FI66178C - PROCEDURE FOR FRAMSTATION OF AV 1 - ((4-DIARYLMETHYL-1-PIPERAZINYL) ALKYL) -BENIMIMIDAZOLDERIVAT ANVAENDBARA SOM ANTIHISTAMINER OCH ANTIANAFYLAKTISKA MEDEL - Google Patents

Description

, Γ ^, .1 ... __ ANNOUNCEMENT £ .ί \ ηο «ΒΓ» W <11> UTLÄCONIMO $ SK »lfT ° · £ & $ & (45) ILL ..» ^ · (51) Kwj £ flm. O? C 07 D 235/26, 401/06 // C 07 D 403/06 FINLAND — FINLAND pi) r «-» —— r «—771020 (22) H» Lnil ^ lN »—AwBhiilm ^ H 01.04.77 ( 23) ΑΜαφβΜ · —GlMgtwtadag 01.04.77 (41) TWhK (vlklMksI - ββ * Κ oftaMNf 03.10.77 Jä (^ Hi ^ SvUcNdsiioa j® ΙβΒββ ^ ΜΐΙίΛΝβΑ

Petal * · och ieglateratyralaan * * AmMcm Htfefd «k ucUkriften pafcMcand 31.05.84 (32) (33) (31) * rr *** r ·« <»* -« kw »Hortwt 02.04.76 21.12.76 USA ) 672919, 753062 (71) Janssen Pharmaceutica Naamloze Vennootschap, Turnhoutsebaan, 30,

Beerse, Belgium-Belgien (BE) (72) Jan Vandenberk, Beerse, Ludo E.J. Kennis, Vosselaar, Marcel J.M.C.

Van der Aa, Vosselaar, Albert H.M. Th. Van Heertum, Vosselaar, Belgium-Belgien (BE) (74) Oy Kolster Ab (54) Method for the use of 1 - {/ 4-diarylmethyl-1-piperazinyl] benzyl i-benzyl for the preparation of imidazole derivatives - For the preparation of imidazole derivatives 1 - {/ 4-diaryl-methyl-1-piperazine-7-alkyl] -benzimidazole compounds with antihistamines and antianaphylactic agents

The invention relates to a process for the preparation of 1- [4-ylaryl: α-ethyl-1-piperazinyl / alkyl] -benzimidazole derivatives of the formula I or pharmaceutically acceptable salts thereof for use as antihistamines and antiana-phylactic agents, / ~ ~ 1 BC HL -N N -CH-Ar '(I) n 2n \ / I 9 N' Ar 1 2 wherein Ar ga Ar each independently represents phenyl, substituted phenyl or pyridyl, wherein the substituted phenyl contains 1-2 substituents which are 66178 independently halogens, lower alkyl, lower alkoxy, trifluoromethyl or nitro groups, n is an integer of 2, 3, 4, 5 or 6, provided that when CnH2n is a branched alkylene group in the linear chain atom B connecting the group B to the nitrogen atom of the piperazine, at least 2 (a) a radical of formula:

II

, \ L-N ^ "n- \ ....... /

/ V

"" "r 2 1 2 wherein R and R each independently represent hydrogen, halogen, lower alkyl or trifluoromethyl and L is hydrogen, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, phenyl, phenylmethyl, lower allylcarbyl, lower , or (b) a radical of formula

M

C

Wherein N and R 1 2 each independently represent hydrogen, halogen, lower alkyl or trifluoromethyl and M is hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, lower alkylthio, amino, lower alkylcarbonylamino, lower alkoxycarboxy or lower alkoxycarboxy Cycloalkyl of 3 to 6 carbon atoms.

Several 1- (Z-heterocyclyl) alkyl / piperazine and 4- (diarylmethoxy) piperidine derivatives with pharmacological properties are known. These compounds are described in U.S. Patent Nos. 3,362,956, 3,472,854, 3,369,022, 2,882,271 and 3,956,328.

U.S. Pat. Nos. 3,472,854 and 3,362,956 generally disclose a wide variety of certain 1- (benzimidazolyl) lower alkyl piperazines in which the 4-position of the piperazine backbone may be subsubstituted, e.g. benzhydryl group. However, these publications do not mention any compounds within the scope of the present application and do not provide examples. In addition, the compounds mentioned in these publications are useful as sedatives, adrenolytics, hypothermic agents, anticonvulsants, hypotensives and cardiovascular agents, while the compounds of the present application can be used as anti-anaphylactic agents and antihistamines.

Other mentioned references describe piperazine derivatives having antihistamine properties, but all of these compounds differ considerably in structure from the compounds of the present application. The structural differences are mainly in the nature of the 1- and / or 4-position substituents on the piperazine backbone. For example, U.S. Patent No. 2,882,271 describes 1-cinnamyl-4-benzhydrylpiperazines, U.S. Patent No. 3,369,022 describes 3-piperazinylalkyl-2-benzoxazolinones in which the 4-position of the piperazine group is substituted with non-diarylmethyl substituents. U.S. Pat. No. 3,956,328 describes 2- [3- (4-diphenylmethyl-1-piperazinyl) -propyl] -β-triazolo [1,5-a] pyridine.

The term "lower alkyl" as used in the foregoing and later definitions means straight or branched chain hydrocarbon radicals having from 1 to 6 carbon atoms, such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentane. style, hexyl or the like, the term "lower alkenyl" means straight or branched chain alkenyl radicals having 2 to 6 carbon atoms, such as ethenyl, 1-methylethenyl, 1-propenyl, 2-propenyl, 2-butenyl-1-methyl- 2-butenyl, 2-pentenyl-2-hexenyl or the like, the term "cycloalkyl" means cyclic hydrocarbon radicals having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, the expression "cn ^ 2n" means straight-chain or branched , 2,6-carbon alkylene chains having a linear moiety of at least 2 carbon atoms connecting a group B to the nitrogen atom of piperazine, such as 1,2-ethanediyl, 1,3-propanediyl, 2-methyl-1,3-propane diyl, 1,4-butanediyl, 2-methyl-1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like, and the term "halogen" is a common name for halogens having an atomic weight of less than 127, i. fluorine, chlorine, bromine and iodine.

4 66178

The compounds of formula (I) according to the invention are prepared by a) a reactive ester of the formula: B'-CH -W (II) n 2n wherein B 'is the same as B as defined above but other than 2-amino -1H-benzimidazol-1-yl radical of formula: NH2 N N-

K

r 2 and W is a suitable reactive ester function derived from the corresponding alcohol, is reacted with a compound of formula:

Ar1 / "Λ / HN N-CH C UH) V / 2 preferably in a reaction-inert solvent and in the presence of a base at elevated temperature to give a compound of formula: / -V / Ar1 B'-C H_ -N N-CH C (I ') n 2n \ / 0' -f Ar or b) decarboxylation under hydrolytic conditions of a compound of formula: 5 66178 NH-COO (lower alkyl) I Ar1 \ Vc „H2n '\ ._ y'ch' \ at2 ΓΛ r "bl so as to give a compound of formula: NH2 1 I 2 _ / Ar> C ~ -, / \ / (Ia) N NC H„ -N N-CH x \ / n2n ^ 'XAr2 / ... ..

R 1 '· R 2 or c) ring closure of a compound of formula (IV) / Ar 1/1 / H 2 N NH-C 1 -N n-ch (iv) R 1 · 2' R 2 is performed using a suitable ring-forming reagent and methods known in the art to give the compound with the formula: 0 1 II Ar / _Λ · ', ic, HN NC H. -N N-CH \ C) / n 2 n \ / \ 0 t' (~ "r R1 V- -" · R2 66178 or M1 I a 1 // / \ / ΆΓ N NC H- -N ti-CHv 9 (Id) \ / n 2n \ / Ar ^ / ~ (

R 1> v 2 - -, R 2 wherein M is hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, amino, lower alkoxycarbonylamino or cycloalkyl or d) deprotecting P by conventional methods from a compound of formula: .. - Cvx. / ~ \ / P-N N-C H, -N N-CH ((V) \ ...... / "2n V- / \ Ar ^ r2 to give a compound of formula:? ___ Är '

, .- 'C'. / \ .......... A

HN N-C H, -N N-CH (I-c) \ / \ at2 «f \ R1 \ == *. r2 or e) acylating a compound of formula (I-a) above using conventional N-acylation methods to give a compound of formula: NH-CO- (lower alkyl) A 1,

N N-C H_ -N N-CH

\ / n 2n \, '0 \ /' Ar / T ~ \ «-«>

R1 = <R2 7 66178 or f) coupling a group by a known method to a compound of formula (I-c) above to give a compound of formula: 0 Λ 1

Il XAr 1 / \ / L / -CnH2nt rCH, (I-f) \ _ / v-y XAr2

O

wherein L is lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl lower alkyl, carboxy lower alkyl, phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl or lower alkenyl provided that BC is in which said lower alkenyl has a double bond other than -N \ h (XVI) n 2n yy with a reactive ester of the formula: ____- -Ar1 W-CH (XVII) \ Ar2 wherein W is the same as above, preferably in a reaction-inert organic solvent in the presence of a suitable base at elevated temperature so that a compound of formula: is obtained: / Ar1B-cnH2n'N2; CH \ Ar2 dg) and, if desired, pharmaceutically acceptable acid addition salts are prepared from the products of steps a) -g).

8 66178

In reaction variant a), the reactive ester function W is e.g. halogen, methanesulfonyl, 4-methylbenzenesulfonyl and the like.

This condensation reaction is preferably carried out in a suitable reaction-inert organic solvent, e.g. a lower alkanol such as methanol, ethanol, propanol, butanol or a similar alkanol, an aromatic hydrocarbon such as benzene, methylbenzene, dimethylbenzene and the like, ether such as 1,4-dioxy , 1'-oxybispropane or the like, a ketone such as 4-methyl-2-pentanone, N, N-dimethylformamide, nitrobenzene, etc. A suitable base such as an alkali metal or alkaline earth metal may be added to bind the acid liberated during the reaction. -metal metal carbonate or an equivalent hydrogen carbonate. A small amount of a suitable metal iodide, such as sodium or potassium iodide, may be added to promote the reaction. In order to obtain a better reaction rate, it is preferable to use elevated temperatures, and the reaction is preferably carried out at the reflux temperature of the reaction mixture.

In all reaction alternatives, the reaction products are isolated from the reaction mixture and, if necessary, further purified by methods commonly used in the art.

In reaction variant b), a suitable strong acid such as hydrochloric acid, hydrogen bromide or sulfuric acid is used in the acid hydrolysis and a suitable strong base such as sodium or potassium hydroxide in the base hydrolysis.

It may be noted that when the group B is a 2- (lower alkoxycarbonylamino) -1H-benzimidazol-1-yl radical or a 2- (lower alkylcarbonylamino) -1H-benzimidazol-1-yl radical in the compounds of formula (I) or in their intermediates, radicals can exist in different tautomeric forms with the following structural formulas: 66178 N-COO (lower alkyl) ψΗ-CQO (lower alkyl) Jj, Ηϊί N- \ _. V, V '- \ V - Λ X ·' 2 y r2 rr NH-CO- (lower alkyl) (C0 alkyl)

t / 0. OF

N ^ V «N N-

\ / \ - X

(> \. -.........- / '$

V-χ / X- · X

V '2 \' 2

R1 R R

These tautomeric forms of the compounds of formula (I) are, of course, intended to be embraced within the scope of this invention.

Reaction variant c) uses a suitable ring-forming reagent known in the art for the preparation of compounds of formula (I-c) to prepare 1,3-dihydro-2H-benzimidazol-2-ones starting from 1,2-benzenediamines.

Useful ring-forming reagents include, for example, urea, carbonyl dichloride, and alkali metal isocyanates, and the ring-forming reaction can be performed according to methods well known in the art. For example, when a urea is used as a ring-forming reagent, compounds of formula (I-c) are readily obtained when the reactants are mixed and heated together without any solvent. In the preparation of compounds of formula (I-d), ring-forming reagents are used to prepare 1H-benzimidazoles from 1,2-benzenediamines. For example, the following ring-forming reagents may be used depending on the nature of the group M contained in the compounds (I-d).

When M is hydrogen, formic acid or a suitable tri (alkyloxy) methane can be used as the ring-forming reagent.

When lower alkyl, phenyl, phenylmethyl or cycloalkyl, a carboxylic acid of the formula: R5-COOH (VI) wherein R is lower alkyl, phenyl, phenylmethyl or cycloalkyl, or a functional form of this acid, can be used as the ring-forming reagent. a derivative such as an acyl halide, ester, amide or nitrile, or an imino ester of formula (VII): N 2 - (lower alkyl) HN = C (VII) ^ R 5 wherein R "* is as defined above, or (VIII) aldehyde:

O

r5-c: '(VIII)

B

or an adduct thereof with an alkali metal hydrogen sulfite. When the ring-forming reagent is an aldehyde, a suitable oxidant such as nitrobenzene, mercuric oxide, copper (2) or lead (2) salts or other suitable oxidants may be added to the reaction mixture, or the aldehyde itself may act as an oxidant in excess.

When M is mercapto, e.g., carbon sulfide, thiourea, carbonothioic acid dichloride, ammonium thiocyanate, and the like can be used as the ring-forming reagent.

When M is an amino group, the ring formation can be carried out using cyanamide or a metal salt thereof, preferably an alkali or alkaline earth metal salt, or BrCN.

When lower alkyloxycarbonylamino is used, for example, a suitable lower alkyl (iminomethoxymethyl) carbamate of formula (IX) can be used as the ring-forming reagent: NH 0

Il II

H C-O-C-HN-C-O (lower alkyl) or (IX) lower alkyl / T (lower alkoxycarbonylamino) - (R 1 -thio) -methylene-7-carbamate of formula (X):

OF

O S O

il) il (lower alkyl) -O-CNC = NC-O (lower alkyl) (X) 11 66178 wherein R 6 is hydrogen or methyl, or a lower alkyl carbonoisothiocyanatidate of formula (XX): f (lower alkyl) -OC-NCS (XI) or a lower alkyl-lower alkyl carbamothiate of formula (XII)

S

II

(lower alkyl) -NH-C-O- (lower alkyl) (XII) or a lower alkyl alkyl cyanimidodicarbonate of formula (XIII).

0

II

E (lower alkyl) -O-C 1 N 7 CN (XIII)

All of the ring-forming reactions described above can be performed using known methods described in the literature.

Examples of protecting groups to be used in process variant d) include a lower alkyloxycarbonyl and a substituted ethenyl group of the formula: R-CH = C- k 13 wherein R and R may be different groups relative to each other, but preferably R is lower alkyl and R is hydrogen , lower alkyl or phenyl.

When the protecting group is lower alkyloxycarbonyl, it is easily removed by base hydrolysis, and when the protecting group is a substituted ethenyl group, it is easily removed by performing acid hydrolysis on the corresponding intermediate of formula (V). In acid hydrolysis to remove a substituted ethenyl group from compound (V), many types of protic acids can be used, e.g., inorganic acids such as hydrochloric acids, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or organic acids such as acetic acid, propionic acid, acetic acid, acetic acid in inert organic solvents commonly used in this type of hydrolytic reaction, e.g. lower alkanols such as methanol, ethanol, 2-propanol and the like.

12 66178

In process variant c) the N-acylation is carried out, for example, by reacting a compound of formula (I-a) with an alkylcarbonyl halide or an anhydride derived from a lower alkyl carboxylic acid.

In method option f), depending on the nature of group L, the following methods can be used for coupling.

When L is lower alkyl, lower alkoxycarbonyl lower alkyl, phenylmethyl or lower alkenyl using sym-11 bol L, the addition of said group L to compound (Ic) is directly effected by reacting compound (Ic) with a suitable compound of formula L- W, 1a (XIV), wherein L is as defined above and W is as defined for the starting materials of formula (II).

The condensation of the compound (XIV) with the compound (I-c) can be carried out under conditions similar to those described above for the condensation of the reactive esters of the formula (II) and the intermediates of the formula (III).

In order to increase the reaction rate, it is in some cases advantageous to add a small amount of a suitable macrocyclic polyether to the reaction mixture, such as, for example, 2,3,11,12-dibenzo-1,4,7,10,13,16-hexoxacyclooctadeca-2,11-diene.

When L is lower alkoxycarbonylethyl, said group may alternatively be attached by reacting compound (I-c) with (lower alkyl) -2-propenoate of formula (XV).

(Lower alkyl) OOC-CH (XV)

Said reaction is preferably carried out in a reaction-inert organic solvent, e.g. an aromatic hydrocarbon such as benzene, methylbenzene, dimethylbenzene, etc., in an ether such as 1,1'-oxybisethane, 2,21-oxybispropane, tetrahydrofuran, 1,4-dioxane and the like. preferably in the presence of a suitable ammonium hydroxide such as N, N, N-triethylbenzenemethan hydroxide.

Compounds of formula (I-f) in which L is carboxy-lower alkyl can be readily derived from the corresponding lower alkyloxycarbonyl-lower alkyl-substituted compounds by hydrolysis in the usual manner, e.g. in aqueous base, to give the acid 13 661 78 from the ester.

When the group L is lower alkylcarbonyl, said group is preferably coupled by reacting compound (I-c) with a suitable acylating reagent derived from the corresponding lower alkylcarboxylic acid, such as e.g. a halide, preferably chloride, or anhydride according to conventional N-acylation procedures.

When 1? is lower alkylaminocarbonyl, it may be coupled by reacting compound (I-c) with the corresponding isocyanatoalkane in a suitable reaction-inert solvent such as ethers such as 1,1'-oxybisethane, 2,2'-oxybispropane, 1,4-dioxane and the like.

When L is a hydroxymethyl group, the coupling is preferably carried out by reacting compound (I-c) with formaldehyde in a suitable organic solvent such as, for example, N, Ν-dimethylformamide.

Several intermediates of formula (II) are known compounds, some of which are described in U.S. Pat.

597,793, filed July 21, 1975, and U.S. Patent Application no. 620,727, filed October 8, 1975, and may all be prepared by methods well known in the art. Depending on the nature of the group B contained in said intermediates (II), the following methods may be used in their preparation.

Intermediates of formula (II-a) can be prepared as follows: O (HN 2 N-CnH 2n-W, II-a)

/ W

R 1a = XR2

The correspondingly substituted 2-chloronitrobenzene of formula (XVIII) is reacted with the corresponding aminoalkanol of formula (XIX) by refluxing the reactants in a reaction-inert organic solvent such as lower alkanols such as ethanol, propanol, 2-propanol, butanol and the like. ., to give the E (2-nitrophenyl) amino7alkanol of formula (XX), the nitro group of which in turn is reduced to the amino group by applying e.g.

14 66178 catalytic hydrogenation using Raney nickel catalyst. The intermediate (XXI) thus obtained is then reacted with a suitable ring-forming reagent in the same manner as described above for the preparation of compounds (I-o) from compounds (IV), and the alcohol of formula (XXII) thus obtained is converted to the desired compound of formula (II). -a) to a reactive ester. The halides are preferably prepared by reacting compound (XXII) with a suitable halogenating reagent such as, for example, sulfinyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride and the like. When the reactive ester is iodide, it is preferably derived from the corresponding chloride or bromide by replacing said halogen with iodine. Other reactive esters such as methanesulfonates and 4-methylbenzenesulfonates are prepared by reacting an alcohol with a corresponding sulfonyl halide such as methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride.

The reactions described above are illustrated in more detail by the following reaction schemes.

o2n Cl

δ + H2N-CnH2n-OH

K R2 (XVIII) (XIX)

00N, ΝΗ-C H- -OH

2 W n 2n H, / RaNi 0 \ _t __________ ^ 1, ys / = - <2 r 'rz (XX) HN NH-C H, -OH ring closure vi \ / n 2n \ ri ------ 7 R \ r2 (XXI)

X

15 661 78

O

Formation of a reactive ester of N, N-C 2 H 2 -OH 1'X '' '2

R R

(XXII)

Alternatively, compounds of formula (II-a) may be prepared by reacting a compound of formula (XXIII) wherein R and R are as defined above with a haloalkanol of formula (XXIV) following conventional N-alkylation procedures, and obtaining an alcohol of formula (XXV), ii) converting the hydroxyl function of compound (XXV) to a reactive ester group in the usual manner as described above, and ii) removing the substituted ethenyl group of compound (XXVI) thus obtained by acid hydrolysis as described above for preparing compounds (Ic) from compounds (V). ).

Coupling of the hydroxyalkyl chain to compound (XXIII) to give compound (XXIV) can also be accomplished by reacting compound (XXIII) with the corresponding 2- (haloalkyloxy) tetrahydro-2H-pyran (XXVII) to give an intermediate of formula (XXVIII) which the ether function is opened hydrolytically, e.g. by treatment with aqueous hydrochloric acid.

When the reactive ester (II-a) is a halide, (II-a-1), it can alternatively be prepared by reacting compound (XXIII) with an equivalent amount of the corresponding dihaloalkane (XXIX) in the presence of a suitable strong base such as sodium methoxide or following the Mackosza procedure using an aqueous alkali solution and a quaternary ammonium catalyst such as Ν, Ν, Ν-triethylbenzenenetethanaminium chloride to give an intermediate of formula (XXVI-a) from which the substituted ethenyl group is removed by acid hydrolysis to give the desired halide of formula (II-a-1) .

It should be noted that the same methods may be used if the substituted ethenyl group is replaced by another suitable protecting group, but methods suitable for removing that particular group must be used for removal.

The reactions described above are illustrated by the following scheme.

16 66178 0 <~ t <0 Λ

1 O

a γη «χ« s ο X M Ä γΗ G X I (0

Ο X C X

I - 'C \ i | ^ ΟΧ C Γ-

rH C -— 'OJ I

«J Ο <ΰ X 1¾

Λ I CM I + C I

Zvy ^ · es m s o m /> _> t CM 1-1 / ¾¾. ! ^ YT ~ / ci— (¾ Z '' 'Ai;: ^ 4> XQ3 / 41 5/5 / i / 03' Y y> a o.

CM ^ I H

se m · s m

c H CM M

O> X>

CM IX S3 X

X / «^ O X O X

iXi-4 ^ -CO-r, 1 en I π i

o— «o—« M

41 41. M

0 o

1 I

a «5 \ ra \ o \ 'ö \ o \ 3 \ Θ> v + .5 + χ \ o

\, -M

se j *. w o v ®

c ^ x S

CM> O S S

X M I Hl ex e> e

O X CM -H CM

1 w x 4 = o e t e rH O "m o

I CM S I CM

* o = rft; * ^ γτ I

in X in 0–03 w O – 03

II II

T * '—1 o o

I I

ta a 66178 17

Intermediates of formula (II-b): 0

2 A

L N-cnH2rrw (XI-b)

// A

AX

wherein R, R, n and W are as defined above and L may be lower alkyl, lower alkenyl, lower alkyloxycarbonyl-lower alkyl, phenyl, phenylmethyl or lower alkylaminocarbonyl, may be readily prepared by side chain addition of a reactive ester to the starting material of formula (XXX)

l2-n "c nNH

\ A

// W

2

R R

(XXX) following the same procedures as described above for the preparation of intermediates of formula (XXVI) starting from compound (XXIII).

Intermediates of formula (II-c): 0

II

a

HOCH2-N N-CnH2n-K

A V; \ ... \ Λ ..... 'λ 2

R R

can be prepared by hydroxymethylation of the corresponding compound (II-a) with formaldehyde in a conventional manner.

18 66178

Intermediates of formula (II-d):

M

except those in which M is mercapto or lower alkylthio, can be readily prepared by attaching a reactive ester to the starting material of formula (XXXI) as a side chain.

M

i

N ^ JH

Λ \ ίκ- 'Λ 2

R R

(XXXI)

The Cnii2n-W * -i: * group can follow the same methods as described above for attaching said group to starting materials of formula (XXIII).

Intermediates of formula (ΙΙ-e): M1, C-

K J-CnH2n-W

R 1 R 2 (II-e) 1 2 1 wherein R, R, M, n and W are as defined above can be prepared by ring-closing the corresponding alcohol of formula (XXI) with a suitable ring-forming reagent as described above and converting the resulting formula (XXXII) ) to a reactive ester group.

1 9 66178 M1 ring formation N ^ c "nC H0 -OH reactive ester (XXI) -------------------- - \ / n 2n ------- -------————-— y 4>, - formation (Il-e) X = X 2

R1 R

(XXXII)

Intermediates of formula (ΙΙ-g): NH-CO- (lower alkyl)

N "/ N-CnH2n-W

; '/' X; R. by reacting compound (II-h) with the corresponding lower alkyl carbonyl halide or an anhydride derived from the corresponding lower alkyl carboxylic acid.

Intermediates of formula (IV) are prepared by condensing the corresponding reactive ester of formula (XXXIV) with a piperazine derivative of formula (III) and then reducing the nitro group of the intermediate (XXXV) thus obtained to the amino group following conventional procedures for reducing nitro to amino, e.g. with the resulting hydrogen or by catalytic hydrogenation in the presence of a suitable catalyst such as Raney nickel.

20 6 6 1 78

0 „N NH-C H„ -W

2. n 2n X ^ x + (III) -........ -............— R1 R2 (XXXIV) ^ Ar1 0 „N NH-C H0 -N N- CH. 2 2 \ / n 2n \ / —Ar! / reduction of nitron tX 'a ........-........... (IV> RR to amine (XXXV) The reactive esters of formula (XXXIV) used herein as starting materials are readily prepared in formula (XX). ) by converting its hydroxyl function to a reactive ester group using the usual methods described above.

Intermediates of formula (V) may be prepared by condensing a reactive ester of formula (XXXVI) with a piperazine derivative of formula (III).

0

P

1 n

P-N N-C H_ —W

\ n 2n Α - + (III) ______ \ (V) X. The reactive ester (XXXVI) used herein as starting material can in turn be prepared by attaching a CnH2nW group to the starting material of formula (XXXVII): 2 '66178

O

.’Ck ρ-ΐί pm V / R1 R2 (XXXVII) following the methods described above.

Intermediates of formula (XVI) may be prepared by reacting a reactive ester of formula (II) with a piperazine derivative of formula (XXXVIII) wherein Q is a suitable protecting group such as phenylmethyl or lower alkyloxycarbonyl and then removing said protecting group Q from the resulting intermediate. (XXXIX) according to conventional methods known in the art, e.g. by catalytic hydrogenation using palladium on carbon when Q is phenylmethyl or base hydrolysis when Q is lower alkyloxycarbonyl as catalyst.

(II) + HNn ^ JQ -------------- ^ B "CnH2n" N \ __ / N "Q

(XXXVIII) (XXXIX) Delete group Q \ ---------------------------------------- ------- η (XVI)

Intermediates of formula (XVl-a):

O

Il / - \

Hicy-cnH2 n- ^ j »h fx \ -A 2

R R

(XVI-a) may alternatively be prepared by reacting compound (XXXVI) with compound (XXXVIII) to give an intermediate of formula (XL) and then deprotecting P and Q according to methods well known in the art. .

Ji - \ ____ p-N c ^ ηβ2η- N f'0 (XXXVI) + (XXXVIII) ';—(' —f o / Mj

R R

(XL) 9 / - · \

™ P p0iS “HN ^ · N-CnH2n-N ^ J) -Q

p ’// \ R r2 (XXXIX-a) Delete group Q ------------------). (XVI-a)

Q

The intermediates of formula (II) are all generally known and can be prepared using known methods. Such intermediates can be prepared, e.g., by first subjecting the corresponding aroyl halide to a Friedel-Crafts reaction with a suitable arene 1 2 to give Ar, Ar methanone, which in turn is reduced in the usual manner, e.g. with sodium borohydride, to the corresponding methanol. The latter compound is then converted to the reactive ester (XVII) following the usual methods for preparing reactive esters from alcohols, and then intermediates (III) can be prepared by reacting compound (XVII) with piperazine.

The primary starting materials used in all of the reactions described above are well known and can all be prepared by methods known to those skilled in the art.

The compounds of formula (I) may be converted into therapeutically active non-toxic acid addition salts by treatment with a suitable acid such as inorganic acids such as hydrogen halides (e.g. hydrogen chloride, hydrogen bromide, etc.), sulfuric acid, nitric acid, phosphoric acid, etc., organic acid, etc. 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-dihydroxybutane , 2-hydroxy-1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenyl-2-propenoic acid, c <-hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methyl-benzenesulfonic acid, 2-methyl-benzenesulfonic acid, cyclohexanoic acid, cyclo 4-Amino-2-hydroxybenzoic acid or the like The salt can be restored to the free base by base treatment.

The compounds of formula (I) which are the subject of this invention have potent antianaphylactic and antihistamine activity which make them useful in the treatment of humans and animals. The beneficial antianaphylactic and antihistamine properties of the compounds of this invention will become apparent from the experimental results described below.

A. Test methods (a) "In vivo" antianaphylactic and antihistamine effects

The antianaphylactic and antihistamine effects of the compounds of the invention (I) and their salts are studied in guinea pigs "in vivo".

Guinea pigs weighing 400-500 g are sensitized to ovalbumin by injecting 0.05 ml of antiserum into the base of the left hind paw (m.p.). The animals are then fasted and orally administered physiological saline (= control animals) or the desired dose of test compound 24 hours after sensitization.

A histamine injection (dose 50 μg) is given to the right hind paw, m.p. 2 hours after oral administration of the compound. The diameters of both hind paws are measured before the injection of histamine and 10 minutes after the injection. Thirty minutes after histamine injection, the animals are administered 0.6 mg of ovalbumin intravenously. All control animals experience typical primary symptoms of anaphylactic shock (coughing, difficulty breathing, convulsions) and 85% of these control animals die within 15 minutes of ovalbumin injection. Avoidance of death is considered a criterion for potential drug effect and the tables below give the estimated ED5Q values for those oral doses that have a protective effect in 50% of the guinea pigs.

The mean histamine-induced paw edema in 200 control animals 10 minutes after histamine injection is 15 units (1 unit = 0.1 nun). Reactions of less than 10 units that occur in less than 5% of control animals are defined as effective inhibition of histamine edema in compound-treated animals, and the following tables also indicate the oral dose levels at which this effective inhibition is observed.

b) "In vitro" antihistamine activity

The guinea pig ileum strips are suspended in 100 ml of a Tyro deco bath at 37.5 ° C with a pre-charge of 0.75 grams and a gas mixture of 95% and% CO 2 is passed through.

Histamine-induced seizures (0.5 mg / l) are recorded chymographically with an isotonic lever giving a 5-fold magnification. The interaction between the test compound (incubation time 5 minutes) and the operator muscle is monitored, and the tables below give the concentrations (mg / l) of the various compounds that effectively inhibit histamine-induced contractions (50%).

The compounds (I) of the invention and their pharmaceutically acceptable salts have generally been found to be antiallergic in the experiments described above when administered to warm-blooded animals orally in doses ranging from about 0.25 to about 20 mg per kilogram of body weight.

In view of their beneficial antihistamine and antianaphylactic activity, the compounds of this invention may be incorporated into various pharmaceutical compositions. To prepare the pharmaceutical compositions of this invention, an amount of the desired compound having an effective antihistamine or anti-anaphylactic effect, in base or acid addition salt form, is admixed with a pharmaceutically acceptable carrier as appropriate, depending on the requirements of the desired route of administration.

These pharmaceutical compositions is preferred to be administered orally, rectally or parenterally injectable dose forms are used. For example, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, e.g. water, glycols, oils, alcohols, etc., and in the case of powders, pills, capsules and tablets solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants, etc. Because of their ease in use, tablets and capsules represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers are obviously employed. In parenteral compositions, the lozenge is formed, at least in large part, from sterile water, but other agents, for example, to aid solubility, may also be present. The solution for injection may contain, for example, physiological saline, glucose solution or a mixture of physiological saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Since the acid addition salts of formula (I) are more soluble in water than the corresponding base forms, they are also more suitable for the preparation of aqueous mixtures.

It is highly advantageous to formulate the pharmaceutical compositions described above into unit dosage forms which are uniform and easy to use. Dosage forms used in this specification and claims refer to physically pleasing unit dosage forms, each containing a predetermined amount of the active ingredient desired to produce the desired therapeutic effect, and the required pharmaceutical carrier. Such unit dosage forms include, for example, tablets (including scored and coated tablets), capsules, pills, powder packets, cachets, solutions or suspensions for injection, teaspoons, tablespoons, and the like.

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The following are examples. intended to illustrate and not to limit the present invention. All parts are by weight unless otherwise indicated.

Preparation of starting materials:

Preparation I

To a stirred hot mixture of 54 parts of 1,3-dihydro-1- (phenylmethyl) -2H-benzimidazol-2-one, 47.25 parts of 1-bromo-3-chloropropane and 6 parts of Ν, Ν, Ν-triethylbenzenemethanaminium chloride -dia, 450 parts of 60% sodium hydroxide solution are added dropwise at 60 ° C. After the addition, stirring is continued for 6 hours at 60 ° C. The reaction mixture is cooled and poured into water, the oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. When the residue is crystallized from 2,21-oxybispropane and dried, 42 parts (58%) of 1- (3-chloropropyl) -1,3-dihydro-3- (phenylmethyl) -2H-benzimidazol-2-one are obtained.

In a similar manner were prepared: 0 1 i.

L-N N- (CH_) -Cl2 n 4 /, '\ 7

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Preparation II

Following the procedure of Preparation I, but starting from an equivalent amount of the corresponding 1H-benzimidazole, the following residues were obtained: 33 66178

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Preparation III

A mixture of 20 parts of 3- [7- (2-amino-4-chlorophenyl) amino] -1'-propanol, 50 parts of acetic acid and 150 parts of 4N hydrochloric acid solution is refluxed overnight with stirring. The reaction mixture is cooled and evaporated. The residue is dissolved in water and the solution is made alkaline with ammonium hydroxide. The product is extracted with trichloromethane.

The extract is dried, filtered and evaporated. When the residue is crystallized from a mixture of 4-methyl-2-pentanone and 2'2-oxybispropane, 6.5 parts (28%) of 5-chloro-2-methyl-1H-benzimidazole-1-propanol are obtained.

In a similar manner, 5-chloro-2-ethyl-1H-benzimidazole-1-propanol was prepared by reacting 3- (12-amino-4-chlorophenyl) amino] -1-propanol with propanoic acid.

Preparation IV

To a refluxed (water separator) and at the same time stirred mixture of 30 parts of 3- (72-amino-4-chlorophenyl) amino] -1-propanol and 0.1 part of 4-methylbenzenesulfonic acid in 405 parts of methylbenzene is added dropwise a solution of 34 parts of part of cyclohexanecarboxaldehyde in 45 parts of methylbenzene. After the addition, stirring is continued for another 1 hour at reflux temperature with a water separator. The methylbenzene is evaporated off in vacuo and the residue is triturated with 2,2'-oxybispropane. The product is filtered off and dried, yielding 16.5 parts (38%) of 5-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol, m.p. 95 ° C.

Preparation V

A mixture of 30 parts of 3 - [(2-amino-4-chlorophenyl) amino] -1-propanol, 44.8 parts of sodium β-hydroxybenzene ethanesulfonate and 120 parts of ethanol is refluxed for 30 minutes with stirring. evaporate and the residue is suspended in water, the oily product is extracted with trichloromethane, and the extract is dried, filtered and evaporated to give 45 parts (100%) of 5-chloro-2- (phenylmethyl) -1H-benzimidazole-1-propanol.

In a similar manner there was prepared 6-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol, m.p. 120.1 ° C. by reacting 3 - [(2-aramino-5-chlorophenyl) -amin] -7-propanol with sodium (Λ-hydroxycyclohexanemethanesulfonate).

Preparation VI

To a stirred mixture of 93 parts of 3- (2-aminophenyl) amino-1-propanol, 45.5 parts of potassium hydroxide and 600 parts of 85% aqueous ethanol is added dropwise 60.8 parts of carbon disulfide. After the addition, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated and the residue is suspended in 1500 parts of water. The suspension is filtered with hyflo and the filtrate is acidified with acetic acid. the oily product solidifies on scratching. The product is filtered off, washed with water and dried, yielding 92 parts (78.9%) of 2-mercapto-1H-benzimidazole-1-propanol, m.p. 110 ° C.

A mixture of 20.8 parts of 2-mercapto-1H-benzimidazole-1-propanol, 15.62 parts of iodomethane and 120 parts of methanol is stirred overnight at room temperature. The reaction mixture is evaporated and the residue is dissolved in 500 parts of water. The solution is filtered with hyflo and the filtrate is basified with solid potassium hydroxide. the oily product is extracted with trichloromethane. When the extract is dried, filtered and evaporated, 19 parts (85.5%) of 2- (methylthio) -1H-benzimidazole-1-propanol are obtained as a residue.

To a stirred solution of 19 parts of 2- (methylthio) -1H-benzimidazole-1-propanol, 15.2 parts of Ν, Ν-diethylethanamine and 195 parts of dichloromethane are added dropwise 11.5 parts of methanesulfonyl chloride. . After the addition, stirring is continued for 1 hour at reflux temperature. After cooling, water is added and the layers are separated. After drying, filtration and evaporation of the organic phase, 19 parts of oily 3-Z2- (methylthio) -1H-benzimidazol-1-ylpropylmethanesulfonate are obtained as a residue.

Preparation VII

A mixture of 30 parts of 1H-benzimidazole, 49 parts of 2- (4-chlorobutoxy) tetrahydro-2H-pyran, 21 parts of potassium hydroxide and 200 parts of ethanol is refluxed overnight with stirring. The reaction mixture is cooled to room temperature, filtered and the filtrate is evaporated. The residue is mixed with water and acidified with dilute hydrochloric acid solution. The mixture thus obtained is heated for 30 minutes in a water bath with Selma with stirring. The mixture is cooled to room temperature and the product is extracted with methylbenzene. The aqueous phase is separated and basified with ammonium hydroxide. The product is extracted with dichloromethane. When the extract is dried, filtered and evaporated, 50 parts of oily 1H-benzimidazole-1-butanol are obtained as a residue.

Preparation VIII

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

In a similar manner the following 1- (chloroalkyl) -1H-benzimidazoles were prepared: 66178 36 Λ N- (CH2) -Cl

O

sM '6

R

M n Base or Melting point ____ salt form__ C-Hc-CH_ 3 5-C1 base 6 5 2 CH3 3 5-Cl C_H_ 3 5-Cl

£ D

(!) 35 5-Cl HCl 211.7 ° C

C ^ H-H. 3 H base 112 ° C

6 5 2

3 6-Cl HCl 227.5 ° C

C_H_ 2 H base

Δ D

H 4 H "

Preparation IX

A mixture of 113.2 parts of 1,2,4-trichloro-5-nitrobenzene, 75 parts of 3-amino-1-propanol, 0.2 parts of potassium iodide and 200 parts of butanol is refluxed overnight with stirring. The butanol is evaporated off in vacuo and water is added to the residue. The product is extracted with 4-methyl-2-pentanol. The extract is washed several times with water, dried, filtered and evaporated, the oily residue is purified by column chromatography on silica gel using 5% methanol in trichloromethane as eluent. The pure crystals are collected and the eluent is evaporated. The residue is triturated with 2,21-oxybispropane. When the product is filtered off, crystallized from 2,2'-oxybispropane and a mixture of 2-propanol, 31.7 parts of 3- (34,5-dichloro-2-nitrophenyl) amine-1-propanol are obtained, m.p. At 97 ° C.

In a similar manner there were prepared: 3- [2-nitro-4- (trifluoromethyl) phenyl] amino] -1-propanol, 2 - [(2-nitro-4- (trifluoromethyl) phenyl) amino) ethanol, mp 74.9 ° C.

66178 37

Preparation X

To a stirred mixture of 39.2 parts of 3- (2-nitrophenyl) amino-1-propanol and 225 parts of trichloromethane is added dropwise 35.7 parts of sulfinyl chloride (exothermic reaction: temperature rises to 45 ° C). After completion of the reaction, stirring is continued for 6 hours at reflux temperature. Evaporation of the reaction mixture gives 43 parts (100%) of N- (3-chloropropyl) -2-nitrobenzeneamine.

In a similar manner there were prepared: N- (3-chloropropyl) -2-nitro-4- (trifluoromethyl) benzeneamine residue 4,5-dichloro-N- (3-chloropropyl) -2-nitrobenzeneamine, m.p. 78 ° C N- (2-chloroethyl) -2-nitro-4- (trifluoromethyl) benzeneamine

Preparation XI

A mixture of 21.5 parts of N- (3-chloropropyl) -2-nitrobenzeneamine, 22.68 parts of 1- (diphenylmethyl) piperazine, 20 parts of N, N-diethylethanamine and 180 parts of N, N-dimethylacetamide was heated 6 hours at 100 ° C with stirring. The reaction mixture was evaporated and the oily product was mixed with water, the oily product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol, ethanol and 2,2-oxy-bispropane. After filtration and drying, 15.5 parts (36.9%) of 4- (diphenylmethyl) -N- (2-nitrophenyl) -1-piperazinepropanamine hydrochloride, m.p. 228 ° C.

In a similar manner there were prepared: N- (4,5-dichloro-2-nitrophenyl) -4- (diphenylmethyl) -1-piperazinepropanamine as a residue

4- (diphenylmethyl) -N- [2-nitro-4- (trifluoromethyl) phenyl] -1-piperazinepropanamine, m.p. 113.7 ° C

4- (diphenylmethyl) -N- [2-nitro-4- (trifluoromethyl) phenyl) -1-piperazineethanamine, m.p. 152.1 ° C

Preparation XII

A mixture of 15 parts of 4- (diphenylmethyl) -N- (2-nitrophenyl) -1-piperazinepropanepropanamine hydrochloride in 160 parts of methanol is hydrogenated at room temperature at room temperature with 5 parts of Raney nickel catalyst. When the calculated amount of hydrogen is bound, the catalyst is filtered off with hyflo and the filtrate is evaporated. The solid residue is crystallized from a mixture of 2-propanol and 2,21-oxybispropane.

38 66178

The product is filtered off and dried, yielding 12 parts (78.9%) of N- (2-aminophenyl) -4- (diphenylmethyl) -1-piperazinepropanaramine hydrochloride, m.p. 223.1 ° C.

In a similar manner there were prepared: 4,5-dichloro-N1- (3- [4- (diphenylmethyl) -1-piperazinyl / propyl) -1,2-benzenediamine as an oily residue 1__-N- [3- [4- (diphenylmethyl) -1 -piperazinyl / propyl, -4- (trifluoromethyl) -1,2-benzenediamine

N- [2- [4- (diphenylmethyl) -1-piperazinyl] ethyl] -4- (trifluoromethyl) -1,2-benzenediamine as an oily residue Preparation XIII

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 400 parts of 4-methyl-2-pentanone were refluxed for 20 hours with a water separator while stirring. The reaction mixture was cooled, water was added and the layers were separated. When the organic layer was acknowledged, filtered and evaporated, 70 parts (100%) of 1,3-dihydro-1- (1-methylethenyl) -3- [3- [4- (phenylmethyl) -1-piperazinyl] propyl] -2H-benzimidazol-2 were obtained. -one as a residue.

In a similar manner there was prepared 1,3-dihydro-1- [2- [4- (phenylmethyl) -1-piperazinyl] ethyl] -2H-benzimidazol-2-one, m.p. 136.5 ° C. Preparation XIV

To a stirred solution of 70 parts of 1,3-dihydro-1- (1-methylethenyl) -3- [3- [4- (phenylmethyl) -1-piperazinyl] propyl] -2H-benzimidazol-2-one in 240 parts of ethanol , 55 parts of 6N hydrochloric acid solution were added. The mixture thus obtained was stirred for 2 hours at 40-50 ° C. The reaction mixture was evaporated and the residue was stirred in dilute ammonium hydroxide solution. the oily product was extracted with trichloromethane.

When the extract was dried, filtered and evaporated, 63 parts (100%) of 1,3-dihydro-1- [1- [4- (phenylmethyl) -piperazinyl] propyl] -2H-benzimidazol-2-one were obtained as a residue. Preparation XV

- f

A mixture of 63 parts of 1,3-dihydro-1- [3- [7- (phenylmethyl) -1-piperazinyl] propyl} -2H-benzimidazol-2-one in 400 parts of methanol is hydrogenated under normal pressure and at room temperature. part of the palladium catalyst on the carbon surface (10%). When the calculated amount of hydrogen is bound, the catalyst is filtered off with hyflo and the filtrate is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2-propanol 661 78 39. The product is filtered off and dried, yielding 29.5 parts (63%) of 1,3-dihydro-1- [E- (1-piperazinyl) propyl] -2H-benzimidazol-2-one, m.p. 157.5 ° C.

In a similar manner there were prepared: 1,3-dihydro-1- [2- (1-piperazinyl) ethyl] -2H-benzimidazol-2-one, m.p. 122.6 ° C.

Preparation XVI

To a stirred mixture of 20 parts of aluminum chloride and 100 parts of fluorobenzene is added dropwise 20.5 parts of 2,4-dichlorobenzoyl chloride. After the addition, the mixture is refluxed for 5 minutes with stirring. The reaction mixture is poured onto crushed ice and the product is extracted with 1,1'-oxybisethane. When the extract is dried and evaporated, 30 parts of (2,4-dichlorophenyl) (4-fluorophenyl) methanone are obtained in the form of an oily residue.

In a similar manner were prepared:

(4-fluorophenyl) -4-pyridinyl) methanone, m.p. 85.5 ° C

Manufacture XVII

To a stirred and refluxed mixture of 23.4 parts of (4-chlorophenyl) (2-fluorophenyl) methanone in 280 parts of 2-propanol was added in small portions 3.7 parts of sodium borohydride. After the addition, stirring was continued for 2 hours at reflux temperature (-80 ° C). The reaction mixture was cooled and quenched by the addition of water. The 2-propanol was evaporated and the residual product was extracted with trichloromethane. After the extract was dried, filtered and evaporated, 23.6 parts of 4-chloro-N- (2-fluorophenyl) -benzenemethanol were obtained as a residue.

In a similar manner were prepared:

2,4-dichloro-α- (4-fluorophenyl) benzenemethanol as a residue O'- (4-fluorophenyl) -4-pyridinemethanol, m.p. 138.2 ° C O'- (4-fluorophenyl) -3-pyridinemethanol hydrochloride, m.p. 158.3 ° C

4-Methoxy- <2 - (- 3- (trifluoromethyl) phenyl) benzenethanol as a residue

Manufacture XVIII

A mixture of 22 parts of 2,4-dichloro-N- (4-fluorophenyl) -benzenemethanol and 240 parts of 12N hydrochloric acid solution is stirred for 40 hours at room temperature. The reaction mixture is poured into ice water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. When the residue is distilled, 13.2 parts of 2,4-661 7 $ 40 dichloro-1- / chloro- (4-fluorophenyl) methyl / benzene b.p. 146 at a pressure of 0.15 mm.

In a similar manner there were prepared: -chloro-λλ - (4-methoxyphenyl) methyl.7-3- (trifluoromethyl) benzene as a residue

1-Chloro- (4-methylphenyl) methyl-4-fluorobenzene as a residue Preparation XIX

To a stirred mixture of 23.6 parts of 4-chloro-O ** - (2-fluorophenyl) benzenemethanol in 108 parts of benzene is added dropwise 24 parts of sulfinyl chloride. After the addition, the mixture is heated to reflux for 5 hours and then stirred overnight at room temperature. Evaporation of benzene and distillation of the residue gives 16.5 parts of 1-chloro-4H-chloro-α- (2-fluorophenyl) methyl / benzene, b.p. 122-125 ° C at 0.1 mm.

In a similar manner there were prepared: 3-chloro-ck- (4-fluorophenyl) methyl / pyridine hydrochloride as an oily residue 3- (N-chloro-C 1-8 - (4-chlorophenyl) methyl / pyridine hydrochloride as a residue 4- / c cA- (4-fluorophenyl) methyl / pyridine hydrochloride, m.p.

198-200 ° C

1- (chlorophenylmethyl) -2,3-dimethylbenzene, b.p. 137 ° C at 0.7 mm 1- (chlorophenylmethyl) -2,4-dimethylbenzene, b.p. 137 ° C at 0.7 mm 2- (chlorophenylmethyl) -1,4-dimethylbenzene, b.p. 136 ° C at 0.7 mm 1- (chlorophenylmethyl) -2-fluorobenzene, b.p. 108-109 ° C at 0.4 mm

Preparation XX

A mixture of 121 parts of piperazine, 54 parts of 3- (N-chloro-β- (4-chlorophenyl) methyl / pyridine hydrochloride and 315 parts of N, N-dimethylformamide is stirred for 20 hours at room temperature. The reaction mixture is evaporated and 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 basified with 60% sodium hydroxide solution and the product is further extracted with methylbenzene. The extract is dried, filtered and evaporated, the oily residue is converted into the nitrate salt in ethanol. When the salt is filtered off, washed with ethanol and 2,2'-oxybispropane and crystallized from ethanol, 48 parts of 1- [4- (4-chlorophenyl)] - (3-pyridinyl) methyl] piperazine trinitrate are obtained, m.p. 132.9 ° C.

In a similar manner there were prepared: 1- [e- (4-chlorophenyl) - <* - (-fluorophenyl) methyl] piperazine 1- [3, - (4-fluorophenyl) -cK- (4-pyridinyl) methyl] piperazine,

1-7 (2-chlorophenyl) (3-chlorophenyl) methyl] piperazine 1 - [(2-fluorophenyl) phenyl] piperazine dioate (1: 1), m.p. 195.5 ° C

1 - [(4-fluorophenyl) (4-methoxyphenyl) methyl] piperazine ethanedioate (1: 2), m.p. 280.1 ° C

1 - / '(4-nitrophenyl) phenylmethyl / piperazine dihydrochloride Manufacture of finished products:

Example 1

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, refluxed overnight with a water separator while stirring. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using 5% methanol in trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, the oily residue is crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol. When the product is filtered off and dried, 2 parts (23%) of 1- (3-) - (4- (diphenylmethyl) -1-piperazinyl / propyl) -1,3-dihydro-2H-benzimidazol-2-one are obtained, m.p. . 153.6 ° C.

The following compounds were prepared in a similar manner in the free base form or in the form of an addition salt by treating the free base with the corresponding acid: 66178 42

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Example 2

In analogy to Example 1, the following were prepared: 4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] propyl] -1,3-dihydro-2H-benzimidazole-2 -oni, sp. 197.3 ° C, by reacting 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one methanesulfonate with 1-Zbis (4-fluorophenyl (methyl) piperazine.

1- (3- [4- (Diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-3-methyl-2H-benzimidazol-2-one dihydrochloride hydrate, mp 201.8 ° C, by placing 1,3-dihydro 1- (3-iodopropyl) -3-methyl-2H-benzimidazol-2-one for reaction with 1- (diphenylmethyl) piperazine.

Example 3

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 refluxed overnight with a water separator while stirring. The reaction mixture is cooled to room temperature, water is added and the layers are separated. The residue is stirred for 30 minutes at reflux temperature in a mixture of 12 parts of hydrochloric acid solution in 40 parts of ethanol. Evaporation of the mixture and crystallization of the residue from ethanol gives 5 parts (46%) of 1- (5- [4- (diphenylmethyl) -1-piperazinyl-7-pentyl) -1,3-dihydro-2H-benzimidazol-2-one dihydrochloride hydrate, m.p. 215.3 ° C.

In a similar manner were prepared: O. Ar 1

HN 2 N- (CH 2) -N 7 V -CH

\ / 2 n V __ / \ 2 w__

1 2 Base or Sp. ° C

n__Ar__Ar__protection ____________ 5 4-F-C6H4 4-F-CgH4 2HCl1H2O 203.7 4 CgH5 4-F-C6H4 base 172.3 3 C6H5 2-Cl-C6H4 base 149 3 3-Cl-CgH4 2-Cl-CgH4 base H20 139.1 3 C6H5 2.4 “C12 ~ base 160.1 C6H3 6 C6H5 C6H5 base 189.7 6 4-F-CgH4 4-F-CgH4 2HCl1 204.5 ______________i___ 66178 46

Example 4

To a stirred solution of 76 parts of (diphenylmethyl) -1-piperazinyl / propyl) -1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one in 280 parts of ethanol is added 120 parts of hydrochloric acid solution and 250 parts of water. The mixture thus obtained is stirred for 30 minutes at room temperature. The product precipitates when the reaction mixture is cooled in an ice bath. After filtration of the product, washing with 2-propanone and 2,2'-oxybispropane and drying, 43 parts (55%) of 1- [3- [4- (diphenylmethyl) -1-piperazinyl] -propyl) -1,3-dihydro -2H-benzimidazol-2-one dihydrochloride hydrate, m.p.

237.5 ° C.

In a similar manner were prepared: O. 1

ΗΚΧ N-C H. -N N-CH

\ / λ 2n / λ) - ('...... 7' Ar2 __ ^ _

R1 C H- Ar1 Ar2 Mp ° C

n 2n H (CH2) 3 3-pyridinyl 4-Cl-C6H4 160.2 H (CH2> 3 4-pyridinyl 4-F-C8H4 183.2 H (CH2) 3 4-Cl-C6H4 4-OCH3-C6H4 199.3 H (Ch2) 3 CgH5 2-F-CgH4 157.7 5- CH3 <CH2) 3 CgH5 CgH5 178.3 6- CH3 (CH2) 3 C6H5 C6H5 195.7 H CH - CH (CH -) - 4-FC, H. 4-F-C, H, 176 3 3 6 4 6 4 CH2

Example 5

A mixture of 3.6 parts of N1- [2- [4- (diphenylmethyl) -1-piperazinyl] ethyl] -4- (trifluoromethyl) -1,2-benzenediamine and 1.8 parts of urea was stirred for 3 hours in an oil bath 190 ° C. The reaction mixture was cooled, water and trichloromethane were added and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol 47,661,788 (95: 5) as eluent. When the pure fractions were collected and the eluent was evaporated, 1.5 parts (41.5%) of 1- (2- [4- (diphenylmethyl) -1-piperazinyl] ethyl) -1,3-dihydro-5- (trifluoromethyl) were obtained. ) -2H-oenzimidazol-2-one, mp 163.7 ° C.

In a similar manner there were prepared: 1- {3- [4- (diphenylmethyl) -1-piperazinyl] propyl) -1,3-dihydro-5- (trifluoromethyl) -2h-benzimidazol-2-one, m.p. 152.7 ° C.

5,6-Dichloro-1- (3-ZJ- (diphenylmethyl) -1-piperazinyl-propyl] -1,3-dihydro-2H-benzimidazol-2-one, mp 214.7 ° C.

Example 6

A mixture of 2.3 parts of 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-2H-benzimidazol-2-one, 4.5 parts of a 40% formaldehyde solution and 45 parts of N, N-dimethylformamide are heated for 2 hours at 100 ° C with stirring. The reaction mixture is cooled and diluted with water. When the precipitated product is collected by filtration, crystallized from methylbenzene and dried, 1.5 parts (66%) of 1- (3- [4- (diphenylmethyl) -1-piperazinyl] propyl) -1,3-dihydro-3- (hydroxymethyl) -2H are obtained. -benzimidazol-2-one, m.p. 102.5 ° C.

Example 7

A mixture of 1.55 parts of acetic anhydride, 3 parts of 1- (3- / 4- (diphenylmethyl) -1-piperazinyl / propyl) -1,3-dihydro-2H-benzimidazol-2-one and 22.5 parts of methylbenzene , stirred overnight at reflux temperature. Water is added to the reaction mixture and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5) as eluent. When the pure fractions are collected and the eluent is evaporated, 1.1 part (33.5%) of 1-acetyl-3- (3- [4- (diphenylmethyl) -1-piperazinyl] propyl) -1,3-dihydro-2H- benzimidazol-2-one, m.p. 124.4 ° C.

Example 8

A mixture of 1.1 parts of ethyl 2-propenoate, 3 parts of 1- (3- [4- (diphenylmethyl) -1-piperazinyl] -7-propyl] -1,3-dihydro-2H-benzimidazol-2-one, a few A drop of Ν, Ν, Ν-trimethylbenzenemethanaminium hydroxide in 40% methanol and 25 parts of 1,4-dioxane is stirred for 24 hours at reflux temperature, the reaction mixture is evaporated. recovered and the eluent is evaporated.

48 661 78 The residue is converted into the hydrochloride salt in a mixture of 2-propanol and ethanol. When the salt is filtered off and dried, 1.4 parts (32.5%) of ethyl-3- [3-74- (diphenylmethyl) -1-piperazinyl] propyl] -2,3-dihydro-2-oxo-1H-benzimidazole-1-one are obtained. propanoate dihydrochloride dihydrate, m.p. 204 ° C.

Example 9

A mixture of 3 parts of 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -3β-dihydro-2H-benzimidazol-2-one, 1 part of isocyanomethane and 25 parts of 1.4 -dioxane, stirred overnight at reflux temperature. The reaction mixture is evaporated and the residue is purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5) as eluent. The pure fractions are collected and the eluent is evaporated. When the residue is crystallized from a mixture of methylbenzene and 2,2'-oxybispropane, 0.8 part (23.5%) of 3- [3-] is obtained.

4- (diphenylmethyl) -1-piperazinyl] propyl} -2,3-dihydro-N-methyl-2-oxo-1H-benzimidazole-1-carboxamide, m.p. 153.1 ° C.

Example 10

To a stirred solution of 9.4 parts of 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-2H-benzimidazol-2-one and 180 parts of methylbenzene are added 0.8 parts of 75 The sodium hydride dispersion and the mixture thus obtained are heated for 60 minutes at 90 ° C with stirring. The reaction mixture is cooled to 30 [deg.] C. and 0.2 part of 2,3,11,12-dibenzo-1,4,4,10,11,16-hexaoxacyclooctadeca-2,11-diene is added and stirring is continued. 10 minutes. 4.2 parts of ethyl 2-bromoacetate are then added and the mixture is stirred overnight at reflux temperature. The reaction mixture is cooled to 90 ° C, 50 parts of water are added and the layers are separated while still hot. Evaporation of the organic phase gives 10 parts of ethyl 3- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl) -2,3-dihydro-2-oxo-1H-benzimidazole-1-acetate as a residue.

A mixture of 9.8 parts of ethyl S-Z- (4-diphenylmethyl) -1-piperazinyl] propyl} -2,3-dihydro-2-oxo-1H-benzimidazole-1-acetate, 1.2 parts of sodium hydroxy and 150 parts of part of water, stir for 5 minutes at reflux temperature (oy80oC). When the reaction mixture is filtered and the pH of the filtrate is adjusted to 5.8-6 with acetic acid, a sticky precipitate forms. It is separated and crystallized from ethanol and water.

After filtration and drying under vacuum at 100 [deg.] C. for 3 hours, 6 parts of 3- [3- [4- (diphenylmethyl) -1-piperazinyl] -propyl} -2,3-dihydro-2-oxo- 1H-benzimidazole-1-acetic acid hemihydrate, m.p. 138.7 ° C.

Example 11

A mixture of 5.2 parts of 1,3-dihydro-1- [3- (1-piperazinyl) propyl] -2H-benzimidazol-2-one, 5.28 parts of 2- (chlorophenylmethyl) pyridine hydrochloride, 5.3 parts sodium carbonate and 90 parts of N, N-dimethylformamide are heated overnight at 50 ° C with stirring. The reaction mixture is cooled and poured into ice water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. When the product is filtered off and dried, 2 parts (23.4%) of 1,3-dihydro-1- [3- [4- (phenyl- (2-pyridyl) methyl] -1-piperazinyl propyl] -2H-benzimidazole are obtained. -3-one, mp 141.7 ° C.

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Example 12

A mixture of 4.9 parts of 1- (3-chloropropyl) -1H-benzimidazole, 5.76 parts of 1- [bis (4-fluorophenyl) methyl] piperazine, 5.3 parts of sodium carbonate, 0.1 part of potassium iodide and 200 parts of 4-methyl-2-pentanone, stirred for 20 hours at reflux temperature with a water separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,21-oxybis-propane. When the product is filtered off and dried, 5.5 parts (59.3%) of 1- [3- [4-Z- (4- (4-fluorophenyl) methyl] -1-piperazinyl] propyl] -1H- are obtained. benzimidazole hydrate, mp 108.4 ° C.

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Example 13 1- (3- (4- (Diphenylmethyl) -1-piperazinyl (7-propyl)) -2- (methylthio) -1H-benzimidazole trihydrochloride, m.p. 203.4 ° C, prepared according to the procedure of Example 2 by carrying 2 - [2- (methylthio) -1H-benzimidazol-1-yl] propyl methanesulfonate for reaction with 1- (diphenylmethyl) piperazine.

Example 14

A mixture of 4.37 parts of N- (2-aminophenyl) -4- (diphenylmethyl) -1-piperazinepropanamine hydrochloride, 38 parts of carbon disulfide, 2 parts of sodium carbonate and 40 parts of ethanol is stirred for 20 hours at reflux temperature. The reaction mixture is evaporated and water is added to the residue. The precipitated product is filtered off, washed with water and dissolved in trichloromethane. The solution is dried, filtered and evaporated. When the residue is crystallized from 4-methyl-2-pentanone, 2 parts (45.5%) of 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-2H-benzimidazole-2 -tionia, sp. 181.8 ° C.

Example 15

A mixture of 60 parts of N- (2-aminophenyl) -4- (diphenylmethyl) -1-piperazinepropanamine, 20 parts of methyl (iminomethoxymethyl) carbamate, 42 parts of acetic acid and 450 parts of trichloromethane is stirred overnight at reflux temperature. The reaction mixture is evaporated and the residue is taken up in water. The mixture is decanted and the residue is mixed again with water. The resulting mixture is made alkaline with dilute ammonium hydroxide solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue was eluted with a mixture of trichloromethane and methanol (95: 5). The pure fractions are collected and the eluent is evaporated. When the residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,21-oxybispropane, 13.5 parts of methyl N- [3- (1- (diphenylmethyl) -1-piperazinyl] propyl) -1H-benzimidazol-2-yl] carbamate are obtained. , sp. 137.8 ° C.

A mixture of 12 parts of methyl N- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -1H-benzimidazol-2-ylcarbamate, 60 parts of concentrated hydrochloric acid and 80 parts of ethanol is stirred overnight at reflux temperature. . The reaction mixture is evaporated and water is added to the residue. The base is liberated in the usual manner with ammonium hydroxide and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol. The product is filtered off and dried, yielding 4.3 parts (40%) of 1- [3- [4- (6,617,855) (diphenylmethyl) -1-piperazinyl] -pxophyl] -1H-benzimidazol-2-amine, m.p. 228.7 ° C.

A mixture of 10.7 parts of 1- (3- [4- (diphenylmethyl) -1-piperazinyl] propyl) -1H-benzimidazol-2-amine, 5.1 parts of acetic anhydride and 90 parts of methylbenzene, stirred for 5 hours at reflux temperature. The reaction mixture is evaporated and the residue is taken up in water. The resulting mixture is basified with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol. After filtration and drying, 6.6 parts (56.5%) of N-α-β- [14- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-2H-benzimidazole are obtained. 2-ylideneacetamide, m.p. 143.3 ° C.

Example 16

A mixture of 13 parts of 1,3-dihydro-1- [3- (1-piperazinyl) propyl] -2H-benzimidazol-2-one, 12.4 parts of 1,1 '- (hydrobromene) bis / benzene, 7, 6, 6 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone are stirred overnight with a water separator at reflux temperature. The mixture is cooled to room temperature, water is added and the layers are separated. The organic layer is dried, filtered and evaporated. When the residue is crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol, 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-2H-benzimidazol-2-one is obtained. mp. 153 ° C.

Example 17

The following compounds were prepared according to the procedure of Example 6, but using equivalent amounts of the corresponding starting materials: 1- [2-, 1,4- [bis (4-fluorophenyl) methyl] -1-piperazinyl) ethyl] -1,3-dihydro-2H-benzimidazol-2- onihemihydrate, m.p. 131.5 ° C.

1-γ2- [4- (diphenylmethyl) -1-piperazinyl] ethyl-1,3-dihydro-2H-benzimidazol-2-one, m.p. 218 ° C.

4-Zb is- (4-fluorophenyl) methyl] -1-piperazinyl-4-propyl-1,3-dihydro-2H-benzimidazol-2-one, m.p. 198 ° C.

Claims (2)

A process for the preparation of 1 ', N-diarylmethyl-1-piperazinyl-7-alkyl-3-benzimidazole derivatives of the formula I and their pharmaceutically acceptable salts, B-CnH2n-Ar-1-Ar-Ar / Ar 1 2 wherein Ar and Ar each independently represent phenyl, substituted phenyl or pyridyl, wherein the substituted phenyl contains 1-2 substituents which are independently halogen, lower alkyl, lower alkoxy, trifluoromethyl or nitro groups, n is an integer of 2, 3, 4, 5 or 6, provided that when CnH2n is a branched alkylene group in the linear chain linking group B to the nitrogen atom of piperazine there are at least 2 carbon atoms and B is a) a radical of formula: O kk LN N-W / ΓΛ 2 R 2 wherein R and R each independently represent hydrogen, halogen, lower alkyl or trifluoromethyl and L is hydrogen, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, phenyl, phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl or lower alkenyl, or b) a radical of formula: 66178 57 M 'CN N- [// R- // 1 V * 2 R * 'R 12 wherein R and R each independently represent hydrogen, halogen, lower alkyl or trifluoromethyl and M is hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, lower alkylthio, amino, lower alkylcarbonylamino, lower alkoxycarbonylamino or 3-6 carbonylamino or 3-6 cycloalkyl, characterized in that a) a reactive ester of the formula: B'-C H0 -W (II) n 2n wherein B 'is the same as B defined above but other than 2-amino-1H-benzimidazole-1 -yl radical of formula NH_A. N N- / f, i · / R 'R2 and W is a suitable reactive ester function derived from the corresponding alcohol, is reacted with a compound of formula: / Ar ^ HN N-CH (III)' XAr2 preferably in a reaction inert solvent and in the presence of a base at elevated temperature to give a compound of formula: 661 78 58 7. Ar1 (I.) B'-CH2 -NN-CH'n 2n \ ". 2 Ar or b) decarboxylating under hydrolytic conditions a compound of formula: NH - COO (lower alkyl) C / Ar1 A ™ Ar2 U'b) // \ 1 \ -: / '\ 2 RR to give a compound of formula is: NH 1, -Ar 1 ^ \ 'N NC H „-N N-CH (Ia) \ / n 2n' / \ Ar 2 R 2 or c) ring closure is performed on a compound of formula (IV) Ar 'H„ N NH-C H_ -N N-CH 2 \ / n 2n * / o; - <7 \ -Ar 2 (IV) <li '·>. ·· · / ^ 2 RR using a suitable ring-forming reagent and methods known in the art to give a compound which the formula is: 66178 59 ° Ä 1 / 'C \ / \ HN NC H. -N N-CH V / ^ -y \ Ar2 / ^ R1' w / R2 or «1, C - '\ ^ Ar N NC H_ -N N-CH 0 (Id) \ / n 2n. 2 H, wherein M is hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, amino, lower alkoxycarbonylamino or cycloalkyl, or d) deprotecting P by conventional methods of a compound of formula: 0 ί. __ Ar1 - / \ ^ - ΑΓ P-N N-C -N N-CH (V) VV '\ Ar2 / \. r1 '· V2 to give a compound of formula: f - - Ar1 HN NC H_ -N N-CH (I_c) W ^ Ar2 R1A._ /. R2 or e) acylation of a compound of the above formula (Ia) using standard N-acylation methods to give a compound of formula: 60 661 78 NH-CO- (lower alkyl) Aj_1, - C .. / "\ N 'NC H_ -N N-CH \ / n 2n / ^ 9 '/ Ar // \ * I_e * or f) a group iJ is attached to a compound of formula (Ic) by the above-mentioned methods to give a compound of formula: OH __ iic. / \ Ar L -NN "CnH2n_iq (If ) \, \ _ / is 1 \. . / / 2 having lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl lower alkyl, carboxy lower alkyl, phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl or lower alkenyl provided that the condenser in said lower alkenyl has a position other than, cA B-C H- -N NH (XVI) n with a 2N / reactive ester of formula; Ar 1 W-CH (XVII) "--Ar 2 wherein W is the same as above, preferably in a reaction-inert organic solvent in the presence of a suitable base at elevated temperature to give a compound of formula: 61 66178 ^ Ar 1 / ~~ λ BC H. - Pharmaceutically acceptable acid addition salts are prepared from N N-CH n 2n, _ --- / Ar (Ig) and, if desired, the products of steps a) -g) 62 661 78 For the preparation of framstollen from 1- [4-diarylmethyl-1-piperazinyl / alkyl) -benzimidazole compounds of formula I with anti-histamine and anti-anaphylactic medication and pharmaceutical salt form, / ^ 1 (I) BC -N N-CH-Ar '' n 2n \ _ / i, Ar 1 2 i vilken Formula Ar and Ar are substituted by a phenyl ring, substituted with phenyl or pyridyl, colors substituted with a phenyl moiety 1-2 substituents, brominated by a halo-generic, halo-generic, halo-realoxy, trifluoromethyl- or nitro group, , 3, 4, 5 or 6 groups, the groups of CnH2 are also alkylated pp, är ätminstone 2 kolatomer närvarande i den linjära delen av kedjan som förenar Gruppen B med kväveatomen i piperazinet och B B a) a radical med formuleln: O II LN N- K yX / \ 2 1 2 värv R Rhh R räda oberoende av varandra betecknar Väte, halogen, alkyl alkyl or trifluoromethyl and hydrogen chloride, alkyl alkylcarbonyl, lasalkoxycarbonylglycyl, carboxylglycarbyl, phenyl, phenylmethyl, lasalalkylaminocarbonyl, hydroxymethyl HR ^. = - / r2 1 2 color R och R R is used as a precursor for the addition of halogen, alkyl alkyl or trifluoromethyl and hydrogen, alkyl alkyl, phenyl, phenylmethyl, mercapto, lasalalkylthio, amino, lasalalkylcarbonylamino, lasgrealkoxycarbonylamino 3-6 cholatomers, which are unreacted to give a reactive ester with the formula: B'-C H- -W (II) n 2n color B 'is decomposed with the definition of B, to give 2-amino -1H-benzimidazole-1-yl radical with the formula: NH 2 i? CV H h 'X: · "R2 and W is a hot reactive ester function having the same alcohol, as defined in the formula: / - \ / Ar1 HN N-CH ^ 1111 \ ----- 7"' -Ar2 for this reaction, the reaction medium and the nervous system are at the same temperature as the temperature of the formulation: 66178 64 Λ 1 __ At / B'-C Η_ -N Ä-CH η 2η. \ ο \ / ^ Ar (Ι ·) or b) under hydrolytic decarboxylates and decarboxylates in the form of: NH-COO (equivalent) NC „H2n-N N-CH | I-bJ V - .. / V- ... ....- ΑΓ2 / \ RJ <A „2 för erhällande av en förening med Formeln: f * 2 ...., Αγ1 ^ -C \ x. A N rCnH2n '\ _. \ U ~ a) / - \ x * Ar ^ / \ v 2 RK R eller c) en förening med formuleln (IV) cyclicer Ar1 / 'A „2 * 2 Γ \ (IV,„, V - 2 R' r "* for the purpose of warming up the cyclic reagents and using the following conditions for the formulation: 66178 65? / Ar1 / Q / \ HN NC H0 -N N-CH iT_ri \ /" 2 "/" ^ Ar2 ' '/ ........ \ Κ'λ _: -> - Β2 eller "1 I Sr -i> C \ /“ \ N NC H- -Nx N CI? \ / "" Vy ^' Ar2 ( I, d, /; XR ^: _ / -. R2 color M är väte, lgre alkyl, phenyl, phenylmethyl, mercapto, amino, legreakoxycarbonylamino or cycloalkyl, or d) a preferred group of conventional methods according to the formula: 0 II / '- Ar1 c / / \ PN NC -N N-CH (V) / n \ _ / 2 --------- ^ Ar // V' V - / t'N - / -s 2 RR for the range of the form: 0 Λ 1 l |. Ar / c \ / \ HN NC H_ -N N-CH (Ic) n 2 n / „'' \ ........ / \ ---- Ar2 // \\ A. Ά 2 ----- R or e) in the case of the above-mentioned form (Ia) acyleras under conventional convention N-acylation methods for the use of 66 66178 in the form of the formula: NH-CO- (lactic alkyl) I 1 / Ar / -CnH2n - ^ _. / NC <ftr2 <I-> R ^ _ =) Cr2 or f) Group L in the form of the above form (ic) medelst kända metoder för erh & llande av en förening med formeln: ___ ^ Ar1 1. Cx- / L -N »-CnH2n-N2 / N-CH2 2 (If) /......^ R, 'W ^' R2 color is alkyl, carbonyl, carbonyl, carbonylglycarbonyl, carboxylatedglycyl, phenylmethyl, glasshalkylaminocarbonyl, hydroxymethyl or carbonyl alkenyl, furtsat, with double alkylation närvarande i en annan ställning än &, eller g) en förening med formula: B-CnH2n- "w NH (XVII condenser with en react Ester with formula W-CH (XVII) Ar2 color W is decomposed somewhere, for which the reaction is inert organic leachate in the nervous system and at the same temperature as in the case of the food industry: