HK1005592B - Benzimidazole derivatives, process for their preparation and therapeutic application - Google Patents

Description

The present invention relates to benzimidazole derivatives, their preparation and their therapeutic application.

Benzimidazole derivatives and imidazopyridine derivatives have been described by several authors (EP-A-0099139 EP-A-0144101; EP-A 0151826; EP-A-0151824; US-A-4281005).

The compounds of the invention differ mainly from those described in the previous art in that the substitution pattern of the 4-aminopiperidinyl radical differs by the position of the benzimidazole substituents, respectively imidazopyridine and 2-pyrimidine in the molecule.

The compounds of the invention conform to the formula (I) given in Annex 1 in which X is CH or N, R1 is either a hydrogen atom or a benzyl radical with 1 to 3 substituents chosen from halogen atoms, the trifluoromethyl radicals, (C1−4) alkyls, (C1−4) alcoxy, cyano, methylthio, methylsulfinyl and methylsulfonyl, or a heterocycle-methyl radical in which the heterocycle may be a pyridinyl, thienyl or furannyl radical, R2 is a hydrogen atom or a radical (C1−4) alkyl, R3 is a hydrogen atom or the hydroxy radical, R4 is a hydrogen atom or a radical (C1−4) alkyl.

Addition salts formed by compounds (I) with pharmaceutically acceptable acids are part of the invention.

The preferred compounds of the invention are those in which X is CH or N, R1 is a fluoro-4 benzyl radical and R2, R3 and R4 have the meanings given in claim 1.

Among the compounds of the invention in which X is CH, the compounds of choice are those in which R1 is a benzyl radical with one or two substituents, and more particularly those in which a single substituent is present at position 4 which is a fluorine or chlorine atom or the methyl, methoxy, methylthiol, trifluoromethyl, cyano or methylsulfinyl radical.

When R3 is OH and R4 is H, the tautomeric forms of the compounds are part of the invention (see Appendix 1).

According to the invention, the compounds (I) can be prepared according to the two main reaction schemes given in Annex 2, the methods A, B, C, D of which are illustrated below.

The most general method C applies to all compounds, while method D is only applicable to compounds in which R2 is different from H. Methods A and B are only applicable when R1 is different from H.

The method of the invention consists in reacting a compound of formula (II) with a (R2) ((R) amino-4 piperidine of formula - What? where R2 = H or (C1−4) alkyl and R represents . either a hydrogen atom, or a (C1−4) alcoxycarbonyl group, or the group (R3=H or OH, R4=H or (C1−4) alkyl, and, when R is H, the pyrimidinyl group is introduced in a second step. When R is a (C1−4) alcoxycarbonyl group, this group is removed by hydrolysis and then the pyrimidinyl group is introduced.

Method A condenses a compound (II) with a (R2) ((alcoxycarbonyl) amino-pipéridine (III) by heating at about 150°C, then hydrolyzes the compound (IV) obtained by bromic acid in acetic medium to a compound (V) reacted with a pyrimidine (VI) in which Y is a starting group such as SCH3, Cl, Br or I, whether or not a solvent is present, at 50 to 200°C.

Method B is to react a compound (II) with a (R2) amino-pipperidine in the presence of potassium carbonate in an alcoholic solvent and then to condense the compound (V) with a pyrimidine (VI) in which Y is a leaving group such as SCH3, Cl, Br or I, whether or not a solvent is present, at 50 to 200 °C.

Method C: a compound (II) is reacted with a compound (VIII) (obtained by alkylation of a benzyl-1 or ethoxycarbonyl-1 amino-4 piperidine with a halogen-2 or alkylthio-2 pyrimidine (VI), followed by catalytic debenzylation or hydrolysis to remove the protective group at position 1), in an alcoholic solvent at reflux temperature.

According to method D, a compound (II) in which R1 is H is taken and condensed with an (R2) ((alcoxycarbonyl) aminopiperidine (III) by heating at 150°C, the compound obtained (X) is alkylated by an alkyl halide to obtain the compound (IV) which is hydrolysed, and then the compound (V) is condensed with a pyrimidine (VI) as in method A.

In the reaction patterns shown in Annex 2 the radicals have the meanings given above.

The compounds of formulae (II, with X = CH), (VI) and (VII) are described in the literature; the compounds of formulae (II, with X = N), (III), (IV), (V) and (VIII, with R3=OH) are new. The following examples illustrate the invention: IR and MRI analyses and spectra confirm the structure of the compounds.

The following is the list of active substances which are to be classified in the additive:

The following substances are to be classified in the same category as the active substance: 1.1.1. Solubilise 19 g (0.09 mole) of piperidinyl-4 carbamate ethyl hydrochloride in 120 ml of methanol and neutralize with 17.2 ml of sodium methyl 5,3 N. Filter and evaporate dry. Then mix the evaporation residue with 21.6 g (0.083 mole) of chlor-2 [fluoro-4 phenyl) methyl]-1 1H-benzimidazole and heat at 140°C for 5 hours. Reaction mass is taken up with methylene chloride, alkalinized with 2N solder. Wash the organic phase with water, dry, filter, evaporate. Oncheatograph the obtained oil on silica (select: methylene chloride 97, methanol).The result is the [fluoro-4 phenyl]methyl-1 1H-benzimidazolyl-2-1 piperidinyl-4] ethyl carbamate. F = 136°C.1.1.2. To an ice-cooled suspension of 3.3 g (0.068 mole) 50% sodium hydride in 40 ml dimethylformamide, add in half an hour or so, drop by drop, 21.6 g (0.054 mole) of the previously obtained compound in solution in 40 ml dimethylformamide. Return the mixture to room temperature and stir for 2 h. Cool again with an ice bath, and add 4.7 ml (0.075 mole) of methyl iodide (d = 2.28) in solution in 30 ml DMF.The reaction mixture is poured into a mixture of water, hexane and isopropyl ether and stirred until crystallized. The precipitate is filtered and dried. The result is [[[fluoro-4phenyl]methyl]-1 1H-benzimidazolyl-2]-1 piperidinyl-4 N-methyl ethyl carbamate. F = 125°C.1.1.3. Place 7 g (0.017 mole) of the previously obtained compound at reflux temperature for 1.5 h in a solution of 140 ml acetic acid and 140 ml 48% bromic acid. Evaporate dry, add water, alkalize with 2N soda. Add ether and stir until the product crystallizes.This is the monohydrate of fluorophenylmethyl-1 1H-benzimidazolyl-2-1 N-methyl piperidinamine-4. The test chemical is a hydrolysed hydrolysed water solution. At reflux temperature, 8.7 g (0.05 mole) of methyl-4-pipperidine (as acetate), 13 g (0.05 mole) of (fluoro-4-benzyl) - 1 chloro-2 benzimidazole and 13.8 g (0.1 mole) of potassium carbonate are added to 250 ml of isomyl alcohol for 192 h. You cool the mixture, you evaporate it dry, you take the residue with a mixture of water and ether, and you shake it until it crystallizes, you filter the V compound that you get as a hydrate, you take the precipitate with toluene, you shake it until it dissolves, and you dry the solution with magnesium sulfate,The residual oil is crushed in petroleum ether, the solid product is filtered and dried, and the compound is obtained, which melts at 77-80°C.1.3. The reaction mass is chromatographed on a silica column (elevent = dichloromethane/methanol 97/3) after cooling, and the compound is recrystallized in ethanol. F is 217 degrees.

The following is the list of active substances which are to be classified in the Annex to this Regulation:

The following substances are to be classified in the same category as the active substance: 14.5 g of [fluoro-4 phenyl) methyl]-1 1H-benzimidazolyl-2-1 piperidinyl-4 ethyl carbamate is brought to the reflux temperature for 2 h in a solution of 250 ml acetic acid and 250 ml 48% bromine hydrochloride. It is evaporated dry, picked up with water, alkalinized with 2N soda, filtered with precipitate, washed with water and dried. A mixture of 1.71 g (0.005 mole) of fluorine-methyl-1 benzimidazolyl-2-1 piperidinamine-4 0.57 g (0.005 mole) of chlorine-pyrimidine and 0.43 g (0.052 mole) of sodium bicarbonate and 19 ml of ethanol is carried at reflux temperature for 2 days and 2 nights. You get the product that you crystallize in ether. F is 190 degrees.

The following is added to the list of active substances in Annex I to Regulation (EC) No 1907/2006 by adding the following additional substances:

The following definitions apply to the following substances: The following substances are to be classified in the same category as the active substance: In a nitrogen-circulated balloon with a vapour outlet connected to a bleach system, place 36 g (0.193 mol) of methyl methyl-4-piperidine-1-carboxylate in the presence of 27.44 g (0.193 mol) of S-methyl thiouracil and 730 ml of xylene, heat to the solvent reflux temperature for about 50 h. The solvent is then evaporated at vacuum drying and the resulting solid product is dissolved in reflux butyl acetate.The compound melts at 177-179°C.3.1.2. [(Piperidinyl-4) (methyl) amino]-2 1H-pyrimidinone-4. The solution of 19.73 g (0.07 mol) of the above compound is heated at the reflux temperature for 1 1⁄4 h in 150 ml of 48% hydrobromic acid and 150 ml of acetic acid. The acids are evaporated at dry steam. The residue is taken up by a little water and re-evaporated at dry steam, this operation being repeated 3 times. Finally, the remainder is taken up by cooling with an excess solution of concentrated soda, then the resulting suspension is shaken in a sonic bath, cooled in ice and dried.The solid is pressed, washed with very little ice water and then rinsed thoroughly with ether. The following substances are to be classified in the same heading as the active substance: 1.3 g (5.10−3 mole) of chlorine-2 [fluoro-4 phenyl) methyl]-1 3H-imidazo[4,5-b]pyridine, 1.1 g (5.10−3 mole) of [pipéridinyl-4) (methyl) amino]-2 1H-pyrimidinone-4 are heated at the reflux temperature for 5 h in 50 ml of methyl-3 butanol-1 and left to rest for one night, and 0.7 g (5.10−3 mole) of potassium carbonate is added.The evaporation residue is taken up with water, extracted with ethyl acetate, the organic phase is washed with water, dried on magnesium sulphate, filtered and evaporated.

The following is a list of the active substances that may be used in the preparation of the active substance:

The test chemical is a chemical that is used to determine the concentration of a substance in a solution. 32.7 g (0.15 mole) of (pipperidinyl-4) N-methyl tertiobutyl carbamate, 20.8 g (0.136 mole) of chloro-2 1H-benzimidazole are heated at the reflux temperature for 4 1⁄2 h in 275 ml of methyl-3 butanol-1. The solvent is evaporated in a vacuum, and the residue is taken with 20 ml of hot methanol, 28,5 ml of sodium methyl 5.3 N and 200 ml of water are added, the precipitate is washed with water and dried. A solid is obtained by melting at 242 °C.4.2 (Cyano-4 phenylmethyl)-1 [1H benzimidazolyl-2]-1 piperidinyl-4]-N-methyl carbamate of t-butyl. With a suspension of 1,14 g (0.0237 mole) of 50% NaH in 30 ml of dimethylformamide, add 6.04 g (0.02 mole) of the previous product in portions and shake 1 hour after the end of the introduction. Cool the mixture to 0°C and add 4.5 g (0.023 mole) of bromethyl-4 benzonitrile in solution to 15 ml of dimethylformamide. Shake the mixture for 2 h at 0°C and then pour into water. Extract the ether, with the organic phase with water, dry, filter and evaporate. The product is purified by chromatography on a silica column (dichloromethane/methanol 98/2) to obtain the melting product at 146°C.The following substances are to be classified in the same category as the active substance: The solution is heated at 50°C for 1 hour, 4.8 g (0.0107 mole) of the previous product in 20 ml of 3N hydrochloric acid. When the hydrolysis is complete, the solution is cooled, alkalinized with 5N soda, extracted with dichloromethane. At reflux temperature, 3.5 g (0.01 mole) of the previous product, 1.4 g (0.01 mole) of S-methyl thiouracil are carried for 168 h in 35 ml of toluene, the mixture is cooled, evaporated dry and the residue is chromatographed on a silica column (dichloromethane/methanol 98/2 and then 96/4).The product is then melted at 198°C.

The compounds of the invention prepared as examples are shown in the following table (I). The intermediates of formula (IV) which are new are shown in the following table (II).

The compounds have been subjected to various pharmacological trials showing mainly their antagonistic activity on histamine and for some on serotonin.

In vitro activity: isolated test tube ileum

The test was carried out using the Magnus method modified by Savini (Arch. Int. Pharmacodyn., 1957, 113, 157), on male tricolor guinea pigs weighing about 300 g, on an 18-hour fast. A fragment of ileum is taken, placed at 39°C in a tyrode bath with a current of carboxylic acid (02 95%, CO2 5%) and connected to an isotonic sensor with a maximum voltage of 2.5 g. The contractions are recorded by means of a Ugo Basile microdynamometer. Contractions are induced by the various spasmogenic agents whose concentration causing a submaximal response is determined (histamine: 1 to 8.10−8 g/ml). The compounds of the invention dissolved in distilled water or a 0.1 N solution of methanesulfonic acid are brought into contact with the ileon for 1 minute before the introduction of the spasmogenic substance. The CA50 (concentration decreasing by 50% the histamine-induced contractions) of the compounds of the invention range from 10−7 to 10−8 molar.

In vivo activity: inflammation induced by histamine

Intra-plant administration of histamine (2 mg) into one of the rat' s hind legs caused edema measured 1 hour after injection using a Ugo Basile mercury plethysmometer. The compounds of the invention, suspended in tween in 1% solution in distilled water, are administered as p.o.; (0.5 ml/100 g) 1 hour before the injection of the inflammatory agent.

The DA40 (dose which reduces the volume of edema by 40%) of the compounds of the invention ranges from 0.2 to 10 mg/kg.

The compounds of the invention are of low toxicity, and their oral LD50 is greater than 1000 mg/kg.

The compounds of the invention can therefore be used for the treatment of allergies such as respiratory allergies, skin allergies, eye allergies and various allergic manifestations. Some of the compounds of the invention are highly selective for histamine (H1) receptors and have no anticholinergic and antiserotoninergic activity at therapeutic doses. The invention therefore covers all pharmaceutical formulations containing the compounds and/or their salts as active ingredients, in combination with any excipients suitable for oral or parenteral administration.

The daily dose can range from 1 to 100 mg by mouth.

Claims (12)

1. Process for preparing the benzimidazole derivatives corresponding to the formula (I) in which X is CH or N, R₁ is a hydrogen atom or a benzyl radical which can bear 1 to 3 substituents chosen from halogen atoms and trifluoromethyl, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, cyano, methylthio, methylsulphinyl and methylsulphonyl radicals, or alternatively a methyl radical bearing a heterocyclic substituent in which the heterocyclic system can be a pyridyl, thienyl or furyl radical, R₂ is a hydrogen atom or a (C₁₋₄)alkyl radical, R₃ is a hydrogen atom or a hydroxy radical, and R₄ is a hydrogen atom or a (C₁₋₄)alkyl radical, where appropriate, in tautomeric form when R₃ is OH, as well as their addition salts with pharmaceutically acceptable acids, which process is characterized in that a compound of formula (II) is reacted with a 4-[(R₂)(R)amino]piperidine of formula in which R₂ is H or (C₁₋₄)alkyl and R denotes a hydrogen atom, a (C₁₋₄)alkoxycarbonyl group, or the group (R₃ = H or OH, R₄ = H or (C₁₋₄)alkyl), and

   · when R is H, the pyrimidinyl group is introduced in a second stage,

   · when R is a (C₁₋₄)alkoxycarbonyl group, this group is removed by hydrolysis and the pyrimidinyl group is then introduced.
2. Preparation process according to Claim 1, characterized in that 2-[[1-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-4-piperidyl]methylamino]-4-pyrimidinol is prepared.
3. Preparation process according to Claim 1, characterized in that 2-[[1-[1-[(4-methoxyphenyl)methyl]-1H-benzimidazol-2-yl]-4-piperidyl]methylamino]-4-pyrimidinol is prepared.
4. Preparation process according to claim 1, characterized in that 2-[[1-[1-[(4-fluorophenyl)methyl]-3H-imidazo[4,5-b]-pyrid-2-yl]-4-piperidyl]methylamino]-4-pyrimidinol is prepared.