DE1620702A1 - Benzimidazolone derivatives - Google Patents

Description

The invention relates to new benzimidazolones (2-oxo-benzimid.azoline) of the formula %, which are substituted on a nitrogen base.

(D

and acid addition salts thereof. In formula I, R denotes a straight or branched alkylene radical having 2 to 4 carbon atoms; R, means a hydrogen atom or together with R _? an · alkylene radical with 2 to 4 carbon atoms; R «also denotes an alkyl radical with 1 to 3 carbon atoms, or together with R, an alkylene radical with 4 to 6 O atoms; R also denotes a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms; R. is in the 5- or 6-position and denotes a hydrogen atom, a halogen atom

Case 197 C

0 0 9811/1662

or an alkyl radical containing 1 to 3 carbon atoms; and R- denotes a hydrogen atom, a halogen atom or an alkyl radical having 1 to 3 carbon atoms.

The invention also relates to processes for the preparation of the benzimidazolone derivatives according to formula I.

The compounds mentioned are pharioalcologically active substances, the properties of which indicate their usefulness as antidepressants and anticonvulsants in particular. While these two directions of action occur to a similar extent with some representatives of the substance group, one or the other of the two directions of action is in the foreground with others. In the case of the products substituted in the 5-position and in particular in the δ-position, the antidepressant effect is particularly pronounced, with the compounds substituted in the 1-phenyl radical - preferably in the p-position - the anticonvulsant effect is particularly pronounced. As Substitusnten R. and R- are halogen atom © _f especially chloro, is preferred. The basic side chain in the 3-position is preferably a γ-dimethylaminopropyl, γ-diethylaminopropyl or γ-pyrrolidin-1 ^ yl-propyl roast. Examples of compounds which are particularly effective in the anticonvulsant direction are 1-p-chlorophenyl- ^ - Y-diethylaminopropyl-benzimidazolone and 1-p-chlorophonyl-3-Y-PyTrOUdIn-I * -yl-propyl-benziizaazolone and their acid addition salts, for in Compounds particularly effective in antidepressant direction are l-Phsnyl ^ -Y-dimethylaminopropyl-ö-chloro-benziiaiaazolon and its acid-aid salts.

Compounds of the formula I are obtained - if m on in benzimidazolones of the formula:

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Jiorln R. and R- have the abovementioned meaning "a basic radical of the formula -R (R ₁ J-NRpR-, in which R, R., R" and R _{5 have} the meaning given. The introduction of the basic radical er it follows that the compound of the formula II, expediently in an inert solvent such as benzene, dioxane, dimethylformamide, dimethyl sulfoxide or mixtures thereof, is mixed with an alcohol of the formula:

HO-R- N ^ * (III),

wherein R, R ₁ , R 2 and R- have the meaning given earlier, treated, preferably at elevated temperature and, if necessary, after prior or with the simultaneous action of a condensing agent. Such inorganic and organic acids come into consideration as esters, for example hydrohalic acid, sulfuric acid, sulfonic acid or carbonic acid esters. When using carbonic acid esters, the condensation agent can generally be dispensed with, while when using the other esters specified _t usually one has to be used. * Alkali metals, their hydrides and amides and other alkali metal compounds, e.g. Sodium amide, sodium hydride, phenyl sodium, alkyl lithium or potassium t-butoxide. In the

Benzimidazolones of formula II used in this reaction are e.g. by reacting appropriately substituted phenylenediamines according to the formula:

where R. and R- have the meaning given earlier, with a

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BATH ORIGINAL

reactive carbonic acid derivative, such as phosgene, accessible.

Insofar as R- denotes hydrogen in formula I, the desired ones are obtained Benzimidazolones also by making esters of alcohols the formula:

in which R, R. and R- have the meanings given earlier, for example hydrohalic acid, sulfuric acid or sulfonic acid esters, with an amine of the formula HNRgR ,, in which R ₂ and R are as defined above. Esters of alcohols of the formula V are in turn obtained, for example, by reacting compounds of the formula II with a preferably mixed diester of an alkylene glycol containing 2 to 4 carbon atoms, for example with a chlorobromoalkane, if necessary after prior or simultaneous action of a condensing agent. On the other hand, compounds of the formula II can also be used initially with an alkylene oxide or alkylene halohydrin containing 2 to 4 carbon atoms or with an alkylene halohydrin tetrahydropyranyl ether of the formula:

-O

H
Halogen - R - 0 - <> (.VI)

treat and then - in the latter case after splitting off the protective group - Form the desired ester e.g. by reaction with a thionyl halide or a hydrohalic acid.

Products according to formula I, in which R _{1 is} hydrogen, are also formed by introducing radicals R ₂ and R_ into primary amines of the formula:

0 0 9 8 1 1/1 6 6 # 50 L

(VII),

in which R, R. and R _{5 have} the meaning given earlier, for example by reacting the latter with esters, in particular hydrohalic acid esters, of alcohols of the formulas HO-Rp or HO-R ₂ -R, -0H, or by reacting the primary amines by the reductive alkylation method either using hydrogen in the presence of a catalyst or using a reducing agent such as formic acid with corresponding aldehydes. The starting materials of the formula VII are in turn obtained, for example, by reacting esters of the alcohols of the formula V with ammonia or by reducing the corresponding nitriles.

Compounds of the formula I are also obtained if o-phenylenediamine derivatives of the formula %

(VIII),

in which R / R-, R ₂ , R ", R. and R ~ have the meaning given earlier, preferably in the presence of an inert solvent, with a reactive derivative of carbonic acid, for example phosgene, diethyl carbonate, urine stuff and the like, optionally after prior or simultaneous action of a condensing agent. They are used as solvents and condensation agents

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BAD 'GFHGINAL

substances previously mentioned for these purposes are considered. The starting materials of formula VIII is obtained, for example, by condensation of the ester of an alcohol according to formula III with a phenylenediamine derivative according to formula IV, if necessary after prior or simultaneous action of a condensing agent of the type mentioned above, optionally with intermediate acylation of at least the primary amino group.

Finally, compounds according to formula I are obtained in which R- and / or R, - denote a halogen atom by adding one in the relevant Position other substituents are exchanged for the desired halogen atom, for example by diazotization and subsequent Sandmeyer reaction of the corresponding amino compounds, which in turn are accessible by reducing the corresponding nitro compounds.

The basic substituted obtained by one of the processes described Benzimidazlones according to formula I can be used both as free bases and in the form of their addition salts with suitable Acids such as hydrohalic acids, sulfuric acid, nitric acid, Phosphoric acid, acetic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid or toluenesulfonic acid, obtained and used.

example 1

7.5 g of 1-phenyl-benzimidazolone (l-phenyl-2-oxo-benzimidazoline) in 50 ml of absolute dioxane are mixed with 1.68 g of powdered sodium amide Boiled under reflux for 1 hour. After adding 5.4 g of ß-dimethylaminoethyl chloride in 30 ml of benzene, a further 16 hours heated to boiling. After the reaction mixture has been concentrated to dryness in vacuo, the residue is between benzene and water distributed. The basic components are removed from the lipoid phase by exhaustive extraction with dilute acetic acid. From the combined extracts precipitated with concentrated ammonia solution

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Base is taken up in benzene. The benzene solution is washed several times with water and dried over sodium sulfate and concentrated to dryness. After clarification in a benzene solution on clay, benzene / petroleum ether and acetone / petroleum ether are obtained 8.8 g (88 # of theory) of l-phenyl-3-ß-dimethylaminoethyl-benzimi-

dazolon with a melting point of 116-117 ⁰ C.

Example 2 - '

6.1 g of l-phenyl-6-chlorobenzimidazolone are refluxed with potassium t-butoxide (from 1.0 g of potassium) in 40 ml of t-butanol for 10 minutes. After Sinengen of the reaction mixture to dryness in vacuo, the potassium compound is charged with 40 ml dimethylformamide and heated with 4.8 g of freshly distilled l-methyl-3-chloromethyl-piperidine 18 hours 5Q ⁰ C.

When working up as in Example 1, 3.4 g of a crystalline neutral substance are obtained, which for the most part consists of 1-phenyl-6-chlorobenzimidazolone (starting material). As the base, one obtains 2.7 g of l-Phenyx - ^ - il'-methyl-piperidyl ^ ¹⁾ methyl-6-chloro-benzimidazolone in the form of colorless needles melting at 112-114 ⁰ C (from ether / petroleum ether) to give , taking into account 2 $ a g of recovered pure starting material, a yield of 58? £ corresponds to theory.

Example 3

7.3 β l-phenyl-6-chlorobenzimidazolone in 40 ml of absolute dioxane are treated with potassium t-butoxide (from 1.2 g of potassium) in 30 ml of t-butanol Boiled under reflux for 1 hour and after adding 5.7 g of trimethylene chlorobromide refluxed for a further 7 hours.

After concentrating the reaction mixture in vacuo, the residue is partitioned between ether and water, while something is filtered off Substance that is insoluble in both phases. The ether solution washed with water gives a vacuum on evaporation 6.4 g residue of a brown resin. This is with 5.0 g

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Dimethylamine boiled in 20 ml of dioxane for 18 hours in the containment tube. Customary work-up gives 4.9 g of 1-phenyl-3-Y-dimethylaminopropyl-benzimidazolone with a boiling point of 163 ° C./0.03 torr. Its hydrochloride forms from acetone / methanol / ether, crystals of melting point 188-191 ⁰ C.

Example 4

6.3 l-Phenyl-3 - ^ - aminopropyl ~ 6-chloro-benzimidazolone be with 10 ml 90% formic acid and 5 ml 35% formaldehyde Heated to 100 0 for 15 hours. The reaction mixture is after

Addition of 2 ml of 38% hydrochloric acid concentrated to dryness in vacuo and the residue is dried. Is l-phenyl-3-Y-dimethylaminopropyl-6-chloro-benzimidazolone hydrochloride by recrystallization of the residue from methanol / acetone / ether using activated charcoal 6.1 g of melting point 180-182 ⁰ C.

Example 5

12.3 g of N - phenyl-N ₂ - (ß-dimethylamino) ethyl-o-phenylene diamine are heated with 4.0 g of urea for 15 hours under nitrogen üeberleiten to 200 ⁰ C. 8.4 g of 1-phenyl-3-ß-dimethylaminoethyl-benzimidazolone identical to the product of Example 1 are obtained from the basic fractions separated off as in Example 1.

Example 6

8.7 g of lp-aminophenyl-3-Y ^ -pyrrölidin-l'-yl-propyl-benzimidazolone are dissolved in 100 ml of 1N hydrochloric acid and at ⁰ ° C. with a solution of 1.9 g of sodium nitrite in 10 ml of water diazotized. The diazonium solution becomes, within 10 minutes, a ^{copper chloride solution which is stirred at 8O 0} O and which is made up in the customary manner from 5.3 g of copper sulfate and 5.3 g of sodium chloride in 25 ml of water while passing in

00 98 11/1662

.von 'Sehweef eldioxydgas was produced, and the temperature is maintained until 30 minutes after the evolution of gas has subsided and works it up in the usual way. The residue is taken up in petroleum ether solution and clarified on aluminum oxide, whereupon it is obtained from cold petroleum ether in crystalline form _a . One gets so 5 »6 g lp-chlorophenyl-3-Υ-pyrrolidin-l'-yl-propyl-benzimidaaolon a melting point of 54-56 ⁰ C.

By proceeding in the same way as in the preceding examples, the products listed in the table below are still obtained, for example. In the table, R, R-, Rp, R ,, R. and R _{5 are} the corresponding groups according to formula I with the meaning given earlier. In the column on the right, the solvents or solvent mixtures from which the crystallization took place are indicated in brackets; here mean Ac = acetone Ae = ether, Me = methanol, Pe = petroleum ether, and Pn = pentane.

0 9 8 11/1662

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009811/1662

O O CD OO

17th - < ^CH 2> 5-O 6-Cl
1 H Ba3e: Snip. 97-99 ° C (Ac / Pq) 18th - (UIIp) ₃ -NlI-CH ₃ 6-Cl H Base: m.p. 80-90 ⁰ C (Ae / Pe) .19 TT «-Π1 Base: 5mp, 52-54 ⁰ C (Pn)
* 20th - {CIi ₂ ) ₃ -II (CH ₅ ) ₂ 6-cr P-Cl Earse: Gn «p, 102-103 ° C (Ae / Pe) ?1 - ^(0H 2> 3-O H *
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² Mi-CII ₃ H P-Cl 'Hydrochloride: ^{m.p. from 217 0} C (decomp.)
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009811/1662

Claims (1)

Claims in which R straight or branched alkylene with 2 to 4 carbon atoms, R, hydrogen or together with Rg alkylene with 2 to 4 carbon atoms, Rg also alkyl with 1 to 3 carbon atoms, or together with E * alkylene with 4 to 6 carbon atoms, VL also hydrogen or alkyl with 1 to 3 carbon atoms9 R. hydrogen or Ea3.og © n cdsr alkyl with 1 to 3 carbon atoms in the 5- or 6-position, and Rc hydrogen halogen or alkyl having 1 to 3 carbon atoms, and acid addition salts thereof. 2, a process for the preparation of bensimidazolone derivatives geo according to claim 1, characterized in that in benzimidazolones of the formula: in which R, and R- have the meaning given in claim 1, .4p - 009811/1662 - ". it x _ · - * SAO cpifi i ^ Jeue Unteriason; ArL7k'iAbs.2i-jr.is.tz3dMl «i« iira ^ «ti4ftlsti7i a basic radical of the formula -R (S ^) - NR2IU, where R, R2 and R, which are mentioned in claim 1, introduces »whereupon the reaction product is isolated as a free base or in the form of an addition salt with an inorganic or organic acid means, characterized in that esters of alcohols of the formula: and R., which> in in which R, R. and R- have the meaning given in claim 1, with an amine dor formula HNRgR ,,, in which claim 1 mentioned meaning have, uasatzt, whereupon the reaction product is isolated as a free base or in the form of an addition salt with an inorganic or organic acid. 4. A process for the preparation of Benzicaidazolonäerivaten according to claim 1, in which R- denotes hydrogen, characterized in that in primary amines of the formula: (VII), 009 811/1662 wherein R9 K ^ and R5 di «in Pat * nt * nepruoh 1 ani «gtbtnt Itdtutunf, radicals R- and R- introduces the meaning mentioned in claim 1, whereupon the reaction product is isolated as a free base or in the form of an addition salt with an inorganic or organic acid Claim 1, characterized in that substituted o-phenylenediamine derivatives of the formulaί (VIII), in which R, R », Rp, R5, R- and R5 have the meaning given in claim 1, are reacted with a reactive carbonic acid derivative, whereupon the reaction product is reacted isolated as a free base or in the form of an addition salt with an inorganic or organic acid, 6. Process for the preparation of benzimidazolone derivatives according to Pate Claim 1, in which R. and / or R1 denote halogen, characterized in that other substituents in the relevant position are exchanged for halogen in the case of corresponding compounds, whereupon the reaction product is used as a free base or in the form of an addition salt with an inorganic or organic acid isolated. RAV-XRu / XlH Der / tatentanwalt 1.9.1969 CIL -; ■ ^ 009811/1662 WHEEL ORIGINAL