) 0.67 g of the crude product obtained under b) is dissolved in 18 ml of methanol and mixed with 0.82 ml of orthobutyric acid trimethyl ester. The reaction mixture is refluxed for 8 hours, concentrated by evaporation after cooling and taken up in ethyl acetate. By treatment with ultrasound a precipitation of the product was achieved, which was suctioned off and dried. 0.32 g of 2-[4-(3-methoxy-2-propyl-lbenzimidazolylmethyl)-phenyl]-benzoic acid methyl ester with a melting point of 205°C was obtained.
d) 0.31 g of the ester obtained under c) is stirred in 0.15 N ethanolic sodium hydroxide solution for 20 hours at room temperature. Then the mixture is concentrated by evaporation, taken up with water and washed with ether. The pH of the aqueous solution is adjusted to pH = 5.5 with 1 N hydrochloric acid, the resulted precipitate is suctioned off and dried on phosphorus pentoxide. 0.16 g of 2-[4-(4-methoxy-2-propyl-lbenzimidazolylmethyl)-phenyl]-benzoic acid with a melting point of 262-267°C is obtained.
e) 1.0 g of the compound produced under d) is refluxed for 2 hours in 40 ml of 48% hydrobromic acid. After cooling, it is separated from a brown oily film. The precipitated substance is suctioned off, washed with ethanol and ether and dried in a vacuum. 70 mg of 2-[4-(4-hydroxy-2-propyl-lbenzimidazolylmethyl)-phenyl]-benzoic acid with a melting point of 266-270°C is obtained.
Example 3
2[4-(6-Carboxy-2-propyl-l-benzimidazolylmethyl)-phenyl]-benzoic acid
2-Propyl-5-benzimidazolcarboxylic acid benzyl ester (example 6 c) was reacted with 4'-bromomethyl-biphenyl-2-carboxylic acid methyl ester analogously to example 6d and 6e. The resulting product was saponified with NaOH,and 2-[4-(6-carboxy-2-propyl-lbenzimidazolylmethyl)-phenyl]-benzoic acid with a melting point of 280—282°C was obtained.
Example 4
2-[4-(6-Hydroxymethyl-2-propyl-l-benzimidazolylmethyl)-phenyl]benzoic acid
a) 555 mg of 2-[4-6-benzyloxycarbonyl-2-propyl-lbenzimidazolylmethyl)-phenyl]-benzoic acid methyl ester, hydrochloride (example 3a) is stirred with ethyl acetate/sodium bicarbonate solution, the organic phase is dried, concentrated by evaporation and the residue is dissolved in 40 ml of methanol.
It is hydrogenated for 1 hour in the presence of 200 mg of palladium/carbon (10%) under standard pressure, filtered~~from the catalyst, the filtrate is concentrated by evaporation. 380 mg of l-{(2'-methoxycarbonylbiphenyl-4-yl)-methyl}-2—propyl-6benzimidazole carboxylic acid with a melting point of 216-227°C is obtained.
b) 323 mg of the compound described under a) is mixed under ice cooling and argon protective gas with 5 ml of a one-molar borane-tetrahydrofuran complex solution and stirred for 16 hours at room temperature. It is mixed under ice cooling with methanol, stirred for 1 hour at room temperature and concentrated by evaporation. The residue is mixed with 20 ml of a one-molar ethereal hydrochloric acid solution and stirred for 1 hour at room temperature, concentrated by evaporation and mixed with ethyl acetate/sodium bicarbonate solution. The organic phase is dried, concentrated by evaporation and the residue is separated on a silica gel column with acetone/dichloromethane 1+1. 202 mg of 2-(4-(6-hydroxymethyl-2-propyl-l-benzimidazolylmethyl)16 phenyl]-benzoic acid with a melting point of 177-179°C (from ethyl acetate/hexane) is obtained.
Example 5
2-(4-(6-Hydroxy-2-propyl-l-benzimidazolylmethyl)-phenyl]-benzoic acid, hydrobromide
Starting from 1,2-diamino-4-methoxybenzene, dihydrochloride, 2-(4-(6-methoxy-2-propyl-l-benzimidazolylmethyl)-phenyl]-benzoic acid was obtained in reactions analogous to examples lb, c, d.
It was converted by hydrobromic acid analogously to example-2 e into the hydrobromide of 2-[4-(6-hydroxy-2-propyl-lbenzimidazolylmethyl)-phenyl]-benzoic acid with a melting point of 119-120°C.
Example 6
1—{[2'-(5-Tetrazolyl)-biphenyl-4-yl]-methyl}-2-propyl-6benzimidazole carboxylic acid
a) 5-((4z—bromomethyl—biphenyl)—2—yl]—2—triphenylmethyl—2H— tetrazole is produced from 5-((4-methylbiphenyl)-2-yl]-2triphenylmethyl-2H-tetrazole and N-bromosuccinimide analogously to example 8c.
b) 1.54 g of 3,4-diaminobenzoic acid is mixed with 40 ml of Ira ethereal hydrochloric acid, concentrated by evaporation after 15 minutes and the residue is refluxed in 30 ml of methanol with
3.3 ml of orthobutyric acid trimethyl ester for 3 hours. The reaction mixture is concentrated by evaporation and triturated
with diethyl ether. 2 g of 2-propyl-5- benzimidazole carboxylic acid with a melting point of 185-188°C is obtained.
c) 10 g of the compound obtained under b) is suspended in 50 ml of benzyl alcohol and 200 ml of benzene, mixed with 10.5 g of p-toluenesulfonic acid and refluxed for 24 hours on a water separator. The clear solution is washed three times with saturated sodium bicarbonate solution, the organic phase is dried on sodium sulfate, concentrated by evaporation and the residue is recrystallized from ethyl acetate/hexane. 11.3 g of 2-propyl-5benzimidazole carboxylic acid benzyl ester with a melting point of 99-100°C is obtained.
d) 1.06 g of the compound obtained under c) is dissolved in ml of dimethylformamide and mixed at 0°C with 1.11 g of sodium hydride (80%) and after 30 minutes mixed with 1.65 g of 5-[(4'bromomethyl-biphenyl)-2-yl]-2-triphenylmethyl-2H-tetrazole in 15 ml of dimethylformamide. After 16 hours at room temperature it is concentrated by evaporation, the residue is taken up in ethyl acetate/water and the organic phase is washed twice with water, dried and again concentrated by evaporation. The residue is chromatographed on silica gel with an ethyl acetate-cyclohexane mixture 1+1. 720 mg of 1-([2'(2-triphenylmethyl)-2H-5tetrazolyl-4-yl]biphenyl-4-yl]-methyl)-2-propyl-6-benzimidazole carboxylic acid benzyl ester with a melting point of 134-135°C is obtained (from ethyl acetate/hexane).
e) 250 mg of the compound obtained under d) is stirred in a mixture of 7.5 ml of methanol, 7.5 ml of tetrahydrofuran and 3 ml of two-molar sodium hydroxide solution for 24 hours at room temperature. Then it is partially concentrated by evaporation, mixed with 5 ml of methanol, 20 ml of water and 30 ml of acetic acid and heated in 1 hour to 100°C. It is partially concentrated by evaporation, combined with 20 ml of four-molar sodium hydroxide solution and extracted twice with diethyl ether. The aqueous phase is adjusted to pH 4 with dilute hydrochloric acid. The resulting precipitate is suctioned off and washed with water. After crystallization from aqueous methanol 127 mg of l-{[2'-(5tetrazolyl)-biphenyl-yl]-methyl}-2-propyl-6-benzimidazole carboxylic acid with a melting point of 192-194°C was obtained.
Example 7
2-[4-(6-Carboxy-4-methyl-2-propyl-l-benzimidazolylmethyl)phenyl]-benzoic acid
a) 3.45 g of 4-bromo-2-methyl-6-nitroaniline in 200 ml of tetrahydrofuran is hydrogenated in 5 hours in the presence of 2 g of Raney nickel under standard pressure. It is filtered from the catalyst and concentrated by evaporation. After recrystallization from diisopropyl ether/hexane, 2.8 g of 2amino-4-bromo-6-methylaniline with a melting point of 64°C is obtained.
b) 2.8 g of the compound obtained under a) is reacted with orthobutyric acid trimethyl ester as described in example 6a.
L9
3.1 g of 6-bromo-4-methyl-2-propylbenzimidazole with a melting point of 175—176°C is obtained.
c) 1.4 g of the compound obtained under b) is reacted with (4-broraomethyl-biphenyl)2-carboxylic acid tert-butyl ester as described in example 6c. 2-[4-(6-bromo-4-methyl-2-propyl-lbenzimidazolyl methyl)-phenyl]-benzoic acid tert-butyl ester with a melting point of 125-127°C is obtained.
d) 830 mg of the compound obtained under c) is dissolved in 10 ml of absolute tetrahydro furan and mixed at -90°C with 1.2 ml of a 1.6-molar n-butyllithium solution. After 2 hours at -78°C it is poured onto solid carbon dioxide, mixed with 20 ml of a one-molar sodium hydroxide solution and the aqueous phase is extracted twice with diethyl ether. The aqueous phase is acidified to pH 5, the precipitate is suctioned off and recrystallized from aqueous methanol. 550 mg of l-[(2'-(tertbutylcarbonylbiphenyl-4-y1)-methyl]-4-methyl-2-propyl-6benzimidazole carboxylic acid with a melting point of 134-140°C is obtained.
e) 530 mg of the compound obtained under d) is dissolved in 10 ml of trifluoroacetic acid and stirred for 2 hours at room temperature. It is concentrated by evaporation, the residue is dissolved in 25 ml of a one-molar sodium hydroxide solution, washed twice with diethyl ether and adjusted to pH 4 with dilute hydrochloric acid. The precipitate is suctioned off, washed with water and recrystallized from aqueous methanol. 300 mg of 2-(4(6-carboxy-4-methyl-2-propyl-l-benzimidazolylmethyl)-phenyl]benzoic acid with a melting point of 257-265°C is obtained.
Example 8
2- 4-(4-Methyl-2-propyl-l-benzimidazolylmethyl)-3-fluorophenyl benzoic acid
a) 4.7 g of 2-fluoro-4-iodotoluene in 100 ml of absolute tetrahydrofuran is mixed at -70°C under argon protective gas with ml of 1.6 molar n-butyllithium solution and stirred for 2 hours at -70°C. It is combined with 9.2 ml of boric acid triisopropyl ester in 50 ml of absolute tetrahydrofuran at 90°C. After 2 hours at -70°C, it is heated to room temperature and combined with 100 ml of three-molar hydrochloric acid.
After 1 hour, the aqueous phase is extracted twice with diethyl ether/ ethyl acetate, the organic phases are combined, washed neutral with water, dried on sodium sulfate and concentrated by evaporation. After crystallization from ethyl acetate/hexane 2 g of 3-fluoro-4-methylphenylboronic acid with a melting point of 243-244°C is obtained.
b) 2 g of the compound obtained under a), 3.7 g of 2iodobenzoic acid methyl ester and 460 mg of tetrakis[triphenylphosphine]-palladium in 10 methanol, 40 ml of toluene and 13 ml of two-molar sodium carbonate solution are heated for hours to 100°C. It is combined with water/ethyl acetate and the organic phase is washed twice with water. 3.2 g of 2-(321 fluoro-4-methylphenyl)benzoic acid methyl ester with a boiling point of 90-95°C (0.01 torr) is obtained from the organic phase after distilling off the solvent and high-vacuum distillation of the residue.
c) 3.2 g of the compound obtained under b) is dissolved in 35 ml of tetrachloromethane and mixed in boiling heat with 2.3 g of N-bromosuccinimide and 100 mg of bibenzoyl peroxide. It is refluxed for 8 hours under simultaneous radiation with a 100watt lamp, suctioned off and concentrated by evaporation. 4.2 g of 2-(4-bromomethyl-3-fluorophenyl)-benzoic acid methyl ester is obtained.
d) The compound produced according to c) and 4-methyl-2propylbenzimidazole are reacted analogously to example lc and Id and 2-[4-(4-methyl-2-propyl—1-benzimidazolylmethyl)-3fluorphenyl]-benzoic acid of a melting point of 266-268°C is obtained.
Example 9
1-[3-Fluoro-2'-(5-tetrazolyl)-biphenyl-4-yl-methyl]-4-methyl-2propylbenzimidazole
a) 6.4 g of 3-fluoro-4-methylphenyl boronic acid (example 8a) is reacted with 9.1 g of 2-bromobenzonitrile analogously to example 8b. 7 g of 2-(3-fluoro-4-methylphenyl)benzonitrile with a boiling point of 85-87°C (from diisopropyl ether) and with a boiling point of 110°C (0.06 torr) is obtained.
b) 6.7 g of the compound obtained under a) is heated in 200 ml of dimethylformamide with 2.1 sodium azide and 4.5 g of triethylammonium chloride for 16 hours to 140°C. It is mixed with water, acidified under ice cooling, extracted with ethyl acetate, the organic phase is washed with water, dried and concentrated by evaporation. After recrystallization from ethyl acetate/hexane, 7.9 g of 5-(3'-fluoro-4'-methylbiphenyl-2-yl)2H-tetrazole with a melting point of 153-156°C is obtained.
c) 1 g of the compound obtained under b) and 1.2 g of triphenylchloromethane are suspended in 20 ml of dichloromethane and stirred for 2 hours with 0.6 ml of triethylamine. The clear reaction solution is washed with water, dried and concentrated by evaporation. After recrystallization from diisopropyl ether, 1.8 g of 5-(3'-fluoro-4'-methylbiphenyl-2-yl)-2-triphenylmethyl-2H-tetrazole with a melting point of 156-158°C is obtained.
d) 5 g of the compound obtained under c) and 1.8 g of Nbromosuccinimide are reacted as described in example 8c. 5.8 g of 5-(4'-bromoraethyl-3'-fluorobiphenyl-2-yl)-2-triphenylmethy12H-tetrazole is obtained.
e) The compound obtained according to d) is reacted with- 4methyl-2-propyl-benzimidazole analogously to example 6c, and 1{[2' -(2-triphenylmethyl-2H-5-tetrazolyl)-biphenyl-4-yl]-methyl}23
4-methyl-2-propylbenzimidazole with a melting point of 144-145°C in a yield of 47% of theory results.
f) 600 mg of the compound obtained under e) is dissolved in 20 ml of acetic acid, mixed with 20 ml of water and heated to 100°C in 30 minutes. It is suctioned off, the filtrate is concentrated by evaporation, the residue is dissolved in 25 ml of 2n sodium hydroxide solution, washed twice with diethyl ether and the aqueous phase is adjusted to pH 5 with dilute hydrochloric acid. The precipitate is suctioned off and recrystallized from aqueous methanol. 335 mg of 1-[3-fluoro-2'-(5-tetrazolyl)biphenyl-4-yl-methyl)-4-methyl)-2-propylbenzimidazole with a melting point of 137-138°C is obtained.
Example 10
1-[3-Fluor-2*- (5-tetrazolyl)-biphenyl-4-yl-methyl]-4-methyl-2propyl-6- benzimidazole carboxylic acid
a) 1.1 g of 6-bromo-4-methyl-2-propylbenzimidazole (example 7b) and 900 mg of copper(I) cyanide are heated in 30 ml of dimethyl acetamide for 16 hours to 180°C, again mixed with 360 mg copper(I) cyanide and heated for 8 more hours to 180°C. It is concentrated by evaporation, stirred with 30 ml of concentrated ammonia and 30 ml of ethyl acetate for 4 hours at room temperature, the organic phase is dried and concentrated by evaporation. The residue is purified on a silica gel column (system: ethyl acetate/cyclohexane 1+1) and recrystallized from ethyl acetate/hexane. 800 mg of 4-methyl-2-propyl-624 benzimidazole carbonitrile with a melting point of 188-189°C is obtained.
b) 500 mg of the compound obtained under a) is dissolved in ml of absolute ethanol, the ethanolic solution is saturated with hydrochloric acid gas and refluxed for 6 hours. It is concentrated by evaporation, mixed with ethyl acetate/sodium bicarbonate solution, the organic phase is dried and concentrated by evaporation. 600 mg of 4-methyl-2-propyl-6-benzimidazole carboxylic acid ethyl ester is obtained as oil. -
c) By reaction of the compound obtained under b) with 5(47-bromomethyl-3'-fluorobiphenyl-2-yl)-2-triphenylmethyl-2Htetrazole (example 9d) analogously to example 6d and subsequent alkaline and acid hydrolysis analogously to example 6e, l-[3fluoro-2'- (5-tetrazolyl)-biphenyl-4-yl-methyl]-4-methyl- 2propyl-6-benzimidazole carboxylic acid with a melting point of 227-228°C is obtained.
Claims (6)
1. Benzimidazole derivatives of formula I in which R 1 means H, alkyl, Br or OH, R 2 means H, COOH, CH2OH or OH,and R 1 and R 2 cannot be hydrogen at the same time and R 1 cannot be CH3, if R 2 and R 3 at the same time mean hydrogen or R means CH 2 OH, R 3 means hydrogen or fluorine and R 4 means COOH or 2-tetrazolyl as well as their acid or base addition salts.
2. Process for the production of benzimidazole derivatives of formula I, characterized in that in a way known in the art a) a benzimidazole of formula II Ri 1 1 · piT -N i ί Γ II . Π NH in which R 1 and R 2 have the above-indicated meanings, is reacted with an alkylation reagent of formula III μ in which R 3 and R 4 have the above-indicated meanings and R 5 means Cl, Br, OSO 2 CH 3 , OSO 2 C 6 H 4 CH 3 (p) , or b) a phenylenediamine derivative of formula IV in which R 1 , R 2 , R 3 and R 4 have the above-indicated meanings, is reacted with an orthocarboxylic acid ester of formula V (R 6 O) 3 C-C 3 H 7 (V), in which R 6 means C,-C 4 alkyl, and the ester is saponified.
3. Pharmaceutical agents consisting of one or more compounds of claim 1 and the usual auxiliary agents and vehicles -274. A compound substantially as hereinbefore described with reference to the Examples.
4. 5. A composition substantially as hereinbefore described with reference to the Examples.
5.
6. A process substantially as hereinbefore described with reference to the Examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4006693A DE4006693A1 (en) | 1990-03-01 | 1990-03-01 | NEW BENZIMIDAZOLE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND THEIR PHARMACEUTICAL USE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE910686A1 true IE910686A1 (en) | 1991-09-11 |
Family
ID=6401349
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE068691A IE910686A1 (en) | 1990-03-01 | 1991-03-01 | New benzimidazole derivatives, process for their production¹and their pharmaceutical use |
Country Status (6)
| Country | Link |
|---|---|
| AU (1) | AU7257891A (en) |
| DE (1) | DE4006693A1 (en) |
| IE (1) | IE910686A1 (en) |
| PT (1) | PT96922A (en) |
| WO (1) | WO1991013063A1 (en) |
| ZA (1) | ZA911538B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0461040A1 (en) * | 1990-06-08 | 1991-12-11 | Roussel Uclaf | Imidazol derivatives, their process for production, intermediates, their application as medicaments and the pharmaceutical compositions containing them |
| KR920021542A (en) * | 1991-05-16 | 1992-12-18 | 배리 안토니 뉴샘 | Benzofuran derivatives |
| GB9218449D0 (en) | 1992-08-29 | 1992-10-14 | Boots Co Plc | Therapeutic agents |
| SE9903028D0 (en) | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
| AU2008261102B2 (en) | 2007-06-04 | 2013-11-28 | Bausch Health Ireland Limited | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| WO2009149279A2 (en) | 2008-06-04 | 2009-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| AU2014235209B2 (en) | 2013-03-15 | 2018-06-14 | Bausch Health Ireland Limited | Guanylate cyclase receptor agonists combined with other drugs |
| US9708367B2 (en) | 2013-03-15 | 2017-07-18 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase and their uses |
| US10011637B2 (en) | 2013-06-05 | 2018-07-03 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase C, method of making and using same |
| US9828348B2 (en) | 2013-11-08 | 2017-11-28 | Purdue Pharma L.P. | Benzimidazole derivatives and use thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4880804A (en) * | 1988-01-07 | 1989-11-14 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking benzimidazoles |
| DE3928177A1 (en) * | 1989-04-08 | 1991-02-28 | Thomae Gmbh Dr K | BENZIMIDAZOLE, MEDICAMENTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| EP0400835A1 (en) * | 1989-05-15 | 1990-12-05 | Merck & Co. Inc. | Substituted benzimidazoles as angiotensin II antagonists |
| GB8911854D0 (en) * | 1989-05-23 | 1989-07-12 | Ici Plc | Heterocyclic compounds |
| IE70593B1 (en) * | 1989-09-29 | 1996-12-11 | Eisai Co Ltd | Biphenylmethane derivative the use of it and pharmacological compositions containing same |
-
1990
- 1990-03-01 DE DE4006693A patent/DE4006693A1/en not_active Withdrawn
-
1991
- 1991-02-28 AU AU72578/91A patent/AU7257891A/en not_active Abandoned
- 1991-02-28 WO PCT/DE1991/000186 patent/WO1991013063A1/en unknown
- 1991-03-01 IE IE068691A patent/IE910686A1/en unknown
- 1991-03-01 ZA ZA911538A patent/ZA911538B/en unknown
- 1991-03-01 PT PT96922A patent/PT96922A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DE4006693A1 (en) | 1991-09-05 |
| AU7257891A (en) | 1991-09-18 |
| ZA911538B (en) | 1992-02-26 |
| PT96922A (en) | 1991-10-31 |
| WO1991013063A1 (en) | 1991-09-05 |
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