DE2143614A1 - 2-SUBSTITUTED BENZIMIDAZOLES AND METHOD FOR MANUFACTURING THEREOF - Google Patents

Description

j i ATEKTAMWTCTE

DR. E. WIEGAND DIPL-ING. W. NIEMANN DR. M. KÜHLER DIPL-ING. C. GERNHARDT

MÖNCHEN HAMBURG

TELEPHONE: 55 5476 TELEGRAMS: CARPATENT

8000 MUNICH 15,

NUSSBAUMSTRASSE TO

Yo. August 1971

W. 4o 627/71 7 / RS

AH. Robins Company, Incorporated Richmond, Virginia (V.Sb.A.)

2-O-substituted Benzimidazoles and Processes to their manufacture

The invention relates to certain new heterocyclic, organic compounds that can be referred to as substituted benzimidazoles and relates to in particular 2- (1-substituted-2-pyrrolidinyl) benzimidazoles and 2- (1-substituted-4-piperidinyl) benzLmidazo-Io as well as preparations with these compounds, and processes for their production.

The invention particularly relates to the new benzimidazo! Compounds the general formula

(D

3098U / 1 UO

2U36H

in which R is lower-alkyl, phenyl, phenyl-lower-alkyl, Phenoxy-lower-alkyl, lower-alkoxyphenoxy-lower-alkyl, BenzoyL-lower-alkyl or 1,4-benzodioxan-2-ylmefchyl means and η is a positive integer from 1 to 2 and their pharmaceutically acceptable acid addition salts.

The compounds according to the invention with the above general formula (I) are generally characterized by important pharmacological activity, which is indicative of their use to counteract physiological abnormalities in the animal body. The connections are AnaLgetica and TranquLLLzer. The analytical and tranquilizer activity of the novel compounds according to the invention disclosed above was determined by standard laboratory procedures. When the compounds are tested by such procedures, the results indicate that the compounds aiii Anaige ti ca and TranquiLizer are effective. In particular, the pre-compounds of the formula L ₁ in which η is 1 are AnaLgetica, while compounds of the formula I in which η is 2 have been shown to have tranquilizer properties.

Me analytical activity was determined by the method of P. Nilson, Acta, Pharmacol. Toxicol. 18, Io (1961). ^T he TranquiLizereigenschaften have been shown by the method of DAVANZO, JP inter alia, Psychopharmaeologia j), 21o (1966).

It is accordingly an object of the invention to provide new useful 2- (1-substituted-3-pyrrolidinyl) benzimidazoles and 2- (1-substituted-4-piperidinyl) benzimidazoles as well as pharmaceutical preparations dam Lt and processes for their Manufacture to create. Other purposes of the invention are

309814 / 1H0

2U36U

can be seen from the description below.

When defining the symbols of the above formula I and wherever they appear in the description, the terms have the following meanings:

The term "lower alkyl" as used herein includes straight and branched chain residues up to 8 carbon atoms and is represented, for example, by groups such as methyl, ethyl, propyl, isopropyl, tert.-butyl, Amyl, isoamyl, hexyl, heptyl, octyl or the like. shown. "Lower-alkoxy" has the formula -O-lower-alkyl. In the term "phenyl-lower alkyl" are Groups such as benzyl, phenethyl, methylbenzyl, phenpropyl or the like. locked in.

Suitable acid addition salts are those of mineral acids, such as acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid, and organic acids such as citric acid, lactic acid, fumaric acid, maleic acid or Y ^"r einsäure are derived. The preferred acid addition salt is the hydrochloride.

The acid addition salts are prepared by either adding the free base in an aqueous solution, which contains the acid in question, dissolves and the salt is isolated by evaporating the solution, or by that reacting the free base and the chosen acid in an organic solvent, in this case the salt is usually deposited immediately or in the usual way by concentrating the lorning or the like. can be won. Conversely, the free base can be obtained by acidic in the usual way Additionalals with an appropriate base like

3098U / 1 UO

2H36U

Ammonia, ammonium hydroxide, sodium carbonate or the like. neutralized, the released base with a suitable solvent, for example ethyl acetate or benzene, extracted, the extract dried and evaporated to dryness or fractionally distilled or in any

other usual way 'worked up.

The process for the preparation of the new compound according to the invention can be represented as follows:

-CN

-> U

-COOH

(Hi)

COOH

NH ₂

(IV)

(I)

RX

(V)

N-H

In the formulas, R and η have the meanings given above, and X is halogen or -N (CH ^) ₂ ..

It can be worked as follows:

A l-E-3-cyanopyrrolidine of lOrmal (II), which like in U.S. Patent 3,518,9o8 is dissolved in concentrated mineral acid, e.g. hydrochloric acid, and the acidic solution is at a temperature in the range from about 20 ° G to about

3098U / 1U0

flow temperature for a period of about 2 to Stirred for hours. In general, a concentration of about 1 g of the cyanopyrrolidine to about 5 ml of the chosen is Mineral acid satisfactory. A solution of o-phenylenediamine in the same dilute mineral acid is added to the mixture and the resulting reaction mixture is kept at reflux temperature during stirred for a period of about 10 to 80 hours; a blanket of an inert gas, e.g. nitrogen, come into use. The reaction mixture is cooled, the acidic solution is using made basic by dilute aqueous alkali solution or concentrated ammonium hydroxide to form the new compound of Pormel I. The product is collected by suction filtration and extracted from a suitable solvent or recrystallized in the solvent system.

In a procedure for the preparation of the new compounds of the formula I in which η is 2, a heterocyclic carboxylic acid of the formula IV, for example isonipecotic acid, and a equivalent amount of o-phenylenediamine in a suitable one dilute mineral acid solution, e.g. in dilute hydrochloric acid, for a period of about 10 to Boiled under reflux for 80 hours. The cooled acidic acid mixture is diluted using a alkaline aqueous solution or concentrated ammonium hydroxide, causing precipitation of the crystalline Product according to formula V brings about. The crude crystalline product is collected by filtration and crystallized from a suitable solvent or solvent system to give the compound V to obtain.

30981A / 1 1 AO

" ⁶ " 2U36U

The compound of formula V prepared by the method described above represents a compound which is particularly useful for the preparation of new and useful compounds within the scope of formula I. Thus, the hydrogen atom of the secondary Amingfuppe of Piperidinkerns contains all -the reactive properties of the secondary amino group and easily goes into conventional displacement reactions with a variety of reactive compounds including, for example alkyl halides, phenyl-lower-Alkylhalog eniden, Ar oyloxy alkyl halides, Aroyialky! Amines, N -mono- and Ν, Ν-disubstituted carbainoyl halides or the like. a.

Generally speaking, a compound of the formula V which is prepared as described above is reacted with a compound containing a reactive halogen atom in a lower alkanol as a solvent, e.g. ethanol, an alkali salt, e.g. sodium carbonate, being included as an acid binder. the The reaction is preferably carried out at the reflux temperature of the solvent used, and after the reaction time water is added to the reaction mixture and the product is dissolved in an organic solvent, preferably benzene, extracted. After washing and drying the organic solution, the solvent is evaporated and the product present in the residue is purified by crystallization. If necessary that will .Product which is sometimes precipitated in the form of a crystalline solid when water is added to the cooled reaction mixture is added, collected by suction filtration and further purified by crystallization. if the reactive moiety is an aroylalkylamine, the reaction is preferably carried out in a solvent such as Dimethylformamide, and the displaced di-lower-alkylamine is from the reaction medium by a

3098U / 1 UO

2H3614

Flushed away stream of inert gas.

For specific explanation of the type of candidate reactions of intermediates therefor and the type of the new versions of the new compounds and reactions a number is below _r of specific examples given.

example 1

2- (3-pyrrolidinyl) benzimidazole dihydrochloride

A solution of 27.7 g (0.1 mol) 2- (l-benzyl-3-pyrrolidinyl) benzimidazole, 10 ml of 12N hydrochloric acid and 200 ml of ethanol were treated with about 4 g of Raney nickel. The mixture was shaken for a few hours, filtered and the piltrate with 7 g of a palladium material Treated with a content of $ 10 palladium on charcoal. The mixture was in three atmospheres Y / hydrogen shaken for 16 hours at 60 ° C until the pressure decrease indicated that one equivalent of hydrogen had been absorbed. The suspension was cooled, filtered and the solvent evaporated under reduced pressure. The residue was recrystallized from a mixture of methanol and isopropanol. The white connection melted with decomposition at 269 to 27o ° C and had a weight of 13 g (50 # yield).

Analysis: Calculated for ^C n ^H i5 ^N 5 ^C1 2 ^c 5o, 78 H 5.81 N 16.15 Found C, 5o, 75 H 5,94 N 16,45

3098 U / 1 UO

2U3614

Example 2

2- (4 ~ piperidinyl) benzimidazole

A solution of lo, 8 g ( 0.1 mol ) of o-phenylenediamine, 12.9 g (0.1 mol) of isonipecotic acid and 8o ml of 6ri-hydrochloric acid was refluxed for 16 hours, cooled and the solution using concentrated Ammonium hydroxide made basic. The crystalline product which separated out was collected by filtration and dried. The crude compound was dissolved in a hot benzene-isopropanol mixture, charcoal was added, the solution was filtered and the filtrate was treated with isooctane. The recrystallized white product weighed 9.2 g ($ 46 yield) and melted at 238 to 240 ° C. with decomposition.

Analysis: Calculated for Ci2 ^H 15 ^N 3 ^C ^ ^{1 '61} H 2o N 7.51, found C 88 71,4o H 7.44 N 2o 7o

Example 3

2- (1-ethyl-3-pyrrolidinyl) benzimidazole

. A solution of 24.8 g (0.2o mol) I-Athy1-3-cyanopyrrolidine in 162 g of concentrated hydrochloric acid was refluxed for 4 hours. Then a solution of 16.2 g (0.15 mol) of o-phenylenediamine in 250 ml of a 5% solution Hydrochloric acid was added to the reaction mixture. The mixture was refluxed for 16 hours, cooled and with made basic with concentrated ammonium hydroxide. That I Product separating from the aqueous basic solution was collected by filtration and extracted from a water-methanol mixture recrystallized. The compound weighed Io g ($ 34 yield) and melted at 104-186 ° C. After recrystallization from the same solvent system

3098 U / IHO

2U36U

the product melted at 186 to 187 ⁰ C.

Analyzes calcd for C ₁₅ H ₁₇ N ₅ C 72.52, H 7.96, N 19.52 found C 72.55 H 7.91 N 19.62

Pharmacology: The analgesic EDj -.- value in mice was from the pharmacological values intraperitoneally below Use of the standard Nilson test procedure with calculated at a value of 14.5 mg / kg.

• ■ B bis ρ ie 1 4. ■ ^v

2- (1-phenethyl-3-pyrrolidinyl) benzimidazole

A solution of 5o g (0.25 mol) of 3-cyano-l-phenethylpyrrolidine in 300 ml of concentrated hydrochloric acid was refluxed for 4 hours and then the acidic mixture was mixed with a solution of 27 g of Co, 25 mol) of o-phenylenediamine in 500 ml of lo ^ iger hydrochloric acid treated. The resulting mixture was refluxed for 14 hours, cooled and the acidic mixture made basic using concentrated ammonium hydroxide. The precipitating crystalline material was filtered and dried to j, the crude product weighed 3o g (41 $ yield) and melted at 152 to 154 ⁰ C. The pure compound melted at 154-155 ⁰ C after recrystallized from a mixture of benzene and isooctane had been.

Analysis: Calculated for C ₁₉ H ₂₁ N ₅ C 78.31 H 7.27 N 14.42 found C 78.33 H 7.42 N 14.27

309814/1140

⁴⁰ 2H36H

Pharmacology: The analgesic ED ₅ value in mice was calculated from the pharmacological words iritraperitoneal using the standard test procedure of Uilson with a value of 19.0 mg / kg.

Example 5 r

2- (l-benzyl-3-pyrrolidinyl) benz imidazole

A solution of 108 g (0.057 mol) 3-Cyano-l-benzylpyrrolidin.in 500 ml of concentrated hydrochloric acid was stirred at room temperature for 2 hours. A solution of 75.7 g (0.70 mol) o- Phenylenediamine in 500 ml of lo ^ iger hydrochloric acid. The mixture was refluxed for 84 hours under a nitrogen atmosphere. The dark blue acidic solution was cooled and made basic with 25% sodium hydroxide solution * The solid which separated out was collected and the crystalline material was washed with warm water. The dry product had a weight of 92 g ($ 58 yield) and melted at 21o to 212 ⁰ O. The white compound melted at 214 to 215 ° C after it had been recrystallized from methanol and water.

Analysis: calculated for CJ ₁₈ H ₁₉ N ₅ G 77.94 H 6.91 B ^- 15.15 found 'σ 78, o8 H 7, oil ΪΪ 15.38.

Pharmacology: The analgesic ED ^ value in mice was from the pharmacological values intraperitoneally using the standard Hilsen test procedure a value of 13.7 mg / kg calculated.

14/1140

2U3614

Example 6

2- _< / ~ l ~ (2-phenylethyl) -4 ~ piperidinyl7benzimidazole

A suspension of 6.0 g (o, o3 mol) 2- (4-piperidini ~ nyl) benzimidazole, 5.6 g (o, o3 mol) 2-phenethyl bromide, 15 g potassium carbonate and 100 ml of pure ethanol was used for 16 hours refluxed. The mixture was cooled, treated with 100 ml of water and the pesticide which separated out was collected by filtration. The crude product was dissolved in chloroform, the solution was washed several times with water and the solvent was evaporated. The crystalline residue was recrystallized from a mixture of benzene and isooctane. The white product which had a weight of 3.8 g (41 $ yield), began at 23o ° C to be brown and melted with decomposition at 243-245 ⁰ C.

Analysis: Calculated for C ₂₀ H ₂₅ N ₅ C 78.65 H 7.59 found - C 78.61 H 7.58.

Example 7

2 - ^ * "l- _l / 2- (o-Methoxyphenoxy) ethyl7-4-piperidinyl> benzimidazole

A mixture of lo, lg (0.05 mol) 2- (4-piperidinyl) benzimidazole, 11.6 g (0.05 mol) 2- (o-methoxyphenoxy) ethyl bromide, 20 g potassium carbonate and 100 ml ethanol was 60 Boiled under reflux for hours. Dj q suspension was cooled, then 2oo ml of water were added and the mixture extracted with benzene. The benzene mixture was concentrated and the residue was recrystallized several times from a mixture of benaol and isopropyl ether. The white compound weighed 6.2 & (46 $ yield) and melted with decomposition at a temperature of 2o2 to 2O4 ° C _o

3 0 9 8 U / 1 U 0

2U36U

Analysis: calculated for ^c ₂ i ^H 25 ^N 3 ° 2 ^{C 71} » ^{77 H 7} » ^{17 Ή}

found C 71.91 H 7.08 12.00

Example 8

2- / Ί.- (1,4-Benzodioxan-2-ylmethyl) -4-piperidinyl-7-benzimidazole

A mixture of lo, l g (o, o5 mol) 2- (4-piperidinyl) -benzimidazole, 9.2 g (0.05 mol) of 2-chloromethyl-1,4-benzodioxane, 20 g of potassium carbonate and 100 ml of 2-butanol became 72 Boiled under reflux for hours. After the suspension was cooled and filtered, the filtrate became at concentrated under reduced pressure. A hot solution of the residue of methanol and water was treated with charcoal and filtered. The product separating from the cooled filtrate melted at a temperature between 196 and 200 ° C and weighed 7.2 g (41 $ yield). The pure connection melted at a temperature between 2o4 and 2o6 ° C after it had recrystallized from a benzene-isooctane mixture had been.

Analysis: Calculated for 0 ₂ 1 ^Η 23 ^Ν 3 ° 2 ^C 72.18 H 6.63 N 12, o3 found C 72.2o H 6.58 Ii 12.11.

Example 9

2- _< / ~ 1- (2-phenoxyethyl) -4-piporidinyl7benzimidazole

A mixture of lo.1g (0.05 mol) 2- (4-piperidinyl) benzimidazole, lo.1g (0.05 mol) 2-phenoxyethyl bromide, 20 g potassium carbonate and 100 ml ethanol was refluxed for 16 hours. The cooled mixture was treated with 100 ml of water. The white solid which separated out was first made up of methanol and water and then made up; Benzene and Jnooetaii uinkristalliso.ert. The product, which had a weight of 9.2 g ($ 57 yield), was used in oil »

3 0 98V (/ 1U0

2U3614

wa 210 ° C soft and melted with decomposition at a temperature of 214 to 26 ° C.

Analysis: Calculated for C ₂₀ II ₂₅ N ₃ O 0 74.74 H 7.21 N 13.07

C 74.81 H 7.35 N 13.16

Example Io ^r

2- ^ "" 1- (2-Benzoylethyl) -4-piperidinyl7benzimidazole

A stirred mixture of 8 g (o, o39 mol) of 2- (4-piperidinyl) benzimidazole, 8.6 g (o, o39 mol) of 2-Benzoyläthyldimethylaminhydrοchlorid and 6 g Kaliumcarbonat.in loo ml of dimethylformamide was to 5o to 60 ⁰ C. heated while bubbling a stream of nitrogen through the mixture. After 18 hours the mixture was treated with 600 ml of water. The product which separated out was extracted to benzene. The benzene solution was dried over magnesium sulfate and evaporated to a pesticide under reduced pressure. The solid was ground with ether and filtered to give 6.5 g (50 $). The . Recrystallization of the solid from ethyl acetate gave 4 g of the pure product which melted at a temperature of 182-184 ⁰ C.

Analysis. Calculated for C ₂₁ H ₂₅ N ₃ OC 75.64 H 6.95 N 12.60 found C 75.64 H 6.88 N 12.69

Pharmacology: The compound was effective at blocking of the aggressive behavior of the animals tested below $ 80 Using the standard testing procedure of Da Vanzo and others.

The invention also relates to pharmaceutical preparations, those as active. Boa shared at least one Compounds according to the invention in connection with a

14/11 U 0

2H36U

pharmaceutical carriers or excipients. The connections are then presented in a suitable form for oral or parenteral administration. So are for example the preparations for oral administration solid or liquid and they can take the form of capsules, tablets, coated tablets, suspensions or the like. have, these carriers or excipients, which are expedient in the pharmaceutical technology are used. Suitable tableting excipients include lactose, potato and corn starch, talc, gelatin and stearic and salicylic acid, magnesium stearate and polyvinylpyrrolidone a*

For parenteral administration, the carrier or excipient can be a sterile, parenterally acceptable liquid, e.g., water, or a parenterally acceptable oil, e.g., ampouled arachis oil.

Although very small amounts of active materials according to the present invention are effective when a Therapy to a lesser extent is associated with it or in cases when administration to living beings receiving a If you have relatively low body weight, the dosage units are usually 5 mg or more and preferably 25, 50 or 100 mg or even higher, depending of course on the urgency of the case and the desired special result. 5 to 50 mg appears to be the optimum per unit dose, although common larger ranges of 1 to 500 mg per dosage unit appear to be the optimum. The active means according to the invention can with other pharmacologically active agents. or mib buffers, antiacidics or the like. can be used together for administration, and the proportions of the active Mit to Lu in the preparation can be used in wide limits have been changed. However, Eo is required

"ί Π ^f ) HIW 1 UO ·

. ^ v BAD OR) GiNAL

2U36U

borrowed that the active ingredient in an effective amount that is, a suitable effective dosage will be obtained in accordance with the dosage form used will.

Examples of preparations are given below: ^r

Example of formulations (1) capsules

Capsules of 5 mg, 25 mg and 50 mg of an active ingredient per capsule are produced.

Typical mix for the

Wrapping as salt Per capsule, mg; Active ingredient, 5.0 Lactose 295.7 strength 129, o Magnesium stearate Total: 4.3 434. ο

The selected active ingredient became uniform mixed with lactose, starch and magnesium stearate and encapsulated the mixture.

(2) tablets

A typical formulation for a tablet with a content of ^r j, r mg of active ingredient per tablet is given below. The formulation can be adapted for other strengths of active ingredient by adjusting the weight of dicalcium phosphate.

3 U 9 S i U / 1 η i:

BAD ORlGJNAt

(1) Active ingredient, as salt

(2) corn starch

(3) corn starch (paste)

(4) lactose

(5) dicalcium phosphate

(6) calcium stearate

- 21 43614 total Per tablet, mg salt 5, o 13.6 3.4 79.2 68, o r o, 9 : 170.1

• The ingredients (1), (2), (4) and (5) are mixed uniformly. The component (3) is ala loosely made paste in water. The mixture is granulated with starch paste and the wet mass through a screen with a clear mesh size of 2.4 mm (eight mesh screen) pressed. The wet granules will

dried and passed through a sieve with a clear. Mesh size of 1.7 mm (twelve mesh screen) classified. The dried granules are made with calcium stearate mixed and pressed.

(3) Injectable 2 $ sterile solution ~~~ Each ecm

Active ingredient 2o mg

Preservatives,

e.g. chlorobutanol 0.5 wt.

Water for injection q.s.

(in the required amount)

The solution was made, clarified by filtration, filled into vials, sealed off and autoclaved treated.

3098U / 1U0

Claims (1)

2U36U Claims 1.) 2-Substituted benzimidazoles of the general formula (D in which R is lower-alkyl, phenyl, phenyl-lower-alkyl, Phenoxy-lower-alkyl, lower-alkoxyphenoxy-lower-alkyl, Benzoyl-lower-alkyl or 1,4-benzodioxan-2-ylmethyl means And η is a positive integer from 1 to 2 and its pharmaceutically acceptable acid addition salts. 2. 2- (1-lower alkyl-3-pyrrolidinyl) benzimidazole. 3. 2- (1-Phenyl-lower-alkyl-3-pyrrolidinyl) benzimidazole. 4. 2- (1- ethyl-3-pyrrolidinyl) benzimidazole. 5. 2- (1-Benzyl-3-pyrrolidinyl) benzimidazole. 6. 2- (1-Phenethyl-3-pyrrolidinyl) benzimidazole. ·. 7. 2- ^ I- (2-Benzoylethyl) -3-piperidinyl7benzimidazole, 8. 2- / I- (1,4-Benzodioxan-2-y! Methyl) -3-piperidinyl-7-benzimidazole. 30981 4 / 1U0 2U36U 9. Process for the preparation of 2-substituted benzimidazoles of the general formula (D in which R is lower-alkyl, phenyl, phenyl-lower-alkyl, phenoxy-lower-alkyl, lower-alkoxyphenoxy-lower-alkyl, Benzoyl-lower-alkyl or 1,4-benzodioxan-2-ylmethyl means and η is a positive integer from 1 to, characterized in that one (1) a heterocyclic compound of the general formula: / R-N in which R and η have the meaning given above, hydrolyzed, and (2) The heterocyclic carboxylic acid prepared in step (1) with o-phenylenediamine to form a compound the general formula condensed, in which R and η have the meaning given above. Io. Process for the preparation of a compound of the general formula 3 O 9 8 U / 1 U O 2H36H in which R is lower-alkyl, phenyl, phenyl-lower-alkyl, Phenoxy-lower-alkyl, lower-alkoxyphenoxy-lower-alkyl, Benzoyl-lower-alkyl or 1,4-benzodioxan-2-ylmethyl means and η is a positive integer from 1 to, characterized in that one (1) o-Phenylenediamine with a heterocyclic carboxylic acid the formula H-N V-COOIi to a compound of the formula (CIk) ₁ / in which η has the meaning given above, condenses, and (2) the compound established in step (l) with a compound of the general formula RX, in which X is halogen and R and η have the meanings given above, alkylated. 11. Pharmaceutical preparation with analgesic effect that (a) an effective amount of about 1 to 500 mg of a 2- (1-substituted-3-pyrrolidinyl) benzimidazole the general formula 3098U / 1U0 2H36H in which R is lower-alkyl, phenyl or phenyl-lower-alkyl is and (b) comprises a pharmaceutically acceptable carrier therefor, 12. Pharmaceutical preparation with tranquilizer effect, the (a) an effective amount of about 1 to 500 mg of one
2- (1-substituted-3-pyrrolidinyl) benzimidazole
the general formula NO in which R is phenyl-lower-alkyl, lower-alkoxyphenpxy-lower-alkyl, phenoxy-lower-alkyl, benaoyl-lower-alkyl or 1,4-benzodioxan-2-ylmethyl,
and (b) comprises a pharmaceutically acceptable carrier therefor, 3098U / 1 UO