DE1695048A1 - 1-Aryl-imidazoles and process for their preparation - Google Patents

Description

J. R. GEIGY A.G. BASEL

Dr. F. Zumsiein - Dr. E. Assmann

Dr. R. Koeniy Berger Dipi. Phys. R. {Ichbauer

Patent attorneys Mönchen % Bräuhausstrafse 4 / l! L

4-2501 / GC 241 *

1-Aryl-ind.dazole and process for their production

The present invention relates to imidazole derivatives with interesting pharmacological properties, in particular I-Arylimidasols and their Säurisa.ddditnssalze, as well as processes for their manufacture j further pharKaseniische Sfroffsusasanensätzeeii, which the- -: ^T "" idaijc-lds ".!: Iviite odsr ihra pl -armaceuticalsb. annebiabsran acid addi-

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BATH

It has now been found that compounds of the general formula I and their addition salts with inorganic and organic Acids the biosynthesis of the neural bark hormone aldosterone (ll (3,21-dihydroxy-3,20-dio>: o-4-pregnen-IS-al 'in significant Wise aetnmsa, v.nd ^ was in speifischr-i- wise by inhibition cUl · "Jr-change from li-De? 5xycorticcsi; eron in Aldostsron; in the fDxgsnzs ™ di-ese HeiiHiuag is also called Henm-ng der 18-HydroKvIierar-g bsseish = net,

So it was found in screening tests that dis -srfi "-dungsga ~ äss2n connection vind in particular the 4,5-Dir.3thyl""J.--.>" - = "flucrp? I? .Nyl) - ! i iiid-3z - "l _s si _:.; to:. .'_ ji'k honed effect on ^cas; i :; £ iÄ

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BATH

will; they also show effects on the circulatory system.

The compounds of the general formula according to the invention I are produced by converting from a compound of the general formula II,

(II)

in which

X denotes the hydroxyl group or the mercapto group and R ,, R "and Ro have the meaning given above, or from a compound tautomeric therewith, which group X is eliminated in a manner known per se and replaced by hydrogen. The elimination the group X of compounds of the general formula II in which X is the mercapto group includes desulphurization of l-aryl-2-mercaptoimidazoles and of the corresponding, therewith tautomeric thiono compounds. Related elimination procedures can be oxidative or reductive in nature; suitable desulfurizing agents are Raney nickel, nitric acid and hydrogen peroxide. The desulfurization of 2-mercaptoimidazoles of the general formula II can for example be carried out in such a way that one such a compound in a lower alkanol solution, e.g. in ethanol or isopropanol, treated with Raney nickel at reflux temperature, whereby the mercapto group is eliminated and replaced by hydrogen. The resulting imidazole derivative of the general formula I is separated from the reaction mixture by conventional methods,

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The desulfurization of 2-mercaptoimidazoles of the general Formula II using nitric acid is carried out in such a way that the 2-mercaptoimidazole is added to a stirred solution of sodium nitrite and conc. Adding nitric acid in water at 0 °, allowing the reaction to continue for some time, then making it alkaline and the corresponding imidazole derivative of the general formula I from the reaction mixture isolated by conventional methods.

If hydrogen peroxide is used to desulfurize 2-mercaptoimidazoles of the general formula II, it is advantageous an approx. 3% hydrogen peroxide solution in a lower alkanol, e.g. drop in ethanolic solution of 2-mercaptoimidazole at a slightly elevated temperature with stirring and after the addition is complete Let the reaction continue for about an hour while stirring and increasing the temperature to approx. 60 °. The thereby formed Imidazole derivative of the general formula I is isolated from the reaction mixture in the customary manner.

From compounds of the general formula II in which X denotes the hydroxyl group, these are eliminated in such a way that such a 2-hydroxyimidazole or an imidazol-2-one tautomeric with it, Treated with lithium alanate in an inert solvent, eliminating the oxygen function and replacing it with hydrogen will. In one embodiment of this method, the imidazolone placed in the sleeve of a Soxhlet extraction apparatus and an abs. essential solution of lithium alanate in the round bottom flask this apparatus, in which it is heated to boiling under anhydrous conditions under reflux. When the reaction is complete, in Worked up in the usual way and the resulting imidazole of general formula I is isolated.

1 0 9 K 1 R / 2 1 5 3

The l-aryl-2-mercaptoimidazoles used as starting materials of the general formula II can be represented by, for example, of known, appropriately substituted phenylisothio- ' cyanates goes out and this with suitable oc-amino-oxoalkanes, in which the oxo group is protected by acetalization with lower alkanols or 1,2-diols, under suitable conditions. Further these starting materials can be obtained by using the protected oc-amino-oxoalkanes in the manner just described with thiophosgene converts and the resulting oc-isothiocyano-oxoalkanes then treated with appropriately substituted anilines. These procedures are further elaborated in some of the examples below made clear. The oc-amino-oxoalkanes mentioned are either known compounds or can be obtained from known precursors by known processes getting produced,

1-Aryl-2-hydroxy-imidazoles used as starting materials of the general formula II, or the tautomeric 1-aryl-imidazol-2-ones, can be prepared from known precursors by known processes, cf. Elderfield, "Heterocyclic Compounds", Volume 5, Page 246, Wiley + Sons,

The compounds according to the invention can be used as such or in the form of their non-toxic, pharmaceutically acceptable acid addition salts administered orally or parenterally as an aqueous solution of these acid addition salts.

Non-toxic, pharmaceutically acceptable acid addition salts, i.e. addition salts with acids that are pharmacologically harmless in the effective doses can be used directly to produce Compositions of substances are used for oral or parenteral administration. They are made from the compounds according to the invention

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prepared in the usual way by using organic or inorganic acids suitable for salt formation, such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, Methanesulfonic acid, ethanesulfonic acid, 0-hydroxyethanesulfonic acid, acetic acid, Citric acid, benzoic acid, aminoacetic acid, lactic acid, Succinic acid, malic acid, aconitic acid, phthalic acid, fumaric acid, salicylic acid, maleic acid, tartaric acid, phenylacetic acid or mandelic acid,

For oral or parenteral administration of the inventive Compounds in therapeutically effective doses are substance compositions and dosage unit forms such as tablets, coated tablets and ampoules containing about 250 mg of a compound of the invention or a pharmaceutically acceptable acid addition salt thereof. Unit dose forms for oral use contain between 1% and 90% of a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. Such unit dose shapes can be produced, for example, by mixing the active ingredient with solid, powdery carrier substances, such as lactose, Sucrose, sorbitol or mannitol; Starches such as potato or corn starch or amylopectin; furthermore laminaria powder or citrus pulp powder; Cellulose derivatives or gelatin, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols (Carbowaxen) of suitable molecular weight, and from these mixtures tablets or tablet cores are formed. The cores are coated, e.g. with concentrated sugar solutions, e.g. Gum arabic, talc and / or titanium dioxide may contain, or with a film-forming polymer, which as a solution in volatile

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organic solvents or mixtures thereof is used. This one Dyes can also be added to coatings, for example between to be able to distinguish the different contents of active substance,

Ampoules for parenteral use, in particular for intravenous application, contain the active ingredient in the form of a water-soluble, pharmaceutically acceptable acid addition salt of a compound of formula I at a concentration of 0.5% to 5% in aqueous solution, if necessary together with suitable stabilizers and buffer substances.

In the following examples, the temperatures are given in degrees Celsius, percentages are percentages by weight.

1 0 9 B 1 B / 2 1 B 3

example 1

4,5-dimethyl-1- (4-fluorophenyl) imidazole hydrochloride

To a solution of 2.30 g of l- (4-fluorophenyl) -4,5-dimethyl-> 2-mercaptoimidazole (m.p. 260-263 °) in 70 ml of ethanol is about 10 g given wet Raney nickel. The mixture is for 4 hours on Heated to reflux, filtered and the filtrate evaporated to dryness in vacuo. The residue is dissolved in ethanolic hydrochloric acid and the solution is then evaporated in vacuo, the residue is crystallized from butanol and the crystals (m.p. 189.5-190.5 °) are through Sublimation at 0.1 Torr / 150 "further purified. The melting point of the sublimed 4,5-dimethyl-1- (4-fluorophenyl) -imidazole hydrochloride was unchanged at 189.5-190.5 °.

In the above process, isopropanol can be used in place of ethanol. The product can also be recrystallized from ethanol-ether will.

Example 2

1- (4-fluorophenyl) imidazole

To a stirred and cooled to 0 solution of 0 ^ 5 g sodium nitrite, 24 ml conc. Nitric acid in 70 ml of water is slowly added to 18 g of 1 - ^ - FUiorphenylJ ^ -mercaptoimidazole with a melting point of 205-207 °. The reaction mixture is stirred for a further 15 minutes, then made alkaline with solid sodium carbonate and extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate, filtered and the filtrate is evaporated to dryness in vacuo. The residue is distilled 3 times in vacuo and gives the oily 1- (4-fluorophenyl) imidazole with a boiling point of 108-109 ^: / 0.27 Torr.

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16950Λ8

Example 3 5-methyl-1- (4-fluorophenyl) imidazo!

To the solution of 2 g of 5-methyl-1- (4-fluorophenyl) -2-mer ~

in 100 ml of ethanol

captoimidazole (melting point 265-268 "and decomp.) / 10 g of Raney nickel are added and the mixture is refluxed for 3 hours. After cooling, it is filtered and the filtrate is evaporated to dryness in vacuo. The residue is evaporated to dryness sublimes at 80 "/ 0.45 Torr and gives 5-methyl-1- (4-fluorophenyl) -imidazole with a melting point of 1O3.5-1O5 ^C "

Example 4

5-methyl-1- (2-methoxyphenyl) imidazole nitrate

a) A mixture of 1.65 g of 5-methyl-1- (2-methoxyphenyl) -2-mercaptoimidazole and 8.0 g of Raney nickel in 300 ml of isopropanol is refluxed for 3 hours. The hot solution is filtered and the filtrate evaporated to dryness in vacuo. 1.2 ml of conc. Nitric acid are added to the residue at 0 °, and the resulting Solution is evaporated in vacuo. The residue is taken up in ethanol, the ethanolic solution is treated with animal charcoal and then concentrated, leaving the 5-methyl-1- (2-methoxyphenyl) imidazole nitrate of m.p. 158-160 ° (dec.) is obtained.

The mercaptoimidazole used as the starting material is produced as follows:

b) To a mixture of 12.5 g of thiophosgene, 15.0 g of calcium carbonate, 35 ml of water and 10 ml of chloroform, a solution of 11.7 g of 1-amino-2,2-ethylenedioxypropane in 25 ml of chloroform is added with stirring added dropwise. The reaction temperature is below 10 °

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held. After the end of the dropwise addition, the reaction mixture is during Stirred for 3 more hours at room temperature and then filtered, The organic phase is separated off, dried over sodium sulfate and filtered, and the filtrate is evaporated to dryness in vacuo. After distillation the residue becomes the liquid 2,2-ethylenedioxypropyl isothiocyanate obtained from bp 107-108 ° / 12 Torr, which is used directly.

c) To a stirred solution of 1.59 g of 2,2-ethylenedioxypropyl isothiocyanate in 80 ml abs. Ethanol are given 1.65 g of o-anisidine at room temperature. The mixture is for 30 minutes heated to reflux, whereupon 0.8 ml of conc. Hydrochloric acid is added and the mixture is refluxed for a further hour. To The precipitate formed of 5-methyl-1- (2-methoxyphenyl) -2-mercaptoimidazole, melting point 233-235 °, is filtered off and used for the implementation described under a).

Example 5

5-methyl-1- (3-methoxyphenyl) imidazole nitrate

a) A mixture of 2.95 g of 5-methyl-1- (2-methoxyphenyl) -2-mercaptoimidazole and 15.0 g of Raney nickel in 500 ml of isopropanol is refluxed for 3 hours. The catalyst is filtered off while hot and the filtrate is evaporated to dryness in vacuo. High vacuum distillation of the residue at 160-200 ° / 0.05 Torr (air bath) gives 5-methyl-1- (3-methoxyphenyl) imidazole.

0.48 g of this oily product are in 0.4 ml at 0 °

conc. Dissolved nitric acid and evaporated the solution in vacuo.

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The residue is crystallized from ethanol, the 5-methyl-1- (3-methoxyphenyl) imidazole Nitrate m.p. 169-171 ° (dec.) Is obtained.

The 2-mercaptoimidazole used as the starting material is obtained as follows:

b) A solution of 12.31 g is added at 15 ° to a vigorously stirred aqueous suspension of 14.94 g of thiophosgene in 150 ml of water Added dropwise m-anisidine in 60 ml of chloroform. It will be during Stirring was continued for 15 minutes, then the chloroform phase was separated off, dried over calcium chloride, filtered and then distilled. The fraction of 3-methoxyphenyl isothiocyanate obtained at 74-76 ° / 0.075 Torr is used for the implementation described under c).

c) To 2.8 g of 3-methoxyphenyl isothiocyanate in 13.7 ml of abs. Ethanol is added dropwise 1.99 g of 1-amino-2,2-ethylenedioxypropane with stirring. The reaction mixture is refluxed for 30 minutes , then cooled to 25 ° and 1.37 ml of conc. Hydrochloric acid are added. The mixture is then refluxed for a further hour. The precipitate of 5-methyl-1- (3-methoxyphenyl) -2-mercaptoimidazole, m.p. 192-193 ^; , is filtered off and used for the reaction described under a).

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Example 6

5-methyl-1- (4-methoxyphenyl) imidazole

A mixture of 6 g of 2-mercapto-1- (4-methoxyphenyl) -5-methylimidazole (melting point 224-227 °) and Raney nickel in ethanol is refluxed for 4 hours, after which the reaction mixture is cooled and filtered. The filtrate is evaporated in vacuo and the residue is distilled 3 times, 5-methyl-1- (4-methoxyphenyl) -imidazole, b.p. 115-117 ° / 0.003 Torr, which crystallizes spontaneously and gives colorless crystals with a melting point of 60 , 5-62 ⁶ results.

Example 7

5-methyl-1- (4-methoxyphenyl) imidazole

In a Soxhlet apparatus, in the case of which there is 3.47 g 1- (4-methoxyphenyl) -5-methylimidazol-2-one (m.p. 195-196) are, and in the round bottom flask 1.9 g of lithium aluminum hydride in 200 ml of abs. Ether are presented, the imidazolone is extracted into the reaction solution under reflux. The reaction will take place during 3 weeks performed under anhydrous conditions. Then the ethereal solution 2N hydrochloric acid is added carefully, the aqueous-acidic phase is separated off, made alkaline with sodium hydroxide solution and extracted with ether. The ether extract is dried and evaporated in vacuo, The residue worked up according to Example 6 gives 5-methyl-1- (4-methoxyphenyl) imidazole.

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Example 8

4,5-dimethyl-1- (4-fluorophenyl) imidazole hydrochloride

A solution of 2.2 g of 4,5-dimethyl-l- (4-fluorophenyl) -2-mercaptoimidazole (mp. 260-263 ° C) in 40 ml of ethanol under stirring with 36 ml of 3% Co ⁰ I ^tro Pf ^enwe i ^se shifted. After the addition has ended, stirring is continued at 50-60 ° for 60 minutes. Then some animal charcoal is added and the solution is briefly boiled, then filtered and made strongly alkaline with 50% potassium hydroxide solution, diluted with approx. 50 ml of water and thoroughly extracted with ether. The ether extract is dried over sodium sulfate, filtered and evaporated in vacuo. The solid residue is dissolved in ethanolic hydrochloric acid, the solution is evaporated and the residue is crystallized from ethanol-ether, the 4,5-dimethyl-1- (4-fluorophenyl) -imidazole hydrochloride having a melting point of 189.5-190.5 ° is received "

Example 9

Coated tablets

Components K

(1) 5-methyl-1- (4-fluorophenyl) imidazole 250.0

(2) milk sugar 80.0

(3) corn starch 70.0

(4) Soluble starch 15.0

(5) Magnesium stearate 5.0

420.0

The components (1), (2) and (3) are mixed thoroughly, the mixture is with the addition of an aqueous solution of (4) granulated, the dried granulate is mixed with (5) and the whole thing is compressed into 1000 tablets. Each tablet contains 250.0 mg of the active ingredient (1) and can be coated by customary methods, it being possible to add dyes to the coating.

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Claims (1)

Claims 1. Process for the preparation of compounds of general formula 1, ^R 3 ν / ^R 2 N NR ₁ (I) in which R, a halogen or a lower alkoxy group in 2-, 3- or 4-position substituted phenyl group, R ₉ and Ro independently of one another denote hydrogen or a lower alkyl group, characterized in that one from a compound of the general Formula II, ^R 3 ^R 2 N ^ NR ₁ (II) X
in which X denotes the hydroxyl group or the mercapto group, and R ,, Rj and Ro have the meaning given above, or a compound tautomeric therewith which eliminates group X in a manner known per se and replaces it with hydrogen, and if desired a compound thus obtained is converted into an acid addition salt with an inorganic or organic acid. 10 9 8 15/2153 2, compounds of general formula I, N NR ₁ (I) in which R-, a halogen or a lower alkoxy group in 2-, 3- or k -position substituted phenyl group, \ R _? and Ro is independently hydrogen or a lower alkyl group, as well as their acid addition salts with inorganic and organic SMurs. DAP / yes / 10/18/67 1098 15/2 153