CH634317A5 - Process for preparing piperazine and piperidine derivatives - Google Patents

Description

634317

2nd

PATENT CLAIMS 1. Process for the preparation of piperazine and piperidine derivatives of the general formula I

/ ■ - '"V

B-C H_ -N A- (O) -CH-Ar1

11 2n v_y m J,

Ar

(I)

nylmethyl, mercapto, lower alkylthio, lower alkylcarbonylamino, lower alkyloxycarbonylamino or cycloalkyl radical having 3 to 6 carbon atoms, characterized in that a corresponding s reactive ester of the general formula

B-CnH2n-W

(II)

and their salts with acids,

in the

Ar1 and Ar2 independently of one another each represent a phenyl, substituted phenyl or pyridinyl radical, the substituted phenyl radical being substituted by 1 or 2 mutually independent substituents from the group halogen atoms, lower alkyl, lower alkoxy, trifluoromethyl and nitro radicals,

m has the value 0 or 1,

A J> N- and> CH-, with the proviso that if A r ^ = N-, m has the value 0 and if A> CH, m has the value 1,

n is an integer with a value from 2 to 6, with the proviso that when CnH2n is a branched alkylene chain, at least 2 carbon atoms are present in the linear portion of the chain that connects B to the pipidin or piperazine nitrogen atom, and B either a) a radical of the general formula in which

R1 and R2 independently of one another each represent a hydrogen or halogen atom, a lower alkyl radical or the trifluoromethyl group and

Y represents an oxygen or sulfur atom or a substituted nitrogen atom of the formula Zi ^ NL, where L represents a hydrogen atom, a lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl-lower-alkyl, carboxy-lower-alkyl, phenyl- , Phenylmethyl, lower alkylamino-carbonyl, hydroxymethyl or lower alkenyl radical, or b) a radical of the general formula in which

R 'and R2 independently of one another each represent a hydrogen or halogen atom, a lower alkyl radical or the trifluoromethyl group and

M is a hydrogen atom, a lower alkyl, phenyl, Phe

in which B has the meaning given above and W is a corresponding ester function derived from a corresponding alcohol, with a compound of the general formula III

15

'in

HN A- (O) -CH

\ _y

(III '

ÂP

2nd

reacted and, if necessary, the products produced are converted into the corresponding salts with acids.

2. The method according to claim 1, characterized in that the reaction takes place in the presence of an inert organic solvent in the reaction and a corresponding base at elevated temperatures.

3. The method according to claim 1 or 2, characterized

30 shows that l- {3- [4- (DiphenylmethyI) -l-piperazinyl] -propyl} -l, 3-dihydro-2H-benzimidazol-2-one by reacting l- (3-chloropropyl) -l , 3-dihydro-2H-benzimidazol-2-one with 1 - (diphenylmethyl) -piperazine and optionally converted into a salt with an acid.

4. The method according to claim 1 or 2, characterized in that l- [3- {4- [bis- (4-fluorophenyl) methyl] -l-piperazinyl} -propyl] -l, 3-dihydro-2H -benzimidazol-2-one by reacting 1,3-dihydro-l- (3-hydroxypropyl) -2H-benzimidazol-2-one-methanesulfonate with l- [bis- (p-fluoro-

40 phenyl) methyl] piperazine and optionally converted into a salt.

5. The method according to claim 1 or 2, characterized in that l- [4- {4- [bis- (4-fluorophenyl) methyl] -l-piperazinyl} -butyl] -1,3-dihydro-2H- benzimidazol-2-one

45 by reacting l- (4-chlorobutyl) -l, 3-dihydro-2H-benzimidazol-2-one with l- [bis- (p-fluorophenyl) methyl] piperazine and optionally in a salt with transferred to an acid.

6. The method according to claim 1 or 2, characterized

50 shows that 1 - {4- [4- (diphenylmethyl) -1 -piperazinyl] -butyl} -l, 3-dihydro-2H-benzimidazol-2-one is obtained by reacting l- (4-chlorobutyl) -l , 3-dihydro-2H-benzimidazol-2-one with l- (diphenylmethyl) piperazine and optionally converted into a salt with an acid.

55 7. The method according to claim 1 or 2, characterized in that l- {3- [4- (Diphenylmethyl) -l-piperazinyl] -propyl} -lH-benzimidazole by reaction of l- (3-chloropropyl) -lH-benzimidazole with l- (diphenylmethyl) -piperazine and optionally converted into a salt with an acid

60 leads.

8. The method according to claim 1 or 2, characterized in that l- [4- {4 - [(4-fluorophenyl) phenylmethyl] -l-piperazinyl} -butyl] -lH-benzimidazole by reaction of l- (4th -Chlorbutyl) -lH-benzimidazole with l - [(4-fluorophenyl) -

65 phenylmethylj-piperazine and optionally converted into a salt with an acid.

9. The method according to claim 1 or 2, characterized in that l- [4- {4- [bis- (4-fluorophenyl) methyl] -l-

3rd

634317

piperazinyl> -but 1] -1 H-benzimidazole by reacting l- (4-chlorobutyl) -l H-benzimidazole with l- [bis- (p-fluorophenyl) methyl] piperazine and optionally in a salt transferred with an acid.

lower alkyl, phenyl, phenylmethyl, lower alkylamino-carbonyl, hydroxymethyl or lower alkenyl radical, or b) a radical of the general formula

The object of the invention is a process for the preparation of piperazine and piperidine derivatives.

A number of l - [(heterocyclyl) alkyl] piperazines and 4- (diarylmethyl) piperazines and 4- (diarylmethoxy) piperidines substituted in the 1-position are known with valuable pharmacological properties. Such compounds are described in the following references: US Pat. No. 3,362,956,

U.S. Patent 3,472,854,

U.S. Patent 3,369,022,

U.S. Patent 3,882,271,

U.S. Patent 3,956,328 and C.A., Vol. 64 (1966), 3499e.

The process according to the invention for the preparation of piperazine and piperidine derivatives of the general formula I

t \, X 1

B-C H -N A- O) -CH-Ar n 2n \ ■ J m I

I 2

Ar

10th

R "R '

15 in

R1 and R2 each independently represent a hydrogen or halogen atom, a lower alkyl radical or the trifluoromethyl group and

M represents a hydrogen atom, a lower alkyl, phenyl, Phe-20 nylmethyl, mercapto, lower alkylthio, lower alkylcarbonylamino, lower alkyloxycarbonylamino or cycloalkyl radical having 3 to 6 carbon atoms, is characterized in that a corresponding reactive esters of the general formula

25th

(X)

B-CnH2n-W

(II)

and their salts with acids,

in the

Ar 'and Ar2 each independently represent a phenyl, substituted phenyl or pyridinyl radical, the substituted phenyl radical being substituted by 1 or 2 mutually independent substituents from the group halogen atoms, lower alkyl, lower alkoxy, trifluoromethyl and nitro radicals,

m has the value 0 or 1,

A 2iN-and XTH-, with the proviso that if A isN-, m has the value 0 and if A J> CH, m has the value 1,

n is an integer with a value from 2 to 6, with the proviso that when CnHin is a branched alkylene chain, there are at least 2 carbon atoms in the linear portion of the chain that connects B to the pipidin or piperazine nitrogen atom, and B either a) a radical of the general formula in which B has the meaning given above and W denotes a corresponding ester function derived from a corresponding alcohol, with a compound of the general formula III

r

Ar

35

in the

R1 and R2 each independently 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 nitrogen atom of the formula> N-L, where L is a hydrogen atom, a lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl-lower-alkyl, carboxy-

\ /

HN A- (0) -CH

(III)

40

reacted and, if necessary, the products produced are converted into the corresponding salts with acids.

The reaction is preferably carried out in the presence of an organic solvent which is inert in the reaction and a corresponding base at elevated temperatures.

The compounds which can be prepared according to the invention differ from the above compounds especially in the nature of the B-CnH2n group, which is present in the 1-position of the piperazine or piperidine residue, and / or by the nature of those in the 4-position of the Piperazine or piperidine residues present diarylmethyl or diarylme thoxy residues.

The term “lower alkyl radical” is understood to mean straight-chain or branched hydrocarbon radicals having 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 radical” means straight-chain or branched alkenyl radicals having 2 to 6 carbon 60 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 radical” means cyclic hydrocarbon radicals having 3 to 6 carbon atoms, for example the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

The term “CnH2n” means straight-chain or branched alkylene radicals with 2 to 6 carbon atoms, the min-

634317

4th

at least have 2 carbon atoms in the linear chain which connects the B group to the piperidine or piperazine nitrogen atom, for example the 1,2-ethanediyl, 1,3-propanediyl, 2-methyl-1,3-propanediyl, 1,4-butanediyl, 2-methyl-l, 4-butanediyl, 1,5-pentanediyl or 1,6-hexanediyl group.

The term "halogen atoms" generally means halogen atoms with an atomic weight of less than 127, i.e. Fluorine, chlorine, bromine or iodine atoms.

The compounds of the general formula I can be prepared according to the invention by using a corresponding reactive ester of the general formula II, in which n has the above meaning and B also has the above meaning, and in which W a corresponding reactive ester derived from a corresponding alcohol Represents ester-5 function, 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, Ar1 and Ar2 have the above meaning, according to the following reaction equation io :

Ar

"At*

/ ~ "\, x

HH A- (0) -CH

V-V »^ 2

>

(I)

(II)

(III)

20th

The above condensation reaction is preferably carried out in a corresponding organic solvent which is inert in the reaction. Examples of corresponding solvents are lower alkanols, such as methanol, ethanol, propanol and butanol, aromatic hydrocarbons, such as benzene, methylbenzene and dimethylbenzene,

Ethers such as 1,4-dioxane and l, l'-oxybispropane, ketones such as 4-methyl-2-pentanone, N, N-dimethylformamide and nitro-benzene. The addition of a corresponding 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 of a corresponding metal iodide, for example sodium or potassium iodide, can be added as a reaction accelerator. Slightly elevated temperatures are usually suitable for accelerating the reaction rate. The reaction is preferably carried out at the reflux temperature of the reaction mixture.

In the above and the reaction methods described below, the reaction products can be separated from the reaction mixture by conventional methods and, if appropriate, further purified. 25 The compounds of the general formula I in which B denotes a 2-amino-1H-benzimidazol-1-yl radical, i.e. the compounds of the general formula I-a can generally be readily obtained from the corresponding compounds of the general formula I in which B denotes a 2- (lower-alkyloxycar-30 bonylamino) -l H-benzimidazol-l-yl radical, i.e. from compounds of the general formula Ib, by decarboxylating the latter compounds 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.

NH — C00 (lower alkyl)

y

A— (0) —CH v r n 2n \ / m -s.

Ar

(r-b)

^ 2 Ar1

N ^^ ÏI-C H, -H A— (0) -Ca "

- '»2a \ / ^ 2

(I-a)

H + or OHES, it should be noted that if the radical B in the compound 6S is alkylcarbonylamino) -1 H-benzimidazole-1 -yl radical,

fertilize the general formula I or in the corresponding- these residues in the different explained below,

Intermediate products can be in a 2- (lower alkyloxycarta- tomeric forms:

bonylamino) -! H-benzimidazol-l-yl residue or a 2- (lower

634317

N-COO (not alkyl) "

Ü-

N-CO- (iai eder alkyl)

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

Compounds of the general formula Ic can generally also be obtained by ring-closing an appropriate intermediate of the general formula IV with an appropriate cyclizing agent, such as is used for the preparation of 1,3-dihydro-2H-benzimidazol-2-25 ones from 1,2- Benzene diamines are known per se, manufacture, y-ru. Corresponding cyclizing agents, which advantageously

/ \. . Urea can be used, for example,

N "/ ^ 'm" "' phosgene and alkali metal isocyanates. The cyclization reaction can be carried out according to conventional methods

, Ar

Ar

To be 30. For example, when urea is used as the cyclizing agent, compounds of the general formula I-c can easily be obtained by heating the reactants in the absence of a solvent with stirring.

35 The above implementation can be explained by the following reacts in R1, R2, m, n, A, Ar1 and Ar2, the above equation of meaning:

.1

(I-c)

naV / n-VW

- • Qa-ioi ^ -ch

:H

R

Ar

Ar

(IV)

Cyclizing agent

(I-c).

The compounds of the general formula I-c can also be prepared from compounds of the general formula V in the general formula

P-N

-Van

-i / V-

^ Ar1 (°) _- CH

Ar

R4-CH = C-

I.

R3

55

(V)

in which R1, R2, n, A, m, Ar1 and Ar2 have the above meaning and P represents a corresponding protective group by removing this protective group by methods which are customary per se. Examples of such protective groups are lower alkyloxycarbonyl radicals and substituted ethenyl radicals, where R3 and R4 can mean different groups and R3 preferably denotes a lower alkyl radical and R4 preferably denotes a hydrogen atom, a lower alkyl or phenyl radical.

60 If there is a lower alkyloxycarbonyl radical as a protective group, this can be easily removed, for example, by alkaline hydrolysis. If a substituted ethenyl radical is present as the protective group, it can be expediently removed by using the corresponding intermediate

65 product of the general formula V subject to acid hydrolysis. When performing acidic hydrolysis to remove the ethenyl group from the compound of general formula V, a number of protonic acids can be used

634317

6

can be used, including mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as acetic acid, propanoic acid and ethanedioic acid. Furthermore, the reaction can be carried out in an organic solvent which is inert to the reaction, as is used in such hydrolytic reactions. Examples of these are lower alkanols, such as methanol, ethanol and 2-propanol.

The compounds of the general formula I-d can generally be prepared by a process similar to that for the preparation of the compounds of the general formula I-c from a compound of the general formula IV

/ - \ Xkx

^ N ~ CnH2n ~ N \ / A "" (0} 2

or use an addition product thereof with an alkali metal bisulfite. If an aldehyde is used as the cyclizing agent, the reaction mixture can be mixed with an appropriate oxidizing agent, for example with nitrobenzene, mercury oxide, Cu (II) and Pb (II) salts or other customary oxidizing agents. The aldehyde itself can also serve as an oxidizing agent in excess.

If M1 is a mercapto radical, for example carbon disulfide, thiourea, thiophosgene or ammonium thiocyanate can be used as the cyclizing agent.

If M1 represents an amino group, the ring closure can be carried out in the presence of cyanamide or a metal salt thereof, preferably an alkali or alkaline earth metal salt, or with BrCN.

If M1 denotes a lower alkyloxycarbonylamino radical, it is possible, for example, to use corresponding compounds of the following general formulas as the cyclizing agent: lower alkyl (iminomethoxymethyl) carbamates of the general formula IX

25th

NH O

H3C-0-C-NH-C-0 (lower alkyl)

(IX)

(i-d)

in which R ', R2, n, A, m, Ar1 and Ar2 have the above meaning and M1 denotes a hydrogen atom, a lower alkyl, phenyl, phenylmethyl, mercapto, lower alkyloxycarbonylamino or cycloalkyl radical, by a compound of general formula IV with a corresponding cyclizing agent by conventional methods for the preparation of 1 H-benzimidazoles from 1,2-benzenediamines. Depending on the nature of M1 in the compounds of the general formula I-d, the following cyclizing agents can be used, for example:

When M1 represents a hydrogen atom, formic acid or a corresponding tri (alkyloxy) methane can be used as the cyclizing agent.

If M1 is a lower alkyl, phenyl, phenylmethyl or cycloalkyl radical, a carboxylic acid of the general formula VI

lower alkyl - [(lower alkoxycarbonylamino) -R6-thio) -methylene] carbamates of the general formula X

30 R6

!

OSO

Il I II

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

(X)

35

wherein R6 represents a hydrogen atom or a methyl group; Compounds of the general formula XI O

II

(lower alkyl) -0-C-N CS

(XI)

lower alkyl-lower alkyl carbamothioates of the general formula XII

45

R5-COOH

• (VI)

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

(XII)

in which R5 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 nitrii of this acid, or an imino ester of the general formula VII

and di-lower alkylcyanimidodicarbonates of the general formula XIII

HN = C

/

0- (lower alkyl)

O

[(lower alkyl) -0-C] 2N-CN

(XIII)

(vii)

55

The above cyclization reactions can be carried out according to conventional methods. Compounds of the general formula I-e in which R5 has the above meaning, or an aldehyde 60 of the general formula VIII

NH-C0-lower alkyl)

Ar

1

R5-C

1

/

\

O

(VIII)

H

î ^ iî-c h „-n '\ ~ (0) -ch n 2n \ __ y m \ Ai2

(I-e)

7

634317

can generally also be prepared by acylation of a corresponding 2-amino-1H-benzimidazol-l-yl derivative of the general formula Ia by customary N-acylation processes, for example by reacting a compound of the general formula Ia with a corresponding lower alkylcarbonyl halide or acid anhydride derived from a lower alkyl carboxylic acid.

Compounds of general formula I-f general formula III has been described. In order to accelerate the reaction rate, in some cases small amounts of a corresponding macrocyclic polyether, such as 2,3,22,12-dibenzo-5 l, 4,7,10,13,16-hexaoxacyclooctadeca-2, l 1-diene, be added as a reaction accelerator.

If the group L1 to be introduced is a lower alkyloxycarbonylethyl radical, this introduction can also be carried out by reacting the compound of the general formula I-c with io a (lower alkyl) -2-propenoate of the general formula XV

.Ar

8 / V /

L1-r> CH, -S A- (O) -CH

a2B w 111

1 (lower alkyl) OOC-CH = CH2

(XV)

(I-f)

20th

25th

in which R1, R2, n, A, m, Ar1 and Ar2 have the meaning given above and L1 is a lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl-lower alkyl, carboxy-30 lower alkyl, phenylmethyl , lower alkylaminocar bonyl, hydroxymethyl or lower alkenyl radical, the double bond in the lower alkenyl radical not being in the a position, can generally be prepared by converting the radical L 'into a compound of the general formula Ic fi

HN'C> -C H-n

-N ^ \ -

Ar

(° VCH

Ar

40

45

(I-c)

introduces.

Depending on the nature of the L1 group to be introduced, the following procedures can be used:

When L1 is a lower alkyl, lower alkyloxycarbonyl-lower alkyl, phenylmethyl or lower alkenyl radical, i.e. is a radical denoted by L'a, the introduction of L'a into the compound of the general formula Ic can be carried out by reacting the latter compound with a corresponding reactive ester of the general formula XIV L'a-W, where L'a is the has the above meaning and W has the same meaning as in the starting compound of the general formula II, are carried out.

The condensation of a compound of the general formula XIV with a compound of the general formula I-c 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

50

be carried out.

This reaction is conveniently carried out in an organic solvent inert to the reaction, such as an aromatic 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 amine hydroxide, such as N, N, N- Triäthylbenzolmethanaminhydroxid, are carried out.

Compounds of the general formula If, in which L 'denotes a carboxy-lower-alkyl radical, can generally be easily removed from the corresponding lower-alkyloxycar bonyl-lower-alkyl-substituted compounds by hydrolysis in a conventional manner, for example using an aqueous Alkali compound, releasing the acid from the ester.

If L 'is a lower alkylcarbonyl radical, this group can conveniently be introduced by adding a compound of the general formula Ic to an appropriate acylating agent derived from a corresponding lower alkylcarboxylic acid, for example a halide, preferably the chloride, or an anhydride usual N-acylation processes.

If L1 is a lower alkylaminocarbonyl radical, this can generally be introduced by reacting a compound of the general formula Ic with a corresponding isocyanatoalkane in a corresponding organic solvent which is inert to the reaction, for example in an ether such as 1,1'-oxybisethane , 2,2'-oxy-bispropane or 1,4-dioxane.

If L 'is the hydroxymethyl group, the introduction of this group can conveniently be carried out by reacting a compound of the general formula I-c with formaldehyde in a corresponding organic solvent, such as N, N-dimethylformamide.

Compounds of general formula I-g

55

B-CnH2n - \ _ / -

Ar

"Ar

1

65

(I-g)

in which B, n, Ar1 and Ar2 have the above meaning can also be prepared by using a piperazine derivative of the general formula XVI with a corresponding reactive ester of the general formula XVII in which Ar1, Ar2 and W have the above meaning , under conditions similar to those described above for producing the connection

634317

8th

fertilizers of general formula I from compounds of general formula II and III have been described, condensed according to the following reaction equation:

r ~ \

3-C H9 -N NH

n 2n \ /

(XVI)

Compounds of the general formula I-h y

W-CH \

Ar

1

Link alkyl) / \

-CH.-n 2 n

■ N

A- (0) -CH ra

Ar

Ar

->

(i-g)

(l-h)

can also be expediently from the corresponding

Ar (XVII)

Prepare -SH-substituted derivatives by conventional methods 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 alkanol, e.g. Ethanol, propanol, 2-propanol or butanol.

A number of the intermediates of general formula II are known compounds, some of which are described in U.S. Patent Applications No. 597,793 of July 21, 1975 and 20 No. 620727 of October 8, 1975.

In general, these compounds can all be prepared by processes which are customary per se. Depending on the nature of B in these intermediates of general formula II, the following procedures can be used:

Intermediates of the general formula Il-a

> -CnK2n-W

(Il-a)

(XVIII) R1

50

can be produced as follows, for example:

A correspondingly substituted 2-chloronitrobenzene of the general formula XVIII is refluxed with a corresponding aminoalkanol of the general formula XIX in a corresponding organic solvent which is inert to the reaction, such as a lower alkanol, e.g.

Ethanol, propanol, 2-propanol or butanol implemented. The obtained [(2-nitrophenyl) amino] alkanol of the general formula XX is subjected to a reduction of the nitro group to the amino group, for example by catalytic hydrogenation using Raney nickel as a catalyst. The intermediate product of the general formula XXI obtained is then reacted with a corresponding cyclizing agent, as explained above for the preparation of the compounds of the general formula I-c from compounds of the general formula IV. The alcohol of the general formula XXII obtained is then converted into the desired reactive ester of the general formula II-a by conventional methods. Halides are expediently prepared by reacting a compound of the general formula XXII with a corresponding halogenating agent, for example with sulfinyl chloride, sulfuryl chloride, phosphorus pentochloride, phosphorus pentabromide or phosphoryl chloride. If the reactive ester is an iodide, it is preferably obtained from the corresponding chloride or bromide by replacing the halogen with iodine. Other reactive esters, such as methanesulfonates and 4-methylbenzenesulfonates, are obtained by reacting the alcohol with a corresponding sulfonyl halide, for example methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride. The above reactions are illustrated by the reaction scheme below:

+

H2N-CnH2 "-OH

(XIX)

9

634317

y, / H-Van "015

Hh / RaNi

(XX)

¥ \ / NH-Van-03

Ring closure

M-c ^ -on

Formation of a reactive ester

> (Il-a)

(XXII)

The intermediates of the general formula II-a can also be prepared, for example, in the following way:

I) A compound of the general formula XXIII, in which RJ and R4 have the meaning given above, is reacted by conventional N-alkylation processes with a haloalkanol of the general formula XXIV to give an alcohol of the general formula XXV.

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

III) The substituted ethenyl group of the compound of the general formula XXVI obtained in this way is, as described above for the preparation of compounds of the general formula I-c from compounds of the general formula V, removed by acid hydrolysis.

The introduction of the hydroxyalkyl chain into 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 ether function of the intermediate product of the general formula XXVIII formed is usually hydrolytically split, 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, for example, by adding a compound of the general formula XXIII to an equivalent amount of a corresponding dihaloalkane of the general formula XXIX in 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 N, N, N-triethylbenzene methanaminium chloride. This produces an intermediate of the general formula XXVI-a, the substituted ethenyl group of which is then removed, for example by acid hydrolysis, to form the desired halide of the general formula II-a-1.

It should be noted that the same procedure can normally also be used if the substituted ethenyl group has been replaced by another corresponding protective group. It is advisable to remove this 65 protective group according to the appropriate procedures adapted to the special protective group.

The above reactions can be illustrated by the reaction scheme below:

r4-ch = c - ^ c \ h k3 // \

Halogen-CnHhn-OH (XXIV)

S

-C ,, l3W-C «" - 0H «

1 2 R 'R

(XXV)

^ Formation of the reactive ester

H0 -W

i3H

'n 2n

H

A 2

R 'R

(XXVI)

R1 R2

R

(XXIII)

^ i0-Cn "2n-0-r °")

v [/ (XXVII)

0

"C! T ^" CnI'2n_0tD

Halogen-CnH2n-Halogen (XXIX)

H5 ~ Halogen y a \ / n

R

1 ■ 2 R R

(XXVIII)

(Il-a)

(xxvi-a)

8K

HN ^ C ^> - CnH2n- halogen

R 'R

(II-a-1)

11

634317

Intermediates of the general formula Il-b

-cnH2n-w

M [

(IX ~ b)

E 'E'

in which R1, R2, n and W have the above meaning and L2 is a lower alkyl, lower alkenyl, lower alkyl-oxy-carbonyl-lower-alkyl, phenyl, phenylmethyl or lower alkylaminocarbonyl radical, can be conveniently prepared by converting the reactive ester side chain into a starting compound of the general formula XXX

{n-d)

10th

with the exception of compounds in which M represents a mer capto or lower alkylthio group, are expediently prepared by converting the reactive ester side chain into a starting compound of the general formula XXXI

. r

20th

(XXX)

25th

(XXXI)

by methods similar to those described above for the preparation of the intermediates of the general formula XXVI starting from compounds of the general formula XXIII.

Intermediates of the general formula II-c

30th

introduces. The introduction of the CnH2n-W residue can be carried out by methods similar to those described above for the introduction of this group into starting compounds of the general formula XXIII.

Intermediates of the general formula Il-e

35

HIGH

Van "«

(II-c)

ir-cy ^ -w

(II-e)

can generally be fertilized from the corresponding compound of the general formula II-a by hydroxymethyl in which R1, R2, M1, n and W have the meaning given above, 45 can be prepared, for example, by adding an appropriate alcohol of the general formula XXI to the subject described above to the ring closure with an appropriate cyclizing agent. Subsequently, the hydroxyl group of the intermediate product of the general formula obtained in this way with formaldehyde, which is obtained in this way, is normally converted into a reactive ester group by the intermediate product of the general formula II-d XXXII.

(XXI) cyclization

7

H5 -OH n 2ri

Formation of the reactive ester

(H-e)

(XXXII)

634317

12

Intermediates of the general formula Il-f

S- (lower alky1)

CnHan-w

R R '

(Il-f)

can be conveniently prepared by S-alkylating with a corresponding halogen-lower alkane, a corresponding intermediate of the general formula and then the hydroxyl group

XXXII, in which M1 denotes a mercapto group (XXXII-a), compound of the general formula obtained in this way is converted into a reactive ester group by conventional S-alkylation processes, for example XXXIII.

SH!

n 2n

S- (lower-alkyl)

N ^> - CnH2n0H

S-alkylation

(XXXII-a)

R 'R

(XXXIII)

Formation of the reactive ester

(ii-D

Intermediate product of the general formula Il-g

NH-CO- (ai eder-alkyl) H0 -W

n 2n

(xi-g)

can be conveniently by N-acylation of the corresponding amino compound of the general formula II-h

NILE

"nn2n-W

(n-h)

according to conventional methods, for example genid or with an anhydride derived from a corresponding lower one by reacting the compound of the general formula alkyl carboxylic acid.

Il-h with a corresponding lower alkylcarbonylhalo- The intermediates of general formula IV

13

for example 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 of the nitro group of the intermediate product of the general formula s obtained

XXXV to an amino group according to the usual Ver

(XXXIV)

634317

drive to the reduction of nitro groups to amino groups, for example by reacting the nitro compound with nascent hydrogen or by catalytic hydrogenation in the presence of a corresponding catalyst, for example Raney nickel.

+ (HI)

NH-CnH2a "H ^ A" (0) »" CH

\ /

'm

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 the starting product, can generally be easily prepared from an alcohol of the general formula XX by converting the hydroxyl group into a reactive ester group in accordance with the conventional manner described above

Establish process.

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

(m)

(V)

(XXXVI)

The reactive esters of the general formula XXXVI, which are used as starting materials, can normally be prepared by converting the CnH2nW radical into a starting compound of the general formula XXXVII

P-tf

(XXXVII)

634317

14

according to the usual method described above.

The intermediates of the general formula XVI can generally 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. The protective group Q is usually removed from the intermediate of the general formula XXXIX formed by conventional methods, for example by catalytic hydrogenation using palladium-on-carbon if Q is phenylmethylgrappe or by alkaline hydrolysis if Q is a lower alkyloxycarbonyl group means.

(II)

HN N-Q

(XXXVIII)

(XXXIX)

Removal of Q

(XVI)

Intermediates of the general formula XVI-a

(XVI-a)

can generally also be prepared by reacting an intermediate product of the general formula XL and by binding the general formula XXXVI with a subsequent connection removal of the protective groups P and Q by applying the general formula XXXVIII to form a corresponding, conventional process.

(XXXVI) + (XXXVIII)

CK ^ -IT N-Q n 2n w

distance from

(XXXIX-a)

distance from

-► (XVI-a)

15

634317

Intermediates of the general formula III in which A denotes the radical J> N- 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 II I-a can be prepared, for example, by subjecting an appropriate aroyl halide to a Friedel-Crafts reaction with an appropriate arene and hydrogenating the Ar ', Ar2-methanone formed to the corresponding methanol in a conventional manner, for example with sodium borohydride. The latter compound is then normally converted into a reactive ester of the general formula XVII by customary processes for the preparation of reactive esters from alcohols.

The desired intermediates of the general formula III-a are then generally obtained by reacting the compound of the general formula XVII with piperazine.

5 intermediates of the general formula III, in which A denotes the radical ^ ÜCH- and m has the value 1 (IH-b), can expediently be prepared by adding a 4-piperidinol of the general formula XLI, in which Q is a corresponding, protective group defined above means

io O-alkylated with a corresponding reactive ester of the general formula XVII and then the protective group of the compound of the general formula XLII obtained is removed in a conventional manner.

W-CH

Ar

OH

\ Ar '

Q- / y ~ Q-CH ^

Ar

ArÄ

1

(XLI)

(XVII)

(XLII)

Removal of Q

Hl / ^ 0-

CH

Ar '

Ar

(Ill-b)

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

The compounds of the general formula I can be converted into salts with acids, in particular into therapeutically active, non-toxic salts, by treatment with appropriate acids. Examples of corresponding acids are inorganic acids, such as hydrohalic acids, for example hydrochloric acid and hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid,

and 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-dihydro -xybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenyl-2-propenoic acid, a-hydroxybenzene acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid and 4-amino-2-hydroxy-benzoic acid. The salts can be converted into the corresponding free bases, for example by treatment with alkalis.

The compounds of the general formula I and their pharmacologically tolerable salts with acids have, for example, a strong action as an anti-anaphylactic and an antihistamine and are therefore valuable active ingredients in human and veterinary medicine.

The valuable pharmacological properties of the compounds which can be prepared according to the invention are explained below:

40

45

50

55

65

A. Materials and Methods a) In vivo study of the antianaphylactic and antihistamine effects

Compounds of general formula I and their salts are examined in vivo in guinea pigs. Guinea pigs weighing 400 to 500 g are sensitized to ovalbumin by subplantar (s.p.) injection of 0.05 ml of antiserum into the left posterior portal. The animals are then left to starve and treated 24 hours after sensitization either with pure saline (= control animals) or with a special dose of the compound to be examined.

2 hours after the oral pretreatment, the animals are injected 50 g of histamine subplantarly into the right hind pate. The diameters of both hind paws are measured first before the histamine injection and again 10 minutes after the injection. 30 minutes after the histamine injection, the animals are injected intravenously All control animals develop typical primary symptoms of anaphylactic shock (cough, difficulty breathing and convulsions), 85 percent of the control animals die within 15 minutes after the ovalbumin injection and the survival of the animals is used as a criterion for a possible drug effect. The ED 50 value, that is the oral dose at which guinea pigs have 50 percent protection, is shown in the tables below.

The average histamine-induced paw edema in 200 control animals was 15 units 10 minutes after the histamine injection (one unit = 0.1 mm). Reactions below 10 units, which occur in less than 5 percent of the control animals, are considered an effective inhibitor of the

634 317 16

Histamine edema viewed in treated animals. The elixirs and solutions, or solid carriers, such as various oral doses, in which this inhibitory effect occurs, the types of starch, sugar, kaolin, lubricants, binders are also given in the tables below. and disintegrants, for the production of powders, pills, chapter b) in vitro antihistamine activity and tablets. Because of the ease of administration, guinea pig ileum strips are the most preferred at 37.5 ° C in s, tablets and capsules are the most preferred 100 ml Tyrode bath with a preload of 0.75 g form for oral administration, in which case suspended and gassed with 95 percent O2 and 5 percent CO2. naturally solid carriers are used. For parenteral preparations to be administered terally induced by histamine (0.5 mg / liter), the carrier consists of being recorded kymographically with an isotonic lever, which generally results in a 5-fold magnification from sterile at least for the most part. The change 10 water. However, other constituents can also contain an interaction between the compound to be investigated (5, for example substances which increase the solubility. Inji minutes of incubation time) and the agonist. Determinable solutions can be used, for example. In the tables below, the effective condensation of saline, glucose solution or a concentration in mg / liter of the individual compounds is made up of a mixture of saline and glucose solution as a carrier, with a significant inhibition (50 percent) of the 15. To produce injectable suspensions measured by histamine-induced contraction. Corresponding liquid carriers, Suspen-From the tests described above, diermittel and the like are preferably used. Salts of the compounds that the compound of the general formula I and general formula I with acids are, owing to their salts, which are pharmacologically acceptable in general, generally higher in water solubility than the bases for the manufacture of valuable antiallergic active ingredients in the systemic administration of aqueous preparations usually better suited to warm-blooded animals in cans of about 0.25 to about.

Represent 20 mg / kg body weight. It is particularly advantageous to use the aforementioned medicinal products.

The active substances which can be prepared according to the invention can be processed separately to form uniform doses for reasons of easy administration and the various pharmacological dosage forms,

be working. An effective amount of a unit dose is usually understood to mean physically discrete speaking compound in the form of the base or a salt.

with an acid with a pharmacologically acceptable certain amount of active ingredient, which is calculated so that

Carrier mixed thoroughly. Depending on the desired administration, the desired therapeutic effect in connection with the type of treatment, various carriers can be used. the necessary pharmacological carrier occurs.

The pharmaceutical preparations are preferably in unit doses. There are 30 examples of corresponding forms of unit doses which are suitable for oral or rectal administration or for tablets (including notched or coated parenteral injection. For the production of orally to tablets), capsules, pills, powder packs, wafers , inji-

In the case of preparations for administration, customary media, disposable solutions or suspensions, teaspoons and quantities can be used, for example water, glycols, oils and tablespoons as well as divided multiple packs

Alcohols for liquid preparations such as suspensions, syrups, 35 of them.

Table la

L R1 R2 CnHün R6 R7 base against oral histamine, anti-anaphylactic or salt effective effective dose in vitro guinea pig, mg / kg ion (ileum),

mg / liter survival histamine edema

H

H

H

(CH2) 2

H

H

base

0.01

0.63

1.25

H

■ 5-C1

H

(CH2) 2

H

H

base

0.01

0.63

1.25

H

H

6-C1

(CH2) 2

H

H

base

0.02

2.5

2.5

H

5 CFs

H

(CH2) 2

H

H

base

0.02

0.31

1.25

H

5-CHa

H

(CH2) 2

H

H

base

0.01

1.25

1.25

H

H

H

(CH2) 2

4-F

H

base

0.02

0.31

0.16

H

H

H

(CH2) 2

4-F

4-F

Base I / 2H2O

0.02

0.63

0.63

H

H

H

(CH2) 3

H

H

base

0.005

0.10

0.31

H

5-C1

H

(CH2) 3

H

H

base

0.01

0.63

1.25

H

5-CH3

H

(CH2>

H

H

base

0.01

0.08

0.16

H

H

6-C1

(CH2>

H

H

base

0.04

0.63

0.63

H

H

6-CH3

(CH2) 3

H

H

base

0.01

0.16

0.31

H

H

7-C1

(CH2) Î

H

H

base

0.08

^ 2.5

-

H

5-C1

6-C1

(CH2) 3

H

H

base

X0.16

2.5

2.5

17th

Table la (continued)

634317

L

R1

R2

CnH: "

R «

R '

Base or salt against histamine, oral, antianaphylactically effective an effective dose in vitro guinea pigs, mg / kg tion (ileum),

mg / liter survival histamine edema

H

5-cfa

H

(CH2) 3

H

H

base

0.02

0.31

0.31

CH2 = C-

l

H

H

(CH2) 3

H

H

base

0.01

0.16

0.31

1

ch3

C2H5-OOC-

H

H

(CH2) 3

H

H

2HC1.2H20

0.005

0.63

0.63

(CH2) 2-

C6H5-CH2

H

H

(CH2) 3

H

H

2 HCl

0.16

1.25

1.25

CH3-CO-

H

H

(CH2) 3

H

H

base

0.005

0.10

0.31

CHj-NH-CO-

-H

H

(CH2) 3

H

H

base

0.02

-

-

CH3-

H

H

(CH2) 3

H

H

2HCI.H2O

0.01

1.25

2.5

2-

h h

(CH2) 3

H

H

base

0.01

0.31

0.31

CsHs-

5-c1

H

(CH2) 3

H

H

2HCI.I / 2H2O

0.08

-

-

H

H

H

(CHZ) 3

4-f

H

base

0.01

0.31

0.31

H

H

H

(ch2) 3

4-c1

H

base

0.01

1.25

0.63

H

H

H

(ch2) 3

3-c1

H

base

0.01

0.63

1.25

h h

H

(ch2) 3

4-f

4-f

base

0.01

0.31

0.16

H

5-c1

H

(ch2) 3

4-f

4-f

base

0.04

1.25

1.25

H

H

6-c1

(ch2) 3

4-f

4-f

Base.H20

0.02

0.63

1.25

H

H

H

(ch2) 3

2-f

4-c1

base

0.02

0.31

1.25

H

H

H

(CH2) 4

H

H

base

0.01

0.16

0.31

H

H

H

(ch2) 4

4-f

4-f

2HCI.H2O

0.01

0.16

0.31

i / 2c2h5oh

h h

H

(ch2) 5

h h

2HCI.H2O

0.01

0.63

2.5

h h

H

(ch:) 5

4-f

4-f

2HCI.H2O

0.01

1.25

2.5

h h

H

(ch2) 6

h h

base

0.01

1.25

2.5

h h

H

-ch2-ch-ch2-

4-f

4-f

base

0.02

1.25

1.25

-U

h h

H

(ch2) 3

H

2-c1

base

0.08

-

-

H

H

H

• (ch2) 3

4-c1

4-c1

base

0.16

<2.5

<2.5

h h

H

(CH2) Ï

H

4-Br

base

0.16

<2.5

<2.5

h h

H

(ch2>

H

2-f

base

0.02

<2.5

<2.5

H

H

H

(ch2) 3

4-f

4-ch3

base

0.16

<2.5

<2.5

H

H

H

(ch2) 3

H

4-ch3

base

0.08

<2.5

<2.5

H

H

H

(ch2) 3

H

4-NO2

base

0.16

<2.5

<2.5

hooc-CH2

H

H

(ch2) 3

H

H

Base I / 2H2O

0.08

<2.5

<2.5

Table Ib

M

R1

cnh: n

R "

R7

Base or salt against histamine effective in vitro concentration (ileum), mg / liter oral, anti-anaphylactic dose in guinea pigs, mg / kg

Survival histamine edema h

H

(ch2) 2

h h

base

0.005

1.25

1.25

c2h5-

H

(ch2) 2

h h

3hc1.H20

à 0.16

-

-

h h

(ch2) 3

h h

base

0.0025

0.08

0.16

ch3-s-

H

(ch2) 3

h h

3hci.H2O

0.16

1.25

1.25

634317

18th

Table Ib (continued)

M

R '

CnH: n

R6

R '

Base or salt against histamine effective in vitro concentration (ileum), mg / liter oral, anti-anaphylactic dose in guinea pigs, mg / kg

Survival histamine edema

CHa

H

(CH2) J

H

H

base

0.02

2.5

2.5

CsHs-

H

(CH2) 3

H

H

base

0.08

-

-

HS-

H

(CH2) 3

H

H

base

0.01

0.63

1.25

Cyclohexyl

H

(CH2) 3

H

H

base

^ 0.16

2.5

2.5

C6H5-ch2-

H

(CH2) 3

H

H

3HC1.H20

ï-0.16

-

-

CH3OOC-NH-

H

(CH2) 3

H

H

base

^ 0.16

2.5

2.5

CH3-CO-NH-

H

(CH2) 3

H

H

base

^ 0.16

2.5

-

C2Hs-

H

(CH2) 3

H

H

3HC1.H20

0.01

2.5

2.5

Cyclohexyl

5-C1

(CH2) 3

H

H

base

-

0.63

2.5

C2H5-

5-CL

(CH2) 3

H

H

3HC1.H20

0.01

-

-

C6H5-ch2-

5-C1

(CH2) 3

H

H

3HC1.H20

-

2.5

-

CöHs-

6-C1

(CH2) 3

H

H

base

-

2.5

-

Cyclohexyl

6-C1

(CH2) 3

H

H

base

-

2.5

-

H

H

(CH2) 3

4-F

H

base

0.005

0.31

0.31

H

H

(CH2) 3

2-C1

H

3HC12H20

0.01

1.25

1.25

H

H

(CH2) 3

4-C1

H

base

0.01

0.08

0.31

H

H

(CH2>

4-F

4-F

Base H20

0.02

0.16

0.31

H

H

(CH2) 4

H

H

base

0.0025

0.16

0.16

cm

H

(CH2) 4

H

H

base

0.005

1.25

1.25

H

H

(CH2) 4

4-F

H

base

0.005

0.08

0.16

H

H

(CH2) 4

3-C1

H

3HCI.h2o

I / 2CH3-

CHOHCTh

0.01

1.25

1.25

H

H

(CH2>

4-F

4-F

base

0.005

0.31

0.31

H

H

CH2-CH (CH3) -

ch2

H

H

3HCI1 / 2H20

0.02

-

-

h h

CH2-CH (CH3) -

4-F

4-F

3HC11 / 2H20

0.02

0.63

1.25

C Hz

Base or salt against histamine effective in vitro concentration (ileum), mg / liter oral, anti-anaphylactic dose in guinea pigs, mg / kg survival histamine edema

S

O

2 HCl 2 HCl

1/2 HzO

0.01 0.01

1.25 0.63

1.25 2.5

19th

Table Id

634317

R

CnH: "

R6

Base or salt against histamine effective in vitro concentration (ileum), mg / liter oral, anti-anaphylactic dose in guinea pigs, mg / kg survival histamine edema

0 (CH2) 2H

HNC_X

ö

H

HCl

0.0025

0.31

0.16

HN rJ—

ö

(CH2) 3H

H

base

0.0025

0.63

1.25

ö

(CH2) 4H

H

base

0.005

0.63

0.31

0 (CH2) 2 4-F 4-F HCI.I / 2H2O 0.0025 0.31 0.31

IIN ^, N-

0 (CH2) 3 4-F 4-F HC1.1 / 2H20 0.0025 0.63 0.63

HN (^, N-

Ö

(CH2) 3 H H base 0.0025 0.16 0.16

634 317 20

Table le

Ar1 Ar2 base against histamine oral, antianaphylactic

or salt effective in vitro dose at sea

Piggy concentration, mg / kg

(Ileum), mg / liter survival histamine edema

CöHs 2-pyridinyl base 0.16-2.5

CeHs 3-pyridinyl base 0.08 - <2.5

CôHs 2.5- (CH3) 2-C6H3 base 0.16

4-C1-C6H4 3-pyridinyl base 0.08 1.25 2.5

4-F-CóH4 3-pyridinyl base 0.08 <2.5 <2.5

4-F-C6H4 4-pyridinyl base 0.16 - ^ 2.5

The examples illustrate the process according to the invention and the preparation of the starting materials. Unless otherwise stated, all parts are based on weight.

example 1

A mixture of 54 parts l, 3-dihydro-l- (phenylmethyl) -2H-benzimidazol-2-one, 47.25 parts l-bromo-3-chloropropane and 6 parts N, N, N-triethylbenzene methanaminium chloride is at 60 ° C dropwise with 450 parts of a 60 percent sodium hydroxide solution. After the addition has ended, the mixture is stirred at 60 ° C. for a further 6 hours. 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 been crystallized from 2,2'-oxybispropane and dried, 42 parts (58 percent of theory) of 1 - (3-chloropropyl) -1,3-dihydro-3- (phenylmethyl) -2H-benzimidazole- are obtained. 2-one.

The compounds listed below are prepared in a corresponding manner:

L

R '

n

Kp.

CH2 = C (CH3)

5-CH3

3rd

140 ° C / 0.015 Torr

CH2 = C (CH3)

6-CH3

3rd

140 ° C / 0.02 Torr

CsHs

5-C1

3rd

-

CH2 = C (CH3)

H

4th

-

CH2 = C (CH3)

H

5

-

CH2 = C (CH3)

H

6

-

25 Example 2

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

M

C "H:"

CH3 / \

(CH2) 3

(f)

(CH2) 3

C2H5

(CH2) 3

H

CH2-CH-CH2

1

1

CH3

CôHS

(CH2) 3

CH3

(CH2) 4

Example 3

ss A mixture of 20 parts of 3 - [(2-amino-4-chlorophenyl) amino] -1-propanol, 50 parts of acetic acid and 150 parts of a 4N hydrochloric acid solution is stirred overnight and heated under reflux. The reaction mixture is then cooled and evaporated. The residue is dissolved in 60 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 been crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, 6.5 65 parts (28 percent of theory) of 5-chloro-2-methyl-1 H -benzimidazole are obtained -1-propanol.

In a corresponding manner, by reaction of 3 - [(2-amino-4-chlorophenyl) amino] -l-propanol with propane

21st

634317

Acid 5-chloro-2-ethyl-1 H-benzimidazole-1-propanol produced.

Example 4

A mixture of 30 parts of 3 - [(2-amino-4-chlorophenyl) amino] -l-propanol and 0.1 part of 4-methylbenzenesulfonic acid in 405 parts of methylbenzene is added dropwise with stirring while under reflux (water separator) Solution of 34 parts of cyclohexane carboxaldehyde in 45 parts of methylbenzene. After the addition has ended, the mixture is stirred for a further hour at the reflux temperature using the water separator. The methylbenzene is then removed under reduced pressure and the residue is triturated with 2,2'-oxybispropane. The product is filtered off and dried. 16.5 parts (38 percent of theory) of 5-chloro-2-cyclohexyl-1 H-benzimidazole-1-propanol of melting point 95 ° C. are obtained.

Example 5

A mixture of 30 parts of 3 - [(2-amino-4-chlorophenyl) amino] -l-propanol, 44.8 parts of sodium a-hydroxybenzene ethanesulfonate and 120 parts of ethanol is stirred for 30 minutes and heated under reflux. 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. 45 parts (100 percent of theory) of 5-chloro-2- (phenylmethyl) -1 H-benzimidazole-1-propanol are obtained as a residue.

Similarly, by reacting 3 - [(2-amino-5-chlorophenyl) amino] -l-propanol with sodium a-hydroxycyclohexane methanesulfonate, 6-chloro-2-cyclohexyl-1 H-benzimidazole-1-propanol of F. Made at 120.1 ° C.

Example 6

A mixture of 93 parts of 3- (2-aminophenyl) amino-l-propanol, 45.5 parts of potassium hydroxide and 600 parts of 85 percent aqueous ethanol is mixed dropwise 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. Then it is 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 (78.9 percent of theory) of 2-mercapto-1 H-benzimidazole-1-propanol of melting point 110 ° C. are obtained.

A mixture of 20.8 parts of 2-mercapto-1 H-benzimi-dazol-1-propanol, 15.62 parts of iodomethane and 120 parts of methanol is 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. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. 19 parts (85.5 percent of theory) of 2- (methylthió) -lH-benzimidazole-1-propanol are obtained as a residue.

A mixture of 19 parts of 2- (methylthio) -IH-benzimi-dazol-1-propanol, 15.2 parts of N, N-diethylethane amine and 195 parts of dichloromethane is added dropwise to benzene with stirring, 75 parts of 3-amino-1-propanol, 0.2 part of potassium iodide and 200 parts of butanol are 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

mixed with 11.5 parts of methanesulfonyl chloride. After the addition has ended, the mixture is stirred under reflux for a further hour. After cooling, water is added. The phases formed are separated. The organic phase s is dried, filtered and evaporated. 19 parts of 3- [2- (methylthio) -1 H-benzimidazol-1-yl] propyl methanesulfonate are obtained as an oily residue.

Example 7

io A mixture of 30 parts of 1 H-benzimidazole, 49 parts of 2- (4-chlorobutoxy) tetrahydro-2H-pyran, 21 parts of potassium hydroxide and 200 parts of ethanol is stirred overnight and heated under reflux. The reaction mixture is then cooled to room temperature and filtered. The residue obtained after u evaporation of the filtrate is stirred in water and acidified with dilute hydrochloric acid. The mixture is then stirred and heated in a water bath for 30 minutes. After cooling to room temperature, the product is extracted with methylbenzene. The 20 aqueous phase is separated off and made alkaline with ammonia. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. 50 parts of 1 H-benzimidazole-1-butanol are obtained as an oily residue.

25th

Example 8

A mixture of 5 parts of 4-chloro-l, 3-dihydro-3- (3-hydro-xypropyl) -2H-benzimidazol-2-one and 75 parts of trichloromethane is mixed dropwise with 8 parts of sulfinyl-30 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-pen-tanone. The product is then filtered off and dried. 3.5 parts of 4-chloro-3- (3-chloropropyl) -1, 3-dihydro-2H-benzimidazol-2-one are obtained.

The following l- (chloroalkyl) -1 H-benzimidazoles are prepared in a corresponding manner:

40

45

50

60

65

M

—R

n

R '

Base or salt

F.

C6H5-CH2

3rd

5-C1

base

CH3

3rd

5-C1

base

-

C2H5 / —— \

3rd

5-C1

base

-

(iL)

3rd

5-C1

HCl

211.7 ° C

\ 1 1 *

C6H5-CH2

3rd

H

base

112 ° C

©

3rd

6-cl

HCl

227.5 ° C

\ ■■■ ■ /

C2H5

2nd

H

base

H

4th

H

base

634317

22

Example 9

A mixture of 113.2 parts l, 2,4-trichloro-5-nitro, 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 off. The residue is triturated with 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of 2,2'-oxybis propane and 2-propanol. 31.7 parts are obtained

3 - [(4,5-dichloro-2-nitrophenyl) amino] -1-propanol, mp 97 ° C.

The following connections are made in a corresponding manner:

3 - {[2-nitro-4- (trifluoromethyl) phenyl] amino} -1-propanol and

2 - {[2-Nitro-4- (trifluoromethyl) phenyl] amino} ethanol, mp 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-l-propanol and 225 parts of trichloromethane with stirring, the temperature rising to 45 ° C. under 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-nitrobenzene amine are obtained as a residue.

The following connections are made in a corresponding manner:

N- (3-chloropropyl) -2-nitro-4- (trifluoromethyl) -benzolamine as residue, 4,5-dichloro-N- (3-chloropropyl) -2-nitrobenzene-amine with melting point 78 ° C and N- (2-chloroethyl) -2-nitro-4- (trifluoromethyl) benzolamine.

Example 11

A mixture of 21.5 parts of N- (3-chloropropyl) -2-nitro-benzolamine, 22.68 parts of l- (diphenylmethyl) piperazine, 20 parts of N, N-diethylethanolamine and 180 parts of N, N-dime is thylacetamide Stirred for 6 hours and warmed to 100 ° 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'-Qxy-bispropane. The product is filtered off and dried. 15.5 parts (36.9 percent of theory) are obtained

4- (Diphenylmethyl) -N- (2-nitrophenyl) -1 -piperazinopropane-amine hydrochloride at F 228 ° C.

The following connections are made in a corresponding manner:

N- (4,5-dichloro-2-nitrophenyl) -4- (diphenylmethyl) -1-pipe-razinpropanamine as residue,

4- (Diphenylmethyl) -N- [2-nitro-4- (trifluoromethyl) -phenyl] -1-piperazinopropanamine, mp 113.7 ° C and

4- (DiphenyImethyI) -N- [2-nitro-4- (trifluoromethyl) phenyl] -1-piperazinethanolamine, mp 152.1 ° C.

Example 12

A mixture of 15 parts of 4- (diphenylmethyl) -N- (2-nitrophenyl) -l-piperazinpropanamine hydrochloride in 160 parts of methanol is hydrogenated at atmospheric 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'-oxybispropane. The product is filtered off and dried. 12 parts (78.9 percent of theory) of N-2-aminophenyl) -4- (diphenylmethyl) -1 -piperazinopropanamine hydrochloride, melting at 223.1 ° C., are obtained.

The following connections are made in a corresponding manner:

4,5-dichloro-N '- {3- [4- (diphenylmethyl) -l-piperazinyl] -propyl} -l, 2-benzenediamine as an oily residue,

N1- {3- [4- (diphenylmethyl) -l-piperazinyl] -propyl} ~ 4- (tri-fluoromethyl) -l, 2-benzenediamine and

N '- {2- [4- (Diphenylmethyl) -1 -piperazinyl] ethyl) ~ 4- (trifluoromethyl) -1, 2-benzenediamine as an oily residue.

Example 13

A mixture of 60.5 parts of l- (3-chloropropyl) -l, 3-dihydro-3- (l -methylethenyl) -2H-benzimidazol-2-one, 31.68 parts of l- (phenylmethyl) -piperazine, 21 , 2 parts of sodium carbonate, 0.1 part of potassium iodide and 400 parts of 4-methyl-2-pentanone are 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) of 1,3-dihydro-l- (l-methylethenyl) -3 - (3- [4- (phenylmethy {) - 1 -piperazinyI] -propyl} -2H- benzimi-dazol-2-one as residue.

In a corresponding manner, 1,3-dihydro-1 - {2- [4- (phenylmethyl) -1-piperazinyl] ethyl} -2H-benzimidazol-2-one of mp 136.5 ° C. is prepared.

Example 14

A mixture of 70 parts of 1,3-dihydro-l- (l-methylethen-yl) -3- {3- [4- (phenylmethyl) -l-piperazinyl] propyl) ~ 2H-benzimidazol-2-one in 240 parts of ethanol are mixed with 55 parts of 6N hydrochloric acid with stirring. The reaction mixture is then stirred at 40 to 50 ° C. for 2 hours 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 - {3- [4- (phenylmethyl) -1-piperazinyl] propyl) - 2H-benzimidazol-2-one are obtained as a residue.

Example 15

A mixture of 63 parts of 1,3-dihydro-l- {3- [4- (phenyl-methyl) -l -piperazinyl] -propyl) -2H-benzimidazol-2-one in 400 parts of methanol is at atmospheric pressure and at Room temperature hydrogenated with 10 parts 10% palladium-on-carbon as a catalyst. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off through a filter aid (Hyflo) and the filtrate is 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) of 1,3-dihydro-l- [3- (1-piperazinyl) propyl] -2H-benzimi-dazol-2-one of mp 157.5 ° are obtained C.

In a corresponding manner, 1,3-dihydro-l- [2- (l-piperazinyl) ethyl] -2H-benzimidazol-2-one with a melting point of 122.6 ° C. is prepared.

Example 16

20.5 parts of 2,4-dichlorobenzoyl chloride are added dropwise to a mixture of 20 parts of aluminum chloride and 100 parts of fluorobenzene with stirring. When the addition is complete, the mixture is heated to the reflux temperature and stirred under reflux for 5 minutes. The reaction mixture is then poured onto crushed ice. The product is extracted with 1,1'-oxybisethane. The extract is dried and evaporated. You get 30

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

23

634317

Parts (2,4-dichlorophenyl) - (4-fluorophenyl) methanone as an oily residue.

In a corresponding manner, (4-fluorophenyl) - (4-pyridinyl) -methanone of mp 85.5 ° C. is produced.

Example 17

A mixture of 23.4 parts of (4-chlorophenyl) - (2-fluoro-phenyl) -methanone in 280 parts of 2-propanol is added in portions with 3.7 parts of sodium borohydride. After the addition has ended, the mixture is stirred for a further 2 hours at the reflux temperature (± 80 ° C.). 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-a- (2-fluorophenyl) benzene-methanol are obtained as a residue.

The following connections are made in a corresponding manner:

2,4-dichloro-a- (4-fluorophenyl) benzene methanol as residue,

a- (4-fluorophenyl) -4-pyridinemethanol, melting point 138.2 ° C,

a- (4-fluorophenyl) -3-pyridinemethanol hydrochloride of mp 158.3 ° C and

4-methoxy-a- [3- (trifluoromethyl) phenyl] benzene methanol as residue.

Example 18

A mixture of 22 parts of 2,4-dichloro-a- (4-fluorophenyl) benzene methanol and 240 parts of 12N 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. 13.2 parts of 2,4-dichloro-1- [chloro- (4-fluorophenyl) methyl] benzene, having a boiling point of 146 ° C./0.15 Torr, are obtained.

The following connections are made in a corresponding manner:

l - [(x-chloro-a- (4-methoxyphenyl) methyl] -3- (trifluoromethyl) benzene as residue and

1 - [Chloro (4-methylphenyl) methyl] -4-fluorobenzene as a residue.

Example 19

A mixture of 23.6 parts of 4-chloro-a- (2-fluorophenyl) benzene-methanol in 108 parts of benzene is added dropwise with 24 parts of sulfinyl chloride. After the addition has ended, the reaction mixture is heated to the reflux temperature and then stirred for 5 hours at the reflux temperature and then overnight at room temperature. The benzene is then evaporated off and the residue is distilled. 16.5 parts of l-chloro-4- [a-chloro-a- (2-fluorophenyl) methyl] benzene, bp 122 to 125 ° C./0.1 torr, are obtained.

The following connections are made in a corresponding manner:

3- [a-chloro-a- (4-fluorophenyl) methyl] pyridine hydrochloride as an oily residue,

3- [a-chloro-a- (4-chlorophenyl) methyl] pyridine hydrochloride as residue,

4- [a-chloro-a- (4-fluorophenyl) methyl] pyridine hydrochloride, melting point 198 to 200 ° C.,

1 - (chlorophenylmethyl) -2,3-dimethylbenzene, bp 137 ° C / 0.7 Torr,

1 - (chlorophenylmethyl) -2,4-dimethylbenzene, bp 137 ° C / 0.7 Torr,

2- (chlorophenylmethyl) -1,4-dimethylbenzene from

Bp. 136 ° C / 0.7 torr and l- (chlorophenylmethyl) -2-fluorobenzene of bp. 108 to 109 ° C / 0.4 torr.

5 Example 20

A mixture of 121 parts of piperazine, 54 parts of 3- [a-chloro-a- (4-chlorophenyi) methyl] pyridine hydrochloride and 315 parts of N, N-dimethylformamide is stirred at room temperature for 20 hours. 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% acetic acid solution. The acidic aqueous phase is made alkaline with a 60 percent sodium hydroxide solution. The product is then extracted again with methylbenzene. 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. 48 parts of l- [a- (4-chlorophenyl) -a- (3-pyridinyl) methyl] piperazine trinitrate of mp 132.9 ° C. are obtained.

The following connections are made in a corresponding manner:

25th

l- [a- (4-chlorophenyl) -a- (2-fluorophenyl) methyl] piperazine, 1 - [a- (4-fluorophenyl) -a- (4-pyridinyl) methyl] piperazine from F. 108.4 ° C,

l - [(2-chlorophenyl) - (3-chlorophenyl) methyl] piperazine, 30 l - [(2-fluorophenyl) phenylmethyl] piperazine ethaneioate (1: 1), mp 195.5 ° C,

l - [(4-fluorophenyl) - (4-methoxyphenyl) methyl] piperazine ethaneioate (1: 2), mp 280.1 ° C and l - [(4-nitrophenyl) phenylmethyl] piperazine dihydrochloride .

35

Example 21

A mixture of 21.5 parts of ethyl 4-hydroxy-l-piperidine carboxylate, 35.2 parts of bis (4-fluorophenyl) bromoethane and 8.6 parts of potassium carbonate is stirred for 3 hours and in an oil bath at 140 ° C warmed. The reaction mixture is then cooled to room temperature and water is added. The product is extracted with methylbenzene. The extract is washed successively with water, dilute hydrochloric acid and sodium bicarbonate solution, dried, filtered and evaporated. After distilling off a first run to the point of 143 ° C./0.5 to 1 torr, 29 parts of ethyl 4- [bis- (4-fluorophenyl) methoxy] -1-piperidincarboxylate are obtained as an oily residue.

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

50

60

65

Example 22

A mixture of 29 parts of ethyl 4- [bis- (4-fluorophenyl) methoxy] l-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 (78 percent of theory) of 4- [bis- (4-fluorophenyl) methoxy] piperidine hydrochloride, melting point 161.8 ° C., are obtained.

In a corresponding manner, 4- (diphenylmethoxy) -pipe-ridine hydrochloride with a melting point of 209.8 ° C. is produced.

634317

24th

Example 23

A mixture of 5.3 parts of l- (3-chloropropyl) -l, 3-dihydro-2H-benzimidazol-2-one, 5 parts of l- (diphenyl-methyl) -piperazine, 6.4 parts of sodium carbonate and 200 parts of 4 -Methyl-2-pentanone is stirred using a water separator overnight and heated under reflux. After cooling, water is added. The phases are separated. The 4-methyl-2-pentanone phase is dried, filtered and evaporated. The 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. The eluent is evaporated. The oily residue is crystallized from a mixture of 2,2'-oxy-bispropane and a small amount of 2-propanol. The product is filtered off and dried. 2 parts (23 percent of theory) of l- {3- [4- (diphenylmethyl) -l-pipe-razinyl] -propyl} -l, 3-dihydro-2H-benzimidazol-2-one of F are obtained 153.6 ° C.

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

C, H: "

Ar1

Ar3

Base or salt

F., ° C

H

5-CI

(CH2) 3

CôHs

CôHs

base

175

H

6-C1

(CH2) 3

CôHs

CôHs

base

206.1

H

H

(CH2) 2

4-F-CôH4

4-F-CôH4

Base 1/2 H2O

132

H

H

(CH2) 2

CôHs

4-F-C6H4

base

172.4

H

5-CH3

(CH2) 2

CôHs

CôHs

base

214.6

CH2 =

= C (CH3)

H

(CH2) 3

CôHs

CôHs

base

-

CH2 =

= C (CHa)

5-CH3

(CH2) 3

CôHs

CôHs

base

-

CH2 =

= C (CHj)

6-CH3

(CH2) 3

C6H5

CôHs

base

-

H

H

(CH2) 2

CôHs

CôHs

base

218

H

H

(CH2) 3

CôHs

4-F-CÔH4

base

153.6

H

H

(CH2) 3

CôHs

4-C1-CôH4

base

180.2

H

H

(CH2) 3

4-CL-CôH4

2-F-C0H4

base

136

H

5-C1

(CH2) 3

4-F-CôH4

4-F-C0H4

base

205.8

H

6-C1

(CH2) 3

4-F-CôH4

4-F-C0H4

Base - H2O

132.9

H

H

(CH2) 4

CôHs

CôHs

base

196.6

H

6-C1

(CH2) 2

GHs

CôHs

base

204.1

H

5-C1

(CH2) 2

C6H5

CôHs

base

203.6

H

H

(CH2) 4

CôHs

CôHs

Base 1/2 H2O

197.8

CôHs-

-CH2

H

(CH2) 3

CôHs

CôHs

2 HCl

199.6

H

H

(CH2) 4

4-F-CeH4

4-F-C0H4

2HC1-H2Û

184.4

ch2 =

= C (CHj)

H

CH2-CH (CH3) -CH2

4-F-CÔH4

4-F-CôH4

base

-

CH2 =

= C (CH3)

H

(CH2) 3

3-pyridinyl

4-C1-CôH4

base

-

ch2 =

= C (CH3)

H

(CH2) 3

4-pyridinyl

4-F-CôH4

base

-

CH; =

= C (CH3)

H

(CH2) 3

4-C1-C6H4

4-OCH3-CôH4

base

-

H

H

(CH2) 3

CeHs

4-NO2-C0H4

base

103.6

CH2 =

= C (CHj)

H

(CH2) 3

CsHs

2-F-CôH4

base

-

H

H

(CH2) 3

4-OCH3-C6H4

4-F-C0H4

base

157.4

H

H

(CH2) 3

CôHs

4-Br-CôH4

base

189.7

H

H

(CH2) 4

4-F-CöH4

4-F-C0H4

2 HCl * H2O

172.9

1/2 C2H5OH

H

H

(CH2) 3

Côhs

3-C1-CôH4

base

112.7

H

7-C1

(CHî) 3

CsHs

CôHs

base

196.9

CôHs

5-C1

(CH2) 3

Côhs

CôHs

2HC1-1 / 2 H2O

184.2

H

H

(CH2) 3

CsHs

CôHs

Base * H20

156.6

25th

634317

Example 24

The following compounds are prepared according to Example 23:

1 - [3- {4- [Bis- (4-fluorophenyl) methyl] -1 -piperazinyl} -propyl] -l, 3-dihydro-2H-benzimidazol-2-one, mp 197.3 ° C Reaction of 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one-mc.; An-sulfonate with l- [bis- (4-fluorophenyl) methylj-piperazine;

1 - {3- [4- (Diphenylmethyl) -1 -piperazinyl] -propyl} -1,3-dihydro-3-methyl-2H-benzimidazol-2-one dihydrochloride hydrate of mp 201.8 ° C Reaction of 1,3-dihydro-1- (3-iodopropyl) -3-methyl-2H-benzimidazol-2-one with l- (diphenylmethyl) piperazine;

3- {3- [4- (Dipheiiy.:ixethyl) -l-piperazinyl] -propyl} -2 (3H) -ben-zothiazolone-dihydrochloride hemihydrate of mp 186.1 ° C by reaction of 3- (3rd -Bromopropyl) -2 (3H) -benzothia-zolon with l- (diphenylmethyl) piperazine; and 3- {3- [4- (Diphenylmethyl) -1 -piperazinyl] propyl} -2 (3H) -benzoxazolone dihydrochloride, mp 212.4 ° C, by reaction 20 of 3- (3-chloropropyl) -2 (3H) -benzoxazolone with l- (diphenylmethyl) piperazine.

The following connections are made in a corresponding manner:

1

(CH2) n— / ~ Y

v_y s **

CH

\ ■ 2 ares

15

n

Ar '

Ar2

Base or salt

F., ° C

5

4-F-C "H4

4-F-COH4

2HC1-H20

203.7

4th

CôHs

4-F-C6H4

base

172.3

3rd

CôHs

2-C1-C6H4

base

149

3rd

3-Cl-C6H4

2-C1-C6H4

Base-mO

139.1

3rd

CôHs

2,4-Cl2-CeH3

base

160.1

6

CôHs

CöHs

base

189.7

6

4-F-CôH4

4-F-C «H4

2HC1

204.5

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 l- (diphenyimethyl) piperazine, 5 , 30 parts of sodium carbonate, 0.1 part of potassium iodide and 160 parts of 4-methyl-2-pentanone are stirred overnight using a water separator and heated under reflux. The reaction mixture is then cooled to room temperature and water is added. The phases are separated. The organic phase is dried, filtered and evaporated. The residue is stirred for 30 minutes with 12 parts of a hydrochloric acid solution in 40 parts of ethanol and heated under reflux. The reaction mixture is then evaporated and the residue is crystallized from ethanol. 5 parts (46 percent of theory) of 1- {5- [4- (diphenylmethyl) -1-piperazinyl] pentyl} -1, 3-dihydro-2H-benzimi-dazol-2-one are obtained. dihydrochloride hydrate, mp 215.3 ° C.

25 Example 26

A mixture of 4.9 parts of l- (3-chloropropyl) -IH-benzimidazole, 5.76 parts of l- [bis- (4-fluorophenyl) -methyl] -pipe-razin, 5.3 parts of sodium carbonate, 0 , 1 part of potassium iodide and 200 parts of 4-methyl-2-pentanone are 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. The residue is crystallized from a mixture of 4-methyl-2-35 pentanone and 2,2'-oxybispropane. The product is filtered off and dried. 5.5 parts (59.3 percent of theory) of 1- [3- {4- [bis- (4-fluorophenyl) methyl] -1-piperazinyl} propyl] -1 H -benzimidazole are obtained -hydrate of F. 108.4 ° C. The following connections 40 are produced in a corresponding manner:

A3?

^ N-CÎT

n 2n v_y \ 4 2

Ar *

M

R '

CnH: n

Ar '

Ar2

Base or salt

F., ° C

H

H

(CH2) 2

CôHs

CôHs

base

192.3

H

H

(CH2) j

CôHs

3-C1-CôH4

3HCI.h2o

191.1

I / 2CH3-CHOH-CH3

CeHs

H

(CH2) 3

CôHs

CôHs

base

130.5

CaHs

5-C1

(CH2) 3

CôHs

CôHs

base

143.9

CôHs

H

(CH2) 2

CeHs

CôHs

3HC1.H20

198.3

CôHs

5-C1

(CH2) 3

CôHs

CôHs

base

127.8

GHs-CH2

H

(CH2) 3

CôHs

CôHs

3HC1.3H2Û

179.9

CôHs-CH2

5-C1

(CH2) 3

CôHs

CôHs

3HC1.H20

198.2

H

H

(CH2) 3

CôHs

CôHs

base

132.3

H

H

(CH2>

CôHs

4-F-CôH4

base

102.5

H

H

(CH2) 3

CôHs

4-C1-CôH4

base

90.8

634317

26

M

R '

OnHzn

Ar '

Ar-

Base or salt

F., ° C

H H H H

H

CH3

CHs

CHs

C2H5

C2H5

CzHs

<3>

(£>

H H H H

H

H

H

5-C1 H H H

5-C1 H

5-C1

6-C1 H

(CH2) 4 (CH2) 4 (CH2) 4

CH2-CH-CH2

I.

CH3 CH2-CH-CH2

I.

CH3 (CH2) 3 (CH2) 3 (CH2) 4 (CH2) 2 (CH2) 3 (CH2>

(CH2) 3

(CH2) 3

(CH2) 3 (CH2) 3

CôHs CôHs 4-F-C6H4 CôHs

4-F-C6H4

CôHs CôHs CôHs CôHs CôHs CôHs

CôHs

CôHs

CôHs CôHs

CôHs 4-F-C0H4 4-F-CÔH4 CôHs

4-F-C0H4

CôH5 CôHs CôH5 CôHs CÔH5 CôHs

CôHs

CôHs CôHs

3-C1-CÔH4

Base Base Base

3HCII / 2H2O

3HCII / 2H2O

base

3 HCl H2O base

3 HCl H2O 3HC1H2O 3 HCl H2O

base

base

base

3HC1.2H20

106 114.9 86.3 237.3

223.4

121.2

226.4 118.7

208.5 224.5 233.1

106.5

114.9

173.6 '182.9

Example 27 t B

According to Example 26, by reacting 3- [2- (Me-

thylthio) -! H-benzimidazol-l-yl] propyl methanesulfonate with l- (diphenyimethyl) piperazine 1 - {3- [4- (diphenyimethyl) -1 - 35 piperazinyl] propyl} -2- (methylthio) -1 H- Benzimidazole trihy-hydrochloride hydrate of F. 203.4 ° C produced.

Example 28

A mixture of 4.8 parts of 1 - (3-chloropropyl) -1,3- 40

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 are stirred overnight using a water separator and heated under reflux. The reaction mixture is then cooled 45 and water is added. The phases are separated. The 4-methyl-2-pentanone phase is 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 crystallized from 4-methyl-2-pentanone. 4.2 parts (48 percent of theory) of l- {3- [4- (diphenylmethoxy) -l-piperidinyl] -propyl} -l, 3-dihydro-2H-benzimidazol-2-one of F. 149.2 ° C.

The following connections are made in a corresponding manner:

1

Ar '

Ar3

Base or salt F., ° C

SS

HN ^ N-

^ Ar

B- (CH2) n ~ N ~ y ° ~ CH

x ar

CôHs

CôHs

HCl

253.1

4-F-C0H4 4-F-CôH4 HCl 1/2 167.2 H2O

4-F-C0H4 4-F-C0H4 HCl 1/2 251.4 H2O

CôHs

CôHs

base

152

CôHs

CôHs

base

110.2

B