DE2714437A1 - PIPERAZINE AND PIPERIDE DERIVATIVES, PROCEDURES FOR THEIR MANUFACTURING AND MEDICINAL PREPARATIONS - Google Patents

Description

"Piperazine and piperidine derivatives, processes for their production and medicinal products ¹¹

The subject matter of the invention is defined in the claims.

It is a series of 1 ~ / rHeterocyclyl) -alkyl_7-piperazines and 4- (diarylmethyl) piperazines substituted in the 1-position and 4- (diarylmethoxy) piperidines with valuable pharmacological properties Properties known. Such compounds are described in the following references:

U.S. Patent 3,362,956; U.S. Patent 3,472,854; U.S. Patent 3,369,022, U.S. Patent 2,882,271, U.S. Patent 3,956,328 and

CA., 64: 3499c 709842/0793 (1966)

to 27U437

The compounds of the invention differ from the above compounds primarily in the nature of the B-C Hp group, those in the 1-position of the piperazine or piperidine residue is present, and / or by the nature of the 4-position of the piperazine or piperidine residue present diarylmethyl or diaryl methoxy radicals.

The term "lower alkyl" means straight-chain or to understand branched hydrocarbon radicals with 1 to 6 carbon atoms, for example the methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl or Hexyl group.

The term "lower alkenyl" means straight-chain or branched alkenyl groups having 2 to 6 carbon atoms, for example the ethenyl, 1-methylethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-pentenyl or 2-hexenyl group.

The term "cycloalkyl" means cyclic hydrocarbon radicals with 3 to 6 carbon atoms, for example the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

The term "C _n Ho _n " means straight or branched alkylene radicals of 2 to 6 carbon atoms having at least 2 carbon atoms in the linear chain connecting the B group to the piperidine or piperazine nitrogen atom, 709842/0793

27U437

for example the 1,2-ethanediyl, 1,3-propanediyl, 2-methyl-1,3-propanediyl, 1,4-butanediyl, 2-methyl-1,4-butanediyl, 1,5-pentanediyl or 1,6-hexanediyl group.

The term "halogen atoms" generally means halogen atoms having an atomic weight of less than 127, i.e. fluorine, chlorine, Bromine or iodine atoms.

The compounds of general formula I, with the exception of the Compounds in which B is the 2-amino-1H-benzimidazol-1-yl group can be conveniently prepared by adding a corresponding reactive ester of the general formula II, in which η has the above meaning and B also has the has the above meaning, but with the exception that there is no 2-amino-1H-benzimidazol-1-yl radical of the general formula

1 2
in which R and R are as defined above, and in which W is a corresponding reactive ester function derived from a corresponding alcohol, for example a halogen atom, or the methanesulfonyl or 4-methylbenzenesulfonyl group, with a corresponding piperidine or piperazine derivative of the general Formula III in which A, m, Ar

709842/07 93

ä "27U437

ρ
and Ar have the preceding meaning according to the following

Implements reaction equation:

Ar (II) (HD

The above condensation reaction is preferably carried out in a corresponding organic which is inert during the reaction Solvent carried out. Examples of corresponding solvents are lower alkenols such as methanol, ethanol, propanol and butanol, aromatic hydrocarbons such as benzene and methylbenzene and dimethylbenzene, ethers such as 1,4-dioxane and 1,1'-oxybispropane, Ketones such as 4-methyl-2-pentanone, N, N-dimethylformamide and nitrobenzene. The addition of an appropriate base, for example an alkali metal or alkaline earth metal carbonate or hydrogen carbonate, can serve to absorb the acid released during the reaction. A small amount a corresponding metal iodide, for example sodium or Potassium iodide can be added as a reaction accelerator. Slightly higher temperatures are suitable for acceleration the reaction rate. The reaction is preferably carried out at the reflux temperature of the reaction mixture .

709842/0793

SO 27U437

In the above reaction modes and those described below the reaction products can be separated off from the reaction mixture by processes customary per se and, if appropriate further cleaned.

The compounds of the general formula I in which B is a 2-amino-1H-benzimidazol-1-yl radical, i.e. the compounds of the general formula I-a, can easily be derived from the corresponding compounds of the general formula I, in B is a 2- (lower-alkyloxycarbonylamino) -1H-benzimidazol-1-yl radical means, i.e. to produce from compounds of the general formula I-bj by adding the last-mentioned compounds decarboxylated under hydrolytic conditions, for example by acid hydrolysis using an appropriate strong acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or by alkaline hydrolysis, using an appropriate strong base, such as sodium or Potassium hydroxide.

-COO (lower-alkyl) ^ 1 _

/ - \ y W or OH

AiO ^ CH>

(MO.

Ar ¹

09842/0793

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It is noted that if the group B in the compounds of general formula I or the corresponding intermediates a 2- (lower alkyloxycarbonylamino) -1H-benzimi- dazol-1-yl radical or a 2- (lower-alkylcarbonylamino) - 1H-benzimidazol-1-yl radical means that these radicals can exist in the different tautomeric forms explained below:

NH-COO (. Lower- alkyl)

NH-CO- (hi eder-alkyl)

N-COO (lower alkyl)

N-CO- (hi eder-alkyl)

These tautomeric forms of the compounds of the general formula I also belong to the subject of the invention.

Compounds of the general formula I-c

Ar

(O) -CH. ^m ^

R ² 70 984 2/0793 (Ic)

- 9-

Ä 271U37

12 1 2
in which R, R, n, A, Ar and Ar have the above meanings, can also be obtained by ring closure of a corresponding intermediate of the general formula IV with a corresponding cyclizing agent, as is used for the preparation of 1, J-dihydro ^ H-benzimidazole S-ons from 1,2-benzene diamines is known per se to produce.

Corresponding cyclizing agents which can advantageously be used are, for example, urea and phosgene and alkali metal isocyanates. The cyclization reaction can be carried out by methods which are customary per se. For example If urea is used as the cyclizing agent, compounds of the general formula I-c can easily be obtained obtained by heating the reactants in the absence of a solvent with stirring.

The above reaction is explained by the following reaction equation:

Ar

(IV)

Cyclizing agent ^ (

70984270793

^ 27U437

The compounds of general formula I-c can also from compounds of the general formula V.

12 12

in which R, R, n, A, m, Ar and Ar have the above meaning and P denotes a corresponding protective group, by removing this protective group by methods customary per se. Examples of such protective groups are lower alkyloxycarbonyl radicals and substituted ethenyl radicals of the general formula

R ⁴ -CH = C-

XL ·. ' T ₁

where R ^ and R can mean different groups and R ^

L ·.

preferably a lower alkyl radical and R preferably a hydrogen atom, a lower alkyl or phenyl radical means.

If the protective group is a lower alkyloxycarbonyl radical, this can easily be removed by alkaline hydrolysis. If a substituted ethenyl radical is present as the protective group, then this can be conveniently removed by adding the corresponding intermediate of the general formula V of

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subject to acid hydrolysis. When performing acid hydrolysis to remove the ethenyl group from the compound of general formula V, a number of protic acids can be used, including mineral acids such as hydrogen chloride acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as acetic acid, propanoic acid and ethanedioic acid. Furthermore, the implementation in an organic solvent which is inert during the reaction, as used in such hydrolytic reactions, be performed. Examples are lower alkanols such as methanol, ethanol and 2-propanol.

Following a similar procedure to that used to make the joints of the general formula I-c from a compound of the general formula IV can be the compounds of the general Prepare formula I-d

Ar ¹

n-c H- -n \ - (o) -dH

^{n 2n} \ y ^m

12 1 2

in which R, R, n, A, m, Ar and Ar have the above meaning

have and M is a hydrogen atom, a lower alkyl, phenyl, , Phenylmethyl, mercapto, amino, lower alkyloxycarbonylamino or Cycloalkyljest means by adding a compound

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of the general formula IV with an appropriate cyclizing agent according to conventional processes for the preparation of 1H-benzimidazoles from 1,2-benzenediamines.

1
Depending on the nature of M in the compounds of the general formula Id, for example the following cyclizing agents can be used.

If M is a hydrogen atom, formic acid or a corresponding tri- (alkyloxy) methane as a cyclizing agent be used.

If M is a lower alkyl, phenyl, phenylmethyl or cycloalkyl radical, one can use a carboxylic acid of the general Formula VI

R ⁵ -COOH (VI)

in the B? denotes a lower alkyl, phenyl, phenylmethyl or cycloalkyl radical, or a functional derivative of this acid, for example an acyl halide, an ester, an amide or a nitrile of this acid, or an imino ester of the general formula VII

0- (lower alkyl) HN = C

(VII) 709842/0793

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in which R ^ has the preceding meaning, or an aldehyde of the general formula VIII

Ir-C (VIII)

or an addition product thereof with an alkali metal hydrogen sulfite use. If an aldehyde is used as the cyclizing agent, the reaction mixture can be mixed with a corresponding one Oxidizing agents are added, for example with nitrobenzene, mercury oxide, Cu (II) - and Pb (II) salts or other common oxidizing agents. The aldehyde itself can also act as an oxidizing agent in excess to serve.

If M is a mercapto radical, then, for example Carbon disulfide, thiourea, thiophosgene or ammonium thiocyanate can be used as cyclizing agents.

If M is an amino group, the ring closure in Presence of cyanamide or a metal salt thereof, preferably an alkali or alkaline earth metal salt, or with BrCN be performed.

If M is a lower alkyloxycarbonylamino radical, suitable cyclizing agents can be used, for example

709842/0793

Use compounds of the following general formulas: Lower alkyl (iminomethoxymethyl) carbamates of the general Formula IX

NH 0

Il N

H ₅ COC-NH-CO (lower alkyl)

(IX)

lower alkyl- / C-lower-alkoxycarbonylamino) - (K -thio) -methylene7-carbamate of the general formula X

P ⁶

OgO

Il? Il

(lower-alkyl) -0-C-N-C = N-C-O- (lower-alkyl)

(X)

where R represents a hydrogen atom or a methyl group; Compounds of the general formula XI

) -0-C-l

(lower-alkyl) -O-C-NCS (XI)

lower alkyl-lower-alkylcarbamothioates of the general Formula XII

(lower-alkyl) -NH-C-O- (lower-alkyl) (XII)

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and di-lower-alkylcyanimidodicarbonates of the general formula

0 / T lower-alkyl) -0-C7 ₂ N-CN

(XIII)

The above cyclization reactions can be carried out by processes which are customary per se.

Compounds of the general formula I-e

NH-CO- (pi eder-alkyl)

(I-e)

can also be obtained by acylation of a corresponding 2-amino-IH-benzimidazol-1-yl derivative of the general formula I-a by customary processes for N-acylation, for example by reacting a compound of the general formula I-a with a corresponding lower alkyl carbonyl halide or acid anhydride derived from a lower alkyl carboxylic acid.

Compounds of the general formula I-f

709842/0793

.Ar

«ΑηΛ / - ⁽⁰⁾ « - ^C «

(I-f)

12 12

in which R, R, η, A, m, Ar and Ar have the above meaning

and L is a lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl-lower-alkyl, carboxy-lower-alkyl, phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl or lower alkenyl radical, the double bond in the lower alkenyl radical not being in α-position can be established by c
bond of the general formula Ic

can be produced by inserting the remainder L into a

-N V- (O) -CH (I-c)

introduces.

Depending on the nature of the L group to be introduced, the following procedures can be used for this.

709942/0793

-27HA37-

If L is a lower alkyl, lower alkyloxycarbonyl-lower alkyl, Phenylmethyl or lower alkenyl, i.e.

a remainder denoted by L, means that the unit can

1
Leading L into the compound of the general formula Ic by reacting the last-mentioned compound with a corresponding reactive ester of the general formula XIV L -W,

el

where L has the above meaning and W has the same meaning as in the starting compound of the general formula II has to be carried out.

The condensation of a compound of the general formula XIV with a compound of the general formula Ic can be carried out under conditions similar to those described above for the condensation of the reactive esters of the general formula II with the intermediates of the general formula III. In order to accelerate the reaction rate, small amounts of a corresponding macrocyclic polyether, such as 2,3,11,12-dibenzo-1,4,7, ^/ 10,13> 16-hexoxyoxacyclooctadeca-2,11-diene, can in some cases be used , can be added as a reaction accelerator.

If the group to be introduced L is a lower alkyloxycarbonylethyl radical is, this introduction can also be carried out by reacting the compound of the general formula I-c with a (lower-alkyl) -2-propenoate of the general formula XV

709842/0793

(lower-alkyl) 00C-CH = CH ₂ (XV)

are executed.

This reaction is expediently carried out in an organic solvent which is inert during the reaction, such as an aromatic one Hydrocarbon, e.g. benzene, methylbenzene or dimethylbenzene, an ether such as 1,1'-oxybisethane, 2,2'-oxybispropane, tetrahydrofuran or 1,4-dioxane, preferably in the presence of a corresponding one Amine hydroxides, such as Ν, Ν, Ν-triethylbenzene methanamine hydroxide, be performed.

Compounds of the general formula I-f in which L is a Carboxy-lower-alkyl means can easily be derived from the corresponding lower-alkyloxycarbonyl-lower-alkyl-substituted Compounds by hydrolysis in a conventional manner, for example with an aqueous alkali compound, with release the acid from the ester.

When L represents a lower alkylcarbonyl radical, this group can be introduced in two ways by adding a Compound of the general formula I-c with a corresponding acylating agent which is different from a corresponding lower Alkylcarboxylic acid derived, for example a halide, preferably the chloride, or an anhydride, according to conventional methods

709842/0793

drive to N-acylation.

If L is a lower alkylaminocarbonyl radical, this can be introduced by adding a compound of the general Formula I-c with a corresponding isocyanatoalkane in one appropriate organic solvent inert during the reaction, for example in an ether such as 1,1'-oxybisethane, 2,2'-oxybispropane or 1,4-dioxane.

If L represents the hydroxymethyl group, the introduction of this group may be conveniently carried out by reacting a compound of the general formula Ic with formaldehyde in an appropriate organic solvent, such as N ₁ N-dimethylformamide are reacted.

Compounds of the general formula I-g

A p

in which B, n, Ar and Ar have the above meaning can also be prepared by a piperazine derivative of the general formula XVI with a corresponding reactive ester of the

1 2 general formula XVII, in which Ar, Ar and W the above Have meaning under conditions similar to those used above for the preparation of the compounds of general formula I

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Compounds of the general formula II and III have been described, condensed according to the reaction equation below

(XVI)

Compounds of the general formula I-h

S-member alkyl)

A ^ _/ . ^. Ar ¹

- VcHN A- (O) -CH

(I-h)

can also expediently be prepared from the corresponding -SH-substituted derivatives by customary processes for S-alkylation, for example by reacting the mercapto compound with a corresponding halogen-lower alkane in a corresponding organic solvent, such as a lower alkenol, e.g. ethanol, propanol, 2-propanol or butanol.

A number of the intermediates of the general formula II are known compounds, some of which are described in the DT-OSes

709842/0793

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26 32 870 and 26 45 125 are described.

These compounds can all be prepared by methods which are customary per se produce. Depending on the nature of B in these intermediate products of the general formula II, the following can be used for this Procedures are applied.

Intermediate products of the general formula II-a

(II-a)

can be produced as follows:

A correspondingly substituted 2-chloronitrobenzene of the general formula XVIII is with a corresponding aminoalkanol of the general formula XIX under reflux in a corresponding organic solvent inert during the reaction, such as a
lower alkanol, such as ethanol, propanol, 2-propanol or
Butanol implemented. The resulting ^ 2-nitrophenyl) -amino7-alkanol of the general formula XX is subjected to a reduction of the nitro group to the amino group, for example by catalytic

709842/0793

S "27H437

Hydrogenation using Raney nickel as a catalyst. The intermediate product of the general formula XXI obtained is then with an appropriate cyclizing agent, as above for the preparation of the compounds of general Formula I-c explained from compounds of the general formula IV, implemented. The alcohol of the general formula XXII obtained is then converted into the desired reactive ester of the general formula II-a by processes customary per se. Halides are expediently prepared by a compound of the general formula XXII with a corresponding Haiogenierungsmittel converts, for example with Sulfinyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus pentabromide or phosphoryl chloride. When the reactive ester is an iodide, it is preferably made from the corresponding one Chloride or bromide obtained by replacing the halogen with iodine. Other reactive esters such as methanesulfonates and 4-methylbenzenesulfonates is obtained by reacting the alcohol with a corresponding sulfonyl halide, for example methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride. The foregoing Reactions are illustrated by the reaction scheme below:

709842/0793

(XVIII)

(XX)

(XXII)

271U37

egg

R ¹ R ²

(XIX)

R ¹ R ²

H ₉ / RaNi

H ₂ N

R ¹ R ²

(XXI) Ring closure

"NC _n H _2n -OH

R ¹ R ² Formation of a reactive Eete'rs

(Il-a)

709842/0793

The intermediates of the general formula II-a can be

also manufacture in the following way:

I) A compound of the general formula XXIII, in which H ^ and R has the above meaning is, according to customary processes for N-alkylation with a haloalkanol, the general Formula XXIV converted to an alcohol of the general formula XXV.

II) The hydroxyl function of the compound of the general formula XXV is converted to a reactive ester group in the usual manner as described above.

III) The substituted ethenyl group of the compound of the general formula XXVI obtained in this way is} like
above for the preparation of compounds of the general formula Ic from compounds of the general formula
V was removed by acid hydrolysis.

The introduction of the hydroxyalkyl chain in compounds of the general formula XXIII to form compounds of the general formula XXIV can also be carried out by reacting a compound of the general formula XXIII with a corresponding 2- (haloalkyloxy) tetrahydro-2H-pyran of the general formula XXVII. The etheric function of the thereby formed
Intermediate of the general formula XXVIII is cleaved hydrolytically, for example by treatment with aqueous hydrochloric acid.

Reactive esters of the general formula II-a, which are in the form of a halide (II-a-1), can also be prepared
by a compound of the general formula XXIII with
an equivalent amount of a corresponding dihaloalkane ■ of the general formula XXIX in the presence of a corresponding strong base, such as sodium methylate, or according to a Mackosza process with aqueous alkali and a quaternary ammonium catalyst, such as Ν, Ν, Ν-triethylbenzenemethanaminium chloride, to

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puts. This produces an intermediate of the general formula XXVI-a, the substituted ethenyl group of which is then formed is removed by acid hydrolysis to form the desired halide of the general formula II-a-1.

It should be noted that the same procedure can also be used when the substituted ethenyl group has been replaced by another corresponding protective group. The Removal of this protective group is carried out according to appropriate methods adapted to the specific protective group.

The above reactions are illustrated by the reaction scheme below.

709842/0793

co

OB Ν »

CD

Halogen-C

R ¹ R ^fc (XXV)

φ Formation of the reactive ester

-W

(XXVIII)

R ¹ R ² (XXVI) Halogen_C _M H _{0vi -halogen} (XXIX)

Ii ¹ R ²

(XXW-a)

- halogen

(II-a-1)

co

271U37

Intermediate products of the general formula II-b

Ί 2

in which R, R, η and W have the above meaning and L is a lower alkyl, lower alkenyl, lower alkyloxycarbonyl-lower-alkyl, Phenyl, phenylmethyl or lower alkylaminocarbonyl radicals can be conveniently produce by converting the reactive ester side chain into a starting compound of the general formula XXX

(XXX)

by processes similar to those used for the preparation of the intermediates of the general formula XXVI were described starting from compounds of the general formula XXIII, introduces.

Intermediates of the general formula II-c

709842/0793

- 26 -

H4

R '

(ii-c)

can be obtained from the corresponding compounds of the general formula II-a by hydroxyinethylation with formaldehyde produce in a conventional manner.

Intermediates of the general formula II-d

with the exception of compounds in which M is a mercapto or means lower alkylthio group, v / ground expediently prepared by converting the reactive ester side chain into a Starting compound of the general formula XXXI

N ^ VH

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introduces. The introduction of the CH -W remainder can follow similar ones Process as explained above for the introduction of this group in starting compounds of the general formula XXIII has been made.

Intermediate products of the general formula II-e

(II-e)

12 1
in which R, R, M, η and V / have the meaning given above,

can be prepared by adding a corresponding alcohol of the general formula XXI to that described above
Way subjected to the ring closure with an appropriate cyclizing agent. Then the hydroxyl group des
intermediate product of the general formula XXXII obtained in this way is converted into a reactive ester group.

. Formation of the (XXI) cyclization ^ JT ^ ⁷ YC H ^ -OH reactive ester (n- _e )

(XXXII)

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Intermediates of the general formula II-f

S- (lower alkyl)

(II-f)

can be expediently produced by having a corresponding Intermediate of the general formula XXXII, in which M is a mercapto group (XXXII-a) per se customary process for S-alkylation, for example with a corresponding halogen-lower alkane, S-alkylated and then the hydroxyl group of the compound of the general formula XXXIII obtained in this way into a reactive ester group convicted.

S-alkylation

S- (lower alkyl)

(XXXII-a)

η 2n

OH

Education dee

reactive ester ^ ( II-f )

7098A2 / 0793

Intermediates of the general formula II-g

NH-CO- (^ i eder-alkyl)

(ii-g)

can be expediently by N-acylation of the corresponding Amino compound of the general formula II-h

by conventional processes per se, for example by reacting the compound of the general formula II-h with a corresponding lower alkyl carbonyl halide or with one derived from a corresponding lower alkyl carboxylic acid Anhydride.

The intermediates of the general formula IV are by condensation of a corresponding reactive ester of the general Formula XXXIV with a piperazine or piperidine derivative of the general formula III and by subsequent reduction the nitro group of the intermediate product of the general formula XXXV obtained to an amino group according to the customary per se Process for reducing nitro groups to amino groups, for example by reacting the nitro compound with nascent Hydrogen or by catalytic hydrogenation in the presence

709842/0793

an ent sp drawing catalyst, for example Raney nickel, manufactured.

(HD

(XXXIV)

Ar '

Ar

Reduction of the nitro group to the amino group

(IV)

(XXXV)

The reactive esters of the general formula XXXIV, which are used as starting materials can be used easily from an alcohol of the general formula XX with conversion of the hydroxyl group into a reactive ester group according to the processes described above which are customary per se.

The intermediates of the general formula V can be obtained by condensation of a reactive ester of the general formula XXXVI with a piperazine or piperidine derivative of the general Formula III obtained.

R ¹ R '

(XXXVI)

(HD

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(V)

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The reactive esters of the general formula XXXVI, which are used as starting materials, can be prepared by adding the CH _? W radical in a starting compound of the general formula XXXVII

(XXXVII)

by per se customary, processes explained above

The intermediates of the general formula XVI can be prepared by reacting a reactive ester of the general formula II with a piperazine derivative of the general formula XXXVIII, in which Q denotes a corresponding protective group, for example a phenylmethyl or lower alkyloxycarbonyl group, _f . The protective group Q is removed from the intermediate product of the general formula XXXIX formed by conventional methods, for example by catalytic hydrogenation using palladium-on-activated carbon if Q is a phenylmethyl group or by alkaline hydrolysis if Q is a lower alkyloxycarbonyl group.

(II)

(XXXVIII) "(XXXIX)

Removal of Q ^ (XVI)

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Intermediates of the general formula XVI-a

(XVI-a)

can also be achieved by reacting a compound of the general formula XXXVI with a compound of the general formula XXXVIII with formation of an intermediate of the general formula XL and subsequent removal of the protective groups Prepare P and Q by appropriate, per se customary processes.

(XXXVI)

(XXXVIII)

-C

distance from

η 2n

y ^.

(XXXIX-a)

Removal of (χγΐ-a) Q

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Intermediate products of the general formula III in which A denotes the radical JR- and m has the value 0 (III-a) are generally known and can be prepared by processes which are customary per se. These intermediates of the general formula III-a can be prepared, for example, by subjecting a corresponding aroyl halide to a Friedel-Crafts reaction with a corresponding arene and the Ar formed

Ar methanone in the usual way, for example with sodium borohydride, hydrogenated to the corresponding methanol. The latter compound is then made by conventional methods for the preparation of reactive esters from alcohols converted into a reactive ester of the general formula XVII. the desired intermediates of the general formula III-a are then made by reacting the compound of the general Formula XVII obtained with piperazine.

Intermediates of the general formula III, in which A is the remainder J ^ CH- and m has the value 1 (III-b), can expediently can be made by making an A-piperidinol of the general formula XLI, in which Q denotes a corresponding protective group as defined above, with a corresponding one reactive esters of the general formula XVII O-alkylated and then the protective group of the compound of the general formula XLII obtained is removed in the customary manner.

O _H ^ kJ - ^ Ar ¹

<V, W-CH "^ QN Vo-CH OH

^(XLI) (XVII) (XLII)

Removal of Q ^ Vo-CH

(III-b)

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The most important starting compounds that are used in all of the aforementioned manufacturing processes are in generally known and can be prepared by processes which are customary per se.

The compounds of general formula I can be treated by treatment convert with corresponding acids into salts with acids, especially into therapeutically active, non-toxic salts. Examples of corresponding acids are inorganic acids, such as halogenated hydrogen acids, for example hydrogen chloride acid and hydrobromic acid, sulfuric acid, Nitric acid and phosphoric acid, as well as organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, propanedioic acid, butanedioic acid, (Z) -2-butenedioic acid, (E) -2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propane tricarboxylic acid, Benzoic acid, 3-phenyl-2-propenoic acid, oc-hydroxybenzene acetic acid, Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, Cyclohexanesulfamic acid, 2-hydroxybenzoic acid and 4 ~ amino-2-hydroxybenzoic acid. The salts can be converted into the corresponding free bases by treatment with alkalis.

The compounds of general formula I and their pharmacological properties Compatible salts with acids have a strong effect as an anti-anaphylactic and antihistamine and are therefore valuable active ingredients in human and veterinary medicine.

The invention thus also relates to medicinal preparations with anti-anaphylactic and antihistamine action, which are characterized by a content of a compound of the general formula I or a pharmacologically acceptable salt of these compounds.

The valuable pharmacological properties of the compounds of the invention are illustrated below.

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A. Material! On and methods

a) in vivo investigation of the anti-anaphylactic and anti- histamine effects;

Compounds of the general formula I and their salts are investigated in vivo on guinea pigs. G guinea pigs weighing 400 to 500 sensitized by subplantar (sp) injection of 0.05 ^m l antiserum in the left hind paw against ovalbumin. The animals are then left to starve and treated 24 hours after the sensitization either with pure saline solution (= control animals) or a special dose of the compound to be examined.

2 hours after the oral pretreatment, the animals are given 50 ng Histamine injected subplantar into the right hind paw. The diameters of both hind paws are first measured in front of the Histamine injection and measured again 10 minutes after the injection. 30 minutes after the histamine injection, the animals will irritated by intravenous administration of 0.6 mg ovalbumin. All control animals develop typical primary symptoms anaphylactic shock (cough, difficulty breathing and cramps). 85 percent of the control animals die within 15 minutes after the ovalbumin injection. Survival of the Animals is used as a criterion for a possible drug effect used. The ED ^ value, i.e. the oral dose at which at Guinea pigs are given 50 percent protection is listed in the tables below.

The average histamine-related paw edema was 200 Control animals is 10 minutes after the histamine injection 15 units (one unit = 0.1 mm). Reactions below 10 units, which occur in less than 5 percent of the control animals are considered to be effective in inhibiting histamine edema in the treated animals. The oral doses at which this hemorrhage occurs are also as follows Tables given.

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27UA37

b) in vitro antihistamine action

Guinea pig ileum strips are placed in a 100 ml Tyrode bath at 37-5 ° C suspended at a previous exposure of 0.75 E and gassed with 95 percent Op and 5 percent COp. The one through histamine (0.5 mg / liter) induced spasms are kymographsch with an isotonic lever giving a 5X magnification. The interaction between the under study Connection (5 minutes incubation time) and the agonist is established. In the tables below is the effective one Concentration in mg / liter of the individual compounds listed, being a significant inhibition (50 percent) by histamine induced contraction is measured.

From the investigations described above, it can be seen that the compounds of general formula I and their pharmacological Compatible salts are generally valuable antiallergic active ingredients when administered systemically to warm-blooded animals at doses from about 0.25 to about 20 mg / kg body weight represent.

The active ingredients of the invention can lead to various pharmacological Dosage forms are processed. For this purpose, an effective amount of an appropriate compound in the form of Base or a salt with an acid with a pharmacological compatible carrier thoroughly mixed. Various carriers can be used according to the desired mode of administration.

Preferably the pharmaceutical preparations of the invention are in unit doses which are suitable for oral or rectal administration or for parenteral injection. For production of Conventional media, for example water, glycols, oils and alcohols, can be used for preparations to be administered orally for liquid preparations such as suspensions, syrups, elixirs and solutions, or solid carriers such as various types of starch, Sugar, kaolin, lubricants, binders and disintegrants, for

709842/0793

^ 27U437

Manufacture of powders, pills, capsules and tablets. Due to the ease of administration make tablets and capsules is the most preferred form for oral administration, in which case, of course, solid carriers are used will. For preparations to be administered parenterally, the carrier material generally consists at least for the most part sterile water. However, it can also contain other components, for example substances that increase solubility. Injectable solutions can be made using, for example, saline, gluten or a mixture made from saline and glucose solution as a carrier. For the preparation of injectable suspensions, appropriate liquid carriers, suspending agents and the like are used. Salts of the compounds of general formula I with acids due to their higher water solubility compared to the bases better suited for the production of aqueous preparations.

It is particularly advantageous to use the aforementioned medicinal preparations for reasons of ease of administration and uniformity Process dosage to unit doses. Unit doses are to be understood as physically discrete units of quantity, where each unit contains a predetermined amount of active ingredient, the so is calculated that the desired therapeutic effect in conjunction with the required pharmacological carrier entry. Examples of such unit dose forms are tablets (including scored or coated Tablets), capsules, pills, powder packs, wafers, injectable solutions or suspensions, teaspoon quantities and tablespoon quantities as well as divided multipacks thereof.

709842/0793

Table I-a

- 38 -

L. R ¹ R ² C-_H /> - R ⁶ R ¹ R- against histamine ■ oral e, antianaphylactic "effective b.Meerschw. , mgAg η 2η base effective in vitro . same dose 1 R ⁷ or Conc entrati on - Histamine modem Salt. (Ileum), mg / liter survive O H H H (CH ₂ ) ₂ H 1.25 (O H 5-Cl H (CH ₂ J ₂ H 0.01 0.63 1.25 OO H H 6-Cl (CH ₂ ) ₂ H H base 0.01 0.63 2.5 ro H 5-CF ₃ H (CH ₂ ) ₂ H H base 0.02 ² f5 1.25 σ
«J H 5-CH ₃ H (CH ₂ J ₂ H H base 0.02 0.31 1.25 (O H H H (CH ₂ ) ₂ 4-F H base 0.01 1.25 0.16 Ul H H H (CH ₂ ) ₂ 4-F H base 0.02 0.31 0.63 H H H (CH ₂ ) ₃ H H base 0, Q2 0.63 '0.31 H 5-Cl H (CH ₂ ) ₃ H 4-F Basei / 2H ₂ 0 0.005 0.10 1.25 H 5-CH ₃ H (CH ₂ J ₃ H H base 0.01 0.63 0.16 κ>
⁷ "j H H 6-Cl (CH ₂ J ₃ H H base 0.01 0.08 0.63 - * H H ' 6-CH .. (CH ₂ J ₃ H H base 0.04 0.63 £ 0.31 H H 7-Cl ~ (CH ₂ J ₃ H H base 0.01 0.16 - to
- «j H 5-Cl 6-Cl (CH ₂ J ₃ H H base 0.08 > ² , 5 2.5 II base > O, 16 2.5 H base

Table Ia (cont.)

- 39 -

L. H CH ₃ R ¹ . R ^{2 1 c} n ^H 2n R. I 1 Il \ ase
or against histamine
effective in_yi-i
tro concentra m oral, anti-anaphylactic
same dose b. Guinea pig, mg / kg Histamine modem C ₂ H ₅ -OOC- 5-CF ₃ H (ch ₂ ) ₃ H _7 salt tion (ileum)
mg / liter survive 0.31 (CH ₂ ) ₂ H H (CH ₂ ) ₃ H R ' base 0.02 0.31 0.31 C ₆ H ₅ -CH ₂ - H base 0.01 0.16 CH ₃ -CO- H H (CH ₂ ), H H 0.63 CH ₃ -NH-CO- HCl, 2H ₂ O 0.005 0.63 O
en CH ₃ - H H (CH ₂ J ₃ H H 1.25 OO HIGH ₀ - H H (CHg) ₃ H 2 HCl 0.16 1.25 0.31 ISJ H . II (CHg) ₃ H H base 0.005 0.10 - O H H H (CH ₂ ) ₃ H H base 0.02 - 2.5 Ό
W. H H H (CH ₂ ) ₃ II H > HC1.H ₂ O 0.01 1.25 0.31 H 5-Cl H (CH ₂ ) ₃ H H base 0.01 0.31 - H H H (CH ₂ ) ₃ 4-F H > HC1.1 / 2H ₂ O 0.08- - 0.31 H II II (CH ₂ ) ₃ 4-Cl H base 0.01 0.31 0.63 H H H 3-Cl H base 0.01 1.25 ¹ ? ²⁵ κ. H H (CH ₂ ) ₃ 4-F H base 0.01 0.63 0.16 -J 5-Cl H (CH ₂ ) ₃ 4-F H base 0.01 0.31 1.25 J ^ II 6-Cl (CH ₂ ) 3 4-F 4-F base 0.04 1.25 4-Γ Base.H ₂ O 0.02 0.63 4-F

Table I-a (Ports.)

L. H R ¹
• R ^{2 c} n ^H 2n R ⁶ R ⁷ Base - COCfATi TTi ^ f "flTTii τι Drale, antianapnylactic effect rle he piggy . 2.5 • - H H H (CH ₂ J ₃ 2-F 4-Cl or .
salt S Vn VU 1 r ί O ν "111 IJI
effective in vi same dose b. 2.5 <2.5 H H H < ^CH ₂ ) ₄ H H base tro concentration. ·
tion (ileum)
mg / liter rnpAPT Histanine edema 1 _r 25 <2.5 H H (C » ₂ ) ₄ 4-F 4-F base 0.02 survive 1.25 <2.5 H 2HCLH ₂ O 0.01 0.31 0.31 <2.5 H H H (CH ₂ ) ₅ H II 1 / 2C ₂ H ₅ OH 0.01 0.16 0.31 <2.5 ro H H H (CH ₂ ) ₅ 4-F 4-F 2HCLH ₂ O 0.16 <2.5 ^ H H H (CH ₂ ) ₆ H H I 2HCLH ₂ O 0.01 <2.5 5 α
co H H -CH ₉ -CH-CH ₂ - 4-F 4-F I base 0.01 0.63 00
* ·. H CH ₃ base 0.01 1.25 rs)
^^ H H H (CH ₂ J ₃ H 2-Cl 0.02 1.25 ^%
O H H H (CH ₂ ) ₃ 4-Cl 4-Cl base 1.25 ■ -j
co H H II (CH ₂ ) ₃ H 4-Br base 0.08 CJ H H H (CM ₂ ) ₃ H 2-F base 0.16 - H H H (CH ₂ ) ₃ 4-F 4-CH ₁ base 0.16 <2.5 II H H (CH ₂ ) ₃ II 4-CH * base 0.02 <2.5 HOOC-CH ₂ H H (CH ₂ ) ₃ II 4-NOj base 0.16 < ² > 5 H II (CH ₂ ) ₃ II H Base. 0.08 <2.5 Base 1 / 2H ₂ C 0.16 <2.5 0.08 <2.5 < ² '5

Table I-b

i R ¹ C H «· R ⁶ R ⁷ Base or against histamine oral, anti-anaphylactic effects fleerschw. mg / kg M. - ₂ ^H 5 ~ η 2η salt effective in vitro same dose b. Histamine edema W. H (CH ₂ ) ₂ H H base [concentration survive 1.25 : h ₃ -s- H (CH ₂ ) ₂ H H 3HCLH ₂ O 0.005 1.25 _ 3H ₃ - H (CH ₂ ) ₃ H H base > O, 16 - ■ 0.16 ³ 6 ^H 5 " H (CH ₂ ) ₃ H H 31ICLH ₂ O 0.0025 0.08 1.25 HS- H (CH ₂ ) ₃ H H base 0.16. 1.25 2.5 Cyclohexyl H (CH ₂ ) ₃ H H base 0.02 2.5 C ₆ H ₅ -CH ₂ - H (CH ₂ ) ₃ II H ■ Base 0.08 - · 1.25 CH ₃ OOC-NH- H (CH ₂ J ₃ H H base 0.01 0.63 2.5 I ₂ N- H (CH ₂ ) ₃ H U 3HCLH ₂ O > O, 16 2.5 ■ - CH ₃ -CO-NH- H (CH ₂ ) ₃ H H base > O, 16 - - 2.5 C ₂ H ₅ - H (CH ₂ ) ₃ H H base ^ 0.16 2.5 2.5! 2 Cyclohexyl H (CH ₂ ) ₃ H H base ^ 0.16 2.5 H (CH ₂ J ₃ H II 3HCLH ₂ O > O, 16 2.5 2.5 4 ^ D ₆ H ₅ -CH ₂ - 5-Cl (CH ₂ ) ₃ H H base o, ot 2.5 5-Cl (CH ₂ ) ₃ H H 3HCLH ₂ O - 0.63 - 5-Cl (CH ₂ ) ^ H H 3HCLH ₂ O 0.01 - - - ■ 2.5

Table I-b (cont.)

M. R ¹ η dJi R ⁶ H base
or against histamine
effective in vi
"t" T »n ~ Tf nn 7. pntTfi— oral, anti-anaphylactic
effective dose b. sea
piggy, mg / kg Hi st amino dem J. C ₆ H ₅ - • (CH ₂ J ₃ H H survive _ cyclohexyl 6-Cl (CH ₂ J ₃ . H H base - 2.5 - H 6-Cl (CH ₂ J ₃ 4-F H base - 2.5 0.31 H H (CH ₂ J ₃ 2-Cl H base 0.005 0.31 1.25 O H H (CH ₂ J ₃ 4-Cl 4-F 3HC12H ₂ O 0.01 1.25 0.31 (O
GO H H (CH ₂ J ₃ 4-F H base 0.01 0.08 0.31 H H (CH ₂ J ₄ H H Base H ₂ O 0.02 0.16 0.16 ^! ^CH 3 H (CH ₂ J ₄ H H base 0.0025 0.16 1.25 O • J
H H (CH ₂ J ₄ 4-F H base 0.005 1.25 0.16 (O H H (CH ₂ J ₄ 3-Cl base 0.005 0.08 1.25 H 4-F 3HCLH ₂ O 0.01 1.25 H (CH ₂ J ₄ 4-F H 1 / 2CH ₃ CHOHCH, 0.31 H H CH ₂ -CH (CH ₃ J-CH ₂ H 4-F base 0.005 0.31 - Il H CH ₂ -CH (CH ₃ J-CH ₂ 4-F 3HC11 / 2H ₂ O 0.02 - 1.25
ro H 3HC11 / 2H ₂ O 0.02 0.63

Table I-c

- 4-3 -

Y Base or salt effective against histamine in
vitro concentration (ileum)
mg / liter oral, anti-anaphylactic
Same dose t>. Guinea pig
mg / kg Histamine edema S.
0 2 HCl. 1/2 H ₂ O
2 HCl 0.01
0.01 survive 1.25
^2/5 1.25
0.63

Table I-d

- 44 -

B. • ^C n ^H 2n R ⁶ R ^ Base.
or effective against histamine oral, anti-anapnylactic effect Histamine edema • 0.31 4th
ISJ salt same in vitro con- 'same dose b. Guinea pig , mgAg 0.16. 0.16 ^ω
t Ha- (CH ₂ ) ₂ H H HCl centration (ilevm)
mp / liter survive 0.31 Q fry 0025 0.31 CO () - 1.25 00 \ CH / j J η H H base N>
■> * . 0.0025 0.63 O CO
CJ • I cvt \
\ III). Jy, H H base Η.Λ - 0.005 0.63 "Ä- (CH ₂ J ₂ 4-F 4-F BC1.1 / SIV 4-F 4-F HCl. 1 / 2H ₂ C 0.0025 0.31 (CH ₂ J ₃ i H H base 0.0025 0.63 0.0025 0.16

Table I-e

Ar ¹ Ar ² base
or
salt effective against histamine
same in vitro conc
tration (ileum)
mg / liter oral, anti-anaphylactically effective
Dose b. Guinea pigs, mg / kg Histamine edema ^C 6 ^H 5
^C 6 »5
^C 6 ^H 5
4-Cl-C ^ H.
ο 4
4-FC ₆ H ₄
4-FC ₆ H ₄ 2-pyridinyl
3-pyridinyl
2,5- (CH ₃ ) ₂ -C ₆ H ₃
3-pyridinyl
3-pyridinyl
4-pyridinyl base
base
base
base
base
base 0.16
0.08
0.16
• 0.08 ■ *
0.08
0.16 survive 2.5
<2.5
2.5
<2.5
• £ 2.5
I. 1 * 25
<2.5

The examples illustrate the invention. Unless otherwise indicated, all parts of the data relate to weight.

example 1

A mixture of 54 parts of 1,3-dihydro-1- (phenylmethyl) -2H-benzimidazol-2-one, 47.25 parts of i-bromo-3-chloropropane and 6 parts

Ν, Ν, Ν-Triäthylbenzolmethanaminiumchlorid is added dropwise at 60 ⁰ C with 450 parts of a 60 percent sodium hydroxide solution was added. After completion of the addition for a further 6 hours at 6O ⁰ C is stirred. The reaction mixture is then cooled and poured into water. The oily product is extracted with trichloromethane. The extract is dried, filtered off and evaporated. After the residue has crystallized from 2,2'-oxybispropane and dried, 42 parts (58 percent of theory) 1- (3-chloropropyl) -1,3-dihydro-3- (phenylmethyl) -2H-benzimidazole are obtained -2-on.

In a corresponding manner, the compounds listed below manufactured:

L. R ¹ η : Xp. CH ₂ = C (CH ₃ )
CH ₂ = C (CH ₃ )
^C 6 ^H 5
CH ₂ = C (CH ₃ )
CH ₂ = C (CH ₃ )
CH ₂ = C (CH ₃ ) 5-CH ₃
6-CH ₃
5-Cl
H
H
H 3
3
3
4th
5
6th 140 ⁰ C / 0.015 torr
140 ⁰ C / 0.02 torr
•

709842/0793

- Uf--

Example 2

According to Example 1, using equivalent amounts of corresponding 1H-benzimidazoles as starting compounds, the received the following products as a residue:

- ^C n ^H 2n- ^C1

M. ^C n ^H 2n ^CH 3 (CH ₂ ) ₃ \ ^H / (CH ₂ ) ₃ C ₂ H ₅ (CH ₂ ) ₃ H
^C 6 ^H 5 CH ₂ -CH-CH ₂
CH ₃
(CH ₂ ) ₃ CH ₃ ( ^CH 2> 4

709842/0793

271U37

Example 3

A mixture of 20 parts of 3- / C2-amino-4-chlorophenyl) -amino7-1-propanol, 50 parts of acetic acid and 150 parts of a 4 η hydrochloric acid solution is stirred overnight and heated under reflux. The reaction mixture is then cooled and evaporated. The residue is dissolved in water. The solution is made alkaline with ammonia. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. After the residue has crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, 6.5 parts (28 percent of theory) of 5-chloro-2-methyl-1H-benzimidazole-1-propanol are obtained.

In a corresponding manner, by reacting 3- / C2 ~ amino-4-chlorophenyl) -aminp_7-1-propanol with propanoic acid 5-chloro-2-ethyl-IH-benzimidazole-1-propanol manufactured.

Example 4

A mixture of 30 parts of 3- / r2-amino-4-chlorophenyl) -amino7-1-propanol and 0.1 part of 4-methylbenzenesulfonic acid in 405 parts of methylbenzene is stirred and refluxed (water separator) dropwise with a solution of 34 parts of cyclohexanecarboxaldehyde added in 45 parts of methylbenzene. After the addition has ended, a further hour at the reflux temperature is below Use of the water separator stirred. The methylbenzene is then removed under reduced pressure and the residue with 2,2'-oxybispropane triturated. The product is filtered off and dried. 16.5 parts (38 percent of theory) of 5-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol are obtained from P. 95 ° C.

Example 5

A mixture of 30 parts of 3 - / ^ 2-amino-4-chlorophenyl) -amino7-1-propanol, 44.8 parts of sodium oc-hydroxybenzenethanesulfonate and 120 parts of ethanol is stirred for 30 minutes and heated under reflux. The reaction mixture is then evaporated

709842/0793

and the residue taken up in water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. 45 parts (100 percent of theory) of 5-chloro-2- (phenylmethyl) -1H-benzimidazole-1-propanol are obtained as a residue.

In a corresponding manner, by reacting 3- / T2-amino-5-chlorophenyl) -amino7-1-propanol with sodium oc-hydroxycyclohexanemethanesulfonate, 6-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol with a melting point of 120, 1 ⁰ C produced.

Example 6

A mixture of 93 parts of 3- (2-aminophenyl) -amino-1-propanol, 45.5 parts of potassium hydroxide and 600 parts of 85 percent aqueous ethanol is added dropwise with stirring with 60.8 parts of carbon disulfide. After the addition has ended, the mixture is stirred at the reflux temperature for a further 6 hours. The reaction mixture is then evaporated under reduced pressure and the residue is taken up in 1500 parts of water. It is then filtered through a filter aid (Hyflo) and the filtrate is acidified with acetic acid. The oily product solidifies when scratched. This product is filtered off, washed with water and dried. 92 parts are obtained (78.9 percent of theory) of 2-mercapto-1H-benzimidazole-1-propanol, mp 110 ⁰ C.

A mixture of 20.8 parts of 2-mercapto-1H-benzimidazole-1-propanol, 15/62 parts of iodomethane and 120 parts of methanol stirred overnight at room temperature. The reaction mixture is then evaporated and the residue is dissolved in 500 parts of water. The solution is then filtered through a filter aid (Hyflo) and the filtrate is made alkaline with solid potassium hydroxide made. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. 19 parts (85.5 percent of theory) of 2- (methylthio) -1H-benzimidazole-1 are obtained -propanol as residue.

709842/0793

A mixture of 19 parts of 2- (methylthio) -1H-benzimidazole-1-propanol, 15> 2 parts Ν, Ν-diethylethanamine and 195 parts 11.5 parts of methanesulfonyl chloride are added dropwise with stirring to dichlorine than. When the addition is complete, a stirred under reflux for a further hour. After cooling, water is added. The phases formed are separated. the organic phase is dried, filtered and evaporated. 19 parts of 3- / 2- (methylthio) -1H-benzimidazol-1-yl7-propyl methanesulfonate are obtained as an oily residue.

Example 7

A mixture of 30 parts of 1H-benzimidazole, 49 parts of 2- (4-chlorobutoxy) -tetrahydro-2H-pyran, 21 parts potassium hydroxide and 200 Parts of ethanol are stirred overnight and heated under reflux. The reaction mixture is then cooled to room temperature and f-filtered. That obtained after evaporation of the filtrate The residue is stirred in water and acidified with dilute hydrochloric acid. The mixture is then stirred and 30 minutes in heated in a water bath. After cooling to room temperature, the product is extracted with methylbenzene. The aqueous phase is separated and made alkaline with ammonia. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. 50 parts of 1H-benzimidazole-1-butanol are obtained as an oily residue.

Example 8

A mixture of 5 parts of 4-chloro-i, 3-dihydro-3- (3-hydroxypropyl) -2H-benzimidazol-2-one and 75 parts of trichloromethane is added dropwise with stirring with 8 parts of sulfinyl chloride. After the addition has ended, the mixture is stirred at the reflux temperature for a further 3 hours. The reaction mixture is then cooled and evaporated. The residue is stirred in a small amount of 4-methyl-2-pentanone. The product is then filtered off and dried. 3.5 parts of 4-chloro-3- (3-chloropropyl) -1 ^ -di are obtained

709842/0793

27H437

The following 1- (chloroalkyl; -1H-benzimidazoles manufactured:

M. η R ¹ Base or
salt F. ·. .v C ₆ H ₅ -CH ₂ 3 5-Cl base - CH ₃ 3 5-Cl base - C ₂ H ₅ 3 5-Cl base - vV 3 5-Cl HCl 211.7 ° C ^C 6 ^H 5 ~ " ^CH 2 3 H base 112 ° C C ¹ L / 3 6-Cl HCl 227.5 ^β 0 C ₂ H ₅ 2 H _x base H 4th H base I.

709842/0793

271U37

Example 9

A mixture of 113.2 parts of 1,2,4-trichloro-5-nitrobenzene, 75 parts of 3-amino-1-propanol, 0.2 part of potassium iodide and 200 parts of butanol is stirred overnight and heated under reflux. The butanol is then evaporated off under reduced pressure and water is added to the residue. The product is extracted with 4-methyl-2-pentanone. The extract is washed a few times with water, dried, filtered and evaporated. The oily residue is purified by column chromatography on silica gel using a mixture of trichloromethane and 5 percent methanol as the eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated with 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of 2,2'-oxybispropane and 2-propanol. This gives 31.7 parts of 3- / T4.5-dichloro-2-nitrophenyl) -amino7-1-propanol from P. 97 ⁰ C.

The following compounds are prepared in a corresponding manner: 3- j ^ -nitro-4- (trifluoromethyl) -phenyl7-aminoj -1-propanol and 2- i ^ -Nitro-4- (trifluoromethyl) -phenyl_7-aminoj -ethanol vom 74.9 ° C.

Example 10

35.7 parts of sulfinyl chloride are added dropwise to a mixture of 39.2 parts of 3- (2-nitrophenyl) -amino-1-propanol and 225 parts of trichloromethane while stirring, the temperature rising ^{to 4-5 ° C. with an exothermic reaction.} After the addition has ended, the mixture is stirred at the reflux temperature for a further 6 hours. The reaction mixture is then evaporated. 43 parts (100 percent of theory) of N- (3-chloropropyl) -2-nitrobenzolamine are obtained as a residue.

The following connections are established in a corresponding manner:

N- (3-chloropropyl) -2-nitro-4 ~ (trifluoromethyl) benzene amine as Residue,

709842/0793

27U437

4,5-dichloro-N- (3-chloi'propyl) -2-nitrobenzola] nin of mp 78 ° C and N- (2-chloroethyl) -2-nitro-4- (trifluoromethyl) benzolamine.

Example 11

A mixture of 21.5 parts of N- (3-chloropropyl) -2-nitrobenzolamine, 22.68 parts of 1- (diphenylmethyl) piperazine, 20 parts of N, N-diethylethanamine and 180 parts of Ν, Ν-dimethylacetamide is stirred for 6 hours and heated to 100 ⁰ C. The reaction mixture is then evaporated and the residue is taken up in water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanol, ethanol and 2,2'-oxybispropane. The product is filtered off and dried. 15.5 parts (36.9 percent of theory) of ^ (diphenylmethyl) -N- (2-nitrophenyl) -1-piperazine propanamine hydrochloride with a melting point of 228 ° C. are obtained.

The following connections are established in a corresponding manner:

N- (4,5-dichloro-2-nitrophenyl) -4- (diphenylmethyl) -1-piperazine propanamine as a residue,

4- (Diphenylmethyl) -N- / 2- nitro-4- (trifluoromethyl) -phenyl_7-1-piperazine propanamine of 113.7 ° C and

4- (diphenylmethyl) -N- / 2 ~ -nitro-4- (trifluoromethyl) -phenyl7-1-piperazinäthanamin, mp 152.1 ⁰ C.

Example 12

A mixture of 15 parts of 4- (diphenylmethyl) -N- (2-nitrophenyl) -i-piperazinepropanamine hydrochloride in 160 parts of methanol is hydrogenated at normal pressure and room temperature in the presence of 5 parts of Raney nickel as a catalyst. After the calculated amount of hydrogen has been taken up, the catalyst is filtered through a filter aid (Hyflo) and the filtrate is evaporated. The solid residue is crystallized from a mixture of 2-propanol and 2,2'-oxy bispropane. The product is filtered off and

709842/0793

271U37

dries. 12 parts are obtained (78.9 percent of theory) of N- (2-aminophenyl) -4- (diphenylmethyl) -1-piperazinpropanamin hydrochloride, mp 223.1 ⁰ C.

The following connections are established in a corresponding manner:

4,5-dichloro-N -j 3 - / ^ - (diphenylmethyl) -1-piperazinyl7-propyl ^ 1,2-benzenediamine as an oily residue, N - ( 3 - /% - (diphenylmethyl) -1 -piperazinylT-propylv -4- (trifluoromethyl) -1,2-benzenediamine and

N ' ^l -i2 - / ^ - (Diphenylmethyl) -1-piperazinyl-7-ethyl | -4- (trifluoromethyl) -1,2-benzenediamine as an oily residue.

Example 13

A mixture of 60.5 parts of 1- (3-chloropropyl) -1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one, 31.68 parts of 1- (phenylmethyl) piperazine, 21 , 2 parts of sodium carbonate, 0.1 part of potassium iodide and ^ K) O parts of 4-methyl-2-pentanone is stirred for 20 hours using a water separator and heated under reflux. The reaction mixture is then cooled and water is added. The phases are separated. The organic phase is dried, filtered and evaporated. 70 parts (100 percent of theory) 1,3-dihydro-1- (1-methylethenyl) -3-i 3 - /% - (phenylmethyl) -1-piperazinyl7-propylv-2H-benzimidazole-2- are obtained on as a residue.

In a corresponding manner, 1,3-dihydro-1- [2- / 5- (phenylmethyl) -1-piperazinyl-7-ethyl? -2H-benzimidazol-2-one is used from P. 136.5 ° C.

Example 14

A mixture of 70 parts of 1,3-dihydro-1- (1-methylethenyl) -3-i3- ^ - (phenylmethyl) -1-piperazinyl7-propylj -2H-benzimidazol-2-one in 240 parts of ethanol is stirred with 55 parts of 6 η hydrochloric acid offset. Then the reaction mixture is 2 hours

709842/0793

"27U437

stirred at 40 to 50 ⁰ C and then evaporated. The residue is taken up in dilute ammonia solution. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. 63 parts (100 percent of theory) of 1,3-dihydro-1- ί3 - / ^ - (phenylethyl) -1-piperazinyl-7-propyl} -2H-benzimidazol-2-one are obtained as residue.

Example 15

A mixture of 63 parts of 1,3-dihydro-1- $ 3- / 4- (pllenylmethyl) -1-piperazinyl7'-propylj ^ H-benzimidazol ^ -one in 400 parts of methanol is at normal pressure and at room temperature with 10 Parts of 10 percent palladium on activated carbon as a catalyst hydrogenated. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off through a filter aid (Hyflo) and the filtrate evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2-propanol. The product is filtered off and dried. 29.5 parts (63 percent of theory) 1,3-dihydro-1- / 3 ~ - (1-piperazinyl) -propyl_7 ~ are obtained 2H-benzimidazol-2-one, mp 157.5 ° C.

(1-piperazinyl) -äthyl7-2H-benzimidazol-2-one, mp 122.6 ⁰ C - in a corresponding manner, 3-dihydro-1/2 ~ is first

Example 16

A mixture of 20 parts of aluminum chloride and 100 parts of fluorobenzene is added dropwise with stirring to 20.5 parts 2,4-dichlorobenzoyl chloride added. After the addition is complete the mixture was heated to reflux temperature and 5 minutes stirred under reflux. The reaction mixture is then poured onto crushed ice. The product is made with Iji'-oxybisethane extracted. The extract is dried and evaporated. 30 parts of (2,4-dichlorophenyl) - (4-fluorophenyl) methanone are obtained as an oily residue.

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271U37

(4-Fluorophenyl) - (4-pyridinyl) methanone is obtained in a corresponding manner with a temperature of 85.5 ° C.

Example 17

A mixture of 23.4 parts of (4-chlorophenyl) - (2-fluorophenyl) methanone in 280 parts of 2-propanol is mixed in portions with 3-7 parts of sodium borohydride while stirring. After completion of the addition for a further 2 hours at the reflux temperature · (+ 80 ⁰ C) is stirred. The reaction mixture is then cooled and decomposed by adding water. The 2-propanol is evaporated and the residue extracted with trichloromethane. The extract is dried, filtered and evaporated. 23.6 parts of 4-chloro-ot- (2-fluorophenyl) -benzene-methanol are obtained as residue.

The following connections are established in a corresponding manner:

2,4-dichloro-a- (4-fluorophenyl) -benzenemethanol as residue, a- (4-fluorophenyl) -4-pyridinemethanol with a melting point of 138.2 ° C,

α- (4-Fluorophenyl) -3-pyridinemethanol hydrochloride, mp 158.3 ° C

4-Methoxy-oc- / 3 "- (trifluoromethyl) -phenyl-7-benzene-methanol as

Residue.

Example 18

A mixture of 22 parts of 2,4-dichloro- <x- (4-fluorophenyl) -benzenemethanol and 240 parts of 12 η hydrochloric acid is stirred for 40 hours at room temperature. The reaction mixture is then poured onto ice water. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is distilled. This gives 13.2 parts of 2,4-dichloro-I-ZOhIor- (4-fluorophenyl) -methyl7-benzene, bp. 146 ^e C / 0.15 Torr.

709842/0793

% 27UA37

The following compounds are produced in a corresponding manner

1- ^ t'-chloro-a- (4-methoxyphenyl) -inethyl7-3- (trifluoromethyl) -benzene as residue and
1 - / chloro- (4-methylphenyl) -methyl7-4-fluorobenzene as residue.

Example 19

A mixture of 23.6 parts of 4-chloro- <x- (2-fluorophenyl) -benzenemethanol 24 parts of sulfinyl chloride are added dropwise to 108 parts of benzene. When the addition is complete, the reaction mixture becomes heated to the reflux temperature and then 5 hours at the reflux temperature and then overnight at Room temperature stirred. The benzene is then evaporated off and the residue is distilled. 16.5 parts of 1-chloro-4 - / ^ c-chloro-α- (2-fluorophenyl) -methyl7-benzene are obtained from bp 122 to 125 ° C / 0.1 Torr.

The following connections are established in a corresponding manner:

3- / ct-chloro-a- (l ^{z-fluorophenyl)} -methyl7 ^r pyridine hydrochloride as an oily residue,

3- / ä-chloro-cx- (4-chlorophenyl) -metbyl_7-pyridine hydrochloride as Residue,

4- / cx-chloro ~ a .- (4-fluorophenyl) -methyl7-pyridine hydrochloride, melting at 198-200 ⁰ C,

1- (chlorophenylmethyl) -2,3-dimethylbenzene with a boiling point of 137 ° C / O, 7 Torr, 1- (chlorophenylmethyl) -2,4-dimethylbenzene with a boiling point of 137 ° C / O, 7 Torr,

2- (Chlorophenylmethyl) -1,4-dimethylbenzene with a boiling point of 136 ° C / 0.7 Torr

1- (Chlorophenylmethyl) -2-fluorobenzene with a boiling point of 108 to 109 ° C / 0.4

Torr.

Example 20 A mixture of 121 parts of piperazine, 54 parts of 3- / pc-chloro-a-

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271U37

(4-chlorophenyl) methyl7-pyridine hydrochloride and 315 parts of Ν, Ν-dimethylformamide is stirred for 20 hours at room temperature. The reaction mixture is then evaporated. 250 parts of water are added to the residue. The product is extracted with methylbenzene. The organic phase is washed with water and extracted with 10 percent acetic acid solution. The acidic aqueous phase is made alkaline with a 60% sodium hydroxide solution. The product is then extracted again with ethylbenzene. The extract is dried, filtered and evaporated. The oily residue is converted into the nitrate in ethanol. The salt is filtered off, washed with ethanol and 2,2'-oxybispropane and crystallized from ethanol. This gives 48 parts of 1 - / ^ - (4-chlorophenyl) -a- (3-pyTidinyl) -methyl7-piperazin-trinitrate, mp 132.9 ⁰ C.

The following compounds are prepared in a corresponding manner: 1- ^ x- (4-chlorophenyl) -oc- (2-fluorophenyl) -methyl7-piperazine, 1 - / ^ x- (4-fluorophenyl) -cx- (4-pyridinyl) -methyl7-piperazine from M.p. 108.4 ° C,

1 - / ("2-GhI orphenyl) - (3-chlorophenyl) -met hyl7-pip er az i η,

1- / i "2-fluorophenyl) -phenylmethyl7'-piperazin-äthandioat (1: 1), mp 195.5 ⁰ C.

1 - / C ^ - fluorophenyl) - (4-methoxyphenyl) -methyl7-piperazin-äthandioat (1: 2), mp 280.1 ⁰ C and

1- / T4-nitrophenyl) phenylmethyl7-piperazine dihydrochloride.

Example 21

A mixture of 21.5 parts of ethyl 4-hydroxy-i-piperidine carboxylate, 35.2 parts of bis (4-fluorophenyl) bromoethane and 8.6 parts Potassium carbonate is stirred for 3 hours and heated to 140 ° C. in an oil bath. The reaction mixture is then brought to room temperature cooled and mixed with water. The product is extracted with methylbenzene. The extract is successively mixed with water,

709842/0793

_ 27H437

washed with dilute hydrochloric acid and sodium hydrogen carbonate solution, dried, filtered and evaporated. After distilling off a first running to Kp. 143 ° C / O, from 5 to 1 torr is obtained 29 parts of ethyl 4- / bis- (4-f luorphenyl) -methox ^ 7 ^r lpiperidincarboxylat as an oily residue.

In a corresponding manner, ethyl 4- (diphenylmethoxy) -1-piperidinecarboxylate is used with a bp of 150 ° C / 0.4 Torr.

Example 22

A mixture of 29 parts of ethyl 4- / b ~ is- (4-fluorophenyl) methox ^ 7 1-piperidinecarboxylate, 25 parts of potassium hydroxide, 1 part of water and 160 parts of 2-propanol is stirred for 4 hours and heated under reflux. The solvent is then evaporated off and water is added to the residue. The product is extracted with methylbenzene. The extract is washed a few times with water, dried, filtered and evaporated. The oily residue is converted into the hydrochloride at room temperature in 4-methyl-2-pentanone and 2-propanol. The salt is filtered off and dried. 20.5 parts obtained (78 percent of theory) of 4- / bis (4-fluorophenyl) -methoxv7-piperidine hydrochloride, mp 161.8 ⁰ C.

In a corresponding manner ^ is - (diphenylmethoxy) -piperidine prepared, mp 209.8 ⁰ C.

Example 23

A mixture of 5.3 parts of 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one, 5 parts of 1- (diphenylmethyl) piperazine, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone stirred and refluxed overnight using a water separator. After cooling, water is added. The phases are separated. The 4-methyl-2-pentanone phase is dried, filtered and evaporated. The residue is column chromatographed on silica gel using a

709842/0793

-6Θ--

Mixture of trichloromethane and 5 percent methanol as eluent cleaned. The pure fractions are collected. That Eluent is evaporated. The oily residue is made from a mixture of 2,2'-oxybispropane and a small amount 2-propanol crystallizes. The product is filtered off and dried. Nan receives 2 parts (23 percent of theory) 1- (3- / 4- (kiphenylmethyl) -1-piperazinyl7-propylV-1,3-dihydrO-PiI-benzimidazol-2-one of 153.6 ° C.

In a corresponding manner, the compounds listed below in the form of the free base or after treatment of the free base prepared with a corresponding acid in the form of a salt with an acid:

709842/0793

φ a in , _ CM φ VD in I. in I. in OO I. r- kO 27 I. I. SC SC vo co OO 37 O
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CM I ο CM O CM O υ Ü c- co M- I. Ü CM CO t
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(O PQ VD VD VD PQ (O VC SC X Q) 1 PP Ü Ü υ FQ O cn I M " M. M. SC CM CO co < SC SC VO CM CM CM in SC SC VO VD ^ "! in O X SC X SC VO Ü O SC I r— SC in I. O O υ vo VD O I. I. vo I U VD SC do m co CO Ü in O L ·. U * O I <J ϋ VO I. SC SC SC X I. I. O M- VD Ü
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VO p m SC CO I.
in H I.
VD SC O υ SC I.
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27UA37

U VO _ C- VO OO VO OO I. I. • I. CM I. I. co vo I. in SC σ \ ι SC. Φ VO co t ^ O\ * ~ SC co C- VO OO ' ü xi σ » in
X O O CT \ O co υ O υ C- I O O Τ VD CM CM * ~ * ~ CM O Ph O BC I. O) N
co "~ CM CM CM O ■ sr (O r X SC SC m ^ra O Q) CM rH H O) Q) Φ Q) SC Q) U) α> ι Ο) CM φ Q) N. O CJ IO (O SC IO CO VD Q) U) (O CO IO X to co SC SC
CM <0 (O co * ö (O O CO (O pq η O (O η SC pq pq X PP pq I. Π) pq pq I CM pq pq pq Q)
co CM CJ CJ PP U «J O <3 m Il vo W. X ^ - SC CM O ac as ι VD in ac SC VO X X I. VO SC VD VD! O SC VO Ü O VD CO O VO O O " I. VO υ I. Ü CM I. CJ I I in in in in in CJ I. iH I. K CM U. U ι SC S3 K ac X I. O O O Dl. i «] V- VO VO VO VO vo «R I. I. I. a υ O O CJ CJ Vj ' ^ CV (H & SC •H •H co I. VD ic Ό Ό SC co in CJ
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as CM in
ac in
X in O Il VO I.
-st- VD « SC VO VO VO I. I.
co "Γ CM vo Ü O I Ü O O CO ac CJ ac CJ CO CJ co CM * r? CO co CM co ι CM CM O ^ CM co CM X CM I CM CM CM CJ I. K CM X O as ι X X ac CM O SC CJ CJ j CJ CJ O O O ^^ I H X OS CJ CJ ac SC as * "^ I VO in X CM ^>
CO co ac co I.
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7098A2 / 0793

L. R ^{1 C} n ^H 2n Ar ¹ Ar ² Base or
salt F., ⁰ C. H H (CHg) ₄ 4-F-CgH ₄ 4-F-CgH ₄ 2 HCl.HpO 172.9 1/2 C ₂ H ₅ OH H H (CHg) ₃ ^C 6 ^H 5 3-Cl-CgH ₄ 3ase 112.7 H 7-Cl (CHg) ₃ ^C 6 ^H 5 ^C 6 ^H 5 base 196.9 ^C 6 ^H 5 5-Cl (CHg) ₃ ^C 6 ^H 5 ^C 6 ^H 5 2HCl.1 / 2HgO 184.2 H H (CHg) ₃ ^C 6H ₅ ^C 6 ^H 5 Base. HgO - 156.6

27UA37

Example 24 According to Example 23, the following compounds are produced:

1- ^ / 5- [4- / bis- (4- fluorophenyl) -methyl_7-1-piperazinyIj -propylZ-1,3-dihydro-2H-benzimidazol-2-one from mp 197.3 ° C by reacting 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzi! τπ.dazol-2-one-methanmit 1- ^ bis (4-fluorophenyl) methyl7-piperazine;

'1- [3 - / ^ - (diphenylmethyl) -1-piperazinyl7-propyl (1,3-dihydro ~ 3-methyl-2H-benzimidazol-2-on-dihydrüchlorid hydrate, mp 201.8 ⁰ C. Reaction of 1,3-dihydro-1- (3-iodopropyl) -3-methyl-2H-benzimidazol-2-one with 1- (diphenylmethyl) piperazine;

3-j3 - ^ - (Eiphenylmethyl) -1-piperazinyl7-pΓopylj-2 (3H) -benzothiazolone-dihydrochloride-hämihydraΐ of M. 186.1 ⁰ C by reaction of 3- (3-bromopropyl) -2 (3H) - benzothiazolone with 1- (dipheny] methyl) piperazine; and

3- £ 3- ^ ~ (Diphenylraethyl) -1-piperazinyl] 7-propylj-2 (3H) -benzoxazolone dihydrochloride of m.p. 212.4 ° C by reaction of 3- (3-chloropropyl ) -2 (3H) -bonzoxazolon with 1 - (] jipheny3 metliyl) -piperazine.

Example 25

A mixture of 6.95 parts of 1- (5-chloropentyl) -1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one, 5.15 parts of 1- (diphenylmethyl) piperazine, 5.30 parts of sodium carbonate, 0.1 part of potassium iodide and 160 parts of 4-methyl-2-pentanone are used a water separator is stirred overnight and heated under reflux. The reaction mixture is then brought to room temperature cooled and mixed with water. The phases are separated. The organic phase is dried, filtered and evaporated. The residue is 30 minutes with 12 parts of a Hydrochloric acid solution was stirred in 40 parts of ethanol and heated under reflux. The reaction mixture is then evaporated and the residue crystallized from ethanol. You get

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271U37

5 parts (46 percent of theory) ^/ l- [i5-A (diphenylmethyl) -1-piperazinyl_7-pentylj -1,3-dihydro-2H-benzimidazol-2-one dihydrochloride hydrate, melting at 215.3 ⁰ C.

The following connections are established in a corresponding manner:

- (CH ₀ V-:

Ar '

ii Ar ¹ Ar ² Base or
salt F., ⁰ C. 5 4-FC ₆ H ₄ 4 "FC ₆ H ₄ 2HCl.H ₂ O 203.7 4th ^C 6 ^H 5 4-FC ₆ H ₄ base 172.3 3 ^C 6 ^H 5 2-Cl-C ₆ H ₄ Base 149 3 3-Cl-C ₆ H ₄ 2-Cl-C ₆ H ₄ Base. H ₂ O 139.1 3 ^C 6 ^H 5 2,4-Cl ₂ - base 160.1 6th ^C 6 ^H 5 ^C 6 ^H 3
^C 6 ^H 5 base 189.7 6th ^ -FC ₆ H ₄ 4-FC ₆ H ₄ 2HCl 204.5

Example 26

A solution of 76 parts 1- | 3 - / ^ "- (Diphenylmethyl) -1-piperazinylT-propylj-1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one in 280 parts of ethanol, 120 parts of a hydrochloric acid solution and 250 parts of water are added while stirring. Then the reaction mixture is stirred for 30 minutes at room temperature. The product precipitated after cooling in an ice bath is filtered off, washed with 2-propanone and 2,2'-oxybispropane and dried. 43 parts (55 percent of theory) are obtained. / ^ - (DiphenyImethyl) -1-piperazinyl7-propylJ -1,3-dihydro-2H-benzimidazol-2-one dihydrochloride hydrate of 237.5 ° C.

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$ 4

The following compounds are produced in a corresponding manner

R ^{1 C} n ^H 2n Ar ¹ Ar ^{2 0} C H (CHg) ₃ 3-rypiainyl 4-Cl-CgH ₄ 160.2 H t ΓΊ3 \ 4-pyridinyl 4-F-CgH ₄ 183.2 H (CHg) ₃ 4-Cl-CgH ₄ 4-OCH-jC ^ H.
3 0 4 199.3 H (CHg) ₃ ^C 6 ^H 5 2-F-CgH ₄ 157.7 5-CH ₃ (CHg) ₃ ^C 6 ^H 5 ^C 6 ^H 5 178.3 6-CH (CHg) ₃ ^C 6 ^H 5 ^C 6 ^H 5 195.7 H CH ₃ -CH (CH ₃ ) - 4-F-CgH ₄ 4-FC ₆ H ₄ 176 CHg ■■

Example 2?

A mixture of 3.6 parts of N A 2- / 4- (diphenylmethyl) -1-piperazinyl7-äthylj-4- (trifluoromethyl) -1,2-benzenediamine and 1.8 parts of urea is 3 hours at 190 ⁰ C in a Stirred oil bath. The reaction mixture is then cooled and water and trichloromethane are added. The phases are then separated off. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95 ^ 5) as the eluent. The pure fractions are collected and the eluent is evaporated. 1.5 parts (4-1.5 percent of theory) 1- ^ 2-A- (diphenylmethyl) -1-piperazinyl-7-ethyl-1,3-dihydro-5- (trifluoromethyl) -2H-benzimidazole are obtained -2-on, mp 163.7 ° C.

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27UA37

The following connections are established in a corresponding manner:

1- [3- / 4- (phenylmethyl) -1-piperazinyl7'-propylj-1,3-dihydro-5- (trifluoromethyl) -2H-benzimidazol-2-one of 152.7 ° C and

5,6-DiChIOr-I-j 3- / 4- (diphenylmethyl) -1-piperazinylT-propylj-1,3-dihydro-2H-benzimidazol-2-one with a mp of 214.7 ° C.

Example 28

A mixture of 2.3 parts of 1-j 3- / 4 "- (diphenylmethyl) -1-piperazinyl_7-propylj-1, 3-dihydro-2H-frenzimidazol-2-one, 4.5 parts of a 40 percent formaldehyde solution and 45 parts N, N-Dimethylformainid is stirred for 2 hours and heated to 10O ⁰ C. Then the reaction mixture is cooled and diluted with water. the precipitated product is crystallized filtered and recrystallized from methylbenzene. After drying, 1.5 parts obtained (66 percent d. Th.) of 1- [3 - / ^ - (diphenylmethyl) -1-piperazinyl7-propylr -1, 3-dihydro-3- (hydroxyrnethyl) -2H-benzimidazol-2-one, mp 102.5 ⁰ C.

Example 29

A mixture of 1.55 parts Essigsäureanhydrdd, 3 parts of 1- / 3- / 4- (diphenylmethyl) -1-propyl piperazinyl_7 ^r (-1, 3-dihydro-2H-benzimidazol-2-one and 22.5 parts of methylbenzene The mixture is stirred overnight and heated under reflux. Water is then added to the reaction mixture. The phases are separated. The organic phase is dried, filtered and evaporated. The residue is column chromatographed on silica gel using a mixture of trichloromethane and methanol (95: 5 The pure fractions are collected and the eluent is evaporated to give 1.1 parts (33.5 percent of theory) of 1-acetyl-3- [3- / ZT- (diphenylmethyl) -1-piperazinyl7 -propylj-1,3-dihydro-2H-benzimidazol-2-one, mp 124.4 ° C.

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27UA37

Example 30

A mixture of 1.1 parts of ethyl 2-propenoate, 3 parts of 1- [3- ^ i- (Diphenylmethyl) -1-piperaziny27 ^r -propylj -1, 3-dihyd.ro-2H-benzimidazol-2-one, a few drops of a 40 per cent solution of Ν, Ν, Ν-Tiamethylbenzolmethanaminiumhydroxid in methanol and 25 parts of 1,4-dioxane is stirred for 2 ^l \ hours and heated under reflux. The reaction mixture is then evaporated. The residue is purified by column chromatography on silica gel using a mixture of trichloride and methanol (95 ^: 5) as ^an eluent. The pure fractions are collected and the eluent is evaporated. The residue is in 2-propanol and ethanol in the Hydrochloric! convicted. The salt is filtered off and dried. 1.4 parts (32.5 percent of theory) of ethyl 3- £ 3-A- (diphenylmethyl) -1-piperazinyl / ^r -propylj-2,3-dihydro-2-oxo-1H- are obtained l) enzimidazole-1-propanoate dihydrochloride dihydrate of F. 204 ⁰ C.

Example ⁷ / \

A mixture of 3 parts 1- {3- / 4- (Diphenylracthyl) - ^/ 1-piperazinyl7-propylj -1,3-dihydro-2H-benzimidazol-2-one, 1 part Jco cyanatomethane and 25 parts ji, 4-dioxane is stirred and refluxed overnight. The reaction mixture is then evaporated and the residue is purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5) as the eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2'-oxybispropane. 0.8 parts (23.5 percent of theory) 3- ^ 3 - / ^ - (Diphenylraethyl) -1-piperazinylJ7-propylj-2,3-dihydro-N-methyl-2-oxo-1H- are obtained benzimidazole-1-carboxamide, mp 153.1 ° C.

Example 32

A mixture of 9.4 parts of 1-i3- / 4- (diphenylmethyl) -1-piperazinyl_7-propylj-1,3-dihydro-2H-benzimidazol-2-one and 180 parts

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271U37

0.8 part of a 75 percent dispersion of sodium hydride is added to methylbenzene while stirring. The mixture is stirred for 60 minutes and heated to 90 ⁰ C. After cooling to 30 ⁰ C, 0.2 part of 2,3,11,12-dibenzo-i, added 4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene. The mixture is then stirred for a further 10 minutes. 4.2 parts of ethyl 2-bromoacetate are then added. The mixture is stirred and refluxed overnight. The reaction mixture is then ^{cooled to 90 °} C. and 50 parts of water are added. The phases are separated while hot. The organic phase is evaporated. 10 parts of ethyl 3- ^ 3- / 4- (diphenylmethyl) -1-piperazinyl-7-propylj -2, 3-dihydro-2 ~ oxo-1H-benzimidazole-1-acetate are obtained as a residue.

A mixture of 9.8 parts of ethyl I- [3- / 5- (diphenylmethyl) -1-piperazinyl_7-propyl I-2,3-dihydro-2-oxo-1H-benzimidazole-1-acetate, 1.2 parts of sodium hydroxide and I50 parts V / is stirred for 5 minutes and heated under reflux (■ (ater -. 8O ⁰ C) is then filtered off the reaction mixture and the filtrate acidified with acetic acid to pH 5.8 to 6 in this case, a tough forms. This precipitate is separated off and crystallized from ethanol and water. The product is then filtered off and ^{dried for 3 hours under reduced pressure at 100 °} C. 6 parts of 3- ^ 3- / 4 "- (diphenylmethyl) -1 are obtained -piperazinyl_7-propylj-2,3-dihydro-2-oxo-1H-benzimidazol-1-essigsäurehämihydrat, mp 138.7 ⁰ C.

Example 33

A mixture of 5 ₅ 2 parts 1, 3-dihydro ~ 1- / 3 ~ - (1-piperazinyl) -propyl7-2H-benzimidazol-2-one, 5 »28 parts 2- (chlorophenylroethyl) -pyridine hydrochloride, 5 "3 parts of sodium carbonate and 90 parts of N, N-dimethylformamide is stirred overnight and heated to 5O ⁰ C. The reaction mixture is then cooled and poured onto ice water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. Of the

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The residue is made from a mixture of 4 ~ methyl-2-pentanone and 2,2'-Oxybispropane crystallizes. The product is filtered off and dried. 2 parts (23.4 percent of theory) of 1,3-dihydro-1- / 3- {4 - / ^ henyl- (2-pyridinyl) -niethyl7-1-piiierazinylj- are obtained propyl7-2H-benzimidazol-2-one of F. 14-1

nor

The following compounds are produced in a corresponding manner

(CH ₂ ) ₃ -N

N-CH

Ar

Ar

Ar ¹ Ar ² F., oc 3-pyridinyl 4-FC ₆ H ₄ 154.1 3 ~ pyridinyl ^C 6 ^H 5 162.6 4-FC ₆ H ₄ 4-CH ₃ -C ₆ H ₄ 147.8 4-Cl-C ₆ H ₄ 4-Cl-C ₆ H ₄ 209.5 4-FC ₆ H ₄ 2,4-Cl ₂ -C ₆ H ₃ 160.1 ^C 6 ^H 5 2,3- (CH ₃ ) ₂ - 169.8 ^C 6 ^H 3 3-CF ₃ -C ₆ H ₄ 4-OCH ₃ -C ₆ H ₄ 153.4 ^C 6 ^H 5 4-CH ₃ -C ₆ H ₄ 178.3 ^C 6 ^H 5 2 _t 4- (CH ₃ ) ₂ - 115.8 • ^C 6 ^H 3 ^C 6 ^H 5 2,5- (CH ₃ ) ₂ - 156.3 . ^C 6 ^H 3

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271U37

Example 3 ^

A mixture of 4-, 9 parts of 1- (3-chloropropyl) -1H-benzimidazole, 5.76 parts of 1- / BIs - (^ - fluorophenyl) -inethyl_7-piperazine, 5.3 parts of sodium carbonate, 0.1 part of potassium iodide and 200 parts of 4-methyl-2-pentanone are stirred and refluxed for 20 hours using a water separator. The reaction mixture is then cooled and water is added. The phases are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentarione and 2,2'-oxybispropane. The product is filtered off and dried. 5 »5 parts (59.3 percent of theory) 1 -β- £ 4 - / sis- (4-fluorophenyl) -methyl / -1-piperazinylj-propylT-IH-benzimidazole hydrate from F. 10Ö, 4 ° C.

The following connections are established in a corresponding manner:

N ^ N-CH ^ -N ^ Yc

7098A2 / 0793

271U37

Γ) CM co σ » a ΙΛ σ> CO co σ \ CvI co ΙΛ co I I. : »Ο a CV? O cT CO co σ \ CO CM CM O I. C.
O O a co CO 0Λ CM σ » CO O ο oa CMl O a co Φ I .a O ω I rHO CM CM O (O I pi (U OCM Φ Φ Φ CM OJ Φ FQ I 4) in a'N «^ cn in in cn in Ti S. CO T- IO Hi ιΰ » to IO O PQ FQ H rH PQ PP O O O OJ N a * a «Η Γ-j VO co co co a ι iö ro O VD I PQCO I. O I - I I i O a H 1 I. VD O I ΙΛ co O I I CM a ΙΛ ΙΛ ΙΛ ΙΛ ΙΛ ΙΛ ΙΛ Jf * I. ^ ι a a a a a a fc. ΙΛ I Ü VO νο VD VD VO VD VD VD I. Eu I ΙΛ O O O O O O O VD I a CO ΙΛ ΙΛ ΙΛ ΙΛ ΙΛ ΙΛ ΙΛ O I VO CM a a a a CO I υ a VD VD VD VO VD VD VO VD CM I CM O O O O O O O O O a ι CM CO co CM co CO CO CO CO ο ι a CM CAJ CM CM CM CM CM CM O a a a a a a O O O υ O O a H H a O O a ΙΛ a I.
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709842/0793

O U CM • 04 VD σ » CO co ** ■ - S3 CM SJ- CO CO IA IA 2 «- r-i
O t ο Q) te O VD for co VD SS CO ^ j- CO I I.
IA χί τ— CO co CM CM CM O O CM CO I IA ο υ V- CM CM τ- CM CM CM CM
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t \ te rc te
■ ο ο — ο CO co CM CM CO CO I te CM CM O- CM CM CM te CM CM CM! υ rc te CM as as S3 O te te te ι * - ' O O SS O O - ■ O O 3 ι ^> - ■ ^w O ¹ - ^{w 1} - * - ' I. as SS r-l
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IA S3 S3 - co IA IA co S3 te te as S3 O CM CM te SS SS υ O O

2I7UA37

709842/0793

M. H · ^C n ^H 2n Ar ¹ Ar ² Base or
Salt . ■ - F., ⁰ C. 5-Cl (CH ₂ J ₃ ^C 6 ^H 5 ^C 6 ^H 5 base 106.5 6-Cl (CH ₂ ) ₃ ^C 6 ^H 5 ^C 6 ^H 5 base 114.9 H (CH ₂ ) ₃ ^C 6 ^H 5 ^C 6 ^H 5 base 173.6 • H
• (CH ₂ ) ₃ ^C 6 ^H 5 3-Cl-C ₆ H ₄ 3HCl.2H ₂ O 182.9

- 27U437

Example 35

According to Example 34, by reacting 3- / 2- (methylthio) -IH-benzimidazol-i-ylZ-propyl-raethanesulfonate with 1- (diphenylmethyl) -piperazine 1- £ 3- / 4- (diphenylinethyl) - 1- piperazinyl_7-propylJ-2- (methylthio) ~ 1H-benzimidazole trihydrochloride hydrate produced 203.4 ⁰ C mp.

Example 36

A mixture of 4.37 parts of N- (2-aminophenyl) -4- (diphenylmethyl) -i-piperazinpropanamine hydrochloride, 33 parts of carbon disulfide, 2 parts of sodium carbonate and 40 parts of ethanol is stirred for 20 hours and heated under reflux. The reaction mixture is then evaporated and the residue is treated with water. The precipitate formed is filtered off, washed with water and dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. 2 parts (45.5 percent of theory) 1- ^ 3- / 4- (diphenylmethyl) -1-piperazinyl7-propylj-1,3-dihydro-2H-benzimidazole-2-thione from P. 181 are obtained, 8 ⁰ C.

Example 37

A mixture of 60 parts of N- (2-aminophenyl) -4- (diphenylmethyl) -1-piperazine propanamine, 20 parts of methyl (iminomethoxymethyl) carbamate, 42 parts of acetic acid and 450 parts of trichloromethane is stirred overnight and heated under reflux. The reaction mixture is then evaporated and the residue is dissolved in water touched. The water is decanted and the residue is taken up again in water. Then the mixture is diluted with Ammonia solution made alkaline. The product is then extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is column chromatographed on silica gel using a mixture of Purified trichloromethane and methanol (95: 5) as eluents. The pure fractions are collected and the eluent is collected is evaporated. The residue is made from a mixture of

709842/0793

_ 27U437

4-methyl-2-pentanone and 2,2'-oxybispropane crystallized. Obtained 1j5,5 parts of methyl - ^ / T / 3/4 "- (diphenyl methyl) -1--piperazinyl_7 propylj-1 H-benzimidazol-2-yl / -carbac at mp 137.8 ⁰ C. .

A mixture of 12 parts of methyl-A-j 3- / 3 "- (diphenylmethyl) -1-piperazinylT-propylj -1H-benz.imidazol-2-yl / carbainate, 60 parts concentrated hydrochloric acid and 80 parts of ethanol is stirred overnight and heated under reflux. The reaction mixture is then evaporated and the residue is treated with water. the The free base is released in the usual way with ammonia and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol. The product is filtered off and dried. 4.3 parts (40 percent of theory) of 1- [3-A- (diphenylmethyl) -1-piperazinyl-7-propylj-iH-benzimidazol-2-amine are obtained of 228.7 ° C.

A mixture of 10.7 parts of 1- [3- / 4- (diphenylmethyl) -1-piperazinyl_7-propylj-1H-benzimidazol-2-amine, 5.1 parts of acetic anhydride and 90 parts of methylbenzene are stirred for 5 hours and heated to reflux. The reaction mixture is then evaporated and the residue is stirred in water. Then it is made alkaline with ammonia. The product is made with trichloromethane extracted. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol. The product is filtered off and dried. 6.6 parts are obtained (56.5 percent of theory) N - ^ - £ 3-A- (Diphenylmethyl) -1-piperazinyl7 ~ propylj-1 ^ -dihydro ^ H-benzimidazole ^ -ylidene-acetamide from F. 143.3 ° C.

Example 38

A mixture of 13 parts of 1,3-dihydro-1- / 3 _ (- i_ _p ip _erazinyl ) _p _ro _ pyl7-2H-benzimidazol-2-one, 12.4 parts of 1,1 '- (bromomethylene) -bis- / b ~ enzol7, 6.6 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone are stirred overnight using a water separator and heated under reflux. After cooling down

709842/0793

- 27Η437

W.

Water is added at room temperature. The phases are separated. The organic phase is dried, filtered and evaporated. The residue is made from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol crystallized. 1- [3 - / ^ - (Diphenylmethyl) -1-piperazinyl-7-propyl-1,3-dihydro-2H-benzimidazol-2-one is obtained from 153 ° C.

Example 39

According to Example 38, the following compounds are prepared using equivalent amounts of the corresponding starting compounds:

1 - / ^ - jA- / Bis- (A-fluorophenyl) -methyl7-1-piperazinylj-ethyl / -1,3-dihydro-2H-benzimidazol-2-one hemihydrate the mp 131-5 ° C; 1-12- / 4- (Diphenylmethyl) -1-piperazinyl_7-ethylJ-1,3-dihydro-2H-benziinidazol-2-one with a temperature of 218 ° C and

1- / 3-14- / bis- (4 ~ fluorophenyl) -methyl7-1-piperazinylV-propyl / - i- t - - ^J __ /

1,3-dihydro-2H-benzimidazol-2-one, mp 198 ° C.

Example 40

A mixture of 4.8 parts of 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one, 6.1 parts of 4- (diphenylmethoxy) piperidine hydrochloride, 7.5 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight using a water separator. The reaction mixture is then cooled and mixed with water. The phases are separated. The 4-methyl-2-pentanone phase is dried, filtered and evaporated. The oily residue is column chromatographed on silica gel using a mixture of trichlorine than and 5 percent methanol as the eluent cleaned. The pure fractions are collected and the eluent is evaporated. The residue will be off 4-methyl-2-pentanone crystallizes. 4.2 parts (48 Percent of theory) 1- | 3 - / ^ - (Diphenylmethoxy) -1-piperidinyl7-propyl | -

709842/0793

271U37

1,3-dihydro-2H-benzimidazol-2-one of P. 149, 2 ° C.

The following compounds are produced in a corresponding manner

Ar

-N VO-CH

B. η Ar ¹ . Ar ² Base ~.
or
salt F-V
⁰ C ο '" 2 ^C 6 ^H 5 ^C 6 ^H 5 HCl 253.1 Il 3 4-F-CgH ₄ 4-F-CgH ₄ HCl 1/2
H ₂ O 167.2 • I 2 4-F-CgH ₄ 4-F-CgH ₄ HCl 1/2 251.4 H ₂ O η 4th ^C 6 ^H 5 ^C 6 ^H 5 base 152 3 ^C 6 ^H 5 ^C 6 ^H 5 base 110.2

709842/0793

Claims (18)

DIPL-CHEM. DR. VOLKER VOSSIUS PATENTANWALT 8? JiOr! CK'L: N Ge, SIEBEFtISTFiASSE P.O. BOX CS 07 67PHONE: (0 «9) 47 40 CABLE ADDRESS: BEN2OLPATENT MÖNCHEN TELEX 5-23453 VOPAT D - ν uZ: M 100 Case: JAB 208 JANSSEN PHARMACEUTICA NV Beerse, Belgium 271U37" Piperazine and piperidine derivatives, process for their production and Medicinal Preparations "Priority: April 2, 1976, V.St.A., No. 6-2,919 December 21, 1976, V.St.A., No. 753 062 claims 1. Piperazine and piperidine derivatives of the general formula I B-G H -N / A- (O) -CH-Ar η 2n ~ y / '"' m ι (D as well as their salts with acids, in aer 1 2
Ar and Ar are each independently a phenyl, substituted phenyl or pyridinyl radical, where 709842/0793 ORIGINAL INSPECTED 271U37 the substituted phenyl radical with 1 or 2 independent of one another Substituents from the group halogen atoms, Triluomethyl lower Substituted alkyl, lower alkoxy and nitro radicals m has the value 0 or 1, A Tl- and J ^ jDH-, means, with the proviso that if A is N-, m has the value 0 and if A is _JjDH-, m has the value 1, η is an integer from 2 to 6, with the proviso that when C Hp is a branched alkylene chain, at least 2 carbon atoms are present in the linear portion of the chain connecting B to the pipervidin or piperazine nitrogen atom , and B either
a) a radical of the general formula in the 1 2
R and R, independently of one another, each represent a hydrogen or halogen atom, a lower alkyl radical or the trifluoromethyl group and Y is an oxygen or sulfur atom or a substituted one Nitrogen atom of the formula J ^ N-L denotes, where L is a 709842/0793 271U37 Hydrogen atom, a lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl-lower-alkyl-, carboxy-lower-alkyl-, Phenyl, phenylmethyl, lower alkylaminocarbonyl, Denotes hydroxymethyl or lower alkenyl radical, or b) denotes a best of the general formula in the 1 2 R and R independently of one another each represent a hydrogen or halogen atom, a lower alkyl radical or the trifluoromethyl group means and M is a hydrogen atom, a lower alkyl, phenyl, Phenylmethyl, mercapto, lower alkylthio, amino, lower alkylcarbonylamino-, lower alkyloxycarbonylamino- or is a cycloalkyl radical having 3 to 6 carbon atoms. 2.13 - / ^ - phenylmethyl) -1-piperazinyl7 "-propyli -1,3-dihydro-2H-benzimidazol-2-one and its salts with acids. 3 · 1- / 3 * -) 4 - / ^ 5is- (4-f luophenyl) -methyl7-1-piperazinyl {-propyl7_ 1,3-dihydro-2H-benzimidazol-2-one and its salts with acids. 709842/0793 271U37 4. 1-A- [4- / bis- (4-fluorophenyl) -methyl7-1-piperazinylj-butyl7- 1, 3-dihydro-2H-benzimidazol-2-one and its salts with acids. 5. 1-f4- / 4- (Diphenymethyl) -1-piperazinyl7-butylj -1,5-dihydro-2H-benzimidazol-2-one and its salts with acids. 6. 1-J3 - / ^ - (Diplienylmethyl) ^-1-r piperazinyl7 -propylj -1H-benzimidazole and salts thereof with acids. 7. 1 - / ^ T-f 4- / T ^ -Fluorophenyl) -phenylmethyl7'-1-piperazinylj -butyl_7-iH-benzimidazole and its salts with acids. 8. 1- / ZT- [4- / bis- (4-fluorophenyl) -methyl_7-1-piperazinyl] -butyl / ⁷ -1H-benzimidazole and its salts with acids. 709842/0703 27U437 9. Process for the preparation of piperazine and piperidine derivatives of the general formula I. ir ² as well as their salts with acids, in the 1 2
Ar and Ar, independently of one another, each denote a phenyl, substituted phenyl or pyridinyl radical, the substituted phenyl radical having 1 or 2 mutually independent substituents from the group consisting of halogen atoms, Tr i fluorine thy lower Substituted alkyl, lower alkoxy and / and nitro radicals m has the value 0 or 1, A JS- and .CH-, means, with the proviso that if A "^ N- is, m has the value 0 and if A ^^ is CH, m has the value 1, η is an integer with a value from 2 to 6, with the proviso that when CH is a branched alkylene chain, at least 2 carbon atoms are present in the linear portion of the chain connecting B to the piperidine or piperazine nitrogen atom, and B either
a) a radical of the general formula 709842 / 07-3 27H437 in the 1 2 R and R independently of one another are each hydrogen or Halogen atom, a lower alkyl radical or the trifluoromethyl group means and Y is an oxygen or sulfur atom or a substituted one N-L denotes nitrogen atom of formula ^ __, where L is a Hydrogen atom, a lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl-lower-alkyl-, carboxy-lower-alkyl-, Denotes phenyl, phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl or lower alkenyl radical, or b) denotes a radical of the general formula in the 1 2 R and R, independently of one another, each denote a hydrogen or halogen atom, a lower alkyl radical or the trifluoromethyl group and
M is a hydrogen atom, a lower alkyl, phenyl, Phenylmethyl, mercapto, lower alkylthio, amino, 709842/0793 271U37 lower alkylcarbonylamino, lower alkyloxycarbonylamino or is a cycloalkyl radical with 3> to 6 carbon atoms, characterized in that one a) a corresponding reactive ester of the general formula B ¹ -C Ho -W η 2η in which B ^{1 has} the same meaning as B; but does not represent a 2-amino-IH-benzimidazol-i-yl radical of the general formula and W denotes a corresponding ester function derived from a corresponding alcohol, with a compound of the general formula III HN A- (O) -CH ^wm - (ΠΙ) preferably in the presence of an organic solvent which is inert during the reaction and an appropriate base at elevated temperatures to form a compound of the general formula I ' 709842/0793 271U37 Ar "• Ar ² (I ¹ ) b) a compound of the general formula I-b H-COO (lower alkyl) Ar (I-b) under hydrolytic conditions to a compound of the general formula I-a Ar Ar (I-a) decrboxylated or c) a compound of the general formula IV 709842/0793 H ₂ N _1n -CiT Ar ¹ , (IV) with a corresponding cyclizing agent per se customary processes to form a compound of general formula I-c or I-d R ¹ R ² (I-C) or Ar ¹ -CH
\ 2 subject to ring closure, where M ^{1 is} a hydrogen atom, 709842/0793 27U437 a lower alkyl, phenyl, phenylmethyl, mercapto, amino, lower alkyloxycarbonylamino or cycloalkyl radical means or d) a protective group P of a compound of the general formula V according to processes customary per se Ar ¹ Ar removed, whereby a compound of the general formula I-c Ar (I-c) arises, or e) a corresponding compound of the general formula I-a by customary processes for N-acylation to give a compound of the general formula I-e 709842/0793 271U37 NH-CO-- (lower-alkyl) (i-e) acylated or f) according to the usual procedures in connection with the general formula I-f Ar (I-i) a group L * - introduces, where L * is a lower alkyl, lower Alkylcarbonyl-, lower alkyloxycarbonyl-lower-alkyl-, Carboxy-lower-alkyl-, phenylmethyl-, lower alkylaminocarbonyl-, Hydroxymethyl or lower alkenyl radical means, with the proviso that the double bond in the lower The alkenyl radical is not in the α-position, or g) a compound of the general formula XVI 709842/0793 (XVI) 271U37 with a corresponding reactive ester of the general formula XVII W-CH (XVU) * where W has the above meaning, preferably in the presence of an organic which is inert during the reaction Solvent and a corresponding base at elevated temperatures to a compound of the general formula I-g Ar ¹ r H -N N-CH (I-g) condensed or h) a compound of the general formula I-h S- (lower alkyl) 709842/0793 271U37 proceeding according to conventional methods for S-alkylation of the corresponding -SH-substituted compound and if appropriate, the products prepared according to steps a) to h) are converted into the corresponding salts with acids. 10. The method according to claim 9, characterized in that 1-) 3 / 3- (diphenylmethyl) -1-piperazinyl_7-propylJ-1,3-dihydro-2H-benzimidazol-2-one by reacting 1_ (3_Chlorpropyl) -1,3-dihydro-2H-benzimidazol-2-one with 1- (Diphenylmethyl) -piperazine produces and optionally converted into a salt with an acid. 11. The method according to claim 9, characterized in that that 1- / 3- [4 - / ^ is- (4-fluorophenyl) -methyl7-1-piperazinyll-propyl7-1,3-dihydro-2H-benzimidazoi-2-one by reacting 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one methanesulfonate with 1 - / ^ is- (p-fluorophenyl) -methyl_7-piperazine and possibly converted into a salt. 12. The method according to claim 9, characterized in that 1 - / ^ - {4- / bis (4-fluorophenyl) -raethyl7-1-piperazinyljf-butyl7-1,3-dihydro-2H-benzimidazol-2-one by reacting 1- (4- chlorobutyl) -1,3-dihydro-2H-benzimidazol- 2-one with 1- ^ is- (p-fluorophenyl) -methyl7-piperazine and optionally converted into a salt with an acid. 709842/0793 27UA37 13. The method according to claim 9, characterized in that that 1- [4- / 5T- (diphenylmethyl) -1-piperazinyl7-butylj -1, 3-dihydro-2H-benzimidazol-2-one through Conversion of 1- (4-chlorobutyl) -1,3-dihydro-2H-benzimidazol-2-one with 1- (diphenylmethyl) piperazine and optionally converted into a salt with an acid. 14. The method according to claim 9, characterized in that 1-j3- / £ - (diphenylmethyl) -1-piperazinyl7-propylj-1H-benzimidazole by reacting 1- (3-chloropropyl) -1H-benzimidazole with 1- (diphenylmethyl) piperazine and optionally converted into a salt with an acid. 15. Method according to claim 9, characterized in that that 1- / 4- ^ 4- / J4-fluorophenyl) -phenylmethyl7-1-piperazinylj-butyl7-1H-benzimidazole by reacting 1- (4-chlorobutyl) -1H-benzimidazole with 1- / C4-fluorophenyl) -phenylmethyl_7-piperazine and optionally converted into a salt with an acid. 16. The method according to claim 9, characterized in that 1 -fö- \ 4- / bis (4-fluorophenyl) -methylT-i-piperazinylj-butylT-IH-benzimidazole by reaction of 1- (4-chlorobutyl) - 1H-benzimidazole with 1- / bis- (p-fluorophenyl) -methyl7-piperazine produces and, if necessary, converted into a salt with an acid. 709842/0793 27UA37 17. Medicinal preparations with an antihistamine effect or anti-anaphylactic agent, characterized in that it contains a compound as claimed in claim 1. 18. Medicinal preparations with an effect as antihistamine or Antianaphylactic, characterized by a content of 1-i3 - / ^ - (dipnenylmethyl) -1-pipera2inyl7-propylJ-1,3-dihydro-2H-benzimidazol-2-one or their pharmacologically acceptable salts with acids. 709842/0793